Total synthesis of Spongistatin 1: A synthetic strategy exploiting its latent pseudo-symmetry

Article abstract of DOI:10.1002/anie.200502008

(Chemical Equation Presented) The challenging structure and potent growth inhibition properties against a variety of human cancer cell lines make Spongistatin 1 (1) an exciting target for total synthesis. Enantioselective total synthesis has been achieved

Full text of DOI:10.1002/anie.200502008

Angewandte
Chemie
lines. These unique natural products were isolated independ-
ently by Pettit, Kitagawa and Fusetani in 1993,[1] although the
absolute structure remained unknown until confirmation by
synthesis in 1997.[2] The spongistatin family includes 9macro-
lides, all of which possess remarkable growth inhibition
properties against the US National Cancer Instituteꢀs panel of
sixty human cancer cell lines. Spongistatin 1 (1) was extremely
potent against a subset of highly chemoresistant tumor types,
with typical GI50 values of 2.5–3.5 ” 10ꢀ1m. Cell lines derived
from human melanoma were also found to be especially
sensitive to Spongistatin 1,[1f,h] the most active of this family of
macrolides (Scheme 1).
Natural Product Synthesis
DOI: 10.1002/anie.200502008
Total Synthesis of Spongistatin 1:
A Synthetic Strategy Exploiting Its Latent
Pseudo-Symmetry**
Matthew Ball, Matthew J. Gaunt, David F. Hook,
Alan S. Jessiman, Shigeru Kawahara, Paolo Orsini,
Alessandra Scolaro, Adam C. Talbot, Huw R. Tanner,
Shigeo Yamanoi, and Steven V. Ley*
Scheme 1. Structure and retrosynthetic analysis of Spongistatin 1 (1).
TES=triethylsilyl, TBS=tert-butyldimethylsilyl,
PMB=p-methoxybenzyl.
The spongistatins comprise an important family of architec-
turally complex marine macrolides that display extraordinary
antitumor activities against a variety of human cancer cell
Spongistatin 1 (1) comprises a 42-membered macrolide
ring, 24 asymmetric centers, a chlorodiene sidechain, two
spiroketals (of which only one contains full anomeric
stabilization) and two pyranyl units. The complex molecular
architecture and exciting biological profile of these natural
products have attracted significant interest resulting in total
syntheses by six groups.[2–3] Our initial synthetic analysis for 1
was consistent with established endgame strategies and
[*] Dr. M. Ball, Dr. M. J. Gaunt, Dr. D. F. Hook, A. S. Jessiman,
S. Kawahara, P. Orsini, A. Scolaro, A. C. Talbot, H. R. Tanner,
Dr. S. Yamanoi, Prof. Dr. S. V. Ley
Department of Chemistry, University of Cambridge
Lensfield Road, Cambridge, CB21EW (UK)
Fax: (+44)122-333-6442
ꢀ
corresponded to a C1 C41(OH) macrolactonization and
E-mail: svl1000@cam.ac.uk
ꢀ
C28 C29Wittig olefination, resulting in two advanced frag-
[**] The authors thank Novartis for the Novartis Research Fellowship
(S.V.L.) and a fully funded studentship (H.T.), the British Ramsey
Trust and Magdalene College, Cambridge for a research fellowship
(M.J.G.), Pfizer Global Research and Development, Sandwich (UK)
(A.S.J.), Pharmacia, Italy (P.O. and A.S.), Ajinomoto Inc., Japan
(S.K.), the Uehara Memorial Foundation for a postdoctoral fellow-
ship (S.Y.), the EPSRC for studentships (A.C.T. and D.F.H.) and a
postdoctoral fellowship (M.B.). We also acknowledge the contri-
bution of Dr. Richard Turner (University of Cambridge) whose
expertise in preparative HPLC proved invaluable.
ments (ABCD fragment 2 and EF fragment 3) and hence
enabling a convergent approach to the target (Scheme 1).[2–3]
Furthermore, we recognized the utility of the anti-selective
aldol coupling demonstrated by the groups of Evans,[2a]
Paterson,[3d] Heathcock[3f] and more recently Smith[3a] and
Crimmins,[3e] to join the AB and CD units together to form
the basis of fragment 2 in their total syntheses. Accordingly,
we envisaged that appropriately protected AB aldehyde 4 and
Angew. Chem. Int. Ed. 2005, 44, 5433 –5438
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5433

Communications
CD ketone 5 would be suitable coupling partners for this
transformation (Scheme 2).
