CL-150188
Received: March 11, 2015 | Accepted: June 5, 2015 | Web Released: June 13, 2015
An Expedient Strategy towards an Advanced Pyrrolidine Intermediate
for the Synthesis of Pyrrolizidine Alkaloids
Smritilekha Bera,*1 Dhananjoy Mondal,1 and Bhaskar Chatterjee2
1School of Chemical Sciences, Central University of Gujarat, Gandhinagar-382030, India
2Department of Chemistry, University of Kalyani, West Bengal, India
(E-mail: beras@cug.ac.in)
The asymmetric synthesis of a new pyrrolidine intermediate
of prominence among carbon-carbon bond-forming reactions.6
Although there have been significant advances in catalytic
asymmetric variants of the aldol reaction,7 auxiliary-based
approach still remains a valuable and widely employed strategy
for the synthesis of the β-hydroxy carbonyl functionality. The
pioneering work of Evans et al. demonstrates the efficient use
of boron enolates of N-acyl-1,3-oxazolidin-2-one in the con-
struction of syn aldol adducts.8 The diastereoselection in the
aldolization techniques was further investigated by Crimmins
et al. who used titanium enolates of N-acyl-1,3-oxazolidin-2-
one and thiazolidine-2-thione derivative using (¹)-sparteine.9
Proper tuning of the reaction conditions would hence provide
access to the requisite diastereomers in sufficient diastereomeric
excess. Herein, we report an efficient synthetic strategy for the
pyrrolidine moiety 7 using Crimmins’ modified Evans aldol
protocol that represents an advanced intermediate for the
synthesis of (¹)-isoretronecanol (1).10 The strategy also dem-
onstrated the synthesis of the γ-amino-β-(hydroxylmethyl)hep-
tanediol motif (6) as an effort to obtain other pyrrolizidine
alkaloids such as cremastrine (2), (+)-laburmine (4), (¹)-tra-
chalanthimide (5), and oxocane derivative 3. This crucial
building block would also provide an access to other hitherto
known biologically active natural products and natural-product-
like molecules (Figure 1).
Our retrosynthetic plan was to construct the pyrrolidine
derivative 7 that is the key precursor to the pyrrolizidine
alkaloids isoretronecanol 1 and cremastrine 2. It involves the
stereoselective generation of two contiguous chiral centers,
which take into account the enantioselective construction of
chiral hydroxy functionality; the precursor to chiral amine
including the adjacent hydroxymethyl group. The architectural
framework of the chiral building block could thus be primed
via Crimmins’ modified Evans aldol reaction of N-acyl-1,3-
oxazolidin-2-one 9 with 4-benzyloxybutyraldehyde (10) that
could be easily obtained from 1,4-butanediol (11). The latter
served as the single precursor to both the chiral auxiliary and the
aldehyde (Figure 2).
and a preceding amino triol derivative was accomplished using
Crimmins’ modified Evans aldol reaction as the key step. The
synthetically useful pyrrolidine intermediate is expected to serve
as the immediate precursor of biologically important pyrrolizi-
dine alkaloids (¹)-isoretronecanol and (¹)-cremastrine. In
addition, the amino triol subunit acts as a useful intermediate
for the synthesis of oxocane heterocycles.
Asymmetric syntheses of biologically important heterocy-
clic molecules and their key intermediates have been in rising
demand in the pharmaceutical industry. Amongst them, the
pyrrolidine moiety has emerged as a potential target particularly
owing to its diversification into various classes of molecules.1 In
particular, the aza-bicycles, pyrrolizidine, indolizidine alkaloids,
many other related natural products, and natural-product-like
molecules all contain a pyrrolidine ring and have set a platform
for biological understanding, thereby paving the way for
different synthetic approaches by different groups.2 With the
advent of newer techniques, several groups have directed their
synthetic endeavors toward these diverse series of heterocyclic
molecules.3 In this aspect, it could be visualized that the
pyrrolidine derivative 7 acts as an important constructive
precursor of pyrrolizidine alkaloids isoretronecanol (1)4 and
cremastrine (2)5 (Figure 1). It was also observed that an amino
triol intermediate 6 could function as a chiral building block for
a series of N-heterocyclic pyrrolizidine alkaloids and oxygen
heterocycles like oxocane derivative 3. During the past two
decades the asymmetric aldol reaction has risen to a position
OH
O
OH
H
OMOM
H
N
H
O
NBoc
N
7
OH
(-)-isoretronecanol (1)
cremastrine (2)
MOMO
Accordingly, the synthetic strategy began with the selective
protection of 1,4-butanediol (11) as monobenzyl ether with
benzyl bromide and NaH (1 equiv) in 1:1 solvent mixture of
dimethylformamide (DMF) and tetrahydrofuran (THF) to give
the monobenzylated product 12 in 71% yield. Then, one-pot
preparation of both acid and aldehyde, required for N-acylation
and Crimmins’ aldol reaction was completed. For this, the free
hydroxy group of 12 was oxidized with pyridinium dichromate
(PDC) in CH2Cl2-DMF mixture (1:1) producing a separable
mixture of acid 13 and aldehyde 10 in 45% and 51% yields,
respectively. The acid 13 was converted to the N-acyl
oxazolidinone 9 in 81% yield by coupling with (4S)-4-
benzyloxazolidin-2-one (14) via a mixed anhydride formation
HO
OH
NHBoc
6
NH2
OH
H
HO
OH
H
N
O
(-)-trachalanthimide (5)
oxocane derivative 3
N
(+)-laburmine (4)
Figure 1. Novel chiral precursor for the synthesis of pyrroli-
zidine alkaloids and oxocane hetreocycles.
© 2015 The Chemical Society of Japan
Bera, Smritilekha
