Total synthesis of (+)-superstolide A

Article abstract of DOI:10.1021/jo801794s

(Chemical Equation Presented) A convergent and highly stereocontrolled total synthesis of the cytotoxic macrolide (+)-superstolide A is described. Key features of this synthesis include the use of bimetallic linchpin 36b for uniting the C(1)-C(15) (43) and the C(20)-C(27) (38) fragments of the natural product, a late-stage Suzuki macrocyclization of 49, and a highly diastereoselective transannular Diels-Alder reaction of macrocyclic octaene 4. In contrast, the intramolecular Diels-Alder reaction of pentaenal 5 provided the desired cycloadduct with lower stereoselectivity (6:1:1).

Full text of DOI:10.1021/jo801794s

Total Synthesis of (+)-Superstolide A
Mariola Tortosa,† Neal A. Yakelis,‡ and William R. Roush*,†
Department of Chemistry, Scripps Florida, Jupiter, Florida 33458, and Department of Chemistry,
UniVersity of Michigan, Ann Arbor, Michigan 48109
roush@scripps.edu
ReceiVed August 13, 2008
A convergent and highly stereocontrolled total synthesis of the cytotoxic macrolide (+)-superstolide A
is described. Key features of this synthesis include the use of bimetallic linchpin 36b for uniting the
C(1)-C(15) (43) and the C(20)-C(27) (38) fragments of the natural product, a late-stage Suzuki
macrocyclization of 49, and a highly diastereoselective transannular Diels-Alder reaction of macrocyclic
octaene 4. In contrast, the intramolecular Diels-Alder reaction of pentaenal 5 provided the desired
cycloadduct with lower stereoselectivity (6:1:1).
Introduction
In 1994, Minale and co-workers reported the isolation and
structural determination of superstolides A (1) and B (2) (Figure
1) from the New Caledonian sponge Neosiphonia superstes.1,2
The superstolides are highly cytotoxic against several cancer
cell lines including murine P388 leukemia cells (IC50 ) 3 ng/
mL for both 1 and 2), human nasopharyngeal cells (IC50 ) 5
ng/mL for 2), and non-small cell lung carcinoma cells (IC50
)
4 ng/mL for both 1 and 2). Due to their interesting chemical
structures and potent biological properties, the superstolides have
attracted considerable attention as synthetic targets. Efforts
toward the C(21)-C(26) fragment have been reported by
D’Auria,3 Jin,4 Romea and Urpi,5 Paterson,6 and Marshall7 as
well as our group.8 In 1996, we published a highly diastereo-
selective synthesis of the cis-fused octahydronaphthalene
FIGURE 1. Superstolides A and B.
nucleus,9and a few years later, Jin and co-workers reported a
different approach toward this part of the molecule.10 Recently,
we reported the first total synthesis of (+)-superstolide A11 by
a route that proceeds via the transannular Diels-Alder reaction
of macrocyclic octaene 4, an element of the synthesis that is
presumably biomimetic in nature.12,13 We report herein a full
account of the evolution of the synthetic strategy that led to the
† Scripps Florida.
‡ University of Michigan.
(1) D’Auria, M. V.; Debitus, C.; Paloma, L. G.; Minale, L.; Zampella, A.
J. Am. Chem. Soc. 1994, 116, 6658.
(2) D’Auria, M. V.; Paloma, L. G.; Minale, L.; Zampella, A.; Debitus, C. J.
Nat. Prod. 1994, 57, 1595.
(3) Zampella, A.; D’Auria, M. V. Tetrahedron: Asymmetry 2001, 12, 1543.
(4) Yu, W.; Zhang, Y.; Jin, Z. Org. Lett. 2001, 3, 1447.
(5) Solsona, J. G.; Romea, P.; Urpi, F. Org. Lett. 2003, 5, 4681.
(6) Paterson, I.; Mackay, A. C. Synlett 2004, 1359.
(7) Marshall, J. A.; Mulhearn, J. J. Org. Lett. 2005, 7, 1593.
(8) (a) Roush, W. R.; Hertel, L.; Schnaderbeck, M. J.; Yakelis, N. A.
Tetrahedron Lett. 2002, 43, 4885. (b) Yakelis, N. A.; Roush, W. R. J. Org.
Chem. 2003, 68, 3838.
(9) Roush, W. R.; Champoux, J. A.; Peterson, B. C. Tetrahedron Lett. 1996,
37, 8989.
(10) Hua, Z.; Yu, W.; Su, M.; Jin, Z. Org. Lett. 2005, 7, 1939.
(11) Tortosa, M.; Yakelis, N. A.; Roush, W. R. J. Am. Chem. Soc. 2008,
130, 2722.
(12) Stocking, E. M.; Williams, R. M. Angew. Chem., Int. Ed. 2003, 42,
3078.
(13) Oikawa, H.; Tokiwano, T. Nat. Prod. Rep. 2004, 21, 321.
10.1021/jo801794s CCC: $40.75
Published on Web 10/29/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 9657–9667 9657

Tortosa et al.
SCHEME 1. Retrosynthetic Analysis
successful synthesis of 1 and of the difficulties that were
encountered along the way.
Therefore, we designed a strategy that would allow us to
adjust the timing of the Diels-Alder reaction relative to the
macrocyclization step late in the synthesis (i.e., use of 3 vs 4
as key intermediates, Scheme 1). On the basis of this analysis,
we targeted functionalized pentaenal 5 as a common precursor
to 3 and 4. In the synthetic direction, the aldehyde unit of 5
could be transformed into a vinylmetal intermediate capable of
being coupled with iodide 6, either prior to or after the
Diels-Alder reaction. Finally, pentaenal 5 could be assembled
by coupling of suitably functionalized fragments 7-9, via
olefination of 8 and 9 followed by a metal catalyzed cross-
coupling reaction with 7.18
Synthetic Strategy
From the outset of our work on superstolide A, we intended
to synthesize the highly substituted cis-octahydronaphthalene
unit by a Diels-Alder reaction performed in either the intramo-
lecular (IMDA)9 or transannular (TDA) mode.8a We established
in early studies that the IMDA reaction of a model substrate
provided the cis-octahydronaphthalene nucleus with 6:1:1
selectivity.9 Although this was a promising result, a plan to
pursue a transannular Diels-Alder reaction of the 24-membered
octaene 4 also seemed attractive since several TDA reactions
are known to be much more stereoselective than analogous
IMDA cyclizations.14 We have successfully demonstrated this
principle in several syntheses,15,16 and superstolide A provided
another challenging test case to explore the generality of this
concept. We recognized that there were several possible TDA
reactions that could occur within macrocycle 4, however we
anticipated that the proposed cyclization would predominate
owing to the favorable kinetics of closure of a 6-membered ring
at C(9)-C(14). While a 6-membered ring could also be closed
by a TDA reaction of a C(2,3)-dienophile and a C(18-21)-
diene, this cyclization would require the lactone to adopt a
disfavored s-cis conformation. IMDA reactions of substrates
with esters in the connecting chain are generally highly
disfavored.14,17 Although the proposed transannular cyclization
offered potential advantages in terms of stereoselectivity, we
were aware of the chemical sensitivity of the two conjugated
tetraene units of 4.
