Stereoselective synthesis of C-amino-substituted D-mannopyranosides. Easy preparation of novel inhibitors for mannosidases

Full text of DOI:10.1021/jo961875s

6056
J . Org. Chem. 1997, 62, 6056-6059
periments with glycofuranosides showed the proposed
Ster eoselective Syn th esis of
approach to be a highly efficient and stereoselective
method of preparing C-glycofuranosides.9 Our earlier
results for the condensation of stabilized sulfur ylides
with readily, available protected glycopyranoses to pro-
duce epoxy amides in high yields and with high stereo-
selectivity revealed the usefulness and efficiency of our
method.10 Fully protected monosaccharides such as the
2,3;4,6-di-O-isopropylidene-D-mannopyranose (2)11 were
an appropriate choice for synthesizing C-glycopyranoses
by the same approach. In this paper, we report the
condensation of mannopyranose 2 with the sulfur ylide
1a , which is generated in situ from the sulfonium salt
1b by the “two-phase method”.12 Intramolecular cycliza-
tion of the resulting epoxides leads to C-glycopyranoses
containing a hydroxyl group on the carbon bridge. These
products are of interest on account of the synthetic
flexibility of the hydroxyl group. Thus, we converted 4
into the amino derivative and subjected it to enzyme
inhibition experiments. The discovery of new inhibitors
for mannosidases is of great interest owing to the
frequent occurrence of mannose residues in the carbo-
hydrate chains of mammalian surface cells (mannosi-
dases are involved in the biosynthesis of those chains).13
C-Am in o-Su bstitu ted D-Ma n n op yr a n osid es.
Ea sy P r ep a r a tion of Novel In h ibitor s for
Ma n n osid a ses
Fidel J . Lo´pez-Herrera,* Francisco Sarabia-Garc´ıa,
A. Heras-Lo´pez, and M. S. Pino-Gonza´lez
Departamento de Bioqu´ımica, Biolog´ıa Molecular y Qu´ımica
Orga´nica, Facultad de Ciencias Universidad de Ma´laga,
29071 Ma´laga, Spain
Received October 3, 1996
In tr od u ction
C-Glycosides are becoming useful as building blocks1
for the total synthesis of various types of physiologically
active natural products such as palytoxin,2 brevetoxin,3
and polyether antibiotics.4 In addition, they are used in
enzymatic and metabolic studies. As a result, new and
stereoselective synthetic methods for C-pyranosides have
been developed in the last few years. The biological
interest in these products lies in their potential inhibitory
action on glycosidases. Thus, assays of glycosidase
inhibitors as potential therapeutic agents against HIV,
diabetes, and cancer testify to the increasing demand for
these products.5 On the basis of the knowledge of the
enzyme’s active site for glycosidases, a wide variety of
C-glycosides have been designed. It has been postulated,
and in some cases demonstrated, that the agent respon-
sible for the hydrolysis of the O-glycosidic bond is a
carboxyl group of an amino acid residue. In theory, any
C-glycoside could inhibit these enzymes; however, if the
C-bridge is correctly modified, the inhibitory power can
be enhanced. Thus, C-glycopyranoses with an amine
group on the carbon bridge, which can form an am-
monium salt intermediate with the carboxyl group, are
potent inhibitors for glycosidases.6 Similarly, diazo sugar
derivatives have been described as irreversible inhibitors
by alkylation of the carboxylic acid.7 This paper reports
a new, stereoselective method for the synthesis of C-
pyranoses with a hydroxyl group on the C-bridge by using
stabilized sulfur ylides, which have previously been used
to prepare epoxy amides in a stereoselective fashion, by
condensation with aldehydic sugars.8 Preliminary ex-
Resu lts a n d Discu ssion
Thus, 2 was reacted with the sulfonium salt 1b, in
methylene chloride and 10% sodium hydroxide solution,
to obtain almost quantitatively and with complete ste-
reoselectivity epoxy amide 3.10 Alternatively, the con-
densation could be accomplished by the same “two-phase
method” but using 50% sodium hydroxide. In this case,
however, too long exposure times, or excess base, led to
the isolation of C-mannopyranose 4 together with small
amounts of epoxide 5 and R-C-glycoside 6 (Scheme 1).
We must emphasize that this method provides an easy
and efficient stereoselective two-chiral carbon integration
of pyranoses to acyclic epoxy amides and can be consid-
ered an alternative to the very well-known multistep
method based on the Wittig reaction and Sharpless
epoxidation.14 The absolute configurations of the two new
chiral sites were established by chemical degradation of
product 3 with periodic acid to afford epoxy aldehyde 7.
The optical rotation of 7 was compared with that for the
product obtained by reaction of the well-known epoxy
amide 8 with periodic acid, which gave epoxide 9.
