Synthesis of Glycosyl Cyanides by the Reaction of 1-S-Phosphorothioates of Carbohydrates with Trimethylsilyl Cyanide

Article abstract of DOI:10.1515/znb-1998-1107

A new procedure is described for the synthesis of α,β-glycosyl cyanides by the reaction of per-O-benzylated S-α-D-glycopyranosyl phosphorothioates with trimethylsilyl cyanide in the presence of Lewis acid. Starting S-glycosyl phosphorothioates are prepare

Full text of DOI:10.1515/znb-1998-1107

Synthesis of Glycosyl Cyanides by the Reaction of 1-5-Phosphorothioates
of Carbohydrates with Trimethylsilyl Cyanide
Wieslawa Kudelska
Institute of Chemistry, Faculty of Pharmacy, Medical University of Lodz,
90-151 Lodz, Muszyriskiego 1, Poland
Z. Naturforsch. 53 b, 1277-1280 (1998); received July 23, 1998
S-Glycosylphosphorothioates, Glycosyl Cyanides, Synthesis
A new procedure is described for the synthesis of a,/?-glycosyl cyanides by the reaction
of per-O-benzylated S-a-D-glycopyranosyl phosphorothioates with trimethylsilyl cyanide in
the presence of Lewis acid. Starting S-glycosyl phosphorothioates are prepared, directly, from
O-benzyl protected reducing D-hexopyranoses (gluco-, galacto-, manno-) and alkylammonium
salt of phosphorothioic acid under Lewis acid catalysis.
Introduction
Results and Discusion
Glycosyl cyanides are versatile, synthetic inter-
mediates for the preparation of compounds of bio-
logical and chemical interest, irreversible enzyme-
inhibitors and are of interest as chiral synthons for
many natural products.
Per-0-acetylated glycosyl cyanides have been
prepared by the reaction of furanosyl and pyranosyl
halides [1 -4 ] with metal cyanides, most frequently
mercuric cyanide, the reaction of 1-O-acyl sugars
with trimethylsilyl cyanide in the presence of Lewis
acids [5, 6], by dehydratation of amides of anhy-
droaldonic acids [7] and reductive dehydratation
of glycosylnitromethanes [8]. O-Benzyl protected
glycosyl cyanides have been obtained from glyco-
syl fluorides [9], glycosyl iodides generated in situ
from 1-O-acetates [10], and from 1-O-acyl sugars
with trimethylsilyl cyanide [11].
Previously, S-glycosyl phosphorodithioates, hav-
ing glycosylating properties, have been used in the
stereoselective synthesis of O-glycosides [12], N-
glycosides [13], oligosaccharides [14, 15] and gly-
cosyl 1-O-esthers [16].
We report here new application of 1-S-glycosyl
phosphorothioates 5 - 7 , stable, odorless and non-
toxic reagents, in the synthesis of glycosyl cyanides
8 - 12 under mild conditions and in high yields in
the reaction with trimethylsilyl cyanide and Lewis
acid catalysis.
Recently we have described [17] that, catalysed
by boron trifluoride etherate, the reaction of 2,3,4,6-
tetra-O-benzyl-D-glucopyranose (2) with the tri-
ethylammonium salt of 2-hydroxy-5,5-dimethyl-
2-thioxo-l,3,2-dioxaphosphorinane (1) [18] af-
fords per-O-benzylated S-Of-glycopyranosyl phos-
phorothioate 5, stereoselectively. The catalysed
phosphorylation of 1-O-unprotected sugars was
now extended to 2,3,4,6-tetra-O-benzyl-D-galacto-
pyranose (3) [19, 20] and 2,3,4,6-tetra-O-benzyl-
D-mannopyranose (4) [20]. The reaction of 3 with
1 (according to 31P NMR) was accomplished after
24 h, to yield a mixture of three phosphorus contain-
ing products [<531P NMR (ppm): 20.5, 19.25, 17.7
(integration) 1:6.6:0.9] from which product 6 was
isolated in 51% yield (6 31P NMR (ppm): 19.25).
Similarly, when 4 was allowed to react with 1 af-
ter 24 h ,31P NMR analysis indicated that the crude
reaction mixture also consisted of three P-products
[6 3IP NMR (ppm): 20.5, 19.8, 17.7 (integration)
1:1.7:6.5] from which product 7 is isolated in 38%
yield (6 31P NMR (ppm): 17.7). The ^-configuration
at the anomeric carbon atom of products 6 and 7 was
assigned on the basis of 'H and 13C NMR spectra
and of optical rotation values (see experimental).
