Approaches to the synthesis of (+/-)-strychnine via the cobalt-mediated [2 + 2 + 2] cycloaddition: rapid assembly of a classic framework.

Article abstract of DOI:10.1021/ja016333t

Five synthetic approaches to racemic strychnine (1), with the cobalt-mediated [2 + 2 + 2] cycloaddition of alkynes to indoles as the key step, are described. These include the generation and attempted cyclization of macrocycle 8 and the synthesis of dihydrocarbazoles 15, 22, and 26 and their elaboration to pentacyclic structures via a conjugate addition, dipolar cycloaddition, and propellane-to-spirofused skeletal rearrangement, respectively. Finally, the successful total synthesis of 1 is discussed. The development of a short, highly convergent route (14 steps in the longest linear sequence) is highlighted by the cyclization of enynoylindole 40 with acetylene and the formal intramolecular 1,8-conjugate addition of amine 49 to form pentacycle 50. Numerous attempts toward the formation of the piperidine ring of 1 from vinyl iodide 56 were made and its successful formation via palladium-, nickel-, and radical-mediated processes is described.

Full text of DOI:10.1021/ja016333t

9324
J. Am. Chem. Soc. 2001, 123, 9324-9337
Approaches to the Synthesis of (()-Strychnine via the
Cobalt-Mediated [2 + 2 + 2] Cycloaddition: Rapid Assembly of a
Classic Framework
Michael J. Eichberg, Rosa L. Dorta,† Douglas B. Grotjahn,‡ Kai Lamottke,§
Martin Schmidt, and K. Peter C. Vollhardt*
Contribution from the Center for New Directions in Organic Synthesis, Department of Chemistry,
UniVersity of California at Berkeley, and the Chemical Sciences DiVision, Lawrence Berkeley National
Laboratory, Berkeley, California 94720-1460
ReceiVed June 1, 2001
Abstract: Five synthetic approaches to racemic strychnine (1), with the cobalt-mediated [2 + 2 + 2]
cycloaddition of alkynes to indoles as the key step, are described. These include the generation and attempted
cyclization of macrocycle 8 and the synthesis of dihydrocarbazoles 15, 22, and 26 and their elaboration to
pentacyclic structures via a conjugate addition, dipolar cycloaddition, and propellane-to-spirofused skeletal
rearrangement, respectively. Finally, the successful total synthesis of 1 is discussed. The development of a
short, highly convergent route (14 steps in the longest linear sequence) is highlighted by the cyclization of
enynoylindole 40 with acetylene and the formal intramolecular 1,8-conjugate addition of amine 49 to form
pentacycle 50. Numerous attempts toward the formation of the piperidine ring of 1 from vinyl iodide 56 were
made and its successful formation via palladium-, nickel-, and radical-mediated processes is described.
Introduction
Strychnine (1, Figure 1), the infamous poisonous alkaloid,
has been known to man for thousands of years, and to Western
medicine since the sixteenth century. Although in the past it
has found application as a mild stimulatory tonic and appetite
enhancer, its most common uses today are as a rodenticide and
animal stimulant. Isolated in quantity from the Southeast Asian
Strychnos nux-Vomica and Strychnos ignatii, in which the
alkaloid is present in as much as 1.5-2%, strychnine toxicity
arises from the blocking of postsynaptic inhibition in the spinal
cord and lower brain stem where it acts as a competitive ligand
at the neuronal receptor for glycine, an inhibitory neurotrans-
mitter.1 As a high-affinity and highly selective antagonist, the
alkaloid has been useful as a tool for the structural characteriza-
tion of this receptor, as well as in numerous biochemical studies
of the nervous system.2 For an adult human, a lethal dose of
strychnine is in the range of 100-300 mg. Death is caused by
asphyxiation, a result of the intense convulsions induced by
acoustic, tactile, or visual stimuli and the subsequent respiratory
paralysis.3
Figure 1. The strychnine (1) structure with numbering and ring labeling
used throughout this paper.
Strychnine holds a special place in the history of organic
chemistry. First isolated in 1818, it was one of the first alkaloids
to be obtained in pure form.4 The pursuit of its molecular
structure presented a formidable challenge for classical degra-
dative strategies and lasted more than 60 years, resulting in the
publication of hundreds of papers and communications.5 The
experimental work of Leuchs and Robinson stands out as the
most notable among these,6 and it was the latter who, in 1946,
proposed the correct structure for strychnine.7 In the following
year, Woodward independently suggested the same framework.8
This accomplishment signaled the culmination and the end of
the era of classical structure elucidation. Only four years later,
final confirmation of the structure of 1 was obtained by X-ray
crystallography.9
* To whom correspondence should be addressed.
† Current address: I.U.B.O., “A.G.”, Universidad de La Laguna, 38206
La Laguna, Tenerife, Spain.
‡ Current address: Department of Chemistry, San Diego State University,
San Diego, CA 92182-1030.
(4) (a) Pelletier, P. J.; Caventou, J. B. Ann. Chim. Phys. 1818, 8, 323.
(b) Pelletier, P. J.; Caventou, J. B. Ann. Chim. Phys. 1819, 810, 142.
(5) For a review, see: Smith, G. F. In The Alkaloids; Manske, R. H. F.,
Ed.; Academic Press: New York, 1965; Vol. 8, pp 591-671.
(6) (a) Leuchs, H. Ber. Dtsch. Chem. Ges. 1939, 72, 1588. (b) Briggs,
L. H.; Openshaw, H. T.; Robinson, R. J. J. Chem. Soc. 1946, 903.
(7) Openshaw, H. T.; Robinson, R. J. Nature 1946, 157, 438.
(8) (a) Woodward, R. B.; Brehm, W. J. J. Am. Chem. Soc. 1948, 70,
2107. (b) Woodward, R. B.; Brehm, W. J.; Nelson, A. L. J. Am. Chem.
Soc. 1947, 69, 2250.
§ Current address: Bicoll GmbH, Schwindstrasse 29, 80798 Mu¨nchen,
Germany.
(1) Aprison, M. H. In Glycine Neurotransmission; Otterson, O. P., Strom-
Mathisen, J., Eds.; Wiley: New York, 1990; pp 1-23.
(2) For recent reviews see: (a) Chebib, M.; Johnston, G. A. R. Clin.
Exp. Pharmacol. Physiol. 1999, 26, 937. (b) Breitinger, H. G.; Becker, C.
M. Curr. Pharmacol. Des. 1998, 4, 315. (c) Be´chade, C.; Sur, C.; Triller,
A. Bioessays 1994, 16, 735.
(3) Klaassen, C. D. In The Pharmacological Basis of Therapeutics, 9th
ed.; Hardman, J. G., Limbid, L. E., Eds.; McGraw-Hill: New York, 1995;
pp 1689-1690.
(9) (a) Robertson, J. H.; Beevers, C. A. Acta Crystallogr. 1951, 4, 270.
(b) Bokhoven, C.; Schoone, J. C.; Bijovet, J. M. Acta Crystallogr. 1951, 4,
275. (c) Peerdemann, A. F. Acta Crystallogr. 1956, 9, 824.
10.1021/ja016333t CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/30/2001

Synthesis of (()-Strychnine
J. Am. Chem. Soc., Vol. 123, No. 38, 2001 9325
When Woodward began his total synthesis of strychnine in
1948, the construction of a molecule of such complexity had
never before been undertaken. Its completion in 1954 remains
a landmark in organic chemistry and helped usher in the era of
modern organic synthesis.10 The challenge posed by the
molecule, with its seven rings and six stereocenters displayed
across a framework of only 24 atoms, combined with its
historical significance, has resulted in the continued attraction
of the alkaloid as a synthetic target. Remarkably, nearly 40 years
elapsed before Woodward’s seminal achievement was equaled,
with the report of numerous syntheses within the last 10 years.11
These include the relay total synthesis of (-)-strychnine by
Magnus;12 the asymmetric total syntheses by Overman,13
Kuehne,14 and Bosch;15 and the assembly of the racemic form
by Kuehne,16 Rawal,17 Stork,18 Martin,11a,19 and our laboratory.20
Here we offer a complete description of our efforts toward the
synthesis of 1 employing a cobalt-mediated [2 + 2 + 2]
cycloaddition reaction and the ultimate development of a
successful approach. 21
Scheme 1. Cobalt-Mediated [2 + 2 + 2] Cycloadditions to
Indoles
The Cobalt Way to Strychnine
The cobalt-mediated [2 + 2 + 2] cycloaddition has proven
to be a powerful tool for the construction of complex, polycyclic
molecules. The ability of cyclopentadienylcobalt to effect the
cyclization of three unsaturated functionalities with a high degree
of chemo-, regio-, and stereoselectivity has resulted in the
synthesis of several complex natural22 and unnatural23 products.
Among the wide variety of unsaturated functionalities which
participate in this reaction are a number of aromatic heterocyclic
double bonds, such as those in pyrrole,24a imidazole,24b thiophene,
furan,24c and benzofuran.24d The indole nucleus is also active
in these cyclizations, as exemplified by the selections in Scheme
Scheme 2. Retrosynthetic Analysis of a Cobalt-Mediated
Approach to 1 from N-(4-Pentynoyl)indoles
(10) (a) Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.;
Daeniker, H. U.; Schenker, K. J. J. Am. Chem. Soc. 1954, 76, 4749.(b)
Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker, H. U.;
Schenker, K. J. Tetrahedron 1963, 19, 247. (c) Nicolaou, K. C.; Sorensen,
E. J. Classics in Total Synthesis; VCH: Weinheim, 1996; pp 21-40.
(11) For reviews see: (a) Bonjoch, J.; Sole, D. Chem. ReV. 2000, 100,
3455. (b) Beifuss, U. Angew. Chem., Int. Ed. Engl. 1994, 33, 1144.
(12) Magnus, P.; Giles, M.; Bonnert, R.; Johnson, G.; McQuire, L.;
Deluca, M.; Merritt, A.; Kim, C. S.; Vicker, N. J. Am. Chem. Soc. 1993,
115, 8116.
(13) Knight, S. D.; Overman, L. E.; Pairaudeau, G. J. Am. Chem. Soc.
1995, 117, 5776.
(14) Kuehne, M. E.; Xu, F. J. Org. Chem. 1998, 63, 9427.
(15) Sole´, D.; Bonjoch, J.; Garc´ıa-Rubio, S.; Peidro´, E.; Bosch, J. Chem.
Eur. J. 2000, 6, 655.
(16) Kuehne, M. E.; Xu, F. J. Org. Chem. 1993, 58, 7490.
(17) Rawal, V. H.; Iwasa, S. J. Org. Chem. 1994, 59, 2685.
(18) Stork, G. Reported at the Ischia Advanced School of Organic
Chemistry, Ischia Porto, Italy, September 21, 1992.
(19) Martin, S. F.; Clark, C. W.; Ito, M.; Mortimore, M. J. Am. Chem.
Soc. 1996, 118, 9804.
(20) Eichberg, M. J.; Dorta, R. L.; Lamottke, K.; Vollhardt, K. P. C.
Org. Lett. 2000, 2, 2479.
(21) Some of this work has appeared as preliminary communications:
(a) Grotjahn, D. B.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1990, 112, 5653.
(b) Reference 20.
(22) Saa, C.; Crotts, D. D.; Hsu, G.; Vollhardt, K. P. C. Synlett 1994,
487 and references therein.
(23) Vollhardt, K. P. C.; Mohler, D. L. AdVances in Strain in Organic
Chemistry; JAI Press: Greenwich, CT, 1996; Vol. 5, pp 121-160.
(24) (a) Sheppard, G. S.; Vollhardt, K. P. C. J. Org. Chem. 1986, 51,
5496. (b) Boese, R.; Kno¨lker, H. J.; Vollhardt, K. P. C. Angew. Chem., Int.
Ed. Engl. 1987, 26, 1035. (c) Boese, R.; Harvey, D. F.; Malaska, M. J.;
Vollhardt, K. P. C. J. Am. Chem. Soc. 1994, 116, 11153. (d) Pe´rez, D.;
Siesel, B. A.; Malaska, M. J.; David, E.; Vollhardt, K. P. C. Synlett 2000,
366. (e) Pelissier, H.; Rodriguez, J.; Vollhardt, K. P. C. Chem. Eur. J. 1999,
5, 3549.
1.25 Indoles, including those substituted at C3, can be cyclized
both intra- and intermolecularly. Additionally, a wide variety
of functionalized alkynes can participate in the reaction, often
with a high degree of regioselectivity. Finally, the cyclizations
give the cis orientation of the H and R substituents at C2 and
C3. Consideration of 1 as a multiply fused indole derivative
suggested the application of the cobalt-mediated [2 + 2 + 2]
cycloaddition as a unique entry into the strychnine framework.
In our proposed approach (Scheme 2), the partly intramo-
lecular cyclization of N-(4-pentynoyl)indole derivatives B would
furnish a dihydrocarbazole system A constituting the A,B,C,D
frame of 1. Construction of the E ring was envisaged to involve
nucleophilic attack of the nitrogen on the D ring diene unit.
Ring F was thought to be accessible by a transition metal
catalyzed coupling of an appropriately functionalized N-alkenyl
function, thus providing the strychnine derivative, isostrychnine
(2). Closure of the final ring would then proceed through the
(25) (a) Grotjahn, D. B.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1986,
108, 2091. (b) Boese, R.; Van Sickle, A. P.; Vollhardt, K. P. C. Synthesis
1994, 1374.

