Development of a solid-phase 'asymmetric resin-capture-release' process: Application of an ephedrine chiral resin in an approach to γ- butyrolactonest

Article abstract of DOI:10.1039/b408836k

The potential of a solid-phase asymmetric resin-capture-release strategy for high-throughput synthesis has been evaluated. Fukuzawa's Sm(II)-mediated, asymmetric approach to γ-butyrolactones was selected to illustrate the feasibility of such a process. α,β-Unsaturated esters immobilised on an ephedrine chiral resin have been applied in an asymmetric approach to γ-butyrolactones. Lactone products are obtained in moderate isolated yields with selectivities up to 96% ee. In addition, we have shown that the ephedrine resin can be conveniently recovered and recycled although in some cases lower yields were obtained on reuse of the chiral resin. A short synthesis of a moderate DNA-binding microbial metabolite using asymmetric resin-capture-release is also described.

Full text of DOI:10.1039/b408836k

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A R T I C L E
Development of a solid-phase ‘asymmetric resin-capture–release’
process: application of an ephedrine chiral resin in an approach to
-butyrolactones†
Nessan J. Kerrigan,a Panee C. Hutchison,a Tom D. Heightmanb and David J. Procter*a
a
Department of Chemistry, University of Glasgow, The Joseph Black Building, Glasgow,
UK G12 8QQ. E-mail: davidp@chem.gla.ac.uk
GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, UK CM19 5AW
b
Received 11th June 2004, Accepted 8th July 2004
First published as an Advance Article on the web 4th August 2004
The potential of a solid-phase asymmetric resin-capture–release strategy for high-throughput synthesis has been evaluated.
Fukuzawa’s Sm(II)-mediated, asymmetric approach to -butyrolactones was selected to illustrate the feasibility of such a
process. ,-Unsaturated esters immobilised on an ephedrine chiral resin have been applied in an asymmetric approach to
-butyrolactones. Lactone products are obtained in moderate isolated yields with selectivities up to 96% ee. In addition, we
have shown that the ephedrine resin can be conveniently recovered and recycled although in some cases lower yields were
obtained on reuse of the chiral resin. A short synthesis of a moderate DNA-binding microbial metabolite using asymmetric
resin-capture–release is also described.
enantiomerically enriched lactone product from the resin, while
Introduction
simultaneously regenerating the chiral ephedrine resin (Scheme 1).
Solid phase organic synthesis in which organic substrates are
Our interest in new linker systems for solid-phase synthesis6 has
manipulated whilst linked to an insoluble polymer is an important
led us to develop a pseudoephedrine resin for asymmetric solid
tool for the synthetic chemist who wishes to prepare collections of
phase synthesis.7 Furthermore, we have demonstrated the potential
compounds in an efficient manner.1 The area of solid-phase syn-
of the chemistry for asymmetric library synthesis.7b In this contribu-
thesis continues to evolve and recently a shift towards the use of
tion we describe in full our studies8 on the use of an ephedrine resin
solid-supported reagents to effect the transformation of substrates
in the development of an asymmetric resin-capture–release process,
in solution has been seen.2 ‘Resin-capture–release’is a new concept
employing Fukuzawa’s -butyrolactone synthesis5 to illustrate the
which may also play a role in the future of solid-phase synthesis.3
concept.
Resin-capture–release is a hybrid technique that combines ele-
ments of traditional solid-phase synthesis and the use of supported
reagents. In a conventional resin-capture–release process, a small
Results and discussion
We began by preparing the chiral ephedrine resin necessary to
investigate an asymmetric resin-capture–release process based
on Fukuzawa’s asymmetric reductive-coupling methodology.5
Inexpensive (1R,2S)-ephedrine was immobilised on commercially
available bromo Wang resin selectively through nitrogen and in one
step, by adaptation of a literature procedure.9 The efficiency and
chemoselectivityoftheimmobilisationstepwasclearlyillustratedby
the following solution phase model reaction. Benzyl bromide (1 eq.)
was heated with (1R,2S)-ephedrine (2 eq.) at 85 °C in DMF. After
4 days, (1R,2S)-N-benzyl ephedrine was obtained in near quantita-
tive yield with no trace of (1R,2S)-O-benzyl ephedrine10 observed
in the crude 1H NMR of the reaction. The loading of the resultant
ephedrine resin 1 was found to be approximately 1 mmol g−1.7,11
Straightforward esterification of the resin with acryloyl or crotonyl
chloride then gave the desired resins 2 (max(CO) 1724 cm−1) and
3 (max(CO) 1734 cm−1), respectively (Scheme 2).
Using acetophenone and acrylate resin 2, optimised conditions
for the asymmetric-release step were developed. Typically, ketyl
radical anion–olefin couplings of this type are carried out by add-
ing a mixture of the carbonyl compound and the acrylate to a solu-
tion of SmI2.12 Using solution phase model studies, we found that
changing the order of addition, i.e. adding SmI2 to a mixture of the
resin and the carbonyl compound, a prerequisite for a convenient
solid-phase experimental procedure, did not significantly lower the
enantioselectivities obtained. For example, adding acetophenone,
alcohol and acrylate to SmI2 at 0 °C, gave lactone 4 in 73% ee,
while adding SmI2 to acetophenone, alcohol and acrylate, gave 4
in 68% ee. The yields obtained using both orders of addition were
also similar, 84% and 79% respectively.
molecule B is trapped as an activated polymer intermediate A–B,
by a functionalised resin A. The addition of a second reaction
partner C transforms the polymer-bound intermediate and releases
a product B–C into solution whilst generating a modified polymer
(Fig. 1a).3
We envisaged that the use of a functionalised chiral resin as an
immobilised chiral auxiliary4 would give rise to an ‘asymmetric
resin-capture–release’ process (Fig. 1b). Attachment of a substrate
B to a chiral resin followed by asymmetric addition of a second
reaction partner C generates an activated, diastereoisomeric inter-
mediate. This breaks down to release a non-racemic product B–C*
into solution. Crucially, the chiral resin is regenerated directly and
should be recyclable.
To explore the feasibility of such a process we choose to use
Fukuzawa’s Sm(II)-mediated, asymmetric route to -butyrolactones5
in our proof of concept studies. In Fukuzawa’s studies, ,-un-
saturated esters bearing an ephedrine chiral auxiliary are reacted
with aldehydes and ketones in the presence of SmI2 to give -
butyrolactones.5 Several features of the process make it ideal for
illustrating the concept of asymmetric resin-capture–release: Firstly,
the ephedrine auxiliary should be amenable for linkage to a solid-
phase thus giving a functionalised chiral resin. Secondly, immobi-
lised ephedrinyl ,-unsaturated esters should be easily accessible
by acylation of a chiral ephedrine resin. Finally, after asymmetric
radical addition, an unstable diastereoisomeric polymer-bound
intermediate will be formed which should collapse to release an
† Electronic supplementary information (ESI) available: Additional
1
experimental and characterisation data, H and 13C NMR for new com-
Temperature was found to have a dramatic effect on the effi-
ciency of the asymmetric catch–release process. At −78 °C, only
a trace of lactone 4 was detected, while at −40 °C, a disappointing
1
pounds, H NMR for literature compounds, general chiral GC conditions,
chiral GC traces for lactone products and FTIR spectra of resins. See
http://www.rsc.org/suppdata/ob/b4/b408836k/
2 4 7 6
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 4 7 6 – 2 4 8 2
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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Fig. 1 (a) Conventional ‘resin-capture–release’. (b) Asymmetric ‘resin-capture–release’.
