Enantioselective synthesis

Enantioselective synthesis: Sharpless epoxidation

Enantioselective synthesis, also called chiral synthesis, asymmetric synthesis or stereoselective synthesis, is organic synthesis that introduces one or more new and desired elements of chirality.^[1][2][3] This methodology is important in the field of pharmaceuticals because the different enantiomers or diastereomers of a molecule often have different biological activity.

Approaches

There are three main approaches to enantioselective synthesis:

• chiral pool synthesis
• chiral auxiliaries
• enantioselective catalysis

It is often advantageous to combine two or all of these approaches.

Chiral pool synthesis

Chiral pool synthesis is the easiest approach: A chiral starting material is manipulated through successive reactions using achiral reagents that retain its chirality to obtain the desired target molecule. This is especially attractive for target molecules having the similar chirality to a relatively inexpensive naturally occurring building-block such as a sugar or amino acid. However, the number of possible reactions the molecule can undergo is restricted, and tortuous synthetic routes may be required. Also, this approach requires a stoichiometric amount of the enantiopure starting material, which may be rather expensive if not occurring in nature, whereas chiral catalysis requires only a catalytic amount of chiral material.

Enantioselective induction

What many strategies in chiral synthesis have in common is asymmetric induction. The aim is to make enantiomers into diastereomers, since diastereomers have different reactivity, but enantiomers do not. To make enantiomers into diastereomers, the reagents or the catalyst need to be incorporated with an enantiopure chiral center. The reaction will now proceed differently for different enantiomers, because the transition state of the reaction can exist in two diastereomers with respect to the enantiopure center, and these diastereomers react differently.

Enantioselective induction can also occur intramolecularly when given a chiral starting material. This enantioinduction can be exploited, especially when the goal is to make several consecutive chiral centers to give a specific enantiomer of a specific diastereomer. An aldol reaction, for example, is inherently diastereoselective; if the aldehyde is enantiopure, the resulting aldol adduct is diastereomerically and enantiomerically pure.

Chiral auxiliary

One enantioinduction strategy is the use of a chiral auxiliary, which forms an adduct to the starting materials and physically blocks the other trajectory for attack, leaving only the desired trajectory open. Assuming the chiral auxiliary is enantiopure, the different trajectories are not equivalent, but diastereomeric. The auxiliary shares problems similar to protecting groups; like protecting groups, auxiliaries require a reaction step to add and another to remove, increasing cost and decreasing yield.

Enantioselective catalysis

The oldest enantioselective synthesis is the enantioselective decarboxylation of the malonic acid 2-ethyl-2-methylmalonic acid mediated by brucine (forming the salt) as reported by Willy Marckwald in 1904:^[4][5]

Small amounts of chiral, enantiomerically pure (or enriched) catalysts promote reactions and lead to the formation of large amounts of enantiomerically pure or enriched products.^[6][7][8] Mostly, three different kinds of chiral catalysts are employed:

1. metal ligand complexes derived from chiral ligands
2. chiral organocatalysts
3. biocatalysts.

The first methods were pioneered by William S. Knowles and Ryōji Noyori (Nobel Prize in Chemistry 2001). Knowles in 1968 ^[9] replaced the achiral triphenylphosphine ligands in Wilkinson's catalyst by the chiral phosphine ligands P(Ph)(Me)(Propyl), thus creating the first asymmetric catalyst. This experimental catalyst was employed in an asymmetric hydrogenation with a modest 15% enantiomeric excess result. The methodology was ultimately used by him (while working for the Monsanto Company company) in an enantioselective hydrogenation step in the industrial production of L-DOPA:

In the same year and independently, Noyori ^[10] published his chiral ligand for a cyclopropanation reaction of styrene. In common with Knowles' findings, Noyori's results for the enantiomeric excess for this first-generation ligand was disappointingly low: 6%.

Examples of enantioselective catalysis include:

• BINAP, a chiral phosphine, used in combination with compounds of ruthenium or rhodium. These complexes catalyse the hydrogenation of functionalised alkenes well on only one face of the molecule. This process also developed by Ryōji Noyori is commercialized as the industrial synthesis of menthol using a chiral BINAP-rhodium complex.
• The other part of that Nobel prize concerned the Sharpless bishydroxylation
• Naproxen is synthesized with a chiral phosphine ligand in a hydrocyanation reaction
• asymmetric catalytic reduction and oxidation

Biocatalysis & organocatalysis

Biocatalysis makes use of enzymes to effect chemical reagents stereoselectively. Some small organic molecules can also be used to help accelerate the desired reaction; this method is known as organocatalysis. If the organic molecule is chiral, it may react preferentially with a particular enantiomer or diastereomer of substrate.

Alternatives

Apart from enantioselective synthesis, racemic mixtures of compounds can be resolved by various techniques in chiral resolution. Where the cost in time and money of making such racemic mixtures is low, or if both enantiomers may find use, this approach may remain cost-effective.

Planning the synthesis

Chirality must be introduced to the substance first. Then, it must be maintained. Care needs to be taken when planning the synthesis: a chemical change that makes the substance isotropic renders it achiral. This process is called epimerization. For example, a S_N1 substitution reaction converts a molecule that is chiral by merit of non-planarity into a planar molecule, which has no handedness. (To visualise, draw the outlines of both of your hands on paper, and cut the images out. You can now superimpose the images, even if the hands themselves do not superimpose.) In a S_N2 substitution reaction, on the other hand, the chirality inverts, i.e., when you start with a right-handed mixture, you'll end up with left-handed one. (A visualization could be inverting an umbrella. The mechanism looks just the same.)

See also

• Aza-Baylis–Hillman reaction, for the use of a chiral ionic liquid in enantioselective synthesis.
• Chiral Lewis Acid

References

1. ^ IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version:  (2006–) "asymmetric synthesis".
2. ^ IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version:  (2006–) "stereoselective synthesis".
3. ^ K. Mislow (2002). "Stereochemical Terminology and Its Discontents". Chirality 14: 126–134. doi:10.1002/Chir.10069. 
4. ^ Marckwald, W. (1904). "Ueber asymmetrische Synthese". Berichte der deutschen chemischen Gesellschaft 37: 349. doi:10.1002/cber.19040370165. 
5. ^ Marckwald, W. (1904). "Ueber asymmetrische Synthese". Berichte der deutschen chemischen Gesellschaft 37: 1368. doi:10.1002/cber.19040370226. 
6. ^ a) Comprehensive Asymmetric Catalysis (Jacobsen, Pfaltz, Yamamoto), Springer, 1999; b) Catalytic Asymmetric Synthesis, (Ojima), Wiley, 2000.
7. ^ M. Heitbaum, F. Glorius and I. Escher (2006). "Asymmetric Heterogeneous Catalysis". Angewandte Chemie International Edition 45 (29): 4732–4762. doi:10.1002/anie.200504212. PMID 16802397. 
8. ^ Asymmetric Catalysis on Industrial Scale, (Blaser, Schmidt), Wiley-VCH, 2004.
9. ^ Nobel prize 2001 www.nobelprize.org Link
10. ^ H. Nozaki, H. Takaya, S. Moriuti, R. Noyori (1968). "Homogeneous catalysis in the decomposition of diazo compounds by copper chelates: Asymmetric carbenoid reactions". Tetrahedron 24 (9): 3655–3669. doi:10.1016/S0040-4020(01)91998-2.