Synthesis of a peptidomimetic tricyclic tetrahydrobenzo[ij]quinoline as a VLA-4 antagonist

Full text of DOI:10.1021/jo991162k

J . Org. Chem. 2000, 65, 6743-6748
6743
Sch em e 1
Syn th esis of a P ep tid om im etic Tr icyclic
Tetr a h yd r oben zo[ij]qu in olin e a s a VLA-4
An ta gon ist
Wen-Bin Ho*,† and Chris Broka*
Roche Bioscience, Palo Alto, California 94304
who@fibrogen.com
Received J uly 21, 1999
Development of inhibitors that block leukocyte recruit-
ment by interfering with cell-cell and cell-matrix
interactions has been the focus of considerable attention.
Multiple molecular targets have been characterized in
the process of leukocyte adhesion to endothelial cells and
extracellular matrix proteins.1 Integrin R4â1, very late
antigen (VLA-4), expressed in stimulated monocytes and
lymphocytes binds to cytokine-activated endothelial cells
through recognition of vascular cell adhesion molecule-1
(VCAM-1) as well as to the extracellular matrix protein
fibronectin (FN) within the alternatively spliced CS-1
region. This adhesion process has been implicated in the
pathogenesis of a variety of diseases. A monoclonal
antibody against R4â1 has demonstrated efficacy in a
number in vitro and in vivo studies.2 In addition, several
peptide-based VLA-4 antagonists have been reported,3,4
and some have been evaluated in clinical trials for the
treatment of asthma and multiple sclerosis.
Lobl and Cardarelli have reported a cyclic pentapep-
tide, RC*D(ThioP)C* (the asterisks denote residues
bridged by a disulfide bond) to be a potent inhibitor of
R4â1-mediated cell adhesion to CS-1 site and VCAM2
with IC50 ranging from 2 to 9 µM in cell adhesion assays.
This rigid peptide, which does not inhibit cell adhesion
to other extracellular matrix proteins including laminin
and vitronectin or trigger platelet aggregation, represents
a starting point for the design of nonpeptidic inhibitors.
Recently, a similar series of cyclic peptides based on
XC*DPC* have been reported to be low nanomolar cell
adhesion inhibitors.5 Also a series of â-turn mimics based
on the CS-1 fragment LDV sequence have been synthe-
sized by combinatorial methods and showed low micro-
molar inhibition.6
Molecular modeling together with NMR analysis of
C*DPC* led us to identify a tricyclic framework, 2,3,6,7-
tetrahydro-1H,5H-benzo[ij]quinoline (1),7 that mimics the
cyclic pentapeptide backbone. This iso-julolidine template
can be found as a part of the aporphine alkaloid struc-
ture.8 The two crucial carboxylic acid moieties presented
by the aspartate and C-terminal cystein of XC*DPC*
would be mimicked by carboxylates at the 3 and 9
positions of 1. The amino group corresponding to the
N-terminus needs to be placed at the 7 position of 1 in a
stereospecific fashion. Here we report the synthesis of
the novel molecule 2 via a nonclassical Friedel-Crafts
cyclization/1,2-sigmatropic rearrangement tandem reac-
tion (Scheme 1).
The synthesis started with coupling of 3-methoxyphen-
ethylamine (3) and 4-pentenoyl chloride (4). The resulting
amide 5 was cyclized via a Bischler-Napieraski reaction
to give the dihydroisoquinoline which, without purifica-
tion, was reduced with sodium cyanoborohydride to
tetrahydroisoquinoline 6 in 87% yield over three steps
(Scheme 2). The olefin functional group tethered at the
C1 position of 6 will be manipulated for effective closure
of the C-ring.
† Current address: FibroGen, Inc., 225 Gateway Boulevard, So. San
Francisco, CA 94080.
(1) Leukocyte Recruitment in Inflammatory Disease; Peltz, G., Ed.;
Chapman & Hall: New York, 1996.
Taylor et al. have demonstrated an effective six-
membered ring Friedel-Crafts cyclization of an epoxide
for the formation of tetrahydronaphthalene.9 To follow
this protocol, the nitrogen of tetrahydroisoquinoline 6 was
protected as a benzyloxycarbanoyl (Cbz) and the resulting
(2) (a) Laberge, S.; Rabb, H.; Issekutz, T. B.; Martin, J . G. Am. J .
Respir. Crit Care Med. 1995, 151, 822. (b) Barbadillo, C.; G-Arroyo,
A.; Salas, C.; Mulero, J .; Sanchez-Madrid, F.; Andreu, J . L. Springer
Semin. Immunopathol. 1995, 16, 375. (c) Podalski, D. K. N. Engl. J .
Med. 1991, 325, 928.
(3) Lin, K.-C.; Zimmerman, A. C.; Lee, W.-C.; Hammond, C. E.;
Ateeq, H. S.; Hsiung, S. H.; Chong, L. T.; Liao, Y.; Almquist, R. G.;
Kalkunte, S.; Adam, S. P. 213th ACS Natioal Meeting, Medicinal
Chemistry Division # 315, San Francisco, 1997.
(7) Numbering system of 1 is based on its close analogue, julolidine,
(4) Nowlin, D. M.; Gorcsan, F.; Moscinski, M.; Chiang, S.-L.; Lobl,
T. J .; Cardarelli, P. M. J . Biol. Chem. 1993, 268, 20352.
(5) J ackson, D. Y.; Quan, C.; Artis, D. R.; Rawson, T.; Blackburn,
B.; Struble, M.; Fitzgerald, G.; Chan, K.; Mullins, S.; Burnier, J . P.;
Fairbrother, W. J .; Clark, K.; Berisini, M.; Chui, H.; Renz, M.; J ones,
S.; Fong, S. J . Med. Chem. 1997, 40, 3359.
(6) Souers, A. J .; Virgilio, A. A.; Schurer, S. S.; Ellman, J . A.; Kogan,
T. P.; West, H. E.; Ankener, W.; Vanderslice, P. Bioorg. Med. Chem.
Lett. 1998, 8, 2297.
2,3,6,7-tetrahydro-1H,5H-benzo[ij]quinolizine. For a review of the
chemistry of julolidine, see: The Total Synthesis of Natural Products;
ApSimon, J ., Ed.; J ohn Wiley and Sons: New Yorks, 1977; Vol. 3, pp
494-515.
