α-1-C-Alkyl-1-deoxynojirimycin derivatives as potent and selective inhibitors of intestinal isomaltase: Remarkable effect of the alkyl chain length on glycosidase inhibitory profile

Article abstract of DOI:10.1016/j.bmcl.2004.09.086

A series of α- and β-1-C-alkyl-1-deoxynojirimycin derivatives was prepared and evaluated as glycosidase inhibitors. Biological assays showed a marked dependence of the selectivity and potency of the inhibitors upon the position of the alkyl chain (α-1-C-, β-1-C- or N-alkyl derivatives). In addition, the efficiency of α-1-C-alkyl-1-deoxynojirimycin derivatives as intestinal isomaltase inhibitors increases with the length of the alkyl chain. The strongest inhibition was found for α-1-C -nonyl-1- deoxynojirimycin with an IC₅₀ = 3.5 nM (25x more potent inhibitor than the shorter chain homologue carrying a C₈ chain). These results demonstrate that subtle changes in the aglycon fragment may result in remarkable enzyme specificity.

Full text of DOI:10.1016/j.bmcl.2004.09.086

Bioorganic & Medicinal Chemistry Letters 14 (2004) 5991–5995
a-1-C-Alkyl-1-deoxynojirimycin derivatives as potent and
selective inhibitors of intestinal isomaltase: remarkable effect of
the alkyl chain length on glycosidase inhibitory profile
a,
b
Guillaume Godin,a Philippe Compain,a,* Olivier R. Martin, Kyoko Ikeda,
*
Liang Yub and Naoki Asanob
a
´ ´ ´
Institut de Chimie Organique et Analytique, Universite d’Orleans, CNRS UMR 6005, BP 6759, 45067 Orleans, France
bFaculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa 920-1181, Japan
Received 9 July 2004; revised 30 September 2004; accepted 30 September 2004
Available online 26 October 2004
Abstract—A series of a- and b-1-C-alkyl-1-deoxynojirimycin derivatives was prepared and evaluated as glycosidase inhibitors. Bio-
logical assays showed a marked dependence of the selectivity and potency of the inhibitors upon the position of the alkyl chain (a-1-
C-, b-1-C- or N-alkyl derivatives). In addition, the efficiency of a-1-C-alkyl-1-deoxynojirimycin derivatives as intestinal isomaltase
inhibitors increases with the length of the alkyl chain. The strongest inhibition was found for a-1-C -nonyl-1-deoxynojirimycin with
an IC50 = 3.5nM (25· more potent inhibitor than the shorter chain homologue carrying a C8 chain). These results demonstrate that
subtle changes in the aglycon fragment may result in remarkable enzyme specificity.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
sidases4 and by the careful design of structure–activity
relationship studies. An important structural feature
shared by most iminosugars of therapeutic interest5 is
N-alkylation. For example, N-butyl-1-deoxynojirimycin
(ZavescaTM) has been approved as a drug for the treat-
ment of GaucherÕs disease6 since 2003 and N-nonyl deriva-
tives of 1-deoxynojirimycin or of 1-deoxygalactono-
jirimycin constitute a promising class of antiviral agents.7
In connection with our recent work on iminosugar C-gly-
cosides,8 we synthesized a range of lipophilic derivatives
of 1-deoxynojirimycin bearing an alkyl chain attached to
the pseudo-anomeric position.9 Measurements with gly-
cosidases were made in order to assess their aglycon spe-
cificity with respect to the length and the position of the
alkyl chain (a-1-C-, b-1-C- or N-alkyl derivatives). We fo-
cused our biological evaluation on intestinal glucosidases
since they represent valuable targets for the management
of type 2 diabetes as it has been demonstrated recently by
the introduction of new drugs based on this concept10
such as acarbose (GlucobayTM), voglibose (BasenTM) and
miglitol (GlysetTM).
Glycosidases form a widespread group of enzymes
responsible for the hydrolysis of the carbohydrate glycos-
idic bond. These enzymes are found in all organisms and
are involved in numerous biological processes, ranging
from the trimming of cell- and viral-surface oligosaccha-
rides to the lysosomal catabolism of glycoconjugates.
