Asymmetric Synthesis Asymmetric induction: Asymmetric induction involves the preferential formation of one enantiomer or diastereomer over the other in a chemical reaction by the influence of a chiral group present in the substrate or by the influence of a chiral reagent or catalyst. The stereoselective synthetic transformation using asymmetric induction is known an asymmetric synthesis.
The Meerwein-Ponndorf-Verley reaction The reduction of aldehydes and ketones into their corresponding alcohols by refluxing with excess isopropanol in the presence of aluminum isopropoxide as the catalyst is known as the Meerwein-Ponndorf-Verley reduction (MPV reduction). The alcoholic solvent (iPrOH) serves as the hydride source for this reduction and in the course of the reaction it is oxidized to acetone. Lewis acids, such as Al(OR)3, are employed so as to facilitate hydride transfer by forming a complex with the alkoxide ion and carbonyl compound.
Mechanism: The key step of the MPV reduction is thought to involve the transfer of hydride from the aluminium isopropoxide to the electrophilic carbonyl group via a six-membered cyclic transition state. The aluminum center of the aluminium alkoxide catalyst is a good Lewis acid and hence it readily coordinates to the carbonyl oxygen to form a Lewis acid-Lewis base complex I. Formation of this complex enhances both the hydride acceptor ability of the carbonyl group and the hydride donor ability of isopropoxide as oxygen gets positive charge and aluminium gets negative charge upon coordination. Rate-limiting intramolecular transfer of hydride from the isopropyl group to the carbonyl carbon center through a six-membered chair-like cyclic transition state generates mixed aluminum alkoxide II and acetone. The intermediate II reacts with the solvent isopropanol to yield the product alcohol and aluminum isopropoxide. Since aluminum isopropoxide is regenerated in the reaction, it acts as a catalyst in the overall process. Since the reaction is reversible, the equilibrium can be shifted to complete the reduction by continuous removal of the acetone from the equilibrium mixture by distillation.
What is “Enantioselective Synthesis”? M.P.V reduction of acetophenone with (S)-2-butanol in presence of aluminium-2-butoxide gives mainly the S-alcohol. Give explanation with mechanism.
Answer:
The reaction in which an achiral substrate produces a pair of enantiomers in unequal amounts by the influence of a chiral reagent or chiral catalyst is called an Enantioselective reaction and the synthetic transformation using this Enantioselective reaction is called Enantioselective Synthesis.
In the following M.P.V. reduction of acetophenone using optically pure (S)-2-butanol in aluminium alkoxide, the S-alcohol is formed as the major product. This can be explained as follows. The two faces of acetophenone are enantiotopic. Therefore, in the initially formed metal complex of acetophenone, the prochiral carbonyl carbon of acetophenone reacts with the chiral alkoxide group of aluminium alkoxide by two ways through the formation of two diastereomeric six-membered cyclic transition state, X and Y. The transition state (X) for hydride transfer to Si-face of acetophenone is energetically less stable than the corresponding transition state (Y) for hydride transfer to Re-face. This is because the former TS involves a syn-axial interaction between a bulky phenyl group and a methyl group, whereas the latter TS involves interaction between a less bulky ethyl group and a methyl group. Consequently, the TS Y is sterically favored over the TS X, leading to the formation of S- alcohol as the major enantiomer.
Diastereoselectivity:
The addition of nucleophiles to carbonyl carbon of aldehyde or ketone adjacent to α-chiral can give two diastereomeric products (Scheme 1).
The chiral center being in close proximity to a prochiral reaction center will exhibit the strongest influence on the diastereoselectivity in the above reaction and one diastereomer will predominate over the other. A number of stereo-chemical models have been proposed to explain the observed diastereoselectivity based on the preferential addition of the nucleophile to the most sterically favored face of the carbonyl group. In all the basic models, the common assumptions are: i) the substituents on the chiral center are labeled L, M and S reflecting their approximate size. The presence of chirality in the substrate causes the two faces of the carbonyl to be diastereotopic. ii) The nucleophile approaches orthogonally with respect to the plane of the carbonyl group, and iii) the transition state is reactant-like. Models for 1,2-asymmetric induction:
Cram Non-chelate Model:
In 1952, D. J. Cram formulated semiempirical rules for explaining and predicting the diastereoselectivity of a reaction involving nucleophilic addition to prochiral center of a carbonyl group by the influence of α-chiral center within the same molecule. If no electron-withdrawing polar substituent is present on the α-stereo center, according to Cram proposal the preferred reactive conformation will be the one in which RL is oriented anti to the carbonyl group, placing RM and RS on different sides of the carbonyl group. He proposed this conformation as the low energy reactive conformation because the steric interaction to be avoided was considered to be between the large substituent L and the carbonyl group (which was assumed to be sterically larger because of metal complexation). In this conformation a nucleophile will preferentially attack from the side of the less o sterically hindered substituent (RS), leading to the formation of major diastereomer He considered 90 trajectory of the approaching nucleophile. Crams non-chelate model correctly predicts the stereochemical outcome of many diastereo-face differentiating nucleophilic additions.
