Application of the 4-trifluoromethylbenzenepropargyl ether group as an unhindered, electron deficient protecting group for stereoselective glycosylation

Article abstract of DOI:10.1021/jo7023398

(Chemical Equation Presented) 4-Trifluoromethylbenzenepropargyl ethers are stable and sterically minimal alcohol protecting groups that are readily cleaved in a single step by exposure to lithium naphthalenide. In conjunction with the 4,6-O-benzylidene protecting group, glycosylation reactions of 2-O-(4-trifluoromethylbenzenepropargyl)-protected mannosyl donors are extremely β-selective.

Full text of DOI:10.1021/jo7023398

protocol, namely an initial treatment with the base followed by
catalytic osmylation of the resulting allenyl ether.2 Subsequently,
to facilitate deprotection, the propargyl ether system was
modified in such a way as to be cleavable in a single step,
orthogonal to the ubiquitous benzyl ethers. This was achieved
through the use of the naphthyl propargyl system, which is
removed in a single step with DDQ.3 Donors 2 and 3, however,
had two limitations: incompatibility with glycosylation reactions
owing to cyclization onto the oxacarbenium ion and direct
reaction of the electron rich triple bond with glycosidation
promoters. Nevertheless, the naphthylpropargyl system was ideal
for use at the 3-O-position of donors, as in 4, provided that it
was used in conjunction with the sulfoxide glycosylation method
and a sacrificial alkene.3 Extending this series we now describe
an electron-poor arylpropargyl system compatible with the 2-O-
position and removable under dissolving metal conditions.
Application of the
4-Trifluoromethylbenzenepropargyl Ether Group
as an Unhindered, Electron Deficient Protecting
Group for Stereoselective Glycosylation
David Crich and Maheswaran S. Karatholuvhu*
Department of Chemistry, Wayne State UniVersity,
5101 Cass AVenue, Detroit, Michigan 48202, and
Department of Chemistry, UniVersity of Illinois at Chicago,
845 West Taylor Street, Chicago, Illinois 60607
maheswar@chem.wayne.edu
ReceiVed October 30, 2007
SCHEME 1. Model Protection and Deprotection of
D-Glucofuranose
4-Trifluoromethylbenzenepropargyl ethers are stable and
sterically minimal alcohol protecting groups that are readily
cleaved in a single step by exposure to lithium naphthalenide.
In conjunction with the 4,6-O-benzylidene protecting group,
glycosylation reactions of 2-O-(4-trifluoromethylbenzenepro-
pargyl)-protected mannosyl donors are extremely ꢀ-selective.
Alkylation of 1,2:5,6-di-O-acetone-D-glucofuranose with so-
dium hydride and 4-trifluoromethylphenyl propargyl bromide
54 gave the model ether 6, with which different reductive
conditions were explored (Scheme 1). Exposure of 6 to
samarium iodide, generated under standard conditions,5 resulted
in no reaction. When 6 was exposed to samarium iodide
generated by mixing samarium and iodine,6 partial loss of an
isopropylidene group was observed with no formation of the
desired product. Presumably unreacted iodine acted as a Lewis
acid resulting in the loss of an isopropylidene group.7However,
sodium in liquid ammonia8 and lithium naphthalenide9 proved
effective in removing the electron-deficient propargyl ether and
in affording the required deprotected sugar in good yield.
To examine the effect of the new electron-poor protecting
group on the stereoselectivity of glycosylation reactions when
located at O2, donor 8 was prepared by reaction of glycoside 7
with propargyl bromide 5 (Scheme 2).
Protecting groups continue to play a central role in modern
organic synthesis,1 and the ability/inability to achieve selective
deprotection of one protecting group in the presence of another
is often key to the success/failure of a synthetic route. In
response to a problem arising from the influence of protecting
group size on the stereoselectivity of a glycosylation reaction,
we described the application of a propargyl ether as a sterically
minimal donor protecting group for ꢀ-mannosylation with donor
1.2
SCHEME 2. Preparation of Donor 8
(2) Crich, D.; Jayalath, P. Org. Lett. 2005, 7, 2277. For use of electron-
withdrawing groups in mannopyranoside synthesis, see: (b) Srivastava, V. K.;
Schuerch, C. J. Org. Chem. 1981, 46, 1121. (c) Crich, D.; Hutton, T. K.; Banerjee,
A.; Jayalath, P.; Picione, J. Tetrahedron: Asymmetry 2005, 16, 105.
