sign in sign up
<<
Home , Asymmetric induction, Chiral auxiliary, Chiral pool, Stereochemistry

Subject

Paper No and Title 1; -I (Nature of Bonding and ) Module No and 27; Asymmetric Synthesis Title Module Tag CHE_P1_M27

CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry Module No. 27: Asymmetric Synthesis

TABLE OF CONTENTS

1. Learning Outcomes

2. Introduction

3. Asymmetric Synthesis 3.1 Asymmetric Synthesis: Borrowing From Nature’s 3.2 The strategy 3.3 Chiral and chiral catalysts

4. Summary

CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry Module No. 27: Asymmetric Synthesis

1. Learning Outcomes

After studying this module, you shall be able to

 Know what is the meaning of asymmetric synthesis  Understand various aspects and definitions of asymmetric synthesis  Learn about nature’s chiral pool and its importance in asymmetric synthesis  Analyse various examples based on nature’s chiral pool serving as precursors for asymmetric synthesis  Study other examples and case studies relating to asymmetric synthesis

2. Introduction

Absolute asymmetric synthesis or is the synthesis of optically active products from achiral or racemic precursors without employing optically active catalysts or auxiliaries. The synthesis of a racemic (50:50 mixture of both ) version was historically accepted as a successful outcome but that is no longer the case. Synthetic organic remain interested not only in mimicking nature but also in synthesising totally novel chiral structures. If organic chemists wish to synthesise the produced by nature, then they must be able to prepare the same which occurs naturally. For example, for a perfumer or flavour and fragrance manufacturer, the distinction between enantiomers of the same is clearly of great importance. In this module, we shall learn about different aspects and some very fascinating aspects about asymmetric synthesis, which will help in kindling a new enthusiasm about this topic.

3. Asymmetric Synthesis

In actual words asymmetric synthesis means: "A reaction that uses optically inactive reactants and catalysts cannot produce a product that is optically active. Any chiral product must be formed as a because

CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry Module No. 27: Asymmetric Synthesis

the transition states leading to the two enantiomers are themselves enantiomeric and

therefore equal in energy." Or

"Reaction between two optically inactive (achiral) partners always leads to an optically inactive product– either racemic or meso.”

“Also optical activity does not occur from optically inactive products; optically active products can't be produced from optically inactive reactants."

Fig. 1: Asymmetric synthesis Asymmetric synthesis or asymmetric induction is only tenuously different from . The difference is that the asymmetric instead of being in the molecule to begin with, is introduced in the course of the reaction. A fine example is the synthesis of glucononitrile and mannononitrile from (+)-arabinose. Since the two products are diastereoisomeric, thus the transition states leading to them would also be expected to be diastereoisomeric. This makes them different in their respective free energies. Since the starting state [(+)-arabinose] is the same for the two reactions, the activation energies are expected to differ, and the rate at which the two products are formed will also be different. In fact, before the actual findings, it was believed that the mannonic acid nitrile predominated to such an extent that it was believed to be the product of this reaction.

CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry Module No. 27: Asymmetric Synthesis

3.1 Asymmetric Synthesis: Borrowing From Nature’s Chiral Pool Most asymmetric syntheses generally require more than one or two steps from chiral pool constituents. If there happens to be an existing chiral centre, the two possible TS’s are diastereomeric and can be of different energy. Thus one of the new stereogenic centre can be produced in a larger amount.

Fig. 2: Production of one stereoisomer in larger quantity

CASE STUDIES: Case 1: Male bark beetles belonging to the genus Ips produces a pheromone that is a mixture of several enantiomerically pure compounds. One of them being a simple diene (S)-(– )-ipsenol. In the 1970s, Japanese chemists noted the similarity of part of the structure of ipsenol (in black) to the widely available (S)-leucine and decided to exploit this in

CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry Module No. 27: Asymmetric Synthesis

a chiral pool synthesis, using the stereogenic centre (green ring) of leucine to provide the stereogenic centre of ipsenol.