Treatment of epoxy amide 3 with sodium hydride in
anhydrous THF at rt led to C-mannopyranose 4 in
virtually quantitative yield and with complete stereose-
lectivity. The establishment of the absolute configuration
of the starting epoxy amide allowed the configuration of
the resulting cyclic product to be assigned. Furthermore,
NMR spectroscopic data were in agreement with the
proposed configurations and unequivocally revealed a
â-configuration in the light of the coupling constant value
(1) Postema, M. H. D. Tetrahedron 1992, 48, 8545 and references
cited therein.
(2) Lewis, M. D.; Cha, J . K.; Kishi, Y. J . Am. Chem. Soc. 1982, 104,
4976.
(3) (a) Nicolaou, K. C.; Duggan, M. E.; Hwang, C. K.; Sommers, P.
K. J . Chem. Soc., Chem. Commun. 1985, 1359. (b) Nicolaou, K. C.;
Theodorakis, E.; Rutjes, F. P.J .T.; Tiebes, J .; Sato, M.; Untersteller,
E. J . Am. Chem. Soc. 1995, 117, 1171. (c) Nicolaou, K. C.; Theodorakis,
E.; Rutjes, F. P.J .T.; Tiebes, J .; Sato, M.; Untersteller, E. J . Am. Chem.
Soc. 1995, 117, 1173.
(4) Paterson, I.; Mansuri, M. M. Tetrahedron 1985, 41, 3569.
(5) (a) Sinnot, M. L. Enzyme Mechanisms; The Royal Society of
Chemistry: London, 1987; p 259. (b) Elbein, A. D. Comprehensive
Medicinal Chemistry; Pergamon Press: New York, 1990; Vol. 2,
Chapter 8, p 365. (c) Tvaroska, I.; Bleha, T. Adv. Carbohydr. Chem.
Biochem. 1987, 47, 45. (d) Kaushal, G. P.; Elbein, A. D. Trends
Glycosci. Glycotechnol. 1993, 5, 209. (e) Yoshikuni, Y. Trends Glycosci.
Glycotechnol. 1991, 3, 184.
(9) Valpuesta-Ferna´ndez, M.; Durante-Lanes, P.; Lo´pez-Herrera, F.
J . Tetrahedron 1993, 49, 9547.
(10) Lo´pez-Herrera, F. J .; Heras-Lo´pez, A.; Pino-Gonza´lez, M. S.;
Sarabia-Garc´ıa, F. J . Org. Chem. 1996, 61, 8839.
(11) Gelas, J .; Horton, D. Carbohydr. Res. 1978, 67, 371.
(12) Lo´pez-Herrera, F. J .; Pino-Gonza´lez, M. S.; Sarabia-Garc´ıa, F.;
Heras-Lo´pez, A.; Ortega-Alca´ntara, J . J .; Pedraza-Cebria´n, G. M.
Tetrahedron: Asymmetry 1996, 7, 2065.
(6) (a) Dietrich, H.; Schmidt, R. R. Carbohydr. Res. 1993, 250, 161.
(b) Lai, W.; Martin, O. R. Carbohydr. Res. 1993, 250, 185. (c) Liu, P.
S. J . Org. Chem. 1987, 52, 4717. (d) Burgess, K.; Henderson, I.
Tetrahedron 1992, 48, 4045.
(7) BeMiller, J . N.; Gilson, R. J .; Myers, R. W.; Santoro, M. M.
Carbohydr. Res. 1993, 250, 101.
(8) Valpuesta-Ferna´ndez, M.; Durante-Lanes, P.; Lo´pez-Herrera, F.
J . Tetrahedron 1990, 46, 7911.
(13) Fukuda, M.; Hindsgaul, O. Molecular Glycobiology; Oxford
University Press: New York, 1994.
(14) Reed, L. A., III; Ito, Y.; Masamune, S.; Sharpless, K. B. J . Am.
Chem. Soc. 1982, 104, 6468.
S0022-3263(96)01875-0 CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 17, 1997 6057
Sch em e 1
Sch em e 2
17 and 19 showed inhibitory activity against â-mannosi-
dase. We are currently continuing these biological stud-
ies with these and other related products in order to
determine the Ki values.
Exp er im en ta l Section
Melting points are uncorrected. NMR spectral data were
obtained in CDCl3, unless other solvents are stated. Chemical
shifts (δ, ppm), relative to the residual solvent peaks. Mi-
croanalyses were performed by the “Servicio de Microana´lisis
de la Universidad de Ma´laga”. Silica gel for column chroma-
tography was Merck silica gel 60 No. 7736. Preparative thin-
layer chromatography was performed on Merck silica gel 60 No.
7747.
