Evaluation of a new linker system cleaved using samarium(II) iodide. Application in the solid phase synthesis of carbonyl compounds

Article abstract of DOI:10.1039/b506294b

A new linker design for solid phase synthesis has been developed that is cleaved under mild, neutral conditions using samarium(II) iodide. The feasibility of the linker approach has been illustrated in the solid phase synthesis of ketones and amides using

Full text of DOI:10.1039/b506294b

View Online / Journal Homepage / Table of Contents for this issue
A R T I C L E
Evaluation of a new linker system cleaved using samarium(II) iodide.
Application in the solid phase synthesis of carbonyl compounds
Fiona McKerlie,a Iain M. Rudkin,c Graham Wynneb and David J. Procter*c
a Department of Chemistry, The Joseph Black Building, University of Glasgow, Glasgow,
UK G12 8QQ
b OSI Pharmaceuticals (UK) Ltd, Watlington Road, Oxford, UK OX4 6LT
c School of Chemistry, University of Manchester, Oxford Rd, Manchester, UK M13 9PL.
E-mail: david.j.procter@manchester.ac.uk
Received 5th May 2005, Accepted 1st June 2005
First published as an Advance Article on the web 24th June 2005
A new linker design for solid phase synthesis has been developed that is cleaved under mild, neutral conditions using
samarium(II) iodide. The feasibility of the linker approach has been illustrated in the solid phase synthesis of ketones
and amides using an oxygen linker. Insights into the mechanism of the samarium(II) iodide cleavage reaction are
described and the potential of a sequential cleavage carbon–carbon bond forming process is assessed.
including natural product synthesis,8 the stereoselective prepa-
Introduction
ration of unsaturated esters and amides, including isotopically
Solid phase organic synthesis remains an important tool
labelled analogues,9 and the development of new methods for
for synthetic chemists who wish to prepare collections of
asymmetric protonation.10 We felt the impressive specificity of
compounds in an efficient manner.1 At the heart of solid
the reducing agent for the a-heteroatom substituted carbonyl
phase synthesis lie linker groups.2 The design of new linker
motif would be an ideal feature for a new linker system.
strategies is crucial to the continued development of the field.
In our linker approach, if the ‘X’ group in Fig. 1 represents
Our interest in new linker systems for synthesis has led us to
a heteroatom linkage to solid support, then the overall reaction
develop ephedrine-based linkers for asymmetric solid phase
represents cleavage from the support and introduction of a
synthesis.3 Furthermore, we have demonstrated the potential
proton at the point of cleavage. We refer to this new class of
of the chemistry for asymmetric library synthesis.3b Here we
linker as an a-Hetero-Atom Substituted Carbonyl or HASC
report the evaluation of a potential family of linkers cleaved
linker.11 In this article we describe in detail the realisation of our
using electron-transfer reagents such as samarium(II) iodide
linker approach and illustrate its application in the solid-phase
(SmI2).4 The new linker can be described as being traceless,
synthesis of acyclic carbonyl compounds using an oxygen-based
the most common definition of which is when an aliphatic
HASC linker.12
or aromatic proton is introduced at the point of cleavage.2c,d
Traceless linkers are often the most useful type of linker as no
Results and discussion
residual functionality is left at the point of attachment.
Cleavage of the linker described here relies on the well-
established reduction of a-heteroatom substituted carbonyl
compounds with SmI2 (Fig. 1). In 1986, Molander carried out
the first detailed studies on the reduction of a-heterosubstituted
ketones5a and a,b-epoxy ketones.5b Shortly afterwards, Inanaga
reported conditions for the reduction of the analogous ester sub-
strates using the SmI2–HMPA reagent system.5c,d The reduction
of a-heterosubstituted amides has only recently been reported
by Simpkins.6
At the outset of our studies few examples of the use of SmI2
in solid-phase chemistry had been described.13 It was therefore
important not only to assess the feasibility of our proposed
linker system but also to further verify the compatibility of the
reagent with polymeric supports. We therefore decided to begin
our studies by investigating the solid phase synthesis of simple
amides and ketones from c-butyrolactone immobilized by an
oxygen linkage a to the lactone carbonyl (Scheme 1).
Fig. 1 (a) The reduction of a-heteroatom substituted carbonyl com-
pounds with SmI2: (b) The a-Hetero-Atom Substituted Carbonyl or
HASC linker strategy.
Scheme 1 An approach to simple amides and ketones from an
immobilized lactone.
The mild, neutral conditions of the SmI2 process and its appli-
cability to different classes of carbonyl compound have allowed
the reaction to be employed extensively in organic synthesis,
often on complex substrates bearing sensitive functionality. The
reaction has recently found application in a variety of areas7
As shown in Scheme 1, we chose to establish the linkage
through the reaction of a phenol resin with an a-halo carbonyl
compound. This immobilisation approach was selected due to
the ready availability of a-halo carbonyl compounds and the
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 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 8 0 5 – 2 8 1 6
2 8 0 5
©

View Online
predicted ease of the etherification reaction with phenols. Phenol
resin 1 was readily prepared from commercially available bromo
Wang resin in two steps and in good overall yield (Scheme 2).
In the only previous example of the reduction of a-alkoxy
amides, prior to our work, Simpkins reported that LiCl14 was
an efficient promoter of the reaction.6 In our systems, the use
of LiCl often led to incomplete cleavage of the a-aryloxy group.
After a brief study, we found that the use of DMPU as an
additive in the reduction gave excellent results.15 Treatment of
6 with samarium(II) iodide and DMPU at room temperature
resulted in complete conversion to amide 7 (81% isolated yield)
and benzyloxyphenol (83% isolated yield) after 2 h (Scheme 4).
Scheme 2 Reagents and conditions: i, 4-TBDMSOC6H4OH 4 eq, NaH
5 eq, DMF, rt, 18 h; ii, TBAF (1 M in THF) 6 eq, THF, rt, 15 h (resin
re-treated under the same conditions): Overall yield ∼80%.
The loading of phenol resin 1 was determined by cleavage
with TFA–CH2Cl2 (1 : 1) and isolation of hydroquinone, in
conjunction with bromine elemental analysis of the resin.
Before solid phase studies were begun, solution model studies
using benzyloxyphenol as a model for resin 1 were carried out.
The reaction of benzyloxyphenol with a-bromo-c-butyrolactone
(K2CO3, DMF, 18-crown-6, 60 ◦C, 24 h) gave lactone 2 in 74%
yield. Ring-opening and Weinreb amide formation followed by
protection of the primary hydroxyl group then gave 3 (Scheme 3).
Finally, reaction with EtMgCl gave ketone 4, a model substrate
for the samarium(II) cleavage reaction, in good overall yield.
Pleasingly, treatment of 4 with samarium(II) iodide at 0 ◦C
resulted in complete conversion to ketone 5 (93% isolated yield)
and benzyloxyphenol (90% isolated yield) in less than 5 min.
This sequence shows the potential of our linker approach and
illustrated the compatibility of the linkage with strongly basic
and Lewis acid conditions. In addition, the link proved to be
stable during the addition of Grignard reagents to the amide
carbonyl group. The solution model studies also suggested the
possibility of recovering and reusing the phenol resin 1.
Scheme 4 Reagents and conditions: i, AlMe3 3 eq, pyrrolidine 3 eq,
toluene, rt to 50 ◦C; ii, TBDPSCl 2 eq, imidazole 4 eq, DMF, rt, 71% (2
steps); iii, SmI2 6 eq, DMPU 16 eq, THF: amide 7 81%, benzyloxyphenol
83%.
Finally, we investigated the introduction of additional di-
versity using our model system. Lactone 2 was alkylated
(LDA, THF, −45 ◦C, allyl bromide), ring-opened with 1,2,3,4-
tetrahydroisoquinoline at 50 ◦C and protected to give amide 9.
We were pleased to find that treatment of 9 with samarium(II)
iodide and DMPU at 50 ◦C for 2 h resulted in complete conver-
sion to amide 10 (76% isolated yield) and benzyloxyphenol (95%
isolated yield), thus illustrating the feasibility of preparing more
substituted carbonyl compounds using the approach (Scheme 5).
We also carried out solution phase model studies to assess
the feasibility of preparing amides. Lactone 2 was ring-opened
with pyrrolidine under Lewis acid conditions and protected to
give amide 6, a solution phase model for an immobilised amide.
Cleavage of a-heteroatom substituents in amide substrates has
been found to be more difficult than for analogous ketones.6
Scheme 5 Reagents and conditions: i, LDA 1.4 eq, THF, −45 ◦C, 30 min
then allyl bromide −45 ◦C to rt, 72%; ii, AlMe3 (2.0 M in hexane) 3 eq,
1,2,3,4-tetrahydroisoquinoline·HCl, 3 eq, toluene, rt to 50 ◦C, 24 h; ii,
TBDPSCl 2 eq, imidazole 4 eq, DMF, rt, 78% (2 steps); iii, SmI2 7 eq,
DMPU 16 eq, THF: amide 10 76%, benzyloxyphenol 95%.
Scheme 3 Reagents and conditions: i, AlMe3 3 eq, NH(Me)(OMe)·HCl
3 eq, toluene, rt to 50 ◦C; ii, TBDPSCl 2 eq, imidazole 4 eq, DMF, rt,
79% (2 steps); iii, EtMgCl 2.5 eq, THF, 0 ◦C to rt, 72%; iv, SmI2 3 eq,
THF, 0 ◦C, <5 min: ketone 5 93%, benzyloxyphenol 90%.
Satisfied that our linker approach was feasible, we considered
solid phase routes from immobilised c-butyrolactone 11 to
simple, functionalised carbonyl compounds which embraced a
2 8 0 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 8 0 5 – 2 8 1 6

View Online
variety of reaction conditions. The key aspects of the routes are
illustrated in Scheme 6. Lewis acid mediated ring-opening of
11 with a variety of secondary amines was carried out followed
by subsequent silylation or acetylation of the resultant alcohols
12 (see Scheme 6). In addition, tert-butyldiphenylsilyl-protected
morpholine amides were converted to ketones 15 by reaction
with Grignard reagents. Immobilised amide substrates 13, and
ketone substrates 15 underwent smooth cleavage from the resin
when exposed to the conditions developed in our model solution
phase studies. Amide and ketone products were obtained in
moderate to good overall yields and purities (Fig. 2). Crucially,
we have found that the link can be cleaved in the presence of
ester groups (14c and 14d), thus illustrating the mild and neutral
nature of the cleavage conditions.
column of silica gel, after which they were found to give
1
satisfactory H and 13C NMR spectra. Standard, flash chro-
matography was required to separate the more polar acetates
14c and 14d from DMPU. Unfortunately, attempts to utilize
the approach illustrated in Scheme 5 to access more substituted
amide products gave poor yields of product. This was due to the
inefficiency of the lactone alkylation step on solid phase.
In an attempt to improve the overall yields obtained using the
linker system, we investigated the use of Brown’s phenol resin,
prepared by Friedel–Crafts acylation of polystyrene followed by
Baeyer–Villiger rearrangement and ester hydrolysis.16 We felt
this phenol resin might prove more robust than 1 and lead
to higher yields in the solid phase sequences. The synthesis of
morpholine amide 14a using Brown’s phenol resin however gave
the product in a similar yield after 4 steps (18%).
The synthesis of cyclopropyl ketone 16c was designed to probe
the mechanism of cleavage from the resin. If the SmI2 cleavage
reaction proceeds through the generation of a cyclopropylmethyl
radical anion, fragmentation of the cyclopropane would be
expected to occur.17 Treatment of 17 with SmI2 gave a 6 :
1 mixture of ring-closed (16c) and ring-opened product (18)
(Scheme 7). Preparation of the solution phase model compound
19 allowed us to study the cleavage in more detail. Careful
titration of 19 with SmI2 gave 16c in 72% (isolated yield) and
benzyloxyphenol (79% isolated yield), with no trace of ring-
opened product 18 by 1H NMR. This indicates that the isolation
of small amounts of 18 from the solid phase reaction results from
over-reduction of the cleaved product 16c.18
Scheme 6 Reagents and conditions: i, a-bromo-c-butyrolactone 10
eq, K2CO3 16 eq, DMF, 60 ◦C, 18 h; ii, pyrrolidine/morpholine/
1,2,3,4-tetrahydroisoquinoline 6 eq, AlMe3 (2 M in hexanes) 6 eq,
toluene, 50 ◦C, 20–24 h; iii, TBDPSCl 4 eq, imidazole 8 eq, DMF,
rt, 16 h or Ac2O 10 eq, pyridine, rt, 20 h; iv, SmI2 5 eq, DMPU 16 eq,
THF, rt or 50 ◦C, 6–12 h; v, i-PrMgCl/BnMgCl/c-PrMgBr 6 eq, THF,
0 ◦C to rt; 20 h; vi, SmI2 4 eq, THF, rt, 4–6 h.
No aqueous work up is necessary on completion of the
reduction. Products were conveniently separated from DMPU
and inorganic by-products by simple filtration through a short
Scheme 7 Reagents and conditions: i, SmI2 1 eq (based on theoretical
loading), THF, rt, 3 h: 6 : 1 ratio of 16c : 18, 18% (5 steps from 1).
Fig. 2 Amide and ketone products obtained. HPLC purities (254 nm) are given in parentheses after chemical yields. aOverall yield for 4 steps from
1. bOverall yield for 5 steps from 1. cObtained as a 6 : 1 mixture of ring-closed (16c) and ring-opened (18) product.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 8 0 5 – 2 8 1 6
2 8 0 7

