Stereoselective

Organic Reactions
3 named organic reactions in organic synthesis and their recent
applications in the multi-step syntheses of molecules.

Abdulqadir Aziz Singapore Wala

Introduction..........................................................................................................................................3

The Oxa-Michael Reaction....................................................................................................................4

Olefin Metathesis.................................................................................................................................8

The Aldol Reaction.............................................................................................................................12

Conclusion..........................................................................................................................................15

Appendix A.........................................................................................................................................16

References.........................................................................................................................................18

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Introduction

The increasing development of new medicines and the synthesis of existing natural products of
important medicinal value have resulted in a need and a constant effort by chemists to develop
stereoselective synthetic methods. This is due to the nature of medicines and biological molecules in
general, whose usefulness is dependent on stereoselection, due to the specific nature of the
enzymatic processing of such molecules in the body.

While the required product can be extracted from a mixture, this would be tedious, time consuming,
and an inefficient use of chemical resources. Stereoselective syntheses would thus reduce costs, and
save resources, whilst simplifying the extraction process.

Thus, this essay will focus on three reactions, namely the oxa-Michael reaction, olefin metathesis
and aldol reactions, due to their importance in stereoselective synthesis of natural products, as will
be highlighted with recent examples of their use in multi-step syntheses. The syntheses detailed in
this essay are of great medicinal value, as they are important in the development of drugs against
diseases such as cancer and AIDS.

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The oxa-Michael reaction
1
The Michael reaction involves the conjugate addition of a doubly stabilized carbon nucleophile to a
α,β-unsaturated carbonyl compound. The wide range of nucleophiles may be reacted with a wide
range of acceptors, usually with a high degree of stereocontrol and good yields. This results in the
Michael reaction being a highly favourable and frequently used reaction in organic synthesis.

Ironically, perhaps, hetero-michael reactions, which are the addition of non-carbon nucleophiles
such as amines, thiols, phosphorus and alcohols to α,β-unsaturated carbonyl compounds, had been
of little interest until recent years. This might be true especially for the oxa-Michael reaction (also
called oxo-Michael or oxy-Michael), which specifically involves the conjugate addition of alcohols.

The general mechanism of this reaction is shown in Figure 1 1a. The mechanism involves the addition
of an alcohol nucleophile to the β-carbon of the Michael acceptor. This produces an enolate which is
protonated to form the final carbonyl product.

Figure 1: Mechanism of oxa-Michael reaction

The advantage of this reaction is the production of enolates, which can be used as substrates for
other reactions. Until recently, the disadvantages, and probably the reason for the lack of interest in
it, have been the lack of stereoselectivity and the issue of reversibility of the reaction, which means
less of the product is produced from it than desired.

However, recent advances have somewhat addressed both these issues. In terms of reactivity and
reversibility of the reaction, catalysts in the form of carefully selected bases for the deprotonation of
the alcohol to enhance its nucleophilicity as well as Lewis or Brønsted acids for the activation of the
conjugate acceptor have been found or developed.

Furthermore, the use of chiral auxiliaries have allowed stereoselectivity in the reaction, through
steric hindrance and directing groups. However, the scope of this is limited due to the nature of
different groups that may be present in reactant molecules.

The use of organocatalysts1,2 has become increasingly popular in recent years due to their propensity
for asymmetric induction, caused by steric factors and directing groups. In fact, the use of such
catalysts, many of which are not only useful in asymmetric induction but also can act as both bases
and acids for the activation of the oxa-Michael reaction, has resulted in the oxa-Michael reaction
being used for its stereoselectivity, and issue for which it was unpopular in the first place. An
example of such a usage is the synthesis of (+)-Inophyllum B and (+)-Calanolide A 3 in 2003, both of
which have shown promise in anti-HIV activity.

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(+)-Inophyllum B and (+)-Calanolide A were first isolated in 1992 from the Calophyllum Ianegerum
tree, which is native to Southeast Asia. (+)-Calanolide A is now being produced as an experimental
drug in the United States, while (+)-Inophyllum B is being investigated for its inhibition of HIV reverse
transcriptase, which is essential for the virus to pass its genetic information to its host cell.
3
Ishikawa and co-workers have utilized the oxa-Michael reaction for the synthesis of (+)-Inophyllum
B and (+)-Calanolide A, the structure of which are both shown below in Figure 2 3. There have been
no previous reports on the enantioselective synthesis of (+)-Inophyllum B. Though (+)-Calanolide A
has been synthesized previously, the untilization of the oxa-Michael reaction provides another
synthetic route to achieve this product.

