Catalytic asymmetric synthesis of palmerolide a via organoboron methodology

Article abstract of DOI:10.1021/ja906429c

(Chemical Equation Presented) A catalytic enantioselective synthesis of the antimelanoma marine natural product (-)-palmerolide A was accomplished using a longest sequence of 21 steps and without resorting to stoichiometric chiral auxiliaries or the chiral pool. The right half was constructed with a new variant of the Claisen-Ireland rearrangement exploiting an alkenylboronate as a masked hydroxyl. The left half featured the first application of a diol·SnCl₄-catalyzed enantioselective crotylboration in the context of a complex target. This distinct strategy could pave the way to the design of simplified analogues of palmerolide.

Full text of DOI:10.1021/ja906429c

Published on Web 09/17/2009
Catalytic Asymmetric Synthesis of Palmerolide A via Organoboron Methodology
Marlin Penner, Vivek Rauniyar, Ludwig T. Kaspar, and Dennis G. Hall*
Department of Chemistry, UniVersity of Alberta, Edmonton, AB T6G 2G2, Canada
Received July 30, 2009; E-mail: dennis.hall@ualberta.ca
Numerous natural products and their synthetic derivatives are used
as pharmaceutical drugs.1 Ongoing efforts to identify new substances
with extraordinary properties have recently uncovered palmerolide A
(1), a complex polyunsaturated macrolide isolated by Baker and co-
workers from a marine invertebrate (Synoicum adareanum) found in
the Antarctic Ocean.2 Palmerolide A embeds five stereogenic centers
and seven unsaturations, including a dienamide. It demonstrates a very
potent and unusually selective antitumor activity when assayed with
melanoma cell lines, and its potency is ascribed to a low-nanomolar
inhibition of vacuolar ATPase.2 The need for treatment of metastatic
melanoma is dire, as few cancers are as aggressive and current
chemotherapies are rarely effective.3 Because the ecosystem from
which palmerolide A originates is remote and fragile, the development
of efficient synthetic routes could ensure its supply or lead to improved
analogues. Groups led by De Brabander4 and Nicolaou and Chen5
revised the stereochemistry of palmerolide A and achieved total
syntheses of its correct structure. Approaches to various fragments were
also reported.6 Taking those reports into account, we envisioned a
distinct retrosynthesis of 1 that would exploit catalytic asymmetric
organoboron methodologies developed in our group for C-C bond
formation and control of the four secondary carbinols.
3-boronoacrolein pinacolate (6) serving the dual functions of hetero-
diene and substrate for allylboration with intermediate cycloadduct 7:
The construction of fragment 2 required as a precursor the sensitive
ꢀ,γ-unsaturated aldehyde 8 (Scheme 1).4,5 Enantioselective E-crotylbo-
ration7 of freshly distilled 8 catalyzed by p-F-Vivol[7] ·SnCl4 produced
the anti propionate 9 in a remarkable yield of 95% with 90% ee.11
Inversion of configuration with concomitant protection of the secondary
alcohol gave 10. This step was followed by oxidative cleavage of the
terminal alkene and Wittig olefination; the resulting unsaturated ester 11
was further extended to give dienoate 12. In turn, the alkenyl iodide unit
of 12 was extended into iodobutadiene 2 in a high-yielding three-step
sequence based on a Sonogashira coupling and alkyne hydrozirconation.
Scheme 1
Figure 1. Structure of (-)-palmerolide A (1) and proposed retrosynthesis.
The projected retrosynthesis of Figure 1 foresaw a macrolacton-
ization preceded by a convergent assembly of two fragments, 2 and
3, via an sp2-sp3 B-alkyl Suzuki coupling. The left fragment 2
contains a syn propionate unit that could be accessed using our chiral
Brønsted acid-catalyzed enantioselective crotylboration methodology.7
It was thought that the right, 13-carbon fragment 3 could be derived
from pyran 4, which would originate from an unprecedented
Claisen-Ireland [3,3] rearrangement on an alkenylboronate substrate,
5.8 This strategy would exploit the boronate substituent as a masked
alcohol and provide the requisite differentiation of the C11 secondary
alcohol over those of C10 and C7. Precursor 5 would come from our
enantioselective hetero[4 + 2] cycloaddition/allylboration reaction9
catalyzed by Jacobsen’s chiral chromium complex (eq 1),10 with
The synthesis of fragment 3 began with the preparation of pyranyl
alkenylboronate 13 via a catalytic enantioselective hetero[4 + 2]
cycloaddition/allylboration involving 2 mol of 6 and ethyl vinyl ether
(Scheme 2).9 Acylation of the alcohol with 14 afforded the requisite
precursor for the key Claisen-Ireland rearrangement.8 Subsequent
formation of enolsilane 15 required 2 equiv of base (the first equivalent
most likely being trapped by the Lewis acidic boronate), and warming
the mixture triggered the desired rearrangement to give 16. As depicted
