Catalytic asymmetric synthesis of either enantiomer of the calabar alkaloids physostigmine and physovenine

Article abstract of DOI:10.1021/ja980788+

A potentially versatile asymmetric route to hexahydropyrrolo[2,3-b]indoles having carbon substituents at C-3a (Scheme 1) is demonstrated through enantioselective total syntheses of the Calabar alkaloids (-)physostigmine (2), (-)-physovenine (10), and their enantiomers. The synthesis of enantiopure (-)physostigmine proceeds from commercially available 2-butyn-1-ol (11) and N-methyl-p-anisidine (15) in 15-20% overall yield by way of eight isolated and purified intermediates. The central step is catalytic asymmetric Heck cyclization of (Z)-2-methyl-2-butenanilide 17 to-form oxindole aldehyde (S)-19 in 84% yield and 95% ee.

Full text of DOI:10.1021/ja980788+

6500
J. Am. Chem. Soc. 1998, 120, 6500-6503
Catalytic Asymmetric Synthesis of Either Enantiomer of the Calabar
Alkaloids Physostigmine and Physovenine
Takaharu Matsuura,1a Larry E. Overman,* and Daniel J. Poon1b
Contribution from the Department of Chemistry, 516 Physical Sciences 1, UniVersity of California,
IrVine, California 92697-2025
ReceiVed March 9, 1998
Abstract: A potentially versatile asymmetric route to hexahydropyrrolo[2,3-b]indoles having carbon substituents
at C-3a (Scheme 1) is demonstrated through enantioselective total syntheses of the Calabar alkaloids (-)-
physostigmine (2), (-)-physovenine (10), and their enantiomers. The synthesis of enantiopure (-)-
physostigmine proceeds from commercially available 2-butyn-1-ol (11) and N-methyl-p-anisidine (15) in 15-
20% overall yield by way of eight isolated and purified intermediates. The central step is catalytic asymmetric
Heck cyclization of (Z)-2-methyl-2-butenanilide 17 to form oxindole aldehyde (S)-19 in 84% yield and 95%
ee.
Introduction
A hexahydropyrrolo[2,3-b]indole ring having a carbon sub-
stituent at C-3a (1) is the defining structural feature of a diverse
collection of natural products. The best known members of
this group are alkaloids found in seeds of the African Calabar
bean,2 exemplified by (-)-physostigmine (2), which was isolated
in pure form as early as 1864.3 Ring system 1 is found
throughout the natural products kingdom and is displayed in a
wide variety of structural formats.4 Representative examples
include flustramine B (3) isolated from a marine bryozoan4,5
and the 3a-bishexahydropyrrolo[2,3-b]indole alkaloids chaetocin
(4), isolated from a fungus,6 and quadrigemine C (5), isolated
from a New Caledonian plant.7
Some success has been recorded recently in asymmetric
synthesis of pyrroloindolines of this type, either from 3a-
unsubstituted pyrrolo[2,3-b]indolines8 or through asymmetric
alkylation of 3-substituted oxindoles.9 We have pursued an
alternate strategy in which 3a-substituted pyrroloindolines 1 are
prepared from acyclic precursors by a sequence whose central
Figure 1. Representative hexahydropyrrolo[2,3-b]indole alkaloids
having a quaternary center at C-3a.
step is an asymmetric intramolecular Heck reaction (Scheme
1).10 Besides the simplicity of employing achiral aromatic
precursors, the catalytic asymmetric approach outlined in
Scheme 1 provides convenient access to either pyrrolo[2,3-b]-
indoline enantiomer and potentially could allow a wide variety
of substituents to be incorporated at C-3a, including those not
readily introduced through alkylation processes. The use of an
intramolecular Heck reaction to assemble a hexahydropyrrolo-
[2,3-b]indole in racemic form, in this case from cyclization of
a pyrroline-2-one aminal, was first reported by Hoffmann.11
As our initial natural product targets in this area we chose
the Calabar alkaloids, which are the simplest members of this
group yet display important pharmacological properties.4 (-)-
(1) (a) On leave from Shionogi & Co. Ltd., Discovery Research
Laboratories I, 12-4, Sagisu, 5-Chome, Fukushima-Ku, Osaka, 553-0002,
Japan. (b) Current address: Department of Chemistry, Colorado State
University, Fort Collins, CO 80523-1872.
