Copper Catalyzed Asymmetric Propargylation of Aldehydes

Abstract

The highly enantio- and regioselective copper catalyzed asymmetric propargylation of aldehydes with a propargyl borolane reagent is reported. The methodology demonstrated broad functional group tolerance and provided high enantioselectivities for aliphatic, vinyl, and aryl aldehydes. The utility of the TMS homopropargylic alcohols was demonstrated by the facile conversion to a chiral dihydropyranone.

1.04 Regio-, Diastereo-, and Enantioselective Addition of Organocopper Reagents onto CO and CN Bonds

“…It promotes the clean addition of a propargyl borolane reagent mainly on aromatic and heteroaromatic aldehydes in THF at −10°C and allows the preparation of homopropargylic alcohols with enantiomeric excesses in the range of 90-99% (equation 54). 115 Interestingly, the propargylic versus allenic products ratio was found to be highly dependent on the nature of the diphosphine ligand used, from 2/1 for the use of BINAP to 93/1 with MeO-BIBOP 134. A simple change of the copper ligand allows the development of a catalytic and asymmetric protocol for the propargylation of ketones in nearly the same reaction conditions.…”

Flow Asymmetric Propargylation: Development of Continuous Processes for the Preparation of a Chiral β‐Amino Alcohol

“…The connected continuous process of allene dissolution, lithiation, Li-Zn transmetallation, and asymmetric propargylation provides homopropargyl b-amino alcohol 1 with high regio-and diastereoselectivity in high yield. [3,4] Them ost commonly used propargylation reagents are allenyl boronic acids prepared via Hgcatalyzed magnesiation of propargyl bromide. Judicious selection of mixers based on the chemistry requirement and real-time monitoring of the process using process analytical technology (PAT)e nabled stable and scalable flow chemistry runs.…”

“…[1] Recently,wer equired apractical manufacturing process to access chiral homopropargyl bamino alcohol 1. [3,4] Them ost commonly used propargylation reagents are allenyl boronic acids prepared via Hgcatalyzed magnesiation of propargyl bromide. Despite these advances,e stablished methods require low reaction temperatures to avoid substrate epimerization when applied to carbonyl substrates with a-stereogenic centers.…”

“…Despite these advances,e stablished methods require low reaction temperatures to avoid substrate epimerization when applied to carbonyl substrates with a-stereogenic centers. [3,4] Them ost commonly used propargylation reagents are allenyl boronic acids prepared via Hgcatalyzed magnesiation of propargyl bromide. [5] Theu se of mercury,t he corrosiveness of propargyl bromide,a nd the pyrophoric nature of the allenyl boronic acid raise significant environmental and safety concerns when using these reagents for large-scale applications.T he direct lithiation of allene, ar eadily available and inexpensive starting material, is ap otential alternative to propargyl bromide magnesiation if apractical lithiation/transmetallation process could be developed.…”

Ruthenium‐Catalyzed Multicomponent Reactions: Access to α‐Silyl‐β‐Hydroxy Vinylsilanes, Stereodefined 1,3‐Dienes, and Cyclohexenes

“…[9] It has found application in the copper-and zinc-catalyzed asymmetric propargylation of aldehydes, ketones, imines, and trifluoroketones. [10][11][12][13][14] Therefore, it is quite astonishing that the hydrosilylation of 1 can be performed in presenceo fa na ldehyde without the generation of the propargyl alcohol as byproduct. Benzyldimethyl silane was chosen as the hydrosilylation agent because of its excellence in the Hiyama cross-coupling,w hich will be discussed later in this report.…”