Formation of medium-size bridged ring systems via ring-closing metathesis of 2,5-disubstituted-2,3-dihydro-1H-pyrroles

Article abstract of DOI:10.1039/a908272g

A series of 2,5-disubstituted-2,3-dihydro-1H-pyrroles were prepared via diastereoselective alkylations of sulfone 10. Ring-closing metathesis (RCM), using Grubbs catalyst, provided bridged ring systems with newly formed 9-to 12-membered rings in moderate to good yields. The 9-membered ring was formed as a single Z-isomer whereas the 10- to 12-membered rings were formed as mixtures of E- and Z-isomers. It was shown that the minor diastereomer obtained from the alkylation product 11c failed to undergo RCM, illustrating the crucial aspect of substrate conformation.

Full text of DOI:10.1039/a908272g

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Formation of medium-size bridged ring systems via ring-closing
metathesis of 2,5-disubstituted-2,3-dihydro-1H-pyrroles
Samantha J. Bamford, Kees Goubitz, Hester L. van Lingen, Tim Luker, Henk Schenk and
Henk Hiemstra*
1
Laboratories of Organic Chemistry and Crystallography, Institute of Molecular Chemistry,
University of Amsterdam, Nieuwe Achtergracht 129, 1018 WS Amsterdam, The Netherlands
Received (in Cambridge, UK) 15th October 1999, Accepted 18th November 1999
A series of 2,5-disubstituted-2,3-dihydro-1H-pyrroles were prepared via diastereoselective alkylations of sulfone
10. Ring-closing metathesis (RCM), using Grubbs’ catalyst, provided bridged ring systems with newly formed 9- to
12-membered rings in moderate to good yields. The 9-membered ring was formed as a single Z-isomer whereas the
10- to 12-membered rings were formed as mixtures of E- and Z-isomers. It was shown that the minor diastereomer
obtained from the alkylation product 11c failed to undergo RCM, illustrating the crucial aspect of substrate
conformation.
Introduction
In conjunction with our studies towards the total synthesis of
roseophilin 1 we set out to investigate the formation of
medium-size bridged rings.1 Due to its interesting structural
Scheme 1 Reagents and conditions: a) allylmagnesium bromide, Et2O,
0 ЊC, 3 h; NaBH3CN, 6 M HCl, rt, 24 h, 79%; b) nBuLi, THF, Ϫ78 ЊC,
2 h; TsCl, Ϫ78 ЊC to rt, 16 h, 68%; c) KHMDS, THF, Ϫ78 ЊC, 2 h;
Comins’ reagent, Ϫ78 ЊC to 0 ЊC, 1 h; d) Pd2dba3, AsPh3, CO, MeOH,
Et3N, THF, 60 ЊC, 19 h, 68% over 2 steps; e) DIBAL-H, THF, Ϫ78 ЊC
to 0 ЊC, 1.5 h, 96%; f) PPh3, imidazole, I2, Et2O, MeCN, 0 ЊC, 1 h, 88%;
g) PhSO2Na, DMF, 50 ЊC, 3 h, 81%.
and biological properties roseophilin is currently a target for
many synthetic groups.2 Roseophilin possesses a core bridged
tricyclic structure and our aim was to develop an efficient
methodology for the construction of such systems. RCM now
offers one of the most effective ways of constructing medium-
size rings, but as yet we are unable to accurately predict the
suitability of a substrate for RCM and relatively little is known
about the construction of bridged ring systems.3 Studies con-
cerning the formation of bridged ring systems are thus of great
value in assimilating a store of knowledge that will aid our
understanding of the RCM process. Initially we have chosen to
explore the formation of model bridged bicyclic rings. The sub-
strates for the RCM reactions are diastereomerically enriched
2,5-disubstituted-2,3-dihydro-1H-pyrroles, possessing an allyl
substituent at the 5-position and a sulfone substituted alkyl
chain with a terminal double bond at the 2-position. Herein we
describe the synthesis of [6.2.1], [7.2.1], [8.2.1] and [9.2.1]
bridged bicycles 2a–d using RCM as the key ring forming
reaction.
A one-pot procedure was used for introduction of the allyl
group and reduction to form the allylated lactam 4.4 Grignard
addition occurred at only one of the carbonyl groups and after
acidification the intermediate iminium ion was reduced in situ
with NaBH3CN. Recently we have reported the value of enol
triflate chemistry for the functionalisation of N-protected
lactams and we wished to utilise this methodology for incorpor-
ating the second substituent onto the 5-membered ring.5 We
found that palladium-catalysed methoxycarbonylation of enol
triflate 6 readily provided multigram quantities of ester 7. When
this reaction was performed at room temperature in DMF up to
60% of lactam 5 was also recovered and this caused problems
due to the difficult chromatographic separation of ester 7 and
lactam 5. However, in THF at 60 ЊC no lactam was recovered
and ester 7 was obtained in 68% yield over 2 steps. Standard
procedures then gave iodide 9, which sometimes contained up
to 20% of the regioisomer obtained via an SN2Ј process. How-
ever, during formation of the sulfone equilibration to the
desired thermodynamically favoured regioisomer was observed.
Sulfone 10 was then alkylated with four alkenyl iodides
ranging from 1-iodobut-3-ene to 1-iodohept-6-ene to provide
Results and discussion
The synthesis of sulfone 10, starting from succinimide, is illus-
trated in Scheme 1. In order to explore the scope of the RCM
reaction in our system we required a route to the RCM pre-
cursors that allowed a series of compounds to be readily
accessed.
J. Chem. Soc., Perkin Trans. 1, 2000, 345–351
This journal is © The Royal Society of Chemistry 2000
345

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Table 1 Yields and product ratios of reactions a–c in Scheme 2a
Reaction a yield (%)
Reaction b
yield (%)
(Z:E ratio)
(crude diastereomeric ratio)b
(ratio submitted to reaction b)
Reaction c
yield (%)
n
1
2
3
4
90 (95:5) (95:5)
99 (93:7) (100:0)
65 (87:13) (100:0)
82 (79:21) (79:21)
48 (0:100)
81 (21:79)
84 (31:69)
77 (40:60)
100
100
100
89
a All yields are isolated yields; see Scheme 2 for reactions a, b and c.
b All ratios determined from crude 400 MHz 1H NMR spectra.
Fig. 1 Model illustrating the stereochemical outcome of the alkyl-
ation reactions of sulfone 10.
Fig. 2 X-Ray crystallographic structure of 2b.
carried out using 20 mol% Grubbs’ catalyst in dichloromethane
at 40 ЊC for 16 h, at a concentration of 1 mM. Cyclisation to the
bridged ring system was successful in each case, with newly
formed ring sizes of 9- to 12-membered rings (Scheme 2, Table
1). The bridged ring containing a 9-membered ring (12a) was
formed as a single Z-isomer, presumably due to the high level of
ring strain that would be involved in forming the E-isomer.
Formation of product 12a proceeded in a significantly lower
yield than the remaining RCM reactions. No other products,
including starting material or dimeric species were isolated
from the reaction, thus we hypothesise that polymerisation
reactions occurred. The increased strain energy present in the
9-membered ring makes the RCM process less efficient and this
result suggests that we are approaching the lower limit of the
newly formed ring size that can be formed in such systems.
The bridged rings 12b–d were all formed in high yield as
mixtures of E- and Z-isomers, with increasing proportions of
the E-isomer as the ring size increased. NOE experiments were
performed to determine the ratio of E- and Z-isomers as the
Scheme 2 Reagents and conditions: a) nBuLi, THF, HMPA, Ϫ78 ЊC,
1 h; I(CH2)nCH2CH᎐CH2, Ϫ78 ЊC to 0 ЊC, 1.5 h; b) (Cy3P)2Cl2Ru᎐
᎐
᎐
CHPh, DCM, 40 ЊC, 16 h, 1 mM; c) PtO2, H2, EtOAc, rt, 16 h. Yields
and product ratios given in Table 1.
the metathesis precursors 11a–d (Scheme 2, Table 1). In all cases
a high yield and a high level of diastereoselectivity was observed.
Only partial separation of the diastereomers was possible by
careful column chromatography. However, a proportion of the
major isomer could often be obtained diastereomerically pure.
