Stereocontrolled synthesis of D- and l-β-rhamnopyranosides with 4-0-6-5-α-cyanobenzylidene-protected 6-thiorhamnopyranosyl thioglycosides

Article abstract of DOI:10.1021/jo8022439

The synthesis of both enantiomers of a 4-(9-6-S-a-cyanobenzylidene- protected 6-thiorhamnopyranosyl thioglycoside is described starting from d-mannnose and l-arabinose derivatives for the d- and l-series, respectively. This donor is effective in the prepa

Full text of DOI:10.1021/jo8022439

Stereocontrolled Synthesis of D- and L-ꢀ-Rhamnopyranosides with
4-O-6-S-r-Cyanobenzylidene-Protected 6-Thiorhamnopyranosyl
Thioglycosides
David Crich*,†,‡ and Linfeng Li†
Department of Chemistry, Wayne State UniVersity, 5101 Cass AVenue, Detroit, Michigan 48202, and
Institut de Chimie des Substances Naturelles, Centre National de la Recherche Scientifique, AVenue de la
Terrasse, 91198 Gif-sur-YVette, France
dcrich@icsn.cnrs-gif.fr
ReceiVed October 07, 2008
The synthesis of both enantiomers of a 4-O-6-S-R-cyanobenzylidene-protected 6-thiorhamnopyranosyl
thioglycoside is described starting from D-mannnose and L-arabinose derivatives for the D- and L-series,
respectively. This donor is effective in the preparation of the corresponding ꢀ-glycosides using the
1-benzenesulfinyl piperidine/trifluoromethanesulfonic anhydride protocol. Following desulfurization and
concomitant debenzylation with Raney nickel, the so-formed 6-thio-ꢀ-mannosides are converted in high
yield to the ꢀ-rhamnopyranosides.
Introduction
of a series of 6-mono-, di-, and trifluororhamnopyranosyl donors,
with good success for coupling to more reactive alcohols but
only limited selectivity for the less reactive, carbohydrate-based
acceptor alcohols.4 In the L-series the Ito group recently has
provided a practical solution to this problem through their
adaptation5 of the Hindsgaul intramolecular aglycone delivery
method,6 but the method is not readily extended to the D-series
owing to the very limited availability of D-rhamnose other than
through synthesis. Accordingly, in the D-series we have
developed first and second generation methods based on the
use of 4,6-O-acetal protected mannopyranosyl donors followed
by reductive radical fragmentation reactions leading directly to
the ꢀ-D-rhamnopyranosides.7 Although we have successfully
applied this type of methodology to the synthesis of a ꢀ-(1f3)-
rhamnotetraose and other ꢀ-rhamnoside and 6-deoxy-ꢀ-man-
noheptoside containing oligosaccharides,8 its reliance on a
The 4,6-O-benzylidene-directed ꢀ-mannosylation reaction has
provided a practical, convenient solution to the long-standing
problem of the sterecontrolled formation of the ꢀ-mannopyra-
nosides.1 ꢀ-Rhamnopyranosides, the 6-deoxy congeners of
ꢀ-mannopyranosides, remain problematic as a result of their
6-deoxy nature. Mechanistic considerations2 led to the study
of a series of L-rhamnopyranosyl donors carrying strongly
electron-withdrawing groups on O23 and also to the investigation
† Wayne State University.
‡ Centre National de la Recherche Scientifique.
(1) (a) Crich, D.; Sun, S. J. Org. Chem. 1997, 62, 1198–1199. (b) Crich, D.;
Sun, S. Tetrahedron 1998, 54, 8321–8348. (c) Crich, D.; Smith, M. J. Am. Chem.
Soc. 2001, 123, 9015–9020. (d) Crich, D.; Smith, M. J. Am. Chem. Soc. 2002,
124, 8867–8869. (e) Crich, D.; Banerjee, A.; Li, W.; Yao, Q. J. Carbohydr.
Chem. 2005, 24, 415–424. (f) Code´e, J. D. C.; Kro¨ck, L.; Castagner, B.;
Seeberger, P. H. Chem. Eur. J. 2008, 14, 3987–3994. (g) Kim, K. S.; Kim, J. H.;
Lee, Y. J.; Lee, Y. J.; Park, J. J. Am. Chem. Soc. 2001, 123, 8477–8481. (h)
Kim, K. S.; Fulse, D. B.; Baek, J. Y.; Lee, B.-Y.; Jeon, H. B. J. Am. Chem. Soc.
2008, 130, 8537–8547. (i) Weingart, R.; Schmidt, R. R. Tetrahedron Lett. 2000,
41, 8753–8758. (j) Tsuda, T.; Sato, S.; Nakamura, S.; Hashimoto, S. Heterocycles
2003, 59, 509–515. (k) Yun, M.; Shin, Y.; Chun, K. H.; Jen, S. Bull. Chem.
Soc. Kor. 2000, 21, 562–566. (l) Tanaka, S.-i.; Takashima, M.; Tokimoto, H.;
Fujimoto, Y.; Tanaka, K.; Fukase, K. Synlett 2005, 2325–2328. (m) Crich, D.;
Li, H. J. Org. Chem. 2000, 56, 801–805. (n) Crich, D.; Sharma, I. Org. Lett.
2008, 10, 4731–4734.
(2) (a) Crich, D.; Sun, S. J. Am. Chem. Soc. 1997, 119, 11217–11223. (b)
Crich, D.; Chandrasekera, N. S. Angew. Chem., Int. Ed. 2004, 43, 5386–5389.
(3) (a) Crich, D.; Picione, J. Org. Lett. 2003, 5, 781–784. (b) Crich, D.;
Hutton, T. K.; Banerjee, A.; Jayalath, P.; Picione, J. Tetrahedron: Asymmetry
2005, 16, 105–119. (c) Bedini, E.; Carabellese, A.; Barone, G.; Parrilli, M. J.
Org. Chem. 2005, 70, 8064–8070.
(4) Crich, D.; Vinogradova, O. J. Am. Chem. Soc. 2007, 129, 11756–11765.
(5) (a) Lee, Y. J.; Ishiwata, A.; Ito, Y. J. Am. Chem. Soc. 2008, 130, 6330–
6331. (b) Ishiwata, A.; Munemura, Y.; Ito, Y. Eur. J. Org. Chem. 2008, 4250–
4263.
(6) (a) Barresi, F.; Hindsgaul, O. J. Am. Chem. Soc. 1991, 113, 9376–9377.
(b) Barresi, F.; Hindsgaul, O. Synlett 1992, 759–761. (c) Barresi, F.; Hindsgaul,
O. Can. J. Chem. 1994, 72, 1447–1465. (d) Stork, G.; Kim, G. J. Am. Chem.
Soc. 1992, 114, 1087–1088. (e) Stork, G.; La Clair, J. J. J. Am. Chem. Soc.
1996, 118, 247–248. (f) Jung, K.-H.; Müller, M.; Schmidt, R. R. Chem. ReV.
2000, 100, 4423–4442.
(7) (a) Crich, D.; Yao, Q. Org. Lett. 2003, 5, 2189–2191. (b) Crich, D.;
Bowers, A. A. J. Org. Chem. 2006, 71, 3452–3463.
(8) (a) Crich, D.; Bowers, A. A. Org. Lett. 2006, 8, 4327–4330. (b) Crich,
D.; Yao, Q. J. Am. Chem. Soc. 2004, 126, 8232–8236. (c) Crich, D.; Banerjee,
A. J. Am. Chem. Soc. 2006, 128, 8078–8086.
10.1021/jo8022439 CCC: $40.75
Published on Web 12/05/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 773–781 773

Crich and Li
SCHEME 1. Synthesis of Two D-Rhamnopyranosyl Donors
anticipated to improve selectivity on the basis of its electron-
withdrawing ability, which was predicated to counteract the
expected detrimental effect of the replacement of O6 by a sulfur
atom. In addition we anticipated that the electron-withdrawing
cyano group would deactivate the oxathiane ring system toward
the promoter employed to bring about glycosylation. The
equatorial location of the phenyl substituent on the oxathiane
ring in 3 was established by NOE correlations between the acetal
hydrogen and hydrogens 4 and 6ax of the pyranose ring. The
acetal hydrogen in 3 exhibits a chemical shift in CDCl3
somewhat downfield from that found in the more common
benzylidene acetals (dioxanes), but this is in keeping with other
1,3-oxathianes and is considered to be the result of the reduced
reverse Perlin effect of the ring sulfur.13 The stereochemistry
of the cyanoacetal moiety in 4 is assigned on the basis of
analogy with earlier cyanoacetals prepared in this laboratory,
which were assigned rigorously by X-ray crystallography,7b and
is the result of the minimal steric bulk of the cyano group in
combination with the role of the anomeric effect in the formation
of this derivative.
Coupling reactions with 3, carried out by means of the
1-benzenesulfinylpiperidine (BSP)/trifluoromethanesulfonic an-
hydride preactivation protocol1c in the presence of the hindered
base 2,4,6-tri-tert-butylpyrimidine (TTBP),14 were both complex
and difficult to reproduce owing to the apparent incompatibility
of the oxathiane ring system with the activation conditions
coupled with poor diastereoselectivity. Similar results were
observed on activation with 4-nitrobenzenesulfenyl chloride15
in combination with silver trifluoromethanesulfonate. Therefore,
we rapidly moved to the cyanoacetal 4 and were fortunate to
find both a high degree of chemo- and stereoselectivity in
couplings conducted by the BSP/Tf2O/TTBP method as set out
for the examples in Table 1. With methyl 2,3-O-isopropylidene-
R-L-rhamnopyranoside as acceptor, inspection of the crude
coupling reaction mixture by NMR spectroscopy revealed the
formation of only a single glycoside, the ꢀ-product 5, in
excellent yield (Table 1, entry 1). With the less reactive methyl
2,3,6-tri-O-acetyl-R-D-glucopyranoside as acceptor, the ꢀ:R ratio
was somewhat reduced but was still respectable at 4.9:1 (Table
1, entry 2). A primary carbohydrate acceptor, methyl 2,3,4-tri-
O-benzoyl-R-D-glucopyranoside, gave only the desired ꢀ-gly-
coside (Table 1, entry 3). Finally, with 1-adamantanol the
observed anomeric ratio was 10.5:1 in favor of the ꢀ-isomer
(Table 1, entry 4). Desulfurization was affected by means of
Raney nickel in methanol at reflux and was complemented by
the removal of all benzyl ether protecting groups, resulting in
the formation of the ꢀ-D-rhamnosides presented in Table 1.
temperature-sensitive radical fragmentation reaction is likely to
preclude its widespread applicability. Here, we describe our
investigations into the synthesis, glycosylation, and subsequent
desulfurization of a set of 4-O-6-S-cyclic monothioacetals of
6-thiomannopyranose in both the D- and L-series.9
Results and Discussion
In a seminal contribution10 Bols and co-workers revealed the
disarming effect of 4,6-O-benzylidene groups on glycosyl donors
to be due to a combination of a torsional effect, as originally
postulated by the Fraser-Reid group for the 4-pentenyl 4,6-O-
benzylidene-glucopyranosides,11 and more importantly, the
locking of the O5-C5-C6-O6 torsion angle in the antiperipla-
nar conformation (tg conformation) thereby maximizing the
electron-withdrawing effect of O6. In line with this rational a
4,7-O-alkylidene protected D-glycero-D-mannoheptosyl donor
studied in this laboratory was found to be lacking in selectivity
owing to the greater conformational mobility of the seven-
membered system, which mitigates any effects based on changes
in torsional strain and precludes the adoption of the tg
conformation about O5-C5-C6-O6.8c On this basis and taking
into account the lower electronegativity of sulfur compared to
that of oxygen and the greater C-S bond length, it was by no
means clear at the onset of this work that a 4-O-6-S-acetal
protected 6-thiomannopyranosyl donor would exhibit the req-
uisite ꢀ-selectivity. Furthermore, our ability to activate a
thioglycoside selectively in the presence of an oxathiane ring
was open to question.
