Design of concise, scalable route to a cholecystokinin 1 (CCK 1) receptor antagonist

Article abstract of DOI:10.1021/jo071166m

(Chemical Equation Presented) Development of efficient, scalable routes for the synthesis of (S)-3-[5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol- 3-yl]-2-m-tolyl propionic acid, a selective cholecystokinin 1 (CCK 1) receptor antagonist, is descri

Full text of DOI:10.1021/jo071166m

Design of Concise, Scalable Route to a Cholecystokinin 1 (CCK 1)
Receptor Antagonist
Jimmy T. Liang, Neelakandha S. Mani,* and Todd K. Jones
Department of Drug DiscoVery, Johnson & Johnson Pharmaceutical Research and DeVelopment, L.L.C.,
3210 Merryfield Row, San Diego, California 92121
nmani@prdus.jnj.com
ReceiVed June 1, 2007
Development of efficient, scalable routes for the synthesis of (S)-3-[5-(3,4-dichlorophenyl)-1-(4-
methoxyphenyl)-1H-pyrazol-3-yl]-2-m-tolyl propionic acid, a selective cholecystokinin 1 (CCK 1) receptor
antagonist, is described. A key feature of the scale-up route is a concise construction of the complete
pyrazole framework in a single step by reacting an aryl hydrazine with an elaborated acetylenic
ketone. This route was then further refined incorporating efficient enantioselective strategies to
obtain the desired S-enantiomer in high optical purity. The first strategy involved an efficient, recyclable,
kinetic resolution by enzyme-catalyzed hydrolysis of the racemic ester. In the second-generation
route, the requisite stereochemistry at the chiral center was generated at an early stage in the synthesis
involving a remarkable diastereoselective addition of inexpensive (S)-(-)-ethyl lactate to an alkylaryl
ketene. Both methods furnished optically pure (>99% ee) final drug substance as its crystalline sodium
salt.
Introduction
disorders such as GI motility diseases, dyspepsia, and irritable
bowel syndrome (IBS).2
Cholecystokinin (CCK) is a polypeptide hormone (33 amino
acids) located both in the gastrointestinal system and in the
central nervous system.1 Triggered by ingestion of food, the
release of CCK hormone is the primary event that leads to the
myriad of physiological effects in the GI tract. CCK appears to
stimulate basal acid secretion, regulate GI motility, inhibit
gastrin-stimulated acid secretion, regulate gall bladder emptying,
stimulate the endocrine and exocrine functions of the pancreas,
and mediate hunger after meal. These effects of the CCK
hormone are initiated by binding to two G-protein-coupled
receptors: CCK 1 and CCK 2. Some of the important physi-
ological events, such as stimulation of gall bladder contraction,
pancreatic enzyme secretion, duodenal motility, and gastric
secretion, have been attributed specifically to the agonism of
the CCK 1 receptor by the hormone. Development of selective,
small molecule antagonists of CCK 1 receptors therefore offers
considerable potential in the treatment of GI or pancreatic
Recent efforts from our “Hit-to-Lead” group have led to the
discovery of a novel class of pyrazole compounds showing
potent CCK 1 antagonist activity and efficacy in animal models
for early stage pancreatitis.3 Among these, compound 1 was
identified as a promising candidate for further profiling due to
its excellent CCK 1/CCK 2 selectivity, pharmacokinetics, and
a number of other desirable pharmacological properties. A
practical synthesis suited for large-scale preparation was
therefore needed. We wish to report herein the development of
a concise and scalable synthetic route to this promising
candidate. Our investigations demonstrate the advantages of
acetylenic ketones as a more desirable substrate for the synthesis
of complex pyrazole structures compared to the traditionally
(2) de Tullio, P.; Delarge, J; Pirotte, B. Exp. Opin. InVest. Drugs 2000,
9, pp 129-146; Patent WO 2004/007463 A1.
(3) (a) McClure, K.; Hack, M.; Huang, L.; Sehon, C.; Morton, M.; Li,
L.; Barrett, T. D.; Shankley, N.; Breitenbucher, J. G. Bioorg. Med. Chem.
Lett. 2006, 16, 72-76. (b) Sehon, C.; McClure, K.; Hack, M.; Morton, M.;
Li, L.; Barrett, T. D.; Shankley, N.; Breitenbucher, J. G. Bioorg. Med. Chem.
Lett. 2006, 16, 77-80.
(1) (a) Ivy, A. C.; Oldberg, E. Am. J. Physiol. 1928, 86, 599-613. (b)
Mutt, V.; Jorpes, E. Biochem. J. 1971, 125, 57-58.
10.1021/jo071166m CCC: $37.00 © 2007 American Chemical Society
Published on Web 09/22/2007
J. Org. Chem. 2007, 72, 8243-8250
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Liang et al.
used 1,3-dicarbonyl substrates. Two stereoselective strategies,
one, a kinetic resolution using enzymatic ester hydrolysis, and
the second, involving a versatile 1,4-asymmetric induction
protocol were developed as efficient methods to prepare the
drug substance in high (>99%) enantiopurity.
second, the differentiated electrophilic centers of acetylenic
ketones offer potential for a better control of regioselectivity.9
The more electrophilic acetylenic carbon can be expected to
react preferentially with the more nucleophilic nitrogen of the
hydrazine and thus should afford preferentially the 1,5-regioi-
somer in the case of aromatic hydrazines.10 Our approach for 1
is outlined in eq 1.
Results and Discussions
Optically active compound 1 was originally prepared in
milligram quantities by a racemic synthesis3a followed by chiral
chromatographic separation of enantiomers utilizing a prepara-
tory SFC Chiralpak AD column with 40% IPA as eluent. The
(S)-acid was converted to its sodium salt to obtain the drug
substance. In our initial large-scale preparation of the drug
substance, we employed an asymmetric variant of this route4
based on Evans’s enantioselective enolate-alkylation strategy.5
Though this route was optimized to provide us multigram
quantities of 1 and satisfied our initial requirements, the lengthy
route involving multiple functional group manipulations, column
chromatographic purifications, and, in particular, use of an
expensive chiral auxiliary prompted us to explore other ap-
proaches to this molecule that are more practical for large-scale
synthesis.
