Total Synthesis and Structure Revision of the Marine Metabolite Palmerolide A

Abstract

A unique natural product termed palmerolide A was recently isolated from the Antarctic marine tunicate Synoicum adareanum by Baker and coworkers. 1 The structure and absolute stereochemistry of palmerolide A, expressed by formula 1 (Scheme 1), was solved by NMR studies and reveals a 20-membered macrolide decorated with a poly-unsaturated N-acyl dienamine side chain distinct from the N-acyl enamine found in salicylihalamide and related natural products. 2 Palmerolide is a differential cytotoxin with an activity profile that correlates to VATPase inhibitors. 1 Subsequent in vitro studies confirmed that palmerolide A is indeed a potent inhibitor of bovine brain VATPase (IC 50 ∼2 nM). 1, 3 Palmerolide was isolated from an organism found in one of the most inaccessible areas of the world, and in conjunction with commercial exploitation prohibited by the 'Antarctic Treaty' will severely limit access to this compound from natural sources. 4 Therefore, total synthesis remains as the only option to assure investigation of palmerolide's promising antitumor properties. Herein, we present our synthetic efforts that led to the conclusion that (-)-palmerolide A is in fact a diastereomer of the proposed structure 1, i.e. structure ent-24 (Scheme 4).We envisioned constructing palmerolide from fragments 2-4 via cross-coupling (3 + 4), followed by esterification with enoic acid 2 -a fragment with a keto-phosphonate positioned to induce macrocyclization via Horner-Wadsworth-Emmons olefination (Scheme 1). A Curtius rearrangement followed by isocyanate-trapping with 2-Me-propenylmagnesium bromide will install the sensitive N-acyl dienamine functionality at the final stages. 5The synthesis of fragment 3 began by a vinylogous Mukaiyama aldol addition of vinylketene silyl N,O-acetal 5 6 to aldehyde 6 7 according to Kobayashi et al. 6 to furnish alcohol 7 in excellent yield and diastereoselectivity (Scheme 2). 8 A Mitsunobu inversion provided the desired syn-isomer 8. Simultaneous reductive cleavage of the auxiliary and the benzoate provided an aldehyde that was homologated with PPh 3 CHCO 2 Me. Cross-coupling partner 3 was thus obtained in 49% overall yield from 5.The synthetic equivalent of fragment 4, alkenylboronate 13, was derived from D-arabitol. Benzylidene acetal formation and oxidative α-diol cleavage yielded aldehyde 9 (Scheme 3). 9 Silylation, Wittig homologation and hydrogenation gave diol 11. Bis-silylether formation and ester reduction then provided aldehyde 12 -a material that was condensed with pinacol dichloromethylboronate (CrCl 2 , LiI) to yield vinylboronate 13. 10 E-mail: jef.debrabander@utsouthwestern.edu. Supporting Information Available: Experimental procedures and characterization data for new compounds (PDF, CIF). This material is available free of charge via the Internet at http://pubs.acs.org. propenylmagnesium bromide to the isocyanate generated from heating acyl azide 21 yielded 22 (76%). NIH Public AccessSelective trimethylsilyl ether deprotection enabled introduction of the carbamate at C11 (23, 95%) 18 ...

Catalyzed Vinylogous Mukaiyama Aldol Reactions with Controlled Enantio‐ and Diastereoselectivities

“…[5,6] As part of our ongoing studies on the use of sulfoximines in metal catalysis, [7] we recently reported that C 1 -symmetric amino sulfoximines 1 and oxazolinyl sulfoximines 2 were effective ligands in asymmetric copper catalyses. [8][9][10] We now describe the use of sulfoximine 1 a in copper-catalyzed VMARs between various cyclic dienol silanes and ketonic electrophiles.…”

The Vinylogous Mukaiyama Aldol Reaction in Natural Product Synthesis

“…In a synthetic approach toward the fascinating natural product (−)-zampanolide (68), l-serine methyl ester (64) was subjected to a one-pot reduction/VMAR for the construction of fragment 67 to avoid epimerization at the stage of the aldehyde (Scheme 2.16) [36]. The VMAR coupling was efficiently carried out via a three-step one-pot protocol [37], where 64 was first reduced to aldehyde 65 according to a racemization-free operation [DIBAL-H and TiCl 2 (O i Pr) 2 mixture] and the aldehyde was subjected in situ to the subsequent vinylogous aldol reaction.…”

“…One of the most challenging approaches in this field is probably the total synthesis of palmerolide A (144). It is noteworthy that the independent and contemporaneous development of VMAR products 142 and 143 in 2007-2008 by Nicolaou [62,63] and De Brabander [64] demonstrates the extreme viability and sustainability of this process (Scheme 2.34). The VMAR of 140 with aldehyde 141 under the conditions described by Kobayashi produced hydroxy vinyl iodide 142 in 83% yield and 89% de.…”

Stereoselective Vinylogous Mukaiyama Aldol Reaction of .ALPHA.-Haloenals

“…Indeed, VMAR has successfully been utilized in natural product syntheses by many groups [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] including ourselves. [21][22][23][24][25] However, a,b-unsaturated aldehyde is not generally a good substrate for VMAR in terms of yield (i.e., low to moderate).…”