Very strong inhibition of glucosidases by C(2)-substituted tetrahydroimidazopyridines

Article abstract of DOI:10.1002/(SICI)1522-2675(20000119)83:1<58::AID-HLCA58>3.0.CO;2-K

The C(2)-substituted imidazoles 11, 15-17, 19, 21, 23/24, 28-31, 37, and 38 have been prepared from the known 2,3-unsubstituted imidazole 7 via the iodoimidazole 10, and tested as inhibitors of β- and α-glucosidases. Introduction of hydrophobic and flexible substituents, such as in 28 and 29, led to a very strong inhibition of β-glucosidases, with K(i) values for 29 of 1.2 and 0.11 nm against β-glucosidases from almonds and Caldocellum saccharolyticum, respectively. A slow onset of the inhibition was observed for the strongly inhibiting 16, 28-31, 37, and 38. While the introduction of a hydroxymethyl or a phenethyl substituent as in 17 and 30 led to stronger inhibition, the 1'-hydroxyphenethyl derivatives 37 and 38 were weaker inhibitors than 16 and 29. This result is interpreted in the light of a conformational change of the substrate on the way to the transition state. The substituent at C(2) has only a moderate influence on the selectivity of the inhibition of two β- and one α-glucosidases, increasing it by a maximal factor of ca. 10 (16), or decreasing it by a maximal factor of ca. 15 (37).

Full text of DOI:10.1002/(SICI)1522-2675(20000119)83:1<58::AID-HLCA58>3.0.CO;2-K

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Helvetica Chimica Acta ± Vol. 83 (2000)
Very Strong Inhibition of Glucosidases by C(2)-Substituted
Tetrahydroimidazopyridines
by Narendra Panday, Yves Canac, and Andrea Vasella*
Laboratorium für Organische Chemie, ETH-Zentrum, Universitätstrasse 16, CH-8092 Zürich
The C(2)-substituted imidazoles 11, 15 ± 17, 19, 21, 23/24, 28 ± 31, 37, and 38 have been prepared from the
known 2,3-unsubstituted imidazole 7 via the iodoimidazole 10, and tested as inhibitors of b- and a-glucosidases.
Introduction of hydrophobic and flexible substituents, such as in 28 and 29, led to a very strong inhibition of b-
glucosidases, with Ki values for 29 of 1.2 and 0.11 nm against b-glucosidases from almonds and Caldocellum
saccharolyticum, respectively. A slow onset of the inhibition was observed for the strongly inhibiting 16, 28 ± 31,
37, and 38. While the introduction of a hydroxymethyl or a phenethyl substituent as in 17 and 30 led to stronger
inhibition, the 1'-hydroxyphenethyl derivatives 37 and 38 were weaker inhibitors than 16 and 29. This result is
interpreted in the light of a conformational change of the substrate on the way to the transition state.
The substituent at C(2) has only a moderate influence on the selectivity of the inhibition of two b- and one
a-glucosidases, increasing it by a maximal factor of ca. 10 (16), or decreasing it by a maximal factor of
ca. 15 (37).
Introduction. ± Tetrahydropyridoimidazoles are the strongest glycosidase inhibitors
of the pyridoazole type [1 ± 3], interacting most favourably with both the catalytic acid
and the catalytic nucleophile at the active site [4]. Still stronger inhibitors may result
from the introduction of aglycon mimicking substituents into the imidazole ring. A
pKHA/Ki correlation of the 2- and 3-acetamido d-gluco- and d-manno-imidazopyridines
1 ± 4 has shown that the acetamido group at C(3) interacts unfavourably with retaining
b-glycosidases of family 1, while the acetamido group at C(2) does not noticeably
influence the inhibition [5]. This result is in agreement with molecular modeling, which
indicates that only substituents at C(2) project into the aglycon binding subsite of such
b-glycosidases, while substituents at C(3) interact unfavourably with the active site.
Hence, introducing substituents at C(2) may lead to stronger inhibitors.

Helvetica Chimica Acta ± Vol. 83 (2000)
59
Aglycon-mimicking groups may be introduced by N-acylation of the 2-amino-
imidazoles that were prepared as intermediates in the synthesis of 1 and 2 [5].
However, 2-acylamino substituents lower the basicity as evidenced by the pKHA values
of 1, 2, 5, and 6 [5]. Lowering the basicity impairs the interaction of the azole moiety
with the catalytic acid and the catalytic nucleophile, with a negative effect on the
inhibition. According to the Hammett s constant of the amino group, 2-(alkylamino)-
imidazopyridines should be more strongly basic than 5 or 6, but we had reasons to
suspect that they would not be sufficiently stable [5]. We have, therefore, prepared and
tested the imidazoles 11, 15 ± 17, 19, 21, 23/24, 28 ± 31, 37, and 38 (Scheme) which possess
a range of hydrophilic and hydrophobic substituents at C(2). They should be readily
accessible from the known imidazole 7.
Synthesis. ± The tetrabenzylated 2,3-unsubstituted imidazole 7 [2] was transformed
into the 2-iodoimidazole 101) by analogy with the procedure described by Tatsuta et al.
for the preparation of a protected galacto-configured 2-bromoimidazole [6]. Treatment
of 7 with 10 equiv. of NIS at 708 in DMF gave the 2,3-diiodoimidazole 8 in 83 ± 92%
yield. Milder conditions (5 equiv. of NIS, 608) led mainly to the 3-iodoimidazole 9
(63%, besides 24% of 8), in agreement with the known reactivity of imidazoles [6 ± 8].
Regioselective deiodination of 8 at C(3) by sequential treatment with EtMgBr2) and
H2O at 108 followed by crystallization gave the desired 2-iodoimidazole 10 (82 ±
94%). The deprotected 2-iodoimidazole 11 was obtained in 63% yield by BCl3-
promoted debenzylation [9] of 10.
The structure of the diiodoimidazole 8 was established by X-ray analysis (Fig. 1).
6
3
This imidazole adopts a conformation between H7 ) and a sofa with C(7) below the
ring plane, as conditioned by the 1,5-interaction between the I substituent at C(3) and
the BnOCH2 group at C(5)4). The position of the I substituent in 9 and 10 has been
assigned on the basis of the upfield shift of the 13C-NMR signal of the iodinated C-atom
and by comparison of the J(H,H) values of 9 and 10 to those of the diiodide 8 and the
parent 7 [2] (Table 1). J(H,H) Values of 8 and 9 show that in solution both piperidines
adopt a sofa conformation, similar to that found for 8 in the solid state. The coupling
constants of the 2-iodoimidazole 10, however, agree well with those of 7 (7H6/6H7 2 :1
[2]), confirming that 8 was de-iodinated at C(3).
To prepare the hydroxymethylated and the aminomethylated imidazoles 16 and 17,
we treated the organomagnesium derivative of 10 with either DMF or TsCN [10 ± 15].
This yielded 85% of the 2-formylimidazole 12 and 89% of the imidazole-2-carbonitrile
13, respectively. Reduction of the aldehyde 12 with LiAlH4 provided 87% of the
(hydroxymethyl)imidazole 14. Its deprotection by hydrogenolysis was accompanied by
deoxygenation of the HOCH2 group, yielding 71% of the 2-methylimidazole 15 that
1
)
Exploratory metal/halogen exchange reactions and Pd-mediated coupling of the corresponding 2-
bromoimidazole were much less satisfactory.
Similar results were obtained when 8 was treated with BuLi at 788.
Since the direction of numbering of azolopyridines (cf. 7 in the Scheme) is opposite to that of pyranosides,
the sides above and below the plane of the imidazopyridines, as defined by the clockwise and
counterclockwise numbering, are interchanged with those defined according to carbohydrate numbering.
A similar 1,5 interaction has been noticed between the 3-acetamido group and the BnOCH2 group at C(5)
of the protected gluco- and manno-configured 3-acetamidoimidazoles [5].
2
3
)
)
4
)

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Helvetica Chimica Acta ± Vol. 83 (2000)
Scheme
a) N-Iodosuccinimide (NIS), DMF, 808; 83 ± 92% of 8. b) NIS, DMF, 608; 63% of 9, 24% of 8. c) EtMgBr, THF
of CH2Cl2, 08; 82 ± 94%. d) BCl3, CH2Cl2, 788 ! 08; 63% of 11, 83% of 16 from 14; 74% of 37/38 from 33/34;
73% of 37 from 33; 71% of 38 from 34. e) 1. EtMgBr, 2. DMF 85%. f) 1. EtMgBr, 2. TsCN; 89%. g) LiAlH4/
THF, 788; 87%. h) H2, AcOEt/MeOH/AcOH, Pd/C; 63% of 15, 85% of 19, 82% of 28. i) 1. EtMgBr, 2.
PhNCO; 95%. j) AcOH/TFA 1:1, Pd/C, H2; 79%. k) 1. EtMgBr, 2. ZnBr2, 3. [Pd(PPh3)4], PhI; 72%; l) MeOH,
H2O, AcOH 9 :2 :1, Pd/C (10%), H2; 55% of 21, 60% of 23/24. m) 1. EtMgBr, 2. ZnBr2, 3. [Pd(PPh3]4], 2-
Bromopyridine; 77%. n) Methyl acrylate, Pd(OAc)2[P(2-Tolyl)3]2, K2CO3, DMF; 92% of 25. o) Styrene,
Pd(OAc)2[P(2-Tolyl)3]2, K2CO3, DMF/H2O 6 :1; 59% of 26. p) Acrylonitrile, Pd(OAc)2, Ph3P, K2CO3, DMF;
41% of 27. q) 1. Pd/C, H2, 2. BCl3, CH2Cl2; 88% from 26. r) Phenylacetylene, Pd(PPh3)4, CuI, Et3N, DMF; 82%
of 32. s) Aq. HCl, 408; quant. t) BnLi, N,N,N',N'-tetramethylethylenediamine (TMEDA); 64%. u) 2-Naphthoyl
chloride, pyridine; 35: 32%; 36: 36%. v) NaOMe,608, 98% of 33, 96% of 34.

Helvetica Chimica Acta ± Vol. 83 (2000)
61
Fig. 1. ORTEP Representation of the diiodoimidazole 8
Table 1. Selected 13C-NMR Chemical Shifts and J(H,H) Values of the Protected 2,3-Unsubstituted Imidazole 7
and the Protected Iodoimidazoles 8 ± 10
Compound
C(2)
C(3)
J(5,6)
J(6,7)
J(7,8)
7
8
9
129.62
81.28
130.04
81.77
117.57
97.07
102.15
122.88
7.5
1.9
2.0
7.5
7.5
4.1
4.2
7.5
5.3
3.8
3.7
5.4
10
was also obtained (63%) by hydrogenolysis of the aldehyde 12. However, BCl3-promoted
deprotection of 14 gave the desired (hydroxymethyl)imidazole 16 in 83% yield. The
CH2NH2 derivative 17 was prepared by hydrogenolysis at 6 bar of the imidazole-
carbonitrile 13 in AcOH/CF3CO2H 1:1 (79%). Hydrogenolysis in the absence of
CF3CO2H considerably prolonged the reaction (32 instead of 8 h), but still led to the

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desired (aminomethyl)imidazole (78%). In MeOH, however, hydrogenolysis of 13
remained incomplete even after 76 h, and was accompanied by reductive deamination
of the NH2CH2 group, as evidenced by the 1H-NMR spectrum of the crude.
The (phenylcarbamoyl)imidazole 19 was obtained by treatment of the organo-
magnesium derivative of 10 with PhNCO (95% of 18), followed by hydrogenolytic
debenzylation (85%). The protected 2-phenyl- and 2-pyridylimidazoles 20 and 22 were
prepared according to a method described by Minato et al. [16] for bromomagnesium-
pyrroles. Following their protocol, the organomagnesium derivative of 10 was treated
with ZnBr2 and then with either PhI or 2-bromopyridine in the presence of [Pd(PPh3)4
]
to yield 72% of 20 and 77% of 22, respectively. The phenylimidazole 20 was
hydrogenolytically deprotected to the tetrol 21 (68%), while hydrogenolysis of 22 also
reduced the piperidine moiety and led to a 1:1 mixture of the diastereoisomeric
piperidinylimidazoles 23 and 24 (60%).
To prepare the [(methoxycarbonyl)ethyl]-, the (phenethyl)-, the (aminopropyl)-
and the (carboxyethyl)imidazoles 28 ± 31, respectively, we subjected the 2-iodoimida-
zole 105) to standard Heck conditions (Pd(OAc)2, Ph3P, Et3N, or K2CO3, DMF 60 ±
808) with methyl acrylate, styrene, and acrylonitrile. This gave the coupling products
25 ± 27 in 63, 42, and 41% yield, respectively, along with variable amounts of 7 and of
starting material 10. Attempts to improve the yields by using other commercially
available Pd catalysts, varying the base, or adding tetrabutylammonium salts6)
remained unsuccessful. A black precipitate (Pd0?) appeared at elevated temperatures
(>1008), independently of the catalyst used. Addition of excess Ph3P or trifurylphos-
phine led to 10 ± 15% of the phosphonium salts 39 or 407), and reduced the yield of the
desired coupling products. Addition of H2O (14% (v/v)) [28] increased the yield of the
(phenylvinyl)imidazole 26 from 43 to 51%, but had no influence on the yield of either
the (cyanovinyl)imidazole 27 or the [(methoxycarbonyl)vinyl]imidazole 25. However,
replacing Pd(OAc)2/PPh3, by Herrmannꢀs palladacycle [29] improved the yield of 25
from 63 to 92%. This catalyst also improved the yield of the (phenylvinyl)imidazole 26
from 51 to 59% but had no effect on the yield of the (cyanovinyl)imidazole 27.
Hydrogenation of 25 and 27 (Pd/C in AcOH) gave the deprotected [(methoxy-
carbonyl)ethyl]- and (aminopropyl)imidazoles 28 and 30 in 82 and 59% yield,
respectively. Under the same conditions, the CˆC bond of the stilbene analogue 26 was
readily reduced, while debenzylation proceeded very slugglishly, even after adding
fresh catalyst and increasing the H2 pressure. Debenzylation was completed by treating
the crude in CH2Cl2 with BCl3, providing 88% of the deprotected (phenethyl)imida-
zole 29. The overall yield of 29 from the iodoimidazole 10 was significantly increased
by proceeding via the (phenylethynyl)imidazole 32, obtained in 82% by Sonogashira
coupling of 10 with ethynylbenzene. The propionic acid 31 was obtained quantitatively
as the hydrochloride by hydrolysis of the methyl propionate 28 in 1m HCl.
5
)
)
)
For examples of Heck reactions with iodoimidazoles, see [17 ± 24]. In most cases, the coupling products
have been obtained in moderate yields.
6
7
The rate- and yield-increasing influence of tetraalkylammonium salts in Heck reactions has been
documented [25].
Formation of tetraarylphosphonium salts by PdII-mediated coupling of halogenoarenes with triarylphos-
phines is known [26][27]. As the crude reaction was worked up with sat. aq. NH4Cl, 39 and 40 are assumed
to have chloride counterions.

