Synthesis of 4-azacyclopent-2-enones and 5,5-dialkyl-4-azacyclopent-2- enones

Article abstract of DOI:10.1016/j.tet.2004.01.046

Three different methods are reported for the preparation of 4-azacyclo-2-enones 1, two of which allow the preparation of the compounds in optically active form. In addition, a facile route to 4-aza-5,5- dimethylcyclopent-2-enones 2 is disclosed.

Full text of DOI:10.1016/j.tet.2004.01.046

Tetrahedron 60 (2004) 2559–2567
Synthesis of 4-azacyclopent-2-enones and
5,5-dialkyl-4-azacyclopent-2-enones
a
Jerome Dauvergne, Alan M. Happe, Vasudev Jadhav, David Justice,
a
a
b
,
*
´ ˆ
Marie-Christine Matos,a Peter J. McCormack,c Michael R. Pitts,c Stanley M. Roberts,a,b
Sanjay K. Singh,a Timothy J. Snapea and John Whittallc
aCharterhouse Therapeutics Ltd, Robert Robinson Building, University of Liverpool, Liverpool L69 7ZD, UK
bStylacats Ltd, Development Labs, Cheshire Manufacturing Park, Ellesmere Port, Cheshire, UK
cStylacats Ltd, Research Labs, Robert Robinson Building, University of Liverpool, Liverpool L69 7ZD, UK
Received 22 October 2003; revised 10 December 2003; accepted 15 January 2004
Abstract—Three different methods are reported for the preparation of 4-azacyclo-2-enones 1, two of which allow the preparation of the
compounds in optically active form. In addition, a facile route to 4-aza-5,5-dimethylcyclopent-2-enones 2 is disclosed.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
same two-step transformation could be applied more
broadly and, for example, was accomplished by reacting
hydroxyketone 3 with N-tosylisocyanate to afford com-
pound 5 (44%), which was converted into the desired
product 9 (68%) on treatment with base. Similarly the
compound 10 was prepared in 42% overall yield through the
intermediate formation of urethane 6.
4-Aza-cyclopentenones 1 and 2 are potentially interesting
scaffolds for parallel synthesis/combinatorial chemistry and
are possibly useful building blocks for the construction of
carbocyclic nucleosides.1 Paradoxically, little work has
been reported in the literature concerning the synthesis of
such compounds.2 In our laboratories we were keen to
access these materials in racemic and optically active form
in connection with our studies concerning the anti-viral
activity of simple cyclopentenones.3
The synthesis of the phenoxycarbonyl compound 11
suffered from a low yield (27%) in the first step, although
the rearrangement/decarboxylation of 7 proceeded in almost
quantitative yield. Interestingly, reaction of the alcohol 3
with chloroacetyl isocyanate gave the rearranged product 12
directly in 40% yield.
Overall, this pathway suffered from some drawbacks. First,
the overall yields were only modest to good. In addition, the
decarboxylative rearrangements of some other inter-
mediates (for example those derived by reaction of 3 with
cyclohexyl- or tert-butyl-isocyanate) were capricious and
none of the desired product could be detected. One of our
target compounds, 4-tert-butoxycarbonylaminocyclopent-
2-enone 13 could not be obtained. Finally, the hydroxy-
ketone 3 is not readily available in optically active form,5
and therefore access to optically active compounds was not
facile.
2. Results and discussion
Initially, the earlier studies of Harris attracted our attention.4
Harris showed that 4-hydroxycyclopent-2-enone 3 could be
converted into the urethane 4 which itself was transformed
into the 4-anilino-compound 8 (with loss of CO2) on
treatment with triethylamine (Scheme 1). We found that the
The second methodology investigated, specifically to
prepare compound 13, involved, in the first step, the
cycloaddition of the nitroso-compound derived from 14 and
cyclopentadiene (Scheme 2) to furnish the bicyclic
compound 15. This proceeded as reported previously,6,7 as
Keywords: 4-Aza-cyclopentenones; 4-Aza-cyclopent-2-en-1-ols;
Asymmetric synthesis of aminocyclopentenols; Lipase resolution.
*
Corresponding author. Tel.: þ44-151-794-3501; fax: þ44-151-794-2304;
e-mail address: smrsm@liv.ac.uk
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.01.046

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J. Dauvergne et al. / Tetrahedron 60 (2004) 2559–2567
Scheme 1.
Scheme 2. Reagents and conditions: (i) (n-Bu)4NIO4, CH2Cl2, 1 h, 79%; (ii) Mo(CO)6, CH3CN, H2O, then NaBH4, reflux, 3 h, 65%; OR Na/Hg, Na2HPO4,
˚
C2H5OH, 0 8C, 1.5 h, 74%; (iii) PCC, CH2Cl2, 4 A mol. sieve, 2 h, 83%; OR TEMPO, H5IO6, CH2Cl2, 2.5 h, 97%.
did the N–O bond cleavage using Mo(CO)6.6 However, we
were anxious to find a replacement for the latter reagent and
we found that sodium amalgam was a suitable alternative,8
leading to a cleaner reaction providing the protected amino
alcohol 16 in 74% yield in a protocol more suitable for
scale-up. Oxidation of the alcohol 16 to the enone 13
proceeded smoothly using pyridinium chlorochromate, or
periodate and a catalytic amount of TEMPO.9
The intermediacy of alcohol 16 in this pathway suggested
this might be a suitable substrate for enzyme-controlled
kinetic resolution.10 Incubation with Amano PS-C II lipase
Scheme 3. Reagents and conditions: (i) Amano PS-C II lipase, CH2CHOAc, CH2Cl2, 35 8C, 72 h, 42% of (þ)-17 and 55% of (2)-16; (ii) LiOH, C2H5OH,
H2O, 4 h, 95%; (iii) CH3COCl, CH2Cl2, 0 8C, 18 h, 84%; Amano PS-C II lipase, (CH3)2CO, pH 7.4 buffer, 35 8C, 54 h, 73% of (2)-17 and 20% of (þ)-16;
(iv) LiOH, C2H5OH, H2O, 100%.

