Asymmetric Total Synthesis of Vincadifformine Enabled by a Thiourea-Phosphonium Salt Catalyzed Mannich-Type Reaction

Article abstract of DOI:10.1002/chem.201900896

An asymmetric total synthesis of vincadifformine is described. The limited tactics with chiral cation-directed catalysis in total synthesis inspired the development of our strategy for accessing this alkaloid in enantionrich form. The route features a thiourea–phosphonium salt catalyzed Mannich-type reaction, a phosphine-promoted aza-Morita–Baylis–Hillman reaction and a trifluoroacetic acid promoted deprotection/amidation cascade process.

Full text of DOI:10.1002/chem.201900896

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Title: Asymmetric Total Synthesis of Vincadifformine Enabled by
Thiourea-Phosphonium Salts Catalyzed Mannich-type Reaction
Authors: Gang Zhao
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10.1002/chem.201900896
Chemistry - A European Journal
COMMUNICATION
Asymmetric Total Synthesis of Vincadifformine Enabled by
Thiourea-Phosphonium Salts Catalyzed Mannich-type Reaction
Lu Pan, Chang-Wu Zheng, Guo-Sheng Fang, Hao-Ran Hong, Jun Liu, Long-Hui Yu, Gang Zhao*
Abstract: A novel asymmetric total synthesis of Vincadifformine is
described. The limited tactics with Chiral cation-directed catalysis in
total synthesis inspired the development of our strategy for accessing
this alkaloid in enantionrich form. The route features Thiourea-
Phosphonium Salts catalyzed Mannich-type reaction, Phosphine
promoted Aza-Morita-Barrie-Hillman reaction and TFA promoted
deprotection/ amidation cascade process.
rings as well as the C12/C19 stereogenic centers in one pot. More
recently, Andrew reported an elegant approach to introduce the
enantioenriched E ring and C19/C5 stereogenic centers by the
domino Micheal/Mannich/N-alkylation reactions. Chiral auxiliaries
play indispensable roles in controlling the stereoselectivity in both
previous works. In 2017, Jiang and co-workers established a
divergent and practical synthesis toward Vincadifformine and
related alkaloids through Fischer indolization reaction. In his work,
a chiral pool based intermolecular [4+2] cycloaddition was utilized
to forge C12/C19 stereogenic centers. Besides the strategy with
chiral auxiliary and chiral pool, MacMillan et al successfully
completed a series of monoterpene indole alkaloids synthesis
based on an impressive organocatalytic cascade method. Despite
the numerous successful syntheses of Vincadifformine, the
asymmetric synthesis of Vincadifformine utilizing Chiral cation-
directed catalysis still remains desirable as scarce examples of
this catalytic strategy have been applied to total syntheses.
Structurally complex monoterpenoid indole alkaloids from the
species of the genus Aspidosperma comprise over 250 unique
[1]
members and show a considerable structural diversity.
The
structures of these compounds are striking in that they contain a
cage-like [6.5.6.6.6] fused pentacyclic skeleton. It bears three
contiguous cis-stereogenic centers, two of which are all carbon
quaternary centers. (Figure 1a) Vincadifformine, one of its
representative members, is originally isolated from Vincadifformis
in 1962 by Djerassi and Janot et al.[2] Both Vincadifformine and its
analogues display remarkable cytotoxicity in vitro against a total
of 60 human tumor cell lines derived from nine cancer types.[3]
Given its fascinating structure and distinguished pharmacological
activities, many synthetic chemists have devoted great efforts
toward its syntheses. [4]
NHBoc
SePh
BocN
CO2Me
CO2Me
Et
N
O
N
Boc
Bn
This work
Chiral cation-directed catalysis
(Mannich reaction)
MacMillan (2011)
Organocatalysis
(Diels-Alder reaction)
a) Vincadifformine
D
N
C
5
19
12
[6.5.6.6.6] fused pentacyclic skeleton
3 contigous cis-sterocenters
E
O
N
B
A
S
tBu
Et
2 all-carbon quanternary chiral centers
CO2Me
N
H
Li
Cl
CO2Me
Br
Vincadifformine
O
OTs
N
CO2t-Bu
N
b) Aspidosperma alkaloids
O
Boc
CO2Me
N
CO2Me
N
R2
H
N
N
SO2Ph
N
R1
R3
Jiang (2017)
Pandey (2011)
Andrade (2013)
OH
O
Chiral pool
([4 + 2] cycloaddition)
Chiral auxiliary
Chiral auxiliary
CO2Me
(Iminium Ion-enamine reaction) (Micheal-Mannich-N-alkylation)
N
O
N
N
H
H
Me
O
Dasyrachine
common motif
Minovine
Figure 2. Asymmetric synthetic strategies leading to Vincadifformine and our
unique approach.
