Synthesis of fusion-isomeric imidazopyridines and their evaluation as inhibitors of syn- and anti-protonating glycosidases

Article abstract of DOI:10.1002/hlca.200490287

The galacto- and gluco-configured imidazopyridines 4 and 5 were synthesised as potential inhibitors of syn-protonating β-glycosidases. Methyl α-D-lyxopyranoside (9) was transformed into the 3,4-anhydro-β-L- riboside 16, which, upon treatment with Et₂

Full text of DOI:10.1002/hlca.200490287

100
Helvetica Chimica Acta ± Vol. 88 (2005)
Synthesis of Fusion-Isomeric Imidazopyridines and Their Evaluation as
Inhibitors of syn- and anti-Protonating Glycosidases
by Narinder Mohal and Andrea Vasella*
Laboratorium für Organische Chemie, ETH-Hönggerberg, HCI, Wolfgang-Pauli-Strasse 10, CH-8093 Zürich
The galacto- and gluco-configured imidazopyridines 4 and 5 were synthesised as potential inhibitors of syn-
protonating b-glycosidases. Methyl a-d-lyxopyranoside (9) was transformed into the 3,4-anhydro-b-l-riboside
16, which, upon treatment with Et2AlCN, gave the nitrile 17 (76 ± 85%). Reaction of 17 with the dimethyl
aluminate of aminoacetaldehyde dimethyl acetal led directly to the branched chain lyxo-configured imidazole
27 (53%) that was hydrolysed to an equilibrating mixture of 4 and 28 ± 30. Oxido reduction of 27 provided the
arabino-configured imidazole 42 (ca. 48% from 27). Hydrolysis of 42 led to the mixture 5/45 (63 ± 90%). anti-
Protonating b-galactosidases and b-glucosidases (families 1 and 2) were only weakly inhibited by 4/28 ± 30 and 5/
45, respectively. Also the syn-protonating cellulase (Cel7A) was weakly inhibited by the monosaccharide
mimics 5/45, suggesting either that monosaccharide mimics are too small to inhibit Cel7A, or that fusion
isomeric tetrahydroimidazo[1,2-a]pyridines are not a suitable scaffold for the inhibition of syn-protonating
glycosidases.
Introduction. ± Selective inhibitors of anti- and syn-protonating glycosidases [1] will
be useful to specify the (relative) position of the catalytic acid; they also have the
potential of being highly selective. Of particular interest are complementary inhibitors
of syn- and anti-protonating glycosidases possessing a common scaffold, as this would
facilitate a comparative interpretation of the inhibitory activity. However, there are as
yet no inhibitors selective for syn-protonating (a- or b-) glycosidases.
The anti- and syn-protonating glycosidases differ by the trajectory of the proton
transfer from the catalytic acid AH to the glycosidic oxygen (I and II) and the
tetrahydroimidazo[1,2-a]pyridines of type 1 are strong (about nanomolar) inhibitors of
ꢀ 2005 Verlag Helvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta ± Vol. 88 (2005)
101
anti-protonating b-glycosidases, interacting in a cooperative way with the catalytic acid
and the catalytic base of the enzyme [2 ± 17]. Tetrahydroimidazo[1,5-a]pyridines of type
2 [18 ± 24] do not possess a ꢁglycosidic heteroatomꢂ ± a heteroatom that is located (more
or less) in the same place as OÀC(1) of glycosides ± that could interact with the
catalytic acid AH of either an anti- or a syn-protonating glycosidase. Not unexpectedly,
these imidazoles are relatively weak glycosidase inhibitors. We wondered about the
isomeric tetrahydroimidazo[1,2-a]pyridines of type 3. These isomers do not have a
ꢁglycosidic heteroatomꢂ either, but N(1), although not ideally located, could interact
with the catalytic acid AH of a syn-protonating glycosidase, provided the catalytic acid
is (sufficiently) flexible, as it has indeed been advocated [25 ± 27]. This consideration
led us to first synthesise the monosaccharide-derived galacto- and gluco-configured
imidazoles 4 and 5 (Scheme 1). These imidazoles will presumably exist in equilibrium
with their open-chain aldehyde tautomers 4a and 5a, and be configurationally labile at
HOÀC(5). We were, however, confident that 4 and 5 would be sufficiently stable to be
isolated and tested, and that, upon binding to a specific glycosidase, they would adapt
their configuration at C(5) to the one of the preferred substrate.
Scheme 1
The plan for the synthesis of the imidazopyridines 4 and 5 is outlined in Scheme 1. It
is based on the assumption that glycoside hydrolysis of the branched-chain imidazolyl
glycoside 6 or 7 is followed by equilibration of the resulting hemiacetals and
corresponding hydroxyaldehydes 4a and 5a, and that further equilibration will lead to
the desired tetrahydroimidazopyridines 4 and 5. The branched-chain glycoside 6 should
be obtained by regioselective ring opening of the known anhydroribo-b-l-pyranoside 8
[28] and transformed into its isomer 7.
Results and Discussion. ± 1. Synthesis of the galacto-Imidazole 4. Methyl a-d-
lyxopyranoside (9) [28] was obtained in a yield of 77% by Fischer glycosidation of d-
lyxose with AcCl in anhydrous MeOH (Scheme 2). This controlled generation of HCl
led to results that compare favourably with those of known procedures [28][29].
Isopropylidenation of 9 [30] with acetone and Amberlyst-15 resulted consistently in
yields of at least 85 ± 90% of 10. Tosylation to 11 [29] was followed by hydrolysis to the
hydroxy toluenesulfonate 12. Treatment of 12 with t-BuOK in THF provided the
epoxide 8 in a maximal yield of 83 ± 92% (33 ± 40% from d-lyxose; 10 ± 30-mmol
scale). Lower yields resulted from using MeONa in MeOH [28].
The epoxide 8 in CDCl3 adopts almost exclusively the oH1 conformation, as
evidenced by J(1,2) ˆ 2.8 Hz. The energy difference between the 1Ho and oH1

102
Helvetica Chimica Acta ± Vol. 88 (2005)
Scheme 2
a) Amberlyst-15, 4-Š mol. sieves, Me2CO. b) TsCl, pyridine; 84% from 9. c) 80% aq. AcOH; 93%. d) tBuOK
THF; 83%. e) Et2AlCN, Et2O. f) Amberlyst-15, Me2CO, 4-Š mol. sieves; 17% of 15 and 20% of 13 from 8. g)
TIPSOTf (TIPS ˆ (i-Pr)3Si), 2,6-lutidine; 80 ± 96%. h) Et2AlCN, Et2O; 76 ± 85%.
conformers is small, and the barriers for their interconversion are low [31], so that
trans-diaxial opening of the oxirane 8 is not sufficient to control regioselectivity.
Ammonia and amines attack 8 preferentially at the less hindered C(4) [32], and
treatment of 8 with HBr provided methyl 4-bromo-4-deoxy-d-lyxoside [28]. However,
all attempts to introduce an imidazolyl moiety at C(4) (or at C(3)) by treating 8 with
protected imidazolyl anions failed under a variety of conditions [11 ± 13][33]. We,
therefore, planned to introduce a CN group, and to transform it into the imidazolyl
moiety via the corresponding amide and thioamide [2][4][6 ± 8][34 ± 36]. Treating the
epoxide 8 with Et2AlCN [37] resulted in an inseparable 1:1 mixture of the trans-
hydroxy carbonitriles 13 and 14 (66%). Treatment of this mixture with acetone in the
presence of Amberlyst-15 transformed 14 to 15, which was readily separated from 13;
this isopropylidenation establishes the constitution of 13 and 14, and the configuration
of 13 (Scheme 2). Unlike in a related favourable case [38], complexation of Et2AlCN
with MeOÀC(1) led neither to (regioselective) intramolecular delivery of cyanide nor
to a sufficiently biased conformation. We then speculated that protection of HOÀC(2)
of 8 with the bulky (i-Pr)3Si (TIPS) group would prevent the formation of a H-bond
from HOÀC(2) to the incipient oxyanion center, resulting from attack at C(3), that the
1
TIPSO group would prefer a pseudoequatorial orientation, favour the Ho conforma-
tion, and lead to a preferential attack of cyanide at C(4). The desired silyl ether 16 was
readily obtained and characterised as a ca. 1:1 mixture of the oH1 and 1Ho conformers
by J(1,2) ˆ 4.6 Hz. Opening of the oxirane ring of 16 by Et2AlCN provided almost

Helvetica Chimica Acta ± Vol. 88 (2005)
103
exclusively 171). The minor regioisomer resulting from attack at C(3) of 16 was
isolated in maximal 5% and desilylated to 13. An alternative substitution of 16 with
KCN in DMSO was inefficient and proceeded with concomitant O-desilylation; it led
regioselectively to 14.
1
The H-NMR spectrum of 13 in CD3OD and in CDCl3 displayed a characteristic
1
HÀC(3) t with J(2,3) ꢀ J(3,4) ꢀ 7.8 Hz, evidencing that it is mostly adopting the C4
conformation. The HÀC(4) of 17 resonates at 3.01 ppm as a td with J(3,4) ˆ J(4,5ax) ˆ
9.6; also J(4,5eq) ˆ 4.5 Hz. J(1,2) ˆ 2.4, J(2,3) ˆ 3.0 Hz are in agreement with a
preferred 4C1 conformation. The data are consistent with coupling constants calculated
4
for the C1 conformer of a-d-lyxose (J(1,2) ˆ 2.1, J(2,3) ˆ 3.1, J(3,4) ˆ 8.8, J(4, 5eq) ˆ
5.8, J(4,5ax) ˆ 10.5 Hz) [40], which is more stable than the 1C4 conformer by ca. 0.9 kcal/
mol. These interpretations are supported by MM3 calculations [40]. Crystalline methyl
a-d-lyxopyranoside also adopts the 4C1 conformation [41].
According to a literature precedent [38], 17 was transformed to the amides 18 and
19 in ratios varying from 3 :2 to 7:3, reflecting the migration of the TIPSgroup [42]
(Scheme 3). Desilylation of the mixture 18/19 (TBAF ´ 3 H2O)2) provided 20 in > 95%
yield. Isopropylidenation of 20 gave 21 besides ca. 10% of the 1,3-oxazin-4-one 22;
formation of an oxazinone under such conditions appears to be unprecedented.
Lawessonꢂs reagent transformed the amide 21 to the thioamide 23 (84%). Treatment of
23 with aminoacetaldehyde dimethyl acetal under a variety of conditions yielded
neither an amidine nor an imidazole, but transformed 23 back to the nitrile 15. We also
attempted to synthesise an imidazole via the acetylated amide 24 and thioamide 25.
Treatment of 25 with aminoacetaldehyde dimethyl acetal in the presence of a variety of
thiophilic reagents such as Hg(OAc)2, HgO, and PbO afforded only the acetylated
carbonitrile 26. No reaction occurred in the absence of thiophilic reagents up to a
temperature of 1108. An attempt to transform the carbonitriles 15, 17, and 26 to
amidines by aminolysis of the corresponding nitrilium salts, generated under conditions
of the Pinner reaction [43] or in the presence of a Lewis acid [44][45], and further to
imidazoles also failed, as did the formation of an imidazole ring from the amides 21 or
24.
Unexpectedly, however, the imidazole 27 was obtained (53%) in an attempt at
transforming the carbonitrile 17 into the corresponding amidine by treatment with the
aluminum amide derived from aminoacetaldehyde dimethyl acetal and Me3Al (1:1), as
suggested by the work of Weinreb and co-workers [46], Garigipati [47], and Moss et al.
[48] (Scheme 4). This unprecedented one-pot synthesis of an imidazole from a
carbonitrile is, however, not general and depends on the presence of the vicinal
HOÀC(3) group3). The lyxopyranoside 27 was hydrolysed with 20% aq. HCl in 80%
aq. AcOH at 1108 to provide a ca. 60 :8 :14 :18 equilibrium mixture of the galacto-
1
)
In an exploratory experiment, 16 was treated with Me3SiCN in the presence of activated MgO or CaO
[39]; this also led to regioselective opening at C(4) with simultaneous silylation of HOÀC(3). The
activation of MgO or CaO was essential to secure good yields. We thank Florian Kleinbeck for performing
this experiment.
2
3
)
Less-satisfactory conditions include heating with 50% aq. AcOH and treatment with 20% aq. HCl in
EtOH at 238, the poor yield under hydrolysis conditions reflecting partial glycoside hydrolysis.
A similar treatment of a few representative carbonitriles lacking a corresponding OH group led (in high
yields) to amidines.
)

104
Helvetica Chimica Acta ± Vol. 88 (2005)
Scheme 3
a) 30% H2O2, K2CO3, Me2CO/H2O 3 :2; 86 ± 95%. b) TBAF ´ 3 H2O, THF; 85 ± 95%, or 50% aq. AcOH; 50%,
or 20% aq. HCl/EtOH 1:1; 50%. c) Amberlyst-15, Me2CO, 4-Š mol. sieves; 81% of 21 and 12% of 22. d)
Lawessonꢀs reagent, toluene; 84% of 23; 76% of 25. e) NH2CH2CH(OMe)2, Hg(OAc)2, THF; 86% of 15;
> 95% of 26. f) Ac2O, 4-(dimethylamino)pyridine (DMAP), pyridine; 65%.
Scheme 4
a) Me3Al, NH2CH2CH(OMe)2, toluene; 46 ± 53%. b) 20% aq. HCl, 80% aq. AcOH; 70%. c) NaCNBH3,
MeOH/AcOH; 90%. d) Et3SiCl, 2,6-lutidine, pyridine; 16% of 32, 22% of 33, 8% of 34.

Helvetica Chimica Acta ± Vol. 88 (2005)
105
configured fused imidazole 4, its talo-isomer 28, and the branched-chain anomeric
lyxopyranoses 29 and 30. The desired galacto-imidazole 4 was the main component of
this mixture between pH 5.5 and 8. In agreement with the interpretation of the complex
NMR spectra of the hydrolysis products, reduction of the mixture 4/28 ± 30 with
NaCNBH3 provided the tetrol 31 in high yields (90%). Triethylsilylation of 4/28 ± 30
and flash chromatography provided the galacto-configured imidazoles 32 and 33, and
the talo-configured imidazole 34 in 16, 22, and 8% yield, respectively. As expected,
desilylation of 32 and 34 with aq. HCl in CD3OD at 248 for 36 h led in each case to the
mixture 4/28 ± 30.
The HÀC(4') and HÀC(5') of the imidazole moiety of 27 give rise to a
4
characteristic br. s at 6.97 ppm. The preferred C1 conformation of 27 agrees well
with J(1,2) ˆ 2.2, J(2,3) ˆ 3.0, J(3,4) ˆ 9.9, J(4,5ax) ˆ 10.5, and J(4,5eq) ˆ 4.8 Hz. The
C(4') and C(5') signals of the imidazole moiety of 27 appear as two broad ds at 127.83
and 115.19 ppm, respectively. Upon addition of a catalytic amount of AcOH they
appear as a sharp d at 119 ppm. The constitution of 4 is evidenced by the characteristic s
of C(8a) at 145.70, and by ds of C(2), C(3), and C(5) at 127.42, 118.23, and 81.58 ppm,
respectively. J(5,6) ˆ 7.2, J(6,7) ˆ 1.5, J(7,8) ˆ 3.6 Hz are in agreement with a 7H6 as the
predominant conformation and with the galacto-configuration of 4. The tetrakis(tri-
7
ethylsilyl) ether 32 adopts the H6 conformation in CDCl3 solution in agreement with
J(5,6) ˆ 6.9, J(6,7) ˆ 1.5, J(7,8) ˆ 3.0 Hz. In CD3OD solution, it exists as mixture of the
6
7
7H6 and H7 conformers with a predominant contribution from the H6 conformer as
indicated by J(5,6) ˆ 5.4, J(6,7) ˆ 1.5, J(7,8) ˆ 4.2, J(8,CHa) ˆ 7.2, J(8,CHb) ˆ 5.7, and
7
6
J(CHa,CHb) ˆ 9.9 Hz. The galacto-alcohol 33 exists as ca. 2 :1 mixture of H6 and H7
conformers, respectively, as evidenced by J(5,6) ˆ 4.5, J(6,7) ˆ 2.1, J(7,8) ˆ 6.3, J
7
(8,CHa) ˆ 5.4, J (8,CHb) ˆ 8.4, and J(HÀC(7),OH) ˆ 4.2 Hz. The H6 conformation
and talo-configuration of 34 is in agreement with J(5,6) ˆ 3.9, J(6,7) ˆ 2.1, J(7,8) ˆ 4.2,
J(8,CHa) ˆ 4.2, J(8,CHb) ˆ 10.8 Hz, and a J(5,7) w-coupling of 1.8 Hz. The large value
of J(HÀC(7),OH) ˆ 7.2 Hz for 34 indicates a H-bond between HOÀC(7) and
Et3SiOÀC(5).
2. Synthesis of the gluco-Imidazole 5. Oxidation ± reduction or inverting substitution
at C(3) of 17 and subsequent transformations should provide the desired imidazole 5,
but both transformations proved difficult (Scheme 5). Oxidation of 17 with Dess ±
Martinꢀs periodinane [49], PCC, tetrapropylammonium perruthenate (TPAP) and
NMO [50], or with DMSO/(COCl)2 and Et3N [51]) failed to provide the ketone 35.
Mitsunobu substitution with 4-nitrobenzoic acid [52] did not lead to a nitrobenzoate,
but partially transformed 17 into a complex mixture. The readily prepared triflate 36
was stable to chromatography on silica gel and to prolonged storage at À 208, but
reacted with NaNO2, AcONa, AcOK, AcOCs, or Bu4NOAc in DMF to provide only
the unsaturated carbonitrile 38 without any indication of a substitution product. The
corresponding methanesulfonate 37 was either not affected under the same conditions
of attempted substitution, or also transformed to 38, presumably on account of the
acidity of HÀC(4). As HÀC(4) of imidazolyl analogues should be considerably less
acidic, we used the (tert-butoxy)carbonyl (Boc) derivative 39 of 27 as the starting
material.
While attempted substitution of HOÀC(3) of 39 under Mitsunobu conditions
either did not affect the starting material or gave intractable mixtures, Dess ± Martin