We began with the synthesis of a simple benzylidene
monothioacetal 3, employing the thio-Mitsunobu reaction12 to
access the 6-thio system from a suitably protected D-mannopy-
ranoside as set out in Scheme 1. In anticipation of the
inadequacy of this simple system, a cyanoacetal 4 was also
introduced through a two-step, orthoester exchange, cyanation
protocol (Scheme 1). The cyano group in donor 4 was
With a successful, practical entry to the ꢀ-D-rhamnopyrano-
sides in hand, it was of interest to investigate its extrapolation
to the L-series. In view of the cost of L-mannose, this required
a de novo synthesis of an appropriately functionalized 6-thio-
L-mannose derivative. This was achieved as set out in Scheme
2 from allyl 3,4-O-isopropylidene-L-arabinopyranoside 13,16
which was converted conventionally to the 3,4-di-O-benzyl-2-
O-naphthylmethyl hemiacetal 15 with palladium-mediated
cleavage of the allyl glycoside.17 Wittig olefination18 afforded
(9) For earlier uses of sulfur-based ring systems as a means of controlling
glycosylation selectivity with subsequent desulfurization in the synthesis of 2,6-
dideoxyglucopyranosides, see: (a) Toshima, K.; Mukaiyama, S.; Ishiyama, T.;
Tatsuta, K. Tetrahedron Lett. 1990, 31, 3339–3342. (b) Toshima, K.; Tatsuta,
K. Chem. ReV. 1993, 93, 1503–1531.
(13) (a) Juaristi, E.; Cuevas, G.; Flores-Vela, A. Tetrahedron Lett. 1992,
33, 6927–6930. (b) Juaristi, E.; Cuevas, G. Acc. Chem. Res. 2007, 40, 961–970.
(14) Crich, D.; Smith, M.; Yao, Q.; Picione, J. Synthesis 2001, 323–326.
(15) Crich, D.; Cai, F.; Yang, F. Carbohydr. Res. 2008, 343, 1858–1862.
(16) (a) Finch, P.; Iskander, G. M.; Siriwardena, A. H. Carbohydr. Res. 1991,
210, 319–325. (b) Takeo, K.; Nakagen, M.; Teramoto, Y.; Nitta, Y. Carbohydr.
Res. 1990, 201, 261–275.
(10) Jensen, H. H.; Nordstrom, L. U.; Bols, M. J. Am. Chem. Soc. 2004,
126, 9205–9213.
(11) (a) Fraser-Reid, B.; Wu, Z. C.; Andrews, W.; Skowronski, E. J. Am.
Chem. Soc. 1991, 113, 1434–1435. (b) Andrews, C. W.; Rodebaugh, R.; Fraser-
Reid, B. J. Org. Chem. 1996, 61, 5280–5289.
(12) Volante, R. P. Tetrahedron Lett. 1981, 22, 3119–3122.
774 J. Org. Chem. Vol. 74, No. 2, 2009

Synthesis of D- and L-ꢀ-Rhamnopyranosides
TABLE 1. Formation of ꢀ-D-Rhamnopyranosides by Means of
Donor 4
the alkene 16, which was subjected to dihydroxylation with the
Sharpless (DHQD)2PYR catalyst,19 resulting in a mixture of
diols that was converted directly to the acetonide derivative 17
in good overall yield. In this sequence the in-built selectivity
of the allylic ether system20 for the desired isomer is reinforced
by the use of the chiral ligand, leading to the formation of a
workable 6.5:1 selectivity for the mannitol isomer.21 Swern
oxidation of the primary alcohol was followed by release of
the acetal, resulting in the formation of the L-mannopyranose
derivative 18, which was converted to the corresponding
thioglycoside by acetylation and then exposure to thiophenol
and BF3 etherate.22 After removal of the naphthylmethyl ether
and the residual acetate group, diol 20 was obtained, whose
R-anomer was spectroscopically identical in all respects to
compound 1, thereby confirming the identity of the major isomer
resulting from the osmoylation reaction. Thereafter the remain-
ing steps of the synthesis of donor 22 mirrored exactly those of
the enantiomer 4, except that an anomeric mixture of thiogly-
cosides was carried through the sequence.
Donor 22 was then coupled to three of the same alcohols as
its enantiomer 4 leading to the results presented in Table 2. A
fourth coupling involved the use of 1,2;5,6-di-O-isopropylidene-
R-D-glucofuranose as acceptor. As with the D-series, Table 1,
yields and selectivities in these coupling reactions were generally
excellent. Raney nickel was again the reagent of choice for the
final desulfurization step, with concomitant removal of any
benzyl ethers.
The comparison of entry 2 in Tables 1 and 2 reveals an
obvious case of diastereomeric matching and mismatching23 in
glycosylation reactions. Such phenomena were alluded to several
decades ago by Paulsen24 and then were highlighted by van
Boeckel and co-workers.25 Other examples of the phenomenon
have been established by Ziegler for intramolecular aglycone
delivery,26 and the phenomenon has been discussed more
recently in the guise of reciprocal donor acceptor selectivity
(RDAS) by Fraser-Reid and co-workers.27,28 The striking
difference in selectivities for the two couplings to methyl 2,3,6-
tri-O-acetyl-R-D-glucopyranoside presented here highlight the
a
1
Determined by H NMR spectroscopy on the crude reaction mixture.
b Ratio determined after chromatographic purification. c Desulfurization
was conducted with anomerically pure ꢀ-mannosides.
SCHEME 2. Synthesis of Enantiomeric Donor 22
(17) Zhang, J.; Zhu, Y.; Kong, F. Carbohydr. Res. 2001, 336, 229–235.
(18) (a) Lancelin, J.-M.; Pougny, J.-R.; Sinay¨, P. Carbohydr. Res. 1985, 136,
369–374. (b) Sisu, E.; Sollogoub, M.; Mallet, J.-M.; Sinay¨, P. Tetrahedron 2002,
58, 10189–10196. (c) Koruienko, A.; d’Alareao, M. Tetrahedron Lett. 1997,
38, 6497–6500. (d) Chen, Q.; Du, Y. Tetrahedron Lett. 2006, 47, 8489–8492.
(e) Ye, X.-S.; Sun, F.; Liu, M.; Li, Q.; Wang, Y.; Zhang, G.; Zhang, L.-H.;
Zhang, X.-L. J. Med. Chem. 2005, 48, 3688–3691. (f) Nadein, O. N.; Kornienko,
A. Org. Lett. 2004, 6, 831–834.
(19) (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K. S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu, D.;
Zhang, X.-L. J. Org. Chem. 1992, 57, 2768–2771. (b) Kolb, H. C.; Van
Nieuwenhze, M. S.; Sharpless, K. B. Chem. ReV. 1994, 94, 2483–2549.
(20) (a) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron 1984, 40, 2247–
2255. (b) Cha, J. K.; Kim, N.-S. Chem. ReV. 1995, 95, 1761–1795.
(21) In the absence of the chiral ligand the selectivity was 3.7:1.
(22) Prolonged exposure of this apparent kinetic mixture to the reaction
conditions in an attempt to bring about equilibration to a thermodynamic mixture
resulted in decomposition.
(23) (a) Horeau, A.; Kagan, H.-B.; Vigneron, J. P. Bull. Soc. Chim. Fr. 1968,
3795–3797. (b) Masamune, S.; Choy, W.; Peterson, J. S.; Sita, L. R. Angew.
Chem., Int. Ed. 1985, 24, 1–30.
(24) Paulsen, H. In SelectiVity a Goal for Synthetic Efficiency; Bartmann,
W., Trost, B. M., Eds.; Verlag Chemie: Weinheim, 1984; pp 169-190.
(25) Spijker, N. M.; van Boeckel, C. A. A. Angew. Chem., Int. Ed. 1991,
30, 180–183.
(26) Ziegler, T.; Lemanski, G. Eur. J. Org. Chem. 1998, 163–170.
(27) (a) Fraser-Reid, B.; Lo´pez, J. C.; Go´mez, A. M.; Uriel, C. Eur. J. Org.
Chem. 2004, 1387–1395. (b) Jayaprakash, K. N.; Chaudhuri, S. R.; Murty,
C. V. S. R.; Fraser-Reid, B. J. Org. Chem. 2007, 72, 5534–5545.
(28) Also see:(a) Doores, K. J.; Davis, B. G. Org. Biomol. Chem. 2008, 6,
2692–2696. (b) Cid, M. B.; Alonso, I.; Alfonso, F.; Bonilla, J. B.; Lo´pez-Prados,
J.; Mart´ın-Lomas, M. Eur. J. Org. Chem. 2006, 3947–3959.
J. Org. Chem. Vol. 74, No. 2, 2009 775

Crich and Li
TABLE 2. Formation of ꢀ-L-Rhamnopyranosides by Means of
Donor 22
FIGURE 1. Diagnostic chemical shifts.
normal value. In the absence of this convenient indicator we
1
fall back on the measurement of anomeric JCH anomeric
coupling constants, which follow the well-established pattern,
for the assignment of anomeric stereochemistry.
Conclusion
The stereocontrolled synthesis of ꢀ-rhamnopyranosides may
be conveniently achieved through prior activation of a 4-O-6-
S-cyclic cyanoacetal-protected 6-thiorhamnopyranosyl thiogly-
coside followed by introduction of the acceptor alcohol and
subsequent desulfurization with Raney nickel. The presence of
the electron-withdrawing cyano group, which serves inter alia
to protect the oxathiane ring from attack by the glycosylation
promoter, is essential to the success of the coupling reaction.
Experimental Section
Phenyl
2,3-Di-O-benzyl-1,6-dithio-r-D-mannopyranoside
(2). To an ice-cooled solution of PPh3 (1.22 g, 4.64 mmol) in THF
(10 mL) was added DIAD (914 µL, 4.64 mmol) dropwise. The
reaction mixture was stirred at 0 °C for 1 h, and 11d (1.40 g, 3.09
mmol) in THF (5 mL) was then added followed by AcSH (442
µL, 6.18 mmol). The cooling bath was removed, and the reaction
mixture was stirred at room temperature for 12 h. After TLC showed
no starting material remained, the reaction mixture was cooled to
0 °C, and LiAlH4 (352 mg, 9.27 mmol) was added portion wise.
After 15 min, the cooling bath was removed, and the reaction
mixture was stirred at room temperature for 3 h. The reaction
mixture was again cooled to 0 °C, before water was added dropwise
to quench the reaction. The reaction mixture was then diluted with
CH2Cl2 and washed with 1 N HCl and brine. The organic layer
was dried over Na2SO4 and concentrated. Chromatographic puri-
a
1
Determined by H NMR spectroscopy on the crude reaction mixture.
b Ratio determined after chromatographic purification. c Desulfurization
was conducted with anomerically pure ꢀ-mannosides
difficulties faced by any attempt at the development of any truly
general glycosylation methodology and underline the need for
considerable caution in and critical appraisal of the results from
lengthy oligosaccharide synthesis conducted on polymeric
supports in an automated manner.29
In our work on the use of 4,6-O-benzyldiene protected
mannopyranosyl donors, we have repeatedly emphasized the
chemical shift of the mannose H5 proton as being a ready
indicator of the stereochemistry at the anomeric center. Thus,
in the ꢀ-series H5 typically resonates in an otherwise largely
empty spectral window from δ 3.0-3.4, whereas in the
corresponding R-isomers the corresponding signal is to be found
from δ 3.6-3.9. This simple, completely reliable tool unfor-
tunately does not extend to the acetal protected 6-thio series
studied here for which H5 in the ꢀ-series is found to resonate
at a more typical value of ∼δ 3.4-3.5 for an axial proton on a
cyclohexane chair. It is apparent from this change in chemical
shift between the standard 4,6-O-benzylidene series and the
oxathianes presented here that the unusual upfield shift in the
former is due to the shielding of H5 by the axial lone pairs on
O4 and O6 coupled with the absence any deshielding from the
anomeric position (Figure 1). In the oxathiane series the longer
C-S bond coupled with the less tightly held, more diffuse S
lone pair suffices to return the H5 chemical shift to a more
fication on silica gel (15% ethyl acetate in hexane) afforded 2 (1.23
1
g, 85%) as a colorless oil: [R]16 +54.0 (c 1.0, CHCl3); H NMR
D
(500 MHz, CDCl3) δ 7.52-7.50 (m, 2H), 7.39-7.26 (m, 13H),
5.60 (s, 1H), 4.70 (d, J ) 12.5 Hz, 1H), 4.58 (d, J ) 11.5 Hz, 1H),
4.57 (d, J ) 12.0 Hz, 1H), 4.45 (d, J ) 12.0 Hz, 1H), 4.14 (t, J )
9.0 Hz, 1H), 4.04-4.00 (m, 2H), 3.67-3.65 (dd, J ) 2.5, 9.5 Hz,
1H), 3.00-2.96 (dd, J ) 9.5, 11.5 Hz, 1H), 2.83-2.77 (dt, J )
7.0, 14.0 Hz, 1H), 2.42 (d, J ) 1.5 Hz, 1H), 1.59 (t, J ) 8.5 Hz,
1H); 13C NMR (125.9 MHz, CDCl3) δ 137.7, 137.6 134.0, 132.0,
129.1, 128.7, 128.5, 128.1, 128.00, 127.96, 127.9, 127.7, 86.0, 79.6,
75.4, 74.2, 72.1, 71.6, 69.1, 26.5; HRESIMS calcd for
C26H28O4S2Na [M + Na]+, 491.1322; found, 491.1328.
