Rapid two-directional synthesis of the F-J fragment of the gambieric acids by iterative double ring-closing metathesis

Article abstract of DOI:10.1002/anie.200501925

(Chemical Equation Presented) D-glucal is the starting point for the efficient synthesis of the F-J fragment of the gambieric acids (see scheme). The hiring diol was subjected to double two-directional alkynyl ether formation, carbocupration ring-closing

Full text of DOI:10.1002/anie.200501925

Angewandte
Chemie
Synthetic Methods
DOI: 10.1002/anie.200501925
Rapid Two-Directional Synthesis of the F–J
Fragment of the Gambieric Acids by Iterative
Double Ring-Closing Metathesis**
J. Stephen Clark,* Marc C. Kimber, Jerod Robertson,
Christopher S. P. McErlean, and Claire Wilson
The gambieric acids A–D are potent antifungal agents, first
isolated by Yasumoto and co-workers from a culture of the
marine dinoflagellate Gambierdiscus toxicus (GII1strain)
collected near the Gambier Islands in French Polynesia
(Scheme 1).[1] The structures of these complex fused poly-
ether natural products and the relative stereochemistry of the
[*] Prof. Dr. J. S. Clark, Dr. M. C. Kimber, Dr. J. Robertson,
Dr. C. S. P. McErlean, Dr. C. Wilson
School of Chemistry
University of Nottingham
University Park, Nottingham NG72RD (UK)
Fax: (+44)115-951-3564
E-mail: j.s.clark@nottingham.ac.uk
[**] This work was funded by the Engineering and Physical Sciences
Research Council, UK (grant numbers GR/M30654/01 and GR/
S15761/01).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Scheme 1. The structures of the gambieric acids A–D.
trans-fused ring system (rings B–J) were determined by using
NMR spectroscopic analysis in conjunction with mass-spec-
trometric analysis.[1b] Absolute stereochemical assignments
were later established by NMR spectroscopic analysis of
compounds obtained by derivatization as the Mosher ester
followed by oxidative cleavage of the side chain attached to
the J ring, and by functionalization of the carboxylic acid
functionality by using a chiral anisotropic reagent.[1c]
The gambieric acids are potent and selective antifungal
agents—they display significant activity against filamentous
fungi but are inactive against yeasts—that exhibit up to 2000-
fold higher activity against some fungi than amphotericin B in
certain assays.[2] The gambieric acids are also cytotoxic, but
they do not possess the significant neurotoxicity associated
with most other large marine fused-polyether natural prod-
ucts, such as the brevetoxins, ciguatoxins, yessotoxins, and
maitotoxins.[2] Interestingly, although the gambieric acids do
not function as potent neurotoxins, gambieric acid A does
inhibit binding of the brevetoxin B derivative PbTx-3 to site 5
of voltage-gated sodium channels of excitable membranes.[3]
The obvious synthetic challenges presented by the gam-
bieric acids, coupled with their potent antifungal activity,
make them alluring targets for total synthesis. Recently,
elegant total syntheses of the related marine polyether
natural products brevetoxin A,[4] brevetoxin B,[5] ciguatoxin
CTX-3,[6] gambierol,[7] and gymnocin[8] have been reported. In
contrast, there is a paucity of published work that concerns
the synthesis of the polycyclic ether framework of the
gambieric acids or even small subunits of these natural
products.[9]
We recently initiated a program to synthesize the gam-
bieric acids based on the ring-closing metathesis (RCM)
methodology that we had developed to address the general
problem of fused-polyether construction[10] and have recently
described a concise synthesis of the A ring fragment of the
gambieric acids by using copper-carbenoid chemistry.[11] To
construct the full ten-ring polyether system of the gambieric
acids, we intend to pursue a highly convergent synthetic
strategy in which the target will be constructed by the union of
a tetracyclic A–D fragment and a pentacyclic F–J fragment
followed by final closure of the E ring. Retrosynthetic
disconnection of the F–J fragment I by removal of the side
chain (R1) and functional group interconversion suggests the
enol ether II as an advanced precursor (Scheme 2). Scission of
the F and J rings then leads to the tricyclic intermediate III,
and removal of the acyclic ether substituents leads to the diol
Scheme 2. Retrosynthetic analysis of the F–J fragment of the gambieric
acids.
