Enantioselective Pd-Catalyzed Allylic Alkylation Reactions of Dihydropyrido[1,2-a]indolone Substrates: Efficient Syntheses of (?)-Goniomitine, (+)-Aspidospermidine, and (?)-Quebrachamine

Article abstract of DOI:10.1002/anie.201608138

The successful application of dihydropyrido[1,2-a]indolone (DHPI) substrates in Pd-catalyzed asymmetric allylic alkylation chemistry facilitates rapid access to multiple alkaloid frameworks in an enantioselective fashion. Strategic bromination at the indole C3 position greatly improved the allylic alkylation chemistry and enabled a highly efficient Negishi cross-coupling downstream. The first catalytic enantioselective total synthesis of (?)-goniomitine, along with divergent formal syntheses of (+)-aspidospermidine and (?)-quebrachamine, are reported herein.

Full text of DOI:10.1002/anie.201608138

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201608138
German Edition: DOI: 10.1002/ange.201608138
Total Synthesis
Enantioselective Pd-Catalyzed Allylic Alkylation Reactions of
Dihydropyrido[1,2-a]indolone Substrates: Efficient Syntheses of (ꢀ)-
Goniomitine, (+)-Aspidospermidine, and (ꢀ)-Quebrachamine
Beau P. Pritchett, Jun Kikuchi, Yoshitaka Numajiri, and Brian M. Stoltz*
Dedicated to Professor K. C. Nicolaou on occasion of his 70th birthday
Abstract: The successful application of dihydropyrido[1,2-
a]indolone (DHPI) substrates in Pd-catalyzed asymmetric
allylic alkylation chemistry facilitates rapid access to multiple
alkaloid frameworks in an enantioselective fashion. Strategic
bromination at the indole C3 position greatly improved the
allylic alkylation chemistry and enabled a highly efficient
Negishi cross-coupling downstream. The first catalytic enan-
tioselective total synthesis of (ꢀ)-goniomitine, along with
divergent formal syntheses of (+)-aspidospermidine and (ꢀ)-
quebrachamine, are reported herein.
M
onoterpene indole alkaloids have been extensively
studied by chemists and biologists alike due to their vast
structural diversity and broad biological activity.[1] (ꢀ)-
Goniomitine (1), isolated from the bark of Gonioma mala-
gasy, is an Aspidosperma alkaloid with
a
unique
octahydroindolo[1,2-a][1,8]naphthyridine core (Figure 1).[2]
Scheme 1. A) Biogenesis of goniomitine from vincadifformine.
B) Effects of C3 substitution on indole–iminium cyclization. C) Retro-
synthetic analysis of 5.
a C2-tethered iminium moiety (5, Scheme 1B) are remark-
ably chemoselective. In the case of a C3-substituted indole
1
ꢀ
fragment (e.g., 5, R ¼ H), cyclization proceeds via C N bond
Figure 1. Skeletally diverse Aspidosperma alkaloids.
formation to furnish aminal-containing tetracycle 6, as seen in
previous syntheses of goniomitine (1).[5–7] Conversely, a C3-
1
ꢀ
unsubstituted indole fragment (5, R = H) undergoes C C
The key structural differences between goniomitine (1) and
many Aspidosperma alkaloids (e.g., 2–4, Figure 1)[3] are the
aminal functional group at C21 and the vestigial (2-hydroxy)-
ethyl moiety at C7.[4]
bond formation followed by rearomatization to arrive at
alternative tetracycle 7, a core that is present in numerous
alkaloids (e.g., 2 and 4).[8] We anticipated that iminium
intermediates such as 5 could be accessed in straightforward
fashion from compounds containing a dihydropyrido[1,2-
a]indolone (DHPI) core (Scheme 1C). Retrosynthetically, we
envisioned that the propylamine fragment in 5 could arise
from an anti-Markovnikov hydroamination of the allyl
functionality in a-quaternary lactam 8. Given our long-
standing interest in the asymmetric synthesis of all-carbon
quaternary centers, we believed that we could employ our Pd-
catalyzed allylic alkylation chemistry to construct the quater-
nary stereocenter at C20 in an enantioselective fashion.[9,10]
We expected that a cross-coupling reaction could enable
optional substitution at the C3 position of the DHPI scaffold,
thereby providing selective routes to tetracycles 6 and 7.
Therefore, development of this versatile substrate class in our
Pd-catalyzed allylic alkylation chemistry would provide
Biosynthetically, these features are believed to arise from
oxidative degradation of the tryptamine fragment in vinca-
difformine (4, Scheme 1A) followed by fragmentation and
N1 C21 recombination.[5] Cyclizations between an indole and
ꢀ
[*] B. P. Pritchett, J. Kikuchi, Dr. Y. Numajiri, Prof. Dr. B. M. Stoltz
Warren and Katharine Schlinger Laboratory for Chemistry and
Chemical Engineering
Division of Chemistry and Chemical Engineering
California Institute of Technology
1200 E. California Blvd. MC 101-20, Pasadena, CA 91125 (USA)
E-mail: stoltz@caltech.edu
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201608138.
