Synthesis of a C29-C51 subunit of spongistatin 1 (altohyrtin A) starting from (R)-3-benzyloxy-2-methylpropan-1-ol

Article abstract of DOI:10.1021/jo991642b

A protected C₂₉-C₅₁ subunit ((+)-38) of spongistatin 1 has been obtained. Key steps involve the aldol condensation of (3S,4R)-3-methyl-7-[(p- methoxybenzyl)oxy]-4-[(triethylsilyl)oxy]octan-2-one ((-)-6) with (tert- butyl)dimethylsilyl 4-deoxy-2,3-di-O-(methoxymethyl)-4-methyl-6-O-(tert- butyl)dimethylsilyl)-β-D-glycero-L-gluco-heptodialdo-1,5-pyranoside ((+)-7) and a C-glycosidation of (4R,7RandS,E)-7,8-dichloro-2-methylidene-1- (trimethylsilyl)oct-5-en-4-yl p-methoxybenzoate (16). Aldehyde (+)-7 was derived from (R)-3-benzyloxy-2-methylpropan-1-ol ((+)-10) in 13 formal steps but requiring the isolation of five intermediate products only. The longest linear synthetic scheme converts (+)-10 into (+)-38 in 2% overall yield (isolation of 11 intermediate products).

Full text of DOI:10.1021/jo991642b

3346
J . Org. Chem. 2000, 65, 3346-3356
Syn th esis of a C29-C51 Su bu n it of Sp on gista tin 1 (Altoh yr tin A)
Sta r tin g fr om (R)-3-Ben zyloxy-2-m eth ylp r op a n -1-ol
Sandrine Lemaire-Audoire* and Pierre Vogel
Section de Chimie, Universite´ de Lausanne, BCH, CH-1015 Lausanne-Dorigny, Switzerland
Received October 20, 1999
A protected C29-C51 subunit ((+)-38) of spongistatin 1 has been obtained. Key steps involve the
aldol condensation of (3S,4R)-3-methyl-7-[(p-methoxybenzyl)oxy]-4-[(triethylsilyl)oxy]octan-2-one
((-)-6) with (tert-butyl)dimethylsilyl 4-deoxy-2,3-di-O-(methoxymethyl)-4-methyl-6-O-(tert-butyl)-
dimethylsilyl)-â-D-glycero-L-gluco-heptodialdo-1,5-pyranoside ((+)-7) and a C-glycosidation of
(4R,7R&S,E)-7,8-dichloro-2-methylidene-1-(trimethylsilyl)oct-5-en-4-yl p-methoxybenzoate (16). Al-
dehyde (+)-7 was derived from (R)-3-benzyloxy-2-methylpropan-1-ol ((+)-10) in 13 formal steps
but requiring the isolation of five intermediate products only. The longest linear synthetic scheme
converts (+)-10 into (+)-38 in 2% overall yield (isolation of 11 intermediate products).
The spongistatins1,2 and altohyrtins3,4 are cytotoxic
(50-chloro-substituted congeners)4 in which both rings E
and F are formed.
macrolides isolated in minute amounts from marine
organisms. They display especially powerful growth
inhibitory activity in vitro against multidrug-resistant
cancer cells, probably resulting from inhibition of tubulin
polymerization.2 A first total synthesis of spongistatin 1
(altohyrtin A), which is among the most potent congeners,
has been reported by Kishi and co-workers,5 a few weeks
after the report of the group of Evans6 on the total
synthesis of spongistatin 2 (altohyrtin C).7 Several other
groups have already reported on the preparation of
various fragments of this extremely important class of
natural products.8 In a preliminary report we converted
(R)-(+)-3-benzyloxy-2-methylpropan-1-ol into a 4-deoxy-
4-methyl-D-threo-L-gluco-heptanopyranose derivative and
had studied its C-glycosidation, generating the C37-C45
F-ring fragment of the spongistatins.9 We show now that
similar chemistry can be used to prepare a protected form
of the C29-C51 subunit of spongistatin 1, 3, 4, 5, and 9
(1) Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Herald, C. I.; Boyd, M. R.;
Schmidt, J . M.; Hooper, J . N. A. J . Org. Chem. 1993, 58, 1302-1304.
Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Herald, C. I.; Boyd, M. R. J . Chem.
Soc., Chem. Commun. 1993, 1166-1168. Pettit, G. R.; Herald, C. I.;
Cichacz, Z. A.; Gao, F.; Schmidt, J . M.; Boyd, M. R.; Christie, N. D.;
Boettner, F. E. J . Chem. Soc., Chem. Commun. 1993, 1805-1807.
Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Herald, C. I.; Boyd, M. R.; Schmidt,
J . M.; Hamel, E.; Bai, R. J . Chem. Soc., Chem. Commun. 1994, 1605-
1606. Pettit, G. R. Pure Appl. Chem. 1994, 2271-2281.
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J . M.; Williams, M. D.; Kepler, J . A.; Pettit, G. R.; Hamel, E. Mol.
Pharmacol. 1995, 47, 965-976. Bai, R.; Taylor, G. F.; Cichacz, Z. A.;
Herald, C. I.; Kepler, J . A.; Pettit, G. R.; Hamel, E. Biochemistry 1995,
34, 9714-9721.
Retr osyn th etic P la n . Our retrosynthetic analysis for
the construction of spongistatin 1 (and other 50-chloro
congeners) resembles that adopted by several groups.4,5,8b,c,e
It implies the joining of a suitably protected C29-C51
subunit A with a C1-C28 fragment B via a Wittig
olefination (Scheme 1), followed by a regioselective mac-
rocyclization involving the diol at C-41, C-42.5b The
subunit A will result from a â-C-glucosidation (stereo-
control by steric hindrance due to the protected alcoholic
moiety at C-42) combining the synthetic intermediates
1 and 2 or analogues. Compound 1 is expected to be
formed with high stereoselectivity through asymmetric
allylation with 410 using an enantiomerically pure Lewis
acid as promoter.11 The long-chain pyranoside 2 must
bear orthogonal protective groups P at C-35, C-38, P′ at
C-41, C-42, and P′′ at C-29. Indeed, the terminal C-29
center of A should be deprotected selectively to allow its
conversion into a phosphonium iodide while maintaining
all other alcoholic moieties protected from the Wittig
olefination. Furthermore, once A is combined with B, the
diol at C-41, C-42 should be selectively liberated for the
macrocyclization.
(3) Kobayashi, M.; Aoki, S.; Sakai, H.; Kihara, N.; Saski, T.;
Kitagawa, I. Chem. Pharm. Bull. 1993, 41, 989-991. Kobayashi, M.;
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Hayward, M. M.; Kishi, Y. Angew. Chem., Int. Ed. 1998, 37, 187-192.
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Coleman, P. J . Angew. Chem., Int. Ed. Engl. 1997, 36, 2741-2744.
Evans, D. A.; Trotter, B. W.; Coˆte´, B.; Coleman, P. J .; Dias, L. C.; Tyler,
A. N. Angew. Chem., Int. Ed. Engl. 1997, 36, 2744-2747.
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C.; Rajapakse, H. A.; Tyler, A. N. Tetrahedron 1999, 55, 8671-8726.
10.1021/jo991642b CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/06/2000

C29-C51 Subunit of Spongistatin 1
J . Org. Chem., Vol. 65, No. 11, 2000 3347
Sch em e 1
We thus opted for a p-methoxybenzyl ether at C-29,
methoxymethyl ethers at C-41, C-42, and silyl ethers at
C-35, C-37, C-38, C-47. Synthetic intermediate 2 should
result from a cross-aldolization between methyl ketone
(-)-6 and aldehyde (+)-7, giving aldols 3 that must be
converted through appropriate protection, diastereo-
selective ketone reduction, and oxidation to a 37-keto
derivative, precursor of 2. Methyl ketone (-)-6 will be
prepared applying methods established by Evans and his
group12 via the syn R-methyl-â-hydroxyimide (+)-8. Al-
dehyde (+)-7 will result from a diastereoselective dihy-
droxylation of the enediester 9, followed by lactonization,
reduction, and protection. Compound 9 will be derived
from (+)-10 following a procedure developed by us and
presented earlier.9
(8) (a) Claffey, M. M.; Heathcock, C. H. J . Org. Chem. 1996, 61,
7646-7647. Hayes, C. J .; Heathcock, C. H. J . Org. Chem. 1997, 62,
2678-2679. (b) Paterson, I.; Oballa, R. M.; Norcross, R. D. Tetrahedron
Lett. 1996, 37, 8581-8584. Paterson, I.; Keown, L. E. Tetrahedron Lett.
1997, 38, 5727-5730. Paterson, I.; Oballa, R. M. Tetrahedron Lett.
1997, 38, 8241-8244. Paterson, L.; Wallace, D. J .; Gibson, K. R.
Tetrahedron Lett. 1997, 38, 8911-8914. Paterson, I.; Wallace, D. J .;
Oballa, R. M. Tetrahedron Lett. 1998, 39, 8545-8548. Paquette, L. A.;
Zuev, D. Tetrahedron Lett. 1997, 38, 5115-5118. Paquette, L. A.;
Braun, A. Tetrahedron Lett. 1997, 38, 5119-5122. (c) Smith, A. B.;
Zhuang, L.; Brook, C. S.; Boldi, A. M.; McBriar, M. D.; Moser, W. H.;
Murase, N.; Nakayama, K.; Verhoest, P. R.; Lin, Q. Tetrahedron Lett.
1997, 38, 8667-8670. Smith, A. B.; Zhuang, L.; Brook, C. S.; Lin, Q.;
Moser, W. H.; Lee Trout, R. E.; Boldi, A. M. Tetrahedron Lett. 1997,
38, 8671-8674. Smith, A. B.; Lin, Q.; Nakayama, K.; Boldi, A. M.;
Brook, C. S.; McBriar, M. D.; Moser, W. H.; Sobukawa, M.; Zhuang,
L. Tetrahedron Lett. 1997, 38, 8675-8678. (d) Hermitage, S. A.;
Roberts, S. M.; Watson, D. J . Tetrahedron Lett. 1998, 39, 3567-3570.
Evans, D. A.; Trotter, B. W.; Coˆte´, B. Tetrahedron Lett. 1998, 39, 1709-
1712. Terauchi, T.; Nakata, M. Tetrahedron Lett. 1998, 39, 3795-3798.
Boyes, A. I.; Wild, M. Tetrahedron Lett. 1998, 39, 6725-6728. Crim-
mins, M. T.; Washburn, D. G. Tetrahedron Lett. 1998, 39, 7487-7490.
Micalizio, G. C.; Roush, W. R. Tetrahedron Lett. 1999, 40, 3351-3354.
Smith, A. B.; Lin, Q.; Pettit, G. R.; Chapuis, J . C.; Schmidt, J . M.
Bioorg. Med. Chem. Lett. 1998, 8, 567-568. Dunkel, R.; Mentzel, M.;
Hoffmann, H. R. M. Tetrahedron 1997, 53, 14929-14936. Dunkel, R.;
Hoffmann, H. R. M. Tetrahedron 1999, 55, 8385-8396. Dunkel, R.;
Treu, J .; Hoffmann, H. R. M. Tetrahedron: Asymmetry 1999, 10, 1539-
1549. Kary, P. D.; Roberts, S. M.; Watson, D. J . Tetrahedron: Asym-
metry 1999, 10, 213-216. Kary, P. D.; Roberts, S. M. Tetrahedron:
Asymmetry 1999, 10, 217-219. (e) Fernandez-Megia, E.; Gourlaouen,
N.; Ley, S. V.; Rowlands, G. J . Synlett 1998, 991-994.
P r ep a r a tion of th e C44-C51-Allyla tin g Agen t. Chlo-
rination of methyl (E)-penta-2,4-dienoate (11)13 in chlo-
roform at 0 °C produced methyl (E)-4,5-dichloropent-2-
enoate (12) in 76% yield. Reduction of 12 with (i-Bu)2AlH
in CH2Cl2 gave the corresponding allylic alcohol 13 (80%
yield), which was directly oxidized by Dess-Martin
periodinane14 to give enal 14 (81% yield). In the presence
of 0.1 equiv of the enantiomerically pure titanium alco-
holate derived from the mixing of (S)-BINOL (0.2 equiv)
and Ti(O-i-Pr)4 (0.1 equiv) in CH2Cl2, enal 14 added to
{2-[(trimethylsilyl)methyl]prop-2-enyl}triphenylstan-
nane (4),10 giving alcohol 15 (60% yield). This relatively
unstable compound was esterified without purification
with p-MeO-C6H4COOCl in dry pyridine in the presence
(11) (a) Keck, G. E.; Geraci, L. S. Tetrahedron Lett. 1993, 34, 7827-
7828. (b) Bedeschi, P.; Casdari, S.; Costa, A. L.; Tagliavini, E.; Umari-
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A.; Nakashima, H.; Ishiba, A.; Yamamoto, H. J . Am. Chem. Soc. 1996,
118, 4723-4724. (d) Casdari, S.; Cozzi, P. G.; Oriali, P.; Tagliavini,
E.; Umani-Ronchi, A. J . Chem. Soc., Chem. Commun. 1997, 2123-2124.
(12) (a) Cage, J . R.; Evans, D. A. Org. Synth. 1989, 339-343. (b)
Evans, D. A.; Rieger, D. L.; J ones, T. K.; Kaldor, S. W. J . Org. Chem.
1990, 55, 6260-6268.
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S. S.; Tolstikov, G. A.; Miniakhmetov, I. A.; Lomakina, S. I.; Khalilov,
L. M. J . Org. Chem. USSR (Engl. Transl.) 1990, 26, 837-840. (c)
Bellasia, F.; Ghelfi, F.; Pagnoni, U. M.; Pinetti, A. Gazz. Chim. Ital.