Helvetica Chimica Acta ± Vol. 83 (2000)
63
Considering the strong inhibition (see below) by the (hydroxymethyl)imidazole 16
and the phenethyl derivative 29, we also prepared the diastereoisomeric (a-
hydroxyphenethyl)imidazoles 37 and 38. Addition of BnLi to the formylimidazole 12
gave a 45 :55 mixture of the (a-hydroxyphenethyl)imidazoles 33 and 34 (64%, along
with 12% of 7), which could not be separated by crystallization, FC, or HPLC. The 2-
naphthoates 35 and 36, however, were separated by TLC and isolated by HPLC (32%
of 35 and 36% of 36). Attempts to crystallize either 35 or 36 from various solvents
failed, but the diastereoisomeric alcohols 33 and 34, obtained in 98% and 96% yield by
denaphthoylation of 35 and 36, crystallized readily from Et2O/hexane. They were
debenzylated (BCl3) to 37 (73%) and 38 (71%). X-Ray analysis of the (R)-alcohol 338)
at low temperature (Fig. 2) established the configuration at C(1') of 33 and thereby
also of 34 ± 38.
Fig. 2. ORTEP Representation of (a-hydroxyphenethyl)imidazole 33. Non-H-atoms are refined isotropically
(cf. Exper. Part)
8
)
The (S)-alcohol 34 gave cotton-like crystals that were not suitable for X-ray analysis.

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Helvetica Chimica Acta ± Vol. 83 (2000)
With the exception of the additional signals of the functional groups at C(2) and
1
their influence on the chemical shifts of H C(3), C(2), and C(3), the H-NMR and
13C-NMR spectra of the protected and unprotected C(2)-functionalized imidazoles
12 ± 38 closely resemble those of the 2,3-unsubstituted imidazoles 4 and 7. Thus, the
7
6
protected C(2)-functionalized imidazoles exist as 2 :1 mixtures of the H6 and H7
7
conformers, while the deprotected imidazoles adopt the expected H6-conformation.
The H C(5), H C(6), CH2C(5)-, and H C(3) signals of the phosphonium salts 39
and 40 are strongly shielded as compared to those of 7, while the H C(8) signal of 39
and 40 is strongly deshielded (Table 2). The J(5,6), J(6,7), and J(7,8) values of 39 and
40 indicate a conformation close to 6H7.
1
Table 2. Selected H-NMR Chemical Shifts and J(H,H) Values of the Protected 2,3-Unsubstituted Imidazole 7
and the Phosphonium Salts 39 and 40
Compound
H
C(5)
H
C(6)
H
C(7)
H
C(8) CH C(5) CH' C(5) J(5,6) J(6,7) J(7,8)
7
39
40
4.20
3.92
3.99
3.88
3.64
3.75
4.11
4.01
4.13
4.77
6.06
6.14
3.76
2.54
3.02
3.88
3.11
3.28
7.8
4.7
4.7
7.8
4.6
4.5
5.6
2.8
3.2
Enzymatic Tests and Discussion. ± The C(2)-functionalized imidazoles 11, 15 ± 17,
19, 21, 23/24, 28 ± 31, 35, and 36 inhibit b-glucosidases from almonds and Caldocellum
saccharolyticum, and the a-glucosidase from yeast in a competitive, mixed, or non-
competitive fashion (Table 3). The two b-glucosidases are inhibited about as strongly
by the methylimidazole 15 as by the 2,3-unsubstituted imidazole 5, indicating that the
Me group of 15 does not significantly interact with the aglycon binding subsite. The
almost isosteric iodoimidazole 11 inhibits the two b-glucosidases some 5 ± 7 times less
strongly than 15 and 5, in agreement with its reduced basicity. The (hydroxymethyl)-
imidazole 16 inhibits the b-glucosidases from almonds ca. 10 times and the b-
glucosidase from C. saccharolyticum ca. 4 times more strongly than 5 or 15. This is very
likely due to H-bonding. Such an interaction appears particularly probable in view of
the lower pKHA of the hydroxymethylated 16, relative to that of 5. A probable H-bond
acceptor is the carbonyl O-atom of the catalytic acid. This assumption is supported by
fitting the (hydroxymethyl)imidazole 16 into the active site of the b-glycosidase from
Sulfolobus solfataricus 9) (Fig. 3), another member of the family 1 glycosidases.
9
)
X-Ray structure of the native enzyme solved at 2.6-Š resolution by Aguilar et al. [30].

Helvetica Chimica Acta ± Vol. 83 (2000)
65
Table 3. Inhibition Constants Measured at pH 6.8 and pKHA of C(2)-Functionalized Imidazoles Compared to
Those of the 2,3-Unsubstituted Parent Imidazole 5
Compound
pKHA
b-Glucosidases
b-Glucosidase
a-Glucosidase
from almondsa)
from Caldocellum s.b)
from brewerꢀs yeasta)
5
11
15
16
17
19
21
23/24
28
29
30
31
37
38
6.12
4.62
6.46
5.22
100 nm
1280 nmc)
260 nmc)
11 nm
20 nm(a ˆ 3.2)
170 nm
59 mm
1850 mmc)
72 mmc)
25 nmc)
5 nm
69 mmc)
4.08/ > 9.0
1600 nmc)
3000 nm
100 nm (a ˆ 7.0)
3000 nmc)
9.9 nmd)
1.2 nm
150 nmc)
140 nm
2060 mmc)
2150 mmc)
554 mmc)
> 3400 mmc)
25 mmc)
< 3.0
4.99
18 nm
600 nm
e
)
6.17
6.03
1.8 nm (a ˆ 2.5)
0.11 nm (a ˆ 15)
25 nmc)
0.5 mmc)
185 mmc)
242 mmc)
3 mm
5.32/ > 9.0
4.06/7.05
70 nmc)
55 nmc)
18 nmc)
16 nm
7 nm
e
)
)
63 nm
41 nm
e
10 mm
a) At 378. b) At 558. c) IC50 d) Non-competitive inhibition. e) Not determined.
.
In contrast to the effect of the CH2OH group at C(2), the CH2NH2 group at C(2)
reduces the inhibition considerably, as evidenced by the IC50 values of 17. This may be
due to unfavourable interactions of the ammonium group with the enzyme, the lower
basicity of the imidazole, and/or H-bonding with the imidazole N(1)-atom that impair
the interaction with the catalytic acid. In keeping with the weak inhibition by the
(aminomethyl)imidazole 17, the diastereoisomeric piperidinylimidazoles 23/24 (1:1)
inhibit the b-glucosidases also much less strongly than 5.
In spite of its lower pKHA value, the phenylimidazole 21 inhibits the b-glucosidases
as strongly as 5, indicating a favourable interaction of the Ph group with the aglycon
binding subsite that compensates for the effects of the lower basicity. Such a
compensation is not observed for the (phenylcarbamoyl)imidazole 19 (pKHA <3)10) as
reflected by its weaker inhibition of the b-glucosidases.
A very significant increase of the inhibitory strength is observed for the
[(methoxycarbonyl)ethyl]imidazole 28 and particularly for the (phenethyl)imidazole
29. To the best of our knowledge, the phenethyl derivative 29 is the strongest inhibitor
of a b-glucosidase described so far. This competitive inhibition of the almond b-
glucosidases and the almost competitive inhibition of the C. saccharolyticum b-
glucosidase most probably results from the interaction of the substituent at C(2) with
the aglycon binding subsite. The strong inhibitory properties of 28 and 29, as compared
to those of the phenylimidazole 21 or the (phenylcarbamoyl)imidazole 19, may reflect
the higher flexibility of the substituents at C(2) of 27 and 28. The (aminopropyl)imi-
dazole 30 and the carboxylic acid 31 inhibit the two b-glucosidases 5 ± 227 times less
strongly than the [(methoxycarbonyl)ethyl]imidazole 28 and the (phenethyl)imidazole
29. It is tempting to conclude that these b-glucosidases prefer hydrophobic aglyca.
However, the inhibition has only been determined at pH 6.8, where both the
10
)
No inflection of the titration curve was observed between pH values of 3.0 and 9.0 upon attempted
determination of the pKHA of 21. It is, therefore, assumed that its pKHA is below 3.0.

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Helvetica Chimica Acta ± Vol. 83 (2000)
Fig. 3. (Hydroxymethyl)imidazole 16 fitted into the active site of b-Glucosidase from Sulfolobus solfataricus
monoammonium salt of 30 and the carboxylic acid 31 are expected to form a strong
intramolecular H-bond to N(1) that may have to be cleaved upon binding of the
enzyme. Indeed, while sweet almond b-glucosidases prefer hydrophobic aglycons [31],
this is presumably not so for the b-glucosidase from C. saccharolyticum, natural
substrate of which appears to be cellobiose [32]. Irrespective of these considerations,
the strong inhibition by the phenethyl derivative 29 may reflect hydrophobic
interactions of the substituent at C(2) with putative aromatic residues close to the
aglycon binding site of the glucosidases. Aromatic residues at this site have, e.g., been
demonstrated in cellobiohydrolase I of Trichoderma reesei [33]11).
11
)
The importance of hydrophobic interactions in the binding of biologically active compounds to their
receptors has recently been reviewed by Teague and Davis [34].

Helvetica Chimica Acta ± Vol. 83 (2000)
67
The difference between the inhibition of the two diastereoisomeric hydroxyphe-
nethyl derivatives 37 and 38 is small, the (1'S)-diastereoisomer 38 inhibiting the two
enzymes slightly more strongly than the (1'R)-configured 37. Remarkably, both the
hydroxyphenethyl derivatives 37 and 38 inhibit the b-glucosidases from almonds and C.
saccharolyticum 34 ± 145 times less strongly than the phenethyl derivative 29 and 1.4 ±
5.7 times less strongly than the hydroxymethyl derivative 16. To rationalize this finding,
we considered the change of the ring conformation of the glycon in the course of the
enzymatic glycoside hydrolysis. A conformational change is required for the
pseudoaxial orientation of the scissile bond, as postulated by the theory of stereo-
electronic control [35] and evidenced by X-ray analysis of two endo-b-glucosidases
[36][37]. This conformational change implies that, on the way to the transition state,
the glycosidic O-atom is shifted above the average plane of the 1 site [38] of the
undistorted substrate. The position of the catalytic acid should change in a
complementary fashion. For anti-protonating [39] b-glucosidases, this suggests that A
represents the relevant conformer of the hydroxymethyl derivative 16. The ꢁupwardꢀ
shift of the pseudoaxial aglycon would be mimicked by conformer B of the phenethyl
derivative 29. It is not possible to combine the hypothetically preferred conformers A
and B while maintaining the optimal position of both the OH and the phenethyl group,
as in conformers A and B. The small difference between the inhibition of the
diastereoisomeric hydroxyphenethyl derivatives 37 and 38 may indicate that the
position of the OH group in conformer C of 38 is sterically less favourable than the
position of the OH group in conformer D of 37 but that D may form an intramolecular
H-bond, as shown below, impairing the interaction of the N(1)-atom with the catalytic
acid.
The imidazoles 16, 28 ± 31, 37, and 38 are slow binding inhibitors of the two b-
glucosidases, as evidenced by the asymptotic activity curve (initial burst after addition
of the b-glucosidase to the substrate/inhibitor solution and gradual decrease of the
enzymatic activity) (Fig. 4). According to the activity curves, the steady-state kinetics
was reached after a period of ca. 20 min. For the determination of the IC50 and Ki
values, the enzymatic reaction was started by addition of the substrate after
preincubating the b-glucosidase in the presence of the inhibitor for 30 min12).
Slow inhibition is a well-documented phenomenon [40 ± 44] that has also been
observed for some inhibitors of glycosidases [45][46]. It has been attributed to the
isomerization of the initial enzyme-inhibitor complex (EI) into a complex (EI*) which
binds the inhibitor much more tightly. Approximate values for k3 (forward isomeri-
12
)
Almost identical IC50 or Ki values were obtained after preincubation for 1 h.

68
Helvetica Chimica Acta ± Vol. 83 (2000)
Fig. 4. Time-dependent decrease of the activity of the b-Glucosidase from Caldocellum saccharolyticum in the
presence of 28
zation rate of EI) and k4 (reverse isomerization rate of EI*) were determined for 28 and
29 (Table 4) by a procedure given in [43] (cf. Exper. Part). According to the ratio k3/k4,
the inhibition increases with time by a factor of 79 ± 400 compared to the initial
inhibition. This ratio correlates with the lifetime of EI* and is significant in view of a
potential in vivo application of the inhibitor, since the reverse isomerization rate of EI*
(k4) is not affected by the inhibition-induced upstream accumulation of the substrate
[43].
Table 4. Rate Constants k3 and k4 for 28 and 29 According to Eqn. 1 and Ki Values Determined with and without
Preincubation of the Enzyme and the Inhibitor
k1
*
)
k3
*
)
E ‡ I
EI
EI*
(1)
k2
k4
Compound
b-Glucosidase
k3
k4
k3/k4
Ki(initial)a)
Ki(end)b)
1
1
1
1
1
1
28
29
29
Almonds
Almonds
Caldocellum
0.0597 s
0.0325 s
0.0400 s
0.00015 s
0.00041 s
0.00023 s
400
80
174
1.0 mm
0.1 mm
0.01 mm
0.0099 mm
0.0012 mm
0.0001 mm
a) No preincubation of enzyme and inhibitor. b) Preincubation of enzyme and inhibitor during 30 min.
The 2,3-unsubstituted imidazole 5, like other basic inhibitors of the lactone type,
inhibits both b- and a-glucosidases. This lack of selectivity has been rationalized by
pointing out that the less favourable steric relation, in a-glucosidases, between the basic
site and the catalytic acid may be compensated by coulombic interactions resulting
from (partial) protonation of the inhibitor [47]. One, therefore, expects the basic

