Asymmetric Total Syntheses of (-)-Jerantinines A, C, and E, (-)-16-Methoxytabersonine, (-)-Vindoline, and (+)-Vinblastine

Article abstract of DOI:10.1021/acs.orglett.7b03694

A concise and stereocontrolled strategy for the syntheses of oxygenated Aspidosperma and Vinca alkaloids, via a stereoselective intermolecular inverse-electron-demand [4 + 2] cycloaddition, a challenging α,β-unsaturated ketone indolization rearrangement with excellent regio- and stereoselectivity, and an efficient Pd/C-catalyzed one-pot cascade reaction. The strategy has been demonstrated by the efficient asymmetric syntheses of antitumor drug (+)-vinblastine and five other oxygenated Aspidosperma alkaloids.

Full text of DOI:10.1021/acs.orglett.7b03694

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Asymmetric Total Syntheses of (−)-Jerantinines A, C, and E, (−)-16-
Methoxytabersonine, (−)-Vindoline, and (+)-Vinblastine
Nengzhong Wang,† Jianrong Liu,† Chen Wang,† Leiyang Bai,† and Xuefeng Jiang*,†,‡
†Shanghai Key Laboratory of Green Chemistry and Chemical Process, School of Chemistry and Molecular Engineering, East China
Normal University, 3663 North Zhongshan Road, Shanghai 200062, P. R. China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Road, Shanghai 200032, P. R. China
S
* Supporting Information
ABSTRACT: A concise and stereocontrolled strategy for the syntheses of oxygenated Aspidosperma and Vinca alkaloids, via a
stereoselective intermolecular inverse-electron-demand [4 + 2] cycloaddition, a challenging α,β-unsaturated ketone indolization
rearrangement with excellent regio- and stereoselectivity, and an efficient Pd/C-catalyzed one-pot cascade reaction. The strategy
has been demonstrated by the efficient asymmetric syntheses of antitumor drug (+)-vinblastine and five other oxygenated
Aspidosperma alkaloids.
inblastine (1) and vincristine (2), isolated from the leaves
of Catharanthus roseus in 19581 and 1961,2 respectively,
resistant and -sensitive human oral epidermoid carcinoma cell
lines.7 Therefore, total syntheses of vinblastine,8 vincristine,9
and oxygenated Aspidosperma alkaloids10−12 are particularly
attractive and in demand. These challenging complex structures
collectively contain a pentacyclic (ABCDE rings) skeleton,
bearing three contiguous cis-stereocenters (C5, C12, and C19)
with two all-carbon quaternary chiral centers (C5 and C12). In
particular, vinblastine and vincristine with all six carbon
stereocenters of the C-ring are even more arduous synthetic
targets. Despite the great endeavors made over the past decades,
only one synthesis of jerantinine E13 and 10 syntheses of
vinblastine8 and vincristine9 have been reported to date.
Inspired by our divergent alkaloid synthesis concept,14 we
report a concise and stereocontrolled strategy for the oxy-
genated Aspidosperma and Vinca alkaloids, which Waser and co-
workers demonstrated to be challenging targets due to the
instability of highly oxygenated synthetic intermediates.13
Nitrogen from natural amino acid and aniline is the best and
logical choice for alkaloid’s N source, which is also naturally
abundantly available. The N-9 of vinblastine could be
introduced from D-pyroglutamic acid with the five-membered
E ring, which possesses space-approach with three consecutive
cis-stereocenters (C5, C12, and C19) including two all-carbon
quaternary chiral centers (C5 and C12). Meanwhile, N-1
V
have been widely applied as well-known antitumor drugs for
chemotherapy as marketed by Eli Lilly (Figure 1).3 Vindesine
Figure 1. Representative pharmaceuticals of Vinca alkaloids.
(3),4 vinorelbine (5),5 and vinflunine (6),6 which originated
from this alkaloid family, have been further developed for
different cancer therapies. Notably, all these structures possess
nearly identical vinblastine units and are slightly altered from the
original structure resulting in exclusive pharmacological effects,
respectively. It is worth noting that jerantinines A−G were
isolated in 2008 by the Kam group from leaves of the Malayan
plant Tabernaemontana corymbosa, which exhibits potent
cytotoxic activity (IC50 = 0.68−2.55 μM) against vincristine-
Received: November 29, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03694
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
connected to the aromatic A ring could be supplied from
arylamine through a stereospecific and regiospecific indolization
rearrangement. On the basis of these considerations, retro-
synthetic analysis of vinblastine is illustrated in Scheme 1. We
Scheme 2. Syntheses of Pentacyclic Skeleton 24a and 24b
Scheme 1. Retrosynthetic Analysis for Vinblastine
Table 1. Selectivity Evaluation of α,β-Unsaturated Ketone
a
Indolization Rearrangement.
envisioned that tetracyclic α,β-unsaturated imines 12, a
promising synthetic precursor, could be highly efficiently
converted to Vinca alkaloids via a cascade cyclization process
and Boger coupling, which could be successively constructed via
a stereoselective intermolecular inverse-electron-demand [4 +
2] cycloaddition of 3-ethyl-5-bromo-2-pyrone 16 and chiral
enecarbamate (R)-17, followed by a regio- and stereoselective
indolization rearrangement of α,β-unsaturated ketone 13 with
unsymmetric arylhydrazines 14. For the synthesis of the C−E
rings, the stereoselective construction of three consecutive cis-
stereocenters with one all-carbon quaternary chiral center was
expected to be controlled via the configuration of (R)-17.
