Synthesis of glucuronic, mannuronic, and galacturonic acid-derived imidazoles as inhibitors of bovine liver β-glucuronidase

Article abstract of DOI:10.1002/hlca.200690137

The gluco-, manno-, and galacto-configured imidazopyridine-5-carboxylates 5-7, respectively, were synthesixed and evaluated as inhibitors of bovine liver β-glucuronidase. The gluconolactam 15 was transformed into the gluco- and manno-imidazoles 5 and 6 in nine steps and in an overall yield of 9 and 12%, respectively. Oxidation and esterification of the selectively protected gluco- and manno-configured hydroxymethyl-imidaxopyridines 23 and 25, respectively (both obtained from gluconolactam 15), provided the benzhydryl esters 24 and 26. respectively. Hydrogenolysis afforded the gluco-imidazopyridine-carboxylic acid 5 and the manno-isomer 6. Similarly, the hydroxymethyl-imidazopyridine 33, obtained from galactonolactam 27, was subjected to oxidation, esterification, and deprotection to afford the galacto-configured imidazopyridine-carboxylate 7 in ten steps from the galactonolactam 27 and in an overall yield of 13%. The gluco-configured imidazole 5 is the strongest known inhibitor of β-glucuronidases (K_i = 12 nM), while the manno- and galacto-configured imidazoles 6 and 7 are micromolar inhibitors of bovine β-glucuronidase. The small difference between the inhibitory strength of the imidazopyridine-carhoxylic acid 5 and the tetrazolopyridine-carboxylic acid 1, and the difference between the configurational selectivity of 5-7 as compared to the unselectivity of the corresponding lactams 3 and 4 are discussed. Verlag Helvetica Chimica Acta AG.

Full text of DOI:10.1002/hlca.200690137

Helvetica Chimica Acta – Vol. 89 (2006)
1373
Synthesis of Glucuronic, Mannuronic, and Galacturonic Acid-Derived
Imidazoles as Inhibitors of Bovine Liver b-Glucuronidase
by Jagadish Pabba, Narinder Mohal, and Andrea Vasella*
Laboratorium für Organische Chemie, Departement Chemie und Angewandte Biowissenschaften,
ETH-Zürich, HCI, CH-8093 Zürich
(phone: +41446325130)
The gluco-, manno-, and galacto-configured imidazopyridine-5-carboxylates 5–7, respectively, were
synthesized and evaluated as inhibitors of bovine liver b-glucuronidase. The gluconolactam 15 was trans-
formed into the gluco- and manno-imidazoles 5 and 6 in nine steps and in an overall yield of 9 and 12%,
respectively. Oxidation and esterification of the selectively protected gluco- and manno-configured
hydroxymethyl-imidazopyridines 23 and 25, respectively (both obtained from gluconolactam 15), pro-
vided the benzhydryl esters 24 and 26, respectively. Hydrogenolysis afforded the gluco-imidazopyri-
dine-carboxylic acid 5 and the manno-isomer 6. Similarly, the hydroxymethyl-imidazopyridine 33,
obtained from galactonolactam 27, was subjected to oxidation, esterification, and deprotection to afford
the galacto-configured imidazopyridine-carboxylate 7 in ten steps from the galactonolactam 27 and in an
overall yield of 13%. The gluco-configured imidazole 5 is the strongest known inhibitor of b-glucuroni-
dases (Ki =12 nM), while the manno- and galacto-configured imidazoles 6 and 7 are micromolar inhibitors
of bovine b-glucuronidase. The small difference between the inhibitory strength of the imidazopyridine-
carboxylic acid 5 and the tetrazolopyridine-carboxylic acid 1, and the difference between the configura-
tional selectivity of 5–7 as compared to the unselectivity of the corresponding lactams 3 and 4 are dis-
cussed.
Introduction. – Lactone-type inhibitors of retaining b-glycosidases possessing an
annulated imidazole ring with a N-atom correctly located to mimic the glycosidic O-
atom are stronger inhibitors1) than the corresponding tetrazoles and triazoles2); they
are also stronger inhibitors than the corresponding glyconolactams and hydroximolac-
tams [3][6–14]. The strength of the inhibition by such N-heterocycles correlates with
their basic properties and with the extent of their interaction with the catalytic acid
of the glycosidases [2][10][11]. This correlation should also be valid for the inhibition
of b-glucuronidases3), and imidazopyridine-5-carboxylates are expected to be stronger
glycuronidase inhibitors than the corresponding known glycarolactam and tetrazolo-
pyridine-5-carboxylates [17][18]. This expectation is also in agreement with the obser-
1
)
)
For reviews on glycosidase inhibitors, see [1][2].
1,2,3-Triazoles and imidazoles with an incorrectly located glycosidic heteroatom [3–5] are weak
inhibitors of retaining b-glycosidases.
2
3
)
For other inhibitors of b-glucuronidases, see [15–17].
© 2006 Verlag Helvetica Chimica Acta AG, Zürich

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Helvetica Chimica Acta – Vol. 89 (2006)
vation that b-glucuronidases, b-galactosidases, and b-mannosidases belong to the same
family 24) of glycosidases.
We have recently reported the synthesis and evaluation of glycarolactams and tet-
razolopyridine-5-carboxylates as inhibitors of bovine liver b-glucuronidase [17][18].
The tetrazolopyridine-5-carboxylate 1, glucaro-1,5-lactam 3, and galactaro-1,5-lactam
4 inhibit bovine liver b-glucuronidase to the same extent (Ki =25–32 nM), while the ga-
lacto-configured tetrazole 2 (Ki =6.3 mM) is a ca. 200-fold weaker inhibitor of this
enzyme than galactaro-1,5-lactam 4 [15][17]. We were, therefore, interested in the imi-
dazopyridine-5-carboxylate 5, and in the manno- and galacto-configured analogues 6
and 7 to test the effect of the imidazole ring and of the configuration on the inhibition
of bovine liver b-glucuronidase. We planned to prepare the gluco-configured imidazole
5 [17][18] either by annulating the imidazole ring to the glucaro-1,5-lactam 8 according
to a known method [4][10], or by oxidising the selectively protected imidazole 23 that
should be readily obtained from the gluconolactam 15 [4]. We expected the manno-
configured isomer 6 as by-product of the synthesis of 5, while the galacto-configured
imidazole 7 should be readily prepared from either the galactarolactam 14 or the ga-
A
Results and Discussion. – We first attempted to synthesize the imidazopyridine-car-
boxylic acids 5–7 by annulating the imidazole ring to the glucaro-1,5-lactam 8 [17] and
galactaro-1,5-lactam 14. Acetylation of 8 to 9, followed by thionation, yielded 79% of
the thionolactam 10 (Scheme 1). However, treatment of 10 with aminoacetaldehyde
dimethyl acetal in the presence of Hg(OAc)2 [4][10] led only to the 2,3,6-trisubstituted
pyridine 11 by b-elimination of the AcO and of the BnO group; the desired amidine
was not observed. Similar b-eliminations of uronic acid derivatives were first reported
by Kiss [20]. They are also catalysed by lyases in the course of the degradation of some
polysaccharides and glycosaminoglycans [21]. To suppress the facile elimination of the
AcO group at C(4), we replaced it by a Et3SiO (TESO) group. The silyl ether 12 indeed
A
reacted with aminoacetaldehyde dimethyl acetal to provide a mixture of amidines 13.
This mixture, however, decomposed upon mild treatment with TsOH·H2O or
BF3 ·Et2O. The known galacturonic acid-derived methoxymethyl acetal 14 [17] decom-
A
posed already upon treatment with Lawesson’s reagent; not surprisingly, b-elimination
4
)
Glycosidases are classified into families based on their sequence similarities [19]. A regularly
updated database is available on the internet (http://afmb.cnrs-mrs.fr/CAZY/index.html).

