The formal total synthesis of (±)-strychnine via a cobalt-mediated [2 + 2 + 2]cycloaddition

Article abstract of DOI:10.1021/ol006131m

(equation presented) A short, highly convergent total synthesis of racemic isostrychnine, and thus strychnine, has been completed. The route involves 14 steps in the longest linear sequence and is highlighted by a cobalt-mediated [2 + 2 + 2]cycloaddition of an alkynylindole nucleus to acetylene.

Full text of DOI:10.1021/ol006131m

ORGANIC
LETTERS
2
000
Vol. 2, No. 16
479-2481
The Formal Total Synthesis of
±)-Strychnine via a Cobalt-Mediated [2
2 + 2]Cycloaddition
2
(
+
Michael J. Eichberg,* Rosa L. Dorta, Kai Lamottke, and K. Peter C. Vollhardt*
Department of Chemistry, UniVersity of California at Berkeley, and
the Chemical Sciences DiVision, Lawrence Berkeley National Laboratory,
Berkeley, California 94720-1460
eichberg@socrates.berkeley.edu
Received May 30, 2000
ABSTRACT
A short, highly convergent total synthesis of racemic isostrychnine, and thus strychnine, has been completed. The route involves 14 steps
in the longest linear sequence and is highlighted by a cobalt-mediated [2 + 2 + 2]cycloaddition of an alkynylindole nucleus to acetylene.
Strychnine (1), the most famous of the Strychnos alkaloids
and a commonly used rat poison, has long held the
fascination of organic chemists. The elucidation of the
structure of this heptacycle took more than a century, and
its construction by R. B. Woodward, first reported in 1954,
framework of only 24 atoms, has resulted in the continued
appeal of the alkaloid as a target on which to demonstrate
the utility of novel synthetic methods.
1
remains a landmark in organic synthesis. Since then, several
2
3
syntheses of 1, including those of both enantiomers, have
been achieved. Indeed, the inherent complexity of strychnine,
with its seven rings and six stereocenters displayed across a
(1) (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.
We approached the total synthesis of 1 as part of our
(
2) Racemic syntheses of 1: (a) Magnus, P.; Giles, M.; Bonnert, R.;
Kim, C. S.; McQuire, L.; Merritt, A.; Vicker, A. J. Am.. Chem. Soc. 1993,
15, 8116. (b) Stork, G. Reported at the Ischia Advanced School of Organic
ongoing work in expanding the scope and utility of the
4
cobalt-mediated [2 + 2 + 2]cycloaddition reaction. The
1
Chemistry, Ischia Porto, Italy, September 21, 1992. (c) Kuehne M. E.; Xu,
F. J. Org. Chem. 1993, 58, 7490. (d) Rawal, V. H.; Iwasa, S. J. Org. Chem.
ability of cyclopentadienyl cobalt to effect the cycloaddition
of three unsaturated functionalities with a high degree of
chemo-, regio-, and stereoselectivity has resulted in the
1
994, 59, 2685.
3) Enantioselective syntheses of 1: (a) Knight, S. D.; Overman, L. E.;
(
Pairaudeau, G. J. Am. Chem. Soc. 1995, 117, 5776. (b) Kuehne, M. E.; Xu,
F. J. Org. Chem. 1998, 63, 9427. (c) Sol e´ , D.; Bonjoch, J.; Garc ´ı a-Rubio,
S.; Peidr o´ , E.; Bosch, J. Angew. Chem., Int. Ed. 1999, 38, 395. (d). Sol e´ ,
D.; Bonjoch, J.; Garc ´ı a-Rubio, S.; Peidr o´ , E.; Bosch, J. Chem. Eur. J. 2000,
5
assembly of a number of complex natural products. The
(4) For an earlier report of our efforts toward the synthesis of 1, see:
Grotjahn, D. B.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1990, 112, 5653.
6
, 655.
1
0.1021/ol006131m CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/08/2000

