Total synthesis of the Strychnos alkaloid (+)-minfiensine: Tandem enantioselective intramolecular Heck-iminium ion cyclization

Article abstract of DOI:10.1021/ja800163v

A 1,2,3,4-tetrahydro-9a,4a-(iminoethano)-9H-carbazole (4) is a central structural feature of the Strychnos alkaloid minfiensine (1) and akuammiline alkaloids such as vincorine (5) and echitamine (6). A cascade catalytic asymmetric Heck-iminium cyclization

Full text of DOI:10.1021/ja800163v

Published on Web 02/28/2008
Total Synthesis of the Strychnos Alkaloid (+)-Minfiensine:
Tandem Enantioselective Intramolecular Heck-Iminium Ion
Cyclization
Amy B. Dounay,† Philip G. Humphreys, Larry E. Overman,* and Aaron D. Wrobleski‡
Department of Chemistry, UniVersity of California, IrVine, 1102 Natural Sciences II,
IrVine, California 92697-2025
Received January 8, 2008; E-mail: leoverma@uci.edu
Abstract: A 1,2,3,4-tetrahydro-9a,4a-(iminoethano)-9H-carbazole (4) is a central structural feature of the
Strychnos alkaloid minfiensine (1) and akuammiline alkaloids such as vincorine (5) and echitamine (6). A
cascade catalytic asymmetric Heck-iminium cyclization was developed that rapidly provides 3,4-dihydro-
9a,4a-(iminoethano)-9H-carbazoles in high enantiomeric purity. Two sequences were developed for
advancing 3,4-dihydro-9a,4a-(iminoethano)-9H-carbazole 27 to (+)-minfiensine. In our first-generation
approach, a reductive Heck cyclization was employed to form the fifth ring of (+)-minfiensine. In a second
more concise total synthesis, an intramolecular palladium-catalyzed ketone enolate vinyl iodide coupling
was employed to construct the final ring of (+)-minfiensine. This second-generation total synthesis of
enantiopure (+)-minfiensine was accomplished in 6.5% overall yield and 15 steps from 1,2-cyclohexanedione
and anisidine 13. A distinctive feature of this sequence is the use of palladium-catalyzed reactions to form
all carbon-carbon bonds in the transformation of these simple precursors to (+)-minfiensine.
Introduction
Minfiensine (1), a secoiridoid indole alkaloid, was isolated
from the African plant Strychnos minfiensis by Massiot and co-
1
workers in 1989.1 Its structure was assigned using H and 13C
NMR spectroscopy (C-H and H-H COSY, NOESY), with
long-range coupling of the C15 methine hydrogen to the C17
allylic methylene and C19 vinylic hydrogens being particularly
diagnostic. Although a variety of Strychnos alkaloids having a
molecular formula of C19H22N2O have been isolated (e.g., 1–3,
Figure 1), the structure of minfiensine has no precedent.2 No
details of its biosynthesis are known, but its genesis from a
corynantheine precursor is likely.
The 1,2,3,4-tetrahydro-9a,4a-(iminoethano)-9H-carbazole (4)
moiety is the defining structural feature of minfiensine (1)
(Figure 2). Although rare in Strychnos alkaloids, this tetracyclic
ring system is found in a number of akuammiline alkaloids such
as vincorine (5) and echitamine (6).3 Extracts containing
akuammiline alkaloids are used throughout the world in the
practice of traditional medicine, with some heightened interest
in the medicinal potential of pure akuammiline alkaloids being
seen in recent years.4 Dihydro-9a,4a-(iminoethano)-9H-carba-
Figure 1. Minfiensine (1) and two additional C19H22N2O Strychnos
alkaloids.
zoles (4 having a 1,2- or 2,3-double bond) could serve as
versatile platforms for constructing alkaloids of the types
illustrated in Figure 2. Stitching an ethylideneethano unit
between the pyrrolidine nitrogen and C3 of such a precursor
would generate the ring system of minfiensine, whereas inserting
such a unit between the pyrrolidine nitrogen and C2 would
generate the ring system of vincorine and congeners.
In this article, we report the development of an efficient
catalytic enantioselective synthesis of 3,4-dihydro-9a,4a-(imi-
noethano)-9H-carbazoles by combining a palladium-catalyzed
asymmetric Heck cyclization with an intramolecular iminium
ion cyclization. We also describe the details of our use of such
an intermediate to complete the first total synthesis of min-
fiensine (1)5 and our development of an improved end play that
† Current address: Pfizer, Inc., Groton Laboratories, Eastern Point Road,
Groton, CT 06340.
‡ Current address: Lilly Research Laboratories, Lilly Corporate Center,
Drop Code 0548, Indianapolis, IN 46285.
(1) Massiot, G.; Thépenier, P.; Jacquier, M.-J.; Le Men-Olivier, L.;
Delaude, C. Heterocycles 1989, 29, 1435–1438.
(2) For review, see: Higuchi, K.; Kawasaki, T Nat. Prod. Rep 2007, 24,
843–868, and earlier articles in this series.
(3) Anthoni, U.; Christophersen, C.; Nielsen, P. H. In Alkaloids: Chemical
and Biological PerspectiVes; Pelletier, S. W., Ed.; Wiley: New York,
1999; Vol. 13, pp 163–236..
(4) Ramirez, A.; Garcia-Rubio, S. Curr. Med. Chem. 2003, 10, 1891–
1915.
(5) Dounay, A. B.; Overman, L. E.; Wrobleski, A. D. J. Am. Chem. Soc.
2005, 127, 10186–10187.
9
5368 J. AM. CHEM. SOC. 2008, 130, 5368–5377
10.1021/ja800163v CCC: $40.75
2008 American Chemical Society

Total Synthesis of the Strychnos Alkaloid (+)-Minfiensine
A R T I C L E S
Scheme 2
Figure 2. Representative alkaloids containing a 1,2,3,4-tetrahydro-9a,4a-
(iminoethano)-9H-carbazole.
