Asymmetric Total Syntheses of (?)-α-Lycorane, (?)-Zephyranthine, and Formal Synthesis of (+)-Clivonine

Article abstract of DOI:10.1002/asia.201700555

An asymmetric route to (?)-α-lycorane and (?)-zephyranthine, and a formal total synthesis of (+)-clivonine were achieved. A pivotal intermediate, which serves as a potent precursor for the divergent syntheses of these natural products, was accessed by a diastereoselective Pd-catalyzed cinnamylation of an N-tert-butanesulfinyl imine.

Full text of DOI:10.1002/asia.201700555

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Accepted Article
Title: Asymmetric Total Syntheses of (−)-α-Lycorane, (−)-
Zephyranthine and Formal Synthesis of (+)-Clivonine
Authors: Xing-Wen Sun, Yong-Jian Chen, Sen-Lin Cai, Chuan-Chuan
Wang, Jin-Duo Cheng, and Søren Kramer
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Chemistry - An Asian Journal
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Asymmetric Total Syntheses of (−)-α-Lycorane, (−)-Zephyranthine
and Formal Synthesis of (+)-Clivonine
Yong-Jian Chen, Sen-Lin Cai, Chuan-Chuan Wang, Jin-Duo Cheng, Søren Kramer, Xing-Wen Sun*
Abstract: We report the successful achievement of an asymmetric
route to (−)-α-lycorane and (−)-zephyranthine as well as a formal
total synthesis of (+)-clivonine. A pivotal intermediate, which serves
as a potent precursor for the divergent syntheses of these natural
structure have been established. Importantly, enantioselective
synthesis accessing (−)-zephyranthine is unprecedented. In
1994, Oppolzer and coworkers reported the first enantioselective
synthesis of (+)-trianthine (11), the enantiomer of (−)-
zephyranthine (4).[ In this case, the enantioenriched, chiral
starting material (+)-10 was generated by means of biocatalysis
via microbial oxidation[10] of chlorobenzene 9 (Scheme 1B).
Considering the specificity of biocatalysis, the optically pure (−)-
4d]
products, was accessed by
a diastereoselective Pd-catalyzed
cinnamylation of an N-tert-butanesulfinyl imine.
The Amaryllidaceae alkaloids are widespread in plants of the
Amaryllidaceae family, which have been exploited as
pharmaceuticals for a long time due to their potent antiviral,
antitumor, and antifungal bioactivities.[1] Lycorine-type[2] alkaloids,
members of a subclass of the Amaryllidaceae alkaloids, bear an
intriguing and challenging tetracyclic core structure. Accordingly,
in combination with the increasing interest in drug development,
this class of alkaloids appeal to both chemists and biologists.
At an early stage of exploring this class of alkaloids,
transformations connecting the different members were
investigated. In this context, natural products containing the
1
0 could not be generated by this approach. Accordingly, the
enantioselective total synthesis of (−)-zephyranthine is still to be
achieved.
[
3]
tetracyclic core structure such as α-lycorane (2) , zephyranthine
[
4]
[5]
(
(
3) , lycorine (6) , dihydrolycorine (7)[5a], and α-dihydrocaranine
8)[4c,6] could all be derived from intermediate 1. The carbon-
carbon double bond in ring C of intermediate 1 played an
important role in the divergent syntheses of these natural
alkaloids. In previous works, intermediate
1 was either
synthesized in racemic form[4c,5a] or derived from the optically
[4c]
[7]
pure natural product, (−)-lycorine (6).
Lycorenine-type
[
8]
Amaryllidaceae alkaloid (+)-clivonine (5) could be synthesized
via a lycorine-type precursor 4 by a “ring-switching” strategy
according to the procedure reported by Oppolzer and co-
workers.[
8e,8f]
We surmised that the lycorine-type precursor 4
could also be accessed through the common intermediate 1. In
this way, we could establish the relationship between lycorine-
type
Amaryllidaceae
alkaloids
and
lycorenine-type
Amaryllidaceae alkaloids as shown in Scheme 1A.
Synthetic efforts have continued in the following years,
providing approaches for Amaryllidaceae constituents.[9]
However, among these admirable works to the syntheses of
lycorine-type alkaloids, the examples of enantioselective total
syntheses[3g-i,3k-n,4d,5e,5f,9a] from simple, readily available materials
mainly focus on α-lycorane (3)[3g-i,3k-n]
molecules with functionalization on C ring of the common
. Limited efforts on
Scheme 1. A) Selected Amarryllidaceae alkaloids and the net of their
transformation. B) First enantioselective synthesis of (+)-trianthine (11).
