Enantioselective palladium-catalyzed decarboxylative allylation of carbazolones and indolones: Formal synthesis of (+)-kopsihainanineA

Article abstract of DOI:10.1002/anie.201209069

Adding value: A four-step synthesis of enantioenriched carbazolone and indolone derivatives has been developed using an enantioselective Pd-catalyzed decarboxylative allylation. The scope of this reaction is broad, and the materials are suited for natural product synthesis, shown with the completion of a formal synthesis of (+)-kopsihainanine (see scheme). Copyright

Full text of DOI:10.1002/anie.201209069

Angewandte
Chemie
DOI: 10.1002/anie.201209069
Stereoselective Catalysis
Enantioselective Palladium-Catalyzed Decarboxylative Allylation of
Carbazolones and Indolones: Formal Synthesis of
(+)-Kopsihainanine A**
Christopher J. Gartshore and David W. Lupton*
The elaboration of readily available nitrogen heterocycles to
complex targets is integral to medicinal and natural products
chemistry, as such new strategies to derivatize heterocycles
retain relevance. As part of ongoing studies on alkaloid
synthesis,[1] we noted a lack of direct enantioselective methods
for the assembly of C3-chiral carbazolones (i.e., 1), motifs
common in medicinal[2] and natural products chemistry
(Scheme 1).[3] This is a striking observation, as a host of
methods for the stereoselective installation of functionality
a to the carbonyl functionality of the parent carbazolone
should potentially be viable. Furthermore, our examination of
the literature reveals only one, ultimately unsuccessful,
attempt to demonstrate this strategy.[4]
Motivated by the notion that direct access to chiral
carbazolones, such as 1, should provide a valuable chiral
synthon useful in target directed synthesis,[5] we commenced
studies on this topic. Herein, we report the realization of this
strategy with a four-step synthesis of a diverse range of
enantioenriched carbazolones and indolones (i.e., 1) by
exploiting the enantioselective Pd-catalyzed decarboxylative
allylation of 2 (Scheme 2).[6] Preliminary studies on the utility
of carbazolones 1 have been undertaken, resulting in the
completion of a formal synthesis of (+)-kopsihainanine A
(3).[7]
Scheme 2. Enantioselective Pd-catalyzed decarboxylative allylation
described herein.
Although Pd-catalyzed decarboxylative allylation[8,9] of
carbazolones are yet to be reported,[10,11] the transformations
of related vinylogous esters and thioesters are known.[12] In
these studies, the enhanced enantioselectivity of the thioester
relative to the ester is attributed to the modest p-donation of
the sulfur atom. We postulated that carbazolones should
behave as vinylogous amides,[13,14] thus appropriate indole
protection should allow attenuation of the p-donation of the
nitrogen atom and induce high enantioselectivity. Supporting
the viability of such a strategy is a recent report by Stoltz and
co-workers, who demonstrate improved enantioselectivity
with the allylation of lactams that bear electron-withdrawing
N-protection.[15] Hence, our studies commenced with an
investigation of the role of N-protection on enantioselectivity.
When N-methyl-protected carbazolone 4a was subjected
to conditions developed by Stoltz and co-workers,[16] namely
the PHOX ligand (L1)[17] and [Pd2(dba)3] at room temper-
ature, no reaction occurred. However, heating to 808C
provided allyl carbazolone 1a in 69% yield and 66% ee
(Table 1, entry 1). Trostꢀs ligand L3 was unsuitable for this
reaction at any temperature (Table 1, entry 2). Changing from
N-methyl to N-benzyl protection was tolerated, although
carbazolone 1b formed with decreased enantioselectivity
Scheme 1. C3-chiral carbazolones 1 and representative medicinal and
natural products.
[*] C. J. Gartshore, Dr. D. W. Lupton
School of Chemistry, Monash University
Clayton 3800, Victoria (Australia)
E-mail: david.lupton@monash.edu
[**] The authors thank the Australian Research Council (ARC
DP0881137) and Monash University Research Accelerator Program
for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201209069.
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Table 1: Selected optimization.
[Eq. (1)], while using the preferred ligand L2 at 508C,
provided carbazolone 1e in 94% ee.
Having identified optimal conditions the scope of the
reaction was examined (Table 2). The reaction tolerated
additional carbonyl functionalities, with ester- and ketone-
Entry
4
PG
L
T
[8C]
t
[h]
Yield
[%][a]
ee
Table 2: Decarboxylative allylation of carbazolones 4.[a,b]
[%][b]
1
2
3
4
5
6
7
8
4a
4a
4b
4c
4d
4d
4d
4d
CH3
CH3
Bn
L1
L3
L1
L1
L1
L1
L4
L2
80
80
80
80
80
50
80
80
0.5
12
1
4
4
4
4
4
69
–
66
–
78
98
94
92
90
82
37
83
81
78
16
87
Ts
Boc
Boc
Boc
Boc
[a] Yield of isolated product following flash column chromatography.
[b] Enantiomeric excess determined by HPLC analysis on various chiral
stationary phases. The entry in bold highlights the optimized reaction
conditions.
(Table 1, compare entries 1 and 3). In contrast, electron-
withdrawing tosyl protection improved the enantioselectivity,
providing allyl carbazolone 1c in 98% yield and 83% ee
(Table 1, entry 4), while Boc-protected carbazolone 4d per-
formed equally well (Table 1, entry 5). Because of the
ubiquity of Boc protection, 4d was used in subsequent
optimizations. Lowering the temperature to 508C had no
effect on the outcome, while switching from L1 to BINAP
(L4) provided 1d with decreased enantioselectivity (Table 1,
entries 6 and 7). Finally, use of the tert-butyl-substituted
ligand L2 provided allyl carbazolone 1d in an improved
87% ee (Table 1, entry 8).
[a] Yields of isolated products following flash column chromatography.