S'-a-Glycopyranosyl phosphorothioates 5 - 7
were reacted with trimethylsilyl cyanide in acetoni-
trile in the presence of boron trifluoride etherate.
The reaction of S-glucosyl phosphorothioate 5 gave
a mixture of ß- and a-D-glucopyranosyl cyanide (8)
[9, 11, 21] in 72% yield. Product 8 was analysed as
* Reprint requests to Dr. W. Kudelska.
0932-0776/98/1100-1277 $ 06.00 © 1998 Verlag der Zeitschrift für Naturforschung, Tübingen • www.znaturforsch.com
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W. Kudelska • Synthesis o f G lycosyl Cyanides
\
/%
®
HNEtj
1
Bn=CH2C6H5
,OBn
BnO ^OBn
^OBn
\BnO r\
BnO-^T^---°.
BnO----
BnO—
\
BnO- \ ^ ' 0
BnO— ----^ V l ^ ' Rl
BnO
I
R.
BnO
2 R!=H, R2=OH
3 R,=H; R2=OH
4 R,=H; R2=OH
Fig. 1. Sugar substrates (2 - 4)
were reacted with to give
5 R,=H; R2= S — P
6 R,=H; R2=S— P
7 R,=H; R2= S — P
1
S-glycosylphosphorothioates
(5 - 7), from which glycosyl
cyanides (8 -12) were obtained.
"o
l|Xo
"o
o °
o °
o °
8 R,=H; R2=CN
Ri=CN; R2=H
9
R,=H; R2=CN
11 Ri=H; R2=CN
12 Ri=CN; R2=H
10 R,=CN; R2=H
a mixture of anomers because attempts to separate
a from ß by PLC failed. The a:ß ratio was 3.3:5,
as determined byl3C NMR. Similarly, S-galactosyl
phosphorothioate 6 afforded a mixture a- (9) and
/3-D-galactopyranosyl cyanide (10) [11] in 28% and
35% yields, respectively. In the case S-a mannosyl
phosphorothioate 7 also a mixture of a- and ß-D-
mannopyranosyl cyanide 11 and 12, in 54% and
24% yields, was obtained. Both anomeric mixtures
(a,/3-galacto and a,/?-manno) were isolated and
separated by preparative layer chromatography, and
all glycosyl cyanides were characterized by spectro-
scopic analyses (see experimental). Of the three S-
glycosyl phosphorothioates 5 -7 examined, galacto
derivative 6 proved to be the most reactive towards
the silyl reagent and the manno derivative 7 was the
least reactive.
trometer. 1H, l3C and 31P NMR were measured in CDCI3
solutions on a Bruker DPX spectrometer operating at
250,13 MHz, 62,9 MHz and 101,25 MHz, respectively.
Elemental analyses were performed by Microanalytical
Laboratory of this Institute on a Perkin Elmer PE 2400
CHNS analyzer. Preparative layer chromatography was
performed on 2 0
x 2 0 cm glass plates coated with 1
mm or 2 mm of silica gel 60 F254 (Merck). Detection was
effected by exposure to iodine vapours and UV lamp. Sol-
vents were dried and distilled prior to use. Trimethylsilyl
cyanide was purchased from Aldrich.
Preparation of S-glycosyl phosphorothioates 6 and 7
Boron trifluoride etherate (3 mmol) was added to the
solution of glycosyl substrates 3 or 4 (1 mmol) and
organophosphorus reagent
1 (1 mmol) in 1 ,2 -dichloro-
ethane (25 ml). The course of reaction was monitored by
31P and 'H NMR spectroscopy. The mixture was kept at
ambient temperature for 24 h, washed with satd. NaHC0 3
( 3 x 1 5 ml) and water (15 ml), dried (MgS0 4 ), concen-
trated in vacuo and the products were purified by crys-
tallisation.
Attempts to synthesize of glycosyl cyanides from
sugar thiophosphates and cyanide polymer sup-
ported (Fluka) catalysed by Lewis acid were un-
successful.
In conclusion, the acid-catalysed formation of
1-S-a-glycosylphosphorothiate from 1-OH unpro-
tected sugars and alkylammonium salt of 0 ,0 -di-
alkylphosphorothioic acid and the subsequent acid
catalysed C-glycosidation is reported. This method
is applied to the new synthesis of anomeric pairs of
per-O-benzylated D-hexopyranosyl cyanides (2,6-
anhydroheptononitriles).
