Synthesis of hydroxy pyrrolidines and piperidines via free-radical cyclisations

Article abstract of DOI:10.1039/a707740h

The tin hydride-mediated cyclisation of a variety of α- and β-amino aldehydes to form substituted pyrrolidines and piperidines under mild, neutral reaction conditions has been investigated. The amino aldehyde precursors, prepared from the corresponding amino ester or alcohol, are purified or immediately reacted with Bu₃SnH-AIBN in boiling benzene. The method is shown to be general and cyclisation of the intermediate O-stannyl ketyl is observed using a variety of (electron poor or rich) acceptor carbon-carbon double bonds to afford hydroxy-pyrrolidines or -piperidines after work-up. Related cyclisations using an alkyne or α,β-unsaturated amide radical acceptor are shown to be problematic and low-yielding. Radical cyclisation of allylic O-stannyl ketyls, generated from reaction of α,β-unsaturated ketones with tin hydride, are also shown to have application in pyrrolidine/piperidine synthesis. A dilution study suggests that the cyclisation onto a cinnamyl double bond is irreversible.

Full text of DOI:10.1039/a707740h

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Synthesis of hydroxy pyrrolidines and piperidines via free-radical
cyclisations
Andrew F. Parsons* and Robert M. Pettifer
Department of Chemistry, University of York, Heslington, York, UK YO1 5DD
The tin hydride-mediated cyclisation of a variety of á- and â-amino aldehydes to form substituted
pyrrolidines and piperidines under mild, neutral reaction conditions has been investigated. The amino
aldehyde precursors, prepared from the corresponding amino ester or alcohol, are purified or immediately
reacted with Bu3SnH–AIBN in boiling benzene. The method is shown to be general and cyclisation of the
intermediate O-stannyl ketyl is observed using a variety of (electron poor or rich) acceptor carbon–carbon
double bonds to afford hydroxy-pyrrolidines or -piperidines after work-up. Related cyclisations using an
alkyne or á,â-unsaturated amide radical acceptor are shown to be problematic and low-yielding. Radical
cyclisation of allylic O-stannyl ketyls, generated from reaction of á,â-unsaturated ketones with tin
hydride, are also shown to have application in pyrrolidine/piperidine synthesis. A dilution study suggests
that the cyclisation onto a cinnamyl double bond is irreversible.
The preparation of hydroxylated pyrrolidines and piperidines
has attracted considerable interest in recent years.1 These are
attractive targets because of their widespread occurrence in
natural products and the variety of biological activities which
they exhibit. Medicinally important examples include lacta-
cystin,2 oxazolomycin,3 bulgecinine,4 deoxynojirimicin,5 pyrrol-
izidine alkaloids6 (such as retronecine) and indolizidine
alkaloids (which include castanospermine and pumiliotoxin
B).7 Although tin hydride-mediated radical cyclisation reac-
tions have been widely employed8 in substituted pyrrolidine/
piperidine synthesis the application of this approach to
hydroxylated derivatives, starting from carbonyl precursors, has
received little attention. Thus while halide, selenide, xanthate
and related precursors have been extensively used for many
years, it is only recently that the cyclisation of aldehyde and
ketone substrates using Bu3SnH (rather than e.g. Na,9 Zn10 or
Mg11) has been adopted.12 This is surprising as the use of carb-
onyl precursors not only leads to products which retain a vers-
atile hydroxy group but the tin by-products are more easily
removed than, for example, tin chlorides or bromides. Enholm
and co-workers13 first demonstrated the cyclisation of O-
stannyl ketyls, generated from reaction of tributyltin hydride
with aldehydes or ketones, onto electron poor alkenes to pro-
duce cycloalkanols. It was found that an activating or electron-
withdrawing function on the alkene acceptor was an essential
prerequisite for the success of the cyclisation. (It should be noted
that related cyclisations have been reported using catalytic
Bu3SnH in the presence of PhSiH3.14) In addition to O-stannyl
ketyls, the cyclisation of allylic O-stannyl ketyls, prepared from
α,β-unsaturated ketones, to give substituted cycloalkanes is
also possible.15 These studies on carbocyclic systems suggested
that related cyclisations could find application in hydroxy
pyrrolidine/piperidine synthesis. Hence cyclic amino alcohols
have recently been prepared from tin hydride-mediated cyclisa-
tion of aldehydes/ketones containing an oxime ether (as radical
acceptor)16 and the pyrrolidine ring present in bulgecinine has
been assembled following cyclisation of an O-stannyl ketyl
onto an ∆4,5-oxazolidinone.17 We now report18 the preparation
of hydroxy pyrrolidines/piperidines 3 on cyclisation of N-
protected α- or β-amino aldehydes 1 which contain a variety of
carbon–carbon double bond acceptors (Scheme 1). The effect
of the radical acceptor and ring size on the yield of cyclisation
of the intermediate O-stannyl ketyl 2 has been examined and
preliminary results centred on the application of O-allylic ketyl
cyclisations in pyrrolidine/piperidine synthesis are reported.
R1
R1
OSnBu3
O
Bu3SnH
R
R
n
n
N
P
1
N
P
2
AIBN, 80 °C,
benzene
n = 1,2
R1
OH
R
n
N
P
3
Scheme 1
Initial studies centred on the preparation of aldehyde pre-
cursors bearing electron rich alkenes and both a reductive and
oxidative approach to these compounds was investigated.
Methyl esters 5a–d were prepared in good yield from the glycine
derivative 4 while amino alkanols 6a,b were elaborated to alco-
hols 7a–d and the key step in both syntheses involved the
N-alkylation of secondary sulfonamides (Schemes 2 and 3).
The synthesis and subsequent cyclisation of N-sulfonyl alde-
hydes 8a–d was then explored (Scheme 2, Table 1). Reduction
of 5a–d using DIBAL-H at Ϫ78 ЊC for 1.5 h gave rise to the
desired aldehyde cyclisation precursors 8a–d after work-up and,
for example, the formation of 8a was evident from the 1H NMR
spectrum of the crude reaction mixture which showed a singlet
corresponding to the aldehydic proton at δ 9.38. Reaction of
the crude N-allyl derivative 8a with Bu3SnH (1.5 equiv.) and
AIBN (0.2 equiv.) in boiling benzene (0.1 ) for 2 h gave rise to
the desired pyrrolidinol 9a, as an inseparable 1:1 mixture of
diastereoisomers, in 36% overall yield after column chrom-
atography (Table 1, entry 1). A small amount (10%) of methyl
ester 5a starting material was also isolated. Similar yields and
diastereoselectivities were observed on reduction and cyclis-
ation of the related aldehydes 8b–d (Table 1, entries 2–4). In
some cases the cyclisation reactions were slow and further
AIBN was added until all the starting material had been
J. Chem. Soc., Perkin Trans. 1, 1998
651

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Table 1 Tin mediated radical cyclisations of aldehydes 8a–d
Entry
Ester 5
R
R1
Aldehyde 8
Yield of 9 (%)
Diastereomer ratio
1
2
3
4
a
b
c
H
H
Me
H
H
a
b
c
40a
50
42
1.0:1b
1.2:1
1.2:1
1.6:1
Me
Me
Ph
d
d
52
a Yield based on recovered ester 5a (10%). b Diastereoisomer ratio determined from the 1H NMR spectrum.
R1
R1
OH
R
CO2Me
R
(i)
HN
SO2Ph
CO2Me
N
N
SO2Ph
4
SO2Ph
7c–d
5a–d
a R = R1 = H (72%)
(i)
b R = H, R1 = Me (64%)
c R = R1 = Me (64%)
d R = H, R1 = Ph (93%)
R1
O
(ii)
R
N
R1
R1
SO2Ph
OH
(iii)
R
CHO
R
10
a R = H, R1 = Ph
b R = R1 = H
N
N
SO2Ph
SO2Ph
(ii)
(ii)
9a–d
8a–d
OH
OH
N
Scheme 2 Reagents and conditions: (i) NaH, DMF, 0 ЊC then R1(R)C᎐
CHCH2X; (ii) DIBAL-H, toluene, Ϫ78 ЊC; (iii) Bu3SnH, AIBN, ben-
zene, 80 ЊC (see Table 1)
Me
᎐
Ph
N
SO2Ph
SO2Ph
R1
56%
40%
11a
11b
R
CH2OH
+
+
OH
(i)–(iv)
H2N
OH
n
Ph
n
OH
N
6
SO2Ph
7
a n = 1
b n = 2
N
N
a R = R1 = H; n = 1 (59%)
b R = H, R1 = Ph; n = 1 (61%)
c R = R1 = H; n = 2 (62%)
d R = H, R1=Ph; n = 2 (75%)
SO2Ph
8%
SO2Ph
7d
4%
12
+
Scheme 3 Reagents and conditions: (i) TBDMSCl, Et3N, DMAP,
CH2Cl2; (ii) PhSO2Cl, Et3N, DMAP, CH2Cl2; (iii) NaH, DMF, 0 ЊC
OH
then R1(R)C᎐CHCH2X; (iv) TsOH, MeOH
᎐
N
consumed. Attempted cyclisation of 8d at higher temperature
in boiling toluene, rather than benzene, was less successful and
the yield of pyrrolidinol 9d dropped from 52 to 17%.
SO2Ph
7%
7c
The preparation and subsequent cyclisation of aldehyde 8d,
derived from oxidation of alcohol 7b, was also explored. Initial
reactions using TPAP, PCC or PDC as the oxidising agent
proved unsuccessful but Swern oxidation at Ϫ60 ЊC was found
to be an efficient and clean method for the preparation of 8d.
Treatment of the crude oxidation product with Bu3SnH
resulted in the formation of the pyrrolidinol 9d in identical
yield (52%) and diastereoselectivity (1.6:1) to that obtained
earlier starting from methyl ester 5d. This approach could also
be extended to piperidinol synthesis and oxidation of the pri-
mary alcohol 7d to 10a followed by reaction with Bu3SnH
(added over 3 h) gave rise to the desired secondary alcohol 11a
in 56% yield after column chromatography (Scheme 4). This
resulted from a 6-exo-trig cyclisation process and the stereo-
chemistry of the two separable diastereoisomers, isolated in a
Scheme 4 Reagents and conditions: (i) (COCl)2, DMSO, Et3N, CH2Cl2,
Ϫ60 ЊC; (ii) Bu3SnH, AIBN, benzene, 80 ЊC
ratio of 1.3:1, was not deduced. In addition to 11a a small
amount of the primary alcohol 7d, derived from simple reduc-
1
tion of the intermediate aldehyde, was also formed. The H
NMR spectrum of the oxidation reaction showed clean alde-
hyde formation and so the isolation of 7d was attributed to the
Bu3SnH reaction rather than recovery of unreacted starting
material. Reaction of the N-allyl derivative 7c, under the same
conditions, afforded piperidinol 11b in 40% yield and alcohol
7c (derived from reduction of aldehyde 10b) in 7% yield. In
addition, the azepane 12 was formed in 8% yield and this pre-
sumably arises from a competitive 7-endo cyclisation of the
intermediate O-stannyl ketyl radical. These results contrast
652
J. Chem. Soc., Perkin Trans. 1, 1998

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with the previously reported hept-6-enyl-1-oxy cyclisations.13 In
this case 6-exo cyclisation, to form a cyclohexanol, was only
possible when an activated alkene was present. The introduc-
tion of an ester substituent on the alkene (which lowered the
energy of the LUMO) was shown to result in a bonding
interaction with the (high energy) SOMO of the electron-rich
O-stannyl ketyl radical. Clearly alkene activation (with an
electron-withdrawing group) is not essential for the cyclisations
reported here and this highlights the importance of the amino
linkage in facilitating this type of reaction.
Table 2 Tin mediated radical cyclisations of aldehydes 19a–d
Entry Aldehyde 19
R
R1
n
Products [yield (%)]
1
2
3
4
a
b
c
CO2Et
H
CO2Et
H
H
CO2Et
H
1
1
2
2
20a (27) ϩ 21a (29)
20a (33) ϩ 21a (32)
20b (23) ϩ 21b (25)a
20b (29) ϩ 21b (27)
d
CO2Et
a Crude aldehyde 19c was used and the yield is based on precursor
alcohol 18c.
The cyclisation of a precursor bearing an alkyne as the
radical acceptor was also undertaken as shown in Scheme 5.
