The total synthesis of allosamidin. Expansions of the methodology of azaglycosylation pursuant to the total synthesis of allosamidin. A surprising enantiotopic sense for a lipase-induced deacetylation

Article abstract of DOI:10.1021/ja960526c

Allosamidin, recently isolated from mycelial extracts of Streptomyces sp. 1713, is a powerful and selective chitinase inhibitor. The total synthesis of allosamidin is described herein. The electric eel acetylcholinesterase-mediated enantioselective hydrolysis of (trans,trans)-2-(benzyloxy)cyclopentene-1,3-diol diacetate accessed a monoacetyl derivative. Five additional steps produced a protected version of the aglycon ('allosamizoline') sector of allosamidin. An allal derivative stereoselectively reacted with benzenesulfonamide in the presence of a halonium source to afford a 2β-halo-1α-sulfonamidohexose. Treatment of this product with a strong base generated an intermediate 1,2-sulfonylaziridine, which was trapped with a protected allal derivative to provide a disaccharide glycal. Reiteration of this scheme gave access to the required trisaccharide. Following deprotection, the total synthesis of allosamidin was accomplished. In addition, the method, with modification, gave access to several allosamidin analogs.

Full text of DOI:10.1021/ja960526c

9526
J. Am. Chem. Soc. 1996, 118, 9526-9538
The Total Synthesis of Allosamidin. Expansions of the
Methodology of Azaglycosylation Pursuant to the Total
Synthesis of Allosamidin. A Surprising Enantiotopic Sense for
a Lipase-Induced Deacetylation
David A. Griffith and Samuel J. Danishefsky*,†
Contribution from the Department of Chemistry, Yale UniVersity, New HaVen, Connecticut 06520
ReceiVed February 20, 1996X
Abstract: Allosamidin, recently isolated from mycelial extracts of Streptomyces sp. 1713, is a powerful and selective
chitinase inhibitor. The total synthesis of allosamidin is described herein. The electric eel acetylcholinesterase-
mediated enantioselective hydrolysis of (trans,trans)-2-(benzyloxy)cyclopentene-1,3-diol diacetate accessed a
monoacetyl derivative. Five additional steps produced a protected version of the aglycon (“allosamizoline”) sector
of allosamidin. An allal derivative stereoselectively reacted with benzenesulfonamide in the presence of a halonium
source to afford a 2â-halo-1R-sulfonamidohexose. Treatment of this product with a strong base generated an
intermediate 1,2-sulfonylaziridine, which was trapped with a protected allal derivative to provide a disaccharide
glycal. Reiteration of this scheme gave access to the required trisaccharide. Following deprotection, the total synthesis
of allosamidin was accomplished. In addition, the method, with modification, gave access to several allosamidin
analogs.
Background on AllosamidinsA Paradigm Case for
Chitinase Inhibition
it could well be advantageous to achieve species specific
chitinase inhibition. Since chitinases may function in beneficial
roles, blanket inhibition of the enzyme throughout an ecosystem
could be undesirable. For example, chitinases (such as those
isolated from the digestive tract of certain insectivorous
vertebrates) are thought to aid in digestion.11 While no chitinous
structures are known in higher order plants, plant chitinase
production has been observed to increase during times of fungal
infection.12 These glycosidases appear to operate defensively
against invading fungi.13,14
Allosamidin (1), isolated from mycelial extracts of Strepto-
myces sp. 1713, was heralded as an early success in the search
for selective chitinase inhibitors. It (1) consists15,16 of a 3,3′-
epi-chitobiose moiety â-linked to the novel aglycon sector
termed “allosamizoline” (8), which has the absolute configu-
ration indicated in Figure 1.17 Thus, the carbohydrate sector
of allosamidin is a small molecule “look-alike” of chitin. A
(7) Misato, T.; Kakiki, K.; Hori, M. In AdVances in Pesticide Science;
Geissbuhler, H., Ed.; Pergamon Press: New York, 1979; p 458. Gooday,
G. W. Prog. Ind. Microbiol. 1989, 27, 139.
(8) Verloop, A.; Ferrell, D. Pesticide ACS Symp. Ser. 1977, 37, 237.
(9) Muzzarelli, R. A. A. The Insect Integument; Hepburn, H. R., Ed.;
Elsevier: New York, 1976.
(10) Sakuda, S.; Nishimoto, Y.; Ohi, M.; Watanabe, M.; Takayama, S.;
Isogai, A.; Yamada, Y. Agric. Biol. Chem. 1990, 54, 1333.
(11) Lundblad, G.; Hederstedt, B.; Lind, J.; Steby, M. Eur. J. Biochem.
1974, 46, 367. Jeuniaux, C. Nature 1961, 192, 135.
(12) Mauch, F.; Hadwigwer, L. A.; Boller, T. Plant Physiol. 1984, 76,
607. Pegg, G. F.; Young, D. H. Physiol. Plant Pathol. 1982, 21, 389. Pegg,
G. F.; Vessey, J. C. Physiol. Plant Pathol. 1973, 3, 207.
Chitin,1 composed substantially of an array of â-1,4-linked
N-acetylglucosamine units, is the major component of the insect
exoskeleton.2 It is also the primary cell wall polysaccharide in
several groups of fungi.3 Chitin synthases are employed by
nature to build chitinous structures, while chitinases facilitate
their degradation. For example, molting fluids secreted by
insects in preparation for ecdysis contain chitinases which
degrade and weaken the old cuticle.4 Also, the primary septum
between mother and daughter yeast cells at the time of budding
is composed primarily of chitin.5 Accordingly, chitin-maintain-
ing enzymes are necessary to ensure proper cell division.6 Since
chitin has a specialized role in nature, compounds capable of
disrupting chitin biosynthesis are ideal targets as potential
growth inhibitors of chitin containing organisms. For instance,
chitin synthase inhibitors have been studied and used as
inhibitors of fungal7 and insect8 growth.
It has been suggested that chitinase inhibitors could also
function as selective insecticides9 and fungicides.10 Moreover,
† Current address: Laboratory for Bioorganic Chemistry, Sloan-Kettering
Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center,
New York, New York 10021, and the Department of Chemistry, Columbia
University, New York, New York 10027.
X Abstract published in AdVance ACS Abstracts, September 1, 1996.
(1) Chitin, Chitosan, and Related Enzymes; Zikakis, J. P., Ed.; Academic
Press, Inc.: New York, 1984.
(2) Andersen, S. O. Annu. ReV. Entomol. 1979, 24, 29. Rudall, K. M.;
Kenchington, W. Biol. ReV. 1973, 49, 597.
(13) Schlumbaum, A.; Mauch, F.; Vo¨geli, U.; Boller, T. Nature 1986,
324, 365. Tsukamoto, T.; Koga, D.; Ida, A.; Ishibashi, T.; Horino-
Matsushige, M.; Yagishita, K.; Imoto, T. Agric. Biol. Chem. 1984, 48, 931.
Boller, T.; Gehri, A.; Mauch, F.; Vo¨geli, U. Planta 1983, 157, 22. Nichols,
E. J.; Beckman, J. M.; Hadwiger, L. A. Plant Physiol. 1980, 66, 199.
(14) Mauch, F.; Mauch-Mani, B.; Boller, T. Plant Physiol. 1988, 88,
936. Molano, J.; Polacheck, I.; Duran, A.; Cabib, E. J. Biol. Chem. 1979,
254, 4901.
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Kodama, H.; Suzuki, A. Agric. Biol. Chem. 1987, 51, 3251.
(17) Sakuda, S.; Isogai, A.; Matsumoto, S.; Suzuki, A.; Koseki, K.;
Kodama, H.; Yamada, Y. Agric. Biol. Chem. 1988, 52, 1615.
(3) Cabib, E.; Shematek, E. M. In Biology of Carbohydrates; Ginsburg,
V., Robbins, P., Eds.; John Wiley & Sons, Inc.: New York, 1981; Vol. 1,
p 60.
(4) Kramer, K. J.; Dziadik-Turner, C.; Koga, D. In ComprehensiVe Insect
Physiology Biochemistry and Pharmocology; Kerkut, G. A., Gilbert, L. I.,
Eds.; Pergamon Press, Inc.: New York, 1985; p 75.
(5) Molano, J.; Bowers, B.; Cabib, E. J. Cell Biol. 1980, 85, 199.
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138, 97. Shaw, A. J.; Mol, P. C.; Bowers, B.; Silverman, S. J.; Valdivieso,
M. H.; Dura´n, A.; Cabib, E. J. Cell Biol. 1991, 114, 111. Kuranda, M. J.;
Robbins, P. W. J. Biol. Chem. 1991, 266, 19758. Cabib, E.; Sburlati, A.;
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S0002-7863(96)00526-4 CCC: $12.00 © 1996 American Chemical Society

Total Synthesis of Allosamidin
J. Am. Chem. Soc., Vol. 118, No. 40, 1996 9527
into the fourth instar larvae of B. mori during the feeding stage
at a dose greater than 4 µg.24 Furthermore, administration of
allosamidin to the fifth and last instar larvae of the common
army worm Leucania separata prevented larval and pupal
ecdysis, respectively.
Chitinases from several yeasts were also efficiently inhibited
by the allosamidins; the level of inhibition was dependent, in a
subtle way, upon the inhibitor structure. Whereas the dem-
ethylallosamidins were 10-100 times more efficient than the
N,N-dimethylated analogs as inhibitors of Candida albicans
ATCC 10231 and Saccharomyces cereVisiae chitinases, the
Trichoderma sp. AF6-T8 chitinase was inhibited nearly equally
by these allosamidins.20 Didemethylallosamidin (3) was about
10-fold less active than 2 against B. mori, Trichoderma sp., and
Sa. cereVisiae chitinases.25 The configuration at C-3 of the
interior sugar appears to have only a slight effect on the
inhibition efficiency. It is interesting that the two pseudodi-
saccharides 9 and 10 inhibited the chitinase of C. albicans as
well as the allosamidins, yet displayed no inhibition against the
other yeast chitinases. Furthermore, the inhibition of C. albicans
chitinase activity by 1 was shown to be competitive at low
concentrations, while at higher concentration the inhibition is
irreversible.
As a consequence of its novel structure and in response to
the difficulties that have been encountered in attempts to obtain
adequate amounts of compound for biological investigation, a
program directed toward the total synthesis of allosamidin was
initiated. Other laboratories have had similar goals. The large
number of syntheses of aglycon 826-31 and pseudotrisaccharide
132-34 which have appeared in the literature attest to the high
level of interest in allosamidin. In this paper, we document
and expand upon our earlier disclosure which described the first
total synthesis of allosamidin.35 We do this within the broader
context of azaglycosylation,36 which is a central element in our
ongoing program directed toward oligosaccharide synthesis.37-39
We also provide some new insights into structure-activity
relationships in the allosamidin series.
(24) Sakuda, S.; Isogai, A.; Matsumoto, S.; Suzuki, A. J. Antibiot. 1987,
40, 296.
(25) Kinoshita, M.; Sakuda, S.; Yamada, Y. Biosci., Biotechnol., Bio-
chem. 1993, 57, 1699.
(26) (a) Trost, B. M.; Van Vranken, D. L. J. Am. Chem. Soc. 1990, 112,
1261. (b) Trost, B. M. Van Vranken, D. L. J. Am. Chem. Soc. 1993, 115,
444.
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1991, 32, 5123. (b) Nakata, M.; Akazawa, S.; Kitamura, S.; Tatsuta, K.
Tetrahedron Lett. 1991, 32, 5363.
(28) (a) Simpkins, N. S.; Stokes, S.; Whittle, A. J. Tetrahedron Lett.
1992, 33, 793. (b) Simpkins, N. S.; Stokes, S.; Whittle, A. J. J. Chem.
Soc., Perkin Trans. 1 1992, 2471.
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Biochem. 1993, 57, 1906.
(30) Goering, B. K.; Ganem, B. Tetrahedron Lett. 1994, 35, 6997.
(31) Shrader, W. D.; Imperiali, B. Tetrahedron Lett. 1996, 37, 599. This
synthesis supports the assignment of stereochemistry of the azaglycon
reported herein.
(32) (a) Maloisel, J.-L.; Vasella, A.; Trost, B. M.; Van Vranken, D. L.
J. Chem. Soc., Chem. Commun. 1991, 1099. (b) Maloisel, J.-L.; Vasella,
A. HelV. Chim. Acta 1992, 75, 1491. (c) Maloisel, J.-L.; Vasella, A.; Trost,
B. M.; Van Vranken, D. L. HelV. Chim. Acta 1992, 75, 1515.
(33) Takahashi, S. T.; Terayama, H.; Kuzuhara, H. Tetrahedron Lett.
1992, 33, 7565.
Figure 1. Structures of the Allosamidins.
recently published crystal structure of allosamidin bound in a
plant chitinase/lysozyme18 indicated that the aglycon portion
was bound in the center of the active site. The aminooxazoline
portion of the carbocycle serves to mimic the stabilization of
positive charge at C-1 by the oxygen of the neighboring N-acetyl
group, an apparent intermediate in the hydrolysis of chitin.
More recently, several compounds that are structurally related
to allosamidin (Figure 1) were also found to exhibit strong
chitinase inhibition.19,20 In addition, the two pseudodisaccha-
rides 9 and 10 (Figure 1) were isolated upon mild hydrolysis
of allosamidin and glucoallosamidin A (6), respectively.17
Finally, recent studies with isotopically labeled materials have
provided information about the biosynthesis of the allosami-
dins.21
Early reports on the activity of allosamidin were concerned
with the inhibition of insect chitinases. Allosamidin strongly
inhibits chitinases22 from the silkworm Bombyx mori, in Vitro,
while the inhibition of bacterial chitinases from Streptomyces
griseus and Serratia marcescens was 500-fold less. Moreover,
no inhibition was observed with yam chitinase, human or egg-
white lysozymes, or â-N-acetyl-D-glucosaminidases from B.
mori. Interestingly, allosamidin producing Streptomyces sp. AJ
9463 synthesizes two unique chitinases; one is strongly inhibited
by 1, while the other in not inhibited at concentrations of 2
mg/mL.23 Methylallosamidin (4),16 demethylallosamidin (2),
and pseudodisaccharide 9 all displayed inhibition levels similar
to 1 against B. mori chitinase activity.19 In the Chitin Azure
assay system, allosamidin and demethylallosamidin (2) inhibited
B. mori chitinase with IC50 values of 0.20 and 0.25 µg/mL,
respectively. However, allosamizoline (8) displayed no inhibi-
tion. These findings indicate that a glycosidic residue on the
aglycon is essential for activity.
More significant than its in Vitro chitinase inhibition is the
fact that allosamidin inhibits insect growth, in ViVo. The
compound prevented larval ecdysis in all cases when injected
(18) Terwisscha van Scheltinga, A. C.; Armand, S.; Kalk, K. H.; Isogai,
A.; Henrissat, B.; Dijkstra, B. W. Biochemistry 1995, 34, 15619.
(19) Isogai, A.; Sato, M.; Sakuda, S.; Nakayama, J.; Suzuki, A. Agric.
Biol. Chem. 1989, 53, 2825.
(20) Nishimoto, Y.; Sakuda, S.; Takayama, S.; Yamada, Y. J. Antibiot.
1991, 44, 716.
(21) Zhou, Z.-Y.; Sakuda, S.; Kinoshita, M.; Yamada, Y. J. Antibiot.
1993, 46, 1582. (b) Zhou, Z.-Y.; Sakuda, S.; Yamada, Y. J. Chem. Soc.,
Perkin Trans. 1 1992, 1649.
(22) Koga, D.; Isogai, A.; Sakuda, S.; Matsumoto, S.; Suzuki, A.; Kimura,
S.; Ide, A. Agric. Biol. Chem. 1987, 51, 471.
(34) Blattner, R.; Furneaux R. H.; Kemmitt, T.; Tyler, P. C.; Ferrier, R.
J.; Tide´n, A.-K. J. Chem. Soc., Perkin Trans. 1 1994, 3411.
(35) Griffith, D. A.; Danishefsky, S. J. J. Am. Chem. Soc. 1991, 113,
5863.
(36) Griffith, D. A.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112,
5811.
(37) Danishefsky, S. J.; Gervay, J.; Peterson, J. M.; McDonald, F. E.;
Koseki, K.; Griffith, D. A.; Oriyama T.; Marsden, S. J. Am. Chem. Soc.
1995, 117, 1940.
(38) McClure, K. F.; Randolph, J.; Ruggeri, R.; Danishefsky, S. J. Science
1993, 260, 1307.
(23) Wang, Q.; Zhou, Z.-Y.; Sakuda, S.; Yamada, Y. Biosci., Biotechnol.,
Biochem. 1993, 57, 467.
(39) Roberge, J.; Beebe, X.; Danishefsky, S. J. Science 1995, 269, 202.