(3) Crich, D.; Wu, B. Org. Lett. 2006, 8, 4879. (b) Crich, D.; Wu, B.; Jayalth,
P. J. Org. Chem. 2007, 72, 6806.
Although the propargyl ethers were readily introduced (in
90% isolated yields) and had the anticipated effect on stereo-
selectivity (>95:5 ꢀ/R), they required a two-step deprotection
(4) This compound was prepared using a two-step literature procedure starting
from commercially available 1-bromo-4-trifluoromethylbenzene, see: Wrobel,
J.; Li, Z.; Dietrich, A.; McCabel, M.; Mihan, B.; Sredy, J.; Sullivan, D. J. Med.
Chem. 1998, 41, 1084.
(1) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic Synthesis;
Wiley and Sons: New York, 2007. (b) Kocienski, P. J. Protecting Groups;
Thieme: Stuttgart, 1994.
(5) (a) Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980, 102,
2693. (b) Molander, G. A.; Mckie, J. A. J. Org. Chem. 1992, 57, 3132.
10.1021/jo7023398 CCC: $40.75
Published on Web 06/05/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 5173–5176 5173

Treatment of 8 with triflic anhydride in the presence of BSP10
and TTBP11 at -70 °C in CH2Cl2, to give an intermediate
glycosyl triflate,11 followed by addition of 1-adamantanol
resulted in the formation of the ꢀ-mannoside 9 with impeccable
selectivity (Table 1, entry 1). A number of further couplings
were then conducted with more standard glycosyl acceptors,
leading to the yields collected in Table 1.
TABLE 2. Cleavage of 4-Trifluoromethylbenzenepropargyl Ethers
TABLE 1. Coupling Reactions of Donor 8
a Isolated yields after column chromatography.
Exposure of mannoside 9 to Na in liquid ammonia cleanly
gave fully deprotected 1-adamantanyl ꢀ-D-mannopyranoside 27
(Scheme 3).
SCHEME 3. Complete Deprotection
To conclude, we report the development of the electron-poor
4-trifluoromethylbenzenepropargyl ether system as an alcohol
protecting group. In conjunction with the BSP glycosylation
method, when introduced at the 2-position of 4,6-O-benzylidene-
protected mannosyl donors, this system affords extremely
ꢀ-selective coupling reactions and the possibility of orthogonal
cleavage in a single step with lithium naphthalenide.
a Reactions were performed at 0.03 M concentration, using 2 equiv of
b
acceptor. Isolated yields after column chromatography. 1H NMR
spectroscopy of crude reaction mixtures revealed only
ꢀ isomer
formation in all cases. c In all cases, the hydrolysis product 17 (R ) H)
was the main side product. d Reaction was performed at 0.05
concentration, using 4 equiv of acceptor.
M
Selective deprotection was achieved using lithium naphtha-
lenide in THF by warming a -70 °C reaction mixture to 0 °C
over a period of 2-3 h when 18 was obtained in 85% yield.
This strategy was extended to glycosides 10 to 16 (Table 2). In
almost all cases, minor amounts of debenzylated products were
obtained as the side products.
(6) Li, J.; Xu, H.; Zhang, Y. Tetrahedron Lett. 2005, 46, 1931.
(7) Szarek, W. A.; Zamojski, A.; Tiwari, K.; Ison, E. Tetrahedron Lett. 1986,
27, 3827.
(8) Iserloh, U.; Dudkin, V.; Wang, Z.-G.; Danishefsky, S. J. Tetrahedron
Lett. 2002, 43, 7027.
(9) Liu, H-J.; Yip, J.; Shia, K.-S. Tetrahedron Lett. 1997, 38, 2253.
