Stereocontrolled synthesis of cis-dibenzoquinolizine chlorofumarates: Curare-like agents of ultrashort duration

Article abstract of DOI:10.1021/jo010032k

The quaternizations of dibenzoquinolizines 9 and 14 with 3-halo-1-propanols are highly cis-selective (94-100% cis), results consistent with the N-methylation of O-methylcapaurine (7b), but in contrast to the proposed trans-stereochemistry of dibenzo[a,h]quinolizine methiodide 10 and the analogous quaternizations of 1-benzyl- and 1-phenylisoquinoline congeners 5b and 5c. In this report, we describe stereoselective preparation of the unique cisdibenzoquinolizinium propanols 15 and 16 and their transformation into bis- and mixed-onium chlorofumarates 19, 20ab, and 26. Dibenzo[a,g]quinolizinium propanol 15 was prepared enantioselectively in three steps from dihydroisoquinoline 11. Asymmetric transfer hydrogenation of 11 in the presence of triethylamine/formic acid and Noyori's chiral ruthenium catalyst 12 produced R-(-)-5',8-dimethoxynorlaudanosine (13) in 98% yield and 87% ee. Pictet-Spengler cyclization of 13 in formalin/formic acid afforded the dibenzo[a, g]quinolizine 14 in 65% yield. Quaternization of 14 with 3-chloro-l-propanol under Finkelstein conditions generated cis-dibenzoquinolizinium propanol 15 in 85% yield with >94% cis- selectivity. The cis-dibenzo [a,h] quinolizinium propanol 16 was obtained as a single stereoisomer by reaction of the known tetramethoxyquinolizine 9 with neat 3-iodo-1-propanol. Bis-onium chlorofumarates 18 and 19 and the mixed-onium derivative 20ab were prepared by a pool synthesis procedure from (1-R)-trans-6a, 16, and chlorofumaryl chloride (17). Mixed-onium α-chlorofumarate 26 was synthesized from (1S)-trans-6d, 15 and (±)-trans-2,3-dichlorosuccinic anhydride (22), employing a recently disclosed chlorofumarate mixed-diester synthesis. The title compounds (19, 20ab, and 26) displayed curare-like effects of ultrashort duration in rhesus monkeys.

Full text of DOI:10.1021/jo010032k

J . Org. Chem. 2001, 66, 3495-3501
3495
Ster eocon tr olled Syn th esis of cis-Diben zoqu in olizin e
Ch lor ofu m a r a tes: Cu r a r e-Lik e Agen ts of Ultr a sh or t Du r a tion
Istvan Kaldor, Paul L. Feldman, Robert A. Mook, J r., J ohn A. Ray, Vicente Samano,
Andrea M. Sefler, J ames B. Thompson, Benjamin R. Travis, and Eric E. Boros*
Division of Medicinal Chemistry, GlaxoSmithKline Research & Development, Five Moore Drive, Research
Triangle Park, North Carolina 27709
eeb39577@gsk.com
Received J anuary 11, 2001
The quaternizations of dibenzoquinolizines 9 and 14 with 3-halo-1-propanols are highly cis-selective
(94-100% cis), results consistent with the N-methylation of O-methylcapaurine (7b), but in contrast
to the proposed trans-stereochemistry of dibenzo[a,h]quinolizine methiodide 10 and the analogous
quaternizations of 1-benzyl- and 1-phenylisoquinoline congeners 5b and 5c. In this report, we
describe stereoselective preparation of the unique cis-dibenzoquinolizinium propanols 15 and 16
and their transformation into bis- and mixed-onium chlorofumarates 19, 20a b, and 26. Dibenzo-
[a,g]quinolizinium propanol 15 was prepared enantioselectively in three steps from dihydroiso-
quinoline 11. Asymmetric transfer hydrogenation of 11 in the presence of triethylamine/formic
acid and Noyori’s chiral ruthenium catalyst 12 produced R-(-)-5′,8-dimethoxynorlaudanosine (13)
in 98% yield and 87% ee. Pictet-Spengler cyclization of 13 in formalin/formic acid afforded the
dibenzo[a,g]quinolizine 14 in 65% yield. Quaternization of 14 with 3-chloro-1-propanol under
Finkelstein conditions generated cis-dibenzoquinolizinium propanol 15 in 85% yield with >94%
cis-selectivity. The cis-dibenzo[a,h]quinolizinium propanol 16 was obtained as a single stereoisomer
by reaction of the known tetramethoxyquinolizine 9 with neat 3-iodo-1-propanol. Bis-onium
chlorofumarates 18 and 19 and the mixed-onium derivative 20a b were prepared by a pool synthesis
procedure from (1R)-trans-6a , 16, and chlorofumaryl chloride (17). Mixed-onium R-chlorofumarate
26 was synthesized from (1S)-trans-6d , 15 and (()-trans-2,3-dichlorosuccinic anhydride (22),
employing a recently disclosed chlorofumarate mixed-diester synthesis. The title compounds (19,
20a b, and 26) displayed curare-like effects of ultrashort duration in rhesus monkeys.
In tr od u ction
its depolarizing mechanism of action produces a number
of unwanted side-effects. Nondepolarizing1,5 NMBs such
as 3 and 4 are devoid of the side-effects typically
associated with depolarizing relaxants and anesthesiolo-
gists have long recognized the need for a nondepolarizing
succinylcholine replacement.