(8) For aporphine review, see: The Total Synthesis of Natural
Products; ApSimon, J ., Ed.; J ohn Wiley and Sons: New York, 1977;
Vol. 3, pp 1-272.
(9) Taylor, S. K.; Hockerman, G. H.; Karrick, G. L.; Lyle, S. B.;
Schramm, S. B. J . Org. Chem. 1983, 48, 2449.
10.1021/jo991162k CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/13/2000

6744 J . Org. Chem., Vol. 65, No. 20, 2000
Notes
Sch em e 2
Sch em e 3
7a was oxidized by m-CPBA to give epoxide 8 as a
mixture of two diastereomers. Taylor’s condition (SnCl4,
1 equiv, -20 °C) was employed to effect the cyclization
of the C-ring. This reaction, however, led to several
products with the predominant one being the pyranose
11 (Scheme 2).10 A possible mechanism for its formation
involves electrophilic cyclization to the intermediate 9,
which then rearranges to iminium salt 10. Cyclization
via a nucleophilic attack of the hydroxyl group accounts
for the formation of 11.This process is not unprecedented;
a similar observation has been reported by Harcourt et
al.11
We reasoned that a more strongly electron-withdraw-
ing group on nitrogen should disfavor formation of the
iminium salt 10. Thus, the amino group of 6 was
protected as its triflate (7b) and, upon oxidation, the
resulting epoxide 12 was subjected to stannic chloride-
mediated (SnCl4, -78 °C) cyclization. As anticipated, the
desired tricyclic product 13 was obtained in around 10%
yield along with starting material (50% recovery). To
optimize the reaction, a study varying reaction conditions
was carried out. Among Lewis-acid catalysts studied
stannic chloride promoted the cyclization with the best
yield, proving superior to TiCl4 and BF3‚Et2O. Compa-
rable yields were obtained whether one or two equiva-
lents of stannic chloride were used, and the optimum
reaction temperature was -20 to 0 °C. Lower tempera-
tures resulted in lower product yield and more recovered
starting material. Thus, under optimized condition (1
equiv of SnCl4, -20 to 0 °C in CH2Cl2) epoxide 12 was
cyclized to give the tricyclic ring of 13 in 75% yield as a
mixture of two diastereomers.12 Having the core template
constructed, remaining tasks involved the functional
group transformations of hydroxymethyl to amino at
position 7 and methoxy to carboxylic acid at position 9,
the incorporation of the acetate group at 3 position, and
separation of the diastereomers.
Scheme 3 illustrates these subsequent functional group
transformations. Alcohol 13 was converted to ketone 14
via a three-step reaction sequence, where the hydroxyl
was first converted to the seleno ether according to the
Grieco’s procedure,13 followed by m-CPBA mediated
(10) The proton NMR spectrum of 11 (available in the Supporting
Information section) indicated the disappearance of the benzylic proton,
and its mass spectrum (m/e+ ) 367) was consistent with the molecular
formula.
(11) Harcourt, D. N.; Hussain, F.; Taylor, N. J . Chem. Soc., Perkin
Trans. 1 1986, 1329.
(12) Attempted cyclization of olefin 7b using phenylselenenyl chlo-
ride or NBS were unsuccessful, resulting in starting material.
(13) Grieco, P. A.; Nishizawa, M.; Oguri, T.; Burke, S. D.; Marinovic,
N. J . Am. Chem. Soc. 1977, 99, 5773.

Notes
J . Org. Chem., Vol. 65, No. 20, 2000 6745
Sch em e 4
Sch em e 5
jected to palladium-mediated carboxylation17 to anchor
the second carboxy group at the C9 position.
Ketone 20 was then reduced to 21.18 Proton NMR
showed a diastereomeric ratio of 4.5:1 in favor of the
equatorial alcohol. This assignment was confirmed by the
13C NMR spectrum in which two distinct peaks at 69.4
and 66.7 ppm, corresponding to carbons bearing equato-
rial alcohol and axial alcohol,19 respectively, were ob-
served in an intensity ratio of ca. 5:1. The diastereomeric
mixtures of 21, upon treatment with diphenylphosphoryl
azide,20 was converted to azides 22 and 23 as two readily
separable diastereomers with 50% and 15% yield, re-
spectively, after chromatography. Modeling reveals that
C-ring of 22 and 23 possesses a half-chair conformation
with pseudoaxial and pseudoequatorial substituents at
oxidative deselenation. The resulting olefin was further
oxidized by OsO4 and NaIO4 to give tetralone 14. We
were unable to demethylate 14 using boron tribromide,
trimethylsilyl iodide,14 potassium iodide,15 and PhSNa;16
mostly, decomposition was observed. The carbonyl group
of 14 was, therefore, reduced to benzylic hydroxyl group
and subjected to boron tribromide treatment. It was
found that desired phenol 15 was obtained in a good
yield in the presence of the benzyl alcohol functional
group.
To remove the triflate protecting group, 15 was then
treated with LiAlH4 under the refluxing toluene condi-
tions and, surprisingly, only resulted in ring opening of
tetrahydroisoquinoline, yielding 17 quantitatively where
the triflate remained intact. The reaction may take place
via methaquinone intermediate 16 since trifluoromethane-
sulfonamide is a good leaving group and the presence of
a p-hydroxy group would allow the formation of 16.
Accordingly, phenol of 15 was protected as its benzyl
ether, and the resulting 18 was reduced under the same
conditions (LiAlH4, refluxing toluene condition) to suc-
cessfully unmask the secondary amine in an excellent
yield. The amine intermediate was then coupled with
methyl bromoacetate to provide 19.
1
the C7 position. The H NMR spectrum of 22 shows that
the benzylic proton at the C7 position is a triplet having
a coupling constant of 4.2 Hz, whereas the corresponding
proton of 23 is doublet of doublet (dd) having coupling
constants of 8.2 and 5.9 Hz. This observation confirms
that the azide group of 22 is in the pseudoaxial position.
Having azide 22 with the desired stereochemistry in
hand, it was reduced to amine 24 via hydrogenation to
yield the desired tricyclic template with desired func-
tional groups and correct stereochemistry. Amine 24 was
not purified. Instead, it was characterized as 25 and 26
after coupling with 1-adamantane acetic acid and 1-fluo-
renecarboxylic acid, respectively. Subsequent base hy-
drolysis afforded the final products 27 and 28 (Scheme
5).
