Application of an ephedrine chiral linker in a solid-phase, 'asymmetric catch-release' approach to γ-butyrolactones

Article abstract of DOI:10.1039/b302471g

A Sm(II)-mediated, asymmetric, intermolecular ketyl-olefin addition employing α,β-unsaturated esters linked to resin through an ephedrine 'chiral link' has been applied in a direct 'asymmetric catch-release' approach to γ-butyrolactones.

Full text of DOI:10.1039/b302471g

Application of an ephedrine chiral linker in a solid-phase, ‘asymmetric
catch-release’ approach to g-butyrolactones
a
a
b
a
Nessan J. Kerrigan, Panee C. Hutchison, Tom D. Heightman and David J. Procter*
a
Department of Chemistry, The Joseph Black Building, University of Glasgow, Glasgow, Scotland, UK G12
QQ. E-mail: davidp@chem.gla.ac.uk
GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, UK CM19 5AW
8
b
Received (in Cambridge, UK) 5th March 2003, Accepted 11th April 2003
First published as an Advance Article on the web 13th May 2003
A Sm(II)-mediated, asymmetric, intermolecular ketyl-olefin
addition employing a,b-unsaturated esters linked to resin
through an ephedrine ‘chiral link’ has been applied in a
direct ‘asymmetric catch-release’ approach to g-butyr-
olactones.
remains immobilised. Our approach also introduces the possi-
bility of recovering the chiral resin by simple filtration, and
recycling the support. The proposed methodology also points
toward future applications in high-throughput asymmetric
synthesis.
Inexpensive (1R, 2S)-ephedrine was immobilised on com-
mercially available bromo Wang resin selectively through
nitrogen and in one step, by adaptation of a literature
1
2
Our interest in new solid-phase linker technologies, has led us
to consider readily available and inexpensive ephedrine and
pseudoephedrine derivatives as ‘chiral linkers’ for solid phase
synthesis. These linkers would allow substrates to be linked to
resin and control the stereochemistry of reactions carried out on
the substrate. Importantly, the ‘one-step’ attachment of the
commercially available ephedrine or pseudoephedrine unit to
resin through either oxygen or nitrogen is straightforward
leading to robust ether or amine linkages (Fig. 1).
7
procedure. The loading of the resultant ephedrine resin 1 was
2
1 8
found to be approximately 1 mmol g
. Straightforward
esterification of the resin with acryloyl chloride then gave the
desired acrylate resin 2, in which the ester moiety is bound to
2
1
resin through an ephedrine chiral link (nmax(CNO) 1724 cm
)
(Scheme 2).
Fig. 1 Ephedrine and pseudoephedrine chiral linkers.
Scheme 2 Reagents and conditions: i, (1R, 2S)-ephedrine, DMF, 85 °C; ii,
acryloyl chloride or crotonyl chloride, NEt , Et O, rt.
3
2
We have recently described the first application of this
strategy in a pseudoephedrine linker approach (linkage mode A)
for the asymmetric alkylation of amide enolates.3 In this
communication we describe the application of an ephedrine
chiral link, using selective immobilisation through nitrogen
Using acetophenone and acrylate resin 2, optimised condi-
tions for the reaction were developed. Typically, ketyl-olefin
couplings of this type are carried out by adding a mixture of the
9
2
carbonyl compound and the acrylate to a solution of SmI .
(
mode B), in intermolecular radical additions on solid-phase.4
Crucially, we found that changing the order of addition, i.e.
adding SmI to a mixture of the resin and the carbonyl
Fukuzawa has described a highly enantioselective synthesis
2
of g-butyrolactones via the Sm(II)-mediated, intermolecular
coupling of carbonyl compounds and a,b-unsaturated ephe-
drinyl esters.5 We realised that adaptation of Fukuzawa’s
methodology would give rise to a solid phase ‘asymmetric
catch-release’ approach to g-butyrolactones. Thus the resin
compound, a prerequisite for a convenient solid-phase experi-
mental procedure, did not significantly lower the enantiose-
lectivities obtained.† Temperature was found to have a dramatic
effect on the efficiency of the catch-release process. At 278 °C,
only a trace of lactone 4 was detected, while at 240 °C, a
disappointing 23% yield of 4 was isolated. Carrying out the
reaction at 215 °C, however, gave a satisfactory isolated yield
of lactone 4 (50%) in good enantiomeric excess (74% ee).