Intravenous administration of the naturally occurring
bis-benzylisoquinoline d-tubocurarine (curare) (1) to
induce skeletal muscle relaxation (neuromuscular block-
ade) during surgical procedures revolutionized the prac-
tice of anesthesia.1 Since that time, a number of synthetic
and semisynthetic neuromuscular blockers (NMBs) have
been introduced into the clinic with varying time courses
of NMB (curare-like) activity. Examples of these adjuncts
to anesthesia include the ultra-short-acting NMB succi-
nylcholine1 (2), the short-acting2 bis-benzyl isoquinoline
mivacurium3 (Mivacron) (3), and the long-acting2 agent
doxacurium4 (Nuromax) (4).
We have been interested in the stereoselective synthe-
sis of ultra-short-acting isoquinoline-based NMBs as
possible replacements for succinylcholine. A common
problem in the synthesis of 3 and 4 and their congeners
is the N-quaternization reaction of tetrahydroisoquino-
lines 5 which generates a mixture of cis and trans
isoquinolinium propanols (6) (eq 1). In this report we
describe the stereocontrolled synthesis of conformation-
ally constrained analogues of trans-6b and trans-6c and
their conversion into the ultra-short-acting curare-like
agents 19, 20a b, and 26.
Succinylcholine (2) is the only rapid onset, ultra-short-
acting NMB currently available in the clinic; however,
(1) Skeletal muscle relaxants or neuromuscular blockers (NMBs)
are adjuncts to anesthesia and are used to provide skeletal muscle
relaxation during surgery and to facilitate tracheal intubation. For a
review of the chemistry and pharmacology of NMBs and their
antagonists, see: Savarese, J . J .; Miller, R. D.; Lien, C. A.; Caldwell,
J . E. Anesthesia, 4th ed.; Miller, R. D., Ed.; Churchill Livingstone: New
York, 1994; pp 417-488.
(2) NMBs are defined by their duration of action as ultrashort (8
min), short (20 min), intermediate (50 min), and long acting (. 50
min), see: Bedford, R. F. Anesthesiology 1995, 82, 33A.
Resu lts a n d Discu ssion
Benzylisoquinolinium propanols 6a 3,6 and 6b4 are the
penultimate intermediates in the synthesis of 3 and 4,
respectively. Mivacurium (3) is derived from (R)-5′-
(3) Swaringen, R. A., J r.; El-Sayad, H. A.; Yeowell, D. A.; Savarese,
J . J .; (Wellcome Foundation Ltd. and General Hospital Corp.) Eur. Pat.
Appl. EP 181,055, May 14, 1986; Chem. Abstr. 1986, 105, 172809y.
(4) El-Sayad, H. A.; Yeowell, D. A.; Swaringen, R. A., J r. (Wellcome
Foundation Ltd.) Eur. Pat. Appl. EP 54,309, J un 23, 1982; Chem. Abstr.
1982, 97, 163306w.
(5) Nondepolarizing NMBs are nicotinic acetylcholine receptor
(NChR) antagonists and depolarizing NMBs are NChR agonists (see
ref 1).
(6) El-Sayad, H. A.; Swaringen, R. A.; Yeowell, D. A.; Crouch, R.
C.; Hurlbert, S.; Miller, R. W.; McPhail, A. T. J . Chem. Soc., Perkin
Trans. 1 1982, 2067-2077.
10.1021/jo010032k CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/25/2001

3496 J . Org. Chem., Vol. 66, No. 10, 2001
Kaldor et al.
neuromuscular potency relative to their bis-benzyliso-
quinoline congeners, but produce more rapid onsets of
neuromuscular blockade. Interestingly, quaternization of
the 1-phenyl isoquinolines 5c and 5d with 3-iodo-1-
propanol also yield cis/ trans mixtures of the correspond-
ing onium compounds 6c and 6d in ratios comparable to
those observed for the 1-benzyl analogues 6a and 6b (e.g.,
cis:trans ratio ∼1:3).
Faced with the moderate stereoselectivity (∼75% trans)
in the formation of 6a -d , we focused part of our synthetic
effort on the preparation of conformationally constrained
isoquinolines in the hopes of enhancing the stereoselec-
tivity of N-alkylation and perhaps improving biological
activity. Accordingly, we embarked on the synthesis of
the cis-dibenzoquinolizinium propanols 15 and 16 (cis
with respect to the benzylic methine hydrogen and the
3-hydroxypropyl side chain), as conformationally re-
stricted analogues of the trans isomers of 6b and 6c,
respectively.
Variable stereoselectivities have been reported for
quaternization reactions involving the dibenzoquinolizine
family of compounds (e.g., 7 and 9). For example, N-
alkylation of (()-xylopinine (7a ) with iodomethane pro-
vides a mixture of stereoisomers (8a ) from which the
trans isomer was isolated in ca. 51% yield8 (trans with
respect to the benzylic methine hydrogen and N-methyl
substituent). Conversely, N-methylation of O-methylca-
paurine (7b) yields exclusively the cis-product9 (cis-8b)
based on IR spectroscopy and 13C NMR. Interestingly,
quaternization of the symmetrical dibenzo[a,h]quinoliz-
ine 9 with iodomethane affords a single stereoisomer of
10 that was proposed to have a trans relationship
between the bridgehead methine hydrogen and N-methyl
group.10
methoxylaudanosine ((R)-5a ) while doxacurium (4) is
obtained from the racemic 5′,8-dimethoxylaudanosine
(()-5b. Isoquinolinium propanols 6a and 6b are gener-
ated as mixtures of cis and trans stereoisomers (cis/ trans
refers to the relationship between the benzylic substitu-
ent at C-1 and the 3-hydroxypropyl side chain at N-2)
by reaction of the corresponding tetrahydroisoquinolines
(5) with 3-iodo-1-propanol generated in situ under Finkel-
stein conditions (cis:trans ratio ∼1:3) (eq 1). In the
synthesis of 3, the cis/ trans mixture of 6a is carried
through the final coupling stage with octenedioyl chloride
whereas the racemate of trans-6b is first isolated and
then reacted with succinyl chloride to give 4. Mivacurium
(3) is obtained as a mixture of the trans-trans, trans-cis,
and cis-cis isomers and doxacurium is isolated as a
mixture of the meso isomer (4) and the corresponding dl-
pair.
