Diastereoselective synthesis of glycosylated prolines as α-glucosidase inhibitors and organocatalyst in asymmetric aldol reaction

Article abstract of DOI:10.1016/j.bmcl.2006.12.002

1,3-Dipolar cycloaddition of azomethine ylides and glycosyl E-olefins in presence of LDA led to diastereoselective formation of C-glycosylated proline esters. The selected esters on regioselective hydrolysis with LiOH gave C-glycosyl prolines. Few of the

Full text of DOI:10.1016/j.bmcl.2006.12.002

Bioorganic & Medicinal Chemistry Letters 17 (2007) 1321–1325
Diastereoselective synthesis of glycosylated prolines as
a-glucosidase inhibitors and organocatalyst in
asymmetric aldol reactionq
Jyoti Pandey,a Namrata Dwivedi,a Nimisha Singh,a A. K. Srivastava,b
A. Tamarkarb and R. P. Tripathia,*
aMedicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226001, India
bBiochemistry Division, Central Drug Research Institute, Lucknow 226001, India
Received 22 September 2006; revised 22 November 2006; accepted 1 December 2006
Available online 3 December 2006
Abstract—1,3-Dipolar cycloaddition of azomethine ylides and glycosyl E-olefins in presence of LDA led to diastereoselective for-
mation of C-glycosylated proline esters. The selected esters on regioselective hydrolysis with LiOH gave C-glycosyl prolines. Few of
the proline esters exhibited very good a-glucosidase inhibitory activity. The organocatalytic activity of the proline derivatives in a
prototype Aldol reaction has also been investigated.
Ó 2007 Published by Elsevier Ltd.
Dipolar cycloaddition reactions has found many useful
synthetic applications both in solution- and solid-phase
synthesis particularly with respect to the preparation of
compounds with new chiral centres.1,2 This approach to-
wards asymmetric synthesis is of major importance in
both the pharmaceutical and agricultural industries.
1,3-Dipolar cycloaddition reactions, in general, are of
paramount importance for the construction of polyfunc-
tionalised five membered cyclic rings.2 Application of
azomethine ylides and alkenes in such dipolar reactions
has been extensively used for the synthesis of pyrroli-
dines and many alkaloids as chemotherapeutics or chiral
catalysts or as building blocks in organic synthesis.3
Highly substituted pyrrolidines are known for their glu-
cosidase inhibitory activity and consequently possess
potent antiviral, antibacterial, antidiabetic and antican-
cer activities.4 Glycosylated prolines as constituent of
hydroxyproline-rich plant glycoproteins (HRGPs)5
impart them many biological functions in plants. The
main thrust in this area is to generate enantioriched
compounds in a single step with minimum number of
reagents used. Asymmetric catalysis or application of
at least one chiral substrate in such reaction led to gen-
erate optically active compounds in enantioselective or
diastereoselective manner.6
Although the enantioselective cycloaddition and pericy-
clic reactions via organometallic asymmetric catalysis
have played a pivotal role in this area yet, the applica-
tion of chiral organometallic catalyst sometimes is unde-
sired due to metallic impurity associated with the final
products limiting the utility in the synthesis of
chemotherapeutics.7
Azomethine ylides have principally been generated by
the reaction of an amine with an aldehyde to form an
iminium species, which under experimental condition
led to the formation of carbanion in situ, as they are
very labile. Asymmetric 1,3-dipolar cycloaddition with
azomethine ylide and dienophile has been achieved8
via any of the three strategies; (a) by attaching a chiral
auxiliary to the imino or to the electron withdrawing
group of the dipole (b) by attaching chiral auxiliary to
the electron withdrawing group of the alkene or (c) by
employing a chiral Lewis acid which chelates both the
substrates. It is believed that like other cycloaddition
reactions, 1,3-dipolar cycloaddition is also a concerted
process and proceeds via Woodward Hoffmann Rule.
Pure E-a, b-unsaturated esters or ketones with chiral
substituent at the c-position were employed in regiose-
lective and diastereoselective cycloaddition to get the
pyrrolidine derivatives.9,10
Keywords: Glycosyl prolines; 1,3-Dipolar cycloaddition; a-Glucosi-
dase; Tetrasubstituted pyrrolidines.
q
CDRI Communication No. 7057.