106
Helvetica Chimica Acta ± Vol. 88 (2005)
Scheme 5
a) Tf2O, DMAP, pyridine; > 95%. b) MsCl, pyridine; 89%. c) CsOAc, DMF; 90%. d) Boc2O, DMAP, MeCN.
e) Dess ± Martin periodinane, CH2Cl2; 58% of 40 and 11% of 41, from 27. f) NaBH4, CeCl3 ´ 7 H2O, MeOH;
81% of 42, or NaBH4, MeOH; 48% of 39 and 26% of 42. g) Et3N, MeOH; 71%. h) NaBH4, MeOH; 56%. i)
20% aq. HCl, 80% aq. AcOH; 63 ± 90%. j) NaCNBH3, AcOH/MeOH; 65%. k) Et3SiCl, 2,6-lutidine, pyridine;
43% of 47/48.
oxidation [49] gave readily the ulopyranoside 40 (58%) besides the doubly epimerised
41 (10%), and proved superior to oxidation under Swern conditions [51]. The ketone
1
41 was formed only during chromatography, as evidenced by the H-NMR spectra of
the crude, and its formation may be rationalised by a reversible elimination ± addition
of MeOH.
Reduction of 40 with NaBH4 in the presence of CeCl3 ´ 7 H2O [53] gave exclusively
the a-d-arabinopyranoside 42 (80%), presumably as the consequence of the complex-
ation of CeIII with the C(3)ˆO and MeOÀC(1) groups affecting the conformation of
the pyranose ring and preventing the axial approach of hydride. Reduction of 40 with
NaBH4/MeOH gave a nearly 1:1 to 2 :3 mixture of the lyxo-configured 39 and the
arabino-configured 42. Workup and chromatography, however, yielded typically 46%
of 39 and 26% of 42, and ca. 20% of a 4 :1 to 9 :1 mixture of tert-butyl carbonate 43 and

Helvetica Chimica Acta ± Vol. 88 (2005)
107
its epimer. The yields and ratio of 39 and 42 reflect the migration of the N-Boc group to
HOÀC(3) of 42 and, considerably more slowly, also of 39. The migration is catalysed
by base; treating pure 42 with Et3N in MeOH yielded 71% of 43. A related case of this
type of N,O-carbonyl exocyclic rearrangement for N-carbonyl-oxazolidin-2-ones has
been reported [54][55]. To confirm the structure, we reduced 41 with NaBH4 in MeOH
to the b-d-xylopyranoside 44 (56%).
4
The ulopyranoside 40 adopts a flattened C1 conformation in agreement with
J(1,2) ˆ 1.8, J(4,5eq) ˆ 6.6, and J(4,5ax) ˆ 11.1 Hz. C(1) of 40 appears as d at 104.76, C(3)
as s at 201.12 ppm. A C(1) d at 107.40, and J(1,2) ˆ 7.5, J(4,5eq) ˆ 6.3, and J(4,5ax) ˆ
11.4 Hz are consistent with a flattened 4C1 conformation and with the configuration of
41. The vicinal J(1,2) ꢀ 1.2, J(2,3) ˆ 3.0, J(3,4) ˆ 2.1, J(4,5eq) ˆ 4.0, J(4,5ax) ˆ 11.1, and a
4
J(3,5eq) w-coupling of 1.2 Hz are consistent with the C1 conformation and the a-d-
arabino-configuration of 42. An intramolecular H-bond from HOÀC(3) to N(3') of 42
is evidenced by a d (J ˆ 5.4 Hz) at 4.95 ppm. In the IR (CHCl3) spectrum of 42, the
characteristic band at 3505 cmÀ1 for HOÀC(3) did not change upon dilution (0.11m,
0.17m, 0.51m, 0.85m, 1.27m, 1.76m), evidencing an intramolecular H-bond. The
disappearance of two ds at 7.34 (J(4',5') ˆ 1.8, HÀC(5')) and 6.86 ppm (J(4',5') ˆ 1.8,
HÀC(4')), and the appearance of two br. s at 7.0 (HÀC(4')), and 6.96 ppm (HÀC(5'))
1
in the H-NMR spectrum of 43 evidences the migration of the N-Boc group to
4
HOÀC(3). A ca. 1:1 mixture of C1 and 1C4 conformers of 43 is evidenced by J(1,2) ˆ
4.5, J(2,3) ˆ 6.0, J(3,4) ˆ 4.2, J(4,5eq) ˆ 4.2, and J(4,5ax) ˆ 6.0 Hz. The b-d-xylo-config-
4
uration and the C1-conformation of 44 agrees with J(1,2) ˆ 7.5, J(2,3) ˆ 8.7, J(3,4) ꢀ
J(4,5ax) ꢀ 10.5, J(4,5eq) ˆ 4.2 Hz, and the downfield shift of C(1) at 105.46 ppm.
J(HÀC(3), HO) ˆ 3.6 Hz agrees with an intramolecular H-bond to the equatorial
imidazolyl or TIPSO group.
Hydrolysis of 42 (20% aq. HCl in 80% aq. AcOH) at 1108 provided a ca. 1:1
equilibrium mixture of the d-gluco-configured 5 and its d-manno-isomer 45, accounting
for more than 95% of product. In keeping with the structure of 5/45, reduction with
NaCNBH3 provided the tetrol 46 (66%). Silylation of 5/45 and chromatography gave
the d-manno-imidazole 47 (27%) and the d-gluco-imidazole 48 (16%).
The d-gluco-configuration and predominant 7H6 conformation of 5 is evidenced by
J(5,6) ˆ 7.2, J(6,7) ꢀ J(7,8) ꢀ 9.3 Hz; the manno-configuration of 45, and its (prepon-
dering) 6H7 and 7H6 conformations are in agreement with J(5,6) ˆ 3.6, J(6,7) ˆ 8.4, and
6
J(7,8) ˆ 7.5 Hz. The gluco-configured silyl ether 48 adopts a H7 conformation with
pseudo-axial silyloxy and (silyloxy)methyl groups as evidenced by J(5,6) ˆ 1.8, J(6,7) ˆ
3.6, J(7,8) ꢀ 1.2, J(8,CHa) ꢀ 10.8, J(8,CHb) ˆ 5.4 Hz, and a w-coupling of J(5,7) ꢀ
0.9 Hz. There is precedent for the preferred axial orientation of silyloxy groups [56 ±
63]. The manno-imidazole 47 adopts preferentially the B5,8 conformation in accordance
with J(5,6) ˆ 1.8, J(6,7) ˆ 5.1, J(7,8) ꢀ 1.2, J(8,CHa) ˆ 5.1, and J(8,CHb) ˆ 10.5 Hz.
Inhibition Studies. Exploratory inhibition experiments indicate that the d-galacto/d-
talo and d-lyxo-configured imidazoles 4/28 ± 30, and d-gluco/d-manno-configured
imidazoles 5/45 respectively, inhibit ± at best ± very weakly the anti-protonating b-
glycosidases from family 1 and 2 (IC50 in the mm range). The mixture 4/28 ± 30
containing the d-galacto-imidazole 4 was assayed against b-galactosidases from E. coli
(family 2 [64]), bovine liver, and A. oryzae [65]). The b-galactosidases from E. coli and
bovine liver were not inhibited by 4/28 ± 30 up to a concentration of 7 mm, while the b-

108
Helvetica Chimica Acta ± Vol. 88 (2005)
galactosidase from A. oryzae was weakly inhibited (IC50 ꢀ 1 mm, [S ]ˆ 0.56 mm, 50 mm
AcONa buffer, pH 4.9).
The b-glucosidase from Caldocellum saccharolyticum (family 1) and the b-
glucosidases from sweet almonds were weakly inhibited by the d-gluco/d-manno
mixture 5/45 (IC50 ꢀ 500 mm, [S ]ˆ 2.02 mm, 50 mm AcONa buffer, pH 4.9) and (IC50 ꢀ
760 mm, [S ]ˆ 2.45 mm, 100 mm phosphate buffer, pH 6.9), respectively. Not unexpect-
edly, the monosaccharide imidazoles 5/45 inhibited the syn-protonating cellulase Cel7A
from T. reesei (family 7) only weakly (IC50 ꢀ 24 mm at 508; no inhibition up to 7.2 mm at
308, [S ]ˆ 0.722 mm, 50 mm AcONa buffer, pH 4.9); a significant inhibition requires at
least a disaccharide analogue [66 ± 68].
We thank the Swiss National Science Foundation and F. Hoffmann-La Roche AG, Basel, for generous
support. We thank Dr. B. Bernet for checking the Exper. Part, and Dr. B. Bernet and Dr. Chepuri Venkata
Ramana for valuable discussions. We thank Dr. Anu Koivula, VTT Biotechnology and Food Research, VTT,
Espoo, Finland, for a generous gift of Cel7A.
Experimental Part
General. All reactions were carried out under N2 unless specified otherwise. THF and Et2O were distilled
over Na/benzophenone, and DMF, MeCN, and CH2Cl2 were distilled over CaH2. TLC: Alugramꢃ silica gel 60
GF254 plates; detection by heating with ꢁmostainꢂ (400 ml of 10% aq. H2SO4 soln., 20 g of (NH4)6Mo7O24 ´ 6 H2O,
0.4 g of Ce(SO4)2) or 10% aq. H2SO4 soln. or 2% KMnO4 in 4% aq. NaHCO3 soln. Flash chromatography (FC):
silica gel Fluka 60 (0.04 ± 0.063 mm). M.p.: uncorrected. Optical rotations: 1-dm cell at 258, 589 nm. FT-IR
spectra: KBr or ca. 2% soln. in CHCl3; absorption in cmÀ1. 1H- and 13C-NMR spectra: chemical shifts d in ppm,
1
referenced at 7.26 ppm for H- and 77.1 ppm for 13C-NMR, respectively, for CHCl3; coupling constant J in Hz.
MALDI- and HR-MALDI-MS: 2,5-dihydroxybenzoic acid (DHB). b-Galactosidase from bovine liver
(3.2.1.23, as lyophilised powder), b-galactosidase from E. coli (3.2.1.23, as lyophilised powder), b-galactosidase
from A. oryzae (3.2.1.23, as lyophilised powder), b-glucosidase from Caldocellum saccharolyticum (3.2.1.21, as
lyophilised powder), and b-glucosidases from sweet almonds (3.2.1.21, as lyophilised powder), and all
nitrophenyl b-d-glycopyranosides were purchased from Sigma and used without further purification.
Methyl a-d-Lyxopyranoside (9) [28][30]. To an ice cold soln. of d-lyxose (17.33 g, 115.5 mmol) in anh.
MeOH (110 ml) was slowly added AcCl (Fluka, > 99%; 1 ml, 14.08 mmol). The resulting soln. (ca. 1% w/v) was
heated under reflux for ca. 4 h until disappearance of d-lyxose. The cooled mixture was neutralised with Ag2CO3
(ca. 2 g, pH ca. 7), treated with activated charcoal, and filtered through a short plug of Celite (2 Æ Â 2 cm). The
filtrate (ca. 160 ml, including washings with MeOH) was evaporated. The residue, solidifying upon cooling, was
recrystallised in hot AcOEt (50 ml) to give pure 9 (14.6 g, first crop, 77%). Colourless solid. Rf (CHCl3/MeOH
4 :1) 0.48. M.p. 107.4 ± 1088 ([69]:108 ± 1098). [a]2D5 ˆ ‡55.2 (c ˆ 0.62, H2O). IR (KBr): 3302s, 3200s, 2992m,
2968s, 2921s, 2876s, 2840m, 1464s, 1454s, 1384m, 1352s, 1150s, 1128s, 1106s, 1060s, 1013s, 971s, 879s, 848s, 776w.
1H-NMR (300 MHz, CD3OD): 4.55 (d, J ˆ 3.6, HÀC(1)); 3.76 ± 3.62 (m, HÀC(2), HÀC(3), HÀC(4),
HeqÀC(5)); 3.39 (dd, J ˆ 11.4, 8.4, HaxÀC(5)); 3.30 (s, MeO). 13C-NMR (75 MHz, D2O): 102.01 (d, C(1)); 71.39
(d, C(3)); 70.21 (d, C(2)); 67.65 (d, C(4)); 63.28 (t, C(5)); 56.15 (q, MeO). Anal. calc. for C6H12O5 (164.16):
C 43.90, H 7.37; found: C 44.01, H 7.31.
Methyl 2,3-O-Isopropylidene-a-d-lyxopyranoside (10) [28][29]. To a soln. of 9 (8.97 g, 54.70 mmol) in anh.
‡
acetone were added powdered molecular sieves (4 Š; 11.21 g) and Amberlyst-15 (H form, 807 mg). The
resulting suspension was stirred at 238 for 4 h (consumption of 9), and filtered through a short plug of Celite
(3.8 ù Â 4 cm; washing with additional 100 ml of acetone). Evaporation of the combined filtrate and washings
gave 10 as viscous oil (11.4 g, quant.), which solidified upon storage. It was used for the next step without any
further purification. A pure sample of 10 was obtained by FC (hexane/AcOEt 3 :1). Colourless solid. Rf
(hexane/AcOEt 3 :2) 0.55. M.p. 51.4 ± 52.68 ([29]: 40 ± 418; [28]: 49 ± 528). [a]2D5 ˆ ‡48.3 (c ˆ 0.8, EtOH). IR
(2%, CHCl3): 3580w (sh), 3450w, 2992w, 2938w, 2839w, 1602w, 1450w, 1384m, 1374m, 1164m, 1140m, 1095s,
1073s, 1009s, 982m, 954m, 908w, 871w, 854m. 1H-NMR (300 MHz, CDCl3): 4.63 (d, J ˆ 3.0, HÀC(1)); 4.20 (dd,
J ˆ 6.0, 4.8, HÀC(3)); 4.10 (dd, J ˆ 6.0, 2.7, HÀC(2)); 3.82 ± 3.76 (m, addn. of D2O ! change, HÀC(4),
HeqÀC(5)); 3.67 (dd, J ˆ 12.9, 6.9, HaxÀC(5)); 3.44 (s, MeO); 3.18 (d, J ˆ 7.5, exchanged with D2O, HOÀC(4));