Con d en sa tion of Su lfon iu m Sa lt 1 w ith 2,3:4,6-Di-O-
isop r op ylid en e-r-D-m a n n op yr a n ose (2). To a solution con-
taining 1.0 g (3.84 mmol) of 211 in 10 mL of dichloromethane,
2.5 mL of a 10% solution of NaOH in water, and 0.933 g (4.41
mmol) of dimethylsulfonium (N,N-diethylcarbamoyl)methylide
(1b) were added. After 2 h under vigorous stirring, the crude
mixture was diluted with 20 mL of water, and the organic layer
was separated. The aqueous phase was extracted with tert-
butylmethyl ether (5 × 20 mL), and the combined organic layers
were dried over anhydrous sodium sulfate, filtered, and concen-
trated. The crude mixture was purified by column chromatog-
raphy on silica gel (3:1 hexane:EtOAc) to provide 1.4 g of product
3 (98%). When the reaction was performed using 50% NaOH
and starting from 1 g of 2, the result, after purification by column
chromatography on silica gel, was 0.955 g of â-C-glycoside 4
(67%), 0.085 g of epoxy amide 5 (6.0%), and 0.170 g of R-C-
glycoside 6 (12%).
J 2,3 ) 8.9 Hz. Acetylated derivatives of 3 and 4 (10 and
11 respectively) were synthesized in order to confirm the
structural assignment (Scheme 2).
C-Mannopyranoside 4 was successfully converted into
the amino derivative by conventional reactions. Firstly,
4 was treated with tosyl chloride in pyridine to give the
corresponding tosylated product 12 in 98% yield. Treat-
ment with sodium azide in refluxing DMF gave the azide
derivative 13 in 75% yield after purification by column
chromatography on silica gel. Azide 13 was transformed
into the amino derivatives 14 and 15 in quantitative
yields by reaction with triphenylphosphine and lithium
aluminum hydride, respectively (Scheme 3). While 15
required no further purification, attempts to purify the
amino derivative 14 from the crude reaction mixture by
column chromatography on silica gel proved impossible.
Consequently, 14 was transformed into the less polar
carbamate Boc derivative 16, which was readily purified.
The products, depicted in Figure 1, were obtained from
4, 16, and 15, respectively, by acid hydrolysis with 2 N
HCl. Whereas the products 17 and 19 were obtained in
quantitative yields and with a high degree of purity, the
hydrolysis of 16 furnished a mixture of products in which
18 was the major compound (ca. 30% from the crude
mixture). Mild hydrolysis conditions were attempted, but
in all cases the results were unsuccessful. For this
reason, we decided to perform the inhibition experiments
with the C-mannopyranoses 17 and 19. These biological
assays utilized commercially available â-mannosidase
(isolated from snails) and p-nitrobenzyl â-mannoside as
the substrate.15 These preliminary results revealed that
N,N-Dieth yl-2,3-a n h yd r o-4,5:6,8-d i-O-isop r op ylid en e-D-
er yth r o-L-a ltr o-octon a m id e (3): [R]20 -58.6° (c 7.5, MeOH);
D
IR 3416, 2996, 1653 cm-1; 1H NMR δ 4.52 (dd, 1H, J ) 6.7, 2.9
Hz), 3.98 (t, 1H, J ) 6.7 Hz), 3.89 (dd, 1H, J ) 7.2, 2.9 Hz), 3.64
(ddd, 1H, J ) 9.9, 7.3 Hz), 3.56 (d, 1H, J ) 2.0 Hz), 3.48 (dd,
1H, J ) 6.7, 2.0 Hz), 3.55-3.30 (m, 6H), 1.49, 1.48, 1.37, 1.34
(4s, 12H), 1.25 and 1.12 (2t, 6H, J ) 7.2, 7.1 Hz); 13C NMR δ
168.5, 109.5, 98.8, 76.7, 75.3, 72.0, 64.8, 63.6, 55.7, 52.1, 41.6,
40.9, 28.4, 26.7, 25.4, 19.1, 14.7, 12.3; MS m/z 358 (M+ - 15, 5),
300 (1.2), 272 (16.6), 214 (7.3), 198 (1.9), 131 (6.6), 100 (100), 72
(36.9), 59 (58.3). Anal. Calcd for C18H31O7N: C, 57.90; H, 8.31;
N, 3.75. Found: C, 57.60; H, 8.40; N, 3.76.
N,N-Dieth yl-2,3-a n h yd r o-4,5:6,8-d i-O-isop r op ylid en e-D-
er yth r o-L-glu co-octon a m id e (5): [R]20D -88.9° (c 0.9, MeOH);
IR 3416, 2996, 1653 cm-1; 1H NMR δ 4.26 (dd, 1H, J ) 7.7, 3.7
Hz), 4.12 (dd, 1H, J ) 7.7, 4.9 Hz), 3.61 (d, 1H, J ) 1.9 Hz),
3.34 (dd, 1H, J ) 4.9, 1.9 Hz), 3.95-3.55 (m, 4H), 3.55-3.30
(2dq, 4H), 1.44, 1.41, 1.37 (3s, 12H), 1.23, 1.12 (2t, 6H, J ) 6.8,
6.8 Hz); 13C NMR δ 165.7, 110.2, 98.7, 78.3, 74.7, 72.6 64.3, 63.3,
57.5, 51.3, 41.4, 40.7, 28.0, 26.8, 26.4, 19.3, 14.5, 12.7; MS m/z
358 (M+ - 15, 4), 300 (1.2), 272 (15), 214 (8.3), 198 (2.4), 130
(7.4), 100 (100), 72 (36.7), 59 (49.6), 43 (34.6).