(2) For a review of the Calabar alkaloids, see: Takano, S.; Ogasawara,
K. Alkaloids 1989, 36, 225-251.
(3) Jobst, J.; Hesse, O. Ann. Chem. Pharm. 1864, 129, 115.
(4) For a review, see: Hino, T.; Nakagawa, M. Alkaloids 1989, 34, 1-75.
(5) For a review, see: Kobayashi, J.; Ishibashi, M. Alkaloids 1992, 41,
52-57.
(6) Weber, H. P. Acta Crystallogr., Sect. B 1972, 28, 2945.
(7) Gue´ritte-Voegelein, F.; Se´venet, T.; Pusset, J.; Adeline, M. T.; Gillet,
B.; Beloeil, J. C.; Gue´nard, D.; Potier, P. J. Nat. Prod. 1992, 55, 923.
(8) (a) Bruncko, M.; Crich, D.; Samy, R. J. Org. Chem. 1994, 59, 5543.
(b) Marsden, S. P.; Depew, K. M.; Danishefsky, S. J. J. Am. Chem. Soc.
1994, 116, 11143.
(10) For our initial report of this strategy, see: Ashimori, A.; Overman,
L. E. J. Org. Chem. 1992, 57, 4571.
(11) Hoffmann, H. M. R.; Schmidt, B.; Wolff, S. Tetrahedron 1989, 45,
6113.
(9) Lee, T. B. K.; Wong, G. S. K. J. Org. Chem. 1991, 56, 872.
S0002-7863(98)00788-4 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/20/1998

Calabar Alkaloids Physostigmine and PhysoVenine
J. Am. Chem. Soc., Vol. 120, No. 26, 1998 6501
Scheme 1
Scheme 2
Physostigmine (2) is a powerful inhibitor of acetyl cholinesterase
and has been an invaluable tool in elucidating pharmacological
and physiological mechanisms. Physostigmine is clinically used
to reduce intraocular pressure in glaucoma, to treat postoperative
intestinal atony and myasthenia gravis, and has recently been
found useful for relieving symptoms of Alzheimer’s disease.4,12
However, the therapeutic usefulness of physostigmine is limited
by its short duration of action, narrow therapeutic window, and
lack of selectivity toward the two subtypes of human cholinest-
erase enzymes.12a A number of physostigmine analogues have
recently been evaluated, such as the phenyl carbamate congener,
phenserine (9), which in promising preclinical studies shows
improved phamacokinetic properties, low toxicity, and good
selectivity in inhibiting human erythrocyte acetylcholinest-
erase.12,13 As is often the case, biological activity of the Calabar
alkaloids is highly dependent upon absolute configuration; for
example, (+)-ent-physostigmine has little effect on acetyl
cholinesterase in vitro and is a weak centrally acting cholinergic
agonist.12
the related hexahydrofurano[2,3-b]indole alkaloid (-)- physo-
venine (10) and its enantiomer ent-10.
Results and Discussion
The key asymmetric intramolecular Heck step of our enan-
tioselective approach to hexahydropyrrolo[2,3-b]indoles 1 con-
taining a methyl substituent at C-3a should proceed with high
enantioselection if carried out under “neutral” Heck conditions
with a (Z)-2-methyl-2-butenanilide cyclization precursor.18,19
Since commercially available N-methyl-p-anisidine can be
converted in one step into o-iodo derivative 15,20 the (Z)-2-
butenanilide 17 required for the synthesis of physostigmine was
prepared by coupling 15 with (Z)-butenoic acid 12 (Scheme
2). This acid was prepared in 70% overall yield from com-
mercially available 2-butyn-1-ol (11) through a standard three-
step sequence.19 However, the junction of these components
to prepare (Z)-butenanilide 17 was not straightforward. At-
tempted conversion of 12 to the corresponding acid chloride as
a prelude to condensation with aniline 15 resulted in cleavage
of the triisopropylsilyl (TIPS) group to deliver butenolide 13.21
Condensation of 12 and 15 in the presence of dicyclohexylcar-
bodiimide (DCC) and N-hydroxybenzotriazole (HOBT) in
refluxing THF provided 17 in 55% yield. The efficiency of
In an impressive early accomplishment in alkaloid synthesis,
physostigmine was first prepared in racemic form in 1935 by
Julian and Pikl.14 Since then, numerous total syntheses have
been accomplished including several asymmetric total synthe-
ses.4,15,16 Of particular note is the recent success of Brossi,
Greig, and co-workers in elaborating and optimizing the
Hoechst-Roussel asymmetric modification of the original Julian
approach9 to provide practical access to enantiopure physos-
tigmine (2) and phenserine (9).13,17
In this paper we report full details of our asymmetric total
syntheses of (-)- and (+)-physostigmine (2 and ent-2)10 and
(12) For recent reviews of pharmacology, see: (a) Grieg, N. H.; Pei, X.
