Enantio and Diastereoselective Addition of Phenylacetylene to Racemic α-chloroketones

Silvia Alesi,Andrea Gualandi,Montse Guiteras Capdevila,Diego Petruzziello,Enrico Emer,Pier Giorgio Cozzi

doi:10.3390/molecules16065298

Abstract

In this report, we have presented the first diastereoselective addition of phenylacetylene to chiral racemic chloroketones. The addition is controlled by the reactivity of the chloroketones that allowed the stereoselective reaction to be performed at –20 °C. Chiral racemic chloroketones are used in the reaction. By carefully controlling the temperature and the reaction time we were able to isolate the corresponding products in moderate yields and with good, simple and predictable facial stereoselection. Our reaction is a rare example of the use of chiral ketones in an enantioselective alkynylation reaction and opens new perspectives for the formation of chiral quaternary stereocenters.

Highlights

The addition of carbon nucleophiles to reactive electrophilic functions, such as C=O and C=N double bonds, is a process of fundamental importance in the development of chemical synthesis [1,2].Among the various nucleophilic species available, alkynes are excellent reagents for mild and selectiveC-C bond forming reactions [3,4,5]
In 2005, we found that mixtures of Me2Zn and acetylenes are able to promote the room temperature alkynylation of aldehydes, ketones and imines to furnish propargylic alcohols in good to excellent yields [6]
We have developed an enantioselective addition of Molecules 2011, 16 phenylacetylene to ketones based on this concept [7]

Summary

Introduction

The addition of carbon nucleophiles to reactive electrophilic functions, such as C=O and C=N double bonds, is a process of fundamental importance in the development of chemical synthesis [1,2]. Organocatalytic reactions have made possible the simple preparation of optically active α-chloro- or α-bromoketones, useful starting materials for the preparation of densely functionalized building blocks [14]. These useful starting material are difficult to isolate and the subsequent reaction needs to be performed in situ. If the addition of a nucleophile to a racemic haloketone is realized in the presence of a chiral catalyst in a stereoselective manner, highly densely functionalized building blocks containing a quaternary stereocenter could be prepared (Scheme 1). We report a successful realization of this concept using the Zn(Salen) promoted addition of acetylene to racemic α-chloroketones

Results and Discussion

General

Addition of Alkynes to Chloroketones

Conclusions

Calculated transition state structures