IV. Removal of the methyl group and retrosynthetic dehy-
dration then reveals the bis(enol ether) V, and scission of the
G and I rings leads to the monocyclic intermediate VI, which
corresponds to the H ring. The tetrahydropyran unit can then
be straightforwardly disconnected through the diol VII to
reveal d-glucal as the chiral-pool starting material.
The use of a two-directional double-RCM reaction twice
in the synthetic sequence to construct the tetrahydropyran G
and I rings simultaneously and then the nine-membered F
ring and the six-membered F ring and the six-membered J
ring simultaneously is intrinsic to the retrosynthetic analysis
shown in Scheme 2. In the forward direction, this approach
would involve double RCM of a bis(enol ether) VI and then
hydroboration of the tricyclic product V to give the diol VIII
after oxidative work-up (Scheme 3).[10a,e,12] The diol VIII
would then be converted into the triene enol ether III; a
second double two-directional RCM reaction would then
deliver the pentacyclic F–J fragment to which the requisite
side chain could be attached.
The anticipated strategy involves two-directional synthe-
sis by iterative double simultaneous (as opposed to sequen-
tial) ring closure. Although there have been some early
examples of two-directional synthesis, the potential of simul-
taneous two-directional homologation has only been fully
appreciated within last decade.[13] Some of the most elegant
examples of this approach have been reported by Schreiber
and co-workers in connection with their syntheses of the
polyol-containing natural products mycotycins and hizikimy-
cin.[14] The implementation of a synthetic strategy that
involves simultaneous two-directional homologation is attrac-
tive because such a reflexive approach can, in principle,
improve the efficiency of both linear and convergent synthe-
ses.[15] However, unless the target molecule is entirely sym-
metrical, it must be possible to perform reactions simulta-
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Scheme 3. The use of iterative double-RCM reactions to construct the
F–J fragment of the gambieric acids.
Scheme 4. Synthesis of the armed H-ring fragment 7. a) NaOMe,
MeOH, RT; b) tBu2Si(OTf)2, DMF, pyridine, ꢀ408C; c) NaH, BnBr,
THF/DMF, 08C!RT (85%, 3 steps); d) DMDO, CH2Cl2, 08C, then
CH2CHCH2MgCl, THF, 08C (82%); e) (COCl)2, DMSO, Et3N, CH2Cl2,
ꢀ788C!RT; f) MeLi, PhMe, ꢀ788C (76%, 2 steps); g) (HF)3·NEt3,
THF, 08C (98%); h) Tf2O then Et3SiOTf, 2,6-lutidine, CH2Cl2, ꢀ788C
(88%); i) nBu3SnCHCH2, nBuLi, CuCN, THF, ꢀ788C then TBAF, THF,
08C (78%); j) HCCSiMe3, nBuLi, DMPU, THF, 08C, then TBAF, THF,
08C (96%); k) H2, the Lindlar catalyst, quinoline, EtOAc, RT (82%);
l) KH, Cl2CCHCl, THF, 08C then nBuLi, Et2O, ꢀ78!ꢀ408C (88%).
DMF=dimethylformamide, DMDO=dimethyldioxirane, DMSO=di-
methyl sulfoxide, TBAF=tetrabutylammonium fluoride, DMPU=N,N’-
dimethyl-N,N’-propyleneurea.
neously at both ends of the molecule while being able to
differentiate the termini at various stages along the synthetic
route.
We have recently demonstrated that it is possible to
construct tricyclic polyether fragments that possess a variety
of ring sizes in good-to-excellent yield by performing
simultaneous double ring construction by using RCM.[16]
Substrates bearing enol ethers, allylic ethers, and alkynyl
ethers or mixtures of these functional groups were employed
as substrates for the double-RCM reactions. The objective of
the investigation described herein was to demonstrate that
the F–J fragment of the gambieric acids could be assembled
by a two-directional approach, in which simultaneous double-
RCM reactions are used twice, and that many of the other
reactions used to assemble the pentacyclic unit could be
performed in a simultaneous or sequential two-directional
fashion.