Our investigations into the N-quaternization of diben-
zoquinolizines 9 and 14 with 3-halo-1-propanols (Scheme
1) have found these reactions to proceed with 94-100%
cis-stereoselectivity, a result consistent with the N-
methylation of O-methylcapaurine9 (7b) and in contrast
to the implied trans-stereochemistry of 10.10 Stereose-
Recent research in our laboratories7 has focused on the
preparation of novel ultra-short-acting2 nondepolarizing
NMBs as potential replacements for succinylcholine.
Some of these analogues incorporate 1-aryl tetrahy-
droisoquinolinium groups (e.g., 6c and 6d ) linked by a
chemically labile chlorofumarate inter-onium diester. The
resulting bis-phenylisoquinolines have significantly lower
(8) Kametani, T.; Huang, S.-P.; Koseki, C.; Ihara, M.; Fukumoto,
K. J . Org. Chem. 1977, 42, 3040-3046.
(7) Boros, E. E.; Bigham, E. C.; Boswell, G. E.; Mook, R. A., J r.; Patel,
S, S.; Savarese, J . J .; Ray, J . A.; Thompson, J . B.; Hashim, M. A.;
Wisowaty, J . C.; Feldman, P. L.; Samano, V. J . Med. Chem. 1999, 42,
206-209 and references therein.
(9) Takao, N.; Iwasa, K.; Kamigauchi, M.; Sugiura, M. Chem. Pharm.
Bull. 1977, 25, 1426-1435.
(10) Bishop, D. C.; Tucker, M. J . J . Chem. Soc. (C) 1970, 2184-
2186.

Synthesis of cis-Dibenzoquinolizine Chlorofumarates
J . Org. Chem., Vol. 66, No. 10, 2001 3497
Sch em e 1
lective preparation of cis-dibenzoquinolizinium propanols
15 and 16 and their transformation into bis- and mixed-
onium chlorofumarates 19, 20a b, and 26 by pool syn-
thesis techniques and chlorofumarate mixed-diester meth-
odology are described herein.
Et2O provided the pure enantiomer. Assignment of the
R-configuration to (-)-13 is empirical and is based on the
analogous asymmetric synthesis of cryptostyline II utiliz-
ing the enantiomer of 12.14a To our knowledge, pure
enantiomers of 5′,8-dimethoxynorlaudanosine (13) have
not been previously described in detail. Pictet-Spengler
cyclization15 of 13 in the presence of formaldehyde
provided the requisite dibenzo[a,g]quinolizine 14 in 65%
yield following flash chromatography.
Achiral tetramethoxy dibenzo[a,h]quinolizine 9 was
prepared from 1-(3,4-dimethoxyphenyl)-3,4-dihydro-6,7-
dimethoxyisoquinoline and bromoacetaldehyde oxime
using a published procedure.10 Asymmetric synthesis of
the hexamethoxy dibenzo[a,g]quinolizine 14 and quat-
ernizations of 9 and 14 employing 3-halo-1-propanols are
illustrated in Scheme 1. We wished to prepare the
R-enantiomer of 14 since the (1R)-trans configuration of
the isoquinolinium moiety generally provides optimum
neuromuscular potency.7,11 Dihydroisoquinoline 11 was
prepared from mescaline and 3,4,5-trimethoxypheny-
lacetyl chloride using standard methods.12,13 Asymmetric
transfer hydrogenation of 11 with triethylamine/formic
acid in the presence of Noyori’s chiral ruthenium catalyst
1214a provided tetrahydroisoquinoline 13 in 98% yield and
We next turned our attention to the quaternization of
dibenzoquinolizines 9 and 14 with 3-halo-1-propanols.
Reaction of dibenzo[a,h]quinolizine 9 with neat 3-iodo-
1-propanol provided a single stereoisomer (16) in 99%
yield. Analysis of the product by 2D 1H NMR NOESY
spectroscopy supported a cis relationship between the
benzylic methine hydrogen and propanol side chain which
was also confirmed by X-ray crystal structure analysis
(see Supporting Information). On the basis of the cis-
stereochemistry of 16, we conclude that the stereochem-
ical relationship between the bridgehead proton and the
N-methyl group in methiodide 1010 is also cis.
Alkylation of the dibenzo[a,g]quinolizine 14 was ac-
complished with 3-chloro-1-propanol in refluxing methyl
ethyl ketone (MEK) in the presence of NaI. Under these
conditions, the cis-dibenzoquinolizine 15 was obtained in
85% yield with >94% cis-selectivity. The cis-stereochem-
istry in 15 was confirmed by 2D 1H NMR ROESY
spectroscopy (see Supporting Information).
One possible explanation for the high cis-stereoselec-
tivity observed in the quaternizations shown in Scheme
1 is that the cis-conformers of 9 and 14 (cis with respect
to the nitrogen lone pair and benzylic methine hydrogen)
present less sterically hindered nitrogen lone pairs for
the electrophile during the activation process compared
to the trans forms (eqs 2 and 3).16,17 However, this
87% ee as determined by chiral HPLC. Flash chroma-
tography on silica gel followed by recrystallization from
(11) Patel, S. S.; Maehr, R. B.; Savarese, J . J .; J ackson, M. M.;
Wastila, W. B.; Wisowaty, J . C. Eur. J . Pharm. Sci. 1997, 5, 253-266.