Corresponding author. Tel.: +91 522 2612412x4462; fax: +91 522
26123405; e-mail: rpt_56@yahoo.com
*
0960-894X/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2006.12.002

1322
J. Pandey et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1321–1325
Keeping in mind the above facts and in continuation of
our effort to develop a-glucosidase inhibitors11,12 and
new organocatalysts13 from simple sugars we were inter-
ested to synthesize functionalized chiral pyrrolidines and
see their a-glucosidase inhibitory activity and catalytic
efficiency in organic synthesis. Thus, the present com-
munication deals with the 1,3-dipolar cycloaddition of
different azomethine ylides and chiral alkenes bearing
its spectroscopic data and microanalysis. The stereo-
chemistry in compound 3 was speculated on the basis
of literature precedents and the mechanism involved in
this reaction.8–10 It has earlier been reported9 that in
such cycloadditions involving a chiral dienophile and
azomethine ylide the relative orientation of substituents
at C2/C3 and C3/C4 is anti and at C4/C5 is syn in major
1
isomers of the reaction products. In H NMR spectrum
1,2-O-isopropylidene-b-L-threo-pentofuranosyl
moiety at the c-position.
sugar
of compound 3, the coupling constant J4,5 was found to
be 8.2 Hz, while J3,4 was <1.0 Hz indicating syn and anti
orientation of substituents at C4/C5 and C3/C4 as ob-
served earlier in such a study.14 It has been proved8–10
that this stereochemistry is attained via regiospecific
endo cycloaddition of the dipole to the E configured
dipolarophiles in the ester series. It is appropriate to
mention here that we did carry out above reaction under
different experimental conditions (Table 1) including the
use of DBU/LiBr as mentioned earlier9,10 and after 6 h
of reaction only the b,c-unsaturated ester15 was isolated
as the major product of the reaction along with a small
amount of the desired product (TLC).
To start with [(3-nitro-benzylidene)-amino]-acetic acid
ethyl ester (1a) was prepared by reaction of 3-nitrobenz-
aldehyde and ethyl glycinate in presence of anhy.
MgSO4. The azomethine ylide of 1a was generated
in situ by reacting it with lithium diisopropyl amide in
anhydrous tetrahydrofuran at 0 °C for half an hour.
The ylide, so generated, on reaction with ethyl-1,2-O-
isopropylidene-3-O-benzyl-b-L-threo-hept-5-eno-furano-
syl uronate (2a) led to the formation of the required tet-
rasubstituted pyrrolidine (3) as major product along
with small amount of un-reacted starting materials 1a
and 2a as observed on TLC plate. The major product
was isolated by column chromatography and was char-
acterized as ethyl (2S,3S,4S,5R)-3-(1,2-O-isopropyl-
idene-3-O-benzyl-b-L-threo-furanos-4-yl)-5-(3-nitro-
phenyl)-pyrrolidine-2,4-dicarboxylate (3) on the basis of
Similarly, reaction with [(3-chloro-benzylidene)-amino]-
acetic acid ethyl ester (1b), [(4-bromo-benzylidene)-ami-
no]-acetic acid ethyl ester (1c), [(3-pyridyl-methylidene)-
amino]-acetic acid ethyl ester (1d), [(2,5-dichloro-
benzylidene)-amino]-acetic acid ethyl ester (1e) and
Table 1. Synthesis of tetrasubstituted pyrrolidines from chiral olefinic ester and benzylidene glycinate under different reaction conditions
Alkene
Benzylidene glycinate
Ar
R
Catalyst
Time (h)
Temp (°C)
Yield
2a
2a
2a
2a
1a
1a
1a
1a
3-Nitrophenyl
3-Nitrophenyl
3-Nitrophenyl
3-Nitrophenyl
CH2Ph
CH2Ph
CH2Ph
CH2Ph
DBU/LiBr
Et3N/LiBr
LDA
6
8
4
4
25–80
25
Isomerised product
No reaction
70%
0–30
À78
LDA
72%
O
(i)Et3N, THF
(ii) anh. MgSO4
COOC2H5
H2N
.HCl
+
N
COOC2H5
Ar
H
Ar
(i) THF/ LDA/ 0oC/ 30min
O
CMe2
(ii) 2a or 2b, THF/ 0 - 30 oC
O
O
OCH2Ph
C2H5OOC
Isomerised product
O
CMe2
O
O
O
CMe2
O
O
other unisolated
products
C2H5OOC
Ar
+
OR
COOC2H5
OR
N
2a, R=CH2Ph
2b, R=CH3
C2H5OOC
H
3-12
Scheme 1. Synthesis of tetrasubstituted prolines.