The desired acetylenic ketone 4 can be prepared very
efficiently from inexpensive reagents in two steps as outlined
in eq 2. The lithium enolate of ethyl m-tolyl acetate was treated
The Knorr pyrazole synthesis6 involving the condensation of
a hydrazine with a 1,3-dicarbonyl substrate is perhaps the most
widely used method for the construction of simple pyrazole
structures. However, in the case of complex molecules with a
pyrazole core, construction of highly elaborated, unsymmetrical
1,3-dicarbonyl substrates is not always very practical. Initial
construction of the basic pyrazole core and subsequent elabora-
tion as exemplified in our earlier syntheses3a,4 is thus the strategy
most often adopted. In this context, pyrazole synthesis by the
condensation of acetylenic ketones with hydrazines7 offers some
distinct advantages. First, alkynones with substituents carrying
sensitive functionalities can now be readily constructed by a
variety of acetylenic coupling reactions8 under very mild
conditions, offering substantial advantage in step economy;
with propargyl bromide in THF to give the propargyl ester 3 in
72% yield after fractional distillation. Palladium-catalyzed
Sonogashira coupling of 3 with 3,4-dichlorobenzoyl chloride
proved more problematic than we anticipated. Thus, the standard
protocol (using PdCl2(PPh3)2 and CuI as catalysts and triethyl
amine in THF at room temperature) gave poor yield (ca. 30%)
of the desired acetylenic ketone 4. Formation of a number of
intractable side products was observed, and proton NMR of the
crude product showed vinylic protons suggesting isomerization
of the acetylene to the corresponding diene and its further
decomposition. Isomerization of alkynes to thermodynamically
more stable conjugated dienes is a rarely observed occurrence
due to the kinetic barrier for the prototropic shift of a methylene
proton from the allene intermediate.11 However, the situation
(4) See Supporting Information for details of this route.
(5) (a) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc.
1982, 104, 1737-1739. (b) Evans, D. A. In Asymmetric Synthesis; Morrison,
J. D., Ed.; Academic Press: New York, 1984; Vol. 3, pp 1-110. (c) Ghosh,
A. K.; Duong, T. T.; McKee, S. P. J. Chem. Soc., Chem. Commun. 1992,
1673-1674. (d) Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L.
J. Am. Chem. Soc. 1990, 112, 4011-4030. (e) Evans, D. A.; Britton, T. C.;
Ellman, J. A. Tetrahedron Lett. 1987, 28, 6141-6144.
(6) (a) Kost, A. N.; Grandberg, I. I. AdV. Heterocycl. Chem. 1966, 6,
347-429. (b) Elguero, J. Pyrazoles. In ComprehensiVe Heterocyclic
Chemistry; Potts, K. T., Ed.; Pergamon: Oxford, 1984; Vol. 5, pp 167-
303. (c) Elguero, J. Pyrazoles. In ComprehensiVe Heterocyclic Chemistry;
Shinkai, I., Ed.; Pergamon: Oxford, 1996; Vol. 3, pp 1-75. (d) Murray,
W.; Wachter, M. J. Heterocycl. Chem. 1989, 26, 1389-1392.
(7) (a) Moureu, Ch.; Delange, R. Bull. Soc. Chim. Fr. 1901, 25, 302-
313; Ann. Chim. Phys. 1902, 25, 239. (b) Claisen, L. Ber. Dtsch. Chem.
Ges. 1903, 36, 3664-3674.
(9) (a) Cabarrocas, G.; Ventura, M.; Maestro, M.; Mahia, J.; Villalgordo,
J. M. Tetrahedron: Asymmetry 2000, 11, 2483-2493. (b) Miller, R. D.;
Reiser, O. J. Heterocycl. Chem. 1993, 30, 755-763.
(10) Bishop, B. C.; Brands, K. M. J.; Gibb, A. D.; Kennedy, D. J.
Synthesis 2004, 1, 43-52.
(8) (a) Chowdhury, C.; Kundu, N. G. Tetrahedron 1999, 55, 7011-7016.
(b) Grotjahn, D. B.; Van, S.; Combs, D.; Lev, D. A.; Schneider, C.; Rideout,
M.; Meyer, C.; Hernandez, G.; Mejorado, L. J. Org. Chem. 2002, 67, 9200-
9209.
(11) (a) Acetylenic Compounds in Organic Synthesis; Accademic Press:
New York, 1995. (b) The Chemistry of Carbon-Carbon Triple Bond, Part
1; John Wiley and Sons: New York, 1978; Chapter 10, pp 381-445.
8244 J. Org. Chem., Vol. 72, No. 22, 2007

Design of Concise, Scalable Route to CCK 1
SCHEME 1
SCHEME 2
A practical solution to the problem was achieved by develop-
ing an efficient crystallization of the sodium salt. Thus, alkaline
hydrolysis of the crude mixture of the pyrazole esters furnished
the corresponding regioisomeric mixture of acids (6 + 8). Salt
formation by treatment with concentrated aqueous NaOH in
THF followed by crystallization from a 1:1 mixture of THF/
acetonitrile, we were pleased to find, crystallized the 1,5-
regioisomer 9, completely rejecting the 1,3-regioisomer in
excellent recovery. Thus, using the acetylenic route, we avoided
the functional group manipulations involved in the dicarbonyl-
based route and were able to prepare the racemic drug substance
9 in five steps very efficiently starting from readily available
starting materials.
is considerably different in systems with activated methylene
groups such as 4-pentynoic acid derivatives, and a proclivity
for this base-catalyzed prototropic shift has been noted.12 We
reasoned that use of a milder base could potentially alleviate
this difficulty. A number of organic bases were thus screened,
and N-methylmorpholine was found to be the most suitable to
avoid the isomerization. A 1:1 mixture of THF/toluene was
found to be the most preferred solvent system, furnishing the
acetylenic ketone 4 as pale yellow oil in 69% isolated yield.
We also found that the acetylenic ketone 4 is very sensitive
to aqueous acidic media and that care should be taken to avoid
strongly acidic conditions during workup. Thus, a solution of 4
in ethyl acetate when exposed to aqueous 1 N HCl was found
to hydrate cleanly to form the corresponding 1,3-diketone.
