Total synthesis of (±)-Eusiderin G and (±)-Eusiderin M

Article abstract of DOI:10.1002/jccs.200100011

(±)-Eusiderin G and (±)-Eusiderin M were first synthesized from pyrogallol, in which the Claisen Rearrangement was used to afford two important C₆-C₃ units.

Full text of DOI:10.1002/jccs.200100011

JournaloftheChineseChemicalSociety, 2001, 48, 59-63
59
Total Synthesis of (±)-Eusiderin G and (±)-Eusiderin M
Xiaobi Jing (
), Wenxin Gu (
), Xinfeng Ren (
),
任新鋒
顧文鑫
景崤壁
Pingyan Bie (
) and Xinfu Pan* (
)
潘鑫複
別平彥
DepartmentofChemistry,NationalLaboratoryofAppliedOrganicChemistry,
Lanzhou Uni ver sity, Lanzhou 730000, P. R. China
( )-Eusiderin G and ( )-Eusiderin M were first syn the sized from pyrogallol, in which the Claisen Re ar-
rangementwasusedtoaffordtwoimportantC6-C3 units.
INTRODUCTION
RESULTS AND DISCUSSION
During the last years, 1,4-benzodioxins and 1,4-
benzodioxaneshaveattractedconsiderableinterest,mainly
duetotheirveryinterestingbiologicalactivities. Someof
them act as - or -block ing re agents and could be used in
antidepression or antihypertension ther apy.1 Othersexhibit
antihyperglycemicproperties,2 or could act as in hib i tors of
5-lipoxygenase.3 More over, these com pounds could also be
used for use ful syn thetic trasformations.4
As shown in Scheme I, pyrogallol was eas ily con verted
into trimethyl pyrogallol (2). Treat ment of 2 with ZnCl2 and
propionic acid gave 2,6-dimethoxy phe nol (3) in 81% yield.12
Compound(4),readilyavailableinnearquantitativeyieldby
the re ac tion of 3 with allyl bromide, was sub mit ted to a
Claisen Re ar range ment in a sealed tube to give 5 in >99%
yield. Com pound 5 was treated with PdCl2 in meth a nol to af-
fordcompound( 6) in 88% yield.
( )-Eusiderin G and ( )-Eusiderin M (Fig. 1) are two
neolignans isolated from the bark of Aniba5 and Licaria
chiysophylla.6 This type of nat u ral prod ucts con tain ing the
1,4-benzodioxane ring have cytotoxic and hepatoprotective7
andotherbiologicalactivity.8
Syn the sis of the other unit (12) also be gan from pyro-
gallol, which was se lec tively pro tected by (CH3)2SO4 un der
the pro tec tion of Na2B4O7 10H2O to af ford com pound (7). 7
was con verted into com pound (8) and (9) in high yield by a
proceduresimilartothatusedfor5.
Al though many syn the ses of 1,4-benzodioxane neo-
lignans have been re ported,9-11 the syn the sis of 1,4- benzo-
dioxane neolignans which have 4-hydroxy-3,5-dimethoxy
aryl groups have not been re ported, be cause it is dif fi cult to
syn the size the C6-C3 units of 4-hydroxy-3,5-dimethoxy aryl
group. Herein, we de vel oped a fac ile syn thetic route to ( )-
Eusiderin G and ( )-Eusiderin M, in which the Claisen Re ar-
range ment re ac tion was used to af ford the 4-hydroxy- 3,5-
dimethoxy aryl group (5) and 3,4-dihydroxy-5-methoxy aryl
group (9).
Com pound9 was treated with PdCl2 in meth a nol to af-
ford com pound (10). Com pound 10 was con verted into com-
pound (11) by SeO2 af ter the pro tec tion of Ac2O.Compound
11 was treated with NaHCO3 in meth a nol/wa ter to af ford
com pound12.
Compound(13) was readily avail able as a mix ture of
iso mer (cis and trans ca. 1:7 by 1HMR) by the cou pling of6
and 12 with silveroxideasanoxidizingreagent.13 Then 13
was protected by CH3I in a base con di tion to af ford ( )-
Eusiderin G. In this re ac tion cis iso mer was con verted to
OMe
O
OMe
O
OMe
OMe
O
O
HO
OHC
OMe
OMe
Eusiderin G
Eusiderin M
OMe
OMe
Fig. 1.