5174 J. Org. Chem. Vol. 73, No. 13, 2008

-49.3 (c 1, CHCl3). 1H NMR (500 MHz, CDCl3): δ 1.32 (s, 3H),
1.36 (s, 3H), 1.54 (s, 3H), 3.34 (s, 3H), 3.31-3.40 (m, 4H),
3.60-3.62 (m, 1H), 3.66-3.71 (m, 2H), 3.96 (t, J ) 10.2 Hz, 1H),
4.08 (d, J ) 5.5 Hz, 1H), 4.15-4.18 (m, 2H), 4.22 (d, J ) 3.5 Hz,
1H), 4.28 (dd, J ) 10.5 Hz, J ) 5 Hz, 1H), 4.76-4.79 (m, 2H),
4.81 (s, 1H), 4.85-4.87 (m, 2H), 5.05 (s, 1H), 5.61 (s, 1H),
7.22-7.26 (m, 3H), 7.34-7.41 (m, 5H), 7.49-7.52 (m, 4H), 7.56
(d, J ) 8.5 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ 17.7, 26.4,
27.8, 54.9, 60.6, 64.0, 67.6, 68.6, 72.5, 76.0, 76.1, 77.4, 77.9, 78.3,
78.7, 84.9, 88.4, 97.8, 99.9 (JC-H ) 158.7 Hz), 101.4, 109.5, 125.2,
125.3, 126.0, 126.7, 127.5, 128.2, 128.3, 128.9, 132.1, 137.5, 138.3.
19F-NMR (471 MHz, CDCl3): δ -64.38. ESI-HRMS calcd for
C40H43F3O10Na [M + Na]+ 763.2706, found 763.2672.
Experimental Section
General Procedure for Coupling of Mannosyl Donor 8
with Acceptors. To a stirred solution of donor 8 (0.10 g, 0.16 mmol,
1 equiv), BSP (1.5 equiv), TTBP (2 equiv), and 4 Å molecular
sieves in 3.2 mL (0.05 M) of dichloromethane at -70 °C under an
Ar atmosphere was added Tf2O (1.1 equiv) slowly. The resulting
yellow mixture was stirred at this temperature for 30 min, and then
a solution of acceptor (2.0 equiv) in dichloromethane 2 mL was
added. The stirring was continued for another 30 min, and the
reaction mixture was poured into saturated aqueous NaHCO3
solution. The crude product was extracted with dichloromethane
(3 × 4 mL). The organic layer was separated, dried (MgSO4), and
concentrated. The residue was purified by column chromatography
(hexane/ethyl acetate) on silica gel to give the coupled products.
1-Adamantanyl 4,6-O-benzylidene-2-O-[3-(4-trifluorometh-
ylphenyl)-prop-2-ynyl]-3-O-benzyl-ꢀ-D-mannopyranoside (9). Vis-
cous oil. [R]25D -37.5 (c 1, CHCl3). 1H NMR (500 MHz, CDCl3):
δ 1.58-1.67 (m, 6H), 1.78-1.87 (m, 6H), 2.26 (s, 3H), 3.32-3.37
(m, 1H), 3.68 (dd, J ) 10 Hz, J ) 3.2 Hz, 1H), 3.93 (t, J ) 8.1
Hz, 1H), 4.07 (d, J ) 2.5 Hz, 1H), 4.16 (t, J ) 9.7 Hz, 1H), 4.28
(dd, J ) 10 Hz, J ) 4.7 Hz, 1H), 4.80-4.92 (m, 5H), 5.61 (s, 1H),
7.23 (m, 4H), 7.38 (m, 5H), 7.53 (m, 5H). 13C NMR (125 MHz,
CDCl3): δ 30.6, 36.2, 42.4, 60.8, 67.2, 68.8, 72.5, 75.5, 76.9, 78.5,
84.8, 88.7, 94.7, 101.4 (JC-H ) 161.3 Hz), 125.2, 126.1, 126.8,
127.5, 128.3, 128.4, 128.9, 132.1, 137.7, 138.4. 19F-NMR (471
MHz, CDCl3): δ -64.33. ESI-HRMS calcd for C40H41F3O6Na [M
+ Na]+ 697.2753, found 697.2749.