Phenyl 2,3-Di-O-benzyl-4-O,6-S-benzylidene-1,6-dithio-r-D-
mannopyranoside (3). Compound 2 (178 mg, 0.380 mmol), CSA
(8.8 mg, 38.0 µmol), and benzaldehyde dimethyl acetal (114 µL,
0.760 mmol) were dissolved in DMF (5 mL) and heated on a rotary
evaporator at 50 °C for 4 h. The reaction mixture was cooled to
room temperature and neutralized by the addition of triethylamine.
DMF was removed under vacuum, and the reaction residue was
diluted with EtOAc and washed with saturated NaHCO3. The
aqueous phase was extracted with EtOAc, and the combined organic
(29) Solid Support Oligosaccharide Synthesis and Combinatorial Carbohy-
drate Libraries; Seeberger, P. H., Ed.; Wiley-Interscience: New York, 2001.
776 J. Org. Chem. Vol. 74, No. 2, 2009

Synthesis of D- and L-ꢀ-Rhamnopyranosides
phase was washed with water and brine, dried, and concentrated.
Chromatographic purification (5% ethyl acetate in hexane) afforded
3 (181 mg, 85%) as a colorless oil: [R]12D +139.6 (c 1.0, CHCl3);
1H NMR (500 MHz, CDCl3) δ 7.52-7.41 (m, 2H), 7.39-7.26 (m,
18H), 5.98 (s, 1H), 5.52 (s, 1H), 4.76-4.70 (m, 3H), 4.64 (d, J )
12.0 Hz, 1H), 4.43-4.38 (dt, J ) 3.5, 10.0 Hz, 1H), 4.13 (t, J )
9.5 Hz, 1H), 4.02 (d, J ) 1.5 Hz, 1H), 3.96-3.94 (dd, J ) 3.0,
10.0 Hz, 1H), 3.32-3.27 (dd, J ) 11.0, 13.0 Hz, 1H), 2.85-2.81
(dd, J ) 4.0, 13.0 Hz, 1H); 13C NMR (125.9 MHz, CDCl3) δ 138.3,
138.1, 137.7, 134.0, 131.4, 129.2, 128.6, 128.5, 128.4, 128.2, 127.9,
127.8, 127.7, 127.6, 126.1, 86.4, 83.9, 81.2, 77.7, 76.3, 73.3, 72.8,
68.0, 32.2; HRESIMS calcd for C33H32O4S2Na [M + Na]+,
579.1635; found, 579.1636.
yield of 97.4 mg (89%). Colorless oil; [R]19D -36.0 (c 0.5, CHCl3);
1H NMR (500 MHz, CDCl3) δ 7.68-7.66 (m, 2H), 7.46-7.43 (m,
5H), 7.33-7.21 (m, 8H), 4.95 (s, 1H), 4.91 (d, J ) 12.5 Hz, 1H),
4.87 (s, 1H), 4.83 (d, J ) 12.0 Hz, 1H), 4.55 (t, J ) 9.5 Hz, 1H),
4.53 (d, J ) 13.0 Hz, 1H), 4.48 (d, J ) 13.0 Hz, 1H), 4.12-4.09
(m, 2H), 3.96 (d, J ) 3.0 Hz, 1H), 3.69-3.65 (m, 3H), 3.61-3.58
(dd, J ) 3.0, 9.5 Hz, 1H), 3.51-3.46 (dt, J ) 3.0, 9.5 Hz, 1H),
3.41 (s, 3H), 2.95-2.91 (dd, J ) 3.5, 13.0 Hz, 1H), 1.49 (s, 3H),
1.36 (d, J ) 5.5 Hz, 3H), 1.34 (s, 3H); 13C NMR (125.9 MHz,
CDCl3) δ 138.5, 138.1, 135.4, 130.2, 128.8, 128.4, 128.3, 128.1,
127.6, 127.54, 127.50, 115.9, 109.3, 99.5 (1JCH ) 158.6 Hz), 97.9
(1JCH ) 168.7 Hz), 78.8, 78.3, 78.0, 77.9, 77.8, 76.1, 75.6, 74.6,
71.8, 69.5, 64.1, 55.0, 31.5, 28.0, 26.4, 17.7; HRESIMS calcd for
C38H43NO9SNa [M + Na]+, 712.2551; found, 712.2551.
Phenyl 2,3-Di-O-benzyl-4-O,6-S-(1-cyano)benzylidene-1,6-
dithio-r-D-mannopyranoside (4). To a stirred solution of 2 (181
mg, 386 µmol) and CSA (17.9 mg, 77.2 µmol) in CH2Cl2 (800
µL) was add trimethyl orthobenzoate (663 µL, 3.86 mmol) at room
temperature. After 4 h, the reaction mixture was diluted with
CH2Cl2, washed with aqueous NaHCO3 and brine, and dried over
Na2SO4. The organic layer was concentrated and subjected to
chromatographic purification on silica gel (5% ethyl acetate in
hexane) to give the orthoester. To an ice-cooled solution of this
orthoester and TMSCN (193 µL, 1.54 mmol) in CH2Cl2 (1.7 mL)
was added BF3 ·Et2O (19 µL, 154 µmol) dropwise. The reaction
mixture was stirred at 0 °C for 1 h and another 2 h at room
temperature, before saturated NaHCO3 was added and stirring was
continued for ∼10 min. The reaction mixture was then diluted with
CH2Cl2 and washed with saturated NaHCO3 and brine. The organic
layer was dried over Na2SO4 and concentrated. Chromatographic
purification on silica gel (5% ethyl acetate in hexane) afforded 4
Methyl ꢀ-D-Rhamnopyranosyl-(1f4)-2,3-O-isopropylidene-r-
L-rhamnopyranoside (6). Prepared by the general desulfurization
procedure with a yield of 22.1 mg (79%). Colorless oil; [R]12
:
D
1
-61.9 (c 1.0, CH3Cl); H NMR (500 MHz, CD3OD) δ 4.87 (s,
1H), 4.81 (s, 1H), 4.13 (t, J ) 6.0 Hz, 1H), 4.09 (d, J ) 5.5 Hz,
1H), 3.86 (d, J ) 3.0 Hz, 1H), 3.63-3.60 (m, 2H), 3.39-3.36 (dd,
J ) 3.5, 9.5 Hz, 1H), 3.36 (s, 3H), 3.33-3.29 (m, 1H), 3.33-3.29
(m, 1H), 3.20-3.13 (m, 1H), 1.49 (s, 3H), 1.33 (s, 3H), 1.31 (d, J
) 6.0 Hz, 3H), 1.27 (d, J ) 5.5 Hz, 3H); 13C NMR (125.9 MHz,
CD3OD) δ 109.1, 98.6 (1JCH ) 159.9 Hz), 97.9 (1JCH ) 172.5 Hz),
78.4, 77.8, 76.0, 73.8, 72.6, 72.4, 71.3, 64.0, 53.8, 26.8, 25.3, 16.66,
16.62; HRESIMS calcd for C16H28O9Na [M + Na]+, 387.1626;
found, 387.1626.
Methyl
2,3-Di-O-benzyl-4-O,6-S-(1-cyano)benzylidene-ꢀ-
D-mannopyranosyl-(1f4)-2,3,6-tri-O-acetyl-r-D-glucopyranoside
(7ꢀ) and Methyl 2,3-Di-O-benzyl-4-O,6-S-(1-cyano)benzylidene-
r-D-mannopyranosyl-(1f4)-2,3,6-tri-O-acetyl-r-D-glucopyranoside
(7r). Prepared by the general glycosylation procedure with a
combined yield of 132.2 mg (67%, R/ꢀ ) 1:4.9). 7ꢀ: colorless oil;
(166 mg, 74%) as a colorless oil: [R]23 +130.0 (c 1.0, CHCl3);
D
1H NMR (500 MHz, CDCl3) δ 7.72-7.70 (m, 2H), 7.47-7.45 (m,
3H), 7.38-7.26 (m, 15H), 5.50 (s, 1H), 4.78 (d, J ) 12.0 Hz, 1H),
4.73 (d, J ) 12.0 Hz, 1H), 4.69 (t, J ) 10.0 Hz, 1H), 4.67 (d, J )
12.5 Hz, 1H), 4.61 (d, J ) 12.5 Hz, 1H), 4.44-4.39 (dt, J ) 3.5,
10.0 Hz, 1H), 4.03 (d, J ) 2.0 Hz, 1H), 3.94-3.92 (dd, J ) 3.0,
9.5 Hz, 1H), 3.63-3.58 (dd, J ) 11.0, 13.0 Hz, 1H), 2.90-2.87
(dd, J ) 4.0, 13.0 Hz, 1H); 13C NMR (125.9 MHz, CDCl3) δ 138.1,
137.7, 135.4, 133.7, 131.2, 130.2, 129.3, 128.8, 128.5, 128.4, 128.2,
127.9, 127.8, 127.7, 125.5, 115.9, 86.7, 78.7, 78.2, 77.5, 75.9, 73.1,
72.9, 67.2, 31.4; HRESIMS calcd for C34H31NO4S2Na [M + Na]+,
604.1587; found, 604.1575.
[R]22 +20.0 (c 1.5, CHCl3); 1H NMR (500 MHz, CDCl3) δ
D
7.67-7.65 (m, 2H), 7.46-7.27 (m, 13H), 5.52 (t, J ) 9.5 Hz, 1H),
4.89-4.82 (m, 2H), 4.81 (d, J ) 12.5 Hz, 1H), 4.78 (d, J ) 12.5
Hz, 1H), 4.57 (s, 2H), 4.51 (t, J ) 9.5 Hz, 1H), 4.37 (s, 1H),
4.24-4.22 (dd, J ) 1.5, 12.0 Hz, 1H), 4.16-4.12 (dd, J ) 4.0,
12.0 Hz, 1H), 3.84 (d, J ) 2.5 Hz, 1H), 3.82-3.78 (ddd, J ) 2.5,
3.5, 10.0 Hz, 1H), 3.74 (t, J ) 9.5 Hz, 1H), 3.58-3.53 (m, 2H),
3.48-3.45 (dd, J ) 3.5, 9.5 Hz, 1H), 3.43 (s, 3H), 3.02-2.99 (dd,
J ) 3.5, 13.0 Hz, 1H), 2.11 (s, 3H), 2.09 (s, 3H), 2.06 (s, 3H); 13
C
General Glycosylation Procedure Using the BSP/TTBP/
Tf2O System. To a stirred solution of donor (1 equiv), BSP (1.2
equiv), TTBP (1.5 equiv), and 4 Å molecular sieves in CH2Cl2 (0.05
M in donor) at -60 °C was added Tf2O (1.2 equiv). After 30 min
of stirring at -60 °C, a 0.15 M solution of the glycosyl acceptor
(1.5 equiv) in CH2Cl2 was slowly added. The reaction mixture was
stirred for a further 2 h at -60 °C, before saturated NaHCO3 was
added to quench the reaction. The reaction mixture was allowed to
reach room temperature, filtered through a pad of Celite, and washed
with CH2Cl2, after which the filtrate was washed with saturated
NaHCO3 and brine. The organic layer was separated, dried over
Na2SO4, and concentrated. Purification by column chromatography
on silica gel, eluting with hexane/ethyl acetate mixtures, afforded
the corresponding coupled products.
General Procedure for Raney Nickel Desulfurization. To a
stirred solution of ꢀ-mannoside in MeOH/CH2Cl2 (6:1, 0.02 M)
was added a solid portion (∼30.0 g/mmol) of wet Raney nickel
slurry (W. R. Grace and Co. Raney2800, Aldrich). The reaction
mixture was heated to reflux with stirring under hydrogen (1 atm)
until TLC showed that all the starting material was consumed. The
mixture was filtered through a pad of Celite and washed with
MeOH, and the filtrate was concentrated. Chromatographic puri-
fication on silica gel (∼10% MeOH in CH2Cl2) afforded the
corresponding ꢀ-rhamnoside.
