Total synthesis of the originally proposed and revised structures of palmerolide A and isomers thereof

Article abstract of DOI:10.1021/ja710485n

Palmerolide A is a recently disclosed marine natural product possessing striking biological properties, including potent and selective activity against the melanoma cancer cell line UACC-62. The total syntheses of five palmerolide A stereoisomers, including the originally proposed (1) and the revised [ent-(19-epi-20-epi-1)] structures, have been accomplished. The highly convergent and flexible strategy developed for these syntheses involved the construction of key building blocks 2, 19-epi-2, 20-epi-2, ent-2, 3, ent-3, 4, and enf-4, and their assembly and elaboration to the target compounds. For the union of the building blocks, the Stille coupling reaction, Yamaguchi esterification, Horner-Wadsworth-Emmons olefination, and ring-closing metathesis reaction were employed, the latter being crucial for the stereoselective formation of the macrocycle of the palmerolide structure. The Horner-Wadsworth-Emmons olefination and the Yamaguchi lactonization were also investigated and found successful as a means to construct the palmerolide macrocycle. The syntheses were completed by attachment of the enamide moiety through a copper-catalyzed coupling process.

Full text of DOI:10.1021/ja710485n

Published on Web 02/26/2008
Total Synthesis of the Originally Proposed and Revised
Structures of Palmerolide A and Isomers Thereof
K. C. Nicolaou,* Ya-Ping Sun, Ramakrishna Guduru, Biswadip Banerji, and
David Y.-K. Chen*
Contribution from Chemical Synthesis Laboratory@Biopolis, Institute of Chemical and
Engineering Sciences (ICES), Agency for Science, Technology and Research (A*STAR),
11 Biopolis Way, The Helios Block, #03-08, Singapore 138667
Received November 20, 2007; E-mail: kcn@scripps.edu; david_chen@ices.a-star.edu.sg
Abstract: Palmerolide A is a recently disclosed marine natural product possessing striking biological
properties, including potent and selective activity against the melanoma cancer cell line UACC-62. The
total syntheses of five palmerolide A stereoisomers, including the originally proposed (1) and the revised
[ent-(19-epi-20-epi-1)] structures, have been accomplished. The highly convergent and flexible strategy
developed for these syntheses involved the construction of key building blocks 2, 19-epi-2, 20-epi-2, ent-
2, 3, ent-3, 4, and ent-4, and their assembly and elaboration to the target compounds. For the union of the
building blocks, the Stille coupling reaction, Yamaguchi esterification, Horner-Wadsworth-Emmons
olefination, and ring-closing metathesis reaction were employed, the latter being crucial for the stereoselective
formation of the macrocycle of the palmerolide structure. The Horner-Wadsworth-Emmons olefination
and the Yamaguchi lactonization were also investigated and found successful as a means to construct the
palmerolide macrocycle. The syntheses were completed by attachment of the enamide moiety through a
copper-catalyzed coupling process.
Introduction
in its structural revision through the total synthesis of its
enantiomer (De Brabander et al.)3a and then in its total synthesis
Treacherous habitats often harbor creatures that produce
secondary metabolites possessing extraordinary molecular ar-
chitectures and distinct biological properties that contribute to
the organisms’ survival and continuing existence. Palmerolide
A (1, originally proposed structure, Figure 1) is such a
compound. Isolated from circumpolar tunicate Synoicum adar-
eanum collected from around Anvers Island on the Antarctic
Peninsula, palmerolide A was reported by the Baker group in
2006.1 This naturally occurring substance was found to exhibit
potent cytotoxicities against the melanoma cancer cell line
UACC-62 (LC50 of 18 nM). Strikingly, palmerolide A demon-
strated only modest activity against colon cancer cell line HCC-
2998 (LC50 ) 6.5 µM) and renal cancer cell line RXF 393 (LC50
) 6.5 µM) and virtually no activity against all other cell lines
tested within the 60 cell line panel of the National Cancer
Institute (NCI). This remarkable 103 in vitro selectivity index
for the melanoma cells over the most sensitive cell lines tested
prompted further evaluation of the compound, which revealed
its activity in the NCI’s hollow fiber assay and its potent
inhibitory action against vacuolar ATPase (IC50 ) 2 nM). This
biological profile correlates well with other enamide-containing
V-ATPase inhibitors.2
(Nicolaou et al.).4 In this article, we describe in detail our work
in the area that resulted in the total syntheses of the originally
proposed structure of palmerolide A (1), the revised structure
ent-(19-epi-20-epi-1), and the palmerolide A isomers 19-epi-1,
20-epi-1, and 19-epi-20-epi-1 (Figure 1).
Results and Discussion
Retrosynthetic Analysis. In view of our intended structural
and biological investigations and to assess the feasibility of a
variety of options for closing the palmerolide A macrocycle,
we opted for a modular and flexible approach as we pondered
its retrosynthetic analysis. The originally proposed palmerolide
A structure (1) is characterized by a 20-membered macrolide
system containing four E-olefinic bonds, two of which were
conjugated to each other. The macrocycle of the molecule is
adorned with four stereogenic centers carrying two hydroxyl
groups, a carbamate moiety, and a side chain, itself featuring
an additional stereogenic center and a conjugated enamide.
Shown in Scheme 1 is our general retrosynthetic analysis encom-
passing the various disconnections we applied to the molecule,
which led to the three key building blocks required for its con-
struction, fragments 2 (C16-C23), 3 (C9-C15), and 4 (C1-C8).
Relying on a Stille coupling reaction, an enamide coupling
The intriguing structural motifs and biological properties of
palmerolide A prompted synthetic studies that culminated first
(3) (a) Jiang, X.; Liu, B.; Lebreton, S.; De Brabander, J. K. J. Am. Chem. Soc.
2007, 129, 6386-6387. For another synthetic study towards palmerolide
A, see (b) Kaliappan, P. K.; Gowrisankar, P. Synlett 2007, 10, 1537-1540.
(4) Nicolaou, K. C.; Guduru, R.; Sun, Y.-P.; Banerji, B.; Chen, D. Y.-K. Angew.
Chem., Int. Ed. 2007, 46, 5896-5900.
(1) Diyabalanage, T.; Amsler, C. D.; McClintock, J. B.; Baker, B. J. J. Am.
Chem. Soc. 2006, 128, 5630-5631.
(2) Xie, X.-S.; Padron, D.; Liao, X.; Wang, J.; Roth, M. G.; De Brabander, J.
K. J. Biol. Chem. 2004, 279, 19755-19763.
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J. AM. CHEM. SOC. 2008, 130, 3633-3644
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A R T I C L E S
Nicolaou et al.
Scheme 2. Construction of C16-C23 Vinyl Iodide Fragments 2 and
ent-2a
a Reagents and conditions: (a) 7 (2.5 equiv), n-Bu2BOTf (1.0 M in
CH2Cl2, 1.2 equiv), Et3N (1.0 equiv), CH2Cl2, -78 °C, 12 h, 46% (>95%
de); (b) TBSOTf (1.2 equiv), i-Pr2NEt (1.5 equiv), CH2Cl2, 0 °C, 30 min,
84%; (c) NaBH4 (5.0 equiv), THF/H2O (5:1), 0 f 23 °C, 3 h, 66%; (d)
DMP (1.2 equiv), NaHCO3 (5.0 equiv), CH2Cl2, 23 °C, 30 min; (e)
PPh3dC(Me)CO2Et (3.0 equiv), CH2Cl2, 23 °C, 12 h, 56% for the two
steps; (f) DIBAL-H (1.0 M in toluene, 2.5 equiv), CH2Cl2, -78 °C, 30
min, 80%; (g) TBAF (1.0 M in THF, 1.5 equiv), THF, reflux, 2 h, 85%;
(h) TBSCl (1.2 equiv), Et3N (1.5 equiv), 4-DMAP (0.2 equiv), CH2Cl2, 0
f 23 °C, 2 h, 92%. Bn ) benzyl, THF ) tetrahydrofuran, OTf )
trifluoromethanesulfonate, DMP ) Dess-Martin periodinane, DIBAL-H
) diisobutylaluminum hydride, TBAF ) tetra-n-butylammonium fluoride,
4-DMAP ) 4-dimethylaminopyridine.
