Total synthesis of (±)-strychnine via a [4 + 2]-cycloaddition/ rearrangement cascade

Article abstract of DOI:10.1021/ol062728b

(Chemical Equation Presented) A new strategy for the synthesis of the Strychnos alkaloid (±)-strychnine has been developed and is based on an intramolecular [4 + 2]-cycloaddition/rearrangement cascade of an indolyl-substituted amidofuran. The critical D-r

Full text of DOI:10.1021/ol062728b

ORGANIC
LETTERS
2
007
Vol. 9, No. 2
79-282
Total Synthesis of (
±)-Strychnine via a
2
[4 +
2]-Cycloaddition/Rearrangement
Cascade
Hongjun Zhang, Jutatip Boonsombat, and Albert Padwa*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
chemap@emory.edu
Received November 7, 2006
ABSTRACT
A new strategy for the synthesis of the Strychnos alkaloid (
±
)-strychnine has been developed and is based on an intramolecular [4
+
2]-cycloaddition/rearrangement cascade of an indolyl-substituted amidofuran. The critical D-ring was assembled by an intramolecular palladium-
catalyzed enolate-driven cross-coupling of an N-tethered vinyl iodide.
Strychnos alkaloids belonging to the curane type constitute
complex heptacyclic structure, containing 24 skeletal atoms
and six contiguous stereogenic centers, has fascinated organic
chemists for the past 60 years. Nearly 40 years after
Woodward’s pioneering achievement of strychnine, a num-
ber of other research groups have reported on its synthesis.8
an important group of architecturally complex and widely
1,2
distributed monoterpenoid indole alkaloids. The curane
family is characterized by the presence of a pentacyclic 3,5-
ethanopyrrolo[2,3-d]carbazole framework (i.e., 1) bearing a
two-carbon appendage at C-20 and an oxidized one-carbon
7
3
substituent (C-17) at the C-16 position (Figure 1). The
synthesis of various members of the Strychnos family has
been an area of interest ever since the structural elucidation
of strychnine (4), the most famous of this group of alkaloids,
4
by Robinson in 1946. Strychnine was first isolated in 1818
5
from the Indian poison nut (Strychnos nux Vomica) and
possesses highly toxic properties as a result of its interaction
with the glycine receptor site, thereby blocking the flux of
6
chloride ions and disruption of nerve-cell signaling. Its
(
1) For leading reviews of Strychnos alkaloids, see: (a) Bosch, J.;
Bonjoch, J.; Amat, M. Alkaloids 1996, 48, 75 and references cited therein.
b) Bonjoch, J.; Sol e´ , D. Chem. ReV. 2000, 100, 3455.
2) Creasey, W. A. In The Monoterpene Indole Alkaloids; Saxton, J. E.,
Ed.; Interscience: New York, 1983; p 800.
3) The biogenetic numbering is used for pentacyclic structures such as
; see: Le Men, J.; Taylor, W. I. Experientia 1965, 21, 508.
4) (a) Robinson, R. Experientia 1946, 2, 28. (b) Holmes, H. L.;
(
(
(
1
(
Openshaw, H. T.; Robinson, R. J. Chem. Soc. 1946, 908. (c) Openshaw,
H. T.; Robinson, R. Nature 1946, 157, 438.
Figure 1. Some representative Strychnos alkaloids.
(5) Pelletier, P. J.; Caventou, J. B. Ann. Chim. Phys. 1818, 8, 323.
1
0.1021/ol062728b CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/24/2006

