Enantioselective Synthesis of (-)-Vallesine: Late-Stage C17-Oxidation via Complex Indole Boronation

Article abstract of DOI:10.1021/acs.orglett.8b01428

The first enantioselective total synthesis of (-)-vallesine via a strategy that features a late-stage regioselective C17-oxidation followed by a highly stereoselective transannular cyclization is reported. The versatility of this approach is highlighted by the divergent synthesis of the archetypal alkaloid of this family, (+)-aspidospermidine, and an A-ring-oxygenated derivative, (+)-deacetylaspidospermine, the precursor to (-)-vallesine, from a common intermediate.

Full text of DOI:10.1021/acs.orglett.8b01428

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Enantioselective Synthesis of (−)-Vallesine: Late-Stage C17-Oxidation
via Complex Indole Boronation
Alyssa H. Antropow, Nicholas R. Garcia, Kolby L. White, and Mohammad Movassaghi*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
*
S Supporting Information
ABSTRACT: The first enantioselective total synthesis of (−)-vallesine via a strategy that features a late-stage regioselective C17-
oxidation followed by a highly stereoselective transannular cyclization is reported. The versatility of this approach is highlighted
by the divergent synthesis of the archetypal alkaloid of this family, (+)-aspidospermidine, and an A-ring-oxygenated derivative,
(
+)-deacetylaspidospermine, the precursor to (−)-vallesine, from a common intermediate.
7
8
he aspidosperma alkaloids, a family containing over 250
structurally diverse members, have been a subject of
(+)-haplocidine (5) and (−)-cylindrocarpidine (6). Recently,
we reported the first total synthesis of alkaloid (+)-5 through a
strategy employing highly stereoselective cyclization events and
T
significant interest over several decades because of their
1
,2
3e
structural complexity and diverse biological activity. The
development of a unified strategy to access this diverse family
of natural products is critical to enable access to a multitude of
these alkaloids for comprehensive chemical and biological
studies. Our group has pursued a unified strategy to allow
diversification of complex intermediates en route to various
regioselective late-stage A-ring functionalization. This strategy
relies on the in situ masking of the C9-amine via opening of the
C19-hemiaminal to form an iminium ion, which is subject to
directed palladium-catalyzed ortho-C−H acetoxylation of the
aspidosperma indoline core. While this strategy provided direct
access to oxidized members of the fendleridine subfamily, it is
not a viable approach for alkaloid (−)-1 and related alkaloids
without C21-oxidation. We therefore sought a strategy toward
these alkaloids as part of our interest in biogenetically inspired
late-stage arene oxidation of aspidosperma alkaloids. Herein we
describe the first total synthesis of (−)-vallesine (1) based on a
late-stage regioselective complex indole boronation strategy.
This strategy provides access to both (+)-deacetylaspidosper-
mine (3) and (+)-aspidospermidine (4) from a common
advanced intermediate.
3
members of this alkaloid family. One intriguing subset of the
aspidosperma alkaloids are those that contain C17-oxidation,
including the antiplasmodial alkaloid (−)-vallesine (1) (Figure
4
5
1
), (−)-aspidospermine (2), and (+)-deacetylaspidospermine
6
(
3). Related compounds include the C21-oxygenated variants
9
,10
While aspidospermine (2)
has served as an archetypal
target for C17-oxidized aspidosperma alkaloids, most current
synthetic routes rely on a late-stage Fischer indole synthesis
9a
utilizing 2-methoxyphenylhydrazine. Recent advances include
the synthesis of alkaloid (−)-2 through an intramolecular
10b
cycloaddition cascade strategy and the palladium-catalyzed
decarboxylative asymmetric allylation approach toward alkaloid
10c
(
+)-(2). The reliance on introducing C17-oxidation from
commercial materials is a shared concept in all prior approaches
to alkaloid 2. We identified an opportunity to apply a strategy
1
1,12
for regioselective indole boronation
to offer a new
Figure 1. Structures of (−)-vallesine (1) and related aspidosperma
alkaloids.
Received: May 6, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01428
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
3
c,e,f
opportunity for diversification of key intermediates en route to
aspidosperma alkaloids.
Our retrosynthetic analysis of the C17-oxidized aspidosper-
ma alkaloids is illustrated in Scheme 1, wherein we envisioned
a disubstituted indole,
possibly allowing a direct regiose-
12c,e,f
lective C17-boronation (Scheme 2B).
We have previously demonstrated the synthesis of lactam
(+)-8 with >99% ee via an asymmetric alkylation strategy
utilizing the synthetic (+)-(1R,2R)-pseudoephenamine chiral