Results and Discussion
Synthesis of Allylic Alcohols 7a,b. The synthesis of allylic
alcohols 7a,b started with the asymmetric allylation (96:4 dr)
of known aldehyde 10 using Brown’s dIpc2Ballyl reagent under
salt-free conditions (Scheme 2).19 O-Methylation of the resulting
secondary alcohol followed by ketal hydrolysis afforded diol
11 in 53% yield over three steps. Selective formation of the
primary trityl ether followed by protection of the secondary
hydroxyl group gave triether 12. After ozonolysis of the double
bond of 12, the resulting aldehyde was subjected to Horner-
Wadsworth-Emmons olefination according to the Still-
Gennari20 procedure, which afforded (Z)-enoate 13 in 74% over
four steps. Deprotection of the primary trityl ether of 13 followed
by oxidation of the resulting alcohol using Parikh-Doering
conditions provided aldehyde 14 (90%).21 This intermediate was
elaborated to vinyl iodide 7a (79%) and vinylboronate 7b (89%)
by using Takai22 or modified Takai23 conditions followed by
DIBAL-H reduction of the ester.
Synthesis of Trienyl Iodide 20. Trienyl iodide 20 was
(14) (a) Takao, K.-i.; Munakata, R.; Tadano, K. Chem. ReV. 2005, 105, 4779.
(b) Deslongchamps, P. Aldrichim. Acta 1991, 24, 43. (c) Roush, W. R. In
ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford,
1991; Vol. 5, pp 513-550. (d) Craig, D. Chem. Soc. ReV. 1987, 16, 187.
(15) Roush, W. R.; Koyama, K.; Curtin, M. L.; Moriarty, K. J. J. Am. Chem.
Soc. 1996, 118, 7502.
synthesized from the known allylic alcohol 1624 as outlined in
(18) Review of palladium-catalyzed cross-coupling reactions in total
synthesis: Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed.
2005, 44, 4442.
(16) (a) Mergott, D. J.; Frank, S. A.; Roush, W. R. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 11955. (b) Winbush, S. M.; Mergot, D. J.; Roush, W. R. J.
Org. Chem. 2008, 73, 1818.
(19) Smith, A. B.; Chen, S. S.-Y.; Nelson, F. C.; Reichert, J. M.; Salvatore,
B. A. J. Am. Chem. Soc. 1997, 119, 10935.
(20) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
(21) Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505.
(17) Boeckman, R. K., Jr.; Flann, C. J. Tetrahedron Lett. 1983, 24, 5035.
9658 J. Org. Chem. Vol. 73, No. 24, 2008

Total Synthesis of (+)-Superstolide A
SCHEME 2. Synthesis of Allylic Alcohols 7a,b
SCHEME 4. Synthesis of the IMDA Precursor 22
anhydride and triethylamine in dichloromethane at 0 °C. The
reaction was then diluted with acetone, and lithium bromide
was added at 23 °C to effect SN2 displacement giving dienylic
bromide 17 in 77% yield. Treatment of 17 with PBu3 in a
mixture of CH3CN and THF provided phosphonium salt 8a.
The Wittig reaction of the ylide generated from phosphonium
salt 8a and aldehyde 188b furnished trienyl stannane 19 in 80%
yield with (E)-selectivity greater than 10:1. Initially, we had
considered using Horner-Wadsworth-Emmons and Julia ole-
fination sequences for the synthesis of trienyl stannane 19.
However, these strategies were ultimately abandoned due to the
low yields and poor stereoselectivities realized in the synthesis
of (E,E,E)-triene 19 by using these reactions.
SCHEME 3. Synthesis of Trienyl Iodide 20
Trienylstannane 19 was a viable Stille cross-coupling partner
for 7a, but conversion to iodide 20 would be required for cross-
coupling with vinylboronate 7b. Careful titration of trienylstan-
nane 19 with 1 equiv of iodine afforded 20 in 95% yield. Iodide
20 was found to be very sensitive, with olefin isomerization
occurring if any excess of iodine was used in the reaction with
19, and product decomposition occurred during attempted
chromatographic purification of 20 on silica gel or alumina.
IMDA Approach: Initial Studies. With all the cross-
coupling partners in hand, we looked for optimal conditions
for the fragment assembly (Scheme 4). Treatment of a mixture
of iodide 7a and trienylstannane 19 with catalytic Pd(PPh3)4
furnished allylic alcohol 22 in low yield (21%).25 In contrast,
the Suzuki cross-coupling between 7b and 20 in the presence
of thallium(I) carbonate26 gave 22 in excellent yield (95%).
Hoping to minimize the manipulations of this sensitive inter-
mediate, we attempted to use enal 21 in a Suzuki coupling with
20, but unfortunately, this reaction was unsuccessful.
Oxidation of allylic alcohol 22 with SO3-pyridine21 afforded
5, which was then subjected to the intramolecular Diels-Alder
Scheme 3. Evans had previously reported the conversion of 16
to the dienylic bromide 17 using carbon tetrabromide and
triphenylphosphine.24 This reaction provided bromide 17 in
variable yield and purity; therefore, a much cleaner method with
higher and more reliable yields was developed. The dienylic
mesylate was generated by treatment of 16 with methanesulfonic
(22) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408.
(23) Takai, K.; Shinomiya, N.; Kaihara, H.; Yoshida, N.; Moriwake, T. Synlett
1995, 963.
(24) Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114,
9434.
(25) Stille, J. K.; Groh, B. L. J. Am. Chem. Soc. 1987, 109, 813.
(26) Marko´, I. E.; Murphy, F.; Dolan, S. Tetrahedron Lett. 1996, 37, 2507.
J. Org. Chem. Vol. 73, No. 24, 2008 9659

Tortosa et al.
SCHEME 5. IMDA of Pentaenal 5
SCHEME 6. Elaboration of the IMDA Adduct 23
SCHEME 7. Synthesis of Iodide 6
reaction conditions previously developed in our group for the
superstolide synthesis.9 Specifically, heating a solution of 5 in
2,2,2-trifluoroethanol at 70 °C gave a ca. 6:1:1 mixture of
products favoring the endo adduct 23 (65%) (Scheme 5).27
The relative stereochemistry of the cis-fused bicyclic octahy-
dronaphthalene unit of 23 was assigned on the basis of NOE
interactions between H(9), H(10), H(14), H(17), and Me(30)
(Figure 2). This assignment is in agreement with the NOE’s
measured on the natural product1 and the results observed in
the intramolecular Diels-Alder studies of model substrates.9
olefination using phosphonate 2830 to give enoate 29 (77%).
Treatment of 29 with iodine in CH2Cl2 provided iodide 6 in
61% yield.
Treatment of a mixture of 24 and 6 in wet THF with
thallium(I) carbonate26 and catalytic Pd(PPh3)4 furnished the
trienoate ester 3 in 66% yield (Scheme 6). We thought this
intermediate would undergo global silyl deprotection upon
treatment with a suitable fluoride source. However, treatment
of 3 with TAS-F afforded 25 with a TBS ether remaining on
C(23).31 Unfortunately, further attempts to effect global depro-
tection with a model substrate failed under a variety of
conditions. It was clear from these results that the macrocy-
clization substrate must have an easily removable protecting
group on C(23)-OH. Accordingly, we decided to protect C(23)-
FIGURE 2. 1H NOE interactions in the IMDA adduct 23.
