Enolate enantioselective conjugate addition

Ferrocen-l,l -diylbismetallacycles are conceptually attractive for the development of bimetal-catalyzed processes for one particular reason the distance between the reactive centers in a coordinated electrophile and a coordinated nucleophile is self-adjustable for specific tasks, because the activation energy for Cp ligand rotation is very low. In 2008, Peters and Jautze reported the application of the bis-palladacycle complex 56a to the enantioselective conjugate addition of a-cyanoacetates to enones (Fig. 31) [74—76] based on the idea that a soft bimetallic complex capable of simultaneously activating both Michael donor and acceptor would not only lead to superior catalytic activity, but also to an enhanced level of stereocontrol due to a highly organized transition state [77]. An a-cyanoacetate should be activated by enolization promoted by coordination of the nitrile moiety to one Pd(II)-center, while the enone should be activated as an electrophile by coordination of the olefinic double bond to the carbophilic Lewis acid [78],... 

A number of other chiral catalysts can promote enantioselective conjugate additions of silyl enol ethers, silyl ketene acetals, and related compounds. For example, an oxazaborolidinone derived from allothreonine achieves high enantioselectivity in additions of silyl thioketene acetals.323 The optimal conditions for this reaction also include a hindered phenol and an ether additive. 

Enantioselective conjugate addition can also be carried out with cyclic enones. Shuichi Oi and Yoshio Inoue of Tohoku University in Sendai report (Tetrahedron Lett. 2004, 45, 5051) that a BINAP complex of Rh catalyzes the enantioselective conjugate addition of alkenyl Zr species such as 5, to give 7 in high enantiomeric excess. Alkenyl Zr species such as 5 are readily prepared by hydridozirconation of alkynes. It is particularly important that addition of TMS-C1 to the reaction mixture at the end of the conjugate addition leads cleanly to the enol ether 6. 

Mixed aggregates of chiral lithium amide and lithium ester enolate have been employed in the enantioselective conjugate addition on a,/S-unsaturated esters.27 Michael adducts have been obtained in ees up to 76% combining a lithium enolate and a chiral 3-aminopyrrolidine lithium amide. The sense of the induction has been found to be determined by both the relative configuration of the stereogenic centres borne by the amide and the solvent. 

Enol Amination. The Cu[(S,5)-t-Bu-box] (OTf)2 complex was found to be optimal for promoting the enantioselective conjugated addition of enolsilanes to azodicarboxylate derivatives (eq 13). This methodology provides an enantioselective catalytic route to differentially protected ot-hydrazino carbonyl compounds. Isomerically pure enolsilanes of aryl ketones, acylpyrroles, and thioesters add to the azo-imide in greater than 95% ee. The use of an alcohol additive was critical to achieve catalyst turnover. Amination of cyclic enolsilanes was also possible. For example, the enolsilane of 2-methylindanone provides the adduct containing a tetrasubstituted stereogenic center in 96% ee and high yield. Acyclic (Z)-enolsilanes react in the presence of a protic additive with enantioselection up to 99%. ... 

The preparation of silyl enol ethers from carbonyl compounds represents one of the major uses of TMSOTf. Recently, the stereochemistry and regiospeciflcity of such transformation has been addressed for aldehydes and Q -(lV-alkoxycarbonylamino) ketones, respectively. On the other hand, enantiopure silyl enol ethers can be formed by addition of TMSOTf to zinc enolates, which are obtained from the copper-catalyzed enantioselective conjugate addition of dialkyIzinc reagents to cyclic (eq 36) and acyclic enones. ... 

Alternatively, the iminium-activation strategy has also been apphed to the Mukaiyama-Michael reaction, which involves the use of silyl enol ethers as nucleophiles. In this context, imidazolidinone 50a was identified as an excellent chiral catalyst for the enantioselective conjugate addition of silyloxyfuran to a,p-unsaturated aldehydes, providing a direct and efficient route to the y-butenolide architecture (Scheme 3.15). This is a clear example of the chemical complementarity between organocatalysis and transition-metal catalysis, with the latter usually furnishing the 1,2-addition product (Mukaiyama aldol) while the former proceeds via 1,4-addition when ambident electrophiles such as a,p-unsaturated aldehydes are employed. This reaction needed the incorporation of 2,4-dinitrobenzoic acid (DNBA) as a Bronsted acid co-catalyst assisting the formation of the intermediate iminium ion, and also two equivalents of water had to be included as additive for the reaction to proceed to completion, which... 

More recent studies on asymmetric PTC Michael reactions involving ketones, have sown that the A-alkylated cinchonidinium cation 61 mediates the enantioselective conjugate addition of acetophenone to chalcones (Scheme 2.34) [103]. In the proposed transition state of the reaction, the acetophenone enolate and the a,P-enone are contact... 

In the enantioselective conjugate addition, the use of p,P-disubstituted enones to create quaternary chiral centers is more difficult because of the steric hindrance of the P-position [21]. Alexakis showed that Cu complexes with the chiral carbene ligand 49 are capable of catalyzing domino conjugate additions to the trisubstituted enone 50 in a one-pot process (Scheme 11.11). The magnesium enolates reacted poorly with alkyl halides, but their reactivity improved with use of an HMPA/THF... 

Scheme 2.40 Enantioselective conjugate addition catalyzed by bimetallic complex 135 and consecutive aldol addition of aluminum enolate 136.

Using the achiral lithium amide derived from Af-trimethylsilylbenzylamine, an enantioselective conjugate addition followed by alkylation has been realized by Tomioka and coworkers by using the chiral additive 1,2-diphenyl-1,2-dimethoxyethane [149]. Various enantioselective conjugate additions of nitrogen, oxygen, and sulfur nucleophiles under in situ protonation of the intermediate enolate, without trapping with other electrophiles have been described [144]. 

In the context of catalytic enantioselective conjugate additions, preformed enolates play two different roles as enolates, mainly those of silicon, they add to Michael acceptors under activation by a catalyst. On the other hand, enolates are involved in a second different function as intermediates, if any nucleophile reacts with a,P-unsaturated carbonyl compounds they may be quenched by protonation or reaction with different electrophiles in a stereoselective manner. 

Scheme 5.106 Enantioselective formation of metal enolate 409 in conjugate addition and quenching by protonation. Selection of ligands 410-416 frequently used in enantioselective conjugate addition.

Scheme 5.107 Formation of zinc enolate 418 by enantioselective conjugate addition,...

Scheme 5.109 Copper-catalyzed enantioselective conjugate addition of dimethyl zinc and enolate trapping by palladium-catalyzed allylic alkylation to ketone 427. Application to a synthesis of pumiliotoxin C.

Scheme 5.112 Rhodium-catalyzed enantioselective conjugate addition and subsequent diastereoselective aldol addition/allylation of boron enolate 438. Model for rationalizing the stereochemical outcome.

In 1981, Wynberg and Hiemstra already identified the unmodified cinchona alkaloids as chiral bifunctional catalysts for enantioselective conjugate additions to cycloalkenones [3]. They proposed that the OH group of cinchonine would act as a hydrogen bond donor site and stabilize the enolate-Uke transition state of the conjugate addition reaction (Scheme 6.1). 

Enantioselective Conjugate Additions of Enolates and other Stabilized Carbon Nucleophiles... 

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