9528 J. Am. Chem. Soc., Vol. 118, No. 40, 1996
Griffith and Danishefsky
Scheme 1
Scheme 3
In the present effort, selective deacetylation of the diacetate
17 provided monoacetate ent-19 in 95% yield (Scheme 3). To
determine the enantioselectivity of the enzymatic hydrolysis,
base-catalyzed deacetylation of 17 (K2CO3, methanol, THF) was
used to provide the racemic monoacetate rac-19 in 42% yield.
Formation of the Mosher ester43 (pyridine, (+)-MTPA-Cl,
CH2Cl2, 0 °C) proceeded smoothly to provide a mixture of
diastereomers, which could be clearly analyzed by 490 MHz
1H NMR spectroscopy. Evidence for the presence of primarily
one diastereomer was observed in the crude reaction mixture
of the (+)-MTPA ester derived from enzymatically differentiated
ent-19. Thus it was concluded at the time that ent-19 had been
formed in >95% enantiomeric excess (Vide infra).
Scheme 2
It had been anticipated that the enzymatic hydrolysis of
diacetate 18 would proceed to afford the desired acetate 19. In
actual practice, however, enzymatically mediated deacylation
had occurred in the opposite enantiotopic sense to that which
was observed by Deardorff et al. with the parent diacetate 15.44
The absolute configuration of ent-19 obtained through this route
was established only upon its eventual conversion to (+)-
allosamizoline (ent-8), which displayed an optical rotation
opposite in sign to that observed for the naturally derived
material (Vide infra).
We note, however, that the reversal of selectivity in enzyme-
mediated hydrolyses, upon substitution of the carbocyclic ring
in the substrate, is not without precedent. The selectivity
observed in the enzyme-mediated hydrolyses of cyclopentane
diacetates has been demonstrated to bear a subtle dependence
on the substitution pattern in the five-membered ring.45-47 Thus,
while it had not been known at this stage in the synthesis of
allosamidin which antipode had in fact been secured, we started
with what seemed, superficially, the simplest analogy. The
structures drawn at this stage and in schemes thereafter,
anticipate later rigorously adduced findings.
Acylation of monoacetate ent-19 with phenyl chloroformate
afforded a phenyl carbonate, which upon treatment with
methanolic ammonia and subsequent deacetylation with added
potassium carbonate provided carbamate ent-20 in 71% yield
(Scheme 4). The hydroxyl group was protected in the usual
way with TBDMS-Cl, giving rise to silyl ether ent-21 (96%).
It had been anticipated that the epoxide derived from ent-21
would provide a substrate appropriate for cyclization to 23, but
the olefin linkage proved to be remarkably resistant to epoxi-
dation. Fortunately, oxidation with 3,5-dinitroperoxybenzoic
acid48 stabilized by 4,4′-thiobis(6-tert-butyl-3-methylphenol)49
Planning
In studying the structure of allosamidin, from the perspective
of an exploration in total synthesis, three problems virtually
impose themselves. The carbohydrate domain consists of a
novel constellation of two 2-N-acetylallose (AllNAc) residues.
These are glycosidically â-linked through the 4-R-hydroxyl
group of the AllNAc moiety at the reducing end of the
carbohydrate sector. Finally, this AllNAc is â-linked to a
substituted cyclopentyl residue, itself fused to a (dimethylami-
no)oxazoline ring.
Our consideration of the allosamidin synthesis began with
thoughts about the construction of the glycosidic linkages
(Scheme 1). We envisioned that the two allal residues 11 and
12 could be oxidatively coupled to give rise to a disaccharide
glycal of type 13. Combination of the latter (13) with a
protected allosamizoline derivative (cf. 18), in a similar fashion,
would then provide core structure 14. The allosamizoline
synthon 18 would be assembled (Scheme 2) from desymme-
trization of meso system 17 on the basis of precedents elegantly
demonstrated by Deardorff for 15.40 It is with the preparation
of the required antipode of a suitably protected allosamizoline
derivative that our account begins.
Allosamizoline
The synthesis of the aglycon commenced with the peracet-
ylation of the known and readily available 2-[(benzyloxy)-
methyl]-4-cyclopentene-1,3-diol41 to provide diacetate 17 in 89%
yield. It was imagined that an enzyme-mediated hydrolysis of
this meso-diacetate (17) would provide, enantioselectively, the
monoacetate 19. As noted above, Deardorff et al. had observed
that the action of electric eel acetylcholinesterase (eeACE) on
meso-diacetate 14 affords an excellent yield of alcohol 15 in
>95% enantiomeric excess after one recrystallization.40 This
work was recently applied in our laboratory to the synthesis of
PG F2R.42
(43) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512. Dale,
J. A.; Dull, J. A.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543.
(44) Roberts and co-workers have assigned the opposite configuration
to our product based on their work with porcine pancreatic lipase (see refs
71 and 72).
(45) Hultin, P. G.; Mueseler, F.-J.; Jones, J. B. J. Org. Chem. 1991, 56,
5375.
(46) Semlicka, J.; Craine, L. E.; Heeg, M.-J.; Oliver, J. P. J. Org. Chem.
1988, 53, 937.
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Soc. 1983, 105, 4049.
(48) Rastetter, W. H.; Richard, T. J.; Lewis, M. D. J. Org. Chem. 1978,
43, 3163.
(49) Kishi, Y.; Aratani, M.; Tanino, H.; Fukuyama, T.; Goto, T.; Inoue,
S.; Sugiura, S.; Kakoi, H. J. Chem. Soc., Chem. Commun. 1972, 64.
(40) Deardorff, D. R.; Matthews, A. J.; McMeekin, D. S.; Craney, C. L.
Tetrahedron Lett. 1986, 27, 1255.
(41) Madhavan, G. V.; Martin, J. C. J. Org. Chem. 1986, 51, 1287.
(42) Danishefsky, S. J.; Cabal, M. P.; Chow, K. J. Am. Chem. Soc. 1989,
111, 3456.

Total Synthesis of Allosamidin
J. Am. Chem. Soc., Vol. 118, No. 40, 1996 9529
Scheme 4
Scheme 6
thereby obtained, was protected as its benzylidene acetal (30)
upon treatment with benzaldehyde dimethylacetal. Attempted
oxidation of sulfide 30 in the usual manner57 with m-chloro-
perbenzoic acid (MCPBA) gave rise to a surprisingly complex
mixture. However, treatment of 30 with 3,3-dimethyldioxirane58
cleanly afforded the desired sulfoxide. The latter underwent
[2,3]-sigmatropic rearrangement in the presence of diethyl-
amine59 to provide 31 in 96% yield. Finally, glycal 31 was
O-benzylated to afford allal derivative 32.
Scheme 5
At this stage it was necessary to manipulate the glycal linkage
in compound 32 such that the product would function as an
azaglycosylation donor. While such capabilities were, in
principle, known (nitrosyl chlorination,60 azidonitration,61 chloro
amidation,62 acyl nitrene addition,63 iodophosphoramidation,64
and dialkyl azodicarboxylate cycloaddition65), in the case at
hand, we had to deal with a special stereochemical problem.
Thus, to reach our goal structure containing AllNAc residues,
we needed to activate the glycal in a manner which would serve
to introduce the aza precursor to the R-face of 33 at C-2 (see
Scheme 7). This face is clearly the more hindered as a
consequence of the R-disposed ether function at C-3 in the allose
series.
A variety of potential strategies were surveyed to address
this challenge. These were summarized elsewhere.66 Here, we
focus on the one which was successfully followed. The logic
involved taking advantage of a stereoelectronically (rather than
steric hindrance) governed reaction. When the generalized
reagent E+ N- adds to the glycal 33 in a strictly trans-diaxial
fashion (Scheme 7), the former electrophilic function emerges
(tbp) in refluxing 1,2-dichloroethane provided a 45% yield of
the desired epoxide 22. However, all attempts to cyclize 22 to
urethane 23 under basic conditions (NaH,50 t-BuONa/THF,51
or LHMDS) proved to be unsuccessful. Indeed, all of the
products isolated from such reactions had lost their carbamate
functionalities.
At this juncture, a synthesis of (()-allosamizoline by Trost
and Van Vranken26a appeared in the literature. The approach
described by these authors, albeit in racemic form, was quite
similar to the route which had been independently undertaken
in this effort. Moreover, it began with the same starting
material. In order to allow for a timely investigation of the
coupling of the aglycon to a disaccharide, an intermediate in
Trost’s route was intercepted to allow us to complete the
synthesis of the aglycon using the Stanford protocols. Treatment
of a THF solution of carbamate ent-20 with triethylamine/
trifluoroacetic anhydride gave oxazolidinone ent-24 in 60% yield
(Scheme 5). Following the route published by Trost and Van
Vranken, ent-24 was then converted to the (dimethylamino)-
oxazoline (ent-25). Epoxidation and subsequent hydration
provided the corresponding R-epoxide (ent-26; 32%) and an
allosamizoline derivative, now formulated as ent-27 (46%).
Even as the issues associated with the synthesis of an
appropriately protected aglycon derivative were being explored,
development of a route to the pseudotrisaccharide region of
allosamidin was progressing. The synthesis of 4,6-O-benz-
ylidene-D-allal (31) from glucose had been reported.52 For our
purposes, however, we prepared compound 31 in a rather more
concise way (Scheme 6).53,54 Our route started with peracetyl-
glucal 28, which was converted by Ferrier rearrangement55 to
compound 29 following a published procedure.56 The latter was
deacetylated with methanolic sodium methoxide. The diol,
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(59) (a) Evans, D. A.; Andrews, G. C. Acc. Chem. Res. 1974, 7, 147.
(b) Tang, R.; Mislow, K. J. Am. Chem. Soc. 1970, 92, 2100.
(60) (a) Lemieux, R. U.; James, K.; Nagabhushan, T. L. Can. J. Chem.
1973, 51, 48. (b) Lemieux, R. U.; Ito, Y.; James, K.; Nagabhushan, T. L.
Can. J. Chem. 1973, 51, 7. (c) Lemieux, R. U.; Nagabhushan, T. L. Can.
J. Chem. 1968, 46, 413.
(61) (a) Bovin, V.; Zurabyan, S. EÄ .; Khorlin, A. Y. Carbohydr. Res. 1981,
98, 25. (b) Lemieux, R. U.; Ratcliffe, R. M. Can. J. Chem. 1979, 57, 1244.
(62) Driguez, H.; Vermes, J.-P.; Lessard, J. Can. J. Chem. 1978, 56,
120.
(63) (a) Kozlowska-Gramsz, E.; Descotes, G. Can. J. Chem. 1982, 60,
558. (b) Kozlowska-Gramsz, E.; Descotes, G. Tetrahedron Lett. 1981, 22,
563.
(64) (a) Lafont D.; Descotes, G. Carbohydr. Res. 1988, 175, 35. (b)
Lafont D.; Descotes, G. Carbohydr. Res. 1987, 166, 195.
(65) (a) Leblanc, Y.; Fitzsimmons, B. J. Tetrahedron Lett. 1989, 30, 2889.
(b) Fitzsimmons, B. J.; Leblanc, Y.; Chan, N.; Rokach, J. J. Am. Chem.
Soc. 1988, 110, 5229.
(50) Roush, W. R.; Adam, M. A. J. Org. Chem. 1985, 50, 3752. Roush,
W. R.; Brown, R. J.; DiMare, M. J. Org. Chem. 1983, 48, 5083.
(51) Minami, N.; Ko, S. S.; Kishi, Y. J. Am. Chem. Soc. 1982, 104,
1109.
(52) Lemieux, R. U.; Fraga, E.; Watanabe, K. A. Can. J. Chem. 1968,
46, 61. Sharma, M.; Brown, R. K. Can. J. Chem. 1966, 44, 2825.
(53) Wittman, M. D.; Halcomb, R. L.; Danishefsky, S. J. J. Org. Chem.
1990, 55, 1979.
(66) Griffith, D. A. Ph.D. Dissertation, Yale University, New Haven,
CT, 1993.

