Protecting-group-free total synthesis of (E)- and (Z)-alstoscholarine

Article abstract of DOI:10.1002/anie.201100257

Looking for hidden symmetry: The first asymmetric total synthesis of pentacyclic compounds 1 and 2 has been accomplished starting from a cyclic meso-anhydride. The absolute configuration of the final products was set by an organocatalytic desymmetrization of the meso-anhydride. The economic synthesis is protecting-group-free and confirms the assigned absolute configuration.

Full text of DOI:10.1002/anie.201100257

Communications
DOI: 10.1002/anie.201100257
Natural Product Synthesis
Protecting-Group-Free Total Synthesis of (E)- and (Z)-
Alstoscholarine**
Thibaud Gerfaud, Chunsong Xie, Luc Neuville,* and Jieping Zhu*
Monoterpenoid indole alkaloids, for their structural complex-
ity and important bioactivities, have fascinated chemists for
over a century.[1] The complexity of some of these alkaloids is
such that they stand as molecular benchmarks to test new
synthetic strategies and methodologies.[2] In spite of the
skeletal diversity of these alkaloids, all of them are believed to
be biosynthetic products from tryptamine and secologanine.[3]
It is therefore not surprising that the tryptamine unit is readily
recognized in most of these indole alkaloids.[4]
Recently, Luo and co-workers isolated (E)-alstoscholar-
ine (1) and (Z)-alstoscholarine (2), from leaves of Alstonia
scholaris, a plant used in traditional medicine in South and
Southeast Asia (see Scheme 1 for structures).[5] Compounds 1
and 2 have an atypical pentacyclic structure characterized by:
1) a bridged [3.1.3] bicycle fused with an indole ring on one
side and a pyrrole ring on the other, a structural feature
absent in all other indole alkaloids, 2) a lack of an apparent
tryptamine subunit, despite the existing belief that these are
derived from tryptamine, and 3) two additional carbon atoms
compared to other monoterpenic indole alkaloids. Herein, we
Scheme 1. Retrosynthetic analysis of alstoscholarines.
report the first enantioselective total synthesis of 1 and 2 by a
route that is sufficiently concise and easily diverted at a late
stage to access natural product analogues.
8, which could in turn be prepared by deracemization of
meso-anhydride 9.
Our retrosynthetic analysis of 1 and 2 is outlined in
Scheme 1. We envisioned reaching the natural products by
installing the olefin and formyl groups on pentacycle 3, which
could in turn be prepared by the Pictet–Spengler reaction of
4. As no obvious, simple, and readily available indole
derivative could be used for the construction of 4, we thought
to build the indole unit at this stage, using the palladium-
catalyzed heteroannulation of ortho-iodoaniline (5) with
aldehyde 6. Dialdehyde 7, the ring-opened form of 6, could
be obtained by oxidative cleavage of cyclohexene derivative
Our synthesis began with the desymmetrization of meso-
anhydride 9 (Scheme 2). Treatment of cis-1,2,3,6-tetrahy-
drophthalic anhydride in diethyl ether with MeOH
(10.0 equiv) in the presence of catalyst 10 (0.05 equiv)
following the protocol developed by Song afforded hemiester
11 in 95% yield with 93% ee.[6] Conversion of the carboxylic
À
acid function in 11 into 2-pyridylthioester (PyS SPy, PPh3,
[*] Dr. T. Gerfaud, Dr. C. Xie, Dr. L. Neuville, Prof. Dr. J. Zhu
Centre de Recherche de Gif
Institut de Chimie des Substances Naturelles, CNRS
91198 Gif-sur-Yvette Cedex (France)
E-mail: luc.neuville@icsn.cnrs-gif.fr
Prof. Dr. J. Zhu
Institut of Chemical Sciences and Engineering
Ecole Polytechnique Fꢀdꢀrale de Lausanne
EPFL-SB-ISIC-LSPN, 1015 Lausanne (Switzerland)
E-mail: jieping.zhu@epfl.ch
[**] Financial support from CNRS, ICSN, and ANR is gratefully
acknowledged.
Scheme 2. Preparation of intermediate 6. Reagents and conditions:
a) 10 (0.05 equiv), MeOH (10.0 equiv) in Et2O (c=0.1m), RT, 95%,
93% ee; b) 2,2’-dipyridyldisulfide, PPh3, THF, RT; then pyrrylmagne-
sium bromide, THF, À208C, 76%; c) OsO4 (0.1 equiv), N-methylmor-
pholine-N-oxide, tBuOH/THF/H2O (13:9:1), RT; d) NaIO4, acetone/
H2O (1.7:1), RT, 78% over two steps. THF=tetrahydrofuran.
Supporting information for this article, including experimental
1
procedures, product characterization, and copies of the H and
13C NMR spectra of synthetic compounds, is available on the WWW
under http://dx.doi.org/10.1002/anie.201100257.
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Angew. Chem. Int. Ed. 2011, 50, 3954 –3957

