Synthesis of (-)-pseudotabersonine, (-)-pseudovincadifformine, and (+)-coronaridine enabled by photoredox catalysis in flow

Article abstract of DOI:10.1021/ja506170g

Natural product modification with photoredox catalysis allows for mild, chemoselective access to a wide array of related structures in complex areas of chemical space, providing the possibility for novel structural motifs as well as useful quantities of less abundant congeners. While amine additives have been used extensively as stoichiometric electron donors for photocatalysis, the controlled modification of amine substrates through single-electron oxidation is ideal for the synthesis and modification of alkaloids. Here, we report the conversion of the amine (+)-catharanthine into the natural products (-)-pseudotabersonine, (-)-pseudovincadifformine, and (+)-coronaridine utilizing visible light photoredox catalysis.

Full text of DOI:10.1021/ja506170g

Communication
pubs.acs.org/JACS
Synthesis of (−)-Pseudotabersonine, (−)-Pseudovincadifformine, and
(+)-Coronaridine Enabled by Photoredox Catalysis in Flow
Joel W. Beatty and Corey R. J. Stephenson*
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States
S
* Supporting Information
Scheme 1. Catharanthine Fragmentation Provides Access to
Structurally Diverse Alkaloids
ABSTRACT: Natural product modification with photo-
redox catalysis allows for mild, chemoselective access to a
wide array of related structures in complex areas of
chemical space, providing the possibility for novel
structural motifs as well as useful quantities of less
abundant congeners. While amine additives have been
used extensively as stoichiometric electron donors for
photocatalysis, the controlled modification of amine
substrates through single-electron oxidation is ideal for
the synthesis and modification of alkaloids. Here, we
report the conversion of the amine (+)-catharanthine into
the natural products (−)-pseudotabersonine, (−)-pseudo-
vincadifformine, and (+)-coronaridine utilizing visible light
photoredox catalysis.
unable and selective methods for the controlled redox
Tmanipulation of complex substrates are essential to
successful semisynthetic efforts, and photoredox catalysis offers
unique opportunities in this regard.1 While photoredox catalysis
has been utilized to great effect in a substantial body of
methodology, examples of its use in natural product synthesis are
comparatively limited.2 Furthermore, the photooxidation of
amine substrates has generally been limited to the functionaliza-
tion of highly activated tetrahydroisoquinoline derivatives,3,4
while the use of complex amines as a platform for synthesis has
garnered minimal attention.3 In light of the abundance of
alkaloids with amine functionality, we set out to explore the
synthesis of a number of structurally related natural products to
further test the limits of photoredox catalysis in a complex
setting.
Natural product modification for the production of bio-
logically active compounds holds significant potential for
material access, as the need for a multistep synthesis of starting
material can be obviated by biological production on scale. The
natural product (+)-catharanthine 1 was identified as an ideal
entry point for the synthesis of a number of structurally related
alkaloids through a common α-aminonitrile intermediate
(Scheme 1). While catharanthine itself lacks notable bioactivity,5
it has been the subject of much research due to its ability to
undergo a unique fragmentation of its C16−C21 bond,6 which
has chiefly been exploited in the synthesis of the clinically
approved chemotherapeutic agent vinblastine7 and analogs
thereof.8 Catharanthine’s abundance has contributed to the
rationale behind the development of a semisynthetic strategy to
vinblastine, as synthetically useful quantities are available from
cell cultures.6 A variety of oxidative,8,9 reductive,10 electro-
chemical,11 and photolytic12 methods for the fragmentation of 1
have been reported, and we set out to investigate the synthetic
utility of catharanthine fragmentation in the synthesis of a
number of related alkaloids.
Chief among our interests was the alkaloid (−)-pseudota-
bersonine 2 (Scheme 1), which was first generated from
catharanthine by Gorman et al. by refluxing catharanthine in
glacial acetic acid for 16 h.13 Unfortunately, catharanthine’s
potential as a chiral pool material in such investigations was
hampered by an estimated 90% racemization of the starting
material and only 20% yield.14 Kutney et al. also reported
formation of pseudotabersonine from catharanthine through a
two-step reduction10-oxidation15 procedure, affording 2 in 18%
overall yield, also with low enantiopurity.14 Alternative examples
of pseudotabersonine total syntheses are exclusively racemic.16
Visible light irradiation of catharanthine in the presence of
polyfluorinated catalyst Ir(dF(CF3)ppy)2(dtbbpy)PF617 5 and 2
equiv of trimethylsilyl cyanide (TMSCN) provided the cyanated
Received: June 19, 2014
© XXXX American Chemical Society
A
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Journal of the American Chemical Society
Communication
fragmentation product 6 in 93% after 3 h (Scheme 2A).18 We
further evaluated the efficiency of the transformation in a flow
product in 90% yield after 3 h (Scheme 2C). While this process
provided the natural product in high yield, our sample displayed
significantly lower optical rotation ([α]2D6 = −172 (c 1.0 MeOH))
than that reported for the antipodal natural sample ([α]2D6 = +320
(MeOH));23 further analysis showed that the alkaloid was
obtained in an enantiomeric ratio of only 2:1. While this ratio
could be improved to 20:1 by performing the reaction at 60 °C,
the improved enantioselectivity was accompanied by a reduction
in reaction efficiency, with inconsistent yields ranging from 5 to
24%. This inconsistency in yield was also observed for the redox
byproducts 7 and 8 and can likely be attributed to reduced
solubility of both reactants and products as inhomogeneity was
observed at these temperatures. Upon formation of the internal
iminium ion, a transannular Pictet−Spengler reaction provides
the natural product, and the configuration of C14 (Scheme 2B)
dictates the stereochemical outcome of the transformation. The
racemization mechanism is expected to involve iminium
tautomerization at C14, which is possible from both proposed
dihydropyridinium intermediates.
Scheme 2. Synthesis of (−)-Pseudotabersonine
To eliminate the possibility of epimerization from the initial
iminium ion intermediate, hydrogenation of the fragmentation
product 6 was performed to yield 9 with high diastereoselectivity
(Scheme 3), which we anticipated would provide (−)-pseudo-
Scheme 3. Synthesis of (+)-Coronaridine
photochemical reactor19 with the intention to decrease reaction
time, improve scalability, and allow for the safe, controlled
generation of HCN.20 In a flow reactor with a 1.34 mL internal
volume, the fragmentation reaction was complete with a
residence time of only 2 min and with a slightly improved yield
of 96%.
vincadifformine 3 as the rearrangement product. Interestingly,
subjection of crude 9 to the aminonitrile rearrangement
conditions did not provide 3 but instead yielded the natural
product (+)-coronaridine 4 as the sole product in 48% yield over
two steps. This is the highest yielding preparation of coronaridine
from catharanthine reported to date13 and represents a net
hydrogenation of catharanthine with diastereoselectivity oppo-
site that dictated by the substrate. The diastereomeric hydro-
genation product (+)-dihydrocatharanthine was prepared in 93%
yield from catharanthine as a single diastereomer through
hydrogenation with Adams’ catalyst.24
Our difficulties in producing pseudovincadifformine through
iminium isomerization led us to investigate an alternative
photocatalysis approach to the natural product.15 Hydrogenation
of aminonitrile 6 with heterogeneous palladium followed by
workup with sodium borohydride provided the tertiary amine 11
in 98% yield with a 12:1 diastereomeric ratio in favor of the
desired β-epimer (Scheme 4). Exposure of the resultant amine to
oxidative photoredox conditions in flow led to the formation of
(−)-pseudovincadifformine in 58% yield using diethyl 2-bromo-
2-methylmalonate 12 as the terminal oxidant.25 While the C3
and C21 methylene units are both aligned well for oxidation, the
steric accessibility of C3 may provide an explanation for the
selectivity observed.
As the demonstrated photocatalytic fragmentation of
catharanthine is redox neutral, we hoped that an isohypsic
synthesis of pseudotabersonine could be achieved through an
iminium isomerization/transannular Pictet−Spengler cascade
from 6 (Scheme 2B). Acidic conditions proved effective to
facilitate iminium isomerization; refluxing 6 in toluene with 4
mol % benzoic acid for 1 h provided a mixture of three
compounds, including pseudotabersonine which was isolated in
13% yield (Scheme 2C). The reaction also yielded cyanated
pseudotabersonine 7 and reduced starting material 8, which is
symptomatic of redox-disproportionation. Interestingly, when 7
and 8 were combined in a 1:1 ratio and subjected to the
optimized rearrangement conditions at reflux (vide infra),
pseudotabersonine was isolated in 65% as the only product
from the reaction, suggesting a role for these species as possible
intermediates in the transformation of 6 to pseudotabersonine.