Helvetica Chimica Acta ± Vol. 88 (2005)
109
1.49, 1.34 (2s, Me2C). 13C-NMR (75 MHz, CDCl3): 109.51 (s, Me2C); 99.88 (d, C(1)); 77.36 (d, C(3)); 74.45 (d,
C(2)); 63.29 (t, C(5)); 62.29 (d, C(4)); 55.58 (q, MeO); 27.69, 25.73 (2q, Me2C). Anal. calc. for C9H16O5 (204.22):
C 43.90, H 7.37; found: C 44.01, H 7.31.
Methyl 2,3-O-Isopropylidene-4-O-[(4-methylphenyl)sulfonyl]-a-d-lyxopyranoside (11) [28][29]. A soln. of
10 (11.40 g, 55.88 mmol) in dry pyridine (14 ml) was treated with TsCl (15.34 g, 80.46 mmol). The resulting thick
slurry was stirred at 238 for 22 h, diluted with AcOEt (150 ml), washed with 10% aq. HCl (2 Â 25 ml), H2O (2 Â
25 ml), and brine (25 ml), dried (Na2SO4), and evaporated. FC (ca. 150 g of silica gel; ca. 300 ml of hexane/
AcOEt 13 :7) and two crystallisations from CH2Cl2/hexane gave 11 (16.45 g, 84% from 9). Colourless solid. Rf
(hexane/AcOEt 13 :7) 0.66. M.p. 105 ± 1068 ([29]: 105 ± 1068. [a]2D5 ˆ À14.8 (c ˆ 0.91, EtOH) ([29]: [a]D25 ˆ À18.3
(c ˆ 0.91, EtOH)). IR (CHCl3): 3028w, 2992w, 2938w, 1599w, 1451w, 1446w, 1375s, 1308w, 1176m, 1140m, 1095s,
1019s, 1017s, 995m, 962w, 925m, 830s. 1H-NMR (300 MHz, CDCl3): 7.83 (d, J ˆ 8.4, 2 arom. H); 7.34 (d, J ˆ 8.4, 2
arom. H); 4.71 (d, J ˆ 1.5, HÀC(1)); 4.39 (ddd, J ˆ 9.6, 6.9, 5.1, HÀC(4)); 4.14 (dd, J ˆ 6.3, 5.4, HÀC(3)); 4.04
(dd, J ˆ 5.4, 1.5, HÀC(2)); 3.77 (dd, J ˆ 12.0, 5.1, HeqÀC(5)); 3.63 (dd, J ˆ 12.0, 9.3, HaxÀC(5)); 3.38 (s, MeO);
2.44 (s, Me); 1.25, 1.17 (2s, Me2C). 13C-NMR (75 MHz, CDCl3): 144.92, 133.08 (2s); 129.93 (d, 2 C); 128.2 (d,
2 C); 109.91 (s, Me2C); 98.66 (d, C(1)); 76.95, 75.59, 74.62 (3d, C(2), C(3), C(4)); 58.54 (t, C(5)); 55.58 (q,
MeO); 27.57, 26.29 (2q, Me2C); 21.84 (q, Me). Anal. calc. for C16H22O7S(358.41): C 53.62, H 6.19; found:
C 53.73, H 6.16.
Methyl 4-O-[(4-Methylphenyl)sulfonyl]-a-d-lyxopyranoside (12) [28][29].
A soln. of 11 (11.18 g,
31.22 mmol) in glacial AcOH (48 ml) was warmed to 100 ± 1108, stirred for 5 min, treated with H2O (12 ml),
and stirred for 25 min at 100 ± 1108 when TLC showed completion of the reaction. Evaporation without any
further heating gave a solid, which was crystallised from CH2Cl2/hexane to give 12 (8.89 g, 89%). Colourless
solid. Rf (hexane/AcOEt 2 :3) 0.28. M.p. 93.4 ± 94.28 ([29]: 94 ± 958). [a]2D5 ˆ 59.2 (c ˆ 0.86, EtOH) ([29]: [a]2D5
ˆ
61.21 (c ˆ 0.88, EtOH)). IR (CHCl3): 3569m, 3390w (sh), 3038w, 2937w, 2837w, 1598m, 1495w, 1465w, 1446w,
1403m, 1369m, 1177s, 1134s, 1100s, 1060s, 1017s, 976s, 956m, 824s. 1H-NMR (300 MHz, CDCl3): 7.82 (d, J ˆ 8.4,
2 arom. H); 7.35 (d, J ˆ 8.4, 2 arom. H); 4.62 (d, J ˆ 2.7, HÀC(1)); 4.60 (td, J ˆ 8.4, 5.7, HÀC(4)); 3.96 (dt, J ˆ 8.1,
3.7, addn. of D2O ! dd, J ˆ 8.1 3.7, HÀC(3)); 3.90 (q, J ˆ 3.0, addn. of D2O ! t, J ˆ 3.0, HÀC(2)); 3.64 (dd, J ˆ
11.6, 5.2, HeqÀC(5)); 3.58 (dd, J ˆ 11.6, 8.8, HaxÀC(5)); 3.37 (s, MeO); 2.93 (d, J ˆ 3.9, exchanged with D2O,
HOÀC(3)); 2.58 (d, J ˆ 3.0, exchanged with D2O, HOÀC(2)); 2.46 (s, Me). 13C-NMR (75 MHz, CDCl3): 145.33,
132.86 (2s); 129.98 (d, 2 C); 127.94 (d, 2 C); 100.42 (d, C(1)); 77.25 (d, C(4)); 70.27, 68.85 (2d, C(2), C(3)); 59.78
‡
‡
(t, C(5)); 55.59 (q, MeO); 21.85 (q, Me). HR-MALDI-MS: 341.0668 ([ M ‡ Na] , C13H18NaO7S ; calc.
341.0665). Anal. calc. for C13H18O7S(318.34): C 49.05, H 5.70; found: C 48.97, H 5.82.
Methyl 3,4-Anhydro-b-l-ribopyranoside (8) [28]. A mixture of anh. THF (25 ml)) in a flame-dried 100-ml
two-necked flask and t-BuOK (2.77 g, 24.70 mmol), under N2, was cooled to ca. 38, and treated with a soln. of 13
(6.45 g, 20.6 mmol) in anh. THF (45 ml) over a period of 15 min. The mixture was stirred for 45 min at 38.
During this time, stirring became sluggish. After dilution with anh. THF (40 ml), the mixture was stirred for
20 min, poured into sat. aq. NH4Cl soln. (15 ml), and stirred for ca. 30 min. The liquid phase was decanted and
filtered through a short pad of Celite (2 ù Â 2 cm). The residue was treated with AcOEt (150 ml) and filtered.
Evaporation of the combined filtrate and filtration through silica gel (ca. 20 g; ca. 120 ml of hexane/AcOEt 2 :3)
1
gave 8 (2.77 g, 92%; homogeneous by H-NMR spectroscopy). An anal. sample was obtained by FC (hexane/
AcOEt 3 :2). Colourless oil. Rf (hexane/AcOEt 11:9) 0.24. M.p. < r.t. [a]2D5 ˆ ‡542.8 (c ˆ 1.01, CHCl3) ([28]:
[a]2D5 ˆ ‡98.6 (c ˆ 1.4, Me2CO)). IR (CHCl3): 3554m, 3027m, 3013m, 2960m, 2946m, 2919m, 2869w, 2839w,
1602w, 1466w, 1448m, 1405m, 1351m, 1327w, 1251m, 1149s, 1096s, 1071s, 1046s, 1017s, 1003m, 985s, 955m, 866s,
845m. 1H-NMR (300 MHz, CDCl3): 4.36 (d, J ˆ 2.5, HÀC(1)); 3.96 (dd, J ˆ 13.3, 1.25, HeqÀC(5)); 3.90 (br. d,
J ˆ 13.3, HaxÀC(5)); 3.75 (ddd, J ˆ 9.9, 4.4, 2.5, addn. of D2O ! dd, J ˆ 4.4, 2.5, HÀC(2)); 3.49 (t, J ˆ 4.4,
HÀC(3)); 3.39 (s, MeO); 3.34 (ddd, J ˆ 4.4, 1.5, 0.9, HÀC(4)); 2.66 (d, J ˆ 9.9, exchanged with D2O,
HOÀC(2)). 13C-NMR (75 MHz, CDCl3): 99.84 (d, C(1)); 64.86 (d, C(2)); 58.06 (t, C(5)); 55.63 (q, MeO); 51.86,
51.57 (2d, C(3), C(4)). Anal. calc. for C6H10O4 (146.14): C 49.31, H, 6.90; found: C 49.30, H 6.85.
Methyl 3-Cyano-3-deoxy-b-l-xylopyranoside (13) and Methyl 4-Cyano-4-deoxy-2,3-O-isopropylidene-a-d-
lyxopyranoside (15). A cooled soln. (ca. À 158) of 8 (557 mg, 3.82 mmol) in anh. Et2O (10 ml, 0.38m) was slowly
treated with ca. 1m soln. of Et2AlCN (7.5 ml, 7.5 mmol, 1.96 equiv.) in toluene. The mixture was allowed to warm
to r. t. and then boiled under reflux for ca. 4 h. After the disappearance of 8, the mixture was cooled in an ice-
bath, treated dropwise (caution: exothermic reaction!) with sat. aq. NH4Cl soln. (ca. 20 ml), and diluted with
AcOEt (50 ml). The org. layer was washed with 10% aq. HCl (20 ml) and H2O (25 ml), dried (Na2SO4), and
evaporated. A soln. of the residue was dissolved in hexane/AcOEt 1:2, and passed through a short plug of silica
gel (8 g of silica gel; hexane/AcOEt 1:2) to give a mixture of 13 and 14 (421 mg), which could not be separated
and was used for the next step without further purification.

110
Helvetica Chimica Acta ± Vol. 88 (2005)
A soln. of the above mixture (421 mg, 21.9 mmol, ca. 90% pure) in dry acetone (25 ml) was treated with
‡
powdered molecular sieves (4 Š; ca. 3.2 g) and Amberlyst-15 (H form, 171 mg), stirred for ca. 11 h at 248, and
filtered through a short plug of Celite (washings with additional acetone). Evaporation and FC (8 g of silica gel;
hexane/AcOEt 7:3 ! 1 :2) gave 15 (142 mg, 17% from 8) and 13 (135 mg, 21% from 8).
Data of 13: Colourless solid. Rf (hexane/AcOEt 1 :4) 0.57. M.p. 121.4 ± 121.88 (CH2Cl2/hexane). [a]D25
ˆ
‡85.4 (c ˆ 0.48, CHCl3). IR (CHCl3): 3602m, 3370w, 3018w, 2935w, 2249w, 1449w, 1256w 1154m, 1101s, 1067s,
1037s, 984w, 878w, 833w. 1H-NMR (300 MHz, CDCl3): 4.31 (d, J ˆ 5.4, HÀC(1); 4.12 (dd, J ˆ 12.0, 3.9,
HeqÀC(5)); 4.04 (m, addn. of D2O ! change, HÀC(4)); 3.72 (dt, J ˆ 7.8, 5.1, irrad. at 4.31 ! dd, J ˆ 7.8, 4.8,
addn. of D2O ! dd, J ˆ 7.8, 4.8, HÀC(2)); 3.52 (s, MeO); 3.43 (dd, J ˆ 11.7, 6.9, HaxÀC(5)); 2.92 (d, J ˆ 4.8,
exchanged with D2O, HOÀC(2)); 2.87 (t, J ˆ 7.8, HÀC(3)); 2.70 (d, J ˆ 5.7, exchanged with D2O, HOÀC(4)).
1H-NMR (300 MHz, CD3OD): 4.08 (d, J ˆ 7.5, HÀC(1)); 3.91 (dd, J ˆ 11.1, 4.8, HeqÀC(5)); 3.80 (td, J ꢀ 10.2,
4.8, HÀC(4)); 3.46 (s, MeO); 3.42 (dd, J ˆ 10.5, 7.2, HÀC(2)); 3.21 (dd, J ˆ 11.1, 9.9, HaxÀC(5)); 2.64 (t, J ꢀ
10.2, HÀC(3)). 13C-NMR (75 MHz, CD3OD): 120.17 (s, CN); 106.19 (d, C(1)); 70.44, 69.29 (2d, C(2), C(4));
67.73 (t, C(5)); 57.25 (q, MeO); 44.07 (d, C(3)). Anal. calc. for C7H11NO4 (173.16): C 48.55, H 6.40, N 8.09;
found: C 48.64, H 6.43, N 8.00.
Data of 15: Colourless solid. Rf (hexane/AcOEt 4 :1) 0.32. M.p. 85.5 ± 85.88(hexane). [a]2D5 ˆ ‡9.0 (c ˆ 1.0,
CHCl3). IR (CHCl3): 3027m, 2993s, 2938s, 2841w, 2246w, 1602w, 1465w, 1385m, 1375m, 1350w, 1288w, 1245m,
1162m, 1140s, 1128s, 1097s, 1063m, 1018m, 980w, 956w, 893m, 850m. 1H-NMR (300 MHz, CDCl3): 4.87 (d, J ˆ
1.2, HÀC(1)); 4.38 (dd, J ˆ 8.4, 5.1, HÀC(3)); 4.04 (dd, J ˆ 5.1, 1.2, HÀC(2)); 3.78 (d, J ˆ 7.2, 2 HÀC (5)); 3.41
(s, MeO); 2.66 (q, J ꢀ 7.8, HÀC(4)); 1.54, 1.37 (2s, Me2C). 13C-NMR (75 MHz, CDCl3): 118.04 (s, CꢁN); 110.28
(s, Me2C); 98.40 (d, C(1)); 72.88, 72.22, (2d, C(2), C(3)); 56.62 (t, C(5)); 55.62 (q, MeO); 32.29 (d, C(4)); 28.28,
26.23 (2q, Me2C). Anal. calc. for C11H15NO4 (173.17): C 56.33, H 7.09, N 6.57; found: C 56.55, H 7.05, N 6.35.
Methyl 3,4-Anhydro-2-O-(triisopropylsilyl)-b-l-ribopyranoside (16). A soln. of 8 (2.77 g, 18.99 mmol) in
anh. DMF (5 ml) was treated with 2,6-lutidine (4.4 ml, 37.8 mmol), cooled to 38, slowly treated with
triisopropylsilyl (TIPS) triflate (5.3 ml, 19.65 mmol) over a period of 15 min, and stirred at 38 until
disappearance of 8 (ca. 3.5 h). The mixture was diluted with AcOEt (100 ml) and washed with 25% aq. CuSO4
soln. (2 Â 25 ml), H2O (25 ml), and brine (25 ml), dried (Na2SO4), and evaporated. FC (ca. 65 g of silica gel;
hexane/AcOEt 19 :1 ! 9 :1) gave 16 (4.71 g, 76% from 12). Colourless oil. Rf (hexane/AcOEt 17:1) 0.40.
M.p. < r.t. [a]2D5 ˆ ‡98.6 (c ˆ 0.94, CHCl3). IR (CHCl3): 3028w, 3006w, 2945s, 2868s, 1465m, 1390w, 1319w, 1146s,
1
1122s, 1093w, 1054m, 997s, 957w, 882m. H-NMR (300 MHz, CDCl3): 4.30 (d, J ˆ 4.2, HÀC(1)); 4.05 (dd, J ˆ
13.2, 2.4, HeqÀC(5)); 3.93 (dt, J ˆ 13.5, 1.0, HaxÀC(5); 3.92 (dd, J ˆ 4.5, 3.0, HÀC(2)); 3.39 (br. dd, J ˆ 6.6, 0.5,
HÀC(4)); 3.39 (s, MeO); 3.36 (ddd, J ˆ 6.9, 2.7, 0.9, HÀC(3)). 13C-NMR (75 MHz, CDCl3): 101.84 (d, C(1));
68.93 (d, C(2)); 60.81 (t, C(5)); 56.35 (q, MeO); 54.32, 53.17 (2d, C(3), C(4)); 18.11, 18.08 (2q, (Me2CH)3Si);
12.48 (d, (Me2CH)3Si). Anal. calc. for C15H30O4Si (302.48): C 59.56, H, 10.00; found: C 59.64, H 10.01.
Methyl 4-Cyano-4-deoxy-2-O-(triisopropylsilyl)-a-d-lyxopyranoside (17). A cooled soln. (ca. 38) of 16
(4.71 g, 15.88 mmol) in anh. Et2O (58 ml, 0.27m) was slowly treated with ca. 1m soln. of Et2AlCN in toluene
(19 ml, 19 mmol), allowed to warm to r.t., and then heated under reflux for ca. 4 h until disappearance of 16. The
mixture was cooled in an ice-bath and treated dropwise with sat. aq. NH4Cl soln. (ca. 20 ml) (caution:
exothermic reaction!). The mixture was stirred for an additional 2 h, the liquid phase was decanted, and the
solid was thoroughly washed with AcOEt (2 Â 25 ml). Evaporation of the combined filtrate, washings, and FC
(100 g of silica gel; hexane/AcOEt 9 :1 ! 17:3) gave 17 (4.52 g, 88%). Colourless solid. Rf (hexane/AcOEt
17:3) 0.34; Rf (hexane/AcOEt 9 :1) 0.46. M.p. 78 ± 78.38 (MeOH/H2O). [a]2D5 ˆ À17.1 (c ˆ 1.01, CHCl3). IR
(CHCl3): 3562w, 3018w, 2946s, 2869s, 2249w, 1464m, 1389w, 1369w, 1149s, 1132s, 1070s, 1030s, 998w, 973w, 883m.
1H-NMR (300 MHz, CDCl3): 4.61 (d, J ˆ 2.4, HÀC(1)); 4.03 (td, J ˆ 9.6, 3.0, addn. of D2O ! dd, J ˆ 9.6, 3.0,
HÀC(3)); 3.98 (dd, J ˆ 3.0, 2.4, irrad. at 4.61 ! d, J ˆ 3.0, HÀC(2)); 3.87 (dd, J ˆ 11.1, 4.5, HeqÀC(5)); 3.78 (dd,
J ˆ 11.1, 10.2, HaxÀC(5)); 3.38 (s, MeO), 3.01 (td, J ꢀ 9.6, 4.5, HÀC(4)); 2.44 (d, J ˆ 9.3, exchanged with D2O,
HOÀC(3)); 1.08 (br. s, (Me2CH)3Si). 13C-NMR (75 MHz, CDCl3): 118.28 (s, CN); 101.31 (d, C(1)); 69.94, 68.41
(2d, C(2), C(3)); 59.01 (t, C(5)); 55.63 (q, MeO); 32.53 (d, C(4)); 18.18, 18.10 (2q, (Me2CH)3Si); 12.65 (d,
‡
‡
(Me2CH)3Si). MALDI-MS: 681.4 ([2M ‡ Na] , C32H62N2NaO8Si2 ; calc. 681.3937). Anal. calc. for C16H31NO4Si
(329.51): C 58.32, H 9.48, N 4.25. found: C 58.18, H 9.59, N 4.22.
Methyl 4-Carbamoyl-4-deoxy-2-O-(triisopropylsilyl)-a-d-lyxopyranoside (18) and Methyl 4-Carbamoyl-4-
deoxy-3-O-(triisopropylsilyl)-a-d-lyxopyranoside (19). A cold (0 ± 58) soln. of 17 (2.01 g, 6.10 mmol) in Me2CO/
H2O 3 :2 (50 ml) was treated with 1m aq. K2CO3 soln. (12.5 ml, 12.5 mmol) and 30% aq. H2O2 (3 ml, 26.4 mmol),
warmed to 258, stirred for ca. 16 h (disappearance of 17), and treated with sat. aq. NaHSO3 soln. (5 ml). After
evaporation, the residue was taken up in AcOEt (200 ml), washed with 20% aq. HCl soln. (40 ml), H2O (20 ml),
and brine (20 ml), and dried (Na2SO4). Evaporation gave crude 18/19 ca. 1 :1 (2.21 g), which was used for the