In summary, the use of a Bischler-Napieraski reaction
and Friedel-Crafts cyclization via an epoxide allows the
construction of a novel tricyclic ring system 25 intended
to mimic the cyclic pentapeptide backbone of XC*DPC*.
The diacids 27 and 28 were only weakly active in our
jurkat cell adhesion assay (IC50 ) 0.5 mM). This activity
The next task was the introduction of the carboxy
group into the aromatic ring. As shown in Scheme 4, 19
was converted to 20 through a sequence of reactions, in
which the benzylic alcohol was oxidized to the ketone,
benzyl ether was deprotected, and the resulting phenol
was converted to the triflate. This compound was sub-
(17) Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron
Lett. 1986, 27, 3931.
(18) This reaction was accompanied with 22% yield of the over-
reduced product due to the reduction of acetate functional group.
(19) Gunther, H. NMR Spectroscopy, 2nd ed.; J ohn Wiley & Sons:
England, 1995; p 501.
(14) J ung, M. E.; Lyster, M. A., J . Org. Chem. 1977, 42, 3761.
(15) Harrison, I. T., J . Chem. Soc., Chem. Commun. 1969, 616.
(16) Feutrill, G. I.; Mirrington, R. N., Tetrahedron Lett. 1970, 1327.
(20) Thompson, A. S.; Humphrey, G. R.; DeMarco, A. M.; Mathre,
D. J .; Grabowski, E. J . J . J . Org. Chem. 1993, 58, 5886.

6746 J . Org. Chem., Vol. 65, No. 20, 2000
Notes
(3/1 hexanes-EtOAc) to give a syrupy product 7b (30.3 g, 0.09
mol) in 76% yield: 1H NMR (MHz, CDCl3) δ 6.97-6.66 (m, 3
H), 5.83 (m, 1 H), 5.11-5.05 (m, 2 H), 4.85 (d, J ) 8.8, 5.5 Hz,
1 H), 4.02 (m, 1 H), 3.78 (s, 3 H), 3.61 (m, 1 H), 3.08 (m, 1 H),
2.80 (m, 1 H), 2.22 (m, 2 H), 2.01-1.78 (m, 2 H); 13C NMR
(CDCl3) δ 158.7, 137.1, 133.0, 127.9, 122.0, 117.7, 115.5, 113.8,
112.9, 57.5, 55.3, 40.0, 36.6, 30.3, 27.6; IR 2941, 1614, 1504, 1466,
1327, 1277, 1248 cm-1; MS 349 (M+), 294, 161.
did, however, seem to be due to VLA-4 antagonism rather
than to nonspecific toxicity since the compounds were
inactive in cell adhesion assays that did not involve this
ligand.
Exp er im en ta l Section
Gen er a l Meth od s. All the reactions were carried out under
a nitrogen atmosphere. All solvents and reagents were obtained
from commercial sources and were used without further puri-
fication except where noted. Flash chromatography purification
was performed on silica gel 60 (230-400 mesh). 1H NMR and
13C NMR spectra were recorded at 300 and 75 MHz, respectively,
and the chemical shifts were expressed in parts per million
downfield from tetramethylsilane. Melting points are uncor-
rected. Infrared (IR) was recorded on a FT-IR spectrometer using
KBr disks or as neat liquids.
N-(4-P en ten oyl) 3-Meth oxyp h en eth ylca r boxa m id e (5).
A solution of oxalyl chloride (2 M in CH2Cl2) (150 mL, 0.3 mol)
was added slowly to pentenoic acid (30.0 g, 0.3 mol) at 0 °C.
The solution was stirred at 0 °C for 1 h and then at room
temperature until gas evolution ceased. The mixture was
concentrated at <10 °C at reduced pressure. The volatile acid
chloride, after being taken up in CH2Cl2 (400 mL), was added
slowly to a solution of 3-(methoxy)phenylethylamine (3) (45.4
g, 0.3 mol) and triethylamine (45.5 g, 0.45 mol) in CH2Cl2 (600
mL) at 0 °C. After being stirred overnight (18 h) at 0 °C to room
temperature, the mixture was concentrated and partitioned
between EtOAc and 1 N HCl solution. The aqueous layer was
extracted with EtOAc. The combined organic layers were washed
with brine and dried over MgSO4. Solvent was evaporated to
give vinyl amide 5 (63.0 g, 0.27 mol) as a brown oil in 90% yield.
This product was used for the next reaction without purification.
An analytical sample was obtained by vacuum distillation (200
°C, 0.5 Torr): 1H NMR (CDCl3) δ 7.26 (m, 4 H, Ph), 6.78 (m, 2
H), 5.77 (m, 1H), 5.52 (br s, 1 H), 5.05 (m, 2 H), 3.80 (s, 3 H),
3.52 (dd, J ) 12.9, 6.8 Hz, 2 H), 2.78 (t, J ) 6.8 Hz, 2 H), 2.37
(m, 2 H), 2.22 (m, 2 H); IR 3385-3236, 2957, 1678, 1633, 1539
cm-1; MS 233 (M+), 134. Anal. Calcd for C14H19NO2: C, 72.07;
H, 8.21; N, 6.00. Found: C, 71.67; H, 8.31; N, 6.12.
1-(3-Bu t e n yl)-6-m e t h oxy-1,2,3,4-t e t r a h yd r oisoq u in o-
lin e (6). To a solution of vinyl amide 5 (35.0 g, 0.15 mol) in
anhydrous CH3CN (800 mL) was added freshly distilled POCl3
(100 mL, 1.06 mol) in N2 atmosphere at room temperature. The
mixture was refluxed for 1.5 h. After being cooled to room
temperature, it was carefully poured into aqueous K2CO3 at 0
°C (pH 9-10). The product was extracted into EtOAc. The
organic layer was dried over K2CO3. Solvent was removed to give
the imine intermediate (32.8 g). This intermediate, after being
taken up with glacial acetic acid (700 mL), was treated with
NaBCNH3 (8.95 g, 0.14 mol) in portions at 0 °C. The mixture
was stirred at room temperature for 2 h and quenched with H2O
(500 mL). Most of the solvent was removed on a rotovapor at
ca. 50 °C. The residue was basified at 0 °C with 5 N NaOH
solution to pH ) 10. The product was extracted into EtOAc. The
combined organic layers were washed with brine, dried over K2-
CO3, filtered, and concentrated to give a crude residue. It was
triturated in EtOAc (100 mL) at 0 °C. Undissolved solid was
filtered off, and the filtrate was concentrated to get the tetrahy-
dro-isoquinoline 6 (31.6 g, 0.145 mol) in 97% yield as a brown
syrup. This product was used for the next reaction without
purification: 1H NMR (300 MHz, CDCl3) δ 7.267.04 (d, J ) 8.5
Hz, 1 H), 6.72 (dd, J ) 8.5, 2.8 Hz, 1 H), 6.61 (d, J ) 2.7 Hz, 1
H), 5.87 (m, 1 H), 5.1-4.85 (m, 2 H), 3.93 (dd, J ) 9.0, 3.5 Hz),
3.78 (s, 3 H), 3.21 (m, 1 H), 2.97 (m, 1 H), 2.88-2.67 (m, 2 H),
2.21 (m, 2 H), 1.96-1.72 (m, 2 H).
