Formal synthesis of palmerolide A, featuring alkynogenic fragmentation and syn-selective vinylogous aldol chemistry

Article abstract of DOI:10.1021/ol400014e

An enantioselective route to palmerolide A is described. The approach features original syntheses of three subunits, which are then assembled to produce a known late-stage intermediate and formally provide the highest overall yield of the natural product

Full text of DOI:10.1021/ol400014e

ORGANIC
LETTERS
2013
Vol. 15, No. 4
886–889
Formal Synthesis of Palmerolide A,
Featuring Alkynogenic Fragmentation and
syn-Selective Vinylogous Aldol Chemistry
Marilda P. Lisboa, David M. Jones,† and Gregory B. Dudley*
Department of Chemistry and Biochemistry, Florida State University, Tallahassee,
Florida 32306-4390, United States
gdudley@chem.fsu.edu
Received January 2, 2013
ABSTRACT
An enantioselective route to palmerolide A is described. The approach features original syntheses of three subunits, which are then assembled to
produce a known late-stage intermediate and formally provide the highest overall yield of the natural product reported to date. Recent innovations
in alkynogenic fragmentation and vinylogous aldol methodology figure prominently in the synthesis of the C1ꢀC15 and C16ꢀC25 subunits,
respectively.
Macrolides from the palmerolide1 family of Antarctic
marine natural products are important targets for chemical
synthesis. Preliminary cytotoxicity assays indicate that these
compounds may be valuable for melanoma research,2 and
chemical synthesis is likely the best option for producing a
reliable supply of palmerolide A and congeners.3 Pioneering
efforts from groups led by De Brabander4 and Nicolaou/Chen5
resulted in the total synthesis, structural reassignment, and
several synthetic analogs6 of palmerolide A. Hall and co-
workers elegantly leveraged organoboron chemistry to
achieve a third total synthesis,7 and the Maier,8 Kaliappan,9
and Prasad10 laboratories have each formally completed
synthetic routes to palmerolide A. Several groups,11 including
(6) (a) Nicolaou, K. C.; Sun, Y.-P.; Guduru, R.; Banerji, B.; Chen, D.
Y.-K. J. Am. Chem. Soc. 2008, 130, 3633–3644. (b) Nicolaou, K. C.;
Leung, G. Y. C.; Dethe, D. H.; Guduru, R.; Sun, Y.-P.; Lim, C. S.; Chen,
D. Y.-K. J. Am. Chem. Soc. 2008, 130, 10019–10023. (c) Ravu, V. R.;
Leung, G. Y. C.; Lim, C. S.; Ng, S. Y.; Sum, R. J.; Chen, D. Y.-K. Eur. J.
Org. Chem. 2011, 463–468.
(7) Penner, M.; Rauniyar, V.; Kaspar, L. T.; Hall, D. G. J. Am.