View Online
The isolation of 16c, where the cyclopropyl ring is intact,
suggests that a radical is not formed at the carbonyl carbon
during cleavage (cf. 20).17,18 This appears to indicate that cleavage
occurs by direct reduction of the carbon–oxygen link, to give
a radical such as 21, rather than by elimination of the a-
heteroatom substituent after reduction of the carbonyl.5 To the
best of our knowledge, direct reduction of an a-substituent in
ketone substrates, has not previously been proposed (Fig. 3).19
To increase the potential of our new linker approach, we
sought to evaluate a multidirectional cleavage strategy in which
the intermediate samarium(III) enolate formed upon cleavage
could be trapped with electrophiles. In principle, this would
allow a single resin bound intermediate to furnish a variety
of products depending upon the electrophile employed in
the cleavage step, thus effectively amplifying the size of any
synthetic library.
The intermolecular trapping of samarium(III) enolates with
electrophiles has relatively limited precedent.20 Arguably the
most elegant application of such chemistry to date is
Skrydstrup’s selective alkylation of peptides via reductive
samariation.21
We chose to investigate the sequential cleavage–enolate trap-
ping by returning to a solution phase model system. After
optimization, treatment of ketone 23 with SmI2–DMPU at
◦
−78 C, employing cyclohexanone and tetrahydropyran-4-one
as electrophiles, gave aldol adducts 24 and 25 in excellent yield
(78% and 76% respectively). No products were obtained if the
carbon electrophile was not employed as an in situ trap. DMPU
was also found to be essential for successful reaction and the
use of higher temperatures was found to result in significant
retro-aldol reaction. Sequential cleavage–Michael addition was
less successful. Adduct 26 was obtained in an unoptimised
yield of 11% after cleavage in the presence of methyl acrylate22
(Scheme 8).
Although of synthetic and mechanistic interest, we feel the
conditions required for successful cleavage–trapping are unlikely
to lead to a practical solid-phase protocol. Improved HASC
linker systems better suited to multidirectional cleavage are
currently under development in our laboratory.
Fig. 3 Proposed mechanism of cleavage.
To probe the nature of the reactive intermediate formed
upon cleavage, the reduction of solution phase model 23 was
carried out under various conditions. In the presence of 1 eq
of MeOD, ketone 16a was isolated with complete deuterium
incorporation a to the carbonyl group. Reduction of 23 using
SmI2 in d8-THF gave unlabelled ketone 16a. Finally, reduction
of 23 followed by quenching with MeOD after 2 minutes gave
only 36% deuterium incorporation. These experiments suggest
the intermediacy of a samarium(III) enolate (cf. 22) that is
protonated rather than a radical (cf. 21) that is quenched by
hydrogen atom capture from solvent. Our studies also suggest
that the intermediate enolate readily undergoes protonation
even under ‘anhydrous’ conditions.
As previously mentioned, our solution model studies sug-
gested the possibility of recovering and reusing the phenol resin
1 without the need for chemical reactivation. To investigate
the feasibility of recycling 1, the resin from the synthesis of
morpholine amide 14a (26%) was washed, dried and reused in
the preparation of pyrrolidine amide 7. Unfortunately, upon
cleavage with SmI2, 7 was isolated in a disappointing overall
yield (5%). This preliminary study shows that recycling of the
support is currently not practical.
Conclusions
In summary, we have developed and evaluated a new linker
design for solid phase synthesis. Our linker strategy is based on
the mild, neutral reduction of a-heteroatom substituted carbonyl
compounds using samarium(II) iodide. The feasibility of the
linker approach has been illustrated initially in solution and
then in a solid phase approach to ketones and amides using an
oxygen linker. Insights into the mechanism of the samarium(II)
iodide cleavage reaction have been made during our studies.
Finally, we have assessed the potential of a sequential cleavage,
carbon–carbon forming process.
Experimental
General considerations
All experiments were performed under an atmosphere of Ar or
N2, using anhydrous solvents, unless stated otherwise. Reactions
Scheme 8 Reagents and conditions: i, SmI2 6 eq, DMPU 24 eq, cyclohexanone 16 eq, THF, −78 ◦C, 45 min, 78% (24), 10% (23), benzyloxyphenol
recovered in 86% yield. ii, SmI2 6 eq, DMPU 20 eq, tetrahydropyran-4-one 16 eq, THF, −78 ◦C, 1 h, 76% (25), 12% (16a), benzyloxyphenol recovered
in 100% yield. iii, SmI2 4.4 eq, methyl acrylate 2.2 eq, 0 ◦C to rt, 11% (26), 86% (16a), benzyloxyphenol recovered in 91% yield.
2 8 0 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 8 0 5 – 2 8 1 6

View Online
were carried out using oven-dried glassware. THF was distilled
from sodium–benzophenone. CH2Cl2, Et2O and i-Pr2NH were
distilled from CaH2. Et3N was distilled from CaH2 and stored
over KOH and under Ar–N2. HMPA and DMPU were dried by
refluxing with CaH2 followed by fractional distillation under
reduced pressure. Commercially available bromo-Wang resin
with a loading of 1.2 mmol g−1 was employed throughout.
Reactions on immobilized substrates were carried out in round-
bottomed flasks and agitated by slow stirring, or in Bond Elut
cartridges fitted with polyethylene frits and agitated by rotation
on a blood tube rotator. In general, resin was washed with THF
(30 mL), THF : H2O (2 : 1) (3 × 30 mL), THF : H2O (1 : 1) (3 ×
30 mL), THF : H2O (1 : 2) (3 × 30 mL), THF (2 × 30 mL), then
alternate washings with CH2Cl2 (3 × 30 mL) and MeOH (3 ×
30 mL), finishing with THF (2 × 30 mL). The resin was then
left to dry for 10 min under water pump pressure before being
dried for 6 h under high vacuum. THF used for washing resin
was distilled prior to use. 1H NMR and 13C NMR were recorded
on a Fourier transform spectrometer with chemical shift values
being reported in ppm relative to residual chloroform (dH = 7.27
or dC = 77.2) as internal standard unless otherwise stated. NMR
signals were assigned using DEPT-135, HMQC and COSY
spectra. All coupling constants (J) are reported in Hertz (Hz). IR
spectra were recorded using a Fourier transform spectrometer.
Mass spectra and microanalyses were recorded at the University
of Glasgow and the University of Manchester. HPLC data was
obtained using an Xterra MS C18 7 lm column (19 × 150 mm)
at 254 nm wavelength using mixtures of 0.1% TFA in acetonitrile
and 0.1% TFA in water were used as the solvent systems.
Samarium(II) iodide was prepared by the method of Imamoto23
with the modification that the samarium–iodine suspension in
THF was heated at 60 ◦C rather than at reflux.
4-(tert-Butyldimethylsilyloxy)phenol24. Imidazole (4.08 g,
60.0 mmol) and TBDMSCl (4.50 g, 30.0 mmol) were added
to a solution of benzyloxyphenol (3.00 g, 15.0 mmol) in DMF
(30 mL) at room temperature and the mixture stirred for 4 h.
The reaction was quenched with aqueous saturated NaHCO3
(30 mL) and distilled H2O (20 mL). The aqueous layer was
extracted with 30% EtOAc–petroleum ether (3 × 50 mL), the
organic extracts combined, dried (Na2SO4) and concentrated
in vacuo to give crude product O-tert-butyldimethylsilyl benzy-
loxyphenol (4.71 g, 15.0 mmol, 100%) as a white crystalline solid
which was used without further purification: mmax ATR/cm−1
3044 (w), 2931(s), 1508 (s), 1258 (S) and 1103 (m); dH (400 MHz;
CDCl3) 0.18 (6H, s, (CH3)2Si), 0.98 (9H, s, SiC(CH3)3), 5.00
(2H, s, ArCH2O), 6.75–6.87 (4H, m, ArH) and 7.30–7.52 (5H,
m, ArH); dC (100 MHz; CDCl3) −4.5 (Si(CH3)2 × 2), 18.2
(SiC(CH3)3), 25.7 (3 × C(CH3)3), 70.6 (ArCH2), 115.6 (ArCH ×
2), 120.6 (ArCH × 2), 127.5 (ArCH × 2), 127.8 (ArCH), 128.5
(ArCH × 2), 137.3 (ArC × 2) and 138.1 (ArC); LRMS (EI+)
314.2 (M+ 98%), 257 (21), 223 (77), 91 (66) and 73 (55); HRMS
calculated for C19H26O2Si 314.1702, found 314.1699.
added to a flask containing a suspension of bromo Wang
resin (9.25 g, 11.1 mmol) which had been pre-swollen in DMF
(100 mL). NaH (1.33 g, 55.5 mmol) was subsequently added
and the mixture stirred slowly at room temperature. After
12 h the resin was filtered, washed and dried according to the
standard washing procedure, to give Wang supported 4-(tert-
butyldimethylsilyloxy)phenol: mmax ATR/cm−1 3026 (w), 2918
(w), 1603 (m), 1508 (s) and 1219 (s).
Wang phenol resin 1. Wang supported 4-(tert-
butyldimethylsilyloxy)phenol (4.50 g, 4.64 mmol) was swollen
in THF (15 mL) in a 25 mL Bond Elut cartridge. TBAF (1.0 M
in THF, 27.8 mL, 27.8 mmol) was then added and the mixture
rotated at room temperature for 18 h. The resin was then
filtered, washed and dried according to the standard washing
procedure. Re-treatment of the resin under the same reaction
conditions gave 1: mmax ATR/cm−1 3025 (m) O–H, 2914 (w),
1602 (m), 1506 (s) and 1219 (m).
Determination of loading of resin 1. Phenol resin 1 (249 mg,
0.288 mmol) was swollen in CH2Cl2 (1 mL). TFA (1 mL) was
subsequently added and the reaction stirred slowly at room
temperature for 1.5 h. The suspension was then filtered and
the resin washed with CH2Cl2 (3 × 15 mL). The washings
were collected and concentrated in vacuo to give hydroquinone
(26 mg, 0.236 mmol, 82%). The loading of resin 1 was therefore
approximately 0.96 mmol g−1, 82% that of the maximum
theoretical loading (1.17 mmol g−1). This result was confirmed
by microanalysis of resin 1 which found 16% bromine content,
corresponding to approximately 84% loading.
3-(4-Benzyloxyphenoxy)dihydrofuran-2-one2. K2CO3 (3.46g,
25.0 mmol) was added to a solution of a-bromo-c-butyrolactone
(1.66 mL, 20.0 mmol) and 4-benzyloxyphenol (1.00 g, 4.99
mmol) in DMF (75 mL) and the mixture stirred at room
temperature for 16 h. The reaction was quenched with aqueous
saturated NH4Cl (50 mL) and distilled H2O (40 mL). The
aqueous layer was extracted with 30% EtOAc–petroleum ether
(3 × 30 mL), the organic extracts combined, dried (Na2SO4)
and concentrated in vacuo to give the crude product as a
yellow oil. Recrystallisation from methanol gave 2 (1.02 g,
◦
3.59 mmol, 72%) as a white crystalline solid: mp 116–117 C;
mmax KBr/cm−1 2923 (s), 1782 (s) C O, 1507 (s), 1296 (s), 1234
=
(s) and 1189 (s); dH (400 MHz; CDCl3) 2.47 (1H, apparent dq, J
=
8.1, 13.1 Hz, 1H from CH2CH2OC O), 2.64–2.70 (1H, m, 1H
from CH2CH2OC O), 4.31–4.37 (1H, m, 1H from CH2OC O),
=
=
=
4.49–4.55 (1H, m, 1H from CH2OC O), 4.84 (1H, apparent
t, J 7.8 Hz, CHC O), 5.03 (2H, s, ArCH2), 6.91–7.01 (4H,
m, ArH) and 7.33–7.44 (5H, m, ArH); dC (100 MHz; CDCl3)
=
=
=
29.8 (CH2CH2OC O), 65.3 (CH2OC O), 70.6 (ArCH2), 73.5
(CHC O), 115.8 (ArCH × 2), 117.4 (ArCH × 2), 127.4
=
(ArCH × 2), 127.9 (ArCH), 128.6 (ArCH × 2), 137.0 (ArC),
+
=
151.6 (ArC), 154.3 (ArC) and 195.5 (C O); LRMS (EI ) 284.1
(M+, 22%) 91 (99), 85 (3), 65 (6) and 43 (10); Anal. calculated
C17H16O4: C, 71.82; H, 5.67%. Found: C, 71.76; H, 5.68%.
To a solution of O-tert-butyldimethylsilyl benzyloxyphenol
(4.71 g, 15.0 mmol) in ethanol (45 mL) was added 10%
Pd/C (0.70 mg, 15% weight) under hydrogen (balloon) and
the reaction stirred at room temperature for 5 h. The reaction
mixture was then poured onto a short column of silica gel and
eluted with40% EtOAc/petroleumether, which upon concentra-
tion in vacuo gave 4-(tert-butyldimethylsilyloxy)phenol (3.33 g,
14.8 mmol, 99%) as a white crystalline solid: m.p. 57–59 ◦C;
mmax ATR/cm−1 3271 (b), 2928 (m), 1505 (s), 1216 (s) and
1096 (m); dH (400 MHz; CDCl3) 0.17 (6H, s, (CH3)2Si), 0.98
(9H, s, SiC(CH3)3), 4.56 (1H, br s, OH) and 6.68–6.74 (4H,
apparent s, ArH); dC (100 MHz; CDCl3) −4.5 (Si(CH3)2 × 2),
18.2 (SiC(CH3)3), 25.7 (SiC(CH3)3 × 3), 115.9 (ArCH × 2), 120.8
(ArCH × 2), 149.4 (ArC) and 149.8 (ArC); Anal. calculated for
C12H20O2Si: C, 64.24; H, 8.98%. Found: C, 64.30; H, 8.97%.
2-(4-Benzyloxyphenoxy)-4-(tert-butyldiphenylsilyloxy)-N-meth-
oxy-N-methylbutyramide 3. AlMe3 (2.0
M in hexanes,
3.18 mmol, 1.59 mL) was added dropwise to a solution of N,O-
dimethylhydroxylamine hydrochloride (310 mg, 3.18 mmol)
in toluene (6 mL) at 0 ◦C and the reaction warmed to room
temperature. After 0.5 h at room temperature the reaction
mixture was once again cooled to 0 ◦C and lactone 2 (300 mg,
1.06 mmol) was added to the reaction mixture. The reaction
mixture was then allowed to warm to room temperature
and stirred for 3 h. The reaction was quenched with K/Na
tartrate (20 mL) and distilled H2O (10 mL). The aqueous
layer was extracted with CH2Cl2 (3 × 10 mL), the organic
extracts combined, dried (Na2SO4) and concentrated in vacuo
to give crude 2-(4-benzyloxyphenoxy)-4-hydroxy-N-methoxy-
N-methylbutyramide as a clear yellow oil (345 mg, 1.00 mmol,
100%) which was used without further purification: dH
Wang supported 4-(tert-butyldimethylsilyloxy)phenol. 4-
(tert-Butyldimethylsilyloxy)phenol (9.95 g, 44.4 mmol) was
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 8 0 5 – 2 8 1 6
2 8 0 9

