New route to 4-aminocyclopent-2-en-1-ols: Synthesis and enantioselective rearrangement of 4-amino-substituted cyclopentene oxides

Article abstract of DOI:10.1016/S0040-4020(00)00911-X

A new route for the asymmetric synthesis of 4-aminocyclopent-2-en-1-ols (90% ee) for carbocyclic nucleoside analogue synthesis is described. The approach involves the stereoselective preparation of cis 4-amino-substituted cyclopentene oxides and subsequent chiral base-mediated rearrangement to the corresponding allylic alcohols. Full details on the synthesis and stereoselectivity of epoxidation of 4-amino-substituted cyclopentenes are presented. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00911-X

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 9633±9640
New Route to 4-Aminocyclopent-2-en-1-ols: Synthesis and
Enantioselective Rearrangement of 4-Amino-substituted
Cyclopentene Oxides
*
Stephen Barrett, Peter O'Brien, H. Christian Steffens, Timothy D. Towers and Matthias Voith
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Received 17 July 2000; revised 15 September 2000; accepted 29 September 2000
AbstractÐA new route for the asymmetric synthesis of 4-aminocyclopent-2-en-1-ols (90% ee) for carbocyclic nucleoside analogue
synthesis is described. The approach involves the stereoselective preparation of cis 4-amino-substituted cyclopentene oxides and subsequent
chiral base-mediated rearrangement to the corresponding allylic alcohols. Full details on the synthesis and stereoselectivity of epoxidation of
4-amino-substituted cyclopentenes are presented. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
Some time ago, Schneller and co-workers reported that
50-noraristeromycin 4 possessed anti-viral activity but had
reduced toxicity.3 Because of the biological interest in
carbocylic nucleoside analogues, we decided to develop a
novel, general strategy for the asymmetric construction of
the 4-aminocyclopent-2-en-1-ol core of these molecules.
Carbocyclic nucleosides such as the naturally occurring
aristeromycin 1 and neoplanacin A 2 exhibit potent anti-
viral activity and these compounds as well as analogues
such as 3 and 4 have attracted considerable synthetic interest
in recent times.1,2 Unfortunately, the anti-viral potential of
aristeromycin 1 has been limited due to its toxicity.
Our approach to carbocyclic nucleoside analogues involved
a novel synthesis of 4-aminocyclopent-2-en-1-ols 7 as
outlined in Scheme 1. Trost4 and Miller5 have independently
shown the synthetic usefulness of amino alcohols like 7 in
the carbocyclic nucleoside arena and Zwanenburg et al.2
have developed a cycloaddition route to such compounds.
Our route to amino alcohols 7 makes use of the chiral base-
mediated rearrangement of epoxides cis-6 to allylic alcohols
7 as the key step. The stereoselective synthesis of epoxides 6
and the preparation of the alkenes 5 were also of signi®cant
interest as little was known about the preparation of these
types of compounds when we started our endeavours in this
area.6
Results and Discussion
Initially, we required access to a wide range of mono and
diprotected amino cyclopentenes 5 and three approaches
were used (Scheme 2; Table 1): (i) monoprotection of
known7±11 hydrochloride salt 9 to give alkenes 5a±d and
5f±g; (ii) Mitsunobu substitution of cyclopenten-3-ol 8 with
an appropriately chosen amine derivative 10a±c or phthal-
imide to give alkenes 5h±k and (iii) deprotection of a
diprotected alkene 5h to give the monoprotected alkene
5e. For the monoprotection route, full details of the prepara-
tion of amides 5a12 and 5b9 and carbamate 5f8 have been
previously reported. In addition, the dibenzoylation of
Keywords: amino alcohols; epoxidation; stereocontrol; nucleosides.
* Corresponding author. Tel.: 144-1904-432535; fax: 144-1904-432516;
e-mail: paobl@york.ac.uk
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00911-X

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S. Barrett et al. / Tetrahedron 56 (2000) 9633±9640
to generate the amine which was isolated as hydrochloride
salt 9 in 65% yield over the three steps without puri®cation
of any of the intermediates. A range of amides, sulfon-
amides and carbamates (5a±d and 5f±g) were prepared
from salt 9 via standard N-monoprotection reactions
(Scheme 2, Table 1, entries 1±4 and 6±7).
We have prepared diprotected alkenes 5h±k by Mitsunobu
reactions of cyclopenten-3-ol 8 (Scheme 2, Table 1, entries
8±11). Of the wide range of Mitsunobu reagents18 available
for the introduction of nitrogen,19 we chose phthalimide
(because of its commercial availability), Weinreb's
TsNHBoc reagent 10c20 and Fukuyama's NsNHPMB
reagent 10a.21 Weinreb's and Fukuyama's reagents were
selected because their use in Mitsunobu reactions was
well documented and they had relatively easily removable
N-protecting groups. In addition, a novel Weinreb±
Fukuyama hybrid reagent NsNHBoc 10b was prepared in
which the tosyl group is replaced by the more readily
cleaved nosyl group. Sulfonamide 10a was prepared in
89% yield by simple nosylation of 4-methoxybenzylamine
and the product conveniently crystallised from methanol.21
N-Boc protected sulfonamides 10b (89% yield) and 10c
(93% yield) were prepared by reaction of the corresponding
Scheme 1.
hydrochloride salt 9 has been described.13 The Mitsunobu
route is more novel with the only previously reported
examples involving Mitsunobu reactions of cyclopenten-3-
ol 8 with heterocyclic bases (e.g. 3-benzoylthymine).14±16
The synthesis of hydrochloride salt 9 has been reported a
number of times before using three different approaches.7±11
However, each route was either many steps or low yielding
or both. Therefore, a new synthesis of salt 9 was developed.
