Total synthesis of SR 121463 A, a highly potent and selective vasopressin V2 receptor antagonist

Article abstract of DOI:10.1021/jo0004658

SR 121463 A, 1, is a promising nonpeptide prototype for potent and selective antagonism of the vasopressin V₂ receptor subtype and, thus, a candidate for control of the clinically debilitating condition of hyponatremia and its associated syndromes. In the present work, we present a novel and stereoselective synthesis that stems from the preparation of three key intermediates: the substituted benzenesulfonyl chloride 2, the N-protected oxindole 3, and protected dibromide 4. The synthesis of 1 has been achieved in good overall yield, each step proceeding in greater than 80% yield. In addition, intermediate 2 and the syn isomer of 1 were prepared with complete control of stereochemistry. The latter reduction appears to proceed by lithium cation mediated chelation control. Molecular mechanics calculations with the MM3* and MMFF force fields underscore geometric and energetic aspects of the reaction.

Full text of DOI:10.1021/jo0004658

VOLUME 66, NUMBER 11
J UNE 1, 2001
© Copyright 2001 by the American Chemical Society
Articles
Tota l Syn th esis of SR 121463 A, a High ly P oten t a n d Selective
Va sop r essin V2 Recep tor An ta gon ist
Hariharan Venkatesan,*,† Matthew C. Davis, Yesim Altas, J ames P. Snyder, and
Dennis C. Liotta*
Department of Chemistry, Emory University, Atlanta, Georgia 30322
hvenkate@prius.jnj.com
Received March 28, 2000
SR 121463 A, 1, is a promising nonpeptide prototype for potent and selective antagonism of the
vasopressin V2 receptor subtype and, thus, a candidate for control of the clinically debilitating
condition of hyponatremia and its associated syndromes. In the present work, we present a novel
and stereoselective synthesis that stems from the preparation of three key intermediates: the
substituted benzenesulfonyl chloride 2, the N-protected oxindole 3, and protected dibromide 4. The
synthesis of 1 has been achieved in good overall yield, each step proceeding in greater than 80%
yield. In addition, intermediate 2 and the syn isomer of 1 were prepared with complete control of
stereochemistry. The latter reduction appears to proceed by lithium cation mediated chelation
control. Molecular mechanics calculations with the MM3* and MMFF force fields underscore
geometric and energetic aspects of the reaction.
In tr od u ction
Arginine vasopressin (AVP) is a cyclic nonapeptide
containing a disulfide linkage between cysteines at
position 1 and 6 and a three amino acid tail with arginine
at the 8 position.1 Several crucial physiological actions
for AVP have been identified. These actions are mediated
through three different receptor subtypes referred to as
V2, V1a, and V1b.2
† Current address: R. W. J ohnson Pharmaceutical Research Insti-
tute, 3210 Merryfield Row, San Diego, CA 92121
(1) (a) Albright, J . D.; Chan, P. S. Curr. Pharmaceutical. Design
1997, 3, 615. (b) Freidinger, R. M.; Pettibone, D. J . Med. Res. Rev.
1997, 17 (1), 1. (c) Laszlo, F. A.; Laszlo, F., J r.; DeWied, D. Pharmacol
Rev. 1991, 43, 73.
(2) (a) Thibonnier, M. Regulatory Pept. 1992, 38, 1 (b) Laszlo, F. A.;
Laszlo, F. J r. Drug News Perspectives 1993, 6, 591-599. (c) Kokko, J .
K.; Tannen, R. L. In Fluids and Electrolytes, 3rd ed.; 1996.
10.1021/jo0004658 CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/20/2001

3654 J . Org. Chem., Vol. 66, No. 11, 2001
Venkatesan et al.
In the kidney, the primary function of AVP is to
increase the water permeability of the luminal mem-
branes present in the collecting ducts, leading to water
reabsorption.3 The antidiuretic action of AVP is mediated
through specific binding of AVP to V2 receptors.4 Vaso-
pressin levels are found to be high for patients with
congestive heart failure, liver cirrhosis, central nervous
system injuries, and syndrome of the inappropriate
release of antidiuretic hormone (SIADH). The presence
of excess vasopressin leads to water retention. Typical
diuretic agents used to treat these diseases result in loss
of essential cations, such as sodium and potassium,
resulting in hyponatremia. It has been proposed that
compounds which specifically block the action of AVP on
V2 receptors may result in specific water excretion
without causing deleterious side effects sometimes as-
sociated with diuretic agents.5 Intensive research has
been carried out in the past several years to design
selective ligands for AVP receptors. Both peptide and
non-peptide analogues have been synthesized and evalu-
ated.6 SR 121463 A (1), a recently characterized V2
receptor antagonist that is orally active in the rat, was
reported to be more potent than the first reported
nonpeptidyl V2 antagonist, OPC-31260.6
efficacy of the newly designed and synthesized com-
pounds with a known standard, we chose to synthesize
the very selective V2 receptor antagonist SR 121463 A.
Although this interesting molecule has no stereogenic
centers, it embodies two important structural features:
the spiro cyclohexyl ring R to the carbonyl in the oxindole
ring, and the “syn” disposition of the ethoxy morpholino
group in the cyclohexane ring with respect to the carbonyl
group of the oxindole ring.
The synthesis reported in the patent literature lacks
details with respect to both experimental procedures and
yields.9 In that work, the oxindole ring was constructed
via a classical Fischer indole synthesis (Figure 1) using
two separately prepared precursors, A and B. In addition,
the conditions for the reaction were harsh, requiring high
temperature (180 °C). The morpholino group was intro-
duced via a two-step sequence involving reductive ring
opening of the ketal. Importantly, the selectivity achieved
in this process was not reported. Furthermore, the
synthesis involves a tedious separation of a mixture of
syn and anti isomers in the final step. We wish to report
herein a novel stereoselective approach to the total
synthesis of SR 121463 A (1) that circumvents these
problems.
Retr osyn th etic Str a tegy
A reasonable and efficient retrosynthetic disconnection
was devised as shown in Figure 2. Retrosynthetic cleav-
age of the SR 121463 A bonds highlighted in Figure 2
furnishes the substituted benzenesulfonyl chloride 2, the
N-protected oxindole 3, and a protected dibromide 4 as
the three key intermediates. The synthesis of oxindoles
has been studied extensively by several groups.10 Of the
available methods, we chose to employ the strategy of
C-H insertion into R-diazo keto esters.11 The spiro
cyclohexane was envisioned to be accessible by enolate
alkylation of the protected oxindole.