Example:
Mechanism:
Cram-Chelate Model: When the α-chiral center of aldehydes or ketones have oxygen, nitrogen or sulphur containing substituent shows different diastereoselectivity, which cannot be predicted on the basis of cram non-chelate model. This selectivity can be predicted by considering a cyclo-chelated conformation in which the hetero atom of the α-substituent is chelated with the metal part of the nucleophilic reagent. This puts the other two substituents (RM and RS) on opposite sides of the carbonyl group and the nucleophile will preferentially attack the diastereotopic face of the carbonyl group from the side of the smaller group, RS.
Example:
Mechanism:
Limitations of Cram’s Model: i) It has been shown that by increasing the steric bulk of the carbonyl substituent, the stereoselectivity has increased which is contrary to Cram’s rule. For example;
ii) As the reaction center is rehybridizing from sp2 to sp3 under the influence of the approaching nucleophile, the Cram’s model suffer from large tortional strain due to the nearly eclipsed conformation of the addition product.
Felkin Model: The assumptions of the Felkin model are: i) the transition states are reactant-like. ii) To avoid the tortional strain, the preferred conformation in the transition state is staggered with the carbonyl substituent R skew with respect to two groups on adjacent chiral center and the RL is placed orthogonal to the carbonyl group. iii) The dominating steric hindrance involves around carbonyl substituent R but not around the activated carbonyl oxygen. ii) There is a maximum separation between the incoming nucleophile and the larger substituent (RL) or the electronegative α-substituent and therefore, the nucleophile approaches anti to the substituent RL. Moreover, the reaction pathway is advantageous compared to the Cram’s pathway since it leads directly to a staggered conformation in the product.
Major drawbacks of Felkin model: i) The major drawbacks of the Felkin model is that the assumption of steric minimization around the carbonyl substituent R cannot be applied to aldehyde molecules which gives opposite result as predicted by Felkin model. This is because with aldehyde the important steric interaction between RM and R is removed. Therefore, according Felkin model, in the preferred conformation RM is predicted to be adjacent to H rather than the carbonyl oxygen because activated carbonyl oxygen produces greater steric interaction in compared to hydrogen. Nucleophilic addition to this conformation gives the incorrect stereochemistry of the major product. ii) In Felkin model, electron-withdrawing substituents are regarded as RL independent of their steric bulk and the incoming nucleophile approaches anti (antiperiplanar approach) to the electronegative α-substituent. But there is no proper justification for why this phenomenon is observed.
Felkin-Anh Model:
To rectify these limitations, Anh and Eisenstein provided some improvements to the Felkin model and the new model is known as Felkin-Anh model. In the first modification, Burgi-Dunitz angle idea allowed Anh and Eisenstein to postulate a non-periplanar attack of the nucleophile on the carbonyl carbon. According to this postulate the attack of the nucleophile onto the carbonyl group does not occur in a 90° but rather in a 107° angle with respect to the carbonyl group and therefore, the nucleophile attacks from the side of the small substituent RS, i.e., it experiences the least steric repulsion by the chiral center. The Felkin-Anh model focuses on the steric interaction of the substituent of the chiral center with the entering nucleophile but not with the carbonyl substituent R.
Secondly, the incoming nucleophile approaches anti (antiperiplanar approach) to the electronegative α- substituent because the electronic factors play a pivotal role in stabilizing the transition state with the incoming nucleophile. In this antiperiplanar approach, the low-lying σ*C-X orbital of the electronegative substituent is aligned parallel with the π- and π*-orbital of the carbonyl group so that it can interact with the σ orbital of the incipient C-Nu bond to provide an electronic stabilization to the incoming nucleophile. Therefore, in the polar Felkin-Anh model, the electronegative substituent with the low-lying antibonding orbital (σ*C-X) is oriented anti- periplanar to the newly forming C-Nu bond. This is called anti-periplanar effect.
Diastereo selectivity in Aldol reaction (Zimmerman-Traxler model): 1 2 In the base catalyzed mixed aldol reaction of an unsymmetrical ketone, R COCH2R , with an aldehyde of the type R3CHO, the Z-enolate gives syn (or threo) aldol product and the E-enolate gives anti (erythro) aldol product as major diastereomer.
This stereochemical outcome of the mixed aldol reaction can be explained by the Zimmerman-Traxler model of conformational analysis. According to this model the reaction proceeds through a six-membered chair-like transition state in which the metal cation is chelated with the two oxygen atoms of two reactant molecules and the R3 group of the aldehyde prefers to occupy the equatorial position rather than axial to avoid the destabilizing 1,3-syn axial interactions in the cyclic transition state. Thus, for the reaction between Z-enolate with an aldehyde there is equilibrium between two chair-like transition states X and Y. The chair TS X in which the R3 group of the aldehyde oriented equatorially is preferred one and gives the syn diastereomer as major product. In the alternative chair TS Y there is an unfavourable 1,3-syn axial interaction between the R1 group of enolate and the R3 group of the aldehyde molecule. Similarly, with E- enolate, the more stable chair TS (P) in which the R3 group oriented equatorially gives the anti diastereomer as the major product.