Condensation of acetylenic ketone 4 with 4-methoxyphenyl-
hydrazine, as expected, resulted in the formation of the desired
pyrazole 5 as the major regioisomer. However, a significant
amount of the undesired 1,3-regioisomer was also formed (see
Scheme 1). Our attempts at improving the regioselectivity
revealed some intriguing solvent dependency on the regiochem-
istry. For example, at room temperature, in polar, aprotic
solvents such as THF and DMF, the desired 1,5-regioisomer 5
was obtained as the major product along with 15-20% of
the undesired 1,3-regioisomer 7. In protic solvents such as
MeOH, EtOH, and IPA, however, the undesired 7 was the major
product along with a small amount of the desired isomer 5. All
our attempts to obtain exclusively the desired 1,5-regioisomer
were thus unsuccessful. The crude pyrazole product was isolated
as an oil, and our attempts at purification by crystallization were
also equally unsuccessful. The isomeric mixture was therefore
purified by silica gel column chromatography. Although the
undesired regioisomer could be easily separated by chromatog-
raphy, this raised a concern for large-scale synthesis.
With a concise route to the racemic form of the drug
substance now in hand, we next focused our attention on how
to use this approach to prepare the drug substance in enantiopure
form.
Hydrolytic enzymes such as esterases and lipases have been
used for the kinetic resolution of racemic acids by ester
hydrolysis on industrial scale.13 High selectivity, mild reaction
conditions, and environmentally sound technology makes bio-
catalysis an attractive option for large-scale synthesis. The most
advantageous scenario for us would be to find an enzyme that
selectively hydrolyzes the (S)-aryl propionate ester to the (S)-
aryl propionic acid 10. This would allow further improvement
to the process by recycling the unhydrolyzed (R)-aryl propionate
ester 11 by a base-catalyzed racemization process (as outlined
in Scheme 2).
A variety of commercially available hydrolytic enzymes were
screened for stereoselective hydrolysis. Typically, an enzymatic
hydrolysis screen was carried out in an aqueous phosphate buffer
containing enzyme catalyst (50 mg) with the substrate ester (25
mg) dissolved in a minimum amount of an organic solvent
(isopropanol or toluene) and an incubation time of 24-48 h.
Of the 54 enzymes14 tested, only two enzymes provided
noteworthy selectivity for the (S)-ester. We found the enzymes
lipase mucor miehei and the Altus #8 (obtained from Altus
Biologics) similarly catalyzed hydrolysis of our substrate with
(13) (a) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org.
Biomol. Chem. 2006, 4, 2337-2347. (b) Armstrong, J. D., III; Martinelli,
M. J.; Senanayake, C. S. Tetrahedron: Asymmetry 2003, 14, 3425-3426.
(c) Kataoka, M.; Shimizu, K.; Sakamoto, K; Yamada, H.; Shimizu, S. Appl.
Microbiol. Biotechnol. 1995, 43, 974-977. (d) Shimizu, S.; Kataoka, M.;
Shimizu, K; Hirakata, M.; Sakamoto, K.; Yamada, H. Eur. J. Biochem.
1992, 209, 383-390. (e) Shimizu, S.; Kataoka, M. Ann. N.Y. Acad. Sci.
1996, 799, 650-659.
(12) Trost, B. M.; Schmidt, T. J. Am. Chem. Soc. 1988, 110, 2301-
2303 and references cited therein.
J. Org. Chem, Vol. 72, No. 22, 2007 8245

Liang et al.
SCHEME 3
Looking at the synthesis of the acetylenic ketone, it appeared
to us that the arylpentynoic acid should be a good point to
introduce chirality (see eq 3). A number of methods based on
the extensive work reported on the synthesis of nonsteroidal
anti-inflammatory (NSAI) agents with 2-arylpropionic acid
pharmacophore15 appeared suitable to access this chiral center.
Among these, we were particularly attracted to the possibility
of taking advantage of a remarkable 1,4-asymmetric induction
observed during the addition of chiral alcohols to ketenes.16
Merck scientists have further developed this reaction and have
shown that, in the case of alkylaryl ketenes, the addition of
R-hydroxyesters and lactones proceeds with impressive dias-
tereoselectivity.17 They have also shown that addition of (S)-
hydroxy acid such as (S)-ethyl lactate to an arylketene predict-
ably introduced S-configuration in the newly formed chiral
center. The desired (S)-arylpentynoic acid derivative could thus
be derived from inexpensive, natural (S)-ethyl lactate as outlined
in eq 4.
a high degree of enantioselectivity. With the screen results in
hand, we proceeded to scale up the enzymatic hydrolysis (as
outlined in Scheme 3). The racemic ester dissolved in a
minimum amount of IPA (12% by weight) to form a clear
solution was added to a solution containing lipase mucor miehei
in aqueous phosphate buffer at pH 7. Monitoring the reaction
by chiral HPLC analysis showed a very selective but slow
hydrolysis. After stirring for 10 days at room temperature, when
80% of the (S)-ester was consumed, the reaction was arrested.
Extractive workup and chromatographic purification afforded
the enriched (S)-aryl propionic acid 10 in 40% yield with a high
degree of enantioselectivity (>90% ee). Higher enantioselec-
tivity of >99% ee was further achieved by salt formation and
recrystallization to obtain the (S)-sodium carboxylate salt 1 in
88% yield. The enriched (R)-aryl propionate ester 11 was easily
recycled to racemic 5 in 90% yield upon treatment with
potassium ethoxide in ethanol at room temperature. Interestingly,
other alkoxide bases such as lithium and sodium ethoxide in
ethanol failed to racemize the ester efficiently at room temper-
ature.
Racemic pentynoic acid 13 was prepared by the alkylation
of m-tolyl acetic acid with propargyl bromide in excellent yields
(Scheme 4). The acid chloride 14 was prepared by treatment
SCHEME 4
Synthesis of 1 thus was achieved in five steps with an overall
yield of 13%. In a 10 g batch, one racemization and recycling
step increased the overall yield to about 20%.
While the kinetic resolution proved to be very practical on
multigram scale, high cost of the enzyme catalyst, long reaction
time, the need for chromatographic purification of 5, and the
need to recycle to improve efficiency were of some concern to
us. Although these issues could be overcome by further
refinement, we reasoned that perhaps by introducing the chiral
center at an early stage through a more cost-effective chiral
technology should make the synthesis more efficient.
with oxalyl chloride. Following the reported procedure, the acid
chloride was then reacted with dimethylethyl amine in toluene
at 0 °C to generate the ketene 15. Quenching the reaction with
neat (S)-ethyl lactate at -78 °C furnished the lactate ester 16
in 90% yield with 83% de. Since the lactate ester could result
from both ketene as well as the racemic acid chloride, it is
important to ensure complete transformation of acid chloride
to ketene for high diastereoselectivity. Using ReactIR in-process
(14) Two screening test kits were purchased. Screening kit ChiroScreen-
EH containing 30 enzymes was purchased from Altus Biologics Inc., 625
Putnam Ave., Cambridge, MA 02139-4211. Web site: www.Altus.com.