Very recently, our group developed a diastereoselective Pd-
catalyzed cinnamylation and further applied this method to
syntheses of (+)-lycoricidine and (+)-7-deoxypancratistatin.[
Based on the inspiration from previously reported synthetic
works as well as our recent efforts toward natural product
synthesis, we disclose an asymmetric synthetic route for rapid
construction of the pivotal intermediate 1, which can serve as a
versatile platform for accessing many Amaryllidaceae alkaloids.
Y.-J. Chen, S.-L. Cai, C.-C. Wang, J.-D. Cheng, Prof. Dr. X.-W. Sun
Department of Chemistry
Fudan University
11]
220 Handan Road, Shanghai, 200433, (China)
E-mail: sunxingwen@fudan.edu.cn
S. Kramer,
Department of Chemistry, Technical University of Denmark,
2800 Kgs. Lyngby (Denmark)
Supporting information for this article is given via a link at the end of
the document.
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Further transformations from 1 leading to natural products are
also included.
We initiated our study by introducing Evans’ auxiliary[12] to
TBS-protected 4-hydroxybutanoic acid 17 (readily accessible
from the simple starting material butane-1,4-diol 16 [13]), giving
1
9 in 90% yield. The ensuing asymmetric α-carbonyl allylation
was achieved smoothly affording 20 in 68% yield (> 20:1 d.r.).
Then, the chiral auxiliary was easily removed under LiBH
4
conditions giving alcohol 21 in 84% yield. Oxidation of alcohol 21
using Dess-Martin periodinane provided aldehyde 22 in 83%
yield and then 22 converted into imine 15 with (R)-N-tert-
4
butanesulfinyl amine 23 in 96% yield in the presence of Ti(OEt) .
The other building block (14) could be conveniently synthesized
from 24, using Jiao’s methodology, in 68% yield (Scheme 3).[
11,14]
Scheme 2. Retrosynthetic analysis of Amarryllidaceae alkaloids. LG = leaving
group
The retrosynthetic analysis of the target molecules is shown
in Scheme 2. We envisioned that the cyclohexene motif in ring C
of intermediate 1 could be generated through a ring-closing
metathesis (RCM) strategy. With the aid of a proper base, a
subsequent intramolecular substitution reaction could lead to the
formation of ring D. The corresponding homoallylic amine
precursor 13 could be constructed by merging cinnamyl acetate
Scheme 4. Influence of the α-imino stereocenter on the stereochemical
outcome of the diastereoselective Pd-catalyzed cinnamylation. Ph = phenyl.
14
and N-tert-butanesulfinyl imine 15 using our own
methodology (Scheme 2).
The Pd-catalyzed cinnamylation, connecting the two building
blocks, and subsequent spontaneous cyclization generated the
desired product 26 in 53% yield (> 20:1 d.r.). Using this tandem
sequence, two consecutive stereocenters as well as ring B were
established in one pot. When imine 15’, derived from racemic
aldehyde, was subjected to the same reaction conditions with
cinnamyl acetate 14, the corresponding product 26’ was
obtained in 49% yield and nearly 1:1 products ratio (See
Supporting Information). This result demonstrated that the
stereochemistry of the α-imino-position on imine building block
had minimal influence on the stereochemical outcome of this
sequence (Scheme 4). These results fit with the transition state
proposed in previous reports.[
11,15]
The chiral center at α-imino
position made little differences during the formation of the “six-
member ring” transition state.
Scheme 3. Syntheses of the two building blocks. TBS = tert-butyldimethylsilyl,
DMSO = dimethyl sulfoxide, Bn = benzyl, Piv = pivaloyl, THF = tetrahydrofuran,
HMDS = 1,1,1,3,3,3-hexamethyldisilazane, DMP = Dess-Martin periodinane,
Et = ethyl, Me = methyl, Ac = acetyl
Scheme 5. Synthesis of key intermediate 1. Ms = methanesulfonyl, tBu = tert-
butyl.