‘
catches’ a reactive intermediate, the ephedrine link controls the
stereochemistry of addition, and the resulting product under-
goes spontaneous, cyclative cleavage from the resin (Scheme
1
).
Hence, we envisaged that simply stirring a carbonyl com-
pound with SmI and a loaded ephedrine resin would give the
Employing our optimised conditions (SmI
15 °C), the asymmetric catch-release process with acrylate
resin 2 and a range of ketones and aldehydes was investigated
Table 1). Significant ketyl-radical homo-coupling was not
2
, tert-butanol, THF,
2
2
enantiomerically enriched g-butyrolactone directly. Lying
somewhere between solid-phase chemistry and solid supported
reagents, this methodology avoids the cleavage step tradition-
ally associated with solid phase synthesis.6 In addition,
purification should be simpler as the ephedrine auxiliary
(
observed and few by-products were visible in the product
mixtures. In general, the isolated yields obtained using 2
5
compare favourably with the GC yields of Fukuzawa.
The analogous crotonate resin 3 was also prepared from
2
1
ephedrine resin 1 (nmax(CNO) 1734 cm ). Treatment of 3 with
aldehydes under our optimised conditions gave the expected g-
butyrolactones in good yield and high enantiomeric excess.
1
Only the cis-lactones were observed in the crude H NMR of
these reactions5 (Table 2).
,10
g-Butyrolactone 8 is a moderate DNA-binding metabolite
isolated from Streptomyces GT61115.11 To illustrate the utility
of our approach, we have undertaken a short synthesis of 8
(
Scheme 3).
Diol 5 was prepared from d-valerolactone according to a
literature method.12 Mono-protected diol 6 was prepared by bis-
Scheme 1 An ‘asymmetric catch-release’ approach to g-butyrolactones.
protection followed by cleavage of the primary TMS ether
1
402
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Table 1 g-Butyrolactones formed using acrylate resin 2a
4
R = Me, 50% (74%ee)b
b
R = Et, 73% (70%ee)
R = Pr, 43% (74%ee)b
3
5
5
7% (71%ee)b
6% (70%ee)c
6% (81%ee)b
Scheme 3 Reagents and conditions: i, MeLi (1.5 M in Et
to rt, 66%; ii, a) TMSCl, NEt , CH Cl , rt . b) K CO , MeOH, 0 °C, 96%
for two steps; iii, Dess Martin periodinane, CH Cl , rt, 98%; iv, Acrylate
(0.1 M in THF), 215 °C, THF, BuOH, 50%.
2
O), THF, 278 °C
3
2
2
2
3
2
2
t
resin 2, SmI
2
award, P. C. H.) and the University of Glasgow (University
Scholarship, P. C. H) for financial support.
6
6% (76%ee)b
a
b
Yields are isolated yields. Enantiomeric excess determined by chiral GC
c
Notes and references
(see ref. 14). Enantiomeric excess determined by optical rotation.
†
To investigate the effect of the order of addition on the enantioselectivity
of the reaction we carried out solution phase model studies. For example,
adding acetophenone, alcohol and acrylate to SmI at 0 °C, gave lactone 4
in 73% ee, while adding SmI to acetophenone, alcohol and acrylate, gave
in 68% ee. The yields obtained using both orders of addition were also
similar.
Table 2 g-Butyrolactones formed using crotonate resin 3a
2
2
4
5
6
5
6% (93%ee)b
1
For recent reviews on linkers for solid phase organic synthesis see: (a)
I. W. James, Tetrahedron, 1999, 55, 4855; (b) F. Guillier, D. Orain and
M. Bradley, Chem. Rev., 2000, 100, 2091; (c) A. C. Comely and S. E.
Gibson (née Thomas), Angew. Chem. Int. Ed.., 2001, 40, 1012.