RT), and subsequent addition of pyrrylmagnesium bromide
according to the method developed by Nicolaou provided the
2-ketopyrrole 8 as the only regioisomer in 76% yield.[7] The
use of acyl chloride instead of pyridin-2-yl thioester led to the
formation of a significant amount of 3-ketopyrrole derivative.
Dihydroxylation of 8 afforded the corresponding diol when
subjected to Upjohn conditions.[8] The diol was submitted,
without purification, to oxidative cleavage (NaIO4, Me2CO/
H2O (1.7:1), RT) to provide bis(aldehyde) 7. Compound 7
cyclized spontaneously in situ to give the desired six-mem-
bered hemiaminal 6 as a mixture of two diastereoisomers
(78% overall yield). The lack of stereoselectivity in the
hemiaminal formation is of no consequence, as this stereo-
genic center will be destroyed transiently in the subsequent
annulation conditions are responsible for the observed
epimerization in the preparation of pentacycle 12/3 from 5
and 6.
The relative stereochemistry of C15 and C16 (natural
product numbering) was deduced from coupling constants
between H15 and H16 in 3 and 12 (JH15-H16 = 6.3 Hz for 3 and
J
H15-H16 = 1.1 Hz for 12). To fully determine the stereochem-
ical identity of 3, aldehyde 13 (for which epimerization at C16
is impossible) was synthesized by a similar strategy as that
detailed for 6. Palladium-catalyzed heteroannulation between
aniline 5 and 13, and subsequent acid-promoted Pictet–
Spengler reaction afforded two diastereomers 14a and 14b
resulting from the epimerization at C15 (Scheme 4). By
À
C C bond-forming event. Notably, this highly regioselective
hemiaminal-forming process served three functions in our
synthesis: 1) to form the D ring of the natural product
À
through formation of a C N bond, 2) to differentiate two
sterically and electronically similar aldehydes, thus setting the
required functionality for construction of the indole ring, and
3) to build the latent iminium functionality (hemiaminal)
necessary for the subsequent construction of the C ring.
The key palladium-catalyzed heteroannulation between
ortho-iodoaniline (5) and aldehyde 6 took place under our
standard conditions (Pd(OAc)2 (0.1 equiv), DABCO
(3.0 equiv), DMF, 858C)[9,10] to provide indole 4 as a mixture
of diastereoisomers (Scheme 3). The hemiaminal function,
Scheme 4. Alternative synthesis of 3 confirming its stereochemical
integrity. Reagents and conditions: a) Pd(OAc)2 (0.05 equiv), DABCO
(3.0 equiv), DMF, 858C, 40 min; b) HCO2H, RT, 55% over two steps,
ratio 14a/14b=1:1; c) nBu4NOH, THF, H2O, 608C, 4 h, 93%; d) IBX
(1.0 equiv), DMSO, 2 h; e) NaClO2, NaH2PO4, amylene, tBuOH, THF,
H2O, RT, 1.5 h; f) TMSCHN2, CH2Cl2, MeOH, 30 min, 82% over three
steps. DMSO=dimethylsulfoxide, IBX=2-iodoxybenzoic acid, Piv=
pivaloyl, TMS=trimethylsilyl.
following a four-step sequence, the protected primary alcohol
in 14b was converted into the corresponding methyl ester,
which was found to be identical to 3 in all respects including
the sign of the optical rotation. These results allowed us to
conclude that the absolute configuration of 3 was 3S,15R,16R
and that partial epimerization during the heteroannulation of
5 and 6 occurred only at C15.
With the stereochemistry of pentacycle 3 now assigned,
we came back to the total synthesis endeavor and proceeded
to optimize the conditions for the palladium-catalyzed syn-
thesis of indole 3 from 5 and 6. It was found that epimeriza-
tion could be minimized by shorten the reaction time. Finally,
under optimized conditions (Pd(OAc)2 (0.3 equiv), DABCO
(2.0 equiv), DMF, 858C, 40 min), the desired pentacycle 3 was
obtained in 50% yield over two steps (Scheme 3). Interest-
ingly, the Fischer indole synthesis using N-phenyl hydrazine
and aldehyde 6 as reaction partners under a variety of acidic
conditions led to the complete degradation of aldehyde 6.[12]
Conversion of the ketone moiety into an ethylidene
turned out to be quite challenging. Ethyltriphenylphospho-
nium halide was found to be inactive toward 3 under a variety
of reaction conditions. Nucleophilic addition of ethylmagne-
Scheme 3. Reagents and conditions: a) Pd(OAc)2 (0.3 equiv), DABCO
(2.0 equiv), DMF, 858C, 40 min; b) HCO2H, RT, 60% over two steps,
ratio 12/3=1:5. DABCO=1,4-diazabicyclo[2.2.2]octane, DMF=N,N-
dimethylformamide.
known to participate in the palladium-catalyzed heteroannu-