View Online
=
(400 MHz; CDCl3) 2.04–2.13 (2H, m, CH2CHC O), 3.15
(3H, s, NCH3), 3.52 (3H, s, NOCH3), 3.75–3.86 (2H, m,
to give the crude product as a pale yellow oil. Purification by
column chromatography (silica, 5% EtOAc–petroleum ether)
=
CH2OH), 4.93 (2H, s, ArCH2), 5.08 (1H, m, CHC O), 6.81
gave 5 (13 mg, 0.037 mmol, 93%) as a clear colourless oil: mmax
(neat)/cm−1 3071 (w), 2932 (m), 2858 (m), 1716 (s) C O, 1110
=
(4H, apparent s, ArH) and 7.07–7.35 (5H, m, ArH). Imidazole
(272 mg, 4.00 mmol) and TBDPSCl (520 lL, 2.00 mmol) were
added to a solution of 2-(4-benzyloxyphenoxy)-4-hydroxy-N-
methoxy-N-methylbutyramide (345 mg, 1.00 mmol) in DMF
(3 mL) and the reaction stirred at room temperature for 12 h.
The reaction was quenched with aqueous saturated NaHCO3
(20 mL) and distilled H2O (10 mL). The aqueous layer was
extracted with 30% EtOAc–petroleum ether (3 × 30 mL), the
organic extracts combined, dried (Na2SO4) and concentrated in
vacuo to give the crude product as a pale yellow oil. Purification
by column chromatography (silica, 30% EtOAc–petroleum
ether) gave 3 (461 mg, 0.790 mmol, 79%) as a clear colourless oil:
=
(s); dH (400 MHz; CDCl3) 1.05 (3H, t, J 7.3 Hz, CH3CH2C O),
=
1.06 (9H, s, C(CH3)3), 1.84 (2H, m, CH2CH2C O), 2.42 (2H, q,
=
=
J 7.3 Hz, CH3CH2C O), 2.53 (2H, t, J 6.1 Hz, CH2CH2C O),
3.67 (2H, t, J 7.3 Hz, CH2OSi), 7.36–7.45 (6H, m, ArH) and
7.64–7.67 (4H, m, ArH); dC (100 MHz; CDCl3) 7.8 (CH3),
=
19.2 (C(CH3)3), 26.7 (CH2CH2C O), 26.8 (C(CH3)3 × 3),
=
=
35.9 (CH3CH2C O), 38.7 (CH2CH2C O), 63.1 (CH2OSi),
127.6 (ArCH × 4), 129.6 (ArCH × 2), 133.8 (ArC × 2), 135.5
+
+
=
(ArCH × 4) and 211.5 (C O); LRMS (CI ) 355.2 ((M + H) ,
99%), 297 (92), 277 (80), 199 (13) and 99 (50); HRMS calculated
for C22H31O2Si 355.2093, found 355.2092.
mmax neat/cm−1 3069 (s), 2858 (s), 1737 (s) C O, 1508 (s), 1210
(m) and 1096 (s); dH (400 MHz; CDCl3) 0.96 (9H, s, (CH3)3CSi),
1.99–2.09 (2H, m, CH2CHC O), 3.12 (3H, s, NCH3), 3.60
(3H, s, NOCH3), 3.75 (1H, apparent quintet, J 4.9 Hz, 1H
from CH2OSi), 3.91 (1H, dt, J 4.5, 9.6 Hz, 1H from CH2OSi),
=
2-(4-Benzyloxyphenoxy)-4-(tert-butyldiphenylsilyloxy)-1-(pyrro-
lidin-1-yl)-butan-1-one 6. AlMe3 (2.0 M in hexane, 2.78 mL,
5.55 mmol) was added dropwise to a solution of pyrrolidine
(463 lL, 5.55 mmol) in toluene (3 mL) and the solution stirred at
room temperature for 20 min. A solution of lactone 2 (525 mg,
1.85 mmol) in toluene (13 mL) was then added dropwise to
the mixture and the reaction heated to 50 ◦C overnight. The
reaction was quenched carefully with 1 M HCl (5 mL) at
=
=
4.94 (2H, s, ArCH2O), 5.24 (1H, dd, J 8.5, 3.5 Hz, CHC O),
6.79 (4H, apparent s, ArH), 7.17–7.34 (11H, m, ArH) and
7.49–7.58 (4H, m, ArH); dC (100 MHz; CDCl3) 19.2 (C(CH3)3),
=
26.7 (C(CH3)3 × 3), 32.5 (NCH3), 35.2 (CH2CHC O), 59.4
◦
0 C and distilled H2O (10 mL) was subsequently added. The
=
(CH2OSi), 61.6 (NOCH3), 70.6 (PhCH2O), 71.9 (CHC O),
aqueous layer was extracted with CH2Cl2 (3 × 30 mL), the
organic extracts combined, dried (Na2SO4) and concentrated
in vacuo to give crude 2-(4-benzyloxyphenoxy)-4-hydroxy-1-
(pyrrolidin-1-yl)butan-1-one (592 mg, 1.67 mmol, 90%) as a
clear yellow oil which was used without further purification:
dH (400 MHz; CDCl3) 1.74–1.95 (4H, m, CH2CH2N × 2),
2.13–2.23 (2H, m, CH2CH2OH), 3.34–3.68 (4H, m, CH2N ×
2), 3.82–3.92 (2H, m, CH2OH), 4.86 (1H, apparent t, J 6.5 Hz,
115.8 (ArCH × 2), 116.6 (ArCH × 2), 127.4 (ArCH × 2), 127.6
(ArCH × 4), 127.8 (ArCH), 128.5 (ArCH × 2), 129.6 (ArCH ×
2), 133.3 (ArC), 133.5 (ArC), 135.5 (ArCH × 4), 137.2 (ArC),
+
=
138.1 (ArC), 152.5 (ArC) and 153.5 (C O); LRMS (EI ) 583.2
(M+, 18%), 526 (80), 135 (41) and 91 (100); HRMS calculated
for C35H41O5Si, 583.2754, found 583.2751.
4-(4-Benzyloxyphenoxy)-6-(tert-butyldiphenylsilyloxy)hexan-
3-one 4. Ethyl magnesium bromide (1.0 M in THF, 550 lL,
0.550 mmol) was added dropwise to a solution of 3 (53 mg,
0.091 mmol) in THF (1 mL) at 0 ◦C over a period of 6.5 h.
The reaction mixture was then allowed to warm to room
temperature overnight. The reaction was quenched with
aqueous saturated NH4Cl (5 mL) and distilled H2O (3 mL). The
aqueous layer was extracted with 30% EtOAc–petroleum ether
(3 × 10 mL), the organic extracts combined, dried (Na2SO4)
and concentrated in vacuo to give the crude product as a pale
yellow oil. Purification by column chromatography (silica, 30%
EtOAc–petroleum ether) gave 4 (36 mg, 0.065 mmol 72%)
as a clear colourless oil: mmax (neat)/cm−1 2929 (w), 2856 (w),
1714 (m) C O, 1504 (s), 1225 (s) and 1105 (s); dH (400 MHz;
CDCl3) 0.92 (3H, t, J 6.8 Hz, CH3CH2C O), 0.95 (9H, s,
(CH3)3CSi),1.85–2.01 (2H, m, CH2CHC O), 2.40 (1H, dq, J
7.3, 18.6 Hz, 1H from CH2C O), 2.55 (1H, dq, J 7.3, 18.6 Hz,
1H from CH2C O), 3.69–3.80 (2H, m, CH2OSi), 4.71 (1H,
dd, J 4.0, 9.2 Hz, CHC O), 4.91 (2H, s, ArCH2O), 6.71–6.83
(4H, m, ArH), 7.18–7.36 (11H, m, ArH) and 7.48–7.58 (4H, m,
=
CHC O), 5.02 (2H, s, ArCH2O), 6.83–6.91 (4H, m, ArH) and
7.15–7.44 (5H, m, ArH).
tert-Butyldiphenylsilyl chloride (869 lL, 3.34 mmol) and
imidazole (421 mg, 6.68 mmol) were added to a solution
of 2-(4-benzyloxyphenoxy)-4-hydroxy-1-(pyrrolidin-1-yl)butan-
1-one (592 mg, 1.67 mmol) in DMF (3 mL) and the solution
stirred at room temperature for 3.5 h. The reaction was quenched
with aqueous saturated NaHCO3 (5 mL) and distilled H2O
(2 mL). The aqueous layer was extracted with 30% EtOAc–
petroleum ether (3 × 30 mL), the organic extracts were
combined, dried (Na2SO4) and concentrated in vacuo to give
the crude product as a yellow oil. Purification by column
chromatography (silica, 40% EtOAc–petroleum ether) gave 6
(785 mg, 1.32 mmol, 79%,) as a clear colourless oil: mmax
=
=
(neat)/cm−1 3069 (m), 2930 (s), 2879 (s), 1633 (s) C O, 1227
=
=
=
(s) and 1107 (s); dH (400 MHz; CDCl3) 0.95 (9H, s, (CH3)3Si),
=
=
1.68–1.86 (4H, m, CH2CH2NC O × 2), 2.01–2.06 (2H, m,
=
=
CH2CHC O), 3.34–3.50 (4H, m, CH2N × 2), 3.73–3.89 (2H,
m, CH2OSi), 4.88 (1H, t, J 6.5 Hz, CH), 4.94 (2H, s, PhCH2O),
6.23–6.82 (4H, m, ArH), 7.17–7.36 (11H, m, ArH) and 7.48–
7.58 (4H, m, ArH); dC (100 MHz; CDCl3) 19.1 ((CH3)3CSi),
23.6 (CH2CH2N), 26.3 (CH2CH2N), 26.8 (C(CH3)3 × 3), 34.9
(CH2CH2OSi), 46.0 (CH2N), 46.3 (CH2N), 59.7 (CH2OSi), 70.6
(CH2Ph), 74.6 (CH), 115.8 (ArCH × 2), 116.2 (ArCH × 2),
127.4 (ArCH × 2), 127.6 (ArCH × 2), 127.7 (ArCH × 2),
127.9 (ArCH × 2), 128.5 (ArCH × 2), 129.6 (ArCH × 2), 129.7
ArH); dC (100 MHz; CDCl3) 7.1 (CH3CH2), 19.1 (C(CH3)3),
=
=
26.8 (C(CH3)3 × 3), 30.8 (CH2C O), 35.3 (CH2CHC O), 59.3
=
(CH2OSi), 70.6 (ArCH2O), 80.2 (CHC O), 115.9 (ArCH ×
4), 125.8 (ArC), 127.5 (ArCH × 2), 127.6 (ArCH × 2), 127.7
(ArCH × 2), 127.9 (ArCH), 128.6 (ArCH × 2), 129.6 (ArCH),
129.7 (ArCH), 133.4 (ArC), 135.5 (ArCH × 4), 137.1 (ArC),
+
=
152.3 (ArC), 153.4 (ArC) and 213.0 (C O); LRMS (EI ) 552.2
(M+, 3%), 417 (35), 219 (12), 199 (10), 135 (17) and 91 (100);
HRMS calculated for C35H40O4Si 552.2696, found 552.2692.
(ArCH), 133.3 (ArC), 133.5 (ArC), 135.5 (ArCH × 2), 137.2
+
=
(ArC), 152.2 (ArC), 153.4 (ArC), 169.7 (C O); LRMS (FAB )
617.7 ((M + Na)+100%), 595 (39), 537 (71), 338 (53), 135 (69)
and 92 (54); HRMS calculated for C37H43NO4SiNa, 616.2859,
found 616.2866.
6-(tert-Butyldiphenylsilyloxy)hexan-3-one 5. Ketone
4
(21 mg, 0.04 mmol) was dissolved in THF (0.50 mL) and
methanol (0.43 mL). SmI2 (0.1 M in THF, 1.20 ml, 0.12 mmol)
was then added dropwise to the mixture at 0 ◦C and the resulting
solution allowed to warm to room temperature. After 45 min,
the reaction was quenched with aqueous saturated NaHCO3 (10
mL) and distilled H2O (5 mL). The aqueous layer was extracted
with 30% EtOAc–petroleum ether (3 × 10 mL), the organic
extracts combined, dried (Na2SO4) and concentrated in vacuo
4-(tert-Butyldiphenylsilyloxy)-1-(pyrrolidin-1-yl)butan-1-one
7. SmI2 (0.1 M solution in THF, 4.00 mL, 0.400 mmol) was
added to a solution of amide 6 (54 mg, 0.091 mmol) and
DMPU (154 lL, 1.28 mmol) and MeOH (1.05 mL) in THF
(0.2 mL). The reaction mixture was then stirred for 2 h and
was quenched with aqueous saturated NaHCO3 (10 mL) and
2 8 1 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 8 0 5 – 2 8 1 6