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Table 1: Pd-catalyzed asymmetric allylic alkylation of DHPI substrates.[a]
a powerful tool for divergent enantioselective syn-
theses of multiple Aspidosperma alkaloids.
Owing to its antiproliferative activity and
unusual structure, several groups have targeted
goniomitine (1) for total synthesis.[6,7] While
modern approaches to this molecule have improved
upon the seminal report by Takano and co-work-
ers,[7a] a synthesis of goniomitine (1) that employs
asymmetric catalysis to achieve stereocontrol has not
yet been demonstrated. To date, asymmetric synthe-
ses of goniomitine (1) have relied on either enzy-
matic resolutions or chiral pool materials.[7] Further-
more, in previous syntheses of goniomitine, unless
the (2-hydroxy)ethyl moiety was incorporated using
a tryptophol-derived starting material, a multi-step
sequence from an unsubstituted C7 position was
required. We instead anticipated that a cross-cou-
pling reaction between a C3-brominated DHPI and
Entry
R (13!14)
Solvent Pd2(pmdba)3 Ligand t [h] Yield [%][b] ee [%][c]
[mol%]
[mol%]
1
2
CH2CH2OBn toluene
10
25
72
24
38
59
89
87
(13a!14a)
CH2CH2OBn
TBME
10
25
(13a!14a)
3
4
5
6
Br (13b!14b) toluene
Br (13b!14b) TBME
H (13c!14c) toluene
H (13c!14c) TBME
5
5
10
5
12.5
12.5
25
24
8
48
24
21
83
54
71
93
96
92
94
12.5
a suitable organometallic reagent would enable [a] Reactions were performed in stated solvent (0.033m) at 608C. [b] Yield of
isolated product. [c] Determined by chiral SFC. [d] pmdba=4,4’-dimethoxydiben-
zylideneacetone.
efficient access to the (2-hydroxy)ethyl fragment in
the natural product. Realization of this synthetic
plan would deliver the first catalytic enantioselective
total synthesis of (ꢀ)-goniomitine (1).
Our synthesis of (ꢀ)-goniomitine (1) commenced from
known N-acyl indole 9,[11] which underwent regioselective
bromination to give heteroaryl bromide 10 in 95% yield
(Scheme 2). Treatment of 10 with potassium (2-benzylox-
alkylation reactions, their strategic implementation for cross-
coupling events following the allylic alkylation is compara-
tively limited.[15] Gratifyingly, brominated b-amidoester 13b
reacted to give the desired quaternary alkylated product 14b
(Entries 3 and 4), which in TBME was afforded in 83% yield
and 96% ee with no observable interference from the C3
bromide (Entry 4). Given that the successful inclusion of
ꢀ
a C3 H substrate in our allylic alkylation chemistry would
enable divergent construction of additional alkaloids (see
Scheme 1B), we were pleased to find that b-amidoester 13c
could deliver a-quaternary lactam 14c in 71% yield and 94%
ee (Entry 6).
We next turned our attention toward the cross-coupling of
brominated a-quaternary lactam 14b with a suitable hydrox-
yethyl surrogate. Unfortunately, we found that the Suzuki
reaction between 14b and trifluoroborate 11 could not be
improved beyond a 50% yield of inseparable olefin isomers
Scheme 2. Suzuki cross-coupling of a 3-bromoindole fragment. [a]
AtaPhos=di-tert-butyl(4-dimethylamino)phenylphosphine.
y)ethyl trifluoroborate (11) and catalytic PdCl2(AtaPhos)2
afforded cross-coupled product 12 in 86% yield.[12,13] Facile
C-acylation and -alkylation of tricycles 9, 10, and 12 posi-
tioned us to investigate the heretofore untested asymmetric
allylic alkylation of the dihydropyrido[1,2-a]indolone (DHPI)
substrate class.[14]
ꢀ
14a in a 5:1 ratio (Scheme 3A). We hypothesized that a Pd H
species was responsible for this undesired isomerization
pathway, and sought to identify an alternative Csp3 nucleo-
Exposure of (2-benzyloxy)ethyl-substituted DHPI 13a to
standard Pd-catalyzed decarboxylative allylic alkylation con-
ditions yielded the a-quaternary product 14a in 38% yield
and 89% enantiomeric excess (Table 1, Entry 1). Switching
from toluene to TBME as solvent greatly improved the
reaction rate and yield, albeit with a minor decrease in
enantioselectivity (Entry 2). Previous studies by our group
have revealed that electron-withdrawing substituents on the
lactam nitrogen atom provide the best results in the allylic
alkylation chemistry.[9b] As the enolate intermediate would be
in cross-conjugation with the arene p-system, we postulated
that a bromide at the C3 position could provide both
a beneficial electronic effect and a handle for cross-coupling
downstream. While there are numerous reports of aryl
bromides withstanding the conditions of Pd-catalyzed allylic
Scheme 3. Cross-coupling reactivity of a-quaternary DHPI 14b.