The major and minor diastereomer obtained from the alkyl-
ation reactions can be differentiated by their characteristic
chemical shift of the C(4)-hydrogen (Scheme 2) in the 1H NMR
spectra and from these results we can confidently predict that
the major diastereomer of products 11a–d all possess the same
relative configuration at the two stereogenic centres. The stereo-
chemistry of the major product was eventually determined after
RCM and hydrogenation by using X-ray crystallography (vide
infra).
1
alkene signals in the 400 MHz H NMR spectra were either
unresolved or overlapping.
Finally, hydrogenation of the RCM products in the presence
of platinum() oxide resulted in the selective reduction of the
disubstituted double bond to give the products 2a–d as single
diastereomers (Scheme 2, Table 1).
A ‘chiral relay effect’, whereby the non-stereogenic N-tosyl
group acts to relay and amplify the chirality of the allyl ring
substituent, can be invoked to explain the diastereoselectivity
of the alkylation reaction (Fig. 1).6 The tosyl group is forced,
due to steric factors, into a pseudo-trans orientation relative to
the allyl substituent of the ring. (More precisely, the endocyclic
double bond, the nitrogen, and the sulfur of the tosyl group are
approximately planar, whilst the sulfur–oxygen bonds of the
tosyl group point upwards and the aryl group points down-
ward.) The sulfone group adopts an orientation so as to avoid
steric interactions with the tosyl group, and the electrophile
then approaches the planar delocalised anion from the opposite
face of the ring to that in which the tosyl group lies.
The X-ray crystallographic structure of compound 2b is
shown in Fig. 2. This shows the relative stereochemistry of the
two stereogenic centres that is determined during the alkylation
reaction. The observed stereochemistry is that which would be
predicted if the ‘chiral relay effect’ was operating in the alkyl-
ation reaction.
In all of the RCM reactions performed where there was a
mixture of diastereomers present in the starting material no
cyclised product from the minor alkylation diastereomer was
isolated. In order to confidently ascertain the fate of the minor
alkylation products in the RCM reaction we set out to obtain
one of these compounds as the major component. Thus, an
experiment was performed whereby the alkylation product 11c
was deprotonated with n-butyllithium in THF and HMPA at
Ϫ78 ЊC, and after one hour was quenched rapidly with a large
excess of methanol. This gave a 69:31 mixture of diastereo-
The four RCM precursors 11a–d were then treated with
Grubbs’ catalyst, the ratio of diastereomers present in the RCM
substrates is indicated in Table 1. The RCM reactions were all
346
J. Chem. Soc., Perkin Trans. 1, 2000, 345–351

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mers, in favour of that previously obtained as the major
diastereomer from the alkylation reaction. However, careful
flash column chromatography allowed the attainment of a
77:23 mixture in favour of the previous minor diastereomer ꢀ-
11c (Scheme 3). Upon subjection of this mixture to the stand-
Scheme 3
Scheme 4
ard RCM conditions ꢀ-11c was recovered, with no RCM prod-
ucts, whilst ꢁ-11c expectedly underwent RCM and gave 12c. We
hypothesise that, in the case of the unreactive diastereomer, the
sulfone substituent serves to force the terminal double bonds
out of proximity and no RCM can take place under the reac-
tion conditions employed, whilst the major alkylation diaster-
eomer has a low energy conformation in which the double
bonds participating in the metathesis reaction are relatively
close in space.
We anticipate that the lowest energy conformation of the
major isomer of the alkylation products 11a–d will be as shown
in Scheme 3 for ꢁ-11c, whereby one of the groups of the stereo-
genic centre lies perpendicular to the plane of the ring, thus
minimising allylic strain, and the smallest substituent (H) is
placed in proximity to the N-tosyl group. In the case of the
minor diastereomer obtained from the alkylation reactions a
conformation suitable for RCM, one in which the terminal
double bonds are placed in close proximity, would also place
the sulfone and the tosyl groups into close proximity. It seems
the high energy of such a reaction conformation inhibits
RCM.
A related example of this phenomenon was reported by
Fuchs and co-workers during their studies on the synthesis of
roseophilin (Scheme 4).2 Only one of the two diastereomers
of 13 underwent RCM upon treatment with Grubbs’ catalyst.
They tentatively assigned the stereochemistry of the reactive
diastereomer ꢁ-13 as shown. ꢁ-13 is able to adopt a low energy
conformation in which the terminal double bonds are close
in space. Conversely, in ꢀ-13 steric interactions between the
carbonyl oxygen and the OTIPS groups occur in the con-
formation in which the terminal double bonds are proximal.
These results illustrate the same concept as that used to explain
our results, that is, one of the two diastereomers of a RCM
substrate possesses a low energy conformation in which the
double bonds participating in the reaction are close in space,
whereas the strain involved in placing the reacting centres
together in the alternative diastereomer is sufficiently great to
inhibit RCM.
Experimental
General methods and materials
Unless otherwise noted materials were obtained from com-
mercial suppliers and used without further purification. Tetra-
hydrofuran and dichloromethane were freshly distilled from
sodium–benzophenone and calcium hydride, respectively.
Petroleum ether (bp 60–80 ЊC) was distilled before use. Triethyl-
amine was distilled from calcium hydride and stored over
potassium hydroxide pellets under an atmosphere of nitrogen.
2-[N,N-Bis(trifluoromethylsulfonyl)amino]-5-chloropyridine
was Kugelrohr distilled before use and stored at 0 ЊC under an
atmosphere of nitrogen. All reactions were stirred under an
inert atmosphere of dry nitrogen unless otherwise indicated.
During workup, where drying of the organic solutions is indi-
cated, Na2SO4 was used with subsequent filtration in all
cases. Column chromatography was performed by using Acros
Chimica silica gel (0.030–0.075 mm).
Infrared spectra were recorded from CHCl3 solutions using
a Bruker IFS 28 spectrophotometer and the frequency
absorptions are reported in units of cmϪ1. Nuclear magnetic
resonance (NMR) spectra were obtained using a Bruker
ARX 400 (400 MHz) and measured in CDCl3 unless other-
wise indicated. Chemical shifts are reported in units of ppm
on the δ scale relative to an internal standard of residual
chloroform (7.27 ppm for H NMR and 77.0 for 13C NMR).
1
J values are in hertz. All diastereomeric ratios were obtained
1
from H NMR spectra. Carbon resonances were detected by
using attached proton test (ATP). Mass spectra and accurate
mass determinations were determined using the electron-
impact method unless otherwise indicated; with data reported
as m/z (relative intensity). Measurements were performed on
a JEOL JMS SX/SX102A four-sector mass spectrometer,
coupled to a JEOL MS-MP7000 data system. Elemental anal-
yses were performed by Dornis u. Kolbe Mikroanalytisches
Laboratorium, Mülheim a.d. Ruhr, Germany. Melting points
are uncorrected.
In summary, we have synthesised a series of bicyclic bridged
compounds possessing [6.2.1], [7.2.1] [8.2.1] and [9.2.1] ring
structures, using RCM to form the 9- to 12-membered rings. We
have also demonstrated the importance of substrate conform-
ation in the RCM reaction.
Crystal structure determination of 2b
A crystal with dimensions 0.25 × 0.40 × 0.45 mm approxi-
mately was used for data collection, recrystallised from ethyl
acetate.
J. Chem. Soc., Perkin Trans. 1, 2000, 345–351
347

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¯
Crystal data for 2b. C24H29NO4S2, MR = 459.6, triclinic, P1,
was extracted with dichloromethane (2 × 60 ml). The combined
a = 8.2243(5), b = 10.4546(8), c = 14.535(3) Å, α = 80.443(7),
β = 84.476(8), γ = 70.578(5)Њ, V = 1161.1(3)Å3, Z = 2, Dx = 1.315
g cmϪ3, λ(Cu-Kα) = 1.5418 Å, µ(Cu-Kα) = 23.3 cmϪ1, F(000) =
488, room temperature, final R = 0.069 for 3749 observed reflec-
tions. CCDC reference number 207/387. See http://www.rsc.org/
suppdata/p1/a9/a908272g for crystallographic files in .cif
format.
organic layers were dried and most of the solvent was removed
in vacuo. The remaining solvent was removed using an oil pump
with no water bath so that the evaporating solvent cooled the
crude sample maintaining the internal temperature at 0–10 ЊC.