Figure 1. Representatives of Aspidosperma alkaloids and their analogues.
Although the monoterpenoid indole alkaloids possess
extraordinary structural diversity, when considered broadly. If
certain elements of these molecules are considered in isolation, a
common motif featuring a tertiary carbon stereogenic center
adjacent to indoline and tertiary amine are frequently shared by
these alkaloids (Figure 1b). [7] We hypothesize that this common
motif could be introduced by the Mannich reaction between N-
Boc indole aldimine 1 and a nucleophile reagent. Inspired by
recent work of our groups (Scheme 1), in which the asymmetric
Mannich reaction catalyzed by amino acids-derived chiral
organocatalysts gave the related products in excellent yield and
enantiopurity.[8] Herein we developed a novel method to
construct this key structure 2.
Since the isolation and structure elucidation of Vincadifformine,
four splendid syntheses in asymmetric versions have been
achieved. [5] Each has its own feature in assembling the three-
contiguous cis-stereocenters in E ring. In 2011, Pandey et al
demonstrated a cascade strategy to simultaneously construct C/E
[a]
L. Pan, C.-W. Zheng, G.-S. Fang, H.-R. Hong, J. Liu, L.-H. Yu, Prof.
G. Zhao
Key Laboratory of Synthetic Chemistry of Natural Substances,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032 (R. P. China)
E-mail: zhaog@mail.sioc.ac.cn
Supporting information for this article is given via a link at the end of the
document.((Please delete this text if not appropriate))
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10.1002/chem.201900896
Chemistry - A European Journal
COMMUNICATION
the best of our knowledge, this synthon has only been used by
Johnson group to synthesize enantioenriched β-amino-keto
esters via dynamic kinetic resolution. [10] The application of N-Boc
indole aldimine 1 in the catalytic asymmetric Mannich reaction
remains unexplored.
Bn
NHBoc
CO2Me
CO2Me
PPh2
NBoc
catalyst (5 mol%)
methyl acrylate (5 mol%)
S
NH
NH
+
DCM, RT, 3h
F
MeO2C
CO2Me
92% ee
F
93% yield
O2N
Our synthesis is associated with the exploration of thiourea-
phosphonium salts catalyzed asymmetric Mannich-type reaction,
between N-Boc indole aldimine 1 and dimethyl ethylmalonate.