(6) (a)Yamamura, Y.; Ogawa, H.; Yamashita, H.; Chihara, T.;
Miyamoto, H.; Nakamura, S.; Onogawa, T.; Yamashita, T.; Hosokawa,
T.; Mori, T.; Tominaga, M.; Yabuuchi Y. Br. J . Pharmacol 1992, 105,
787. (b) Serradeil-Le Gal.; Lacour C.; Valette G.; Garcia G.; Foulon,
L.; Galindo, G.; Bankir, L.; Pouzet, B.; Guilon, G.; Barberis, C.; Chicot,
D.; J ard, S.; Vilain, P.; Garcia, C.; Marty, E.; Raufaste, D.; Brossard,
G.; Nisato, D.; Maffrand, J . P.; Le Fur, G. J . Clin. Invest. 1996, 98,
2729. (c) Albright, D. J .; Reich, M. F.; Delos Santos, E. G.; Dusza, J .
P.; Sum, F.-W.; Venkatesan, A. M.; Coupet, J .; Chan, P. S.; Ru, X.;
Mazandarani, H.; Bailey, T. J . Med. Chem. 1998, 41, 2442. (d) Tahara,
A.; Tomura, Y.; Wada, K.; Kusayama, T.; Tsukada, J .; Ishii, N.; Yatsu,
T.; Uchida, W.; Tanaka, A. Peptides 1998, 19 (4), 691. (e) Yamamura,
Y.; Nakamura, S.; Itoh, S.; Hirano, T.; Onogawa, T.; Yamashita, T.;
Yamada, Y.; Tsujimae, K.; Aoyama, M.; Kotosai, K.; Ogawa, H.;
Yamashita, H.; Kondo, K.; Tominaga, M.; Tsujimoto, G.; Mori, T. J .
Pharmacol. Exp. Ther. 1998, 287 (3), 860. (f) Ohtake, Y.; Naito, A.;
Hasegawa, H.; Kawano, K.; Morizono, D.; Taniguchi, M.; Tanaka, Y.;
Matsukawa, H.; Naito, K.; Oguma, T.; Ezure, Y.; Tsuriya, Y. Bioorg.
Med. Chem. 1999, 7, 1247.
(7) For a comprehensive treatment on the subject, see: 3D QSAR.
In Drug Design; Kubinyi, H., Folkers, G., Martin, Y. C., Eds.; Kluwer
Academic Publishers: Norwell, MA, 1998; Vol 1-3.
(8) (a) Vedani, A.; Zbinden, P.; Snyder, J . P.; Greenidge, P. A. J .
Am. Chem. Soc. 1995, 117, 4987. (b) Zbinden, P.; Dobler, M.; Folkers,
G.; Vedani, A. Quant. Struct-Act. Relat. 1998, 17, 122. (c) Wang, M.;
Xia, X.; Kim, Y.; Hwang, D.; J ansen, J . M.; Botta, M.; Liotta, D. C.;
Snyder, J . P. Organic Lett. 1999, 1, 43-46.
We have initiated a program directed at the discovery
of novel non-peptide V2 receptor antagonists using a
rational drug design approach.7 In brief, this approach
involves construction of a minireceptor (a 3-D mimic of
the binding site), development of a quantitative correla-
tion between experimental and calculated Kis (and the
associated ∆Gs), and predictions of binding constants for
novel candidate antagonists.8 To compare the in vitro
(3) Morel, F., M. Imbert-Teboul, Charbardes, D. Kidney Int. 1987,
31, 512.
(4) (a) Mah, S. C.; Hofbauer, K. G. Drugs Future 1987, 12, 1055. (b)
Manning, M., Sawyer, W. H. J . Lab. Clin. Med. 1989, 114, 617. (c)
Sorensen, J . B.; Andersen, M. K.; Hansen, H. H. J . Int. Med. 1995,
238 97. (d) Goldsmith, S. R.; Dodge-Brown, D. L.; Katz, A. J .
Cardiovasc. Pharmacol. 1989, 14, 425. (e) Gavras, H. Clin. Chem. 1991,
37, 10(B), 1828.
(9) Foulon, L.; Garcia, G.; Serradeil-Le Gal, C.; Valette, G. WO
9715556, J an 5, 1997.
(10) Comprehensive Heterocyclic Chemistry; Sundberg, R. J ., Bird,
C. W., Cheeseman, G. W., Eds.; Pergamon Press: Oxford, 1984; Vol.
4, p 313.
(5) (a) Zerbe, R.; Stropes, L.; Robertson, G. Annu. Rev. Med. 1980,
31, 315. (b) Huffman, W. F.; Kinter, L. B.; Moore, M. L.; Stassen, F. L.
Ann. Rep. Med. Chem. 1988, 23, 91. (c) Verbalis, J . G. Trends
Endocrinol. Metab. 1992, 3, 1.
(11) (a) Doyle, M. P.; Shanklin, M. S.; Pho, Hoan, Q.; Mahapatro,
S. N. J . Org. Chem. 1988, 53, 1017. (b) EtKin, N.; Babu, S. D.; Fooks,
C. J .; Durst, T. J . Org. Chem. 1990, 55, 1093. (c) Liu, B.; Wee, A. G.
Heterocycles 1993, 36 (3) 445.

Total Synthesis of SR 121463
J . Org. Chem., Vol. 66, No. 11, 2001 3655
F igu r e 1. Patented synthesis of SR 121463 A, 1.
F igu r e 2. Retrosynthetic analysis of SR 121463 A; PG ) protecting group.
Hydrolysis of the spirane ketal and subsequent reduc-
tion of the corresponding ketone should provide access
to an alcohol, which can be alkylated with 2-chloroeth-
ylmorpholine. We expected that intermediate 2 could be
synthesized in a regioselective manner by allowing
4-chloro-3-methoxy-sulfonylbenzoyl chloride12 to react
with tert-butylamine.
(12) Fedyunyaeva, I. A.; Shershukov, V. M. Chem. Heterocycl.
Compd. (Engl. Transl.) 1993, 29 (2), 204.

3656 J . Org. Chem., Vol. 66, No. 11, 2001
Venkatesan et al.
Sch em e 1a
Sch em e 3a
a
(a) Ti(iPrO)4, EtMgBr; (b) NBS, CCl4; (c) ethylene glycol, PPTS,
HC(OEt)3.
Sch em e 4a
a
(a) PhCHO, EtOH; (b) NaBH4, MeOH; (c) ClCOCH2COOMe,
Et3N, CH2Cl2; (d) MeSO2N3, Et3N; (e) Nafion H.
Sch em e 2a
a
(a) H2SO4, 3% SO3; (b) KOH, Me2SO4; (c) PCl5; (d) Et3N,
a
tBuNH2.
(a) Diketene, Et3N, THF; (b) MeSO2N3, Et3N, THF; (c) KOH,
CH3CN; (d) Rh2OAc4, CH2Cl2.
ously. Great care had to be taken in monitoring the
course of the reaction, which proceeded most effectively
when the reagents were added 5 times in succession with
a 0.5 h interval between each addition. We have repro-
duced this reaction on a 20-g scale without observing
other products.