Helvetica Chimica Acta ± Vol. 83 (2000)
69
character of the C(2)-substituted imidazoles to be particularly important for the
inhibition of a-glucosidases. The orientation of the substituent at C(2) in the plane of
the imidazole ring is expected to be unfavourable for the inhibition of a-glucosidases
and may lead to an improved selectivity of C(2)-substituted imidazoles towards b-
glucosidases. However, the IC50 values (Table 3) determined against yeast a-
glucosidase show that the substituent at C(2) may also favourably interact with this
enzyme. Thus, the (hydroxymethyl)imidazole 16 inhibits the a-glucosidase about as
strongly as the more highly basic 5 and 15, suggesting that C(1') OH is again involved
in H-bonding. The [(methoxycarbonyl)ethyl]imidazole 27, the (phenethyl)imidazole
29, and the two diastereoisomeric (a-hydroxyphenethyl)imidazoles 37 and 3813) are
significantly stronger inhibitors than 5 or 15. This may result from the conformational
flexibility of the substituent at C(2) of 28, 29, 37, and 38. The stronger inhibition by the
[(methoxycarbonyl)ethyl]imidazole 28 and the (phenethyl)imidazole 29 as compared
to that of the (aminopropyl)imidazole 30 and the carboxylic acid 31 suggests that
hydrophobic interactions contribute significantly to the binding of the inhibitors. The
importance of the basicity of the imidazoles is illustrated by the 26-fold weaker
inhibition of the yeast a-glucosidase by the iodoimidazole 11 than by the isosteric, but
more strongly basic methylimidazole 15. Also the (phenylcarbamoyl)imidazole 19 and
the phenylimidazole 21 are weaker inhibitors than 5. In contradistinction to the
inhibition of the b-glucosidases, where 21 and 5 are about equipotent, the lower basicity
of 21 is not compensated by a favourable interaction of the Ph group with the yeast a-
glucosidase. The amines 17 and 23/24 are again weak inhibitors, possibly for reasons
analogous to those discussed above.
As expected for inhibitors designed for b-glucosidases, 5 and all C(2)-functionalized
imidazoles described here inhibit the b-glucosidases significantly more strongly than
yeast a-glucosidase, with the (hydroxymethyl)imidazole 16 and the phenylimidazole 21
showing the highest and the (a-hydroxyphenethyl)imidazoles 37 and 38 the lowest
selectivities. High selectivity for the b-glucosidases, particularly for the C. saccharo-
lyticum b-glucosidase, is also observed for the rather weakly inhibiting (amino-
methyl)imidazole 17, the 1:1 mixture of the piperidinylimidazoles 23/24, and the
(phenylcarbamoyl)imidazole 19, while the selectivity of the strongly inhibiting
(phenethyl)imidazole is not higher than that of the 2,3-unsubstituted imidazole 5. As
compared to the selectivity of 5, which inhibits b-glucosidases from almonds 590 times
and b-glucosidase from C. saccharolyticum 2950 times more strongly than a-glucosidase
from yeast, the introduction of a substituent at C(2) reduces the selectivity by a
maximal factor of ca. 15 (37) and enhances it by a maximal factor of ca. 10 (16). We
take these low values as an indication that the inhibition of b-glucosidases, and the
selectivity may be further improved by judicious choice of the side chain at C(2).
We thank Dr. B. Schweizer for the determination of the X-ray structures of 8 and 33, Dr. I. Billault for
providing crystals of 8, J. Schneider and D. Manser for the pKHA determinations, M. Terinek for a generous
sample of 7, Dr. B. Bernet for checking the experimental part, and the Swiss National Science Foundation and
Oxford Glycosciences Ltd., Abingdon (UK), for generous support.
13
)
The diastereoisomeric hydroxyphenethyl derivatives 37 and 38 inhibit the a-glucosidase from yeast 6 ± 10
times less strongly than 29. In contradistinction to the inhibition of the b-glucosidases, the (1'R)-
diastereoisomer 37 is a slightly stronger inhibitor than the (1'S)-diastereoisomer 38.

70
Helvetica Chimica Acta ± Vol. 83 (2000)
Experimental Part
General. Solvents were distilled before use. Normal workup implies distribution of the crude product
between Et2O and sat. aq. soln. of NH4Cl, and ice, unless indicated otherwise, drying of the org. layer (MgSO4),
filtration, and evaporation of the filtrate. M.p.: uncorrected. TLC: Merck silica gel 60F-254 plates; detection by
heating with mostain (400 ml of 10% H2SO4 soln., 20 g of (NH4)6Mo7O24 ´ 6 H2O, 0.4 g of Ce(SO4)2). Flash
chromatography (FC): silica gel Fluka 60 (0.04 ± 0.063mm). IR Spectra: KBr or 3% CHCl3 soln. 1H-NMR (300
MHz, if not indicated otherwise) and 13C-NMR (75 MHz, if not indicated otherwise) were measured at 258:
Chemical shifts d in ppm and coupling constants J in Hz. FAB- and CI-MS: 3-nitrobenzyl alcohol and NH3 as
matrix, resp., unless indicated otherwise.
(5R,6R,7S,8S)-Tris(benzyloxy)-5-[(benzyloxy)methyl]-2,3-diiodo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine
and (5R,6R,7S,8S)-6,7,8-Tris(benzyloxy)-5-[(benzyloxy)methyl]-3-iodo-5,6,7,8-tetrahydroimidazo[1,2-a]pyri-
dine (8 and 9, resp.). a) A soln. of 7 (290 mg, 0.52 mmol) in DMF (3.5 ml) was treated with N-iodosuccinimide
(NIS; 1.16 g, 5.18 mmol) and kept at 808 for 6 h. The brown mixture was diluted with Et2O, washed successively
with a sat. aq. NH4Cl soln., a 5% aq. NaS2O3 soln., and H2O, dried (MgSO4), and filtered. Evaporation and FC
(hexane/AcOEt 9 :1) gave 8 (389 mg, 92%), which was recrystallized in hexane/Et2O (colourless crystals,
suitable for X-ray analysis). Reaction performed on a larger scale (2.70 g, 4.82 mmol) gave 8 (3.23 g, 83%).
b) A soln. of 7 (96 mg, 0.171 mmol) in DMF (1 ml) was treated with NIS (192 mg, 0.855 mmol) and kept at
608 for 8 h. Workup and FC as described in a gave 9 (74 mg, 63%) and 8 (33 mg, 24%).
Data of 8: Rf (hexane/Et2O 1:1) 0.65. M.p. 76 ± 778. UV (CHCl3): 269 (3.2). IR (CHCl3): 3008w, 2959w,
2927s, 2856s, 1727w, 1683w, 1602w, 1455m, 1376w, 1262s, 1097s, 1016s, 864w. 1H-NMR (CDCl3): 3.63 (dd, J ˆ 9.3,
4.4 CH C(5)); 3.71 (dd, J ˆ 9.7, 8.7, CH' C(5)); 4.07 (t, J ˆ 4.1, irrad. at 4.68 ! d, J ꢀ 4.0, H C(7)); 4.33
(dd, J ˆ 4.4, 1.9, irrad. at 4.07 ! d, J ꢀ 1.5, H C(6)); 4.41 (s, PhCH2); 4.45 (ddd, J ˆ 8.7, 4.7, 1.9, H C(5)); 4.47
(d, J ˆ 11.8, PhCH); 4.55 (d, J ˆ 11.8, PhCH); 4.57 (d, J ˆ 11.8, PhCH); 4.67 (d, J ˆ 12.1, PhCH); 4.68 (d, J ˆ 3.8,
H
C(8)); 4.81 (d, J ˆ 12.1, PhCH); 5.10 (d, J ˆ 12.1, PhCH); 7.17 ± 7.43 (m, 20 arom. H). 13C-NMR (CDCl3):
60.88 (d, C(5)); 69.49 (t, CH2 C(5)); 72.32, 72.92, 73.10, 73.27 (4t, 4 PhCH2); 72.16, 73.27, 78.13 (3d, C(6), C(7),
C(8)); 81.28 (s, C(2)); 97.09 (s, C(3)); 127.87 ± 128.72 (several d); 137.60, 137.78, 137.81, 138.37 (4s); 149.26
(s, C(8a)). CI-MS (NH3): 813 (3, [M ‡ 1] ), 685 (1, [M I] ), 599 (1), 493 (6), 91 (100).
‡
‡
X-Ray Analysis of 8: Orthorhombic P21; a ˆ 9.571(7), b ˆ 10.995(4), c ˆ 32.009(6); Vˆ 3368(3)Š3, Dcalc
ˆ
1.507 Mg/m3, Z ˆ 4. The reflexions were measured on an Enraf-Nonius-CAD4-diffractometer (graphite
monochromator, MoKa, l ˆ 0.71073) at 293 K. R ˆ 0.0908, Rw ˆ 0.2061. Part of the structure was solved by
direct methods, the remaining non-H-atoms were found from a difference Fourier map with SHELXS-96. The
non-H-atoms were refined anisotropically with SHELX-97. H-Atoms were calculated at idealized positions and
included in the structure factor calculation with fixed isotropic displacement parameters.
Data of 9: Rf (Et2O/hexane 1:1) 0.59. UV (CHCl3): 296 (2.9). IR (CHCl3): 3008w, 2928w, 2857s, 1734w,
1603w, 1497w, 1455m, 1362w, 1262m, 1096s, 1028m, 908w, 607w. 1H-NMR (CDCl3): 3.63 (dd, J ˆ 9.9, 4.6,
CH C(5)); 3.72 (t, J ˆ 9.6, CH' C(5)); 4.07 (t, J ˆ 4.2, 3.7, irrad. at 4.69 ! d, J ꢀ 4.0, H C(7)); 4.35 (dd, J ˆ
4.2, 2.0, H C(6)); 4.41 (s, PhCH2); 4.42 ± 4.51 (m, H C(5)); 4.48 (d, J ˆ 11.2, PhCH); 4.56 (d, J ˆ 12.0, PhCH);
4.59 (d, J ˆ 11.6, PhCH); 4.67 (d, J ˆ 11.4, PhCH); 4.69 (d, J ˆ 3.7, H C(8)); 4.84 (d, J ˆ 12.0, PhCH); 5.10
(d, J ˆ 12.0, PhCH); 7.07 ± 7.39 (m, 20 arom. H,
H
C(2)). 13C-NMR (CDCl3): 58.13 (d, C(5)); 69.33
(t, CH2 C(5)); 72.40, 72.19, 73.32, 73.39 (4t, 4 PhCH2); 72.50, 73.39, 78.42 (3d, C(6), C(7), C(8)); 102.15
(s, C(3)); 127.83 ± 128.72 (several d); 130.04 (d, C(2)); 137.76, 137.84, 137.92, 138.50 (4s); 145.20 (s, C(8a)).
(5R,6R,7S,8S)-6,7,8-Tris(benzyloxy)-5-[(benzyloxy)methyl]-2-iodo-5,6,7,8-tetrahydroimidazo[1,2-a]pyri-
dine (10). A soln. of 8 (515 mg, 0.63 mmol) in THF (10 ml) was treated at 08 with a 1m soln. of EtMgBr in THF
(0.95 ml), stirred for 10 min, and treated with a sat. aq. NH4Cl soln. (1 ml). Workup and FC (hexane/AcOEt
85 :15) gave 10 (407 mg, 94%) as a solid. The reaction performed on a larger scale (3.20 g, 3.94 mmol) gave 10
(2.22 g, 82%) after recrystallization in Et2O/hexane (colourless crystals). Rf (hexane/Et2O 1:1) 0.57. M.p. 898.
[a]2D0 ˆ ‡39.4 (c ˆ 1, CHCl3). UV (CHCl3): 269 (2.72). IR (CHCl3): 3159w, 3067w, 3008s, 2915m, 2869m, 1953w,
1878w, 1811w, 1603w, 1497s, 1454s, 1424m, 1362m, 1334w, 1152w, 1097s, 1028s, 946m, 912w, 629w, 608w. 1H-NMR
(CDCl3, 200 MHz): 3.71 (dd, J ˆ 10.4, 5.4, CH C(5)); 3.81 (t, J ˆ 7.5, irrad. at 4.11 ! d, J ꢀ 7.0, H C(6)); 3.81
(dd, J ˆ 10.3, 2.9, CH' C(5)); 4.11 (dd, J ˆ 7.5, 5.4, irrad. at 4.74 ! d, J ꢀ 7.5, H C(7)); 4.21 (ddd, J ˆ 7.9, 5.4,
2.9, H C(5)); 4.45 (d, J ˆ 12.0, PhCH); 4.50 (d, J ˆ 11.6, PhCH); 4.52 (d, J ˆ 12.0, PhCH); 4.67 (d, J ˆ 11.2,
PhCH); 4.74 (d, J ˆ 5.4, irrad. at 4.11 ! s, H C(8)); 4.81 (d, J ˆ 11.6, PhCH); 4.83 (d, J ˆ 11.2, PhCH); 4.85
(d, J ˆ 11.6, PhCH); 5.16 (d, J ˆ 11.6, PhCH); 7.15 (s, H C(3)); 7.17 ± 7.44 (m, 20 arom. H). 13C-NMR (CDCl3,
50 MHz): 57.93 (d, C(5)); 67.80 (t, CH2 C(5)); 72.22, 72.88, 73.42, 73.61 (4t, 4 PhCH2); 73.11, 75.39, 80.95 (3d,
C(6), C(7), C(8)); 81.77 (s, C(2)); 122.88 (d, C(3)); 127.6 ± 128.22 (several d); 136.76, 137.07, 137.30, 137.68 (4s);