CO2Et
O
N
OH
OH
HO
(i)
EtO2C
+
O
n
n
n
N
N
SO2Ph
SO2Ph
SO2Ph
N
16 n = 1 (90%)
17 n = 2 (81%)
18a n = 1 (30%)
18c n = 2 (25%)
18b n = 1 (31%)
18d n = 2 (24%)
SO2Ph
(ii)
(i)
(ii)
O
R1
O
EtO2C
OH
OH
OH
O
(iii)
R
+
n
n
n
N
N
N
N
N
SO2Ph
20a–b
SO2Ph
19a–d
SO2Ph
21a–b
SO2Ph
SO2Ph
32%
13
13
+
Scheme 6 Reagents and conditions: (i) Ph3P᎐CHCO2Et, CH2Cl2,
40 ЊC; (ii) (COCl)2, DMSO, Et3N, CH2Cl2, Ϫ60 ЊC; (iii) Bu3SnH,
AIBN, benzene, 80 ЊC (see Table 2)
᎐
OH
OH
Bu3Sn
N
N
yield. Cyclisation of this aldehyde resulted in the formation of
the desired trans-pyrrolidine 20a and cis-bicycle 21a in 27 and
29% yield respectively (Table 2, entry 1). Both products resulted
from an initial 5-exo radical cyclisation and the bicycle 21a was
thought to arise from a second cyclisation involving attack of
the tin alkoxide onto the ester. Considerably lower yields of 20a
and 21a were isolated when cyclisation of the crude aldehyde
19a was attempted. The cyclisation of aldehyde 19b (derived
from alcohol 18b) bearing a trans-alkene produced 20a and 21a
in similar yields and so the precursor double bond stereo-
chemistry was shown to have little effect on the diastereo-
selectivity of the cyclisation reaction (Table 2, entry 2). This
method was also applied to piperidine synthesis and similar
yields of 6-exo cyclisation, to produce 20b and 21b, were
obtained starting from aldehydes 19c,d which in turn were
derived from the corresponding alcohols 18c,d (Table 2, entries
3 and 4). It should be noted that no primary alcohol resulting
from simple reduction of aldehyde 19a–d was isolated from
these reactions. Lactol 16 could alternatively be reacted with
phosphorane 22, derived from α-bromo-γ-butyrolactone, to
afford trisubstituted alkene 23 (as the trans-isomer), which
unfortunately could not be separated from triphenylphosphine
oxide even after extensive column chromatography (Scheme 7).
However, a pure sample of 23 could be obtained from chrom-
atography of the corresponding (and more nonpolar) O-silyl
ether followed by acid desilylation. Cyclisation of the crude
aldehyde prepared on oxidation of 23 was also successful
and secondary alcohol 24 was isolated as a mixture of three
diastereoisomers (in a ratio of 1.3:1.3:1) in 48% yield over the
two steps. A small amount (6%) of the secondary sulfonamide
25 (which may result from β-elimination of the intermediate
O-stannyl ketyl radical) was also isolated.
SO2Ph
SO2Ph
15
14%
14
Scheme 5 Reagents and conditions: (i) (COCl)2, DMSO, Et3N, CH2Cl2,
Ϫ60 ЊC; (ii) Bu3SnH, AIBN, benzene, 80 ЊC
The N-prop-2-ynyl sulfonamide 13, prepared from the protected
glycine 4, was oxidised and subjected to radical cyclisation con-
ditions. However, the major product after purification was the
primary alcohol 13 derived from simple reduction of the inter-
mediate aldehyde. The minor product, isolated in 14% yield,
was characterised as stannane 14 which was thought to result
from addition of the tributyltin radical to the alkyne followed
by 5-exo cyclisation onto the aldehyde carbonyl.19 None of
the expected 4-exo-methylene pyrrolidine 15 was evident and
this may reflect the nucleophilic nature of the intermediate
O-stannyl ketyl radical which results in no interaction with the
electron rich C᎐C triple bond (and consequently no cyclis-
᎐
᎐
ation).
An alternative strategy was employed for the preparation of
aldehyde precursors bearing electron deficient double bonds.
This involved oxidative cleavage of the alkene present in 7a
using ozone at Ϫ78 ЊC to give lactol 16, as a stable white solid,
in 90% yield (Scheme 6). The 1H NMR spectrum of 16 in
CDCl3 showed the absence of any open chain hydroxy aldehyde
in accord with that observed for related compounds.20 Similar
oxidation of the propanol derivative 7c gave 17 which surpris-
ingly existed entirely as the 7-membered ring lactol (from the 1H
NMR spectrum). Wittig reaction of 16 with ethyl (triphenyl-
phosphoranylidene)ethanoate in CH2Cl2 at 40 ЊC for 12 h
followed by careful column chromatography afforded pure
samples of the cis- and trans-unsaturated esters, 18a and 18b, in
30 and 31% yield respectively. Reaction of related hemiacetals21
with stabilised phosphoranes have also given rise to high levels
of the cis-alkene isomer and a similar alkene Z:E ratio was
observed on reaction of lactol 17 to afford 18c,d.
It was also envisaged that substituted pyrrolidinones could be
prepared by radical cyclisation onto an electron poor unsatur-
ated amide double bond. In order to investigate this approach
the N-benzyl cinnamide 26 was prepared starting from N-benzyl
glycine methyl ester (Scheme 8). Oxidation and subsequent
treatment of the crude aldehyde with Bu3SnH resulted in a slow
Swern oxidation of the cis-alkene 18a and purification using
column chromatography afforded pure aldehyde 19a in 65%
J. Chem. Soc., Perkin Trans. 1, 1998
653

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column chromatography. Related work15 has established that
O
O
very high levels of diastereoselectivity (>50:1) can be obtained
when the concentration of reactants is reduced from 0.1 to
0.01 . These observations have been attributed to the rever-
sibility of the cyclisation and the decreased availability of the
Bu3SnH. However, when the cyclisation of 28b was carried out
under dilute conditions (0.01 ) the piperidine 29b was pro-
duced in similar yield (71%) and diastereoselectivity (2.6:1) to
that obtained earlier. This suggested that cyclisation of the
allylic O-stannyl ketyl radical onto the styrene double bond
was irreversible.
This work has demonstrated the radical cyclisation of a
range of α- and β-amino aldehydes containing a variety of
double bonds. The method is general and both electron rich and
poor alkenes can be utilised to afford substituted pyrrolidines
or piperidines. No products derived from hydrostannylation
of the alkene precursors were isolated but this reaction did
prove problematic when an alkyne radical acceptor was used.
The application of allylic O-stannyl ketyl cyclisations in
N-heterocycle synthesis has also been demonstrated for the first
time and future work will concentrate on the use of this method
in natural product synthesis.
O
HO
OH
(i)–(iii)
N
N
SO2Ph
SO2Ph
51%
16
23
(iv)–(v)
O
O
O
O
OH
+
NH
N
SO2Ph
SO2Ph
6%
48%
25
24
Scheme7 Reagentsandconditions:(i)3-triphenylphosphoranylidene-2-
oxotetrahydrofuran 22, CH2Cl2, 40 ЊC; (ii) TBDMSCl, Et3N, DMAP,
CH2Cl2; (iii) TsOH, MeOH; (iv) (COCl)2, DMSO, Et3N, CH2Cl2,
Ϫ60 ЊC; (v) Bu3SnH, AIBN, benzene, 80 ЊC
Ph
Experimental
OH
OH
Ph
IR spectra were recorded on an ATI Mattison Genesis FT IR
(i)–(ii)
spectrometer. H and 13C NMR spectra were recorded on a
1
N
O
O
N
JEOL EX 270 spectrometer; the carbon spectra were assigned
using DEPT experiments. Coupling constants (J) were re-
corded in Hz to the nearest 0.5 Hz. Mass spectra were recorded
on a Fisons Instruments VG Analytical Autospec Spectrometer
system. Thin layer chromatography (TLC) was performed on
Merck aluminium-backed silica gel plates. Compounds were
visualised under a UV lamp, using basic KMnO4 solution,
ninhydrin and/or iodine. Column chromatography was per-
formed using silica gel (Matrix Silica 60, 70–200 micron Fisons
or ICN flash silica 60, 32–63 microns). Solvents were purified/
dried using standard literature methods. Light petroleum refers
to the fraction with bp 40–60 ЊC. Bu3SnH was purchased from
Lancaster Synthesis Ltd and distilled before use. Elemental
analyses were performed by the Chemical Analytical Services
Unit, University of Newcastle.
Bn
Bn
37% (2.1:1)
27
26
Scheme 8 Reagents and conditions: (i) (COCl)2, DMSO, Et3N, CH2Cl2,
Ϫ60 ЊC; (ii) Bu3SnH, AIBN, benzene, 80 ЊC
conversion to the desired pyrrolidinone 27 as a 2.1:1 mixture of
inseparable diastereoisomers. However, only a modest unopti-
mised yield of 37% was obtained for this reaction even though
no starting material or any by-products could be isolated.
Finally, the application of allylic O-stannyl ketyls in pyrrol-
idine/piperidine synthesis was briefly explored. In this case an
unsaturated ketone would act as a free-radical precursor rather
than an acceptor as commonly employed in 1,4-addition reac-
tions. The precursor dienes 28a,b were prepared in good yield
from Wittig reaction of aldehydes 8d and 10a using an excess (5
equiv.) of (triphenylphosphoranylidene)propan-2-one (Scheme
9). Treatment of these dienes with Bu3SnH (0.1  in benzene)
General procedure for the alkylation of sulfonamide 4
To a stirred solution of sulfonamide 4 (1.38–5.27 mmol) in
anhydrous DMF (5–10 cm3) was added NaH (1.66–6.32 mmol)
under a nitrogen atmosphere. After stirring for 0.2 h at room
temperature the mixture was cooled to 0 ЊC and a solution of
the halide (2.07–7.91 mmol) in anhydrous DMF (1 cm3) was
added gradually via a syringe. The reaction was then allowed to
warm to room temperature and stirred until the starting
material had been consumed as shown by TLC (2–10 h). EtOAc
(20 cm3) and water (20 cm3) were added and the mixture was
stirred vigorously for 0.5 h. The organic layer was separated,
washed with more water (2 × 20 cm3) and brine (20 cm3), dried
(MgSO4), concentrated and purified by column chromato-
graphy (silica; light petroleum–Et2O) to afford 5a–d (64–93%)
as a colourless oil or a white crystalline solid.
Ph
COCH3
Ph
O
(i)
n
n
N
N
SO2Ph
SO2Ph
28a n = 1 (72%)
28b n = 2 (64%)
8d n = 1
10a n = 2
(ii)
Ph
COCH3
Methyl (N-allyl-N-phenylsulfonylamino)ethanoate 5a. Rf 0.4
(petroleum ether–Et2O, 1:1); νmax(thin film)/cmϪ1 1753 (s),
1446 (m), 1419 (w), 13 743 (s), 1214 (m), 1162 (s), 1092 (m);
δH(270 MHz, CDCl3) 7.96–7.44 (5H, m, aromatics), 5.85–5.70
n
N
SO2Ph
29a n = 1 (61%)
29b n = 2 (76%)
(1H, m, CH ᎐CH), 5.30–5.23 (2H, app. t, J 9, CH ᎐CH), 4.12
᎐
᎐
2
2
(2H, s, NCH2CO), 4.00 (2H, d, J 6.5, NCH2CH), 3.70 (3H,
s, CO2Me); δC(67.5 MHz, CDCl3) 169.2 (CO2Me), 139.7
Scheme 9 Reagents and conditions: (i) Ph3P᎐CHCOCH3, CH2Cl2;
᎐
(ii) Bu3SnH, AIBN, benzene, 80 ЊC
(C᎐CH), 132.7 (CH ᎐CH), 132.0, 129.0, 127.2 (CH᎐C), 119.9
᎐
᎐
᎐
2
resulted in clean cyclisation and the desired disubstituted
N-heterocycles 29a and 29b were isolated in 61 and 76% yield
respectively. Both products were isolated as diastereomeric
mixtures, in the ratio 2.6–1.5:1, which were not separable on
(CH ᎐CH), 52.0 (CO Me), 50.7, 46.7 (2 × NCH ); m/z (CI,
᎐
2 2 2
NH3) 287 (M ϩ NH4ϩ, 100%), 270 (M ϩ Hϩ, 51), 210 (18),
200 (6), 128 (52) (Found: M ϩ Hϩ, 270.0799. C12H15NO4S
requires M ϩ Hϩ, 270.0800).
654
J. Chem. Soc., Perkin Trans. 1, 1998

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Methyl (N-phenylsulfonyl-N-but-2-enylamino)ethanoate 5b.
Rf 0.5 (light petroleum–Et2O, 1:1); νmax(thin film)/cmϪ1 1752
(s), 1445 (m), 1341 (m), 1161 (s), 970 (w), 925 (w); δH(270 MHz,
CDCl3) 7.88–7.48 (5H, m, aromatics), 5.64–5.52 (1H, m,
MeCH᎐C), 5.45–5.24 (1H, m, MeCH᎐CH), 4.02 (2H, s,
(2H, t, J 5.5, CH2O), 3.27 (2H, t, J 5.5, NCH2CH2), 2.35 (1H,
br s, CH OH); δ (67.5 MHz, CDCl ) 139.2 (C᎐CH), 132.7,
᎐
2
C
3
129.2, 128.2, 127.1 (CH᎐C and CH ᎐CH), 119.3 (CH ᎐C),
᎐
᎐
᎐
2
2
60.8 (CH2O), 52.0, 49.6 (2 × NCH2); m/z (CI, NH3) 259
(M ϩ NH4ϩ, 53%), 242 (M ϩ Hϩ, 67), 210 (10), 160 (12), 102
(100) (Found: M ϩ Hϩ, 242.0845. C11H15NO3S requires
M ϩ Hϩ, 242.0851).
