Toward the Development of a General Chiral Auxiliary. 9. Highly Diastereoselective Alkylations and Acylations to Form Tertiary and Quaternary Centers

Abstract

[reaction--see text] Enolates of a new camphor-derived lactam auxiliary are shown to monoalkylate with very high diastereoselectivity. A second alkylation occurs with reactive alkylating agents to afford quaternary centers also with high diastereoselectivity. In accord with a proposed model for diastereoselection, lithium and sodium enolates provide products with an opposite sense of asymmetric induction.

Stereodefined acyclic trisubstituted metal enolates towards the asymmetric formation of quaternary carbon stereocentres

“…Based on molecular mechanics calculations, the authors assumed that the orientation of sodium enolate is perpendicular to the endocyclic p-system of the lactam that prevents unfavorable electronic interactions. 33 The approach of an electrophilic alkylating reagent then occurs from the least sterically hindered enolate stereoface. Cleavage of the chiral auxiliary has been achieved by transesterification with LiOBn and proceeds with an almost quantitative recovery of the lactam, leading to the a-quaternary benzyl ester in 80% yield (Scheme 3).…”

The Development of a Convergent and Efficient Enantioselective Synthesis of the Bengamides via a Common Polyol Intermediate

“…of BuLi in hexanes (57 mmol) was added to a soln. of 8.0 g (52 mmol) of 21 [18] in 100 ml of THF at À 208. The mixture was stirred at 08 for 45 min and cooled to À 788.…”

“…We next explored various other acyl electrophiles like activated thioesters [19], acyl imidazolides, and mixed anhydrides (Table, Entry 4), however, each of these experiments resulted in the recovery of the starting material. Changing the counterion from Li to Na did not improve the reactivity, in contrast to alkylation [18], suggesting that the Me group adjacent to the N-atom of 20 is, perhaps, bulky enough to hinder the approach of electrophiles.…”

“…Selective formation of the (Z)-enolate 16 by deprotonation and metallation of 20, was anticipated based on our prior studies regarding the alkylation of glycolates [18]. The (Z)-enolate 22 is favored kinetically over the corresponding (E)-enolate 23 owing to −allylic strain× in the latter.…”

“…The (Z)-enolate 22 is favored kinetically over the corresponding (E)-enolate 23 owing to −allylic strain× in the latter. Electrophiles approach the less-hindered a-face (Si-face) of the enolate, avoiding C(7) with its two Me groups (see Figure) [18]. We chose (1R,4S)-2-(2-methoxyacetyl)-1,7,7-trimethyl-2-azabicyclo[2.2.1]heptan-3-one (20) as a model for asymmetric acylation (Table).…”