2-S-(2,3,4,6-Tetra-0-benzyl-a-D-galactopyranosyl)-2-
oxo-5,5-dimethyI-1,3,2-dioxaphosphorinane (6)
Crystallisation from CCU-hexane gave
6 (0.223 g,
31.7%) m. p. 94-6 °C. Evaporation of mother liquors gave
syrup, which crystallised from CCU-hexane gave an ad-
ditional amount of 6 (0.136 g, 19.3%) m.p. 81-90 °C.
Second crystallisation CCU-hexane gave 6 m.p. 100-2
°C; [a]578 + 105.6° (c 1.25, CHCI3); IR (KBr) v 1285
cm“ 1 (P = 0);31P NMR (CDCI3 ) b\ 19.25 ppm; 'H NMR
(CDCI3 ) 6 :0.77, 1.23 (2s, 6 H, 5,5-diMe), 3.57 - 3.91 (m.
3 H, H-5,6,6'), 4.02 (m, 1 H. H-4), 4.12 (dd, 1 H, J2,3 =
10.5 Hz. y3.4 = 5.5 Hz, H-3), 4.34 (dd, 1H. J\.2 = 5.5 Hz,
H-2), 6.24 (dd, 1 H, 7,.P = 8.5 Hz, H-l), 4.0 - 5.0 (m.
Experimental
Melting points were determined with Boetius PHMK
05 apparatus and are uncorrected. Optical rotations were
determined with the Polamat A polarimeter. IR spectra
were obtained by using the Infinity MI-60 FT-IR spec-
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W. Kudelska • Synthesis o f G lycosyl Cyanides
1279
12 H, 4 x benzyl, 2 x OCH2), 7.26 - 7.4 (m, 20 H, Ph);
,3C NMR (CDC13) 6 : 20.3 (d, V c.p = 1.05 Hz, Meeq),
21.9 (Meax), 32.2 (d, 37P,C = 6.7 Hz, C(Me)2), 75.7 (d,
Vp.c =6.2 Hz, C-2), 86.1 (d, 2JC,p = 2.5 Hz, C-l), 77.4 (d,
27c,p = 7.2 Hz, OCH2), 78.0 (d, 2JC.p = 7.2 Hz, OCH2),
68.2 (C-6 ), 72.2, 72.5, 73.2, 73.5, 74.4, 78.8, 79.1 [C-3,
C-4, C-5, C-6 , 4 x CH2 (benzyl)], 127.3 - 128.4 (20C,
Ph), 137.7, 137.9, 138.4, 138.4 (4C, ipso Ph).
(CDCI
3
, 300 MHz) /?-anomer 6 : 3.42 (ddd, 1 H, 74,5 =
9.5 Hz, H-5), 3.60, 3.66 (2t, 2 H, 72,3 = 73,4 = 8.9 Hz, H-3,
H-4), 3.69 (m, 2 H, H-6 ), 3.78 (dd, 1 H, J,,2 = 10.2 Hz,
H-2), 4.06 (d, 1 H, H-l). a-anomer 6 : 3.61 - 3.93 (m, 6
H, H-2, H-3, H-4, H-5, H-6 ), 4.60 (d, 1 H, 7,,2 = 6.1 Hz,
H-l)]; l3C NMR (CDCI ) 6 : 66.9, 67.5, 67.7, 68.1, 73.5,
3
73.6, 73.9, 75.2, 75.2, 75.8, 75.8, 76.8, 76.1, 76.2, 76.9,
77.0,76.6,79.9, 83.1 (C-l, a), 85.5 (C-l, ß), 115.4(CN),
116.8 (CN), 127.7 - 128.1 (4xPh), 128.3 - 128.7 (4xPh).
C39H45O8PS (704.75)
Calcd C 66.46 H 6.43 %,
Found C 66.31 H 6.76 %.