9530 J. Am. Chem. Soc., Vol. 118, No. 40, 1996
Griffith and Danishefsky
Scheme 7
Scheme 9
Scheme 10
Scheme 8
on the â-face at C-2 and the N-function (which serves as the
N-acetyl precursor) enters the R-face at C-1 (35). In the second
stage, the E-function is expelled with suprafacial moVement of
the N-function to C-2 from the hindered R-face.67 In the best
case scenario, the nucleophile to be glycosylated penetrates at
C-1 to give the desired AllNAc â-glycoside 36.
Several specific protocols discussed elsewhere were surveyed
in an attempt to reduce this central paradigm to practice.66 For
the present purposes, we note that it was the pursuit of this
allosamidin goal which led us to sulfonamidoglycosylation as
a comprehensive method for converting glycals to 1â-glycosides
of 2R-N-acetyl sugars, including the AllNAc system of interest
here.
Returning to the allosamidin problem, allal derivative 32 was
converted to its 2â-bromo-1R-phenylsulfonamido addition
product 37, as previously described.36 This compound would
serve as the donor for the azaglycosylation of an O-4-
unprotected allal acceptor. However, with ent-27 in hand,
coupling to the unprotected diol was investigated (Scheme 8).
We had hoped that the acceptor would react with acceptable
selectivity at O-4. In practice the base-promoted coupling of
bromosulfonamide 37 with this aglycon acceptor afforded 4-O-,
5-O-, and di-O-glycosylated products 38, 39, and 40 in 33, 17,
and 36% yields, respectively. Therefore, prospects for positively
controlled monoprotection of the diol moiety present in ent-27
were examined.
some diacetylated material (42, 30%). Silylation of alcohol 41
in DMF then afforded silyl ether 43 (71%), which was
quantitatively deacetylated with methanolic sodium methoxide.
The coupling of aglycon derivative 44 to an appropriate
azaglycosylation donor could now be investigated.
We focused our efforts on preparing a suitable disaccharide
donor for coupling with 44 en route to reaching the pseudo-
trisaccharide goal series. Toward this end, we had need to
identify the 4-hydroxyl group of an allal derivative as the
acceptor site through differential protection of the axial hydroxyl
group at C-3. Accordingly, glycal 31 upon treatment with
[2-(trimethylsilyl)ethoxy]methyl chloride (SEM-Cl) gave com-
pound 45 in quantitative yield (Scheme 10). Dissolving metal
reduction of 45 afforded diol 46 (99%), which was selectively
benzylated at C-6 by way of its stannylene derivative68 to deliver
alcohol 47 in 69% yield. The acceptor site had indeed been
distinguished. In the event, base-promoted coupling of alcohol
47 with bromosulfonamide 37 occurred under standard condi-
tions to provide disaccharide 48 in 81% yield (95% based on
recovered 47).
To this end, diol ent-27 was acetylated to provide the desired
4-O-protected aglycon 41 in 50% yield (Scheme 9), along with
Since we had an efficient preparation of the disaccharide
glycal at our disposal, it was now opportune to reiterate the
(67) Nicolau, K. C.; Ladduwahetty, T.; Randall, J. L.; Chucholowski,
A. J. Am. Chem. Soc. 1986, 108, 2466.
(68) Nagashima, N.; Ohno, M. Chem. Lett. 1987, 141.

Total Synthesis of Allosamidin
J. Am. Chem. Soc., Vol. 118, No. 40, 1996 9531
Scheme 11
in the structure or relatiVe stereochemistry of one or more of
our synthetic intermediates. Alternatively, all such assignments
were indeed correct, but the absolute configuration of our
aglycon was opposite to that which was presumed by the
superficial analogy of 15 and 17, with respect to enzymatic
deacetylation. We came to favor this latter interpretation.
This interpretation was confirmed. Thus, hydrogenolysis of
diol ent-27 provided (+)-allosamizoline (ent-8). The optical
rotation observed ([R]D +22.2° (c 0.7, water)) for ent-8 was
equal in magnitude but opposite in sign to the value reported
([R]22D -22.2° (c 0.5, water)) for authentic allosamizoline (8).16
It is on this basis that we now confer the ent designation to
compounds 19 and 24-27.
In order to secure natural (-)-allosamizoline (8), the synthetic
sequence outlined above would have to be conducted starting
with compound 19 rather than with ent-19, as had been done.
We were mindful that pig liver esterase mediated hydrolysis70
of the parent diacetate 15 had been reported to provide the
opposite enantiomer to that which had been observed with
eeACE40 and might therefore serve to produce the desired
monoacetate 19. Further complicating matters in retrospect is
the fact that Cotterill et al.71 had later examined the hydrolysis
of diacetate 17 with porcine pancreatic lipase (PPL) and had
determined by chemical correlation that the absolute configu-
ration of the isolated monoacetate (ee > 95%) was opposite to
that which was measured for the monoacetate obtained using
eeACE. However, the optical rotation reported for the monoace-
tate from PPL deacetylation ([R]23D +63.2° (c 1.0, CHCl3)) was
equal in sign and magnitude to that which we had observed
with eeACE. Unfortunately, the origin of this discrepancy
remains unresolved,72 although we are fully confident of our
assignment since we did reach natural allosamidin (Vide infra).
While it may have been possible to find an appropriate
enzyme to produce 19, an alternate solution was possible. It
took advantage of the fact that a nearly enantiospecific, and
high yielding, route to ent-19 had already been developed. The
idea was to so manipulate ent-19 that we could enter a “product
line” which would have been available from 19, itself inacces-
sible when eeACE was used.
We proceeded as follows. Protection of alcohol ent-19 with
TBDMS-Cl gave rise to a silyl ether, which was then deacet-
ylated with methanolic ammonia (Scheme 12). Alcohol 59, thus
produced, had the opposite absolute configuration relative to
monoacetate ent-19 and was obtained in quantitative yield. After
installation of the carbamate in the usual way (82%), the silyl
ether was cleaved with 2% aqueous HF in acetonitrile (94%).
Carbamate 20 was subsequently converted to allosamizoline
derivative 27 by the route used in the enantiomeric series.
Finally, hydrogenolysis of 27 proVided (-)-allosamizoline (8),
which was identical in all respects, including optical rotation,
with material isolated from natural sources.16
azaglycosylation reaction. Pursuant to this goal, glycal 48 was
treated with N,N-dibromobenzenesulfonamide under the usual
experimental conditions. A 57% yield of trans-bromosulfona-
mide 49 was obtained. Base-mediated coupling of 49 with
aglycon derivative 44 was conducted in the usual manner. This
reaction afforded only a very low yield (6%) of a 4-O-linked
trisaccharide subsequently shown to be compound 50. Also
obtained was a 5% yield of the 3-O-linked trisaccharide 51 as
well as recovered alcohol 44 (32%) and the 4-O-silylated
aglycon derivative 52 (31%). The regiochemical assignments
of the pseudotrisaccharides 50 and 51 were based upon 490
MHz 1H NMR studies of acetylated derivatives 54 and 57 (Vide
infra). The principal message of these studies, however, was
that an unanticipated migration of the silyl ether group in 44
had occurred under the strongly basic coupling conditions. This
process resulted in an additional complication to an already
difficult coupling.
Before dealing with the problem which this low-yielding
coupling portended, we first relate the results of experiments
which confidently corroborated the structural assignment of our
formulated products. Fluoride-promoted deprotection of pseu-
dotrisaccharide 50 readily cleaved the silyl ether, but these
conditions failed to remove the SEM group. However, the
benzylidene and SEM69 acetal linkages were readily cleaved
with 5% concentrated HCl in methanol (73%). Dissolving metal
reduction of 53 provided the fully deprotected product, which
was peracetylated (acetic anhydride, pyridine) to give nonaac-
etate 54 (13% overall). Finally, cleavage of the oxygen bound
acetyl groups with methanolic ammonia afforded pseudotrisac-
charide 55 (90%). While the 1H NMR spectrum of compound
55 was similar to that of allosamidin (1), it was apparent, on
closer inspection, that the spectra measured under identical
conditions were not identical.
Similarly, deprotection of pseudotrisaccharide 51 proceeded
in the same fashion as discussed in the sequence 50 f 55
(Scheme 11), leading, eventually, to peracetate 57 and depro-
tected 58. Again, while the 1H NMR spectrum of 58 was similar
to that of allosamidin (1), there were small but clear cut
differences. That trisaccharides 55 and 58 had the same
molecular formula as allosamidin (1) was demonstrated by high-
resolution mass spectrometry.
Of course, 58 and allosamidin were nonidentical, in any case,
given the incorrect linkage of the aglycon and carbohydrate
sectors. However, the noncongruence of what we now know
to be 55 with allosamidin called for a basic structural reappraisal.
One possibility was that there had been an incorrect assignment
Benefiting from our hard-learned lessons in the ent aglycon
series, the unsuitability of selective protection of diol 27 as the
corresponding TBDMS ether was clear. This protection motif
had been undermined by the silyl migration which had, in turn,
further eroded the yield of the azaglycosylation of O-4 under
basic glycosylation conditions (see Scheme 10).
Fortunately, the C-3 hydroxyl group of diol 27 could be
selectively benzylated by way of stannylene methodology
(70) Laumen, K.; Reimerdes, E. H.; Schneider, M. Tetrahedron Lett.
1985, 26, 407. Laumen, K.; Schneider, M. Tetrahedron Lett. 1984, 25, 5875.
(71) Cotterill, I. C.; Cox, P. B.; Drake, A. F.; LeGrand, D. M.;
Hutchinson, E. J.; Latouche, R.; Pettman, R. B.; Pryce, R. J.; Roberts, S.
M.; Ryback, G.; Sik, V.; Williams, J. O. J. Chem. Soc., Perkin Trans. 1
1991, 3071.
(69) Pinto, B. M.; Buiting, M. M. W.; Reimer, K. B. J. Org. Chem.
1990, 55, 2177.
(72) LeGrand, D.; Roberts, S. M. J. Chem. Soc., Perkin Trans. 1 1992,
1751.

9532 J. Am. Chem. Soc., Vol. 118, No. 40, 1996
Griffith and Danishefsky
Scheme 12
Figure 2. Structures of potential chitinase inhibitors.
Scheme 14
Scheme 13
disaccharide 66 were chosen as targets (Figure 2). Given the
apparent sensitivity of various chitinases to modifications of
the allosamidins, we embarked on the synthesis of analogs 64-
66. The synthesis of several other allosamidin analogs have
recently been reported in the literature.73-75
The syntheses of these analogs led us to explore an important
new departure in the benzenesulfonamide-based azaglycosyla-
tion methodology. This expansion is described below.
Glucitol derivative 67, prepared in a single step from
commercially available 5-keto-D-fructose,76 was kindly provided
by Dumas and Wong. Initial studies concerned the selective
protection of this derivative. It was hoped that acetonide
formation would selectively provide the cis-acetonide 68;
molecular mechanics calculations indicated that the trans-isomer
should be less stable by 5.7 kcal/mol.77 Additionally, modeling
(Scheme 13) to provide dibenzylated aglycon 60 in 35% yield
(44% based on recovered 27). Azaglycosylation of 60 with
bromosulfonamide 49 under basic conditions provided the
desired pseudotrisaccharide 61 in 42% yield (76% based on
recovered 60). Following our findings in the “allo” series, the
SEM and benzylidene protecting groups were cleaved by
treatment with 5% HCl in methanol. Dissolving metal reduction
then deblocked the sulfonamides and benzyl ethers, and the fully
deprotected product was peracetylated to provide allosamidin
heptaacetate (62) in 36% yield from 61. Finally, cleaVage of
the acetyl esters with methanolic ammonia afforded allosamidin,
identical in all respects with authentic material.
1
studies suggested that H NMR coupling constants would be
diagnostic of the isomer formed. In the event, selective
acetonide formation occurred smoothly with 2,2-dimethoxypro-
pane to provide cis-acetonide 68 in 77% yield (Scheme 14).
The observed 1H NMR coupling constants were in good
agreement with the values predicted for the cis-isomer. More-
over, long range w-coupling observed between H-3 and H-5
was consistent with the cis structure. Diol 68 was then
selectively benzylated by way of the derived stannylene acetal
to provide 69 in 65% yield (81% based on recovered 68).
It was envisioned that sulfonamidoglycosylation methodol-
ogy36 would be employed to synthesize the azasugars 64-66.
Development of the SES Azaglycosylation Method
Preliminary studies of several compounds synthesized during
this total synthesis of allosamidin were performed in collabora-
tion with Dr. Chi-Huey Wong and Dr. David Dumas at the
Scripps Research Institute. Synthetic allosamidin (1) showed
potent chitinase inhibition, while neither natural (-)-(8) nor
unnatural (+)-allosamizoline (ent-8) functioned as inhibitors.
Interestingly, Wong and Dumas had noted that azasugar 63
displays stronger chitinase inhibition than (-)-allosamizoline
(8). They therefore postulated that a pseudodisaccharide or
pseudotrisaccharide that included 63 might be a strong chitinase
inhibitor; allodisaccharide 64, allotrisaccharide 65, and gluco-
(73) (a) Corbett, D. F.; Dean, D. K.; Robinson, S. R. Tetrahedron Lett.
1993, 34, 1525. (b) Corbett, D. F.; Dean, D. K.; Robinson, S. R. Tetrahedron
Lett. 1994, 35, 459.
(74) Takahashi, S.; Inoue, H.; Kuzuhara, H. J. Carbohydr. Chem. 1995,
14, 273.
(75) Terayama, H.; Kuzuhara, H.; Takahashi, S.; Sakuda, S.; Yamada,
Y. Biosci., Biotechnol., Biochem. 1993, 57, 2067.
(76) Reitz, A. B.; Baxter, E. W. Tetrahedron Lett. 1990, 31, 6777.
(77) Monte Carlo conformational searches using the MM3 force field
as implemented in MacroModel were employed. Still, W. C. MacroModel
version 3.5x, Columbia Unviversity, NY, 1992.