The two-directional synthesis of the F–J fragment of the
gambieric acids commenced with deacetylation of the com-
mercially available triacetate 1 (Scheme 4). Conversion of the
resulting d-glucal into ether 2 was accomplished by protection
of the primary and proximal secondary hydroxy groups with a
di-tert-butylsilylene group and benzylation of the remaining
hydroxy group.[16,17] The enol ether 2 was then subjected to
highly diastereoselective oxidation with dimethyldioxirane[18]
and the resulting anomeric epoxide underwent ring opening
with allylmagnesium chloride to give the alcohol 3 in good
yield.[19] Swern oxidation followed by treatment of the
resulting ketone with methyllithium at low temperature
afforded the tertiary alcohol 4 in good yield and with a
reasonable level of diastereocontrol (d.r. = 6:1). Subsequent
removal of the di-tert-butylsilylene protecting group afforded
the corresponding triol 5 in high yield, and sequential
treatment of this triol with trifluoromethanesulfonic anhy-
dride and triethylsilyl trifluoromethanesulfonate in the pres-
ence of 2,6-lutidine in a one-pot procedure gave the primary
triflate with concomitant protection of the secondary hydroxy
group. Introduction of the alkene side chain was then
accomplished in a single operation by displacement of the
triflate group with the higher-order cyanocuprate, generated
from vinyllithium (formed in situ by transmetalation from tri-
n-butylvinylstannane) and copper(i) cyanide at low temper-
ature,[20] and the diol 6 was obtained in good yield thereafter
by desilylation of the secondary hydroxy site. The alkenyl side
chain was also constructed by displacement of the triflate with
lithium trimethylsilylacetylide followed by treatment of the
alkyne product with fluoride and partial hydrogenation using
the Lindlar catalyst in the presence of quinoline. The overall
yield of the diol 6 obtained by using the less-direct route was
similar to that obtained by using the higher-order cyanocup-
rate to displace the triflate directly. Diol 6 was then converted
into the bis(alkynyl ether) 7 by using the one-pot alkynylation
procedure developed by Greene and co-workers.[21] The
alkynylation reaction was the first two-directional reaction
in our synthetic sequence, and it is noteworthy that both
alkynyl ethers were generated simultaneously in excellent
yield and that the highly hindered tertiary alcohol underwent
reaction cleanly.
The bis(enol ether) required for the first double-RCM
reaction was prepared from the bis(alkynyl ether) 7 by using
sequential carbocupration reactions (Scheme 5).[22] The first
side chain was introduced by a completely regioselective
addition of a homocuprate reagent at the less sterically
encumbered alkynyl ether. An acetal-containing side chain
was then installed by reaction of the remaining hindered
alkynyl ether with an excess of the cyanocuprate generated
from equimolar amounts of the Grignard reagent 1,3-
dioxolan-2-ylethylmagnesium bromide and copper(i) cya-
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phenyl selenocyanate and tri-n-butylphosphine followed by
oxidation of the intermediate selenide with buffered hydro-
gen peroxide and thermal elimination of selenoxide in situ.[27]
Removal of the silicon protecting group afforded the alcohol
12, and subsequent oxidation and stereoselective addition of
methylmagnesium iodide to the intermediate ketone deliv-
ered the tertiary alcohol 13 in a highly diastereoselective
manner.
Acetal 13 was then elaborated to give the F–J ring
fragment of the gambieric acids by using the sequence shown
in Scheme 6. Acetal 13 was converted into the corresponding
Scheme 5. Synthesis of the tricyclic G–I fragment 13. a) PMBO-
(CH2)3MgBr, CuBr, LiBr, THF, ꢀ95!ꢀ788C (85%);
b) (OCH2CH2O)CH(CH2)2MgBr, CuCN, LiCl, THF, ꢀ788C (84%);
c) catalyst 14 (10 mol%), PhMe, 708C (89%); d) thexyl borane, THF,
08C!RT then NaBO3·4H2O, pH 7 buffer (62%); e) TsOH, MeOH, RT
(71%); f) tBuMe2SiCl, DMAP, Et3N, CH2Cl2, RT; g) CAN, MeCN, H2O,
RT (56%, 2 steps); h) o-O2NC6H4SeCN, nBu3P, THF, RT then H2O2,
NaHCO3 aq., 408C; i) TBAF, THF, RT (83%, 2 steps); j) Dess–Martin
periodinane, CH2Cl2, 08C; k) MeMgI, PhMe, ꢀ788C (83%, 2 steps).