Treatment of potassium salt 16 with PCl5 yielded
4-chlorosulfonyl-3-methoxybenzoyl chloride 17 in good
overall yield (40%). As expected, treatment of the dichlo-
ride with Et3N and tert-butylamine at -78 °C and slow
warming to room temperature produced 2 in good yield
(80%). It is important to note that selective addition to
the carbonyl chloride was achieved.
Syn th esis of th e In ter m ed ia tes
Recently it was reported that Nafion-H, a perfluori-
nated ion-exchange resin, could efficiently catalyze de-
carboxylative cyclization of R-carbomethoxy-R-diazoacet-
anilides.11 We investigated this method for the construc-
tion of the protected oxindole intermediate as shown in
Scheme 1. Reductive amination of p-phenetidine with
benzaldehyde yielded 6 (95%). Treatment of 6 with
methylmalonyl chloride, followed by diazo transfer with
mesyl azide, yielded 7 (90%). However, much to our
disappointment, the key reaction involving decarboxyla-
tive cyclization using Nafion H proceeded in only 20-
30% yield. Substituting H for the carbomethoxy group
in 7 circumvented this problem.
Con ver gen t Syn th esis of 1
Compound 10 could easily be prepared using Doyle’s
procedure (Scheme 2).11a Thus, treatment of N-benzyl-
p-phenetidine with diketene, followed by diazo transfer
using methanesulfonyl azide and subsequent deacylation
using KOH, resulted in the cyclization substrate 10.
Rhodium(II) acetate catalyzed decomposition of the diazo
compound furnished the desired N-benzyl-protected ox-
indole 8 in high overall yield (70%).
Having completed the syntheses of the three inter-
mediates, the final operations to complete the molecular
skeleton of SR 121463 A were undertaken. Treatment of
the N-protected oxindole 8 with 2 equiv of LHMDS and
1 equiv of dibromide 4, either in the presence or absence
of HMPA, did not produce the spiro derivative in accept-
able yields. Instead, difficultly separated mixtures of 18,
the monoalkylated species, and other products were
obtained. However, treatment of 8 with 4 equiv of NaH
and 1.5 equiv of the dibromide in DME furnished the
desired spiro compound 18 in excellent yield (90%,
Scheme 5).
Parallel with this, the protected dibromide was easily
assembled using an established procedure in good overall
yield (Scheme 3).1
Synthesis of the substituted sulfonyl chloride moiety
2 commenced with m-hydroxybenzoic acid 14 (Scheme
4).14 Sulfonylation using sulfuric acid containing 3% SO3
proceeded smoothly to furnish the benzenesulfonic acid
derivative 15. Selective methylation of the phenoxyl
group using KOH and Me2SO4 yielded the potassium salt
of 4-sulfo-3-methoxybenzoic acid, 16. The methylation
reaction proved to be more difficult than reported previ-
(13) (a) Sviridov, S. V.; Vasilevskii, D. A.; Kulinkovich, O. G. J . Org.
Chem. USSR (Engl. Transl.) 1991, 27(7), 1251; Kulinkovich, O. G.;
Sviridov, S. V.; Vasilevskii, D. A.; Synthesis 1991, 234. (b) Gleiter, R.;
Ramming, M.; Weigl, H.; Wolfart, V.; Irngartunger, H.; Oeser, T.
Liebigs Ann./ Recueil 1997, 1545.
(14) Shah, M. S. J . Chem. Soc. 1930, 1293.

Total Synthesis of SR 121463
J . Org. Chem., Vol. 66, No. 11, 2001 3657
Sch em e 5a
a
(a) NaH, DME, then 4; (b) PPTS, acetone/H2O; (c) NaBH4, MeOH; (d) NaH, toluene, 2-chloroethylmorpholine, 100 °C; (e) Li/NH3, -78
°C; (f) KOtBu, then 2.
Sch em e 6a
2. Although the transformation was efficient, separation
of the syn and anti isomers proved to be tedious and time-
consuming. Nevertheless, SR 121463 A was isolated in
50% yield. The anti isomer was also isolated in 25% yield.
To improve selectivity in the overall process, we
reinvestigated the crucial reduction step in the synthesis
(19 f 20). The use of NaBH4/LiBr, LiAlH4, and N-
Selectride led to selectivities of 3:1, 4:1, and 4:1, respec-
tively, in favor of the syn isomer. Even better, we
succeeded in synthesizing the syn isomer 24 selectively
(66:1) in good yield (85%) when L-Selectride was used
as the reducing agent (Scheme 6). Clearly, both the bulky
selectride reagent and the Li cation combine to effect the
larger stereoselective outcome. Addition of the mor-
pholino moiety, deprotection of the benzyl group without
oxindole reduction to give 26, and subsequent coupling
with the sulfonyl chloride as before yielded SR 121463 A
in good overall yield.
a
(a) L-Selectride, THF, -78 °C; (b) NaH, toluene, 2-chloro-
ethylmorpholine; (c) Li, NH3, -78 °C; (d) KOtBu, then 2.
Regiosp ecific L-Selectr id e Red u ction of 19 to 24
While 13C NMR indicated the presence of a single
isomer from the L-Selectride reduction of 19, definitive
Deprotection of the ketal with PPTS and subsequent
reduction of the ketone 19 with NaBH4 yielded the
alcohol 20 as a 2:1 mixture of syn and anti isomers (90%).
Exposure of the alcohol to NaH in toluene at 100 °C for
1.5 h, followed by the treatment with freshly distilled
2-chloroethylmorpholine15 and refluxing for 14 h, resulted
in the desired product 21 in 80% yield. Deprotection of
the N-benzyl group in 21 proved to be more difficult than
anticipated. Standard catalytic hydrogenolysis conditions
at 40 or 80 psi of H2 or heating with ammonium formate
or cyclohexadiene in the presence of Pd/C resulted in
complete recovery of the starting material. However,
treatment of 21 with 4-5 equiv of Li/NH3 furnished the
deprotected compound 22 in excellent yield (90%).16 The
final step in the total synthesis was accomplished easily
by treatment of 22 with t-BuOK and the sulfonyl chloride
proof that it was the desired syn epimer 24 was obtained
from X-ray crystallography. The substance crystallizes
in the alternative chair cyclohexane conformation and,
surprisingly, the OH group is axial, 24′.
The latter can be understood by an examination of
nonbonded interactions in the solid state. Figure 3
illustrates that two symmetry-related intermolecular
(15) Mason, j. P.; Block, H. W. J . Am. Chem. Soc. 1940, 62, 1443.
(16) Webster, F. X.; Millar, J . G.; Silverstein, R. M. Tetrahedron Lett.
1986, 27 (41), 4941.

3658 J . Org. Chem., Vol. 66, No. 11, 2001
Venkatesan et al.
