Azomethine ylide cycloaddition/reductive heterocyclization approach to oxindole alkaloids: Asymmetric synthesis of (-)-horsfiline

Article abstract of DOI:10.1021/jo015854w

The intermolecular [3 + 2] with 2(2-nitrophenyl)acrylate dienophiles followed by reductive heterocyclization affords the spiro(indole-pyrrolidine) ring system. Hence, this enable us to accomplish a concise and highly enantioselective synthesis of (-)-horsfiline 1, based on chiral auxiliary-directed π-face discrimination in the 1,3-dipolar cycloaddition of (1S,2R)- 2-phenyl-1-cyclohexyl ester 4f with N-methylazomethine ylide.

Full text of DOI:10.1021/jo015854w

J . Org. Chem. 2001, 66, 8447-8453
8447
Azom eth in e Ylid e Cycloa d d ition /Red u ctive Heter ocycliza tion
Ap p r oa ch to Oxin d ole Alk a loid s: Asym m etr ic Syn th esis of
(-)-Hor sfilin e
Giancarlo Cravotto,† Giovanni Battista Giovenzana,‡ Tullio Pilati,§ Massimo Sisti,| and
Giovanni Palmisano*,|
Dipartimento di Scienza e Tecnologia del Farmaco, Universita` di Torino, via Giuria 9,
0125 Torino, Italy, Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, v.le
Ferrucci 33, Universita` del Piemonte Orientale, 28100 Novara, Italy, Centro di Studio delle Relazioni fra
Struttura e Reattivita` Chimica - CNR, via Golgi 19, 20133 Milano, Italy, and Dipartimento di Scienze
Chimiche, Fisiche e Matematiche, Universita` dell’Insubria, via Valleggio 11, 22100 Como, Italy
giovanni.palmisano@uninsubria.it
Received J une 21, 2001
The intermolecular [3 + 2] annulation of azomethine ylides with 2(2-nitrophenyl)acrylate dienophiles
followed by reductive heterocyclization affords the spiro(indole-pyrrolidine) ring system. Hence,
this enable us to accomplish a concise and highly enantioselective synthesis of (-)-horsfiline 1,
based on chiral auxiliary-directed π-face discrimination in the 1,3-dipolar cycloaddition of (1S,2R)-
2-phenyl-1-cyclohexyl ester 4f with N-methylazomethine ylide.
In tr od u ction
The spiro(indole-pyrrolidine) ring system is a fre-
quently encountered structural motif in many pharma-
cologically relevant alkaloids, as typified by vincristine,
vinblastine, and spirotryprostatins. Further structural
classification divides this alkaloid family into several
F igu r e 1. (-)-Horsfiline.
subgroups (e.g., Aspidosperma, Strychnos) among which
oxindoles deserve mention.1 A structural feature shared
Horsfiline has become a popular target for testing
synthetic methods involving either a radical cyclization5
or an internal Mannich reaction of an oxindole precursor
derived from 5-methoxytryptamine.6 Fuji and co-workers7
recently described an efficient asymmetric nitro-olefina-
tion of oxindoles using a chiral â-nitroenamine and
applied this approach to the synthesis of (-)-1 as well.
Shortly afterward, Carreira8 reported a synthesis of rac-1
based on a Lewis acid-promoted ring-expansion reaction
of a spiro(cyclopropane-1,3′-indol)-2′-one in the presence
of an aldimine. Finally, we should quote a sometimes
overlooked synthesis of rac-coerulescine (i.e., 5-demethoxy
horsfiline) by Kuehne9 in a pilot study en route to
vincadifformine, 20 years prior to its isolation from
Phalaris coerulescens.10
by these compounds is an oxygen function at C-2 (indole
numbering) which biosynthetically derives from an oxi-
dative rearrangement of â-carboline precursors. Oxindole
alkaloids have aroused a great deal of synthetic effort,
and several syntheses of both racemic and enantioen-
riched forms have been achieved, culminating in the
recent syntheses of (-)-spirotryprostatin B.2
(-)-Horsfiline 1 (Figure 1), a representative tricyclic
oxindole alkaloid, was first isolated in 1990 by Bodo and
co-workers3 from the leaves of Horsfieldia superba Warb.
(Myristicaceae), a small tree native to Malaysia and used
as a source of intoxicating snuffs. By synthesis from
chiral nonracemic â-carboline precursors, the absolute
configuration of (-)-horsfiline has been shown to be (R),
as in 1.4
(4) a) Pellegrini, C.; Stra¨ssler, C.; Weber, M.; Borschberg, H.-J .
Tetrahedron: Asymmetry 1994, 5, 1979. (b) For the total synthesis of
other related oxindoles [i.e., (+)-elacomine and (-)-isoelacomine]:
Pellegrini, C.; Weber, M.; Borschberg, H.-J . Helv. Chim. Acta 1996,
79, 151.
(5) a) J ones, K.; Wilkinson, J . J . Chem. Soc., Chem. Commun. 1992,
1767. For radical cyclization to related oxindoles, see: Cossy, J .; Cases,
M.; Gomez Pardo, D. Tetrahedron Lett. 1998, 39, 2331. Hilton, S. T.;
Ho, T. C. T.; Pljevaljcic, G.; J ones, K. Org. Lett. 2000, 2, 2639.
(6) Bascop, S.-I.; Sapi, J .; Laronze, J .-Y.; Le´vy, J . Heterocycles 1994,
38, 725.
(7) Lakshmaiah, G.; Kawabata, T.; Shang, N.; Fuji, K. J . Org. Chem.
1999, 64, 1699.
(8) Fischer, C.; Meyers, C.; Carreira, E. M. Helv. Chim. Acta 2000,
83, 1175.
(9) Kuehne, M. E.; Rolans. D. M.; Hafter, R. J . Org. Chem. 1978,
43, 3705.
† Universita` di Torino.
‡ Universita` del Piemonte Orientale.
§ Centro di Studio delle Relazioni fra Struttura
Chimica - CNR.
e Reattivita`
| Universita` dell’Insubria.
(1) (a) For an excellent survey of oxindole alkaloids which includes
discussion of chemistry, biosynthesis, and pharmacology, see: Cordell,
G. A. Introduction to Alkaloids- A Biogenetic Approach; Wiley-Inter-
science: New York, 1981. (b) Bindra, J . S. Oxindole Alkaloids In The
Alkaloids- Chemistry and Physiology; Manske, R. H. F., Ed.; Academic
Press: New York, 1973; Vol. XIV, pp 83-121.
(2) (a) Sebahar, P. R.; Williams, R. M. J . Am. Chem. Soc. 2000, 122,
5666. (b) von Nussbaum, F.; Danishefsky, S. J . Angew. Chem., Int. Ed.
2000, 39, 2175. (c) Wang, H.; Ganesan, A. J . Org. Chem. 2000, 65,
4685. (d) Overman, L. E.; Rosen, M. D. Angew. Chem., Int. Ed. 2000,
39, 4596.
(3) J ossang, A.; J ossang, P.; Hadi, H. A.; Sevenet, T.; Bodo, B. J .
Org. Chem. 1991, 56, 6527.
(10) Anderton, J .; Cockrum, P. A.; Colegate, S. M.; Edgar, J . A.;
Flower, K.; Vit, I.; Willing, R. I. Phytochemistry 1998, 48, 437.
10.1021/jo015854w CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/17/2001

8448 J . Org. Chem., Vol. 66, No. 25, 2001
Cravotto et al.
Sch em e 1. F ir st Gen er a tion Retr osyn th etic
Sch em e 2. Secon d Gen er a tion Retr osyn th etic
An a lysis of (-)-Hor sfilin e (r ef 9a )
An a lysis of (-)-Hor sfilin e
Before exploring the chemistry of chiral nonracemic
acrylates (e.g., 4c-g), we first prepared and explored
the reactivity of the parent, achiral methyl ester 4b
(Scheme 3).