tion should enable interception of our original routes to AB
(4) and CD (5) subunits. Towards this goal, the AB spiroketal
unit 6 requires one-carbon homologation in the C3 sidechain
to generate the allyl ester 4. In contrast, the CD unit 7
requires conversion of the exocyclic alkene into a ketone
followed by effective formyl extrusion (via decarboxylation)
from the C19terminus to afford the ethyl ketone 5. The utility
of this pseudo-symmetric strategy hinges upon the ability to
efficiently facilitate sidechain interconversion and is of
central importance to the success of our second-generation
synthetic strategy (Scheme 2).
The synthesis begins with the preparation of the acyclic
precursor 8. We have previously prepared key aldehyde 9
from (S)-glycidol in the first-generation synthesis of the CD
ketone.[4a] Formation of alkyne 10 as an epimeric mixture at
C5 was achieved by adaptation of previously developed
chemistry towards the AB spiroketal, in this case employing
racemic epichlorohydrin as the central electrophilic compo-
nent.[4b] Addition of the anion of alkyne 10 (formed through
treatment with iPrMgCl) to aldehyde 9 generated a prop-
argylic alcohol as a 1:1 mixture of diastereomers in 85% yield.
Oxidation with Dess–Martin periodinane lead to ynone 11,
which afforded acyclic spiroketal precursor 12 in excellent
yield by double conjugate addition of 1,3-propanedithiol
(83% over 3 steps, Scheme 3).
We have previously reported independent syntheses of
both the AB (4) and CD (5) fragments,[4] employing
ꢀ
acetylide–aldehyde C C-bond formation–oxidation followed
by addition of 1,3-propanedithiol to the resulting ynone as the
key coupling approach for polyketide synthesis. Despite the
high efficiency in these syntheses (average yield per step:
89% (4); 92% (5)), we felt that the overall sequence length,
(64 discrete steps to assemble the ABCD precursors)
precludes the synthesis of significant quantities of the
spongistatins. As a result, we have developed an innovative
second-generation route towards the ABCD bis(spiroketal)
moiety 2, which is reported here along with completion of the
synthesis of the natural product.[5]
Close examination of the ABCD fragment 2 of Spongis-
tatin 1 reveals a high level of latent C2-symmetry about the
C15 atom namely, the carbon framework from C1 to C14 is
very similar to that of C16 to C28 (Scheme 2).[6] The A and D
rings of the spiroketals are essentially identical and differ
principally due to their anomeric arrangements and the C11
and C19stereocenters, which are oppositely configured. We
have already shown that the functionality at both C9and C21
can be introduced through a carbonyl group interconver-
sion.[4] Therefore, C1–C12 and C18–C28 differ by only one
carbon atom and one stereocenter. Furthermore, the sp2-
carbon atoms at C13 and C17 are pseudo-symmetric about
C15, as are the methyl groups at C14 and C16. These
observations suggest that it may be possible to access the C1–
C15 and C15–C28 fragments from an epimeric mixture of
acyclic precursor 8, dramatically decreasing the number of
steps required to assemble the ABCD fragment (Scheme 2).
From an acyclic precursor 8, one C5 epimer will furnish
the AB spiroketal core 6, whilst the opposite C5 epimer would
yield the CD framework 7. Post-spiroketalization modifica-
Treatment of ketone 12 with dilute perchloric acid
generated three different spiroketals corresponding to the
AB double anomeric stabilized unit 13 (ABAA) and the two
CD anomeric isomers, bis-anomeric 14 (CDAA) and mono-
anomeric 15 (CDAE), in
a ratio of ABAA/CDAA/CDAE
1.00:0.74:0.26 (Scheme 4). The three spiroketals were sepa-
rated by preparative HPLC[7] to afford the key cores of the
AB and CD fragments in a total of only 26 discrete steps (17
longest linear sequence). The bis-anomeric 14 (CDAA
)
spiroketal was equilibrated under calcium perchlorate epi-
Scheme 2. Pseudo-symmetric retrosynthetic analysis of the ABCD bis(spiroketal) fragment 2.