1,6-Anhydro-4-O-{4,6-O-benzylidene-2-O-[3-(4-trifluorometh-
ylphenyl)-prop-2-ynyl]-3-O-benzyl-ꢀ-D-mannopyranosyl}-2,3-
O-isopropylidene-ꢀ-D-mannopyranose (13). Viscous oil. [R]15
D
1
-68.5 (c 0.9, CHCl3); H NMR (500 MHz, CDCl3): δ 1.30 (s,
3H), 1.53 (s, 3H), 3.34-3.39 (m, 1H), 3.68 (dd, J ) 10 Hz, J ) 3
Hz, 1H), 3.77 (t, J ) 7 Hz, 1H), 3.94 (t, J ) 10 Hz, 1H), 3.98 (d,
J ) 7 Hz, 1H), 4.02 (dd, J ) 6 Hz, J ) 3 Hz, 1H), 4.09 (s, 1H),
4.20 (t, J ) 9.5 Hz, 1H), 4.25 (d, J ) 3 Hz, 1H), 4.32 (d, J ) 10.5
Hz, J ) 5 Hz, 1H), 4.37 (d, J ) 6 Hz, 1H), 4.59 (d, J ) 6 Hz, 1H),
4.77-4.89 (m, 5H), 5.33 (d, J ) 2.5 Hz, 1H), 5.62 (s, 1H),
7.23-7.26 (m, 4H), 7.33 -7.41 (m, 5H), 7.49-7.57 (m, 5H); 13
C
NMR (125 MHz, CDCl3): δ 25.9, 26.0, 61.0, 64.3, 67.7, 68.4, 72.1,
72.4, 72.8, 74.9, 75.3, 76.1, 78.4, 85.1, 88.0, 99.5, 99.9 (JC-H
)
157.3 Hz), 110.0, 125.2, 125.3, 126.0, 126.6, 127.6, 128.3, 128.4,
129.0, 132.1, 137.3, 138.0; 19F-NMR (471 MHz, CDCl3): δ -64.39;
ESI-HRMS calcd for C39H39F3O10Na [M + Na]+ 747.2393, found
747.2373.
Methyl 2,3,6-Tri-O-benzyl-4-O-[4,6-O-benzylidene-2-O-[3-(4-
trifluoromethylphenyl)-prop-2-ynyl]-3-O-benzyl-ꢀ-D-mannopy-
ranosyl]-r-D-glucopyranoside (10). Viscous oil. [R]14 -13.4 (c
D
3-O-[4,6-O-Benzylidene-2-O-[3-(4-trifluoromethylphenyl)-
prop-2-ynyl]-3-O-benzyl-ꢀ-D-mannopyranosyl]-1,2:5,6-di-O-iso-
1
0.5, CHCl3). H NMR (500 MHz, CDCl3): δ 3.02-3.07 (m, 1H),
propylidene-r-D-glucofuranose (14). Viscous oil. [R]23 -18.8
3.35 (s, 3H), 3.38-3.40 (m, 1H), 3.50-3.56 (m, 2H), 3.60 (d, J )
9 Hz, 1H), 3.67-3.77 (m, 2H), 3.86-3.89 (m, 2H), 3.92-3.96 (m,
1H), 4.03-4.07 (m, 2H), 4.35 (d, J ) 12 Hz,1H), 4.45 (s, 1H),
4.63-4.68 (m, 3H), 4.72 (d, J ) 7 Hz, 2H), 4.79-4.83 (m, 3H),
5.05 (d, J ) 10.5 Hz, 1H), 5.52 (s, 1H), 7.24-7.27 (m, 6H),
7.30-7.37 (m, 8H), 7.40-7.41 (m, 4H), 7.43-7.44 (m, 5H), 7.48
(dd, J ) 8 Hz, J ) 1.5 Hz, 3H), 7.52 (d, J ) 8 Hz, 2H). 13C NMR
(125 MHz, CDCl3): δ 55.4, 60.6, 67.2, 68.5, 68.6, 69.6, 72.7, 73.6,
D
(c 1.2, CHCl3). 1H NMR (500 MHz, CDCl3): δ 1.25 (s, 3H), 1.37
(s, 3H), 1.44 (s, 3H), 1.49 (s, 3H), 3.33 (m, 1H), 3.68 (d, J ) 8
Hz, 1H), 3.92 (t, J ) 10.2 Hz, 1H), 4.09 (d, J ) 8.5 Hz, 1H),
4.16-4.18 (m, 2H), 4.21-4.22 (m, 2H), 4.31-4.32 (m, 2H),
4.37-4.40 (m, 2H), 4.50 (s, 1H), 4.62 (s, 1H), 4.71-4.79 (m, 3H),
4.90 (d, J ) 12.5 Hz, 1H), 5.62 (s, 1H), 5.85 (s, 1H), 7.25-7.27
(m, 3H), 7.35-7.38 (m, 5H), 7.48-7.49 (m, 2H), 7.55-7.56 (m,
4H). 13C NMR (125 MHz, CDCl3): δ 25.6, 26.2, 26.5, 26.7, 60.6,
66.0, 67.7, 68.4, 73.0, 73.5, 75.8, 77.8, 78.6, 80.3, 80.6, 82.6, 85.3,
87.9, 99.5 (JC-H ) 155.0 Hz), 101.5, 104.9, 108.5, 111.9, 125.3,
126.0, 126.5, 127.6, 127.8, 128.3, 128.4, 129.0, 132.1, 137.4, 138.1.
