Synthesis of N-Glycoside Analogs via Thionolactones

Article abstract of DOI:10.1081/CAR-120026472

Indolyl N-glycoside analogs were obtained by a two-step sequence via indole N-thioamides. Treatment of thionobutyrolactone with indolylmagnesium bromide provides the corresponding indole N-thioamide. The use of 10:1 toluene:THF as solvent is important in favoring N- over C3-acylation. Treatment of the ω-hydroxy-thioamide with 2 equiv of Meerwein's reagent followed by sodium borohydride gives the corresponding N-(tetrahydrofuranyl)indole. Addition of carbon nucleophiles gives access to ketose nucleoside analogs, while activation of the ω-hydroxyl group can give access to tetrahydrothiophene N-glycosides.

Full text of DOI:10.1081/CAR-120026472

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Synthesis of N‐Glycoside Analogs via Thionolactones
Wendong Wang a , Pornpun Rattananakin a & Peter G. Goekjian a b
a Department of Chemistry , Mississippi State University , Mississippi State, Mississippi,
39762, USA
b Laboratoire Chimie Organique II/UMR 5622 , Université Claude Bernard‐Lyon 1 , Bâtiment
308‐CPE,43, Blvd du 11 Novembre 1918, Villeurbanne Cedex, 69622, France
Published online: 23 Feb 2007.
To cite this article: Wendong Wang , Pornpun Rattananakin & Peter G. Goekjian (2003) Synthesis of N‐Glycoside Analogs via
Thionolactones , Journal of Carbohydrate Chemistry, 22:7-8, 743-751, DOI: 10.1081/CAR-120026472
To link to this article: http://dx.doi.org/10.1081/CAR-120026472
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JOURNAL OF CARBOHYDRATE CHEMISTRY
Vol. 22, Nos. 7 & 8, pp. 743–751, 2003
Synthesis of N-Glycoside Analogs via Thionolactonesy
*
Wendong Wang, Pornpun Rattananakin, and Peter G. Goekjian
Department of Chemistry, Mississippi State University,
Mississippi State, Mississippi, USA
ABSTRACT
Indolyl N-glycoside analogs were obtained by a two-step sequence via indole N-
thioamides. Treatment of thionobutyrolactone with indolylmagnesium bromide
provides the corresponding indole N-thioamide. The use of 10:1 toluene:THF as
solvent is important in favoring N- over C3-acylation. Treatment of the o-hydroxy-
thioamide with 2 equiv of Meerwein’s reagent followed by sodium borohydride gives
the corresponding N-(tetrahydrofuranyl)indole. Addition of carbon nucleophiles gives
access to ketose nucleoside analogs, while activation of the o-hydroxyl group can give
access to tetrahydrothiophene N-glycosides.
Key Words: Azole N-thioamides; Thioacylation; Azole N-glycosides;
Alkoxyiminium ions; Tetrahydrothiophene N-glycosides; Nucleoside analogs.
y
many contributions to carbohydrate chemistry.
This paper is dedicated to Professor Ge´rard Descotes on the occasion of his 70th birthday for his
*
Correspondence: Professor Peter Goekjian, Laboratoire Chimie Organique II/UMR 5622,
Universite´ Claude Bernard-Lyon 1, Baˆtiment 308-CPE, 43, Blvd du 11 Novembre 1918, 69622
Villeurbanne Cedex, France; Fax: +33 (0)4 72 44 83 49; E-mail: goekjian@univ-lyon1.fr.
743
DOI: 10.1081/CAR-120026472
0732-8303 (Print); 1532-2327 (Online)
www.dekker.com
Copyright D 2003 by Marcel Dekker, Inc.

