Enantioselective palladium-catalyzed decarboxylative allylation of carbazolones: Total synthesis of (-)-aspidospermidine and (+)-kopsihainanineA

Article abstract of DOI:10.1002/anie.201209878

Functionalized chiral carbazolones with α-quaternary carbon centers are formed through the ligand-controlled Pd-catalyzed enantioselective decarboxylative allylic alkylation of carbazolones (see scheme). This catalytic asymmetric reaction was employed as the key step in the total synthesis of aspidospermidine and (+)-kopsihainanineA. Copyright

Full text of DOI:10.1002/anie.201209878

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Chemie
DOI: 10.1002/anie.201209878
Alkaloid Synthesis
Enantioselective Palladium-Catalyzed Decarboxylative Allylation of
Carbazolones: Total Synthesis of (ꢀ)-Aspidospermidine and
(+)-Kopsihainanine A**
Zeqian Li, Shaoxiong Zhang, Shoutao Wu, Xiaolei Shen, Liwei Zou, Fengqun Wang, Xiang Li,
Fangzhi Peng, Hongbin Zhang, and Zhihui Shao*
The Aspidosperma alkaloids represent the largest family of
monoterpenoid indole alkaloids, with more than 250 mem-
bers isolated from various biological sources.[1] Because of
their structural and stereochemical complexity, their central
biosynthetic role in plants, and their interesting biological
activity, Aspidosperma alkaloids have attracted attention
from the synthetic community for over 40 years and have
remained a focus of extensive research activity to the present
day.[2] Aspidospermidine (Scheme 1), the archetypal member,
is among the most highly sought Aspidosperma alkaloid
Scheme 1. Selected Aspidosperma and Kopsia alkaloids. The core struc-
ture of these alkaloids is the piperidine-fused hydrocarbazole ring
system.
targets. Because it comprises the basic skeletal features of this
family of natural products, particularly the complex and
characteristic pentacyclic ABCDE framework, it has been the
primary target of most syntheses toward Aspidosperma
alkaloids and has served as the ideal proving ground for the
development of new synthetic methods and strategies.[3,4]
Since the 1960s,[3a] aspidospermidine has been synthesized
by over 40 research groups in racemic[3] and nonracemic[4]
forms. The majority of these syntheses follow one of the
following three synthetic strategies: 1) the Fischer indole
approach used by Stork and co-workers,[3a] 2) the indoloqui-
nolizidine rearrangement approach used by Harley-Mason
and co-workers,[3c] and 3) E-ring-closing approach.[3p] Despite
the numerous successful syntheses of aspidospermidine, there
are only few reports on the employment of catalytic
asymmetric strategies.[4f,l] In 2002, Rawal and co-workers
reported an elegant catalytic enantioselective total synthesis
of (+)-aspidospermidine. In this approach, a highly enantio-
selective Diels–Alder reaction between 1-amino-3-siloxy-
diene and 2-ethylacrolein catalyzed by the chiral CrIII–salen
complex developed by Jacobsen was exploited to form the
C ring, which bears a quaternary carbon center at C4, and
subsequently the DABE ring system was formed sequentially
(the E-ring-closing approach).[4f] Recently, MacMillan and co-
workers described an impressive organocatalytic asymmetric
total synthesis of (+)-aspidospermidine based on a cascade
Diels–Alder/cyclization sequence.[4l] The development of
a general, efficient, and conceptually new strategy for the
catalytic enantioselective total synthesis of aspidospermidine
still remains important and challenging.
We sought to develop a general catalytic asymmetric
strategy for the synthesis of aspidospermidine and related
natural products in a concise and divergent manner. In this
regard, we selected kopsihainanine A, a member of the
Kopsia alkaloid family, which has not been synthesized in
asymmetric form, as our second target to demonstrate the
feasibility of our strategy. Structurally, aspidospermidine and
kopsihainanine A contain a common functionalized tetracy-
clic framework that features a hydrocarbazole core with
[*] Z. Li,[+] S. Zhang,[+] S. Wu,[+] X. Shen, L. Zou, F. Wang, X. Li, F. Peng,
Prof. H. Zhang, Prof. Z. Shao
Key Laboratory of Medicinal Chemistry for Natural Resource
(Yunnan University), Ministry of Education, School of
Chemical Science and Technology, Yunnan University
Kunming, Yunnan 650091 (China)
E-mail: zhihui_shao@hotmail.com
[+] These authors contributed equally to this work.
a
crucial all-carbon quaternary stereogenic center
(Scheme 1). In addition to the formation of this all-carbon
quaternary stereogenic center, another key challenge for the
divergent asymmetric synthesis is the cis-fused C/D ring in
aspidospermidine and several other members of the family of
Aspidosperma alkaloids (such as limaspermidine, cylindro-
carine, minovincine, and vincadifformine), whereas the C’/D’
ring in kopsihainanine A is trans-fused (Scheme 1).