Scheme 1
allows a notably efficient and concise catalytic asymmetric
construction of this structurally unique Strychnos alkaloid to
be realized.
of cyclohexadienyl carbamate 10 from aniline 11 and 1,2-
cyclohexanedione (12).
Results and Discussion
Enantioselective Formation of the 3,4-Dihydro-9a,4a-
(iminoethano)-9H-carbazoles by Tandem Enantioselective
Intramolecular Heck-Iminium Ion Cyclization. The sequence
developed to prepare the cyclohexadienyl aryl triflate cyclization
precursor 21 is summarized in Scheme 2. Although acid-
catalyzed condensation of 1,2-cyclohexanedione (12) with
anisidine 138 was low-yielding under all the conditions that we
examined, the related condensation with morpholine enamine
149 in the presence of 1 equiv of p-toluenesulfonic acid (p-
Synthesis Plan. We envisaged minfiensine (1), as well as
alkaloids of the vincorine family, to be accessible from 3,4-
dihydro-9a,4a-(iminoethano)-9H-carbazole 7 (Scheme 1). The
central transformation in our total synthesis plan is catalytic
enantioselective formation of tetracyclic intermediate 7 from
cyclohexadienyl carbamate 10. In this pivotal conversion, an
intramolecular catalytic asymmetric Heck reaction would gener-
ate dihydrocarbazole 9 and form the critical quaternary carbon
stereocenter.6,7 Selective in situ protonation of the enecarbamate
double bond of diene product 9 would generate N-acyloxy-
iminium ion 8, which was expected to be trapped by the tethered
amine to form dihydro(iminoethano)carbazole 7. One attractive
feature of this sequence was the expected ready construction
(7) The challenge of constructing quaternary carbon stereocenters is the
subject of several recent reviews and one monograph; see: (a)
Quaternary Stereocenters: Challenges and Solutions for Organic
Synthesis; Christoffers, J., Baro, A., Eds.; Wiley-VCH: Weinheim,
Germany, 2005. (b) Christoffers, J.; Baro, A. AdV. Synth. Catal. 2005,
347, 1473–1482. (c) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 5363–5367. (d) Christoffers, J.; Baro, A. Angew.
Chem., Int. Ed. 2003, 42, 1688–1690. (e) Denissova, I.; Barriault, L.
Tetrahedron 2003, 59, 10105–10146. (f) Christoffers, J.; Mann, A.
Angew. Chem., Int. Ed. 2001, 40, 4591–4597. (g) Corey, E. J.;
Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388–401.
(8) Kondo, Y.; Kojima, S.; Sakamoto, T. J. Org. Chem. 1997, 62, 6507–
6511.
(6) The notable utility of catalytic asymmetric intramolecular Heck
reactions for constructing quaternary carbon stereocenters is discussed
in several recent reviews; see: (a) Steven, A.; Overman, L. E. Angew.
Chem., Int. Ed. 2007, 46, 5488–5508. (b) Shibasaki, M.; Vogl, E. M.;
Ohshima, T. In ComprehensiVe Asymmetric Catalysis, Supplement 1;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag:
Berlin, 2004; pp 73–81. (c) Dounay, A.; Overman, L. E. Chem. ReV.
2003, 103, 2945–2964. (d) Link, J. T. In Organic Reactions; Overman,
L. E., Ed.; Wiley-VCH: Hoboken, NJ, 2002; Vol. 60, pp 157–534.
(9) Ohashi, M.; Takahashi, T.; Inoue, S.; Sato, K. Bull. Chem. Soc. Jpn.
1975, 48, 1892–1896.
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A R T I C L E S
Dounay et al.
Scheme 3
TsOH) in warm benzene provided 2-anilino-2-cyclohexenone
15 in high yield.10 Attempts to protect the nitrogen of this
intermediate prior to elaboration to the cyclohexadiene were
complicated by competitive reaction of the ketone. For example,
deprotonation of intermediate 15 with a strong base (lithium,
sodium or potassium bis(trimethylsilyl)amide, or NaH), followed
by addition of ClCO2Me, yielded mixtures of carbamate 16 and
products resulting from reaction of the ketone enolate on oxygen
or carbon.5 We eventually discovered that the aniline nitrogen
could be selectively masked by reaction of the lithium salt of
aniline 15 with Mander’s reagent.11 The optimum condition
identified involved dropwise addition of 3 equiv of lithium
bis(trimethylsilyl)amide (LHMDS) to a THF solution of ami-
nocyclohexenone 15 and excess methyl cyanoformate at -78
°C, in which case crystalline carbamate 16 was formed in 89%
yield. When 1.5 or 2.0 equiv of LHMDS was used, significant
amounts of cyclohexenone 15 were recovered.12 Addition of
sodium bis(trimethylsilyl)amide (NaHMDS) to a THF solution
of carbamate enone 16 and the Comins’ triflating reagent 17
(5-chloro-2-[N,N-bis(trifluoromethylsulfonyl)ami-
no]pyridine)13 at -78 °C provided cyclohexadienyl triflate 18
in 82% yield. A ꢀ-aminoethyl side chain was then introduced
in 71% yield by Suzuki cross-coupling of triflate 18 with the
alkylborane generated in situ by hydroboration of enecarbamate
1914 with 9-borabicyclo[3.3.1]nonane (9-BBN).15 Finally, silyl-
protected phenol 20 was transformed in one step and 85–95%
yield to dienyl aryl triflate 21 upon reaction at room temperature
with triflating reagent 17 in DMF in the presence of CsF and
Cs2CO3.16 In order to obtain reproducibly high yields in this
transformation, it was critical to use freshly dried cesium salts.
Comins’ reagent was used rather than N-phenyltriflamide
(PhNTf2) to ensure a rapid triflation of the cesium phenoxide
and to facilitate purification of the aryl triflate product. Without
these precautions, the triflation reaction was sluggish and
irreproducible, with cyclic carbamate 22 being occasionally
formed as a major byproduct. By the sequence summarized in
Scheme 2, Heck cyclization precursor 21 was prepared in five
steps and 46% overall yield from aniline 13 and 2-morpholino-
2-cyclohexenone (14).