(12) Franck, B.; Blaschke, G. J ustus Liebigs Ann. Chem. 1966, 695,
144-157.
(13) Falck, J . R.; Miller, L. L.; Stermitz, F. R. Tetrahedron 1974,
30, 931-934.
(14) For examples of asymmetric tetrahydroisoquinoline syntheses,
see: (a) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R.
J . Am. Chem. Soc. 1996, 118, 4916-4917. (b) Munchhof, M. J .; Meyers,
A. I. J . Org. Chem. 1995, 60, 7086-7087. (c) Kitamura, M.; Hsiao, Y.;
Ohta, M.; Tsukamoto, M.; Ohta, T.; Takaya, H.; Noyori, R. J . Org.
Chem. 1994, 59, 297-310 and references therein.
(15) Whaley, W. M.; Govindachari, T. R. Org. React. 1951, 6, 151-
206.
(16) Conformational analyses of dibenzo[a,g]- and dibenzo[a,h]-
quinolizines typically evaluate one trans and two cis forms (see refs
17a and 17b).

3498 J . Org. Chem., Vol. 66, No. 10, 2001
Kaldor et al.
Sch em e 2
reasoning does not explain the ca. 51% yield of trans
product observed in the N-methylation of (()-xylopinine
(7a ).8
dibenzo[a,g]quinolizines toward the cis forms has been
ascribed to this effect.9,17a A severe steric interaction also
exists between the C-1 and C-13 hydrogens in the rigid
trans conformer of dibenzo[a,h]quinolizine 9 (internuclear
separation ca. 1 Å based on Dreiding models), and its
manifestation during the activation process would further
explain the high cis-selectivity observed in the N-alky-
lation of this compound.
With a practical synthesis of the constrained isoquino-
linium alkanols 15 and 16 in hand, we pursued their
conversion to curare-like agents of ultrashort duration.
A chlorofumarate inter-onium linker is known to produce
ultrashort duration of NMB effect, and the incorporation
of disparate onium nuclei in the same molecule (mixed-
onium) can improve neuromuscular potency and diminish
unwanted cardiovascular side effects.7,19 For these rea-
sons, the preparation of bis- and mixed-onium chlorofu-
marate derivatives of 15 and 16 were of interest.
A pool synthesis of bis-onium chlorofumarates 18 and
19 and mixed-onium chlorofumarate 20a b was accom-
plished by reacting chlorofumaryl chloride (17)20 with an
equimolar solution of 16 and (1R)-trans-6a 21 in DCE at
ambient temperature (Scheme 2). This reaction produced
the expected statistical mixture of bis- and mixed-onium
products (18, 19, and 20a b) which were isolated by
preparative HPLC. The mixed-onium derivative (20a b)
Assuming no equilibration of cis/ trans isomers under
the reaction conditions, the high cis-selectivities observed
in the N-alkylations of O-methylcapaurine (7b)9 and 14
are probably controlled by an intramolecular repulsive
interaction between the C-1 methoxy substituent and the
C-13 hydrogens in the transition state leading to the
trans product.9 This steric interaction, which is alleviated
in one of the cis conformations,17a should raise the energy
of activation18 for the formation of trans isomer and
therefore increase the proportion of cis product. A shift
in the conformational equilibrium of C-1-substituted
(19) Bigham, E. C.; Boswell, G. E.; Savarese, J . J .; Swaringen, R.
A., J r.; Patel, S. S.; Boros, E. E.; Mook, R. A., J r.; Samano, V. (Glaxo
Group Ltd. and Cornell Research Foundation Inc.) PCT Int. Appl. WO
98/42675, Oct 1, 1998; Chem. Abstr. 1998, 129, 275845.
(20) Akhtar, M.; Botting, N. P.; Cohen, M. A.; Gani, D. Tetrahedron
1987, 43, 5899-5908.
(21) For a preliminary account of the chlorofumarate mixed-diester
methodology, see: Samano, V.; Ray, J . A.; Thompson, J . B.; Mook, R.
A., J r.; J ung, D. K.; Koble, C. S.; Martin, M. T.; Bigham, E. C.; Regitz,
C. S.; Feldman, P. L.; Boros, E. E. Org. Lett. 1999, 1, 1993-1996.
(17) (a) Kametani, T.; Fukumoto, K.; Ihara, M.; Ujiie, A.; Koizumi,
H. J . Org. Chem. 1975, 40, 3280-3283. (b) Vlaeminck, F.; De Cock,
E.; Tourwe, D.; Van Binst, G. Heterocycles 1981, 15, 1213-1218.
(18) The Curtin-Hammett principle applies to the quaternization
of tertiary amines, and the geometry of the dibenzoquinolizine skeleton
at the transition state of quaternization should resemble that of the
corresponding dibenzoquinolizine conformer, see: Bottini, A. T. Selec-
tive Organic Transformations, Thyagarajan, B. S., Ed.; Wiley-Inter-
science: New York, 1970; pp 89-142.

Synthesis of cis-Dibenzoquinolizine Chlorofumarates
J . Org. Chem., Vol. 66, No. 10, 2001 3499
Sch em e 3
Sch em e 4
was isolated as a 1:1 mixture of inseparable R- and
â-chlorofumarate regioisomers (20a and 20b).
rosuccinate monoester 23 with the necessary stereo-
chemistry to yield the desired chlorofumarate (24) upon
elimination of HCl. Treatment of 23 with DBU (2 equiv)
in acetonitrile induced regio- and stereoselective elimina-
tion of HCl and afforded R-chlorofumarate monoester 24
in 34% overall yield from 15 following recrystallization
from DCE.