9
14216 J. AM. CHEM. SOC. 2009, 131, 14216–14217
10.1021/ja906429c CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3
in the chairlike transition structure (15), the diastereoselectivity was
controlled by the configuration of C8. Without delay, the alkylboronate
group of crude product 16 was oxidized with retention of stereochem-
istry to give 17, and the carboxylic acid was esterified by treatment
with diazomethane to produce 18 as a single stereoisomer with a good
overall yield of 55% over five stages.12 From 18, an efficient sequence
led to terminal alkene 21. Finally, hydrolysis of the acetal and a Wittig
olefination of the resulting hydroxyaldehyde gave fragment 3 after
silylation of the C7 hydroxyl.
Scheme 2
The left half featured the first application of a Vivol ·SnCl4-catalyzed
enantioselective crotylboration in the context of a complex target. This
distinct strategy centered on organoboron methodology could pave the
way to the design of simplified analogues of palmerolide.
Acknowledgment. This work was funded by the Natural Sciences
and Engineering Research Council (NSERC) of Canada and the
University of Alberta. The authors thank NSERC (M.P.) and the
Alberta Ingenuity Foundation (M.P., V.R.) for graduate scholarships
and the DAAD (Germany) for a postdoctoral fellowship to L.T.K.
We also thank Blake Lazurko for the HPLC purification of synthetic
1, Mark Miskolzie for help with NMR spectroscopy, and Dr. Robert
McDonald for the X-ray crystallographic analysis.12
Supporting Information Available: Full experimental details and
reproductions of NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2007, 70, 461.
(2) (a) Diyabalanage, T.; Amsler, C. D.; McClintock, J. B.; Baker, B. J. J. Am.
Chem. Soc. 2006, 128, 5630. (b) Lebar, M. D.; Baker, B. J. Tetrahedron
Lett. 2007, 48, 8009.
(3) Prisant, L. M. J. Clin. Pharmacol. 2008, 48, 225.
(4) Jiang, X.; Liu, B.; Lebreton, S.; De Brabander, J. K. J. Am. Chem. Soc.
2007, 129, 6386.
(5) (a) Nicolaou, K. C.; Guduru, R.; Sun, Y. P.; Banerji, B.; Chen, D. Y. K.
Angew. Chem., Int. Ed. 2007, 46, 5896. (b) Nicolaou, K. C.; Sun, Y. P.;
Guduru, R.; Chen, D. Y. K. J. Am. Chem. Soc. 2008, 130, 3633. (c)
Nicolaou, K. C.; Leung, Y. C. G.; Dethe, D. H.; Guduru, R.; Sun, Y. P.;
Lim, C. S.; Chen, D. Y. K. J. Am. Chem. Soc. 2008, 130, 10019.
(6) (a) Kaliappan, K. P.; Gowrisankar, P. Synlett 2007, 1537. (b) Cantagrel,
G.; Meyer, C.; Cossy, J. Synlett 2007, 2983. (c) Chandrasekhar, S.;
Vijeender, K.; Chandrasekhar, G.; Reddy, C. R. Tetrahedron: Asymmetry
2007, 18, 2473. (d) Ja¨gel, J.; Schmauder, A.; Binanzer, M.; Maier, M. E.
Tetrahedron 2007, 63, 13006. Formal synthesis: (e) Ja¨gel, J.; Maier, M. E.
Synthesis 2009, 2881.
The key B-alkyl Suzuki coupling of fragments 2 and 3 was
successful, giving 22 in 50-77% unoptimized yield (Scheme 3).
Selective hydrolysis of the methyl ester set the stage for the Yamaguchi
macrolactonization, which occurred uneventfully to produce 23 in 90%
yield. Transformation of the dienoate of 23 into dienamide 24 through
a Curtius rearrangement followed the approach of De Brabander and
co-workers.4 The synthesis of 1 was then completed via nucleophilic
cleavage of the PMB ether, carbamate formation, and simultaneous
deprotection of the C7 and C10 hydroxyls. Although these final
operations were not yet optimized, a sufficient amount of purified
sample was obtained to confirm the authenticity of synthetic 1.13
This total synthesis of (-)-palmerolide A was accomplished from
6 in a longest sequence of 21 steps (0.8% overall yield) without
resorting to stoichiometric chiral auxiliaries or the chiral pool. The
right half was constructed with a new variant of the Claisen-Ireland
rearrangement exploiting an alkenylboronate as a masked hydroxyl,
which provided the requisite differentiation of two secondary carbinols.
(7) (a) Rauniyar, V.; Hall, D. G. Angew. Chem., Int. Ed. 2006, 45, 2426. (b)
Rauniyar, V.; Zhai, H.; Hall, D. G. J. Am. Chem. Soc. 2008, 130, 8481. (c)
Rauniyar, V.; Hall, D. G. J. Org. Chem. 2009, 74, 4236.
(8) (a) Burke, S. D.; Fobare, W. F.; Pacofsky, G. J. J. Org. Chem. 1983, 48,
5221. (b) Pietruszka, J.; Scho¨ne, N. Eur. J. Org. Chem. 2004, 5011.
(9) (a) Gao, X.; Hall, D. G. J. Am. Chem. Soc. 2003, 125, 9308. (b) Gao, X.;
Hall, D. G.; Deligny, M.; Favre, A.; Carreaux, F.; Carboni, B. Chem.sEur.
J. 2006, 12, 3132.
(10) Gademann, K.; Chavez, D. E.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2002, 41, 3059.
(11) The reported7c p-F-Vivol[8] · SnCl4 catalyst gave 95% yield and 84% ee.
(12) The relative stereochemistry of 18 was determined by X-ray crystallographic
analysis of the C10 p-nitrobenzoate (CCDC 742294).
(13) See details and comparison of spectral data in the Supporting Information.
JA906429C
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