View Online
distilled H2O (5 mL). The aqueous layer was extracted with
EtOAc (3 × 20 mL), the organic extracts combined, dried
(Na2SO4) and concentrated in vacuo to give the crude product
as a yellow oil. Purification by column chromatography (silica,
50% EtOAc–petroleum ether) gave 7 as a clear colourless oil
(29 mg, 0.073 mmol, 81%): mmax (neat)/cm−1 2931 (s), 2858 (s),
4-en-1-one (117 mg, 0.256 mmol) in DMF (1 ml) and the
mixture stirred at room temperature overnight. The reaction
was quenched with aqueous saturated NaHCO3 (20 mL) and
distilled H2O (10 mL). The aqueous layer was extracted with
30% EtOAc–petroleum ether (3 × 15 mL), the organic extracts
combined, dried (Na2SO4) and concentrated in vacuo to give
the crude product as a pale yellow oil. Purification by column
chromatography (silica, 10% EtOAc–petroleum ether) gave
9 (138 mg, 0.198 mmol, 78% over 2 steps) as a pale yellow
=
1644 (s) C O, 1428 (s) and 1111 (s); dH (400 MHz; CDCl3)
=
1.06 (9H, s, C(CH3)3), 1.81–1.98 (6H, m, CH2CH2NC O ×
=
=
2, CH2CH2C O), 2.39 (2H, t, J 7.6 Hz, CH2C O), 3.32
(2H, apparent t, J 6.8 Hz, 2H from CH2NC O), 3.38 (2H,
apparent t, J 6.8 Hz, 2H from CH2NC O), 3.66 (2H, t, J
6.0 Hz, CH2OSi), 7.36–7.45 (6H, m, ArH) and 7.65–7.67
oil:mmax (neat)/cm−1 3069 (m), 2930 (s), 2857 (s), 1633 (s) C O,
=
=
=
=
1504 (s) C C, 1428 (m), 1206 (s), 1108 (s); (complex mixture
of rotamers) dH (400 MHz; CDCl3) 0.99–1.09 (9H, m), 2.36
(1H, apparent quintet, J 7.3 Hz), 2.48–2.79 (4H, m), 2.93–2.99
(1H, m), 3.62–3.75 (2H, m), 3.98–4.11 (2H, m), 4.64–4.81 (2H,
m), 4.94–5.12 (4H, m), 5.69–5.71 (1H, m), 6.33–6.84 (4H, m),
6.93–7.21 (4H, m), 7.32–7.41 (11H, m) and 7.59–7.74 (4H, m);
LRMS (FAB+) 718 ((M + Na)+10%), 696 (10), 496 (16), 440
(34), 418 (100), 197 (90); HRMS (FAB+,M + Na+) calculated
for C45H49O4NSiNa 718.3333, found 718.3329.
(4H, m, ArH); dC (100 MHz; CDCl3) 19.2 (C(CH3)3), 24.4
=
=
(CH2CH2C O), 26.1 (CH2CH2NC O), 26.8 ((CH3)3C × 3),
=
=
=
27.8 (CH2CH2NC O), 31.1 (CH2C O), 45.5 (CH2NC O),
=
46.5 (CH2NC O), 63.2 (CH2OSi), 127.6 (ArCH × 4), 129.6
(ArCH × 2), 133.9 (ArC), 135.5 (ArCH × 4), 138.1 (ArC) and
+
+
=
171.4 (C O); LRMS (CI ) 396.3 ((M + H) 11%), 338 (100)
and 318 (22); HRMS calculated for C24H34NO2Si, 396.2359,
found 396.2358. Further elution gave benzyloxyphenol (15 mg,
0.075 mmol, 83%) as a pale yellow solid.
2-[2-(tert-Butyldiphenylsilyloxy)ethyl]-1-(3,4-dihydro-1H-iso-
quinolin-2-yl)pent-4-en-1-one 10. SmI2 (0.1 M solution in
THF, 2.38 ml, 0.238 mmol) was added to a solution of amide
9 (24 mg, 0.034 mmol) in DMPU (66 ll, 0.544 mmol) and
THF (0.2 ml) and the reaction stirred for 2 h. The reaction
was quenched with aqueous saturated NaHCO3 (15 ml) and
distilled H2O (10 ml). The aqueous layer was extracted with
EtOAc (3 × 20 ml), the organic extracts combined, dried
(Na2SO4) and concentrated in vacuo to give the crude product
as a yellow oil. Purification by column chromatography (silica,
30% EtOAc–petroleum ether) gave 10 (13 mg, 0.026 mmol,
76%) as a clear colourless oil: mmax KBr/cm−1 3070 (m), 2929 (s),
3-Allyl-3-(4-benzyloxyphenoxy)dihydrofuran-2-one 8. n-BuLi
(1.6 M in hexane, 154 ll, 0.250 mmol) was added dropwise
to a solution of diisopropylamine (35 ll, 0.250 mmol) in THF
(1 ml) at −45 ◦C and the solution stirred for 30 min. A solution
of lactone 2 (50 mg, 0.176 mmol) in THF (1 ml) was then added
via cannula at −45 ◦C to the LDA solution. After 30 min,
allyl bromide (76 ll, 0.88 mmol) was added and the reaction
mixture allowed to warm to room temperature. The reaction was
quenched with aqueous saturated NH4Cl (10 mL) and distilled
H2O (5 mL). The aqueous layer was extracted with 30% EtOAc–
petroleum ether (3 × 10 mL), the organic extracts combined,
dried (Na2SO4) and concentrated in vacuo to give the crude prod-
uct as a pale yellow oil. Purification by column chromatography
(silica, CH2Cl2) gave 8 (42 mg, 1.13 mmol, 72%) as a pale yellow
=
=
1689 (s) C O, 1643 (s), (CH CH2), 1428 (s) and 1110 (m); dH
(400 MHz; CDCl3) 1.07 (9 H, s, C(CH3)3), 1.70–1.77 (1H, m, 1H
=
=
from CH2CHC O), 1.90–1.98 (1H,m, 1H from CH2CHC O),
2.18–2.25 (1H, m, 1H from CH2CH CH2), 2.39–2.49 (1H,
=
oil: mmax (neat)/cm−1 2985 (w), 2916 (w), 1774 (s) C O, 1643
=
=
=
m, CH2CH CH2), 2.81–2.89 (2H, m, CH2CH2NC O),
2.19–3.29 (1H, m, CHC O), 3.60–3.86 (4H, m, CH2OSi,
CH2CH2NC O), 4.69–4.83 (2H, m, ArCH2NC O), 4.95–
5.10 (2H, m, H2C CH), 5.71–5.84 (1H, m, H2C CH),
6.96–7.23 (4H, m, ArH), 7.28–7.46 (6H, m, ArH), 7.59–7.68
(4H, m, ArH); dC (100 MHz; CDCl3) 19.2 (C(CH3)3), 26.9
(C(CH3)), 28.8 (CH2CH2NC O), 29.8 (CH2CH2NC O), 35.2
(CH2CH2C O), 36.6 (CH2CH CH2), 37.5 (CHC O), 39.9
=
(w) C C, 1502 (s), 1203 (m), 1012 (s); dH (400 MHz; CDCl3)
=
2.27–2.34 (1H, m, CH2CH2O), 2.47–2.57 (2H, m, 1 H from
CH2CH2O and 1H from CH2 CHCH2), 2.77 (1H, dd, J 14.7,
7.1 Hz, 1 H from CH2 CHCH2), 4.18–4.27 (2H, m, CH2O),
5.00 (2H, s, ArCH2O), 5.18–5.29 (2H, m, CH2 CH), 5.81–5.91
(1H, m, CH2 CH), 6.85–6.98 (4H, m, ArH) and 7.30–7.42
(5H, m, ArH); dC (100 MHz; CDCl3) 31.3 (CH2CH2OC O),
39.2 (CH2 CHCH2), 64.9 (CH2OC O), 70.4 (ArCH2), 82.2
=
=
=
=
=
=
=
=
=
=
=
=
=
=
=
=
=
=
(CH2CH2NC O), 43.3 (CH2CH2NC O), 44.3 (ArCH2), 47.4
(ArCH2), 61.4 (CH2OSi), 61.5 (CH2OSi), 116.5 (CH2 CH),
=
=
(CC O), 115.5 (ArCH × 2), 120.4 (CH CH2), 123.3 (ArCH ×
=
2), 127.5 (ArCH × 2), 128.0 (ArCH), 128.5 (ArCH × 2),
126.1 (ArCH), 126.3 (ArCH), 126.5 (ArCH × 2), 126.7
(ArCH), 127.6 (ArCH), 127.7 (ArCH), 128.3 (ArCH), 128.8
(ArCH), 129.6 (ArCH), 129.7 (ArCH × 2), 132.9 (ArC), 133.8
(ArC), 134.2 (ArC), 135.2 (ArC), 135.5 (ArCH × 2), 136.0
=
131.1 (CH2 CH), 136.8 (ArC), 147.8 (ArC), 155.6 (ArC) and
+
+
=
175.7 (C O); LRMS (EI ) 324.1 (M , 18%); HRMS calculated
for C20H20O4 324.1362, found 324.1359; Anal. calculated for
C20H20O4: C, 74.06; H, 6.21%. Found: C, 73.75; H, 6.21%.
=
=
=
=
(CH2 CH), 136.1 (CH2 CH), 174.2 (C O), 174.3 (C O);
LRMS (CI+) 498 ((M + H)+15%); HRMS (EI+,M+) calculated
for C32H39O2NSi 497.2754, found 497.2750. Further elution
gave 4-benzyloxyphenol (6.5 mg, 0.032 mmol, 95%) as a pale
yellow solid.
2-(4-Benzyloxyphenoxy)-2-[2-(tert-butyldiphenylsilyloxy)-
ethyl]-1-(3,4-dihydro-1H-isoquinolin-2-yl)pent-4-en-1-one
9.
AlMe3 (2.0 M in hexane 0.39 ml, 0.767 mmol) was added
to a solution of 1,2,3,4-tetrahydroisoquinoline·HCl (130 mg,
0.767 mmol) in toluene (1 ml) and the solution stirred at
room temperature for 20 min. Lactone 8 (83 mg, 0.256
mmol) in toluene (1 ml) was then added dropwise via cannula
to the reaction mixture which was then heated to 50 ◦C
for 24 h. The reaction was quenching using 1.0 M HCl
(2 mL) which was added dropwise at 0 ◦C. The aqueous
layer was extracted with CH2Cl2 (3 × 10 mL). The organic
layer was then washed with distilled H2O (20 mL) dried
(Na2SO4) and concentrated in vacuo to give the crude product
2-(4-benzyloxyphenoxy)-1-(3,4-dihydro-1H-isoquinolin-2-yl)-
2-(2-hydroxyethyl)pent-4-en-1-one (117 mg, 0.256 mmol) as a
pale yellow oil which was used without further purification.
Imidazole (71 mg, 1.04 mmol) and TBDPSCl (135 ll, 0.519
mmol) were added to a solution of 2-(4-benzyloxyphenoxy)-
1-(3,4-dihydro-1H-isoquinolin-2-yl)-2-(2-hydroxyethyl)pent-
Wang supported 3-(4-hydroxyphenoxy)dihydrofuran-2-one 11.
Phenol resin 1 (1.31 g, 1.26 mmol) was swollen in DMF (30 mL).
a-Bromo-c-butyrolactone (1.67 mL, 20.2 mmol) was then added
followed by K2CO3 (1.74 g, 12.6 mmol) and the reaction mixture
stirred slowly at 60 ◦C for 24 h. The resin was then drained,
washed and dried according to the standard washing procedure
to give solid supported lactone 11: mmax KBr/cm−1 3024 (w), 2922
=
(w), 1787 (s) C O, 1610 (s), 1507 (s) and 1220 (s).
General procedure for the ring opening of immobilised lactone 11
to give supported amides 12
Wang supported 4-hydroxy-2-(4-hydroxyphenoxy)-1-(morpho-
lin-4-yl)butan-1-one. AlMe3 (2.0 M in hexane, 1.5 mL,
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 8 0 5 – 2 8 1 6
2 8 1 1

