Palladium-catalyzed dynamic kinetic asymmetric transformations of vinyl aziridines with nitrogen heterocycles: Rapid access to biologically active pyrroles and indoles

Article abstract of DOI:10.1021/ja1071509

We report that nitrogen heterocycles can serve as competent nucleophiles in the palladium-catalyzed dynamic kinetic asymmetric alkylation of vinyl aziridines. The resulting alkylated products were obtained with high regio-, chemo-, and enantioselectivity.

Full text of DOI:10.1021/ja1071509

Published on Web 10/15/2010
Palladium-Catalyzed Dynamic Kinetic Asymmetric
Transformations of Vinyl Aziridines with Nitrogen
Heterocycles: Rapid Access to Biologically Active Pyrroles
and Indoles
Barry M. Trost,* Maksim Osipov, and Guangbin Dong
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080, United States
Received August 19, 2010; E-mail: bmtrost@stanford.edu
Abstract: We report that nitrogen heterocycles can serve as competent nucleophiles in the palladium-
catalyzed dynamic kinetic asymmetric alkylation of vinyl aziridines. The resulting alkylated products were
obtained with high regio-, chemo-, and enantioselectivity. Both substituted 1H-pyrroles and 1H-indoles were
successfully employed to give exclusively the branched N-alkylated products. The synthetic utility of this
process was demonstrated by applying this method to the preparation of several medicinal chemistry lead
compounds and bromopyrrole alkaloids including longamide B, longamide B methyl ester, hanishin,
agesamides A and B, and cyclooroidin.
Introduction
The Pd-catalyzed asymmetric allylic alkylation (Pd-AAA) has
become a powerful tool for the construction of stereocenters
and has engendered a number of versatile methods for the total
synthesis of natural products and other biologically active
targets.1 Unlike other asymmetric reactions, the Pd-AAA is
capable of constructing several different types of bonds in an
enantioselective fashion, including C-C, C-N, C-O, and C-S
bonds. Furthermore, this transformation is highly chemoselective
and can be performed in the presence of a large number of
functional groups. Despite its versatility, the Pd-AAA typically
requires the use of soft stabilized nucleophiles such as malonates
or imides and has been limited in its ability to accommodate
hard nucleophiles. Our group has extended the scope of this
reaction to include hard nucleophiles such as alkoxides, lithium
enolates, and benzylic anions employing a family of diphe-
nylphosphino benzoic acid-derived ligands (Figure 1).2 How-
ever, hard nitrogen nucleophiles, specifically, nitrogen hetero-
cycles, largely remain unexplored in this transformation (eq 1).3
Likewise, the scope of electrophiles used in the Pd-AAA has
been limited to allylic ester derivatives.1 Other, unstabilized
leaving groups, such as ethers and amines, are difficult to
employ. By taking advantage of ring strain to facilitate ring-
opening, vinyl epoxides have been successfully employed in
Figure 1. Diphenylphosphino benzoic acid-based ligands.
the Pd-AAA.4 To date, the analogous vinyl aziridines have
remained a challenge in this transformation despite their
potential to construct chiral 1,2 diamines (eq 1).
(1) (a) Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996, 96, 395–422.
(b) Trost, B. M.; Crawley, M. L. Chem. ReV. 2003, 103, 2921–2944.
(c) Trost, B. M. J. Org. Chem. 2004, 69, 5813–5837. (d) Trost, B. M.;
Machacek, M. R.; Aponick, A. Acc. Chem. Res. 2006, 39, 747–760.
(e) Trost, B. M.; Fandrick, D. R. Aldrichim. Acta 2007, 40, 59–72.
(2) (a) Trost, B. M.; Schroeder, G. M. J. Am. Chem. Soc. 1999, 121, 6759–
6760. (b) Trost, B. M.; Zhang, T. Org. Lett. 2006, 8, 6007–6010. (c)
Trost, B. M.; Thaisrivongs, D. A. J. Am. Chem. Soc. 2008, 130, 14092–
14093. (d) Trost, B. M.; Thaisrivongs, D. A. J. Am. Chem. Soc. 2009,
131, 12056–12057.
Heterocycle-bearing chiral 1,2 diamines (see eq 1) are present
in a large number of natural products and small molecule
pharmaceuticals.5 One important class of natural products
containing this structural motif, the bromopyrrole alkaloids,
(4) Trost, B. M.; Bunt, R. C.; Lemoine, R. C.; Calkins, T. L. J. Am. Chem.