Fig. 3: Possible retrosynthesis of (S)-(-)-ipsenol The amino group needs to be converted to a hydroxyl group with retention of configuration. The process of diazotization followed by hydrolysis performs the same reactions because of neighbouring group participation from the .

Fig. 4: NGP by carboxylic acid group THP derivative was prepared for the protection of the alcohol. Reduction of the acid, via the , allows the introduction of the tosyl leaving group, which was displaced to make an . The epoxide reacted with a Grignard carrying the diene portion of the target molecule.

Fig. 5: Preparative reactions of the target molecule Case 2: Another insect pheromone synthesis illustrates one of the drawbacks of chiral pool approaches. The ambrosia beetle aggregation pheromone is called sulcatol and is chemically a simple alcohol. This pheromone poses a rather unusual synthetic problem: the beetles produces it as a 65:35 mixture of enantiomers so, in order to mimic the pheromone’s effect. Thus, the challenge for the remains to synthesize both enantiomers separately and mix them together in the right proportion.

CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry Module No. 27: Asymmetric Synthesis

Fig. 6: (R)-sulcatol and (S)-sulcatol

One approach to the (R)-enantiomer employs the sugar found in DNA, 2-deoxy-D-, as a source of .

Fig. 7: 2-deoxy-D-ribose, as a source of chirality Only one (ringed with green again) of the two defined chiral centres in the sugar appears in the product so, after protecting the hemiacetal, the two free hydroxyl groups were removed by mesylation, substitution by iodide, and reduction. A simple olefination gave (R)-sulcatol. Sugars often need simplifying in this way, because only rarely are all their chiral centres needed in the final product.

Fig. 8: Rarely are all chiral centres present in sugars needed in the final product Since the L-sugar is unavailable (even D-deoxyribose is quite expensive), thus, (S)-Sulcatol cannot be made by this route, So an alternative synthesis was needed that could be adapted to give either isomer. The solution is to go back to another hydroxy-acid, ethyl lactate, which is more widely available as its (S)-enantiomer, but which can be converted simply to either enantiomer of a key epoxide intermediate. From (S)-ethyl lactate, protection of the alcohol, reduction of the ester, and tosylation allows ring closure to one enantiomer of the epoxide; tosylation of the secondary hydroxyl group followed by reduction and ring closure gives the other enantiomer.

CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry Module No. 27: Asymmetric Synthesis

Fig. 9: Two enantiomers are possible to be made from (S)-ethyl acetate For this reason, the two enantiomers of propylene oxide are commonly used as ‘chiral pool’ starting materials. These react with the appropriate to give either enantiomer of the sulcatol.

Fig. 10: ‘chiral pool’ starting materials For target molecules having more than one stereogenic centre, only one needs to be borrowed from the chiral pool, provided diastereoselective reactions can be employed to introduce the others with control over relative stereochemistry. Since the first chiral centre has defined , any diastereoselective reaction that controls the relative stereochemistry of a new chiral centre also defines its absolute configuration. In this synthesis of the rare amino sugar methyl mycamino- side, only one chiral centre comes directly from the chiral pool—the rest are introduced diastereoselectively.

Fig. 11: In this synthesis only one chiral centre comes directly from the chiral pool—the rest are introduced diastereoselectively.

The ring was built up from acetylated (S)-lactic acid, and a cyclization step introduced the second chiral centre—the goes pseudoequatorial while the pseudoaxial position is preferred by the methoxy group because of the anomeric effect. CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry Module No. 27: Asymmetric Synthesis

Fig. 12: Note that the pseudoaxial position is preferred by the methoxy group because of the anomeric effect. The third stereogenic centre was controlled by axial reduction of the to give the equatorial alcohol, which then directed introduction of the fourth and fifth stereogenic centres by epoxidation.

Fig. 13: Axial reduction of the ketone

CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry Module No. 27: Asymmetric Synthesis

Finally, the simple nucleophilic amine Me2NH attacks the epoxide with inversion of configuration to give methyl mycaminoside. The conformational drawing shows that all are equatorial except the MeO group, which prefers to be axial because of the anomeric effect.

