A stereoselective synthesis of 1,3,4-substituted β-lactams from polymer-supported chiral oxazolidine aldehyde

Article abstract of DOI:10.1016/S0040-4039(00)01516-1

The synthesis of a polymer supported chiral oxazolidine aldehyde is described. This intermediate has great potential for the synthesis of biologically interesting compounds. A solid phase stereoselective synthesis of an array of chirally pure β-lactams in high purity is described as a first application of the system. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01516-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8621–8625
A stereoselective synthesis of 1,3,4-substituted b-lactams
from polymer-supported chiral oxazolidine aldehyde
Kirsteen Gordon, Michael Bolger, Nawaz Khan and Shankar Balasubramanian*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
Received 26 July 2000; accepted 22 August 2000
Abstract
The synthesis of a polymer supported chiral oxazolidine aldehyde is described. This intermediate has
great potential for the synthesis of biologically interesting compounds. A solid phase stereoselective
synthesis of an array of chirally pure b-lactams in high purity is described as a first application of the
system. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: polymer support; chiral aldehyde; b-lactam; oxazolidine.
As the number of synthetic organic reactions and multi-step transformations reported on solid
phase has increased, many elegant linker strategies have been developed.1 Linkers which contain
a generic core of chemical functionality that can lead to a variety of classes of interesting
compounds are desirable. One such system we have been interested in is the oxazolidine
aldehyde first reported by Garner.2 Chiral oxazolidine aldehydes have the capacity to undergo
a wide variety of interesting and useful transformations and also serve as a chiral directing
group. Chiral oxazolidine aldehydes have been successfully employed in solution for the
synthesis of several natural products (e.g. sphingosines,3 b-amino alcohols,4 a-amino b-hydroxy
acids5) serving as an amino alcohol equivalent. Such systems have also been exploited as a chiral
auxiliary in cycloaddition reactions for the synthesis of b-lactams bearing b-amino alcohol side
chains6 which can subsequently be rearranged to form pyrrolidinones.7
In this paper we describe the chemistry of generating a polymer supported chiral oxazolidine
aldehyde equivalent. The linker incorporates a masked b-amino alcohol and derives its stereo-
genic centre from N-Boc-protected -serine. A first application of this resin-bound intermediate
L
has been exemplified with the stereoselective synthesis of an array of 1,3,4-substituted b-lactams
on solid phase (Fig. 1).
* Corresponding author. Tel: +44 (0)1223 336347; fax: +44 (0)1223 336913; e-mail: sb10031@cam.ac.uk
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01516-1

8622
Fig. 1. A polymer supported chiral oxazolidine aldehyde approach to b-lactam synthesis
The linker was pre-assembled in solution using the pivaloyl protected ketone 1 (Scheme 1).
TMS–OTf promoted ketonide formation, in the presence of isopropoxytrimethylsilane, gave the
ester 2 in 73% yield using nearly equimolar quantities of ketone and amino acid.8 Subsequent
reduction of 2 with concomitant removal of the pivaloyl protecting group furnished the alcohol
3 which was oxidised to the aldehyde equivalent 4.
Scheme 1. Linker assembly. Reagents and conditions: (i) PivꢀCl/DMAP/Pyr; (ii) N-Boc-protected L-serine methyl
ester/1% TMSOTf/Isopropoxytrimethyl silane/DCM; (iii) LiBH4/THF; (iv) (COCl)2/DMSO/DCM/Et3N
The chiral integrity of all key intermediates was confirmed throughout the synthesis.† This was
augmented by a Mosher ester study of the synthesis of a non-diastereomeric model aldehyde
derived from N-Boc- -serine under identical conditions, using cyclohexanone as the protecting
L
group. The Mosher esters were formed from the corresponding alcohols after reduction of the
ester (model of 2) and the target aldehyde (model of 4). Both esters gave single peaks when
analysed by 19F NMR spectroscopy, whereas when racemic N-Boc-
-serine was used as a
L
control, two 19F peaks were clearly visible in the 19F NMR spectrum in a 1:1 ratio.
The aldehyde 4 was subsequently attached to resin via a carbonate linkage under mild
conditions (Scheme 2). Hydroxymethyl polystyrene resin was activated by formation of its
4-nitrophenol carbonate 5 and was then substituted by reaction with the phenolic group of 4 to
give the immobilised chiral equivalent 6 (loading 0.932 mmol/g, based on nitrogen elemental
† Optical rotations of intermediates: 2 [h]D −19 (MeOH, c=1), 3 [h]D −18 (MeOH, c=1), 4 [h]D −12 (MeOH, c=1).