F.; Soncrant, T. T.; Ingram, D. K.; Brossi, A. Med. Res. ReV. 1995, 15, 3.
(b) Sano, M.; Bell, K.; Marder, K.; Stricks, L. Clinical Pharm. 1993, 16,
61.
(13) For a review, see: Brossi, A.; Pei, X.-F.; Greig, N. H. Aust. J. Chem.
1996, 49, 171.
(14) Julian, P. L.; Pikl, J. J. J. Am. Chem. Soc. 1935, 57, 563, 755.
(15) For asymmetric total syntheses published since Takano’s review,
see refs 9, 15, 18 and the following: (a) Takano, S.; Moriya, M.; Iwabuchi,
Y.; Ogasawara K. Chem. Lett. 1990, 109. (b) Takano, S.; Sato, T.; Inomata,
K.; Ogasawara, K. Heterocycles 1990, 31, 411. (c) Takano, S.; Moriya,
M.; Ogasawara K. J. Org. Chem. 1991, 56, 5982. (d) Node, M.; Itoh, A.;
Masaki, Y.; Fuji, K. Heterocycles 1991, 32, 1705. (e) Marino, J. P.; Bogdan,
S.; Kimura, K. J. Am. Chem. Soc. 1992, 114, 5566. (f) Node, M.; Hao, X.,
Nishide, K.; Fuji, K. Chem. Pharm. Bull. 1996, 44, 715.
(16) Ashimori, A.; Matsuura, T.; Overman, L. E.; Poon, D. J. J. Org.
Chem. 1993, 58, 6949.
(18) Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J. J. Am.
Chem. Soc. 1998, 120, 6477-6487.
(19) Ashimori, A.; Bachand, B.; Govek, S.; Overman, L. E.; Poon, D. J.
J. Am. Chem. Soc. 1998, 120, 6488-6499.
(20) (a) Horne, S.; Taylor, N.; Collins, S.; Rodrigo, R. J. Chem. Soc.,
Perkin Trans. 1 1991, 3047. (b) Katritzky, A. R.; Fan, W.-Q.; Akutagawa,
K. Tetrahedron 1986, 42, 4027.
(17) Pei, X.-F.; Yu, Q.; Lu, B.; Greig, N. H.; Brossi, A. Heterocycles
1996, 42, 229.
(21) Kayser, M. M.; Breau, L.; Eliev, S.; Morand, P.; Ip, H. S. Can. J.
Chem. 1986, 64, 104.

6502 J. Am. Chem. Soc., Vol. 120, No. 26, 1998
Matsuura et al.
Scheme 3
yield, 63% overall yield is reported on a larger scale25) to
enantiopure natural (-)-physostigmine (1): mp 103-104 °C,
[R]25D -116 ° (c 0.4, C6H6); salicylate salt [R]25D -75 ° (c 0.5,
EtOH).26 Direct reduction of enantiopure (S)-19 with excess
LiAlH4 at room temperature provided tricyclic aminal (S)-22
in 94% yield. This intermediate was transformed in a similar
fashion (in 55% yield) to (-)-physovenine (10): [R]25 -87°
D
(c 0.3, EtOH); lit.15a [R]25 -90 ° (c 0.09, EtOH).
D
Heck cyclization of (Z)-butenanilide 17 with Pd-(R)-BINAP
in the presence of PMP followed by acid hydrolysis and
recrystallization provided enantiopure (R)-19, which was con-
verted in an identical way to enantiopure (+)-physostigmine
(ent-2) and (+)-physovenine (ent-10).