1991, 121, 559-561.
(9) Lemaire-Audoire, S.; Vogel, P. Tetrahedron Lett. 1998, 39, 1345-
1348.
(10) Clive, D. L. J .; Paul, C. C.; Wang, Z. J . Org. Chem. 1997, 62,
7028-7032.
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Ireland, R. E.; Lin, L. J . Org. Chem. 1993, 58, 2899.

3348 J . Org. Chem., Vol. 65, No. 11, 2000
Lemaire-Audoire and Vogel
Sch em e 4
Sch em e 2
Sch em e 3
P r ep a r a tion of th e C29-C36 Meth yl Keton e. Treat-
ment of pentane-1,5-diol (18) with 0.8 equiv of NaH, 0.9
equiv of paramethoxybenzyl chloride, and Bu4NI (cata-
lyst) provided the semiprotected diol 19 in 58% yield.
Oxidation of 19 with pyridinium chlorochromate18 gave
aldehyde 20 (82% yield), which was reacted with the
boron enolate derived from carboximide (+)-21 and
Bu2BOTf.19 The syn-R-methylaldol (+)-8 was obtained in
68% yield, as a single diastereomer (Scheme 3). Forma-
tion of a Weinreb amide,20b followed by silylation of the
secondary alcohol and reaction with methylmagnesium
chloride, allowed efficient formation of methyl ketone (-)-
6. The syn relative configuration has been confirmed by
the 1H NMR data of (-)-6A (see below). The absolute
configuration of alcohol (+)-8 was deduced from its mode
of formation and in analogy with a large number of
related cross-aldolizations using (+)-21.12,20 We confirmed
the absolute configuration of (-)-6 by the 1H NMR
spectra of Mosher’s esters (+)-6M(R) and (-)-6M(S)
obtained as shown in Scheme 4 via esterification with
(R)-(-)-R-methoxy-R-(trifluoromethyl)-R-phenylacetyl chlo-
ride and the (S)-enantiomer, respectively.21
of 4-(dimethylamino)pyridine (DMAP), affording ester
(+)-16 in 75% yield (based on 14, 1:1 mixture of C(50)
diastereomers that could not be separated). Treatment
of (+)-16 with DBU in THF (50 °C, 45 min) provided
triene (+)-17 in 80% yield (Scheme 2).
The enantiomeric excess of (+)-17 was established as
follows. Esterification of alcohol 15 with (S)-(-)-R-meth-
oxy-R-(trifluoromethyl)-R-phenylacetyl chloride,15 fol-
lowed by treatment with DBU/THF (50 °C), afforded the
Mosher’s ester 17M, the 19F NMR spectrum of which
established an ee ) 90% (δF -71.75 ppm (major), -71.96
ppm (minor)). The (47S) configuration of 15-17 was
deduced from its mode of formation and the analogy with
several related asymmetric allylations of aldehydes
promoted by the Lewis acid used here.16 It has been
confirmed in the following way. Ozonolysis of 15 (O3,
Me2S, CH2Cl2, -78 °C) gave a keto-aldehyde that was
oxidized (H2CrO4/acetone) into the corresponding keto-
carboxylic acid. Baeyer-Villiger oxidation of the latter
with metachloroperbenzoic acid gave a diacid that was
extracted with aqueous NaHCO3. Acidification liberated
The syn relative configuration of (-)-6 was confirmed
by its conversion into acetonide (-)-6A, the 13C NMR
(17) Henrot, S.; Larcheveˆque, M.; Petit, Y. J . Chem. Soc., Chem.
Commun. 1986, 183-190.
(18) (a) Waelchili, P. C.; Eugster, C. H. Helv. Chim. Acta 1978, 61,
885-898. (b) Ashton, M. J .; Hills, S. J .; Newton, O. G.; Taylor, J . B.;
Tondu, S. C. D. Heterocycles 1989, 28, 1015-1035.
(19) Inoue, T.; Mukaiyama, T. Bull. Chem. Soc. J pn. 1989, 53, 174-
178.
(20) (a) Evans, D. A.; Bender, S. L.; Morris, J . J . Am. Chem. Soc.
1988, 110, 2506-2526. (b) Evans, D. A.; Rieger, D. L.; J ones, T. K.;
Kaldor, S. W. J . Org. Chem. 1990, 55, 6260-6268. (c) Evans, D. A.;
Black, W. C. J . Am. Chem. Soc. 1993, 115, 4497-4513. (d) Keck, G.
E.; Park, M.; Krishnamurthy, D. J . Org. Chem. 1993, 58, 3787-3788.
(e) Clark, D. L.; Heathcock, C. H. J . Org. Chem. 1993, 58, 5878-5879.
(f) Robichaud, A. J .; Berger, G. D.; Evans, D. A. Tetrahedron Lett. 1993,
34, 8403-8406. (g) Golec, J . M. C.; Gillepsie, R. J . Tetrahedron Lett.
1993, 34, 8167-8168. (h) Paterson, I.; Hulme, A. N. J . Org. Chem.
1995, 60, 3288-3300. (i) Dahmann, G.; Hoffmann, R. W. Liebigs Ann.
1994, 837-846. (j) Canc, D. E.; Luo, G. J . Am. Chem. Soc. 1995, 117,
6633-6634. (k) Carreira, E. M.; Bois, J . D. J . Am. Chem. Soc. 1995,
117, 8106-8125. (l) Smith, A. B.; Qiu, Y.; J ones, D. R.; Kobayashi, K.
J . Am. Chem. Soc. 1995, 117, 12011-12012. (m) Evans, D. A.; Fitch,
D. M. J . Org. Chem. 1997, 62, 454-455. (n) Mapp, A. K.; Heathcock,
C. H. J . Org. Chem. 1999, 64, 23-27.
L-(-)-malic acid ((S)-malic acid), [R]25 ) -25.3 (c ) 0.8,
D
pyridine), lit.17 [R]20 ) -28.7 (c ) 5.5, pyridine) thus
D
proving the (47S) configuration of 15.
(15) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543-2549.
(16) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J . Am. Chem. Soc. 1993,
115, 8467-8468.
(21) Dale, T. A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512-
519.

C29-C51 Subunit of Spongistatin 1
J . Org. Chem., Vol. 65, No. 11, 2000 3349
Sch em e 5
spectrum of which showed δC ) 30.1, 19.7 ppm for the
methyl groups of the acetonide (chair conformation). Its
1H NMR spectrum showed typical coupling constants
Emmons reaction with triethylphosphonoacetate,27 gave
pure diester (-)-28 in 71% yield based on (+)-26 (after
flash chromatography on silica gel). Contrary to the
dihydroxylation of (+)-23 with N-methylmorpholine,
catalyzed with OsO4, which was not face selective, (-)-
28 was oxidized under these conditions,30 giving a major
diol, the treatment of which with concentrated HCl in
tetrahydrofuran provided lactone (-)-29 isolated as a
single stereoisomer in 96% yield and with ee > 99% (19F
NMR of the corresponding Mosher’s ester).
3
3J (H-4,H-5) ) 2.3 Hz and J (H-5,H-6) ) 2.2 Hz for vicinal
equatorial/axial proton pairs. Furthermore, the 2D NOE-
1
SY H NMR spectrum of (-)-6A displayed cross-peaks
for the signal pair at δH 4.12 (H-4) and 1.43 ppm (Me-
C(2)), on one hand, and for the signal pair at δH 3.85 (H-
6) and 1.43 ppm, on the other hand. Product (-)-6A was
obtained in 64% overall yield by desilylation of (-)-6
(HF-pyridine, THF, 0 °C), followed by syn selective aldol
reduction (Et2BOMe, NaBH4, THF, MeOH)22 and acetal-
ization with acetone and 2,2-dimethoxypropane in the
presence of p-toluenesulfonic acid as catalyst.
Chemoselective reduction of the lactone moiety of (-)-
29 was possible on exposure to 3 equiv of DIBAL-H in
CH2Cl2 at -78 °C for 10 min and quenching with MeOH.
The resulting crude lactol was directly silylated with (t-
Bu)Me2SiOSO2CF3/2,6-lutidine in CH2Cl2 (2 h, 0 °C),
giving the uronic derivative (+)-30 in 64% yield (2 steps).
P r ep a r a tion of th e C37-C43 Ald eh yd e. The starting
(R)-(+)-3-benzyloxy-2-methylpropan-1-ol ((+)-10) was pre-
pared by enzymatic resolution, as reported by Sant-
aniello23 with 90% ee. Alternatively, (+)-10 (with ee
>98%) was derived from the commercially available (+)-
methyl L-â-hydroxyisobutyrate (ee >98%) by benzyl-
ation,24 followed by reduction of the methyl ester with
LiAlH4.25 After quantitative oxidation of the primary
alcohol under Swern’s condition,26 a Wadworth-Horner-
Emmons reaction with triethylphosphonoacetate27 pro-
vided the R,â-unsaturated ester (+)-23 in 80% yield.
Treatment of (+)-23 with enriched AD-mix-â28 (t-BuOH/
H2O 1:1, CH3SO2NH2, 12 h, 20 °C) led to a 4:1 mixture
of diols 24 and 25 that could not be separated. Protected
as bis(methoxymethyl)diethers 26 and 27, the diastereo-
isomers were separated by flash chromatography (Scheme
5).29 Hydrogenolysis of pure (+)-26 (H2/Pd-C, MeOH),
followed by Swern oxidation and Wadworth-Horner-
1
The H NMR spectrum of (+)-30 showed coupling con-
stants for the vicinal proton pairs of the pyranoside
3
3
(3J (43,42) ) 7.4 Hz, J (42,41) ) 9.2 Hz, J (41,40) ) 10.3
3
Hz, J (40,39) ) 10.4 Hz) typical for axial/axial proton
pairs, thus proving the â-L-gluco configuration of the
pyranoside. This assignment was confirmed by the 2D
NOESY 1H NMR spectrum of (+)-30 that showed cross-
peaks for signals at δH 4.47 (H-43), 3.23 (H-41), and 3.51
ppm (H-39). The relative configuration (D-glycero) of C-38
of (+)-30 was deduced from that of C-39 (cis double
hydroxylation of the (E)-enoate (-)-28) (Scheme 5).
When the 4:1 mixture of (+)-26 and (-)-27 was used
instead of pure (+)-26, a 4:1 mixture of ethyl uronates
(+)-30 and (-)-31 was obtained and could be readily
separated by flash chromatography on silica gel. The â-L-
altro configuration of the pyranoside moiety of (-)-31 was
1
confirmed by its H NMR spectrum (3J (43,42) ) 1.0 Hz,
3
3
3J (42,41) ) 3.6 Hz, J (41,40) ) 3.3 Hz, J (40,39) ) 10.7
(22) Narasaka, K.; Pai, F. G. Tetrahedron 1984, 40, 2233-2238.
Chen, K. M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro, M. J .
Tetrahedron Lett. 1987, 28, 155-158.
Hz).
(23) Grisenti, P.; Ferraboschi, P.; Manzocchi, A.; Santaniello, E.
Tetrahedron 1992, 48, 3827-3834.
(28) Sharpless, K. B.; Amberg, W.; Bennani, Y. I.; Crispino, G. A.;
Hartung, J .; J eong, K.; Kwong, H.; Morikawa, K.; Wang, Z.; Xu, D.;
Zhang, X. J . Org. Chem. 1992, 57, 2768-2771. Kolb, H. C.; Van
Nieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2488-2547.
(29) Using an AD mixture prepared with other chiral ligands such
as (DHQ)2PHAL or (DHQD)2PYR resulted in a loss of selectivity.
(30) Park, C. Y.; Kim, B. M.; Sharpless, K. M. Tetrahedron Lett.
1991, 32, 1003-1006.
(24) White, J . D.; Reddy, N. G.; Spessard, G. O. J . Am. Chem. Soc.
1988, 110, 1624-1626.
(25) Kawabata, T.; Kimura, Y.; Ito, Y.; Terashima, S.; Sasaki, A.;
Sunagawa, M. Tetrahedron 1988, 44, 2149-2166.
(26) Mancuso, A. J .; Huang, S.-L.; Swern, D. J . Org. Chem. 1978,
43, 2480-2482. Tidwell, T. T. Org. React. 1990, 39, 287.
(27) Rathke, M. W.; Nowak, M. J . Org. Chem. 1985, 50, 2624-2626.

3350 J . Org. Chem., Vol. 65, No. 11, 2000
Lemaire-Audoire and Vogel
Sch em e 6
Reduction of uronic ester (+)-30 with DIBAL-H in
CH2Cl2 (-78 °C, 30 min, quenching with MeOH) afforded
the corresponding primary alcohol, which was not puri-
fied but directly oxidized into aldehyde (+)-7 with Dess-
Martin periodinane.14 The overall yield for the conversion
of (+)-10 into (+)-7 was 27% (13 formal steps, isolation
of five intermediate products only!).
(TsOH as catalyst, 20 °C)32 gave methyl R-pyranuloside
(+)-36 in 77% yield, the structure of which was confirmed
by its 2D NOESY 1H NMR spectrum in C6D6. In particu-
lar, the relative configuration of C-37, C-35, and C-34 was
confirmed by the observation of cross-peaks for signals
at δH 3.38 (MeO-C(37)) and 5.39 ppm (HO-C(35),
3J (OH,H-35) ) 5.1 Hz, vanishes on adding D2O), on one
hand, and for signals at δH ) 0.78 (Me-C(34)) and 4.15
ppm (H-35), on the other hand.