Aldehyde 23 was subjected to modified Takai conditions23
using dichloromethylboronate 1528 to provide pinacol vinylbo-
ronate 24 in 95% yield (Scheme 6). With 24 in hand, we focused
on the synthesis of its cross-coupling partner (Scheme 7).
Aldehyde 2729 was subjected to Horner-Wadsworth-Emmons
(30) Cushman, M.; Casimiro-Garcia, A.; Hejchman, E.; Ruell, J. A.; Huang,
M.; Schaeffer, C. A.; Williamson, K.; Rice, W. G.; Buckheit, R. W. J. J. Med.
Chem. 1998, 41, 2076.
1
(27) IMDA cyclization of 5 was attempted in toluene at 70-80 °C, but H
NMR analysis showed lower conversion and decomposition of 5.
(28) Wuts, P. G.; Thompson, P. A. J. Organomet. Chem. 1982, 234, 137.
(29) Dominguez, B.; Pazos, Y.; de Lera, A. R. J. Org. Chem. 2000, 65, 5917.
(31) Compound 25 could not be fully characterized due to the small quantities
1
obtained from these experiments, but H NMR spectra showed a TBS ether on
C(23).
9660 J. Org. Chem. Vol. 73, No. 24, 2008

Total Synthesis of (+)-Superstolide A
SCHEME 8. Revision of the Synthetic Strategy
Second Generation Strategy. At this point, it became
apparent that a different strategy was required to construct the
C(1)-C(7) fragment of superstolide A. The new approach was
designed to proceed from the four building blocks 35-38
(Scheme 10). Again, we intended that the timing of the
Diels-Alder reaction relative to the macrocyclization event
could be adjusted late in the synthesis. We thought a Wittig
reaction between phosphonium salt 35 and aldehyde 37 could
avoid the isomerization of the labile (Z)-trisubstituted double
bond C(8)-C(9) demonstrated in Scheme 9. Although we had
already developed a synthesis of the Suzuki cross-coupling
partner 20 (Scheme 3), the sequence proved not to be highly
reproducible on a multigram scale. Therefore, use of the
bifunctional linchpin 36 with orthogonal cross-coupling func-
tional groups was considered for synthesis of the C(14)-C(21)
tetraene.35
SCHEME 9. Unexpected Z/E Isomerization during Takai
Olefination of 32
Development of a Bimetallic Diene Linchpin. The bifunc-
tional linchpin 36 was designed such that the two termini would
bear functional groups capable of undergoing sequential cross
coupling reactions. Initially vinylsilane/vinylstannane 36a and
vinylboronate/vinylstannane 36b were targeted (Scheme 11).
Vinylsilane 36a was prepared by olefination of 4429 using
lithiated bis(trimethylsilyl)methane,36 albeit in low yield. Other
bases were screened for deprotonation of bis(trimethylsilyl)-
methane (methyllithium, tert-butyllithium, TMEDA as additive)
but with no improvement in reaction efficiency.
The homologation of aldehyde 44 to the vinylboronate 36b
was also problematic. Olefination under Takai conditions using
pinacol dichloromethylboronate gave 36b with no Z/E selectiv-
ity, and use of bis(1,3,2-dioxaborin-2-yl)methane37 was ham-
pered by the difficulty and unpredictability of its preparation.
We also hoped that homologation of aldehyde 44 to alkyne
45 would allow opportunities for hydrometalation (Scheme 12).
Alkyne 45 was prepared from aldehyde 44 by treatment with
lithiotrimethylsilyldiazomethane.33 Unfortunately, attempted hy-
drozirconation of 45 using the Schwartz reagent38 did not give
the desired compound, and hydroboration with catechol or
pinacol borane were also unsuccessful. Gratifyingly, hydrobo-
ration of 45 according to Snieckus’ procedure39 provided 36b
in good yield (50-67%).
Synthesis of Pentaenoate 43a. Phosphonium salt 35a was
synthesized from alcohol 7a by conversion to the corresponding
allylic bromide (98%) followed by treatment with PBu3 (89%,
Scheme 13). The synthesis of the aldehyde coupling partner
37a started from hydroxybutenolide 39.40 Horner-Wadsworth-
Emmons olefination of 39 with the ꢀ-phosphonoester 40
provided 41a (88%). Reduction of the carboxylic acid via the
mixed anhydride followed by oxidation of the primary alcohol
using the Dess-Martin periodinane41 gave 37a in 68% yield.
This aldehyde was then coupled with phosphonium salt 35a to
provide the isomerically pure pentaenoate 43a in 81% yield.
Synthesis of the C(16)-C(27) Fragment 47. Vinylboronate
47 was synthesized starting from alcohol 46 (Scheme 14).8b
Temporary protection of C(25)-OH of 46 as a TES ether
OH as a triethylsilyl ether. Aldehyde 26 was synthesized
following the same sequence shown for the TBS ether 23.
However, despite considerable efforts, we were unable to
accomplish the Takai olefination of this intermediate with 15
to give the corresponding pinacol vinylboronate.
Synthesis of Iodo Boronate 30. Due to the difficulties
encountered in Scheme 6, we decided to install the vinylboronate
unit prior to the IMDA cycloaddition. We thought 30 would be
a suitable intermediate for joining the different fragments of
the molecule (Scheme 8). Importantly, this modified strategy
would still allow us to establish the octahydronaphthalene unit
via an intramolecular or transannular Diels-Alder reaction.
Oxidation of alcohol 7a under Parikh-Doering conditions21
provided aldehyde 32 in 90% yield (Scheme 9). Surprisingly,
the Takai olefination of 32 with dichloromethylboronate 15
resulted in complete Z/E isomerization of the (Z)-trisubstituted
double bond to give (E)-33 as a single isomer. Since only one
boronic ester was isolated from the Takai olefination, this
isomerization was not suspected in our initial trials, in which
aldehyde 32 was used directly as the crude product from
oxidation of 7a. However, silica gel chromatographic purifica-
tion of 32 provided material that was a 70:30 Z:E mixture of
enals. When this mixture was subjected to Takai olefination with
16, 33 was again obtained as a single (E) product, as determined
by NOE analysis.
We also tried to introduce the vinylboronate moiety through
a hydroboration reaction of an alkyne derived from 32. However,
despite extensive efforts to convert 32 to the requisite enyne
(Seyferth-Gilbert,32
trimethylsilyldiazomethane,33
and
Corey-Fuchs34 conditions), we were unable to devise a high-
yielding and highly stereoselective synthesis of the enyne, and
this approach was ultimately abandoned. Here again, isomer-
ization of the trisubstituted olefin was a significant complication.
(35) (a) Coleman, R. S.; Walczak, M. C. Org. Lett. 2005, 7, 2289. (b)
Coleman, R. S.; Lu, X. Chem. Commun. 2006, 423.
(36) Gro¨bel, B. T.; Seebach, D. Chem. Ber. 1977, 110, 852.
(37) Matteson, D. S.; Moody, R. J. Organometallics 1982, 1, 20.