Conclusion
The synthesis summarized in Schemes 2 and 3 constitutes
an efficient method for preparing either enantiomer of physos-
tigmine. The overall yield from commercially available 2-bu-
tyn-l-ol (11) and N-methyl-p-anisidine is 15-20%. The syn-
thesis of (-)-physostigmine proceeds from 11 by way of eight
isolated and purified intermediates.27 At its present refinement,
this route to (-)-physostigmine and congeners is less practical
than the optimized NIH synthesis.13,17 Nonetheless, the in-
tramolecular Heck strategy could find wide utility since it will
likely be applicable to the asymmetric construction of a variety
of 3a-substituted hexahydropyrrolo[2,3-b]indoles, including
those containing 3a substituents that could not be incorporated
by alkylation of an oxindole precursor (e.g., the aryl and tertiary
substituents found in 4 and 5). Efforts to address the total
synthesis of more complex hexahydropyrrolo[2,3-b]indoles
using asymmetric Heck cyclizations as the central step are
ongoing and will be reported in due course.
this conversion could be increased to 67% by first condensing
12 with benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (BOP) 1422 to provide acyloxybenzotria-
zole derivative 16, which was isolated in 84% yield after
chromatography on silica gel. Subsequent condensation of this
derivative with aniline 15 at 60 °C in the absence of solvent
provided 17 in 67% overall yield from 12. The absence of even
a trace of a diagnostic signal for the â-vinylic hydrogen of the
E stereoisomer of 17 in the 500 MHz 1H NMR spectrum
suggests that (Z)-anilide 17 was >98% isomerically pure.
Asymmetric Heck cyclization19 of 17 with 20% Pd-(S)-
BINAP (formed in situ from 10% Pd2(dba)3‚CHCl3 and 23%
(S)-BINAP)23 at 100 °C in N,N-dimethylacetamide (DMA) in
the presence of excess 1,2,2,6,6-pentamethylpiperidine (PMP)
afforded predominantly (diastereoselectivity ) 98:2) the oxin-
dole (E)-enoxysilane (S)-18. This intermediate was isolated by
chromatography on silica gel and subsequently hydrolyzed in
dilute HCl to provide oxindole aldehyde (S)-19 in 84% yield
from 17. Sodium borohydride reduction of (S)-19 and analysis
of the derived primary alcohol (S)-20 by chiral HPLC24
established that 19 was formed with excellent enantiopurity
(95% ee). A single recrystallization of (S)-19 from ethyl
acetate-hexane provided enantiopure (S)-19 in 67% overall
yield from anilide 17.
Experimental Section28
2′-Iodo-4′-methoxy-N-methyl-(Z)-4-(triisopropylsiloxy)-2-methyl-
2-butenanilide (17). The BOP coupling reagent 14 (448 mg, 1.01
mmol) was added to a solution of (Z)-acid 1219 (276 mg, 1.01 mmol),
Et3N (0.13 mL, 1 mmol), and CH2Cl2 (3 mL) at room temperature.
After 30 min, H2O (6 mL) and two drops of 1 M HCl were added, the
organic layer was separated and washed with brine (6 mL), dried
(MgSO4), and concentrated. Purification of the residue by sgc (4:1
hexanes-EtOAc) gave acyl benzotriazole 16 (329 mg, 84%): 1H NMR
(300 MHz, CDCl3) δ 8.08 (d, J ) 8.0 Hz, 1H), 7.52-7.62 (m, 1H),
7.44 (t, J ) 7.8 Hz, 2H), 6.63-6.71 (m, 1H), 4.70-4.77 (m, 2H), 2.26
(q, J ) 1.7 Hz, 3H), 0.99-1.17 (m, 21H); 13C NMR (75 MHz, CDCl3)
δ 162.4, 155.9, 143.5, 128.7, 128.5, 124.8, 120.5, 120.0, 108.2, 62.5,
18.9, 17.9, 11.8; IR (film) 1781, 1643 cm-1; HRMS (CI) m/z 390.2197
(390.2212 calcd for C20H32N3O3Si).