Soc. 2000, 122, 5968–5976.
(3) (a) Trost, B. M.; Kriche, M. J.; Grenzer, E. M. Org. Lett. 2002, 4,
2005–2008. (b) Trost, B. M.; Dong, G. J. Am. Chem. Soc. 2006, 128,
6054–6055. (c) Trost, B. M.; Dong, G. Org. Lett. 2007, 9, 2357–
2359.
(5) (a) Somei, M.; Yamada, F. Nat. Prod. Rep. 2005, 22, 73–103. (b)
Thirumalairajan, S.; Pearce, B. M.; Thompson, A. Chem. Commun.
2010, 46, 1797–1812.
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Access to Biologically Active Pyrroles and Indoles
A R T I C L E S
Figure 2. Representative bromopyrrole alkaloids.
These indole-fused heterocycles are present in a large number
of drug candidates as well as medicinal chemistry lead com-
pounds.11 Recently, these compounds have been patented for
their H3 antagonist activity, which can be used to treat obesity,
cardiovascular disorders, Alzheimer’s disease, and other neu-
rological disorders.10
Figure 3. Representative medicinal chemistry lead compounds.
Due to the abundance of biologically active compounds that
contain a heterocycle-bearing 1,2 diamine (see eq 1 and Figures
2 and 3), the development of catalytic asymmetric methods to
generate these moieties is an important challenge. While many
asymmetric alkylation methods exist for functionalizing het-
erocycles at the carbon atom,12 relatively few examples are
known for the direct asymmetric alkylation at nitrogen. Chen
and co-workers reported an organocatalytic intermolecular
asymmetric N-alkylation of various substituted indoles with
Morita Baylis-Hillman carbonates.13 Likewise, Bandini et al.
have disclosed that cinchona alkaloid-derived catalysts can
facilitate enantioselective N-alkylations of indoles in an in-
tramolecular fashion.14 Most recently, Hartwig et al. reported
an elegant Ir-catalyzed chemo-, regio- and enantioselective
allylation of indoles with linear allyl carbonates.15 Our group
has utilized heterocycles as nitrogen nucleophiles in the Pd-
AAA in the context of natural product total syntheses.3 However,
no general method has yet been disclosed utilizing these
molecules as nucleophiles in the Pd-AAA.
The Pd-AAA can operate through a variety of mechanisms
to induce chirality. Unlike many other asymmetric transforma-
tions, the Pd-AAA can convert racemic starting materials to
enantioenriched products through a dynamic kinetic asymmetric
transformation (DYKAT).1e In contrast to a kinetic resolution,
which is limited to a maximum theoretical yield of 50% and
involves consumption of only one enantiomer of the starting
material, a DYKAT has a theoretical yield of 100%. In this
transformation, both enantiomers of the starting material are
present a significant synthetic challenge due to the presence of
numerous contiguous stereocenters, nitrogen-rich polar func-
tional groups, and sensitive pyrrole nuclei (Figure 2). Due to
their intriguing structures and biological activities, the bro-
mopyrrole alkaloids have been the target of numerous total
syntheses.6 The agelastatins contain a fused tetracyclic structure
and possess a variety of interesting biological activities including
nanomolar activities against several cancer cell lines.7 Palau’amine
possesses a strained hexacylic skeleton, flanked by eight
contiguous stereocenters and nine nitrogen atoms and has shown
antibiotic, antifungal, as well as immunosuppressant activity.8
Other bromopyrrole alkaloids, including longamide B and its
methyl ester, hanishin, agesamides A and B, and cyclooroidin
contain pyrrole-fused piperazinones, and possess significant
antibiotic and cytotoxic activities.9
Like the piperazinones found in pyrrole alkaloids, indole-
fused piperazinones and piperazines (Figure 3) have also shown
a broad array of biological activities.10 Indole-fused piperazi-
nones are known for their ability to act as conformationally rigid
peptidomimetics and have been shown to act as antagonists of
the histamine 3 (H3) receptor, which is expressed in the central
nervous system and controls histamine levels in the brain.10
(6) For a review on their total syntheses, see: (a) Weinreb, S. M. Nat.
Prod. Rep. 2007, 24, 931–948. (b) Christophersen, C. In The Alkaloids;
Brossi, A., Ed.; Academic Press.: Orlando, 1985; Vol. 24, pp 25-98.
(c) Hao, E.; Fromont, J.; Jardine, D.; Karuso, P. Molecules 2001, 6,
130–141.