PMB=pentamethylbenzyl, Cy=cyclohexyl, Mes=mesityl, Bn=benzyl,
TBS=tert-butyldimethylsilyl, Ts=para-toluenesulfonyl, DMAP=4-di-
methylaminopyridine , CAN=cerium(iv) ammonium nitrate.
Scheme 6. Completion of the pentacyclic F–J fragment 19. a) HCl aq.,
THF, 608C; b) NaBH4, MeOH, 08C (84%, 2 steps); c) o-O2NC6H4-
SeCN, nBu3P, THF, RT then H2O2, NaHCO3 aq., 408C (96%);
d) CH2CH(CH2)3Br, nBu4NI, THF/DMF, reflux (66% (81% brsm));
e) KH, Cl2CCHCl, THF, 08C then nBuLi, Et2O, ꢀ78!ꢀ408C; f) H2,
Lindlar catalyst, quinoline, EtOAc, RT (49%, 2 steps); g) catalyst 14
(10 mol%), PhMe, 808C (60%).
nide.[23] The yields for both carbocupration reactions were
excellent and the exceptionally high level of regiocontrol
obtained during the first carbocupration reaction of the
sequence is remarkable.
cyclic hemiacetal by treatment with aqueous acid, and
subsequent reduction with sodium borohydride gave diol 15.
Dehydration of the side chain was effected by formation of
selenide, oxidation, and elimination of selenoxide (cf. 11!12,
Scheme 5), but protection of the secondary alcohol was not
required in this case. Selective monoalkylation of the
secondary hydroxy group of diene 16 was accomplished by
sequential treatment with sodium hydride and 5-bromo-1-
pentene in the presence of tetra-n-butylammonium iodide.
The remaining hydroxy group of triene 17 was then converted
into the requisite vinyl ether by sequential alkynyl ether
formation and Lindlar reduction,[16] thus giving the second
double-RCM precursor 18 in reasonable yield. The final
crucial double-RCM reaction to give the required nine- and
six-membered cyclic ethers was then effected by treatment of
the tricyclic compound 18 with the ruthenium complex 14.[24]
The pentacyclic array 19, which corresponds to the F–J ring
fragment of the gambieric acids, was obtained from the
reaction in 60% yield. Analysis of partially cyclized material
isolated from the reaction suggested that ring closure of the
enol ether proceeds at a much faster rate than formation of
the nine-membered ring.
The bis(enol ether) 8 was subjected to double RCM by
treatment with ruthenium catalyst 14,[24] and the tricyclic
product 9 was obtained in excellent yield from this two-
directional ring-closure reaction (Scheme 5).[16] Double
hydroboration of the metathesis product 9 was accomplished
by using an excess of thexylborane, and mild oxidation of the
intermediate organoborane with sodium perborate delivered
the required diol in 62% yield.[25] Treatment of the diol with
para-toluenesulfonic acid in methanol yielded the tetracyclic
acetal 10 in excellent yield and resulted in differentiation of
the two secondary hydroxy groups. The free secondary
alcohol was then protected as its tert-butyldimethylsilyl
ether and the para-methoxybenzyl ether side chain was
cleaved with CAN. The resulting alcohol 11 was a crystalline
solid, and both the structure and relative stereochemistry of
this tetracyclic intermediate were confirmed by X-ray crys-
tallographic analysis.[26]
The alkene required for the second double-RCM reaction
was installed by dehydration of the side chain (Scheme 5).
Thus, the primary alcohol 11 was treated with ortho-nitro-
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968; d) M. Inoue, M. Hirama, Synlett 2004, 577 – 595; e) M.