Table 1 ‘Asymmetric resin-capture–release’ with acrylate resin 2
Entry
Substrate
Product
Isolated yield
1–3
4 R = Me, 50% (74% ee)a
5 R = Et, 73% (70% ee)a
6 R = Pr, 43% (74% ee)a
Scheme 1 ‘Asymmetric resin-capture–release’: proof of concept studies
using Fukuzawa’s asymmetric approach to -butyrolactones.
4
37% (71% ee)a
5
6
7
52% (66% ee)a
56% (70% ee)b
56% (81% ee)a
Scheme 2 Reagents and conditions: i, (1R,2S)-ephedrine, DMF, 85 °C;
ii, acryloyl chloride or crotonyl chloride, NEt3, Et2O, rt.
23% yield of 4 was isolated. Carrying out the reaction at −15 °C
using an excess of the acrylate resin 2, however, gave a satisfac-
tory isolated yield of lactone 4 (50%) in good enantiomeric excess
(74% ee). Higher temperatures may be essential for efficient cycla-
tive cleavage of the diastereoisomeric intermediate from the resin.
Our adaptation of Fukuzawa’s methodology to the solid-phase
represents one of a limited number of examples of the addition of
radicals to immobilised acceptors.13
Employing the optimised conditions, the asymmetric
resin-capture–release process involving acrylate resin 2 and a range
of ketones and aldehydes was investigated (Table 1). Phenyl alkyl
ketones were found to give the corresponding lactones in moderate
yield and enantiomeric excess (70–74% ee) (entries 1–3). In gene-
ral, aldehydes were found to give higher enantioselectivities upon
reaction with acrylate resin 2 (up to 81% ee) (entries 4–8), with
more substituted aldehydes giving the highest enantioselectivities
(entries 7 and 8). Significant ketyl-radical homo-coupling was not
8
66% (76% ee)a
See Experimental Section for details. a Enantiomeric excess determined by
chiral GC (see Electronic Supporting Information). b Enantiomeric excess
determined by optical rotation.
1
observed and few by-products were visible in the crude H NMR
Although our studies aim to illustrate the general feasibility of
asymmetric resin-capture–release processes rather than to provide
a solid-phase process superior to solution-phase methodology,5 it
is interesting to compare the two processes. Enantioselectivities
obtained from reactions using acrylate resin 2 are lower than those
reported in solution.5 It is likely this difference originates from the
different temperatures at which the two processes are carried out
(−78 °C versus −15 °C). As previously stated, the yields obtained
using 2 compare favourably with the GC yields of Fukuzawa5 al-
though the use of an excess of 2 is important to give satisfactory
conversion. Enantioselectivities in reactions using crotonate resin 3
are comparable to those obtained in solution despite the difference
in the reaction temperatures.
spectra. In general, the isolated yields obtained using 2 compare
favourably with the GC yields of Fukuzawa5 although the use of an
excess of 2 is important to give satisfactory conversion.
Treatment of the analogous crotonate resin 3 with aldehydes
under optimised conditions gave the expected -butyrolactones in
good yield and high enantiomeric excess. Enantioselectivities were
considerably higher than those obtained using acrylate resin 2 at
the same temperature (−15 °C). Again, more substituted aldehydes
give the highest enantioselectivities (entries 1 and 2). In line with
Fukuzawa’s observations, only the cis-lactones were observed in
1
the crude H NMR spectra of the reactions with aldehydes.14 In
contrast, the reaction with 2-hexanone gave 17 as an inseparable
3:1 mixture of diastereoisomers (entry 6) (Table 2).
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 4 7 6 – 2 4 8 2
2 4 7 7

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Table 2 ‘Asymmetric resin-capture–release’ with crotonate resin 3
using acrylate resin 2 (average 73% ee), at −15 °C, are more diffi-
cult to explain. Such a difference in selectivity may arise from the
different reactivities of the two radical acceptors. Lewis acid activa-
tion of the less reactive crotonate acceptor is likely to be important,
thus addition only occurs to the chelated substrate (Fig. 2) where the
diastereofacial selectivity is strictly controlled by the auxiliary. The
more reactive acrylate may undergo a non-selective background
reaction through a non-chelated transition structure thus eroding
the enantiomeric excess of the products.
Entry
Substrate
Product
Isolated yield
1
56% (93% ee)a
Our studies have shown that asymmetric resin-capture–release
is a viable strategy for solid-phase synthesis. The efficacy of any
such process clearly depends on the careful design/selection of the
key reaction with regard to the asymmetry-controlling auxiliary,
reagent compatibility with the polymer support, and the mechanism
of product release. In our original outline of the process (Fig. 1), we
highlighted that regeneration of the chiral resin after product release
should allow recovery and reuse of the chiral resin. Again using
Fukuzawa’s methodology to illustrate this feature of the process, we
have carried out preliminary studies into the feasibility of recycling
the chiral ephedrine resin 1. For example, employing crotonate
resin 3 with pivalaldehyde gave lactone 12 in 54% yield and 92%
ee. Recovery of the resin 1 and re-esterification with crotonyl
chloride gave recycled 3. Re-treatment with pivalaldehyde gave 12
in virtually identical yield and enantiomeric excess (56%, 92% ee).
However, recovering and using the resin a third time gave 12 in
substantially lower yield (27%) although the enantioselectivity of
the reaction was still high (86% ee). (Scheme 3).
Attempts to recycle the acrylate resin 2 were less successful.
For example, employing acrylate resin 2 with pivalaldehyde, gave
lactone 10 in 50% yield and 79% ee. Recovery of the resin 1 and
re-esterification with acryloyl chloride gave recycled 2. Treatment
of the recycled resin with pivalaldehyde gave 10 in substantially
lower yield and enantiomeric excess (27%, 68% ee) (Scheme 4).
Although we have shown the feasibility of recycling the chiral
ephedrine resin, some difficulties remain to be addressed. The drop
in yield encountered using recovered resin may be due either to a
build up of inorganic salts in the polymer support or less likely,
could be caused by background reduction of the acrylate and
crotonate resins by SmI2.15 Thus repeated re-charging and reuse
of the resin would lead to the observed drop in the efficacy of the
resin and the yield of the reaction. Studies are currently under way
to develop a more efficient protocol for the recycling of the resin,
which will allow multiple runs to be carried out, making different
lactone products in each cycle.