This observation supports the possibility of intermolecular
hydride transfer as an operative mechanism, but does not exclude
the alternative possibility of azomethine ylide isomerization.21
The rearrangement conditions were modified to include a full
equivalent of trifluoroacetic acid with the aim of stoichiometri-
cally forming the corresponding dihydropyridinum ion.22 These
conditions provided pseudotabersonine as the only observed
A mechanistic proposal consistent with the observed reactivity
red
proceeds with oxidation of the substrate (E1/2 = +0.60 V vs
SCE)11 by the excited state of photocatalyst 5 (E1/2
*
/II = +1.21
III
V vs SCE) (Scheme 5).17a The resultant radical cation 13
B
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Journal of the American Chemical Society
Communication
Scheme 4. Synthesis of (−)-Pseudovincadifformine
Scheme 6. Photocatalytic Fragmentation of Hydrogenated
Iboga Alkaloids
Scheme 7. Homodesmotic Strain Release Values
Scheme 5. Proposed Catalytic Cycle for Fragmentation
the thermodynamic aspects of the catharanthine fragmentation,
this driving force is clearly mitigated by alkene hydrogenation.
In conclusion, the utility of photoredox catalysis as a tool for
alkaloid manipulation has been demonstrated in the semisyn-
thesis of (−)-pseudotabersonine, (−)-pseudovincadifformine,
and (+)-coronaridine in 86%, 55%, and 46% overall yield from
catharanthine, respectively (Scheme 8). To the best of our
undergoes fragmentation to produce the ring opened radical
cation 14 which is then trapped stereoselectively by cyanide.
Reduction and protonation of 15 then affords the cyanated
fragmentation product and regenerates the Ir(III) species.
Interestingly, when cyanide was excluded from the reaction
catharanthine was recovered unchanged, suggesting reversibility
of the fragmentation event.
Scheme 8. Synthetic summary
With both coronaridine 4 and dihydrocatharanthine 10 in
hand, the generality of the light-mediated fragmentation reaction
could be studied in more detail. Both 4 and 10 were subjected to
the fragmentation conditions but required elevated temperature
(50 °C) in addition to a residence time 21 times longer. A 25%
yield of fragmented material was obtained from 4, with slightly
higher fragmentation efficiency observed for 10. The decreased
reaction efficiency observed for the hydrogenated substrates in
comparison to catharanthine led us to computationally examine
the role of ring-strain in fragmentation efficiency, beginning with
B3LYP/6-31G* geometry optimization of relevant structures for
each of the three Iboga alkaloids (Scheme 6).26 Consistent with
the high experimental efficiency observed, homodesmotic
cleavage27 of the C16−C21 bond of catharanthine releases
4.23 kcal/mol upon fragmentation.18 Ring strain is clearly less of
a driving force in the fragmentation of the hydrogenated
alkaloids, as 4 gains 0.08 kcal/mol and 10 releases 0.00 kcal/mol
(Scheme 7). Energy comparison of 4 and 10 reveals that axial
orientation of the ethyl group contributes 3.15 kcal/mol of
energy to the ring-closed starting material; while this energy
difference is significant, it is balanced by a similar energy
difference between the ring-opened diastereomers 17 and 11.
Although ring-strain release seems to contribute significantly to
knowledge, for each natural product this represents the highest
yielding synthetic route reported to date. Significantly, the
synthesis of (−)-pseudovincadifformine relies upon visible light
photoredox catalysis for two of the three total steps. The ability
to efficiently generate natural products from a common advanced
intermediate in this manner allows for rapid access to alternate
alkaloid scaffolds, ultimately paving the way for further synthetic
efforts toward structural analogs and more complex synthetic
targets.
C
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Journal of the American Chemical Society
Communication
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ASSOCIATED CONTENT
* Supporting Information
Experimental details, computational details, characterization
data, and complete ref 26. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
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Tetrahedron Lett. 1991, 32, 3035. (b) Cocquet, G.; Rool, P.; Ferroud, C.
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AUTHOR INFORMATION
Corresponding Author
crjsteph@umich.edu
Notes
■
The authors declare no competing financial interest.
(15) Kutney, J. P.; Brown, R. T.; Piers, E.; Hadfield, J. R. J. Am. Chem.
Soc. 1970, 92, 1708.
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(18) See the Supporting Information for details.
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ACKNOWLEDGMENTS
■
The authors thank Dr. Joseph W. Tucker for preliminary
experimental contributions and Dr. James Devery, Dr. James
Douglas, Mr. John Nguyen, and Professor Paul Zimmerman for
their helpful discussions and suggestions. Financial support for
this research from the NIH-NIGMS (R01-GM096129), the
Alfred P. Sloan Foundation, the Camille Dreyfus Teacher-
Scholar Award Program, Eli Lilly, Novartis, and the University of
Michigan is gratefully acknowledged.
(20) For a review see: Garlets, Z. J.; Nguyen, J. D.; Stephenson, C. R. J.
Isr. J. Chem. 2014, 54, 351.
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