Neopeltolide is a marine macrolide that was isolated from a deep-sea sponge of the Neopeltidae family by Wright and coworkers (Scheme 1).[1] The gross structure, including the relative stereochemistry, was determined based on extensive 2D-NMR analysis. Recently, two independent total syntheses of this natural product, from the research groups of Panek [2] and Scheidt, [3] have resulted in the stereochemical reassignment of the originally proposed structure 1 and the unambiguous determination of the absolute stereostructure, as represented by structure 2 (Scheme 1). Two additional reports on the total synthesis of 2 have appeared to date. [4,5] The intriguing biological activity of 2 includes extremely potent inhibition of the in vitro proliferation of the A-549 human lung adenocarcinoma, the NCI-ADR-RES human ovarian sarcoma, and the P388 murine leukemia cell lines with nanomolar IC 50 values. Additionally, this natural product is a potent inhibitor of the growth of the fungal pathogen Candida albicans (MIC 0.62 mg mL À1 ). However, the molecular mode of action of this intriguing natural product has yet to be elucidated because of its limited supply from the natural sources. Herein we report an efficient total synthesis of (+)-neopeltolide (2) that exploits a Suzuki-Miyaura coupling/ ring-closing metathesis (RCM) sequence for the synthesis of 2,4,6-trisubstituted tetrahydropyrans. [6,7] Our plan for the synthesis of 2 is summarized in Scheme 2. Mitsunobu reaction [8] of macrolactone 3 with oxazole-containing carboxylic acid 4 [9] accompanied by inversion of the configuration at C5 would afford 2. In turn, 3 could be derived from tetrahydropyran 5 through macrolactonization under the Yamaguchi conditions.[10] For the construction of the 2,4,6-trisubstituted tetrahydropyran substructure found in 5, all of the previous total syntheses of 2 involved either intra-or intermolecular cyclization reaction via an oxocarbenium ion. In contrast, we envisioned that 5 could be constructed by Suzuki-Miyaura coupling of enol phosphate 6 and alkylborate 7 (generated in situ from iodide 8) [11] and subsequent RCM.[12] Therefore, the highly functionalized tetrahydropyran 5 could be rapidly elaborated from the readily available acyclic precursors 6 and 8.The synthesis of enol phosphate 6 started with the asymmetric allylation [13] of aldehyde 9, giving alcohol 10 in 98 % yield (Scheme 3). Protection of 10 as its MPM ether was followed by olefin cross-metathesis, [14] providing enoate 11 in 58 % yield. After reduction of 11 to allylic alcohol 12 (80 %), Sharpless asymmetric epoxidation delivered epoxide 13 in 97 % yield as a single diastereomer, which was elaborated to Scheme 1. The proposed and revised structures of neopeltolide.Scheme 2. Retrosynthetic analysis of (+)-neopeltolide (2). BOM = benzyloxymethyl, MPM = 4-methoxyphenylmethyl, TIPS = triisopropylsilyl.

The stereocontrolled total synthesis of the originally proposed (1) and correct (2) structures of (+)-neopeltolide, a novel marine macrolide natural product with highly potent antiproliferative activity against several cancer cell lines as well as potent antifungal activity, has been achieved by exploiting a newly developed Suzuki-Miyaura coupling/ring-closing metathesis strategy. Alkylborate 44, which was generated in situ from iodide 34, was coupled with enol phosphate 8 by a Suzuki-Miyaura coupling. Ring-closing metathesis of the derived diene 45 followed by stereoselective hydrogenation afforded tetrahydropyran 47 as a single stereoisomer in high overall yield from 34. Our convergent strategy enabled us to construct the 14-membered macrolactone core structure of 2 in a rapid and efficient manner. Total synthesis and biological evaluation of synthetic intermediates and designed synthetic analogues, performed to establish the structure-activity relationships of 2, led to the discovery of a structurally simple yet potent cytotoxic analogue, 9-demethylneopeltolide (54).

Neopeltolide is a marine macrolide that was isolated from a deep-sea sponge of the Neopeltidae family by Wright and coworkers (Scheme 1).[1] The gross structure, including the relative stereochemistry, was determined based on extensive 2D-NMR analysis. Recently, two independent total syntheses of this natural product, from the research groups of Panek [2] and Scheidt, [3] have resulted in the stereochemical reassignment of the originally proposed structure 1 and the unambiguous determination of the absolute stereostructure, as represented by structure 2 (Scheme 1). Two additional reports on the total synthesis of 2 have appeared to date. [4,5] The intriguing biological activity of 2 includes extremely potent inhibition of the in vitro proliferation of the A-549 human lung adenocarcinoma, the NCI-ADR-RES human ovarian sarcoma, and the P388 murine leukemia cell lines with nanomolar IC 50 values. Additionally, this natural product is a potent inhibitor of the growth of the fungal pathogen Candida albicans (MIC 0.62 mg mL À1 ). However, the molecular mode of action of this intriguing natural product has yet to be elucidated because of its limited supply from the natural sources. Herein we report an efficient total synthesis of (+)-neopeltolide (2) that exploits a Suzuki-Miyaura coupling/ ring-closing metathesis (RCM) sequence for the synthesis of 2,4,6-trisubstituted tetrahydropyrans. [6,7] Our plan for the synthesis of 2 is summarized in Scheme 2. Mitsunobu reaction [8] of macrolactone 3 with oxazole-containing carboxylic acid 4 [9] accompanied by inversion of the configuration at C5 would afford 2. In turn, 3 could be derived from tetrahydropyran 5 through macrolactonization under the Yamaguchi conditions.[10] For the construction of the 2,4,6-trisubstituted tetrahydropyran substructure found in 5, all of the previous total syntheses of 2 involved either intra-or intermolecular cyclization reaction via an oxocarbenium ion. In contrast, we envisioned that 5 could be constructed by Suzuki-Miyaura coupling of enol phosphate 6 and alkylborate 7 (generated in situ from iodide 8) [11] and subsequent RCM.[12] Therefore, the highly functionalized tetrahydropyran 5 could be rapidly elaborated from the readily available acyclic precursors 6 and 8.The synthesis of enol phosphate 6 started with the asymmetric allylation [13] of aldehyde 9, giving alcohol 10 in 98 % yield (Scheme 3). Protection of 10 as its MPM ether was followed by olefin cross-metathesis, [14] providing enoate 11 in 58 % yield. After reduction of 11 to allylic alcohol 12 (80 %), Sharpless asymmetric epoxidation delivered epoxide 13 in 97 % yield as a single diastereomer, which was elaborated to Scheme 1. The proposed and revised structures of neopeltolide.Scheme 2. Retrosynthetic analysis of (+)-neopeltolide (2). BOM = benzyloxymethyl, MPM = 4-methoxyphenylmethyl, TIPS = triisopropylsilyl.

No abstract

No abstract