Our synthesis (Scheme 2) starts with easily prepared17
cyclopenten-3-ol 8 which was mesylated and subsequently
reacted with sodium azide in DMF (808C, 16 h) to furnish
the corresponding azido cyclopentene. Then, triphenyl-
phosphine-mediated reduction in aqueous THF was used
Scheme 2.
Table 1. Synthesis and stereoselective epoxidation of 4-aminocylopentenes 5
Entry
SMa
Conditions for alkene synthesis
R1
R2
Alkene
Yield (%)b
Epoxide
m-CPBAc cis:trans TFDOd cis:trans
1
2
3
4
5
6
9
9
9
9
5h
9
Et3N, BzCl, DMAP, CH2Cl2
Et3N, TFAA, pyridine, CH2Cl2
Et3N, MsCl, DMAP, CH2Cl2
Et3N, TsCl, DMAP, CH2Cl2
CAN, water, MeCN
Bz
H
5a
5b
5c
5d
5e
5f
83
64
100
94
74
78
6a
6b
6c
6d
6e
6f
97:3
98:2
98:2
84:16
84:16
82:18
70:30
38:62
±
40:60
±
CF3CO
Ms
Ts
H
H
H
H
H
Nse
Cbz
Et3N, BnOCOCl, DMAP,
CH2Cl2
±
7
8
9
10
11
9
8
8
8
8
Et3N, Boc2O, DMAP, CH2Cl2
10a, PPh3, DEAD, CH2Cl2
10b, PPh3, DEAD, THF
10c, PPh3, DEAD, THF
Boc
Ns
Ns
Ts
H
5g
5h
5i
5j
5k
77
52
64
76
71
6g
6h
6i
6j
6k
75:25
26:74
2:98
2:98
2:98
52:48
±
2:98
2:98
±
PMB
Boc
Boc
Phthalimide, PPh3, DEAD, THF Phthalimido
a Starting material for monoprotection or Mitsunobu reactions.
b Isolated yield of alkenes 5 after chromatography.
c Epoxidation conditions: m-CPBA, NaHCO3, CH2Cl2, rt, 16 h, ratio of diastereoisomers determined by 1H NMR spectroscopy on the crude product mixture.
d Tri¯uoroacetone, Na2EDTA(aq), NaHCO3, Oxonew, MeCN±water, 08C, 4 h, ratio of diastereoisomers determined by 1H NMR spectroscopy on the crude
product mixture.
e Nsˆ2-NO2C6H4SO2±.

S. Barrett et al. / Tetrahedron 56 (2000) 9633±9640
9635
sulfonamide with Boc2O according to a literature protocol.22
With the sulfonamides 10a±c in hand, the Mitsunobu
reactions with cyclopenten-3-ol 8 proceeded smoothly in
moderate to good yields (Scheme 2, Table 1, entries
8±11) and it was especially pleasing to note that the
Weinreb±Fukuyama reagent 10b performed well (64%
yield of alkene 5h, Table 1, entry 8).
diastereomeric epoxides 6 are generated with methyl(tri-
¯uoromethyl)dioxirane.
The following conclusions may be drawn about the
epoxidation results. With m-CPBA, monoprotected alkenes
5a±g are epoxidised with cis selectivity and diprotected
alkenes 5h±k are epoxidised with trans selectivity. This is
presumably a consequence of hydrogen bonded directed
attack with monoprotected alkenes and steric control with
diprotected alkenes in line with the literature precedent
discussed previously. In terms of the hydrogen bonded
directed epoxidation, amides (e.g. 5a and 5b) and sterically
small sulfonamides (e.g. 5c) give the highest levels of cis
selectivity. Sterically large sulfonamides (e.g. 5d and 5e)
and carbamates (e.g. 5f and 5g) are worse cis directors of
epoxidations.
There have been sporadic reports on the stereoselective
epoxidation of 4-aminocyclopentenes 5. For example,
highly stereoselective amide-directed23,24 epoxidation of
alkenes 5a and 5b has been reported as a good method for
preparing epoxides cis-6a and cis-6b.9,12 Reduced cis
selectivity has been observed with carbamate protecting
groups (such as Boc and Cbz).8,25 In a similar fashion, cis-
selectivity has been observed when the nitrogen is part of a
heterocyclic base.15,16 In contrast, when the nitrogen
possessed two benzamide groups, a completely trans
selective epoxidation was observed presumably as a result
of steric factors.13
The trans selectivity of epoxidation with diprotected
alkenes is highest when two large groups are attached
(e.g. 5i±k) and the trans selectivity observed with alkenes
5i and 5j is insensitive to changes in epoxidising reagent.
However, the cis selectivity of monoprotected alkenes with
m-CPBA is lost when methyl(tri¯uoromethyl)dioxirane is
used due to interference with the hydrogen bonding. Only
approximately 50:50 mixtures of cis and trans epoxides are
produced from the methyl(tri¯uoromethyl)dioxirane-
mediated epoxidation of monoprotected alkenes 5a, 5b,
5d and 5g re¯ecting the fact that one of the substituents
on nitrogen is a sterically insigni®cant proton.
Initially, the epoxidations of alkenes 5a±j were carried out
using standard m-CPBA conditions (m-CPBA, NaHCO3,
CH2Cl2, room temperature, 16 h) and the crude products
1
were analysed by H NMR spectroscopy to determine the
degree of stereoselectivity (Scheme 2, Table 1). The major
products of epoxidation of monoprotected alkenes 5a±g
(Table 1, entries 1±7) were assigned as having cis stereo-
chemistry by analogy with the known epoxidations of 5a
1
and 5b.9,12 These assignments were consistent with a H
NMR spectroscopy correlation: dH(CHO) signal for cis
monoprotected epoxides is more down®eld than that for
trans epoxidesÐexamples: 3.57 ppm for cis-5a, 3.54 ppm
for trans-5a; 3.49 ppm for cis-5d, 3.40 ppm for trans-5d;
3.53 ppm for cis-5e, 3.44 ppm for trans-5e; 3.47 ppm for
cis-5f, 3.40 ppm for trans-5f; 3.58 ppm for cis-5g,
3.54 ppm for trans-5g.
