Platinum‐ and Gold‐Catalyzed Rearrangement Reactions of Propargyl Acetates: Total Syntheses of (−)‐α‐Cubebene, (−)‐Cubebol, Sesquicarene and Related Terpenes

Abstract

Propargyl acetates, in the presence of catalytic amounts of late transition-metal salts such as PtCl(2) or AuCl(3), represent synthetic equivalents of alpha-diazoketones. This notion is corroborated by a concise approach to various sesquiterpene natural products starting from readily available substrates. Specifically, (+)-carvomenthone (17) is converted into propargyl acetate (S)-26 by a sequence involving Stille cross-coupling of its kinetic enol triflate 18, regioselective hydroboration/oxidation of the resulting 1,3-diene 19, and addition of an alkynyl cerium reagent to aldehyde 21 thus obtained. Since the latter step was found to be unselective, the configuration of the reacting propargyl acetate was unambiguously set by oxidation followed by diastereoselective transfer hydrogenation by using Noyori's catalyst 25. Compound (S)-26, on treatment with PtCl(2) in toluene, converted exclusively to the tricyclic enol acetate 27, which was saponified to give norcubebone 11 in excellent overall yield. The conversion of this compound into the sesquiterpene alcohol (-)-cubebol (6) was best achieved with MeCeCl(2) as the nucleophile, whereas the formation of the parent hydrocarbon (-)-alpha-cubebene (4) was effected in excellent yield by recourse to iron-catalyzed cross coupling methodology developed in this laboratory. Since norketone 11 has previously been transformed into (-)-beta-cubebene (5) as well as (-)-4-epicubebol 8, our approach constitutes formal total syntheses of these additional natural products as well. Along similar lines, the readily available propargyl acetates 1, 33 and 47 were shown to give access to 2-carene 44, sesquicarene 39, and episesquicarene 51 in excellent overall yields. In this series, however, the cycloisomerization reaction was best achieved with catalytic amounts of AuCl(3) in 1,2-dichloroethane as the solvent. In addition to these preparative results, our data provide some insight into the mechanism of these remarkable skeletal rearrangement reactions. Transformations of this type are likely triggered by initial coordination of the alkyne unit of the substrate to the carbophilic transition-metal cation. Formal attack of the alkene moiety onto the resulting pi-complex engenders the formation of an electrophilic cyclopropyl carbene species which subsequently reacts with the adjacent acetate unit to give the final product. The alternative phasing of events, implying initial attack of the acetate (rather than the alkene moiety) onto the metal-alkyne complex, is inconsistent with the stereochemical data obtained during this total synthesis campaign.

Gold and Platinum Catalysis of Enyne Cycloisomerization

“…[43] Interestingly, an essentially identical approach to (À)-cubebol was communicated independently by Fehr and Galindo. [44] …”

Gold‐Catalyzed Cycloisomerization of Cyclopropyl Alkynyl Acetates: A Versatile Approach to 5‐, 6‐, and 7‐Membered Carbocycles

“…[7,8] To access the Rautenstrauch rearrangement products of larger ring sizes we decided to construct a homologous system such as 1 a (Scheme 2). [9] The reaction in the presence of catalytic amounts of AuCl 3 was aimed to probe the behavior of canonical carbenoid 2 which could subsequently arise from the Au-promoted 1,2-acetate migration.…”

“…The reactions were all carried out on gram scale under very mild conditions. [9] Alkyl (Table 2, entries 1-4) and aryl (Table 2, entry 5) substituents on the double bonds were tolerated, and the products (8) were obtained in good to excellent yields. As expected, sterically hindered substrate 1 i resulted in a slower reaction, but full conversion was achieved after 6 hours, giving bicyclic compound 8 i in an excellent yield of 90 % upon isolation ( Table 2, entry 8).…”

Natural sesquiterpenoids

“…181 Other authors have reported the synthesis of this sesquiterpene and of the hydrocarbon (−)-a-cubebene. 94 New oplopane sesquiterpenes 181-186 have been isolated from Ligularia narynensis. 182, 183 Another compound of this type 187 has been found in an extract from the brown alga Dictyopteris divaricata.…”