Linker-modified quinoline derivatives targeting HIV-1 integrase: Synthesis and biological activity

Article abstract of DOI:10.1016/j.bmcl.2004.03.005

A novel series of HIV-1 integrase inhibitors was synthesized and tested in both in vitro and ex vivo assays. These inhibitors are featured by the presence of a quinoline subunit and an ancillary aromatic ring linked by functionalized spacers such as amide

Full text of DOI:10.1016/j.bmcl.2004.03.005

Bioorganic & Medicinal Chemistry Letters 14 (2004) 2473–2476
Linker-modified quinoline derivatives targeting HIV-1 integrase:
synthesis and biological activity
a,b
a
a
Christophe Benard, Fatima Zouhiri,a,b Marie Normand-Bayle, Michele Danet,
ꢀ
ꢁ
a,
b
c
c
*
€
ꢀ
Didier Desmaele, Herve Leh, Jean-Franßcois Mouscadet, Gladys Mbemba,
Claire-Marie Thomas,b Sabine Bonnenfant,b Marc Le Bretc and Jean d’Angeloa,*
aCNRS UMR 8076, Centre d’Etudes Pharmaceutiques, Chimie Organique, 5 rue J.-B. Clꢀement, 92296 Ch^atenay-Malabry, France
bBioAlliance Pharma, 59 Bd du Gꢀenꢀeral Martial Valin, 75015 Paris, France
cCNRS UMR 8113, Ecole Normale Supꢀerieure, 61 av. du Prꢀesident Wilson, 94235 Cachan, France
Received 9 December 2003; revised 4 February 2004; accepted 2 March 2004
Abstract—A novel series of HIV-1 integrase inhibitors was synthesized and tested in both in vitro and ex vivo assays. These
inhibitors are featured by the presence of a quinoline subunit and an ancillary aromatic ring linked by functionalized spacers such as
amide, hydrazide, urea and 1-hydroxyprop-1-en-3-one moiety. Amide derivatives are the most promising ones and could serve as
leads for further developments.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
OH
HO 2C
N
OH
AIDS is essentially a viral disease and should be treated
with antiretroviral agents. Although the advent of
combination therapy with reverse transcriptase and
protease inhibitors has made it possible to suppress the
replication of HIV-1 in infected persons to such an
extent that it becomes almost undetectable in the plasma
for more than two years, the virus persists in reservoirs
such as peripheral blood mononuclear cells or resting
T-lymphocytes. This means that AIDS can be tempo-
rarily controlled, but not eradicated with current treat-
ments.1–3 It is therefore important to identify new agents
targeting HIV-1 at a step of its replicative cycle, which is
not yet affected by the above combination therapy. In
this respect, we have recently reported that polyhydr-
oxylated styrylquinolines, exemplified by 1, are micro-
molar inhibitors of the third essential enzyme of HIV-1:
integrase (IN), block the replication of the virus in cell
culture and are devoid of cytotoxicity (Fig. 1).4
OH
1
Figure 1. Example of polyhydroxylated styrylquinoline.
aromatic nucleus by means of an ethylenic linker. To
date, most of the synthetic efforts in the area have been
directed towards modification of the two aromatic/het-
eroaromatic subunits.4a;b;g;h
Herein, we report the preliminary results of our
expanded SAR investigation directed towards the
replacement of the central ethylenic linker by function-
alized spacers (amide, hydrazide, urea, 1-hydroxyprop-
1-en-3-one moieties).
2. Preparation of the quinoline subunits
Drugs of the styrylquinoline family are featured by the
presence of a quinoline moiety connected to an ancillary
Although styrylquinolines of type 1 were efficiently
elaborated through Perkin condensation between the
known 8-hydroxyquinaldine-7-carboxylic acid 2a and
an aromatic aldehyde,4a it appeared that a synthetic
sequence directed to the introduction of functionalized
spacers should require from the outset the protection of
Keywords: Antivirals; Enzyme inhibitors; Quinolines; Amides; Ureas.