Figure 1. Structures of palmerolide A isomers synthesized in this work.
Scheme 1. General Retrosynthetic Analysis of Originally
Proposed Structure for Palmerolide A (1) and Building Blocks 2, 3,
and 4a
structures. Furthermore, the macrocycle could, in principle, be
forged by one of four different reactions as outlined in Scheme
1. It was our intention to explore as many of these possibilities
as possible once we had secured the required building blocks
(2-4), whose constructions were also devised with optimum
flexibility in mind with regards to stereochemical control.
Construction of Building Blocks. Having defined the
required building blocks, their constructions began in earnest.
Two syntheses of vinyl iodide 2 were developed. The first route
(Scheme 2) began with the boron-mediated syn-aldol reaction
between ethyl ketone 6, derived from (S)-(+)-4-benzyl-2-
oxazolidinone (5) (n-BuLi, EtCOCl, 92% yield),5 and vinyl
iodide aldehyde 7 (prepared in two steps from 3-butyn-1-ol,
81% yield)6 under the standard conditions (n-Bu2BOTf-Et3N)5
1
to afford â-hydroxy ketone 8 in 46% yield [>95% de, by H
NMR (600 MHz) analysis] as shown in Scheme 2. The rather
modest yield in this reaction was attributed to the sensitivity of
aldehyde 7 under the reaction conditions, and whereas a much
improved yield was obtained under TiCl4/(-)-sparteine-mediated
a MOM ) methoxymethyl; TBS ) tert-butyldimethylsilyl.
reaction, a Yamaguchi esterification, a Wittig or Horner-
Wadsworth-Emmons olefination, and an olefin metathesis, this
analysis offered the opportunity to devise one or more highly
convergent strategies toward the target molecule and related
(5) (a) Evans, D. A.; Takacs, J. M.; McGee, L. R.; Ennis, M. D.; Mathre, D.
J.; Bartroli, J. Pure Appl. Chem. 1981, 53, 1109-1127. (b) Evans, D. A.;
Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127-2129.
(6) (a) Ma, S.; Negishi, E. J. Org. Chem. 1997, 62, 784-785. (b) Roethle, P.
A.; Trauner, D. Org. Lett. 2006, 8, 345-347.
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Structures of Palmerolide A and Isomers
A R T I C L E S
conditions,7 a diastereo-random mixture (ca. 1:1) was observed
under the reaction conditions. Protection of â-hydroxy ketone
8 as its TBS ether (TBSOTf, i-Pr2NEt, 9, 84% yield), followed
by reductive removal of the oxazolidinone chiral auxiliary
(NaBH4, 66% yield) and oxidation of the resulting primary
alcohol (10) with DMP (for abbreviations of reagents and
protecting groups, see legends in schemes)8 afforded aldehyde
11. Extension of this aldehyde through Wittig reaction
[PPh3dC(Me)CO2Et, 56% yield for the two steps from 10]
followed by DIBAL-H reduction of the resulting enoate (12)
furnished allylic alcohol 13 (80% yield), whose desilylation
(TBAF, 85% yield)/resilylation (TBSCl, Et3N, 92% yield) led
to the targeted vinyl iodide 2.
Scheme 3. Alternative Synthesis of C16-C23 Vinyl Iodide
Fragments 2 and ent-2, and Construction of Anti Isomers 19-epi-2
and 20-epi-2.a
Alternatively, application of a vinylogous aldol reaction on
aldehyde 7 offered a more direct and expedient entry into the
C16-C23 backbone of vinyl iodide 2 and its isomers, as shown
in Scheme 3. Thus, the reaction of imide 15 [prepared by
unifying (R)-(+)-4-benzyl-2-oxazolidinone (ent-5) and E-2-
methyl-2-pentenoic acid in the presence of PivCl, Et3N, and
LiCl, 91% yield] with NaHMDS followed by interception of
the transient enolate with TBSCl afforded dienol silyl ether 16
in 95% yield and as a single geometrical isomer. The vinylogous
aldol reaction of 16 with aldehyde 7 under the conditions
described by Kobayashi9 (TiCl4) yielded hydroxy vinyl iodide
17 in 83% yield and in a 18:1 diastereomeric ratio (by 1H NMR
spectroscopic analysis, 600 MHz). Reductive cleavage of the
oxazolidinone moiety from 17 (LiBH4, 93% yield) afforded diol
19-epi-14, whose monosilylation (TBSCl, Et3N, 94%) yielded
vinyl iodide 19-epi-2. An oxidation (DMP, 93% yield) /
reduction [LiAlH(Ot-Bu)3, 91% yield] sequence also allowed
entry into vinyl iodide 2 through the intermediacy of ketone
18. The reduction step of this sequence proceeded in high yield
but furnished a mixture (ca. 3:1) of 2 and 19-epi-2, the two
isomers yielding to chromatographic separation after desilylation
with TBAF (87% yield). The individual diols (14 and 19-epi-
14) were then silylated at the primary position (TBSCl, Et3N,
92% yield) to afford pure vinyl iodides 2 and 19-epi-2. A similar
oxidation/reduction sequence could also be performed on alcohol
17 to obtain a C19 mixture of stereoisomers albeit with no
selectivity (ca. 1:1 ratio). Starting with ent-6 and ent-15 and
following a similar sequence as that shown in Schemes 2 and
3, the preparations of ent-2 and 20-epi-2 were also accomplished,
thus completing the set of all four stereoisomers of vinyl iodide
2.
a Reagents and conditions: (a) E-2-methyl-2-pentenoic acid (1.0 equiv),
Et3N (2.5 equiv), PivCl (1.0 equiv), CH2Cl2, -78 f 23 °C, 1 h; then ent-
5, LiCl (1.5 equiv), CH2Cl2, 23 °C, 12 h, 91%; (b) NaHMDS (1.5 equiv),
TBSCl (2.0 equiv), THF, -78 °C, 1.5 h, 95%; (c) 7 (2.0 equiv), TiCl4 (1.0
equiv), CH2Cl2, -78 °C, 19 h, 83% (18:1 dr); (d) LiBH4 (1.5 equiv), Et2O/
MeOH (20:1), 0 °C, 4 h, 93%; (e) TBSCl (1.2 equiv), Et3N (1.5 equiv),
4-DMAP (0.2 equiv), CH2Cl2, 0 f 23 °C, 2 h, 94%; (f) DMP (1.2 equiv),
NaHCO3 (5.0 equiv), CH2Cl2, 23 °C, 20 min, 93%; (g) LiAlH(Ot-Bu)3 (1.0
M in THF, 3.0 equiv), LiI (5.0 equiv), Et2O, -78 °C, 1 h, 91% (ca. 3:1
mixture of syn/anti diastereomers); (h) TBAF (1.0 M in THF, 1.2 equiv),
THF, 23 °C, 1 h, 14: (65%), 19-epi-14: (22%); (i) TBSCl (1.2 equiv),
Et3N (1.5 equiv), 4-DMAP (0.2 equiv), CH2Cl2, 0 f 23 °C, 2 h, 92%. Piv
) trimethylacetyl, NaHMDS ) sodium hexamethyldisilazide.
The vinyl stannane 3 and its enantiomer, ent-3, were prepared
from TMS acetylene aldehyde 19 as summarized in Scheme 4.