In summary, we have demonstrated that the F–J fragment
of the gambieric acids can be assembled by a rapid and
efficient two-directional approach in which simultaneous
double-RCM reactions are employed in an iterative
manner. The formation of alkynyl ethers and carbocupration
have also been performed in a two-directional manner, and it
should be noted that by reordering some of the steps in the
synthetic sequence, other reactions (e.g., the formation of
selenide, oxidation, and elimination of selenoxide) could also
be performed simultaneously, thus leading to an even more
efficient route. The synthesis of the F–J fragment with the
appropriate functionalities for the attachment of the A–D
fragment is currently in progress, and results of these
synthetic studies will be reported in due course.
Inoue, K. Miyazaki, H. Uehara, M. Maruyama, M. Hirama,
Proc. Natl. Acad. Sci. USA 2004, 101, 12013 – 12018.
[7] a) H. Fuwa, M. Sasaki, M. Satake, K. Tachibana, Org. Lett. 2002,
4, 2981– 2984; b) H. Fuwa, N. Kainuma, K. Tachibana, M.
Sasaki, J. Am. Chem. Soc. 2002, 124, 14983 – 14992; c) I. Kadota,
H. Takamura, K. Sato, A. Ohno, K. Matsuda, Y. Yamamoto, J.
Am. Chem. Soc. 2003, 125, 46 – 47; d) I. Kadota, H. Takamura, K.
Sato, A. Ohno, K. Matsuda, M. Satake, Y. Yamamoto, J. Am.
Chem. Soc. 2003, 125, 11893 – 11899; e) H. W. B. Johnson, U.
Majumder, J. D. Rainier, J. Am. Chem. Soc. 2005, 127, 848 – 849.
[8] a) C. Tsukano, M. Sasaki, J. Am. Chem. Soc. 2003, 125, 14294 –
14295; b) C. Tsukano, M. Ebine, M. Sasaki, J. Am. Chem. Soc.
2005, 127, 4326 – 4335.
[9] a) I. Kadota, N. Oguro, Y. Yamamoto, Tetrahedron Lett. 2001,
42, 3645 – 3647; b) I. Kadota, H. Takamura, Y. Yamamoto,
Tetrahedron Lett. 2001, 42, 3649 – 3651.
[10] a) J. S. Clark, J. G. Kettle, Tetrahedron Lett. 1997, 38, 123 – 126;
b) J. S. Clark, J. G. Kettle, Tetrahedron Lett. 1997, 38, 127 – 130;
c) J. S. Clark, O. Hamelin, R. Hufton, Tetrahedron Lett. 1998, 39,
8321– 8324; d) J. S. Clark, G. P. Trevitt, D. Boyall, B. Stammen,
Chem. Commun. 1998, 2629 – 2630; e) J. S. Clark, J. G. Kettle,
Tetrahedron 1999, 55, 8231– 8248; f) J. S. Clark, F. Elustondo,
G. P. Trevitt, D. Boyall, J. Robertson, A. J. Blake, C. Wilson, B.
Stammen, Tetrahedron 2002, 58, 1973 – 1982; g) J. S. Clark, F.
Elustondo, M. C. Kimber, Chem. Commun. 2004, 2470 – 2471.
[11] J. S. Clark, T. C. Fessard, C. Wilson, Org. Lett. 2004, 6, 1773 –
1776.
[12] For other examples of the polyether construction by RCM of
enol ethers, see: a) J. D. Rainier, S. P. Allwein, J. Org. Chem.
1998, 63, 5310 – 5311; b) J. D. Rainier, J. M. Cox, S. P. Allwein,
Tetrahedron Lett. 2001, 42, 179 – 181; c) J. D. Rainier, S. P.
Allwein, J. M. Cox, J. Org. Chem. 2001, 66, 1380 – 1386.
[13] For a review of two-directional approaches to natural-product
synthesis, see: S. R. Magnuson, Tetrahedron 1995, 51, 2167 –
2213.
[14] a) S. L. Schreiber, M. T. Goulet, J. Am. Chem. Soc. 1987, 109,
8120 – 8122; b) N. Ikemoto, S. L. Schreiber, J. Am. Chem. Soc.
1992, 114, 2524 – 2536; c) C. S. Poss, S. D. Rychnovsky, S. L.
