Natural Enantiomers - Molecules-2022

molecules
Review
Natural Enantiomers: Occurrence, Biogenesis and
Biological Properties
Jin-Hai Yu 1 , Zhi-Pu Yu 1 , Robert J. Capon 2, * and Hua Zhang 2, *
1 School of Biological Science and Technology, University of Jinan, Jinan 250022, China;
yujinhai12@sina.com (J.-H.Y.); yuzhipu911108@163.com (Z.-P.Y.)
2 Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Brisbane, QLD 4072, Australia
* Correspondence: r.capon@uq.edu.au (R.J.C.); bio_zhangh@ujn.edu.cn (H.Z.)
Abstract: The knowledge that natural products (NPs) are potent and selective modulators of impor-
tant biomacromolecules (e.g., DNA and proteins) has inspired some of the world’s most successful
pharmaceuticals and agrochemicals. Notwithstanding these successes and despite a growing number
of reports on naturally occurring pairs of enantiomers, this area of NP science still remains largely
unexplored, consistent with the adage “If you don’t seek, you don’t find”. Statistically, a rapidly
growing number of enantiomeric NPs have been reported in the last several years. The current review
provides a comprehensive overview of recent records on natural enantiomers, with the aim of advanc-
ing awareness and providing a better understanding of the chemical diversity and biogenetic context,
as well as the biological properties and therapeutic (drug discovery) potential, of enantiomeric NPs.
Keywords: enantiomers; natural products; biogenesis; biological properties

1. Introduction
Citation: Yu, J.-H.; Yu, Z.-P.; Capon, Natural products (NPs) are usually regarded as small molecule organic compounds
R.J.; Zhang, H. Natural Enantiomers:
which are produced in the metabolic processes of living organisms [1]. Although studies on
Occurrence, Biogenesis and
NPs have informed many areas of science, industry and commerce, including flavorings,
Biological Properties. Molecules 2022,
perfumes, cosmeceuticals and nutraceuticals, arguably, their most important contribution
27, 1279. https://doi.org/10.3390/
to society has been as pharmaceuticals and agrochemicals [2]. For example, NPs and NP-
molecules27041279
inspired chemical entities still account for more than two thirds of all the drugs approved
Academic Editor: Míriam Pérez by Food and Drug Administration (FDA) in the USA in roughly the past four decades [2].
Trujillo The vast majority of reported NPs are chiral molecules that exist in nature as sin-
Received: 4 January 2022
gle enantiomers [3]. However, as the adage goes, “Beware of exceptions to the rule”;
Accepted: 10 February 2022
indeed, there is increasing evidence that both enantiomers of selected NPs exist in nature.
Published: 14 February 2022
Surprisingly, NPs were generally believed to exist as single enantiomers until the 1970s,
despite reports of several exceptions, probably owing to the standpoint of the famous
Publisher’s Note: MDPI stays neutral
French chemist/microbiologist Louis Pasteur, i.e., that life processes were asymmetrical [4].
with regard to jurisdictional claims in
Benefiting from scientific and technical advances in our understanding of NP biosynthesis,
published maps and institutional affil-
there is increasing acceptance and documentation of the occurrence of natural enantiomers.
iations.
Finefield et al. reported this trend in a 2012 review, documenting the occurrence and
biogenesis (where applicable) of the well-known NP enantiomers reported before 2012 [3].
During our research into bioactive NPs from medicinal plants and other sources, we
Copyright: © 2022 by the authors.
have regularly encountered NP enantiomers and have documented differences in their
Licensee MDPI, Basel, Switzerland. bioactivities [5–9]. Surveying the scientific literature revealed the aforementioned report by
This article is an open access article Finefield et al. as the only systematic record of the occurrence of natural enantiomers [3],
distributed under the terms and supported by a 2018 review by Cass et al. on the techniques for separation and absolute
conditions of the Creative Commons configuration (abs. config.) assignment of enantiomeric NPs [10]. This survey also revealed
Attribution (CC BY) license (https:// a dramatic increase in the number of publications on natural enantiomers, especially in the
creativecommons.org/licenses/by/ last few years. Against this background, the present review seeks to summarize advances
4.0/). in this fascinating field over the period of January 2012 to December 2019.
Molecules 2022, 27, 1279. https://doi.org/10.3390/molecules27041279 https://www.mdpi.com/journal/molecules

Molecules 2022, 27, 1279 2 of 73
2. Enantiomers from Kingdom Plantae

The kingdom Plantae is an important part of nature, providing rich resources and
a beautiful environment for human beings. In the field of medicine, various plants have
served as the basis of traditional herbal medication to treat a variety of diseases for thou-
sands of years. Phytochemical research on herbs has provided thousands of structural
models or leads for modern drug discovery, and some NPs can even be used directly as
drugs, such as taxol. NPs derived from plants have been well studied for decades, and
a comprehensive system of classification has been devised. On the other hand, new NPs
from kingdom Plantae are being identified all the time due to the abundance of resources.
Accordingly, enantiomers produced by plants occupy the vast majority of enantiomeric
NPs from natural sources.
In this section, natural enantiomers from kingdom Plantae will be classified into
fourteen subcategories on the basis of their structural type, i.e., lignans, coumarins, simple
phenylpropanoids, alkaloids, flavonoids, terpenoids, phloroglucinols, naphthalene and
phenanthrenes, chromanes, acetophenones, diarylheptanoids, triphenylmethanes, fatty acid
and miscellaneous. Where appropriate, their biogenesis and structure will also be described.
2.1. Lignans
Lignans are a common class of NPs which is widely distributed in the plant kingdom
and which exhibits a broad spectrum of bioactivities including antioxidant, antitumor,
anti-inflammatory, antineurodegenerative, antiviral and antimicrobial properties [11,12].
Lignans usually consist of two (sometimes three or even more) C6 -C3 units (also known
as phenylpropanoids). Their structural diversity arises from the different degrees of
oxidation, as well as various substitution and connection patterns. Consistent with IUPAC
recommendations [13], lignans are normally divided into classical lignans (only direct
8,80 -connection between the two C6 -C3 units), neolignans (non-8,80 and direct connection
between the two C6 -C3 units), oxyneolignans (ether oxygen linkage between the two C6 -C3
units), and higher lignans (above two C6 -C3 units, e.g., sesquineolignans and dineolignans).
However, this classification is suggested mainly as a means of clarifying the confusing
lignan nomenclature in the past, and is far from sufficient to assort the vast number of
natural lignans. In general, NP chemists tend to sort lignans according to their detailed
structural types, such as dibenzylbutanes, arylnaphthalenes, benzofurans, etc. [14].
Based on structural features, and for the convenience of discussion, the lignan enan-
tiomers in the period covered by this review are classified into three subcategories: acyclic
lignans, cyclic lignans and sesquineolignans. Acyclic lignans refer to those without extra
rings except for the existing aromatic rings in the phenylpropanoid units, whereas cyclic
lignans possess additional rings. According to the reported compound numbers, acyclic
lignans are further divided into 8-40 -oxyneolignans and other acyclic lignans, while cyclic
lignans will be presented as furan-incorporating lignans and other cyclic lignans. In the
interests of brevity, only the structure of one enantiomer of each pair is provided; this rule
applies to all structural classes in the current review.
2.1.1. Acyclic Lignans

8,40 -Oxyneolignans. 8,40 -Oxyneolignans (for structures, see Figure 1; for names, see
Table S1 in Supplementary Materials) are formed via 8-O-40 ether bonds. Also, the C-7
in these lignans is usually oxidized in a nonstereoselective manner. Then, erythro- or
threo-isomers are generated, leading to the occurrence of two pairs of enantiomers.
Molecules 2022, 27, 1279 3 of 73
Figure 1. Structures of 8,40 -oxyneolignans.
The first reported cases in the period covered by this study were 1a/1b and 2a/2b,
isolated from Paeonia lactiflora in 2015 [15]. Compounds 1 and 2 have the same constitutional
structure but different relative configurations (rel. configs.). The erythro rel. config. for 1,
and the threo rel. config. for 2, were determined via the J7,8 values (3.5 Hz for 1 vs. 6.8 Hz
for 2), while their absolute configurations (abs. configs.) were established by the time-
dependent density functional theory electronic circular dichroism (TDDFT-ECD) method.
In the same year, three dinorneolignan pairs 19a/19b−21a/21b, along with a neolignan
pair 25a/25b, were reported and found as scalemic mixtures in Acorus tatarinowii [16]. The
determination of their abs. configs. was based on ECD data analysis and the TDDFT-ECD
method. A modified Mosher’s method was also used to further confirm the abs. configs.
of 19a/19b. In 2016, Gu and coworkers reported the presence of 13a/13b−16a/16b in
Euphorbia sikkimensis [17], among which 13a/13b and 14a/14b and their rel. configs. had
been reported in 2001 [18]. In addition, compounds 13 and 14 are diastereoisomers, as is
the case for 15 and 16. In 2017, compounds 6a/6b and 7a/7b were isolated from Rubus
idaeus [19]. In 2019, Song and colleagues discovered 3a/3b−5a/5b, 22a/22b and 23a/23b
from Crataegus pinnatifida [20], as well as 8a/8b−12a/12b from Ailanthus altissima [21].
Among them, compounds 3 and 4 possess identical planar structures but different rel.
configs., as is the case for 8 and 9.
Due to the structural flexibility of 8,40 -oxyneolignans, it has often been a challenge
to correctly assign their configurations at C-7 and C-8. In order to solve this prob-
lem, three empirical rules have been developed to determine the rel. configs.: the com-
parison of J7,8 coupling constants [22,23], and the utilization of 13 C (∆δ(C-8−C-7) ) [24]
and 1 H (∆δ(H-9a−H-9b) ) [25] NMR chemical shift differences, although each method has
its limitations.
The application of the J7,8 value, first reported by Ruveda et al. in 1984 [23], is the
simplest and most commonly used method (data see Table 1), but different substituents
and their substitution positions could significantly impact the magnitude of J7,8 , and
sometimes even result in close J7,8 values for erythro and threo configurations. Additionally,
the use of different deuterated solvents for NMR measurements will also influence the J7,8
Molecules 2022, 27, 1279 4 of 73
value. Therefore, the configuration assignments based on this empirical rule are sometimes
ambiguous or even improper due to misuse. Shi and coworkers have summarized three
types of 8,40 -oxyneolignans that are suitable for the application of this rule, i.e., aglycones
(J7,8 ≤ 5.0 Hz for erythro and J7,8 ≥ 7.0 Hz for threo), aglycone acetonides (J7,8 > 7.0 Hz
for erythro and J7,8 < 2.0 Hz for threo) and glycoside acetates (J7,8 ≤5.3 Hz for erythro and
J7,8 ≥ 6.3 Hz for threo); the NMR solvent must be CDCl3 [22]. As reflected by the previously
reported data shown in Table 1, some researchers tend to apply this method without
being aware of the aforementioned limitations, which could have resulted in incorrect
configuration assignments and caused confusion in later studies of other NPs.
Table 1. J7,8 Values, specific optical rotations and ECD data of 8,40 -oxyneolignians.
J7,8 Values Specific Optical Rotations ECD Data

C-7 & C-8
No.
Configurations J7,8 (Hz) Solvent [α]D Solvent T (◦ C) ∆ε λ (nm)
1a (7R,8S)-erythro 3.5 CD3 OD +3.3 MeOH 25 +2.25 239
1b (7S,8R)-erythro 3.5 CD3 OD −4.7 MeOH 25 −2.75 239
2a (7R,8R)-threo 6.8 CD3 OD −21.7 MeOH 25 −3.45 231
2b (7S,8S)-threo 6.8 CD3 OD +16.0 MeOH 25 +2.83 232
3a (7S,8S)-threo 8.8 CDCl3 +18.0 MeOH 20 −1.12 239
3b (7R,8R)-threo 8.8 CDCl3 −20.0 MeOH 20 +1.40 237
4a (7R,8S)-erythro 2.6 CDCl3 +20.5 MeOH 20 +2.38 245
4b (7S,8R)-erythro 2.6 CDCl3 −22.0 MeOH 20 −1.89 243
5a (7R,8S)-erythro 3.3 CDCl3 +32.0 MeOH 20 +0.25 238
5b (7S,8R)-erythro 3.3 CDCl3 −28.2 MeOH 20 −0.01 238
6a (7S,8S)-threo 6.9 CDCl3 +36.7 MeOH 20 +8.92 239
6b (7R,8R)-threo 6.9 CDCl3 −33.5 MeOH 20 −6.50 240
7a (7R,8R)-threo 8.0 CDCl3 −28.5 MeOH 20 +9.64 230
7b (7S,8S)-threo 8.0 CDCl3 +26.9 MeOH 20 −8.74 230
8a (7R,8S)-erythro 7.2 CDCl3 −31.0 MeOH 20 −3.55 240
8b (7S,8R)-erythro 7.2 CDCl3 +29.0 MeOH 20 +2.80 240
10a (7R,8R)-threo 6.5 CDCl3 −28.0 MeOH 20 +16.90 240
10b (7S,8S)-threo 6.5 CDCl3 +32.0 MeOH 20 −17.65 238
11a (7R,8R)-threo 7.6 CDCl3 −20.0 MeOH 20 −6.57 238
11b (7S,8S)-threo 7.6 CDCl3 +21.0 MeOH 20 +8.87 242
12a (7R,8S)-erythro 4.7 CDCl3 −31.0 MeOH 20 −3.55 240
12b (7S,8R)-erythro 4.7 CDCl3 +29.0 MeOH 20 +2.80 240
13a (7S,8R)-erythro 3.0 CDCl3 +17.1 CHCl3 20 −1.03 232
13b (7R,8S)-erythro 3.0 CDCl3 −16.2 CHCl3 20 +1.03 232
14a (7S,8S)-threo 6.3 CDCl3 −35.1 CHCl3 20 −1.14 240
14b (7R,8R)-threo 6.3 CDCl3 +32.6 CHCl3 20 +1.17 240
15a (7R,8R)-threo 8.1 CDCl3 +30.4 CHCl3 20 +1.58 240
15b (7S,8S)-threo 8.1 CDCl3 −29.8 CHCl3 20 −1.54 240
16a (7S,8R)-erythro 3.3 CDCl3 +16.6 CHCl3 20 +3.18 234
16b (7R,8S)-erythro 3.3 CDCl3 −16.4 CHCl3 20 −3.20 234
17a (7R,8R)-threo 8.0 CDCl3 +7.0 MeOH 20 - -
17b (7S,8S)-threo 8.0 CDCl3 −7.0 MeOH 20 - -
18a (7S,8R)-erythro 4.7 CDCl3 +20.0 MeOH 20 +11.17 230
18b (7R,8S)-erythro 4.7 CDCl3 −18.0 MeOH 20 −4.00 235
19a (7S,8S)-threo 6.1 CD3 OD +18.0 MeOH 20 +1.70 230
19b (7R,8R)-threo 6.1 CD3 OD −18.0 MeOH 20 −1.20 230
20a (7R,8S)-erythro 4.8 CD3 OD −10.0 MeOH 20 +2.70 232
20b (7S,8R)-erythro 4.8 CD3 OD +8.0 MeOH 20 −2.82 233
21a (7S,8R)-erythro 5.4 CD3 OD +15.0 MeOH 20 +3.15 228
21b (7R,8S)-erythro 5.4 CD3 OD −15.0 MeOH 20 −2.65 228
Molecules 2022, 27, 1279 5 of 73
Table 1. Cont.
J7,8 Values Specific Optical Rotations ECD Data

C-7 & C-8
No.
Configurations J7,8 (Hz) Solvent [α]D Solvent T (◦ C) ∆ε λ (nm)
22a (7S,8S)-threo 7.7 CDCl3 +17.2 MeOH 20 −0.59 233
22b (7R,8R)-threo 7.7 CDCl3 −19.0 MeOH 20 +0.51 232
23a (7R,8R)-threo 7.6 CDCl3 −24.5 MeOH 20 - -
23b (7S,8S)-threo 7.6 CDCl3 +26.0 MeOH 20 - -
24a (7R,8S)-erythro 4.6 CDCl3 −18.0 MeOH 20 +12.20 241
24b (7S,8R)-erythro 4.6 CDCl3 +22.0 MeOH 20 −10.81 241
The ∆δ(C-8−C-7) value was introduced to differentiate between erythro and threo 8,40 -
oxyneolignans by Gan et al. [24,26], whereas only a few lignans are applied as reference
compounds, and their ∆δ(C-8−C-7) values also vary in different deuterated solvents, thus
causing this method to lack universality. In 2019, the third method of use of ∆δ(H-9a−H-9b)
value was developed by Zhang and coworkers [25]. However, as with the rule of ∆δ(C-8−C-7)
value, lack of enough model compounds has limited its application. In summary, the rel.
config. determination for 8,40 -oxyneolignans could be very complicated due to their
structural flexibility and diversity, and special cautions are always suggested to avoid
erroneous assignments.
Up to now, three methods, i.e., direct ECD analysis by utilizing the Cotton effect at
235 ± 5 nm, TDDFT-ECD method and modified Mosher’s method, have been used to
establish the abs. configs. of 8,40 -oxyneolignans. For the first method, it is claimed that
the positive Cotton effect at around 235 ± 5 nm is related to 8S-configuration, while a
negative one corresponds to 8R-configuration [22]. However, different substituents on the
aryl group, C-7, C-8 and C-9 would cause evident impact on the Cotton effects and the
corresponding wavelengths. Caution thus should be taken when applying this rule, as
improper applications have often been encountered in the literature. The TDDFT-ECD
method is to theoretically predict the ECD spectra of the two possible enantiomers and then
compare the calculated curves with the experimental ones. It is by far the most commonly
used approach to assign abs. configs. of natural enantiomers owing to its easy operability,
without the need for chemical derivatization and for constructing theoretical mechanisms to
explain the observed properties [27]. Although this method is nowadays readily accessible
to nonexperts, experience is still required since unexpected wrong assignments are easily
made. As shown in Table 1, the abs. configs. determined by the first two methods are
often inconsistent, and those assigned via the TDDFT-ECD method are usually accepted as
the final determination in these reports. The third one is modified Mosher’s method that
requires chemical derivatization, and its accuracy and feasibility have been proved and
accepted by almost all chemists. Nonetheless, a secondary alcohol and enough amount of
sample for derivatization are a must for this method, and only pure enantiomers are suitable
for investigation. In addition, it is worthwhile to note that the specific optical rotation data
have no straight-forward correlation with the abs. configs. of studied structures (Table 1).
Other acyclic lignans. In addition to 8,40 -oxyneolignans, many other acyclic lignan
enantiomers with various connection patterns were reported in this period, as shown in
Figure 2 (names see Table S2 in Supplementary Materials). Owing to the limited numbers,
they have all been put together and are discussed in the current section.
Molecules 2022, 27, 1279 6 of 73
Figure 2. Structures of other acyclic lignans.
Compounds 26 and 27 from Acorus tatarinowii are rare cases of naturally occurring
7,70 -oxyneolignans [28]. The threo-configurations for C-7/C-8 and C-70 /C-80 of 26 were
first determined by the large J7,8 and J70 ,80 values (both 6.5 Hz), which was further con-
firmed by single crystal X-ray diffraction analysis, while the abs. configs. for 26a/26b and
27a/27b were established by comparing the calculated and experimental ECD curves. The
9,90 -oxyneolignan 28 with an ester linkage was obtained as a racemic mixture from Bulbo-
phyllum retusiusculum [29]. Compounds 29−32 from the trunk of Torreya yunnanensis are
rare examples of 8,90 -neolignans and all feature a 1,3-dioxane motif by acetalization with a
2-methoxy-cinnamaldehyde [30]. Yao and coworkers reported two 8,90 -neolignans (33 and
34) and one 7,80 -neolignan (35) as racemic mixtures from Acorus tatarinowii [28]. The J7,8
values (7.6 Hz for 33 and 6.1 Hz for 34 in CD3 OD) were used by the authors to determine
the threo and erythro rel. configs for 33 and 34, while the rel. configs for 35 was assigned by
single crystal X-ray diffraction analysis. An 8,80 -lignan (36), an 8,30 -neolignan (37) and a
7,20 -neolignan (38) were isolated from Liriodendron hybrid [31], Selaginella moellendorffii [32]
and Syringa pinnatifolia [33], respectively. Sasaki et al. acquired a pair of novel 8,80 -lignan
enantiomers (39a/39b) with rearranged skeleton (also known as secolignan) from Brachan-
themum gobicum, with the abs. configs. being determined by comparing the ECD and
specific optical rotation data with those of (−)-lucidenal [34]. The plausible biosynthetic
pathway of 39 was also proposed as shown in Scheme 1, with the nonstereospecific free
radical coupling being the key factor to generate enantiomers.
Scheme 1. Plausible biosynthetic pathway for 39.