N,N-Dieth yl-3,7-a n h yd r o-4,5:6,8-d i-O-isop r op ylid en e-D-
er yth r o-L-a llo-octon a m id e (6): [R]20 -88.9° (c 9.5, MeOH);
D
IR 3453, 2997, 2944, 2884, 1648 cm-1; 1H NMR δ 4.68 (d, 1H, J
) 9.2 Hz), 4.27 (dd, 1H, J ) 5.1, 2.3 Hz), 4.03 (dd, 1H, J ) 9.2,
2.3 Hz), 4.02 (dd, 1H, J ) 7.8, 5.1 Hz), 3.75 (dd, 1H, J ) 10.6,
5.7 Hz), 3.65 (dd, 1H, J ) 9.9, 7.9 Hz), 3.54 (dd, 1H, J ) 10.6,
(15) â-Mannosidase was purchased from Sigma-Aldrich, ref M-9400.

6058 J . Org. Chem., Vol. 62, No. 17, 1997
Notes
Sch em e 3
to obtain the peracetylated product, virtually pure (63% yield
for 10 and 77% yield for 11).
N,N-Dieth yl-7-O-a cetyl-2,3-a n h yd r o-4,5:6,8-d i-O-isop r o-
p ylid en e-D-er yth r o-L-a ltr o-octon a m id e (10): [R]20 -4.1° (c
D
2.1, CHCl3); IR 2992, 2946, 2883, 1751, 1654 cm-1; H NMR δ
1
5.00 (ddd, 1H, J ) 8.8, 6.0, 5.0 Hz), 4.31 (dd, 1H, J ) 6.8, 1.6
Hz), 4.07 (t, 1H, J ) 6.8 Hz), 4.04 (dd, 1H, J ) 12.1, 5.3 Hz),
4.01 (dd, 1H, J ) 8.8, 1.7 Hz), 3.63 (dd, 1H, J ) 12.1, 6.2 Hz),
3.49 (d, 1H, J ) 1.9 Hz), 3.40 (dd, 1H, J ) 6.8, 1.9 Hz), 3.55-
3.30 (2dq, 4H), 2.05 (s, 3H), 1.47, 1.35, 1.31 (3s, 12H), 1.25, 1.12
(2t, 6H, J ) 7.1 Hz); 13C NMR δ 170.1, 165.6, 110.0, 99.7, 76.9,
75.4, 69.0, 67.3, 61.9, 55.3, 52.1, 41.6, 40.9, 26.7, 26.4, 25.4, 20.9,
20.6, 14.8, 12.9; MS m/z 400 (M+ - 15, 4.5), 342 (1.6), 272 (8.4),
242 (4.4), 214 (3.8), 142 (6.9), 130 (3.9), 100 (100), 58 (7.7), 43
(98.2).
F igu r e 1.
10.0 Hz), 3.05 (ddd, 1H, J ) 10.0, 9.9, 5.7 Hz), 3.55-2.87 (2dq,
4H), 1.52, 1.46, 1.38, 1.31 (4s, 12H), 1.18, 1.05 (2t, 6H, J ) 7.1,
7.1 Hz); 13C NMR δ 168.8, 109.5, 99.7, 77.2, 76.1, 73.0, 72.9, 71.6,
70.0, 61.8, 42.5, 41.1, 28.9, 28.4, 26.2, 18.8, 14.7, 12.9; MS m/z
358 (M+ - 15, 3.3), 283 (0.9), 273 (8.8), 215 (7.7), 190 (2.6), 131
(22.1), 100 (100), 72 (46.4), 43 (34.5).
N,N-Dieth yl-2-O-a cetyl-3,7-a n h yd r o-4,5:6,8-d i-O-isop r o-
pyliden e-D-er yth r o-L-ma n n o-octon am ide (11): [R]20D ) -81.3°
1
(c 2.6, CHCl3); IR 3002, 2953, 2896, 1750, 1657 cm-1; H NMR
δ 5.45 (d, 1H, J ) 9.5 Hz, H-2), 4.30 (dd, 1H, J ) 5.2, 2.5 Hz),
4.17 (dd, 1H, J ) 9.5, 2.5 Hz), 4.03 (dd, 1H, J ) 8.0, 5.2 Hz),
3.79 (dd, 1H, J ) 10.7, 5.6 Hz), 3.66 (dd, 1H, J ) 10.0, 8.0 Hz),
3.56 (dd, 1H, J ) 10.7, 10.0 Hz), 3.07 (ddd, 1H, J ) 10.1, 10.0,
5.7 Hz), 3.55-3.20 (2dq, 4H), 2.06 (s, 3H), 1.51, 1.47, 1.38, 1.30
(3s, 12H), 1.22, 1.06 (2t, 6H, J ) 7.1 Hz); 13C NMR δ 169.4, 167.3,
109.4, 99.5, 75.6, 72.8, 69.7, 67.4, 61.5, 41.7, 40.6, 28.7, 28.2,
26.0, 20.2, 18.6, 13.7, 12.3; MS m/z 400 (M+ - 15, 9.4), 356 (5.3),
300 (6.1), 244 (16.6), 202 (26.1), 142 (20.8), 100 (100), 72 (47.5),
59 (13.0), 43 (62.3).