The Claisen condensation of commercially available
2-nitro-5-methoxytoluene 2 with diethyl oxalate (1.1
equiv) was readily effected with sodium ethoxide (1.5
equiv) in diethyl ether (rt, 3 h). Although the intermedi-
ate ethyl 2-nitro-5-methoxyphenylpyruvate could be puri-
fied by chromatography (53% recovery), we found it
convenient to carry this compound without purification
through the whole reaction sequence. Oxidative demoli-
tion using the conditions by Blaikie and Perkin (NaOH,
H2O2, rt, 1 h)15 (f 3a ), followed by esterification (MeOH,
Amberlyst15, reflux, 2 h),16 gave 3b (67% yield). In the
approach to 3a /3b, alternatives to Scheme 3 were exam-
ined which proved less successful or less direct. For
instance, nitrile 617 could be derived from 4-nitroanisole
5 by direct cyanoalkylation via a vicarious nucleophilic
substitution (VNS)18 of hydrogen with (4-chlorophenoxy)-
acetonitrile19 (1.2 equiv) in the presence of t-BuOK (2.4
equiv) at -10 °C (30 min) in DMF. It could be converted
to 3b in 47% overall yield by methanolysis (MeOH,
TMSCl, 45 °C, 6 h).20
Herein we disclose an efficient asymmetric approach
to (-)-horsfiline 1, based on chiral auxiliary-directed
π-face discrimination in an intermolecular [3 + 2] annu-
lation of N-methylazomethine ylide with 2-(2-nitrophe-
nyl)acrylate dienophiles.
Resu lts a n d Discu ssion
A distinctive structural feature of tricyclic oxindole
alkaloids is the presence of a quaternary carbon (the
spirocenter C-3) bearing a substituted aromatic ring; the
installation of this stereocenter is the critical step in
planning the enantiosynthesis of any of these alkaloids.11
We have recently12a described a novel route to (-)-1,
proceeding by way of the [3 + 2] cycloaddition of enan-
tiopure dipolarophile B13 to thermally generated N-
methylazomethine ylide C, as outlined antithetically in
Scheme 1.14
We did not pursue this route because it was not “atom-
economic”; moreover, it showed a modest facial diaste-
reoselectivity with (1R,2S,5R)-menthyl ester B. We rather
aimed at the alternative disconnection depicted in Scheme
2, as we believed that an asymmetric [3 + 2] cycloaddition
combined with a reductive lactamization could provide
a straightforward entry to (-)-1 and thus skip the task
of removing an extra CO2X* group (i.e., the detachment
of the chiral auxiliary X* followed by radical decarboxy-
lation) (Scheme 2).
With ester 3b in hand, we focused on a Mannich-type
reaction to achieve the desired functionalization at the
activated methylene group.21 Thus, 3b was first treated
with NaH in dry THF at room temperature, and then a
suspension of dimethyl(methylene)iminium iodide
(Eschenmoser’s salt)22 (2.5 equiv) in THF was added to
give the crude amine 7, which was converted (MeI, THF,
rt, 8 h) to crude methiodide 8. Treatment of 8 with 1,5-
diazabicyclo[5.4.0]undec-5-ene (DBU) in refluxing diox-
ane (45 min), followed by silica gel chromatography,
afforded a 33% overall yield of the desired acrylate 4b.
On treatment of 3b with paraformaldehyde (10 equiv)
in the presence of K2CO3 and tris[2-(2-methoxyethoxy)-
ethyl]amine] (TDA-1) (10 mol %)23 as a solid-liquid
phase-transfer catalyst in toluene at 85 °C for 3 h, clean
methylenation pleasingly ensued to produce the acrylate
4b in 76% yield.24 This process proved useful enough to
(11) For
a review of catalytic enantioselective methods for the
synthesis of quaternary carbon stereogenic centers, see: Corey, E. J .;
Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388. See, also:
Martin, S. F. Tetrahedron 1980, 36, 419.
(12) (a) Palmisano, G.; Annunziata, R.; Papeo, G.; Sisti, M. Tetra-
hedron: Asymmetry 1996, 7, 1. For conceptually related approaches,
see: (b) Nyerges, M.; Gajdics, L.; Szo¨llo˜sy, AÄ .; To˜ke, L. Synlett 1999,
1, 111. (c) Bell, S. E. V.; Brown, R. F. C.; Eastwood, F. W.; Horvath, J .
M. Aust. J . Chem. 2000, 53, 183. (d) Fejes, I.; Nyerges, M.; Szo¨llo˜sy,
AÄ .; Blasko´, G.; To˜ke, L. Tetrahedron 2001, 57, 1129.
(13) For recent results concerning intermolecular 1,3-dipolar cy-
cloaddition of achiral azomethine ylides to chiral dipolarophiles, see:
Takahashi, T.; Kitano, K.; Hagi, T.; Nihonmatsu, H.; Koizumi, T. Chem.
Lett. 1989, 597. Wee, A. G. H. J . Chem. Soc., Perkin Trans 1 1989,
1363. Annunziata, R.; Cinquini, M.; Cozzi, F.; Raimondi, L.; Pilati, T.
Tetrahedron: Asymmetry 1991, 2, 1329. Coulter, T.; Grigg, R.; Malone,
J . F.; Sridharan, V. Tetrahedron Lett. 1991, 32, 5417. Kanemasa, S.;
Hayashi, T.; Tanaka, J .; Yamamoto, H.; Sakurai, T. J . Org. Chem.
1991, 56, 4473. Stack, J . A.; Heffner, T. A.; Geib, S. J .; Curran, D. P.
Tetrahedron 1993, 49, 995. Waldmann, H.; Blaser, E.; J ansen, M.;
Letschert, H.-P. Angew. Chem., Int. Ed. 1994, 33, 683. Grigg, R.
Tetrahedron: Asymmetry 1995, 6, 2475. Fray, A. H.; Meyers, A. I. J .
Org. Chem. 1996, 61, 3362. Lynch, J . K.; Plagge, F.; Chu, D. T. W.
Tetrahedron: Asymmetry 1997, 8, 883. Gothelf, K. V.; J ørgensen, K.
A. Chem. Rev. 1998, 98, 863. Karlsson, S.; Han, F.; Ho¨gberg, H.-E.;
Caldirola, P. Tetrahedron: Asymmetry 1999, 10, 2605; Carey, J . S. J .
Org. Chem. 2001, 66, 2526.
(15) (a) Blaikie, K. G.; Perkin, W. H. J . Chem. Soc. 1924, 296. (b)
Beckett, A. H.; Daisley, R. W.; Walker, J . Tetrahedron 1968, 24, 6093.
(16) Petrini, M.; Ballini, R.; Marcantoni, E.; Rosini, G. Synth.
Commun. 1988, 18, 847.
(17) Mıkosza, M.; Danikiewicz, W.; Wojciechowski, K. Liebigs Ann.
Chem. 1988, 203.
(18) Reviews: (a) Chupakhin, O. N.; Charushin, V. N.; Van der Plas,
H. C. Nucleophilic Aromatic Substitution of Hydrogen; Academic
Press: San Diego, 1994. (b) Mıkosza, M.; Wojciechowski, K. Hetero-
cycles 2001, 54, 445.
(19) Grochowski, E.; Eckstein, Z. Bull. Acad. Pol. Sci.; Ser. Sci.
Chim. 1963, 11, 443.
(20) Luo, F.-T.; J eevanandam, A. Tetrahedron Lett. 1998, 39, 9455.
(21) Danishefsky, S.J .; Kitahara, T.; McKee, R.; Schuda, P. F. J .
Am. Chem. Soc. 1976, 98, 6715.
(22) Schreiber, J .; Haag, M.; Hashimoto, N.; Eschenmoser, A. Angew.
Chem., Int. Ed. Engl. 1971, 10, 330.
(14) For a recent review on enantioselective synthesis of pyrro-
lidines, see: Denmark, S. E.; Marcin, L. R. J . Org. Chem. 1995, 60,
3221.
(23) Soula, G. J . Org. Chem. 1985, 50, 371.

Asymmetric Synthesis of (-)-Horsfiline
J . Org. Chem., Vol. 66, No. 25, 2001 8449
Sch em e 3. Syn th eses of th e Ra cem ic Dip ola r op h ile 4a a
a
Reagents and conditions: (a) (CO2Et)2, NaOEt, Et2O, rt; (b) H2O2, NaOH, H2O, rt, then pH 1; (c) MeOH, Amberlyst 15, rfx; (d) (CH2O)n,
K2CO3, TDA-1, toluene, 85 °C; (e) 2M aq NaOH, rfx, then pH 1, 0 °C; (f) ROH, DCC, HOBt, DMAP, CH2Cl2, rt then rfx; (g)
(4-ClC6H4)OCH2CN, tBuOK, DMF, -10 °C; (h) MeOH, TMSCl, 45 °C; (i) (-)-8-Ph-menthol, DCC, DMAP, MeCN, rt; (j) Me2N+dCH2I-,
NaH, THF, rt; (k) MeI, THF, rt; (l) DBU, dioxane, rfx.