Molecules 2022, 27, 1279 7 of 73
2.1.2. Cyclic Lignans

Furan-incorporating lignans. Furan-incorporating lignans are a class of common NPs
with one or more or modified furan rings in the structures. These lignan enantiomers
reported in this period mainly comprise three subtypes, namely, normal furan-type (40 and
41), benzofuran-type (42–57) and furofuran-type (58–63) (for structures, see Figure 3; for
names, see Table S3 in Supplementary Materials).
Figure 3. Structures of Furan-incorporating lignans.
Compound 40, a normal furan-type lignan enantiomer pair with 8-70 and 7-O-80
connections, was reported as a racemic mixture from magnolia salicifolia in 1984 [35], and was
synthesized in 1992 [36]; however, its chiral separation and abs. config. determination were
only realized by Lu et al. in 2018 [16]. The chiral separation and abs. config. assignment
of 41, whose structure with rel. config. was reported in 1996 [37], were accomplished by
Zhang and coworkers in their phytochemical investigation of Acorus tatarinowii in 2016 [38].
Benzofuran-type lignan enantiomer pairs 42−44, 45 and 46 were discovered from
Jatropha integerrima in 2015 [39], Brachanthemum gobicum in 2018 [34] and Picrasma quassioides
in 2018 [40], respectively. The 7,8-trans configurations for 42−46 were determined by
the large J7,8 values (7.5 Hz for 42−45 in CDCl3 , and 6.7 Hz for 46 in DMSO-d6 ) and
NOE analyses, while the abs. config. assignments for these compounds were based
on the reversed helicity rule [39,41]. According to this empirical rule, P-helicity of the
nonaromatic ring will lead to a positive Cotton effect within the 1 Lb band (around 280 nm)
and M-helicity will result in a negative Cotton effect. Phytochemical investigation into
the plants Rubus idaeus [42,43] and Phyllanthus glaucus [44] led to the isolation of three
enantiomer pairs 47−49, and their abs. configs. were established by TDDFT-ECD method.
Compounds 50−52 incorporating an α,β-unsaturated aldehyde unit were obtained from
Brachanthemum gobicum [34] and Picrasma quassioides [40], with the abs. configs. also being
assigned by the reversed helicity rule, where their 1 Lb (α) bands red shifted to around
340 nm due to the conjugation effect from the α,β-unsaturated aldehyde group. In 2018,
Huang et al. discovered compound 53 as a racemic mixture from Rubus ideaus and further
Molecules 2022, 27, 1279 8 of 73
resolved it into two enantiomers (53a/53b), with the abs. configs. being assigned by
application of the TDDFT-ECD method [43]. In fact, compound 53 had been previously
reported as an optically pure molecule from Broussonetia papyrifera in 2009, with a much
smaller [α]D value [45], suggesting its potential scalemic nature. Compounds 54−57 are a
group of dinorneolignans and were isolated from Rubus idaeus [42,43] and Brachanthemum
gobicum [34].
In 2019, Song and colleagues obtained the trinorneolignan furolactone 58 as a racemic
mixture from Rubus idaeus and resolved it into a pair of enantiomers (58a/58b), the abs.
configs. of which were established by analyses of the calculated shielding tensor values and
ECD data [46], while the enantiomer 58b had been reported as an optically pure molecule
from Lycium chinense in 2013 [47]. The other two pairs of furolactone enantiomers 59a/59b
and 60a/60b were isolated from Archidendron clypearia in 2018 [48] and Dendrobium nobile
in 2016 [49], respectively. Song and coworkers reported 61a/61b, from Rubus idaeus in 2019
and assigned their abs. configs. by using the TDDFT-ECD method [47]. Compounds 62
and 63 represent another two pairs of furofuran-type lignan enantiomers isolated from
Morinda citrifolia [50] and Acorus tatarinowii [16], respectively.
Other cyclic lignans. Except for the aforementioned Furan-incorporating lignan enan-
tiomers, there are also some other cyclic lignan enantiomers with diverse ring systems as
listed in Figure 4 (names see Table S4 in Supplementary Materials).
Figure 4. Structures of other cyclic lignans.
The unusual dinorneolignans 64a/64b incorporating a 1,4-dioxane motif and the

arylnaphthalene-type lignans 67a/67b bearing a 20 ,90 -epoxy ring were separated from
Pithecellobium clypearia in 2018, with their abs. configs. being determined by the TDDFT-
ECD method [51]. In 2015, Zhang et al. reported a pair of 7,80 -epoxy-8,70 -oxyneolignans
(65a/65b) and a pair of oxidized arylnaphthalene-type lignans (68a/68b) from Acorus
tatarinowii, and the abs. configs. of the two pairs were established by employing the
TDDFT-ECD method and comparing the Cotton effect at 315 nm with those of known
analogues, respectively [38]. The other pair of enantiomeric arylnaphthalenes 66a/66b
were also isolated from Acorus tatarinowii, with their abs. configs. being assigned by
comparing the Cotton effect at 285 nm with those of known analogues [28]. Compounds
69a/69b featuring a cyclobutane ring via 7,70 and 8,80 connections represent a pair of
[2 + 2] cycloaddition adducts of two phenylpropanoid units and were obtained from Isatis
indigotica in 2019 [52]. Isolated from Tylopilus eximius in 2012 are two pairs of enantiomers
70a/70b and 71a/71b both incorporating a cyclopentenone ring formed by 7,80 and 9,70
linkages [53]. The rel. config. of racemic 71 was established by X-ray crystallography,
while the abs. configs. of 70a/70b and 71a/71b were confirmed by TDDFT-ECD method.
In 2015, two pairs of rare spirodienone neolignans (72a/72b and 73a/73b) were reported
Molecules 2022, 27, 1279 9 of 73
from Cinnamomum subavenium, with the absolute structures being elucidated by X-ray
crystallographic analysis and TDDFT-ECD method [54].
2.1.3. Sesquineolignans
Sesquineolignans refer to lignans bearing three phenylpropanoid units with various
connection patterns. Ten pairs of enantiomeric sesquineolignans were reported in this
period, and their structures are shown in Figure 5, with the names being listed in Table S5
in Supplementary Materials.
Figure 5. Structures of sesquineolignans.
In 2015, Zhang and colleagues obtained 74−78 from Phyllanthus glaucus, with the 7,8-
cis configuration of 74 being determined via the small J7,8 value (2.1 Hz) and the abs. configs.
of 74a/74b being assigned by comparing ECD data with those of known analogues [44].
In addition, the 7”,8”-threo configurations of 75 and 76 and 7”,8”-erythro configurations
of 77 and 78 were determined by the J7”,8” values (6.1 Hz in CDCl3 for 75 and 6.3 Hz in
Me2 CO-d6 for 76; 5.1 Hz in CD3 OD for 77 and 4.2 Hz in Me2 CO-d6 for 78). In 2015, Yin
and coworkers reported 79 and 80 from Brachanthemum gobicum and applied the reversed
helicity rule to assign the abs. configs. at C-70 and C-80 [34], while the assignments of abs.
configs. at C-7” and C-8” were established by Rh2 (OCOCF3 )4 -induced ECD analysis. On
the basis of the bulkiness rule for secondary alcohols, a positive Cotton effect at around
350 nm (E band) in the Rh2 (OCOCF3 )4 -induced ECD spectrum indicated a S-configuration,
while a negative Cotton effect implied a R-configuration. In 2014, Yu’s group discovered a
pair of novel enantiomeric tetrahydrofuran spirodienone sesquineolignans (81a/81b) from
Xanthium sibiricum and proposed coniferyl alcohol as the biosynthetic precursor (Scheme 2),
and the nonstereospecific radical coupling between the two C6 -C3 units was the key factor
to result in enantiomers [55]. Song and coworkers reported 82 and 83 from Rubus idaeus in
2019 and assigned their abs. configs. by using the TDDFT-ECD method [47].
In summary, a large number of lignans (except lignan glycosides) have been discov-
ered as racemic or scalemic mixtures and chirally separated in recent years, and their
structural types, from simple to complex (via rearrangement), cover more than half of the
known classes. It is self-evident from the aforementioned examples that enantiomerism
widely occurs in the structural categories of lignans especially for 8,40 -oxyneolignans and
furan-incorporating lignans. These lignan enantiomers exist as either racemic or scalemic
mixtures in plants and can be relatively easily separated by commercially available chiral
chromatographic columns. Therefore, it is conceivable that many examples previously
reported as optically pure lignans could in fact be scalemic mixtures, and NP researchers
should pay extra attention to the enantiomeric purity of lignans in their future work.
Molecules 2022, 27, 1279 10 of 73
Scheme 2. Plausible biosynthetic pathways for 81a/81b.
2.2. Coumarins
‘Coumarin’ is the general name of ortho-hydroxycinnamate lactones that are derived
from the Shikimate biosynthetic pathway1 (for structures, see Figure 6; for names, see
Table S6 in Supplementary Materials). As the core backbone of coumarins does not contain
chiral factors, the generation of their enantiomersim usually comes from the chiral carbons
of substituents (e.g., prenyl substitution) or axial chirality of oligomers. Coumarins are
important secondary metabolites in plants and have shown various biological properties
such as antitumor, anti-HIV, antimicrobial and anti-inflammatory activities [56,57].
Compounds 84a−87a are a group of angular dihydropyranocoumarins and were
obtained as 30 S,40 S-configured pure enantiomers from Peucedanum japonicum in 2017 [58],
while their corresponding 30 R,40 R-enantiomers (84b−87b) had been previously reported
from Angelica morii in 1974 [59], Peucedanum praeruptorum in 2012 [60], Seseli gummiferum in
1971 [61] and Angelica furcijuga in 2000 [62], respectively. Another eight pairs of analogues
88−95 were found to be present as scalemic mixtures in Peucedani Radix [63] and were
successfully separated into pure enantiomers for the first time. Except 88a, 89b, 92a and
92b, the others have been formerly reported as optically pure compounds [63], but the small
[α]D values compared with those for the purified enantiomers suggested their scalemic
natures. Tang and coworkers isolated two pairs of coumarin enantiomers (96a/96b and
97a/97b) from Toddalia asiatica and assigned the rel. and abs. configs. of 96a/96b via
X-ray diffraction experiment and TDDFT-ECD method, respectively [64]. From Sapium
baccatum, three coumarin enantiomer pairs incorporating one additional α-pyrone ring
(98−100) were assigned the abs. configs. by comparing their specific optical rotations
with those of known analogues [65]. Compounds 102 and 103 are two pairs of hybrid
dimer enantiomers from Cnidium monnieri and they were also total synthesized for further
biological test [66]. The most complex coumarin enantiomers so far are the oligomeric
coumarin hybrids 104 and 105 bearing a spirodienone-sesquiterpene skeleton, and they
were isolated from Toddalia asiatica in 2016 [67]. The only coumarin enantiomers generated
by axial chirality are the prenylated coumarin dimers 101a/101b, with the abs. configs.
being determined by TDDFT-ECD method [68].
Molecules 2022, 27, 1279 11 of 73
Figure 6. Structures of coumarins.
2.3. Simple Phenylpropanoids

Simple phenylpropanoids are naturally occurring phenolic substances containing only
one C6 -C3 biosynthetic block. They often exist as racemic or scalemic mixtures in nature
(for structures, see Figure 7; for names, see Table S7 in Supplementary Materials). They
are also derived from the Shikimate biosynthetic pathway [1]. Many phenylpropanoids
play vital roles in plant growth regulation and pathogen defense by acting as essential
components of cell wall, as protectants against high light and UV radiation, and as phy-
toalexins against herbivores and pathogens [69]. It is generally difficult to acquire high
quality crystals for X-ray diffraction analysis due to the rotary nature of the sidechains in
most phenylpropanoids, so normally their rel. configs. are assigned by J values and the
abs. configs. are determined on the basis of Snatzke’s rule, modified Mosher’s method or
TDDFT-ECD calculation.
Qiu and coworkers reported two pairs of phenylpropanoid enantiomers, 106a/106b
and 107a/107b, from the leaves of Eucommia ulmoides and assigned their rel. and abs.
configs. by analysis of J7,8 values and Snatzke’s method, respectively [70]. The planar
structure of 108 had already been reported in 2001 [71], but its enantiomeric nature was
not revealed by Liu et al. until 2017, with the abs. configs. being determined by Snatzke’s
rule [72]. Two pairs of rare chlorine-containing enantiomers (109a/109b and 110a/110b)
were isolated from Acorus tatarinowii in 2017, and their rel. and abs. configs. were estab-
lished by analyzing J7,8 values and employing modified Mosher’s method, respectively [73].
The enantiomer pairs 111a/111b−115a/115b were obtained from Acorus tatarinowi in 2017
by Gao’s group, among which 111b and 113b had been reported previously [74]. Com-
pounds 115a/115b are the first cases in nature of asarone-derived phenylpropanoids with
an isopropyl fragment tethered to the benzene core, and their abs. configs. were assigned
by TDDFT-ECD method [74]. Song and colleagues isolated 116a/116b and 117a/117b from
Molecules 2022, 27, 1279 12 of 73
the fruit of Crataegus pinnatifida in 2018 and applied the TDDFT-ECD method to establish
their abs. configs [74]. Compounds 118−126 with an extra phenyl group on the sidechain
are also considered to be 1,2-diphenylpropane derivatives. The enantiomer pairs 118−120
were separated from Rubus idaeus in 2018 with their abs. configs. being determined via the
TDDFT-ECD method [75]. Compounds 121 and 122 were first reported as racemic mixtures
from Casearia grewiifolia in 2012 [76] and were resolved into two pairs of enantiomers by
Qiu et al. in 2018, with the rel. and abs. configs. being determined by analyzing J7,8 values
and applying TDDFT-ECD method, respectively [77]. Compounds 123a/123b−126a/126b
featuring a 1,3-dioxane ring derived from condensation of diol with different aldehydes,
were obtained from Crataegus pinnatifida with their abs. configs. being determined by
TDDFT-ECD method [78].
Figure 7. Structures of simple phenylpropanoids.
2.4. Alkaloids
The term “alkaloids” traditionally describes nitrogen-containing small molecule or-
ganic compounds with basicity, although there is no unified definition. In this section, we
include all nitrogen-bearing NPs in this category. Based on the structural types, natural
alkaloid enantiomers from plants in the period of 2012–2019 are classified into indole
alkaloids, quinoline and isoquinoline alkaloids, β-carboline and carbazole alkaloids, piperi-
dine alkaloids, thiohydantoin alkaloids, indolizidine and quinolizidine alkaloids, and
other alkaloids.
2.4.1. Indole Alkaloids

Indoles are biogenetically derived from tryptophan or tryptamine and make up one
of the largest groups of alkaloid metabolites. They have attracted tremendous attention
because of their therapeutic values such as anti-inflammatory, antinociceptive, antitumor,
antioxidant and antimicrobial effects [79,80]. The structures of indole alkaloid enantiomers
reported in this period are depicted in Figure 8 and the names summarized in Table S8 in
Supplementary Materials.
Molecules 2022, 27, 1279 13 of 73
Figure 8. Structures of indole alkaloids.
Song and coworkers reported two pairs of oxindole enantiomers 127a/127b and
128a/128b from Isatis tinctoria in 2019 [81], while 128b had been previously reported in
optically pure form from Isatis indigotica in 2012 [82]. In 2017, Zhang and colleagues discov-
ered two pairs of enantiomers bearing two prenyl groups (129a/129b and 130a/130b) from
Clausena lansium and assigned the rel. config. of 129b by converting it into an acetonide
derivative [83]. Two pairs of novel enantiomers including the indole 3,4-dihydronaphthalen-
1(2H)-one hybrids (131a/131b) and the indolizino [7,8-b]indol alkaloids (139a/139b) were
found to exist as scalemic mixtures in Juglans regia [84]. In 2018, Liu et al. reported
132−135 featuring a spiropyrrolizidine oxindole skeleton from Isatis indigotica [85]. Re-
ported from Isatis indigotica in 2019, the enantiomers 136a/136b incorporate an interesting
spiro-oxindole skeleton [86]. Concurrently isolated with 136a/136b is another pairs of
enantiomers 146a/146b featuring a pyrrolo[2,3-b]indolo[5,5a,6-b,a]quinazoline skeleton
that had also been reported from the same species in 2012 [82]. The abs. configs. of
146a/146b were determined by using the bulkiness rule for the Rh2 (OCOCF3 )4 -induced
ECD data, wherein the E band (around 350 nm) was demonstrated to be useful for de-
termining the abs. configs. of chiral secondary and tertiary alcohols [82]. Characterized
by the presence of a dihydrothiopyran ring and a 1,2,4-thiadiazole ring in the structure,
the oxindole alkaloid enantiomers 137a/137b and 138a/138b were reported from Isatis
indigotica by Shi’s research group in 2018 and 2012, respectively [87,88]. The iboga-type
indole alkaloid 140a was obtained as an optically pure molecule from Tabernaemontana
corymbosa in 2016 [89] with the rel. config. being determined by X-ray diffraction analy-
sis, while its enantiomer 140b was reported from Ervatamia hainanensis in 2015 [90]. Two
pairs of rare indole-styrene hybrid derivatives 141a/141b and 142a/142b were isolated
from Isatis indigotica [91]. The rearranged rutaecarpine-type indole alkaloid enantiomers
143a/143b from Evodia rutaecarpa incorporate an unprecedented 6/5/5/7/6 skeleton [92].
The dimeric isoechinulin-type indole alkaloid enantiomers 144a/144b and 145a/145b from
Uncaria rhynchophylla feature an intriguing and complex skeleton with a symmetrical cy-
clobutane ring, and their rel. configs. were assigned by X-ray crystallography [93]. Except
for 146a/146b, the abs. configs. of other indole enantiomers were assigned by using the
Molecules 2022, 27, 1279 14 of 73
TDDFT-ECD method, with the abs. config. of 138a being further confirmed by modified
Mosher’s method.
It is interesting to note that suitable crystals for X-ray diffraction analysis of the enan-
tiomeric mixtures seem relatively easy to be obtained in these reports, but the acquisition
of high quality crystals of pure single enantiomers appears difficult. As above described,
from simple indoles (e.g., 127) to monoterpenoid indole hybrids (e.g., 140), from single
indoles (e.g., 129) to dimeric indoles (e.g., 134), from one-chiral-center examples (e.g., 131)
to complex multiple-chiral-center indole dimers (e.g., 144), natural indole alkaloid enan-
tiomers spread in a wide range of structural subtypes. Therefore, checking enantiomeric
purity for this important class of NPs appears to be key in the future work.
2.4.2. Quinoline and Isoquinoline Alkaloids

