Synthesis of the C1-C15 region of palmerolide A using refined claisen-type addition-bond cleavage methodology

Article abstract of DOI:10.1055/s-0029-1218565

Synthesis of the eastern hemisphere (C1-C15) of palmerolide A is described. A re-optimized Claisen-type condensation of vinylogous acyl triflates provides efficient entry into the C1-C8 subunit, setting up a convergent Horner-Wittig olefination to deliver the eastern portion of palmerolide A.

Full text of DOI:10.1055/s-0029-1218565

LETTER
223
Synthesis of the C1–C15 Region of Palmerolide A Using Refined Claisen-Type
Addition–Bond Cleavage Methodology
Synthesis of the
C
1
a
–C15
R
egi
v
on of Palme
i
rolide
A
d M. Jones, Gregory B. Dudley*
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA
Fax +1(850)6448281; E-mail: gdudley@chem.fsu.edu
Received 14 September 2009
efficient synthesis of the key fragments thus becomes a
priority. Recent methodology in our lab can contribute.
Abstract: Synthesis of the eastern hemisphere (C1–C15) of pal-
merolide A is described. A re-optimized Claisen-type condensation
of vinylogous acyl triflates provides efficient entry into the C1–C8
subunit, setting up a convergent Horner–Wittig olefination to deliv-
er the eastern portion of palmerolide A.
HWE or metathesis
O
1
esterification
O
Key words: vinylogous acyl triflate, fragmentation, total synthesis,
palmerolide, methodology
H
N
22
19
7
O
enamide
OH
synthesis
HWE or RCM
HO
15
cross-
coupling
Natural products research in the Antarctic can provide
tantalizing leads for drug discovery and development.1
The isolated, cold-adapted Antarctic marine ecosystem is
dominated by invertebrate predator–prey relationships,
with interspecies chemical warfare playing a central role
in survival.2 However, an international treaty prohibits ex-
ploitation of Antarctic resources for commercial develop-
ment,3 so it falls on the research community to translate
promising discoveries into viable drug development can-
didates.
Palmerolide A,4 isolated by Baker and co-workers from
the Antarctic tunicate Synoicum adareanum, is among the
more exciting current problems in natural products syn-
thesis. It is a potent inhibitor of vacuolar ATPase
(IC50 = 2nM), and it displays selective5 cytotoxicity
against human melanoma cancer cells (NCI UACC-62,
LC50 = 18 nM). As noted above,3 chemical synthesis ap-
pears to be the only option at present for obtaining a reli-
able supply for further exploration of this exciting marine
metabolite.
O
14
palmerolide A (1)
O
NH2
Figure 1 Palmerolide A and strategic disconnections
We have been interested in the preparation of alkynyl
ketones using a tandem addition and C–C bond cleavage
reaction of vinylogous acyl triflates.7 The bond cleavage
pathway is reminiscent of the Eschenmoser–Tanabe8 and
related Grob-type9 fragmentations, but with broader
scope: the Eschenmoser–Tanabe fragmentation provides
alkynyl ketones and aldehydes from cyclic enones, where-
as vinylogous acyl triflates are suitable for the synthesis of
a diverse range of carbonyl derivatives (Scheme 1).7c,10
The two-step process – synthesis and fragmentation of
vinylogous acyl triflates – enables conversion of cyclic,
symmetrical diones into acyclic, differentially functional-
ized building blocks. Homopropargyl alcohols are avail-
able from b-keto lactones (heterocyclic diones) by a
related reaction.11
Several groups have reported on the synthesis of palm-
erolide A.6 The De Brabander6a and Nicolaou6b labs inde-
pendently described its total synthesis (and structural
reassignment) in 2007. The Maier group6c achieved a for-
mal synthesis, and several others6d–6f have disclosed syn-
thetic approaches to this important target. Most recently,
the Hall group reported a catalytic asymmetric synthesis
of palmerolide A.6h
The Claisen-type condensation of vinylogous acyl
triflates7d was originally optimized using the lithium eno-
late of acetophenone as the nucleophilic trigger. As shown
in Table 1, excess enolate (2.2 equiv) was required for
complete conversion (entries 1 and 2), and direct exten-
sion of this methodology to the synthesis of b-keto phos-
phonates 4b was not practical (entries 2 and 3).
Reoptimizing this system for the preparation of olefina-
tion reagents revealed an advantage of the phosphine ox-
ide over the phosphonate (entries 3 and 4). In stark
contrast to enolate nucleophiles, addition–bond cleavage
reaction of the lithiated phosphine oxide required only 1.1
equivalents of nucleophile (entry 5). A further reexamina-
tion of this methodology is in progress; meanwhile, we
obtained efficient access to b-keto phosphine oxide 4c12
for application towards the synthesis of palmerolide A.
The chemical synthesis of palmerolide A requires ad-
dressing several independent challenges. Hydrocarbon re-
gions isolate multiple stereogenic centers within the
macrocyclic core, which is ideal for convergent fragment
assembly strategies. Most synthetic approaches are fo-
cused on a few strategic bond disconnections (Figure 1);
SYNLETT 2010, No. 2, pp 0223–0226
x
x.
x
x.
2
0
1
0
Advanced online publication: 11.12.2009
DOI: 10.1055/s-0029-1218565; Art ID: S10509ST
© Georg Thieme Verlag Stuttgart · New York
Lindlar hydrogenation of 4c provided the corresponding
Z-olefin13 (96% yield), which was subjected to olefin

