An amide orthoesterification route to N-(1′-alkylthioglucopyranosyl) indoles

Article abstract of DOI:10.1016/j.tetlet.2005.09.135

The addition of 3-methylindolylmagnesium bromide to tetra-O-benzyl-α- d-gluconothionolactone yields the expected indole N-gluconothioamide as its hemiorthothioamide tautomer. The thiol function is alkylated to yield the corresponding orthothioamide, a 1′-

Full text of DOI:10.1016/j.tetlet.2005.09.135

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8117–8120
An amide orthoesterification route to
N-(10-alkylthioglucopyranosyl)indoles
Tahar Belhadj and Peter G. Goekjian*
ˆ
Laboratoire Chimie Organique II-Glycochimie, UMR 5181, Universite´ Claude Bernard-Lyon 1, Batiment 308-CPE,
43 Blvd du 11 Novembre 1918, 69622 Villeurbanne cedex, France
Received 8 August 2005; revised 16 September 2005; accepted 21 September 2005
Available online 10 October 2005
Abstract—The addition of 3-methylindolylmagnesium bromide to tetra-O-benzyl-a-D-gluconothionolactone yields the expected
indole N-gluconothioamide as its hemiorthothioamide tautomer. The thiol function is alkylated to yield the corresponding ortho-
thioamide, a 10-alkylthio-substituted N-glycoside. Alternatively, the 10-alkylthio-N-glycoside can be accessed from the correspond-
ing indole N-gluconamide via a boron trifluoride-etherate mediated orthoesterification with ethanethiol. Radical reduction of the
orthothioamide yields the N-glycosides in 2:1 stereoselectivity in favor of the b-N-glycoside, while reduction via the oxonium ion
leads to an improved 6:1 selectivity.
ꢀ 2005 Elsevier Ltd. All rights reserved.
We recently reported a reductive strategy toward N-gly-
cosides from thionolactones (Scheme 1),1 which is
OBn
N
extended here to the carbohydrate series. The chemical
behavior is quite distinct from that observed for the sim-
ple thionolactones, and we report herein two routes to a
family of novel 10-alkylthio-substituted N-glycosides.2,3
These compounds may be interesting N-glycoside ana-
logs, as well as polyvalent intermediates for the synthesis
of other classes of analogs.2,4,5
N
O
S
MgBr
S
OBn OBn
2a
BnO
OBn
toluene
(32%)
BnO
OBn
OBn OH
1
OBn
N
OBn
N
CH I, NEt
3
3
O
SH
The acylation conditions were applied to the known
tetra-O-benzyl-a-D-gluconothionolactone 16 (Scheme 2).
Treatment of a solution of 3-methylindolylmagnesium
bromide in toluene with thionolactone 1 in THF yields
N-[10-sulfhydryl-a-D-glucopyranosyl]-3-methylindole 2b
in a modest 32% yield. It is nonetheless noteworthy that,
O
SMe
OBn
CH Cl (85%)
2
2
BnO
OBn
BnO
OBn
2b
OBn
3
Scheme 2. Synthesis of hemiorthothioamide 2b and orthothioamide 3.
in contrast to the model thionobutyrolactone system,
the expected thioamide 2a exists preferentially as the
cyclic hemiorthothioamide tautomer 2b.7,8
N
N
Me3OBF4
O
MgBr
N
S
O
S
OH
Ref. 1
THF-
toluene
NaBH4
H
The hemiorthothioamide structure is assigned based on
13
the C NMR chemical shift of the C10 carbon, at
Scheme 1. Reductive N-glycosylation.1
104.0 ppm versus 208.3 ppm for the open form indole
N-thioamide reported previously.1 The coupling con-
0
0
0
0
stants around the pyranose ring (J4 ,5 = 9.7, J4 ,3
=
Keywords: Indole N-thioamide; Hemiorthothioamide; Orthothio-
amide; N-Glycoside; Glycosylated bis(indolyl)maleimides.