The chosen route relied on Brown’s hydroxy-crotylation tech-
nology.10 Thus, treatment of aldehyde 19 (prepared from
4-pentyn-1-ol in two steps, 90% yield)11 with in situ-generated
[(Z)-γ-(methoxymethoxy)allyl]-(-)-diisopinocampheylborane,
[(-)-20], (from methoxymethyl allyl ether, s-BuLi, (-)-Ipc2-
BOMe and BF3‚OEt2) in THF at -78 to 23 °C afforded, upon
desilylation (K2CO3, MeOH), hydroxy acetylene 21 in good
overall yield (78% for the two steps) and excellent diastereo-
1
selectivity [>95% de, H NMR spectroscopic analysis (600
1
MHz); >90% ee, H NMR (600 MHz) analysis of the corre-
sponding R and S Mosher esters].12 Attachment of the carbamate
group [Cl3CC(O)NCO, K2CO3, MeOH, 100% yield]13 onto
alcohol 21 followed by treatment with NBS and AgNO3
furnished bromide 23 (90% yield) through acetylenic 22. Finally,
exposure of 23 to n-Bu3SnH in the presence of catalytic amounts
of Pd(dba)2 led to the targeted fragment 3 in 77% yield. We
chose to adopt this two-step procedure14 to introduce the vinyl
stannane moiety into acetylene 22 (and later alkyne intermedi-
ates) as our initial attempts to directly hydrostannate acetylene
(7) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org. Chem.
2001, 66, 894-902.
(8) (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287.
(b) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(9) Shirokawa, S.; Kamiyama, M.; Nakamura, T.; Okada, M.; Nakazaki, A.;
Hosokawa, S.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 13604-13605.
(10) Brown, H. C.; Jadhav, P. K.; Bhat, K. S. J. Am. Chem. Soc. 1988, 110,
1535-1538.
(12) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512-519.
(13) Kocovsky, P. Tetrahedron Lett. 1986, 27, 5521-5524.
(14) Boden, C. D. J.; Pattenden, G.; Ye, T. J. Chem. Soc., Perkin Trans. 1 1996,
20, 2417-2419.
(11) Makabe, H.; Higuchi, M.; Konno, H.; Murai, M.; Miyoshi, H. Tetrahedron
Lett. 2005, 46, 4671-4675.
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A R T I C L E S
Nicolaou et al.
Scheme 4. Construction of C9-C15 Vinyl Stannane Fragments 3
and ent-3a
Scheme 5. Construction of C1-C8 Carboxylic Acid Fragments 4
and ent-4a
a Reagents and conditions: (a) Methoxymethyl allyl ether (1.3 equiv),
s-BuLi (1.0 equiv), THF, -78 °C, 30 min; then (-)-Ipc2BOMe (1.0 M in
THF, 1.0 equiv), -78 °C, 1 h; then BF3‚Et2O (1.25 equiv), 19 (1.0 equiv),
-78 f 23 °C, 15 h; (b) K2CO3 (3.0 equiv), MeOH, 23 °C, 7 h, 78% for
the two steps from 19; (c) trichloroacetyl isocyanate (3.0 equiv), CH2Cl2,
23 °C, 1 h; then K2CO3 (3.0 equiv), MeOH, 23 °C, 1 h, 100%; (d) NBS
(1.1 equiv), AgNO3 (0.1 equiv), acetone, 23 °C, 1 h, 90%; (e) Pd(dba)2
(0.05 equiv), PPh3 (0.2 equiv), n-Bu3SnH (2.2 equiv), THF, 23 °C, 1 h,
77%. Ipc ) isopinocampheyl, NBS ) N-bromosuccinimide, DBA )
dibenzylideneacetone.
a Reagents and conditions: (a) m-CPBA (1.3 equiv), NaHCO3 (2.0 equiv),
CH2Cl2, 0 f 23 °C, 2 h, 90%; (b) (R,R)-N,N′-bis(3,5-di-t-butylsalicylidene)-
1,2-cyclohexanediaminato(2-)]cobalt (II) (5 mol %), AcOH (0.01 equiv),
H2O (0.55 equiv), CH2Cl2, 0 f 23 °C, 24 h, 25: (43%, >90% ee), 26:
(47%, >90% ee); (c) p-TsCl (1.0 equiv), n-Bu2SnO (0.2 equiv), Et3N (1.0
equiv), CH2Cl2, 23 °C, 2 h, 78%; (d) K2CO3 (1.5 equiv), MeOH/CH2Cl2
(10:1), 0 f 23 °C, 2 h, 82%; (e) Me3S+I- (4.0 equiv), n-BuLi (1.6 M in
THF, 5.8 equiv), THF, -30 f 23 °C, 5 h, 90%; (f) MOMCl (4.0 equiv),
i-Pr2NEt (2.0 equiv), CH2Cl2, 0 f 23 °C, 6 h, 85%; (g) TBAF (1.0 M in
THF, 1.2 equiv), THF, 23 °C, 2 h, 95%; (h) DMP (1.5 equiv), NaHCO3
(5.0 equiv), CH2Cl2, 23 °C, 2 h, 95%; (i) Ph3PdCHCO2Me (1.0 equiv),
CH2Cl2, 23 °C, 16 h, 90%; (j) KOH (5.0 equiv), dioxane/H2O (4:1), 23 °C,
24 h, 85%. m-CPBA ) meta-chloroperoxybenzoic acid; p-TsCl ) para-
toluenesulfonyl chloride.
22 [Pd(PPh3)2Cl2, n-Bu3SnH] led to a mixture of regioisomeric
stannanes. In a similar fashion, ent-3 was prepared starting with
19 and employing (+)-Ipc2BOMe as shown in Scheme 4.
Fragments 4 and ent-4 were prepared from the TBS-protected
5-hexene-1-ol (24) through the application of a Jacobsen
hydrolytic kinetic resolution15a as shown in Scheme 5. Thus,
m-CPBA-mediated epoxidation of 24 (90% yield), followed by
exposure of the resulting racemic epoxide to 5 mol % of (R,R)-
N,N′-bis(3,5-di-t-butylsalicylidene)-1,2-cyclohexanediaminato-
(2-)]cobalt(II) (Jacobsen catalyst), acetic acid (0.01 equiv), and
H2O (0.55 equiv) in CH2Cl2 led to the smooth formation of
enantiomerically enriched diol 25 [43% yield, >90% ee by
measurement of its optical rotation and that of later intermediates
ent-26 and ent-27, and Mosher ester 1H NMR (600 MHz)
analysis of ent-27, vide infra] and epoxide 26 [47% yield, >90%
Assembly of Building Blocks and Completion of the Total
Synthesis of the Originally Proposed Structure of Palm-
erolide A. With all of the required building blocks in hand, we
then proceeded to assemble them toward the targeted structure
that was originally proposed for palmerolide A (1). From all of
the possible strategies, we first opted to pursue the one involving
the olefin metathesis18 reaction to construct the macrocycle of
the molecule. To that end, and as is shown in Scheme 6, vinyl
iodide 2 and vinyl stannane 3 were coupled under Stille
conditions19 [Pd(dba)2 catalyst, AsPh3, LiCl] to afford tetraene
33 in 67% yield. Presented with its free hydroxyl group at C19,
the latter compound was esterified with carboxylic acid 4 under
Yamaguchi conditions20 (2,4,6-trichlorobenzoyl chloride, Et3N,
4-DMAP) furnishing 34 in 61% yield. The same intermediate
34 could be reached from intermediates 2-4 by reversing the
order of their coupling (i.e., 2 + 4; then 3), a sequence that
proceeded through intermediate 35, which gave a higher overall
yield (59% for the two steps). From hexaene ester 34, and on
the basis of what we learned in scouting the road ahead, we
decided at this juncture to follow the sequence depicted in
Scheme 6 toward our final destination. Thus, desilylation of 34
(TBAF, 78% yield) followed by DMP oxidation of the resulting
alcohol (36, 84% yield) led to aldehyde 37, whose Takai iodo-
1
ee by Mosher ester H NMR (600 MHz) analysis of 27, vide
infra].15b The diol was converted to the primary tosylate (TsCl,
n-Bu2SnO, 32, 78% yield),16 and thence to epoxide ent-26 (K2-
CO3, MeOH, 82% yield). Epoxide 26 was reacted with the sulfur
ylide derived from Me3S+I- (n-BuLi)17 to afford hydroxy olefin
27 (90% yield), which was protected as a MOM ether (MOMCl,
i-Pr2NEt, 85% yield) and desilylated (TBAF, 95% yield), leading
to primary alcohol 29 via intermediate 28. Finally, DMP
oxidation of 29 furnished aldehyde 30 (95% yield), whose Wittig
reaction with PPh3dCHCO2Me (90% yield) led, upon saponi-
fication (KOH, 85% yield) to carboxylic acid fragment 4.