2
66% (96% ee)b
3
4
55% (91% ee)a
50% (91% ee)a
5
6
43% (88% ee)a
36% (89% ee)a,c
See Experimental Section for details. a Enantiomeric excess determined by
chiral GC (see Electronic Supporting Information). b Enantiomeric excess
determined by optical rotation. A 3:1 mixture of cis (89% ee) and trans
(76% ee) diastereoisomers was obtained. The cis-product was assumed to
be the major diastereoisomer.
c
Despite the utility of Fukuzawa’s asymmetric approach to -
butryolactones,5 no explanation has been advanced for the high
selectivities observed. It is clear that chelation of the ephedrine
auxiliary to samarium(III) is important as it has been reported that
racemic products were obtained when HMPA was employed as an
additive.5 In addition, the original screen of auxiliaries, suggests that
both the phenyl and the amino group play a key role.5 To account
for the observed enantio- and diastereoselectivity in the reaction,
we therefore propose the transition structure shown in Fig. 2. Coor-
dination of samarium(III) to both the auxiliary and to the incoming
ketyl-radical anion gives rise to a well-ordered transition structure.
Such chelation is only possible when the substrate adopts a s-trans
conformation. In this conformation, the lower face of the substrate
is blocked by the phenyl group of the ephedrine auxiliary so the
radical addition occurs from the top face. The chelation not only
orders the transition structure but also leads to Lewis acid activation
of the substrate towards radical addition (Fig. 2).
To illustrate the utility of asymmetric resin-capture–release for
the synthesis of biologically active compounds, we have undertaken
a short synthesis of -butyrolactone 21, a moderate DNA-binding
metabolite isolated from Streptomyces GT61115.16 Diol 18 was
prepared from -valerolactone according to a literature method.17
Mono-protected diol 19 was prepared by bis-protection followed
by cleavage of the primary TMS ether under basic conditions.
Dess–Martin oxidation18 of 19 then gave aldehyde 20 in excellent
yield. On treatment with acrylate resin 2 and SmI2 in the presence of
tert-butanol, aldehyde 20 gave 21, after loss of the TMS protection
during work up, in 50% yield and 73% ee.19 Our synthesis confirms
the postulated absolute stereochemistry of 21 (Scheme 5).16
Conclusions
The greater selectivities we have observed in additions to the
crotonate resin 3 (average 92% ee) compared to those obtained
In summary, we have sought to evaluate ‘asymmetric resin-capture–
release’ as a potential process for the asymmetric, solid-phase syn-
thesis of small molecules. We have utilised an asymmetric approach
to -butyrolactones in our proof of concept studies. In the resultant
process, an ephedrine chiral resin is loaded and the immobilised
substrate undergoes asymmetric transformation through capture
of a reactive intermediate from solution. Cyclative cleavage gives
-butyrolactones in moderate yield and good enantiomeric excess.
We have proposed an explanation for the origin of enantioselecti-
vity in the process and have shown that the ephedrine chiral resin
can be recovered and reused although in some cases reduced yields
and enantioselectivities were observed. Finally, we have applied
Fig. 2 Possible origin of selectivity in the reaction.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 4 7 6 – 2 4 8 2
2 4 7 8

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Scheme 3 Reagents and conditions: i, SmI2 (0.1 M in THF), THF, −15 °C, t-BuOH; ii, crotonyl chloride, NEt3, Et2O, rt.
Scheme 4 Reagents and conditions: i, SmI2 (0.1 M in THF), THF, −15 °C, t-BuOH; ii, acryloyl chloride, NEt3, Et2O, rt.
THF (3 × 25 mL), THF–water; 2:1 (3 × 25 mL), THF–water; 1:1
(3 × 25 mL), THF–water; 1:2 (3 × 25 mL), (MeOH, 25 mL then
CH2Cl2, 25 mL) × 3, and MeOH (3 × 25 mL). The acrylate resin 2
was then dried in vacuo: max (Golden Gate)/cm−1 1724s (CO).
Preparation of (1R,2S)-N-Wang bound ephedrinyl crotonate 3
To a suspension of (1R,2S)-N-Wang bound ephedrine 1 (3.48 g,
4.07 mmol, 1 equiv.) in Et2O (36.0 mL) was added triethylamine
(1.36 mL, 9.78 mmol, 2.4 equiv.) followed by trans-crotonyl
chloride (1.04 mL, 9.78 mmol, 2.4 equiv.). The resulting suspension
was allowed to stir at room temperature for 24 h. After this time,
the reaction suspension was filtered and the resin was washed with
THF (3 × 50 mL), THF–water; 2:1 (3 × 50 mL), THF–water; 1:1
(3 × 50 mL), THF–water; 1:2 (3 × 50 mL), (MeOH, 50 mL then
CH2Cl2, 50 mL) × 3, and MeOH (3 × 50 mL). The crotonate resin 3
was then dried in vacuo: max (Golden Gate)/cm−1 1734s (CO).
Scheme 5 Reagents and conditions: i, MeLi (1.5 M in Et2O), THF, −78 °C
to rt, 66%; ii, a) TMSCl, NEt3, CH2Cl2, rt, b) K2CO3, MeOH, 0 °C, 96% for
two steps; iii, Dess Martin periodinane, CH2Cl2, rt, 98%; iv, acrylate resin 2,
SmI2 (0.1 M in THF), THF, −15 °C, t-BuOH, 50%.
the asymmetric resin-capture–release process in a short asymmetric
synthesis of a moderate DNA-binding metabolite.
Our studies have shown that asymmetric resin-capture–release is
a viable and potentially powerful strategy for solid-phase synthesis.
We are currently developing other asymmetric resin-capture–release
processes and investigating the application of this concept in high-
throughput asymmetric synthesis.
General procedure A. Reaction of (1R,2S)-N-Wang bound
ephedrinyl acrylate/crotonate with ketones and aldehydes
A suspension of (1R,2S)-N-Wang bound ephedrinyl acrylate/
crotonate resin, 2 or 3, (3.2 equiv.) in THF (5 mL) under argon
was gently stirred for 15 min prior to the addition of an aldehyde
(1 equiv.) or a ketone (1 equiv.) and t-BuOH (2 equiv.). The
resultant suspension was then allowed to stir for another 1 hour
at room temperature before being cooled to −15 °C. A pre-cooled
SmI2 solution (0.1 M in THF, 5.5 equiv.) was then added and the
dark blue–black solution was allowed to stir at −15 °C until TLC
analysis showed that the reaction was complete. The reaction was
then allowed to warm to room temperature over 5–6 hours before
filtration. The filtered resin was washed repeatedly with THF. The
filtrate was then concentrated to about 30 mL and washed with
aqueous saturated NaCl (4 mL). The aqueous layer was separated
and washed with Et2O (3 × 15 mL). The combined organic layers
were then dried (Na2SO4) and concentrated in vacuo. The crude
product was purified by column chromatography on silica to afford
the purified product as a pale yellow or colourless oil.