Sch em e 4. Syn th esis of Ch ir a l Non r a cem ic
mildness of the reaction conditions, and the high product
yields. Accordingly, thermal in situ generation (refluxing
toluene for 8-15 h) of the putative N-methylazomethine
ylide C from sarcosine (N-methylglycine) (3 equiv) and
paraformaldehyde (12 equiv) in the presence of 4b yielded
the desired pyrrolidine 9b as the major product, albeit
in modest and erratic yields (20-45%) together with
significant amounts of the starting material 4b. In the
course of optimization studies, we found that the main-
tenance of anhydrous conditions using a Soxhlet ap-
paratus filled with oven-dried 3-Å molecular sieves
helped either to accelerate the cycloaddition reaction
[about 6 h for disappearance of 4b (TLC)] or to signifi-
cantly reduce the amount of competitive side reactions
(66% isolated yield). Interestingly, the choice of molecular
sieves was crucial, and the use of 4-Å or 5-Å resulted in
lower yields and longer reaction times.34 Finally, the
amino function release necessary for lactam formation
was achieved by catalytic hydrogenation at ambient
pressure (H2, 10% Pd/C, MeOH) to uneventfully provide
rac-horsfiline 1 in near quantitative yields. This finding
brought out the potential of the two-step cycloaddition/
reductive heterocyclization protocol for the enantioselec-
Dip ola r op h iles 4c-g a n d Access to (-)-1a
a
Reagents and conditions: (a) sarcosine, (CH2O)n, 3 Å MS,
PhMe, rfx; (b) H2, 10% Pd/C, MeOH.
prepare multigram quantities of 4b.27 With the required
dipolarophile 4b in hand, the stage was then set to
attempt 1,3-dipolar cycloaddition (Scheme 4) and to
further proceed toward target molecule 1.
A number of methods have been developed to generate
(non)stabilized azomethine ylides.32 We opted for the
Tsuge route33 (viz. decarboxylation of R-amino acid imi-
nium salts) because of the ready availability of the
reagents, the simplicity of the procedure, the reasonable
(32) For lead references on azomethine ylides, see: (a) Huisgen, R.
1,3-Dipolar Cycloadditions Chemistry; Padwa, A., Ed.; Wiley: New
York, 1984; Vol 1, pp 1-164. (b) Lown, J . W. In 1,3-Dipolar Cycload-
dition Chemistry; Padwa, A., Ed.; Wiley: New York, 1984. Vol.1, pp
663-732. (c) Pearson, W. H. In Studies in Natural Products Chemistry;
Rahman, A., Ed.; Elsevier: Amsterdam, 1988; Vol. 1, pp 323-358. (d)
Vedejs, E. In Advances in Cycloaddition; Curran, D. P., Ed.; J AI
Press: Greenwich, CT, 1988; Vol. 1, pp 33-51. (e) Tsuge, O.; Kane-
masa, S. Adv. Heterocycl. Chem. 1989, 45, 231-349. (f) Padwa, A. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 4, pp 1111-1168. (g) Pichon, M.;
Figade`re, B. Tetrahedron: Asymmetry 1996, 7, 927. (h) Clark, R. B.;
Pearson, W. H. Org. Lett. 1999, 1, 349. (i) Gehert, A.; Linden, A.;
Heimgartner, H. Heterocycles 2001, 54, 691 and references therein.
(33) Tsuge, O.; Kanemasa, S.; Ohe, M.; Takenaka, S. Chem. Lett.
1986, 973.
(24) Reagents that are usually effective for methylenation, e.g.,
N,N,N′,N′-tetramethylmethylenediamine (TMMDA)/Ac2O25 or 1,3,5-
trioxane in the presence of N-methylanilinium trifluoroacetate26 were
also screened without success.
(25) de Solms, S. J . J . Org. Chem. 1976, 41, 2650.
(26) Gras, J .-L. Tetrahedron Lett. 1978, 34, 2111
(27) Attempts to prepare 4b directly from 3-iodo-4-nitroanisole28 and
the readily available methyl 3-(tri-n-butylstannyl)propenoate29 (1.5
equiv) through Stille cross-coupling reaction30 by application of Lie-
beskind’s protocol31 [10 mol % Pd(Ph3P)4, CuI (0.75 equiv), DMF, rt,
48 h] gave unacceptably low yields.
(28) Hodgson, H. H.; Moore, F. H. J . Chem. Soc. 1927, 632.
(29) Cochran, J . C.; Bronk, B. S.; Terence, K. M.; Phillips, H. K.
Tetrahedron Lett. 1990, 31, 6621.
(30) Levin, J . I. Tetrahedron Lett. 1993, 34, 6211.
(31) Liebeskind, L. S.; Fengl, R. W. J . Org. Chem. 1990, 55, 5359.
(34) See: Mikami, T.; Yoshida, A. Synlett 1995, 29. Koga, Y.;
Sodeoka, M.; Shibasaki, M. Tetrahedron Lett. 1994, 35, 1227.

8450 J . Org. Chem., Vol. 66, No. 25, 2001
Cravotto et al.
diastereoselection (86% de by HPLC).39 It also proved to
be the only chiral auxiliary in which the major (slower
moving) and the minor diastereomers 9f were separable
by standard silica gel chromatography.40 Unfortunately,
we were unable to assign the configuration from the NMR
spectra of these compounds; however, after numerous
recrystallizations, crystals of the major diastereomer that
were suitable for X-ray analysis could be grown by the
liquid-diffusion method41 (diisopropyl ether-MeOH mix-
ture).
F igu r e 2. Attempted coupling of 4a with (S)-(-)-R-methyl-
benzylamine gave the azetidinone 10 as a 1:1 diastereomeric
mixture.
Ta ble 1. Dia ster eoselective Cycloa d d ition of
N-Meth yla zom eth in e Ylid e to Ch ir a l Dip ola r op h iles 4c-g
Single-crystal X-ray structure elucidation42 on the
major diastereomer 9f unambiguously established the
relative configuration and, hence, the absolute stereo-
chemistry at the newly installed spirocenter C-3 as (R),
i.e., the one corresponding to natural (-)-horsfiline.
We were pleased to find these diastereomers readily
separable by fractional recrystallization from a diisopro-
pyl ether/propan-2-ol mixture. Ultimately, on exposure
to catalytic hydrogenation at ambient pressure (H2,10%
Pd/C, MeOH, rt), (R)-9f suffered reduction with concomi-
tant detachment of the chiral inductor to provide (R)-
(-)-horsfiline 1, [R]20 -7.1 (c 0.54, MeOH) {lit.3 [R]20
entrya
chiral auxiliary
yield, %b
dec
1
2
3
4
5
c
d
e
f
78
65
63
78
69
41
43
16
86d
10
g
a
The cycloaddition conditions were as follows: 4c-g, sarcosine
(3 equiv), paraformaldehyde (12 equiv), 3 Å MS, toluene, reflux
b
(8-15 h). The total yield of diastereomers 9 is reported. c Dias-
tereomeric ratios of 9 were determined by HPLC analysis of the
crude reaction mixtures. HPLC conditions to assess de: symmetry
C18 column (4.6 × 250 mm, 100 Å, 1 mL/min) eluting with
D
D
-7.2 (c 1, MeOH)}, in 70% overall yield referred to
acrylate 4f. The synthetic material was compared with
an authentic sample of (-)-horsfiline, kindly provided by
Dr. Borschberg (ETH, Zu¨rich) and was found to be
d
MeOH-H2O-Et2NH (70:30:0.5). Upgraded to >98% de by re-
crystallization of the crude mixture of 9f from iPr2O/iPrOH.
