Optically active sugar thioamides from δ-gluconolactone

Article abstract of DOI:10.1016/S0957-4166(00)00140-3

This paper describes a facile and rapid approach to N-alkyl- and N-aryl-thiogluconamides employing δ-gluconolactone as starting material. The protocol involves a three-step sequence to afford the corresponding thioamides as crystalline substances in moder

Full text of DOI:10.1016/S0957-4166(00)00140-3

Tetrahedron: Asymmetry 11 (2000) 1985±1995
Optically active sugar thioamides from d-gluconolactone
Marõa J. Arevalo, Martõn Avalos, Reyes Babiano, Andres Cabanillas, Pedro Cintas,
Jose L. Jimenez* and Juan C. Palacios
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Departamento de Quõmica Organica, Facultad de Ciencias, Universidad de Extremadura, E-06071 Badajoz, Spain
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Received 17 March 2000; accepted 6 April 2000
Abstract
This paper describes a facile and rapid approach to N-alkyl- and N-aryl-thiogluconamides employing
d-gluconolactone as starting material. The protocol involves a three-step sequence to a€ord the corre-
sponding thioamides as crystalline substances in moderate to good yields. The Lawesson reagent was
found to be the reagent of choice to accomplish the key transformation amide±thioamide. # 2000 Elsevier
Science Ltd. All rights reserved.
1. Introduction
Carbohydrates represent the most ubiquitous source of chiral pool in nature and are therefore
ideal precursors to access enantiomerically pure targets. Carbohydrate templates are available in
a wide variety of chain lengths, cyclic and acyclic structures, and remarkably they are endowed
with a plethora of stereochemical and conformational features which can be exploited in synthesis.1
Moreover, methods for the transformation of sugar molecules into synthetically useful, yet chiral
derivatives are likewise relevant.1a,b Recently, we have developed several syntheses of sugar
thioamides,2,3 which serve as suitable precursors of optically active heterocycles4 and of other
functional groups.5 7 Traditional methods have been based on the reaction of glycosyl cyanides
with hydrogen sul®de,8 and more recently, on the condensation of aldonodithioates with hetero-
cyclic amines9 and reactions of aminosugars with dithiocarboxylic esters or O-ethyl thioformate.10
These protocols have been applied to cyclic sugars, especially glycopyranosyl or ribopyranosyl
derivatives to nucleosides and their analogs.
* Corresponding author. E-mail: pecintas@unex.es
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00140-3

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M. J. Arevalo et al. / Tetrahedron: Asymmetry 11 (2000) 1985±1995
1986
2. Results
2.1. Syntheses
Herein we describe a short synthesis of O-protected N-alkyl and N-arylthiogluconamides
starting from d-gluconolactone, which is an inexpensive and readily available monosaccharide
derivative (Scheme 1).11 It is known that aldonolactones undergo ring opening by aminolysis of
the lactone group. However, the process has largely been restricted to reactions with ammonia,
N,N-dialkylamines,12 and long-chain primary amines in the search of emulsifying agents,13,14 or
liquid crystals.15 Some gluconamides also exhibit biological activity.16 We have extended the
transformation to a series of alkyl and arylamines to yield the unprotected gluconamides in high
yields. Reactions of d-gluconolactone with aromatic amines (neat or in 50% pyridine±amine
mixtures) were faster than those of alkyl derivatives, although they were essentially complete
within 24 h in all cases. Conventional O-protection with acetic anhydride gave the acetylated
sugars as crystalline solids in good yields. The apparently trivial transformation of converting the
carbonyl group into a thiocarbonyl was dicult to carry out, as several reaction conditions gave
only partial conversions. The thermal reaction of gluconamides with P4S10 in benzene proceeded
slowly. Reasoning that a major drawback arises from the heterogeneous character of the reaction
mixture, we attempted to accelerate the mass transfer by ultrasonic irradiation in THF at 40ꢀC, a
strategy which proved to be successful for simple amides17 and glycopyranosyl amides.3 Never-
theless, reactions in an ultrasonic bath were unpractical, albeit they could be improved using a
sonic probe (20 kHz, 600 W, ꢁ50% conversion).
Scheme 1.

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M. J. Arevalo et al. / Tetrahedron: Asymmetry 11 (2000) 1985±1995
1987
Next, we turned our attention to the Lawesson reagent, 2,4-bis(4-methoxyphenyl)-1,3-dithia-
2,4-diphosphetane-2,4-disul®de, one of the most ecient thiation reagents.18,19 Reactions of the
latter with the corresponding gluconamides in re¯uxing benzene for 24 h resulted in complete
conversions as detected by TLC and NMR monitoring. The use of HMPA as solvent,18a instead
of benzene, gave dark and complex reaction mixtures. These O/S-exchange reactions, mediated
by the Lawesson reagent, can also be conducted under milder conditions using an ultrasonic bath
(ꢁ35 kHz, THF, 40±50ꢀC), although conversions were never greater than 50%. The fact that
ultrasonic agitation is less ecient than conventional heating is also consistent with the ionic
mechanism assumed for this transformation, since ionic processes are insensitive to the chemical
role of ultrasound and only a physical component, in the case of heterogeneous processes, should
be expected (`false sonochemistry').20
3. Discussion
3.1. Structural characterization
All compounds gave satisfactory combustion analyses with the sole exception of the thioglucon-
amide derivative 23, which was obtained as an amorphous solid, but homogeneous by chroma-
tography and NMR analyses. IR spectra of compounds 2±17 show the typical amide band at
ꢁ1650 cm^1,21 which is absent in their thiogluconamide counterparts 18±25. As expected, ring-
opening of d-gluconolactone does not modify the stereochemistry at C-2, and hence the sign of
optical rotation is always positive, consistent with the fact that the con®guration at the ®rst ste-
reogenic center (C-2) must be R.22
Compounds 2±17 show 13C resonances at ꢁ170 ppm, attributable to the amide carbonyl group,
1
whereas thioamides 18±25 display the thiocarbonyl group at ꢁ195 ppm. H NMR spectra of
gluconamides and their thioanalogs could fully be interpreted. In the case of per-O-acetyl-
gluconamides, the chemical shifts of the acyclic side chain follow the order: H-3>H-4>H-2>
H-5>H-6>H-60, while for the protected thiogluconamides the sequence of proton resonances is:
H-3>H-2>H-4>H-5>H-6>H-60. The large chemical shift di€erences between amides and
thioamides observed for H-2 (Áꢀ ꢁ0.4 ppm) and for H-3 at a lesser extent (Áꢀ ꢁ0.24 ppm), which
can be attributed to the greater anisotropy exerted by the CˆS group, are remarkable.23 A further
0
analysis of the coupling constants J2,3, J3,4, J4,5, J5,6 and J5,6 reveals that there is a conforma-
tional equilibrium for both the amides 10±17 and thioamides 18±25 in solution. Although the
conformer 2G^ should be prevalent,24 the values of the apparent coupling constants J2,3, J3,4, and
J4,5 suggest a signi®cant contribution of P and G+ conformations, despite these arrangements
2
being less stabilized owing to 1,3-interactions between the acetate groups (P) or between the
O-acyl and the amide groups (2G+) at C-2 and C-4 (Scheme 2).
