Enantioselective formal synthesis of palmerolide A

Article abstract of DOI:10.1021/ol201604c

Enantioselective formal synthesis of macrolactone palmerolide A, a polyketide marine natural product, is described. Key strategies in the synthesis include the oxidative furan ring-opening of a chiral furyl carbinol for the installation of the 1,4-dienol

Full text of DOI:10.1021/ol201604c

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4252–4255
Enantioselective Formal Synthesis of
Palmerolide A
Kavirayani R. Prasad* and Amit B. Pawar
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
prasad@orgchem.iisc.ernet.in
Received June 15, 2011
ABSTRACT
Enantioselective formal synthesis of macrolactone palmerolide A, a polyketide marine natural product, is described. Key strategies in the
synthesis include the oxidative furan ring-opening of a chiral furyl carbinol for the installation of the 1,4-dienol core and a Jung nonaldolÀaldol
reaction for the dienamide core.
A large number of natural products isolated from various
sources continue to play a pivotal role in drug discovery. In
a quest of natural products with potent activity, Baker and
co-workers isolated palmerolide A 1, a 20-membered
macrolactone from the marine tunicate Synoicum adarea-
num found in the Antarctic region.1 Palmerolide A 1
possesses seven unsaturations that include a conjugated
dienamide, conjugated diene, R,β-unsaturated ester, 1,
4-alkenol with an adjacent carbamate, and five chiral
centers. Palmerolide A is found to exhibit excellent anti-
tumor activity against melanoma cancer cells, which is
attributed to its potent inhibitory activity against vacuolar
ATPase. Owing to the useful biological profile of 1 and the
treaty that prohibits commercial exploitation of Antarctic
resources, the development of a synthetic strategy that
allows the synthesis of palmerolide A and an array of its
analogues is warranted. De Brabander’s group disclosed
the first total synthesis of 1 and revised the stereochemistry
of the natural product.2a Two more total syntheses from
the groups of Nicolaou2bÀd and Hall2e were reported
recently, while two formal syntheses3 and approaches to
various fragments of 1 have also appeared.4 Key discon-
nections in the reported syntheses include assembly of the
macrolactone core of 1 employing an intramolecular Wit-
tigÀHorner olefination, ring-closing metathesis (RCM),
intramolecular Heck reaction, and Yamaguchi lactoniza-
tion by the De Brabander, Nicolaou, Maier, and Hall
groups, respectively. Notable approaches for construction
of the 1,4-alkenol C7ÀC11 fragment include an intramo-
lecular Wittig reaction followed by reduction and a Clai-
senÀIreland rearrangement of an alkenylboronate, while
approaches for the synthesis of the C16ÀC23 fragment
include, in general, either an aldol reaction or crotylbora-
tion. Herein, we report the synthesisof1, different from the
previous reported syntheses for the installation of the
(1) (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) (a) Jagel, J.; Maier, M. E. Synthesis 2009, 2881. (b) Gowrisankar,
P.; Pujari, S. A.; Kaliappan, K. P. Chem.;Eur. J. 2010, 16, 5858.
(4) (a) Jones, D. M.; Dudley, G. B. Synlett 2010, 223. (b) Lebar,
M. D.; Baker, B. J. Tetrahedron 2010, 66, 1557. (c) Prasad, K. R.; Pawar,
A. B. Synlett 2010, 1093. (d) Kaliappan, K. P.; Gowrisankar, P. Synlett
2007, 1537. (e) Cantagrel, G.; Meyer, C.; Cossy, J. Synlett 2007, 2983. (f)
Chandrasekhar, S.; Vijeender, K.; Chandrasekhar, G.; Reddy, C. R.
(2) (a) Jiang, X.; Liu, B.; Lebreton, S.; De Brabander, J. K. J. Am.
Chem. Soc. 2007, 129, 6386. (b) Nicolaou, K. C.; Guduru, R.; Sun, Y. P.;
Banerji, B.; Chen, D. Y. K. Angew. Chem., Int. Ed. 2007, 46, 5896. (c)
Nicolaou, K. C.; Sun, Y. P.; Guduru, R.; Chen, D. Y. K. J. Am. Chem.
Soc. 2008, 130, 3633. (d) 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. (e) Penner, M.; Rauniyar, V.; Kaspar, L. T.; Hall,
D. G. J. Am. Chem. Soc. 2009, 131, 14216.
€
Tetrahedron: Asymmetry 2007, 18, 2473. (g) Jagel, J.; Schmauder, A.;
Binanzer, M.; Maier, M. E. Tetrahedron 2007, 63, 13006.
r
10.1021/ol201604c
Published on Web 07/27/2011
2011 American Chemical Society