9326 J. Am. Chem. Soc., Vol. 123, No. 38, 2001
Eichberg et al.
Figure 2. Synthetic approaches to E ring and the Wieland-Gumlich aldehyde (3).
well-known isostrychnine-strychnine isomerization (eq 1).26,27
The AB f ABCD f ABCDEF Approach to 1
In a first attempt to implement the general strategy of Scheme
2, we envisioned the cyclization of 5 with an appropriate alkyne
leading to an ABCD intermediate 4 (Scheme 3). Subsequent
manipulation might eventually lead to 2 and hence 1. The
attractions of this strategy were the early control of the
stereochemistry at C21-C22 and the similarly early installation
of the C14-C21 connection.
The strategy described here presents a previously unexplored
approach to the strychnine heptacycle. Not only does the early
formation of the tetrahydropyridone ring C differ fundamentally
from those routes which culminate in the conversion of the
Wieland-Gumlich aldehyde (3) to 128,29 (Figure 2, eq 1), but
also a cobalt-mediated ring assembly presents a topologically
novel entry into the isostrychnine system when compared to
other syntheses (Figure 3). The establishment of the C7
quaternary center, which in most syntheses is associated with
formation of the pyrrolidine E ring, is a crucial step in the
synthesis of 1. Whereas Bosch and co-workers used a Claisen
rearrangement to solve this problem, and the groups of Martin
and Stork both applied a base-catalyzed skeletal rearrangement,
most strategies have utilized an intermediate imine species to
form the necessary carbon-carbon bond. Apart from our
approach, only Rawal has addressed this issue through a
cycloaddition reaction by employing the classical [4 + 2]
process.
To investigate the feasibility of this cyclization, the model
system 8 was chosen (Scheme 4). Tryptamine was alkylated
with commercially available 2,3-dibromo-1-propene to afford
6 in 59% yield. After protection of the amine function as a
carbamate,30 the indole nitrogen was acylated with 4-pentynoyl
chloride,31 giving 7 in 50% yield.32 Finally, intramolecular
coupling was achieved using palladium and Cu(I) in triethyl-
amine under high dilution conditions.33 Attempts to improve
the moderate yields of 8 (27%) by variation of reaction
temperature or concentration of the substrate were unsuccessful.
Unfortunately, upon exposure to 1-methoxy-2-trimethylsi-
lylethyne (9) in the presence of CpCo(CO)2 in refluxing
m-xylene, 8 gave cyclobutadiene complexes 11 as a 12:1 mixture
of regioisomers in 64% overall yield. The incorporation of the
alkyne cocyclization partner 9 and cyclopentadienyl cobalt was
evident from the electron-impact MS (M+ ) 630) and 1H NMR
spectrum, which displayed trimethylsilyl peaks at δ 0.20 (s, 9H)
and 0.23 (s, 9H) ppm, methoxy signals at δ 3.59 (s, 3H) and
(26) Prelog, V.; Battegay, J.; Taylor, W. I. HelV. Chim. Acta 1948, 31,
2244.
(27) Formation of 2 from 1: Leuchs, H.; Schulte, H. Chem. Ber. 1942,
75, 1522.
(28) Anet, F. A. L.; Robinson, R. Chem. Ind. 1953, 245.
(29) Formation of 3 from 1: (a) Wieland, H.; Gumlich, W. Liebigs Ann.
Chem. 1932, 494, 191. (b) Wieland, H.; Kaziro, K. Liebigs Ann. Chem.
1933, 506, 60. (c) Anet, F. A. L.; Robinson, R. J. Chem. Soc. 1955, 2253.
(d) Hymon, J. R.; Schmid, H.; Karrer, P.; Boller, A.; Els, H.; Fahrni, P.;
Fu¨rst, A. HelV. Chim. Acta 1969, 52, 1564. (e) Szabo, L.; Clauder, O. Acta
Chim. Acad. Sci. Hung. 1977, 95, 85. (f) Kapoor, V. K.; Sharma, S. K.;
Chagti, K. K.; Singh, M. Ind. J. Chem. 1988, 27B, 641.
(30) Carpino, L. A. Acc. Chem. Res. 1973, 6, 191.
(31) (a) Schulte, K. E.; Reisch, J. Arch. Pharm. (Weinheim, Ger.) 1959,
292, 51. (b) Prepared by a modification of the method for 5-hexanoyl
chloride reported in: Earl, R. A.; Vollhardt, K. P. C. J. Org. Chem. 1984,
49, 4786.
(32) Kikugawa, Y. Synthesis 1981, 460.
(33) (a) Sonogashira, K. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1990; Vol. 3, p 521.
(b) Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara, N. Synthesis
1980, 627. (c) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 15, 4467.

Synthesis of (()-Strychnine
J. Am. Chem. Soc., Vol. 123, No. 38, 2001 9327
Figure 3. Synthetic approaches to isostrychnine (2).
Scheme 3. Synthetic Approach to 1 via a [2 + 2 + 2]
Cycloaddition of Macrocycle 5
Scheme 4. Synthesis and Cyclization of Model Macrocycle
8a
3.48 (s, 3H) ppm, and Cp absorptions at δ 4.73 (s, 5H) and
4.75 (s, 5H) ppm for the major and minor isomers, respectively.
Corresponding resonances for the aromatic pyrrole at δ 7.06
(s, 1H) and 7.14 (s, 1H) ppm indicated that the aromatic indole
nucleus was still intact. The regiochemistry of the two isomers
could not be assigned using 1D or 2D NOE experiments. The
exclusive formation of 11 was disappointing, considering that
9 had typically been an excellent [2 + 2 + 2] cocyclization
partner in N-(4-pentynoyl)indole cyclizations.25a
a Conditions: (a) 2,3-dibromo-1-propene (0.5 equiv), toluene, 111
°C, 1.75 h, 59%; (b) (t-BuO2C)2O (1 equiv), CH2Cl2, room temperature,
1 h, 87%; (c) i. KOH, glyme, room temperature, 15 min; ii. 4-pentynoyl
chloride (1.5 equiv), glyme, 0 °C, 1 min, 50%; (d) Pd(PPh3)2Cl2 (2.5
mol %), CuI (5 mol %), HNEt2, 55 °C, 24 h, 27%.
cyclobutadiene 12 as a single isomer of unknown configuration
in 40% yield. The failure of 8 to undergo [2 + 2 + 2]
cycloaddition could originate from a metallacyclopentadiene
intermediate (see, e.g., Scheme 13) too strained to coordinate
and insert the enamine double bond of the indole moiety.
Alternatively, preferential formation of the undesired metalla-
cyclopentadiene regioisomer, placing the vinyl substituent R to
Variation of the reaction conditions in an attempt to favor
addition to the indole system was unsuccessful. In analogous
cyclizations, it was found that lowering the reaction temperature
increased the yield of the six-membered-ring relative to the four-
membered-ring product.24a However, reaction of 8 at room
34
temperature using CpCo(C2H4)2 gave again only 11 (29%),
in addition to unreacted starting material (19%). Use of another
cocyclization partner, namely acetylenic ester 10, generated
(34) Jonas, K.; Deffense, E.; Habermann, D. Angew. Chem., Int. Ed. Engl.
1983, 22, 716.

