ChemInform Abstract: A Convenient Transformation of 2‐Alkylidenecycloalkanones into Alkyl‐Substituted Bicyclo[n.1.0]alkan‐1‐ols: Application to the Synthesis of Capsaicin.

Abstract

An efficient procedure is developed via conditions A) (formation of β‐iodoketones) followed by conditions B) in the presence of either TmsCl or TiCl(O‐iPr)3.

Generation of Mixed Anhydrides via Oxidative Fragmentation of Tertiary Cyclopropanols with Phenyliodine(III) Dicarboxylates

“…Thus, the oxidative fragmentation of cyclopropanol 1a with reagent 2e was completed within 2 h (entry 9), producing the corresponding mixed anhydride in 98% yield and only trace amount of β-acyloxyketone side product 5e. The structure of mixed anhydride 3e was firmly confirmed by 13 C-NMR and HMBC correlation spectra and supported by HRMS data (see the Supplementary Materials). The oxidation reaction can be further accelerated with Brønsted acid catalysts with the rate enhancement order TfOH>MsOH>TFA, corresponding to increasing acid strength (Entries 10-12).…”

“…Without the amine additive, the reaction between 1a and PIDA in CDCl 3 slowly generated the corresponding mixed anhydride 3a, which was produced in 50% yield after 10 h reaction time (Entry 3). The structure of 3a was confirmed by 13 C-NMR and HMBC correlation spectra, showing two distinct signals of carbonyl groups in 3a at δ C 168.7 and 166.5 ppm (see the Supplementary Materials), while HRMS analysis of the crude reaction mixture revealed a mass peak with m/z = 215.0670, expected for a 3a-derived molecular ion C 11 H 12 O 3 Na + . Although rather high (~90%) conversion of the starting materials was observed after 10 h reaction time, the modest 50% yield of anhydride 3a was attained due to the generation of several oxidation side products, e.g., β-acyloxyketone 5a (R = Me) [50].…”

“…The remarkable progress in the field has been largely driven by the two following reasons. First, the hydroxy-substituted cyclopropanes are readily available compounds [8], which can be prepared by a number of high-yielding methods, including titanium-catalyzed cyclopropanation of carboxylic esters with Grignard reagents (the Kulinkovich reaction) [9,10], cyclopropanations with zinc carbenoids [11,12], 1,3-cyclization reactions [13,14] and via transformations of different cyclopropane precursors [15][16][17][18][19]. Second, the internal ring strain and the presence of electron-donating hydroxyl group facilitate ring-opening reactions of cyclopropanols under mild conditions, well tolerated by other functionalities.…”

“…Oxidative ring scissoring of cyclopropanols with phenyliodine(III) diacetate (PIDA) or more reactive bis(trifluoroacetate) (PIFA) has been frequently utilized in total synthesis of natural products (selected examples are presented in Scheme 1). Intramolecular ring cleavage of bicyclic cyclopropanols is especially powerful since it allows installation of both ester function and a stereodefined double bond in a single preparative step [13,27]. For example, Kirihara and co-workers utilized oxidative fragmentation as the key step in Oxidative ring scissoring of cyclopropanols with phenyliodine(III) diacetate (PIDA) or more reactive bis(trifluoroacetate) (PIFA) has been frequently utilized in total synthesis of natural products (selected examples are presented in Scheme 1).…”

“…For example, Kirihara and co-workers utilized oxidative fragmentation as the key step in Oxidative ring scissoring of cyclopropanols with phenyliodine(III) diacetate (PIDA) or more reactive bis(trifluoroacetate) (PIFA) has been frequently utilized in total synthesis of natural products (selected examples are presented in Scheme 1). Intramolecular ring cleavage of bicyclic cyclopropanols is especially powerful since it allows installation of both ester function and a stereodefined double bond in a single preparative step [13,27]. For example, Kirihara and co-workers utilized oxidative fragmentation as the key step in the short synthesis of an alkaloid (−)-pinidine [28,29], while our group reported synthesis of natural macrolactone (+)-recifeiolide via the ring opening-macrolactonization cascade in an aprotic solvent [30].…”