Chem. Soc. 2009, 131, 14216–14217.
(8) Jaegel, J.; Maier, M. E. Synthesis 2009, 2881–2892.
† Current address: Dow AgroSciences, 9330 Zionsville Rd, Indianapolis,
IN 46268.
(1) (a) Diyabalanage, T.; Amsler, C. D.; McClintock, J. B.; Baker,
B. J. J. Am. Chem. Soc. 2006, 128, 5630–5631. (b) Lebar, M. D.; Baker,
B. J. Tetrahedron Lett. 2007, 48, 8009–8010. (c) Riesenfeld, C. S.;
Murray, A. E.; Baker, B. J. J. Nat. Prod. 2008, 71, 1812–1818. (d)
Noguez, J. H.; Diyabalanage, T.; Miyata, Y.; Xie, X.-S.; Valeriote,
F. A.; Amsler, C. D.; McClintock, J. B.; Baker, B. J. Bioorg. Med. Chem.
2011, 19, 6608–6614.
(2) The LC50 of palmerolide A against UACC-62 (melanoma) cells is
18 nM. Nanomolar activity was reported for other palmerolides and
against other melanoma cell lines in the NCI’s 60-cell line panel, whereas
activity against nonmelanoma cell lines did not drop below micromolar
levels. See ref 1.
(3) Geographical barriers and geopolitical restrictions make the
natural source effectively inaccessible. The Antarctic Treaty (http://
www.ats.aq) prohibits exploitation of Antarctic resources, which would
include harvesting of the Antarctic tunicate Synoicum adareanum to
secure large quantities of palmerolide A.
(4) Jiang, X.; Liu, B.; Lebreton, S.; De Brabander, J. K. J. Am. Chem.
Soc. 2007, 129, 6386–6387.
(5) Nicolaou, K. C.; Guduru, R.; Sun, Y.-P.; Banerji, B.; Chen, D. Y.-K.
(9) (a) Gowrisankar, P.; Pujari, S. A.; Kaliappan, K. P. Chem.;Eur.
J. 2010, 16, 5858–5862. (b) Pujari, S. A.; Gowrisankar, P.; Kaliappan,
K. P. Chem.;Asian J. 2011, 6, 3137–3151.
(10) (a) Prasad, K. R.; Pawar, A. B. Org. Lett. 2011, 13, 4252–4255.
(b) Prasad, K. R.; Pawar, A. B. Chem.;Eur. J. 2012, 18, 15202–15206.
(11) (a) Kaliappan, K. P.; Gowrisankar, P. Synlett 2007, 1537–1540.
(b) Chandrasekhar, S.; Vijeender, K.; Chandrashekar, G.; Reddy, C. R.
Tetrahedron: Asymmetry 2007, 18, 2473–2478. (c) Jaegel, J.; Schmauder,
A.; Binanzer, M.; Maier, M. E. Tetrahedron 2007, 63, 13006–13017. (d)
Cantagrel, G.; Meyer, C.; Cossy, J. Synlett 2007, 2983–2986. (e) Lebar,
M. D.; Baker, B. J. Tetrahedron 2010, 66, 1557–1562. (f) Jones, D. M.;
Dudley, G. B. Synlett 2010, 223–226. (g) Prasad, K. R.; Pawar, A. B.
Synlett 2010, 1093–1095. (h) Lisboa, M. P.; Jeong-Im, J. H.; Jones,
D. M.; Dudley, G. B. Synlett 2012, 23, 1493–1496. (i) Wen, Z.-K.; Xu,
Y.-H.; Loh, T.-P. Chem.;Eur. J. 2012, 18, 13284–13287.
Angew. Chem., Int. Ed. 2007, 46, 5896–5900.
r
10.1021/ol400014e
Published on Web 02/01/2013
2013 American Chemical Society

