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Asymmetric Synthesis of Secondary and Tertiary Propargylic Alcohols by Umpolung of Acetylenic Sulfones and Ortho-Sulfinyl Carbanions Ricardo I. Rodriguez, Elsie Ramírez, Francisco Yuste, Ruben Sanchez-Obregon, and José Alemán J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 15 Jan 2018 Downloaded from http://pubs.acs.org on January 15, 2018
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The Journal of Organic Chemistry
Asymmetric Synthesis of Secondary and Tertiary Propargylic Alcohols by Umpolung of Acetylenic Sulfones and Ortho-Sulfinyl Carbanions Ricardo I. Rodríguez,† Elsie Ramírez,† Francisco Yuste,†,* Rubén Sánchez-Obregón† and José Alemán‡,§,* †
Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Cd. Universitaria, Coyoacán 04510, México City, México ‡
Departamento de Química Orgánica (módulo-1), Universidad Autónoma de Madrid, Cantoblanco, 28049-Madrid, Spain § Institute
for Advanced Research in Chemical Sciences (IAdChem), Universidad Autónoma de Madrid, 28049, Madrid, Spain
KEYWORDS. Organolithium, sulfoxides, alkynes, umpolung, asymmetric synthesis.
ABSTRACT: The generation of diasteromerically enriched secondary benzyl propargyl alcohols by the asymmetric addition of ortho-sulfinylbenzyl carbanions to sulfonylacetylene derivatives via formation of Csp-Csp3 bond is described. This reaction proceeds through an unusual α-attack (antiMichael addition) of the ortho-sulfinylbenzyl carbanions, followed by elimination of the arylsulfonyl moiety. The scope of this alkynylation reaction is also discussed. Moreover, the development of a new approach for the synthesis of optically active tertiary benzylpropargyl alcohols is described, discussing the possible stereocourse of the reaction so as the influence of the ether 18-crown-6 and steric importance of acetylenic substituent.
INTRODUCTION The asymmetric synthesis of secondary and tertiary alcohols continues to be of considerable interest. The importance thereof stems from their ubiquitous presence in natural products, pharmaceutical agents, and other biologically active compounds.1 In addition, secondary and tertiary alcohols are important substrates for a large number of subsequent transformations2 and starting materials for the synthesis of natural products.3 Several research groups have described the addition of diverse organometallic species to acetylenic aldehydes and ketones in the presence of asymmetric ligands, leading to enantiomerically enriched secondary and tertiary alcohols (equations a and b, Scheme 1). Two main approaches have been described for the synthesis of these important propargylic alcohols. One route thereto involves the enantioselective reduction of the carbonyl moiety (equation a). Unfortunately, this synthesis is unpractical because of the limited accessibility and stability of the alkynyl ketones (very reactive Michael acceptors).4
A more useful approach involves the enantioselective addition of alkyl acetylide anions to aldehydic or ketonic carbonyl groups5 (equation b, Scheme 1). A large number of catalytic systems have been developed for this addition reaction, including alkynyl zinc reagents, among others. Unfortunately, this approach is often associated with high catalyst loadings, long reaction times, and large reagent excesses.6 Most of these methods also require the use of transition metals for the formation of the Csp-Csp3 bond, which is often considered to be a handicap by pharmaceutical companies, especially for large-scale syntheses.7 In 2012, we reported that organolithium reagents underwent an unexpected addition to the carbon atom alpha to the sulfonyl moiety of arylsulfonylacetylenes (antiMichael addition) with subsequent beta elimination of lithium arylsulfinate to generate disubstituted acetylenes.8 This transition metal free process occurred with both alkyl and aryl lithium reagents. The purpose of this work is to describe the extension of this methodology to the synthesis of secondary and tertiary propargylic alco-
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hols beginning with the carbanion derived from the optically pure protected o-(p-tolylsulfinyl)benzyl alcohols9 shown in equation c, Scheme 1. In addition, we describe conditions for removal of the alcohol protecting group as well as the tolylsulfinyl moiety from some of the products.
expected facile removal of this moiety and easy transformation to alkyl-alkyne derivatives. Table 1. Screening of different protecting groups for the alkynylation process.a
Entry 1 2 3 4
Scheme 1. Previous work and present work described in this communication (PG = protecting group).
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RESULTS AND DISCUSSION
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PG
Base
d.r.b
Yield (%)c
MOM
LDA
>98:98:98:98:98:98:
