Generation of All-Carbon Quaternary Stereocenters at the C-3 Carbon of Lactams via [3,3]-Sigmatropic Rearrangement and Revision of Absolute Configuration: Total Synthesis of (-)-Physostigmine

Article abstract of DOI:10.1021/acs.orglett.7b03537

A diastereoselective (up to >99%) route to all carbon quaternary stereocenters at the C-3 position of cyclic lactams has been developed via Johnson-Claisen rearrangement of ?-hydroxy-α,β-unsaturated lactams. It has been observed that olefin geometry plays an important role in the development of the absolute stereochemistry of the product. Dependence of product configuration on the olefin geometry is explained by postulating probable transition states. The success of this method has been shown for multigram-scale synthesis of these substituted lactams from commercially available cheap starting materials. The synthetic usefulness of this method is also demonstrated by carrying out the total synthesis of (a-)-physostigmine.

Full text of DOI:10.1021/acs.orglett.7b03537

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Generation of All-Carbon Quaternary Stereocenters at the C‑3
Carbon of Lactams via [3,3]-Sigmatropic Rearrangement and
Revision of Absolute Configuration: Total Synthesis of
(−)-Physostigmine
Ganesh Pandey,* Jagadish Khamrai, and Akash Mishra
Molecular Synthesis and Drug Discovery Laboratory, Centre of Biomedical Research, SGPGIMS Campus, Lucknow 226014, India
S
* Supporting Information
ABSTRACT: A diastereoselective (up to >99%) route to all carbon quaternary
stereocenters at the C-3 position of cyclic lactams has been developed via Johnson−
Claisen rearrangement of γ-hydroxy-α,β-unsaturated lactams. It has been observed
that olefin geometry plays an important role in the development of the absolute
stereochemistry of the product. Dependence of product configuration on the olefin
geometry is explained by postulating probable transition states. The success of this method has been shown for multigram-scale
synthesis of these substituted lactams from commercially available cheap starting materials. The synthetic usefulness of this
method is also demonstrated by carrying out the total synthesis of (−)-physostigmine.
3,3-Dialkyl-substituted cyclic lactams or their corresponding
amines are privileged structural motifs constructing the core of
many biologically active alkaloids (1−2)1 and pharmaceuticals
(3−5) (Figure 1).2 Although few attractive chiral auxiliary based
challenge associated with the construction of 3,3-dialkyl cyclic
lactams/amines, we evaluated using 3,3-sigmatropic shift
(Johnson−Claisen rearrangement)9,10 strategy from the sub-
strate of type 6 for the construction of all carbon quaternary
stereocenters at the C-3 position of cyclic lactams as shown in
Scheme 1. We have reported this concept previously,11 but
during the synthesis of leucophyllidine (2)12 we realized that the
absolute configuration at C-3 position was incorrectly assigned.
Scheme 1. Proposed General Concept for the Construction
of All-Carbon Quaternary Stereocenters of Lactams
Figure 1. Representative examples containing all-carbon quaternary
centers at the C-3 position of lactams/amines.
Therefore, we disclose herein the correct assignment of
absolute configuration at the C-3 position of lactams and the
success of our concept as outlined above for preparing lactams of
type 7 in high yield (88−97%) and excellent diastereoselectivity
(up to >99%). It was also found that the stereochemistry of 7 is
dependent both on the olefin geometry as well as on the
configuration of the secondary alcohol 6 and the advantage of
the same is exploited to produce both enantiomers of 7.