᎐
᎐
NCH2CO), 3.83 (2H, d, J 7, NCH2CH), 3.61 (3H, s, CO2Me),
1.65 (3H, dd, J 6 and 1.5, MeCH᎐C); δ (67.5 MHz, CDCl )
᎐
C
3
169.4 (CO Me), 139.9 (C᎐CH), 132.6, 131.9, 128.9, 127.3 (CH᎐C
2-(N-Phenylsulfonyl-N-cinnamylamino)ethanol 7b. Rf 0.3
(Et2O–light petroleum, 3:1); νmax(thin film)/cmϪ1 3515 (s), 3060
(w), 3031 (w), 2936 (m), 1147 (m), 1333 (s), 1159 (s); δH(270
MHz, CDCl3) 8.00–7.31 (10H, m, aromatics), 6.56 (1H, d, J 16,
᎐
᎐
2
and MeCH᎐C), 123.6 (MeCH᎐CH), 52.1 (CO Me), 50.1, 46.6
᎐
᎐
2
ϩ
(2 × NCH ), 17.7 (MeCH᎐C); m/z (CI, NH ) 301 (M ϩ NH ,
᎐
2
3
4
16%), 284 (M ϩ Hϩ, 41), 247 (24), 214 (22), 142 (43), 83 (70),
49 (100) (Found: M ϩ Hϩ, 284.0953. C13H17NO4S requires
M ϩ Hϩ, 284.0957).
PhCH), 6.11 (1H, dt, J 16 and 7, PhCH᎐CH), 4.15 (2H, d, J 7,
᎐
NCH2CH), 3.86 (2H, t, J 5, CH2O), 3.42 (2H, t, J 5, NCH2-
CH2), 2.25 (1H, s, CH2OH); δC(67.5 MHz, CDCl3) 139.4, 135.9
Methyl (N-phenylsulfonyl-N-3-methylbut-2-enylamino)ethan-
oate 5c. Rf 0.5 (light petroleum–Et2O, 1:1); νmax(thin film)/
cmϪ1 3060 (m), 2986 (m), 2943 (m), 2919 (m), 1745 (s), 1145 (s),
1338 (s), 1309 (m), 1217 (m), 1158 (s), 1097 (m), 1073 (m);
δH(270 MHz, CDCl3) 7.91–7.52 (5H, m, aromatics), 5.07 (1H, t,
(C᎐CH), 134.3 (PhCH᎐C), 132.8, 129.2, 128.6, 128.1, 127.2,
᎐
᎐
126.4 (CH᎐C), 123.6 (PhCH᎐CH), 61.1 (CH O), 51.6, 49.7
᎐
᎐
2
(2 × NCH2); m/z (CI, NH3) 335 (M ϩ NH4ϩ, 20%), 318
(M ϩ Hϩ, 16), 219 (46), 202 (24), 176 (56), 117 (100) (Found:
M ϩ Hϩ, 318.1175. C17H19NO3S requires M ϩ Hϩ, 318.1164).
3-(N-Allyl-N-phenylsulfonylamino)propanol 7c. Rf 0.5 (Et2O);
νmax(thin film)/cmϪ1 3520–3402 (br, s), 2937 (m), 2879 (m), 1446
(w), 1334 (s), 1159 (s); δH(270 MHz, CDCl3) 7.94–7.56 (5H, m,
J 7.5, C᎐CHCH ), 4.05 (2H, s, NCH CO), 3.96 (2H, d, J 7.5,
᎐
2
2
NCH2CH), 3.65 (3H, s, CO2Me), 1.72, 1.60 (6H, 2 × s,
Me C᎐CH); δ (67.5 MHz, CDCl ) 169.3 (CO Me), 139.7, 139.0
᎐
2
C
3
2
(C᎐CH, MeC᎐CH), 132.4, 128.7, 127.0 (CH᎐C), 117.6 (Me C᎐
᎐
2
᎐
᎐
᎐
CH), 51.8 (CO2Me), 46.3, 45.1 (2 × NCH2), 25.5, 17.4
aromatics), 5.70 (1H, ddt, J 17, 10 and 6.5, CH ᎐CH), 5.29–
᎐
2
(Me C᎐CH); m/z (CI, NH ) 315 (M ϩ NH ϩ, 69%), 298 (13),
5.20 (2H, m, CH ᎐C), 3.93 (2H, d, J 6.5, NCH CH), 3.83 (2H,
᎐
᎐
2
3
4
2
2
247 (100), 228 (26), 156 (96) (Found: M ϩ NH4ϩ, 315.1377.
t, J 6, CH2O), 3.37 (2H, t, J 6, NCH2CH2), 2.26 (1H, br s,
CH2OH), 1.83 (2H, quintet, J 6, CH2CH2CH2); δC(67.5 MHz,
C14H19NO4S requires M ϩ NH4ϩ, 315.1379).
Methyl (N-phenylsulfonyl-N-cinnamylamino)ethanoate 5d.
Mp 69–71 ЊC; Rf 0.4 (light petroleum–Et2O, 2:1); νmax(thin
film)/cmϪ1 1756 (s), 1146 (s), 1340 (s), 1206 (m), 1161 (m), 918
(m), 750 (m), 693 (m); δH(270 MHz, CDCl3) 7.82–7.16 (10H, m,
CDCl ) 140.1 (C᎐CH), 133.3, 133.1, 129.6, 127.5 (CH᎐C and
᎐ ᎐
3
CH ᎐CH), 119.7 (CH ᎐C), 59.1 (CH O), 51.5 (NCH CH), 44.3
᎐
᎐
2
2
2
2
(NCH2CH2), 31.1 (CH2CH2CH2); m/z (CI, NH3) 273 (M ϩ
NH4ϩ, 17), 256 (M ϩ Hϩ, 100), 210 (9), 114 (40) (Found:
M ϩ Hϩ, 256.1000. C12H17NO3S requires M ϩ Hϩ, 256.1007).
3-(N-Phenylsulfonyl-N-cinnamylamino)propanol 7d. Rf 0.4
(Et2O); νmax(thin film)/cmϪ1 3291 (s), 3051 (m), 3029 (s), 2930
(m), 1450 (s), 1341 (m), 1152 (s); δH(270 MHz, CDCl3) 7.98–
aromatics), 6.38 (1H, d, J 16, PhCH᎐CH), 5.95 (1H, dt, J 16
᎐
and 7, PhCH᎐CH), 4.00–3.99 (4H, m, 2 × NCH ), 3.51 (3H, s,
᎐
2
CO2Me); δC(67.5 MHz, CDCl3) 169.3 (CO2Me), 139.7, 135.8
(C᎐CH), 134.8 (PhCH᎐CH), 132.7, 128.9, 128.6, 128.1, 127.3,
᎐
᎐
126.5 (CH᎐C), 123.0 (PhCH᎐CH), 52.1 (CO Me), 50.4, 46.9
7.31 (10H, m, aromatics), 6.54 (1H, d, J 16, PhCH᎐C), 6.06
᎐
᎐
᎐
2
ϩ
(2 × NCH2); m/z (CI, NH3) 363 (M ϩ NH4
,
8%), 346
(1H, dt, J 16 and 7, PhCH᎐CH), 4.10 (2H, d, J 7, NCH -
᎐
2
ϩ
(M ϩ Hϩ, 1), 247 (54), 204 (49), 117 (100) (Found: M ϩ NH4
363.1377. C18H19NO4S requires M ϩ NH4ϩ, 363.1379).
,
CH᎐C), 3.85 (2H, t, J 6, CH O), 3.43 (2H, t, J 6, NCH CH ),
᎐
2
2
2
2.32 (1H, br s, CH2OH), 1.85 (2H, quintet, J 6, CH2CH2CH2);
δ (67.5 MHz, CDCl ) 139.7, 135.7 (C᎐CH), 134.1 (PhCH᎐CH),
᎐
᎐
C
3
General procedure for the preparation of sulfonamides 7a–d
132.6, 129.2, 128.6, 128.0, 127.1, 126.4 (CH᎐C), 123.6 (PhCH᎐
᎐ ᎐
To a solution of amino alcohol 6a–b (13.3–65.6 mmol) in dry
CH2Cl2 (50–100 cm3) was added Et3N (14.6–72.1 mmol),
TBDMSCl (14.6–72.1 mmol) and a catalytic quantity of
DMAP. The reaction was then allowed to stir at room temper-
ature for 12 h. Water (100 cm3) was added, the mixture was
stirred vigorously for 0.1 h and the organic layer was separated,
washed with more water (50 cm3), brine (50 cm3), dried
(MgSO4) and evaporated in vacuo to afford crude silylated
alcohol which was dissolved in CH2Cl2 (10–100 cm3) and cooled
to 0 ЊC. Et3N (14.6–72.1 mmol) followed by PhSO2Cl (14.6–
72.1 mmol) [dissolved in CH2Cl2 (5–10 cm3)] was then added
gradually over 0.1 h and the reaction allowed to warm to room
temperature and stirred for 1 h. The solvent was then removed
in vacuo and the residue dissolved in EtOAc, washed with water,
brine, dried (MgSO4) and evaporated in vacuo to afford an oil.
Column chromatography (silica) afforded the desired protected
amino alcohols (82–85%) as colourless oils. The sulfonamide
was then N-alkylated using the same method as described
earlier for the preparation of 5a–d and the resultant silyl pro-
tected alcohol (0.67–1.37 mmol) was dissolved in MeOH (10–20
cm3), containing a catalytic quantity of p-TsOH. The solution
was allowed to stir overnight at room temperature and evapor-
ation of the solvent in vacuo followed by column chromato-
graphy (silica; Et2O or Et2O–light petroleum) afforded alcohol
7a–d (72–88%) as a colourless oil.
CH), 58.7 (CH2O), 50.5, 43.9 (2 × NCH2), 30.8 (CH2CH2CH2);
m/z (CI, NH3) 349 (M ϩ NH4ϩ, 20%), 332 (M ϩ Hϩ, 70), 233
(35), 216 (19), 190 (43), 134 (32), 117 (100) (Found: M ϩ Hϩ,
332.1322. C18H21NO3S requires M ϩ Hϩ, 332.1320).
General procedure for the synthesis and cyclisation of á-amino
aldehydes 8a–d
To a solution of methyl ester 5a–d (0.54–0.81 mmol) in dry
toluene (10–100 cm3) was added DIBAL-H (1  solution in
hexanes, 0.92–1.38 mmol) dropwise while stirring at Ϫ78 ЊC
under a nitrogen atmosphere. After 1.5 h MeOH (1–2 cm3)
was added dropwise to quench the reaction, followed by 10%
aqueous citric acid (20–50 cm3) to solubilise the complex. The
mixture was allowed to warm to room temperature and stirred
for 1 h. EtOAc (20 cm3) was added and the organic layer was
separated, washed with brine, dried (MgSO4) and evaporated in
vacuo to afford the crude amino aldehyde 8a–d as a clear oil.
This was immediately dissolved in degassed benzene (5–8 cm3)
and Bu3SnH (0.81–1.22 mmol) and AIBN (0.10–0.16 mmol)
were added in degassed benzene (0.5 cm3) under a nitrogen
atmosphere. The reaction mixture was then heated at reflux
until starting material was consumed as indicated by TLC (2–12
h) [additional portions of AIBN (0.1 mmol) were added at 2 h
intervals]. The reaction mixture was then concentrated in vacuo
and the crude product was separated by flash column chrom-
atography (silica; Et2O–light petroleum) to afford pyrroldinol
9a–d (36–52%) as a colourless oil or a white solid.
2-(N-Allyl-N-phenylsulfonylamino)ethanol 7a. Rf 0.4 (Et2O);
νmax(thin film)/cmϪ1 3400–3357 (br, m), 1148 (w), 1372 (m), 1347
(m), 1159 (s), 1089 (s); δH(270 MHz, CDCl3) 7.87–7.50 (5H, m,
aromatics), 5.65 (1H, ddt, J 17, 10 and 6.5, CH ᎐CH), 5.23–
1-Phenylsulfonyl-4-methylpyrrolidin-3-ol 9a. Rf 0.2 (Et2O–
light petroleum, 3:1); νmax(thin film)/cmϪ1 3514 (br, s), 1472 (w),
1447 (m), 1333 (s), 1219 (m), 1162 (s), 1094 (s), 1074 (m), 1054
᎐
2
5.14 (2H, m, CH ᎐CH), 3.87 (2H, d, J 6.5, NCH CH), 3.74
᎐
2
2
J. Chem. Soc., Perkin Trans. 1, 1998
655

View Article Online
(m); δH(270 MHz, CDCl3) (two diastereomers) 7.93–7.58 (5H,
m, aromatics), 4.20 and 3.93 (1H, 2 × br m, CHOH), 3.64–3.53
(2H, m, 2 × NCH), 3.43 (1H, dd, J 11.5 and 1.46, NCH), 3.26
(1H, dd, J 10.5 and 3.5, NCH), 2.17–2.12 (1H, m, MeCH), 1.95
(1H, br s, CHOH), 1.06 and 0.94 (3H, d, J 7, MeCH); δC(67.5
MHz, CDCl ) (2 diastereomers) 137.4, 137.0 (C᎐CH), 133.1,
m, PhCH2CH), 1.57 (1H, br s, OH); δC(67.5 MHz, CDCl3)
139.9, 137.5 (C᎐CH), 133.2, 133.1, 129.7, 129.5, 129.1, 128.9,
᎐
127.8, 127.7, 126.9, 128.8 (CH᎐C), 71.6 (CHOH), 57.2, 50.8
᎐
(2 × NCH2), 46.5 (PhCH2CH), 32.9 (PhCH2CH); m/z (CI,
NH3) 318 (M ϩ Hϩ, 100%), 176 (48), 158 (18), 130 (14) (Found:
M ϩ Hϩ, 318.1166. C17H19NO3S requires M ϩ Hϩ, 318.1164).