5434
www.angewandte.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2005, 44, 5433 –5438

Angewandte
Chemie
Scheme 3. Reagents and conditions: a) iPrMgCl, 10, THF, 2 h, RT;
then 9, THF, ꢀ208C, 1 h; b) Dess–Martin periodinane, CH2Cl2, RT , 1 h,
85% over two steps; c) HS(CH2)3SH, NaOMe, MeOH–CH2Cl2,
ꢀ108C!RT, 16 h, 97%.
Scheme 5. Reagents and conditions: a) TBSCl, imidazole, CH2Cl2, RT ,
17 h, 94% ; b) I2, aq. NaHCO3, MeCN, 08C, 1 h, 99%; c) MeLi, CeCl3,
THF, ꢀ788C, 1 h, 94%; d) DDQ, pH 7 buffer, CH2Cl2, 2 h, RT, 98%;
merization conditions[3a,4] and cleanly converted into the
desired mono-anomeric spiroketal 15 (CDAE) (87% yield
after a 3-step recycle sequence). The equilibration process
required 16 h to afford a 3:1 mixture in favor of the desired
isomer. Interestingly, the presence of the primary hydroxy
group in the C19sidechain increased the proportion of 15
(CDAE) after equilibration. This observation is in agreement
with the results of Evans et al.[2a] and Smith et al.[3a] and in
accord with our findings in our earlier CD fragment synthesis,
which lacked oxygen substitution in the C19sidechain [4a] (first
e) p-TsCl, CH Cl2, pyridine, RT, 19 h, 97%; f) NaCN, DMF, 708C, 6 h,
2
80%. DDQ=2,3-dichloro-5,6-dicyano-p-benzoquinone; p-TsCl=p-tol-
uenesulfonyl chloride; DMF=N,N-dimethylformamide.
organocerium reagent derived from MeLi and CeCl3 formed
the tertiary alcohol 18 as a single diastereomer (d.r. > 20:1).
Oxidative cleavage of the p-methoxybenzyl ether with DDQ
and subsequent mono-tosylation of the resulting primary
alcohol activated the C3 sidechain for carbon homologation.
Tosylate displacement with NaCN[9] afforded 20 in good yield.
Cyanide 20 was converted into the corresponding acid 21
via reduction to the aldehyde followed by Pinnick oxidation
(Scheme 6).[10] Alkylation of the carboxy group by allyl
bromide–cesium carbonate furnished the full AB spiroketal
skeleton 22. Selective acetylation of the secondary alcohol
followed by TES protection of the tertiary hydroxy group
formed 24 in good yield over two steps. HF–pyridine complex
removed the tert-butylsilyl group and subsequent oxidation of
the primary hydroxy group using Dess–Martin periodinane[11]
generation CDAA/CDAE = 1.0:2.2, second generation CDAA
/
CDAE = 1.0:3.0). With an efficient method for the formation
of both AB and CD spiroketal core structures now available,
we investigated subsequent side-chain manipulation to afford
the aldol-coupling fragments 4 and 5.
Elaboration of spiroketal 13 began by the selective
protection of the primary hydroxy group as its silyl ether
followed by iodine-facilitated cleavage of the dithiane unit[8]
to afford the corresponding ketone 17 in excellent yield over
two steps (Scheme 5). Methyl group addition mediated by the
Scheme 4. Reagents and conditions: a) 10% aq. HClO4, MeCN–CH2Cl2, RT, 30 min, 86%; b) 3.5% aq. HClO , 5 equiv Ca(ClO4)2·4H2O, MeCN–
4
CH2Cl2, RT, 18 h, 87% after three recycles.
