Synthesis of Ultra-Short-Acting Neuromuscular Blocker GW 0430: A Remarkably Stereo- and Regioselective Synthesis of Mixed Tetrahydroisoquinolinium Chlorofumarates

Article abstract of DOI:10.1021/ol9911573

(Matrix Presented) The stereo- and regioselective synthesis of ultra-short-acting nondepolarizing neuromuscular blocker GW 0430 (5a) is de scribed. Key steps involved the enantioselective transfer hyrogenation of imine 8 employing Noyori's catalyst, the stereoselective catallization and methanolysis of trans-betains 11 and 12, and the stereo- and regioselective trans elimination of hydrogen chloride 'from 14. The latter transformation allowed complete control of the position of the chloro substituent and stereochemistry at the double bond of the linker in 15.

Full text of DOI:10.1021/ol9911573

ORGANIC
LETTERS
1999
Vol. 1, No. 12
1993-1996
Synthesis of Ultra-Short-Acting
Neuromuscular Blocker GW 0430: A
Remarkably Stereo- and Regioselective
Synthesis of Mixed
Tetrahydroisoquinolinium
Chlorofumarates
Vicente Samano,* John A. Ray, James B. Thompson, Robert A. Mook, Jr.,
David K. Jung, Cecilia S. Koble, Michael T. Martin, Eric C. Bigham,
Craig S. Regitz, Paul L. Feldman, and Eric E. Boros*
Department of Chemistry, Glaxo Wellcome Research and DeVelopment,
FiVe Moore DriVe, Research Triangle Park, North Carolina 27709
Vs43467@glaxowellcome.com
Received October 18, 1999
ABSTRACT
The stereo- and regioselective synthesis of ultra-short-acting nondepolarizing neuromuscular blocker GW 0430 (5a) is described. Key steps
involved the enantioselective transfer hydrogenation of imine 8 employing Noyori’s catalyst, the stereoselective crystallization and methanolysis
of trans-betaines 11 and 12, and the stereo- and regioselective trans elimination of hydrogen chloride from 14. The latter transformation
allowed complete control of the position of the chloro substituent and stereochemistry at the double bond of the linker in 15.
Neuromuscular blockers (NMBs) are widely used in anes-
thesia to provide skeletal muscle relaxation during surgery
and facilitate intubation of the trachea. Nondepolarizing
NMBs are a highly desirable class due to their excellent
clinical and safety profiles.1 NMBs possessing an ultra-short
duration of action are required in emergency, routine surgical,
and postoperative settings.2 Presently, there is no ultra-short-
acting nondepolarizing NMB in clinical use.1a Herein we
describe the stereo- and regioselective synthesis of GW 0430
(5a), a novel nondepolarizing ultra-short-acting NMB that
is undergoing clinical development.
As part of a program to discover an ultra-short-acting
nondepolarizing NMB, we synthesized a mixture of the
bistetrahydroisoquinolinium chlorofumarates and mixed tet-
rahydroisoquinolinium chlorofumarates 5-7 via the non-
selective route illustrated in Scheme 1. Included in this
mixture was a mixed tetrahydroisoquinolinium chlorofuma-
rate (5ab, Scheme 4) isolated as a 1:1 mixture of inseparable
regioisomers. Preclinical studies demonstrated that 5ab is a
potent ultra-short-acting nondepolarizing NMB (ED95 0.2 mg/
kg) in the rhesus monkey.3 To evaluate the pharmacological
properties of 5a and 5b separately, a highly stereo- and
(1) (a) Kopman, A. J. Clin. Anesth. 1993, 5, 39S-45S. (b) Savarese, J.
J.; Miller, R. D.; Lien, C. A.; Caldwell, J. E. Pharmacology of Muscle
Relaxants and Their Antagonists. In Anesthesia, 4th ed.; Miller R. D., Ed.;
Churchill Livingstone: New York, 1994; pp 417-488.
(3) Boros, E. E.; Bigham, E. C.; Boswell, G. E.; Mook, R. A., Jr.; 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.
(2) Bevan, D. R. Pharmacol. Toxicol. 1994, 74, 3-9.
10.1021/ol9911573 CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/18/1999