Cou p lin g of th e Va r iou s F r a gm en ts in to a C29
-
C51 Su bu n it. The lithium enolate of methyl ketone (-)-6
obtained on treatment with (i-Pr)2NLi in THF at -78 °C
reacted with aldehyde (+)-7 (-78 °C, 20 min) to yield a
major aldol product that was not isolated but acetylated
with Ac2O/pyridine/DMAP (0 °C, 40 min) to give the
corresponding acetate (+)-32 with a diastereomeric ratio
>95:5 and 75% yield. The relative configuration of the
acetate was not established, as it will be transformed
later into a ketone (Scheme 6). Selective desilylation of
the triethylsilyl ether of (+)-32 with HF-pyridine in THF
(0 °C) followed by syn-selective reduction of the inter-
mediate â-hydroxyketone under Narasaka conditions
(Et2BOMe, NaBH4)22 gave a diol that was protected by
silylation with Et3SiOTf/2,6-lutidine in CH2Cl2 at -30 °C,
furnishing (+)-33. The syn relative configuration at C-9
and C-11 of (+)-33 was confirmed in the following way.
Protection of the intermediate 1,3-diol arising from the
Narasaka reduction as an acetonide (Me2C(OMe)2, ace-
tone, TsOH) gave 34, the 13C NMR spectrum of which
displayed two different signals at δC 19.4 and 29.6 ppm
typical for the syn relative configuration.31 All our at-
tempts to hydrolyze (K2CO3, MeOH; NaOMe, MeOH;
NH3, MeOH) the acetate moiety of (+)-33 failed to give
the expected alcohol. Finally the acetate was reduced
with (i-Bu)2AlH in CH2Cl2 at -78 °C, and the intermedi-
ate alcohol was oxidized with Dess-Martin periodinane,14
providing the desired ketone (+)-35 (80%). Chemoselec-
tive desilylation (TES vs TBS) of (+)-35 with HF-
pyridine, followed by Fischer glycosidation in methanol
Selective desilylation of the â-L-glucopyranoside with-
out cleavage of the silyl ether at C-6 was possible by
treating (+)-36 with 1.1 equiv of Bu4NF in THF at -30
°C. The resulting pyranose was directly acetylated with
Ac2O/pyridine and DMAP (catalyst) at 0 °C to produce
diacetate 37 (75%), an unstable compound that was
directly used in the C-glycosidation of silane 16. The
latter reaction33 was run in nitromethane, a solvent
known to favor â-allylation,34 requiring an excess of 16
and of the Lewis acid promoter Me3SiOSO2CF3. A mix-
ture of compounds was obtained that was not purified
but heated in THF (50 °C) in the presence of 3 equiv of
DBU to induce the HCl elimination, providing a 4:1
mixture (42%) of â-C-glycoside (+)-38 and its R-anomer.35
Pure (+)-38 was obtained after a second column chro-
matography on silica gel, in 30% yield. The â-L-gluco-
pyranoside configuration of fragment C-9-C-13 of (+)-
1
38 was confirmed by its H NMR data (3J (H-43,H-42) )
(32) Ziegler, F. E.; Cain, W. T. J . Org. Chem. 1989, 54, 3347-3353.
(33) Hosomi, A.; Sakata, Y.; Sakurai, H. Tetrahedron Lett. 1984, 25,
2383-2386. Hosomi, A.; Sakata, Y.; Sakurai, H. Carbohydr. Res. 1987,
171, 223-232. Passek, J . S.; Sparks, M. A. J . Org. Chem. 1989, 54,
2034-2038. Luengo, J . I.; Gleason, J . G. Tetrahedron Lett. 1992, 33,
6911-6914. Hung, S.-C.; Lin, C.-C.; Wong, C.-H. Tetrahedron Lett.
1997, 38, 5419-5422. Fuchs, T.; Schmidt, R. R. Synthesis 1998, 753-
758. Bombard, S.; Maillet, M.; Capman, M.-L. Carbohydr. Res. 1995,
275, 433-440. Bertozzi, C.; Bednarski, M. Carbohydr. Res. 1992, 223,
243-253.
(34) BeMiller, J . N.; Yadav, M. P.; Kalabokis, V. N.; Myers, R. W.
Carbohydr. Res. 1990, 200, 111-126. Compare with: Giannis, A.;
Sandhoff, K. Tetrahedron Lett. 1985, 26, 1479-1482. Hoffmann, M.
G.; Schmidt, R. R. Liebigs Ann. Chem. 1985, 2403-2419.
(35) Under similar conditions, the C-glycosidation of triene (+)-17
failed and led to decomposition only.
(31) Rychnovsky, S. D.; Rogers, B. N.; Richardson, T. I. Acc. Chem.
Res. 1998, 31, 9-17, and references cited therein.

C29-C51 Subunit of Spongistatin 1
J . Org. Chem., Vol. 65, No. 11, 2000 3351
10.0 Hz, 3J (H-42,H-41) ) 9.1 Hz, 3J (H-41,H-40) ) 9.0 Hz,
3J (H-40,H-39) ) 11.1 Hz).
one, 7.4 g, 17.4 mmol) was stirred at 20 °C for 1.5 h. Diethyl
ether (40 mL), a saturated aqueous solution of NaHCO3 (40
mL), and Na2S2O3 (28 g) were added. After vigorous shaking
for 5 min, the aqueous layer was extracted with Et2O. The
combined etheral extracts were washed with a saturated
aqueous solution of NaHCO3, then with brine, and dried
(MgSO4). Solvent evaporation in vacuo afforded a pale yellow
oil (1.08 g, 81%) that was not purified further. Rf (1:4 EtOAc/
Con clu sion
A convergent approach to the synthesis of a protected
form of the C29-C51 fragment of spongistatin 1 (altohyrtin
A) has been presented. The allylsilane 16 (C44-C51
fragment) used in the C-glycosidation of the F-ring
4-deoxy-4-methyl-L-glucopyranoside moiety was derived
from methyl (E)-penta-2,4-dienoate in four steps and 37%
overall yield. The methyl ketone (-)-6 (C29-C36 fragment)
was derived from pentane-1,5-diol in five steps and 21%
overall yield. Aldehyde (+)-7 (C37-C43 fragment) was
derived from (R)-(+)-3-benzyloxy-2-methylpropan-1-ol
((+)-10) in 12 steps and 27% overall yield. In fact the
method required the isolation of only five intermediate
products during the conversion of (+)-10 into (+)-7. Thus
(+)-10 was converted into (+)-38 in 20 steps and 2%
overall yield, the longest linear synthetic scheme requir-
ing the isolation of only 11 intermediate products. Our
approach can be compared with that of Kishi and
co-workers5 in which their C29-C51 fragment was derived
from 2-[tris(isopropyl)silyloxy]ethanol in 26 steps and
0.8% overall yield. Compound (+)-38 bears six different
alcoholic protective groups that have been chosen in such
a way that (+)-38 should be useful in its condensation
with suitable C1-C28 fragments to generate spongistatin
1 and derivatives.
1
light petroleum ether) ) 0.46. H NMR (400 MHz, CDCl3): δ
9.64 (d, J ) 7.4 Hz, 1H), 6.78 (dd, J ) 15.5, 7.4 Hz, 1H), 6.38
(ddd, J ) 15.5, 7.4, 1.1 Hz, 1H), 4.73 (m, 1H), 3.90 (dd, J )
11.4, 5.0 Hz, 1H), 3.75 (dd, J ) 11.4, 8.4 Hz, 1H). 13C NMR
(100.6 MHz, CDCl3): δ 192.0, 149.4, 134.6, 57.2, 46.2.
1:1 Mixtu r e of (4S,7R,E) a n d (4S,7S,E)-7,8-Dich lor o-2-
m eth ylid en e-1-(tr im eth lysilyl)oct-5-en -4-yl p-Meth oxy-
ben zoa te (16). A 1 M solution of freshly distilled Ti(O-i-Pr)4
in anhydrous CH2Cl2 (196 µL, 0.196 mmol) was added to a
stirred solution of (S)-BINOL ((S)-(-)-2,2′-dihydroxy-1,1′-di-
naphthyl, Fluka, 112 mg, 0.392 mmol) in anhydrous CH2Cl2
(7.5 mL) at 25 °C for 45 min. The dark red solution was cooled
to 0 °C under an Ar atmosphere, and 14 (0.3 g, 1.96 mmol) in
solution in anhydrous CH2Cl2 (2 mL) was added, followed by
the addition of {2-[(trimethylsilyl)methyl]prop-2-enyl}tri-
phenylstannane10 (4) (1.22 g, 2.55 mmol). After stirring at 0
°C for 3 h, EtOAc (10 mL) and a saturated aqueous solution
of NaHCO3 (2 mL) were added under vigorous stirring. After
stirring for 1 h at 20 °C, the layers were separated and the
aqueous phase extracted with CH2Cl2 (5 mL, twice). The
combined organic extracts were dried (MgSO4), and the solvent
was evaporated in vacuo. The residue was purified by flash
chromatography on silica gel (1:8 EtOAc/light petroleum
ether), affording a pale yellow oil (330 mg, 60%). Because of
its instability, this oil could not be purified further and was
dissolved in anhydrous pyridine (11 mL), and the solution was
cooled to 0 °C. p-Methoxybenzoyl chloride (0.49 mL, 0.638
mmol) and 4-(dimethylamino)pyridine (15 mg) were added.
After stirring at 0 °C for 1 h, EtOAc (25 mL) and H2O (25 mL)
were added, and the mixture was shaken vigorously at 20 °C
for 1 h. The layers were separated, and the aqueous phase
was extracted with EtOAc. The combined organic extracts were
washed first with 1 N aqueous HCl, then with saturated
aqueous solution of NaHCO3, and finally with brine. After
drying (MgSO4), solvent evaporation, and flash chromatogra-
phy on silica gel (1:10 EtOAc/light petroleum ether), 16 was
obtained as a colorless oil (363 mg, 75%). Rf (1:10 EtOAc/light
petroleum ether) ) 0.44. [R]25D ) 11 (c ) 0.5, CH2Cl2). 1H NMR
(400 MHz, CDCl3): δ 8.03, 6.95 (2d, J ) 8.8 Hz, 4H), 5.99 (dd,
J ) 15.3, 5.8 Hz, 1H), 5.84 (dm, J ) 15.3 Hz, 1H), 5.72 (m,
1H), 4.72, 4.65 (2 br s, 2H), 4.56-4.50 (m, 1H), 3.89 (s, 3H),
3.78, 3.67 (2m, 2H), 2.51 (dd, J ) 14.1, 7.6 Hz, 1H), 2.35 (dd,
J ) 14.1, 6.1 Hz, 1H), 1.60 (br s, 1H), 0.05 (s, 9H). 13C NMR
(100.6 MHz, CDCl3): δ 165.3, 163.4, 142.1, 134.1, 131.7, 128.5,
122.6, 113.6, 111.1, 71.43, 59.9, 55.5, 47.6, 43.3, 16.7, -1.4.
Anal. Calcd for C20H28O3SiCl2 (415.43): C, 57.82; H, 6.79.
Found: C, 57.80; H, 6.68.
Exp er im en ta l Section
Gen er a l Rem a r k s. See ref 36. 1H NMR spectrum signal
assignments were confirmed by 2D COSY and 2D NOESY 1H
NMR spectra.
Met h yl (E)-4,5-Dich lor op en t -2-en oa t e (12). Cl2 was
bubbled through a solution of methyl (E)-penta-2,4-dienoate
(11, Fluka, 5 mL, 43 mmol) in CHCl3 (60 mL) stirred at 0 °C
for 30 min. Excess Cl2 was removed by bubbling Ar for 5 min.
After solvent evaporation the residue was distilled under
vacuum (Vigreux column) to give a pale yellow oil (6.0 g, 76%).
Bp: 74 °C (0.07 Torr). 1H NMR (400 MHz, CDCl3): δ 6.91 (dd,
1H), 6.16 (dd, 1H), 4.65-4.59 (m, 1H), 3.86 (dd, 1H), 3.79 (s,
3H), 3.71 (dd, 1H). 13C NMR (100.6 MHz, CDCl3): δ 165.6,
142.2, 125.0, 57.6, 52.0, 46.5. Anal. Calcd for C6H8O2Cl2
(183.03): C, 39.34; H, 4.37; Cl, 38.80. Found: C, 39.48; H, 4.52;
Cl, 38.62.
(E)-4,5-Dich lor op en t-2-en ol (13). One molar (i-Bu)2AH in
CH2Cl2 (41 mL, 0.41 mmol) was added over 30 min to a stirred
solution of 12 (2.5 g, 0.135 mmol) in anhydrous CH2Cl2 (70
mL) cooled to -78 °C. After stirring at -78 °C for 1 h, the
cooling bath was removed and the mixture stirred for 1 h.
Methanol (10 mL) was added under vigorous stirring and the
mixture poured into 1 M aqueous HCl (120 mL). The aqueous
layer was extracted with CHCl3. The combined organic extracts
were dried (MgSO4), and the solvent was evaporated. The
residual oil was purified by flash chromatography on silica gel
(1:3 EtOAc/light petroleum ether), affording a colorless oil (1.7
g, 80%), Rf (1:4 EtOAc/light petroleum ether) ) 0.24. 1H NMR
(400 MHz, CDCl3): δ 6.03 (dtd, J ) 15.3, 4.8, 0.7 Hz, 1H), 5.82
(ddt, J ) 15.3, 8.4, 1.7 Hz, 1H), 4.55 (m, 1H), 4.24 (m, 2H),
3.81 (dd, J ) 11.9, 5.4 Hz, 1H), 3.69 (dd, J ) 11.9, 8.0 Hz,
1H). 13C NMR (100.6 MHz, CDCl3): δ 134.9, 127.6, 62.2, 59.9,
47.6. Anal. Calcd for C5H8OCl2 (155.02): C, 38.70; H, 5.16; Cl,
45.16. Found: C, 38.85; H, 5.15; Cl, 44.98.
(4S)-7-Ch lor o-2-m eth ylid en e-1-(tr im eth ylsilyl)octa -5,7-
d ien -4-yl p-Meth oxyben zoa te ((+)-17). A mixture of (+)-
16 (30 mg, 0.072 mmol), anhydrous THF (1.5 mL), and DBU
(1,8-diazabicyclo[5.4.0]undec-7-ene, Fluka, 33 µL, 0.21 mmol)
was warmed to 50 °C for 45 min. The solution was poured into
H2O (8 mL) and extracted with Et2O (10 mL, 3 times). The
combined ethereal extracts were washed successively with 1
N aqueous HCl, a saturated aqueous solution of NaHCO3, and
brine. After drying (MgSO4) and solvent evaporation in vacuo,
the residue was purified by flash chromatography on silica gel
(1:15 EtOAc/light petroleum ether), affording a colorless oil
(22 mg, 80%). Rf (1:10 EtOAc/light petroleum ether) ) 0.53.