(38) Buchwald, S. L.; LaMaire, S. J.; Nielsen, R. B.; Watson, B. T.; King,
S. M. Tetrahedron Lett. 1987, 28, 3895.
(39) Kalinin, A. V.; Scherer, S.; Snieckus, V. Angew. Chem., Int. Ed. 2003,
42, 3349.
(40) Fell, S. C. M.; Harbridge, J. B. Tetrahedron Lett. 1990, 31, 4227.
(41) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(32) (a) Seyferth, D.; Marmor, R. S.; Hilbert, P. J. Org. Chem. 1971, 36,
1379. (b) Gilbert, J. C.; Weerasooriya, U. J. Org. Chem. 1982, 47, 1837.
(33) Ohira, S.; Okai, K.; Moritani, T. J. Chem. Soc., Chem. Commun. 1992,
721.
(34) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
J. Org. Chem. Vol. 73, No. 24, 2008 9661

Tortosa et al.
SCHEME 10. Second-Generation Retrosynthesis of Superstolide A
SCHEME 11. Studies on the Synthesis of a Bimetallic
Linchpin
SCHEME 13. Synthesis and Wittig Coupling of 35a and
Aldehyde 37a
SCHEME 12. Synthesis of Bimetallic Linchpin 36b
SCHEME 14. Synthesis of the C(16)-C(27) Fragment 47
followed by ozonolysis of the alkene provided the corresponding
22,42
aldehyde. Treatment of this intermediate with CrCl2-CHI3
and deprotection of C(25)-OH gave 38 in 76% yield over four
steps. Attempted Stille cross-coupling reaction between 38 and
bimetallic linchpin 36b, using catalytic Pd2(dba)3 and AsPh3 in
THF at 50 °C,43 gave only decomposition of the bimetallic
fragment. However, treatment of 38 and 36b with catalytic
Pd(CH3CN)2Cl2 in DMF afforded vinylboronic ester 47 in
50-60% overall yield.44
envisioned two possible ways to combine the two fragments: a
Suzuki cross-coupling reaction followed by a macrolactonization
(path a, Scheme 15) or a cross-esterification prior to the Suzuki
reaction (path b, Scheme 15). Path a initially seemed more
attractive to us since intermediate 48 would be a suitable
Fragment Assembly and Total Synthesis of Superstolide
A. With tetraenoate 43a and vinylboronic ester 47 in hand, we
9662 J. Org. Chem. Vol. 73, No. 24, 2008

Total Synthesis of (+)-Superstolide A
SCHEME 15. Fragment Assembly Strategies
SCHEME 16. Macrolactonization Pathway for Superstolide Synthesis
precursor to test both the intramolecular and transannular
Diels-Alder cycloadditions.
Deprotection of the methyl ester of 48 by treatment with
KOSiMe3 gave seco acid 50.47 Although in some trials we could
obtain isomerically pure 50, this reaction was not reproducible,
and inseparable mixtures of compounds derived from isomer-
ization of the labile C(2)-C(9) tetraenoate unit were usually
obtained. Pure carboxylic acid 50 was subjected to macrolac-
tonization conditions. Unfortunately, treatment of 50 under
Yamaguchi conditions48,49 or with 2-methyl-6-nitrobenzoic
anhydride50 gave a complex mixture of products.
After this result, we turned our attention to the approach
shown in path b. Not surprisingly after the difficulties encoun-
tered with 48, attempted deprotection of methyl ester 43a was
problematic (Scheme 17). Under various ester cleavage condi-
tions, we obtained 50 as mixtures of E/Z isomers at the
Treatment of 43a and 47 in wet THF with TlOEt and catalytic
Pd(PPh3)4 provided isomerically pure polyunsaturated ester 48
in 62% yield (Scheme 16).45 Heating a solution of 48 in
CF3CH2OH resulted in decomposition probably due to acidity
of the solvent. When the IMDA reaction of 48 was attempted
in toluene, the 1H NMR spectrum of the crude product showed
low conversion and decomposition of 48. Slightly better results
(ca. 40% of a mixture of diastereomers) were obtained by
treatment of 48 with Otera’s catalyst 52,46 but there was
evidence that 48 decomposed upon heating.
(42) Evans, D. A.; Black, W. C. J. Am. Chem. Soc. 1993, 115, 4497.
(43) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585.
(44) Bimetallic linchpin 36 provided an alternative route to access IMDA
precursors analogous to 22 and 5 for the synthesis of IMDA adduct 26 (see the
Supporting Information). This sequence was more reliable than that previously
described in Schemes 3 and 4.
(47) Laganis, E. D.; Chenard, B. L. Tetrahedron Lett. 1984, 25, 5831.
(48) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
(45) Frank, S. A.; Chen, H.; Kunz, R. K.; Schnaderbeck, M. J.; Roush, W. R.
Org. Lett. 2000, 2, 2691.
(46) Otera, J.; Dan-oh, N.; Nozaki, H. J. Org. Chem. 1991, 56, 5307.
(49) Hikota, M.; Tone, H.; Horita, K.; Yonemitsu, O. J. Org. Chem. 1990,
55, 7.
(50) Shiina, I.; Kubota, M.; Ibuka, R. Tetrahedron Lett. 2002, 43, 7535.
J. Org. Chem. Vol. 73, No. 24, 2008 9663

Tortosa et al.
SCHEME 17. Synthesis of Carboxylic Acid 53
Elaboration of 54 to superstolide A proceeded smoothly
(Scheme 18). Removal of the TBDPS ether by treatment with
TBAF followed by treatment of the resulting alcohol with
trichloroacetyl isocyanate53 installed the carbamate moiety at
C(13) in 65% yield from 54. Finally, treatment of the resulting
carbamate with TFA, to remove the Boc and acetonide protect-
ing groups, followed by addition of Ac2O and Et3N provided
synthetic (+)-superstolide in 42% yield from 54. Comparison
of the 1H and 13C NMR data of synthetic and natural superstolide
A showed excellent agreement.1
Summary
We have achieved the first total synthesis of (+)-superstolide
A by a convergent and highly stereoselective sequence. High-
lights of this work include an intramolecular Suzuki coupling
reaction and a highly stereoselective transannular Diels-Alder
cycloaddition of 4 to assemble the tricyclic skeleton of super-
stolide A. This work demonstrates that conformational prefer-
ences imposed by the macrocycle improve the stereoselectivity
of the key Diels-Alder step, since conventional intramolecular
Diels-Alder cycloaddition of 5 gives a 6:1:1 mixture of three
cycloadducts. Additionally, the example described herein ex-
pands the number of successful applications of Suzuki macro-
cyclizations to highly functionalized late-stage intermediates in
the total synthesis of complex natural products.52
A significant part of our efforts in this synthetic venture
concerned the efficient and stereoselective synthesis of polyene
fragments. Many of the late-stage intermediates were extremely
sensitive toward acid, base, or even storage which required the
optimization of each individual transformation to avoid isomer-
ization of the double bonds. The solutions found, as well as the
synthetic strategies described herein, should be useful for the
synthesis of superstolide analogs and other polyene-containing
macrolactones.