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Next, we attempted the RCM reaction on diene 26. Although
the desired product was obtained, partial removal of the N-tert-
butanesulfinyl group had also occurred. To circumvent this issue,
we instead subjected 26 to acidic conditions to remove both
protecting groups, giving rise to alcohol 27 in 96% yield.
Subsequent methanesulfonylation of the hydroxyl group with
methanesulfonic anhydride delivered methanesulfonate 28 in
Reduction of the lactam moiety of 30 with LiAlH
afforded (−)-α-lycorane (2) in 89% yield.
4
in refluxing THF
OsO system
For the synthesis of (−)-zephyranthine, NMO-K
2
4
was first considered in the dihydroxylation procedure for the
functionalization of the double bond and the cis-diol obtained
with 7:2 d.r. in this reaction system. Since the major product was
the precursor of (−)-zephyranthine (3) and the minor product
was the desired diol in the route to another natural alkaloid (+)-
clivonine (5), it was essential to improve the diastereoselectivity
of dihydroxylation. Sharpless asymmetric dihydroxylation[16] of 1
with AD-mix-β improved d.r. to 8:1 gave cis-diol 31 in 73%
isolated yield. Direct reduction of the lactam moiety of 31, by
9
6% yield which set the stage for installing ring D. Now, the
RCM reaction of bisolefin 28 catalyzed by Hoveyda-Grubbs 2nd
generation catalyst in toluene at 70 oC was performed. Due to
the poor solubility of 29 in toluene, a simple filtration of the
reaction mixture afforded cyclohexene 29 in 79% yield and in
93% yield totally after isolating the leftover from mother liquor.
4
LiAlH in refluxing THF, afforded (−)-zephyranthine (3) in 62%
The closure of ring D was achieved by an intramolecular S
N
2
yield. In contrast, if dihydroxylation of 1 was performed using
AD-mix-α (5:2 d.r. See Supporting Information) followed by
protection of the diol with 2,2-dimethoxypropane 32, acetonides
33a (51% yield) and 33b (22% yield) were obtained respectively.
The latter one 33b corresponded to the lycorine-type
intermediate 4 in the total synthesis of the lycorenine-type
reaction. Too strong base like NaH may lead to a partial
isomerization where the double bond conjugated with aromatic
motif[3c]. Consequently, choosing tBuOK as the weaker and
bulky base, the important intermediate 1 was obtained in 93%
yield.
natural product (+)-clivonine (5) through
process (Scheme 6). The absolute configuration of 33a could
be determined through X-ray crystal analysis (Figure 1).
a “ring-switching”
[
8f]
In conclusion, a versatile cyclohexene intermediate 1 was
successfully synthesized from readily available material in an
asymmetric fashion by applying
a diastereoselective Pd-
catalyzed cinnamylation as the key strategy. This intermediate
provides a platform for divergent asymmetric syntheses of
various Amaryllidaceae alkaloids. Furthermore, access to (−)-α-
lycorane (8% yield from butane-1,4-diol 16, 15 steps) and the
first enantioselective synthesis of (−)-zephyranthine (5% yield
from butane-1,4-diol 16, 15 steps) were accomplished.
Compared with the limitation on enantiomeric selectivity in
related works, our synthetic work gives a more general approach
to these natural alkaloids in which all stereocenters can be
selectively controlled and conducted. Further investigations
targeting these and related alkaloids are currently ongoing in our
laboratory.
Scheme 6. Divergent synthesis of Amaryllidaceae alkaloids
Acknowledgements
The authors gratefully acknowledge the financial support from
the National Natural Science Foundation of China (21472019).
Keywords: Amaryllidaceae alkaloids • asymmetric synthesis •
-lycorane • total synthesis • zephyranthine
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Yong-Jian Chen, Sen-Lin Cai, Chuan-
Chuan Wang, Jin-Duo Cheng, Søren
Kramer, Xing-Wen Sun*
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Title Asymmetric Syntheses of (−)-α-
Lycorane, (−)-Zephyranthine and
Formal Synthesis of (+)-Clivonine
An asymmetric route to (−)-α-lycorane and (−)-zephyranthine as well as a formal
total synthesis of (+)-clivonine was successfully achieved. A pivotal intermediate,
which serves as a potent precursor for the divergent syntheses of these natural
products, was accessed by a diastereoselective Pd-catalyzed cinnamylation of an
N-tert-butanesulfinyl imine.
This article is protected by copyright. All rights reserved.