Conjugate Addition/Ireland−Claisen Rearrangements of Allyl Fumarates:  Simple Access to Terminally Differentiated Succinates

Abstract

The conjugate addition of dialkylzinc reagents to allyl fumarates with subsequent Ireland-Claisen rearrangement has been accomplished yielding substituted unsymmetrical succinic acid derivatives. This one-pot reaction creates two new carbon-carbon bonds at contiguous stereogenic centers. The reaction proceeds for several alkylzinc reagents and substituted allyl fumarates. The products contain distinguishable functional handles for further manipulation.The conjugate addition of nonstabilized organometallic nucleophiles to α,β-unsaturated carbonyls is a staple of organic synthesis, but the fumarate and maleate electrophile subclass in this reaction family has received scant attention relative to simple enones and enoates. The comparative lack of research activity is surprising since maleic and fumaric acid derivatives represent cheap progenitors to functionalized succinic acids. Notable advances in this area have been reported. Ibuka and co-workers disclosed organocopper(I)-Lewis acid additions to fumarate esters that afforded good yields of the addition products; however, olefin reduction was a competing reaction pathway. 1 Hayashi and co-workers have reported enantioselective rhodium-catalyzed 1,4-additions of arylboronic acids to fumarates and maleates.2 While these examples provide useful conjugate adducts, a nonobvious feature of the reported additions is that the carbonyls in the products are still functionally equivalent and therefore challenging to distinguish. In this paper, we describe the conjugate addition of dialkylzinc reagents to diallyl fumarates with subsequent Ireland-Claisen rearrangement to give unsymmetrical succinate products. A defining characteristic of the title reaction is chemodifferentiation of the two carbonyls that can be exploited in further selective manipulations. 4 We envisioned that by using an allyl fumarate as the conjugate acceptor with an organometallic nucleophile, the metal enolate or derived silyl ketene acetal generated in situ would undergo a subsequent ester enolate Claisen rearrangement (Scheme 2). 5 In accord with precedent, the use of a chlorotrialkylsilane was projected to both accelerate the conjugate addition and generate the requisite silyl ketene acetal. 6,7

Tandem Sequences Involving Michael Additions and Sigmatropic Rearrangements

“…Johnson and co-worker developed the use of dialkylzinc reagents as nucleophiles for the tandem process involving copper-catalyzed conjugate addition to allyl fumarates and Ireland-Claisen rearrangement. 5 Disubstituted unsymmetrical succinic esters bearing two contiguous stereocenters were obtained in high yields in the presence of catalytic amounts of bis(N-tert-butylsalicylideneaminato)copper(II). The diastereoselectivity was inversely proportional to the size of the nucleophile and was explained as a result of the preferred chairlike transition state for the rearrangement step, the allylic moiety approaching syn to the ester group (Scheme 5).…”

Copper-Catalyzed Dimerization/Cyclization of Itaconates

“…The enolate intermediate formed in this process or by reductive addition can further react with an electrophile under the same reaction conditions, leading to a domino mode of reaction, which is highly desirable in organic synthesis. Applications of the conjugate reduction-derivated enolates have been reported in Negishi coupling carboannulation [8], aldolization [9,10], the Mannich reaction [11,12,13], and Ireland rearrangement [14].…”

Regio‐ and stereospecific synthesis of polysubstituted alkenes by carbozincation of acetylenic sulfones

“…Organozinc compounds are very useful and versatile reagents for a variety of transformations in organic synthesis for the reason that organozinc reagents have distinct advantages compared with other organometallic reagents because they show high tolerance for functional groups 17–21. Knochel et al reported nickel‐catalyzed carbozincation of alkynes and its application in organic synthesis 22–24.…”