R=Pr : (+)-caladoline A

R=Ph : (+)-inophyllum B
Figure 2: Structure of (+)-Inophyllum B and (+)-Calanolide A

Interestingly, the oxa-Michael reaction used in the synthesis of these products was catalysed by
quinine (Figure 38), a compound better known for its own medicinal value, once being extremely
popular as a drug to treat malaria. Quinine has other lesser known uses as well, including being a key
ingredient in tonic water, and has been used as a catalyst for over two decades.

Figure 3: Structure of Quinine

The key step in the stereoselective syntheses of both (+)-Inophyllum B and (+)-Calanolide A is the
oxa-Michael reaction, the products of which undergo further reactions to attain the desired
products. The reaction is outlined in Figure 4 3, below.

cis trans
Figure 4: Outline of oxa-Michael reaction used in synthesis

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In the case where R=Pr (for the synthesis of (+)-caladoline A), the cis (desired) product had a yield of
67% with 98% ee while the trans product had a yield of 21% with 39% ee.

In the case where R=Ph (for the synthesis of (+)-inophyllum B), the cis (desired) product had a yield
of 72% with 97% ee while the trans product had a yield of 21% with 52% ee.

Other commercially available cinchona alkaloids were tested to examine their effect on the
stereoselectivity of the abovementioned reaction. The results may be viewed in Table 1 3 of Appendix
A.

It was found that cinchonidine and cinchonine, which have a hydrogen in place of the methoxy
group in quinine and quinidine respectively, catalysed a reaction that favoured the trans product
rather than the cis product.

From this observation, it was realised that the methoxy group (or the lack of it) played a major role
in the stereoselection mechanism of the reaction. A mechanism for this reaction was proposed by
Ishikawa and co-workers, as shown in Figure 5 below.

Figure 5: Supposed mechanism for cinchona alkaloid catalysed oxa-Micheal reaction

The catalytic nature of quinine stems from its ability to perform a dual role (of acid and base, as
mentioned earlier) in the catalysis of the oxa-Michael reaction. Firstly, the tertiary nitrogen acts as a
base to enhance the nucleophilicity of the hydroxide group, either by turning it into an enolate, or by
simply lengthening the hydrogen-oxygen bond enough for the reaction to proceed. Secondly, the

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hydroxide group activates the keto group through either hydrogen bonding or as a Brønsted acid,
giving up a proton that will activate the keto group, causing it to draw electrons from the double
bond, thereby activating the reaction.

For the stereoselectivity of the catalysed reaction, the proposed mechanism involves the π –π
interaction of the dimethoxybenzene ring in the coumarin, which is electron rich due to the methoxy
groups, and the pyridine unit in the cinchona alkaloid. In the event where the cinchona alkaloid has
H for its R group (mechanism T-1), this effect is proposed to be attractive. This would result in syn
addition due to the close proximity of the proton and the oxygen anion, which would still face some
force of attraction, producing the trans compound.

However, when the cinchona alkaloid has a methoxy R group (mechanism T-2), this effect is
proposed to be repulsive, due to the methoxy group in the alkaloid which will increase the electron
density within the aromatic pyridine ring. The result of this is that instead of attraction, the π- π
interaction becomes repulsive. Thus, the oxygen anion produced by the basic nitrogen in the catalyst
would be further from the proton, resulting in anti addition to the c-c double bond. This would
produce the cis compound.

From the coumarin produced in this oxa-Michael reaction, more synthetic steps resulted in
production of the desired products, which may have heavy implications in the field of medicine and
pharmaceuticals.

7
Olefin Metathesis
4
The word metathesis originates from the Greek word of the same name (μεταθεσιζ), which literally
means transposition. Indeed, in olefin metathesis, transposition is carried out, whereby carbenes of
olefins are exchanged to give new, more symmetric products. Metathesis reactions, and in
particular, olefin metathesis is a very important and widely used reaction in organic synthesis as it
can shorten many multi-step processes.

Olefin metathesis is principally an equilibrium reaction. This creates obvious problems in producing
good yields from such a reaction. One way around this problem has been to use terminal alkenes
which result in the formation of ethylene or alkenes terminating in an ethylidene group which
produces 2-butenes. Both ethylene and 2-butene are volatile and would be eliminated in the
reaction, especially under reduced pressure. This would constantly change the equilibrium to favour
the forward reaction.

Also, olefin metathesis is further complicated due to the production of a mixture of both E and Z
isomers of the same product. Alkyne metathesis does not produce this problem due to its being a
linear molecule, but it is ironically less used and developed in organic synthesis.

Several theories to the mechanism of catalysed olefin metathesis were developed, but all of them
were disproven through experimentation, until the proposal of Chauvin’s mechanism in 1971, which
was confirmed by many scientists after that. The mechanism is summarised in Figure 6 4, below.