The triflate was dissolved in benzene (20 ml) and filtered
through cotton-wool (to remove the excess of Comins’ reagent)
and the solvent was removed as described above. The cold
triflate was used without further purification. On one occa-
sion column chromatography (1:5→1:1 dichloromethane–
petroleum ether) afforded the pure triflate 6 in 85% yield as a
colourless oil: 1H NMR (400 MHz, C6D6) δ 7.67 (2H, d, J 8.3,
Ar-H), 6.69 (2H, d, J 8.3, Ar-H), 5.72 (1H, ddt, J 17.2, 10.2, 7.0,
5-Allylpyrrolidin-2-one (4)7
To a solution of succinimide (10.0 g, 101 mmol) in tetrahydro-
furan (300 ml) at 0 ЊC was added dropwise allylmagnesium
bromide (303 ml of a 1.0 M solution in diethyl ether, 303 mmol,
3.0 equiv.) and the mixture was stirred for 3 h. Sodium
cyanoborohydride (7.60 g, 121 mmol, 1.2 equiv.) was added and
then a solution of hydrochloric acid (6 M) until pH 2–3 was
reached. After addition of more sodium cyanoborohydride
(3.50 g, 55.7 mmol, 0.55 equiv.) the thick white solution was
mechanically stirred for 24 h. The reaction mixture was neutral-
ised with an aqueous solution of potassium hydroxide (2 M)
and the aqueous layer was extracted with dichloromethane
(6 × 200 ml). The combined organic layers were dried and the
solvent was removed in vacuo. Column chromatography (ethyl
acetate→1:1 ethyl acetate–acetone) afforded lactam 4 (10.0 g,
79%) as a colourless oil: 1H NMR (400 MHz) δ 6.10–5.94 (1H,
CH CH᎐CH ), 5.03–4.93 (2H, m, CH CH᎐CH ), 4.42 (1H, dd,
᎐
᎐
2
2
2
2
J 3.1, 2.2, 3-H), 3.98 (1H, m, 5-H), 2.33 (1H, m, CH CH᎐CH ),
᎐
2
2
2.17 (1H, m, CH CH᎐CH ), 1.83 (3H, s, CH ), 1.56 (1H, m,
᎐
2
2
3
4-H), 1.32 (1H, m, 4-H).
5-Allyl-1-(4-tolylsulfonyl)-4,5-dihydro-1H-pyrrole-2-carboxylic
acid methyl ester (7)
Tris(dibenzylideneacetone)dipalladium(0) (48 mg, 52 µmol,
0.05 equiv.) and triphenylarsine (77 mg, 0.25 mmol, 0.23 equiv.)
were added to a solution of crude triflate 6 (ca. 0.45 g, 1.1
mmol) in tetrahydrofuran (6 ml) and the mixture was flushed
with carbon monoxide for 10 min. Triethylamine (1.8 ml, 12.9
mmol, 12 equiv.) and methanol (2.1 ml, 51.8 mmol, 47 equiv.)
were added and the solution was stirred under carbon mon-
oxide and heated at 60 ЊC for 19 h. After the solution was
flushed with air, ethyl acetate (15 ml) and water (10 ml) were
added and the organic layer was separated. The aqueous layer
was extraced with ethyl acetate (2 × 15 ml), the combined
organic layers were washed with brine (2 × 15 ml) and dried,
and the solvent was removed in vacuo. Column chromatography
(5:2 ethyl acetate–petroleum ether) afforded ester 7 (240 mg,
68% over 2 steps) as a colourless oil: νmax/cmϪ1 2952, 1738, 1641,
br s, NH), 5.80–5.69 (1H, m, CH CH᎐CH ), 5.15–5.11 (2H, m,
᎐
2
2
CH CH᎐CH ), 3.75–3.68 (1H, m, 5-H), 2.36–2.16 (4H, m, 3-H ,
᎐
2
2
2
CH CH᎐CH ), 1.80–1.68 (2H, m, 4-H ).
᎐
2
2
2
5-Allyl-1-(4-tolylsulfonyl)pyrrolidin-2-one (5)
To a solution of lactam 4 (5.00 g, 40.0 mmol) in tetrahydro-
furan (250 ml) at Ϫ78 ЊC was added dropwise nBuLi (31.0 ml
of a 1.6 M solution in hexanes, 49.6 mmol, 1.2 equiv.) and the
solution was stirred for 2 h. A solution of toluene-p-sulfonyl
chloride (9.66 g, 50.6 mmol, 1.3 equiv.) in the minimum amount
of tetrahydrofuran was added dropwise and the reaction mix-
ture was warmed to room temperature overnight. A saturated
solution of ammonium chloride (40 ml) was added and the
aqueous layer was extracted with diethyl ether (4 × 200 ml).
The combined organic layers were dried and the solvent was
removed in vacuo. Column chromatography (2:3 ethyl actetate–
petroleum ether) afforded N-tosyllactam 5 (7.58 g, 68%) as a
white solid: mp 102–103 ЊC (from ethyl acetate); νmax/cmϪ1 2961,
1
1598, 1357, 1166; H NMR (400 MHz) δ 7.73 (2H, d, J 8.2,
Ar-H), 7.30 (2H, d, J 8.2, Ar-H), 6.05 (1H, dd, J 3.3, 2.9, 3-H),
5.78–5.68 (1H, m, CH CH᎐CH ), 5.07–5.04 (2H, m, CH CH᎐
᎐
᎐
2
2
2
CH2), 4.19–4.13 (1H, m, 5-H), 3.86 (3H, s, OCH3), 2.42 (3H, s,
CH ), 2.38–2.24 (2H, m, CH CH᎐CH ), 2.15–1.96 (2H, m,
᎐
3
2
2
4-H); 13C NMR (100 MHz) δ 162.5 (CO2CH3), 144.0, 136.5,
133.9, 129.4, 127.9 (2) (Ar-C), 132.7 (CH CH᎐CH ), 126.8 (3),
᎐
2
2
118.4 (CH CH᎐CH ), 61.8 (5), 52.3 (OCH ), 40.0 (CH CH᎐
᎐
᎐
2
2
3
2
CH2), 33.3 (4), 21.5 (CH3); m/z 321 (Mϩ, 11%), 280 (33), 91
1
(100) (Found Mϩ: 321.1037. Calc. for C16H19NO4S: 321.1035).
1732, 1597, 1358, 1168; H NMR (400 MHz) δ 7.92 (2H, d,
J 8.2, Ar-H), 7.29 (2H, d, J 8.2, Ar-H), 5.71–5.60 (1H, m,
CH CH᎐CH ), 5.11–5.07 (2H, m, CH CH᎐CH ), 4.45–4.41
᎐
᎐
2
2
2
2
[5-Allyl-1-(4-tolylsulfonyl)-4,5-dihydro-1H-pyrrol-2-yl]-
methanol (8)
(1H, m, 5-H), 2.67–2.62 (1H, m, CH CH᎐CH ), 2.52–2.43 (2H,
᎐
2
2
m, 3-H, CH CH᎐CH ), 2.39 (3H, s, CH ), 2.30–2.23 (1H, m,
᎐
2
2
3
3-H), 2.16–2.06 (1H, m, 4-H), 1.90–1.87 (1H, m, 4-H); 13C
NMR (100 MHz) δ 173.5 (2), 144.9, 135.7, 129.4, 128.2 (Ar-C),
To a solution of ester 7 (636 mg, 1.98 mmol) in tetrahydrofuran
(6 ml) at Ϫ78 ЊC was added diisobutylaluminum hydride (4.7 ml
of a 1.5 M solution in toluene, 7.05 mmol, 3.5 equiv.) and the
solution was warmed to 0 ЊC over 90 min. The reaction was
carefully quenched with a saturated solution of potassium
sodium tartrate. Water (250 ml) was added and the solution was
extracted with ethyl acetate (4 × 80 ml). The combined organic
layers were filtered through Celite, dried, and the solvent was
removed in vacuo to afford allylic alcohol 8 (565 mg, 96%) in
virtually pure form as a yellow oil. On one occasion column
chromatography (2:1 ethyl acetate–petroleum ether) afforded
the pure alcohol 8 as a colourless oil: νmax/cmϪ1 3532 (br), 2927,
132.2 (CH CH᎐CH ), 119.4 (CH CH᎐CH ), 59.3 (5), 38.9,
᎐
᎐
2
2
2
2
30.6, 22.8 (3, 4, CH CH᎐CH ), 21.5 (CH ); m/z 280 (Mϩ, 40%),
᎐
2
2
3
240 (100), 174 (100), 91 (100) (Found: C, 60.2; H, 6.2; N, 5.1.