᎐
3
129.5, 127.8 (CH᎐C), 76.7, 66.3 (CHOH), 56.8, 54.6, 53.1, 52.3
Minor diastereoisomer; Rf 0.2 (Et2O–light petroleum, 2:1); νmax-
᎐
(2 × NCH2), 41.4, 38.9 (MeCH), 15.7, 11.2 (MeCH); m/z (CI,
NH3) 259 (M ϩ NH4ϩ, 23%), 242 (M ϩ NH4ϩ, 100), 100 (26)
(Found: M ϩ Hϩ, 242.0849. C11H15NO3S requires M ϩ Hϩ,
242.0851).
1-Phenylsulfonyl-4-ethylpyrrolidin-3-ol 9b. Major diastereo-
isomer; Rf 0.4 (Et2O–light petroleum, 4:1); νmax(thin film)/cmϪ1
3515 (br, s), 1446 (m), 1332 (s), 1163 (s), 1094 (m); δH(270 MHz,
CDCl3) 7.78–7.42 (5H, m, aromatics), 4.13 (1H, t, J 3.5,
CHOH), 3.44 (1H, app. t, J 9, NCH), 3.36–3.33 (2H, m,
2 × NCH), 2.91 (1H, app. t, J 10, NCH), 1.97–1.16 (4H, m,
MeCH2, MeCH2CH and CHOH), 0.93 (3H, t, J 7.5, MeCH2);
(thin film)/cmϪ1 3448 (br, s), 1446 (m), 1335 (s), 1160 (s),
1096 (m), 1074 (m), 1034 (m); δH(270 MHz, CDCl3) 7.77–
6.97 (10H, m, aromatics), 3.98–3.93 (1H, m, CHOH), 3.54 (1H,
dd, J 11 and 5.5, NCH), 3.33 (1H, dd, J 10 and 7.0, NCH), 3.11
(1H, dd, J 11 and 3.5, NCH), 3.02 (1H, dd, J 10 and 5, NCH),
2.54 (1H, dd, J 14 and 7, PhCH), 2.36 (1H, dd, J 14 and 7,
PhCH), 2.27–2.12 (1H, m, PhCH2CH), 1.57 (1H, br s, OH);
δ (67.5 MHz, CDCl ) 138.6, 136.5 (C᎐CH), 132.8, 129.1, 128.7,
᎐
C
3
127.4, 126.6 (CH᎐C), 74.5 (CHOH), 54.3, 50.6 (2 × NCH ), 48.0
᎐
2
ϩ
,
(PhCH2CH), 32.9 (PhCH2CH); m/z (CI, NH3) 335 (M ϩ NH4
14%), 318 (M ϩ Hϩ, 100), 247 (8), 176 (32), 158 (18) (Found:
M ϩ Hϩ, 318.1166. C17H19NO3S requires M ϩ Hϩ, 318.1164).
δ (67.5 MHz, CDCl ) 137.0 (C᎐CH), 132.7, 129.1, 127.2
᎐
C
3
(CH᎐C), 71.3 (CHOH), 56.7, 50.4 (2 × NCH ), 48.0 (MeCH -
᎐
2
2
CH), 26.5 (MeCH2), 12.0 (MeCH2); m/z (CI, NH3) 255
(M ϩ Hϩ, 11%), 224 (5), 170 (13), 141 (100), 114 (75) (Found:
M ϩ Hϩ, 255.0927. C12H17NO3S requires M ϩ Hϩ, 255.0929).
Minor diastereoisomer; Rf 0.37 (Et2O–light petroleum, 4:1);
νmax(thin film)/cmϪ1 3515 (br, m), 1462 (m), 1446 (m), 1333 (s),
1162 (s), 1094 (m); δH(270 MHz, CDCl3) 7.79–7.43 (5H, m,
aromatics), 3.91–3.86 (1H, m, CHOH), 3.47–3.33 (2H, m,
2 × NCH), 3.10 (1H, dd, J 10.5 and 4, NCH), 2.94 (1H, dd,
J 10.5 and 5.5, NCH), 1.87–1.75 (2H, m, MeCH2), 1.10–0.83
(2H, m, MeCH2CH and CHOH), 0.79 (3H, t, J 7.5,
General procedure for oxidation and cyclisation of alcohols 7c–d
DMSO (1.74–5.44 mmol) was added dropwise to a solution of
(COCl)2 (0.88–2.73 mmol) in dry CH2Cl2 (10–20 cm3) at Ϫ60 ЊC
under nitrogen and the resulting mixture was stirred for 0.25 h
at the same temperature. A solution of alcohol 7c–d (0.29–1.36
mmol) in dry CH2Cl2 (5 cm3) was added dropwise and the reac-
tion was stirred for 0.5 h. Et3N (2.03–6.80 mmol) was then
added dropwise and the mixture was stirred for 0.5 h while
warming to 0 ЊC. The suspension was poured into water (50
cm3) and the mixture was extracted with Et2O (2 × 20 cm3). The
organic extracts were washed with more water, dried (MgSO4)
and evaporated to give 10a–b as a pale yellow liquid. This was
immediately dissolved in degassed benzene (3–25 cm3) and
Bu3SnH (0.58–1.86 mmol) and AIBN (0.03–0.30 mmol) were
added in degassed benzene (0.5 cm3) under a nitrogen atmos-
phere. The reaction mixture was then heated at reflux until
starting material was consumed (2–12 h) [additional portions
of AIBN (0.1 mmol) were added at 2 h intervals if required],
then concentrated in vacuo and the crude product was separated
by flash column chromatography (silica).
MeCH ); δ (67.5 MHz, CDCl ) 136.4 (C᎐CH), 132.8, 129.3,
᎐
2
C
3
127.4 (CH᎐C), 75.0 (CHOH), 54.5, 50.9 (2 × NCH ), 48.3
᎐
2
(MeCH2CH), 24.1 (MeCH2), 12.0 (MeCH2); m/z (CI, NH3)
255 (M ϩ Hϩ, 10%), 170 (7), 114 (65), 77 (64), 42 (100) (Found:
M ϩ Hϩ, 255.0938. C12H17NO3S requires M ϩ Hϩ, 255.0929).
1-Phenylsulfonyl-4-isopropylpyrrolidin-3-ol 9c. Major dia-
stereoisomer; Rf 0.3 (Et2O–light petroleum, 2:1); νmax(thin film)/
cmϪ1 3515 (s), 2960 (m), 2875 (m), 1469 (m), 1447 (m), 1335 (s),
1164 (s), 1097 (m), 1075 (m), 1026 (m); δH(270 MHz, CDCl3)
7.86–6.50 (5H, m, aromatics), 4.06 (1H, app. q, J 5.5, CHOH),
3.47–3.39 (2H, m, NCH2), 3.13 (1H, dd, J 10.5 and 4.5, NCH),
2.93 (1H, dd, J 11 and 7.0, NCH), 2.05 (1H, br s, CHOH),
1.80–1.40 (2H, m, Me2CH and Me2CHCH), 0.92 (3H, d, J 7,
MeCH), 0.83 (3H, d, J 7, MeCH); δC(67.5 MHz, CDCl3) 135.9
1-Phenylsulfonyl-3-benzylpiperidin-4-ol 11a. Following the
general procedure, alcohol 7d (96 mg, 0.29 mmol) was oxidised
to aldehyde 10a; νmax(thin film)/cmϪ1 2924 (s), 2554 (m), 1722
(s), 1448 (m), 1338 (m), 1559 (s); δH(270 MHz, CDCl3) 9.74 (1H,
d, J 1, CHO), 7.86–7.20 (5H, m, aromatics), 6.42 (1H, d, J 16,
(C᎐CH), 132.8, 129.0, 127.6 (CH᎐C), 73.4 (CHOH), 55.0, 49.9
᎐
᎐
(2 × NCH2), 55.1 (Me2CHCH), 29.3 (Me2CH), 21.7, 21.3
(Me2CH); m/z (CI, NH3) 287 (M ϩ NH4ϩ, 22%), 270 (M ϩ Hϩ,
100), 128 (26) (Found: M ϩ Hϩ, 270.1150. C13H19NO3S
requires M ϩ Hϩ, 270.1164). Minor diastereoisomer; Rf 0.3
(Et2O–light petroleum, 2:1); νmax(thin film)/cmϪ1 3516 (br, m),
2959 (m), 2874 (m), 1468 (m), 1146 (m), 1368 (s), 1333 (s), 1221
(m), 1163 (s), 1003 (s), 1054 (m), 757 (m); δH(270 MHz, CDCl3)
7.89–7.45 (5H, m, aromatics), 4.24–4.22 (1H, m, CHOH), 3.53
(1H, app. t, J 8.5, NCH), 3.42–3.41 (2H, m, 2 × NCH), 3.04
(1H, app. t, J 10, NCH), 1.91 (1H, br s, CHOH), 1.77–1.47
(2H, m, Me2CH and Me2CHCH), 0.93 (3H, d, J 6.5, MeCH),
PhCH᎐CH), 5.96 (1H, dt, J 16 and 7, PhCH᎐CH), 3.97 (2H,
᎐ ᎐
d, J 7, NCH CH᎐CH), 3.48 (2H, t, J 7, NCH CH ), 2.85 (2H, t,
᎐
2
2
2
J 7, NCH2CH2). Crude 10a was then treated with Bu2SnH (167
mg, 0.58 mmol) and AIBN (5 mg, 0.03 mmol) and flash column
chromatography (silica; Et2O–light petroleum, 4:1) afforded
piperidinol 11a (55 mg, 56%) as separable diastereoisomers in
the ratio 1.3:1 and alcohol 7d (4 mg, 4%) which was inseparable
from the major diastereoisomer. Major diastereoisomer; Rf 0.3
(Et2O–light petroleum, 4:1); νmax(thin film)/cmϪ1 3454 (br, s),
1452 (w), 1334 (m), 1161 (s), 1085 (m), 1062 (m), 1019 (m), 751
(m); δH(270 MHz, CDCl3) 7.69–7.09 (10H, m, aromatics), 3.64
(1H, m, CHOH), 3.41–3.27 (2H, m, 2 × NCH), 2.78–2.61 (1H,
m, NCH), 2.56–2.48 (3H, m, PhCH2 and NCH), 2.01–1.95
(1H, m, PhCH2CH), 1.73–1.68 (2H, m, CH2CH2CH2), 1.52
0.86 (3H, d, J 6.5, MeCH); δ (67.5 MHz, CDCl ) 137.6 (C᎐CH),
᎐
C
3
133.1, 129.6, 128.0 (CH᎐C), 71.3 (CHOH), 57.6, 50.3 (2 ×
᎐
NCH2), 52.5 (Me2CHCH), 26.5 (Me2CH), 21.9, 21.4 (Me2CH);
m/z (CI, NH3) 287 (M ϩ NH4ϩ, 19%), 270 (M ϩ Hϩ, 100), 219
(6), 128 (16) (Found: M ϩ Hϩ, 270.1151. C13H19NO3S requires
M ϩ Hϩ, 270.1164).
1-Phenylsulfonyl-4-benzylpyrrolidin-3-ol 9d. Major diastereo-
isomer (Found: C, 64.14; H, 6.25; N, 4.39. C17H19NO3S requires
C, 64.33; H, 6.03; N, 4.41%); Rf 0.3 (Et2O–light petroleum,
2:1); νmax(thin film)/cmϪ1 3514 (br, s), 1446 (m), 1333 (m), 1161
(s), 1092 (m), 1056 (m); δH(270 MHz, CDCl3) 7.78–7.04 (10H,
m, aromatics), 4.03–4.02 (1H, m, CHOH), 3.42–3.28 (3H, m,
3 × NCH), 3.03 (1H, app. t, J 11, NCH), 2.72 (1H, dd, J 14 and
8, PhCH), 2.55 (1H, dd, J 14 and 7.5, PhCH), 2.23–2.15 (1H,
(1H, s, OH); δ (67.5 MHz, CDCl ) 139.0, 136.2 (C᎐CH), 133.7,
᎐
C
3
129.0, 128.6, 128.4, 127.9, 127.5, 126.3 (CH᎐C), 64.7 (CHOH),
᎐
45.7 (NCH2), 42.1 (PhCH2CH), 41.1 (NCH2), 34.8, 32.3
ϩ
,
(PhCH2CH and CH2CH2CH2); m/z (CI, NH3) 349 (M ϩ NH4
37%), 332 (M ϩ Hϩ, 100), 192 (49), 172 (12) (Found: M ϩ Hϩ,
332.1314. C18H21NO3S requires M ϩ Hϩ, 332.1320). Minor
diastereoisomer; Rf 0.2 (Et2O–light petroleum, 4:1); νmax(thin
film)/cmϪ1 3454 (br, s), 1542 (m), 1334 (m), 1161 (s), 1085 (m),
1062 (m), 1019 (m), 751 (m); δH(270 MHz, CDCl3) 7.79–7.08
(10H, m, aromatics), 3.44–3.22 (2H, m, CHOH and NCH),
2.88 (1H, dd, J 14 and 5, NCH), 2.72–2.29 (3H, m, NCH and
656
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
PhCH2), 1.98–1.77 (2H, m, NCH and PhCH2CH), 1.69–1.51
(2H, m, CH2CH2CH2), 1.49 (1H, br s, OH); δC(67.5 MHz,
column chromatography (silica; light petroleum–Et2O, 1:1)
afforded stananne 14 (102 mg, 14%) and alcohol 13 (104 mg,
32%). Stannane 14. Rf 0.4 (light petroleum–Et2O, 1:1); δH(270
MHz, CDCl3) 7.86–7.52 (5H, m, aromatics), 6.01 (1H, d, J 2,
CDCl ) 139.4, 136.7 (C᎐CH), 133.2, 129.0, 128.5, 127.5, 126.8
᎐
3
(CH᎐C), 70.6 (CHOH), 47.7, 44.2 (2 × NCH2), 44.6
᎐
(PhCH2CH), 36.4, 32.4 (PhCH2CH and CH2CH2CH2); m/z (CI,
NH3) 349 (M ϩ NH4ϩ, 45%), 332 (M ϩ Hϩ, 100), 233 (10), 192
(55), 172 (16) (Found: M ϩ Hϩ, 332.1313. C18H21NO3S requires
M ϩ Hϩ, 332.1320).