Application of this method is also demonstrated by developing a
synthetic route to (−)-physostigmine.
strategies for the construction of 3,3-dialkylated pyrrolidinone
and piperidinone moieties are known, diastereoselectivities in
most of these cases remains low to moderate.3−5 Our own
approach in this regard, using Birch reduction followed by
alkylation of (S)-prolinol derived nicotinic acid derivative
further functional group transformation, provides >99% ee of
the 3,3-dialkylated piperidinone moiety. Moderate yield coupled
with the limitation to only one enantiomer of the piperidinone
moiety restricts its wide applicability.6 Recently, palladium-
catalyzed decarboxylative allylic alkylation of lactams to form
3,3-dialkyl-substituted lactams in good to excellent enantiomeric
excess (88−99%) was reported.7
Initially, we evaluated establishing the validity of the concept
(Scheme 1) by constructing all-carbon quaternary stereocenters
at the C-3 position of the piperidinone ring system. Toward this
Because of our continuing interest in the synthesis of
Received: November 15, 2017
structurally complex biologically active alkaloids6,8 and the
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03537
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Organic Letters
Letter
end, a multigram scale (25.0 g, 99% yield) preparative route for
11 and 12 (de = 11:12 = 1:1.5) was worked out using Wittig−
Horner olefination13 of 9 with −OTBS-protected L-lactaldehyde
(10).14 Precursor 9 was obtained in 65% yield by the reaction of
the 1-benzylpiperidin-2-one (8) with LiHMDS followed by the
addition of diethyl chlorophosphate (Scheme 2). Pure
Scheme 2. [3,3]-Sigmatropic Rearrangement of 13 and 14
Figure 2. Transition state for [3,3]-sigmatropic rearrangement.
Scheme 4. [3,3]-Sigmatropic Shift of 22 and 23
diastereomers were easily purified by column chromatography
(230−400 mesh silica; EtOAc/n-hexane as an eluent). In order
to proceed further with the 3,3-sigmatropic rearrangement, the
silyl groups of 11 and 12 were deprotected separately using p-
toluenesulfonic acid in methanol.
Compound 13 was subjected to standard Johnson−Claisen
rearrangement (triethyl orthoacetate, propionic acid, re-
flux),15,16 which gave 15 in 97% isolated yield and >99%
enantiomeric purity (determined by chiral-phase HPLC
analysis, Chiralcel OD-H, 2-propanol/n-hexane; 10:90).17
Under the same reaction conditions, however, 14 produced
the corresponding opposite isomer 16 in 97% yield and >99%
enantiomeric excess. In order to confirm this observation, the
configuration of secondary alcohol 13 was inverted by the
Mitsunobu’s reaction18 followed by the ester hydrolysis using
LiOH and H2O. The resultant 18 on usual rearrangement
produced 16 in 93% yield (ee = 97%) (Scheme 3).19a
Furthermore, we desired to extend this method to construct
an oxindole framework containing all-carbon quaternary
stetreocenters at the C-3 position. 3,3-Dialkyl-substituted
oxindole derivatives serve as precursors for the synthesis of
spirooxindoles, pyrroloindolines, and furanoindolines ring
systems, which are privileged heterocyclic structural frameworks
composed of a large number of biologically active natural
products and pharmaceutically active agents.20 Although there
are several interesting approaches known for the construction of
enantomerically pure 3,3-disubtituted oxindoles,21−30 develop-
ing another conceptually new strategy, as shown in Scheme 6,
would enhance the repertoire of synthetic methodologies in this
field. Thus, in order to prepare oxindole rearrangement
precursor 29 and 30, Wittig−Horner olefination of 26a
produced 27a and 28a (1:4) in total 89% yield. Johnson−
Claisen rearrangement of the corresponding −OTBS depro-
tected 29a as well as 30a, produced 31a (ee = 77%) and 32a (ee
= 79%),17 respectively, in excellent yield. It may be worth
mentioning that, unlike in the case of 13−14 and 22−23, here
enantioselectivity was comparatively low. This result led us to
speculate that isomerization of the olefin geometry during the
reaction may possibly be responsible for this observation.
Therefore, appropriate controlled experiments were carried out
which ascertained that isomerization of the olefinic double bond
does happen both in the presence of room light as well as with
propionic acid.31 The generality of this rearrangement was also
established by studying various other substrates (29b−d and
30b−d) as shown in Scheme 5.