Calc. for C14H17NO3S: C, 60.2; H, 6.1; N, 5.0%).
Trifluoromethanesulfonic acid 5-allyl-1-(4-tolylsulfonyl)-4,5-
dihydro-1H-pyrrol-2-yl ester (6)
To a solution of potassium bis(trimethylsilyl)amide (23.0 ml of
a 0.5 M solution in toluene, 11.5 mmol, 1.4 equiv.) in tetra-
hydrofuran (45 ml) at Ϫ78 ЊC was added lactam 5 (2.23 g, 7.99
mmol) in tetrahydrofuran (20 ml) and the pale yellow solution
was stirred for 2 h. A solution of 2-[N,N-bis(trifluoromethyl-
sulfonyl)amino]-5-chloropyridine (3.69 g, 9.39 mmol, 1.2
equiv.) in tetrahydrofuran (10 ml) was added in one portion.
The solution was stirred for 75 min at Ϫ78 ЊC and then warmed
to 0 ЊC. A saturated solution of ammonium chloride (30 ml),
followed by dichloromethane (75 ml) and water (30 ml) were
added, and the organic layer was separated. The aqueous layer
1
1597, 1346, 1162; H NMR (400 MHz, C6D6) δ 7.76 (2H, d,
J 8.2, Ar-H), 6.79 (2H, d, J 8.2, Ar-H), 5.84–5.75 (1H, m,
CH CH᎐CH ), 5.06–5.01 (2H, m, CH CH᎐CH ), 4.80 (1H, s,
᎐
᎐
2
2
2
2
3-H), 4.51 (1H, d, J 14.3, CH2OH), 4.42 (1H, d, J 14.3, CH2-
OH), 4.08–4.02 (1H, m, 5-H), 2.50–2.38 (2H, m, CH CH᎐CH ),
᎐
2
2
1.91 (3H, s, CH3), 1.89–1.82 (1H, m, 4-H), 1.64 (1H, m, 4-H);
13C NMR (100 MHz, C6D6) δ 144.2, 144.1, 130.4, 128.3 (Ar-C),
134.3 (CH CH᎐CH ), 128.9 (2), 118.7 (CH CH᎐CH ), 114.0
᎐
᎐
2
2
2
2
(3), 62.8 (5), 60.3 (CH OH), 41.8 (CH CH᎐CH ), 33.1 (4), 21.8
᎐
2
2
2
348
J. Chem. Soc., Perkin Trans. 1, 2000, 345–351

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(CH3); m/z 293 (Mϩ, 28%), 252 (90), 222 (100), 91(100), 80 (91)
iodobut-1-ene (52 µl, >290 µmol, >1.2 equiv.) afforded 11a (102
(Found Mϩ: 293.1083. Calc. for C15H19NO3S: 293.1086).
mg, 90%) as a white solid and as a 95:5 mixture of diastereo-
mers: νmax/cmϪ1 3072, 2952, 1641, 1597, 1350, 1308, 1168, 1151;
1H NMR (400 MHz, C6D6) major diastereomer (2S*, 1ЈS*)
δ 8.01 (2H, d, J 7.5, Ar-H), 7.74 (2H, d, J 8.3, Ar-H), 7.70 (1H, t,
J 7.5, Ar-H), 7.60 (2H, t, J 7.5, Ar-H), 7.23 (2H, d, J 8.3, Ar-H),
2-Allyl-5-iodomethyl-1-(4-tolylsulfonyl)-2,3-dihydro-1H-pyrrole
(9)
To a solution of the alcohol 8 (1.40 g, 4.78 mmol) in diethyl
ether–acetonitrile (3:2, 22 ml) at 0 ЊC was added sequentially
triphenylphosphine (2.44 g, 9.31 mmol, 1.9 equiv.), imidazole
(700 mg, 10.3 mmol, 2.1 equiv.) and iodine (2.92 g, 11.5 mmol,
2.1 equiv.) and the solution was stirred for 1 h. Ethyl acetate
(250 ml) was added and the organic layer was sequentially
washed with an aqueous solution of sodium thiosulfate (5%,
150 ml), a saturated solution of copper sulfate (2 × 150 ml) and
brine (150 ml), and dried. After removal of the solvent in vacuo
column chromatography (1:5 ethyl acetate–petroleum ether)
5.92 (1H, m, 4-H), 5.79–5.71 (1H, m, 4Ј-H or CH CH᎐CH ),
᎐
2
2
5.70–5.61 (1H, m, 4Ј-H or CH CH᎐CH ), 5.10–5.08 (2H, m, 5Ј-
᎐
2
2
H or CH CH᎐CH ), 5.06–5.04 (1H, m, 1Ј-H), 5.00–4.95 (2H,
᎐
2
2
m, 5Ј-H or CH CH᎐CH ), 3.89–3.87 (1H, m, 2-H), 2.49–2.40
᎐
2
2
(1H, m, CH CH᎐CH ), 2.40 (3H, s, CH ), 2.36–1.91 (7H, m
᎐
2
2
3
CH2); characteristic peak of minor diastereomer (2S*, 1ЈR*)
δ 5.46 (1H, m, 4-H); 13C NMR (100 MHz, C6D6) δ 143.8, 138.6,
136.3, 136.3, 134.5, 129.5, 129.2, 128.7, 127.9 (Ar-C, 5), 133.7,
133.2 (4Ј, CH CH᎐CH ), 118.2 (5Ј or CH CH᎐CH ), 117.4 (4),
᎐
᎐
2
2
2
2
115.9 (5Ј or CH CH᎐ CH2), 62.0, 61.1 (2, 1Ј), 39.6
᎐
2
1
afforded iodide 9 (1.70 g, 88%) as a yellow oil: H NMR (400
MHz) δ 7.66 (2H, d, J 8.2, Ar-H), 7.29 (2H, d, J 8.2, Ar-H),
(CH CH᎐CH ), 32.7, 31.7, 29.9 (3, 2Ј, 3Ј), 21.5 (CH ); m/z
᎐
2
2
3
(FABϩ) 472 (MHϩ, 100%), 430 (35), 330 (67), 288 (70), 154
(92), 136 (80), 91 (75) (Found: C, 63.7; H, 6.2; N, 2.9; S, 13.7.
Calc. for C25H29NO4S2: C, 63.7; H, 6.2; N, 3.0; S, 13.6%).
5.92–5.82 (1H, m, CH CH᎐CH ), 5.49 (1H, s, 4-H), 5.13–5.09
᎐
2
2
(2H, m, CH CH᎐CH ), 4.61–4.58 (1H, m, 2-H), 4.20–4.11 (2H,
᎐
2
2
m, CH I), 2.42 (3H, s, CH ), 2.47–2.19 (2H, m, CH CH᎐CH ),
᎐
2
3
2
2
1.85–1.78 (2H, m, 3-H2); 13C NMR (100 MHz) δ 143.9, 134.7,
133.3, 129.7, 127.4 (Ar-C, CH CH᎐CH ), 141.0 (5), 118.3
2-Allyl-5-(1-phenylsulfonylhex-5-enyl)-1-(4-tolylsulfonyl)-2,3-
dihydro-1H-pyrrole (11b). According to general procedure A,
the alkylation of sulfone 10 (102 mg, 245 µmol) with 5-
iodopent-1-ene (72 µl, >370 µmol, >1.5 equiv.) afforded 11b
(118 mg, 99%) as a colourless oil and as a 93:7 mixture of
diastereomers: νmax/cmϪ1 3072, 2934, 1640, 1597, 1349, 1308,
᎐
2
2
(CH CH᎐CH ), 117.8 (4), 62.2 (2), 40.1, 32.6 (3, CH CH᎐CH ),
᎐
᎐
2
2
2
2
21.5 (CH3), Ϫ1.9 (CH2I).