1-(3,4-E p oxyb u t yl)-2-(N-t r iflu or om et h a n esu lfon yl)-6-
m eth oxy-1,2,3,4-tetr a h yd r oisoqu in olin e (12). m-CPBA (57-
86%) (30.0 g) was added portionwise to a solution of olefin 7b
(30.0 g, 86.0 mmol) in CH2Cl2 (500 mL) at room temperature.
The mixture was stirred for 18 h. Solid was filtered off, and the
filtrate was concentrated. The residue was partitioned between
EtOAc and 7% K2CO3 aqueous solution. The organic layer was
washed with brine, dried over MgSO4, filtered, and concentrated
to give a crude residue. This was purified by flash chromatog-
raphy over silica gel (3/1 hexanes-EtOAc) to afford the epoxide
12 (25.2 g, 69.0 mmol) in 80% yield. (This product is a 1:1
diastereomeric mixture judged by the proton NMR spectrum):
1
mp 70.2-74.1 °C; H NMR (300 MHz, CDCl3) δ 7.00 (m, 1 H),
6.78-6.66 (m, 2 H), 4.87 (m, 1 H), 4.02 (m, 1 H), 3.79 (s, 3 H),
3.61 (m, 1 H), 3.14-2.74 (m, 4 H), 2.53 (m, 1 H), 2.0-1.4 (m, 4
H); 13C NMR (CDCl3) δ 158.8, 135.9, 132.9, 127.9, 127.8, 127.6,
121.3, 117.9, 113.8, 113.0, 57.8, 57.4, 55.3, 51.7, 51.4, 47.0, 46.9,
39.9, 33.6, 29.3, 29.0, 27.5; IR 2953, 1614, 1504, 1387, 1279, 1248,
1224, 1188, 1153 cm-1; MS 365 (M+), 294, 232, 161. Anal. Calcd
for C15H18NO4F3: C, 49.31; H, 4.96; N, 3.83. Found: C, 49.45;
H, 4.95; N, 3.89.
3-(N -Tr iflu or om e t h a n e su lfon yl)-7-h yd r oxym e t h yl-9-
m eth oxy-2,3,6,7-tetr a h yd r o-1H,5H-ben zo[ij]qu in olin e (13).
Tin tetrachloride (1 M in CH2Cl2) (100 mL, 100 mmol) was added
dropwise to a solution of epoxide 12 (23.5 g, 64.4 mmol) in
anhydrous CH2Cl2 (700 mL) at -20 °C. After completion of the
addition (ca. 30 min), the mixture was stirred at -20 °C for 1.5
h and then at 0 °C for 2 h. It was carefully quenched with water
(500 mL) at 0 °C, and the resulting mixture was vigorously
stirred for 30 min. The aqueous layer was extracted with CH2-
Cl2. The combined organic layers were washed with saturated
NaHCO3 aqueous solution, brine, dried over MgSO4, filtered, and
concentrated. The crude residue was purified by flash chroma-
tography over silica gel (2/1 hexanes-EtOAc) to give 13 (17.0 g,
46.6 mmol) as an oil in 73% yield: 1H NMR (300 MHz, CDCl3)
δ 6.82 (d, J ) 2.9 Hz, 0.5 H), 6.74 (d, J ) 2.5 Hz, 0.5 H), 6.59
(m, 1 H), 4.67 (br s, 1 H), 4.13 (m, 1 H), 4.01 (dd, J ) 10.8, 5.1
Hz, 0.5 H), 3.91 (dd, J ) 10.8, 6.0 Hz, 0.5 H), 3.80 (s, 1.5 H),
3.79 (s, 1.5 H), 3.74 (m, 1 H), 3.30-2.95 (m, 2 H), 2.72 (m, 2 H),
2.37 (m, 1 H), 2.12 (m, 1 H), 1.95-1.46 (m, 2 H); IR 3404, 2943,
1610, 1593, 1477, 1387, 1327, 1280, 1224, 1188, 1151 cm-1; MS
365 (M+), 320, 294, 232, 214.
3-(N-Tr iflu or om eth an esu lfon yl)-7-oxo-9-m eth oxy-2,3,6,7-
tetr a h yd r o-1H,5H-ben zo[ij]qu in olin e (14). To a solution of
alcohol 13 (21.0 g, 57.5 mmol) in anhydrous THF (225 mL) at
room temperature was added 2-nitrophenylselenocyanate (16.8
g, 74.0 mmol) and tri-tert-butylphosphine (19 mL, 75.8 mmol).
The mixture was stirred for 1 h at room temperature and
concentrated. The residue was subjected to silica gel chroma-
tography (3.5/1 hexanes-EtOAc) to give the selenide (28.1 g).
It was taken up with CH2Cl2 (1 L) and saturated NaHCO3 (330
mL) aqueous solution and to which m-CPBA (57-86%) (12.5 g)
was added portionwise at 0 °C with strong mechanical stirring.