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Leroy, S.; Pietra, F. J. Chem. Soc., Chem. Commun. 1993, 1305–
1306. (b) D’Ambrosio, M.; Guerriero, A.; Chiasera, G.; Pietra, F. HelV.
Chim. Acta 1994, 77, 1895–1902. (c) D’Ambrosio, M.; Guerriero, A.;
Ripamonti, M.; Debitus, C.; Waikedre, J.; Pietra, F. HelV. Chim. Acta
1996, 79, 727–735. (d) Maijer, L.; Thunnissen, A. M.; White, A. W.;
Garnier, M.; Nikolic, M.; Tsai, L. H.; Walter, J.; Cleverley, K. E.;
Salinas, P. C.; Wu, Y. Z.; Biernat, J.; Mandelkov, E. M.; Kim, S. H.;
Pettit, G. R. Chem. Biol. 2000, 2, 51–63.
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S. PCT Int. Appl. WO 02/072584 A2, 2002. (b) Jolidon, S.;
Narquizian, R.; Norcross, R. D.; Pinard, E. PCT Int. Appl. WO US
2006/0128712 A1, 2006. (c) Nettekoven, M.; Plancher, J.-M.; Richter,
H.; Roche, O.; Taylor, S. PCT Int. Appl. WO US 2007/0135416 A1,
2007.
(11) Dinsmore, C. J.; Beshore, D. C. Org. Prep. Proced. 2002, 34, 367–
404.
(8) (a) Kinnel, R. B.; Gehrken, P.-H.; Scheuer, P. J. J. Am. Chem. Soc.
1993, 115, 3376–3377. (b) Seiple, I. B.; Su, S.; Young, I. S.; Lewis,
C. A.; Yamaguchi, J.; Baran, P. S. Angew. Chem., Int. Ed. 2010, 49,
1095–1098.
(12) For recent examples, see: (a) Austin, J. F.; Macmillan, D. W. C. J. Am.
Chem. Soc. 2002, 124, 1172–1173. (b) Evans, D. A.; Scheidt, K. A.;
Fandrick, K. R.; Lam, H. W.; Wu, J. J. Am. Chem. Soc. 2003, 125,
10780–10781. (c) Trost, B. M.; Quancard, J. J. Am. Chem. Soc. 2006,
128, 6314–6315. (d) Trost, B. M.; Mu¨ller, C. J. Am. Chem. Soc. 2008,
130, 2438–2439.
(9) (a) Mancini, I.; Guella, G.; Amade, P.; Roussakis, C.; Pietra, F.
Tetrahedron Lett. 1997, 38, 6271–6274. (b) Umeyama, A.; Ito, S.;
Yuasa, E.; Arihara, S.; Yamada, T. J. Nat. Prod. 1998, 61, 1433–
1434. (c) Srinivasa Reddy, N.; Venkateswarlu, Y. Biochem. Syst. Ecol.
2000, 28, 1035–1037. (d) Fattorusso, E.; Taglialatela-Scafati, O.
Tetrahedron Lett. 2000, 41, 9917–9922. (e) Tsuda, M.; Yasuda, T.;
Fukushi, E.; Kawabata, J.; Sekiguchi, M.; Fromont, J.; Kobayashi, J.
Org. Lett. 2006, 8, 4235–4238.
(13) Cui, H.-L.; Feng, X.; Peng, J.; Lei, J.; Jiang, K.; Chen, Y.-C. Angew.
Chem., Int. Ed. 2009, 48, 5737–5740.
(14) Bandini, M.; Eichholzer, A.; Tragni, M.; Umani-Ronchi, A. Angew.
Chem., Int. Ed. 2008, 47, 3238–3241.
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5740.
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A R T I C L E S
Trost et al.
Table 1. Selected Optimization Conditionsa
both electron-rich and electron-deficient vinyl aziridines could
be used. Our group has studied these compounds in the Pd-
AAA but required the use of isocyanates to activate the vinyl
aziridine.17a Thus, the utility with these useful, nitrogen-
containing electrophiles has been limited, and nucleophiles such
as nitrogen heterocycles have remained understudied. The
reactions of vinyl aziridines with nitrogen heterocycles, such
as pyrrole and indole, would provide access to useful, enan-
tioenriched, heterocycle-bearing diamine products, which com-
prise the core of several biologically relevant compounds.
entry
ligand
solvent
% yieldb
% eec
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L2
L2
L2
L2
L2
DCE
DCE
DCE
DCE
PhMe
PhCF3
THF
DME
Dioxane
73
99
77
<5
50
52
52
44
60
61
89
72
9
89
88
89
89
93
Results and Discussion
Reaction Optimization. To determine conditions under which
nitrogen heterocycles could serve as competent nucleophiles in
the Pd-AAA, we studied the reaction of 1H-pyrrole-2-carboni-
trile (2a) with vinyl aziridine 1a17a (Table 1). Treatment of this
system with 2 mol % Pd2(dba)3 ·CHCl3, and 6 mol % of ligand
L1 in 1,2 dichloroethane (DCE) provided the desired N-alkylated
product 3a in a promising 73% yield and 61% ee (entry 1).
