Ring-closing metathesis: Development of a cyclisation-cleavage strategy for the solid-phase synthesis of cyclic sulfonamides

Article abstract of DOI:10.1039/b313686h

A series of novel 7-membered cyclic sulfonamides have been synthesised using a solid-phase cyclisation-cleavage RCM strategy. Model solution studies indicated the sulfonamides were suitable substrates for RCM using the Grubbs' catalyst 2. Starting from either 2-carboxyethyl polystyrene (21) or Merrifield resin, various seven-membered sulfonamides were prepared in good to excellent yields at low catalyst loadings (2.5-5 mol%) using a flexible spacer between the polymer and the substrate. In addition, a novel double-armed linker was shown to allow efficient RCM cleavage of sulfonamides with as little as 1 mol% of the ruthenium alkylidene complex 2.

Full text of DOI:10.1039/b313686h

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Ring-closing metathesis: development of a cyclisation–cleavage
strategy for the solid-phase synthesis of cyclic sulfonamides
Jean-Dominique Moriggi,†a Lynda J. Brown,a José L. Castrob and Richard C. D. Brown*a
a School of Chemistry, University of Southampton, Highfield, Southampton, UK SO17 1BJ.
E-mail: rcb1@soton.ac.uk; Fax: (0)23 80596805; Tel: (0)23 80594108
b Merck Sharp & Dohme Research Laboratories, Terlings Park, Harlow, UK CM20 2QR
Received 30th October 2003, Accepted 5th January 2004
First published as an Advance Article on the web 16th February 2004
A series of novel 7-membered cyclic sulfonamides have been synthesised using a solid-phase cyclisation–cleavage
RCM strategy. Model solution studies indicated the sulfonamides were suitable substrates for RCM using the
Grubbs’ catalyst 2. Starting from either 2-carboxyethyl polystyrene (21) or Merrifield resin, various seven-membered
sulfonamides were prepared in good to excellent yields at low catalyst loadings (2.5–5 mol%) using a flexible spacer
between the polymer and the substrate. In addition, a novel double-armed linker was shown to allow efficient RCM
cleavage of sulfonamides with as little as 1 mol% of the ruthenium alkylidene complex 2.
providing an alternative catalytic pathway.5a However, the use
Introduction
of any unwanted additive is undesirable in solid-phase cleavage
In recent years the widespread use of solid-phase techniques
reactions, and in the case of metathesis reactions, might lead to
within academic research groups and the pharmaceutical indus-
a variety of cross-metathesis products. In a separate study,
try has provided impetus for the development of methods for
Blechert and co-workers reported the cyclisation–cleavage of
the solid-phase synthesis of small organic molecules.1 Efficient
a cyclic tetrapeptide from Wang resin in only 30% yield.5b
solid-phase synthesis relies heavily on the choice of linker, and
However, when an 8-carbon spacer was employed between
the polymer and the first double bond, the yield increased
significantly to 70% without the need for an olefin co-factor.
Blechert’s results suggested that the use of a flexible spacer may
many novel linkers and cleavage strategies have been reported.2
One attractive strategy is cyclisation–cleavage, where the neces-
sary cleavage step has the added benefit of introducing a key
structural feature into the target molecule.3
be sufficient to allow efficient catalytic cyclisation–cleavage by
Cyclisation–cleavage methods have enjoyed widespread use
RCM.
in solid-phase synthesis, although the majority of applications
Isosteric replacement and conformational restriction are
to date have involved carbon–heteroatom bond formation
commonly employed strategies in drug discovery.8 Given the
rather than C–C bond formation (Scheme 1). Ring closing
prevalence of amides in biologically active molecules, isosteric
metathesis (RCM) provides an attractive method to achieve
replacement by sulfonamides and subsequent cyclisation to
cyclisation–cleavage via C–C bond formation, and has been used
cyclic sulfonamides should provide interesting novel scaffolds
to release cyclic olefins of various ring sizes from the solid-
for combinatorial chemistry.9–11 Our interest in cyclisation–
phase.3–7 Van Maarseveen and co-workers first reported that
cleavage strategies in general, and more specifically in develop-
if an appropriate diene substrate were to be attached to the
polymer core through one of its double bonds, RCM would
ing efficient RCM-based approaches, led us to examine the solid-
phase synthesis of seven-membered cyclic sulfonamides.5h,11
simultaneously form the ring (7-membered lactams) and effect
As part of our investigation, we chose to evaluate a strategy
employing a novel double-armed linker, the idea being that
a domino-sequence of RCM reactions would regenerate a
catalytically active alkylidene carbene complex in solution
the cleavage from the resin in one step.5a However, their early
studies suffered from the limitation that large amounts of
ruthenium alkylidene complex were required to effect cleavage
in satisfactory yields.
(Scheme 2, pathway B). In order to determine whether any
benefit was realised from the use of a double-armed linker, the
corresponding single-armed analogue would also be prepared
for comparison. Here we provide a full account of these studies,
part of which was communicated previously.5h
Results and discussion
Our synthetic approach began with the assembly of the single-
Scheme 1 RCM cyclisation–cleavage approach to cyclo-olefins.
and double-armed substrates 19 and 20 in solution prior to
attachment to the solid-phase, to ensure that the key RCM
reaction was viable (Scheme 3). The final approach would
require the substrate to be directly assembled on the solid-
phase, attached through a robust linkage that would be stable to
a broad range of conditions. However, the development of the
solid-phase chemistry was simplified by initially employing an
ester linkage that would allow facile cleavage of intermediates
from the resin in order to monitor the success of the individual
solid-phase steps. As a solid support for the preliminary studies,
we chose to make use of a 2-carboxyethyl polystyrene (21)
which is readily prepared from Merrifield resin.12
Inspection of the RCM reaction pathway on the solid-phase
implies that the release of a cyclised product would lead to an
intermediate resin-bound ruthenium alkylidene species 5, which
might be inefficient as a propagating species due to site isolation
effects within the resin (Scheme 2, pathway A). To solve this
problem, Van Maarseveen et al. suggested the use of an olefin
co-factor to regenerate an active ruthenium species in solution,
† Present address: Inpharzam Ricerche SA, Via ai söi, CP 328 6807,
Taverne, Switzerland.
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
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 8 3 5 – 8 4 4
835

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Scheme 2 Possible pathways for cyclisation–cleavage reactions on single- and double-armed substrates.
Scheme 3 Reagents: i, DHP, p-TSA, THF, CH2Cl2; ii, MsCl, i-Pr2NEt, CH2Cl2; iii, dimethyl malonate, NaH, DMF; iv, KOAc, DMSO, heat;
v, p-TSA, MeOH; vi, NH4OH (aq.); vii, (Boc)2O, i-Pr2NEt, DMAP, CH2Cl2; viii, DEAD, PPh3, THF; ix, LiAlH4, Et2O; x, 21, DIC, DMAP, CH2Cl2;
xi, 2 (50 mol%), CH2Cl2.
The synthesis began by monoalkylation and dialkylation of
dimethyl malonate with the known allylic chloride 7, which
provided malonates 8 and 9.13 Krapcho dealkoxycarbonylation
of 8 and 9 afforded the monoesters 10 and 11 in 84% and 81%
yield respectively.14 Removal of the protecting groups provided
the alcohols 12 and 13, which underwent Mitsunobu coupling
with sulfonamide 16 prepared from 3-butene-1-sulfonyl
chloride.15–17 Reduction of the ester groups present in 17 and 18
proceeded smoothly, allowing multigram quantities of alcohols
19 and 20 to be prepared for solid-phase coupling. The resin-
bound RCM precursors 22 and 23 were obtained in the first
instance by coupling alcohols 19 and 20 to the 2-carboxyethyl
polystyrene (21) using a mixture of DIC and excess DMAP.
IR spectroscopy and LiBH4 reductive cleavage of the alcohols
19 and 20 from the resin confirmed success of these coupling
reactions.
At this point we wanted to verify that metathesis reaction
of the linker-diene adduct 17 would give the desired cyclic
sulfonamide 24 in solution, and to determine the influence of
concentration on the cyclisation. Treatment of the substrate 17
with 1 mol% of the Grubbs’ catalyst 2 at concentrations of 0.1,
0.5 and 1.0 mM with respect to the substrate in CH2Cl2 all
proceeded to give 24 in excellent yield (>90%). For the pre-
liminary solid-phase RCM cyclisation–cleavage studies, resins
22 and 23 were refluxed in CH2Cl2 with 50 mol% Grubbs’
catalyst 2 and we were pleased to observe formation of the
desired 7-membered sulfonamide 24.
Having confirmed the viability of the cyclisation–cleavage
reaction, attention turned to the synthesis of the linker and
substrates directly on the solid-phase (Scheme 4). The esters 10
and 11 were reduced to the alcohols 25 and 26 in good yields
using LiAlH4 and subsequently coupled to 2-carboxyethyl
polystyrene (21) under standard conditions. Consecutive THP
deprotection and Mitsunobu reaction with sulfonamide 16
afforded the resin-bound RCM precursors 22 and 23. IR
spectroscopy or LiBH4 reduction confirmed the success of
the different reactions throughout the sequence and provided
estimated loadings for 22 and 23.18
The resins 22 and 23 were submitted to different amounts
of Grubbs catalyst 2 (2.5–50 mol%) in refluxing CH2Cl2 (see
Table 1). In addition, a co-factor, 1-octene,5a was also added to
the reactions containing the single-armed resin 22 to determine
whether this additive had any beneficial effect. The yields were
generally satisfactory; however, little difference was observed
between the single- and double-armed linker. No real benefit
was obtained in the cleavage reactions of the single-armed
linker substrate 22 containing the olefin co-factor and the
purity of the crude sulfonamide 24 was reduced, probably
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 8 3 5 – 8 4 4
836

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Table 1 Ring-closing metathesis cyclisation–cleavage reactions of
resins 22 and 23
Table 2 Ring-closing metathesis cyclisation–cleavage reactions of
resins 36 and 37
Entry
Substrate
Co-factora
Catalyst (mol%)b
Yield (%)c
Entry
Substrate
Catalyst (mol%)a
Yield (%)b
1
2
3
4
5
6
7
8
9
22
22
22
22
22
22
22
23
23
23
23
No
No
No
No
Yes
Yes
Yes
No
No
No
No
2.5
5.0
10.0
50.0
2.5
5.0
10.0
2.5
66
61
62
41
53
38
56
61
43
52
55
1
2
3
4
5
6
7
8
36
36
36
36
37
37
37
37
1.0
2.5
5.0
50.0
1.0
2.5
31
45
100 (100)c
53 (60)c
91
100
5.0
50.0
100 (100)c
78 (84)c
5.0
10.0
50.0
a Quantities are calculated on the basis of the estimated loadings of
resins 36 and 37.20 b Yields estimated by GC analysis of the crude
reaction mixture. c Isolated yields.20
10
11
a One equivalent of 1-octene was used as the olefin co-factor were
indicated. b Quantities are calculated on the basis of the theoretical
loadings of resins 22 and 23 (0.76 and 1.24 mmol S gϪ1) calculated
from 2-carboxyethylpolystyrene (1.0 mmol CO2H gϪ1). c Yields refer to
purified material.
for 2-carboxyethyl resins 22 and 23, and we were delighted
to obtain quantitative cleavage of the product 24 in some
instances.21 The most striking observation was that when less
than 5.0 mol% of catalyst 2 was used, higher yields were
obtained for the double-armed linker in comparison to the
single-armed analogue. Hence the double-armed linker
appeared to be more efficient than the single-armed linker when
a low amount of the ruthenium complex 2 is used.