8.8 Hz) are consistent with a cyclic form.9 Alkylation
of hemiorthothioamide 2b with iodomethane and trieth-
ylamine yields the corresponding orthothioamide 3.10
*
Corresponding author. Tel./fax: +33 472 44 83 49; e-mail: goekjian@
univ-lyon1.fr
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.135

8118
T. Belhadj, P. G. Goekjian / Tetrahedron Letters 46 (2005) 8117–8120
OBn
N
N
OBn
N
OBn
N
OBn
N
MgBr
(a)
or
O
O
O
SR
O
O
OBn OBn
O
THF - toluene
H
H
+
o
BnO
OBn
BnO
-20 C (quant.)
(b)
BnO
OBn
BnO
OBn
BnO
OBn
OBn
OBn OH
OBn
OBn
OBn
4
2
7β
7α
OBn
N
OBn
SEt
SEt
Scheme 4. Stereoselectivity of the reduction of orthothioamides.
Reagents and conditions: (a) R = Et; Bu3SnH, AIBN, toluene, reflux.
7b:7a = 2:1; (b) R = H; Me3OBF4, CH3CN, ꢀ20 ꢁC, then NaBH4,
ꢀ20 ꢁC–rt. 7b:7a = 6:1.
BF .Et O
3
2
O
SEt
O
EtSH, CH CN
3
o
-35 C (59%, or
BnO
OBn
BnO
OBn
73% after 2
recycles)
OBn
OBn
5
6
TBSO
BnO
O
OH
OBn OBn
OBn OBn
Scheme 3. Synthesis of orthothioamides via amides.
a
b
BnO
OBn OH
OBn OMPM
This compound is related to the 10-thiophenyl nucleo-
sides synthesized by Kumamoto et al. by an alternative
route.2 The orthothioamide structure was further estab-
8
Bn
Bn
N
N
O
N
O
1
lished based on the analogy of the H and 13C NMR
O
O
N
spectra to those of the corresponding bisindolylmale-
imide 10-ethylthio-N-glycoside 10 described below.
N
c
N
H
H
A more efficient route was sought to the 10-thio-substi-
tuted N-glycoside compounds such as 2b or 3. An alter-
native would be to convert the indole N-amide to the
corresponding thioamide. Treatment of 2,3,4,6-tetra-O-
benzylgluconolactone11 with 3-methylindolylmagnesium
bromide at ꢀ20 ꢁC in toluene/THF yielded amide 4
(Scheme 3). As in our previous study, however, treat-
ment of amide 4 with either Lawessonꢀs reagent12 or Bel-
leauꢀs reagent13 under standard conditions failed to give
even traces of thioamide 2a or 2b. Nonetheless, treat-
ment of amide 4 with ethanethiol and BF3-etherate at
ꢀ35 ꢁC in acetonitrile for 3 h was found to yield ortho-
thioamide 5 in a respectable 59% yield.14 While such a
conversion is well established for C-glycosides (ketone
to monothioketal equilibrium), it is unusual at the higher
oxidation state corresponding to the indolyl N-amide
(amide to orthothioamide equilibrium).8 Pushing the
reaction to higher conversion, via higher temperatures
or longer reaction times, led to the formation of dithio-
orthoester 6. Running the reaction to low conversion
and recycling the recovered starting material led to a
slight improvement, to a 73% yield after two recycles.
O
SEt
O
OBn
BnO
BnO
BnO
OBn
OBn
OBn OMPM
OBn
9
10
Scheme 5. Synthesis of orthothioamide 10. Reagents and conditions:
(a) (i) p-methoxybenzyl chloride, NaH, THF–DMF (70%); (ii) TBAF,
THF (93%); (iii) TEMPO, NaOCl, KBr, Bu4NCl, NaHCO3, THF–
H2O (72%). (b) (i) 1-Dimethylamino-1-chloro-2-methylpropene, CH2Cl2
(Ghosezꢀs reagent); (ii) N-benzyl-2,3-bis(indolyl) maleimide, Cs2CO3,
THF–DMF (50% for two steps). (c) BF3Æetherate, ethanethiol,
CH3CN, ꢀ20 ꢁC (75%).
in situ with sodium borohydride to yield the glucopyr-
anosyl indoles 7b and 7a in a 6:1 ratio, in favor of axial
hydride addition, along with orthothioamide 3.