Scheme 2.

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1988
On the other hand, the close similarity for 13C chemical shifts from C-2 to C-5 also support the
existence of an acyclic structure.25 For the protected amides 10±17, 13C resonances lie in the order:
C-3>C-2>C-4>C-5>C-6, whereas the sequence for thioamides is C-2>C-3>C-4>C-5>C-6,
again consistent with the enhanced anisotropy provided by a thioamide group.
In conclusion a concise synthesis of N-substituted thiogluconamides has been reported. It is
hoped that these materials will be appropriate synthons in asymmetric reactions, and current
e€orts focus on this application.
4. Experimental
4.1. General methods
Melting points were determined with a Gallenkamp apparatus and are uncorrected. Optical
rotations were measured at 20þ5ꢀC with a Perkin±Elmer 241 polarimeter. IR spectra were
recorded on KBr pelletes with a Perkin±Elmer 399 spectrophotometer. TLC analyses were con-
ducted on silica gel GF254 (Merck) using benzene±acetonitrile solvent mixtures (3:1, 5:1, and 10:1)
as eluents, followed by detection with UV light or iodine vapor. Flash chromatography was
performed on SiO2 (Merck) using the method described by Still et al.26 1H and 13C NMR spectra
were recorded with a Bruker AC 200-E or a Bruker 400 AC/PC spectrometer. Assignments were
1
1
con®rmed by H±1H COSY and H±13C heteronuclear techniques, and DEPT (Distortionless
Enhanced Proton Transfer) experiments. Elemental microanalyses were determined on a Perkin±
Elmer 240C analyzer.
4.2. N-Alkyl(aryl)-d-gluconamides. General procedure
A solution of 1 (5.0 g, 28.0 mmol) in a commercial solution of amine (0.3 mol) in the cases of
methylamine (40% aqueous solution) and ethylamine, or in a 1:1 (v/v) amine±pyridine solution
(40 mL, 0.3 mol) in the cases of n-propylamine, isopropylamine, cyclohexylamine, aniline,
4-methoxyaniline, and 4-bromoaniline, was kept at room temperature for 24 h. The solvent was
evaporated and the residue was treated with ethanol and diethyl ether to a€ord the corresponding
gluconamides as crystalline solids, which were further recrystallized from ethanol or 96%
aqueous ethanol.
4.2.1. N-Methyl-d-gluconamide 2
Yield: 96%, mp 158±160ꢀC, [ꢁ]D +29 (c 0.5, N,N-dimethylformamide); IR (KBr) ꢂmax 3300,
1635, 1560, 1270 cm^1; 1H NMR (200 MHz, DMSO-d6) ꢀ 7.67 (m, 1H, N-H), 4.62±3.36 (m, 11H),
2.61 (d, J=4.7 Hz, 3H, CH3); 13C NMR (50.3 MHz, DMSO-d6) ꢀ 173.2 (C-1), 73.8, 72.5, 71.6,
70.3, 63.5 (C-6), 25.6 (CH3). Anal. calcd for C7H15NO6: C, 40.19; H, 7.23; N, 6.69. Found: C,
39.85; H, 7.42; N, 6.97.
4.2.2. N-Ethyl-d-gluconamide 3
Yield: 93%, mp 138±140ꢀC, [ꢁ]D +26 (c 0.5, N,N-dimethylformamide); IR (KBr) ꢂmax 3300,
1665, 1550, 1310 cm^1; 1H NMR (200 MHz, DMSO-d6) ꢀ 7.67 (t, J=5.6 Hz, 1H, N-H), 5.40±3.36
(m, 11H), 3.13 (m, 2H, CH2), 1.02 (t, J=7.2 Hz, 3H, CH3); 13C NMR (50.3 MHz, DMSO-d6) ꢀ

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172.4 (C-1), 73.7, 72.5, 71.6, 70.2, 63.5 (C-6), 33.2 (CH2), 15.0 (CH3). Anal. calcd for C8H17NO6:
C, 43.04; H, 7.68; N, 6.27. Found: C, 43.20; H, 7.52; N, 6.10.
4.2.3. N-Propyl-d-gluconamide 4
Yield: 93%, mp 149±151ꢀC, [ꢁ]D +31 (c 0.5, N,N-dimethylformamide); IR (KBr) ꢂmax 3300,
1660, 1540, 1290 cm^1; 1H NMR (200 MHz, DMSO-d6) ꢀ 7.66 (t, J=5.8 Hz, 1H, N-H), 5.43±3.38
(m, 11H), 3.05 (q, J=6.6 Hz, 2H, N-CH2), 1.43 (q, J=7.3 Hz, 3H, CH2), 0.84 (t, J=7.3 Hz, 3H,
CH3); 13C NMR (50.3 MHz, DMSO-d6) ꢀ 172.7 (C-1), 73.9, 72.7, 71.7, 70.3, 63.6 (C-6), 39.9
(N-CH2), 22.3 (CH2), 11.6 (CH3). Anal. calcd for C9H19NO6: C, 45.60; H, 8.07; N, 5.90. Found:
C, 45.47; H, 8.22; N, 5.79.