Most quinoline and isoquinoline alkaloids biosynthetically originate from anthranilic
acid or from indoles via rearrangement [94]. Quinoline & isoquinoline alkaloids have
attracted great interest from researchers worldwide because of their wide-range biological
activities, including antitumor, antiparasitic and insecticidal, antibacterial and antifungal,
cardioprotective, antiviral, antiinflammatory, hepatoprotective, antioxidant, anti-asthma,
antitussive, and other activities [95,96]. The structures and names of these alkaloid enan-
tiomers in the covered stage are summarized in Figure 9 and Table S9 in Supplementary
Materials, respectively.
Compounds 147a/147b, featuring a furoquinoline core hybridized with a phenyl-
propanoid unit via a 1,4-dioxane ring, were separated and characterized from Zanthoxylum
nitidum in 2018 [97]. Three 2-quinolinone enantiomer pairs 148−150 were reported from
Isatis tinctoria by Song and coworkers in 2019 [81], and in the same year, Zhang et al. discov-
ered the same type of alkaloid enantiomers 151a/151b from the roots of Isatis indigotica [86].
The last example of quinolinone enantiomer pair is compound 152 also from I. indigotica,
and it incorporates an additional anthranilic acid residue [98].
Compounds 153−158 are a series of isoquinoline enantiomers, among which 154a/154b
were acquired from Corydalis hendersonii in 2016 [99] and the others were obtained from
Corydalis mucronifera in 2018 [100]. Compounds 154a/154b were proposed to be derived
from the condensation of a benzylisoquinoline and a succinic acid [99]. In 2016, Hua and
colleagues reported from Macleaya cordata five dihydrobenzophenanthridine enantiomer
pairs 159−163 and a racemate 164, among which 162 and 163 had been previously isolated
in racemic form from Macleaya cordata [101] and here is the first record of their chiral
separation [102]. Three same type of enantiomer pairs 165, 166 and 173 were isolated and
characterized from Corydalis ambigua var. amurensis by Han and coworkers, and three
racemic mixtures 167−169 were also acquired and analyzed by chiral chromatography but
without further separation due to their limited amount [103]. As for structure elucidation,
single-crystal X-ray diffraction analysis was applied to determine the abs. config. of 165a,
followed by the abs. config. assignments for 165b and 166a/166b via comparing the ECD
curves with that of 165a. In addition, Ye’s group reported a pair of berberine-type alkaloid
enantiomers 170a/170b from Coptis chinensis in 2014 [104]. Sai et al. discovered from
Corydalis ambigua two pairs of alkaloid dimers 171a/171b and 172a/172b, featuring a novel
dimerization pattern from two different types of monomers via a C–C single bond [105].
The plausible biosynthetic pathways for 171 and 172 were also proposed as shown in
Scheme 3 by the authors, and the nonstereospecific nucleophilic addition was assumed
to be the key factor to generate enantiomers [105]. As with the aforementioned indole
alkaloids, the assignments of abs. configs. for most quinoline and isoquinoline enantiomers
have been based on the TDDFT-ECD method.
Molecules 2022, 27, 1279 15 of 73
Figure 9. Structures of quinoline and isoquinoline alkaloids.

Molecules 2022, 27, 1279 16 of 73
Molecules 2022, 27, x FOR PEER REVIEW 17 of 77
Scheme3.3.Plausible
Scheme Plausiblebiosynthetic
biosyntheticpathways
pathwaysfor
for171
171and
and172.
172.
2.4.3. β-Carbolineand
2.4.3.β-Carboline andCarbazole
CarbazoleAlkaloids
Alkaloids
β-Carbolinesand
β-Carbolines andcarbazoles
carbazolesareareamong
amongthe themost
mostintriguing
intriguingalkaloid
alkaloidgroups;
groups;they
they
derive
derivefrom
fromvarious
varioussources.
sources.They
Theyhavehavegained
gainedincreasing
increasingattention
attentiondue
duetototheir
theirbroad
broad
spectrum
spectrumofofbiological
biologicalactivities
activities[106,107].
[106,107]. Seven β-carboline(174,
Sevenβ-carboline (174,178 −183), three
178−183), three β-
β-
carboline-carbazole − 177) nine carbazole (184 −
carboline-carbazole hybrid (175−177) and nine carbazole (184−192) enantiomer pairshave
hybrid (175 and 192) enantiomer pairs have
been
beenreported
reportedininthis
thisperiod
period(for
(forstructures,
structures,see
seeFigure
Figure10;
10;for
fornames,
names,see
seeTable
TableS10
S10inin
Supplementary
SupplementaryMaterials).
Materials).The
Theabs.
abs.configs.
configs.for
forall
allseparated
separatedenantiomers
enantiomersininthis
thissection
section
were
weredetermined
determinedbybythetheTDDFT-ECD
TDDFT-ECDmethod methodunless
unlessotherwise
otherwisespecified.
specified.
Song and coworkers phytochemically studied the stems of Picrasma quassioides to
detect four enantiomer pairs 174a/174b−177a/177b. While 174a/174b possess a β-
carboline-phenylpropanoid hybrid skeleton [108], the latter three pairs represent alkaloid
heterodimers of a β-carboline and a carbazole units which are linked via a C4 fragment.
Alkaloids 178a/178b−180a/180b are dimeric β-carbolines obtained as trifluoroacetates
from Picrasma quassioides in different years [109,110]. Compounds 181a/181b, as β-
carboline-quinazoline hybrid dimers from Peganum harmala, were biogenetically
produced through Mannich/Pictet–Spengler-type and intermolecular Michael addition
Molecules 2022, 27, 1279 17 of 73
Figure 10. Structures of β-carboline and carbazole alkaloids.
Song and coworkers phytochemically studied the stems of Picrasma quassioides to de-
tect four enantiomer pairs 174a/174b−177a/177b. While 174a/174b possess a β-carboline-
phenylpropanoid hybrid skeleton [108], the latter three pairs represent alkaloid heterodimers
of a β-carboline and a carbazole units which are linked via a C4 fragment. Alkaloids
178a/178b−180a/180b are dimeric β-carbolines obtained as trifluoroacetates from Pi-
crasma quassioides in different years [109,110]. Compounds 181a/181b, as β-carboline-
quinazoline hybrid dimers from Peganum harmala, were biogenetically produced through
Mannich/Pictet–Spengler-type and intermolecular Michael addition reactions [111]. Com-
pounds 182 and 183 from Pausinystalia yohimbe were characterized in racemic forms in 2018
without further chiral separation, and their racemic nature was further proved by X-ray
diffraction analysis [112]. Interestingly, the enantiomerism of 182 results from the N-4 chiral
center which is very rare in nature [112].
The enantiomerism of carbazole alkaloids comes from the axial chirality of dimers or
from the chiral centers in the additional structural fragments. Four pairs of biscarbazole
atropisomers (184a/184b−187a/187b) and a pair of dihydropyranocarbazole enantiomers
(188a/188b) were discovered by Jiang and colleagues from Clausena dunniana, where the
planar structure of 185 had been previously described from Clausena wallichii in 2011 [113].
The same authors from Jiang’s group further reported 189a/189b−192a/192b from Murraya
Molecules 2022, 27, 1279 18 of 73
microphylla [114,115], with the rel. config. of 189 being confirmed by X-ray crystallographic
data [115].
2.4.4. Piperidine Alkaloids

Piperidine alkaloids that have one or more piperidine rings in the structures are
generally believed to be biogenetically derived from lysine [1]. During the period covered
by this review, fifteen pairs of piperidine enantiomers (for structures, see Figure 11; for
names, see Table S11 in Supplementary Materials) have been reported.
Figure 11. Structures of piperidine alkaloids.
The enantiomer pairs 193−197 were isolated from Anacyclus pyrethrum in 2018 [116].
Among them, compounds 193 and 194 possess novel dimeric piperidine backbones with
6/5/6/6 and 6/5/6 ring systems, respectively, while 195a/195b incorporate a rare cyclopen-
tane-piperidine framework. In 2017, compounds 198−205 were obtained from Viola tians-
chanica. All of them bear more than one nitrogen atom and incorporate fascinating hetero-
cyclic architectures such as the 6/5/6/5 and 6/5/5/6/5 ring systems in 198 and 201–202,
respectively [117]. The abs. configs. of these alkaloid enantiomers were established by the
TDDFT-ECD method. Compounds 206 and 207 were found to occur as enantiomeric pairs
in Clausena lansium with only 206 being successfully resolved into pure enantiomers. The
rel. and abs. configs. of 206a/206b were established by X-ray crystal data and comparing
ECD and specific optical rotation data with calculated ones [118].
The biogenetic origins of these piperidines, especially of those with highly complex
skeletons and multiple chiral centers like 198 and 201–202, have not been examined, and
this intriguing puzzle definitely deserves further investigations.
2.4.5. Thiohydantoin Alkaloids

Naturally occurring thiohydantoin alkaloids are a rare class of NPs. Compounds
208a/208b−218a/218b (for structures, see Figure 12, names see Table S12 in Supplementary
Materials), a panel of thiohydantoin derivatives of two structural groups, were initially
obtained as racemic mixtures from Lepidium meyenii and further resolved into eleven pairs
of enantiomers [119]. Among them, an unidentified enantiomer of 208 had been reported
as a synthetic product in 2007 [120]. Although the biogenesis of these alkaloids has never
been studied, they very likely belong to the imidazole class originating from histidine on
the basis of their core structures [1].
Molecules 2022, 27, 1279 19 of 73
Figure 12. Structures of thiohydantoin alkaloids.
2.4.6. Indolizidine and Quinolizidine Alkaloids

Both indolizidine and quinolizidine alkaloids are biogenetically originated from lysine [1],
and an equal number of four pairs of indolizidine (219−222) and quinolizidine (223−226) enan-
tiomers (for structures, see Figure 13; for names, see Table S13 in Supplementary Materials) have
been reported in the period covered by this review.
Figure 13. Structures of indolizidine and quinolizidine alkaloids.
Alkaloid 219 from Ficus fistulosa var. tengerensis was identified as a scalemic mixture
by [α]D , ECD and X-ray crystallographic data [121], while 220 as a long-known NP re-
isolated from Tylophora indica [122] was demonstrated to be a nearly racemic mixture
with only a slight excess of the R-enantiomer [123]. Compounds 221a/221b, a pair of
enantiomeric indolizidine alkaloid dimers from Dendrobium crepidatum, were assigned the
abs. configs. by single-crystal X-ray diffraction analysis [124]. Enantiomers 222a/222b,
whose structures were also confirmed by X-ray diffraction analysis to be indolizidine dimers
linked via a cyclobutane ring, were obtained from the same species as 219 [121]. Zhang et al.
discovered four pairs of neosecurinane-type alkaloid enantiomers 223a/223b−226a/226b
of the quinolizidine class from Flueggea virosa in 2017, and it is the first time to report
the enantiomerism of this interesting type of alkaloids [5]. The rel. and abs. configs.
of 223a/223b−226a/226b were characterized by a variety of techniques including X-ray
crystallography and ECD experiments.
2.4.7. Other Alkaloids

In addition to the aforementioned alkaloid enantiomers occurring naturally in plants,
there are also many other types of alkaloid enantiomers reported in this period, as summa-
rized in Figure 14 (names see Table S14 in Supplementary Materials).
Molecules 2022, 27, 1279 20 of 73
Figure 14. Structures of other alkaloids.
Compounds 227a/227b−230a/230b are a panel of quinazoline enantiomer pairs ob-

tained from Peganum harmala in 2018 [125], Isatis indigotica in 2019 [86], I. indigotica in
2016 [98] and P. harmala in 2016 [126], respectively. Biogenetically, quinazoline alkaloids
have been demonstrated to be derived from anthranilic acid [1].
Qin and coworkers discovered two pairs of adenine alkaloids 231a/231b and 232a/232b
from Juglans regia in 2016 [84]. Compounds 233a/233b, along with its scalemic analogue
224, were reported from Geijera parviflora, and they feature a novel heterotrimer struc-
ture incorporating a norsesquiterpenoid unit between a coumarin moiety and a proline
residue [127]. Compounds 235a/235b from Juglans regia possess a benzo[b]azepine-2-
carboxamide skeleton [84], while 236a/236b from Peganum harmala are amphoteric alka-
loids with a four-membered N-heterocyclic ring [126].
Compounds 237−252 are amide alkaloid enantiomers with miscellaneous backbones.
The simplest cases are 237a/237b bearing a thiazolidin-2-one ring and they were isolated
from Isatis indigotica [87]. Zhang and coworkers discovered 238a/238b from Clausena
lansium and assigned their abs. configs. by using modified Mother’s method [83], and
two pairs of germacrane-type sesquiterpenoid lactams 239 and 240 were obtained from
Curcuma phaeocaulis by Qiu and colleagues [128]. Compounds 241a/241b and 242a/242b
are flavonoid alkaloid enantiomers reported from Scutellaria moniliorrhiza in 2018 [129],
Molecules 2022, 27, 1279 21 of 73
while 243a/243b represent a pair of 9,10-dihydrophenanthrene alkaloid enantiomers

from Bletilla striata [130]. The enantiomer pairs 244a/244b and 245a/245b featuring a
spiro[benzofuranone-benzazepine] skeleton from Juglans mandshurica [131], as well as
246a/246b incorporating a benzo[f ][1,3,5]triazocine backbone from Isatis tinctoria [81],
were all reported by the research team of Song and Huang. Compounds 247a/247b are a
pair of enantiomers formed by an oxyneolignan and a phenethylamine units from Lycium
chinense [132], while 248a/248b and 249a/249b are rearranged nor-lignan amide enan-
tiomers featuring a unique benzo-angular triquinane skeleton from Cannabis sativa [133].
Alkaloids 250−252 were obtained as racemic mixtures from Endiandra kingiana without
further chiral separation, and their racemic nature was claimed on the basis of their zero
[α]D values [134].
Except for the specified ones, the abs. configs. of the alkaloid enantiomers in this
section were all established by applying the TDDFT-ECD method.
2.5. Flavonoids
Flavonoids are a large family of secondary metabolites that exist widely in the plant
kingdom. They exhibit a variety of bioactivities such as anti-inflammatory, antioxidant, an-
tibacterial, antiviral, anticancer and neuroprotective effects [135]. Traditionally, flavonoids
mainly refer to compounds incorporating a 2-phenylchromone core, and nowadays, this
term has extended to all structures with two phenyl units linked via a C3 fragment [14].
In addition, some NPs such as xanthones and furanochromones are also included in this
structural family as atypical flavonoids. Flavonoid enantiomers reported in this period are
classified into three subgroups: flavones and isoflavones, chalcones and xanthones
2.5.1. Flavones and Isoflavones

In this section, the definition ‘flavones’ refers to all those incorporating the basic 2-
phenylchromone backbone, including classical flavones, flavanones, flavanes, etc. The abs.
configs. of these enantiomers are mostly determined by the TDDFT-ECD method unless
otherwise specified. Their structures and names are shown in Figure 15 and Table S15 in
Supplementary Materials, respectively.
The biflavonoid enantiomers 253a/253b were isolated from Selaginella trichoclad by
Tan and coworkers in 2019 [136], with the abs. configs. being assigned by an empirical rule
developed by Gaffield [137]. This rule was described as that 2S-configured flavanones and
2R,3R-configured 3-hydroxyflavanones have a positive Cotton effect at ~330 nm caused
by the n→π* transition and a negative Cotton effect due to the π→π* transition at around
280−290 nm. In 2017, a pair of enantiomers hybridized from a flavonol and a coumarin
via a prenyl unit (254a/254b) were isolated from Cnidium monnieri, and their constitutional
structure was further confirmed by semi-synthesis through condensation of the monomeric
precursors [66]. Compounds 255a/255b and 256a/256b are flavanol-phenylpropanoid
adducts and were discovered from Uncaria rhynchophylla in 2017 [138,139]. Muhammad
and colleagues reported a pair of 6-formylated flavanone enantiomers 257a/257b from Eu-
genia rigida and also semi-synthesized them for further biological studies [140]. Two pairs of
flavanones coupled with a propionate residue (258a/258b and 259a/259b) were separated
from the aerial parts of Abrus precatorius in 2019 by Li et al. [141]. Wang and coworkers
reported three pairs of flavanone-stilbene hybrid enantiomers 260a/260b−262a/262b from
Cajanus cajan, and 261a/261b feature a cyclopenta[1,2,3-de]isobenzopyran-1-one tricyclic
unit with cajanolactone A being proposed as the biosynthetic precursor [142]. Two preny-
lated flavones 263 and 264 were isolated from Morus nigra and successfully resolved into
two pairs of enantiomers in 2019 [143], while 264 had been previously reported as a racemic
mixture in 2018 [144]. Compounds 263a/263b incorporate an interesting framework with
a novel 7/6/6 heterocyclic ring system. Flavanes 265 and 266 were characterized as two
racemic mixtures by X-ray diffraction analysis but without further separation into pure
enantiomers [145]. Compounds 267a/267b−270a/270b are four pairs of diprenylated
flavane enantiomers from Daphne giraldii, with the abs. configs. being determined by
Molecules 2022, 27, 1279 22 of 73
Rh2 (OCOCF3 )4 induced ECD method [146]. Compounds 271a/271b, as heterodimers de-
rived from a flavane and a diphenylpropanoid, were isolated from Dracaena cochinchinensis
in 2016 [147].
Figure 15. Structures of flavones and isoflavones.
Compounds 272a/272b−278a/278b, seven pairs of enantiomeric diprenylated isoflav-