[R]25 ) 62 (c ) 0.3, CH2Cl2). 1H NMR (400 MHz, C6D6): δ
D
8.23, 6.68 (2d, J ) 9.0 Hz, 4 H), 6.47 (dd, J ) 15.0, 5.7 Hz,
1H), 6.41 (d, J ) 15.0 Hz, 1H), 6.10 (m, 1H), 5.16, 4.91 (2d, J
) 1.1 Hz, 2H), 4.87, 4.72 (2br s, 2H), 3.17 (s, 3H), 2.57 (dd, J
) 14.2, 8.7 Hz, 1 H), 2.35 (dd, J ) 14.2, 5.8 Hz, 1H), 1.63, 1.59
(2d, J ) 13.7 Hz, 2H), 0.04 (s, 9H). 13C NMR (100.6 MHz,
C6D6): δ 165.1, 163.4, 142.4, 137.9, 133.3, 131.8, 128.8, 123.1,
116.4, 113.7, 111.0, 71.7, 54.5, 43.6, 26.5, -1.7.
(E)-4,5-Dich lor op en t-2-en a l (14). A mixture of 13 (1.35
g, 8.7 mmol), anhydrous CH2Cl2 (50 mL), and Dess-Martin
periodinane (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-
(36) Kraehenbuehl, K.; Picasso, S.; Vogel, P. Helv. Chim. Acta 1998,
81, 1439-1479.

3352 J . Org. Chem., Vol. 65, No. 11, 2000
Lemaire-Audoire and Vogel
5-[(p-Meth oxyben zyl)oxy]p en ta n -1-ol (19). A mixture of
pentane-1,5-diol (2.56 g, 24.6 mmol, Fluka), anhydrous THF
(75 mL), and 55% NaH in oil (858 mg, 19.6 mmol) was stirred
at 0 °C for 10 min under an Ar atmosphere. p-Methoxybenzyl
chloride (3 mL, 22 mmol) and Bu4NI (0.2 g) were added. The
mixture was stirred at 0 °C for 1 h, then at 20 °C for 2 h, and
was left overnight at 45 °C. The mixture was poured into a
vigorously stirred saturated aqueous solution of NaHCO3 (250
mL). The aqueous layer was extracted with EtOAc. The
combined organic extracts were dried (MgSO4), and the solvent
was evaporated in vacuo. The residue was purified by flash
chromatography on silica gel (1:1 EtOAc/light petroleum
ether), affording a pale yellow oil (3.18 g, 58%). Rf (1:4 EtOAc/
7.65 mmol) was added slowly. After the end of gas evolution,
the solution was stirred at 20 °C for 30 min. The solution was
cooled to 0 °C, and (+)-8 (870 mg, 1.91 mmol) in solution in
anhydrous THF (4 mL) was added. After stirring at 0 °C for
25 min, the mixture was poured into a vigorously stirred
mixture of CH2Cl2 (110 mL) and 0.5 M HCl (70 mL) and cooled
to 0 °C. The aqueous layer was extracted with CH2Cl2. The
combined organic extracts were washed with brine and dried
(MgSO4), and the solvent was evaporated. The pale yellow
residue was dissolved in anhydrous DMF (10 mL) and the
solution cooled to 0 °C. Imidazole (260 mg, 3.82 mmol) and
Et3SiCl (385 µL, 2.29 mmol) were added successively. After
stirring at 0 °C for 1 h, the mixture was allowed to stand at
20 °C for 2 h. It was poured into H2O (50 mL). The aqueous
layer was extracted with Et2O. The combined organic extracts
were dried (MgSO4), and the solvent was evaporated. Flash
chromatography on silica gel (1:4 EtOAc/light petroleum ether)
afforded a colorless oil (636 mg, 73%). Rf (1:2 EtOAc/light
petroleum ether) ) 0.70. [R]25D ) 6 (c ) 1.1, CH2Cl2). 1H NMR
(400 MHz, CDCl3): δ 7.25, 6.87 (2d, J ) 8.7 Hz, 4H), 4.42 (s,
2H), 3.95-3.91 (m, 1H), 3.80 (s, 3H), 3.65 (s, 3H), 3.43 (t, J )
6.6 Hz, 2H), 3.16 (br s, 3H), 2.96 (br s, 1H), 1.64-1.49, 1.47-
1.39 (2m, 6H), 1.16 (d, J ) 6.9 Hz, 3H), 0.97 (t, J ) 7.8 Hz,
9H), 0.63 (q, J ) 7.8 Hz, 6H). 13C NMR (100.6 MHz, CDCl3):
δ 176.6, 159.0, 130.8, 129.1, 113.6, 73.8, 72.4, 70.1, 61.3, 55.2,
1
light petroleum ether) ) 0.15. H NMR (400 MHz, CDCl3): δ
7.26 (d, J ) 5.7 Hz, 2H), 6.88 (d, J ) 5.7 Hz, 2 H), 4.22 (s,
2H), 3.81 (s, 3H), 3.64 (t, J ) 6.5 Hz, 2H), 3.46 (t, J ) 6.5 Hz,
2H), 1.66-1.55, 1.48-1.46 (2m, 6H), 1.54 (br s, 1H). 13C NMR
(100.6 MHz, CDCl3): δ 159.1, 130.6, 129.2, 113.7, 72.5, 69.9,
62.8, 55.2, 32.5, 29.4, 22.4. Anal. Calcd for C13H20O3 (224.30):
C, 69.61; H, 8.99. Found: C, 69.52; H, 9.01.
5-[(p-Meth oxyben zyl)oxy]p en ta n a l (20). A mixture of 19
(3.12 g, 13.3 mmol), anhydrous CH2Cl2 (90 mL), and pyri-
dinium chlorochromate (4.81 g, 22.3 mmol, Fluka) was stirred
at 20 °C for 3 h. The black precipitate was taken off by
filtration on a pad of silica gel (elution with 800 mL of Et2O).
Solvent evaporation and flash chromatography on silica gel
(1:4 EtOAc/light petroleum ether) afforded a colorless oil (2.42
g, 82%). Rf (1:4 EtOAc/light petroleum ether) ) 0.34. 1H NMR
(400 MHz, CDCl3): δ 9.75 (t, J ) 1.7 Hz, 1H), 7.25 (d, J ) 8.7
Hz, 2H), 6.88 (d, J ) 8.7 Hz, 2H), 4.42 (s, 2H), 3.80 (s, 3H),
40.9, 35.8, 32.1, 30.0, 21.3, 14.5, 7.0, 5.1. Anal. Calcd for C24H43
-
NO5Si (453.70): C, 63.58; H, 9.49; N, 3.09. Found: C, 63.51;
H, 9.32; N, 3.10.
(3S ,4R )-3-Me t h yl-7-[(p -m e t h oxyb e n zyl)oxy]-4-[(t r i-
m eth ylsily)oxy]octa n -2-on e ((-)-6). A 3 M solution of
MeMgCl in anhydrous THF (2.65 mL, 7.94 mmol) was added
dropwise to a solution of (+)-22 (0.6 g, 1.32 mmol) in anhydrous
THF (10 mL) stirred at 0 °C under an Ar atmosphere. After
stirring at 0 °C for 3 h the mixture was poured into a
vigorously stirred saturated aqueous solution of NH4Cl (50
mL). H2O (5 mL) was added to dissolve the precipitate, and
the aqueous layer was extracted with Et2O. The combined
organic extracts were dried (MgSO4). Solvent evaporation and
flash chromatography on silica gel (1:8 EtOAc/light petroleum
ether) afforded a colorless oil (488 mg, 90%). Rf (1:4 EtOAc/
3
3.46 (t, J ) 6.5 Hz, 2H), 2.44 (td, J ) 7.0, 1.7 Hz, 2H), 1.75-
1.61 (m, 4H). 13C NMR (100.6 MHz, CDCl3): δ 202.5, 159.1,
130.5, 129.2, 113.7, 72.5, 69.4, 55.2, 43.5, 29.1, 18.9. Anal.
Calcd for C13H18O3 (222.28): C, 69.64; H, 8.93. Found: C,
69.72; H, 8.88.
(2′S,3′R,5S)-5-Ben zyl-N-{7-[(p -m et h oxyb en zyl)oxy]-3-
h yd r oxy-2-m eth ylh ep toyl}-2-oxa zolid in on e ((+)-8). In a
Schlenk tube (100 mL, flame dried) (5S)-5-benzyl-2-oxazoli-
dinone ((+)-21, 1.5 g, 6.44 mmol, prepared according to ref 12a)
was dissolved in anhydrous CH2Cl2 (32 mL) under an Ar
atmosphere. After cooling to 0 °C, Bu2BOTf 19 (2.12 g, 7.72
mmol) dissolved in anhydrous CH2Cl2 (3 mL) was added. Et3N
(1.25 mL, 9 mmol) was then added dropwise at 0 °C. After
stirring at 0 °C for 45 min the solution was cooled to -78 °C,
and 20 (1.57 g, 7.08 mmol) in solution in anhydrous CH2Cl2
(3 mL) was added slowly. The mixture was stirred at -78 °C
for 1 h, then at -20 °C for 1 h, and at 0 °C for 1 h. Phosphate
buffer (pH 7, 20 mL) was added, followed by MeOH (50 mL).
The resulting mixture was then added dropwise into a stirred
solution of MeOH (80 mL) and 35% H2O2 (7 mL) and cooled to
0 °C. After stirring at 0 °C for 1 h, H2O (120 mL) was added.
The aqueous layer was extracted with CHCl3 (130 mL, three
times). The combined organic extracts were washed with a
saturated aqueous solution of NaHCO3, then with brine, and
dried (MgSO4). Solvent evaporation and flash chromatography
on silica gel (1:1 EtOAc/light petroleum ether) afforded pure
(+)-8 (single stereoisomer) as a colorless oil (1.99 g, 68%). Rf
(1:2 EtOAc/light petroleum ether) ) 0.13. [R]25D ) 47 (c ) 0.2,
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.37-7.27 (m, 5 H),
7.26 (d, J ) 8.7 Hz, 2H), 6.88 (d, J ) 8.7 Hz, 2H), 4.70 (dddd,
J ) 9.4, 7.5, 3.3, 3.2 Hz, 1H), 4.43 (s, 2H), 4.23 (dd, J ) 16.6,
7.5 Hz, 1H), 4.19 (dd, J ) 16.6, 3.2 Hz, 1H), 3.97-3.93 (m,
1H), 3.80 (s, 3H), 3.76 (qd, J ) 7.1, 2.7 Hz, 1H), 3.46 (t, J )
6.4 Hz, 2H), 3.25 (dd, J ) 13.4, 3.3 Hz, 1H), 2.80 (dd, J ) 13.4,
9.4 Hz, 1H), 1.67-1.62 (m, 2H), 1.58-1.54, 1.47-1.41 (2m, 4H),
1.26 (d, J ) 7.1 Hz, 3H). 13C NMR (100.6 MHz, CDCl3): δ
177.5, 159.1, 153.0, 135.0, 130.7, 129.4, 129.2, 128.9, 127.4,
113.7, 72.5, 71.3, 69.9, 66.1, 55.2, 55.1, 42.1, 37.8, 33.6, 22.7,
29.5, 10.4. Anal. Calcd for C26H33NO6: C, 68.57; H, 7.25; N,
3.08. Found: C, 68.45; H, 7.29; N, 3.09.
light petroleum ether) ) 0.73. [R]25 ) -32 (c ) 0.2, CH2Cl2).
D
1H NMR (400 MHz, CDCl3): δ 7.26, 6.88 (2d, J ) 8.7 Hz, 4H),
4.43 (s, 2H), 3.93 (m, 1H), 3.81 (s, 3H), 3.43 (t, J ) 6.5 Hz,
2H), 2.63 (qd, J ) 7.0, 4.7 Hz, 1H), 2.18 (s, 3H), 1.65-1.56 (m,
2H), 1.49-1.30 (m, 4H), 1.06 (d, J ) 7.0 Hz, 3 H), 0.96 (t, J )
8.0 Hz, 9H), 0.60 (q, J ) 8.0 Hz, 6H). 13C NMR (100.6 MHz,
CDCl3): δ 211.7, 159.0, 130.1, 129.2, 113.7, 73.6, 72.5, 69.8,
55.2, 52.0, 34.5, 30.0, 29.8, 22.3, 11.4, 6.9, 5.1. Anal. Calcd for
C
23H40O4Si (408.65): C, 67.65; H, 9.80; Si, 6.86. Found: C,
67.68; H, 9.91; Si, 6.97.