From a synthetic viewpoint, the easiest cis monoprotected
epoxides to obtain as single diastereoisomers after puri®ca-
tion by chromatography were epoxides cis-6a (79% isolated
yield) and cis-6b (73% isolated yield). For the trans
epoxides, we isolated diprotected epoxide trans-6i in 84%
yield and epoxide trans-6j in 88% yield after chromato-
graphy.
In contrast, m-CPBA epoxidations of diprotected alkenes
5h±k were trans selective (Table 1, entries 8±11). In
these cases, the major products were assigned as trans
epoxides by comparison with the known epoxidation of
the dibenzamide 5 (R1ˆR2ˆBz).13 Additional support for
all of the assignments of stereochemistry came from the
The chiral base-mediated rearrangement of epoxides to
allylic alcohols28 was the ®rst reaction to be rendered asym-
metric using chiral lithium amide bases.29 Since then, it has
proved to be a versatile and useful reaction for asymmetric
synthesis.30 Indeed, Asami used the enantioselective
rearrangement of a meso 4-substituted cyclopentene oxide
as a pivotal step in an asymmetric synthesis of carbovir.31
Also, Hodgson has used a similar process for the production
of cyclopentenol building blocks for carbocyclic nucleoside
analogue synthesis.32 Most of the previous work in our
group has focused on the rearrangement of meso cyclo-
hexene oxides.33
1
following two reactions (with H NMR spectra compari-
son): (i) N-diprotected epoxide cis-6j was the major product
obtained by Boc protection of the 84:16 mixture of N-mono-
protected epoxides cis- and trans-6d and (ii) N-mono-
protected epoxide trans-6e was the major product
obtained from the CAN-mediated deprotection of the
74:26 mixture of N-diprotected epoxides trans- and cis-6h.
Reaction of N-diprotected epoxides trans-6i and 6j with two
equivalents of the chiral base derived from Singh's diamine
1134 (our usual conditions33) failed to generate any allylic
alcohol. In the case of epoxide trans-6i, a 65% yield of the
starting epoxide was recovered after chromatography.
Since there was literature precedent to suggest that directed
epoxidation could occur with amides and carba-
mates,9,12,23,24 the epoxidations were repeated with in situ
generated methyl(tri¯uoromethyl)dioxirane,26,27 a reagent
that does not hydrogen bond (Table 1). Epoxidation of
diprotected alkenes 5i and 5j are still completely trans
selective even with methyl(tri¯uoromethyl)dioxirane
(Table 1, entries 9 and 10) but there is a signi®cant lowering
of cis selectivity with a range of monoprotected alkenes
(Table 1, entries 1, 2, 4 and 7). In all of the monoprotected
alkene examples, synthetically useless mixtures of
Next, the enantioselective rearrangement of monoprotected
epoxide cis-6a (Scheme 3, Table 2, entry 1) was attempted
using three equivalents of the chiral base derived from
Singh's diamine 11 due to the presence of the acidic NH
proton on the amide. Allylic alcohol 7a was generated in
73% yield and had 60% ee (as shown by chiral HPLC). The

9636
S. Barrett et al. / Tetrahedron 56 (2000) 9633±9640
Experimental
General methods
Water is distilled water. Optical rotations were recorded on
a Jasco DIP-370 polarimeter (using the sodium D line;
589 nm) and [a]D are given in units of 1021 deg cm2 g21
.
n-Butyllithium was titrated against diphenylacetic acid
before use. m-CPBA (approx. 70% pure) was used as
supplied by Aldrich Chemical Company Ltd. Petrol refers
to the fraction of petroleum ether boiling in the range
40±608C and was redistilled in Winchester quantities before
use. Proton (270 MHz) and carbon (67.9 MHz) NMR
spectra were recorded on a Jeol EX-270 spectrometer
using an internal deuterium lock.
Scheme 3.
4-Aminocyclopentene Hydrochloride 9. Et3N (8.0 mL,
57.3 mmol) and MsCl (3.6 mL, 45.8 mmol) were added
dropwise to a stirred solution of cyclopenten-3-ol 8 (3.2 g,
38.2 mmol) in CH2Cl2 (80 mL) at 08C under N2. After
30 min, water (80 mL) was added and the layers were sepa-
rated. The aqueous layer was extracted with CH2Cl2
(2£80 mL) and the combined organic extracts were washed
with 2 M HCl(aq) (2£80 mL) and then water (80 mL), dried
(Na2SO4) and evaporated under reduced pressure to give the
crude product as a yellow oil. The crude product was
dissolved in DMF (150 mL) and NaN3 (4.5 g, 68.7 mmol)
was added. The mixture was heated at 808C for 16 h and
after cooling, Et2O (300 mL) was added and the mixture
was washed with brine (5£100 mL). The solvent was evapo-
rated by atmospheric distillation through a Vigreux column.
The residue was dissolved in THF (140 mL), PPh3 (14.4 g,
55.0 mmol) was added and the solution was stirred at rt for
1.5 h. Water (8.0 mL) was added and the mixture was
heated at re¯ux for 16 h. After cooling, CH2Cl2 (40 mL)
and 1 M HCl(aq) (80 mL) were added and the layers sepa-
rated. The aqueous layer was washed with CH2Cl2
(3£40 mL) and evaporated under reduced pressure to give
the crude product. Trituration with EtOH and repeated
evaporation gave known9 hydrochloride salt 9 (3.6 g,
65%) as light brown crystals, mp 217±2188C (lit.9 219±
2218C).