ones with diverse ring systems, were reported from Maclura tricuspidata by Lee’s research
group in 2018 [148]. The enantiomer pairs 279a/279b and 280a/280b were obtained from
the stems of Pisonia umbellifera and characterized as hybrids from an isoflavone and a
phenylpropanoid [149].
As can been from the above-mentioned structures, the enantiomerism of these flavones
mainly comes from either the chirality of flavanone/flavane core or that of additional
Molecules 2022, 27, 1279 23 of 73
structural units especially prenyl group(s), or both. Meanwhile, the enantiomerism of the
described isoflavones arises exclusively from the chirality of extra structural units, i.e.,
prenyl group(s) and phenylpropanoid fragment for the current cases.
2.5.2. Chalcones
Chalcones are open-chain flavonoids which have attracted increasing attention from
researchers due to the wide range of their bioactivities, including antimicrobial, antimalarial,
anticancer, anti-inflammatory, antiprotozoal, anti-HIV, antioxidant properties, etc. [150].
The chalcone enantiomers covered by this review, including monomers and dimers, are
summarized in Figure 16 (Names see Table S16 in Supplementary Materials). Similarly, the
determination of abs. configs. by TDDFT-ECD method will not be specified.
Figure 16. Structures of chalcones.
Compounds 281a/281b are a pair of dihydrochalcone enantiomers from Pteris en-

siformis [151] with the abs. configs. being determined by Rh2 (O2 CCF3 )4 -induced ECD
method. Zhang and coworkers reported three chalcone dimers formed by [2 + 2] (282a/282b
and 283a/283b) and [2 + 4] (284a/284a) cycloaddition reactions from Oxytropis chiliophylla
in 2018 [152]. The hydroxycinnamoylated chalcones, including four pairs of separated
enantiomers 285a/285b−288a/288b and one racemate 289, were obtained from Populus bal-
samifera, with the abs. configs. for 285b being established by single-crystal X-ray diffraction
Molecules 2022, 27, 1279 24 of 73
analysis [153]. Li and coworkers reported two pairs of enantiomeric dimers formed by a
dihydrochalcone and a deoxohydrochalcone (290a/290b) and by a deoxohydrochalcone and
a homoisoflavane (291a/291b) from Dracaena cochinchinensis in 2016 [147]. From Horsfieldia
tetratepala, compounds 292−296 were obtained as scalemic deoxohydrochalcone dimers
without chiral separation [154].
2.5.3. Xanthones
Xanthones are polyphenolic compounds incorporating a common 9H-xanthen-9-one
scaffold with various substituents, making them ‘privileged structures’ which are likely
to bind to a variety of biological targets. They have been shown to display significant
bioactivities including antimicrobial, antioxidant, cytotoxic activities, and so on [155]. Most
xanthone enantiomers reported in this period are prenylated; their structures are listed in
Figure 17 (names see Table S17 in Supplementary Materials).
Figure 17. Structures of xanthones.
Hua and coworkers reported a pair of diprenylated xanthone enantiomers 297a/297b

with only one chiral center from Cratoxylum cochinchinense in 2019 [156]. The deoxoxan-
thone enantiomers 298a/298b and 299a/299b incorporating a phenylpropanoid unit were
isolated from Uvaria valderramensis in 2014 [157]. Also in 2014, three pairs of prenylx-
anthone enantiomers (300a/300b−302a/302b) were isolated from Cratoxylum formosum,
with the abs. configs. being established by X-ray crystallographic experiment [158]. As
shown in Scheme 4, the generation of enantiomeric 300a/300b−302a/302b is plausibly
derived from diallylxanthone through a key process of nonstereospecific Claisen rearrange-
ment [158]. In addition to 300−302, eleven pairs of caged prenylxanthone enantiomers
303a/303b−307a/307b and 308a/308b−313a/313b were reported from Garcinia bracteata
in 2018 [159] and from Garcinia propinqua in 2017 [160], respectively, with the abs. config. of
313a being determined by single-crystal X-ray diffraction analysis. The biogenetic origins
of those xanthones with multiple chiral centers are indeed interesting topics that deserves
further investigations.
Molecules 2022, 27, 1279 25 of 73
Scheme 4. Plausible biosynthetic pathways for 300a/300b−302a/302b.
2.6. Terpenoids
Terpenoids are probably the biggest family of NPs with diverse structures and various
biological activities [3]. All terpenoids are initially assembled from the head-to-tail conden-
sation of repeated isoprene units (C5 ), and according to the number of isoprene residues,
terpenoids are normally classified into monoterpenoids (C10 ), sesquiterpenoids (C15 ), diter-
penoids (C20 ), sesterterpenoids (C25 ) and triterpenoids (C30 ). Additionally, meroterpenoids
are also an interesting class of terpenoid products with mixed biogenesis [3]. To the best of
our knowledge, enantiomeric cases have been reported for all terpenoid subclasses except
triterpenoids.
2.6.1. Sesquiterpenoids
Sesquiterpenoids are constructed from three isoprenyl fragments. Among all the
terpenoid classes, they have the most diverse carbon skeletons and are probably the largest
group of terpenoid NPs. Corresponding to their various structural types, natural sesquiter-
penoids have also exhibited a myriad of biological properties [161], and this has been well
reflected by the success of artemisinin (for malaria), the most famous sesquiterpenoid
whose discovery was rewarded the Nobel prize in Physiology or Medicine in 2015. Enan-
tiomeric sesquiterpenoids reported in this period include 16 pairs (314−329) with different
backbones (for structures, see Figure 18, names see Table S18 in Supplementary Materials).
Enantiomers 314a/314b represent the first examples of 1,2-seco bisabolane-type sesquiter-
penoid lactones from Artabotrys hexapetalus, with the abs. configs. being determined by
employing the helicity rule to analyze the Cotton effect at around 220 nm [162]. Qiu
and coworkers reported four pairs of megastigmane-type norsesquiterpenoid enantiomers
315a/315b−317a/317b and 325a/325b from Eucommia ulmoides in 2017, while the racemic
mixtures of 315 and 325, along with pure enantiomers 316b and 317b, had been previously
reported [163]. Compounds 318a/318b and 319a/319b are two pairs of enantiomeric ger-
macrane type sesquiterpenes from Curcuma phaeocaulis reported in 2017 [128]. Chai and
colleagues discovered 320a/320b−324a/324b with a humulane framework and 329a/329b
incorporating a rare 2,2,5,9-tetramethylbicyclo[6.3.0]-undecane skeleton from Syringa pinnat-
ifolia [164]. The abs. configs. of these compounds were established by single-crystal X-ray
diffraction analysis, modified Mosher’s method and TDDFT-ECD calculation [164]. Com-
pounds 326a/326b and 327a/327b were isolated from Commiphora myrrha [165] and Daphne
Molecules 2022, 27, 1279 26 of 73
genkwa [166], respectively. The guaianolide sesquiterpenoid 328 was reported as a racemic
mixture as indicated by X-ray crystallography from Kadsura interior in 2013 [167].
Figure 18. Structures of sesquiterpenoids.
2.6.2. Diterpenoids
Diterpenoids are biosynthesized from the head-to-tail condensation of four isoprene
(C20 ) units, and have the second largest number of carbon backbones in the terpenoid
family. Like sesquiterpenoids, they are also well-known in the NP community for their
diverse bioactivities particularly antitumor effects with therapeutic values [168]. As is well
known, the most notable diterpenoid is taxol, which has been used as a cancer treatment for
over three decades. Nine pairs of enantiomeric diterpenoids 330a/330b−338a/338b (for
structures, see Figure 19, names see Table S19 in Supplementary Materials) with different
structural skeletons were recorded in the study period.
Figure 19. Structures of diterpenoids.
Yue and coworkers phytochemically investigated Croton mangelong to afford two

pairs of macrocyclic diterpenoid enantiomers 330a/330b and 331a/331b featuring a bi-
cyclo[9.3.1]pentadecane core and a rare bridgehead double bond, with the abs. config.
for 330b being determined by single-crystal X-ray diffraction analysis [169]. Compounds
332a/332b are bis-seco-abietane diterpenoids from Cryptomeria fortune and were asymmet-
rically synthesized through a readily made intermediate orthoquinone from sugiol [170].
Compounds 333a/333b are a pair of norditerpenoid enantiomers from the roots of Salvia
miltiorrhiza [171]. Compounds 334a/334b, rearranged abietane-type diterpeniods featuring
a 5/6/6 tricyclic architecture with the five-membered ring formed via C-2–C-11 single bond,
Molecules 2022, 27, 1279 27 of 73
were isolated and characterized from Salvia prionitis in 2015 [171]. Compounds 335a/335b
are a pair of diterpenoid enantiomers with a highly oxygenated novel backbone obtained
from Swertia leducii in 2014, with the rel. config. being determined by X-ray diffraction
analysis and the abs. configs. by TDDFT-ECD method [172]. In the same year, compounds
336a/336b were isolated from Paeonia veitchii [173], and they incorporate an aromatized
norditerpenoid skeleton, with the rel. config. being confirmed by X-ray crystallography.
Compounds 337a/337b and 338a/338b, two pairs of norditerpenoid enantiomers with
unusual 5,5-spiroketal core, were obtained from Hypericum japonicum in 2016, with the abs.
configs. being assigned by a combination of TDDFT-ECD calculation, modified Mosher’s
method and quantum chemical predictions (QCP) of 13 C NMR data [174].
2.6.3. Meroterpenoids
The term meroterpenoid was first proposed by Cornforth in 1968 to describe NPs of
mixed biosynthetic origin which are partially derived from terpenoids [175]. Enantiomeric
meroterpenoids reported in the covered period are exclusively formed by the condensation
of phenolic compounds with a monoterpenoid or a sesquiterpenoid via at least one ether
bond, and the chirality generating enantiomerism all exists in the terpenoid part except
for 340. There are 27 pairs of enantiomeric meroterpenoids reported in this period (for
structures, see Figure 20; for names, see Table S20).
Figure 20. Structures of meroterpenoids.

Molecules 2022, 27, 1279 28 of 73
Compounds 339a/339b−346a/346b are eight pairs of enantiomeric meromonoter-

penoids with diverse heterocyclic frameworks from Rhododendron nyingchiense [176]. Among
them, 339a/339b possess a rare 6/7/5/5 heterocyclic ring system, while 340a/340b incor-
porate a 6/6/5 tricyclic backbone with an extra oxirane ring coupled to the quinone motif.
The assignments of abs. configs. for 339a and 341a were based on X-ray crystallographic
experiment, while those for the others were via TDDFT-ECD method. Four enantiomeric
meromonoterpenoid pairs 347a/347b−350a/350b, along with three merosesquiterpenoid
pairs 351a/351b−352a/352b, were isolated and identified from Rhododendron capitatum
by Hou and coworkers [177,178]. Of these interesting molecules, compounds 348 and
349 bear unprecedented 6/6/6/5 and 6/6/5/5 ring systems, respectively, while 350 and
351−333 possess unique 6/6/6/4 and 6/6/5/4 heterocyclic architectures, respectively.
In addition, the abs. configs. of 350−353 pairs were confirmed by X-ray diffraction and
ECD analyses. Compounds 354a/354b−360a/360b, seven pairs of bibenzyl-based meroter-
penoid enantiomers, were obtained from the Chinese liverwort Radula sumatrana in 2017 by
Lou’s group [179]. Compounds 361a/361b−365a/365b are five pairs of magnolol-derived
lignan-monoterpenoid hybrid enantiomers that have been isolated from Magnolia officinalis
in 2019 [180].
2.7. Phloroglucinols
Phloroglucinol derivatives represent a unique class of NPs featuring one or more intact
or modified phloroglucinol units, with alkylation and acylation as the common structural
modifications [181]. The chirality of them arises usually from their prenyl/terpenyl sub-
stituents and/or from the dearomatization of phloroglucinol core. In most cases, they can
also be classified into the ‘meroterpenoid’ group, but here we describe them separately
owing to the considerable number of reports and their popularity among NP workers in
recent years. Phloroglucinal enantiomers reported in this period all incorporate one or more
acyl groups including acetyl, isobutyryl, benzoyl, cinnamoyl and dihydrocinnamoyl, and
their structures are shown in Figure 21 (names see Table S21 in Supplementary Materials).
Wherever the abs. configs. are determined by the TDDFT-ECD method, it will be not
specifically mentioned in this section.
Ye and coworkers reported a pair of enantiomeric isobutyrylated phloroglucinol dimers
366a/366b from Myrtus communis in 2019 and also completed their total synthesis in the same
year [182]. Laphookhieo and colleagues discovered the benzoylated phloroglucinol enan-
tiomers 367a/367b from Cratoxylum sumatranum ssp. Neriifolium and assigned their abs. con-
figs. by comparing the specific optical rotations with those of known analogues [183]. Com-
pounds 368a/368b−371a/371b, as phloroglucinol-monoterpenoid hybrids, were reported
from Hypericum japonicum in 2016, with the abs. configs. of 370b and 371b being determined
by single-crystal X-ray diffraction analysis [184]. Compounds 368a/368b and 369a/369b
incorporate interesting pyrano[3,2-b]pyran and 2-oxabicyclo[3.3.1]nonane skeletons, respec-
tively, while 370a/370b possess a benzo[b]cyclopenta[e]oxepine ring system. Laphookhieo
and coworkers also obtained acetylated (372a/372b) and cinnamoylated (373a/373b)
phloroglucinol enantiomers from Mallotus philippensis in 2019 and established their abs.
configs. on the basis of X-ray crystallographic studies [185]. Hans et al. re-acquired myrtu-
commulone A (374) from Myrtus communis in 2015 and proved that, by converting it into sep-
arable derivatives, 374 consisted of the racemate and the meso form in a ca. 1:1 ratio [186].
Compounds 375a/375b−377a/377b, dihydrocinnamoylated and rearranged phloroglu-
cinol dimers, were isolated from Xanthostemon chrysanthus in 2019 [187]. Compounds
375a/375b feature an bis-phenylpropanoyl-benzo[b]cyclopent[e]oxepine tricyclic back-
bone and 376a/376b and 377a/377b represent the first examples of 1-(cyclopentylmethyl)-
3-(3-phenylpropanoyl)benzene scaffold [187]. Compounds 378a/378b and 379a/379b,
cinnamoylated phloroglucinol dimers from Cleistocalyx operculatus, possess a polycyclic
skeleton with a highly functionalized dihydropyrano[3,2-d]xanthene tetracyclic core, and
the enantiotropy could be derived from the nonstereoselective hetero-Diels-Alder [4 + 2]
cycloaddition as shown in the proposed plausible biosynthetic pathway (Scheme 5) [188].
Molecules 2022, 27, 1279 29 of 73
The benzoylated phloroglucinol 380a was isolated from Triadenum japonicum in 2015 [189]
and identified as the enantiomer of (+)-nemorosonol (380b) previously reported from
Clusia nemorosa [190]. Compounds 381a/381b are a pair of digeranylated phloroglucinol
enantiomers from Garcinia multiflora and feature a caged tetracyclo[5.4.1.11,5 .09,13 ]tridecane
skeleton, with the generation of enantiomerism being likely from the intramolecular Diels-
Alder [4 + 2] cycloaddition on different sides as shown in Scheme 6 [191]. Compounds
382a/382b−385a/385b, four similar type of enantiomer pairs as 381, were obtained from
Garcinia multiflora, and 382a/382b are characterized by the coupling of two novel caged
fragments, i.e., 2,11-dioxatricyclo[4.4.1.03,9 ]undecane and tricyclo[4.3.1.03,7 ]decane, with
the rel. config. being determined by X-ray diffraction analysis [192].
Figure 21. Structures of phloroglucinols.

Molecules 2022, 27, 1279 30 of 73
Scheme 5. Plausible biosynthetic pathways for 378a/378b and 379a/379b.

Molecules 2022, 27, x FOR PEER REVIEW 33 of 77
Molecules 2022, 27, 1279 31 of 73
2.8. Naphthalenes and Phenanthrenes

The enantiomerism of naphthalene and phenanthrene derivatives is generally
2.8. Naphthalenes and Phenanthrenes
attributable to chiral centers and, in many cases, axial chirality. The structures of the
The enantiomerism
naphthalene of naphthalene
and phenanthrene and reported
enantiomers phenanthrene
in thisderivatives
period areisdisplayed
generally in
at-
tributable to chiral centers and, in many cases, axial chirality. The structures of the
Figure 22 (names see Table S22 in Supplementary Materials). The abs. configs. of most of naph-
thalene and phenanthrene enantiomers reported in this period are displayed in Figure 22
these enantiomers were determined by the TDDFT-ECD method, unless otherwise
(names see Table S22 in Supplementary Materials). The abs. configs. of most of these
specified.
enantiomers were determined by the TDDFT-ECD method, unless otherwise specified.
Figure 22. Structures of naphthalene and phenanthrenes.

