Synthesis of cyclohexane containing 5′-O-Glycine derivatives of uridine as potential inhibitors of UDP-glucuronosyltransferase

Article abstract of DOI:10.1007/PL00010276

Summary. In order to design potential inhibitors of UDP-glucuronosyltransferase, two different pathways for the synthesis of cyclohexane containing 5′-O-glycine derivatives of uridine were developed, one starting with the cyclohexyl moiety, and a second o

Full text of DOI:10.1007/PL00010276

Monatshefte fuÈr Chemie 130, 937±943 (1999)
Synthesis of Cyclohexane Containing
50-O-Glycine Derivatives of Uridine
as Potential Inhibitors of UDP-
glucuronosyltransferase
Dimitar K. Alargov1;Ã, Roumyana G. Gugova1, Pavleta S. Denkova2, Gunther
MuÈller3, and Evgeny V. Golovinsky1
1
Institute of Molecular Biology, Bulgarian Academy of Sciences, BG-1113 So®a, Bulgaria
2
Institute of Organic Chemistry, Bulgarian Academy of Sciences, BG-1113 So®a, Bulgaria
È
Institut fuÈr Hygiene und Arbeitsmedizin, Universitat Essen, D-45122 Essen, Germany
3
Summary. In order to design potential inhibitors of UDP-glucuronosyltransferase, two different
pathways for the synthesis of cyclohexane containing 50-O-glycine derivatives of uridine were
developed, one starting with the cyclohexyl moiety, and a second one beginning with the uridine
moiety. Thus, 50-O-(cyclohexylcarboxyl-glycyl)-20,30-O-isopropylideneuridine and 50-O-(cyclo-
hexylpropionyl-glycyl)-20,30-O-isopropylideneuridine were obtained. According to the results, the
second approach is more convenient.
Keywords. Uridine; 50-O-Amino acid derivatives; Cyclohexanecarboxylic acid; Cyclohexylpro-
pionic acid; UDP-Glucuronosyltransferase.
Synthese von cyclohexylsubstituierten 50-O-Glycin-uridinderivaten als potentielle Inhibitoren
der UDP-Glukuronosyltransferase
Zusammenfassung. Mit dem Ziel, potentielle Inhibitoren der UDP-Glukuronosyltransferase
herzustellen, wurden zwei verschiedene Synthesewege fuÈr 50-O-Glycinderivate entwickelt. Der erste
Syntheseweg beginnt mit dem Cyclohexylfragment, der zweite mit dem Uridinest. Es wurden 50-O-
(Cyclohexylcarboxyl-glycyl)-20,30-O-isopropylidenuridin und 50-O-(Cyclohexylpropionyl-glycyl)-
20,30-O-isopropylidenuridin hergestellt. Entsprechend den Ergebnissen ist die zweite Methode
besser geeignet.
Introduction
UDP-Glucuronosyltransferase (UGT, EC 2.4.1.17) is a multigenic family of
membrane-bound isoenzymes involved in the biotransformation and detoxication
of various exogenous and endogenous compounds [1]. These enzymes catalyze
the transfer of glucuronic acid from UDP-glucuronic acid (UDP-GlcA) to the
Ã
Corresponding author

938
D. K. Alargov et al.
respective aglycones (RXH) containing hydroxyl, amino, carboxyl, or sulfhydryl
groups, forming water soluble ꢀ-(D)-glucuronides which are readily excreted due
to the hydrophilicity of the glucuronic acid moiety.
Enzymatic glucuronidation also plays a pivotal role in the biotransformation of
drugs. Various drugs, including the anti-HIV agent AZT (30-azido-30-deoxythymi-
dine) are extensively converted to their inactive glucuronides and excreted from the
organism [2,3]. Thus, the inhibition of UGT could increase the plasma level and
therapeutic ef®cacy of a number of drugs. Simultaneously, the development of
selective inhibitors of UGT could also provide a useful approach in studying the
active sites of different UGT isoforms.
In the last years, several classes of UGT inhibitors have been developed [4±7].
According to the current concepts, the UDP part or the uridine moiety is thought to
provide most of the free binding energy of the ligand-enzyme complex [8].
Linkage of lipophilic aryl or arylalkyl residues to UDP and uridine have led to
powerful UGT inhibitors considered as possible transition state analogs [9±13].