wide variety of functionalities which participate in this
reaction include a number of aromatic heterocyclic double
Scheme 1
6
a
6b
bonds, such as those of pyrrole, imidazole, furan,
6c
6d
thiophene, and benzofuran. More pertinently, the indole
nucleus is also active in these cyclizations, providing an
efficient entry into polycyclic, alkaloid-like structures, and
suggesting its use in a cobalt-mediated approach to 1. As
shown in Figure 1, indoles, including those substituted at
core of 1. Thus, in THF solution, 3 was converted to
1
0
tetracyclic lactam 4 in the presence of CpCo(C
2
H
4
)
2
and
1
1
acetylene gas. The reaction proceeded with complete
selectivity, producing 4 in 47% yield as a single diastere-
1
2
omer.
Synthesis of acid chloride 2 began with propiolic acid and
is outlined in Scheme 2. The acid was selectively iodinated13
Scheme 2
Figure 1. Some cobalt-mediated [2 + 2 + 2]cyclizations of the
indole nucleus.
to the cis isomer and then esterified with the methoxy-
ethoxymethyl group to afford 5. Protection of the carboxy
function proved to be necessary for the success of the
subsequent Sonogashira-type coupling of 5 with trimethy-
silylacetylene. Acidic hydrolysis of the resulting ester 6
afforded the acid, which, on reaction with oxalyl chloride,
was converted to acid chloride 2. This five-step sequence
proceeds in 42% overall yield to afford multigram quantities
of 2.
The synthesis of strychnine continued with the organo-
metallic intermediate 4 as shown in Scheme 3. The exocyclic
nitrogen was deprotected with KOH in boiling methanol-
water, highlighting the use of the CpCo diene moiety as a
protecting group. Closure of the pyrrolidine ring occurred
C-3, can be cyclized, both intra- and intermolecularly, with
a wide variety of alkynes to yield functionalized products
in moderate to good yields.7
Our strategy begins with tryptamine, which is converted
into the tetracyclic core of strychnine as shown in Scheme
1
4
1
. The commercial starting material was first acylated at its
8
primary amino group with acetic anhydride and then at the
indole nitrogen with the enynoyl chloride 2 under phase-
transfer conditions, with in situ deprotection of the alkyne,
to afford the N-protected enynoylindole 3.9
The production of 3 set the stage for a partly intramolecular
[2 + 2 + 2]cycloadditon which would construct the carbazole
(
5) Saa, C.; Crotts, D. D.; Hsu, G.; Vollhardt, K. P. C. Synlett 1994,
87 and references therein.
6) (a) Sheppard, G. S.; Vollhardt, K. P. C. J. Org. Chem. 1986, 51,
496. (b) Boese, R.; Kn o¨ lker, H. J.; Vollhardt, K. P. C. Angew. Chem., Int.
(10) Jonas, K.; Deffense, E.; Habermann, D. Angew. Chem., Intl. Ed.
Engl. 1983, 22, 716.
4
5
(
(11) Critical to the success of this reaction is the addition rate of the
cobalt reagent, the initial concentration of 3 (0.05 M), the temperature (0
°C), and the rate of the acetylene addition, which must be moderated by a
concomitant nitrogen or argon purge of the reaction mixture.
(12) The primary byproducts of this reaction, isolated in 20-30%, yield
are the cis- and trans-cinnamic amides of N-acetyltryptamine. Presumably,
these arise from the cyclization of the terminal acetylene of enyne 3 with
two acetylene molecules and subsequent stereoequilibriation.
(13) Moss, R. A.; Wilk, B.; Krogh-Jespersen, K.; Westbrook, J. D. J.
Am. Chem. Soc. 1989, 111, 6729.
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) P e´ rez, D.;
Siesel, B. A.; Malaska, M. J.; David, E.; Vollhardt, K. P. C. Synlett 2000,
3
66.
(7) (a) Grotjahn, D. B.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1986,
1
1
08, 2091. (b) Boese, R.; Van Sickle, A. P.; Vollhardt, K. P. C. Synthesis
994, 1374.
(8) Sp a¨ th, E.; Lederer, E. Chem Ber. 1930, 63, 120.
(
9) (a) Illi, V. O. Synthesis 1979, 397. (b) Oldroyd, D. L.; Weedon, A.
(14) Abarbri, M.; Parrain, J.-L.; Cintrat, J.-C.; Duch eˆ ne, A. Synthesis
1996, 82.
C. J. Org. Chem. 1994, 59, 1333.
2480
Org. Lett., Vol. 2, No. 16, 2000

