Stereoselective Synthesis of N‐Propargyl Alkynes and Axial Chiral N‐Allenes with Epimeric Pyrroloimidazolone Auxiliaries

Abstract

An N-propargyl pyrroloimidazolone with syn stereochemistry derived from L-proline serves as a starting material for the diastereoselective synthesis (> 95:5 dr) of propargyl alkynes or allenamides by direct quench of its lithiated intermediate with alkylating agents or aldehydes/ketones, respectively. Use of the epimeric anti pyrroloimidazolone starting material results in reversal of stereochemistry at the propargyl position in the products, without the need to prepare a separate substrate from D-proline. Lithiation of the syn pyrroloimidazolone and quench with prochiral benzaldehydes without prior transmetalation gives allenamides with crystallographically verified atypical stereochemistry of the benzylic alcohol in > 95:5 dr. The epimeric series of benzylic alcohols may also be obtained in > 95:5 dr by employing transmetalation with chlorotitanium triisopropoxide prior to aldehyde quench. Density Functional Theory (DFT) computational studies provide a rationale for the change in benzylic alcohol stereochemistry by virtue of differing stereofacial attack in 6,5-bicyclic (Li) or 6-membered (Ti) transition states.

Direct Asymmetric α‐C−H Addition of N‐unprotected Propargylic Amines to Trifluoromethyl Ketones by Carbonyl Catalysis

“…For example, after protecting the NH 2 group with ketones, [4] carbonyl derivatives, [5] or dibenzyl groups, [6] treatment with a strong base afforded the corresponding active α‐amino carbanions or N‐allene intermediates, which then reacted with various electrophiles, producing the corresponding α‐substituted propargylic amines (Figure 1b). When using chiral protecting groups [5b–d] or chiral electrophiles, [4a, 6e] diastereoselective version of the transformation was achieved, delivering optically active propargylic amines.…”

Deciphering the Chameleonic Chemistry of Allenols: Breaking the Taboo of a Onetime Esoteric Functionality

“…The methodology was also applied for the kinetic resolution of racemic aldehydes, and further generation of the butenolide core of the natural product (+)-xilogiblactone A. 110 − 113 …”

“…Both regiochemical and stereochemical outcomes of the reaction are explained through a Curtin-Hammet-type transition state 49 , selectively favoring γ-addition products 50 and providing excellent chiral and central enantioselectivities (Scheme ). The methodology was also applied for the kinetic resolution of racemic aldehydes, and further generation of the butenolide core of the natural product (+)-xilogiblactone A. − …”

Stereoselective Synthesis of 1,1’,2,2’‐Tetrasubstituted Ferrocenes by Double Lithiation of a 1,1’‐Disubstituted Ferrocenyl Pyrroloimidazolone

“…[13] Applications of pyrrolimidazolones have since been extended [14a] to the diastereoselective synthesis of products with tertiary [14b] and quaternary [15] chiral centres at sp 3 -hybridized carbon atoms, in addition to the stereoselective synthesis of axial chiral Nsubstituted allenes. [16] In this paper we investigate whether a 1,1'-disubstituted ferrocenyl pyrroloimidazolone can undergo stereoselective double lithiation-substitution to give 1,1',2,2'tetrasubstituted products in high diastereomeric ratio (dr) favoring the C 2 -symmetric products 10 upon electrophile quench.…”