ours,11f,h have reported approaches to palmerolide A and,
more recently, to palmerolide C.12 Collectively, these studies
provide insight into how one might generate significant
quantities of synthetic palmerolides, but no current route
reportedly produces palmerolide A in greater than 1% over-
all yield.
acyl triflate 5,13 part of our ongoing alkynogenic fragmenta-
tion methodology,14 to prepare alkynyl ketone 615 on a multi-
gram scale (98%, two steps).16 Conversion of 6 into 2 is
achieved by Lindlar semihydrogenation of the alkyne (6 f 7,
90%), followed by Grubbs cross-metathesis (7 f 2, 82%).
The cross-metathesis event optimally requires adding tita-
nium tetraisopropoxide, which likely prevents the Lewis
basic β-keto phosphonate from binding to the ruthenium
metal center and inhibiting metathesis.17
Scheme 1. Retrosynthetic Analysis: Identification of Three Key
Subunits for Assembly to Palmerolide A
The synthesis of aldehyde 3 (Scheme 3) begins with
Sharpless asymmetric dihydroxylation of known enoate
8,18 as we previously reported (75%, 99.6% ee).11f Here the
alkyne serves as a masked alkene to avoid potential
regioselectivity problems in the dihydroxylation. After
the diol is in place, Lindlar semihydrogenation reveals
the terminal alkene (98%), and the diol is converted to
the p-methoxyphenyl (PMP) methylidene acetal (98%) to
give rise to ester 9. Treatment of 9 with excess DIBAL
results in ester reduction and reductive acetal ring opening
to give PMB-protected triol 10 (92%). The regioselective
formation of 10 is consistent with internal coordination of
an aluminum alkoxide (from ester reduction) to the prox-
imal acetal oxygen to guide the reductive ring-opening
event (cf. 9a).19 The primary alcohol of 10 is temporarily
masked as a pivalate ester (93%), which is later removed
using DIBAL after installing the secondary TIPS ether
(92%, two steps). DessꢀMartin oxidation (95%) then
affords aldehyde 3.
The consensus synthetic strategy for palmerolide A
involves the convergent assembly of key subunits, but the
questions of which subunits and how best to prepare and
assemble them remain open. Here we disclose original,
efficient, and stereoselective syntheses of key subunits 2, 3,
and 4 (Scheme 1). We also describe how to assemble these
subunits in good overall yield to provide macrolactone 1, a
late-stage intermediate in the Hall synthesis.7 This work
moves us significantly closer to the goal of developing a
practical, scalable synthesis of palmerolide A; unresolved
tactical challenges are presented and discussed throughout
the manuscript.
The third subunit, iodide 4 (Scheme 4), is available using
Kalesse’s new syn-selective variant20 of the Kobayashi
vinylogous aldol reaction.21 Coupling of chiral N,O-ketene
acetal 1120a with iodo-aldehyde 1222 in the presence of
titanium tetrachloride provides 13 (69%). Many different
tactics have been reported for controlling the C19ꢀC20
stereochemistry,4ꢀ12 but this syn-selective vinylogous aldol
(13) Lisboa, M. P.; Hoang, T. T.; Dudley, G. B. Org. Synth. 2011, 88,
353–363.
(14) (a) Kamijo, S.; Dudley, G. B. J. Am. Chem. Soc. 2005, 127, 5028–
5029. (b) Kamijo, S.; Dudley, G. B. Org. Lett. 2006, 8, 175–177.
(c) Jones, D. M.; Kamijo, S.; Dudley, G. B. Synlett 2006, 936–938.
(d) Kamijo, S.; Dudley, G. B. J. Am. Chem. Soc. 2006, 128, 6499–6507.
(e) Tummatorn, J.; Dudley, G. B. J. Am. Chem. Soc. 2008, 130, 5050–
5051. (f) Tummatorn, J.; Dudley, G. B. Org. Lett. 2011, 13, 158–160. (h)
Tummatorn, J.; Dudley, G. B. Org. Lett. 2011, 13, 1572–1575.
(15) Jones, D. M.; Lisboa, M. P.; Kamijo, S.; Dudley, G. B. J. Org.
Chem. 2010, 75, 3260–3267.
Scheme 2. Synthesis of Phosphonate 2a
(16) All yields refer to isolated quantities of material purified by
column chromatography on silica gel or other methods and judged to be
g95% pure by 1H NMR spectroscopic analysis; see Supporting Infor-
mation for details. For a commentary on the limitations of reporting
yields by these and related techniques, see: Wernerova, M.; Hudlicky, T.
Synlett 2010, 2701–2707.
€
(17) (a) Furstner, A.; Langemann, K. J. Am. Chem. Soc. 1997, 119,
9130–9136. (b) Michaunt, A.; Boddaert, T.; Coquerel, Y.; Rodriguez, J.
Synthesis 2007, 18, 2687–2871.
(18) Prepared in two steps (one pot) from 4-pentynol (85% yield); see:
a See Supporting Information for complete experimental details.
ꢀ
Vatele, J.-M. Tetrahedron Lett. 2006, 47, 715–718.
(19) For a related example, see: Heapy, A. M.; Wagner, T. W.;
Brimble, M. M. Synlett 2007, 15, 2359–2362.
The synthesis of each of the three subunits is illustrated in
Schemes 2ꢀ4, respectively. For phosphonate 2 (Scheme 2),
we use nucleophile-triggered fragmentation of vinylogous
(20) (a) Symkenberg, G.; Kalesse, M. Org. Lett. 2012, 14, 1608–1611.
(b) Mukaeda, Y.; Kato, T.; Hosokawa, S. Org. Lett. 2012, 14, 5298–
5301.
(21) Shirokawa, S.-i.; Kamiyama, M.; Nakamura, T.; Okada, M.;
Nakazaki, A.; Hosokawa, S.; Kobayashi, S. J. Am. Chem. Soc. 2004,
126, 13604–13605.
(12) Florence, G. J.; Wlochal, J. Chem.;Eur. J. 2012, 18, 14250–
14254.
(22) Marshall, J. A.; Eidam, P. Org. Lett. 2004, 6, 445–448.
Org. Lett., Vol. 15, No. 4, 2013
887