1
identical by H and 13C NMR spectra. Furthermore, this
tive synthesis of (-)-horsfiline 1 (Scheme 2). Toward this
end, a series of esters and amides 9c-g bearing a chiral
auxiliary attached to the dipolarophile was prepared (63-
78% range yield) through a coupling between 4a and
auxiliaries in the presence of 1-hydroxybenzotriazole
hydrate (HOBt) (2 equiv), N,N-dicyclohexylcarbodiimide
(DCC) (1.1 equiv), and catalytic 4-N,N-(dimethylamino)-
pyridine (DMAP) in refluxing dichloromethane.35 The
carboxylic function in 4a proved to be reluctant to
esterification under milder conditions; undoubtedly, this
is due to steric hindrance caused by the ortho substitu-
tion. When (-)-8-phenylmenthol was reacted under the
same conditions, there was no evidence for an acyl
transfer to have occurred. Attempts to prepare 4h
through methylenation of (-)-8-phenylmenthyl ester 3h
provided only trace conversions. Furthermore, the forma-
tion of amide 9i from (S)-(-)-R-methylbenzylamine (dichlo-
romethane, r.t., 24 h) was plagued by an overwhelming
Michael addition followed by amidation reaction that
yielded azetidin-2-one 10 as a 1:1 diastereomer mixture
(Figure 2).36
procedure allowed recovery (95%) of pure (+)-(1S,2R)-2-
phenyl-1-cyclohexanol (98% ee) which could be reused,
offsetting the expense met in employing this chiral
auxiliary. The stereochemical outcome of the [3 + 2]
cycloaddition could be rationalized by assuming that, in
the presence of π-stacking contribution and in uncata-
lyzed reactions, the acrylate unit in 4f adopts a s-cis
conformation, disfavoring the approach of N-methyla-
zomethine ylide from the Si-face of the dipolarophile
displaying the Ph group embodied in the chiral auxiliary.
In summary, a previous multistep approach from the
(-)-menthyl ester of an isatin precursor to (-)-1, featur-
ing intermolecular pyrrolidine annulation via a [3 + 2]
cycloaddition, lacked stereoselectivity.12a We have now
developed a successful access to (-)-1, commencing with
chiral nonracemic acrylate 4f, wherein the crucial ste-
reocenter was installed through an highly diastereose-
lective azomethine ylide cycloaddition followed by reduc-
tive lactamization.
Finally, we examined the auxiliary-induced facial
diastereoselection of 1,3-dipolar cycloadditions by 4c-g
under conditions that had served well in the model study.
This approach was also chosen because it circumvented
the well-documented propensity of oxindole alkaloids to
undergo racemization at the spirocenter through a retro
Mannich-Mannich reaction.1,37 Among the chiral auxil-
iaries examined (Table 1), only Whitesell’s (1S,2R)-2-
phenyl-1-cyclohexanol38 provided an acceptable level of
Exp er im en ta l Section
Reaction flasks were oven-dried or flame-dried, assembled
hot, and cooled under a stream of dry nitrogen. All chemicals
were purchased from Aldrich Chemical Co. or Lancaster
Synthesis GmbH. Chemicals were used without purification,
unless stated otherwise. To prepare anhydrous solvents used
in reaction mixtures, the following procedures were used:
(38) (a) Whitesell, J . K.; Chen, H.-H.; Lawrence, R. M. J . Org. Chem.
1985, 50, 4663. (b) For an excellent review on cyclohexyl-based chiral
auxiliaries, see: Whitesell, J . K. Chem. Rev. 1992, 92, 953.
(39) HPLC analyses were performed using a Symmetry C18 column
(4.6 × 250 mm, 100 Å, 1 mL/min) eluting with MeOH-H2O-Et2NH
(70:30:0.5).
(35) Access to 4c-g from 4a by direct conversion to the acid chloride
with oxalyl chloride (dichloromethane, cat. DMF, rt) and condensation
with chiral auxiliaries (in the presence of DMAP) were sluggish and
resulted in a complex mixture of compounds.
(36) In consonance with two previous papers (Romanova, N. N.;
Tallo, T. G.; Bundel’, Yu. G. Russ. J . Org. Chem. 1995, 31, 375.
Romanova, N. N.; Budylin, V. A.; Grishina, G. V.; Potapov, V. M.;
Torocheshnikov, V. N. Chem. Heterocycl. Compd. 1984, 20, 1354)
addition of (S)-(-)-R-methylbenzylamine to 2-phenylacrylic acid pro-
ceeds without stereoselectivity.
(40) Whitesell, J . K.; Wong, M. S. J . Org. Chem. 1991, 56, 4552.
(41) J ones, P. G. Chem. Br. 1981, 17, 223.
(42) Ortep is available in the Supporting Information. Crystal-
lographic data for the structure (R)-9f reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre as deposi-
tion No. CCDC 162938. Copies of the data can be obtained, free of
charge, on application to the CCDC, 12 Union Rd, Cambridge CB2
1EZ, UK; fax: +44(1223)336 033.e-mail: deposit@ccdc.cam.ac.uk.
(37) Wenkert, E.; Udelhofen, J . H.; Bhattacharyya, N. K. J . Am.
Chem. Soc. 1959, 81, 3763.

Asymmetric Synthesis of (-)-Horsfiline
J . Org. Chem., Vol. 66, No. 25, 2001 8451
ethanol was distilled from magnesium, THF was distilled from
sodium benzophenone ketyl; dichloromethane, MeCN, and
dioxane were distilled from CaH2; toluene (HPLC grade) and
DMF were dried and stored over activated 4 Å molecular
with water and brine. The solvent was removed under reduced
pressure, and the residue was subjected to chromatography
(hexanes-ether 1:1) to give nitrile 6 (344 mg, 55%) as a tan
solid. An analytical sample was obtained by recrystallization
from EtOAc/hexanes, mp 80-81 °C (lit.18 79-81 °C). Dry
MeOH (5 mL), TMSCl (0.184 mL, 1.46 mmol) and nitrile 6
(140 mg, 0.73 mmol) were sequentially added in a dry flask
blanketed with nitrogen at room temperature. The reaction
mixture was heated at 45 °C for 6 h. After the reaction was
cooled to room temperature, water (1 mL) was added , followed
by the addition of solid potassium carbonate (200 mg) and
dichloromethane. The dried extract was evaporated and chro-
matographed (hexanes-ether, 2.1) to give the title compound
3b (140 mg, 85%) as a pale yellow solid.
(1R,2S,5R)-8-P h en ylm en th yl 5-m eth oxy-2-n itr op h en y-
la ceta te (3h ). 5-Methoxy-2-nitrophenyl acetic acid (3a , 40 mg,
0.19 mmol), (-)-8-phenylmenthol (44 mg, 0.19 mmol) and
4-(N,N-dimethylamino)pyridine (2 mg, 0.019 mmol) were dis-
solved in anhydrous acetonitrile (5 mL). N,N-Dicyclohexylcar-
bodiimide (78 mg, 0.38 mmol) in acetonitrile (2 mL) was slowly
added, and the color of reaction mixture turned blood red. After
12 h at room temperature, TLC analysis (hexanes-ethyl
acetate 85:15) showed complete disappearance of starting
material. The reaction mixture was filtered and evaporated,
and the solid residue was chromatographed over silica gel
(hexanes-ethyl acetate 85:15) to afford 3h as a colorless solid
(34 mg, 42% yield). Mp 89 °C (hexanes-ethyl acetate); 1H NMR
0.89 (d, 3H, J ) 6.0 Hz), 1.15 (m, 1H), 1.18 (m, 1H), 1.21 (s,
3H), 1.32 (s, 3H), 1.44-1.49 (m, 2H), 1.62 (m, 1H), 1.74 (m,
1H), 1.91 (m, 1H), 2.07 (m, 1H), 3.15 (d, 1H, J ) 17.0 Hz),
3.54 (d, 1H, J ) 17.0 Hz), 3.91 (s, 3H), 4.86 (td, 1H, J ) 10.0,
4.0 Hz), 6.63 (d, 1H, J ) 6.0 Hz), 6.87 (dd, 1H, J ) 9.4, 2.0
Hz), 7.17-7.35 (m, 5H), 8.16 (d, 1H, J ) 9.4 Hz). 13C NMR
22.4, 24.7, 26.9, 28.9, 31.7, 34.9, 40.1, 40.6, 41.9, 50.6, 56.3,
75.5, 113.0, 119.0, 125.6, 126.0, 128.3, 133.3, 142.2, 152.2,
sieves. Melting points were determined on
a Bu¨chi 510
apparatus and were uncorrected. Unless stated otherwise, all
NMR spectra (400 and 100.6 MHz on a Bruker Avance 400
spectrometer) were recorded in CDCl3 using solvent (δC 77.0
ppm) or residual CHCl3 (δH 7.27 ppm) as internal standards.