60 J. Chin. Chem. Soc., Vol. 48, No. 1, 2001
Jing et al.
Scheme I
OH
OH
OH
OMe
OH
O
4
MeO
OMe
MeO
v
OMe
HO
OH MeO
i
OMe MeO
ii
OMe MeO
iii
OMe
iv
5
1
2
3
6
OH
O
OH
OH
HO
OMe
HO
OMe
HO
OMe
iii
HO
OH
vi
iv
9
8
7
1
OH
OH
OAc
HO
OMe
HO
OMe
AcO
OMe
ix
vii/viii
v
12
10
11
CHO
CHO
OMe
OMe
OMe
O
O
O
O
O
O
xi
x
xii
6+12
OMe
OMe
OMe
OMe
OMe
HO
OHC
OH
OHC
Eusiderin M
Eusiderin G
OMe
OMe
OMe
i: NaOH, (CH3)2SO4 98%; ii: ZnCl2, propionic acid, re flux 81%; iii: K2CO3 Allylbromide98%;iv:ClaisenRear-
range ment >99%; v: PdCl2 methanol88%;vi:Na2B4O710H2O, K2CO3, (CH3)2SO4 85%; vii: Ac2O/Py 95%; viii:
SeO2/ethanol72%(fromvii);ix:NaHCO3,methanol,water,95%;x:Ag2O,benzene/acetone(5:1,v/v);xi:KOH,
CH3I, ac e tone, 35%(from x); xii: LAH/AlCl3 90%.
transisomerexclusivelyinabasecondition.10 ( )-Eusiderin
G was treated with LAH/AlCl3 in THF to afford ( )-
Eusiderin M in 88% yield.
EXPERIMENTAL
Melting points were mea sured on a Kofler ap pa ra tus

To tal Syn the sis of (±)-Eusiderin G and (±)-Eusiderin M
J. Chin. Chem. Soc., Vol. 48, No. 1, 2001 61
and were uncorrected. Mass spectra were recorded on a
ZAB-HSspectrometer.Elementalanalyseswereperformed
on a Carlo-Erba 1106 in stru ment. 1H-NMR spec tra were re-
corded on a Bruker AC-80 and AM-400 instrument.13C-
NMRspectrawererecordedonaBrukerAM-400instrument.
ChemicalshiftsarereferencedtoTMSonthe“ ” scale. Stan-
dardflashchromatographywasemployedtopurifythecrude
reactionmixtureusing200-300meshsilicagelunderaposi-
tivenitrogenpressure.
com bined ex tracts were dried (Na2SO4). The Et2O was dis-
tilled off. The res i due was flash chromatographed us ing pe-
tro leum ether as eluent to af ford a yel low liq uid4 (1.86 g,
yield 98%). EI-MS (m/z): 194 (M+, 24), 153 (100), 110 (49),
95 (39), 65 (17), 39 (60); 1H-NMR (80 MHz, CDCl3): 3.88
(s, 6H, Ar-OMe), 4.46 (d, J = 8.0 Hz, 2H, -CH2CH=CH2),
5.0-5.9 (m, 3H, -CH2CH=CH2), 6.42 (s, 3H, Ar-H).
2,6-dimethoxy-3-allylphenol (5)
Com pound4 (1.5 g, 0.0077 mol) was put into a tube.
Then it was sealed on fire. Af ter wards the tube was put in hot
oil (150oC) for a week. Com pound5 was af forded as a yel low
liquidquantitatively.EI-MS(m/z): 194 (M+, 76), 167 (29),
1,2,3-trimethoxybenzene (2)
To a stirred so lu tion of pyrogallol1 (2.00 g, 15.9 mmol)
in 25 mL eth a nol was added NaOH (1.9 g). The mix ture was
stirredat room tem peraturefor30minundertheat mosphere
of ni tro gen and (CH3)2SO4 (4.6 mL, 47.6 mmol) was added
dropwise over 15 min. The mix ture was stirred for 10 h at
room tem per a ture. The sol vent was evap o rated in vacuo.
Crude prod ucts were dis solved in wa ter and then ex tracted
with Et2O (50 mL × 3). The com bined ex tracts were dried
(Na2SO4), the Et2O was dis tilled off, the res i due was flash
chromatographed us ing pe tro leum ether and ethyl ac e tate
(50:1, v/v) as eluent to af ford 2 (2.6 g, yield 98%) as a white
solid. mp.: 41-42 oC; EI-MS (m/z): 168 (M+, 100), 153 (70),
125 (47), 110 (55), 1H-NMR (80 MHz, CDCl3): 3.81 (s, 9H,
-Me), 6.39-7.09 (m, 3H, Ar-H).
1
151 (26), 119 (47), 91 (96), 77 (69), 39 (100); H-NMR (80
MHz, CDCl3): 3.36 (d, J = 6.51 Hz, 2H, -CH2CH=CH2),
3.88 (s, 6H, Ar-OMe), 5.16 (d, J = 13.8 Hz, 2H, -CH=CH2),
5.93 (m, 1H, -CH=CH2), 6.42 (s, 2H, Ar-H).
1-(3,5-dimethoxy-4-hydroxy-phenol) propene (6)
Com pound5 (2 g, 10.3 nmol) was stirred for 24 h with a
catalyticamountofPdCl2 in meth a nol (80 mL). Then the salt
wasfiltratedandthesolventwasevaporated.Theresiduewas
flash chromatographed us ing pe tro leum ether and ethyl ac e-
tate (6:1, v/v) as eluent to af ford the yel low liq uid6 (1.76 g,
yield 88%). EI-MS (m/z ): 194 (M+, 76), 167 (29), 151 (26),
1
119 (47), 91 (96), 77 (69), 39 (100); H-NMR (400 MHz,
1,3-dimethoxy-2-hydroxybenzene (3)
CDCl3): 1.85 (dd, J = 1.63, 6.60 Hz, 3H, -CH=CHCH3),
3.86 (s, 3H, Ar-OMe), 3.87 (s, 3H, Ar-OMe), 6.05-6.14 (m,
2H, CH=CHMe), 6.41 (s, 1H, Ar-H), 6.57 (s, 1H, Ar-H).
To a stirred so lu tion of an hy drous ZnCl2 (3 g, 0.022
mol) in 20 mL propionic acid was added dropwise the so lu-
tion of 2 (2.5 g, 0.015 mol ) in 10 mL propionic acid over 5
min. Then the so lu tion was refluxed for 2 h un der an at mo-
sphere of ni tro gen. The sol vent was evap o rated in vacuo.
Crude prod ucts were dis solved in wa ter and then ex tracted
with Et2O (20 mL 3). The com bined ex tracts were dried
(Na2SO4). The Et2O was dis tilled off. The res i due was flash
chromatographed using pe tro leum ether and ethylacetate
(6:1, v/v) as eluent to af ford the white solid of 3 (1.86 g, yield
81%) mp: 46-47 oC; EI-MS (m/z): 154 (M+, 100), 139 (55),
114 (45), 96 (40); 1H-NMR (80 MHz, CDCl3): 3.86 (s, 6H,
-Me), 6.71-7.10 (m, 3H, Ar-H).
3-methoxy-1,2-benzenediol (7)
To a stirred so lu tion of pyrogallol (4 g, 31.7 mmol) in
50 mL eth a nol was added dropwise a so lu tion of 12.1 g
Na2B4O7 10H2O in 20 mL H2O. Af ter stir ring for 30 min to
the so lu tion was added 4.38 g K 2CO3 and 3.1 mL (CH3)2SO4.
The mix ture was stirred over night. Then H2O (10 mL) was
added and the mix ture was ex tracted with CH2Cl2 (25 mL
3). The com bined ex tracts were dried (Na2SO4); the CH2Cl2
was dis tilled off; the res i due was flash chromatographed us-
ingpe troleum etherandethyl ac e tate (4:1, v/v)aseluent toaf-
1
ford the liq uid 7 (3.8 g, yield 85%). H-NMR (80 MHz,
2-allyoxy-1,3-dimethoxybenzene (4)
CDCl3): 3.81 (s, 3H, - Me), 6.71-7.10 (m, 3H, Ar-H).
Underanitrogenatmosphere,tothesolutionof3 (1.5 g,
9.7 nmol) in 20 mL ac e tone was added NaOH (0.39 g, 9.7
nmol). Af ter stir ring for 30 min, to the mix ture was added
allyl bro mide (0.84 mL, 0.0097 mol) dropwise over 30 min.
Themixturewasthenstirredfor6hatroomtemperature.The
sol vent was evap o ratedin vacuo. Crude prod ucts were dis-
solvedinwaterandthenextractedwithEt2O (50 mL 3). The
2-allyoxy-3-methoxyphenol (8)
Thesynthesisof8 was the same as that of4.Compound
8 (yield 98%) was yel low liq uid. EI-MS (m/z ): 180 (M+, 4),
153 (100), 139 (25), 125 (43), 110 (46), 93 (35), 65 (15), 39
(53); 1H-NMR (80 MHz, CDCl3): 3.85 (s, 3H, Ar-OMe),
1.46 (d, J = 6.8 Hz, 2H, -CH2CH=CH2), 5.0-5.9 (m, 3H,

62 J. Chin. Chem. Soc., Vol. 48, No. 1, 2001
Jing et al.
-CH2CH=CH2), 5.87-5.97 (m, 1H, -CH2-CH=CH2), 6.3-6.45
(m, 3H, Ar-H).
1H-NMR (80 MHz, CDCl3): 3.86 (s, 3H, Ar-OMe), 6.4-6.6
(m, 4H, Ar-H, Ar-CH=CH-CHO), 9.4 (d, J = 8 Hz, -CHO,
1H).
3-methoxy-5-allyl-1,2-benzenediol (9)
Thesynthesisof9 was the same as that of5.Compound
9 (yield>99%)wasyellowliquid.EI-MS( m/z): 180 (M+, 86),
165 (19), 147 (39), 119 (51), 103 (21), 91 (100), 65 (61), 39
(84); 1H-NMR (80 MHz, CDCl3): 3.27 (d, J = 6.8 Hz, 2H,
-CH2CH=CH2), 3.85 (s, 3H, Ar-OMe), 5.0-5.3 (m, 3H,
-CH2CH=CH2), 6.30 (s, 1H, Ar-H), 6.45 (s, 1H, Ar-H).
( )-Eusiderin G
Sil ver ox ide (168 mg) was added to a so lu tion of6 (140
mg, 0.72 mmol) and 12 (140 mg, 0.72 mmol) in ben zene/ac e-
tone (5:1, v/v, 25 mL). The so lu tion was stirred for 24 h at
roomtemperature,thenitwasfiltered.Thesolventsweredis-
tilled off. The res i due was added into a flask. Then 25 mL ac-
e tone, 45 mg KOH and 0.5 mL (CH3)2SO4 was added. Af ter
stir ring for 8 h, the so lu tion was fil tered and the ac e tone was
dis tilled off. Then the res i due was flash chromatographed us-
ingpe troleum etherandethyl ac e tate (3:1, v/v)aseluent toaf-
ford ( )-Eusiderin G as a vis cous oil (101 mg, yield 35%).
EI-MS (m/z): 400 (M+, 5), 208 (30), 195 (33), 193 (30), 83
(100); 1H-NMR (400 MHz, CDCl3): 1.33 (d, J = 6.71 Hz,
3H, 9-H), 3.85 (s, 3H, -OMe), 3.91 (s, 6H, -OMe), 3.94 (s,
3H, -OMe), 4.08-4.13 (m, 1H, 8-H), 4.52 (d, J = 8 Hz, 1H,
7-H), 6.59 (s, H-2, H-6), 6.57 (dd, J = 8, 16 Hz, H-8’), 6.73
(d, J = 2 Hz, H-6’), 6.89 (d, J = 2 Hz, H-2’), 7.36 (d, J = 16
Hz, H-7’), 9.62 (d, J = 8 Hz, H-8’); 13C-NMR (100 MHz):
136.0 (1-C), 107.5 (2-C), 149.7 (3-C), 137.3 (4-C), 149.6
(5-C), 104.4 (6-C), 85.8 (7-C), 78.6 (8-C), 21.6 (9-C), 136.1
(1’-C), 108.3 (2’-C), 143.3 (3’-C), 138.0 (4’-C), 143.0
(5’-C), 102.9 (6’-C), 128.5 (7’-C), 142.5 (8’’-C), 194.3
(9’-C), 60.5, 64.7 (OMe); Found: C, 65.99; H, 6.04 C22H24O7
re quires C, 66.06; H, 6.10%. The above data were in agree-
mentwiththosefoundintheliterature.5
1-(3-methoxy-4,5-dihydroxy-phenol) propene (10)
The syn the sis of 10 was the same as that of 6. Com-
pound 10 (yield 88%) was yel low liq uid. EI-MS (m/z): 180
(M+, 80), 165 (20), 119 (51), 103 (21), 91 (100), 65 (61), 39
(84); 1H-NMR (80 MHz, CDCl3): 1.64 (d, J = 6.60 Hz, 3H,
-CH=CHCH3), 3.87 (s, 3H, Ar-OMe ), 6.04-6.12 (m, 2H,
-CH=CHMe), 6.47 (1H, Ar-H), 6.59 (1H, Ar-H).
