Stereodivergent Construction of Cyclic Ethers by a Regioselective and Enantiospecific Rhodium‐Catalyzed Allylic Etherification: Total Synthesis of Gaur Acid

Abstract

The transition-metal-catalyzed intermolecular allylic etherification is a fundamentally important cross-coupling strategy for the construction of enantiomerically enriched allylic ethers. [1] Although there are numerous examples of the use of simple primary alcohols as nucleophiles, secondary or tertiary alcohols have been used in relatively few studies, [2] partially because of the poor nucleophilicity of these alcohols and the high basicity of the corresponding alkali-metal alkoxides. In response to these underlying problems, we recently reported a regioselective and enantiospecific rhodium-catalyzed allylic etherification with copper(i) alkoxides as nucleophiles. [3] The transmetalation of an alkali-metal alkoxide served to diminish its basicity, thereby promoting the etherification of a soft metal-allyl electrophile. [4] Herein, we now describe a two-step stereodivergent synthesis of cyclic ethers. The stereospecific etherification of the acyclic enantiomerically enriched allylic carbonate I with secondary alkenyl alcohols (R)-and (S)-II followed by ringclosing metathesis (RCM) affords the cis-and trans-disubstituted cyclic ethers III and IV, respectively (Scheme 1; n = 0-3). [5][6][7] The inherent advantage of this approach is the ability to vary both ring size and relative configuration as a direct Scheme 1. General approach for the stereodivergent construction of cyclic ethers. LG = leaving group.

Rhodium-Catalyzed Allylation Reactions

“…In 2004, the Evans group reported a method for the stereodivergent synthesis of cyclic ethers via enantiospecific and regioselective Rh-catalyzed allylic etherification (Scheme 41). 46 The advantage of this approach is that the relative configuration is a direct function of the alkenyl al-cohol nucleophile employed in the cross-coupling reaction, and the ability to vary ring size makes this protocol superior. In addition, the enhancement of stereospecificity resulted from modification of the copper(I) alkoxide with trimethyl phosphite, which decreased the rate of -- isomerization and promoted rapid nucleophilic attack on the Rh-allyl electrophile.…”

Regio- and Enantioselective Allylic Substitution with Less Active N- or O-Nucleophiles Catalyzed by Iridium-Complex of Bis(oxazolinyl)pyridine

“…[20][21][22][23][24] The regioselectivities in reactions using rhodium, [25][26][27][28][29][30][31][32][33] iridium, [34][35][36][37][38] and ruthenium [39][40][41] complexes are quite different from those of palladium-catalyzed reaction. Therefore, chiral iridium complexes controlling regio-and enantioselectivities have been a subject of current interest.…”

Stereodivergent routes in organic synthesis: marine natural products, lactones, other natural products, heterocycles and unnatural compounds

“…Final treatment with AcSK at 95 ºC gave the most odorous and pleasant trans-isomer of the roasted meat aroma. Evans and co-workers 86 have performed diastereodivergent routes to cyclic ethers by a regioselective and enantiospecific Rh-catalyzed allylic etherification followed by ring-closing metathesis. Starting from Boc-protected (S)-3-buten-2-ol, etherification with copper(I) alkenyl (R)-alkoxides using Wilkinson catalyst, the corresponding cyclic trans-disubstituted ethers, dihydrofuran, dihydropyran, tetrahydrooxepane, and tetrahydrooxocine were obtained (Scheme 56).…”