Previous work with vinyl aziridines showed that changing the
ligand had a profound impact on both reactivity and selectivity
of the transformation.17a Further screening (entries 2-4)
revealed that ligand L2, containing a naphthyl moiety, provided
the desired product 3a in 99% yield and 89% ee. Additionally,
the choice of solvent (Table 1, entries 5-8) was found to have
a dramatic effect on the course of this transformation: conducting
the reaction in aromatic solvents (entries 5 and 6) or polar
solvents (entries 7-9) had a detrimental effect on the reactivity
while showing little impact on the levels of enantioselectivity.
a All reactions were performed with 1.0 equiv of 2a and 1.1 equiv of
1a at ambient temperature at 0.25 M in the designated solvent. b Isolated
yield. c Determined by chiral HPLC.
converted into a single, optically active, product. This type of
process is desirable, as it minimizes waste and increases the
overall synthetic efficiency and atom economy of a reaction by
employing all of the starting material.16
While racemic vinyl epoxides have been shown to undergo
a Pd-catalyzed DYKAT with a number of carbon and hetero-
atom nucleophiles, examples with vinyl aziridines remain
scant.17 Typically, vinyl aziridines require a strong electron-
withdrawing group on the nitrogen atom to increase the
electrophilicity of the adjacent carbon atoms.18 The necessity
of such a group imposes a limitation on the system, and ideally
Table 2. Reaction Scope of Pyrroles with Vinyl Aziridinesa
a All reactions were performed with 1.0 equiv of pyrrole nucleophile and 1.1 equiv of 1 at ambient temperature. Isolated yield. % ee was determined
by chiral HPLC. b Cs2CO3 (1.1 equiv) was added.
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A R T I C L E S
Table 3. Reaction Scope of Indoles with Vinyl Aziridinesa
a All reactions were performed with 1.0 equiv of indole nucleophile and 1.1 equiv of 1 at ambient temperature. Isolated yield. % ee was determined
by chiral HPLC. b Cs2CO3 (1.1 equiv) was added.
The combination of ligand L2 in DCE was found to be optimal
for this transformation. Under all the conditions that were
evaluated, the branched, N-alkylated product was observed
exclusively, demonstrating the profound chemo- and regiose-
lectivity of the transformation.
Substrate Scope. With optimized conditions in hand, we next
studied the scope of this transformation using other substituted
pyrroles and vinyl aziridines (Table 2). Vinyl aziridines
substituted at R1 with either PMB (1a) or Bn (1b) groups reacted
smoothly and typically resulted in similar levels of enantiose-
lectivity. A variety of functional groups were tolerated on the
pyrrole nucleus at both the C2- and C3-positions and afforded
the branched N-alkylated products in high yield and % ee. The
presence of an electron-withdrawing group on the pyrrole ring
was necessary for the reaction to proceed, and only starting
materials were recovered when an electron-rich or unsubstituted
pyrrole was used as the nucleophile (3i,j). To investigate whether
C-alkylation could occur, N-methyl pyrrole was subjected to
the optimized reaction conditions but resulted in only slight
decomposition of the starting materials. The reaction between
methyl 1H-pyrrole-2-carboxylate with vinyl aziridines 1a and
1b afforded homoallyl amines 3c and 3d, respectively, as acyclic
products which could be stored at -20 °C for several weeks
without appreciable cyclization to the piperazinone. The cyclic
pyrrole-fused piperazinones could be accessed by heating the
acyclic products to 40 °C for 16 h. In cases where lower yields
were obtained, such as 3b and 3c, only unreacted pyrrole was
observed, with little to no decomposition. On the other hand,
unreacted vinyl aziridine was rarely observed at the end of the
reaction. When 3-nitro-1H-pyrrole was used, the addition of 1.1
equiv of Cs2CO3 was needed to facilitate the reaction (3h).