Figure 22. Structures of naphthalene and phenanthrenes.
2.8.1.
2.8.1.Naphthalenes
Naphthalenes
Compounds
Compounds 386−397
386−397are are1212pairs
pairsofofnaphthalene
naphthaleneenantiomers
enantiomersreported
reportedininthis
thisperiod.
period.
Among
Among them,
them, 386−391
386−391were
wereisolated
isolatedfrom
fromthetheroots
rootsof
ofMorinda officinalis
Morinda officinalis var.
var. officinalis
officinalis and
and identified as prenylated methyl 2-naphthoates by the authors’ team, with
identified as prenylated methyl 2-naphthoates by the authors’ team, with the rel. configs. of the rel.
configs. of 386
386 and 388 and
being 388 being
confirmed confirmed
by X-ray by X-ray
diffraction analysis and 13 C NMR
diffraction analysis and 13C respec-
calculation, NMR
calculation,
tively [8]. Compounds [8].−Compounds
respectively392 394, three pairs392−394, three pairs of 3,4-dihydro-4-naphthyl-
of 3,4-dihydro-4-naphthyl-naphthalen-1(2H)-
naphthalen-1(2H)-one
one enantiomers, wereenantiomers,
obtained fromwere obtained
Juglans regia infrom Juglans
2019 [193]. regia in 2019
Compounds [193].
395a/395b
Compounds 395a/395bwere
from Rubia oncotricha fromcharacterized
Rubia oncotrichaby Tanwere
andcharacterized
coworkers as by Tannaphthoquinone
novel and coworkers
dimers
as novelwith an unprecedented
naphthoquinone dimers spiro[4.5]
with an carbon core [194]. Another
unprecedented spiro[4.5]pair of dimeric
carbon naph-
core [194].
Another pair of dimeric naphthoquinone enantiomers 396a/396b were also reportedfrom
thoquinone enantiomers 396a/396b were also reported by the same research team by
Rubia
the samealata in 2014,team
research withfrom
the rel. config.
Rubia alatabeing corroborated
in 2014, with the by
rel.X-ray crystallographic
config. exper-
being corroborated
Molecules 2022, 27, 1279 32 of 73
iment [195]. Compounds 397a/397b are simple tetrahydronaphthoquinone enantiomers

reported from Eremurus altaicus in 2015 [196].
2.8.2. Phenanthrenes
Phenanthrene enantiomers (398a/398b−408a/408b) in this period have been solely
reported from Bletilla striata by Li’s and Hou’s research teams in 2019 [130], and they can be
divided into three groups, namely, phenanthrene monomer (405), phenanthrene dimers (404
and 406−408) and phenanthrene-phenylpropanoid hybrids (398−403). The enantiomerism
of these compounds has been generated from the axial chirality of phenanthrene moiety
and/or from the chiral centers of phenylpropanoid unit. Notably, compounds 404−408
with only axial chirality were able to be separated into five pairs of enantiomers. Axial
chirality, although well known to organic chemists, has often been overlooked by NP
researchers, owing to its rare presence in natural molecules. Therefore, the enantiomeric
purity of NPs with axial chirality is strongly recommended to be checked no matter they
are new or known.
2.9. Chromanes
Chromane derivatives are a class of NPs having a chromane core or a modified one
(e.g., chromone, chromanone) in their structures. Enantiomeric chromane derivatives
reported in this period are listed in Figure 23 (names see Table S23 in Supplementary Mate-
rials). Compounds 409a/409b−415a/415b had been studied previously in many occasions
as pure enantiomers, scalemic mixtures or racemates, and as natural molecules, biotransfor-
mation products or synthetic intermediates, but none of these reports had paid attention to
the enantiomerism of this group of structures. They were separated from the flower buds
of Tussilago farfara in the authors’ lab in 2018, with the abs. configs. being determined by
chemical method as well as TDDFT-ECD calculation and ECD comparison [7]. Compounds
416a/416b were proposed to be a pair of norbisabolane sesquiterpenoid enantiomers yet
incorporating a chromone core and were obtained from Curcuma longa in 2019 [197]. Com-
pounds 417a/417b−421a/421b are five pairs of prenylated chromone enantiomers isolated
from Harrisonia perforate in 2014, whereas only the abs. configs. of 417a/417b were assigned
by Mosher’s method [198]. From the same plant, 422a/422b were reported as a pair of
enantiomeric molecules by Yuan et al. in 2017 [199].
Figure 23. Structures of chromanes (* abs. configs. undetermined).
2.10. Acetophenones
Acetophenones are a rare class of NPs bearing normal or rearranged acetophenone
units in their structures. To date, ten pairs of acetophenone enantiomers have been re-
ported, and their structures are depicted in Figure 24 and names listed in Table S24 in
Supplementary Materials. Kong and coworkers reported four pairs of diprenylated and
rearranged acetophenone enantiomers 423a/423b−426a/426b from the leaves of Melicope
ptelefolia in 2019 and assigned their abs. configs. by a combination of modified Mosher’s
and TDDFT-ECD methods [200], while 423a/423b and 424 in racemic form had been previ-
Molecules 2022, 27, 1279 33 of 73
ously isolated from Evodia lepta by Tang et al. in 2018 [201]. Also identified as rearranged
acetophenones, compounds 427a/427b coupled with a phenylpropanoid fragment were
isolated from Xanthostemon chrysanthus in 2019 [187]. Compounds 428a/428b are preny-
lated hydroacetophenone enantiomers obtained from Melicope viticina in 2019 [202], while
429a/429b and 430a/430b with intact acetophenone unit were discovered from Eupatorium
chinense in 2013 [203]. Compounds 431a/431b and 432a/432b, rearranged acetophenones
with a novel 9-oxatricyclo[3.2.1.13,8 ]nonane core from Melicope ptelefolia, were assigned the
abs. configs. by single-crystal X-ray diffraction analysis [204].
Figure 24. Structures of acetophenones.
2.11. Diarylheptanoids
Diarylheptanoids, a class of NPs characteristic of a 1,7-diphenylheptane core, have
been increasingly recognized as potential therapeutic agents for their diverse biological
properties including antiinflammatory, antitumor, antioxidant, antiestrogen, hepatoprotective,
antileishmania and neuroprotective activities [205]. Nine pairs of diarylheptanoid enantiomers
(433−441, for structures, see Figure 25; for names, see Table S25 in Supplementary Materials)
have been documented in the covered period. The occurrence of enantiomerism in these
compounds results from the chiral centers generated by oxidation or Diels-Alder cycloaddition
with other molecules.
Figure 25. Structures of diarylheptanoids.
The enantiomeric pairs of diarylheptanoid-monnoterpene adduct (433 & 434) and

diarylheptanoid-sesquiterpene hybrid (435–437) from Alpinia officinarum, were hypothe-
sized to be produced via a crucial Diels-Alder cycloaddition between the diarylheptanoids
and corresponding terpenyl units. The rel. configs. for the chiral centers in the cyclohexene
ring were assigned by comparing the experimental and calculated 13 C NMR data, followed
by the establishment of the abs. configs. via the TDDFT-ECD method [206]. Compounds
438−441 are four pairs of diarylheptanoid enantiomers acquired from Dioscorea villosa in
2012, with the abs. configs. being determined by the modified Mosher’s method [207].
Molecules 2022, 27, 1279 34 of 73
Compounds 438 and 439 incorporate an extra tetrahydropyran ring formed via C-1 and
C-5, while 440 and 441 are normal linear examples.
2.12. Triphenylmethanes
Triphenylmethanes are a unique class of NPs with one central carbon being linked
by three aryl groups. They have been discovered to have a wide range of biological
activities including antioxidant, antitumor, anti-HPK (histidine protein kinases) activities,
etc. [208]. Six pairs of triphenylmethane enantiomers (442−447, Figure 26, Table S26 in
Supplementary Materials) were reported in this period; their enantiomerism is attributable
to chiral centers (442 and 443) or axial chirality (444−447).
Figure 26. Structures of triarylmethanes.
Compounds 442a/442b and 443a/443b are two pairs of triarylmethane enantiomers

reported from Securidaca inappendiculata in 2018, with the abs. configs. being determined by
X-ray crystallography [209]. In addition, bio-inspired total syntheses for these compounds
were also completed [209]. Compounds 444−447 occurred as racemates generated by
axial chirality in the plant Selaginella pulvinate [210], and subsequent chiral fractionation
divided 444 and 447 into 444a/444b and 447a/447b, respectively, with the abs. configs.
being assigned by TDDFT-ECD method. However, 445 and 446 had not been enantiomeri-
cally separated.
2.13. Fatty Acids

Five pairs of enantiomeric fatty acid esters (448a/448b−452a/452b) were recorded in
this covered stage and their structures are listed in Figure 27, with names being shown
in Table S27 in Supplementary Materials. Usually, the generation of chirality in these
compounds derives from the nonstereoselective oxidations on the aliphatic chain (448−451)
or substitution on the glycerol moiety (452). Compounds 448a/448b−452a/452b from
Plantago depressa were characterized as four pairs of 9-oxo octadecanoid derivatives by the
authors’ group, with 451 bearing a rare chlorine atom [6]. We have also isolated 452a/452b
as octadecanoid monoglycerides from the seeds of Ipomoea nil in 2019 and established their
abs. configs. via an in situ dimolybdenum ECD method [9].
Figure 27. Structures of fatty acids.
2.14. Miscellaneous
Other enantiomeric NPs from plants reported in this period are displayed in Figure 28
(names see Table S28). The abs. configs. of all these enantiomers were assigned by the
TDDFT-ECD method unless otherwise specified.
Molecules 2022, 27, 1279 35 of 73
Figure 28. Structures of miscellaneous classes.
Compounds 453−456 are four pairs of enantiomeric phthalide derivatives, all of

which were isolated and characterized from Angelica sinensis in 2018 [211]. Phthalides are
a rare class of NPs referring to lactones of 2-hydroxymethyl benzoic acids. They exist in
nature as monomers or oligomers, and the latter are generally produced via [2 + 2] or
[4 + 2] cycloaddition to form a number of complex polycyclic skeletons with multiple chiral
centers [211]. Among them, 453 and 454 are dimers, while 455 and 456 are trimers.
Compounds 457a/457b and 458a/458b are enantiomeric stilbenoids that have 1,2-
diphenylethylene (stilbene) as their basic scaffold and exist as monomers or oligomers in
nature. They normally act as phytoalexins to assist plants in their resistance to pathogens
or stress factors [212]. Compounds 457a/457b, prenylated stilbenoid dimers isolated
from Cajanus cajan in 2014, possess an interesting dimerization pattern generated from
nonstereoselective radical addition as shown in Scheme 7, and their structures including the
abs. configs. were determined by a combination of X-ray diffraction analysis and TDDFT-
ECD calculation [213]. Compounds 458a/458b are enantiomeric stilbenoid trimers obtained
from Cyperus rhizomes in 2012, and their abs. configs. were established by comparing the
[α]D and ECD data with those of known analogues [214,215].
Compounds 459a/459b are butenolide derivatives isolated from Dendrobium nobile in
2016 [49], while 460a/460b, with an unprecedented skeleton incorporating both butyro-
lactone and butenolide moieties, were obtained from Melicope viticina in 2019 [202]. Com-
pounds 461a/461b featuring an oxabicyclo[3.2.1]octane ring were discovered from Ligus-
ticum chuanxiong in 2019 [216], and 462a/462b are a pair of enantiomeric cyclohexylethanoid
dimers acquired from Incarvillea younghusbandii in 2012 [217]. Compounds 463a/463b from
Dendrobium nobile were identified as a pair of spirodiketone enantiomers in 2016 [218].
Styrylpyrone monomer (464a/464b) and dimer (465) enantiomers were reported from San-
rafaelia ruffonammari and Ophrypetalum odoratum, respectively, but the dimer 465 was only
obtained as a racemate without further chiral separation [219]. Compounds 466a/466b are
a pair of enantiomeric 2,3-dihydro-1H-indene derivatives discovered from Streblus indicus
in 2016 [220].
Molecules 2022, 27, 1279 36 of 73
3. Enantiomers from Kingdom Fungi

Enantiomers originating from fungi, i.e., from phyla Ascomycota and Basidiomycota,
will be presented in this section. The structural classification of NPs from fungi is not as
regular and clear as those from plants; a myriad of fungal NPs belong to the super family
of polyketides that derive biogenetically from the acetate pathway [1]. Also, considering
the limited number of molecules described in this section, the enantiomers described here
are simply divided into nonalkaloids and alkaloids. Where applicable, their biogenesis and
structure will also be described.
Molecules 2022, 27, 1279 37 of 73
3.1. Enantiomers from Phylum Ascomycota

3.1.1. Nonalkaloids
Nonalkaloid enantiomers from phylum Ascomycota show great structural diversity and
biological importance. The structures of those documented in the covered period are summa-
rized in Figure 29a,b, and their names are presented in Table S29 in Supplementary Materials.
The abs. configs. of those established by TDDFT-ECD method are not specifically mentioned
in this section.
Figure 29. Cont.

Molecules 2022, 27, 1279 38 of 73
Figure 29. (a) Structures of nonalkaloids from phylum Ascomycota (Part 1). (b) Structures of
nonalkaloids from phylum Ascomycota (Part 2).
Zhang and co-authors discovered a racemic polyketide 467, together with four pairs
of analogue enantiomers 468a/468b–471a/471b, from the starfish-symbiotic fungus Peni-
cillium sp. GGF16-1-2 in 2019 [221]. The enantiomeric cyclopentenones 472a/472b and
spiro-butenolides 473a/473b were isolated from Aspergillus Sclerotiorum in 2019 [222]. Gao
and coworkers investigated three endolichenic fungal strains Nigrospora sphaerica, Al-
ternaria alternata and Phialophora sp. in 2016 and obtained the same polyketide enantiomers
474a/474b, whose abs. configs. were determined by modified Mosher’s method [223].
Compounds 475a/475b incorporating a benzannulated 6,6-spiroketal skeleton were iso-
lated from the mangrove-derived fungus Penicillium dipodomyicola HN4-3A. Compounds
476a/476b, a pair of ketal enantiomers from Paraconiothyrium sporulosum, were assigned
the abs. configs. by application of Snatzke’s chirality rule for cyclopentenones [224]. The
isocoumarins 477 and 478 were reported as racemic mixtures from Penicillium coffeae MA-
314 in 2019 [225]. Compounds 479a/479b and 480a/480b are spiro-orthoester enantiomers
bearing a novel 1,4,6-trioxaspiro[4,5]decane-7-one unit from Penicillium minioluteum, and
their rel. configs. were assigned by single-crystal X-ray diffraction analysis [226]. Com-
pounds 481a/481b were characterized as a pair of cyclopentaisochromenone enantiomers
from Alternaria sp. TNXY-P-1 in 2018 [227]. Puno and coworkers discovered 482a/482b
as dibenzo-α-pyrones bearing a diepoxy-cage-like moiety from an Endophytic Alternaria
sp. in 2019 and confirmed their rel. configs. by X-ray crystallography [228]. Also eluci-
dated as dibenzo-α-pyrones, 483a/483b and 484a/484b were reported from the endophytic
fungus Alternaria alternate in 2014 [229]. Compounds 485a/485b, a pair of enantiomeric
chromone derivatives from the marine-derived fungus Taeniolella sp. BCC31839, were
Molecules 2022, 27, 1279 39 of 73
established the abs. configs. by the modified Mosher’s method in 2019 [230]. Compound
486 was obtained as a racemate from Periconia sp. in 2015, without further chiral fraction-
ation [231], while 487a/487b and 488a/488b were isolated from the endophytic fungus
Aspergillus Fumigatus in 2018 [232]. Compound 489 was elucidated as a racemic mixture
from the cordyceps-colonizing fungus Fimetariella sp. in 2012, and it incorporates a novel
spiro[chroman-3,70 -isochromene]-4,60 (80 H)-dione skeleton [233]. Compounds 490a/490b
were characterized as a pair of enantiomeric isochromanes from an endophytic fungus
Aspergillus fumigatus in 2019 [234]. Enantiomers 491a/491b and 492a/492b were identi-
fied as p-terphenyl derivatives from the endolichenic fungus Floricola striata [235], with
the abs. configs. being determined by using the helicity rule for α,β-unsaturated ketone.
Compounds 493a/493b and 494a/494b, as xanthene enantiomers with an unprecedented
hexacyclic heterocylic backbone, were isolated from Xylaria feejeensis GM06 in 2018 [236].
The abs. config. assignment for 493a/493b was based on the X-ray crystallographic ex-
periment. Compounds 495a/495b were characterized as a pair of dimeric polyketide
enantiomers from a mangrove endophytic fungus Ascomycota sp. SK2YWS-L [237], with
the absolute structures being determined by X-ray diffraction analysis and TDDFT-ECD
calculation. Compounds 496a/496b are a pair of 2,3-diaryl indone atropisomers isolated
from Ascomycota sp. SK2YWS-L in 2018 [238].
Compounds 497a/497b were identified as simple δ-lactone enantiomers from the
fungus Aspergillus terreus in 2018 [239], while 498 is a α-pyrone derivative obtained as a
nearly racemic mixture from the endolichenic fungus Tolypocladium sp. in 2017 [240]. Pei
and coworkers discovered two pairs of dimeric α-pyrone enantiomers (499a/499b and
500a/500b), which was formed via intermolecular nonstereoselective [2 + 2] cycloaddi-
tion reaction (Scheme 8), from the endophytic fungus Phoma sp. YN02-P-3 in 2017, and
499a/499b possess a novel 6/4/5/6 tetracyclic ring system. Moreover, the rel. config.
assignment for 500a/500b was confirmed by single-crystal X-ray diffraction analysis [241].
Compounds 501 and 502 were elucidated as C-ring open flavonoids from Pochonia chlamy-
dosporia var. spinulospora FKI-7537 in 2018, and 502 was successfully resolved into two
enantiomers but without assigning the abs. configs., while 501 was not subjected to chi-
ral separation due to limited amount [242]. Compounds 503a/503b and 505a/505b are
two pairs of polyketides isolated from Penicillium chrysogenum MT-12 in 2017, where the
racemic mixture of 505 had been previously reported from an endophytic fungus Aspergillus
sp [243]. Compounds 504a/504b, a pair of funicone enantiomers, were obtained from the
mangrove sediment-derived fungus Penicillium pinophilum SCAU037 [244]. The polyketide
dimers 506a/506b and 507a/507b bearing a rare pentacyclic dihydrobenzo[1,4]dioxine core
were isolated from Penicillium canescens in 2019 [245]. Enantiomers 508a/508b, a pair of
caged norsesquiterpenoids with a novel tricyclo[4.4.01,6 .02,8 ]decane carbon skeleton, were
obtained from the endophytic fungus Preussia isomera in 2019, with the rel. config. being
confirmed by X-ray diffraction data [246]. Kong and coworkers discovered 509a/509b,
featuring a prenylated chlorobenzophenone backbone, from the plant endophytic fungus
Pestalotiopsis sp. in 2017 [247]. Compounds 510a/510b are 2-benzofuran-1(3H)-one deriva-
tives isolated from a mangrove-derived fungus Eurotium rubrum MA-150 in 2016 [248].
Compounds 511a/511b−513a/513b, three prenylated dibenzo[b,e]oxepinone enantiomer
pairs, were reported from a wetland soil-derived fungus Talaromyces flavus in 2016 [249], and
the same type of enantiomers 514a/514b were obtained from an endophytic fungus Xylaria
sp. in 2015 [250]. The benzophenone-hemiterpene adducts 515a/515b were separated from
the endophytic fungus Cytospora rhizophorae in 2019 [251]. Compounds 516a/516b are a
pair of enantiomeric polyketides incorporating a 6/6/6/6/5/6/6 heptacyclic backbone
and were isolated from fungus Alternaria sp. MG1 in 2019 [252]. Compounds 517a/517b
were identified as dimeric polyketide enantiomers from a marine-derived fungus Eurotium
sp. SCSIO F452 in 2019 [253].
Molecules 2022, 27, 1279 40 of 73
Scheme 8. Plausible biosynthetic pathways for 499a/499b and 500a/500b.
3.1.2. Alkaloids
Alkaloid enantiomers found in phylum Ascomycota during the reported period are
displayed in Figure 30, with their names being shown in Table S30 in Supplementary
Materials. The abs. configs. of those established by TDDFT-ECD method are not specifically
mentioned in this section.
Compounds 518−537 are a series of indole alkaloid derivatives reported from dif-
ferent fungal species. Except for the bisindole enantiomers 518a/518b (from Fusarium sp.
XBB-9), whose abs. configs. were assigned by X-ray diffraction analysis [254], all other
alkaloids possess a cyclodipeptide scaffold (also known as diketopiperazine) formed from
tryptophan and a second amino acid. Four pairs of enantiomers (519a/519b−522a/522b)
biosynthesized from tryptophan and proline were isolated from the marine-derived species
Aspergillus versicolor OUCMDZ-2738 in 2019 [255], while the tryptophan-alanine dipep-
tide enantiomers 523a/523b−525a/525b bearing rare thiomethyl and N-methoxy groups
were obtained from an alga-derived endophytic fungus Acrostalagmus luteoalbus TK-43 in
2019 [256]. Wang and coworkers discovered the spirocyclic alkaloids 526a/526b−529a/529b
from Eurotium sp. SCSIO F452 in 2019 and proposed their biosynthetic pathways as shown
in Scheme 9 [257], while 529a/529b had also been reported from Aspergillus effuses H1-1
in 2012 [258]. Compounds 530a/530b, whose abs. configs. were determined by X-ray
crystallography, incorporate a novel 6/5/4/5/6 pentacyclic motif and were acquired from
the mangrove endophytic fungus Aspergillus sp. SK-28 in 2019. As shown in Scheme 10,
the nonenzymatic catalyzed [2 + 2] cycloaddition could be the plausible key biosynthetic
step to generate both enantiomers of 530 [259]. Alkaloids 531a/531b with a 30 ,3a0 ,50 ,60 -
tetrahydrospiro[piperazine-2,20 -pyrano[2,3,4-de]chromene] ring system were isolated from
a mangrove rhizosphere soil derived fungus Aspergillus effuses H1-1 in 2012 [258], and
compounds 532a/532b−534a/534b as three pairs of variecolortide enantiomers were re-
ported from the fungus Eurotium sp. [260]. Wang and coworkers disclosed three spirocyclic
diketopiperazine enantiomer pairs (535a/535b−537a/537b) from the marine-derived fun-
gus Eurotium sp. SCSIO F452 in 2019 and proposed their plausible biosynthetic pathways
as shown in Scheme 11 [261]. Compounds 535a/535b possess a highly functionalized
seco-anthronopyranoid structural unit with a 2-oxa-7-azabicyclo[3.2.1]octane core, while
536a/536b and 537a/537b represent rare examples of diketopiperazines with a 6/6/6/6
tetracyclic cyclohexene-anthrone fragment.
Molecules 2022, 27, 1279 41 of 73
Figure 30. Structures of alkaloids from phylum Ascomycota.