The IR spectra (CHCl3 solutions) were recorded on a Shimadzu
FT-IR 8001 spectrophotometer. The mass spectra [EI and/or
CI+(isobutane)] were measured on a Finnigan Mat TSQ70
instrument. Optical rotations were measured on a Perkin-
Elmer 241 polarimeter. Elemental analyses were obtained on
a Perkin-Elmer 120 instrument. HPLC analyses were per-
formed with a Gilson 305 pump equipped with a Gilson 133
refractive index detector. Flash column chromatography was
43
performed according to the procedure of Still (J . T. Baker,
silica gel, 40 µm) and monitored by TLC. Analytical TLC was
carried out using Merck Kieselgel 60F254 plates with visualiza-
tion by UV, phosphomolybdic acid, or iodine stain. Single-
crystal X-ray diffraction measurements were performed on a
Bruker P4 diffractometer, graphite monochromator, Mo-KR
radiation (λ ) 0.71073 Å).
5-Meth oxy-2-n itr op h en yla cetic Acid (3a ). Finely cut
sodium wires (1.24 g, 53.8 mmol) were added portionwise to
dry ethanol (5 mL) at 0 °C and stirred until evolution of
hydrogen ceased. Diethyl oxalate (5.76 g, 39.5 mmol) and
3-methyl-4-nitroanisole (6.00 g, 35.9 mmol) in dry ether (100
mL) were added to the resulting sodium ethanolate solution.
The deep red mixture was set aside at room temperature under
N2 atmosphere for 3 h, and then water (100 mL) was added.
The reaction mixture was made basic (pH 9) with 2 M NaOH.
The ether layer was discarded, and 30% hydrogen peroxide
solution (55 mL) was added dropwise to the aqueous phase;
an exothermic reaction ensued, and the temperature was
maintained to room temperature with ice-bath cooling for 1
h. 2 M aqueous HCl was added to adjust the pH to 1. A copious
dark yellow precipitate was formed, collected and dried under
vacuum. The mother liquor was extracted (2×) with ether.
After removal of the solvent, a second crop of 3a was isolated
as a yellow solid (5.08 g overall, 67% yield), mp 177 °C (EtOH/
163.6, 169.6. MS (CI) 426, 400, 176. Anal. Calcd for C25H31
-
NO5 (425.52): C, 70.57; H, 7.34; N, 3.29. Found: C, 70.35; H,
7.53; N, 3.18. Rf 0.19 (hexanes-ethyl acetate 9:1).
Meth yl 2-(5-Meth oxy-2-n itr oph en yl)acr ylate (4b). Route
a: via one-pot methylenation of 3b. Compound 3b (500 mg,
2.2 mmol) was dissolved in dry toluene (25 mL) and to the
resulting solution were sequentially added anhydrous K2CO3
(614 mg, 4.4 mmol), paraformaldehyde (660 mg, 22.0 mmol),
and TDA-1 (71 mg, 0.22 mmol). Heating the mixture to 85 °C
for 3 h resulted in the complete disappearance of starting
material and formation of 4b. The cooled solution was thor-
oughly washed with water, dried, filtered, and evaporated. The
waxy residue was purified by silica gel chromatography
(hexanes-diethyl ether 2:3) to give analytically pure 4b (397
mg, 76% yield).
1
H2O). H NMR (DMSO-d6) 3.90 (s, 3H), 4.00 (s, 2H), 7.05 (d,
1H, J ) 2.0 Hz), 7.10 (dd, 1H, J ) 7.4, 2.0 Hz), 8.15 (d, 1H, J
) 7.4 Hz), 12.45 (s, 1H). 13C NMR (DMSO-d6) 40.4, 56.8, 113.9,
114.1, 119.5, 119.9, 128.2, 134.6, 142.2, 163.9, 172.1. MS (CI+)
212 (MH+). Anal. Calcd for C9H9NO5 (211.17): C, 51.19; H,
4.30; N, 6.63. Found: C, 50.98; H, 4.54; N, 6.49. Rf 0.35
(hexanes-ethyl acetate-acetic acid 10:10:1).
Meth yl 5-Meth oxy-2-n itr op h en yla ceta te (3b). Route a:
A solution of 3a (4.80 g, 21.3 mmol) and Amberlyst-15 (2.0 g)
in methanol (200 mL) was refluxed until TLC analysis showed
complete esterification (2 h). The cooled mixture was filtered
and evaporated and the residue partitioned between dichlo-
romethane and saturated aqueous NaHCO3. The organic
phases were dried, filtered, and evaporated, leading to crude
3b. Recrystallization from hexanes-Et2O gave the title com-
pound (4.82 g, 95% yield) as a light yellow solid, mp 66 °C. 1H
NMR 3.75 (s, 3H), 3.92 (s, 3H), 4.05 (s, 2H), 6.81 (d, 1H, J )
4.5 Hz), 6.92 (dd, 1H, J ) 9.5, 4.5 Hz), 8.21 (d, 1H, J ) 9.5
Hz). MS (CI+) 226 (MH+). Anal. Calcd for C10H11NO5
(225.20): C, 53.33; H, 4.92; N, 6.22. Found: C, 53.08; H, 5.05;
N, 6.09. Rf 0.22 (hexanes-Et2O 3:2).
Route b: via vicarious nucleophilic substitution (VNS)
reaction. A solution of commercially available 4-methoxyni-
trobenzene 5 (500 mg, 3.26 mmol) and (4-chlorophenoxy)-
acetonitrile19 (694 mg, 3.91 mmol) in anhydrous DMF (5 mL)
was added dropwise to a solution of potassium tert-butoxide
(878 mg, 7.82 mmol) in DMF (10 mL) at -10 °C. The reaction
mixture was stirred at this temperature for 30 min and then
was poured onto ice-concd HCl, and the reaction products
extracted with ether. The extract was exhaustively washed
Route b: via compounds 7 and 8. Compound 3b (350 mg,
1.55 mmol) was dissolved in dry THF (50 mL) and cooled to 0
°C. Hexane-washed sodium hydride (68 mg of a 60% dispersion
in mineral oil, 1.70 mmol) was added in two portions and the
solution stirred at 0 °C for 1 h. Dimethyl(methylene)iminium
iodide (715 mg, 3.87 mmol) was added, and the solution was
allowed to warm to room temperature and stirred for 3 h. The
reaction was quenched with water, acidified (pH 1) with 2 M
HCl, and extracted with ethyl acetate. The aqueous layers
were made basic with a saturated aqueous Na2CO3 solution
and extracted with ethyl acetate. The combined organic layers
were dried (Na2SO4), filtered, and evaporated to give crude 7.
To a solution in THF (5 mL) of this material was added methyl
iodide (0.37 mL, 5.94 mmol), and the solution was stirred for
8 h and evaporated. The crude product dissolved in dry dioxane
(5 mL) was used in the next step without characterization.
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU, 0.45 mL, 3.01 mmol)
was added, and the reaction mixture was refluxed for 45 min.
2 M aqueous HCl (20 mL) was added, the mixture was
extracted twice with ethyl acetate, and the combined organic
layers were dried, filtered, and evaporated to give a dark
brown residue. Purification by repeated crystallizations from
hexanes-Et2O gave pure 4b (121 mg, 33% yield) as colorless
needles, mp 109 °C. 1H NMR 3.75 (s, 3H), 3.92 (s, 3H), 5.82
(s, 1H), 6.51 (s, 1H), 6.82 (d, 1H, J ) 3.5 Hz), 6.92 (dd, 1H, J
(43) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

8452 J . Org. Chem., Vol. 66, No. 25, 2001
Cravotto et al.
) 8.7, 3.5 Hz), 8.20 (d, 1H, J ) 8.7 Hz). 13C NMR 56.6, 59.5,
113.9, 114.0, 117.9, 127.7, 127.8, 136.1, 140.8, 141.0, 163.0,
165.7. MS (CI+) 238 (MH+), 206. Anal. Calcd for C11H11NO5
(237.21): C, 55.70; H, 4.67; N, 5.90. Found: C, 55.82; H, 4.91;
N, 5.95. Rf 0.40 (hexanes-Et2O 2:3).
Found: C, 68.98; H, 6.25; N, 3.70. Rf 0.25 (hexanes-dichlo-
romethane 2:3).