9328 J. Am. Chem. Soc., Vol. 123, No. 38, 2001
Eichberg et al.
the cobalt, would preclude the desired insertion. In either case,
formal reductive elimination to form the cyclobutadiene complex
is the most favored alternative pathway. In view of these
difficulties, the macrocycle approach was abandoned.
Scheme 5. Formation of E Ring via Intramolecular
Conjugate Additiona
Unsuccessful AB f ABCD f ABCDE f ABCDEF
Approaches to 1: Formation of Ring E from ABCD
Intermediates
Given the impeded cyclization of the large constrained ring
in 8, an alternative route to 1 was developed via the successive
formation of the E, F, and G rings of 1 from readily available
N-(4-pentynoyl)indole cyclization products A (Scheme 2), such
as those shown in Scheme 1. This strategy involved the synthesis
of a highly functionalized ABCD ring system that would allow
the closure of the E and F rings in a minimum number of steps.
Thus, the following studies focused on the selection of an
appropriate [2 + 2 + 2] cyclization partner for the alkyne-
tethered indole system and the subsequent formation of the
necessary C-N and C-C bonds. While ultimately unsuccessful,
they provided some interesting insights into the virtually
unknown chemistry of the dihydrocarbazole nucleus A (Scheme
2) accessed by our methodology.
E Ring via Intramolecular Conjugate Addition. The
presence of a double bond at C15-C16 in the cycloaddition
products suggested the use of a Michael addition for the
formation of the C-N bond and the pyrrolidine ring. For this
purpose, the unsaturated aldehyde 18 was synthesized as shown
in Scheme 5. Cyclization precursor 14 was prepared from
tryptamine in three steps and cyclized with 3-trimethylsilylpro-
pyn-1-ol to yield 15 (34% from tryptamine), along with a small
amount of internally cyclized 16 (5% from 14). Structural and
regiochemical assignments of the cyclohexadiene products were
based on the ample precedent provided by similar systems21a,25,35
and utilized the anisotropy of cobalt in 1H NMR spectra. While
spectrally similar to 15, the identification of silyl ether 16 was
based on mass spectrometry (M+ ) 666, indicating a loss of
CH4 with respect to 15), the lack of a hydroxy group absorption
in the IR spectrum, and the presence of two singlets at δ 0.38
(3H) and 0.24 (3H) ppm in the 1H NMR spectrum.36 Hydrolysis
of the silicon-carbon bond in 15 and 16 with fluoride ion
followed by demetalation with iron(III) afforded free ligand 17,
a Conditions: (a) i. PhCHO (1.1 equiv), MeOH, 25 °C, 1 h; ii. NaBH4
(0.6 equiv), 25 °C, 10 min; iii. (t-BuO2C)2O (1.4 equiv), CH2Cl2, 25
°C, 10 min, 84%; (b) i. KOH, glyme, 20 min; ii. 4-pentynoyl chloride,
0 °C, 5 min, 74%; (c) 3-trimethylsilylpropyn-1-ol (2 equiv), CpCo(CO)2
(1.7 equiv), pyridine (0.5 equiv), m-xylene, reflux, 15 h; (d) i. Me3BnNF
(1.1 equiv), THF, reflux, 2-4 h; ii. Fe(NO3)3‚9H2O (3 equiv), THF, 0
°C, 5 min, 83%; (e) activated MnO2 (13.2 mmol), CH2Cl2, 25 °C, 4 h,
88%; (f) i. TMSI (1.6 equiv), CH2Cl2, 25 °C, 20 min; ii. NaHCO3,
H2O-MeOH, 25 °C, 0.5 h, 53%.
37
which was oxidized with MnO2 to form the R,â-enal 18.
Finally, treatment of the aldehyde with TMSI gave the penta-
cycle 19 in 53% yield.38
J value of 10.5 Hz.39 Attempts to isomerize 19 with base (DBN,
THF, 25 °C, 1 d) failed.
Consistent with the formation of the pyrrolidine ring, the 13
C
NMR-DEPT spectrum showed the disappearance of the methine
carbon at δ 145.4 ppm and the quaternary carbon signal at δ
133.7 ppm assigned to C16 and C14, respectively, in 18 and
two new methine signals upfield at δ 72.1 (C16) and 31.2 (C14)
ppm. In the 1H NMR spectrum, the signal assigned to the C16
methine at δ 6.26 (s, 1H) ppm in 18 was replaced by a signal
E Ring via an Intramolecular Dipolar Cycloaddition.
Another attractive method for the formation of the C-N bond
involved an intramolecular [2 + 3] cycloaddition of an azide
moiety with an enol ether unit at C15-C16,40 followed by acid-
catalyzed expulsion of nitrogen to form the desired pyrrolidine
ring.41 The precursor for this transformation was readily
available in six steps from indole-3-ethanol42 (Scheme 6).
Cyclization of the silyl ether 20 with alkyne 9 afforded the
desired product 21 in 60% yield.25a Simple functional group
manipulation gave the azide 22 in 70% yield from 21. Dipolar
cycloaddition studies were conducted at mild temperatures (80-
90 °C) to avoid nitrene formation and at low concentration
1
at δ 3.38 (s, 1H) ppm. The H NMR spectrum of 19 also
displayed a doublet at δ 4.27 (1H) ppm that was assigned to
the hydrogen at C8, exhibiting a coupling constant of 3.9 Hz.
This value is consistent with the presence of the undesired cis
relationship between the C8 and C13 methine hydrogens. In
strychnine, the corresponding trans configured protons have a
(35) Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl. 1984, 23, 539.
(36) For precedence, see: (a) Uemura, M.; Kobayashi, T.; Isobe, K.;
Minami, T.; Hayashi, Y. J. Org. Chem. 1986, 51, 2859. (b) Hillard, R. L.,
III; Vollhardt, K. P. C. Tetrahedron 1980, 36, 2435.
(39) Carter, J. C.; Luther, G. W.; Long, T. C. J. Magn. Reson. 1974, 15,
122.
(40) (a) Scriven, E. F. V.; Turnbull, K. Chem. ReV. 1988, 88, 351. (b)
Padwa, A. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.;
Wiley: New York, 1984; Vol. 2, p 277.
(41) Uhle, F. C. J. Org. Chem. 1967, 32, 1596.
(42) Nogrady, T.; Doyle, T. W. Can. J. Chem. 1964, 43, 485.
(37) Fatiadi, A. J. Synthesis 1976, 65.
(38) (a) Greene, T. W.; Wuts, P. G. M. ProtectiVe Group in Organic
Synthesis, 3rd ed.; Wiley: New York, 1999; p 521. (b) Olah, G. A.; Narang,
S. C. Tetrahedron 1982, 38, 2225.

Synthesis of (()-Strychnine
J. Am. Chem. Soc., Vol. 123, No. 38, 2001 9329
Scheme 6. Preparation and Dipolar Cycloaddition of Azide
Scheme 7. Oxidative Cyclization and Rearrangement of
22a
2621a
the desired (albeit oxidized) pyrrolidine ring was gratifying.44,45
However, the incorporation of oxygen into these products,
despite efforts to exclude it, indicates that the cycloaddition
intermediates (which may be either zwitterionic46 or radical47
in nature) are remarkably efficient scavengers of O2.48 Never-
theless, diene 25 represented a promising ABCDE intermediate
and contained the desired C12-C13 double bond of isostrych-
nine (2). The required cis fusion of the pyrrolidine ring system
was anticipated to be available by a selective reduction of the
imine. However, we chose to abandon this approach given the
poor yields of the dipolar cycloaddition and the difficulty of
the piperidine ring formation employing the enol ether func-
tionality encountered in studies of 28 and 30b (vide infra).
E Ring via Oxidative Cyclization and Rearrangement and
Attempts to Elaborate to F Ring. The most promising lead
for a successful utilization of structures of type A (Scheme 2)
was provided by the discovery that complex 26, prepared as in
Scheme 1, could be converted to the propellane 27 by oxidation
with Cp2FePF6 and subsequently rearranged to the ABCDE
framework of strychnine in 28 upon removal of the cyclopen-
tadienyl cobalt unit under oxidative conditions in 65% overall
yield (Scheme 7).21a Thus, with efficient access to the desired
pentacyclic system in hand, the opportunity presented itself to
utilize the functionalized D ring for the formation of the F ring
and in the process restore the required cis juncture between the
C and D rings. Attempts to hydrolyze the dienol ether system
in 28, however, were unsuccessful, resulting in either no reaction
(THF/H2O/HOAc (3:3:1), 25 °C, 5 d) or decomposition (CF3-
CO2H or HCl, ∆). Presumably, this difficulty is due to
protonation of the tertiary nitrogen and the subsequent dipolar
repulsion slowing the rate of hydrolysis. Attempts to obviate
this problem by replacing the N-benzyl moiety with an electron-
withdrawing substituent were thwarted by the resistance of 28
to catalytic hydrogenation (Pd-C, HOAc/MeOH) at 1 atm of
H2 and its decomposition at higher pressures (3 atm). An
alternative strategy for the activation of 28 toward hydrolysis
a Conditions: (a) t-BuSiMe2Cl (1.2 equiv), imidazole (2 equiv),
DMF, 25 °C, 24-36 h; (b) i. KOH (1.2 equiv), glyme, 0 to 25 °C, 10
min; ii. 4-pentynoyl chloride (1.3 equiv), 0 °C, 20 min, 56% (2 steps);
(c) 9 (2.5 equiv), CpCo(CO)2 (1.8 equiv), m-xylene, reflux, 28 h, 60%;
(d) Bu4NF, THF, 25 °C, 1.25 h, 100%; (e) i. MeSO2Cl (2 equiv), Et3N,
CH2Cl2, 0 °C, 10 min; ii. NaN3 (1.6 equiv), DMF, 70 °C, 8 h, 86%; (f)
CuCl2‚2H2O (5 equiv), Et3N (2 equiv), 0 °C, 15 min, 80%.
(0.005 M) to suppress intermolecular reactions. Thermolysis in
toluene gave, after 3 days, two products, 23 and 24, in the ratio
of 2:1 in 51% overall yield. Switching to a more polar solvent43
(DMF, 80 °C, 7 d) gave a 5:1 ratio of the cyclized products in
53% overall yield.
The presence of a hydroxy group in 23 was indicated by a
strong, broad absorption at 3300 cm-1 in the infrared spectrum
and its location at C13 by a singlet for the C8 methine at δ
4.36 (1H) ppm in the 1H NMR spectrum. The stereochemistry
of the hydroxy group could not be determined unequivocally
from the spectral data. The presence of the imine and enol ether
functionalities was evident from 13C NMR signals at δ 169.2
(C16), 154.6 (C15), and 108.8 (C14) ppm and a peak at δ 5.16
(s, 1H) ppm corresponding to the olefinic proton. Chemical
support for this assignment was given by the acetylation of 23
and subsequent elimination to form 25 (eq 2). The presence of
the imine and silylated acetal functionalities in 24 was suggested
by quaternary carbon resonances at δ 169.87 (C16) and 92.76
(C15) ppm, as well as by 1H NMR NOE experiments. Irradiation
of the singlet at δ 0.17 (3H) ppm, corresponding to the
trimethylsilyl group, led to an enhancement of the methoxy
singlet at δ 3.04 (3H) ppm and the olefinic signal at 5.74 (s,
1H) ppm. Furthermore, the singlet resonance at δ 4.41 (1H)
ppm for the C8 methine hydrogen indicated unsaturation at the
adjacent C13.
(44) Logothetis, A. L. J. Am. Chem. Soc. 1965, 87, 749.
(45) For examples of the application of the imine products of a 1,3-
dipolar cycloaddition of azides and olefins toward alkaloid synthesis, see:
(a) Pearson, W. H.; Schkeryantz, J. M. J. Org. Chem. 1992, 57, 6783. (b)
Bennet , R. B., III; Chooi, J.-R.; Montgomery, W. D.; Cha, J. K. J. Am.
Chem. Soc. 1989, 111, 2580. (c) Taber, D. F.; Deker, P. B.; Fales, H. M.;
Jones, T. H.; Lloyd, H. A. J. Org. Chem. 1988, 53, 2968.
(46) (a) Smith, P. A. S.; Chou, S. P. J. Org. Chem. 1981, 46, 3970. (b)
Scheiner, P. In SelectiVe Organic Transformations; Thyagarajan, B. S., Ed.;
Wiley: New York, 1970; p 327.
(47) (a) Pearson, W. H.; Bergmeier, S. C.; Degan, S.; Lin, K.-C.; Poon,
Y.-F.; Schkeryantz, J. M.; Williams, J. P. J. Org. Chem. 1990, 55, 5719.
(b) Broeckx, W.; Overbregh, N.; Samyn, C.; Smets, G.; L’abbe´, G.
Tetrahedron 1971, 27, 3527. (c) Reference 46b, p 347.
Although the lack of an isolable 1,2,3-triazoline intermediate
precluded the application of Uhle’s acid-catalyzed decomposi-
tion to an amine, the isolation of the analogous imines displaying
(48) Nelsen, S. F.; Teasley, M. F.; Kapp, D. L. J. Am. Chem. Soc. 1986,
108, 5503.
(43) Kadaba, P. K. Synthesis 1973, 71.