Since glycoside cleavage is a biologically prevalent proc-
ess, glycosidase inhibitors constitute leads for the devel-
opment of new therapeutic agents in a wide range of
diseases such as diabetes, viral infections and lysosomal
storage disorders.1 Iminosugars are a very important
class of carbohydrate-processing enzyme inhibitors2
and are known to display potent activity towards glyco-
sidases.3 The main drawback associated with the use of
such ÔazasugarsÕ is their lack of selectivity as a- or b-glyco-
sidase inhibitors, which may lead to detrimental side
effects in therapeutic applications. One major challenge
is therefore to identify iminosugar-based inhibitors that
specifically modulate the activity of a given glycosidase
of therapeutic interest. This goal may be achieved by a
better understanding of the mechanism of action of glyco-
2. Synthesis of 1-C-alkyl-1-deoxynojirimycin analogues
Keywords: Iminosugars; Glycosidase inhibitors; Isomaltase.
*
a-1-C-Alkyl-1-deoxynojirimycin derivatives 3a–c were
synthesized according to the versatile strategy we
Corresponding authors. Fax: +33 2 38 41 72 81; e-mail addresses:
philippe.compain@univ-orleans.fr; olivier.martin@univ-orleans.fr
0960-894X/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.09.086

5992
G. Godin et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5991–5995
and with excellent stereoselectivity, as the (E)-stereo-
isomer was the only product detected by NMR
spectroscopy.12
O
O
O
a
8 steps
L
-sorbose
64%
Ref. 8a
BnN
OBn
R = allyl 84%
R = hexyl 59%
R = octyl 61%
OBn
1
After removal of the protecting groups and reduction of
the double bond, a-1-C-nonyl-1-deoxynojirimycin (3d)
was obtained in 90% yield from 6. Finally, a-1-C-but-
yl-1-deoxynojirimycin 3e and its b-epimer 3f were pre-
pared according to the synthetic strategy we already
reported.8a
O
H
N
OH
O
O
b, c, d
H
HO
HO
OBn
BnN
H
R = allyl 63%
OH
R = hexyl 39%
R = octyl 61%
OBn
R
R
3a R = propyl
3b R = hexyl
3c R = octyl
2a R = allyl
2b R = hexyl
2c R = octyl
3. Biological evaluation13,14
3.1. Results
Scheme 1. Reagents and conditions: (a) AllMgBr, hexylMgBr or
octylMgBr (3equiv), Et2O, 0–20ꢁC, 24h. (b) TFA/H2O (9/1), 30h. (c)
NaBH3CN(4equiv), AcOH (1equiv), MeOH, 30h. (d) H 2, Pd/C, HCl
5Ncat., MeOH, 24h.
Having prepared the iminoglycolipids 3, we first investi-
gated the influence of the position of the alkyl chain on
glycosidase inhibition by comparing the IC50 values ob-
tained for N-butyl-1-deoxynojirimycin, a- and b-1-C-
butyl-1-deoxynojirimycin. The results reported in Table
1 indicate clearly that a simple 1,2-shift of the alkyl
chain from the endocyclic nitrogen to the pseudo-ano-
meric carbon having a b-configuration is detrimental
to the inhibition towards a-glycosidases. b-1-C-Butyl-
1-deoxynojirimycin is indeed a weak inhibitor of a-gly-
cosidases and is devoid of activity towards b-glycosid-
ases and trehalase.
recently developed.8a Chain extension of imine 1 with
allyl-, hexyl- or octylmagnesium bromide proceeded in
good yields and high diastereoselectivity (Scheme 1).
Deprotection of the acetal function in aqueous TFA,
followed by intramolecular reductive amination and
hydrogenation of the resulting piperidinols afforded
the expected nojirimycin C-glycosides 3a–c in good
yields after purification by chromatography on ion-
exchange resin [Dowex 1-X2, (OHꢀ form)].11
In contrast, IC50 values found for a-1-C-butyl-1-deoxy-
nojirimycin are higher but relatively close to those ob-
tained for its N-butyl analogue with the exception of
rat intestinal isomaltase. The IC50 value of 150nM ob-
tained for this latter enzyme is improved by an 18-fold
a-1-C-Nonyl-1-deoxynojirimycin was prepared by an-
other route using a cross-metathesis reaction as the
key step (Scheme 2).