Recently, we have synthesized novel uridinyl analogs modi®ed at the 50-O-
position by protected and unprotected amino acids [14] and oligopeptides [15]. The
inhibitory potency of these compounds on the glucuronidation of 4-nitrophenol (4-
NP) and phenolphthalein (PPh) by rat liver microsomes has also been tested. Some
of them have been found to be inhibitors of both 4-NP and PPh-glucuronidation
[16]. To estimate the contribution of the different parts of the inhibitors to the
active site binding, a quantitative structure-activity relationship (QSAR) study was
also performed [17].
Continuing our studies on the design and the structure-activity relationships of
effective UGT inhibitors, we decided to synthesize a series of compounds
containing lipophilic residues attached to amino acid derivatives of uridine. Here
we report the synthesis of cyclohexane containing 50-O-glycine derivatives of
uridine as potential inhibitors of UDP-glucuronosyltransferase.
Results and Discussion
For the synthesis of the compounds, two different pathways were tried, one starting
with the cyclohexyl moiety and a second one beginning with the uridine residue.
According to the ®rst approach (Scheme 1), cyclohexanecarboxyl glycine benzyl
ester (1) was prepared from cyclohexanecarboxylic acid and glycine benzyl ester
using the DCC (dicyclohexylcarbodiimide) method [18] in 94% yield after
recrystallisation from EtOAc/PE. The benzyl group of 1 was then deprotected
by catalytic hydrogenolysis over 10% Pd/C/ammonium formate [19] to yield
cyclohexanecarboxyl glycine (2). Then, 2 was esteri®ed with 20,30-O-isopropyl-
ideneuridine to provide 3 using 4-dimethylaminopyridine as the catalyst [20]. The
rather low yield of 3 (20%, 15% overall yield based on 20,30-O-isopropylidene-
uridine) was due to the poor solubility of 2 in solvents like DMF or DMSO. To
avoid this problem, we decided to try another approach.
According to the second approach (Scheme 2), 3 was prepared by a three-step
synthesis starting from 50-O-(N-benzyloxycarbonyl-glycyl)-2-0,30-O-isopropyl-
ideneuridine (4). The latter was prepared from N-benzyloxycarbonyl glycine and
20,30-O-isopropylideneuridine in analogy to 3 in 94% yield. In the next step, the

50-O-Glycine Derivatives of Uridine
939
Scheme 1
Scheme 2
benzyloxycarbonyl group (Z) of 4 was deprotected by catalytic hydrogenolysis in
the same way as for 2 to give 50-O-glycyl-20,30-O-isopropylideneuridine (5) which
was used in the next step without further puri®cation. A 76% yield of 3 was
obtained after esteri®cation of 5 with cyclohexanecarboxylic acid. The overall
yield based on 20,30-O-isopropylideneuridine was 71%. In a similar way as de-
scribed above, cyclohexylpropionyl glycine benzyl ester (6), cyclohexylpropionyl
glycine (7), and 50-O-(cyclohexylpropionyl-glycyl)-20,30-O-isopropylideneuridine

940
D. K. Alargov et al.
(8) were prepared. The new derivatives were TLC pure and were characterized by
1H NMR, MS, and elemental analyses.
Conclusions
In order to design potential inhibitors of UDP-glucuronosyltransferase, two
different pathways for the synthesis of cyclohexane containing 50-O-glycine
derivatives of uridine were developped. According to the results, the second
approach (Scheme 2) is more convenient and should therefore be used for the
synthesis of similar compounds.
Experimental
The amino acid derivatives were purchased from Bachem Biochemica GmbH (Heidelberg). 20,30-O-
Isopropylideneuridine was obtained from Sigma. All other chemicals were of analytical grade.
Melting points were measured with a BuÈchi 535 apparatus. TLC analysis was performed on
aluminium sheets Silica gel 60 F254 (Merck) using the following chromatographic systems: A:
BuOH:AcOH:H2O (3:1:1), B: CHCl3:MeOH (9:1); the spots were visualized by UV light or by
spraying with the appropriate reagents (Reindel [21], ninhydrin). For column chromatography,
Merck Kieselgel 60 (76±230mesh ASTM) was used. Optical rotation was determined with a Polamat
1
A Carl-Zeiss instrument. The H NMR spectra were obtained on a Bruker DRX-250 instrument
(250 MHz). Elemental analyses were performed with a Perkin-Elmer M 240 apparatus; the results
were in good agriment with the calculated values. Mass spectra were recorded with a Jeol JMS D100
spectrometer.
Cyclohexylcarboxyl glycine benzyl ester (1; C16H21NO3)
2.28 g Cyclohexanecarboxylic acid (17.8 mmol) and 1.48 g DCC (8.9 mmol) were stirred in 10 cm3
DMF for 30 min at 0ꢀC. Then, 2.0 g glycine benzyl ester p-tosylate (5.9 mmol) and 0.82 cm3
Et3N (5.9 mmol) were added, and stirring was continued for 24 h at room temperature. The
N,N0-dicyclohexyl urea was removed by ®ltration. EtOAc was added to the ®ltrate, and the organic
phase was washed with a 5% solution of NaHCO3 and H2O. The EtOAc solution was dried over
anhydrous Na2SO4 and evaporated to dryness in vacuo. The residue was recrystallized from EtOAc/
PE to give 1.52 g pure 1 (94%) as white crystals.
M.p.: 90.5±104ꢀC; Rf (A) ˆ 0.86, Rf (B) ˆ 0.87; 1H NMR ((CD3)2SO, ꢁ, 250 MHz): 8.17 (bt, 1H,
NH), 7.35 (s, 5H, H-arom), 5.1 (s, 2H, CH2-benzl), 3.84 (d, 2H, H-ꢂ (Gly), Jꢂ,NH ˆ 5.96 Hz), 2.14
(m, 1H, H-ꢂ (Ch ring), 1.69±1.58 (m, 5H, 2ÂCH2-ꢀ and H-ꢁ (Ch ring)), 1.36±1.04 (m, 5H, 2ÂCH2-ꢃ
‡
and H-ꢁ (Ch ring)) ppm; MS: m/z ˆ 275 (M ), 253, 220, 209, 184, 168, 154, 141, 111, 91
‡
(C6H5CH2 ), 83 (100%), 76, 67, 55.
Cyclohexylcarboxyl glycine (2; C9H15NO3)
0.5 g Cyclohexylcarboxyl glycine benzyl ester (1, 1.7 mmol) was dissolved in 20 cm3 absolute
MeOH. Then, 10% Pd/C and 0.32 g ammonium formate (5.0 mmol) were added. The reaction
mixture was stirred at room temperature for 10 min. The catalyst was removed by ®ltration and the
®ltrate concentrated in vacuo. The raw product was recrystallized from EtOAc/PE to give 0.25 g 2
(81%) as chromatographically pure crystals.
M.p.: 66.7±67ꢀC; Rf (A) ˆ 0.73; 1H NMR ((CD3)2SO, ꢁ , 250 MHz): 7.22 (bt, 1H, NH), 3.38 (d,
2H, H-ꢂ(Gly), Jꢂ,NH ˆ 3.76 Hz), 2.11 (m, 1H, H-ꢂ (Ch ring)), 1.68±1.56 (m, 5H, 2ÂCH2-ꢀ and H-ꢁ

50-O-Glycine Derivatives of Uridine
941
‡
(Ch ring)), 1.33±1.07 (m, 5H, 2ÂCH2-ꢃ and H-ꢁ (Ch ring)) ppm; MS: m/z ˆ 185 (M ), 167, 141,
130, 117, 112, 110, 83, 76, 73, 73, 67, 60, 55 (100%).
50-O-(Cyclohexylcarboxyl-glycyl)-20,30-O-isopropylideneuridine (3; C21H29N3O8)
2.07 g cyclohexylcarboxyl glycine (7.0 mmol) and 0.77 g DCC (3.7 mmol) were stirred in 10 cm3
DMF for 30 min at 0ꢀC. Then, 0.7 g 20,30-O-isopropylideneuridine (2.5 mmol) and 0.035 g
4-dimethylaminopyridine (0.25 mmol) were added, and stirring was continued for 48 h at room
temperature. N,N0-Dicyclohexyl urea was removed by ®ltration. EtOAc was added to the ®ltrate, and
the organic phase was washed with a 5% solution of NaHCO3 and H2O. The EtOAc solution was
dried over anhydrous Na2SO4 and evaporated to dryness in vacuo. The residue was recrystallized
from EtOAc/PE to give chromatographically pure 0.23 g 3 (20%).