Helvetica Chimica Acta – Vol. 89 (2006)
1375
Scheme 1
a) Ac2O, pyridine. b) Lawesson’s reagent, toluene, 808; 79% (from 8). c) NH2CH2CH(OMe)2,
Hg(OAc)2, THF, 08; 56%. d) 1. Et3SiCl, pyridine, 608; 2. Lawesson’s reagent, toluene, 808; 48%.
AHCTREUNG
e) NH2CH2CH(OMe)2, Hg(OAc)2, THF, 08.
of this galacturonate, possessing an axial leaving group at C(4), occurred particularly
readily. It is known that aminoacetaldehyde dimethyl acetals substituted with an elec-
tron-withdrawing group are less reactive towards thionolactams than the unsubstituted
analogue [22][23]. The scope of this method for the formation of imidazopyridines
from thionolactams and aminoacetaldehyde dimethyl acetals thus depends sensibly
on the nucleophilicity of the acetal and of the intermediate amidine.
In view of these results we planned to prepare the glycarolactam-derived imidazo-
pyridine-carboxylic acids 5–7 by oxidation of the HOCH2 group of the partially pro-
tected imidazoles 23, 25, and 33. Thionation of the gluconolactam-derived diacetate
15 [4] (Scheme 2) gave the thionolactam 16 (99%) that was condensed with aminoace-
taldehyde dimethyl acetal in the presence of Hg(OAc)2 [4][10] to the corresponding
amidines. Their cyclisation in the presence of TsOH·H2O in wet toluene was accompa-
nied by deacetylation. Silylation of the crude with iPr3
SiOTf gave a 1:1 mixture (52%)
G
of the monosilylated gluco- and manno-imidazopyridines 17 and 185), besides minor
amounts of the disilyl ethers 19 (14%) and 20 (13%). The mixture 17/18 was O-benzy-
lated, and the epimeric benzyl ethers were separated by chromatography to provide the
gluco-configured tribenzyl ether 21 (37%) and its manno-isomer 22 (37%). Desilyla-
tion of 21 gave the primary alcohol 23 (91%). It was oxidised with Jones’ reagent,
and the crude product was esterified by treatment with diphenyl diazomethane
(Ph2CN2) to yield 70% of the benzhydryl ester 24. Hydrogenolytic deprotection of 24
provided the gluco-configured imidazopyridine-carboxylate 5 (80%). Similarly, the
manno-configured imidazole 22 was desilylated to the alcohol 25 (94%), which was oxi-
5
)
The direction of numbering of imidazopyridines (cf. 17/18 in Scheme 2) is opposite to that of pyrano-
sides. Thus, the sides above and below the plane of the imidazoles, as defined by clockwise and coun-
terclockwise numbering, are interchanged relative to those defined by carbohydrate nomenclature.

1376
Helvetica Chimica Acta – Vol. 89 (2006)
Scheme 2
a) Lawesson’s reagent, toluene, 808; 99%. b) 1. NH2CH2CH(OMe)2, Hg(OAc)2, THF; 2. TsOH·H2O,
i
toluene/H2O 10 :1, 648; 3. Pr3
ACHTREUNG
of 20. c) BnBr, NaH, DMF; 37% of 21 and 37% of 22. d) Bu
AHCTREUNG
25. e) 1. Jones’ oxidation; 2. Ph2CN2, acetone; 70% of 24; 73% of 26. f) H2, 10% Pd/C, EtOH; 80%
of 5; 99% of 6.
dised and transformed into the benzyhydryl ester 26 in 73% yield. Catalytic hydroge-
nolysis of 26 provided the manno-configured imidazopyridine-carboxylate 6 (99%).
The galacto-configured selectively O-benzylated imidazopyridine 33 was prepared
from the partially benzylated galactono-1,5-lactam 27 [17] (Scheme 3). Acetylation of
27 to the diacetate 28 (99%), treatment with Lawesson’s reagent to afford the thiono-
lactam 29 (85%), and annulation of the imidazole ring as described for 16 provided the
dihydroxyimidazopyridine 30. Regioselective silylation of 30 to 31 (84%), followed by
O-benzylation, provided the tribenzyl ether 32 (66%) that was desilylated to yield 85%
of the desired primary alcohol 33. It was similarly oxidized as described for 23 and 25,
and the resulting acid was transformed into the benzhydryl ester 34 that was obtained in
34% yield besides unreacted alcohol 336) (18%). Hydrogenolysis of 34 gave the fully
deprotected D-galacto-imidazopyridine-carboxylate 7 (98%).
The structure of the 2,3,6-trisubstituted pyridine 11 was deduced from 1H-NMR ds
at 6.89 (HꢀC(4)) and 7.42 (HꢀC(5)) ppm with a J(4,5)=8.0 Hz. Formation of the benz-
hydryl esters 24, 26, and 34 is evidenced by the 13C s (C=O) at 166.90 (24), 167.12 (26),
and 166.35 ppm (34), the 13C-NMR d (Ph2CH) at 75.25 (24), 77.91 (26), and 78.39 ppm
(34), the 1H-NMR s (Ph2
ance of H2
ACHTREUNG
AHCTREUNG
6
)
Longer duration of the oxidation led to unidentified side products.

Helvetica Chimica Acta – Vol. 89 (2006)
1377
Scheme 3
a) Ac2O, pyridine; 99%. b) Lawesson’s reagent, toluene, 808; 85%. c) 1. NH2CH2CH(OMe)2,
t
Hg(OAc)2, THF, 08; 2. TsOH·H2O, toluene/H2O 12 :3, 758. d) Bu(Me)2
N
G
no)pyridine (DMAP), DMF; 84% from 29. e) BnBr, NaH, DMF; 66%. f) Bu
AHCTREUNG
85%. g) 1. CrO3, 1M H2SO4, acetone; 2. Ph2CN2, acetone; 34% of 34, and 18% of 33. h) H2 (6 bar),
10% Pd/C, MeOH/H2O 2 :1; 98%.
configured imidazopyridine 24 adopts predominantly the 7H6 conformation in CDCl3 as
6
evidenced by J(5,6)=3.0, J(6,7)=5.1, and J(7,8)=3.3 Hz. The H7 conformer of 24 is
destabilised by the steric interaction between the substituents at C(5) and C(6). The
coupling constants of the manno-imidazopyridine 26 could not be determined due to
7
signal overlap, and we tentatively assigned the H6 conformation to 26 by analogy to
the gluco-configured 24. The galacto-configured imidazopyridine 34 exists as a ca.
7
6
1:3 mixture of H6 and H7 conformers as evidenced by J(5,6)=4.7, J(6,7)=1.9, and
J(7,8)=8.1 Hz (Table 3 in Exper. Partand modelling with MM3*). Similar to their tet-
razolopyridine analogues [17], the deprotected imidazopyridine-carboxylic acids 5–7
6
adopt the H7 conformation in D2
A
Enzymatic Tests and Discussion. – The imidazopyridine-carboxylic acids 5–7 were
tested as inhibitors of bovine liver b-glucuronidase (acetate buffer, 308, pH 5.0) with 4-
nitrophenyl b-D-glucuronide as substrate. The inhibition data (Ki) and the pK values of
the inhibitors are summarized in Table 1.
Table 1. Comparison of the Ki Values [mM] of the Inhibition of b-Glucuronidase from Bovine Liver by the
Imidazoles 5, 6, and 7, and the Tetrazoles 1 and 2 at pH 5.0 and 5.7
pH
Imidazoles
Tetrazoles
5
6
7
1
2
pKHA
Ki
6.5
0.012
(a=2.4)
0.007b)
6.6
14.0
6.6
6.7
(a=1.3)
3.25b)
2.53a)
0.025a)
(a=1.9)
2.52a)
6.3a)
(a=5.4)
5.0
5.7
(non-competitive)
5.85b)
a) Data taken from [17]. b) IC50/2 in mM.