l-Deoxy-2,3,4,6-tetra-0-benzyl-a-D-galactopyranosyl
cyanide (9)and 1-deoxy-2,3,4,6-tetra-0-benzyl-ß-D-
galactopyranosyl cyanide (10)
2-S-(2,3,4,6-Tetra-0-benzyl-a-D-mannopyranosyl)-2-
oxo-5,5-dimethyl-l,3,2-dioxaphosphorinane (7)
The solution of 6 (0.434 g, 0.61 mmol), trimethylsi-
lyl cyanide (1.2 ml, 0.892 g, 9 mmol), boron trifluoride
etherate (5 drops) and molecular sieves 4MS in acetoni-
trile (6 ml) was stirred at ambient temperature for 0.5 h
under argon. The reaction mixture was concentrated in
vacuo and the residue chromatographed by preparative
layer chromatography using hexane-ethyl acetate (3:1) as
the eluent. The faster running band (R f = 0.52, lit. [11]
R f = 0.52) afforded a solid, which crystallized from ethyl
acetate-hexane (3:1) to give 9 (0.095 g, 28,1%) m.p. 85-
7 °C (lit. [11] m. p. 84-5 °C); [a]578 +30.7° (c 1.1, CHCI3)
[lit. [11] +29.6° (c 1, CDCI3)]; ‘H NMR (CDCI3) <5: 3.45
- 3.56 (m, 2 H, H-6 ,6 '), 3.80 (dd, 1 H, 72,3 = 9.75 Hz,
73.4 = 2.5 Hz, H-3), 3.95 - 4.00 (m, 2 H, H-4, H-5), 4.10
(dd, 1 H, 7, ,2 = 6.25 Hz, H-2), 4.36 - 4.93 (m, 9 H, H-l,
4xC H 2Ph), 7.25 - 7.35 (m, 20 H, Ph) [lit. [11] 'H NMR
(CDCI3, 300 MHz) 6 : 3.50 (m, 2 H, H-6 ,6 '), 3.81 (dd, 1
H, 72,3 = 9.8 Hz, 7 3.4 = 2.8 Hz, H-3), 3.95 - 4.16 (m, 2 H,
H-4, H-5), 4.10 (dd, 1 H, 7, 2 = 6.0 Hz, H-2), 4.68 (d, 1
H, H-l)].
The slower running band (Rf = 0.36, lit. [11] RF =
0.36) afforded 10 (0.118 g, 35%) m.p. 86-7 °C (lit. [11]
m.p. 85-6 °C); [c*]578 +13.48° (c 1.3, CHC13) [lit. [11]
+ 12.71° (c 1, CHCI3)]; 'H NMR (CDCI3) 6 : 3.43 - 3.62
(m, 2 H, H-6 ,6 '), 3.93 (d, 1 H, 73.4 =2 .5 Hz, H-4), 4.01 (d,
1 H, 7i,2 = 10 Hz, H-l), 4.17 (t, 1 H, 72.3 = 10 Hz, H-2),
4.42 - 4.96 (m, 8 H, 4xC H 2Ph), 7.25 - 7.35 (m, 20 H,
Ph), [lit. [11] *H NMR (CDCI3, 300 MHz) 6 : 3.47 - 3.55
(m, 4 H, H-3, H-5, H-6 ,6 ’), 3.93 (dd, 1 H, J3A = 2.8 Hz,
J4.5 < 1 Hz, H-4), 4.02 (d, 1 H, 7U2 = 9.8 Hz, H-l), 4.18
(t, 1 H, J2,3 = 9.6 Hz, H-2)].
Crystallisation by trituration with diethyl ether. The
product 7 was filtered off (0.27 g, 38.4%) m. p. 105-17 °C.
Two crystallisation from CCL-l.p. ether (94-7 °C) gave
7, m.p. 118-20 °C; [a]578 + 18.4° (c 1.14, CHCI3); IR
(KBr) v 1287 cm" 1 (P=0); 3,P NMR (CDCI3) 6 : 17.7
ppm;1H NMR (CDCI3) 6 :0.73, 1.23 (2s, 6 H, 5,5-diMe),
3.67 - 4.01 (m, 5 H, H-2, H-4, H-5, H-6 ,6 '), 4.10 (dd, 1
H, J2,3 = 3.75 Hz, 7 3,4 = 12.5 Hz, H-3), 4.0 - 5.0 (m, 10
H, 4 x benzyl,2 x CH2), 6.08 (dd, 1 H, 7
i,p = 11.3 Hz, H-l), 7.23 - 7.40 (m, 20 H, Ph); 13C NMR
(CDCI3) 6 : 20.1 (Meeq), 22.0 (Meax), 32.2 (d, 37 =
i
,2 = 1.6 Hz,
7
c
.p
6.62 Hz, C(Me)2), 69.1, 71.6, 71.9, 73.5, 74.1, 75.1, 75.4,
77.6.78.9 (C-2, C-3, C-4, C-5, C-6 , 4 x CH2 Ph), 78.5 (d,
27c ,p = 7.24 Hz, OCH2), 77.7 (d, 27c ,p = 9.8 Hz, OCH2),
82.3 (C-l), 127.5 - 128.4(20C, Ph), 137.6, 137.8, 138.1,
138.2 (4C, ipso Ph).
C39H450 8PS (704.75)
Calcd C 66.46 H 6.43 %,
Found C 66.52 H 6.73 %.