In connection with our recent work,8b we were indeed
interested in exploring the reactivity of properly func-
tionalized iminosugars towards various types of olefins.
Reaction of a-1-C-allyl-1-deoxynojirimycin derivative
58b with 1-octene in the presence of GrubbsÕ catalyst 8
provided the expected iminoglycolipid 6 in 82% yield
Table 1. Evaluation of N- or 1-C-butyl-1-deoxynojirimycin derivatives
as glycosidase inhibitors
Enzyme
IC50 (lM)
R
OH
H
OH
OH
H
N
N
N
HO
HO
HO
HO
HO
HO
R
O
OH
OH
OBn
OH
O
R
O
a
5 steps
NTroc
AcO
BnO
R = H R = C4H9
DNJ
R = C4H9 R = C4H9
3f
NAPN
OBn
46%
Ref. 8b
82%
OAc
N-Bu-DNJ 3e
OBn
a-Glucosidase
Rice
5
4
0.05a
190b
0.36c
0.21c
0.3c
0.42
NId
2.1c
58c
11
61
NI
OBn
H
N
Yeast
465
12
OBn
NTroc
Maltasee
Sucrasee
Isomaltasee
210
155
115
b
AcO
BnO
AcO
BnO
3.6
0.15
OAc
92%
OAc
6 (n=5)
2.7c
( )n
( )n
7 (n=5)
b-Glucosidase
Sweet almond
Caldocellum
81b
55
N
NI
I
N
I
N
OH
H
N
N
Mes
Ph
NI
NI
Mes
N
c,d
HO
HO
saccharolyticum
Cl
Cl
Ru
PCy3
98%
OH
3d (n=5)
Trehalase
Porcine kidney
( )n
40
NI
780
NI
8
a Taken from Ref. 15.
b Taken from Ref. 16.
c Taken from Ref. 17.
Scheme 2. Reagents and conditions: (a) 1-octene (5equiv), GrubbsÕ
catalyst 8 (12mol%), CH2Cl2, D, 72h. (b) Zn (30equiv), Et2O/AcOH
(2/1), 4h. (c) Na, MeOH, 4h. (d) H2, Pd/C, HCl 5Ncat., MeOH, 48h.
NAP = 2-naphthylmethyl.
d NI: less than 50% inhibition at 1000lM.
e From rat intestine.

G. Godin et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5991–5995
Table 2. Evaluation of a-1-C-alkyl-1-deoxynojirimycins 3a–e as glycosidase inhibitors
5993
Enzyme
IC50 (lM)
OH
H
N
HO
HO
OH
R
R = C3H7
3a
R = C4H9
3e
R = C6H13
3b
R = C8H17
3c
R = C9H19
3d
a-Glucosidase
Rice
15
11
0.8
52
0.59
25
1.5
56
Yeast
630
43
465
12
Maltasea
Sucrasea
Isomaltasea
3.5
1.2
0.31
1.9
1.5
4.0
2.5
39
0.53
3.6
0.15
0.09
0.0035
b-Glucosidase
Sweet almond
Caldocellum saccharolyticum
NIb
NDc
NI
NI
12
NI
27
110
150
80
a From rat intestine.
b NI: less than 50% inhibition at 1000lM.
c Not determined.
Table 3. Evaluation of N-alkyl-1-deoxynojirimycins 9a–d as glycosi-
dase inhibitors
factor and is comparable to that of 1-deoxynojirimycin
(DNJ).
Enzyme
IC50 (lM)
These results encouraged us to explore further the acti-
vity of a-1-C-alkyl-1-deoxynojirimycins since it seemed
possible to reach selective inhibition with this family of
compounds. A range of nojirimycin a-C-glycoside deriva-
tives bearing a linear alkyl chain (C3, C4, C6, C8 and C9)
was thus evaluated as glycosidase inhibitors (Table 2).