After being vigorously stirred for 5 min at 0 °C and for 1 h at
room temperature, the two phases were separated. The aqueous
layer was extracted with CH2Cl2. The combined organic layers
were washed with saturated NaHCO3 aqueous solution, brine,
dried over MgSO4, filtered, and concentrated. The crude residue
was purified by flash chromatography over silica gel (5/1
hexanes-EtOAc) to give the olefin intermediate (12.0 g, 34.7
mmol) as a pale yellow solid in 60% yield. An analytical sample
was obtained by triturating the product in hexanes followed by
filtration: mp 113.0-113.8 °C; 1H NMR (300 MHz, CDCl3) δ
7.01 (d, J ) 2.6 Hz, 1 H), 6.64 (d, J ) 2.5 Hz, 1 H), 5.51 (br s, 1
H), 5.07 (br s, 1 H), 4.65 (br m, 1 H), 4.10 (m, 1 H), 3.82 (s, 3 H),
3.23 (m, 1 H), 3.01 (m, 1 H), 2.75-2.70 (m, 3 H), 2.34 (m, 1 H),
1.89-1.79 (m, 1 H); IR 1601, 1471, 1377, 1363, 1261, 1224, 1190,
1149, 1138 cm-1; MS 347 (M+), 294, 214, 185. Anal. Calcd for
1-(3-Bu ten yl)-2-(N-tr iflu or om eth an esu lfon yl)-6-m eth oxy-
1,2,3,4-tetr a h yd r oisoqu in olin e (7b). To a solution of tetrahy-
droquinoline 6 (25.0 g, 0.12 mol) in anhydrous CH2Cl2 (245 mL)
at -78 °C were added dropwise triflic anhydride (35.7 g, 0.13
mol) and triethylamine (12.8 g, 0.13 mol). The mixture was
stirred at - 78 °C for 2 h and concentrated. The residue was
partitioned between EtOAc and 0.5 N HCl. The organic layer
was washed with saturated NaHCO3 aqueous solution and brine,
dried over MgSO4, filtered, and concentrated to give a crude
product. It was purified by flash chromatography over silica gel

Notes
J . Org. Chem., Vol. 65, No. 20, 2000 6747
C15H16NO3F3S: C, 51.87; H, 4.64; N, 4.03. Found: C, 52.09; H,
4.67; N, 4.13.
triflate 18 (1.55 g, 3.63 mmol) in anhydrous toluene (45 mL) at
room temperature. The mixture was refluxed for 4 h and
quenched at 0 °C successively with H2O (0.8 mL), 1 N NaOH
(2.8 mL), and H2O (0.2 mL). The resulting mixture was stirred
at 0 °C for 30 min to precipitate the inorganic salt and then
diluted with EtOAc (200 mL). The solid was filtered off and
rinsed with EtOAc. The filtrate, after drying over MgSO4, was
concentrated, and the residue was triturated with EtOAc. Once
again, the solid was filtered off and the filtrate was concentrated
to give the amine intermediate (0.99 g, 3.35 mmol) as a white
solid in 92% yield: MS 295 (M+).
To a suspension of the olefin intermediate (11.3 g, 32.6 mmol)
in dioxane (110 mL) and H2O (35 mL) at room temperature was
added OsO4 solid. The color of the mixture became dark brown
after being stirred for 5 min. NaIO4 solid was added in portions
at such a rate that the temperature of the mixture maintained
at 24-26 °C. The tan-colored slurry was stirred at room
temperature for an additional 3 h. The mixture was partitioned
between ether and H2O. The aqueous layer was extracted with
ether. The combined organic layer was washed with brine, dried
over MgSO4, filtered, and concentrated. The crude residue was
purified by flash chromatography over silica gel (5/1 to 3/1
hexanes-EtOAc) to give 14 (6.0 g, 17.2 mmol) as a white solid
in 53% yield: mp 108.5-111.0 °C; 1H NMR (CDCl3) δ 7.47 (d, J
) 2.8 Hz, 1 H), 6.95 (d, J ) 2.7 Hz, 1 H), 4.95 (br m, 1 H), 4.20-
4.15 (m, 1 H), 3.85 (s, 3 H), 3.19 (m, 1 H), 3.04 (m, 1 H), 2.9-2.5
(m, 4 H), 2.25 (ddd, J ) 17.5, 12.4, 5.0 Hz, 1 H); 13NMR (300
MHz, CDCl3) δ 195.3, 159.0, 135.7, 133.5, 129.6, 121.0, 110.2,
55.6, 54.8, 42.8, 37.5, 31.7, 30.3; IR 1686, 1606, 1475, 1389, 1346,
1296, 1282, 1224, 1188, 1151 cm-1; MS 349 (M+), 293, 216, 215,
188, 160. Anal. Calcd for C14H14NO4F3S: C, 48.14; H, 4.04; N,
4.01. Found: C, 48.00; H, 4.05; N, 3.96.
3-(N-Tr iflu or om et h a n esu lfon yl)-7,9-d ih yd r oxy-2,3,6,7-
tetr a h yd r o-1H,5H-ben zo[ij]qu in olin e (15). To a solution of
14 (5.1 g, 14.6 mmol) in anhydrous ether (150 mL) was added
LiAlH4 solution (1 M in THF) (14.3 mL) at 0 °C. The mixture
was stirred at room temperature for 30 min and then quenched
with 1 N NaOH at 0 °C. The product was extracted with EtOAc.
The combined organic layers were washed with brine and dried
over MgSO4. Solvent was evaporated to give the alcohol inter-
mediate (5.1 g) in quantitative yield: MS 351 (M+), 333, 323,
200, 190. To a solution of this intermediate (5.0 g, 14.2 mmol)
in anhydrous CH2Cl2 (200 mL) at -78 °C was added BBr3
solution (1 M in CH2Cl2) (130 mL). The mixture was stirred at
-78 °C for 30 min, at -20 to -10 °C for 2 h, and at room
temperature for additional 2 h. After being cooled to -20 °C,
the mixture was quenched carefully with excess ether, warmed
to room temperature, stirred for 30 min, and concentrated. The
residue was taken up with 200 mL of H2O followed by the
addition of THF so as to make the mixture becoming a clear
solution. The resulting mixture was stirred at room temperature
for 18 h. AgNO3 solid (excess) was added and, after 30 min of
stirring, was filtered off. The product was extracted with CH2-
Cl2. The combined organic layer was washed with brine, dried
over MgSO4, filtered, and concentrated. The residue was purified
by flash chromatography over silica gel (1/1 EtOAc-hexanes)
to afford 15 (2.8 g, 8.2 mmol) as a gummy solid in 58% yield.