Following a similar sequence, epoxide ent-26 was converted to
ent-4 (Scheme 5).
(15) (a) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen,
K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc.
2002, 124, 1307-1315. (b) Preparation of ent-26 using an identical
procedure has been previously reported: Myers, A.; Lanman, B. A. J. Am.
Chem. Soc. 2002, 124, 12969-12971.
(16) Martinelli, M. J.; Nayyar, N. K.; Moher, E. D.; Dhokte, U. P.; Pawlak, J.
M.; Vaidyanathan, R. Org. Lett. 1999, 1, 447-450.
(17) Alcaraz, L.; Harnett, J. J.; Mioskowski, C.; Martel, J. P.; Le Gall, T.; Shin,
D.-S.; Falck, J. R. Tetrahedron Lett. 1994, 35, 5449-5452.
(18) (a) Grubbs, R. H. Tetrahedron 2004, 60, 7117-7140. (b) Nicolaou, K. C.;
Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490-4527.
(c) Gradillas, A.; Perez-Castells, J. Angew. Chem., Int. Ed. 2006, 45, 6086-
6101.
(19) Yin, L.; Liebscher, J. Chem. ReV. 2007, 107, 133-173.
(20) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem.
Soc. Jpn. 1979, 52, 1989-1993.
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Structures of Palmerolide A and Isomers
A R T I C L E S
olefination21 (CrCl2, CHI3, 80% yield) gave iododiene 38. The
obligatory removal of both MOM protecting groups prior to
the ring-closing metathesis (the ring-closing metathesis did not
proceed as we expected with the MOM groups on) proved
challenging but eventually was achieved satisfactorily under the
influence of TMSCl22 to afford diol 39 (67% yield), together
with small amounts of the cyclic carbonate byproduct 40 (10%).
With precursor 39 in hand, we were pleased to find that its
exposure to Grubbs II catalyst18a in CH2Cl2 (c ) 0.005 M) at
ambient temperature led to the formation of the much anticipated
macrocycle 41 as a single geometrical isomer and in 81% yield.
The E geometry of the newly generated double bond was proven
by 1H NMR spectroscopy (J8,9 ) 15.5 Hz). Both the requirement
of the free hydroxyl group on the ring-closing metathesis
substrate and the stereoselectivity of the ring closure are
interesting. We have no clear explanation for these observations
except for a speculation regarding coordination phenomena. The
final hurdle before arrival at the targeted structure was overcome
when dienyl iodide 41 was successfully coupled to amide 42
under the conditions developed by Buchwald et al.23 (CuI, Cs2-
CO3, and N,N′-dimethylethylenediamine), furnishing the orig-
inally proposed structure of palmerolide A (1) in 24% yield,
together with decarbamated 43 (10% yield) and recovered
starting material (41, 36%). Decarbamated 43 could be signifi-
cantly reduced by exchanging Cs2CO3 with rigorously dried (by
heating under vacuum) K2CO3, thereby furnishing 1 with an
improved yield of 31% and trace amounts of 43 (<5%).
Decarbamated 43 was also accessed via the ring-closing olefin
metathesis of cyclic carbamate 40 (Grubbs II catalyst, 72%
yield), followed by hydrolysis of the resulting cyclic carbamate
44 (Et3N-MeOH-H2O, 57% yield) and enamide coupling (42,
CuI, K2CO3, N,N′-dimethylethylenediamine, 45% yield). Whereas
43 may serve as an interesting analog for biological evaluation,
the palmerolide A structure synthesized did not exhibit the same
spectroscopic data as those reported in the isolation article.1 At
this juncture we became convinced that the originally proposed
structure for palmerolide A (1) was incorrect.
Scheme 6. Coupling of Fragments 2, 3, and 4, and Completion of
the Total Synthesis of the Originally Proposed Structure of
Palmerolide A (1) and Its Decarbamated Version 43a
Total Syntheses of Alternative Palmerolide A Structures
19-epi-20-epi-1, 19-epi-1, and 20-epi-1. Faced with the non-
identity of synthetic 1 with the natural substance, we revisited
the original publication disclosing the structure of palmerolide
A in search of alternative structures that may fit the reported
spectroscopic data.1 Whereas in that study, Mosher ester analysis
suggested the absolute configuration at C7, C10, and C11, the
stereochemical assignments of C19 and C20 were deduced
indirectly on the basis of NOE correlations for the protons
situated on the chain spanning C11 to C21. Our analysis of the
Baker spectroscopic data based on manual molecular modeling
suggested that 19-epi-20-epi-1 [possessing the 19(S),20(S)
configuration, Figure 1] also fulfilled the observed NOEs and
coupling constant (1H J19,20) observed for the natural product.
In addition to this structure, we also decided to target 19-epi-1
[19(S),20(R), Figure 1] and 20-epi-1 [19(R),20(S), Figure 1], if
nothing else, for their value in structure activity relationship
studies that we intended to carry out.
a Reagents and conditions: (a) Pd(dba)2 (0.15 equiv), AsPh3 (3.0 equiv),
LiCl (3.0 equiv), NMP, 23 °C, 12 h, 33: (67%, via 2+3), 34: (67%, via
3+35); (b) 2,4,6-trichlorobenzoyl chloride (1.1 equiv), Et3N (1.5 equiv), 4
(1.1 equiv), 4-DMAP (1.1 equiv), 23 °C, 12 h, 34: (61%, via 4+33), 35:
(88%, via 2+4); (c) TBAF (1.0 M in THF, 1.5 equiv), THF, 23 °C, 2 h,
78%; (d) DMP (1.2 equiv), NaHCO3 (5.0 equiv), CH2Cl2, 23 °C, 30 min,
84%; (e) CrCl2 (10.0 equiv), CHI3 (3.0 equiv), THF/dioxane (1:6), 23 °C,
2 h, 80% (>95:5 E/Z); (f) TMSCl (10 equiv), MeOH, 40 °C, 1 h, 39: (67%),
40: (10%); (g) Grubbs II catalyst (0.05 equiv), CH2Cl2 (c ) 0.005 M), 23
°C, 1 h, 81% (>95:5 E/Z); (h) 42 (2.0 equiv), CuI (1.5 equiv), K2CO3 (6.0
equiv), N,N′-dimethylethylenediamine (3.0 equiv), DMF, 23 °C, 1 h, 1:
(31%), 43: (<5%), 41: (10%); (i) Grubbs II catalyst (0.2 equiv), CH2Cl2
(c ) 0.005 M), 23 °C, 4 h, 72% (>95:5 E/Z); (j) Et3N/MeOH/H2O (1:5:1),
40 °C, 4 h, 57%; (k) 42 (2.0 equiv), CuI (1.5 equiv), K2CO3 (5.0 equiv),
N,N′-dimethylethylenediamine (2.0 equiv), DMF, 23 °C, 1 h, 45%. NMP
) N-methylpyrrolidone; DMF ) N,N′-dimethylformamide, TMS ) trim-
ethylsilyl.