However, no base was required in other cases, and the amide
anion in the π-allyl Pd intermediate (see eq 1) was sufficiently
basic to deprotonate the pyrrole N-H and facilitate the
transformation.
(16) (a) Trost, B. M. Science 1991, 254, 1471–1477. (b) Trost, B. M.
Angew. Chem., Int. Ed. 1995, 34, 259–281.
(17) (a) Trost, B. M.; Fandrick, D. R. J. Am. Chem. Soc. 2003, 125, 11836–
11837. (b) Trost, B. M.; Fandrick, D. R.; Brodmann, T.; Stiles, D. T.
Angew. Chem., Int. Ed. 2007, 46, 6123–6125.
(18) For Pd catalysis with vinyl aziridines, see: (a) Butler, A. C. D.; Inman,
G. A.; Alper, H. J. Org. Chem. 2000, 65, 5887–5890. (b) Dong, C.;
Alper, H. Tetrahedron: Asymmetry 2004, 15, 1537–1540. (c) Sebelius,
S.; Olsson, V. J.; Szabo´, K. J. Am. Chem. Soc. 2005, 127, 10478–
10479. (d) Fontana, F.; Tron, G. C.; Barbero, N.; Ferrini, S.; Thomas,
S. P.; Aggarwal, V. K. Chem. Commun. 2010, 46, 267–269.
To further expand the generality of this process, indoles were
employed as nucleophiles in the transformation. Like pyrroles,
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Trost et al.
Table 4. Reactions of Nitrogen Heterocycles with Vinyl Aziridines to Access Piperazinonesa
a All reactions were performed with 1.0 equiv of heterocyclic nucleophile and 1.1 equiv of 1 at ambient temperature. Isolated yield. % ee was
determined by chiral HPLC. b Cs2CO3 (1.1 equiv) was added. c Performed using 2.5 mol % [Pd(C3H5)Cl]2 7.5 mol % (R,R)-L1, in CH2Cl2 at rt.
Scheme 1. Synthesis of Medicinal Chemistry Lead Compounds
electron-deficient indoles reacted smoothly under the optimized
reaction conditions providing the desired products in high yield
and % ee (Table 3). Although indoles have a high propensity
to undergo substitution at C3 in the presence of a Pd source
and an allylic electrophile, only the N-alkylated, branched
products were observed.19 We postulated that N-alkylation could
be suppressed in favor of C3 alkylation in the absence of an
electron-withdrawing group, or in the presence of an electron-
donating group at C2. However, using 2-methyl-1H-indole or
unsubstituted indole (4l) led to only unreacted starting materials.
Substitution on either the azole, or benzene portion of the indole
moiety, was sufficient to facilitate the reaction. However, a
strong electron-withdrawing group was necessary to obtain high
levels of reactivity and enantioselectivity. When weak electron-
withdrawing groups were employed, such as Cl or Br, both the
yield and % ee of the product decreased (4j,k); 2-phenyl-1H-
indole only afforded trace quantities of the desired product (4m).
As for the cases with pyrroles, nitrile (4e,f), ester (4i), halide
(4j,k), ketone (4h), and nitro (4c,d,g) functional groups were
all tolerated in the transformation and little to no decomposition
of the indole nucleophile was observed, demonstrating the high
functional group compatibility of this transformation.
5a was obtained in 97% yield and 90% ee from vinyl aziridine
1a and pyrrole containing a trifluoromethyl ketone at the
2-position. Switching R2 from a trifluoromethyl ketone to a
methyl ester also afforded the desired cycloadduct 5b. Like
pyrroles, indoles could also be employed as nucleophiles, to
afford indole-fused piperazinones utilizing either 1a or 1b as
the vinyl aziridine. Piperazinones containing a pyrrole moiety
like the one found in 5b, represent the core structure of a number
of bromopyrrole alkaloids including longamide B, agesamides
A and B, hanishin and cyclooroidin.9 Piperazinones containing
indole moieties such as 5c and 5d have also found broad use in
medicinal chemistry and show significant biological activities.10
The indole products isolated from this cyclization were readily
transformed into the core of several patented piperazinones
(Scheme 1).10 Hydroboration of compound 5d followed by
oxidation afforded primary alcohol 6 as the only product, in
85% yield. Oxidation of the alcohol 6 with PhI(OAc)2 in the
presence of catalytic TEMPO provided the known carboxylic
acid 7 in 81% yield. The sign and magnitude of the optical
rotation of this acid was in agreement with previous reports,
confirming the absolute configuration from the Pd-AAA.10,14
Compound 5d was easily reduced upon treatment with LiAlH4
to give the corresponding piperazine 8 in 85% yield. Indole-
fused piperazines of this general structure are also found in a
large number of medicinal chemistry leads, and have been
shown to be useful in treating central nervous system disorders,
gastrointestinal disorders, diabetes, obesity, and sleep apnea.10
Hydroboration of piperazine 8, followed by oxidation, provided
the known alcohol 9 in 93% yield. Although we only show the
Piperazinone Functionalization and Synthesis of Medicinal
Chemistry Leads. When heterocycles containing certain acyl
substituents at the 2-position were employed in the transforma-
tion, a cyclization occurred, providing access to enantioenriched
piperazinones (Table 4). For instance, pyrrole-fused piperazinone
(19) Kagawa, N.; Malerich, J. P.; Rawal, V. H. Org. Lett. 2008, 10, 2381–
2384.