Total Synthesis of Allosamidin
J. Am. Chem. Soc., Vol. 118, No. 40, 1996 9533
Scheme 15
Scheme 16
Scheme 17
However, the intermediacy of a benzenesulfonyl moiety would
necessitate deprotection by reductive desulfonylation. Such
conditions could also deblock the secondary amine of the
azasugar, thereby necessitating acetylation of the C-2 amine in
the presence of the secondary amine. To avoid such complica-
tions, we developed the SES-sulfonamidoglycosylation method,
which was subsequently used in our synthesis of the sialyl Lewis
X antigen.78 It was this methodology which was employed in
the analog syntheses. The feasibility of early installation of
the acetamide moiety in the allose-like sectors demonstrated
the utility of the SES strategy.
The synthesis of allosyl analog 64 required the synthesis of
a new N,N-dibromosulfonamide (71). In the event, bromination
of SESNH2 (70) in 4% aqueous sodium hydroxide gave a
modest yield (35%) of N,N-dibromo-2-(trimethylsilyl)ethane-
sulfonamide (SESNBr2, 71) (Scheme 15). Subsequent reaction
of 71 with allal derivative 32 afforded, after reduction of the
remaining bromine-nitrogen bond with ammonium iodide,
trans-bromosulfonamide 72 in 46% yield. Additional material
was isolated as a mixture of trans and cis (1:1.8) isomers (26%).
was coupled with azasugar 69 to provide trisaccharide 78 in
43% yield (90% based on recovered 69). Unfortunately,
fluoride-promoted desulfonylation of 78 or the compound
produced upon cleavage of the acetal and ketal moieties failed
to provide diacetamido-containing material (79; R ) acetal or
Ac). Although the structures of the products formed after
fluoride treatment are unknown, it was clear that both allose
rings were not intact; only one anomeric carbon was observed
by 13C NMR spectroscopy.
Finally, the synthesis of the glucosyl-linked analog 66 was
explored. Reaction of SESNH2 (70) with tri-O-benzyl-D-glucal
(80) and iodonium di-sym-collidine perchlorate provided a 78%
yield of trans-iodosulfonamide 81 (Scheme 17). Silver-assisted
glycosylation of azasugar 69 with trans-iodosulfonamide 81
provided a 49% yield of disaccharide 82 (83% based on
recovered 69). Desulfonylation was conducted in the presence
of cesium fluoride in DMF at 95 °C. However, it was necessary
to add an equivalent of acetic anhydride during the deblocking
procedure to drive the reaction to completion. Acetylation of
the remaining free amine provided a good yield of the acetamide
(83, 76%). Finally, hydrogenolysis of diol 84, obtained in 82%
yield after cleavage of the acetonide present in 83, afforded the
desired disaccharide 66 in 81% yield.
Glycosylation of azasugar 69 with 72 in the usual manner
provided an 80% yield of disaccharide 73 (92% based on
recovered 69). Fluoride-promoted desulfonylation afforded an
amine, which was acylated to yield 74 (79%). Next, the acetal
and ketal moieties were cleaved with 5% concentrated HCl in
methanol to give tetraol 75 (92%). Finally, hydrogenolysis of
75 provided the desired analog 64 in 85% yield.
The prospects for the synthesis of a trisaccharide using the
SES methodology was examined. Thus, base-promoted gly-
cosylation of glycal 47 with bromosulfonamide 72 (Scheme 16)
gave disaccharide glycal 76 in 63% yield (76% based on
recovered 47). Bromosulfonamide 77, isolated as a 6.5:1
mixture of R- and â-anomers from 76 in the usual fashion (46%),
(78) (a) Danishefsky, S. J.; Gervay, J.; Peterson, J. M.; McDonald, F.
E.; Koseki, K.; Griffith, D. A.; Oriyama, T.; Marsden, S. P. J. Am. Chem.
Soc. 1995, 117, 1940. (b) Danishefsky, S. J.; Koseki, K.; Griffith, D. A.;
Gervay, J.; Peterson, J. M.; McDonald, F. E.; Oriyama, T. J. Am. Chem.
Soc. 1992, 114, 8331. (c) Danishefsky, S. J.; Gervay, J.; Peterson, J. M.;
McDonald, F. E.; Koseki, K.; Oriyama, T.; Griffith, D. A. J. Am. Chem.
Soc. 1992, 114, 8329.

9534 J. Am. Chem. Soc., Vol. 118, No. 40, 1996
Griffith and Danishefsky
(dd, J ) 9.2, 7.4 Hz, 1 H, CHHOBn), 2.35 (br s, 1 H, OH), 2.28 (dq,
J ) 7.3, 4.9 Hz, 1 H, H-5), 2.03 (s, 3 H, COCH3); 13C NMR (63 MHz,
CDCl3) δ 170.6, 138.3, 137.5, 131.7, 128.3, 127.5, 79.0, 77.8, 73.3,
69.8, 55.4, 20.9; MS (CI) m/e (rel intensity) 263 (M + H+, 50), 246
(31), 245 (82), 204 (21), 203 (79), 185 (50), 181 (20), 157 (22), 155
(43), 139 (31), 137 (81), 119 (55), 113 (24), 111 (32), 107 (30), 96
(57), 95 (76), 92 (60), 91 (100). Anal. Calcd for C15H18O4: C, 68.69;
H, 6.92. Found: C, 68.40; H, 6.68.
Summary
In summary, a total synthesis of allosamidin (1) has been
achieved by way of the sulfonamidoglycosylation method. This
method subsequently had a major impact on our glycal-based
methodology for assembling complex oligosaccharides. Here,
it was the key to assembling the novel arrangement of AllNAc
residues and in coupling them to aglycons. From these studies
we went on to apply the method to the synthesis of adhesion
molecules, blood group determinants, tumor antigens, and
glycopeptides. Thus, the quest for a concise solution to the
challenges posed by a total synthesis of allosamidin has had a
broad impact in the much larger subject of glycoconjugate
constructs.36-39 Expansion of azaglycosylation methodology to
embrace SES sulfonoamidation has expanded our capability,
because it enables us to deal effectively with a broader range
of nitrogen-containing acceptors. It also allows for a single-
step fluoride-induced unveiling of alcohols and amines initially
bearing silyl ether or â-silylethylsulfonamide (SES) protecting
groups.
Moreover, in the course of this journey, we encountered a
surprising reversal of selectivity in the enzymatically mediated
hydrolysis of meso-diacetate 17 during the synthesis of allo-
samizoline (8). As a result, two diastereomers of allosamidin
were prepared (55 and 58). The synthetic strategy developed
in this effort was thus applicable not only to the synthesis of
allosamidin but also to analogs, whose biological profiles will
be disclosed shortly. Moreover, it raises an important cautionary
note in extrapolating the enantiotopic sense of enzymatic
processes based upon intuitively reasonable but still superficial
analogies.
S-Phenyl 4,6-O-Benzylidene-2,3-dideoxy-1-thio-r-D-erythro-hex-
2-enopyranoside (30). A methanolic (10 mL) solution of thioglycoside
29 (0.886 g, 2.75 mmol) was deacetylated for 1 h with 25% sodium
methoxide (60 µL, 0.28 mmol). The reaction was concentrated under
reduced pressure and then concentrated from added benzene (2 × 25
mL) to remove any methanol still present. A DMF solution (5 mL) of
the residue was treated with benzaldehyde dimethylacetal (1.2 mL, 8.2
mmol) and p-toluenesulfonic acid (104 mg, 0.55 mmol). After 2 h,
the reaction was heated to 30 °C under reduced pressure (10 Torr) for
an additional 7 h and then concentrated under high vacuum. The
greenish solid thus produced was extracted from saturated aqueous
NaHCO3 (75 mL) with diethyl ether (2 × 100 mL), the combined
organic layers were dried (MgSO4) and concentrated, and the residue
was crystallized from ethyl acetate/hexanes to provide the benzylidene
acetal 30 (0.572 g, 64%) as colorless needles. The mother liquor was
chromatographed (silica gel, 10 f 15% ethyl acetate in hexanes) to
provide additional acetal as an off-white solid (77 mg, 9%). For 30:
mp 122.5-123.5 °C; [R]D +413° (c 1.2, CHCl3); IR (KBr) υmax 3050,
2990, 2940, 2900, 2880, 1580, 1480, 1385, 1310, 1135, 1110, 1085,
1020, 1005 cm-1; 1H NMR (250 MHz, CDCl3) δ 7.57-7.26 (m, 10 H,
ArH), 6.12 (d, J ) 10.1 Hz, 1 H, H-3), 5.96 (dt, J ) 10.1, 2.5 Hz, 1
H, H-2), 5.81 (q, J ) 2.2 Hz, 1 H, H-1), 5.62 (s, 1 H, O2CHPh), 4.35
(dd, J ) 10.3, 4.7 Hz, 1 H, H-6e), 4.29 (dq, J ) 8.7, 2.0 Hz, 1 H, H-4),
4.20 (td, J ) 9.2, 4.6 Hz, 1 H, H-5), 3.86 (t, J ) 9.9 Hz, 1 H, H-6a);
13C NMR (63 MHz, CDCl3) δ 137.3, 135.2, 131.4, 129.1, 128.9, 128.3,
127.4, 127.1, 126.2, 102.1, 84.5, 75.0, 69.2, 64.3; MS (EI) m/e (rel
intensity) 326 (M+, 27), 217 (80), 171 (100), 149 (20), 143 (62), 111
(40), 91 (28), 83 (90). Anal. Calcd for C19H18O3S: C, 69.91; H, 5.56;
S, 9.82. Found: C, 69.82; H, 5.58; S, 10.01.
Experimental Section
(1r,2â,3r)-2-[(Benzyloxy)methyl]-4-cyclopentene-1,3-diol Diace-
tate (17). To a 0 °C solution of 2-[(benzyloxy)methyl]-4-cyclopentene-
1,3-diol (9.60 g, 43.6 mmol) in dichloromethane (150 mL) were added
triethylamine (18.2 mL, 131 mmol), DMAP (0.53 g, 4.36 mmol), and
acetic anhydride (10.3 mL, 109 mmol). The mixture was stirred 1 h
and then extracted from water (200 mL) with diethyl ether (3 × 100
mL). The combined organic layers were dried (Na2SO4) and concen-
trated, and the residue was chromatographed (silica gel, 20% ethyl
acetate in hexanes) to provide the diacetate (17; 11.9 g, 89%) as a
slightly yellowed oil: IR (neat) υmax 3060, 3020, 2930, 2880, 1735,
1,5-Anhydro-4,6-O-benzylidene-2-deoxy-D-ribo-hex-1-enopyra-
nose (31). A solution of 3,3-dimethyldioxirane in acetone (0.04 M,
∼1 equiv) was added to a -78 °C dichloromethane solution (50 mL)
of thioglucoside 30 (1.24 g, 3.80 mmol) until the sulfide (30) was
consumed as indicated by TLC. The suspension thus produced was
concentrated under reduced pressure to a colorless solid, dissolved in
THF (25 mL), and treated with diethylamine (1.6 mL, 15 mmol). The
reaction was stirred overnight and then extracted from brine (30 mL)
with dichloromethane (2 × 100 mL). The combined organic layers
were dried (Na2SO4) and concentrated, and the residue was chromato-
graphed (silica gel, 50 f 66% diethyl ether in hexanes) to provide the
desired allal derivative 31 (0.853 g, 96%) as a colorless solid (mp 82.5-
83.5 °C). The product was recrystallized (diethyl ether/hexanes) to
provide colorless needles of 31 (0.77 g, 86%): mp 84.5-85.5 °C; [R]D
+206° (c 1.7, CHCl3); IR (KBr) υmax 3150, 3060, 2980, 2930, 2860,
1365, 1230, 1105, 1025 cm-1; H NMR (490 MHz, CDCl3) δ 7.35-
1
7.24 (m, 5 H, ArH), 6.02 (d, J ) 0.9 Hz, 2 H, olefinic), 5.53 (dd, J )
4.0, 0.8 Hz, 2 H, CHOAc), 4.54 (s, 2 H, OCH2Ph), 3.71 (d, J ) 5.1
Hz, 2 H, CH2OBn), 2.40-2.35 (m, 1 H, H-2), 2.04 (s, 6 H, COCH3);
13C NMR (63 MHz, CDCl3) δ 170.7, 138.2, 134.2, 128.3, 127.5, 79.1,
73.2, 69.0, 51.4, 21.1; MS (CI) m/e (rel intensity) 305 (M + H+, 2),
246 (20), 245 (93), 155 (25), 139 (26), 137 (100), 95 (20), 91 (68).
Anal. Calcd for C17H20O5: C, 67.09; H, 6.62. Found: C, 67.34; H,
6.90.
[1(S)-(1r,4r,5â)]-4-(Acetyloxy)-5-[(benzyloxy)methyl]-2-cyclo-
penten-1-ol (ent-19). Diacetate 17 (20.5 g, 67.4 mmol) was rapidly
stirred, while care was taken to prevent a strong vortex, with a solution
of glass-distilled water (390 mL), 1.45 M NaH2PO4 buffer (pH 6.9,
260 mL), sodium azide (66 mg), and electric eel acetylcholinesterase
(Sigma; 10 000 units, 30 mg). After 6 days, the mixture was extracted
with 1:1 ethyl acetate/diethyl ether (3 × 300 mL). The combined
organic layers were dried (Na2SO4) and concentrated, and the residue
was chromatographed (silica gel, 33 f 50% ethyl acetate in hexanes)
to afford the desired monoacetate ent-19 (16.8 g, 95%) as a colorless
liquid. A portion of ent-19 was bulb-to-bulb (170 °C, 0.05 Torr)
distilled: [R]D +61.8° (c 1.1, CHCl3); IR (neat) υmax 3420, 3060, 3030,
2860, 1730, 1455, 1365, 1245, 1100, 1025 cm-1; 1H NMR (490 MHz,
CDCl3) δ 6.01 (dt, J ) 5.7, 1.6 Hz, 1 H, H-3), 5.86 (ddd, J ) 5.7, 1.9,
1.4 Hz, 1 H, H-2), 5.38 (ddt, J ) 5.0, 2.2, 1.1 Hz, 1 H, H-4), 4.58
(ddt, J ) 4.6, 2.0, 1.0 Hz, 1 H, H-1), 4.54 (ABq, J ) 12.2 Hz, υ ) 6.9
Hz, 2 H, OCH2Ph), 3.77 (dd, J ) 9.2, 5.1 Hz, 1 H, CHHOBn), 3.61
1635, 1455, 1405, 1380, 1245, 1225, 1145, 1105, 1090, 1035 cm-1
;
1H NMR (250 MHz, CDCl3) δ 7.55-7.37 (m, 10 H, ArH), 6.47 (d, J
) 6.1 Hz, 1 H, H-1), 5.68 (s, 1 H, O2CHPh), 5.04 (t, J ) 6.0 Hz, 1 H,
H-2), 4.49 (dd, J ) 10.5, 5.3 Hz, 1 H, H-6e), 4.32-4.27 (m, 1 H, H-3),
4.23 (td, J ) 10.2, 5.3 Hz, 1 H, H-5), 3.87 (dd, J ) 10.3, 3.1 Hz, 1 H,
H-4), 3.84 (t, J ) 10.4 Hz, 1 H, H-6a), 2.49 (d, J ) 1.8 Hz, 1 H, OH);
13C NMR (63 MHz, CDCl3) δ 146.2, 137.1, 129.2, 128.3, 126.2, 101.8,
101.0, 78.1, 68.5, 63.9, 60.1.
1,5-Anhydro-3-O-benzyl-4,6-O-benzylidene-2-deoxy-D-ribo-hex-
1-enopyranose (32). A THF solution (15 mL) of 4,6-O-benzylidene-
D-allal (31; 3.01 g, 12.8 mmol) was added dropwise to a 0 °C suspension
of sodium hydride (60% dispersion in oil; 0.62 g, 15.5 mmol) in THF
(25 mL). The reaction was stirred at room temperature for 30 min,
cooled to 0 °C, and then tetrabutylammonium iodide (0.52 g, 1.4 mmol)
and benzyl bromide (2.0 mL, 17 mmol) were added. The mixture was
stirred for 14 h at room temperature and extracted from 1:1 brine/water
with diethyl ether (2 × 75 mL). The combined organic layers were
dried (MgSO4) and concentrated, and the orange solid was chromato-
graphed (50 f 75% dichloromethane in hexanes) to provide the
protected glycal 32 (4.01 g, 96%) as an off-white solid. A portion