Schreiber, J. Am. Chem. Soc. 1993, 115, 3360 – 3361; d) C. S. Poss,
S. L. Schreiber, Acc. Chem. Res. 1994, 27, 9 – 1 7.
[15] S. H. Bertz, New J. Chem. 2003, 27, 870 – 879.
[16] J. S. Clark, O. Hamelin, Angew. Chem. 2000, 112, 380 – 382;
Angew. Chem. Int. Ed. 2000, 39, 372 – 374.
[17] J. O. Hoberg, Carbohydr. Res. 1997, 300, 365 – 367.
[18] R. L. Halcomb, S. J. Danishefsky, J. Am. Chem. Soc. 1989, 111,
6661– 6666.
[19] a) W. M. Best, V. Ferro, J. Harle, R. V. Stick, D. M. G. Tilbrook,
Aust. J. Chem. 1997, 50, 463 – 472; b) D. A. Evans, B. W. Trotter,
B. CôtØ, Tetrahedron Lett. 1998, 39, 1709 – 1712; c) J. D. Rainier,
S. P. Allwein, J. Org. Chem. 1998, 63, 5310 – 5311.
[20] H. Tanaka, K. Kawai, K. Fujiwara, A. Murai, Tetrahedron 2002,
58, 10017 – 10031.
[21] A. Moyano, F. Charbonnier, A. E. Greene, J. Org. Chem. 1987,
52, 2919 – 2922.
[22] S. E. Denmark, V. Guagnano, J. A. Dixon, A. Stolle, J. Org.
Chem. 1997, 62, 4610 – 4628.
[23] D. Liu, L. M. Stuhmiller, T. C. McMorris, J. Chem. Soc. Perkin
Trans. 1 1988, 2161 – 2167.
[24] M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett. 1999, 1,
953 – 956.
[25] a) D. S. Matteson, R. J. Moody, J. Org. Chem. 1980, 45, 1091 –
1095; b) G. W. Kabalka, J. T. Maddox, T. Shoup, K. R. Bowers,
Org. Synth. 1996, 73, 116 – 122; c) A. McKillop, W. R. Sanderson,
J. Chem. Soc. Perkin Trans. 1 2000, 471– 476.
Received: June 2, 2005
Published online: August 31, 2005
Keywords: cyclization · metathesis · natural products ·
.
polyethers
[1] a) H. Nagai, K. Torigoe, M. Satake, M. Murata, T. Yasumoto, H.
Hirota, J. Am. Chem. Soc. 1992, 114, 1102 – 1103; b) H. Nagai,
M. Murata, K. Torigoe, M. Satake, T. Yasumoto, J. Org. Chem.
1992, 57, 5448 – 5453; c) A. Morohashi, M. Satake, H. Nagai, Y.
Oshima, T. Yasumoto, Tetrahedron 2000, 56, 8995 – 9001.
[2] H. Nagai, Y. Mikami, K. Yazawa, T. Gonoi, T. Yasumoto, J.
Antibiot. 1993, 46, 520 – 522.
[3] M. Inoue, M. Hirama, M. Satake, K. Sugiyama, T. Yasumoto,
Toxicon 2003, 41, 469 – 474.
[4] a) K. C. Nicolaou, Z. Yang, G.-Q. Shi, J. L. Gunzner, K. A.
Agrios, P. Gärtner, Z. Yang, Nature 1998, 392, 264 – 269; b) K. C.
Nicolaou, M. E. Bunnage, D. G. McGarry, S. Shi, P. K. Somers,
P. A. Wallace, X.-J. Chu, K. A. Agrios, J. L. Gunzner, Z. Yang,
Chem. Eur. J. 1999, 5, 599 – 617; c) K. C. Nicolaou, P. A. Wallace,
S. Shi, M. A. Ouellette, M. E. Bunnage, J. L. Gunzner, K. A.
Agrios, G.-Q. Shi, P. Gärtner, Z. Yang, Chem. Eur. J. 1999, 5,
618 – 627; d) K. C. Nicolaou, G.-Q. Shi, J. L. Gunzner, P. Gärtner,
P. A. Wallace, M. A. Ouellette, S. Shi, M. E. Bunnage, K. A.
Agrios, C. A. Veale, C.-K. Hwang, J. Hutchinson, C. V. C.