744
Wang, Rattananakin, and Goekjian
INTRODUCTION
The isolation of biologically active alkaloids having novel N-glycoside structures
has led us to investigate new synthetic routes to N-glycosides.[1] The indolocarbazole
bis-N-glycoside alkaloids such as staurosporine and K252a have generated significant
synthetic and pharmaceutical interest.[2–7] These alkaloids bear two N-glycoside bonds,
with a defined regiochemical relationship between the N-glycosides and the remote
indolocarbazole lactam carbonyl. This aspect suggests a non-classical retrosynthetic
disconnection of the exocyclic C–C or C–H bond of the N-glycoside, which leads to a
carboxylic acid derivative (disconnection b, Scheme 1). The thioamide of an aromatic
nitrogen heterocycle seems a viable candidate as starting material, based on pioneering
work in the synthesis of O-glycosides via thioesters.[8,9] Extending these methodologies
to the nitrogen series presents several interesting issues: creating the key C–N bond by
acylation rather than glycosylation may provide important differences in regioselec-
tivity and functional group compatibility; thioamides of azole heterocycles, whose
fulvenoid character may lead to unusual reactivity, have not been studied extensively to
our knowledge; finally, the rich chemistry of sulfur in nucleophilic, radical, single
electron transfer, and transition–metal-catalyzed chemistry may provide access to novel
structures and to new synthetic routes. The synthesis of simple indolyltetrahydrofurans
from thionobutyrolactone as model N-glycosides is described herein.
RESULTS AND DISCUSSION
A variety of thioacylation conditions are available, although precedents for the
specific case of azole heterocycles are rare.[10] The direct thioacylation of indole with a
thionolactone is appealing in terms of synthetic efficiency, and in view of the fact that
the corresponding thionolactones are known in the carbohydrate series (Scheme 2).[8,11]
The addition of thionobutyrolactone[12] to a solution of indolylmagnesium bromide in
Scheme 1. Retrosynthetic disconnections for N-glycosides.

Synthesis of N-Glycoside Analogs
745
Scheme 2. Synthesis of indole w-hydroxythioamides.
toluene led to the desired thioamide 1, accompanied by the corresponding amide 2 and
varying amounts of the C-3 adduct.a The thioamide shows characteristic NMR
1
resonances at 208.5 ppm in the 13C NMR (thiocarbonyl) and 9.11 ppm in the H NMR
(indole H-7, deshielded by the thiocarbonyl), while the amide shows corresponding
resonances at 171.6 and 8.43 ppm, similar to those of N-acetylindole.[13]
The competition between N-1 and C-3 acylation of indole salts is well do-
cumented, and is dependent on the solvent and the nature of the metal salt[14] How-
ever, we found that the thioacylation was unsuccessful using other indole salts (Li, Na,
K, or Cs), or in coordinating solvents such as THF. Nonetheless, we found that using a
10:1 mixture of toluene:THF suppressed the formation of the thioketone and gave an
acceptable 59% yield of the thioamide 1, accompanied by 27% of the corresponding
amide 2. Use of TMEDA or HMPA as additive was unsuccessful. We were unable to
suppress the formation of the amide completely, either by using rigorously anhydrous
experimental conditions or by changing the quench and workup conditions. An
alternative approach to the thioamide consists of converting the amide 2 into the
thioamide 1. However, treatment of the amide with 2,4-bis(4-methoxyphenyl)-1,3-
dithia-2,4-diphosphetane-2,4-disulfide (Lawesson’s reagent)[15,16] under standard con-
ditions failed to produce even traces of the desired thioamide in our hands.
Several routes can be envisioned for converting the thioamide into an N-glycoside
analog, and an efficient route is presented in Scheme 3. Treatment of the thioamide
with 2 equiv of trimethyloxonium tetrafluoroborate (Meerwein’s reagent)[17] leads to
the alkoxyiminium ion 3, via a sequence of alkylation, cyclization, alkylation, and
elimination, which is then reduced in situ with sodium borohydride to give the N-
glycoside model 4 in 61% yield. The proton NMR spectrum of 4 shows diastereotopic
protons on the tetrahydrofuran ring, confirming the formation of a stereogenic center at
C.1, and the EIMS matches that of the published spectrum.[18] The yield of the reaction
is modest, yet acceptable in view of the complexity of the reaction sequence. An
efficient protocol was developed, in which the thioamide was purified by silica gel
filtration and carried on to the next step, giving a respectable 50% yield for the two-
step conversion of thiobutyrolactone to the indolyltetrahydrofuran 5.
Several exploratory experiments were undertaken to investigate other potential
opportunities. Addition of carbon nucleophiles to the alkoxyiminium 3 gives access to
aThe C3-thioketone adduct was isolated as a red, gummy, insoluble solid, which hydrolyzed
spontaneously to the corresponding C3-ketone. The structure of the C3 ketone was assigned based
1
on H NMR alone.