[b] Enantiomeric excesses determined by HPLC analysis on chiral
stationary phases. [c] Reaction performed using ligand L1.
containing carbazolones 1 f and 1g produced in high yield and
enantioselectivity, 91 and 89% ee, respectively. Ethyl-con-
taining carbazolone 1h was prepared in 80% ee, while
methyl- and benzyl-bearing carbazolones 1i and 1j were
formed in 88 and 87% ee, respectively. Next, azide 4k was
assembled. As with nitrile 4e, this substrate bears function-
ality suited for reductive annulation to generate the piper-
idine ring common to many aspidosperma alkaloids (see
below). The decarboxylative allylation of 4k provided 1k in
82% yield and 91% ee. Finally, introduction of methoxy
substituents into the substrate, as observed with alkaloids
such as aspidophytine (Scheme 1),[19] was addressed using
carbazolone 4l. While its transformation to 1l was achieved
using the non-optimal ligand L1, the reaction proceeded with
good enantioinduction.
The apparent temperature-insensitive enantioselectivity
using carbazolone 4d (Table 1, compare entries 5 and 6) was
re-examined with nitrile-substituted carbazolone 4e [Eq. (1)].
The generality of the decarboxylative allylation was
examined with other N-containing heterocycles. Indolones
were selected because of their use as precursors to natural
products and their popularity as scaffold in medicinal
chemistry.[20] Pd-catalyzed decarboxylative allylation of Boc-
protected indolones 5 proceeded using the conditions pre-
viously described to provide allylated materials (Table 3). In
most cases, slightly decreased enantioselectivity relative to
the carbazolone series was observed (compare Tables 2 and
We postulated that the behavior of 4d might arise from
stabilizing coordination of the C-bound Pd–enolate through
the ester carbonyl, hence impeding epimerization that is
necessary for enantioselectivity.[18] When the decarboxylative
allylation of nitrile 4e was examined at 808C, carbazole 1e
formed in 85% ee (using ligand L1). When the reaction was
repeated at 508C, the enantioselectivity increased to 90% ee
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Table 3: Decarboxylative allylation of indolones 5.[a,b]
[a] Yields of isolated products following flash column chromatography.
[b] Enantiomeric excesses determined by HPLC analysis on chiral
stationary phases.
Scheme 3. Derivatization.
3). For example, nitrile- (5b), ester- (5c), and ketone-bearing
substrates (5d) afforded allylated indolones 6b–d in 86, 85,
and 85% ee in comparison to 94, 91, and 89% ee for the
analogous carbazolones. Ethyl-bearing indolone 6e formed in
87% ee, while the methyl- (6 f) and benzyl-bearing (6g)
substrates formed in 80 and 82% ee. Finally, azide 6h formed
in 82% ee and excellent yield.
1e, hydrolysis with formic acid with concomitant Boc group
removal gave amide 10. Benzyl protection then provided 11,
intercepting an intermediate in the synthesis of the racemic
product and completing the formal total synthesis of (+)-kop-
sihainanine, the natural stereoisomer of this material.
The direct enantioselective synthesis of carbazolone and
indolone heterocycles has been achieved using Pd-catalyzed
decarboxylative allylation. Central to achieving good levels of
enantioinduction was the use of electron-withdrawing N-
protection of the heterocycle. Using these conditions, a broad
range of enantioenriched carbazolones and indolones con-
taining a quaternary carbon center can be assembled in four
steps. Preliminary studies on the derivatization of these
materials have led to procedures for oxidative cleavage of the
allyl group and annulations. In addition, a formal synthesis of
(+)-kopsihainanine has been achieved. Future studies will
focus on the application of chiral carbazolones in the synthesis
of aspidosperma and kopsia natural products, and as scaffolds
for medicinal chemistry.
With access to a range of carbazolones, their conversions
to intermediates that are potentially valuable in complex-
target synthesis where undertaken (Scheme 3). Of interest
was the oxidative cleavage of the allyl group, and the
annulation to form the piperidine ring common in aspido-
sperma alkaloids. Oxidative cleavage of the allyl group using
ozonolysis provided complex mixtures, however, OsO4-cata-
lyzed dihydroxylation followed by periodate cleavage and
reduction provided the somewhat unstable alcohol 7. Pinnick
oxidation of the aldehyde intermediate and esterification
provided the methyl ester 8. The former compound is well
suited for the synthesis of fendleridine,[21] the latter has
functionality represented in aspidophytine.[19] Reductive
annulation with nitrile 1e could not be realized without
concomitant reduction of the allyl group.[22] In contrast,
cyclization of azide 1k using SnCl2 provided imine 9 and the
uncyclized amine, which, after heating in toluene, gave
a serviceable yield of imine 9. During the course of these
studies, Xie and She reported the use of carbazolones
containing quaternary carbon atoms (i.e., (rac)-11) in the
synthesis of racemic kopsihainanine A.[7] This aspidosperma
alkaloid was isolated from Kopsia hainanensis in 2011 by
Gao,[23] and has been used as a traditional folk medicine in the
Hainan Province for a range of ailments. Starting with nitrile
Please note: Minor changes have been made to this manuscript since
its publication in Angewandte Chemie Early View. The Editor.
Received: November 12, 2012
Published online: January 30, 2013
Keywords: allylation · carbazolone · enantioselectivity ·
.
kopsihainanine · palladium
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