8623
analysis of 5). The reaction was monitored by the disappearance of the NO2 peaks in the FTIR
spectrum (1596 and 1348 cm−1) and was characterised by the appearance of three resolvable
carbonyl absorbances (1764, 1758, 1710 cm−1). A study in solution with the model aldehyde
(model of 4) confirmed that the stereogenic centre was preserved under the coupling conditions
(DIPEA and DMAP) as judged by analysis of the corresponding Mosher ester. Coupling of the
aldehyde using a stronger base (e.g. NaH) led to epimerisation and some degree of decomposi-
tion as judged from the observation of by-products by TLC.
Scheme 2. Utilisation of the chiral oxazolidine aldehyde in the synthesis of a b-lactam library. Reagents and
conditions: (i) 4-nitrophenylchloroformate/DIPEA/DMAP/DCM; (ii) Linker 4/DIPEA/DMAP/DMF; (iii) R1NH2/
2
,
DCM/4 A sieves then DCM/Et3N/R CH2COCl/DCM; (iv) 10% TFA/DCM
b-Lactam library synthesis
To explore the application of the resin-bound chiral oxazolidine aldehyde equivalent 6, the
synthesis of a small array of b-lactams was carried out. Such compounds are renowned for their
biological activity but surprisingly, have received scant attention by solid phase chemists.9–12
A
versatile reaction for the synthesis of this heterocycle involves a cycloaddition reaction of an
imine and a ketene. The reaction is believed to occur via a two-step mechanism which can be
controlled to exclusively yield b-lactams with cis stereochemistry.6 The aldehyde 6 was thus
condensed with four amines chosen to represent different electronic and steric properties. The
resulting resin-bound imines subsequently underwent cycloaddition reactions with ketenes,
which were formed in situ from their corresponding acid chlorides. Acid chlorides, with
a-heteroatoms (oxygen or nitrogen) were chosen, to achieve control of stereochemistry. The
resulting resin-bound b-lactams 7a–g were treated with 10% TFA in DCM to remove the N-Boc
protecting group and cleave the now unstable oxazolidine moiety to unmask the amino alcohol
functionality (Scheme 2).
A simple extraction of the final products into H2O generated the expected lactams 8a–g in
1
generally excellent purity (ꢀ90%) and reasonable yields (53–62%) as judged by HPLC and H
NMR spectroscopy (Table 1).‡ All products 8a–g gave a coupling constant of J=5–5.5 Hz for
the methine protons on the b-lactam ring which is consistent with cis-stereochemistry.13 The
absolute stereochemistry of the b-lactam products (as their TFA salts) was evaluated by
‡ No rearrangement to pyrrolidinone was observed in the cleavage conditions given. This reaction has been
investigated but remains to be optimised.

8624
polarimetry. An optical rotation was measured for each b-lactam and b-lactam 8e was de-salted
and its optical rotation ([h]D=−38) was comparable to the literature value ([h]D=−36.5).6 The
opposite antipode to b-lactam 8f ([h]D=−23) was also synthesised in solution and had an
opposite but equal rotation ([h]D=+22 MeOH, c=1). It would thus appear that both the
relative and absolute stereochemistries were controlled in all steps from the solid phase
equivalent assembly to the chiral b-lactam products.
Table 1
8
R1
R2
LCMS
% Purityc
% Yielda
[h]D (c=1)
a
b
c
d
e
f
Bn
OPh
OPh
OPh
OPh
OBn
OBn
313
306
329
279
327
343
382
93
92
95
77b
93
89
96
54
53
62
45
60
59
58
−26 (MeOH)
−79 (MeOH)
−72 (MeOH)
−85 (MeOH)
−38 (DCM)e
−23 (MeOH)
+83 (MeOH)
Cyclohexyl
PMPd
nBu
Bn
PMP
Bn
g
a Yields are based on the loading of resin 5 as determined by elemental analysis (N).
b The main impurity in this case was the N-Boc-protected b-lactam.
c Purity based on HPLC with UV detection at 220 nm.
d PMP=p-methoxyphenyl.
e Literature value −36.56.
Conclusion
A polymer-supported synthesis of an array of a chirally pure b-lactams in high purity has
been demonstrated. There are many possibilities for further exploitation of the resin-bound
chiral oxazolidine aldehyde 6, which will be explored in due course.
Acknowledgements
We would like to thank the BBSRC and EPSRC (Grant No 97/A1/B/03098). K.G. is an SCI
Messel Scholar.

8625
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