(rR,3S,4R)-3-Met h yl-8-[(p -m et h oxyb en zyl)oxy]-4-[r-
m et h oxy-r-(t r iflu or om et h yl)-r-p h en yla cet oxy]oct a n -2-
on e ((+)-6M(R). A mixture of (-)-6 (50 mg, 0.123 mmol),
anhydrous THF (6 mL), and HF-pyridine (0.32 µL) was stirred
at 0 °C for 1 h. The mixture was poured into a saturated
aqueous solution of NaHCO3 (15 mL) and extracted with
EtOAc. The combined organic extracts were washed with H2O
and dried (MgSO4). Solvent evaporation in vacuo gave a pale
yellow oil (36 mg, 100%, (3S,4R)-4-hydroxy-3-methyl-7-[(p-
methoxybenzyl)oxy]octan-2-one), from which 20 mg (0.06
mmol) was dissolved in anhydrous CH2Cl2 (1 mL) and cooled
to 0 °C. Pyridine (16 µL, 0.2 mmol) and (R)-(-)-R-methoxy-R-
(trifluoromethyl)-R-phenylacetyl chloride (19 µL, 0.1 mmol)
were added. After stirring at 0 °C for 15 min, the mixture was
stirred at 20 °C for 4 h. After the addition of EtOAc (10 mL),
the solution was washed successively with 1 N aqueous HCl
(2 mL), NaHCO3 (2 mL), and H2O (2 mL). After drying
(MgSO4), the solvent was evaporated. Flash chromatography
on silica gel (1:4 EtOAc/light petroleum ether) afforded a
colorless oil (29 mg, 83%). Rf (1:4 EtOAc/light petroleum ether)
(2S,3R)-N-Met h oxy-N-2-d im et h yl-7-[(p-m et h oxyb en z-
yl)oxy]-3-[(tr ieth ylsilyl)oxy]h ep ta n a m id e ((+)-22). (MeO)-
MeNH-HCl (746 mg, 7.65 mmol) was suspended in anhydrous
THF (14 mL) in a Schlenk tube under an Ar atmosphere. After
cooling to 0 °C, a 2 M solution of AlMe3 in heptane (3.82 mL,
) 0.37. [R]25 ) 5 (c ) 0.3, CH2Cl2). 1H NMR (400 MHz,
D
CDCl3): δ 7.55-7.52, 7.39-7.38 (2m, 5H), 7.25, 6.88 (2d, J )
8.7 Hz, 4H), 5.44 (m, 1H), 4.42 (s, 2H), 3.81 (s, 3H), 3.53 (s,
3H), 3.41 (t, J ) 6.3 Hz, 2H), 2.75 (dd, J ) 7.0, 4.7 Hz, 1H),
2.06 (s, 3H), 1.71-1.56, 1.43-1.36 (2m, 6H), 1.05 (d, J ) 7.1

C29-C51 Subunit of Spongistatin 1
J . Org. Chem., Vol. 65, No. 11, 2000 3353
Hz, 3H). 13C NMR (100.6 MHz, CDCl3): δ 207.8, 166.3, 159.4,
132.2, 130.6, 129.6, 129.3, 128.4, 127.3, 122.1, 113.8, 76.7, 72.6,
69.5, 55.5, 55.3, 49.5, 31.6, 29.3, 29.0, 22.3, 11.1. Anal. Calcd
for C27H33O6F3 (510.55): C, 63.52; H, 6.51. Found: C, 63.66; H,
6.63.
The aqueous layer was extracted with EtOAc. The combined
organic extracts were washed with brine, dried (MgSO4), and
concentrated in vacuo. Flash chromatography on silica gel (1:6
EtOAc/light petroleum ether) afforded a colorless oil (7.16 g,
80%). Rf (1:10 EtOAc/light petroleum ether) ) 0.35. [R]25D ) 6
1
(rS,3S,4R)-3-Met h yl-8-[(p -m et h oxyb en zyl)oxy]-4-[r-
m et h oxy-r-(t r iflu or om et h yl)-r-p h en yla cet oxy]oct a n -2-
on e ((-)-6M(S)). The same procedure as for the preparation
of (+)-6M(R) was adopted, starting with 16 mg of (3S,4R)-3-
4-hydroxymethyl-7-[(paramethoxybenzyl)oxy]-octan-2-one and
using (S)-(+)-R-methoxy-R-(trifluoromethyl)-R-phenylacetyl chlo-
ride (Fluka). (-)-6M(S) was obtained as a colorless oil (22.6
(c ) 1, CH2Cl2). H NMR (400 MHz, CDCl3): δ 7.38-7.29 (m,
5H), 6.96 (dd, J ) 15.8, 7.1 Hz, 1 H), 5.87 (dd, J ) 15.8, 1.4
Hz, 1H), 4.53 (s, 2H), 4.20 (q, J ) 7.1 Hz, 2H), 3.43 (dd, J )
9.2, 6.8 Hz, 1H), 3.39 (dd, J ) 9.2, 6.3 Hz, 1H), 2.69-2.66 (m,
1H), 1.30 (t, J ) 7.1 Hz, 3H), 1.11 (d, J ) 6.8 Hz, 3H). 13C
NMR (100.6 MHz, CDCl3): δ 166.7, 151.1, 138.2, 128.4, 127.6,
121.0, 73.9, 73.1, 60.2, 36.8, 16.0, 14.2. Anal. Calcd for C15H20O3
(248.32): C, 72.58; H, 8.06. Found: C, 72.64; H, 8.14.
g, 81%). Rf (1:4 EtOAc/light petroleum ether) ) 0.36. [R]25
)
D
1
-132 (c ) 0.4, CH2Cl2). H NMR (400 MHz, CDCl3): δ 7.51,
7.38 (2m, 5H), 7.24, 6.88 (2d, J ) 8.7 Hz, 4H), 5.48, 5.44 (m,
1H), 4.40 (s, 2H), 3.81 (s, 3H), 3.50 (s, 3H), 3.37 (t, J ) 6.4 Hz,
2H), 2.72 (qd, J ) 7.0, 4.5 Hz, 1H), 2.17 (s, 3H), 1.68-1.50,
1.31-1.25 (2m, 6H), 1.10 (d, J ) 7.1 Hz, 3 H). 13C NMR (100.6
MHz, CDCl3): δ 208.8, 166.2, 159.2, 132.0, 130.6, 129.6, 128.4,
127.5, 113.8, 76.4, 72.6, 69.5, 55.4, 55.3, 49.6, 31.6, 29.3, 29.0,
22.1, 10.8. Anal. Calcd for C27H33O6F3 (510.55): C, 63.52; H,
6.51. Found: C, 63.65; H, 6.58.
(2S,3R,4S)-Eth yl 5-Ben zyloxy-4-m eth yl-2,3-bis[(m eth oxy-
m eth yl)oxy]p en ta n oa te ((+)-26) a n d (2R,3S,4S)-Eth yl
5-Ben zyloxy-4-m eth yl-2,3-bis[(m eth oxym eth yl)oxy]p en -
ta n oa te ((-)-27). A mixture of (+)-23 (11.4 g, 46.1 mmol),
t-BuOH (90 mL), H2O (90 mL), methanesulfonamide (4.38 g,
46 mmol), and enriched AD-mix-â (70 g, K3Fe(CN)6, 47.7 g;
K2CO3, 20.05 g; (DHQD)2PHAL, 1.88 g, K2OsO2(OH)4, 370 mg)
was stirred at 20 °C for 12 h. EtOAc (200 mL) and anhydrous
Na2SO3 (55 g) were added, and the mixture was stirred at 20
°C for 45 min. The precipitate was filtered off and the solution
diluted with H2O (200 mL) and extracted with EtOAc. The
combined organic extracts were washed with 1 M aqueous HCl,
then with brine, and dried (MgSO4). Solvent evaporation
afforded a 4:1 mixture of diols 24 and 25 as a pale yellow oil,
which was dissolved (13 g, 46.1 mmol) in anhydrous CH2Cl2
(300 mL). After cooling to 0 °C, EtN(i-Pr)2 (95 mL, 0.553 mmol)
and MeOCH2Cl (28 mL, 0.369 mol) were added dropwise.
Bu4NI (50 mg) was then added, and the mixture was stirred
at 20 °C for 12 h. The solution was poured into vigorously
stirred 1 M aqueous HCl (500 mL). The aqueous layer was
extracted with CH2Cl2. The combined organic extracts were
dried (MgSO4). Solvent evaporation and flash chromatography
on silica gel (1:6 EtOAc/light petroleum ether) afforded a 4:1
mixture of (+)-26 and (-)-27 (14.6 g, 85%), which can be
separated at this stage by a second flash chromatography to
obtain an analytical sample. For preparative purposes, the
mixture of (+)-26 and (-)-27 can be used as such in the
following steps (see below: mixture of (+)-30 and (-)-31).
Da ta for (+)-26: Rf (1:4 EtOAc/light petroleum ether) )
(4S,5R,6S)-2,2,4,5-Tet r a m et h yl-6-{4[(p -m et h oxyb en z-
yl)oxy]bu tyl}-1,3-d ioxa n e ((-)-6A). A mixture of (-)-6 (165
mg, 0.41 mmol), anhydrous THF (15 mL), and HF-pyridine
(1 mL) was stirred at 0 °C for 1 h. It was then poured into a
saturated aqueous solution of NaHCO3 and extracted with
EtOAc. The combined organic extracts were washed with H2O
and dried (MgSO4), and the solvent was evaporated in vacuo.
The residue was dissolved in THF (2 mL) and MeOH (0.5 mL)
and cooled to -78 °C. One molar Et2BOMe in THF (0.6 mL,
0.6 mmol) was added. The mixture was stirred at -78 °C for
15 min, and NaBH4 (23 mg, 0.61 mmol) was added. After
stirring at -78 °C for 45 min, AcOH (20 µL) was added and
the mixture was poured into a saturated aqueous solution of
NaHCO3 (10 mL) and extracted with EtOAc. The combined
organic extracts were washed with brine and dried (MgSO4).
The solvent was evaporated in vacuo and the residue dissolved
in MeOH (3 mL). The solvent was evaporated in vacuo. The
same operation was repeated once more. The resulting color-
less oil was dissolved in a mixture of acetone (1 mL) and 2,2-
dimethoxypropane (1 mL), containing p-toluenesulfonic acid
(6 mg). After stirring at 20 °C for 90 min the solvent was
evaporated and the residue purified by flash chromatography
on silica gel (1:8 EtOAc/light petroleum ether), affording a pale
0.35. [R]25 ) 20 (c ) 1.0, CH2Cl2). 1H NMR (400 MHz,
D
CDCl3): δ 7.35-7.28 (m, 5H), 4.71, 4.68 (2s, 4H), 4.53 (d, J )
11.6 Hz, 1H), 4.48 (d, J ) 11.6 Hz, 1H), 4.27-4.17 (m, 3H),
4.03 (dd, J ) 4.8 Hz, 1H), 3.51 (dd, J ) 9.2, 6.3 Hz, 1H), 3.40
(dd, J ) 9.2, 6.2 Hz, 1H), 3.69, 3.35 (2s, 6H), 2.10-2.06 (m,
yellow oil (88 mg, 64%). Rf (1:8 EtOAc/light petroleum ether)
1
) 0.40. [R]25 ) -103 (c ) 0.2, CH2Cl2). H NMR (400 MHz,
D
3
CDCl3): δ 7.27, 6.88 (2d, J ) 8.7 Hz, 4H), 4.44 (s, 2H), 4.12
(qd, J ) 6.9, 2.3 Hz, 1H), 3.85 (ddd, J ) 8.8, 5.0, 2.2 Hz, 1H),
3.81 (s, 3H), 3.45 (t, J ) 6.6 Hz, 2H), 1.66-1.60, 1.38-1.27
(2m, 7H), 1.43, 1.40 (2s, 6H), 1.13 (d, J ) 6.4 Hz, 3H), 0.84 (d,
J ) 6.9 Hz, 3H). 13C NMR (100.6 MHz, CDCl3): δ 159.1, 130.7,
129.2, 113.8, 98.7, 73.2, 72.5, 69.9, 69.0, 55.3, 35.9, 32.6, 30.1,
29.7, 22.3, 19.7, 19.0, 4.3. Anal. Calcd for C20H32O4 (336.47):
C, 71.39; H, 9.59. Found: C, 71.45; H, 9.56.
1H), 1.30 (t, J ) 7.1 Hz, 3H), 1.05 (d, J ) 6.9 Hz, 3 H). 13C
NMR (100.6 MHz, CDCl3): δ 170.8, 138.4, 128.3, 127.6, 127.5,
98.2, 96.8, 79.7, 78.0, 73.0, 72.3, 61.0, 56.4, 56.2, 35.5, 14.1,
12.5. Anal. Calcd for C19H30O7 (370.44): C, 61.62; H, 8.11.
Found: C, 61.65; H, 8.14.
Da ta for (-)-27: Rf (1:4 EtOAc/light petroleum ether) )
0.24. [R]25 ) -66 (c ) 0.3, CH2Cl2).