P er iod ic Acid Oxid a t ion of E p oxy Am id es 3 a n d 5.
Syn th esis of (2R,3R)- a n d (2S,3S)-N,N-Dieth yl-2,3-Ep oxy-
3-for m ylp r op ion a m id e (7) a n d (9). A solution containing
0.050 g (0.134 mmol) of the epoxy amide in 2 mL of water was
treated with 0.13 g (0.572 mmol) of periodic acid. After 24 h,
the reaction was complete and produced epoxy aldehydes 7 and
9, respectively, in quantitative yield. The specific rotation of 7
was +10.2 (c 1.2, H2O), and that of 9 was -8.97. A reference
sample of epoxy amide 8 was treated with periodic acid under
similar conditions to obtain epoxy aldehyde 9 with a negative
specific rotation [-8.9° (c 1.2, H2O)].12
N,N-Dieth yl-3,7-a n h yd r o-4,5:6,8-d i-O-isop r op ylid en e-2-
O-tosyl-D-er yth r o-L-m a n n o-octon a m id e (12). To a solution
of 7.6 g (0.02 mol) of pyranose 4 in 50 mL of anhydrous pyridine
was added 6.5 g of p-toluenesulfonyl chloride (50% excess) at 0
°C, and the crude mixture was allowed to stand at rt for 12 h.
Then, cold water was added, and the mixture extracted with
chloroform (50 mL, 4 × 1). The combined organic layers were
washed once with 1 N HCl (100 mL), saturated sodium hydrogen
carbonate, and water, dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo to obtain 10.5 g (98%) of 12
as a white solid: mp 61 °C; [R]20D -51.4° (c 0.5, CHCl3); IR 2998,
1653, 1381, 1217 cm-1; 1H NMR δ 7.74 (d, 2H, J ) 8.2 Hz), 7.26
(d, 2H, J ) 8.2 Hz), 5.48 (d, 1H, J ) 9.2 Hz, H-2), 4.26 (dd, 1H,
J ) 5.2, 2.4 Hz), 4.07 (dd, 1H, J ) 9.2, 2.4 Hz), 3.98 (dd, 1H, J
) 7.8, 5.2 Hz), 3.75 (dd, 1H, J ) 10.4, 5.6 Hz), 3.63 (dd, 1H, J )
N,N-Dieth yl-3,7-a n h yd r o-4,5:6,8-d i-O-isop r op ylid en e-D-
er yth r o-L-m a n n o-octon a m id e (4). To a solution containing
7.6 g (0.02 mol) of epoxide 3 in 20 mL of anhydrous THF was
added 4 g of 60% sodium hydride. The suspension was stirred
under a nitrogen atmosphere and at rt for 3 h, after which time
the reaction was complete as checked by TLC analysis. The
suspension was then filtered and the filtrate washed with ether.
The ether solution was then washed with a saturated aqueous
solution of ammonium chloride and water, and the combined
aqueous phases were extracted with chloroform (3 × 1). The
combined organic layers were dried over anhydrous sodium
sulfate, filtered, and concentrated to obtain 7.6 g of the pure
pyranose 4 as a colorless syrup (100%): [R]20 -57.4° (c 9.6,
D
HCCl3); IR 3444, 2936, 1637 cm-1; H NMR δ 4.57 (d, 1H, J )
1
8.9 Hz), 4.40 (dd, 1H, J ) 5.0, 2.2 Hz), 3.96 (dd, 1H, J ) 7.8, 5.0
Hz), 3.70 (dd, 1H, J ) 14.2, 7.2 Hz), 3.65 (dd, 1H, J ) 10.0, 7.8
Hz), 3.59 (dd, 1H, J ) 8.9, 2.2 Hz), 3.55-3.10 (2dq, 4H), 3.15
(dd, 1H, J ) 14.2, 7.2 Hz), 2.93 (ddd, 1H, J ) 9.9, 7.3, 7.2 Hz),
1.47, 1.41, 1.31 (3s, 12H), 1.08, 1.05 (2t, 6H, J ) 7.2, 7.2 Hz);
13C NMR δ 171.5, 109.3, 99.3, 79.0, 75.6, 73.2, 72.8, 69.7, 65.6,
61.6, 40.9, 40.4, 28.6, 28.2, 26.1, 18.5, 13.7, 12.2; MS m/z 358
(M+ - 15, 9.1), 297 (2.9), 273 (20.5), 215 (15.1), 202 (11.6), 130
(24.1), 100 (100), 72 (41.4), 43 (30.1). Anal. Calcd for
C
18H31O7N: C, 57.90; H, 8.31; N, 3.75. Found: C, 57.97; H, 8.17;
N, 3.51.