(25) Yu, Q.-S.; Brossi, A. Heterocycles 1988, 27, 745.
(26) Comparison data for authentic (-)-physostigmine obtained from
Aldrich Chemical Co., Inc. are mp 104-105 °C.; [R]25 -117 ° (c 0.4,
D
C6H6). A rotation of [R]D +75 ° (c 0.5, EtOH) has been reported for the
Condensation of enantiopure (S)-19 with methylamine fol-
lowed by reduction of the derived crude imine with excess
salicylate salt of (+)-physostigmine.25
(27) Since 25% of the steps are involved in preparing (Z)-siloxybutenoic
acid 12, we investigated Heck cyclizations of anilides prepared from
commercially available methacrylic acid. Although carbonylative Heck
cyclizations could be realized (eq 1), enantioselection was never satisfactory.
Results of these investigations are briefly summarized in the Supporting
Information.
LiAlH4 in refluxing THF afforded (-)-esermethole (21), [R]25
D
-141 ° (c 0.4, C6H6); lit.15a [R]25 -134 ° (c 0.3, C6H6), in
D
88% yield (Scheme 3). Using conditions optimized by Brossi,
this intermediate was transformed in two steps (31% overall
(22) Castro, B.; Dormoy, J. R.; Evin, G.; Selve, C. Tetrahedron Lett.
1975, 1219.
(23) BINAP ) 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl: Takaya, H.;
Mashima, K.; Koyano, K.; Yagi, M.; Kumobayashi, H.; Taketomi, T.;
Akutagawa, S.; Noyori, R. J. Org. Chem. 1986, 51, 629.
(24) A Diacel Chiralcel OD column (9:1 hexane-i-PrOH) provided
baseline resolution of enantiomers; chromatograms are provided in the
Supporting Information.
(28) General experimental details have been described.19 Conventional
silica gel flash chromatography is abbreviated as sgc.

Calabar Alkaloids Physostigmine and PhysoVenine
J. Am. Chem. Soc., Vol. 120, No. 26, 1998 6503
A mixture of this sample of 16 (329 mg, 0.845 mmol) and
o-iodoaniline 1520 (452 mg, 1.72 mmol) was heated at 60 °C for 4 h.
After cooling to room temperature, the crude product was purified by
sgc (5:1 hexanes-EtOAc) to give anilide 17 (350 mg, 80%): 1H NMR
(300 MHz, CDCl3, a 3:1 mixture of amide rotamers) major rotamers
δ 7.38 (d, J ) 2.8 Hz, 1H), 7.25 (d, J ) 8.7 Hz, 1H), 6.81 (dd, J )
8.7, 2.8 Hz, 1H), 5.38 (br t, J ) 6.5 Hz, 1H), 4.29-4.38 (m, 2H), 3.80
(s, 3H), 3.23 (s, 3H), 1.58 (br s, 3H), 1.02-1.20 (m, 21H); minor
rotamersδ 7.41 (d, J ) 2.8 Hz, 1H), 7.09 (d, J ) 8.7 Hz, 1H), 6.94
(dd, J ) 8.7, 2.8 Hz, 1H), 5.68 (br t, J ) 6.6 Hz, 1H), 4.38-4.43 (m,
2H), 3.80 (s, 3H), 3.27 (s, 3H), 2.06 (br s, 3H), 1.02-1.20 (m, 21H);
13C NMR (75 MHz, CDCl3) major rotamersδ 171.0, 158.9, 137.9,
133.4, 130.6, 128.5, 124.3, 114.6, 98.5, 61.3, 55.4, 36.5, 19.8, 17.9,
11.8; minor rotamersδ 170.8, 158.8, 137.6, 132.6, 131.4, 129.1, 124.5,
115.4, 97.8, 61.1, 60.1, 38.6, 20.8, 17.9, 11.8; IR (film) 1652, 1594
cm-1; HRMS (CI) m/z 518.1582 (518.1589 calcd for C22H37INO3Si).
Anal. Calcd for C22H36INO3Si: C, 51.06; H, 7.01; N, 2.71. Found:
C, 51.15; H, 7.02; N, 2.66.