4.2.4. N-Isopropyl-d-gluconamide 5
Yield: 97%, mp 179±181ꢀC (dec.), [ꢁ]D +24 (c 0.5, N,N-dimethylformamide); IR (KBr) ꢂmax
1
3300, 1640, 1565, 1320 cm^1; H NMR (200 MHz, DMSO-d6) ꢀ 7.33 (d, J=8.2 Hz, 1H, N-H),
5.37±3.37 (m, 11H), 3.89 (m, 1H, N-CH), 1.07 (d, J=6.6 Hz, 6H, CH3), 0.84 (t, J=7.3 Hz, 3H,
CH3); 13C NMR (50.3 MHz, DMSO-d6) ꢀ 171.6 (C-1), 73.6, 72.5, 71.6, 70.2, 63.5 (C-6), 40.3
(N-CH), 22.4 (2C, CH3). Anal. calcd for C9H19NO6: C, 45.60; H, 8.07; N, 5.90. Found: C, 45.45;
H, 8.32; N, 5.93.
4.2.5. N-Cyclohexyl-d-gluconamide 6
Yield: 87%, mp 187±189ꢀC, [ꢁ]D +28 (c 0.5, N,N-dimethylformamide); IR (KBr) ꢂmax 3300,
1
1640, 1560 cm^1; H NMR (200 MHz, DMSO-d6) ꢀ 7.36 (d, J=8.2 Hz, 1H, N-H), 4.66±3.37 (m,
12H), 1.65±1.14 (m, 10H); 13C NMR (50.3 MHz, DMSO-d6) ꢀ 171.6 (C-1), 73.7, 72.5, 71.5, 70.2,
63.5 (C-6), 47.3, 33.8, 32.4, 25.3, 24.8, 24.5. Anal. calcd for C12H23NO6: C, 51.97; H, 8.36; N,
5.05. Found: C, 52.35; H, 8.08; N, 5.33.
4.2.6. N-Phenyl-d-gluconamide 7
Yield: 90%, mp 178±180ꢀC, [ꢁ]D +24 (c 0.5, N,N-dimethylformamide); IR (KBr) ꢂmax 3300,
1
1660, 1540, 1300 cm^1; H NMR (200 MHz, DMSO-d6) ꢀ 9.53 (s, 1H, N-H), 7.71±7.07 (m, 5H,
Ph), 5.70±3.40 (m, 11H); 13C NMR (50.3 MHz, DMSO-d6) ꢀ 171.7 (C-1), 138.6, 128.8 (2C), 123.6,
119.7 (2C), 74.4, 72.5, 71.7, 70.5, 63.5 (C-6). Anal. calcd for C12H17NO6: C, 53.12; H, 6.31; N,
5.16. Found: C, 53.21; H, 6.57; N, 4.92.
4.2.7. N-(4-Methoxyphenyl)-d-gluconamide 8
Yield: 80%, mp 158±160ꢀC (dec.), [ꢁ]D +26 (c 0.5, N,N-dimethylformamide); IR (KBr) ꢂmax
3300, 1655, 1530, 1300 cm^1; 1H NMR (200 MHz, DMSO-d6) ꢀ 9.43 (s, 1H, N-H), 7.62±6.87 (m,
4H, Ph), 5.76±3.53 (m, 11H), 3.72 (s, 3H, OCH3); 13C NMR (50.3 MHz, DMSO-d6) ꢀ 171.1 (C-1),
155.3, 131.8, 121.1 (2C), 113.7 (2C), 74.2, 72.4, 71.6, 70.3, 63.4 (C-6), 55.2 (OCH3). Anal. calcd
for C13H19NO7: C, 51.82; H, 6.35; N, 4.65. Found: C, 51.66; H, 6.17; N, 4.83.
4.2.8. N-(4-Bromophenyl)-d-gluconamide 9
Yield: 61%, mp 158±160ꢀC (dec.), [ꢁ]D +40 (c 0.5, pyridine); IR (KBr) ꢂmax 3300, 1650, 1520,
1350 cm^1; 1H NMR (200 MHz, DMSO-d6) ꢀ 9.71 (s, 1H, N-H), 7.72±7.48 (m, 4H, Ph), 4.74±3.36
(m, 11H); 13C NMR (50.3 MHz, DMSO-d6) ꢀ 170.1 (C-1), 138.2, 132.1 (2C), 121.6 (2C), 115.2,
74.5, 72.4, 71.7, 70.5, 63.5 (C-6). Anal. calcd for C12H16BrNO6: C, 41.16; H, 4.61; N, 4.00.
Found: C, 41.02; H, 4.54; N, 4.00.

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4.2.9. 2,3,4,5,6-Penta-O-acetyl-N-alkyl(aryl)gluconamides. General procedure
The unprotected aldonamides (3.0 g) were suspended in pyridine (10 mL), cooled at 0ꢀC, acetic
anhydride (10 mL) was added, and the mixtures were stirred for 24 h. Then the solutions were
poured into ice-water, and the resulting solids were recrystallized from 96% ethanol.