Tr ea tm en t of Ep oxy Am id e 3 a n d Ma n n op yr a n osid e 4
w ith Acetic An h yd r id e. Syn th esis of th e Acetyla ted
P r od u cts 10 a n d 11: Gen er a l P r oced u r e. The product (1.34
mmol) was dissolved in 2 mL of anhydrous pyridine, and to the
resulting mixture was then added 0.4 mL of acetic anhydride
at rt. After 12 h, the solution was diluted with cold water (4
mL) and extracted with chloroform (5 mL, 3 × 1). The organic
phase was then washed once with 2 N HCl (5 mL), saturated
sodium bicarbonate (5 mL), and water (5 mL). Finally, it was
dried over anhydrous sodium sulfate, filtered, and concentrated

Notes
J . Org. Chem., Vol. 62, No. 17, 1997 6059
10.0, 7.8 Hz), 3.52 (dd, 1H, J ) 10.4, 10.0 Hz), 3.42-3.20 (2dq,
4H), 3.03 (dt, 1H, J ) 10.0, 5.6 Hz), 2.38 (s, 3H), 1.49, 1.44, 1.35,
1.25 (4s, 12H), 1.18, 0.96 (2t, 6H, J ) 7.1, 7.0 Hz); 13C NMR δ
165.4, 144.7, 133.4, 129.4, 127.7, 109.5, 99.4, 75.3, 72.7, 72.1,
70.9, 69.8, 61.4, 41.7, 40.6, 28.6, 28.1, 25.8, 21.3, 18.5, 13.8, 12.0;
MS m/z 512 (M+ - 15, 3), 412 (1), 356 (11), 314 (18), 242 (9),
155 (18), 142 (9), 100 (100), 91 (20), 72 (29). Anal. Calcd for
1.35, 1.27 (4s, 12H), 0.92 (t, 6H, J ) 7.1 Hz); 13C NMR δ 109.5,
99.4, 78.5, 76.3, 74.8, 73.1, 69.5, 61.8, 54.9, 50.3, 47.6, 28.9, 28.3,
26.0, 18.7, 11.7; MS m/z 343 (M+ - 15, 4), 115 (2), 100 (1), 87
(21), 86 (100), 71 (13), 57 (10), 43 (10). Anal. Calcd for
C18H34O5N2: C, 60.33; H, 9.49; N, 7.82. Found: C, 59.84; H,
9.40; N, 7.26.
N,N-Dieth yl-3,7-an h ydr o-2-[(ter t-bu toxycar bon yl)am in o]-
2-d eoxy-4,5:6,8-d i-O-isop r op ylid en e-D-er yth r o-L-glu co-oc-
ton a m id e (16). To a solution of the crude mixture resulting
from the reaction of azide 13 (0.30 g) with triphenylphosphine
in 5 mL of THF were added 0.30 g of triethylamine and 0.70
mL of Boc2O. After 12 h, the solution was concentrated to
dryness under vacuum to obtain a syrup. Column chromatog-
raphy on silica gel (eluent 8:1 Hex:AcOEt) of the resulting syrup
provided 0.31 g of the pure Boc-derivative 16 as a colorless liquid
C
25H37O9NS: C, 56.92; H, 7.02; N, 2.65. Found: C, 56.75; H,
7.12; N, 2.49.
N,N-Diet h yl-3,7-a n h yd r o-2-a zid o-2-d eoxy-4,5:6,8-d i-O-
isop r op ylid en e-D-er yth r o-L-glu co-octon a m id e (13). A sus-
pension containing 2 g (3.79 mmol) of the tosyl derivative 12
and 2 g of sodium azide (8-fold excess) in 20 mL of DMF was
heated under reflux for 3 h, after which time the reaction was
complete. Then, the crude mixture was cooled and diluted with
50 mL of chloroform. Next, the organic solution was washed
with water twice and the aqueous solution extracted with
chloroform (50 mL, 2 × 1). The combined organic layers were
dried over anhydrous sodium sulfate, filtered, and concentrated
under high vacuum to remove the solvents. Column chroma-
tography on silica gel (eluent 8:1 Hex:AcOEt) of the resulting
syrup provided 1.1 g of the pure azido derivative 13 as a white
solid (75%): mp 101 °C; [R]20D ) -36.7° (c 2.7, CHCl3); IR 2997,
(75%). 16: [R]20 -61.4° (c 2.1, CHCl3); IR 3338, 2991, 1707,
D
1636, 1382 cm-1; 1H NMR δ 4.07 (dd, 1H, J ) 5.4, 2.3 Hz), 3.98