Compounds 16 and (R)-17 were readily obtained in three steps
from commercially available DL-malic acid15 and D-pyroglutamic
acid,16 respectively.
To evaluate the key α,β-unsaturated ketone indolization, we
commenced our endeavor with the synthesis of α,β-unsaturated
ketone 13, which is the core structure of Aspidosperma and Vinca
alkaloids (Scheme 2). We employed enecarbamate (R)-17 as the
cyclic enamide dienophile for stereoselective intermolecular
inverse-electron-demand [4 + 2] cycloaddition to deliver exo-
bridged tricycliclactone 20 (6.12 g, brsm 72%, exo/endo 6.5:1).
Subsequently, the hydrolysis of tert-butyl ester 20 with
trifluoroacetic acid in dichloromethane afforded carboxylic
acid 21 (4.38 g) in 99% yield. The configuration of 21 was
further confirmed through X-ray analysis. Compound 21 was
successfully converted to 2-bromoallyl alcohol 22 in 68% overall
yield over three steps, including photoinduced decarboxylation/
reduction/Wittig olefination. Oxidation of 22 with Dess−
Martin periodinane afforded α,β-unsaturated ketone 13 (9.10 g)
in 96% yield. With a large quantity of 13 in hand, we focused on
optimizing the key Fischer indolization with the α,β-unsaturated
ketone substrate. As shown in Table 1, our initial attempt to
construct ABCE rings 12a with 3-methoxyphenyldrazine
hydrochloride 14a was unsuccessful (entry 1). No related 3-
temp time
yield of
b
c
entry
1
conditions
solvent
(°C)
(h) 12a (%) 12a:12a′
Na2CO3, 4 Å
M.S.
Na2CO3, 4 Å
M.S. then TFA
AcOH
TFA
TFA
benzene
80
48
0
0
2
toluene
110
26
55
3:1
3
4
5
120
80
80
24
24
24
34
50
57
8:1
55:1
>100:1
DCE
t-BuOH
a
Reaction conditions: 13 (0.1 mmol), 3-MeOC6H4NHNH2HCl (2.2
b
equiv), TFA (20.0 equiv), solvent (1.0 mL), 24−48 h. Isolated
c
yields. The regioselectivity values of 12a/12a′ were determined by
LC−MS analysis. TFA = trifluoroacetic acid, DCE = 1,2-dichloro-
ethane.
methoxyphenylhydrazone was detected due to the low reaction
activity of conjugated α,β-unsaturated ketone. Therefore,
treatment of condensation in refluxing toluene with addition
of 4 Å molecular sieves successfully afforded 3-methoxyphe-
nylhydrazone, which was subsequently converted to the desired
α,β-unsaturated imine 12a in 55% yield with a single
diastereomer but low regioselectivity (3:1) (entry 2).
Furthermore, the transformation in acetic acid at reflux
promoted regioselectivity to 8:1 but in lower yield (34%), due
to the sensitive α,β-unsaturated bond (entry 3). Delightfully,
further improvements both in yield and regioselectivity (50%
and 55:1) were achieved via increasing acidity and lowering
temperature (entry 4). Finally, utilizing tert-butyl alcohol, the
yield and regioselectivity of 12a were increased to 57% and over
100:1 (entry 5).
B
DOI: 10.1021/acs.orglett.7b03694
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On the basis of the data for α,β-unsaturated ketone
indolization rearrangement, high regio- and stereoselectivity
can be explained through four different configurations of
transition states (TS-1, TS-2, TS-3, and TS-4), which are
shown in Scheme 3A. The concave skeleton of the C−E ring and
ring transition state when substituted conditions of C5 altered
the configuration of the entire molecule (Scheme 3B).
Afterward, Pd(0)-catalyzed methoxycarbonylation of 12a and
12b installed methyl ester affording α,β-unsaturated esters 23a
(1.88 g) and 23b (3.39 g) in 70% and 81% yields, respectively
(see the Supporting Information). To our delight, 23a and 23b
were efficiently transformed into pentacyclic skeleton lactams
24a (1.04 g) and 24b (1.98 g) in excellent yields (83% and 82%)
via a one-pot Pd/C-catalyzed Cbz-deprotection/hydrogenation
of α,β-unsaturated ester/cyclization amidation/hydrogenation
α,β-unsaturated imine/isomerization, efficiently establishing a
D-ring with a conjugated enamine−ester moiety.