9330 J. Am. Chem. Soc., Vol. 123, No. 38, 2001
Eichberg et al.
Scheme 8. Attempted Pd-Mediated Conversion of Enol
could involve the π-complexation of a metal cation to the
electron-rich diene system. On the basis of the well-known Pd-
(II)-mediated addition of nucleophiles to alkenamines, it was
anticipated that the enol ether function in 28 would add H2O in
the presence of Pd(II).49 Interestingly, exposure of 28 to a slight
excess of Pd(OAc)2 led to the isolation of 29 in 32% yield (eq
3).
Ether 30 to Hexacycle 33
The 13C NMR-DEPT spectrum of 29 indicated the presence
of a ketone by displaying a quaternary carbon signal at δ 199.43
ppm, in addition to peaks at δ 182.22 and 165.54 ppm
corresponding to the acetate and amide carbonyls, respectively.
This observation also supported the structural assignment of 29
as a σ-palladium complex rather than as the π-oxoallyl or π-allyl
derivative, as did the signal assigned to the methine carbon R
to the palladium atom at δ 43.74 ppm, significantly upfield from
typical palladium complexed π-allyl terminal carbons.50 Ad-
ditionally, a strong, high-energy absorbance at 1684 cm-1 in
the IR spectrum, assigned to both the amide and ketone
carbonyls,51 discounted the association of the Pd center with
the D ring carbonyl (an equally strong absorbance at 1570 cm-1
was assigned to the Pd-coordinated acetate ligand).
Scheme 9. Synthetic Approach to 2 via a Double Conjugate
Addition
The isolation of 29 suggested the exploitation of the existing
Pd-C linkage for carbon-carbon bond formation with an
appropriate nitrogen side chain. In particular, the intramolecular
syn insertion of the allylic double bond in the trans-butenyl
substituent in 30a and subsequent syn â-hydride elimination
would give the desired E-alkene 33 (Scheme 8). This proposal
was examined with alkene 30b21a as a model. Upon exposure
to Pd(OAc)2 under the conditions used for 28, only a low yield
(ca. 25%) of impure complex 31b, tentatively identified by the
similarity of its spectral properties to 29, was obtained, perhaps
due to competing Wacker-type oxidation of the alkene function.
Reaction of 30b in the absence of water gave 32, tentatively
1
identified as the hydrolyzed enone based on H NMR and on
IR peaks at 1722 and 1691 cm-1 for the ketone and amide
carbonyls, respectively. Thus, despite the successful rearrange-
ment of 26 to form the E ring, difficulties in elaborating ring D
in 28 led to the abandonment of this strategy.
cumbersome even if successful. Instead, a more streamlined
synthesis was sought that would eliminate the need for auxiliary
substitution of the D ring. Scheme 9 illustrates such a strategy.
In this approach, formation of the E and F rings would proceed
via nucleophilic addition to an extended π-system activated by
the amide carbonyl function. More specifically, the pyrrolidine
ring E would be made by a formal intramolecular 1,8-Michael
addition of precursor 35 and the piperidine ring via the conjugate
addition of a Z-4-hydroxy-2-butenyl unit, properly functionalized
at the 2-position, to C14 in 34. The required 35 was anticipated
to be readily available by [2 + 2 + 2] cycloaddition of an
enynoylindole of the type 36 to bis(trimethylsilyl)acetylene
(BTMSA), followed by desilylation, or to acetylene, a previously
untried cocyclization partner for the indole and related systems.25a
First Synthesis of Enynoylindole 40. We envisioned a
straightforward synthesis of the cyclization precursor 40 via an
acylation of acetyltryptamine52 (37) with cis-3-iodoacryloyl
chloride,53 followed by Pd-mediated coupling with trimethyl-
silylacetylene and desilylation. Surprisingly, conditions that had
The AB f ABCD f ABCDE f ABCDEF Approach to
1: Successful Strategy via an ABCD Trienamide
Up to this point, the attempts to form rings E and F involved
functional group placement on the D ring to facilitate the
necessary C-N and C-C bond formation reactions. However,
as this work progressed, it became clear that the required
chemistry was not only not forthcoming, but that it would be
(49) (a) Tsuji, J. Palladium Reagents and Catalysis; Wiley: New York,
1995; pp 21-50. (b) Holton, R. A.; Kjonaas, R. A. J. Am. Chem. Soc.
1977, 99, 4177. (c) Alyea, E. C.; Dias, S. A.; Ferguson, G.; McAlees, A.
J.; McCrindle, R.; Roberts, P. J. J. Am. Chem. Soc. 1977, 99, 4985. (d)
McCrindle, R.; Ferguson, G.; Khan, M. A.; McAlees, A. J.; Ruhl, B. L. J.
Chem. Soc., Dalton Trans. 1981, 986.
(50) (a) Pregosin, P. S.; Salzmann, R. Coord. Chem. ReV. 1996, 115,
35. (b) Hunt, D. A.; Quante, J. M.; Tyson, R. L.; Dasher, L. W. J. Org.
Chem. 1984, 49, 5262.
(51) (a) Ito, Y.; Aoyama, H.; Hirao, T.; Mochizuki, A.; Saegusa, T. J.
Am. Chem. Soc. 1979, 101, 494. (b) Ito, Y.; Nakatsuka, M.; Kise, N.;
Saegusa, T. Tetrahedron Lett. 1980, 21, 2873.
(52) Spa¨th, E.; Lederer, E. Chem. Ber. 1930, 63, 120.