Scheme 4
a low propensity for promoting double-bond migration.19 The
Pd[(phosphinoaryl)oxazoline]-catalyzed Heck cyclization of
dienyl aryl triflate 21 was initially explored using the com-
mercially available isopropyl-substituted PHOX ligand 26a
(Scheme 4). The Heck reaction of triflate 21 using Pd(OAc)2
(20 mol %), ligand 26a, and PMP in toluene provided the cross-
conjugated dihydrocarbazole 25 in 79% yield (92% yield based
on consumed 21) and 88% ee after heating at 100 °C for 70 h.20
The conjugated alkene isomer 23 was not observed under these
reaction conditions. Improved enantioselectivity (96% ee) was
achieved when the reaction was conducted in acetonitrile at 85
°C; however, alkene isomerization occurred to a limited extent
(ca. 10%) in this more polar solvent. Optimal results were
obtained using the tert-butyl-substituted PHOX ligand 26b,19a
in which case dihydrocarbazole 25 was produced in 75–87%
yield and 99% ee; dihydrocarbazole 23, the product of double-
bond migration, was not detected. The only disadvantage of
the palladium-phosphinooxazoline catalyst is the long reaction
The asymmetric Heck cyclization of dienyl aryl triflate 21
was initially examined using Pd(OAc)2/BINAP as the precatalyst
(Scheme 3). Under these conditions, intramolecular Heck
reaction of 21 proceeded readily at 80 °C in acetonitrile (or
toluene) in the presence of 1,2,2,6,6-pentamethylpiperidine
(PMP) to give dihydrocarbazole 23 (ca. 60% yield).17 The
conjugated cyclohexadiene product is undoubtedly produced by
Pd-H-mediated isomerization of the initially formed Heck
product (24 f 23). Use of a large excess of PMP or the stronger
base 1,8-bis(dimethylamino)naphthalene, which has been re-
ported to minimize double-bond migration,18 did not prevent
the formation of the 1,3-cyclohexadiene product.
Chiral (phosphinoaryl)oxazolines have been shown to be
effective ligands for asymmetric Heck reactions and to exhibit
(10) Polozov, G. I.; Tishchenko, I. G. USSR Vestn. Belorus Un-ta, Ser. 2
1986, 1, 67–69.
(11) Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1983, 24, 5425–5428.
(12) We speculate that LHMDS and NCCO2Me react to some extent under
these conditions.
(18) (a) Hii, K. K.; Claridge, T. D. W.; Brown, J. M. Angew. Chem., Int.
Ed. Engl. 1997, 36, 984–987. (b) Dounay, A. B.; Hatanaka, K.;
Kodanko, J. J.; Oestreich, M.; Overman, L. E.; Pfeifer, L.; Weiss,
M. M. J. Am. Chem. Soc. 2003, 125, 6261–6271.
(13) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299–6302.
(14) (a) Hart, R. Bull. Soc. Chim. Belg. 1956, 65, 291–296. (b) Schulz,
R. C.; Hartmann, H. Monatsh. Chem. 1961, 92, 303–309.
(15) Kamatani, A.; Overman, L. E. J. Org. Chem. 1999, 64, 8743–8744.
(16) Overman, L. E.; Watson, D. A. J. Org. Chem. 2006, 71, 2587–2599.
(17) This compound was not isolated in isomerically pure form, as it
contained traces of other diene isomers.
(19) (a) Loiseleur, O.; Meier, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl.
1996, 35, 200–202. (b) Ripa, L.; Hallberg, A. J. Org. Chem. 1997,
62, 595–602.
(20) Enantiomer ratios were determined by enantioselective HPLC analysis
of tetracyclic product 27.
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Total Synthesis of the Strychnos Alkaloid (+)-Minfiensine
A R T I C L E S
Scheme 5
Scheme 6
time (ca. 70 h). In order to increase the rate of this transforma-
tion, we investigated the effects of microwave heating.21 Larhed,
Hallberg, and co-workers reported significant acceleration of
intermolecular asymmetric Heck reactions using microwave
heating, although enantioselectivities were reduced somewhat.22
Under microwave heating, the Heck reaction of 21 was complete
in only 30–45 min at 170 °C, with no erosion of yield or
enantiomeric purity of dihydrocarbazole 25 being observed (87%
yield, 99% ee). This microwave-promoted Heck cyclization was
carried out reproducibly on synthetically useful scales (ca.
500–600 mg). Furthermore, the shorter reaction times allowed
the catalyst loading to be reduced to 10 mol % of Pd.
The tandem reaction sequence to form 3,4-dihydro-9a,4a-
(iminoethano)-9H-carbazole 27 was achieved in 75% overall
yield from dienyl aryl triflate 21 by adding excess trifluoroacetic
acid (TFA, 10 equiv) to the crude Heck reaction product after
the reaction vessel was removed from the microwave reactor
and cooled to 0 °C. A large excess of TFA was required in this
one-pot sequence because excess PMP and the basic phosphine
ligand were both present in the crude Heck reaction product.
The 4aR,9aR absolute configuration of dihydro(iminoethano)-
carbazole 27 was not established at this point, but at a later
stage of the synthesis (vide infra).
avoiding the possibility that pentacyclic palladium alkyl inter-
mediate 29 could decompose by syn-ꢀ-hydride elimination.
Either ketone 31 or R-epoxide 32 were seen as plausible
precursors of dienyl iodide intermediate 30.