C᎐CHSn), 4.35–4.31 (1H, m, CHOH), 3.82 (1H, dd, J 14 and 2,
᎐
NCH), 3.77 (1H, dd, J 14 and 6, NCH), 3.48 (1H, dd, J 10.5
and 5.5, NCHCH), 3.27 (1H, dd, J 10.5 and 5.5, NCHCH),
1.68–1.18 [18H, m, 3 × Sn(CH2)3Me], 0.87 [9H, t, J 7.5,
3 × Sn(CH ) Me]; δ (67.5 MHz, CDCl ) 154.0 (C᎐CHSn),
᎐
2
3
C
3
Oxidation and radical cyclisation of 3-(N-allyl-N-phenylsulfonyl-
amino)propanol 7c
135.6 (C᎐CH), 132.9, 129.1, 127.8, 126.8 (CH᎐C, C᎐CHSn),
᎐ ᎐ ᎐
72.6 (CHOH), 56.1, 52.9 (2 × NCH2), 28.9, 27.2 [SnCH2-
(CH2)2Me], 13.6 [SnCH2(CH2)2Me], 10.5 [SnCH2(CH2)2Me];
m/z (CI, NH3) 529 (119M ϩ Hϩ, 68%), 472 (77), 433 (18), 388
(16), 358 (15), 330 (15), 308 (39), 291 (36), 257 (21), 240 (100)
(Found: 116M ϩ Hϩ, 526.1748. C23H39NO3SSn requires 116M ϩ
Hϩ, 526.1755).
Following the general procedure, alcohol 7c (237 mg, 0.93
mmol) was oxidised to aldehyde 10b; δH(270 MHz, CDCl3) 9.69
(1H, t, J 1, CHO), 7.77–7.43 (5H, m, aromatics), 5.62–5.49 (2H,
m, CH ᎐CH), 5.12 (1H, app. t, J 8, CH ᎐CH), 3.75 (2H, d, J 6.5,
᎐
᎐
2
2
NCH CH᎐CH), 3.36 (2H, t, J 7.5, NCH CH ), 2.76 (2H, td,
᎐
2
2
2
J 7.5 and 1, NCH2CH2CHO). Crude 10b was then treated with
Bu3SnH (541 mg, 1.86 mmol) and AIBN (15 mg, 0.10 mmol)
and flash column chromatography of the residue (silica; Et2O–
light petroleum, 4:1), afforded piperidinol 11b (98 mg, 40%) as
separable diastereoisomers in the ratio 1.2:1, azepane 12 (18
mg, 8%) and alcohol 7c (16 mg, 7%).
1-Phenylsulfonyl-3-methylpiperidin-4-ol 11b. Major diastereo-
isomer (Found: C, 56.31; H, 6.98; N, 5.39. C12H17NO3S requires
C, 56.45; H, 6.71; N, 5.49%); Rf 0.3 (Et2O–light petroleum,
4:1); νmax(thin film)/cmϪ1 3450 (br, s), 1454 (w), 1331 (m), 1162
(s), 1089 (m), 1020 (m), 986 (w), 750 (m), 580 (w); δH(270 MHz,
CDCl3) 7.85–7.49 (5H, m, aromatics), 3.84–3.77 (2H, m,
CHOH and NCH), 3.45–3.32 (1H, m, NCH), 2.80–2.70 (1H,
m, NCH), 2.47 (1H, t, J 11, NCH), 1.98–1.89 (1H, m, MeCH),
1.86–1.80 (2H, m, CH2CH2CH2), 1.59 (1H, br s, OH), 1.00 (3H,
General procedure for ozonolysis of 7a and 7c
To a solution of alkene 7a or 7c (3.41–43.6 mmol) in MeOH at
Ϫ78 ЊC was passed ozone until the solution became pale blue. A
stream of oxygen, followed by nitrogen was then passed through
the solution for 0.2 h. The reaction mixture was then treated
with DMS (6.82–87.2 mmol), warmed to room temperature and
stirred under a nitrogen atmosphere for 0.5 h. The methanol
was then removed in vacuo and the residue was purified by col-
umn chromatography (silica) to afford lactol 16–17 (81–90%).
2-Hydroxy-4-phenylsulfonylmorpholine 16. Mp 191–193 ЊC
(Found: C, 49.51; H, 5.44; N, 5.42; S, 13.15. C10H13NO4S
requires C, 49.37; H, 5.39; N, 5.76; S, 13.18%); Rf 0.4 (Et2O–
light petroleum, 9:1); νmax(thin film)/cmϪ1 3467–3444 (br, s),
1636 (w), 1449 (m), 1346 (s), 1271 (s), 1168 (s), 1122 (m), 1090
(s), 1056 (m), 967 (s); δH(270 MHz, CDCl3) 7.83–7.53 (5H, m,
aromatics), 4.96 (1H, dd, J 5.5 and 2.5, CHOH), 4.07–3.99 (1H,
m, NCH), 3.72–3.64 (1H, m, NCH), 3.30 (1H, dd, J 11.5 and
1.5, NCH), 3.16–3.09 (1H, m, CH2O), 2.90–2.82 (1H, m,
CH2O), 2.70 (1H, dd, J 11.5 and 5.5, NCH), 1.71 (1H, br s,
d, J 6.5, MeCH); δ (67.5 MHz, CDCl ) 139.5 (C᎐CH), 132.8,
᎐
C
3
128.9, 127.5 (CH᎐C), 67.2 (CHOH), 47.0 (NCH CH), 40.8
᎐
2
(NCH2CH2), 34.9 (MeCH), 32.9 (CH2CH2CH2), 14.1 (MeCH);
m/z (CI, NH3) 273 (M ϩ NH4ϩ, 9%), 256 (M ϩ Hϩ, 100), 116
(56) (Found: M ϩ Hϩ, 256.1004. C12H17NO3S requires M ϩ
Hϩ, 256.1007). Minor diastereoisomer; Rf 0.24 (Et2O–light
petroleum; 4:1); νmax(thin film)/cmϪ1 3394 (br, s), 2942 (m),
1451 (w), 1337 (m), 1164 (s), 1089 (m), 1057 (m), 1021 (m), 753
(w); δH(270 MHz, CDCl3) 7.78–7.51 (5H, m, aromatics), 3.72–
3.58 (2H, m, CHOH, NCH), 3.15 (1H, dd, J 9.5 and 4, NCH),
2.49 (1H, td, J 11.5 and 3, NCH), 2.14 (1H, dd, J 11.5 and
10, NCH), 2.02–1.93 (1H, m, MeCH), 1.77–1.50 (3H, m,
CH2CH2CH2 and CHOH), 0.95 (3H, d, J 6.5, MeCH); δC(67.5
CHOH); δ (67.5 MHz, CDCl ) 135.1 (C᎐CH), 133.3, 129.3,
᎐
C
3
127.8 (CH᎐C), 91.1 (CHOH), 61.6 (CH2O), 50.2, 45.0
᎐
(2 × NCH2); m/z (CI, NH3) 261 (M ϩ NH4ϩ, 58%), 244
(M ϩ Hϩ, 73), 226 (75), 102 (100) (Found: M ϩ Hϩ, 244.0640.
C10H13NO4S requires M ϩ Hϩ, 244.0644).
2-Hydroxy-1,4-oxazepane 17. Rf 0.2 (Et2O–light petroleum,
4:1); νmax(thin film)/cmϪ1 3460–3358 (m), 1447 (m), 1333 (s),
1158 (s), 1092 (s), 1044 (s), 1027 (s); δH(270 MHz, CDCl3) 7.82–
7.50 (5H, m, aromatics), 5.21 (1H, dd, J 7.5 and 4, CHOH),
4.06–3.97 (1H, m, NCH), 3.87–3.61 (3H, m, 3 × NCH), 3.04–
2.85 (3H, m, CH2O and CHOH), 2.04–1.80 (2H, m, CH2CH2-
MHz, CDCl ) 136.4 (C᎐CH), 132.8, 129.2, 127.7 (CH᎐C), 73.2
᎐
᎐
3
(CHOH), 50.7 (NCH2CH), 44.8 (NCH2CH2), 38.2 (MeCH),
33.1 (CH2CH2CH2), 15.1 (MeCH); m/z (CI, NH3) 273
(M ϩ NH4ϩ, 22%), 256 (M ϩ Hϩ, 100), 114 (26) (Found:
M ϩ Hϩ, 256.1003. C12H17NO3S requires M ϩ Hϩ, 256.1007).
1-Phenylsulfonyl-4-hydroxyazepane 12. Rf 0.2 (Et2O–light
petroleum, 4:1); νmax(thin film)/cmϪ1 3439 (br, s), 1448 (w), 1329
(m), 1158 (s), 1092 (m), 1042 (w), 730 (w), 579 (w); δH(270 MHz,
CDCl3) 7.82–7.45 (5H, m, aromatics), 3.99–3.92 (1H, m,
CHOH), 3.44–3.15 (4H, m, 2 × NCH2), 2.07–1.60 (7H, m,
NCH2CH2CH, CH2CH2CH2CH, CH2CH2CH2 and CHOH);
CH ); δ (67.5 MHz, CDCl ) 139.0 (C᎐CH), 132.7, 129.1, 126.9
᎐
2
C
3
(CH᎐C), 94.3 (CHOH), 60.9 (CH O), 53.5, 49.0 (2 × NCH ),
᎐
2
2
30.6 (CH2CH2CH2); m/z (CI, NH3) 275 (M ϩ NH4ϩ, 81%), 257
(M ϩ Hϩ, 100), 240 (35), 233 (9), 219 (15) (Found: M ϩ NH4
275.1067. C11H15NO4S requires M ϩ NH4ϩ, 275.1066).
,
ϩ
General procedure for the preparation of alkenes 18a–d
To a solution of lactol 16–17 (1.15–2.91 mmol) in dry CH2Cl2
δ (67.5 MHz, CDCl ) 139.1 (C᎐CH), 132.4, 129.1, 127.0
(10–25 cm3) at room temperature was added Ph P᎐CHCO Et
᎐
᎐
C
3
3
2
(CH᎐C), 73.0 (CHOH), 48.8, 42.6 (2 × NCH ), 37.9, 34.8 (2 ×
(2.30–5.82 mmol). The reaction was then heated at reflux under
a nitrogen atmosphere until the starting material had been con-
sumed as shown by TLC (8–12 h). The CH2Cl2 was removed in
vacuo and Et2O (25 cm3) added. A white precipitate was formed
which was removed by filtering the mixture through Celite. The
filtrate was then concentrated and column chromatography
(silica) afforded the desired alkenes 18a–d (24–31%).
(Z)-Ethyl 4-[N-phenylsulfonyl-N-(2-hydroxyethyl)amino]but-
2-enoate 18a. Rf 0.3 (Et2O–light petroleum, 9:1); νmax(thin film)/
cmϪ1 3518–3427 (m), 2392 (m), 1711 (s), 1411 (m), 1336 (s),
1164 (s), 1093 (m), 1031 (m); δH(270 MHz, CDCl3) 7.87–7.51
᎐
2
CH2CHOH), 22.4 (CH2CH2CH2); m/z (CI, NH3) 273 (M ϩ
NH4ϩ, 7%), 256 (M ϩ Hϩ, 78), 238 (10), 114 (100), 96 (15),
85 (25) (Found: M ϩ Hϩ, 256.1004. C12H17NO3S requires
M ϩ Hϩ, 256.1007).