Tel: 1-888-258-2532. Fax: 1-617-299-2999. Screening set CHIRAZYME
Lipases & Esterases containing 24 enzymes were purchased from BioCata-
lytics, 129 Hill Ave., Suite 103, Pasadena, CA 91106-1955. Tel: (626)
585-9797. Fax: (626) 356-3999. Both enzyme sets are suited for hydrolysis
and transesterification reactions.
8246 J. Org. Chem., Vol. 72, No. 22, 2007

Design of Concise, Scalable Route to CCK 1
SCHEME 5
monitoring,18 we found that the ketene formation is quite rapid
and was complete in about 5 min at 0 °C.
a fully elaborated acetylenic ketone, avoiding protecting groups
and oxidation-reduction manipulations. The two asymmetric
methods, namely, kinetic resolution by enzymatic hydrolysis
and the diastereoselective trapping of alkylaryl ketene using (S)-
ethyl lactate, are very efficient and appear to be suited for large-
scale synthesis of the drug substance.
Sonogashira coupling of the lactate ester 16 with the 3,4-
dichlorobenzoyl chloride using our modified procedure furnished
the acetylenic ketone 17 in 80% yield (Scheme 5). Proton NMR
showed no appreciable changes in diastereomeric ratio (∼9/1),
indicating that no racemization of the newly formed chiral center
took place during this step. Reacting 17 with 4-methoxyphe-
nylhydrazine hydrochloride in THF, using Cs2CO3 as base,
furnished the desired pyrazole 18 as the major regioisomer in
3:1 ratio. This crude product was subjected to acid-catalyzed
hydrolysis, and the resulting free carboxylic acid was treated
with aqueous NaOH in THF to form the sodium salt. A single
recrystallization of the crude sodium salt, to our delight,
completely rejected the 1,3-regioisomer as well as the minor
R-stereoisomer, furnishing the drug substance 1 in 63% overall
yield and >99% ee. Complete synthesis of 1 was thus achieved
in seven steps from commercial starting materials with an overall
yield of 33%.
Experimental Section
2-m-Tolylpent-4-ynoic Acid Ethyl Ester (3). A 2 L, three-
necked, round-bottomed flask equipped with a magnetic stirring
bar, nitrogen inlet, and a thermometer was charged with diisopropyl
amine (34.6 mL, 0.246 mol) and anhydrous THF (300 mL). The
solution was cooled to 0 °C, and n-butyllithium 2.5 M in hexane
(100 mL) was added. The solution was stirred for 0.5 h then cooled
to -78 °C. Ethyl m-tolyl acetate (2, 40 mL, 0.224 mol) was added
neat to the LDA solution. After stirring for 1 h, propargyl bromide
(80 wt % in toluene; 26.8 mL, 0.240 mol) was added dropwise
while maintaining the reaction temperature between -75 and
-78 °C. The reaction mixture was allowed to slowly warm up to
room temperature overnight then quenched with saturated aqueous
ammonium chloride (100 mL) and ethyl acetate (100 mL). The
layers were separated, and the organic layer was washed with brine
(150 mL), dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure to an orange oil. Distillation under reduced
pressure furnished 40 g (82%) of ester 3 as a colorless oil. 1H NMR
spectrum of the product indicated the presence of about 5% starting
material ethyl m-tolyl acetate. The product was the further purified
by fractional distillation using a vigreux column (8′). The main
fraction distilling 83-85 °C/500 mTorr was collected to recover
35 g (72%) of the pure ester 3 as a colorless liquid: Rf ) 0.54
(hexanes/ethyl acetate, 4/1); 1H NMR (400 MHz, CDCl3) δ 7.23-
7.19 (m, 1H), 7.11-7.08 (m, 3H), 4.22-4.09 (m, 2H), 3.75 (dd, J
) 8.6, 7.1 Hz, 1H), 2.92 (ddd, J ) 2.5, 8.6, 16.6 Hz, 1H), 2.61
(ddd, J ) 2.5, 7.1, 16.6 Hz, 1H), 2.34 (s, 3H), 1.95 (t, J ) 2.5 Hz,
1H), 1.22 (t, J ) 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
172.5, 138.4, 137.6, 128.6, 128.5, 128.4, 124.8, 81.6, 69.8, 61.0,
50.8, 23.1, 21.4, and 14.1; HRMS m/z calcd for C14H17O2 [M +
H]+ 217.1223, found 217.1221.
In conclusion, we have developed an efficient, enantioselec-
tive route to the CCK 1 antagonist 1. Efficiency is derived from
the concise assembly of the substituted pyrazole structure from
(15) (a) Lubell, W. D.; Rapoport, H. J. Am. Chem. Soc. 1988, 110, 7447-
7455. (b) Castaldi, G.; Cavicchioli, S.; Giordano, C.; Uggeri, F. J. Org.
Chem. 1987, 52, 3018-3027. (c) Honda, Y.; Ori, A.; Tsuchihashi, G. Bull.
Chem. Soc. Jpn. 1987, 60, 1027-1036. (d) Ando, A.; Shioiri, T. J. Chem.
Soc., Chem. Commun. 1987, 656-658. (e) Rieu, J.-P.; Boucherle, A.;
Cousse, H.; Mouzin, G. Tetrahedron 1986, 42, 4095-4131. (f) Piccolo,
O.; Spreafico, F.; Visentin, G. J. Org. Chem. 1985, 50, 3945-3946.
(16) (a) Weiss, R. Mh. Chem. 1919, 40, 391; Anders, E.; Ruch, E. Angew.
Chem., Int. Ed. Engl. 1973, 12, 25-29. (b) Jaehme, J.; Ruechardt, C. Angew.