After intensive modification of the catalyst structure and screening
several reaction conditions, we found this asymmetric Mannich-
type reaction could be accomplished under the condition of 5 mol%
catalyst G in toluene, using 4Å molecular sieves as additive to
give 2 in 92% yield and good enantiopurity (84% ee). the
enantiopurity of the major diasomer could be elevated to 97%
catalyst
PPh2Bn
NHBoc
SO2Ph
NHBoc
R2
S
NH
catalyst (5 mol%)
KOH, toluene
NH
Br
NO2
ee: 96%
yield: 79%
+
catalyst
O2N
R2
Scheme 1. Prior arts of asymmetric Mannich-type reaction in our group
easily
through
recrystallization
downstream
at
tert-
butyldimethylsilylation stage. The reaction was readily adapted to
the gram-scale without impacting its efficiency. (Scheme 3)
Based on this strategy, a retrosynthetic analysis is shown in
Scheme 2. The quaternary stereocenter C12 and E rings could
be introduced by alkylation at the 3-position of indole, followed by
a
trimethylphosphine promoted Aza-Morita-Baylis-Hillman
CO2Me
BocHN
BocN
CO2Me
reaction. Noteworthily, the conjugate addition between the
nucleophilic phosphine and a sterically hindered activated alkene
with a γ-quaternary carbon center is insurmountable. [9] Then the
catalyst (5 mol%)
Cs2CO3
Et
Et
+
-10 oC, toluene
MeO2C
CO2Me
N
N
Boc
Boc
intermediate
10
could
be
easily
obtained
by
1
2
deprotection/amidation in the presence of trifluoroacetic acid and
N-acetylation from 8. The prolonged carbon chains at C-5, which
is required in the construction of E ring, could be extended by
Horner-Wadsworth-Emmons olefination from the diesters. The
C19 tertiary carbon stereogenic center in 2, which is essential for
controlling the stereoselectivity of following reactions, could be
obtained through the asymmetric Mannich-type reaction between
N-Boc indole aldimine 1 and dimethyl ethylmalonate by Chiral
cation-directed catalysis.
Bn
Bn
Bn
PBnPh2
PBnPh2
Br
PBnPh2
S
NH
NH
O
NH
NH
S
NH
NH
F3C
F3C
Br
Br
O2N
CF3
CF3
92% yield, 84%ee
85% yield, 81%ee
75% yield, 53% ee
Bn
P
CF3
Bn
Me
PBnPh2
P
Ph2
Ph2
S
NH
NH
S
NH
S
NH
NH
F3C
F3C
NH
CF3
F3C
Deprotection
Br
Br
Br
and Amidation
Heathcock-Toczko
Spirocyclization
Acetylation
O
O
N
H
N
H
CF3
78% yield, 80% ee
CF3
78% yield, 82% ee
N
CF3
83% yield, 63%ee
Br
N
N
H
CO2Me
N
H
CO2Me
CO2Me
12
Vincadifformine
Scheme 3. Optimization of conditions and evaluation of chiral catalysts.
10
Aza-Morita-Baylis-Hillman
reaction and DDQ oxidation
To inhibit the retro-Mannich reaction, the resulted 2 was
reduced intermediately with DIBAL-H to give diol 3 (86% yield, 89%
ee). It is worth noting that the reduced product would either be
decomposed or partially racemized when other reductants such
as LiBH4, NaBH4 or LiAlH4 were used. We proposed that partial
racemization occurred due to the retro-Mannich/Mannich reaction
which is promoted by the reductants with Li+ or Na+ such as LiBH4,
NaBH4 or LiAlH4. Selective protecting one of the hydroxyl group
Wittig-Horner
-Emmons reaction
Phase-transfer-Catalysis
Asymmetric Mannich reaction
CO2Me
CO2Me
CO2Me
BocN
BocHN
BocHN
CO2Me
N
N
N
Boc
Boc
Boc
1
8
2
Scheme 2. Retrosynthetic analysis of Vincadifformine
in
3
with tert-butyldimethylsilyl chloride afforded
a
chromatographically separable diastereomeric mixtures 4 and 4’
(73% yield, 3 : 1 dr, 90% ee). The enantiopurity of the major
diastereomer 4, could be improved to 97% ee after a simple
recrystallization in methanol. Its absolute configuration was fully
secured by a crystallographic verification.