2-Allyl-5-phenylsulfonylmethyl-1-(4-tolylsulfonyl)-2,3-dihydro-
1H-pyrrole (10)
1
1162, 1151; H NMR (400 MHz, C6D6) major diastereomer
(2S*, 1ЈS*) δ 8.00 (2H, d, J 7.5, Ar-H), 7.74 (2H, d, J 8.2,
Ar-H), 7.69 (1H, t, J 7.5, Ar-H), 7.59 (2H, t, J 7.5, Ar-H), 7.23
(2H, d, J 8.2, Ar-H), 5.89 (1H, m, 4-H), 5.80–5.68 (1H, m, 5Ј-H
To a solution of iodide 9 (200 mg, 496 µmol) in N,N-dimethyl-
formamide (4 ml) at 50 ЊC was added benzenesulfonic acid
sodium salt (163 mg, 993 µmol, 2.0 equiv.) and the solution was
stirred for 3 h. Ethyl acetate was added and the organic layer
was sequentially washed with water (3 × 20 ml), a saturated
solution of sodium bicarbonate (20 ml), brine (20 ml) and
dried. After removal of the solvent in vacuo column chroma-
tography (2:5 ethyl actetate–petroleum ether) afforded sulfone
10 (168 mg, 81%) as a white solid: mp 124.5 ЊC (from ethyl
acetate); νmax/cmϪ1 3019, 2976, 1599, 1350, 1322, 1166, 1046; 1H
NMR (400 MHz) δ 7.96 (2H, d, J 7.6, Ar-H), 7.65 (1H, t, J 7.5,
Ar-H), 7.56 (4H, m, Ar-H), 7.26 (2H, d, J 7.6, Ar-H), 5.66–5.56
or CH CH᎐CH ), 5.68–5.58 (1H, m, 5Ј-H or CH CH᎐CH ),
᎐
᎐
2
2
2
2
5.09–5.05 (2H, m, 6Ј-H or CH CH᎐CH ), 5.05–5.03 (1H, m, 1Ј-
᎐
2
2
H), 4.92–4.84 (2H, m, 6Ј-H or CH CH᎐CH ), 3.90–3.84 (1H,
᎐
2
2
m, 2-H), 2.48–2.40 (1H, m, CH CH᎐CH ), 2.39 (3H, s, CH ),
᎐
2
2
3
2.25–2.17 (1H, m, CH CH᎐CH ), 2.06–1.79 (6H, m, CH ),
᎐
2
2
2
1.69–1.58 (1H, m, 3Ј-H), 1.49–1.43 (1H, m, 3Ј-H); characteristic
peaks of minor diastereomer (2S*, 1ЈR*) δ 5.47 (1H, m, 4-H),
4.01–3.95 (1H, m, 2-H); 13C NMR (100 MHz, C6D6) δ 143.8,
138.7, 137.3, 136.3, 134.5, 133.6, 133.3, 129.5, 129.1, 128.8,
127.9 (Ar-C, 5Ј, 5, CH CH᎐CH ), 118.1 (6Ј or CH CH᎐CH ),
᎐
᎐
2
2
2
2
(2H, m, 4-H, CH CH᎐CH ), 5.05–4.98 (2H, m, CH CH᎐CH ),
᎐
᎐
2
2
2
2
117.3 (4), 115.2 (6Ј or CH CH᎐CH ), 62.5, 61.1 (2, 1Ј), 39.6
᎐
2
2
4.98 (1H, d, J 15.2, CH2SO2Ph), 4.08 (1H, d, J 15.2, CH2-
SO2Ph), 3.95–3.88 (1H, m, 2-H), 2.40 (3H, s, CH3), 2.22–2.15,
(CH CH᎐CH ), 32.9, 32.7, 31.5 (3, 2Ј, 4Ј), 25.0 (3Ј), 21.5 (CH );
᎐
2
2
3
m/z (FAB) 486 (MHϩ, 100%), 444, (63), 302 (55), 188 (53), 148
(60), 91 (70) (Found MHϩ: 486.1768. Calc. for C26H32NO4S2:
486.1773).
2.03–1.88 (4H, m, 3-H, CH CH᎐CH ); 13C NMR (100 MHz)
᎐
2
2
δ 144.1, 139.0, 133.9, 133.8, 130.7 129.7, 129.0, 128.5, 127.4
(Ar-C, 5), 133.4 (CH CH᎐CH ), 122.2 (4), 118.1 (CH CH᎐
᎐
᎐
2
2
2
CH ), 62.0 (2), 55.3 (CH SO Ph), 39.8, 32.9 (3, CH CH᎐CH ),
᎐
2
2
2
2
2
21.5 (CH3); m/z 417 (Mϩ, 11%), 376 (43), 262 (31), 234 (100),
162 (41), 91 (66) (Found: C, 60.4; H, 5.3; N, 3.25; S, 15.5. Calc.
for C21H23NO4S2: C, 60.4; H, 5.55; N, 3.35; S, 15.4%).
2-Allyl-5-(1-phenylsulfonylhept-6-enyl)-1-(4-tolylsulfonyl)-
2,3-dihydro-1H-pyrrole (11c). According to general procedure
A, the alkylation of sulfone 10 (108 mg, 259 µmol) with 6-
iodohex-1-ene (0.12 ml, >570 µmol, >2.2 equiv.) afforded 11c
(84 mg, 65%) as a colourless oil and as a 87:13 mixture of
diastereomers: νmax/cmϪ1 3072, 2930, 1641, 1598, 1349, 1308,
General procedure A: preparation of RCM precursors 11a–d via
alkylation of sulfone 10
1
1168, 1152; H NMR (400 MHz, C6D6) major diastereomer
To a solution of sulfone 10 (100 mg, 240 µmol) in tetrahydro-
furan (3 ml) at Ϫ78 ЊC was added nBuLi (0.18 ml of a 1.6 M
solution in hexanes, 288 µmol, 1.2 equiv.) and hexamethylphos-
phorous triamide (74 µl, 600 µmol, 2.5 equiv.) and the solution
was stirred for 1 h. Iodoalkene (480 µmol, 2.0 equiv.) was added
and after 90 min the solution was warmed to ca. 0 ЊC. Water (15
ml) and ethyl acetate (30 ml) were added and the organic layer
was separated. The aqueous layer was extracted with ethyl acet-
ate (2 × 15 ml), the combined organic layers were washed with
water (4 × 15 ml) and brine (15 ml) and dried. After removal of
the solvent in vacuo column chromatography (1:5 ethyl acetate–
petroleum ether) afforded metathesis precursors 11a–d.
(2S*, 1ЈS*) δ 8.02 (2H, d, J = 7.5, Ar-H), 7.77 (2H, d, J = 8.2,
Ar-H), 7.70 (1H, t, J = 7.5, Ar-H), 7.61 (2H, t, J = 7.5, Ar-H),
7.26 (2H, d, J = 8.2, Ar-H), 5.89 (1H, m, 4-H), 5.76–5.68 (2H,
m, 6Ј-H, CH CH᎐CH ), 5.10–5.07 (2H, m, 7Ј-H or CH CH᎐
᎐
᎐
2
2
2
CH2), 5.06–5.03 (1H, m, 1Ј-H), 4.95–4.89 (2H, m, 7Ј-H or
CH CH᎐CH ), 3.88–3.86 (1H, m, 2-H), 2.48–2.41 (1H, m,
᎐
2
2
CH CH᎐CH ), 2.40 (3H, s, CH ), 2.25–2.20 (1H, m, CH -
᎐
2
2
3
2
CH᎐CH ), 2.04–1.82 (5H, m, CH ), 1.58–1.53 (1H, m, CH ),
᎐
2
2
2
1.42–1.25 (4H, m, CH2); characteristic peaks of minor diastere-
omer (2S*, 1ЈR*) δ 5.61 (1H, m, 4-H), 4.34–4.29 (1H, m, 2-H);
13C NMR (100 MHz, C6D6) δ 143.7, 138.8, 136.3, 134.6, 133.6,
129.5, 129.1, 128.7, 127.9 (Ar-C, 5), 138.3, 133.3 (6Ј, CH2-
CH᎐CH ), 118.1 (7Ј or CH CH᎐CH ), 117.2 (4), 114.6 (7Ј or
᎐
᎐
2
2
2
2-Allyl-5-(1-phenylsulfonylpent-4-enyl)-1-(4-tolylsulfonyl)-
2,3-dihydro-1H-pyrrole (11a). According to general procedure
A, the alkylation of sulfone 10 (100 mg, 240 µmmol) with 4-
CH CH᎐CH ), 62.5 (1Ј), 61.1 (2), 39.6 (CH CH᎐CH ), 33.1,
᎐ ᎐
2 2 2 2
32.6, 31.2, 28.2, 25.3 (3, 2Ј, 3Ј, 4Ј, 5Ј), 21.5 (CH3); m/z (FAB)
500, (MHϩ, 70%), 458 (43), 358 (45), 316 (55), 202 (92), 162
J. Chem. Soc., Perkin Trans. 1, 2000, 345–351
349

View Article Online
(92), 91 (100) (Found MHϩ: 500.1911. Calc. for C27H34NO4S2:
500.1929).
