De novo asymmetric synthesis of anthrax tetrasaccharide and related tetrasaccharide

Article abstract of DOI:10.1021/jo800691v

(Chemical Equation Presented) A de novo asymmetric approach to the natural product anthrax tetrasaccharide 1 and an analogue 2 with an anomeric hexyl azide group has been developed from acetylfuran. The construction of the tetrasaccharide was achieved by

Full text of DOI:10.1021/jo800691v

VOLUME 73, NUMBER 14
July 18, 2008
Copyright 2008 by the American Chemical Society
De Novo Asymmetric Synthesis of Anthrax Tetrasaccharide and
Related Tetrasaccharide
Haibing Guo and George A. O’Doherty*
Department of Chemistry, West Virginia UniVersity, Morgantown, West Virginia 26506
george.odoherty@mail.wVu.edu
ReceiVed March 27, 2008
A de novo asymmetric approach to the natural product anthrax tetrasaccharide 1 and an analogue 2 with
an anomeric hexyl azide group has been developed from acetylfuran. The construction of the tetrasaccharide
was achieved by a traditional [3 + 1] glycosylation strategy. An iterative diastereoselective palladium-
catalyzed glycosylation, Luche reduction, diastereoselective dihydroxylation, and regioselective acylation
were employed for the assembly of the L-rhamno-trisaccharide building block. The anthrose building
block also required a palladium-catalyzed azide allylation and a triflate inversion to set the gluco-
stereochemistry in addition to Luche reduction and dihydroxylation.
Introduction
as a biological weapon. Therefore, it is highly desirable to
develop an effective and inexpensive vaccine as well as a
method to detect this dangerous bacterium.
Bacillus anthracis, one of the most well-known members of
the Bacillaceae family, is a Gram-positive, spore-forming
bacterium which when inhaled causes anthrax, a fatal infectious
disease in humans and other mammals.1 Like most bacteria of
Bacillus species, B. anthracis forms endospores. The mature
spore exhibits high resistance to harsh chemicals, desiccation,
extreme temperatures, radiation, and physical damage, which
allows the spore to persist in soil for many years.2 These same
Bacillus anthracis properties make for the potential for its use
Anthrax tetrasaccharide 1 (Figure 1) was isolated from the
surface of the exosporium glycoprotein BC1A of B. anthracis
by Turnbough, who also elucidated its structure in 2004.3 The
structure of anthrax tetrasaccharide 1 consists of three L-
rhamnose sugars and a D-sugar, called anthrose, which is unique
to B. anthracis and not found in other spores Bacillus species.
Because of its unique structure and the general resistance to
evolutionary change of carbohydrates, the anthrax tetrasaccha-
ride 1 has become a target for anthrax detection. Similarly,
carrier protein conjugates of the anthrax tetrasaccharide are
desired for anthrax vaccine development.4 Since the first
(1) (a) Mock, M.; Fouet, A. Annu. ReV. Microbiol. 2001, 55, 647–671. (b)
Sylvestre, P.; Couture-Tosi, E.; Mock, M. Mol. Microbiol. 2002, 45, 169–178.
(2) (a) Nicholson, W. L.; Munakata, N.; Horneck, G.; Melosh, H. J.; Setlow,
P. Microbiol. Mol. Biol. ReV. 2000, 64, 548–572.
(3) Daubenspeck, J. M; Zeng, H.; Chen, P.; Dong, S.; Steichen, C. T; Krishna,
N. R.; Pritchard, D. G.; Turnbough, C. L., Jr J. Biol. Chem. 2004, 279, 30945–
30953.
(4) Tamborrini, M.; Werz, D. B.; Frey, J.; Pluschke, G.; Seeberger, P. H.
Angew. Chem., Int. Ed. 2006, 45, 6581–6582.
10.1021/jo800691v CCC: $40.75
Published on Web 06/19/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 5211–5220 5211

Guo and O’Doherty
SCHEME 2. First-Generation Approach to Anthrose
Monosaccharide Building Block 18
FIGURE 1. Anthrax tetrasaccharide 1 and analogue 2.
SCHEME 1. Retrosynthetic Analysis of Anthrax
Tetrasaccharide 1 and Analogue 2
synthesis of an anthrax tetrasaccharide analogue by Seeberger,5
several carbohydrate approaches to the anthrax tetrasaccharide
and related tri- and pentasaccharides have been reported.6 These
routes featured the traditional carbohydrate approaches to draw
their stereochemistry from the known rare D-fucose, D-galactose,
or less common sugar L-rhamnose as a precursor. Previously,
we have been investigating a de novo asymmetric methodology
and its application to synthesize mono-, di-, and oligosaccharides
via palladium-catalyzed reaction.7 Herein, we describe the full
account of our successful de novo asymmetric synthesis of
anthrax tetrasaccharide 1 as well as the anthrax tetrasac-
charide analogue 2.8 The terminal hexyl azide group of
tetrasaccharide analogue 2 could serve as a point of attachment
(e.g., carrier protein conjugation for vaccine development). This
de novo asymmetric strategy features iterative use of palladium-
catalyzed glycosylation and starts from commercially available
and inexpensive acetylfuran.
glycosylation of trisaccharides 5 or 6 with imidate 7. The
trisaccharides 5 and 6 could be assembled from pyranone 8
building block via iterative use of diasteroselective palladium-
catalyzed glycosylation, Luche reduction, and Upjohn dihy-
droxylation. Eventually, the pyranone 8 and its enantiomer could
be obtained from the achiral starting material acetylfuran 9
through asymmetric Noyori reduction and Achmatowicz oxida-
tive ring expansion.
Results and Discussion
Our approach to the anthrose monosaccharide building block
began with our efforts to introduce the D-stereochemistry of the
anthrose sugar, which could be derived from the (R)-furyl
alcohol 10. Previously, we have shown that either the (R)- or
(S)-furyl alcohol could be readily derived by an asymmetric
Noyori reduction9 of commercially available starting material
acetylfuran 9 (Scheme 2). Noyori reduction of acetylfuran 9
produced the enantiomerically pure (>96% ee)10 furfuryl alcohol
10, which was subsequently exposed to oxidative rearrangement
under typical Achmatowicz conditions (NBS/H2O)11 resulting
in the formation of a ring-expanded hemiacetal 11. The anomeric
Our de novo approach to anthrax tetrasaccharide and its
analogue is outlined in Scheme 1. We envisioned the anthrax
tetrasaccharides 1 or 2 could be prepared from tetrasaccharides
3 or 4 respectively, which in turn could be derived from the
(5) Werz, D. B.; Seeberger, P. H. Angew. Chem., Int. Ed. 2005, 44, 6315–
6318.
(6) (a) Adamo, R.; Saksena, R.; Kovac., P. Carbohydr. Res. 2005, 340, 2579–
2582. (b) Saksena, R.; Adamo, R.; Kovac, P. Bioorg. Med. Chem. Lett. 2006,
16, 615–617. (c) Adamo, R.; Saksena, R.; Kovac, P. HelV. Chim. Acta 2006,
89, 1075–1089. (d) Mehta, A. S.; Saile, E.; Zhong, W.; Buskas, T.; Carlson, R.;
Kannenberg, E.; Reed, Y.; Quinn, C. P.; Boons, G.-J. Chem. Eur. J. 2006, 12,
9136–9149. (e) Crich, D.; Vinogradova, O. J. Org. Chem. 2007, 72, 6513–6520.
(f) Werz, D. B.; Adibekian, A.; Seeberger, P. H. Eur. J. Org. Chem. 2007, 1976–
1982.
(9) (a) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1996, 118, 2521–2522. (b) Noyori, R.; Ohkuma, T. Angew. Chem.,
Int. Ed. 2001, 40, 40–73.
(10) The absolute stereochemistry and the level of enantioexcess of 10 and
its enantiomer ent-10 were determined by the method of Mosher; see: (a) Sullivan,
G. R.; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973, 38, 2143–2147. (b)
Yamaguchi, S.; Yasuhara, F.; Kabuto, K. T. Tetrahedron 1976, 32, 1363–1367.
Similarly, the optical activity for these products was consistent with that reported
in the literature; see: (d) Drueckhammer, D. G.; Barbas, C. F., III; Nozoki, K.;
Wong, C.-H.; Wood, C. Y.; Ciufolini, M. A J. Org. Chem. 1993, 58, 4511–
4512.
(7) (a) Babu, R. S.; O’Doherty, G. A. J. Am. Chem. Soc. 2003, 125, 12406–
12407. (b) Babu, R. S.; Zhou, M.; O’Doherty, G. A. J. Am. Chem. Soc. 2004,
126, 3428–3429.
(8) A portion of this work was originally communicated; see:(a) Guo, H.;
O’Doherty, G. A. Angew. Chem., Int. Ed. 2007, 46, 5206–5208.
5212 J. Org. Chem. Vol. 73, No. 14, 2008

Asymmetric Synthesis of Anthrax
SCHEME 3. Syntheses of Anthrose Monosaccharide
Building Blocks 5 and 24
alcohol of hemiacetal 11 was converted to Boc-pyranone ent-8
with a diastereoselectivity of 3:1 (R/ꢀ) by treatment with Boc2O
at -78 °C.12 It is worth noting that this route provides Boc-
pyranone ent-8 in 60% overall yield (three steps) with only one
chromatographic purification and this route is also reliable on
scales as large as 100 g for both Boc-pyranone ent-8 and its
enantiomer 8. Palladium-catalyzed glycosylation (Pd(0)/PPh3,
1:2) of the pyranone ent-8 with either methanol or p-methoxy-
benzyl alcohol afforded pyranones 12a and 12b as single
diastereomers, both in excellent yields (82% and 96%, respec-
tively). Diastereoselective Luche reduction (NaBH4/CeCl3)13 of
both 12a and 12b gave allylic alcohols 13a and 13b, which
were treated with methyl chloroformate in the presence of a
catalytic amount of DMAP to deliver allylic carbonates 14a
and 14b in good yields for the two steps (68% and 92%,
respectively). The methyl carbonates 14a and 14b underwent
Pd-catalyzed azide allylation to regio- and stereoselectively
generate allylic azide products 15a and 15b (TMSN3, (allyl-
PdCl)2/DPPB, 82% and 93%, respectively).14 Exposing the
allylic azides 15a and 15b to the Upjohn conditions (OsO4/
NMO)15 afforded the diols 16a and 16b with manno-stereo-
chemistry in excellent yields (96% and 98%, respectively).
Regioselective protection of the equatorial hydroxyl group of
16a yielded PMB-ether 17 via a tin acetal intermediate (93%).16
Finally, we attempted to prepare the anthrose monosaccharide
precursor with an anomeric floride by employing the procedure
developed by Nicolaou.17 Unfortunately, we did not observe
any sign of desired product 18. Thus, we turned our attention
to an alternative approach to prepare an anthrose monosaccha-
ride building block (Scheme 3).
SCHEME 4. Enantioselective Synthesis of Monosaccharide
Ley-spiroketal 28
The alternative approach to anthrose monosaccharide building
block started from ent-8. Tin-mediated selective protection of
the equatorial hydroxyl group at the C-4 of 16b afforded the
benzyl ether 19 in excellent yield (99%). To install the gluco-
stereochemistry of the anthrose precursor 21 from 19, an
inversion of the C-2 axial alcohol was required. Unfortunately,
all efforts to directly convert 19 to 22 by a Mitsunobu inversion
were unsuccessful. Instead, the free hydroxyl group of 19 was
treated with triflic anhydride and pyridine to form triflate 20,
which was subsequently subjected to SN2-type displacement
(NaNO2/DMF) to provide equatorial alcohol 21 in 56% yield.6a,18
Esterification of the C-2 alcohol in 21 (LevOH/DCC/DMAP),
followed by an oxidative PMB deprotection (DDQ/H2O),
resulted in anomeric alcohol 23 in good yield (85%, two steps).