Scheme 1. Nonselective Synthesis of Bis- and Mixed Onium Chlorofumarates 5, 6, and 7
regioselective synthesis of these mixed tetrahydroisoquino-
linium chlorofumarates was developed.
to provide a statistical mixture of bisonium chlorofumarate
and mixed onium chlorofumarate diesters 5-7. Title com-
pounds 5ab were the major products isolated in 15% yield
by preparative HPLC as an inseparable 1:1 mixture of
chlorofumarate regioisomers.8
The nonselective synthesis of bisonium chlorofumarates
and mixed onium chlorofumarates 5-7 (Scheme 1) com-
menced by reacting in parallel enantiopure (R)-(-)-5′-
methoxylaudanosine4 (1) and (S)-(+)-cryptostyline III5 (2b)
with 3-chloro-1-propanol and sodium iodide in refluxing
2-butanone.6 This provided trans/cis mixtures (trans/cis refers
to the relationship of the 1-benzyl or 1-phenyl substituent
and the 3-hydroxy-1-propyl chain at N-2) of the correspond-
ing quaternary ammonium iodides in ∼3:1 ratios, as indicated
by 1H NMR spectroscopy and HPLC analysis. Ion exchange
followed by preparative HPLC (12% methanol/dichlo-
romethane/0.25 mL of methanesulfonic acid/L) provided
(1R)-trans-1-benzyl headgroup 3a (∼95% trans) in 35%
yield. The (1S)-trans/cis-1-phenyl mixture 4ab was used in
the next step without further purification. An equimolar
mixture of 3a and 4ab in 1,2-dichloroethane was treated with
1 equiv of chlorofumaryl chloride7 at ambient temperature
Three significant synthetic hurdles had to be overcome to
develop a stereo- and regioselective synthesis of 5a and 5b.
The first obstacle was the development of an efficient
enantioselective synthesis of (S)-(+)-cryptostyline III5 (2b).
While (R)-(-)-5′-methoxylaudanosine4 (1) is readily avail-
able, 2b is prepared in low yield by a tedious classical
resolution5 and N-methylation sequence starting from racemic
2a. We prepared 2a via an efficient asymmetric transfer
hydrogenation of 1-phenyl-3,4-dihydroisoquinoline 89 (Scheme
3) employing Noyori’s ruthenium catalyst 9 in the presence
of formic acid and triethylamine.10 Chiral HPLC analysis
(Chiralpak AS, isopropyl alcohol/hexane/triethylamine) of
the crude reaction mixture showed the desired product 2a
in 83% ee and this was further improved when the formic
(4) (a) Stenlake, J. B.; Waigh, R. D.; Dewar, G. H.; Hughes, R.; Chapple,
D. J.; Coker, G. G. Eur. J. Med. Chem. 1981, 16, 515-524. (b) Swaringen,
R. A., Jr.; El-Sayad, H. A.; Yeowell, D. A.; Savarese, J. J. (Burroughs
Wellcome Co., General Hospital Corporation) U. S. Patent 4,761,418; Aug
2, 1988.
(5) Brossi, A.; Teitel, S. HelV. Chim. Acta 1971, 54, 1564-1571.
(6) Patel, S. S.; Maehr, R. B.; Savarese, J. J.; Jackson, M. M.; Wastila,
W. B.; Wisowaty, J. C. Eur. J. Pharm. Sci. 1997, 5, 253-266.
(7) Akhtar, M.; Botting, N. P.; Cohen, M. A.; Gani, D. Tetrahedron 1987,
43, 5899-5908.
(8) Determined by 1H NMR spectroscopy. The vinylic hydrogen for each
chlorofumarate regioisomer 5a and 5b appeared at 7.12 and 7.16 ppm,
respectively, as distinct singlets.
(9) Prepared by Bishler-Napieralski cyclization as described in Whaley
and Govindachari: Whaley, K. W.; Govindachari, T. R. Org. React. 1951,
6, 74-150.
(10) (a) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R.
J. Am. Chem. Soc. 1996, 118, 4916-4917. (b) Kitamura, M.; Hsiao, Y.;
Ohta, M.; Tsukamoto, M.; Ohta, T.; Takaya, H.; Noyori, R. J. Org. Chem.
1994, 59, 297-310 and references therein.
1994
Org. Lett., Vol. 1, No. 12, 1999