(3H, s, CH3), 2.13–1.51 (8H, m, CH2); E-isomer δ 7.99 (2H, d,
J 7.5, Ar-H), 7.78–7.76 (2H, m, Ar-H), 7.69 (1H, t, J 7.5, Ar-
H), 7.59 (2H, t, J 7.5, Ar-H), 7.22 (2H, d, J 8.1, Ar-H), 5.88–
5.86 (1H, m, 11-H), 5.82–5.74 (1H, m, 6-H or 7-H), 5.34–5.30
(1H, m, 6-H or 7-H), 4.91–4.89 (1H, m, 2-H), 4.03–4.01 (1H, m,
9-H), 2.40 (3H, s, CH3), 2.41–2.33, 2.24–2.17, 2.04–1.99, 1.92–
1.87, 1.79–1.73 (10H, 5 × m, CH2); 13C NMR (100 MHz, C6D6)
both isomers δ 143.6, 138.5, 135.5, 134.8, 133.6, 129.5, 129.1,
128.7, 128.1 (Ar-C, 1), 137.5 (6 or 7), 123.0, 120.3 (6 or 7, 11),
64.1, 61.6 (2, 9), 35.6, 32.1, 31.3, 26.9, 25.8 (CH2), 21.5 (CH3);
m/z 457 (Mϩ, 20%), 316 (90), 149 (75), 91 (100) (Found Mϩ:
457.1390. Calc. for C24H27NO4S2 457.1382).
2-Allyl-5-(1-phenylsulfonyloct-7-enyl)-1-(4-tolylsulfonyl)-2,3-
dihydro-1H-pyrrole (11d). According to general procedure A,
the alkylation of sulfone 10 (120 mg, 288 µmol) with 7-
iodohept-1-ene (0.13 ml, >570 µmol, >2.0 equiv.) afforded 11d
(121 mg, 82%) as a colourless oil and as a 79:21 mixture of
diastereomers: νmax/cmϪ1 3071, 2926, 1641, 1598, 1350, 1308,
1
1168, 1152; H NMR (400 MHz, C6D6) major diastereomer
(2S*, 1ЈS*) δ 8.02 (2H, d, J 7.4, Ar-H), 7.76 (2H, d, J 8.2,
Ar-H), 7.70 (1H, t, J 7.4, Ar-H), 7.61 (2H, t, J 7.4, Ar-H), 7.30
(2H, d, J 8.2, Ar-H), 5.89 (1H, m, 4-H), 5.81–5.70 (2H, m, 7Ј-H,
CH CH᎐CH ), 5.10–5.07 (2H, m, 8Ј-H or CH CH᎐CH ), 5.06–
(2S*,10S*,E)-
and
(2S*,10S*,Z)-2-Phenylsulfonyl-13-
᎐
᎐
2
2
2
2
5.03 (1H, m, 1Ј-H), 4.98–4.90 (2H, m, 8Ј-H or CH CH᎐CH ),
(toluene-4-sulfonyl)-13-azabicyclo[8.2.1]trideca-1(12),7-diene
(12c). According to general procedure B, a metathesis reaction
on triene 11c (9.5 mg, 19 µmol) afforded bicycle 12c (7.5 mg,
84%) as a colourless oil and as a 31:69 mixture of E/Z-isomers
[the Z-isomer could be crystallised from the mixture: mp 217–
221 ЊC (partial decomposition), (from ethyl acetate)]: νmax/cmϪ1
2930, 2854, 1597, 1346, 1307, 1166, 1117; 1H NMR (400 MHz,
C6D6) Z-isomer δ 8.03 (2H, d, J 7.6, Ar-H), 7.75 (1H, t, J 7.6,
Ar-H), 7.65 (2H, t, J 7.6, Ar-H), 7.22 (2H, d, J 8.2, Ar-H),
7.08 (2H, d, J 8.2, Ar-H), 6.11 (1H, br s, 12-H), 5.57–5.45 (2H,
m, 7-H, 8-H), 4.75 (1H, d, J 9.0, 2-H), 4.05–4.00 (1H, m, 10-H),
2.37 (3H, s, CH3) 2.53–1.37 (12H, m, CH2); characteristic peaks
of E-isomer δ 6.06 (1H, br s, 12-H) 3.96–3.94 (1H, m, 10-H);
13C NMR (100 MHz, C6D6) both isomers δ 143.7, 143.6, 139.2,
138.8, 138.2, 134.2, 134.0 (Ar-C, 1), 133.6, 133.2, 132.3 (Ar-C,
7 or 8), 129.5, 129.4, 129.0, 128.8, 127.5, 127.4 (Ar-C), 126.8,
124.1, 120.0, 118.9 (7 or 8, 12), 63.5, 63.3, 62.2, 61.1 (2, 10),
39.5, 33.3, 32.4, 29.7, 29.2, 28.2, 26.4, 24.8, 23.7, 23.2, 21.5, 21.1
(CH2), 21.5 (CH3); m/z 471 (Mϩ, 12%), 330 (90), 262 (38), 162
(92), 91 (100) (Found Mϩ: 471.1551. Calc. for C25H29NO4S2:
471.1538).
᎐
2
2
3.91–3.85 (1H, m, 2-H), 2.49–2.40 (1H, m, CH CH᎐CH ), 2.40
᎐
2
2
(3H, s, CH ), 2.25–2.18 (1H, m, CH CH᎐CH ), 2.06–1.77,
᎐
3
2
2
1.56–1.27 (12H, m, CH2); characteristic peaks of minor diastere-
omer (2S*, 1ЈR*) δ 5.46 (1H, m, 4-H), 3.97–3.94 (1H, m, 2-H);
13C NMR (100 MHz, C6D6) δ 143.8, 138.9, 138.8, 136.5, 134.7,
133.7, 133.4, 129.6, 129.2, 128.8, 128.0 (Ar-C, 5, 7Ј), 118.2 (8Ј or
CH CH᎐CH ), 117.3 (4), 114.4 (8Ј or CH CH᎐CH ), 62.6, 61.2
᎐
᎐
2
2
2
2
(2, 1Ј), 39.7 (CH CH᎐CH ), 33.5, 32.8, 32.6, 28.6, 28.4, 25.8
᎐
2
2
(CH2), 21.6 (CH3); m/z 513 (Mϩ, 10%), 472 (32), 330 (43), 234
(37), 162 (60), 91 (100) (Found Mϩ: 513.2017. Calc. for
C28H35NO4S2: 513.2008).
General procedure B: preparation of macrocycles 12a–d via
ring-closing metathesis
A solution of triene 11a (71 mg, 0.15 mmol) in dichlorometh-
ane (150 ml, 1 mM concentration) was thoroughly degassed
with a vigorous stream of nitrogen and Grubbs’ catalyst
(Cy P) Cl Ru᎐CHPh (25 mg, 0.20 equiv.) was added. The solu-
᎐
3
2
2
tion was heated at 40 ЊC for 16 h. After cooling to room tem-
perature a stream of air was bubbled through the solution and
the solvent was removed in vacuo. Column chromatography
(1:6 ethyl acetate–petroleum ether) afforded macrocycle 12a.
(2S*,11S*,E)- and (2S*,11S*,Z)-2-Phenylsulfonyl-14-(4-
tolylsulfonyl)-14-azabicyclo[9.2.1]tetradeca-1(13),8-diene (12d).
