Enantioselective Total Synthesis and Absolute Configuration Assignment of (+)-Tronocarpine Enabled by an Asymmetric Michael/Aldol Reaction

Article abstract of DOI:10.1002/anie.201914868

We present the first asymmetric total synthesis and absolute configuration determination of (+)-tronocarpine. The [6.5.7.6.6] pentacyclic core was constructed at an early stage by using a sequential cyclization strategy through a newly developed catalytic asymmetric Michael/aldol cascade to build the aza[3.3.1]-bridged cycle and a tandem reduction/hemiamidation procedure to assemble the seven-membered lactam. The side-chain functionalities were incorporated at a late stage by several appropriately orchestrated manipulations under mild conditions. The synthesis of enantiomerically pure (+)-tronocarpine was achieved through a 20-step longest linear sequence from tryptamine.

Full text of DOI:10.1002/anie.201914868

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Enantioselective Total Synthesis and Absolute Configuration
Assignment of (+)-Tronocarpine Enabled by an Asymmetric
Michael/Aldol Reaction
Authors: Fu-She Han, Dong-Xing Tan, Jie Zhou, and Chao-You Liu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201914868
Angew. Chem. 10.1002/ange.201914868
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10.1002/anie.201914868
Angewandte Chemie International Edition
DOI: 10.1002/anie.200((will be filled in by the editorial staff))
Natural Product Synthesis
Enantioselective Total Synthesis and Absolute Configuration Assignment
of (+)-Tronocarpine Enabled by an Asymmetric Michael/Aldol Reaction
Dong-Xing Tan,a,b Jie Zhou,a,c Chao-You Liu,a and Fu-She Han*,a,b
Abstract: We present the first asymmetric total synthesis and
absolute configuration determination of (+)-tronocarpine. The
[6.5.7.6.6]-pentacyclic core was constructed at early stage by using
a sequential cyclization strategy via a newly developed catalytic
asymmetric Michael/aldol cascade to build the aza[3.3.1]-bridged
cycle and a tandem reduction/hemiamidation procedure to assemble
the seven-membered lactam. The side-chain functionalities were
incorporated at a late stage by several appropriately orchestrated
manipulations under mild conditions. The synthesis of enantiopure
(+)-tronocarpine was achieved within a 20-step longest linear
sequence from tryptamine.
due to the paucity of natural sources, which can only be addressed
by chemical synthesis. Thus, we chose (+)-tronocarpine 1 as our
first target for synthesis.
OH
H
O
NH
H
CO2Me
Me19
18
5
4
NH
H
CO2Me
21NH
R
H
15
O
10
16
17
N 2
3
N
H
R
N
H
14
12
MeO
OH
H
OH
OH
R = OMe, Chippiine (2)
R = H, Demethoxychippiine (3)
Tronocarpine (1)
Dippinine A (4)
O
O
NH
Me
Me
N
3
4
N
H
CO2Me
H
H
H
The plants of the genus Tabernaemontana have yielded a group of
CO2Me
structurally novel chippiine-dippinine-type post-iboga indole
alkaloids[1] (Figure 1, 1‒6). The members of this subfamily possess
a strained [6.5.7.6.6]-pentacyclic core fused around a hemiaminal-
containing aza[3.3.1]-bridged cycle, which represents an unique
skeletal class in indole alkaloids. The unique ring skeletal class
together with the existence of multiple stereocenters with one being
an all-carbon quaternary stereocenter at C16 bridgehead and one
labile hemiaminal at C3 composes the synthetic challenges.
Therefore, these molecules are ideal targets for the development of
new synthetic strategies and methodologies. Biologically, this type
of natural products display appreciable cytotoxicity against either
vincristine-sensitive or resistant KB cells.[1b] Notably, the latter
property is appealing because reversing multidrug resistance
constitutes a major hurdle in cancer therapy.
Although the chippiine-dippinine-type alkaloids have garnered
much attention since their structures have been exposed to synthetic
community for over 30 years, a total synthesis has not been reported
except for many racemic synthetic efforts toward the construction of
the fused polycyclic skeleton[2] and one semisynthesis of ent-
dippinine B from the naturally available (+)-catharanthine[3] (Figure
1, 7). With our constant interest in the synthetic study of indole
natural products,[4] we set this type of alkaloids as our target for
synthesis. Among the members, tronocarpine[1c] (1) is a skeletal
variant in the subfamily whose major structural difference from
other siblings is, unlike the N4‒C21 connection in 2‒6, the linkage of
the seven-membered lactam to the bridgehead quaternary carbon C16.
