Enantioselective Alkylation of Acyclic α,α‐Disubstituted Tributyltin Enolates Catalyzed by a {Cr(salen)} Complex

Abstract

Catalytic a-carbonyl CÀC bond-forming reactions represent a proven strategy for the construction of quaternary stereocenters.[1] Most approaches involve the addition of enolates to carbon-centered electrophiles in which both the p-facial selectivity and the enolate geometry govern the stereoselectivity of the C À C bond-forming event.[2-8] Unfortunately, the synthesis of stereodefined enolates from simple a,a-disubstituted carbonyl compounds that lack either tethered substituents or specific chelating functionality remains a significant challenge in organic synthesis.[9] As a result, successful examples of asymmetric catalytic enolate addition reactions that generate a-carbonyl quaternary stereocenters are limited to b-cyano esters, b-keto esters, and cyclic ketones, and relatively little progress has been made with simple acyclic systems.[10] Our own efforts in the area of enantioselective reactions with enolates have led to the recent discovery of a {Cr(salen)}-catalyzed asymmetric a-alkylation of cyclic tin enolates to provide 5-, 6-, and 7-memberedring ketones that contain a quaternary stereocenters (salen=N,N'-bis(salicylidene)ethylenediamine dianion; Scheme 1).[11] While the preparation of acyclic a,a-disubstituted tin enolates leads inevitably to mixtures of E and Z isomers, tin enolates are known to undergo tautomerization between their O-stannyl and C-stannyl forms in solution. [12] We were intrigued by the possibility that enantioselective alkylation of acyclic enolates might be achievable by a dynamic mechanism such as that outlined in Scheme 2, wherein mixtures of acyclic tin enolates might undergo reaction selectively through one geometric isomer under the {Cr(salen)}-catalyzed alkylation conditions. Herein, we report our progress to this end, and discuss how these studies have enhanced our understanding of the mechanism of the catalytic reaction.Initial studies were performed using the tributyltin enolate of 3-methyl-2-pentanone 2 a, which was prepared as a 1.8:1 mixture of E and Z isomers.[13] Treatment of 2 a with allyl bromide and the [Cr(salen)Cl] complex 1 a at 4 8C afforded the alkylation product 3 a in 80 % yield and 21 % ee (Table 1, entry 1). Variation of the substituents on the salen ligand revealed that the OTIPS derivative 1 b was both more reactive and more enantioselective than the tBu derivative (Table 1, entry 2, 84 % yield, 36 % ee).[14] A significant effect of the catalyst counterion on enantioselectivity and conversion was observed (Table 1, entries 2-4), with the iodide complex 1 d catalyzing the alkylation reaction in 93 % yield and 56 % ee (3.6:1 e.r.). [15] This result established unambiguously that the enantioselectivity of the alkylation product 3 a was not limited by the E/Z ratio of enolate isomers of 2 a (see below). Interestingly, a small increase in enantioselectivity was observed in reactions run with 5 mol % Bu 3 SnOMe as an additive (Table 1, entries 5 and 6), perhaps as a result of acceleration of enolate tautomerization and equilibration. Further variation of the r...

A New Family of Halogen‐Chelated Hoveyda–Grubbs‐Type Metathesis Catalysts

“…Although electron‐deficient iodoarenes can form stable complexes with nucleophilic pyridine derivatives to give various architectures through halogen bonding,2, 3 manifestation of the σ‐donor properties of organic halides is far less common. Few examples, such as the formation of hydrogen bonds with halogens,4 the anchimeric assistance of epoxide opening in the synthesis of chlorosulpholipid,5 and studies in which metal–halogen coordination was observed6 or postulated as an intermediate interaction,7 have been described in the literature.…”

Catalytic enantioselective synthesis of quaternary carbon stereocentres

“…57 Other promising methods reported recently to exploit catalytically generated nucleophiles in the construction of quaternary stereocenters include the enantioselective insertion of diazoesters into the carbon–carbon bond of aryl aldehydes using an oxazaborolidinium catalyst, 58 and the enantioselective alkylation of acyclic tributyltin enolates in the presence of a Cr(salen) catalyst. 59 …”

Regio‐ and Stereoselective Synthesis of Fully Substituted Silyl Enol Ethers of Ketones and Aldehydes in Acyclic Systems

“…[4] From the reductive ring opening of diastereoisomerically pure bicyclic lactams [5] to thes tereospecific enolization of acyclic a-alkylbutyramides, [6] or conjugated addition [7] through the double stereodifferentiation deprotonation of enantiomerically enriched a-branched esters, [8] the formation of stereodefined fully substituted enolates of amides and esters 1 have been achieved with agreat efficiency.Inthis context, we have reported the carbometalation reaction of ynamides [9] followed by as tereo-retentive oxidation reaction [10] providing the expected fully substituted enolate of amides 1 as asingle isomer where the stereochemistry of the enolate was predetermined during the regio-and stereoselective carbometalation step. [11] Although few additional studies have been reported, [12] one can consider that the stereoselective formation of acyclic b,b-disubstituted enolates of amides and esters (1)n ol onger represents am ajor synthetic problem. On the other hand, and despite all these efforts,t he stereoselective formation of fully substituted enolates of ketones (2)i ss till challenging since one needs to control the regio-and stereoselectivity of the enolization process (Scheme 1, path a).…”