Figure 6: Scheme of Chauvin’s proposed mechanism for catalysed olefin metathesis

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This mechanism involves the formation of an intermediate from the nucleophilic addition of the
metal alylidene to an olefin. This would result in a cyclic intermediate. A new olefin and metal
carbine is formed when they break apart. The products can participate in further metathesis with
the reactants, producing more arrangements. Any ethylene produced is eliminated, and degenerate
metathesis result in the production of the reactants again.

With this mechanism in mind, many catalysts were developed over the years, including Grubb’s first
and second generation ruthenium-based catalysts, which are the most used catalysts worldwide
(Figures 7 & 8)8.

Figure 7: 1st generation Grubb’s catalyst Figure 8: 2nd generation Grubb’s catalyst

Different applications of olefin metathesis have been developed over the years, summarised in
Figure 94.

Figure 9: Different applications of olefin metathesis

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Of these, one of the most popular among organic chemists is the RCM, or ring closing metathesis,
due to its ability to form cyclic compounds, many of which are important in biological molecules.
Indeed, it was this ring closing metathesis process that formed part of the RC-ROM (ring closing –
ring opening metathesis) process used by Charette and Barbe en-route to the synthesis of (+)-
Lepadin B5 (Figure 105), which was recently identified as a blocker of neuronal nicotinic acetylcholine
receptors. These receptors play a role in several neurological disorders, and this increases the
medicinal value of the compound.

Figure 10: Lepadin B

Prior to applying the RC-ROM process, the precursor to the reaction was produced from simple
inexpensive materials, which include a ring opened pyridine, an easily available allyl Grignard
reagent, and methyl acrylate.

Using this precursor, which is actually composed of a quinuclidine with a terminal alkene, an RC-
ROM process was conducted with 2 mol % of the second generation Grubb’s catalyst. The desired
product was produced with 79% yield at 80°C for just 2 minutes. No exclusion of air and moisture
was required, and when the reaction was carried out under those conditions, there was no
significant difference in yield. The reaction was carried out under different conditions to note the
effects and find the optimal conditions. The results of this experiment may be viewed in Table 2 5 of
Appendix A.

From the success of the RC-ROM process, two possible mechanistic pathways were proposed, as can
be seen in Figure 115.

Figure 11: Possible mechanistic pathways

To investigate the first step of (B), testing the effect of a protecting group on the proximal secondary
alcohol (Bn in the precursor is replaced with H) revealed that 0% of the product was produced
without a protecting group. Then a competitive study was done as shown in Figure 12 5a.

Figure 12: Competitive study conducted

In the competitive study, a bis-allyl analogue was used instead, to see how much a five-member ring
formation would compete with a process similar to (B). It was found that in the case of the alcohol
being unprotected, none of the desired product was produced, as expected from the results of the
protection test. However, the lack of a protecting group did stop the formation of a ruthenium
carbene, seeing that 86% of the 5-member ring product was formed. In the protected alcohol, both
products could form, with the 5-member ring more dominant. However, this is enough to show (B)
as the main pathway for the RC-ROM process, from the results of all three tests conducted.

The stereoselectivity of the reaction becomes obvious when explained by Chauvin’s mechanism,
which includes a cyclic intermediate with the metal, which is also shown in Figure 11. The reaction
resulted in a cis-fused decahydroquinoline structure, which could then be processed into Lepadin B.

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The Aldol Reaction
6
The aldol reaction involves the nucleophilic addition of a ketone elonate to an aldehyde to form a β-
hydroxy ketone, or aldol (aldehyde + alcohol). Discovered in 1872, it has since become one of the
most important tools used by chemists for C-C bond formations. The aldol formed from this reaction
can go through a condensation reaction to form an α,β-unsaturated ketone (as stated earlier, a
precursor to the Michael reaction), as shown in Figure 13 8 below.

Figure 13: A typical aldol reaction

From here, we can observe the production of two chiral centres, making the control of the
configurations of the reactants crucial to achieving the desired product. In order to be able to do
this, the mechanism of the reaction must be understood, as shown in Figure 14 8a below.

Figure 14: Mechanism for aldol reaction

The aldol reaction can be acid catalysed or base catalysed. In the case of acid catalysis, the ketone is
activated by the acid to form an enol by protonation of the carbonyl group, rendering it electrophilic.
Meanwhile, the α-carbon of the enol becomes nucleophilic, allowing a reaction to take place with an
aldehyde.

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In the base catalysed reaction, instead of an enol, an enolate is formed, while the rest of the reaction
is similar to that of the acid catalysed one.

Using this mechanism, several methods have been developed to ensure stereoselectivity of the
reaction. These include chiral auxiliaries, careful selection of the metal cation in the enolate
formation for base catalysed reactions, preadjustment of R-groups of the reactants, and of course,
organocatalysis, which was the method used by Hamada and co-workers in the synthesis of (2S,3R)-
3-Hydroxy-3-methyl-proline or OHMePro7 (Figure 157).