3-(3-methoxy-4,5-dicarbethoxy-phenyl) propenal(11)
To a stirred so lu tion of10 (1 g, 5.55 mmol) in 50 mL
CH2Cl2 was added dropwise 0.53 mL Ac2O and a drop of
pyridine. Afterthesolutionwasstirredovernightitwasevap-
oratedin vacuo. Crude prod ucts were dis solved in wa ter and
then ex tracted with Et2O (50 mL 3).Thecombinedextracts
were dried (Na2SO4). The Et2Owasdistilledoff. Theresidue
was dis solved in 95% eth a nol and then 0.6 g SeO2 was added.
Af ter the so lu tion was refluxed for 4 h it was evap o ratedin
vacuo. Crude prod ucts were dis solved in wa ter and then ex-
tracted with Et2O (50 mL 3). The com bined ex tracts were
dried (Na2SO4). The Et2O was dis tilled off. The res i due was
flash chromatographed using petroleum ether and ethyl-
acetate (10:1, v/v) as eluent to af ford the yel low solid of 11
(1.1 g, yield 72% from 10). mp.: 122-124 C; EI-MS (m/z):
278 (M+, 40), 257 (20), 236 (10), 194 (100), 166 (60), 151
(40); 1H-NMR (80 MHz, CDCl3): 1.89 (s, 6H, Ar-CO-Me),
3.86 (s, 3H, Ar-OMe), 6.4-6.6 (m, 4H, Ar-H, Ar-CH=CH-
CHO), 9.4 (s, -CHO, 1H).
( )-Eusiderin M
Inaglassreactorundernitrogenfittedwithacondenser
andmechanicalstirredwasslowlyaddedindryTHF(20mL)
at -10 C 9.5 mg of LAH and 6.5 mg of AlCl3. Then the so lu-
tion of ( )-Eusiderin G (100 mg) in 20 mL THF was added
dropwise. Afterstirringforovernightatroomtemperature,
the mix ture was cooled to 0 C. The ex cess of LAH was de-
com posed by care ful ad di tion of 30% KOH so lu tion. The in-
or ganic salts were fil tered off and washed with CH2Cl2 (20
mL 3). The so lu tion was re moved un der vac uum. Then the
res i due was flash chromatographed us ing pe tro leum ether
and ethyl ac e tate (3:1, v/v) as eluent to af ford ( )-Eusiderin
M (90 mg, 90%) as a yel low liq uid. EI-MS (m/z ): 402 (M+),
198, 196, 151, 149, 105; 1H-NMR (400 MHz, CDCl3): 1.24
(d, J = 6.10 Hz, 3H, 9-H), 3.84 (s, 3H, -OMe), 3.91 (s, 9H,
-OMe), 4.05-4.13 (m, 1H, 8-H), 4.52 (d, J = 7.71 Hz, 1H,
7-H), 4.70 (dd, J = 6.5, 1.5 Hz, H-9’), 6.15 (dt,J =16, 6.5 Hz,
H-8’), 6.55 (d, J = 16 Hz, 1H, 7’-H), 6.59 (s, H-2, H-6), 6.63
(d, J = 2 Hz, H-2’), 6.73 (d, J = 2 Hz H-6’), 13C-NMR (100
3-(3-methoxy-4,5-dihydroxy-phenol) propenal (12)
Asolutionof11 (1 g, 5.2 nmol) in 40 mL meth a nol and
20 mL wa ter was treated with 20 mL sat u rated so dium bi car-
bonatesolutionandstirredatroomtemperatureovernightun-
dernitrogen.Thesolutionwasacidifiedwith10%hydrochlo-
ric acid and ex tracted with ethyl ac e tate. The ethyl ac e tate
was dis tilled off. The res i due was flash chromatographed us-
ing pe tro leum ether and ethylacetate (3:1, v/v) as eluent to af-
ford the yel low solid of 12 (0.63 g, yield 95%). mp: 112-116
C EI-MS (m/z): 194 (M+), 177, 166, 163, 151, 123, 105;

To tal Syn the sis of (±)-Eusiderin G and (±)-Eusiderin M
J. Chin. Chem. Soc., Vol. 48, No. 1, 2001 63
MHz): 136.0 (1-C), 107.5 (2-C), 149.7 (3-C), 137.3 (4-C),
149.6 (5-C), 104.4 (6-C), 85.8 (7-C), 78.6 (8-C), 21.6 (9-C),
136.1 (1’-C), 108.3 (2’-C), 143.3 (3’-C), 138.0 (4’-C), 143.0
(5’-C), 102.9 (6’-C), 128.5 (7’-C), 122.7 (8’-C), 63.3 (9’-C),
60.5, 64.7 (OMe); Found: C, 65.66; H, 6.51. C22H26O7 re-
quires C, 65.58; H, 6.58%. The above data were in agree ment
withthosefoundintheliterature.6
1354-1357. (e) Quaglia, W.; Pigini, M.; Tayebati, S. K.;
Piergentili, A.;. Giannella, M ; Leonardi, A.; Taddei, C.;
Melchiorre, C. J. Med. Chem. 1996, 39, 2253-2258.