(3R)-4,4-Dim eth yl-2-oxotetr ah ydr ofu r an -3-yl 2-(5-Meth -
oxy-2-n itr op h en yl)a cr yla te (4g). Colorless foam, 45% yield.
1H NMR 1.04 (s, 3H), 1.23 (s, 3H), 3.93 (s, 3H), 4.04 (m, 2H),
5.45 (s, 1H), 5.94 (s, 1H), 6.62 (s, 1H), 6.88 (d, 1H, J ) 2.7
Hz), 6.99 (dd, 1H, J ) 9.0, 2.7 Hz), 8.24 (d, 1H, J ) 9.0 Hz).
13C NMR 20.1, 23.4, 40.2, 45.6, 47.3, 55.9, 78.4, 113.9, 117.4,
126.7, 127.6, 136.0, 141.0, 141.7, 163.8, 164.4. MS(CI) 336, 206,
178, 150, 131. Anal. Calcd for C16H17NO7 (335.31): C, 57.31;
H, 5.11; N, 4.18. Found: C, 57.02; H, 5.30; N, 4.15. Rf 0.33
(toluene-diethyl ether 9:1).
Gen er a l P r oced u r e for [3 + 2] Cycloa d d ition Rea c-
tion s. Paraformaldehyde (108 mg, 3.6 mmol) was added to a
stirring solution of 4b-g (0.3 mmol) in dry toluene (50 mL).
The 100-mL flask was fitted with a Soxhlet extractor with a
thimble filled with 3-Å molecular sieves, and the solution was
heated to reflux under nitrogen. Sarcosine (80 mg, 0.9 mmol)
was portionwise added in 1 h to the reaction mixture which
was refluxed for a further 4-6 h. After cooling, the solution
was filtered and concentrated. The residue was purified by
chromatography on silica gel (hexanes-ethyl acetate 3:7) to
provide pure 9b-g.
Meth yl 3-(5-Meth oxy-2-n itr op h en yl)-1-m eth ylp yr r oli-
d in e-3-ca r boxyla te (9b). Colorless glass, 66% yield. 1H NMR
2.45 (s, 3H), 2.10-2.70 (m, 2H), 3.00 (m, 2H), 3.10 (d, 1H, J )
16.0 Hz), 3.16 (d, 1H, J ) 16.0 Hz), 3.68 (s, 3H), 3.92 (s, 3H),
6.82 (dd, 1H, J ) 8.5, 3.5 Hz), 7.29 (d, 1H, J ) 3.5 Hz), 8.08
(d, 1H, J ) 8.5 Hz). Rf 0.37 (dichloromethane-methanol 92:
8).
(1R,2S,5R)-Men th yl 3-(5-Meth oxy-2-n itr op h en yl)-1-m e-
th ylp yr r olid in e-3-ca r boxyla te (9c). Colorless foam, com-
bined yield 78%. Minor diastereomer: 1H NMR 0.69 (d, 3H, J
) 7.0 Hz), 0.80 (d, 3H, J ) 7.0 Hz), 0.87 (d, 3H, J ) 6.7 Hz),
0.80-1.60 (m, 9H), 2.16-3.33 (m, 6H), 2.40 (s, 3H), 3.89 (s,
3H), 4.62 (m, 1H), 6.80 (dd, 1H, J ) 8.0, 2.6 Hz), 7.27 (d, 1H,
J ) 2.6 Hz), 8.06 (d, 1H, J ) 8.0 Hz). 13C NMR (CDCl3) 20.7,
20.8, 22.0, 23.2, 26.0, 31.3, 34.2, 38.0, 41.8, 46.8, 55.7, 55.9,
57.3, 66.2, 75.6, 110.7, 115.8, 128.0, 144.0, 144.5, 163.3, 178.0.
Major diastereomer: 1H NMR 0.69 (d, 3H, J ) 7.0 Hz), 0.80
(d, 3H, J ) 7.0 Hz), 0.87 (d, 3H, J ) 6.7 Hz), 0.80-1.60 (m,
9H), 2.33-3.33 (m, 6H), 2.49 (s, 3H), 3.90 (s, 3H), 4.63 (m, 1H),
6.84 (dd, 1H, J ) 8.0, 2.6 Hz), 7.16 (d, 1H, J ) 2.6 Hz), 8.09
(d, 1H, J ) 8.0 Hz). 13C NMR 15.9, 16.0, 22.1, 23.2, 26.1, 31.4,
34.2, 36.9, 41.8, 46.9, 55.6, 56.0, 57.2, 65.5, 76.0, 111.1, 116.0,
128.4, 141.0, 141.5, 163.4, 173.0.
(1S,2R,4S)-Bor n yl 3-(5-Meth oxy-2-n itr op h en yl)-1-m e-
th ylp yr r olid in e-3-ca r boxyla te (9d ). Pale yellow foam, com-
bined yield 65%. Minor diastereomer: 1H NMR 0.74 (s, 3H),
0.80 (s, 3H), 0.85 (s, 3H), 0.91-3.33 (m, 13H), 2.41 (s, 3H),
3.90 (s, 3H), 4.77 (ddd, 1H, J ) 10.0, 4.0, 2.0 Hz), 6.82 (dd,
1H, J ) 9.5, 3.0 Hz), 7.29 (d, 1H, J ) 3.0 Hz), 8.24 (d, 1H, J
) 9.5 Hz). 13C NMR 13.3, 18.8, 19.6, 27.0, 27.8, 36.1, 37.8, 41.8,
44.8, 47.8, 48.2, 55.8, 56.1, 57.2, 66.5, 81.2, 110.8, 115.7, 128.0,
141.0, 142.0, 163.3, 174.0. Major diastereomer: 1H NMR 0.73
(s, 3H), 0.81 (s, 3H), 0.85 (s, 3H), 0.96-3.33 (m, 13H), 2.42 (s,
3H), 3.90 (s, 3H), 4.76 (ddd, 1H, J ) 10.0, 4.0, 2.0 Hz), 6.83
(dd, 1H, J ) 9.5, 3.0 Hz), 7.23 (d, 1H, J ) 3.0 Hz), 8.08 (d, 1H,
J ) 9.5 Hz). 13C NMR 13.4, 18.8, 19.6, 27.0, 27.8, 36.1, 37.6,
41.9, 44.8, 47.8, 48.2, 55.8, 56.0, 57.2, 66.3, 81.3, 110.8, 115.7,
128.1, 141.0, 142.0, 163.0, 174.0.
(1S,2S,3S,5R)-Isop in oca m p h eyl 3-(5-Meth oxy-2-n itr o-
p h en yl)-1-m eth ylp yr r olid in e-3-ca r boxyla te (9e). Colorless
glass, combined yield 63%. Minor diastereomer: 1H NMR 0.89
(s, 3H), 1.05 (s, 3H), 1.17 (s, 3H), 0.87-3.03 (m, 13H), 2.43 (s,
3H), 3.88 (s, 3H), 4.98 (m, 1H), 6.81 (dd, 1H, J ) 9.0, 3.5 Hz),
7.26 (d, 1H, J ) 3.5 Hz), 8.05 (d, 1H, J ) 9.0 Hz). 13C NMR
20.4, 23.6, 27.4, 33.3, 35.1, 38.0, 38.1, 41.0, 41.8, 43.6, 47.4,
56.1, 55.8, 57.0, 66.4, 75.4, 111.0, 115.7, 128.0, 141.0, 142.0,
163.3, 173.4. Major diastereomer: 1H NMR 0.89 (s, 3H), 1.04
(s, 3H), 1.17 (s, 3H), 0.88-3.02 (m, 13H), 2.40 (s, 3H), 3.88 (s,
3H), 4.98 (m, 1H), 6.80 (dd, 1H, J ) 9.0, 3.5 Hz), 7.27 (d, 1H,
J ) 3.5 Hz), 8.06 (d, 1H, J ) 9.0 Hz). 13C NMR 20.4, 23.7,
27.4, 33.2, 35.4, 38.0, 38.1, 41.1, 41.8, 43.4, 47.4, 56.1, 55.7,
57.0, 66.4, 75.4, 111.0, 115.7, 128.0, 141.0, 142.0, 163.3, 173.5.
2-(5-Meth oxy-2-n itr op h en yl)a cr ylic Acid (4a ). A sus-
pension of 4b (678 mg, 2.9 mmol) in aqueous 2 M NaOH (25
mL) was refluxed for 1 h. The homogeneous solution was cooled
to 0 °C and carefully acidified with 2 M aqueous HCl to pH 1.