Helvetica Chimica Acta ± Vol. 83 (2000)
71
‡
145.45 (s, C(8a)). CI-MS (NH3): 687 (5, M ), 561 (2), 473 (3), 347 (11), 239 (23), 132 (15), 108 (74), 91 (100).
Anal. calc. for C36H35IN2O4 (686.16): C 62.98, H 5.14, N 4.08; found: C 63.03, H 5.03, N 4.03.
(5R,6R,7S,8S)-5-(Hydroxymethyl)-2-iodo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol (11). A soln.
of 10 (20 mg, 0.029 mmol) in CH2Cl2 at 788 was treated with a 1m soln. of BCl3 in CH2Cl2 (0.4 ml), stirred until
the mixture had reached a temp. of 238 (ca. 3 h), cooled to 788, and treated with H2O (2 ml). Evaporation of
the solvent and FC (AcOEt/MeOH 10 :1) gave 11 (6 mg, 63%). Rf (AcOEt/MeOH) 0.12. 1H-NMR (CD3OD):
3.64 (dd, J ˆ 9.3, 8.9, H C(7)); 3.76 (br. t, J ˆ 9.0, 8.5, H C(6)); 3.84 ± 3.91 (m, H C(5), CH C(5)); 4.08 ±
4.14 (m, CH C(5)); 3.89 (d, J ˆ 8.2, H C(8)); 7.40 (s, H C(3)). 1H-NMR (CD3OD ‡ 2 equiv. CF3CO2H):
3.77 (dd, J ˆ 9.6, 8.3, H C(8)); 3.90 (br. t, J ˆ 9.0, H C(6)); 3.99 (dd, J ˆ 12.1, 4.2, CH C(5)); 4.10 ± 4.19
(m, H C(5)); 4.22 (dd, J ˆ 12.0, 2.5, H C(5)); 4.71 (dd, J ˆ 8.3, H C(8)); 7.84 (s, H C(3)). 13C-NMR
(CDCl3): 61.06 (t, CH2 C(5)); 63.89 (d, C(5)); 68.45, 68.54, 74.65 (3d, C(6), C(7), C(8)); 125.85 (d, C(3));
150.52 (s, (C(8a)). Anal. calc. for C8H11IN2O4 (326.09): C 29.47, H 3.40, N 8.59; found: C 29.34, H 3.20, N 8.79.
(5R,6R,7S,8S)-6,7,8-Tris(benzyloxy)-5-[(benzyloxy)methyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-car-
baldehyde (12). A soln. of 10 (200 mg, 0.3 mmol) in THF (5 ml) was treated at 08 with a 1m soln. of EtMgBr in
THF (0.5 ml, 0.5 mmol), stirred for 5 min, treated with DMF (5 ml), and stirred for 90 min. The mixture was
cooled to 308 and treated with a sat. aq. NH4Cl soln. Workup and FC (hexane/AcOEt 2 :1) gave 12 (150 mg,
85%). Rf (AcOEt/hexane 1:1) 0.72. UV (CHCl3): 268 (3.9). IR (CHCl3): 3067w, 3007m, 2869m, 2236m, 1688s,
1539m, 1497m, 1455w, 1363w, 1338w, 1112s, 1028m, 909m. 1H-NMR (CDCl3): 3.75 (dd, J ˆ 10.6, 5.6, CH C(5));
3.84 (dd, J ˆ 8.1, 6.9, H C(6)); 3.85 (dd, J ˆ 10.6, 2.8, CH' C(5)); 4.12 (dd, J ˆ 6.9, 5.0, H C(7)); 4.26
(ddd, J ˆ 8.1, 5.6, 2.8, H C(5)); 4.44 (d, J ˆ 12.1, PhCH); 4.47 (d, J ˆ 11.2, PhCH); 4.50 (d, J ˆ 12.1, PhCH);
4.63 (d, J ˆ 11.5, PhCH); 4.76 (d, J ˆ 5.0, H C(8)); 4.77 (d, J ˆ 11.8, PhCH); 4.79 (d, J ˆ 11.5, PhCH); 4.84
(d, J ˆ 11.8, PhCH); 5.10 (d, J ˆ 11.5, PhCH); 7.06 ± 7.46 (m, 20 arom. H); 7.75 (s, H C(3)); 9.90 (s, CHO).
13C-NMR (CDCl3): 58.68 (d, C(5))9, 67.98 (t, CH2 C(5)); 72.74, 73.55, 73.81, 74.02 (4t, 4 PhCH2); 73.29, 76.06,
81.19 (3d, C(6), C(7), C(8)); 124.25 (d, C(3)); 128.05 ± 128.09 (several d); 137.18, 137.55, 137.71, 137.99 (4s);
‡
142.26 (s, C(2)); 146.14 (s, C(8a), 186.47 (d, CHO). FAB-MS: 589 (100, [M ‡ 1] ).
(5R,6R,7S,8S)-6,7,8-Tris(benzyloxy)-5-[(benzyloxy)methyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-car-
bonitrile (13). A soln. of 10 (100 mg, 0.15 mmol) in THF (0.5 ml) was treated at 08 with a 1m soln. of EtMgBr in
THF (0.5 ml), stirred for 5 min, and treated with a suspension of TsCN (300 mg, 1.66 mmol) in THF (2 ml).
After stirring for 30 min, the mixture was cooled to 308 and treated with a sat. aq. soln. of NH4Cl. Workup and
FC (hexane/AcOEt 2 :1) gave 13 (79 mg; 89%). Rf (Et2O/hexane 1:1) 0.12. UV (CHCl3): 283 (3.8). IR
(CHCl3): 3067w, 3001m, 2926m, 2871m, 2236m, 1626s, 1530w, 1497w, 1454w, 1423w, 1362w, 1098s, 1028m, 909w.
1H-NMR (CDCl3): 3.67 (dd, J ˆ 10.6, 6.2, CH C(5)); 3.77 (dd, J ˆ 10.9, 2.5, CH' C(5)); 3.79 (t, J ˆ 7.2,
H
C(6)); 4.08 (dd, J ˆ 6.9, 5.3, H C(7)); 4.20 (td, J ˆ 6.2, 2.8, H C(5)); 4.41 (d, J ˆ 11.8, PhCH); 4.46 (d, J ˆ
11.2, PhCH); 4.48 (d, J ˆ 11.8, PhCH); 4.61 (d, J ˆ 11.5, PhCH); 4.67 (d, J ˆ 5.0, H C(8)); 4.74 (d, J ˆ 12.1,
PhCH); 4.78 (d, J ˆ 11.5, PhCH); 4.81 (d, J ˆ 11.8, PhCH); 5.06 (d, J ˆ 11.8, PhCH); 7.15 ± 7.45 (m, 20 arom. H);
7.54 (s, H C(3)). 13C-NMR (CDCl3): 59.02 (d, C(5)); 68.24 (t, CH2 C(5)); 72.85 (br. t, 2 PhCH2); 73.57, 73.95
(2t, 2 PhCH2); 73.98, 75.60, 80.70 (3d, C(6), C(7), C(8)); 114.45 (s, CN): 126.92 (d, C(3)); 128.13 ± 128.93
(several d); 130.64 (s, C(2)); 137.00 (s); 137.40 (s); 137.60 (s); 137.76 (s); 145.96 (s, C(8a)). FAB-MS: 586 (100,
‡
[M ‡ 1] ).
(5R,6R,7S,8S)-6,7,8-Tris(benzyloxy)-5-[(benzyloxy)methyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-
methanol (14). At 788, a soln. of 12 (100 mg, 0.17 mmol) in THF (5 ml) was treated with a 0.2m suspension of
LiAlH4 in THF (1 ml) and stirred until the temp. had reached 308 (ca. 1 h). The soln. was cooled to 788 and
treated with H2O (1 ml). Normal workup and FC (AcOEt) gave 14 (88 mg, 87%). Colourless oil that crystallized
upon standing. Rf (AcOEt/hexane 1 :1) 0.13. IR (CHCl3): 3614w, 3090w, 3066m, 2925s, 2869s, 1946w, 1869w,
1806w, 1468m, 1454m, 1362m, 1240m, 1097s, 1028s, 910w, 857w, 698s. 1H-NMR (CDCl3): 2.80 ± 3.20 (br. s,
exchange with CD3OD, OH); 3.73 (dd, J ˆ 10.3, 5.3, CH C(5)); 3.83 (dd, J ˆ 10.2, 3.1, CH' C(5)); 3.85
(dd, J ˆ 8.1, 7.5, C(6)); 4.08 (dd, J ˆ 7.5, 5.4, H C(7)); 4.16 (ddd, J ˆ 8.1, 5.3, 3.1, H C(5)); 4.44 (d, J ˆ 12.1,
PhCH); 4.49 (d, J ˆ 11.8, 2 PhCH); 4.62 (s, CH2 C(2)); 4.67 (d, J ˆ 11.2, PhCH); 4.73 (d, J ˆ 5.6, H C(8));
4.80 (d, J ˆ 11.2, PhCH); 4.83 (d, J ˆ 11.5, 2 PhCH); 5.12 (d, J ˆ 11.8, PhCH); 6.98 (s, H C(3)); 7.01 ± 7.58
(m, 20 arom. H). 13C-NMR (CDCl3): 58.18 (d, H C(5)); 58.82 (t, CH2 C(2)); 68.49 (t, CH2 C(5)); 72.80,
73.42, 74.03, 74.24 (4t, 4 PhCH2), 74.24, 76.14, 81.93 (3d, C(6), C(7), C(8)); 114.98 (d, C(3)); 127.83 ± 128.78
(several d, s of C(2)); 137.55 (s); 137.87 (s); 138.07 (s); 138.58 (s); 142.45 (s, C(8a)). FAB-MS: 591 (100, [M ‡
‡
1] ).
(5R,6R,7S,8S)-2-Methyl-5-(hydroxymethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol Hydrochlor-
ide (15 ´ HCl). A soln. of 12 (20 mg, 0.039 mmol) in AcOEt/MeOH/AcOH 1 :1:1 was treated with 10% Pd/C
(10 mg) and hydrogenated at 6 bar for 36 h. Filtration, evaporation, and ion-exchange chromatography

72
Helvetica Chimica Acta ± Vol. 83 (2000)
‡
(Amberlite CG-120, H form, elution with 1m HCl) gave 15 ´ HCl (86.3 mg, 63%). Colourless hygroscopic resin.
Rf (AcOEt/MeOH 5 :1) 0.31. 1H-NMR (D2O): 2.31 (s, Me); 3.87 (dd, J ˆ 10.0, 8.7, H C(7)); 3.98 (dd, J ˆ 10.0,
8.7, H C(6)); 4.07 (dd, J ˆ 12.5, 2.9, CH C(5)); 4.13 ± 4.20 (m, H C(5)); 4.24 (dd, J ˆ 12.5, 2.1, CH' C(5));
4.80 (d, J ˆ 9.6, H C(8)); 7.50 (s, H C(3)). 13C-NMR (D2O): 9.30 (q, Me); 58.34 (t, CH2 C(5)); 61.96
(d, C(5)); 66.50, 66.98, 73.45 (3d, C(6), C(7), C(8)); 116.15 (d, C(3)); 132.14 (s, C(2)); 144.40 (s, C(8a)). CI-
‡
MS: 215 (65, [M ‡ 1] ), 133 (100). Anal. calc. for C9H14N2O4 ´ HCl ´ 1.5 H2O (277.70): C 38.93, H 6.53, N 10.99;
found: C 38.65, H 6.81, N 9.87.
(5R,6R,7S,8S)-2,5-Bis(hydroxymethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol Hydrochloride
(16 ´ HCl). At 788, a soln. of 14 (85 mg, 0.145 mmol) in CH2Cl2 (3 ml) was treated dropwise with a 1m soln.
of BCl3 in CH2Cl2 (2 ml, 2 mmol), stirred until the mixture had reached a temp. of 238 (ca. 3 h), cooled to 788,
and treated with H2O (2 ml). Evaporation of the solvent, FC (AcOEt/MeOH 10 :1) and ion-exchange
‡
chromatography (Amberlite CG-120, H form, elution with 1m HCl) gave 16 ´ HCl (32 mg, 83%) as a colourless
hygroscopic resin. Rf (AcOEt/MeOH 5 :1) 0.13. 1H-NMR (D2O): 3.88 (dd, J ˆ 10.3, 9.0, H C(7)); 3.98 (dd, J ˆ
10.0, 8.7, H C(6)); 4.06 (dd, J ˆ 12.8, 3.1, CH C(5)); 4.17 ± 4.20 (m, H C(5)); 4.24 (dd, J ˆ 12.8, 2.5,
CH C(5)); 4.65 (s, CH2 C(2)); 4.83 (d, J ˆ 8.7, H C(8)); 7.57 (s, H C(3)). 1H-NMR (D2O in the presence of
5% of NH3): 3.81 (dd, J ˆ 10.0, 9.0, H C(7)); 3.93 (dd, J ˆ 10.0, 9.0, H C(6)); 4.02 ± 4.07 (m, H C(5),
CH C(5)); 4.19 ± 4.23 (m, CH' C(5)); 4.65 (s, CH2 C(2)); 4.68 (d, J ˆ 8.7, H C(8)); 7.37 (s, H C(3)).
13C-NMR (D2O): 56.52 (t, CH2 C(2)); 61.13 (t, CH2 C(5)); 64.95 (d, C(5)); 69.35, 69.70, 76.14 (3d, C(6),
‡
C(7), C(8)); 120.09 (d, C(3)); 137.53 (s, C(2)); 148.71 (s, C(8a)). FAB-MS: 231 (100, [M ‡ 1] ). Anal. calc. for
C9H14N2O5 ´ HCl ´ 1.8 H2O (299.11): C 36.14, H 6.27, N 9.37; found: C 35.98, H 6.45, N 9.09.
(5R,6R,7S,8S)-2-(Aminomethyl)-5-(hydroxymethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol (17).
a) A soln. of 13 (28 mg, 0.048 mmol) in AcOH/CF3CO2H 1 :1 (3 ml) was treated with 10% Pd/C (20 mg) and
hydrogenated at 6 bar for 8 h. Filtration, evaporation of the solvent, and ion-exchange chromatography
‡
(Amberlite CG-120, NH4 form, elution with 0.1m aq. NH3) gave 17 (9 mg, 79%). Colourless, hygroscopic foam.
b) As described in a) but with AcOH instead of the 1:1 AcOH/CF3CO2H mixture and hydrogenating
during 32 h instead of during 8 h gave 17 (78%).
c) As described in a but with MeOH instead of the 1:1 AcOH/CF3CO2H mixture. The reaction was
incomplete after 76 h. According to its 1H-NMR, the crude contained 17 and 15 in ratio of ca. 3 :1.
Data of 17: Rf (AcOEt/MeOH 5 :1) 0.06. 1H-NMR (D2O): 3.88 (dd, J ˆ 9.3, 9.0, H C(7)); 3.89 (br. s,
CH2 C(2)); 3.96 (t, J ˆ 9.6, H C(6)); 4.02 ± 4.15 (m, H C(5), CH C(5)); 4.25 (dd, J ˆ 12.8, 2.2, CH' C(5));
4.63 (d, J ˆ 9.3, H C(8)); 7.26 (s, H C(3)). 1H-NMR (D2O, 2 equiv. of CF3COOH): 3.81 (dd, J ˆ 10.0, 8.7,
H
C(7)); 3.93 (dd, J ˆ 10.0, 8.7, H C(6)); 4.04 ± 4.08 (m, H C(5), CH C(5)); 4.18 (s, CH2 C(2)); 4.20 ± 4.23
(m, CH C(5)); 4.68 (d, J ˆ 8.7, H C(8)); 7.51 (s, H C(3)). 1H-NMR (D2O, 2 equiv. of HCl): 3.90 (dd, J ˆ
10.0, 9.0, H C(7)); 3.98 (t, J ˆ 10.0, H C(6)); 4.04 ± 4.08 (m, CH C(5)); 4.21 ± 4.28 (m, H C(5), CH C(5));
4.34 (s, CH2 C(2)); 4.86 (d, J ˆ 9.7, H C(8)); 7.82 (s, H C(3)). 13C-NMR (D2O); 35.74 (t, CH2 C(2)); 61.28
(CH2 C(5)); 65.41 (d, C(5)); 69.26, 69.70, 75.91 (3d, C(6), C(7), C(8)); 123.21 (d, C(3)); 129.86 (s, C(8a)).
‡
FAB-MS: 230 (100, [M ‡ 1] ).
(5R,6R,7S,8S)-6,7,8-Tris(benzyloxy)-5-[(benzyloxy)methyl]-N-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyr-
idine-2-carboxamide (18). At 08, a soln. of 10 (50 mg, 0.074 mmol) in THF (2 ml) was treated with a 1m soln. of
EtMgBr in THF (0.14 ml, 0.14 mmol), stirred for 10 min, treated with PhNCO (0.1 ml, 0.92 mmol), and warmed
to 238 within 30 min. Workup and FC (AcOEt/hexane 1 :2) gave 18 (48 mg, 95%). Rf (AcOEt/hexane 1:2) 0.51.
UV (MeOH): 263 (3.2). IR (CHCl3): 3380w, 3008m, 1709s, 1597m, 1561m, 1521m, 1499m, 1421s, 1326w, 1098m,
1028w, 590w. 1H-NMR (CDCl3): 3.75 (dd, J ˆ 10.3, 5.0, CH C(5)); 3.85 (dd, J ˆ 10.6, 3.4, CH C(5)); 3.91
(dd, J ˆ 8.1, 7.5, H C(6)); 4.10 (dd, J ˆ 7.5, 5.9, H C(7)); 4.17 ± 4.21 (m, H C(5)); 4.45 (s, PhCH2); 4.48
(d, J ˆ 11.2, PhCH); 4.72 (d, J ˆ 11.5, PhCH); 4.73 (d, J ˆ 5.9, H C(8)); 4.83 (d, J ˆ 11.2, 2 PhCH); 4.89 (d, J ˆ
11.5, PhCH); 5.15 (d, J ˆ 11.5, PhCH); 7.07 ± 7.58 (m, 24 arom. H); 7.71 ± 7.74 (m, 1arom. H); 7.77 (s, H C(3));
9.00 (s, slow exchange with CD3OD, NH). 13C-NMR (CDCl3): 58.76 (d, C(5)); 67.72 (t, CH2 C(5)); 73.10,
73.58, 74.29, 74.46 (4t, 4 PhCH2); 74.16, 75.94, 81.80 (3d, C(6), C(7), C(8)); 119.93 (d, 2arom. C); 121.13
(d, arom. C); 124.10 (d, C(3)); 128.23-129.61 (several d); 133.91, 137.35, 137.70, 137.94, 138.39 (5s); 144.34
(s, C(2)); 149.00 (s, C(8a)); 160.86 (s, CˆO).
(5R,6R,7S,8S)-6,7,8-Trihydroxy-5-(hydroxymethyl)-N-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-
carboxamide (19). A soln. of 18 (40 mg, 0.059) in AcOEt/MeOH/AcOH 1:1:1 (2 ml) was treated with 30 mg of
Pd/C (10%) and hydrogenated at 6 bar for 12 h. Filtration, evaporation, FC (AcOEt/MeOH/H2O 20 :1:1), and
recrystallization in H2O gave 19 (16 mg, 85%). Colourless solid. Rf (AcOEt/MeOH/H2O 20 :2 :1) 0.34. UV
(MeOH): 261 (3.1). IR (CHCl3): 3398m (br.), 3044m, 2923m, 2853m, 1710s, 1596m, 1563m, 1498m, 1401s,
1291m, 1225m, 1072m, 751s, 689s, 589s. 1H-NMR (D2O): 3.78 (dd, J ˆ 9.7, 9.0, irrad. at 4.60 ! d, J ꢀ 9.5,