In addition, its absolute configuration has not yet been determined
N
H
N
H
1 N
Me
CO2Me
H
OH
OH
Dippinine B (5)
(+)-Catharanthine (7)
Dippinine C (6)
Figure 1. Selected structures of chippiine-dippinine alkaloids.
An insight into the reported unsuccessful efforts[2] suggests that a
feasible route should be such one that could build the strained
polycyclic skeleton at the early stage, but leaving the incorporation
of labile and/or reactive functionalities such as hemiaminal and
acetyl groups at the late stage under the conditions as mild as
possible. Such a strategy takes the advantage of diminishing the
possible side-reactions arising from the excessively strained ring
tension and the lability of side-chain functional groups. Accordingly,
we designed a retrosynthetic strategy as shown in Figure 2A. The
hemiaminal and acetyl groups in 1 were to be introduced at the final
stage through the manipulation of indole lactam and alkynyl group
in the advanced intermediate A. The alkynyl functionality in A
could be incorporated via Sonogashira coupling from enone B,
which might be synthesized through Saegusa-type oxidation of
ketone C. We planed to construct the seven-membered lactam in C
by adopting a reduction/amidation cascade of a cyano and amino
group from the aza[3.3.1]-bridged cycle D. Scission of D led to
nitrile E, whose asymmetric Michael/aldol cascade with acrolein
would furnish D. Finally, E might be derived from the commercially
available tryptamine.
In the devised strategy, the asymmetric Michael/aldol cascade
reaction for constructing chiral aza[3.3.1]-bridged cycle D is crucial.
If successful, it would promote the development of enantioselective
syntheses of other related natural products. However, to our
knowledge, such reaction has not been investigated for the indole-
based substrates although a few examples using the cyclic 1,3-
dicarbonyl substrates possessing sufficiently high reactivity as well
as well-differentiated Michael and aldol reaction sites have been
reported.[5] The key challenges for the indole substrate E to be
investigated herein would arise from: (i) the base-mediated
regioselective generation of carbon anion with the existence of a
similarly weak acidic proton at C14; and (ii) the following
regioselective Michael addition at the sterically more hindered
tertiary C16 vs. secondary C14; (iii) the influence of the amino group
at N4 and base sensitive indoyl lactam at N1[6] under basic conditions;
(iv) finally, the efficient discrimination of enantioface due to the
nearly planar conformation of the substrates.
[a]
D.-X. Tan, J. Zhou, C.-Y. Liu, and Dr. F.-S. Han (D. X. Tan and
J. Zhou contributed equally to this work)
CAS Key Lab of High-Performance Synthetic Rubber and its
Composite Materials, Changchun Institute of Applied Chemistry
Chinese Academy of Sciences, 5625 Renmin Street
Changchun, Jilin 130022 (China)
E-mail: fshan@ciac.ac.cn
[b] D.-X. Tan
University of Science and Technology of China, Hefei, Anhui,
230026 (China)
[c]
J. Zhou
The University of Chinese Academy of Sciences, Beijing 100864
(China)
Supporting information for this article is available on the WWW
1
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10.1002/anie.201914868
Angewandte Chemie International Edition
Sonogashira
coupling
Saegusa
oxidation
A)
16 vs C-17) and H-bond donor (i.e, C-6 vs C-19 to C-23 and C-24
vs C-25) on the asymmetric reaction suggests that appropriate
bifunctional ion-paring/H-bonding interaction is essentially
important for the desired reaction. Stimulated by these outcomes, we
attempted to improve the reaction efficiency by varying the N-
protecting group tethered at C3 position on the substrates 12 aiming
at tuning the nature of H-bonding. Eventually, this variation
associated with a minor change of the general parameters screened
out in Figure 3 enabled us to establish a set of conditions (see Figure
4 and Table S1 for details) that could achieve the asymmetric
Michael/aldol cascade reaction in good yield and excellent ee.
Namely, with the use of Phth as protecting group, 14b was obtained
in 56% yield over two steps with 94% ee. Most importantly, the
reaction could be reliably performed on multigram scale without
compromising the yield and ee (vide infra).