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Helvetica Chimica Acta – Vol. 89 (2006)
The gluco-imidazopyridine-carboxylic acid 5 (Ki =12 nM) inhibits b-glucuronidase
from bovine liver only two times more strongly than the corresponding tetrazole 1.
The galacto-isomer 7 (Ki =6.7 mM) is a much weaker inhibitor of this glucuronidase.
However, there is again only a small difference between the inhibition by the (galacto)
imidazopyridine 7 and the corresponding tetrazolopyridine 2 (6.3 mM). The configura-
tional selectivity of the inhibition by the gluco-imidazopyridine 5 is further demon-
strated by a Ki value of 14 mM for the manno-imidazopyridine 6 that is three orders
of magnitude weaker than 5, similarly as the galacto-isomer 7.
Increasing the pH of the assay from 5.0 and 5.77) improves the inhibition by each
one of the imidazopyridines 5–7 ca. twofold (Table 1). This rather slight increase of
the inhibition suggests that 5–7 exist largely as zwitterions at these pH values
(Schemes 2 and 3). This is in keeping with the pKHA values8) for 5 (6.5), 6 (6.6), and
7 (6.6). Although only somewhat stronger than the corresponding tetrazolopyridine
1, the gluco-imidazopyridine 5 is the strongest known inhibitor of b-glucuronidases.
The strong configurational dependence of the inhibition of bovine liver b-glucuro-
nidase by the imidazopyridines 5–7 and by the tetrazolopyridines 1 and 2 contrasts sur-
prisingly with the absence of a dependence on the configuration at C(4) of the inhibi-
tion by the glucaro-1,5-lactam 39) and galactaro-1,5-lactam 4 (Ki ꢁ30 nM) [17]; it is
rationalised by the higher flexibility of the lactams. Such a difference between the con-
figurational selectivity of azoles and lactams is not observed for family-1 glucosidases
[4][9][10][25][26], while the configurational selectivity of these types of inhibitors
for glycosidases belonging to other families is not known. The different configurational
selectivities for lactams and azoles suggest that the restriction of flexibility may increase
the selectivity both of inhibitors mimicking the reactive intermediate and those mim-
icking the reactive conformation of the substrate [27].
Both bovine liver b-glucuronidase and E. coli b-galactosidase belong to family 2.
Similar to the inhibition of bovine liver b-glucuronidase, the inhibition of E. coli b-ga-
lactosidase is sensitive to the configuration at C(4). The galacto-imidazopyridine 36 is a
very strong inhibitor of E. coli b-galactosidase, while the gluco-isomer 35 is inactive
(Fig.) [9]; this configurational selectivity appears to be a characteristic feature of glyco-
sidases of family 2.
The above mentioned small difference between the inhibition of bovine liver b-glu-
curonidase by the tetrazolopyridine 1 and the imidazopyridine 5 contrasts with the
large difference between the inhibition of glucosidases of family 1 by analogous imi-
dazo- and tetrazolopyridines. Thus, the b-glucosidases from sweet almonds and from
Caldocellum saccharolyticum are inhibited ca. 1500- and 3000-fold more strongly by
the gluco-configured imidazopyridine 35 [10] (Fig.) than by the tetrazolopyridine 37
[4]. This difference was explained by the much stronger interaction of the imidazole
with the catalytic acid of the enzyme. The similar inhibition of bovine liver b-glucuro-
nidase by the tetrazolopyridine 1 and the imidazopyridine 5 suggests that the interac-
tion of 5 with the catalytic acid of the enzyme is impaired by the protonation of the imi-
7
)
The pH optimum of the related rat liver b-glucuronidase is 5.1 [24]; hydrolysis of the substrate was
very slow above pH 5.7.
A single inflection of the titration curve was observed between pH values 2.0 and 7.0.
The inhibition by mannaro-1,5-lactams and the corresponding tetrazoles is not known.
8
9
)
)

Helvetica Chimica Acta – Vol. 89 (2006)
1379
Figure. Inhibition (Ki in mM) of b-Galactosidase from E. coli by the Imidazoles 35 and 36 [9][28] and
of b-Glucosidases from Sweet Almonds and Caldocellum saccharolyticum by the Imidazole 35 and the
Tetrazole 37 [4][10]
dazole in its zwitterionic form. We assume that 1 interacts with both the catalytic acid
and the catalytic nucleophile, while the zwitterionic form of 5 does not interact with the
catalytic acid, but particularly strongly with the catalytic nucleophile. In agreement
with this rationalisation, the interaction of the tetrazolopyridine 37 with the catalytic
acid and the catalytic nucleophile of a b-glucosidase was indeed estimated as ca. 2
kcal/mol each, cooperativity increasing the effect, while the interaction of the proto-
nated imidazopyridine 35 with the catalytic nucleophile was estimated as ca. 6 kcal/
mol [2].
We thank the Swiss National Foundation and F. Hoffmann La Roche, Basel, for generous support, M.
Schneider and P. Kälin for the pKHA determination, and Dr. B. Bernet for checking the manuscript.
Experimental Part
General. See [17].
6-Ethyl 4-O-Acetyl-5-amino-2,3-di-O-benzyl-5-deoxy-D-glucarate-1,5-thiolactam (10). A soln. of 8
(20 mg, 0.05 mmol) in pyridine (2 ml) and Ac2O (1 ml) was kept for 2 h and evaporated. A soln. of the
residue (i.e., 9) and Lawesson’s reagent (20 mg, 0.05 mmol) in toluene (2 ml) was heated to 808, and stir-
red for 30 min. Normal workup (AcOEt/H2O) and FC (AcOEt/hexane 1:4) gave 10 (18 mg, 79%). Rf
1
(AcOEt/cyclohexane 1:4) 0.46. H-NMR (300 MHz, CDCl3): 8.34 (br. s, NH); 7.38–7.26 (m, 10 arom.
H); 5.33 (dd, J=8.1, 3.0, HꢀC(4)); 4.90 (d, J=11.5, PhCH); 4.68 (d, J=11.8, PhCH); 4.60 (d, J=12.4,
PhCH); 4.55 (d, J=11.8, PhCH); 4.48 (d, Jꢁ3.0, HꢀC(2)); 4.43 (dd, J=8.1, 2.1, HꢀC(5)); 4.21 (q,
J=7.2, MeCH2
A
Ethyl 5-(Benzyloxy)-6-[(2,2-dimethoxyethyl)amino]pyridine-2-carboxylate (11). A soln. of 10 (18
mg, 0.04 mmol) in THF (3 ml) was cooled to 08, treated with Hg(OAc)2 (64 mg, 0.04 mmol) and
H2NCH2CH(OMe)2 (22 ml, 0.2 mmol), stirred for 2 h, diluted with Et2O (5 ml), filtered through Celite,
U
and evaporated. FC (AcOEt/cyclohexane 1:4) gave 11 (8 mg, 56%). Rf (AcOEt/cyclohexane 1:1)
0.50. 1H-NMR (300 MHz, CDCl3): 7.42 (d, J=8.0, HꢀC(5)); 7.39–7.37 (m, 5 arom. H); 6.89 (d,
J=8.0, HꢀC(4)); 5.29 (t, J=5.8, NH); 5.12 (s, PhCH2); 4.56 (t, J=5.4, OCHO); 4.35 (q, J=7.2, MeCH2
A
3.71 (t, J=5.4, NHCH2); 3.44 (s, 2 MeO); 1.38 (t, J=7.2, MeCH2O).
6-Ethyl 5-Amino-2,3-di-O-benzyl-5-deoxy-4-O-(triethylsilyl)-D-glucarate-1,5-thiolactam (12). A soln.
of 8 (35 mg, 0.09 mmol) and Et3SiCl (75 ml, 0.44 mmol) in pyridine (2 ml) was heated to 608, stirred for
N
2 h, cooled to 258, and evaporated. A soln. of the crude (45 mg) in toluene (2 ml) was treated with Law-
esson’s reagent (35 mg, 0.09 mmol), heated to 808, and stirred for 30 min. Normal workup (AcOEt/H2O)