The pharmacodynamic evaluation and potential de-
velopment of any mixed-onium chlorofumarate regioiso-
mer, such as 20a or 20b, required a selective synthesis.
To achieve the desired chlorobutenedioate geometry and
regiochemistry, a selective chlorofumarate mixed-diester
synthesis was developed.21 This practical methodology is
exemplified herein by the synthesis of mixed-onium
R-chlorofumarate 26 (Scheme 3). Chlorination of maleic
anhydride (21) in the presence of 0.02 mol % benzoyl
peroxide provided trans-dichlorosuccinic anhydride 2222
in 65% yield as a white hygroscopic solid. Reaction of 22
with quinolizinium propanol 15 in DCE gave the dichlo-
The chlorofumarate regiochemistry in 24 is based on
the hypothesis that DBU first abstracts the carboxyl
proton of 23, thereby decreasing the acidity of the
hydrogen R to the carboxylate group. This in turn leads
to removal of the proton R to the ester carbonyl and loss
of chloride R to the carboxylate through an E2 elimination
mechanism (Scheme 4). The R-chloro regiochemistry of
24 is also supported by proton-carbon multiple bond
(22) Feuer, H.; Rubinstein, H. J . Org. Chem. 1959, 24, 811-813.

3500 J . Org. Chem., Vol. 66, No. 10, 2001
Kaldor et al.
and CH2Cl2 (20 mL) was degassed for 5 min with nitrogen,
and ruthenium catalyst 1214a (136 mg, 0.22 mmol) was added.
The reaction mixture was stirred at room temperature over-
night, quenched with saturated NaHCO3 solution and ex-
tracted with EtOAc. The combined EtOAc layers were dried
over Na2SO4, filtered, and concentrated to provide the crude
product (3.5 g, 98% yield) as a dark oil. Chiral HPLC analysis
(see below) indicated 87% ee and 99% chemical purity. Flash
chromatography on silica gel eluting with 10% MeOH/EtOAc
followed by recrystallization from Et2O provided a single
correlation NMR spectroscopy (HMBC) of the related
chlorofumarate monoester 27, which was prepared by a
similar procedure.21 Conversion of 24 to the mixed onium
R-chlorofumarate diester 26 was accomplished by conver-
sion to its acid chloride derivative (25) followed by
treatment with (1S)-trans-6d .21
enantiomer (13) (1.6 g, 45% overall yield) as an off-white
1
solid: [R]25 ) -34.7° (c ) 1.11, CHCl3); H NMR (CDCl3) δ
D
6.51 (2H, s), 6.45 (1H, s), 4.30 (1H, dd, J ) 10, 3), 4.04 (3H, s),
3.90 (9H, s), 3.88 (6H, s), 3.25 (1H, ddd, J ) 15, 11, 5), 3.11
(1H, dd, J ) 6, 3), 3.01 (1H, m), 2.80-2.95 (2H, m), 2.65 (1H,
br dt, J ) 15, 3), 1.89 (1H, br); ES+ MS m/z 404 (M+, 100), 222
(55); HPLC: one major peak (100%) at 9.44 min (Daicel
Chiralcel OD-H column, eluent 30% IPA/hexane/0.1% TEA).
(R)-1,2,3,9,10,11-H exa m et h oxy-5,8,13,13a -t et r a h yd r o-
6H-d iben zo[a ,g]qu in olizin e (14). A mixture of 13 (150 mg,
0.37 mmol), 37% formalin (1 mL), and 96% formic acid (0.5
mL) was heated at reflux for 2 h. The reaction mixture was
cooled to room temperature, basified with NaOH solution, and
extracted with EtOAc. The EtOAc extracts were washed with
water and brine, dried over MgSO4, filtered, and concentrated
at reduced pressure. Flash chromatography on silica gel
eluting with 2% MeOH/CH2Cl2 gave 14 as an oil (100 mg, 65%
yield): [R]25D ) +229.9° (c ) 0.575, CH2Cl2); 1H NMR (CDCl3)
δ 6.42 (2H, s), 4.07 (1H, d, J ) 16), 3.88 (3H, s), 3.87 (3H, s),
3.85 (3H, s), 3.83 (6H, s), 3.81 (3H, s), 3.88-3.81 (2H,
obscured), 3.42 (1H, dd, J ) 16, 3), 3.08 (1H, m), 2.99 (1H, m),
2.80-2.60 (3H, m); HPLC: one major peak (97%) at 2.89 min
(Altima C-18 column, eluent 70-100% CH3CN/H2O/0.1%
TEA); HRMS (M + H)+ calcd for C23H30NO6: 416.2074.
Found: 416.2027.