(21) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408-
7410.
(22) Beumer, R.; Bayon, P.; Bugada, P.; Ducki, S.; Mongelli, N.; Sirtori, F. R.;
Telser, J.; Gennari, C. Tetrahedron 2003, 59, 8803-8820.
(23) Jiang, L.; Job, G. E.; Klapars, A.; Buchwald, S. L. Org. Lett. 2003, 5,
3667-3669.
9
J. AM. CHEM. SOC. VOL. 130, NO. 11, 2008 3637

A R T I C L E S
Nicolaou et al.
Scheme 7. Coupling of Building Blocks 19-epi-2, 20-epi-2, and
ent-2 with Fragments 3 and 4 to Generate Intermediates 49, 50
and 51a
Scheme 8. Elaboration of Intermediate 49 Leading to Palmerolide
A Isomer 19-epi-1 and Its Decarbamated Version 58a
a Reagents and conditions: (a) Pd(dba)2 (0.3 equiv), 3 (1.3 equiv), AsPh3
(2.0 equiv), LiCl (3.0 equiv), NMP, 23 °C, 12 h, 46: (61%), 47: (63%),
48: (50%); (b) 2,4,6-trichlorobenzoyl chloride (1.5 equiv), Et3N (5.0 equiv),
4 (1.5 equiv), 4-DMAP (1.0 equiv) 23 °C, 12 h, 49: (63%), 50: (74%),
51: (50%).
a Reagents and conditions: (a) TBAF (2.0 equiv), THF, 23 °C, 2 h, 87%;
(b) DMP (1.5 equiv), NaHCO3 (5.0 equiv), CH2Cl2, 23 °C, 30 min, 80%;
(c) CrCl2 (10.0 equiv), CHI3 (3.0 equiv), THF/dioxane (1:6), 23 °C, 2 h,
81% (>95:5 E/Z); (d) 3 N HCl/EtOH (1:5), 80 °C, 50 min, 55: (67%),
mono-deprotected products: (15%), 56: (10%); (e) Grubbs II catalyst (0.2
equiv), CH2Cl2 (c ) 0.002 M), 23 °C, 2 h, 62% (>95:5 E/Z); (f) 42 (2.0
equiv), CuI (1.0 equiv), K2CO3 (5.0 equiv), N,N′-dimethylethylenediamine
(3.0 equiv), DMF, 23 °C, 1 h, 19-epi-1: (37%), 58: (10%); (g) NaOMe
(15 equiv), MeOH, 23 °C, 2 h, 56%; (h) Grubbs II catalyst (0.2 equiv),
CH2Cl2 (c ) 0.002 M), 23 °C, 2 h, 65% (>95:5 E/Z); (i) 42 (2.0 equiv),
CuI (1.5 equiv), K2CO3 (6.0 equiv), N,N′-dimethylethylenediamine (3.0
equiv), DMF, 23 °C, 1 h, 45%.
The syntheses of 19-epi-1, 20-epi-1, and 19-epi-20-epi-1
followed the same general sequence already developed for the
originally proposed structure of palmerolide A (1). Scheme 7
outlines the assembly of the appropriate building blocks, 19-
epi-2, 20-epi-2, ent-2, and 3, to afford tetraenes 46 (61% yield),
47 (63% yield), and 48 (50% yield) through Stille coupling
reactions [Pd(dba)2 catalyst, AsPh3, LiCl], which were converted
to hexaene esters 49 (63% yield), 50 (74% yield), and 51 (50%
yield), respectively, through Yamaguchi reactions (2,4,6-trichlo-
robenzoyl chloride, Et3N, 4-DMAP) in readiness for further
elaboration at the C23 terminus to the desired vinyl iodides. As
outlined in Schemes 8-10 and starting from 49 (Scheme 8),
50 (Scheme 9), and 51 (Scheme 10), TBAF desilylation, DMP
oxidation, and Takai olefination faithfully delivered the targeted
vinyl iodides 54, 63, and 72 in 56, 56, and 50% yields,
respectively, over the three steps. Upon removal of the methoxy
methyl ethers guarding the two allylic hydroxyls (55 and 64 by
ethanolic HCl,24 and 73 by TMSCl), ring-closing metathesis
(24) Auerbach, J.; Weinreb, S. M. Chem. Commun. 1974, 8, 298-299.
9
3638 J. AM. CHEM. SOC. VOL. 130, NO. 11, 2008

Structures of Palmerolide A and Isomers
A R T I C L E S
Scheme 10. Elaboration of Intermediate 51 Leading to
Scheme 9. Elaboration of Intermediate 50 Leading to Palmerolide
A Isomer 20-epi-1 and Its Decarbamated Version 67a
Palmerolide A Isomer 19-epi-20-epi-1 and Its Decarbamated
Version 76a
a Reagents and conditions: (a) TBAF (2.0 equiv), THF, 23 °C, 2 h, 85%;
(b) DMP (1.5 equiv), NaHCO3 (5.0 equiv), CH2Cl2, 23 °C, 30 min, 81%;
(c) CrCl2 (10.0 equiv), CHI3 (3.0 equiv), THF/dioxane (1:6), 23 °C, 2 h,
81% (>95:5 E/Z); (d) 3 N HCl/EtOH (1:5), 80 °C, 50 min, 64: (62%),
mono-deprotected products: (18%), 65: (13%); (e) Grubbs II catalyst (0.2
equiv), CH2Cl2 (c ) 0.002 M), 23 °C, 2 h, 66% (>95:5 E/Z); (f) 42 (2.0
equiv), CuI (1.0 equiv), K2CO3 (5.0 equiv), N,N′-dimethylethylenediamine
(3.0 equiv), DMF, 23 °C, 1 h, 20-epi-1: (40%), 67: (11%); (g) NaOMe
(15 equiv), MeOH, 23 °C, 2 h, 55%; (h) Grubbs II catalyst (0.05 equiv),
CH2Cl2 (c ) 0.002 M), 23 °C, 2 h, 63% (>95:5 E/Z); (i) 42 (2.0 equiv),
CuI (1.5 equiv), K2CO3 (6.0 equiv), N,N′-dimethylethylenediamine (3.0
equiv), DMF, 23 °C, 1 h, 42%.
a Reagents and conditions: (a) TBAF (1.0 M in THF, 1.5 equiv), THF,
23 °C, 2 h 77%; (b) DMP (1.2 equiv), NaHCO3 (5.0 equiv), CH2Cl2, 23
°C, 30 min, 85%; (c) CrCl2 (10.0 equiv), CHI3 (3.0 equiv), THF/dioxane
(1:6), 23 °C, 2 h, 77% (>95:5 E/Z); (d) TMSCl (10 equiv), MeOH, 40 °C,
1 h, 73: (74%), 74: (12%); (e) Grubbs II catalyst (0.05 equiv), CH2Cl2 (c
) 0.005 M), 23 °C, 1 h, 80% (>95:5 E/Z); (f) 42 (2.0 equiv), CuI (1.5
equiv), K2CO3 (6.0 equiv), N,N′-dimethylethylenediamine (3.0 equiv), DMF,
23 °C, 1 h, 19-epi-20-epi-1: (55%), 76: (<5%), 75: (7%); (g) Grubbs II
catalyst (0.2 equiv), CH2Cl2 (c ) 0.005 M), 23 °C, 4 h, 76% (>95:5 E/Z);
(h) Et3N/MeOH/H2O (1:5:1), 40 °C, 6 h, 62%; i) 42 (2.0 equiv), CuI (1.5
equiv), K2CO3 (5.0 equiv), N,N′-dimethylethylenediamine (3.0 equiv), DMF,
23 °C, 1 h, 54%.
facilitated by the Grubbs II catalyst smoothly afforded macro-
cycles 57 (Scheme 8), 66 (Scheme 9), and 75 (Scheme 10) (42,
41, and 59% yields for the two steps, respectively), setting the
stage for the final installation of the enamide moiety. The later
objective was accomplished through copper-mediated coupling
with primary amide 42 under the Buchwald conditions as
described earlier (CuI, K2CO3, N,N′-dimethylethylenediamine),
furnishing 19-epi-1 (37% yield, Scheme 8), 20-epi-1 (40% yield,
Scheme 9), and 19-epi-20-epi-1 (55% yield, Scheme 10),
accompanied by their corresponding decarbamated products (58,
10% yield, Scheme 8; 67, 11% yield, Scheme 9; 76, <5% yield,
9
J. AM. CHEM. SOC. VOL. 130, NO. 11, 2008 3639

A R T I C L E S
Nicolaou et al.