1380
Helvetica Chimica Acta – Vol. 89 (2006)
and FC (AcOEt/hexane 1:4) gave 1210) (22 mg, 48%). Rf (AcOEt/cyclohexane 1:4) 0.62. 1H-NMR (300
MHz, CDCl3): 8.24 (br. s, NH); 7.41–7.23 (m, 10 arom. H); 4.93 (d, J=11.5, PhCH); 4.71 (d, J=11.8,
PhCH); 4.57 (d, J=11.2, PhCH); 4.51 (br. d, Jꢁ2.8, HꢀC(2)); 4.39 (d, J=11.2, PhCH); 4.36–4.29
(hidden signal, HꢀC(5)); 4.29 (q, J=7.2, MeCH2
ACHTREUNG
HꢀC(3)); 1.30 (t, J=7.2, MeCH2O); 0.91 (t, J=8.1, (MeCH2)3
A
ACHTREUNG
2,6-Di-O-acetyl-5-amino-3,4-di-O-benzyl-5-deoxy-D-glucono-1,5-thiolactam (16). A soln. of 15 (988
mg, 2.24 mmol) and Lawesson’s reagent (580 mg, 1.43 mmol) in toluene (6 ml) was heated to 808, and
stirred for 45 min. Normal workup (AcOEt/H2O/brine) and FC (AcOEt/hexane 3 :7) gave 16 (1.1 g,
99%). Light-yellow solid. Rf (AcOEt/hexane 3 :7) 0.12. M.p.: 123–1248. [a]2D5 =+133.7 (c=0.44,
CHCl3). IR (CHCl3): 3361w, 2962w, 2914w, 1742s, 1513s, 1455w, 1371m, 1311w, 1263m, 1241s, 1070s,
1
1044m, 1026m, 808w. H-NMR (300 MHz, CDCl3): 8.06 (br. d, J=12.6, NH); 7.38–7.24 (m, 10 arom.
H); 5.60 (d, J=8.1, HꢀC(2)); 4.80 (d, J=11.4, PhCH); 4.77 (br. s, PhCH2); 4.56 (d, J=11.1, PhCH);
4.36 (dd, J=12.0, 4.5, HꢀC(6)); 3.95 (t, J=7.8, HꢀC(3)); 3.93 (dd, J=12.0, 3.0, H’ꢀC(6)); 3.73 (t,
J=8.1, HꢀC(4)); 3.69–3.67 (m, HꢀC(5)); 2.11, 2.06 (2s, 2 AcO). 13C-NMR (75 MHz, CDCl3): 198.55
(s, C=S); 170.00, 169.93 (2s, 2 C=O); 137.43, 136.89 (2s); 128.68 (2d); 128.58 (2d); 128.51 (2d); 128.38
(d); 128.09 (3d); 79.67 (d, C(3)); 75.99, 75.89 (2d, C(2), C(4)); 74.36 (t, 2 PhCH2); 62.77 (t, C(6));
57.72 (d, C(5)); 21.13, 20.79 (2q, 2 Me). HR-MALDI-MS: 480.1443 ([M+Na]+, C24
A
G
N
480.1451). Anal. calc. for C24H27N2O6S (457.55): C 63.00, H 5.95, N 3.06; found: C 62.81, H 6.01, N 3.06.
Preparation of the Imidazopyridines 17–20. A soln. of 16 (944 mg, 2.06 mmol) in THF (4 ml) was
treated with Hg(OAc)2 (1.26 g, 3.97 mmol) and NH2CH2CH(OMe)2 (1.1 ml, 10.2 mmol), and stirred
for 45 min. The mixture was treated with H2O (5 ml), extracted with AcOEt (3×50 ml), washed with
H2O (25 ml), sat. aq. NaHCO3 soln. (10 ml), dried (Na2SO4), and evaporated. A soln. of the residue
(942 mg) in toluene/H2O 10:1 (20.2 ml) was treated with TsOH·H2O (880 mg, 4.58 mmol), stirred at
648 for 19 h, treated with sat. aq. NaHCO3 soln. (5 ml), and extracted with AcOEt (2×50 ml). The com-
bined org. layers were washed with brine, dried (Na2SO4), and evaporated. A soln. of the residue (320 mg,
0.86 mmol) in DMF (2 ml) was cooled to 38, treated with 1H-imidazole (168 mg, 0.1 mmol) and iPr3
SiOTf
E
(0.197 ml, 0.105 mmol), warmed to 258, and stirred for 18 h. Normal workup (AcOEt/H2O/brine) and FC
(AcOEt/hexane 1:4 ! 1:1) gave 19 (81 mg, 14%), 20 (74 mg, 13%) and an inseparable 1:1 mixture of 17
and 18 (234 mg, 52%).
Data of (5R,6R,7S,8S)-6,7-Bis(benzyloxy)-5,6,7,8-tetrahydro-8-(triisopropylsilyloxy)-5-[(triisopro-
pylsilyloxy)methyl]imidazo[1,2-a]pyridine (19). Colourless oil. Rf (AcOEt/hexane 1:4) 0.29.
[a]2D5 =+46.9 (c=1.25, CHCl3). IR (CHCl3): 3160w, 3090w, 3067w, 2945s, 2892s, 2867s, 1682w, 1534w,
1496w, 1463m, 1384w, 1365w, 1319w, 1290w, 1262w, 1094s, 1067s, 1028w, 1014m, 996m, 909m, 883m,
843s. 1H-NMR (300 MHz, CDCl3): see Table 2; additionally, 7.41–7.27 (m, 10 arom. H); 7.22 (d,
J=0.9), 7.01 (d, J=1.5) (HꢀC(2), HꢀC(3)); 4.74 (d, J=11.7, PhCH); 4.65 (d, J=11.4, PhCH); 4.58
(d, J=12.0, PhCH); 4.44 (d, J=11.7, PhCH); 1.17–0.97 (m, 2 (Me
N
N
CDCl3): see Table 2; additionally, 137.68, 137.62 (2s); 128.38 (2d); 128.56 (2d); 127.92 (3d); 127.84 (d);
127.72 (2d); 127.67 (d, C(2)); 117.54 (d, C(3)); 72.14, 72.09 (2t, 2 PhCH2); 18.26, 18.12, 18.05 (3q, 2
(Me2
A
Si); 12.58, 12.5 (2d, 2 (Me2CH)3
Si). HR-MALDI-MS: 693.4464 ([M+H]+, C40
U
G
G
E
calc. 693.4477).
Data of (5R,6R,7S,8R)-6,7-Bis(benzyloxy)-5,6,7,8-tetrahydro-8-(triisopropylsilyloxy)-5-[(triisopro-
pylsilyloxy)methyl]imidazo[1,2-a]pyridine (20). Colourless oil. Rf (AcOEt/hexane 1:4) 0.19.
[a]2D5 =–21.5 (c=0.62, CHCl3). IR (CHCl3): 3158w, 2945s, 2892s, 2867s, 1496w, 1463m, 1384w, 1367w,
1316w, 1273w, 1134m, 1099s, 1072m, 1051w, 1014m, 997m, 910s, 884m, 836s. 1H-NMR (300 MHz,
CDCl3): see Table 2; additionally, 7.41–7.27 (m, 10 arom. H); 7.19, 6.98 (2d, J=1.2, HꢀC(2), Hꢀ
C(3)); 4.97 (d, J=11.4, PhCH); 4.85 (d, J=11.7, PhCH); 4.73 (d, J=11.1, PhCH); 4.67 (d, J=11.4,
PhCH); 1.21–0.96 (m, 2 (Me
N
N
10
)
The thionolactam 12 was transformed to the amidine 13 by treating with H2NCH2CH(OMe)2 and
Hg(OAc)2.