Eventually, the two glycosyl donors imidate 7 and phosphate
24 were synthesized by treatment of the anomeric alcohol of
23 with trichloroacetonitrile (40% NaH) and diphenyl chloro-
phosphate (2 equiv of DMAP), respectively (7: 83%, 24: 89%).
With the D-anthrose monosaccharide precursor in hand, we
proceeded to the synthesis of L-rhamno-trisaccharide building
block. The assembly of L-rhamno-monosaccharide moiety 28
(Scheme 4) also started from the inexpensive acetylfuran 9.
Noyori asymmetric reduction of acetylfuran followed by Ach-
matowicz oxidative rearrangement afforded hemiacetal ent-11,
which was acylated with Boc2O to provide Boc-pyranone 8
(60%, three steps). Exposure of the Boc-pyranone and benzyl
alcohol to our palladium-catalyzed glycosylation conditions
(0.25% Pd(0)/ 0.5% PPh3) generated the benzyl pyranone 25
in excellent yield (90%) and with complete retention of
stereochemistry. Diastereoselective reduction of the ketone 25
via Luche procedures (NaBH4/CeCl3) gave allylic alcohol 26
(89%) which was subsequently dihydroxylated using Upjohn
conditions to form rhamno-stereochemistry triol 27 in excellent
yield (94%). Selective protection of the C-3/C-4 diequatorial
(11) (a) Achmatowicz, O.; Bielski, R. Carbohydr. Res. 1977, 55, 165–176.
For its recent use in carbohydrate synthesis, see:(b) Guo, H.; O’Doherty, G. A.
Org. Lett. 2005, 7, 3921–3924.
(12) The relative stereochemistry and the level of diastereoselective induction
were determined by analysis of the allylic coupling constants in the 1H NMR
spectra; see:(a) Babu, R. S.; Guppi, S. R.; O’Doherty, G. A. Org. Lett. 2006, 8,
1605–1608. (b) Guppi, S. R.; O’Doherty, G. A. J. Org. Chem. 2007, 72, 4966–
4969.
(13) (a) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226–2227. (b) Haukaas,
M. H.; O’Doherty, G. A. Org. Lett. 2001, 3, 401–404. (c) Abrams, J. N.; Babu,
R. S.; Guo, H.; Le, D.; Le, J.; Osbourn, J. M.; O’Doherty, G. A. J. Org. Chem.
2008, 73, 1935–1940.
(14) (a) de Oliveira, R. N.; Cottier, L.; Sinou, D.; Srivastava, R. M.
Tetrahedron 2005, 61, 8271–8281. (b) Guo, H.; O’Doherty, G. A. Org. Lett.
2006, 8, 1609–1612. (c) Guo, H.; O’Doherty, G. A. Tetrahedron 2008, 64, 304–
313.
(15) (a) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
17, 1973–1976. (b) Shan, M.; O’Doherty, G. A. Org. Lett. 2006, 8, 5149–5152.
(16) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 17,
1973-1976.
(17) Nicolaou, K. C.; Ladduwahetty, T.; Randall, J. L.; Chucholowski, A.
J. Am. Chem. Soc. 1986, 108, 2466–2467.
(18) Wyn, D.; Jones, C.; Nash, R. J.; Bell, E. A.; Williams, J. M. Tetrahedron
Lett. 1985, 26, 3125–3126.
J. Org. Chem. Vol. 73, No. 14, 2008 5213

Guo and O’Doherty
SCHEME 6. Synthesis of Trisaccharide 40 via
SCHEME 5. Synthesis of Disaccharide 35 via
Palladium-Catalyzed Glycosylation
Palladium-Catalyzed Glycosylation
catalyzed glycosylation of disaccharide 35 with Boc-pyranone
8 followed by Luche reduction provided allylic alcohol 37 in
excellent yield (84%, two steps). The equatorial alcohol of 37
was protected with acetic anhydride to generate acetate which
subsequently underwent Upjohn dihydroxylation to give diol
38 in excellent yield (93%, two steps). Finally, the trisaccharide
40 was furnished through orthoester formation and regiospecific
hydrolysis of diol 38 by treatment with trimethyl orthoacetate
and acetic acid (95%). The tetraacetate trisaccharide could also
be synthesized by a two-step procedure. Upjohn dihydroxylation
of allylic alcohol 37 followed by regioselective acylation yielded
the trisaccharide 40 with excellent yield (91%).
To efficiently synthesize the tetrasaccharide 41 (Scheme 7),
a traditional glycosylation approach was employed for the
coupling of building blocks trisaccharide 40 and monosaccharide
7 or 24. However, any attempt at glycosylation of trisaccharide
40 with either phosphate 24 or imidate 7 failed to form
tetrasaccharide 41; instead, the Ley-spiroketal protecting group
was removed under these Lewis acidic conditions (e.g., 10%
TMSOTf).
hydroxyl groups by the Ley-spiroketal procedure19 furnished
the Ley-spiroketal monosaccharide 28 in 88% yield.
Encouraged by the successful synthesis of monosaccharide
28, we next employed the same strategy for the synthesis of
disaccharide 35 (Scheme 5). Monosaccharide 28 was glycosy-
lated with Boc-pyranone 8 to yield the pyranone 29 as a single
isomer in the presence of Pd(0) and PPh3 (86%). Luche
reduction of pyranone 29, followed by diastereoselective dihy-
droxylation resulted in triol 31 in excellent overall yield (84%,
two steps). The C-2/C-4 hydroxyl groups of triol 31 were
protected as diacetate 35 via orthoester formation, acylation (32
to 33), and regioselective ring opening (33 to 35, via 34) in
excellent yield (97%). Specifically, the triol 31 was treated with
trimethyl orthoacetate in the presence of catalytic amount of
TsOH to selectively protect the C-2/C-3 cis-hydroxyl group to
an orthoester 32. The remaining free alcohol was converted to
intermediate acetate 33 by treatment with Ac2O. Regiospecific
acidic hydrolysis of the five-membered ring orthoester 33
afforded diacetate 35 through intermediate 34.20
To prepare the more acid-stable glycosyl acceptor trisaccha-
ride 5, we decided to switch the Ley-spiroketal protecting group
SCHEME 7. Attempted Synthesis of Tetrasaccharide 41 via
Glycosylation
Analogously, the tetraacetate trisaccharide 40 (Scheme 6) was
prepared by a sequence of reactions involving palladium-
catalyzed glycosylation, Luche reduction, Upjohn dihydroxy-
lation, and regioselective acylation. Once again, palladium-
(19) (a) Ley, S. V.; Woods, M.; Zanotti-Gerosa, A. Synthesis 1992, 52–54.
(b) Ley, S. V.; Leslie, R.; Tiffin, P. D.; Woods, M. Tetrahedron Lett. 1992, 33,
4767–4770.
(20) (a) King, J. F.; Allbutt, A. D. Can. J. Chem. 1970, 48, 1754–1769. (b)
Tsvetkov, Y. E.; Shashkov, A. S.; Knirel, Y. A.; Zahringer, U. Carbohydr. Res.
2001, 335, 221–243.
5214 J. Org. Chem. Vol. 73, No. 14, 2008

Asymmetric Synthesis of Anthrax
TABLE 1. Synthesis of Tetrasaccharides 3 and 4
SCHEME 8. Synthesis of Trisaccharide 5
SCHEME 9. Synthesis of Trisaccharides 6a and 6b
acceptor
donor
product
yield (%)
5
6a
5
7
7
24
3
4
3
90
82
85
in the presence of Ag2O, delivered the methyl ethers 47 and 48
in excellent yields (47: 90%, and 48: 87%, two steps). It is worth
mentioning that we found it was very difficult to prepare the
methyl ether in the presence of all the acetate groups. After
failing screening various solvents, bases, and methyl source for
the methylation, we found the use of neat methyl iodide as
solvent and Ag2O as base were the optimal conditions.5 A one-
SCHEME 10. Completion of Anthrax Tetrasaccharide (1)
and Its Analogue (2)
to acetates. The equatorial alcohol of 40 (Scheme 8) was coupled
with levulinic acid in presence of DCC and DMAP to produce
the levulinate. Hydrolysis of the Ley-spiroketal (TFA/H2O)
provided the diol 42, which was subsequently subjected to
acylation with Ac2O to afford hexaacetate 43. Finally, removal
of the levulinate protecting group by treatment with hydrazine
acetate generated the free alcohol of trisaccharide 5 in excellent
overall yield for four steps (91%). Having these acid stable
protecting groups in 43 allowed for the synthesis of the
trisaccharides 6a and 6b with the appropriate side chains for
protein conjugation (Scheme 9). Hydrogenolysis of the benzyl
ether of 43 formed the hemiacetal 44, which was converted to
imidate 45 at room temperature (Cl3CN/NaH(cat.)) in good yield
(75%, two steps). Glycosylation of imidate 45 with 6-benzoxy-
lhexanol or 6-(4-methoxybenzyloxy)hexanol by traditional gly-
cosylation approach led to trisaccharides 46a and 46b in good
yields (46a: 82%, 46b: 86%, R/ꢀ ) 10:1 for both reactions).
Eventually, the acid stable trisaccharide 6a and 6b were
synthesized by deprotection of the levulinate protecting group.
Once again glycosylation of trisaccharides 5 and 6a with either
monosaccharides 24 or 7 delivered the corresponding tetrasac-
charides 3 or 4 in excellent yields (82-90%) (Table 1). In both
of these glycosylations, the C-2 levulinate groups in monosac-
charides 5 and 6a were used as an anchimeric direction groups
to ensure ꢀ-selectivity.
Deprotection of levulinate protecting groups in 3 and 4
(Scheme 10), followed by an etherification with methyl iodide
J. Org. Chem. Vol. 73, No. 14, 2008 5215

Guo and O’Doherty
resulting mixture was extracted with CH2Cl2 (3 × 200 mL), dried
(Na2SO4), and concentrated under reduced pressure. The crude
product was purified using silica gel flash chromatography eluting
with 5% EtOAc/hexane to give 2.70 g (13.35 mmol, 75%) of
carbonate 14a as a colorless oil: Rf (30% EtOAc/hexane) ) 0.67;
[R]25D ) +178 (c ) 1.1, CH2Cl2); IR (thin film, cm-1) 2981, 2959,
pot condition has been employed to reduce the azides 47 and
48 to amines along with global deprotection of the acetate groups
to generate the free alcohol (PEt3/LiOH/H2O). Selective peptide
coupling of primary amine and 3-hydroxy-3-methylbutanioc acid
(HBTU/Et3N) afforded amides 49 and 50 in excellent yields
(86% for both 49 and 50 in two steps). Removal of the benzyl
groups in 49 and 50 under the hydrogenolysis conditions (H2,
Pd/C) provided the natural product anthrax tetrasaccharide 1
and 6-hydroxyhexyloxyl anthrax tetrasaccharide 51 in excellent
yields (1: 96%, and 51: 97%). Synthetic tetrasaccharide 1 had
identical spectra data as the isolated natural material.3 Finally,
an anthrax tetrasaccharide analogue 2 was also achieved by a
two-step procedure. Selective mesylation of primary alcohol 51,
followed by SN2-type displacement with NaN3 produced the
6-azidohexyloxyl anthrax tetrasaccharide 2 (50%), which should
be ready for conjugation to carrier protein and anthrax detector/
vaccine development.
