Enantioselective, protecting-group-free total synthesis of sarpagine alkaloids-A generalized approach

Article abstract of DOI:10.1002/anie.201407280

A generalized synthetic access to sarpagine alkaloids through a joint synthetic sequence has been accomplished. Its applicability is showcased by the enantioselective total syntheses of vellosimine (1), N-methylvellosimine (3 ), and 10-methoxyvellosimine (8). The synthetic sequence is concise (eight steps) from known compound 13, and requires no protecting groups. The indole heterocycle was introduced in the last step. This strategy allows access to sarpagine alkaloids through a shared synthetic route leading to precursor 10, which we term "privileged intermediate". Starting from this intermediate, all sarpagine alkaloids can be synthesized using phenylhydrazines with different substitution patterns (15-17). Our approach brings about the advantage, that synthesis optimization only needs to be performed once for many natural products. The key features of the synthesis are a [5+2]-cycloaddition and a ring enlargement.

Full text of DOI:10.1002/anie.201407280

Angewandte
Chemie
DOI: 10.1002/anie.201407280
Natural Product Synthesis
Enantioselective, Protecting-Group-Free Total Synthesis of Sarpagine
Alkaloids—A Generalized Approach**
Sebastian Krꢀger and Tanja Gaich*
Dedicated to Professor Johann Mulzer on the occasion of his 70th birthday
Abstract: A generalized synthetic access to sarpagine alkaloids
through a joint synthetic sequence has been accomplished. Its
applicability is showcased by the enantioselective total synthe-
ses of vellosimine (1), N-methylvellosimine (3), and 10-
methoxyvellosimine (8). The synthetic sequence is concise
(eight steps) from known compound 13, and requires no
protecting groups. The indole heterocycle was introduced in the
last step. This strategy allows access to sarpagine alkaloids
through a shared synthetic route leading to precursor 10, which
we term “privileged intermediate”. Starting from this inter-
mediate, all sarpagine alkaloids can be synthesized using
phenylhydrazines with different substitution patterns (15–17).
Our approach brings about the advantage, that synthesis
optimization only needs to be performed once for many
natural products. The key features of the synthesis are a [5+2]-
cycloaddition and a ring enlargement.
Unfortunately the scarcity of the natural products themselves,
and the lack of synthetic analogues of comparable complexity
have so far hampered further biological investigations.
When we launched our synthetic program on sarpagine
alkaloids (1–9), we not only aimed at solving the problem of
material supply for a single family congener, but at accom-
plishing a joint synthetic sequence that enables access to
a large number of sarpagines through a shared late-stage
synthetic intermediate, which we term “privileged intermedi-
ate”. At the outset we had to define the molecular structure of
this intermediate. Therefore, the individual congeners were
analyzed for common structure patterns as well as differences
in stereochemistry and oxidation states.
Important structural variations such as: 1) additional rings
[gardnutine (6), Figure 1], 2) variability of the absolute
S
arpagine alkaloids belong to the group of
monoterpenoid indole alkaloids. Their family
consists of more than 90 congeners, which
were mainly isolated from the plant family
Apocynaceae (specifically from the genus
Rauvolfia).[1] Cook et al. accomplished very
elegant total syntheses of some sarpagines
using Pictet–Spengler type chemistry (early
introduction of the indole core).[2] With
regard to the biosynthesis of these complex
molecular architectures, primary as well as
secondary cyclizations are well investigated
by Stçckigt et al.[3] Yet, the biological poten-
tial of these beautiful architectures, especially
when it comes to the investigation of synthetic
analogues, is by far underexplored. Substruc-
tures of sarpagines were synthesized by
Waldmann et al. for library design, and
revealed potent tyrosine kinase inhibitors.[4]
Figure 1. Selected family members of sarpagine alkaloids.
configuration at C16 [biosynthetic numbering; highlighted
in green in Figure 1], and 3) hydroxylation pattern of the
indole core (highlighted in red in Figure 1) were identified.