Efficient approaches toward the Strychnos pentacyclic
framework would allow the synthesis of not only other
members of this family of natural products (i.e., strych-
nopivotine (2) and akuammicine (3)) but also related non-
natural products possessing biological activity. Along these
lines, we have recently become involved in the development
and optimization of a new approach for the construction of
the pentacyclic framework of the Strychnos system. In this
paper, we report a concise stereocontrolled total synthesis
of (()-strychnine (4) wherein an efficient [4 + 2]-cycload-
dition/rearrangement method previously developed in our
laboratories plays a crucial role.9
Scheme 1
In Rawal and Iwasa’s elegant synthesis of (()-strychnine,8e
an ingenious palladium-catalyzed intramolecular Heck reac-
tion was used as the key step for the creation of the D-ring.
7
As in Woodward’s original approach, isostrychnine (5) was
the final critical intermediate used in this synthesis. Its
Prelog-Taylor cyclization to strychnine10 (Scheme 1),
however, suffers from an unfavorable 3:1 equilibration ratio
of these two compounds. From this perspective, the alterna-
tive biomimetic route to strychnine involving condensation
of the Wieland-Gumlich aldehyde (6) with an acetate
equivalent for the formation of the G ring seemed to us to
be the more attractive approach, as it avoids the unfavorable
equilibration ratio. As illustrated in Scheme 2, our retrosyn-
thetic analysis of strychnine (4) relies upon the efficient
construction of the tetracyclic substructure 8, containing the
ABCE rings of 4, by an intramolecular [4 + 2]-cycloaddition/
rearrangement cascade of 2-amidofuran 7. The synthetic plan
also involves closure of the D-ring by a palladium-catalyzed
intramolecular coupling of an amido-tethered vinyl iodide
1
2,13
with a keto enolate (i.e., 9 f 10).
11
Scheme 2
(6) (a) Aprison, M. H. In Glycine Neurotransmission; Otterson, O. P.,
Strom-Mathisen, J., Eds.; Wiley: New York, 1990; pp 1-23. (b) Gren-
ningloh, G.; Rienitz, A.; Schmitt, B.; Methfessel, C.; Zensen, M.; Beyreuther,
K.; Gundelfinger, E. D.; Betz, H. Nature 1987, 328, 215. (c) Kleckner, N.
W.; Dingledine, R. Science 1988, 241, 835.
(7) Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker,
H. U.; Schenker, K. J. Am. Chem. Soc. 1954, 76, 4749. Woodward, R. B.;
Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker, H. U.; Schenker, K.
Tetrahedron 1963, 19, 247.
(8) (a) Magnus, P.; Giles, M.; Bonnert, R.; Kim, C. S.; McQuire, L.;
Merritt, A.; Vicker, N. J. Am. Chem. Soc. 1992, 114, 4403. 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. (b) Stork, G.
Presented at the Ischia Advanced School of Organic Chemistry, Ischia Porto,
Italy, September 21, 1992. (c) Knight, S. D.; Overman, L. E.; Pairaudeau,
G. J. Am. Chem. Soc. 1993, 115, 9293. Knight, S. D.; Overman, L. E.;
Pairaudeau, G. J. Am. Chem. Soc. 1995, 117, 5776. (d) Kuehne, M. E.; Xu,
F. J. Org. Chem. 1993, 58, 7490. Kuehne, M. E.; Xu, F. J. Org. Chem.
1
998, 63, 9427. (e) Rawal, V. H.; Iwasa, S. J. Org. Chem. 1994, 59, 2685.
(f) Sol e´ , D.; Bonjoch, J.; Garc ´ı a-Rubio, S.; Peidr o´ , E.; Bosch, J. Angew.
Chem., Int. Ed. 1999, 38, 395. Sol e´ , D.; Bonjoch, J.; Garc ´ı a-Rubio, S.;
Peidr o´ , E.; Bosch, J. Chem.sEur. J. 2000, 6, 655. (g) Eichberg, M. J.;
Dorta, R. L.; Lamottke, K.; Vollhardt, K. P. C. Org. Lett. 2000, 2, 2479.
Eichberg, M. J.; Dorta, R. L.; Grotjahn, D. B.; Lamottke, K.; Schmidt, M.;
Vollhardt, K. P. C. J. Am. Chem. Soc. 2001, 123, 9324. (h) Ito, M.; Clark,
C. W.; Mortimore, M.; Goh, J. B.; Martin, S. F. J. Am. Chem. Soc. 2001,
1
1
2
4
23, 8003. (i) Nakanishi, M.; Mori, M. Angew. Chem., Int. Ed. 2002, 41,
934. Mori, M.; Nakanishi, M.; Kajishima, D.; Sato, Y. J. Am. Chem. Soc.
003, 125, 9801. (j) Bodwell, G. J.; Li, J. Angew. Chem., Int. Ed. 2002,
1, 3261. (k) Ohshima, T.; Xu, Y.; Takita, R.; Shimizu, S.; Zhong, D.;
Some years ago, we commenced a program of research
based on the intramolecular [4 + 2]-cycloaddition/rearrange-
Shibasaki, M. J. Am. Chem. Soc. 2002, 124, 14546. Ohshima, T.; Xu, Y.;
Takita, R.; Shibasaki, M. Tetrahedron 2004, 60, 9569. (l) Kaburagi, Y.;
Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2004, 126, 10246.
(12) (a) Sol e´ , D.; Peidr o´ , E.; Bonjoch, J. Org. Lett. 2000, 2, 2225. (b)
Sol e´ , D.; Diaba, J.; Bonjoch, J. J. Org. Chem. 2003, 68, 5746. (c) Bonjoch,
J.; Diaba, F.; Puigb o´ , G.; Peidr o´ , E.; Sol e´ , D. Tetrahedron Lett. 2003, 44,
8387. (d) Sol e´ , D.; Urbaneja, X.; Bonjoch, J. AdV. Synth. Catal. 2004, 346,
1646. (e) Sol e´ , D.; Urbaneja, X.; Bonjoch, J. Org. Lett. 2005, 7, 5461.
(13) For some other examples of intramolecular Pd-catalyzed vinylations,
see: (a) Piers, E.; Oballa, R. M. Tetrahedron Lett. 1995, 36, 5857. (b) Yu,
J.; Wang, T.; Liu, X.; Deschamps, J.; Flippen-Anderson, J.; Liao, X.; Cook,
J. M. J. Org. Chem. 2003, 68, 7565.
(9) (a) Wang, Q.; Padwa, A. Org. Lett. 2004, 6, 2189. (b) Padwa, A.;
Ginn, J. D. J. Org. Chem. 2005, 70, 5197. (c) Padwa, A.; Bur, S. K.; Zhang,
H. J. Org. Chem. 2005, 70, 6833. (d) Zhang, H.; Padwa, A. Org. Lett.
2
2
8
006, 8, 247.
10) Prelog, V.; Battegay, J.; Taylor, W. I. HelV. Chim. Acta 1948, 31,
244.
(
(11) Anet, F. A. L.; Robinson, R. Chem. Ind. 1953, 245. See also ref
a,c.
280
Org. Lett., Vol. 9, No. 2, 2007