Prasad, W. W. Ogilvie, Z. Yang, Chem. Eur. J. 1999, 5, 628 –
645; e) K. C. Nicolaou, J. L. Gunzner, G.-Q. Shi, K. A. Agrios, P.
Gärtner, Z. Yang, Chem. Eur. J. 1999, 5, 646 – 658.
[5] a) K. C. Nicolaou, C.-K. Hwang, M. E. Duggan, D. A. Nugiel, Y.
Abe, K. B. Reddy, S. A. DeFrees, D. R. Reddy, R. A. Awartani,
S. R. Conley, F. P. J. T. Rutjes, E. A. Theodorakis, J. Am. Chem.
Soc. 1995, 117, 10227 – 10238; b) K. C. Nicolaou, E. A. Theo-
dorakis, F. P. J. T. Rutjes, M. Sato, J. Tiebes, X.-Y. Xiao, C.-K.
Hwang, M. E. Duggan, Z. Yang, E. A. Couladouros, F. Sato, J.
Shin, H.-M. He, T. Bleckman, J. Am. Chem. Soc. 1995, 117,
10239 – 10251; c) K. C. Nicolaou, F. P. J. T. Rutjes, E. A. Theo-
dorakis, J. Tiebes, M. Sato, E. Untersteller, J. Am. Chem. Soc.
1995, 117, 10252 – 10263; d) K. C. Nicolaou, E. A. Theodorakis,
F. P. J. T. Rutjes, J. Tiebes, M. Sato, E. Untersteller, X.-Y. Xiao, J.
Am. Chem. Soc. 1995, 117, 1171 – 1172; e) K. C. Nicolaou,
F. P. J. T. Rutjes, E. A. Theodorakis, J. Tiebes, M. Sato, E.
Untersteller, J. Am. Chem. Soc. 1995, 117, 1173 – 1174; f) K. C.
Nicolaou, Angew. Chem. 1996, 108, 644 – 664; Angew. Chem. Int.
Ed. Engl. 1996, 35, 589 – 607.
[6] a) M. Hirama, T. Oishi, H. Uehara, M. Inoue, M. Maruyama, H.
Oguri, M. Satake, Science 2001, 294, 1904 – 1907; b) M. Inoue, H.
Uehara, M. Maruyama, M. Hirama, Org. Lett. 2002, 4, 4551–
4554; c) M. Inoue, M. Hirama, Acc. Chem. Res. 2004, 37, 961–
[26] Crystal data for the acetal 11: C32H52O8Si, Mr = 592.85, colorless
block cut from lath, crystal dimensions 0.52 ” 0.48 ” 0.32 mm3,
Angew. Chem. Int. Ed. 2005, 44, 6157 –6162
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
6161

Communications
orthorhombic, space group P212121, a = 9.287(4), b = 24.984(11),
c = 43.067(19) Š, V= 9993(8) Š3, Z = 12, 1calcd = 1.182 Mgmꢀ3
,
m(MoKa) 0.117 mmꢀ1, T= 150(2) K; 28321 reflections collected
of which 15595 independent, 2qmax = 508, absorption correction
made using multi-scan method (SADABS), Tmin/max = 0.562/1.00.
Structure solved by direct methods (SHELXS-97) and refined by
full-matrix least squares against F2 (SHELXTL), R1 = 0.106,
wR2 = 0.248, 1101 parameters. One tBuMe2Si group showed
disorder and was modeled over two sites with occupancies
0.577(7) and 0.423(7) and isotropic atomic displacement param-
eters. All hydrogen atoms were placed in geometrically calcu-
lated positions, except those of OH groups which were located
from difference Fourier syntheses and refined as rigid rotors.
Maximum and minimum residual electron density = 0.66 and
ꢀ0.50 eŠꢀ3. CCDC-273286 contains the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[27] P. A. Grieco, S. Gilman, M. Nishizawa, J. Org. Chem. 1976, 41,
1485 – 1486.
6162
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Angew. Chem. Int. Ed. 2005, 44, 6157 –6162