D
(4S,5R,6S,E)-Dieth yl 5,6-Bis[(m eth oxym eth yl)oxy]-4-
m eth ylh ep t-2-en e-d ioa te ((-)-28). A mixture of (+)-26 (10
g, 27 mmol), MeOH (400 mL), and 5% Pd on charcoal (0.6 g)
was degassed and then pressurized with H2 (1 atm). After
shaking at 20 °C for 12 h the catalyst was filtered off on a pad
of silica gel (eluting with EtOAc). Solvent evaporation afforded
(2R,3R,4S)-ethyl 5-hydroxy-2,3-bis[(methoxymethyl)oxy]-4-
methylpentanoate as a colorless oil (7.4 g, 98%). DMSO (4.5
mL, 63.6 mmol) was added to a stirred solution of oxalyl
chloride (2.6 mL, 30.4 mmol) in anhydrous CH2Cl2 (150 mL)
cooled to -78 °C. After stirring at -78 °C for 15 min, the crude
(2S,3R,4S)-ethyl 5-hydroxy-4-methyl-2,3-bis[(methoxymethyl)-
oxy]pentanoate in solution in anhydrous CH2Cl2 (75 mL) was
added dropwise under stirring. After stirring at -78 °C for 30
min, Et3N (20 mL) was added and stirring was continued at
-30 °C for 30 min. The mixture was poured into H2O and
extracted with Et2O. The combined organic extracts were
washed with brine, dried (MgSO4), and concentrated in vacuo
to afford (2S,3R,4S)-ethyl 2,3-bis[(methoxymethyl)oxy]-4-
methyl-5-oxopentanoate as a pale yellow oil (7.12 g, 97%). A
mixture of LiBr (7.8 g, 89.6 mmol), MeCN (150 mL), and
(4S,E)-Eth yl 5-Ben zyloxy-4-m eth ylp en t-2-en oa te ((+)-
23). DMSO (6.2 mL, 87 mmol) was added to a stirred solution
of oxalyl chloride (3.57 mL, 41.5 mmol) in anhydrous CH2Cl2
(175 mL) cooled to -78 °C. After stirring at -78 °C for 20 min,
(+)-10 (prepared according ref 24 and 25; 6.5 g, 36.1 mmol) in
solution in anhydrous CH2Cl2 (75 mL) was added dropwise.
After stirring at -78 °C for 20 min, Et3N (25 mL) was added
and the mixture stirred at -30 °C for 30 min. The mixture
was poured into H2O (300 mL) and extracted with Et2O (400
mL, three times). The combined organic extracts were washed
with brine (250 mL), dried (MgSO4), and concentrated in vacuo
to afford a pale yellow oil ((R)-3-benzyloxy-2-methylpropanal).
A mixture of LiBr (4.5 g, 52 mmol), MeCN (110 mL), and
triethyl phosphonoacetate (7.8 mL, 39.1 mmol) was stirred at
20 °C for 5 min. EtN(i-Pr)2 (8.4 mL, 48.8 mmol) was added
portionwise, and stirring was continued for an additional 10
min. A solution of the crude (R)-3-benzyloxy-2-methylpropanal
(5.8 g, 32.5 mmol) in MeCN (20 mL) was added, and the
mixture was stirred at 20 °C for 11 h. The mixture was then
poured into 1 M aqueous HCl (250 mL) under vigorous stirring.

3354 J . Org. Chem., Vol. 65, No. 11, 2000
Lemaire-Audoire and Vogel
triethyl phosphonoacetate (13.3 mL, 66.6 mmol) was stirred
at 20 °C under an Ar atmosphere for 5 min. EtN(i-Pr)2 (14.4
mL, 84.5 mmol) was added, and the mixture stirred for an
additional 10 min. The crude aldehyde obtained above dis-
solved in MeCN (10 mL) was added, and the mixture was
stirred at 20 °C overnight. It was then poured into 1 M aqueous
HCl under vigorous stirring. The aqueous layer was extracted
with EtOAc. The combined organic extracts were washed with
brine and dried (MgSO4). Solvent evaporation and flash
chromatography on silica gel (1:4 EtOAc/light petroleum ether)
afforded a colorless oil (6.6 g, 71%). Rf (1:2 EtOAc/light
5.7 Hz, 2H), 4.47 (d, J ) 7.4 Hz, 1H), 4.37 (d, J ) 1.9 Hz, 1H),
4.22-4.19 (m, 2H), 3.51 (dd, J ) 10.4, 1.9 Hz, 1H), 3.45, 3.43
(2s, 6H), 3.31 (dd, J ) 9.2, 7.4 Hz, 1 H), 3.23 (dd, J ) 10.3,
10.2 Hz, 1H), 1.99-1.93 (m, 1H), 1.29 (t, J ) 7.1 Hz, 1H), 1.03
(d, J ) 6.6 Hz, 1H), 0.93, 0.87 (2s, 18H), 0.13, 0.07, 0.05, 0.03
(4s, 12H). 13C NMR (100.6 MHz, CDCl3): δ 172.1, 98.7, 98.3,
97.7, 82.0, 81.9, 78.9, 71.7, 61.1, 56.4, 56.3, 36.5, 25.8, 25.6,
18.4, 17.7, 14.0, 13.0, -4.0, -4.4, -5.1, -5.6. Anal. Calcd for
C
26H54O9Si2 (566.88): C, 55.12; H, 9.54; Si, 9.89. Found: C,
55.24; H, 9.58; Si, 9.72.
Eth yl [(ter t-Bu tyl)dim eth ylsilyl 4-Deoxy-2,3-di-O-(m eth -
oxym et h yl)-4-m et h yl-6-O-(ter t-b u t yl)d im et h ylsilyl-â-D-
glycer o-L-a ltr o-h ep t op yr a n osid ]u r on a t e ((-)-31). When
the synthesis started with a 4:1 mixture of (+)-26 and (-)-27,
(-)-31 was isolated in the above flash chromatography. Rf (1:4
petroleum ether) ) 0.47. [R]25 ) -25 (c ) 0.4, CH2Cl2). 1H
D
NMR (400 MHz, CDCl3): δ 7.05 (dd, J ) 15.8, 7.8 Hz, 1H),
5.87 (dd, J ) 15.8, 1.2 Hz, 1H), 4.73, 4.69 (2d, J ) 7.0 Hz, 2
H), 4.68, 4.66 (2d, J ) 6.9 Hz, 2H), 4.25-4.16 (m, 5H), 3.90
(dd, J ) 6.9, 3.3 Hz, 1H), 3.42, 33.5 (2s, 6H), 2.79-2.76 (m,
1H), 1.32-1.27 (m, 6H), 1.18 (d, J ) 6.8 Hz, 3H). 13C NMR
(100.6 MHz, CDCl3): δ 170.6, 166.4, 149.9, 121.7, 97.8, 96.9,
81.6, 76.6, 61.2, 60.3, 56.7, 56.4, 38.4, 15.3, 14.2, 14.1. Anal.
Calcd for C16H28O8 (348.39): C, 61.62; H, 8.11. Found: C,
61.65; H, 8.14.
EtOAc/light petroleum ether) ) 0.71. [R]25 ) -23 (c ) 0.5,
D
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 4.99 (d, J ) 1.0 Hz,
1H), 4.84, 4.64 (2d, J ) 6.4 Hz, 2H), 4.75, 4.70 (2d, J ) 6.8
Hz, 2H), 4.30 (d, J ) 2.1 Hz, 1H), 4.24-4.13 (m, 2H), 3.88 (dd,
J ) 10.7, 3.1 Hz, 1H), 3.74 (dd, J ) 3.6, 3.3 Hz, 1H), 3.58 (dd,
J ) 3.6, 1.0 Hz, 1H), 3.41, 3.38 (2s, 6H), 2.34-2.32 (m, 1H),
1.30 (t, J ) 7.2 Hz, 3 H), 0.94 (d, J ) 8.3 Hz, 3 H), 0.94, 0.87
(2s, 18H), 0.16, 0.10, 0.07, 0.04 (4s, 12H). 13C NMR (100.6 MHz,
CDCl3): δ 172.3, 97.3, 97.0, 94.3, 79.7, 77.6, 73.7, 72.5, 60.8,
55.8, 55.4, 29.5, 25.9, 25.8, 18.4, 17.9, 14.1, 12.4, -3.9, -4.1,
-5.1, -5.5. Anal. Calcd for C26H54O9Si2 (566.88): C, 55.12; H,
9.54; Si, 9.89. Found: C, 55.22; H, 9.42; Si, 9.91.
E t h yl 4-Deoxy-5,6-d i-O-(m et h oxym et h yl)-4-m et h yl-D-
glycer o-L-ga la cto-h ep ta r -1-a te-7,3-la cton e ((-)-29). A 0.1
M solution of OsO4 in CCl4 (5.4 mL, 0.54 mmol, 7% mol) was
added dropwise to a stirred solution of (-)-28 (2.7 g, 7.7 mmol)
and N-methylmorpholine-N-oxide (2.64 g, 19.4 mmol) in
acetone (40 mL) and H2O (5 mL). The mixture was stirred at
20 °C for 12 h. After dilution with EtOAc (150 mL) and cooling
to 0 °C, Na2S2O5 (9.5 g) was added portionwise and the mixture
stirred at 0 °C for 45 min. The precipitate was filtered off, and
EtOAc (200 mL) was added. The solution was washed with 1
M aqueous HCl, then with brine. The aqueous layers were
extracted with EtOAc. The combined organic extracts were
dried (MgSO4), and the solvent was evaporated in vacuo. The
resulting pale yellow oil was dissolved in THF (60 mL), and
concentrated aqueous HCl (15 drops) was added at 0 °C. After
stirring at 0 °C for 1 h, NaHCO3 was added portionwise and
the mixture stirred at 20 °C for 10 min. The precipitate was
filtered off, and the solvent was evaporated to afford (-)-29
as a pale yellow oil pure enough for the next steps (2.5 g, 96%).
An analytical sample of (-)-29 was obtained by flash chroma-
tography (2:3 EtOAc/light petroleum ether), giving a white
solid. Mp: 85-87 °C. Rf (2:3 EtOAc/light petroleum ether) )
(ter t-Bu tyl)d im eth ylsilyl 4-Deoxy-2,3-d i-O-(m eth oxy-
m eth yl)-4-m ethyl-6-O-(ter t-butyl)dim eth ylsilyl)-â-D-glycer o-
L-glu co-h ep tod ia ld o-1,5-p yr a n osid e ((+)-7). One molar (i-
Bu)2AlH in CH2Cl2 (9.3 mL, 93 mmol) was slowly added to a
stirred solution of (+)-30 (2.1 g, 37 mmol) in anhydrous CH2Cl2
(30 mL) cooled to -78 °C. After stirring at -78 °C for 30 min,
MeOH (5 mL) was added and the mixture poured into 1 M
aqueous HCl (60 mL). The aqueous layer was extracted with
CHCl3. The combined organic extracts were dried (MgSO4).
After solvent evaporation in vacuo the residue was dissolved
in anhydrous CH2Cl2 (18 mL), and Dess-Martin periodinane
(1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, 2.8 g,
65 mmol) was added. After stirring at 20 °C for 90 min, Et2O
(30 mL), a saturated aqueous solution of NaHCO3 (40 mL),
and anhydrous Na2S2O3 (12 g) were added. After vigorous
stirring for 5 min, the aqueous layer was extracted with Et2O
(50 mL, twice). The combined organic extracts were washed
with a saturated aqueous solution of NaHCO3, then with HCl,
and dried (MgSO4). Solvent evaporation and flash chromatog-
raphy on silica gel (1:4 EtOAc/light petroleum ether) afforded
a colorless oil (1.74 g, 90%). Rf (1:4 EtOAc/light petroleum
0.24. [R]25 ) -22 (c ) 0.4, CH2Cl2). 1H NMR (400 MHz,
D
CDCl3): δ 4.97, 4.77 (2d, J ) 6.7 Hz, 2H), 4.91, 4.70 (2d, J )
7.0 Hz, 2H), 4.45 (dd, J ) 10.5, 1.5 Hz, 1H), 4.33 (q, J ) 7.2
Hz, 2H), 4.21 (d, J ) 7.1 Hz, 1H), 3.70 (dd, J ) 8.9, 7.1 Hz,
1H), 3.44, 3.43 (2s, 6H), 3.16 (br s, 1H), 2.41-2.34 (m, 1H),
1.32 (t, J ) 7.2 Hz, 3H), 1.23 (d, J ) 6.7 Hz, 3H). 13C NMR
(100.6 MHz, CDCl3): δ 171.4, 169.4, 97.4, 96.9, 81.7, 78.2, 76.0,
69.5, 62.6, 56.3, 35.4, 14.2, 14.1. Anal. Calcd for C14H24O9
(336.33): C, 50.00; H, 7.14. Found: C, 50.03; H, 7.19.
ether) ) 0.69. [R]25 ) +51 (c ) 0.5, CH2Cl2). 1H NMR (400
D
MHz, CDCl3): δ 9.69 (d, J ) 1.0 Hz, 1H), 5.01, 4.74 (2d, J )
6.8 Hz, 2H), 4.97, 4.72 (2d, J ) 6.3 Hz, 2H), 4.44 (d, J ) 7.5
Hz, 1H), 4.11-4.09 (m, 2H), 3.45, 3.43 (2s, 6H), 3.44 (masked
dd, 1H), 3.33 (dd, J ) 9.1, 7.5 Hz, 1H), 3.22 (dd, J ) 10.3, 9.1
Hz, 1H), 2.03-1.96 (m, 1H), 1.00 (d, J ) 6.5 Hz, 3H), 0.95,
0.88 (2s, 18H), 0.11, 0.09, 0.05, 0.04 (4s, 12H). 13C NMR (100.6
MHz, CDCl3): δ 205.1, 98.7, 98.2, 97.6, 81.7, 81.6, 79.1, 76.7,
56.4, 56.3, 36.4, 25.7, 25.6, 17.7, 12.7, -4.2, -4.3, -5.0, -5.3.
Anal. Calcd for C24H50O8Si2 (522.83): C, 55.14; H, 9.64.
Found: C, 55.58; H, 9.62.
Eth yl [(ter t-Bu tyl)dim eth ylsilyl 4-Deoxy-2,3-di-O-(m eth -
oxym et h yl)-4-m et h yl-6-O-(ter t-b u t yl)d im et h ylsilyl-â-D-
glycer o-L-glu co-h eptapyr an osid]u r on ate ((+)-30). One mo-
lar (i-Bu)2AlH in CH2Cl2 (55 mL, 55 mmol) was added dropwise
to a stirred solution of (-)-29 (6.2 g, 18.4 mmol) in anhydrous
CH2Cl2 (140 mL) cooled to -78 °C. After stirring at -78 °C
for 10 min, MeOH (10 mL) was added and the mixture was
poured into vigorously stirred 1 M aqueous HCl (300 mL). The
aqueous layer was extracted with CHCl3. The combined
organic extracts were dried (MgSO4), and the solvent was
evaporated in vacuo, affording a pale yellow oil (4.74 g, 76%
of pyranose), which was dissolved in anhydrous CH2Cl2 (120
mL) and cooled to 0 °C. 2,6-Lutidine (8.1 mL, 70 mmol) and
(t-Bu)Me2SiOSO2CF3 (9 mL, 39 mmol) were added. After
stirring at 0 °C for 2 h, the mixture was poured into 2 M
aqueous NaOH. The aqueous layer was extracted with CHCl3.