Experimental
General considerations
See the Electronic Supporting Information.†
Preparation of (1R,2S)-N-Wang bound ephedrine 1
To a suspension of bromo Wang resin (4.23 g, 5.90 mmol, 1 equiv.)
in DMF (42 mL) was added (1R,2S)-ephedrine (5.87 g, 35.5 mmol,
6 equiv.). The resulting suspension was heated at 85 °C and stirred
gently for 4 days. After this time, the reaction suspension was
filtered and the resin was washed with EtOH (3 × 50 mL), water
(3 × 50 mL), THF–water; 1:1 (3 × 50 mL), THF (3 × 50 mL), and
EtOH (3 × 50 mL). Resin 1 was then dried in vacuo: max (Golden
Gate)/cm−1 2919m, 1606m, 1508s.
Preparation of (1R,2S)-N-Wang bound ephedrinyl acrylate 2
(S)-5-Methyl-5-phenyl dihydro-furan-2-one 45
To a suspension of (1R,2S)-N-Wang bound ephedrine 1 (2.15 g,
2.69 mmol, 1 equiv.) in Et2O (21.5 mL) was added triethylamine
(0.90 mL, 6.46 mmol, 2.4 equiv.) followed by acryloyl chloride
(0.54 mL, 6.46 mmol, 2.4 equiv.). The resulting suspension was
allowed to stir at room temperature for 24 h. After this time, the
reaction suspension was filtered and the resin was washed with
As for general procedure A. Reaction of acetophenone (18 L,
0.16 mmol, 1.0 equiv.) with (1R,2S)-N-Wang bound ephedrinyl
acrylate 2 (0.50 mmol, 3.2 equiv.) and purification by column
chromatography on silica gel (eluting with 20% EtOAc/petroleum
ether (40–60 °C)) gave 4 (13.8 mg, 50%) as a pale yellow oil:
[]D −31.3 (c 0.63 in MeOH); lit.,5 (90% ee) []D −34.1 (c 0.21 in
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 4 7 6 – 2 4 8 2
2 4 7 9

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MeOH);max (neat)/cm−1 3028s, 1772s(CO);H (400MHz, CDCl3)
7.31–7.21 (5H, m, ArH of Ph), 2.62–2.31 (4H, m, CH2CH2CO),
1.66 (3H, s, CH3C); C (100 MHz, CDCl3) 170.6 (CO), 144.7
(ArC), 128.9 (ArCH), 128.0 (2 × ArCH), 124.5 (2 × ArCH), 87.4
(C–O), 36.6 (CH2CO), 29.8 (CH3C), 29.3 (CH2C); m/z (EI+ mode)
176 (M+, 15%), 161 (100), 121 (30), 105 (23), 82 (10), 77 (18)
(Found M+ 176.0837. C11H12O2 requires 176.0837).
1.76–1.73 (1H, m, 1H from CH2CH), 1.64–1.57 (1H, m, 1H from
CH2CH), 1.48–1.32 (4H, m, 2 × CH2), 0.92 (3H, t, J 7.2, CH3); C
(100 MHz, CDCl3) 177.3 (C(O)), 81.0 (CH), 35.3 (CH2CH), 28.9
(CH2C(O)), 28.0 (CH2CH2C(O)), 27.3 (CH2), 22.4 (CH2), 13.9
(CH3); m/z (CI+ mode, isobutane) 143 ((M + H)+, 100), 81 (8)
(Found (M + H)+ 143.1074. C8H15O2 requires 143.1072).
66% ee, determined by chiral GC (see supporting information).
74% ee, determined by chiral GC (see supporting information†).
(S)-5-Isopropyl dihydro-furan-2-one 95
(S)-5-Ethyl-5-phenyl dihydro-furan-2-one 55
As for general procedure A. Reaction of isobutyraldehyde (23 L,
0.25 mmol, 1.0 equiv.) with (1R,2S)-N-Wang bound ephedrinyl
acrylate 2 (0.78 mmol, 3.2 equiv.) and purification by column
chromatography on silica gel (eluting with 20% EtOAc/petroleum
ether (40–60 °C)) gave 9 (17.6 mg, 56%) as a pale yellow oil:
[]D +26.9 (c 0.02 in MeOH); lit.,5 (93% ee) []D +35.6 (c 0.2–1.0
in MeOH); H (400 MHz, CDCl3) 4.20 (1H, td, J 8.5, 7.0, CHO),
2.60–2.52 (2H, m, CH2CO), 2.26 (1H, apparent sextet, J 6.5, 1H
from CH2CH2CO), 1.96–1.79 (2H, m, 1H from CH2CH2CO
and CH(CH3)2), 1.03 (3H, d, J 6.7, CH(CH3)2), 0.94 (3H, d, J 6.8,
CH(CH3)2); C (100 MHz, CDCl3) 177.3 (CO), 85.8 (CHO), 33.0
(CH), 29.1 (CH2CO), 25.6 (CH2CH2CO), 18.4 (CH3), 17.3
(CH3); m/z (EI+ mode) 128 (M+, 25%), 95 (15), 85 (100), 69 (22), 57
(30), 56 (25) (Found M+ 128.0834. C7H12O2 requires 128.0837).
70% ee, determined by chiral GC (see supporting information).
As for general procedure A. Reaction of propiophenone (21 L,
0.16 mmol, 1.0 equiv.) with (1R,2S)-N-Wang bound ephedrinyl
acrylate 2 (0.50 mmol, 3.2 equiv.) and purification by column
chromatography on silica gel (eluting with 20% EtOAc/petroleum
ether (40–60 °C)) gave 5 (22.1 mg, 73%) as a pale yellow oil:
max (neat)/cm−1 2963m, 1776s (CO), 1448m, 1232m, 1196m;
H (400 MHz, CDCl3) 7.39–7.21 (5H, m, ArH), 2.65–2.39 (4H,
m, 2 × CH2), 2.00 (2H, q, J 7.4, CH2CH3), 0.82 (3H, t, J 7.4,
CH2CH3); C (100 MHz, CDCl3) 177.0 (CO), 143.1 (ArC), 128.9
(2 × ArCH), 127.9 (2 × ArCH), 125.1 (ArCH), 90.2 (C–O), 35.7
(CH2CH3), 35.0 (CH2), 29.1 (CH2CO), 8.6 (CH3C); m/z (EI+
mode) 190 (M+, 2.5%), 161 (100), 133 (10), 105 (30) (Found M+
190.0994. C12H14O2 requires 190.0994).
70% ee, determined by chiral GC (see supporting information).
(S)-5-tert-Butyl dihydro-furan-2-one 105
(S)-5-Propyl-5-phenyl dihydro-furan-2-one 6
As for general procedure A. Reaction of pivalaldehyde (27 L,
0.25 mmol, 1.0 equiv.) with (1R,2S)-N-Wang bound ephedrinyl
acrylate 2 (0.78 mmol, 3.2 equiv.) and purification by column
chromatography on silica gel (eluting with 20% EtOAc/petroleum
ether (40–60 °C)) gave 10 (19.3 mg, 56%) as a pale yellow oil: H
(400 MHz, CDCl3) 4.19 (1H, dd, J 6.9, 8.8, CH), 2.55–2.50 (2H, m,
CH2CO), 2.16–2.08 (1H, m, 1H from CH2), 2.02–1.94 (1H, m, 1H
from CH2), 0.95 (9H, s, 3 × (CH3)C); C (100 MHz, CDCl3) 177.8
(CO), 88.6 (C–O), 34.2 (C), 29.7 (CH2CO), 25.3 (3 × CH3),
23.3 (CH2); m/z (CI+ mode) 143 ((M + H)+, 30%), 57 (100) (Found
(M + H)+, 143.1073. C8H15O2 requires 143.1072).