19F-NMR (471 MHz, CDCl3): δ -64.47. ESI-HRMS calcd for
C42H45F3O11Na [M + Na]+ 805.2812, found 805.2806.
75.3, 76.4, 77.7, 78.6, 79.1, 80.2, 88.4, 98.4, 101.3, 101.4 (JC-H
)
158.8 Hz), 125.2, 126.1, 127.3, 127.4, 127.6, 127.8, 127.9, 128.1,
128.2, 128.24, 128.3, 128.6, 128.9, 132.0, 137.5, 137.6, 138.3,
138.5, 139.3. 19F-NMR (471 MHz, CDCl3): δ -64.40. ESI-HRMS
calcd for C58H57F3O11Na [M + Na]+ 1009.3751, found 1009.3744.
Methyl 2,3,6-Tri-O-benzyl-6-O-[4,6-O-benzylidene-2-O-[3-(4-
trifluoromethylphenyl)-prop-2-ynyl]-3-O-benzyl-ꢀ-D-mannopy-
6-O-[4,6-O-Benzylidene-2-O-[3-(4-trifluoromethylphenyl)-
prop-2-ynyl]-3-O-benzyl-ꢀ-D-mannopyranosyl]-1,2:3,4-di-O-iso-
propylidene-r-D-galactopyranose (15). Viscous oil. [R]15D -76.2
ranosyl]-r-D-glucopyranoside (11). Viscous oil. [R]14 -6.0 (c
D
1
0.7, CHCl3). H NMR (500 MHz, CDCl3): δ 3.20-3.25 (m, 1H),
1
3.34 (s, 3H), 3.47-3.50 (m, 3H), 3.54 (dd, J ) 9.7 Hz, J ) 3.5
Hz, 1H), 3.78 (m, 1H), 3.90 (t, J ) 10.5 Hz, 1H), 4.01 (t, J ) 9
Hz, 1H), 4.05-4.14 (m, 4H), 4.27 (dd, J ) 9.7 Hz, J ) 4.5 Hz,
1H), 4.55 (d, J ) 3.5 Hz, 1H), 4.59 (d, J ) 11.7 Hz, 1H), 4.65 (d,
J ) 11.7 Hz, 1H), 4.77-4.78 (m, 2H), 4.79-4.83 (m, 4H), 4.84
(d, J ) 8.5 Hz, 1H), 4.88 (d, J ) 11.5 Hz, 1H), 5.00 (d, J ) 11
Hz, 1H), 5.58 (s, 1H), 7.21-7.23 (m, 8H), 7.39-7.33 (m, 15H),
7.43-7.45 (m, 2H), 7.49-7.52 (m, 4H). 13C NMR (125 MHz,
CDCl3): δ 55.1, 60.4, 67.4, 68.3, 68.5, 69.6, 72.5, 73.4, 74.8, 75.0,
76.1, 76.6, 77.4, 78.5, 79.9, 82.2, 85.4, 88.1, 97.9, 101.4, 102.0
(JC-H ) 157.5 Hz), 125.3, 126.0, 127.6, 127.7, 127.8, 127.9, 128.1,
128.2, 128.3, 128.4, 128.5, 128.9, 132.1, 137.5, 138.0, 138.3, 138.4,
138.6. 19F-NMR (471 MHz, CDCl3): δ -64.34. ESI-HRMS calcd
for C58H57F3O11Na [M + Na]+ 1009.3751, found 1009.3744.