Molecules 2022, 27, 1279 42 of 73
Scheme 9. Plausible biosynthetic pathways for 526/526b−529a/529b.
Scheme 10. Plausible biosynthetic pathway for 530a/530b.

The decalin-containing 4-hydroxy-2-pyridones (538a/538b) and their four pairs of
rearranged analogues (539a/539b−542a/542b) were isolated from the solid culture of fun-
gus Coniochaeta cephalothecoides in 2017 [262]. In 2019, Liu and colleagues investigated the
metabolites of fungus Xylaria longipes to detect two highly conjugated alkaloids, 543a/543b
and 548a/548b. The former possesses a 5/6/6/5/5 fused ring system with a unique 2-
azaspiro[4.4]nonane substructure [263]. From the same fungal species, the same authors re-
ported 544a/544b and their dimers 545a/545b [264] as thiopyranodipyridine enantiomers.
Compounds 546a/546b and 547a/547b were identified as N,N 0 -ketal quinazolinone alka-
loid enantiomers from an ascidian-derived fungus Penicillium sp. 4829 in 2019 [265] and
from an algicolous Talaromyces sp. in 2016 [266], respectively. Compounds 549a/549b are a
pair of enantiomeric 4-oxabicyclo[4.3.0]lactam derivatives from the marine-derived fun-
gus Penicillium griseofulvum reported in 2017 [267]. The aromatic polyketide enantiomers
550a/550b with a 5/6/6/6/5 heterocyclic architecture were separated from Penicillium
canescens in 2019 [245], while the enantiomeric phthalimidine derivatives 551a/551b were
acquired from the sponge-derived fungus Stachylidium sp. in 2012 [268]. Compounds
552a/552b were characterized as a pair of N-furanone amide enantiomers from the solid
culture of Trichoderma atroviride S361 in 2018 [269], and 553a/553b, a pair of enantiomeric
hydantoin (imidazolidin-2,4-dione) derivatives, were obtained from the fungus Fusarium
sp. in 2015 [270]. Compounds 554−557 were isolated as bisabolane sesquiterpenoid amide
racemates from the plant endophytic fungus Paraconiothyrium brasiliense in 2015, but only
Molecules 2022, 27, 1279 43 of 73
554 was chirally separated into pure enantiomers [271]. Compounds 558a/558b are a pair
of enantiomeric alkaloid dimers with a symmetrical spiro[oxazinane-piperazinedione]
skeleton from Pestalotiopsis sp. in 2015 [272].
Scheme 11. Plausible biosynthetic pathways for 535a/535b−537a/537b.

Molecules 2022, 27, 1279 44 of 73
3.2. Enantiomers from Phylum Basidiomycota

It is interesting to note that all natural enantiomers from phylum Basidiomycota
collected in this period, with only one exception (Granulobasidium vellereum), were re-
ported from species of the well-known medicinal macrofungus genus Ganoderma. More
interestingly, all the enantiomers from Ganoderma fungi, with one exception., are hydro-
quinone derivatives (602). In addition, the majority of these enantiomers belong to the
meroterpenoid class (hydroquinone-terpenoid hybrid), and the terpenyl units here are
usually monoterpenoid or sesquiterpenoid. Their structures and names are summarized
in Figure 31a,b and Table S31, respectively. The abs. configs. of these enantiomers in this
section have all been determined by TDDFT-ECD calculation unless otherwise specified.
Figure 31. Cont.

Molecules 2022, 27, 1279 45 of 73
Figure 31. (a) Structures of metabolites from phylum Basidiomycota (Part 1); (b) Structures of
metabolites from phylum Basidiomycota (Part 2).
Compounds 559–584 represent monomeric hydroquinone-terpenoid enantiomers.

Cheng and coworkers discovered a pair of hydroquinone-trinorsesquiterpenoid enan-
tiomers (559a/559b) possessing a fused 6/5/6/6/5 polycyclic skeleton from G. lucidum
in 2019 [273]. Compounds 560a/560b−563a/563b, identified as a series of hydroquinone-
mononorsesquiterpenoid hybrids from G. cochlear in 2014, possess a spiro[4,5]decane ring
system (560−562) and an eight-membered ring (563), with the abs. configs. being assigned
by single-crystal X-ray diffraction analysis [274]. Compounds 564a/564b from G. lucidum
are a pair of rotary door-shaped hydroquinone-normonoterpenoid enantiomers with an
unusual 5/5/6/6 ring system, and their abs. configs. were established by interpretation of
X-ray crystallographic data [275]. Compounds 565a/565b, a pair of macrocyclic meroter-
penoid enantiomers derived from a hydroquinone and an intact sesquiterpenoid, were
isolated from G. resinaceum by Chen et al. in 2017 [276]. The hydroquinone-monoterpenoid
enantiomers 566a/566b with an unusual dioxacyclopenta[c,d]inden motif were reported
from G. applanatum in 2016 [277]. Nine pairs of enantiomers 567a/567b−575a/575b incor-
porating either monoterpenoid or sesquiterpenoid fragments were obtained from G. ap-
planatum in 2015 [278], and 570a/570b was also reported from G. lucidum in the same
Molecules 2022, 27, 1279 46 of 73
year with the abs. configs. being not assigned [279]. Compounds 576a/576b featuring
an interesting polycyclic meroterpenoid skeleton with a glycerol unit were isolated from
G. applanatum in 2017 [280]. Five pairs of hydroquinone-sesquiterpenoid enantiomers
577a/577b−581a/581b and a racemate 582, all bearing a butenolide fragment, were iso-
lated from G. sinense in 2016 [281]. Compounds 583a/583b and 584a/584b, two pairs
of farnesylated hydroquinone enantiomers incorporating a p-hydroxycinnamoyl residue,
were discovered from G. sinense in 2016 [281].
Compounds 585–600 represent dimeric hydroquinone-terpenoid enantiomers. Enan-
tiomers 585a/585b were elucidated as hydroquinone dimers hybridized with a highly
oxygenated monoterpenoid moiety from G. applanatum in 2016 [282]. They feature an
unprecedented dioxaspirocyclic skeleton constructed from a 6/6/6/6 tetracyclic system
0 0
and an unusual tricyclo[4.3.3.03 ,7 ]dodecane unit, and their abs. configs. were determined
by single-crystal X-ray diffraction analysis [282]. Also from G. applanatum, Cheng and
coworkers separated three pairs of dimeric hydroquinone-monoterpenoid enantiomers
586a/586b−588a/588b [283]. Two types of meroterpenoid heterodimer enantiomers
(589a/589b & 590a/590b; 591a/591b–593a/593b) from G. cochlear were reported by the
same authors from Cheng’s group, and their abs. configs. were assigned by compar-
ing the ECD curves with those of reported analogues [284,285]. Five pairs of enan-
tiomers (594a/594b−598a/598b) of the same type as 591–593, along with the novel hybrid
dimers (599a/599b & 600a/600b) formed by a hydroquinone-pyridine and a hydroquinone-
monoterpenoid, were also isolated and characterized from G. cochlear in 2015 [286].
Compounds 601a/601b were identified as a pair of hydroquinone-pyridine alkaloid
enantiomers from G. luteomarginatum in 2019 [287], while butyrolactone 602 from G. lucidum
was chirally separated without assigning the abs. configs. of the enantiomers [279]. In 2015,
sesquiterpenoids 603a and 604a [288] from the fungus Granulobasidium vellereum were identi-
fied as the enantiomers of illidin M (603b) [289] and dihydroilludin (604b) [290], respectively.
4. Enantiomers from Kingdom Prokaryota

Few enantiomers have been reported from the kingdom Prokaryota, i.e., only five pairs
(605–609) to date, all of which were discovered from actinomycetes. Their structures and
names are provided in Figure 32 and Table S32 in Supplementary Materials, respectively.
Figure 32. Structures of metabolites from actinomycetes.
Compounds 605a/605b are a pair of angucyclinone enantiomers featuring a unique

epoxybenzo[f ]naphtho[1,8-bc]oxocine heterocyclic scaffold, and were isolated from a Strep-
tomyces sp. in 2019, with the abs. configs. being determined by X-ray diffraction analy-
sis [291]. Compound 606, a simple prenylated indole alkaloid bearing a rare cyano group,
was isolated as a racemate without further chiral separation from Streptomyces sp. ZZ820
in 2019 [292]. Compounds 607a/607b−609a/609b are three pairs of enantiomeric indole
alkaloids with a spiro indolinone-naphthofuran skeleton reported from a Streptomyces sp.
in 2017 [293].
5. Enantiomers from Kingdom Animalia

Compared with those from plants and microorganisms, compounds from animals
only account for a small proportion of the large NP family, and have been mainly reported
from lower animals such as sponges and corals. Therefore, the number of enantiomers from
Molecules 2022, 27, 1279 47 of 73
kingdom Animalia is also limited. According to their biological source, animal-derived

enantiomers will be divided into the following three subcategories.
5.1. Enantiomers from Phylum Porifera

Animals from phylum Porifera (also termed Spongia) are generally known as sponges.
They also represent a very important source of bioactive NPs. Natural enantiomers from
sponges mainly include terpenoids and alkaloids; see Figure 33 and Table S34.
Figure 33. Structures of metabolites from phylum Porifera.

Molecules 2022, 27, 1279 48 of 73
5.1.1. Terpenoids
Compounds 610a/610b were identified as a pair of valerenane-type sesquiterpene
enantiomers from a Spongia sp. in 2019 [294], while the trinorsesquiterpenoid enantiomers
611a/611b incorporating furan and butenolide rings were isolated from the Beihai sponge
Spongia officinalis in 2018, with the abs. configs. being determined by biomimetic to-
tal synthesis and modified Mosher’s method [295]. The three C17 norditerpenoid pairs
612−614 with a γ-lactone unit, together with two pairs of sesterterpenoids 615 and 616
with a butenolide unit, were obtained from a Cacospongia sp. in 2019. Among them, all
enantiomeric pairs except 614 were successfully separated. Compounds 617a/617b are a
pair of sesterterpenoid enantiomers featuring a bicyclo[4.2.0]octene core and were isolated
from Hippospongia lachne in 2017 [296]. Compounds 618−621 are four pairs of furanosestert-
erpene tetronic acids from a Psammocinia sp., and 618 and 619 were found to be geometrical
isomers of two pairs of enantiomers as revealed by chiral HPLC analysis. Similar to the
case of 618 and 619, compounds 620 and 621 were also proved to be two enantiomeric pairs,
but only 620 was finally separated into pure enantiomers [297].
5.1.2. Alkaloids
Interestingly, alkaloid enantiomers from sponges were discovered from species col-
lected in South China Sea, with most of them belonging to the pyrrole alkaloid family,
incorporating a pyrrole-2-carboxylic acid residue. Compounds 622a/623b−628a/628b
were characterized as a panel of bromopyrrole enantiomers from an Agelas sp. in 2016
by Zhu et al. [298]. Except 622a/622b and 627a/627b, the abs. configs. of the others
were assigned by one of the three following methods including TDDFT-ECD calculation,
ECD exciton chirality method and ECD comparison with known analogues [298]. Pyr-
role alkaloids 629a/629b−631a/631b are three pairs of enantiomers obtained from Agelas
aff. Nemoechinata in 2017, and 631a/631b possess an interesting cyclopentane-fused imi-
dazole ring system [299]. Compounds 632a/632b−634a/634b are also pyrrole alkaloid
enantiomer pairs obtained from Agelas nakamurai in 2017 [300]. Alkaloids 635a/635b fea-
turing an unusual spiro bisheterocyclic quinoline-imidazole backbone were reported from
Fascaplysinopsis reticulate in 2015 [301], while 636a/636b represent a pair of trinorsesquiter-
penoid amide enantiomers isolated from the Beihai sponge Spongia officinalis in 2018 [295].
5.1.3. Lipids
Compounds 637a/637b, a pair of interesting C20 bisacetylenic lipid enantiomers, were
discovered from the marine sponge Callyspongia sp. in 2013, with the abs. configs. being
determined by modified Mother’s method [302]. The lipid zwitterions 638a and 639a were
separated from Spirastrella abata in 2012 [303], and their respective enantiomers (638b and
639b) had been previously reported from the same species in 2002 [304].
5.2. Enantiomers from Phylum Arthropoda

Compounds 640a/640b−643a/643b (Figure 34, names see Table S34 in Supplementary
Materials) bearing a 2,3-dihydrobenzo[b][1,4]dioxin fragment were separated from the
insect Blaps japanensis in 2015 [305], with the abs. config. of 640a being determined by
X-ray crystallographic analysis. Compounds 644a/644b and 645 were characterized as
N-acetyldopamine dimer and trimer, respectively, from the insect Aspongopus chinensis in
2014, and 645 possesses a novel tetrahydrobenzo[a]dibenzo[b,e][1,4]dioxine moiety and
occurs as a racemate [306]. Compounds 646a/646b are a pair of dimeric N-acetyldopamine
enantiomers obtained from the insect Polyphaga plancyi in 2016 [307].
Molecules 2022, 27, 1279 49 of 73
Figure 34. Structures of metabolites from phyla Arthropoda and Chordata.
5.3. Enantiomers from Phylum Chordata

There have been only two pairs of enantiomers reported from the animals of phy-
lum Chordata (see Figure 34 and Table S34 in Supplementary Materials). Compounds
647a/647b, a highly nitrogenated enantiomer pair with a novel heterocyclic scaffold in-
corporating two extra phenol units, were isolated from a marine ascidian Eudistoma sp.
in 2016 [308]. A pair of oxygenated myristic acid enantiomers bearing a tetrahydrofuran
moiety (648a/648b) was obtained from a larval sea lamprey Petromyzon marinus in 2015,
with the abs. configs. being determined by modified Mosher’s method [309].
6. Biological Properties
As is well known, NPs, on one hand, play a decisive role in maintaining their source
organisms’ health, helping defend against internal or external adverse stresses and enticing
favorable stimuli. On the other hand, NPs in the form of herbal medicines have long
been used by humans as therapeutic agents against various diseases, thus guaranteeing
the continuation of human civilization. With the advances of science and technology,
NPs and their derivatives still shine in the research field of modern drug discovery and
development [2].
It is widely accepted that chirality, as an important feature of most NPs, is closely
related with their bioactivities. Normally, life systems tend to produce/utilize only one
molecule of an enantiomeric pair. For example, humans only take in D-glucose and L-amino
acids as nutrients. The fact that a pair of enantiomers can exert utterly different bioactivities
was recognized as far back as the 1960s, when the ‘Phocomelia infants event’ caused by the
(S)-enantiomer of the synthetic drug thalidomide taught the pharmaceutical industry an
important lesson. For many years, however, NP workers failed to recognize the widespread
occurrence of enantiomerism in nature, and failed to explore the differences in bioactivity
between pairs of enantiomers. Fortunately, as data on natural enantiomers increase in
scope, more and more biological properties of different classes of enantiomeric pairs have
also been reported, and this has provided more examples with which to investigate the
differences in bioactivity among enantiomers.
As bioassay protocols vary in different research labs and even in different batches
from the same lab, it should be clarified that we do not intend to invite direct comparisons
regarding the activity potency by tabulating the assay data from different reports. Instead,
bioactivity comparisons between different labs will be completely avoided in the current
review and the use of potency descriptors will also be kept to a minimum. Meanwhile,
we will not list the biological data of all reported enantiomers, and only selective cases
with obvious activity differences at the enantiomeric level are discussed, under the fol-
lowing subcategories: cytotoxic, antiviral, antibacterial, antifungal, anti-inflammatory,
Molecules 2022, 27, 1279 50 of 73
antioxidative, cell protective, enzyme inhibitory, β-amyloid (Aβ) aggregation inhibitory