Angew. Chem. Int. Ed. 2005, 44, 5433 –5438
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5435

Communications
Scheme 6. Reagents and conditions: a) DIBAL-H (1m in CH2Cl2),
CH2Cl2 ꢀ788C!RT, 6 h; b) NaClO , tBuOH, 2-methyl-2-butene, pH 7
2
buffer, RT, 2 h; c) allyl bromide, Cs CO3, THF, RT, 17 h, 51% over three
2
steps; d) Ac2O, pyridine, DMAP, CH2Cl2, RT, 65 h, 86%; e) TESOTf,
2,6-lutidine, ꢀ78!08C, 1 h, 99%; f) HF·pyridine, pyridine–THF, RT
7 h; g) Dess–Martin periodinane, py, CH2Cl2, RT, 3 h, 66% over two
steps. DIBAL-H=diisobutylaluminum hydride; DMAP=4-(N,N-di-
methylamino)pyridine; Tf=trifluoromethanesulfonyl.
Scheme 7. Reagents and conditions: a) 2 equiv PhI(Tfa)2, MeOH, 08C,
40 min; b) aq. NaHCO3, AcOH–THF–H2O, 308C, 6 h; c) TBSCl, imida-
zole, DMF, RT, 14 h, 82% over three steps; d) NaBH , CeCl3·7H2O,
4
THF, MeOH, ꢀ788C, 1 h, 87%; e) NaH, MeI, THF, 08C!RT, 22 h,
96%; f) HF·Pyridine, pyridine–THF, RT, 7 h, 75%. Tfa=trifluoroacetyl.
afforded key aldehyde 4 that was used immediately in the
aldol coupling.
After efficient generation of the anomeric 15 (CDAE
)
spiroketal unit we began its manipulation towards the CD
ethyl ketone 5 (Scheme 7). Initially, two-step dithiane cleav-
age via the dimethylketal afforded ketone 25 in good yield;
this procedure circumvents product decomposition that
occurred under a variety of other cleavage conditions.[4a,12]
Treatment of diol 25 with TBSCl and imidazole in DMF
formed the bis(silyl ether) in excellent yield over the opening
sequence (82% over 3 steps). Reduction under modified
Luche conditions[13] afforded the desired equatorial C15
alcohol as essentially one diastereomer 27 (d.r. > 20:1),
arising from the expected axial hydride delivery. Methylation
proceeded with excellent yield, followed by selective primary
silyl ether cleavage, forming the basis for investigation into
the required carbon extrusion chemistry. Results from model
studies on formyl group expulsion indicated that decarbox-
ylation of a b-ketoacid would be the most reliable tactic.
To this end, oxidation of alcohol 29 with Dess–Martin
periodinane[11] followed by Pinnick oxidation[10] afforded the
acid 30, and brief treatment with ozone in dichloromethane
cleanly delivered the b-ketoacid 31 without affecting the
primary p-methoxybenzyl ether (Scheme 8). The crude mate-
rial could be smoothly decarboxylated with gentle heating in a
toluene/pyridine (2:1) mixture, efficiently delivering the CD
Scheme 8. Reagents and conditions: a) Dess–Martin periodinane,
CH2Cl2, RT, 1 h; b) NaClO , tBuOH, 2-methyl-2-butene, pH 7 buffer, RT,
2
2 h; c) O3, CH2Cl2, ꢀ788C, 3 min; then Me2S, concentrate; d) toluene/
pyridine (2:1), 408C, 3 h, 57% over four steps.
5436
www.angewandte.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2005, 44, 5433 –5438

Angewandte
Chemie
ethyl ketone spiroketal unit 5 ready for use in the aldol
coupling.
With gram-quantities of the key fragments available, we
investigated the aldol union of the CD ketone 5 and AB
aldehyde 4 (Scheme 9). Initially, we used the aldol conditions
the subtle structural differences between our substrates and
the Evans fragments[2a] we initiated a solvent screen which
showed that upon switching to diethyl ether[3d] the reaction
efficiency was greatly increased (78% yield) to afford a 5:1
mixture of diasterosiomers (65% of desired anti-adduct).
Subsequent acetylation, PMB ether cleavage and oxidation
proceeded in high yield to furnish ABCD aldehyde 2, ready
for Wittig coupling with the EF phosphonium salt 3.