1
2900, 1746, 1442, 1253, 1052, 1024, 962; H NMR (600 MHz,
CDCl3) δ 5.90 (d, J ) 10.2 Hz, 1H), 5.80 (ddd, J ) 10.2, 3.0, 1.8
Hz, 1H), 4.84 (ddd, J ) 9.6, 3.0, 1.8 Hz, 1H), 4.82 (d, J ) 1.8 Hz,
1H), 3.92 (dq, J ) 9.0, 6.6, 1H), 3.77 (s, 3H), 3.40 (s, 3H), 1.25
(d, J ) 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 155.4, 129.2,
128.0, 95.4, 74.6, 64.6, 55.8, 55.0, 17.9; CIHRMS calcd for
[C9H14O5Na+] 225.0739, found 225.0738.
(2R,3S,6S)-3-Azido-3,6-dihydro-6-methoxy-2-methyl-2Hpyran
(15a). To a stirring solution of carbonate 14a (1.3 g, 6.4 mmol),
allylpalladium chloride dimer (25 mg, 1.0 mmol %), and 1,4-
bis(diphenylphosphino)butane (110 mg, 4.0 mmol %) in dry THF
(6.4 mL) was added TMSN3 (1.27 mL, 9.6 mmol) under argon
atmosphere. The reaction mixture was stirred at room temperature
for 0.5 h, solvent was evaporated under reduced pressure, and the
product was purified using silica gel flash chromatography eluting
with 3% EtOAc/hexane to give 886 mg (5.25 mmol, 82%) of allylic
Conclusions
azide 15a as colorless oil: Rf (20% EtOAc/hexane) ) 0.70; [R]25
D
In conclusion, a highly enantio- and diastereocontrolled
approach to natural product anthrax tetrasaccharide 1 as well
as its analogue 2 has been developed in a convergent [3 + 1]
manner, where both the mono- and trisaccharide fragments were
assembled from achiral starting materials by use of asymmetric
catalysis. This de novo asymmetric route illustrates the utilities
of Noyori reduction, palladium-catalyzed glycosylation, pal-
ladium-catalyzed azide allylation, diastereoselective dihydroxy-
lation, Luche reduction, and selective acylation. The anthrax
tetrasaccharide 1 was achieved in 25 steps and 13% overall yield
from achiral starting material acetylfuran 9, which has compa-
rable efficiency to previous carbohydrate approaches. Further
application of this approach to the synthesis of various analogues
and biological activity testing is ongoing.
) +186 (c ) 0.5, CH2Cl2); IR (thin film, cm-1) 2979, 2934, 2898,
2094, 1398, 1189, 1049, 963; 1H NMR (600 MHz, CDCl3) δ 5.96
(d, J ) 10.2 Hz, 1H), 5.89 (ddd, J ) 10.2, 3.0, 1.8 Hz, 1H), 4.84
(d, J ) 1.2 Hz, 1H), 3.80 (dq, J ) 9.6, 6.6, 1H), 3.54 (dd, J ) 9.6,
1.8 Hz, 1H), 3.43 (s, 3H), 1.35 (d, J ) 6.6 Hz, 3H); 13C NMR
(150.8 MHz, CDCl3) δ 128.7, 128.5, 95.3, 65.9, 60.3, 55.8, 18.6;
CIHRMS calcd for [C7H11N3O2Na+] 192.0743, found 192.0749.
(2S,3R,4S,5S)-5-Azidotetrahydro-2-methoxy-6-methyl-2H-pyran-
3,4-diol (16a). To a 2-methyl-2-propanol/acetone (22.8 mL, 1:1 (v/
v)) solution of allylic azide 15a (1.92 g, 11.4 mmol) at 0 °C was
added a solution of N-methylmorpholine N-oxide/water (50% w/v,
11.4 mL). Crystalline OsO4 (29 mg, 1 mol %) was added, and the
reaction was allowed to stir for 18 h. The reaction mixture was
quenched with 50 mL of saturated Na2S2O3 solution, extracted with
EtOAc (3 × 200 mL), dried (Na2SO4), concentrated under reduced
pressure, and then purified using silica gel flash chromatography
eluting with 50% EtOAc/hexane to afford diol 16a (2.13 g, 10.9
mmol, 96%): Rf ) 0.20 (50% EtOAc/hexane); mp ) 83-85 °C;
[R]25D ) + 114 (c ) 1.0, CH2Cl2); IR (thin film, cm-1) 3387, 2978,
2937, 2837, 2109, 1613, 1385, 1131, 1061, 95, 967; 1H NMR (600
MHz, CDCl3) δ 4.66 (d, J ) 1.2 Hz, 1H), 3.88 (dd, J ) 3.6, 1.2
Hz, 1H), 3.81 (dd, J ) 9.6, 3.6 Hz, 1H), 3.74 (s, 1H), 3.72 (s, 1H),
3.54 (dq, J ) 9.6, 6.6, 1H), 3.32 (s, 3H), 3.29 (dd, J ) 9.6, 9.6 Hz,
1H), 1.33 (d, J ) 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ
100.7, 70.4, 70.1, 66.7, 65.6, 55.0, 18.3; CIHRMS calcd for
[C7H13N3O4Na+] 226.0804, found 226.0803.
Experimental Section21
(2R,3S,6S)-3,6-Dihydro-6-methoxy-2-methyl-2H-pyran-3-ol (13a).
A solution of pyranone 12a (3.6 g, 25.4 mmol) in dry CH2Cl2 (25.4
mL) and 0.4 M CeCl3/MeOH (25.4 mL) was cooled to -78 °C.
NaBH4 (985 mg, 25.4 mmol) was added, and the reaction mixture
was stirred for 4 h at -78 °C. The resulting solution was diluted
with Et2O (300 mL) and was quenched with 150 mL of saturated
NaHCO3, extracted (3 × 300 mL) with Et2O, dried (Na2SO4),
and concentrated under reduced pressure. The crude product was
purified using silica gel chromatography eluting with 20% EtOAc/
hexane to give 3.32 g (23.1 mmol, 91%) of allylic alcohol 13a as
a colorless oil: Rf ) 0.26 (30% EtOAc/hexane); [R]25D ) +104 (c
) 1.5, CH2Cl2); IR (thin film, cm-1) 3396, 2975, 2934, 2894, 1449,
1399, 1040, 960; 1H NMR (600 MHz, CDCl3) δ 5.92 (d, J ) 10.2
Hz, 1H), 5.73 (ddd, J ) 10.2, 3.0, 1.8 Hz, 1H), 4.81 (d, J ) 1.8
Hz, 1H), 3.79 (dd, J ) 9.0, 6.6 Hz, 1H), 3.67 (m, 1H), 3.42 (s,
(2S,3R,4S,5R)-4-(4-Methoxybenzyloxy)-5-azidotetrahydro-2-
methoxy-6-methyl-2H-pyran-3-ol (17). A stirring mixture of diol
16a (363 mg, 1.79 mmol) and n-Bu2SnO (459 mg, 1.84 mmol) in
toluene (26 mL) was refluxed for 3 h. After the mixture was cooled
to room temperature, CsF (330 mg), tetrabutylammonium iodide
(726 mg, 1.97 mmol), and PMBBr (0.22 mL, 1.87 mmol) were
added, and the mixture was refluxed for 2 h. The solution was
cooled to room temperature. The reaction mixture was diluted in
100 mL of saturated NaHCO3 solution and then extracted with ethyl
ether (3 × 100) and dried (Na2SO4). The extraction was concen-
trated under reduced pressure and then purified using silica gel
chromatography eluting with 25% EtOAc/hexane to give PMB-
ether 17 (538 mg, 1.66 mmol, 93%) as a colorless oil: Rf ) 0.32
(40% EtOAc/hexane); [R]25D ) +123 (c ) 1.8, CH2Cl2); IR (thin
film, cm-1) 3457, 2935, 2836, 2110, 1612, 1513, 1246, 1063, 995,
818; 1H NMR (600 MHz, CDCl3) δ 7.31 (d, J ) 8.4 Hz, 2H), 6.90
(d, J ) 8.4 Hz, 2H), 4.68 (d, J ) 1.2 Hz, 1H), 4.62 (d, J ) 11.4
Hz, 1H), 4.58 (d, J ) 11.4 Hz, 1H), 3.93 (dd, J ) 3.6, 1.2 Hz,
1H), 3.80 (s, 3H), 3.68 (dd, J ) 9.6, 3.6 Hz, 1H), 3.49 (dq, J )
9.6, 6.6 Hz, 1H), 3.38 (dd, J ) 9.6, 9.6 Hz, 1H), 3.33 (s, 3H), 2.59
3H), 1.92 (d, J ) 1.8 Hz, 1H, OH), 1.32 (d, J ) 6.6 Hz, 3H); 13
C
NMR (150.8 MHz, CDCl3) δ 140.0, 126.0, 95.3, 69.4, 67.9, 55.5,
17.9.
(2R,3S,6S)-6-(4-Methoxy)-3,6-dihydro-2-(methyl)-2H-pyran-3-
yl Methyl Carbonate (14a). To a stirring solution of allylic alcohol
13a (2.6 g, 17.8 mmol), pyridine (17.8 mL), and DMAP (769 mg,
6.3 mmol) in dry CH2Cl2 (173 mL), was dropwise added methyl
chloroformate (5.03 mL, 71.2 mmol) at 0 °C. After the reaction
proceeded for 1 h at 0 °C, water (100 mL) was added, and the
(21) Presented in this Experimental Section are the experimental procedures
and spectral data for the new compounds required for the synthesis of the anthrax
tetrasaccharide and its analogue. Complete experimental procedures and spectral
data for all compounds are presented in the Supporting Information.
5216 J. Org. Chem. Vol. 73, No. 14, 2008

Asymmetric Synthesis of Anthrax
(s, 1H, OH), 1.32 (d, J ) 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3)
δ 159.6, 129.8, 128.6, 114.0, 100.2, 78.0, 71.6, 67.2, 66.5, 63.9,
55.3, 55.0, 18.3; CIHRMS calcd for [C15H21N3O5Na+] 346.1373,
found 346.1379.
NaHCO3 solution (10 mL), extracted with Et2O (3 × 50 mL), dried
(Na2SO4), concentrated under reduced pressure and purified by
passing a pad of silica gel eluting with 70% EtOAc/hexane to give
709 mg (0.712 mmol, 82%) trisaccharide 46a as white foam, mp:
57-64 °C; Rf ) 0.59 (70% EtOAc/hexane); [R]25 ) -35 (c )
(3S,4S,5S)-2-((3S,4S,5S)-2-((3S,4S,5S)-2-hydroxytetrahydro-4,5-
diacetoxy-6-methyl-2H-pyran-3-yloxy)tetrahydro-3,5-diacetoxy-6-
methyl-2H-pyran-4-yloxy)-3,5-diacetoxytetrahydro-6-methyl-2H-
pyran-4-yl 4-Oxopentanoate (44). To a solution of Bn-ether 43 (1.53
g, 1.7 mmol) in 5 mL of MeOH was added 10% Pd/C (100 mg).