Helvetica Chimica Acta – Vol. 89 (2006)
1381
Table 2. Selected 1H-NMR Chemical Shifts [ppm] and Coupling Constants [Hz], and 13C-NMR Chemical
Shifts [ppm] of the Protected Imidazoles 19–23, 25, and 31–33 in CDCl3
19
20
21
22
23
25
31
32
33
HꢀC(5)
HCꢀC(5)
H’CꢀC(5)
HꢀC(6)
HꢀC(7)
HꢀC(8)
J(5,CH)
J(5,CH’)
4.32
4.18
3.98
3.64
4.11
5.11
2.7
4.00
3.85
3.70
4.19
3.80
5.24
2.7
4.18–4.10
4.18–4.10
3.96
4.18–4.10
3.84
4.09–4.01
4.09–4.01
3.89
4.30
3.88
4.09
4.05
3.93
3.87
4.12
4.75
3.0
4.05
3.98
3.79
4.35
3.96
4.81
3.6
4.15
4.19
4.02
4.51
3.97
4.84
4.4
4.34
4.13
3.95
4.38
4.08
4.80
2.8
4.42
4.14–4.06
4.03
4.45
4.12
4.76
4.1
10.7
4.74
4.81
a
a
)
)
7.5
8.4
6.0
7.2
7.2
6.0
6.5
8.1
J(CH,CH’) 10.8
10.2
10.5
10.5
12.0
11.7
10.0
10.9
11.8
6.3
1.9
3.9
a
J(5,6)
J(6,7)
J(7,8)
C(5)
8.1
2.7
3.3
7.2
9.3
2.4
)
7.5
5.7
7.2
9.3
3.3
62.10
64.99
74.01
80.34
67.92
142.84
7.2
7.5
5.7
59.39
60.85
6.9
9.3
3.0
4.4
2.2
5.6
5.6
1.6
4.4
59.37 62.18 60.09
63.34 65.84 63.66
78.40 73.29 74.22b)
82.36 82.03 81.71
66.31 64.28 75.65b)
145.24 144.87 143.86
61.68 58.66 59.70 58.04
63.35 64.24 64.15 62.18
CH2ꢀC(5)
C(6)
74.13b) 74.11 67.67 71.64 70.96
81.49
75.70b) 68.23 72.80 73.67 73.54
144.01 143.15 143.31 141.86 142.51
C(7)
C(8)
80.03 80.57 77.73 76.46
C(8a)
a) Not assigned. b) Assignments may be interchanged
137.85 (2s); 128.56 (2d), 128.49 (d); 128.39 (2d); 128.27 (2d); 127.87 (d); 127.70 (2d); 127.58 (d, C(2));
119.55 (d, C(3)); 74.72, 72.04 (2t, 2 PhCH2); 18.32, 18.13, 18.12 (3q, 2 (Me2CH)3Si); 12.64, 11.89 (2d, 2
(Me2CH)3 H65N2O4
Si). HR-MALDI-MS: 693.4464 ([M+H]+, C40 Si2þ ; calc. 693.4477).
A
ACHTREUNG
A
G
U
G
ACHTREUNG
Data of (5R,6R,7S,8S)- and (5R,6R,7S,8R)-6,7-Bis(benzyloxy)-5,6,7,8-tetrahydro-5-[(triisopropylsi-
lyloxy)methyl]imidazo[1,2-a]pyridin-8-ol (17 and 18, resp.). Colourless oil. Rf (AcOEt/hexane 1:1)
0.48. IR (CHCl3): 3067w, 3031w, 3012w, 2945s, 2892s, 2868s, 1603w, 1496w, 1455m, 1363w, 1309w,
1
1268w, 1166w, 1110s, 1066w, 1028m, 882m. H-NMR (300 MHz, CDCl3; 17/18 1:1): 7.41–7.27 (m, 20
arom. H); 7.18, 7.13, 7.03 (2 H) (3d, J=1.2, HꢀC(2), HꢀC(3)); 5.36 (d, J=3.3, HꢀC(8) of 18); 5.18
(d, J=11.4), 5.12 (d, J=11.7), 5.04 (d, J=11.4), 4.97 (d, J=11.4) (2 PhCH2); 4.85 (d, J=6.9, HꢀC(8)
of 17); 4.87 (d, J=11.4), 4.77 (d, J=11.4), 4.74 (d, J=11.4), 4.67 (d, J=11.7) (2 PhCH2); 4.26 (dd,
J=11.7, 4.5), 4.17–4.04 (m), 4.01–3.84 (m) (HꢀC(5), HꢀC(6), HꢀC(7), H2CꢀC(5)); 1.14–0.90 (m,
(Me
N
N
138.16 (4s); 129.19–128.05 (several d, including C(2)); 118.86, 117.55 (2d, C(3)); 83.38, 79.99 (2d,
C(7)); 75.42, 75.34, 75.13, 75.01 (4t, 2 PhCH2); 73.85, 72.00 (2d, C(6)); 67.56, 62.40 (2d, C(8)); 65.49,
63.99 (2t, CH2ꢀC(5)); 61.60, 61.19 (2d, C(5)); 18.30 (q, (Me2
C
G
G
Data of (5R,6R,7S,8S)-6,7,8-Tris(benzyloxy)-5,6,7,8-tetrahydro-5-[(triisopropylsilyloxy)methyl]-
A
CHCl3). IR (CHCl3): 3067w, 3032w, 3010w, 2946s, 2868s, 1603w, 1496w, 1455m, 1363m, 1332w, 1220w,
1091s, 1028m, 882w. 1H-NMR (300 MHz, CDCl3): see Table 2; additionally, 7.47–7.26 (m, 15 arom.
H); 7.21 (d, J=1.2), 7.13 (d, J=1.5) (HꢀC(2), HꢀC(3)); 5.26 (d, J=11.8, PhCH); 4.93 (d, J=11.7, 2
PhCH); 4.85 (d, J=11.1, PhCH); 4.60 (d, J=11.1, 2 PhCH); 1.10–0.99 (m, (Me
N
N
(75 MHz, CDCl3): see Table 2; additionally, 138.26, 137.80, 137.62 (3s); 129.23 (d, C(2));

1382
Helvetica Chimica Acta – Vol. 89 (2006)
128.40–127.49 (several d); 117.68 (d, C(3)); 74.28, 74.18 (3t, 3 PhCH2); 18.12 (q, (Me2
N
N
(Me2CH)3 H51N2O4
A
G
U
G
ACHTREUNG
C38H50N2O4Si (626.34): C 72.93, H 8.00, N 4.53; found: C 72.80, H 8.04, N 4.47.
Data of (5R,6R,7S,8R)-6,7,8-Tris(benzyloxy)-5,6,7,8-tetrahydro-5-[(triisopropylsilyloxy)methyl]-
imidazo[1,2-a]pyridine (22). Colourless oil. Rf (AcOEt/hexane 1:1) 0.39. [a]2D5 =ꢀ40.1 (c=1.35,
CHCl3). IR (CHCl3): 3068w, 2945s, 2868s, 1604w, 1496w, 1455m, 1366w, 1269w, 1108s, 1027m, 915w,
882m. 1H-NMR (300 MHz, CDCl3): see Table 2; additionally, 7.47–7.27 (m, 15 arom. H); 7.24 (d,
J=1.2), 7.08 (d, J=1.5) (HꢀC(2), HꢀC(3)); 5.07 (d, J=11.8, PhCH); 4.76 (d, J=11.4, PhCH); 4.73
(d, J=11.1, PhCH); 4.69 (d, J=12.0, PhCH); 4.67 (d, J=12.0, PhCH); 4.57 (d, J=12.0, PhCH);
1.06–0.97 (m, (Me
137.89 (3s); 128.47 (d, C(2)); 128.43–127.56 (several d); 119.52 (d, C(3)); 75.00, 71.59, 70.32 (3t, 3
PhCH2); 17.94 (q, (Me2CH)3Si); 11.79 (d, (Me2CH)3 H51N2-
Si). HR-MALDI-MS: 627.3622 ([M+H]+, C38
4Si+; calc. 627.3613). Anal. calc. for C38H50N2O4Si (626.91): C 73.29, H 8.05, N 4.62; found: C 72.80, H
8.04, N 4.47.
(5R,6R,7S,8S)-6,7,8-Tris(benzyloxy)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-5-methanol (23).
soln. of 21 (123 mg, 0.196 mmol) in THF (2 ml) was cooled to 08, treated with Bu4NF·3 H2O (89 mg,
A
N
A
G
U
G
ACHTREUNG
A
ACHTREUNG
A
AHCTREUNG
0.28 mmol), and stirred for 1.5 h. Evaporation and FC (AcOEt/hexane 1:1 ! AcOEt ! MeOH/
AcOEt 1:9) gave 23 (84 mg, 91%). Colourless solid. Rf (AcOEt/hexane 4 :1) 0.17. M.p. 144–1468.
[a]2D5 =+68.2 (c=0.72, CHCl3). IR (CHCl3): 3410w, 3067w, 2963m, 2892w, 2867s, 1604w, 1496w, 1483m,
1454m, 1362w, 1262m, 1090s, 1070s, 1028w. 1H-NMR (300 MHz, CDCl3): see Table 2; additionally,
7.42–7.27 (m, 15 arom. H); 7.14 (d, J=1.8), 7.05 (d, J=1.5) (HꢀC(2), HꢀC(3)); 5.17 (d, J=11.4,
PhCH); 4.89 (d, J=11.7, 2 PhCH); 4.83 (d, J=11.4, PhCH); 4.70 (d, J=11.1, PhCH); 4.62 (d, J=11.4,
PhCH); 2.05 (br. s, OH). 13C-NMR (75 MHz, CDCl3): see Table 2; additionally, 138.04, 137.61, 137.52
(3s); 129.25 (d, C(2); 128.45–127.55 (several d); 116.98 (d, C(3)); 74.12, 74.06, 72.79 (3t, 3 PhCH2).
HR-MALDI-MS: 471.2287 ([M+H]+, C29
(470.55): C 74.02, H 6.43, N 5.95; found: C 74.04, H 6.55, N 5.90.
A
G
N
Diphenylmethyl
(5R,6R,7S,8S)-6,7,8-Tris(benzyloxy)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-5-
carboxylate (24). A soln. of 23 (65 mg, 0.138 mmol) in acetone (10 ml) was treated with Jones’ reagent
i
(0.25 ml, 0.7M aq. soln.), stirred for 1 h, treated with PrOH, and evaporated. A soln. of the residue in
H2O (5 ml) was extracted with AcOEt (3×50 ml). The combined org. layers were washed with brine
(5 ml), dried (Na2SO4), and evaporated. A soln. of the residue in acetone (5 ml) was treated with
Ph2CN2 (85 mg, 0.44 mmol) and stirred for 1 h. Evaporation and FC (AcOEt/hexane 1:4) gave 24 (63
mg, 70%). Colourless oil. Rf (AcOEt/hexane 2 :3) 0.42. [a]2D5 =+49.3 (c=2.2, CHCl3). IR (CHCl3):
3063w, 3032m, 3013w, 2966w, 2866w, 1738s, 1602m, 1496m, 1454w, 1265s, 1213s, 1087s, 1003m, 909w,
821w. 1H-NMR (300 MHz, CDCl3): see Table 3; additionally, 7.38–7.18 (m, 24 arom. H, HꢀC(3));
6.96 (br. dd, J=7.8, 1.5, 1 arom. H); 6.84 (d, J=1.2, HꢀC(2)); 6.74 (s, Ph2
G
Ph2CH); 72.47 (t, PhCH2); 72.26 (t, 2 PhCH2). HR-MALDI-MS: 651.3 ([M+H]+, C42
calc. 651.2853).
(5R,6R,7S,8S)-5,6,7,8-Tetrahydro-6,7,8-trihydroxyimidazo[1,2-a]pyridine-5-carboxylic Acid (5). A
soln. of 24 (48 mg, 0.74 mmol) in EtOH (5 ml) was treated with 10% Pd/C (30 mg), stirred under H2
for 48 h, and filtered through Celite (washing with 5 ml of EtOH). After evaporation, the solid residue
was washed several times with hot AcOEt. A soln. of the solid in H2O was lyophilised to give 5 (13
mg, 80%). Colourless powder. Rf (AcOEt/MeOH/AcOH 7:2.8 :2) 0.45. M.p. 238–2448 (dec.).
pKHA =6.5. [a]2D5 =ꢀ13.9 (c=0.1, MeOH). IR (ATR): 3211m, 3148m, 2921w, 1617s, 1599s, 1530w,
1387m, 1297m, 1167m, 1083s, 1057s, 1011m, 879m. 1H-NMR (300 MHz, D2
ACHTREUNG
7.41 (d, J=2.1), 7.25 (d, J=2.4) (HꢀC(2), HꢀC(3)). 13C-NMR (75 MHz, D2
ACHTREUNG
121.97, 120.31 (2d, C(2), C(3)).
(5R,6R,7S,8R)-6,7,8-Tris(benzyloxy)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-5-methanol (25).
A
soln. of 22 (125 mg, 0.199 mmol) in THF (2.5 ml) was cooled to 08, treated with Bu4NF·3 H2O (95 mg,
AHCTREUNG