Helvetica Chimica Acta ± Vol. 88 (2005)
111
next step without further purification. Colourless solid. Rf (AcOEt/hexane 3 :2) 0.22. IR (CHCl3): 3525m,
3494m, 3406m, 3360w, 3194w, 3007m, 2946s, 2868s, 1684s, 1559m, 1464m, 1407w, 1386m, 1366m, 1148s, 1107s,
1
1061s, 1014s, 973s, 919w, 883w, 862w. H-NMR (300 MHz, CDCl3; 18/19 ca. 1:1): 6.73, 6.30, 6.13, 6.10 (4 br. s,
slowly exchanged with D2O, NH2); 4.68 (d, J ˆ 1.8, 0.5 H), 4.62 (d, J ˆ 2.1, 0.5 H) (HÀC(1)); 4.40 (dd, J ˆ 9.3,
3.0, 0.5 H), 4.01 (td, J ˆ 9.9, 3.6, addn. of D2O ! dd, J ˆ 9.9, 3.3, 0.5 H) (HÀC(3)); 3.91 (br. q, J ꢀ 1.8, addn. of
D2O ! br. t, J ꢀ 1.8, 0.5 HÀC(2)); 3.84 (br. dd, J ˆ 12.0, 5.1, 0.5 HeqÀC(5)); 3.80 ± 3.63 (m, 0.5 HÀC(2), 0.5
HeqÀC(5), HaxÀC(5)); 3.32, 3.31 (2s, MeO); 2.82 (td, J ˆ 10.8, 5.1, 0.5 H), 2.75 (td, J ˆ 10.5, 5.4, 0.5 H)
(HÀC(4)); 2.73 (d, J ˆ 9.3, exchanged with D2O, 0.5 HOÀC(3)); 2.66 (d, J ˆ 1.8, exchanged with D2O, 0.5
HOÀC(2); 1.09 ± 1.01 (m, (Me2CH)3Si). 13C-NMR (75 MHz, CDCl3; 18/19 ca. 1:1): 174.27, 173.54 (2s, CˆO);
101.05, 100.84 (2d, C(1)); 70.49, 69.58, 68.88, 67.69 (4d, C(2), C(3)); 60.21, 59.35 (2t, C(5)); 55.11, 55.08 (2q,
MeO); 46.34, 44.51 (2d, C(4)); 18.43, 18.08 (2q, (Me2CH)3Si); 12.62 (d, (Me2CH)3Si).
Methyl 4-Carbomyl-4-deoxy-a-d-lyxopyranoside (20). A stirred soln. of 18/19 ca. 1:1 (2.21 g, 6.35 mmol)
and TBAF ´ 3 H2O (2.6 g, 8.34 mmol) in dry THF (10 ml) was kept for 3 h at 838. Evaporation, FC (24 g of silica
gel; AcOEt ! AcOEt/MeOH 9 :1), and recrystallisation in AcOEt/MeOH gave 20 (916 mg, 78% from 17).
Colourless solid. Rf (MeOH/AcOEt 1:9) 0.24. M.p. 128.7 ± 129.88(MeOH/AcOEt). [a]2D5 ˆ ‡52.3 (c ˆ 0.52
EtOH). IR (KBr): 3409s, 3225s, 3175s, 3007m, 2956s, 2938s, 2885m, 1682s, 1641s, 1621s, 1439s, 1384s, 1355s,
1250s, 1142s, 1126s, 1089s, 1059s, 1009s, 964s, 941w, 881w, 846w. 1H-NMR (300 MHz, D2O): 4.65 (d, J ˆ 2.1,
HÀC(1)); 3.98 (dd, J ˆ 10.8, 3.0, irrad. at 2.79 ! change, HÀC(3)); 3.73 (dd, J ˆ 3.0, 2.1, HÀC(2)); 3.71 (dd, J ˆ
11.1, 5.4, irrad. at 2.79 ! change, HeqÀC(5)); 3.62 (t, J ꢀ 11.1, irrad. at 2.79 ! change, HaxÀC(5)); 3.27 (s, MeO);
2.79 (td, J ꢀ 11.1, 5.4, irrad. at 3.98 ! dd, J ˆ 11.1, 5.4, HÀC(4)). 13C-NMR (75 MHz, D2O): 175.54 (s, CˆO);
101.05 (d, C(1)); 67.96, 66.07 (2d, C(2), C(3)); 59.63 (t, C(5)); 54.74 (q, MeO); 44.86 (d, C(4)). Anal. calc. for
C10H17O5N (231.25): C 51.94, H 7.41; N 6.06; found: C 52.07, H 7.27, N 6.02.
Isopropylidenation of 20. A soln. of 20 (592 mg, 3.1 mmol) in anh. Me2CO (20 ml) was treated with
‡
powdered molecular sieves (4 Š; 670 mg) and Amberlyst-15 (H form, 215 mg), stirred at 248 for 4 h, and
filtered through a short plug of Celite (washing with 15 ml of Me2CO). Evaporation and FC (ca. 15 g of silica gel;
300 ml of hexane/AcOEt 4 :1) gave 21 (582 mg, 81%), and 22 (85 mg, 12%, containing traces of 21).
Methyl 4-Carbamoyl-4-deoxy-2,3-O-isopropylidene-a-d-lyxopyranoside (21). Colourless solid. Rf (hexane/
AcOEt 2 :3) 0.21. M.p. 159 ± 159.88 (CH2Cl2/hexane). [a]2D5 ˆ ‡21.0 (c ˆ 1.01, CHCl3). IR (ca. 3%, CHCl3):
3502m, 3386m, 3007m, 2937m, 2838m, 1682s, 1589s, 1466w, 1385s, 1370s, 1248w, 1142s, 1093s, 1057s, 1006m, 908w,
953w, 851m. 1H-NMR (300 MHz, CDCl3): 6.28, 5.36 (2 br. s, exchanged with D2O, NH2); 4.88 (br. s, J < 1.5,
HÀC(1)); 4.36 (dd, J ˆ 9.3, 5.4, HÀC(3)); 4.02 (dd, J ˆ 5.4, 1.8, HÀC(2)); 3.84 (dd, J ˆ 12.3, 4.8, HeqÀC(5));
3.72 (dd, J ˆ 12.3, 10.8, HaxÀC(5)); 3.39 (s, MeO); 2.66 (ddd, J ꢀ 10.5, 9.3, 4.8, HÀC(4)); 1.58, 1.37 (2s, Me2C).
13C-NMR (75 MHz, CDCl3): 173.84 (s, CˆO); 109.68 (s, Me2C); 98.54 (d, C(1)); 73.52, 72.94 (2d, C(2), C(3));
57.11 (t, C(5)); 55.14 (q, MeO); 44.46 (d, C(4)); 28.42, 26.30 (2q, Me2C). Anal. calc. for C10H17O5N (231.245):
C 51.94, H 7.41, N 6.06; found: C 52.07, H 7.27, N 6.02.
Methyl 4-Carbamoyl-4-deoxy-3-O,41-N-isopropylidene-a-d-lyxopyranoside (22). Colourless oil. Rf (hex-
ane/AcOEt 2 :3) 0.21. [a]2D5 ˆ ‡43.0 (c ˆ 0.7, CHCl3). IR (CHCl3): 3599w, 3500w, 3396w, 3017m, 2936w, 1667s,
1
1591w, 1426m, 1389w, 1373w, 1215s, 1161m, 1125m, 1091w, 1055s, 1017m, 999m. H-NMR (300 MHz, CDCl3):
6.70 (br. s, slowly exchanged with D2O, NH); 4.74 (d, J ˆ 1.5, HÀC(1)); 4.02 (dd, J ˆ 11.7, 4.8, HeqÀC(5)); 4.01
(dd, J ˆ 10.8, 2.7, HÀC(3)); 3.94 (td, J ꢀ 3.0, 1.5, addn. of D2O ! dd, J ꢀ 3.0, 1.5, HÀC(2)); 3.62 (t, J ꢀ 11.4,
HaxÀC(5)); 3.37 (s, MeO); 2.66 (td, J ꢀ 11.1, 4.8, HÀC(4)); 2.41 (d, J ˆ 3.0, exchanged with D2O, HOÀC(2));
1.49, 1.48 (2s, Me2C). 13C-NMR (75 MHz, CDCl3): 168.84 (s, CˆO); 100.86 (d, C(1)); 85.90 (s, Me2C); 68.25,
67.61 (2d, C(2), C(3)); 57.76 (t, C(5)); 55.16 (q, MeO); 37.61 (d, C(4)); 31.21, 27.78 (2q, Me2C). HR-EI-MS:
‡
‡
216.0873 ([MÀMe] , C9H14NO4 ; calc. 216.0877).
Methyl 4-(Aminothiocarbonyl)-4-deoxy-2,3-O-isopropylidene-a-d-lyxopyranoside (23). A soln. of 21
(30 mg, 0.129 mmol) in dry toluene (1 ml) was treated with Lawessonꢀs reagent (35.4 mg, 0.88 mmol) at 238,
heated to 708, and stirred for 15 min (disappearance of 21). Evaporation and FC (ca. 2 g of silica gel; hexane/
AcOEt 7:3) gave 23 (27 mg, 84%). Yellowish solid. Rf (hexane/AcOEt 7 :3) 0.22. M.p. 139 ± 139.58 (CH2Cl2/
hexane). [a]2D5 ˆ À8.2 (c ˆ 0.96, CHCl3). IR (ca. 1%, CHCl3): 3468w, 3337w, 2992m, 2937w, 1601m, 1400m,
1385m, 1370w, 1246w, 1161w, 1140m, 1092s, 1055s, 1005m, 954w, 894w, 856m. 1H-NMR (300 MHz, CDCl3): 7.78,
7.59 (2 br. s, exchanged slowly with D2O, NH2); 4.88 (br. s, J < 1, HÀC(1)); 4.39 (dd, J ˆ 8.7, 5.4, HÀC(3)); 4.03
(dd, J ˆ 5.4, 0.5, HÀC(2)); 3.88 (dd, J ˆ 12.1, 4.8, HeqÀC(5)); 3.80 (dd, J ˆ 12.1, 9.6, HaxÀC(5)); 3.39 (s, MeO);
2.83 (ddd, J ꢀ 9.6, 8.7, 4.8, HÀC(4)); 1.57, 1.36 (2s, Me2C). 13C-NMR (75 MHz, CDCl3): 207.82 (s, C ˆ S); 109.62
(s, Me2C); 98.45 (d, C(1)); 74.92, 73.67 (2d, C(2), C(3)); 59.33 (t, C(5)); 55.22 (q, MeO); 50.06 (d, C(4)); 28.53,
‡
‡
26.29 (2q, Me2C). HR-MALDI-MS: 232.0644 ([M À Me] , C9H14NO4S ; calc. 232.0628). Anal. calc. for
C10H17NO4S(249.30): C 48.57, H 6.93, N 5.66; found: C 49.11, H 7.04, N 5.54.

112
Helvetica Chimica Acta ± Vol. 88 (2005)
Transformation of 23 to 15. At À 158, a soln. of 23 (10 mg, 0.0405 mmol) in THF (1 ml) was treated with
aminoacetaldehyde dimethyl acetal (87 ml, 0.81 mmol) and then with Hg(OAc)2 (13 mg, 0.41 mmol). The
mixture was stirred for 35 min (complete consumption of 23), and filtered through a short plug of Celite
(washed with AcOEt). The combined org. layers (ca. 15 ml) were washed with sat. aq. NaHCO3 soln., dried
(Na2SO4), and evaporated. FC (silica gel, hexane/AcOEt 4 :1) gave 15 (7 mg, 81%), which could not be
distinguished from a sample of 15 prepared from 8.
Methyl 2,3-Di-O-acetyl-4-carbamoyl-4-deoxy-a-d-lyxopyranoside (24).
A mixture of 20 (83 mg,
0.43 mmol) in dry pyridine (1 ml) was treated with Ac2O (0.3 ml, 0.88 mmol) and DMAP (2 mg, 0.016 mmol),
stirred for 16 h at 23.58, diluted with AcOEt (25 ml), washed with H2O (5 ml) and 5% aq. HCl (5 ml), dried
(Na2SO4), and filtered through a short column (ca. 1 g of silica gel). Evaporation of the filtrate and
crystallisation from (CH2Cl2/hexane) gave 24 (92 mg, 74%). Colourless solid. Rf (hexane/AcOEt 3 :2) 0.70. M.p.
192 ± 193.38 (CH2Cl2/hexane). [a]2D5 ˆ ‡13.3 (c ˆ 0.35, CHCl3). IR (ca. 1%, CHCl3): 3408w, 3015w, 2876w,
2839w, 1749s, 1692m, 1592w, 1374m, 1255w, 1134m, 1076m, 1048m, 1024s, 973w, 904w, 877m. 1H-NMR
(300 MHz, CDCl3): 5.63 (br. s, exchanged with D2O, NH); 5.49 (dd, J ˆ 11.1, 3.3, HÀC(3)); 5.43 (br. s,
exchanged with D2O, NH); 5.21 (dd, J ˆ 3.3, 1.8, HÀC(2)); 4.67 (d, J ˆ 1.8, HÀC(1)); 3.95 (t, J ꢀ 11.4,
HaxÀC(5)); 3.86 (dd, J ˆ 11.4, 5.1, HeqÀC(5)); 3.39 (s, MeO); 3.00 (td, J ꢀ 11.1, 4.8, HÀC(4)); 2.14, 2.01 (2s, 2
AcO). 13C-NMR (75 MHz, CDCl3): 171.66 (s, H2NCˆO); 169.99, 169.54 (2s, 2 OCˆO); 98.92 (d, C(1)); 67.76
(d, C(2), C(3)); 60.23 (t, C(5)); 55.26 (q, MeO); 44.55 (d, C(4)); 20.94, 20.82 (2q, 2 Me). HR-MALDI-MS:
‡
‡
298.0893 ([M ‡ Na] , C11H17NNaO7 ; calc. 298.0897). Anal. calc. for C11H17NO7 (275.26): C 48.00, H 6.22,
N 5.09; found: C 48.17, H 6.20, N 5.02.
Methyl 2,3-Di-O-acetyl-4-(aminothiocarbonyl)-4-deoxy-a-d-lyxopyranoside (25). A stirred mixture of 24
(102 mg, 0.37 mmol) and Lawessonꢀs reagent (95 mg, 0.225 mmol) in dry toluene (2 ml) was kept at 988 for
20 min (disappearance of 24). Evaporation and FC (ca. 3 g of silica gel; hexane/AcOEt 7 :3 ! 2 :3) gave 25
(82 mg, 76%). Colourless solid. Rf (hexane/AcOEt 3 :2) 0.48. M.p. 195 ± 1978 (CH2Cl2/hexane). [a]2D5 ˆ ‡3.6
(c ˆ 1.08, CHCl3). IR (ca. 1%, CHCl3): 3488w, 3373w, 3197w, 3017w, 2839w, 1748s, 1603m, 1426w, 1374m, 1320w,
1294w, 1240s, 1133m, 1075s, 1022s, 977w, 909w, 861m. 1H-NMR (300 MHz, CDCl3): 7.61 (br. s, exchanged with
D2O, NH); 7.14 (br. s, exchanged with D2O, NH); 5.58 (dd, J ˆ 11.1, 3.3, HÀC(3)); 5.22 (dd, J ˆ 3.2, 1.8,
HÀC(2)); 4.68 (d, J ˆ 1.8, HÀC(1)); 4.03 (t, J ꢀ 11.1, HaxÀC(5)); 3.88 (dd, J ˆ 11.1, 4.8, HeqÀC(5)); 3.40 (s,
MeO); 2.83 (td, J ꢀ 11.1, 4.8, HÀC(4)); 2.14, 1.98 (2s, 2 AcO). 13C-NMR (75 MHz, CDCl3): 204.76 (s, CˆS);
169.79, 169.48 (2s, 2 CˆO); 99.05 (d, C(1)); 69.85, 68.02 (2d, C(2), C(3)); 62.94 (t, C(5)); 55.47 (q, MeO); 50.39
(d, C(4)); 21.12, 20.91 (2q, 2 Me). Anal. calc. for C11H17NO6S(291.32): C 45.35, H 5.88, N 4.78; found: C 45.17,
H 5.66, N 4.78.
Methyl 2,3-Di-O-acetyl-4-cyano-4-deoxy-a-d-lyxopyranoside (26). A soln. of 25 (52 mg, 0.178 mmol) in
THF (2 ml) was cooled to 08, treated with NH2CH2CH(OMe)2 (100 ml, 0.93 mmol) and Hg(OAc)2 (81 mg,
0.254 mmol), stirred for 5 h (consumption of 25), diluted with AcOEt (25 ml), and filtered through a short plug
of Celite (AcOEt). The filtrate (ca. 25 ml) was washed with H2O (5 ml) and brine (25 ml), dried (Na2SO4), and
evaporated. FC (ca. 2 g of silica gel; hexane/AcOEt 7:3) gave 26 (33 mg, 77%). Colourless solid. Rf (hexane/
AcOEt 7 :3) 0.38. M.p. 121 ± 1228. [a]2D5 ˆ ‡9.4 (c ˆ 0.9, CHCl3). IR (CHCl3): 3038w, 2961w, 2928s, 2841w,
2250w, 1751s, 1602w, 1463w, 1375m, 1295w, 1261m, 1156m, 1134s, 1077s, 1026m, 978w, 920w, 903w, 875w, 850m.
1H-NMR (300 MHz, CDCl3): 5.40 (dd, J ˆ 11.4, 3.0, HÀC(3)); 5.19 (dd, J ˆ 3.0, 2.1, HÀC(2)); 4.67 (d, J ˆ 2.1,
HÀC(1)); 3.98 (dd, J ˆ 11.4, 6.3, HeqÀC(5)); 3.94 (dd, J ˆ 11.4, 10.5, HaxÀC(5)); 3.41 (s, MeO); 3.26 (ddd, J ˆ
11.4, 10.5, 6.0, HÀC(4)); 2.14, 2.08 (2s, 2 Me). 13C-NMR (75 MHz, CDCl3): 169.53, 169.09 (2s, 2 CˆO); 116.44
(s, CN); 98.81 (s, C(l)); 67.02, 66.64 (2d, C(2), C(3)); 58.78 (t, C(5)); 55.71 (q, MeO); 29.22 (d, C(4)); 20.95,
20.77 (2q, 2 Me). Anal. calc. for C11H15NO6 (257.2399): C 51.36, H 5.88, N 5.44; found: C 51.48, H 5.76, N 5.43.
Methyl 4-Deoxy-4-(1H-imidazol-2-yl)-2-O-(triisopropylsilyl)-a-d-lyxopyranoside (27). A cold (38) soln. of
17 (4.3 g, 13.06 mmol) in anh. toluene (40 mmol) was treated with a premixed soln. of Me3Al and
NH2CH2CH(OMe)2 in toluene (24 ml, 21.6 mmol, ca. 0.9m), warmed slowly to 238, and kept for 26 h at 908.
The mixture was allowed to cool and treated carefully with a sat. aq. NH4Cl soln. (25 ml) to allow precipitation
of the aluminium salts. After filtration and washing with AcOEt (350 ml), the combined org. layers were washed
with H2O (2 Â 40 ml) and brine, dried (Na2SO4), and evaporated. FC (ca. 105 g, hexane/AcOEt 9 :1 ! 7:3) gave
17 (620 mg, 14%) and 27 (2.54 g, 53%). Yellow solid. Rf (AcOEt) 0.34. M.p. 113.9 ± 114.88 (hexane). [a]D25
ˆ
‡3.0 (c ˆ 1.01, CHCl3). UV (EtOH, qualitative, lmax): 210 nm. IR (1.5%, CHCl3): 3551m, 3423m, 2946s, 2869s,
1541m, 1464m, 1437m, 1371m, 1268m, 1132s, 1111s, 1086m, 1070s, 1020s, 998m, 967m, 910m, 884m, 838w.
1H-NMR (400 MHz, CDCl3; assignment based on a DQFCOSY and a HSQC spectrum): 9.98 (br. s, NH,
exchanged with D2O); 6.97 (br. s, HÀC(4'), HÀC(5')); 4.68 (d, J ˆ 2.2, HÀC(1)); 4.16 (dd, J ˆ 11.7, 5.1,
HeqÀC(5)); 4.05 (br. s, addn. of D2O ! dd, J ˆ 9.9, 3.0, HÀC(3)); 3.96 (t, J ꢀ 2.5, HÀC(2)); 3.85 (dd, J ˆ 11.7,