If dihydro(iminoethano)carbazole 27 could be epoxidized
stereoselectively from the R-face, a concise route to Heck
cyclization precursor 30 could likely be developed. For this
reason, we examined this possibility even though a preliminary
examination of molecular models of tetracyclic alkene 27 did
not suggest a significant steric bias for approach of an oxidant
from either alkene face. To our delight, standard epoxidation
of alkene 27 with m-chloroperoxybenzoic acid (m-CPBA)
proceeded with 10:1 stereoselectivity to give, after separation
on silica gel, the R-epoxide 34 in 87% yield; the ꢀ-epoxide
stereoisomer was also isolated in 9% yield (Scheme 6). The
relative configuration of epoxide 34 was assigned on the basis
of analogy to the major (8:1) epoxide stereoisomer 35 produced
by m-CPBA epoxidation of methoxy congener 33. In this latter
case, the epoxide was obtained as single crystals, allowing the
relative configuration of epoxide 35 to be secured by X-ray
analysis.23
To examine what was responsible for the 10:1 selectivity
observed in the epoxidation of tetracyclic alkene 27, this
intermediate was modeled computationally. This study showed
a 1.2–2.5 kcal/mol preference for the cyclohexene ring of 27
to exist in the half-chair conformation illustrated in Figure 3.24
Assuming for steric reasons that C-O bond formation is more
advanced at alkene carbon b, torsional effects would favor
epoxidation from the alkene stereoface anti to the indoline
bridge, as depicted in Figure 3.25
Attempts to Construct the Minfiensine Ring System by an
Intramolecular
Asymmetric
Heck
Reaction-Carbon-
ylation Sequence. From the outset, we envisaged constructing
minfiensine (1) from a 3,4-dihydro-9a,4a-(iminoethano)-9H-
carbazole intermediate such as 27 by the sequence outlined
retrosynthetically in Scheme 5. The central step in this elabora-
tion would be the formation of pentacyclic ester 28 from
tetracyclic precursor 30 by a Heck cyclization-carbon monoxide
insertion sequence.6d Assembling the cyclization precursor 30
with the R-orientation of the allylic oxygen substituent was
anticipated to favor the desired cascade reaction sequence by
Without success, we explored initially the possibility of
converting tetracyclic epoxide 34 to allylic alcohol 36 using
lithium amide bases at various temperatures (Scheme 6).26 For
(21) For a review of microwave-accelerated homogenous catalysis, see:
(23) See Supporting Information.
Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res. 2002, 35, 717–
(24) Geometry optimizations performed at three levels of theory using
Spartan 04: molecular mechanics (MMFF force field), Hartree-Fock
(6-31G*), and density-functional theory (B3LYP 6-31G*).
(25) Lucero, M. J.; Houk, K. N. J. Org. Chem. 1998, 63, 6973–6977.
727.
(22) Nilsson, P.; Gold, H.; Larhed, M.; Hallberg, A. Synthesis 2002, 1611–
1614.
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A R T I C L E S
Dounay et al.
Scheme 7
Figure 3. Proposed rationale for stereoselection in the epoxidation of alkene
27. Model (6-31G*) of the most stable conformation of alkene 27 showing
the favored approach of an oxidant to alkene carbon b.
example, reaction of epoxide 34 with lithium diethylamide in
THF at -40 °C led to rapid loss of the methyl carbamate group.
Cleavage of the methyl carbamate group occurred more slowly
when lithium diisopropylamide (LDA) was used as a base;
however, an allylic alcohol product was never isolated, even
after reactions conducted in THF were heated at 45 °C for
several hours.
To avoid base-promoted side reactions, we turned to the
organoselenide method developed by Sharpless and Lauer.27 As
expected, epoxide 34 reacted regioselectively with sodium
phenylselenide to generate a single ꢀ-hydroxy selenide product.
Oxidation of this intermediate to the selenoxide, followed by
heating at 60 °C, delivered allylic alcohol 36 in 50% yield from
epoxide precursor 34. Protection of alcohol 36 as a benzyl ether
proceeded uneventfully under standard conditions to give
tetracyclic allylic ether 37.
Scheme 8
To our surprise, attempts to cleave the Boc group of
intermediate 37 under standard acidic conditions [trifluoroacetic
acid (TFA), CH2Cl2, 0 °C] led to the formation of indole 38.
This fragmentation was rapid, occurring instantaneously at 0
°C to provide indole aldehyde 38 in 92% yield. 1H and COSY
NMR spectra confirmed the presence of an unsaturated aldehyde,
with a large vinylic coupling constant (15.7 Hz) indicating the
E geometry for the 4-oxo-2-butenyl side chain. Because of the
facility of this rearrangement under acidic conditions, other
methods were briefly investigated for removing the Boc group.
Attempted thermolytic fragmentation upon conventional heating
in dimethylsulfoxide (DMSO, 120–150 °C) or in a microwave
reactor did not afford the desired secondary amine product.
Likewise, attempted deprotection of 37 with ceric ammonium
nitrate (CAN)28 provided only recovered starting material and
indole aldehyde 38.
A plausible sequence for formation of indole 38 from
tetrahydro(iminoethano)carbozle precursor 37 is suggested in
Scheme 7. In the presence of acid, aminal 37 should be in
equilibrium with tricyclic N-acyloxyiminium ion 39.29 In a
process that undoubtedly would be exothermic, fragmentation
of bond a of this intermediate would generate indole oxocar-
benium ion 40. This latter intermediate would be expected to
be trapped with trifluoroacetate to form allylic trifluoroacetate
41 and its allylic isomers. Upon aqueous workup, 41 and/or its
E allylic isomer would deliver indole 38.
The sequence that was ultimately developed for advancing
epoxide 34 to Heck cyclization precursor 48 is summarized in
Scheme 8. As the alkoxycarbenium ion potentially generated
by fragmentation of the cyclohexane ring of epoxide 34 would
be less stable than that produced from allylic ether 37 (Scheme
7), exchange of the Boc group of epoxy carbamate 34 for an
allyloxycarbonyl (Alloc) protecting group was straightforward.
Rearrangement of the epoxide functionality of Alloc product
43 and triethylsilyl (TES) protection of the resultant allylic
alcohol provided allylic silyl ether 45 in 68% overall yield from
Boc-protected epoxide 34. Removal of the Alloc group of
intermediate 45 using Pd(PPh3)4 and excess pyrrolidine pro-
ceeded cleanly to yield tetracyclic amine 46. The Heck
cyclization precursor 48 was then secured in 96% yield by
reaction of secondary amine 46 with 2 equiv of allylic tosylate
4730 in hot MeCN in the presence of K2CO3.