ment cascade of 2-amidofurans as a strategy for the synthesis
of different classes of alkaloids.14 Intramolecular cyclo-
addition reactions often benefit from higher reactivity and
greater control of stereoselectivity relative to their inter-
molecular counterparts. Specifically, connecting the two
π-fragments via a “tether” generally facilitates the rate of
the [4 + 2]-cycloaddition reaction. Our earlier experience
with this domino sequence prompted us to apply the cascade
approach toward (()-strychnine. With this in mind, we
prepared furanylindole 7 by acylation of the mixed anhydride
stereoselective reduction of the keto group of 8 with NaBH
4
followed by N-deacetylation using NaOMe (Scheme 4). The
Scheme 4
15
of 2-(1-acetyl-1H-indol-3-yl)acetic acid with the N-lithiate
anion of tert-butyl furan-2-ylcarbamate followed by Boc
1
6
4 2
deprotection with Mg(ClO ) and subsequent N-alkylation
using 1-(bromomethyl)-2-methylbenzene in 55% overall
yield for the three-step procedure. We suspect that the
presence of the large o-methylbenzyl group on the amido
nitrogen atom causes the reactive s-trans rotamer to be more
highly populated and probably helps promote the [4 +
2]-intramolecular cycloaddition. Indeed, the cycloaddition/
rearrangement cascade of 7 was remarkably efficient given
that two heteroaromatic systems are compromised in the
reaction. Thus, heating a sample of 7 at 150 °C (toluene) in
a microwave reactor for 30 min in the presence of catalytic
MgI
2
afforded the desired aza-tetracycle 8 in 95% yield
(Scheme 3). This reaction cascade can be rationalized by a
Scheme 3
γ-lactam carbonyl group was then reduced with LiAlH
the resulting enamine was further reduced using NaBH-
OAc) to give alcohol 13 as the major diastereomer in 65%
4
, and
(
3
1
7
yield over the four-step sequence. Removal of the o-
methylbenzyl group by catalytic hydrogenation furnished 14
in 70% isolated yield. This was followed by N-alkylation
with (Z)-1-bromo-2-iodo-4-(methoxymethoxy)but-2-ene to
give alcohol 15 in 80% yield. Condensation of the indoline
nitrogen present in 15 with 2,4-dimethoxybenzaldehyde in
the presence of NaBH(OAc)
dimethoxybenzylamine (DMB) in 86% yield. Oxidation of
the resulting secondary alcohol to the corresponding ketone
18
19
3
afforded the N-protected 2,4-
20
9
occurred smoothly in 80% yield using tetrapropylammo-
nitrogen-assisted ring opening of the initially formed cy-
cloadduct 11 to produce N-acyliminium ion 12. A subsequent
deprotonation followed by ketonization of the resulting enol
accounts for the formation of 8.
2
1
nium perruthenate (TPAP). The stage was now set for the
completion of the synthesis. The critical D-ring of strychnine
was constructed by a palladium-catalyzed intramolecular
Our synthesis of the more advanced tetracycle 9 required
for eventual D-ring cyclization of strychnine began by
(
17) Attempts to introduce the vinyl iodide moiety earlier in the synthesis
were unsuccessful due to the competitive loss of the iodo group during the
reduction step.
(
14) (a) Padwa, A.; Brodney, M. A.; Dimitroff, M. J. Org. Chem. 1998,
3, 5304. (b) Bur, S. K.; Lynch, S. M.; Padwa, A. Org. Lett. 2002, 4, 473.
c) Ginn, J. D.; Padwa, A. Org. Lett. 2002, 4, 1515.
15) Padwa, A.; Brodney, M. A.; Lynch, S. M.; Rashatasakhon, P.; Wang,
Q.; Zhang, H. J. Org. Chem. 2004, 69, 3735.
16) (a) Young, F. G.; Frostick, F. C.; Sanderson, J. J.; Hauser, C. R. J.
(18) The synthesis of the required allylic bromide is described in the
Supporting Information.
(19) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C.
A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849.
(20) The DMP group was selected as it was readily removed under the
acidic conditions employed in the hydrolysis of 10 to the Wieland-Gumlich
aldehyde (6) (see Scheme 5).
6
(
(
(
Am. Chem. Soc. 1950, 72, 3635. (b) Mao, C.-L.; Frostick, F. C.; Man, E.
H.; Manyik, R. M.; Wells, R. L.; Hauser, C. R. J. Org. Chem. 1969, 34,
425.
(21) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
1
Org. Lett., Vol. 9, No. 2, 2007
281