Scheme 11. Coupling of Fragments 2, ent-3, and ent-4, and
Scheme 10). Decarbamated 58, 67, and 76 were also accessed
via the hydrolysis of cyclic carbamates 56, 65 (NaOMe, 59:
56% and 68:55% yield) and 77 (Et3N-MeOH-H2O, 78:62%
yield), respectively, and ring-closing metathesis (Grubbs II
catalyst, 58:65%, 66:63%, and 77:76% yields) and enamide
coupling (CuI, K2CO3, N,N′-dimethylethylenediamine; 58:45%,
67:42%, and 76:54%). We were pleased to find that, whereas
Completion of the Total Synthesis of the Revised Palmerolide A
Structure, ent-(19-epi-20-epi-1) and Its Decarbamated Version 88a
1
the H NMR spectroscopic data of 19-epi-1 and 20-epi-1 did
not match those reported for the natural product, those of 19-
epi-20-epi-1 did. It was at this juncture that we learned of the
work of De Brabander and co-workers3a in which so elegantly
they synthesized 19-epi-20-epi-1, and proposed, based on
circular dichroism (CD) measurements, its enantiomer [ent-(19-
epi-20-epi-1)] as the true structure of the natural product.25 The
latter compound [ent-(19-epi-20-epi-1)], therefore, became our
next and ultimate target for synthesis.
Total Synthesis of ent-(-19-epi-20-epi-1), the Revised
Structure of Palmerolide A. Having developed all of the
chemistry needed for the total synthesis of the revised structure
of palmerolide A, ent-(19-epi-20-epi-1) was soon reached
starting from fragments 2, ent-3, and ent-4, and proceeding as
outlined in Scheme 11. Thus, Stille coupling of vinyl iodide 2
with vinyl stannane ent-3 under the standard conditions of Pd-
(dba)2 catalyst, AsPh3, and LiCl, followed by Yamaguchi-type
esterification with ent-4, furnished hexaene ester 80 via hydroxy
tetraene 79 in 32% overall yield for the two steps. Reversing
the coupling sequence (2 + ent-4, then ent-3) also led to hexaene
80, with a much improved yield of 55% for the two steps.
Elaboration of 80 to cyclization precursor 85 through the
established, four-step sequence (34% overall yield) allowed us
to reach, through ring-closing metathesis under the Grubbs II
catalyst conditions, macrocycle 87 in 81% yield. The completion
of the synthesis of ent-(19-epi-20-epi-1) required installment
of the enamide tail, a task that was accomplished as before (42,
CuI, K2CO3, N,N′-dimethylethylenediamine, 46% yield plus
<5% of decarbamated 88 and 5-10% recovered starting
material 87). Similar to the chemistry described for the
conversion of 74 to 76 as shown in Scheme 10, cyclic carbonate
86 faithfully delivered decarbamated 88 after a three-step
sequence [(i) Grubbs II catalyst, 75% yield; (ii) Et3N-MeOH-
H2O, 65% yield; and (iii) CuI, K2CO3, N,N′-dimethylethylene-
diamine, 51% yield]. Much to our delight, and as expected,
synthetic ent-(19-epi-20-epi-1) displayed identical physical
properties (1H and 13C NMR spectra, Mass spec) to those
reported for natural palmerolide A1 and exhibited by our
synthetic 19-epi-20-epi-1. Most importantly, the matching CD
curve (Figure 2) and optical rotation (RD) of the synthetic
material with those of the natural product unambiguously
confirmed its structure.26
a Reagents and conditions: (a) Pd(dba)2 (0.15 equiv), AsPh3 (3.0 equiv),
LiCl (3.0 equiv), NMP, 23 °C, 12 h, 79: (56%, via 2+ent-3), 80: (66%,
ent-3+81); (b) 2,4,6-trichlorobenzoyl chloride (1.1 equiv), Et3N (1.5 equiv),
ent-4 (1.1 equiv), 4-DMAP (1.1 equiv), 23 °C, 12 h, 80: (58%, via ent-
4+79), 81: (84%, via 2+ent-4); (c) TBAF (1.0 M in THF, 1.5 equiv),
THF, 23 °C, 2 h, 76%; (d) DMP (1.2 equiv), NaHCO3 (5.0 equiv), CH2Cl2,
23 °C, 30 min, 84%; (e) CrCl2 (10.0 equiv), CHI3 (3.0 equiv), THF/dioxane
(1:6), 23 °C, 2 h, 79% (>95:5 E/Z); (f) TMSCl (10 equiv), MeOH, 40 °C,
1 h, 85: (67%), 86: (10%); (g) Grubbs II catalyst (0.05 equiv), CH2Cl2 (c
) 0.005 M), 23 °C, 1 h, 81% (>95:5 E/Z); (h) 42 (2.0 equiv), CuI (1.5
equiv), K2CO3 (6.0 equiv), N,N′-dimethylethylenediamine (3.0 equiv), DMF,
23 °C, 1 h, ent-(19-epi-20-epi-1): (46%), 88: (<5%), 87: (5-10%); (i)
Grubbs II catalyst (0.2 equiv), CH2Cl2 (c ) 0.005 M), 23 °C, 4 h, 75%
(>95:5 E/Z); (j) Et3N/MeOH/H2O (1:5:1), 40 °C, 6 h, 65%; (k) 42 (2.0
equiv), CuI (1.5 equiv), K2CO3 (5.0 equiv), N,N′-dimethylethylenediamine
(3.0 equiv), DMF, 23 °C, 1 h, 51%.
Having secured palmerolide A [ent-(19-epi-20-epi-1)] as
described above, we then decided to attempt the daring
maneuver of employing the olefin metathesis reaction as the
last step to construct the molecule. Such an approach required
(25) The absolute stereochemistry of C7 was also subsequently determined by
degradation of natural palmerolide A and comparison of the optical rotation
of a fragment with a synthetic sample, see, Lebar, M. D.; Baker, B. J.
Tetrahedron Lett. 2007, 48, 8009-8010.
(26) Synthetic palmerolide A [ent-(19-epi-20-epi-1)]: [R]D25 ) -95 (MeOH, c
25
) 0.12); natural palmerolide A: [R]D ) -99 (MeOH, c ) 0.24). This
value is significantly higher than that reported in the original isolation
24
paper: [R]D ) -1.6 (MeOH, c ) 0.5); see ref 1. We thank Professor
Bill J. Baker (University of South Florida, Tampa) for kindly providing us
with a sample of authentic palmerolide A.
9
3640 J. AM. CHEM. SOC. VOL. 130, NO. 11, 2008

Structures of Palmerolide A and Isomers
A R T I C L E S
Figure 2. CD spectra of 19-epi-20-epi-1 (top, CHCl3, 25 °C, 0.0013 M) and of ent-(19-epi-20-epi-1) (bottom, CHCl3, 25 °C, 0.0025 M).