The combined organic extracts were washed with 1 M aqueous
HCl, then with brine, and dried (MgSO4). The solvent was
evaporated and the residue purified by flash chromatography
on silica gel (1:15 EtOAc/light petroleum ether), affording a
colorless oil (6.7 g, 64%). Rf (1:4 EtOAc/light petroleum ether)
(ter t-Bu tyl)dim eth ylsilyl 7-O-Acetyl-4,8,10,12,13,14-h exa-
d eoxy-2,3-O-bis(m eth oxym eth yl)-4,10-d im eth yl-15-O-(p-
m eth oxyben zyl)-6-O-(ter t-bu tyl)d im eth ylsilyl]-11-O-(tr i-
eth ylsilyl)-â-D-ga la cto-L-glu co or â-D-gu lo-L-glu co-p en -
ta d ecop yr a n osid -9-u lose ((+)-32). In a Schlenk tube (flame
dried), 1.4 M n-BuLi in hexanes (1.3 mL, 1.83 mmol) was
added to a stirred solution of (i-Pr)2NH (0.3 mL, 2.1 mmol) in
anhydrous THF (18 mL) cooled to -60 °C. After stirring at
-60 °C for 15 min, the mixture was cooled to -78 °C, and (-)-6
(588 mg, 1.44 mmol) in solution in anhydrous THF (1.5 mL)
was added. After stirring at -78 °C for 15 min (+)-7 (683 mg,
1.31 mmol) was added in solution in anhydrous THF (2 mL).
After stirring for 15 min at -78 °C, the mixture was poured
into half-saturated aqueous solution of NH4Cl (50 mL) cooled
to 0 °C. The aqueous layer was extracted with EtOAc. The
combined extracts were washed with brine and dried (MgSO4).
) 0.68. [R]25 ) +8 (c ) 0.5, CH2Cl2). 1H NMR (400 MHz,
D
CDCl3): δ 5.01, 4.74 (2d, J ) 6.8 Hz, 2H), 4.98, 4.73 (2d, J )

C29-C51 Subunit of Spongistatin 1
J . Org. Chem., Vol. 65, No. 11, 2000 3355
After solvent evaporation, the residue was dissolved at 0 °C
in a mixture of pyridine (7 mL) and Ac2O (7 mL), containing
4-(dimethylamino)pyridine (20 mg). After stirring at 0 °C for
40 min, the solvents were evaporated in vacuo to dryness and
the residue was purified by flash chromatography on silica gel
(1:2 EtOAc/light petroleum ether), affording a colorless oil (1.05
3H), 0.60 (q, J ) 8.0 Hz, 12H), 0.14, 0.12, 0.08, 0.07 (4s, 12H).
13C NMR (100.6 MHz, CDCl3): δ 170.0, 159.0, 130.8, 129.1,
113.7, 98.6, 98.2, 97.7, 82.5, 82.0, 77.1, 73.6, 73.5, 72.5, 70.3,
68.7, 56.35, 56.3, 55.2, 40.0, 38.0, 35.5, 34.3, 30.5, 25.8, 25.7,
21.1, 18.1, 17.9, 13.4, 9.2, 7.0, 6.95, 5.4, 5.2, -4.0, -4.4, -4.7,
-5.2. Anal. Calcd for C55H108O13Si4 (1089.45): C, 60.66; H, 9.93;
Si, 10.29. Found: C, 60.52; H, 9.97; Si, 10.13.
g, 75%). Rf (1:4 EtOAc/light petroleum ether) ) 0.48. [R]25
)
D
1
15 (c ) 0.5, CH2Cl2). H NMR (400 MHz, CDCl3): δ 7.25 (d, J
) 8.7 Hz, 2H), 6.88 (d, J ) 8.7 Hz, 2H), 5.35 (dt, J ) 10.0, 2.8
Hz, 1H), 4.98, 4.73 (2d, J ) 6.8 Hz, 2H), 4.94, 4.70 (2d, J )
6.3 Hz, 2H), 4.42 (s, 2H), 4.41 (d, J ) 7.5 Hz, 1H), 4.02 (t, J )
2.8 Hz, 1H), 3.99 (m, 1H), 3.81 (s, 3H), 3.43, 3.42 (2s, 6H),
(ter t-Bu tyl)d im eth ylsilyl 7-O-Acetyl-4,8,10,12,13,14-
h exa d eoxy-2,3-O-bis(m eth oxym eth yl)-4,10-d im eth yl-15-
O-(p -m e t h oxyb e n zyl)-6-O-[(t er t -b u t yl)d im e t h ylsilyl]-
9,11-O-isop r op ylid en -â-D-glycer o-L-id o or l-ta lo-L-glu co-
p a n ta d ecop yr a n osid e (34). Crude (tert-butyl)dimethylsilyl
7-O-acetyl-4,8,10,12,13,14-hexadeoxy-2,3-O-bis(methoxymethyl)-
4,10-dimethyl-15-O-(p-methoxybenzyl)-6-O-[(tert-butyl)dimeth-
ylsilyl]-â-D-glycero-L-ido or l-talo-L-gluco-pentadecopyranoside
obtained as above (50 mg, 0.058 mmol) was dissolved in
acetone (1.2 mL) and 2,2-dimethoxypropane (1.2 mL) contain-
ing paratoluenesulfonic acid (5 mg). After stirring at 20 °C
for 6 h, the solvents were evaporated and the residue was
chromatographied on silica gel (1:8 EtOAc/light petroleum
ether) to afford a colorless oil (42 mg, 80%). 1H NMR (400 MHz,
CDCl3): δ 7.26, 6.88 (2d, J ) 6.7 Hz, 4H), 4.99, 4.70 (2d, J )
6.8 Hz, 2H), 4.94, 4.73 (2d, J ) 6.9 Hz, 2H), 4.50, 4.48 (m,
1H), 4.43 (s, 2H), 4.38 (d, J ) 7.5 Hz, 1H), 4.20 (d, J ) 1.8 Hz,
1H), 3.91, 3.89 (m, 1H), 3.81 (s, 3H), 3.44 (t, J ) 8.1 Hz, 2H),
3.44, 3.42 (2s, 6H), 3.42 (dd, J ) 9.9, 1.8 H, 1H), 3.29 (dd, J )
9.2, 7.5 Hz, 1H), 3.19 (dd, J ) 9.7, 9.2 Hz, 1H), 3.12 (dd, J )
18.1, 8.8 Hz, 1H), 2.30 (dd, J ) 18.1, 3.5 Hz, 1H), 1.94-1.91
(m, 1H), 1.66, 1.59 (m, 2H), 1.43, 1.32 (2s, 6H), 1.43, 1.22 (m,
7H), 1.02 (d, J ) 6.4 Hz, 3H), 0.96, 0.87 (2s, 18H), 0.83 (d, J
) 6.8 Hz, 3H), 0.13, 0.05, 0.04, 0.03 (4s, 12H). 13C NMR (100.6
MHz, CDCl3): δ 209.9, 159.1, 130.7, 129.2, 113.7, 98.8, 98.6,
97.8, 96.1, 82.1, 81.7, 79.7, 78.0, 73.0, 72.5, 69.9, 68.3, 56.3,
55.2, 42.3, 36.4, 34.4, 32.6, 29.8, 29.6, 25.9, 25.6, 22.0, 19.4,
18.3, 17.8, 13.3, 5.2, -4.3, -4.4, -4.7, -5.3. Anal. Calcd for
3
3.42 (t, J ) 6.8 Hz, 2H), 3.27 (dd, J ) 9.1, 7.5 Hz, 1H), 3.22
(dd, J ) 10.6, 2.8 Hz, 1H), 3.16 (dd, J ) 10.0, 9.1 Hz, 1H),
3.02 (dd, J ) 17.8, 10.0 Hz, 1H), 2.91 (dd, J ) 17.8, 2.8 Hz,
1H), 2.50-2.46 (m, 1H), 1.98 (s, 3H), 1.93-1.86 (m, 1H), 1.60-
1.53 (m, 2H), 1.45-1.37 (m, 4H), 1.12 (d, J ) 7.1 Hz, 3H), 1.01
(d, J ) 6.5 Hz, 3H), 0.95 (t, J ) 8.0 Hz, 9H), 0.94, 0.88 (2s,
18H), 0.60 (q, J ) 8.0 Hz, 6H), 0.13, 0.09, 0.07, 0.06 (4s, 12H).
13C NMR (100.6 MHz, CDCl3): δ 210.2, 196.0, 159.0, 130.7,
129.1, 113.7, 98.6, 98.2, 97.9, 82.4, 82.8, 81.8, 78.9, 73.4, 73.0,
72.6, 72.5, 70.0, 56.3, 56.2, 55.2, 52.4, 41.6, 37.1, 35.4, 29.9,
26.0, 25.6, 21.8, 21.0, 18.4, 17.8, 13.4, 12.0, 7.0, 5.2, -4.0, -4.4,
-4.8, -5.3. Anal. Calcd for C49H92O13Si3 (973.52): C, 60.49;
H, 9.47; Si, 8.45. Found: C, 60.08; H, 9.47; Si, 8.64.
(ter t-Bu t yl)d im et h ylsilyl 7-O-Acet yl-4,8,10,12,13,14-
h exa d eoxy-2,3-O-bis(m eth oxym eth yl)-4,10-d im eth yl-15-
O-(p-m eth oxyben zyl)-6-O-[(ter t-bu tyl)d im eth ylsilyl]-9,11-
O-b is(t r iet h ylsilyl)-â-D-glycer o-L-id o or l-ta lo-L-glu co-
p en ta d ecop yr a n osid e ((+)-33). HF-pyridine (1.5 mL) was
added to a stirred solution of (+)-32 (620 mg, 0.637 mmol) in
anhydrous THF (30 mL) cooled to -20 °C under an Ar
atmosphere. The mixture was stirred at -20 °C for 15 min
and at 0 °C for 1 h. It was poured into a saturated aqueous
solution of NaHCO3 (40 mL). The aqueous layer was ex-
tracted with EtOAc. The combined organic extracts were
washed with brine and dried (MgSO4). Solvent evaporation in
vacuo afforded a pale yellow oil (547 mg, 100% (tert-butyl)-
dimethylsilyl 7-O-acetyl-4,8,10,12,13,14-hexadeoxy-2,3-O-bis-
(methoxymethyl)-4,10-dimethyl-15-O-(p-methoxybenzyl)-6-O-
[(tert-butyl)dimethylsilyl]-â-D-galacto-L-gluco- or â-D-gulo-L-
gluco-pentadecopyranosid-9-ulose), which was dissolved in
THF (4 mL) and MeOH (1 mL). After cooling to -78 °C 1 M
Et2BOMe22 in THF (0.83 mL, 0.83 mmol) was added. After
stirring at -78 °C for 15 min, NaBH4 (34 mg, 0.89 mmol) was
added and the stirring continued for 1 h at -78 °C. AcOH (10
drops) was added and the mixture poured into a saturated
aqueous solution of NaHCO3 (20 mL) under vigorous stirring.
The aqueous layer was extracted with EtOAc. The combined
organic extracts were washed with brine and dried (MgSO4).
The solvent was evaporated in vacuo. The residue was taken
up in MeOH (4 mL) and the solvent evaporated in vacuo. This
operation was repeated once to afford a pale yellow oil (427
mg, 78%, of (tert-butyl)dimethylsilyl 7-O-acetyl-4,8,10,12,13,
14-hexadeoxy-2,3-O-bis(methoxymethyl)-4,10-dimethyl-15-O-
(p-methoxybenzyl)-6-O-[(tert-butyl)dimethylsilyl]-â-D-glycero-
L-ido or l-talo-L-gluco-pentadecopyranoside), which was dis-
solved in dry DMF (4 mL). After cooling to 0 °C, imidazole
(169 mg, 2.48 mmol) and Et3SiCl (267 µL, 1.59 mmol) were
added and the mixture stirred at 20 °C for 3 h. The mixture
was then poured into H2O (20 mL), and the aqueous layer was
extracted with Et2O. The combined organic extracts were
washed with brine and dried (MgSO4). Solvent evaporation and
flash chromatography on silica gel (1:7 EtOAc/light petroleum
C
44H80O12Si2 (857.28): C, 61.65; H, 9.41. Found: C, 61.42; H,
9.35.
(ter t-Bu t yl)d im et h ylsilyl 4,8,10,12,13,14-H exa d eoxy-
2,3-O-b is(m et h oxym et h yl)-4,10-d im et h yl-15-O-(p -m et h -
oxyb en zyl)-6-O-[(ter t-b u t yl)d im et h ylsilyl]-9,11-(b is(t r i-
e t h y ls ily l)-â-D -g u l o-L -g l u co-p e n t a d e c o p y r a n o s id -7-
u lose ((+)-35). A mixture of (+)-33 (300 mg, 0.276 mmol),
anhydrous CH2Cl2 (3 mL), and 1 M (i-Bu)2Al in CH2Cl2 (827
µL, 0.827 mmol) was stirred at -78 °C for 10 min under an
Ar atmosphere. MeOH (0.5 mL) was added and the mixture
poured into 1 M aqueous HCl (15 mL) cooled to 0 °C. The
aqueous layer was extracted with CHCl3. The combined
organic extracts were dried (MgSO4). After solvent evapora-
tion, the residue (260 mg, 0.248 mmol) was dissolved in
anhydrous CH2Cl2 (3 mL), and 1,1,1-triacetoxy-1,1-dihydro-
1,2-benziodoxol-3(1H)-one (158 mg, 0.372 mmol) was added.
