Seyferth-Gilbert

The tetraacetylenic compound (-)-minquartynoic acid was synthesized in the laboratory of B.W. Gung from commercially available azelaic acid monomethyl ester using a one-pot three-component Cadiot-Chodkiewitz reaction as the key step. This natural product shows strong anti-cancer and anti-HIV activity. One of the alkyne components was prepared using the modified Seyferth-Gilbert homologation. 

The stereoselective synthesis of the C5-C20 subunit of the aplyronine family of polyketide marine macrolides was accomplished by J.A. Marshall and co-workers. The C15-C20 moiety was prepared using the original Seyferth-Gilbert homologation conditions. The diazophosphonate was deprotonated with potassium fert-butoxide at low temperature, and then the solution of the aldehyde was added slowly also at low temperature. Interestingly, the alternative Corey-Fuchs alkyne synthesis was unsuccessful on this substrate, since extensive decomposition was observed. 

Seyferth-Gilbert homologation Synthesis of alkynes from aldehydes. 402... 

Aldehyde 126 was converted to the terminal alkyne (142) in 61% yield by Seyferth-Gilbert homologation (Scheme 23) [60]. These basic conditions were well tolerated and no C-8 epimerization or C-2 deacetylation was observed. Alkyne 142 was coupled with various azides under copper(I)-catalyzed click reaction conditions to afford 1,4-disubstituted-l,2,3-triazoles (143-145) in 88% yield. Similar conditions were used to generate unsubstituted 1,2,3-triazoles. Alkyne 142 was coupled to azidomethyl pivalate under click reaction conditions to give the pivalyl triazole (146) in 88% yield. The pivalyl triazole was then treated with IN NaOH to remove both the pivalyl group and the C-2 acetyl group. These conditions also led to C-8 epimerization. Acetylation of the epimeric mixture under standard conditions (AC2O, pyridine) and preparative scale separation by TLC furnished the C-8 epimeric N-unsubstituted triazoles (147) in 54% yield over three steps in a ratio of 4 6 (C-8 epi-C-8). 

This Seyferth-Gilbert reagent is conveniently prepared through trifluoroacetylation and diazo transfer with concomitant detrifluoroacetylation. ... 

It is proposed that this reaction occurs via a mechanism similar to the Wittig Reaction In detail, deprotonation of the Seyferth-Gilbert reagent by potassium -butoxide generates a carbanion, which adds to the carbonyl group to yield an oxaphosphatane then subsequent elimination of dimethylphosphate leads to the formation of a vinyl diazo intermediate from which the vinyl carbene forms by evolution of nitrogen gas final 1,2-migration of the substituent on vinyl carbene yields the alkyne. An illustrative mechanism is displayed here. 

Other references related to the Seyferth-Gilbert homologation are cited in the literature. H. REFERENCES... 

To avoid the direct manipulation with hazardous azides, methods using Cu(I)situ generation of azides were developed as one-pot procedures, for example, with substitution reaction of alkyl hahdes by NaN3 [493] or with nitrosation of aromatic primary amines by tBuONO followed by trimethylsilyl azide [494]. Vice versa, the alkyne component has been generated in situ, for example, by sequential Seyferth-Gilbert reaction (homologation of aldehydes with diazophosphonates) and reaction with azides in a Cu(l)-catalyzed cycloaddition [495]. 

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