A light yellow solid precipitated and collected by filtration.
Trituration of the residue with an ether/hexanes mixture
resulted in acid 4a as a pale yellow fluffy solid (510 mg, 80%
1
yield). H NMR (DMSO-d6) 3.92 (s, 3H), 5.81 (s, 1H), 6.45 (s,
1H), 6.91 (d, 1H, J ) 3.0 Hz), 7.00 (dd, 1H, J ) 8.3, 3.0 Hz),
8.18 (d, 1H, J ) 8.3 Hz), 12.12 (bs, 1H). 13C NMR (DMSO-d6)
57.1, 114.9, 118.1, 127.7, 127.8, 136.5, 141.3, 141.5, 164.0,
166.6. MS (CI+) 224 (MH+), 206. Anal. Calcd for C10H9NO5
(223.18): C, 53.82; H, 4.06; N, 6.28. Found: C, 53.51; H, 4.09;
N, 6.17.
Gen er a l P r oced u r e for th e Ester ifica tion of 4a . The
acid 4a (446 mg, 2.0 mmol) was dissolved in dry dichlo-
romethane (40 mL), and the chiral auxiliary (2.0 mmol),
4-(N,N-dimethylamino)pyridine (24 mg, 0.20 mmol), and 1-hy-
droxybenzotriazole hydrate (31 mg, 0.20 mmol) were sequen-
tially added. N,N-Dicyclohexylcarbodiimide (812 mg, 4.00
mmol) in dichloromethane (10 mL) was added dropwise during
30 min. The resulting red solution was stirred at room
temperature for 30 min and then refluxed for 18-24 h, filtered,
and evaporated. The solid dicyclohexylurea was removed by
filtration and washed with ether. The combined washings were
evaporated and the residue purified by silica gel chromatog-
raphy (toluene) to provide the corresponding esters 4c-g.
(1R,2S,5R)-Men th yl 2-(5-Meth oxy-2-n itr op h en yl)a cr yl-
a te (4c). Colorless plates, mp 64 °C (hexanes-ethyl acetate),
1
83% yield. H NMR 0.74 (d, 3H, J ) 6.9 Hz), 0.85 (d, 3H, J )
7.0 Hz), 0.90 (d, 3H, J ) 7.0 Hz), 0.98-1.07 (m, 3H), 1.28 (m,
1H), 1.45 (m, 1H), 1.62-1.68 (m, 2H), 1.80 (m, 1H), 2.06 (m,
1H), 3.93 (s, 3H), 4.75 (dt, 1H, J ) 10.8, 4.4 Hz), 5.80 (s, 1H),
6.46 (s, 1H), 6.82 (d, 1H, J ) 2.6 Hz), 6.95 (dd, 1H, J ) 8.0,
2.6 Hz), 8.19 (d, 1H, J ) 8.0 Hz). 13C NMR 16.8, 21.0, 14.0,
26.8, 31.7, 34.3, 40.8, 47.3, 56.4, 75.9, 113.8, 117.4, 126.3, 127.6,
136.4, 141.2, 141.6, 163.8, 164.8. MS (CI+) 362 (MH+). Anal.
Calcd for C20H27NO5 (361.44): C, 66.46; H, 7.53; N, 3.88.
Found: C, 66.30; H, 7.70; N, 3.75. Rf 0.30 (toluene).
(1S,2R,4S)-Bor n yl 2-(5-Meth oxy-2-n itr op h en yl)a cr yl-
a te (4d ). Colorless crystals, mp 72 °C (hexanes-ethyl acetate),
40% yield. 1H NMR 0.80 (s, 3H), 0.85 (s, 3H), 0.90 (s, 3H),
1.05-1.25 (m, 3H), 1.50-1.65 (m, 3H), 2.35 (m, 1H), 3.92 (s,
3H), 4.90 (m, 1H), 5.80 (s, 1H), 6.45 (s, 1H), 6.85 (d, 1H, J )
3 Hz), 6.95 (dd, 1H, J ) 10.0, 3.0 Hz), 8.25 (d, 1H, J ) 10.0
Hz). 13C NMR 13.5, 18.9, 19.7, 27.1, 28.1, 36.8, 45.0, 47.9, 48.7,
75.9, 113.6, 117.4, 126.3, 127.6, 136.3, 141.6, 141.7, 163.9,
164.6. MS (CI+) 360 (MH+), 206. Anal. Calcd for C20H25NO5
(359.42): C, 66.84; H, 7.01; N, 3.90. Found: C, 66.61; H, 7.35;
N, 3.69. Rf 0.16 (toluene).
(1S,2S,3S,5R)-Isop in oca m p h eyl 2-(5-Meth oxy-2-n itr o-
p h en yl)a cr yla te (4e). Colorless foam, 53% yield. 1H NMR
0.95 (m, 1H), 0.96 (s, 3H), 1.09 (d, 3H, J ) 7.4 Hz), 1.21 (s,
3H), 1.65-1.72 (m, 2H), 1.91-2.03 (m, 2H), 2.32 (m, 1H), 2.60
(m, 1H), 3.93 (s, 3H), 5.09 (td, 1H, J 1 ) 5.5 Hz, J 2 ) 3.5 Hz),
5.82 (s, 1H), 6.51 (s, 1H), 6.84 (d, 1H, J ) 2.0 Hz), 6.96 (dd,
1H, J ) 8.0, 2.0 Hz), 8.19 (d, 1H, J ) 8.0 Hz). MS (CI+) 360
(MH+), 206. Anal. Calcd for C20H25NO5 (359.42): C, 66.84; H,
7.01; N, 3.90. Found: C, 66.72; H, 6.79; N, 3.65. Rf 0.32
(toluene-diethyl ether 9:1).
(1S,2R)-2-P h en yl-1-cycloh exyl 2-(5-Met h oxy-2-n it r o-
p h en yl)a cr yla te (4f). Colorless foam, 88% yield.1H NMR
1.26-2.26 (m, 8H), 2.55 (dt, 1H, J ) 12.0, 4.0 Hz), 3.86 (s,
3H), 4.86 (dt, 1H, J ) 12.0, 4.3 Hz), 5.57 (s, 1H), 6.17 (s, 1H),
6.53 (d, 1H, J ) 4.0 Hz), 6.91 (dd, 1H, J ) 9.0, 4.0 Hz), 7.01-
7.30 (m, 5H), 8.13 (d, 1H, J ) 9.0 Hz). 13C NMR 24.6, 25.7,
31.8, 33.3, 49.5, 55.9, 77.9, 113.5, 117.0, 125.7, 126.0, 127.0,
127.4, 128.0, 135.0, 135.9, 140.7, 142.9, 163.2. IR 1720, 1577,
1514, 1450, 1344, 1319, 1198 cm-1. MS (CI) 382 (MH+), 206.
Anal. Calcd for C22H23NO5 (381.43): C, 69.28; H, 6.08; N, 3.67.

Asymmetric Synthesis of (-)-Horsfiline
J . Org. Chem., Vol. 66, No. 25, 2001 8453
(1S,2R)-2-P h en yl-1-cycloh exyl 3-(5-Met h oxy-2-n it r o-
p h en yl)-1-m et h ylp yr r olid in e-3-ca r b oxyla t e (9f). Com-
bined yield 78%. Minor diastereomer: 1H NMR 1.19-2.77 (m,
15H), 2.12 (s, 3H), 3.88 (s, 3H), 4.93 (td, 1H, J ) 9.0, 4.7 Hz),
6.76 (dd, 1H, J ) 8.7, 3.8 Hz), 7.03 (d, 1H, J ) 3.8 Hz), 7.20-
7.33 (m, 5H), 7.95 (d, 1H, J ) 8.7 Hz). 13C NMR 24.6, 25.8,
32.0, 34.1, 37.4, 41.4, 49.9, 55.7, 55.8, 57.5, 65.4, 77.2, 110.7,
115.8, 128.0, 141.1, 142.2, 163.0, 173.0. Major diastereomer:
colorless needles, mp 161 °C (diisopropyl ether/MeOH). 1H
NMR 1.20-2.76 (m, 15H), 2.15 (s, 3H), 3.88 (s, 3H), 4.93 (td,
1H, J ) 9.0, 4.7 Hz), 6.78 (dd, 1H, J ) 8.7, 3.8 Hz), 7.05 (d,
1H, J ) 3.8 Hz), 7.19-7.32 (m, 5H), 7.98 (d, 1H, J ) 8.7 Hz).