(d, 1H, J ) 8.1 Hz), 3.92 (dd, 1H, J ) 8.1, 2.3 Hz), 3.84 (dd, 1H,
J ) 10.9, 5.8 Hz), 3.67 (m, 3H), 3.55-3.30 (4q, 4H), 3.08 (m,
1H), 1.47, 1.44, 1.41, 1.37 (4s, 12H), 1.38 (s, 9H), 1.18, 1.06 (2t,
6H, J ) 7.1, 7.0 Hz): 13C NMR δ 168.8, 157.5, 109.5, 99.5, 77.8,
76.1, 73.2, 72.9, 69.5, 61.8, 51.2, 42.5, 40.5, 28.9, 28.4, 26.1, 18.8,
28.2, 27.6, 14.1, 12.8; MS m/z 415 (M+ - 57, 3), 330 (27), 272
(26), 142 (1), 100 (100), 72 (67), 33 (30). Anal. Calcd for
1
2113, 1641, 1381, 1217 cm-1; H NMR δ 4.29 (dd, 1H, J ) 9.1,
2.4 Hz), 4.19 (d, 1H, J ) 9.1 Hz), 4.17 (dd, 1H, J ) 5.7, 2.4 Hz),
4.01 (dd, 1H, J ) 8.0, 5.7 Hz), 3.93 (dd, 1H, J ) 10.9, 5.7 Hz),
3.69 (t, 1H, J ) 10.9 Hz), 3.64 (dd, 1H, J ) 10.0, 8.0 Hz), 3.56-
3.22 (4q, 4H), 3.12 (ddd, 1H, J ) 10.9, 8.0, 5.7 Hz), 1.47, 1.45,
1.37, 1.19 (4s, 12H), 1.18, 1.06 (2t, 6H, J ) 7.1, 7.0 Hz); 13C NMR
δ 165.6, 109.5, 99.5, 76.3, 75.9, 73.1, 72.7, 69.3, 61.7, 58.6, 42.5,
40.9, 28.8, 28.2, 25.9, 18.5, 14.3, 12.7; MS m/z 355 (M+ - 15-
28, 6), 312 (3), 201 (5), 183 (6), 143 (17), 127 (10), 101(12), 100
(29), 85 (12), 72 (100), 59 (20), 43 (40). Anal. Calcd for
C
23H40O8N2: C, 58.47; H, 8.47; N, 5.93. Found: C, 58.20; H,
8.40; N, 5.80.
Acid Hyd r olysis of P yr a n oses 4, 15, a n d 16. Syn th esis
of t h e Un p r ot ect ed Ma n n op yr a n oses 17, 19, a n d 18.
Gen er a l P r oced u r e. A solution of 0.1 mmol of the sugar
derivative in 1 mL of absolute ethanol was treated with 0.2 mL
of 2 N HCl at rt for 1 h. Then the crude mixture was
concentrated to dryness under high vacuum to obtain the
unprotected sugar derivative quantitatively as a syrup. Redis-
solution in water and subsequent lyophilization gave crystalline
products.
C
18H30O6N4: C, 54.27; H, 7.53; N, 14.07. Found: C, 54.55; H,
7.52; N, 13.94.
N,N-Diet h yl-2-a m in o-3,7-a n h yd r o-2-d eoxy-4,5:6,8-d i-O-
isop r op ylid en e-D-er yth r o-L-glu co-octon a m id e (14). To a
solution containing 0.54 g (1.54 mmol) of azido derivative 13 in
5 mL of THF was added 0.5 g of triphenylphosphine (25%
excess). The crude mixture was stirred at rt for 12 h, and 15
mL of water was added. The mixture was kept under strong
stirring for a further 12 h more and then separated. The
aqueous solution was extracted with THF (5 mL, 3 × 1). The
combined organic layers were dried over anhydrous sodium
sulfate, filtered, and concentrated to obtain a crude mixture
consisting of the amino derivative 14 and triphenylphosphine
oxide. Purification by column chromatography on silica gel
(eluent 1:1 Hex:AcOEt and then AcOEt) was unsuccessful, and
pure amino derivative 14 was isolated in a low yield. This
required derivatization of 14 to a lower polarity product, viz.
the Boc-amino 16, which is described below. 14: IR 3386, 3320,
N ,N -D ie t h y l-3,7-a n h y d r o -D-er yt h r o-L-m a n n o-o c t o n -
1
a m id e (17): [R]20 -23.5° (c 2.0, H2O); H NMR (MeOD-D2O)
D
δ 4.52 (d, 1H, J ) 8.1 Hz), 3.61-3.4 (m, 7H), 3.2-3.1 (m, 4H),
1.1-1.0 (2t, 6H, J ) 7.1 Hz); 13C NMR (MeOD-D2O) δ 173.7,
81.1, 79.8, 75.3, 68.9, 67.9, 65.7, 61.9, 43.2, 42.1, 14.4, 12.8.