The reaction suspension was stirred under a hydrogen balloon for
24 h, filtered by passing through a Celite pad, and concentrated
under reduced pressure and in vacuo to give 1.26 g of anomeric
alcohol 44 (1.56 mmol, 92%) as a white foam: mp 78-84 °C; Rf
) 0.51 (80% EtOAc/hexane); [R]25D ) -19 (c ) 1.0, CH2Cl2); IR
(thin film, cm-1) 3446, 2940, 2983, 1745, 1371, 1222, 1038, 914;
1H NMR (600 MHz, CDCl3) δ 5.28 (dd, J ) 9.6, 3.6 Hz, 1H),
5.21 (dd, J ) 3.6, 1.8 Hz, 1H), 5.16 (d, J ) 1.8 Hz, 1H), 5.15 (dd,
J ) 9.6, 3.0 Hz, 1H), 5.08 (dd, J ) 9.6, 9.6 Hz, 1H), 5.05 (dd, J
) 3.6, 1.8 Hz, 1H), 5.04 (dd, J ) 9.6, 9.6 Hz, 1H), 5.02 (dd, J )
9.6, 9.6 Hz, 1H), 4.93 (d, J ) 1.8 Hz, 1H), 4.80 (d, J ) 1.8 Hz,
1H), 4.14 (dd, J ) 9.6, 3.0 Hz, 1H), 4.06 (dq, J ) 9.6, 6.6
Hz, 1H), 4.02 (dd, J ) 3.6, 1.8 Hz, 1H), 3.89 (dq, J ) 9.0, 6.6 Hz,
1H), 3.85 (dq, J ) 9.6, 6.6 Hz, 1H), 3.06 (br., 1H, OH), 2.72 (ddd,
J ) 18.6, 8.4, 5.4 Hz, 1H), 2.61 (ddd, J ) 18.6, 6.6, 5.4 Hz, 1H),
2.51 (ddd, J ) 18.6, 8.4, 5.4 Hz, 1H), 2.43 (ddd, J ) 18.6, 6.6, 5.4
Hz, 1H), 2.15 (s, 3H), 2.13 (s, 3H), 2.11 (s, 3H), 2.08 (s, 3H), 2.07
(s, 3H), 2.03 (s, 3H), 2.02 (s, 3H), 1.21 (d, J ) 6.6 Hz, 3H), 1.20
(d, J ) 6.6 Hz, 3H), 1.15 (d, J ) 6.6 Hz, 3H);13C NMR (150.8
MHz, CDCl3) δ 206.2, 171.3, 170.5, 170.4, 170.3, 170.2 (2 C),
169.8, 99.4, 98.7, 93.3, 77.4, 74.3, 72.1, 71.4, 71.3, 70.7, 70.3, 70.1,
68.9, 67.5, 67.3, 66.4, 37.7, 29.7, 27.9, 21.0, 20.9 (2 C), 20.8 (2
C), 20.7, 17.6, 17.4, 17.2; CIHRMS calcd for [C35H50O21Na+]:
829.2737, found 829.2743.
D
1.0, CH2Cl2); IR (thin film, cm-1) 2983, 2937, 2861, 1743, 1370,
1220, 984; 1H NMR (600 MHz, CDCl3) δ 7.25-7.34 (m, 5H), 5.21
(dd,
J ) 3.6, 1.8 Hz, 1H), 5.19 (dd, J ) 9.6, 3.6
Hz, 1H), 5.17 (dd, J ) 9.6, 3.6 Hz, 1H), 5.09 (dd, J ) 9.6, 9.6 Hz,
1H), 5.06 (dd, J ) 9.6, 9.6 Hz, 1H), 5.05 (dd, J ) 3.0, 1.8 Hz,
1H), 5.00 (dd, J ) 9.6, 9.6 Hz, 1H), 4.93 (d, J ) 1.8 Hz, 1H), 4.79
(d, J ) 1.8 Hz, 1H), 4.70 (d, J ) 1.8 Hz, 1H), 4.49 (s, 2H), 4.14
(dd, J ) 9.6, 3.6 Hz, 1H), 3.96 (dd, J ) 3.0, 1.8 Hz, 1H), 3.89 (dq,
J ) 9.6, 6.6 Hz, 1H), 3.86 (dq, J ) 9.6, 6.6 Hz, 1H), 3.80 (dq, J
) 9.6, 6.6 Hz, 1H), 3.63 (dt, J ) 9.6, 6.6 Hz, 1H), 3.45 (t, J ) 6.6
Hz, 2H), 3.38 (dt, J ) 9.6, 6.6 Hz, 1H), 2.73 (ddd, J ) 18.0, 7.2,
7.2 Hz, 1H), 2.62 (ddd, J ) 18.0, 7.2, 7.2 Hz, 1H), 2.52 (ddd, J )
18.0, 6.6, 6.6 Hz, 1H), 2.43 (dd, J ) 18.0, 7.2, 6.6 Hz, 1H), 2.17
(s, 3H), 2.15 (s, 3H), 2.13 (s, 3H), 2.12 (s, 3H), 2.08 (s, 3H), 2.07
(s, 3H), 2.02 (s, 3H), 1.60 (m, 4H), 1.37 (m, 4H), 1.22 (d, J ) 6.6
Hz, 3H), 1.20 (d, J ) 6.6 Hz, 3H), 1.17 (d, J ) 6.6 Hz, 3H); 13C
NMR (150 MHz, CDCl3) δ 206.1, 171.3, 170.5, 170.3 (2 C), 170.2,
170.1, 169.8, 137.8, 128.4, 127.7, 127.6, 99.5, 99.7, 98.6, 77.4,
74.3, 73.0, 72.2, 71.5, 71.3, 70.8, 70.7, 70.4, 70.1, 68.9, 68.0, 67.4,
67.3, 66.3, 37.7, 29.8, 29.7, 29.4, 27.9, 26.1 26.0, 21.1, 21.0, 20.9,
20.86,20.8(2C),17.6,17.5,17.2;CIHRMScalcdfor[C48H68O22Na+]:
1019.4100, found 1019.4101.
(3S,4S,5S)-2-((3S,4S,5S)-2-((3S,4S,5S)-2-(6-(4-methoxybenzyloxy)-
hexyloxy)-tetrahydro-4, 5-diacetoxy-6-methyl-2H-pyran-3-yloxy)-tet-
rahydro-3, 5-diacetoxy-6-methyl-2H-pyran-4-yloxy)-3, 5-diacetoxy-
tetrahydro-6-methyl-2H-pyran-4-yl 4-oxopentanoate (46b). To a
solution of trisaccharide imidate 45 (600 mg, 0.639 mmol) and 6-(4-
methoxybenzyloxy)hexan-1-ol (305 mg, 1.28 mmol) in 2.0 mL
CH2Cl2 with molecular sieve at 0 °C was added TMSOTf (28 mg,
0.174 mmol). The reaction was stirred at 0 °C for 0.5 h, quenched
with saturated NaHCO3 solution (10 mL), extracted with Et2O (3
× 50 mL), dried (Na2SO4), concentrated under reduced pressure
and purified by passing a pad of silica gel eluting with 70% EtOAc/
hexane to give 564 mg (0.55 mmol, 86%) trisaccharide 46b; Rf )
(3S,4S,5S)-2-((3S,4S,5S)-2-((3S,4S,5S)-2-(2,2,2-trichloroacetoy-
loxy)-tetrahydro-4,5-diacetoxy-6-methyl-2H-pyran-3-yloxy)-tet-
rahydro-3,5-diacetoxy-6-methyl-2H-pyran-4-yloxy)-3,5-diacetoxy-
tetrahydro-6-methyl-2H-pyran-4-yl 4-oxopentanoate (45). To a
CH2Cl2 (7 mL) solution of alcohol 44 (1.06 g, 1.31 mmol) and
trichloroacetonitrile (7.4 mL) was added catalytic amount NaH (15
mg) at 0 °C. The reaction mixture was stirred for 1.5 h at 0 °C,
The solvent was removed under reduced pressure, and purified using
silica gel flash chromatography eluting with pure ether to give
imidate 45 (996 mg, 1.06 mmol, 81%) as colorless oil: Rf ) 0.70
(80% EtOAc/hexane); major product: IR (thin film, cm-1) 2983,
0.57 (80% EtOAc/hexane); [R]25 ) -29 (c ) 0.9, CH2Cl2); IR
D
(thin film, cm-1) 2984, 2938, 2858, 1746, 1370, 1222, 985; 1H NMR
(600 MHz, CDCl3) δ 7.24 (d, J ) 8.4 Hz, 2H), 6.87 (d, J ) 8.4
Hz, 2H), 5.22 (dd, J ) 3.6, 1.8 Hz, 1H), 5.19 (dd, J ) 9.6, 3.6 Hz,
1H), 5.16 (dd, J ) 9.6, 3.6 Hz, 1H), 5.09 (dd, J ) 9.6, 9.6 Hz,
1H), 5.06 (dd, J ) 9.6, 9.6 Hz, 1H), 5.05 (dd, J ) 3.0, 1.8 Hz,
1H), 5.00 (dd, J ) 9.6, 9.6 Hz, 1H), 4.94 (d, J ) 1.8 Hz, 1H), 4.79
(d, J ) 1.8 Hz, 1H), 4.69 (d, J ) 1.8 Hz, 1H), 4.42 (s, 2H), 4.14
(dd, J ) 9.6, 3.6 Hz, 1H), 3.96 (dd, J ) 3.0, 1.8 Hz, 1H), 3.90 (dq,
J ) 9.6, 6.6 Hz, 1H), 3.86 (dq, J ) 9.6, 6.6 Hz, 1H), 3.80 (dq, J
) 9.6, 6.6 Hz, 1H), 3.79 (s, 3H), 3.63 (dt, J ) 9.6, 6.6 Hz, 1H),
3.64 (dt, J ) 9.6, 6.6 Hz, 1H), 3.45 (t, J ) 6.6 Hz, 2H), 3.39 (dt,
J ) 9.6, 6.6 Hz, 1H), 2.72 (ddd, J ) 18.0, 7.2, 7.2 Hz, 1H), 2.62
(ddd, J ) 18.0, 7.2, 7.2 Hz, 1H), 2.52 (ddd, J ) 18.0, 6.6, 6.6 Hz,
1H), 2.43 (ddd, J ) 18.0, 7.2, 6.6 Hz, 1H), 2.17 (s, 3H), 2.15 (s,
3H), 2.13 (s, 3H), 2.12 (s, 3H), 2.08 (s, 3H), 2.07 (s, 3H), 2.02 (s,
3H), 1.60 (m, 4H), 1.37 (m, 4H), 1.22 (d, J ) 6.6 Hz, 3H), 1.20
(d, J ) 6.6 Hz, 3H), 1.17 (d, J ) 6.6 Hz, 3H); 13C NMR (150
MHz, CDCl3) δ 206.1, 171.3, 170.5, 170.3 (2 C), 170.2, 170.1,
169.8, 159.2, 130.9, 129.3, 113.9, 99.5, 98.7, 98.6, 77.3, 74.3, 72.6,
72.2, 71.5, 71.3, 70.8, 70.7, 70.1(2 C), 68.9, 68.1, 67.4, 67.3, 66.3,
55.4, 37.8, 31.0, 29.8, 29.7, 29.4, 27.9, 26.1 26.0, 21.1, 21.0, 20.9,
20.8 (2 C), 17.6, 17.5, 17.2; CIHRMS calcd for [C49H70O23Na+]:
1049.4200, found 1049.4206.