3c
15
Scheme 1. Retrosynthetic Analysis
auxiliary, prepared in four steps from commercial materials.
For the purposes of this study, we required lactam (−)-8, which
we chose to synthesize through a parallel strategy utilizing the
commercially available (+)-(1S,2S)-pseudoephedrine chiral
3a
16
auxiliary to provide lactam (−)-8 in 80% ee. In order to
access the indole substrate for the planned boronation, we
conducted removal of the N1-p-methoxybenzyl group from
lactam (−)-8 under Birch reductive conditions using sodium
metal in liquid ammonia to afford lactam 9 in 91% yield
(
Scheme 3), followed by hydrogenation to afford indole 10 in
Scheme 3. Synthesis of C17-Oxidized Intermediate Phenol
12
(
−)-vallesine (1) to arise from N1-formylation of (+)-deace-
tylaspidospermine (3). Informed by our studies of transannular
cyclization via amide activation
tions, we envisioned alkaloid (+)-3 to arise from lactam 7.
The necessary oxidation state at C17 would be introduced via
regioselective boronation of indole 10, a compound related to
intermediates that we have employed in syntheses of other
3c,d
and key prior contribu-
1
3
3c
aspidosperma alkaloids without A-ring oxygenation.
Consistent with our interest in functionalization of complex
indole-derived compounds and inspired by advances in Ir-
12
catalyzed boronation of various arenes, our group has
reported a direct and scalable method for the one-pot
conversion of C3-alkylindoles, including tryptophans and
tryptamines, to the corresponding C7-boronated compounds
9
9% yield. Importantly, complete and regioselective boronation
of indole 10 was accomplished using [Ir(cod)OMe] and
2
pinacolborane to provide boronic ester 11, which was then
subjected to oxidation using a solution of aqueous hydroxyl-
amine to provide phenol 12 in 31% yield over two steps
1
1
(Scheme 2A). Central to this strategy is a diboronation/
(
Scheme 3).
Scheme 2. Indole Boronation Strategy
Next, we required optimal conditions for transannular
cyclization to secure the pentacyclic aspidosperma core of
(
−)-vallesine (1). While we have previously promoted
transannular cyclization of lactam (−)-8 through an electro-
philic amide activation strategy to enable access to the
corresponding C19-iminium ion for further derivatization,
3
we envisioned that a partial reduction strategy would be more
effective in conversion of intermediate 12 to alkaloid (−)-1.
13
Inspired by seminal reports using lithium aluminum hydride
for the partial reduction of related lactams, we chose the milder
diisobutylaluminum hydride to enable the direct, efficient
formation of imine 13 from lactam 10 as a model substrate for
the projected cyclization en route to alkaloid (−)-1.
Intermediate imine 13 was reduced using lithium aluminum
2
,3c
hydride to afford (+)-aspidospermidine (4)
over two steps from lactam 10 (Scheme 4).
in 77% yield
With the optimized conditions for reductive transannular
cyclization in hand, we evaluated their application to the
requisite C17-oxygenated aspidosperma intermediate. Methyl-
ation of phenol 12 with iodomethane in the presence of cesium
carbonate afforded C17-methyl ether 7 in 98% yield as the
optimal substrate for transannular cyclization (Scheme 5). In
the event, exposure of lactam 7 to diisobutylaluminum hydride
led to transannular cyclization, and the resultant imine was
protodeboronation sequence that takes advantage of the
increased nucleophilicity and basicity at C2 of the C3-
substituted indoles. Related advances include the regioselective
C6-boronation of tryptophan derivatives, wherein a triisopro-
pylsilyl blocking group influences the regiochemical outcome.
In our planned boronation strategy toward C17-oxygenated
14
aspidosperma alkaloids, the synthetic intermediate 10 contains
B
DOI: 10.1021/acs.orglett.8b01428
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Synthesis of (+)-Aspidospermidine (4)
AUTHOR INFORMATION
Corresponding Author
E-mail: movassag@mit.edu.
■
*
ORCID
Mohammad Movassaghi: 0000-0003-3080-1063
Notes
The authors declare no competing financial interest.
Scheme 5. Synthesis of (+)-Deacetylaspidospermine (3) and
(−)-Vallesine (1)
ACKNOWLEDGMENTS
We are grateful for financial support from NIH NIGMS
GM074825) and Amgen. A.H.A. acknowledges an Amgen
■
(
Graduate Fellowship in Synthetic Chemistry. N.R.G. acknowl-
edges support from the MIT Undergraduate Research
Opportunity Program. K.L.W. acknowledges a National Science
Foundation Graduate Fellowship and an Amgen Graduate
Research Fellowship. We thank Dr. Marius Mewald, a
postdoctoral fellow in the Movassaghi group, for helpful
discussions.
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(
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D
DOI: 10.1021/acs.orglett.8b01428
Org. Lett. XXXX, XXX, XXX−XXX