F igu r e 4. Oxindole 19/19′ with the cyclohexanone ring in a
twist-boat conformation, 28. Both the cyclohexanone and the
amide CdO moieties are coordinated to a tetrahedral lithium
cation further coordinated by two molecules of tetrahydrofuran
solvent. Shaded atoms are oxygen and nitrogen.
F igu r e 3. The pairwise intermolecular hydrogen bonds
between C2 dimers of axial 24′ found in the solid state.
the ketone and amide carbonyl groups, capturing the
cyclohexanone in a twist-boat conformation. The latter
is only 2.7 kcal/mol above the chair conformer, while the
activation barrier for inversion is 4.0 kcal/mol.21 Both
values are considerably lower than for cyclohexane.
The situation is reminiscent of many reported cases
of stereocontrol promoted by cationic coordination.22
Complex 28 not only presents the appropriate ring face
to the reducing agent but also establishes a highly
polarized carbonyl group to facilitate rapid reduction.
Mediation of the reaction by such a complex likewise
explains why LiAlH4, but not NaBH4, shows selectivity.
To verify that complex 28 is energetically reasonable,
we subjected ligand 19 to MacroModel calculations in
which the methylammonium cation (CH3NH3+) serves as
a surrogate for Li+. The cation substitution was neces-
sitated by the lack of Li+ parameters in the MM3* and
MMFF force fields. Optimizations were performed on
chelated structures virtually identical in geometry to 28
(i.e. 29) and on 19 hydrogen bonded to CH3NH3+ through
the amide carbonyl (30) (cf. Figure 5). With the MM3*/
GBSA/CHCl3 and MMFF/GBSA/CHCl3 protocols (the
CHCl3 continuum model used as a THF replacement and
a charge damping factor), complex 29 is more stable than
hydrogen bonds between the amide carbonyl and the
axial OH link pairs of molecules of 24′ in the crystal. The
observation is compatible with A-value determinations
for cyclohexanol and substituted cyclohexyl ethers and
acetates. In solution the axial isomers are less stable than
the equatorial forms by only ∆G ) 0.5-1.0 kcal/mol,
corresponding to axial populations of 15-30%.18 In
reasonable accord, the MM3* and MMFF force fields
implemented in MacroModel19 posit axial-24′ to be less
stable than 24 by 2.0 and 1.1 kcal/mol, respectively. All
things considered, the solid state H-bonds are clearly
more than sufficient to override the 1,3-diaxial inter-
actions in the cyclohexane portion of 24′.
What remains unexplained is the unusual improve-
ment in the stereoselectivity of 24 relative to 27 as the
reducing agent is varied from NaBH4 to LiAlH4 and then
to L-Selectride (LiBH(sec-Bu)3). The latter is known to
reduce cyclohexanones by approaching from the less
hindered equatorial face of the ring.20 Were conforma-
tions 19 and 19′ attacked from this face, compounds 27
and 24/24′ would result, respectively. Given that the
three sec-butyl groups on boron are undoubtedly distant
from the oxindole rings in CdO-localized transition states
stemming from 19 or 19′, the origin of the observed
selectivity must arise from a source unrelated to the bulk
of the sec-butyl substitutents. One possibility is that
conformer 19′ is considerably more stable than 19 and
thereby competes effectively with the reducing agent to
give 24/24′. This would not, of course, explain why 19′
would not be equally effective at interacting with LiAlH4
and NaBH4. Indeed, MM3* and MMFF optimizations for
19 and 19′ suggest the latter to be less stable than the
former by 2.3 and 2.6 kcal/mol, respectively. Thus, if
relative conformational stability were operating as the
guide to product, the anti-epimer 27, not 24/24′, is
expected to be the reduction product.
+
30 by 3.7 and 6.7 kcal/mol, respectively. When CH3NH3
is placed at the cyclohexanone carbonyl, the system is
competitive with the chelated species 29; i.e. -0.6 and
1.6 kcal/mol for MM3* and MMFF, respectively. We
believe these values to be on the order of magnitude that
Li+ stabilizes 28 relative to single-center coordination
alternatives. Complex 28 thus serves as both a geometric
and energetic model to explain the advantageous regio-
selectivity of L-Selectride reduction of 19.
Con clu sion
The synthesis of SR 121463 A has been achieved in
good overall yield. Although the number of steps em-
ployed is large, the yield in each step in the total
synthesis is greater than 80%. The construction of the
spiro ring does not require harsh conditions. Intermediate
We propose that syn-alcohol 24/24′ arises from pre-
organization of 19 to give 28 as pictured in Figure 4. The
powerful lithium cation Lewis acid coordinates to both
(17) Taber, D. F.; Ruckle, J r. R. E.; Hennessy, M. J . J . Org. Chem.
1986, 51, 4077.
(18) Eliel, E. L.; Wilen, S. H., Eds. Stereochemistry of Organic
Compounds; J ohn Wiley & Sons: New York, 1994; pp 696.
(19) Mohamadi, F.; Richards, N. G. J .; Guida, W. C.; Liskamp, R.;
Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J .
Comput. Chem. 1990, 11, 440; cf. http://www.schrodinger.com/
macromodel2.html.
(20) Brown, H. C.; Krishnamurthy, S. J . Am. Chem. Soc. 1972, 94,
7159; Krishnamurthy, S.; Brown, H. C.. J . Am. Chem. Soc. 1976, 98,
3383.
(21) Anet, F. A. L.; Chmurny, G. N.; Krane, J . J . Am. Chem. Soc.
1973, 95, 4423.
(22) (a) Weisenburger, G. A.; Faibish, N. C.; Pippel, D. J .; Beak P.
J . Am. Chem. Soc. 1999, 121, 9522; Anderson, D. R.; Faibish, N. C.
Beak, P. J . Am. Chem. Soc. 1999, 121, 7553 and references therein.
(b) Snieckus, V. Chem. Rev. 1990, 90, 879. (c) Beak, P.; Basu, A.;
Gallagher, D. J .; Park, Y. S.; Thayumanayan, S. Acc. Chem. Res. 1996,
29, 552. (d) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. Engl. 1997,
36, 2282.

Total Synthesis of SR 121463
J . Org. Chem., Vol. 66, No. 11, 2001 3659
1
and recrystallized from H2O (29.36 g, 79%): mp >250 °C; H
NMR (DMSO-d6, 400 MHz) δ 10.5 (s, 1H), 7.58 (d, J ) 8.2 Hz,
1H), 7.4 (d, J ) 6.9 Hz, 1H), 7.3 (s, 1H), 3.85 (s, 1H); 13C NMR
(DMSO-d6, 100 MHz) δ 166.98, 153.38, 134.56, 133.36, 127.77,
119.80, 117.56. Anal. Calcd for C7H5O6K‚H2O: C, 30.65; H,
2.55; S, 11.68. Found: C, 31.09; H, 2.51; S, 11.9.