O
Me
PG
PG
NH
N
N
O
O
O
N
N
N
O
OH
H
O
O
Tronocarpine (1)
A
B
Reductive
amidation
Asymmetric
Michael/aldol
cascade
NHPG
NHPG
PG
4
N
CN
CN
O
16
N
N
O
N
O
14
OH
O
O
C
E
D
B)
H-Bonding
PG
H-Bonding
H
H
PG
N
O
NHCO2Me
a) NaBH4
NHCO2Me
c) acrolein (2.0 equiv)
X
PG
N
O
H
X
CN
L
or
cat. (10 mol%)
O
CN
CN
L
Y
aq. KOH (5 equiv)
(84%)
S
N
O
S
Y
N
O
N
O
Ion-pairing
PhMe/CHCl3 (1:6)
-30 oC, 12 h
b) TMSCN
N
O
Ion-pairing
OEt
BF3•
2
TS1
(86%)
TS2
12a
11
NHCO2Me
Figure 2. Retrosynthetic analysis of tronocarpine (A), and the proposed
enantioselectivity model for asymmetric Michael/Aldol cascade reaction (B).
PG stands for protecting group.
NHCO2Me
CN
N
Y
10
CN
X
R
11
d) DMP
Ar
RO
N
O
To achieve the asymmetric reaction with high efficiency, we
proposed an ion-pairing/H-bonding bifunctional catalysis model
(Figure 2B, TS1 or TS2) which has been frequently adopted for
designing asymmetric reactions.[7] Expectedly, a chiral catalyst with
an appropriate ion-pairing and H-bonding functionalities as
scaffolding elements may form with the substrates a more rigid
transition state conformation through properly positioning of the
N
O
S
N
OH
O
13a /13a
chiral PTC
14a
N
HO
N
HO
X
Br
interaction sites, and thereby inducing
a better regio- and
Ar
enantioselectivity than the catalyst possessing a single interaction
site. Accordingly, a few tartrate-derived chiral guanidine catalysts[8]
were examined using 12a (Figure 3) as model compound which
could be readily prepared over 10 g scales from the known
compound 11[4e,9] through reduction followed by substitution with
TMSCN.[10] Disappointedly, the desired reaction did not proceed
with the starting material remained intact under various conditions
presumably due to the weak basicity of guanidines.
We were then drawn to the chiral phase-transfer catalysts (PTCs)
derived from cinchona bases because of the ease of preparation and
tuning the basicity of aqueous phase.[5] Delightedly, an extensive
screening of the conditions enabled us to establish a set of
preliminary conditions affording a couple of separable products
13aand 13a in 70% total yield with ca. 1:1 diastereomeric ratio
(dr) and 35% ee using C-1 as catalyst[11] (Figure 3). Interestingly,
both diastereoisomers exhibited similar enantioselectivity after
being oxidized to ketone 14a, respectively. Thus, the ee values
given in the following screening were deduced from the two
diastereoisomers.
NO2
N
N
C-1, Ar = p-MeC6H4 (70% yield, 35% ee)
C-2, Ar = p-tBuC6H4 (70% yield, 38% ee)
C-3, Ar = 1-naphthyl (70% yield, 45% ee)
C-4, Ar = 2-naphthyl (70% yield, 45% ee)
C-5, Ar = p-NH2C6H4 (18% yield, 54% ee)
C-6, Ar = p-NO2C6H4(42% yield, 82% ee)
C-7, Ar = p-CF3C6H4 (41% yield, 76% ee)
C-8, Ar = 8-NO2-2-naphthyl (58% yield, 47% ee)
C-9, Ar = 5-NO2-2-naphthyl (67% yield, 58% ee)
C-10, Ar = p-MeSO2C6H4 (29% yield, 57% ee)
C-11, Ar = o-NO2C6H4(60% yield, 28% ee)
C-12, Ar = 3,5-(NO2)2C6H3 (no reaction)
C-13, Ar = 2,4-(NO2)2C6H3 (no reaction)
C-14, X = Cl (42% yield, 81% ee)
C-15, X = PF6 (45% yield, 78% ee)
C-16, X = BF4 (41% yield, 78% ee)
C-17, X = I (no reaction)
N
HO
Br
NO2
C-18 (38% yield, 79% ee)
N
N
RHN
Br
N
AllylO
Br
NO2
N
NO2
C-19 (no reaction)
N
C-22, R = Boc
(10% yield, -26% ee)
Next, we carried out a thorough evaluation of an array of chiral
PTCs[11] by varying the patterns of Ar (C-1 to C-13), counterion X-
(C-14 to C-17), olefin moiety (C-18), chirality and functional
groups at C10 and C11 (C-19 to C-23), and substituents on quinolinyl
ring (C-24 and C-25) (Figure 3). This survey led us to identify that
C-6 with a strong electron-withdrawing p-NO2 group in phenyl ring
was the most promising candidate providing 13a (ca. 1:1 mixture of
13a and 13a) in 42% yield and 82% ee.[12] More importantly, in
good agreement with our assumption (Figure 2B), the observation of
a remarkable effect of the nature of counterion (C-6 and C-14 to C-
C-23, R = 3,5-(CF3)2C6H3NHC(S)
(no reaction)
N
HO
10
Br
11
N
HO
Br
NO2
RO
N
NO2
C-20 (10R, 11S)
(36% yield, 13% ee)
C-21 (10S, 11R)
N
C-24, R = H (no reaction)
C-25, R = Me (40% yield, 78% ee)
(68% yield, -8% ee)
2
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10.1002/anie.201914868
Angewandte Chemie International Edition
Figure 3. Screening of Chiral Catalysts. [a] General conditions: 12a (100 mg,
0.32 mmol), acrolein (2.0 equiv), PTC (10 mol %), and aq. KOH (50%, 5
equiv) in mixed PhMe/CHCl3 (v/v = 1:6, 16 mmol/L) at -30 oC for 12 h; the
yield was the total yield of 13a and 13a; the ee % was determined by
chiral HPLC.