Total Synthesis of Allosamidin
J. Am. Chem. Soc., Vol. 118, No. 40, 1996 9535
was recrystallized (diethyl ether/hexanes) to provide colorless needles
of 32: mp 103-103.5 °C; [R]D +163° (c 1.0, CHCl3); IR (KBr) υmax
3050, 3020, 2900, 2860, 1625, 1450, 1400, 1385, 1240, 1225, 1145,
CH2Si), 3.55-3.49 (m, 1 H, C-6 OH), 3.42 (br s, 1 H, C-4 OH), 0.99-
0.90 (m, 2 H, OCH2CH2Si), 0.02 (s, 9 H, Si(CH3)3); 13C NMR (63
MHz, CDCl3) δ 147.0, 99.5, 94.8, 70.5, 67.7, 66.3, 63.0, 18.5, -1.0;
MS (CI) m/e (rel intensity) 277 (M + H+, 0.5), 201 (51), 185 (21),
157 (40), 145 (23), 129 (100), 117 (19), 111 (47), 103 (38), 101 (33),
91 (16), 85 (45), 83 (21), 81 (20). Anal. Calcd for C12H24O5Si: C,
52.14; H, 8.75. Found: C, 52.52; H, 9.00. For 47: [R]D +190° (c
1.0, CHCl3); IR (neat) υmax 3520, 2950, 2890, 1645, 1255, 1110, 1080,
1030 cm-1; 1H NMR (490 MHz, CDCl3) δ 7.40-7.25 (m, 5 H, ArH),
6.49 (d, J ) 6.0 Hz, 1 H, H-1), 4.92 (t, J ) 5.8 Hz, 1 H, H-2), 4.81
(ABq, J ) 6.8 Hz, υ ) 12.6 Hz, 2 H, OCH2OCH2CH2Si), 4.63 (s, 2 H,
OCH2Ph), 4.06 (dd, J ) 5.4, 4.2 Hz, 1 H, H-3), 3.97 (ddd, J ) 10.6,
5.4, 2.2 Hz, 1 H, H-5), 3.89 (dd, J ) 10.8, 2.2 Hz, 1 H, H-6), 3.87-
3.83 (br m, H-4), 3.79 (dd, J ) 10.8, 5.5 Hz, 1 H, H-6), 3.73-3.61
(m, 2 H, OCH2CH2Si), 3.22 (d, J ) 8.9 Hz, 1 H, OH), 0.96 (t, J ) 8.4
Hz, 1 H, OCH2CH2Si), 0.03 (s, 9 H, Si(CH3)3); 13C NMR (63 MHz,
CDCl3) δ 146.6, 138.1, 128.2, 127.6, 127.5, 98.6, 94.1, 74.6, 73.5, 69.7,
69.3, 66.5, 65.6, 18.0, -1.5; MS (CI) m/e (rel intensity) 219 (40), 201
(31), 173 (75), 155 (98), 141 (26), 129 (25), 119 (33), 107 (72), 105
(23), 103 (37), 101 (41), 91 (100). Anal. Calcd for C19H30O5Si: C,
62.26; H, 8.25. Found: C, 62.45; H, 8.54.
1
1115, 1090, 1060, 1040, 1010 cm-1; H NMR (250 MHz, CDCl3) δ
7.61-7.28 (m, 10 H, ArH), 6.43 (d, J ) 6.1 Hz, 1 H, H-1), 5.63 (s, 1
H, O2CHPh), 4.98 (t, J ) 6.0 Hz, 1 H, H-2), 4.96 (d, J ) 12.0 Hz, 1
H, OCHHPh), 4.72 (d, J ) 12.0 Hz, 1 H, OCHHPh), 4.51 (dd, J )
10.3, 5.3 Hz, 1 H, H-6e), 4.38 (td, J ) 10.1, 5.3 Hz, 1 H, H-5), 4.09
(dd, J ) 5.9, 3.5 Hz, 1 H, H-3), 3.99 (dd, J ) 10.2, 3.6 Hz, 1 H, H-4),
3.87 (t, J ) 10.2 Hz, 1 H, H-6a); 13C NMR (63 MHz, CDCl3) δ 145.6,
138.9, 137.5, 129.1, 128.3, 127.7, 127.4, 126.2, 102.0, 100.2, 79.5,
72.9, 68.8, 67.0, 64.5; MS (EI) m/e (rel intensity) 218 (54), 187 (59),
127 (15), 105 (18), 97 (43), 91 (100), 81 (16); HRMS (CI) calcd for
C20H21O4 (M + H+) 325.1440, found 325.1432. Anal. Calcd for
C20H20O4: C, 74.06; H, 6.21. Found: C, 74.08; H, 6.34.
1,5-Anhydro-4,6-O-benzylidene-2-deoxy-3-O-[[2-(trimethylsilyl)-
ethoxy]methyl]-D-ribo-hex-1-enopyranose (45). To a solution of 4,6-
O-benzylidene-D-allal (31; 5.00 g, 21.3 mmol) in dichloromethane (20
mL) at 0 °C were added N,N-diisopropylethylamine (14.8 mL, 85 mmol)
and (2-(trimethylsilyl)ethoxy)methyl chloride (7.5 mL, 43 mmol). The
mixture was stirred for 5 h at room temperature, then diluted with
diethyl ether (250 mL), and washed with water (2 × 50 mL) and brine
(50 mL). The organic layer was dried (MgSO4) and concentrated, and
the residue was chromatographed (5 f 10% ethyl acetate in hexanes)
to afford allal derivative 45 (7.75 g, 100%) as a colorless oil. A small
portion of 45 was bulb-to-bulb distilled (190 °C, 0.06 Torr) for
analysis: [R]D +88.3° (c 1.0, CHCl3); IR (neat) υmax 3060, 3030, 2950,
O-[2-Benzenesulfonamido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-
D-allopyranosyl]-â-(1f4)-1,5-anhydro-6-O-benzyl-2-deoxy-3-O-[[2-
(trimethylsilyl)ethoxy]methyl]-D-ribo-hex-1-enopyranose (48). Po-
tassium hexamethyldisilazide (0.5 M in toluene, 4.09 mmol) was added
dropwise to a -40 °C stirred solution of trans-bromosulfonamide 3737
(1.09 g, 1.95 mmol) and glycal 47 (857 mg, 2.34 mmol) in DMF (15
mL). The reaction mixture was stirred for 30 min at -40 °C and then
allowed to slowly warm to room temperature. After 17 h, the reaction
was poured into 5:1 water/saturated aqueous NH4Cl (300 mL) and then
extracted with diethyl ether (4 × 150 mL). The combined organic
layers were dried (MgSO4) and concentrated, and the residue was
chromatographed (silica gel, 5 f 10% ethyl acetate in toluene) to
provide 48 (1.33 g, 81%) followed by recovered alcohol 47 (250 mg,
29%). For 48: colorless foam; [R]D +26.4° (c 1.0, CH2Cl2); IR (KBr)
υmax 3340, 3060, 3030, 2940, 2880, 1645, 1450, 1340, 1160, 1095,
1
2890, 1635, 1380, 1245, 1140, 1115, 1090, 1025 cm-1; H NMR (63
MHz, CDCl3) δ 7.54-7.48 (m, 2 H, ArH), 7.40-7.33 (m, 3 H, ArH),
6.44 (d, J ) 6.2 Hz, 1 H, H-1), 5.60 (s, 1 H, O2CHPh), 4.99 (t, J ) 6.0
Hz, 1 H, H-2), 4.82 (d, J ) 6.9 Hz, 1 H, OCHHOCH2CH2Si), 4.49 (d,
J ) 6.9 Hz, 1 H, OCHHOCH2CH2Si), 4.47 (dd, J ) 10.4, 5.3 Hz, 1 H,
H-6e), 4.31 (dd, J ) 6.1, 3.6 Hz, 1 H, H-3), 4.25 (td, J ) 10.3, 5.3 Hz,
1 H, H-5), 3.94 (dd, J ) 10.4, 3.7 Hz, 1 H, H-4), 3.83 (t, J ) 10.0 Hz,
1 H, H-6a), 3.78 (td, J ) 9.8, 7.1 Hz, 1 H, OCHHCH2Si), 3.59 (td, J
) 9.8, 7.0 Hz, 1 H, OCHHCH2Si), 1.02-0.90 (m, 2 H, OCH2CH2Si),
0.02 (s, 9 H, Si(CH3)3); 13C NMR (63 MHz, CDCl3) δ 145.7, 137.4,
128.9, 128.2, 126.1, 101.7, 100.2, 94.4, 78.6, 68.8, 65.1, 64.4, 64.0,
18.1, -1.4; MS (CI) m/e (rel intensity) 365 (M + H+, 0.4), 291 (14),
245 (16), 218 (26), 217 (100), 201 (34), 179 (12), 171 (59), 149 (10),
143 (16), 111 (19), 107 (15), 103 (24), 101 (22), 91 (20), 81 (10).
Anal. Calcd for C19H28O5Si: C, 62.61; H, 7.74. Found: C, 62.39; H,
7.51.
1,5-Anhydro-2-deoxy-3-O-[[2-(trimethylsilyl)ethoxy]methyl]-D-
ribo-hex-1-enopyranose (46) and 1,5-Anhydro-6-O-benzyl-2-deoxy-
3-O-[[2-(trimethylsilyl)ethoxy]methyl]-D-ribo-hex-1-enopyranose (47).
To a -78 °C solution of glycal 45 (1.28 g, 3.51 mmol) in THF (130
mL) and ammonia (370 mL) were added small pieces of sodium until
a deep blue color was maintained for 1 min. The mixture was then
quenched with solid NH4Cl and concentrated with a stream of nitrogen,
and the residue was extracted from 1:4 water/brine (250 mL) with
chloroform (3 × 150 mL). The combined organic layers were dried
(Na2SO4) and concentrated to provide diol 46 as an oil (0.963 g, 99%),
which was pure enough for the subsequent step.
1030 cm-1 1H NMR (490 MHz, CDCl3) δ 7.75-7.70 (m, 2 H,
;
SO2C(CHCH)2CH), 7.55-7.50 (m, 1 H, SO2C(CHCH)2CH), 7.48-
7.19 (m, 17 H, ArH), 6.37 (d, J ) 5.9 Hz, 1 H, H-1), 5.49 (s, 1 H,
O2CHPh), 5.09 (d, J ) 8.4 Hz, 1 H, NH), 4.97 (d, J ) 11.2 Hz, 1 H,
OCHHPh), 4.84 (d, J ) 6.7 Hz, 1 H, OCHHOCH2CH2Si), 4.82 (t, J )
5.9 Hz, 1 H, H-2), 4.72 (d, J ) 8.3 Hz, 1 H, H-1′), 4.68 (d, J ) 6.7
Hz, 1 H, OCHHOCH2CH2Si), 4.58 (d, J ) 12.0 Hz, 1 H, OCHHPh),
4.46 (d, J ) 11.2 Hz, 1 H, OCHHPh), 4.44 (d, J ) 12.0 Hz, 1 H,
OCHHPh), 4.33 (dd, J ) 10.4, 5.2 Hz, 1 H, H-6e′), 4.11 (dd, J ) 6.0,
3.6 Hz, 1 H, H-3), 4.09 (t, J ) 2.6 Hz, 1 H, H-3′), 4.02 (td, J ) 9.9,
5.1 Hz, 1 H, H-5′), 3.91 (dd, J ) 10.9, 3.6 Hz, 1 H, H-4), 3.78 (td, J
) 10.0, 6.5 Hz, 1 H, OCHHCH2Si), 3.74 (dt, J ) 10.9, 2.4 Hz, 1 H,
H-5), 3.72 (t, J ) 10.3 Hz, 1 H, H-6a′), 3.67 (dd, J ) 9.5, 2.2 Hz, 1 H,
H-4′), 3.54 (td, J ) 9.9, 6.4 Hz, 1 H, OCHHCH2Si), 3.46 (td, J ) 8.6,
3.1 Hz, 1 H, H-2′), 3.41 (dd, J ) 11.1, 2.1 Hz, 1 H, H-6), 3.34 (dd, J
) 11.1, 2.9 Hz, 1 H, H-6), 1.02-0.91 (m, 2 H, OCH2CH2Si), 0.06 (s,
9 H, Si(CH3)3); 13C NMR (63 MHz, CDCl3) δ 146.0, 141.0, 137.9,
137.6, 137.1, 132.4, 129.1, 128.8, 128.5, 128.4, 128.2, 128.0, 127.9,
127.8, 126.9, 126.0, 102.1, 100.7, 99.7, 94.7, 80.0, 76.4, 75.8, 74.9,
73.5, 72.2, 69.0, 68.0, 67.7, 64.9, 63.4, 57.2, 18.1, -1.4; MS (FAB)
m/e (rel intensity) 868 (M + Na+, 13), 698 (11), 373 (183), 372 (77),
266 (26), 246 (17), 245 (100), 226 (24); HRMS (FAB) calcd for C45H55-
NNaO11SSi (M + Na+) 868.3165, found 868.3212. Anal. Calcd for
C45H55NO11SSi: C, 63.88; H, 6.55; N, 1.65; S, 3.79. Found: C, 63.93;
H, 6.74; N, 1.66; S, 4.06.
A methanolic (40 mL) suspension of 46 (0.963 g, 3.48 mmol) and
dibutyltin oxide (0.87 g, 3.5 mmol) were refluxed until homogeneous
(1 h). The solution was concentrated under reduced pressure and then
concentrated from benzene (3 × 50 mL) to remove any methanol still
present. The stannylene acetal thus produced was rapidly stirred for
24 h with benzyl bromide (0.62 mL, 5.2 mmol) and dry cesium fluoride
(0.84 g, 5.5 mmol) in DMF (20 mL). The mixture was extracted from
water (250 mL) with ethyl acetate (2 × 200 mL), the combined organic
layers were dried (Na2SO4) and concentrated, and the residue was
chromatographed (silica gel, 2% Et3N, 5 f 10 f 33 f 50% ethyl
acetate in toluene) to provide the desired diprotected glycal 47 (887
mg, 69%) as a colorless oil, followed by diol 46 (200 mg, 20%) as a
yellow oil. For 46: The oil was bulb-to-bulb distilled to provide a
colorless oil of 46: [R]D +228° (c 1.1, CHCl3); IR (neat) υmax 3420,
O-[2-Benzenesulfonamido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-
D-allopyranosyl]-â-(1f4)-6-O-benzyl-2-bromo-2-deoxy-3-O-[[2-(tri-
methylsilyl)ethoxy]methyl]-r-D-altropyranosyl Benzenesulfonamide
(49). A solution of glycal 48 (980 mg, 1.16 mmol) in dichloromethane
(1.5 mL) was added dropwise to a stirred suspension of N,N-
dibromobenzenesulfonamide (372 mg, 1.18 mmol) in dichloromethane
(0.7 mL) at 0 °C. Ethanol (6 mL) and NH4I (140 mg, 1.22 mmol)
were added to the reaction after 1 h, and the resultant mixture was
stirred an additional 1.5 h at room temperature, diluted with diethyl
ether (250 mL), and reduced with saturated aqueous Na2S2O3 (50 mL).
The organic layer was dried (MgSO4) and concentrated, and the residue
1
2950, 2920, 2890, 1645, 1250, 1105, 1030 cm-1; H NMR (63 MHz,
CDCl3) δ 6.45 (d, J ) 5.9 Hz, 1 H, H-1), 4.93 (t, J ) 5.8 Hz, 1 H,
H-2), 4.80 (s, 2 H, OCH2OCH2CH2Si), 4.06-4.01 (m, 1 H, H-3), 4.01-
3.81 (m, 4 H, H-4, H-5, H-6, and H-6), 3.80-3.56 (m, 2 H, OCH2-