(26) Crandall, J. K.; Apparu, M. Base-Promoted Isomerization of Epoxides.
In Organic Reactions; Dauben, W. G., Ed.; John Wiley & Sons: New
York, 1983; Vol. 29, pp 345–444..
(27) Sharpless, K. B.; Lauer, R. F. J. Am. Chem. Soc. 1973, 95, 2697–
2699.
(28) Hwu, J. R.; Jain, M. L.; Tsay, S.-C.; Hakimelahi, G. H. Tetrahedron
Lett. 1996, 37, 2035–2038.
We explored briefly a second sequence for elaborating
dihydro(iminoethano)carbazole 27 to an appropriate precursor
(29) von Fritz, H.; Fischer, O. Tetrahedron 1964, 20, 1737–1753.
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Total Synthesis of the Strychnos Alkaloid (+)-Minfiensine
A R T I C L E S
Scheme 9
Scheme 10
for forming the fifth ring of minfiensine (Scheme 9). Toward
that end, tetracyclic alkene 27 was allowed to react with
borane-methyl sulfide complex at room temperature, followed
by oxidation with tetrapropylammonium perruthenate/N-meth-
ylmorpholine-N-oxide (TPAP/NMO) to provide a chromato-
graphically separable mixture of ketones 49 (63% yield) and
50 (21% yield). As has been reported several times previously
in hydroborations of structurally related alkenes, reaction of
tetracyclic alkene 27 with BH3 placed boron preferentially at
the more hindered neopentylic position.31,32 Although the minor
ketone isomer was not of immediate interest (vide infra), it did
allow the absolute configuration of the product 27 of tandem
asymmetric Heck-iminium ion cyclization to finally be estab-
lished. Thus, reduction of ketone 50 with sodium borohydride
provided a 1:1 mixture of separable alcohol products. Reaction
of the lower Rf epimer with p-bromobenzoyl chloride yielded
crystalline ester 51. Single-crystal X-ray analysis of this
derivative allowed its relative and absolute configuration to be
determined,33 proving the sense of stereoinduction in the
asymmetric Heck cyclization of 21 to give (R)-dihydrocarbazole
25 (Scheme 4).
appropriate precursor for closing the final ring of minfiensine
had been developed (see Scheme 8), this strategy was pursued
no further.
We turned to examine forming the final ring of minfiensine
and simultaneously installing the remaining carbon atom by the
Heck cyclization-carbonylation sequence posited in Scheme
5. To this end, tetracyclic vinyl iodide 48 was subjected to a
number of standard conditions that had been used by others to
carry out cascade intramolecular Heck reaction-carbonylation
reactions (Scheme 10).7d A variety of palladium precatalysts
[Pd(OAc)2, PdCl2(PPh3)2, Pd(PPh3)4], ligands [Ph3P, 1,3-bis-
(diphenylphosphoryl)propane, and 1,4-bis(diphenylphospho-
ryl)butane], bases (triethylamine, K2CO3), cosolvents (DMF,
MeCN, toluene), and CO pressures (1 atm to 150 psi) were
explored in various combinations. However, under no reaction
condition that we examined was the desired pentacyclic ester
55 detected. Besides recovered dienyl iodide 48, secondary
amine 46,36 the R,ꢀ-unsaturated ester 56 resulting from carbo-
nylation of the vinyl iodide side chain, and a pentacyclic product
57, whose structure was revealed after additional experimenta-
tion (vide infra), were isolated from these experiments.
Reductive Heck Cyclization to Form the Fifth Ring.
Completion of the First Total Synthesis of (+)-Min-
fiensine. Our inability to accomplish a cascade Heck cycliza-
tion-carbonylation reaction prompted us to examine the pivotal
ring-forming step under reductive conditions.7d In this context,
the intramolecular Heck reaction of vinyl iodide 48 was carried
In an attempt to process the major ketone isomer to a suitable
precursor for forming the final ring of minfiensine, tetracyclic
ketone 49 was dehydrogenated by reaction with 2-iodoxybenzoic
acid (IBX) (Scheme 9).34 Subsequent cleavage of the Boc group
with TFA provided cyclohexenone 53 in 40% yield for the two
steps. To our surprise, attempted N-allylation of secondary
amine 53 with allylic tosylate 4730 yielded dienone 54 as the
major product. The formation of this dihydroindolone likely
arises from deprotonation of intermediate 53 at the γ-position
to give a dienolate anion, which ꢀ-eliminates the aniline
carbamate conjugate base.35 As an alternate route to an
(30) Rawal, V. H.; Michoud, C. Tetrahedron Lett. 1991, 32, 1695–1698.
(31) (a) Edamura, F. Y.; Nickon, A. J. Org. Chem. 1970, 35, 1509–1515.
(b) Aberhart, D. J.; Caspi, E. J. Am. Chem. Soc. 1979, 101, 1013–
1019.
(32) See also: Shi, X.; Miller, B. Tetrahedron Lett. 1994, 35, 223–226.
(33) The absolute configuration was assigned by refinement of the Flack
parameter; see: Flack, H. D. Acta Crystallogr. 1983, A39, 876–881.
(34) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000,
122, 7596–7597.
(35) Addition of excess TFA to a CH2Cl2 solution of hydroindolone 54 at
room temperature led to the formation of a new product, whose NMR
data suggested that the dihydro(iminoethano)carbazole ring system had
re-formed. However, upon workup with saturated aqueous NaHCO3,
this product reverted back to dienone 54.
9
J. AM. CHEM. SOC. VOL. 130, NO. 15, 2008 5373

A R T I C L E S
Dounay et al.