Methyl 4-O-[4,6-O-Benzylidene-2-O-[3-(4-trifluoromethylphe-
nyl)-prop-2-ynyl]-3-O-benzyl-ꢀ-D-mannopyranosyl]-2,3-O-iso-
(c 1.1, CHCl3). H NMR (500 MHz, CDCl3): δ 1.32 (s, 6H), 1.4
(s, 3H), 1.50 (s, 3H), 3.33-3.35 (m, 1H), 3.63-3.69 (m, 2H), 3.92
(t, J ) 10.2 Hz, 1H), 4.05 (dd, J ) 8 Hz, J ) 2 Hz, 1H), 4.13-4.17
(m, 2H), 4.2 (dd, J ) 8 Hz, J ) 1.5 Hz, 1H), 4.28 (d, J ) 3 Hz,
1H), 4.30-4.34 (m, 2H), 4.60 (dd, J ) 8 Hz, J ) 2.5 Hz, 1H),
4.63 (s, 1H), 4.77 (d, J ) 6 Hz, 1H), 4.8 (d, J ) 2H, 1H), 4.83 (s,
1H), 4.86 (d, J ) 3.5 Hz, 1H), 7.55 (d, J ) 5 Hz, 1H), 5.6 (s, 1H),
7.18-7.22 (m, 4H), 7.30-7.33 (m, 2H), 7.36-7.40 (m, 3H),
7.48-7.51 (m, 2H), 7.53-7.56 (m, 3H). 13C NMR (125 MHz,
CDCl3): δ 24.4, 25.1, 26.0, 60.8, 67.4, 68.1, 68.5, 70.1, 70.7, 71.5,
72.6, 75.8, 78.5, 84.8, 88.5, 96.3, 101.5, 102.5 (JC-H ) 157.5 Hz),
108.8, 109.6, 125.2, 126.0, 126.8, 127.5, 127.6, 128.2, 128.3, 128.9,
132.1, 132.2, 137.5, 138.2. 19F-NMR (471 MHz, CDCl3): δ -64.38.
ESI-HRMS calcd for C42H45F3O11Na [M + Na]+ 805.2812, found
805.2787.
Methyl 2-Azido-3,6-di-O-benzyl-4-O-[4,6-O-benzylidene-2-O-
[3-(4-trifluoromethylphenyl)-prop-2-ynyl]-3-O-benzyl-ꢀ-D-man-
nopyranosyl]-r-D-glucopyranoside (16).12 To facilitate easier
separation of 16 from excess acceptor and hydrolysis product 17,
the crude mixture from the workup was acetylated under standard
propylidene-r-L-rhamnopyranoside (12). Viscous oil. [R]16
D
(10) Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015.
(11) Crich, D.; Smith, M.; Yao, Q.; Picione, J. Synthesis 2001, 2, 323.
J. Org. Chem. Vol. 73, No. 13, 2008 5175

conditions and purified. Viscous oil. [R]22 -2.6 (c 1.5, CHCl3).
was separated, dried (MgSO4), and concentrated. The residue was
purified by column chromatography on silica (3, 5, 10, 15, 20, 25%
Ethyl acetate/Hexane) to afford 18 (21 mg, 85%). Viscous oil.