Scheme 3. Synthesis of Aldehyde 3a
Scheme 4. Synthesis of Iodide 4a
a See Supporting Information for complete experimental details.
Mitsunobu inversion with p-nitrobenzoic acid (74%) and
selective cleavage of the p-nitrobenzoate ester (in the
presence of the ethyl ester) with sodium azide in methanol
(84%).27 Attempts to produce 15 selectively using reagent
control have not yet been successful, and we continue to
seek practical solutions to this challenge.28 Silylation and
saponification of 15 give acid 17, the C1ꢀC15 section of
palmerolide A.
Esterification of acid 17 with alcohol 4using the Yamaguchi
procedure (91%) is followed by Heck macrocyclization
(59%) toprovide 1. The Maierlab8 reporteda similarHeck
cyclization in the context of their formal synthesis of
palmerolide A, and Hall and co-workers7 converted
macrolactone 1 into the natural product in six additional
steps (8% yield).
In summary, innovative routes to three key subunits (2,
3, and 4) have been developed, and these subunits have
been assembled to produce 1, an advanced precursor of
synthetic palmerolide A. We have prepared macrolactone
1 in 16% overall yield by a linear sequence of 16 steps
from 4-pentynol, plus two auxiliary steps to invert alcohol
16 f 15.
Diastereoselective C7 ketone reduction is perhaps the
most overt challenge that remains to be addressed, and
refinement of the protecting group strategy is also in order:
late-stage cleavage of the PMB and TIPS ethers are
reportedly inefficient (16% combined). Improvements in
these two areas would impact the quantitativemetrics (e.g.,
step-count and overall yield) associated with the efficiency
of this route. A third challenge relates to the instability of
iodo-aldehyde 12, which imposes practical constraints
on the otherwise ideal Kalesse vinylogous aldol reaction
(11 f 13).
a See Supporting Information for complete experimental details. PMP =
p-methoxyphenyl.
reaction is perhaps ideal for the task at hand. N,O-Ketene
acetal 11 is robust and easy to handle and delivers the
desired C19ꢀC20 syn-isomer with excellent diastereo-
selectivity,23 so 11 is a valuable building block for con-
struction of the palmerolide side chain. Iodo-aldehyde 12,
on the other hand, is unstable to storage, and it has a
propensity to decompose even during the course of the
reaction. We use excess 12 for the preparation of 13, but
alternative solutions could be useful here.24 Homologation
of 13 is achieved by DIBAL reduction of the imide and
Wittig olefination of the resulting aldehyde to furnish
subunit 4 (67%, two steps).
Our assembly of the three subunits is presented in
Scheme 5. HornerꢀWadsworthꢀEmmons (HWE) reac-
tion of 2 and 3 was initially confounded by a tendency of
phosphonate 2 to undergo base-mediated cyclization onto
the tethered Michael acceptor (i.e., the unsaturated ester).
Barium hydroxide25 effectively suppresses the Michael-
type intramolecular cyclization of 2 in favor of the desired
intermolecular HWE olefination of aldehyde 3 to generate
enone 14 in excellent yield (96%).
Borohydride reduction of 14 provides diastereomeric
alcohols 15 and 16 (93%) in an approximately 1:1 ratio.
These isomers are separable by chromatography on silica
gel;26 the undesired isomer (16) can be converted into 15 by
(23) Based on 1H NMR analysis, we estimate the diastereoselectivity
of the aldol reaction to be 97:3. The minor product is removed during
chromatographic purification.
(24) In our hands, subunits 2 and 3 are significantly easier to prepare
on a large scale than subunit 4. This factor contributed to our strategic
decision to introduce subunit 4 last during the assembly process.
(25) (a) Alvarezibarra, C.; Arias, S.; Banon, G.; Fernandez, M. J.;
Rodriguez, M.; Sinisterra, V. J. J. Chem Soc., Chem. Commun. 1987,
1509–1511. (b) Paterson, I.; Yeung, K.-S.; Smaill, J. B. Synlett 1993,
774–776. For recent examples of using Ba(OH)2 for HWE reactions, see:
(c) Crimmins, M. T.; Shamszad, M.; Mattson, A. E. Org. Lett. 2010, 12,
2614–2617. (d) Crimmins, M. T.; O’Bryan, E. A. Org. Lett. 2010, 12,
The remaining challenges not withstanding, this work
marks a significant step toward the goal of providing
cost-effective access to synthetic palmerolide A. Virtues
of this formal synthesis include the nucleophile-triggered
€
ꢁ
4416–4419. (e) Giannis, A.; Heretsch, P.; Sarli, V.; Stossel, A. Angew.
(27) Gomez-Vidal, J. A.; Forrester, M. T.; Silverman, R. B. Org.
Chem., Int. Ed. 2009, 48, 7911–7914. (f) Winbush, S. M.; Mergott, D. J.;
Roush, W. R. J. Org. Chem. 2008, 73, 1818–1829.
(26) Purification of the crude mixture on silica gel afforded pure 15
(38%), pure 16 (39%), and mixed fractions (15%) that were collected
and repurified separately. See Supporting Information.
Lett. 2001, 3, 2477–2479.
(28) See ref 10 for related efforts using reagent control. We also
explored the option of deferring this reduction until after the Heck
cyclization to the macrolactone, but the cyclic ketone turns out to be a
highly mismatched case; see also ref 4, pp S19ꢀS20.
888
Org. Lett., Vol. 15, No. 4, 2013

Scheme 5. Assembly of Subunits 2, 3, and 4 To Complete the Formal Synthesis of Palmerolidea
a See Supporting Information for complete details and experimental conditions.
alkynogenic fragmentation (5f6) en route to subunit 2,
the efficient barium hydroxide-mediated HWE coupling
(2 þ 3 f 14), a concise synthesis of subunit 4 by new
vinylogous aldol chemistry, and facile annulation by the
Yamaguchi/Heck sequence to deliver macrolactone 1.
Efforts to resolve the issues outlined above and to generate
useful quantities of synthetic palmerolide A are in progress
and will be fully disclosed in due course.
0749918) and by the FSU Department of Chemistry and
Biochemistry. M.P.L. is a recipient of the CAPES-Fulbright
Graduate Research Fellowship (2008). We are profoundly
grateful to these agencies for their support.
Supporting Information Available. Experimental pro-
cedures, characterization data, and copies of NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This research was supported by a
grant from the National Science Foundation (NSFꢀCHE
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 4, 2013
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