224
D. M. Jones, G. B. Dudley
LETTER
O
Table 1 Claisen-Type Condensation of Vinylogous Acyl Triflate 2
R
Me
R–M
EWG
O
Me
O
[EWG–CH2]– Li+
Me
(15)
OTf
O
Me
2
THF
OTf
NHPh
Ph
Bn
2
4
O
Me
O
Me
O
Me
Entry [EWG–CH2]–Li+ (15) 15 (equiv)
4
Yield of 4 (%)
84%
93%
73%
OLi
1a
2a
1.2
2.2
4a
56
85
Ph
OEt
MeO
15a
OMe
S
S
P
O
OLi
O
O
4a
4b
4c
4c
Me
Ph
O
Me
O
Me
Me
15a
O
P
21%
3a
4b
5b
2.2
2.2
1.1
21
Li
OMe
OMe
88%
74%
(needed for this study)
Scheme 1 Brief overview of the addition–bond cleavage reactions
of vinylogous acyl triflate 27
15b
O
P
75
Li
Ph
Ph
cross-metathesis with ethyl acrylate. The best result (87%
yield of 5) was obtained using 4 mol% of Grubbs second-
generation catalyst and a substoichiometric amount (15
mol%) of titanium tetraisopropoxide14 at 100 °C in
CH2Cl2 in a sealed tube (Scheme 2). The presumed role of
Ti(Oi-Pr)4 is to coordinate to the b-keto phosphine oxide,
which could otherwise bind to and inhibit activity of the
ruthenium metal center. Armed now with an efficient syn-
thesis of C1–C8 b-keto phosphine oxide 5, we focused on
the synthesis of C9–C15 aldehyde 8.
15c
O
P
81–89
Li
Ph
Ph
15c
a Reproduced from reference 7d.
b See Supporting Information.
7 using acetone, not CH2Cl2, as the solvent. Controlled
ester reduction using diisobutylaluminum hydride provid-
ed aldehyde 8, which was used immediately in the key
Horner–Wittig olefination (5 + 8 → 9).
The synthesis of aldehyde 8 began with Sharpless asym-
metric dihydroxylation15 of a,b-unsaturated ester 616
(Scheme 2), which produced the syn-diol17 in 75% yield
(99.6% ee). The diol was smoothly converted to acetonide
O
O
1
EtO
1. Tf2O, pyridine
95–100%
1. Lindlar H2, MeOH, 96%
O
O
2. ethyl acrylate, Grubbs II
Ti(Oi-Pr)4, CH2Cl2, 100 °C
87%
2. Ph2P(O)CH2Li
THF, –78 to 60 °C
81–89%
O
Ph
Ph
P
Ph
Ph
P
O
O
3
8
4c
5
O
O
O
DIBAL-H
1. AD-mix-α, 75%, 99.6% ee
O
O
9
OEt
H
OEt
2. 2,2-dimethoxypropane
CSA, acetone, 99%
CH2Cl2
95–100%
O
O
15
6
7
8
O
O
1
EtO
EtO
1. (R)-CBS, THF
89%, ca. 75:25 dr
NaH (1.0 equiv), THF
7
5 + 8
O
OTBS
then 8 (1.5 equiv), 89%
2. TBSOTf, 2,6-lutidine
CH2Cl2, 94%
9
O
O
15
O
O
9
10
Scheme 2 Synthesis of the C1–C15 (eastern) portion of palmerolide A
Synlett 2010, No. 2, 223–226 © Thieme Stuttgart · New York