Scheme 12. Total Synthesis of Palmerolide A
practical in its delivery of the palmerolide A structure, it was
of interest to us, at least for comparison purposes, to explore
[ent-(19-epi-20-epi-1)] through Olefin Metathesis as the Final Stepa
other modes of cyclization to construct the macrocycle of the
molecule. As depicted in Scheme 1, and already discussed
above, the alternative methods for macrocycle formation
included the intramolecular versions of the HWE olefination,
the Stille coupling, the Yamaguchi esterification, and the
Mitsunobu reaction. All four strategies required pre-installation
of the C8/C9 trans-olefinic linkage followed by further manipu-
lation to the appropriate macrocyclization precursors. The two
initially needed intermediates, alcohol 98 and methyl ester 99,
were synthesized as summarized in Scheme 13. Thus, the
previously synthesized (Scheme 4) hydroxy acetylene 21 was
sequentially converted to PMB ether 92 (NaH, PMBCl, 91%
yield), TMS acetylene 93 (n-BuLi, TMSCl, 92% yield), and
hydroxy derivative 94 (CBr4, i-PrOH, 69% yield).27The latter
deprotection to liberate the allylic hydroxyl group was deemed
important for the success of the intended cross-metathesis in
light of our experience with the metathesis-based ring closure
(vide supra) where a free OH group was required. Indeed, cross
a Reagents and conditions: (a) 42 (2.0 equiv), CuI (1.5 equiv), K2CO3
metathesis between allylic alcohols 94 and 27 (2.0 equiv,
(6.0 equiv), N,N′-dimethylethylenediamine (3.0 equiv), DMF, 23 °C, 1 h,
prepared as per Scheme 5) in the presence of Grubbs II catalyst
yielded the desired trans-olefin 95 in 41% yield (unoptimized),
together with the cross metathesis dimer of 27, which could be
employed instead of 27 for the cross metathesis reaction with
94, thus minimizing the losses from this side-reaction. The
conversion of 95 to 98 and 99 required further functional group
manipulations as follows: (i) TBDPSCl, imid (96, 84% yield);
(ii) AcOH, p-TsOH (97, 77% yield); (iii) NBS, AgNO3, (98,
78% yield);28 and (iv) DMP oxidation, followed by olefination
with Ph3PdCHCO2Me (99, 76% yield for the two steps).
Construction of macrocycle 105 through intramolecular HWE
olefination was the first mode of macrocyclization attempted;
the results are shown in Scheme 14. The required ester
46%; (b) Grubbs II catalyst (0.2 equiv), CH2Cl2 (c ) 0.005 M), 23 °C, 2
h, 73% (>95:5 E/Z).
octaolefin 91 (Scheme 12) as a precursor, a compound that was
obtained from vinyl iodide 85 through coupling with enamide
42 in the presence of CuI, K2CO3, and N,N′-dimethylethylene-
diamine (46% yield). Pleasantly, when subjected to the metath-
esis conditions (Grubbs II catalyst, CH2Cl2, 23 °C), octaolefin
91 underwent smooth ring closure to produce palmerolide A
[ent-(19-epi-20-epi-1)] in 73% yield. Considering the presence
of so much carbon unsaturation and several functional groups
in substrate 91, this application of the olefin metathesis reaction
is impressive indeed and demonstrates the extreme power of
this process for complex molecule construction.18b,c
(27) Lee, A. S. Y.; Hu, Y. J.; Chu, S. F. Tetrahedron 2001, 57, 2121-2126.
Alternative Macrocyclization Strategies. Whereas the ring-
closing metathesis reaction proved to be both pleasing and
(28) Nishikawa, T.; Shibuya, S.; Hosokawa, S.; Isobe, M. Synlett 1994, 7, 485-
486.
9
J. AM. CHEM. SOC. VOL. 130, NO. 11, 2008 3641

A R T I C L E S
Nicolaou et al.
Scheme 13. Construction of Enynes 98 and 99a
Scheme 14. Construction of Macrocycle 105 through
Intramolecular Horner-Wadsworth-Emmons Olefinationa
a Reagents and conditions: (a) PPh3 (0.2 equiv), Pd(dba)2 (0.1 equiv),
n-Bu3SnH (2.0 equiv), THF, 23 °C, 1 h, 89%; (b) 101 (2.0 equiv), DCC
(2.0 equiv), 4-DMAP (0.5 equiv), CH2Cl2, 23 °C, 12 h, 85%; (c) 96 (1.0
equiv), Pd(dba)2 (0.3 equiv), AsPh3 (2.0 equiv), LiCl (3.0 equiv), NMP, 23
°C, 12 h, 74%; (d) DMP (1.5 equiv), NaHCO3 (5.0 equiv), CH2Cl2, 23 °C,
20 min, 85%. DCC ) N,N′-dicyclohexylcarbodiimide.
Table 1. Construction of Macrocycle 105 via Intramolecular
Horner-Wadsworth-Emmons Olefinationa
temperature
time
(h)
yield
(%)b
a Reagents and conditions: (a) NaH (1.3 equiv), PMBCl (1.2 equiv),
DMF, 23 °C, 5 h, 91%; (b) n-BuLi (1.3 equiv), TMSCl (1.2 equiv), THF,
-70 °C, 2 h, 92%; (c) CBr4 (0.2 equiv), i-PrOH, 82 °C, 2 h, 69%; (d) 27
(2.0 equiv), Grubbs II catalyst (0.1 equiv), CH2Cl2, 23 °C, 12 h, 41% (>95:5
E/Z); (e) TBDPSCl (2.5 equiv), imidazole (8.0 equiv), DMF, 23 °C, 8 h,
84%; (f) p-TsOH (catalyst), HOAc/H2O (7:1), 23 °C, 3 h, 77%; (g) AgNO3
(1.0 equiv), NBS (1.1 equiv), acetone, 23 °C, 12 h, 78%; (h) DMP (1.5
equiv),NaHCO3 (5.0equiv),CH2Cl2,23°C,20min,86%;(i)Ph3PdCHCO2Me
(1.2 equiv), CH2Cl2, 23 °C, 12 h, 88%. PMB ) para-methoxybenzyl,
TBDPS ) tert-butyldiphenylsilyl, p-TsOH ) para-toluenesulfonic acid.
entry
base
solvent
(
°C)
1
K2CO3 (12.0 equiv)/
toluene
25
12
12
6
66
73
62
50
18-Crown-6
2
3
4
i-Pr2NEt (10.0 equiv)/ acetonitriled
25
25
LiClc
NaH (2.7 equiv)
with 4 Å MS
NaHMDS (2.0 equiv)
THF
THF
-78 f 0
2
a All reactions were carried out on 0.015 mmol scale, c ) 0.001 M,
under an argon atmosphere. b Isolated yield. c LiCl was dried over a heatgun
under vacuum for 20 min before use. d Anhydrous acetonitrile was used as
received without further distillation.
phosphonate aldehyde precursor 104 was secured through Stille
coupling [Pd(dba)2, AsPh3, LiCl, 74% yield] of vinyl stannane
100 [obtained by the Pd(dba)2-catalyzed addition of n-Bu3SnH
to bromo acetylene 98, 89% yield] with vinyl iodide 102
(prepared by the DCC esterification of hydroxy vinyl iodide 2
with carboxylic acid 101, 85% yield) followed by DMP
oxidation of the resulting hydroxy ester 103 (85% yield). Table
1 shows the four different conditions tried for the cyclization
of phosphonate aldehyde 104, all of which proved to be
successful in producing the desired E R,â-unsaturated macrolide
105 in yields ranging from 50 to 73%.3a The Masamune-Roush
protocol29 (i-Pr2NEt, LiCl) gave the best result in this instance,
making this procedure comparable with the RCM method
discussed above.