Su m m a r y
In closing, the novel, conformationally constrained
isoquinolinium propanols 15 and 16 were synthesized in
good yield and in a stereocontrolled fashion by quater-
nization of their corresponding dibenzoquinolizines 9 and
14 with 3-halo-1-propanols. The N-quaternization reac-
tions of 9 and 14 are highly cis-selective (94-100% cis)
in contrast to the quaternization of their 1-benzyl- and
1-phenyltetrahydroisoquinoline congeners (6b and 6c)
and the N-methylation of (()-xylopinine (7a ). Moreover,
the products (15 and 16) incorporate distal hydroxyl
groups suitable for further transformation into dicationic
skeletal muscle relaxants. Bis- and mixed-onium chlo-
rofumarates 19 and 20a b were prepared nonselectively
from 16 while mixed-onium R-chlorofumarate 26 was
obtained from 15 by a regiocontrolled chlorofumarate
mixed-diester synthesis. The bis- and mixed-onium chlo-
rofumarates described herein produced curare-like effects
of ultrashort duration in rhesus monkeys.23
(7S,13a R)-1,2,3,9,10,11-Hexa m eth oxy-7-(3-h yd r oxyp r o-
p yl)-5,8,13,13a -t et r a h yd r o-6H -d ib en zo[a ,g]q u in olizin i-
u m Ch lor id e (15). A mixture of 14 (720 mg, 1.73 mmol), NaI
(1.04 g, 6.93 mmol), Na2CO3 (92 mg, 0.865 mmol), and 3-chloro-
1-propanol (655 mg, 6.93 mmol) in MEK (10 mL) was heated
at reflux for 48 h. The solvent was removed at reduced
pressure, and the resulting material was dissolved in water
and extracted with EtOAc to remove excess 3-chloro-1-pro-
panol. The aqueous layer was saturated with NaCl and
extracted with CHCl3. The combined CHCl3 extracts were
dried over Na2SO4, filtered, and concentrated. The solid was
redissolved in water and stirred for 15 min over Dowex 1 ×
8-50 ion-exchange resin. The resin was removed by filtration,
and the filtrate was saturated with NaCl and extracted with
CHCl3. The combined CHCl3 extracts were dried over Na2SO4,
filtered, and concentrated to yield 15 (500 mg) as a rigid foam.
Back-extraction of the original EtOAc layers with water and
workup of the aqueous phase as described above with Et2O in
place of EtOAc provided an additional 250 mg of 15 (85%
Exp er im en ta l Section
Gen er a l. All reagent chemicals were used without purifica-
tion and yields are unoptimized. Analytical HPLC analyses
were performed on 4 × 250 mm 5µ Si60 LiChrosorb columns
(E. Merck, Darmstadt, Germany) at a flow rate of 1.6 mL/min.
Preparative HPLC separations were performed on twin Porasil
(15-20 µm) cartridges (Waters/Millipore, Milford, MA) at a
flow rate of 60 mL/min. The mobile phase for analytical and
preparative HPLC separations consisted of 0-25% MeOH/CH2-
Cl2 mixtures containing 0.25 mL methanesulfonic acid (MSA)/
L. Elemental analyses were performed by Atlantic Microlabs,
combined yield): [R]25 ) +94° (c ) 0.69, CHCl3); 1H NMR
D
1
Norcross, GA. All H NMR spectra were recorded at 300, 400,
(DMSO-d6) δ 6.78 (1H, s), 6.75 (1H, s), 4.96 (1H, dd, J ) 11,
5), 4.78 (1H, br t, J ) 5), 4.76 (1H, d, J ) 16), 4.64 (1H, d, J
) 16), 3.90 (3H, s), 3.85 (3H, s), 3.80 (3H, s), 3.76 (6H, s), 3.73
(3H, s), 3.66 (2H, m), 3.47 (2H, m), 3.38 (2H, m), 3.22 (1H, dd,
J ) 18, 5), 3.14 (2H, m), 2.99 (1H, dd, J ) 18, 11), 2.03 (1H,
m), 1.90 (1H, m); HPLC: one major peak (95%) at 10.54 min
(BDS-hypersil C-8 column, eluent 30-50% CH3CN/H2O/0.1%
TEA); HRMS (M+) calcd for C26H36NO7: 474.2493. Found:
474.2483.
or 500 MHz and coupling constants are in Hz. Chemical shifts
are reported in ppm relative to the residual protonated solvent
resonance of DMSO-d6 (δ 2.50), CDCl3 (δ 7.24) and acetone-d6
(δ 2.04). Positive ion flow injection electrospray mass spectra
(MS) are reported in the form m/z (singly or doubly charged
positive ion, relative intensity).
The 2′- and 6′-protons on the trimethoxyphenyl substituent
of (1S)-trans-6d and its mixed-onium derivative 26 are non-
equivalent by H NMR (DMSO-d6) and appear as very broad
signals. Heating the sample produces coalescence of these
peaks. This phenomenon is also observed for the corresponding
3′- and 5′-methoxy protons and is presumed to result from
hindered rotation of the trimethoxyphenyl group.
(1R)-6,7,8-Tr im eth oxy-1-(3,4,5-tr im eth oxyp h en yl)m e-
th yl-1,2,3,4-tetr a h yd r oisoqu in olin e (13). A solution of 11
(3.54 g, 8.82 mmol) in 5:2 formic acid/triethylamine (4 mL)
1
7-(3-Hyd r oxyp r op yl)-5,8,9,13b-tetr a h yd r o-2,3,11,12-tet-
r a m eth oxy-6H-d iben zo[a ,h ]qu in olizin iu m Ch lor id e (16).
A solution of 910 (4.00 g, 11.20 mmol) in 3-iodo-1-propanol (20
mL) was stirred at 100 °C for 20 min. The solution was diluted
with Et2O and stirred for 12 h. The iodide of 16 precipitated
from solution as a white solid and was collected by filtration
1
(6.08 g, 99% yield): ES+ MS m/z 414 (M+, 20), 356 (100); H
NMR (DMSO-d6) δ 6.93 (2H, s), 6.75 (2H, s), 5.69 (1H, s), 4.77
(1H, t, J ) 5), 3.76 (6H, s), 3.73 (4H, m), 3.66 (6H, s), 3.44
(4H, m), 3.08 (4H, m), 1.99 (2H, m). A portion of this material
(3.00 g, 5.50 mmol) was dissolved in water (100 mL) and
(23) The NMB activity of 18 in rhesus monkeys has been described
in detail (see ref 7).

