Total Synthesis of Swinholide A

Full text of DOI:10.1021/ja954211t

J. Am. Chem. Soc. 1996, 118, 3059-3060
3059
Total Synthesis of Swinholide A
K. C. Nicolaou,* K. Ajito, A. P. Patron, H. Khatuya,
P. K. Richter, and P. Bertinato
Department of Chemistry, The Scripps Research Institute
10666 N. Torrey Pines Road, La Jolla, California 92037
Department of Chemistry and Biochemistry
UniVersity of California, San Diego 9500 Gilman DriVe
La Jolla, California 92093
ReceiVed December 15, 1995
Swinholide A (1, Figure 1) is a marine natural product
isolated1a,2 from the sponge Theonella swinhoei and fully
characterized by NMR and X-ray crystallographic techniques.2
Faulkner and co-workers1b have recently demonstrated, contrary
to previous beliefs, that the producer organisms of this natural
product are heterotrophic unicellular bacteria rather than cy-
anobacteria. This complex natural product displays impressive
biological properties including antifungal activity and potent
cytotoxicity2 against a number of tumor cells. Its cytotoxicity
has been attributed to its ability to dimerize actin and disrupt
the actin cytoskeleton.3 The molecular structure of swinholide
A (1) is distinguished by a C2 symmetric 44-membered
macrolide ring, two conjugated diene systems, two trisubstituted
pyran systems, and two disubstituted dihydropyran systems. In
addition, a total of 30 stereogenic centers are present in the
carbon backbone of 1. The important biological properties of
swinholide A (1) and its natural scarcity, coupled with its
challenging molecular architecture, made it a prime target for
synthesis.4-6 Paterson and his group at Cambridge have already
reported the first total synthesis7 of 1. In this communication
we wish to report an alternative strategy for the total synthesis
of 1 that includes a number of conceptually new elements and
is flexible enough to allow entry into a variety of designed
members of the swinholide class.
Figure 1. Structure of swinholide A (1) and retosynthetic analysis.
in 1 defined a macrolactonization and an esterification as the
final key reactions in the synthesis. Two Wadsworth-Horner-
Emmons reactions (see Figure 1) pointed to a common
precursor, a C3-C31 fragment, for both halves of the target
molecule (compound 10, Scheme 1). Disconnection of the
C17-C18 and C17′-C18′ bonds using a retro dithiane8 -cyclic
sulfate9 coupling reaction allowed the utilization of the two
segments C3-C17 and C18-C31 [see compounds 3 and 4
(Scheme 1)]. Finally, disassembly of the dihydropyran systems
as shown identified a Ghosez cyclization10 as a potential means
to construct these systems. The execution of this strategy
proceeded as follows.
Diol 26b was converted to cyclic sulfate 3 in 95% yield upon
treatment9 with SOCl2 in the presence of Et3N followed by
oxidation with RuCl3 catalyst and NaIO4. Coupling of this
sulfate with the lithio derivative of dithiane 4,6a generated by
the action of t-BuLi in the presence of HMPA, followed by
aqueous acid treatment led to dithiane 5 in 72% overall yield.
The success of this coupling method with such complex
substrates is unprecedented to our knowledge and bodes well
for the potential of this method in complex molecule synthesis.
Figure 1 outlines the retrosynthetic analysis which led to the
evolution of the synthetic strategy that culminated in the present
total synthesis of swinholide A (1). The symmetry of the
molecule allowed the double disconnections indicated and the
adoption of a highly convergent plan using simple building
blocks. Thus, sequential disconnection of the two ester linkages
11
Removal of the dithiane moiety from 5 with NBS and AgClO4
revealed ketone 6, which upon reduction with NaBH4 in the
presence of n-Bu3B12 followed by basic hydrogen peroxide
workup gave the requisite â-alcohol in 92% yield. Protection
of the generated syn-1,3-diol as a p-methoxybenzylidene system
was then carried out with p-methoxybenzaldehyde dimethyl
acetal and a catalytic amount of CSA, furnishing intermediate
7 in 90% yield. Sequential removal of the benzoate (Dibal-H,
95%) and TBS (HF‚pyr, 90%) groups afforded diol 9 via
compound 8. Aldehyde 10 was then generated in 99% yield
from allylic alcohol 9 by selective oxidation with MnO2.
Extension of this aldehyde via a Wadsworth-Horner-Emmons
olefination reaction using the lithio derivative obtained from
trimethyl phosphonoacetate and n-BuLi furnished selectively
the (E,E)-ester 11 in 97% yield. Finally, hydrolysis of the
methyl ester in 11 was achieved by exposure to NaOH in
aqueous MeOH-THF to give hydroxy acid 12 (92%) from
which the trimethylsilyl ether 13 was generated by treatment
with TMSOTf in the presence of Hu¨nig’s base (89%).
(1) (a) Carmely, S.; Kashman, Y. Tetrahedron Lett. 1985, 26, 511. (b)
Bewley, C. A.; Holland, N. D.; Faulkner, D. J. Experientia, in press, 1996.