In order to extend the methodology to provide a small
collection of cyclic sulfonamides we examined the synthesis
of a series of N-alkylated analogues starting from resins 36 and
37. Removal of the Boc group was achieved under standard
conditions to afford immobilised sulfonamides 38 and 39
(Scheme 5). Subsequent N-alkylation with a range of alkyl
halides was initially performed using DBU as the base,22 how-
ever subsequent RCM cleavage reactions showed the alkylation
step to be incomplete (about 50% alkylated product obtained
after a double alkylation). Replacing DBU with t-BuOK and
performing double couplings proved much more effective,
providing a series of N-alkylated RCM precursors 40–47.23
To demonstrate that several steps could be carried out on our
resin-bound sulfonamides, sulfonamide 38 was subjected to
N-alkylation with t-butyl bromoacetate followed by removal
of the t-butyl ester and subsequent amide bond formation with
benzylamine to give the diene 56 (Scheme 6). A variety of resins
bearing single and double-armed linkers 38–47, 53 and 56 were
then submitted to the cyclisation–cleavage conditions, and
the corresponding sulfonamides obtained in good to excellent
yields (Schemes 5 and 6, Table 3). Again, it appeared that at
lower catalyst loading the double-armed linker outperformed
the single-armed linker (see entries 4 and 5, Table 3).
To gain some insight into the rate of cyclisation–cleavage, the
release of the cyclic sulfonamide 24 was monitored over time by
removal of aliquots and GC analysis using phenanthrene as an
internal standard. Although the RCM cyclisation–cleavage
reactions were typically left for 15 h, it was shown that the
release of 24 from resins 36 and 37 was 70–80% complete after
1 h using 5 mol% of the Grubbs’ catalyst 2 and 90% complete
after 3 hours.
An important issue with any cleavage protocol is the presence
of impurities derived from the reagents or catalyst in the
final product. In the present case, all crude products (and
the recovered resin) obviously contained ruthenium-derived
impurities,24 which were removed by column chromatography.
However, removal of these coloured impurities was less
straightforward when higher catalyst loadings were employed,
underscoring the importance of developing conditions that
allow efficient catalytic cyclisation–cleavage. Future studies
relating to the RCM cyclisation–cleavage approach should
address the issue of catalyst removal, particularly if high-
throughput approaches are to be applied.24
Scheme 4 Reagents: i, LiAlH4, THF; ii, 21, DIC, DMAP, CH2Cl2; iii,
p-TSA, MeOH; iv, 16, DEAD, PPh3, THF; v, 2 (2.5–50 mol%), CH2Cl2.
due to the presence of cross metathesis by-products. In fact,
when the metathesis product 24 was resubmitted to the Grubbs’
catalyst 2 in the presence of 1-octene, slow degradation was
observed.
The use of 2-carboxyethyl polystyrene (21) had proved suc-
cessful in our initial RCM studies by allowing us to monitor
individual solid-phase reaction steps as well as permitting direct
attachment of an RCM precursor to the solid-phase. However,
the ester linkage does not display sufficient stability under basic
and nucleophilic conditions to be broadly applicable in solid-
phase synthesis. To provide a more robust attachment to the
resin, alcohols 25 and 26 were coupled directly to Merrifield
resin 31 by reaction of the corresponding sodium alkoxides in
DMF at 60 ЊC (Scheme 5). The resin-bound alcohol 34 and diol
35 were obtained by deprotection of the THP ethers 32 and 33
respectively,19 and Mitsunobu coupling with sulfonamide 16
afforded the RCM precursors 36 and 37.20
Resins 36 and 37 were then submitted to varying quantities
of Grubbs’ catalyst 2 in refluxing CH2Cl2 (see Table 2).
An olefin co-factor was not used, since it had not proved
advantageous with the 2-carboxyethyl polystyrene-supported
substrates. The RCM cyclisation–cleavage from ether-linked
resins 36 and 37 proceeded in better yields than those seen
It was mentioned above that the resins recovered after RCM
cleavage were typically coloured brown, suggesting that some
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 8 3 5 – 8 4 4
837

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Table 3 Ring-closing metathesis cyclisation–cleavage reactions to form N-substituted sulfonamides 48–52, 55 and 57
Entry
Substrate
Product
R
Catalyst (mol%)a
Yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
38
39
40
42
43
42
43
42
43
44
45
46
47
53
56
48
48
49
50
50
50
50
50
50
51
51
52
52
55
57
H
H
CH3
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
5.0
5.0
5.0
1.0
1.0
2.5
2.5
5.0
5.0
5.0
5.0
5.0
5.0
2.5
5.0
98
97
[74]c
[45]c
[100]c
[94]c
[100]c
[100]c
[100]c
58
CH2Ph
CH2(o-Br)C6H4
CH2(o-Br)C6H4
CH2(2,5-(CH3)2)C6H3
CH2(2,5-(CH3)2)C6H3
CH2CO2 Bu
CH2CONHCH2Ph
92
59
58
95
t
92
a Quantities are calculated on the basis of the calculated loadings of resins 38–47, 53 and 56. b Isolated yields. c GC yields.
Scheme 5 Reagents: i, 25 or 26, NaH, DMF, 60 ЊC; ii, p-TSA, MeOH; iii, 16, DEAD, PPh3, THF; iv, 2 (1.0–50 mol%), CH2Cl2; v, TFA, CH2Cl2; vi,
t-BuOK, MeI or BnBr or 2-bromobenzyl bromide or 2,5-dimethylbenzyl chloride, THF.
experiments the dimerisation product (E)-7-tetradecene was
observed. It may also be of interest to note that the coloured
resins were stored open to the air for several months prior to
these cross metathesis experiments.
Conclusions
A series of novel 7-membered cyclic sulfonamides have been
prepared by a solid-phase approach in good to excellent yields
using an RCM cyclisation–cleavage reaction as the key step.
Initial model studies in solution indicated the sulfonamide-
linker adducts were suitable substrates for RCM. Transferring
the model to the solid-phase, firstly using an ester linkage
and then an ether linkage, we were pleased to observe that
the yields for the cyclisation–cleavage were good to excellent
without the use of an olefin co-factor. Two flexible linkers have
been studied and both produced good yields of sulfonamides
using 5.0 mol% of catalyst 2. The introduction of the
Scheme 6 Reagents: i, t-BuOK, t-butyl bromoacetate, THF; ii, TFA,
double-armed linker was justified by the realisation of efficient
CH2Cl2; iii, BnNH2, DIC, DMAP, THF; iv, 2 (2.5–5 mol%), CH2Cl2.
RCM cleavage using very low amounts of catalyst (1–2.5
mol%). Although we can not confirm that the hypothetical
ruthenium species had been trapped/attached within the resin.25
To determine whether the recovered resins could be used as
metathesis catalysts themselves, the coloured resins were added
to a solution of 1-octene in refluxing CH2Cl2 and in all the
RCM pathway B (Scheme 2) is operating, the present study
does show that efficient cyclisation–cleavage of sulfonamides
can be achieved using the double-armed linker at low catalyst
loadings.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 8 3 5 – 8 4 4
838

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Na]ϩ, 100); HRMS m/z (ESϩ) 405.2253; C21H34O6Na requires
405.2247.
Experimental
IR spectra were recorded on a Perkin-Elmer 1600 FT-IR
instrument, a Bio-Rad FTS 135 instrument using a Golden
Gate accessory or a Nicolet Impact 400 instrument using a
Thunderdome accessory. UV studies were carried out on a
Perkin-Elmer Lambda 2 UV/VIS spectrometer or a Hewlett-
Methyl (Z )-6-hydroxy-4-hexenoate (12)
To an ice-cooled solution of ester 10 (200 mg, 0.88 mmol)
in CH3OH (10 mL) was added 4-toluenesulfonic acid (36 mg,
0.18 mmol). The ice bath was removed and the solution was
stirred for 3 h. The reaction was quenched with sat. aq.
NaHCO3 (20 mL) and the product extracted twice with Et2O
(25 mL). The combined organic layers were washed with brine
(10 mL), dried (MgSO4) and concentrated in vacuo. Purification
by silica gel flash chromatography (1.5 × 3 cm; hexane : Et2O
1 : 1) afforded a colourless oil (84 mg, 0.58 mmol, 66%). νmax
(film)/cmϪ1 3411 (br, OH), 2953, 1736 (s, CO), 1438 (m), 1365,
1166 (m), 1094, 1025 (m), 984, 850; 1H NMR (300 MHz,
CDCl ) 5.71–5.62 (m, 1H, CH᎐CH), 5.50–5.41 (m, 1H, CH᎐
1
Packard 8452A diode array spectrophotometer. H NMR and
13C NMR spectra were recorded on JEOL GX270, Bruker
AC300, Bruker AM300 or Bruker DPX400 spectrometers. Low
resolution mass spectra were obtained on a Fisons VG platform
single quadrupole mass spectrometer in electron spray ionis-
ation mode. Melting points were measured on a Gallenkamp
electrothermal melting point apparatus. GC analyses were
carried out on a Varian 3800 fitted with a 30 m x 0.25 mm
DB120 fused silica column. All loadings of resins, amounts of
reagents and yields in solid-phase reactions are calculated from
the measured loadings of intermediate resins 21, 34, and 35,
assuming quantitative conversion for subsequent solid-phase
reactions.