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philic coupling partner that would not allow for facile b-
Furthermore, treatment of 14c with the aforementioned
hydride elimination. Recognizing that a reduction would
ultimately be required to convert the amide present in 14b to
the aminal present in goniomitine (1), we decided to
incorporate a substituent in a higher oxidation state via the
cross-coupling, thereby allowing concomitant unveiling of the
(2-hydroxy)ethyl moiety at a later stage. After investigating
a multitude of Negishi conditions, we were thrilled to find that
Reformatsky reagent 15 could be efficiently coupled with
heteroaryl bromide 14b using catalytic PdCl2(AtaPhos)2 to
deliver arylated product 16 in 98% yield without any
detectable amount of undesired olefin isomers (Sche-
me 3B).[16]
With the requisite carbon–carbon bonds established, we
began investigating methods to effect an anti-Markovnikov
hydroamination of the terminal olefin of 16. To this end, we
employed a one-pot hydrozirconation/amination sequence
reported by Hartwig and co-workers.[17] To our knowledge,
this is the first implementation of Hartwigꢀs hydrozirconation/
amination procedure in the context of natural product
synthesis. Following this formal hydroamination, we were
pleased to find that complete reduction of the tert-butyl ester
of 17 could be achieved alongside partial reduction of the
amide carbonyl in one pot using a single reductant. In the
event, primary amine 17 was subjected to LiAlH4 in THF,
followed by acidic workup, to afford (ꢀ)-goniomitine (1) in
30% yield from 16 (Scheme 4).
hydroamination conditions followed by a mild amide
ꢀ
exchange furnishes free N H a-quaternary d-lactam 18 in
66% yield over two steps, constituting an asymmetric formal
synthesis of (ꢀ)-quebrachamine (3).[18]
In summary, we have completed the first catalytic
enantioselective total synthesis of (ꢀ)-goniomitine (1) in 11
steps and 8% overall yield from indole, or 7 steps and 17%
overall yield from known DHPI 9. The redox efficiency and
freedom from protecting-group manipulations is a marked
improvement from previous nonracemic syntheses, which
deliver the target in 10–28 steps and 0.25–3.2% overall yield
from commercial materials. Rationally designed heteroaryl
bromide 13b underwent Pd-catalyzed allylic alkylation to
deliver the a-quaternary product (14b) in 83% yield and
ꢀ
96% ee. The surprisingly robust Caryl Br bond served as
a handle for a subsequent Negishi cross-coupling. The
compatibility of aryl bromides in our allylic alkylation
reactions, along with the identification of cross-coupling
conditions that do not isomerize the allyl group, provide
a powerful platform for the convergent synthesis of complex
organic molecules. Additionally, by completing formal syn-
theses of (+)-aspidospermidine (2) and (ꢀ)-quebrachamine
(3), we demonstrate the ability of the DHPI scaffold to
provide divergent, enantioselective access to structurally
diverse alkaloid frameworks. Efforts to expand upon the
capabilities of allylic alkylation/cross-coupling sequences and
to further exploit the utility of DHPIs in the context of
alkaloid total synthesis will be reported in due course.
Acknowledgements
The authors wish to thank NIH-NIGMS (R01GM080269),
Amgen, the Gordon and Betty Moore Foundation, and
Caltech for financial support. B.P.P. thanks the NSF for
a predoctoral fellowship (Grant DGE-1144469). Y.N. thanks
Toray Industries Inc. for a postdoctoral fellowship. The
authors thank Mona Shahgholi and Naseem Torian for mass
spectrometry assistance, and Dr. Scott Virgil (Caltech) and
the Caltech Center for Catalysis and Chemical Synthesis, for
instrumentation assistance.
Scheme 4. Completion of the synthesis of (ꢀ)-goniomitine.
Having completed the total synthesis of (ꢀ)-goniomitine
(1), we sought to leverage the flexibility of the DHPI scaffold
by exploiting the chemoselectivity in cyclizations of an indole
with a C2-tethered iminium functionality (Scheme 1B).
Indeed, the synthesis of 14c completes an enantioselective
formal synthesis of (+)-aspidospermidine (2, Scheme 5).[6c]
Keywords: alkaloids · allylic alkylation · asymmetric catalysis ·
quaternary centers · total synthesis
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[16] Multiple parameters were investigated for the Suzuki reaction,
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Received: August 19, 2016
Revised: September 7, 2016
Published online: && &&, &&&&
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Total Synthesis
B. P. Pritchett, J. Kikuchi, Y. Numajiri,
B. M. Stoltz*
&&&& — &&&&
Enantioselective Pd-Catalyzed Allylic
Alkylation Reactions of
Dihydropyrido[1,2-a]indolone Substrates:
Efficient Syntheses of (ꢀ)-Goniomitine,
(+)-Aspidospermidine, and (ꢀ)-
Quebrachamine
Magnum (DH)PI: Application of
catalytic enantioselective total synthesis
dihydropyrido[1,2-a]indolone (DHPI)
substrates in Pd-catalyzed asymmetric
allylic alkylation chemistry enables rapid
access to multiple alkaloid frameworks in
an enantioselective fashion. The first
of (ꢀ)-goniomitine, along with divergent
formal syntheses of (+)-aspidospermi-
dine and (ꢀ)-quebrachamine are
reported.
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!