Oxidation and cyclisation of 2-(N-phenylsulfonyl-N-prop-2-ynyl-
amino)ethanol 13
Following the general procedure, alcohol 13 (326 mg, 1.36
mmol) was oxidised to the amino aldehyde; δH(270 MHz,
CDCl3) 9.68 (1H, s, CHO), 7.71–7.05 (5H, m, aromatics), 4.05
᎐
(2H, d, J 2.5, NCH C᎐C), 3.97 (2H, s, NCH CHO), 2.02 (1H, t,
(5H, m, aromatics), 6.25 (1H, dt, J 11.5 and 6, NCH CH᎐C),
᎐
2
5.86 (1H, d, J 11.5, CH OCOCH᎐C), 4.46 (2H, d, J 6, NCH -
᎐
2 2
᎐
2
2
᎐
J 2.5, C᎐CH). The crude aldehyde was immediately treated
᎐
with Bu3SnH (594 mg, 2.04 mmol) and purification by flash
CH), 4.16 (2H, q, J 7, MeCH2CO2), 3.76 (2H, t, J 5.5, CH2O),
J. Chem. Soc., Perkin Trans. 1, 1998
657

View Article Online
3.32 (2H, t, J 5.5, NCH2CH2), 2.43 (1H, br s, CH2OH), 1.27
(3H, t, J 7, MeCH2CO); δC(67.5 MHz, CDCl3) 165.9 (CO2CH2),
329.1176. C14H17NO5S requires M ϩ NH4ϩ, 329.1171). Alde-
hyde 19a was then reacted with Bu3SnH (236 mg, 0.81 mmol)
and AIBN (9 mg, 0.05 mmol) and after 2 h the solvent was
removed in vacuo and flash column chromatography (silica;
Et2O) yielded 20a (30 mg, 27%) and 21a (27 mg, 29%).
(3R*,4S*)-1-Phenylsulfonyl-4-(ethoxycarbonylmethyl)pyrrol-
idin-3-ol 20a. Rf 0.3 (Et2O); νmax(thin film)/cmϪ1 3446 (br, m),
1726 (s), 1340 (s), 1268 (m), 1163 (s), 1097 (m), 1030 (m), 606
(m), 574 (m); δH(270 MHz, CDCl3) 7.84–7.52 (5H, m, aro-
matics), 4.13 (2H, q, J 7, OCH2Me), 4.03–3.97 (1H, m, CHOH),
3.64 (1H, dd, J 10.5 and 6.5, NCH), 3.58–3.49 (1H, m, NCH),
3.09 (1H, dd, J 10.5 and 5.5, NCH), 3.04–2.95 (2H, m, NCH
and CHCH2CO), 2.34 (2H, d, J 5, CHCH2CO), 1.25 (3H, t, J 7,
MeCH2CO); δC(67.5 MHz, CDCl3) 172.6 (CO2CH2), 136.1
145.8 (NCH CH᎐C), 139.0 (C᎐CH), 132.9, 129.3, 127.2
᎐
᎐
2
(CH᎐C), 121.8 (CH CO CH᎐C), 61.0, 60.5 (CH CO CH᎐C
᎐
᎐
᎐
2
2
2
2
and CH2O), 51.3, 48.0 (2 × NCH2), 14.2 (MeCH2); m/z (CI,
NH3) 331 (M ϩ NH4ϩ, 18%), 314 (M ϩ Hϩ, 100), 268 (11), 219
(12), 202 (9) (Found: M ϩ Hϩ, 314.1055. C14H19NO5S requires
M ϩ Hϩ, 314.1062).
(E)-Ethyl 4-[N-phenylsulfonyl-N-(2-hydroxyethyl)amino]but-
2-enoate 18b. Rf 0.2 (Et2O–light petroleum, 9:1); νmax(thin film)/
cmϪ1 3506–3455 (m), 2929 (m), 1715 (s), 1660 (m), 1446 (m),
1336 (s), 1272 (s), 1160 (s), 1089 (m), 1039 (m); δH(270 MHz,
CDCl3) 7.87–7.51 (5H, m, aromatics), 6.72 (1H, dt, J 16 and
6, NCH CH᎐C), 5.92 (1H, d, J 16, CH OCOCH᎐C), 4.17
᎐
᎐
2
2
(2H, q, J 7.5, MeCH2CO2), 4.06 (1H, d, J 6, NCH2CH), 3.76
(2H, t, J 5.5, CH2O), 3.30 (2H, t, J 5.5, NCH2CH2), 2.16
(1H, br s, CH2OH), 1.27 (3H, t, J 7.5, MeCH2CO); δC(67.5
(C᎐CH), 132.9, 129.1, 127.6 (CH᎐C), 74.9 (CHOH), 61.2
᎐ ᎐
(OCH2Me), 54.1, 51.2 (2 × NCH2), 42.4 (CHCH2CO), 36.0
(CHCH2CO), 14.1 (MeCH2CO); m/z (CI, NH3) 331 (M ϩ
NH4ϩ, 36%), 314 (M ϩ Hϩ, 100), 174 (36) (Found: M ϩ Hϩ,
314.1064. C14H19NO5S requires M ϩ Hϩ, 314.1062).
MHz, CDCl ) 165.6 (CO CH ), 142.1 (NCH CH᎐C), 139.1
᎐
3
2
2
2
(C᎐CH), 133.2, 129.3, 127.2, (CH᎐C), 124.2 (CH OCO-
᎐
᎐
2
CH᎐C), 60.9, 60.6 (CH CO CH᎐C and CH O), 50.3, 50.0
(1R*,5R*)-7-Phenylsulfonyl-2-oxa-7-azabicyclo[3.3.0]octan-
3-one 21a. Rf 0.1 (Et2O); νmax(thin film)/cmϪ1 1779 (s), 1447 (w),
1345 (m), 1166 (s), 1105 (m), 1043 (m), 1023 (m); δH(270 MHz,
CDCl3) 7.77–7.47 (5H, m, aromatics), 4.90 (1H, t, J 7, CH2-
CHOCO), 3.55 (1H, d, J 11.5, NCH), 3.20–3.08 (3H, m,
3 × NCH), 3.06–2.95 (1H, m, CH2CHCH2), 2.75 (1H, dd,
J 18.5 and 9.5, CHCHCO2), 2.39 (1H, dd, J 18.5 and 3.5,
CHCHCO2); δC(67.5 MHz, CDCl3) 175.4 (CO2CH2), 134.8
᎐
᎐
2
2
2
ϩ
(2 × NCH2), 14.2 (MeCH2); m/z (CI, NH3) 331 (M ϩ NH4
,
100%), 314 (M ϩ Hϩ, 63), 282 (12), 268 (11), 219 (61), 202
(36), 172 (21) (Found: M ϩ Hϩ, 314.1068. C14H19NO5S
requires M ϩ Hϩ, 314.1062).
(Z)-Ethyl 4-[N-phenylsulfonyl-N-(3-hydroxypropyl)amino]-
but-2-enoate 18c. Rf 0.4 (light petroleum–EtOAc, 3:2); νmax(thin
film)/cmϪ1 3529–3439 (m), 2943 (m), 1715 (s), 1446 (m), 1331
(s), 1280 (m), 1163 (s), 1094 (m), 1042 (w); δH(270 MHz, CDCl3)
7.86–7.50 (5H, m, aromatics), 6.19 (1H, dt, J 11.5 and 6,
NCH CH᎐C), 5.84 (1H, d, J 11.5, CH CO CH᎐C), 4.44 (2H, d,
(C᎐CH), 133.5, 129.4, 127.9 (CH᎐C), 81.8 (CH CHCO), 54.0,
᎐
᎐
2
53.7 (2 × NCH2), 37.6 (CH2CHCH2), 34.0 (CHCH2CO); m/z
(CI, NH3) 285 (M ϩ NH4ϩ, 100%), 160 (11), 145 (9), 128 (77)
(Found: M ϩ NH4ϩ, 285.0913. C12H13NO4S requires M ϩ
NH4ϩ, 285.0990).
᎐
᎐
2
2
2
J 6, NCH2CH), 4.16 (2H, q, J 7, MeCH2CO2), 3.80 (2H, t, J 6,
CH2O), 3.30 (2H, t, J 6, NCH2CH2), 2.00 (1H, br s, CH2OH),
1.75 (2H, quintet, J 6, CH2CH2CH2), 1.28 (3H, t, J 7, MeCH2);
δ (67.5 MHz, CDCl ) 165.9 (CO CH ), 146.1 (NCH CH᎐C),
Oxidation and cyclisation of (Z)-ethyl 4-[N-phenylsulfonyl-N-
(3-hydroxypropyl)amino]but-2-enoate 18c
᎐
C
3
2
2
2
139.2 (C᎐CH), 132.8, 129.3, 127.1 (CH᎐C), 121.5 (CH OCO-
᎐
᎐
2
CH᎐C), 60.5, 58.7 (CH CO CH᎐C and CH O), 47.1, 45.7
Following the general procedure, alcohol 18c (153 mg, 0.47
mmol) was oxidised to afford crude aldehyde 19c which was
immediately reacted with Bu3SnH (205 mg, 0.91 mmol) and
AIBN (16 mg, 0.1 mmol). After 3 h, the solvent was removed in
vacuo to give crude product which was purified by flash column
chromatography (silica; Et2O) to afford 20b (36 mg, 23%) and
21b (34 mg, 25%) as colourless oils.
᎐
᎐
2
2
2
(2 × NCH2), 30.9 (CH2CH2CH2), 14.2 (MeCH2); m/z (CI,
NH3) 345 (M ϩ NH4ϩ, 15%), 328 (M ϩ Hϩ, 61), 275 (65),
257 (100), 240 (44), 216 (11), 186 (14), 160 (12) (Found:
ϩ
ϩ
M ϩ NH4
328.1219).
(E)-Ethyl 4-[N-phenylsulfonyl-N-(3-hydroxypropyl)amino]-
, 328.1224. C15H21NO5S requires M ϩ NH4 ,
but-2-enoate 18d. Rf 0.3 (light petroleum–EtOAc, 3:2); νmax
-
(4R*,5R*)-1-Phenylsulfonyl-5-(ethoxycarbonylmethyl)piper-
idin-4-ol, 20b. Rf 0.3 (Et2O); νmax(thin film)/cmϪ1 3515 (s), 1727
(s), 1496 (m), 1467 (m), 1335 (s), 1310 (s), 1291 (m), 1270 (m),
1166 (s), 1091 (m), 1025 (m), 970 (w); δH(270 MHz, CDCl3)
7.93–7.59 (5H, m, aromatics), 4.24 (2H, q, J 5, OCH2Me), 3.74–
3.38 (3H, m, 2 × NCH and CHOH), 2.75–2.35 (4H, m,
2 × NCH and CHCH2CO), 2.26–2.18 (1H, m, CHCH2CO),
2.09–1.71 (3H, m, NCH2CH2 and CHOH), 1.23 (3H, t, J 5,
MeCH2CO); δC(67.5 MHz, CDCl3) 172.7 (CO2CH2), 136.4
(thin film)/cmϪ1 3531–3442 (m), 2941 (w), 1716 (s), 1446 (w),
1335 (m), 1276 (m), 1161 (s), 1115 (w), 1091 (m), 1042 (m);
δH(270 MHz, CDCl3) 7.94–7.59 (5H, m, aromatics), 6.80 (1H,
dt, J 15.5 and 6, NCH CH᎐C), 5.98 (1H, d, J 15.5, CH -
᎐
2
2
CO CH᎐C), 4.25 (2H, q, J 7.5, MeCH ), 4.06 (2H, d, J 6,
᎐
2
2
NCH2CH), 3.81 (2H, t, J 6, CH2O), 3.39 (2H, t, J 5.5,
NCH2CH2), 2.11 (1H, br s, CH2OH), 1.82 (2H, quintet, J 6,
CH2CH2CH2), 1.35 (3H, t, J 7.5, MeCH2); δC(67.5 MHz,
CDCl ) 165.9 (CO CH ), 142.5 (NCH CH᎐C), 139.7 (C᎐CH),
(C᎐CH), 132.9, 129.2, 127.5 (CH᎐C), 71.0 (CHOH), 60.9
᎐ ᎐
᎐
᎐
3
2
2
2
133.7, 129.3, 127.4 (CH᎐C), 124.7 (CH OCOCH᎐C), 61.1, 59.2
(OCH2Me), 48.4, 44.2 (2 × NCH2), 39.7 (CHCH2CO), 36.4,
32.7 (CHCH2CO and CH2CH2CH2), 14.2 (MeCH2CO); m/z
(CI, NH3) 345 (M ϩ NH4ϩ, 4%), 328 (M ϩ Hϩ, 100), 310 (22),
282 (11), 264 (6), 186 (28), 168 (65) (Found: M ϩ Hϩ, 328.1226.
C15H21NO5S requires M ϩ Hϩ, 328.1219).
(1R*,5S*)-7-Phenylsulfonyl-2-oxa-7-azabicyclo[4.3.0]nonan-
3-one 21b. Rf 0.3 (Et2O); νmax(thin film)/cmϪ1 1781 (s), 1446 (s),
1345 (s), 1237 (m), 1166 (s), 930 (m); δH(270 MHz, CDCl3)
7.84–7.53 (5H, m, aromatics), 4.56 (1H, dd, J 8 and 4,
CH2CHOCO), 3.69–3.52 (2H, m, 2 × NCH), 2.80–2.54 (3H,
m, 2 × NCH, 1 × CHCH2O), 2.29–2.01 (4H, m, 1 × CHCH2O,
CH2CH2CH2 and CH2CHCH2); δC(67.5 MHz, CDCl3) 175.6
᎐
᎐
2
(CH OCOCH᎐C and CH O), 49.4, 45.3 (2 × NCH ), 31.2
᎐
2
2
2
(CH2CH2CH2), 14.6 (MeCH2); m/z (CI, NH3) 345 (M ϩ
NH4ϩ, 100%), 328 (M ϩ Hϩ, 57), 275 (12), 233 (62), 216 (34)
(Found: M ϩ Hϩ, 328.1223. C15H21NO5S requires M ϩ Hϩ,
328.1219).