746
Wang, Rattananakin, and Goekjian
Scheme 3. Synthesis of N-glycoside analogs from w-hydroxythioamides.
ketose nucleoside analogs. The thioamide 1 was treated with two equiv of Meerwein
reagent, followed by a variety of carbon nucleophiles. Allylsilanes, allylstannanes, and
hypervalent allyl silicates gave no addition, and the amide hydrolysis product was
recovered after workup. Neither alkyllithiums, nor alkyl or allyl Grignard reagents,
yielded the desired product. Ethylmagnesium bromide gave traces of a product
identified as the ethyl adduct by proton NMR, but the reaction was not reproducible,
presumably due to the instability of the product to the MgBrBF4 produced in the
reaction. Treatment of the alkoxyiminium ion 3 with trimethylsilyloxypropene gave the
adduct 6 in 21% yield (Scheme 3). The poor yield in this case may be attributed to
polymerisation of the enol ether in the presence of HBF4 produced during the formation
of the alkoxyiminium ion. This reaction was not pursued further on this system but
these results demonstrate that electron-rich carbon nucleophiles can be added, although
the alkoxyiminium ion is fairly unreactive.
Additional exploratory experiments were performed to determine whether acti-
vation of the hydroxyl group instead of the thiocarbonyl of the thioamide could give
access to tetrahydrothiophenes (Scheme 4). Indeed, treatment of the thioamide 1 with
methanesulfonyl chloride and triethylamine, followed by sodium borohydride gave the
1
indolyltetrahydrothiophene 7. The reaction was clean based on the H NMR spectrum
of the crude product, although the isolated yield was poor. The sequence of addition of
the reagents (sulfonyl chloride followed by the base) was essential, as the thioamide is
unstable to basic conditions. Stronger bases (e.g., DBU) gave only decomposition,
while weak bases (e.g., lutidine, 1 equiv DMAP) or the absence of base gave the
Scheme 4. Synthesis of tetrahydrothiophenes from w-hydroxythioamides.

Synthesis of N-Glycoside Analogs
747
tetrahydrofuran (S-activation). The appropriate balance must be found, and acceptable
results may be obtained in systems in which the thioamide is less electrophilic.
We have demonstrated that indolylmagnesium bromides can be thioacylated re-
gioselectively with thionolactones in THF:toluene mixtures, and that these thioamides
can be converted to aldose, ketose, and tetrahydrothiophene nucleoside analogs. The
current system is structurally very simple, yet presents, in our opinion, certain inte-
resting features of azole thioamides and alkoxyiminium salts. This methodology may
offer a complementary approach in cases where traditional N-glycosylation is unsuit-
able for reasons of regiochemistry, stereochemistry, or chemoselectivity. The appli-
cation of this methodology to carbohydrate thiolactones is currently under investigation.
EXPERIMENTAL
General methods. General experimental procedures were described previously.[19]
NMR spectra were collected on a General Electric QE-300 spectrometer, low- and
high-resolution mass spectra were obtained using a JEOL AX-505H or a JEOL SX-102A
spectrometer. NMR assignments are interpreted based on literature precedents,[20,21] and
1
on H–13C HSQC data for compound 4.
