Stereogenic centers carbonyl

Similarly, the two faces at a trigonal earbon in a molecule containing a stereogenic center are diastereotopie. Both ehiral and achiral reactants can distinguish between these diastereotopie faces. Many examples of diastereotopie transformations of sueh eompounds are known. One of the cases that has been examined elosely is addition reactions at a trigonal center adjacent to an asymmetric carbon. Particular attention has been given to the case of nucleophilie addition to carbonyl groups. 

The stereochemical outcome of the Michael addition reaction with substituted starting materials depends on the geometry of the a ,/3-unsaturated carbonyl compound as well as the enolate geometry a stereoselective synthesis is possible. " Diastereoselectivity can be achieved if both reactants contain a stereogenic center. The relations are similar to the aldol reaction, and for... 

Johnson s classic synthesis of progesterone (1) commences with the reaction of 2-methacrolein (22) with the Grignard reagent derived from l-bromo-3-pentyne to give ally lie alcohol 20 (see Scheme 3a). It is inconsequential that 20 is produced in racemic form because treatment of 20 with triethyl orthoacetate and a catalytic amount of propionic acid at 138 °C furnishes 18 in an overall yield of 55 % through a process that sacrifices the stereogenic center created in the carbonyl addition reaction. In the presence of propionic acid, allylic alcohol 20 and triethyl orthoacetate combine to give... 

Scheme 5 details the asymmetric synthesis of dimethylhydrazone 14. The synthesis of this fragment commences with an Evans asymmetric aldol condensation between the boron enolate derived from 21 and trans-2-pentenal (20). Syn aldol adduct 29 is obtained in diastereomerically pure form through a process which defines both the relative and absolute stereochemistry of the newly generated stereogenic centers at carbons 29 and 30 (92 % yield). After reductive removal of the chiral auxiliary, selective silylation of the primary alcohol furnishes 30 in 71 % overall yield. The method employed to achieve the reduction of the C-28 carbonyl is interesting and worthy of comment. The reaction between tri-n-butylbor-... 

The stereoselectivity of an addition reaction is considerably lower when the reactions are conducted in polar solvents, complexing additives such as /V./V,A. A, -tetramethylethylenedi-arnine arc used, or when the stereogenic center carries a methoxy group instead of a hydroxy group. This behavior is explained as competition between the cyclic model and a dipolar model, proposed for carbonyl compounds bearing a polar substituent such as chlorine with a highly... 

In contrast to the open-chain and dipolar models, which are based on conformations of the carbonyl compound not representing energy minima, Karabatsos proposed a different model assuming an early, reactant-like transition state in which the most stable conformation of the free carbonyl compound is preserved1314. Thus, the C-M bond eclipses the carbonyl double bond and, in order to minimize the energy of the transition state, the nucleophile approaches close to the small substituent on the stereogenic center (Figure 5). 

Nonperpendicular attack of the nucleophile explains Felkin s hypothesis for the predominance of interactions involving R1 and R2 over interactions involving the carbonyl oxygen. Additionally, as R1 increases in bulk, the nucleophile is pushed towards the stereogenic center and can better feel" the difference between the substituents, resulting in an increase in stereoselectivity. 

With a-alkyl-substituted chiral carbonyl compounds bearing an alkoxy group in the -position, the diastereoselectivity of nucleophilic addition reactions is influenced not only by steric factors, which can be described by the models of Cram and Felkin (see Section 1.3.1.1.), but also by a possible coordination of the nucleophile counterion with the /J-oxygen atom. Thus, coordination of the metal cation with the carbonyl oxygen and the /J-alkoxy substituent leads to a chelated transition state 1 which implies attack of the nucleophile from the least hindered side, opposite to the pseudoequatorial substituent R1. Therefore, the anb-diastereomer 2 should be formed in excess. With respect to the stereogenic center in the a-position, the predominant formation of the anft-diastereomer means that anti-Cram selectivity has occurred. 

In this case, /6 -attack at the carbonyl group is induced by the stereogenic center at the metal. This fact is best explained by an approach of the aldehyde trans to the nitroso group, forming a chair-like six-membered transition state in the lower half-sphere which is not shielded by the cyclopentadiene residue. 

In a chiral aldehyde or a chiral ketone, the carbonyl faces are diastereotopic. Thus, the addition of an enolate leads to the formation of at least one stereogenic center. An effective transfer of chirality from the stereogenic center to the diastereoface is highly desirable. In most cases of diastereoface selection of this type, the chiral aldehyde or ketone was used in the racemic form, especially in early investigations. However, from the point of view of an HPC synthesis, it is indispensable to use enantiomerically pure carbonyl compounds. Therefore, this section emphasizes those aldol reactions which are performed with enantiomerically pure aldehydes. 

The effect of stereogenic centers along the chain, connecting the 7t-nueleophile and the nitrogen atom, has been studied. For substituents adjacent to the nitrogen atom, an axial orientation is preferred in order to avoid A 1-31 strain between the substituent and the carbonyl function of the A-acyl group146. 

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