4.2.10. 2,3,4,5,6-Penta-O-acetyl-N-methyl-d-gluconamide 10
Yield: 75% from 2, mp 199±201ꢀC, [ꢁ]D +30 (c 0.5, chloroform); IR (KBr) ꢂmax 3230, 1740,
1650, 1570, 1240 cm^1; 1H NMR (200 MHz, CDCl3) ꢀ 6.26 (m, 1H, N-H), 5.66 (t, J=5.1 Hz, 1H,
H-3), 5.46 (dd, J=5.1 Hz, J=6.5 Hz, 1H, H-4), 5.31 (d, J=5.1 Hz, 1H, H-2), 5.06 (m, 1H, H-5),
4.32 (dd, J=3.9 Hz, J=12.3 Hz, 1H, H-6), 4.12 (dd, J=5.7 Hz, J=12.3 Hz, 1H, H-60), 2.82 (d,
J=4.9 Hz, 3H, N-CH3), 2.20 (s, 3H, OAc), 2.09 (s, 3H, OAc), 2.08 (s, 3H, OAc), 2.07 (s, 3H,
OAc), 2.06 (s, 3H, OAc); 13C NMR (50.3 MHz, CDCl3) ꢀ 170.6 (CO, OAc), 169.8 (CO, OAc),
169.8 (CO, OAc), 169.6 (CO, OAc), 169.2 (CO, OAc), 166.6 (CO, amide), 71.4 (C-2), 69.2 (C-4),
69.0 (C-3), 68.6 (C-5), 61.5 (C-6), 26.1 (N-CH3), 20.7 (OAc), 20.6 (OAc). Anal. calcd for
C17H25NO11: C, 48.68; H, 6.01; N, 3.34. Found: C, 48.69; H, 6.05; N, 3.33.
4.2.11. 2,3,4,5,6-Penta-O-acetyl-N-ethyl-d-gluconamide 11
Yield: 85% from 3, mp 158±160ꢀC, [ꢁ]D +27 (c 0.5, chloroform); IR (KBr) ꢂmax 3300, 1765,
1
1670, 1575, 1240 cm^1; H NMR (200 MHz, CDCl3) ꢀ 6.19 (t, J=3.8 Hz, 1H, N-H), 5.68 (t,
J=5.2 Hz, 1H, H-3), 5.45 (dd, J=5.1 Hz, J=6.3 Hz, 1H, H-4), 5.30 (d, J=5.2 Hz, 1H, H-2), 5.04
(m, 1H, H-5), 4.32 (dd, J=3.9 Hz, J=12.3 Hz, 1H, H-6), 4.13 (dd, J=5.5 Hz, J=12.3 Hz, 1H,
H-60), 3.29 (m, 2H, N-CH2), 2.21 (s, 3H, OAc), 2.12 (s, 3H, OAc), 2.10 (s, 3H, OAc), 2.06 (s, 3H,
OAc), 2.05 (s, 3H, OAc), 1.13 (t, J=7.2 Hz, 3H, CH3); 13C NMR (50.3 MHz, CDCl3) ꢀ 170.5
(CO, OAc), 169.8 (2C, CO, OAc), 169.6 (CO, OAc), 169.1 (CO, OAc), 165.8 (CO, amide), 71.6
(C-2), 69.2 (C-4), 68.9 (C-3), 68.6 (C-5), 61.4 (C-6), 34.3 (N-CH2), 20.7 (OAc), 20.6 (OAc), 20.3
(OAc), 14.5 (CH3). Anal. calcd for C18H27NO11: C, 49.88; H, 6.28; N, 3.23. Found: C, 49.99; H,
6.34; N, 3.23.
4.2.12. 2,3,4,5,6-Penta-O-acetyl-N-propyl-d-gluconamide 12
Yield: 72% from 4, mp 130±132ꢀC, [ꢁ]D +25 (c 0.5, chloroform); IR (KBr) ꢂmax 3280, 1755,
1
1665, 1575, 1240 cm^1; H NMR (200 MHz, CDCl3) ꢀ 6.42 (t, J=5.5 Hz, 1H, N-H), 5.69 (t,
J=5.0 Hz, 1H, H-3), 5.46 (dd, J=5.0 Hz, J=6.0 Hz, 1H, H-4), 5.30 (d, J=5.0 Hz, 1H, H-2), 5.09
(m, 1H, H-5), 4.32 (dd, J=3.8 Hz, J=12.2 Hz, 1H, H-6), 4.13 (dd, J=5.4 Hz, J=12.2 Hz, 1H,
H-60), 3.23 (m, 2H, N-CH2), 2.21 (s, 3H, OAc), 2.11 (s, 3H, OAc), 2.10 (s, 3H, OAc), 2.06 (s, 3H,
OAc), 2.05 (s, 3H, OAc), 1.51 (q, J=7.4 Hz, 2H, CH2), 0.91 (t, J=7.4 Hz, 3H, CH3); 13C NMR
(50.3 MHz, CDCl3) ꢀ 170.3 (CO, OAc), 169.6 (CO, OAc), 169.5 (CO, OAc), 169.4 (CO, OAc),
168.9 (CO, OAc), 165.7 (CO, amide), 71.5 (C-2), 69.1 (C-4), 68.8 (C-3), 68.4 (C-5), 61.2 (C-6),
40.8 (N-CH2), 20.4 (CH2), 20.4 (OAc), 10.9 (CH3). Anal. calcd for C19H29NO11: C, 51.00; H,
6.53; N, 3.13. Found: C, 50.82; H, 6.57; N, 3.10.
4.2.13. 2,3,4,5,6-Penta-O-acetyl-N-isopropyl-d-gluconamide 13
Yield: 95% from 5, mp 162±164ꢀC, [ꢁ]D +28 (c 0.5, chloroform); IR (KBr) ꢂmax 3300, 1765,
1
1665, 1565, 1240 cm^1; H NMR (200 MHz, CDCl3) ꢀ 5.97 (d, J=5.5 Hz, 1H, N-H), 5.69 (t,
J=5.0 Hz, 1H, H-3), 5.44 (dd, J=5.0 Hz, J=6.0 Hz, 1H, H-4), 5.26 (d, J=5.0 Hz, 1H, H-2), 5.03
(m, 1H, H-5), 4.32 (dd, J=4.1 Hz, J=12.2 Hz, 1H, H-6), 4.13 (dd, J=5.4 Hz, J=12.2 Hz, 1H,
H-60), 4.05 (m, 1H, N-CH), 2.21 (s, 3H, OAc), 2.11 (s, 3H, OAc), 2.10 (s, 3H, OAc), 2.06 (s, 3H,

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OAc), 2.05 (s, 3H, OAc), 1.15 (d, J=6.6 Hz, 6H, CH3); 13C NMR (50.3 MHz, CDCl3) ꢀ 170.5
(CO, OAc), 169.7 (2C, CO, OAc), 169.5 (CO, OAc), 169.0 (CO, OAc), 164.9 (CO, amide), 71.7
(C-2), 69.2 (C-4), 68.9 (C-3), 68.6 (C-5), 61.3 (C-6), 41.4 (N-CH), 22.3 (CH3), 22.2 (CH3), 20.6
(OAc), 20.5 (OAc), 20.3 (OAc). Anal. calcd for C19H29NO11: C, 51.00; H, 6.53; N, 3.13. Found:
C, 50.72; H, 6.37; N, 3.11.