In connection with our initial interests,1 we applied this
methodology to N-benzyl-2,3-bis(1H-indol-3-yl)male-
imide (Scheme 5). The acid chloride was prepared from
the differentially protected carboxylic acid 8 by treat-
ment with Ghosezꢀs reagent.15,16 Monoacylation of the
protected bis(indolyl)maleimide gave monoamide 9 in
50% yield for the two steps from the acid, along with
the expected bisamide and recovered starting material.
Treatment of the amide with boron trifluoride-etherate
and ethanethiol at ꢀ20 ꢁC, without the need for prior
removal of the p-methoxybenzyl protecting group, gave
orthothioamide 10 in 75% yield.17
Kahne et al.5 and Kumamoto et al.2 have shown that 10-
thioalkyl-substituted glycosides are useful intermediates
for radical-mediated substitution chemistry. The reduc-
tion of the sulfur group was thus investigated in order
to determine the stereoselectivity of the reaction (Scheme
4). In the event, radical reduction of orthothioamide 5
yielded the corresponding alpha- and beta-glucopyr-
anosylindoles 7b and 7a as a 2:1 ratio of stereoisomers.
The stereoselectivity is thus considerably lower than that
observed by Kahne in the corresponding O-glycoside ser-
ies.5 The oxonium-mediated reduction conditions devel-
oped in our previous study were therefore applied to this
case. Treatment of hemiorthothioamide 2b with tri-
methyloxonium tetrafluoroborate (Meerweinꢀs reagent)
gives the corresponding oxonium ion, which is treated
Crystals of compound 10 were obtained of sufficient
quality to obtain a partial X-ray crystal structure in
which the C4 benzyl protecting group carbons were
not located precisely. The structure in Figure 1 confirms
the orthothioamide, 10-thioethyl-substituted N-glycoside
structure, as well as the b-(equatorial) stereochemistry of
the indole ring. The S1-C28-N3-C21 (S-C10-N-C2) dihe-
dral angle is near 0ꢁ, indicating minimal overlap between

T. Belhadj, P. G. Goekjian / Tetrahedron Letters 46 (2005) 8117–8120
8119
Figure 1. Partial X-ray structure of 10.
2. Kumamoto, H.; Murasaki, M.; Haraguchi, K.; Anamura,
A.; Tanaka, H. J. Org. Chem. 2002, 67, 6124–6130;
Haraguchi, K.; Itoh, Y.; Matsumoto, K.; Hashimoto, K.;
Nakamura, K. T.; Tanaka, H. J. Org. Chem. 2003, 68,
2006–2009.
the indole ring p system and the r* orbital of the axial
C–S bond. The thioethyl group is oriented in the
expected exo-anomeric conformation, and the confor-
mation of the bis(indolyl)maleimide moiety is similar
to that observed in the crystal structure of the parent
bis(indolyl)maleimide.18
3. For other 1,1-bis-heteroatom substituted sugars, please
see: (a) Praly, J.-P.; Descotes, G. Tetrahedron Lett. 1982,
23, 849–852; (b) Meuwly, R.; Vasella, A. Helv. Chim. Acta
1985, 68, 997–1009; (c) Praly, J.-P.; Di Stefano, C.;
Bouchu, M.-N.; El Kharraf, Z.; Faure, R.; Descotes, G.
Tetrahedron 1993, 49,43, 9759–9766; (d) Huerzeler, M.;
Bernet, B.; Maeder, T.; Vasella, A. Helv. Chim. Acta 1993,
76, 1779–1801; (e) Praly, J.-P.; Boye, S.; Joseph, B.; Rollin,
P. Tetrahedron Lett. 1993, 34, 3419–3420; (f) Traynor, A.
J.; Hall, E. T.; Walker, G.; Miller, W. H.; Melancon, P.;
Kuchta, R. D. J. Med. Chem. 1996, 39, 2894–2899; (g)
Bernet, B.; Maeder, T.; Vasella, A. Helv. Chim. Acta 1997,
80, 1260–1279; (h) Gimisis, T.; Castellari, C.; Chatgilialo-
glu, C. Chem. Commun. 1997, 2089–2090.