9536 J. Am. Chem. Soc., Vol. 118, No. 40, 1996
Griffith and Danishefsky
was chromatographed (silica gel, 10% ethyl acetate in toluene) to afford
trans-sulfonamide 49 (708 mg, 57%), followed by fractions which
contained a 2:1 R/â mixture of sulfonamides (144 mg, 12%). For 49:
colorless foam; IR (KBr) υmax 3330, 3060, 3030, 2950, 2900, 1450,
1340, 1170, 1095 cm-1; 1H NMR (490 MHz, CDCl3) δ 7.96-7.91 (m,
2 H, SO2C(CHCH)2CH), 7.68-7.63 (m, 2 H, SO2C(CHCH)2CH),
7.60-7.20 (m, 26 H, ArH), 6.84 (d, J ) 10.1 Hz, 1 H, NH), 5.51 (d,
J ) 10.1 Hz, 1 H, H-1), 5.46 (s, 1 H, O2CHPh), 5.02 (d, J ) 8.5 Hz,
1 H, NH ′), 4.90 (d, J ) 11.2 Hz, 1 H, OCHHPh), 4.71 (ABq, J ) 6.8
Hz, υ ) 15.1 Hz, 2 H, OCH2OCH2CH2Si), 4.61 (d, J ) 8.3 Hz, 1 H,
H-1′), 4.55 (d, J ) 12.2 Hz, 1 H, OCHHPh), 4.36 (d, J ) 12.2 Hz, 1
H, OCHHPh), 4.35 (d, J ) 11.2 Hz, 1 H, OCHHPh), 4.32 (dd, J )
10.8, 5.3 Hz, 1 H, H-6e′), 4.30 (dd, J ) 10.0, 2.9 Hz, 1 H, H-4), 4.25
(t, J ) 2.9 Hz, 1 H, H-3), 4.16 (d, J ) 2.8 Hz, 1 H, H-2), 4.02 (td, J
) 9.9, 5.2 Hz, 1 H, H-5′), 3.89 (t, J ) 2.4 Hz, 1 H, H-3′), 3.82 (td, J
) 9.5, 7.1 Hz, 1 H, OCHHCH2Si), 3.66 (t, J ) 10.4 Hz, 1 H, H-6a′),
3.61 (td, J ) 9.3, 7.1 Hz, 1 H, OCHHCH2Si), 3.58 (dd, J ) 9.7, 1.9
Hz, 1 H, H-4′), 3.27 (td, J ) 8.4, 3.1 Hz, 1 H, H-2′), 3.19 (br d, J )
10.0 Hz, 1 H, H-5), 3.15 (dd, J ) 11.0, 2.7 Hz, 1 H, H-6), 2.61 (dd,
J ) 10.9, 2.0 Hz, 1 H, H-6), 1.04-0.96 (m, 2 H, OCH2CH2Si), 0.11
(s, 9 H, Si(CH3)3); 13C NMR (63 MHz, CDCl3) δ 141.4, 141.1, 137.7,
137.0, 132.5, 132.3, 129.1, 128.8, 128.7, 128.5, 128.3, 128.2, 128.0,
127.9, 127.7, 127.1, 127.1, 126.8, 126.0, 102.1, 100.8, 96.2, 81.9, 79.8,
77.2, 75.8, 74.8, 73.3, 71.5, 68.8, 67.6, 66.7, 66.5, 63.4, 56.9, 46.3,
18.1, -1.4; MS (FAB) m/e (rel intensity) 1103 (M + Na+, 3), 1024
(10), 1023 (15), 480 (10), 373 (21), 372 (100), 356 (10), 320 (13), 318
(11), 307 (10); HRMS (FAB) calcd for C51H61BrN2NaO13S2Si (M +
Na+) 1103.2467, found 1103.2492. Anal. Calcd for C51H61BrN2O13S2Si:
C, 56.61; H, 5.68; N, 2.59; S, 5.93. Found: C, 56.78; H, 5.72; N,
2.58; S, 5.84.
cm-1; 1H NMR (250 MHz, CDCl3) δ 7.40-7.28 (m, 5 H, ArH), 5.94-
5.87 (m, 2 H, H-2 and H-3), 5.46 (5.1, 1 H, H-1), 4.95 (br s, 2 H,
OCONH2), 4.64 (d, J ) 4.8 Hz, 1 H, H-4), 4.56 (ABq, J ) 12.1 Hz, υ
) 15.1 Hz, 2 H, OCH2Ph), 3.69 (d, J ) 4.6 Hz, 2 H, CH2OBn), 2.22
(p, J ) 4.8 Hz, 1 H, H-5), 0.90 (s, 9 H, SiC(CH3)3), 0.08 (s, 3 H,
SiCH3), 0.06 (s, 3 H, SiCH3); 13C NMR (63 MHz, CDCl3) δ 156.8,
138.2, 138.0, 131.2, 128.2, 127.6, 127.4, 79.3, 76.6, 73.2, 68.1, 55.3,
25.8, 18.0, -4.6, -4.7; MS (CI) m/e (rel intensity) 378 (M + H+, 1),
318 (31), 317 (100), 246 (43), 211 (67), 209 (21), 169 (48), 160 (27),
138 (30), 118 (36), 91 (95). Anal. Calcd for C20H31O4NSi: C, 63.62;
H, 8.28; N, 3.71. Found: C, 63.40; H, 7.99; N, 3.71.
[1(R)-(1r,2â,3r)]-2-[(Benzyloxy)methyl]-4-cyclopentene-1,3-di-
ol Monocarbamate (20). A solution of 2% HF in acetonitrile (26
mL, 26 mmol) was added to a solution of carbamate 21 (4.71 g, 12.5
mmol) in acetonitrile (50 mL). The mixture was stirred for 9 h and
then extracted from 1:3 saturated aqueous NaHCO3/water (200 mL)
with ethyl acetate (4 × 50 mL). The combined organic layers were
dried (MgSO4) and concentrated, and the residue was recrystallized
(ethyl acetate/hexanes) to provide the desired carbamate 20 (2.98 g,
91%) as colorless crystals: mp 114-114.5 °C; [R]D +58.0° (c 1.0,
THF); IR (KBr) υmax 3420, 3310, 3270, 3200, 2870, 1685, 1610, 1410,
1
1355, 1115, 1105, 1050 cm-1; H NMR (250 MHz, CDCl3) δ 7.40-
7.28 (m, 5 H, ArH), 6.02 (dt, J ) 5.6, 1.4 Hz, 1 H, H-5), 5.91 (dt, J
) 5.6, 1.6 Hz, 1 H, H-4), 5.33-5.28 (m, 1 H, H-1), 4.76 (br s, 2 H,
OCONH2), 4.62-4.55 (m, 1 H, H-3), 4.56 (s, 2 H, OCH2Ph), 3.81
(dd, J ) 9.2, 5.2 Hz, 1 H, CHHOBn), 3.63 (dd, J ) 9.2, 7.8 Hz, 1 H,
CHHOBn), 2.44 (d, J ) 3.9 Hz, 1 H, OH), 2.31 (dq, J ) 7.7, 4.9 Hz,
1 H, H-2); 13C NMR (63 MHz, CDCl3) δ 156.5, 138.1, 137.2, 132.0,
128.4, 127.7, 79.6, 78.1, 73.4, 70.0, 55.3; MS (CI) m/e (rel intensity)
264 (M + H+, 9), 246 (61), 203 (65), 185 (42), 157 (22), 152 (20),
138 (67), 131 (20), 119 (56), 111 (32), 107 (36), 97 (27), 96 (50), 92
(60), 91 (100). Anal. Calcd for C14H17NO4: C, 63.86; H, 6.51; N,
5.32. Found: C, 63.73; H, 6.24; N, 5.26.
[3a(R)-(3ar,6r,6ar)]-6-[(Benzyloxy)methyl]-3,3a,6,6a-tetrahydro-
2H-cyclopentoxazol-2-one (24). To a -78 °C solution of carbamate
20 (2.99 g, 11.4 mmol) in THF (250 mL) were added triethylamine
(12.7 mL, 92 mmol) and trifluoroacetic anhydride (4.80 mL, 34 mmol).
The reaction was warmed to room temperature over 4 h, and water (30
mL) was added. The mixture was stirred an additional 1 h, then diluted
with diethyl ether (500 mL), and washed with 1 M aqueous HCl (2 ×
200 mL), saturated aqueous NaHCO3 (200 mL), and brine (200 mL).
The organic layer was dried (MgSO4) and concentrated, and the orange-
yellow residue was filtered through a short plug of silica gel (66%
ethyl acetate in hexanes). The yellow oil thus produced was chro-
matographed (silica gel, 30 f 35 f 40% ethyl acetate in dichlo-
romethane) to provide the oxazolone 24 (1.74 mg, 63%) as an off-
white solid (mp 84.5-86 °C). Recrystallization (diethyl ether/hexanes)
provided colorless crystals of 24: mp 87.5-88 °C; [R]D -201° (c 1.0,
CHCl3); IR (neat) υmax 3270, 2900, 2870, 1720, 1385, 1330, 1230, 1215,
1070, 1040 cm-1; 1H NMR (490 MHz, CDCl3) δ 7.38-7.28 (m, 5 H,
ArH), 5.88 (dd, J ) 5.9, 2.6 Hz, 1 H, olefinic), 5.85 (br s, 1 H, NH),
5.81 (dt, J ) 5.9, 1.8 Hz, 1 H, olefinic), 5.02 (d, J ) 7.1 Hz, 1 H),
4.72 (d, J ) 7.1 Hz, 1 H), 4.51 (s, 2 H, OCH2Ph), 3.58 (dd, J ) 9.4,
4.8 Hz, 1 H, CHHOBn), 3.41 (dd, J ) 9.4, 5.7 Hz, 1 H, CHHOBn),
3.26-3.23 (m, 1 H, H-6); 13C NMR (63 MHz, CDCl3) δ 159.6, 137.8,
133.6, 131.4, 128.3, 127.6, 127.4, 82.3, 73.0, 70.1, 61.7, 52.7; MS (CI)
m/e (rel intensity) 247 (48), 246 (M + H+, 100), 91 (75). Anal. Calcd
for C14H15NO3: C, 68.56; H, 6.16; N, 5.71. Found: C, 68.46; H, 6.18;
N, 5.51.
[1(R)-(1r,4r,5â)]-5-[(Benzyloxy)methyl]-4-[(tert-butyldimethyl-
silyl)oxy]-2-cyclopenten-1-ol (59). To a 0 °C solution of monoacetate
ent-19 (3.95 g, 15.1 mmol) in dichloromethane (50 mL) was added
imidazole (3.88 g, 57.0 mmol) and tert-butyldimethylsilyl chloride (4.32
g, 28.7 mmol). The mixture was stirred for 30 min, diluted with diethyl
ether (200 mL), washed successively with 1 M aqueous HCl (2 × 50
mL) and saturated aqueous NaHCO3 (50 mL), dried (MgSO4), and
concentrated. The oil thus produced was deacetylated with methanolic
ammonia (150 mL) for 48 h and concentrated, and the residue was
chromatographed (silica gel, 20 f 25% ethyl acetate in hexanes) to
provide the desired alcohol 53 (5.10 g, 100%) as a colorless oil. A
portion of 53 was bulb-to-bulb distilled (170 °C, 0.06 Torr) for
analysis: [R]D -49.2° (c 1.1, CHCl3); IR (neat) υmax 3370 (br), 3050,
3020, 2950, 2920, 2850, 1360, 1255, 1100, 1055 cm-1; 1H NMR (250
MHz, CDCl3) δ 7.50-7.28 (m, 5 H, ArH), 5.89 (d, J ) 5.7 Hz, 1 H,
olefinic), 5.81 (d, J ) 5.7 Hz, 1 H, olefinic), 4.57 (ABq, J ) 12.0 Hz,
υ ) 11.3 Hz, 2 H, OCH2Ph), 5.53 (d, J ) 5.5 Hz, 2 H, H-1 and H-4),
3.76 (dd, J ) 9.2, 4.5 Hz, 1 H, CHHOBn), 3.63 (dd, J ) 9.2, 6.2 Hz,
1 H, CHHOBn), 2.50 (s, 1 H, OH), 2.12 (p, J ) 5.4 Hz, 1 H, H-5),
0.91 (s, 9 H, SiC(CH3)3), 0.09 (s, 3 H, SiCH3), 0.07 (s, 3 H, SiCH3);
13C NMR (63 MHz, CDCl3) δ 138.3, 136.0, 134.6, 128.4, 127.7, 127.6,
77.4, 76.8, 73.3, 69.0, 59.1, 25.8, 18.1, -4.5, -4.7; MS (CI) m/e (rel
intensity) 335 (M + H+, 1), 317 (46), 211 (24), 203 (21), 169 (28), 91
(100). Anal. Calcd for C19H30O3Si: C, 68.22; H, 9.04. Found: C,
67.98; H, 8.75.
[1(R)-(1r,4r,5â)]-5-[(Benzyloxy)methyl]-4-[(tert-butyldimethyl-
silyl)oxy]-2-cyclopenten-1-ol Carbamate (21). To a 0 °C solution
of alcohol 59 (5.10 g, 15.2 mmol) in dichloromethane (50 mL) were
added pyridine (3.0 mL, 38 mmol) and phenyl chloroformate (2.3 mL,
18 mmol). The mixture was stirred for 15 min, then diluted with diethyl
ether (250 mL), washed with water (50 mL), 1 M aqueous HCl (2 ×
25 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL), dried
(MgSO4), and concentrated. The phenyl carbonate thus produced was
treated for 15 h with methanolic ammonia (200 mL) and concentrated,
and the residue was dissolved in diethyl ether (400 mL) and washed
with 1 M aqueous NaOH (3 × 50 mL) and brine (50 mL). The
combined organic layers were dried (Na2SO4) and concentrated, and
the residue was chromatographed (20 f 25 f 30% ethyl acetate in
hexanes) to provide 21 (4.72 g, 82%) as a viscous, light-yellow oil. A
portion of 21 was bulb-to-bulb distilled (180 °C, 0.040 Torr) to afford
a colorless, viscous oil: [R]D +3.9° (c 1.1, CHCl3); IR (neat) υmax 3490,
3340, 2950, 2930, 2860, 1720, 1595, 1390, 1365, 1310, 1105, 1055
[3a(R)-(3ar,6r,6ar)]-6-[(Benzyloxy)methyl]-3,6a-dihydro-N,N-
dimethyl-6H-cyclopentoxazol-2-amine (25). Methyl trifluoromethane-
sulfonate (1.62 mL, 14.2 mmol) was stirred with a dichloromethane (6
mL) solution of oxazolone 24 (1.76 g, 7.18 mmol) for 5 h and then
concentrated with a stream of nitrogen. Dimethylamine (56 mL) was
condensed into the flask with the residue at 0 °C, and the mixture was
stirred for 2 days at room temperature and then extracted from 4:1
saturated aqueous K2CO3/water (250 mL) with dichloromethane (3 ×
100 mL). The combined organic layers were dried (Na2SO4) and
concentrated, and the residue was chromatographed (silica gel, 2% Et3N,
10% methanol in ethyl acetate) to provide the aminooxazoline 25 (1.69
g, 87%) as a light-yellow oil: [R]D -213° (c 1.1, CH2Cl2); IR (neat)
υ
max 2860, 1655, 1405, 1185, 1120, 1100, 1070, 1025 cm-1; 1H NMR

