Diastereoselective Conjugate Additions to t-Leucine-Derived N-Enoyl 1,3-Oxazolidin-2-ones

Abstract

Conjugate addition reactions of cuprate reagents to t-leucine-derived N-enoyl 1,3-oxazolidin-2-ones proceed with high diastereofacial differentiation. Additional functional groups in the substrates like enoate, acetal, and hydrazone moieties are readily tolerated.Conjugate addition reactions to a,b-unsaturated carbonyl compounds are among the most fundamental C-C-bond forming reactions in organic synthesis. 1 In the past substantial progress has been achieved with regard to the issue of absolute sterochemical control in this reaction. Chiral Michael donors 2 as well as chiral Michael acceptors 3 and most recently chiral catalysts 4 have been developed towards this goal. In particular, chiral auxiliaries attached to a,b-unsaturated carboxylic acids have proven to be very useful chiral controllers, e. g. 1,3-oxazolidin-2-ones, 3a-c camphersultams, 3d,e and 1,3-imidazolidin-2-ones. 3f-h For example, Hruby and Williams have reported asymmetric cuprate additions to N-enoyl 1,3-oxazolidin-2-ones derived from phenylglycine and phenylalanine with the former one being the superior chiral auxiliary in most cases. 3a,b The asymmetric induction, however, was not generally high. Reactions with phenyl-, allyl-, and vinylcuprates turned out to be excellent, whereas simple alkylcuprates gave inferior results. Davies developed the "quat"-1,3-oxazolidin-2-ones as chiral auxiliaries which were superior to the usual 1,3-oxazolidin-2-ones. 5 On the other hand, Kunz and co-workers have reported diastereoselective conjugate addition reactions of dialkylaluminum chlorides to sugar-derived Nenoyl 1,3-oxazolidin-2-ones with very high levels of absolute stereocontrol. 6In the course of our investigations to evaluate the synthetic potential of the products of the silyloxy-Cope rearrangement of syn-aldols 7 we have had the occasion to study conjugate addition reactions to chiral a,b-unsaturated imides. Because the chiral induction displayed by the standard 4-benzyl-1,3-oxazolidin-2-one was unsatisfactory in accordance to the results reported by others, we turned our attention to the bulkier 4-tert-butyl-1,3-oxazolidin-2-one derived from the unnatural amino acid t-leucine. This auxiliary had already been recommended for Diels-Alder reactions of difficult substrates by Evans 8 and was used for hetero Diels-Alder reactions of 1-oxabutadienes by Tietze. 9 It is now commercially available from various sources.As a model compound crotonoyl imide 1 was treated with various types of cuprate reagents among which the Yamamoto-type monoorganocuprate/Lewis acid combination or the Normant-type mono-and diorganocuprate reagents turned out to be the most satisfactory ones (Scheme 1). Thus, for example, reaction of 1 with 3 equivalents of BuCu·LiI in the presence of either Me 2 AlCl or BF 3 ·OEt 2 in THF at -78°C gave the diastereoisomeric addition products 2b and 3b in good yields, but in different ratios (Table 1, Entries 2 and 3). Whereas the Me 2 AlCl-mediated reaction gave the stereoisomer 2b with the excellent stereoselection of >95:5, the opposite st...

Highly Stereoselective and Efficient Synthesis of Functionalized Cyclohexanes with Multiple Stereocenters

“…Although the yield of this domino process12 was only moderate at best, the stereoselectivity of the overall reaction was surely remarkable considering the formation of two new σ‐bonds and three new contiguous chiral centers. In accordance with our previous observations on the conjugate additions of organocuprates to enimides,10 it is reasonable to assume that the addition took place on the Al‐chelated imide complex A (Scheme ); the lower face of the double bond is shielded by the bulky t Bu group that directs the conjugate addition towards the upper side. A directly related Al‐chelate complex has been proposed by Evans et al for the Me 2 AlCl‐mediated Diels–Alder reaction of unsaturated N ‐acyl oxazolidinones and was later confirmed experimentally by Castellino et al13 The enolate formed subsequently attacked the aldehyde in an intramolecular aldol reaction.…”

“…Secondly, since a new stereogenic center is generated, the stereoselectivity of the conjugate addition is crucial to the success of the whole process. In preliminary experiments, we discovered that the tert‐ leucine‐derived oxazolidinone with a t Bu substituent served this purpose much better than the standard benzyl‐substituted oxazolidinone 10. With regard to the reagent choice, we concentrated on the use of cuprate and aluminum reagents in accordance with the results of Näf and Nozaki.…”

The Silyloxy-Cope Rearrangement of Syn-Aldol Products: Evolution of a Powerful Synthetic Strategy

“…In addition, the external Lewis acid Me 2 AlCl may be omitted when using the Grignard reagents because the MgBr 2 formed in situ apparently served as a bidentate Lewis acid effectively, too. 30 The great bonus of this approach is that the 4-and 5-substituents in the cyclohexanol structure may be broadly varied by using the appropriate substrates easily obtained through the silyloxy-Cope rearrangement of aldol products.…”

Stoichiometric asymmetric processes

“…124 The addition of various cuprate and organocopper reagents to unsaturated tert-leucine oxazolidinone acceptors has been investigated with and without an added Lewis acid with excellent levels of diastereoselectivity. 125 Similar acceptors have been used in the synthesis of kalkitoxin, 126 an α,β-substituted histidine analogue 127 and 3ЈO,4ЈO-dimethylfuniculosin (Scheme 17). 128 Organocopper and organoaluminium reagents have also been used in domino Michael-aldol and Michael-Mannich reactions with chiral oxazolidinones to construct highly functionalised cyclohexane frameworks.…”