We were pleased to observe for some enzymes a remark-
able correlation between the chain length and the inhibi-
tion values. With the exception of the C6-analogue 3b,
the potency and selectivity of a-1-C-alkyl-1-deoxynojir-
imycin as intestinal isomaltase inhibitor increased regu-
larly with the length of the alkyl chain. Remarkably, the
simple extension of the alkyl chain by only one CH2
(from octyl to nonyl) is sufficient to promote a 25-fold
increase of activity. To our knowledge, a-1-C-nonyl-1-
deoxynojirimycin (3d) is the most potent and selective
inhibitor of intestinal isomaltase reported to date, with
an IC50 of 3.5nM.18 In addition, iminosugar 3d shows
45,000-fold and 570-fold more potent inhibition towards
isomaltase than acarbose and voglibose, respectively.19
OH
N
R
HO
HO
OH
R = C3H7 R = C6H13 R = C8H17 R = C9H19
9a
9b
9c
9d
a-Glucosidase
Rice
2.0
NIb
7.0
2.0
1.4
0.70
N
0.08
0.08
Yeast
I
N
I
N
Maltasea
Sucrasea
Isomaltasea
3.7
1.5
1.3
0.45
0.45
0.66
0.28
0.66
0.23
b-Glucosidase
Sweet almond
Caldocellum
900
100
350
450
34
160
150
80
saccharolyticum
a From rat intestine.
b NI: less than 50% inhibition at 1000lM.
(a-limit dextrins).22 Crystallographic studies associated
with site-directed mutagenesis have provided structural
basis to understand the mechanism of this family of
enzymes (oligo-1,6-glucosidases–EC 3.2.1.10).19 Three
carboxylic acid residues (Glu or Asp) have been clearly
identified as essential catalytic-binding site residues,
consistent with a double-displacement mechanism.
In the first step, one of the carboxylic group protonates
the glycosidic oxygen. In their anionic carboxylate
form, the second one generates a covalent glycosyl-en-
zyme complex and the third one activates the water
hydroxylating the anomeric position.
In light of the results obtained for a-1-C-alkyl deriva-
tives 3c–d, a series of N-alkyl analogues 9a–d was syn-
thesized20,21 and evaluated as glucosidase inhibitors to
verify the decisive role of the lipophilic chain position
(Table 3). These N-alkyl-1-deoxynojirimycin derivatives
were found to be less efficient and less selective as iso-
maltase inhibitors than the parent a-C-glycosides 3.
These results further underline a-1-C-alkyl-1-deoxynoji-
rimycins as potent and selective inhibitors of intestinal
isomaltase and validate the preliminary study performed
with the iminosugars bearing a butyl chain (Table 1).
The detrimental effect of the b-alkyl chain in nojirimycin
C-glycoside analogues may be rationalized by unfavour-
able interactions with one of the catalytic carboxylate
residues. The affinity of N-alkyl- or a-1-C-alkyl-1-deoxy-
nojirimycin derivatives for intestinal isomaltase may be
3.2. Discussion
Rat intestinal isomaltase is a retaining a-glucosidase
that hydrolyses a-1,6-branching links in a-glucans

5994
G. Godin et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5991–5995
2. (a) Compain, P.; Martin, O. R. Bioorg. Med. Chem. 2001,
9, 3077; (b) Compain, P.; Martin, O. R. Curr. Top. Med.
Chem. 2003, 3, 541; (c) Schramm, V. L.; Tyler, P. C. Curr.
Top. Med. Chem. 2003, 3, 525; (d) Lee, R. E.; Smith, M.
D.; Pickering, L.; Fleet, G. W. J. Tetrahedron Lett. 1999,
40, 8689; (e) Costin, G. E.; Trif, M.; Nichita, N.; Dwek, R.
A.; Petrescu, S. M. Biochem. Biophys. Res. Commun. 2002,
293, 918; (f) Jakobsen, P.; Lundbeck, J. M.; Kristiansen,
M.; Breinholt, J.; Demuth, H.; Pawlas, J.; Candela, M. P.
T.; Andersen, B.; Westergaard, N.; Lundgren, K.; Asano,
N. Bioorg. Med. Chem. 2001, 9, 733.
explained in terms of an aglycon-binding site having an
extended hydrophobic region.18 The lipophilic chain is
supposed to mimic the hydrophobic face23 of the mono-
saccharide unit a-glucosylated at O-6. However, an alkyl
chain at C-1 with the appropriate a-configuration seems
to be better positioned for suitable interactions with the
putative lipophilic pocket.