* Corresponding authors. Tel.: +33-(0)146835699; fax: +33-(0)14683-
5752; e-mail: jean.dangelo@cep.u-psud.fr
0960-894X/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.03.005

2474
C. Bꢀenard et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2473–2476
R
R
CO2Me
R
R1O2C
N
Me
t-BuO2C
N
OR 2
OC Ot-Bu
O
O
MeO
O
Ph
MeO
OH
O
O
Ph
O
Ph
OH
Ph
2
3
a: R1 = H, R2 = H
a : R = OH
7
5
6
b: R1 = n-Bu,R2 = H
a :
b :
c :
d :
R = CO2Me
R = CO2H
a : R = NO2
b : R = NH2
O
N
b : R =
c: R1 = Cl3CCH2, R2 = H
R = NHCO2CH2CH2TM S
R = NH2
O
d: R1 = Cl3CCH , R2 = t-BuCO
c : R = N3
2
e: R1 = t-Bu,R2 = t-BuCO
R1
CO2Me
CH2NH3 TsO
R1
R2
O
R4
R2
t-BuO2C
N
NHR
O
Ph
O
Ph
R3
O
Ph
Ph
OC Ot-Bu
4
8
9
10
a : R1 = OH, R2 = H
b : R1 = Cl, R2 = H
c : R1 = N3, R2 = H
d : R1 = NH2, R2 = H
e : R1 = NH2, R2 = OMe
a: R = CO2Bn
b: R = H
a : R1 = R2 = OH, R3 = R4 = H
b : R1 = R3 = OH, R2 = R4 = H
c : R1 = R4 = H, R2 = R3 = OH
d : R1 = R3 = H, R2 = R4 = OH
e : R1 = R2 = R3 = OH, R4 = H
Figure 2. Quinoline subunits.
these phenolic and carboxylic acid functions. Esterifi-
cation of the carboxylic acid function of 2a was inves-
tigated first. Treatment of the latter compound with
n-butanol at 100 ꢁC in the presence of polyphosphoric
acid (PPA)5 gave the n-butyl ester 2b with a 80% yield.
However, the use of the strongly basic conditions
required for the cleavage of this ester at the final stage
having resulted in the destruction of target molecules,
this protecting group was not suited to the task.
Figure 3. Ancillary aromatic subunits.
MeOH, 96%; 7b fi 7c: (PhO)2P(O)N3, TMS–CH2–
CH2OH, Et3N, 80 ꢁC, toluene, 89%;12 7c fi 7d: 1 N
n-Bu4NF in THF, 50 ꢁC, CH3CN, 80%). Benzylamines
8a–e (as their tosylate salts) were prepared according to
known procedures.13 Amine 10d was synthesized from
the known ester 914 (9 fi 10a: LAH, 88%; 10a fi 10b:
MsCl, cat. DMAP, 86%; 10b fi 10c: NaN3, DMF,
quantitative; 10c fi 10d: PPh3, THF–H2O, 54%). Amine
10e was prepared in a similar fashion from ester 7a
(Fig. 3).
Alternatively, the 2,2,2-trichloroethyl ester 2c was pre-
pared by condensing 2a with 2,2,2-trichloroethanol at
100 ꢁC in the presence of PPA (60% yield). However, the
target molecules were found to be again deteriorated
under the conditions required for the cleavage of this
ester function (Zn, AcOH6 or Se, NaBH4).7
The group that was ultimately adopted for protecting
the carboxylic acid of 2a was the tert-butyl ester. For
that purpose, the hydroxyl of 2c was first protected as
the pivaloyl derivative 2d (t-BuCOCl, pyridine, 85%
yield), which was next transesterified into 2e (t-BuONa,
20 ꢁC, THF, 60% yield). Benzylic oxidation of 2c (SeO2,
refluxing pyridine)8 afforded with a 80% yield the acid
3a, which was condensed with N-hydroxysuccinimide in
the presence of DCC to give 3b (80% yield). Conden-
sation of NaN3 with 3b (DMF) led quantitatively to
azide 3c, which was converted into carbamate 4a
(BnOH, refluxing toluene, 57% yield). Finally, hydro-
genolysis of 4a (4 bar of H2, Pd/C, EtOH) gave quanti-
tatively the primary amine 4b (Fig. 2).