and miscellaneous activities.
6.1. Cytotoxicity
Cytotoxic evaluations of chemical entities were likely the most important primary strat-
egy in the past in the search for potential chemotherapies for cancers, and remain among
the most popular bioassays for NPs. The cytotoxic activities of selective enantiomeric pairs
against a series of human tumor cell lines are summarized in Table 2.
Table 2. Cytotoxic activities of enantiomers. (a) part 1; (b) part 2.
Cell lines Compds. IC50 (µM) Reference Cell Lines Compds. IC50 (µM) Reference
(a)
HL-60 (+)-171a 5.62 [105] HCT-116 (−)-314a 1.38 [162]
(−)-171b 3.51 [105] (+)-314b >10 [162]
(±)-171 2.65 [105] HepG2 (−)-314a 3.30 [162]
(+)-172a 9.64 [105] (+)-314b >10 [162]
(−)-172b 8.16 [105] BGC-823 (−)-314a 6.51 [162]
(±)-172 5.58 [105] (+)-314b >10 [162]
Hep3B (−)-268a >10 [146] NIC-H1650 (−)-314a 8.19 [162]
(+)-268b 5.1 [146] (+)-314b >10 [162]
HL-60 (+)-297a 12.08 [156] A2780 (−)-314a 2.14 [162]
(−)-297b 19.24 [156] (+)-314b >10 [162]
MDA-MB-
(+)-297a >50 [156] SF-268 (+)-536a 12.5 [261]
231
(−)-297b 18.46 [156] (−)-536b >100 [261]
HCT-116 (+)-312a inactive [160] (+)-537a 30.1 [261]
(−)-312b 14.23 [160] (−)-537b >100 [261]
A549 (−)-390a 4.64 [8] HepG2 (+)-536a 15.0 [261]
(+)-390b 10.54 [8] (−)-536b >100 [261]
MCF-7 (−)-390a 5.60 [8] (+)-537a 37.3 [261]
(+)-390b 15.52 [8] (−)-537b >100 [261]
MDA-MB-
(−)-390a 3.86 [8]
231
(+)-390b 11.86 [8]
(b)
HL-60 (+)-381a 3.42 [191,192] MCF-7 (+)-381a 4.18 [191,192]
(−)-381b >20 [191,192] (−)-381b >20 [191,192]
(−)-382a 16.54 [191,192] (−)-382a 14.44 [191,192]
(+)-382b >40 [191,192] (+)-382b >40 [191,192]
(±)-382 14.44 [191,192] (±)-382 36.00 [191,192]
(−)-383a 3.15 [191,192] (−)-383a 5.85 [191,192]
(+)-383b 2.35 [191,192] (+)-383b 10.76 [191,192]
(±)-383 18.08 [191,192] (±)-383 17.05 [191,192]
(−)-384a 3.45 [191,192] (−)-384a 3.17 [191,192]
(+)-384b 2.36 [191,192] (+)-384b 3.08 [191,192]
(±)-384 2.93 [191,192] (±)-384 11.92 [191,192]
(−)-385a 2.63 [191,192] (−)-385a 14.60 [191,192]
(+)-385b 5.41 [191,192] (+)-385b 15.02 [191,192]
(±)-385 13.90 [191,192] (±)-385 15.47 [191,192]
SMMC-7721 (+)-381a 4.19 [191,192] SW480 (+)-381a 7.22 [191,192]
(−)-381b >20 [191,192] (−)-381b >20 [191,192]
(−)-382a 16.20 [191,192] (−)-382a 17.43 [191,192]
(+)-382b >40 [191,192] (+)-382b >40 [191,192]
(±)-382 22.83 [191,192] (±)-382 27.73 [191,192]
Molecules 2022, 27, 1279 51 of 73
Table 2. Cont.
Cell lines Compds. IC50 (µM) Reference Cell Lines Compds. IC50 (µM) Reference
(−)-383a 5.55 [191,192] (−)-383a 3.04 [191,192]
(+)-383b 12.30 [191,192] (+)-383b 5.53 [191,192]
(±)-383 20.71 [191,192] (±)-383 13.60 [191,192]
(−)-384a 3.80 [191,192] (−)-384a 1.99 [191,192]
(+)-384b 10.83 [191,192] (+)-384b 1.52 [191,192]
(±)-384 15.36 [191,192] (±)-384 7.62 [191,192]
(−)-385a 12.53 [191,192] (−)-385a 3.39 [191,192]
(+)-385b 13.21 [191,192] (+)-385b 4.31 [191,192]
(±)-385 14.82 [191,192] (±)-385 8.84 [191,192]
A549 (+)-381a 4.51 [191,192] A549 (±)-383 24.02 [191,192]
(−)-381b >20 [191,192] (−)-384a 2.96 [191,192]
(−)-382a 17.27 [191,192] (+)-384b 18.78 [191,192]
(+)-382b >40 [191,192] (±)-384 15.44 [191,192]
(±)-382 17.30 [191,192] (−)-385a 22.36 [191,192]
(−)-383a 4.40 [191,192] (+)-385b 9.53 [191,192]
(+)-383b 16.33 [191,192] (±)-385 10.24 [191,192]
The antiproliferative activities of the alkaloid racemates (±)-171 and (±)-172, along
with their respective enantiomers, against human HL-60 tumor cells were assessed in
Hua’s lab. While the levoisomers (171b and 172b) showed slightly better inhibitory activity
than their respective dextroisomers (171a and 172a), the racemic mixtures exhibited more
potency than both enantiomers, indicating a likely synergistic effect [105]. The flavane
enantiomers 268a/268b were reported to show cytotoxicity against human Hep3B cells,
and the dextroisomer 268b was obviously more active than the levoisomer 268a [146]. The
xanthones 297a/297b were able to inhibit the proliferation of human HL-60 and MDA-MB-
231 cancer cells, and the (−)-enantiomer 297b showed much stronger inhibitory activity
than its (+)-enantiomer 297a against MDA-MB-231 cells [156]. The levorotatory enantiomer
312b was found to inhibit the proliferation of colorectal HCT-116 cell line with an IC50 of
14.23 µM, but its antipodal enantiomer 312a was considered to be inactive [160].
The bisabolene-derived sesquiterpenoids 314a/314b were tested in vitro for their
cytotoxicities against five human tumor cell lines (HCT-116, HepG2, BGC-823, NIC-H1650
and A2780), and the (−)-enantiomer 314a exerted significant inhibition against all tested
cell lines with IC50 values in the range of 1.38−8.19 µM, while the (+)-enantiomer 314b
was considered inactive (IC50 > 10 µM) [162]. In contrast, the (+)-enantiomer 381a, an
acylphloroglucinol derivative, showed cytotoxic activities against the tested tumor cell
lines (HL-60, SMMC-7721, A549, MCF-7 and SW480) with IC50 values in the range of
3.42−7.22 µM, while its (−)-enantiomer 381b was taken inactive (IC50 > 20 µM) [191].
The same research group that reported 381a/381b also screened the cytotoxicities of both
racemates and pure enantiomers of acylphloroglucinols 382a/382b−385a/385b against
the aforementioned tumor cell lines [192], and as a result, the levorotary series exhibited
higher potency than both the dextrorotary series and the racemates for most cells [192]. Of
particularly note, the racemate (±)-383 showed apparently decreased activity compared
with its both enantiomers against all cell lines especially toward HL-60 cells (5.7- and
7.7-fold decrements), indicative of an antagonistic action between the two enantiomers, and
similar effects were also observed for 384a/384b and 385a/385b on selective cell lines [192].
The methyl 2-naphthoate enantiomers 390a/390b were found to show inhibition
against the proliferation of three types of cancer cells (A549, MCF-7 and MDA-MB-231),
with the levoisomer 390a being ca. three times more active than the dextroisomer 390b [8].
In addition, only the dextrorotary enantiomers of the spirocyclic diketopiperazines 536 and
537 showed growth inhibition against SF-268 and HepG2 tumor cell lines [261], but their
corresponding levoisomers were inactive (>100 µM).
Molecules 2022, 27, 1279 52 of 73
6.2. Antiviral
The antiviral activities of the enantiomers described in this review are shown in Table 3.
The coumarins 254a/254b did not show significant inhibition differences against either the
herpes simplex virus 1 (HSV-1) or the host cell between enantiomers, but their racemate (±)-
254 exhibited obviously increased activity which was suggestive of a strong synergistic ac-
tion [66]. Similar synergistic effects of enantiomers were also observed for another two pairs
of coumarins, 104a/104b and 105a/105b, with the racemates (±)-104 and (±)-105 display-
ing 3.2- to 6.1-fold antiviral activity against the influenza virus A (H3N2) compared with the
pure enantiomers [67]. Four pairs of phloroglucinol enantiomers 368a/368b−371a/371b
were subjected to antiviral assay against Kaposi’s sarcoma-associated herpes virus (KSHV);
they all showed certain degrees of bioactivity differences at the enantiomeric level [184].
The fungus-derived alkaloid enantiomers 558a/558b and the racemate (±)-558 all exhibited
antiviral activity against EV71 virus, with the dextrorotary enantiomer being nearly five
times as active as its antipodal isomer [272].
Table 3. Antiviral activities of enantiomers a .
Virus/Host Compds. EC50 (µM) IC50 (µM) SI Reference

(+)-254a 6.41 19.25 3.0 [7]
(−)-254b 3.70 16.02 4.3 [7]
HSV-1/Vero
(±)-254 1.23 2.14 1.7 [7]
Acyclovir b >100 0.41 >243.9 [7]
(+)-104a 9.86 19.25 1.9 [67]
(−)-104b 11.11 77.61 6.9 [67]
(±)-104 3.13 6.42 2.1 [67]
Virus A (−)-105a 8.62 77.61 7.9 [67]
(H3N3)/MDCK (+)-105b 17.46 57.74 3.3 [67]
(±)-105 2.87 25.87 9.0 [67]
Oseltamivir b 3.38 3073 910.5 [67]
Ribavirin b 6.19 4771 770.7 [67]
(+)-368a 8.75 140.6 16.06 [184]
(−)-368b 29.13 173.7 5.96 [184]
(+)-369a 202.9 >500 >2.46 [184]
(−)-369b 140.9 >500 >2.55 [184]
KSHV/Vero (+)-370a 17.67 211.1 12.51 [184]
(−)-370b 39.80 >300 >7.50 [184]
(+)-371a 40.00 >300 >7.50 [184]
(−)-371b 158.50 >300 >1.89 [184]
Acyclovir b 0.41 99.18 241.9 [184]
(−)-558a 69.1 143.7 2.1 [272]
(+)-558b 14.2 130.2 9.2 [272]
EV71/Vero
(±)-558 14.2 126.6 7.9 [272]
Ribavirin b >256.1 4098 >16 [272]
a EC50 represents concentration required to inhibit virus growth by 50%; IC50 represents concentration required to
inhibit host cell growth by 50%; SI (Selectivity index) = IC50 /EC50 . b Positive controls.
6.3. Antibacterial
It appears that most of the antibacterial enantiomeric pairs collected in this review
showed remarkably differentiable activities between enantiomers. Nonetheless, a few
exceptions were still found and are listed in Table 4. The furoquinoline alkaloid enantiomers
147a/147b were reported to have antibacterial activity against Enterococcus faecalis, and
the (–)-enantiomer showed about two-fold activity as the (+)-enantiomer [97]. The p-
hydroxycinnamoylated dihydrochalcone enantiomers 285a/285b−288a/288b exhibited
in vitro antibacterial activity against Staphylococcus aureus with IC50 values ranging from
0.61 to 6.0 µM [153], and it appeared that all the dextrorotary enantiomers were more
Molecules 2022, 27, 1279 53 of 73
effective than their respective levorotary isomers, with 288a/288b showing the greatest
activity difference, i.e., 3.7 fold [153].
Table 4. Antibacterial activities of enantiomers.
Bacterial Strains Compds. Activities Reference

Enterococcus faecalis (+)-147a MIC = 21.97 µg/mL [97]
(−)-147b MIC = 12.54 µg/mL [97]
Penicilin a MIC < 2.96 µg/mL [97]
Staphylococcus aureus (+)-285a IC50 = 1.27 µM [153]
(−)-285b IC50 = 1.79 µM [153]
(+)-286a IC50 = 2.27 µM [153]
(−)-286b IC50 = 4.3 µM [153]
(+)-287a IC50 = 3.6 µM [153]
(−)-287b IC50 = 6.0 µM [153]
(+)-288a IC50 = 0.61 µM [153]
(−)-288b IC50 = 2.27 µM [153]
Chloramphenicol a IC50 = 0.43 µM [153]
a Positive controls.
6.4. Antifungal
Few reports have been published on the antifungal activities of the enantiomers
mentioned in this review, although a handful of examples have shown about two-fold
bioactivity differences between enantiomers (Table 5). The δ-lactone enantiomer (−)-464a
was reported to display inhibitory activity against Candida albicans with an MIC of 26.4 µM,
while its antipodal enantiomer (+)-464b was considered inactive [219]. In addition, both
levorotary enantiomers of compounds (±)-483 and (±)-484 exhibited better antifungal
activity again C. albicans than their respective dextrorotary isomers [229], and similar
effect against Fusarium solani was also recorded for the indole-piperidine enantiomer pair
(±)-524 [256].
Table 5. Antifungal activities of enantiomers.
Fungal Strains Compds. Activities Reference

Candida albicans (−)-464a MIC = 26.2 µM [219]
(+)-464b inactive [219]
Candida albicans (+)-483a MIC80 = 19.5 µg/mL [229]
(−)-483b MIC80 = 48.8 µg/mL [229]
(+)-484a MIC80 = 24.0 µg/mL [229]
(−)-484b MIC80 > 50.0 µg/mL [229]
Fusarium solani (+)-524a MIC > 64 µg/mL [256]
(−)-524b MIC = 32 µg/mL [256]
6.5. Anti-Inflammation
The anti-inflammatory activities of NPs have often been evaluated by testing their
inhibitory capability against NO release in LPS-induced BV-2 microglial cells or RAW
264.7 macrophages (Table 6). The benzofuran-type lignan enantiomers 43a/43b and
44a/44b were tested for their NO production inhibitory effect in LPS-induced BV-2 mi-
croglial cells, with (−)-43b and (+)-44a exhibiting pronounced activity with IC50 values of
8.9 and 5.9 µM, being nearly twice as active as their respective antipodal enantiomers [39].
The levorotary spirodienone lignan enantiomers (−)-82b and (−)-83b showed significant
inhibition against NO production in LPS-induced RAW 264.7 macrophages, with both
being >3 fold as active as their respective dextrorotary enantiomers [54]. In the same
bioassay model, the indolizidine dextroisomer 221a displayed much stronger inhibitory
activity (6.3 fold) than the levoisomer 221b [124,128,164]. In contrast, the levorotary enan-
tiomer 407b was much more active (ca. 5 fold) than its antipodal enantiomer 407a in the
LPS-induced NO release assay in BV-2 cells [130,132,226,265].
Molecules 2022, 27, 1279 54 of 73
Table 6. Anti-inflammatory activities of enantiomers.
Assay Model Compds. IC50 (µM) Reference

BV-2/NO (+)-43a 26.4 [39]
(−)-43b 8.9 [39]
(+)-44a 5.9 [39]
(−)-44b 14.7 [39]
Quercetin a 17.0 [39]
RAW 264.7/NO (+)-82a 17.9 [54]
(−)-82b 5.6 [54]
(+)-83a 15.1 [54]
(−)-83b 4.3 [54]
RAW 264.7/NO (+)-221a 3.6 [124]
(−)-221b 22.8 [124]
(±)-221 14.7 [124]
Indomethacin a 42.2 [124]
BV-2/NO (+)-407a 6.9 [130]
(−)-407b 1.4 [130]
(±)-407 1.0 [130]
Minocyclinebe a 27.2 [130]
a positive controls.
6.6. Antioxidation
The DPPH and ABTS radical scavenging assay models have been widely used to
evaluate the antioxidative capacity of NPs, although not many of the listed enantiomers
in this review have been tested with these bioassays. Owing to their radical mechanism,
most tested enantiomers displayed equal potency in both assays as expected, whereas the
tryptophan-alanine dipeptide enantiomers 527a/527b–529a/529b showed some activity
differences at the enantiomeric level, particularly for dextroisomers 527a and 528a, that
showed obviously enhanced radical scavenging activity (4.1 and 2.5 fold, respectively)
compared with their levoisomers in the DPPH assay model (Table 7) [257].
Table 7. Antioxidative activities of enantiomers.
Assay Model Compds. IC50 (µM) Reference

DPPH (+)-527a 5.8 [257]
(−)-527b 23.5 [257]
(+)-528a 9.8 [257]
(−)-528b 24.9 [257]
(+)-529a 3.7 [257]
(−)-529b 6.1 [257]
Ascorbic acid a 23.0 [257]
a Positive control.
6.7. Cell Protection

Cell protection assays are usually performed in neuronal cells to explore new chemi-
cals that could be developed for the treatment of neurodegenerative disorders, but which
could likely also be used in the search for molecules with which to treat other diseases
(Table 8). Generally speaking, a >10% cell viability difference can be considered significant.
The protective activity of neolignan enantiomers 24a/24b against H2 O2 -induced cell in-
jury in human neuroblastoma SHSY5Y cells was tested and the (+)-enantiomer showed
obviously better activity than the (−)-enantiomer [20]. In a same assay model by Zhou
et al., the analogous enantiomeric pair 72a/72b also exhibited a similar trend of bioactivity
difference, with the dextroisomer displaying better protective effect than the reference drug
and the levoisomer being found to be inactive [46]. Further investigations revealed that
(+)-72a could significantly decrease the percentages of both early and late apoptotic cells.
Molecules 2022, 27, 1279 55 of 73
The phenylpropanoid dextrorotary enantiomer 119a presented much better neuroprotective

activity than its levorotary enantiomer in the H2 O2 -treated SH-SY5Y cell injury assay, with
nearly 20% cell viability increment [75]. Further studies demonstrated that (+)-119a could
selectively inhibit the apoptosis induction and reactive oxygen species (ROS) accumulation
by enhancing the activity of catalase (CAT). Compared with their respective antipodal
enantiomers, indole alkaloids (−)-129b and (+)-130a also increased the cell viability by
about 20% in an OKA-induced PC12 cell damage assay [83]. The isoquinoline alkaloids
(−)-165a, (−)-166a and (+)-173b exhibited slightly better protective effects (51%−55% cell
viability) than the positive control on hypoxic H9C2 cells, while (+)-166b were less ac-
tive (45% cell viability) and (+)-165b and (−)-173a were considered inactive [103]. Two
pairs of acetophenone enantiomers 423a/423b and 426a/426b exerted excellent protection
on human vein endothelial cells (HUVEC) against extreme glucose-induced oxidative
stress at 1 µM [200], with both dextrorotary enantiomers being much more active than
their levorotary counterparts and showing complete cell protection. The (+)-enantiomer
of diarylheptanoids (±)-433 significantly increased the cell viability of cortical neurons
compared with the control group (MPP+ treatment alone), while its (−)-enantiomer was
inactive [206].
Table 8. Cell protective activities of enantiomers.
Cell/Inducing
Compds. Cell Viability Reference
Agents
SH-SY5Y/H2 O2 (−)-24a 54.7% at 50 µM [21]
(+)-24b 70.5% at 50 µM [21]
Trolox a ~69.0% at 50 µM [21]
SH-SY5Y/H2 O2 (+)-72a ~69% at 25 µM [46]
(−)-72b inactive at 25 µM [46]
Trolox a ~62% at 25 µM [46]
SH-SY5Y/H2 O2 (+)-119a 76.29% at 50 µM [75]
(−)-119b 56.48% at 50 µM [75]
PC12/OKA (+)-129a 65.4% at 10 µM [83]
(−)-129b 83.4% at 10 µM [83]
(+)-130a 91.2% at 10 µM [83]
(−)-130b 69.5% at 10 µM [83]
H9C2/ischemia-
(−)-165a ~51% at 0.1 µM [103]
hypoxia
(+)-165b inactive [103]
(−)-166a ~55% at 0.1 µM [103]
(+)-166b ~45% at 0.1 µM [103]
(−)-173a inactive [103]
(+)-173b ~52% at 0.1 µM [103]
Salvianolic acid B a ~46% at 0.1 µM [103]
HUVEC/glucose (+)-423a 102.6% at 1 µM [200]
(−)-423b 79.9% at 1 µM [200]
(+)-426a 102.6% at 1 µM [200]
(−)-426b 79.9% at 1 µM [200]
Cortical
(+)-433a ~90% at 16 µM [206]
neurons/MPP+
(−)-433b inactive [206]
6.8. Enzyme Inhibition

A number of diseases are caused by the dysfunction of enzymes, so the discovery of
enzyme inhibitors is one the most important tasks of the study of NPs. The enantiomers in
this review have been shown to exert inhibitory activities against many enzymes includ-
ing phosphodiesterase-9A (PDE9A), acetylcholinesterase (AChE), butyrylcholinesterase
Molecules 2022, 27, 1279 56 of 73
(BChE), α-glucosidase, tyrosinase, protein tyrosine phosphatase 1B (PTP1B), serine protease