Table 2. Enantioselective rearrangements of 4-aminocyclopentene oxides
Entry Epoxide
R1
R2 Diamine Alcohol Yield (%)a ee (%)b
1
2
3
4
6a
6a
6b
6b
Bz
Bz
CF3CO
CF3CO
H
H
H
H
11
12
11
12
7a
7a
7b
7b
73
51
52
73
60
92
46
88
a Isolated yield after chromatography.
b Enantiomeric excess determined by chiral HPLC and/or by formation
of Mosher's esters.
absolute stereochemistry was established by formation of
the Mosher's esters35 and analysis of the 1H NMR spectrum
of the diastereomeric mixture (Kakisawa's method36). The
sense of induction was consistent with our expectations for
diamine 11.33,34
The scope of the reaction was investigated by rearranging
epoxides cis-6a and cis-6b with the chiral base derived from
Singh's diamine 11 and from diamine 12 developed in our
laboratory (Scheme 3, Table 2).33 With each epoxide, we
found that the highest enantioselectivity was obtained with
our improved diamine 12 (Table 2, entries 2 and 4) and this
enabled synthetically useful 4-aminocyclopent-2-en-1-ols
7a and 7b to be prepared in high enantiomeric excess
(approx. 90% ee). Our results suggest that the presence of
a deprotonated amide cis to the epoxide is crucial for
facilitating such rearrangement reactions. Similarly high
enantioselectivity has been obtained by Asami but those
reactions require the preparation of a structurally complex
diamine.25
4-Benzamidocyclopentene 5a. Benzoyl chloride (0.98 mL,
12.6 mmol) was added dropwise to a stirred solution of
hydrochloride salt 9 (502 mg, 4.2 mmol), Et3N (1.7 mL,
12.6 mmol) and DMAP (52 mg, 0.43 mmol) in CH2Cl2
(20 mL) at 08C under N2. After 16 h at rt, the solvent was
evaporated under reduced pressure and the residue dissolved
in EtOAc (50 mL). The organic layer was washed with 1 M
HCl(aq) (50 mL), water (50 mL) and brine (50 mL), dried
(Na2SO4) and evaporated under reduced pressure. Puri®ca-
tion by chromatography (25:1 CHCl3±MeOH) gave
known12 alkene 5a (652 mg, 83%) as white crystals, mp
119±1218C (lit.12 1268C).
Conclusion
In summary, we have described a novel route for the
preparation of 4-aminocyclopent-2-en-1-ol 7a (92% ee), a
key building block for carbocyclic nucleoside analogue
synthesis. Along the way, we have developed a new
synthesis of hydrochloride salt 9 and some new methods
for the synthesis of diastereomerically pure 4-amino-
substituted cyclopentene oxides 6. In addition, we have
highlighted the importance of a deprotonated amide cis to
the epoxide in chiral base-mediated rearrangement reactions
of such epoxides.
4-Tri¯uoroacetamidocyclopentene 5b. A solution of
tri¯uoroacetic anhydride (0.52 mL, 3.86 mmol) in CH2Cl2
(3.5 mL) was added dropwise to a stirred solution of hydro-
chloride salt 9 (400 mg, 3.54 mmol) and Et3N (0.54 mL,
3.84 mmol) in pyridine (4.8 mL) at 08C under N2. After
4.5 h, CH2Cl2 (15 mL) was added and the organic layer
was washed with 1 M HCl(aq) (4£15 mL), dried (Na2SO4)

S. Barrett et al. / Tetrahedron 56 (2000) 9633±9640
9637
and evaporated under reduced pressure to give known9
alkene 5b (389 mg, 64%) as light brown crystals, mp 60±
618C (lit.9 628C).
N-(4-Methoxybenzyl)-2-nitrobenzenesulfonamide 10a.
4-Methoxybenzylamine (2.5 mL, 19.0 mmol) was added
dropwise to a stirred solution of 2-nitrobenzenesulfonyl
chloride (4.63 g, 21.0 mmol) and Et3N (2.9 mL,
21.0 mmol) in CH2Cl2 (100 mL) at rt under N2. After 24 h
at rt, water (50 mL) was added and the two layers separated.
The aqueous layer was extracted with CH2Cl2 (2£50 mL)
and the combined organic extracts were washed with brine
(50 mL), dried (MgSO4) and evaporated under reduced
pressure. Trituration of the residue with MeOH gave
sulfonamide 10a (5.44 g, 89%) as needles, mp 117±
1198C; Rf (1:1 EtOAc±petrol) 0.6; IR (Nujol) 3307, 1367,
1334, 1160 cm21; 1H NMR (CDCl3): d 8.01 (dd, 1H, Jˆ2,
8 Hz), 7.83 (dd, 1H, Jˆ2, 8 Hz), 7.72±7.62 (m, 2H), 7.13 (d,
2H, Jˆ9 Hz), 6.75 (d, 2H, Jˆ9 Hz), 5.60 (br s, 1H), 4.24 (br
s, 2H), 3.76 (s, 3H); 13C NMR (CDCl3): d 159.4, 147.8,
133.7, 133.3, 132.7, 131.1, 129.3, 127.4, 125.2, 114.0,
55.3, 47.4.