Scheme 11
Scheme 12
out in the presence of sodium formate with the expectation that
pentacycle 58 would result (Scheme 11). However, reaction of
alkenyl iodide 48 with 10 mol % of Pd(OAc)2, 1,4-bis(diphe-
nylphosphoryl)butane (dppb), Et3N, and NaO2CH in acetonitrile
did not produce pentacyclic product 58, but rather pentacyclic
isomer 57 and the product 46 of N-dealkylation. The presence
of sodium formate had no apparent effect on this reaction, with
pentacyclic allylic alcohol 57 being isolated in 48% yield in a
reaction carried out in the absence of sodium formate and
triethylamine. Removal of the TES group from pentacyclic
product 57 provided the crystalline alcohol 59, whose structure
was established by single-crystal X-ray analysis. Remarkably,
pentacyclic product 57 produced by Pd(0)-catalyzed cyclization
of tetracyclic dienyl iodide 48 is the product of formal C-H
insertion of the alkenylpalladium side chain at the allylic carbon
of the cyclohexene ring.
Insertion of an alkenylpalladium species into a C-H σ-bond
is not expected under Heck reaction conditions.7d,37 We surmised
that the formation of product 57 could result from the lability
of the aminal functionality of the pyrrolidinoindoline moeity.30
This lability provides a straightforward pathway for migration
of the cyclohexene double bond (Scheme 12). Thus, ring
opening of tetracyclic aminal 48 to give iminium ion 60, likely
promoted by some protic or Lewis acidic species (illustrated
by H+ in Scheme 12), could readily lead to the formation of
dienamine 61. Protonation of this intermediate at the terminal
carbon would provide conjugated iminium cation 62, which
upon ring closure would deliver isomer 63 of the original Heck
cyclization substrate. Standard 5-exo-Heck cyclization of this
intemediate would lead directly to the observed tetracyclic
product 57.
cyclization substrate 48. First, we examined whether the alkene
isomerization would take place in the absence of a palladium
species. Accordingly, dienyl iodide 48 and dppb (20 mol %)
were heated in d3-acetonitrile at 75 °C. After 12 h, ca. 25% of
diene 48 had isomerized to isomer 63.38 This experiment showed
that double-bond migration could take place in the absence of
palladium. However, the rate of this isomerization was slower
than the rate at which pentacyclic product 57 was formed during
the Heck reaction. Accordingly, it was reasoned that the double-
bond migration was proceeding by an additional pathway. As
a Pd(II) species could be present and these are well-known to
promote alkene isomerization,39 dienyl iodide 48 was exposed
to 12 mol % of PdCl2(MeCN)2 in d3-acetonitrile at 75 °C. After
40 min, isomerization to diene isomer 63 was ca. 80% complete.
As the enoxysilane double-bond isomer was not observed, we
believe that a Pd(II) species formed in situ is functioning as a
Lewis acid to activate the aminal functionality toward ring
cleavage and facilitate double-bond migration in the conversion
of 48 f 57 (Scheme 11).
High catalysis rates are often observed with the phosphine-
free Heck reaction conditions initially reported by Jeffery
(inorganic bases and tetraalkylammonium halides).40,41 In the
hope that Heck cyclization might be faster than double-bond
isomerization, we turned to examine the reaction of dienyl iodide
(38) The isomerization of diene 48 to 63 was first observed during
chromatographic purification of 48 on silica gel.
(39) Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E., Ed.; Wiley-Interscience: New York, 2002; Vol 1, Part
IV, 2783–2788.
(40) (a) Jeffery, T. Tetrahedron Lett. 1985, 26, 2667–2670. (b) Jeffery, T.
Tetrahedron 1996, 52, 10113–10130.
To gain experimental evidence for the proposed double-bond
(41) (a) For a discussion of anionic versions of the Heck reaction, see :
Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314–321. (b) The
formation of palladium nanoparticles under these conditions has been
described: Reetz, M. T.; Westermann, E. Angew. Chem., Int. Ed. 2000,
39, 165–168. (c) For a recent analysis of mechanistic studies of Heck
reactions carried out under phosphine-free conditions, see: Schmidt,
A. F.; Al Halaiqa, A.; Smirnov, V. V. Synlett 2006, 2861–2878. (d)
For an in depth review of the nature of the active species in Heck
couplings, see: Phan, N. T. S.; Van der Sluys, M.; Jones, C. W. AdV.
Synth. Catal. 2006, 348, 609–679.
migration, a series of NMR studies were carried out with
(36) Deallylation has been observed previously in attempted Heck cycliza-
tions of substrates containing N-2-iodo-2-butenyl side chains; see for
example: Birman, V. B.; Rawal, V. H. J. Org. Chem. 1998, 63, 9146–
9147.
(37) Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E., Ed.; Wiley-Interscience: New York, 2002; Vol 1, Part
IV.
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Total Synthesis of the Strychnos Alkaloid (+)-Minfiensine
A R T I C L E S
Scheme 13
Scheme 14
48 under these conditions.42 After some optimization, we found
that reductive Heck cyclization of dienyl iodide 48 to form
pentacyclic product 58 (80% yield) took place in DMF within
30 min at 80 °C in the presence of 1 mol % of Pd(OAc)2, K2CO3
(5 equiv), (n-Bu)4NCl (2.5 equiv), and NaO2CH (1.2 equiv).
Under these conditions, pentacyclic isomer 57 was not detected,
and the secondary amine 46 resulting from deallylation was
produced to only a limited extent (ca. 10% yield). After removal
of the TES group from Heck product 58, single-crystal X-ray
analysis of alcohol 64 confirmed that the minfiensine ring system
had been assembled (Scheme 13).
To advance tetracyclic alcohol 64 to minfiensine (1) required
that a double bond and a one-carbon side chain be installed in
the cyclohexane ring. These elaborations were accomplished
as follows (Scheme 14). Oxidation of alcohol 64 with
Dess-Martin periodinane43 provided ketone 65. The lithium
enolate of this ketone upon reaction with methyl cyanoformate11
gave ꢀ-keto ester 66, which existed nearly exclusively as the
enol tautomer, in 70% yield over the two steps. Upon reaction
with excess NaBH4 in THF/MeOH at 0 °C, ꢀ-keto ester 66 was
converted to largely one ꢀ-hydroxy ester product 67; the relative
configuration of the alcohol and ester substituents of this
intermediate was not determined, as these stereocenters are
cleared in the subsequent step. After more traditional methods
to dehydrate ꢀ-hydroxy ester 67 to R,ꢀ-unsaturated ester 68,
such as reaction with methanesulfonyl chloride or triflic
anhydride and triethylamine, met with failure, this conversion
was accomplished by a two-step sequence. The sterically
hindered secondary alcohol was first activated by reaction with
benzoyl triflate44 and pyridine in CH2Cl2 at 60 °C (sealed tube).