Total Synthesis of Allosamidin
J. Am. Chem. Soc., Vol. 118, No. 40, 1996 9537
(490 MHz, CD2Cl2) δ 7.37-7.26 (m, 5 H, ArH), 5.85 (dt, J ) 5.8, 1.9
Hz, 1 H, olefinic), 5.63 (dt, J ) 5.8, 2.0 Hz, 1 H, olefinic), 4.93 (dq,
J ) 7.1, 1.7 Hz, 1 H), 4.84 (d, J ) 7.1 Hz, 1 H), 4.51 (s, 2 H, OCH2-
Ph), 3.52 (dd, J ) 9.3, 5.2 Hz, 1 H, CHHOBn), 3.29 (dd, J ) 9.3, 7.7
Hz, 1 H, CHHOBn), 3.15-3.10 (m, 1 H, H-6), 2.83 (s, 6 H, N(CH3)2);
13C NMR (63 MHz, CD2Cl2) δ 162.3, 139.0, 135.6, 130.0, 128.7, 128.0,
127.9, 86.0, 76.0, 73.6, 72.1, 53.9, 37.9; MS (EI) m/e (rel intensity)
272 (M+, 31), 165 (18), 151 (15), 91 (69), 80 (18), 72 (100). Anal.
Calcd for C16H20N2O2: C, 70.56; H, 7.40; N, 10.28. Found: C, 70.42;
H, 7.22; N, 10.10.
10 f 20% ethyl acetate in toluene) to provide the desired diprotected
aglycon 60 (247 mg, 35%) as a colorless solid (mp 115.5-117.5 °C),
followed by recovered diol 27 (114 mg, 21%) as a colorless solid. For
60: colorless needles (recrystallization, ethyl acetate/hexanes): mp
119-120 °C; [R]D -19.6° (c 1.2, CH2Cl2); IR (KBr) υmax 3170 (br),
3010, 2900, 2870, 1650, 1410, 1200, 1110, 1030 cm-1; 1H NMR (250
MHz, CD2Cl2) δ 7.45-7.23 (m, 10 H, ArH), 4.82 (d, J ) 11.8 Hz, 1
H, OCHHPh), 4.66 (d, J ) 11.8 Hz, 1 H, OCHHPh), 4.64 (dd, J )
6.0, 3.0 Hz, 1 H, H-1), 4.56 (s, 2 H, OCH2Ph), 4.16 (dd, J ) 8.9, 4.6
Hz, 1 H, H-2), 3.87 (dd, J ) 9.3, 7.1 Hz, 1 H, H-4), 3.86 (br s, 1 H,
OH), 3.71-3.65 (m, 3 H, H-3, H-6, and H-6), 2.89 (s, 6 H, N(CH3)2),
2.28-2.15 (m, 1 H, H-5); 13C NMR (63 MHz, CD2Cl2) δ 162.1, 139.2,
138.8, 128.7, 128.5, 128.2, 127.9, 127.7, 92.3, 82.5, 75.4, 73.5, 72.6,
71.9, 69.7, 51.4, 37.8; MS (CI) m/e (rel intensity) 397 (M + H+, 1),
305 (10), 273 (29), 185 (11), 184 (100), 166 (15), 165 (58), 155 (10),
91 (44), 72 (15). Anal. Calcd for C23H28N2O4: C, 69.68; H, 7.12; N,
7.06. Found: C, 69.69; H, 7.09; N, 7.05.
[1a(S)-(1ar,1br,4ar,5r,5ar)]-5-[(Benzyloxy)methyl]-N,N-dimethyl-
1a,1b,4a,5a-tetrahydro-5H-oxireno[4,5]cyclopent[1,2-d]oxazol-3-
amine (26) and 6-O-Benzyl-(-)-allosamizoline (27). To a 0 °C
dichloromethane (8 mL) solution of aminooxazoline 25 (1.72 g, 6.32
mmol) was added 3.6 M trifluoroperacetic acid (3.51 mL, 12.7 mmol).
The mixture was stirred 2 h, and water (32 mL) and sodium bisulfite
(860 mg, 8.2 mmol) were added. The solution was heated to 40 °C
for 5.5 h, and the reaction was extracted from water (150 mL) with
dichloromethane (4 × 200 mL). The combined organic layers were
dried (Na2SO4) and concentrated, and the residue was chromatographed
(silica gel, 1% Et3N, 5 f 10 f 20% methanol in ethyl acetate) to
provide R-epoxide 26 (0.67 g, 37%) followed by diol 27 (0.84 g, 44%).
The waxy, yellow solid was rechromatographed (silica gel, 1% Et3N,
5 f 10% methanol in ethyl acetate) to provide a colorless oil of 26:
[R]D -91.7° (c 1.0, CH2Cl2); IR (neat) υmax 3020, 2920, 2860, 1655,
1455, 1410, 1185, 1105, 1080, 1030 cm-1; 1H NMR (250 MHz, CD2Cl2)
δ 7.41-7.25 (m, 5 H, ArH), 4.72 (d, J ) 8.1 Hz, 1 H, H-4a), 4.50 (s,
2 H, OCH2Ph), 4.41 (dd, J ) 8.1, 1.8 Hz, 1 H, H-1b), 3.56-3.52 (m,
1 H, H-5a), 3.53 (d, J ) 5.0 Hz, 2 H, CH2OBn), 3.49 (dd, J ) 2.5, 1.1
Hz, 1 H, H-1a), 2.84 (s, 6 H, N(CH3)2), 2.70 (t, J ) 5.0 Hz, 1 H, H-5);
13C NMR (63 MHz, CD2Cl2) δ 162.5, 138.6, 128.8, 128.1, 127.9, 88.1,
73.7, 70.8, 69.6, 61.5, 61.6, 47.1, 37.8; MS (EI) m/e (rel intensity) 288
(M+, 42), 167 (8), 112 (100), 83 (20). Anal. Calcd for C16H20N2O3:
C, 66.65; H, 6.99; N, 9.72. Found: C, 66.47; H, 6.90; N, 9.63. The
off-white solid (mp 130-143 °C) was recrystallized (ethyl acetate/
hexanes) to afford colorless needles of 27: mp 143-144 °C; [R]D
+15.6° (c 1.0, CH2Cl2); IR (KBr) υmax 3350, 3300, 2970, 2910, 2850,
1645, 1450, 1410, 1265, 1190, 1150 cm-1; 1H NMR (250 MHz, CD2Cl2)
δ 7.40-7.24 (m, 5 H, ArH), 6.02 (s, 2 H, OH), 4.74 (dd, J ) 9.3, 6.6
Hz, 1 H, H-1), 4.54 (ABq, J ) 12.0 Hz, υ ) 9.0 Hz, 2 H, OCH2Ph),
3.96 (dd, J ) 9.3, 5.0 Hz, 1 H, H-2), 3.80-3.58 (m, 4 H, H-3, H-4,
H-6, and H-6), 2.85 (s, 6 H, N(CH3)3), 2.17-2.03 (m, 1 H, H-5); 13C
NMR (63 MHz, CD2Cl2) δ 162.5, 139.1, 128.6, 127.9, 127.8, 85.1,
82.5, 74.4, 73.4, 72.9, 69.3, 50.7, 37.9; MS (EI) m/e (rel intensity) 306
(M+, 7), 247 (34), 245 (46), 215 (31), 190 (46), 185 (76), 141 (26),
139 (24), 138 (20), 125 (50), 113 (36), 112 (52), 97 (30), 91 (91), 89
(95), 72 (100). Anal. Calcd for C16H22N2O4: C, 62.73; H, 7.24; N,
9.14. Found: C, 62.46; H, 7.47; N, 9.00.
O-[2-Benzenesulfonamido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-
D-allopyranosyl]-â-(1f4)-O-[2-benzenesulfonamido-6-O-benzyl-2-
deoxy-3-O-[[2-(trimethylsilyl)ethoxy]methyl]-D-allopyranosyl]-â-
(1f4)-3,6-di-O-benzyl-(-)-allosamizoline (61). To a -40 °C solution
of trans-bromosulfonamide 49 (556 mg, 0.514 mmol) in DMF (1 mL)
was added a DMF solution (2.5 mL) of allosamizoline derivative 60
(146 mg, 0.368 mmol), followed by dropwise addition of potassium
hexamethyldisilazide (0.5 M in toluene, 2.8 mL, 1.4 mmol). The
reaction mixture was stirred for 1 h at -40 °C, slowly warmed to room
temperature, stirred an additional 10 h, and then extracted from 1:1
water/brine (200 mL) with diethyl ether (3 × 75 mL). The combined
organic layers were dried (Na2SO4) and concentrated, and the residue
was chromatographed (silica gel, 1% Et3N, 0 f 10% methanol in ethyl
acetate) to provide pseudotrisaccharide 61 (215 mg, 42%), followed
by recovered aglycon 60 (66 mg, 45%). For 61: colorless glass; [R]D
-40.6° (c 1.0, CH2Cl2); IR (KBr) υmax 3330, 3190, 3060, 3030, 2880
1
(br), 1655, 1450, 1405, 1340 cm-1; H NMR (490 MHz, CD2Cl2) δ
7.85-7.81 (m, 2 H, SO2C(CHCH)2CH), 7.87-7.83 (m, 2 H,
SO2C(CHCH)2CH), 7.51-7.15 (m, 31 H, ArH), 5.98 (d, J ) 8.2 Hz,
1 H, NH ′), 5.46 (s, 1 H, O2CHPh), 5.12 (d, J ) 8.4 Hz, 1 H, NH ′′),
4.89 (d, J ) 11.3 Hz, 1 H, OCHHPh), 4.68 (d, J ) 6.5 Hz, 1 H,
OCHHOCH2CH2Si), 4.66 (s, 2 H, OCH2Ph), 4.60 (dd, J ) 6.7, 2.1
Hz, 1 H, H-1), 4.57 (ABq, J ) 11.4 Hz, υ ) 14.2 Hz, 2 H, OCH2Ph),
4.56 (d, J ) 8.4 Hz, 1 H, H-1′′), 4.53 (d, J ) 8.2 Hz, 1 H, H-1′), 4.50
(d, J ) 6.5 Hz, 1 H, OCHHOCH2CH2Si), 4.44 (d, J ) 11.9 Hz, 1 H,
OCHHPh), 4.39 (d, J ) 11.3 Hz, 1 H, OCHHPh), 4.34 (d, J ) 11.9
Hz, 1 H, OCHHPh), 4.20 (dd, J ) 10.3, 5.2 Hz, 1 H, H-6e′′), 4.02 (dd,
J ) 9.0, 4.4 Hz, 1 H, H-2), 3.91 (td, J ) 10.0, 5.2 Hz, 1 H, H-5′′),
3.90-3.85 (m, 2 H, H-4 and H-3′′), 3.80 (td, J ) 9.2, 7.8 Hz, 1 H,
OCHHCH2Si), 3.73 (t, J ) 2.7 Hz, 1 H, H-3′), 3.63 (td, J ) 9.4, 7.6
Hz, 1 H, OCHHCH2Si), 3.62-3.53 (m, 6 H, H-3, H-6, H-6, H-4′, H-4′′,
and H-6a′′), 3.43 (dt, J ) 9.8, 2.4 Hz, 1 H, H-5′), 3.33 (ABq of ABX,
JAB ) 11.0 Hz, JAX ) 3.0 Hz, JBX )2.9 Hz, υ ) 12.8 Hz, 2 H, H-6′
and H-6′), 3.25 (td, J ) 8.3, 3.0 Hz, 1 H, H-2′′), 3.18 (td, J ) 8.1, 2.8
Hz, 1 H, H-2′), 2.91 (s, 6 H, N(CH3)2), 1.67-1.62 (m, 1 H, H-5), 1.10-
1.05 (m, 2 H, OCH2CH2Si), 0.08 (s, 9 H, Si(CH3)3); 13C NMR (63
MHz, CD2Cl2) δ 161.7, 142.2, 141.4, 139.6, 138.9, 138.5, 137.9, 133.0,
132.7, 129.5, 129.4, 129.2, 128.9, 128.8, 128.6, 128.5, 128.4, 128.1,
128.0, 127.7, 127.6, 127.2, 126.6, 102.5, 101.2, 99.8, 97.5, 90.6, 82.2,
81.4, 80.3, 76.8, 76.5, 75.2, 73.8, 73.6, 72.9, 72.1, 71.7, 69.4, 69.3,
68.4, 66.9, 63.9, 57.4, 56.6, 50.2, 37.9, 18.6, -1.2; HRMS (FAB) calcd
for C74H89N4O17S2Si (M + H+) 1397.5434, found 1397.5509. Anal.
Calcd for C74H88N4O17S2Si: C, 63.59; H, 6.34; H, 4.01; S, 4.59.
Found: C, 63.30; H, 6.46; H, 3.94; S, 4.72.
(-)-Allosamizoline (8). A mixture of benzyl derivative 27 (30.7
mg, 0.100 mmol) and 10% Pd/C catalyst (20 mg) in 1:9 acetic acid/
methanol (2 mL) was shaken for 16 h under 40 psi of H2, filtered
through Celite, and concentrated to provide the acetic acid salt of (+)-
allosamizoline (8; 23.3 mg, 84%) as a colorless glass: [R]D -21.7° (c
0.8, water); 1H NMR (490 MHz, D2O + 0.5% CD3CO2D) δ 5.35 (dd,
J ) 9.0, 5.2 Hz, 1 H, H-1), 4.32 (dd, J ) 9.0, 4.9 Hz, 1 H, H-2), 4.07
(dd, J ) 6.9, 4.9 Hz, 1 H, H-3), 3.88 (dd, J ) 11.5, 4.5 Hz, 1 H, H-6),
3.82 (t, J ) 7.8 Hz, 1 H, H-4), 3.72 (dd, J ) 11.5, 7.3 Hz, 1 H, H-6),
3.08 (s, 6 H, N(CH3)2), 2.45-2.38 (m, 1 H, H-5); 13C NMR (63 MHz,
D2O + 0.5% CD3CO2D) δ 161.2, 87.3, 82.2, 75.5, 64.2, 59.9, 51.9,
38.0; HRMS (FAB) calcd for C9H17N2O4 (M + H+) 217.1188, found
217.1194.
3,6-Di-O-benzyl-(-)-allosamizoline (60). A methanolic (20 mL)
suspension of diol 27 (540 mg, 1.76 mmol) and dibutyltin oxide (0.44
g, 1.8 mmol) was refluxed until the mixture became homogeneous (1
h). The solution was concentrated under reduced pressure and then
concentrated from benzene (3 × 50 mL) to remove any methanol still
present. The stannylene acetal was rapidly stirred in DMF (20 mL)
and treated with benzyl bromide (0.31 mL, 2.6 mmol) and dry cesium
fluoride (0.53 g, 3.5 mmol). After 12 h, the suspension was extracted
from 0.5 M aqueous Na2CO3 (100 mL) with ethyl acetate (2 × 150
mL). The combined organic layers were dried (Na2SO4) and concen-
trated, and the residue was chromatographed (silica gel, 2% Et3N, 5 f
Allosamidin Heptaacetate (62). Pseudotrisaccharide 61 (215 mg,
0.154 mmol) was treated for 4 h with 5% concentrated aqueous HCl
in methanol (10 mL), and the mixture was quenched with saturated
aqueous K2CO3, diluted with dichloromethane (100 mL), dried
(Na2SO4), filtered through Celite, and concentrated. To a -78 °C
solution of this residue in THF (2 mL) and ammonia (25 mL) were
added small pieces of sodium until a deep blue color was maintained
for 1 h. The mixture was quenched with solid NH4Cl and then
concentrated with a stream of nitrogen. The residue was acetylated
for 2 days with pyridine (5 mL) and acetic anhydride (2 mL),
concentrated under reduced pressure, and extracted from 0.5 M aqueous