C(8)-C(9)-trisubstituted alkene. It was clear that synthesis of
this sensitive substrate would require a different protecting group
strategy for the carboxylic acid of immediate precursors.
Accordingly, we elected to use a ꢀ-trimethylsilylethyl ester.
Horner-Wadsworth-Emmons olefination of hydroxybutenolide
3940 and ꢀ-phosphonoester 2830 afforded 41b in 76% yield.
Reduction of the carboxylic acid via the mixed anhydride
followed by oxidation of the dienylic alcohol using Dess-Martin
conditions41 provided aldehyde 37b in 85% yield. Wittig
olefination of this aldehyde using phosphonium salt 35a
provided ester 43b (85%). Selective deprotection of the ester
by treatment with TASF in DMF gave carboxylic acid 53 as a
single isomer in 75% yield.51
Experimental Section54
Synthesis of Ester 49. To a 0 °C solution of vinyl iodide 43b
(167 mg, 0.217 mmol) in anhydrous DMF (2 mL) was added TAS-F
(0.62 mL of a 0.5 M solution in DMF freshly prepared, 0.31 mmol).
The mixture was stirred at room temperature for 1 h and quenched
with 10% aq NaHCO3 (0.5 mL). Water (2 mL) and EtOAc (5 mL)
were added. The organic phase was washed with water (2 × 2 mL)
and brine, dried over anhydrous Na2SO4, filtered, and concentrated
to afford carboxylic acid 53 (109 mg, 0.163 mmol, 75%) as a
colorless oil, which was immediately used in the next reaction.
To a solution of the crude acid 53 (133 mg, 0.198 mmol) in
THF (2 mL) was added triethylamine (0.14 mL, 0.99 mmol)
followed by 2,4,6-trichlorobenzoyl chloride (50 µL, 0.32 mmol).
The mixture was stirred for 1 h at room temperature. Hexanes (3
mL) were added, and the slurry was filtered through Celite and
concentrated. The crude product was dissolved in toluene (2 mL)
and was added to a solution of alcohol 47 (93 mg, 0.18 mmol) and
DMAP (98 mg, 0.80 mmol) in toluene (2 mL). The reaction mixture
was stirred for 12 h at room temperature, diluted with EtOAc (4
mL), and poured into water (4 mL). The aqueous phase was
extracted with EtOAc (3 × 4 mL). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4, filtered,
Coupling of the carboxylic acid 53 and alcohol 47 by using
the Yamaguchi esterification procedure48,49 (53, trichlorobenzoyl
chloride, Et3N, then 47 and DMAP) gave ester 49 in 65% yield
(Scheme 18). Treatment of a 0.001 M solution of 49 in wet
THF with TlOEt and catalytic P(PPh3)4 effected an intramo-
lecular Suzuki reaction that provided the macrocyclic octaene
4 (35-40%).52 We also isolated products believed to arise from
bimolecular cross coupling of 49. Gratifyingly, macrocycle 4
underwent a highly diastereoselective transannular Diels-Alder
cyclization at 23 °C over 5 days, or in 2 h at 80 °C, to give 54
as the only observed cycloadduct in 30-35% overall yield (two
steps from 49). Interestingly, 1H NMR analysis of 54 at 23 °C
showed doubling of the 1H resonances for many protons in the
vicinity of the N-Boc unit, but also distal protons including H(3)
and H(6). This observation suggested that 54 exists as a dynamic
mixture of N-Boc rotamers along with conformational isomers
within the newly formed 16-membered ring; this deduction was
1
confirmed by variable temperature H NMR studies.
(53) Kocovsky, P. Tetrahedron Lett. 1986, 27, 5521.
(51) Scheidt, K. A.; Chen, H.; Follows, B. C.; Chemler, S. R.; Coffey, D. S.;
Roush, W. R. J. Org. Chem. 1998, 63, 6436.
(52) (a) For recent examples of Suzuki macrocyclization reactions, see: Jia,
Y.; Bois-Choussy, M.; Zhu, J. Org. Lett. 2007, 9, 2401. (b) Wu, B.; Liu, Q.;
Sulikowski, G. A. Angew. Chem., Int. Ed. 2004, 43, 6673. (c) Molander, G. A.;
Dehmel, F. J. Am. Chem. Soc. 2004, 126, 10313.
(54) The spectroscopic and physical properties (e.g., 1H NMR, 13C NMR,
IR, mass spectrum, and/or C,H analysis) of all new compounds were fully
consistent with the assigned structures. Yields refer to chromatographically and
spectroscopically homogeneous materials (unless noted otherwise). Experimental
procedures and tabulated spectroscopic data for other new compounds are
provided in the Supporting Information.
9664 J. Org. Chem. Vol. 73, No. 24, 2008

Total Synthesis of (+)-Superstolide A
SCHEME 18. Completion of the Total Synthesis of Superstolide A
and concentrated. Purification by flash chromatography (1 g of
Davisil, 5% EtOAc/hexanes) afforded ester 49 (128 mg, 0.109
mmol, 61%) as a yellow oil. The isolated product was contaminated
with a small amount of 47 and was immediately used in the next
reaction without further purification: 1H NMR (400 MHz, C6D6) δ
7.76 (ddd, J ) 14.4, 12.2, 2.0 Hz, 1H), 7.63-7.59 (m, 4H),
7.43-7.30 (m, 7H), 6.87 (d, J ) 15.6 Hz, 1H), 6.70 (d, J ) 15.6
Hz, 1H), 6.48 (dd, J ) 14.4, 7.2 Hz, 2H), 6.09 (d, J ) 15.6 Hz,
1H), 6.07 (d, J ) 12.4 Hz, 1H), 6.02 (d, J ) 11.2 Hz, 1H), 5.78
(d, J ) 14.8 Hz, 1H), 5.76-5.69 (m, 1H), 5.51 (d, J ) 17.6 Hz,
1H), 5.39 (t, J ) 7.4 Hz, 1H), 5.24 (td, J ) 7.5, 2.8 Hz, 1H), 4.26
(m, 1H), 3.98-3.95 and 3.81-3.78 (2 m, 1H combined), 3.68 (ddd,
J ) 10.0, 8.1, 4.7 Hz, 1H), 3.32-3.27 (m, 1H), 3.19 (s, 3H),
2.63-2.55 (m, 1H), 2.40-2.25 (m, 2H), 2.07-2.00 (m, 1H), 2.00
(s, 3H), 1.91 (s, 3H), 1.88 (s, 3H), 1.79-1.72 (m, 1H), 1.60-1.50
(m, 1H), 1.57 and 1.52 (2 s, 3H combined), 1.47 and 1.41 (2 s, 3H
combined), 1.45 and 1.44 (2 s, 9H combined), 1.26 (s, 3H), 1.11
and 1.07 (2 d, J ) 6.3 Hz, 3H combined), 1.07-1.04 (m, 3H
overlapped), 1.05 (s, 9H), 0.91 and 0.88 (m, 3H); 13C NMR (400
MHz, C6D6) δ 166.2, 151.7, 151.4, 148.5, 146.4, 142.6, 139.2,
139.0, 138.9, 136.2, 136.1, 135.6, 135.5, 134.4, 134.1, 134.0, 133.8,
132.2, 130.1, 129.3, 129.0, 128.5, 124.9, 121.1, 121.0, 93.3, 92.5,
82.9, 79.2, 78.8, 77.7, 77.3, 77.0, 76.9, 75.6, 75.5, 74.2, 56.0, 54.9,
54.7, 42.2, 41.2, 41.1, 34.4, 34.2, 31.6, 30.1, 28.6, 28.4, 27.6, 27.2,
25.1, 24.95, 24.91, 23.9, 21.0, 20.3, 19.5, 17.5, 17.4, 14.1, 13.4,
12.9, 9.8, 9.5 [note: the carbon attached to boron was not observed
due to quadrupole broadening caused by the 11B nucleus]; IR (neat)
2977, 2934, 2280, 1698, 1609, 1455, 1428, 1391, 1342, 1254, 1145,
1106, 993, 703 cm-1; HRMS (ESI) m/z for C63H91BINO9SiNa [M
+ Na]+ calcd 1194.5504, found 1194.5502.