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Tetrahedron Lett. 1982, 23, 4017-4020. (d) Bellucci, G.; Berti, G.;
Bianchini, R.; Vecchiani, S. Gazz. Chim. Ital. 1988, 118, 451-456. (e)
Buschmann, H.; Scharf, H.-D.; Hoffmann, N.; Esser, P. Angew. Chem. 1991,
103, 490-518. (f) Fehr, C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2567-
2587. (g) Donohoe, G.; Satchell, D. P. N.; Satchell, R. S. J. Chem. Soc.,
Perkin Trans. 2 1990, 1671-1674. (h) Hodous, B. L.; Ruble, J. C.; Fu, G.
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E. J. J. J. Am. Chem. Soc. 1989, 111, 7650-7651.
6-(3,4-Dichlorophenyl)-6-oxo-2-m-tolylhex-4-ynoic Acid Ethyl
Ester (4). A 1 L, one-necked, round-bottomed flask equipped with
a magnetic stirring bar and nitrogen inlet was charged sequentially
with 3,4-dichlorobenzoyl chloride (17.43 g, 0.083 mol) then
acetylenic ester 3 (15 g, 0.069 mol) in anhydrous THF (100 mL)
(18) Acid chloride-ketene transformation was monitored using a ReactIR
instrument with a silicon probe by following the disappearance of the acid
chloride band at 1790 cm-1 and the appearance of the ketene band at 2200
cm-1
.
J. Org. Chem, Vol. 72, No. 22, 2007 8247

Liang et al.
and anhydrous toluene (100 mL). Catalysts PdCl2(PPh3)2 (100 mg,
8.6 × 10-5 mol) and CuI (100 mg, 5.2 × 10-4 mol) were then
added followed by N-methylmorpholine (15.4 mL, 0.140 mol). The
reaction was stirred at room temperature for 14 h when TLC
indicated almost complete consumption of starting material. The
reaction mixture was quenched with water (100 mL) and ethyl
acetate (100 mL) then transferred to a separatory funnel. The layers
were separated, and the organic layer was washed twice with water
(2 × 100 mL), brine (50 mL), then dried over anhydrous MgSO4.
After filtration, the solvents were evaporated to yield 4 as a yellow
oil. The crude product was purified by silica gel chromatography
(9/1 hexanes/ethyl acetate) to obtain 19 g (69%) of 4 as pale-yellow
pyrazole ester 11 as a pale yellow oil: 1H NMR (400 MHz, CDCl3)
δ 7.31-7.07 (m, 8H), 6.91-6.86 (m, 3H), 6.21 (s, 1H), 4.22-
4.01 (m, 3H), 3.82 (s, 3H), 3.54-3.45 (dd, J ) 14.9, 9.6 Hz, 1H),
3.11-3.06 (dd, J ) 14.9, 6.0 Hz, 1H), 2.35 (s, 3H), 1.20-1.16 (t,
J ) 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.5, 159.0,
151.0, 140.9, 138.8, 138.2, 132.8, 132.6, 132.2, 130.6, 130.3, 130.2,
128.6, 128.5, 128.1, 127.7, 126.6, 125.0, 114.3, 107.2, 60.8, 55.5,
51.5, 32.3, 21.5, and 14.1; HRMS m/z calcd for C28H27Cl2N2O3
[M + H]+ 509.1393, found 509.1406. After the enriched (R)-
pyrazole ester 11 was recovered from the column, the eluent was
changed to 1/1 hexanes/ethyl acetate with 2-3% methanol to obtain
5.6 g (40%) of acid 10 as an oil: 1H NMR (400 MHz, CDCl3) δ
7.31-7.09 (m, 8H), 6.91-6.86 (m, 3H), 6.21 (s, 1H), 4.12-4.08
(dd, J ) 9.6, 5.8 Hz, 1H), 3.82 (s, 3H), 3.54-3.49 (dd, J ) 14.9,
9.6 Hz, 1H), 3.13-3.08 (dd, J ) 14.9, 5.8 Hz, 1H), 2.35 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 178.4, 159.0, 150.6, 141.0, 138.4,
138.2, 132.6, 132.5, 132.2, 130.4, 130.3, 130.2, 128.8, 128.6, 128.4,
127.7, 126.6, 125.1, 114.3, 107.2, 55.5, 51.2, 31.7, and 21.4; HRMS
m/z calcd for C26H23N2Cl2O3 [M + H]+ 481.1080, found 481.1084.
Anal. Calcd for C26H22N2Cl2O3: C, 64.87; H, 4.61; N, 5.82.
Found: C, 64.80; H, 4.85; N, 6.0.
1
oil: Rf ) 0.49 (9/1 hexanes/ethyl acetate); H NMR (400 MHz,
CDCl3) δ 8.03 (d, J ) 2.0 Hz, 1H), 7.65 (dd, J ) 8.3, 2.0 Hz, 1H),
7.45 (d, J ) 8.3 Hz, 1H), 7.29-7.25 (br m, 1H), 7.16-7.13 (m,
3H), 4.25-4.12 (m, 2H), 3.88 (t, J ) 7.83 Hz, 1H), 3.16 (dd, J )
17.2, 7.6 Hz, 1H), 2.98 (dd, J ) 17.2, 7.8 Hz, 1H), 2.35 (s, 3H),
1.20 (t, J ) 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.2,
171.9, 138.7, 138.5, 136.8, 136.3, 133.1, 131.0, 130.5, 128.8, 128.3,
124.8, 94.5, 80.0, 61.4, 49.7, 23.6, 21.3, and 14.0; HRMS m/z calcd
for C21H19Cl2O3 [M + H]+ 389.1805, found 389.1812.
(S)-Sodium-3-[5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-
1H-pyrazol-3-yl]-2-m-tolyl Propionate (1). To a stirred solution
of the pyrazole acid 10 (3.8 g, 0.008 mol) in THF (40 mL) was
added NaOH (0.35 g, 0.009 mol) in H2O (2 mL) at room
temperature. The mixture was stirred for 60 min then concentrated
to an oil under reduced pressure using a rotary evaporator (30 °C).
The oil was diluted in THF (25 mL), and acetonitrile was added
whereupon precipitation developed. The solids were stirred for 2 h
then filtered, and the solids were washed with acetonitrile to afford
3-[5-(3,4-Dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-
3-yl]-2-m-tolyl Propionic Acid Ethyl Ester (5). To a stirred
solution of the acetylenic ketone 4 (9.55 g, 0.024 mol) in THF
(125 mL) was added Cs2CO3 (8.8 g, 0.027 mol) followed by
4-methoxyphenyl hydrazine HCl (6.5 g, 0.037 mol). The resulting
slurry reaction mixture was stirred at room temperature overnight
then quenched with 1 N HCl until pH 2-3. The contents were
transferred to a separatory funnel, and after separation of layers,
the aqueous layer was washed with ethyl acetate (3 × 75 mL).