4. Synthesis and biological activity of the target
molecules
The synthesis of the target molecules was realized by
coupling first the quinoline subunits with the ancillary
aromatic moieties under the operating conditions
reported below. Subsequent removal of the protecting
groups was performed in all cases by treating the
resulting adducts with TFA at 20 ꢁC in CH2Cl2 in the
presence of guaiacol.15 Amides 11 and 12 were prepared
in 75% yield by condensing 3b with 5b and 7d, respec-
tively, at 20 ꢁC in dry pyridine. Amide 13 was prepared
from 4b (PhCOCl, pyridine, cat. DMAP, 70%). Amides
14–19 were synthesized from 3b and the corresponding
benzylamines 8a–e and 10e (pyridine, 20 ꢁC, 60–90%).
Hydrazides 20 and 21 were obtained by condensing 3b
with phenylhydrazine and 2,4-dinitrophenylhydrazine,
respectively (pyridine, 20 ꢁC, 75–95%). Ureas 22–24
were prepared by heating azide 3c in refluxing toluene
until complete nitrogen evolution (2–5 min), followed by
all at once addition of the requisite amines: 5b,
p-methoxybenzylamine and 10d, respectively (25–40%).
Ketoenol 25 was synthesized by condensing the lithium
3. Preparation of the ancillary aromatic subunits
Aniline 5b was synthesized from the known nitro com-
pound 5a9 (3 bar of H2, Raney Ni, EtOH, 85%). Aniline
7d was prepared from the known ester 610 (6 fi 7a:
Ph2CCl2, neat, 170 ꢁC, 94%;11 7a fi 7b: 3 N NaOH,

C. Bꢀenard et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2473–2476
2475
Table 1. Structure–activity relationships for linker-modified quinoline
derivatives16
In vitro IC50 was determined as the drug concentration
that inhibits 50% of the recombinant integrase activity
in a standard 30-processing assay.4a Ex vivo IC50 was
determined as the drug concentration that inhibits 50%
of viral particles production in de novo infection assay
of CEM cells. TC50 was the drug concentration that
corresponds to 50% of cells survival as determined by a
standard MTT assay.4b Results are illustrated in Table
1. Remarkably, all these compounds exhibit no signifi-
cant cytotoxicity; in contrast, the styrylquinoline 28 in
which the ancillary phenyl ring is unsubstituted and
compound 26, equivalent to 1, in which the ethylenic
linker has been hydrogenated, proved to be notably
cytotoxic (Table 2).4a;b Among amides 11–19, compound
13, in which the nitrogen atom is attached to the quin-
oline subunit, and amide 17 in which the ancillary
phenyl nucleus possesses two hydroxyls at C-30 and C-50
display no in vitro activity. In contrast the correspond-
ing styryquinolines 28 and 29 show a significant in vitro
activity (Table 2). Other amides where the phenyl half is
substituted by at least a hydroxyl group at C-40 show
good activities in both in vitro and ex vivo assays. It is
worthy of note that a nearly micromolar antiviral
activity was observed with amides 12, 16 and 18, com-
parable to that of reference styryquinolines 1 and 27
(Table 2). Hydrazides 20, 21 and ureas 22–24 are devoid
of biological activity, with the exception of the 2,4-di-
nitrophenylhydrazide 21, for which a substantial anti-
integrase activity was restored. Since the ketoenol linker
has been recognized as a potential pharmacophore in
the design of HIV-IN inhibitors,3 we have also evaluated
the activity of 25. However, no antiviral activity was
observed with this compound, possibly because of the
absence of hydroxyl groups on the ancillary phenyl ring.
In conclusion, among the various linker-modified
Compounda
Biological activity
b
c
d
IC50
IC50
TC50
H
N
Quin
Quin
OH
11
0.9
6.5
30
>100
O
O
OH
OH
H
N
12
13
2
100
OH
OMe
O
Quin
Quin
>100
>100
>100
N
H
H
N
14
15
5
5
40
10
>100
>100
OH
OH
O
OH
OH
OH
H
N
Quin
Quin
O
O
OH
OH
H
N
16
17
5
2
>100
>100
H
N
>100
>100
Quin
Quin
OH
OH
O
O
H
N
18
1.5
4
>100
OH
OH
OH
OH
H
N
19
20
6.5
25
45
100
Quin
Quin
OMe
O
O
H
N
>100
>100
N
H
Table 2. Biological activity for reference styrylquinoline derivatives4a;b
NO2
H
N
Quin
Compounda
21
22
23
24
3
>100
>100
>100
30
>100
>100
>100
55
>100
70
Biological activity
N
H
O
b
c
d
NO2
IC50
2.4
IC50
TC50
Quin
Quin
OH
OH
OH
O
O
1
1
>100
61
Quin
Quin
OH
OH
N
N
H
H
26
2.3
NR
OH
OH
OH
>100
>100
>100
N
H
N
H
OMe
Quin
O
27
28
0.7
5.3
3.2
12
>100
31
Quin
Quin
OH
OH
N
H
N
H
OMe
Quin
Quin
NRe
25
>100
OH O
OH
a Quin ¼
29
>100
>100
.