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A R T I C L E S
Scheme 2. Concise Synthesis of Bromopyrrole Alkaloids
Mechanistic Discussion and Rationalization of Asymmetric
Induction. We propose the following mechanistic rationale for
the observed stereochemistry based on the “wall and flap” model
previously reported.1d,22 Initial ionization of the two enantiomers
of the vinyl aziridine 1 (Scheme 3) with the (R,R)-enantiomer
of the Pd-ligand complex proceeds rapidly in both a matched
and mismatched manner to provide two possible zwitterionic
π-allyl Pd complexes 18 and ent-18, respectively. These two
intermediates can interconvert through a rapid π-σ-π equili-
bration. Nucleophilic attack of the pyrrole nucleophile 2 on the
π-allyl palladium species 18, at the more substituted terminus,
provides the desired product 3.
To obtain high levels of enantioselectivity, a Curtin-Hammet
situation must be established such that π-σ-π interconversion
is rapid and much faster than the subsequent nucleophilic attack.
By using a larger ligand, L2, a more sterically encumbered
environment is established, which slows down the rate of
nucleophilic attack and increases the time allowed for π-σ-π
interconversion. An unfavorable steric interaction between one
of the two diastereomeric π-allyl Pd intermediates determines
which enantiomer of the product is formed, such that k1 is much
larger than k2. The absolute configuration of the product from
this transformation, as well as related reactions with vinyl
epoxides, support this model.4
elaboration of a simple indole into the core of biologically active
piperazinone 7 and piperazine 8, utilizing substituted indoles
should provide access to more complex members of this
substrate class.
Concise Synthesis of Bromopyrrole Alkaloids. Bromopyrrole
alkaloids are an important class of natural products with a range
of biological activities.6 Many of these alkaloids contain a
piperazinone core that can be accessed through the Pd-AAA of
a vinyl aziridine with a bromopyrrole nucleophile. To demon-
strate the versatility of the method described herein, the
syntheses of several bromopyrrole alkaloids were pursued
(Scheme 2). Piperazinone 5b served as a scaffold that was
elaborated to a common intermediate from which many bro-
mopyrrole alkaloids were synthesized. Hydroboration of 5b with
9-BBN, followed by oxidation, provided the desired primary
alcohol 10 in 82% yield. Cleavage of the dimethoxybenzyl
(DMB) group with tetrahydrothiophene followed by bromination
with NBS furnished alcohol 11 in 96% over two steps. Alcohol
11 was readily oxidized to longamide B (12) with PhI(OAc)2
in the presence of catalytic TEMPO. Longamide B (12) could
then be converted to three additional natural products. Esteri-
fication of the free acid in longamide B (12) under known
literature conditions20 with either a methyl or ethyl group affords
longamide B methyl ester (13), and hanishin (14) respectively.
Two additional bromopyrrole alkaloids, agesamides A and B,
were readily accessed from alcohol 11. Oxidation of 11 with
Dess-Martin periodinate, followed by treatment with potassium
cyanide and ammonium carbonate, lead to both agesamides A
(15) and B (16). Likewise, installation of the amino-imidazole
moiety onto the free acid, affords cyclooroidin (17).21
Pd-catalyzed allylic alkylation of monosubstituted π-allyl-
Pd intermediates typically favors the achiral, linear product. To
rationalize the exclusive regioselectivity for the branched
product, we propose that nucleophilic attack proceeds through
a five-membered transition state (Scheme 4). In this transition
(21) (a) Papeo, G.; Go´mez-Zurita Frau, M. A.; Borghi, D.; Varasi, M.