4-Methanesulfonamidocyclopentene 5c. MsCl (0.04 mL,
0.44 mmol) was added dropwise to a stirred solution of
hydrochloride salt 9 (50 mg, 0.42 mmol), Et3N (0.18 mL,
1.26 mmol) and DMAP (6 mg, 0.04 mmol) in CH2Cl2
(5 mL) at 08C under N2. After 16 h at rt, the solvent was
evaporated under reduced pressure and the residue was puri-
®ed by chromatography (25:1 CHCl3±MeOH) to give
alkene 5c (67 mg, 100%) as white crystals, mp 55±578C;
Rf (25:1 CHCl3±MeOH) 0.6; IR (CDCl3) 3381, 1333,
1
1150 cm21; H NMR (CDCl3): d 5.69 (s, 2H), 4.67 (d,
1H, Jˆ8 Hz), 4.15 (tq, 1H, Jˆ4, 8 Hz), 2.98 (s, 3H), 2.77
(dd, 2H, Jˆ8, 15 Hz), 2.33 (dd, 2H, Jˆ4, 15 Hz); 13C NMR
(CDCl3): d 128.5, 53.2, 41.2, 40.5; MS (CI, NH3) m/z 179
(M1NH4)1, 82; HRMS (CI, NH3) m/z calcd for C6H10NO2S
(M1NH4)1 179.0854, found 179.0855.
N-(tert-Butoxycarbonyl)-2-nitrobenzenesulfonamide 10b.
Boc2O (1.78 g, 8.16 mmol) was added in one portion to a
stirred solution of 2-nitrobenzenesulfonamide (1.49 g,
7.42 mmol), Et3N (1.14 mL, 8.16 mmol) and DMAP
(92 mg, 0.75 mmol) in CH2Cl2 (15 mL) at rt under N2.
After 2 h at rt, the solvent was evaporated under reduced
pressure. The residue was dissolved in EtOAc (60 mL) and
washed with 1 M HCl(aq) (50 mL), water (50 mL) and brine
(50 mL), dried (MgSO4) and evaporated under reduced
pressure. Puri®cation by recrystallisation from EtOAc±
petrol gave sulfonamide 10b (1.72 g, 77%) as white
crystals, mp 194±1968C; IR (CHCl3) 3382, 1751, 1545,
4-tert-Butoxycarbonamidocyclopentene 5g. Using the
procedure described above, Boc2O (42 mg, 0.19 mmol),
hydrochloride salt 9 (20 mg, 0.17 mmol), Et3N (0.07 mL,
0.50 mmol) and DMAP (2 mg, 0.02 mmol) in CH2Cl2
(2 mL) gave the crude product which was puri®ed by
chromatography (25:1 CHCl3±MeOH) to give known8
alkene 5g (24 mg, 77%) as white crystals, mp 71±738C
(lit.8 70±728C).
4-(4-Methylbenzenesulfonamido)cyclopentene 5d. TsCl
(287 mg, 1.51 mmol) was added in one portion to a stirred
solution of hydrochloride salt 9 (150 mg, 1.26 mmol), Et3N
(0.53 mL, 3.77 mmol) and DMAP (15 mg, 0.13 mmol) in
CH2Cl2 (8 mL) at rt under N2. After 16 h at rt, water
(20 mL) was added and the layers separated. The aqueous
layer was extracted with CH2Cl2 (2£20 mL) and the
combined organic extracts were washed with water
(2£20 mL), dried (Na2SO4) and evaporated under reduced
pressure. Puri®cation by chromatography (EtOAc) gave
alkene 5d (278 mg, 94%) as white crystals, mp 79±818C;
1
1415, 1363, 1148 cm21; H NMR (CDCl3): d 8.37±8.34
(m, 1H), 7.87±7.78 (m, 3H), 7.41 (s, 1H), 1.43 (s, 9H);
13C NMR (CDCl3): d 149.4, 147.5, 135.0, 132.5, 132.3,
131.2, 124.4, 85.5, 27.4; MS (CI, NH3) m/z 320 M1NH14 ;
HRMS (CI, NH3) m/z calcd for C11H14N2O6S M1NH41
320.0916, found 320.0911; Anal. calcd for C11H14N2O6S:
C, 43.7; H, 4.7; N, 9.3. Found: C, 43.6; H, 4.4; N, 9.1.
N-(tert-Butoxycarbonyl)-4-methylbenzenesulfonamide
10c. Using the procedure described above, Boc2O (5.61 g,
25.70 mmol), p-toluenesulfonamide (4.00 g, 23.36 mmol),
Et3N (3.58 mL, 25.70 mmol) and DMAP (285 mg,
2.34 mmol) in CH2Cl2 (30 mL) gave the crude product
which was puri®ed by recrystallisation from Et2O±petrol
to give known20 sulfonamide 10c (5.90 g, 93%) as white
crystals, mp 117±1198C (lit.20 117±1198C); IR (CHCl3)
1
Rf (EtOAc) 0.7; IR (CDCl3) 1340, 1159 cm21; H NMR
(CDCl3): d 7.77 (d, 2H, Jˆ8 Hz), 7.32 (d, 2H, Jˆ8 Hz),
5.61 (s, 2H), 4.73 (d, 1H, Jˆ8 Hz), 3.96±3.89 (m, 1H),
2.54 (dd, 2H, Jˆ8, 15 Hz), 2.44 (s, 3H), 2.12 (dd, 2H,
Jˆ5, 15 Hz); 13C NMR (CDCl3): d 143.2, 137.4, 129.4,
128.2, 126.5, 52.8, 40.0, 21.2; MS (EI) m/z 237 M1, 172,
155, 91, 82; HRMS (EI) m/z calcd for C12H15NO2S M1
237.0824, found 237.0821.
1
3389, 1746, 1348, 1148 cm21; H NMR (CDCl3): d 7.75
(d, 2H Jˆ8 Hz), 7.35 (d, 2H, Jˆ8 Hz), 2.45 (s, 3H), 1.38
(s, 9H); 13C NMR (CDCl3): d 149.2, 144.7, 135.9, 129.4,
128.2, 84.0, 27.8, 21.6; MS (CI, NH3) m/z 289 M1NH14 ;
HRMS (CI, NH3) m/z calcd for C12H17NO4S M1NH41
289.1222, found 289.1224.
