Alkynides synthesis

R,8S)-(+)-Disparlure (12) is the female sex pheromone of the gypsy moth (Lymantria dispar). Advent of Sharpless asymmetric dihydroxylation (AD) allowed several new syntheses of 12 possible. Sharpless synthesized 12 as shown in Scheme 17 [27]. Scheme 18 summarizes Ko s synthesis of 12 employing AD-mix-a [28]. He extended the carbon chain of A by Payne rearrangement followed by alkylation of an alkynide anion with the resulting epoxide to give B. Keinan developed another AD-based synthesis of 12 as shown in Scheme 19 [29]. Mit-sunobu inversion of A to give B was the key step, and the diol C could be purified by recrystallization. 

Sodium alkynides are useful intermediates for the synthesis of other alkynes. 

This synthesis fails when secondary or tertiary halides are used because the alkynide ion acts as a base rather than as a nucleophile, and the major results is an E2 elimination. 

However, the synthesis as written would fail because the alkyne is a weaker acid than the alcohol (Section 11-8), and the alkynide anion would react much more rapidly with the acidic proton of the alcohol than it would displace bromide ion from carbon ... 

Numerous applications of this chemistry to the synthesis of leukotrienes have been reported, as illustrated for the preparation of 12-hydroxyeicosatetraenoic acid (189 Scheme 41).154 Reaction of the carbe-noid precursor (190) with furan in the presence of rhodium(II) acetate generated a furanocyclopropane, which on standing reverted to predominantly the (Z, )-isomer (191). Reduction of the dicarbonyl compound (191) gave the diol (192), which was then selectively converted to the bromide (193). Subsequently, (193) was coupled with the alkynide (194), followed by Lindlar reduction and deprotection to produce (189). The overall procedure is quite general and has been applied to a range of related compounds (195-199)135-138 and useful synthetic fragments (200 and 201).153... 

The synthesis of unsymmetrical derivatives has been reported, which involves stepwise treatment of an alkenyldialkylborane with lithium alkynide followed by boron trifluoride. Protonolysis of the intermediate affords in a good yield the iso-merically pure unsymmetrical (Z, )-dicnc (Eq. 83) U1). 

Several examples of alkynic ketone formation have been recorded since Weinreb s first examples. A Diels-Alder strategy for Ae synthesis of mevinolin required the preparation of alkynic ketone (24). Standard methods, calling for the addition of the alkynide anion to an aldehyde followed by oxidation, lead to extensive degradation and by-product formation. The Weinreb methodology was clearly more effective (Scheme 8). ... 

Jacobi s synthesis of ( )-paniculide-A involves an intramolecular Diels-Alder reaction of the alkynic ketone (31). This compound was prepared in >90% yield (Scheme 9) by acylation of a lithium alkynide with the A7-methoxy-A7-methylamide (30). Addition of the anion to other derivatives related to (30) such as an acid chloride, a trifluoroacetic mixed anhydride, an acyl imidazole, S-(2-pyridyl) thiolates and a mixed carbonic anhydride (from ethyl chloroformate) led to either bis-addition or to proton abstraction. Notice should be made of the stability exhibited by the A7-methoxy-A7-methylamide group while the oxa-zole moiety was being introduced. ... 

A more recent example of a functionalized alkyne addition can be seen in Crimmin s synthesis of tala-romycin A (equation 42). ° This particular alkynide is an equivalent of the formyl acetone dianion and its use has been generalized as an entry into the spiroketal portion of the milbemycins (Scheme 20). This approach differs from the Hanessian strategy in that formation of the C(17> (21) pyran ring is constructed last, through use of the alkynic unit. 

The highly reactive carbonyl of lactone (60), an intermediate in the synthesis of forskolin, was easily converted to propargyl ketone (61) by addition of the lithium alkynide as shown in equation (48). It is possible that the intermediate ketal alkoxide was not stable in solution because of ring strain however, no multiple addition products were reported, nor was there any Michael addition of the alkoxide to the resulting ynone. 

One final example of acylation of alkynes by lactones forms part of the synthesis of neomethynolide by Yamaguchi. The Prelog-Djerassi lactone serves as the acylating agent (equation 49). The functionalized alkynide undergoes addition very selectively at the lactonic carbonyl group, despite the presence of a relatively unhindered primary ester. ... 

Lithium alkynylcuprates react with haloallenes to give similar skipped diacetylenes (see below). The related skipped enynes can be prepared by treatment of (pentadienyl)iron(tricarbonyl) halide complexes with dilithium trialkynylcuprates, the compounds being isolated as the iron(tricarbonyl)(diene) complexes (Scheme 4). Further examples of alkylation reactions of copper alkynides are illustrated in Scheme 5. Reaction between a lithium cyanoaikynecuprate and an iodoallene leads to a skipped diacetylene. This useful reaction has been used by Corey in his synthesis of hybridalactone (Scheme 6). °... 

---