As for general procedure A. Reaction of butyrophenone (26 L,
0.18 mmol, 1.0 equiv.) with (1R,2S)-N-Wang bound ephedrinyl
acrylate 2 (0.57 mmol, 3.2 equiv.) and purification by column
chromatography on silica gel (eluting with 20% EtOAc/petroleum
ether (40–60 °C)) gave 6 (15.9 mg, 43%) as a pale yellow oil:
[]D −33.0 (c 0.01 in MeOH); max (neat)/cm−1 2960s, 2873m, 1780s
(CO), 1448m, 1324m, 1297m, 1228s; H (400 MHz, CDCl3)
7.32–7.20 (5H, m, ArH), 2.55–2.33 (4H, m, 2 × CH2), 1.91–1.81
(2H, m, CH2), 1.34–1.25 (1H, m, 1H from CH2) 1.08–0.97 (1H, m,
1H from CH2), 0.77 (3H, t, J 7.4, CH2CH3); C (100 MHz, CDCl3)
177.1 (CO), 143.4 (ArC), 128.9 (2 × ArCH), 127.9 (2 × ArCH),
125.0 (ArCH), 89.9 (CO), 45.1 (CH2), 35.5 (CH2), 29.1 (CH2CO),
17.6 (CH2CH3), 14.4 (CH3C); m/z (EI+ mode) 204 (M+, 2.5%), 161
(100), 149 (2.5), 105 (25), 77 (15) (Found M+ 204.1148. C13H16O2
requires 204.1150).
81% ee, determined by chiral GC (see supporting information).
(S)-5-Cyclohexyl dihydro-furan-2-one 115
As for general procedure A. Reaction of cyclohexane-
carboxaldehyde (29 L, 0.23 mmol, 1.0 equiv.) with (1R,2S)-N-
Wang bound ephedrinyl acrylate 2 (0.75 mmol, 3.2 equiv.) and
purification by column chromatography on silica gel (eluting with
20% EtOAc/petroleum ether (40–60 °C)) gave 11 (26.0 mg, 66%)
as a pale yellow oil: []D +29.8 (c 0.01 in MeOH); lit.5 (96% ee)
[]D +26.2 (c 0.2–1.0 in MeOH); H (400 MHz, CDCl3) 4.14 (1H,
dt, J 8.0, 7.4, CHO), 2.54–2.50 (2H, m, CH2CO), 2.25 (1H, ap-
parent sextet, J 6.7, 1H from CH2CH2CO), 1.98–1.90 (2H, m, 1H
from CH2CH2CO and 1H from CH2), 1.80–1.76 (2H, m, CH2),
1.72–1.65 (2H, m, CH2), 1.57–1.51 (1H, m, CH), 1.29–1.16 (3H, m,
CH2), 1.06–1.00 (2H, m, CH2); C (100 MHz, CDCl3) 177.3 (CO),
85.1 (CO), 42.7 (CH), 29.0 (CH2), 28.9 (CH2), 27.7 (CH2), 26.2
(CH2), 25.7 (CH2), 25.6 (CH2), 25.5 (CH2); m/z (EI+ mode) 168 (M+,
8%), 140 (10), 111 (15), 85 (100), 67 (10), 55 (28), 41 (16) (Found
M+ 168.1149. C10H16O2 requires 168.1150).
74% ee, determined by chiral GC (see supporting information).
(R)-5-n-Pentyl dihydro-furan-2-one 75
As for general procedureA. Reaction of hexanal (25 L, 0.21 mmol,
1.0 equiv.) with (1R,2S)-N-Wang bound ephedrinyl acrylate 2
(0.66 mmol, 3.2 equiv.) and purification by column chromatography
on silica gel (eluting with 20% EtOAc/petroleum ether (40–60 °C))
gave 7 (11.9 mg, 37%) as a pale yellow oil: H (400 MHz, CDCl3)
4.48 (1H, apparent q, J = 7.6, CH), 2.53 (2H, dd, J 6.3, 8.4,
CH2CO), 2.32 (1H, dt, J 6.6, 13.7, 1H from CH2CH2CO),
1.90–1.24 (9H, m, 4 × CH2CH2, and 1H from CH2CH2CO), 0.90
(3H, t, J 6.9, CH3C); C (100 MHz, CDCl3) 177.7 (CO), 81.5
(CHO), 35.9 (CH2CH), 31.9 (CH2C(O)), 29.3 (CH2), 28.4 (CH2),
25.3 (CH2), 22.9 (CH2), 14.3 (CH3); m/z (EI+ mode) 156.2 (M+, 2),
138 (3), 128 (5), 100 (5), 84 (100), 49 (10) (Found M+ 156.1143.
C9H16O2 requires 156.1150).
76% ee, determined by chiral GC (see supporting information).
71% ee, determined by chiral GC (see supporting information).