Figure 15: (2S,3R)-3-Hydroxy-3-methyl-proline (OHMePro)

OHMePro is one of the key components of polyoxypeptins, which have shown promise in anti-cancer
activity. Interestingly, as part of the synthesis developed by Hamada and co-workers, OHMePro is
the catalyst in the stereospecific aldol reaction. Thus, the product of the synthesis can be used to
catalyse more synthesis of the product. However, the obvious drawback of this is that if no product
has been produced, the synthesis cannot take place (unless the product is purchased initially).

Several methods for the development of OHMePro had already been developed, including
diastereoselective SmI2-mediated cyclization, optical resolution of racemic N-tosyl-OHMePro-OH
using (-)-cinchonidine, and a tandem Michael-aldol reaction. However, all these methods have a
drawback of requiring more than 1 equiv of a chiral auxiliary, which would later have to be
separated from the products. Therefore, a catalytic stereoselective synthesis using a small amount of
a chiral catalyst would be a better way of producing the desired product. The benefit of this is
increased in this particular case due to the fact that the product is the catalyst.

The key step in the synthesis of OHMePro was an intramolecular aldol reaction, catalysed by
OHMePro. Proline was first tested as the catalyst for the reaction, but achieved poor enantiomeric
excess and syn/anti ratio (the syn product is desired in this case). Interested in the ability of the final
product to act as a chiral organocatalyst, Hamada and co-workers tested it under different
conditions and found a syn-favoured reaction with much higher enantiomeric excess (See Table 3 7 of
Appendix A for full results).

The reaction mechanism has not been determined yet, but a plausible mechanism was proposed, as
shown in Figure 167below.

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 Figure 16: A Plausible Mechanism

The mechanism involves the formation of a bicyclic ring between the 3-hydroxy group and the
carboxyl group in the catalyst, giving it a rigid structure. Steric factors would then favour the
formation of the syn product in a base-catalysed mechanism similar to that in Figure 14.

From the product of this reaction, a few more synthetic steps result in the production of OHMePro,
with high yield and enantiomeric excess, and no use for chiral auxiliaries.

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Conclusion

The reactions described in this essay may not necessarily be new, but new methods are always being
developed for these old reactions to ensure greater feasibility and economic synthetic methods in
the production of organic, especially biological and pharmaceutical, compounds.

Stereoselectivity is an area where considerable research is being done, as shown from the syntheses
described earlier, though it is only a tiny fraction of the research being conducted constantly around
the world. Much of this research centres on the development of new catalysts, and in particular,
chiral organocatalysts, which would ensure stereoselectivity without the need for tedious chiral
auxiliaries. Also, determining the suitable conditions for such catalysts to work as well as the
mechanisms involved in such catalysts is vital to future research in producing even higher yielding
and more stereoselective methods.

Recent research has also turned to solid-phase syntheses 9 of certain organic compounds. This
involves the molecules being bound to a polymeric bead and then being synthesized step-by-step in
various reactant solutions, which is very useful as it does not require much effort to isolate the
product; just a simple filtration process. Furthermore, excess reagents can be used to force a
reaction to completion (since separation isn’t a problem anymore), and this process has great
potential for automation.

In future, I envision that such research would enable drugs to be available cheaply to those who
need it most, especially to poor people in countries where diseases are rampant.

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Appendix A

Table 1: Effect of other commercially available cinchona alkaloids on the stereoselectivity of the
intra-molecular oxa-Michael reaction

Table 2: Effect of different conditions on RC-ROM process

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Table 3: Effects of different catalysts and conditions on intra-molecular aldol reaction

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References

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[1a] Adapted from above source

[2] J. Seayad and B. List, Org. Biomol. Chem., 2005, 3, 719, and references cited therein

[3] E. Sekino, T. Kumamoto, T. Tanaka, T. Ikeda, and T. Ishikawa, J. Org. Chem., 2004, 69, 2760,
and references cited therein

[4] D. Astruc, New J. Chem., 2005, 29, 42, and references cited therein

[5] G. Barbe and A. B. Charette, J. Am. Chem. Soc., 2008, 130, 13873, and references cited
therein

[5a] Adapted from above source

[6] C. Palomo, M. Oiarbide and J. M. García, Chem. Soc. Rev., 2004, 33, 65, and refrences cited
therein

[7] Y. Yoshitomi, K. Makino, and Y. Hamada, Org. Lett., 2007, 2457, and references cited therein

[8] Diagrams taken from www.wikipedia.org

[8a] Adapted from above source

[9] P. Blaney, R. Grigg, and V. Sridharan, Chem. Rev. 2002, 102, 2607

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