᎐
᎐
3
CH ), 4.17 (d, 2H, J = 6.6 Hz, CH2OH), 3.44 (s, 3H, OCH3),
2.92 (br s, 1H, OH), 2.40–2.38 (m, 4H, CH2CH2CO2Me); 13C
NMR (75 MHz, CDCl3) 173.9 (CO), 130.6 (CH), 130.2 (CH),
58.2 (CH2OH), 51.8 (OCH3), 33.7 (CH2), 22.7 (CH2); m/z (EI)
(rel. intensity) 84 ([(M Ϫ CO2Me) ϩ H]ϩ, 100); HRMS
m/z (ESϩ) 167.0678; C7H12O3Na requires 167.0678.
Dimethyl 2,2-di[(Z )-4-tetrahydro-2H-2-pyranyloxy)-2-butenyl]
propanedioate (9)
To a solution of dimethyl malonate (1.1 mL, 10.0 mmol) in
DMF (100 mL) was added a 60% dispersion of NaH in mineral
oil (1 g, 25.0 mmol). When the gas evolution had ceased,
chloride 7 (5.75 g, 30.0 mmol) was added and the reaction
mixture was stirred at rt for 15 h. The reaction was quenched
with water (50 mL) and the product was extracted with Et2O
(3 × 50 mL). The combined organic layers were washed with
brine (25 mL), dried (MgSO4) and concentrated in vacuo. Puri-
fication by silica gel flash chromatography (5 × 5 cm; hexane :
Et2O 1 : 0 to 1 : 1) afforded a colourless oil (3.65 g, 8.3 mmol,
83%). νmax (film) 2944, 1734 (s, CO) cmϪ1; 1H NMR (300 MHz,
Methyl (Z )-6-hydroxy-2-[(Z )-4-hydroxy-2-butenyl]-hexanoate
(13)
To an ice-cooled solution of ester 11 (3.44 g, 9 mmol) in MeOH
(70 mL) was added PTSA (340 mg, 1.8 mmol). The ice bath
was removed and the solution stirred for 3 h. The reaction was
quenched with sat. aq. NaHCO3 (10 mL). The product was
extracted with Et2O (3 × 10 mL), the combined organic layers
were dried (MgSO4) and concentrated in vacuo. Purification
by silica gel flash chromatography (3 × 5 cm; hexane–Et2O)
afforded a colourless oil (1.79 g, 8.4 mmol, 93%). νmax (film)/
1
cmϪ1 3348 (br, OH), 2953, 1725 (s, CO); H NMR (300 MHz,
CDCl ) 5.71–5.63 (m, 2H, CH᎐CH), 5.43–5.34 (m, 2H,
᎐
3
CDCl ) 5.65 (dt, 2H, J = 11.0, 7.0 Hz, CH᎐CH), 5.37 (dt, 2H,
᎐
3
CH᎐CH ), 4.58 (t, 2H, J = 3.3 Hz, OCH), 4.21 (dd, 2H, J = 12.5,
᎐
J = 11.0, 7.0 Hz, CH᎐CH ), 4.12 (dd, 2H, J = 13.0, 7.0 Hz,
᎐
5.9 Hz, CHHO), 4.01 (dd, 2H, J = 12.5, 7.3 Hz, CHHO), 3.87–
3.79 (m, 2H, CHHO), 3.68 (s, 6H, OCH3), 3.48–3.43 (m, 2H,
CHHO), 2.66 (d, 4H, J = 8.1 Hz, (CH2)2C(CO2Me)2), 1.83–1.46
(m, 12H, CH2CH2CH2); 13C NMR (75MHz, CDCl3) 171.3
CHaHbOH), 4.05 (dd, 2H, J = 13.0, 7.0 Hz, CHaHbOH), 3.60
(s, 3H, OCH3), 2.50 (q(5), 1H, J = 7.0 Hz, COCH ), 2.39 (dt,
2H, J = 14.0, 7.5 Hz, CHCHaHb), 2.23 (dt, 2H, J = 14.0, 7.5 Hz,
CHCHaHb), 2.20 (br, 2H, CH2OH); 13C NMR (75 MHz,
(CO), 130.4 (CH᎐CH), 125.9 (CH᎐CH), 98.2 (OCHO), 62.8
᎐
᎐
CDCl ) 175.8 (CO), 131.3 (CH᎐CH), 128.5 (CH᎐CH), 58.2
᎐
᎐
3
(CH2O), 62.3 (CH2O), 57.4 (C(CO2Me)2), 52.7 (OCH3), 30.9
(CH2), 30.7 (CH2), 25.5 (CH2), 19.6 (CH2); m/z (ESϩ) (rel.
intensity) 463.4 ([M ϩ Na]ϩ, 100); HRMS m/z (ESϩ) 463.2303;
C23H36O8Na requires 463.2302; C23H36O8 requires C: 62.71;
H: 8.24; found C: 62.36; H: 8.53%.
(CH2OH), 51.9 (OCH3), 45.0 (CHCO), 29.1 (CH2CH); m/z
(EI) (rel. intensity) 237.1 ([M ϩ Na]ϩ, 100); HRMS m/z (ESϩ)
237.1102; C11H18O4Na requires 237.1097.
3-Butene-1-sulfonamide (15)
Methyl (Z )-6-(tetrahydro-2H-2-pyranyloxy)-2-[(Z )-4-(tetra-
hydro-2H-2-pyranyloxy)-2-butenyl]-4-hexenoate (11)
Sulfonyl chloride 1415 (4.0 g, 26.0 mmol) was added to an
ice cooled 30% solution of ammonia in water (40 mL). The
reaction mixture was stirred for 10 minutes. The product
was extracted with CH2Cl2 (20 mL), Et2O (20 mL) and EtOAc
(20 mL). The combined organic layers were washed with brine
(10 mL), dried (MgSO4) and concentrated in vacuo to give a
white solid (2.53 g, 19 mmol, 72%). mp 41–42 ЊC; νmax (film)/
cmϪ1 3346 (m), 3255 (m), 3070, 2986, 1640, 1301 (s, SO2), 1133
To a solution of malonate 9 (4.79 g, 10.8 mmol) and water
(400 µL) in DMSO (30 mL) was added KOAc (2.15 g, 22
mmol). The mixture was stirred at 140 ЊC for 5 h. The solution
was allowed to cool to rt and poured into water (250 mL). The
product was extracted with a 1 : 1 (v/v) mixture of Et2O and
hexane (3 × 100 mL). The combined organic layers were washed
with water (75 mL), sat. aq. NaHCO3 (75 mL), dried (MgSO4)
and concentrated in vacuo. Purification by silica gel flash
chromatography (4 × 5 cm; hexane : Et2O 1 : 0 to 1 : 1) afforded
a colourless oil (3.35 g, 8.7 mmol, 81%). νmax (film)/cmϪ1 2942,
1
(s, SO2); H NMR (300 MHz, CDCl3) 5.84 (ddt, 1H, J = 16.9,
10.4, 6.5 Hz, CH᎐CH ), 5.20–5.11 (m, 2H, CH᎐CH ), 4.93 (br s,
᎐
᎐
2
2
2H, NH2), 3.25–3.19 (m, 2H, CH2SO2), 2.65–2.58 (m, 2H,
CH2CH2SO2); 13C NMR (75 MHz, CDCl ) 134.1 (CH᎐CH ),
᎐
3
2
117.4 (CH᎐CH ), 54.4 (CH2SO2), 28.2 (CH2CH2SO2);
1
᎐
2
1735 (s, CO); H NMR (300 MHz, CDCl3) 5.67–5.56 (m, 2H,
C4H9NO2S requires C: 35.54; H: 6.71; N: 10.36; found C: 35.70;
H: 6.77; N: 10.40%.