Exposure of the resulting benzoate to 2 equiv of potassium
bis(trimethylsilyl)amide (KHMDS) in THF at -78 °C then
delivered enoate 68 in 83% yield for the two steps. Lithium
aluminum hydride reduction of R,ꢀ-unsaturated ester 68 pro-
vided allylic alcohol derivative 69, which upon reaction with
NaOH in MeOH/H2O at 100 °C gave (+)-minfiensine (1) in
85% yield for the two steps. Synthetic (+)-minfiensine (1)
displayed 1H and 13C NMR spectral data identical to that
reported for the natural product.1 The optical rotation of
synthetic (+)-minfiensine (1) was [R]D +125 (c 0.82, CHCl3),
which compared well to the rotation of +134 reported under
identical conditions for the natural isolate.1
Second-Generation Total Synthesis of (+)-Minfiensine: A
Much Improved End Play. In our first-generation total synthesis,
facile ring opening of the aminal linkage of the pyrrolidinoin-
doline fragment (see Scheme 6) significantly hindered elabora-
tion of (iminoethano)carbazole 37 to (+)-minfiensine. To side
step these obstacles, a second-generation approach should
obviate the possibility of double-bond migration during forma-
tion of the final ring and minimize the likelihood of fragmenta-
tion of the 3,4-dihydro-9a,4a-(iminoethano)-9H-carbazole ring
system by avoiding intermediates having an electron-donating
heteroatom substituent adjacent to the quaternary benzylic
carbon. Constructing the final ring by an intramolecular Pd(0)-
catalyzed coupling of a ketone enolate and a vinyl iodide side
chain, as posited in Scheme 15 (70 f 71f 72), should
accomplish these objectives. To our knowledge, this ring-
forming tactic was first used by Piers in the total synthesis of
triquinanes.45 In recent years, the use of palladium-catalyzed
intramolecular R-vinylation of ketone enolates to assemble
complex alkaloid ring systems has been demonstrated by
insightful studies from the Cook46 and Bonjoch47 laboratories.48
An additional attractive feature of this strategy was the
anticipated ease with which ketone 72 could be elaborated to
(45) (a) Piers, E.; Marais, P. C. J. Org. Chem. 1990, 55, 3454–3455. (b)
Piers, E.; Renaud, J. J. Org. Chem. 1993, 58, 11–13.
(46) (a) Wang, T.; Cook, J. M. Org. Lett. 2000, 2, 2057–2059. (b) Zhao,
S.; Liao, X.; Cook, J. M. Org. Lett. 2002, 4, 687–690. (c) Cao, H.;
Yu, J.; Wearing, X. Z.; Zhang, C.; Liu, X.; Deschamps, J.; Cook,
J. M. Tetrahedron Lett. 2003, 44, 8013–8017. (d) Yu, J.; Wang, T.;
Liu, X.; Deschamps, J.; Flippin-Anderson, J.; Liao, X.; Cook, J. M.
J. Org. Chem. 2003, 68, 7565–7581. (e) Zhao, S.; Liao, X.; Cook,
J. M. Org. Lett. 2004, 6, 249–252. (f) Yu, J.; Wearing, X.; Cook,
J. M. J. Org. Chem. 2005, 70, 3963–3979.
(42) For an illustrative example of using Jeffrey-type Heck reaction
conditions in alkaloid total synthesis, see: Rawal, V. H.; Michoud,
C.; Monestel, R. F. J. Am. Chem. Soc. 1993, 115, 3030–3031.
(43) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287.
(44) Brown, L.; Koreeda, M. J. Org. Chem. 1984, 49, 3875–3880.
9
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A R T I C L E S
Dounay et al.
Scheme 15
Scheme 17
Scheme 16
of 88%. Although regioselection of this hydroboration was only
modest, ketone 50 was obtained in 63% yield by this two-step
sequence. The Boc-protecting group was readily removed by
allowing ketone 50 to react with excess TFA at room temper-
ature. Alkylation of the resulting secondary amine with allylic
bromide 7343 then provided the ketone vinyl iodide cyclization
substrate 70 in 65% yield for the two steps.
(+)-minfiensine because this ketone can enolize in only one
direction; enolization at the allylic R-carbon would generate a
high-energy, anti-Bredt enolate.
With tetracyclic iodoketone 70 in hand, we turned to forming
the final ring of (+)-minfiensine by palladium-catalyzed in-
tramolecular enolate/vinyl iodide coupling (Scheme 17). Ex-
posure of this iodoketone to catalytic Pd(PPh3)4 and KOt-Bu
(1.5–4 equiv) in various solvents (THF, DMF, DMF/t-BuOH)46
gave none of the pentacyclic product 72. Elimination of HI to
form the corresponding tetracyclic propargylic amine was the
major reaction under these conditions, a competing pathway
identified by Piers in his seminal report.45a Cook employed
weaker bases, typically K2CO3, to realize palladium-catalyzed
enolate R-vinylation reactions in the total synthesis of a number
of alkaloids.47 In our initial examination of these conditions,
ketone 70 was exposed to 10 mol % of PdCl2(dppf)2 ·CH2Cl2
and excess K2CO3 in either DMF or MeCN [dppf ) 1,1′-
bis(diphenylphosphino)ferrocene]. Alkyne formation was sup-
pressed; however, the only product detected, 74, under these
conditions arose from loss of the (Z)-2-iodo-2-butenyl side
chain.46c Deallylation was also the major pathway when the
identical reaction was carried out in 9:1 DMF/water; nonetheless,
in this case, pentacyclic ketone 72 was formed in 30–35% yield.