Oxidation and cyclisation of (Z)-ethyl 4-[N-phenylsulfonyl-N-
(2-hydroxyethyl)amino]but-2-enoate 18a
Following the general procedure, alcohol 18a (169 mg, 0.54
mmol) was oxidised and passed through a silica plug (Et2O) to
afford (Z)-ethyl 4-(N-formylmethyl-N-phenylsulfonylamino)but-
2-enoate 19a (109 mg, 65%); δH(270 MHz, CDCl3) 9.58 (1H, t,
J 1, CHO), 7.77–7.42 (5H, m, aromatics), 6.23 (1H, dt, J 11 and
(CO CH ), 135.8 (C᎐CH), 133.2, 129.4, 127.6 (CH᎐C), 75.6
᎐
᎐
2
2
(CH2CHOCO), 45.8, 41.1 (2 × NCH2), 34.5 (CH2CHCH2),
34.4 (CHCH2CO), 27.0 (CH2CH2CH2); m/z (CI, NH3) 299
(M ϩ NH4ϩ, 25%), 282 (M ϩ Hϩ, 48), 264 (15), 268 (13), 267
(51), 149 (41), 140 (100) (Found: M ϩ Hϩ, 282.0797. C13H15-
NO4S requires M ϩ Hϩ, 282.0800).
6, NCH CH᎐CH), 5.89 (1H, d, J 16, OCOCH᎐CH), 4.38 (2H,
᎐
᎐
2
d, J 6, NCH2CH), 4.15 (2H, q, J 7, OCH2Me), 3.91 (2H, d, J 1,
NCH2CHO), 1.28 (3H, t, J 7, MeCH2CO); m/z (CI, NH3) 329
ϩ
,
(M ϩ NH4ϩ, 10%), 312 (M ϩ Hϩ, 14) (Found: M ϩ NH4
658
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
2-{N-Phenylsulfonyl-N-[2-(2-oxotetrahydrofuran-3-ylidene)-
ethyl]amino}ethanol 23
179.3 (CO CH ), 136.0 (C᎐CH), 133.1, 129.2, 127.5 (CH᎐C),
᎐ ᎐
2 2
73.7 (CHOH), 67.7 (CH2CH2OCO), 53.7, 50.6 (2 × NCH2),
46.7, 42.4 (CH2CHCH and CH2CHCH), 28.2 (OCH2CH2CH);
m/z (CI, NH3) 329 (M ϩ NH4ϩ, 100%), 312 (M ϩ Hϩ, 71), 172
(26), 170 (34) (Found: M ϩ Hϩ, 312.0902. C14H17NO5S requires
M ϩ Hϩ, 312.0906).
To a solution of the lactol 16 (1.50 g, 6.17 mmol) in dry CH2Cl2
(10 cm3) at room temperature was added 3-triphenylphosphor-
anylidene-2-oxotetrahydrofuran 22 (2.35 g, 5.82 mmol). The
reaction was then heated at reflux under a nitrogen atmosphere
for 2 h, the CH2Cl2 was removed in vacuo, Et2O (25 cm3) was
added and a white precipitate was observed to form. The mix-
ture was then filtered through Celite, and the filtrate concen-
trated to afford a yellow oil. This oil was dissolved in dry
CH2Cl2 (5 cm3) and treated with Et3N (0.69 g, 6.79 mmol),
TBDMSCl (1.86 g, 12.34 mmol) and a catalytic quantity of
DMAP. The mixture was then allowed to stir at room temper-
ature for 4 h. Work-up and column chromatography (silica;
Et2O–light petroleum, 4:1) afforded the O-silyl ether (1.61 g,
61%) as a colourless oil. A solution of silyl ether (1.54 g, 3.63
mmol) in MeOH (20 cm3), containing a catalytic quantity of
p-TsOH was allowed to stir for 3 h at room temperature.
Evaporation of the solvent in vacuo followed by column chro-
matography of the residue (silica; EtOAc) afforded the desired
alcohol 23 (941 mg, 83%) as a colourless oil; Rf 0.3 (EtOAc);
νmax(thin film)/cmϪ1 3452 (br, s), 2924 (w), 1751 (s), 1446 (w),
1332 (s), 1213 (s), 1159 (s), 1089 (w), 1031 (m); δH(270 MHz,
CDCl3) 7.86–7.50 (5H, m, aromatics), 6.56–6.49 (1H, m,
1-Phenylsulfonylamino-2-(2-oxotetrahyrofuran-3-ylidene)-
ethane 25. Rf 0.8 (EtOAc–light petroleum, 4:1); νmax(thin film)/
cmϪ1 3272 (s), 1751 (s), 1445 (m), 1327 (m), 1207 (m), 1160 (s),
1092 (w); δH(270 MHz, CDCl3) 7.93–7.41 (5H, m, aromatics),
6.45–6.38 (1H, m, CH CHC᎐C), 4.81 (1H, t, J 6, NH), 4.29
᎐
2
(2H, t, J 7, CCH2CH2O), 3.76–3.70 (2H, m, NCH2), 2.86–
2.78 (2H, m, CH2CH2OCO); δC(67.5 MHz, CDCl3) 170.3
(CO CH ), 139.7 (C᎐CH), 133.3, 133.1, 129.3, 127.0 (CH᎐C
᎐
᎐
2
2
and CH CH᎐C), 128.5 (CH᎐CCH ), 73.7 (CHOH), 65.5
᎐
᎐
2
2
(CH2CH2OCO), 42.1 (NCH2), 25.1 (OCH2CH2C); m/z (CI,
NH3) 285 (M ϩ NH4ϩ, 100%), 175 (73), 130 (36) (Found: M ϩ
NH4ϩ, 285.0910. C14H13NO4S requires M ϩ NH4ϩ, 285.0909).
1,3-Dibenzyl-4-hydroxypyrrolidin-2-one 27
Following the general procedure, alcohol 26 (120 mg, 0.43
mmol) was oxidised to the aldehyde and immediately treated
with Bu3SnH (188 mg, 0.65 mmol). Column chromatography
(silica; Et2O) afforded 27 (43 mg, 37%) as a 2.1:1 mixture of
CH CH᎐C), 4.40 (2H, t, J 7.5, CCH CH O), 4.13 (2H, d, J 7,
NCH2CH), 3.81 (2H, t, J 6, NCH2CH2O), 3.32 (2H, t, J 6,
NCH2CH2), 2.98–2.91 (2H, m, CCH2CH2O); δC(67.5 MHz,
diastereoisomers. Major diastereoisomer; Rf 0.4 (Et2O); νmax-
᎐
2
2
2
(thin film)/cmϪ1 3376 (br, s), 1665 (s), 1604 (w), 1494 (m), 1451
(m), 1269 (m); δH(270 MHz, CDCl3) 7.40–7.15 (10H, m, aro-
matics), 4.43 (2H, br s, PhCH2N), 4.21–4.17 (1H, m, CHOH),
3.42–3.14 (2H, m, 2 × NCH), 3.05–2.72 (3H, m, PhCH2CH
and PhCH2CH), 2.17 (1H, br s, CHOH); δC(67.5 MHz, CDCl3)
CDCl ) 170.7 (CO CH ), 138.9 (C᎐CH), 134.0, 133.0, 129.2,
᎐
3
2
2
126.8 (CH᎐C, CH CH᎐C), 128.2 (C᎐CHCH ), 65.7, 61.0
᎐
᎐
᎐
2
2
(2 × CH2O), 50.4, 48.0 (2 × NCH2), 24.8 (CCH2CH2O); m/z
(CI, NH3) 329 (M ϩ NH4ϩ, 100%), 312 (M ϩ Hϩ, 32), 219 (19),
170 (16) (Found: M ϩ NH4ϩ, 329.1172. C14H17NO5S requires
M ϩ NH4ϩ, 329.1171).
173.6 (NCO), 138.3, 135.9 (C᎐CH), 129.1, 128.8, 128.7, 128.0,
᎐
127.6, 126.7 (CH᎐C), 69.4 (CHOH), 52.8 (NCH ), 46.4
᎐
2
(PhCH2), 34.9 (PhCH2CH); m/z (CI, NH3) 282 (M ϩ Hϩ,
100%), 192 (6), 91 (5) (Found: M ϩ Hϩ, 282.1491. C18H19NO2
requires M ϩ Hϩ, 282.1491). Minor diastereoisomer—the pres-
Oxidation and cyclisation of alcohol 23
1
Following the general procedure, alcohol 23 (233 mg, 0.72
mmol) was oxidised and immediately treated with Bu3SnH (419
mg, 1.44 mmol) followed by flash column chromatography
(silica; Et2O) to afford three fractions containing 24 (69 mg,
31%) (shown to be a 1.3:1 mixture of inseparable diastereo-
isomers) as a pale yellow oil, 24 (38 mg, 17%) (single diastereo-
isomer) as a clear oil and 25 (12 mg, 6%) as a white solid.
1-Phenylsulfonyl-4-(2-oxotetrahydrofuran-3-yl)pyrrolidin-3-ol
24. Major diastereoisomer 1; Rf 0.2 (EtOAc–light petroleum,
4:1); νmax(thin film)/cmϪ1 3436 (br, s), 1760 (s), 1340 (m), 1162
(w); δH(270 MHz, CDCl3) 7.85–7.15 (5H, m, aromatics), 4.15
(2H, t, J 8, CH2OCO), 4.11–4.02 (3H, m, CHOH and 2 ×
NCH), 3.62 (1H, dd, J 10.5 and 5, NCH), 3.12 (1H, m, NCH),
2.72–2.68 (2H, m, CH2CH2OCO), 2.45–1.99 (2H, m,
CH2CHCH, CH2CHCH), 1.78 (1H, br s, CHOH); δC(67.5
ence of this was indicated by H NMR spectroscopy; δH(270
MHz, CDCl3) 4.41–4.12 (1H, m, CHOH), 2.76–2.67 (1H, m,
PhCH2CH); δC(67.5 MHz, CDCl3) 172.1 (NCO), 138.9, 134.7
(C᎐CH), 72.1 (CHOH), 52.9 (NCH ), 48.5 (PhCH ), 32.2
᎐
2
2
(PhCH2CH).
General procedure for the preparation of dienes 28a–b
Alcohol 8d and 10a (0.63–3.29 mmol) was oxidised under
Swern conditions and then immediately reacted with (triphenyl-
phosphoranylidene)propan-2-one (3.15–16.45 mmol) in dry
CH2Cl2 (10–30 cm3) under nitrogen at room temperature. After
stirring overnight the solvent was removed in vacuo and the
residue was dissolved in Et2O (20–60 cm3), filtered through
Celite, washed with water and brine, dried (MgSO4) and evap-
orated to afford crude product. Column chromatography
(silica) afforded 28a–b (64–72%) as a colourless oil.
MHz, CDCl ) 178.9 (CO CH ), 137.0 (C᎐CH), 134.3, 130.6,
᎐
3
2
2
128.8 (CH᎐C), 72.4 (CHOH), 68.0 (CH CH OCO), 55.3, 50.7
(E)-5-(N-Phenylsulfonyl-N-cinnamylamino)pent-3-en-2-one
28a. Rf 0.5 (Et2O–light petroleum, 3:2); νmax(thin film)/cmϪ1
3055 (w), 3028 (w), 2924 (w), 1665 (s), 1455 (m), 1337 (s),
1160 (s); δH(270 MHz, CDCl3) 7.80–7.13 (10H, m, aromatics),
᎐
2
2
(2 × NCH2), 47.6, 41.6 (CH2CHCH and CH2CHCH), 28.4
(OCH2CH2CH); m/z (CI, NH3) 329 (M ϩ NH4ϩ, 92%), 312
(M ϩ Hϩ, 100), 172 (38), 170 (45) (Found: M ϩ Hϩ, 312.0899.
C14H17NO5S requires M ϩ Hϩ, 312.0906). Minor diastereo-
isomer 2; the presence of this was indicated by 1H NMR
spectroscopy; δH(270 MHz, CDCl3) 3.91 (1H, dd, J 11 and
5, NCH), 3.82 (1H, app. t, J 9, NCH); δC(67.5 MHz, CDCl3)
6.50 (1H, dt, J 16 and 6, CH᎐CHCOMe), 6.33 (1H, d, J 16,
᎐
PhCH᎐CH), 6.04 (1H, d, J 16, CH᎐CHCOMe), 5.84 (1H, dt, J
᎐
᎐
16 and 7, PhCH᎐CH), 3.93–3.86 (4H, m, 2 × NCH ), 2.10 (3H,
᎐
2
s, COMe); δ (67.5 MHz, CDCl ) 197.7 (COMe), 141.3 (CH᎐
᎐
C
3
180.0 (CO CH ), 137.8 (C᎐CH), 134.2, 130.4, 128.6 (CH᎐C),
CHCOMe), 139.8, 135.7 (C᎐CH), 132.9, 132.6 (PhCH᎐CH and
᎐
᎐
᎐ ᎐
2
2
74.5 (CHOH), 68.2 (CH2CH2OCO), 57.5, 50.4 (2 × NCH2),
46.1, 40.0 (CH2CHCH, CH2CHCH), 29.2 (OCH2CH2CH).