1
2939, 1744, 1370, 1221, 1044, 915; H NMR (600 MHz, CDCl3)
δ 8.67 (s, 1H), 5.27 (dd, J ) 9.6, 3.6 Hz, 1H), 5.22 (dd, J ) 3.6,
1.8 Hz, 1H), 5.17 (dd, J ) 9.6, 3.0 Hz, 1H), 5.13 (dd, J ) 9.6, 9.6
Hz, 1H), 5.11 (dd, J ) 9.6, 9.6 Hz, 1H), 5.07 (dd, J ) 3.6, 1.8 Hz,
1H), 5.06 (d, J ) 1.8 Hz, 1H), 5.06 (dd, J ) 9.6, 9.6 Hz, 1H), 4.94
(d, J ) 1.8 Hz, 1H), 4.84 (d, J ) 1.8 Hz, 1H), 4.22 (dd, J ) 3.6,
1.8 Hz, 1H), 4.13 (dd, J ) 9.6, 3.0 Hz, 1H), 4.05 (dq, J ) 9.0, 6.6
Hz, 1H), 3.90 (dq, J ) 9.6, 6.6 Hz, 2H), 2.74 (ddd, J ) 18.6, 8.4,
5.4 Hz, 1H), 2.62 (ddd, J ) 18.6, 6.6, 5.4 Hz, 1H), 2.51 (ddd, J )
18.6, 8.4, 5.4 Hz, 1H), 2.43 (ddd, J ) 18.6, 6.6, 5.4 Hz, 1H), 2.17
(s, 3H), 2.15 (s, 3H), 2.14 (s, 3H), 2.13 (s, 3H), 2.08 (s, 6H), 2.05
(s, 3H), 1.26 (d, J ) 6.6 Hz, 3H), 1.20 (d, J ) 6.6 Hz, 3H), 1.18
(d, J ) 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 206.1, 171.3,
170.4, 170.3, 170.2, 170.1, 169.6, 160.3, 99.5, 98.8, 96.1, 74.8,
74.4, 72.0, 71.2, 70.7, 70.6, 70.2, 70.1, 69.4, 68.9, 67.8, 67.4, 65.9,
37.7, 29.8, 27.9, 21.0 (2 C), 20.9, 20.8 (2 C), 20.7, 17.6, 17.3, 17.2;
CIHRMS calcd for [C36H50Cl3NO21Na+]: 960.1839, found 960.1830.
(3S,4S,5S)-2-((3S,4S,5S)-2-((3S,4S,5S)-2-(6-(benzyloxy)hexyloxy)-
tetrahydro-4,5-diacetoxy-6-methyl-2H-pyran-3-yloxy)-tetrahydro-
3,5-diacetoxy-6-methyl-2H-pyran-4-yloxy)-3,5-diacetoxy-tetrahydro-
6-methyl-2H-pyran-4-yl 4-oxopentanoate (46a). To a solution of
trisaccharide imidate 45 (815 mg, 0.868 mmol) and 6-benzyloxy-
hexanol (361 mg, 1.74 mmol) in 2.2 mL CH2Cl2 with molecular
sieve at 0 °C was added TMSOTf (38 mg, 0.174 mmol). The
reaction was stirred at 0 °C for 0.5 h, quenched with saturated
(3S,4S,5R)-2-((3S,4S,5S)-2-((3S,4S,5S)-2-(6-(benzyloxy)hexyloxy)-
tetrahydro-4,5-diacetoxy-6-methyl-2H-pyran-3-yloxy)-tetrahydro-
3,5-diacetoxy-6-methyl-2H-pyran-4-yloxy)-tetrahydro-4-hydroxy-
6-methyl-2H-pyran-3, 5-yl diacetate (6a). To a solution of levulinoyl
ester 46a (560 mg, 0.56 mmol) in CH2Cl2 (11.2 mL) was added
a solution of hydrazinium acetate (1.5 M, 0.40 mL) in methanol.
J. Org. Chem. Vol. 73, No. 14, 2008 5217

Guo and O’Doherty
The reaction was stirred for 2 h, quenched with saturated
NaHCO3 solution (50 mL), extracted with Et2O (3 × 150 mL),
dried (Na2SO4), concentrated under reduced pressure and purified
using silica gel flash chromatography eluting with pure ether to
give 476 mg (0.53 mmol, 94%) alcohol 6a as white foam, mp:
56-59 °C; Rf ) 0.45 (50% EtOAc/hexane); [R]25D ) -33 (c )
0.62, CH2Cl2); IR (thin film, cm-1) 2981, 2938, 2110, 1742,
1368, 1220, 1037, 912; 1H NMR (600 MHz, CDCl3) δ 7.22-7.31
(m, 5H), 5.17 (dd, J ) 9.6, 3.6 Hz, 1H), 5.15 (dd, J ) 3.6, 1.8
Hz, 1H), 5.05 (dd, J ) 9.6, 9.6 Hz, 1H), 4.98 (dd, J ) 9.6, 9.6
Hz, 1H), 4.95 (d, J ) 1.8 Hz, 1H), 4.87 (dd, J ) 3.6, 1.8 Hz,
1H), 4.81 (dd, J ) 9.6, 9.6 Hz, 1H), 4.75 (d, J ) 1.8 Hz, 1H),
4.67 (d, J ) 1.8 Hz, 1H), 4.47 (s, 2H), 4.11 (dd, J ) 9.6, 3.6
Hz, 1H), 3.94 (dd, J ) 3.6, 1.8 Hz, 1H), 3.85 (dd, J ) 9.6, 3.6
Hz, 1H), 3.84 (dq, J ) 9.6, 6.6 Hz, 1H), 3.78 (dq, J ) 9.6, 6.6
Hz, 2H), 3.62 (dt, J ) 9.6, 6.6 Hz, 1H), 3.43 (d, J ) 6.6 Hz,
2H), 3.37 (dt, J ) 9.6, 6.6 Hz, 1H), 2.36 (d, J ) 9.0 Hz, 1H,
OH), 2.12 (s, 6H), 2.11 (s, 3H), 2.09 (s, 3H), 2.03 (s, 3H), 1.99
(s, 3H), 1.58 (m, 4H), 1.35 (m, 4H), 1.20 (d, J ) 6.6 Hz, 3H),
1.17 (d, J ) 6.6 Hz, 3H), 1.14 (d, J ) 6.6 Hz, 3H); 13C NMR
(150 MHz, CDCl3) δ 171.5, 170.3 (3 C), 170.1, 169.6, 138.7,
128.3, 127.6, 127.4, 99.4, 99.8, 98.5, 77.2, 74.4, 73.9, 72.8(2
C), 72.2, 71.5, 71.4, 70.7, 70.3, 68.1, 67.9, 67.4, 66.8, 66.2,
29.6, 29.3, 26.0, 25.9, 21.0, 20.9 (2 C), 20.7 (2 C), 20.6, 17.5,
17.3, 17.0; CIHRMS calcd for [C43H62O20Na+]: 921.3732, found
921.3734.
(0.82 mmol, 82%) tetrasaccharide 4 as a white foam, mp: 62-65
°C; Rf ) 0.43 (50% EtOAc/hexane); [R]25D ) -6 (c ) 0.8, CH2Cl2);
IR (thin film, cm-1) 2981, 2938, 2860, 2110, 1742, 1368, 1220,
1
1037, 912; H NMR (600 MHz, CDCl3) δ 7.25-7.35 (m, 10H),
5.20 (dd, J ) 9.6, 3.6 Hz, 1H), 5.18 (dd, J ) 3.6, 1.8 Hz, 1H),
5.06 (dd, J ) 9.6, 9.6 Hz, 1H), 4.99 (dd, J ) 9.6, 9.6 Hz, 1H),
4.98 (dd, J ) 9.6, 9.6 Hz, 1H), 4.97 (d, J ) 1.8 Hz, 1H), 4.89 (dd,
J ) 3.6, 1.8 Hz, 1H), 4.88 (dd, J ) 9.6, 9.6 Hz, 1H), 4.78 (d, J )
1.8 Hz, 1H), 4.77 (d, J ) 11.4 Hz, 1H), 4.72 (d, J ) 11.4, Hz,
1H), 4.69 (d, J ) 1.8 Hz, 1H), 4.49 (s, 2H), 4.40 (d, J ) 7.8 Hz,
1H), 4.10 (dd, J ) 9.6, 3.0 Hz, 1H), 3.96 (dd, J ) 3.0, 1.8 Hz,
1H), 3.88 (dd, J ) 9.6, 3.6 Hz, 1H), 3.86 (dq, J ) 9.6, 6.6 Hz,
1H), 3.79 (dq, J ) 9.6, 6.6 Hz, 1H), 3.73 (dq, J ) 9.6, 6.6 Hz,
1H), 3.64 (dt, J ) 9.6, 6.6 Hz, 1H), 3.46 (t, J ) 6.6 Hz, 2H), 3.45
(dd, J ) 9.6, 9.6 Hz, 1H), 3.39 (dt, J ) 9.6, 6.6 Hz, 1H), 3.23 (dq,
J ) 9.6, 6.6 Hz, 1H), 3.16 (dd, J ) 9.6, 7.8 Hz, 1H), 2.76 (ddd, J
) 18.0, 7.2, 7.2 Hz, 1H), 2.66 (ddd, J ) 18.0, 7.2, 7.2 Hz, 1H),
2.50 (t, J ) 7.2 Hz, 2H), 2.14 (s, 6H), 2.13 (s, 3H), 2.09 (s, 3H),
2.07 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H), 1.59-1.64 (m, 4H),
1.31-1.42 (m, 4H), 1.36 (d, J ) 6.6 Hz, 3H), 1.20 (d, J ) 6.6 Hz,
3H), 1.17 (d, J ) 6.6 Hz, 3H), 1.16 (d, J ) 6.6 Hz, 3H); 13C NMR
(150.8 MHz, CDCl3) δ 206.3, 170.3, 170.4 (2 C), 170.3, 170.1,
169.8, 169.7, 138.7, 137.6, 128.4 (2 C), 128.2, 127.9, 127.7, 127.5,
100.8. 99.4, 99.3, 98.5, 81.1, 77.2, 74.7 (2 C), 73.7, 73.4, 72.9,
72.6, 72.2, 71.8, 71.7, 71.5, 70.9, 70.8, 70.4, 68.0, 67.6, 67.3, 67.2,
66.2, 38.0, 29.8, 29.7, 29.4, 27.7, 26.1, 26.0, 21.1, 21.0 (2 C), 20.8
(2C),20.7,18.2,17.6,17.4,17.1;CIHRMScalcdfor[C61H83N3O25Na+]:
1280.5213, found 1280.5210.