A similar low yield of pentacyclic product 72 was realized using
Pd(OAc)2/Ph3P instead of PdCl2(dppf). Increasing the percentage
of water in the solvent from 10 to 50% (using either DMF or
THF as the cosolvent) had no noticeable effect on the outcome
of the reaction; competitive formation of secondary amine 74
Elaboration of the cascade asymmetric Heck/iminium ion
cyclization product 27 to tetracyclic ketone vinyl iodide 70 is
summarized in Scheme 16. As discussed earlier, hydroboration/
oxidation of the double bond of tetracyclic intermediate 27 with
BH3 preferentially functionalizes the neopentylic carbon to
provide ketone 49 after oxidation (see Scheme 9). Accordingly,
we examined hydroboration of this alkene with the sterically
larger reagents catecholborane, thexylborane, and 9-borabicyclo-
3.3.1]nonane (9-BBN) (Scheme 16). Neither catecholborane nor
thexylborane proved sufficiently reactive, returning only un-
changed starting material. Similar results were obtained with
9-BBN in refluxing THF. However, hydroboration with 9-BBN
did take place rapidly in THF at 100 °C in a microwave reactor.
After oxidation of the crude product with TPAP/NMO, ketones
50 and 49 were isolated in a 2.5:1 ratio and a combined yield
(47) (a) Solé, D.; Peidró, E.; Bonjoch, J. Org. Lett. 2000, 2, 2225–2228.
(b) Solé, D.; Diaba, F.; Bonjoch, J. J. Org. Chem. 2003, 68, 5746–
5749. (c) Solé, D.; Urbaneja, X.; Bonjoch, J. Org. Lett. 2005, 7, 5461–
5464.
(48) For a recent contribution to intermolecular palladium-catalyzed
R-vinylation of carbonyl compounds and leading references to earlier
work in this area, see: Huang, J.; Bunel, E.; Faul, M. M. Org. Lett.
2007, 9, 4343–4346.
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Total Synthesis of the Strychnos Alkaloid (+)-Minfiensine
A R T I C L E S
remained problematic. When performing the reaction in 1:1
MeOH/water using PdCl2(dppf) and K2CO3, the yield of
pentacyclic ketone 72 increased to 45–50%, and the formation
of the deallylation byproduct 74 decreased to trace levels.49 The
most significant improvement in yield was registered when the
reaction was conducted in MeOH using 10 mol % of
PdCl2(dppf) and 4 equiv of K2CO3 at 70 °C. Under these
conditions, starting material was consumed within 1 h and
tetracyclic ketone 72 was isolated in 74% yield.
Tetracyclic ketone 72 is ideally constituted for direct elabora-
tion to (+)-minfiensine (Scheme 17). Straightforward conversion
of ketone 72 to the corresponding enol triflate 75, followed by
palladium-catalyzed carbonylation of this intermediate in MeOH,
provided R,ꢀ-unsaturated ester 68 in 77% yield for the two steps.
This product, [R]D -124 (c 1.05, CHCl3), displayed spectro-
scopic properties identical to those of tetracyclic enoate 68
prepared during our first-generation synthesis. As described in
more detail in Scheme 14, R,ꢀ-unsaturated ester 68 can be
converted in two steps and 85% overall yield to (+)-minfiensine,
[R]D +125 (c 0.82, CHCl3).
ring opening of the pyrrolidinoindoline subunit and our inability
to carry out a cascade Heck cyclization-carbonylation sequence
combined to compromise the efficiency of this inaugural
sequence. A second-generation synthesis side stepped these
issues by employing an intramolecular palladium-catalyzed
ketone enolate vinyl iodide coupling (70 f 72, Scheme 17) to
construct the final ring of (+)-minfiensine. Using this approach,
the cyclization precursor 70 was assembled from the product
27 of cascade asymmetric Heck-iminium ion cyclization in four
steps rather than the seven steps required to prepare the related
intermediate 48 in our first-generation synthesis. In addition,
the functionality present in pentacyclic product 72 produced by
enolate R-vinylation allowed the final elaboration to (+)-
minfiensine to be shortened to four transformations. This second-
generation total synthesis of enantiopure (+)-minfiensine was
accomplished in 6.5% overall yield and 15 steps from 1,2-
cyclohexanedione (12) and aniline 13. A distinctive feature of
this concise sequence is the use of palladium-catalyzed reactions
to form all the carbon-carbon bonds in the transformation of
these simple precursors to (+)-minfiensine.
Conclusion
Acknowledgment. Financial support from the NIH NIGMS
(GM-30859), and postdoctoral fellowship support for A.B.D.
(CA94471) and A.D.W. (CA108197) from the NIH National
Cancer Institute, and P.G.H. from Merck-Europe is gratefully
acknowledged. We thank Dr. Joseph Ziller for X-ray analysis
of compounds 35, 51, 54, and 64, and Professor Georges Massiot
for copies of NMR spectra of natural (+)-minfiensine.
A catalytic asymmetric Heck-iminium ion cyclization se-
quence was developed that provides either enantiomer of
differentially protected 1,2,3,4-tetrahydro-9a,4a-(iminoethano)-
9H-carbazole 27 in six steps from 1,2-cyclohexanedione (32%
overall yield). Notable in this sequence is the use of microwave
heating to accelerate the catalytic asymmetric Heck cyclization
of dienyl aryl triflate 21, which even though the reaction
temperature is 170 °C provides dihydrocarbazole 25 in 99% ee
(Scheme 4).
Two sequences were developed for advancing (iminoethano)-
9H-carbazole 27 to (+)-minfiensine. In a first-generation ap-
proach, a reductive Heck cyclization was employed to form the
fifth ring of (+)-minfiensine. Side reactions resulting from facile
Supporting Information Available: Experimental procedures,
spectroscopic and analytical data (1H, 13C, and HPLC) for new
compounds, and CIF files of crystallographic information. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(49) Some starting material remained in this reaction.
JA800163V
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