Trimethylaluminum (TMA)-Catalyzed Reaction of Alkynyllithiums with Ethylene Oxide: Increased Yields and Purity of Homopropargylic Alcohols

Abstract

An efficient protocol was developed to obtain homopropargylic alcohols. Subjecting alkynyllithiums and ethylene oxide to 10-20 mol% of trimethylaluminum provided homopropargylic alcohols in good yields.Successful completion of a synthesis of a natural product possessing moderate complexity typically requires the preparation of starting materials in gram quantities. The syntheses of these relatively simple and low molecular weight precursors are usually the least interesting in a synthetic sequence that may ultimately lead to an interesting bioactive compound via a novel carbon-carbon bond forming reaction. However, low yields in the beginning stages of a synthesis can foil the best of synthetic strategies if key step precursors cannot be accessed in sufficient quantities.Recently, while working towards the synthesis of guanacastepene A, we desired the homopropargylic alcohol 3 in gram quantities. We obtained this alcohol by addition of ethylene oxide (2) to lithiated 3-methyl-1-butyne (1); 1 however, the yields of this reaction suddenly went from 95% to 10%. After some experimentation, the irreproducibility of this reaction was traced to the ethylene oxide. It was observed that an older expired lecture bottle of ethylene oxide gave 95% yields of alkynol 3. Since the older bottle had been discarded, we could only speculate that a contaminant was responsible for the higher yields. Based upon our need for a reliable and cheap protocol for the preparation of gram quantities of homopropargylic alcohol 3, we initiated a systematic investigation into the addition reaction of acetylides to ethylene oxide (Equation 1). Equation 1There are many reports of Lewis acids catalyzing the addition of acetylides to epoxides, the most common of which was developed by Yamaguchi and Hirao 2 using a stoichiometric amount of boron trifluoride etherate. In our hands this protocol was not only technically challenging upon scale up, but inseparable by-products were formed. Another reagent used to facilitate the reaction between epoxides and alkynyllithiums is catalytic amounts of trimethylgallium. 3 This methodology appears to be a very efficient way to form homopropargylic alcohols; however, it seems not to be a very well-liked protocol. It is thought that the cost ($13 per gram) of Me 3 Ga and special handling needs detract from its usefulness.Stoichiometric amounts of trimethylaluminium (TMA) have been reported to promote reaction with epoxides to give good to moderate yields; however, in some cases TMA was not reactive enough and needed to be used in conjunction with stoichiometric amounts of BF 3 ·OEt 2 . 4 In one publication, catalytic TMA could be used only if the acetylide was reacted with an epoxy ether, not a simple epoxide like 5-phenyl-1-pentene oxide. 5 There were also reports of the use of diethylaluminum chloride by Fried, 6 which gave good yields for the addition of the alkynyllithium of octyne, but low yields for more complex alkynes. Herein, we report the use of catalytic TMA for the formation of a variety of homoproparg...

Enantioselective synthesis of (10S)- and (10R)-methyl-anandamides

“…Protection of the acetylenic alcohol 13 afforded terminal alkyne 14 (95% yield), which was metalated with n -BuLi and quenched with excess ethylene oxide to give the two carbon homologated alcohol 15 in 75% yield. As reported earlier, 41 we also observed that ethylene oxide opening with lithium acetylides (e.g., TBDPSO(CH 2 ) 4 C≡CLi) in the presence of boron trifluoride etherate has low reproducibility, especially on large scale, and requires freshly distilled catalyst. Use of hexamethylphosphoramide, 42 which strongly coordinates to lithium cations, is a robust alternative to carry out this conversion.…”

Mixed AggregAte (MAA): A Single Concept for All Dipolar Organometallic Aggregates. 2. Syntheses and Reactivities of Homo/HeteroMAAs

“…The method has been used in the synthesis of 6-nor-fluvirucinin B 1 (Scheme ), in the preparation of chiral building blocks having 1,3- syn -Me groups (Scheme ), and at the beginning of the syntheses of (−)-mycalamide A (Scheme ) and amphidinolide P (Scheme ) . Me 3 Al-catalyzed reactions of alkynyllithiums with oxirane have also been described …”

First Total Synthesis of the Potent Anticancer Natural Product Dideoxypetrosynol A: Preparation of the “Skipped” (Z)‐Enediyne Moiety by Oxidative Coupling of Homopropargylphosphonium Ylide

“…Once we found the proper base to use in the preparation of the Wittig reagent, the synthesis of the target started with the known terminal acetylene 12 , Scheme 23. Homopropargyl alcohol 13 was prepared following a procedure reported by Brummond 24. This procedure employs Me 3 Al as an additive in the ethylene oxide opening reaction and gives a reproducible yield of the desired product.…”