The combined organic layers were dried over anhydrous Na2SO4,
filtered, and concentrated to an oil. The crude oil was purified by
silica gel chromatography (7/3 hexanes/ethyl acetate) to afford 9.46
g (76%) of 5 and 1.74 g (14%) of 7 as dark-orange oils. Compound
5: 1H NMR (400 MHz, CDCl3) δ 7.31-7.07 (m, 8H), 6.91-6.86
(m, 3H), 6.21 (s, 1H), 4.22-4.01 (m, 3H), 3.82 (s, 3H), 3.54-
3.48 (dd, J ) 14.9, 9.6 Hz, 1H), 3.11-3.06 (dd, J ) 14.9, 6.0 Hz,
1H), 2.35 (s, 3H), 1.20-1.16 (t, J ) 7.3 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 173.6, 159.0, 150.9, 140.9, 138.8, 138.2, 132.8,
132.6, 132.2, 130.6, 130.3, 130.2, 128.6, 128.5, 128.1, 127.7, 126.6,
125.0, 114.3, 107.2, 60.8, 55.5, 51.5, 32.3, 21.5, and 14.1; HRMS
m/z calcd for C28H27Cl2N2O3 [M + H]+ 509.1393, found 509.1402.
Compound 7: 1H NMR (400 MHz, CDCl3) δ 7.92-7.91 (d, J )
1.9 Hz, 1H), 7.63-7.61 (dd, J ) 8.3, 2.0 Hz, 1H), 7.45-7.43 (d,
J ) 8.4 Hz, 1H), 7.31-7.26 (m, 1H), 7.21-7.14 (m, 2H), 7.08-
7.06 (d, J ) 7.5 Hz, 1H), 7.00-6.97 (m, 4H), 6.45 (s, 1H), 4.19-
4.02 (m, 3H), 3.87 (s, 3H), 3.82-3.79 (m, 1H), 3.46-3.39 (dd, J
) 9.3, 15.4 Hz, 1H), 2.99-2.94 (dd, J ) 6.2, 15.4 Hz, 1H), 2.30
(s, 3H), 1.18-1.15 (t, J ) 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 172.8, 159.7, 149.0, 142.9, 138.5, 137.7, 133.5, 132.7,
132.4, 131.4, 130.5, 128.7, 128.5, 128.3, 127.4, 127.3, 124.9, 124.8,
114.5, 102.9, 61.1, 55.6, 51.0, 30.2, 21.4, and 14.1; HRMS m/z
calcd for C28H27Cl2N2O3 [M + H]+ 509.1393, found 509.1380
(S)-3-[5-(3,4-Dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyra-
zol-3-yl]-2-m-tolyl Propionic Acid (10). To a stirred solution of
lipase mucor miehei (10.0 g) in phosphate buffer pH 7 (500 mL)
was slowly added pyrazole ester 5 (15.0 g, 0.029 mol) in IPA (60
mL) for over 30 min to form a slurry. The reaction mixture was
monitored every 2 days using chiral HPLC to observe the
enantioselective hydrolysis. After 10 days, the reaction mixture was
adjusted to pH 1-2 using 1 N HCl then diluted with ethyl acetate
(300 mL). The mixture was stirred vigorously for 1 h, then the
emulsion was filtered through a pad of Celite. The filtrate was
transferred to a separatory funnel, and the layers were separated.
The aqueous phase was washed again with ethyl acetate (2 × 75
mL). The combined organic layers were dried with Na2SO4, filtered,
and concentrated to oil. The crude oil was purified by silica gel
chromatography eluting first with 4/1 hexanes/ethyl acetate with
1% methanol to recover 9.0 g (60%, 4/1 R/S) of the enriched (R)-
3.34 g (88%) of 1 as a white crystalline solid: mp 280-285 °C;
1
[R]20 +58.8° (c ) 0.1, EtOH); H NMR (500 MHz, D2O) δ
589
7.14-7.10 (m, 2H), 6.99-6.96 (t, J ) 7.41 Hz, 1H), 6.82-6.80
(d, J ) 8.23 Hz, 2H), 6.74-6.72 (d, J ) 7.41 Hz, 1H), 6.50-6.40
(m, 4H), 6.22 (d, J ) 7.96 Hz, 1H), 5.66 (s, 1H), 3.82-3.80 (m,
1H), 3.42 (s, 3H), 3.37-3.28 (m, 2H), 2.01 (s, 3H); 13C NMR (100
MHz, DMSO-d6) δ 176.4, 158.6, 152.9, 143.6, 140.0, 136.5, 132.7,
131.4, 131.1, 130.8, 129.8, 128.8, 128.4, 127.6, 126.8, 126.2, 125.2,
114.4, 107.6, 55.5, 54.9, 32.9, and 21.3. Anal. Calcd for C25H21-
Cl2N2NaO3: C, 62.04; H, 4.21; N, 5.57. Found: C, 61.98; H, 4.14;
N, 5.43.
Racemization of the Recovered (R)-Aryl Propionate Ester 11.
3-[5-(3,4-Dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-
yl]-2-m-tolyl Propionic Acid Ethyl Ester (5). To a stirred solution
of the (R)-pyrazole ester 11 (13.55 g, 0.026 mol) in EtOH (120
mL) was added potassium ethoxide (5.9 g, 0.029 mol) at room
temperature. Racemization was complete after the reaction was
stirred overnight. The reaction mixture was quenched with cold
H2O (20 mL), concentrated to quarter volume. The mixture was
diluted with ethyl acetate (150 mL) and acidified with 1 N HCl
(150 mL). The contents were transferred to a separatory funnel,
and the layers were separated. The organic layer was washed with
water, brine, dried over anhydrous Na2SO4, filtered, and concen-
trated to oil. The crude oil was purified by silica gel chromatography
(4/1 hexanes/ethyl acetate) to afford 12.2 g (90%) of the racemic
pyrazole ester 5 as an oil: 1H NMR (400 MHz, CDCl3) δ 7.31-
7.07 (m, 8H), 6.91-6.86 (m, 3H), 6.21 (s, 1H), 4.22-4.01 (m,
3H), 3.82 (s, 3H), 3.54-3.48 (dd, J ) 14.9, 9.6 Hz, 1H), 3.11-
3.06 (dd, J ) 14.9, 6.0 Hz, 1H), 2.35 (s, 3H), 1.20-1.16 (t, J )
7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.5, 158.9, 150.9,
140.8, 138.8, 138.2, 132.8, 132.6, 131.1, 130.6, 130.3, 130.2, 128.6,
128.5, 128.1, 127.7, 126.5, 124.9, 114.2, 107.1, 60.7, 55.5, 51.4,
32.3, 21.4, and 14.1; HRMS m/z calcd for C28H27Cl2N2O3 [M +
H]+ 509.1393, found 509.1402.