HO2C
N
OH
OH
b In vitro activity on the 30-end-processing assay (lM).
a Quin ¼
c Ex vivo (lM).
.
HO2C
N
OH
d Toxicity.
b In vitroactivity on the 30-end-processing assay (lM).
c Ex vivo (lM).
d Toxicity.
e NR: not reached.
enolate of benzophenone (preformed by means of LDA
in THF at )78 ꢁC) with 3b (THF, )78 ꢁC, 70%).

2476
C. Bꢀenard et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2473–2476
12. Shioiri, T.; Ninomiya, K.; Yamada, S.-I. J. Am. Chem.
Soc. 1972, 94, 6203–6205.
quinoline derivatives synthesized within this paper,
amides are the most promising ones and could serve as
leads for further developments.
13. Gannett, P. M.; Nagel, D. L.; Reilly, P. J.; Lawson, T.;
Sharpe, J.; Toth, B. J. Org. Chem. 1988, 53, 1064–1071.
14. Kita, Y.; Arisawa, M.; Gyoten, M.; Nakajima, M.;
Hamada, R.; Tohma, H.; Takada, T. J. Org. Chem.
1998, 63, 6625–6633.
Acknowledgement
15. Guaiacol was used as tert-butyl cation scavenger to
prevent the formation of by-products issuing from the
recapture of this cation. In this respect, see: Yajima, H.;
Takeyama, M.; Kanaki, J.; Nishimura, O.; Fujino, M.
Chem. Pharm. Bull. 1978, 26, 3752–3757.
We gratefully acknowledge the financial support of
BioAlliance Pharma as a grant to C.B.
16. Data for 11: yellow solid, mp >350 ꢁC (dec); IR (neat,
cmꢀ1) m 3600–2500, 1645, 1601; 1H NMR (200 MHz,
DMSO-d6) d 10.34 (br s, 1H), 8.38 (d, J ¼ 8:6 Hz, 1H),
8.30 (br s, 1H), 8.17 (d, J ¼ 8:6 Hz, 1H), 7.95 (d,
J ¼ 8:3 Hz, 1H), 7.44 (d, J ¼ 1:5 Hz, 1H), 7.03 (m, 2H),
6.77 (d, J ¼ 8:3 Hz, 1H); 13C NMR (50 MHz, DMSO-d6) d
171.1 (C), 165.3 (C), 162.3 (C), 147.1 (C), 145.2 (C), 142.2
(C), 140.2 (C), 137.6 (CH), 132.5 (C), 130.4 (C), 129.6
(CH), 119.7 (CH), 115.4 (CH), 114.4 (C), 111.0 (2CH),
109.0 (CH). Data for 13: beige solid, mp 224–226 ꢁC; IR
(neat, cmꢀ1) m 3400–2900, 1676, 1616, 1572; 1H NMR
(200 MHz, DMSO-d6) d 11.32 (br s, 1H), 8.42 (d,
J ¼ 9:1 Hz, 1H), 8.37 (d, J ¼ 9:1 Hz, 1H), 8.09 (d,
J ¼ 8:1 Hz, 2H), 7.79 (d, J ¼ 8:6 Hz, 1H), 7.57 (m, 3H),
7.38 (d, J ¼ 8:6 Hz, 1H); 13C NMR (50 MHz, DMSO-d6) d
172.2 (C), 166.9 (C), 158.5 (C), 150.9 (C), 138.8 (CH),
136.2 (C), 133.5 (C), 132.2 (CH), 129.5 (C), 128.2 (4CH),
124.7 (CH), 118.0 (CH), 116.7 (CH), 110.5 (C). Data for
16: brown solid, mp 231–233 ꢁC; IR (neat, cmꢀ1) m 3600–
References and notes
1. Zhang, L.; Ramratnam, B.; Tenner-Racz, K.; He, Y.;
Vesanen, M.; Lewin, S.; Talal, A.; Racz, P.; Perelson, A.;
Korber, B.; Markowitz, M.; Ho, D. N. Engl. J. Med. 1999,
340, 1605–1613.