(4R,5S)-5-tert-Butyl-4-methyl dihydro-furan-2-one 125
(R)-5-n-Butyl dihydro-furan-2-one 820
As for general procedure A. Reaction of pivalaldehyde (16.5 l,
0.15 mmol, 1 equiv.) with (1R,2S)-N-Wang bound ephedrinyl
crotonate 3 (0.49 mmol, 3.2 equiv.) and purification by column
chromatography on silica gel (eluting with 20% EtOAc/petroleum
ether (40–60 °C)) gave 12 (13.2 mg, 56%) as a yellow oil: max
(neat)/cm−1 2924s, 2854m, 1736m (CO), 1458m; H (400 MHz,
CDCl3) 4.09 (1H, d, J 4.9, CHO), 2.76 (1H, dd, J 7.5, 16.6, 1H
of CH2CO), 2.69–2.64 (1H, m, CHCH3), 2.20 (1H, dd, J 1.6,
16.6, 1H of CH2CO), 1.14 (3H, d, J 7.1, CH3CH), 1.08 (9H, s,
As for general procedure A. Reaction of pentanal (18 l,
0.17 mmol, 1.0 equiv.) with (1R,2S)-N-Wang bound ephedrinyl
acrylate 2 (0.54 mmol, 3.2 equiv.) and purification by column
chromatography on silica gel (eluting with 20% EtOAc/petroleum
ether (40–60 °C)) gave 8 (12.4 mg, 52%) as a pale yellow oil:
H (400 MHz, CDCl3) 4.49 (1H, quintet, J 7.6, CHOC(O)),
2.59–2.51 (2H, m, CH2C(O)), 2.33 (1H, apparent sextet, J 6.8, 1H
from CH2CH2C(O)), 1.91–1.83 (1H, m, 1H from CH2CH2C(O)),
2 4 8 0
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 4 7 6 – 2 4 8 2

View Article Online
(4R,5S)-5-Cyclopentyl-4-methyl dihydro-furan-2-one 16
(3 × CH3)3C); C (100 MHz, CDCl3) 177.6 (CO), 90.6 (CH–O),
40.1 (CH2CO), 34.6 (CHCH3), 34.2 (C), 26.9 (3 × (CH3)3C),
As for general procedure A. Reaction of cyclopentane carbox-
aldehyde (19.6 l, 0.18 mmol, 1 equiv.) with (1R,2S)-N-Wang
bound ephedrinyl crotonate 3 (0.57 mmol, 3.2 equiv.) and purifica-
tion by column chromatography on silica (eluting with 20% EtOAc/
petroleum ether (40–60 °C)) gave 16 (13 mg, 43%) as a colourless
oil: max (neat)/cm−1 2958s, 1775s (CO), 1454m, 1421m, 1383m,
1326m; H (400 MHz, CDCl3) 4.15 (1H, dd, J 10.1, 5.1, CHO),
2.74 (1H, dd, J 17.0, 7.6, 1H from CH2CO), 2.58–2.52 (1H, m,
CHCH3), 2.21 (1H, dd, J 17.0, 1.9, 1H from CH2CO), 2.16–2.12
(1H, m, CH), 1.96–1.91 (1H, m, 1H from CH2), 1.79–1.73 (1H, m,
1H from CH2), 1.68–1.56 (4H, m, CH2), 1.50–1.43 (1H, m, 1H from
CH2), 1.26–1.17 (1H, m, 1H from CH2), 1.03 (3H, d, J 7.1, CH3);
C (100 MHz, CDCl3) 177 (CO), 88.2 (CHO), 39.5 (CH), 38.5
(CH2CO), 32.8 (CHCH3), 30.9 (CH2), 27.8 (CH2), 25.4 (CH2),
25.3 (CH2), 14.2 (CH3); m/z (CI+ mode, isobutane) 169 ((M + H)+,
100%) (Found (M + H)+ 169.1231. C10H17O2 requires 169.1229).
88% ee, determined by chiral GC (see supporting information).
+
16.3 (CH3CH); m/z (EI+ mode) 141 (M–CH3 , 10%), 99 (100), 83
(63), 71 (44), 57 (100) and 41 (39) (Found (M − CH3)+, 141.0917.
C8H13O2 requires 141.0916).
93% ee, determined by chiral GC (see supporting information).
(4R,5S)-5-Cyclohexyl-4-methyl dihydro-furan-2-one 135
As for general procedure A. Reaction of cyclohexane
carboxaldehyde (18.4 l, 0.15 mmol, 1 equiv.) with (1R,2S)-
N-Wang bound ephedrinyl crotonate 3 (0.49 mmol, 3.2 equiv.)
and purification by column chromatography on silica (eluting
with 10% EtOAc/petroleum ether (40–60 °C)) gave 13 (18.2 mg,
66%) as a pale yellow solid: []D +53.9 (c 0.5 in MeOH); lit.,5
[]D +56.2 (c 1.0 in MeOH); max (Golden Gate)/cm−1 2927s,
1747s (CO), 1456w, 1174s; H (400 MHz, CDCl3) 3.95 (1H,
dd, J 4.7, 9.8, CHO), 2.65 (1H, dd, J 7.4, 16.9, 1H of CH2CO),
2.50–2.47 (1H, m, CHCH3), 2.12 (1H, dd, J 1.1, 16.9, 1H of
CH2CO), 2.00–1.96 (1H, m, 1H of CH2 of cyclohexane ring),
1.71–1.62 (4H, m, 2 × CH2 cyclohexane ring), 1.58–1.53 (2H, m,
1H of CH2 of cyclohexane ring and CHCHO), 1.22–1.07 (2H, m,
CH2 of cyclohexane ring), 1.00–0.99 (1H, m, 1H of CH2 of cyclo-
hexane ring), 0.95 (3H, d, J 12.9, CH3CH), 0.92–0.83 (1H, m, 1H
of CH2 of cyclohexane ring); C (100 MHz, CDCl3) 177.4 (CO),
88.1 (CHO), 39.2 (CH2CO), 37.8 (CHCHO), 32.4 (CHCH3),
30.7 (CH2 of cyclohexane ring), 28.4 (CH2 of cyclohexane ring),
26.5 (CH2 of cyclohexane ring), 25.8 (CH2 of cyclohexane ring),
25.7 (CH2 of cyclohexane ring), 13.9 (CH2 of cyclohexane ring);
m/z (EI+ mode) 182 (M+, 13%), 154 (28), 99 (100), 84 (41),
83 (29) and 49 (34) (Found M+ 182.1306. C11H18O2 requires
182.1307).
(5R,4R)-5-n-Butyl-4,5-dimethyl dihydrofuran-2-one 17
As for general procedure A except, due to the lower reactivity of
the ketone, 2-hexanone (3 equiv.) was reacted with the resin (1
equiv.). Reaction of 2-hexanone (78 l, 0.62 mmol, 3.0 equiv.)
with (1R,2S)-N-Wang bound ephedrinyl crotonate 3 (0.21 mmol,
1.0 equiv.) and purification by column chromatography on silica
gel (eluting with 20% EtOAc/petroleum ether (40–60 °C)) gave
17 (12.7 mg, 36%) as a pale yellow oil and as an inseparable
3:1 mixture of diastereoisomers: For the major diastereoisomer:
max (neat)/cm−1 2959s, 2872s, 1772s (CO), 1460m, 1382m; H
(400 MHz, CDCl3) 2.59 (1H, dd, J 16.6, 7.5, 1H from CH2CO),
2.39–2.24 (2H, m, 1H from CH2CO and CHCH3), 1.66–1.31 (6H,
m, 3 × CH2), 1.39 (3H, s, CH3), 1.00 (3H, d, J 6.8, CHCH3), 0.93
(3H, t, J 7.1, CH2CH3); C (100 MHz, CDCl3) 176.1 (CO), 88.7
(CO), 41.3 (CHCH3), 36.9 (CH2CO), 34.5 (CH2), 25.6 (CH2), 24.3
(CH3), 23.2 (CH2), 14.0 (CH3), 13.9 (CH3); m/z (CI+ mode, isobu-
tene) 171 (M + H+, 100%), 113 (3), 85 (5), 71 (4) (Found (M + H)+
171.1384. C10H19O2 requires 171.1385).
96% ee, determined by optical rotation.