HLE, isocitrate lyase deubiquitinating enzyme USP7, isocitrate lyase, Na+ /K+ -ATPase and
cyclooxygenase 2 (COX-2). Selective enantiomeric pairs with activity differences between
enantiomers are listed in Table 9.
Table 9. Enzyme inhibitory activities of enantiomers.
Enzymes Compds. IC50 (µM) Reference

AchE (+)-157a >100 [100]
(−)-157b 28.3 [100]
Galanthamine a 1.9 [100]
AchE (+)-523a 2.3 [256]
(−)-523b 13.8 [256]
(±)-523 9.5 [256]
Tacrine a 0.14 [256]
α-Glucosidase (+)-495a 63.7 [237]
(−)-495b 27.9 [237]
(±)-495 36.1 [237]
Acarbose a 477.0 [237]
PTP1B (−)-339a Inactive [176]
(+)-339b 43.6 [176]
(+)-340a 38.1 [176]
(−)-340b Inactive [176]
(−)-341a 61.0 [176]
(+)-341b Inactive [176]
(−)-342a 58.2 [176]
(+)-342b Inactive [176]
Oleanolic acid a 2.5 [176]
COX-2 (+)-641a 2.52 [305]
(−)-641b 6.04 [305]
(+)-644a 17.8 [305]
(−)-644b 9.7 [305]
Celecoxib a 0.016 [305]
Isoquinoline enantiomers 157a/157b were evaluated for their anti-AChE activity, with
the (−)-enantiomer being >3.5 fold more active than the (+)-enantiomer [100]. In the same
assay from another lab, the dextrorotary indole-diketopiperazine enantiomer 523a was
reported to be six times as active as its antipodal enantiomer, and their racemate showed
a compromised activity [256]. The fungus-originated xanthones 495a/495b and their
racemate (±)-495 were identified as potent α-glucosidase inhibitors with the levoisomer
showing stronger activity [237]. The meroterpenoid enantiomers (+)-339b, (+)-340a, (−)-
341a and (−)-342a displayed inhibitory effects against PTP1B with IC50 values ranging
from 38.1 to 61.0 µM [176], while their respective antipodal enantiomers were considered
inactive [178]. Two pairs of N-acetyldopamine enantiomers (641 and 644) derived from
insect exhibited inhibitory activity against COX-2 with IC50 values in the range of 2.52–17.8
µM [305], and (+)-641a and (−)-644b were around two times as active as their respective
antipodal enantiomers.
6.9. Aβ Aggregation Inhibition

Eleven pairs of plant-originated enantiomers including lignans (1a/1b, 2a/2b, 6a/6b,
7a/7b, 73a/73b and 76a/76b) and alkaloids (132a/132b, 133a/1333b, 241a/241b and
242a/242b) were evaluated for their inhibitory effects on β-amyloid (Aβ) aggregation,
which had been considered as a central event in the pathogenesis of Alzheimer’s disease
according to the “amyloid hypothesis”. Still, most enantiomeric pairs did not show much
difference in Aβ aggregation inhibitory activity. Nevertheless, four pairs (6a/6b, 73a/73b,
Molecules 2022, 27, 1279 57 of 73
133a/1333b and 242a/242b) did display obvious activity variations at the enantiomeric
level (Table 10). Notably, the 8,40 -oxyneolignan pair 6a/6b presented a significant gap in
their inhibition against Aβ aggregation, with the (−)-enantiomer showing a 141% activity
increment compared with the (+)-enantiomer [17].
Table 10. Aβ aggregation inhibition of enantiomers.
Compds. Inhibition (%) Reference

(+)-6a 31.2 [19]
(−)-6b 75.3 [19]
Curcumin a 62.1 [19]
(+)-73a 62.1 [51]
(−)-73b 81.6 [51]
(+)-132a 85.8 [85]
(−)-132b 73.6 [85]
(+)-242a 33.9 [131]
(−)-242b 50.6 [131]
6.10. Miscellaneous Activities

In addition to the above-described biological properties, the enantiomers covered by
the current review also showed positive responses in a variety of other bioassays. Those
with obvious activity differences between enantiomers are listed in Table 11. The levorotary
indole-diketopiperazine enantiomer (−)-145a exerted impact on MT1 and MT2 receptors
with agonistic rates of 11.26% and 52.44% (at 0.25 mM), respectively, while its enantiomer
(+)-145b was evaluated as inactive [93]. The (−)-enantiomer of diterpenoid 330 exhibited
NF-κB inhibition with an IC50 value of 7.27 µM, while its (+)-enantiomer was considered
inactive [169]. The fungus-derived indole-diketopiperazine enantiomer (+)-530b displayed
antifouling activity against the barnacle Balanus reticulatus with an adhesive rate of 48.4%
at 10 µg/cm2 , while the (−)-enantiomer 530a was inactive [259]. The nitrogen-rich alkaloid
enantiomer (−)-647b was identified as a moderate protein-protein interaction inhibitor of
HIF-1α and p300, while its antipodal enantiomer (+)-647a was inactive [308]. Lastly, the
fish-produced dextrorotary lipid enantiomer (+)-648a elicited a strong olfactory response on
the sea lamprey, and its levorotary enantiomer (−)-648b only showed weak activity [309].
Table 11. Miscellaneous activities of enantiomers.
Models Compds. Activities Reference

MT1 receptor agonistic activity (−)-145a agonistic rate = 11.26% [93]
(+)-145b inactive [93]
MT2 receptor agonistic activity (−)-145a agonistic rate = 52.44% [93]
(+)-145b inactive [93]
NF-κB inhibition (+)-330a inactive [169]
(−)-330b IC50 = 7.27 µM [169]
Antifouling activity (−)-530a inactive [259]
(+)-530b adhesive rate = 48.4% [259]
Protein-protein interaction
(+)-647a inactive [308]
inhibition
(−)-647b modestly [308]
Olfactory responses (+)-648a strong [309]
(−)-648b weak [309]
Molecules 2022, 27, 1279 58 of 73
7. Conclusions
As can be seen from Figure 35, the number of identified natural enantiomers steadily
increased during the period covered by this study, albeit with slight drops in 2013 and 2018.
Notably, more than 100 enantiomers have been reported in the last three years (2017–2019),
indicating rapid development in this field. It is also worth noting that plant-derived
enantiomers made up 72% of all cases (Figure 36) in the study period, which suggests the
continuing vitality of phytochemical studies, despite severe funding cutbacks for traditional
NP research in recent years [3]. Another set of statistics (Figure 37) revealed that alkaloid
enantiomers represent the biggest group of molecules from plants, followed by lignans
and flavonoids.
Figure 35. A comparison of enantiomeric pairs from plants and other sources.
Figure 36. Distributions of enantiomers in kingdoms Plantae, Fungi, Animalia and Prokaryota.
7.1. Natural Distribution of Enantiomers

As demonstrated by the examples in this review, natural enantiomers have been
widely reported from species of all kingdoms except Protoctista, which could be attributed
to the fact that few NP researchers have been focusing on Protoctista organisms since
they are not well-known sources of interesting molecules. Therefore, the discovery of
enantiomers from Protoctista species in the near future is to be expected if NP workers
continue to focus on them. From another perspective, the enantiomers collected in the
period covered in this review have a broader distribution at the originated species level,
from microbial fungi (e.g., mold) to macrofungi (e.g., mushrooms), from lower plants
(e.g., moss) to higher plants (e.g., herbs), and from lower animals (e.g., sponges) to higher
Molecules 2022, 27, 1279 59 of 73
animals (e.g., fishes). Another noteworthy point is the distribution of enantiomers in

different structural families, which can be clearly revealed by the examples in the current
and previous reviews [3] that were discovered in all major structural classes such as
terpenoids, alkaloids, flavonoids and polyketides (mainly from a biogenetic view). At the
lower level of classification, it seems that there have been no enantiomeric cases reported
for triterpenoids and steroids. The above-mentioned two points clearly demonstrate the
universal occurrence of enantiomerism in nature.
Figure 37. Statistics of different types of enantiomeric pairs from plants.
7.2. Natural Formation of Enantiomers

It is interesting to note that unlike the previous report [3], in which many enantiomeric
examples were obtained from different species, the majority of the cases collected in
the current study were isolated from the same species as scalemic or racemic mixtures.
Although Williams and colleagues predicted in 2012 [3] that the biogenetic studies of
natural enantiomers would be “a fertile area for future inquiry and discovery”, there has
been no significant progress in this research field since then. Nonetheless, some common
reasons or rules regarding enantiomeric production can still be rationalized on the basis
of currently available knowledge: (1) For cases in which the two antipodal enantiomers
are produced by two different species (from the same or different genus or even different
families), such as (+) and (–)-limonenes [3], two distinct enzymes and mechanisms are
involved in their biosynthesis; (2) When an enantiomeric pair (racemic or scalemic mixture)
is discovered from the same species, the lack (partially or completely) of stereo-specificity
of the catalytic enzyme could be responsible for the enantiodivergent formation; (3) The
absence of enzyme substrate or a completely chemical process would also lead to the
production of two enantiomers, which is especially true for many NPs with only one chiral
center. The following two explanations, though not as reasonable as the above-mentioned
three, could also not be excluded. (4) In some biochemical processes which involve radicals,
though normally stereo-controlled by enzymes, the generation of enantiomers is possible
due to the extremely high reactivity of radicals. (5) The extraction and isolation procedures
of NPs could also lead to the formation of new chiral centers, and thus, the production of
enantiomers [310,311]. At this point, these enantiomeric molecules should be classified as
NP derivatives or artifacts.
7.3. Structures Tend to Exist as Enantiomers in Nature

With the discovery of more and more enantiomeric NPs containing diverse structures,
it can be concluded that enantiomerism may occur for each structural type, although no
enantiomers have been reported for triterpenoids and steroids. Compared with enan-
tiomers from plants, those from microorganisms are able to incorporate more complicated
structures, e.g., with high molecular weights. It is possible that the enzyme systems in
Molecules 2022, 27, 1279 60 of 73
microorganisms are not fully developed and stereoselectivity is lacking. With this investi-
gation into the structures of enantiomers reported from 2012–2019 in hand, we can easily
conclude which structures or which groups in the structures tend to exist in nature as
enantiomers. (1) NPs contain C6-C3 units in their structures, such as lignans, flavones,
coumarins, simple phenylpropanoids, and hybrids between C6-C3 units and other struc-
tures. The enantiomerism for those structures presumably derives from the nonstereoselec-
tive oxidation of the C3 unit or nonstereoselective coupling of the C6-C3 units, through
enzymatic or nonenzymatic reactions. (2) NPs formed by combination of 2~4 isopentenyl
units, such as monoterpenoids, sesquiterpenoids, diterpenoids, and meroterpenoids, or
having isopentenyl units as side chains, can exist in the form of enantiomers, and need to
be further researched. (3) Alkaloid NPs have a variety of structural types, each of which
may exist in the form of enantiomers. (4) When NPs with long chain, e.g., fatty acids
and diarylheptanoids, have chiral centers, testing whether they are enantiomers or not is
necessary. (5) NPs with axial chirality tend to exist as enantiomers in nature.
7.4. Identification of the Presence of Enantiomers

The criteria of enantiomeric presence vary, and a confirmative conclusion should be
made based on comprehensive considerations. Ideally, the enantiomeric purity of every
NP should be checked, but apparently this is neither economical nor technically feasible.
Nevertheless, some general guidelines can still be summarized. Firstly, if a NP belongs to a
structural group with strong enantiomeric tendency as listed in this review, such as 8,40 -
oxyneolignans, caution is required. Secondly, for a previously undescribed NP, when its
[α]D value is very small (e.g., <5) or close to zero, the presence of an enantiomeric mixture
should be considered. However, this method is not always fully indicative, as some chiral
compounds naturally have low [α]D . For a known NP, regardless of whether the magnitude
of [α]D value is big or small, if it obviously deviates from the reported datum, the occurrence
of enantiomerism is possible, and the purity of the tested NP should first be guaranteed.
Thirdly, ECD measurement can also be used to check the enantiomeric purity of a NP (in
case it shows a response in the experiment). A good-quality ECD curve usually looks
smooth with clear Cotton effect(s) in the normal wavelength range (mostly 190–400 nm); if
not, there is a high probability of enantiomeric presence. The aforementioned empirical
knowledge is only based on general cases, and in fact, determination of the presence
of enantiomers can be complicated. Notably, when the natural e.e. value of a pair of
enantiomers is very high, as in the case of neosecurinane alkaloids [5], the researchers’ level
of experience and sensitivity to chirality will make the difference.
7.5. Separation and Differentiation of Enantiomers

The separation (use of different chiral stationary materials) and differentiation (abs.
config. assignment of an enantiomeric pair) of natural enantiomers were well documented
in the review by Cass and Batista Jr. [10] and will not be included here. However, we do
wish to emphasize that no omnipotent separation material and single technique can be
applied for the purification and abs. config. determination, respectively, for all types of
enantiomers, and any doubt regarding enantiomeric purity deserves further investigation.
7.6. Stereochemistry–Bioactivity Relationship of Enantiomers

As for the stereochemistry–bioactivity relationship (SBR) of natural enantiomers, anal-
yses of the biological data gathered in this review do not provide many meaningful clues,
and the relevance between the bioactivity and the chirality (dextroisomer or levoisomer)
of a pair of enantiomers seems random and irregular in both enzymatic and cellular level
bioassays. Although factors regarding the ‘chirality’ of life systems are well-known (e.g., D-
glucose and L-amino acids as primary metabolites), there is still a long way to go before we
are able to reveal the secrets of the exact SBR of enantiomers. Nevertheless, some general
conclusions can still be reached according to the presently accessible information, similar to
what Prof. Mori described for insect pheromones [4]. For a specific bioassay model: (1) One
Molecules 2022, 27, 1279 61 of 73
enantiomer is active, while the opposite enantiomer is less or not active, and the mixture of
them does not result in any extra effect; (2) Both enantiomers are equally active, and their
mixture does not result in any extra effect; (3) Both enantiomers are inactive or active, but
their mixture is active or more active, suggestive of a synergistic action; (4) One enantiomer
is active, whereas the antipodal enantiomer exhibits antagonistic activity, and thus, their
mixture will exert an offset effect. Please note that the aforementioned general rules vary
for different bioassays and are thus to be taken on a case-by-case basis, because all NPs
are produced by the source organisms for their own use, and not for use by humans; we
simply take advantage of their biological properties.
All in all, notwithstanding the rapidly growing number of reports and improving
awareness of natural enantiomers in recent years, there are still a number of questions
which remain to be answered. Our understanding of this fascinating natural phenomenon
is only in its infancy
Here, we would like to say to the NP community that enantiomerism in nature is
ubiquitous and vital. We hope that this review will prompt future researchers to routinely
ask “Is my natural product enantiomerically pure, and if so, which enantiomer have I
obtained?”, and in so doing, to perhaps even alter the methods applied by scientists in
the future.
Supplementary Materials: The following supporting information can be downloaded at: Tables S1−S34
contain names, source species and references of all collected enantiomers. Refs [312–316] are cited in the
Supplementary Materials.
Author Contributions: Conceptualization, H.Z. and R.J.C.; formal analysis, J.-H.Y.; data curation,
J.-H.Y. and H.Z.; writing—original draft preparation, J.-H.Y. and Z.-P.Y.; writing—review and editing,
H.Z. and R.J.C.; supervision, H.Z.; funding acquisition, H.Z. All authors have read and agreed to the
published version of the manuscript.
Funding: This research was funded by National Natural Science Foundation of China (82073729 and
21807040), Natural Science Foundation of Shandong Province (JQ201721), Innovation Team Project of
Jinan Science & Technology Bureau (No. 2018GXRC003).
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
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Natural Enantiomers - Molecules-2022

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molecules

Keywords: enantiomers; natural products; biogenesis; biological properties

Molecules 2022, 27, 1279. https://doi.org/10.3390/molecules27041279 https://www.mdpi.com/journal/molecules

2. Enantiomers from Kingdom Plantae

2.1.1. Acyclic Lignans

Figure 1. Structures of 8,40 -oxyneolignans.

J7,8 Values Specific Optical Rotations ECD Data

J7,8 Values Specific Optical Rotations ECD Data

Figure 2. Structures of other acyclic lignans.

Scheme 1. Plausible biosynthetic pathway for 39.

2.1.2. Cyclic Lignans

Figure 3. Structures of Furan-incorporating lignans.

Figure 4. Structures of other cyclic lignans.

The unusual dinorneolignans 64a/64b incorporating a 1,4-dioxane motif and the

Figure 5. Structures of sesquineolignans.

Scheme 2. Plausible biosynthetic pathways for 81a/81b.

Figure 6. Structures of coumarins.

2.3. Simple Phenylpropanoids

Figure 7. Structures of simple phenylpropanoids.

2.4.1. Indole Alkaloids

Figure 8. Structures of indole alkaloids.

2.4.2. Quinoline and Isoquinoline Alkaloids

Figure 9. Structures of quinoline and isoquinoline alkaloids.

Figure 10. Structures of β-carboline and carbazole alkaloids.

2.4.4. Piperidine Alkaloids

Figure 11. Structures of piperidine alkaloids.

2.4.5. Thiohydantoin Alkaloids

Figure 12. Structures of thiohydantoin alkaloids.

2.4.6. Indolizidine and Quinolizidine Alkaloids

Figure 13. Structures of indolizidine and quinolizidine alkaloids.

2.4.7. Other Alkaloids

Figure 14. Structures of other alkaloids.

Compounds 227a/227b−230a/230b are a panel of quinazoline enantiomer pairs ob-

while 243a/243b represent a pair of 9,10-dihydrophenanthrene alkaloid enantiomers

2.5.1. Flavones and Isoflavones

Figure 15. Structures of flavones and isoflavones.

Compounds 272a/272b−278a/278b, seven pairs of enantiomeric diprenylated isoflav-

Figure 16. Structures of chalcones.

Compounds 281a/281b are a pair of dihydrochalcone enantiomers from Pteris en-

Figure 17. Structures of xanthones.

Hua and coworkers reported a pair of diprenylated xanthone enantiomers 297a/297b

Scheme 4. Plausible biosynthetic pathways for 300a/300b−302a/302b.

Figure 18. Structures of sesquiterpenoids.

Figure 19. Structures of diterpenoids.

Yue and coworkers phytochemically investigated Croton mangelong to afford two

Figure 20. Structures of meroterpenoids.

Compounds 339a/339b−346a/346b are eight pairs of enantiomeric meromonoter-

Figure 21. Structures of phloroglucinols.

Scheme 5. Plausible biosynthetic pathways for 378a/378b and 379a/379b.

Scheme 6. Plausible biosynthetic pathways for 381a/381b.

Molecules 2022, 27, 1279 31 of 73

2.8. Naphthalenes and Phenanthrenes

Figure 22. Structures of naphthalene and phenanthrenes.

iment [195]. Compounds 397a/397b are simple tetrahydronaphthoquinone enantiomers

Figure 23. Structures of chromanes (* abs. configs. undetermined).

Figure 24. Structures of acetophenones.

Figure 25. Structures of diarylheptanoids.

The enantiomeric pairs of diarylheptanoid-monnoterpene adduct (433 & 434) and

Figure 26. Structures of triarylmethanes.