Helvetica Chimica Acta ± Vol. 83 (2000)
73
H
C(7)); 3.92 (t, J ˆ 10.0, H C(6)); 4.04 ± 4.13 (m, H C(5)); 4.05 (dd, J ˆ 13.7, 3.1, CH C(5)); 4.24 (dd, J ˆ
13.4, 2.8, CH C(5)); 4.60 (d, J ˆ 8.7, H C(8)); 7.25 (tt, J ˆ 7.5, 1.0, 1 arom. H); 7.43 (t, J ˆ 7.5, 2 arom. H); 7.50
(dd, J ˆ 7.4, 1.2, 2 arom. H); 7.9 (s, H C(3)). 13C-NMR (D2O): 61.54 (t, CH2 C(5)); 63.69 (d, C(5)); 69.99,
70.76, 77.27 (3d, C(6), C(7), C(8)); 124.90 (d); 125.03 (d, 2 arom. C); 128.68 (d, C(3)); 132.26 (d, 2 arom. C);
‡
138.66 (s, arom. C); 139.49 (s, C(2)); 150.57 (s, C(8a)); 166.02 (s, CˆO). CI-MS (NH3): 319 (0.2, [M ‡ 1] ), 119
(1), 44 (100). Anal. calc. for C15H17N3O5 ´ 2H2O (355.37): C 50.70, H 5.39, N 11.82, found: C 50.45, H 5.18,
N 11.57.
(5R,6R,7S,8S)-6,7,8-Tris(benzyloxy)-5-[(benzyloxy)methyl]-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyr-
idine (20). At 08, a stirred suspension of 10 (0.150 g, 0.22 mmol) in THF (2 ml) was treated dropwise with a 3m
soln. of EtMgBr in Et2O (0.145 ml, 0.44 mmol) and stirred for 10 min. A suspension of anh. ZnBr2 (0.148 g,
0.65 mmol) in THF (1 ml) was added. The mixture was stirred for 15 min at 08, treated with [Pd(PPh3)4]
(0.025 g, 0.022 mmol) and iodobenzene (0.049 ml, 0.44 mmol), allowed to reach r.t., stirred for 2 h, cooled to
308, and treated with sat. aq. NH4Cl soln. Workup and FC (hexane/AcOEt 4 :1) gave 20 (0.100 g, 72%).
Colorless solid. Rf (AcOEt/hexane 1 :3) 0.18. UV (CHCl3): 292 (7.2). IR (CHCl3): 3065w, 3007w, 2961w, 2868w,
1722m, 1607w, 1496w, 1454m, 1437w, 1361w, 1261s, 1156w, 1095s, 1027m, 818w. 1H-NMR (CDCl3): 3.80 (dd, J ˆ
10.6, 5.6, irrad. at 4.24 ! d, J ꢀ 10.4, CH C(5)); 3.91 (t, J ˆ 7.8, irrad. at 4.15 ! change, H C(6)); 3.92 (dd, J ˆ
10.6, 2.5, irrad. at 4.24 ! change, CH' C(5)); 4.15 (dd, J ˆ 7.8, 5.6, irrad. at 4.83 ! change, H C(7)); 4.21 ± 4.24
(m, H C(5)); 4.48 (d, J ˆ 12.1, PhCH); 4.54 (d, J ˆ 12.1, PhCH); 4.55 (d, J ˆ 11.2, PhCH); 4.73 (d, J ˆ 11.2,
PhCH); 4.83 (d, J ˆ 5.6, irrad. at 4.15 ! s, H C(8)); 4.84 (d, J ˆ 13.7, PhCH); 4.88 (d, J ˆ 11.2, PhCH); 4.97
(d, J ˆ 11.5, PhCH); 5.29 (d, J ˆ 11.5, PhCH); 7.22 ± 7.43 (m, 21 arom. H,
H
C(3)); 7.51 (br. d, J ˆ 7.9,
2 arom. H); 7.82 (br. d, J ˆ 7.5, 2 arom. H). 13C-NMR (CDCl3): 58.34 (d, C(5)); 68.47 (t, CH2 C(5)); 72.80,
73.47, 74.27, 74.48 (4t, 4 PhCH2); 74.40, 76.31, 82.27 (3d, C(6), C(7), C(8)); 113.49 (d, C(3)); 125.28
(d, 2 arom. C); 127.00 (d, arom. C); 127.97 ± 128.90 (several d); 134.84 (s, C(2)); 137.71, 138.06, 138.32, 138.71
‡
(4s); 142.41 (s); 144.65 (s, C(8a)). FAB-MS: 637 (100, [M ‡ 1] ).
(5R,6R,7S,8S)-6,7,8-Tris(benzyloxy)-5-[(benzyloxy)methyl]-2-(pyridin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]-
pyridine (22). A soln. of 10 (250 mg, 0.36 mmol) in THF (3 ml) at 08 under Ar was treated dropwise with a 3m
soln. of EtMgBr in Et2O (0.24 ml, 0.73 mmol), stirred for 10 min, treated with a suspension of anh. ZnBr2
(0.246 g, 1.09 mmol) in THF (1 ml), cooled to 08, stirred for 15 min, and treated with [Pd(PPh3)4] (0.042g,
0.036 mmol) and 2-bromopyridine (0.071 ml, 0.73 mmol). The soln. was allowed to reach 238, stirred for 2 h,
cooled to 308, treated with sat. aq. NH4Cl soln. (5 ml), and warmed to 238. Workup and FC (hexane/AcOEt
1:3) gave 22 (0.179 g, 77%). Colourless oil. Rf (AcOEt/hexane 3 :1) 0.35. UV (CHCl3): 294 (7.7). IR (CHCl3):
3067w, 2928w, 2855w, 1600s, 1454m, 1261s, 1100s, 1013s, 818m. 1H-NMR (CDCl3): 3.86 (dd, J ˆ 10.3, 4.4, irrad. at
4.23 ! d, J ꢀ 10.4, CH C(5)); 3.95 (dd, J ˆ 10.4, 2.8, irrad. at 4.23 ! change, CH' C(5)); 3.96 (t, J ˆ 7.8, irrad.
at 4.14 ! s, H C(6)); 4.14 (dd, J ˆ 7.8, 5.9, irrad. at 3.96 ! change, H C(7)); 4.21 ± 4.27 (m, H C(5)); 4.48
(d, J ˆ 12.1, PhCH); 4.50 (d, J ˆ 11.2, PhCH); 4.53 (d, J ˆ 11.2, PhCH); 4.73 (d, J ˆ 11.5, PhCH); 4.82 (d, J ˆ 5.9,
irrad. at 4.14 ! s, H C(8)); 4.86 (d, J ˆ 11.2, PhCH); 4.88 (d, J ˆ 11.2, PhCH); 4.96 (d, J ˆ 11.5, PhCH); 5.29
(d, J ˆ 11.5, PhCH); 7.14 (td, J ˆ 5.9, 1.1, 1 arom. H); 7.24 ± 7.40 (m, 18 arom. H); 7.47 ± 7.52 (m, 2 arom. H); 7.72
(td, J ˆ 8.0, 1.9, 1 arom. H); 7.77 (s, H C(3)); 8.07 (br. d, J ˆ 8.0, 1 arom. H); 8.57 (br. d, J ˆ 4.1, 1 arom. H).
13C-NMR (CDCl3): 58.40 (d, C(5)); 67.87 (t, CH2 C(5)); 72.75, 73.39, 74.18, 74.36 (4t, 4 PhCH2); 74.37, 76.12,
82.18 (d, C(6), C(7), C(8)); 113.76 (d, C(3)); 117.09 (d, ar. C); 119.19 (d, arom. C); 128.11 ± 128.72 (several d);
136.71 (d, arom. C); 137.57, 137.89, 138.14, 138.46 (4s); 142.58 (s); 144.84 (s); 149.32 (d); 153.73 (s, C(8a)). FAB-
‡
MS: 639 (100, [M ‡ 1] ).
(5R,6R,7S,8S)-5-(Hydroxymethyl)-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol (21). A soln.
of 20 (320 mg, 0.50 mmol) in MeOH/H2O/AcOH 9 :2 :1 (2.5 ml) was treated with 10% Pd/C (300 mg),
hydrogenated at 6 bar for 3 days, and filtered through Celite. Evaporation, FC (CH3OH/AcOEt 1:9), and
crystallization from MeOH gave 21 (76 mg, 55%). Colourless crystals. M.p. 1948. Rf (AcOEt/MeOH 8 :2) 0.39.
UV (MeOH): 291 (4.0). IR (KBr). 3932 ± 3421s, 1734w, 1718w, 1700w, 1684w, 1654m, 1647w, 1636w, 1609w,
1560w, 1508m, 1458m, 1437w, 1328m, 1081s. 1H-NMR (CD3OD): 3.74 (t, J ꢀ 8.4, H C(7)); 3.85 (t, J ꢀ 8.6, irrad.
at 3.74 ! change, H C(6)); 3.92 ± 3.96 (m, H C(5)); 3.99 (dd, J ˆ 11.8, 4.0, CH C(5)); 4.23 (dd, J ˆ 11.8, 2.2,
CH C(5)); 4.56 (d, J ˆ 7.8, irrad. at 3.74 ! change, H C(8)); 7.21 (td, J ˆ 0.9, 7.5, 1 arom. H); 7.34 (br. t, J ˆ 7.6,
2 arom. H)); 7.62 (s, H C(3)); 7.77 (dd, J ˆ 0.9, 7.5, 2 arom. H). 13C-NMR (CD3OD): 61.64 (t, CH2 C(5));
63.14 (d, C(5)); 69.47, 70.08, 76.83 (3d, C(6), C(7), C(8)); 114.91 (d, C(3)); 126.30 (d, 2 arom. C); 128.14
(d, 1 arom. C); 129.84 (d, 2 arom. C); 135.70 (s, C(2)); 143.50 (s, 1 arom. C); 148.64 (s, C(8a)). FAB-MS: 277
‡
(100, [M ‡ 1] ). Anal. calc. for C14H16N2O4 ´ 0.1 CH3OH (279.49): C 58.27, H 5.56, N 9.30; found: C 58.52,
H 5.48, N 9.42.

