Total synthesis and structure revision of the marine metabolite palmerolide A

Article abstract of DOI:10.1021/ja0715142

We describe a highly convergent and flexible synthesis of the novel antarctic marine metabolite palmerolide Aan effort leading to a reformulation of palmerolide A as ent-24, the enantiomer of the C19,C20-bis-epimer of the original proposed structure 1. Our total synthesis features a highly stereoselective vinylogous Mukaiyama aldol reaction to introduce the C19,C20-stereodiad, an efficient Suzuki cross-coupling to install the endocyclic diene unit, and an intramolecular Horner-Wadsworth-Emmons olefination to close the macrocycle. Starting from fragments 2, 3 (ent-3), and 13 (prepared in five to eight steps each, 38-70% overall yield) the synthesis of the proposed structure 1 and the enantiomer of palmerolide A (24) was completed in an additional 14 steps (22 steps longest linear sequence). Copyright

Full text of DOI:10.1021/ja0715142

Published on Web 04/26/2007
Total Synthesis and Structure Revision of the Marine Metabolite
Palmerolide A
Xin Jiang, Bo Liu, Sylvain Lebreton, and Jef K. De Brabander*
Department of Biochemistry and Harold C. Simmons ComprehensiVe Cancer Center, The UniVersity of Texas
Southwestern Medical Center at Dallas, 5323 Harry Hines BouleVard, Dallas, Texas 75390-9038
Received March 3, 2007; E-mail: jef.debrabander@utsouthwestern.edu
Scheme 1
A unique natural product termed palmerolide A was recently
isolated from the antarctic marine tunicate Synoicum adareanum
by Baker and co-workers.1 The structure and absolute stereochem-
istry of palmerolide A, expressed by formula 1 (Scheme 1), was
solved by NMR studies and reveals a 20-membered macrolide
decorated with a polyunsaturated 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 V-ATPase
inhibitors.1 Subsequent in vitro studies confirmed that
palmerolide A is indeed a potent inhibitor of bovine brain V-ATPase
(IC50 ≈ 2 nM).1,3 Palmerolide was isolated from an organism
found in one of the most inaccessible areas of the world,
which 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 ensure investigation of palmerolide’s
Scheme 2
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, that is, 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 olefi-
nation (Scheme 1). A Curtius rearrangement followed by isocyan-
ate-trapping with 2-Me-propenylmagnesium bromide will
install the sensitive N-acyl dienamine functionality at the final
Scheme 3 a
stages.5
The synthesis of fragment 3 began by a vinylogous Mukaiyama
aldol addition of vinylketene silyl N,O-acetal 56 to aldehyde 67
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 PPh3CHCO2Me. 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
R-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 (CrCl2,
LiI) to yield vinylboronate 13.10
After substantial experimentation, we found that Suzuki coupling
of vinyl iodide 3 and vinylboronate 13 was best performed with
catalytic Pd(PPh3)4 and thallium carbonate as the base (Scheme
4).11 The coupled diene 14 thus obtained was esterified with
fragment 2.12,13 Stirring the corresponding ester 15 in acidic MeOH
a Conditions: (a) Ph3PCHCO2Me, PhMe, reflux (99%); (b) TIPSOTf,
2,6-lutidine, CH2Cl2, 0 °C; (c) Pd/C, H2, EtOAc, room temp (95%, two
steps); (d) TESCl, imidazole, DMF, room temp (93%); (e) DIBAL, CH2Cl2,
-78 °C (93%); (f) CrCl2, LiI, THF, room temp (84%).
then provided diol 16. Selective oxidation14 of the primary alcohol
followed by Horner-Wadsworth-Emmons mediated macrocy-
clization yielded macrolactone 17 (70%).15 Silylation (f 18), CBS-
reduction (f 19, dr ) 4:1),16 and protection furnished TBS-ether
20. Ester hydrolysis ((Bu3Sn)2O, 81%)17 set the stage for a Curtius
rearrangement via azide 21. Addition of 2-Me-propenylmagnesium
9
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10.1021/ja0715142 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4 a
a Conditions: (a) cat. Pd(Ph3)4, Tl2CO3, THF/H2O, room temp (79%); (b) 2, 2,4,6-Cl3BzCl, NEt3, DMAP, PhMe, room temp (69%); (c) PPTS, MeOH,
0 °C (95%); (d) PhI(OAc)2, TEMPO, CH2Cl2/H2O, room temp; (e) K2CO3, 18-crown-6, PhMe, 60 °C (70%, two steps); (f) TMSCl, Et3N, cat. DMAP,
CH2Cl2, room temp (91%); (g) (S)-CBS, BH3, THF, -40 °C (99%); (h) TBSOTf, 2,6-lutidine, CH2Cl2, -78 °C (94%); (i) (Bu3Sn)2O, PhMe, 80 °C (81%);
(j) (PhO)2P(O)N3, NEt3, benzene, room temp (92%); (k) benzene, reflux; (l) 2-Me-1-propenylmagnesium bromide, -78 °C (76%, two steps); (m) HF‚py, py,
THF, room temp (95%); (n) Cl3CC(O)NCO, CH2Cl2, 0 °C; Al2O3, room temp (95%); (o) TBAF, THF, 0 °C (41%).