Synthesis of cis-Dibenzoquinolizine Chlorofumarates
J . Org. Chem., Vol. 66, No. 10, 2001 3501
stirred over Dowex 1 × 8-50 ion-exchange resin (50 g) for 2
h. The mixture was filtered, and the filtrate was saturated
with NaCl and extracted with CH2Cl2. The CH2Cl2 extracts
were dried over MgSO4, filtered, and concentrated to provide
16 (2.21 g, 74% yield) as an off-white foam: Anal. Calcd for
in DCE (8 mL) over 3 Å molecular sieves. After stirring at
room temperature for 3 d, the sieves were removed by
filtration, and the filtrate was concentrated at reduced pres-
sure. The crude material was triturated with Et2O and dried
under high vacuum to provide the dichlorosuccinate monoester
23 (950 mg, 98% yield) as a yellow foam. A solution of 23 (900
mg, 1.33 mmol) in CH3CN (8 mL) was cooled to 0 °C and DBU
(425 mg, 2.79 mmol) in CH3CN (1 mL) was added dropwise.
The reaction mixture was stirred at 0 °C for 2 h and then
allowed to warm to room temperature. The solvent was
evaporated at reduced pressure, and the resulting material
was dissolved in CHCl3 and washed with a 2:1 brine/water
containing 5 µL of MSA/mL. The organic layer was dried over
Na2SO4, filtered, and concentrated. Recrystallization from DCE
afforded 24 as a hygroscopic white solid (290 mg, 34% yield):
1H NMR (DMSO-d6) δ 7.16 (1H, s), 6.750 (1H, s), 6.745 (1H,
s), 4.98 (1H, dd, J ) 11, 5), 4.81 (1H, d, J ) 16), 4.66 (1H, d,
J ) 16), 4.25 (2H, br t, J ∼ 5), 3.89 (3H, s), 3.85 (3H, s), 3.78
(3H, s), 3.77 (1H, m), 3.75 (3H, s), 3.74 (3H, s), 3.73 (3H, s),
3.69 (1H, m), 3.58-3.40 (2H, m), 3.22 (1H, dd, J ) 18, 5), 3.16
(2H, m), 3.00 (1H, dd, J ) 18, 11), 2.35 (1H, m), 2.18 (1H, m),
(carboxyl proton not found); HPLC: one major peak (95%) at
2.04 min (LiChrosorb Si60 column, eluent 6% MeOH/CH2Cl2/
0.25 mL MSA/L); HRMS (M+) calcd for C30H37NO10Cl: 606.2106.
Found: 606.2063.
(Z)-2-Ch lor o-4-{3-[(1S,2R)-6,7-d im et h oxy-2-m et h yl-1-
(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydro-2-isoquinolinio]-
p r o p y l}-1-{3-{(7S ,13a R )-1,2,3,9,10,11-h e x a m e t h o x y -
5,8,13,13a-tetrahydro-6H-dibenzo[a ,g]-7-quinolizinio}propyl}-
bu ten ed ioa te Dich lor id e (26). Chlorofumarate monoester
24 (255 mg, 0.397 mmol) was dissolved in CH2Cl2 (3 mL), and
oxalyl chloride (1 mL, 11.46 mmol) was added followed by DMF
(1 drop). The reaction mixture was stirred for 2.5 h at room
temperature, concentrated at reduced pressure, and dried
under high vacuum. The resulting acid chloride (25) was
dissolved in CH2Cl2 (3 mL), and a solution of (1S)-trans-6d 21
(241 mg, 0.516 mmol) in CH2Cl2 (3 mL) was added dropwise.
The reaction mixture was stirred at room temperature over-
night, the solvent was removed at reduced pressure, and the
product was purified by preparative HPLC as described for
the synthesis of 19 and 20a b. Mixed-onium chlorofumarate
26 was isolated as a white powder (152 mg, 37% yield): 1H
NMR (DMSO-d6) δ 7.19 (1H, br), 7.13 (1H, s), 6.93 (1H, s),
6.76 (1H, s), 6.74 (1H, s), 6.34 (1H, s), 6.08 (1H, br), 5.79 (1H,
s), 5.01 (1H, dd, J ) 10.9, 5.5), 4.85 (1H, d, J ) 15.8), 4.68
(1H, d, J ) 15.8), 4.26 (4H, m), 3.89 (3H, s), 3.84 (3H, s), 3.76
(6H, s), 3.75 (3H, s), 3.73 (6H, s), 3.70 (4H, m), 3.68 (3H, s),
3.60-3.80 (6H, br), 3.55 (3H, s), 3.60-3.40 (4H, m), 3.30-3.10
(5H, m), 3.00 (1H, dd, J ) 18, 11), 2.83 (3H, s), 2.35 (2H, m),
2.27 (3H, s), 2.18 (2H, m); ES+ MS m/z 510 (M2+, 100), 413
(30). Anal. Calcd for C54H69Cl3N2O15‚(5.5 H2O): C, 54.43; H,
6.77; N, 2.35. Found: C, 54.39; H, 6.65; N, 2.32.
C
24H32ClNO5‚(0.7 H2O): C, 62.32; H, 7.28; N, 3.03. Found: C,
62.32; H, 7.30; N, 3.14. A crystal of 16 suitable for X-ray
analysis was obtained by recrystallization from water.