chiral components, relying on the Jung rearrangement and
oxidative furan ring-opening of a chiral furyl carbinol.
The sketch of our approach for the synthesis of 1 is
depicted in Scheme 1. It is envisaged to construct the
macrolactone via an intramolecular Heck coupling of the
twofragments2and 3. SynthesisoftheC16ÀC23 fragment
2 is anticipated through the nonaldolÀaldol reaction
developed by Jung et al.,5 while the C1ÀC15 fragment 3
is envisioned by elaboration of the γ-ketoalkenoic acid 4
derived from the furyl carbinol 5.
Scheme 2. Synthesis of the C16ÀC23 Fragment of Palmerolide A
Scheme 1. Palmerolide A and Retrosynthesis
Accordingly, the synthetic sequence commenced with
the synthesis of allylic alcohol 8 from the known
aldehyde 66 involving a sequence of Wittig olefination
with the ylide Ph3PdC(Me)CO2Et 7 and reduction of
the resultant ester. Epoxidation of the allylic alcohol 8
under Sharpless conditions afforded the epoxide 9
(86% yield).7 Reaction of 9 under Jung reaction con-
ditions with TESOTf and iPr2NEt resulted in the alde-
hyde 10, which without further purification was treated
with the Wittig ylide 7 to afford the R,β-unsaturated
ester 11 in 60% yield for two steps. Deprotection of the silyl
ether in 11 gave the hydroxy ester 12 in 96% yield. Reduc-
tion of 12 with DIBAL-H afforded the diol 13, which on
selective protection of the primary hydroxy group as the
TBS ether furnished the required C16ÀC23 fragment 2 in
86% yield (Scheme 2).
Scheme 3. Synthesis of the γ-Ketoalkenoic Acid
For the synthesis of the C1ÀC15 fragment, transforma-
tion of the furyl carbinol 5 to the alkenoic acid 4 was
(5) (a) Jung, M. E.; D’Amico, D. C. J. Am. Chem. Soc. 1993, 115,
12208. (b) Jung, M. E.; D’Amico, D. C. J. Am. Chem. Soc. 1997, 119,
12150.
(6) (a) Marshall, J. A.; Eidam, P. Org. Lett. 2004, 6, 445. (b) Amans,
D.; Bellosta, V.; Cossy, J. Org. Lett. 2007, 9, 1453.
(7) Enatiopurity of the epoxide 9 was not determined at this stage.
However, a convincing and indirect proof for the high enantiopurity of 9
is evident from its convesrion to enantiopure 2 (Scheme 2), which
exhibited optical rotration and spectral data identical to that reported
by Nicolaou et al. (ref 2c).
€
(8) Furstner, A.; Nagano, T. J. Am. Chem. Soc. 2007, 129, 1906.
(9) For similar oxidation of furans with NBS, see: (a) Kobayashi, Y.;
Nakano, M.; Kumar, G. B.; Kishihara, K. J. Org. Chem. 1998, 63, 7505.
(b) Schreiber., S.; Berger, E. M.; Burke, M. D. J. Am. Chem. Soc. 2004,
126, 14095.
chosen as the pivotal step. Thus, 58 was transformed to the
silylether 14, which on reaction with NBS in presence of
Org. Lett., Vol. 13, No. 16, 2011
4253