74
Helvetica Chimica Acta ± Vol. 83 (2000)
(5R,6R,7S,8S)-5-(Hydroxymethyl)-2-(piperidin-2-yl)-5,6,7,8-tetrahydromidazo[1,2-a]pyridine-6,7,8-triol (23/
24). A soln. of 22 (0.120 g, 0.18 mmol) in MeOH/H2O/AcOH 9 :2 :1 (1.8 ml) was treated with 20%
Pd(OH)2/C (100 mg) and hydrogenated at 6 bar for 2 days. The mixture was filtered through Celite. Evaporation
‡
and ion-exchange chromatography (Amberlite CG-120, NH4 form, elution with 0.1m aq. NH3) gave 23/24 1:1
(0.036 g, 60%, ratio determined by the intensities of the 13C-NMR signals of the piperidinyl substituent):
colourless oil crystallizing upon standing. Rf (AcOEt/MeOH 1:1) 0.16. UV (CH3OH): 292 (5.8). 1H-NMR
(CD3OD): 1.60 ± 2.20 (br. m, 6 H); 3.14 (br. m, 2 H); 3.43 (br. m, 1 H); 3.69 (br. t, J ˆ 8.1, H C(7)); 3.81
(br. t, J ˆ 8.4, irrad. at 3.69 ! change, H C(6)); 3.90 ± 4.30 (br. m, CH2 C(5), H C(5)); 4.49 (br. d, J ˆ 7.5,
irrad. at 3.69 ! change, H C(8)); 7.46 (br. s, H C(3)). 13C-NMR (CD3OD): 29.61, 29.82 (2t); 46.17 (t); 55.82,
55.91 (2d); 61.44 (t, CH2 C(5)); 63.21 (d, C(5)); 69.44, 69.87, 76.62 (3d, C(6), C(7), C(8)); 117.60 (d, C(3));
‡
139.31 (s, C(2)); 148.98 (s, C(8a)). EI-MS: 284 (100, [M ‡ 1] ).
Methyl (E-3-{(5R,6R,7S,8S)-6,7,8-Tris(benzyloxy)-5-[(benzyloxy)methyl]-5,6,7,8-tetrahydroimidazo[1,2-a]-
pyridin-2-yl}prop-2-enoate (25). Triphenyl{(5R,6R,7S,8S)-6,7,8-tris(benzyloxy)-5-[(benzyloxy)methyl]-5,6,7,8-
tetrahydroimidazo[1,2-a]pyridin-2-yl}phosphonium Chloride (39), {(5R,6R,7S,8S)-6,7,8-Tris(benzyloxy)-5-
[(benzyloxy)methyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl}tris[furan-2-yl]phosphonium Chloride (40).
a) A soln. of 10 (250 mg, 0.364 mmol), [Pd(OAc)2(P(2-Tolyl)3)2] (17 mg, 0.018 mmol), K2CO3 or (75 mg,
0.546 mmol, 1.5 equiv.), and methyl prop-2-enoate (0.16 ml, 1.8 mmol) in DMF (5 ml) was stirred at 808 for 2 h
under Ar. Workup and FC (Et2O/hexane 1:1) gave 25 (216 mg, 92%). Yellowish oil.
b) A soln. of 10 (50 mg, 0.073 mmol), [Pd(OAc)2] (2 mg, 0.0089 mmol), Ph3P (2.8 mg, 0.0107 mmol),
K2CO3 (75 mg, 0.546 mmol), and methyl prop-2-enoate (0.1 ml, 1.13 mmol) in DMF (1 ml) was stirred at 808 for
8 h. Workup and FC (Et2O/hexane 1 :1) gave 25 (30 mg, 63%) and 7 (5 mg, 12%).
c) As described in b, but with 14 mg (0.0535 mmol) instead of 2.8 mg of Ph3P, 25 (19 mg, 39%) and 39 (8 mg,
13%) were obtained. Colourless oils.
d) As described in b, but with P(2-furyl)3 instead of Ph3P, 25 (28 mg, 59%) and 7 (4 mg, 10%) were obtained.
e) As described in c but with P(2-furyl)3 instead of Ph3P, 25 (20 mg, 42%) and 40 (9 mg, 17%) were obtained.
Data of 25: Rf (AcOEt/hexane 1 :3) 0.23. UV (CHCl3): 295 (3.3). IR (CHCl3): 3090m, 2952m, 2868m,
1700s, 1643s, 1603w, 1497m, 1454m, 1438m, 1362m, 1302m, 1263s, 1168s, 1097s, 1028m, 979m, 912w, 866w.
1H-NMR (CDCl3): 3.71 (dd, J ˆ 10.4, 5.3, CH C(5)); 3.79 (s, MeO); 3.81 (dd, J ˆ 10.4, 2.8, CH' C(5)); 3.82
(t, J ꢀ 7.8, H C(6)); 4.09 (dd, J ˆ 7.5, 5.6, H C(7)); 4.16 (ddd, J ˆ 8.1, 5.6, 2.8, H C(5)); 4.43 (d, J ˆ 12.1,
PhCH); 4.49 (d, J ˆ 12.1, PhCH); 4.49 (d, J ˆ 11.2, PhCH); 4.67 (d, J ˆ 11.5, PhCH); 4.72 (d, J ˆ 5.6, H C(8));
4.82 (d, J ˆ 11.2, PhCH); 4.83 (d, J ˆ 11.2, PhCH); 4.89 (d, J ˆ 11.5, PhCH); 5.18 (d, J ˆ 11.8, PhCH); 6.62
(dd, J ˆ 15.6, H C(a)); 7.18 (s, H C(3)); 7.19 ± 7.40 (m, 18 arom. H); 7.44 ± 7.46 (m, 2 arom. H); 7.56 (d, J ˆ
15.6, H C(b)). 13C-NMR (CDCl3): 51.55 (q, MeO); 58.39 (d, C(5)); 68.28 (t, CH2 C(5)); 72.82, 73.45, 73.82,
74.15 (4t, 4 PhCH2); 74.31, 75.99, 81.72 (3d, C(6), C(7), C(8)); 115.84, 120.45 (2d, C(a), C(b)); 127.97 ± 128.85
(several d, including C(3)); 136.85, 137.74, 137.99, 138.23, 138.45 (5s, including C(2)); 145.90 (s, C(8a)); 168.53
‡
(s, CˆO). CI-MS: 645 (10, M ), 431 (5), 325 (9), 263 (21), 262 (21), 105 (100), 91 (79).
Data of 39: Rf (AcOEt/hexane 1:5) 0.29. UV (CHCl3): 286 (3.7). IR (CHCl3): 3063m, 3007m, 2977w,
2926w, 2865w, 1496m, 1480m, 1454m, 1435s, 1363m, 1329w, 1098s, 1028m, 909s, 532s. 1H-NMR (CDCl3): 2.54
(dd, J ˆ 10.0, 6.2, CH C(5)); 3.11 (dd, J ˆ 10.0, 5.6, CH' C(5)); 3.64 (t, J ˆ 4.7, H C(6)); 3.92 (td, J ˆ 5.6, 4.5,
H
C(5)); 4.01 (dd, J ˆ 4.6, 2.8, H C(7)); 4.09 (s, PhCH2); 4.34 (d, J ˆ 11.8, PhCH); 4.36 (d, J ˆ 10.6, PhCH);
4.57 (d, J ˆ 11.6, PhCH); 4.99 (d, J ˆ 10.9, PhCH); 5.05 (d, J ˆ 11.5, PhCH); 5.24 (d, J ˆ 11.5, PhCH); 5.86
(s, H C(3)); 6.06 (d, J ˆ 2.8, H C(8)), 7.05 ± 7.39 (m, 29 arom. H); 7.67 ± 7.81 (m, 6arom. H). 31P-NMR
‡
(121 MHz, CDCl3): ‡ 29.82 (s). FAB-MS: 791 (100, M ), 627 (7), 453 (8), 91 (70).
Data of 40: Rf (AcOEt/hexane 1:5) 0.34. UV (CHCl3): 276 (3.9). IR (CHCl3): 3089w, 3008m, 2981m,
2922m, 2867m, 1951w, 1880w, 1813w, 1702m, 1672m, 1599m, 1552m, 1496s, 1454s, 1366s, 1097s, 1012s, 909s, 652w,
1
592s, 537s. H-NMR (CDCl3): 3.02 (dd, J ˆ 10.1, 6.1, irrad. at 3.99 ! d, J ꢀ 10.0, CH C(5)); 3.28 (dd, J ˆ 10.3,
4.7, irrad. at 3.99 ! d, J ꢀ 10.0, CH' C(5)); 3.75 (t, J ˆ 4.7, irrad. at 3.99 ! d, J ꢀ 4.5, irrad. at 4.13 ! d, J ꢀ 4.5,
H
C(6)); 3.99 (dt, J ˆ 4.9, 6.0, irrad. at 3.75 ! t, J ꢀ 6.0, H C(5)); 4.03 (s, 2 PhCH2); 4.13 (dd, J ˆ 4.4, 3.4,
irrad. at 3.75 ! d, J ꢀ 4.5, H C(7)); 4.38 (d, J ˆ 11.8, PhCH); 4.45 (d, J ˆ 10.6, PhCH); 4.59 (d, J ˆ 11.2, PhCH);
5.43 (d, J ˆ 11.2, PhCH); 5.94 (s, H C(3)); 6.14 (d, J ˆ 3.2, irrad. at 4.13 ! s, H C(8)); 6.16 (dd, J ˆ 3.4, 1.6,
3 arom. H) 7.02 ± 7.08 (m, 4 arom. H); 7.16 ± 7.40 (m, 22 arom. H). 13C-NMR (CDCl3): 58.46 (d,C(5)); 70.15
(t, CH2 C(5)); 70.63 (d,C(8)); 72.41, 72.63, 72.66, 72.79 (4t, 4 PhCH2); 75.36, 78.87 (d, C(6), C(7)); 111.13
(dd, J(P,C) ˆ 8.3, 3 C(3')); 124.65 (dd, J(P,C) ˆ 15.48, 3 C(2')); 127.23 ± 128.36 (several d); 137.53 (br. s); 137.56
(s); 137.97 (s); 139.10 (s); 142.47 (s); 143.73 (d, J(P,C) ˆ 83.3, 3 C(1')); 147.65 (dd, J(P,C) ˆ 5.8, 3 C(4')). 31P-
‡
NMR (121 MHz, CDCl3): 22.53 (s). FAB-MS: 703 (100, M ), 627 (7), 453 (8), 91 (70).

Helvetica Chimica Acta ± Vol. 83 (2000)
75
(5R,6R,7S,8S)-6,7,8-Tris(benzyloxy)-5-[(benzyloxy)methyl]-2-[(E)-2-phenylethenyl]-5,6,7,8-tetrahydroimi-
dazo[1,2-a]pyridine (26). a) A soln. of 10 (30 mg, 0.044 mmol), Pd(OAc)2 (1mg, 6.3 mmol), Ph3P (2.8 mg,
10.7 mmol), K2CO3 (9.3 mg, 0.0675 mmol), and styrene (0.1 ml, 0.87 mmol) in DMF (0.7 ml) was stirred at 808
for 12 h. Workup and FC (Et2O/hexane 1:1) gave 26 (14 mg, 42%) and 7 (6 mg, 25%).
b) As described in a, but with Pd2(OAc)2(2-tolyl)3 instead of Pd(OAc)2 and PPh3, 26 (17 mg, 51%), was obtained.
c) As described in a but in DMF/H2O 6 :1, 26 (18 mg, 54%) and 7 (4 mg, 16%) were obtained.
d) As described in c but with [Pd2(OAc)2(2-tolyl)2] instead of [Pd(OAc)2] and PPh3, 26 (20 mg, 59%) and 7
(25 mg, 10%) were obtained.
Data of 26: Rf (Et2O/hexane 1:1) 0.31. UV (CHCl3): 311 (4.42), 300 (4.43), 229 (4.30). IR (CHCl3): 3011w,
2958m, 2858m, 1678w, 1496w, 1467m, 1397w, 1264w, 1110m, 909s, 818w, 651w. 1H-NMR (CDCl3): 3.76 (dd, J ˆ
10.6, 5.6, CH C(5)); 3.86 (dd, J ˆ 10.6, 2.2, CH' C(5)); 3.86 (t, J ꢀ 7.8, H C(6)); 4.11 (dd, J ˆ 7.2, 5.3,
H
C(7)); 4.19 (ddd, J ˆ 8.1, 5.3, 2.8, H C(5)); 4.46 (d, J ˆ 12.1, PhCH); 4.50 (d, J ˆ 12.0, PhCH); 4.51 (d, J ˆ
11.8, PhCH); 4.69 (d, J ˆ 11.5, PhCH); 4.78 (d, J ˆ 5.3, H C(8)); 4.83 (d, J ˆ 11.5, 2 PhCH); 4.89 (d, J ˆ 11.8,
PhCH); 5.22 (d, J ˆ 11.8, PhCH); 7.00 (d, J ˆ 16.2, 1 olef. H); 7.06 (s, H C(3)); 7.18 ± 7.39 (m, 20 arom. H);
7.45 ± 7.52 (5 arom. H, 1 olef. H). 13C-NMR (CDCl3): 58.16 (d, C(5)); 68.47 (t, CH2 C(5)); 72.72, 73.40, 74.07,
74.29 (4t, 4 PhCH2); 74.24, 76.30, 82.03 (3d, C(6), C(7), C(8)); 115.95 (d); 120.93 (d); 126.50 (d, 2 arom. C);
127.21 (d, 2 arom. C); 127.59 (d); 128.12 ± 128.81 (several d); 137.60, 138.13, 138.18, 138.20, 138.57 (5s); 140.93
‡
(s, C(2)); 144.73 (s, C(8a)). FAB-MS: 636 (100, [M ‡ 1] ).
(E)-3-{(5R,6R,7S,8S)-6,7,8-Tris(benzyloxy)-5-[(benzyloxy)methyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-
2-yl}pro-2-enenitrile (27). a) A soln. of 10 (60 mg, 0.087 mmol), [Pd(OAc]2] (4 mg, 0.018 mmol), Ph3P (3.3 mg,
0.0216 mmol), K2CO3 (75 mg, 0.546 mmol), and acrylonitrile (0.1 ml, 1.50 mmol) in DMF (1ml) were stirred at
908 for 16 h. Workup and FC (Et2O/hexane 1:1) gave 27 (22 mg, 41%) and 7 (8 mg, 16%).
b) As described in a but with [Pd2(OAc)2[P(2-tolyl)3]2] instead of [Pd(OAc)2] and PPh3, 27 (23 mg, 42%)
and 7 (7 mg, 14%) were obtained.
Data of 27: Rf (Et2O/hexane 1:1): 0.32. UV (CHCl3): 292 (4.21), 243 (3.67). IR (CHCl3): 3008m, 2926m,
2869m, 2869w, 2215w, 1952w, 1869w, 1628w, 1497w, 1455w, 1361m, 1336w, 1261w, 1095s, 1028m, 958w. 1H-NMR
(CDCl3): 3.70 (dd, J ˆ 10.3, 5.6, CH C(5)); 3.80 (dd, J ˆ 10.3, 2.8, CH' C(5)); 3.81 (dd, J ˆ 8.1, 7.5, H C(6));
4.07 (dd, J ˆ 7.2, 5.6, H C(7)); 4.17 (ddd, J ˆ 8.1, 5.6, 2.8, H C(5)); 4.42 (d, J ˆ 11.8, PhCH); 4.48 (d, J ˆ 11.5,
2 PhCH); 4.67 (d, J ˆ 11.2, PhCH); 4.69 (d, J ˆ 5.3, H C(8)); 4.80 (d, J ˆ 11.2, PhCH); 4.82 (d, J ˆ 11.8,
PhCH); 4.86 (d, J ˆ 11.8, PhCH); 5.14 (d, J ˆ 11.5, PhCH); 6.10 (d, J ˆ 16.2, H C(a)); 7.14 (s, H C(3)); 7.20
(d, J ˆ 16.2, H C(b)); 7.17 ± 7.45 (m, 20 arom. H). 13C-NMR (CDCl3): 58.54 (d, C(5)); 68.26 (t, CH2 C(5));
72.95, 73.45, 74.16, 74.28 (4t, 4 PhCH2); 73.68, 75.85, 81.38 (3d, C(6), C(7), C(8)); 93.67 (d, C(a)); 119.46
(s, CN); 120.56 (d, C(b)); 128.08 ± 128.86 (several d, including C(3)); 137.26 (s); 137.66 (br. s); 137.86 (s); 141.90
‡
(s, C(2)); 146.32 (s, C(8a)). EI-MS: 612 (2, [M ‡ 1] ), 520 (9), 398 (70), 292 (100), 187 (59).
Methyl (5R,6R,7S,8S)-6,7,8-Trihydroxy-5-(hydroxymethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-pro-
pionate (28). A soln. of 25 (110 mg, 0.171 mmol) in MeOH/AcOEt/AcOH 1 :1:1 (5 ml) was treated with 10%
Pd/C (50 mg) and hydrogenated for 24 h at 6 bar. Filtration and crystallization from H2O gave 28 (40 mg, 82%).
Colourless crystals. Rf (AcOEt/MeOH/H2O 10 :1 :1) 0.13. UV (CHCl3): 254 (3.3). IR (CHCl3): 3399m (br.),
3065m, 3044m, 2923m, 2852w, 1710s, 1692s, 1596m, 1498s, 1401s, 1291m, 1071m, 689w. 1H-NMR (CD3OD): 2.66
(t, J ˆ 7.5, 2 H); 2.87 (t, J ˆ 7.5, 2 H); 3.63 (s, MeO); 3.68 (t, J ꢀ 8.4, irrad. at 4.54 ! d, J ꢀ 8.0, H C(7)); 3.81
(t, J ꢀ 9.3, H C(6)); 3.90 ± 3.96 (m, H C(5), CH C(5)); 4.16 (dd, J ˆ 12.3, 3.1, CH' C(5)); 4.54 (d, J ˆ 8.4,
H
C(8)); 7.25 (s, H C(3)). 13C-NMR (CD3OD): 22.80, 34.01 (2t); 52.39 (q, MeO); 61.12 (t, CH2 C(5)); 63.83
(d, C(5)); 69.12, 69.18, 76.15 (3d, C(6), C(7), C(8)); 116.78 (d, C(3)); 138.71 (s, C(2)); 147.56 (s, C(8a)); 174.92
‡
(s, CˆO). CI-MS: 287 (2, [M ‡ 1] ), 227 (100), 145 (4). Anal. calc. for C12H18N2O6 ´ 0.5 H2O (295.29): C 48.55,
H 6.48, N 9.49; found: C 48.55, H6.20, N 9.37.
(5R,6R,7S,8S)-6,7,8-Trihydroxy-5-(hydroxymethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-propanoic
acid Hydrochloride (31 ´ HCl). A soln. of 28 (32 mg, 0.112 mmol) in 1m aq. HCl (1 ml) was stirred for 1 h at 408.
Evaporation of the solvent, dissolution in H2O, and lyophilization gave 31 ´ HCl (34 mg, 100%). Colourless,
hygroscopic resin. Rf (AcOEt/MeOH/H2O 3 :1:1): 0.05. 1H-NMR (D2O): 2.73, 2.96 (2t, J ˆ 7.1, 4 H); 3.84 (t, J ˆ
9.5, H C(7)); 3.96 (t, J ˆ 9.5, H C(6)); 4.04 (dd, J ˆ 13.1, 2.8, CH C(5)); 4.12 ± 4.15 (m, H C(5)); 4.20
(d, J ˆ 12.8, 1.5, CH' C(5)); 4.78 (d, J ˆ 7.8, H C(8)); 7.38 (s, H C(3)). 13C-NMR (D2O): 22.39, 35.06 (2t);
61.04 (t, CH2 C(5)); 64.94 (d, C(5)); 69.18, 69.66, 76.07 (3d, C(6), C(7), C(8)); 119.24 (d, C(3)); 137.11
‡
(s, C(2)); 147.61 (s, C(8a)); 178.34 (s, CˆO). EI-MS: 273 (100, [M ‡ 1] ).
(5R,6R,7S,8S)-5-(Hydroxymethyl)-2-(2-phenylethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol
(29). a) A soln. of 26 (50 mg, 0.075 mmol) in AcOH (5 ml) was treated with 10% Pd/C (50 mg) and
hydrogenated at 6 bar for 68 h. Filtration and evaporation of the solvent gave a mixture (1H-NMR) of partially

