Stereodivergent Construction of Vicinal Acyclic Quaternary–Tertiary Carbon Stereocenters by Michael-Type Alkylation of α,α-Disubstituted N-tert-Butanesulfinyl Ketimines

Abstract

Vicinal quaternary–tertiary carbon stereocenters were constructed with excellent stereoselectivity via aza-enolization of enantioenriched acyclic N-tert-butanesulfinyl ketimines bearing two sterically similar α-linear alkyl substituents followed by conjugate addition to nitroalkenes. Further changes of the absolute configuration of the sulfinyl group and/or the α-stereocenter in the ketimine allowed the facile stereodivergent synthesis of all four diastereomers of the Michael-type alkylation adducts. This reaction is a successful example of acyclic stereocontrol based on stereoselective α-deprotonation for the formation of fully substituted aza-enolates from ketone derivatives.

α-Hydroxylation of α,α-Disubstituted N-tert-Butanesulfinyl Ketimines with Molecular Oxygen: Stereoselective Synthesis of α-Tertiary Hydroxyimines

“…On the basis of our previous work on the stereoselective aza-enolization of α,α-disubstituted N - tert -butanesulfinyl ketimines (Scheme a,b) and their nucleophilic 1,4-addition reactions (Scheme b), we hypothesized that α-oxygenation of stereodefined metalloenamine intermediates bearing two sterically similar β-linear alkyl substituents (e.g., methyl and ethyl groups) would diastereoselectively generate α-tertiary hydroxyimines (Scheme d). We considered molecular oxygen the ideal oxidant for this reaction due to its high availability, low cost, and environmental friendliness …”

“…In this study, we report the use of molecular oxygen as an electrophilic oxygen source for the effective interception of ketimine-derived aza-enolate intermediates (Scheme d). This work is based on the synthetic protocol for the stereodefined formation of β,β-disubstituted metalloenamines by stereoselective deprotonation of chiral N - tert -butanesulfinyl ( N - t BS) ketimines. In contrast, our previous N-methylation of the metalloenamines and subsequent [2,3]-shift could also stereoselectively install a hydroxyl group at the α-position, but the chiral t BS group was simultaneously sacrificed during rearrangement (Scheme a) .…”

“…The absolute configuration of the hydroxylation products was determined on the basis of X-ray crystallography of analogues ( R S ,2 R )- 2b and ( R S ,2 R )- 2z , and their stereochemistry was rationalized by postulating chelated transition states (Scheme ). In this scheme, stereoselective deprotonation of ( R S ,2 S )- 1a results in a geometry-defined ( R S , E )- N -sulfinyl metalloenamine, which undergoes nucleophilic attack by molecular oxygen via a chairlike 6/4-membered bicyclic transition state ( TS-1 ). This favored transition state lacks the pseudo-1,3-diaxial interactions between the bulky t Bu and aryl groups in the unfavorable TS-1′ , and it favors reaction on the re face of metalloenamine, selectively yielding ( R S ,2 R )- 2a .…”

Stereoselective formal alkenylation of β,β-disubstituted enesulfinamides for constructing 1,5- and 1,4-dicarbonyl derivatives bearing less-accessible acyclic α-quaternary stereocenters

“…This is because of the challenges in the geometric control of the enolization of such exocyclic carbonyls. Further, such cyclic aza-enolate intermediates are not accessible via our 1,4-addition protocol [Scheme 1D(ii)], 12 thereby the stereospecific α-deprotonation protocol [Scheme 1D(i)] complements the 1,4-addition protocol in some specialized cases.…”

“…11 Furthermore, we have discovered that the conjugate addition of organocuprates to α,β-unsaturated N-tBS ketimines offers a more convenient route to achieve β,β-disubstituted enesulfinamides, while maintaining high control over the alkene geometry [Scheme 1D(ii)]. 12 These chiral enolates/aza-enolates have been successfully applied in constructing less-accessible quaternary stereocenters via several nucleophilic transformations such as aldol [Scheme 1A-D(i)], 5c,8a,8b,9a,9b,11b Mannich [Scheme 1A, B and D(i)], 5d,8a,11c alkylation [Scheme 1A, C, and D(i)], 5b,e,6,7,11a functionalized allylation [Scheme 1B and D(i)], 8c,11d and alkynylation [Scheme 1D(i)] 11e reactions. To date, alkenylation 13 of the less-accessible β,β-disubstituted enolates/aza-enolates is unknown.…”