Nine-step enantioselective total synthesis of (-)-vincorine

Article abstract of DOI:10.1021/ja402933s

A concise and highly enantioselective total synthesis of the akuammiline alkaloid (-)-vincorine has been accomplished. A key element of the synthesis is a stereoselective organocatalytic Diels-Alder, iminium cyclization cascade sequence, which serves to construct the tetracyclic alkaloid core architecture in one step from simple achiral precursors. The challenging seven-membered azepanyl ring system is installed by way of a single electron-mediated cyclization event initiated from an acyl telluride precursor. The total synthesis of (-)-vincorine is achieved in nine steps and 9% overall yield from commercially available starting materials.

Full text of DOI:10.1021/ja402933s

Communication
pubs.acs.org/JACS
Nine-Step Enantioselective Total Synthesis of (−)-Vincorine
Benjamin D. Horning and David W. C. MacMillan*
Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, United States
S
* Supporting Information
Scheme 1. Akuammiline AlkaloidsRetrosynthesis of
ABSTRACT: A concise and highly enantioselective total
synthesis of the akuammiline alkaloid (−)-vincorine has
been accomplished. A key element of the synthesis is a
stereoselective organocatalytic Diels−Alder, iminium cyc-
lization cascade sequence, which serves to construct the
tetracyclic alkaloid core architecture in one step from
simple achiral precursors. The challenging seven-mem-
bered azepanyl ring system is installed by way of a single
electron-mediated cyclization event initiated from an acyl
telluride precursor. The total synthesis of (−)-vincorine is
achieved in nine steps and 9% overall yield from
commercially available starting materials.
Vincorine
he Vinca alkaloid natural products have historically served
T
as valuable lead candidates in the development of anti-
cancer agents (vinblastine),1a,b vasodilators (vincamine),1c anti-
psychotics, and anti-hypertensives (reserpine).1d Recently,
members of the biologically active akuammiline family of
Vinca alkaloids have emerged as high-profile targets for
chemical synthesis and medicinal chemistry studies.2 Vincorine
(1) is the parent compound of an akuammiline alkaloid
subclass characterized by a synthetically challenging tetracyclic
core that incorporates a strained seven-membered azepanyl ring
and a pyrroloindoline motif. In preliminary assays, the related
alkaloids echitamine (2) and corymine (not shown) were found
to exhibit anti-cancer activity3 and glycine receptor antago-
nism,4 respectively. With the goal of devising a concise
synthesis of this common core structure for further biological
investigation, a number of research laboratories have under-
taken the synthesis of vincorine.5 Indeed, recent total syntheses
by the Qin group6a (35 steps, racemic) and the Ma group6b (18
steps, 64% ee) have served to highlight the significant structural
challenges posed by this cage-like system. In this Communi-
cation, we disclose a highly enantioselective nine-step total
synthesis of (−)-vincorine, which employs organocascade
catalysis7 as a central enabling feature. We anticipate that the
general synthetic strategy described herein will prove readily
adaptable to other bioactive akuammiline alkaloid natural
products and analogues thereof.
structural and stereochemical elements of the akuammiline core
would arise from a single organocatalytic Diels−Alder8 iminium
cyclization cascade event beginning from simple, achiral starting
materials (4 and 5). We have previously demonstrated the
complexity-generating capacity of other organocatalytic9,10
cascade mechanisms in the recent total syntheses of strychnine,
minfiensine,11a and additional selected alkaloids of the
Strychnos, Aspidosperma, and Kopsia families.11b
In the specific context of this vincorine synthesis program, we
envisioned employing a catalytic cascade sequence to effect the
overall conversion of tryptamine 4 to the tetracyclic adduct 7 in
one step. As outlined in Scheme 2, the sequence would begin
with condensation of secondary amine catalyst 6 onto enal 5 to
form an activated iminium ion. In the proposed transition state
(TS-A), orientation of the reactive π-system away from the
catalyst gem-dimethyl group would facilitate effective shielding
of one π-face by the benzyl group, thereby enabling a highly
stereoselective endo Diels−Alder reaction with diene 4, to
deliver enamine cycloadduct 8. Brønsted acid-catalyzed
interconversion of enamine 8 and iminium ion 9 by the
ammonium salt of 6 would precipitate intramolecular 5-exo
Design Plan. From a retrosynthetic standpoint, we
envisioned the disconnection of vincorine via two key steps
(Scheme 1). While previous syntheses of vincorine have relied
on C−N bond formation to forge the strained seven-membered
azepanyl system, we reasoned that an intramolecular single
electron-mediated C−C bond formation (initiated from
compound 3) might offer additional strategic advantages in
that the requisite allylic methine stereochemistry would be