Synthesis of (()-Strychnine
J. Am. Chem. Soc., Vol. 123, No. 38, 2001 9331
Scheme 11. Second Synthesis of 40a
Scheme 10. First Synthesis of 40a
a Conditions: (a) MEMCl (14 equiv), Na2CO3 (12 equiv), DMF,
room temperature, 50 min, 86%; (b) trimethylsilylacetylene (2 equiv),
Pd(PPh3)2Cl2 (0.05 equiv), CuI (0.1 equiv), Et3N, room temperature, 1
h, 98%; (c) i. 3 N HCl, THF, room temperature, 3 d; ii. (COCl)2, room
temperature, 14 h, 83%; (d) 37 (0.76 equiv), NaOH (7.7 equiv), Bu4NCl
(0.9 equiv), H2O (2.5 equiv), CH2Cl2, 0 °C, 50 min, 86% based on 37.
a Conditions: (a) H2 (3.4 atm), 10% Pd-C, 1 N HCl-MeOH (1:1),
room temperature, 2 d; (b) cis-3-iodoacryloyl chloride (1.5 equiv), 2,6-
lutidine (1.4 equiv), CH2Cl2, 0 °C, 25 min, 71% (2 steps); (c)
trimethylsilylacetylene (3.6 equiv), Pd(PPh3)2Cl2 (0.04 equiv), CuI (4.5
equiv), Et3N (2.1 equiv), C6H6, room temperature, 1 h, 78%; (d) MnO2
(20 equiv), C6H6, 90 °C, 25 min, 63%; (e) KF‚2H2O (1.4 equiv), 18-
crown-6 (0.03 equiv), THF, room temperature, 2 h, 85%.
Second Synthesis of 40. The five-step synthesis described
above proved to be too cumbersome for the production of
sufficient quantities of the [2 + 2 + 2] cycloaddition precursor
40 for subsequent studies. For this reason, a more convergent
route to the enynoylindole was developed (Scheme 11).20 This
path involved the construction of the cis enyne before acylation,
by the coupling of cis-3-iodoacrylic acid 2-methoxyethoxy-
methyl ester with trimethylsilylacetylene to afford 41. Conver-
sion to the acid chloride 42 was achieved by ester hydrolysis65
and reaction with oxalyl chloride. Gratifyingly, the indole
nitrogen of 37 could not only be acylated with 42, but the pro-
duct was also simultaneously desilylated by modification of the
original phase-transfer conditions.55 Rapid addition of the acid
chloride to a CH2Cl2 solution of acetyltryptamine in the presence
of powdered NaOH, Bu4NCl, and H2O gave good yields (86%)
of the enynoylindole 40.66,67 This five-step sequence was readily
scaled up to afford multigram quantities of 40.
[2 + 2 + 2] Cycloaddition of 40 with BTMSA and
Acetylene. With enyoylindole 40 in hand, the cocyclization of
40 with acetylene and BTMSA, the latter with potentially
cleavable carbon-silicon bonds, was examined (Scheme 12).
BTMSA is a commonly employed acetylene surrogate in the
cobalt-mediated [2 + 2 + 2] cycloaddition reaction due to its
ease of use and resistance to autocyclization. Indeed, initial
studies proved promising. Utilizing the reactivity of CpCo-
(C2H4)2 at lower temperatures to minimize cyclobutadiene
formation, reaction of unsubstituted enynoylindole 43 gave a
favorable yield of 44 (70%) versus 45 (27%). Encouraged by
this result, the cocyclization of 40 with BTMSA was examined.
However, this reaction gave significantly more of the undesired
cyclobutadiene complex 47a (41%) at the expense of 46a (47%).
This result was not too surprising, given that the effect of
3-substitution on the indole nucleus has previously been shown
to be a significant hindrance to the successful cyclization of
N-(4-penynoyl)indoles with BTMSA.25a Switching to acetylene
was thought to help in this regard and, moreover, would
eliminate the need to remove silyl substituents in later steps.68
previously worked well for the acylation of the indole nitrogen
failed to yield any of the desired unsaturated amide product.
Deprotonation of 37 with KOH in DME32 followed by addition
of the acid chloride returned only the starting indole. The same
results were obtained upon deprotonation with BuLi54 and weak
amine bases53b (Et3N, 2,4-lutidine). Attempted acylation em-
ploying Illi’s phase transfer method was similarly disappoint-
ing.55,56 Notably, the parent indole system also failed to acylate
under these conditions, indicating that competing deprotonation
of the amide hydrogen in 37 (pKa = 17,57 in comparison to
pKa ) 16.6 for 3-methylindole58) was not detrimental.
To facilitate the formation of the amide, the nucleophilicity
of the heterocyclic nitrogen center was increased by the
reduction of the aromatic indole system to indoline (Scheme
10). Thus, catalytic hydrogenation of the indole double bond59
followed by acylation with cis-3-iodoacryloyl chloride in the
presence of 2,6-lutidine gave the amide 38. Palladium-mediated
coupling33 with trimethylsilylacetylene afforded the enyne
system 39 in 78% yield for the three steps. Rearomatization of
the indoline by oxidation with DDQ60 resulted in poor yields
(31%) due to the instability of 39 to the reaction conditions.
Dehydrogenation with Wilkinson’s catalysts61 also destroyed
the rather sensitive indoline. However, oxidation with activated
MnO237,62 in refluxing benzene gave the desired oxidized indole
system in a moderate 63% yield.63 Finally, desilylation with
KF64 afforded the enynoylindole 40 in 36% yield for the entire
sequence.
(53) (a) Moss, R. A.; Wilk, B.; Krogh-Jespersen, K.; Westbrook, J. D.
J. Am. Chem. Soc. 1989, 111, 6729. (b) Wilson, R. M.; Commons, T. J. J.
Org. Chem. 1975, 50, 4467.
(54) De Silva, S. O.; Snieckus, V. Can. J. Chem. 1978, 56, 1621.
(55) Illi, V. O. Synthesis 1979, 387.
(56) For another study of indole acylation, see: Ottoni, O.; Cruz, R.;
Alves, R. Tetrahedron 1998, 54, 13915.
(57) Homer, R. B.; Johnson, C. D. In The Chemistry of Amides; Zabicky,
J., Ed., Wiley: New York, 1970; pp 188-197.
(58) Remers, W. A. In Indoles; Houlihan, W. J., Ed.; Wiley: New York,
1972; Part One, p 14.
(59) Daly, J. W.; Mauger, A. B.; Yonemitsu, O.; Antonov, V. K.; Takase,
K.; Witkop, B. Biochemistry 1967, 6, 648.
(60) (a) Feng, H.; Foxman, B. M.; Snider, B. B. J. Am. Chem. Soc. 1998,
120, 6417. (b) Ono, S.; Yamafuji, T.; Chaki, H.; Morita, H.; Todo, Y.;
Okada, N.; Maekawa, M.; Kitamura, K.; Tai, M.; Marita, H. Chem. Pharm.
Bull. 1995, 43, 1492. (c) Fu, P. P.; Harvey, R. G. Chem. ReV. 1978, 78,
317.
(63) (a) Bonnaud, B.; Bigg, D. C. H. Synthesis 1994, 465. (b) Stamos,
I. K. Tetrahedron 1981, 37, 1813. (b) Kametani, T.; Ohsawa, T.; Ihara, M.
J. Chem. Soc., Perkin Trans. 1 1981, 290.
(64) Carpino, L. A.; Sau, A. C. J. Chem. Soc., Chem. Commun. 1979,
514.
(65) Abarbri, M.; Parrain, J.-L.; Cintrat, J.-C.; Ducheˆne, A. Synthesis
1996, 82.
(66) The choice of the phase-transfer catalyst turned out to be critical to
the success of the reaction. Use of Bu4NHSO4, as was originally described
in Illi’s paper (ref 55), gave no trace of 40, while most other tetraalkylam-
monium salts examined generated at least some of the desired product.
(67) Oldroyd, D. L.; Weedon, A. C. J. Org. Chem. 1994, 59, 1333.
(61) Nishiguchi, T.; Tachi, K.; Fukuzumi, K. J. Org. Chem. 1975, 40,
237.
(62) Fatiadi, A. J. Synthesis 1976, 133.

9332 J. Am. Chem. Soc., Vol. 123, No. 38, 2001
Eichberg et al.
Scheme 12. [2 + 2 + 2] Cycloaddition of
N-(Pent-2-en-4-ynoyl)indoles 40 and 43
Scheme 13. Pathways for Formation of 46b and 48b from
40
Scheme 14. Formation of E Ring during Demetalation of
Complexed Cyclohexadienes
Initial experiments with 40 and acetylene were performed on a
submillimolar scale. When CpCo(C2H4)2 (3.5 equiv) was added
to a solution of 40 (0.12 mmol) in THF that had been saturated
with acetylene gas,69 the desired dihydrocarbazole complex 46b
was formed in 43% yield. Attempts to scale-up the procedure
to 0.5 mmol of 40 or more led to a significant decrease in yield
(17-24%). The main product of the reaction was 48b, isolated
in 50-60% yield as a mixture of cis and trans isomers. The
loss of the cis stereochemistry seems to be associated with
catalysis by the cobalt center, the scope and nature of which is
currently under investigation.70
Cinnamic amide 48b may be formed by two pathways, the
reaction of 40 with C, formed from two molecules of acetylene,
or of either (or both) of the metallacyclopentadiene intermediates
D or E with acetylene (Scheme 13).35,71 Consideration of
Scheme 13 suggested that yields of 46b might be improved by
reducing the steady state acetylene concentration in the reaction
mixture. This modification would retard the formation of C and
the trapping of (the presumably equilibriating)35 D and E by
acetylene. Indeed, by moderating the rate of acetylene addition
and concomitantly purging the mixture with a stream of nitrogen
or argon, performing the cyclization under dilute conditions
(0.05 M as the initial concentration of 40), and maintaining a
temperature of 0 °C, the reaction was optimized at a 1 g (3.5
mmol) scale to afford 46b in 46% with a 20-30% yield of
48b (3:1, cis/trans). Other changes such as solvent (benzene,
EtOAc, Et2O, CH2Cl2), rate or order of addition of the
nongaseous reagents, use of alternative CpCo sources [CpCo-
(CO)2 or Cp*Co(C2H4)272], or additives (PPh3)73 were incon-
sequential or led to reductions in yield.
(68) Indeed, attempted removal of both of the silicon groups in 46a either
failed [Bn(CH3)3NF and CsF] or led to decomposition (CF3CO2H).
(69) Fogg, P. G. T.; Gerrard, W. Solubility of Gases in Liquids; Wiley:
New York, 1991; pp 146-153.
(70) Stirring 48b-cis with substoichiometric amounts of CpCo(C2H4)2
at room temperature led to complete conversion to 48b-trans within 2 h.
(71) (a) Hardesty, J. H.; Koerner, J. B.; Albright, T. A.; Lee, G.-Y. J.
Am. Chem. Soc. 1999, 121, 6055. (b) Diercks, R.; Eaton, B. E.; Gu¨rtzgen,
S.; Jalisatgi, S.; Matzger, A. J.; Radde, R. H.; Vollhardt, K. P. C. J. Am.
Chem. Soc. 1998, 120, 8247.
Demetalation of 46b and Formation of E Ring. Construc-
tion of the fifth ring of 1 is shown in Scheme 14. Notably, the
acetamide function of 46b could be hydrolyzed under the rather
harsh conditions required [KOH (165 equiv), MeOH/H2O (1:
(72) Beevor, R. G.; Frith, S. A.; Spencer, J. L. J. Organomet. Chem.
1981, 221, C25.
(73) Stara, I. G.; Stary, I.; Kollarovic, A.; Teply, F.; Saman, D.; Tichy,
M. J. Org. Chem. 1998, 63, 4046.