To achieve our challenging goal, we developed a diversity-
oriented retrosynthetic analysis (Scheme 2). We planned to
form both the cis-fused C/D ring in aspidospermidine and the
trans-fused C’/D’ ring in kopsihainanine A from the common
[**] We gratefully acknowledge financial support from the NSFC
(20962023, 21162034, 20832005), the Program for New Century
Excellent Talents in University (NCET-10-0907), and Yunnan
government (2012FB114). We sincerely thank Prof. Yong Tang and
Shuli You at Shanghai Institute of Organic Chemistry, CAS, and Prof.
Yonggui Zhou at Dalian Institute of Chemical Physics, CAS, for
valuable discussions. We also thank Prof. Kun Gao at Lanzhou
University for providing us with the spectrum of the natural sample
of kopsihainanine A.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201209878.
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Scheme 3. Selected substrates for the decarboxylative allylation.
a) Stoltz, Ref. [6b]; b) Trost, Ref. [6i]; c) Trost, Ref. [6i]; d) Stoltz,
Ref. [6e].
Scheme 2. Diversity-oriented retrosynthetic analysis.
target molecules. Unlike the decarboxylative allylic alkylation
with simple cyclic ketones,[6b] the decarboxylative allylic
alkylation with carbazolones is more challenging than it
appears at first glance because of the well-known nucleophi-
licity at C3 of indoles[10] and its influence on the proposed
decarboxylative allylic alkylation reaction. We reasoned that
by combining a source of Pd0 with an adequately chosen chiral
ligand, this reaction would be possible.
To explore the feasibility of the proposed synthetic
strategy, we began our study of the Pd-catalyzed decarbox-
ylative allylic alkylation of carbazolones with substrate 1a
(Table 1). Formation of the C3 allylation product was not
observed, however, the unexpected decarboxylative proto-
nation product 2a’ was obtained. Interestingly, when Trostꢀs
ligand L1, which is known to be effective in decarboxylative
allylation reactions of allyl-b-keto esters,[6f,i] was used as the
chiral ligand, the expected product 2a was not obtained. In
contrast, the decarboxylative protonation product 2a’ was
obtained solely (Table 1, entry 1). During the examination of
chiral tetracyclic intermediate C. This intermediate is also
potentially useful for the synthesis of other Aspidosperma
alkaloids, such as limaspermidine and minovincine
(Scheme 1), which can be obtained through diverse trans-
formations at the allyl and amide groups. Intermediate C
would be assembled diastereoselectively and enantioselec-
tively from the highly functionalized carbazolone D through
hydrolysis of the nitrile group followed by selective reduction
and a highly cis-selective cyclization. The key feature of this
approach is the catalytic enantioselective decarboxylative
allylic alkylation of the highly functionalized carbazolone D,
which features an a-quaternary carbon center [Eq. (1)]. After
the development of this reaction, we applied the methodology
to the divergent asymmetric synthesis of natural products.
Both, Aspidosperma alkaloid (ꢀ)-aspidospermidine and
Kopsia alkaloid (+)-kopsihainanine A were synthesized con-
cisely in a catalytic enantioselective fashion, and the absolute
configuration of the latter was unambiguously confirmed.
Table 1: Optimization of reaction conditions.[a]
Recently, transition-metal-catalyzed asymmetric decar-
boxylative allylation has emerged as a powerful transforma-
tion in organic synthesis,[5–7] chiefly because of the pioneering
efforts of the groups of Stoltz,[6a,b] Tunge,[6f] Trost,[6h–i] Naka-
mura,[6l] Murakami,[6m] You,[6t] and others.[6n–u] While a series
of different types of substrates, including cyclic ketones,
vinylogous thioesters, and lactams (Scheme 3), have been
employed successfully in this transformation, there is no
report on the catalytic enantioselective decarboxylative
allylic alkylation of heterocyclic carbazolones.