2. Furtado, M.; Callaway, D.; Phair, J.; Kunstman, K.;
Stanton, J.; Macken, C.; Perelson, A.; Wolinsky, S. N.
Engl. J. Med. 1999, 340, 1614–1622.
3. De Clercq, E. Med. Res. Rev. 2002, 22, 531–565.
€
4. (a) Mekouar, K.; Mouscadet, J.-F.; Desmaele, D.; Subra,
F.; Leh, H.; Savoure, D.; Auclair, C.; d’Angelo, J. J. Med.
ꢀ
Chem. 1998, 41, 2846–2857; (b) Zouhiri, F.; Mouscadet,
€
ꢀ
J.-F.; Mekouar, K.; Desmaele, D.; Savoure, D.; Leh, H.;
Subra, F.; Le Bret, M.; Auclair, C.; d’Angelo, J. J. Med.
Chem. 2000, 43, 1533–1540; (c) Ouali, M.; Laboulais, C.;
1
2500, 1675, 1626; H NMR (400 MHz, DMSO-d6) d 9.73
€
Leh, H.; Gill, D.; Desmaele, D.; Mekouar, K.; Zouhiri, F.;
(t, J ¼ 5:9 Hz, 1H), 8.86 (br s, 1H), 8.73 (br s, 1H), 8.54 (d,
J ¼ 8:5 Hz, 1H), 8.28 (d, J ¼ 8:5 Hz, 1H), 7.92 (d,
J ¼ 8:7 Hz, 1H), 7.48 (d, J ¼ 8:7 Hz, 1H), 6.79 (d,
J ¼ 1:3 Hz, 1H), 6.71 (d, J ¼ 8:1 Hz, 1H), 6.64 (dd,
J ¼ 8:1, 1.3 Hz, 1H), 4.46 (d, J ¼ 5:9 Hz, 2H); 13C NMR
(50 MHz, DMSO-d6) d 168.5 (C), 163.3 (C), 156.4 (C),
148.5 (C), 145.2 (C), 144.3 (C), 137.8 (CH), 137.2 (C),
131.6 (C), 130.1 (C), 128.9 (CH), 120.9 (CH), 118.4 (CH),
116.8 (CH), 115.4 (CH), 114.9 (CH), 112.9 (C), 42.0
(CH2). Data for 20: brown solid, mp 160–162 ꢁC; IR (neat,
cmꢀ1) m 3600–2900, 1666, 1602, 1559; 1H NMR (200 MHz,
DMSO-d6) d 11.25 (br s, 1H), 8.57 (d, J ¼ 8:5 Hz, 1H),
8.23 (d, J ¼ 8:5 Hz, 1H), 7.95 (d, J ¼ 8:7 Hz, 1H), 7.51 (d,
J ¼ 8:7 Hz, 1H), 7.18 (t, J ¼ 7:7 Hz, 2H), 6.84 (d,
J ¼ 7:7 Hz, 2H), 6.75 (t, J ¼ 7:7 Hz, 1H); 13C NMR
(50 MHz, DMSO-d6) d 167.6 (C), 163.1 (C), 155.5 (C),
149.1 (C), 147.6 (C), 137.8 (CH), 137.1 (C), 131.4 (C),
129.3 (CH), 128.7 (2CH), 120.6 (CH), 118.7 (CH), 116.7
(CH), 113.5 (C), 112.3 (2CH). Data for 24: yellow solid,
mp 241–243 ꢁC (dec); IR (neat, cmꢀ1) m 3600–2500, 1697,
d’Angelo, J.; Auclair, C.; Mouscadet, J.-F.; Le Bret, M. J.