4-Benzyloxycarbonamidocyclopentene 5f. Using the
procedure described above, benzyl chloroformate
(0.07 mL, 0.47 mmol), hydrochloride salt
9 (51 mg,
0.42 mmol), Et3N (0.13 mL, 0.93 mmol) and DMAP
(7 mg, 0.06 mmol) in CH2Cl2 (5 mL) gave the crude product
which was puri®ed by chromatography (4:1 hexane±
EtOAc) to give alkene 5f (72 mg, 78%) as white crystals,
mp 56±588C; Rf (4:1 hexane±EtOAc) 0.3; IR (CDCl3)
N-(tert-Butoxycarbonyl)-4-(2-nitrobenzenesulfonamido)-
cyclopentene 5i. Cyclopenten-3-ol 8 (100 mg, 1.19 mmol)
was added in one portion to a stirred solution of PPh3
(936 mg, 3.57 mmol) and sulfonamide 10b (539 mg,
1.78 mmol) in THF (18 mL) at rt under N2. Then, DEAD
(0.47 mL, 2.97 mmol) was added and the solution stirred at
rt for 48 h. The solvent was evaporated under reduced
pressure and the residue was puri®ed by chromatography
(20:1 CH2Cl2±petrol) to give alkene 5i (279 mg, 64%) as
1
1712 cm21; H NMR (CDCl3): d 7.37±7.27 (m, 5H), 5.69
(s, 2H), 5.09 (s, 2H), 4.90 (br s, 1H), 4.41±4.30 (m, 1H),
2.74 (dd, 2H, Jˆ7, 15 Hz), 2.20 (dd, 2H, Jˆ4, 15 Hz); 13C
NMR (CDCl3): d 155.9, 136.4, 128.7, 128.5, 128.0, 66.5,
50.5, 40.3; MS (EI) m/z 217 M1, 156, 126, 91; HRMS (EI)
m/z calcd for C13H15NO2 M1 217.1103, found 217.1103.

9638
S. Barrett et al. / Tetrahedron 56 (2000) 9633±9640
white crystals, mp 100±1038C; Rf (20:1 CH2Cl2±petrol) 0.4;
IR (CHCl3) 1731, 1545, 1367, 1151 cm21 1H NMR
0.51 mmol) in MeCN (13 mL) at 08C. After 3 h at rt, water
(25 mL) was added and the two layers separated. The
aqueous layer was extracted with EtOAc (3£25 mL) and
the combined organic extracts were washed with 20%
Na2SO3(aq) (25 mL) and water (25 mL), dried (MgSO4)
and evaporated under reduced pressure. Trituration of the
residue with 1:1 EtOAc±petrol gave alkene 5e (100 mg,
74%) as a pale yellow solid, Rf (1:1 EtOAc±petrol) 0.6;
;
(CDCl3): d 8.36±8.31 (m, 1H), 7.81±7.71 (m, 3H), 5.69
(s, 2H), 5.17±5.05 (m, 1H), 2.89 (dd, 2H, Jˆ10, 15 Hz),
2.65 (dd, 2H, Jˆ2, 15 Hz), 1.37 (s, 9H); 13C NMR
(CDCl3): d 150.3, 146.0, 134.1, 133.9, 133.2, 131.9,
128.7, 124.3, 85.0, 56.0, 37.9, 27.9; MS (CI, NH3) m/z
386 M1NH14 , 286; HRMS (CI, NH3) m/z calcd for
C16H20N2O6S M1NH14 386.1386, found 386.1391; Anal.
calcd for C16H20N2O6S: C, 52.2; H, 5.5; N, 7.6. Found: C,
52.1; H, 5.5; N, 7.5.
1
IR (Nujol) 3327, 1542, 1372, 1344, 1160 cm21; H NMR
(CDCl3): d 8.19±8.12 (m, 1H), 7.88±7.71 (m, 3H), 5.64 (br
s, 2H), 5.50 (d, 1H, Jˆ8 Hz), 4.15±4.05 (m, 1H), 2.58 (dd,
2H, Jˆ8, 15 Hz), 2.12 (dd, 2H, Jˆ5, 15 Hz); 13C NMR
(CDCl3): d 147.8, 134.4, 133.6, 132.9, 130.8, 128.4,
125.3, 53.9, 39.9; MS (CI, NH3) m/z 286 M1NH14 , 82.
N-(tert-Butoxycarbonyl)-4-(4-methylbenzenesulfonami-
do)cyclopentene 5j. Using the procedure described above,
cyclopenten-3-ol 8 (100 mg, 1.19 mmol), PPh3 (936 mg,
3.57 mmol), sulfonamide 10c (480 mg, 1.78 mmol) and
DEAD (0.47 mL, 2.97 mmol) in THF (18 mL) gave the
crude product which was puri®ed by chromatography
(20:1 CH2Cl2±petrol) to give alkene 5j (305 mg, 76%) as
white crystals, mp 95±988C; Rf (20:1 CH2Cl2±petrol) 0.4;
General procedure for m-CPBA epoxidation
Solid NaHCO3 (3.8 mmol) and m-CPBA (approx. 70% pure
material, 2.9 mmol) were added in portions to a stirred solu-
tion of the alkene 5 (2.1 mmol) in CH2Cl2 (20 mL) at rt
under N2. After 16 h at rt, 20% Na2SO3 (30 mL) was
added and the two layers separated. The aqueous layer
was extracted with CH2Cl2 (2£20 mL) and the combined
organic extracts were washed with 20% Na2SO3(aq)
(30 mL), 5% NaHCO3(aq) (30 mL), water (30 mL), dried
(Na2SO4) and evaporated under reduced pressure to give
1
IR (CHCl3) 1724, 1354, 1154 cm21; H NMR (CDCl3): d
7.79±7.75 (m, 2H), 7.32±7.29 (m, 2H), 5.68 (s, 2H), 5.28
(quin, 1H, Jˆ9 Hz), 2.73 (d, 4H, Jˆ9 Hz), 2.44 (s, 3H), 1.33
(s, 9H); 13C NMR (CDCl3): d 150.5, 143.9, 137.7, 129.3,
128.8, 127.5, 84.2, 55.6, 37.7, 27.9, 21.6; MS (CI, NH3) m/z
355 M1NH14 , 299; HRMS (CI, NH3) m/z calcd for
C17H23NO4S M1NH14 355.1692, found 355.1695; Anal.
calcd for C17H23NO4S: C, 60.5; H, 6.9; N, 4.2. Found: C,
60.2; H, 7.2; N, 4.0.