Another marked dependence of the selectivity and po-
tency upon the length of the alkyl chain is exemplified
by inhibition values observed for configuration-retaining
b-glucosidase from almond. IC50 values in the lM range
were found for a-1-C-hexyl-and a-1-C-octyl-1-deoxyno-
jirimycin whereas the parent propyl and butyl analogues
were devoid of inhibitory activity (Table 2). Further
extension of the alkyl chain, from octyl to nonyl, resulted
in a 6-fold decrease of activity. The IC50 value obtained
for a-C-hexyl-1-deoxynojirimycin (3b) is quite surprising
in light of the fact that 1-deoxynojirimycin derivatives
display generally weak inhibition towards configura-
tion-retaining b-glucosidases such as the one from al-
mond compared to azasugars having nitrogen instead
of the ÔanomericÕ carbon. Various structure–activity rela-
tionship studies, using mainly amino carbasugar probes,
have revealed the positive effect of a hydrophobic agly-
cone on b-glucosidase inhibition.1b This effect may be
sufficient to partially compensate for the unsuitable posi-
tion of the nitrogen atom in 1-deoxynojirimycin deriva-
tives and may explain that 3d displays relatively good
inhibitory activity towards b-glucosidase from almond.
3. (a) Iminosugars as Glycosidase Inhibitors: Nojirimycin and
Beyond; Stutz, A. E., Ed.; Wiley-VCH: New York, 1999;
¨
(b) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W.
J. Tetrahedron: Asymmetry 2000, 11, 1645.
4. (a) Vasella, A.; Davies, G. J.; Bo¨hm, M. Curr. Opin. Chem.
Biol. 2002, 6, 619; (b) Heightman, T. D.; Vasella, A. T.
Angew. Chem., Int. Ed. 1999, 38, 750; (c) Withers, S. G.;
Namchuk, M.; Mosi, R. in Ref. 3a, pp 188–206; (d)
Davies, G.; Sinnott, M. L.; Withers, S. G. Glycosyl
transfer. In Comprehensive Biological Catalysis; Sinnott,
M. L., Ed.; Academic Press Limited: New York, 1997;
Chapter 3; pp 119–208; (e) Legler, G. Adv. Carbohydr.
Chem. Biochem. 1990, 48, 319.
5. Iminosugars: Recent Insights into Their Bioactivity and
Potential as Therapeutic Agents; Martin, O. R., Compain,
P., Eds.; Curr. Top. Med. Chem. 2003, 3(5).
6. (a) Butters, T. D.; Dwek, R. A.; Platt, F. M. Curr. Top.
Med. Chem. 2003, 3, 561; (b) Butters, T. D.; Dwek, R. A.;
Platt, F. M. Chem. Rev. 2000, 100, 4683; (c) Cox, T.;
Lachmann, R.; Hollak, C.; Aerts, J.; van Weely, S.;
Hrebicek, M.; Platt, F.; Butters, T.; Dwek, R.; Moyses, C.;
Gow, I.; Elstein, D.; Zimran, A. The Lancet 2000, 355,
1481.
´
7. (a) Durantel, D.; Branza-Nichita, N.; Carrouee-Durantel,
S.; Butters, T. D.; Dwek, R. A.; Zitzmann, N. J. Virol.
2001, 75, 8987, and references cited therein; (b) Greimel,
4. Conclusion
P.; Spreitz, J.; Stutz, A. E.; Wrodnigg, T. M. Curr. Top.
¨
Med. Chem. 2003, 3, 513.
In conclusion, a range of a- and b-1-C-alkyl-1-deoxyno-
jirimycin derivatives have been synthesized and evalu-
ated as glycosidase inhibitors. This structure–activity
relationship study showed a marked dependence of the
selectivity and potency upon the position and the length
of the alkyl chain. The best result was obtained with a-1-
C-nonyl-1-deoxynojirimycin (3d), a potent and selective
inhibitor of rat intestinal isomaltase (IC50 3.5nM, an
inhibitor 25-fold more potent than the lower a-1-C-octyl
homologue). These findings demonstrate that subtle
changes in the iminosugar aglycone region may result
in remarkable enzyme specificity. Application of this
principle to glycosidases of therapeutic relevance is cur-
rently under investigation in our laboratory.