1.5 h. After cooling to room temperature, excess hydride was
decomposed by adding EtOAc (15 mL) dropwise. Saturated aqueous
NaHCO3 (15 mL) was added, the phases were separated, the aqueous
layer was extracted with EtOAc (2 × 15 mL), and the combined organic
extracts were washed with brine (14 mL), dried (MgSO4), and
concentrated. Purification of the residue by sgc (99:1 to 20:1 CHCl3-
MeOH) gave (-)-esermethole (21, 51.4 mg, 88%, 99%ee29a) as a
slightly yellow solid: mp 53-54 °C; [R]25D -141°, [R]405 -334°, [R]435
-285°, [R]546 -171°, [R]577 -150° (c 0.36, C6H6).
(-)-Physostigmine (2). Following the procedure of Brossi,25 21
(50.2 mg, 0.261 mmol) was converted to (-)-physostigmine (19 mg,
32% overall): mp 103-104 °C; [R]25 -116° (c 0.4, C6H6); (-)-
D
physostigmine salicylate: mp 145-146 °C; [R]25D -75° (c 0.5, EtOH).
(3aS)-3,3a,8,8a-Tetrahydro-5-methoxy-3a,8-dimethyl-2H-furo-
[2,3-b]indole (22). A mixture of aldehyde (S)-19 (151 mg, 0.646
mmol), LiAlH4 (124 mg, 0.328 mmol), and THF (10 mL) was stirred
at room temperature for 40 min. Workup as described for the
preparation of 21 and sgc (4:1f1:1 hexanes-EtOAc) afforded 133
(S)-3-(2-Oxoethyl)-1,2-dihydro-5-methoxy-1,3-dimethyl-2-oxo-
[3H]indole [(S)-19]. A mixture of Pd2(dba)3‚CHCl3 (360 mg, 0.347
mmol), (S)-BINAP (504 mg, 0.809 mmol), and N,N-dimethylacetamide
(DMA, 21 mL) was stirred at room temperature for 65 min. To the
resulting orange solution was added a solution of iodoanilide 17 (1.82
g, 3.51 mmol), 1,2,2,6,6-pentamethylpiperidine (3.2 mL, 18 mmol),
and DMA (18 mL), and the reaction was heated at 100 °C for 90 min.
The resulting dark solution was poured into half-saturated aqueous
NaHCO3 (100 mL) and extracted with ether (3 × 150 mL). The
combined organic extracts were washed with brine (100 mL), dried
(MgSO4), and concentrated, and the residue was purified by sgc (9:1
f 1:1 hexanes-EtOAc) to give oxindole enoxysilane (S)-18 (1.29 g,
mg (0.604 mmol, 94%, 100%ee29b) of 22: mp 35.0-35.5 °C; [R]25
D
-100°, [R]405 -262°, [R]435 -220°, [R]546 -124°, [R]577 -108°, (c
0.4, CHCl3).
(-)-Physovenine (10). Following the general procedure of Brossi,25
22 (103 mg, 0.467 mmol) was demethylated with BBr3. A mixture of
the resulting phenol (82.7 mg, 0.40 mmol), NaH (60% oil dispersion,
1.6 mg, 0.040 mmol), and THF (5.0 mL) was stirred at room
temperature for 5 min, and methylisocyanate (29.0 µL, 0.492 mmol)
was added dropwise. After 10 min, the solution was concentrated, and
the residue was added to a mixture of EtOAc (10 mL) and saturated
aqueous NaHCO3 (5 mL). The phases were separated, the aqueous
layer was extracted with EtOAc (8 mL), and the combined organic
extracts were washed with brine (10 mL), dried (Na2SO4), and
concentrated. Purification of the residue by preparative TLC (1:1
hexanes-EtOAc) and recrystallization (hexanes-EtOAc) gave (-)-
94%) as a 98:2 mixture of geometric isomers: [R]25 -81°, [R]405
D
-224°, [R]435 -182°, [R]546 -98°, [R]577 -85°, (c 0.61, C6H6); 1H NMR
(300 MHz, CDCl3) 6.72-6.84 (m, 3H), 6.35 (d, J ) 12.0 Hz, 1H),
5.19 (d, J ) 12.0 Hz, 1H), 3.80 (s, 3H), 3.17 (s, 3H), 1.44 (s, 3H),
0.99-1.17 (m, 21H); 13C NMR (75 MHz, CDCl3) δ 179.1, 155.9, 142.9,
136.3, 134.9, 112.2, 110.7, 108.3, 55.7, 47.8, 26.3, 23.7, 17.6, 11.9;
IR (film) 1655, 1636, 1600 cm-1; HRMS (CI) m/z 390.2479 (390.2464
calcd for C22H36NO3Si). Anal. Calcd for C22H35NO3Si: C, 67.82; H,
9.05; N, 3.60. Found: C, 67.96; H, 9.19; N, 3.54.