2-m-Tolylpent-4-ynoic Acid (13). A 2 L, three-necked, round-
bottomed flask equipped with a magnetic stirring bar, nitrogen inlet,
and a thermometer was charged with diisopropyl amine (39.2 mL,
0.280 mol) and anhydrous THF (350 mL). The solution was cooled
to 0 °C, and n-butyllithium 2.5 M in hexanes (112 mL) was added.
8248 J. Org. Chem., Vol. 72, No. 22, 2007

Design of Concise, Scalable Route to CCK 1
The solution was stirred for 0.5 h then cooled to -78 °C. m-Tolyl
acetic acid (12, 20 g, 0.133 mol) dissolved in 100 mL of THF was
added to the LDA solution. After 30 min, 15.8 mL of propargyl
bromide (80% in toluene, 0.133 mol) was added slowly to the
reaction mixture. After the addition, the reaction mixture was stirred
for 2 h at -78 °C and the cold bath removed, allowing the reaction
to warm slowly to room temperature. Saturated aqueous ammonium
chloride (150 mL) was added to the reaction flask followed by 200
mL of ethyl acetate. The contents were then transferred to a 2 L
separatory funnel, and the layers were separated. The organic layer
was extracted with brine (50 mL) and dried over anhydrous MgSO4,
and after filtration, the solvents were evaporated under reduced
pressure to obtain a dark-yellow solid. Recrystallization from hot
hexanes afforded the desired carboxylic acid 13 (19.5 g, 78%) as
filtration, the solvents were evaporated under reduced pressure to
yield the acetylenic ketone 17 as yellow oil. The crude product
was purified by filtering through a plug of silica gel (9/1 hexanes/
ethyl acetate) to obtain 17 as a pale-yellow oil (21 g, 80%): 1H
NMR (400 MHz, CDCl3) δ 8.03 (d, J ) 1.9 Hz, 1H), 7.64 (dd, J
) 1.9, 8.3 Hz, 1H), 7.45 (d, J ) 8.3 Hz, 1H), 7.28 (m, 1H), 7.15
(m, 3H), 5.13 (q, J ) 7.08, 14.3 Hz, 1H), 4.09 (q, J ) 7.0 Hz,
2H), 3.97 (t, J ) 7.7 Hz, 1H), 3.2 (dd, J ) 7.3, 17.3 Hz, 1H), 3.0
(dd, J ) 8.0, 17.4 Hz, 1H), 2.35 (s, 3H), 1.47 (d, J ) 7.1 Hz, 3H),
0.88 (t, J ) 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.3,
171.2, 170.0, 138.6, 138.5, 136.2, 136.1, 133.2, 131.1, 130.6, 128.9,
128.8, 128.7, 128.4, 125.0, 94.2, 80.1, 69.5, 61.3, 49.5, 23.7, 21.4,
16.8, and 13.9; HRMS m/z calcd for C24H23O5Cl2 [M + H]+
461.0917, found 461.0905.
1
a white crystalline solid: mp 87-88 °C; H NMR (400 MHz,
(S,S)-3[5-(3,4-Dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyra-
zol-3-yl]-2-m-tolylpropanoic Acid 1-Ethoxycarbonylethyl Ester
(18). To a stirred solution of the acetylenic ketone 17 (15.5 g, 0.033
mol) in THF (150 mL) was added Cs2CO3 (12 g, 0.036 mol)
followed by 4-methoxyphenyl hydrazine HCl (6.5 g, 0.037 mol).
The slurry reaction mixture was stirred at room temperature
overnight then slowly quenched with 1 N HCl until pH 2-3. The
contents were transferred to a separatory funnel, and the layers were
separated. The aqueous layer was washed with ethyl acetate (3 ×
75 mL), and the combined organic layers were dried over anhydrous
Na2SO4, filtered, and concentrated to an oil. The crude oil was
purified by filtering through a plug of silica gel (8.5/1.5 hexanes/
ethyl acetate) to furnish a mixture of regioisomeric pyrazole esters
as a dark orange oil (18.6 g, 95%; 74% 1,5-regioisomer and 26%
CDCl3) δ 7.23 (m, 1H), 7.10 (m, 3H), 3.79 (t, J ) 7.96 Hz, 1H),
2.89 (ddd, J ) 2.56, 8.36, 19.38 Hz, 1H), 2.59 (ddd, J ) 2.60,
6.95, 23.79 Hz, 1H), 2.34 (s, 3H), 1.96 (t, J ) 2.54 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 178.3, 138.5, 136.7, 128.8, 128.7, 128.5,
124.9, 81.1, 70.1, 50.6, 22.5, and 21.4. Anal. Calcd for C12H13O2:
C, 76.57; H, 6.43. Found: C, 76.18; H, 6.82.
(S,S)-2-m-Tolylpent-4-ynoic Acid 1-Ethoxycarbonylethyl Es-
ter (16). A 500 mL, one-necked, round-bottomed flask equipped
with a magnetic stirring bar was charged the carboxylic acid (13,
13 g, 0.069 mol) and 100 mL of dichloromethane. To this solution
at room temperature was added 0.1 mL of DMF. Through a pressure
equalized addition funnel, 7.3 mL of oxalyl chloride was then added
in drops. After stirring at room temperature for 4 h, when a small
sample of the reaction mixture on quenching with methanol showed
complete formation of the methyl ester, the reaction mixture was
evaporated under reduced pressure to obtain the acid chloride 15
as a yellow oil. This crude acid chloride was dissolved in anhydrous
toluene (350 mL). Dimethylethylamine (22.3 mL, 0.207 mol) was
added, and the reaction mixture was stirred at room temperature.