4.2.14. 2,3,4,5,6-Penta-O-acetyl-N-cyclohexyl-d-gluconamide 14
Yield: 83% from 6, mp 166±168ꢀC, [ꢁ]D +27 (c 0.5, chloroform); IR (KBr) ꢂmax 3400, 1770,
1
1690, 1550, 1240 cm^1; H NMR (200 MHz, CDCl3) ꢀ 5.98 (d, J=7.9 Hz, 1H, N-H), 5.69 (t,
J=5.2 Hz, 1H, H-3), 5.44 (dd, J=5.2 Hz, J=6.2 Hz, 1H, H-4), 5.27 (d, J=5.2 Hz, 1H, H-2), 5.04
(m, 1H, H-5), 4.32 (dd, J=4.2 Hz, J=12.2 Hz, 1H, H-6), 4.13 (dd, J=5.1 Hz, J=12.2 Hz, 1H,
H-60), 3.75 (m, 1H, N-CH), 2.21 (s, 3H, OAc), 2.11 (s, 3H, OAc), 2.10 (s, 3H, OAc), 2.06 (s, 3H,
OAc), 2.05 (s, 3H, OAc), 1.90±1.10 (m, 10H, cyclohexyl moiety); 13C NMR (50.3 MHz, CDCl3) ꢀ
170.5 (CO, OAc), 169.8 (2C, CO, OAc), 169.6 (CO, OAc), 169.1 (CO, OAc), 164.9 (CO, amide),
71.8 (C-2), 69.3 (C-4), 69.0 (C-3), 68.5 (C-5), 61.3 (C-6), 48.2 (N-CH), 32.8, 32.6, 25.3, 24.6 (2C),
20.7 (OAc), 20.6 (OAc), 20.3 (OAc). Anal. calcd for C22H33NO11: C, 54.20; H, 6.82; N, 2.87.
Found: C, 54.22; H, 6.92; N, 2.74.
4.2.15. 2,3,4,5,6-Penta-O-acetyl-N-phenyl-d-gluconamide 15
Yield: 95% from 7, mp 168±170ꢀC, [ꢁ]D +40 (c 0.5, chloroform); IR (KBr) ꢂmax 3280, 1750,
1
1675, 1550, 1230 cm^1; H NMR (200 MHz, CDCl3) ꢀ 8.40 (s, 1H, N-H), 7.49±7.09 (m, 5H,
phenyl), 5.73 (t, J=5.0 Hz, 1H, H-3), 5.52 (dd, J=5.0 Hz, J=6.5 Hz, 1H, H-4), 5.37 (d, J=5.0
Hz, 1H, H-2), 5.09 (m, 1H, H-5), 4.31 (dd, J=3.4 Hz, J=12.4 Hz, 1H, H-6), 4.11 (dd, J=5.5 Hz,
J=12.4 Hz, 1H, H-60), 2.14 (s, 3H, OAc), 2.03 (s, 12H, OAc); 13C NMR (50.3 MHz, CDCl3) ꢀ
170.3 (CO, OAc), 169.6 (CO, OAc), 169.5 (CO, OAc), 169.5 (CO, OAc), 169.0 (CO, OAc), 164.1
(CO, amide), 136.5, 128.6 (2C), 124.5, 120.0 (2C), 71 (C-2), 68.6 (C-4), 68.4 (C-3), 68.3 (C-5), 61.2
(C-6), 20.3 (OAc), 20.2 (OAc), 20.1 (OAc), 20.0 (OAc). Anal. calcd for C22H27NO11: C, 54.88; H,
5.65; N, 2.91. Found: C, 54.83; H, 5.67; N, 2.91.
4.2.16. 2,3,4,5,6-Penta-O-acetyl-N-(4-methoxyphenyl)-d-gluconamide 16
Yield: 83% from 8, mp 171±173ꢀC, [ꢁ]D +40 (c 0.5, chloroform); IR (KBr) ꢂmax 3260, 1740,
1
1665, 1540, 1220 cm^1; H NMR (200 MHz, CDCl3) ꢀ 7.98 (s, 1H, N-H), 7.37±6.48 (m, 4H,
phenyl), 5.73 (t, J=5.5 Hz, 1H, H-3), 5.50 (dd, J=5.5 Hz, J=6.7 Hz, 1H, H-4), 5.36 (d, J=5.5
Hz, 1H, H-2), 5.08 (m, 1H, H-5), 4.32 (dd, J=3.7 Hz, J=12.3 Hz, 1H, H-6), 4.13 (dd, J=5.3 Hz,
J=12.3 Hz, 1H, H-60), 3.75 (s, 3H, OCH3), 2.23 (s, 3H, OAc), 2.16 (s, 3H, OAc), 2.09 (s, 3H,
OAc), 2.07 (s, 3H, OAc), 2.06 (s, 3H, OAc); 13C NMR (50.3 MHz, CDCl3) ꢀ 170.6 (CO, OAc),
170.1 (CO, OAc), 169.8 (CO, OAc), 169.6 (CO, OAc), 169.2 (CO, OAc), 163.9 (CO, amide),
156.8, 129.61 (2C), 121.9 (2C), 114.0, 71.7 (C-2), 69.0 (C-4), 68.8 (C-3), 68.6 (C-5), 61.4 (C-6),
55.3 (OCH3), 20.8 (OAc), 20.5 (OAc), 20.3 (OAc). Anal. calcd for C23H29NO12: C, 54.01; H, 5.71;
N, 2.74. Found: C, 54.29; H, 5.77; N, 2.74.