Supporting Information Available: Experimental procedures and
characterization data for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
bromide to the isocyanate generated from heating acyl azide 21
yielded 22 (76%).
Selective trimethylsilyl ether deprotection enabled intro-
duction of the carbamate at C11 (23, 95%),18 an operation that was
followed by fluoride-mediated deprotection to afford target structure
1. Unfortunately, the NMR data obtained for 1 was incongruent
with those reported for the natural isolate, indicating that the relative
stereochemical assignment needed to be revisited.1
References
(1) Diyabalanage, T.; Amsler, C. D.; McClintock, J. B.; Baker, B. J. J. Am.
Chem. Soc. 2006, 128, 5630.
(2) For a review see: Yet, L. Chem. ReV. 2003, 103, 4283.
(3) Xie, X.-S.; Padron, D.; Liao, X.; Wang, J.; Roth, M. G.; De Brabander,
J. K. J. Biol. Chem. 2004, 279, 19755.
Confidence in the stereochemical assignment of synthetic 1 was
founded on (1) Mosher ester analysis of C7-alcohol 19,19 (2) C10,
C11 stereochemistry from D-arabitol, and (3) X-ray analysis of
fragment 7 (C19,20 stereochemistry).8 The natural absolute con-
figuration at C7 and C10 was ascertained by Mosher ester analysis.1
The relative C10-C11 and C19-C20 stereochemistry of natural
palmerolide A also seemed founded on solid footing, including
J-based H-H and C-H coupling constant analysis, and NOE-
difference spectroscopy.1 In contrast, we found the interpretation
of the ROESY data parlaying stereochemistry from C11 to C19
less convincing1 and decided to funnel our synthetic efforts toward
diastereomer 24. Its synthesis followed the chemistry outlined in
Scheme 4 but starting with the enantiomer of vinyl iodide 3,
ent-3.19
(4) For a description of the Antarctic Treaty, see the Antarctic Treaty
Secretariat website: http://www.ats.aq/.
(5) Wu, Y.; Liao, X.; Wang, R.; Xie, X.-S.; De Brabander, J. K. J. Am. Chem.
Soc. 2002, 124, 3245.
(6) Shirokawa, S.-I.; Kamiyama, M.; Nakamura, T.; Okada, M.; Nakazaki,
A.; Hosokawa, S.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 13604.
(7) Marshall, J. A.; Eidam, P. Org. Lett. 2004, 6, 445.
(8) The absolute stereochemistry of 7 was confirmed by crystallographic
analysis, see the Supporting Information.
(9) Urbansky, M.; Davis, C. E.; Surjan, J. D.; Coates, R. M. Org. Lett. 2004,
6, 135 and references cited therein.
(10) (a) Wuts, P. G. M.; Thompson, P. A. J. Organomet. Chem. 1982, 234,
137. (b) Takai, K.; Shinomiya, N.; Kaihara, H.; Yoshida, N.; Moriwake,
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(11) Evans, D. A.; Starr, J. T. J. Am. Chem. Soc. 2003, 125, 13531.
(12) Compound 2 was prepared in five steps from δ-valerolactone (see
Supporting Information).
Gratifyingly, the NMR spectra, TLC, and analytical HPLC
behavior of synthetic 24 and natural palmerolide A are indistin-
guishable.19 To our surprise however, the synthetic and natural
isolate were not completely indistinguishable by virtue of the mirror
image CD-spectra obtained for 24 and natural palmerolide A. The
inescapable conclusion is that the structure of (-)-palmerolide A
has to be revised to structure ent-24.20 Current efforts are underway
to produce the bioactive enantiomer of palmerolide and congeners.
(13) Inanaga, J.; Hirata, K.; Saeki, H.; Kastuki, T.; Yamaguchi, M. Bull. Chem.
Soc. Jpn. 1979, 52, 1989.
(14) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J.
Org. Chem. 1997, 62, 6974.
(15) (a) Stork, G.; Nakamura, E. J. Org. Chem. 1979, 44, 4010. (b) Nicolaou,
K. C.; Seitz, S. P.; Pavia, M. R.; Petasis, N. A. J. Org. Chem. 1979, 44,
4011. (c) Packard, G. K.; Hu, Y.; Vescovi, A.; Rychnovsky, S. D. Angew.
Chem., Int. Ed. 2004, 43, 2822.
(16) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986.
(17) Mata, E. G.; Mascaretti, O. A. Tetrahedron Lett. 1988, 29, 6893.
(18) (a) Kocovsky, P. Tetrahedron Lett. 1986, 27, 5521. (b) Hung, D. T.;
Nerenberg, J. B.; Schreiber, S. L. J. Am. Chem. Soc. 1996, 118, 11054.
(19) See Supporting Information for details.
Acknowledgment. This work was supported by the NIH (Grant
CA90349), the Robert A. Welch Foundation, and Merck Research
Laboratories. We thank Dr. R. Akella for crystallographic analysis
and Prof. B. Baker for a sample of natural palmerolide and helpful
discussions regarding palmerolide stereochemistry.
(20) Prof. Baker informed us that their reported1 absolute stereochemical
assignment is in doubt because of erroneous Cahn-Ingold-Prelog
prioritization of their Mosher ester derivatives.
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