Tetrahedron Lett. 2005, 46, 8635–8638. (b) Patel, J.; Pelloux-Le´on,
N.; Minassian, F.; Valle´e, Y. Tetrahedron Lett. 2006, 47, 5561–5563.
(22) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 4545–4554.
(20) (a) Banwell, M. G.; Bray, A. M.; Willis, A. C.; Wong, D. J. New
J. Chem. 1999, 23, 687–690. (b) Patel, J.; Pelloux-Le´on, N.; Minassian,
F.; Valle´e, Y. J. Org. Chem. 2005, 70, 9081–9084.
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A R T I C L E S
Trost et al.
Scheme 3. Mechanistic Rationale
Scheme 4. Rationale for Observed Regioselectivity
piperazinones were used as synthetic building blocks to access
a series of drug leads that have received extensive attention from
the medicinal chemistry community. Likewise, pyrrole-fused
piperazinones were used as synthetic building blocks to rapidly
assemble the bromopyrrole alkaloids longamide B, longamide
B methyl ester, hanishin, agesamides A and B, and cyclooroidin.
Experimental Section
Typical Procedure for the Pd-Catalyzed Asymmetric Al-
lylic Alkylation of Pyrroles with Vinyl Aziridines. To a flame-
dried microwave vial equipped with a magnetic stir bar was added
1H-pyrrole-2-carbonitrile 2a (18.4 mg, 0.2 mmol) and vinyl
aziridine 1a (48.2 mg, 0.22 mmol). The system was evacuated and
filled with argon (3×) and dry degassed DCE (0.4 mL) was then
added. In a separate flame-dried microwave vial equipped with a
magnetic stir bar was added Pd2(dba)3 ·CHCl3 (4.1 mg, 4.0 × 10-3
mmol) and (R,R)-L2 (9.5 mg, 0.012 mmol). The system was
evacuated and filled with argon (3×), and DCE (0.4 mL) was added.
This vial was stirred at rt for 15-20 min until a bright orange color
persisted and its contents were then cannulated to the first vial.
The reaction mixture was stirred for 48 h at rt, diluted with CH2Cl2
(10 mL) and then poured onto water (10 mL). The organic layer
was separated, and the aqueous layer was extracted with CH2Cl2
(3 × 10 mL). The combined organic fractions were dried over
anhydrous sodium sulfate, filtered, and concentrated en Vacuo. The
crude reaction mixture was purified by flash column chromatog-
raphy on silica gel (30% ethyl acetate in petroleum ether) to provide
56 mg of a yellow oil (3a) (99% yield, 89% ee by HPLC, OJ-H
column, 9:1 heptane/i-propanol, 1.0 mL/min, 254 nm, rt ) 27.4,
30.2 min). Rf ) 0.30 (30% ethyl acetate/petroleum ether). 1H NMR
(CDCl3, 400 MHz): δ 7.20-7.17 (m, 2H), 6.92 (dd, J ) 2.6, 1.7
Hz, 1H), 6.86-6.84 (m, 2H), 6.82 (dd, J ) 3.9, 1.6 Hz, 1H), 6.22
(dd, J ) 3.9, 2.8 Hz, 1H), 5.97 (ddd, J ) 17.1, 10.5, 5.9 Hz, 1H),
5.28 (ddd, J ) 10.5, 1.3, 0.7 Hz, 1H), 5.10 (ddd, J ) 17.2, 1.5, 0.7
Hz, 1H), 4.97-4.92 (m, 1H), 3.79 (s, 3H), 3.72 (q, J ) 12.2 Hz,
2H), 3.13-3.03 (m, 2H), 1.35 (s, 1H). 13C NMR (CDCl3, 101 MHz):
δ 159.2, 135.3, 132.2, 129.7, 124.7, 120.5, 119.0, 114.4, 114.3,
110.3, 104.3, 61.5, 55.7, 53.1, 52.5. IR (film): 3335, 3123, 2917,
2836, 2214, 1610, 1511, 1457 cm-1. [R]D: -31.7 (CH2Cl2, c 1.00).
HRMS (C17H19N3ONa): calculated (M + Na) 304.1426, found (M
+ Na) 304.1428.
state, the amide anion of the vinyl aziridine directs the pyrrole
nucleophile through a hydrogen bond with the pyrrole N-H,
to the proximal end of the π-allyl-Pd moiety. Thus nucleophilic
attack proceeds through the favored five-membered transition
state 19, leading to the observed branched product. This would
preclude the reaction proceeding through a strongly disfavored
seven-membered transition state 20, which contains a trans-
olefin and leads to the achiral linear product.