Furthermore, we assessed an octahydro-1H-2,6-methanoqui-
nolizine system as common structural motif of all sarpagines
(highlighted in blue in Figure 1 for vellosimine (1)).
With this analysis we directly deduced the retrosynthesis
leading us to ketone 10, as the “privileged intermediate”
(Figure 2A). From this last synthetic intermediate all sarpa-
gines can be synthesized in one step, introducing the different
hydroxylation patterns of the respective natural products by
[*] M. Sc. S. Krꢀger, Dr. T. Gaich
Institute of Organic Chemistry, Leibniz University of Hannover
Schneiderberg 1b, 30167 Hannover (Germany)
E-mail: tanja.gaich@oci.uni-hannover.de
[**] We thank the Alexander von Humboldt Foundation for financial
support provided by the Sofja Kovalevskaja prize, and the NMR and
mass spectrometry departments (M. Rettstadt, D. Kçrtje, E. Hofer,
and J. Fohrer, R. Reichel) of the Institute of Organic Chemistry for
extensive analyses.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201407280.
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[5+2] cycloadditions with regioselectivi-
ties around 2:1, typically yielding the
desired regioisomer 12 as a major prod-
uct.[10] When we performed the cyclo-
addition of 13 and 14, we obtained our
desired cycloadduct 19 in a 2:1 ratio (77%
combined yield) in favor of the desired
regioisomer and 93% ee (Scheme 1).
Luckily the stability of the vinyliodide
moiety in 14 allowed the direct assembly
of compound 19 without the need of
protecting groups.
Reductive removal of the bis(sulfox-
ide) after the [5+2] cycloaddition was
affected by treatment of 19 with trifluoro-
acetic anhydride and sodium iodide
affording dithiolane 20 in 68% yield.[10]
The next task was the formation of tri-
cycle 11 through an intramolecular palla-
dium-catalyzed enolate coupling. This
was achieved in a sequential manner by
treating 20 with L-selectride to form
ketone 12, which was reacted with palla-
dium (tetrakis)triphenylphosphine to
yield tricyclic ketone 11 in 88% yield
(Scheme 1).[7] This two-step process was
also performed in one pot, but then the
yields dropped significantly to about
50%.
Figure 2. Retrosynthetic analysis for a generalized synthesis of sarpagines 1, 3, and 8.
using the corresponding phenylhydrazines (15–17) in a Fischer
indole synthesis (Figure 2B).[5] The absolute configuration of
C16 (Figure 2A) can be adjusted to give the a-isomer, which
is thermodynamically favored.[6] Ketone 10 itself was
obtained through ring enlargement from compound 11.[7]
The tricyclic system of 11 was formed through a palladium-
catalyzed enolate coupling[8] starting from bicyclic compound
12. This compound 12 represents the product of a [5+2]-
cycloaddition between oxidopyridinium ion 14 and Aggar-
walꢀs chiral ketene equivalent 13 (prepared in four steps).[9]
Similar pyridinium ions are known to undergo intermolecular
Wittig reaction of 11 and deprotection of the dithiolane
moiety with Meerweinꢀs salt afforded ketone 21
(Scheme 2).[11] This set the stage for the ring enlargement
reaction to give ketone 10 in 80% yield. The ring enlargement
proceeded smoothly and regioselectively, resulting in the
exclusive insertion of the methylene group on the sterically
less hindered side.[12]
With ketone 10 in hands we carried out the Fischer indole
synthesis with phenylhydrazines 15–17.[13] In the course of this
reaction, enol ether 22 was converted to dimethylacetal 23,
1
which we observed by H NMR spectroscopy on the crude
sample. 23 was hydrolyzed in situ affording (+)-vellos-
imine (1) (+)-N-methylvellosimine (3), and (+)-10-
methoxyvellosimine (8) in 52–63% yield. As anticipated,
the desired absolute configuration at C-16 was exclusively
obtained under these reaction conditions in all three
natural products 1, 3, and 8.[14]
An important feature of this synthesis is the strategy to
pursue a “privileged intermediate”, which paves the
synthetic road to most of the sarpagine alkaloids in
a single last transformation—in our case the Fischer
indole synthesis. This avoids synthetic inconveniences
normally observed when substituents have to be varied
at the starting point of a synthesis, which at worst can cause
(partial) redesign of the route.