2. Fagan, G. P.; Chapleo, C. P.; Lane, A. C.; Myers, M.;
Roach, A. G.; Roach, C. F. C.; Stillings, M. R.; Welbourn,
A. P. J. Med. Chem. 1988, 31, 944-948.
3. Satoh, Y.; Pouwers, C.; To ledo, L. M.; Kowalski, T. J.; Pe-
ters, P. A.; Kimble, E. F. J. Med. Chem. 1995, 38, 68-75.
4. (a) Lee, T. V.; Leigh, A. J.; Chapleo, C. B. Tetrahedron
1990, 46, 921-934. (b) Mata, E. G.; Suarez, A. G. Synth.
Commun. 1997, 27, 1291-1300. (c) Moreau, P.;
Guillaumet, G.; Coudert, G. Synth. Commun. 1994, 24,
1781-1787.
ACKNOWLEDGMENT
WearegratefultotheNationalNatureScienceFounda-
tion of China (No. 29772012) for fi nan cial sup port.
5. Dias, S. M. C.; Fernandes, J. B.; Maia, J. G. S.; Gottlieb,
O. R.; Gottlieb, H. E. Phytochemistry 1986, 25, 213-217.
6. Silva, M. S. D.; Barbosa-Filho, J. M.; Yoshida, M.;
Gottlieb, O. R. Phytochemistry 1989, 28, 3477-3482.
7. Antus, S.; Baitz-Gacs, E.; Bauer, R.; Wag ner, H. Liebigs
Ann. Chem. 1989, 1147.
Received May 22, 2000.
Key Words
( )-Eusiderin M; ( )-Eusiderin G; Noelignan;
Total synthesis; Pyrigallol.
8. Yamauchi, S.; Taniguchi, E. Biosci. biotech. biochem.
1992, 50, 630.
9. Merlini , B. L.; Zanarotti, A. J. C. S. Perkin I 1980, 775.
10. She, X. G.; Jing, X. B.; Pan, X. F. TetrahedronLetters
1999, 40, 4567.
REFERENCES
11. Matsumoto, K.; Takahashi, H.; Miyake, Y.; Fukuyama, Y.
TetrahedronLetters 1999, 40, 3185.
12. Wu, A. X.; Wang, M. Y.; Pan, X. F. Huaxue Tongbao
(Chin) 1997, 8, 42-42.
1. (a) Nel son, W. L.; Wennerstrom, J. E.; Dyer, D. C.; Engel,
M. J. Med. Chem. 1977, 20, 880-885. (b) Marciniak, G.;
Delgado, A.; Leclerc, G.; Velly, J.; Decker, N.; Schwartz,
J. J. Med. Chem. 1989, 32, 1402-1407. (c) Ruffolo Jr., R.
R.; Boudinell, W.; Hieble, J. P. J. Med. Chem. 1995, 38,
3681-3716. (d) Giardina, D.; Bertini, R.; Brancia, E.;
Brasili, L.; Melchiore, C. J. Med. Chem. 1985, 28,
13. Antus, S.; Baitz-Gacs, E.; Wagner, H. Liebigs. Ann.
Chem. 1989, 1147.