(two diastereomers): 1H NMR (CDCl3) δ 6.94 (d, J ) 2.4 Hz,
0.5 H), 6.75 (d, J ) 2.5 Hz, 0.5 H), 6.58 (d, J ) 2.3 Hz, 1 H),
5.15 (m, 0.5 H), 4.79-4.36 (m, 1.5 H), 4.05 (m, 1 H), 3.20 (m, 1
H), 2.97 (m, 1 H), 2.70 (m, 1 H), 2.48-2.24 (m, 2 H), 1.80-1.54
(m, 2 H); 13C NMR (CDCl3) δ 155.1, 154.8, 142.2, 140.4, 134.2,
122.4, 115.1, 114.1, 113.5, 110.3, 69.4, 66.3, 60.5, 53.1, 52.7, 42.4,
41.9, 29.7, 29.4; IR: 3416, 2945, 1618, 1471, 1385, 1280, 1224,
1190, 1149 cm-1; MS 337 (M+), 319, 309, 186, 149.
To a mixture of the amine (0.97 g, 3.29 mmol) and KHCO3
(0.43 g, 4.30 mmol) in anhydrous THF (20 mL) at 0 °C was added
dropwise methyl bromoacetate (0.65 g, 4.22 mmol). After being
stirred at 0 °C for 30 min and at room temperature for 2.5 h,
the mixture was partitioned between ether and half- saturated
NaHCO3 aqueous solution. The aqueous layer was extracted
with ether. The combined organic layers were washed with brine,
dried over NaSO4, filtered, and concentrated. The crude product
was purified by flash chromatography over silica gel (EtOAc) to
give 19 (0.92 g, 2.49 mmol) as a gummy product in 76% yield
(two diastereomers): 1H NMR (CDCl3) δ 7.45-7.31 (m, 5 H),
6.98 (d, J ) 2.6 Hz, 0.5 H), 6.86 (d, J ) 2.6 Hz, 0.5 H), 6.67 (d,
J ) 2.6 Hz, 0.5 H), 6.40 (d, J ) 2.6 Hz, 0.5 H), 5.04 (s, 2 H),
4.78-4.67 (m, 1 H), 5.04 (s, 3 H), 3.62-3.46 (m, 3 H), 3.17-2.91
(m, 3 H), 2.72 (m, 1 H), 2.4-2.1 (m, 1 H), 2.03 (m, 2 H), 1.70 (m,
1 H); IR 3426, 2947, 1743, 1606, 1466, 1273, 1194, 1159, 1026
cm-1; MS 366 (M - H)+, 349, 339, 308, 294, 280, 266, 248, 91.
3-[N-(Meth oxyca r bon yl)m eth yl]-7-oxo-9-m eth oxyca r bo-
n yl-2,3,6,7-tetr a h yd r o-1H,5H-ben zo[ij]qu in olin e (20). To a
mixture of alcohol 19 (30 mg, 0.08 mmol), powdered NaOAc, and
Celite in anhydrous CH2Cl2 (1 mL) at 0 °C was added pyridium
chlorochromate (PCC) (31 mg, 0.10 mmol). The mixture was
stirred for 2 h and diluted with 2 mL of ether. EtOAc (20 mL)
was added, and the solid was filtered off through a pad of Celite.
The filtrate was concentrated, and the residue was purified by
preparative TLC (2/1 EtOAc/hexanes) to give the gummy te-
tralone (16 mg, 0.044 mmol) in 54% yield: 1H NMR (CDCl3) δ
7.48 (d, J ) 2.7 Hz, 1 H), 7.44-7.32 (m, 5 H), 6.97 (d, J ) 2.7
Hz, 1 H), 5.09 (s, 2 H), 3.88 (d, J ) 13.8, 5.2 Hz, 1 H), 3.75 (s, 3
H), 3.60 (dd, AB, J ) 11.3, 6.9 Hz, 2 H), 3.21-3.05 (m, 3 H),
2.79 (m, 2 H), 2.56 (m, 1 H), 2.40 (m, 1 H), 1.92-1.76 (m, 1 H);
IR: 2964, 1736, 1682, 1604, 1464, 1379, 1352, 1317, 1292, 1201,
1165 cm-1; MS 365 (M+), 364, 306, 292, 274.
A mixture of tetralone (410 mg, 1.12 mmol) and Pd/C (10%)
in EtOAc (10 mL) was stirred under H2 atmosphere (balloon
pressure) for 2 h. Catalyst was filtered off through a pad of
Celite, and the filtrate was concentrated to give the phenol
intermediate (295 mg). This intermediate was dissolved in
anhydrous CH2Cl2 (10 mL) and treated at -78 °C with triflic
anhydride (364 mg, 1.29 mmol) and triethylamine (141 mg, 1.39
mmol). After being stirred for 3 h at -78 °C, the mixture was
partitioned between EtOAc and saturated NaHCO3 aqueous
solution. The two phases were separated, and the aqueous layer
was extracted with EtOAc. The combined organic layers was
washed with brine, dried over MgSO4, filtered, and concentrated.
The crude product was purified by preparative TLC (2/1 EtOAc/
hexanes) to give the triflate intermediate (262 mg, 0.64 mmol).
This intermediate, after being taken up with anhydrous DMF
(2 mL), was treated with NEt3 (130 mg, 1.28 mmol), Pd(OAc)2
(9 mg, 0.039 mmol), bis-(diphenylphosphino)ferrocene (45 mg,
0.081 mmol), and MeOH (0.52 mL). The resulting mixture was
purged with CO for 5 min and heated to 60 °C under CO
atmosphere (balloon pressure) for 3 h. After being cooled to room
temperature, the mixture was quenched with half saturated
NaHCO3 aqueous solution. The product was extracted to EtOAc.
The organic layer was washed with brine, dried over Na2SO4,
filtered, and concentrated. The residue was purified by prepara-
tive TLC (2/1 EtOAc-hexanes) to give diester 20 (180 mg, 0.56
mmol) (51% in three steps): 1H NMR (CDCl3) δ 8.50 (d, J ) 1.8
Hz, 1 H), 7.99 (d, J ) 1.5 Hz, 1 H), 4.02 (dd, J ) 12.1, 3.6 Hz, 1
H), 3.92 (s, 3 H), 3.76 (s, 3 H), 3.65 (s, 2 H), 3.24-3.20 (m, 3 H),
2.84 (m, 2 H), 2.67-2.44 (m, 2 H), 1.87 (m, 1 H); IR 2953, 1724,
1690, 1606, 1435, 1317, 1248, 1209, 1149 cm-1; MS 317 (M+),
316, 286, 261, 258, 244.