(3S,4S,5R)-2-((3S,4S,5S)-2-((3S,4S,5S)-2-(6-(4-methoxybenzyloxy)-
hexyloxy)-tetrahydro-4, 5-diacetoxy-6-methyl-2H-pyran-3-yloxy)-tet-
rahydro-3,5-diacetoxy-6-methyl-2H-pyran-4-yloxy)-tetrahydro-4-hy-
droxy-6-methyl-2H-pyran-3, 5-yl diacetate (6b). To a solution of
levulinoyl ester 46b (706 mg, 0.688 mmol) in CH2Cl2 (13.8 mL)
was added a solution of hydrazinium acetate (1.5 M, 9.2 mL) in
methanol. The reaction was stirred for 2 h, quenched with saturated
NaHCO3 solution (60 mL), extracted with Et2O (3 × 120 mL),
dried (Na2SO4), concentrated under reduced pressure and purified
using silica gel flash chromatography eluting with pure ether to
give 620 mg (0.66 mmol, 96%) alcohol 6b as a white foam, mp:
(2S,3S,4S,5R)-2-((2S,4S,5S)-2-((2S,4S,5S)-2-((2R,4S,5S)-2-(6-(Ben-
zyloxy)hexyloxy)tetrahydro-4,5-diacetoxy-6-methyl-2H-pyran-3-
yloxy)tetrahydro-3,5-diacetoxy-6-methyl-2H-pyran-4-yloxy)tet-
rahydro-3,5-diacetoxy-6-methyl-2H-pyran-4-yloxy)-5-azido-4-
(benzyloxy)tetrahydro-6-methyl-2H-pyran-3-ol (48a). To a solution
of levulinoyl ester 4 (600 mg, 0.477 mmol) in CH2Cl2 (9.5 mL)
was added a solution of hydrazinium acetate (1.5 M, 0.36 mL) in
methanol. The reaction was stirred for 2 h, quenched with saturated
NaHCO3 solution (50 mL), extracted with Et2O (3 × 100 mL),
dried (Na2SO4), concentrated under reduced pressure, and purified
using silica gel flash chromatography eluting with 60% EtOAc/
hexane to give 363 mg (0.45 mmol, 95%) of alcohol 48a as a white
foam: mp 64-67 °C; Rf ) 0.60 (50% EtOAc/hexane); [R]25D ) -
10 (c ) 1.0, CH2Cl2); IR (thin film, cm-1) 2983, 2938, 2894, 2110,
1742, 1372, 1223, 1039, 912; 1H NMR (600 MHz, CDCl3) δ
7.25-7.40 (m, 10H), 5.21 (dd, J ) 9.6, 3.6 Hz, 1H), 5.19 (dd, J )
3.6, 1.8 Hz, 1H), 5.07 (dd, J ) 9.6, 9.6 Hz, 1H), 5.03 (dd, J ) 9.6,
9.6 Hz, 1H), 5.00 (dd, J ) 9.6, 9.6 Hz, 1H), 4.98 (dd, J ) 3.6, 1.8
Hz, 1H), 4.94 (d, J ) 11.4 Hz, 1H), 4.93 (d, J ) 1.2 Hz, 1H), 4.79
(d, J ) 11.4 Hz, 1H), 4.78 (d, J ) 1.2, Hz, 1H), 4.70 (d, J ) 1.8
Hz, 1H), 4.50 (s, 2H), 4.21 (d, J ) 7.8 Hz, 1H), 4.10 (dd, J ) 9.6,
3.0 Hz, 1H), 3.96 (dd, J ) 3.0, 1.8 Hz, 1H), 3.89 (dd, J ) 9.6, 3.6
Hz, 1H), 3.87 (dq, J ) 9.6, 6.6 Hz, 1H), 3.80 (dq, J ) 9.6, 6.6 Hz,
1H), 3.79 (dq, J ) 9.6, 6.6 Hz, 1H), 3.64 (dt, J ) 9.6, 6.6 Hz, 1H),
3.47 (t, J ) 6.6 Hz, 2H), 3.45 (dd, J ) 9.6, 9.6 Hz, 1H), 3.36 (dq,
J ) 9.6, 6.6 Hz, 1H), 3.31 (dd, J ) 9.6, 9.6 Hz, 1H), 3.21 (dt, J )
9.6, 6.6 Hz, 1H), 3.07 (dd, J ) 9.6, 7.8 Hz, 1H), 2.15 (s, 3H), 2.13
(s, 3H), 2.11 (s, 3H), 2.10 (s, 3H), 2.06 (s, 3H), 2.02 (s, 3H),
1.56-1.64 (m, 4H), 1.33-1.42 (m, 4H), 1.32 (d, J ) 6.6 Hz, 3H),
1.20 (d, J ) 6.6 Hz, 3H), 1.19 (d, J ) 6.6 Hz, 3H), 1.17 (d, J )
6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 170.9, 170.5, 170.4,
170.3, 170.2, 169.8, 138.7, 138.1, 128.5, 128.4, 128.3, 127.9, 127.7,
127.6, 104.0. 99.4, 99.2, 98.5, 82.2, 77.3, 75.4, 75.0, 74.9, 74.7,
72.9, 72.6, 72.4, 72.2, 71.7, 71.5, 70.9, 70.8, 70.4, 68.0, 67.3, 67.1,
67.0, 66.2, 29.7, 29.4, 26.1, 26.0, 21.2, 21.1 (2 C), 20.8 (2 C), 20.7,
18.3, 17.6, 17.5, 17.1; CIHRMS calcd for [C56H77N3O23Na+]
1182.4846, found 1182.4845.
68-72 °C; Rf ) 0.47 (50% EtOAc/hexane); [R]25 ) -32 (c )
D
1.0, CH2Cl2); IR (thin film, cm-1) 2978, 2939, 1743, 1374, 1226,
1
1040, 986; H NMR (600 MHz, CDCl3) δ 7.25 (d, J ) 8.4 Hz,
2H), 6.87 (d, J ) 8.4 Hz, 2H), 5.20 (dd, J ) 9.6, 3.6 Hz, 1H), 5.17
(dd, J ) 3.6, 1.8 Hz, 1H), 5.08 (dd, J ) 9.6, 9.6 Hz, 1H), 5.00 (dd,
J ) 9.6, 9.6 Hz, 1H), 4.97 (d, J ) 1.8 Hz, 1H), 4.89 (dd, J ) 3.0,
1.8 Hz, 1H), 5.83 (dd, J ) 9.6, 9.6 Hz, 1H), 4.77 (d, J ) 1.8 Hz,
1H), 4.69 (d, J ) 1.8 Hz, 1H), 4.42 (s, 2H), 4.14 (dd, J ) 9.6, 3.6
Hz, 1H), 3.96 (dd, J ) 3.0, 1.8 Hz, 1H), 3.87 (dd, J ) 9.6, 3.6 Hz,
1H), 3.86 (dq, J ) 9.6, 6.6 Hz, 1H), 3.70 (dq, J ) 9.6, 6.6 Hz,
2H), 3.79 (s, 3H), 3.62 (dt, J ) 9.6, 6.6 Hz, 1H), 3.43 (t, J ) 6.6
Hz, 2H), 3.39 (dt, J ) 9.6, 6.6 Hz, 1H), 2.15 (s, 6H), 2.13 (s, 3H),
2.12 (s, 3H), 2.06 (s, 3H), 2.02 (s, 3H), 1.58 (m, 4H), 1.35 (m,
4H), 1.22 (d, J ) 6.6 Hz, 3H), 1.20 (d, J ) 6.6 Hz, 3H), 1.16 (d,
J ) 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 171.7, 170.4 (2
C), 170.3, 170.2, 169.7, 159.2, 130.8, 129.3, 113.8, 99.5, 98.8, 98.5,
77.2, 74.5, 74.0, 72.9, 72.6, 72.3, 71.6, 71.5, 70.8, 70.1, 68.3, 68.0,
67.5, 66.8, 66.2, 55.3, 29.7, 29.4, 26.1, 26.0, 21.1, 20.0 (2 C), 20.8
(2 C), 20.7, 17.6, 17.4, 17.1; CIHRMS calcd for [C44H64O21Na+]:
951.3838, found 951.3837.
(2S,3S,4S,5R)-2-((2S,4S,5S)-2-((2S,4S,5S)-2-((2R,4S,5S)-2-(6-(ben-
zyloxy)hexyloxy)-tetrahydro-4, 5-diacetoxy-6-methyl-2H-pyran-3-
yloxy)-tetrahydro-3,5-diacetoxy-6-methyl-2H-pyran-4-yloxy)-tet-
rahydro-3,5-diacetoxy-6-methyl-2H-pyran-4-yloxy)-5-azido-4-
(benzyloxy)-tetrahydro-6-methyl-2H-pyran-3-yl 4-oxopentanoate
(4). To a solution of trisaccharide 6a (898 mg, 1 mmol) and imidate
7 (782 mg, 1.5 mmol) in 2 mL CH2Cl2 with molecular sieve at 0
°C was added TMSOTf (66 mg, 0.168 mmol). The reaction was
stirred at 0 °C for 0.5 h, quenched with saturated NaHCO3 solution
(10 mL), extracted with Et2O (3 × 100 mL), dried (Na2SO4),
concentrated under reduced pressure and purified by passing through
a pad of silica gel eluting with 50% EtOAc/hexane to give 1.03 g
(2S,4S,5S)-4-((2S,3S,4S,5R)-5-Azido-4-(6-(benzyloxy)hexyloxy)-
tetrahydro-3-methoxy-6-methyl-2H-pyran-2-yloxy)-2-((2S,4S,5S)-
2-((2R,4S,5S)-2-benzyloxy-4,5-diacetoxytetrahydro-6-methyl-2H-
pyran-3-yloxy)-3,5-diacetoxytetrahydro-6-methyl-2H-pyran-4-
5218 J. Org. Chem. Vol. 73, No. 14, 2008

Asymmetric Synthesis of Anthrax
yloxy)tetrahydro-6-methyl-2H-pyran-3,5-yl Diacetate (48). To a
mixture of alcohol 48a (625 mg, 0.54 mmol) and silver(I) oxide
(2.5 g, 10.9 mmol) was added 3 mL of CH3I. The reaction
suspension was stirred at 55 °C for 3 days. The reaction mixture
was then passed through a Celite pad with 200 mL of Et2O,
concentrated under reduced pressure, and purified using silica
gel flash chromatography eluting with 50% EtOAc/hexane to
give 582 mg (0.50 mmol, 92%) of methyl ether 48 as a white
30.8, 30.6, 27.2, 27.1, 18.3, 18.2, 18.1, 18.0; CIHRMS calcd for
[C45H69NO17Na+] 918.4458, found 918.4463.