P ool Syn th esis of 18, 19, a n d 20a b. Chlorofumaryl
chloride (17)20 (0.95 g, 5.00 mmol) was added to a stirred
solution of 16 (2.21 g, 4.9 mmol) and (1R)-trans-6a 21 (2.4 g,
4.9 mmol) in 1:4 CHCl3/1,2-dichloroethane (125 mL), and the
reaction was stirred 30 min at room temperature. The solvent
was removed at reduced pressure and the products were
separated by preparative HPLC (see General Experimental
Section). Fractions containing the desired compound were
diluted with CHCl3 and partially concentrated to remove the
MeOH (note: bis- and mixed-onium chlorofumarate diesters
are susceptible to transesterification). The remaining CHCl3
solution was washed with 1:1 brine/water, dried over Na2SO4,
filtered, and concentrated. Lyophilization from water provided
19 (0.97 g, 18% yield) and 20a b (1.4 g, 27% yield) as white
powders. The synthesis and characterization of 18 have been
described.7
(Z)-2-Ch lor o-b is{3-(5,8,9,13b -t et r a h yd r o-2,3,11,12-t et -
r a m et h oxy-6H -d ib en zo[a ,h ]-7-q u in olizin io)p r op yl}-2-
1
bu ten ed ioa te Dich lor id e (19). H NMR (DMSO- d6) δ 7.09
(1H, s), 6.91 (4H, s), 6.73 (2H, s), 6.72 (2H, s), 5.78 (1H, s),
5.75 (1H, s), 4.25 (4H, m), 3.80 (8H, m), 3.74 (12H, s), 3.64
(12H, s), 3.55 (4H, m), 3.08 (8H, m), 2.28 (4H, m); ES+ MS
m/z 471 (M2+, 100), 356 (10). Anal. Calcd for C52H63Cl3N2O12
(5 H2O): C, 56.54; H, 6.66; N, 2.53. Found: C, 56.53; H, 6.58;
N, 2.53.
‚
(Z)-2-Ch lor o-4-{3-(5,8,9,13b -t et r a h yd r o-2,3,11,12-t et -
r a m eth oxy-6H-d iben zo[a ,h ]-7-qu in olizin io)p r op yl}-1-{3-
{(1R,2S)-6,7-dim eth oxy-2-m eth yl-1-[(3,4,5-tr im eth oxyph e-
n yl)m eth yl]-1,2,3,4-tetr a h yd r o-2-isoqu in olin io}p r op yl}-
2-bu ten edioate Dich lor ide an d (Z)-2-Ch lor o-1-{3-(5,8,9,13b-
t et r a h yd r o-2,3,11,12-t et r a m et h oxy-6H -d ib en zo[a ,h ]-7-
q u in o lizin io )p r o p y l}-4-{3-{(1R ,2S )-6,7-d im e t h o x y -2-
m e t h y l-1-[(3,4,5-t r im e t h o x y p h e n y l)m e t h y l]-1,2,3,4-
tetr a h yd r o-2-isoqu in olin io}p r op yl}-2-bu ten ed ioa te Di-
1
ch lor id e (1:1) (20a b). H NMR (CDCl3) δ 7.65 (1H, s), 7.64
(1H, s), 6.77 (2H, s), 6.76 (2H, s), 6.62 (6H, m), 6.49 (2H, s),
6.46 (2H, s), 5.96 (1H, s), 5.83 (1H, s), 5.75 (1H, s), 5.73 (1H,
s), 5.18 (1H, br d, J ) 9.1), 5.06 (1H, br d, J ) 7.8), 4.30 (8H,
m), 4.05 (8H, m), 3.88 (12H, s), 3.83 (6H, s), 3.82 (6H, s), 3.80
(12H, m), 3.77 (6H, s), 3.76 (6H, s), 3.74 (6H, s), 3.72 (12H, s),
3.39 (6H, s), 3.40-3.10 (14H, m), 2.78 (2H, m), 2.60-2.30 (8H,
m); ES+ MS m/z 487 (M2+, 100), 315 (20). Anal. Calcd for
C
53H67Cl3N2O13‚(4.5 H2O): C, 56.46; H, 6.79; N, 2.48. Found:
C, 56.45; H, 6.62; N, 2.48.
(()-tr a n s-2,3-Dich lor osu ccin ic An h yd r id e (22). A solu-
tion of maleic anhydride (21) (10.6 g, 108 mmol) and benzoyl
peroxide (5 mg, 0.02 mmol) in CHCl3 (250 mL) was saturated
with chlorine gas, and the resulting yellow solution was stirred
for 5 h at room temperature. The mixture was degassed with
nitrogen and the product (22) crystallized from solution and
was collected by filtration as a white solid (11.9 g, 65% yield):
mp 90-92 °C; 1H NMR (acetone-d6) δ 5.68 (2H, s); Anal. Calcd
for C4H2Cl2O3: C, 28.43; H, 1.19; Cl, 41.97. Found: C, 28.29;
H, 1.32; Cl, 41.90.
Ack n ow led gm en t. The authors thank G. Evan
Boswell, Eric C. Bigham, and J ames C. Wisowaty for
helpful discussion. The analytical and structural sup-
port provided by William R. Hall, Steven Brown, J r.,
Randy D. Rutkowske, and Mill Lambert is gratefully
acknowledged. We also thank Peter S. White (Univer-
sity of North Carolina, Chapel Hill) for the X-ray
analysis of 16.
(Z)-2-Ch lor o-1-{3-{(7S,13aR)-1,2,3,9,10,11-Hexam eth oxy-
5,8,13,13a -t et r a h yd r o-6H -d ib en zo[a ,g]-7-q u in olizin io}-
p r op yl} Hyd r ogen -2-bu ten ed ioa te Mon och lor id e (24).
Dichlorosuccinic anhydride 22 (400 mg, 2.37 mmol) was added
portionwise to a predried solution of 15 (690 mg, 1.35 mmol)
Su p p or tin g In for m a tion Ava ila ble: 2D 1H NMR ROESY
spectra of 15 and X-ray crystal data for 16. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O010032K