CH᎐CH), 5.55–5.45 (m, 2H, CH᎐CH ), 4.60 (br s, 2H, OCH),
᎐
᎐
4.22 (dt, 2H, J = 12.4, 6.4 Hz, CHHO), 4.13–3.99 (m, 2H,
CHHO), 3.88–3.81 (m, 2H, CHHO), 3.68 (s, 3H, OCH3),
3.51–3.47 (m, 2H, CHHO), 2.49–2.23 (m, 5H, CH2CHCO2-
Me), 1.85–1.50 (m, 12H, CH2CH2CH2); 13C NMR (75 MHz,
N-(3-Butene-1-sulfonyl) tert-butylcarbamate (16)
To an ice cooled solution of sulfonamide 15 (1.35 g, 10 mmol),
DMAP (12 mg, 0.1 mmol) and diisopropylethylamine
(1.73 mL, 12 mmol) in CH2Cl2 (100 mL) was added dropwise
a solution of di-tert-butyl dicarbonate (2.5 g, 11 mmol) in
CH2Cl2 (10 mL). The ice bath was removed. The reaction
CDCl ) 175.2 (CO), 129.4 (CH᎐CH), 128.6 (CH᎐CH), 98.0
᎐
᎐
3
(OCHO), 62.7 (CH2O), 62.2 (CH2O), 51.7 (OCH3), 45.5
(CHCO2Me), 30.7 (CH2), 29.7 (CH2), 25.6 (CH2), 19.6 (CH2);
m/z (ESϩ) (rel. intensity) 400.4 ([M ϩ NH4]ϩ, 65), 405.4 ([M ϩ
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 8 3 5 – 8 4 4
839

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mixture was stirred for 2.5 h and was then concentrated
in vacuo. The residue was partitioned between EtOAc (60 mL)
and a 1 M aqueous solution of HCl (40 mL). The organic layer
was washed with water (20 mL), brine (20 mL), dried (MgSO4)
and concentrated in vacuo. Purification by silica gel flash
chromatography (3 × 5 cm, hexane : Et2O 1 : 0 to 1 : 1) afforded
a colourless oil (2.35 g, 10 mmol, 100%). νmax (film)/cmϪ1 3236
(br, NH), 2982, 1740 (s, CO), 1643, 1346 (s, SO2), 1135 (s, SO2);
1H NMR (300 MHz, CDCl3) 7.78 (br s, 1H, NH), 5.79 (ddt, 1H,
J = 16.9, 9.9, 6.6 Hz, CH᎐CH ), 5.18–5.08 (m, 2H, CH᎐CH ),
0.55 mmol) in Et2O (1 mL). The ice bath was removed and the
solution was stirred at rt for 6 h. Excess LiAlH4 was carefully
destroyed at 0 ЊC with vigorous stirring by dropwise addition of
water (0.5 mL), a 15% aqueous solution of NaOH (0.5 mL) and
after 5 min water (1.5 mL). The product was then extracted
twice with Et2O and CH2Cl2 (5 mL). The combined organic
layers were washed with brine (5 mL), dried (MgSO4) and
concentrated in vacuo. After column chromatography 19 was
obtained as a colourless oil (170 mg, 0.51 mmol, 93%). νmax
(film)/cmϪ1 3424 (br, OH), 2935, 1725 (s, CO), 1642, 1357 (s,
SO2), 1147 (s, SO2); 1H NMR (300 MHz, CDCl3) 5.79 (ddt, 1H,
J = 16.9, 10.3, 6.6 Hz, CH᎐CH ), 5.58–5.48 (m, 2H, CH᎐CH),
᎐
᎐
2
2
3.49–3.43 (m, 2H, CH2SO2), 2.61–2.53 (m, 2H, CH2CH2SO2),
1.52 (s, 9H, C(CH3)3); 13C NMR (75 MHz, CDCl3) 150.1 (CO),
᎐
᎐
2
133.7 (CH᎐CH ), 117.7 (CH᎐CH ), 84.4 (OC(CH ) ), 52.2
5.18–5.09 (m, 2H, CH᎐CH ), 4.31 (d, 2H, J = 5.9 Hz, CH N),
᎐
2
᎐
᎐
2
2
3
3
2
(CH2SO2), 28.1 (C(CH3)3), 27.6 (CH2CH2SO2); m/z (ESϩ) 493
([2M ϩ Na]ϩ); HRMS m/z (ESϩ) 258.0772; C9H17NO4SNa
requires 258.0770; C9H17NO4S requires C: 45.94; H: 7.28; N:
5.95; found C: 45.51; H: 7.41; N: 5.81%.
3.63 (t, 2H, J = 6.2 Hz, CH2OH), 3.54–3.48 (m, 2H, CH2SO2),
2.57–2.50 (m, 2H, CH2CH2SO2), 2.26 (q, 2H, J = 6.6 Hz,
CH2CH2CH2OH), 2.05 (br s, 1H, OH), 1.66 (quintet, 2H,
J = 6.6 Hz, CH2CH2OH), 1.53 (s, 9H, C(CH3)3); 13C NMR
(75 MHz, CDCl3) 151.6 (CO), 133.8 (CH), 133.3 (CH), 125.4
(CH), 117.6 (CH᎐CH ), 85.0 (OC(CH ) ), 61.6 (CH OH), 53.6
᎐
Methyl (Z )-6-[N-(3-butene-1-sulfonyl)-N-(tert-butoxycarbonyl)-
amino]-4-hexenoate (17)
2
3
3
2
(CH2SO2), 43.5 (CH2N), 32.1 (CH2CH2OH), 28.1 (C(CH3)3),
27.7 (CH2CH2SO2), 23.4 (CH2CH2CH2OH); m/z (ES) (rel.
intensity) 351 ([M ϩ NH4]ϩ, 100); C15H27NO5S requires C:
54.03; H: 8.16; N: 4.20; found C: 53.59; H: 8.19; N: 4.14%.
To a solution of alcohol 12 (91 mg, 0.63 mmol), PPh3 (165 mg,
0.63 mmol) and Boc-sulfonamide 16 (148 mg, 0.63 mmol) in
THF (6 mL) was added dropwise a solution of DEAD (250 µL,
0.63 mmol) in THF (2 mL) at rt. The solvent was removed in
vacuo, triphenylphosphine oxide was precipitated by addition
of Et2O and collected by filtration.. The filtrate was concen-
trated in vacuo to give a yellow oil. Purification by silica gel flash
chromatography (2 × 4 cm; hexane : Et2O 1 : 0 to 1 : 1) afforded
a colourless oil (166 mg, 0.46 mmol, 73%). νmax (film)/cmϪ1 1727
(s, CO), 1357 (s, SO2), 1147 (s, SO2); 1H NMR (300 MHz,
2,2-Di-{(Z )-4-[N-(3-butene-1-sulfonyl)-N-(tert-butoxycarb-
onyl)-amino]-but-2-en-1-yl} ethanol (20)
The procedure described above for the reduction of 17 to 19
was followed, using ester 18 (620 mg, 0.95 mmol). Purification
by silica gel flash chromatography (2 × 4 cm; hexane–Et2O)
afforded 20 as a colourless oil (513 mg, 0.83 mmol, 87%). νmax
(film)/ 3538 (br, OH), 2979, 1722 (s, CO), 1642, 1353 (s, SO2)
cmϪ1; 1H NMR (300 MHz, CDCl3) 5.79 (ddt, 2H, J = 16.9, 10.3,
6.6 Hz, CH᎐CH ), 5.61–5.47 (m, 4H, CH᎐CH), 5.18–5.10 (m,
CDCl ) 5.76 (ddt, 1H, J = 16.9, 10.3, 6.6 Hz, CH᎐CH ), 5.52
᎐
3
2
(dt, 1H, J = 10.3, 5.9 Hz, CH᎐CH), 5.49 (dt, 1H, J = 10.3, 5.9
᎐
Hz, CH᎐CH ), 5.19–5.08 (m, 2H, CH᎐CH ), 4.31 (d, 2H, J = 5.9
᎐
᎐
᎐
᎐
2
2
4H, CH᎐CH ), 4.40–4.25 (m, 4H, CH N), 3.54–3.48 (m, 6H,
Hz, CH2N), 3.67 (s, 3H, OCH3), 3.53–3.45 (m, 2H, CH2SO2),
2.60–2.36 (m, 6H, CH2CH2SO2 & CH2CH2CO2Me), 1.52 (s,
9H, C(CH3)3); 13C NMR (75 MHz, CDCl3) 173.5 (COO), 151.5
᎐
2
2
CH2SO2 & CH2OH), 2.57–2.50 (m, 4H, CH2CH2SO2), 2.36–
2.26 (m, 2H, CHHCHCH2OH), 2.18–2.09 (m, 2H, CHHCH-
CH2OH), 1.99 (br s, 1H, OH), 1.69–1.59 (m, 1H, CHCH2OH),
1.54 (s, 18H, C(CH3)3); 13C NMR (75 MHz, CDCl3) 151.6
(CO), 133.8 (CH᎐CH ), 131.8 (CH᎐CH), 126.3 (CH᎐CH),
(NCO), 133.8 (CH᎐CH ), 131.5 (CH᎐CH), 126.2 (CH᎐CH),
᎐
᎐
᎐
2
117.6 (CH᎐CH ), 84.7 (OC(CH ) ), 53.5 (CH SO ), 51.7
᎐
2
3
3
2
2
(OCH3), 43.3 (CH2N), 33.7 (CH2), 28.1 (C(CH3)3), 27.7
(CH2CH2SO2), 22.9 (CH2); m/z (ES) (rel. intensity) 384 ([M ϩ
Na]ϩ, 28), 379 ([M ϩ NH4]ϩ, 100); HRMS m/z (CI) 362.16303
C16H28NO6S requires 362.16373.
᎐
᎐
᎐
2
117.6 (CH᎐CH ), 85.0 (OC(CH ) ), 63.5 (CH OH), 53.6
᎐
2
3
3
2
(CH2SO2), 43.7 (CH2N), 41.3 (CHCH2OH), 28.8 (CH2CH-
CH2OH), 28.2 (C(CH3)3), 27.7 (CH2CH2SO2); m/z (ES)
(rel. intensity) 643 ([M ϩ Na]ϩ, 100).
Methyl 2,2-di-{(Z )-4-[N-(3-butene-1-sulfonyl)-N-(tert-butoxy-
carbonyl)-amino]-but-2-en-1-yl} ethanoate (18)
Functionalised carboxyethyl resin 22
From 19. To a suspension of carboxyethyl resin 21 (200 mg,
1.0 mmol OH gϪ1, 0.2 mmol) in CH2Cl2 (4 mL) were added DIC
(100 µL, 0.6 mmol), DMAP (74 mg, 0.6 mmol) and alcohol 19
(200 mg, 0.6 mmol). The mixture was stirred for 15 h. The resin
was collected by filtration, washed with CH2Cl2 (3 × 10 mL) and
dried in vacuo at 50 ЊC for 5 h. For on-bead IR data see below.
