Synthesis of Propargylic Alcohols

Since allenes are easily obtained from the corresponding olefins [6, 7], the route olefin-allene-allylborane-carbonyl addition is general sequence and is a viable alternative to Grignard-based process for the synthesis of complex structures. 

Propargylic alcohols are valuable intermediates in the synthesis of many natural products like prostaglandins [1], steroids [2], carotenoids [3], and leukotrienes [4]. These alcohols are generally prepared by addition of alkynyl metals (Li, Na, K, Mg, Zn, and Al) to aldehyde [5]. However, many times it leads to mixtures of products, as they are highly nucleophilic and react with variety of functional groups, and their strong basicity also causes based-induced eliminations. 

The reaction of B-alkynyl-9-BBN compounds with propionaldehyde are summarized in Table 6.11 [6]. 

Unlike alkynyllithium, B-alkynyl-9-BBN compounds are prepared and stored until needed. These compounds thus add to carbonyl moiety in a Grignard-like fashion. 

Further, their generality is established as B-l-(3-dimethylbutynyl)-9-BBN reacts with a variety of aldehydes and ketones (Table 6.12) [6] to afford the corresponding proporgylic alcohols in high yields. 

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In 2002, Braga el al. employed a chiral C2-symmetric oxazolidine disulfide as a ligand for the enantioselective synthesis of propargylic alcohols by direct addition of alkynes to aldehydes (Scheme 3.64). Good yields but moderate enantioselectivities (<58% ee) were obtained for the enantioselective alkyny-lation of aldehydes in the presence of ZnEt2. 

Scheme 5.9. Zn-catalyzed asymmetric synthesis of propargyl alcohols.

An extension of the original methodology has seen the synthesis of propargylic alcohols in moderate to good yields from silver acetylides via zirconium acetylides (Scheme 1.45).108... 

ENANTIOSELECTIVE SYNTHESIS OF PROPARGYL ALCOHOLS AS MULTIFUNCTIONAL SYNTHONS... 

Before venturing into describing various strategies developed for the synthesis of propargyl alcohols in optically pure form, it would be interesting to look at various bioactive natural products and derivatives synthesized starting from this multifunctional... 

In the synthesis of propargylic alcohols, we saw the reaction of an alkynyl nucleophile (either the anion RC=CNa or the Grignard RC CMgBr, both prepared from the alkyne RC CH) with a carbonyl electrophile to give an alcohol product. Such acetylide-type nucleophiles will undergo Sn2 reactions with alkyl halides to give more substituted alkyne products. With this two-step sequence (deprotonation followed by alkylation), acetylene can be converted to a terminal alkyne, and a terminal alkyne can be converted to an internal alkyne. Because acetylide anions are strong bases, the alkyl halide used must be methyl or 1° otherwise, the E2 elimination is favored over the Sn2 substitution mechanism. 

A double transmetallation sequence from the lithium-sparteine complex to zinc to mixed zinc-copper species is illustrated in the synthesis of propargylic alcohol 45 (eq 59). 

Fluoride ion, an effective nucleophile towards Si, enhances the nucleophilicity of alkynylsilanes towards carbonyl compounds, so that Bu"4NF is a useful catalyst in the synthesis of propargylic alcohols by this method. Similarly, Me NF is useful for generation of a vinylidenecarbene (98) from an a-chlorovinylsilane (99) the carbene is useful for synthesis of alkylidenecyclopropanes. ... 

Propose at least three approaches to the asymmetric (enantioselective) synthesis of propargylic alcohol 91. (Prostaglandins-14)... 

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