Scheme 15 depicts the construction of macrocycle 105 from
vinyl iodide vinyl stannane precursor 108 through the intramo-
lecular Stille coupling reaction. Precursor 108 was prepared from
bromo acetylene 99 by a three-step sequence involving: (i)
reaction with n-Bu3SnH in the presence of Pd(dba)2 catalyst
(to afford stannane 106); (ii) saponification with Me3SnOH30
(to afford carboxylic acid 107); and (iii) esterification with
hydroxy vinyl iodide 2 under the influence of 2,4,6-trochlo-
(29) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune,
(30) Nicolaou, K. C.; Estrada, A. A.; Zak, M.; Lee, S. H.; Safina, B. S. Angew.
Chem., Int. Ed. 2005, 44, 1378-1382.
S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183-2186.
9
3642 J. AM. CHEM. SOC. VOL. 130, NO. 11, 2008

Structures of Palmerolide A and Isomers
A R T I C L E S
Scheme 15. Construction of Macrocycle 105 through
Scheme 16. Construction of Macrocycle 105 through Yamaguchi
Intramolecular Stille Couplinga
Macrolactonizationa
a Reagents and conditions: (a) 2 (1.0 equiv), Pd(dba)2 (0.3 equiv), AsPh3
(2.0 equiv), LiCl (3.0 equiv), NMP, 23 °C, 12 h, 73%; (b) Me3SnOH (10.0
equiv), 1,2-dichloroethane, 90 °C, 12 h, 86%; (c) 2,4,6-trichlorobenzoyl
chloride (15 equiv), Et3N (20 equiv), THF, 23 °C, 2 h; then 4-DMAP (40
equiv), toluene (c ) 0.001 M), 23 °C, 12 h, 81%.
a Reagents and conditions: (a) PPh3 (0.2 equiv), Pd(dba)2 (0.1 equiv),
n-Bu3SnH (2.1 equiv), THF, 23 °C, 1 h, 68%; (b) Me3SnOH (10.0 equiv),
1,2-dichloroethane, 90 °C, 12 h, 70%; (c) 2,4,6-trichlorobenzoyl chloride
(1.5 equiv), Et3N (5.0 equiv), toluene, 23 °C, 1 h; then 2 (1.2 equiv),
4-DMAP (1.0 equiv), toluene, 23 °C, 3 h, 78%; (d) Pd(dba)2 (0.4 equiv),
AsPh3 (2.0 equiv), LiCl (3.0 equiv), NMP (c ) 0.001 M), 23 °C, 12 h,
45% (plus 22% yield at an unidentified isomer, not separable by chroma-
tography).
Scheme 17. Construction of Macrocycle 105 through Mitsunobu
Cyclizationa
Table 2. Construction of Macrocycle 105 via Mitsunobu
Cyclizationa
entry
azodicarboxylate
solvent
yield (%)b
1
2
3
4
DIAD (10.0 equiv)
DIAD (10.0 equiv)
DEAD (10.0 equiv)
DEAD (10.0 equiv)
THF
benzene
THF
NRc
NRc
113d (40)
toluene
105 (31), 114d (34)
a All of the reactions were carried out with Ph3P (10.0 equiv) in dilute
solution (0.001 M) under an argon atmosphere at 23 °C for 1.5 h. b Isolated
yield. c No reaction. d Structure was suggestive by 1H NMR and LCMS.32
DIAD ) diisopropyl azodicarboxylate; DEAD ) diethyl azodicarboxylate.
robenzoyl chloride, Et3N, and 4-DMAP (37% overall yield).
The Stille coupling-based macrocyclization of 108 proceeded
in the presence of Pd(dba)2 catalyst and AsPh3 and LiCl to afford
the desired product 105 in modest yield (67%, crude). However,
the product was accompanied by an unidentified geometric
isomer, which could not be chromatographically removed,
making this strategy unattractive for further exploitation.
In contrast to the above Stille coupling-based cyclization, the
Yamaguchi protocol proved to be highly efficient in forming
the palmerolide A macrocycle 105 as shown in Scheme 16.
Thus, seco hydroxy acid 110 was prepared by standard
chemistry involving Stille coupling of vinyl stannane 106 with
vinyl iodide 2 [Pd(dba)2 catalyst, AsPh3, LiCl] to afford pentaene
methyl ester 109 (73% yield), which was then saponified in
the presence of Me3SnOH in 86% yield. Reaction of hydroxy
acid 110 with 2,4,6-trichlorobenzoyl chloride in the presence
of Et3N and 4-DMAP furnished macrolide 105 in 81% yield,
proving this method of ring closure to be competitive with the
RCM method described above.
a Reagents and conditions: (a) 19-epi-2 (1.0 equiv), Pd(dba)2 (0.3 equiv),
AsPh3 (2.0 equiv), LiCl (3.0 equiv), NMP, 23 °C, 12 h, 71%; (b) Me3SnOH
(10.0 equiv), 1,2-dichloroethane, 90 °C, 12 h, 80%.
The final macrocyclization study, that involved the intramo-
lecular Mitsunobu31 reaction and required vinyl iodide 19-epi-2
(31) Hughes, D. L. Org. React. 1992, 42, 335-656.
9
J. AM. CHEM. SOC. VOL. 130, NO. 11, 2008 3643

A R T I C L E S
Nicolaou et al.
to deliver macrocycle 105 (as a consequence of the expected
inversion of configuration at C19), is shown in Scheme 17. Thus,
Stille coupling of 106 with 19-epi-2 as before afforded pentaene
111 (71% yield), whose hydrolysis with Me3SnOH furnished
the desired seco hydroxy acid 112 (80% yield). Of the various
Mitsunobu conditions examined (shown in Table 2), the DEAD-
Ph3P reagent combination in toluene proved to be the best in
delivering macrocycle 105 (31% yield). Byproducts in these
reactions included the hydroxy DEAD-conjugate 113 and the
eliminated DEAD-conjugate 114 as indicated in Table 2 and
Scheme 17.32
the power of ring-closing metathesis in the construction of
complex molecular scaffolds.18b,c In addition to providing several
palmerolide A stereoisomers, the described synthetic technolo-
gies are capable of delivering designed analogs of the natural
product for chemical biology studies. Such studies are currently
underway in these laboratories.
Acknowledgment. Professor K.C. Nicolaou is also at the
Department of Chemistry and The Skaggs Institute for Chemical
Biology, The Scripps Research Institute, 10550 North Torrey
Pines Road, La Jolla, California 92037 (USA), and Department
of Chemistry and Biochemistry, University of California, San
Diego, 9500 Gilman Drive, La Jolla, California 92093 (USA).
We thank Ms. Doris Tan (ICES) for high-resolution mass
spectrometric (HRMS) assistance. We also thank Professor Bill
J. Baker (University of South Florida, Tampa) for kindly
providing a sample of authentic palmerolide A. Financial support
for this work was provided by A*STAR, Singapore.
Conclusion
A highly convergent, modular and stereochemically flexible
synthetic strategy allowed access to several palmerolide A
isomers, including the originally proposed (1) and revised [ent-
(19-epi-20-epi-1)] structures of the natural product and stere-
oisomers 19-epi-1, 20-epi-1, and 19-epi-20-epi-1. From the five
different modes of ring closure examined, the most efficient
processes for the construction of the palmerolide A macrocycle
were found to be the olefin ring-closing metathesis18 and the
Yamaguchi macrolactonization.33 The late-stage conversion of
polyolefin 91 to ent-(19-epi-20-epi-1) illustrated, once again,
Supporting Information Available: Experimental procedures
and compound characterization (PDF, CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
JA710485N
(32) For an earlier report of a similar DEAD conjugate, see, Lafontaine, J. A.;
Provencal, D. P.; Gardelli, C.; Leahy, J. W. J. Org. Chem. 2003, 68, 4215-
4234.
(33) Parenty, A.; Moreau, X.; Campagne, J.-M. Chem. ReV. 2006, 106, 911-
939.
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3644 J. AM. CHEM. SOC. VOL. 130, NO. 11, 2008