In conclusion, two routes have been developed to pyra-
nose orthothioamide functions, which can be accessed
conveniently via indole N-amides or N-thioamides.
The unusual reactivity of the latter compounds reflects
both the fulvenoid character of the indole N-amides,
as well as the particular steric and electronic environ-
ment of the pyranose ring. The synthesis is complemen-
tary to that of Kumamoto et al.,2 giving access to the
pyranose series bearing substitutents in the C2 position.
These compounds are interesting N-glycoside analogs,
as well as potential intermediates for the preparation
of other N-glycoside analogs. The scope of this reaction,
as well as the substitution chemistry of this functional
group are currently under investigation.
4. (a) Barrett, A. G. M.; Bezuidenhoudt, B. C. B.; Howell, A.
R.; Lee, A. C.; Russell, M. A. J. Org. Chem. 1989, 54,
2275–2277; (b) Lee, A. C.; Barrett, A. G. M. J. Org. Chem.
1992, 57, 2818–2824.
5. Kahne, D.; Yang, D.; Lim, J. J.; Miller, R.; Paguaga, E. J.
Am. Chem. Soc. 1988, 110, 8716–8717.
6. The thionolactone was prepared via Kahneꢀs straightfor-
ward procedure (Ref. 5) albeit in low conversion, keeping
in mind that Vasellaꢀs procedure may be preferable for less
readily accessible starting materials. Huerzeler, M.; Ber-
net, B.; Vasella, A. Helv. Chim. Acta 1993, 76, 995–
1001.
7. Hemiorthoamides and hemiorthoesters are found in nat-
ural products, although typically in polycyclic systems.
For a recent example, please see: Ralifo, P.; Crews, P. J.
Org. Chem. 2004, 69, 9025–9029; They have also attracted
attention in connection with stereoelectronic effects:
Capon, B.; Dosunmu, M. I. Tetrahedron 1984, 40, 3625–
3633; Perrin, C. L.; Arrhenius, G.; Meichia, L. J. Am.
Chem. Soc. 1982, 104, 2839–2842; Deslongchamps, P.;
Cheriyan, U. Ouseph; Pradere, J. P.; Soucy, P.; Taillefer,
R. J. Nouv. J. Chim. 1979, 3, 343–350; Mock, W. L.
Bioorg. Chem. 1976, 5, 403–414.
Acknowledgements
X-ray crystallography was performed by Daphne Merle
and Alain Thozet at the Centre de Diffractometrie at the
Universite Claude Bernard-Lyon 1. Financial support
from the Region Rhone-Alpes (programme EMER-
GENCE), the Centre National de la Recherche Scientif-
ique (AIP Jeunes equipes) and the Ministere National de
´
`
la Recherche et de la Technologie (Research Fellowship
for T.B.) is gratefully acknowledged.
References and notes
1. Wang, W.; Rattananakin, P.; Goekjian, P. G. J. Carbo-
hydr. Chem. 2003, 22, 743–751.

8120
T. Belhadj, P. G. Goekjian / Tetrahedron Letters 46 (2005) 8117–8120
13. Lajoie, G.; Lepine, F.; Maziak, L.; Belleau, B. Tetrahedron
8. For a general review of orthoester chemistry, please see:
Kantlehner, W. Synthesis of Iminium Salts, Orthoesters,
and Related Compounds, In Comprehensive Organic
Synthesis; Trost, B. M., Flemming, I., Winterfeldt, E.,
Eds.; Pergamon Press: Oxford, 1991; Vol. 6, Chapter 2.7.4,
pp 556–599.
Lett. 1983, 24, 3815.