Helvetica Chimica Acta ± Vol. 88 (2005)
113
10.5, HaxÀC(5a)); 3.37 (s, MeO); 3.29 (td, J ꢀ 10.5, 4.8, HÀC(4)); 2.78 (br. s, exchanged with D2O, HOÀC(3));
1.14 ± 1.04 (m, (Me2CH)3Si). 13C-NMR (100 MHz, CDCl3): 146.73 (s, C(2')); 127.83 (br. d, C(4')); 115.19 (br. d,
C(5')); 101.34 (d, C(1)); 70.56 (d, C(2)); 69.82 (d, C(3)); 60.33 (t, C(5)); 55.04 (q, MeO); 38.02 (d, C(4)); 17.94
‡
‡
(q, (Me2CH)3Si); 12.57 (d, (Me2CH)3Si). HR-MALDI-MS: 393.2172 ([M ‡ Na] , C18H34N2NaO4Si ; calc.
393.2180). Anal. calc. for C18H34N2O4Si (370.23): C 58.34, H 9.25, N 7.56; found: C 58.26, H 9.18, N 7.58.
(5R/S,6S,7R,8R)-5,6,7,8-Tetrahydro-8-(hydroxymethyl)imidazo[1,2-a]pyridine-5,6,7-triol (4/28) and 4-De-
oxy-4-(1H-imidazol-2-yl)-a/b-d-lyxopyranoside (29/30). A stirred soln. of 27 (365 mg, 0.78 mmol) in 80% aq.
AcOH (6.8 ml) was treated with 20% aq. HCl (1.15 ml, ca. 2.3 mmol) was kept at 1138. After stirring for 2.5 h, it
was cooled to 248. Evaporation and FC (9 g of silica gel; AcOEt/MeOH/H2O 13 :6 :1) gave pure 4/28/29/30
‡
(182 mg, 95%), which was filtered through a short plug of Amberlite-CG 120 (H form, 2% NH4OH) and
lyophilised. Hygroscopic solid. Rf (AcOEt/MeOH/H2O 13 :6 :1) 0.52. Rf (AcOEt/MeOH/H2O 7:2 :1) 0.65.
[a]2D5 ˆ ‡0.4 (c ˆ 1.55, EtOH). IR (KBr): 3460s, 2925w, 2855w, 1631w, 1488w, 1452w, 1263w, 1172w, 1092w,
1041w, 928w, 833w. 1H-NMR (300 MHz, CD3OD; 4/28/29/30 ca. 60 :8 :14 :18): 7.08 (br. s, 0.68 H, HÀC(2) of 4/
28); 6.90 ± 6.87 (3 br. s, 1.68 H, HÀC(3) of 4/28, HÀC(4') and HÀC(5') of 29/30); 5.47 (d, J ˆ 3.6, 0.8 H), 5.32
(d, J ˆ 7.2, 0.60 H) (HÀC(5) of 4/28); 5.06 (d, J ˆ 4.8, 0.14 H), 4.67 (br. s, 0.18 H) (HÀC(1) of 29/30); 4.40 ±
3.15 (m) (HÀC(6), HÀC(7), and CH2ÀC(8) of 4, and HÀC(2), HÀC(3), HÀC(4), HÀC(5ax), and HÀC(5eq
)
of 29/30); 4.35 (dd, J ˆ 3.6, 1.5, 0.60 H, HÀC(7) of 4)); 4.20 (dd, J ˆ 10.8, 4.2, 0.60 H, CH2ÀC(8) of 4); 3.84 (dd,
J ˆ 10.8, 9.3, 0.60 H, CH2ÀC(8) of 4); 3.73 (dd, J ˆ 7.2, 1.5, 0.60 H, HÀC(6) of 4); 3.35 ± 3.15 (m, 0.32 H,
HÀC(4) of 29/30); 3.05 ± 2.98 (m), 3.01 (br. ddd, J ˆ 8.4, 4.2, 3.6, 0.6 H) (HÀC(8) of 4/28). 13C-NMR (75 MHz,
CD3OD, 4/28/29/30 ca. 60 :8 :14 :18): 147.39 (s, 0.18 C), 146.91(s, 0.14 C), 145.70 (s, 0.6 C), 144.36 (s, 0.08 C),
(C(8a) of 4/28 and C(2') of 29/30); 128.29 (d, 0.08 C), 127.42 (d, 0.6 C) (C(2) of 4/28); 122.33 (d, 0.28 C), 121.82
(d, 0.36 C) (C(4') and C(5') of 29/30); 119.68 (d, 0.08 C), 118.23 (d, 0.6 C) (C(3) of 4/28); 96.86 (d, 0.14 C),
96.04 (d, 0.18 C) (C(1) of 29/30); 81.58 (d, 0.6 C), 79.24 (d, 0.08 C) (C(5) of 4/28); 75.14 (d, 0.6 C, C(6) of 4);
71.72 (d, 0.08 C), 71.30 (d, 0.18 C), 70.85, (d, 0.14 C), 69.42 (d, 0.18 C), 69.30 (d, 0.14 C), 69.15 (d, 0.08 C) (C(6)
and C(7) of 28, C(2) and C(3) of 29/30); 70.04 (d, 0.6 C, C(7) of 4); 61.44 (t, 0.32 C), 61.43 (t, 0.6 C), 60.99 (t,
0.08 C) (CH2ÀC(8) of 4/28 and C(5) of 29/30); 42.81 (d, 0.6 C), 42.31 (d, 0.14 C), 40.75 (d, 0.08 C), 39.97 (d,
‡
0.18 C) (C(8) of 4/28 and C(4) of 29/30). HR-MALDI-MSof the HCl salts: 201.0871 ([ M ‡ HÀHCl] ,
‡
C8H13N2O4 ; calc. 201.0870).
2-Deoxy-2-(1H-imidazol-2-yl)-d-arabinitol (31). A soln. of 4/28 ± 30 (41 mg, 0.203 mmol) in dry MeOH
(1 ml) was treated with AcOH (100 ml) and NaCNBH3 (53 mg, 0.84 mmol), stirred for 60 h at 268, and
evaporated. FC (ca. 6 g of silica gel; AcOEt ! AcOEt/MeOH 9 :1 ! AcOEt/MeOH/NH4OH 7:2 :1) gave 31
(34 mg, 90%). Colourless syrup. Rf (AcOEt/MeOH/H2O 7:2 :1) 0.45. [a]2D5 ˆ À15.1 (c ˆ 0.1, EtOH). 1H-NMR
(300 MHz, CD3OD): 6.91 (br. s, HÀC(4'), HÀC(5')); 3.90 (dd, J ˆ 10.8, 7.8, irrad. at 3.44 ! change, HaÀC(5));
3.88 (dd, J ˆ 9.0, 2.7, irrad. at 3.44 ! change, irrad. at 3.11 ! change, HÀC(3)); 3.80 (dd, J ˆ 10.8, 6.6, irrad. at
3.44 ! change, HbÀC(5)); 3.67 (dd, J ˆ 11.4, 3.6, irrad. at 3.11 ! d, J ˆ 10.8, HbÀC(1)); 3.51 (dd, J ˆ 11.4, 6.3,
irrad. at 3.11 ! d, J ˆ 10.8, HaÀC(1)); 3.44 (ddd, J ˆ 7.8, 6.6, 2.7, HÀC(4)); 3.11 (ddd, J ˆ 9.6, 6.3, 3.6, irrad. at
3.51 ! change, HÀC(2)). 13C-NMR (75 MHz, CD3OD): 147.94 (s, C(2')); 122.16 (br. s, C(4'), C(5')); 73.82, 71.94
‡
(2d, C(3), C(4)); 65.21. 63.66 (2t, C(1), C(5)); 45.0 (d, C(2)). HR-MALDI-MS: 242.2839 ([ M ‡ K] ,
‡
‡
‡
‡
C8H14KN2O4 ; calc. 242.0669); 225.0846 ([M ‡ Na] , C8H14N2NaO4 ; calc. 225.0840); 203.1026 ([M ‡ H] ,
‡
C8H15N2O4 ; calc. 203.1026).
Silylation of 4/28 ± 30. A soln. of 4/28 ± 30 (470 mg, 1.99 mmol) in dry pyridine (8 ml) at 28 was treated with
2,6-lutidine (1 ml, 8.41 mmol) and Et3SiCl (3.0 ml, 17.88 mmol). The mixture was stirred for 24 h at 278, diluted
with AcOEt (200 ml), washed with H2O (5 Â 20 ml) and brine (5 ml), dried (Na2SO4), and evaporated. FC (ca.
12 g of silica gel; ca. 50 ml of AcOEt/hexane 1 :4) gave 32 (212 mg, 16%), 33 (230 mg, ca. 90% pure, 22%,) and
34 (85 mg, 8%).
(5R,6S,7R,8R)-5,6,7,8-Tetrahydro-5,6,7-tris(triethylsilyloxy)-8-[(triethylsilyloxy)methyl]imidazo[1,2-a]py-
ridine (32). Colourless oil. Rf (hexane/AcOEt 7 :3) 0.81. [a]2D5 ˆ ‡ 0.5 (c ˆ 2.9, CHCl3). IR (CHCl3): 2958s,
2913s, 2878s, 1525w, 1490w, 1458w, 1414w, 1381w, 1255m, 1156m, 1139m, 1093s, 1008s, 962w, 885w, 862w.
1H-NMR (300 MHz, CD3OD): 7.00 (d, J ˆ 1.5, HÀC(2)); 6.90 (d, J ˆ 1.2, HÀC(3)); 5.50 (d, J ˆ 5.4, HÀC(5));
4.49 (dd, J ˆ 4.2, 1.5, HÀC(7)); 4.09 (dd, J ˆ 9.9, 5.7, CHaÀC(8)); 3.93 (dd, J ˆ 9.9, 7.2, CHbÀC(8)); 3.87 (dd, J ˆ
1
5.7, 1.5, HÀC(6)); 3.20 (ddd, J ˆ 7.2, 5.7, 4.2, HÀC(8)); 1.03 ± 0.61 (m, 4 (MeCH2)3Si). H-NMR (300 MHz,
CDCl3): 6.94 (d, J ˆ 1.5, HÀC(2)); 6.91 (d, J ˆ 1.2, HÀC(3)); 5.46 (d, J ˆ 6.9, HÀC(5)); 4.41 (dd, J ˆ 3.0, 1.5,
HÀC(7)); 4.27 (dd, J ˆ 9.9, 5.1, CHaÀC(8)); 3.93 (t, J ꢀ 9.6, CHbÀC(8)); 3.87 (dd, J ˆ 6.6, 1.5, HÀC(6)); 2.93
(br. ddd, J ꢀ 9.0, 5.1, 3.0, HÀC(8)); 1.03 ± 0.56 (m, 4 (MeCH2)3Si). 13C-NMR (75 MHz, CD3OD, assignment
based on a HSQC spectrum): 146.11 (s, C(8a)); 128.89 (d, C(2)); 118.30 (d, C(3)); 82.69 (d, C(5)); 77.82 (d,

