Total synthesis of (+)-scholarisine A

Article abstract of DOI:10.1021/ja211840k

An effective total synthesis and assignment of the absolute configuration of the architecturally challenging compound (+)-scholarisine A has been achieved via a 20-step sequence. Highlights include a reductive cyclization involving a nitrile and an epoxide, a modified Fischer indole protocol, a late-stage oxidative lactonization, and an intramolecular cyclization leading to the indolenine ring system of (+)-scholarisine A.

Full text of DOI:10.1021/ja211840k

Communication
pubs.acs.org/JACS
Total Synthesis of (+)-Scholarisine A
Gregory L. Adams, Patrick J. Carroll, and Amos B. Smith, III*
Department of Chemistry, Laboratory for Research on the Structure of Matter, and Monell Chemical Senses Center, University of
Pennsylvania, Philadelphia, Pennsylvania 19104, United States
S
* Supporting Information
carpine (8)9 and aspidophylline A (9),10 the latter being the
target of a recent elegant racemic total synthesis by Garg.11
ABSTRACT: An effective total synthesis and assignment
of the absolute configuration of the architecturally
Alternatively, 7 could give rise to picrinine (4)12 upon loss of
challenging compound (+)-scholarisine A has been
achieved via a 20-step sequence. Highlights include a
reductive cyclization involving a nitrile and an epoxide, a
modified Fischer indole protocol, a late-stage oxidative
lactonization, and an intramolecular cyclization leading to
the indolenine ring system of (+)-scholarisine A.
the acetoxymethyl moiety from C-16 and oxidation at C-5.
Scholarisine A (1), the target of this study, is proposed to arise
from 4 via initial opening of the oxygen bridge at C-2 via
participation of the indoline nitrogen and cleavage of the N-4−
C-5 bond to furnish an aldehyde at C-5; migration of the
double bond, nucleophilic attack by the resulting enamine
carbon, and capture of the resulting hydroxyl group by the
methyl ester would lead to the lactone ring of 1.1
Given the novel architectural features of 1, in conjunction
with the inherent synthetic challenge and the possibility of
discovering a substrate that would permit a novel enantiose-
lective route to the currently unobtainable akuammiline
alkaloids via a late-stage “retro-biosynthetic” fragmentation,13
we initiated a synthetic program to construct 1 in 2008. We
report here the first total synthesis of (+)-scholarisine A (1),
comprising an enantiospecific strategy.
cholarisine A (1), a monoterpenoid indole alkaloid first
S
isolated in 2008 from the leaves of Alstonia scholaris,
comprises an unprecedented scaffold containing a bridged
lactone inscribed in a cagelike skeleton (Figure 1).1 Although
From the retrosynthetic perspective, we envisioned scholar-
isine A (1) to arise via cyclization and oxidation of indole
lactone 10 (Figure 2). Construction of the latter would entail
Figure 1. Biosynthesis of (+)-scholarisine A (1).
no information on the bioactivity of 1 is currently available,
congeners of a putative biosynthetic precursor, picraline (3),2
have been reported to be potent, selective inhibitors of SGLT2,
a renal cortex membrane protein that regulates glucose
reabsorption, which was recently validated as a target for
type-II diabetes intervention.3
Figure 2. Retrosynthetic analysis of (+)-scholarisine A (1).
Alkaloids that are derived biosynthetically from geissoschi-
zine (5) via a cyclization leading to a bond between C-7 and C-
164 are classified as the akuammiline alkaloids (Figure 1),5
named after akuammiline (7),6 which was first characterized in
1932.7 Loss of the acetoxymethyl moiety leads to strictamine
(6).8 Hydrolysis and further functionalization is envisioned to
provide alkaloids with a furoindoline core such as aspidodasy-
an oxidative lactonization of diol 11 with subsequent
deprotection. Diol 11 in turn could be derived from lactone
12 via homologation and reduction, the latter being obtained
Received: December 19, 2011
Published: January 25, 2012
© 2012 American Chemical Society
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from tricyclic amine 13 upon amine protection, oxidation, and a
Fischer indole annulation. Amine 13, the cornerstone construct
of this synthetic venture, was envisioned to be the product of a
reductive cyclization involving the nitrile and epoxide
functionalities present in lactone 14, which could be prepared
from known bicyclic lactone (−)-15.14
Scheme 2
Toward this end, cyanation of (−)-15 with cyanobenzo-
trizole (Scheme 1) using basic conditions15 provided nitrile
Scheme 1
lactone (+)-1616 in 60% yield after an extractive workup.
Alkylation occurring from the convex face utilizing ethyl iodide
furnished cyanolactone (−)-1716 in 71% yield, which upon
epoxidation with m-chloroperoxybenzoic acid (mCPBA) in