Although N-Boc indole aldimine 1 is shared in plenteous indole
alkaloids and is also a promising building block for their syntheses,
the aromatic electron-rich N-Boc indole aldimine 1 with relatively
low electrophilicity, is a challenging Mannich addition acceptor. To
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Both intermediates 4 and 4’ were used for assembling Vinca-
difformine. As demonstrated in Scheme 4, acetylation of the re-
maining hydroxyl group in 4 followed by desilylation produced the
intermediate 5 in 89% yield, which was then treated with Dess-
Martin periodinane. The obtained aldehyde underwent the
of Lawesson’s reagent to give 9 in 90% yield. The intermediate 9
was treated with Raney-Ni to provide the cyclic amine. Without
further column chromatography purification, the crude product
was directly subjected to the reaction with bromoacetyl chloride to
generate 10 in 90% yield. The absolute configuration of 10 was
confirmed through X-ray analysis.
Horner-Wadsworth-Emmons
olefination
with
trimethyl
phosphonoacetate to afford 6, which was deprotected of acetyl
group under basic condition gave the α, β-unsaturated ester 7 in
90%yield.In a parallel procedure, oxidation of 4’ by Dess-Martin
periodinane provided the corresponding aldehyde which was
subjected to the Horner-Wadsworth-Emmons olefination with
109o
N
N
PMe3, MeOH
PMe3

CO2Me
N
CO2Me
N
trimethyl
phosphonoacetate
and
deprotection
with
13
14
tetrabutylammonium fluoride affording the same α, β-unsaturated
ester 7 in 92% yield. (Scheme 4)
m-o
S
CO2Me
CO2Me
HN
BocHN
BocHN
Et
Et
Et
a-c
d-e
OH
CO2Me
CO2Me
N
N
N
H
Boc
Boc
9
8
7
f-g
2
a
O
O
120o
N
N
N
HO
TBSO
BocHN
Et
HO
Et
Br
h
BocHN
OH
b
BocHN
Et
Et
CO2Me
CO2Me
N
Et
H
11
OH
10
OTBS
+
N
N
N
i
Boc
Boc
Boc
4'
4
3
O
H
O
Me
OEt
O
N
g-i
N
c-d
O
Et
H
Et
N
Me
CO2Me
H
Me3P
N
j-l
CO2Me
O
HO
CO2Me
N
CO2Me
N
H
12
BocHN
BocHN
H
BocHN
Et
Et
Vincadifformine
Et
OAc
OAc
e-f
OH
j
N
N
N
Boc
Boc
Boc
7
5
6
Scheme 4. a) DIBAl-H, CH2Cl2, 0 oC, 86%; b) TBSCl, NaH, THF 0 oC - rt, 73%;
c) Ac2O, Et3N, DMAP, DCM, 92%; d) TBAF,THF,0 oC
rt, 89%; e)
-
DMP,NaHCO3,DCM, rt; f) trimethylpho- sphonoacetate, NaH, THF, 0 oC – rt; g)
DMP, NaHCO3, CH2Cl2, rt, 75%; h) Trimethyl phosphonoacetate, NaH, THF,
0oC - rt, 87%; i) TBAF,THF,0oC-rt, 93%; j) K2CO3, MeOH, rt, 90%. DIBAl-H =
Diisobutylaluminium hydride; TBSCl = tert-Butyldimethylsilyl chloride; DMP =
Dess-Martin periodinane; DMAP = 4-Dimethylaminopyridine; TBAF = Tetrab
utylammonium fluoride; THF = Tetrahydrofuran. catalysts.
Scheme 5. a) Pd/C, H2, THF, 95%; b) DMP,NaHCO3,CH2Cl2, rt, 85%; c)
Trimethyl phosphonoacetate, NaH, THF, 0oC - rt, 92%; d) TFA, CH2Cl2, 0 oC -
rt, 80%; e) Lawesson's Reagent, THF, reflux, 90%; f) Raney-Ni, THF, H2, 95%;
g) bromoacetyl chloride, Et3N, DCM, 90%; h) AgOTf, Et3N, CH2Cl2, 95%; i) PMe3,
MeOH, 92%; j) Lawesson's Reagent, THF, rt, 95%; k) Raney-Ni, THF, H2, 92%;
l) DDQ, CH2Cl2, 75%; m) Raney-Ni, THF, H2, 95%; n) ethylene oxide, MeOH, -
10 oC, 90%; o) MsCl, Et3N, CH2Cl2, 0 oC, 89%. THF = Tetrahydrofuran; DMP =
Dess-Martin periodinane; TFA = Trifluoroacetic acid; DDQ = 2,3-Dichloro-5,6-
dicyano-1,4-benzoquinone; MsCl = Methanesulfonyl chloride.