Synthesis of (()-Strychnine
J. Am. Chem. Soc., Vol. 123, No. 38, 2001 9333
Scheme 15. Synthesis of 56 and 59
Table 1. Oxidative Demetalation of 49
yield of
products, %a
T (°C)
entry oxidizing agentb
solvent
(t [min])
50
51
1
2
3
4
5
6
7
CuCl2‚2H2O/Et3N MeCN/H2O
CuCl2‚2H2O/Et3N MeCN/H2O
0 (10) 51
25 (10) 58
25 (60) 48
0 (20) 66
0 (15) 77
25 (120)
CuCl2‚2H2O
FeCl3‚6H2Oc
Fe(NO)3‚9H2O
MeCN/H2O
MeCN
MeCN/THF/H2O
CH2Cl2
d
Cp2FePF6
37
(NH4)2Ce(NO3)6 MeCN/THF
-78 (15) trace trace
a Isolated yields. b Unless otherwise noted, a 3- to 5-fold excess of
the oxidizing reagent was used. c 2 equiv used. d 1.1 equiv used.
1), reflux, 6 h] without significant decomposition to give the
amine 49 in 93% yield. It is possible that the electron-donating
and bulky CpCo moiety stabilizes the amide bond in ring C,
preventing hydrolysis to the indoline carboxylic acid.12 Gratify-
ingly, the complexed diene could be readily demetalated
oxidatively to form the E ring of strychnine. A number of
reagents were examined for this transformation (Table 1).
Copper(II)21a,24c,25a,35 and two iron(III) systems gave the desired
secondary amine 50 as the only isolable product. The best yields
(77%) were obtained with Fe(NO)3‚9H2O25a (entry 5). Notably,
50 was isolated as the C12-C15 diene, as opposed to the more
stable diene system in conjugation with the carbonyl (i.e., 63,
described below). The 1H NMR spectrum showed olefinic
signals at δ 5.75 (d, J ) 10.0 Hz, 1H), 5.95 (m, 1H), and 6.33
(dd, J ) 10.0, 2.5 Hz, 1H) ppm, assigned to the C14, C12, and
C15 methine hydrogens, respectively. Use of Cp2FePF6 led to
low yields of enamine 51, most likely the result of over-
oxidation of 50.21a The 1H NMR spectrum of 51 showed olefinic
signals at δ 7.20 (d, J ) 9.2 Hz, 1H), 6.38 (d, J ) 9.2 Hz, 1H),
6.24 (dd, J ) 9.7, 2.3 Hz, 1H), and 5.46 (dd, J ) 9.7, 2.0 Hz)
ppm. Reaction with ceric ammonium nitrate gave a complex
mixture of products in which 50 and 51 could be identified in
only trace amounts.
Formation of the E ring also proved sensitive to the nature
of the substituent on the exocyclic nitrogen. Thus, secondary
amine 5274 gave good yields (66%) of the pentacyclic system
53 upon reaction with CuCl2‚2H2O, while the acetylated 46b
underwent only demetalation to form 54 in 77% yield under
similar conditions. Although a formal 1,8-conjugate addition,
the E ring closure occurred under conditions similar to those
used for the rearrangement of 26 to 28 discussed above (Scheme
7) and may proceed through a radical cation cobalt species.21a
Secondary amine 50 represented a useful synthetic intermedi-
ate for the construction of the F ring by allowing the attachment
of whatever functionalized side chain proved necessary for the
critical C14-C21 bond forming reaction. Pursuing the conjugate
addition approach described in Scheme 9, 50 was alkylated with
(Z)-1-bromo-4-tert-butyl(dimethyl)siloxy-2-iodobut-2-ene (55),17
which contained not only a readily activated sp2 carbon-iodine
center amenable to a variety of carbon-carbon bond forming
reactions (vide infra), but also the desired allylic ether stereo-
chemistry present in 1.75 Thus, amine 50 was alkylated with 55
in the presence of Li2CO3 to form 57 in good yields (74%) and
isomerized to the more stable 56 with an alkoxide base (Scheme
15). In an effort to form 56 in a single step, amine 50 was treated
with 55 under a variety of conditions intended to effect both
Table 2. One-Pot Alkylation and Isomerization of 50a
yield of products, %b
entry
base
solvent
56
57
58
1
2
3
4
5
6
7
8
9
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
acetone/DMF (5:1)c
DMF
DMSO
HMPA
HMPA
50
5
3
23
22
trace
18
23
23
64
61
74
47
d
8
Na2CO3 DMF
Li2CO3
DMF
DMFe
DMF
d
K3PO4
DBUd
12f
a Unless otherwise indicated, reactions were run with 5 equiv of base
and 1.1 equiv of 55 at 45 °C for 24 h. b Isolated yields. c See ref 17.
d 2.5 equiv of base used. e Reaction run at room temperature. f A 3:7
mixture of starting amine 50 and its isomer 63 was isolated in 80%
yield.
the alkylation and the isomerization of the diene system into
conjugation with the amide carbonyl (Table 2). A number of
carbonate, phosphate, as well as a hindered amine bases (DBU)
were examined in various polar-aprotic solvents. These reac-
tions either failed to lead to double bond isomerization or were
complicated by formation of the carbamate 58 (in the presence
of strong carbonate bases, entries 2-5)76 or sluggish alkylation
in the case of DBU (entry 9). For the purpose of confirming
the structure and relative stereochemistry of 56 and related
compounds, the allylic ether was deprotected with aqueous HCl
in THF to form the highly crystalline alcohol 59 whose X-ray
crystal structure was determined (Figure 4). The results con-
firmed the overall connectivity and stereochemistry.
Attempted Closure of F Ring via Conjugate Addition. The
first strategy for closing the F ring featured an iodine-metal
exchange and 1,6-conjugate addition to C14. Initial studies with
alkyllithium reagents were disappointing. Addition of BuLi (1
equiv) to a THF solution of 56 at -78 °C followed by LiCu-
(thienyl)CN77 gave a mixture from which only starting material
(74) From the alkylation of 49 with cis-4-tert-butyl(dimethyl)siloxy-1-
bromo-2-butene.
(75) Indeed, this stereochemical “problem” of strychnine synthesis has
been solved by essentially the same approach by Stork (refs 11a and 18),
Rawal (ref 17), and Bonjosch (ref 15).
(76) Go´mez-Parra, V.; Sa´nchez, F.; Torres, T. Synthesis 1985, 282.

9334 J. Am. Chem. Soc., Vol. 123, No. 38, 2001
Eichberg et al.
butenyl side chain, and deprotonation at C15.80 Use of the more
hindered base t-BuLi gave complex mixtures when reacted with
56 alone at -78 °C, or returned starting material combined with
61 on subsequent exposure to LiCu(thienyl)CN81 or MnCl2/
CuCl.82 Addition of TMSCl to activate the enone system also
failed.
Other researchers have encountered similar difficulties in their
attempts to construct the C14-C21 bond of 1 via a carbanion-
mediated conjugate addition reaction. Stork and co-workers
utilized a copper intermediate formed by a t-BuLi mediated
iodine-lithium exchange, followed by the addition of MnCl2/
CuCl to convert diester 65 to the ABDEF intermediate 66 (eq
4).11a,18 However, this reaction proceeded in poor yields (35%)
and was difficult to reproduce.83 Overman and co-workers were
unable to obtain acceptable yields of the conjugate addition of
allylic alcohol 67 to cyclopentenone on route to an early
intermediate in their synthesis of 1, and they eventually
abandoned this approach (eq 5).13 These workers attribute this
difficulty to the destruction of the electrophile via the formation
of allene byproducts,81 a rationale that may also apply to our
observation of amine 63.
Figure 4. ORTEP diagram of 59.
Scheme 16. Attempted Formation of F Ring by Anionic
Conjugate Addition
Other attempts to impart nucleophilicity to C21 of 56 proved
similarly fruitless. Thus, the vinyl iodide could not be activated
with magnesium to form the Grignard reagent84 for subsequent
transmetalation with copper.85 Reactions either returned starting
material (Mg, MeI, Et2O, 40 °C, 4 d) or led to a complex mixture
of products (Mg, TMSCl, 1,2-dibromoethane, THF, 65 °C, 1
d). Attempts at iodide-magnesium exchange with i-Pr2Mg,86
both with and without added Cu(I), led to extensive decomposi-
tion of the starting material. Activated copper87 and zinc systems
were also examined.88 Addition of a THF solution of 56 and
TMSCl to an activated Cu(0) mixture (generated by reduction
of the CuCN‚2LiBr complex at -100 °C with the naphthalene
(80) Direct deprotonation at C15 may be responsible for the recovery of
56. Alkene 61 may result from intramolecular proton transfer to the desired
intermediate vinyl metal from C15.
(81) Angle, S. R.; Fevig, J. M.; Knight, S. D.; Marquis, R. W., Jr.;
Overman, L. E. J. Am. Chem. Soc. 1993, 115, 3966.
(82) Alami, M.; Marquais, S.; Cahiez, G. Org. Synth. 1995, 72, 135.
(83) Stork, G., personal communication, 1999.
(84) (a) Piers, E.; Friesen. R. W. Can. J. Chem. 1992, 70, 1204. (b)
Touet, J.; Baudouin, S.; Brown, E. Tetrahedron: Asymmetry 1992, 3, 587.
(c) Hackett, M.; Whitesides, G. M. J. Am. Chem. Soc. 1988, 110, 1449.
(85) Posner, G. H. Org. React. 1972, 19, 1.
(86) Rottla¨nder, M.; Boymond, L.; Cahiez, G.; Knochel, P. J. Org. Chem.
1999, 64, 1080.
(87) (a) Rieke, R. D.; Klein, W. R.; Wu, T.-C. J. Org. Chem. 1993, 58,
2492. (b) Rieke, R. D.; Stack, D. E.; Dawson, B. T.; Wu, T.-C. J. Org.
Chem. 1993, 58, 2483. (c) Ebert, G. W.; Rieke, R. D. J. Org. Chem. 1988,
53, 4482.
(50%) could be isolated. Greater amounts of lithium reagent (2
equiv) led to complex mixtures containing no identifiable
products. Reaction of BuLi (1.8 equiv) alone78 at -100 °C gave,
after 1 h, a mixture from which only deiodinated alkene 61
(19%) and alkyne 62 (6%)79 could be isolated (Scheme 16).
Analysis of the crude reaction mixture by GC/MS indicated the
presence of a trace of the secondary amine 63. This experiment
indicated that the starting material, under the conditions of
lithium-halogen exchange, was susceptible to a number of side
reactions, including hydrogen iodide elimination, loss of the
(77) Lipshutz, B. H.; Koerner, M.; Parker, D. A. Tetrahedron Lett. 1987,
28, 945.
(78) (a) Cooke, M. P. J. Org. Chem. 1993, 58, 2910. (b) Cooke, M. P.
J. Org. Chem. 1992, 57, 1495.
(79) (a) Seebach, D.; Maestro, M. A.; Sefkow, M.; Adam, G.; Hinter-
mann, S.; Neidlein, A. Liebigs Ann. Chem. 1994, 7, 701. (b) Katzenellen-
bogen, J. A.; Corey, E. J. J. Org. Chem. 1972, 37, 1441.
(88) (a) Hanson, M. V.; Rieke, R. D. J. Am. Chem. Soc. 1995, 117, 10775.
(b) Zhu, L.; Wehmeyer, R. M.; Rieke, R. D. J. Org. Chem. 1991, 56, 1445.
(c) Rieke, R. D. Acc. Chem. Res. 1977, 10, 301. (d) For a comprehensive
review of organozinc reagents in organic synthesis, see: Knochel, P.; Perea,
J. J. A.; Jones, P. Tetrahedron 1998, 54, 8275.