chloroform led to a mixture of epoxides.17 The desired epoxide
(−)-1416 was formed selectively over the undesired (−)-18;16
the ratio was 3:1. Crystallization from toluene provided pure
(−)-14 in 58% yield.
Reductive cyclization of epoxide (−)-14 was then achieved
employing rhodium on alumina18 via hydrogenation with in situ
epoxide ring opening to generate tricylic compound (−)-1316
(Scheme 2). Benzoyl protection of the amine in tricycle (−)-13
followed by oxidation of the hydroxyl group with Dess−Martin
periodinane (DMP)19 then led to ketone (+)-19.16
this one-pot, two-step sequence proceeded in 63% yield.
Nuclear Overhauser effect NMR spectroscopy (NOESY)
studies suggested the average conformation of the carbonyl in
(+)-22 to be that illustrated in Figure 3. External nucleophilic
attack of (+)-22 would explain the high selectivity observed
during the formation of diol (+)-11.
We next turned to installation of the indole ring.20 A Fischer
synthesis utilizing 1-benzyl-1-phenylhydrazine (pyridine-HCl,
110 °C)21 furnished the protected indole lactone (−)-12. We
found that 1-benzyl-1-phenylhydrazine proved highly effective,
whereas use of phenylhydrazine led to complete decom-
position.22 Indole (−)-12 was next reduced with LiAlH4 to
furnish diol (+)-20,16 which cocrystallized with chloroform,
permitting confirmation of the absolute configuration by X-ray
analysis. Diol (+)-20 was next selectively protected as the
TBDPS ether (+)-21,23 which in turn was oxidized with
tetrapropylammonium perruthenate (TPAP) using N-methyl-
morpholine N-oxide (NMO) as a co-oxidant24 to furnish
aldehyde (+)-22. Pleasingly, this four-step sequence proved
highly effective, proceeding in 55% yield. Earlier studies had
indicated that protection of both nitrogen atoms was required
in order to prevent side reactions during the oxidation process.
With aldehyde (+)-22 in hand, treatment with benzylox-
ymethyllithium, derived from benzyloxymethyltributylstannane
and n-BuLi,25 led to diol (+)-11 as the major product after
workup with methanolic KOH to remove the TBDPS group;
Figure 3. NOE analysis of (+)-22 and stereoselectivity in the
formation of (+)-11.
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A two-step oxidative lactonization employing 2-iodoxyben-
zoic acid (IBX) in a 1:1 mixture of tetrahydrofuran (THF) and
dimethyl sulfoxide (DMSO) followed by TPAP/NMO in
methylene chloride was next achieved to access lactone (−)-23
from diol (+)-11 in 57% yield. Stepwise oxidation to generate
the lactol employing IBX26 prevented the formation of the
undesired side products that were observed when diol (+)-11
was subjected directly to the TPAP/NMO conditions.
Subsequent treatment of lactone (−)-23 with AlCl3 in toluene
under sonication conditions then selectively removed the
protecting groups on the oxygen and the indole nitrogen to
furnish alcohol (−)-24 in 83% yield.27
spectral properties identical in all respects to those reported for
the natural product [i.e., 1H and 13C NMR (500 and 125 MHz,
respectively), HRMS parent ion identification, and chiroptic
properties].1
In summary, the first total synthesis and assignment of the
absolute configuration of (+)-scholarisine A has been achieved
with a longest linear reaction sequence of 20 steps from known
lactone (−)-15.31 Highlights of the synthesis include a
reductive cyclization involving a nitrile and an epoxide, a
modified Fischer indole protocol, a late-stage oxidative
lactonization, and an intramolecular cyclization leading to the
indolenine ring system of (+)-scholarisine A.
Various attempts to activate the hydroxyl group in (−)-24 for
cyclization with the indole ring resulted in decomposition, most
likely as a result of intramolecular cyclization involving the basic
tertiary amine. An exchange of nitrogen protection was
therefore required in order to attenuate the reactivity of the
piperidine nitrogen. The latter was achieved via transfer
hydrogenolysis to give amine (+)-1016 followed by treatment
with trifluoroacetylimidazole in THF28 to furnish trifluoroace-
tamide (−)-25 (Scheme 3). Activation of the 1° alcohol with
ASSOCIATED CONTENT
* Supporting Information
Experimental details, spectra, complete ref 3b, and X-ray
crystallographic data (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
smithab@sas.upenn.edu
■
Scheme 3
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the National Institutes of
Health (National Cancer Institute) through CA-19033. We also
thank Drs. George Furst and Rakesh Kohli for help in obtaining
the high-resolution NMR and mass spectral data, respectively.
Thanks to The Digital Library of the Royal Botanical Garden of
Madrid (CSIC) for permission to use the Alstonia scholaris
image for cover art.
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