CH᎐CHCOMe), 134.8, 129.3, 128.6, 128.2, 127.8, 127.1, 126.4
᎐
(CH᎐C), 122.9 (PhCH᎐CH), 50.2, 47.8 (2 × NCH ), 27.1
᎐
᎐
2
Diastereoisomer 3; Rf 0.3 (EtOAc–light petroleum, 4:1); νmax
-
(COMe); m/z (CI, NH3) 373 (M ϩ NH4ϩ, 6%), 356 (M ϩ Hϩ,
19), 272 (20), 214 (33), 117 (100) (Found: M ϩ Hϩ, 356.1309.
C20H21NO3S requires M ϩ Hϩ, 356.1320).
(thin film)/cmϪ1 3489 (br, m), 1759 (s), 1336 (m), 1162 (w), 1021
(w); δH(270 MHz, CDCl3) 7.91–7.10 (5H, m, aromatics), 4.42–
4.14 (3H, m, CH2OCO and CHOH), 3.78–3.61 (1H, m, NCH),
3.46 (1H, dd, J 10 and 8, NCH), 3.01 (1H, dd, J 10 and 7,
NCH), 2.94 (1H, dd, J 10 and 8.5, NCH), 2.55–2.23 (2H,
m, CH2CH2OCO), 2.10–1.86 (2H, m, CH2CHCH and
CH2CHCH), 1.65 (1H, br s, CHOH); δC(67.5 MHz, CDCl3)
(E)-6-(N-Phenylsulfonyl-N-cinnamylamino)hex-3-en-2-one
28b. Rf 0.5 (Et2O–light petroleum, 4:1); νmax(thin film)/cmϪ1
3060 (m), 3027 (m), 3004 (w), 2926 (m), 1674 (s), 1628 (m), 1146
(m), 1339 (m), 1257 (m), 1160 (s), 1091 (m), 974 (m), 736 (m);
δH(270 MHz, CDCl3) 7.96–7.34 (10H, m, aromatics), 6.81 (1H,
J. Chem. Soc., Perkin Trans. 1, 1998
659

View Article Online
dt, J 16 and 7, CH᎐CHCOMe), 6.56 (1H, d, J 16, PhCH᎐CH),
᎐
᎐
Acknowledgements
We thank the EPSRC for financial support and ICI for award-
ing a Scientists Scholarship to R. M. P.
6.14 (1H, d, J 16, CH᎐CHCOMe), 6.05 (1H, dt, J 16 and 7,
᎐
PhCH᎐CH), 4.08 (2H, t, J 7, NCH ), 3.42 (2H, t, J 7, NCH ),
᎐
2
2
3.57 (2H, app. q, J 7, CH2CH2CH), 2.30 (3H, s, COMe); δC(67.5
MHz, CDCl ) 198.2 (COMe), 143.6 (CH᎐CHCOMe), 139.7,
᎐
3
135.8 (C᎐CH), 132.9, 132.7 (PhCH᎐CH and CH᎐CHCOMe),
᎐
᎐
᎐
References
134.9, 129.5, 128.7, 128.1, 127.6, 127.0, 126.9 (CH᎐C), 123.9
᎐
1 T. Harrison, Contemp. Org. Synth., 1995, 2, 209 and 1996, 3, 259;
F. J. Sardina and H. Rapoport, Chem. Rev., 1996, 96, 1825.
2 T. Sunazuka, T. Nagamitsu, K. Matsuzaki, H. Tanaka, S. Õmura and
A. B. Smith, J. Am. Chem. Soc., 1993, 115, 5302; T. Nagamitsu,
T. Sunazuka, H. Tanaka, S. Õmura, P. A. Sprengeler and A. B.
Smith, J. Am. Chem. Soc., 1996, 118, 3584; E. J. Corey and G. A.
Reichard, J. Am. Chem. Soc., 1992, 114, 10 677; H. Uno, J. E.
Baldwin and A. T. Russell, J. Am. Chem. Soc., 1994, 116, 2139;
N. Chida, J. Takeoka, N. Tsutsumi and S. Ogawa, J. Chem. Soc.,
Chem. Commun., 1995, 793.
(PhCH᎐CH), 50.2, 46.0 (2 × NCH ), 31.9 (CH CH CH), 26.9
᎐
2
2
2
(COMe); m/z (CI, NH3) 387 (M ϩ NH4ϩ, 100%), 370 (M ϩ Hϩ,
79), 271 (52), 228 (48), 117 (60) (Found: M ϩ Hϩ, 370.1480.
C21H23NO3S requires M ϩ Hϩ, 370.1477).
General procedure for the cyclisation of dienes 28a–b
To a solution of diene 28a–b (0.45–0.64 mmol) in degassed
benzene (4.5–6.4 cm3) under a nitrogen atmosphere was added
Bu3SnH (0.9–1.28 mmol) and AIBN (0.5–0.1 mmol) in
degassed benzene (0.5 cm3). The mixture was heated to 80 ЊC
until the reaction was shown to be complete by TLC (2–4 h).
The solvent was then removed in vacuo to give a yellow oil
which was purified by flash column chromatography (silica) to
afford 29a–b (61–76%) as an inseparable mixture of diastereo-
isomers.
3 A. S. Kende, K. Kawamura and R. J. DeVita, J. Am. Chem. Soc.,
1990, 112, 4070; M. D. Andrews, A. G. Brewster and M. G.
Moloney, Synlett, 1996, 612.
4 Y. Hirai, T. Terada, Y. Amemiya and T. Momose, Tetrahedron Lett.,
1992, 33, 7893; T. Ohta, A. Hosoi and S. Nozoe, Tetrahedron Lett.,
1988, 29, 329; A. G. M. Barrett and D. Pilipauskas, J. Org. Chem.,
1990, 55, 5194; 1991, 56, 2787.
5 N. Ikota, Heterocycles, 1989, 29, 1469.
6 M. Ikeda, T. Sato and H. Ishibashi, Heterocycles, 1988, 27, 1465;
D. J. Robins, Nat. Prod. Rep., 1995, 12, 413; 1994, 11, 613 and 1993,
10, 487; D. J. Robins, Chem. Soc. Rev., 1989, 18, 375; S. E. Denmark,
D. L. Parker and J. A. Dixon, J. Org. Chem., 1997, 62, 435.
7 M. J. Martín-López and F. Bermejo-González, Tetrahedron Lett.,
1994, 35, 8843.
8 B. Giese, B. Kopping, T. Göbel, J. Dickhaut, G. Thoma, K. J.
Kulicke and F. Trach, Org. React., 1996, 48, 301; F. Aldabbagh and
W. R. Bowman, Contemp. Org. Synth., 1997, 261.
9 S. K. Pradhan, S. R. Kadam, J. N. Koihe, T. V. Radhakrishnan, S. V.
Sohani and V. B. Thaker, J. Org. Chem., 1981, 46, 2622.
10 E. J. Corey and S. G. Pyne, Tetrahedron Lett., 1983, 24, 2821.
11 T. Ikeda, S. Yue and C. R. Hutchinson, J. Org. Chem., 1985, 50,
5193; G. H. Lee, E. B. Choi, E. Lee and C. S. Pak, J. Org. Chem.,
1994, 59, 1428.
12 T. Sugawara, B. A. Otter and T. Ueda, Tetrahedron Lett., 1988, 29,
75.
13 E. J. Enholm and G. Prasad, Tetrahedron Lett., 1989, 30, 4939; E. J.
Enholm and J. A. Burroff, Tetrahedron Lett., 1992, 33, 1835 and
Tetrahedron, 1997, 53, 13 583.
14 D. S. Hays and G. C. Fu, J. Org. Chem., 1996, 61, 4.
15 E. J. Enholm, E. J. Prasad and K. S. Kinter, J. Am. Chem. Soc., 1991,
113, 7784; E. J. Enholm and K. S. Kinter, J. Org. Chem., 1995, 60,
4850.
16 T. Naito, K. Tajiri, T. Harimoto, I. Ninomiya and T. Kiguchi,
Tetrahedron Lett., 1994, 35, 2205.
1-Phenylsulfonyl-3-(2-oxopropyl)-4-benzylpyrrolidine
29a.
Major diastereoisomer; Rf 0.2 (Et2O–light petroleum, 3:1); νmax
-
(thin film)/cmϪ1 1713 (s), 1447 (w), 1340 (s), 1163 (s), 965 (w),
752 (w), 717 (w); δH(270 MHz, CDCl3) 7.76–7.10 (10H, m,
aromatics), 3.51 (1H, dd, J 10 and 7.5, NCH), 3.42–3.36 (1H,
m, NCH), 3.28 (1H, dd, J 10 and 7, NCH), 3.13–2.80 (1H, m,
CHCH2CO), 2.77 (1H, dd, J 10 and 7.5, NCH), 2.61–2.05 (5H,
m, PhCH2CH, PhCH2CH and CH2CO), 2.07 (3H, s, COMe);
δ (67.5 MHz, CDCl ) 208.0 (COMe), 140.1, 136.6 (CH᎐C),
᎐
C
3
132.6, 128.9, 128.7, 128.4, 127.6, 127.4, 127.1 (CH᎐C), 54.1,
᎐
53.9 (2 × NCH2), 51.1 (CH2COMe), 39.9 (PhCH2), 37.0, 36.9
(PhCH2CH and CHCH2CO); m/z (CI, NH3) 358 (M ϩ Hϩ,
95%), 218 (100), 160 (11), 126 (6), 94 (7), 68 (23) (Found:
M ϩ Hϩ, 358.1486. C20H23NO3S requires M ϩ Hϩ, 358.1477).
1
Minor diastereoisomer—this was indicated by H NMR spec-
troscopy; δH(270 MHz, CDCl3) 3.39 (1H, dd, J 14 and 7,
NCH), 2.82 (1H, dd, J 10 and 6.5, NCH), 2.10 (3H, s, COMe);
δ (67.5 MHz, CDCl ) 207.8 (COMe), 139.9, 136.1 (CH᎐C),
᎐
C
3
55.3, 54.0 (2 × NCH2), 49.9 (CH2COMe), 38.7 (PhCH2), 35.9,
34.7 (PhCH2CH and CHCH2CO).
1-Phenylsulfonyl-4-(2-oxopropyl)-5-benzylpiperidine
29b.
Major diastereoisomer; Rf 0.3 (light petroleum–Et2O, 3:1); νmax
-
(thin film)/cmϪ1 1721 (s), 1448 (m), 1333 (m), 1215 (m), 1160 (s),
722 (m); δH(270 MHz, CDCl3) 7.72–7.06 (10H, m, aromatics),
3.57–3.39 (2H, m, 2 × NCH), 2.86–2.00 (6H, m, 2 × NCH,
CH2COMe, PhCH2CH and CH2CHCH2), 2.08 (3H, s, COMe),
1.96–1.51 (3H, m, NCH2CH2 and CH2CHCH2); δC(67.5 MHz,
17 Y. Yuasa, J. Ando and S. Shibuya, J. Chem. Soc., Chem. Commun.,
1994, 1383.
18 Part of this work has appeared as a preliminary communication:
A. F. Parsons and R. M. Pettifer, Tetrahedron Lett., 1997, 38,
5907.
19 A. Nishida, H. Takahashi, H. Takeda, N. Takada and O. Yonemitsu,
J. Am. Chem. Soc., 1990, 112, 902.
CDCl ) 207.4 (COMe), 140.1, 136.6 (CH᎐C), 132.6, 128.9,
᎐
3
128.7, 128.5, 128.4, 127.5, 127.4, 126.4, 126.1 (CH᎐C), 49.7
᎐
20 C. Kashima and K. Harada, J. Chem. Soc., Perkin Trans. 1, 1988,
1521; M. Nicola, G. Gaviraghi, M. Pinza and G. Pifferi,
J. Heterocycl. Chem., 1981, 18, 825.
(CH2COMe), 46.9, 45.3 (2 × NCH2), 41.0, 34.8 (PhCH2CH and
CHCH2CO), 37.5 (PhCH2), 30.5 (COMe), 30.3 (CH2CH2CH2);
m/z (CI, NH3) 389 (M ϩ NH4ϩ, 14%), 372 (M ϩ Hϩ, 100), 230
(26), 172 (6) (Found: M ϩ Hϩ, 372.1632. C21H25NO3S requires
M ϩ Hϩ, 372.1633). Minor diastereoisomer—this was indicated
by 1H NMR spectroscopy; δH(270 MHz, CDCl3) 3.74–3.69 (1H,
m, NCH), 2.11 (3H, s, COMe); δC(67.5 MHz, CDCl3) 207.1
21 B. E. Maryanoff and A. B. Reitz, Chem. Rev., 1989, 89, 863.
(COMe), 138.8, 136.0 (CH᎐C), 48.7 (CH COMe), 46.3, 46.1
(2 × NCH2), 39.7, 33.7 (PhCH2CH and CHCH2CO), 31.5
(PhCH2), 30.5 (COMe), 26.7 (CH2CH2CH2).
Paper 7/07740H
Received 21st October 1997
Accepted 26th November 1997
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2
660
J. Chem. Soc., Perkin Trans. 1, 1998