The Alkyne Zipper Reaction in Asymmetric Synthesis

Asymmetric Synthesis of Functionalizedtrans-Cyclopropoxy Building Block for Grazoprevir

“…With Baeyer–Villiger products 13 secured, we next investigated installation of the terminal alkyne group under zipper reaction conditions. Interestingly, although the alkyne zipper reaction was discovered in 1975 and has been widely applied to prepare terminal alkynes, the evolution of the zipper reaction to a more practical process has received comparatively little attention . 1,3-Diaminopropanide has remained the most commonly used base throughout this time frame. , Treatment of 13 with lithium 1,3-diaminopropanide (Li-DAP) yielded the desired alkyne 14 in ∼80% assay yield (Table ).…”

“…Interestingly, although the alkyne zipper reaction was discovered in 1975 and has been widely applied to prepare terminal alkynes, the evolution of the zipper reaction to a more practical process has received comparatively little attention . 1,3-Diaminopropanide has remained the most commonly used base throughout this time frame. , Treatment of 13 with lithium 1,3-diaminopropanide (Li-DAP) yielded the desired alkyne 14 in ∼80% assay yield (Table ). However, Li-DAP prepared by treating diaminopropane (DAP) with alkyl lithium in hexanes resulted in a thick triphasic slurry, which we viewed as a robustness risk toward implementation for large-scale production.…”

“…Unlike the use of Li-DAP, the elimination of 13 with LiNH­(CH 2 ) 2 NEt 2 or LiNH­(CH 2 ) 3 NEt 2 was then carried out in a homogeneous solution in MeTHF or THF, offering robust control of the reaction performance and resulting in near complete consumption of the corresponding bromoalkene intermediates (<1%). To the best of our knowledge, the use of LiNH­(CH 2 ) 2 NEt 2 or similar lithium amides for the zipper/elimination reaction has not been reported previously . In practice, a mixture of crude stream 13 was treated with LiNH­(CH 2 ) 2 NEt 2 at −15 °C to yield a mixture of alkyne 14 and the corresponding acetate and trifluoroacetate.…”

“…After thorough consideration of the retrosynthetic strategy, readily accessible alkene epoxide 5a emerged as our precursor of choice. As such, we envisioned that transformation of the terminal alkene to the desired alkyne functionality could be realized practically through a bromination−elimination sequence, 12 while the use of the corresponding bromine masked acetylene precursor 3 would eliminate the incompatible reactivity of the unsaturated C−C bond under Baeyer−Villiger oxidation conditions. Treatment of (S)-epichlorohydrin ( 6) with commercially available 3-butenyl magnesium bromide in the presence of 1 mol % CuI afforded chlorohydrin 7 in 94% assay yield with nearly 100% regioselectivity.…”

De NovoAsymmetric Synthesis of Phoracantholide J

“…Previously, we and others have shown that the two-step sequence of a Noyori hydrogen transfer asymmetric reduction followed by a KAPA promoted alkyne zipper reaction can be used to convert achiral ynones into ω-yn-ols ( 8 to 9 ) in good yields and enantiomeric purity (Scheme ). Examples of the synthetic potential of the approach is outlined in Scheme .…”