NMR (125.6 MHz, CDCl3) δ 170.8, 170.7, 169.9, 138.6, 138.2,
135.4, 130.5, 129.0, 128.9, 128.6, 128.3, 127.8, 127.7, 125.7, 115.9,
101.1 (1JCH ) 153.1 Hz), 97.0 (1JCH ) 177.7 Hz), 79.0, 78.1, 77.8,
76.2, 75.6, 74.7, 72.4, 71.2, 69.9, 68.4, 62.5, 55.7, 31.8, 21.4, 21.1,
21.0; HRESIMS calcd for C41H45NO13SNa [M + Na]+, 814.2509;
found, 814.2485. 7r: colorless oil; [R]22 +67.2 (c 0.29, CHCl3);
D
1H NMR (500 MHz, CDCl3) δ 7.67-7.65 (m, 2H), 7.45-7.27 (m,
13H), 5.47 (t, J ) 9.5 Hz, 1H), 4.93-4.81 (m, 4H), 4.68-4.60
(m, 4H), 4.41-4.38 (dd, J ) 1.5, 12.5 Hz, 1H), 4.18-4.15 (dd, J
) 5.0, 12.5 Hz, 1H), 3.98-3.93 (dt, J ) 3.5, 10.0 Hz, 1H),
3.92-3.88 (m, 2H), 3.78 (t, J ) 9.5 Hz, 1H), 3.71-3.69 (m, 1H),
3.53-3.48 (dd, J ) 11.0, 13.0 Hz, 1H), 3.41 (s, 3H), 3.00-2.97
(dd, J ) 3.5, 13.0 Hz, 1H), 2.11 (s, 3H), 2.08 (s, 3H), 1.82 (s, 3H);
13C NMR (125.6 MHz, CDCl3) δ 170.9, 170.5, 169.9, 138.4, 138.2,
135.6, 130.3, 129.0, 128.8, 128.6, 128.1, 127.9, 127.8, 125.7, 116.1,
102.3 (1JCH ) 172.2 Hz), 96.9 (1JCH ) 174.5 Hz), 79.0, 78.1, 77.9,
76.7, 76.2, 73.8, 73.3, 72.0, 71.1, 68.1, 67.7, 63.1, 55.7, 31.4, 21.1,
21.0, 20.8; HRESIMS calcd for C41H45NO13SNa [M + Na]+,
814.2509; found, 814.2467.
Methyl ꢀ-D-Rhamnopyranosyl-(1f4)-2,3,6-tri-O-acetyl-r-D-
glucopyranoside (8). Prepared by the general desulfurization
procedure with a yield of 21.8 mg (69%). Colorless gel; [R]23
D
+78.0 (c 0.15, CHCl3); 1H NMR (500 MHz, CD3OD) δ 5.41 (t, J
) 9.5 Hz, 1H), 4.82-4.79 (dd, J ) 3.0, 10.0 Hz, 1H), 4.48 (s,
1H), 4.41-4.38 (dd, J ) 1.5, 12.0 Hz, 1H), 4.31-4.28 (dd, J )
5.0, 12.5 Hz, 1H), 3.96-3.93 (ddd, J ) 1.5, 4.5, 10.0 Hz, 1H),
3.87 (d, J ) 9.5 Hz, 1H), 3.83 (d, J ) 3.0 Hz, 1H), 3.41 (s, 3H),
Methyl 2,3-Di-O-benzyl-4-O,6-S-[(1-cyano)benzylidene]-ꢀ-D-
mannopyranosyl-(1f4)-2,3-O-isopropylidene-r-L-rhamnopyrano-
side (5). Prepared by the general glycosylation procedure with a
J. Org. Chem. Vol. 74, No. 2, 2009 777

Crich and Li
1
3.31-3.27 (m, 1H), 3.22-3.16 (m, 1H), 2.10 (s, 3H), 2.06 (s, 3H),
2.04 (s, 3H), 1.31 (d, J ) 6.5 Hz, 3H); 13C NMR (125.6 MHz,
CD3OD) δ 171.3, 171.4, 170.6, 100.5, 96.9, 76.2, 73.7, 72.6, 72.4,
71.4, 71.2, 70.5, 68.5, 62.6, 54.5, 20.2, 19.5, 19.3, 17.1; HRESIMS
calcd for C19H30O13Na [M + Na]+, 489.1584; found, 489.1570.
Methyl 2,3-Di-O-benzyl-4-O,6-S-(1-cyano)benzylidene-ꢀ-D
-mannopyranosyl-(1f6)-2,3,4-tri-O-benzoyl-r-D-glucopyrano-
side (9). Prepared by the general glycosylation procedure with a
White solid; mp 156 °C; [R]24 -5.8 (c 0.2, CHCl3); H NMR
D
(400 MHz, CDCl3) δ 4.78 (s, 1H), 3.83 (s, 1H), 3.46-3.40 (m,
2H), 3.29-3.21 (m, 1H), 2.77-2.43 (br s, 3H), 2.16 (s, 3H), 1.84
(d, J ) 11.6 Hz, 3H), 1.78 (d, J ) 11.2 Hz, 3H), 1.65 (d, J ) 12.8
Hz, 3H), 1.60 (d, J ) 12.4 Hz, 3H), 1.33 (d, J ) 6.4 Hz, 3H); 13
C
NMR (100.6 MHz, CDCl3) δ 92.5, 74.9, 73.6, 72.6, 71.4, 42.6,
36.4, 30.9, 18.0; HRESIMS calcd for C16H26O5Na [M + Na]+,
321.1678; found, 321.1694.
yield of 154.9 mg (82%). Colorless gel; [R]24 +10.8 (c 1.0,
Allyl 3,4-O-Isopropylidene-r-L-arabinopyranoside (13r)
and Allyl 3,4-O-Isopropylidene-ꢀ-L-arabinopyranoside (13ꢀ).
Compound 13 was prepared from L-arabinose in two steps according
to literature precedure16 (75%, R/ꢀ ) 1.9:1). Analytically pure
samples of the two anomers were obtained by further purification
of a portion of the product by radial chromatography (20% ethyl
acetate in hexane). 13r: white solid; mp 71-72 °C; [R]22D +225.6
(c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 5.96-5.88 (m, 1H),
5.33-5.28 (dd, J ) 1.5, 17.5 Hz, 1H), 5.24-5.21 (dd, J ) 1.5,
10.5 Hz, 1H), 4.87 (d, J ) 3.5 Hz, 1H), 4.27-4.18 (m, 3H),
4.07-4.02 (dd, J ) 6.0, 13.0 Hz, 1H), 3.99-3.95 (dd, J ) 3.0,
13.0 Hz, 1H), 3.92-3.89 (dd, J ) 1.5, 13.0 Hz, 1H), 3.80-3.77
(dt, J ) 3.5, 7.0 Hz, 1H), 2.30 (d, J ) 10.5 Hz, 1H), 1.52 (s, 3H),
1.35 (s, 3H); 13C NMR (125.6 MHz, CDCl3) δ 133.8, 118.1, 109.4,
97.0 (1JCH ) 170.9 Hz), 76.2, 73.2, 70.3, 68.9, 59.9, 28.2, 26.2;
HRESIMS calcd for C11H18O5Na [M + Na]+, 253.1052; found,
253.1065. 13ꢀ: colorless oil; [R]22D +25.8 (c 2.0, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 5.97-5.88 (m, 1H), 5.33-5.29 (dd, J ) 1.5,
17.5 Hz, 1H), 5.23-5.20 (dd, J ) 1.5, 10.5 Hz, 1H), 4.36-4.31
(ddt, J ) 1.5, 5.5, 12.5 Hz, 1H), 4.25-4.21 (m, 2H), 4.19-4.15
(dd, J ) 3.5, 13.0 Hz, 1H), 4.11-4.06 (m, 2H), 3.79-3.75 (dd, J
) 3.5, 13.0 Hz, 1H), 3.66-3.62 (dt, J ) 3.0, 7.5 Hz, 1H), 2.64 (d,
J ) 2.5 Hz, 1H), 1.53 (s, 3H), 1.36 (s, 3H); 13C NMR (125.6 MHz,
CDCl3) δ 134.0, 118.2, 110.4, 101.3 (1JCH ) 163.4 Hz), 78.3, 73.8,
73.2, 69.9, 63.3, 28.2, 26.3; HRESIMS calcd for C11H18O5Na [M
+ Na]+, 253.1052; found, 253.1050.
Allyl 2-O-(2-Naphthylmethyl)-r-L-arabinopyranoside (14r)
and Allyl 2-O-(2-Naphthylmethyl)-ꢀ-L-arabinopyranoside
(14ꢀ). To a ice-cooled solution of 13rꢀ (9.21 g, 40.0 mmol) and
tetrabutylammonium iodide (1.48 g, 4.00 mmol) in DMF (50 mL)
was added sodium hydride (60% in mineral oil, 2.40 g, 60.0 mmol)
under stirring. After 10 min, 2-(bromomethyl)naphthalene (10.6 g,
48.0 mmol) was added, and stirring was continued for 4 h at room
temperature. The reaction mixture was concentrated. The resulting
residue was dissolved in AcOH: H2O (4:1, 100 mL), and stirred at
80 °C for 3 h. The reaction mixture was concentrated, dissolved in
ethyl acetate, and washed with saturated NaHCO3. The aqueous
phase was extracted with EtOAc three times, and the combined
organic phase was washed with water and brine, dried, and
concentrated. Chromatographic purification (20% ethyl acetate in
hexane to ethyl acetate) on silica gel afforded 14 (11.8 g, R/ꢀ )
1.9:1, 89%). Analytically pure samples of the two anomers were
obtained by further purification of a portion of the product by radial
D
CHCl3); 1H NMR (500 MHz, CDCl3) δ 8.03-7.88 (m, 6H),
7.69-7.22 (m, 24H), 6.21 (t, J ) 9.5 Hz, 1H), 5.52 (t, J ) 9.5 Hz,
1H), 5.31-5.27 (m, 2H), 5.04 (d, J ) 12.5 Hz, 1H), 4.97 (d, J )
12.5 Hz, 1H), 4.58 (t, J ) 9.5 Hz, 1H), 4.53 (s, 2H), 4.50 (s, 1H),
4.35-4.32 (m, 1H), 4.21-4.18 (dd, J ) 1.5, 10.5 Hz, 1H), 4.09
(d, J ) 3.0 Hz, 1H), 3.71-3.67 (dd, J ) 6.5, 11.0 Hz, 1H),
3.61-3.56 (m, 2H), 3.51-3.46 (m, 1H), 3.48 (s, 3H), 2.89-2.86
(dd, J ) 3.5, 13.0 Hz, 1H); 13C NMR (125.6 MHz, CDCl3) δ 166.1,
166.0, 165.8, 138.5, 138.3, 135.6, 133.9, 133.7, 133.4, 130.4, 130.2,
130.1, 129.9, 129.5, 129.3, 129.0, 128.8, 128.7, 128.6, 128.5,
127.87, 127.85, 125.4, 115.9, 102.2 (1JCH ) 155.7 Hz), 97.1 (1JCH
) 177.6 Hz), 79.1, 77.8, 75.6, 75.0, 72.4, 72.2, 70.7, 69.8, 69.7,
69.1, 68.9, 55.8, 31.5; HRESIMS calcd for C56H51NO13SNa [M +
Na]+, 1000.2979; found, 1000.3001.