1-Deoxy-2,3,4,6-tetra-0-benzyl-a, ß-D-glucopyranosyl
cyanide (8 )
The solution of 5 (0.354 g, 0.5 mmol), trimethylsilyl
cyanide (0.9 ml, 0.699 g, 6.74 mmol), boron trifluoride
etherate (4 drops) and molecular sieves 4A in acetonitrile
(7 ml) was stirred at ambient temperature for 3 h under
argon. The reaction mixture was concentrated in vacuo
and the residue chromatographed by preparative layer
chromatography using hexane-ethyl acetate (6 :1 ) as the
eluent to yield 8 (a + ß, R f = 0.31) as a syrup (0.2 g,
72,5%); [a]578 +36.5° (c 1.04, CHCI3); (lit. [2 1 ] [a]D+
36.3° (c 5.3, CHCI3); [9] +31.5° (c 0.75, CHCI3); [11]
+37° (c 1, CHCI3) for a-anomer); (lit. [11] [a]o +29° (c
I, CHCI3) for /3-anomer);1H NMR (CDC13) <5:3.34 (ddd,
1H, 74,5 = 9.5 Hz, H-5), 3.42 - 3.92 (m, H-2, H-3, H-4, H-
6 ,6 '), 4.08 (d, 1 H, J\,2 = 10.0 Hz, H-l ß), 4.34 - 4.99 (m,
H -la, 4xC H 2Ph), 7.14 - 7.37 (m, Ph) [lit. [11] 'H NMR
1-Deoxy-2,3,4,6-tetra-0-benzyl-a-D-mannopyranosyl
cyanide (11) and l-deoxy-2,3,4,6-tetra-0-benzyl-ß-v-
mannopyranosyl cyanide (12)
The solution of 7 (0.168 g, 0.24 mmol), trimethylsilyl
cyanide (0.5 ml, 3.74 mmol), boron trifluoride etherate
(5 drops) and molecular sieves 4A in acetonitrile (5 ml)
was stirred at ambient temperature for 5 h under ar-
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1280
W. Kudelska • Synthesis o f G lycosyl Cyanides
(m, 6 H), 4.84 (d, 1 H, / = 10.7 Hz), 4.95 (d, 1 H, J =
6.25 Hz), 7.15 - 7.45 (m, 20 H) [lit. [10]1H NMR (CDCI3,
250 MHz) 6 : 3.31 - 3.37 (m, 1 H), 3.45 (dd, 1 H, / 2.3 =
9.3 Hz, 73,4 = 2.3 Hz, H-3), 3.61 - 3.63 (m, 2 H), 3.83
(t, 1 H, J = 9.3 Hz, H-4), 3.92 (d, 1 H, J = 2.3 Hz, H-2),
4.12 (s, 1 H, H-1), 4.43 - 4.60 (m, 6 H), 4.76 (d, 1 H, J =
10.8 Hz), 4.83 (d, 1 H, 7= 11.5 Hz), 4.90 (d, J = 11.5 Hz),
7.13-7.48 (m, 20 H, Ph)].
gon. The reaction mixture was concentrated in vacuo and
the residue chromatographed by preparative layer chro-
matography using hexane-ethyl acetate (3:1) as the eluent.
The faster running band (RF = 0.48) gave 11 as a syrup
(0.07 g, 53,8%); [ a ] 578 +36.7 10 (c 1.0, CHC13) ; 1H NMR
(CDCI3)) 6 : 3.68 - 416 (m, H -l, H-2, H-3, H-4, H-5, H-
6 ,6 '), 4.48 - 4.87 (m, 4xC H 2Ph, 7.17 - 7.33 (m, 20 H, 4
x Ph). I3C NMR (CDCI3) 6 : 65.3, 68.4, 72.7, 72.8, 73.4,
74.7, 75.2, 77.0, 79.8 (C-l), 115.4 (CN), 127.7 - 128.6
(4xPh), 137.0, 137.7, 137.9, 138.0 (4C, ipso, Ph).
Acknowledgements
The author would like to express her gratitude to Pro-
fessor M. Michalska for helpful discussion. Financial
support from Medical University of Lodz is gratefully
acknowledged.
The slower running band (Rf = 0.31) gave 12 [10] as
syrup (0.31 g, 24%);1H NMR (CDCI3) 6 : 3.41 - 3.48 (m,
1 H), 3.54 (dd, 1 H, J2,3 = 3 Hz, J3A = 9.25 Hz, H-3),
3.70 - 3.72 (m, 2 H), 3.92 (t, J = 9.25 Hz, H-4), 4.02 (d.
1 H, 7, ,2 = 1.75 Hz, H-2), 4.22 (s, 1 H, H-1), 4.52 - 4.65
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