slowly evaporating CH2Cl2/EtOAc solution, the enantiomeric purity
of 13b in mother liquid might be improved easily to >98% ee.
Removal of the Phth group followed by protecting the amino group
with methoxycarbonyl and oxidation of hydroxy group afforded 14a
in 50% yield and 98.5% ee over three steps. The conversion of
cyano group into aldehyde or ester group toward constructing the
seven-membered lactam was rather problematic owing to the
disruption of ketone and N1-lactam functionalities under various
reductive conditions. However, we found that the reaction could
proceed effectively via a tandem procedure involving reduction of
With the optimized conditions in hand, we examined the
substrate scope of the method[13] (Figure 4). Both electron-donating
(14c and 14d) and electron-withdrawing (14e‒14g) substituents at
different positions of indole ring periphery were compatible. In
addition, the reaction was also tolerant of various substituents on
Phth protecting group (14h‒14k) albeit a slightly diminished yield
and ee was observed for meta-substitution (14h). Finally, a variation
of acrolein substrates revealed that the -substituted acroleins were
also viable substrates to afford -face R4 products (14l‒14n) as a
single diastereoisomer as confirmed by X-ray single crystal
diffraction of 14m. For a -substituted acrolein, the yield and ee
were a bit of diminished (14o). The absolute configuration of the
products was (14S, 16R) for 14a‒14n and (14S, 16S) for 14o as
deduced from the X-ray structure of compound 18 in Scheme 1
(vide infra).
cyano group with Raney-Ni followed by
a
concomitant
intramolecular hemiamidation with the carbamate functionality,
furnishing the seven-membered hemiaminal 15. To compare with
the reported conditions,[14] replacing the acetic acid with TFA and
avoiding the use of NaH2PO2 were pivotal to suppress the side-
reaction resulting from the cleavage of C14‒C15 bond in 14a possibly
via retro-aldol-type reaction. Oxidation of 15 delivered lactim 16 in
53% yield over two steps from 14a.
Having established an efficient route for the construction of the
[6.5.7.6.6]-pentacyclic core, our attention was shifted to the
incorporation of the side-chain functionalities. Stimulated by a few
recent methodological studies on Pd(II)-catalyzed direct ,-
dehydrogenation of carbonyl compounds,[15] we explored the direct
oxidative dehydrogenation of 16 for the synthesis of enone 17 and
found that the reaction proceeded smoothly in high yield by
modifying the conditions reported by Stahl.[15a] Iodination of 17
provided the -iodinated enone 18 with 99.2% ee whose absolute
configuration was (14S, 16S) as confirmed by single crystal X-ray
R2
R2
p
m
a) acrolein (2.1 equiv)
C-6 (20 mol%)
O
O
aq. KOH (10 equiv)
Et2O/CHCl3 (1:6), -10 o
N
N
O
R
O
C
4
3
CN
CN
b) DMP
5
R1
R1
6
R4
N
N
analysis.
Sonogashira
cross-coupling
of
18
with
7
ethynyltrimethylsilane 19 proceeded smoothly to give alkyne 20.
The removal of CO2Me tether to N4 was unexpectedly challenging.