We have previously reported model studies[14] and
recently the completion of the EF phosphonium Wittig salt
3,[15] which we subsequently employed in hemisphere uni-
fication. The difficulties associated with late-stage Wittig
coupling between ABCD aldehyde 2 and EF phosphonium
salt 3 have been widely reported[2,3] and are in accord with our
experience (Scheme 10). After experimentation with a vari-
ety of literature conditions, we used a modification of the
procedure reported by Heathcock and co-workers[3f]
(MeLi·LiBr), employing CaH2 to remove residual water
that may reduce yields due to hydrate formation. Further-
more, the addition of HMPA facilitated ylide formation and
subsequent treatment with aldehyde 2 afforded the cis alkene
32 with comparable[3f] efficiency and selectivity (yield 50%).
Oxidative removal of all p-methoxybenzyl protecting groups
in a biphasic solvent system (CH2Cl2–THF–pH 7 buffer) was
accompanied by complete hydrolysis of the C37 methoxy-
ketal. Cleavage of the allyl ester protecting group with Pd0
efficiently furnished the key secoacid intermediate 33.
Macrolactonization of 33 under modified Yamaguchi con-
ditions[2a] yielded silyl-protected Spongistatin 1 34. Global
Scheme 9. Reagents and conditions: a) BCy2Cl, Et3N, Et2O, ꢀ788C!
08C, 10 min; 08C!ꢀ788C; 4, 1 h; ꢀ788C!ꢀ308C, 16 h, 78%,
d.r.=5:1; b) Ac2O, pyridine, 08C!RT, 5 h; c) DDQ, CH Cl2–pH 7
2
buffer, 08C, 5 h; d) Dess–Martin periodinane, CH2Cl2, RT, 3 h, 66%
over three steps. Cy=cyclohexyl.
described by Evansꢀ group employing pentane as the solvent.
Treatment of ketone 5 with dicyclohexylboron chloride
formed the E-boron enolate and following reaction with
aldehyde 4 formed the anti-aldol product as an 8:1 mixture of
diastereomers (45% yield of desired diastereoisomer). Given
Scheme 10. Reagents and conditions: a) 3 treated with MeLi·LiBr, THF, ꢀ788C; then 2 (after drying over CaH2), ꢀ788C!RT, 50%; b) DDQ, THF–
CH2Cl2–pH 7 buffer, RT, 65%; c) [Pd(PPh )4], morpholine, RT; d) 2,4,6-trichlorobenzoylchloride, iPr2NEt, DMAP, toluene, 908C, 56% over two
3
steps; e) 48% HF, CH3CN, ꢀ218C, 57%.
Angew. Chem. Int. Ed. 2005, 44, 5433 –5438
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5437

Communications
198; Angew. Chem. Int. Ed. 1998, 37, 187; M. M. Hayward, R. M.
Roth, K. J. Duffy, P. I. Dalko, K. L. Stevens, J. Guo, Y. Kishi,
Angew. Chem. 1998, 110, 202; Angew. Chem. Int. Ed. 1998, 37,
190.
silyl group removal by treatment with 48% HF yielded
Spongistatin 1 (1), which was identical in all respects to an
authentic sample.[16]
We have completed a synthesis of Spongistatin 1 (1) using
established synthetic procedures and methods developed
within our research group, including the introduction and
subsequent manipulation of b-keto dithiane precursors.
Furthermore, the pseudo-symmetric strategy used in forming
the ABCD bis(spiroketal) unit 2 represents a new approach
towards the family of Spongistatin natural products. The AB
spiroketal unit 4 was prepared in 36 steps (overall yield 10%
over a 27 step longest linear sequence, average yield 90% per
step) and the CD fragment 5 in 37 steps (overall yield 6%
over a 28 step longest linear sequence, average yield per step
89%). By applying the pseudo-symmetric approach we are
able to access much larger quantities of the key ABCD
fragment 2 than from our original route, hence providing the
basis for a pragmatic and expedient assembly of the ABCD
fragment. By application of the pseudo-symmetric strategy
the route is decreased from 65 to only 46 discrete steps from
commercially available starting materials. Ongoing work in
our laboratories is focusing on further improving the effi-
ciency and scale of the synthetic sequences towards the goal
of producing significant quantities of Spongistatin 1.
[3] a) A. B. Smith III, V. A. Doughty, Q. Lin, L. Zhuang, M. D.
