A Robust, Efficient, and Highly Enantioselective Method for Synthesis of Homopropargyl Amines

Abstract

Catalytic protocols that generate a-branched amines efficiently and enantioselectively facilitate the preparation of many important biologically active molecules. [1] Among such entities are homopropargyl amines, used in the total synthesis of a number of natural products. [2] Several investigations have adopted the chiral auxiliary strategy; the desired products are obtained in high diastereoselectivity as trimethylsilyl-substituted alkynes. [3] In contrast, the corresponding catalytic protocols are scarce. The first relevant report included three examples of reactions of allenyl stannanes with a glyoxylate-derived tosylimine, [4] affording homopropargyl sulfonamides in 34-96% yield and 55:45-93:7 enantiomeric ratio (e.r.). [5] A notable recent advance entails enantioselective additions of a readily available allenylboron to tosylimines catalyzed by a Ag-phosphine catalyst to furnish a wider range of products and higher enantioselectivity (87:13 to more than 98:2 e.r.). Nonetheless, reactions of substrates that do not bear an aryl substituent proved to be less efficient, those of enolizable alkyl-substituted tosylimines were not reported and, as with the aforementioned initial development, removal of the tosyl unit requires strong reducing conditions. [6][7][8] Herein, we present a broadly applicable and efficient catalytic method for enantioselective synthesis of homopropargyl amides (Scheme 1); acid hydrolysis generates the parent amines. Transformations are performed with 0.25-2.0 mol% of a chiral N-heterocyclic carbene (NHC) complex of copper, derived from a readily available chiral imidazolinium salt and CuCl or the more robust CuCl 2 ·2H 2 O, both of which are commercially available. Aryl-, heteroaryl-, alkenyl-, as well as alkyl-substituted N-phosphinoyl imines can serve as substrates. Additions proceed to completion in seven hours or less, delivering homopropargyl amides in 65% to more than 98% yield and 92:8 to more than 98:2 e.r. The Cu-catalyzed process is amenable to gram-scale operations, and can be performed in a common fume hood without the need for strictly anhydrous and/or oxygen-free conditions. We began by probing the capacity of chiral C 1 -symmetric imidazolinium salt [9] 3a (Scheme 2), effective for reactions of allylborons with N-phosphinoyl imines, [10] in serving as the ** Financial support was provided by the NIH (GM-57212). We are grateful to Dr. B. Li for securing X-ray structures and to Frontier Scientific, Inc. for gifts of the allenylboron reagent. We thank Boston College Research Services for providing access to computational facilities.

Simple organic molecules as catalysts for enantioselective synthesis of amines and alcohols

“…Most allylmetal reagents are sensitive to oxygen and moisture; xxiv their use entails vigilantly controlled conditions. Furthermore, transformations with π-allylmetal complexes are usually either not diastereoselective ix,xvii or one possible isomer remains inaccessible xiii,xxiii regardless of whether the E or Z allylic reagent is employed.…”

“…There are inexpensive and efficient mildly acidic methods for removal of the phosphorous-based protecting group and generation of the parent amines. xxiv,xxvi Such protocols tolerate many commonly used functional groups and do not require strongly reductive conditions (e.g., diisobutylaluminum hydride xiii required in Fig. 1c), or costly metal salts (e.g., SmI 2 xviii,xxvii ) and/or alkyllithium reagents x .…”

Coinage Metal Complexes of Chiral N‐Heterocyclic Carbene Ligands: Syntheses and Applications in Asymmetric Catalysis

“…The Cu(I) complex of 21 promotes the addition of Me 2 Zn, ( i‐ Pr) 2 Zn or Ph 2 Zn to both, 5‐ and 6‐membered γ‐keto esters 23 – 26 , to produce alkylated products 27 – 30 , respectively, with significantly higher efficacy [>98% conversion in 17 h versus <15% conversion with Cu(I) complex of 19 ] and greater enantioselectivity [84% ee versus <30% ee with Cu(I) complex of 19 ]. Furthermore, three chiral imidazolinium salts 22 were reported for the Cu‐catalyzed synthesis of homopropargylic amines from allenylboron derivatives and enantioselective propargyl additions to aryl‐substituted aldimines . At the same time, structural analogues of 6 and 22 along with CuCl were studied for their site selectivity and enantioselectivity in the protoboration of alkyl‐ and aryl‐substituted vinylsilanes with B 2 (pin) 2 , which resulted in the synthesis of borosilanes in 33–94% yield and up to 98.5:1.5 er …”