Scheme 3. [3,3]-Sigmatropic Rearrangement of 18
This observation suggests that the stereochemistry of the
Johnson−Claisen rearrangement does not depend only on the
−C−OH stereochemistry but is also guided by the geometry of
the olefin.19b These observations are tentatively explained with
the help of the proposed transition states (TS, 13b−18b) as
shown in Figure 2. It appears that in 13b suprafacial approach of
the incoming −CH2CO2Et group moves the C3−C4 bond
above the plane leading to the formation of 15, whereas 16 is
formed by involving 14b, where owing to the Z-geometry of the
olefinic bond the C3−C2 bond is pushed above the plane by the
−CH2CO2Et group. Furthermore, through 18b it may be clearly
visualized that suprafacial attack of the incoming group forces
C3−C4 bond below the plane for the formation of 16.
Physostigmine (3), isolated from Physostigma venenosum,32 is
a clinically used molecule for the treatment of glaucoma and
myasthenia gravis and also is a therapeutic agent for Alzheimer’s
disease.33 Owing to interesting biological activities associated
with this molecule, the attention of many synthetic chemists is
drawn toward its asymmetric synthesis.34 Because of our
With this promising result in hand, we explored this strategy
further with the pyrrolidinone derivatives 22 and 23 as well by
following the identical experimental conditions as discussed
above and obtained corresponding 3,3-dialkylated derivatives 24
and 25 as shown in Scheme 4.
B
DOI: 10.1021/acs.orglett.7b03537
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Organic Letters
Letter
by Johnson−Claisen rearrangement of corresponding γ-
hydroxy-α,β-unsaturated lactams. The success of this method
has been demonstrated for the synthesis of both enantiomers on
a multigram scale from a common precursor. The application of
this method has been shown by the total synthesis of
(−)-physostigmine. Further exploration of this method in the
synthesis of other biologically active alkaloids is in progress.
Scheme 5. [3,3]-Sigmatropic Rearrangements of Oxindole
Derivatives 29 and 30
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03537.
Details of the experimental procedure and character-
ization data for all new compounds (PDF)
Scheme 6. Total Synthesis of (−)-Physostigmine
Accession Codes
CCDC 1585505 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: gp.pandey@cbmr.res.in.
ORCID
Ganesh Pandey: 0000-0001-7203-294X
Notes
interesting strategy for easily constructing structural frameworks
of type 31 and 32, we were motivated to employ our strategy for
the synthesis of 3. In this context, 33 was prepared in 61% yield
by the reaction of 31d35 with ethanolic methylamine followed by
LiAlH4 reduction. The absolute configuration of 33 was
confirmed through X-ray crystal structure analysis (see the
Supporting Information).
The oxidative cleavage of the olefinic double bond of 33 using
OsO4/NaIO4 produced corresponding aldehyde, which upon
reduction with NaBH4 in methanol gave 34 in 44% yield.
Tosylation (TsCl, pyridine) of 34 followed by reduction with
LAH in refluxing THF produced (−)-esermethole36 (36, 66%),
which was transformed to 3 using previously reported
protocols37 (eight linear steps, 8.8% overall yield starting from
31d). After 3 was synthesized successfully from 32d, it was also
visualized that the furanoindoline heterocyclic moiety could be
constructed from 32 by simplifying its reduction. Furanoindo-
line structural motifs are recently being evaluated as drug
candidates for the treatment of Alzheimer’s disease.38 Thus,
reduction of 32a as well as 32d using LAH (THF, 0 °C) was
carried out to obtain corresponding furanoindolines 37 and 38,
respectively, in excellent yield as shown in Scheme 7.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank DST, New Delhi, for financial support and Dr. Rajesh
G. Gonnade, NCL, Pune, for crystal structure analysis. J.K. and
A.M. thank CSIR, New Delhi, for the award of research
fellowships. We also thank Dr. Sumit Kumar Panja, BHU,
Varanasi, for DFT calculation.
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