McBriar, A. M. Boldi, W. H. Moser, N. Murase, K. Nakayama,
M. Sobukawa, Angew. Chem. 2001, 113, 19 7;Angew. Chem. Int.
Ed. 2001, 40, 191; b) A. B. Smith III, Q. Lin, V. A. Doughty, L.
Zhuang, M. D. McBriar, J. K. Kerns, C. S. Brook, N. Murase, K.
Nakayama, M. Sobukawa, Angew. Chem. 2001, 113, 202; Angew.
Chem. Int. Ed. 2001, 40, 196; c) A. B. Smith III, V. A. Doughty,
C. Sfouggatakis, C. S. Bennett, J. Koyanagi, M. Takeuchi, Org.
Lett. 2002, 4, 783; d) I. Paterson, M. J. Coster, D. Y.-K. Chen,
R. M. Oballa, D. J. Wallace, R. D. Norcross, Org. Biomol. Chem.
2005, 3, 2399; I. Paterson, M. J. Coster, D. Y.-K. Chen, K. R.
Gibson, D. J. Wallace, Org. Biomol. Chem. 2005, 3, 2410; I.
Paterson, M. J. Coster, D. Y.-K. Chen, J. L. Aceꢁa, J. Bach, L. E.
Keown, T. Trieselmann, Org. Biomol. Chem. 2005, 3, 2420; I.
Paterson, D. Y.-K. Chen, M. J. Coster, J. L. Aceꢁa, J. Bach, D. J.
Wallace, Org. Biomol. Chem. 2005, 3, 2431; I. Paterson, D. Y.-K.
Chen, M. J. Coster, J. L. Acena, J. Bach, K. R. Gibson, L. E.
Keown, R. M. Oballa, T. Trieselmann, D. J. Wallace, A. P.
Hodgson, R. D. Norcross, Angew. Chem. 2001, 113, 4179;
Angew. Chem. Int. Ed. 2001, 40, 4055; e) M. T. Crimmins, J. D.
Katz, D. G. Washburn, S. P. Allwein, L. F. McAtee, J. Am. Chem.
Soc. 2002, 124, 5661; f) M. M. Claffey, C. J. Hayes, C. H. Heath-
cock, J. Org. Chem. 1999, 64, 8267, J. L. Hubbs, C. H. Heathcock,
J. Am. Chem. Soc. 2003, 125, 12836; C. H. Heathcock, M.
McLaughlin, J. Medina, J. L. Hubbs, G. A. Wallace, R. Scott,
M. M. Claffey, C. J. Hayes, G. R. Ott, J. Am. Chem. Soc. 2003,
125, 12844.
Received: June 10, 2005
Published online: August 1, 2005
[4] a) M. J. Gaunt, D. F. Hook, H. R. Tanner, S. V. Ley, Org. Lett.
2003, 5, 4815; b) M. J. Gaunt, A. S. Jessiman, P. Orsini, H. R.
Tanner, D. F. Hook, S. V. Ley, Org. Lett. 2003, 5, 4819.
[5] First reported at the Chemistry A European Journal Symposium,
Strasbourg, France, April 15, 2005.
Keywords: dithianes · natural products · pseudo-symmetry ·
spongistatin 1 · total synthesis
.
[6] This structural feature has also been noted by Roush et al. who
applied a double inversion tactic as the basis of forming the AB
and CD spiroketal cores from a common intermediate. E. B.
Holson, W. R. Roush, Org. Lett. 2002, 4, 3719– 3722, E. B.
Holson, W. R. Roush, Org. Lett. 2002, 4, 3723 – 3725.
[7] The spiroketals can also be separated by two successive column-
chromatography operations. However in terms of overall
efficiency, preparative HPLC proved to be the method of
choice. Employing this separation method, multi-gram quanti-
ties of crude spiroketal reaction mixture could be purified and
separated in one day.
[8] M.-K. Chen, G. E. Hardtmann, K. Prasad, O. Repic, M. J.
Shapiro, Tetrahedron Lett. 1987, 28, 155.
[9] R. Baker, M. J. OꢀMahony, C. J. Swain, J. Chem. Soc. Perkin
Trans. 1 1987, 1623.