According to general procedure B, a metathesis reaction on
triene 11d (86 mg, 168 µmol) afforded bicycle 12d (62 mg, 77%)
(2S*,8S*,Z)-2-Phenylsulfonyl-11-(4-tolylsulfonyl)-11-aza-
bicyclo[6.2.1]undeca-1(10),5-diene (12a). According to General
procedure B, a metathesis reaction on triene 11a (71 mg, 0.15
mmol) afforded bicycle 12a (32 mg, 48%) as a white solid and as
as a colourless oil and as a 40:60 mixture of E/Z-isomers: νmax
/
cmϪ1 2924, 2855, 1598, 1343, 1307, 1152; 1H NMR (400 MHz,
C6D6) Z-isomer δ 8.12 (2H, d, J 8.2, Ar-H), 8.03 (2H, d, J 7.3,
Ar-H), 7.67 (1H, t, J 7.3, Ar-H), 7.58 (2H, t, J 7.3, Ar-H), 7.30
(2H, d, J 8.2, Ar-H), 5.91 (1H, s, 13-H), 5.63–5.58 (1H, m, 8-H
or 9-H), 5.46–5.40 (1H, m, 8-H or 9-H), 4.99–4.95 (1H, m,
2-H), 4.14–4.09 (1H, m, 11-H), 2.69–2.66 (1H, m, 10-H), 2.42
(3H, s, CH3), 2.26–1.52 (13H, m, CH2); characteristic peaks of
E-isomer δ 5.19–5.24 (1H, m, 2-H), 4.01–3.96 (1H, m, 11-H);
13C NMR (100 MHz, C6D6) both isomers δ 143.7, 138.7, 135.3,
135.1, 133.5, 129.4, 129.0, 128.6, 128.6 (Ar-C, 1), 135.6, 122.3
(8, 9), 114.9 (13), 62.1, 61.4 (2, 11), 34.4, 33.1, 32.9, 32.4, 27.4,
24.6, 23.8 (CH2), 21.5 (CH3); m/z (FAB) 486 (MHϩ, 15%), 344
(15), 154 (35), 136 (37), 55 (100) (Found MHϩ: 486.1782. Calc.
for C26H32NO4S2 486.1773).
a single Z-isomer: mp 183–184 ЊC (from ethyl acetate); νmax
/
1
cmϪ1 2924, 2853, 1597, 1347, 1307, 1165, 1149; H NMR (400
MHz, C6D6) δ 8.01 (2H, d, J 7.5, Ar-H), 7.71 (1H, t, J 7.5,
Ar-H), 7.62 (2H, t, J 7.5, Ar-H), 7.49 (2H, d, J 8.2, Ar-H), 7.19
(2H, d, J 8.2, Ar-H), 5.92 (1H, m, 10-H), 5.57–5.55 (1H, m, 5-H
or 6-H), 5.48–5.44 (1H, m, 5-H or 6-H), 5.15–5.11 (1H, m,
2-H), 3.99–3.97 (1H, m, 8-H), 2.90–2.87 (1H, m, 4-H), 2.66–
2.61 (1H, m, 7-H), 2.40 (3H, s, CH3), 2.14–1.91 (4H, m, CH2),
1.79–1.74 (1H, m, 9-H), 1.67–1.60 (1H, m, 9-H); 13C NMR (100
MHz, C6D6) δ 143.7, 138.5, 134.5, 133.7, 133.7, 129.4, 129.1,
129.1, 127.8 (Ar-C, 1), 137.1 (5 or 6), 123.7, 122.9 (5 or 6, 10),
62.0, 61.0 (2, 8), 32.7, 30.8, 28.9, 23.6 (3, 4, 7, 9), 21.5 (CH3);
m/z 443 (Mϩ, 67%), 378 (15), 303 (100), 248 (60), 234 (53),
210 (30), 146 (100), 91 (100) (Found Mϩ: 443.1217. Calc. for
C23H25NO4S2: 443.1225).
General procedure C: preparation of reduced macrocycles 2a–d
via hydrogenation reactions
To a solution of bicycle 12b (17 mg, 37 µmol) in ethyl acetate
(3 ml) was added platinum() oxide (6 mg, 21 µmol, 0.57 equiv.)
and the mixture was stirred under an atmosphere of hydrogen
for 16 h. Filtration through Celite and silica and removal of
solvent in vacuo afforded hydrogenated bicycle 2b.
(2S*,9S*,E)-
and
(2S*,9S*,Z)-2-Phenylsulfonyl-12-(4-
tolylsulfonyl)-12-azabicyclo[7.2.1]dodeca-1(11),6-diene (12b).
According to general procedure B, a metathesis reaction on
triene 11b (150 mg, 309 µmol) afforded bicycle 12b (114 mg,
81%) as a colourless oil and as a 21:79 mixture of E/Z-isomers:
νmax/cmϪ1 2927, 2854, 1597, 1343, 1308, 1163, 1152; H NMR
1
(400 MHz, C6D6) Z-isomer δ 8.02 (2H, d, J 7.6, Ar-H), 7.93
(2H, d, J 8.2, Ar-H), 7.67 (1H, t, J 7.6, Ar-H), 7.59 (2H, t, J 7.6,
Ar-H), 7.27 (2H, d, J 8.2, Ar-H), 5.85 (1H, br s, 11-H), 5.41
(2H, m, 6-H, 7-H), 4.79 (1H, d, J 10.3, 2-H), 4.14–4.09 (1H, m,
9-H), 3.09–3.04 (1H, m, 5-H), 2.80–2.75 (1H, m, 8-H), 2.41
(2S*,8S*)-2-Phenylsulfonyl-11-(4-tolylsulfonyl)-11-aza-
bicyclo[6.2.1]undeca-1(10)-ene (2a). According to general pro-
cedure C, hydrogenation of bicycle 12a (19 mg, 43 µmol)
afforded hydrogenated bicycle 2a (19 mg, 100%) as a white
solid: mp 186 ЊC (from ethyl acetate); νmax/cmϪ1 2935 (br), 1597,
350
J. Chem. Soc., Perkin Trans. 1, 2000, 345–351

View Article Online
1344, 1308, 1166, 1149; 1H NMR (400 MHz, C6D6) δ 8.03 (2H,
d, J 7.4, Ar-H), 7.73 (1H, t, J 7.4, Ar-H), 7.63 (2H, t, J 7.4, Ar-
H), 7.33 (2H, d, J 8.1, Ar-H), 7.14 (2H, d, J 8.1, Ar-H), 6.14
(1H, m, 10-H), 4.83 (1H, m, 2-H), 4.00 (1H, m, 8-H), 2.39 (3H,
s, CH3), 2.39–2.34 (1H, m, 3-H), 2.03–2.02 (1H, m, CH2), 1.84–
1.54 (9H, m, CH2), 1.36–1.33 (1H, m, CH2); 13C NMR (100
MHz, C6D6) δ 143.7, 138.8, 138.4, 133.7, 133.7, 129.4, 129.2,
129.1, 127.7 (Ar-C, 1), 122.7 (10), 64.3 (2), 61.0 (8), 35.9, 32.7,
30.3, 30.0, 22.9 (CH2), 21.6 (CH3), 20.0 (6); m/z (FAB) 446
(MHϩ, 22%), 334 (25), 297 (100), 290 (38), 149 (78), 91 (90)
(Found MHϩ: 446.1463. Calc. for C23H28NO4S2: 446.1460).
rapidly and the reaction was allowed to warm to room temper-
ature. Water (15 ml) and ethyl acetate (30 ml) were added and
the organic layer was separated. The aqueous layer was
extracted with ethyl acetate (2 × 15 ml), the combined organic
layers were washed with water (4 × 15 ml) and brine (15 ml) and
dried. The solvent was removed in vacuo to afford ꢀ-11c–ꢁ-11c
(84 mg, 98%) as a colourless oil and as a 31:69 mixture of
diastereomers. Careful column chromatography (1:6 ethyl
acetate–petroleum ether) afforded ꢀ-11c–ꢁ-11c (22 mg) as a
77:23 mixture of diastereomers.