and AIBN generated the desired hexacyclic silyl ether 10,
previously reported by Rawal in his synthesis of 1,2d as a
Scheme 3
1
:1 mixture with its Z-isomer 11 in 71% overall yield.
Apparently arising from the extremely facile isomerization
of the intermediate vinyl radical before the desired 6-exo-
1
7
trig ring-closure, the 1:1 ratio of E/Z isomers could not be
18
further optimized. However, the two isomers were separated
without difficulty by column chromatography. An alternative,
two-step cyclization procedure involved an intramolecular
Heck reaction of 9 to form, following â-elimination of the
C-8 hydrogen and aromatization, the pyridone 12.2d This
4
compound could be selectively reduced by LiAlH to furnish
1
9
1
0.
As in Rawal’s synthesis, deprotection of the silyl ether
under acidic conditions provided isostrychnine (13) in almost
1
13
quantitative yield. Identical by H and C NMR, TLC, and
mp with the natural compound, the alcohol can be converted
to 1 by the well-known base-mediated isomerization of
2
0
Prelog et al.
In conclusion, we have completed the shortest reported
synthesis of the complicated strychnine framework to date.
This synthesis serves to demonstrate the continued utility of
the cobalt-mediated [2 + 2 + 2]cycloaddition reaction in
the construction of complex natural products.
Acknowledgment. We thank the NSF (CHE-0071887
and a predoctoral fellowship for M.J.E.) for their generous
support. We also thank Professor Viresh Rawal for providing
experimental details for the synthesis of (Z)-1-bromo-4-[(tert-
butyldimethylsilyl)oxy]-2-iodobut-2-ene.
upon oxidative demetalation of 7 with iron(III) to afford
pentacycle 8 in a formal [1,8]-conjugate addition of the amine
function to the unsaturated lactam π-system. Alkylation of
the amine nitrogen with (Z)-1-bromo-4-[(tert-butyldimeth-
ylsilyl)oxy]-2-iodobut-2-ene,2d followed by base-catalyzed
isomerization of the diene unit into conjugation with the
amide carbonyl, afforded vinyl iodide 9.
Supporting Information Available: Detailed experi-
mental procedures and complete spectroscopic and analytical
data for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
The vinyl iodide functionality in 9 presents a number of
opportunities for the formation of the desired piperidine ring,
including, metal-iodide exchange/conjugate addition, Pd-
mediated Heck/anion capture sequences,16 and radical-
mediated closure. By far the most successful of these
OL006131M
15
(
17) Stork, G.; Baine, N. H. J. Am. Chem. Soc. 1982, 104, 2321.
(18) For a closely related example reported in the synthesis of the
Strychnos alkaloid mossambine, see: Kuehne, M. E.; Wang, T.; Seraphin,
D. J. Org. Chem. 1996, 61, 7873.
3
methods was the latter. Thus, reaction of 9 with Bu SnH
(19) Interestingly, this step is quite similar to a reduction of a late-stage
pyridone intermediate in Woodward’s original synthesis of strychnine (ref
1b). He attributes the selectivity to the directing effect of a free hydroxyl
present in the substrate, while we rationalize our result by the attack of the
hydride from the less-hindered si face.
(20) Prelog, V.; Battegay, J.; Taylor, W. I. HelV. Chim. Acta 1948, 31,
2244. This ring closure step was also used as the last step in the strychnine
syntheses of Woodward (ref 1), Kuehne (ref 2c), and Rawal (ref 2d).
(
15) These include reaction with alkyllithium reagents, attempted forma-
tion of cuprates or Grignard intermediates, the use of NiCl2/CrCl2, and
activated copper and zinc reagents. Full details of the results of this synthetic
study are to be reported elsewhere.
(
16) Burns, B.; Grigg, R.; Santhakumar, V.; Sridharan, P.; Worakun, T.
Tetrahedron 1992, 48, 7297.
Org. Lett., Vol. 2, No. 16, 2000
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