3-(N-Tr iflu or om eth a n esu lfon yl)-7-h yd r oxy-9-ben zyloxy-
2,3,6,7-tetr a h yd r o-1H,5H-ben zo[ij]qu in olin e (18). Benzyl
bromide (1.1 g, 6.5 mmol) was added to a mixture of phenol 15
(2.2 g, 6.5 mmol) and K2CO3 (4.5 g, 32.6 mmol) in anhydrous
DMSO (20 mL) at room temperature. After being stirred for 20
h, the mixture was partitioned between H2O and ether. The
aqueous layer was extracted with ether. The combined organic
layers were washed with brine, dried over MgSO4, and concen-
trated. The crude product was purified by flash chromatography
over silica gel (3/1 hexanes-EtOAc) to give 18 (1.6 g, 3.7 mmol)
in 57% yield (two diastereomers): 1H NMR (CDCl3) δ 7.45-7.31
(m, 5 H), 7.10 (d, J ) 2.4 Hz, 0.5 H), 6.91 (d, J ) 2.5 Hz, 0.5 H),
6.72 (m, 1 H), 5.17 (m, 0.5 H), 5.08 (s, 1 H), 5.06 (s, 1 H), 4.84 (t,
J ) 4.9 Hz, 0.5 H), 4.70 (m, 1 H), 4.13-4.06 (m, 1 H), 3.22 (m,
1 H), 3.07 (m, 1 H), 2.72 (m, 1 H), 2.49 (m, 1 H), 2.32 (m, 1 H),
2.08 (m, 1 H), 1.70 (m, 1 H); IR 3379, 2939, 1610, 1595, 1497,
1454, 1385, 1279, 1223, 1188, 1149 cm-1; MS 427 (M+), 409, 276,
91.
3-[N-(Meth oxyca r bon yl)m eth yl]-7-h yd r oxy-9-ben zyloxy-
2,3,6,7-tetr a h yd r o-1H,5H-ben zo[ij]qu in olin e (19). LiAlH4
solution (1 M in THF) (20 mL) was added slowly to a solution of
3-[N-(Meth oxyca r bon yl)m eth yl]-7-h yd r oxy-9-m eth oxy-
ca r bon yl-2,3,6,7-tetr a h yd r o-1H,5H-ben zo[ij]qu in olin e (21).

6748 J . Org. Chem., Vol. 65, No. 20, 2000
Notes
To a solution of 20 (150 mg, 0.51 mmol) in MeOH (5 mL) at 0
°C was added NaBH4 (93 mg, 2.46 mmol). After being stirred at
0 °C for 10 min and at room temperature for 1 h, the mixture
was quenched with H2O (10 mL) and allowed to stir for 30 min.
The product was extracted to EtOAc. The organic layer was
washed with brine, dried over MgSO4, filtered, and concentrated.
The crude residue was purified by preparative TLC (5:1 EtOAc-
hexanes) to give 21 (85 mg, 0.27 mmol, 53% yield) as a
diastereomeric mixture of 4.5 to 1 ratio in favor of the (4S,7S)
isomer. A side product, in which one of the ester groups was
reduced, was also isolated (33 mg): 1H NMR (CDCl3) δ 7.96 (s,
1 H), 7.68 (s, 1 H), 4.83 (br t, J ) 7.0 Hz, 1 H), 3.89 (s, 3 H), 3.86
(dd, J ) 11.1, 4.1 Hz, 1 H), 3.74 (s, 3 H), 3.53 (dd, J ) 13.8, 6.8
Hz, AB, 2 H), 3.19-3.05 (m, 3 H), 2.82 (m, 1 H), 2.4-2.2 (m, 2
H), 1.72 (m, 1 H), 1.53 (m, 1 H); 13C NMR (CDCl3) δ 171.4, 167.1,
139.8, 138.8, 134.5, 129.0, 128.5, 126.2, 69.4, 59.0, 54.3, 52.0,
51.7, 51.1, 31.5, 28.4, 26.4; IR: 3406, 2951, 1720, 1435, 1302,
1203, 1161 cm-1; MS 319 (M+), 301, 291, 260, 246, 232, 218;
HRMS calcd for C17H21NO5 319.1420, found 319.1343.
3-[N-(Meth oxyca r bon yl)m eth yl]-7-a zid o-9-m eth oxyca r -
bon yl-2,3,6,7-tetr ah ydr o-1H,5H-ben zo[ij]qu in olin e ((4S,7R)-
22 a n d (4S,7S)-23). To a solution of 21 (70 mg, 0.22 mmol) in
anhydrous toluene (2 mL) at 0 °C was added diphenylphosphoryl
azide (DPPA) (73 mg, 0.26 mmol) followed by DBU (40 mg, 0.26
mmol) dropwise. After being stirred at 0 °C for 2 h and at room
temperature for 18 h, the mixture was partitioned between
EtOAc and H2O. The aqueous layer was extracted with EtOAc.
The combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated. The crude product was
purified by preparative TLC (1/1 hexanes/EtOAc) to obtain two
products, 22 (38 mg, 0.11 mmol, 50% yield) and 23 (11 mg, 0.03
mmol, 15% yield). For 22: 1H NMR (CDCl3) δ 7.79 (s, 1 H), 7.75
(s, 1 H), 4.61 (t, J ) 4.2 Hz, 1 H), 3.91 (s, 3 H), 3.79 (m, 1 H),
3.74 (s, 3 H), 3.57 (dd, J ) 22.2, 17.2 Hz, AB, 2 H), 3.15 (m, 3
H), 2.85 (m, 1 H), 2.11 (m, 3 H), 1.75 (m, 1 H); IR 2951, 2098,
1720, 1435, 1327, 1296, 1215, 1153,cm-1; MS 344 (M+), 313, 285,
271, 261, 243, 228, 196; HRMS calcd for C17H20N4O4 344.1485,
found 344.1473. For 23: 1H NMR (CDCl3) δ 7.87 (s, 1 H), 7.74
(s, 1 H), 4.62 (dd, J ) 8.2, 5.9 Hz, 1 H), 3.91 (s, 3 H), 3.87 (m, 1
H), 3.75 (s, 3 H), 3.55 (dd, J ) 21.1, 16.8 Hz, AB, 2 H), 3.21-
3.03 (m, 3 H), 2.82 (m, 1 H), 2.31 (m, 2 H), 2.03 (m, 1 H).