14. Compound 5: 1H NMR (CDCl3): d 8.00 ppm (1H, d,
J = 8.3 Hz); 7.74 (1H, s); 7.50 (1H, d, J = 7.8 Hz); 7.45–
7.15 (18H, m); 7.10 (1H, dd, J = 8.1, 7.2 Hz); 7.01 (2H,
m); 6.95 (1H, dd, J = 8.4, 7.2 Hz); 4.92 (1H, d, J =
10.7 Hz); 4.86 (1H, d, J = 10.8 Hz); 4.80 (1H, d,
J = 10.8 Hz); 4.68 (1H, d, J = 10.7 Hz); 4.64 (1H, d,
J = 11.7 Hz); 4.52 (1H, d, J = 11.7 Hz); 4.24 (1H, m);
4.17–4.09 (2H, m); 4.01 (1H, d, J = 10.5 Hz); 4.00–3.94
(2H, m); 3.80 (1H, dd, J = 10.4, 0.7 Hz); 3.42 (1H, d,
J = 10.5 Hz); 2.55 (2H, q, J = 7.5 Hz); 2.28 (3H, s); 1.23
(3H, t, J = 7.5 Hz). 13C NMR (CDCl3): d 138.5 ppm (s),
138.2 (s), 137.5 (s), 135.3 (s), 131.5 (s); 128.5 (d); 128.4 (d);
128.3 (d); 128.2 (d); 128.1 (d); 128.0 (d); 128.0 (d); 127.8
(d); 127.8 (d); 127.6 (d); 127.5 (d); 126.3 (d); 121.9 (d),
119.8 (d), 118.8 (d), 115.1 (d); 110.7 (s), 104.1 (s); 83.5 (d);
83.4 (d); 77.2 (d); 75.7 (t), 75.3 (t); 74.9 (t); 74.09 (d); 73.4
(t); 68.5 (t); 21.0 (t); 13.6 (q); 9.6 (q).
9. Compound 2b: 1H NMR (CDCl3): d 7.95 ppm (1H, d,
J = 8.5 Hz); 7.80 (1H, m, J = 0.9 Hz); 7.50 (1H, d,
J = 7.8 Hz); 7.40–7.05 (19H, m); 7.02–6.90 (3H, m); 4.92
(1H, d, J = 10.9 Hz); 4.87 (1H, d, J = 10.9 Hz); 4.82 (1H,
d, J = 10.9 Hz); 4.70 (1H, d, J = 10.7 Hz); 4.62 (1H, d,
J = 11.7 Hz); 4.50 (1H, d, J = 11.7 Hz); 4.41 (1H, ddd,
J = 9.8, 1.9, 1.9 Hz); 4.20 (1H, dd, J = 9.7, 8.8 Hz); 4.10–
3.95 (4H, m); 3.79 (1H, dd, J = 10.7, 1.7 Hz); 3.36 (1H, d,
J = 10.4 Hz); 2.82 (1H, s); 2.29 (3H, d, J = 0.9 Hz). 13C
NMR (CDCl3): d 138.3 ppm (s), 138.2 (s), 138.1 (s), 137.3
(s); 135.2 (s), 131.6 (s), 128.5 (d), 128.4 (d), 128.2 (d), 128.1
(d), 127.9 (d), 127.8 (d), 127.7 (d), 127.6 (d), 127.6 (d),
127.6 (d), 126.3 (d), 122.0 (d), 120.1 (d), 119.0 (d), 115.0
(d), 110.7 (s) 104.0 (s) 82.7 (d); 80.9 (d); 80.6 (d); 76.8 (d);
75.7 (t), 75.3 (t), 74.9 (t), 73.4 (t), 68.2 (t), 9.6 (q). IR
(neat): 2550 cmꢀ1 (weak).
15. Ghosez, L.; George-Koch, I.; Patiny, L.; Houtekie, M.;
Bovy, P.; Nshimyumuzika, P.; Phan, T. Tetrahedron 1998,
54, 9207–9222.