N-((3R,5S,6S)-6-((2S,3S,4S,5S)-2-((2S,3S,4S,5S)-2-((2R,3S,4S,5S)-
2-(6-(Benzyloxy)hexyloxy)-4,5-dihydroxytetrahydro-6-methyl-2H-
pyran-3-yloxy)-3,5-dihydroxytetrahydro-6-methyl-2H-pyran-4-
yloxy)-3,5-dihydroxytetrahydro-6-methyl-2H-pyran-4-yloxy)-4-
(benzyloxy)tetrahydro-5-methoxy-2-methyl-2H-pyran-3-yl)-3-
hydroxy-3-methylbutanamide (50). To a solution of amine 50a (504
mg, 0.56 mmol) in 1.12 mL of THF and Et3N (177 µL, 1.12 mmol)
were added HBTU (205 mg, 0.62 mmol) and 3-hydroxy-3-
methylbutanoic acid (73 mg, 0.62 mmol). The reaction mixture was
stirred for 10 h, solvent was evaporated under reduced pressure,
and the product was purified using silica gel flash chromatography
eluting with 35% MeOH/ EtOAc to give 513 mg (0.52 mmol, 92%)
amide 50 as white powder: mp 112-116 °C; Rf ) 0.63 (20%
foam: mp 61-64 °C; Rf ) 0.62 (50% EtOAc/hexane); [R]25
)
D
-11 (c ) 2.0, CH2Cl2); IR (thin film, cm-1) 2979, 2934, 2857,
2110, 1745, 1370, 1223, 1092, 1041; 1H NMR (600 MHz,
CDCl3) δ 7.25-7.39 (m, 10H), 5.23 (dd, J ) 9.6, 3.6 Hz, 1H),
5.18 (dd, J ) 3.6, 1.8 Hz, 1H), 5.12 (dd, J ) 9.6, 9.6 Hz, 1H),
5.07 (dd, J ) 9.6, 9.6 Hz, 1H), 5.01 (dd, J ) 3.6, 1.8 Hz, 1H),
5.00 (dd, J ) 9.6, 9.6 Hz, 1H), 4.93 (d, J ) 1.2, Hz, 1H), 4.86
(d, J ) 11.4 Hz, 1H), 4.78 (d, J ) 1.8 Hz, 1H), 4.77 (d, J )
11.4 Hz, 1H), 4.70 (d, J ) 1.8 Hz, 1H), 4.49 (s, 2H), 4.30 (d,
J ) 7.8 Hz, 1H), 4.12 (dd, J ) 9.6, 3.0 Hz, 1H), 3.96 (dd, J )
3.0, 1.8 Hz, 1H), 3.89 (dd, J ) 9.6, 3.6 Hz, 1H), 3.87 (dq, J )
9.6, 6.6 Hz, 1H), 3.80 (dq, J ) 9.6, 6.6 Hz, 1H), 3.75 (dq, J )
9.6, 6.6 Hz, 1H), 3.65 (dt, J ) 9.6, 6.6 Hz, 1H), 3.47 (t, J ) 6.6
Hz, 2H), 3.46 (s, 3H), 3.40 (dt, J ) 9.6, 6.6 Hz, 1H), 3.31 (dd,
J ) 9.6, 9.6 Hz, 1H), 3.16 (dq, J ) 9.6, 6.6 Hz, 1H), 3.04 (dd,
J ) 9.6, 9.6 Hz, 1H), 3.02 (dd, J ) 9.6, 7.8 Hz, 1H), 2.16 (s,
3H), 2.14 (s, 3H), 2.10 (s, 6H), 2.06 (s, 3H), 2.02 (s, 3H),
1.56-1.67 (m, 4H), 1.30-1.42 (m, 4H), 1.29 (d, J ) 6.6 Hz,
3H), 1.20 (d, J ) 6.6 Hz, 3H), 1.19 (d, J ) 6.6 Hz, 3H), 1.17
(d, J ) 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 170.5,
170.4, 170.3, 170.2, 170.1, 169.7, 138.7, 138.0, 128.5, 128.4,
128.3, 127.9, 127.7, 127.6, 104.2. 99.4, 99.2, 98.5, 84.0, 82.8,
77.3, 75.4, 75.2, 74.7, 72.9, 72.3 (2 C), 72.2, 71.7, 71.5, 70.8,
70.5, 70.4, 68.0, 67.4 (2 C), 67.3, 66.3, 60.7, 29.7, 29.4, 26.1,
26.0, 21.1 (3 C), 20.8 (3 C), 18.3, 17.6, 17.5, 17.2; CIHRMS
calcd for [C57H79N3O23Na+] 1196.5002, found 1196.5001.
methanol/EtOAc); [R]25 ) -55 (c ) 1.0, MeOH); IR (thin film,
D
cm-1) 3411, 2974, 2934, 2866, 1639, 1454, 1123, 1042, 843; H
1
NMR (600 MHz, CD3OD) δ 7.23-7.37 (m, 10H), 5.07 (d, J )
1.8 Hz, 1H), 4.92 (d, J ) 1.8 Hz, 1H), 4.83 (d, J ) 11.4 Hz, 1H),
4.78 (d, J ) 1.8 Hz, 1H), 4.67 (d, J ) 7.8 Hz, 1H), 4.66 (d, J )
11.4 Hz, 1H), 4.48 (s, 2H), 4.19 (dd, J ) 3.0, 1.8 Hz, 1H), 4.07
(dd, J ) 3.0, 1.8 Hz, 1H), 3.92 (dd, J ) 9.6, 3.0 Hz, 1H), 3.85 (dq,
J ) 9.6, 6.0 Hz, 1H), 3.81 (dd, J ) 9.6, 3.0 Hz, 1H), 3.79 (dd, J
) 3.0, 1.8, Hz, 1H), 3.76 (dd, J ) 9.6, 3.0 Hz, 1H), 3.74 (dq, J )
9.6, 6.0 Hz, 1H), 3.72 (dd, J ) 9.6, 9.6 Hz, 1H), 3.65 (dq, J ) 9.6,
6.0 Hz, 1H), 3.64 (s, 3H), 3.58 (dd, J ) 9.6, 9.6 Hz, 1H), 3.54 (dt,
J ) 9.6, 6.0 Hz, 1H), 3.52 (dd, J ) 9.6, 9.6 Hz, 1H), 3.49 (dq, J
) 9.6, 6.0 Hz, 1H), 3.48 (t, J ) 6.0 Hz, 2H), 3.42-3.49 (m, 1H),
3.40 (dt, J ) 9.6, 6.0 Hz, 1H), 3.36 (dd, J ) 9.6, 9.6 Hz, 1H), 3.19
(dd, J ) 9.6, 7.8 Hz, 1H), 2.29 (s, 2H), 1.59 (m, 4H), 1.39 (m,
4H), 1.30 (d, J ) 6.0 Hz, 3H), 1.25 (d, J ) 6.6 Hz, 3H), 1.24 (d,
J ) 6.6 Hz, 3H), 1.23 (s, 3H), 1.22 (s, 3H), 1.21 (d, J ) 6.6 Hz,
3H); 13C NMR (150 MHz, CD3OD) δ 174.4, 140.2, 140.0, 129.5,
129.4, 129.0, 128.8, 128.7, 128.6, 105.6, 104.0, 103.6, 100.4, 85.9,
83.0, 81.9, 80.3, 79.2, 75.7, 74.5, 74.0, 73.4, 73.2, 72.3, 72.1, 71.9,
71.8, 71.4, 70.7, 70.6, 70.3, 70.0, 68.7, 67.0, 61.1, 57.1, 30.8, 30.6,
29.8, 29.6, 27.2, 27.1, 18.6, 18.3, 18.1, 18.0; CIHRMS calcd for
[C50H77NO19Na+] 1018.4987, found 1018.4988.
N-((3R,5S,6S)-6-((2S,3S,4S,5S)-2-((2S,3S,4S,5S)-2-((2R,3S,4S,5S)-
2-(6-Hydroxyhexyloxy)-4,5-dihydroxy-tetrahydro-6-methyl-2H-py-
ran-3-yloxy)-3,5-dihydroxytetrahydro-6-methyl-2H-pyran-4-yloxy)-
3,5-dihydroxytetrahydro-6-methyl-2H-pyran-4-yloxy)-4-
hydroxytetrahydro-5-methoxy-2-methyl-2H-pyran-3-yl)-3-hydroxy-
3-methylbutanamide (51). To a solution of Bn-ether 50 (350 mg,
0.35 mmol) in 3.5 mL of MeOH was added 10% Pd/C (100 mg).
The reaction suspension was stirred under a hydrogen balloon for
24 h, filtered by passing through a Celite pad, and concentrated
under reduced pressure and vacuo to give 277 mg of alcohol 51
(0. 34 mmol, 97%) as a white powder: mp 101-105 °C; Rf ) 0.40
(30% methanol/EtOAc); [R]25D ) -62 (c ) 1.6, MeOH); IR (thin
film, cm-1) 3366, 2972, 2935, 2876, 1639, 1385, 1123, 1041, 987;
1H NMR (600 MHz, CD3OD) δ 5.13 (d, J ) 1.8 Hz, 1H), 4.98 (d,
J ) 1.8 Hz, 1H), 4.85 (d, J ) 1.8 Hz, 1H), 4.69 (d, J ) 7.8 Hz,
1H), 4.26 (dd, J ) 3.0, 1.8 Hz, 1H), 4.13 (dd, J ) 3.0, 1.8 Hz,
1H), 3.99 (dd, J ) 9.6, 3.0 Hz, 1H), 3.91 (dq, J ) 9.6, 6.0 Hz,
1H), 3.87 (dd, J ) 9.6, 3.0 Hz, 1H), 3.86 (dd, J ) 3.0, 1.8, Hz,
1H), 3.82 (dd, J ) 9.6, 3.0 Hz, 1H), 3.80 (dq, J ) 9.6, 6.0 Hz,
1H), 3.74 (dq, J ) 9.6, 6.0 Hz, 1H), 3.73 (s, 3H), 3.67 (dd, J )
9.6, 9.6 Hz, 1H), 3.64 (dd, J ) 9.6, 9.6 Hz, 1H), 3.63 (dt, J ) 9.6,
6.0 Hz, 1H), 3.62 (t, J ) 6.0 Hz, 2H), 3.59 (dd, J ) 9.6, 9.6 Hz,
1H), 3.50 (dq, J ) 9.6, 6.0 Hz, 1H), 3.49 (dd, J ) 9.6, 9.6 Hz,
1H), 3.48 (dd, J ) 9.6, 9.6 Hz, 1H), 3.43 (dd, J ) 9.6, 9.6 Hz,
1H), 3.09 (dd, J ) 9.6, 7.8 Hz, 1H), 2.45 (m, 2H), 1.67 (m, 2H),
1.62 (m, 2H), 1.48 (m, 4H), 1.37 (d, J ) 6.0 Hz, 3H), 1.36 (s, 3H),
1.35 (s, 3H), 1.32 (d, J ) 6.6 Hz, 3H), 1.31 (d, J ) 6.6 Hz, 3H),
1.28 (d, J ) 6.6 Hz, 3H); 13C NMR (67.5 MHz, CD3OD) δ 174.7,
105.5, 104.0, 103.6, 100.4, 85.7, 81.9, 80.3, 79.2, 75.1, 74.5, 73.4,
73.1, 72.3, 71.9, 71.8, 71.1, 70.8, 70.7, 70.3, 70.0, 68.7, 68.1, 63.0,
(3R,4S,6R)-5-((2S,4S,5S)-4-((2S,4R,5S)-4-((2S,3S,4S,5R)-5-Amino-
4-(6-(benzyloxy)hexyloxy)tetrahydro-3-methoxy-6-methyl-2H-py-
ran-2-yloxy)tetrahydro-3,5-dihydroxy-6-methyl-2H-pyran-2-
yloxy)tetrahydro-3,5-dihydroxy-6-methyl-2H-pyran-2-yloxy)-6-
(benzyloxy)tetrahydro-2-methyl-2H-pyran-3,4-diol (50a). To a
stirring solution of acetate 48 (608 mg, 0.52 mmol) in 5.2 mL of
MeOH/THF/H2O (10/10/1) was added PEt3 (184 mg, 1.56 mmol)
for 10 min, and then LiOH (151 mg, 6.24 mmol) was added. The
reaction was stirred for 2 h, evaporated solvent under reduced
pressure, and purified using silica gel flash chromatography eluting
with 20% MeOH/CH2Cl2. The resulted product was applied to ion-
exchange chromatography (Dowex 1× 8, 200 mesh, H+ form)
eluting with water. Removal of water in vacuo gave 432 mg (0.48
mmol, 93%) of alcohol 50a as a white powder: mp 148-150 °C;
Rf ) 0.44 (20% methanol/EtOAc); [R]25D ) -67 (c ) 1.0, MeOH);
IR (thin film, cm-1) 3381, 2967, 2934, 2855, 1454, 1363, 1123,
1
1063, 986; H NMR (600 MHz, CD3OD) δ 7.22-7.44 (m, 10H),
5.04 (d, J ) 1.2 Hz, 1H), 4.96 (d, J ) 11.4 Hz, 1H), 4.90 (d, J )
1.2 Hz, 1H), 4.81 (d, J ) 11.4 Hz, 1H), 4.75 (d, J ) 1.2 Hz, 1H),
4.72 (d, J ) 7.8 Hz, 1H), 4.46 (s, 2H), 4.16 (dd, J ) 3.0, 1.8 Hz,
1H), 4.05 (dd, J ) 3.0, 1.8 Hz, 1H), 3.92 (dd, J ) 9.6, 3.0 Hz,
1H), 3.81 (dq, J ) 9.6, 6.6 Hz, 1H), 3.78 (dd, J ) 9.6, 3.0 Hz,
1H), 3.77 (dd, J ) 3.0, 1.8 Hz, 1H), 3.74 (dd, J ) 9.6, 3.0 Hz,
1H), 3.72 (dq, J ) 9.6, 6.6 Hz, 1H), 3.65 (dq, J ) 9.6, 6.6 Hz,
1H), 3.62 (dq, J ) 9.6, 6.6 Hz, 1H), 3.57(s, 3H), 3.55 (dt, J ) 9.6,
6.6 Hz, 1H), 3.54 (dd, J ) 9.6, 9.6 Hz, 1H), 3.53 (dq, J ) 9.6, 6.6
Hz, 1H), 3.50 (dd, J ) 9.6, 9.6 Hz, 1H), 3.46 (t, J ) 6.6 Hz, 2H),
3.37 (dt, J ) 9.6, 6.6 Hz, 1H), 3.34 (dd, J ) 9.6, 9.6 Hz, 1H), 3.24
(dd, J ) 9.6, 7.8 Hz, 1H), 2.90 (dd, J ) 9.6, 9.6 Hz, 1H), 1.59 (m,
4H), 1.37 (m, 4H), 1.34 (d, J ) 6.6 Hz, 3H), 1.28 (d, J ) 6.6 Hz,
3H), 1.23 (d, J ) 6.6 Hz, 6H); 13C NMR (150 MHz, CD3OD) δ
140.0, 139.6, 129.5, 129.4, 129.2, 129.0, 128.9, 128.7, 105.7, 104.0,
103.6, 100.4, 85.8, 81.7, 80.2, 80.0, 79.2, 75.6, 74.5, 74.0, 73.4,
73.1, 72.3, 71.9 (2 C), 71.4, 70.7, 70.5, 70.0, 69.5, 68.7, 60.9, 58.0,
J. Org. Chem. Vol. 73, No. 14, 2008 5219

Guo and O’Doherty
61.3, 58.1, 33.7, 30.7, 29.8, 29.7, 27.3, 26.8, 18.6, 18.3, 18.1, 18.0;
CIHRMS calcd for [C36H65NO19Na+] 838.4048, found 838.4045.