physovenine (10, 63 mg, 60%, 100% ee30): mp 125-125.5 °C; [R]26
-87°(c 0.26, EtOH).
D
Acknowledgment. We wish to thank Atsuyuki Ashimori for
his early studies in this area. Support from NIH (GM-30859)
and Shionogi & Co. Ltd.are gratefully acknowledged. Additional
support from Merck, Pfizer, Roche Biosciences, and SmithKline
Beecham is gratefully acknowledged. NMR and mass spectra
were determined at UCI using instruments acquired with the
assistance of NSF and NIH Shared Instrumentation Programs.
A solution of (E)-enoxysilane (S)-18 (1.26 g, 3.23 mmol), 3 M HCl
(10 mL), and THF (25 mL) was maintained at room temperature
overnight. The reaction was then cooled in an ice bath and poured
into saturated aqueous NaHCO3 (100 mL), and the resulting mixture
was extracted with EtOAc (2 × 90 mL). The combined organic extracts
were dried (MgSO4), filtered, and concentrated, and the residue was
purified by sgc (4:1 f 1:2 hexanes-EtOAc) to afford pure aldehyde
(S)-19 (673 mg, 89%, 96% ee24). Recrystallization from EtOAc-
hexane provided enantiopure24 (S)-19 in 80% yield: mp 116-117 °C;
Supporting Information Available: Preparation and char-
acterization data for compound 20, optical rotation and chiral
HPLC data for compounds in the ent series, table and
experimental details for carbonylative Heck cyclization of 23
f 24, experimental details for the conversion of 12 f 13 and
copies of HPLC traces used to determine enantiomeric purity
of crude and pure (S)-19, 21-, and ent-21 and 2 and ent-2 (8
pages, print/PDF). See any current masthead page for ordering
information and Web access instructions.
[R]25 +49°, [R]405 +151°, [R]435 +115°, [R]546 +58°, [R]577 +50° (c
D
1
0.67, C6H6); H NMR (300 MHz, CDCl3) δ 9.52 (s, 1H), 6.75-6.85
(m, 3H), 3.79 (s, 3H), 3.24 (s, 3H), 3.00 (dd, J ) 17.3, 1.2 Hz, 1H),
2.91 (dd, J ) 17.3, 1.9 Hz, 1H), 1.41 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 198.7, 179.1, 156.0, 136.6, 134.0, 112.0, 110.2, 108.5, 55.7,
50.4, 45.3, 26.4, 23.9; IR (CHCl3) 1702, 1601 cm-1; HRMS (CI) m/z
234.1136 (234.1130 calcd for C13H16NO3). Anal. Calcd for C13H15-
INO3: C, 66.94; H, 6.48; N, 6.00. Found: C, 66.98; H, 6.54; N, 6.04.
(-)-Esermethole (21). A mixture of enantiopure aldehyde (S)-19
(58 mg, 0.25 mmol), MeNH2‚HCl (170 mg, 2.5 mmol), Et3N (0.35
mL, 2.5 mmol), MgSO4 (170 mg), and THF (6 mL) was stirred at room
temperature overnight. Solid LiAlH4 (95 mg, 2.5 mmol) was then added
to this suspension, and the resulting mixture was heated at reflux for
JA980788+
(29) The enantiomeric excess was determined by HPLC analysis on a
Diacel Chiralcel OD column using as eluent: (a) 99:1 hexane-i-PrOH;
(b) 99.5:0.5 hexane-i-PrOH.
(30) The enatiomeric excess was determined by HPLC analysis on a
Diacel Chiralcel OJ column (85:15 hexane-i-PrOH).