View Online
3.00 mmol) was added dropwise to a solution of morpholine
(262 lL, 3.00 mmol) in toluene (2 mL) and mixture was
stirred for 20 minutes at room temperature. The solution was
then added via cannula to a suspension of lactone resin 11
(559 mg, 0.498 mmol) in toluene (5 mL) and the reaction
stirred slowly at 50 ◦C for 14 h. The resin was then drained,
washed and dried according to the standard washing procedure
to give Wang supported 4-hydroxy-2-(4-hydroxyphenoxy)-1-
(morpholin-4-yl)butan-1-one: mmax ATR/cm−1 3026 (w), 2922
7.06–7.24 (4H, m, ArH), 7.36–7.45 (6H, m, ArH) and 7.66–7.76
(4H, m, ArH); dC (100 MHz; CDCl3) 19.2 (SiC(CH3)3, 26.9
=
=
(C(CH3)3 × 3), 28.2 (CH2CH2C O), 28.5 (CH2CH2NC O),
=
=
=
29.5 (CH2CH2NC O), 29.9 (CH2C O), 30.2 (CH2C O),
=
=
=
39.6 (CH2NC O), 43.2 (CH2NC O), 44.2 (ArCH2NC O),
=
47.3 (ArCH2NC O), 63.2 (CH2OSi), 125.9 (ArCH), 126.3
(ArCH), 126.4 (ArCH), 126.5 (ArCH), 126.7 (ArCH), 126.8
(ArCH), 127.6 (ArCH × 2), 128.2 (ArCH), 128.9 (ArCH),
129.6 (ArCH × 2), 132.7 (ArC), 133.7 (ArC), 133.8 (ArC),
134.1 (ArC), 134.8 (ArC), 135.2 (ArC), 135.5 (ArCH × 2) and
=
(w), 1631 (m) C O, 1610 (m), 1583 (w), 1504 (s) and 1205 (s).
+
+
=
171.8 (C O); LRMS (CI ) 458.3 ((M + H) , 18%), 400 (100),
380 (12), 202 (7); HRMS (EI+, M+) calculated for C29H35O2NSi,
457.2437, found 457.2433.
General procedure for the TBDPS protection of alcohols 12 to
give solid supported amides 13
Wang supported 4-(tert-butyldiphenylsilyloxyl)-2-(4-hydroxy-
phenoxy)-1-(morpholin-4-yl)butan-1-one. TBDPSCl (520 lL,
2.00 mmol) was added to a suspension of Wang supported
4-hydroxy-2-(4-hydroxyphenoxy)-1-(morpholin-4-yl)butan-1-
one (0.498 mmol), pre-swollen in DMF (5 mL) in a Bond
Elut cartridge. Imidazole (252 mg, 4.00 mmol) was then added
and the mixture rotated at room temperature for 18 h. The
resin was then filtered, washed and dried according to the
standard washing procedure to give Wang supported 4-(tert-
butyldiphenylsilyloxyl)-2-(4-hydroxyphenoxy)-1-(morpholin-
4-yl)butan-1-one:mmax KBr/cm−1 2922 (w), 2852 (w), 1643 (w)
General procedure for the acetylation of alcohols 12
Wang supported 4-acetoxy-2-(4-hydroxyphenoxy)-1-(pyrro-
lidin-1-yl)butan-1-one. Acetic anhydride (481 lL, 5.10 mmol)
was added to a Bond Elut cartridge containing a suspension
of Wang supported 4-hydroxy-2-(4-hydroxyphenoxy)-1-
(pyrrolidin-1-yl)-butan-1-one (0.502 mmol) in pyridine (2 mL)
at room temperature and the reaction mixture rotated for 18 h.
The resin was then filtered, washed and dried according to
the standard washing procedure to give Wang supported 4-
acetoxy-2-(4-hydroxyphenoxy)-1-(pyrrolidin-1-yl)butan-1one:
mmax KBr/cm−1 3025 (w), 2923 (w), 1740 (s) C O, 1612 (s) C O,
1505 (s) and 1223 (m).
=
C O, 1612 (m), 1585 (w), 1504 (s), 1290 (s) and 1219 (s).
=
=
General procedure for the cleavage of amides
General procedure for cleavage of acetates from resin
4-(tert-Butyldiphenylsilyloxy)-1-(morpholin-4-yl)butan-1-one
14a. DMPU (967 lL, 8.00 mmol) was added to a suspension of
Wang supported 4-(tert-butyldiphenylsilyloxyl)-2-(4-hydroxy-
phenoxy)-1-(morpholin-4-yl)butan-1-one (0.498 mmol), in
THF (3 mL). SmI2 (0.1 M in THF, 25 mL, 2.50 mmol) was
added dropwise and the mixture stirred slowly for 12 h. The
reaction mixture was then filtered and washed with THF (100
mL) and concentrated in vacuo to give the crude product as a
yellow oil. The crude mixture was then filtered through a short
pad of silica gel (using 50% EtOAc–petroleum ether), to give
14a (54 mg, 0.131 mmol, 26% for 4 steps from phenol resin 1,
HPLC purity 93%) as a clear colourless oil: mmax (neat)/cm−1
4-Acetoxy-1-(pyrrolidin-1-yl)butan-1-one 14c25. SmI2 (0.1 M
solution in THF, 30.6 mL, 3.06 mmol) was added to a sus-
pension of Wang supported 4-acetoxy-2-(4-hydroxyphenoxy)-1-
(pyrrolidin-1-yl)butan-1-one (0.502 mmol) in THF (2 mL) and
DMPU (987 lL, 8.16 mmol) at room temperature. The mixture
was then stirred slowly at room temperature for 2.5 h. The
reaction mixture was filtered and the resin washed with THF
(100 mL). The filtrate and washings were then concentrated
in vacuo. Purification by column chromatography (silica, 10%
MeOH–EtOAc) gave 14c (16 mg, 0.080 mmol, 16% overall yield
for 4 steps from phenol resin 1) as a clear colourless oil: mmax
=
2856 (m), 1651 (s) C O, 1428 (m), 1271 (w) and 1113 (s);
KBr/cm−1 2972 (m), 2877 (m), 1732 (s) C O, 1618 (s) C O,
=
=
dH (400 MHz; CDCl3) 0.92 (9H, s, C(CH3)3), 1.84–1.91 (2H,
1452 (s), 1244 (s) and 1038 (s); dH (400 MHz; CDCl3) 1.83–
=
=
m, CH2CH2C O), 2.40 (2H, t, J 7.6 Hz, CH2C O) 3.42
=
=
2.04 (6H, m, CH2CH2C O, CH2CH2NC O × 2), 2.05 (3H, s,
=
(2H, apparent t, J 4.8 Hz, CH2NC O), 3.61–3.68 (6H, m,
=
=
CH3C O), 2.34 (2H, t, J 7.4 Hz, CH2C O), 3.42 (2H, t, J
=
CH2O × 2 and CH2NC O), 3.72 (2H, t, J 5.9 Hz, CH2OSi),
=
=
6.9 Hz, CH2NC O), 3.47 (2H, t, J 6.9 Hz, CH2NC O) and
4.15 (2H, t, J 6.4 Hz, CH2O); dC (100 MHz; CDCl3) 21.0
(CH3C O), 24.0 (CH2CH2C O), 24.4 (CH2CH2NC O), 26.1
7.34–7.44 (6H, m, ArH) and 7.62–7.65 (4H, m, ArH); dC
(100 MHz; CDCl3) 19.2 (C(CH3)3), 26.9 (C(CH3)3 × 3), 28.2
=
=
=
=
=
(CH2CH2C O), 29.8 (CH2C O), 41.9 (CH2N), 45.9 (CH2N),
63.1 (CH2OSi), 66.6 (CH2O), 66.9 (CH2O), 127.7 (ArCH × 4),
129.7 (ArCH × 2), 133.8 (ArC × 2), 135.5 (ArCH × 4) and
=
=
=
(CH2CH2NC O), 30.9 (CH2C O), 45.7 (CH2NC O), 46.5
=
=
=
(CH2NC O), 64.0 (CH2O), 170.4 (OC O) and 171.1 (NC O),
LRMS (EI+) 199.1 (M+, 25%), 113 (100), 98 (25), 70 (56), 43 (33);
HRMS calculated for C10H17NO3, 199.1208, found 199.1207.
+
+
=
171.6 (C O); LRMS (CI ) 412.3 ((M + H) , 3%), 354 (100),
334 (12), 156 (8); HRMS calculated for C24H34O3NSi, 412.2308,
found 412.2311.
4-Acetoxy-1-(3,4-dihydro-1H-isoquinolin-2-yl)butan-1-one
14d. SmI2 (0.1 M solution in THF, 21.9 mL, 2.19 mmol)
was added to a suspension of Wang supported 4-acetoxy-2-(4-
hydroxyphenoxy)-1-(3,4-dihydro-1H-isoquinolin-2-yl)butan-1-
one (0.555 mmol) in THF (2 mL) and DMPU (1.06 mL, 8.77
mmol) at room temperature. The mixture was then stirred
slowly for 2.5 h. The reaction mixture was filtered and the
resin washed with THF (100 mL). The filtrate and washings
were then concentrated in vacuo. Purification by column
chromatography (silica, 50% EtOAc–petroleum ether) gave
amide 14d (29 mg, 0.111 mmol, 20% overall yield for 4 steps
from phenol resin 1, HPLC purity 70%) as a clear colourless
oil: mmax (neat)/cm−1 2934 (m), 1736 (s), 1645 (s), 1242 (s)
and 1040 (s); (mixture of rotamers) dH (400 MHz; CDCl3)
4-(tert-Butyldiphenylsilyloxy)-1-(pyrrolidin-1-yl)butan-1-one
7. The precursor resin (0.445 mmol) gave
7 (44 mg,
0.111 mmol, 25% overall yield for 4 steps from phenol resin 1,
HPLC purity 82%) as a pale yellow oil.
4-(tert-Butyldiphenylsilyloxy)-1-(3,4-dihydro-1H-isoquinolin-
2-yl)butan-1-one 14b. The precursor resin (0.478 mmol)
gave 14b (68 mg, 0.149 mmol, 31% overall yield for 4
steps from phenol resin 1, HPLC purity 88%) as a pale
yellow oil; mmax (neat)/cm−1 3069 (m), 2930 (s), 1692 (s),
1648 (s), 1427 (s) and 1109 (s); (mixture of rotamers) dH
(400 MHz; CDCl3) 1.08 (9H, s, C(CH3)3), 1.91–1.99 (2H,
=
=
m, CH2CH2C O), 2.51–2.57 (2H, m, CH2C O), 2.84–2.90
(2H, m, CH2CH2NC O), 3.68 (2H, t, J 5.9 Hz, CH2NC O,
major rotamer), 3.76–3.79 (2H, m, CH2OSi), 3.84 (2H, t, J
=
=
=
=
1.73–2.08 (5H, m, CH2CH2C O, CH3C O), 2.47 (2H, m,
CH2C O), 2.86 (2H, t, J 6.0 Hz, CH2CH2N minor rotamer),
=
=
=
5.0 Hz, CH2NC O, minor rotamer), 4.62 (2H, s, ArCH2NC O
2.91 (2H, t, J 5.8 Hz, CH2CH2N major rotamer), 3.69 (2H, t,
J 6.0 Hz, CH2NC O major rotamer), 3.84 (2H, t, J 6.0 Hz,
=
=
minor rotamer), 4.74 (2H, s, ArCH2NC O major rotamer),
2 8 1 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 8 0 5 – 2 8 1 6