Our work in this field is based on the recognition of
heterocyclic carbazolones,[8] such as E, as a valuable class of
substrates for the Pd-catalyzed enantioselective decarboxy-
lative allylic alkylation [Eq. (1)], thus providing the chiral a-
allylated carbazolone D with the key quaternary carbon
center, a motif that is common in natural products and
medicinal chemistry. The catalytic asymmetric formation of
chiral all-carbon quaternary centers is one of the most
challenging and dynamic research areas in modern organic
synthesis.[9] To the best of our knowledge, there is no catalytic
method available for the asymmetric synthesis of this class of
Entry
L
Solvent
T
[8C]
2a:2a’ Yield of 2a [%][b] e.r. of 2a[c]
1
2
3
4
5
6
7
8
9
10
L1 toluene
L2 toluene
L3 toluene
L4 toluene
L5 toluene
L2 THF
L2 m-xylene 70
L2 benzene 70
L2 toluene
L2 toluene
70
70
70
70
70
70
0:100
19:1
6:1
0
–
96:4
93
75
80
66
51
64
74
57
67
13:87
30:70
61:39
94.5:5.5
96.5:3.5
88:12
94:6
6:1
3:1
1.6:1
3.4:1
4.6:1
1.7:1
2.7:1
55
80
95.5:4.5
[a] Reaction conditions: 1a (100 mg, 0.24 mmol) in solvent (7.5 mL).
[b] Yield of isolated product. [c] Determined by HPLC analysis on a chiral
stationary phase (Chiralpak AD-H). Entry in bold marks optimized
reaction conditions. dba=trans,trans-dibenzylideneacetone.
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other chiral ligands, we found that chiral ligands have a crucial
effect on the results of the decarboxylative process (Table 1,
entries 1–5). Among them, the chelating P/N ligands L2 and
L3 (phosphinooxazolines (PHOX)), which were developed
by Pfaltz, Helmchen, and Williams,[11] and used by Stoltz[6a] in
the decarboxylative allylic alkylation of cyclic ketones, gave
the desired product 2a in moderate to good results. The
solvents and temperatures also had effects on the result of the
reaction (Table 1, entries 6–10). Finally, the desired allylation
product 2a was obtained in 93% yield with e.r. = 96:4 using
ligand L2 in toluene at 708C (Table 1, entry 2).
[Eq. (2)]. The absolute configurations of the allylation
products were assigned on the basis of X-ray crystal-structure
analysis of product 2e (Flack parameter= 0.1(3)).[13] Com-
pound 2b was quantitatively transformed into the chiral
polycyclic product 5 through a tandem sequence of the
selective reduction of the ketone moiety and a cyclization[14]
without loss of the enantiomeric purity.[15]
With the optimized reaction conditions in hand, we
investigated the scope of this asymmetric allylic alkylation.
A variety of carbazolone substrates were converted smoothly
into the desired products in good yields with high enantio-
selectivity (e.r. = 92:8–98.5:1.5; Scheme 4). The reaction is
Having developed this key asymmetric decarboxylative
allylation reaction, we turned our attention to the divergent
asymmetric natural product synthesis. Firstly, we developed
a concise enantioselective synthesis of Aspidosperma alkaloid
(ꢀ)-aspidospermidine (Scheme 5). Mild hydrolysis of the
nitrile group of intermediate 2a gave chiral amide 6, which
was then transformed into the tetracyclic intermediate 7 in
excellent yield without loss of enantiomeric purity through
the chemoselective reduction of the ketone group followed by
diastereoselective cyclization.[14] Following the oxidation to 8,
the angular ethyl side chain was introduced by mercaptalation
and subsequent hydrogenation with Raney nickel to give 10.
Reduction of the amide group with LAH and subsequent N-
debenzylation with Na/NH3 resulted in the formation of the
enantiopure tetracyclic intermediate 12 in 85% yield over two
steps. Following the procedure developed by Toczko and
Heathcock,[3o] compound 12 was transformed into (ꢀ)-
aspidospermidine, which was obtained in 30% yield over
three steps. All spectroscopic and optical data of the synthetic
Scheme 4. Pd-catalyzed enantioselective decarboxylative allylic alkyla-
tion. [a] [Pd2(dba)3] (3.5 mol%), L2 (8.75 mol%). [b] At 558C.
highly tolerant toward a wide range of functionalities (e.g.,
ꢁ
CH2CH2CN, CH2CH2CO2Et, CH2C H, CH2CO2Et and CH3).
The presence of a 1,6-enyne moiety in compound 2c is of
particular interest because of the rich chemistry of 1,6-
enynes.[12] Substituted allyl groups can also be incorporated,
leading to products 2 f and 2g in good yields and high
enantioselectivity (e.r. = 98.5:1.5). Moreover, substrates with
different substituents, including CH3, OCH3, and CF3 groups
on the benzene ring, also afforded the desired products 2h–2j
in good yields and high enantioselectivity (e.r. > 95:5). On the
other hand, the Pd-catalyzed asymmetric allylic alkylation of
compound 3 also proceeded successfully to provide the
corresponding product 4 in good yield and enantioselectivity
Scheme 5. Catalytic enantioselective total synthesis of (ꢀ)-aspidosper-
midine. Reaction conditions: a) HCO2H, RT; b) LiAlH4, THF, ꢀ208C,
then HCl (2m); c) K2OsO4·2H2O, NMO, THF/H2O (1:1), then NaIO4;
d) 1,2-ethanedithiol, BF3·Et2O, CH2Cl2; e) Raney nickel, H2, EtOH,
608C; f) LiAlH4, Et2O, reflux; g) Na/NH3, THF, ꢀ788C. NMO=N-
methylmorpholine-N-oxide.