After stirring at 20 °C for 30 min, Et2O (15 mL), a saturated
aqueous solution of NaHCO3 (15 mL), and Na2S2O3 (0.5 g) were
added. The mixture was stirred at 20 °C for 10 min and
extracted with Et2O. The combined organic extracts were
washed with a saturated aqueous solution of NaHCO3, then
with brine, and dried (MgSO4). Solvent evaporation and flash
chromatography on silica gel (1:5 EtOAc/light petroleum ether)
afforded a colorless oil (231 mg, 80%). [R]25 ) 38 (c ) 0.5,
D
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.27, 6.88 (2d, J ) 8.7
Hz, 4H), 5.00, 4.73 (2d, J ) 6.8 Hz, 2H), 4.95, 4.71 (2d, J )
6.3 Hz, 2H), 4.44 (s, 2H), 4.43 (d, J ) 7.1 Hz, 1H), 4.28-4.26
(m, 1H), 4.24 (d, J ) 1.7 Hz, 1H), 3.81 (s, 3H), 3.74-3.71 (m,
3
1H), 3.51 (dd, J ) 10.4, 1.7 Hz, 1H), 3.46 (t, J ) 6.8 Hz, 2H),
ether) afforded a colorless oil (346 mg, 50%). [R]25 ) 13 (c )
3.45, 3.42 (2s, 6H), 3.26 (dd, J ) 9.1, 7.1 Hz, 1H), 3.20 (t, J )
9.1 Hz, 1H), 2.78 (dd, J ) 17.0, 6.3 Hz, 1H), 2.64 (dd, J ) 17.0,
5.0 Hz, 1H), 1.91-1.87 (m, 1H), 1.65-1.49, 1.43-1.41 (m, 7H),
1.04 (d, J ) 6.5 Hz, 3H), 0.97 (d, J ) 7.6 Hz, 3H), 0.95-0.93
(m, 18H), 0.87 (s, 18H), 0.59 (q, J ) 7.8 Hz, 12 H), 0.13, 0.04,
0.01 (3s, 12H). 13C NMR (100.6 MHz, CDCl3): δ 208.4, 159.0,
130.8, 129.1, 113.7, 98.6, 98.2, 97.7, 82.0, 81.9, 78.8, 78.7, 73.1,
72.5, 70.3, 69.0, 56.3, 55.2, 44.8, 42.3, 36.8, 34.9, 30.2, 25.9,
25.7, 21.0, 18.4, 17.8, 13.3, 10.2, 7.0, 5.3, 5.2, -3.9, -4.0, -4.6,
-5.3. Anal. Calcd for C55H104O12Si4 (1045.75): C, 60.92; H, 9.96.
Found: C, 60.64; H, 9.75.
D
1
0.2, CH2Cl2). H NMR (400 MHz, CDCl3): δ 7.27, 6.88 (2d, J
) 8.3 Hz, 4H), 4.95 (d, J ) 6.8 Hz, 1H), 4.90 (d, J ) 6.4 Hz,
1H), 4.90 (ddd, J ) 10.1, 4.8, 4.7 Hz, 1H), 4.74-4.72 (m, 2H),
4.43 (s, 2H), 4.43 (d, J ) 7.2 Hz, 1H), 3.88 (dd, J ) 4.8, 1.6
Hz, 1H), 3.81 (s, 3H), 3.78 (m, 1H), 3.68-3.66 (m, 1H), 3.45 (t,
J ) 6.3 Hz, 2H), 3.45, 3.42 (2s, 6H), 3.24 (dd, J ) 9.0, 7.2 Hz,
1H), 3.12 (dd, J ) 9.0, 8.9 Hz, 1H), 2.98 (dd, J ) 10.8, 1.6 Hz,
1H), 2.07-1.98 (m, 1H), 1.96 (s, 3H), 1.92-1.85 (m, 3H), 1.68-
1.63 (m, 1H), 1.62-1.33 (m, 6H), 1.07 (d, J ) 6.4 Hz, 3H), 0.96
(t, J ) 8.0 Hz, 18H), 0.91, 0.90 (2s, 18H), 0.87 (d, J ) 7.1 Hz,

3356 J . Org. Chem., Vol. 65, No. 11, 2000
Lemaire-Audoire and Vogel
Meth yl [(ter t-Bu tyl)d im eth ylsilyl 4,8,10,12,13,14-Hexa -
d eoxy-2,3-O-bis(m eth oxym eth yl)-4,10-d im eth yl-15-O-(p-
m eth oxyben zyl)-6-O-[(ter t-bu tyl)d im eth ylsilyl]-â-D-gu lo-
L-glu co-p en ta d ecop yr a n osid ]-7-u lo-7,11-p yr a n osid e ((+)-
36). HF-pyridine (0.23 mL) was added to a stirred solution
of (+)-35 (116 mg, 0.11 mmol) in anhydrous THF (2.4 mL)
cooled to 0 °C. After stirring at 0 °C for 30 min, the mixture
was poured into a saturated aqueous solution of NaHCO3 (15
mL) and then extracted with EtOAc. The solvent was evapo-
rated in vacuo, and the crude oil (7-ulo-7,1-pyranose) was
dissolved in MeOH (1.5 mL). After the addition of p-toluene-
sulfonic acid (4 mg), the mixture was stirred at 20 °C for 2 h.
NaHCO3 (15 mg) was added. After stirring at 20 °C for 5 min
the precipitate was filtered off. Solvent evaporation and flash
chromatography on silica gel (1:6 EtOAc/light petroleum ether)
afforded a colorless oil (71 mg, 77%). Rf (1:4 EtOAc/light
petroleum ether) ) 0.57. [R]25D ) 9 (c ) 0.5, CH2Cl2). 1H NMR
(400 MHz, CDCl3): δ 7.33, 6.91 (2d, 4H), 5.39 (br.d, J ) 5.1
Hz, 1H), 5.25, 4.86 (2d, J ) 6.1 Hz, 2H), 5.24, 4.77 (2d, J )
6.7 Hz, 2H), 4.62 (d, J ) 7.6 Hz, 1H), 4.44 (s, 2H), 4.41 (br s,
1H), 4.15 (m, 1H), 3.68 (dd, J ) 9.2, 7.6 Hz, 1H), 3.45 (t, J )
6.0 Hz, 2H), 3.39-3.26 (m, 3H), 3.38 (s, 3H), 3.34, 3.31 (2s,
6H), 3.27 (s, 3H), 2.21-2.14 (m, 1H), 1.86-1.57 (m, 9H), 1.31
(d, J ) 6.5 Hz, 3H), 1.07, 1.06 (2s, 18H), 0.78 (d, J ) 7.2 Hz,
3H), 0.38, 0.30, 0.17, 0.13 (4s, 12H). 13C NMR (100.6 MHz,
CDCl3): δ 156.7, 132.0, 129.8, 114.5, 99.4, 99.35, 98.3, 96.4,
83.2, 82.7, 79.4, 77.2, 75.4, 73.2, 72.9, 70.6, 56.5, 55.5, 55.2,
38.5, 35.8, 32.6, 32.6, 30.7, 23.7, 26.6, 18.9, 18.7, 14.4, 10.6,
-2.9, -3.8, -4.4, -4.5. Anal. Calcd for C42H78O12Si2 (831.24):
C, 60.69; H, 9.46. Found: C, 60.84; H, 9.31.
(4S,E)-7-Ch lor o-1-{m eth yl 4,8,10,12,13,14-h exa d eoxy-
2,3-O-b is(m et h oxym et h yl)-4,10-d im et h yl-15-O-(p -m et h -
oxyben zyl)-6-[(ter t-bu tyl)d im eth ylsilyl]-â-D-gu lo-L-glu co-
p e n t a d e cos-7-u lo-r-7,11-p yr a n osid -5,1-p yr a n osid }-2-
m et h ylid en e-4-[(p -m et h oxyb en zoyl)oxy]oct a -5,7-d ien e
((+)-38). A mixture of (+)-36 (30 mg, 0.036 mmol), anhydrous
THF (1.1 mL), and 1 M Bu4NF in THF (39 µL, 0.039 mmol)
was stirred at -30 °C for 1.5 h. Solvent evaporation, filtration
through a pad of silica gel (3:1 EtOAc/light petroleum ether),
and solvent evaporation afforded a colorless oil, which was
dissolved at 0 °C in pyridine (0.4 mL) and Ac2O (0.4 mL). After
addition of 4-(dimethylamino)pyridine (3 mg), the mixture was
stirred at 0 °C for 1 h. Solvents were evaporated under high
vacuum (10-2 Torr). The residue was dissolved in CH2Cl2 (8
mL). The solution was washed with 1 M aqueous HCl (2 mL),
then with saturated aqueous solution of NaHCO3 (2 mL) and
finally with H2O (2 mL). After drying (MgSO4), the solvent
was evaporated, affording unstable diacetate 37 as a pale
yellow oil (22 mg, 75%). The crude diacetate 37 (20 mg, 0.025
mmol) was dissolved in CD3NO2 (5 mm NMR tube) and cooled
to -10 °C. 16 (83 mg, 0.2 mmol) and Me3SiOSO2CF3 (31 µL,
0.2 mmol) were added, and the reaction was followed by 1H
NMR at -10 °C. After 3 h at -10 °C the mixture was poured
into a saturated aqueous solution of NaHCO3 (5 mL) and
extracted with EtOAc (8 mL, four times). The combined organic
extracts were washed with brine and dried (MgSO4). After
solvent evaporation in vacuo the residue was dissolved in
anhydrous THF (1.5 mL), and DBU (60 µL) was added. After
stirring at 50 °C for 30 min, the mixture was poured into H2O
(5 mL) and extracted with Et2O. The combined organic extracts
were washed successively with 1 M aqueous HCl, a saturated
aqueous solution of NaHCO3 and brine and then dried
(MgSO4). Solvent evaporation and flash chromatography on
silica gel (1:8 to 1:4 EtOAc/light petroleum ether) afforded a
colorless oil (11 mg, 42%) containing a 4:1 mixture of â/R
C-glycosides. A second flash chromatography on silica gel
afforded pure (+)-38 (8 mg, 30%). Rf (1:16 EtOAc/light petro-
leum ether) ) 0.13. [R]25 ) 65 (c ) 0.3, CH2Cl2). 1H NMR
D
(400 MHz, CDCl3): δ 8.02, 6.93 (2d, J ) 9.0 Hz, 4H), 7.26,
6.88 (2d, J ) 8.7 Hz, 4H), 6.38 (dd, J ) 15.0, 0.9 Hz, 1H), 6.19
(dd, J ) 15.0, 6.2 Hz, 1H), 5.38, 5.31 (2s, 2H), 4.95 (d, J ) 6.8
Hz, 1H), 4.79-4.77 (m, 1H), 4.76, 4.64 (2br s, 2H), 4.73-4.67
(m, 3H), 4.44 (s, 2H), 3.93-3.90 (m, 1H), 3.87, 3.81 (2s, 6H),
3.80 (br s, 1H), 3.70 (d, J ) 11.1 Hz, 1H), 3.55 (dm, J ) 10.0,
1H), 3.47 (t, J ) 7.1 Hz, 2H), 3.45, 3.33 (2s, 6H), 3.38 (dd, J )
9.1, 9.0 Hz, 1H), 3.24 (dd, J ) 10.0, 9.1 Hz, 1H), 3.12 (s, 3H),
2.52 (dd, J ) 14.3, 8.0 Hz, 1H), 2.36 (dd, J ) 14.3, 5.8 Hz,
1H), 2.11 (s, 3H), 2.10-2.06 (m, 2H), 1.86-1.80 (m, 1H), 1.79-
1.56, 1.45-1.28 (2m, 9H), 1.06 (d, J ) 6.5 Hz, 3H), 0.90 (s,
9H), 0.89 (d, J ) 7.1 Hz, 3H), 0.10, 0.07 (2s, 6H). 13C NMR
(100.6 MHz, CDCl3): δ 170.4, 165.4, 163.4, 159.1, 142.2, 137.7,
133.0, 131.7, 130.7, 129.2, 128.5, 122.7, 116.5, 113.7, 113.6,
110.9, 100.8, 98.4, 97.1, 83.6, 79.6, 79.1, 78.3, 72.7, 72.6, 71.8,
70.4, 69.9, 67.6, 56.4, 55.7, 55.4, 55.3, 47.0, 43.4, 37.4, 36.7,
34.5, 32.2, 29.9, 25.9, 22.8, 20.9, 18.4, 13.7, 10.2, -3.1, -4.4.
Anal. Calcd for C55H85O15SiCl (1049.80): C, 62.93; H, 8.16.
Found: C, 62.72; H, 8.05.
Ack n ow led gm en t . We thank the Swiss National
Science Foundation and the Fonds Herbette (Lausanne)
for financial support. We are also grateful to Mr.
Fre´de´ric Carrel for preliminary experiments toward the
synthesis of 14 and Mr. Martial Rey, Francisco Sepulve-
da, and Miss Ce´cile Glanzmann for their technical help.
Su p p or tin g In for m a tion Ava ila ble: Data for (-)-6, (-)-
6A, (-)-6M(S), (+)-6M(R), (+)-7, (+)-8, 12-14, 16, (+)-17, 19,
20, (+)-22, (+)-23, (+)-26, (-)-28, (-)-29, (+)-30, (-)-31, (+)-
32, (+)-33, (+)-35, (+)-36, (+)-38. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O991642B