An Asymmetric Suzuki–Miyaura Approach to Prostaglandins: Synthesis of Tafluprost

Abstract

We report the catalytic asymmetric synthesis of Tafluprost (1), a prostaglandin analogue. This synthesis demonstrates a new approach to prostaglandins involving symmetrization and desymmetrization of a racemic precursor to control the absolute and relative stereochemistry of the cyclopentyl core. Key steps include a diastereo-and enantioselective Rh-catalyzed Suzuki−Miyaura reaction of a racemic bicyclic allyl chloride and an alkenyl boronic acid and a regio-and diastereoselective Pd-catalyzed Tsuji−Trost reaction with an enolate surrogate.

Additions to Racemates: A Strategy for Developing Asymmetric Cross-Coupling Reactions

“…36 We used an enantioand diastereoselective Suzuki-Miyaura coupling to install the alkenyl side-chain and to set the stereochemistry of the hydroxy groups of the cyclopentane core. 37 We then converted the cyclic acetal protecting group into a carbonate as a traceless activating strategy for a palladium-catalyzed diastereo-and regioselective allylic alkylation with a malonate nucleophile. Subsequent decarboxylation and iodolactonization gave 33, which was converted into the target compound in four well-precedented synthetic steps.…”

Unified Strategy to Prostaglandins: Chemoenzymatic Total Synthesis of Cloprostenol, Bimatoprost, PGF2α, Fluprostenol, and Travoprost Guided by Biocatalytic Retrosynthesis

“…Our study commenced with the development of a feasible BVMO-catalyzed stereoselective oxidation of 6a, which has not yet been reported, to the best of our knowledge. In contrast, bicyclo[3.2.0]hept-2-en-6-one (14), a bicyclic ketone lacking the dichloro functionality in comparison to 6a, was routinely employed as the model substrate in BVMO-catalyzed oxidation reactions (Scheme S2) [50][51][52] . A regiodivergent conversion of 14 has been observed for most BVMOs, resulting in the formation of the enantioenriched NL 15 and AL 16 in similar amounts (Scheme S2).…”

“…Because of their valuable medicinal applications and unique chemical structures, tremendous efforts have been devoted to the efficient synthesis of PGs [1][2][3] . In fact, since Corey's landmark synthesis of prostaglandin F2 (PGF2, 3) in the late 1960s 4 , PGs have become one touchstone of state-of-the-art synthetic methodologies [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] , as exemplified in the elegant synthesis recently reported by the groups of Aggarwal 3,5-7 , Hayashi [8][9][10][11][12] , Stoltz 13 , Fletcher 14 , and Baran 23 . Very recently, our group has developed an efficient and modular synthesis of PGs (Scheme S1) 24 .…”

Development of a synthetic equivalent of α,α-dicationic acetic acid leading to unnatural amino acid derivatives via tetrafunctionalized methanes

“…The acidic methylene group readily generates enolate, which reacts with up to two electrophiles, and subsequent hydrolysis and decarboxylation lead to the formation of α,α-disubstituted acetic acids (Scheme 1, upper). 1,2 Through this process, diethyl malonate serves as a synthetic equivalent of α,α-dianionic acetic acid (Fig. 1, upper).…”