Synthesis of (()-Strychnine
J. Am. Chem. Soc., Vol. 123, No. 38, 2001 9335
anion) resulted in no identifiable products. Similar results were
obtained when 56 was added to a slurry of activated Zn(0)
(prepared by reduction of ZnCl2 in THF followed by, after
overnight stirring, the addition of CuCN‚2LiBr, TMSCl, and
BF3‚OEt2). Electron transfer from these active metal species or
from residual naphthalene anion to the conjugated amide system
may be responsible for the instability of the starting material
under these conditions.
Scheme 17. Attempted Formation of a Stannylated Side
Chain
Because of these failures, a milder method for the activation
of the pertinent carbon center was sought. Organochromium
reagents have demonstrated excellent tolerance of functionality
in the course of 1,2-additions to carbonyls.89 Substituted vinyl
halides have also been shown to insert Cr(II) readily.90 Stirring
56 with CrCl2 (3.5 equiv) doped with 5% NiCl291 for 2 days in
DMF returned the starting iodide (36%) and the dehalogenated
alkene 61 (12%). Addition of CuI to the reaction mixture failed
to lead to transmetalation of the intermediate chromium reagent
to a more reactive organocuprate and gave, after 3 days, a 1:1
mixture of 61 and unreacted starting material (80% recovery).
Reaction in DMSO/Me2S gave partially isomerized alkene 61
in 53% yield (1:2, cis/trans)92 (Scheme 16). Further attempts in
pure DMSO, with a large excess of CuCl2/NiCl2,93 the addition
of certain additives (TMSCl), or reaction at elevated temperature
(100 °C) failed.
C11 of the aromatic pyridone ring. Apparently, 60 and 68 result
from the Pd-mediated addition of C21 to the C12-C13 double
bond and either the intermolecular reduction of the Pd-C carbon
bond or â-elimination of the C8 hydrogen (vide infra). At-
tempted installation of the trimethyltin moiety on the butenyl
side chain prior to alkylation of 50 was successful with iodo
alcohol 69 (an intermediate in the synthesis of 55)17 providing
the vinyl tin 70 (Scheme 17). However, any effort to convert
the hydroxy substituent into a leaving group, including bromi-
nation and sulfonate ester formation, resulted in rapid â-elimina-
tion to form allene 71,98 even at -78 °C.99
Palladium- and Nickel-Mediated Formation of the F Ring.
In Rawal and Iwasa’s total synthesis of (()-1, the critical C14-
C21 bond is generated via an intramolecular Heck reaction of
72 to provide 60 (eq 6),17 and it was therefore of interest to
investigate the behavior of 56 under the same or related
conditions (Scheme 18, Table 3). Notably, in the case of 72,
Other mild approaches to potential carbanion formation
involved transient organotin reagents. Recourse to trimethyl-
(tributylstannyl)silane in the presence of cesium fluoride94 led
to deiodinated, desilylated alkene 64 (57%) after 10 h in DMF
at 65 °C (Scheme 16). Reaction in THF gave the deiodinated
alkene 61 (55%), and addition of Lewis acids (TMSCl, BF3‚
OEt2), intended to activate the π-system, returned only starting
material. Therefore, attempts were made at the assembly of an
isolable alkenyltin reagent. Vinylstannanes are readily trans-
metalated by organocuprates95 or Cu(I) salts (CuCl, CuCN).96
Surprisingly, the attempted formation of the corresponding
stannane by treatment of 56 with Me3SnSnMe3 and Pd(PPh3)4
in THF13,97 in a sealed flask heated to 90 °C resulted in a mixture
dominated by amine 63 (59%), but which also contained
hexacyclic pyridone 68 as well as silylated isostrychnine (60)17
in 8% and 5% isolated yields, respectively (Scheme 17). In
contrast to amine 50, (Scheme 14), 63 showed olefinic signals
1
in the H NMR spectrum at δ 6.90 (d, J ) 9.7 Hz, 1H), 6.03
(d, J ) 6.7 Hz, 1H), and 5.97 (d, J ) 9.7 Hz, 1H) ppm,
corresponding to the C12, C14, and C11 methine protons,
respectively. Hexacyclic 68 displayed signals similar to 60 in
the aliphatic region and peaks at δ 6.46 (d, J ) 9.2 Hz, 1H)
and 7.26 (d, J ) 9.2 Hz, 1H) ppm, corresponding to C12 and
while Pd-mediated coupling could terminate in the â-elimination
of either the C8 or C12 hydrogens, only the latter is observed.100
Pentacycle 61 has only the C8 hydrogen available, and indeed,
upon exposure to Rawal’s conditions, only aromatic pyridone
68 is isolated (Scheme 18, Table 3, entry 8). In an effort to
suppress â-elimination, 56 was subjected to Heck cyclization
conditions in the presence of a hydride source. Reactions of
this type have been used to trap the intermediate palladium
σ-complex before elimination or when no elimination pathway
is readily available. Stirring 56 with catalytic Pd(OAc)2/PPh3
in the presence of sodium formate (1.7 equiv) and Et4NCl in
(89) For a comprehensive review of carbon-carbon bond formation with
organochromium reagents, see: (a) Fu¨rstner, A. Chem. ReV. 1999, 99, 991.
(b) Wessjohann, L. A.; Scheid, G. Synthesis 1999, 1.
(90) Kress, M. H.; Ruel, R.; Miller, W. H.; Kishi, Y. Tetrahedron Lett.
1993, 34, 6003.
(91) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986,
108, 5644.
(92) Stereochemical equilibration of trisubstituted iodoolefins in nickel-
catalyzed reactions has been observed. See: (a) Zembayashi, M.; Tamao,
K.; Kumada, M. Tetrahedron Lett. 1975, 16, 1719. (b) Reference 91.
(93) Roe, M. B.; Whittaker, M.; Proctor, G. Tetrahedron Lett. 1995, 36,
8103.
(94) (a) Mori, M.; Isono, N.; Wakamatsu, H. Synlett 1999, 269. (b) Imai,
A. E.; Sato, Y.; Nishida, M.; Mori, M. J. Am. Chem. Soc. 1999, 121, 1217.
(95) Behling, J. R.; Babiak, K. A.; Ng, J. S.; Campbell, A. L.; Moretti,
R.; Koerner, M.; Lipshutz, B. H. J. Am. Chem. Soc. 1988, 110, 2641.
(96) (a) Piers, E.; McEachern, E. J.; Burns, P. A. Tetrahedron 2000, 56,
2753. (b) Piers, E.; Skupinska, K. A.; Wallace, D. J. Synlett 1999, 1867.
(c) Piers, E.; McEachern, E. J.; Burns, P. A. J. Org. Chem. 1995, 60, 2322.
(97) Wulff, W. D.; Peterson, G. A.; Bauta, W. E.; Chan, K.-S.; Faron,
K. L.; Gilbertson, S. R.; Kaesler, R. W.; Yang, D. C.; Murray, C. K. J.
Org. Chem. 1986, 51, 277.
(98) (a) Crandall, J. K.; Batal, D. J.; Lin, F.; Reix, T.; Nadol, G. S.; Ng,
R. A. Tetrahedron 1992, 48, 1427. (b) Aumann, R.; Trentmann, B. Chem.
Ber. 1989, 122, 1977.
(99) A typical example describing an attempt at methyl sulfonyl ester
formation is described in the Experimental Section.
(100) For recent reviews of the intramolecular Heck reaction see: (a)
Ashimori, A.; Overman, L. E. J. Synth. Org. Chem. Jpn. 2000, 58, 718. (b)
Link, J. T.; Overman, L. E. In Metal-Catalyzed Cross Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; p 231.