In conclusion we have accomplished a generalized,
enantioselective access to the sarpagine alkaloid family in
a very concise manner. (+)-Vellosimine (1), (+)-N-meth-
ylvellosimine (3), and (+)-10-methoxyvellosimine (8) were
synthesized in eight steps starting from known compounds
Scheme 1. The [5+2] cycloaddition reaction for the construction of the core
structure. Reagents and conditions: a) NiPr2Et, CH2Cl2, 12h, 77%;
b) TFAA, NaI, MeCN, 08C, 68%; c) L-selectride, THF, À788C, 94%;
d) KOtBu, PhOH, [Pd(PPh3)4], THF, reflux, 88%.
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Chemie
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Scheme 2. Synthesis of intermediate 10, and total syntheses of (+)-vellosimine (1),
(+)-N-methylvellosimine (3), and (+)-10-methoxyvellosimine (8).Reagents and condi-
=
tions: e) MeOCH PPh3; f) TFA, CH2Cl2, Me3OBF4, 58% (2 steps); g) TMSCH2N2, nBuLi,
THF, then MeOH; then silica, 80%; h) AcCl, MeOH, D, then water.
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14 and 13 (12 steps from commercial materials) in 10–13%
overall yields. The joint synthetic sequence requires no
protecting groups, and can be carried out on multigram
scale. Therefore the lack of synthetic analogues and the
limited amount of material, currently hampering detailed
biological testing, is no longer an issue. Our synthetic route
will enable the production of almost every family member on
demand. The syntheses of further sarpagine congeners are
currently performed in our laboratories.
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Received: July 16, 2014
Revised: August 29, 2014
Published online: && &&, &&&&
Keywords: cycloaddition · oxidopyridinium ion ·
.
[9] For
a review on 3-oxypyridinium ion cycloadditions, see:
ring enlargement · sarpagine alkaloid · total synthesis
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[14] NOESY analysis for the configuration of C16 is provided in the
Supporting Information.
[1] For a most recent compilation of newly isolated sarpagine
alkaloids, see: a) S.-H. Lim, Y.-Y. Low, S. K. Sinniah, K.-T. Yong,
K.-S. Sim, T.-S. Kam, Phytochemistry 2014, 98, 204 – 215; For an
overview on sarpagine alkaloids, see: b) M. Lounasmaa, P.
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[2] For most recent publications, see: a) C. R. Edwankar, R. V.
Edwankar, O. A. Namjoshi, J. Deschamps, X. Liao, J. M. Cook, J.
Org. Chem. 2013, 78, 6471 – 6487; b) W. Yin, S. M. Kabir, Z.
Angew. Chem. Int. Ed. 2014, 53, 1 – 4
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Communications
Natural Product Synthesis
S. Krꢁger, T. Gaich*
&&&& — &&&&
Enantioselective, Protecting-Group-Free
Total Synthesis of Sarpagine Alkaloids—A
Generalized Approach
A general synthesis of saragine alkaloids
proceeds through an eight-step se-
quence. The enantioselective total syn-
thesis of (+)-vellosimine, (+)-N-methyl-
vellosimine, and (+)-10-methoxyvellos-
imine has been accomplished without
using protecting groups. A “privileged
intermediate” is generated in the last
step, from which all other members of the
alkaloid family can be synthesized.
4
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Angew. Chem. Int. Ed. 2014, 53, 1 – 4
These are not the final page numbers!