114
Helvetica Chimica Acta ± Vol. 88 (2005)
C(6)); 70.86 (d, C(7)); 61.55 (t, CH2ÀC(8)); 45.68 (d, C(8)); 7.60, 7.56, 7.42, 7.39 (4q, 4 (MeCH2)3Si); 6.28, 5.59
‡
‡
(2t, 4 (MeCH2)3Si). HR-MALDI-MS: 657.4336 ([M ‡ H] , C32H69N2O4Si4 ; calc. 657.4329).
(5R,6S,7R,8R)-5,6,7,8-Tetrahydro-5,6-bis(triethylsilyloxy)-8-[(triethylsilyloxy)methyl]imidazo[1,2-a]pyri-
din-7-ol (33). Colourless oil. Rf (hexane/AcOEt 7:3) 0.61. IR (CHCl3): 3411w, 2959s, 2813s, 2878s, 1525w,
1458m, 1414m, 1338w, 1251m, 1128s, 1090s, 1055s, 885m, 861w. 1H-NMR (300 MHz, CDCl3; ca. 90% pure): 7.00
(d, J ˆ 1.5, HÀC(2)); 6.87 (d, J ˆ 1.5, HÀC(3)); 5.46 (d, J ˆ 4.5, HÀC(5)); 4.50 (ddd, J ˆ 6.3, 4.2, 2.1, irrad. at
3.36 ! change, irrad. at 4.19 ! dd, J ˆ 6.3, 2.1, addn. of D2O ! dd, J ˆ 6.3, 2.1, HÀC(7)); 4.30 ± 4.28 (m, irrad. at
3.36 ! s, CH2ÀC(8)); 4.19 (d, J ˆ 3.9, HOÀC(7), exchanged with D2O); 4.01 (dd, J ˆ 4.8, 2.1, irrad. at 5.46 ! d,
J ˆ 2.1, HÀC(6)); 3.36 (ddd, J ˆ 8.4, 6.9, 5.4, irrad. at 4.50 ! br. dd, J ˆ 7.8, 7.2, HÀC(8)); 1.00 ± 0.94 (m, 3
(MeCH2)3Si); 0.71 ± 0.66 (m, 3 (MeCH2)3Si). 13C-NMR (75 MHz, CDCl3): 143.17 (s, C(8a)); 128.99 (d, C(2));
117.15 (d, C(3)); 81.16 (d, C(5)); 76.31 (d, C(6)); 68.76 (d, C(7)); 64.10 (t, CH2ÀC(8)); 40.35 (d, C(8)); 6.99,
‡
6.93, 6.88 (3q, 3 (MeCH2)3Si); 5.19, 5.17, 4.46 (3t, 3 (MeCH2)3Si). HR-MALDI-MS: 565.3283 ([M ‡ Na] ,
‡
C26H54O5N2NaSi3 ; calc. 565.3284).
(5S,6S,7R,8R)-5,6,7,8-Tetrahydro-5,6-bis(triethylsilyloxy)-8-[(triethylsilyloxy)methyl]imidazo[1,2-a]pyri-
din-7-ol (34). Colourless solid. Rf (hexane/AcOEt 7:3) 0.33. [a]2D5 ˆ À17.0 (c ˆ 0.65, CHCl3). IR (CHCl3):
3506w, 2958s, 2913s, 2878s, 1488m, 1458m, 1378w, 1263m, 1143s, 1119s, 1103s, 1078s, 1007s, 976s, 956m, 864m.
1H-NMR (300 MHz, CDCl3): 7.01 (d, J ˆ 1.2, HÀC(2)); 6.87 (d, J ˆ 1.5, HÀC(3)); 5.60 (dd, J ˆ 3.9, 1.8,
HÀC(5)); 4.46 (dd, J ˆ 9.6, 4.5, CHaÀC(8)); 4.37 (m, addn. of D2O ! dt, J ꢀ 3.9, 2.1, HÀC(7)); 4.14 (dd, J ˆ
10.6, 9.6, CHbÀC(8)); 4.19 (d, J ˆ 7.2, HOÀC(7)); 3.99 (dd, J ˆ 3.3, 2.4, HÀC(6)); 2.93 (dt, J ˆ 10.8, 4.2,
HÀC(8)); 1.04 ± 0.94 (m, 3 (MeCH2)3Si); 0.73 ± 0.64 (m, 3 (MeCH2)3Si). 13C-NMR (75 MHz, CDCl3): 142.64 (s,
C(8a)); 129.38 (d, C(2)); 117.42 (d, C(3)); 80.38 (d, C(5)); 70.70, 69.35 (2d, C(6), C(7)); 59.32 (t, CH2ÀC(8));
42.95 (d, C(8)); 6.99, 6.87, 6.70 (3q, 3 (MeCH2)3Si); 5.08, 4.62 (2t, 3 (MeCH2)3Si). HR-MALDI-MS: 543.3469
‡
‡
([M ‡ H] , C26H55N2O4Si3 ; calc. 565.3464).
Methyl 4-Cyano-4-deoxy-3-O-[(trifluoromethyl)sulfonyl]-2-O-(triisopropylsilyl)-a-d-lyxopyranoside (36).
At À 158, a soln. of 17 (409 mg, 1.24 mmol) in pyridine (2 ml) was treated dropwise with Tf2O (307 ml,
1.86 mmol). The mixture was stirred for 7 h (disappearance of 17), diluted with CH2Cl2 (30 ml), washed with
10% aq. HCl soln. (5 ml), H2O (5 ml) and brine (5 ml), and dried (Na2SO4). Evaporation and FC (20 g of silica
gel; AcOEt/hexane 1:19 ! 3 :17) gave 36 (548 mg, 99%). Colourless oil. Rf (hexane/AcOEt 17:3) 0.46. [a]D25
ˆ
À28.2 (c ˆ 0.54, CHCl3). IR (CHCl3): 2946m, 2893w, 2869m, 2254w, 1464m, 1421s, 1370w, 1339m, 1168s, 1144s,
1067s, 1041m, 1013w, 963s, 909m, 882m, 858s. 1H-NMR (300 MHz, CDCl3): 5.17 (dd, J ꢀ 11, 2.4, HÀC(3)); 4.65
(d, J ˆ 1.8, HÀC(1)); 4.29 (t, J ꢀ 2.4, HÀC(2)); 4.0 (dd, J ˆ 11.4, 5.1, HeqÀC(5)); 3.85 (t, J ꢀ 11.1, HaxÀC(5));
3.57 (td, J ꢀ 11.1, 5.1, HÀC(4)); 3.39 (s, MeO); 1.29 ± 1.06 (m, (Me2CH)3Si). 13C-NMR (75 MHz, CDCl3): 118.38
(q, 1J(C,F) ˆ 317, CF3); 115.32 (s, CꢁN); 101.27 (d, C(1)); 82.97 (d, C(3)); 69.04 (d, C(2)); 59.13 (t, C(5)); 55.56
(q, MeO); 29.18 (d, C(4)); 17.92, 17.89 (2q, (Me2CH)3Si); 12.58 (d, (Me2CH)3Si).
Methyl 4-Cyano-3,4-dideoxy-2-O-(triisopropylsilyl)-b-l-glycero-pent-3-enopyranoside (38). At 28, a soln.
of 36 (325 mg, 0.704 mmol) in dry DMF (2 ml) was treated slowly with CsOAc (157 mg, 0.82 mmol), stirred for
3 h (disappearance of 36), diluted with AcOEt (25 ml), washed with H2O (2 Â 10 ml) and brine (10 ml), and
dried (Na2SO4). Evaporation and FC (ca. 6 g of silica gel; AcOEt/hexane 3 :97) gave 38 (198 mg, 90%).
Colourless oil. Rf (AcOEt/hexane 1:9) 0.51. [a]D25 ˆ ‡175.5 (c ˆ 0.78, CHCl3). IR (CHCl3): 3026w, 2946s, 2868s,
1
2226w, 1464m, 1412w, 1391w, 1371w, 1216s 1152s, 1102s, 1050s, 918w, 882m. H-NMR (300 MHz, CDCl3): 6.54
(dtd, J ꢀ 3.6, 2.1, 0.6, HÀC(3)); 4.62 (br. d, J ˆ 3.0, HÀC(1)); 4.21 (dt, J ꢀ 16.2, 2.2, HÀC(5)); 4.20 (dt, J ꢀ 16.2,
2.2, H'ÀC(5)); 4.08 (ddt, J ꢀ 3.6, 3.0, 2.2, HÀC(2)); 3.47 (s, MeO); 1.15 ± 1.03 (m, Me2(CH)3Si). 13C-NMR
(75 MHz, CDCl3): 141.37 (d, C(3)); 115.75 (s, CꢁN); 113.73 (s, C(4)); 102.08 (d, C(1)); 65.12 (d, C(2)); 60.21 (t,
C(5)); 56.44 (q, MeO); 18.10, 18.07 (2q, (Me2CH)3Si); 12.40 (d, (Me2CH)3Si). Anal. calc. for C16H29NO3Si
(311.49): C 61.69, H 9.38, N 4.50; found: C 61.63, H 9.43, N 4.69.
Methyl 4-Cyano-4-deoxy-3-O-(methylsulfonyl)-2-O-(triisopropylsilyl)-a-d-lyxopyranoside (37). An ice-
cold soln. of 17 (353 mg, 1.07 mmol) in pyridine (2 ml) was treated dropwise with MsCl (160 ml, 2.06 mmol),
warmed to 238 (ca. 2 h) and stirred for 20 h (disappearance of 17). The mixture was diluted with AcOEt (30 ml),
washed with 10% aq. HCl soln., H2O (10 ml) and brine (5 ml), and dried (MgSO4). Evaporation and FC (2 g of
silica gel; AcOEt/hexane/ (3 :15) gave 37 (389 mg, 89%). Colourless solid. Rf (hexane/AcOEt 3 :17) 0.10. M.p.
73.1 ± 73.88. [a]D25 ˆ À19.6 (c ˆ 0.55, CHCl3). IR (CHCl3): 3015w, 2945s, 2892m, 2869s, 2250w, 1464m, 1412w,
1371s, 1351m, 1179s, 1166m, 1066s, 1044m, 1013m, 990m, 964s, 909m, 882m, 844s. 1H-NMR (300 MHz, CDCl3):
5.01 (dd, J ˆ 11.1, 2.7, HÀC(3)); 4.62 (d, J ˆ 1.8, HÀC(1)); 4.26 (t, J ꢀ 2.4, HÀC(2)); 3.97 (dd, J ˆ 11.1, 5.1,
HeqÀC(5)); 3.86 (t, J ꢀ 11.1, HaxÀC(5)); 3.48 (td, J ꢀ 11.4, 5.4, HÀC(4)); 3.39 (s, MeO); 3.18 (s, MsO); 1.29 ±
1.06 (m, (Me2CH)3Si). 13C-NMR (75 MHz, CDCl3): 117.21 (s, CꢁN); 101.60 (d, C(1)); 76.05 (d, C(3)); 69.24 (d,

Helvetica Chimica Acta ± Vol. 88 (2005)
115
C(2)); 59.19 (t, C(5)); 55.67 (q, MeO); 38.83 (q, MsO); 29.14 (d, C(4)); 18.15 (q, (Me2CH)3Si); 12.62 (d,
(Me2CH)3Si). Anal. calc. for C17H33NO6SSi (407.598): C 50.09, H 8.16, N 3.44; found: C 50.21, H 8.03, N 3.40.
Methyl 4-{1-[(tert-Butoxy)carbonyl]-1H-imidazol-2-yl}-4-deoxy-2-O-(triisopropylsilyl)-a-d-lyxopyrano-
side (39). A soln. of 27 (1.288 g, 3.48 mmol) in anh. MeCN (12 ml) was treated with Boc2O (987 mg, 4.5 mmol)
and DMAP (47 mg, 0.385 mmol). The mixture was stirred at 248 for 4 h (disappearance of 27), and evaporated.
A soln. of the residue in AcOEt (30 ml) was washed with H2O (10 ml) and brine (10 ml), dried (Na2SO4), and
evaporated. The resulting thick oil was used for the next step without further purification. An anal. sample of 39
was obtained by FC (silica gel; hexane/AcOEt 4 :1). Colourless oil. Rf (hexane/AcOEt 7:3) 0.42. [a]2D5 ˆ ‡20.5
(c ˆ 0.7, CHCl3). IR (CHCl3): 3556w, 2945s, 2868m, 1750s, 1465m, 1414m, 1372m, 1307s, 1264w, 1142s, 1068s,
1021s, 971w, 908s. 1H-NMR (300 MHz, CDCl3): 7.28 (d, J ˆ 1.8, HÀC(5')); 6.88 (d, J ˆ 1.8, irrad. at 7.29 ! s,
HÀC(4')); 4.68 (d, J ˆ 1.8, irrad. at 4.09 ! s, HÀC(1)); 4.26 ± 4.18 (m, addn. of D2O ! change, irrad. at 3.97 !
change, HÀC(3), HÀC(4)); 4.09 (t, J ꢀ 2.2, irrad. at 4.68 ! d, J ˆ 2.4, irrad. at 4.20 ! br. s, HÀC(2)); 3.97 (t, J ꢀ
10.8, irrad. at 4.20 ! d, J ˆ 10.8, HaxÀC(5)); 3.81 (dd, J ˆ 10.8, 3.6, irrad. at 4.20 ! d, J ˆ 10.8, irrad. at 3.97 !
change, HeqÀC(5)); 3.36 (s, MeO); 2.81 (d, J ˆ 9.3, irrad. at 4.20 ! br. s, exchanged with D2O, HOÀC(3)); 1.60
(s, Me3C); 1.14 ± 1.08 (m, (Me2CH)3Si). 13C-NMR (75 MHz, CDCl3): 149.07 (s, CˆO); 148.26 (s, C(2')); 127.68
(d, C(4')); 118.72 (d, C(5')); 102.04 (d, C(1)); 85.68 (s, Me3C); 71.18, 70.93 (2d, C(2), C(3)); 61.68 (t, C(5)); 55.02
(q, MeO); 38.59 (d, C(4)); 28.01 (q, Me3C); 18.20, 18.18 (2q, (Me2CH)3Si); 12.74 (d, (Me2CH)3Si). HR-
‡
‡
MALDI-MS: 493.2700 ([ M ‡ Na] , C23H42N2NaO6Si ; calc. 493.2704). Anal. calc. for C23H42N2O6Si (470.68):
C 58.69, H, 8.99, N 5.95; found: C 58.70, H, 8.94, N 5.85.
Oxidation of 39 with Periodinane. At 38, a soln. of 39 (1.2 g of crude product, 3.48 mmol) in anh. CH2Cl2
(8 ml) was treated with Dess ± Martinꢂs periodinane (1.24 g, 2.91 mmol). The mixture was stirred until
disappearance of 39 (ca. 3 ± 4 h), diluted with Et2O (50 ml), and treated with sat. aq. NaHCO3 soln. (20 ml). The
aq. layer was washed with Et2O (50 ml). The combined org. layers were washed with sat. aq. NaHCO3 soln. (3 Â
20 ml), dried (Na2SO4), and evaporated. FC (22 g of silica gel; hexane/AcOEt 4 :1) gave 40 (975 mg, 60% from
27) and a mixture of 40 and 41 (522 mg, 32% from 27).
Methyl 4-{1-[(tert-Butoxy)carbonyl]-1H-imidazol-2-yl}-4-deoxy-2-O-(triisopropylsilyl)-a-d-threo-pento-
pyranosid-3-ulose (40). Colourless solid. Rf (hexane/AcOEt 7:3) 0.45. M.p. 83.8 ± 85.18. [a]2D5 ˆ ‡64.1 (c ˆ
1.0, CHCl3). IR (3%, CHCl3): 2945s, 2868m, 1761s, 1741s, 1542w, 1499w, 1465m, 1412m 1372s, 1339s, 1309s,
1264w, 1165s, 1141s, 1066s, 1044s, 1004m, 941w, 883m, 844m. 1H-NMR (300 MHz, CDCl3; assignment based on a
DQFCOSYand a HSQC spectrum): 7.32 (d, J ˆ 1.8, HÀC(5')); 6.90 (d, J ˆ 1.8, HÀC(4')); 5.27 (dd, J ˆ 11.1, 6.6,
HÀC(4)); 4.87 (d, J ˆ 2.4, HÀC(1)); 4.53 (t, J ꢀ 11.0, HaxÀC(5)); 4.28 (dd, J ˆ 11.1, 6.6, HeqÀC(5)); 4.11 (d, J ˆ
1.8, HÀC(2)); 3.41 (s, MeO); 1.54 (s, Me3C); 1.19 ± 1.13 (m, (Me2CH)3Si)); 1.11, 1.09 (2d, J ˆ 6.6, (Me2CH)3Si).
13C-NMR (75 MHz, CDCl3): 201.12 (s, C(3)); 148.25 (s, C(2')); 147.18 (s, OCˆO); 127.76 (d, C(4')); 118.71 (d,
C(5')); 104.76 (d, C(1)); 85.08 (s, Me3C); 76.67 (d, C(2)); 62.57 (t, C(5)); 55.15 (q, MeO); 47.80 (d, C(4)); 27.92
‡
(q, Me3C); 18.04 (br. q, (Me2CH)3Si); 12.27 (d, (Me2CH)3Si). HR-MALDI-MS: 492.2587 ([M ‡ Na] ,
‡
C23H40N2NaO6Si ; calc. 492.2593). Anal. calc. for C23H40N2O6Si (468.66): C 58.94, H 8.60, N 5.98; found:
C 58.89, H 8.44, N 5.92.
Methyl 4-{1-[(tert-Butoxy)carbonyl]-1H-imidazol-2-yl}-4-deoxy-2-O-(triisopropylsilyl)-b-d-erthyro-pento-
pyranosid-3-ulose (41). Colourless oil. Rf (hexane/AcOEt 4 :1) 0.15. [a]2D5 ˆ À14.3 (c ˆ 0.2, CHCl3). IR
(CHCl3): 2945m, 2892m, 2868m, 1758s, 1603w, 1544w, 1465m, 1413m 1372m, 1340m, 1309s, 1261w, 1139s, 1116s,
1
1104s, 1070m, 1020m, 997w, 969w, 919w, 884m, 844w. H-NMR (300 MHz, CDCl3): 7.34 (d, J ˆ 1.8, HÀC(5'));
6.87 (d, J ˆ 1.8, HÀC(4')); 4.63 (dd, J ˆ 11.4, 6.6, HÀC(4)); 4.51 (dd, J ˆ 11.4, 6.3, HeqÀC(5)); 4.34 (d, J ˆ 7.5,
HÀC(1)); 4.30 (d, J ˆ 7.5, HÀC(2)); 4.13 (t, J ꢀ 11.4, HaxÀC(5)); 3.59 (s, MeO); 1.54 (s, Me3C); 1.19 ± 1.13 (m,
(Me2CH)3Si). 13C-NMR (75 MHz, CDCl3): 200.62 (s, C(3)); 147.18 (s, OCˆO); 143.53 (s, C(2')); 127.76 (d,
C(4')); 118.95 (d, C(5')); 107.40 (d, C(1)); 85.44 (s, Me3C); 70.78 (d, C(2)); 63.65 (t, C(5)); 57.15 (q, MeO); 51.28
(d, C(4)); 27.93 (q, Me3C); 18.02, 17.94 (2q, (Me2CH)3Si); 12.57 (d, (Me2CH)3Si). HR-MALDI-MS: 492.2587
‡
‡
([M À Boc ‡ Na] , C23H40N2NaO6Si ; calc. 492.2593).
Methyl 4-{1-[(tert-Butoxy)carbonyl)]-1H-imidazol-2-yl}-4-deoxy-2-O-(triisopropylsilyl)-a-d-arabinopyra-
noside (42). a) At 3 ± 58, a soln. of 40 (975 mg, 2.08 mmol) in dry MeOH (10 ml) was treated with NaBH4
(38 mg, 1.03 mmol). The mixture was stirred for 1 h (disappearance of 40), treated with sat. aq. NH4Cl soln.
(10 ml), and evaporated. The aq. residue was diluted with AcOEt (100 ml). The org. layer was separated,
washed with H2O (20 ml) and brine (20 ml), dried (Na2SO4), and evaporated. FC (ca. 23 g of silica gel; hexane/
AcOEt 7:3) gave 39 (469 mg, 48%), 42 (265 mg, 25%), and an inseparable mixture (240 mg, 25%).
b) At 08, a soln. of 40 (155 mg, 0.33 mmol) in dry MeOH (2 ml) was treated with CeCl3 ´ 7 H2O (130 mg,
0.35 mmol) and NaBH4 (8.6 mg, 0.23 mmol), stirred for 20 min (disappearance of 40), treated with sat. aq.
NH4Cl soln. (10 ml), and diluted with AcOEt (60 ml). The org. layer was separated, washed with brine (5 ml),

