Total Synthesis of (+)-Aspidospermidine

Article abstract of DOI:10.1021/acs.orglett.9b02346

A facile asymmetric total synthesis of (+)-aspidospermidine has been developed, which is accomplished in 11 steps in an overall yield of 9.6%. Key steps involve a palladium-catalyzed enantioselective decarboxylative allylation to install the quaternary ca

Full text of DOI:10.1021/acs.orglett.9b02346

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Total Synthesis of (+)-Aspidospermidine
Hongjin Xu,† He Huang,† Cui Zhao,† Chuanjun Song,*,† and Junbiao Chang*,†,‡
†College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, China
‡Henan Key Laboratory of Organic Functional Molecules and Drug Innovation, Xinxiang 453007, China
S
* Supporting Information
ABSTRACT: A facile asymmetric total synthesis of (+)-aspidospermidine has been developed, which is accomplished in 11
steps in an overall yield of 9.6%. Key steps involve a palladium-catalyzed enantioselective decarboxylative allylation to install the
quaternary carbon stereocenter and a highly efficient reductive amination−carbonyl reduction−dehydration−intramolecular
conjugate addition cascade to build the cis D-ring.
he Aspidosperma alkaloids, originally isolated from the
plant species Aspidosperma genus which grows wild in
on an intramolecular capture of an intermediary iminium ion
by a carbamate.4c Later, a similar ring-closing strategy was
applied by She5q,7 and Shao4m for the synthesis of
( )-aspidospermidine and (−)-aspidospermidine, respectively.
However, multistep functional group transformations under
controlled reaction conditions were required. As part of our
continued interest in natural product synthesis,8 we herein
report a concise total synthesis of (+)-aspidospermidine
featuring a one-pot reductive amination−carbonyl reduc-
tion−dehydration−intramolecular conjugate addition cascade
to build the cis D-ring under mild reaction conditions. Such a
strategy has never been applied previously in the synthesis of
Aspidosperma alkaloids.
T
South America, constitute the largest family of monoterpene
indole alkaloids (>250 members).1 Because of their unique
pharmacological and biological activities, they have long been
used in traditional medicine as antimalaria, analgesic, anti-
inflammatory, anticancer, and psychotropic drugs.2 Aspido-
spermidine 1 (Scheme 1),3 which possesses the iconic
Scheme 1. Retrosynthetic Analysis of (+)-Aspidospermidine
As outlined retrosynthetically in Scheme 1, (+)-aspidosper-
midine 1 could be obtained from amide 2 via intramolecular
alkylation. Amide 2 could be generated by selective N-
acylation of 3. Tetracyclic intermediate 3 was expected to arise
from keto-aldehyde 4 via a one-pot sequence involving
selective reductive amination of the aldehyde functionality,
reduction of the carbazolone keto group, indolic nitrogen-
assisted dehydration, and intramolecular capture of the
intermediary iminium ion with the amino group introduced
during the reductive amination step. This key transformation
was challenging in two aspects. First, the amino group from the
initial reductive amination reaction could likely attack the
carbazolone keto functionality to generate a tetracyclic imine
intermediate,9 the reduction of which would provide the
unwanted trans D-ring.4c Second, conjugation of the indolic
nitrogen made the carbazolone keto group less electrophilic,
and its reduction normally required the use of strong reducing
agents such as LiAlH4. If this is necessarily the case, a
tetrahydropyran rather than the piperidine D-ring would be
formed.4m,5q,7 Keto-aldehyde 4 could be derived from
pentacyclic framework of the Aspidosperma alkaloid, has
stimulated considerable attention among the synthetic
community4−6 and serves as a testing ground for the
development of new synthetic strategies toward more complex
members of this family.4b,f,h,j−n,q−s The most proven
approaches for the synthesis of aspidospermidine include
final B-ring closure via Fisher indole synthesis using a CDE
tricyclic ring system and phenylhydrazine4d,f,h,o−q,5f−k and CE-
ring formation from a ABD-ring derivative.4a,b,k,n,5b,e,m−o
Despite all of these achievements, the development of an
efficient and enantioselective approach to the synthesis of
̈
Aspidosperma alkaloids is still desirable. In 1994, Desmaele and
d’Angelo developed a novel ring-closing sequence toward the
synthesis of (+)-aspidospermidine, in which the crucial cis D-
ring was assembled into an ABC carbazolone derivative based
Received: July 8, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02346
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
carbazolone 5, which in turn was generated from β-ketoester 6
through palladium-catalyzed enantioselective decarboxylative
allylation.10,4m
Our synthesis commenced with the commercially available
carbazolone 7, which was transformed into 8 following a two-