Conclusion
In conclusion, a highly chemo-, regio-, and enantioselective
palladium-catalyzed asymmetric allylic alkylation between
nitrogen heterocycles and vinyl aziridines has been developed.
Both substituted pyrroles and indoles can be utilized as
nucleophiles in the transformation to afford the N-alkylated
branched products exclusively in high yield and % ee. The
presence of an electron-withdrawing group on the nitrogen
heterocycle was necessary for this reaction to proceed, but many
functional groups on the pyrrole and indole nuclei were
tolerated. No electron-withdrawing groups were needed on the
vinyl aziridine to facilitate its opening, adding to the high
generality of this process.
Typical Procedure for the Pd-Catalyzed Asymmetric Al-
lylic Alkylation of Indoles with Vinyl Aziridines. To a flame-
dried microwave vial equipped with a magnetic stir bar was added
methyl 1H-indole-3-carboxylate (35.0 mg, 0.2 mmol) and vinyl
aziridine 1b (48.2 mg, 0.22 mmol). The system was evacuated and
filled with argon (3×) and dry degassed DCE (0.4 mL) was then
By substituting the heterocycles at the C2 position with an
ester derivative, piperazinones were accessed readily through a
formal asymmetric [3 + 3] cycloaddition. The indole-fused
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Access to Biologically Active Pyrroles and Indoles
A R T I C L E S
added. In a separate flame-dried microwave vial equipped with a
magnetic stir bar was added Pd2(dba)3 ·CHCl3 (4.1 mg, 4.0 × 10-3
mmol) and (R,R)-L2 (9.5 mg, 0.012 mmol). The system was
evacuated and filled with argon (3×), and DCE (0.4 mL) was added.
This vial was stirred at rt for 15-20 min until a bright orange color
persisted and its contents were then cannulated to the first vial.
The reaction mixture was stirred for 48 h at rt, diluted with CH2Cl2
(10 mL) and then poured onto water (10 mL). The organic layer
was separated, and the aqueous layer was extracted with CH2Cl2
(3 × 10 mL). The combined organic fractions were dried over
anhydrous sodium sulfate, filtered and concentrated en Vacuo. The
crude reaction mixture was purified by flash column chromatog-
raphy on silica gel (35% ethyl acetate in petroleum ether) to provide
66.0 mg of a clear oil (4i) (91% yield, 93% ee by HPLC, IA column,
95:5 heptane/i-propanol, 0.8 mL/min, 254 nm, rt ) 28.6, 32.8 min.).
J ) 14.2, 6.8 Hz, 2H), 1.40 (s, 1H). 13C NMR (CDCl3, 101 MHz):
δ 165.9, 159.2, 137.1, 135.2, 132.5, 132.1, 129.6, 127.0, 123.2,
122.5, 122.2, 118.7, 114.3, 110.8, 108.1, 59.2, 55.7, 53.7, 51.8,
51.5. IR (film): 2995, 2948, 2835, 1697, 1612, 1532, 1512, 1460
cm-1. [R]D: -19.4 (CH2Cl2, c 1.03). HRMS (C22H24N2O3Na):
calculated (M + Na) 387.1676, found (M + Na) 387.1685.
Acknowledgment. We thank the National Science Foundation
and the National Institutes of Health (GM33049) for their generous
support of our programs. M.O. thanks the John Stauffer Memorial
Fellowship for financial support. G.D. thanks the Stanford Graduate
Fellowship for financial support. Palladium salts were generously
supplied by Johnson-Matthey.
1
Supporting Information Available: Experimental procedures
and characterization data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
Rf ) 0.3 (45% ethyl acetate/petroleum ether). H NMR (CDCl3,
400 MHz): δ 8.21-8.18 (m, 1H), 7.93 (s, 1H), 7.39-7.34 (m, 1H),
7.30-7.23 (m, 2H), 7.13-7.10 (m, 2H), 6.84-6.80 (m, 2H), 6.00
(ddd, J ) 17.3, 10.6, 5.7 Hz, 1H), 5.27-5.24 (m, 1H), 5.10-5.06
(m, 2H), 3.91 (s, 3H), 3.77 (s, 3H), 3.73-3.66 (m, 2H), 3.16 (qd,
JA1071509
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J. AM. CHEM. SOC. VOL. 132, NO. 44, 2010 15807