4.2.17. 2,3,4,5,6-Penta-O-acetyl-N-(4-bromophenyl)-d-gluconamide 17
Yield: 80% from 9, mp 140±141ꢀC, [ꢁ]D +37 (c 0.5, chloroform); IR (KBr) ꢂmax 3360, 1740,
1
1680, 1540, 1220 cm^1; H NMR (400 MHz, CDCl3) ꢀ 8.02 (s, 1H, N-H), 7.45±7.39 (m, 4H,
phenyl), 5.73 (dd, J=5.7 Hz, J=4.5 Hz, 1H, H-3), 5.48 (dd, J=4.5 Hz, J=6.6 Hz, 1H, H-4), 5.33
(d, J=5.7 Hz, 1H, H-2), 5.07 (m, 1H, H-5), 4.35 (dd, J=3.4 Hz, J=12.4 Hz, 1H, H-6), 4.15 (dd,

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J=5.2 Hz, J=12.4 Hz, 1H, H-60), 2.25 (s, 3H, OAc), 2.11 (s, 6H, OAc), 2.08 (s, 6H, OAc); 13C
NMR (100 MHz, CDCl3) ꢀ 170.8 (CO, OAc), 170.2 (CO, OAc), 169.9 (2C, CO, OAc), 169.3 (CO,
OAc), 164.2 (CO, amide), 135.8, 132.0 (2C), 121.6 (2C), 117.7, 77.3 (C-2), 71.6 (C-3), 69.0 (C-4),
68.7 (C-5), 61.6 (C-6), 20.7 (OAc), 20.6 (OAc), 20.4 (OAc). Anal. calcd for C22H26BrNO11: C,
47.12; H, 4.77; N, 2.50. Found: C, 47.28; H, 4.65; N, 2.65.
4.3. 2,3,4,5,6-Penta-O-acetyl-N-alkyl(aryl)thiogluconamides. General procedure
To a solution of the per-O-acylated gluconamide (6.7 mmol) in anhydrous benzene (40 mL)
was added the Lawesson reagent (3.0 g, 7.4 mmol). The mixture was re¯uxed for 24 h and then
the solvent was evaporated. The resulting residue was extracted with diethyl ether and the combined
organic extracts were concentrated until a ®nal volume of 25±30 mL. The resulting thiogluconamide
was puri®ed by ¯ash chromatography and/or crystallized on cooling. Analytical samples were
obtained by recrystallization from 96% aqueous ethanol.
4.3.1. 2,3,4,5,6-Penta-O-acetyl-N-methyl-d-thiogluconamide 18
Yield: 72% yield from 10, mp 141±142ꢀC, [ꢁ]D +63 (c 0.5, chloroform); IR (KBr) ꢂmax 3280,
1
1750, 1560, 1240 cm^1; H NMR (200 MHz, CDCl3) ꢀ 8.23 (m, 1H, N-H), 5.90 (dd, J=4.2 Hz,
J=5.6 Hz, 1H, H-3), 5.71 (d, J=4.2 Hz, 1H, H-2), 5.44 (t, J=5.6 Hz, 1H, H-4), 5.04 (m, 1H, H-5),
4.33 (dd, J=4.7 Hz, J=12.1 Hz, 1H, H-6), 4.15 (dd, J=5.6 Hz, J=12.1 Hz, 1H, H-60), 3.15 (d,
J=4.8 Hz, 3H, N-CH3), 2.24 (s, 3H, OAc), 2.14 (s, 3H, OAc), 2.10 (s, 3H, OAc), 2.06 (s, 3H,
OAc), 2.03 (s, 3H, OAc); 13C NMR (50.3 MHz, CDCl3) ꢀ 195.3 (CˆS), 170.5 (CO, OAc), 169.7
(CO, OAc), 169.6 (CO, OAc), 169.2 (CO, OAc), 168.9 (CO, OAc), 77.0 (C-2), 70.8 (C-3), 69.3 (C-4),
68.7 (C-5), 61.0 (C-6), 32.1 (N-CH3), 20.7 (OAc), 20.5 (OAc). Anal. calcd for C17H25NO10S: C,
46.89; H, 5.78; N, 3.22. Found: C, 46.86; H, 5.81; N, 3.22.
4.3.2. 2,3,4,5,6-Penta-O-acetyl-N-ethyl-d-thiogluconamide 19
Yield: 80% from 11, mp 118±120ꢀC, [ꢁ]D +55 (c 0.5, chloroform); IR (KBr) ꢂmax 3260, 1765,
1
1545, 1240 cm^1; H NMR (200 MHz, CDCl3) ꢀ 8.09 (m, 1H, N-H), 5.90 (dd, J=4.2 Hz, J=5.7
Hz, 1H, H-3), 5.66 (d, J=4.2 Hz, 1H, H-2), 5.42 (t, J=5.7 Hz, 1H, H-4), 5.03 (m, 1H, H-5), 4.33
(dd, J=4.6 Hz, J=12.1 Hz, 1H, H-6), 4.16 (dd, J=5.5 Hz, J=12.1 Hz, 1H, H-60), 3.68 (m, 2H,
N-CH2), 2.24 (s, 3H, OAc), 2.14 (s, 3H, OAc), 2.10 (s, 3H, OAc), 2.06 (s, 3H, OAc), 2.04 (s, 3H,
OAc), 1.25 (t, J=5.2 Hz, 3H, CH3); 13C NMR (50.3 MHz, CDCl3) ꢀ 194.2 (CˆS), 170.5 (CO,
OAc), 169.7 (CO, OAc), 169.7 (CO, OAc), 169.2 (CO, OAc), 168.9 (CO, OAc), 77.0 (C-2), 70.8
(C-3), 69.3 (C-4), 68.7 (C-5), 61.0 (C-6), 40.0 (N-CH2), 20.5 (OAc), 20.1 (OAc). Anal. calcd for
C18H27NO10S: C, 49.65; H, 6.25; N, 3.22. Found: C, 49.68; H, 6.35; N, 2.99.