M.p.: 147.5ꢀC; [ꢂ]D20 ˆ ꢁ10.7 (c ˆ 1.0, CH3OH); Rf (A) ˆ 0.76; 1H NMR ((CD3)2SO, ꢁ, 250MHz):
11.37 (s, 1H, NH-U), 7.78 (d, 1H, H-6, J6,5 ˆ 8.07 Hz), 5.82 (d, 1H, H-10, J1 ;2 ˆ 2.70 Hz), 5.63
0
0
0
(d, 1H, H-5, J5,6 ˆ 8.07 Hz), 5.10 (t, 1H, H-50, J5 ;5 ˆ 10.55 Hz), J5 ;4 ˆ 5.28 Hz), 4.88 (dd, 1H, H-2 ,
0
0
0
0
0
0
0
0
0
0
0
0
0
J2 ;1 ˆ 2.70 Hz, J2 ;3 ˆ 6.35 Hz), 4.74 (dd, 1H, H-3 , J3 ;4 ˆ 3.53 Hz, J3 ;2 ˆ 6.35 Hz), 4.06 (m, 1H,
H-40), 3.62±3.51 (m, 3H, H-ꢂ(Gly) and H-5), 2.14 (m, 1H, H-ꢂ (Ch ring)), 1.70±1.58 (m, 4H,
2ÂCH2-ꢀ (Ch ring)), 1.48 (s, 3H, CH3-isopropylidene), 1.37±1.14 (m, 6H, 2ÂCH2-ꢃ and CH2-ꢁ (Ch
‡
ring)), 1.27 (s, 3H, CH3-isopropylidene) ppm; MS: m/z ˆ 451 (M ), 436, 340, 326, 269, 209, 186,
‡
168, 137, 113 (B‡2H), 111 (B ), 99, 83 (100%), 75, 69, 55.
50-O-(N-Benzyloxycarbonyl-glycyl)-20,30-O-isopropylideneuridine (4; C22H25N3O9)
The title compound was prepared from 1.55 g N-benzyloxycarbonyl glycine (7.4 mmol), 0.76 g DCC
(3.7 mmol), 0.7 g 20,30-O-isopropylideneuridine (2.5 mmol), and 0.03 g 4-dimethylaminopyridine
(0.25 mmol) as described for 7 in 94% (1.12 g) yield.
M.p.: 101.6ꢀC; [ꢂ]D20 ˆ ꢁ1.5 (c ˆ 1.0, CH3OH); Rf (A) ˆ 0.73, Rf (B) ˆ 0.76; 1H NMR ((CD3)2SO,
ꢁ, 250 MHz): 11.40 (s, 1H, NH-U), 7.68 (t, 1H, NH (Gly), JNH,ꢂ ˆ 6.40 Hz), 7.65 (d, 1H, H-6,
J6,5 ˆ 8.09 Hz), 7.37±7.29 (m, 5H, H-arom), 5.80 (d, 1H, H-10, J1 ;2 ˆ 2.14 Hz), 5.64 (d, 1H, H-5,
0
0
J5,6 ˆ 8.09 Hz), 5.03 (s, 2H, CH2-benzl), 5.00 (dd, 1H, H-20, J2 ;1 ˆ 2.14 Hz, J2 ;3 ˆ 6.50 Hz), 4.77
0
0
0
0
(dd, 1H, H-30, J3 ;4 ˆ 3.43 Hz, J3 ;2 ˆ 6.50 Hz), 4.32±4.17 (m, 3H, 2H-5 , H-4 ), 3.79 (d, 2H,
0
0
0
0
0
0
H-ꢂ(Gly), Jꢂ,NH ˆ 6.40 Hz), 1.48 (s, 3H, CH3-isopropylidene), 1.28 (s, 3H, CH3-isopropylide-
‡
‡
ne) ppm; MS: m/z ˆ 475 (M ), 460, 417, 352, 256, 198, 167, 137, 113 (B‡2H), 107, 91 (C6H5CH2 ,
100%), 79, 69, 55.
Cyclohexylpropionyl glycine benzyl ester (6; C18H25NO3)
6 was prepared from 5.64 g cyclohexylpropionic acid (36.0 mmol), 3.7 g DCC (18.0 mmol), 4.05 g
glycine benzyl ester p-tosylate (12.0 mmol), and 1.66 cm3 Et3N (12.0 mmol) in accordance with the
procedure described for 1 in 90% (3.28 g) yield.