organic layers were washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated. The crude product was filtered
through a short pad of Davisil (5% EtOAc-hexane, with 2% Et3N)
to afford macrocyclic octaene 4, which was immediately used in
the next reaction without further purification: 1H NMR (400 MHz,
CDCl3) δ 7.75-7.60 (m, 4H), 7.45-7.30 (m, 6H), 6.60 (d, J )
15.8 Hz, 1H), 6.52 (d, J ) 15.8 Hz, 1H), 6.21 (dd, J ) 14.8, 11.5
Hz, 1H), 6.02 (dd, J ) 15.3, 12.2 Hz, 1H), 5.87 (d, J ) 15.4 Hz,
1H), 5.78 (dd, J ) 17.1, 14.3 Hz, 1H), 5.77 (d, J ) 14.8 Hz, 1H),
5.65 (d, J ) 11.1 Hz, 1H), 5.55 (app td, J ) 15.3, 2.0 Hz, 1H),
5.47-5.32 (m, 3H), 5.06 and 5.04 (2 dd, J ) 7.7, 1.6 Hz, 1H
combined), 4.07 (m, 1H), 3.99 and 3.83 (2 m, 1H combined), 3.71
(m, 1H), 3.04 (s, 3H), 2.97 (m, 1H), 2.33 (m, 2H), 2.18 (m, 1H),
2.00 (m, 2H), 1.96 (s, 3H), 1.77 (s, 3H), 1.75 (s, 3H), 1.56 and
1.51 (2 s, 3H combined), 1.45 (m, 1H overlapped), 1.45-1.43 (2
s, 9H combined), 1.38 and 1.35 (2 s, 3H combined), 1.14 and 1.12
(2 d, J ) 6.2 Hz, 3H combined), 1.08-1.03 (m, 3H), 0.95 and
0.93 (2 d, J ) 7.1 Hz, 3H combined).
A solution of the crude macrolactone 4 and BHT (one crystal)
in toluene (54 mL, 0.001 M) was degassed (three freeze-pump-thaw
cycles), heated at 80 °C for 2 h, and then concentrated in vacuo.
Purification of the crude product by flash chromatography (0-5%
EtOAc-CH2Cl2) afforded 54 (31 mg, 0.034 mmol, 33% two steps)
as a colorless oil: [R]25D ) +58.0 (c 0.70, CHCl3); 1H NMR (400
MHz, CDCl3) δ 7.70-7.68 (m, 4H), 7.44-7.35 (m, 6H), 7.06 and
7.05 (2 dd, J ) 15.5, 10.4 Hz, 1H combined), 6.60 and 6.59 (2 d,
J ) 16.4 Hz, 1H combined), 6.10 and 6.09 (2 d, J ) 15.3 Hz, 1H
combined), 6.00 (d, J ) 10.5 Hz, 1H), 5.86 (d, J ) 10.6 Hz, 1H),
5.73 and 5.72 (2 d, J ) 15.3 Hz, 1H combined), 5.64 (d, J ) 10.7
Hz, 1H), 5.57 and 5.56 (2 d, J ) 16.4 Hz, 1H), 5.51 (dt, J ) 10.3,
3.4 Hz, 1H), 5.37 and 5.34 (2 dd, J ) 15.3, 9.7 Hz, 1H combined),
4.96 and 4.95 (2 dd, J ) 10.5, 3.6 Hz, 1H combined), 3.95 and
3.79 (2 qd, J ) 6.0, 4.6 Hz, 1H combined), 3.88 and 3.85 (2 dd, J
) 10.5, 4.5 Hz, 1H combined), 3.69 (dt, J ) 11.6, 4.9 Hz, 1H),
3.18 (s, 3H), 3.06 (br d, J ) 10.0 Hz, 1H), 2.77 (tt, J ) 11.1, 3.7
Hz, 1H), 2.49-2.39 (m, 2H), 2.03-1.92 (m, 2H), 1.83 (s, 3H),
1.77 (s, 3H), 1.63 (m, 1H), 1.58 and 1.53 (2 s, 3H combined), 1.49
and 1.47 (2 s, 3H combined), 1.48-1.46 (m, 1H), 1.47 and 1.45 (2
Suzuki Macrocyclization of 49 and Transannular Diels-Alder
Reaction of 4: Synthesis of Cycloadduct 54. To a solution of
ester 49 (120 mg, 0.102 mmol) in degassed THF/H2O (3:1) (100
mL, three freeze-pump-thaw cycles) was added a solution of
Pd(PPh3)4 (17 mg, 0.01 mmol) in THF (1 mL) followed by TlOEt
(14 µL, 0.20 mmol). The mixture was stirred for 2 h and then was
filtered through Celite and poured into water (20 mL). The aqueous
phase was extracted with EtOAc (3 × 15 mL). The combined
J. Org. Chem. Vol. 73, No. 24, 2008 9665

Tortosa et al.