116
Helvetica Chimica Acta ± Vol. 88 (2005)
dried (Na2SO4), and evaporated. FC (3 g of silica gel, hexane/AcOEt 7:3) provided 42 (124 mg, 80%).
Colourless oil. Rf (hexane/AcOEt 7:3) 0.34. [a]D25 ˆ À52.1 (c ˆ 1.0, EtOH). IR (CHCl3): 3507w, 3342w, 2945m,
2868m, 1762s, 1602w, 1542w, 1464w, 1373m, 1305s, 1141s, 1101m, 1073w, 1038m, 882w. 1H-NMR (300 MHz,
CDCl3; assignment based on a DQFCOSY and a HSQC spectrum): 7.34 (d, J ˆ 1.8, HÀC(5')); 6.86 (d, J ˆ 1.8,
HÀC(4')); 4.95 (d, J ˆ 5.4, exchanged with D2O, HOÀC(3)); 4.63 (br. s, HÀC(1)); 4.29 (t, J ꢀ 11.8, irrad. at
3.70 ! change, HaxÀC(5)); 4.28 ± 4.22 (overlapped m, addn. of D2O ! change, HÀC(3)); 4.15 (ddd, J ꢀ 11.1,
4.0, 2.1, irrad. at 3.70 ! change, HÀC(4)); 3.95 (dd, J ˆ 3.0, 1.2, irrad. at 4.63 ! d, J ˆ 3.3, HÀC(2)); 3.70 (ddd,
J ꢀ 10.8, 4.0, 1.2, HeqÀC(5)); 3.39 (s, MeO); 1.62 (s, Me3C); 1.08 (br. s, (Me2CH)3Si). 13C-NMR (75 MHz,
CDCl3): 149.10 (s, OCˆO); 147.27 (s, C(2')); 127.11 (d, C(4')); 118.69 (d, C(5')); 101.88 (d, C(1)); 85.82 (s,
Me3C); 70.10 (d, C(2)); 69.14 (d, C(3)); 59.96 (t, C(5)); 55.85 (q, MeO); 36.10 (d, C(4)); 27.99 (q, Me3C); 18.21,
‡
‡
18.06 (2q, (Me2CH)3Si); 12.40 (d, Me2CH)3Si). HR-MALDI-MS: 493.2700 ([M ‡ Na] , C23H42O6N2NaSi ; calc.
493.2710). Anal. calc. for C23H42N2O6Si´ 0.25 H2O (475.18): C 58.14, H 9.04, N 5.90; found: C 57.96, H 8.57, N 5.73.
Methyl 3-O-[(tert-Butoxy)carbonyl)-4-deoxy-4-(1H-imidazol-2-yl)-2-O-(triisopropylsilyl)-a-d-arabinopy-
ranoside (43). A soln. of 42 (17 mg, 0.36 mmol) in dry MeOH/Et3N 10 :1 (1.1 ml) was stirred at 238 for 5 h
(disappearance of 42) and evaporated. FC (5 g of silica gel, hexane/AcOEt 7:3) gave 43 (12 mg, 71%).
Colourless solid. M.p. 124.8 ± 126.28. Rf (hexane/AcOEt 7:3) 0.45. [a]2D5 ˆ À32.9 (c ˆ 0.30, CHCl3). IR (CHCl3):
3246w, 2962m, 2946m, 2868m, 1744s, 1545w, 1464m, 1395w, 1370w, 1280s, 1262s, 1130s, 1099s, 1080s, 1040s, 999s,
919w, 882m, 846m, 821m. 1H-NMR (300 MHz, CDCl3, assignment based on a DQFCOSY and a HSQC
spectrum): 7.00 (br. s, HÀC(4'); 6.96 (br. s, HÀC(5')); 4.85 (dd, J ˆ 6.0, 4.2, irrad. at 3.85 ! change, HÀC(3));
4.40 (d, J ˆ 4.5, irrad. at 3.85 ! s, HÀC(1)); 4.25 (dd, J ˆ 10.6, 6.0, irrad. at 3.75 ! change, HaxÀC(5)); 3.85 (dd,
J ˆ 6.0, 4.5, irrad. at 4.40 ! d, J ˆ 6.0, irrad. at 4.85 ! d, J ˆ 4.5, HÀC(2)); 3.83 (dt, J ˆ 6.0, 4.2, HÀC(4)); 3.78
(dd, J ˆ 10.6, 4.2, HeqÀC(5)); 3.46 (s, MeO); 1.45 (s, Me3C); 1.08 ± 1.04 (m, (Me2CH)3Si). 13C-NMR (75 MHz,
CDCl3, assignment based on a DQFCOSY and a HSQC spectrum): 152.80 (s, OCˆO); 144.96 (s, C(2')); 128.22
(d, C(4')); 115.80 (d, C(5')); 103.50 (d, C(1)); 82.80 (s, Me3C); 75.59 (d, C(3)); 69.67 (d, C(2)); 60.81 (t, C(5));
56.39 (q, MeO); 36.94 (d, C(4)); 27.84 (q, Me3C); 18.10 (q, (Me2CH)3Si); 12.37 (d, (Me2CH)3Si). HR-MALDI-
‡
‡
MS: 471.2875 ([ M ‡ H] , C23H43N2O6Si ; calc. 471.2885). Anal. calc. for C23H42N2O6Si (470.68): C 58.69, H 8.99,
N 5.95; found: C 58.94, H 9.07, N 5.90.
Methyl 4-{1-[(tert-Butoxy)carbonyl]-1H-imidazol-2-yl}-4-deoxy-2-O-(triisopropylsilyl)-b-d-xylopyrano-
side (44). A cold soln. of 41 (70 mg, 0.15 mmol) in dry MeOH (2 ml) was treated with NaBH4 (6.5 mg,
0.17 mmol). The mixture was stirred for 1 h (disappearance of 41), treated with sat. aq. NH4Cl soln. (1 ml), and
evaporated. The aq. residue was diluted with AcOEt (20 ml). The org. layer was separated and washed with
H2O (5 ml) and brine (5 ml), dried (Na2SO4), and evaporated. FC (ca. 6 g of silica gel, hexane/AcOEt 17:3)
gave 44 (38 mg, 54%). Colourless oil. Rf (hexane/AcOEt 7:3) 0.45. [a]2D5 ˆ ‡57.8 (c ˆ 0.47, CHCl3). IR (CHCl3):
3588w, 3018w, 2962m, 2945m, 2867m, 1760m, 1463w, 1372m, 1353w, 1306s, 1262m, 1140s, 1099m, 1071m, 1034m,
1
988w, 908w, 883m, 842m. H-NMR (300 MHz, CDCl3): 7.32 (d, J ˆ 1.8, HÀC(5')); 6.91 (d, J ˆ 1.8, HÀC(4'));
4.20 (ddd, J ˆ 10.5, 8.7, 3.6, irrad. at 3.83 ! change, irrad. at 3.59 ! change, irrad. at 2.78 ! dd, J ˆ 10.5, 8.7, addn.
of CD3OD ! dd, J ˆ 10.5, 8.7, HÀC(3)); 4.17 (d, J ˆ 7.5, irrad. at 3.59 ! change, HÀC(1)); 4.13 (dd, J ˆ 11.1, 4.2,
irrad. at 3.80 ! change, HeqÀC(5)); 3.80 (td, J ꢀ 10.5, 4.2, HÀC(4)); 3.59 (dd, J ˆ 8.7, 7.5, HÀC(2)); 3.49 (s,
MeO); 3.47 (dd, J ˆ 11.1, 10.8, irrad. at 3.80 ! change HaxÀC(5)); 2.78 (d, J ˆ 3.6, exchanged with CD3OD,
HOÀC(3)); 1.61 (s, Me3C); 1.18 ± 1.05 (m, (Me2CH)3Si)). 13C-NMR (75 MHz, CDCl3): 147.69, 147.20 (2s, CˆO,
C(2')); 127.74 (d, C(4')); 119.13 (d, C(5')); 105.46 (d, C(1)); 86.0 (s, Me3C); 76.63, 75.13 (d, C(2), C(3)); 65.01 (t,
C(5)); 56.78 (q, MeO); 43.22 (d, C(4)); 27.94 (q, Me3C); 18.26, 18.21 (2q, (Me2CH)3Si); 12.73 (d, (Me2CH)3Si).
‡
‡
HR-MALDI-MS: 493.2587 ([ M ‡ Na] , C23H42N2NaO6Si ; calc. 493.2593).
(5R,6S,7R,8R)- and (5S,6S,7R,8R)-5,6,7,8-Tetrahydro-8-(hydroxymethyl)-imidazo[1,2-a]pyridine-5,6,7-tri-
ol (5 and 45, resp.). A soln. of 42 (365 mg, 0.78 mmol) in 80% aq. AcOH (6.8 ml) was treated with 20% aq. HCl
(1.15 ml, ca. 2.3 mmol). The stirred mixture was kept for 2.5 h at 1138 and evaporated. FC (9 g of silica gel;
‡
AcOEt/MeOH/H2O 13 :6 :1) and filtration through Amberlite-CG-120 (H form, 2% aq. NH4OH) gave 5/45
(182 mg, 95%). Light yellow hygroscopic solid. M.p. 180 ± 1858 (dec.). 1H-NMR (300 MHz, CD3OD; 5/45
47:53, > 95% pure): 7.14 (d, J ˆ 1.2, 0.47 H), 7.10 (d, J ˆ 1.5, 0.53 H) (HÀC(2)); 6.97 (d, J ˆ 1.5, 0.53 HÀC(3));
6.89 (d, J ˆ 1.2, 0.47 HÀC(3)); 5.89 (d, J ˆ 3.6, 0.53 HÀC(5)); 5.15 (d, J ˆ 7.2, 0.47 HÀC(5)); 4.27 (dd, J ˆ 8.4,
7.5, irrad. at 2.83 ! change, 0.53 H, HÀC(7)); 4.24 (dd, J ˆ 10.8, 3.6, irrad. at 2.83 ! change, 0.53 H), 4.17 (dd,
J ˆ 10.5, 3.9, irrad. at 2.83 ! change, 0.53 H), 4.08 (br. dd, J ˆ 9.6, 3.6, irrad. at 2.83 ! change, 0.47 H), 4.04 (dd,
J ˆ 10.5, 3.9, irrad. at 2.83 ! change, 0.47 H) (CH2ÀC(8)); 3.93 (t, J ˆ 9.3, 0.47 HÀC(7)); 3.85 (dd, J ˆ 8.7, 3.6,
irrad. at 5.89 ! d, J ˆ 8.7, 0.53 HÀC(6)); 3.64 (dd, J ˆ 9.6, 7.2, 0.47 HÀC(6)); 2.97 ± 2.79 (m, HÀC(8)).
Data for 5/45 ´ HCl: Hygroscopic solid. Rf (AcOEt/MeOH/H2O 13 :6 :1) 0.52. [a]2D5 ˆ À52.1 (c ˆ 1.0,
EtOH). IR (KBr): 3400w, 2936m, 1634s, 1535w, 1490m, 1461m, 1376m, 1325m, 1267m, 1176w, 1131s, 1090s,

Helvetica Chimica Acta ± Vol. 88 (2005)
117
1
1067s, 1004m, 938w, 903w, 814w. H-NMR (300 MHz, CD3OD; 5/45 ca. 1:1): 7.22, 7.21 (2d, J ˆ 1.5, HÀC(2));
7.04, 7.03 (2d, J ˆ 1.5, HÀC(3)); 5.72 (d, J ˆ 3.6, 0.5 H, HÀC(5) of 45); 5.26 (d, J ˆ 6.6, 0.5 H, HÀC(5) of 5);
4.26 (dd, J ˆ 11.4, 3.3, 0.5 H, HÀC(7) of 45); 4.21 (dd, J ˆ 12.1, 3.3, 0.5 H, CHaÀC(8) of 45); 4.10 (t, J ꢀ 9.0, 0.5
H, HÀC(7) of 5); 3.98 ± 3.90 (m, 1 H), 3.81 ± 3.70 (m, 1.5 H), (CHbÀC(8) of 45, CH2ÀC(8) of 5, HÀC(6));
3.04 ± 2.97 (m, HÀC(8)). 13C-NMR (75 MHz, CD3OD; 5/45 ca. 1:1): 145.95, 145.30 (2s, C(8a)); 128.58, 128.48
(2d, C(2)); 119.34, 117.81 (2d, C(3)); 82.44 (d, C(5) of 45); 78.40 (d, C(5) of 5); 76.53 (d, C(6) of 45); 72.39 (d,
C(6) of 5); 71.84, 70.93, 70.79, 68.83 (4d, C(2), C(3)); 69.70, 67.55 (2d, C(7)); 62.47, 61.78 (2t, CH2ÀC(8)); 45.05,
‡
‡
44.95 (2d, C(8)). HR-MS-MALDI: 201.0872 ([M ‡ HÀHCl] , C8H13O4N2 ; calc. 201.0870).
4-Deoxy-4-(1H-imidazol-2-yl)-d-arabinitol (46). A cold soln. of 5/45 (43 mg, 0.18 mmol) in MeOH (2 ml)
was treated at 08 with AcOH (0.2 ml) and NaCNBH3 (41 mg, 0.65 mmol), warmed to 288, stirred at that temp.
for 60 h, and co-evaporated with toluene. FC (AcOEt/MeOH/25% aq. NH4OH 14 :5 :1) gave slightly impure 46,
which, upon additional FC (AcOEt/MeOH/25% NH4OH, 7:2 :1), gave 46 ´ HOAc (22 mg, 66%). Hygroscopic
solid. [a]2D5 ˆ À2.9 (c ˆ 0.1, EtOH). Rf (AcOEt/MeOH/25% aq. NH4OH, 7:2 :1) 0.26. IR (KBr): 3427s, 2925w,
2558w, 1666s, 1624s, 1442m, 1366s, 1032w, 1047w, 998w, 834s. 1H-NMR (300 MHz, CD3OD, 46 ´ HOAc): 7.11 (br.
s, HÀC(4'), HÀC(5')); 3.95 ± 3.85 (m, 2 HÀC(1)); 3.93 (dd, J ˆ 9.0, 1.8, irrad. at 3.04 ! dd, J ˆ 9.0, HÀC(3));
3.48 (dd, J ˆ 10.8, 6.0, HaÀC(5)); 3.41 (dd, J ˆ 10.8, 6.0, irrad. at 3.04 ! change, HbÀC(5)); 3.34 (ddd, J ꢀ 9.0,
6.3, 5.1, HÀC(2)); 3.04 (td, J ˆ 6.0, 1.8, HÀC(4)); 1.83 (s, AcO). 13C-NMR (75 MHz, CD3OD, 46 ´ HOAc):
179.31 (s, CˆO); 148.40 (s, C(1')); 121.06 (d, C(4'), C(5')); 72.97, 71.33 (2d, C(2), C(3)); 64.56, 63.32 (2t, C(1),
‡
‡
C(5)); 45.83 (d, C(4)); 22.95 (q, Me). ESI-MS: 203.3 ([M ‡ H] , C8H15N2O4 ; calc. 203.3).
Silylation of 5/45. At 28, a soln. of 5/45 (31 mg, 0.131 mmol) in dry pyridine (2.5 ml) was treated with 2,6-
lutidine (0.07 ml) and Et3SiCl (0.2 ml), stirred for 46 h at 268, diluted with AcOEt (25 ml), washed with H2O
(2 Â 5 ml) and brine (5 ml), dried (Na2SO4), and evaporated. FC (3 g of silica gel; ca. 50 ml of AcOEt/hexane
1:9) gave 47/48 ca. 1:4 (14 mg, 16%) and 47/48 ca. 85 :17 (27 mg, 31%).
(5R,6S,7R,8R)-5,6,7,8-Tetrahydro-5,6,7-tris(triethylsilyloxy)-8-[(triethylsilyloxy)methyl]imidazo[1,2-a]py-
ridine (48): Data for a ca. 1:4 Mixture 47/48. Colourless oil. Rf (hexane/AcOEt 9 :1) 0.31. [a]2D5 ˆ ‡8.5 (c ˆ 0.6,
CHCl3). IR (CHCl3): 2958s, 2913s, 2878s, 1526w, 1485w, 1458m, 1414m 1378w, 1259w, 1094w, 1007s, 973w, 921w,
1
887w, 833m. H-NMR (300 MHz, CDCl3; 47/48 ca. 1 :4): 7.00 (d, J ˆ 1.5, HÀC(2)); 6.92 (d, J ˆ 1.2, HÀC(3));
5.42 (dd, J ˆ 1.8, 0.9, irrad. at 4.49 ! d, J ˆ 1.8, HÀC(5)); 4.49 (ddd, J ꢀ 3.6, 1.2, 0.9, irrad. at 5.42 ! dd, J ˆ 3.3,
1.2, HÀC(7)); 4.07 (dd, J ˆ 3.6, 1.8, irrad. at 5.42 ! d, J ˆ 3.9, irrad. at 4.49 ! d, J ˆ 1.8, HÀC(6)); 4.07 (dd, J ˆ
9.6, 5.4, CHaÀC(8)); 3.75 (dd, J ˆ 11.0, 9.6, irrad. at 4.07 ! d, J ꢀ 11.0, CHbÀC(8)); 3.20 (ddd, J ˆ 10.5, 5.1, 0.5,
irrad. at 4.49 ! dd, J ˆ 10.5, 5.4, irrad at 4.07 ! dd, J ˆ 10.5, 0.5, HÀC(8)); 1.04 ± 0.55 (m, 4 (MeCH2)3Si).
13C-NMR (75 MHz, CDCl3; 47/48 ca. 1:4): 143.13 (s, C(8a)); 128.50 (d, C(2)); 117.59 (d, C(3)); 81.61 (d, C(5));
73.94 (d, C(7)); 67.99 (d, C(6)); 64.02 (t, CH2ÀC(8)); 46.19 (d, C(8)); 7.14, 7.06, 6.97 (3q, 4 (MeCH2)3Si); 5.09,
‡
‡
4.87, 4.60 (3t, 4 (MeCH2)3Si). HR-MALDI-MS: 657.4335 ([M ‡ H] , C32H69N2O4Si4 ; calc. 657.4329).
(5S,6S,7R,8R)-5,6,7,8-Tetrahydro-5,6,7-tris(triethylsilyloxy)-8-[(triethylsilyloxy)methyl]imidazo[1,2-a]pyri-
dine (47): Data for a 85 :15 Mixture 47/48. Colourless oil. Rf (hexane/AcOEt 9 :1) 0.26. [a]2D5 ˆ À15.1 (c ˆ 1.3,
CHCl3). IR (CHCl3): 3017w, 2958s, 2913s, 2878s, 1458w, 1414w, 1354w, 1264w, 1154m, 1092w, 1007m, 967w, 919w,
829m. 1H-NMR (300 MHz, CDCl3; 47/48 ca. 85 :15): 6.99 (d, J ˆ 1.25, HÀC(2)); 6.92 (d, J ˆ 1.25, HÀC(3)); 5.70
(d, J ˆ 1.8, HÀC(5)); 4.51 (dd, J ˆ 5.1, 1.2, irrad. at 2.98 ! d, J ˆ 5.1, HÀC(7)); 4.18 (dd, J ˆ 9.6, 5.1, irrad. at
2.98 ! d, J ꢀ 9.6, CHaÀC(8)); 3.95 (dd, J ˆ 5.1, 1.8, irrad. at 5.70 ! d, J ˆ 5.1, irrad. at 4.51 ! d, J ˆ 1.8,
HÀC(6)); 3.78 (dd, J ˆ 10.5, 9.6, irrad. at 2.98 ! dd, J ˆ 10.5, CHbÀC(8)); 2.98 (ddd, J ˆ 10.5, 5.1, 1.2, irrad. at
4.18 ! br. d, J ˆ 10.5, HÀC(8)); 1.06 ± 0.52 (m, 4 (MeCH2)3Si). 13C-NMR (75 MHz, CDCl3; 47/48 ca. 85 :15):
143.71 (s, C(8a)); 127.56 (d, C(3)); 115.00 (d, C(4)); 78.37 (d, C(5)); 74.24 (d, C(7)); 68.06 (d, C(6)); 64.26 (t,
CH2ÀC(8)); 46.28 (d, C(8)); 7.03, 6.87 (2q, 4 (MeCH2)3Si); 5.05, 4.86, 4.55 (3t, 4 MeCH2)3Si). HR-MALDI-MS:
‡
‡
657.4319 ([M ‡ H] , C32H69N2O4Si4 ; calc. 657.4329).
Inhibition Studies. IC50 Values were determined at a substrate concentration near KM value of the each
enzyme by plotting the reciprocal value of the rate of substrate hydrolysis vs. the inhibitor concentration. After
fitting a straight line to the data by linear regression, the negative [I]-intercept of this plot provided the
appropriate IC50 value.
a) Inhibition of Escherichia coli b-Galactosidase. KM ˆ 0.94 mm ([70]: 0.18 mm). The assay was carried out
at pH 6.9 (NaH2PO4/Na2HPO4 buffer 100 mm) and at 378. The reaction was started by addition of 2-nitrophenyl
b-d-galactopyranoside after preincubating the enzyme in the presence of the inhibitor for 15 min at 378. After
20 min, the reaction was quenched by the addition of 400 mm Na2CO3 soln. The rate of hydrolysis was
determined by measuring the absorption at l 405 nm and subsequently subtracting the absorption of a blank
probe (H2O, buffer, and substrate).