Methyl ꢀ-D-Rhamnopyranosyl-(1f6)-2,3,4-tri-O-benzoyl-r-
D-glucopyranoside (10). Prepared by the general desulfurization
procedure with a yield of 34.0 mg (73%). Colorless gel; [R]22
D
1
+35.2 (c 1.0, CHCl3); H NMR (500 MHz, CDCl3) δ 7.99-7.85
(m, 6H), 7.53-7.26 (m, 9H), 6.16 (t, J ) 10.0 Hz, 1H), 5.63 (t, J
) 10.0 Hz, 1H), 5.30-5.27 (dd, J ) 3.5, 10.0 Hz, 1H), 5.24 (d, J
) 3.5 Hz, 1H), 4.48 (s, 1H), 4.28-4.25 (ddd, J ) 1.5, 5.0, 10.0
Hz, 1H), 4.16-4.12 (m, 2H), 3.75-3.71 (dd, J ) 5.5, 13.0 Hz,
1H), 3.51-3.43 (m, 2H), 3.47 (s, 3H), 3.27-3.23 (m, 1H), 3.10
(s, 1H), 2.95 (s, 1H), 1.90 (s, 1H), 1.34 (d, J ) 6.0 Hz, 3H); 13C
NMR (125.6 MHz, CDCl3) δ 166.1, 166.0, 165.8, 133.8, 133.6,
133.4, 130.2, 130.1, 129.9, 129.4, 129.3, 129.0, 128.8, 128.7, 128.5,
100.6, 97.2, 74.4, 73.4, 72.3, 72.1, 70.73, 70.65, 69.4, 69.0, 68.0,
55.9, 17.7; HRESIMS calcd for C34H36O13Na [M + Na]+, 675.2054;
found, 675.2020.
1-Adamantanyl 2,3-Di-O-benzyl-4-O,6-S-(1-cyano)benzylidene-
ꢀ-D-mannopyranoside (11ꢀ) and 1-Adamantanyl 2,3-Di-O-benzyl-
4-O,6-S-(1-cyano)benzylidene-r-D-mannopyranoside (11r). Prepared
by the general glycosylation procedure with a combined yield of
112.4 mg (87%, R/ꢀ ) 1:10.5). 11ꢀ: white solid; mp 182 °C; [R]15
D
1
+9.5 (c 0.2, CHCl3); H NMR (500 MHz, CDCl3) δ 7.68-7.66
(m, 2H), 7.50-7.44 (m, 5H), 7.37-7.22 (m, 8H), 5.01 (d, J )
12.5 Hz, 1H), 4.95 (d, J ) 12.5 Hz, 1H), 4.73 (s, 1H), 4.58 (t, J )
9.5 Hz, 1H), 4.51 (d, J ) 13.0 Hz, 1H), 4.48 (d, J ) 12.5 Hz, 1H),
3.77 (d, J ) 2.5 Hz, 1H), 3.69-3.64 (dd, J ) 10.5, 13.0 Hz, 1H),
3.58-3.56 (dd, J ) 3.0, 9.5 Hz, 1H), 3.53-3.48 (dt, J ) 3.0, 10.0
Hz, 1H), 2.97-2.93 (dd, J ) 3.5, 13.5 Hz, 1H), 2.17 (s, 3H), 1.86
(d, J ) 11.0 Hz, 3H), 1.76 (d, J ) 11.5 Hz, 3H), 1.66 (d, J ) 12.0
Hz, 3H), 1.61 (d, J ) 12.0 Hz, 3H); 13C NMR (125.9 MHz, CDCl3)
δ 138.5, 138.2 135.5, 130.1, 128.9, 128.8, 128.3, 128.1, 127.55,
127.51, 127.47, 125.5, 115.8, 94.3 (1JCH ) 152.3 Hz), 78.8, 78.3,
77.8, 76.1, 75.4, 74.3, 72.0, 69.0, 42.5, 36.2, 31.6, 30.6; HRESIMS
chromatography (60% ethyl acetate). 14r: white solid; mp 86-87
1
°C; [R]25 +108.5 (c 0.2, CHCl3); H NMR (500 MHz, CDCl3) δ
D
7.84-7.78 (m, 4H), 7.50-7.47 (m, 3H), 5.96-5.87 (m, 1H),
5.35-5.31 (dd, J ) 1.5, 17.0 Hz, 1H), 5.21-5.19 (dd, J ) 1.5,
10.5 Hz, 1H), 4.90 (d, J ) 3.5 Hz, 1H), 4.79 (s, 2H), 4.17-4.13
(ddt, J ) 12.5, 5.0, 1.5 Hz, 1H), 4.07-4.06 (dd, J ) 3.0, 10.0 Hz,
1H), 3.95-3.90 (m, 2H), 3.81-3.76 (m, 2H), 3.67-3.64 (dd, J )
2.0, 12.5 Hz, 1H), 3.03 (s, 1H), 2.99 (s, 1H); 13C NMR (125.6
MHz, CDCl3) δ 135.7, 134.1, 133.5, 133.3, 128.6, 128.2, 128.0,
127.1, 126.5, 126.4, 126.1, 118.0, 96.1 (1JCH ) 174.7 Hz), 77.1,
73.0, 69.3, 68.8, 68.6, 62.3; HRESIMS calcd for C19H22O9Na [M
+ Na]+, 353.1365; found, 353.1377. 14ꢀ: white solid; mp 103 °C;
calcd for C38H41NO5SNa [M + Na]+, 646.2603; found, 646.2589.
1
11r: colorless oil; [R]22 +67.2 (c 0.29, CHCl3); H NMR (500
D
MHz, CDCl3) δ 7.72-7.66 (m, 3H), 7.54-7.22 (m, 12H), 5.01 (d,
J ) 1.0 Hz, 1H), 4.88 (d, J ) 12.5 Hz, 1H), 4.72-4.57 (m, 4H),
4.11-4.08 (dt, J ) 3.5, 10.0 Hz, 1H), 4.01-3.98 (dd, J ) 3.0,
10.0 Hz, 1H), 3.64-3.63 (m, 1H), 3.57-3.52 (dd, J ) 11.5, 13.0
Hz, 1H), 2.87-2.84 (dd, J ) 4.0, 13.5 Hz, 1H), 2.12 (s, 3H),
1.68-1.54 (m, 12H); 13C NMR (125.6 MHz, CDCl3) δ 138.9, 138.6
135.6, 130.5, 129.2, 129.0, 128.6, 128.5, 127.9, 127.7, 125.7, 124.6,
116.2, 92.5 (1JCH ) 168.4 Hz), 78.9, 78.8, 77.7, 76.6, 75.1, 73.7,
73.3, 65.8, 42.4, 36.4, 31.8, 30.8; HRESIMS calcd for
C38H41NO5SNa [M + Na]+, 646.2603; found, 646.2617.
[R]25 +5.4 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ
D
7.86-7.80 (m, 4H), 7.51-7.47 (m, 3H), 5.96-5.88 (m, 1H),
5.34-5.30 (dd, J ) 1.5, 17.5 Hz, 1H), 5.23-5.21 (dd, J ) 1.5,
10.5 Hz, 1H), 4.97 (d, J ) 12.0 Hz, 1H), 4.83 (d, J ) 12.0 Hz,
1H), 4.58 (d, J ) 4.5 Hz, 1H), 4.36-4.32 (dd, J ) 5.0, 13.0 Hz,
1H), 4.10-4.05 (dd, J ) 6.0, 13.0 Hz, 1H), 3.98-3.92 (m, 1H),
1-Adamantanyl ꢀ-D-rhamnopyranoside (12). Prepared by the
general desulfurization procedure with a yield of 25.6 mg (74%).
778 J. Org. Chem. Vol. 74, No. 2, 2009

Synthesis of D- and L-ꢀ-Rhamnopyranosides
3.84-3.77 (m, 2H), 3.68-3.65 (dd, J ) 5.0, 6.5 Hz, 1H), 3.57-3.54
(dd, J ) 3.0, 12.0 Hz, 1H), 3.12 (d, J ) 7.0 Hz, 1H), 2.74 (d, J )
6.5 Hz, 1H); 13C NMR (125.6 MHz, CDCl3) δ 135.6, 133.8, 133.5,
133.3, 128.6, 128.2, 128.0, 127.1, 126.5, 126.3, 126.1, 118.1, 100.5
(1JCH ) 163.4 Hz), 77.7, 74.0, 71.2, 69.6, 66.6, 63.0; HRESIMS
calcd for C19H22O9Na [M + Na]+, 353.1365; found, 353.1380.
3,4-Di-O-benzyl-2-O-(2-naphthylmethyl)-L-arabinopyranose
(15). To a ice-cooled solution of 14rꢀ (12.1 g, 36.6 mmol) and
tetrabutylammonium iodide (1.35 g, 3.66 mmol) in DMF (54 mL)
was added sodium hydride (60% in mineral oil, 3.67 g, 91.6 mmol)
under stirring. After 15 min, benzyl bromide (10.9 mL, 91.6 mmol)
was added, and stirring was continued for 6 h at room temperature.
The reaction mixture was concentrated, dissolved in ethyl acetate,
and washed with brine. The organic layer was concentrated, and
the resulting residue was dissolved in AcOH (135 mL) and water
(15 mL). AcONa (9.01 g, 109.8 mmol) and PdCl2 (2.60 g, 14.6
mmol) were added, and the reaction mixture was stirred at room
temperature for 20 h. The reaction mixture was concentrated,
dissolved in CH2Cl2, and filtered through Celite. The filtrate was
washed with saturated NaHCO3 and brine. The organic layer was
separated, dried over Na2SO4, and concentrated. Chromatographic
purification on silica gel (20% ethyl acetate in hexane) afforded
15 (13.4 g, 78%) as a colorless oil, which was used for the next
step without further purification. HRESIMS calcd for C30H30O5Na
[M + Na]+, 493.1991; found, 493.2004. The sugar proton signals
for the two R/ꢀ anomers are difficult to distinguish, only assignable
peaks from the NMR spectra are listed. 1H NMR (500 MHz, CDCl3)
δ 7.87-7.71 (m), 7.53-7.23 (m), 5.96-5.87 (m, 1H), 5.20 (s),
4.93-4.55 (m), 4.08-4.04 (dd, J ) 9.0, 11.5 Hz), 3.95-3.66 (m),
3.13 (d, J ) 5.0 Hz); 13C NMR (125.6 MHz, CDCl3) δ 138.6, 138.4,
138.3, 137.6, 135.6, 133.4, 133.3, 128.74, 128.71, 128.6, 128.3,
128.2, 128.1, 128.04, 128.97, 127.9, 127.1, 127.0, 126.5, 126.3,
126.1, 126.0, 94.0, 92.4, 76.4, 76.3, 75.7, 74.0, 73.2, 72.9, 72.3,
71.8, 61.2, 58.6.
3,4-Di-O-benzyl-2-O-(2-naphthylmethyl)-L-arabino-hex-1-enitol
(16). To a stirred suspension of methyltriphenylphosphonium
bromide (9.58 g, 26.8 mmol) in THF (35 mL) was added potassium
tert-butoxide (2.88 g, 25.7 mmol) after which the reaction mixture
was stirred at room temperature for 1 h and then cooled to -40
°C. A solution of 15 (5.05 g, 10.7 mmol) in THF (18.5 mL) was
added dropwise to the above suspension, and the resulting mixture
was warmed to 0 °C over 1 h and stirred at 0 °C overnight. Acetone
(25 mL) was added to quench the reaction, and the reaction mixture
was stirred at room temperature for ∼15 min. The reaction mixture
was filtered through Celite and concentrated. The residue was
purified by column chromatography on silica gel to afford 16 (3.60
g, 72%). Colorless oil; [R]24D +19.3 (c 1.0, CHCl3); 1H NMR (500
MHz, CDCl3) δ 7.81-7.76 (m, 2H), 7.47-7.11 (m, 15H),
5.98-5.91 (m, 1H), 5.41-5.33 (m, 2H), 4.82 (d, J ) 12.0 Hz,
1H), 4.77 (d, J ) 11.5 Hz, 1H), 4.74 (d, J ) 11.5 Hz, 1H), 4.51
(d, J ) 12.0 Hz, 1H), 4.46 (d, J ) 11.5 Hz, 1H), 4.32 (d, J ) 11.5
Hz, 1H), 4.11-4.08 (dd, J ) 4.5, 7.5 Hz, 1H), 3.84-3.80 (m, 2H),
3.77-3.11 (m, 2H), 2.18 (t, J ) 6.5 Hz, 1H); 13C NMR (125.6
MHz, CDCl3) δ 138.4, 138.2, 136.1, 135.9, 133.5, 133.2, 128.60,
128.57, 128.5, 128.4, 128.1, 128.0, 127.93, 127.89, 127.0, 126.4,
126.3, 126.1, 119.2, 81.8, 80.8, 79.1, 75.4, 71.9, 70.8, 61.1;
HRESIMS calcd for C31H32O4Na [M + Na]+, 491.2198; found,
491.2184.
dried, and concentrated to give a white solid. To a stirred solution
of this preparation in CH3CN (10 mL) were added 2,2-dimethox-
ypropane (3.40 mL, 26.6 mmol) and CSA (309 mg, 1.33 mmol).