4-Hydroxy-1-indol-1-yl-butane-1-thione (1) and 4-hydroxy-1-indol-1-yl-butane-
1-one (2). A stirred solution of indole (275 mg, 2.35 mmol) in toluene:THF (10:1 4.4
mL) at 45°C under N2 was treated with ethylmagnesium bromide (3M in diethyl ether,
0.8 mL, 2.4 mmol), and the mixture was stirred for 20 min. Freshly distilled g-
butyrothiolactone[12] (110 mL, 120 mg, 1.18 mmol) was added and an off-white
precipitate was observed immediately. The mixture was stirred for 20 min, cooled to rt,
and poured into an aq solution of HCl (0.5N, 4 mL). The mixture was diluted with
ether and washed with brine (3 Â 30 mL). The individual aqueous layers were back-
extracted with ether, and the combined organic layers were dried over Na2SO4 and
concentrated in vacuo. The crude product was applied to a 2 Â 2 cm silica gel column
on a sintered glass funnel and eluted with CH2Cl2, to provide thioamide 1 (yellow oil,
151 mg, 0.688 mmol, 59% yield) and amide 2 (colorless oil, 63.5 mg, 0.312 mmol,
27% yield). 1: IR (cmÀ1): 3344 (O–H), 3065 (Ar C–H), 2980 (C–H), 2872 (C–H),
(no C O) 1H NMR (CDCl3): d 9.11 ppm (1H, d, J = 8.2 Hz, H-7), 7.86 (1H, d,
J = 3.9 Hz, H-2), 7.55 (1H, dd, J = 7.0, 1.0 Hz, H-4), 7.23–7.36 (2H, H-5/H-6), 6.70
(1H, d, J = 3.8 Hz, H-3), 3.76 (2H, t, J = 5.8 Hz, H-4’), 3.47 (2H, t, J = 7.6 Hz, H-2’),
2.16 (2H, m, H-3’). 13C NMR (C6D6): d 208.5 ppm (C1’ S), 138.0 (7a), 132.8 (3a),
127.5 (C2), 126.4 (C6), 125.3 (C4), 121.7 (C5), 118.8 (C7), 110.6 (C3), 61.5 (C4’),
45.0 (C2’), 32.8 (C3’). LRMS(EI): m/z 219 (12, M+), 185 (47, M–H2S), 117 (100,
indole+), 111 (23). HRMS(EI). m/z calcd for C12H13NOS: 219.0718. Found 219.0720.
2: IR (cmÀ1): 3344 (O–H), 3066 (Ar C–H), 2931 (C–H), 2878 (C–H), 1695
1
(C O). H NMR (CDCl3): d 8.43 ppm (1H, d, J = 8.2 Hz, H-7), 7.54 (1H, d, J = 8.2
Hz, H-4), 7.45 (1H, d, J = 3.8 Hz, H-2), 7.30–7.36 (1H, dd, J = 7.2, 8.2 Hz, H-5), 7.26
(1H, dd, J = 7.2, 8.2 Hz, H-6), 6.60 (1H, d, J = 4.9 Hz, H-3), 3.76 (2H, t, J = 5.9 Hz,
H-4’), 3.01 (2H, t, J = 7.0 Hz, H-2’), 2.06 (2H, m, H-3’). 13C NMR (CDCl3): d 171.6
ppm (C1’ O), 135.5 (C7a), 130.3 (C3a), 125.0 (C2), 124.6 (C6), 123.6 (C4), 120.8
(C5), 116.5 (C7), 109.2 (C3), 61.1 (C4’), 32.3 (C2’), 27.2 (C3’). LRMS(EI): m/z 203

748
Wang, Rattananakin, and Goekjian
(18, M+), 117 (100, indole+), 97 (28). HRMS(EI). m/z calcd for C12H13NO2: 203.0946.
Found 203.0946.
N-[Tetrahydrofuran-2-yl]-1H-indole (4).[18] A stirred solution of the thioamide 1
(60 mg, 0.274 mmol) in dry acetonitrile (0.8 mL) at rt under N2 was treated with a
solution of trimethyloxonium tetrafluoroborate (Meerwein’s reagent, 80 mg, 0.55 mmol)
in acetonitrile (0.5 mL). The mixture was stirred for 5 min and cooled to À20°C. Solid
NaBH4 (excess) was added and the mixture was allowed to warm to rt over a period of 1
h. The reaction was quenched with methanol and the solvents were removed in vacuo.
The mixture was diluted with ether and washed 3 times with brine. The aq layers were
back-extracted with ether and the combined organic layers were dried over Na2SO4 and
concentrated in vacuo. Silica gel chromatography (20%, 50%, 100% CH2Cl2:hexane,
diethyl ether) gave the tetrahydrofuran indole 4[18] as a clear colorless oil (31 mg, 0.166
1
mmol, 61% yield). IR (cmÀ1): 3067 (Ar C–H), 2945 (C–H), 1183 (C–O). H NMR
(CDCl3): d 7.62 ppm (1H, dd, J = 7.7, 0.8 Hz, H-7), 7.46 (1H, dd, J = 8.2, 0.7 Hz, H-4),
7.25–7.19 (2H, H-2/H-6), 7.12 (1H, dd, J = 7.6, 7.6 Hz, H-5), 6.53 (1H, d, J = 3.4 Hz, H-
3), 6.25 (1H, dd, J = 6.0, 4.4 Hz, H-2’), 4.13 (1H, ddd, J = 8.4, 7.5, 6.0 Hz, H-5’a), 3.98
(1H, ddd, J = 8.4, 7.1, 6.9 Hz, H-5’b), 2.39 (2H, m, H-4’), 2.17 (2H, m, H-3’). 13C NMR
(CDCl3): d 135.7 ppm (C7a), 129.2 (C3a), 124.0 (C2), 121.8 (C6), 120.9 (C4), 119.9
(C5), 110.0 (C7), 102.3 (C3), 85.8 (C2’), 68.3 (C5’), 31.6 (C4’), 24.8 (C3’). LRMS(EI):
m/z 187 (12, M+), 117 (100, indole+), 71(38, C4H7O+).