Significant decomposition of starting material was observed under
an array of reported conditions[9,16] presumably due to the
excessively strained ring tension as well as the existence of various
reactive functonalities such as ketone, alkynyl and lactam groups.
Thus, we conceived of a Lewis acid-activated nucleophilic
deprotection through an assumed complex 21. As expected, we
found that a combination of CeCl3 and iPrOH could efficiently
cleave the protecting group to give lactam 22 in 91% yield whose
structure was verified by single X-ray crystallographic diffraction.
Of note is that while other Lewis acids such as Sc(OTf)3 were also
effective, the use of CeCl3 offered an advantage of merging the
deprotection and the following Luche reduction into a one-pot
operation, affording 23 in 75% yield.
O
O
O
12
14
14b, R1 = R2 = H (56% yield, 94% ee)
NPhth
14c, R1 = 5-OMe, R2 = H (47% yield, 90% ee)
14d, R1 = 6-OMe, R2 = H (49% yield, 93% ee)
14e, R1 = 4-F, R2 = H (47% yield, 97% ee[b]
14f, R1 = 5-F, R2 = H (55% yield, 95% ee)
14g, R1 = 6-F, R2 = H (59% yield, 99% ee)
14h, R1 = H, R2 = m-Cl (40% yield, 86% ee)
14i, R1 = H, R2 = p-Cl (41% yield, 93% ee)
14j, R1 = H, R2 = p-Br (55% yield, 92% ee)
14k, R1 = H, R2 = p-OMe (50% yield, 88% ee)
CN
R1
)
N
O
(14b-k)
O
NPhth
3
CN
R
R4
N
14l, R3 = H, R4 = Me (69% yield, 94% ee)
14m, R3 = H, R4 = Et (59% yield, 94% ee)
=
nPr (69% yield, 93% ee)
14o, R3 = Me, R4 = H (32% yield, dr = ca. 2.4:1)
(14l-o)
O
O
14n, R3 = H, R4
The direct reduction of carbonyl group in 22 to methylene was
troublesome due to the significant decomposition of substrate under
various conventional and modified Wolff-Kishner-Huang
conditions.[17] However, the deoxygenation of 23 was carried out
efficiently through a two-step procedure involving the formation of
xanthate followed by Barton-McCombie radical deoxygenation,[18]
producing 24 in 60% yield over two steps. Subsequently, selective
reduction of the indolyl -lactam in 24 delivered hemiaminal 25 as a
single diastereoisomer. The stereochemistry for -OH at C3 was
determined by NOESY correlation (see Figure S43). Desilylation of
25 was effected by TBAF to afford alkyne 26. Finally, the Hg-
catalyzed alkyne hydration[19] and acid-promoted concomitant
inversion of -OH to thermodynamically more stable -OH
furnished the asymmetric total synthesis of tronocarpine (1). The
structure of 1 was unambiguously affirmed by NMR, HRMS, and
(90% ee for major isomer)
14m (CCDC 1921095)
NPhth
NPhth
CN
Pd(OAc)2 (20 mol%)
F
F
Cu(OAc)2 (1.0 equiv)
CN
O2 (balloon), DMSO, 60 o
C
N
O
N
O
78%
O
O
14e'
14e
Figure 4. The Evaluation of Substrate Scope. [a] Genaral conditions: 12
(100 mg), acrolein (2.1 equiv), C-6 (20 mol %), and aq. KOH (10‒30%, 10
equiv) in mixed Et2O/CHCl3 (v/v = 1:6, 16 mmol/L) at -10 oC until the
starting materials had disappeared as monitored by TLC; the yield was the
isolated yield of 14 for two-steps; the ee % was determined by chiral HPLC.
[b] The ee% of 14e was determined from its corresponding enone 14e’.
20
X-ray single crystallographic analyses. The data of NMR and []D
{Synthetic: +280 (c 0.1, CH2Cl2); lit.: +231 (c 0.08, CH2Cl2)} of the
synthesized product matched well with those reported.[1c]
Accordingly, the absolute configuration of tronocarpine (1) could be
assigned as (3S, 14R, 16S).