P otassiu m Hydr ogen 4-Su lfo-3-m eth oxyben zoate Mon o-
h yd r a te (16). To a magnetically stirred solution of 15 (27.61
g, 100 mmol) in H2O (61 mL) was added KOH (11.2 g, 200
mmol) in H2O (10 mL) with vigorous stirring, followed by
dimethyl sulfate (9.47 mL, 100 mmol), and the mixture stirred
for 20 min. The sequence was repeated four times, after which
the reaction was heated to 80 °C for 10 min. The reaction was
cooled to room temperature., neutralized with concentrated
H2SO4, and finally acidified to pH 1 with concentrated HCl.
Upon standing, the title compound precipitated and was
filtered (12.75 g, 44%): mp >250 °C; 1H NMR (DMSO-d6, 400
MHz) δ 7.8 (d, J ) 8.25 Hz, 1H), 7.49 (m, 2H), 3.82 (s, 3H),
3.7 (bs, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 167.13, 156.23,
139.03, 132.95, 128.91, 120.74, 112.34, 55.83. Anal. Calcd for
C8H7O6SK‚H2O: C, 33.33; H, 3.12. Found: C, 33.29; H, 3.16
4-Ch lor osu lfon yl-3-m eth oxyben zoyl Ch lor id e (17). A
mixture of 16 (11.75 g, 40 mmol) and phosphorus pentachloride
(27 g, 131 mmol) were heated for 1 h at 80 °C, after which all
solid dissolved. The mixture was cooled to room temperature
and 50 mL of ice and water was added. The title compound
was filtered, dried, and recrystallized from CCl4 (10.5 g,
96%): mp 85 °C; 1H NMR (CDCl3, 400 MHz) δ 8.1 (d, J ) 8.5
Hz, 1H), 7.85 (dd, J ) 1.7 Hz, 8.3 Hz, 1H), 7.8 (s, 1H), 4.17 (s,
3H); 13C NMR (CDCl3, 100 MHz) δ 167.41, 157.44, 140.29,
136.68, 130.49, 122.98, 115.08, 57.38. Anal. Calcd for C8H6O4-
SCl2: C, 35.82; H, 2.24; Cl, 26.12. Found: C, 35.53; H, 2.24;
Cl, 26.38.
4-Ch lor osu lfon yl-3-m et h oxy-ter t-b u t yla m in ob en za -
m id e (2). To a stirred solution of 17 (1 g, 3.7 mmol) and
triethylamine (0.52 g, 3.7 mmol) in CH2Cl2 (5 mL) cooled to
-78 °C was added dropwise tert-butylamine (0.27 g, 3.7 mmol).
The reaction was allowed to warm to room temperature over
1 h and then poured into 10 mL of ice water. The organic layer
was separated and the aqueous phase extracted with CH2Cl2
(3 × 4 mL). The combined organic phases were dried (MgSO4)
and evaporated in vacuo to a white solid. The solid was
chromatographed (CH2Cl2) to obtain the title compound (0.85
g, 75%): mp 150-3 °C (CH2Cl2/CCl4); 1H NMR (CDCl3, 400
MHz) δ 7.94, (d, J ) 8.1 Hz, 1H), 7.59 (s, 1H), 7.23 (dd, J )
1.4 Hz, 8.0 Hz, 1H), 6.05 (bs, 1H), 4.1 (s, 3H), 1.5 (s, 9H); 13C
NMR (CDCl3, 100 MHz) δ 164.8, 157.75, 144.35, 133.49, 130.1,
117.3, 112.99, 57.11, 52.58, 28.88. Anal. Calcd for C12H16NO4-
SCl: C, 47.21; H, 5.25; N, 4.56. Found: C, 47.17; H, 5.31; N,
4.51.
F igu r e 5. Oxindole 19 coordinated to CH3NH3+ by chelation
of the two carbonyl groups (29) and by hydrogen bonding to
the amide carbonyl group alone (30); MM3* optimized struc-
tures. Shaded atoms are oxygen and nitrogen.
2 was synthesized in only four steps using simple, cheap
reagents with complete control of regioselectivity. In
addition, the selective formation of the syn isomer of 1
via 24 was achieved. This avoids the necessity of a
tedious separation of a mixture of isomers as reported
in the patent literature. This strategy can potentially be
employed to construct other analogues in a general
manner.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were determined using
a Thomas-Hoover capillary melting point apparatus and are
reported uncorrected. Proton and carbon NMR spectra were
obtained on General Electric QE-300 (300 MHz) or Varian
Inova-400 (400 MHz) spectrometers. Single-crystal X-ray
analysis for compound 24 was carried out with a Siemens
P4RA automated diffractometer with a rotating-anode Cu
X-ray source, FRS scintillation and Hi-Star area detectors, and
an LT-2 low-temperature system.
TLC was performed on precoated, glass-backed plates (silica
gel 60 F254; 0.25-mm thickness) from EM Science and was
visualized by UV lamp. Chromatography was performed with
silica gel 60 (230-400 mesh ASTM) from EM Science using
the “flash” method. Atlantic Microlab Inc. Norcross, Georgia
performed elemental analyses. All solvents and reagents were
purchased from Aldrich Chemical Co., Milwaukee. The sol-
vents were either dried with molecular sieves (4A) or distilled
before use. The reagents were used as received. Methanesulfo-
nyl azide17 and 413 were prepared by published procedures.
CAUTION: Working with mesyl azide is extremely danger-
ous. Distillation of up to 25 mL of the compound was routinely
carried out behind a blast shield. All reactions were performed
under anhydrous nitrogen atmosphere in oven-dried glass-
ware.
N-Ben zyl-4-eth oxya n ilin e (6). To a magnetically stirred
solution of 5 (16 g, 116 mmol) in 200 mL of MeOH at room
temperature was added dropwise benzaldehyde (11.85 mL, 116
mmol) over 0.5 h. The mixture was heated to reflux for 2 min.
After cooling to room temperature NaBH4 (4.8 g, 127 mmol)
was added in portions with vigorous stirring over 1 h. The
reaction was stirred for another 2 h and then quenched with
H2O (200 mL). After 0.5 h the title compound precipitated and
was filtered and dried (23.31 g, 97%): mp 44-6 °C (hexanes/
1
EtOAc); H NMR (CDCl3, 400 MHz) δ 7.3-7.2 (m, 5H), 6.77
(d, J ) 9.2 Hz, 2H), 6.61 (d, J ) 8.9 Hz, 2H), 4.28 (s, 2H), 3.95
(q, J ) 7 Hz, 2H), 1.37 (t, J ) 7 Hz, 3H); 13C NMR (CDCl3,
100 MHz) δ 151.65, 142.56, 139.85, 128.77, 127.75, 127.35,
115.93, 114.29, 64.27, 49.44, 15.22. Anal. Calcd for C15H17
-
P otassiu m Hydr ogen 4-Su lfo-3-h ydr oxyben zoate Mon o-
h yd r a te (15). To a magnetically stirred solution of 14 (20 g,
145 mmol) in concentrated H2SO4 (27 mL) heated to 90 °C was
added dropwise 30% SO3 in concentrated H2SO4 (3 mL). After
12 h of stirring, a precipitate formed and stirring became
difficult. The mixture was heated at 90 °C further while
mechanically stirred for another 1 h. The reaction was then
cooled to room temperature and H2O (100 mL) was added to
dissolve the reaction mixture. The mixture was stirred while
25% KOH (32.5 mL) was added dropwise. The resulting
precipitate of the title compound was collected by filtration
NO: C, 79.30; H, 7.49; N, 6.17. Found: C, 79.31; H, 7.57; N,
6.08.