118
Helvetica Chimica Acta ± Vol. 88 (2005)
b) Inhibition of Bovine Liver b-Galactosidase. KM ˆ 1.45 mm. The assay was carried out at pH 6.9
(NaH2PO4/Na2HPO4 buffer 100 mm) and at 378. The reaction was started by addition of 2-nitrophenyl b-d-
galactopyranoside after preincubating the enzyme in the presence of the inhibitor for 20 min at 508. After
30 min, the reaction was quenched by the addition of 400 mm Na2CO3 soln. The rate of hydrolysis was
determined by measuring the absorption at l 405 nm and subsequently subtracting the absorption of a blank
probe (H2O, buffer, and substrate).
c) Inhibition of A. oryzae b-Galactosidase. KM ˆ 2.5 mm. The assay was carried out at pH 4.9 (AcONa
buffer 50 mm) and at 308. The reaction was started by addition of 2-nitrophenyl b-d-galactopyranoside after
preincubating the enzyme in the presence of the inhibitor for 10 min at 308. After 30 min, the reaction was
quenched by the addition of 400 mm Na2CO3 soln. The rate of hydrolysis was determined by measuring the
absorption at l 405 nm and subsequently subtracting the absorption of a blank probe (H2O, buffer, and
substrate).
d) Inhibition of Caldocellum saccharolyticum b-Glucosidase. KM ˆ 1.95 mm ([71]: 0.51 mm). The assay was
carried out at pH 4.9 (AcONa buffer 50 mm) and at 558. The reaction was started by addition of 4-nitrophenyl b-
d-galactopyranoside after preincubating the enzyme in the presence of the inhibitor for 10 min at 558. After
20 min, the reaction was quenched by the addition of 400 mm Na2CO3 soln. The rate of hydrolysis was
determined by measuring the absorption at l 405 nm and subsequently subtracting the absorption of a blank
probe (H2O, buffer, and substrate).
e) Inhibition of Sweet Almond b-Glucosidases. KM ˆ 3.2 mm ([72]: 67 ± 80 mm at pH 5.2 ± 6.0). The assay
was carried out at pH 6.9 (NaH2PO4/Na2HPO4 buffer 100 mm) and at 378. The reaction was started by addition
of 4-nitrophenyl b-d-galactopyranoside after preincubating the enzyme in the presence of the inhibitor for
10 min at 378. After 30 min, the reaction was quenched by the addition of 400 mm Na2CO3 soln. The rate of
hydrolysis was determined by measuring the absorption at l 405 nm and subsequently subtracting the
absorption of a blank probe (H2O, buffer, and substrate).
f) Inhibition of T. ressei Cellulase Cel7A. KM ˆ 0.63 ± 0.88 mm ([73]: 0.46 mm). The assay was carried out at
pH 4.9 (AcONa buffer 50 mm) and at 508. The reaction was started by addition of 4-nitrophenyl b-d-
galactopyranoside after preincubating the enzyme in the presence of the inhibitor for 10 min at 508. After
25 min, the reaction was quenched by the addition of 400 mm Na2CO3 soln. The rate of hydrolysis was
determined by measuring the absorption at l 405 nm and subsequently subtracting the absorption of a blank
probe (H2O, buffer, and substrate).
REFERENCES
[1] T. D. Heightman, A. T. Vasella, Angew. Chem., Int. Ed. 1999, 38, 750.
[2] T. Granier, N. Panday, A. Vasella, Helv. Chim. Acta 1997, 80, 979.
[3] N. Panday, T. Granier, A. Vasella, Helv. Chim. Acta 1998, 81, 475.
[4] N. Panday, A. Vasella, Synthesis 1999, 1459.
[5] N. Panday, A. Vasella, Helv. Chim. Acta 2000, 83, 1205.
[6] N. Panday, M. Meyyappan, A. Vasella, Helv. Chim. Acta 2000, 83, 513.
[7] N. Panday, Y. Canac, A. Vasella, Helv. Chim. Acta 2000, 83, 58.
[8] M. Terinek, A. Vasella, Helv. Chim. Acta 2003, 86, 3482.
[9] K. Tatsuta, Pure Appl. Chem. 1996, 68, 1341.
[10] K. Tatsuta, S. Miura, H. Gunji, Bull. Chem. Soc. Jpn. 1997, 70, 427.
[11] K. Tatsuta, S. Miura, Tetrahedron Lett. 1995, 36, 6721.
[12] K. Tatsuta, S. Miura, S. Ohta, H. Gunji, Tetrahedron Lett. 1995, 36, 1085.
[13] K. Tatsuta, S. Miura, S. Ohta, H. Gunji, J. Antibiot. 1995, 48, 286.
[14] T. Aoyagi, H. Suda, K. Uotani, F. Kojima, T. Aoyama, K. Horiguchi, M. Hamada, T. Takeuchi, J. Antibiot.
1992, 45, 1404.
[15] T. Aoyama, H. Naganawa, H. Suda, K. Uotani, T. Aoyagi, T. Takeuchi, J. Antibiot. 1992, 45, 1557.
[16] M. Terinek, A. Vasella, Helv. Chim. Acta 2004, 87, 3035.
[17] M. Terinek, A. Vasella, Helv. Chim. Acta 2005, 88, 10.
[18] E. Dubost, T. Tschamber, J. Streith, Tetrahedron Lett. 2003, 44, 3667.
[19] A. Frankowski, C. Seliga, D. Bur, J. Streith, Helv. Chim. Acta 1991, 74, 934.
[20] A. Frankowski, D. Deredas, J. Streith, T. Tschamber, Tetrahedron 1998, 54, 9033.
[21] J. Streith, H. Rudyk, T. Tschamber, C. Tarnus, C. Strehler, D. Deredas, A. Frankowski, Eur. J. Org. Chem.
1999, 893.

Helvetica Chimica Acta ± Vol. 88 (2005)
119
[22] J. Streith, A. Boiron, A. Frankowski, D. Lenouen, H. Rudyk, T. Tschamber, Synthesis 1995, 944.
[23] F. Gessier, T. Tschamber, C. Tarnus, M. Neuburger, W. Huber, J. Streith, Eur. J. Org. Chem. 2001, 4111.
[24] K. Weinberg, S. Jankowski, D. Le Nouen, A. Frankowski, Tetrahedron Lett. 2002, 43, 1089.
[25] C. V. Ramana, A. Vasella, Helv. Chim. Acta 2000, 83, 1599.
[26] G. J. Davies, L. Mackenzie, A. Varrot, M. Dauter, A. M. Brzozowski, M. Schülein, S. G. Withers,
Biochemistry 1998, 37, 11707.
[27] G. Sulzenbacher, H. Driguez, B. Henrissat, M. Schülein, G. J. Davies, Biochemistry 1996, 35, 15280.
[28] P. W. Kent, P. F. V. Ward, J. Chem. Soc. 1953, 416.
[29] J. P. Verheijden, P. J. Stoffyn, Tetrahedron 1957, 1, 253.
[30] C. V. Varaprasad, D. Averett, K. S. Ramasamy, Tetrahedron 1999, 55, 13345.
[31] J. G. Buchanan, R. Fletcher, K. Parry, W. A. Thomas, J. Chem. Soc. B 1969, 377.
[32] W. G. Overend, A. C. White, N. R. Williams, Chem. Ind. (London) 1963, 1840.
[33] T. Granier, A. Vasella, Helv. Chim. Acta 1995, 78, 1738.
[34] J. Spychala, Synth. Commun. 1997, 27, 3431.
[35] G. Levesque, J. C. Gressier, M. Proust, Synthesis 1981, 963.
[36] D. H. Hua, F. Q. Zhang, J. S. Chen, P. D. Robinson, J. Org. Chem. 1994, 59, 5084.
[37] W. Nagata, M. Yoshioka, T. Okumura, J. Chem. Soc. C 1970, 2365.
[38] A. Knierzinger, A. Vasella, J. Chem. Soc., Chem. Commun. 1984, 9.
[39] K. Sugita, A. Ohta, M. Onaka, Y. Izumi, Chem. Lett. 1990, 481.
[40] M. K. Dowd, W. M. Rockey, A. D. French, P. J. Reilly, J. Carbohydr. Chem. 2002, 21, 11.
[41] A. G. Evdokimov, F. Frolow, Acta Crystallogr., Sect. C 1996, 52, 3218.
[42] J. Alzeer, A. Vasella, Helv. Chim. Acta 1995, 78, 177.
[43] S. Patai, ꢁThe Chemistry of Amidines and Imidatesꢂ, John Wiley & Sons, London, 1975.
[44] G. Rousselet, P. Capdevielle, M. Maumy, Tetrahedron Lett. 1993, 34, 6395.
[45] J. I. Ogonor, Tetrahedron 1981, 37, 2909.
[46] J. I. Levin, E. Turos, S. M. Weinreb, Synth. Commun. 1982, 12, 989.
[47] R. S. Garigipati, Tetrahedron Lett. 1990, 31, 1969.
[48] R. A. Moss, W. Ma, D. C. Merrer, S. Xue, Tetrahedron Lett. 1995, 36, 8761.
[49] D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277.
[50] S. V. Ley, J. Norman, W. P. Griffith, S. P. Marsden, Synthesis 1994, 639.
[51] A. J. Mancuso, D. Swern, Synthesis 1981, 165.
[52] O. Mitsunobu, Synthesis 1981, 1.
[53] J. L. Luche, J. Am. Chem. Soc. 1978, 100, 2226.
[54] S. P. Bew, S. D. Bull, S. G. Davies, E. D. Savory, D. J. Watkin,Tetrahedron 2002, 58, 9387.
[55] S. Knapp, P. J. Kukkola, S. Sharma, T. G. M. Dhar, A. B. J. Naughton, J. Org. Chem. 1990, 55, 5700.
[56] E. L. Eliel, H. Satici, J. Org. Chem. 1994, 59, 688.
[57] M. A. Tius, J. Busch-Petersen, Tetrahedron Lett. 1994, 35, 5181.
[58] T. Hosoya, Y. Ohashi, T. Matsumoto, K. Suzuki, Tetrahedron Lett. 1996, 37, 663.
[59] J. Xu, A. Egger, B. Bernet, A. Vasella, Helv. Chim. Acta 1996, 79, 2004.
[60] H. Yamada, M. Nakatani, T. Ikeda, Y. Marumoto, Tetrahedron Lett. 1999, 40, 5573.
[61] S. Shuto, M. Terauchi, Y. Yahiro, H. Abe, S. Ichikawa, A. Matsuda, Tetrahedron Lett. 2000, 41, 4151.
[62] S. Shuto, M. Terauchi, Y. Yahiro, H. Abe, S. Ichikawa, A. Matsuda, Tetrahedron Lett. 2004, 45, 6819.
[63] G. F. Painter, A. Falshaw, H. Wong, Org. Biomol. Chem. 2004, 2, 1007.
[64] R. H. Jacobson, X. J. Zhang, R. F. DuBose, B. W. Matthews, Nature 1994, 369, 761.
[65] M. Kurogochi, S. I. Nishimura, Y. C. Lee, J. Biol. Chem. 2004, 279, 44704.
[66] A. Varrot, C. A. Tarling, J. M. Macdonald, R. V. Stick, D. L. Zechel, S. G. Withers, G. J. Davies, J. Am.
Chem. Soc. 2003, 125, 7496.
[67] S. Vonhoff, K. Piens, M. Pipelier, C. Braet, M. Claeyssens, A. Vasella, Helv. Chim. Acta 1999, 82, 963.
[68] J. M. Macdonald, R. V. Stick, D. M. G. Tilbrook, S. G. Withers, Aust. J. Chem. 2002, 55, 747.
[69] V. Popsavin, S. Grabe, B. Stojanovic, M. Popsavin, V. Pejanovic, D. Milkjkovic,Carbohydr. Res. 1999, 312, 110.
[70] S. A. Kuby, H. A. Lardy, J. Am. Chem. Soc. 1953, 75, 890.
[71] A. R. Plant, J. E. Oliver, M. L. Patchett, R. M. Daniel, H. W. Morgan, Arch. Biochem. Biophys. 1988, 262, 181.
[72] J. Schwartz, J. Sloan, Arch. Biochem. Biophys. 1970, 137, 122.
[73] J. Stahlberg, C. Divne, A. Koivula, K. Piens, M. Claeyssens, T. T. Teeri, T. A. Jones, J. Mol. Biol. 1996, 264, 337.
Received October 23, 2004