The reaction mixture was stirred at room temperature for 4 h before
triethylamine was added to quench to reaction. The reaction mixture
was concentrated, and radial chromatographic purification (15%
ethyl acetate in hexane) afforded 17 (2.64 g, mannitol/gulitol )
6.5:1, 73%). Colorless oil; [R]22D 3.2 (c 1.0, CHCl3); 1H NMR (500
MHz, CDCl3) δ 7.82-7.70 (m, 3H), 7.47-7.25 (m, 12H), 4.88 (d,
J ) 12.0 Hz, 1H), 4.79-4.70 (m, 3H), 4.59 (d, J ) 11.5 Hz, 1H),
4.40 (d, J ) 11.5 Hz, 1H), 4.30-4.26 (m, 1H), 4.03-3.76 (m,
7H), 2.08-2.05 (m, 1H), 1.45 (s, 3H), 1.33 (s, 3H); 13C NMR (125.6
MHz, CDCl3) δ 138.3, 138.2, 136.0, 133.5, 133.2, 128.8, 128.7,
128.4, 128.2, 128.1, 128.0, 127.9, 127.8, 126.6, 126.3, 126.11,
126.07, 108.8, 79.6, 79.2, 77.4, 76.8, 74.8, 74.6, 71.7, 66.9, 60.2,
26.8, 25.4; HRESIMS calcd for C34H38O6Na [M + Na]+, 565.2566;
found, 565.2564.
2,3-Di-O-benzyl-4-O-(2-naphthylmethyl)-L-mannopyranose
(18). To a stirred solution of DMSO (750 µL, 10.6 mmol) in CH2Cl2
(8.4 mL) at -78 °C was added oxalyl chloride (714 µL, 8.44 mmol)
dropwise. The reaction mixture was stirred at -78 °C for 30 min,
and the solution of 17 (2.29 g, 4.21 mmol) in CH2Cl2 (4.2 mL)
was added slowly. The reaction mixture was stirred for 45 min at
-78 °C. Triethylamine (2.93 mL, 21.1 mmol) was added dropwise,
and the reaction mixture was stirred for 30 min at -78 °C and
then allowed to warm up to 0 °C over 1 h, before water was added
to quench the reaction. The reaction mixture was then diluted with
CH2Cl2 and washed with water and brine. The organic layer was
dried over Na2SO4 and concentrated. The resulting residue was
dissolved in THF/trifluoroacetic acid (4:1, 10 mL). The reaction
mixture was stirred at room temperature for 2 h before solid
NaHCO3 was added and stirring was continued for ∼10 min. The
reaction mixture was concentrated, dissolved in ethyl acetate, and
washed with saturated NaHCO3. The aqueous phase was extracted
with EtOAc, and the combined organic phase was washed with
water and brine, dried, and concentrated to give crude 18 (1.90 g,
90%) as a colorless oil, which was used for the next step without
further purification. HRESIMS calcd for C31H32O6Na [M + Na]+,
523.2097; found, 523.2136. The sugar proton signals for the two
R/ꢀ anomers are difficult to distinguish, only assignable peaks from
the NMR spectra are listed. 1H NMR (400 MHz, CDCl3) δ
7.84-7.78 (m), 7.55-7.27 (m), 5.20 (s), 5.18-5.14 (m), 4.75-4.42
(m), 4.17 (t, J ) 8.0 Hz), 4.03-3.81 (m), 3.66-3.46 (m), 2.95 (d,
J ) 6.0 Hz); 13C NMR (100.6 MHz, CDCl3) δ 138.4, 138.2, 138.0,
135.1, 133.4, 133.3, 128.8, 128.73, 128.69, 128.6, 128.5, 128.4,
128.2, 128.1, 128.04, 128.00, 127.97, 127.9, 127.3, 127.2, 126.7,
126.6, 126.5, 126.07, 126.01, 94.9, 93.0, 78.0, 75.5, 75.2, 74.6,
74.4, 74.1, 73.5, 73.3, 73.0, 72.7, 72.2, 71.1, 66.4, 62.7, 62.6.
Phenyl 6-O-Acetyl-2,3-di-O-benzyl-4-O-(2-naphthylmethyl)-
1-thio-r-L-mannopyranoside (19r) and Phenyl 6-O-acetyl-2,3-
di-O-benzyl-4-O-(2-naphthylmethyl)-1-thio-ꢀ-L-mannopyranoside
(19ꢀ). To a stirred solution of 18rꢀ (1.12 g, 2.24 mmol) and DMAP
(27.4 mg, 0.224 mmol) in CH2Cl2 (11 mL) were added Ac2O (1.27
mL, 13.4 mmol) and triethylamine (2.50 mL, 17.9 mmol) at room
temperature. After 6 h, the mixture was concentrated, dissolved in
CH2Cl2, and washed with saturated NaHCO3 and brine. The organic
layer was dried over Na2SO4 and concentrated. To the stirred
solution of the resulting crude in CH2Cl2 (5.5 mL) at 0 °C was
added PhSH (253 µL, 2.64 mmol), followed by BF3 ·Et2O (553
µL, 4.48 mmol). The solution was stirred at 0 °C for 4 h, before
saturated NaHCO3 was added and stirring was continued for ∼10
min at room temperature. The reaction mixture was then diluted
with CH2Cl2 and washed with saturated NaHCO3 and brine. The
organic layer was dried over Na2SO4 and concentrated. Column
chromatography on silica gel (15% ethyl acetate in hexane) provided
19 (1.11 g, R/ꢀ ) 1:3.5, 78%). Analytically pure samples of the
two anomers were obtained by further purification of a portion of
2,3-Di-O-benzyl-5,6-O-isopropylidene-4-O-(2-naphthylmethyl)-
L-mannitol (17). To a well-stirred suspension of (DHQD)2PYR (58.6
mg, 6.65 µmol), K3Fe(CN)6 (3.28 g, 9.99 mmol), K2CO3 (1.38 g,
9.99 mmol), and OsO4 (834 µL, 2.5% in tert-BuOH, 6.65 µmol)
in tert-BuOH (9 mL) and water (15 mL) at 0 °C was added 16
(3.12 g, 6.65 mmol) in tert-BuOH (6 mL). The reaction mixture
was stirred at 0 °C for 24 h before saturated Na2SO3 was added
and stirring was continued for ∼30 min at room temperature. The
reaction mixture was extracted with EtOAc and washed with
saturated NaHCO3. The aqueous phase was extracted with EtOAc,
and the combined organic phase was washed with water and brine,
the product by radial chromatography (15% ethyl acetate in hexane)
1
on silica gel. 19r: colorless oil; [R]22 -70.0 (c 1.0, CHCl3); H
D
J. Org. Chem. Vol. 74, No. 2, 2009 779

Crich and Li
NMR (500 MHz, CDCl3) δ 7.83-7.75 (m, 3H), 7.48-7.25 (m,
19H), 5.58 (d, J ) 1.5 Hz, 1H), 5.10 (d, J ) 11.0 Hz, 1H), 4.78
(d, J ) 11.0 Hz, 1H), 4.73 (d, J ) 12.5 Hz, 1H), 4.65 (d, J ) 12.5
Hz, 1H), 4.64 (s, 2H), 4.37-4.32 (m, 3H), 4.05-4.01 (m, 2H),
3.94-3.91 (dd, J ) 3.0, 9.5 Hz, 1H), 1.93 (s, 3H); 13C NMR (125.6
MHz, CDCl3) δ 171.1, 138.2, 138.1, 135.8, 134.3, 133.5, 133.3,
131.9, 129.3, 128.73, 128.66, 128.5, 128.2, 128.13, 128.11, 128.08,
128.05, 127.9, 127.8, 127.2, 126.4, 126.3, 126.2, 85.8 (1JCH ) 168.9
Hz), 80.5, 76.3, 75.5, 74.7, 72.3, 72.2, 71.2, 63.7, 21.0; HRESIMS
calcd for C39H38O6SNa [M + Na]+, 657.2287; found, 657.2246.
19ꢀ: colorless oil; [R]22D +45.2 (c 1.0, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 7.83-7.71 (m, 3H), 7.51-7.23 (m, 19H), 5.07 (d, J )
11.0 Hz, 1H), 5.06 (d, J ) 12.0 Hz, 1H), 4.88 (d, J ) 12.0 Hz,
1H), 4.80-4.76 (m, 3H), 4.71 (d, J ) 12.0 Hz, 1H), 4.48-4.45
(dd, J ) 2.0, 11.5 Hz, 1H), 4.27-4.23 (dd, J ) 7.0, 12.0 Hz, 1H),
4.18 (d, J ) 2.0 Hz, 1H), 4.00 (t, J ) 9.5 Hz, 1H), 3.69-3.66 (dd,
J ) 2.5, 9.0 Hz, 1H), 3.59-3.55 (dt, J ) 2.0, 9.0 Hz, 1H), 1.99 (s,
3H); 13C NMR (125.6 MHz, CDCl3) δ 171.1, 138.4, 138.1, 135.7,
135.5, 133.5, 133.3, 131.1, 129.1, 128.8, 128.5, 128.2, 128.1,
4.14 (t, J ) 9.0 Hz, 1H), 4.04-4.00 (m, 2H), 3.67-3.65 (dd, J )
2.5, 9.5 Hz, 1H), 3.00-2.96 (dd, J ) 9.5, 11.5 Hz, 1H), 2.83-2.77
(dt, J ) 7.0, 14.0 Hz, 1H), 2.42 (d, J ) 1.5 Hz, 1H), 1.59 (t, J )
8.5 Hz, 1H); 13C NMR (125.6 MHz, CDCl3) δ 137.9, 137.8 134.2,
132.2, 129.4, 128.9, 128.7, 128.4, 128.25, 128.20, 128.1, 127.9,
86.2 (1JCH ) 167.4 Hz), 79.8, 75.6, 74.4, 72.3, 71.8, 69.3, 26.7;
HRESIMS calcd for C26H28O4S2Na [M + Na]+, 491.1327; found,
491.1342. 21ꢀ: white solid; mp 99 °C; [R]22D +81.4 (c 0.5, CHCl3);
1H NMR (500 MHz, CDCl3) δ 7.58-7.47 (m, 4H), 7.38-7.25 (m,
11H), 4.97 (d, J ) 11.5 Hz, 1H), 4.88 (d, J ) 11.5 Hz, 1H), 4.84
(s, 1H), 4.74 (d, J ) 12.0 Hz, 1H), 4.49 (d, J ) 11.5 Hz, 1H), 4.21
(d, J ) 2.0 Hz, 1H), 3.95-3.90 (dt, J ) 3.0, 9.5 Hz, 1H), 3.43-3.40
(dd, J ) 3.0, 9.5 Hz, 1H), 3.34-3.30 (dt, J ) 1.5, 9.0 Hz, 1H),
2.98-2.92 (dt, J ) 2.5, 12.5 Hz, 1H), 2.86-2.79 (m, 1H), 2.32 (d,
J ) 1.5 Hz, 1H), 1.84-1.80 (dd, J ) 6.0, 11.0 Hz, 1H); 13C NMR
(125.6 MHz, CDCl3) δ 138.1, 137.6, 135.3, 131.1, 129.2, 129.0,
128.6, 128.5, 128.1, 127.6, 88.0 (1JCH ) 154.0 Hz), 83.8, 82.1,
76.4, 75.4, 72.2, 69.7, 27.0. HRESIMS calcd for C26H28O4S2Na
[M + Na]+, 491.1327; found, 491.1353.