(4R,5R)-5-Isopropyl-4-methyl dihydro-furan-2-one 1421
As for general procedure A. Reaction of isobutyraldehyde
(20.6 l, 0.23 mmol, 1 equiv.) with (1R,2S)-N-Wang bound
ephedrinyl crotonate 3 (0.73 mmol, 3.2 equiv.) and purification
by column chromatography on silica (eluting with 10% EtOAc/
petroleum ether (40–60 °C)) gave 14 (17.9 mg, 55%) as a yellow
oil: []D +11.8 (c 0.4 in CHCl3); max (neat)/cm−1 2926s, 2875s,
2362m, 1751s (CO), 1594m, 1457m; H (400 MHz, CDCl3)
3.94 (1H, dd, J 4.8, 10.2, CHO), 2.74 (1H, dd, J 7.4, 16.9, 1H
of CH2CO), 2.58–2.53 (1H, m, CHCH2CO), 2.21 (1H, dd, J
1.1, 16.9, 1H of CH2CO), 1.93–1.86 (1H, m, CH(CH3)2), 1.09
(3H, d, J 6.5, CH3CHCH3), 1.00 (3H, d, J 7.0, CH3CHCH2),
0.91 (3H, d, J 6.6, CH3CHCH3); C (100 MHz, CDCl3) 177.0
(CO), 89.1 (CHO), 39.0 (CH2CO), 31.9 (CHCH2CO),
28.1 (CH(CH3)2), 20.1 (CH3CHCH3), 18.4 (CH3CHCH3), 13.4
(CH3CHCH2); m/z (EI+ mode) 142 (M+, 5%), 114 (16), 99 (70),
84 (100), 71 (37) and 43 (27) (Found M+ 142.0996. C8H14O2
requires 142.0994).
Major (89% ee) and minor (76% ee), the cis-product was
assumed to be the major diastereoisomer, determined by chiral GC
(see supporting information).
5-Methyl-hexane-1,5-diol 1817
To a solution of -valerolactone (1.46 g, 14.6 mmol, 1.0 equiv.)
in THF at −78 °C was added MeLi (1.5 M in Et2O, 29.2 mL,
43.8 mmol, 3.0 equiv.) dropwise. The solution was allowed to
stir at −78 °C for 30 min before being allowed to warm to room
temperature overnight. The reaction was then quenched by drop-
wise addition of acetic acid (1.4 mL, 25.0 mmol, 1.7 equiv.) to the
reaction solution. A white suspension resulted and this was stirred
at room temperature for 4 h before filtration. The precipitate was
washed with THF (3 × 50 mL) and the combined filtrate and wash-
ings were concentrated in vacuo to afford a crude oil. Purification
by dry flash chromatography on silica (90% EtOAc/petroleum
ether (40–60 °C) to 20% MeOH/EtOAc) gave 18 (1.27 g, 66%)
as a colourless oil: max(neat)/cm−1 3350s, 2968s, 2934s, 2867s,
1468m, 1379m, 1201m, 1155m; H (400 MHz, CDCl3) 3.66 (2H,
t, J 6.4, CH2OH), 1.74 (2H, br s, 2 × OH), 1.58 (2H, quintet, J 6.4,
CH2CH2OH), 1.52–1.41 (4H, m, 2 × CH2), 1.22 (6H, s, 2 × CH3);
C (100 MHz, CDCl3) 71.0 (C), 62.6 (CH2OH), 43.3 (CH2), 33.0
(CH2CH2OH), 29.2 (2 × CH3), 20.4 (CH2); m/z (FAB+ mode) 133
((M + H)+, 25%), 115 (100), 97 (28), 60 (8), 56 (8) (Found (M + H)+
133.1229. C7H17O2 requires 133.1230).
91% ee, determined by chiral GC (see supporting information).
(4R,5R)-5-n-Butyl-4-methyl dihydro-furan-2-one 155
As for general procedure A. Reaction of pentanal (14 l,
0.12 mmol, 1.0 equiv.) with (1R,2S)-N-Wang bound ephedrinyl
crotonate 3 (0.39 mmol, 3.2 equiv.) and purification by column
chromatography on silica gel (eluting with 20% EtOAc/petroleum
ether (40–60 °C)) gave 15 (9.6 mg, 50%) as a pale yellow oil: H
(400 MHz, CDCl3) 4.46–4.41 (1H, m, CHO), 2.70 (1H, dd, J 16.9,
7.8, 1H from CH2CO), 2.63–2.54 (1H, m, CHCH3), 2.21 (1H, dd,
J 16.9, 3.9, 1H from CH2CO), 1.70–1.61 (1H, m, 1H from CH2),
1.58–1.45 (2H, m, CH2), 1.42–1.36 (3H, m, CH2), 0.95 (3H, d, J 7.0,
CHCH3), 0.93 (3H, t, J 7.3, CH3CH2); C (100 MHz, CDCl3) 176.9
(CO), 83.7 (CHO), 37.6 (CH2CO), 33.0 (CHCH3), 29.6 (CH2),
28.1 (CH2), 22.5 (CH2), 13.9 (CH3), 13.8 (CH3); m/z (CI+ mode)
157 ((M + H)+, 100%), 113 (6), 81 (8) (Found (M + H)+ 157.1231.
C9H17O2 requires 157.1229).
5-Methyl-5-trimethylsilyloxy-hexan-1-ol 19
To a solution of diol 18 (90 mg, 0.69 mmol, 1.0 equiv.) in CH2Cl2
(8 mL) was added triethylamine (3.8 mL, 27.3 mmol, 40 equiv.) and
trimethylsilyl chloride (1.74 mL, 13.7 mmol, 20 equiv.) and the reac-
tion was allowed to stir at room temperature for 3 days. The reaction
91% ee, determined by chiral GC (see supporting information).
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 4 7 6 – 2 4 8 2
2 4 8 1

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was quenched with water (2 mL), the organic layer was separated
and the aqueous layer was extracted with CH2Cl2 (2 × 15 mL). The
combined organics were dried (Na2SO4) and concentrated in vacuo
to afford the crude product. Purification by column chromatography
on silica (30% EtOAc/petroleum ether (40–60 °C)) gave a colour-
less oil (171.0 mg, 90%) that was shown to be composed mainly of
bis-TMS protected compound by 1H NMR. To this product (144 mg,
0.52 mmol, 1 equiv.) was added potassium carbonate (144 mg,
1.04 mmol, 2.0 equiv.) and anhydrous methanol (2.0 mL). The solu-
tion was stirred at 0 °C for 2.5 h before quenching with acetic acid
(0.06 mL, 1.04 mmol, 2.0 equiv.) and water (2 mL). The aqueous
solution was then extracted with CH2Cl2 (3 × 15 mL) and the com-
bined organics were dried (Na2SO4) and concentrated in vacuo to
afford 19 (108 mg, 92% overall) as a colourless oil, which was used
without further purification: max(neat)/cm−1 3348s, 1468m, 1379m,
1201m, 1155m; H (400 MHz, CDCl3) 3.66 (2H, t, J 6.5, CH2OH),
1.57 (2H, quintet, J 6.5, CH2CH2OH), 1.54–1.37 (4H, m, 2 × CH2),
1.21 (6H, s, 2 × CH3), 0.11 (9H, s, 3 × CH3Si); C (100 MHz,
CDCl3) 74.0 (C), 63.0 (CH2OH), 44.5 (CH2), 33.2 (CH2CH2OH),
29.8 (2 × CH3), 20.5 (CH2), 2.6 (3 × CH3Si); m/z (FAB+ mode) 189
((M − CH3)+, 7%), 131 (100), 84 (12), 73 (50), 55 (16), 43 (15)
(Found (M − CH3)+ 189.1311. C9H21O2Si requires 189.1308).