4.3.3. 2,3,4,5,6-Penta-O-acetyl-N-propyl-d-thiogluconamide 20
Yield: 5% from 12, mp 104±105ꢀC, [ꢁ]D +53 (c 0.5, chloroform); IR (KBr) ꢂmax 3330, 1740,
1
1530, 1240 cm^1; H NMR (200 MHz, CDCl3) ꢀ 8.20 (m, 1H, N-H), 5.90 (dd, J=4.2 Hz, J=5.9
Hz, 1H, H-3), 5.67 (d, J=4.2 Hz, 1H, H-2), 5.42 (t, J=5.9 Hz, 1H, H-4), 5.02 (m, 1H, H-5), 4.33
(dd, J=4.7 Hz, J=12.1 Hz, 1H, H-6), 4.16 (dd, J=5.6 Hz, J=12.1 Hz, 1H, H-60), 3.60 (m, 2H,
N-CH2), 2.24 (s, 3H, OAc), 2.14 (s, 3H, OAc), 2.10 (s, 3H, OAc), 2.06 (s, 3H, OAc), 2.03 (s, 3H,
OAc), 1.70 (m, 2H, CH2), 0.95 (t, J=5.8 Hz, 3H, CH3); 13C NMR (50.3 MHz, CDCl3) ꢀ 194.5
(CˆS), 170.4 (CO, OAc), 169.7 (CO, OAc), 169.6 (CO, OAc), 169.1 (CO, OAc), 168.8 (CO, OAc),
77.0 (C-2), 70.8 (C-3), 69.4 (C-4), 68.8 (C-5), 61.1 (C-6), 46.7 (N-CH2), 20.8 (CH2), 20.5 (OAc),

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M. J. Arevalo et al. / Tetrahedron: Asymmetry 11 (2000) 1985±1995
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20.1 (OAc), 11.1 (CH3). Anal. calcd for C19H29NO10S: C, 49.23; H, 6.31; N, 3.02. Found: C,
49.22; H, 6.39; N, 3.02.
4.3.4. 2,3,4,5,6-Penta-O-acetyl-N-isopropyl-d-thiogluconamide 21
Yield: 60% from 13, mp 77±79ꢀC, [ꢁ]D +50 (c 0.5, chloroform); IR (KBr) ꢂmax 3300, 1640,
1
1565, 1320, 1240 cm^1; H NMR (200 MHz, CDCl3) ꢀ 7.62 (d, J=8.0 Hz, 1H, N-H), 5.92 (dd,
J=4.4 Hz, J=5.7 Hz, 1H, H-3), 5.63 (d, J=4.4 Hz, 1H, H-2), 5.40 (t, J=5.7 Hz, 1H, H-4), 5.03
(m, 1H, H-5), 4.58 (m, 1H, N-CH), 4.34 (dd, J=4.6 Hz, J=12.2 Hz, 1H, H-6), 4.18 (dd, J=5.2
Hz, J=12.2 Hz, 1H, H-60), 2.21 (s, 3H, OAc), 2.11 (s, 3H, OAc), 2.10 (s, 3H, OAc), 2.06 (s, 3H,
OAc), 2.05 (s, 3H, OAc), 1.36 (d, J=8.0 Hz, 3H, CH3), 1.22 (d, J=8.0 Hz, 3H, CH3); 13C NMR
(50.3 MHz, CDCl3) ꢀ 193.1 (CˆS), 170.6 (CO, OAc), 170.0 (CO, OAc), 169.8 (CO, OAc), 169.2
(CO, OAc), 168.8 (CO, OAc), 77.4 (C-2), 70.9 (C-3), 69.5 (C-4), 68.8 (C-5), 61.1 (C-6), 46.7 (N-CH),
20.9 (2C, CH3), 20.8 (OAc), 20.3 (OAc); Anal. calcd for C19H29NO10S: C, 49.23; H, 6.31; N, 3.02.
Found: C, 49.52; H, 6.07; N, 3.35.
4.3.5. 2,3,4,5,6-Penta-O-acetyl-N-cyclohexyl-d-thiogluconamide 22
Yield: 65% from 14, mp 116±118ꢀC, [ꢁ]D +52 (c 0.5, chloroform); IR (KBr) ꢂmax 3310, 1750,
1
1530, 1220 cm^1; H NMR (200 MHz, CDCl3) ꢀ 7.66 (d, J=8.3 Hz, 1H, N-H), 5.92 (dd, J=4.2
Hz, J=5.3 Hz, 1H, H-3), 5.64 (d, J=4.2 Hz, 1H, H-2), 5.40 (t, J=5.3 Hz, 1H, H-4), 5.01 (m, 1H,
H-5), 4.35 (m, 1H, N-CH), 4.33 (dd, J=4.1 Hz, J=12.2 Hz, 1H, H-6), 4.17 (dd, J=5.4 Hz,
J=12.2 Hz, 1H, H-60), 2.24 (s, 3H, OAc), 2.11 (s, 3H, OAc), 2.08 (s, 3H, OAc), 2.06 (s, 3H, OAc),
2.05 (s, 3H, OAc), 1.83±1.12 (m, 10H, cyclohexyl moiety); 13C NMR (50.3 MHz, CDCl3) ꢀ 192.9
(CˆS), 170.5 (CO, OAc), 169.9 (CO, OAc), 169.7 (CO, OAc), 169.1 (CO, OAc), 168.8 (CO, OAc),
77.5 (C-2), 70.9 (C-3), 69.5 (C-4), 68.8 (C-5), 61.1 (C-6), 53.2 (N-CH), 31.1, 25.2, 24.3, 20.7 (OAc),
20.6 (OAc), 20.2 (OAc). Anal. calcd for C22H33NO10S: C, 52.47; H, 6.60; N, 2.78. Found: C,
52.29; H, 6.68; N, 2.75.