The procedure described above for the preparation of sulfon-
amide 17 was followed using diol 13 (1.7 g, 8 mmol) and Boc-
sulfonamide 16 (3.76 g, 16 mmol). Purification by silica gel flash
chromatography (4 × 8 cm; hexane : Et2O 1 : 0 to 1 : 1) afforded
a colourless oil (2.28 g, 3.5 mmol, 44%). νmax (film)/cmϪ1 2978,
1724 (s, CO), 1643, 1354 (s, SO2), 1144 (s, SO2); 1H NMR (300
MHz, CDCl ) 5.79 (ddt, 2H, J = 16.9, 10.3, 6.6 Hz, CH᎐CH ),
᎐
3
2
5.54–5.51 (m, 4H, CH᎐CH), 5.17–5.09 (m, 4H, CH᎐CH ),
From 29. To a suspension of resin 29 (200 mg) swollen in
THF (3 mL) was added PPh3 (140 mg, 0.5 mmol) and 16 (166
mg, 0.5 mmol). DEAD (80 µL, 0.5 mmol) was added dropwise
and the mixture stirred at rt for 15 h. The resin was collected
by filtration, washed with MeOH (2 × 10 mL) and CH2Cl2
(2 × 10 mL) and dried in vacuo at 50 ЊC for 5 h. νmax (neat)/cmϪ1
2922, 1727 (s), 1602, 1360 (s), 1147 (s); sulfur combustion
᎐
᎐
2
4.37–4.20 (m, 4H, CH2N), 3.66 (s, 3H, OCH3), 3.53–3.48
(m, 4H, CH2SO2), 2.56–2.34 (m, 9H, CH2CHCO2Me &
CH2CH2SO2), 1.53 (s, 18H, C(CH3)3); 13C NMR (75 MHz,
CDCl ) 175.3 (COO), 151.5 (NCO), 133.8 (CH᎐CH ), 129.9
᎐
3
2
(CH᎐CH), 127.2 (CH᎐CH), 117.6 (CH᎐CH ), 84.8
᎐
᎐
᎐
2
(OC(CH3)3), 53.6 (CH2SO2), 51.8 (OCH3), 45.3 (CHCO2Me),
43.3 (CH2N), 29.7 (CH2CHCO2Me), 28.2 (C(CH3)3), 27.7
(CH2CH2SO2); m/z (ES) (rel. intensity) 671 ([M ϩ Na]ϩ, 100),
analysis gave an estimated loading of 0.72 mmol S gϪ1
;
reductive cleavage of 19 gave an estimated loading of: 0.73
mmol S gϪ1. The results were in good agreement with the
theoretical loading of the resin 22, which was calculated to be
0.76 mmol gϪ1 based on the loading of carboxyethyl resin 21.
666 ([M
ϩ
NH4]ϩ, 83); HRMS m/z (CI) 671.26376
C29H48N2O10S2Na requires 671.26426.
(Z )-6-[(N-(3-Butene-1-sulfonyl)-N-(tert-butoxycarbonyl)-
amino]-4-hexen-1-ol (19)
Functionalised carboxyethyl resin 23
To an ice-cooled solution of LiAlH4 (25 mg, 0.66 mmol) in
Et2O (2 mL) was added dropwise a solution of ester 17 (200 mg,
From 20. To a suspension of carboxyethyl resin 21 (200 mg,
1.0 mmol OH gϪ1, 0.2 mmol) in CH2Cl2 (4 mL) were added DIC
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 8 3 5 – 8 4 4
840

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(100 µL, 0.6 mmol), DMAP (74 mg, 0.6 mmol) and alcohol 20
(372 mg, 0.6 mmol). The mixture was stirred for 15 h. The resin
was collected by filtration, washed with CH2Cl2 (3 × 10 mL)
and dried in vacuo at 50 ЊC for 5 h. For on-bead IR data see
below.
CH2Cl2 (10 mL) and dried in vacuo at 50 ЊC for 5 h. νmax (neat)/
cmϪ1 2920, 1731 (s), 1601.
Resin 28. Procedure as described for the synthesis of resin 27
using resin 21 (750 mg, 1.0 mmol OH gϪ1, 0.75 mmol) and diol
26 (797 mg, 2.25 mmol). νmax (neat)/cmϪ1 2926, 1731 (s), 1601.
From 30. To a suspension of resin 30 (200 mg) swollen in
THF (3 mL) was added PPh3 (280 mg, 1 mmol) and 16 (235 mg,
1.0 mmol). DEAD (160 µL, 1.0 mmol) was added dropwise
and the mixture stirred at rt for 15 h. The resin was collected by
filtration, washed with MeOH (2 × 10 mL) and CH2Cl2 (2 ×
10 mL) and dried in vacuo at 50 ЊC for 5 h. νmax (neat)/cmϪ1 2922,
1730 (s), 1602, 1362 (s), 1147 (s); sulfur combustion analysis
gave an estimated loading of 1.13 mmol S gϪ1; reductive
Alcohol functionalised resin 29. To a suspension of 27 (740
mg) swollen in a 5 : 1 (v/v) mixture of DME and MeOH (6 mL)
was added PTSA (250 mg, 1.5 mmol). The mixture was stirred
at rt for 15 h. The resin was collected by filtration, washed twice
with MeOH and CH2Cl2 (10 mL each) and dried in vacuo at
50 ЊC for 5 h. νmax (neat)/cmϪ1 3335 (br), 2922, 1729 (s), 1602.
cleavage of 20 gave an estimated loading of: 1.1 mmol S gϪ1
The theoretical loading of resin 23, was calculated to be 1.24
mmol S gϪ1
.
Diol functionalised resin 30. The procedure described for
the preparation of 29 was followed using resin 28 (740 mg). νmax
(neat)/cmϪ1 3336 (br), 2920, 1730 (s), 1601.
.
tert-Butyl 1,1-dioxo-2,3,6,7-tetrahydro-1H-1ꢀ6,2-thiazepine-2-
carboxylate (24)
Resin 32. To a solution of alcohol 25 (280 mg, 1.38 mmol)
in DMF (10 mL) was added NaH (60 mg, 1.5 mmol). When
the gas evolution ceased, the solution was added dropwise to
Merrifield resin (200 mg, loading 2.3 mmol Cl gϪ1, 0.5 mmol)
swollen in THF (5 mL). The reaction mixture was stirred at
60 ЊC for 15 h. Excess NaH was carefully quenched by dropwise
addition of water. The resin was collected by filtration and
washed with DMF (10 mL), H2O (10 mL), DMF (10 mL)
and CH2Cl2 (10 mL). The resin was then dried in vacuo at 50 ЊC
for 5 h. νmax (neat)/cmϪ1 2921, 1601.
To a suspension of the resin 37 (187 mg, 0.127 mmol theoreti-
cal) in CH2Cl2 (2 mL) was added ruthenium complex 2 (1.1 mg,
0.0013 mmol) and the suspension was heated at reflux for 15 h.
The mixture was then filtered, washing the resin with CH2Cl2
(5 × 3 mL). The solvent was then removed from the combined
solutions and the resulting brown oil was purified by column
chromatography to afford the title compound 24 as a pale oil
(28.8 mg, 0.116 mmol, 91%). νmax (neat)/cmϪ1 2926, 1732 (s,
CO), 1362 (s, SO2), 1140 (s, SO2); 1H NMR (300 MHz, CDCl3)
5.93 (dt, 1H, J = 11.5, 5.0 Hz, CH᎐CH), 5.86 (dt, 1H, J = 11.5,
᎐
Resin 33. The procedure described for the preparation of 32
was followed using 26 (490 mg, 1.38 mmol). νmax (neat)/cmϪ1
2921, 1601.
6.2 Hz, CH᎐CH ), 4.25 (d, 2H, J = 5.0 Hz, CH N), 3.30–3.26
᎐
2
(m, 2H, CH2SO2), 2.51–2.46 (m, 2H, CH2CH2SO2), 1.50 (s, 9H,
C(CH3)3); 13C NMR (75 MHz, CDCl3) 151.6 (CO), 131.7 (CH),
130.4 (CH), 84.5 (OC(CH3)3), 51.6 (CH2), 45.0 (CH2), 28.1
(C(CH3)3), 22.2 (CH2CH2SO2); m/z (ES) 270 ([M ϩ Na]ϩ);
HRMS m/z (CI) 270.0776 C10H17NO4SNa requires 270.0770.
Alcohol functionalised resin 34. To a suspension of the resin
32 (300 mg) in MeOH (5 mL) was added p-TSA (180 mg,
0.95 mmol). The mixture was stirred at rt for 15 h. The resin was
collected by filtration, washed with CH2Cl2 (10 mL), MeOH
(10 mL), CH2Cl2 (10 mL) and dried in vacuo at 50 ЊC for 5 h.
νmax (neat)/cmϪ1 3340 (br), 2920, 1601; The loading of the resin
(Z )-6-(Tetrahydro-2H-2-pyranyloxy)-4-hexen-1-ol (25)
The procedure described above for the reduction of 17 to 19
was followed, using ester 10 (2.58 g, 11.3 mmol). Purification
by silica gel flash chromatography (5 × 6 cm, hexane : Et2O 1 : 0
to 1 : 1) afforded a colourless oil (2.10 g, 10.5 mmol, 93%).
The spectroscopic data were consistent with that reported in the
literature.26
was estimated to be 1.02 mmol OH gϪ1 19
.
Diol functionalised resin 35. Following the procedure
described for the preparation of 34 using resin 33 (325 mg),
MeOH (10 mL) and p-TSA (360 mg, 1.9 mmol). νmax (neat)/
cmϪ1 3334 (br), 2920, 1601; The loading of the resin was
(Z )-6-(Tetrahydro-2H-2-pyranyloxy)-2-[(Z )-4-(tetrahydro-2H-
2-pyranyloxy)-2-butenyl]-4-hexenol (26)
estimated as 0.97 mmol OH gϪ1 19
.
Resin 36. To a suspension of the resin 34 (150 mg, 1.02 mmol
OH gϪ1, 0.15 mmol) swollen in THF (5 mL) was added PPh3
(165 mg, 0.6 mmol) and 16 (150 mg, 0.6 mmol). DEAD
(0.1 mL, 0.6 mmol) was added dropwise. The mixture was
stirred at rt for 15 h. The resin was collected by filtration,
washed with CH2Cl2 (3 × 10 mL) and dried in vacuo at 50 ЊC for
5 h. νmax (neat)/cmϪ1 2921, 1723 (s), 1601, 1358 (s), 1148 (s). The
resin loading was estimated to be 0.88 mmol S gϪ1 by sulfur
combustion analysis.20
The procedure described above for the reduction of 17 to 19
was followed, using ester 11 (3.24 mg, 8.5 mmol). Purification
by silica gel flash chromatography (3.5 × 4 cm; hexane : Et2O 1 : 0
to 1 : 2) afforded a colourless oil (2.63 g, 7.4 mmol, 87%).