Helvetica Chimica Acta – Vol. 89 (2006)
1383
Table 3. Selected 1H-NMR Chemical Shifts [ppm] and Coupling Constants [Hz], and 13C-NMR Chemical
Shifts [ppm] of the Protected Imidazoles 24, 26, and 34 in CDCl3 and of the Deprotected Imidazoles 5, 6,
and 7 in D2O
24
26
34
5
6
7
HꢀC(5)
HꢀC(6)
HꢀC(7)
HꢀC(8)
J(5,6)
J(6,7)
J(7,8)
C=O
C(5)
C(6)
C(7)
C(8)
4.69
4.07
4.50
4.97
3.0
5.1
3.3
166.90
60.40
74.88c)
78.54
4.83–4.81
4.83–4.81
3.89–3.85
4.83–4.81
4.75
4.02
4.59
4.97
4.7
1.9
8.1
166.35
58.45
4.61
3.89a)
4.21a)
4.80
6.6
5.08
4.20
4.78
4.80
4.2
4.88
4.65
4.00
5.01
3.1
b
)
b
)
7.8
6.6
5.1
1.5
2.3
9.0
b
)
167.12
61.49
76.67c)
78.88
68.88
143.52
171.93
62.04
69.84
72.20
65.65
144.05
170.20
62.25
67.70
69.96
62.62
144.13
171.39
63.69
64.44
72.00
69.30
144.65
72.59
78.48c)
75.52
70.01
142.64
C(8a)
143.95
a) Assignments may be interchanged. b) Not assigned. c) Assignments may be interchanged with the d of
Ph2CH (24: 75.25, 26: 77.91, 34: 78.39 ppm).
AHCTREUNG
0.30 mmol), and stirred for 1 h. Evaporation and FC (AcOEt/hexane 1:1 ! AcOEt ! MeOH/AcOEt
1:9) gave 25 (88 mg, 94%). Colourless solid. Rf (AcOEt/hexane 4 :1) 0.08. [a]2D5 =ꢀ80.6 (c=0.48,
CHCl3). IR (CHCl3): 3397w, 3067w, 2941m, 2877w, 1603w, 1496m, 1454m, 1365m, 1263m, 1126s, 1090s,
1070s, 1027m, 912w. 1H-NMR (300 MHz, CDCl3): see Table 2; additionally, 7.42–7.27 (m, 15 arom.
H); 7.12 (d, J=1.5), 7.01 (d, J=1.5) (HꢀC(2), HꢀC(3)); 5.02 (d, J=11.4, PhCH); 4.75 (d, J=11.7,
PhCH); 4.71 (d, J=10.8, PhCH); 4.68 (d, J=12.0, PhCH); 4.66 (d, J=12.0, PhCH); 4.56 (d, J=11.7,
PhCH); 3.35 (br. s, OH). 13C-NMR (75 MHz, CDCl3): see Table 2; additionally, 137.95, 137.83, 137.67
(3s); 129.15 (d, C(2); 128.38–127.55 (several d); 118.73 (d, C(3)); 74.84, 71.76, 70.76 (3t, 3 PhCH2).
HR-MALDI-MS: 471.2287 ([M+H]+, C29
A
G
N
H2O (475.06): C 73.32, H 6.47, N 5.90; found: C 74.04, H 6.26, N 5.85.
Diphenylmethyl (5R,6R,7S,8R)-6,7,8-Tris(benzyloxy)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-5-
carboxylate (26). A soln. of 25 (61 mg, 0.129 mmol) in acetone (10 ml) was treated with Jones’ reagent
i
(0.15 ml, 0.7M aq. soln.), stirred for 1 h, treated with PrOH, and evaporated. A soln. of the residue in
H2O (5 ml) was extracted with AcOEt (3×50 ml). The combined org. layers were washed with brine
(5 ml), dried, and evaporated. A soln. of the residue in acetone (5 ml) was treated with Ph2CN2 (100
mg, 0.51 mmol) and stirred for 1 h. Evaporation and FC (AcOEt/hexane 1:4) gave 26 (61 mg, 73%).
Light-yellow oil. Rf (AcOEt/hexane 1:1) 0.55. [a]2D5 =ꢀ56.7 (c=2.35, CHCl3). IR (CHCl3): 3066w,
3033w, 3012w, 2947w, 2873w, 1746s, 1602w, 1496m, 1454m, 1360m, 1264s, 1110s, 1090s, 1003m, 975m,
909s. 1H-NMR (300 MHz, CDCl3): see Table 3; additionally, 7.39–7.18 (m, 25 arom. H); 7.15 (d,
J=1.2), 6.89 (d, J=1.5) (HꢀC(2), HꢀC(3)); 6.79 (s, Ph
G
72.06, 71.11 (3t, 3 PhCH2). HR-MALDI-MS: 651.2854 ([M+H]+, C42
(5R,6R,7S,8R)-5,6,7,8-Tetrahydro-6,7,8-trihydroxyimidazo[1,2-a]pyridine-5-carboxylic Acid (6). A
soln. of 26 (44 mg, 0.61 mmol) in EtOH (5 ml) was treated with 10% Pd/C (28 mg), stirred under H2
for 48 h, and filtered through Celite (washing with 5 ml of EtOH). After evaporation, the solid residue
was washed several times with hot AcOEt. A soln. of the solid in H2O was lyophilised to give 6 (16
mg, 99%). Colourless powder. Rf (AcOEt/MeOH/AcOH 7:2.8 :2) 0.10. pKHA =6.6. [a]2D5 =ꢀ20.6
(c=0.85, MeOH). IR (ATR): 3219m, 3149m, 2933m, 1728w, 1612m, 1594s, 1527m, 1386m, 1297m,