Fig. 14: Observation of anomeric effect again The disadvantage with chiral pool approaches is that the compound you make has to be quite close in structure to one of the natural products that are readily available. Otherwise, if this is not the case, the synthetic route becomes so strenuous that it’s even more wasteful than resolution. The second major disadvantage is the lack of availability of both enantiomers of most natural products, especially useful starting materials like amino acids and sugars—we have just confronted this problem with the synthesis of sulcatol from deoxyribose. As a further example, we can return again to our Japanese beetles. Their pheromone can be made from glutamic acid by a short route. Unfortunately, when widely available (S)-(+)-glutamic acid is used, the product is the enantiomer of the active pheromone, which you will remember is a powerful inhibitor of the natural pheromone. Making the right enantiomer is not economical for a chemist, because (R)-(–)-glutamic acid is about 40 times more expensive than (S)-(+)-glutamic acid.

CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry Module No. 27: Asymmetric Synthesis

Fig. 15: Uneconomical isomer synthesized

3.2 The Chiral Auxiliary Strategy This strategy involves these steps:  An enantiomerically pure compound (usually derived from a simple natural product like an amino acid), called a chiral auxiliary, is attached to the starting material.  A diastereoselective reaction is carried out, which, because of the enantiomeric purity of the chiral auxiliary, gives only one enantiomer of the product.  The chiral auxiliary is removed by, for example, hydrolysis, leaving the product of the reaction as a single enantiomer. The best chiral auxiliaries (of which the example above is one) can be recycled, so although stoichiometric quantities are needed, there is no waste. Racemic mixture is the product of a normal Diels Alder reaction, however, if we replace the achiral benzyl ester group with an derived from the natural amino acid valine. The diastereoselectivity remains the same but the chiral environment created by the single enantiomer covalently bonded to the dienophile has a remarkable effect: only one enantiomer of the product is formed.

CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry Module No. 27: Asymmetric Synthesis

Fig. 16: Chiral auxiliary strategy

3.3 Chiral reagents and chiral catalysts If we want to create a new chiral centre in a molecule, our starting material must have prochirality—the ability to become chiral in one simple transformation. The most common prochiral units that give rise to new chiral centres are the trigonal carbon of and carbonyl groups, which become tetrahedral by addition reactions. A prochiral (we CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry Module No. 27: Asymmetric Synthesis

can count as alkenes for this purpose) reacted selectively on one face because of the influence of the chiral auxiliary, which made the faces of the alkene diastereotopic. One of the simplest transformations you could imagine of a prochiral unit into a chiral one is the reduction of a ketone. Although chiral auxiliary strategies have been used to make this type of reaction asymmetric, you will appreciate that, conceptually, the simplest way of getting the product as a single enantiomer would be to use a chiral reducing agent—in other words, to attach the chiral influence not to the (as we did with chiral auxiliaries) but to the reagent.

Fig. 17: Reduction of ketone to for introduction of a prochiral unit The following table discusses the comparison of all the methods studied in this module to achieve asymmetric synthesis.

CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry Module No. 27: Asymmetric Synthesis

4. Summary

In this module, we have taught you that:  Absolute asymmetric synthesis or asymmetric induction is the synthesis of optically active products from achiral or racemic precursors without employing optically active catalysts or auxiliaries.  Any chiral product must be formed as a racemic mixture because the transition states leading to the two enantiomers are themselves enantiomeric and therefore equal in energy.  Asymmetric synthesis or asymmetric induction is only tenuously different from kinetic resolution. The difference is that the asymmetric atom instead of being in the molecule to begin with, is introduced in the course of the reaction.  Most asymmetric syntheses require rather more than one or two steps from chiral pool constituents. When there is an existing chiral centre, the two possible TS’s are diastereomeric and can be of different energy. Thus one isomer of the new stereogenic centre can be produced in a larger amount.  Various methods for carrying out asymmetric synthesis and their pros and cons are discussed in the module.

CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry Module No. 27: Asymmetric Synthesis