J. Pandey et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1321–1325
1323
[(4-fluoro-benzylidene)-amino]-acetic acid ethyl ester
(1f) with ethyl-1,2-O-isopropylidene-3-O-benzyl-b-L-
threo-hept-5-eno-furanosyl uronate (2a) separately led
to formation of respective tetrasubstituted prolines (4–
8) as major products along with un-reacted olefins and
azomethylidenes (Scheme 1).
the smallest group, hydrogen, present outside the crowd-
ed region. As shown in model A the ylide attacks Re/Re
face of the olefinic ester and the attack is quite similar to
nitrile oxide cycloaddition,16 where the b-L-threose
occupies the stereoelectronically favoured ‘inside posi-
tion’ and the smallest group ‘H’ is at the more sterically
demanding outside position. The relative and absolute
stereochemistry in the products obtained was speculated
on the basis of transition state model and earlier re-
ports6,10 on such 1,3-dipolar cycloaddition of chiral ole-
fin and azomethine ylide (Fig. 1).
The other glycosyl olefin, ethyl-3-O-methyl-1,2-O-iso-
propylidene-b-L-threo-hept-5-eno-furanosyl
uronate
(2b) was similarly reacted with [(4-bromo-benzylidene)-
amino]-acetic acid ethyl ester (1c), [(3-pyridyl-methyli-
dene)-amino]-acetic acid ethyl ester (1d), [(3-nitro-ben-
zylidene)-amino]-acetic acid ethyl ester (1a) and
[(4-chloro-benzylidene)-amino]-acetic acid ethyl ester
(1g) separately to give the respective tetrasubstituted
pyrrolidines diastereoselectively (9–12) in moderate to
good yields (Table 2). The structures of all the products
were established on the basis of spectroscopic data.
As many proline derivatives are known to catalyze a
number of organic reactions we were interested to pre-
pare tetrasubstituted analogs and see their catalytic abil-
ity. Thus, above tetrasubstituted prolines (3–7) having
2,4-carbethoxy substituents were treated with one equiv-
alent of LiOH in THF to give compounds 13–17 in good
yields. To our pleasant finding only 2-carbethoxy group
was regioselectively hydrolysed in all these compounds
leading to respective tetrasubstituted pyrrolidines with
2-carboxyl group. The regioselective hydrolysis of 2-car-
bethoxy group may be explained in terms of sterically
hindered approach of LiOH to the 4-carbethoxy group
and chelation controlled facile delivery of the required
OH group to the carbonyl carbon of 2-carbethoxy group
Formation of the above major product could be ratio-
nalized on the basis of Houk’s transition state model
(A) where the preferred diastereotopic facial attack of
the W shaped dipoles to the chiral dipolarophile takes
place. The major product arises from the transition state
I in which the largest group (b-L-threose) occupies the
anti position with respect to the incoming dipole, while
Table 2. Synthesis of tetrasubstituted pyrrolidines from chiral olefinic esters and benzylidene glycinate
Alkene
Benzylidene glycinate
Ar
R
Product
Time (h)
Yield (%)
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
1a
1b
1c
1d
1e
1f
3-Nitrophenyl
3-Chlorophenyl
4-Bromophenyl
3-Pyridyl
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH3
3
4
4
4
4
4
3
3
3
3
3
3
80
85
80
80
80
70
75
70
80
78
5
6
2,5-Dichlorophenyl
4-Fluorophenyl
4-Bromophenyl
3-Pyridyl
7
8
1c
1d
1a
1g
9
CH3
CH3
10
11
12
3-Nitrophenyl
4-Chlorophenyl
CH3
Me2
C
O
O
O
+
Ph
-
N
EtO
H
H
H
O
O
COOEt
OR
H
C2H5O
A
Me2
C
OC2H5
O
N
Ph
O
O
O
Li
O
H
=
I
O
OR
Figure 1. Transition state model for cycloaddition.