LETTER
Synthesis of the C1–C15 Region of Palmerolide A
225
Our approach to the C1–C15 region of palmerolide A fea-
••
EtO2C
Ph2P
EtO2C
Ph2P
EtO2C
tures a key Horner–Wittig reaction (5 + 8) to prepare the
"H+"
••
D
8,9 E-alkene. The De Brabander lab reported a similar, al-
Ph2P
beit intramolecular, olefination in their synthesis of ent-
palmerolide A (Equation 1).6a Following their lead, we in-
vestigated the intermolecular coupling of 5 and 8. Howev-
er, Michael addition of the b-keto phosphine oxide onto
the enoate (cyclization of 5) was observed using a variety
of bases (Scheme 3).18 The combination of irreversible
base (NaH) and a slight excess of aldehyde 5 gave the best
results, affording enone 9 in 89% yield.
O
O
O
O
O
O
Scheme 3
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
O
O
P
OMe
OMe
OTIPS
This research is supported by a grant from the National Science
Foundation (NSF CHE 0749918).
OHC
HO
O
O
O
References and Notes
EtO
(1) Amsler, C. D.; Iken, K. B.; McClintock, J. B.; Baker, B. J. In
Marine Chemical Ecology; McClintock, J. B.; Baker, B. J.,
Eds.; CRC Press: Boca Raton FL, 2001, 267–300.
(2) Dayton, P. K.; Mordida, B. J.; Bacon, F. Am. Zool. 1994, 34,
90.
O
K2CO3
18-crown-6
toluene, 60 °C
(De Brabander)
8
OTIPS
9
(3) Information available through the Antarctic Treaty
Secretariat: http://www.ats.aq/.
O
O
O
HO
(4) (a) Diyabalange, 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.
(c) Riesenfeld, C. S.; Murray, A. E.; Baker, B. J. J. Nat.
Prod. 2008, 71, 1812.
EtO
Equation 1 Intramolecular HWE reaction reported by De Brabander
(5) Of the NCI’s panel of 60 cancer cell lines, no other cell
line registered a cytotoxic response below micromolar
concentrations.
After olefination, CBS reduction19 of enone 9 provided
the C7 alcohol in 89% yield, albeit with only modest dias-
tereoselectivity (ca. 75:25 dr).20 The selectivity is surpris-
ing in light of a similar CBS-based reduction for which
Chandrasekhar observed 97% de. On the other hand, our
observations are in line with the 4:1 dr reported by De
Brabander for CBS reduction at C7 of a macrocyclic pre-
cursor to palmerolide A. The stereoselective reduction of
the C7 ketone remains an open challenge as we continue
with our studies. TBS protection of the C7 alcohol under
standard conditions furnished 10 in 94% yield.
(6) (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) Jägel, J.; Maier, M. E.
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(8) (a) Eschenmoser, A.; Felix, D.; Ohloff, G. Helv. Chim. Acta
1967, 50, 708. (b) Felix, D.; Shreiber, J.; Ohloff, G.;
Eschenmoser, A. Helv. Chim. Acta 1971, 54, 2896.
(c) Tanabe, M.; Crowe, D. F.; Dehn, R. L. Tetrahedron Lett.
1967, 3943. (d) Tanabe, M.; Crowe, D. F.; Dehn, R. L.;
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In summary, we have prepared 10, which comprises the
eastern hemisphere (C1–C15) of palmerolide A, in seven
linear steps (approximately 42% overall yield) from sym-
metrical dione 3. The optimized addition–bond cleavage
reaction (2 → 4c) provides an efficient entry into a com-
paratively short synthesis of a C1–C8 olefination reagent
for convergent coupling with aldehyde 8. Aldehyde 8 is
prepared in three steps and >99% ee from ester 6.15 This
sequence highlights the utility of vinylogous acyl triflates
in synthesis, and demonstrates a marked improvement
over our previously published Claisen-type condensations
of 2. Ongoing studies directed toward the total synthesis
of palmerolide A will be reported separately.
Synlett 2010, No. 2, 223–226 © Thieme Stuttgart · New York

226
D. M. Jones, G. B. Dudley
LETTER
(10) (a) For a recent application of the fragmentation of vinyl
triflates to the synthesis of allenes, see: Kolakowski, R. V.;
Manpadi, M.; Zhang, Y.; Emge, T. J.; Williams, L. J. J. Am.
Chem. Soc. 2009, 131, 12910. (b) For application of a
related ring fragmentation to the synthesis of tethered
alkynyl aldehydes, see: Draghici, C.; Brewer, M. J. Am.
Chem. Soc. 2008, 130, 3766.
(11) Tummatorn, J.; Dudley, G. B. J. Am. Chem. Soc. 2008, 130,
5050.
(12) For a recent report on the synthesis of b-ketophosphonates
using the classical Claisen condensation, with leading
references, see: Maloney, K. M.; Chung, J. Y. L. J. Org.
Chem. 2009, 74, 7574.
K.; Wang, Z. M.; Xu, D.; Zhang, X.-L. J. Org. Chem. 1992,
57, 2768. (b) For a similar reaction, see: Gurjar, M. K.;
Pramanik, C.; Bhattasali, D.; Ramana, C. V.; Mohapatra,
D. K. J. Org. Chem. 2007, 72, 6591.
(16) Prepared in two steps (one pot) from 4-pentynol (85% yield),
see: Vatele, J.-M. Tetrahedron Lett. 2006, 47, 715.
(17) See Supporting Information, compound B.
(18) Cyclization of 5 predominated using bases including
Ba(OH)2, DBU·LiCl (Masamune–Roush conditions), and
KOt-Bu. A common feature of these bases is that each is
intermediate in basicity between the initial b-keto phosphine
oxide anion and the enolate arising from undesired
cyclization onto the enoate. Therefore, the conjugate acid
may play a role in promoting undesired cyclization
(Scheme 3).
(13) See Supporting Information, compound A.
(14) (a) Fürstner, A.; Langemann, K. J. Am. Chem. Soc. 1997,
119, 9130. (b) Michaunt, A.; Boddaert, T.; Coquerel, Y.;
Rodriguez, J. Synthesis 2007, 18, 2687.
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1986.
(15) (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino,
(20) See Supporting Information, compound C.
G. A.; Hartung, J.; Jeong, K. S.; Kwong, H. L.; Morikowa,
Synlett 2010, No. 2, 223–226 © Thieme Stuttgart · New York

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