(2) (a) Kobayashi, M.; Tanaka, J.; Katori, T.; Matsura, M.; Kitagawa, I.
Tetrahedron Lett. 1989, 30, 2963. (b) Doi, M.; Ishida, T.; Kobayashi, M.;
Kitagawa, I. J. Org. Chem. 1991, 56, 3629. (c) Kitagawa, I.; Kobayashi,
M.; Katori, T.; Yamashita, M. J. Am. Chem. Soc. 1990, 112, 3710. (d)
Kobayashi, M.; Tanaka, J.; Katori, T.; Yamashita, M.; Matsuura, M.;
Kitagawa, I. Chem. Pharm. Bull. 1990, 38, 2409. (e) Kobayashi, M.; Tanaka,
J.; Katori, T.; Kitagawa, I. Chem. Pharm. Bull. 1990, 38, 2960.
(3) Bubb, M. R.; Spector, I.; Bershadsky, A. D.; Korn, E. D. J. Biol.
Chem. 1995, 270, 3463.
(4) (a) Paterson, I.; Cumming, J. Tetrahedron Lett. 1992, 33, 2847. (b)
Paterson, I.; Smith, J. D. J. Org. Chem. 1992, 57, 3261. (c) Paterson, I.;
Yeung, K. Tetrahedron Lett. 1993, 34, 5347. (d) Paterson, I.; Smith, J. D.
Tetrahedron Lett. 1993, 34, 5354. (e) Paterson, I.; Cumming, J. G.; Smith,
J. D.; Ward, R. A. Tetrahedron Lett. 1994, 35, 3405. (f) Paterson, I.; Smith,
J. D.; Ward, R. A.; Cumming, J. G. J. Am. Chem. Soc. 1994, 116, 2615.
(g) Paterson, I.; Cumming, J. G.; Ward, R. A.; Lamboley, S. Tetrahedron
1995, 51, 9393. (h) Paterson, I.; Smith, J. D.; Ward, R. A. Tetrahedron
1995, 51, 9413. (i) Paterson, I.; Ward, R. A.; Smith, J. D.; Cumming, J.
G.; Yeung, K. Tetrahedron 1995, 51, 9437.
(5) (a) Nakata, T.; Komatsu, T.; Nagasawa, K. Chem. ReV. Bull. 1994,
42, 2403. (b) Nakata, T.; Komatsu, T.; Nagasawa, K.; Yamada, H.;
Takahashi, T. Tetrahedron Lett. 1994, 35, 8225. (c) Mulzer, J.; Meyer, F.
Buschmann, J.; Luger, P. Tetrahedron Lett. 1995, 36, 3503.
(6) (a) Patron, A. P.; Richter, P. K.; Tomaszewski, M. J.; Miller, R. A.;
Nicolaou, K. C. J. Chem. Soc., Chem. Commun. 1994, 1147. (b) Richter,
P. K.; Tomaszewski, M. J.; Miller, R. A.; Patron, A. P.; Nicolaou, K. C. J.
Chem. Soc., Chem. Commun. 1994, 1151.
(7) (a) Paterson, I.; Yeung, K.; Ward, R. A.; Cumming, J. G.; Smith, J.
D. J. Am. Chem. Soc. 1994, 116, 9391. (b) Paterson, I.; Yeung, K.; Ward,
R. A.; Smith, J. D.; Cumming, J. G.; Lamboley, S. Tetrahedron 1995, 51,
9467.
Esterification of carboxylic acid 11 with alcohol 13 in the
presence of DIC13 and 4-DMAP at 35 °C gave the expected
coupling product albeit in low yield (4-13%). A higher yield
(8) (a) Corey, E. J.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1965, 4,
1075. (b) Bulman Page, P. C.; Van Niel, M. B.; Prodger, J. C. Tetrahedron
1989, 45, 7643.
(9) Sharpless, K. B.; Gao, Y. J. Am. Chem. Soc. 1988, 110, 7538.
(10) Carretero, J.; Ghosez, L. Tetrahedron Lett. 1988, 29, 2059.
(11) Modified procedure from the following: (a) Corey, E. J.; Erickson,
B. W. J. Org. Chem. 1971, 36, 3553. (b) Cain, E. N.; Welling, L. L.
Tetrahedron Lett. 1975, 16, 1356.
(12) Narasaka, K.; Pai, F. C. Tetrahedron 1984, 40, 2233.