1324
J. Pandey et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1321–1325
as lithium chelates with ring nitrogen and carbonyl oxy-
gen of carbethoxy group (Scheme 2).
those with 3-O-methyl substituent in glycofuranose (9–
12). Further, among compounds having 3-O-benzyl sub-
stituent compounds with nitro, chloro or bromo groups
at various positions in 5-phenyl ring have good inhibi-
tion (65–82% inhibition) of the enzyme. A similar com-
pound having 4-fluoro substituent is comparatively less
active (43% inhibition). Substitution of phenyl ring at
C-5 with pyridyl group results in drastic loss of activity.
Furthermore, all the compounds with 3-O-methyl sub-
Inspired by the work of List et al.17 asymmetric aldol
reaction catalyzed by prolines we have studied the cata-
lytic activity of these prolines 13–17 in one such reaction
of acetone and 3-nitrobenzaldehyde. Thus, reaction of
3-nitrobenzaldehyde with acetone in presence of
20 mol% of the above proline derivatives 13–17 sepa-
rately led to the formation of aldol product 18 in vary-
ing yield (65–85%) and enantioselection (10–90%)
(Scheme 3). Enantioselection in aldol product was
determined by HPLC, using Chiradex column, and 9:1
MeCN–water as eluent. Proline derivative 17 gave best
(90%) enantioselection. Reactions with all the catalysts
were performed under identical reaction condition.
10 mol% of the catalysts resulted in lower yield of the
reaction product.
Table 3. a-Glucosidase inhibitory activity of tetrasubstituted prolines
Compound
% a-glucosidase
IC50 (lM)
Ki (lM)
inhibition (100 lM)
3
82.7
65.5
79.3
29.3
67.2
43.1
26.8
17.1
14.6
21.1
10.3
24.1
8.1
61
96
33
79
4
5
64
36
6
ND
99
ND
65
7
8
75
40
9
10
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
The compounds synthesized were evaluated against the
isolated a-glucosidase from rat intestine following earli-
er protocol.18,19 As evident from Table 3 all the com-
pounds screened inhibited glucosidase enzyme ranging
from 5% to 82.7% at the only concentration of
100 lM used in the present study. A closure look into
a-glucosidase inhibitory activity reveals that among
these compounds, compounds having 3-O-benzyl substi-
tuent (3–8) in the sugar moiety are more active than
11
12
13
14
15
16
5.1
17
Acarbose
10.5
39.0
O
CMe2
O
O
CMe2
O
O
O
COOEt
COOEt
other unisolated products
+
OOCH2Ph
OCH2Ph
1eqiv. LiOH, THF
30 ˚C
COOH
NH
13-17
COOC2H5
Ar
NH
3-7
Ar
Compounds
Ar
% yield
80
85
80
75
13
14
15
16
17
3-nitro-phenyl
3-chloro-phenyl
4-bromo-phenyl
3-pyridyl
2,5-dichloro-phenyl 80
Scheme 2. Synthesis of 2-carboxypyrrolidines.
OH O
O
O
20 mol % of proline derivative
CH3
H
CH3
+
H3C
36 h, 35˚C
NO2
NO2
18
Catalyst
13
14
15
16
% yield
85
70
85
65
% ee
20
80
55
10
90
17
86
Scheme 3. Direct asymmetric Aldol reaction of 3-nitrobenzaldehyde and acetone.

J. Pandey et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1321–1325
1325
4. (a) Elbein, A. D.; Molyneux, R. J. In Iminosugars as
Glycosidase Inhibitors; Nojirimycin and Beyond; Stutz, A.
stituent are very poor inhibitor of the enzyme. Replace-
ment of 2-carbethoxy substituent with carboxyl (13–17)
always results in drastic loss in inhibitory potential. The
best compound of the series (3) inhibited the rat intesti-
nal a-glucosidase up to the extent of 82.7%, while the
standard drug acarbose used in this study has only
39% inhibition.
¨
E., Ed.; Wiley-VCH: Weinheim, 1999; pp 216–251; (b)
Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2000, 11, 1645; (c) Greimel, P.;
Spreitz, J.; Stutz, A. E.; Wrodnigg, T. M. Curr. Top. Med.