νmax (neat)/cmϪ1 3461 (br, OH), 2939 (m); 1H NMR (400 MHz,
(CDCl ) 5.71–5.57 (m, 4H, CH᎐CH), 4.66–4.62 (m, 2H,
᎐
3
OCHO), 4.32–4.19 (m, 2H, CHHOTHP), 4.14–4.01 (m,
2H, CHHOTHP), 3.90–3.82 (m, 2H, CH2CH2CH2CHHO),
3.52–3.49 (m, 4H, CH2CH2CH2CHHO & CH2OH), 2.96 (br s,
1H, OH), 2.26–2.07 (m, 4H, CH2CHCH2OH), 1.85–1.51 (m,
13H, CH2CH2CH2 & CHCH2OH); 13C NMR (100 MHz,
Resin 37. Procedure as described for 36 using 35 (150 mg,
0.97 mmol OH gϪ1, 0.14 mmol). νmax (neat)/cmϪ1 2925, 1724 (s),
1602, 1358 (s), 1145 (s). The resin loading was estimated to be
1.05 mmol S gϪ1 by sulfur combustion analysis.20
(CDCl ) 132.7 (CH᎐CH), 127.2 (CH᎐CH), 98.3 (OCHO), 63.4
᎐
᎐
3
(CH2O), 62.6 (CH2O), 62.3 (CH2O), 41.1 (CHCH2OH), 30.6
(CH2), 28.9 (CH2), 25.5 (CH2), 19.5 (CH2); C20H34O5 requires C:
67.76; H: 9.67; found C: 67.29; H: 9.77%.
Resin 38. To a suspension of resin 36 (150 mg) swollen in
CH2Cl2 (2 mL) was added a 50% solution of TFA in CH2Cl2
(5 mL). The mixture was stirred at rt for 30 min. The resin
was collected by filtration, washed with H2O (2 × 5 mL), Et3N
(2 × 5 mL), CH2Cl2 (2 × 5 mL) and dried in vacuo at 50 ЊC for
5 h. νmax (neat)/cmϪ1 2915, 1601, 1321 (s), 1143 (s).
Resin 27. Carboxyethyl resin 21 (750 mg, 1.0 mmol OH gϪ1
,
0.75 mmol) was swollen in CH2Cl2 (5 mL). Alcohol 25 (450 mg,
2.25 mmol), DIC (350 µL, 2.25 mmol) and DMAP (280 mg,
2.25 mmol) were added and the reaction stirred at rt for 15 h.
The resin was collected by filtration, washed three times with
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 8 3 5 – 8 4 4
841

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Resin 39. Following the procedure described for the prepar-
ation of resin 38 using 37 (150 mg). νmax (neat)/cmϪ1 2914, 1601,
1321 (s), 1141 (s).
6.17–6.08 (m, 1H, CH᎐CH), 5.95 (dt, 1H, J = 11.8, 5.9 Hz, CH᎐
᎐ ᎐
CH ), 3.80 (d, 2H, J = 5.9 Hz, CH2NMe), 3.04–2.99 (m, 2H,
CH2SO2), 2.77 (s, 3H, NCH3), 2.56–2.50 (m, 2H, CH2CH2SO2);
13C NMR (75 MHz, CDCl3) 133.5 (CH), 130.1 (CH), 47.0
(CH2), 46.4 (CH2), 35.1 (NCH3), 22.2 (CH2CH2SO2); m/z (CI)
(rel. intensity) 162 ([MϩH]ϩ, 100); HRMS m/z (EI) 161.0503
C6H11NO2S requires 161.0510.
Resin 40. Sulfonamide resin 38 (150 mg) was swollen in THF
(5 mL) then KOt-Bu (167 mg, 1.5 mmol) was added followed
by methyl iodide (90 µL, 1.5 mmol). The reaction mixture was
stirred at rt for 15 h. The resin was collected by filtration,
washed with CH2Cl2 (3 × 10 mL) and dried in vacuo at 50 ЊC for
5 h. νmax (neat)/cmϪ1 2918, 1601, 1321 (s), 1139 (s).
2-Benzyl-2,3,6,7-tetrahydro-1H-1ꢀ6,2-thiazepine-1,1-dione (50)
Following the general procedure for RCM cyclisation–cleavage
to give 24, using resin 42 and catalyst (2.5 mol%) gave a colour-
less oil (94%) or resin 43 and catalyst (1.0 mol%) gave a
colourless oil (100%). νmax (neat)/cmϪ1 2926, 1347 (s), 1330 (s,
SO2), 1157 (s), 1140 (s, SO2); 1H NMR (300 MHz, CDCl3) 7.43–
Resin 41. Following the general procedure for the alkylation
of resin 38 to give resin 40, reaction of sulfonamide resin 39
(150 mg) and methyl iodide (90 µL, 1.5 mmol) gave resin 41.
νmax (neat)/cmϪ1 2916, 1601, 1320 (s), 1137 (s).
7.21 (m, 5H, C H ), 6.16 (dt, 1H, J = 11.0, 6.6 Hz, CH᎐CH),
᎐
6
5
5.87 (dt, 1H, J = 11.0, 5.9 Hz, CH᎐CH ), 4.24 (s, 2H, NCH Ph),
᎐
2
Resin 42. Following the general procedure for the alkylation
of resin 38 to give resin 40, reaction of sulfonamide resin 38
(150 mg) and benzyl bromide (180 µL, 1.5 mmol) gave resin 42.
νmax (neat)/cmϪ1 2918, 1600, 1328 (s), 1141 (s).
3.63 (d, 2H, J = 5.9 Hz, CH2NBn), 3.14–3.10 (m, 2H, CH2SO2),
2.61–2.55 (m, 2H, CH2CH2SO2); 13C NMR (75 MHz, CDCl3)
135.5 (C), 133.7 (CH), 130.4 (CH), 128.8 (CH), 128.7 (CH),
128.2 (CH), 50.5 (CH2), 49.1 (CH2), 42.0 (CH2), 22.3 (CH2-
CH2SO2); m/z (CI) (rel. intensity) 238 ([M ϩ H]ϩ, 28), 172 (27),
132 (100); HRMS m/z (EI) 237.0823 C12H15NO2S requires
237.0823.
Resin 43. Following the general procedure for the alkylation
of resin 38 to give resin 40, reaction of sulfonamide resin 39
(150 mg) and benzyl bromide (180 µL, 1.5 mmol) gave resin 43.
νmax (neat)/cmϪ1 2920, 1600, 1492, 1450 (m), 1337 (s), 1141 (s),
742, 697 (s).
2-(2-Bromobenzyl)-2,3,6,7-tetrahydro-1H-1ꢀ6,2-thiazepine-1,1-
dione (51)
Resin 44. Following the general procedure for the alkylation
of resin 38 to give resin 40, reaction of sulfonamide resin 38
(150 mg) and 2-bromobenzyl bromide (375 mg, 1.5 mmol) gave
resin 44. νmax (neat)/cmϪ1 2922, 1601, 1321 (s), 1140 (s).
Following the general procedure for RCM cyclisation–cleavage
to give 24, using resin 44 and catalyst (5.0 mol%) gave a white
solid (58%) or resin 45 and catalyst (5.0 mol%) gave a white
solid (92%). Mp 96–97 ЊC; νmax (neat)/cmϪ1 2931, 1350 (s), 1331
1
(s, SO2), 1155 (s), 1139 (s, SO2); H NMR (300 MHz, CDCl3)
Resin 45. Following the general procedure for the alkylation
of resin 38 to give resin 40, reaction of sulfonamide resin 39
(150 mg) and 2-bromobenzyl bromide (375mg, 1.5 mmol) gave
resin 45. νmax (neat)/cmϪ1 2922, 1601, 1492, 1448 (m), 1318 (s),
1140 (s), 1026, 910 (m), 697 (s).
7.60 (d, 1H, J = 8.1 Hz, C6HH3), 7.56 (d, 1H, J = 8.1 Hz,
C6HH3), 7.36 (br t, 1H, J = 7.4 Hz, C6HH3), 7.18 (br t, 1H, J =
8.1 Hz, C HH ), 6.18 (dt, 1H, J = 11.0, 6.6 Hz, CH᎐CH), 6.00
᎐
6
3
(dt, 1H, J = 11.0, 5.9 Hz, CH᎐CH ), 4.39 (s, 2H, NCH Ph), 3.69
᎐
2
(d, 2H, J = 5.9 Hz, CH2NAr), 3.18–3.14 (m, 2H, CH2SO2),
2.64–2.58 (m, 2H, CH2CH2SO2); 13C NMR (75 MHz, CDCl3)
135.3 (C), 133.7 (CH), 133.0 (CH), 130.8 (CH), 130.3 (CH),
129.5 (CH), 128.1 (CH), 123.6 (C), 50.3 (CH2), 49.8 (CH2), 42.8
(CH2), 22.3 (CH2CH2SO2); m/z (CI) (rel. intensity) 318 (50),
316 ([M ϩ H]ϩ, 100); C12H14BrNO2S requires C: 45.58; H: 4.46;
N: 4.43; found C: 45.67; H: 4.39; N: 4.24%.
Resin 46. Following the general procedure for the alkylation
of resin 38 to give resin 40, reaction of sulfonamide resin 38
(150 mg) and 2,5-dimethylbenzyl chloride (220 µL, 1.5 mmol)
gave resin 46. νmax (neat)/cmϪ1 2915, 1603, 1492, 1449 (m), 1319
(s), 1141 (s), 912 (m), 697 (s).
2-(2,5-Dimethylbenzyl)-2,3,6,7-tetrahydro-1H-1ꢀ6,2-thiazepine-
1,1-dione (52)
Resin 47. Following the general procedure for the alkylation
of resin 38 to give resin 40, reaction of sulfonamide resin 39
(150 mg) and 2,5-dimethylbenzyl chloride (220 µL, 1.5 mmol)
gave resin 47. νmax (neat)/cmϪ1 2908, 1602, 1492, 1450 (m), 1327
(s), 1140 (s), 910 (m), 697 (s).