4.3.6. 2,3,4,5,6-Penta-O-acetyl-N-phenyl-d-thiogluconamide 23
Yield: 69% from 15, mp 168±170ꢀC, [ꢁ]D +80 (c 0.5, chloroform); IR (KBr) ꢂmax 3330, 1750,
1
1520, 1230 cm^1; H NMR (400 MHz, CDCl3) ꢀ 9.36 (s, 1H, N-H), 7.70±7.28 (m, 5H, phenyl),
5.95 (t, J=4.5 Hz, 1H, H-3), 5.77 (d, J=4.5 Hz, 1H, H-2), 5.48 (t, J=4.5 Hz, 1H, H-4), 5.06 (m,
1H, H-5), 4.35 (dd, J=4.5 Hz, J=12.1 Hz, 1H, H-6), 4.19 (dd, J=5.2 Hz, J=12.1 Hz, 1H, H-60),
2.28 (s, 3H, OAc), 2.12 (s, 6H, OAc), 2.06 (s, 3H, OAc), 2.04 (s, 3H, OAc); 13C NMR (100 MHz,
CDCl3) ꢀ 193.2 (CˆS), 170.7 (CO, OAc), 170.2 (CO, OAc), 169.8 (CO, OAc), 169.3 (CO, OAc),
169.1 (CO, OAc), 137.5, 129.0 (2C), 127.2, 123.1 (2C), 78.0 (C-2), 71.1 (C-3), 69.5 (C-4), 68.9 (C-5),
61.2 (C-6), 20.8 (OAc), 20.7 (OAc), 20.3 (OAc). The sample was homogeneous by TLC and NMR
analyses, but no satisfactory combustion analysis could be obtained.
4.3.7. 2,3,4,5,6-Penta-O-acetyl-N-(4-methoxyphenyl)-d-thiogluconamide 24
Yield: 60% from 16, mp 118±120ꢀC, [ꢁ]D +87 (c 0.5, chloroform); IR (KBr) ꢂmax 3320, 1750,
1
1530, 1220 cm^1; H NMR (400 MHz, CDCl3) ꢀ 9.21 (s, 1H, N-H), 7.56±6.91 (m, 4H, phenyl),
5.95 (t, J=4.5 Hz, 1H, H-3), 5.77 (d, J=4.5 Hz, 1H, H-2), 5.48 (t, J=4.5 Hz, 1H, H-4), 5.05 (m,
1H, H-5), 4.35 (dd, J=4.6 Hz, J=12.1 Hz, 1H, H-6), 4.19 (dd, J=5.3 Hz, J=12.1 Hz, 1H, H-60),
3.81 (s, 3H, OCH3), 2.28 (s, 3H, OAc), 2.12 (s, 3H, OAc), 2.11 (s, 3H, OAc), 2.06 (s, 3H, OAc),
2.04 (s, 3H, OAc); 13C NMR (100 MHz, CDCl3) ꢀ 193.0 (CˆS), 170.7 (CO, OAc), 170.2 (CO,
OAc), 169.8 (CO, OAc), 169.3 (CO, OAc), 169.0 (CO, OAc), 158.3, 130.4, 124.9 (2C), 114.1 (2C),

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1994
77.9 (C-2), 71.1 (C-3), 69.6 (C-4), 68.9 (C-5), 61.2 (C-6), 55.4 (OCH3), 20.8 (OAc), 20.7 (OAc),
20.4 (OAc). Anal. calcd for C23H29NO11S: C, 52.36; H, 5.54; N, 2.65. Found: C, 52.32; H, 5.50;
N, 2.70.
4.3.8. 2,3,4,5,6-Penta-O-acetyl-N-(4-bromophenyl)-d-thiogluconamide 25
Yield: 60% from 17, mp 105±107ꢀC, [ꢁ]D +85 (c 0.5, chloroform); IR (KBr) ꢂmax 3300, 1740,
1
1580, 1215 cm^1; H NMR (400 MHz, CDCl3) ꢀ 9.30 (s, 1H, N-H), 7.64±7.52 (m, 4H, phenyl),
5.92 (t, J=4.5 Hz, 1H, H-3), 5.72 (d, J=4.5 Hz, 1H, H-2), 5.46 (t, J=4.5 Hz, 1H, H-4), 5.05 (m,
1H, H-5), 4.36 (dd, J=4.3 Hz, J=12.2 Hz, 1H, H-6), 4.19 (dd, J=5.2 Hz, J=12.2 Hz, 1H, H-60),
2.29 (s, 3H, OAc), 2.12 (s, 6H, OAc), 2.07 (s, 3H, OAc), 2.04 (s, 3H, OAc); 13C NMR (100 MHz,
CDCl3) ꢀ 193.6 (CˆS), 170.8 (CO, OAc), 170.3 (CO, OAc), 169.8 (CO, OAc), 169.4 (CO, OAc),
169.1 (CO, OAc), 136.6, 132.1 (2C), 124.6 (2C), 120.2, 77.8 (C-2), 71.0 (C-3), 69.5 (C-4), 68.9 (C-5),
61.3 (C-6), 20.8 (OAc), 20.7 (OAc), 20.4 (OAc). Anal. calcd for C22H26BrNO10S: C, 45.84; H,
4.55; N, 2.43. Found: C, 45.88; H, 4.52; N, 2.72.
Acknowledgements
Financial support from the Ministry of Education and Culture (DGICYT, PB98-0997 and
AMB99-0591) and the Junta de Extremadura-Fondo Social Europeo (IPR98-A065) is gratefully
acknowledged. M.J.A. thanks the Ministry of Education for a predoctoral scholarship.
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