Having successfully established the key C19 stereogenic
center and got the intermediate 7 (90% ee), several functional
group transformations were performed to elaborate intermediate
7 into the desired cyclization precursor 10. Pd/C-catalyzed
hydrogenation of the α, β-unsaturated double bond with
The next stage of the synthesis involved an intramolecular
alkylation, a strategy first employed by Heathcock and Toczko in
the synthesis of Aspidospermidine.[11] Treatment of 10 with silver
subsequent
oxidation
and
Horner-Wadsworth-Emmons
olefination delivered 8 in 74% yield over three steps. The
construction of D ring was efficiently achieved via a TFA promoted
deprotection/ amidation cascade process in high yields. To
facilitate the selective reduction in further steps, the
corresponding amide was converted to thioamide in the presence
trifluoromethanesulfonate in
a mixture of Et3N and DCM
successfully provided the spirocyclic indolenine 11 in 95% yield.
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COMMUNICATION
With the spirocyclic indolenine 11 in hand, we turned our attention
to the formation of E ring. Inspired by kwon’s elegant approach to
ibophyllidine, similar strategy was investigated to close the E ring
in our synthesis. [9d] When spirocyclic indolenine was exposed
under the conditions (PMe3, toluene /MeOH 14:1) as reported, to
our disappointment, the reaction was rather sluggish and only
trace amount of the desired product was detected by LC-MS.
According to the crystallographic analysis of substrate 10, We
assumed that two reasons might be considered account for this.
First, the ethyl group on the quaternary carbon is overlapping with
the antibonding orbital of α, β-unsaturated ester, making the
active alkene more obstructed for the attack by the phosphine.
Second, compared to O-H in protic solvent, N-H on the product is
a much weaker hydrogen bond donor which frustrated the
reaction through the autocatalytic way. Consequently, both
Academy of Sciences (XDB 20020100) is gratefully
acknowledged.
Keywords: Chiral-cation directed catalysis, Asymmetric
Mannich reaction, Alkaloids, Vincadifformine, Total synthesis.
[1] J. E. Saxton, in The Alkaloids，Vol. 51（ Ed.: G. A. Cordell）,
Academic Press, New York, 1998, Chapter 1.
[2] C. Djerassi, H. Budzikiewicz, J. M. Wilson, J. Gosset, J. Le
Men, M. M. Janot, Tetrahedron Lett. 1962, 3, 235-239.
[3] M. G. Hollingshead, M. C. Alley, R. F. Camalier, B. J. Abbott,
J. G. Mayo, L. Malspeis, M. R. Grever, Life Sci. 1995, 57, 131-
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[4] a) G. Lewin, G. Atassi, A. Pierre, Y. Rolland, C. Schaeffer, J.
Poisson, J. Nat. Prod. 1995, 58, 1089-1091; b) G. Lewin, R.
Hocquemiller, C. Schaeffer, A. Pierre, Bioorg. Med. Chem. Lett.
2002 12 371-374.
sterically undemanding phosphine and quantities of protic solvent
[12]
was inevitable to accelerate the reaction.
After exhaustive
[5] For the total synthesis of Vincadifformine in asymmetric form,
see: a) G. Pandey, P. C. Kumara, Org. Lett.2011,13, 4672-
4675; b) S. B. Jones, B. Simmons, A. Mastracchio, D. W. C.
MacMillan, Nature 2011,475,183-188; c) S. Zhao, R. B.