76
Helvetica Chimica Acta ± Vol. 83 (2000)
debenzylated derivatives of 26 with a reduced double bond. The debenzylation proceeded only insignificantly
upon further hydrogenation with fresh catalyst. After filtration and evaporation, the residue was dissolved in
CH2Cl2 (5 ml), treated at 788 with a 1m soln. of BCl3 (0.4 ml) and stirred, until the mixture had attained 238 (ca.
3 h). The soln. was cooled to 788, treated with H2O, and warmed to 238. Evaporation, FC (AcOEt/MeOH/H2O
20 :1:1), and crystallization from AcOEt/MeOH/H2O 10 :1:1 gave 29 (20 mg, 88%).
b) As described in a for 26, but with 32, 29 (21 mg, 91%) was obtained.
1
Data of 29: Rf (AcOEt/MeOH/H2O 10 :1:1): 0.10. H-NMR (CD3OD): 2.78 ± 2.92 (m, 4 H); 3.66 (dd, J ˆ
8.7, 8.1, H C(7)); 3.78 (dd, J ˆ 8.7, 8.1, H C(6)); 3.82 ± 3.84 (m,H C(5)); 3.87 ± 3.92 (m, CH C(5)); 4.11
(dd, J ˆ 11.8, 1.9, CH' C(5)); 4.49 (d, J ˆ 7.8, H C(8)); 7.04 (s, H C(3)); 7.07 ± 7.25 (m, 5 arom. H). 13C-NMR
(CD3OD): 30.56, 36.66 (2t); 61.50 (t, CH2 C(5)); 63.28 (d, C(5)); 69.41, 69.62, 76.59 (3d, C(6), C(7), C(8));
115.72 (d, C(3)); 127.32 (d); 129.65 (2d); 129.69 (2d); 141.69 (s); 143.15 (s); 147.35 (s). CI-MS: 305 (100, [M ‡
‡
1] ), 237 (48), 223 (58), 213 (64), 91 (59), 78 (77). Anal. calc. for C16H20N2O4 ´ 0.7 H2O (304.35): C 60.63,
H 6.80, N 8.84; found: C 60.79, H 6.74, N 8.72.
(5R,6R,7S,8S)-6,7,8-Tris(benzyloxy)5-[(benzyloxy)methyl]-2-(2-phenylethynyl)-5,6,7,8-tetrahydroimida-
zo[1,2-a]pyridine (32). a) A mixture of 10 (400 mg, 0.58 mmol), [Pd(PPh3)4] (34 mg, 0.294 mmol), Et3N
(0.4 ml), CuI (11 mg, 0.058 mmol), and phenylacetylene (0.2 ml, 1.82 mmol) in DMF (10 ml) was stirred for 2 h
at 808 under Ar. Workup, FC (Et2O/hexane 1:2), and crystallization from Et2O/hexane gave 32 (315 mg, 82%)
and 7 (45 mg, 15%). Rf (Et2O/hexane 1:1) 0.46. M.p. 1088. UV (CHCl3): 285 (3.8), 268 (3.78). IR (CHCl3):
3066m, 3008m, 2922w, 2868m, 2220w, 1951w, 1878w, 1810w, 1735w, 1600w, 1496s, 1454s, 1362m, 1337w, 1097s,
1070s, 1028s, 913w, 863w. 1H-NMR (CDCl3): 3.76 (dd, J ˆ 10.3, 5.3, CH C(5)); 3.87 (dd, J ˆ 10.3, 2.8,
CH' C(5)); 3.88 (t, J ˆ 6.9, H C(6)); 4.14 (dd, J ˆ 6.9, 5.0, H C(7)); 4.23 (ddd, J ˆ 7.0, 5.6, 2.8, H C(5)); 4.47
(d, J ˆ 11.8, PhCH); 4.51 (d, J ˆ 11.2, PhCH); 4.53 (d, J ˆ 12.1, PhCH); 4.68 (d, J ˆ 11.5, PhCH); 4.76 (d, J ˆ 5.3,
H
C(8)); 4.81 (d, J ˆ 11.5, PhCH); 4.83 (d, J ˆ 11.5, PhCH); 4.88 (d, J ˆ 11.5, PhCH); 5.10 (d, J ˆ 11.5, PhCH);
7.01 ± 7.47 (m,23 arom. H, H C(3)); 7.54 ± 7.59 (m, 2 arom. H). 13C-NMR (CDCl3): 58.42 (d,C(5)); 68.49
(t, CH2 C(5)); 72.79, 73.47, 73.95, 74.16 (4t, 4 PhCH2); 73.84, 74.16, 81.72 (3d, C(6), C(7), C(8)); 83.63, 89.34
(2s, CꢁC); 122.13 (d, C(3)); 123.71 (s); 124.62 (s); 127.86 ± 128.83 (several d); 131.82 (d, 2 arom. C); 137.48,
‡
137.81, 138.00, 138.44 (4s); 144.47 (s, C(8a)). FAB-MS: 661 (100, [M ‡ 1] ). Anal. calc. for C44H40N2O4 (660.01):
C 79.98, H 6.10, N 4.24; found: C 79.83, H 6.35, N 4.24.
(5R,6R,7S,8S)-2-(3-Aminopropyl)-5-(hydroxymethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol
(30). A soln. of 27 (8 mg, 0.0131 mmol) in MeOH/AcOH 1:1 (2 ml) was treated with 10% Pd/C (10 mg) and
hydrogenated for 17 h at 6 bar. Filtration, evaporation of the solvent, dissolution in H2O, lyophylization, and
‡
ion-exchange chromatography (Amberlite CG-50, NH4 form, elution with 0.1m aq. ammonia) gave 30 (2.6 mg,
59%). Hygroscopic colourless solid. Rf (AcOEt/MeOH/H2O 5 :1:1): 0.03. 1H-NMR (D2O): 1.89 (m,irrad. at
2.62 ! t, J ꢀ 7.0, irrad. at 2.99 ! t, J ꢀ 7.0, 2H C(2')); 2.62 (t, J ˆ 7.5, irrad. at 1.89 ! s, 2 H C(3')); 2.99 (dd, J ˆ
8.1, 7.5, 2 H C(1')); 3.74 (dd, J ꢀ 9.0, 8.7, H C(7)); 3.88 (t, J ˆ 9.0, H C(6)); 3.90 ± 3.93 (m, H C(5)); 4.03
(dd, J ˆ 12.7, 1.9, CH C(5)); 4.17 (dd, J ˆ 12.5, 2.5, CH' C(5)); 4.55 (d, J ˆ 9.0, H C(8)); 7.04 (s, H C(3)).
13C-NMR (CDCl3, 125 MHz): 26.82 (t, C(2')); 29.24 (t, C(1)); 41.42 (t, C(3')); 61.23 (t, CH2 C(5)); 62.81
(d, C(5)); 69.89, 70.65, 77.48 (3d, C(6), C(7), C(8)); 116.63 (d, C(3); 139.34 (s, C(2)); 149.31 (s, C(8a)). EI-MS:
‡
258 (100, [M ‡ 1] ).
(R)- and (S)-2-Phenyl-1-[(5R,6R,7S,8S)-6,7,8-tris(benzyloxy)-5-[(benzyloxy)methyl]-5,6,7,8-tetrahydro-
imidazo[1,2-a]pyridin-2-yl]ethanol (33 and 34, resp.). a) Preparation of a ca. 1.3m BnLi Soln14). A 1.6m soln.
of BuLi in hexane (5 ml, 8 mmol) at 788 was treated with TMEDA (1.2 ml, 8 mmol) and allowed to reach 08.
The mixture was cooled to 788, and toluene (1 ml) was added dropwise. The mixture was allowed to reach 238
within ca. 3 h and stirred for an additional 5 h, when the soln. had adopted a dark orange colour.
b) Preparation of 33 and 34 by Addition of BnLi to 12. A soln. of 12 (257 mg, 0.467 mmol) in THF was
treated at 788 with 0.5 ml of the BnLi soln. prepared as described in a and allowed to reach 238 within 1 h. The
mixture was cooled to 788 and treated with sat. aq. NH4Cl. Workup and FC (AcOEt/Hexane 1:2) gave a ca.
45 :55 mixture of 33 and 34 (213 mg, 64%), not separable by crystallization, FC or HPLC, and 7 (31 mg, 12%).
c) Preparation of 33 by Denaphthoylation of 35. A soln. of 35 (32 mg, 0.038 mmol) in MeOH (4 ml) was
treated with a 1m soln. of MeONa in MeOH (0.4 ml) and stirred at 608 for 40 min. The mixture was treated with
1m aq. HCl until the pH was slightly acidic (ca. 4 ± 5 according to pH-paper), and the solvent was evaporated.
Workup and FC (AcOEt/Hexane 2 :1) gave 33 (26 mg, 98%), which crystallized from Et2O/hexane. Colourless
needles.
14
)
Similar procedures are given in [48][49].