13C NMR 24.6, 25.7, 31.6, 33.7, 37.4, 41.6, 49.9, 55.7, 55.8, 56.8,
66.0, 77.3, 110.6, 115.7, 128.0, 141.0, 142.3, 163.1, 172.6.
(19 µL, 0.13 mmol), 4-(N,N-dimethylamino)pyridine (12 mg,
0.10 mmol) were added. N,N-dicyclohexylcarbodiimide (53 mg,
0.26 mmol) in dichloromethane (2 mL) was added dropwise
during 10 min. The homogeneous yellow solution is stirred at
room temperature for 24 h, filtered, and evaporated. The solid
residue was triturated and washed with diethyl ether, the
combined washings were evaporated, and the residue was
purified by silica gel chromatography (hexanes-ethyl acetate
3:2), to provide 10 (26 mg, 60%) as a 1:1 diastereomeric
mixture. Colorless foam. 1H NMR 1.62 and 1.65 (d, 3H, J )
7.2 Hz), 2.95 and 3.09 (m, 1H), 3.87 and 3.93 (s, 3H), 4.82 and
4.88 (m, 1H), 4.82 and 5.05 (q, 1H, J ) 7.0 Hz), 6.87 and 6.92
(dd, 1H, J ) 6.3, 2.7 Hz), 7.35 (m, 5H), 7.40 and 7.45 (d, 1H,
J ) 2.7 Hz), 8.12 and 8.17 (d, 1H, J ) 6.3 Hz). MS (CI) 327
(MH+).
(3R)-4,4-Dim eth yl-2-oxo-tetr ah ydr ofu r an -3-yl 3-(5-Meth -
oxy-2-n it r op h en yl)-1-m et h ylp yr r olid in e-3-ca r b oxyla t e
(9g). Light yellow solid. Combined yield 69%. Minor diaste-
reomer: 1H NMR 0.78 (s, 3H), 1.13 (s, 3H), 2.13-3.03 (m, 4H),
2.38 (s, 3H), 3.05-3.33 (m, 2H), 3.88 (s, 3H), 3.99 (s, 2H), 5.37
(s, 1H), 6.83 (dd, 1H, J ) 8.5, 2.8 Hz), 7.29 (d, 1H, J ) 2.8
Hz), 8.09 (d, 1H, J ) 8.5 Hz). 13C NMR 19.5, 22.4, 37.2, 40.0,
41.8, 55.8, 55.9, 57.1, 66.5, 75.3, 76.1, 111.3, 115.9, 128.2, 141.0,
(()-Hor sfilin e (1). To a solution of 9b (205 mg, 0.698 mmol)
in MeOH (5 mL) was added 10% Pd/C (25 mg), and the reaction
mixture was hydrogenated at atmospheric pressure for 2 h.
The catalyst was removed by filtration through a pad of Celite
and rinsed with methanol. The filtrates were concentrated,
and the residue was recrystallized from acetone to give racemic
horsfiline 1 (154 mg, 95%) as a colorless solid, mp 154 °C (lit.3
1
1
155-156 °C). H NMR 2.07 (m, 1H), 2.40 m(1H), 2.45 (s, 3H),
141.5, 163.5, 163.6, 172.5. Major diastereomer: H NMR 1.01
2.71-2.90 (m, 4H), 3.81 (s, 3H), 6.72 (dd, 1H, J ) 8.2, 2.8 Hz),
6.81 (d, 1H, J ) 8.2 Hz), 7.04 (d, 1H, J ) 2.8 Hz), 8.63 (bs,
1H). 13C NMR 38.1, 41.9, 54.1, 55.7, 56.6, 66.5, 110.2, 110.6,
112.7, 133.9, 137.8, 156.5, 182.9 ppm. IR 1705 cm-1. MS (CI)
233 (MH+). Anal. Calcd for C13H16N2O2 (232.28): C, 67.22; H,
6.94; N, 12.06. Found: C, 67.02; H, 7.10; N, 11.89.
(s, 3H), 1.23 (s, 3H), 2.23-3.03 (m, 4H), 2.41 (s, 3H), 3.06-
3.34 (m, 2H), 3.89 (s, 3H), 3.98 (s, 2H), 5.36 (s, 1H), 6.83 (dd,
1H, J ) 8.5, 2.8 Hz), 7.26 (d, 1H, J ) 2.8 Hz), 8.08 (d, 1H, J
) 8.5 Hz). 13C NMR 19.5, 22.4, 37.2, 40.0, 41.8, 55.8, 55.9, 57.1,
66.5, 75.3, 76.1, 111.3, 115.9, 128.2, 141.0, 141.5, 163.5, 163.6,
172.5.
(R)-Hor sfilin e (-)-(1). To a stirred solution of ester (R)-9f
X-r a y Str u ctu r e Deter m in a r ion of Ma jor Dia ster e-
om er 9f. C25H30N2O5, Mr ) 438.51, orthorhombic, space group
P212121, a ) 7.4003(10), b ) 7.8599(12), c ) 39.808(4) Å, V )
(76 mg, 0.17 mmol) in MeOH (5 mL) was added 10% Pd-C(10
mg), and the resulting suspension was stirred under
a
hydrogen-filled balloon for 4 h. After this period, the mixture
was filtered through a Celite pad, and the Celite pad was
washed with MeOH. Evaporation of the filtrate gave a residue
which was chromatographed on silica gel (EtOAc, gradient
with 0-10% MeOH) to furnish sequentially (1S,2R)-2-phenyl-
1-cyclohexanol (29 mg, 95%) [R]20D +57.3 (c 5, MeOH) and the
title compound (-)-1 (36 mg, 90%) as colorless crystals, mp
2315.5(5) Å3, Z ) 4, Dc ) 1.258 gcm-3, µ(Mo-KR) ) 0.08 mm-1
;
2730 reflections collected (2θ < 50.°), 2384 independent, Rave
) 0.0202; the structure was solved by SIR-92,44 and refined
on F2 by SHELX-97,45 386 parameters refined, 253 soft
restraints on C-H distances and phenyl groups coplanarity,
Rw(F2) ) 0.0845, R ) 0.715 for all independent reflections
[0.0754 and 0.373, respectively, for 1456 reflections with I >
2σ(I)]. The five-membered ring N,C2,C3,C4,C5 presents an
envelope conformation (E1 according to Boyens46 notation),
being puckering ring pararameters47 æ2 ) -179.6(4)°, Qt )
0.423(5) Å.
123-124 °C (acetone) (lit.3 125-126 °C), [R]20 -7.1 (c 0.54,
D
MeOH) {lit.3 [R]20 -7.2 (c 1, MeOH)}. The 1H and 13C NMR
D
spectra were identical to those published.4a
Ack n ow led gm en t. We gratefully acknowledge fi-
nancial support from the MURST and CNR. We are
indebted to Dr. R. Annunziata, Dipartimento di Chimica
Organica e Industriale, Milano, for obtaining some NMR
spectra and to Dr. H. -J . Borschberg, ETH, Zu¨rich, for
a sample of synthetic (-)-horsfiline.
3-(5-Meth oxy-2-n itr oph en yl)-1-(1-ph en yleth yl)azetidin -
2-on e (10). The acid 4a (30 mg, 0.13 mmol) was dissolved in
dry dichloromethane (5 mL), and (S)-(-)-R-methylbenzylamine
(44) Altomare, A.; Cascarano, G.; Giacovazzo, G.; Guagliardi, A.;
Burla, M. C.; Polidori, G.; Camalli, G. J . Appl. Crystallogr. 1994, 27,
435.
(45) Sheldrick, G. M. “SHELX-97. Program for the Refinement of
Crystal Structures”, 1997, University of Go¨ttingen, Germany.
(46) Boyens, J . C. A. J . Cryst. Mol. Struct. 1978, 8, 317-320.
(47) Cremer, D.; Pople, J . A. J . Am. Chem. Soc. 1975, 97, 1354-
1358.
Su p p or tin g In for m a tion Ava ila ble: ORTEP drawing of
(R)-9F . This material is available free of charge via the
Internet at http://pubs.acs.org.
J O015854W