1384
Helvetica Chimica Acta – Vol. 89 (2006)
1169s, 1056s, 966m, 874m. 1H-NMR (300 MHz, D2
O): see Table 3; additionally, 7.38 (d, J=1.8), 7.31 (d,
A
J=1.8) (HꢀC(2), HꢀC(3)). 13C-NMR (75 MHz, CDCl3): see Table 3; additionally, 123.03, 119.27 (2d,
C(2), C(3)).
4,6-Di-O-acetyl-5-amino-2,3-di-O-benzyl-5-deoxy-D-galactono-1,5-lactam (28). A soln. of 27 (1.0 g,
2.79 mmol) in pyridine (10 ml) was cooled to 08, treated with Ac2O (4 ml), stirred for 6 h, and evaporated
to afford 28 (1.23 g, 99%). Colourless oil. A small sample was purified by FC (AcOEt/cyclohexane 1:4).
Rf (AcOEt/cyclohexane 2 :1) 0.21. [a]2D5 =+112.3 (c=1.05, CHCl3). IR (ATR): 3208w, 3106w, 3063w,
3029w, 2981w, 2933w, 2873w, 1736s, 1707w, 1677s, 1496w, 1454w, 1418w, 1364m, 1310w, 1228s, 1174w,
1
1119m, 1099s, 1064m, 1045m, 1028m, 955w, 913w, 826w. H-NMR (300 MHz, CDCl3): 7.42–7.26 (m, 10
arom. H); 6.90 (br. s, NH); 5.69 (dt, J=2.8, 1.2, HꢀC(4)); 5.16 (d, J=10.9, PhCH); 4.79 (d, J=11.2,
PhCH); 4.72 (d, J=11.5, PhCH); 4.55 (d, J=11.5, PhCH); 4.23 (dd, J=11.2, 5.0, HꢀC(6)); 4.14 (d,
J=9.0, HꢀC(2)); 3.97 (dd, J=10.9, 8.4, H’ꢀC(6)); 3.87 (dd, J=9.3, 2.5, HꢀC(3)); 3.81 (ddd, J=11.2,
5.0, 2.8 HꢀC(5)); 2.12, 2.09 (2s, 2 AcO). 13C-NMR (75 MHz, CDCl3): 171.04, 170.27, 169.73 (3s, 3 C=O);
137.82, 137.13 (2s); 128.31 (2d); 128.18 (2d); 128.09 (2d); 127.90 (2d); 127 81 (d); 127.65 (d); 77.70 (d,
C(3)); 76.47 (d, C(2)); 75.63, 72.02 (2t, 2 PhCH2); 65.61 (d, C(4)); 63.45 (t, C(6)); 51.24 (d, C(5));
20.83, 20.78 (2q, 2 Me). HR-MALDI-MS: 464.1674 (100, [M+Na]+, C24H27NNaO7þ ; calc. 464.1680).
2,6-Di-O-acetyl-5-amino-2,3-di-O-benzyl-5-deoxy-D-galactono-1,5-thiolactam (29). A soln. of 28 (660
mg, 1.49 mmol) in toluene (12 ml) was treated with Lawesson’s reagent (605 mg, 1.49 mmol), heated to
808 for 30 min, cooled to 258, and treated with NaHCO3 (125 mg, 1.29 mmol). FC (AcOEt/cyclohexane
1:4) gave 29 (580 mg, 85%). Yellow foam. Rf (AcOEt/cyclohexane 1:1) 0.55. [a]2D5 =+172.9 (c=1.03,
CHCl3). IR (KBr): 3468w, 3170w, 3031m, 2929w, 2870w, 1956w, 1877w, 1749s, 1555m, 1530m, 1497m,
1
1370m, 1324m, 1226s, 1178w, 1102s, 1078m, 1056m, 1018m, 945w, 917w. H-NMR (300 MHz, CDCl3):
8.14 (br. s, NH); 7.45–7.23 (m, 10 arom. H); 5.62 (br. s, HꢀC(4)); 5.25 (d, J=10.6, PhCH); 4.81 (d,
J=10.6, PhCH); 4.57 (d, J=11.8, PhCH); 4.51 (d, J=11.8, PhCH); 4.32 (dd, J=11.2, 3.7, HꢀC(6));
4.28 (d, J=7.5, irrad. at 3.82 ! s, HꢀC(2)); 4.05 (dd, J=11.2, 9.0, H’ꢀC(6)); 3.87 (ddd, Jꢁ9.0, 4.0, 2.5
HꢀC(5)); 3.82 (dd, J=7.2, 2.5, HꢀC(3)); 2.12, 2.11 (2s, 2 AcO). 13C-NMR (75 MHz, CDCl3): 202.04
(s, C=S); 170.58, 170.07 (2s, 2 C=O); 137.83, 137.31 (2s); 128.89 (2d); 128.70 (2d); 128.60 (2d); 128.22
(4d); 80.33 (d, C(2)); 76.82 (d, C(3)); 75.98, 72.46 (2t, 2 PhCH2); 65.92 (d, C(4)); 63.81 (t, C(6)); 55.16
(d, C(5)); 20.99 (q, 2 Me). HR-MALDI-MS: 458.1634 (100, [M+H]+, C24H28NO6S+; calc. 458.1632).
Anal. calc. for C24H27NO6S (457.16): C 63.00, H 5.95, N 3.06; found: C 62.79, H 5.96, N 3.08.
(5R,6S,7S,8S)-7,8-Bis(benzyloxy)-5-{[(tert-butyl)dimethylsilyloxy]methyl}-5,6,7,8-tetrahydroimida-
G
zo[1,2-a]pyridin-6-ol (31). A soln. of 29 (580 mg, 1.27 mmol) in THF (12 ml) was cooled to 08, treated
with Hg(OAc)2 (444 mg, 1.39 mmol) and H2NCH2CH(OMe)2 (0.75 ml, 6.34 mmol), stirred for 2 h,
diluted with Et
H2O 12 :3 (15 ml) was treated with TsOH·H2O (1.45 g, 7.6 mmol) and stirred at 758 for 24 h. The mixture
was diluted with AcOEt (50 ml) and washed with sat. K2CO3 soln. The aq. layer was extracted with
AcOEt (2×50 ml). The combined org. layers were dried (Na2SO4), filtered, and evaporated. A soln. of
the residue (i.e., 30) in DMF (10 ml) was treated with Et3N (0.73 ml, 2.53 mmol). DMAP (31 mg, 0.253
SiCl (190 mg, 1.27 mmol), and stirred for 16 h. Normal workup (AcOEt/H2O)
2O (50 ml), filtered through Celite, and evaporated. A soln. of the residue in toluene/
A
ACHTREUNG
AHCTREUNG
t
mmol), and Bu(Me)2
ACHTREUNG
and FC (AcOEt/cyclohexane 1:2) afforded 31 (300 mg, 84%). Rf (AcOEt/cyclohexane 1:1) 0.39.
[a]2D5 =+55.3 (c=1.04, CHCl3). IR (ATR): 3513–3164w (br.), 3087w, 3032w, 2928w, 2856w, 1470w,
1454w, 1389w, 1360w, 1305w, 1252m, 1210w, 1131w, 1075s, 1027m, 1005m, 936w, 834s. 1H-NMR (300
MHz, CDCl3): see Table 2; additionally, 7.43–7.25 (m, 10 arom. H); 7.12, 7.10 (2d, J=1.2, HꢀC(2),
HꢀC(3)); 5.15 (d, J=11.5, PhCH); 4.87 (d, J=10.9, PhCH); 4.84 (irrad. at 3.97 ! s); 4.75 (d, J=11.8,
PhCH); 4.66 (d, J=11.5, PhCH); 4.51 (irrad. at 3.97 ! br. d, J=3.7, addition of CD
ACHTREUNG
J=4.0, 2.2); 3.97 (irrad. at 4.84 ! d, J=2.2); 3.47 (br. s, exchange with CD3
ACHTREUNG
t-Bu); 0.08, 0.05 (2s, Me
AHCTREUNG
A
ACHTREUNG
A
G
A
ACHTREUNG
(5R,6S,7S,8S)-6,7,8-Tris(benzyloxy)-5-{[(tert-butyl)dimethylsilyloxy]methyl}-5,6,7,8-tetrahydroimi-
dazo[1,2-a]pyridine (32). A soln. of 31 (422 mg, 0.85 mmol) in DMF (6 ml) was cooled to 08, treated with