View Online
=
CH2NC O minor rotamer), 4.15 (2H, t, J 6.2 Hz, CH2O), 4.63
(2H, s, ArCH2N minor rotamer), 4.74 (2H, s, ArCH2N major
EtOAc–petroleum ether) removed the inorganic by-products
and gave 16b (43 mg, 0.103 mmol, 20% overall yield for 5 steps
from phenol resin 1, HPLC purity 83%) as a clear colourless oil:
rotamer) and 7.10–7.22 (4H, m, ArH); dC (100 MHz; CDCl3)
20.9 (CH3C O), 24.2 (CH2CH2C O), 28.5 (CH2CH2N),
mmax (neat)/cm−1 3069 (w), 2930 (m), 2857 (m), 1713 (s) C O and
=
=
=
=
=
29.4 (CH2CH2N), 29.8 (CH2C O), 30.0 (CH2C O), 39.7
1112 (s); dH (400 MHz; CDCl3) 0.94 (9H, s, C(CH3)3), 1.69–1.75
=
=
=
=
=
(CH2NC O), 43.1 (CH2NC O), 44.2 (ArCH2NC O), 47.2
(2H, m, CH2CH2C O), 2.49 (2H, t, J 7.3 Hz, CH2CH2C O),
3.55 (2H, t, J 6.1 Hz, CH2OSi), 3.59 (2H, s, ArCH2C O),
=
=
(ArCH2NC O), 63.9 (CH2O), 126.0 (ArCH), 126.3 (ArCH),
126.5 (ArCH), 126.6 (ArCH), 126.7 (ArCH), 126.9 (ArCH),
128.2 (ArCH), 129.0 (ArCH), 132.4 (ArC), 133.5 (ArC), 134.0
(ArC), 135.1 (ArC), 170.7 (NC O), 170.8 (NC O) and 171.0
7.10–7.36 (11H, m, ArH) and 7.53–7.55 (4H, m, ArH); dC
=
(100 MHz; CDCl3) 19.2 (C(CH3)3), 26.5 (CH2CH2C O), 26.8
=
=
=
=
(C(CH3)3 × 3), 38.3 (CH2CH2C O), 50.2 (ArCH2C O), 62.8
(CH2OSi), 126.9 (ArCH), 127.6 (ArCH × 4), 128.7 (ArCH ×
2), 129.4 (ArCH × 2), 129.6 (ArCH × 2), 133.8 (ArC × 2),
+
+
=
(CH3OC O); LRMS (EI ) 261.2 (M , 21%), 201 (28), 145 (40),
132 (100), 104 (34), 43 (34); HRMS calculated for C15H19NO3,
261.1365, found 261.1367.
=
134.4 (ArC), 135.5 (ArCH × 4) and 208.3 (C O); LRMS
(FAB+) 417.2 ((M + H)+ 21%), 359 (100), 199 (47), 161 (84), 135
(41) and 92 (44); HRMS calculated for C27H33O2Si, 417.2250,
found 417.2246.
General procedure for the formation of immobilised ketones
Wang supported 5-(tert-butyldiphenylsilyloxy)-3-(4-hydroxy-
phenoxy)-1-phenylpentan-2-one. Benzyl magnesium chloride
(2.0 M in THF, 1.59 mL, 3.18 mmol) was added dropwise
at 0 ◦C to a suspension of Wang supported 4-(tert-butyldi-
phenylsilyloxyl-2-(4-hydroxyphenoxy)-1-(morpholin-4-yl)butan-
1-one (0.516 mmol) in THF (1.5 mL) and the reaction stirred
slowly at 0 ◦C overnight during which time the reaction warmed
to room temperature. The reaction was then quenched using
acetone (40 mL), to destroy any excess Grignard reagent
present, and distilled water (10 mL). The resin was then filtered,
washed and dried according to the standard washing procedure
to give Wang supported 5-(tert-butyldiphenylsilyloxy)-3-(4-
hydroxyphenoxy)-1-phenylpentan-2-one: mmax KBr/cm−1 2926
2-Methyl-6-(tert-butyldiphenylsilyloxy)hexan-3-one
16a.
Wang supported 6-(tert-butyldiphenylsilyloxy)-4-(4-hydroxy-
phenoxy)-2-methylhexan-3-one (0.589 mmol) gave 16a (52 mg,
0.141 mmol, 24% overall yield for 5 steps from phenol resin 1,
HPLC, purity 70%) as a clear colourless oil: mmax (neat)/cm−1
=
3071 (m), 2962 (s), 2859 (s), 1712 (s) C O and 1110 (s); dH
(400 MHz; CDCl3) 1.06 (9H, s C(CH3)3), 1.10 (6H, d, J 7.0 Hz,
=
=
(CH3)2CHC O), 1.82 (2H, m, CH2CH2C O), 2.58 (3H, m,
=
=
CH2C O and (CH3)2CHC O), 3.68 (2H, t, J 6.1 Hz, CH2OSi),
7.36–7.46 (6H, m, ArH) and 7.65–7.67 (4H, m, ArH); dC
(100 MHz; CDCl3) 18.3 ((CH3)2CH × 2), 19.2 (C(CH3)3), 26.6
=
=
(CH2CH2C O), 26.8 (C(CH3)3 × 3), 36.5 (CH2C O), 40.9
=
((CH3)2CHC O), 63.0 (CH2OSi), 127.6 (ArCH × 4), 129.6
=
(w), 1721 (w) C O, 1613 (s), 1509 (s) and 1221 (m).
(ArCH × 2), 133.8 (ArC × 2), 135.5 (ArCH × 4) and 214.7
+
+
Wang supported 6-(tert-butyldiphenylsilyloxy)-4-(4-hydroxy-
phenoxy)-2-methylhexan-3-one. Wang supported 4-(tert-butyl-
diphenylsilyloxyl-2-(4-hydroxyphenoxy)-1-(morpholin-4-yl)butan-
1-one (0.589 mmol), was treated with i-PrMgCl (2.0 M in THF,
1.77 mL, 3.54 mmol) to give Wang supported 6-(tert-butyl-
diphenylsilyloxy)-4-(4-hydroxyphenoxy)-2-methylhexan-3-one:
=
(C O); LRMS (CI ) 369.3 ((M + H) 18%), 311 (100), 291
(27), 199 (23) and 113 (24); HRMS calculated for C23H33O2Si,
369.2250, found 369.2248.
1-Cyclopropyl-4-(tert-butyldiphenylsilyloxy)butan-1-one 16c.
SmI2 (0.1 M solution in THF, 9.78 mL, 0.978 mmol) was added
to a suspension of resin 17 (0.499 mmol) in THF (1.5 mL)
at 0 ◦C. The mixture was then stirred slowly and allowed to
warm to room temperature over 2.5 h. The reaction mixture was
filtered and the resin washed with THF (100 mL). The filtrate
and washings were then concentrated in vacuo. Further filtration
through a short pad of silica gel (10% EtOAc–petroleum ether)
removed the inorganic by-products and gave a 6 : 1 mixture
of ring-closed (16c) and ring-opened (18) product (33 mg,
0.090 mmol, 18% overall yield for 5 steps from phenol resin
1) as a clear colourless oil: For 16c; mmax (neat)/cm−1 3070
mmax KBr/cm−1 3025 (w), 2925 (w), 1721 (m) C O, 1612 (s),
1506 (s) and 1223 (s).
=
Wang supported 4-(tert-butyldiphenylsilyloxy)-1-cyclopropyl-
2-(4-hydroxyphenoxy)butan-1-one 17. A crystal of iodine was
added to a suspension of magnesium powder (244 mg,
10.2 mmol) in minimal THF (0.3 mL). Cyclopropyl bromide
(817 lL, 10.2 mmol) was then added dropwise with THF
(9.7 mL) and the mixture warmed until Grignard formation
began. The mixture was then heated at reflux for approximately
50 min by which time all the magnesium had been consumed. A
portion of the cyclopropyl Grignard reagent (3 mL, 3.06 mmol)
was added dropwise at 0 ◦C to a suspension of Wang sup-
ported 4-(tert-butyldiphenylsilyloxyl)-2-(4-hydroxyphenoxy)-1-
(morpholin-4-yl)butan-1-one (0.499◦ mmol) in THF (1.5 mL)
and the reaction stirred slowly at 0 C overnight during which
time the reaction warmed to room temperature. The reaction
was then quenched using acetone, to destroy any excess Grignard
reagent present, and distilled water (10 ml). The resin was then
filtered, washed and dried according to the standard washing
procedure to give resin 17: mmax KBr/cm−1 2922 (w), 2854 (w),
=
(w), 2913 (m), 2858 (m), 1699 (s) C O and 1111 (s); dH
=
(400 MHz; CDCl3) 0.88–0.92 (2H, m, (CH2)2CHC O), 0.98–
=
1.02 (2H, m, (CH2)2CHC O), 1.07 (9H, s, C(CH3)3), 1.84–1.96
(3H, m, CHC O and CH2CH2C O), 2.68 (2H, t, J 7.2 Hz,
CH2C O), 3.70 (2H, t, J 6.2 Hz, CH2OSi), 7.37–7.45 (6H,
m, ArH) and 7.66–7.68 (4H, m, ArH); dC (100 MHz; CDCl3)
=
=
=
=
=
10.6 ((CH2)2CHC O × 2), 19.2 (C(CH3)3), 20.1 (CHC O),
=
=
26.8 (CH2CH2C O), 26.9 (C(CH3)3 × 3), 39.7 (CH2C O), 63.0
(CH2OSi), 127.6 (ArCH × 4), 129.6 (ArCH × 2), 133.8 (ArC ×
+
=
2), 135.5 (ArCH × 4) and 210.8 (C O); LRMS (FAB ) 367.2
((M + H)+ 10%), 309 (100), 199 (78), 111 (86) and 74 (85); HRMS
calculated for C23H31O2Si, 367.2093, found 367.2090.
=
1697 (w) C O, 1637 (m), 1612 (s), 1508 (s) and 1221 (m).
For 18; mmax (ATR)/cm−1 2935(s), 1713(s) C O, 1427(m) and
=
General procedure for the cleavage of ketones
1096(s); dH (500 MHz; CDCl3) 0.93 (3H, t, J 6.0 Hz, CH3), 1.07
(9H, s, C(CH3)3), 1.61 (2H, apparent sextet, J 6.0 Hz, CH2CH3),
1.85 (2H, quintet, J 5.9 Hz, CH2), 2.40 (2H, t, J 5.9 Hz,
CH3CH2CH2C(O)), 2.54 (2H, t, J 5.9 Hz, CH2C(O)), 3.69 (2H, t,
J 5.9 Hz, CH2O), 7.38–7.44 (6H, m, ArH) and 7.66–7.7.68 (4H,
m, ArH); dC (75 MHz; CDCl3) 13.7 (CH3), 17.3 (CH2CH3),
19.2 (SiC), 26.6 (CH2), 26.8 (C(CH3)3), 39.0 (CH2C(O)), 44.8
(CH3CH2CH2C(O)), 63.0 (CH2O), 127.6 (ArCH × 4), 129.6
(ArCH × 2), 133.8 (ArC × 2), 135.5 (ArCH × 4) and 211.1
5-(tert-Butyldiphenylsilyloxy)-1-phenylpentan-2-one
16b.
SmI2 (0.1 M solution in THF, 15.9 mL, 1.59 mmol) was added to
a suspension of Wang supported 5-(tert-butyldiphenylsilyloxy)-
3-(4-hydroxyphenoxy)-1-phenylpentan-2-one (0.516 mmol) in
THF (2 mL) at 0 ◦C. The mixture was then stirred slowly
and allowed to warm to room temperature over 6 h. The
reaction mixture was filtered and the resin washed with THF
(100 mL). The filtrate and washings were then concentrated in
vacuo. Further filtration through a short pad of silica gel (10%
+
+
=
(C O); LRMS (CI ) 369 ((M + H) 100%), 311 (50), 291 (20)
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 8 0 5 – 2 8 1 6
2 8 1 3