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(ꢀ)-aspidospermidine were in accordance with those
reported previously.[4k]
In summary, we have demonstrated the feasibility of
divergent total syntheses of both Aspidosperma and Kopsia
alkaloids in combination with transition-metal asymmetric
catalysis. Specifically, we have developed the first Pd-cata-
lyzed chemo- and enantioselective decarboxylative allylic
alkylation of carbazolone enolates, leading to highly func-
tionalized chiral carbazolones that feature an a-quaternary
carbon center, which are found in numerous natural products
and pharmacologically active compounds, in good yields with
high enantioselectivity (e.r. of up to 98.5:1.5). With this
protocol, a concise catalytic enantioselective synthesis of (ꢀ)-
aspidospermidine was accomplished. A catalytic asymmetric
strategy for the synthesis of Aspidosperma alkaloids has also
been established. Secondly, the catalytic enantioselective
total synthesis of Kopsia alkaloid kopsihainanine A was
achieved successfully from a common intermediate, and its
absolute configuration was unambiguously confirmed. Fur-
ther application of this methodology to the asymmetric
synthesis of other members of Aspidosperma alkaloids and
investigation of new catalytic asymmetric reactions involving
carbazolones are currently under way in our research group.
The present work also comprises catalytic asymmetric
formal syntheses of (+)-quebrachamine[3g] and (ꢀ)-vincadif-
formine,[4l] as they can be obtained in two steps from the
tetracyclic intermediate 12 and the synthetic (ꢀ)-aspidosper-
midine, respectively, by established methods.
We further extended our strategy to the enantioselective
total synthesis of kopsihainanine A (Scheme 6), which was
recently isolated by Gao and co-workers[16] from the leaves
and stems of a Chinese medicinal plant, Kopsia hainanensis.[17]
Subsequently, She, Xie, and co-workers reported the synthesis
of racemic kopsihainanine A.[14] To date, no asymmetric total
synthesis of kopsihainanine A has been reported.
Received: December 11, 2012
Published online: March 8, 2013
Keywords: aspidospermidine · asymmetric catalysis ·
total synthesis · kopsihainanine A · natural products
.
Scheme 6. Catalytic enantioselective total synthesis of (+)-kopsihaina-
nine A and confirmation of its absolute configuration. Reaction con-
.
ditions: a) BH3 THF, ꢀ208C, then NaBO3, RT; b) MsCl, Et3N, CH2Cl2,
08C, then NaH, DMF, 08C!RT; c) LDA, Na2SO3, O2, 08C!RT;
d) AlCl3, toluene; e) saturated aqueous solution of Rochelle salt, RT,
overnight. DMF=N,N-dimethylformamide, LDA=lithium diisopropyl-
amide, Ms=methanesulfonyl.
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Alkaloids, Wiley, Chichester, 1983; b) J. E. Saxton in The
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We obtained chiral compound 15 through a three-step
transformation of key intermediate 7. Following the proce-
dure developed by She, Xie, and co-workers,[14] treatment of
15 with AlCl3 in anisole at 1008C supposedly gave the target
molecule kopsihainanine A. Interestingly, this synthetic mol-
ecule was insoluble in CHCl3, whereas the natural kopsihai-
nanine A that was isolated by Gao and co-workers was
soluble in CHCl3.[17] Furthermore, we noticed that the
molecule previously synthesized by She, Xie, and co-workers
was also insoluble in CHCl3.[14] To uncover the reason behind
this rather puzzling result, we also synthesized the target
molecule of She, Xie, and co-workers. Our results were in
accordance with their report[14] that this synthetic racemic
molecule was indeed insoluble in CHCl3, but soluble in
DMSO. After extensive analysis and investigations, we
reasoned that the synthetic molecules are not kopsihainani-
ne A, but instead its aluminium complex. To our delight, the
treatment of these synthetic compounds with Rochelle salt
gave (+)-kopsihainanine A and (ꢂ)-kopsihainanine A, which
were both soluble in CHCl3. All spectroscopic data (1H NMR
and 13C NMR) were in accordance with Gaoꢀs report.[17] By
comparing the optical rotation of the synthetic molecule with
natural kopsihainanine A, the absolute configuration of the
latter was unambiguously confirmed. Finally, we accom-
plished the first catalytic enantioselective total synthesis of
natural (+)-kopsihainanine A.
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