127.94, 127.91, 127.5, 127.2, 126.4, 126.3, 126.2, 88.0 (1JCH
)
Phenyl 2,3-Di-O-benzyl-4-O,6-S-(1-cyano)benzylidene-1,6-
dithio-r-L-mannopyranoside (22r) and Phenyl 2,3-Di-
O-benzyl-4-O,6-S-(1-cyano)benzylidene-1,6-dithio-ꢀ-L-manno-
pyranoside (22ꢀ). Following the general procedure for making 4,
21rꢀ was converted to 22 (R/ꢀ ) 1:3.5, 75%). Analytically pure
samples of the two anomers were obtained by further purification
of a portion of the product by radial chromatography (5% ethyl
acetate in hexane). 22r: colorless oil; [R]22D -129.8 (c 1.0, CHCl3);
1H NMR (500 MHz, CDCl3) δ 7.73-7.71 (m, 2H), 7.48-7.26 (m,
18H), 5.51 (s, 1H), 4.78 (d, J ) 12.0 Hz, 1H), 4.74 (d, J ) 12.0
Hz, 1H), 4.69 (t, J ) 9.5 Hz, 1H), 4.67 (d, J ) 12.5 Hz, 1H), 4.61
(d, J ) 12.5 Hz, 1H), 4.44-4.39 (dt, J ) 3.5, 9.5 Hz, 1H),
4.04-4.03 (dd, J ) 1.0, 3.0 Hz, 1H), 3.95-3.92 (dd, J ) 3.0, 9.5
Hz, 1H), 3.63-3.58 (dd, J ) 11.0, 13.0 Hz, 1H), 2.91-2.87 (dd,
J ) 4.0, 13.0 Hz, 1H); 13C NMR (125.6 MHz, CDCl3) δ 138.3,
137.9, 135.6, 133.9, 131.4, 130.4, 129.5, 129.0, 128.7, 128.6, 128.4,
128.1, 128.0, 127.9, 125.8, 116.1, 86.9 (1JCH ) 169.8 Hz), 79.0,
78.4, 77.7, 76.1, 73.3, 73.1, 67.4, 31.6; HRESIMS calcd for
C34H31NO4S2Na [M + Na]+, 604.1592; found, 604.1576. 22ꢀ: white
solid; mp 152-153 °C; [R]22D -6.3 (c 1.0, CHCl3); 1H NMR (500
MHz, CDCl3) δ 7.70-7.67 (m, 2H), 7.52-7.27 (m, 18H), 5.13 (d,
J ) 11.5 Hz, 1H), 4.88 (d, J ) 11.0 Hz, 1H), 4.82 (d, J ) 1.0 Hz,
1H), 4.75 (d, J ) 13.0 Hz, 1H), 4.70 (t, J ) 9.5 Hz, 1H), 4.68 (d,
J ) 12.5 Hz, 1H), 4.20 (d, J ) 2.5 Hz, 1H), 3.74-3.67 (m, 2H),
3.62-3.57 (dt, J ) 4.0, 9.5 Hz, 1H), 3.04-3.00 (dd, J ) 3.5, 13.0
Hz, 1H); 13C NMR (125.6 MHz, CDCl3) δ 138.1, 138.0, 135.5,
135.0, 131.7, 130.5, 129.2, 129.1, 129.0, 128.7, 128.5, 128.1, 128.0,
127.9, 125.7, 116.0, 88.8 (1JCH ) 153.5 Hz), 79.9, 79.0, 78.4, 78.1,
75.9, 73.5, 73.3, 31.6; HRESIMS calcd for C34H31NO4S2Na [M +
Na]+, 604.1592; found, 604.1608.
Methyl 2,3-Di-O-benzyl-4-O,6-S-(1-cyano)benzylidene-ꢀ-L
-mannopyranosyl-(1f4)-2,3-O-isopropylidene-r-L-rhamnopy-
ranoside (23). Prepared by the general glycosylation procedure with
a yield of 96.4 mg (85%). Colorless oil; [R]23D -3.4 (c 1.0, CHCl3);
1H NMR (500 MHz, CDCl3) δ 7.70-7.68 (m, 2H), 7.46-7.44 (m,
5H), 7.34-7.21 (m, 8H), 4.96 (d, J ) 12.5 Hz, 1H), 4.87 (d, J )
12.5 Hz, 1H), 4.85 (s, 1H), 4.65 (s, 1H), 4.59 (t, J ) 9.5 Hz, 1H),
4.54 (s, 2H), 4.43 (t, J ) 6.5 Hz, 1H), 4.12 (d, J ) 6.0 Hz, 1H),
3.96 (d, J ) 3.0 Hz, 1H), 3.72-3.66 (m, 2H), 3.61-3.58 (dd, J )
3.0, 9.5 Hz, 1H), 3.55-3.50 (dt, J ) 3.5, 10.0 Hz, 1H), 3.42-3.36
(m, 1H), 3.39 (s, 3H), 2.99-2.96 (dd, J ) 3.5, 13.0 Hz, 1H), 1.49
(s, 3H), 1.36 (d, J ) 5.5 Hz, 3H), 1.34 (s, 3H); 13C NMR (125.6
MHz, CDCl3) δ 138.5, 138.3, 135.6 130.4, 129.0, 128.8, 128.5,
128.4, 127.80, 127.77, 125.7, 116.0, 109.1, 101.5 (1JCH ) 156.4
Hz), 98.5 (1JCH ) 172.1 Hz), 83.5, 79.1, 78.5, 78.0, 76.9, 75.9,
75.7, 74.7, 72.4, 69.6, 64.2, 55.1, 31.6, 28.4, 26.5, 18.1; HRESIMS
calcd for C38H43NO9SNa [M + Na]+, 712.2556; found, 712.2563.
Methyl ꢀ-L-Rhamnopyranosyl-(1f4)-2,3-O-isopropylidene-
r-L-rhamnopyranoside (24). Prepared by the general desulfur-
ization procedure with a yield of 28.8 mg (76%). Colorless oil;
153.0 Hz), 84.6, 77.9, 77.5, 75.5, 75.3, 74.9, 72.8, 64.2, 21.0;
HRESIMS calcd for C39H38O6SNa [M + Na]+, 657.2287; found,
657.2291.
Phenyl 2,3-Di-O-benzyl-1-thio-r-L-mannopyranoside (20r)
and Phenyl 2,3-Di-O-benzyl-1-thio-ꢀ-L-mannopyranoside
(20ꢀ). To a stirred solution of 19rꢀ (1.10 g, 1.73 mmol) in CH2Cl2/
H2O (10:1, 5.5 mL) was added DDQ (787 mg, 3.46 mmol) at room
temperature. After 2 h, the reaction mixture was diluted with CH2Cl2
and washed with saturated NaHCO3 and brine. The organic layer
was dried over Na2SO4 and concentrated. A stirred solution of the
resulting crude in MeOH/CH2Cl2 (20:1, 10.5 mL) was treated with
K2CO3 (718 mg, 5.19 mmol) and stirred at room temperature for
3 h. The reaction mixture was concentrated, dissolved in CH2Cl2,
and washed with water and brine. The organic layer was dried over
Na2SO4 and concentrated. Chromatographic purification (35% ethyl
acetate in hexane) afforded 20 (634 mg, R/ꢀ ) 1:3.5, 81%).
Analytically pure samples of the two anomers were obtained by
further purification of a portion of the product by radial chroma-
tography (35% ethyl acetate in hexane). 20r: white solid; mp
1
94-95 °C; [R]22 -39.1 (c 1.0, CHCl3); H NMR (500 MHz,
D
CDCl3) δ 7.46-7.27 (m, 15H), 5.58 (d, J ) 1.0 Hz, 1H), 4.69 (d,
J ) 12.5 Hz, 1H), 4.60 (d, J ) 12.0 Hz, 1H), 4.59 (d, J ) 12.0
Hz, 1H), 4.53 (d, J ) 11.5 Hz, 1H), 4.18-4.11 (m, 2H), 4.03-4.02
(dd, J ) 1.5, 3.0 Hz, 1H), 3.91-3.82 (m, 2H), 3.74-3.71 (dd, J )
3.0, 9.5 Hz, 1H), 2.85 (d, J ) 1.5 Hz, 1H), 2.26 (t, J ) 5.0 Hz,
1H); 13C NMR (125.6 MHz, CDCl3) δ 138.0, 137.9, 134.2, 132.1,
129.4, 128.9, 128.7, 128.3, 128.24, 128.15, 128.0, 86.3 (1JCH
)
167.9 Hz), 79.9, 75.9, 73.6, 72.5, 72.1, 67.5, 62.8; HRESIMS calcd
for C26H28O5SNa [M + Na]+, 475.1555; found, 475.1532. 20ꢀ:
1
colorless oil; [R]22 +50.5 (c 1.0, CHCl3); H NMR (500 MHz,
D
CDCl3) δ 7.48-7.26 (m, 15H), 4.98 (d, J ) 11.5 Hz, 1H), 4.86 (s,
1H), 4.85 (d, J ) 11.0 Hz, 1H), 4.76 (d, J ) 11.5 Hz, 1H), 4.20
(d, J ) 2.0 Hz, 1H), 4.10-4.05 (dt, J ) 2.0, 9.5 Hz, 1H), 3.95-3.91
(m, 1H), 3.86-3.22 (m, 1H), 3.48-3.45 (dd, J ) 3.0, 9.5 Hz, 1H),
3.40-3.36 (m, 1H), 2.49 (d, J ) 2.5 Hz, 1H), 2.28 (t, J ) 6.5 Hz,
1H); 13C NMR (125.6 MHz, CDCl3) δ 138.1, 137.7, 135.3, 130.9,
129.3, 129.0, 128.6, 128.5, 128.4, 128.1, 128.0, 127.6, 88.1 (1JCH
) 154.5 Hz), 83.8, 80.3, 76.8, 75.5, 72.4, 67.7, 63.3; HRESIMS
calcd for C26H28O5SNa [M + Na]+, 475.1555; found, 475.1566.
Phenyl
2,3-Di-O-benzyl-1,6-dithio-r-L-mannopyranoside
(21r) and Phenyl 2,3-Di-O-benzyl-1,6-dithio-ꢀ-L-manno-
pyranoside (21ꢀ). Following the general procedure for making 2,
20rꢀ was converted to 21 (R/ꢀ ) 1:3.5, 87%). Analytically pure
samples of the two anomers were obtained by further purification
of a portion of the product by radial chromatography (10% ethyl
acetate in hexane). 21r: colorless oil; [R]23D -53.5 (c 1.0, CHCl3);
1H NMR (500 MHz, CDCl3) δ 7.52-7.50 (m, 2H), 7.39-7.26 (m,
13H), 5.60 (s, 1H), 4.70 (d, J ) 12.5 Hz, 1H), 4.58 (d, J ) 11.5
Hz, 1H), 4.57 (d, J ) 12.0 Hz, 1H), 4.45 (d, J ) 12.0 Hz, 1H),
780 J. Org. Chem. Vol. 74, No. 2, 2009

Synthesis of D- and L-ꢀ-Rhamnopyranosides
1
[R]23 +14.0 (c 0.4, CH3Cl); H NMR (500 MHz, CDCl3) δ 4.85
(dd, J ) 4.0, 11.0 Hz, 1H), 3.83 (d, J ) 2.5 Hz, 1H), 3.81-3.78
(dd, J ) 3.5, 11.0 Hz, 1H), 3.64-3.59 (dd, J ) 11.0, 13.0 Hz,
1H), 3.57-3.51 (m, 2H), 3.50-3.45 (m, 1H), 3.49 (s, 3H),
2.95-2.91 (dd, J ) 3.5, 13.0 Hz, 1H); 13C NMR (125.6 MHz,
CDCl3) δ 166.14, 166.08, 165.5, 138.6, 138.3, 135.6, 133.73,
133.68, 133.4, 130.4, 130.2, 130.1, 129.9, 129.5, 129.4, 129.3,
129.0, 128.8, 128.7, 128.6, 128.4, 127.84, 127.76, 1277.7, 125.4,
116.0, 102.0 (1JCH ) 157.3 Hz), 97.2 (1JCH ) 178.6 Hz), 79.1, 77.9,
77.8, 75.5, 74.8, 72.4, 72.1, 70.61, 70.56, 69.7, 68.9, 68.8, 56.0,
31.5; HRESIMS calcd for C56H51NO13SNa [M + Na]+, 1000.2979;
found, 1000.2957.
D
(s, 1H), 4.65 (s, 1H), 4.25 (t, J ) 7.5 Hz, 1H), 4.13 (d, J ) 5.5 Hz,
1H), 4.01 (s, 1H), 3.72-3.68 (m, 1H), 3.56-3.53 (dd, J ) 7.0, 9.5
Hz, 1H), 3.49-3.40 (m, 2H), 3.37 (s, 3H), 3.31-3.28 (m, 1H),
2.87 (br s, 1H), 2.78 (br s, 1H), 2.67 (br s, 1H), 1.54 (s, 3H), 1.37
(d, J ) 6.5 Hz, 3H), 1.36 (s, 3H), 1.29 (d, J ) 6.5 Hz, 3H); 13C
NMR (125.6 MHz, CDCl3) δ 109.5, 99.7, 98.3; 81.0, 76.7, 76.3,
74.8, 73.5, 72.3, 71.1, 64.8, 55.1, 28.2, 26.4, 17.9, 17.6; HRESIMS
calcd for C16H28O9Na [M + Na]+, 387.1631; found, 387.1640.