Ring closing metathesis of ꢀ-11c and ꢁ-11c
(2S*,9S*)-2-Phenylsulfonyl-12-(4-tolylsulfonyl)-12-aza-
bicyclo[7.2.1]dodeca-1(11)-ene (2b). According to general
procedure C, hydrogenation of bicycle 12b (17 mg, 37 µmol)
afforded hydrogenated bicycle 2b (18 mg, 100%) as a white
solid: mp 191–195 ЊC (from ethyl acetate); νmax/cmϪ1 2935, 2851,
1597, 1346, 1308, 1165, 1150; 1H NMR (400 MHz, C6D6) δ 8.00
(2H, d, J 7.5, Ar-H), 7.74 (1H, d, J 7.5, Ar-H), 7.63 (2H, d,
J 7.5, Ar-H), 7.44 (2H, d, J 8.2, Ar-H), 7.16 (2H, d, J 8.2,
Ar-H), 6.13 (1H, m, 11-H), 5.06 (1H, m, 2-H), 4.06 (1H, m,
9-H), 2.40 (3H, s, CH3), 2.12–1.42 (14H, m, CH2); 13C NMR
(100 MHz, C6D6) δ 143.6, 138.9, 134.7, 133.6, 133.3, 129.4,
129.2, 128.7, 127.4 (Ar-C, 1), 121.5 (11), 64.1, 61.3 (2, 9), 34.7,
33.7, 29.6, 26.6, 23.6, 18.5, 18.0 (CH2), 21.4 (CH3); m/z 459
(Mϩ, 10%), 318 (100), 304 (100), 254 (35), 163 (100), 162
(95), 91 (82) (Found Mϩ: 459.1510. Calc. for C24H29NO4S2:
459.1538).
According to general procedure B, a metathesis reaction on
triene ꢀ-, ꢁ-11c (22 mg, 44 µmol) as a 77:23 mixture of diastereo-
mers at C-1Ј afforded starting material ꢀ-11c (15 mg, 68%) as a
white solid and as a single diastereomer, and bicycle 12c (4 mg,
19%) as a colourless oil and as a 38:62 mixture of E/Z-isomers.
ꢀ-11c: νmax/cmϪ1 3073, 2924, 2853, 1446, 1339, 1307, 1148, 1086;
1H NMR (400 MHz, C6D6) δ 8.03–8.00 (2H, m, Ar-H), 7.67
(2H, d, J 8.1, Ar-H), 6.96–6.94 (3H, m, Ar-H), 6.74 (2H, d,
J 8.1, Ar-H), 5.73–5.62 (2H, m, 6Ј-H, CH CH᎐CH ), 5.35–5.31
᎐
2
2
(2H, m, 4-H, 1Ј-H), 5.01–4.92 (4H, m, 7Ј-H, CH CH᎐CH ),
4.13–4.08 (1H, m, 2-H), 2.44–2.38 (1H, m, CH CH᎐CH ),
2.31–2.22 (1H, m, 3-H), 2.04–1.82 (4H, m, CH2), 1.68–1.20
(6H, m, CH2); 13C NMR (100 MHz, C6D6) δ 144.2, 140.8, 137.6,
139.3, 135.1, 133.9, 130.3, 129.9, 129.7, 129.0, 119.4 (4, 6Ј,
᎐
᎐
2
2
2
2
CH CH᎐CH , Ar-C), 130.0, (CH CH᎐CH ), 118.5, 115.4 (5,
᎐
᎐
2
2
2
2
7Ј), 63.7, 63.3 (2, 1Ј), 40.9, 34.4, 33.6, 30.1, 29.8, 27.8 (CH2),
21.7 (CH3); m/z (FAB) 500 (MHϩ, 62%), 458 (35), 358 (30), 316
(42), 304 (27), 234 (27), 202 (47), 162 (65), 91 (100) (Found
MHϩ: 500.1933. Calc. for C27H34NO4S2: 500.1929). Data for
12c as reported above.
(2S*,10S*)-2-Phenylsulfonyl-13-(4-tolylsulfonyl)-13-aza-
bicyclo[8.2.1]trideca-1(12)-ene (2c). According to general pro-
cedure C, hydrogenation of bicycle 12c (19 mg, 39 µmol)
afforded hydrogenated bicycle 2c (19 mg, 100%) as a white
solid: mp 209 ЊC (from ethyl acetate); νmax/cmϪ1 1598; 1H NMR
(400 MHz, C6D6) δ 8.19 (2H, d, J 8.2, Ar-H), 8.08 (2H, d, J 6.6,
Ar-H), 6.93–6.85 (5H, m, Ar-H), 6.11 (1H, d, J 1.8, 12-H), 5.28
(1H, d, J 8.5, 2-H), 3.86–3.80 (1H, m, 10-H), 2.30–2.24 (1H, m,
CH2), 2.11–2.04 (1H, m, CH2), 1.88 (3H, s, CH3), 1.88–1.80
(2H, m, CH2), 1.78–1.65 (1H, m, CH2), 1.56–1.40 (3H, m, CH2),
1.30–1.03 (8H, m, CH2); 13C NMR (100 MHz, C6D6) δ 144.2,
140.5, 139.4, 136.5, 133.9, 130.4, 129.9, 129.6, 129.5 (Ar-C, 1),
121.0 (12), 64.9, 63.0 (2, 10), 35.4, 32.5, 30.8, 26.9, 26.8, 25.3,
23.4, 21.4 (CH2), 21.8 (CH3); m/z (FAB) (MHϩ, 5%), 305 (40),
261 (50), 149 (38), 81 (73), 69 (100) (Found MHϩ: 474.1744.
Calc. for C25H32NO4S2: 474.1773).
Acknowledgements
For financial support of this work we would like to acknow-
ledge The European Union (TMR fellowship, T. L.) and The
Royal 1851 Commission (S. J. B.).
References
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(2S*,11S*)-2-Phenylsulfonyl-14-(4-tolylsulfonyl)-14-aza-
bicyclo[9.2.1]trideca-1(13)-ene (2d). According to general pro-
cedure C, hydrogenation of bicycle 12d (36 mg, 74 µmol)
afforded hydrogenated bicycle 2d (32 mg, 89%) as a white solid:
mp 211–216 ЊC (partial decomposition) (from ethyl acetate);
1
νmax/cmϪ1 2927, 2853, 1597, 1348, 1307, 1151; H NMR (400
MHz, C6D6) δ 8.02 (2H, d, J 7.5, Ar-H), 7.73 (1H, t, J 7.5,
Ar-H), 7.62 (2H, t, J 7.5, Ar-H), 7.52 (2H, d, J 8.2, Ar-H), 7.13
(2H, d, J 8.2, Ar-H), 6.08 (1H, br s, 13-H), 5.03 (1H, m, 2-H),
3.95 (1H, m, 11-H), 2.38 (3H, s, CH3), 2.19–2.10 (1H, m, CH2),
2.07–1.08 (17H, m, CH2); 13C NMR (100 MHz, C6D6) δ 143.6,
139.2, 134.5, 134.3, 133.5, 129.4, 129.1, 128.6, 127.6 (Ar-C, 1),
121.8 (13), 63.5, 62.5 (2, 11), 35.1, 31.2, 29.6, 28.1, 25.9, 25.2,
22.5, 22.3, 21.1 (CH2), 21.5 (CH3); m/z (FAB) 488 (MHϩ, 15%),
307 (25), 289 (15), 154 (100), 136 (78) (Found MHϩ: 488.1923.
Calc. for C26H34NO4S2: 488.1929).
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(2S*,1ЈR*)-2-Allyl-5-(1-phenylsulfonylhept-6-enyl)-1-(4-
tolylsulfonyl)-2,3-dihydro-1H-pyrrole (ꢀ-11c) and (2S*,1ЈS*)-2-
allyl-5-(1-phenylsulfonylhept-6-enyl)-1-(4-tolylsulfonyl)-2,3-
dihydro-1H-pyrrole (ꢁ-11c). To a solution of ꢁ-11c (86 mg, 17
µmol) in tetrahydrofuran (2 ml) and hexamethylphosphorous
triamide (50 µl) at Ϫ78 ЊC was added dropwise nBuLi (118 µl
of a 1.6 M solution in hexanes, 19 µmol, 1.1 equiv.) and the
mixture was stirred for 1 h. Methanol (0.1 ml) was then added
7 G. A. Kraus and K. Neuenschwander, J. Chem. Soc., Chem.
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Paper a908272g
J. Chem. Soc., Perkin Trans. 1, 2000, 345–351
351