produced along with the embedded heterocycle. The remaining
Received: March 22, 2013
© XXXX American Chemical Society
A
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Communication
The total synthesis of vincorine was initiated with the
preparation of diene 4 in two steps from commercially available
5-methoxy-N′-Boc tryptamine (10), via methylation and then
directed metalation/Negishi coupling13 (Scheme 3). For the
key Diels−Alder/cyclization cascade, a survey of chiral
secondary amines revealed that the first-generation Diels−
Alder imidazolidinone catalyst 6 was both highly efficient and
stereoselective. Using optimized reaction conditions (6·HBF4,
MeCN, −20 °C), the tetracyclic vincorine core system 7 was
generated in 70% yield and 95% ee (Table 1, entry 6).
Scheme 2. Enantioselective Organocatalytic Cascade
Sequence
Table 1. Organocatalytic Diels−Alder/Cyclization Cascade
a
b
entry
HX
temp (°C)
time (h)
yield (%)
ee (%)
1
2
3
4
HClO4
HCl
0
0
4
4
4
6
6
6
38
25
71
75
62
88
73
93
94
94
95
HBF4
HBF4
HBF4
HBF4
0
−10
−10
−20
c
5
d
6
73 (70)
a
b
d
Yield based on SFC analysis relative to an internal standard.
Determined by SFC analysis. Reaction run with 5% v/v water.
Isolated yield.
c
With the majority of the requisite vincorine architecture in
hand, we next sought to rapidly install the final seven-
membered azepanyl ring by way of a 7-exo-dig radical
cyclization. As shown in Scheme 3, Pinnick oxidation14 served
to convert aldehyde 7 to carboxylic acid 11, prior to the
formation of an alkyl radical precursor in the form of an acyl
telluride. Specifically, the telluride 12 was generated in a
sequence involving formation of a mixed anhydride followed by
displacement with sodium phenyl telluride in good yield for the
overall transformation. Installation of a suitable π-system to
amine cyclization via the pendant carbamate group to generate
the tetracyclic product 7.12 Notably, the core structure 7 would
emerge from this transformation bearing three of the four
vincorine stereocentersincluding the all-carbon quaternary
center C(8)with the correct relative and absolute config-
uration.
a
Scheme 3. Nine-Step Enantioselective Catalytic Total Synthesis of Vincorine
a
Reagents and conditions: (a) NaH, DMF, 0 °C; MeI. (b) n-BuLi, DME, −40 °C; ZnCl2, −78 °C to rt; XPhos precatalyst, vinyl iodide. (c) NaClO2,
2-methyl-2-butene, THF, tert-butanol, H2O, 0 °C. (d) Isobutyl chloroformate, N-methylmorpholine, THF; diphenyl ditelluride, NaBH4, THF/
MeOH, rt. (e) TFA, rt. (f) 4-(tert-Butylthio)but-2-ynal, NaBH(OAc)3, CH2Cl2, rt. (g) 1,2-Dichlorobenzene, 200 °C. (h) Pd/C, H2, THF, −15 °C.
B
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Journal of the American Chemical Society
Communication
enable radical-mediated C−C bond cyclization was accom-
plished via Boc-deprotection and subsequent nitrogen
alkylation using 2-butynal-4-tert-butyl sulfide in a reductive
amination step. Notably, the acyl telluride moiety was
successfully maintained through multiple transformations,
readily withstanding exposure to neat trifluoroacetic acid and
sodium triacetoxyborohydride.
The suitability of the acyl telluride unit as the preferred alkyl
radical precursor was determined by comparison to a range of
alternative acyl-X fragmentation partners in the key cyclization
event (13→14, see Table 2).15 Attempts to achieve useful
our knowledge, this example represents the first use of an acyl
telluride as an effective alkyl radical precursor.
In the final step of the synthesis, the terminal unsaturation of
the allene functionality underwent selective hydrogenation
from the less hindered face to provide (−)-vincorine in 80%
yield as a single olefin isomer in nine steps and 9% overall yield
from the commercially available indole 10. The product
generated was identical in all spectroscopic respects to the
natural isolate (see Supporting Information).
In conclusion, we have developed a nine-step synthetic route
to (−)-vincorine from commercially available starting materials.
Key features of the synthesis include an organocatalytic Diels−
Alder/amine cyclization cascade and a 7-exo-dig radical
cyclization initiated from an unusual acyl telluride precursor.
The utility of this new cascade catalysis strategy is now being
explored in the production of a large collection of natural and
un-natural vincorine analogues including echitamine. Findings
from these studies will be reported in due course.
Table 2. Evaluation of Radical Cyclization Substrates
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
dmacmill@princeton.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the NIHGMS (R01
GM078201-07) and kind gifts from Merck, Amgen, and
Abbott. B.D.H. thanks Eli Lilly and Bristol-Myers Squibb for
graduate fellowships. Special thanks to Dr. Christoph Grondal
for work on related earlier studies.
a
b
Yield based on 1H NMR analysis. 1,2-Dichlorobenzene used as
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c
■
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