A Mild Method for the Preparation of g-Hydroxy- a,b-Acetylenic Esters**

The alkynylation of a carbonyl compound is a powerful reaction for forming a carbon–carbon s bond. Highly functionalized g-hydroxy-a,b-acetylenic esters RCH(OH)C C CO2Me (A) are promising synthetic intermediates that can be used as precursors to a variety of complex molecules. Since the procedure was reported by Midland et al., alcohols A have mainly been prepared by the treatment of aldehydes with the lithium acetylide Li C C CO2Me (1). The acetylide 1 can be generated in situ by the addition of n-butyllithium to methyl propiolate (2). Because n-butyllithium is itself a nucleophile toward aldehydes and ketones, the amount of base used must be controlled carefully. Furthermore, as a result of these strongly basic conditions access to A is mostly limited to base-stable compounds. As this widely used method requires a stringent balance in the stoichiometry of the reagents, one of which is moisture sensitive, it is often difficult to obtain satisfactory results. Therefore, a milder and more robust synthetic method with broader scope is needed for the preparation of alcohols A. A recent development in the enantioselective addition of a terminal alkyne to an aldehyde, pioneered by Carreira and co-workers, involves the in situ generation of a zinc acetylide in the presence of a tertiary amine. However, this method did not enable us to couple acetaldehyde with 2 to form the corresponding methyl pentynoate 4 (Scheme 1). Instead, we isolated compound 3 as the major product. We attributed this undesired reaction to the facile conjugate addition of the tertiary amine to 2, followed by loss of one iPr group. These results prompted us to develop alternative reaction conditions under which an aldehyde would undergo condensation with 2 in the absence of a base. The preparation of metal acetylides M C C R (M=Li, Sn, Si, B) often involves the use of a strong base. In contrast, the silver acetylide 5 can be readily prepared in nearly quantitative yield by a known mild protocol on an ~ 8-g scale, and this solid material can be stored at ambient temperature in a vial for many months in the dark without any precaution to avoid moisture (Scheme 2).