RETRACTED ARTICLE: An expeditious route to both enantiomers of all carbon quaternary stereocenters at C-3 carbon of lactams via [3,3]-sigmatropic rearrangement: Total synthesis of (-)-physostigmine

Article abstract of DOI:10.1021/ol503766y

A diastereoselective 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. The dependence of the product configuration on the olefin geometry is explained by postulating probable transition states. The success of this method has been shown for the 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.

Full text of DOI:10.1021/ol503766y

Letter
pubs.acs.org/OrgLett
An Expeditious Route to Both Enantiomers of All Carbon Quaternary
Stereocenters at C‑3 Carbon of Lactams via [3,3]-Sigmatropic
Rearrangement: 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 route to all carbon quaternary stereo-
centers 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. The
dependence of the product configuration on the olefin geometry is
explained by postulating probable transition states. The success of this method has been shown for the 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 that construct the core of
many biologically active alkaloids (1−2)1 and pharmaceuticals
(3−5) (Figure 1).2 Although few attractive chiral auxiliary based
amines, we evaluated using a 3,3-sigmatropic shift (Johnson−
Claisen rearrangement)9,10 strategy from the substrate of type 6
for the construction of all carbon quaternary stereocenters at the
C-3 position of cyclic lactams as shown in Scheme 1.
Scheme 1. Proposed General Concept for the Construction of
All Carbon Quaternary Stereocenters of Lactams
We disclose herein the success of our concept as outlined
above for preparing lactams of type 7 in high yield (88−97%) and
good to excellent diastereoselectivity (de = 61−99%). It was also
found that the stereochemistry of 7 is dependent both on the
olefin geometry and on the configuration of the secondary
alcohol 6, and this advantage is exploited to produce both
enantiomers of 7. Application of this method is also
demonstrated by developing an efficient total synthesis of
(−)-physostigmine.
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
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 olefination11 of 9 with -OTBS protected L-lactaldehyde
(10).12 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
Figure 1. Representative examples containing all carbon quaternary
centers at C-3 position of lactams/amines.
strategies for the construction of 3,3-dialkylated pyrrolidinone
and piperidinone moieties are known, the diastereoselectivities in
most of these cases remain low to moderate.3−5 Our own
approach in this regard using Birch reduction followed by
alkylation of the (S)-prolinol derived nicotinic acid derivative to
further functional group transformation, though, provides >99%
ee of the 3,3-dialkylated piperidinone moiety. The moderate yield
coupled with the limitation to only one enantiomer of the
piperidinone moiety restricts its wide applicability.6 Recently,
Pd-catalyzed decarboxylative allylic alkylation of lactams to form
3,3-dialkyl substituted lactams in good to excellent enantiomeric
excess (88−99%) is reported. However, its scalability is yet to be
established.7
Due to our continuing interest in the synthesis of structurally
complex biologically active alkaloids6,8 and the challenge
associated with the construction of 3,3-dialkyl cyclic lactams/
Received: January 7, 2015
© XXXX American Chemical Society
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Letter
14b, where owing to the Z-geometry of the olefinic bond, the
C3−C4 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 the C3−C2 bond
below the plane for the formation of 16.
Scheme 2. [3,3]-Sigmatropic Shift of 13 and 14
With this interesting 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.
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 orthoace-
tate, propionic acid, reflux)13,14 which gave 15 in 97% isolated
yield and >99% enantiomeric purity (determined by chiral-phase
HPLC analysis, Chiralcel OD-H, iso-propanol/n-hexane;
10:90).15 Under the same reaction conditions, however, 14
produced a 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
Mitsunobu’s reaction16 followed by ester hydrolysis using LiOH,
H2O (Scheme 3). The resultant 18 on usual rearrangement
Furthermore, we desired to extend this method to construct an
oxindole framework containing all carbon quaternary stetreo-
centers at the C-3 position as 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 comprising a large
number of biologically active natural products and pharmaceuti-
cally active agents.18 Although there are several interesting
approaches known for the construction of enantiomerically pure
3,3-disubstituted oxindoles,19−28 developing another concep-
tually new strategy, as shown in Scheme 5, would enhance the
Scheme 3. [3,3]-Sigmatropic Shift to All Carbon Quaternary
Stereocenters of Piperidinone Ring System Using 18
Scheme 5. [3,3]-Sigmatropic Rearrangements of Oxindole
Derivatives 31−32
produced 16 in 93% yield (ee = 97%).17 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.
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, the suprafacial approach of the incoming
−CH2CO2Et group makes the C3−C2 bond above the plane
leading to the formation of 15, whereas 16 is formed by involving
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 corresponding
−OTBS deprotected 29a as well as 30a produced 31a (ee = 77%)
and 32a (ee = 79%),15 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
Figure 2. Transition state for [3,3]-sigmatropic rearrangement.
B
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which ascertained that isomerization of the olefinic double bond
does happen both in the presence of room light and with
propionic acid.29 The generality of this rearrangement was also
established by studying various other substrates (29b−29d and
30b−30d) as shown in Scheme 5.
this method has been shown by the total synthesis of
(−)-physostigmine in 11 linear steps and 4.5% overall yield
from commercially available starting material. Further explora-
tion of this method in the synthesis of other biologically active
alkaloids is in progress.
Physostigmine (3), isolated from the Physostigma venenosum,30
is a clinically used molecule for treatment glaucoma and
myasthenia gravis and also is a therapeutic agent for Alzheimer’s
disease.31 Owing to interesting biological activities associated
with this molecule, the attention of many synthetic chemists is
drawn toward its asymmetric synthesis.32 Due to realizing the
fact that we have an interesting strategy for constructing
structural frameworks of type 31 and 32 easily, we were
motivated to employ our strategy for the synthesis of 3 (Scheme
6). In this context, 33 was prepared in 61% yield by the reaction
ASSOCIATED CONTENT
* Supporting Information
■
S
Details of the experimental procedure, characterization data for
all new compounds, crystallographic data in CIF. This material is
available free of charge via Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: gp.pandey@cbmr.res.in.
Scheme 6. Total Synthesis of (−)-Physostigmine
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank DST, New Delhi for financial support, and J.K. and
A.M. thank CSIR, New Delhi, for the award of a research
fellowship.
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