Helvetica Chimica Acta ± Vol. 83 (2000)
77
d) Preparation of 34 by Denaphthoylation of 36. As described in c for 35, but with 36, 34 (25 mg, 96%) was
obtained. Colourless, cotton-like needles.
Data of 33: M.p.: 1178. Rf (AcOEt/Hexane 1 :1) 0.45. IR (CHCl3): 3593w, 3443w (br.), 3085w, 3004m,
2923m, 2663m, 1954w, 1613w, 1706w, 1491m, 1454s, 1362m, 1095s, 1026m, 909m, 602w. 1H-NMR (CDCl3): 2.57
(br. d, J ˆ 4.7, exchange with CD3OD, OH); 3.07 (dd, J ˆ 13.7, 8.4, H C(2')); 3.20 (dd, J ˆ 13.5, 5.0, H C(2'));
3.70 (dd, J ˆ 10.3, 5.3, CH C(5)); 3.81 (dd, J ˆ 10.6, 3.1, CH' C(5)); 3.86 (t, J ˆ 7.5, H C(6)); 4.09 (dd, J ˆ 7.5,
5.6, H C(7)); 4.14 (ddd, J ˆ 7.5, 5.1, 3.1, H C(5)); 4.41 (d, J ˆ 12.1, PhCH); 4.46 (d, J ˆ 12.1, PhCH); 4.50
(d, J ˆ 11.2, PhCH); 4.69 (d, J ˆ 11.5, PhCH); 4.75 (d, J ˆ 5.0, H C(8)); 4.82 (d, J ˆ 11.5, PhCH); 4.83 (dd, J ˆ
11.2, PhCH); 4.84 (d, J ˆ 11.5, PhCH); 4.94 (br. dt, J ꢀ 9.0, 4.7, H C(1')); 5.14 (d, J ˆ 11.5, PhCH); 6.83
(s, H C(3)); 7.17 ± 7.38 (m, 23 arom. H); 7.41 ± 7.44 (m, 2 arom. H). 13C-NMR (CDCl3): 43.93 (t, C(2')); 58.16
(d, C(5)); 68.42 (t, CH2C(5)); 70.02 (d, C(1')); 72.64, 73.39, 74.07, 74.25 (4t, 4 PhCH2); 74.24, 76.43, 82.03 (3d,
C(6), C(7), C(8)); 116.94 (d, C(3)); 127.10 ± 128.76 (several d); 131.41 (d); 137.60, 138.13, 138.49, 138.84 (4s),
143.60 (s); 145.02 (s).
X-Ray Analysis of 33: Monoclinic P21; a ˆ 5.095(1), b ˆ 26.547(10), c ˆ 13.365(2); Vˆ 1802.0(8)Š3,
Dcalc ˆ 1.255Mg/m3, Z ˆ 2. The reflexions were measured on an Enraf-Nonius-CAD4 diffractometer (graphite
monochromator, CuKa radiation, l ˆ 0.71073) at 170 K. R ˆ 0.0822, Rw ˆ 0.1823. The structures were solved
with the direct-methods routine of SIR97. Because of limited data the non-H-atoms were refined only
isotropically with SHELX-97. H-Atoms were calculated at idealized positions and included in the structure-
factor calculation with fixed isotropic displacement parameters.
Data of 34: M.p.: 918. Rf (AcOEt/Hexane 1:1) 0.45. IR (CHCl3: 3594w, 3444w (br.), 3088w, 3007m, 2922m,
2666m, 1951w, 1611w, 1706w, 1496m, 1454s, 1362m, 1095s, 1026m, 909m, 600w. 1H-NMR (CDCl3): 2.56
(br. d, J ˆ 4.4, exchange with CD3OD, OH): 3.11 (dd, J ˆ 13.7, 8.1, H C(2')); 3.21 (dd, J ˆ 13.7, 5.3, H C(2'));
3.71 (dd, J ˆ 10.3, 5.3, CH C(5)); 3.81 (dd, J ˆ 10.3, 3.1, CH' C(5)); 3.85 (t, J ˆ 7.5, H C(6)); 4.10 (dd, J ˆ 7.5,
5.6, H C(7)); 4.15 (ddd, J ˆ 7.5, 5.1, 3.1, H C(5)); 4.42 (d, J ˆ 12.1, PhCH); 4.47 (d, J ˆ 11.8, PhCH); 4.51
(d, J ˆ 11.2, PhCH); 4.70 (d, J ˆ 11.2, PhCH); 4.75 (d, J ˆ 5.6, H C(8)); 4.83 (d, J ˆ 11.2, PhCH); 4.84 (dd, J ˆ
11.2, PhCH); 4.85 (d, J ˆ 11.5, PhCH); 4.90 ± 4.96 (m, H C(1')); 5.14 (d, J ˆ 11.2, PhCH); 6.84 (s, H C(3));
7.17 ± 7.38 (m, 23 arom. H); 7.42 ± 7.45 (m, 2 arom. H). 13C-NMR (CDCl3): 43.89 (t, C(2')); 58.10 (d, C(5)); 68.39
(t, CH2 C(5)); 69.81 (d, C(1')); 72.56, 73.39, 74.05, 74.21 (4t, 4 PhCH2); 74.21, 76.25, 82.17 (3d, C(6), C(7),
C(8)); 113.78 (d, C(3)); 127.86 ± 128.76 (several d); 129.82 (d); 137.91, 137.99, 138.52, 138.85 (4s), 143.68 (s);
144.81 (s).
(1R)- and (1S)-2-Phenyl-1-{(5R,6R,7S,8S)-6,7,8-tris(benzyloxy)-5-[(benzyloxy)methyl]-5,6,7,8-tetrahydro-
imidazo[1,2-a]pyridin-2-yl]}ethyl Naphthalene-2-carboxylate (35 and 36, resp.). A soln. of 33/34 (45 :55,
100 mg, 0.147 mmol) in pyridine (3 ml) was treated with 2-naphthoyl chloride (100 mg, 0.52 mmol) and stirred
for 6 h at 608. Workup and FC (AcOEt/hexane 1 :4) gave a 45 :55 mixture 35/36 (98 mg, 80%). HPLC
(Spherisorb SW, AcOEt/hexane 1:5) gave 35 (40 m, 32%) and 36 (44 mg, 36%).
Data of 35: Rf (AcOEt/hexane 1:4) 0.21. IR (CHCl3): 3065m, 3008m, 2928m, 2867m, 1710s, 1632w, 1602m,
1
1496m, 1454m, 1356m, 1281s, 1095s, 1028m, 827w. H-NMR (CDCl3): 3.50 ± 3.60 (m, 2H C(2')); 3.68 (dd, J ˆ
10.3, 5.3, CH C(5)); 3.79 (dd, J ˆ 10.6, 3.1, CH' C(5)); 3.86 (dd, J ˆ 7.8, 7.5, H C(6)); 4.11 (dd, J ˆ 7.2, 5.0,
H
C(7)); 4.11 ± 4.16 (m, H C(5)); 4.35 (d, J ˆ 12.1, PhCH); 4.40 (d, J ˆ 12.1, PhCH); 4.50 (d, J ˆ 11.5, PhCH);
4.69 (d, J ˆ 11.2, PhCH); 4.82 (d, J ˆ 11.5, PhCH); 4.84 (d, J ˆ 5.0, H C(8)); 4.84 (br. d, J ˆ 11.2, 2 PhCH); 5.15
(d, J ˆ 11.5, PhCH); 6.36 (t, J ˆ 6.5, H C(1')); 6.99 (s, H C(3)); 7.11 ± 7.35 (m, 22 arom. H); 7.38 ± 7.42
(m, 2 arom. H); 7.49 ± 7.61 (m, 3 arom. H); 7.81 ± 7.92 (m, 3 arom. H); 8.01 ± 8.09 (m, 2 arom. H); 8.59 (s, 1 ar-
om. H). 13C-NMR (CDCl3): 40.53 (t, C(2')); 58.00 (d, C(5)); 68.14 (t, CH2 C(5)); 72.34 (d, C(1')); 72.36, 73.35,
73.87, 74.18 (4t, 4 PhCH2); 73.89, 76.35, 81.98 (3d, C(6), C(7) C(8)); 116.08 (d, C(3)); 125.67, 126.58, 126.73,
127.78, 127.96 (5d); 128.15 ± 128.68 (several d); 129.65 (d); 129.91 (d, 2C); 131.40 (d); 132.76 (s); 135.74 (s);
137.48, 137.89, 138.13, 138.49 (4s), 140.72 (s); 143.89 (s, C(8a)); 166.38 (s, CˆO).
Data of 36: Rf (AcOEt/hexane 1:4) 0.22. IR (CHCl3): 3065m, 3008m, 2928m, 2867m, 1951w, 1708s, 1632w,
1602m, 1496m, 1454m, 1356m, 1281s, 1095s, 1028m, 955m, 866w. 1H-NMR (CDCl3): 3.56 (dd, J ˆ 13.4, 7.5,
H
C(2')); 3.62 (dd, J ˆ 13.5, 7.2,
H
C(2')); 3.72 (dd, J ˆ 10.3, 5.3, CH C(5)); 3.83 (dd, J ˆ 10.3, 2.8,
CH C(5)); 3.85 (dd, J ˆ 7.7, 7.2, H C(6)); 4.13 (dd, J ˆ 7.2, 5.0, H C(7)); 4.13 ± 4.18 (m, H C(5)); 4.39
(d, J ˆ 12.1, PhCH); 4.46 (d, J ˆ 12.1, PhCH); 4.50 (d, J ˆ 11.5, PhCH); 4.68 (d, J ˆ 11.2, PhCH); 4.81 (d, J ˆ
11.5, PhCH); 4.82 (d, J ˆ 5.0, H C(8)); 4.83 (dd, J ˆ 11.2, PhCH); 4.84 (d, J ˆ 11.5, PhCH); 5.15 (d, J ˆ 11.5,
PhCH); 6.38 (t, J ˆ 7.2, H C(1')); 7.07 (s, H C(3)); 7.11 ± 7.35 (m, 22 arom. H); 7.41 ± 7.44 (m, 2 arom. H);
7.50 ± 7.61 (m, 3 arom. H); 7.83 ± 7.94 (m, 3 arom. H); 8.06 ± 8.09 (m, 2 arom. H); 8.62 (s, 1 arom. H). 13C-NMR
(CDCl3): 39.96 (t, C(2')); 57.92 (d, C(5)); 68.22 (t, CH2 C(5)); 71.92 (d, C(1')); 72.17, 73.42, 73.79, 74.18 (4t,
4 PhCH2); 74.00, 76.43, 82.24 (3d, C(6), C(7), C(8)); 116.94 (d, C(3)); 125.76, 126.58, 126.73, 127.30, 127.95 (5d);

78
Helvetica Chimica Acta ± Vol. 83 (2000)
128.15 ± 128.73 (several d); 129.64 (d); 129.93 (d, 2 C); 131.41 (d); 132.76 (s); 135.74 (s), 137.55, 137.90, 138.10,
138.55 (4s), 140.33 (s); 143.84 (s, C(8a)); 166.41 (s, CˆO).
(5R,6R,7S,8S)-5-(Hydroxymethyl)-2-[(R)- and (S)-1-hydroxy-2-phenylethyl]-5,6,7,8-tetrahydromidazo[1,2-a]-
pyridine-6,7,8-triol (37 and 38, resp.). a) A soln. of 33 (30 mg, 0.044 mmol) in CH2Cl2 at 788 was treated
dropwise with a 1m soln. of BCl3 (0.3 ml), stirred until the mixture had reached 08 (ca. 3 h), cooled to 788, and
treated with H2O (0.5 ml). Evaporation of the solvent, FC (AcOEt/MeOH 10 :1), and ion-exchange
‡
chromatography (Amberlite CG-120, NH4 form, elution with 1m NH4OH) gave 37 (10.3 mg, 73%).
b) As described in a for 33, but with 34, 38 (10.0 mg, 71%) was obtained.
Data of 37: Rf (AcOEt/MeOH 5 :1): 0.12. 1H-NMR (300 MHz, D2O): 3.09 (dd, J ˆ 13.5, 7.5, H C(2')); 3.19
(dd, J ˆ 13.7, 6.5, H C(2')); 3.76 (t, J ˆ 9.0, H C(7)); 3.89 (t, J ˆ 9.0, H C(6)); 3.93 ± 4.04 (m, H C(5),
CH C(5)); 4.13 ± 4.17 (m, CH' C(5)); 4.61 (d, J ˆ 8.4,
H
C(8)); 4.97 (br. t, J ˆ 7.0,
H C(1')); 7.11
(s, H C(3)); 7.22 ± 7.35 (m, 5 arom. H). 13C-NMR (300 MHz, D2O): 44.98 (t, C(2')); 61.43 (t, CH2 C(5));
63.45 (d, C(5)); 70.01, 70.59, 71.36, 77.39 (4d, C(6), C(7), C(8), C(1')); 117.81 (d, C(3)); 129.70 (d, 1 arom. C);
131.58 (d, 2 arom. C); 132.83 (d, 2 arom. C); 140.86 (s, 1 arom. C); 145.30 (s, C(2)); 149.05 (s, C(8a)). CI-MS:
‡
321 (100, [M ‡ 1] ).
Data of 38: Rf (AcOEt/MeOH 5 :1): 0.12. 1H-NMR (300 MHz, D2O): 3.07 (dd, J ˆ 13.5, 7.5, H C(2')); 3.20
(dd, J ˆ 13.7, 6.5, H C(2')); 3.75 (t, J ˆ 9.0, H C(7)); 3.88 (t, J ˆ 9.0, H C(6)); 3.95 ± 4.05 (m, H C(5),
CH C(5)); 4.15 (dd, J ˆ 12.6, 2.0, CH' C(5)); 4.59 (d, J ˆ 8.7, H C(8)); 4.95 (br. t, J ˆ 7.0, H C(1')); 7.10
(s, H C(3)); 7.21 ± 7.35 (m, 5 arom. H). 13C-NMR (300 MHz, D2O): 44.83 (t, C(2')); 61.42 (t, CH2 C(5)); 63.45
(d, C(5)); 70.03, 70.57, 71.48, 77.36 (4d, C(6), C(7), C(8), C(1')); 117.79 (d, C(3)); 129.68 (d, 1 arom. C); 131.51
(d, 2 arom. C); 132.56 (d, 2 arom. C); 140.86 (s, 1 arom. C); 145.31 (s, C(2)); 149.00 (s, C(8a)). CI-MS: 321 (100,
‡
[M ‡ 1] ).
Inhibition Studies. Determination of the inhibition constants (Ki) or the IC50 values was performed with a
range of inhibitor concentrations (typically 4 ± 8 concentrations) which bracket the Ki or IC50 value.
a) Inhibition of Sweet Almonds b-Glucosidases. Inhibition constants (Ki) and IC50 values were determined
at 378, using a 0.08m KH2PO4/K2HPO4 buffer (pH 6.8) and 4-nitrophenyl b-d-glucopyranoside as the substrate.
The enzymatic reaction was started after incubation of the enzyme in presence of the inhibitor during 30 min or
1 h by the addition of the substrate. The increase of absorption per min at 400 nm was taken as rate for the
hydrolysis of the substrate. The increase was linear during all measurements (2 min). IC50 Values were
determined by plotting the rate of substrate hydrolysis vs. the inhibitor concentration. Determination of the
inhibitor concentration corresponding to half the rate measured in absence of the inhibitor gave the appropriate
IC50 value. Ki Values were determined by taking the slopes from the Lineweaver-Burk plots [50] and plotting
them vs. the inhibitor concentrations [51]. After fitting a straight line to the data by linear regression, the
negative [I]-intercept of this plot provided the appropriate Ki value. To establish whether an inhibitor is slow
binding or not, IC50 values determined by addition of the substrate after preincubation of the enzyme and the
inhibitor during 30 min were compared to those determined by addition of the enzyme to substrate-inhibitor
solutions.
b) Inhibition of Caldocellum saccharolyticum b-Glucosidase. As described in a, the inhibition constants
(Ki) and IC50 values were determined at 558.
c) Inhibition of Brewerꢀs Yeast a-Glucosidase. As described in a, the inhibition constants (Ki) were
determined using 0.025m KH2PO4/K2HPO4/NaCl buffer (pH 6.8) and 4-nitrophenyl a-d-glucopyranoside as
substrate.
d) Determination of k3 and k4 Values (according to the procedure in [43]). The enzymatic reaction was
started by the addition of the enzyme to the substrate/inhibitor soln. and monitored during 30 min. Intersection
of the tangent to the curve at t ˆ 0 min with the asymptote gave an estimate of k, whereby k ˆ v(initial)/[k4 ´
v(end)]. Using the equations vˆVmax/(1 ‡ [S]/KM), Ki ˆvi ´ [I]/(v vi), and k3/k4 ˆ Ki(initial)/(Ki(end) 1),
the values for k3 and k4, as well as for Ki(initial) and Ki(end) were determined.
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Received October 27, 1999