10. Compound 3: 1H NMR (CDCl3): d 7.99 ppm (1H, d,
J = 8.3 Hz); 7.72 (1H, d, J = 1.0 Hz); 7.50 (1H, d,
J = 8.1 Hz); 7.45–7.10 (18H, m); 7.10 (1H, dd, J = 8.1,
7.2 Hz); 7.03 (2H, m); 7.00 (1H, dd, J = 8.4, 7.2 Hz); 4.92
(1H, d, J = 11.0 Hz); 4.86 (1H, d, J = 10.9 Hz); 4.80 (1H,
d, J = 10.7 Hz); 4.68 (1H, d, J = 10.9 Hz); 4.62 (1H, d,
J = 11.8 Hz); 4.52 (1H, d, J = 11.7 Hz); 4.20–4.08 (3H,
m); 4.03–3.94 (3H, m); 3.80 (1H, dd, J = 10.7, 0.7 Hz);
3.44 (1H, d, J = 10.5 Hz); 2.27 (3H, d, J = 1.0 Hz); 1.97
(3H, s). 13C NMR (CDCl3): d 138.4 ppm (s), 138.1 (s),
137.5 (s), 135.1 (s), 131.5 (s); 129.0 (d); 128.4 (d); 128.4 (d);
128.3 (d); 128.1 (d); 128.0 (d); 127.9 (d); 127.8 (d); 127.7
(d); 127.6 (d); 127.5 (d); 127.5 (d); 125.9 (d); 125.2 (d);
121.9 (d), 119.9 (d), 118.8 (d), 115.0 (d); 110.9 (s), 103.4 (s);
83.4 (d); 83.2 (d); 77.2 (d); 75.6 (t), 75.2 (t); 74.8 (t); 73.9
(d); 73.3 (t); 68.5 (t); 9.6 (q); 9.3 (q).
16. Furstner, A.; Konetzki, I. J. Org. Chem. 1998, 63, 3072–
¨
3080.
17. Compound 10: 1H NMR (CDCl3): d 8.44 ppm (2H, s);
8.00 (1H, d, J = 8.5 Hz); 7.67 (1H, d, J = 2.6 Hz); 7.48
(2H, d, J = 6.8 Hz); 7.40–7.15 (19H, m); 7.10–6.90 (8H,
m); 6.87–6.76 (2H, m); 6.61 (1H, dd, J = 7.2, 8.1 Hz); 4.92
(1H, d, J = 10.8 Hz); 4.85–4.77 (4H, m); 4.66 (1H, d,
J = 10.9 Hz); 4.62 (1H, d, J = 11.9 Hz); 4.50 (1H, d,
J = 11.7 Hz); 4.21–4.05 (5H, m); 3.95 (1H, dd, J = 0.8,
10.5 Hz); 3.78 (1H, dapp, J = 10.5 Hz); 3.72 (1H, d, J =
10.7 Hz); 2.39–2.32 (1H, m); 2.17–2.11 (1H, m); 1.06 (3H,
t, J = 7.5 Hz). 13C NMR (CDCl3): d 171.9 ppm (s); 171.8
(s); 139.2 (s), 139.1 (s), 138.7 (s), 137.9 (s), 136.1 (s), 135.8
(s), 129.9 (s); 129.2 (d), 129.0 (2 · d); 128.9 (s); 128.7 (d);
127.9 (s); 127.9 (d) 127.3 (s), 125.8 (s); 123.0 (d), 122.6
(d), 122.5 (d), 121.6 (d), 120.7 (d), 116.0 (d), 111.4 (d);
107.5 (s), 107.4 (s), 105.5 (s); 83.9 (d), 77.7 (d); 75.6 (t),
75.6 (t); 75.3 (d), 73.5 (d); 75.0 (t), 68.6 (t); 42.1 (t); 21.2 (t);
13.7 (q).
11. Hanessian, S.; Ugolini, A. Carbohydr. Res. 1984, 130, 261–
269.
12. (a) Pedersen, B. S.; Scheibye, S.; Clausen, K.; Lawesson, S.
O. Bull. Soc. Chim. Belg. 1978, 87, 293–297; (b) Scheibye,
S.; Pedersen, B. S.; Lawesson, S. O. Bull. Soc. Chim. Belg.
1978, 87, 229–238.
18. Davis, P. D.; Hill, C. H.; Lawton, G.; Nixon, J. S.;
Wilkinson, S. E.; Hurst, S. A.; Keech, E.; Turner, S. E.
J. Med. Chem. 1992, 35, 177–184.