0002-7863/96/1518-3059$12.00/0 © 1996 American Chemical Society

3060 J. Am. Chem. Soc., Vol. 118, No. 12, 1996
Communications to the Editor
Scheme 2. Final Stages of the Synthesisa
Scheme 1. Construction of Key Intermediates 11 and 13a
10
a
Reagents and conditions: (a) 1.5 equiv of SOCl2 (6 M solution in
CH2Cl2), 4.0 equiv of Et3N, CH2Cl2, 0 °C, 10 min, then 0.03 equiv of
RuCl3, 4.0 equiv of NaIO4, CCl4:CH3CN:H2O (2:2:3, v:v), 0 °C, 1.5 h,
95%; (b) 1.2 equiv of t-BuLi (1 M hexanes), 4.0 equiv of HMPA, THF
(0.25 M), -78 °C, 10 min, then 1:1 equiv of 3 (0.125 M in THF),
-78 °C, 10 min; (c) 2.0 equiv of 10% aqueous H2SO4, THF, 25 °C, 1
h, 72% (2 steps); (d) 2.0 equiv of NBS, 2.2 equiv of AgClO4, 10%
aqueous acetone, 0 °C, 1 min, 90%; (e) 1.1 equiv of n-Bu3B (1 M, in
THF), air, THF, 25 °C, 2 h, then 2.2 equiv of NaBH4, -78 °C, 8 h,
then 30% H2O2, 10% aqueous NaOH, 0 °C, 3 h, 92%; (f) 2.0 equiv of
p-MeO-C6H4CH(OMe)2, 0.1 equiv of CSA, CH2Cl2, 0 °C, 3 h, 90%;
(g) 4.0 equiv of DibalH, CH2Cl2, -78 °C, 2.5 h, 95%; (h) HF‚pyr,
pyr, CH2Cl2, 0 °C, 2 h, 90%; (i) 10.0 equiv of MnO2, CH2Cl2, 25 °C,
4 h, 99%; (j) 20.0 equiv of (MeO)2P(O)CH2CO2Me, 15.0 equiv of
n-BuLi (1.6 M in hexanes), THF, 0 f 25 °C, 18 h, 97%; (k) 4.0 equiv
of NaOH, MeOH:THF:H2O, 25 °C, 6 h, 92%, plus 6% recovered 11;
(l) 12.5 equiv of TMSOTf, 25 equiv of i-Pr2NEt, CH2Cl2, 0 f 25 °C,
18 h, 89%.
a
Reagents and conditions: (a) 1.0 equiv of 13, 3.7 equiv of 2,4,6-
Cl3(C6H2)COCl, 4.5 equiv of Et3N, PhMe, 25 °C, 1.5 h, then add 2
equiv of 11, 1.6 equiv of 4-DMAP, PhMe, 105 °C, 12 h, 46%; (b)
large excess Ba(OH)2‚8H2O, MeOH, 25 °C, 96 h, 83%; (c) 15.0 equiv
of 2,4,6-Cl3(C6H2)COCl, 18.0 equiv of Et3N, PhMe, 25 °C, 2.5 h, then
add 1.65 equiv of 4-DMAP, PhMe, 110 °C, 24 h, 38% based on 75%
consumed acid; (d) aqueous HF, MeCN, 0 °C, 2 h, 60%.
substance available for further biological studies, provides access
to a variety of designed mimics.16
(46%) of the coupling product was obtained when the Yamagu-
chi procedure14 (2,4,6-trichlorobenzoyl chloride, Et3N, 4-DMAP)
was employed affording hydroxy ester 14 (Scheme 2) which
Acknowledgment. We thank Drs. Dee H. Huang and Gary Siuzdak
for their NMR and mass spectroscopy assistance, respectively. This
work was financially supported by the National Institutes of Health,
USA, Merck, Pfizer, Hoffmann La Roche, Schering-Plough, Amgen,
Meiji Seika Kaisha (K.A.), and the ALSAM Foundation.
had suffered concomitant TMS removal.
Selective
saponification7b of the ester 14 [Ba(OH)2, H2O, MeOH, 96 h,
83% yield], followed by macrolactonization of the resultant
hydroxy acid using Yamaguchi’s protocol (0.0005 M in toluene,
25 f 110 °C), gave the protected swinholide A 15 (38% yield,
based on 75% conversion). Finally, concurrent removal of all
the protecting groups from 15 with aqueous HF in acetonitrile
liberated swinholide A (1) in 60% yield. Comparison [TLC,
Supporting Information Available: Listing of selected data for
compounds 3, 6, 9-11, 13-15, and 1 (17 pages). This material is
contained in many libraries on microfiche, immediately follows this
article in the microfilm version of the journal, can be ordered from the
ACS, and can be downloaded from the Internet; see any current
masthead page for ordering information and Internet access instructions.
1
HPLC, H NMR, 13C NMR, IR, and [R]D] with an authentic
sample15 confirmed the identity of the synthetic compound.
The reported total synthesis of swinholide A (1) is character-
ized by a highly convergent strategy, features a number of
relatively new reactions, and besides rendering the natural
JA954211T
(15) We thank Dr. John Faulkner for a sample of authentic swinholide
A (1).
(13) Kappe, T.; Fru¨hwirth, F. J. Prakt. Chem. 1990, 332, 475.
(14) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
(16) All new compounds exhibited satisfactory spectral and exact mass
data. Yields refer to spectroscopically and chromatographically homoge-
neous materials.