N -Be n zyl-N -(4-e t h oxyp h e n yl)-2-d ia zo-3-oxob u t a n a -
m id e (9). To a magnetically stirred solution of 6 (10 g, 44
mmol) in THF (25 mL) at room temperature. was added
dropwise diketene (4.07 mL, 52.8 mmol) over 1 h. The reaction
was then heated to reflux for 0.5 h, after which diketene (0.5
mL, 6.5 mmol) was added again and the reaction was refluxed
for 1 h. The reaction was cooled and an additional 0.5 mL (6.5
mmol) of diketene was added and the reaction was heated to
reflux for 4 h. After this time no 9 was present by TLC (CH2-

3660 J . Org. Chem., Vol. 66, No. 11, 2001
Venkatesan et al.
Cl2/MeOH). The reaction was cooled, and the volatiles were
evaporated in vacuo. The remaining thick brown oil was
dissolved in 25 mL of acetonitrile, and triethylamine (6.4 mL,
46 mmol) was added. To this mixture at room temperature
was added dropwise methanesulfonyl azide (7.05 g, 58 mmol)
dissolved in 20 mL of acetonitrile over 1 h. After stirring for
12 h, the volatiles were evaporated in vacuo and the remaining
residue was partitioned between H2O and Et2O. The organic
phase was separated, dried (MgSO4), and evaporated in vacuo.
The remaining oil was subjected to chromatography to obtain
the title compound as a yellow oil (13.75 g, 93%) that slowly
crystallized on standing: mp 54-6 °C (hexanes/Et2O); 1H NMR
(CDCl3, 400 MHz) δ 7.3-7.1 (m, 5H), 6.92 (d, J ) 9.2 Hz, 2H),
6.81 (d, J ) 8.9 Hz, 2H), 4.92 (s, 2H), 3.95 (q, J ) 7 Hz, 2H),
2.55 (s, 3H), 1.41 (t, J ) 7 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
δ 192.32, 161.21, 159.07, 137.06, 133.75, 129.16, 128.98, 128.7,
127.83, 115.83, 63.99, 54.25, 28.98, 14.87. Anal. Calcd for
acetone was refluxed for 20 h, after which time no ketal
remained by TLC (CH2Cl2/MeOH). The mixture was cooled,
evaporated in vacuo, and subjected to chromatography to
obtain the title compound (3.7 g, 90%) as a pale brown oil that
1
slowly crystallized: mp 125-8 °C (hexanes/EtOAc); H NMR
(CDCl3, 400 MHz) δ 7.35-7.2 (m, 5H), 6.85 (d, J ) 2.5 Hz,
1H), 6.69 (d, J ) 8.6 Hz, 2H), 6.64 (d, J ) 8.6 Hz, 1H), 4.9 (s,
2H), 3.95 (q, J ) 7 Hz, 2H), 3.26-3.18 (m, 2H), 2.95-2.55 (m,
2H), 2.25-2.12 (m, 4H), 1.4 (t, J ) 7 Hz, 3H); 13C NMR (CDCl3,
100 MHz) δ 210.92, 179.2, 155.55, 136.1, 135.38, 134.67,
129.06, 127.87, 127.32, 112.79, 111.34, 109.84, 64.31, 46.08,
43.75, 37.13, 33.99, 15.08. Anal. Calcd for C22H23NO3: C, 75.64;
H, 6.59; N, 4.01. Found: C, 75.36; H, 6.63; N, 3.95.
1′-Ben zyl-5′-eth oxy-4-h yd r oxysp ir o[cycloh exa n e-1,3′-
in d olin ]-2′-on e (24). To a magnetically stirred solution of 19
(415 mg, 1.2 mmol) dissolved in 5 mL of THF at -78 °C was
added dropwise 1 M L-Selectride (1.78 mL, 1.8 mmol) in THF
over 1 h. The reaction was stirred at -78 °C for an additional
2 h and then 0.2 mL of H2O was added. The volatiles were
removed in vacuo, and the residue partitioned between H2O
and CH2Cl2. The organic layer was separated, dried (Na2SO4),
and evaporated in vacuo. 1H NMR analysis demonstrated a
66:1 ratio of syn and anti alcohols. Chromatography afforded
the title compound as a colorless oil (0.38 g, 90%) that slowly
crystallized: mp 125-7 °C (hexanes/EtOAc); 1H NMR (CDCl3,
400 MHz) δ 7.2-7.3 (m, 5H), 6.85 (d, J ) 2.4 Hz, 1H), 6.65
(dd, J ) 2.4 Hz, 8.4 Hz, 1H), 6.55 (d, J ) 8.4 Hz, 1H), 4.85 (s,
2H), 3.95 (q, J ) 6.8 Hz, 2H), 3.9 (m, 1H), 2.3-2.1 (m, 3H),
2.1-1.9 (m, 3H), 1.8-1.6 (m, 2H), 1.4 (t, J ) 6.8 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) δ 179.72, 155.04, 135.89, 128.96,
127.69, 127.32, 112.27, 111.42, 109.38, 69.28, 64.26, 46.33,
43.58, 31.52, 29.96, 15.12. Anal. Calcd for C22H25NO3: C, 75.21;
H, 7.12; N, 3.99. Found: C, 75.35; H, 7.25; N, 3.98.
Other carbonyl reducing agents were employed as follows:
A solution of 19 (140 mg, 0.4 mmol) in 5 mL of absolute EtOH
at 0 °C was treated with solid NaBH4 (23.3 mg, 0.6 mmol).
After 1 h the reaction was warmed at room temperature and
the solvent evaporated. The residue was partitioned between
EtOAc and H2O. The aqueous layer was extracted with EtOAc
(2 × 10 mL). The combined organic layers were washed with
brine and dried with Na2SO4, and the solvent was evaporated.
The product was purified with flash chromatography using
EtOAc/hexane (2:3). A final purification with EtOAc/hexane
(3:2) gave the diastereomeric mixture of 24 (2:1 syn:anti by
NMR).
C
19H19N3O3: C, 67.66; H, 5.64; N, 12.46. Found: C, 67.72; H,
5.73; N, 12.41.