Helvetica Chimica Acta – Vol. 89 (2006)
1385
NaH (60% suspension in oil, 68 mg, 1.71 mmol), stirred for 10 min, treated with BnBr (0.11 ml, 0.935
mmol), stirred for 4 h, treated with MeOH (1 ml), and stirred for 30 min. Normal workup (AcOEt/
NaHCO3 soln.) and FC (AcOEt/cyclohexane 1:2) afforded 32 (330 mg, 66%). Rf (AcOEt/cyclohexane
1:2) 0.39. [a]2D5 =+73.7 (c=1.24, CHCl3). IR (ATR): 3059w, 3030w, 2951w, 2927w, 2884w, 2855w,
1949w, 1872w, 1808w, 1605w, 1496w, 1470m, 1454m, 1389w, 1359w, 1307w, 1255m, 1207w, 1076s, 1066s,
1027m, 1005m, 919w, 835s. 1H-NMR (300 MHz, CDCl3): see Table 2; additionally, 7.37–7.26 (m, 15
arom. H); 7.17, 7.08 (2d, J=1.5, HꢀC(2), HꢀC(3)); 4.99 (d, J=11.8, PhCH); 4.80 (irrad. at 4.08 ! s);
4.78 (d, J=11.8, PhCH); 4.72 (d, J=12.1, PhCH); 4.71 (d, J=12.1, PhCH); 4.65 (d, J=11.8, PhCH);
4.63 (d, J=11.8, PhCH); 4.38 (irrad. at 4.08 ! d, J=5.6); 4.34 (irrad. at 3.95 ! dd, J=5.6, 3.1); 4.13
(irrad. at 3.95 ! d, J=5.6); 4.08 (irrad. at 4.80 ! d, J=1.6); 0.91 (s, t-Bu); 0.02, 0.01 (2s, Me
NMR (75 MHz, CDCl3): see Table 2; additionally, 138.20, 137.81, 137.63 (3s); 128.69 (d, C(2));
128.41–127.50 (several d); 119.41 (d, C(3)); 72.85, 72.38, 71.87 (3t, 3 PhCH2); 26.07 (q, Me3C); 18.38
(s, Me3C); ꢀ5.19, ꢀ5.34 (2q, Me2 H45N2O4
Si). HR-MALDI-MS: 585.3135 (100, [M+H]+, C35 Si+; calc.
585.3143). Anal. calc. for C35H44N2O4Si (584.31): C 71.88, H 7.58, N 4.79; found: C 71.78, H 7.60, N 4.79.
(5R,6S,7S,8S)-6,7,8-Tris(benzyloxy)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-5-methanol (33).
soln. of 32 (330 mg, 0.56 mmol) in THF (6 ml) was cooled to 08, treated with 1M Bu4NF·3 H2O in
3 soln.) and FC (AcOEt/cyclohexane
2Si). 13C-
AHCTREUNG
A
G
U
G
ACHTREUNG
A
AHCTREUNG
THF (0.62 ml) and stirred for 1 h. Normal workup (AcOEt/NaHCO
ACHTREUNG
2 : 1 ! AcOEt) afforded 33 (225 mg, 85%). Rf (AcOEt/cyclohexane 2 :1) 0.15. [a]2D5 =+45.5 (c=1.01,
CHCl3). IR (KBr): 3412m (br.), 3159m, 3085m, 3059m, 3030m, 2922m, 2866m, 1953w, 1875w, 1810w,
1732w, 1606w, 1521w, 1496m, 1482m, 1453s, 1356m, 1306m, 1260m, 1208m, 1130s, 1094s, 1054s, 1027s,
1
914w, 844w, 820w. H-NMR (300 MHz, CDCl3): see Table 2; additionally, 7.38–7.25 (m, 15 arom. H);
7.10 (d, J=1.1, HꢀC(2)); 7.06 (d, J=1.4, HꢀC(3)); 4.88 (d, J=11.8, PhCH); 4.76 (irrad. at 4.12 ! s);
4.71 (d, J=12.1, PhCH); 4.70 (d, J=12.1, PhCH); 4.64 (d, J=11.8, PhCH); 4.59 (d, J=12.1, PhCH);
4.56 (d, J=11.8, PhCH); 4.45 (irrad. at 4.12 ! d, J=6.3); 4.12 (irrad. at 4.76 ! d, J=1.9); 3.41 (br. s,
exchange with CD
G
137.58, 137.30 (3s); 129.79 (d, C(2)); 128.81–127.88 (several d); 118.90 (d, C(3)); 73.24, 72.41, 71.85
(3t, 3 PhCH2). HR-MALDI-MS: 471.2271 (100, [M+H]+, C29 O4þ ; calc. 471.2278). Anal. calc. for
C29H30N2O4 (470.22): C 74.02, H 6.43, N 5.95; found: C 73.76, H 6.60, N 5.99.
Diphenylmethyl (5R,6S,7S,8S)-6,7,8-Tris(benzyloxy)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-5-car-
boxylate (34). A soln. of 33 (95 mg, 0.2 mmol) in acetone (5 ml) was treated with a soln. of CrO3 (101
mg, 1.01 mmol) in 1M H2SO4 (0.9 ml) and stirred for 24 h. The mixture was diluted with AcOEt (20
ml) and washed with H2O. The aq. layer was extracted with AcOEt (2×20 ml), and the combined org.
layers were dried (Na2SO4), filtered, and evaporated. A soln. of the crude in acetone (5 ml) was treated
with Ph2CN2 (59 mg, 0.3 mmol), stirred for 2 h, and evaporated at 358. FC (AcOEt/cyclohexane 1:2 !
AcOEt) gave 34 (45 mg, 34%) and 33 (17 mg, 18%). Rf (AcOEt/cyclohexane 1:2) 0.34. [a]2D5 =+51.2
(c=0.80, CHCl3). IR (KBr): 3062w, 3030w, 2924w, 2869w, 1953w, 1883w, 1808w, 1746s, 1603w, 1586w,
1
1495m, 1453m, 1355w, 1310w, 1276m, 1247m, 1193m, 1172s, 1079s, 1027m, 977s, 911w, 847w. H-NMR
(300 MHz, CDCl3): see Table 3; additionally, 7.33–7.24 (m, 21 arom. H); 7.21–7.18 (m, 2 arom. H);
7.13 (dd, J=5.3, 1.9, 2 arom. H); 7.08 (d, J=1.6, HꢀC(2)); 6.98 (s, Ph2CH); 6.69 (d, J=1.2, HꢀC(3));
A
4.88 (d, J=11.8, PhCH); 4.67 (d, J=11.8, PhCH); 4.59 (irrad. at 4.02 ! d, J=8.1); 4.57 (d, J=12.1,
PhCH); 4.51 (d, J=12.1, PhCH); 4.41 (d, J=11.5, PhCH); 4.36 (d, J=11.8, PhCH); 4.02 (irrad. at 4.75
! d, J=1.9, irrad. at 4.59 ! d, J=4.4). 13C-NMR (75 MHz, CDCl3): see Table 3; additionally, 139.40,
139.31, 138.04, 137.66, 137.29 (5s); 129.42 (d, C(2)); 128.40–126.75 (several d); 119.86 (d, C(3)); 78.39
(d, Ph2CH); 73.40, 73.02, 72.89 (3t, 3 PhCH2). HR-MALDI-MS: 651.2865(100, [M+H]+, C42
A
G
N
calc. 651.2854). Anal. calc. for C42H38N2O5 (650.76): C 77.52, H 5.89, N 4.30; found: C 77.70, H 5.93, N
4.32.
(5R,6S,7S,8S)-6,7,8-Trihydroxy-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-5-carboxylic Acid (7). A
suspension of 34 (40 mg, 0.06 mmol) and 10% Pd/C in MeOH/H2O 2 :1 was hydrogenated (6 bar) for
2 days, filtered through Celite, evaporated, dissolved in H2O (5 ml), and washed with AcOEt (4×).
The aq. layer was lyophillised and dried (P2O5) to yield 7 (13 mg, 98%). pKHA =6.6. [a]2D5 =ꢀ79.7
(c=0.71, H2O). IR (KBr): 3410s (br.), 2923m, 2857m, 2778w, 1631s, 1524w, 1491w, 1390m, 1313m,
1
1267w, 1235w, 1171w, 1102m, 907w, 860w, 831w. H-NMR (300 MHz, D2
A

1386
Helvetica Chimica Acta – Vol. 89 (2006)
7.37, 7.34 (2 br. s, HꢀC(2), HꢀC(3)). 13C-NMR (75 MHz, D2
C
(232.97): C 41.22, H 5.23, N 12.02; found: C 41.05, H 4.76, N 11.60.
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Received April 12, 2006