D
1H NMR (500 MHz, CDCl3): δ 3.03-3.08 (m, 1H), 3.92 (s, 3H),
3.40-3.41 (m, 3H), 3.60 (d, J ) 9 Hz, 1H), 3.70-3.74 (m, 2H),
3.85-3.89 (m, 2H), 4.04-4.08 (m, 3H), 4.37 (d, J ) 12.5 Hz,
1H), 4.44 (s, 1H), 4.68-4.79 (m, 6H), 4.83 (d, J ) 12.5 Hz, 1H),
5.21 (d, J ) 10 Hz, 1H), 5.52 (s, 1H), 7.26-7.29 (m, 6H),
7.33-7.42 (m, 12H), 7.48-7.53 (m, 6H), 13C NMR (125 MHz,
CDCl3): δ 55.7, 61.1, 63.1, 67.4, 68.4, 68.6, 70.5, 73.0, 73.9, 75.3,
76.8, 77.8, 78.8, 78.9, 85.1, 88.4, 98.9, 101.0 (JC-H ) 156.5 Hz),
101.6, 125.4, 125.5, 126.3, 127.6, 127.9, 128.3, 128.4, 128.5, 128.6,
128.8, 129.1, 132.2, 137.6, 137.8, 138.7, 138.7. 19F-NMR (471
MHz, CDCl3): δ -64.4. ESI-HRMS calcd for C51H50F3N3O10Na
[M + Na]+ 944.3346, found 944.3362.
[R]11 -8.7 (c 0.6, CHCl3). 1H NMR (400 MHz, CDCl3): δ
D
1.59-1.66 (m, 6H), 1.77-1.86 (m, 6H), 2.16 (m, 3H), 2.64 (s,
1H), 3.31-3.35 (m, 1H), 3.66 (dd, J ) 9.8 Hz, J ) 3 Hz, 1H),
3.88 (t, J ) 9.8 Hz, 1H), 3.98 (d, J ) 3 Hz, 1H), 4.15 (t, J ) 9.8
Hz, 1H), 4.27 (dd, J ) 9.8 Hz, J ) 5 Hz, 1H), 4.78-4.86 (m, 3H),
7.26-7.32 (m, 4H), 7.33-7.40 (m, 4H), 7.49-7.50 (m, 2H). 13C
NMR (125 MHz, CDCl3): δ 30.7, 36.2, 42.4, 66.7, 68.8, 71.6, 72.3,
75.8, 78.3, 93.3, 126.1, 127.7, 127.9, 128.2, 128.9, 137.6, 138.2;
ESI-HRMS calcd for C30H36O6Na [M + Na]+ 515.2410, found
515.2413.
Global Deprotection with Sodium in Liquid Ammonia:
1-Adamantyl ꢀ-D-mannopyranoside (27). Mannopyranoside 9 (0.1
g, 0.12 mmol, 1 equiv) was dissolved in a mixture of liquid
ammonia (2 mL), THF (4 mL) and tertiary butanol (2 mL). To this
solution at -70 °C was added sodium (0.03 g, 10 equiv) in 4 pieces,
and the reaction mixture was warmed to -40 °C and the intense
blue solution was stirred for 1 h. After the reaction completion
(TLC 10% CH3OH:CHCl3), the reaction mixture at -20 °C was
slowly quenched with saturated aqueous ammonium chloride
solution (4 mL). The product was extracted with dichloromethane
(3 × 4 mL). The organic layer was dried (MgSO4) and concentrated
to afford a crude product that was purified on a silica chromatog-
raphy (2, 4, 5, 8, 10% CHCl3/CH3OH) to afford 27 mg (72%) of
27. White solid: Mp: 218-220 °C: [R]11D -27.4 (c 0.7, CH3OH);
1H NMR (400 MHz, CD3OD): δ 1.63-1.70 (m, 6H), 1.79-1.92
(m, 6H), 2.13 (m, 3H), 3.16-3.20 (m, 1H), 3.45 (dd, J ) 8.8 Hz,
J ) 3.2 Hz, 1H), 3.65-3.69 (m, 2H), 3.82 (dd, J ) 11.6 Hz, J )
2 Hz, 1H), 4.82 (d, 1H). 13C NMR (125 MHz, CD3OD): δ 31.0,
36.2, 42.3, 61.8, 67.3, 72.9, 74.3, 74.8, 76.6, 93.4. ESI-HRMS calcd
for C16H26NaO6 [M + Na]+ 337.1627, found 337.1613.