Scheme 2. Synthesis, Stereoselective Crystallization, and Methanolysis of trans-Betaines 11 and 12
acid salt of 2a precipitated from the reaction mixture in 76%
respectively, in good yield (60-69%) and excellent de (98-
99%). Methanolysis of betaines 11 and 12 under acidic
conditions (acetyl chloride, methanol) provided the required
headgroups 3a and 4a, quantitatively.
yield and 99% ee. Eschweiler-Clarke methylation of 2a with
formic acid and formalin11 gave the N-methyl derivative 2b
(96%).
With enantio- and diastereomerically pure 3a and 4a in
hand, we proceeded to develop a regio- and stereoselective
synthesis of mixed onium chlorofumarates 5a and 5b. Ring
opening of cyclic anhydrides with alcohols14 and subsequent
esterification of the free carboxyl group is a general
procedure for preparing mixed diesters. We envisaged that
ring opening of (()-2,3-dichlorosuccinic anhydride15 [(()-
13] with 3a would generate the 1,2-dichlorosuccinate mo-
noester 14 with the necessary stereochemistry to yield the
trans double bond in 15 upon E2 elimination of hydrogen
chloride (Scheme 4). We also anticipated that the methine
proton adjacent to the ester would be more acidic than the
methine proton adjacent to the resulting carboxylate anion
in 14 allowing the regioselective abstraction and elimination
of hydrogen chloride upon treatment with base. Accordingly,
(()-1315 was reacted with 3a in dichloromethane at ambient
temperature to provide the corresponding monoester 14.
Treatment of 14 with 2 equiv of triethylamine in dichlo-
romethane effected stereo- and regioselective elimination of
hydrogen chloride to provide 15 as a single isomer in 86%
Scheme 3. Asymmetric Transfer Hydrogenation of Imine 8
The second issue to address was the stereoselective
preparation of trans quaternary headgroups 3a and 4a. Cis/
trans mixtures obtained by alkylation of 1 and 2b with
3-chloro-1-propanol/sodium iodide are difficult to separate
even after repetitive chromatography on silica gel. Attempts
to improve the trans selectivity in the alkylation12 of 1 and
2b by modifying the leaving group and the reaction condi-
tions were unsuccessful. In the course of these studies, we
discovered that 1 and 2b were readily quaternized with 1,3-
dioxa-2-thiane 2,2-dioxide13 (10) to give the corresponding
trans/cis betaines in a 3:1 ratio (Scheme 2). Although the
diastereoselectivity was not improved, we were gratified to
discover that the desired (1R)-trans (11) and (1S)-trans (12)
betaines crystallized selectively from acetone and acetonitrile,
1
overall yield. The H NMR of 15 shows a singlet at 7.15
ppm for the vinylic hydrogen. COSY and proton-carbon
multiple bond correlation (HMBC) NMR experiments with
15 support the trans geometry and position of the chlorine
R to the ester carbonyl. The final steps involved conversion
of 15 to its corresponding acid chloride (oxalyl chloride,
dichloromethane) followed by coupling with 4a to give 5a
as a single regioisomer in 84% yield (90% pure by HPLC).
Analytically pure material was obtained by preparative HPLC
and lyophilization from water. Regioisomer 5b was synthe-
sized through a similar sequence which involved ring opening
of (()-2,3-dichlorosuccinic anhydride [(()-13] with 4a,
followed by stereo- and regioselective hydrogen chloride
elimination, acid chloride formation, and coupling with 3a.
The NMB properties of 5a and 5b were evaluated and
revealed that 5a was ∼4-fold more potent than 5b and
(11) Kaluszyner, A.; Galun, A. B. J. Org. Chem. 1961, 26, 3536-3537.
(12) For NMR and X-ray stereochemical studies on quaternization of
1-benzyltetrahydroisoquinolines, see: (a) Stenlake, J. B.; Williams, W. D.;
Dhar, N. C.; Marshall I. G. Eur. J. Med. Chem. 1974, 9, 233-238. (b)
Ribar, B.; Lazar, D.; Kalman, A.; Kobor, J.; Bernath, G. J. Chem. Soc.,
Perkin Trans. 2 1977, 1141-1144. (c) Lindon, J. C.; Ferrige, A. G.
Tetrahedron 1980, 36, 2157-2159. (d) 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 and references
therein.
(13) Cyclic sulfate 10 was prepared from 1,3-propanediol as described
in Gao et al.: (a) Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110,
7538-7539. (b) Guijarro, D.; Guillena, G.; Mancheno, B.; Yus, M.
Tetrahedron 1994, 50, 3427-3436.
(14) Cox, A. Dicarboxylic and Polycarboxylic Acids. In ComprehensiVe
Organic Chemistry, 1st ed.; Sutherland, I. O. Ed.; Pergamon Press: Oxford,
1979; pp 685-690.
(15) Prepared by a modified procedure as described in Feuer et al.: (a)
Feuer, H.; Rubinstein, H. J. Org. Chem. 1959, 24, 811-813. (b) Erickson,
L. E. J. Am. Chem. Soc. 1965, 87, 1867-1875.
Org. Lett., Vol. 1, No. 12, 1999
1995

Scheme 4. Selective Synthesis of Mixed Onium Chlorofumarate 5a
displayed a rapid onset of action at its ED95 dose and ultra-
Acknowledgment. We thank G. Evan Boswell, Mary M.
Jackson, James C. Wisowaty (Department of Chemical
Development), and John J. Savarese (Cornell University
Medical Center) for helpful discussions. The analytical
support provided by Andrea M. Sefler, Randy D. Rutkowski,
Lisa St. John-Williams, and William R. Hall is gratefully
acknowledged.
short duration of NMB effect.3
In summary, we have developed a highly efficient stereo-
and regioselective synthesis of chlorofumarates 5a and 5b.
We applied the Noyori procedure to the enantioselective
synthesis of (S)-(+)-cryptostyline III (2b). Quaternization of
1 and 2b with cyclic sulfate 10 followed by crystallization
and methanolysis gave the required trans headgroups 3a and
4a without the use of chromatography. A stereo- and
regioselective trans elimination of hydrogen chloride from
monoester 14 allowed complete control of the position of
the chloro substituent and stereochemistry at the double bond
of the linker. A full account on the clinical evaluation of 5a
and the structure-activity relationships of this new class of
NMBs will be the subject of future publications.
Supporting Information Available: Experimental pro-
cedures, analytical data (1H NMR, MS, elemental analysis)
for new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL9911573
1996
Org. Lett., Vol. 1, No. 12, 1999