8. (a) Godin, G.; Compain, P.; Masson, G.; Martin, O. R. J.
Org. Chem. 2002, 67, 6960; (b) Godin, G.; Compain, P.;
Martin, O. R. Org. Lett. 2003, 5, 3269.
9. For seminal work concerning the synthesis of 1-C-alkyl-1-
deoxynojirimycin analogues see: Bo¨shagen, H.; Geiger,
W.; Junge, B. Angew. Chem., Int. Ed. Engl. 1981, 20,
806.
10. Perfetti, R.; Barnett, P. S.; Mathur, R.; Egan, J. M.
Diabetes Metab. Rev. 1998, 14, 207.
1
11. Spectral properties (IR, HRMS, H and 13C NMR) of all
new compounds are in good agreement with the proposed
structures. For a representative example see selected data
for compound 3c: 1H NMR (500MHz, CD3OD): d 0.83 (t,
3H, J = 7.3Hz), 1.20–1.30 (m, 11H), 1.36–1.47 (m, 2H),
1.56 (m, 1H), 2.63 (ddd, 1H, J = 3.2, 7.8, 9.6Hz, H-5), 2.93
(ddd, 1H, J = 3.2, 5.5, 11.0Hz, H-1), 3.01 (dd, 1H, J = 8.7,
9.6Hz, H-4), 3.35 (dd, 1H, J = 8.7, 9.6Hz, H-3), 3.39 (dd,
1H, J = 7.8, 11.0Hz, H-6a), 3.51 (dd, 1H, J = 5.5, 9.6Hz,
H-2), 3.81 (dd, 1H, J = 3.2, 11.0Hz, H-6b); 13C N MR
(125MHz, CD3OD): d 14.4, 23.7, 25.7, 27.4, 30.4, 30.7,
30.8, 33.1, 56.1 (C-5), 57.5 (C-1), 63.9 (C-6), 74.26 (C-2),
Acknowledgements
Financial support of this study by grants from CNRS
and the association ÔVaincre les Maladies LysosomalesÕ
is gratefully acknowledged. G.G. thanks the council of
20
74.33 (C-4), 76.1 (C-3); ½aꢁD +49 (c 0.52, MeOH); HRMS
´
Region Centre and the CNRS for a fellowship.
(FAB) m/z 276.2173 [M+H]+ (C14H30NO4 requires
276.2175).
12. For a related example of glycolipids synthesis by way of
cross-metathesis reaction from a- or b-D-allyl galactoside
derivatives see: Plettenburg, O.; Mui, C.; Bodmer-Nark-
evitch, V.; Wong, C.-H. Adv. Synth. Catal. 2002, 344, 622.
13. The a-glucosidases from rice and yeast, and b-glucosidases
from sweet almond and Caldocellum saccharolyticum were
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G. Godin et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5991–5995
5995
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19. Matsuda, H.; Morikawa, T.; Yoshikawa, M. Pure Appl.
Chem. 2002, 74, 1301.
20. The N-alkyl derivatives of 1-deoxynojirimycin 9 were
synthesized according to the method reported for the
preparation of N-alkyl-1-deoxygalactonojirimycins.21
Compounds 9 were prepared by treatment with the
appropriate alkyl bromide and triethylamine (or K2CO3)
for 8h at 80ꢁC in DMF. The resulting reaction mixture
was evaporated in vacuo, and the residual syrup was
redissolved with MeOH and applied to an Amberlyst 15
column, washed with MeOH, and eluted with 1M
NH4OH. The eluate was concentrated and applied to a
Dowex 1-X2 (OHꢀ form) column prepared with 50%
aqueous MeOH and chromatographed with 50% aqueous
MeOH as eluent to give the pure N-alkyl derivatives.
21. Asano, N.; Ishi, S.; Kizu, H.; Ikeda, K.; Yasuda, K.; Kato,
A.; Martin, O. R.; Fan, J.-Q. Eur. J. Biochem. 2000, 267,
4179.
22. Gray, G. M.; Lally, B. C.; Conklin, K. A. J. Biol. Chem.
1979, 254, 6038.
23. Lemieux, R. U. Chem. Soc. Rev. 1989, 18, 347, and
references cited therein.