After 30 min, the reaction mixture was cooled to -78 °C, and neat
ethyl lactate (8.6 mL, 0.075 mmol) was added. After 1 h, the cooling
bath was removed and allowed the reaction to slowly warm up to
room temperature. The reaction was quenched with 100 mL of
water, and the contents were transferred to a separatory funnel
washing the reaction flask with 100 mL of ethyl acetate. The layers
were separated, and the combined organic layers were washed with
water (3 × 100 mL) and dried over anhydrous MgSO4. After
filtration, the solvents were evaporated, and the crude product was
purified by filtering through a plug of silica gel (9/1 hexanes/ethyl
acetate) to furnish 17.8 g (90%) of the lactate ester 16 as a pale-
yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.20 (m, 1H), 7.09 (m,
3H), 5.16 (q, J ) 7.01, 14.40 Hz, 1H), 4.05 (q, J ) 7.0, 14.40 Hz,
2H), 3.82 (t, J ) 8.0 Hz, 1H), 2.90 (ddd, J ) 2.83, 8.0, 19.3 Hz,
1H), 2.61 (ddd, J ) 2.78, 7.0, 19.4 Hz, 1H), 2.34 (s, 3H), 1.97 (t,
J ) 2.53 Hz, 1H), 1.41 (d, J ) 7.0 Hz, 3H), 1.09 (t, J ) 7.33 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 171.8, 170.3, 138.2, 136.8,
128.7, 128.5,128.4, 125.0, 81.3, 70.0, 69.2, 61.2, 50.4, 23.1, 21.4,
16.9, and 13.9; HRMS m/z calcd for C17H21O4 [M + H]+ 289.1434,
found 289.1441.
(S,S)-6-(3,4-Dichlorophenyl)-6-oxo-2-m-tolylhexynoic Acid
1-Ethoxycarbonylethyl Ester (17). A 1 L, one-necked, round-
bottomed flask equipped with a magnetic stirring bar and nitrogen
inlet was charged sequentially with 3,4-dichlorobenzoyl chloride
(14.32 g, 0.684 mol) then acetylenic ester (16, 16.5 g, 0.057 mol)
in anhydrous THF (75 mL) and anhydrous toluene (75 mL).
Catalysts PdCl2(PPh3)2 (100 mg, 8.6 × 10-5 mol) and CuI (100
mg, 5.2 × 10-4 mol) were then added followed by N-methylmor-
pholine (15.0 mL, 0.138 mol). The reaction mixture was stirred at
room temperature for 14 h when TLC indicated almost complete
consumption of the starting material. The reaction was quenched
with water (100 mL) and ethyl acetate (100 mL), and the contents
were transferred to a separatory funnel. The layers were separated,
and the organic layer was washed with water (2 × 100 mL), brine
(1 × 50 mL), and then dried over anhydrous MgSO4. After
1
1,3-regioisomer based on H NMR). This regioisomeric mixture
was used in the next step with out any further purification. A small
sample of pure 18 was obtained by silica gel flash column
chromatography: 1H NMR (400 MHz, CDCl3) δ 7.32-7.13 (m,
8H), 6.85 (m, 3H), 6.23 (s, 1H), 5.10 (q, J ) 7.08, 14.3 Hz, 1H),
4.05 (m, 2H), 3.82 (s, 3H), 3.49 (dd, J ) 9.3, 14.7 Hz, 1H), 3.10
(dd, J ) 6.1, 14.7 Hz, 1H), 2.35 (s, 3H), 1.43 (d, J ) 7.04 Hz,
3H), 1.08 (t, J ) 7.08 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
172.8, 170.4, 159.0, 150.7, 140.9, 138.1, 138.0, 132.8, 132.6, 132.2,
130.6, 130.3, 130.2, 128.9, 128.4, 128.2, 127.7, 126.6, 125.1, 114.3,
107.3, 69.0, 61.2, 55.5, 51.1, 32.2, 21.5, 16.9, and 13.9; HRMS
m/z calcd for C31H31N2O5Cl2 [M + H]+ 581.1605, found 581.1617.
(S)-Sodium-3-[5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-
1H-pyrazol-3-yl]-2-m-tolyl Propionate (1). The crude lactate ester
(18 g, 74% 18) obtained as described above was dissolved in 150
mL of acetic acid. Hydrochloric acid (2 N, 25 mL) was added, and
the reaction mixture was stirred at 85 °C for 4 h when TLC showed
complete hydrolysis. After cooling to room temperature, the contents
were transferred to a separatory funnel and diluted with ethyl acetate
(250 mL) and water (50 mL). The layers were separated, and the
organic layer was washed with water (3 × 50 mL), brine, and dried
over anhydrous Na2SO4. After filtration, the solvents were evapo-
rated under reduced pressure to obtain a brown oil (15 g, 98%).
The crude acid was dissolved in THF (150 mL), and the solution
was cooled to 0 °C. Concentrated aqueous sodium hydroxide (1.26
g in 10 mL of water) was added, and the reaction mixture was
stirred for 2 h. The ice bath was removed, and after warming to
room temperature, the solvents were evaporated. The crude sodium
salt thus obtained was redissolved in anhydrous THF (100 mL),
and 100 mL of acetonitrile was added. On stirring at room
temperature, precipitation of the sodium salt began slowly. After 4
h, the mixture was filtered, washing the solids with 1:1 THF/
acetonitrile. The white solids were collected and dried under house
vacuum to obtain 10 g of the desired sodium salt 1 as white
crystalline solid (63% overall yield, 99.9% ee): mp 280-285 °C;
[R]20 +58.8° (c ) 0.1, EtOH).
589
Acknowledgment. We thank Dr. Guy Breitenbucher and
Dr. Mike Rabinowitz for helpful discussions. We also thank
Dr. Jiejun Wu and Ms. Heather McAllister for analytical support.
J. Org. Chem, Vol. 72, No. 22, 2007 8249

Liang et al.
Supporting Information Available: General experimental
procedures and details of the preparation of 1 by the first-generation
route are provided as supplemental information. Copies of 1H and
13C NMR spectra of all new, isolated compounds are also provided.
This material is available free of charge via Internet at http:
//pubs.acs.org.
JO071166M
8250 J. Org. Chem., Vol. 72, No. 22, 2007