s, 9H combined), 1.39-1.26 (m, 2H), 1.15 and 1.12 (2 d, J ) 6.3
Hz, 3H combined), 1.09 (s, 9H), 1.08 and 1.07 (2 d, J ) 7.0 Hz,
3H combined), 0.86 and 0.85 (2 d, J ) 6.8 Hz, 3H combined); 1H
NMR (400 MHz, C6D6) δ 7.85-7.82 (m, 4H), 7.35 (dd, J ) 15.3,
10.6 Hz, 1H), 7.26-7.22 (m, 6H), 6.78 and 6.77 (2 d, J ) 16.4
Hz, 1H combined), 6.28 (d, J ) 10.2 Hz, 1H), 5.96 and 5.93 (2 d,
J ) 10.0 Hz, 1H combined), 5.94 and 5.90 (2 d, J ) 15.5 Hz, 1H
combined), 5.81-5.77 (m, 2H), 5.63 (br d, J ) 10.0 Hz, 1H), 5.57
and 5.56 (2 d, J ) 16.4 Hz, 1H combined), 5.29 and 5.28 (2 dd, J
) 15.3, 9.7 Hz, 1H combined), 5.30 (d, J ) 10.1 Hz, 1H), 4.10
and 3.87 (2 m, 1H combined), 4.02 and 3.96 (2 dd, J ) 10.6, 4.5
Hz, 1H combined), 3.84 (m, 1H), 3.11 (br d, J ) 10.0 Hz, 1H),
3.00 and 2.99 (2 s, 3H combined), 2.71-2.61 (m, 2H), 2.31-2.21
(m, 2H), 1.96-1.89 (m, 1H), 1.87 (s, 3H), 1.84 (m, 1H), 1.72 and
1.69 (2 s, 3H combined), 1.68 and 1.65 (2 s, 3H combined), 1.65
(s, 3H), 1.64 (m, 1H overlapped), 1.50 and 1.45 (2 s, 9H combined),
1.44 (m, 1H overlapped), 1.22 (s, 9H), 1.20-1.16 (2 d, J ) 6.2
Hz, 3H combined), 0.98 (s, 3H), 0.92 and 0.91 (2 d, J ) 6.7 Hz,
To a solution of the C(13)-alcohol (SI-11, 11.0 mg, 0.016 mmol)
in CH2Cl2 (0.5 mL) was added trichloroacetyl isocyanate (6.0 µL,
0.05 mmol). The solution was stirred at room temperature for 30
min and then loaded directly onto neutral Al2O3 and allowed to
stand for 4 h. The product was flushed from the neutral Al2O3 with
EtOAc, and the filtrate was concentrated in vacuo. Purification of
the crude product by flash chromatography (30-50% EtOAc/
hexanes) afforded the C(13)-carbamate (SI-12, 9.0 mg, 0.012 mmol,
76%) as a white foam: [R]25D ) +64.9 (c 0.74, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.08 and 7.06 (2 dd, J ) 15.3, 10.6 Hz, 1H
combined), 6.67 and 6.65 (2 d, J ) 16.3 Hz, 1H combined), 6.11
(d, J ) 15.3 Hz, 1H), 5.90 (d, J ) 10.7 Hz, 1H), 5.75 and 5.74 (2
d, J ) 15.3 Hz, 1H combined), 5.66 (m, 3H), 5.53 (dt, J ) 10.3,
4.5 Hz, 1H), 5.39 and 5.38 (2 dd, J ) 15.4, 9.7 Hz, 1H combined),
4.97 and 4.96 (2 d, J ) 10.5 Hz, 1H combined), 4.76 (dt, J )
12.5, 4.8 Hz, 1H), 4.65 (br s, 2H), 3.96 and 3.79 (2 m, 1H
combined), 3.88 and 3.86 (2 dd, J ) 10.7, 4.5 Hz, 1H combined),
3.34 (s, 3H), 3.14-3.06 (m, 2H), 2.87 (br s, 1H), 2.44 (m, 1H),
2.25 (br d, J ) 11.4 Hz, 1H), 1.97 (m, 1 H), 1.89 (s, 3H), 1.79 (s,
3H), 1.58 and 1.53 (2 s, 3H combined), 1.50 and 1.47 (2 s, 3H
combined), 1.50-1.40 (m, 2H overlapped), 1.47 and 1.45 (2 s, 9H
combined), 1.30 (m, 1H), 1.17 (s, 3H), 1.12 and 1.09 (2 d, J ) 6.3
Hz, 3H combined), 1.08 and 1.07 (2 d, J ) 6.7 Hz, 3H combined),
0.87 and 0.85 (2 d, J ) 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 167.4, 167.3, 156.0, 151.9, 151.5, 142.0, 141.8, 138.2, 135.3,
135.2, 133.0, 132.9, 131.8, 131.1, 130.51, 130.50, 126.13, 126.09,
125.51, 125.47, 121.3, 121.1, 92.7, 92.3, 79.7, 79.0, 77.5, 77.1,
77.0 (overlapping w/ chloroform), 75.7, 75.6, 72.9, 56.0, 54.5, 43.2,
41.53, 41.51, 41.44, 41.39, 41.3, 36.1, 34.3, 34.0, 33.6, 31.1, 31.0,
30.2, 30.1, 28.6, 28.5, 28.2, 27.3, 24.7, 23.5, 21.1, 17.55, 17.51,
13.7, 13.0, 12.03, 12.01, 9.3, 9.2; IR (neat) 3422, 2977, 1681, 1673,
1632, 1391, 1257, 1112, 1054, 1003, 867 cm-1; HRMS (ESI) m/z
for C42H62N2O8Na [M + Na]+ calcd 745.4398, found 745.4439.
To a solution of carbamate SI-12 (6 mg, 0.008 mmol) in wet
CH2Cl2 (20 µL of water in 0.80 mL of CH2Cl2) was added
trifluoroacetic acid (0.4 mL). The reaction mixture was stirred for
30 min at room temperature and then concentrated in vacuo.
Toluene (1 mL) was added, and the solution was concentrated (×3,
to remove all trifluoroacetic acid). The residue was diluted in THF
(0.8 mL), and triethylamine (12 µL, 0.083 mmol) was added
followed by acetic anhydride (3 µL, 0.03 mmol). The mixture was
stirred overnight at room temperature and then concentrated.
Purification of the crude product by flash chromatography (50-100%
EtOAc/hexanes) afforded totally synthetic (+)-superstolide A (1)
3H combined), 0.64 and 0.63 (2 d, J ) 7.0 Hz, 3H combined); 13
C
NMR (100 MHz, CDCl3) δ 167.4, 167.3, 151.9, 151.5, 142.5, 141.8,
138.2, 135.6, 135.4, 135.3, 134.2, 134.1, 132.7, 132.6, 132.2, 130.8,
129.7, 129.6, 129.5, 127.61, 127.57, 125.80, 125.77, 125.32, 125.28,
122.2, 122.0, 92.7, 92.3, 79.6, 79.0, 77.7, 77.2, 77.0 (overlapping
w/ chloroform), 75.7, 75.6, 71.5, 55.7, 54.5, 43.3, 41.6, 41.52, 41.48,
41.47, 41.4, 41.3, 38.6, 37.1, 34.3, 34.1, 30.81, 30.77, 30.0, 29.9,
28.6, 28.5, 28.2, 27.3, 27.0, 24.7, 23.5, 21.1, 19.3, 17.6, 17.5, 13.7,
13.0, 11.99, 11.97, 9.3, 9.2; IR (neat) 2929, 1695, 1388, 1258, 1110,
1003, 867, 820 cm-1; HRMS (ESI) m/z for C57H79NO7SiNa [M +
Na]+ calcd 940.5518, found 940.5517. [Note: compound 54
1
exhibited coalescence of H NMR signals at 50 °C in C6D6. See
the Supporting Information (2).]
Synthesis of (+)-Superstolide A from Cycloadduct 54. To a
0 °C solution of 54 (20.0 mg, 0.022 mmol) in THF (1 mL) was
added TBAF (0.13 mL of a 0.5 M solution in THF, freshly prepared,
0.066 mmol). The reaction mixture was stirred at room temperature
for 12 h, diluted with EtOAc (3 mL), and poured into water (2
mL). The aqueous phase was extracted with EtOAc (3 × 3 mL).