9538 J. Am. Chem. Soc., Vol. 118, No. 40, 1996
Griffith and Danishefsky
IR (KBr) υmax 3370 (v br), 2920, 1650, 1545, 1410, 1375, 1060 cm-1
Na2CO3 (100 mL) with dichloromethane (2 × 100 mL). The combined
organic layers were dried (Na2SO4) and concentrated, and the residue
was chromatographed (silica gel, 1% Et3N, 1 f 5 f 10 f 15%
methanol in ethyl acetate) to provide material which was extracted from
0.5 M aqueous Na2CO3 (15 mL) with dichloromethane (3 × 8 mL).
The combined organic layers were dried (Na2SO4) and concentrated to
afford allosamidin heptaacetate (62; 50.1 mg, 36%) as a colorless
glass: [R]D -35.1° (c 0.9, CH2Cl2); IR (KBr) υmax 3380 (br), 2940,
;
1H NMR (490 MHz, D2O + 0.5% CD3CO2D) δ 5.38 (dd, J ) 8.8, 4.9
Hz, 1 H, H-1), 4.79 (d, J ) 8.6 Hz, 1 H, H-1′′), 4.78 (d, J ) 8.4 Hz,
1 H, H-1′), 4.38 (dd, J ) 8.8, 4.2 Hz, 1 H, H-2), 4.35 (t, J ) 2.8 Hz,
1 H, H-3′), 4.29 (t, J ) 5.0 Hz, 1 H, H-3), 4.06 (t, J ) 2.9 Hz, 1 H,
H-3′′), 3.93-2.67 (m, 12 H), 3.62 (dd, J ) 12.0, 6.6 Hz, 1 H, H-6′),
3.09 (s, 3 H, NCH3Me), 3.08 (s, 3 H, NCH3Me), 3.67-3.62 (m, 1 H,
H-5), 2.08 (s, 3 H, NHCOCH3), 2.06 (s, 3 H, NHCOCH3); 13C NMR
(123 MHz, D2O + 0.5% CD3CO2D) δ 174.0, 173.8, 160.6, 100.6, 99.9,
86.8, 85.0, 80.5, 76.9, 73.6, 72.6, 70.1, 69.0, 66.4, 64.2, 61.0, 60.9,
59.2, 52.9, 52.6, 51.4, 37.6, 37.4, 22.0; HRMS (FAB) calcd for
C25H43N4O14 (M + H+) 623.2776, found 623.2816.
1
1745, 1655, 1370, 1230, 1045 cm-1; H NMR (490 MHz, CD2Cl2) δ
6.30 (d, J ) 8.3 Hz, 2 H, NH), 5.63 (t, J ) 3.0 Hz, 1 H, H-3′), 5.48
(t, J ) 2.9 Hz, 1 H, H-3′′), 5.13 (dd, J ) 6.7, 3.7 Hz, 1 H, H-3), 4.81
(dd, J ) 10.3, 2.9 Hz, 1 H, H-4′′), 4.75 (dd, J ) 8.8, 6.4 Hz, 1 H,
H-1), 4.65 (d, J ) 7.7 Hz, 1 H, H-1′), 4.57 (dd, J ) 11.9, 3.8 Hz, 1 H,
H-6′), 4.57 (d, J ) 8.6 Hz, 1 H, H-1′′), 4.45 (dd, J ) 11.6, 4.9 Hz, 1
H, H-6), 4.16 (dd, J ) 8.8, 3.6 Hz, 1 H, H-2), 4.12-3.98 (m, 7 H),
3.91 (dt, J ) 8.7, 3.4 Hz, 1 H, H-5′), 3.77 (dd, J ) 9.8, 6.7 Hz, 1 H,
H-4), 3.64 (dd, J ) 9.0, 3.3 Hz, 1 H, H-4′), 2.88 (s, 6 H, N(CH3)2),
2.45-2.39 (m, 1 H, H-5), 2.15 (s, 3 H, COCH3), 2.15 (s, 3 H, COCH3),
2.11 (s, 3 H, COCH3), 2.10 (s, 3 H, COCH3), 2.07 (s, 3 H, COCH3),
2.06 (s, 3 H, COCH3), 1.93 (s, 3 H, COCH3), 1.92 (s, 3 H, COCH3),
1.89 (s, 3 H, COCH3); 13C NMR (63 MHz, CD2Cl2) δ 171.8, 171.6,
171.1, 170.4, 170.1, 170.0, 167.7, 169.5, 162.0, 100.4, 99.0, 82.6, 81.8,
80.2, 74.4, 72.5, 72.3, 70.4, 69.8, 67.0, 63.0, 62.8, 61.1, 51.8, 51.1,
49.3, 37.7, 30.0, 23.0, 22.9, 21.3, 21.1, 21.1, 21.0, 20.8, 20.7, 20.6;
MS (FAB) m/e (rel intensity) 919 (12), 918 (47), 917 (M + H+, 100),
307 (18), 301 (12), 289 (10), 245 (46), 225 (16); HRMS (FAB) calcd
for C39H57N4O21 (M + H+) 917.3515, found 917.3553.
Acknowledgment. This work was supported financially by
the National Institutes of Health (PHS Grant HL 25848). We
gratefully thank Prof. A. Isogai for a sample of natural
allosamidin and Prof. B. M. Trost for a sample of racemic
synthetic allosamizoline. We also thank Dr. D. Dumas and Prof.
C. H. Wong for helpful discussions and for providing compound
67. Kent, Bushnell, and Dox fellowships to D.A.G. are
gratefully acknowledged. We are pleased to dedicate this paper
to the many and continuing accomplishments of Professor
Nelson Leonard.
Supporting Information Available: Experimental details
and characterizations which are not part of the pathway leading
to allosamidin are provided for compounds ent-8, ent-20, ent-
24-ent-27, 41-44, 50-58, 64, 66-71, 73-78, and 81-84 (38
pages). See any current masthead page for ordering information
and Internet access instructions.
Allosamidin (1). A stream of ammonia was passed over a
methanolic solution (15 mL) of allosamidin heptaacetate (62; 50.0 mg,
0.0545 mmol) until the solution had returned to room temperature. The
reaction was stirred for 3 days, concentrated, and chromatographed (Bio-
gel P-2 gel, water) to provide allosamidin (1; 27 mg, 79%) as a colorless
solid: mp 224f270 °C; [R]D -23.9° (c 0.5, 0.1 M acetic acid in water);
JA960526C