N-Ben zyl-N-(4-eth oxyp h en yl)d ia zoa ceta m id e (10). To
a
magnetically stirred solution of 9 (13.75 g, 41 mmol)
dissolved in 40 mL of acetonitrile at room temperature was
added dropwise 16% KOH (30 mL) over 1 h. Stirring was
continued for another 12 h, after which the reaction was
complete by TLC. The volatiles were evaporated in vacuo, and
the remaining residue was partitioned between Et2O and H2O.
The organic phase was separated, dried (MgSO4), and evapo-
rated in vacuo to an orange oil. Chromatography yielded the
title compound as a yellow oil (10.06 g, 84%) that slowly
1
crystallized: mp 49-52 °C (hexanes/Et2O); H NMR (CDCl3,
400 MHz) δ 7.3-7.19 (m, 5H), 6.89 (d, J ) 8.8 Hz, 2H), 6.79
(d, J ) 8.9 Hz, 2H), 4.87 (s, 2H), 4.44 (s, 1H), 3.9 (q, J ) 7 Hz,
2H), 1.4 (t, J ) 7 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 166.4,
158.75, 137.85, 134.01, 129.84, 129.0, 128.58, 127.54, 115.34,
63.88, 53.21, 47.4, 14.97. Anal. Calcd for C17H17N3O2: C, 69.15;
H, 5.76; N, 14.24. Found: C, 69.31; H, 5.87; N, 14.15.
1-Ben zyl-5-et h oxy-2-in d olin on e (8). To a magnetically
stirred solution of rhodium(II) acetate dimer (95.5 mg, 0.2
mmol) in 127 mL of CH2Cl2 at room temperature. was added
dropwise over 1 h a solution of 10 (7.5 g, 25.5 mmol) in 20 mL
of CH2Cl2. The evolution of N2 gradually occurred and the
reaction was stirred for 12 h. The reaction was filtered through
neutral Al2O3 (5 g), then solvent was evaporated in vacuo,
leaving a yellow solid. A single recrystallization (hexanes/
1
EtOAc) furnished 8 (5.96 g, 88%): mp 108-11 °C; H NMR
(CDCl3, 400 MHz) δ 7.35-7.2 (m, 5H), 6.87 (s, 1H), 6.68 (d, J
) 8.8 Hz, 1H), 6.58 (d, J ) 8.6 Hz, 1H), 4.89 (s, 2H), 3.95 (q,
J ) 7 Hz, 2H), 3.6 (s, 2H), 1.37 (t, J ) 7 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 175.00, 155.30, 137.92, 136.14, 128.93,
127.75, 127.52, 125.91, 113.15, 112.70, 109.53, 64.28, 44.01,
36.37, 15.09. Anal. Calcd for C17H17NO2: C, 76.4; H, 6.37; N,
5.24. Found: C, 76.45; H, 6.41; N, 5.17.
Compound 19 (414 mg, 1.2 mmol) was dissolved in 10 mL
of absolute EtOH, and a solution of LiBr in 5 mL of absolute
EtOH (161 mg, 1.2 mmol) was added. After cooling at 0 °C,
solid NaBH4 (70 mg, 1.2 mmol) was added in portions with
vigorous stirring over 1 h. The reaction was stirred for another
2 h at room temperature and then quenched with 15 mL of
H2O. The volatiles were removed in vacuo, and the residue
was partitioned between EtOAc and H2O. The aqueous layer
was extracted with EtOAc (2 × 20 mL). The combined organic
layers were washed with brine, dried with Na2SO4, and
evaporated. The mixture was purified by flash chromatography
as for NaBH4 above to give a 3:1 syn:anti diastereomeric
mixture of 24 (by NMR).
Compound 19 (100 mg, 0.3 mmol) in 2.0 mL of THF at 0 °C
was treated with LiAlH4 (3 mg, 0.3 equiv) in THF. After 5 min,
an additional 3 mg of reducing agent was added. The reaction
was stirred at 0 °C for 1 h, followed by quenching with 3 drops
of saturated NH4Cl. The latter was extracted with CH2Cl2. The
dried organic layer was subjected to GCMS analysis to reveal
two peaks of MW 351 in a ratio of 3:1.
Compound 19 (140 mg, 0.4 mmol) in 2.5 mL of THF at -78
°C was treated with 1M N-Selectride (0.6 mL, 0.6 mmol) in
THF over 1 h. The reaction was stirred at -78 °C for an
additional 2 h, and then 0.1 mL of H2O was added. The
volatiles were removed in vacuo and the residue partitioned
between CH2Cl2 and H2O. The organic layer was separated,
dried with Na2SO4, and evaporated. Purification as above gave
a 4:1 syn:anti diastereomeric mixture of 24 (by NMR).
1′-Ben zyl-5′-et h oxy-4-[2-(4-m or p h olin o)et h oxy]sp ir o-
[cycloh exa n e-1, 3′-in d olin ]-2′-on e (25). To a magnetically
1′-Ben zyl-5′-et h oxysp ir o[cycloh exa n e-1,3′-in d olin e]-
4,2′-d ion e Cyclic 4-Eth ylen e Keta l (18). To a magnetically
stirred solution of 8 (2.67 g, 10 mmol) in DME (70 mL) at 0 °C
was added NaH (0.96 g, 40 mmol). After 15 min of stirring,
dibromide 4 (4.3 g, 15 mmol) was added at 0 °C and the
reaction allowed to warm to room temperature. After 16 h the
reaction was quenched with water (30 mL) at 0 °C and
extracted with ethyl acetate (3 × 60 mL). The combined
organics were washed with brine, dried over Na2SO4, and
concentrated in vacuo. Flash chromatography using 20%
EtOAc/methylene chloride yielded 3.5 g (90%) of 18: 1H NMR
(CDCl3, 400 MHz) δ 7.2-7.3 (m, 5H), 6.95 (d, J ) 2.4 Hz, 1H),
6.65 (dd, J ) 2.4 Hz, 8.4 Hz, 1H), 6.55 (d, J ) 8.4 Hz, 1H),
4.85 (s, 2H), 4.0 (t, J ) 2.1 Hz, 4H), 3.9 (q, J ) 6.8 Hz, 2H),
2.3 (m, 2H), 2.0 (m, 1H), 2.2 (m, 1H), 1.8-1.95 (m, 4H), 1.35
(t, J ) 6.8 Hz, 3H); 13C NMR (CDCl3, 400 MHz) δ 179.64,
155.03, 150.17, 136.15, 135.67, 135.19, 128.67, 127.38, 127.02,
112.34, 111.55, 109.14, 108.13, 64.36, 64.28, 64.05, 46.30,
43.34, 31.51, 30.17, 14.86. Anal. Calcd for C24H27NO4: C, 73.26;
H, 6.92; N, 3.56. Found: C, 73.30; H, 6.95; N, 3.58.