Med. Chem. 2000, 43, 1949–1957; (d) Ouali, M.; Labou-
lais, C.; Leh, H.; Gill, D.; Xhuvani, E.; Zouhiri, F.;
€
Desmaele, D.; d’Angelo, J.; Auclair, C.; Mouscadet, J.-F.;
Le Bret, M. Acta Biochim. Pol. 2000, 47, 11–22; (e)
€
d’Angelo, J.; Mouscadet, J.-F.; Desmaele, D.; Zouhiri, F.;
Leh, H. Pathol. Biol. 2001, 49, 237–246; (f) Burdujan, R.;
€
d’Angelo, J.; Desmaele, D.; Zouhiri, F.; Tauc, P.;
Brochon, J.-C.; Auclair, C.; Mouscadet, J.-F.; Pernot,
P.; Tfibel, F.; Enescu, M.; Fontaine-Aupart, M.-P. Phys.
Chem. Chem. Phys. 2001, 3, 3797–3804; (g) Zouhiri, F.;
€
Desmaele, D.; d’Angelo, J.; Ourevitch, M.; Mouscadet,
J.-F.; Leh, H.; Le Bret, M. Tetrahedron Lett. 2001, 42,
8189–8192; (h) Polanski, J.; Zouhiri, F.; Jeanson, L.;
€
Desmaele, D.; d’Angelo, J.; Mouscadet, J.-F.; Gieleciak,
R.; Gasteiger, J.; Le Bret, M. J. Med. Chem. 2002, 45,
4647–4654; For related styrylheterocycles, see: (i) Lee, J.
Y.; Park, J. H.; Lee, S. J.; Park, H.; Lee, Y. S. Arch.
Pharm. Pharm. Med. Chem. 2002, 335, 277–282; (j) Yoo,
H.; Lee, J. Y.; Park, J. H.; Chung, B. Y.; Lee, Y. S. Il
Farmaco 2003, 58, 1243–1250.
1
1633, 1583; H NMR (200 MHz, DMSO-d6) d 9.96 (br s,
1H), 9.82 (br s, 1H), 8.78 (m, 2H), 8.22 (d, J ¼ 8:8 Hz,
1H), 7.68 (d, J ¼ 8:6 Hz, 1H), 7.41 (d, J ¼ 8:8 Hz, 1H),
7.27 (d, J ¼ 8:6 Hz, 1H), 6.79 (s, 1H), 6.67 (m, 2H), 4.31
(d, J ¼ 5:4 Hz, 2H). Data for 25: yellow solid, mp 194–
196 ꢁC; IR (neat, cmꢀ1) m 3600–2500, 1678, 1598; 1H NMR
(200 MHz, DMSO-d6) d 8.51 (d, J ¼ 8:6 Hz, 1H), 8.29 (d,
J ¼ 8:6 Hz, 1H), 8.10 (m, J ¼ 7:4 Hz, 2H), 7.94
(d, J ¼ 8:6 Hz, 1H), 7.84 (s, 1H), 7.60 (m, 3H), 7.42 (d,
J ¼ 8:6 Hz, 1H); 13C NMR (50 MHz, DMSO-d6) d 184.2
(C), 170.6 (C), 165.2 (C), 161.0 (C), 150.1 (C), 138.6 (C),
137.7 (CH), 134.2 (C), 133.2 (CH), 132.6 (C), 129.0 (2CH),
128.7 (CH), 128.6 (CH), 127.2 (2CH), 120.5 (CH), 111.8
(C), 93.9 (CH).
5. Bader, A. R.; Kontowicz, A. D. J. Am. Chem. Soc. 1953,
75, 5416–5417.
6. Woodward, R. B.; Heusler, K.; Gosteli, J.; Naegeli, P.;
€
Oppolzer, W.; Ramage, R.; Ranganathan, S.; Vorbruggen,
H. J. Am. Chem. Soc. 1966, 88, 852.
7. Huang, Z. Z.; Zhou, X. J. Synthesis 1989, 693–694.
8. Sakasai, T.; Sakamoto, T.; Yamanaka, H. Heterocycles
1979, 13, 235–238.
9. Houwing, H. A.; Van Oene, J. C.; Horn, A. S. Pharm.
Weekblad Sci. Ed. 1983, 5, 177–181.
10. Jurd, L. J. Am. Chem. Soc. 1959, 81, 4606–4610.
€
11. Bengtsson, S.; Hogtberg, T. J. Org. Chem. 1989, 54, 4549–
4553.