Chiral amide bases

Keywords Alkylation, enolate, phase transfer, Cinchona alkaloid, arylation, chiral amide base,... 

Deprotonation of carbonyl compounds by chiral amide bases followed by trapping with silylating agents or aldehydes has become a common method for de-symmetrizing prochiral and conformationally locked 4-substituted cyclohexanones and bicyclic ketones. The literature through 1997 has been reviewed [45]. 

Preparatively more relevant is the use of chiral lithium amide bases, which have been successfully used both for enantioselective generation of allylic alcohols from meso-epoxides and for the related kinetic resolution of racemic epoxides [49, 50]. In many instances, chiral amide bases such as 58, 59, or 60 were used in stoichiometric or over-stoichiometric quantities, affording synthetically important allylic alcohols in good yields and enantiomeric excesses (Scheme 13.28) [49-54], Because of the scope of this review, approaches involving stoichiometric use of chiral bases will not be discussed in detail. 

Lukin, O., Muller, W.M., Muller, U., Kaufmann, A., Schmidt, C., Leszczynski, J., Vogtle, F. Covalent chemistry and conformational dynamics of topologically chiral amide-based molecular knots, Chem. Eur. J. 9 (2003), 3507-3517. 

For a complementary approach of enantioselective enolisation by aid of chiral amide base and subsequent fluorination witch achiral 8 A. Armstrong, B. R. Hayter, Chem. Commun. 1998, 621-622. 

The first successful chiral deprotonation was reported in 1980 by Whitesell, who found that epoxides could be deprotonated with chiral amide bases to generate optically active allylic alcohols with ee s up to 31% [54]. In 1986 Simpkins and Koga independently reported stoichiometric asymmetric deprotonations of ketones. Koga studied the deprotonation of prochiral 4-alkyl-cyclohexanones... 

Simpkins examined the deprotonation of 2,6-dimethylcyclohexanone using a series of chiral amide bases. Enantioselectivity up to 74% was achieved using the bicyclicbase 13,Eq. (17) [57]. 

Reagent-induced diastereoselectivity remains relatively unexplored for the [2,3] Wittig rearrangement. In the presence of the chiral amide base (S,S)-44, rearrangement of the propargyl-oxy acetic acid 45 affords a modest excess of the -alcohol 4676. 

Remarkable improvements in chiral base-mediated reactions of prochiral ketones under external quench (EQ) conditions with TMS-Cl, furnishing enantiomerically pure enol silanes, were found upon deprotonation in the presence of LiCl. [22, 24] Simpkins et al. studied for instance the conversion of 4-tert-butylcyclohexanone 9 into enol silane 10 by employing the chiral amide base 11 (Scheme 9). [24] Applying the TMS-Cl in situ quench (TMS-Cl-ISQ) protocol a higher level of enantiomeric excess was observed compared to external quench conditions (EQ). However, under external quench conditions in the presence of LiCl (EQ-i-LiCl procedure) significantly higher levels of asymme-... 

Perhaps the most interesting developments in the area of selective lithiations to appear this year have been concerned with the control of absolute stereochemistry. The application of chiral amide bases to the enantioselective deprotonation of epoxides was first described some years ago by Whitesell and co-workers, but this year several groups have reported on other aspects of these useful reaqents. Symmetrically substituted ketones (5 R=Me, CH2Ph) have been shown by Simpkins to undergo an enantioselective deprotonation under kinetically controlled conditions to give, after reaction with an electrophile (iodomethane, allyl bromide or acetic anhydride), optically active ketones (6) or enol acetates (7) (Scheme 2). The ability of a number of bases to discriminate between the two prochiral protons present in (5) were evaluated and the most effective of those studied was the camphor derivative (8) deprotonation of (5 R=Me) proceeded in 74% enantiomeric excess... 

In a later study, the team made use of a chiral amide base in order to selectively deprotonate only one of the prochiral alkyl protons of 121, with a 70% enantiomeric excess and a diastereoselectivity of 3 1 (86). The product was then converted via a t/treo-lactone to the unnatural enantiomer of citrinin (116), (+)-citrinin. 

The cooperative function of a hard and a soft Lewis acid [La(lll) and Ag(l), respectively] in a catalyst system that includes chiral amide-based ligand has been shown... 

Asymmetric Crotylation of Axially Chiral Amides Based on this rationale, we modified our strategy in two ways (1) introduction of a more readily removable protecting group at the phenolic hydroxy... 

Deprotonation of prochiral ketones with chiral amide bases such as (50), derived from the readily available enantiomerically pure 1-phenylethylamine, provides an efficient asymmetric synthesis of silyl enol ethers (51). 

Highly enantioselectivity assumed to originate from a mixed aggregate 171 of the trans-lithium enolate of t-butyl propionate 169 and the chiral lithium amide 170 was observed in aldol additions to various aldehydes, as exemplified in Scheme 5.55. Thus, the acylated aldols obtained with benzaldehyde formed in a diastereomeric ratio of 92 8 in favor of the anti-product, with an enantiomeric excess of 94% ee [83]. More recent studies on the structures of mixed aggregates between lithium enolates and chiral amide bases (see also Chapter 3) provided an insight in this type of enantioselective conversion. 

Reactions with Active Methylene Compounds. Enolates of ketones," esters," enediolates," 1,3-dicarbonyl compounds," amides and lactams," as well as nitrile-stabilized carbanions," can be alkylated with benzyl bromide. Cyclohexanone may be benzylated in 92% ee using a chiral amide base." Amide bases as well as alkoxides have been employed in the case of nitrile alkylations." Benzylation of metalloenamines may be achieved and enantioselective reactions are possible using a chiral imine (eq 3). However, reactions between benzyl bromide and enamines proceed in low yield. The benzylation of a ketone via its enol silyl ether, promoted by fluoride, has been observed. ... 

---