(4S,7R)-3-[N-(Meth oxycar bon yl)m eth yl]-7-am in o-9-m eth -
oxyca r b on yl-2,3,6,7-t e t r a h yd r o-1H ,5H -b e n zo[ij]q u in o-
lin e (24). A mixture of 22 (14 mg, 0.04 mmol) and Pd/C (10%)
in 1 mL of EtOAc was stirred vigorously under H2 atmosphere
(balloon pressure) at room temperature for 6 h. Catalyst was
filtered off through a pad of Celite and rinsed with MeOH. The
filtrate was concentrated to give 24 (11 mg, 0.035 mmol) in 84%
yield. This material was used directly for the next coupling
reaction.
rophosphate (HATU) (48 mg, 0.125 mmol), 1-hydroxy-7-azaben-
zotriazole (HOAt) (17 mg, 0.125 mmol), and diisopropylethy-
lamine (24 mg, 0.188 mmol). After being stirred at room
temperature for 18 h, the mixture was quenched with saturated
NaHCO3 aqueous solution. The product was extracted with
EtOAc. The organic layer was washed with brine, dried over
MgSO4, filtered, and concentrated. The crude product was
purified by preparative TLC (1.5/1 hexanes-EtOAc) to give 25
(12 mg, 0.024 mmol) in 75% yield: 1H NMR (CDCl3) δ 7.76 (s, 1
H), 7.70 (s, 1 H), 5.59 (br d, J ) 8.1 Hz, 1 H), 5.19 (m, 1 H), 3.88
(s, 3 H), 3.73 (s, 3 H), 3.71-3.51 (m, 3 H), 3.20-2.80 (m, 4 H),
2.18 (m, 1 H), 2.03-1.62 (m, 20 H); IR 2905, 1720, 1643, 1527,
1437, 1294, 1215, 1153 cm-1; MS 494 (M+), 463, 435, 421, 301,
289, 242; HRMS calcd for C29H38N2O5 494.2781, found 494.2772.
(4S,7R)-3-[N-(Met h oxyca r b on yl)m et h yl]-7-[1-flu or en e-
ca r b on yl)a m in o]-9-m et h oxyca r b on yl-2,3,6,7-t et r a h yd r o-
1H,5H-ben zo[ij]qu in olin e (26). The same procedure as de-
scribed for 25 affords 26 (18 mg, 0.035 mmol, 80% yield) from
24 (14 mg, 0.044 mmol) and 1-fluorenecarboxylic acid (46 mg,
0.221 mmol): 1H NMR (CDCl3) δ 7.91-7.73 (m, 4 H), 7.60-7.34
(m, 5 H), 6.35 (br d, J ) 7.3 Hz, 1 H), 5.41 (m, 1 H), 4.25 (s, 2
H), 3.86 (s, 3 H), 3.76 (s, 3 H), 3.70 (m, 1 H), 3.62 (dd, J ) 31.0,
16.9 Hz, AB, 2 H), 3.25-3.16 (m, 3 H), 2.92 (m, 1 H), 2.20 (m, 3
H), 1.61 (m, 1 H); 13C NMR (CDCl3) δ 171.2, 167.0, 166.7, 143.6,
143.3, 143.0, 140.3, 135.7, 134.7, 131.3, 129.1, 128.8, 127.3, 127.1,
126.7, 125.0, 124.4, 122.4, 119.9, 59.0, 54.8, 52.0, 51.7, 51.1, 46.8,
37.6, 28.8, 27.8, 23.2; IR 3431, 3287, 2951, 1755, 1724, 1628,
1520, 1439, 1296, 1213, 1138 cm-1; MS 510 (M+), 451, 437, 301,
289, 242; HRMS calcd for C31H30N2O5 510.2155, found 510.2154.
(4S,7R)-3-(N-Ca r boxym eth yl)-7-(1-a d m a n ta n yla ceta m i-
d o)-9-ca r b oxy-2,3,6,7-t et r a h yd r o-1H ,5H -b en zo[ij]q u in o-
lin e (27). A mixture of 25 (10 mg, 0.02 mmol) and LiOH‚H2O
(3.4 mg, 0.08 mmol) in 0.6 mL of (1/1) MeOH-H2O was stirred
at room temperature for 15 h. The diacid product was precipi-
tated after the addition of 0.1 mL of acetic acid. The solid was
collected and rinsed with small amount of H2O. It was dried
under vacuum to give 27 as a white solid (5.0 mg, 0.01 mmol)
in 50% yield: 1H NMR (CD3OD-CDCl3) δ 7.91 (s, 1 H), 7.82 (s,
1 H), 5.17 (m, 1 H), 4.47 (m, 1 H), 3.78-3.52 (m, 5 H), 3.23 (m,
2 H), 2.27 (m, 1 H), 2.1-1.6 (m, 20 H); MS (FAB) 467 (M + 1)+,
426, 370, 309, 277, 229, 219; HRMS (FAB) calcd for C27H35N2O5
(M + 1)+ 467.5884 found 467.2545.
(4S,7R)-3-(N-Ca r b oxym et h yl)-7-[(1-flu or en eca r b on yl)-
a m in o]-9-ca r boxym eth yl-2,3,6,7-tetr a h yd r o-1H,5H-ben zo-
[ij]qu in olin e (28). The same procedure described for 27 affords
28 (5 mg, 0.01 mmol, 38% yield) from 26 (14 mg, 0.027 mmol):
IR 3433, 2930, 1705, 1639, 1520, 1454, 1396, 1284 cm-1; MS
(FAB) 483 (M + 1)+; HRMS (FAB) calcd for C29H27N2O5
483.5482, found 483.1920.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
5, 6, 7b, 11-14, 14 precursor, 15, 18, 19, 20 precursor, 21-
23, and 25-27. This material is available free of charge via
the Internet at http://pubs.acs.org.
(4S,7R)-3-[N-(Met h oxyca r b on yl)m et h yl]-7-(1-a d m a n t a -
n yla ce t a m id o)-9-m e t h oxyca r b on yl-2,3,6,7-t e t r a h yd r o-
1H,5H-ben zo[ij]qu in olin e (25). To a solution of 24 (10 mg,
0.031 mmol) and 1-adamantaneacetic acid (25 mg, 0.125 mmol)
in anhydrous DMF (0.5 mL) at room temperature were added
O-(7-azabenzotriazol-1-yl)-1,1,3,3,-tetramethyluronium hexafluo-
J O991162K