The combined organic phases were washed with brine, dried over
anhydrous MgSO4, filtered, and concentrated. Purification of the
crude product by flash chromatography (30-50% EtOAc-hexanes)
afforded the C(13)-alcohol (designated SI-11, 11 mg, 0.016 mmol,
73%) as a white foam: [R]25D ) +76.5 (c 1.00, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.08 and 7.07 (2 dd, J ) 15.5, 10.5 Hz, 1 H
combined), 6.67 and 6.65 (2 d, J ) 16.3 Hz, 1H combined), 6.11
(2 d, J ) 15.3 Hz, 1H combined), 5.89 (d, J ) 10.7 Hz, 1H), 5.76
(d, J ) 10.4 Hz, 1H), 5.75 and 5.74 (2 d, J ) 15.3 Hz, 1H
combined), 5.67 (2 d, 2H overlapped), 5.54 (dt, J ) 10.2, 3.5 Hz,
1H), 5.39 and 5.38 (2 dd, J ) 15.3, 9.7 Hz, 1H combined), 4.97
and 4.96 (2 d, J ) 11.1 Hz, 1H combined), 3.95 and 3.78 (qd and
m, J ) 6.4, 4.9 Hz, 1H combined), 3.88 and 3.85 (2 dd, J ) 10.5,
4.6 Hz, 1H combined), 3.82-3.75 (m, 1H), 3.34 (s, 3H), 3.12 (br
d, J ) 10.0 Hz, 1H), 3.06 (m, 1 H), 2.74 (br s, 1H), 2.44 (m, 1H),
2.17 (br d, J ) 11.8 Hz, 1H), 1.97 (m, 1H), 1.88 (s, 3H), 1.78 (s,
3H), 1.77 (m, 1H), 1.58 and 1.53 (2 s, 3H combined), 1.50 and
1.47 (2 s, 3H combined), 1.47 and 1.45 (2 s, 9H combined),
1.44-1.40 (m, 2H), 1.25 (m, 1H), 1.18 (s, 3H), 1.12 and 1.09 (2 d,
J ) 6.2 Hz, 3H combined), 1.08 and 1.07 (2 d, J ) 6.7 Hz, 3H
combined), 0.87 and 0.85 (2 d, J ) 6.8 Hz, 3H combined); 13C
NMR (100 MHz, CDCl3) δ 167.4, 167.3, 151.9, 151.5, 142.3, 141.8,
138.1, 135.32, 135.28, 132.9, 132.8, 132.0, 131.0, 130.25, 130.23,
126.04, 126.01, 125.45, 125.43, 121.3, 120.9, 92.7, 92.3, 79.7, 79.0,
77.8, 77.1, 76.9, 75.70, 75.66, 70.3, 55.9, 54.51, 54.50, 43.4, 41.9,
41.8, 41.5, 41.4, 41.3, 38.6, 36.73, 36.69, 34.2, 34.0, 31.0, 30.9,
30.2, 30.1, 28.6, 28.5, 28.2, 27.3, 24.7, 23.5, 21.1, 17.55, 17.52,
13.7, 13.0, 12.02, 12.00, 9.3, 9.2; IR (neat) 3460, 2977, 2934, 2873,
1737, 1698, 1456, 1392, 1375, 1253, 1176, 1113, 1052, 1003, 738
cm-1; HRMS (ESI) m/z for C41H61NO7Na [M + Na]+ calcd
702.4340, found 702.4405.
(4 mg, 0.006 mmol, 75%) as an amorphous white solid: [R]25
)
D
+84.0 (c 0.40, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.21 (dd, J
) 15.2, 11.0 Hz, 1H, H-3), 6.87 (d, J ) 16.4 Hz, 1H, H-6), 6.29
(d, J ) 15.2 Hz, 1H, H-20), 6.23 (d, J ) 8.8 Hz, 1H, NH), 5.91 (d,
J ) 11.0 Hz, 1H, H-4), 5.79 (d, J ) 10.7 Hz, 1H, H-18), 5.70 (d,
J ) 14.9 Hz, 1H, H-2), 5.68 (d, J ) 9.6 Hz, 1H, H-16), 5.60 (d, J
) 16.4 Hz, 1H, H-7), 5.52 (dt, J ) 10.1, 3.3 Hz, 1H, H-15), 5.32
(dd, J ) 15.2, 9.6 Hz, 1H, H-21), 4.79 (d, J ) 10.5 Hz, 1H, H-23),
4.77 (m, 1H, H-13), 4.63 (br s, 2H, NH2), 4.19 (m, 1H, H-26),
3.35 (s, 3H, MeO), 3.33 (br s, 1H, OH-25, overlapped), 3.16 (dd,
J ) 10.5, 2.4 Hz, 1H, H-25), 3.10 (m, 1H, H-11), 2.89 (br s, 1H,
H-14), 2.71 (m, 1H, H-22), 2.24 (br d, J ) 10.5 Hz, 1H, H-12),
1.97 (s, 3H, Me-28), 1.92 (s, 3H, Me-29), 1.80 (m, 2H, H-10, H-24),
1.77 (s, 3H, Me-32), 1.48 (m, 1H, H-9), 1.45 (m, 1H, H-10), 1.30
(m, 1H, H-12), 1.15 (s, 3H, Me-30), 1.08 (d, J ) 6.8 Hz, 3H, Me-
33), 1.05 (d, J ) 6.9 Hz, 3H, Me-35), 0.90 (d, J ) 6.8 Hz, 1H,
Me-34); 13C NMR (100 MHz, CDCl3) δ 169.7, 169.0, 156.1, 142.7,
142.6, 139.3, 137.1, 133.1, 132.4, 130.2, 129.4, 125.8, 125.5, 121.3,
120.3, 77.0 (2C overlapping w/ chloroform), 73.1, 72.8, 56.1, 45.5,
42.9, 41.8, 40.9, 40.4, 37.6, 36.0, 33.7, 31.3, 30.8, 23.5, 20.7, 18.0,
12.6, 12.0, 8.8; IR (neat) 3434, 3351, 2961, 2927, 1716, 1692, 1528,
1451, 1376, 1331, 1261, 1100, 1059, 981 cm-1; HRMS (ESI) m/z
for C36H52N2O7Na [M + Na]+ calcd 647.3667, found 647.3666.
When making a detailed comparison of the carbon spectrum of
the synthetic sample of (+)-superstolide A with that from the
9666 J. Org. Chem. Vol. 73, No. 24, 2008

Total Synthesis of (+)-Superstolide A
isolation paper, we noticed that the peak for the ester carbon of
the macrolactone in our spectrum was significantly smaller than
that in the isolation paper. Numerous experiments (increased number
of scans, increased relaxation time, increased temperature) were
tried in order to minimize this difference, but without success.
However, from the proton spectrum it was clear that the isolation
sample had much more water present than the synthetic sample.
Remarkably, addition of 1 µL of water to the NMR sample of
synthetic (+)-superstolide A provided a 13C NMR spectrum that
perfectly matched the 13C NMR spectrum available in the literature
for natural superstolide A.
Acknowledgment. Financial support provided by the National
Institutes of Health (GM026782) is gratefully acknowledged.
We also acknowledge Ministerio de Educacio´n y Ciencia, Spain,
for a postdoctoral fellowship to M.T.
Supporting Information Available: Experimental proce-
dures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO801794S
J. Org. Chem. Vol. 73, No. 24, 2008 9667