Chem. 2003, 11, 513, and references cited therein.; (d)
Fiaux, H.; Popowycz, F.; Favre, S.; Schutz, C.; Vogel, P.;
¨
Gerber-Lemaire, S.; Juillerat-Jeanneret, L. J. Med. Chem.
2005, 48, 4237; (e)Pharmaceuticals; McGuire, J. L., Ed.;
Wiley-VCH: Weinheim, 2000; Vol. 1–4,.
In summary, we have developed a diastereoselective syn-
thesis of tetrasubstituted glycosyl pyrrolidines by 1,3-di-
polar cycloaddition of azomethine ylides and glycosyl
olefins. The compounds displayed a-glucosidase inhibi-
tory activity. The catalytic potential of these prolines
in asymmetric aldol reaction has also been
demonstrated.
5. (a) Shpak, E.; Barbar, E.; Leykam, J. F.; Kieliszewski, M. J.
J. Biol. Chem. 2001, 276, 11272; (b) Showalter, A. M. Plant
Cell 1993, 5, 9; (c) Suzuki, L.; Woessner, J. P.; Uchida, H.;
Kuroiwa, H.; Yuasa, Y.; Waffenschmidt, S.; Goodenough,
U. W.; Kuroiwa, T. J. Phycol. 2000, 36, 571.
6. (a) Carruthers, W. Cycloaddition Reactions in Organic
Synthesis; Pergmon Press: Oxford, 1990; (b) Williams, R.
M.; Zhai, W.; Aldous, D. J.; Aldous, S. C. J. Org. Chem.
1992, 57, 6527; (c) Lown, W. J. In 1,3-Dipolar Cycload-
dition Chemistry; Padwa, A., Ed.; Wiley: New York, 1984;
(d)Padwa, Albert, Pearson, William H., Eds.Synthetic
Applications of 1,3-Dipolar Cycloaddition Chemistry
Toward Heterocycles and Natural Products; Wiley: New
York, 2002; (e) Di, M.; Rein, K. S. Tetrahedron Lett. 2004,
45, 4703; (f) Kano, T.; Hashimoto, T.; Maruoka, K. J.
Am. Chem. Soc. 2005, 127, 11926; (g) Gao, W.; Zhang, X.;
Raghunath, M. Org. Lett. 2005, 7, 4241; (h) Wilson, J. E.;
Fu, G. C. Angew. Chem. Int. Ed. 2006, 45, 1426; (i) Rogue,
D. R.; Neill, J. L.; Antoon, J. W.; Stevens, E. P. Synthesis
2005, 2497.
Acknowledgments
The authors thank RSIC for spectral data and Mr. R. A.
Vishwakarma for HPLC analysis. Jyoti and Namrata
are thankful to CSIR, New Delhi, for JRF and SRF.
Financial assistance as a project ERIP/ER/0502127/M/
01/857 from DRDO, New Delhi, is gratefully
acknowledged.
Supplementary data
7. Fubini, B.; Arean, L. O. Chem. Soc. Rev. 1999, 28, 373.
8. (a) Najera, C.; Sansano, J. M. Angew. Chem. Int. Ed. 2005,
44, 6272; (b) Najera, C.; Sansano, J. M. Curr. Org. Chem.
2003, 7, 1105.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.bmcl.2006.12.002.
9. (a) Annunziata, R.; Clinquini, M.; Cozzi, F.; Raimondi,
L.; Pilati, T. Tetrahedron: Asymmetry 1991, 2, 1329; (b)
Galley, G.; Liebscher, J.; Pa¨tzel, M. J. Org. Chem. 1995,
60, 5005.
References and notes
1. (a)Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Products;
Padwa, A., Pearson, W. H., Eds.; Wiley: New York, 2003;
Vol. 59, (b) Karlsson, S.; Hogberg, H. E. Org. Prep.
Proced. Int. 2001, 33, 103; (c) Gothelf, K. V.; Jørgensen,
K. A. Chem. Rev. 1998, 98, 863; (d) Harju, K.; Yli-
Kauhaluoma, J. J. Mol. Divers. 2005, 9, 187; (e)Compre-
hensive Asymmetric Catalysis; Jacobsen, E. N., Faltz, P.,
Yamamoto, A. H., Eds.; Springer: New York, 1999; pp
467–491.