View Online
and 113 (30); HRMS calculated for C23H32O2Si, 368.2166, found
368.2170.
(27) and 91 (100); HRMS calculated for C36H42O4Si, 566.2852,
found 566.2853.
6-(tert-Butyldiphenylsilyloxy)-4-(1-hydroxycyclohexyl)-2-meth-
ylhexan-3-one 24. Cyclohexanone (50 lL, 0.480 mmol) and
DMPU (58 lL, 0.480 mmol) were added to a solution of ketone
23 (19 mg, 0.034 mmol) in THF (0.5 mL). SmI2 (0.1 M in
THF, 1.2 mL, 0.120 mmol) was then added and the reaction
mixture stirred at −78 ◦C. After 15 min the reaction mixture
changed from a dark blue to a yellow/orange colour and
further portions of DMPU (29 lL, 0.240 mmol) and SmI2
(0.1 M in THF, 0.6 mL, 0.060 mmol) were subsequently added.
The reaction was stirred for a further 25 minutes before being
quenched with aqueous saturated NH4Cl (8 mL) and distilled
H2O (3 mL). The aqueous layer was extracted with EtOAc
(3 × 20 mL), the organic extracts combined, dried (Mg2SO4)
and concentrated in vacuo to give the crude product as a
yellow oil. Purification by column chromatography (silica,
5% EtOAc–petroleum ether) gave starting ketone 23 (2 mg,
0.004 mmol, 10%) as a clear colourless oil. Further elution then
gave 24 as a clear colourless oil (12.5 mg, 0.027 mmol, 78%):
2-(4-Benzyloxyphenoxy)-4-(tert-butyldiphenylsilyloxy)-1-cyclo-
propylbutan-1-one 19. A crystal of iodine was added to a
suspension of magnesium metal (219 mg, 9.12 mmol) in a
minimal amount of THF (0.5 mL). Cyclopropyl bromide
(703 lL, 9.12 mmol) was then added dropwise followed by
THF (9.5 mL) and the resulting mixture heated at reflux for
1 h until the magnesium had been consumed. A portion of
the resultant Grignard reagent (1.67 mL, 1.52 mmol) was
then added dropwise to a solution of 2-(4-benzyloxyphenoxy)-
4-(tert-butyldiphenylsilyloxy)-1-(morpholin-4-yl)butan-1-one
(230 mg, 0.377 mmol) in THF (4 mL) and the reaction
mixture stirred at room temperature for 12 h. The reaction
was quenched using aqueous saturated NH4Cl (40 mL) and
distilled H2O (20 mL). The aqueous solution was extracted
using 30% EtOAc–petroleum ether (3 × 30 mL), the organic
layers combined, dried (Na2SO4) and concentrated in vacuo
to give the crude product as a yellow oil. Purification by
column chromatography (silica, 5% EtOAc–petroleum ether)
gave 19 (177 mg, 0.313 mmol, 83%) as a clear colourless oil;
mmax ATR/cm−1 3485 (b), 2929 (s), 2856 (m), 1691 (s) C O,
=
1464 (m) and 1107 (s); dH (400 MHz; CDCl3) 1.01 (3H, d, J
6.8 Hz, (CH(CH3)2), 1.08 (3H, d, J 6.9 Hz, (CH(CH3)2), 1.08
(9H, s, C(CH3)3), 1.12–1.76 (11H, m, 1H from CH2CH2OSi,
CH2C(OH) × 2, CH2CH2C(OH) × 2, CH2CH2CH2C(OH)),
1.98–2.04 (1H, m, 1H from CH2CH2OSi), 2.76 (1H, septet, J
mmax (neat)/cm−1 3070 (s), 2858 (s), 1697 (s) C O, 1506 (s),
=
1226 (m) and 1111 (s); dH (400 MHz; CDCl3) 0.82–1.08 (13H,
=
m, 2 × (CH2)2CHC O, 3 × C(CH3)3), 2.03–2.18 (2H, m,
=
CH2CH2OSi), 2.25–2.32 (1H, m, (CH2)CHC O), 3.81–3.86
(1H, m, 1H from CH2OSi), 3.93 (1H, dt, J 4.8, 9.6 Hz, 1H
from CH2OSi), 4.84 (1H, dd, J 3.8, 9.3 Hz, OCHC O), 5.03
(2H, s, PhCH2), 6.79–6.91 (4H, m, ArH), 7.29–7.45 (11H, m,
=
6.9 Hz, CH(CH3)2), 2.98 (1H, dd, J 4.3, 8.2 Hz, CH2CHC O),
=
3.33 (1H, s, OH), 3.53–3.59 (1H, m, 1H from CH2OSi), 3.69
(1H, apparent quintet, J 5.5 Hz, 1H from CH2OSi), 7.37–7.46
(6H, m, ArH) and 7.64–7.67 (4H, m, ArH); dC (100 MHz;
CDCl3) 17.2 (CH(CH3)2), 17.7 (CH(CH3)2), 19.2 (C(CH3)3),
21.5 (CH2), 21.9 (CH2), 25.7 (CH2), 26.9 (C(CH3)3 × 3), 30.3
(CH2CH2OSi), 34.8 (CH2C(OH)), 37.4 (CH2C(OH)), 42.5
ArH) and 7.58–7.67 (4H, m, ArH); dC (100 MHz; CDCl3) 11.8
=
=
((CH2)2CHC O × 2), 16.3 ((CH2)2CHC O), 19.2 (C(CH3)3),
26.8 (C(CH3)3 × 3), 35.3 (CH2CH2OSi), 59.4 (CH2OSi),
=
70.6 (PhCH2O), 80.6 (OCHC O)), 115.8 (ArCH × 2), 116.1
(ArCH × 2), 117.1 (ArC), 127.5 (ArCH × 2), 127.6 (ArCH ×
2), 127.7 (ArCH × 2), 127.9 (ArCH), 128.5 (ArCH × 2), 129.6
=
(CH(CH3)2), 53.8 (CHC O), 62.4 (CH2OSi), 72.7 (C(OH)),
127.7 (ArCH × 4), 129.7 (ArCH × 2), 133.5 (ArC × 2), 135.5
(ArCH × 2), 133.4 (ArC), 135.5 (ArCH × 4), 137.2 (ArC),
+
+
=
(ArCH × 4) and 221.9 (C O). LRMS (FAB ) 467.3 ((M + H)
+
=
152.6 (ArC), 153.4 (ArC) and 212.3 (C O); LRMS (FAB )
7%) 311 (24), 193 (100), 135 (23) and 72 (28); HRMS calculated
for C29H43O3Si, 467.2981, found 467.2981. Further elution then
gave 4-benzyloxyphenol (6 mg, 0.030 mmol, 86%) as a pale
yellow solid.
587.2 ((M + Na)+ 18%), 197 (19), 135 (37) and 92 (100); HRMS
calculated for C36H40O4SiNa, 587.2594, found 587.2591.
4-(4-Benzyloxyphenoxy)-6-(tert-butyldiphenylsilyloxy)-2-meth-
ylhexan-3-one 23. i-PrMgCl (2.0 M, in THF 1.59 mL, 3.18
mmol) was added dropwise at 0 ◦C to a solution of amide 6
(643 mg, 1.08 mmol) in THF (10 mL) and the reaction stirred
slowly at 0 ◦C overnight, during which time the reaction warmed
to room temperature. The reaction was quenched with aqueous
saturated NH4Cl (30 mL) and distilled H2O (10 mL). The
aqueous layer was extracted with 30% EtOAc–petroleum ether
(3 × 30 mL), the organic extracts combined, dried (Na2SO4)
and concentrated in vacuo to give the crude product as a pale
yellow oil. Purification by column chromatography (silica, 5%
EtOAc–petroleum ether) gave 23 (501 mg, 0.883 mmol, 82%) as
a clear colourless oil: mmax (neat)/cm−1 3070 (s), 2931 (s), 1714
6-(tert-Butyldiphenylsilyloxy)-4-(4-hydroxytetrahydropyran-4-
yl)-2-methylhexan-3-one
25. Tetrahydro-4H-pyran-4-one
(133 lL, 1.44 mmol) and DMPU (174 lL, 1.44 mmol) were
added to a solution of ketone 23 (50 mg, 0.088 mmol) in THF
(0.5 mL). SmI2 (0.1 M in THF, 3.6 mL, 0.36 mmol) was then
added and the reaction mixture stirred at −78 ◦C. After 25
minutes the reaction mixture changed from a dark blue to a
yellow/orange colour and further portions of DMPU (66 lL,
0.720 mmol) and SmI2 (1.80 mL, 0.180 mmol) were added. The
reaction was stirred for a further 25 min before being quenched
with aqueous saturated NH4Cl (8 mL) and distilled H2O (4 mL).
The aqueous layer was extracted with EtOAc (3 × 20 mL), the
organic extracts combined, dried (Mg2SO4) and concentrated in
vacuo to give the crude product as a yellow oil. Purification by
column chromatography (silica, 2% EtOAc–petroleum ether)
gave ketone 23 (4 mg, 0.011 mmol, 12%) as a clear colourless
oil. Further elution then gave 4-benzyloxyphenol (18 mg,
0.090 mmol, 100%) as a pale yellow solid. Further elution gave
25 (32 mg, 0.068 mmol, 76%) as a clear, colourless oil: mmax
=
(s) C O, 1506 (s), 1227 (m) and 1111 (s); dH (400 MHz; CDCl3)
=
0.97 (3H, d, J 6.8 Hz, (CH3)2CHC O), 1.03 (9H, s, (CH3)3CSi),
=
1.12 (3H, d, J 6.8 Hz, (CH3)2CHC O), 1.94–2.01 (1H, m, 1H
from CH2CH2OSi), 2.07–2.13 (1H, m, 1H from CH2CH2OSi),
3.01 (1H, apparent septet, J 6.8 Hz, (CH3)2CHC O), 3.77–3.82
(1H, m, 1H from CH2OSi), 3.89 (1H, dt, J 4.4, 9.7 Hz,
=
=
CH2OSi), 4.90 (1H, dd, J 3.7, 9.5 Hz, OCHC O), 5.03 (2H, s,
ATR/cm−1 3473 (b), 2958 (m), 2931 (m), 1691 (m) C O, 1468
=
ArCH2), 6.80–6.90 (4H, m, ArH), 7.28–7.45 (11H, m, ArH)
and 7.56–7.66 (4H, m, ArH); dC (100 MHz; CDCl3) 18.1
(CH(CH3)2), 19.1 (CH(CH3)2 and C(CH3)3), 26.8 (C(CH3)3 ×
(m) and 1103 (s); dH (400 MHz; CDCl3) 1.01 (3H, d, J 6.9 Hz,
CH(CH3)2), 1.08 (9H, s, C(CH3)3), 1.09 (3H, d, J 7.2 Hz,
CH(CH3)2), 1.33–1.43 (2H, m, CH2C(OH)CH), 1.55 (1H,
dd, J 1.5, 13.3 Hz, 1H from CH2C(OH)CH), 1.64–1.76 (2H,
m, 1H from CH2(OH)CH, 1H from CH2CH2OSi), 1.98–2.07
(1H, m, CH2CH2OSi), 2.75 (1H, septet, J 6.9 Hz, CH(CH3)2),
=
3), 35.3 (CH2CH2OSi), 35.9 ((CH3)2CHC O), 59.5 (CH2OSi),
=
70.6 (ArCH2O), 79.7 (OCHC O)), 115.9 (ArCH × 2), 116.2
(ArCH × 2), 127.5 (ArCH × 2), 127.6 (ArCH × 2), 127.7
(ArCH × 2), 127.9 (ArCH), 128.5 (ArCH × 2), 129.6 (ArCH),
129.7 (ArCH), 133.3 (ArC), 133.4 (ArC), 135.5 (ArCH ×
=
2.86 (1H, dd, J 4.4, 8.0 Hz, CHC O), 3.54–3.60 (2H, m, 1H
=
4), 137.2 (ArC), 152.6 (ArC), 153.5 (ArC) and 215.6 (C O);
from CH2OSi), 3.60 (1H, d, J 2.1 Hz, OH), 3.70–3.82 (5H, m,
1H from CH2OSi, CH2O × 2), 7.37–7.47 (6H, m, ArH) and
LRMS (EI+) 566.2 (M+ 8%) 431 (89), 233 (26), 199 (20), 135
2 8 1 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 8 0 5 – 2 8 1 6