1
the crude product. Analysis of the crude product by H
NMR spectroscopy revealed the ratio of diastereoisomers
(see Table 1) and where the major epoxide was required
for further reaction, the crude product was puri®ed by
chromatography.
N-(4-Methoxybenzyl)-4-(2-nitrobenzenesulfonamido)cy-
clopentene 5h. Using the procedure described above, cyclo-
penten-3-ol 8 (680 mg, 8.1 mmol), PPh3 (2.1 g, 8.1 mmol),
sulfonamide 10a (2.0 g, 6.2 mmol) and DEAD (1.27 mL,
8.1 mmol) in CH2Cl2 (50 mL) gave the crude product
which was puri®ed by chromatography (20:1 CH2Cl2±
petrol) to give alkene 5h (1.25 g, 52%) as a thick yellow
oil, Rf (CH2Cl2) 0.5; IR (Nujol) 1544, 1372, 1346,
N-(tert-Butoxycarbonyl)-4-(2-nitrobenzenesulfonamido)-
cyclopentene oxide trans-6i. Using the general procedure
for m-CPBA epoxidation, NaHCO3 (320 mg, 3.8 mmol),
m-CPBA (492 mg, 2.9 mmol) and alkene 5i (700 mg,
2.1 mmol) in CH2Cl2 (20 mL) gave a crude product which
contained a 98:2 mixture of epoxides trans- and cis-6i.
Puri®cation by chromatography (9:1 CH2Cl2±petrol) gave
epoxide trans-6i (617 mg, 84%) as white crystals, mp 119±
1238C; Rf (9:1 CH2Cl2±petrol) 0.2; IR (CDCl3) 1735, 1545,
1367, 1152 cm21; 1H NMR (CDCl3): d 8.20±8.16 (m, 1H),
7.71±7.63 (m, 3H), 4.63±4.50 (m, 1H), 3.51 (s, 2H), 2.43
(dd, 2H, Jˆ8, 16 Hz), 2.20 (dd, 2H, Jˆ8, 16 Hz), 1.27 (s,
9H); 13C NMR (CDCl3): d 150.0, 147.4, 134.0, 133.8,
132.5, 131.9, 124.3, 85.5, 56.4, 54.4, 31.4, 27.8; MS (CI,
NH3) m/z 402 M1NH14 , 346; HRMS (CI, NH3) m/z calcd for
C16H20N2O7S M1H1 385.1069, found 385.1070; Anal.
calcd for C16H20N2O7S: C, 50.0; H, 5.2; N, 7.3. Found: C,
50.1; H, 5.2; N, 7.2.
1
1162 cm21; H NMR (CDCl3): d 7.80±7.46 (m, 4H), 7.21
(d, 2H, Jˆ9 Hz), 6.73 (d, 2H, Jˆ9 Hz), 5.62 (br s, 1H), 4.81
(tt, 1H, Jˆ5, 9 Hz), 4.39 (s, 2H), 3.76 (s, 3H), 2.57 (dd, 2H,
Jˆ9, 16 Hz), 2.28 (dd, 2H, Jˆ5, 16 Hz); 13C NMR (CDCl3):
d 158.9, 147.7, 134.4, 133.1, 131.4, 131.2, 129.3, 129.2,
129.1, 124.0, 113.6, 57.1, 55.3, 47.4, 37.0.
4-Phthalimidocyclopentene 5k. Using the procedure
described above, cyclopenten-3-ol 8 (50 mg, 0.59 mmol),
PPh3 (203 mg, 0.77 mmol), phthalimide (113 mg,
0.77 mmol) and DEAD (0.12 mL, 0.77 mmol) in THF
(5 mL) gave the crude product which was puri®ed by chro-
matography (2:1 Et2O±petrol) to give alkene 5k (90 mg,
71%) as white crystals, mp 128±1348C; Rf (2:1 Et2O±
4-(4-Methylbenzenesulfonamido)cyclopentene oxide trans-
and cis-6d. Using the general procedure for m-CPBA
epoxidation, NaHCO3 (71 mg, 0.84 mmol), m-CPBA
(109 mg, 0.63 mmol) and alkene 5d (100 mg, 0.42 mmol)
in CH2Cl2 (2 mL) gave a crude product (98 mg, 92%) as a
white solid which contained a 16:84 mixture of epoxides
trans- and cis-6d. Diagnostic signals for epoxide trans-6d:
1H NMR (CDCl3): d 4.56 (d, 1H, Jˆ9 Hz), 3.45±3.38 (m,
1H), 3.39 (s, 2H), 2.31 (dd, 2H, Jˆ8, 14 Hz), 1.37 (dd, 2H,
Jˆ8, 14 Hz); diagnostic signals for epoxide cis-6d: 1H
NMR (CDCl3): d 4.95 (d, 1H, Jˆ9 Hz), 3.87±3.78 (m,
1H), 3.49 (s, 2H), 1.89±1.85 (m, 4H).