anhydride method and subsequent reduction of the ketone
with NaBH4 in presence of CeCl3 afforded the alcohol 16
in good yield and in excellent stereoselectivity.10 Alcohol
16 was transformed to the corresponding MOM ether
which on reaction with 4-benzyloxybutylmagnesium bro-
mide yielded the ketone 17 in 80% yield (Scheme 3).
Reduction of 17 with an (R)-CBS reagent11 furnished a
separable mixture of alcohols in 90% yield (18/19 = 7:3).
Minor isomer 19 was converted to the required isomer 18
involving Mitsunobu inversion in 64% yield, making it a
convenient processfor thesynthesisof 18. Protection ofthe
secondary alcohol in 18 asthe MOM ether (96% yield) and
subsequent debenzylation using DDQ produced20 in 85%
yield. Oxidation of20withIBX tothe aldehyde and further
Wittig olefination of the resultant aldehyde furnished the
R,β-unsaturated ester 21 in 95% yield. Saponification of 21
with LiOH produced acid 3, the C1ÀC15 fragment of
palmerolide A (Scheme 4).
Scheme 4. Synthesis of the C1ÀC15 Fragment of Palmerolide A
After successfully procuring the alcohol and acid frage-
ments 2 and 3, esterification was effected under Yamagu-
chi conditions12 to yield the ester 22 in 91% yield. Intra-
molecular Heck coupling was performed on 22 to afford
the macrolactone 23 in 60% yield.13 Selective deprotection
of the primary silyl ether in 23 furnished the alcohol 24
(86% yield), which was converted to the vinyl iodide 25
involving oxidation to the aldehyde followed by Takai
olefination.14 Deprotection of the TBS ether in 25 and
introduction of the carbamate yielded 26 in excellent yield.
The MOM ethers were unmasked by treating 26 with
water and pyridine furnished the unsaturated aldehyde 15
in 55% yield.9 Oxidation of the aldehyde with NaClO2
afforded the required acid 4 in 93% yield. Conversion
of the acid to the Weinreb amide utilizing the mixed
Scheme 5. Formal Total Synthesis of Palmerolide A
4254
Org. Lett., Vol. 13, No. 16, 2011

TMSCl in MeOH to furnish 27 in 70% yield the
spectral data of which is in complete agreement with
that reported in literature.2c Since conversion of 27 to
palmerolide A 1 by CuI-mediated coupling with di-
methylacrylamide has been reported in literature, the
present sequence constitutes a formal total synthesis
of palmerolide A 1 (Scheme 5).
In conclusion, a formal total synthesis of palmerolide A
is accomplished from readily available furyl carbinol. The
main feature of the synthesis includes the construction of
the C1ÀC15 fragment by elaboration of the keto acid
derived from oxidation of 2-furylcarbinol. Expedient syn-
thesis of the C16ÀC23 fragment showcased the usefulness
of a Jung nonaldolÀaldol reaction.
(10) Formation of the other diastereomer was not observed within
detectable limits in the 1H NMR.
(11) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986.
(12) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989.
(13) Formation of only the E,E diene is observed within detectable
limits by NMR. For recent approaches involving intramolecular Heck
reaction in macrolactone synthesis, see: (a) Li, P.; Li, J.; Arikan, F.;
Ahlbrecht, W.; Dieckmann, M.; Menche, D. J. Am. Chem. Soc. 2009,
131, 11678. (b) Menche, D.; Hassfeld, J.; Li, J.; Rudolph, S. J. Am.
Chem. Soc. 2007, 129, 6100. (c) Menche, D.; Hassfeld, J.; Li, J.; Mayer,
K.; Rudolph, S. J. Org. Chem. 2009, 74, 7220. (d) Li, P.; Li, J.; Arikan,
F.; Ahlbrecht, W.; Dieckmann, M.; Menche, D. J. Org. Chem. 2010, 75,
2429.
Acknowledgment. This paper is dedicated with warmth
and respect to Prof. Dr. Dieter Hoppe, of University of
Muenster, Germany, on the occasion of his 70th birthday.
We thank the Department of Science and Technology
(DST), New Delhi, for funding of this project. K.R.P. is
a Swarnajayanthi fellow of DST. A.B.P. thanks the Coun-
cil of Scientific and Industrial Research (CSIR), New
Delhi, for a research fellowship.
Supporting Information Available. Full experimental
procedures and NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
(14) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408.
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