General Procedure for Selective Reduction. 1-Adamantyl
3-O-benzyl-4,6-O-benzylidene-ꢀ-D-mannopyranoside (18). Lith-
ium naphthalenide in THF (0.25 M) was generated by dissolving
Li (3-5 mg) in a solution of naphthalene (64 mg, 0.5 mmol) in
THF (2 mL) at room temperature and allowing the reaction mixture
to stir under Ar for 2 h. This dark-green solution of lithium
naphthalide (10 equiv) was dropwise added to a solution of sugar
9 (34 mg, 0.05 mmol, 1 equiv) in THF (1 mL) kept at -78 °C.
The resultant reaction mixture was allowed to warm up to 0 °C
over a period of 3 h and then quenched with a saturated solution
of aqueous ammonium chloride (2.5 mL). The crude product was
extracted with methylene chloride (3 × 4 mL). The organic layer
Methyl 2-Acetamido-3,6-di-O-benzyl-4-O-(4,6-O-benzylidene-
2-O-acetyl-3-O-benzyl-ꢀ-D-mannopyranosyl)-r-D-glucopyrano-
side (26). Sugar 16 was subjected to the general reduction
procedure. Work up was followed by acetylation under standard
conditions to afford 26 in 53% yield after purification.
1
[R]22 +11.6 (c 0.3, CHCl3). H NMR (500 MHz, CDCl3): δ
D
1.83 (s, 3H), 2.17 (s, 3H), 3.07 (dt, J ) 4.5 Hz, J ) 12 Hz, 1H),
3.32 (s, 3H), 3.40 (d, J ) 3.5 Hz, 1H), 3.40 (d, J ) 3.5 Hz, 1H),
3.53 (dd, J ) 10.5 Hz, J ) 20.5 Hz, 2H), 3.65 (t, J ) 10 Hz, 2H),
3.76 (dd, J ) 3.5 Hz, J ) 11 Hz, 1H), 3.86 (t, J ) 9.5 Hz, 1H),
4.08 (t, J ) 10.5 Hz, 1H), 4.10-4.14 (m, 1H), 4.16-4.21 (, 1H),
4.42 (d, J ) 11.5 Hz, 1H), 4.53 (d, J ) 2 Hz,1H), 5.54 (d, J ) 6.5
Hz, 1H), 4.64 (d, J ) 12 Hz, 1H), 4.69 (d, J ) 3.5 Hz, 1H), 4.89
(d, J ) 11.5 Hz, 1H), 5.22 (d, J ) 9 Hz, 1H), 5.40 (d, J ) 3 Hz,
1H), 5.51 (s, 1H), 7.26-7.39 (m, 17H), 7.47-7.49 (m, 2H), 13C
NMR (125 MHz, CDCl3): δ 21.3, 23.6, 52.5, 55.3, 67.1, 68.5, 68.6,
69.5, 70.3, 71.8, 73.7, 74.4, 76.0, 78.0, 78.1, 78.2, 126.3, 127.7,
127.8, 127.9, 128.1, 128.2, 128.3, 128.4, 128.5, 128.6, 128.8, 129.1,
137.7, 137.9, 138.1, 139.2, 169.9, 170.6 ; ESI-HRMS calcd for
C45H51NO12Na [M + Na]+ 820.3309, found 820.3336.
Compounds 19, 20, 21, 23, 24, and 25. The spectral data for
these compounds are consistent with the literature data.13
Acknowledgment. We thank the NIH (GM 57335) for
support of this work. Baolin Wu is acknowledged for providing
the precursor to the acceptor in Table 1, entry 8.
Supporting Information Available: Details of the prepara-
tion of compounds 6 and 8, characterization data for compounds
17 and 22, and copies of 1H and 13C NMR spectra of all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) The acceptor in this example was prepared in 5 steps according to the
literature procedure, see: (a) Westman, J.; Nilsson, M.; Ornitz, D. M.; Svahn,
C.-M. J. Carbohydr. Chem. 1995, 14, 95. (b) Yu, B.; Chen, J.; Lin, F.; Zhou, Y.
Carbohydr. Res. 2006, 341, 1619.
JO7023398
(13) Crich, D.; Jayalath, P.; Hutton, T. K. J. Org. Chem. 2006, 71, 3064.
5176 J. Org. Chem. Vol. 73, No. 13, 2008