F. McKerlie, D. J. Procter and G. Wynne, Chem. Commun., 2002,
2
3
4
6% (96%ee)c
5% (91%ee)b
5
84.
P. C. Hutchison, T. D. Heightman and D. J. Procter, Org. Lett., 2002, 4,
583.
4
Relatively few intermolecular radical additions to immobilised accep-
tors have been reported. For selected examples see: (a) S. Caddick, D.
Hamza and S. N. Wadman, Tetrahedron Lett., 1999, 40, 7285; (b) X.
Zhu and A. Ganesan, J. Comb. Chem., 1999, 1, 157; (c) H. Miyabe, Y.
Fujishima and T. Naito, J. Org. Chem., 1999, 64, 2174; (d) H. Miyabe,
C. Konishi and T. Naito, Org. Lett., 2000, 2, 1443; (e) S. Caddick, D.
Hamza, S. N. Wadman and J. D. Wilden, Org. Lett., 2002, 4, 1775; (f)
D. C. Harrowven, P. J. May and M. Bradley, Tetrahedron Lett., 2003,
a
b
Yields are isolated yields. Enantiomeric excess determined by chiral GC
c
(see ref. 14). Enantiomeric excess determined by optical rotation.
4
4, 503.
5
6
S. Fukuzawa, K. Seki, M. Tatsuzawa and K. Mutoh, J. Am. Chem. Soc.,
1997, 119, 1482.
For a discussion of more conventional, two-step “resin-capture-release”
processes, see: A. Kirschning, H. Monenschein and R. Wittenberg,
Chem. Eur. J., 2000, 6, 4445.
under basic conditions. Dess–Martin oxidation13 of 6 then gave
aldehyde 7 in excellent yield. On treatment with acrylate resin
2
2
and SmI in the presence of tert-butanol, aldehyde 7 gave 8,
after loss of the TMS protection during work up, in 50% yield
and 73% ee.14 Our synthesis confirms the postulated absolute
stereochemistry of 8.11
7
8
J. M. J. Fréchet, E. Bald and P. Lecavalier, J. Org. Chem., 1986, 51,
3
462.
The loading of 1 was determined by esterification with thiophene
carbonyl chloride followed by sulfur elemental analysis of the resin. See
ref 3.
In conclusion, we have described a solid-phase, asymmetric
catch-release approach to g-butyrolactones. In the process, a
substrate immobilised through an ephedrine ‘chiral link’
undergoes asymmetric transformation through capture of a
reactive intermediate from solution. Spontaneous, cyclative
cleavage gives g-butyrolactones in moderate yield and good
enantiomeric excess. The development of methods for the
efficient recycling of the chiral resin and the application of the
methodology to the development of high-throughput asym-
metric processes is currently under investigation.
9 S. Fukuzawa, A. Nakanishi, T. Fujinami and S. Sakai, J. Chem. Soc.,
Perkin Trans. 1, 1988, 1669.See also ref. 5.
0 The diastereoselectivity was confirmed by comparison with Fukuza-
1
1
wa’s H NMR data (ref. 5) and by NOE studies.
1
1 C. Maul, I. Sattler, M. Zerlin, C. Hinze, C. Koch, A. Maier, S. Grabley
and R. Thiericke, J. Antiobiot., 1999, 52, 1124.
1
1
1
2 A. S. Hernández and J. C. Hodges, J. Org. Chem., 1997, 62, 3153.
3 D. B. Dess and J. C. Martin, J. Org. Chem., 1983, 48, 4155.
4 The enantiomeric excess of lactones was determined by chiral GC
(Supelco beta dex™ 120 fused silica capillary column —30 m) and
comparison with authentic, racemic samples.
We thank the Engineering and Physical Research Council
EPSRC) (GR/R72242/01, N.J.K), GlaxoSmithKline (CASE
(
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