M.p.: 166ꢀC; Rf (A) ˆ 0.93, Rf (B) ˆ 0.87; 1H NMR ((CD3)2SO, ꢁ , 250 MHz): 8.28 (bt, 1H, NH),
7.30±7.35 (m, 5H, H-arom), 5.11 (s, 2H, CH2-benzl), 3.89 (d, 2H, H-ꢂ(Gly), Jꢂ,NH ˆ 5.90 Hz), 2.15±
2.09 (m, 2H, H-2 (Chpr)), 1.66±1.62 (m, 5H, 2ÂCH2-ꢀ and H-ꢂ (Ch ring)), 1.42±1.33 (m, 2H, H-3
(Chpr)), 1.16±1.09 (m, 4H, 2ÂCH2-ꢃ (Ch ring)), 0.88±0.79 (m, 2H, 2ÂH-ꢁ (Ch ring)) ppm; Ms:
‡
‡
m/z ˆ 304 (M ), 220, 207, 196, 169, 148, 139, 132, 121, 106, 91 (C6H5CH2 , 100%), 83, 69, 55.
Cyclohexylpropionyl glycine (7; C11H19NO3)
1.0 g cyclohexylpropionyl glycine benzyl ester (3.1 mmol) was dissolved in 20 cm3 absolute MeOH.
Then, 10% Pd/C and 0.59 g ammonium formate (9.4 mmol) were added. The reaction mixture was
stirred at room temperature for 10 min and treated as described for 2 to give 0.61 g 4 (92%).

942
D. K. Alargov et al.
M.p.: 153ꢀC; Rf (A) ˆ 0.79; 1H NMR ((CD3)2SO, ꢁ, 250 MHz): 7.38 (bt, 1H, NH), 5.12 (bs, 1H,
COOH), 3.41 (d, 2H, H-ꢂ(Gly), Jꢂ,NH ˆ 5.06 Hz), 2.08 (m, 2H, H-2 (Chpr)), 1.66±1.62 (m, 5H,
2ÂCH2-ꢀ and H-ꢂ (Ch ring)), 1.35 (m, 2H, 2H, H-3 (Chpr)), 1.17 (m, 4H, 2ÂCH2-ꢃ (Ch ring)), 0.80
‡
(m, 2H, 2ÂH-ꢁ (Ch ring)) ppm; MS: m/z ˆ 214 (M ), 196, 184, 168, 139, 130, 121, 117 (100%),
109, 95, 89, 83, 76, 69, 55.
50-O-(Cyclohexylpropionyl-glycyl)-20,30-O-isopropylideneuridine (8; C23H33N3O8)
Prepared from 1.58 g cyclohexylpropionyl glycine (7.4 mmol), 0.76 g DCC (3.7 mmol), 0.7 g 20,30-O-
isopropylideneuridine (2.5 mmol) and 0.03 g 4-dimethylaminopyridine (0.25 mmol) as described for
6 in 30% (0.36 g) yield.
M.p.: 140.8ꢀC; [ꢂ]D20 ˆ ꢁ6.9 (c ˆ 1.0, CH3OH); Rf (A)ˆ 0.82; 1H NMR ((CD3)2SO, ꢁ, 250 MHz):
11.42 (s, 1H, NH-U), 7.80 (d, 1H, H-6, J6,5 ˆ 8.05 Hz), 5.78 (d, 1H, H-10, J1 ;2 ˆ 2.05 Hz), 5.63
0
0
0
(d, 1H, H-5, J5,6 ˆ 8.00 Hz), 5.8 (dd, 1H, H-20, J200;1 ˆ 2.06 Hz, J2 ;3 ˆ 6.40 Hz), 4.92 (dd, 1H, H-3 ,
0
0
0
0
0
0
0
0
J3 ;4 ˆ 2.06 Hz, J3 ;2 ˆ 6.40 Hz), 4.66 (m, 1H, H-4 ), 4.25 (m, 4H, H-ꢂ(Gly) and H-5 ), 2.27 (m, 2H,
H-2 (Chpr)), 1.67 (m, 5H, 2ÂCH2-ꢀ and H-ꢂ (Ch ring)), 1.48 (s, 3H, CH3-isopropylidene), 1.42
(m, 2H, 2H, H-3 (Chpr)), 1.28 (s, 3H, CH3-isopropylidene), 1.18 (m, 4H, 2ÂCH2-ꢃ (Ch ring)), 0.83
‡
(m, 2H, 2ÂH-ꢁ (Ch ring)) ppm; MS: m/z ˆ 480 (M ), 466, 368, 326, 214, 168, 139 (100%), 137,
121, 113 (B‡2H), 97, 83, 69, 55.