1
petrol) 0.2; IR (CHCl3) 1709 cm21; H NMR (CDCl3): d
7.85±7.68 (m, 4H), 5.08 (s, 2H), 5.01 (tt, 1H, Jˆ8,
10 Hz), 2.86 (dd, 2H, Jˆ8, 15 Hz), 2.68 (dd, 2H, Jˆ10,
15 Hz); 13C NMR (CDCl3): d 168.3, 133.8, 132.1, 129.0,
123.1, 48.5, 36.5; MS (CI, NH3) m/z 231 M1NH14 , 214;
HRMS (CI, NH3) m/z calcd for C13H11NO2 M1NH41
214.0868, found 214.0868.
4-(2-Nitrobenzenesulfonamido)cyclopentene 5e. A solu-
tion of CAN (840 mg, 1.53 mmol) in water (3.3 mL) was
added dropwise to a stirred solution of alkene 5h (200 mg,

S. Barrett et al. / Tetrahedron 56 (2000) 9633±9640
9639
4-Benzamidocyclopentene oxide cis-6a. Using the
general procedure for m-CPBA epoxidation, NaHCO3
(619 mg, 7.3 mmol), m-CPBA (862 mg, 5.0 mmol) and
alkene 5a (620 mg, 3.3 mmol) in CH2Cl2 (20 mL) gave a
crude product which contained a 97:3 mixture of epoxides
cis- and trans-6a. Puri®cation by chromatography (3:1
EtOAc±petrol) gave known12 epoxide cis-6a (534 mg,
79%) as white crystals, mp 90±928C (lit.12 848C).
(dt, 1H, Jˆ3, 15 Hz); 13C NMR (CDCl3): d 167.2, 136.6,
134.2, 133.7, 131.5, 128.4, 126.9, 75.2, 54.0, 40.9; MS (EI)
m/z 203 M1, 105; HRMS (EI) m/z calcd for C12H13NO2 M1
203.0346, found 203.0940; HPLC: Chiralcel OJ, 5% EtOH
in heptane, 1.0 mL min21, 215 nm, 14.6 min [(1S,2R)-7a],
16.8 min [(1R,2S)-7a].
(1S,2R)-4-Tri¯uoroacetamidocyclopent-2-en-1-ol 7b. Using
the procedure described above, n-butyllithium (1.54 mL of a
1.5 M solution in hexane, 2.3 mmol), diamine 12 (505 mg,
2.3 mmol) and epoxide cis-6b (150 mg, 0.77 mmol) in THF
(5 mL) gave the crude product which was puri®ed by
chromatography (23:2 CH2Cl2±MeOH) to give allylic
alcohol (1S,2R)-7b (110 mg, 73, 88% ee) as a pale yellow
syrup, [a]Dˆ155 (c 2.8 in CHCl3); Rf (23:2 CH2Cl2±
4-Tri¯uoroacetamidocyclopentene oxide cis-6b. m-CPBA
(664 mg, 2.70 mmol) was added in one portion to a stirred
solution of alkene 5b (481 mg, 2.69 mmol) in CH2Cl2
(27 mL) at 08C under N2. After 30 min at 08C, the mixture
was stirred at rt for 1.5 h. Cyclopentene (0.1 mL) was added
and after 15 min most of the solvent was evaporated under
reduced pressure. The slurry was ®ltered, the precipitate
washed with CH2Cl2 and the ®ltrate evaporated under
reduced pressure. This process was repeated a further two
times. Then, Et3N (0.5 mL) was added to the ®ltrate and the
solid removed by ®ltration. The solvent was evaporated
under reduced pressure to give the crude product which
was puri®ed by chromatography (CH2Cl2) to give known9
epoxide cis-6b (383 mg, 73%) as off-white crystals, mp 60±
618C (lit.9 628C).
1
MeOH) 0.3; IR (CHCl3) 3604, 3426, 1721 cm21; H NMR
(CDCl3): d 6.12 (td, 1H, Jˆ2, 6 Hz), 5.88 (ddd, 1H, Jˆ1, 2,
6 Hz), 4.88±4.85 (m, 2H), 3.89 (br s, 1H), 2.79 (ddd, 1H,
Jˆ7, 8, 15 Hz), 2.64 (s, 1H), 1.65 (dt, 1H, Jˆ3, 15 Hz); 13C
NMR (75.5 MHz, CDCl3): d 156.5 (q, Jˆ37 Hz), 137.9,
132.4, 115.7 (q, Jˆ288 Hz), 75.1, 54.1, 40.5; MS (CI,
NH3) m/z 213 M1NH14 , 178; HRMS (CI, NH3) m/z calcd
for C7H8F3NO2 M1NH14 213.0851, found 213.0850.
Acknowledgements
General procedure for methyl(tri¯uoromethyl)-
dioxirane epoxidation
We thank The University of York Innovation and Research
Priming Fund for a grant (to T. D. T.), the EU for grants (to
M. V. and H. C. S.) and The University of York for support
(of S. B.). Additional support from Astra-Zeneca Strategic
Research Fund is also gratefully acknowledged.
Chilled tri¯uoroacetone (0.2 mL) was added dropwise to a
M
stirred solution of Na2EDTA (1.0 mL of a 4£1024
aqueous solution) and alkene 5 (0.2 mmol) in MeCN
(1.5 mL) at 08C. Solid NaHCO3 (1.6 mmol) and Oxonew
(1.0 mmol) were crushed together and added in portions
over 1±2 h at 08C. After 2 h at 08C, water (20 mL) and
CH2Cl2 (20 mL) were added and the two layers were sepa-
rated. The aqueous layer was extracted with CH2Cl2
(3£20 mL) and the combined organic extracts were washed
with water (30 mL), dried (Na2SO4) and evaporated under
reduced pressure to give the crude product. Analysis of the
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