A Concise Total Synthesis of the Non‐peptide Bradykinin B1 Receptor Antagonist Velutinol A

Abstract

A concise route to the bradykinin B1 receptor antagonist velutinol A, a natural product isolated from the rhizomatous of mandevilla velutina (Apocynaceae), has been developed. This synthesis features the highly regioselective construction of Δ 14 silyl enol ether 13 from diol 8a followed by stereoselective introduction of a sterically hindered β-hydroxy group at the C14 position by Rubottom oxidation. A prolonged reaction time and the presence of an excess amount of mCPBA

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“…Asymmetric dihydroxylation of 23 with hydroquinine 2,5‐diphenyl‐4,6‐pyrimidinediyl diether ((DHQ) 2 Pyr)8 gave the desired diol 24 a in 77 % yield and diastereomer 24 b in 10 % yield. As previously reported,7 the use of TBSOTf and Et 3 N to protect the 15,16‐diol moiety of 24 a as the TBS ether resulted in the formation of enol 25 as the sole product in 82 % yield 10. Selective hydrolysis of the silyl enol ether moiety of 25 by HCl (1 M aq.)…”

“…As shown in the scheme, the retrosynthetic analysis begins with the deconstruction of the cage‐like frame in the D, E, and F rings of 18 to afford diketo‐diol precursor 19 . Diketo‐diol 19 would be derived from known olefin 22 7 through intermediate 21 via the following three operations: 1) Sharpless asymmetric dihydroxylation8 to set the C16 stereocenter, 2) Baeyer–Villiger oxidation to construct the seco ‐structure, and 3) Wacker oxidation9 to introduce the 17‐oxo‐group. Despite this rather simple strategy, the primary challenge for the synthesis of the argeloside aglycone was handling the easy‐to‐aromatize structure of the β,γ‐dihydroxyketone moiety in 19 , together with the construction of the structurally equivalent F‐ring moiety in 19 10.…”

“…We started the synthesis with the known olefin 23 (Scheme ) 7. Asymmetric dihydroxylation of 23 with hydroquinine 2,5‐diphenyl‐4,6‐pyrimidinediyl diether ((DHQ) 2 Pyr)8 gave the desired diol 24 a in 77 % yield and diastereomer 24 b in 10 % yield.…”

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“…Initial attempts to achieve this oxidation by exposure of ketone 14 to 2‐iodoxybenzoic acid (IBX)30 or through synthesis of an α‐bromo ketone were not successful. The same remained true for a protocol involving the treatment of a cyclic triisopropylsilyl (TIPS) enol ether with Pearlman’s catalyst in the presence of t BuOOH under an O 2 atmosphere 31. Contrarily, α‐selenylation was straightforward (Scheme ).…”

“…The same remained true for aprotocol involving the treatment of ac yclic triisopropylsilyl (TIPS) enol ether with Pearlman's catalyst in the presence of tBuOOH under an O 2 atmosphere. [31] Contrarily, a-selenylation was straightforward (Scheme 4). Upon oxidation of the resulting selenium species, the desired elimination occurred, but was accompanied by aB ayer-Villiger oxidation to yield bicycle 15.…”