Methyl
2,3-Di-O-benzyl-4-O,6-S-(1-cyano)benzylidene-ꢀ-
L-mannopyranosyl-(1f4)-2,3,6-tri-O-acetyl-r-D-glucopyrano-
side (25ꢀ) and Methyl 2,3-Di-O-benzyl-4-O,6-S-(1-cyano)-
benzylidene-r-L-mannopyranosyl-(1f4)-2,3,6-tri-O-acetyl-
r-D-glucopyranoside (25r). Prepared by the general glycosylation
procedure with a combined yield of 98.7 mg (63%, R/ꢀ ) 1:9.6).
25ꢀ: colorless oil; [R]23D +67.2 (c 2, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.68-7.65 (m, 2H), 7.45-7.13 (m, 13H), 5.48 (t, J )
9.0 Hz, 1H), 4.87-4.74 (m, 4H), 4.49-4.40 (m, 5H), 4.36-4.31
(dd, J ) 7.0, 15.0 Hz, 1H), 3.86-3.81 (m, 1H), 3.73-3.9 (m, 2H),
3.61-3.55 (dd, J ) 13.0, 16.0 Hz, 1H), 3.47-3.40 (m, 2H), 3.42
(s, 3H), 2.95-2.91 (dd, J ) 4.0, 16.5 Hz, 1H), 2.08 (s, 6H), 1.90
(s, 3H); 13C NMR (100.6 MHz, CDCl3) δ 170.7, 170.6, 169.6,
138.5, 138.1, 135.5, 130.4, 129.0, 128.7, 128.6, 128.4, 127.9, 127.7,
125.7, 115.8, 102.5 (1JCH ) 162.0 Hz), 96.9 (1JCH ) 172.3 Hz),
79.0, 77.5, 76.5, 76.4, 75.2, 72.4, 72.1, 71.1, 69.8, 68.1, 63.2, 55.6,
31.5, 21.1, 21.0; HRESIMS calcd for C41H45NO13SNa [M + Na]+,
814.2509; found, 814.2465. 25r: colorless oil; [R]22D -15.2 (c 0.25,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.69-7.67 (m, 2H),
7.46-7.27 (m, 13H), 5.41 (t, J ) 9.5 Hz, 1H), 4.89 (d, J ) 12.5
Hz, 1H), 4.86 (d, J ) 4.0 Hz, 1H), 4.78-4.75 (ddd, J ) 1.0, 4.0,
10.0 Hz, 1H),4.73 (s, 1H), 4.69 (d, J ) 12.5 Hz, 1H), 4.68 (d, J )
12.5 Hz, 1H), 4.62-4.56 (m, 2H), 4.17-4.14 (dd, J ) 1.5, 12.5
Hz, 1H), 4.04-4.00 (dd, J ) 4.0, 12.0 Hz, 1H), 3.94-3.89 (dt, J
) 3.5, 10.0 Hz, 1H), 3.84-3.81 (dd, J ) 3.0, 10.0 Hz, 1H), 3.77
(d, J ) 10.0 Hz, 1H), 3.71 (s, 1H), 3.57 (t, J ) 10.0 Hz, 1H),
3.48-3.43 (dd, J ) 11.0, 12.5 Hz, 1H), 3.40 (s, 3H), 2.97-2.93
(dd, J ) 3.5, 13.0 Hz, 1H), 2.10 (s, 3H), 2.06 (s, 3H), 2.04 (s, 3H);
13C NMR (125.6 MHz, CDCl3) δ 170.6, 170.5, 138.5, 138.2, 135.7,
130.3, 129.0, 128.7, 128.6, 128.3, 128.0, 127.9, 125.7, 116.1, 101.0
(1JCH ) 172.6 Hz), 97.1 (1JCH ) 174.0 Hz), 78.9, 78.1, 77.9, 76.6,
76.4, 75.2, 73.9, 73.1, 71.5, 71.2, 68.1, 67.3, 62.1, 55.7, 31.1, 21.5,
21.02, 20.95; HRESIMS calcd for C41H45NO13SNa [M + Na]+,
814.2509; found, 814.2485.
Methyl ꢀ-L-Rhamnopyranosyl-(1f4)-2,3,4-tri-O-benzoyl-
r-D-glucopyranoside (28). Prepared by the general desulfurization
procedure with a yield of 33.2 mg (76%). White solid; mp 156-157
1
°C; [R]23 +91.2 (c 1.0, CHCl3); H NMR (500 MHz, CDCl3) δ
D
8.00-7.87 (m, 6H), 7.53-7.26 (m, 9H), 6.14 (t, J ) 9.5 Hz, 1H),
5.78 (t, J ) 10.0 Hz, 1H), 5.29-5.26 (m, 2H), 4.54 (s, 1H), 4.27
(d, J ) 10.0 Hz, 1H), 4.18-4.15 (dd, J ) 4.0, 11.0 Hz, 1H), 4.00
(s, 1H), 4.04 (d, J ) 10.0 Hz, 1H), 3.80-3.78 (dd, J ) 2.0, 11.0
Hz, 1H), 3.47 (s, 3H), 3.43-3.36 (m, 2H), 3.21-3.15 (m, 1H),
3.05-2.90 (br, 1H), 2.90-2.74 (br, 1H), 2.04-1.84 (br, 1H), 1.05
(d, J ) 6.0 Hz, 3H); 13C NMR (125.6 MHz, CDCl3) δ 166.1, 165.9,
133.7, 133.6, 133.4, 130.2, 130.1, 129.9, 129.44, 129.40, 129.3,
128.7, 128.5, 99.2, 97.5, 74.7, 73.7, 72.5, 71.9, 70.8, 70.7, 69.2,
68.6, 66.3, 56.0, 17.3; HRESIMS calcd for C34H36O13Na [M +
Na]+, 675.2054; found, 675.2016.
2,3-Di-O-benzyl-4-O,6-S-(1-cyano)benzylidene-ꢀ-D-manno-
pyranosyl-(1f3)-1,2:5,6-di-isopropylidene-r-D-glucofuranose
(29). Prepared by the general glycosylation procedure with a yield
1
of 95.5 mg (84%). Colorless oil; [R]23 -12.3 (c 1.0, CHCl3); H
D
NMR (500 MHz, CDCl3) δ 7.70-7.68 (m, 2H), 7.47-7.43 (m,
5H), 7.35-7.23 (m, 8H), 5.92 (d, J ) 3.5 Hz, 1H), 4.90 (s, 2H),
4.79 (d, J ) 3.0 Hz, 1H), 4.63-4.58 (m, 4H), 4.18 (d, J ) 2.5 Hz,
1H), 4.07-4.02 (m, 2H), 3.94-3.90 (m, 2H), 3.85-3.82 (m, 1H),
3.70-3.66 (dd, J ) 4.0, 13.5 Hz, 1H), 3.60-3.56 (m, 2H),
3.07-3.04 (dd, J ) 3.5, 13.0 Hz, 1H), 1.50 (s, 3H), 1.34 (s, 3H),
1.33 (s, 3H), 1.19 (s, 3H); 13C NMR (125.6 MHz, CDCl3) δ 138.2,
135.5, 130.5, 129.05,128.98, 128.6, 128.5, 128.0, 127.92, 127.87,
125.7, 115.9, 112.3, 109.3, 105.7 (1JCH ) 184.1 Hz), 102.8 (1JCH
) 159.0 Hz), 84.4, 83.4, 81.3, 79.1, 78.12, 78.09, 74.9, 74.7, 72.7,
72.6, 69.7, 68.2, 31.6, 27.1, 26.5, 25.6; HRESIMS calcd for
C40H45NO10SNa [M + Na]+, 754.2662; found, 754.2661.
ꢀ-L-Rhamnopyranosyl-(1f3)-1,2:5,6-di-isopropylidene-r-D-
glucofuranose (30). Prepared by the general desulfurization
procedure with a yield of 23.7 mg (77%). Colorless oil; [R]12D -8.7
Methyl
ꢀ-L-Rhamnopyranosyl-(1f4)-2,3,6-tri-O-acetyl-r-D
-glucopyranoside (26). Prepared by the general desulfurization
procedure with a yield of 14.5 mg (72%). Colorless gel; [R]23
D
1
1
(c 0.15, CH3Cl); H NMR (500 MHz, CDCl3) δ 5.93 (d, J ) 4.0
+137.5 (c 0.2, CH3OH); H NMR (500 MHz, CD3OD) δ 5.45 (t,
Hz, 1H), 4.74 (d, J ) 3.5 Hz, 1H), 4.66 (s, 1H), 4.31-4.27 (m,
1H), 4.22 (d, J ) 3.0 Hz, 1H), 4.16-4.13 (dd, J ) 6.5, 9.0 Hz,
1H), 4.11-4.08 (dd, J ) 3.0, 9.0 Hz, 1H), 4.07 (s, 1H), 4.04-4.01
(dd, J ) 5.0, 9.0 Hz, 1H), 3.48-3.42 (m, 2H), 3.36-3.30 (m, 1H),
1.52 (s, 3H), 1.44 (s, 3H), 1.41 (d, J ) 6.0 Hz, 3H), 1.35 (s, 3H),
1.33 (s, 3H); 13C NMR (125.6 MHz, CD3OD) δ 111.8, 109.6, 105.6,
101.7, 84.3, 82.4, 81.1, 73.8, 72.9, 72.7, 72.6, 71.0, 67.1, 26.0, 25.9,
25.3, 24.4, 16.9; HRESIMS calcd for C18H30O10Na [M + Na]+,
429.1737; found, 429.1715.
J ) 10.0 Hz, 1H), 4.80-4.78 (dd, J ) 3.5, 10.5 Hz, 1H), 4.54 (s,
1H), 4.48-4.45 (dd, J ) 1.5, 12.0 Hz, 1H), 4.35-4.31 (dd, J )
5.0, 12.0 Hz, 1H), 3.93-3.90 (ddd, J ) 1.5, 5.5, 10.0 Hz, 1H),
3.86 (t, J ) 9.5 Hz, 1H), 3.72 (d, J ) 2.5 Hz, 1H), 3.40 (s, 3H),
3.38-3.27 (m, 1H), 3.22-3.17 (m, 1H), 2.08 (s, 3H), 2.07 (s, 3H),
2.03 (s, 3H), 1.29 (d, J ) 6.0 Hz, 3H); 13C NMR (125.6 MHz,
CD3OD) δ 171.5, 170.6, 101.2, 96.9, 75.4, 73.8, 72.6, 72.4, 72.3,
71.5, 71.2, 68.3, 63.4, 54.5, 19.7, 19.3, 16.7; HRESIMS calcd for
C19H30O13Na [M + Na]+, 489.1584; found, 489.1557.
Methyl 2,3-Di-O-benzyl-4-O,6-S-(1-cyano)benzylidene-ꢀ-L
-mannopyranosyl-(1f4)-2,3,4-tri-O-benzoyl-r-D-glucopyrano-
side (27). Prepared by the general glycosylation procedure with a
Acknowledgment. We thank Dr. Ming Li (Wayne State
University) for helpful discussions and the NIH (GM57335 and
GM62160) for support of this work.
yield of 134.0 mg (81%). Colorless gel; [R]22 +61.4 (c 2.0,
D
CHCl3); 1H NMR (500 MHz, CDCl3) δ 8.03-7.90 (m, 6H),
7.69-7.22 (m, 24H), 6.21 (t, J ) 9.5 Hz, 1H), 5.64 (t, J ) 9.5 Hz,
1H), 5.29-5.26 (dd, J ) 4.0, 10.0 Hz, 1H), 5.24 (d, J ) 3.5 Hz,
1H), 4.84 (d, J ) 12.5 Hz, 1H), 4.75 (d, J ) 12.5 Hz, 1H), 4.56 (t,
J ) 9.5 Hz, 1H), 4.52 (s, 1H), 4.51 (d, J ) 12.5 Hz, 1H), 4.46 (d,
J ) 12.5 Hz, 1H), 4.29-4.25 (dt, J ) 4.0, 10.0 Hz, 1H), 4.22-4.19
Supporting Information Available: Copies of spectra of all
new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO8022439
J. Org. Chem. Vol. 74, No. 2, 2009 781