Organocuprates, conjugate addition

Scheme 6.1. Diastereoselectivity in conjugate addition of organocuprates to chiral cyclic enones.

Scheme 6.6. Diastereoselectivity in conjugate additions of organocuprates to chiral bicyclic cyclohexenones (TMS = trimethylsilyl).

Conjugate addition of organocuprates has seen many applications in complex synthesis. For example, in the preparation of an opiate alkaloid it was necessary to introduce a methyl group at a late stage of the synthesis.110 The transformation of (47) to (48) was successfully carried out with Me2CuLi in a stereoselective manner (equation 51). 

Scheme 11. Sequential use of the reagent directing o-DPPB group to control stereoselectivity in the course of hydroformylation and subsequent conjugate addition with organocuprates. Reagents and conditions (a) 0.7 mol% [Rh(CO)2acac], 2.8...

Alkenyl aziridines are useful synthetic building blocks and can be converted to allylamines by conjugate addition of organocuprates [29], to pyrroline derivatives by rearrangement [30] and to P-lactams by Pd-catalyzed carbonylation [31]. 

Conjugate additions of organocuprates to (S)-4-benzyl-3-crotonoyl-2,2,5,5-tetramethyloxazolidine in the presence of Chlorotrimethylsilane (1.2 equiv) also proceed in a highly di-astereoselective manner (eq 2) to give, after the acid-catalyzed hydrolytic removal of the chiral auxiliary, optically pure carboxylic acids with p-chirality. ... 

Conjugate addition of organocuprates to the unsaturated bicyclic lactams (see above) affords rapid access to chiral, nonracemic 3- and 4-substituted pyrrolidines and trans-2,3-disubstituted pyrrolidines. ... 

SCHEME 10.62 The stereochemical course of the conjugate addition of organocuprates to a,P-unsaturated esters can be influenced using sugar-based auxiliaries. 

Methyl-a-D-mannopyranoside and methyl-a-D-galactopyranoside have also been used as chiral auxiliaries for conjugate additions of organocuprates to crotonyl esters. For the galactosyl derivative, the crotonyl ester was attached to the 3-hydroxyl group of the galactopyranoside. The addition of vinyl cuprate to ester 191 proceeded with high yield and stereoselectivity (Scheme 10.63). In this case, the diastereomeric esters 192 and 193 delivered the enantiomeric benzyl esters 194 and 195 with 96% ee. 

A sequence of tandem-Mannich-Michael reactions and conjugate additions of organocuprates has been used for the synthesis of enantiomerically pure alkaloids such as (—)-dihydro-pinidine 193, the indolizidine alkaloid (5/, 8a/ )-gephyrotoxin 167B 194 and the decahydroquinoline alkaloid 4a- p/-pumiliotoxin C 195 (Figure 10.18) [150]. 

The mechanistic picture for addition of organocuprates to a,P-unsaturated carbonyl compounds is no less complex than that for substitution reactions. On the basis of current information, conjugate addition of lithiocuprates to a, P-unsaturated ketones and esters may proceed via a initial reversible copper(I)-olefin-lithium association, which then undergoes oxidative addition followed by reductive elimination. ... 

C-Trapping. Alkylation or hydroxy alkylation (i.e., reaction with RCHO) of enolates derived from conjugate addition of organocuprates affords vicinal dialkylated products. However, the reaction is confined to highly reactive alkylating agents such as methyl, allyl, propargyl, benzyl, and a-halocarbonyl compounds or aldehydes. 

Conjugate addition of organocuprates to enones followed by selenenylation of the resultant enolates and oxidation provides a valuable method for P-alkylation with enone restoration, although with double bond rearrangement in the example below. 

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