lation with ortho-iodoaniline,[11] was found to be stable.
Treatment of 4 under optimized conditions for the Pictet–
Spengler reaction (HCOOH, RT) furnished pentacycles 3 and
12 (ratio 1:1) resulting from the partial epimerization of
stereogenic center(s) in this two-step sequence. Submitting
each diastereomerically pure form of compound 4 to the
Pictet–Spengler reaction conditions afforded the diastereo-
merically pure pentacycle 12 or 3, thus indicating that
epimerization was not occurring under acidic Pictet–Spengler
conditions. Therefore we concluded that the basic hetero-
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Communications
sium bromide to the ketone of N-Boc-protected 3, followed
Keywords: alkaloids · enantioselective synthesis · indoles ·
Pictet–Spengler reaction · Takeda olefination
.
by dehydration, did install the olefin unit. However, this was
accompanied by complete epimerization at C16. Finally,
ethylidenation of 3 using Takedaꢀs reagent took place
smoothly to provide the desired compound 15
(Scheme 5).[13] Due to the low stability of 15, it was submitted,
after a rapid filtration of the reaction mixture, to Vilsmeier–
Haack formylation conditions to afford (Z) and (E)-alsto-
scholarine (3:1 ratio) in 40% yield over two steps. The two
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Scheme 5. Total synthesis of alstoscholarines. Reagents and condi-
tions: a) 1,1-bis(phenylthio)ethane (4.0 equiv), [Cp2TiCl2] (10.0 equiv),
P(OEt)3 (20.0 equiv), Mg (12.0 equiv), molecular sieves (4 ꢁ), THF,
708C, 6 h; b) DMF, POCl3, DCE, RT, 31% yield of 1 and 9% yield of 2
over two steps. Cp=cyclopentadienyl, DCE=1,2-dichloroethane.
isomers were readily separated by preparative thin layer
chromatography on silica gel (eluent: EtOAc/heptane = 1:4).
The physical and spectroscopic data of these two synthetic
alstoscholarines were identical to those reported for the
natural products.[14] Therefore, the absolute configuration of
(E)- and (Z)-alstoscholarine is 3S,15R,16R, which was pro-
posed on the basis of their biogenetic origin, is confirmed by
the present synthesis.
In summary, we have completed the first enantioselective
total synthesis of (E)- and (Z)-alstoscholarines, accomplished
in 14% yield over eight steps. We believed that the late-stage
construction of the indole ring has greatly simplified the
present synthesis design, thus allowing the use of simple and
readily accessible starting materials. The synthesis is protect-
ing-group free,[15] with desirable atom-, step-, and redox-
economies.[16–18] Indeed, there is no concession step in this
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[13] a) Y. Horikawa, M. Watanabe, T. Fujiwara, T. Takeda, J. Am.
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[14] The 13C NMR spectra of synthetic materials matched those of
the natural products. There were nevertheless minor typographic
errors in Luoꢀs original attributions (see the Supporting Infor-
mation). In addition, the [a]D value of synthetic materials are
higher than that of natural products reported in Luoꢀs original
À
À
synthesis since each transformation creates new C C and C
N bonds found in the target molecules.[19] Furthermore, the
construction of the indole unit at a late stage of the synthesis
should allow us to access natural product analogues easily.[20]
Efforts aimed at solving the epimerization problem in the
palladium-catalyzed heteroannulation step as well as the
moderate yield of the ethylidenation step are ongoing.
paper.
Synthetic
(E)-alstoscholarine:
[a]D =
À100 degcm3 gÀ1 dmÀ1 (c = 0.05 gcmÀ3, MeOH), natural (E)-
alstoscholarine: [a]D = À53 degcm3 gÀ1 dmÀ1 (c = 0.065 gcmÀ3
,
MeOH);
synthetic
(Z)-alstoscholarine:
[a]D =
À202 degcm3 gÀ1 dmÀ1 (c = 0.05 gcmÀ3, MeOH), natural (Z)-
alstoscholarine: [a]D = À140 degcm3 gÀ1 dmÀ1 (c = 0.05 gcmÀ3
,
MeOH).
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b) R. W. Hoffmann, Synthesis 2006, 3531 – 3541.
[16] Redox economy: N. Z. Burns, P. S. Baran, R. W. Hoffmann,
Angew. Chem. 2009, 121, 2896 – 2910; Angew. Chem. Int. Ed.
2009, 48, 2854 – 2867.
Received: January 12, 2011
Published online: March 31, 2011
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According to the metric equation defined in this article, the
percentage of ideality of the present synthesis approached
100%.
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