9336 J. Am. Chem. Soc., Vol. 123, No. 38, 2001
Scheme 18. Formation of F Ring from 56
Eichberg et al.
Rawal17 and those of an enantiomerically pure sample derived
from natural isostrychnine.107 Thus, isolation of 60 constitutes
a formal synthesis of 1. A radical process involving the
homolytic cleavage of the carbon-iodine bond and subsequent
isomerization of the vinyl radical could be responsible (vide
infra), possibly initiated by electron transfer from Ni(I) formed
during the reaction.108,109
Optimization of the Formation and Reduction of Pyridone
68. The synthesis of 68 (Scheme 18) provided the first
moderately efficient entry into the desired hexacyclic system
of isostrychnine (2). The stereoselective reintroduction of the
C8 methine was all that lay between 68 and 60. Since this task
appeared soluble, some efforts were expanded in optimizing
the production of 68. Best results were obtained with the use
of Pd(OAc)2 and PPh3 in Et3N at 70 °C (Scheme 18, Table 3,
entry 4) or Pd(OAc)2, Bu4NCl, and K2CO3 in DMF110 at 70 °C
(entry 8). Under either of these conditions, the Heck reaction
proceeded in 47-50% yield. While the second gave the pyridone
in relatively short reaction times (2-4 h), reactions in Et3N or
THF with PPh3 as ligand took longer (18-22 h) and tended to
return amine 63. The amine could also be isolated from phase-
transfer reactions which included added water (entry 9).111
Various modifications of these conditions were examined.
Without PPh3, the reaction proceeded poorly in THF and amine
solvents (entries 1 and 2), and other ligands [dppe, P(o-tolyl)3]
also retarded the reaction (entries 6 and 7). The use of the silver
salt AgOTf failed to result in a more efficient reaction giving
68 in approximately 38% yield (entry 5).112 Phosphine ligands
were not required for the phase-transfer reaction to proceed in
acceptable yield, although the reaction failed without added
tetraalkylammonium catalyst (entry 12). The specific choice of
phase-transfer catalyst appeared to have little effect on the
reaction’s outcome.
With reasonable quantities of 68 in hand, the focus became
the reintroduction of the C8 methine hydrogen via a stereo- and
regioselective hydride addition to the aromatic pyridone ring.
In fact, reduction of a C8-C13 double bond has served as a
step in a number of approaches to 1 and similar alka-
loids.10,12,14,16,113 A tactic analogous to one used by Woodward
on route to 1 proved to be the most successful. Reaction of 68
with LiAlH410,114 in THF/Et2O (3:1) at 35 °C for 2 h led to the
isolation of 60 in 39% yield. Reducing the reaction time or
quantity of reducing agent failed to increase the efficiency, but
running the reaction at 0 °C did increase the yield to an
acceptable 54% (eq 7).
DMF101 gave a 21% yield of hexacycle 68 after 15 h at 100
°C. Attempts to flood the system with a 10-fold excess of
sodium formate led to reductive elimination before cyclization
to give 61 (45%). Use of tetralkylammonium formate salts102
or Bu3SnH103 as alternative hydride sources failed to prevent
formation of 68 in favor of 60. Some groups have reported
palladium-catalyzed conjugate additions to enones without the
addition of a hydride source,104 but generally, these systems
lack readily available syn hydrogens for elimination, and their
application to 56 led primarily to 68.
The use of nickel in promoting tandem cyclization-capture
sequences is known and has found successful application in the
formation of piperidine and pyrrolidine rings,105 including in
Curan alkaloid systems analogous to that at hand.105b The
success of this approach relies on the presence of a distal amino
group capable of coordinating with the metal in the transient
vinyl or alkylnickel species, thus preventing Ni-H â-elimination
prior to trapping the intermediates with a hydride source.
Reaction of 56 with Ni(COD)2 in the presence of Et3N in dry
MeCN, followed by the addition of Et3SiH, gave a mixture of
the desired isostrychnine ether 60 (24%), its Z-isomer 73 (21%),
and amine 63 (12%) (Scheme 18).106 When, instead of Et3SiH,
an aqueous acid quench (NH4Cl) was employed, the same
mixture was obtained, albeit in a somewhat altered ratio (60,
21%; 73, 11%; 63, 18%). Silyl ether 60 displayed spectral
characteristics that matched both those previously reported by
Radical-Mediated Closure of F Ring. Simultaneous with
the examination of palladium-mediated methods for the forma-
tion of the piperidine ring, the potential for a radical-mediated
(101) Burns, B.; Grigg, R.; Santhakumar, V.; Sridharan, V.; Stevenson,
P.; Worakun, T. Tetrahedron 1992, 48, 7297.
(102) (a) Namyslo, J. C.; Kaufmann, D. E. Synlett 1999, 114. (b) Cacchi,
S.; Palmieri, G. Synthesis 1984, 575.
(103) (a) Taniguchi, M.; Takeyama, Y.; Fugami, K.; Oshima, K.;
Utimoto, K. Bull. Chem. Soc. Jpn. 1991, 64, 2593. (b) Schmidt, B.;
Hoffmann, H. M. R. Tetrahedron 1991, 47, 9357.
(108) For a closely related example of stereochemical scrambling reported
in the synthesis of the Strychnos alkaloid mossambine, see: Kuehne, M.
E.; Wang, T. S.; Seraphin, D. J. Org. Chem. 1996, 61, 7873.
(109) Readman, S. K.; Marsden, S. P.; Hodgson, A. Synlett 2000, 1628
and references therein.
(110) Jeffery, T. Tetrahedron Lett. 1985, 26, 2667.
(104) (a) Grubb, L. M.; Dowdy, A. L.; Blanchette, H. S.; Friestad, G.
K.; Branchaud, B. P. Tetrahedron Lett. 1999, 40, 2691. (b) Bonjosch, J.;
Solee´, D.; Garcia-Rubio, S.; Bosch, J. J. Am. Chem. Soc. 1997, 119, 7231.
(c) Friestad, G. K.; Branchaud, B. P. Tetrahedron Lett. 1995, 36, 7047. (d)
Stokker, G. E. Tetrahedron Lett. 1987, 28, 3179.
(105) (a) Sole´, D.; Cancho, Y.; Llebaria, A.; Moreto´, J. M.; Delgado, A.
J. Am. Chem. Soc. 1994, 116, 12133. (b) Sole´, D.; Cancho, Y.; Llebaria,
A.; Moreto´, J. M.; Delgado, A. J. Org. Chem. 1996, 61, 5895. (c) Cancho,
Y.; Mart´ın, J. M.; Martinez, M.; Llebaria, A.; Moreto´, J. M.; Delgado, A.
Tetrahedron 1998, 54, 1221.
(111) In addition to being a synthetically useful byproduct, the isolation
of 63 suggested that the moderate yields were due to â-elimination of the
butenyl side chain, perhaps via an intermediate palladium amide complex.
The readiness of this E-butenyl geometry to undergo elimination has been
observed previously (as noted) and may also be partly responsible for the
difficulty in C14-C21 bond formation encountered in other studies which
have followed similar strategies (see refs 11a, 13, 15, and 18).
(112) Crisp, G. T. Chem. Soc. ReV. 1998, 27, 427.
(113) (a) Vercauteren, J.; Bideau, A.; Massiot, G. Tetrahedron Lett. 1987,
28, 1267. (b) Mirand, C.; Massiot, G.; Le Men-Olivier, L.; Le´vy, J.
Tetrahedron Lett. 1982, 23, 1257. (c) Laronze, J. Y.; Cartier, D.; Laronze,
J.; Le´vy, J. Tetrahedron Lett. 1980, 21, 4441.
(106) A trace of both the cis and trans isomers of the reduced, uncyclized
alkene 61 was also observed.
(107) Reaction of isostrychnine (ref 27) with TBSOTf (1.6 equiv) and
2,6-lutidine (1.6 equiv) in CH2Cl2 gave a 64% yield of 60.
(114) Gallagher, T.; Magnus, P.; Huffman, J. C. J. Am. Chem. Soc. 1983,
105, 4750.

Synthesis of (()-Strychnine
J. Am. Chem. Soc., Vol. 123, No. 38, 2001 9337
Table 3. Heck Cyclization of Vinylic Iodide 56
entry
catalyst (equiv)
additives (equiv)
solvent
T (°C) (t [h])
products (yield, %)
1
2
Pd(OAc)2 (0.5)
Et3N
none
Et3N
none
THF
Et3N
THF
Et3N
Et3N
Et3N
Et3N
70 (5)
70 (20)
65 (5)
70 (20)
70 (22)
80 (22)
80 (22)
70 (2)
70 (2)
70 (4)
70 (4)
70 (3)
56 (70)
Pd(OAc)2 (0.5)
56 (25), 68 (18)
63 (66), 68 (17)
63 (49), 68 (47)
68 (38)
3
Pd(PPh3)4 (0.2)
4
Pd(OAc)2 (0.3), PPh3 (0.6)
Pd(OAc)2 (0.2), PPh3 (0.5)
Pd(OAc)2 (0.2), P(o-tolyl)3 (0.4)
Pd(OAc)2 (0.2), dppe (0.3)
Pd(OAc)2 (0.2)
5
AgOTf (1.4)
6
none
none
56 (90)
7
56 (77)
8
K2CO3 (5), Bu4NCl (1.5)
K2CO3 (5), Bu4NCl (1.5)
K2CO3 (5), Bu4NI (1.5)
K2CO3 (5), BnBu3NBr (1.5)
K2CO3 (5)
DMF
68 (50)
9
Pd(OAc)2 (0.2)
DMF/H2O (10:1)
DMF
DMF
DMF
63 (28), 68 (42)
68 (46)
10
11
12
Pd(OAc)2 (0.2)
Pd(OAc)2 (0.2)
68 (47)
68 (trace)
Pd(OAc)2 (0.2)
mentioned above, the alcohol can be converted to 1 by the well-
known base-mediated isomerization of Prelog et al.,26 thus
completing its total synthesis in racemic form.
Conclusions
ring closure was examined.115 Reaction of 56 with Bu3SnH and
Et3B in toluene116 at room temperature for 1 day gave primarily
the deiodinated alkene 61 as a mixture of cis and trans isomers
(3:7) in 41% yield, the desired hexacyclic silyl ether 60 and its
Z-isomer 73 (1:1, 20% combined yield), and recovered 56
(18%). Fortunately, the two hexacyclic isomers were separable
by careful column chromatography. Switching to benzene as
solvent essentially reversed the above outcome, giving a 23%
yield of 61 (2:3, cis/trans), 40% of 60 and 73 (1:1), and
recovered 56 (6%). The recovery of the uncyclized reduced 61
suggested a somewhat sluggish 6-exo-trig closure, giving
opportunity for either an intermolecular reduction of the radical
by Bu3SnH or an intramolecular 1,5-hydrogen shift from the
C15 methylene. Indeed, formation of the uncyclized system
could be minimized by reaction of 56 and Bu3SnH in refluxing
benzene, with AIBN as initiator, giving a 71% yield of 60 and
73, again as a 1:1 mixture (Scheme 18).108 While the facile
isomerization of the intermediate vinyl radical, with an estimated
barrier of 2 kcal/mol,117 cannot be avoided, it was hoped that
variation of the reaction conditions would affect the relative
rates of ring closure of the two isomeric reactive species.
However, reaction of deprotected alcohol 59 failed to improve
the ratio of isomers and ruled out any steric effect of the bulky
tert-butyl(dimethyl)silyl ether. Employment of TMS3SiH as a
radical source118 gave an improved isomer ratio (2:1, 60/73)
but with a lower yield (40%). Similar results were obtained with
Ph3SnH. Finally, reaction with SmI2, which has shown some
selectivity in vinyl radical cyclizations,119 resulted in extensive
decomposition of the starting material.
The approach to 1 discussed in the final section of this paper
constitutes one of the shortest reported syntheses of strychnine
to date. The route to isostrychnine (2) involves 13 steps from
propiolic acid (9 steps from tryptamine) via a radical-mediated
closure of the F ring or a Ni-mediated cyclization, or 14 steps
via a Heck reaction/reduction sequence, and proceeds in 2.8%,
1.9%, and 1.9%, respectively. Moreover, it is the robust nature
of the cobalt-mediated [2 + 2 + 2] cycloaddition of alkynes to
indoles which allows the stereo- and regioselective incorporation
of a variety of functionality into the dihydrocarbazole nucleus,
and the rich carbon-carbon and carbon-nitrogen bond forming
chemistry of the metal-complexed and decomplexed cyclohexa-
diene products that ultimately provide the flexibility to design
such a brief synthesis of strychnine. The effort described here
serves as an example for the potential applicability of this
methodology to the construction of other complex, polycyclic
indole alkaloid targets.
Acknowledgment. We gratefully acknowledge the financial
support by the NSF (CHE-0071887 and a predoctoral fellowship
for M.J.E.) and the Alexander von Humboldt Foundation for a
Feodor-Lynen-Fellowship for M.S. The Center for New Direc-
tions in Organic Synthesis is supported by Bristol-Myers Squibb
as Sponsoring Member.
Supporting Information Available: Experimental proce-
dures and spectroscopic and/or analytical details for all new
compounds (PDF); X-ray crystallography data for 59 (CIF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
As in Rawal’s synthesis, deprotection of the silyl ether 60
under acidic conditions provided isostrychnine (2) in almost
quantitative yield (eq 8).17 The synthetic material was identical
JA016333T
(115) Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. ReV. 1991, 91,
1, 1237.
(116) Takayama, H.; Watanabe, F.; Kitajima, M.; Aimi, N. Tetrahedron
Lett. 1997, 38, 5307.
(117) (a) Jiao, X.-Y.; Bentrude, W. G. J. Am. Chem. Soc. 1999, 121,
6088 and references therein. (b) Stork, G.; Baine, N. H. J. Am. Chem. Soc.
1982, 104, 2321.
(118) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188.
(119) Capella, L.; Montevecchi, P. C.; Navacchia, M. L. J. Org. Chem.
1995, 60, 7424.
with the natural compound by 1H and 13C NMR and TLC.27 As