View Online
7.64–7.66 (4H, m, ArH); dC (100 MHz; CDCl3) 16.9 (CH(CH3)2),
17.9 (CH(CH3)2), 19.1 (C(CH3)3), 26.8 (C(CH3)3 × 3), 29.8
4 For recent reviews on the use of samarium(II) iodide in organic
synthesis: (a) G. A. Molander and C. R. Harris, Chem. Rev., 1996,
96, 307; (b) G. A. Molander and C. R. Harris, Tetrahedron, 1998,
54, 3321; (c) P. G. Steel, J. Chem. Soc., Perkin Trans. 1, 2001, 2727;
(d) H. B. Kagan, Tetrahedron, 2003, 59, 10351; (e) D. J. Edmonds, D.
Johnston and D. J. Procter, Chem. Rev., 2004, 104, 3371.
5 (a) G. A. Molander and G. Hahn, J. Org. Chem., 1986, 51, 1135;
(b) G. A. Molander and G. Hahn, J. Org. Chem., 1986, 51, 2596; (c) K.
Otsubo, J. Inanaga and M. Yamaguchi, Tetrahedron Lett., 1987, 28,
4437; (d) K. Kusuda, J. Inanaga and M. Yamaguchi, Tetrahedron
Lett., 1989, 30, 2945.
=
(CH2CHC O), 35.4 (CH2C(OH)), 37.8 (CH2C(OH)), 42.4
=
(CH(CH3)2), 54.0 (CHC O), 62.1 (CH2OSi), 63.4 (CH2O × 2),
70.1 (CH2C(OH)), 127.7 (ArCH × 4), 129.8 (ArCH × 2), 133.3
+
=
(ArC × 2), 135.5 (ArCH × 4) and 221.9 (C O). LRMS (CI )
469.4 ((M + H)+ 11%) 451 (10), 369 (5), 195 (7) and 57 (100);
HRMS calculated for C28H41O4Si, 469.2774, found 469.2773.
4-[2-(tert-Butyldiphenylsilyloxy)ethyl]-6-methyl-5-oxoheptanoic
acid methyl ester 26. SmI2 (0.1M solution in THF, 1.2 mL,
0.120 mmol) was added dropwise to a solution of ketone 23
(3◦1 mg, 0.055 mmol) in methyl acrylate (54 lL, 0.060 mmol) at
0 C. The solution was allowed to warm to room temperature
and stirred for 20 minutes before further portions of both methyl
acrylate (54 lL, 0.600 mmol) and SmI2 (0.1 M in THF, 1.20 mL,
0.120 mmol) were added and the solution stirred for a further
20 minutes. The reaction was quenched with aqueous saturated
NaHCO3 (5 mL) and distilled H2O (2 mL). The aqueous layer
was extracted with EtOAc, the organic extracts combined,
dried (Na2SO4) and concentrated in vacuo to give the crude
product as a yellow oil. Purification by column chromatography
(silica, 30% EtOAc–petroleum ether) gave ketone 16a (19 mg,
0.052 mmol, 86%) as a clear colourless oil. Further elution then
gave 26 as a (3 mg, 0.007 mmol, 11%) as a clear colourless oil:
mmax (neat)/cm−1 2931 (m), 1738 (s), 1708 (s), 1427 (m) and 1108
(s); dH (400 MHz; CDCl3) 1.04 (3H, d, J 6.9 Hz, CH(CH3)2),
1.06 (9H, s, C(CH3)3), 1.07 (3H, d, J 6.9 Hz, CH(CH3)2),
1.49–1.55 (1H, m, 1H from CH2CH2OSi), 1.63–1.71 (1H,
m, 1H from CH2CH2CO2CH3), 1.78–1.96 (2H, m, 1H from
CH2CH2OSi and 1H from CH2CH2CO2CH3), 2.14–2.32 (2H,
m, CH2CO2CH3), 2.73 (1H, septet, J 6.9 Hz, CH(CH3)2), 3.00
6 A. D. Hughes, D. A. Price and N. S. Simpkins, J. Chem. Soc., Perkin
Trans. 1, 1999, 1295.
7 For selected, recent examples of this reaction, see: (a) J. Castro, A.
Moyano, M. A. Perica`s, A. Riera and A. E. Greene, Tetrahedron:
Asymmetry, 1994, 5, 307; (b) E. Piers and A. M. Kaller, Tetrahedron
Lett., 1996, 37, 5857; (c) G. A. Molander and P. J. Stengel,
Tetrahedron, 1997, 53, 8887; (d) I. Marchueta, E. Montenegro, D.
Panov, M. Poch, X. Verdaguer, A. Moyano, M. A. Perica`s and A.
Riera, J. Org. Chem., 2001, 66, 6400.
8 For selected, recent examples in the context of natural product
synthesis, see: (a) I. Paterson, R. D. Norcross, R. A. Ward, P. Romea
and M. A. Lister, J. Am. Chem. Soc., 1994, 116, 11287; (b) R. A.
Holton, C. Somoza and K.-B. Chai, Tetrahedron Lett., 1994, 35,
1665; (c) B. V. Yang and M. A. Massa, J. Org. Chem., 1996, 61, 5149;
(d) T. Honda and M. Kimura, Org. Lett., 2000, 2, 3925; (e) A. D.
Lebsack, L. E. Overman and R. J. Valentekovich, J. Am. Chem. Soc.,
2001, 123, 4851.
9 (a) J. M. Concello´n, J. A. Pe´rez-Andre´s and H. Rodr´ıguez-Solla,
Angew. Chem., Int. Ed., 2000, 39, 2773; (b) J. M. Concello´n, P. L.
Bernad and H. Rodr´ıguez-Solla, Angew. Chem., Int. Ed., 2001, 40,
3897; (c) J. M. Concello´n, J. A. Pe´rez-Andre´s and H. Rodr´ıguez-
Solla, Chem. Eur. J., 2001, 7, 3062; (d) J. M. Concello´n and H.
Rodr´ıguez-Solla, Chem. Eur. J., 2001, 7, 4266; (e) J. M. Concello´n
and E. Bardales, Eur. J. Org. Chem., 2004, 1523.
10 (a) Y. Nakamura, S. Takeuchi, Y. Ohgo, M. Yamaoka, A. Yoshida
and K. Mikami, Tetrahedron Lett., 1997, 38, 2709; (b) K. Mikami,
M. Yamaoka and A. Yoshida, Synlett, 1998, 607; (c) Y. Nakamura,
S. Takeuchi, Y. Ohgo, M. Yamaoka, A. Yoshida and K. Mikami,
Tetrahedron, 1999, 55, 4595.
11 Janda has reported a single, sulfone example of this linkage as a
member of a different, general class of sulfone linker. Cleavage of the
linker is achieved using sodium/mercury amalgam: X. Zhao, K. W.
Jung and K. D. Janda, Tetrahedron Lett., 1997, 38, 977.
12 For a preliminary account of our work on an oxygen HASC linker,
see: F. McKerlie, D. J. Procter and G. Wynne, Chem. Commun., 2002,
584. We have recently developed a sulfur version of the linkage for
use in solid and fluorous phase synthesis, see: (a) L. A. McAllister, S.
Brand, R. de Gentile and D. J. Procter, Chem. Commun., 2003, 2380;
(b) L. A. McAllister, R. A. McCormick, S. Brand and D. J. Procter,
Angew. Chem., Int. Ed., 2005, 44, 452.
=
(1H, apparent quintet, J 6.6 Hz, CHC O), 3.56–3.69 (5H, m,
CH2OSi and CO2CH3), 7.36–7.46 (6H, m, ArH) and 7.63–8.36
(4H, m, ArH); dC (100 MHz; CDCl3) 17.9 (CH(CH3)2), 18.1
(CH(CH3)2), 19.1 (C(CH3)3), 25.9 (CH2CH2CO2CH3), 26.8
(C(CH3)3 × 3), 31.6 (CH2CO2CH3), 34.0 (CH2CH2OSi), 40.1
=
(CH(CH3)2), 44.9 (CHC O), 51.6 (CO2CH3), 61.3 (CH2OSi),
127.7 (ArCH × 4), 129.7 (ArCH × 2), 133.5 (ArC), 135.5
=
(ArCH × 4), 138.1 (ArC), 173.5 (CO2CH3) and 217.1 (C O);
LRMS (FAB+) 455.3 ((M + H)+ 10%), 397 (45), 199 (100) and
135 (35); HRMS calculated for C27H39O4Si 455.2618, found
455.2614; Further elution gave 4-benzyloxyphenol (11 mg,
0.055 mmol, 91%) as a pale yellow solid.
13 (a) X. Du and R. W. Armstrong, J. Org. Chem., 1997, 62, 5678; (b) X.
Du and R. W. Armstrong, Tetrahedron Lett., 1998, 39, 2281. Further
applications of the reagent on solid phase have since been reported.;
(c) R. M. Myers, S. P. Langston, S. P. Conway and C. Abell, Org.
Lett., 2000, 2, 1349; (d) M. M. Meloni and M. Taddei, Org. Lett.,
2001, 3, 337; (e) M. Gustafsson, R. Olsson and C.-M. Andersson,
Tetrahedron Lett., 2001, 42, 133; (f) M. Tanaka, A. Sudo, F. Sanda
and T. Endo, Macromolecules, 2002, 35, 6845; (g) J. N. P. D’herde and
P. J. DeClercq, Tetrahedron Lett., 2003, 44, 6657; (h) S. N. Baytas, Q.
Wang, N. A. Karst, J. S. Dordick and R. J. Linhardt, J. Org. Chem.,
2004, 69, 6900. See also refs 3c,3d and 12a.
14 R. S. Miller, J. M. Sealy, M. Shabangi, M. L. Kuhlman, J. R. Fuchs
and R. A. Flowers II, J. Am. Chem. Soc., 2000, 122, 7718.
15 For a review of the effects of additives on SmI2 reactions, see: H.
Kagan and J. L. Namy in Lanthanides: Chemistry and Use in Organic
Synthesis; ed. S. Kobayashi, Springer, New York, 1999, p. 155.
16 M. Fisher and R. C. D. Brown, Tetrahedron Lett., 2001, 42,
8227.
Acknowledgements
We thank the Engineering and Physical Research Council
(EPSRC) and OSI Pharmaceuticals for support (F.M.). We also
thank AstraZeneca for the award of a Strategic Research Grant
(D.J.P) and Pfizer for untied funding (D.J.P).
References
1 For selected, recent reviews on solid phase organic synthesis see:
(a) S. Booth, P. H. H. Hermkens, H. C. J. Ottenheijm and D. C. Rees,
Tetrahedron, 1998, 54, 15385; (b) R. C. D. Brown, J. Chem. Soc.,
Perkin Trans. 1, 1998, 3293; (c) R. E. Sammelson and M. J. Kurth,
Chem. Rev., 2001, 101, 137; (d) V. Krchna´k and M. W. Holladay,
Chem. Rev., 2002, 102, 61; (e) R. E. Dolle, J. Comb. Chem., 2003, 5,
693.
2 For reviews on linkers and cleavage strategies 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) S. Bra¨se and S. Dahmen, Chem. Eur. J., 2000, 6, 1899; (d) A. C.
Comely and S. E. Gibson (ne´e Thomas), Angew. Chem., Int. Ed.,
2001, 40, 1012.
3 (a) P. C. Hutchison, T. D. Heightman and D. J. Procter, Org. Lett.,
2002, 4, 4583; (b) P. C. Hutchison, T. D. Heightman and D. J. Procter,
J. Org. Chem., 2004, 69, 790; (c) N. J. Kerrigan, P. C. Hutchison, T. D.
Heightman and D. J. Procter, Chem. Commun., 2003, 1402; (d) N. J.
Kerrigan, P. C. Hutchison, T. D. Heightman and D. J. Procter, Org.
Biomol. Chem., 2004, 2476.
17 Tanko has shown that the ring opening of radical anions derived from
aliphatic cyclopropyl ketones is faster than for the corresponding
neutral cyclopropinyl radical and occurs at a rate >107 s−1. J. P.
Stevenson, W. F. Jackson and J. M. Tanko, J. Am. Chem. Soc., 2002,
124, 4271.
18 The fragmentation of cyclopropyl ketones on treatment with samar-
ium(II) iodide has been exploited previously in both synthetic
and mechanistic contexts. (a) R. A. Batey and W. B. Motherwell,
Tetrahedron Lett., 1991, 43, 6211; (b) G. A. Molander and J. A.
McKie, J. Org. Chem., 1991, 56, 4112; (c) D. P. Curran, X. Gu, W.
Zhang and P. Dowd, Tetrahedron, 1997, 53, 9023; (d) G. Masson, S.
Py and Y. Valle´e, Angew. Chem., Int. Ed., 2002, 41, 1772; (e) T. K.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 8 0 5 – 2 8 1 6
2 8 1 5

View Online
Hutton, K. Muir and D. J. Procter, Org. Lett., 2002, 4, 2345; (f) T. K.
Hutton, K. W. Muir and D. J. Procter, Org. Lett., 2003, 5, 4811.
19 Molander and Inanaga have invoked the direct reduction of the a-
substituent in the case of a-bromo esters (ref. 5a) and a,b-epoxy esters
(ref. 5c), respectively.
20 For selected examples, see: (a) E. J. Enholm and S. Jiang, Tetrahedron
Lett., 1992, 33, 6069; (b) E. J. Enholm and J. A. Schreier, J. Org.
Chem., 1995, 60, 1110; (c) S. Ichikawa, S. Shuto and A. Matsuda,
Tetrahedron Lett., 1998, 39, 4525; (d) T. Mukaiyama, H. Arai and I.
Shiina, Chem. Lett., 2000, 580.
21 (a) M. Ricci, L. Madariaga and T. Skrydstrup, Angew. Chem., Int.
Ed., 2000, 39, 242; (b) M. Ricci, P. Blakskjær and T. Skrydstrup,
J. Am. Chem. Soc., 2000, 122, 12413.
22 Adduct 26 could conceivably be formed by radical addition to
methylacrylate. The analogous reaction using an electronically
matched radical acceptor, ethyl vinyl ether gave no addition products
suggesting 26 is formed by an anionic process.
23 T. Imamoto and M. Ono, Chem. Lett., 1987, 501.
24 A. Stern and J. S. Swenton, J. Org. Chem., 1987, 52, 2763.
25 R. E. Ireland and F. R. Brown, Jr., J. Org. Chem., 1980, 45, 1868.
2 8 1 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 8 0 5 – 2 8 1 6