[10] B. S. Bal, W. E. Childers, H. W. Pinnick, Tetrahedron 1981, 37,
2091.
[11] D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4383.
[12] Conditions based on modification of procedure reported in G.
Stork, K. Zhoa, Tetrahedron Lett. 1989, 30, 287.
[1] a) G. R. Pettit, J. Nat. Prod. 1996, 59, 812; b) G. R. Pettit, Z. A.
Cichacz, F. Goa, C. L. Herald, M. R. Boyd, J. M. Schmidt,
J. N. A. Hooper, J. Org. Chem. 1993, 58, 1302; c) G. R. Pettit,
A. Z. Cichacz, F. Goa, C. L. Herald, M. R. Boyd, J. Chem. Soc.
Chem. Commun. 1993, 1166; d) G. R. Pettit, C. L. Herald, Z. A.
Cichacz, F. Goa, M. R. Boyd, N. D. Christie, J. M. Schmidt, Nat.
Prod. Lett. 1993, 5, 329; e) G. R. Pettit, Z. A. Cichacz, C. L.
Herald, F. Goa, M. R. Boyd, E. Hamel, R. Bai, J. Chem. Soc.
Chem. Commun. 1994, 1605; f) R. Bai, Z. A. Cichacz, C. L.
Herald, G. R. Pettit, E. Hamel, Mol. Pharmacol. 1993, 44, 757;
g) R. K. Pettit, S. McAllister, G. R. Pettit, Antimicrob. Agents
1998, 9, 147; h) R. Bai, G. F. Taylor, Z. A. Chicacz, C. L. Herald,
J. A. Keplar, G. R. Pettit, E. Hamel, Biochemistry 1995, 34, 9714;
i) M. Kobayashi, S. Aoki, H. Sakai, K. Kawazoe, N. Kihara, T.
Sasaki, I. Kitagawa, Tetrahedron Lett. 1993, 34, 2795; j) M.
Kobayashi, S. Aoki, I. Kitagawa, Tetrahedron Lett. 1994, 35,
1243; k) M. Kobayashi, S. Aoki, H. Sakai, N. Kihara, T. Sasaki, I.
Kitagawa, Chem. Pharm. Bull. 1993, 41, 989; l) M. Kobayashi, S.
Aoki, I. K. Gato, I. Kitagawa, Chem. Pharm. Bull. 1996, 44,
2142; m) N. Fusetani, K. Shinoda, S. Matsunaga, J. Am. Chem.
Soc. 1993, 115, 3977.
[2] a) D. A. Evans, P. J. Coleman, L. C. Dias, Angew. Chem. 1997,
109, 2951; Angew. Chem. Int. Ed. Engl. 1997, 36, 2737; D. A.
Evans, B. W. Trotter, B. CôtØ, P. J. Coleman, Angew. Chem. 1997,
109, 2954; Angew. Chem. Int. Ed. Engl. 1997, 36, 2741; D. A.
Evans, B. W. Trotter, B. CôtØ, P. J. Coleman, L. C. Dias, A. N.
Tyler, Angew. Chem. 1997, 109, 2957; Angew. Chem. Int. Ed.
Engl. 1997, 36, 2744; D. A. Evans, B. W. Trotter, P. J. Coleman, B.
CôtØ, L. C. Dias, H. A. Rajapaske, A. N. Tyler, Tetrahedron
1999, 55, 8671; b) J. Guo, K. J. Duffy, K. L. Stevens, P. I. Dalko,
R. M. Roth, M. M. Hayward, Y. Kishi, Angew. Chem. 1998, 110,
[13] A. L. Gemal, J.-L. Luche, J. Am. Chem. Soc. 1981, 103, 5454.
[14] E. Fernandez-Megia, N. Gourlaouen, S. V. Ley, G. J. Rowlands,
Synlett 1998, 991.
[15] S. Kawahara, M. J. Gaunt, A. Scolaro, S. Yamanoi, S. V. Ley,
Synlett 2005, DOI: 10.1055/s-2005-871960.
[16] The authentic sample of Spongistatin 1 (1) was kindly provided
by Professor Pettit.
5438
www.angewandte.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2005, 44, 5433 –5438