3-Methyl-N-[tetrahydrofuran-2-yl]-1H-indole (5). 3-Methylindolemagnesium
bromide (3.2 mmol) in 10:1 toluene:THF (5.5 mL) was treated with thiobutyrolactone
(150 mL, 1.60 mmol) according to the procedure above. The crude product after aqueous
workup was applied in CH2Cl2:toluene (1:1) to a pad of silica gel on a sintered glass
funnel, and eluted with CH2Cl2 until the yellow color was near the bottom of the pad.
The pad was eluted with EtOAc, and the crude product from EtOAc was azeotroped
from toluene (3 Â), and reacted with Meerwein reagent and NaBH4 as above, to yield,
after silica gel chromatography (CH2Cl2 eluant), the 3-methylindole adduct 5 as a clear
colorless oil (160.8 mg, 0.797 mmol, 50% yield from thiobutyrolactone). IR (cmÀ1):
3052 (ArC–H), 2956 (C–H), 2918 (C–H), 2880 (C–H), 1455 (C C), 1052 (C–O). 1H
NMR (CDCl3): d 7.53 ppm (1H, d, J = 7.6 Hz, H-7), 7.39 (1H, d, J = 8.1 Hz, H-4), 7.18
(1H, ddd, J = 8.1, 7.0, 0.9 Hz, H-5), 7.10 (1H, ddd, J = 7.8, 7.1, 0.9 Hz, H-6), 6.92 (1H,
s, H-2), 6.10 (1H, dd, J = 5.6, 5.1 Hz, H-2’), 4.03 (1H, ddd, J = 8.3, 7.5, 6.0 Hz, H-5’a),
3.87 (1H, ddd, J = 8.3, 7.3, 6.6 Hz, H-5’b), 2.36–2.17 (2H, m, H-4’ab), 2.31 (3H, s, C3–
CH3), 2.17–1.90 (2H, m, H-3’ab). 13C NMR (CDCl3): d 136.0 ppm (s, C7a), 129.2 (s,
3a), 121.6 (d, C2 or C6), 121.4 (d, C6 or C2), 119.1 (d, C4), 118.8 (d, C5), 111.3 (s, C3),
109.6 (d, C7), 85.2 (d, C2’), 67.9 (t, C5’), 31.1 (t, C3’), 24.7 (t, C2’), 9.5 (q, C3–CH3).
HRMS(EI). m/z calcd for C13H15NO: 201.1154. Found: 201.1155 LRMS(EI): m/z
201(34, M+), 131(100, 3-methylindole), 71(30, C4H7O+), 43(60, C2H3O+).
Anal. Calcd for C13H15NO: C, 77.58; H, 7.51,N 6.96. Found: C, 77.81 H, 7.67,N 6.98.