Following the general procedure for RCM cyclisation–cleavage
to give 24, using resin 46 and catalyst (5.0 mol%) gave a white
solid (59%) or resin 47 and catalyst (5.0 mol%) gave a white
solid (58%). Mp 118 ЊC; νmax (neat)/cmϪ1 2959, 1348 (s), 1329 (s,
SO2), 1158 (s), 1140 (s, SO2); 1H NMR (300 MHz, CDCl3) 7.11–
2,3,6,7-Tetrahydro-1H-1ꢀ6,2-thiazepine-1,1-dione (48)
Following the general procedure for RCM cyclisation–cleavage
to give 24, using resin 38 and catalyst 2 (5.0 mol%) gave a white
solid (98%) or resin 39 and catalyst (5.0 mol%) gave a white
solid (97%). Mp 66–67 ЊC; νmax (neat)/cmϪ1 3274 (NH), 2930,
1316 (s, SO2), 1135 (s, SO2); 1H NMR (300 MHz, CDCl3)
7.04 (m, 3H, C H ), 6.19 (dt, 1H, J = 13.2, 6.6 Hz, CH᎐CH),
᎐
6
3
5.88 (dt, 1H, J = 11.0, 5.9 Hz, CH᎐CH ), 4.22 (s, 2H, NCH Ar),
᎐
2
3.58 (d, 2H, J = 6.6 Hz, CH2NCH2Ar), 3.15–3.12 (m, 2H,
CH2SO2), 2.62–2.56 (m, 2H, CH2CH2SO2), 2.35 (s, 3H, CH3),
2.33 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3) 135.6 (C), 134.7
(C), 133.7 (CH), 132.7 (C), 130.9 (CH), 130.5 (CH), 129.0 (CH),
48.6 (CH2), 48.5 (CH2), 41.7 (CH2), 22.2 (CH2CH2SO2), 20.9
(CH3), 18.7 (CH3); C14H19NO2S requires C: 63.37; H: 7.22;
N: 5.28; found C: 63.31; H: 7.33; N: 5.21%.
6.09–5.96 (m, 2H, CH᎐CH), 4.58 (br, 1H, NH), 3.67 (dd, 2H,
᎐
J = 6.6, 5.2 Hz, CH2NH), 3.16–3.12 (m, 2H, CH2SO2), 2.58–
2.53 (m, 2H, CH2CH2SO2); 13C NMR (75 MHz, CDCl3) 132.6
(CH᎐CH), 132.3 (CH᎐CH), 52.7 (CH ), 42.0 (CH ), 22.1
᎐
᎐
2
2
(CH2CH2SO2); m/z (ESϩ) (rel. intensity) 170 ([M ϩ Na]ϩ, 100);
C5H9NO2S requires C: 40.80; H: 6.16; N: 9.51; found C: 40.78;
H: 6.34; N: 9.29%.
Resin 53. Following the general procedure for the alkylation
of resin 38 to give resin 40 (double coupling), sulfonamide resin
38 (150 mg) and tert-butyl bromoacetate (220 µL, 1.5 mmol)
gave resin 53. νmax (neat)/cmϪ1 2915, 1735 (s), 1601, 1338 (s),
1140 (s).
2-Methyl-2,3,6,7-tetrahydro-1H-1ꢀ6,2-thiazepine-1,1-dione (49)
Following the general procedure for RCM cyclisation–cleavage
to give 24, using resin 40 and catalyst (5.0 mol%) gave a colour-
less oil (74%). νmax (neat)/cmϪ1 2954 (s), 1471 (m), 1346 (s), 1332
Resin 54. To a suspension of resin 55 (150 mg) swollen in
CH2Cl2 (2 mL) was added a 50% solution of TFA in CH2Cl2
1
(s, SO2), 1158 (s), 1139 (s, SO2); H NMR (300 MHz, CDCl3)
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 8 3 5 – 8 4 4
842

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2091; (c) I. W. James, Tetrahedron, 1999, 55, 4855; (d ) F. Zaragoza,
Angew. Chem., Int. Ed., 2000, 39, 2077; (e) P. Blaney, R. Grigg and
V. Sridharan, Chem. Rev., 2002, 102, 2607.
3 See references 2a–e and: (a) J. H. van Maarseveen, Comb. Chem.
High Throughput Screen, 1998, 1, 185; (b) K. H. Park and
M. J. Kurth, Drug Future, 2000, 25, 1265.
(5mL). The mixture was stirred at rt for 3 h. The resin was
collected by filtration, washed with CH2Cl2 (2 × 5 mL), Et3N
(2 × 5 mL), CH2Cl2 (2 × 5 mL) and dried in vacuo at 50 ЊC for
5 h. νmax (neat)/cmϪ1 2907, 1727 (s), 1600, 1337 (s), 1141 (s).
Resin 56. Benzylamine (186 µL, 1.7 mmol) was added to a
suspension of resin 56 (160 mg) in THF (5 mL) in the presence
of DMAP (200 mg, 1.7 mmol) and DIC (260 µL, 1.7 mmol).
The reaction mixture was left at rt for 15 h. The resin was
collected by filtration, washed with CH2Cl2 (2 × 10 mL) and
dried in vacuo at 50 ЊC for 5 h. νmax (neat)/cmϪ1 2918, 1673 (s),
1602, 1324 (s), 1141 (s).
4 For a selection of olefin metathesis reviews: (a) R. H. Grubbs,
S. J. Miller and G. C. Fu, Acc. Chem. Res., 1995, 28, 446;
(b) M. Schuster and S. Blechert, Angew. Chem. Int. Ed. Engl., 1997,
36, 2037; (c) S. A. Armstrong, J. Chem. Soc., Perkin Trans. 1, 1998,
371; (d ) A. J. Phillips and A. D. Abell, Aldrichimica Acta, 1999,
32, 75; (e) A. Furstner, Angew. Chem., Int. Ed., 2000, 39, 3012;
( f ) S. J. Connon and S. Blechert, Angew. Chem., Int. Ed., 2003, 42,
1900.
5 For previous examples of cyclisation cleavage using RCM:
(a) J. H. van Maarseveen, J. A. J. den Hartog, V. Engelen, E. Finner,
G. Visser and C. G. Kruse, Tetrahedron Lett., 1996, 37, 8249;
(b) J. Pernerstorfer, M. Schuster and S. Blechert, Chem. Commun,
1997, 1949; (c) A. D. Piscopio, J. F. Miller and K. Koch, Tetrahedron
Lett., 1997, 38, 7143; (d ) K. C. Nicolaou, N. Wissinger, J. Pastor,
S. Ninkovic, F. Sarabia, Y. He, D. Vourloumis, Z. Yang, T. Li,
P. Giannakakou and E. Hamel, Nature, 1997, 387, 268; (e) A. D.
Piscopio, J. F. Miller and K. Koch, Tetrahedron Lett., 1998, 39,
2667; ( f ) J. J. N. Veerman, J. H. van Maarseveen, G. M. Visser,
C. G. Kruse, H. E. Schoemaker, H. Hiemstra and F. P. J. T. Rutjes,
Eur. J. Org. Chem., 1998, 2583; (g) A. D. Piscopio, J. F. Miller
and K. Koch, Tetrahedron, 1999, 55, 8189; (h) R. C. D. Brown,
J. L. Castro and J. D. Moriggi, Tetrahedron Lett., 2000, 41, 3681;
(i) S. Sasmal, A. Geyer and M. E. Maier, J. Org. Chem., 2002, 67,
6260.
tert-Butyl 2-(1,1-dioxo-2,3,6,7-tetrahydro-1H-1ꢀ6,2-thiazepin-2-
yl) acetate (55)
Following the general procedure for RCM cyclisation–cleavage
to give 24, using resin 53 the title compound 55 was obtained as
a colourless oil (95%). νmax (neat)/cmϪ1 2977, 1744 (s, CO), 1348
1
(s), 1331 (s, SO2), 1137 (s, SO2); H NMR (300 MHz, CDCl3)
6.11 (dt, 1H, J = 11.0, 6.6 Hz, CH᎐CH), 5.95 (dt, 1H, J = 11.0,
᎐
t
5.9 Hz, CH᎐CH ), 3.92 (d, 2H, J = 5.9 Hz, CH NCH CO Bu),
᎐
2
2
2
t
3.80 (s, 2H, NCH2CO2 Bu), 3.13–3.09 (m, 2H, CH2SO2),
2.59–2.53 (m, 2H, CH2CH2SO2), 1.48 (s, 9H, C(CH3)3); 13C
NMR (75 MHz, CDCl ) 133.7 (CH᎐CH), 130.1 (CH᎐CH),
᎐
᎐
3
82.4 (OC(CH3)3), 50.5 (CH2), 49.5 (CH2), 44.4 (CH2), 28.2
(C(CH3)3), 22.3 (CH2CH2SO2); m/z (ES) 279 ([M ϩ NH4]ϩ);
HRMS m/z (CI) 284.0930; C11H19NO4SNa requires 284.0926.
6 For RCM-based cleavage approaches to release acyclic olefins from
a diene linker: (a) J.-U. Peters and S. Blechert, Synlett, 1997, 348;
(b) L. Knerr and R. R. Schmidt, Synlett, 1999, 1802; (c) L. Knerr
and R. R. Schmidt, Eur. J. Org. Chem., 2000, 2803; (d ) D. Brohm,
S. Metzger, A. Bhargava, O. Müller, F. Lieb and H. Waldmann,
Angew. Chem., Int. Ed., 2002, 41, 307.
N-Benzyl-2-(1,1-dioxo-2,3,6,7-tetrahydro-1H-1ꢀ6,2-thiazepin-2-
yl) acetamide (57)
7 For selected examples of RCM on the solid-phase: (a) S. J. Miller,
H. E. Blackwell and R. H. Grubbs, J. Am. Chem. Soc., 1996,
118, 9606; (b) M. Schuster, J. Pernerstorfer and S. Blechert, Angew.
Chem., Int. Ed. Engl., 1996, 35, 1979; (c) J. Pernerstorfer,
M. Schuster and S. Blechert, Synthesis, 1999, 138; (d ) K. Koide,
J. M. Finkelstein, Z. Ball and G. L. Verdine, J. Am. Chem. Soc.,
2001, 123, 398.
Following the general procedure for RCM cyclisation–cleavage
to give 24, using resin 56 and catalyst 2 (5.0 mol%) gave 57 as
a colourless oil (92%). νmax (neat)/cmϪ1 3251 (br, NH), 2933,
1650 (s, CO), 1325 (s, SO2), 1158 (s), 1138 (s, SO2); H NMR
(300 MHz, CDCl3) 7.34–7.21 (m, 5H, C6H5), 6.93 (br, 1H, NH),
1
6.09 (dt, 1H, J = 11.0, 6.6 Hz, CH᎐CH), 5.94 (dt, 1H, J = 11.0,
᎐
8 G. A. Patani and E. J. LaVoie, Chem. Rev., 1996, 96, 3147.
9 For some selected examples of sulfonamide replacements: HIV
protease inhibitors: (a) M. L. Vazquez, M. L. Bryant, M. Clare,
G. A. DeCrescenzo, E. M. Doherty, J. N. Freskos, D. P. Getman,
K. A. Houseman, J. A. Julien, G. P. Kocan, R. A. Mueller,
H.-S. Shieh, W. C. Stallings, R. A. Stegeman and J. J. Talley, J. Med.