N,N-Diet h yl-2-a m in o-3,7-a n h yd r o-2-d eoxy-D-er yth r o-L-
glu co-octon a m id e (18). These data were obtained from the
crude mixture: 1H NMR (MeOD-D2O) δ 4.57 (d, 1H, J 2,3 ) 8.8
Hz), 3.92-3.80 (m, 2H), 3.72-3.49 (m, 4H), 3.42-3.15 (m, 5H),
1.15 and 1.07 (2t, 6H, J ) 7.1 Hz); 13C NMR (MeOD-D2O) δ
173.4, 81.7, 81.2, 75.4, 70.5, 68.4, 62.8, 52.5, 44.7, 42.2, 14.7,
13.1.
2998, 1653, 1381 cm-1 1H NMR δ 4.15 (dd, 1H, J ) 8.1, 2.4
;
2-Am in o-3,7-a n h yd r o-1,2-d id eoxy-1-(d iet h yla m in o)-D-
er yth r o-L-glu co-octitol (19): [R]20D +7.27° (c 1.6, H2O); 1H NMR
(MeOD-D2O) δ 4.20-4.09 (m, 2H), 3.97-3.89 (m, 2H), 3.80 (d,
1H, J ) 8.3 Hz), 3.75-3.50 (m, 3 H), 3.48-3.40 (m, 2H), 3.36 (q,
4H), 1.35 (t, 6H, J ) 7.1 Hz); 13C-NMR (MeOD-D2O) δ 79.7,
73.1, 72.9, 69.7, 65.8, 60.6, 51.4, 48.4, 7.6.
Hz), 3.97 (dd, 1H, J ) 5.7, 2.4 Hz), 3.90 (dd, 1H, J ) 8.0, 5.7
Hz), 3.89 (dd, 1H, J ) 10.5, 5.7 Hz), 3.87 (d, 1H, J ) 8.1 Hz),
3.71 (t, 1H, J ) 10.5 Hz), 3.55 (dd, 1H, J ) 10.0, 8.0 Hz), 3.55-
3.20 (4q, 4H), 3.14 (ddd, 1H, J ) 10.5, 8.0, 5.7 Hz), 1.49, 1.47,
1.39, 1.21 (4s, 12H), 1.19, 1.08 (2t, 6H, J ) 7.1, 7.0 Hz); 13C NMR
δ 170.7, 109.3, 99.5, 79.7, 75.9, 73.4, 73.1, 69.6, 61.8, 52.5, 42.4,
40.7, 28.9, 28.4, 25.9, 18.7, 14.4, 12.9; MS m/z 372 (M+, 1), 357
(M+ - 15, 9), 273 (14), 272 (100), 214 (53), 156 (77), 138 (13),
129 (35), 100 (26), 85 (13), 72 (56), 69 (35), 43 (30).
Ack n ow led gm en t. This research was funded by the
Direccio´n General de Investigacio´n y Cient´ıfica Te´cnica
(Ref. PB94-1487) and the Direccio´n General de Univer-
sidades e Investigacio´n. Consejer´ıa de Educacio´n y
Ciencia. J unta de Andaluc´ıa (group FQM 0158). F.S.-
G. acknowledges the award of a research grant from the
Consejer´ıa de Educacio´n y Ciencia de la J unta de
Andaluc´ıa.
2-Am in o-3,7-a n h yd r o-1,2-d id eoxy-1-(d ieth yla m in o)-4,5:
6,8-d i-O-isop r op ylid en e-D-er yth r o-L-glu co-octitol (15).
A
solution of 2 mL of anhydrous THF containing 0.1 g of the azido
derivative 13 was treated with 0.1 g of lithium aluminum
hydride (10-fold excess) under a nitrogen atmosphere at rt. The
suspension was vigorously stirred for 1 h. Then, 2 mL of a 10%
aqueous solution of KOH was added slowly and at 0 °C to remove
the excess hydride. Next, the crude mixture was extracted with
dichloromethane (3 × 1). The organic solution was dried over
anhydrous sodium sulfate, filtered, and concentrated in vacuo
to obtain 0.1 g of a white solid corresponding to the pure diamino
derivative 15 (100%). No further purification was required. 15:
mp 92 °C; [R]20D -36.9° (c 0.5, CHCl3); IR 3401, 2977, 1380, 1241,
Su p p or tin g In for m a tion Ava ila ble: Compound charac-
terization data inclusive of NMR peak assignments and copies
of NMR spectra (11 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
1
1217 cm-1; H NMR δ 4.11 (dd, 1H, J ) 5.3, 2.4 Hz), 3.96 (dd,
1H, J ) 8.0, 5.3 Hz), 3.83 (dd, 1H, J ) 10.5, 5.8 Hz), 3.67 (dd,
1H, J ) 10.5, 7.2 Hz), 3.62 (dd, 1H, J ) 8.0, 5.3 Hz), 3.53 (dd,
1H, J ) 6.4, 2.4 Hz), 3.14 (m, 1H), 3.03 (ddd, 1H, J ) 7.2, 5.8,
5.3 Hz), 2.44 (m, 5H), 2.21 (dd, 1H, J ) 12.4, 8.9 Hz), 1.47, 1.43,
J O961875S