1-[2’ -(1-Indolyl)tetrahydrofuran-2-yl]-2-propanone (6). A stirred solution of
the thioamide 1 (34 mg, 0.155 mmol) in dry acetonitrile (0.2 mL) at rt under N2
was treated with a solution of Meerwein’s reagent (45 mg, 0.31 mmol) in acetonitrile
(0.8 mL), and the mixture was stirred for 20 min. The mixture was cooled to À20°C
and 2-trimethylsilyloxypropene (200 mL, 1.02 mmol) was added to the frozen reaction

Synthesis of N-Glycoside Analogs
749
mixture. The reaction was allowed to rise to 0°C over a period of 1 h, and the reaction
was quenched with brine. The mixture was extracted with diethyl ether and washed
with brine 3 times. The aqueous layers were back-extracted with ether and the
combined organic layers were dried over Na2SO4 and concentrated in vacuo. Silica gel
chromatography (CH2Cl2 eluant) gave the ketose nucleoside analog 6 as a clear
colorless oil (8.0 mg, 0.033 mmol, 21% yield). IR (cmÀ1): 3067 (Ar C–H), 2983 (C–
1
H), 2945 (C–H), 1730 (C O), 1184 (C–O). H NMR (CDCl3): d 7.61 ppm (1H, d,
J = 7.4 Hz, H-7@), 7.30 (1H, d, J = 3.4 Hz, H-2@), 7.22–7.09 (3H, H-4@, H-5@, H-6@),
6.47 (1H, d, J = 3.3 Hz, H-3@), 4.11 (1H, ddd, J = 8, 7, 6 Hz, H-5’a), 3.97 (1H, ddd,
J = 7, 7, 7 Hz, H-5’b), 3.31 (1H, d, J = 14.3 Hz, H-1a), 3.18 (1H, d, J = 14.3 Hz, H-
1b), 2.90 (1H, ddd, J = 13.1, 7.8, 3.9 Hz, H-3’a), 2.45 (1H, ddd, J = 13.1, 9.0, 9.0 Hz,
H-3’b), 2.05 (1H,m H-4’a), 1.95 (3H, s, C2(O)CH3), 1.91 (1H, m, H-4’b). 13C NMR
(CDCl3): d 205.5 ppm (C2 O), 136.8 (C7@a), 130.3 (C3@a), 125.2 (C2@), 121.6 (C6@),
121.1 (C4@), 119.7 (C5@), 112.4 (C7@), 101.6 (C3@), 95.6 (C2’), 68.4 (C5’), 51.2 (C1),
36.1 (C3’), 31.6 (C4’), 21.5 (C3). LRMS(EI): m/z 243 (23, M+), 117 (100, indole).
HRMS(EI). m/z calcd for C15H17NO2: 243.1259. Found 243.1261.
N-[Tetrahydrothiophen-2-yl]-1H-indole (7). A stirred solution of thioamide 1
(15 mg, 0.068 mmol) in dry acetonitrile (0.8 mL) at rt under N2 was treated with
methanesulfonyl chloride (8 mL, 0.11 mmol) followed by triethylamine (9 mL, 0.07
mmol). The mixture was stirred at rt for 15 min and solid NaBH4 (excess) was added.
Aqueous workup and silica gel chromatography (1:2 CH2Cl2:hexanes, then CH2Cl2)
provided the tetrahydrothiophene 7 (3.0 mg, 0.015 mmol, 22% yield). 1H NMR
(CDCl3): d 7.61 ppm (1H, d, J = 7.9 Hz, H-7), 7.49 (1H, d, J = 3.3 Hz, H-2), 7.42 (1H,
d, J = 8.2 Hz, H-4), 7.22 (1H, dd, J = 8.2, 7.1 Hz, H-5), 7.12 (1H, dd, J = 7.9, 7.1 Hz,
H-6), 6.52 (1H, d, J = 3.4 Hz, H-3), 6.21 (1H, dd, J = 6.0, 4.4 Hz, H-2’), 3.28 (1H, m,
H-5’a), 3.01 (1H, m, H-5’b), 2.36 (2H, m, H-3’), 2.18 (2H, m, H-4’). LRMS(EI): m/z
205 (4, [M + 2]+), 204 (9, [M + 1]+), 203 (56, M+), 117 (100, indole+). HRMS(EI). m/z
calcd for C12H13NS: 203.0769. Found 203.0767.
ACKNOWLEDGMENTS
Financial support by the donors of the Petroleum Research Fund (29873-G), admi-
nistered by the American Chemical Society, and by the National Institutes of Health
NIGMS (GM55993) are gratefully acknowledged. NMR measurements were made at
the Mississippi Magnetic Resonance Facility at Mississippi State University, supported
by the National Science Foundation (CHE-9214521) and Mississippi State University.
Mass spectra were taken at the Harvard University Mass Spectrometry Laboratory and at
the Centre de Spectrometrie de Masse UMR 5622, Universite´ Claude Bernard-Lyon1.
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Received February21, 2003
Accepted August 5, 2003