N-((3R,5S,6S)-6-((2S,3S,4S,5S)-2-((2S,3S,4S,5S)-2-((2R,3S,4S,5S)-
2-(6-Methanesulfonoylhexyloxy)-4,5-dihydroxytetrahydro-6-
methyl-2H-pyran-3-yloxy)-3,5-dihydroxytetrahydro-6-methyl-2H-
pyran-4-yloxy)-3,5-dihydroxytetrahydro-6-methyl-2H-pyran-4-
yloxy)-4-hydroxytetrahydro-5-methoxy-2-methyl-2H-pyran-3-yl)-
3-hydroxy-3-methylbutanamide (2a). To a solution of primary
alcohol 51 (200 mg, 0.245 mmol) in 1.2 mL of CH2Cl2 and 1.2
mL of pyridine was added a 0.45 M CH2Cl2 solution of MsCl 62
µL at 0 °C. After 0.5 h, another 62 µL of MsCl solution was added
again. The reaction mixture was stirred for 3 h at 0 °C, evaporated
solvent under reduced pressure, and purified using silica gel flash
chromatography eluting with 30% MeOH/CH2Cl2 to give 127 mg
(0.142 mmol, 58%) mesylate 2a as a white powder: mp 128-131
dihydroxytetrahydro-6-methyl-2H-pyran-4-yloxy)-4-
hydroxytetrahydro-5-methoxy-2-methyl-2H-pyran-3-yl)-3-hydroxy-
3-methylbutanamide (2). To a solution of mesylate 2a (134 mg,
0.15 mmol) in 2 mL of DMF was added NaN3 (292 mg, 4.5 mmol).
The reaction mixture was stirred at 60 °C for 15 h, and the solvent
DMF was distilled under vacuo at 60 °C. The residue was purified
using silica gel flash chromatography eluting with 30% MeOH/
EtOAc to give azide anthrax tetrasaccharide 2 (110 mg, 0.13 mmol,
87%) as a white powder: mp 132-134 °C; Rf ) 0.58 (30%
methanol/EtOAc); [R]25 ) -70 (c ) 1.0, MeOH); IR (thin film,
D
cm-1) 3372, 2975, 2935, 2097, 1641, 1452, 1124, 1066; 1H NMR
(600 MHz, CD3OD) δ 5.14 (d, J ) 1.8 Hz, 1H), 4.99 (d, J ) 1.8
Hz, 1H), 4.89 (d, J ) 1.8 Hz, 1H), 4.71 (d, J ) 7.8 Hz, 1H), 4.26
(dd, J ) 3.0, 1.8 Hz, 1H), 4.14 (dd, J ) 3.0, 1.8 Hz, 1H), 3.99 (dd,
J ) 9.6, 3.0 Hz, 1H), 3.92 (dq, J ) 9.6, 6.0 Hz, 1H), 3.87 (dd, J
) 9.6, 3.0 Hz, 1H), 3.86 (dd, J ) 3.0, 1.8 Hz, 1H), 3.82 (dd, J )
9.6, 3.0 Hz, 1H), 3.81 (dq, J ) 9.6, 6.0 Hz, 1H), 3.76 (dq, J ) 9.6,
6.0 Hz, 1H), 3.74 (s, 3H), 3.68 (dd, J ) 9.6, 9.6 Hz, 1H), 3.65 (dd,
J ) 9.6, 9.6 Hz, 1H), 3.62 (dt, J ) 9.6, 6.0 Hz, 1H), 3.59 (dd, J )
9.6, 9.6 Hz, 1H), 3.52 (dd, J ) 9.6, 9.6 Hz, 1H), 3.51 (dq, J ) 9.6,
6.0 Hz, 1H), 3.50 (dt, J ) 9.6, 6.6 Hz, 1H), 3.45 (dd, J ) 9.6, 9.6
Hz, 1H), 3.37 (t, J ) 7.2 Hz, 2H), 3.10 (dd, J ) 9.6, 7.8 Hz, 1H),
2.46 (m, 2H), 1.69 (m, 4H), 1.50 (m, 4H), 1.38 (d, J ) 6.0 Hz,
3H), 1.37 (s, 3H), 1.36 (s, 3H), 1.33 (d, J ) 6.6 Hz, 3H), 1.32 (d,
J ) 6.6 Hz, 3H), 1.29 (d, J ) 6.6 Hz, 3H); 13C NMR (150 MHz,
CDCl3) δ 174.7, 105.5, 104.0, 103.6, 100.4, 85.7, 82.0, 80.3, 79.2,
75.1, 74.5, 73.4, 73.2, 72.4, 72.3, 71.9, 71.8, 70.8, 70.7, 70.3, 70.0,
68.6, 61.3, 58.2, 52.5, 49.7, 30.6, 30.0, 29.8, 29.7, 27.7, 27.0, 18.6,
18.3, 18.1, 18.0; CIHRMS calcd for [C36H64N4O18Na+] 863.4108,
found 863.4113.
°C; Rf ) 0.49 (30% methanol/EtOAc); [R]25 ) -67 (c ) 0.9,
D
MeOH); IR (thin film, cm-1) 3407, 2967, 2933, 2860, 1641, 1456,
1
1349, 1172, 1070, 982; H NMR (600 MHz, CD3OD and CDCl3)
δ 5.34 (d, J ) 1.8 Hz, 1H), 5.19 (d, J ) 1.8 Hz, 1H), 5.06 (d, J )
1.8 Hz, 1H), 4.95 (d, J ) 7.8 Hz, 1H), 4.52 (t, J ) 6.6 Hz, 1H),
4.45 (dd, J ) 3.0, 1.8 Hz, 1H), 4.32 (dd, J ) 3.0, 1.8 Hz, 1H),
4.18 (dd, J ) 9.6, 3.0 Hz, 1H), 4.12 (dq, J ) 9.6, 6.0 Hz, 1H),
4.10 (dd, J ) 3.0, 1.8, Hz, 1H), 4.07 (dd, J ) 9.6, 3.0 Hz, 1H),
4.04 (dd, J ) 9.6, 3.0 Hz, 1H), 4.03 (dq, J ) 9.6, 6.0 Hz, 1H),
3.95 (s, 3H), 3.94 (dq, J ) 9.6, 6.0 Hz, 1H), 3.89 (dd, J ) 9.6, 3.0
Hz, 1H), 3.88 (dd, J ) 9.6, 9.6 Hz, 1H), 3.80 (dt, J ) 9.6, 6.6 Hz,
1H), 3.79 (dd, J ) 9.6, 9.6 Hz, 1H), 3.71 (dd, J ) 9.6, 9.6 Hz,
1H), 3.70 (dq, J ) 9.6, 6.0 Hz, 1H), 3.68 (dt, J ) 9.6, 6.6 Hz, 1H),
3.65 (dd, J ) 9.6, 9.6 Hz, 1H), 3.64 (dd, J ) 9.6, 9.6 Hz, 1H),
3.34 (dd, J ) 9.6, 7.8 Hz, 1H), 3.33 (s, 3H), 2.66 (m, 2H), 2.05
(m, 2H), 1.89 (m, 2H), 1.72 (m, 4H), 1.58 (d, J ) 6.0 Hz, 3H),
1.57 (s, 3H), 1.56 (s, 3H), 1.56 (d, J ) 6.6 Hz, 3H), 1.55 (d, J )
6.6 Hz, 3H), 1.51 (d, J ) 6.6 Hz, 3H); 13C NMR (150 MHz, CD3OD
and CDCl3) δ 174.4, 104.5, 103.4, 102.8, 99.7, 85.0, 82.0, 79.8,
79.1, 74.7, 73.8, 72.6, 72.5, 71.7, 71.2, 71.1, 70.9, 70.4, 70.0, 69.5,
69.3, 68.1, 61.2, 57.5, 37.5, 30.3, 30.0, 29.9, 29.8, 29.7, 29.3, 26.4,
26.0, 18.4, 18.0, 17.9, 17.8; CIHRMS calcd for [C37H67NO21SNa+]
916.3818, found 916.3824.
Acknowledgment. We are grateful to ACS-PRF (47094-
AC1) and NSF (CHE-0415469) for the support of our research
program.
Supporting Information Available: Complete experimental
procedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
N-((3R,5S,6S)-6-((2S,3S,4S,5S)-2-((2S,3S,4S,5S)-2-((2R,3S,4S,5S)-
2-(6-Azidohexyloxy)-4, 5-dihydroxytetrahydro-6-methyl-2H-pyran-
3-yloxy)-3,5-dihydroxytetrahydro-6-methyl-2H-pyran-4-yloxy)-3,5-
JO800691V
5220 J. Org. Chem. Vol. 73, No. 14, 2008