Andrade, J. Am. Chem. Soc. 2013, 135, 13334-13337; d) N. Z.
Wang, S. Du, D. Li, X. F. Jiang, Org. Lett. 2017, 19, 3167-3170.
[6] For the total synthesis of Vincadifformine in racemic form,
see: a) J. P. Kutney, K. K. Chan, A. Failli, J. M. Fromson, C.
Gletsos, V. R. Nelson, J. Am. Chem. Soc. 1968, 90, 3891; b) M.
E. Kuehne, D. M. Roland, R. Hafter, J. Org. Chem. 1978, 43,
3705-3710; c) M. E. Kuehne, T. H. Matsko, J. C. Bohnert, C. L.
Kirke- mo, J. Org. Chem.1979,44, 1063-1068; d) G. Kalaus, I.
Greiner, M. Kajtar-Peredy, J. Brlik, L. Szabo, C. Szantay, J. Org.
Chem. 1993, 58, 1434-1442; e) M. E. Kuehne, T. Wang, P. J.
Seaton, J. Org. Chem. 1996, 61, 6001-6008; f) S. Kobayashi, G.
Peng, T. Fukuyama, Tetrahedron Lett. 1999, 40, 1519-1522; g)
H. Mizoguchi, H. Oikawa, H. Oguri, Nat. Chem. 2014, 6, 57-64;
h) O. Wagnieres, Z. Xu, Q. Wang, J. Zhu, J. Am. Chem. Soc.
2014, 136, 15102-15108; i) P. W. Tan, J. Seayad, D. J. Dixon,
Angew. Chem. Int. Ed. 2016, 55, 13436-13440.
study, the reaction was found to best perform in MeOH with
trimethylphosphine as the nucleophile. The resulted pentacyclic
skeleton was unambiguously confirmed by X-ray crystallography
analysis.
It is rather remarkable that in our initial foray toward the
pentacycle, Rulbita startegy was exploited to construct Spirocyclic
indolnine giving substrate 13. (as indicated in scheme 5) Treating
13 under the optimal condition resulted in intermediate 14, which
was detected by LRMS, HRMS and HNMR with no observed
formation of pentacycle. We proposed that a larger bonding angle
(C-C=O-N: ~120oC) in C ring would push the α, β-unsaturated
ester chain more close to indolenine, which facilitated the
attacking of enolate to imine.
Completion of the synthesis would now require selective
reduction of the lactam and migration of the double bond to deliver
the requisite enamine. Amide 12 was then transformed to
thioamide in the presence of Lawesson’s reagent, subsequent
reductive desulfurization with Raney-Ni and oxidation of the
indoline unit with DDQ to afford Vincadifformine in 65% yield over
three steps.
Notably, the 1H and 13C NMR data of the synthetic
Vincadifformine were identical to that of natural Vincadifformine,
which are different with those from Andrade’s synthesis. We found
that this problem could be solved by adding a trace amount of
TFA during collecting NMR spectroscopic data. [13]
[7] J. E. Saxton, Indoles, Part 4: The Monoterpenoid Indole
Alkaloids, Wiley, Chichester, 1983.
[8] a) D. D. Cao, Z. Chai, J. X. Zhang, Z. Q. Ye, H. Xiao, H. Y.
Wang, G. Zhao, Chem. Commun. 2013, 49, 5972-5974; b) X. Y.
Wu, Q. Liu, Y. Liu, Q. Wang, Y. Zhang, J. Chen, W. G. Cao, G.
Zhao, Adv. Synth. Catal. 2013, 355, 2701. c) D. D. Cao, J. X.
Zhang, H. Y. Wang, G. Zhao, Chem. Eur. J. 2015, 21, 9998-
10004; d) H. Y. Wang, K. Zhang, C. W. Zheng, Z. Chai, D. D.
Cao, J. X. Zhang, G. Zhao, Angew. Chem. Int. Ed. 2015, 54,
1775-1779; e) Y. P. Lou, C. W. Zheng, R. M. Pan, Q. W. Jin, G.