coupling of the amino-tethered vinyl iodide with the keto
enolate derived from 9. The key palladium-catalyzed cy-
Scheme 5
clization was carried out on a sample of 9 using Pd(PPh
3 4
)
and PhOK. Gratifyingly, the reaction proceeded smoothly
2
2
to furnish aza-pentacycle 16 in 56% unoptimized yield.
Our initial attempts to convert the keto group of 16 into
the corresponding enol ether 10 using methoxymethylene-
triphenylphosphorane (MeOCHdPPh ) were unsuccessful,
3
probably as a consequence of steric congestion about the
ketone. Consequently, we turned our attention to the phos-
phine oxide reagent MeOCH
2 2
P(O)Ph whose anion is steri-
cally less demanding and more nucleophilic compared to the
2
3,24
phosphorane MeOCHdPPh
3
.
Thus, treatment of Me-
OCH P(O)Ph with LDA in THF gave the lithio anion which
2
2
reacted smoothly with ketone 16 at 0 °C to provide 10 as a
single diastereomer in 72% isolated yield (Scheme 5). The
last major hurdle involved an acid-promoted deprotection/
hydrolysis of 10 into the Wieland-Gumlich aldehyde (6).
The hydrolysis was satisfactorily accomplished by the
treatment of 10 with 3 N HCl in THF at 55 °C for 10 h
which gave 6 in 54% yield. By using shorter reaction times
and following the reaction by NMR spectroscopy, we found
that the initially formed primary alcohol 17 undergoes a
subsequent deprotection of the DMB group to furnish enol
ether 18. Further stirring of 18 under the acidic conditions
eventually furnished the Wieland-Gumlich aldehyde (6).
Although the conversion of 6 into strychnine had been
reported by Robinson in 1953,11 we decided to reproduce
the described protocol for the sake of a complete total
synthesis. Thus, the final biomimetic condensation of 6 with
malonic acid, acetic anhydride, sodium acetate, and acetic
acid provided (()-strychnine (4) in 80% yield and with a
cross-coupling between the N-tethered vinyl iodide and the
keto group. The short sequence used to synthesize (()-
strychnine should also provide rapid entry into other Strych-
nos alkaloid natural products and is currently under active
investigation in our laboratories.
4.4% overall yield for the 13-step reaction sequence starting
from furanyl indole 7.
In summary, a concise synthesis of the Strychnos alkaloid
Acknowledgment. Dedicated to my colleague and friend
David Goldsmith on the occasion of his 75th birthday. We
appreciate the financial support provided by the National
Institutes of Health (GM 059384) and the National Science
Foundation (CHE-0450779). We thank Professor Larry
Overman (UC Irvine) for providing a proton NMR spectrum
of the Wieland-Gumlich aldehyde (6) for comparison
purposes.
(()-strychnine is reported. A central step in the synthesis
consists of an intramolecular [4 + 2]-cycloaddition/re-
arrangement cascade of an indolyl-substituted amidofuran
which delivers an aza-tetracyclic substructure containing the
ABCE-rings of the natural product. Closure of the remaining
D-ring was carried out from the aza-tetracyclic intermediate
by an intramolecular palladium-catalyzed enolate-driven
Supporting Information Available: Spectroscopic data
and experimental details for the preparation of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(
22) A similar approach was successfully employed in a synthesis of
strychnopivotine (2), and this will be described at a later date.
23) Earnshaw, C.; Wallis, C. J.; Warren, S. J. Chem. Soc., Perkin Trans.
1979, 3099.
24) Patel, D. V.; Schmidt, R. J.; Gordon, E. M. J. Org. Chem. 1992,
7, 7143.
(
1
5
(
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