50-O-(Cyclohexylcarboxyl-glycyl)-20,30-O-isopropylideneuridine (3; C21H29N3O8)
(second approach)
3 was prepared from 1.51 g cyclohexanecarboxylic acid (7.5 mmol), 0.78 g DCC (3.8 mmol), and
1.19 g 50-O-(N-benzyloxycarbonyl-glycyl)-20-30-O-isopropylideneuridine (2.5 mmol) as described
for 2 and 0.35 cm3 Et3N (2.5 mmol) as described for 1 in 76% (1.13 g) yield.
50-O-(Cyclohexylpropionyl-glycyl)-20,30-O-isopropylideneuridine (6; C23H33N3O8)
(second approach)
The title compound was prepared from 1.17 cm3 cyclohexylpropionic acid (7.5 mmol), 0.78 g DCC
(3.8mmol), and 1.19 g 50-O-(N-benzyloxycarbonyl-glycyl)-20,30-O-isopropylideneuridine (2.5mmol)
which were treated as described for 2 and 0.35 cm3 Et3N (2.5 mmol) as described for 1 in 78%
(1.20 g) yield.
Acknowledgements
This work was supported by Grant No K-602 of the National Fund for Scienti®c Research at the
Bulgarian Ministry of Education and Science.
References
[1] Mulder GJ, Coughtrie MWH, Burchell B (1990) Conjugation Reaction in Drug Metabolism.
Taylor & Francis, London
[2] Macleod R, Eacling VA, Sim SM, Back DJ (1992) Biochem Pharmacol 43: 382
[3] Restar A, Minick D, Spector T (1991) Biochem Pharmacol 42: 559
[4] Fournel S, Gregoire B, Magdalou J, Carre M-Ch, Lafaurie Ch, Siest G, Coubere P (1986)
Biochim Biophys Acta 883: 190
[5] Fournel-Gigleux S, Shepherd SRP, Carre M-C, Burchell B, Siest G, Coubere P (1989) Eur J
Biochem 183: 653

50-O-Glycine Derivatives of Uridine
943
[6] Noort D, Coughtrie MWH, Burchell B, van der Marel GA, van Boom JH, van der Gen A, Mulder
GJ (1990) Eur J Biochem 188: 309
[7] Said M, Noort D, Magdalou J, Ziegler JC, van der Marel GA, van Boom JH, Mulder GJ, Siest G
(1992) Biochem Biophys Res Commun 187: 140
[8] Camarasa M-J, Fernandez-Resa P, Garcia-Lopez M-T, de las Heras, FG, Mendez-Castrillon PP,
Alarcon B, Carrasco L (1985) J Med Chem 28: 40
[9] Paul P, Lutz TM, Osborn C, Kyosseva S, Elbein AD, Towbin H, Radominska A, Drake RR (1993)
J Biol Chem 268: 12933
[10] Radominska A, Paul P, Treat S, Towbin H, Pratt C, Little J, Magdalou J, Lester R, Drake R (1994)
Biochem Biophys Acta 1205: 336
[11] Battaglia E, Elass A, Drake RR, Paul P, Treat S, Magdalou J, Fournel-Gigleux S, Siest G,
Vergoten G, Lester R, Radominska A (1995) Biochem Biophys Acta 1243: 9
[12] Cano V, Lorentz C, Magdalou J, Loppinet V, Siest G, Ziegler J (1997) Life Sciences 61: 1
[13] Timmers CM, Dekker M, Buijsman RC, van der Marel GA, Ethell B, Anderson G, Burchell B,
Mulder GJ, van Boom JH (1997) Bioorg Med Chem Lett 7: 1501
[14] Alargov DK, Naydenova Z, Grancharov K, Denkova PS, Golovinsky EV (1997) Monatsh Chem
128: 725
[15] Alargov DK, Naydenova Z, Grancharov K, Denkova PS, Golovinsky EV (1998) Monatsh Chem
129: 755
[16] Naydenova Z, Alargov D, Grancharov K, Golovinsky E (1996) Exp Toxic Pathol [Suppl] 48: 295
[17] Naydenova ZG, Grancharov KC, Alargov DK, Golovinsky EV, Stanoeva IM, Shalamanova LD,
Pajeva IK (1998) Z Naturforsch 53(C): 173
[18] Sheehan JC, Hess GP (1955) J Amer Chem Soc 77: 1067
[19] Anwer MK, Spatola AF (1980) Synthesis 929
[20] Ho¯e G, Steylich W (1972) Synthesis 619
[21] Reindel F, Hoppe W (1954) Chem Ber 87: 1103
Received November 10, 1998. Accepted (revised) December 29, 1998