10. Patzel, M.; Galley, G.; Jones, P. G.; Charapkowsky, A.
¨
Tetrahedron Lett. 1993, 34, 5707.
11. (a) Tewari, N.; Tiwari, V. K.; Mishra, R. C.; Tripathi, R.
P.; Srivastava, A. K.; Ahmad, R.; Srivastava, R.; Srivast-
ava, B. S. Bioorg. Med. Chem. 2003, 11, 2911; (b) Verma,
S. S.; Mishra, R. C.; Tamrakar, A. K.; Tripathi, B. K.;
Srivastava, A. K.; Tripathi, R. P. J. Carbohyd. Chem.
2004, 23, 493.
12. Khan, A. R.; Tiwari, V. K.; Srivastava, A. K.; Tripathi, R.
P. J. Enzyme Inhib. 2004, 19, 107.
2. (a) Waldman, H.; Blaser, E.; Jansen, M.; Letchert, H. P.
Angew. Chem., Int. Ed. Engl. 1994, 104, 683; (b) Sommer-
Knudsn, J.; Bacic, A.; Clarke, A. E. Phytochemistry 1998,
47, 483; (c) Kieliszewski, M. J. Phytochemistry 2001, 57,
319; (d) Khashimova, Z. S. Chem. Nat. Comput. 2003, 39,
229; (e) Carruthers, W. Cycloaddition Reactions in Organic
Synthesis; Pergamon Press: Oxford, 1990; (f) Kanemasa,
S.; Tsuge, O. In Advances in Cycloaddition; Curran, D. P.,
Ed.; Jai Press Inc.: Greenwich, 1993; Vol. 3, p 99; (g)
Grigg, R.; Sridharan, V. In Advances in Cycloaddition;
Curran, D. P., Ed.; Jai Press Inc.: Greenwich, 1993; Vol. 3,
13. Dwivedi, N.; Bisht, S. S.; Tripathi, R. P. Carbohydr. Res.
2006, 341, 2737–2743.
14. Khim, Y. A.; Oh, S. M.; Han, S. Y. Bull. Korean Chem.
Soc. 2001, 22, 327.
15. Tiwari, V. K.; Tripathi, R. P. Indian J. Chem. 2002, 41B,
1681.
16. (a) Houk, K. N.; Paddon-Row, M. N.; Rondan, N. G.;
Wy, Y. D.; Brown, F. K.; Spellmeyer, D. C.; Metz, J.
T.; Li, Y.; Loncharich, R. Science 1986, 231, 1108; (b)
Houk, K. N.; Mosses, S. R.; Wu, Y. D.; Rondan, N.
G.; Jager, V.; Schohe, R.; Fronczek, F. R. J. Am. Chem.
Soc. 1984, 106, 3880; (c) Houk, K. N.; Wu, Y. D.; Duh,
H. Y.; Mosses, S. R. J. Am. Chem. Soc. 1986, 108,
2754.
17. List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem.
Soc. 2000, 122, 2395, and references cited therein..
18. Cogoli, A.; Mosimann, H.; Vock, C.; Balthazar, A. K. V.;
Semenza, G. Eur. J. Biochem. 1972, 30, 7.
´
p 161; (h) Ayerbe, M.; Arrieta, A.; Cossıo, F. P. J. Org.
Chem. 1998, 63, 1795.
3. (a) Asano, N. J. Enzyme Inhib. 2000, 15, 215; (b) Ashry, E.
S. H.; Raashed, N.; Shobier, H. S. Pharmazie 2000, 55,
331; (c) Vasella, T.; Heigtman, T. D. Angew. Chem., Int.
Ed. Engl 1999, 38, 750; (d) Lipper, R. A. Mod. Drug
Discovery 1999, 2, 55; (e) Lipinsky, C. A.; Lombardo, F.;
Dominy, B. W.; Feeney, P. J. Adv. Drug Delivery Rev.
1997, 23, 3.
19. Matsui, T.; Yoshimoto, S.; Osajima, K.; Oki, T.; Osajima,
Y. Biosci. Biotech. Biochem. 1996, 60, 2019.