Having developed a robust and general method for the
asymmetric construction of aza-[3.3.1]-bridged cycle, we then
moved forward to the asymmetric total synthesis of (+)-tronocarpine
(1) (Scheme 1). Asymmetric Michael/aldol reaction of 12b (see SI
for the details of preparation of 12b) was performed on 1.5 g scale
to give 13b in 67% yield with 93% ee. By crystallization from a
3
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10.1002/anie.201914868
Angewandte Chemie International Edition
NPhth
CN
2. N H •
H2O
NHCO2Me
5. Raney-Ni
py/TFA/H2O
70 o
2
4
NPhth
CO2Me
N
1. C6 PTC (20 mol %)
MeOH, 70 o
C
acrolein, aq. KOH, -10 o
C
CN
3. ClCO2Me, aq. NaOH
EtOAc, rt
CN
OH
Et2O/CHCl3 (1:6)
C
N
O
N
O
N
O
N
67% yield, 93% ee
(54% yield, 98.5% ee
after one crystallization)
4. DMP, DCM, rt
50% (3 steps)
15
O
14
OH
O
O
12b
14a
13b ( / = ca. 1:1)
15
53%
(2 steps)
6. DMP, DCM/py
(5:1), rt
CO2Me
CO2Me
O
CO2Me
8. I2, py, DMAP
MeCN/CCl4 (1:1)
40 o
7. Pd(OAc)2
N
N
N
Cu(OAc)2, O2
DMSO, 60 oC
O
O
C
16
N
O
I
N
O
N
O
77%
78%
14
O
O
O
(CCDC 1910736)
9. Pd(PPh3)2Cl2
17
18 (99.2% ee)
16
TMS
82%
CuI, iPr2NH
19
19, THF, 0 o
C
MeO
then NaBH4
MeOH/THF
-78 o
75%
NH
NH
CO2Me
O
HOiPr
O
N
10. CeCl3, iPrOH
N
O
O
O
Ce(III)
THF, 75 o
C
C
O
N
O
TMS
N
O
R
N
O
R
N
O
TMS
OH
R =
TMS
O
O
23
22
21
20
11. NaH, CS2, MeI
19, THF, 0 o
12. AIBN, TMS3SiH
PhMe, 90 o
C
60%
(2 steps)
C
TMS
TMS
rac. 1 (CCDC 1872246)
O
rac. 22 (CCDC 1872295)
NH
Me
NH
15. H2SO4, Hg(OAc)2
NH
14. TBAF
THF, -30 o
88%
13. LiEt3BH
NH
THF/H2O, 40 o
C
THF, -78 o
C
O
16S
C
O
O
O
N
3S
85%
92%
N
N
N
3
HO
14R
OH
H
H
HO
H
25
O
Tronocarpine ( )
1
24
26
Scheme 1. Asymmetric Total Synthesis of Tronocarpine.
Keywords: Indole alkaloid · Natural product · Total synthesis ·
Tronocarpine · Asymmetric Michael-aldol reaction
In summary, the first asymmetric total synthesis of tronocarpine
(1) and the assignment of its absolute configuration have been
achieved. In the synthetic route, the strategic use of a newly
developed asymmetric Michael/aldol cascade reaction and an
intramolecular reduction/hemiamidation cascade reaction enabled us
to build efficiently the fused [6.5.7.6.6]-pentacyclic core at early
stage. The late-stage synthesis was highlighted by a modified Pd-
catalyzed direct dehydrogenation, a CeCl3-promoted deprotection of
methoxycarbonyl, and a Hg-catalyzed acid-promoted hydration of
alkyne and a concomitant inversion of the stereochemistry of
hemiaminal. We believe the synthetic strategy as well as the new
methodologies established in this work would find broad
applications for versatile synthesis of other unconquered members
of the chippiine-dippinine subfamilies and related analogues. The
synthetic study of the relevant natural products is currently
underway.
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Financial support from National Natural Science Foundation of
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Conflict of interest
The authors declare no conflict of interest.
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5
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10.1002/anie.201914868
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
Natural Product Synthesis
Dong-Xing Tan, Jie Zhou, Chao-You
Liu, , and Fu-She Han* __________
Page – Page
Enantioselective Total Synthesis
and
Assignment
Absolute
of
Configuration
Tronocarpine
We present the first asymmetric total synthesis and absolute configuration
Enabled by an Asymmetric
Michael/Aldol Reaction
determination of tronocarpine. The [6.5.7.6.6]-pentacyclic core was constructed at
early stage by using a sequential cyclization strategy via a newly devised catalytic
asymmetric Michael/aldol cascade to build the aza[3.3.1]-bridged cycle and a
tandem reduction/hemiamidation procedure to assemble the seven-membered
lactam. The side-chain functionalities were incorporated at the late stage by several
appropriately orchestrated manipulations under mild conditions. The synthesis of
enantiopure tronocarpine was achieved within a 20-step longest linear sequence
from tryptamine.
6
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