Scheme 3. Mechanism for α,β-Unsaturated Ketone
Indolization Rearrangement
Then, in order to remove the carbonyl group of lactam and
form the double bond in the D ring, miscellaneous methods
were tried. However, unprotected enamine−ester moieties of
24a and 24b were incompatible with a series of directly
reductive methods (such as LiAlH4, BH3, etc.) or double-bond
formation methods (IBX, LDA/PhSeCl/m-CPBA,17 DDQ/
BSTFA,18 etc.). Therefore, thioamides 25a and 25b were
targeted with phosphorus pentasulfide (P2S5), providing
corresponding products in 87% and 82% yields (Scheme 4).
The configuration of 25a was confirmed through X-ray analysis.
Reductive desulfurization of 25b with Raney-Ni afforded 28 in
81% yield, which was delivered to (−)-jerantinine E (11) in 81%
yield via selective demethylation of 28 with oxidation/reduction
of quinone intermediate.13 Next, 25a and 25b also could be
treated with freshly prepared p-toluenesulfinyl chloride
(TolSOCl) to deliver α,β-unsaturated thiolactams 26a and
26b, which were then subjected to methylation with Meerwein’s
salt (Me3OBF4) followed by sodium borohydride (NaBH4)
reduction in situ to afford (−)-16-methoxytabersonine (8) and
27, respectively. Subsequently, (−)-jerantinine A (9) and
(−)-jerantinine C (10) could be obtained according to the
oxidation/reduction demethylation from 27 and 26b, respec-
tively. Importantly, this is the first asymmetric total syntheses of
(−)-jerantinines A, C, and E in 12−13 overall steps. The late-
stage oxidative functionalization from 16-methoxytabersonine
(8) to vindoline (7) was realized in yield of 46% for four
steps.10b,c,19 Finally, Boger coupling of (−)-vindoline (7) with
catharanthine afforded (+)-vinblastine (1) and its C-20′ isomer
quaternary stereocenter at C5 are steric hindrance against the
aromatic ring of phenyldrazine in TS-1 and TS-2. The methoxy
group on phenyldrazine resulted in disfavored sterically
hindered TS-3. TS-4 could afford the best selectivity and yield
predominantly, owing to the stable six-membered transition
state and remote methoxy group. We need to point out that the
indolization rearrangement on both sensitive (α,β-unsaturated
carbonyl is prone to Michael addition when the temperature or
acidity increasing) and inert (the reactivity of the carbonyl group
is depressed in the condensation due to the conjugated C−C
double bonds) α,β-unsaturated ketones 13a and 13b without
quaternary carbon of C5 could never afford the desired products
due to the higher energy of the double-nitrogen six-membered-
Scheme 4. Divergent Total Syntheses of Aspidosperma and Vinca Alkaloids
C
DOI: 10.1021/acs.orglett.7b03694
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Organic Letters
Letter
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(+)-leurosidine in 1.9:1 β/α diastereoselectivity in 17 overall
linear steps.8g,h
In summary, we have developed a concise and stereo-
controlled strategy for the asymmetric syntheses of (−)-jer-
antinines A, C, and E, (−)-16-methoxytabersonine, (−)-vindo-
line, and (+)-vinblastine in 12−17 steps in which (−)-jer-
antinines A, C, and E underwent asymmetric total syntheses for
the first time. The efficient construction via synthesis designs
predicated on highly regio- and stereoselective transformations.
The presented strategy relies on a stereoselective intermolecular
inverse-electron-demand [4 + 2] cycloaddition, a challenging
α,β-unsaturated ketone indolization with excellent regio- and
stereoselectivity, and an efficient Pd/C-catalyzed one-pot
cascade reaction. Commercially and inexpensively available
materials, efficient synthetic routes, and gram-scale quantities all
define this synthetic route as a potential and promising path for
new drug discovery and process. Further investigation of this
strategy for the syntheses of other alkaloids and analogues for
biological studies is currently underway in our group.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03694.
Experimental procedures, NMR spectral, X-ray, and
analytical data for all new compounds (PDF)
Accession Codes
CCDC 1542172 and 1577175 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xfjiang@chem.ecnu.edu.cn.
ORCID
Xuefeng Jiang: 0000-0002-1849-6572
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support provided by The National
Key Research and Development Program of China
(2017YFD0200500), NSFC (21722202, 21672069,
21472050), DFMEC (20130076110023), Fok Ying Tung
Education Foundation (141011), Program for Shanghai Rising
Star (15QA1401800), Professor of Special Appointment
(Eastern Scholar) at Shanghai Institutions of Higher Learning,
and National Program for Support of Top-notch Young
Professionals. We thank Prof. T.-S. Kam from the University
of Malaya for copies of the original NMR spectra of jerantinines
A, C, and E.
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DOI: 10.1021/acs.orglett.7b03694
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