1′-Ben zyl-5′-et h oxysp ir o[cycloh exa n e-1,3′-in d olin e]-
4,2′-d ion e (19). A magnetically stirred solution of 18 (4.64 g,
11.8 mmol), PPTS (0.88 g), 10 mL of H2O, and 100 mL of

Total Synthesis of SR 121463
J . Org. Chem., Vol. 66, No. 11, 2001 3661
stirred solution of 24 (0.3 g, 0.86 mmol) in toluene (5 mL) at
room temperature was added NaH (31 mg, 1.28 mmol) and
the reaction heated to 80 °C for 1.5 h. Freshly distilled
2-chloroethylmorpholine (0.19 g, 1.28 mmol) was then added
as a solution in toluene (1 mL) to the refluxing solution. After
6 h, an additional equivalent of 2-chloroethylmorpholine was
added and the reaction heated to 100 °C for 12 h. The reaction
was cooled to 0 °C, quenched with water (20 mL), and extracted
with ethyl acetate (3 × 30 mL). The combined organic layers
were washed with brine, dried over Na2SO4, and concentrated
in vacuo. Flash chromatography using 4: 1 ethyl acetate/
hexanes and subsequently increasing polarity with small
amounts of MeOH yielded the desired product 25 (0.28 g,
70%): 1H NMR (CDCl3, 400 MHz) δ 7.25-7.13 (m, 5H), 6.83
(d, J ) 2.4 Hz, 1H), 6.57 (dd, J ) 2.4 Hz, 8.4 Hz, 1H), 6.49 (d,
J ) 8.4 Hz, 1H), 4.79 (s, 2H), 3.88 (q, J ) 6.8 Hz, 2H), 3.68 (t,
J ) 4.8 Hz, 3H), 3.62 (t, J ) 5.6 Hz, 2H), 3.5 (m, 1H), 2.6 (t,
J ) 5.6 Hz, 2H), 2.5 (m, 4H), 2.15 (m, 2H), 2.0 (m, 2H), 1.87
(m, 2H), 1.75 (m, 1H), 1.55 (m, 2H), 1.3 (t, J ) 6.8 Hz, 3H);
13C NMR (CDCl3, 100 MHz) δ 179.93, 155.0, 136.39, 136.23,
135.47, 128.89, 127.61, 127.27, 111.96, 111.88, 109.26, 75.97,
67.1, 65.85, 64.21, 58.81, 54.39, 46.79, 43.56, 30.77, 26.33,
15.09. Anal. Calcd for C28H36N2O4: C, 72.39; H, 7.81; N, 6.03.
Found: C, 72.13; H, 7.77; N, 5.97.
1′-[2-Meth oxy-4-(ter t-bu tyla m in oca r boxa m id o)ben ze-
n esu lfon yl]-5′-et h oxy-4-[2-(4-m or p h olin o)et h oxy]sp ir o-
[cycloh exa n e-1,3′-in d olin ]-2′-on e (1). To a magnetically
stirred solution of liquid ammonia (10 mL) at -78 °C were
added small pieces of Li (42 mg, 6 mmol), causing the solution
to turn dark blue. A solution of 25 (0.54 g, 1.16 mmol) in THF
(2 mL) was added and the blue color disappeared within
minutes of stirring. The reaction was quenched with solid
ammonium chloride and warmed to room temperature over 1
h. Water (30 mL) was added and extracted with ethyl acetate
(3 × 30 mL). The combined organic layers were washed with
brine, dried over Na2SO4, and concentrated in vacuo. The crude
product 26 (0.39 g, 90%) was subjected to the next reaction
without further purification.
added in one portion. The cooling bath was removed and the
reaction allowed to warm to room temperature over 1 h. After
stirring an additional 2 h, the reaction was complete by TLC
(CH2Cl2/MeOH). The volatiles were evaporated in vacuo, and
the remaining residue was subjected to chromatography to
provide the title compound (443 mg, 85%) as an oil that slowly
crystallized: mp 210-2 °C (hexanes/EtOAc); 1H NMR (CDCl3,
300 MHz) δ 8.13 (d, J ) 8.0 Hz, 1H), 7.71 (d, J ) 8.0 Hz, 1H),
7.44 (d, J ) 1.2 Hz, 1H), 7.27 (m, 1H), 6.83 (dd, J ) 2.4 Hz,
8.8 Hz, 1H), 6.6 (d, J ) 2.4 Hz, 1H), 6.10 (s, 1H), 4.02 (q, 6.8
Hz, 2H), 3.73 (m, 4H), 3.62 (m, 5H), 3.45 (m, 1H), 2.6 (t, J )
5.2 Hz, 2H), 2.56 (bs, 4H), 2.0 (m, 2H), 1.85 (br m, 4H), 1.6
(m, 2H), 1.46 (s, 9H), 1.42 (t, J ) 6.8 Hz, 3H); 13C NMR (CDCl3,
100 MHz) δ 177.71, 165.21, 157.64, 156.3, 143.06, 134.54,
132.27, 132.05, 128.27, 117.53, 115.02, 112.96, 111.85, 110.14,
75.97, 67.05, 65.77, 64.06, 58.69, 56.24, 54.29, 52.35, 46.5, 31.8,
29.87, 28.82, 26.18, 15.0. Anal. Calcd for C33H45N3O8S: C,
61.68; H, 6.85; N, 6.54. Found: C, 60.63; H, 6.88; N, 6.31.
Molecu la r Mech a n ics Ca lcu la tion s. These were per-
formed on a Silicon Graphics O2 workstation with Macro-
Model, v 6.5.19 Geometry optimizations of 19, 19′, 24, 24′, 27,
29, and 30 were performed with the MM3* and MMFF force
fields in combination with the GBSA/CHCl3 continuum model.23
Ack n ow led gm en t. We are grateful to Drs. J uha
Kokko (Emory University) and Dennis Schafer (Rena-
logics, Inc.) for generous multilevel support of the
project. We are also grateful to Dr. Karl S. Hagen
(Emory University) for X-ray crystallography and Dr.
Albert Padwa (Emory University) for helpful discus-
sions. We thank J ames H. Nettles for excellent technical
assistance in preparing the cover graphic. Cover photo
of Amicalola Falls, GA, taken by J im P. Snyder.
Su p p or tin g In for m a tion Ava ila ble: X-ray crystallo-
graphic data and an ORTEP drawing are available. This
material is available free of charge via the Internet at
http://pubs.acs.org.
To a magnetically stirred solution of 26 (302 mg, 0.8 mmol)
in 5 mL of THF cooled to -78 °C was added potassium tert-
butoxide (90 mg, 0.8 mmol), and then the mixture was allowed
to warm to room temperature. After stirring for10 min, the
reaction was cooled to -78 °C and 2 (246 mg, 0.8 mmol) was
J O0004658
(23) Still, W. C.; Tempczyk, A.; Hawley, R. C.; Hendrickson, T. J .
Am. Chem. Soc. 1990, 112, 6127.