Zhao, Z. Li, Org. Lett. 2015, 17, 688− 691; f) H. Y. Wang, C. W.
Zheng, Z. Chai, J. X. Zhang, G. Zhao, Nat. Commun. 2016, 7,
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G. S. Fang, J. X. Zhang, H.Y. Wang, C. W. Zheng, G. Zhao, J.
Org. Chem. 2016, 81, 9973-9983.
[9] For examples of using Morita-Baylis-Hillman reaction in Total
Synthesis of Natural Products, see: a) T. Motozaki, K.
Sawamura, A. Suzuki, K. Yoshida, T. Ueki, A. Ohara, R.
Munakata, K-i. Takao, K-i. Tadano, Org. Lett. 2005, 7, 2265-
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2008, 3432-3434; d) I. P. Andrews, O. Kwon, Chem. Sci. 2012,
3, 2510-2514.
In summary, we have achieved asymmetric total syntheses of
Vincadifformine. The key C19 stereogenic center capitalized on
a chiral-cation-directed asymmetric Mannich reaction which
catalyzed by our recently developed amino acids derived chiral
bifunctional thiourea-phosphonium salts. Additional salient
features of this synthesis including phosphine promoted Aza-
Morita-Barrie-Hillman reaction for construction of the E ring and
TFA promoted deprotection/amidation cascade process for
construction of D ring. We anticipate that the novel transformation
developed in this project will find further application in synthesis.
Acknowledgements
[10] C. G. Goodman, D. T. Do, J. S. Johnson, Org. Lett.
2013,15, 2446-2249.
[11] M. A.Toczko, C. H. Heathcock, J. Org. Chem. 2000, 65,
2642-2465.
Financial support from the National Natural Science Foundation
of China (Nos. 21272247, 21572247, 21871282) and Chinese
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10.1002/chem.201900896
Chemistry - A European Journal
COMMUNICATION
[12] V. K. Aggarwal, S. Y. Fulford, G. C. Lloyd-Jones, Angew.
Chem. Int. Ed. 2005, 44, 1706-1708.
[13] S. Abouzeid, U. Beutling, F. Surup, F. M. Abdel Bar, M. M.
Amer, F. A. Badria, M. Yahyazadeh, M. Bronstrup, D. Selmar, J.
Nat. Prod. 2017, 80, 2905-2909.
[14]
CCDC 1897172 (12) and CCDC 1897173 (10) CCDC
1897174 (4) contain the supplementary crystallographic
data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre
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10.1002/chem.201900896
Chemistry - A European Journal
COMMUNICATION
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COMMUNICATION
L. Pan, C.-W. Zheng, G.-S. Fang, H.-R.
Hong, J. Liu, L.-H. Yu, Prof. G. Zhao*
Asymmetric Total Synthesis of
Vincadifformine Enabled by Thiourea-
Phosphonium Salts Catalyzed
Mannich-type Reaction
A novel asymmetric total synthesis of Vincadifformine is described. The limited
tactics with Chiral cation-directed catalysis in total synthesis inspired the
development of our strategy for accesing this alkloid in enantionrich form. The route
features Thiourea-Phosphonium Salts catalyzed Mannich-type reaction, Phosphine
promoted Aza-Morita-Barrie-Hillman reaction and TFA promoted deprotection/
amidation cascade process.
[a]
L. Pan, C.-W. Zheng, G.-S. Fang, H.-R. Hong, J. Liu, L.-H.
G. Zhao
Key Laboratory of Synthetic Chemistry of Natural Substanc
Shanghai Institute of Organic Chemistry, Chinese Academ
Sciences, 345 Lingling Road, Shanghai 200032 (R. P. Chi
E-mail: zhaog@mail.sioc.ac.cn
Supporting information for this article is given via a link at the end
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This article is protected by copyright. All rights reserved.