step literature procedure (Scheme 2).5q Treatment of
benzyloxy ethylamine and benzylamine reacted with 4 to give
exclusively the mono-reductive amination products 11a and
11b, respectively, in good isolated yields (entries 1−4).
Treatment of 11a or 11b with LiAlH4 resulted in complete
decomposition, while no reaction occurred when NaBH4 was
applied. Delightfully, desired tetracyclic compound 10b could
be isolated in 8% yield (apart from 11b in 70% yield) when 0.5
equiv of TFA was added to the reaction system of 4,
benzylamine, NaBH3CN, and THF (entry 6).11 A slightly
better result was obtained when NaBH(OAc)3 was applied
(entry 7). The cis configuration of the D-ring in compound
10b was assigned on the basis of NOE correlations of Ha with
the protons of the ethyl group at C-20. Because no trace of
corresponding tetracyclic 10a was observed with benzyloxy
ethylamine (entry 5), benzylamine was used as reactant for the
optimization of reaction conditions. While 10b could be
isolated in 30% yield in the presence of AcOH (entry 8), 11b
was generated exclusively when a stronger acid TsOH was
applied (entry 9). Further optimization indicated that the best
result was obtained when 1.0 equiv of AcOH was applied
(entry 10 vs entries 8 and 11). Surprisingly, formation of 10b
was completely hampered when MeOH was used as a solvent
(entry 12). Finally, the amount of NaBH(OAc)3 and reaction
temperatures were briefly explored, yet a better result could
not be obtained (entries 13−15 vs entry 10).
Scheme 2. Synthesis of Keto-Aldehyde Intermediate 4 for
the Key Cascade Reaction
A plausible mechanism for the formation of 10b is depicted
in Scheme 3. Reductive amination of the aldehyde
functionality in 4 provided 11b. Interaction of boron
tetraacetate and water would regenerate acetic acid, which
preferentially protonated the amino group in 11b to provide
intermediate B. Intramolecular proton transfer of B generated
C with a more electrophilic carbonyl group, which was reduced
by NaBH(OAc)3 to give intermediate D. The indolic nitrogen
atom-assisted elimination yielded E, which spontaneously
cyclized via intramolecular conjugate addition to generate 10b.
With key tetracyclic intermediate 10b in hand, we directed
our attention to the construction of the E-ring to complete the
total synthesis of (+)-aspidospermidine (Scheme 4). Consec-
compound 8 with allyl chloroformate in the presence of
LDA provided keto-ester 6 in 92% yield. The palladium-
catalyzed decarboxylative allylation was then explored, and allyl
carbazolone 5 could be obtained in an optimized 82% yield
and 82% ee by treatment of 6 with the complex derived from
Pd2(dba)3 and (S)-tBu-PHOX.4m,10 Hydroboration−oxidation
of the double bond in compound 5 provided alcohol 9, which
was oxidized to keto-aldehyde 4 with Dess−Martin period-
inane in an excellent yield.
With keto-aldehyde 4 in hand, the key cascade reaction for
the construction of the D-ring was investigated, and the results
are listed in Table 1. Under conventional conditions with
either NaBH(OAc)3 or NaBH3CN as the reductant, both
Table 1. Optimization of Reaction Conditions for the Construction of the D-Ring
entry
R
reductant (equiv)
additive (equiv)
solvent
T (°C)
10 (% yield)
11 (% yield)
1
2
3
4
5
6
7
8
BnO(CH2)2
BnO(CH2)2
Bn
Bn
NaBH(OAc)3 (3)
NaBH3CN (3)
NaBH(OAc)3 (3)
NaBH3CN (3)
NaBH3CN (3)
NaBH3CN (3)
NaBH(OAc)3 (3)
NaBH(OAc)3 (3)
NaBH(OAc)3 (3)
NaBH(OAc)3 (3)
NaBH(OAc)3 (3)
NaBH(OAc)3 (3)
NaBH(OAc)3 (4)
NaBH(OAc)3 (3)
NaBH(OAc)3 (3)
−
−
−
−
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
MeOH
THF
THF
THF
30
30
30
30
30
30
30
30
30
30
30
30
30
20
40
10a (0)
10a (0)
10b (0)
10b (0)
10a (0)
10b (8)
10b (13)
10b (30)
10b (0)
10b (61)
10b (40)
10b (0)
10b (11)
10b (38)
10b (46)
11a (91)
11a (81)
11b (88)
11b (85)
11a (83)
11b (70)
11b (67)
11b (52)
11b (85)
11b (23)
11b (36)
11b (80)
11b (61)
11b (44)
11b (32)
BnO(CH2)2
TFA (0.5)
TFA (0.5)
TFA (0.5)
AcOH (0.5)
TsOH (0.5)
AcOH (1.0)
AcOH (1.5)
AcOH (1.0)
AcOH (1.0)
AcOH (1.0)
AcOH (1.0)
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
9
10
11
12
13
14
15
B
DOI: 10.1021/acs.orglett.9b02346
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Proposed Mechanism for the Formation of 10b
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: chjsong@zzu.edu.cn.
*E-mail: changjunbiao@zzu.edu.cn.
ORCID
Chuanjun Song: 0000-0001-7733-578X
Junbiao Chang: 0000-0001-6236-1256
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to NSFC-Henan (U1804283) for
financial support.
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■
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02346.
General procedure, analytical and spectroscopic data,
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8, 9, 10b, 11a, 11b, and 12, and HPLC spectra of
compound 5 (PDF)
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DOI: 10.1021/acs.orglett.9b02346
Org. Lett. XXXX, XXX, XXX−XXX