P. C. H.) and the University of Glasgow (University Scholarship,
P. C. H.) for financial support. We also thank AstraZeneca for the
award of a Strategic Research Grant (D. J. P.) and Pfizer for untied
funding (D. J. P.).
References
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5 S. Fukuzawa, K. Seki, M. Tatsuzawa and K. Mutoh, J. Am. Chem. Soc.,
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9 J. M. J. Fréchet, E. Bald and P. Lecavalier, J. Org. Chem., 1986, 51,
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11 The loading of 1 was determined by esterification with thiophene
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12 S. Fukuzawa, A. Nakanishi, T. Fujinami and S. Sakai, J. Chem. Soc.,
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13 Few intermolecular radical additions to immobilised acceptors have
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M. P. Sibi, Wiley-VCH, Weinheim, 2001, vol. 2, p. 81; (b) A. Ganesan
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Nicolaou, R. Hanko, W. Hartwig, Wiley-VCH, Weinheim, 2002,
vol. 1, p. 227. For recent examples, see; (c) S. Caddick, D. Hamza
and S. N. Wadman, Tetrahedron Lett., 1999, 40, 7285; (d) X. Zhu
and A. Ganesan, J. Comb. Chem., 1999, 1, 157; (e) H. Miyabe,
Y. Fujishima and T. Naito, J. Org. Chem., 1999, 64, 2174;
(f) H. Miyabe, C. Konishi and T. Naito, Org. Lett., 2000, 2, 1443;
(g) S. Caddick, D. Hamza, S. N. Wadman and J. D. Wilden, Org.
Lett., 2002, 4, 1775; (h) D. C. Harrowven, P. J. May and M. Bradley,
Tetrahedron Lett., 2003, 44, 503.
5-Methyl-5-trimethylsilyloxy-hexanal 20
To Dess–Martin periodinane (470 mg, 1.11 mmol, 1.1 equiv.)
in CH2Cl2 (4.6 mL) was added alcohol 19 (206 mg, 1.01 mmol,
1.0 equiv.) in CH2Cl2 (2 mL) via cannula. The light orange
coloured solution was then stirred at room temperature for 2 h
before dilution with diethyl ether (25 mL) and addition to an
aqueous saturated NaHCO3 (1 mL)/aqueous saturated Na2S2O3
(8 mL) solution. The mixture was stirred for a few minutes before
the organic layer was separated. The organic layer was extracted
with aqueous NaHCO3 (10 mL) and water (12 mL). The organic
layer was then dried (Na2SO4) and concentrated in vacuo to afford
20 (199.6 mg, 98%) as a pale orange oil which was used without
further purification: max(neat)/cm−1 2960s, 2715w, 1728s (CO),
1460m, 1412m, 1383m, 1365m, 1250s; H (400 MHz, CDCl3)
9.67 (1H, t, J 1.8, CHO), 2.33 (2H, td, J 7.3, 1.8, CH2CHO),
1.75–1.67 (2H, m, CH2CH2CHO), 1.46–1.39 (2H, m, CH2), 1.23
(6H, s, 2 × CH3), 0.11 (9H, s, 3 × CH3Si); C (100 MHz, CDCl3)
202.9 (CHO), 73.6 (C), 44.3 (CH2CHO), 44.2 (CH2), 29.8
(2 × CH3), 17.1 (CH2CH2CHO), 2.6 (3 × CH3Si); m/z (EI+ mode)
187 ((M − CH3)+, 8%), 131 (100), 129 (18), 95 (12), 73 (65), 69 (23)
(Found (M − CH3)+ 187.1154. C9H19O2Si requires 187. 1154).
5-(4-Hydroxy-4-methyl-pentyl) dihydro-furan-2-one 21
As for general procedure A. Reaction of aldehyde 20 (48.6 mg,
0.24 mmol, 1.0 equiv.) with (1R,2S)-N-Wang bound ephedrinyl
acrylate 2 (0.77 mmol, 3.2 equiv.) and purification by column
chromatography on silica gel (30% EtOAc/petroleum ether
(40–60 °C) to ethyl acetate) gave 21 (22.6 mg, 50%) as a pale
yellow oil: []D +29.5 (c 0.01 in MeOH). lit.16 []D +42.0 (c 1.0
in MeOH); max(neat)/cm−1 3450s, 2968s, 1767s (CO), 1462m,
1421m, 1363m, 1298w; H (400 MHz, CDCl3) 4.55–4.48 (1H, m,
CHOC(O)), 2.55 (2H, m, CH2CH2C(O)), 2.38–2.30 (1H, m, 1H
from CH2C(O)), 1.92–1.85 (1H, m, 1H from CH2C(O)), 1.77–1.74
(1H, m, 1H from CH2), 1.73–1.48 (5H, m, 1H from CH2, 2 × CH2),
1.65 (6H, s, 2 × CH3); C (100 MHz, CDCl3) 177.2 (CO), 80.9
(CH), 70.8 (C), 43.4 (CH2), 36.1 (CH2), 29.4 (CH3), 29.2 (CH3),
28.8 (CH2C(O)), 28.0 (CH2CH2C(O)), 20.3 (CH2); m/z (CI+ mode,
isobutene) 187 (M+, 5%), 169 (100), 151 (10), 69 (5) (Found M+
187.1337. C10H18O3 requires 187.1334).
14 The diastereoselectivity was confirmed by comparison with Fukuzawa’s
1H NMR data (ref. 5) and by NOE studies.
15 The efficient reduction of ,-unsaturated esters with SmI2 usually
requires the use of an additive such as DMA (N,N-dimethyl acetamide)
or HMPA, see (a) J. Inanaga, S. Sakai, Y. Handa, M. Yamaguchi and
Y. Yokoyama, Chem. Lett., 1991, 2117; (b) A. Cabrera and H. Alper,
Tetrahedron Lett., 1992, 33, 5007.
16 C. Maul, I. Sattler, M. Zerlin, C. Hinze, C. Koch, A. Maier, S. Grabley
and R. Thiericke, J. Antibiot., 1999, 52, 1124.
17 A. S. Hernández and J. C. Hodges, J. Org. Chem., 1997, 62, 3153.
18 D. B. Dess and J. C. Martin, J. Org. Chem., 1983, 48, 4155.
19 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. (See the Electronic
Supporting Information).
20 M. Utaka, H. Watabu and A. Takeda, J. Org. Chem., 1987, 52,
4363.
21 J. Rojo, M. García and J. C. Carretero, Tetrahedron, 1993, 49, 9787.
73% ee, determined by chiral GC (see supporting information).
Acknowledgements
We thank the Engineering and Physical Research Council (EPSRC)
(GR/R72242/01, N. J. K.), GlaxoSmithKline (CASE award,
2 4 8 2
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 4 7 6 – 2 4 8 2