Chem., 1995, 38, 581; (b) Peptidomimetics: J. Gante, Angew. Chem.,
Int. Ed., 1994, 33, 1699; (c) W. J. Moree, G. A. van der Marel
and R. J. Liskamp, J. Org. Chem., 1995, 60, 5157; (d ) M. Gude,
U. Piarulli, D. Potenza, B. Salom and C. Gennari, Tetrahedron Lett.,
1996, 37, 8589; (e) C. Gennari, C. Longari, S. Ressel, B. Salom,
U. Piarulli, S. Ceccarelli and A. Mielgo, Eur. J. Org. Chem., 1998,
2437; ( f ) D. B. A. de Bont, K. M. Sliedregt-Bol, L. J. F. Hofmeyer
and R. M. J. Liskamp, Bioorg. Med. Chem., 1999, 7, 1043; (g) J. van
Ameijde and R. M. J. Liskamp, Tetrahedron Lett., 2000, 41, 1103;
(h) Leukocyte adhesion inhibitors: K. G. Carson, C. F. Schwender,
H. N. Shroff, N. A. Cochran, D. L. Gallant and M. J. Briskin,
Bioorg. Med. Chem. Lett., 1997, 7, 711.
5.9 Hz, CH᎐CH ), 4.43 (d, 2H, J = 5.9 Hz, NHCH Ph), 3.73 (d,
᎐
2
2H, J = 5.9 Hz, CH2N), 3.68 (s, 2H, NCH2CONH), 3.03–2.98
(m, 2H, CH2SO2), 2.54–2.43 (m, 2H, CH2CH2SO2); 13C NMR
(75 MHz, CDCl3) 171.8 (CO), 137.8 (C), 134.4 (CH), 129.8
(CH), 128.5 (CH), 127.8 (CH), 51.0 (CH2), 49.5 (CH2), 44.9
(CH2), 43.6 (CH2), 22.1 (CH2CH2SO2); m/z (ES) 295 ([M ϩ
H]ϩ); C14H18N2O3S requires C: 57.12; H: 6.16; N: 9.51; found C:
56.92; H: 6.28; N: 9.19%.
Acknowledgements
The authors thank The Royal Society for a University Research
Fellowship (R.C.D.B) and Merck Sharp & Dohme for funding
a studentship (J.-D.M).
10 For examples of biologically active cyclic sulfonamides:
Cyclooxygenase inhibitors: (a) E. S. Lazer, C. K. Miao, C. L. Cywin,
R. Sorcek, H.-C. Wong, Z. Meng, I. Potocki, M. Hoermann,
R. J. Snow, M. A. Tschantz, T. A. Kelly, D. W. McNeill, S. J. Coutts,
L. Churchill, A. G. Graham, E. David, P. M. Grob, W. Engel,
H. Meier and G. Trummlitz, J. Med. Chem., 1997, 40, 980; (b)
HIV protease inhibitors: P. Y. Lam, P. K. Jadhav, C. J. Eyermann,
C. N. Hodge, G. V. De Lucca and J. D. Rodgers, USP, 5610294/
1997; (c) bile acid uptake inhibitors: A. L. Handlon, G. L. Hodgson,
C. E. Hyman and E. Clifton, WO 9838182/1998; (d ) herbicides:
K. Makino, T. Sato, K. Morimoto, S. Akiyama, H. Suzuki,
K. Suzuki, T. Nawamaki and S. Watanabe, EP 342456/1989.
11 For the first synthesis of 6- and 7-membered sultams in solution
using a RCM approach see: (a) P. R. Hanson, D. A. Probst,
R. E. Robinson and M. Yau, Tetrahedron Lett., 1999, 40, 4761;
(b) for subsequent RCM approaches to 7-membered sultams see
reference 5h and D. D. Long and A. P. Termin, Tetrahedron Lett.,
2000, 41, 6743.
References
1 (a) P. Seneci and S. Miertus, Mol. Divers., 2000, 5, 75; (b) R. E.
Dolle, J. Comb. Chem., 2000, 2, 383; (c) N. K. Terrett, M. Gardner,
D. W. Gordon, R. J. Kobylecki and J. Steele, Tetrahedron, 1995,
51, 8135; (d ) L. A. Thompson and J. A. Ellman, Chem. Rev., 1996,
96, 555; (e) S. Booth, P. H. H. Hermkens, H. C. J. Ottenheijm
and D. C. Rees, Tetrahedron, 1998, 54, 15385; ( f ) A. R. Brown,
P. H. H. Hermkens, H. C. J. Ottenheijm and D. C. Rees, Synlett,
1998, 817; (g) R. C. D. Brown, J. Chem. Soc., Perkin Trans. 1,
1998, 3293; (h) J. W. Corbett, Org. Prep. Proced. Int., 1998, 30, 489;
(i) J. S. Fruchtel and G. Jung, Angew. Chem., Int. Ed. Engl., 1996, 35,
17; (j) P. H. H. Hermkens, H. C. J. Ottenheijm and D. Rees,
Tetrahedron, 1996, 52, 4527; (k) P. H. H. Hermkens, H. C. J.
Ottenheijm and D. C. Rees, Tetrahedron, 1997, 53, 5643;
(l ) B. A. Lorsbach and M. J. Kurth, Chem. Rev., 1999, 99, 1549;
(m) A. Nefzi, J. M. Ostresh and R. A. Houghten, Chem. Rev., 1997,
97, 449.
2 (a) S. Brase and S. Dahmen, Chem. Eur. J., 2000, 6, 1899;
(b) F. Guillier, D. Orain and M. Bradley, Chem. Rev., 2000, 100,
12 In this work 2-carboxyethyl polystyrene (21) (1.0 mmol gϪ1 of
CO2H) was prepared from Merrifield resin (2.5 mmol gϪ1 Cl) using
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 8 3 5 – 8 4 4
843

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the method reported previously. Loading of 21 was estimated
by DIC coupling with cinnamyl alcohol followed by cleavage
(TMSOK, MeOH, CH2Cl2) and GC quantification. (a)
R. C. D. Brown and M. Fisher, Chem. Commun., 1999, 1547;
(b) R. C. D. Brown, M. L. Fisher and L. J. Brown, Org. Biomol.
Chem., 2003, 1, 2699.
20 The loadings of resins 36 and 37 were estimated as 0.88 mmol of
S gϪ1 and 1.05 mmol of S gϪ1 respectively by combustion analysis.
The values obtained were lower than the theoretical loadings of
0.83 mmol S gϪ1 (36) and 0.68 mmol S gϪ1 (37) based on 34 and 35.
21 The fact that some yields obtained were so high probably reflects an
under estimation of the loading of the hydroxyl resins 34 and 35,
although the RCM reaction must still be efficient process based on
the loadings obtained for 36 and 37.
13 (a) P. Deslongchamps, S. Lamothe and H. Lin, Can. J. Chem., 1987,
65, 1298; (b) Y.-C. Xu, A. L. Roughton, R. Plante, S. Goldstein and
P. Deslongchamps, Can. J. Chem., 1993, 71, 1152.
22 S. M. Dankwardt, D. B. Smith, J. A. Porco and C. H. Nguyen,
Synlett, 1997, 854.
14 A. P. Krapcho, Synthesis, 1982, 805.
15 J. F. King and R. D. K. Harding, J. Am. Chem. Soc., 1976, 98,
23 K. A. Beaver, A. C. Siegmund and K. L. Spear, Tetrahedron Lett.,
1996, 37, 1145.
3312.
16 M. A. Belous and I. Y. Postowskii, Zh. Obshch. Khim., 1950, 20,
1701.
24 For some references describing methods to facilitate the removal
of ruthenium impurities from metathesis products see: (a)
H. D. Maynard and R. H. Grubbs, Tetrahedron Lett., 1999, 40,
4137; (b) L. A. Paquette, J. D. Schloss, I. Efremov, F. Fabris,
F. Gallou, J. Méndez-Andino and J. Yang, Org. Lett., 2000, 2, 1259;
(c) Y. M. Ahn, K. Yang and G. I. Georg, Org. Lett., 2001, 3, 1411.
25 Examples of resin-bound metal alkylidene complexes that catalyse
olefin metathesis have been reported previously: (a) S. T. Nguyen
and R. H. Grubbs, J. Organomet. Chem., 1995, 497, 195; (b)
M. Ahmed, A. G. M. Barrett, D. C. Braddock, S. M. Cramp and
P. A. Procopiou, Tetrahedron Lett., 1999, 40, 8657; (c) M. Ahmed,
T. Arnauld, A. G. M. Barrett, D. C. Braddock and P. A. Procopiou,
Synlett, 2000, 1007.
17 T. Tsuri, N. Haga, T. Matsui, S Kamata, H. Kakushi and K. Uchida,
Chem. Pharm. Bull., 1992, 40, 75.
18 The loading of resin 22 was estimated to be 0.73 mmol of S gϪ1
by reductive cleavage of the alcohol and 0.72 mmol of S gϪ1 by
sulfur analysis, which compared well with the theoretical loading
of 0.76 mmol of S gϪ1. The loading of resin 23 was estimated to
be 1.10 mmol of S gϪ1 by reductive cleavage of the alcohol and
1.13 mmol of S gϪ1 by sulfur analysis (theoretical loading 1.24 mmol
of S gϪ1).
19 The loadings of resins 34 and 35 were estimated as 1.02 mmol OH
g
Ϫ1 and 0.97 mmol OH gϪ1 respectively, by coupling with cinnamoyl
chloride followed by cleavage (KOTMS, MeOH, CH2Cl2) and GC
analysis of the cleaved alcohol.
26 R. M. Williams, M. R. Sabol, H. Kim and A. Kwast, J. Am. Chem.
Soc., 1991, 113, 6621.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 8 3 5 – 8 4 4
844