J. Dauvergne et al. / Tetrahedron 60 (2004) 2559–2567
2561
in dichloromethane containing vinyl acetate gave the
acetate (þ)-17 (42%) and recovered alcohol (2)-16 (55%)
after the biotransformation, followed by work-up in a
conventional manner (Scheme 3). The recovered alcohol
(2)-16 was acetylated and this acetate (2)-17 was
hydrolysed in phosphate buffer using Amano PS-C II lipase
to give optically enriched (2)-17 (73%) and alcohol (þ)-16
(20%). The acetate (þ)- and (2)-17 were readily hydro-
lysed to the alcohols (þ)- and (2)-16, respectively. The
optical purities were measured as 92 and 99% ee by GC
employing a chiral column after oxidation to (þ)- and (2)-
13, respectively.
direct attack at the neopentyl centre. In accord with this
postulate, reaction of tosylate 22 with hexanethiol gave,
under mild conditions, the conjugate addition products 28
and 30 and the enone 26 (ratio 1:1:2). Heating the major
conjugate adduct 28 (trans-stereochemistry) furnished the
enone 26 in high yield, but the cis-isomer 30 remained
unchanged after prolonged heating under the same con-
ditions. In a similar manner, under the appropriate reaction
conditions, octanethiol and the tosylate 22 gave a mixture of
Michael adducts 29 and 31 as well as the enone 27 in a ratio
of 5:4:8. Heating 29 in dichloromethane for 1 h afforded 27
in 89% yield whereas, 31 was stable under these conditions.
To circumvent the loss of material at the stage of the kinetic
resolution a new method was sought to provide optically
active 16 that was less wasteful in material. The initial
findings of this initiative are reported here but full
details will be reported elsewhere. First, the readily
available meso-diacetate 18 could be mono-substituted by
using HN(COt2Bu)2 and a palladium catalyst to give the
racemic acetate 19.11 Treatment of 19 with TFA then gave
the acetate 17 is very short order.
Furthermore, the monoacetate 20 could be prepared from
the corresponding meso-diacetate 18 using an enzyme-
catalysed hydrolysis.12 This hydroxyester 20 was then
directly converted into the bis-protected amine 21 using
similar conditions.13 Mono-deprotection of 21 was then
effected, to provide the protected amine 16 with a
enantiomeric excess of 98% in only 3 high yielding
transformations (Scheme 4).
The preparation of compounds of type 2 involved another
novel transformation in the key step. 2-Methylcyclo-
pentane-1,3-dione was converted into 4-hydroxy-5,5-
dimethylcyclopent-2-enone as prescribed by Yamada
et al.14 and reaction of this alcohol with para-toluene-
sulfonyl chloride gave the tosylate 22. Reaction of 22 with
the appropriate amine gave the amines 23-25 directly in
65–74% yield. It is likely that the reaction proceeds through
conjugate addition of the amine to the enone and secondary
rearrangement through an aziridinium species, rather than
In conclusion, the preparation of 4-azacyclopentenones
according to the method of Harris has been used to access
compounds 8-12. The route does not allow the preparation
of the N-Boc derivative 13. However, this compound can be
made from the alcohol 16, kinetic resolution of 16 using a
lipase allows access to optically active material. However,
the preferred route to optically active 13 involves conver-
sion of the monoester 20 into the diprotected amine 21 in the
Scheme 4. Reagents and conditions: (i) Pd2(dba)3, dppf, NH(Boc)2, BSA, THF, 50 8C, 12 h, 90%; (ii) TFA, CH2Cl2, 20 h, 97%; (iii) see Ref. 12; (iv) Pd2(dba)3,
dppf, NH(Boc)2, BSA, THF, 45 8C, 3 h, 68%; (v) TFA, CH2Cl2, 20 h, 96%.

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key step. The scope of the latter transformation is under
active investigation.
3.1.2. (4-Oxocyclopent-2-enyl)-carbamic acid ethyl ester
(10). Ethoxycarbonyl isocyanate (0.90 mL, 8.72 mmol) was
added to a solution of the enone 3 (1.08 g, 11.0 mmol) in dry
dichloromethane (20 mL) under a nitrogen atmosphere and
the reaction mixture was stirred at room temperature for 5 h.
The dichloromethane was removed in vacuo, then filtered
through a short pad of silica eluting with a 2:1 mixture of
dichloromethane and petrol to give the crude product 6
(1.16 g, 5.45 mmol, 49%) as a brown oil, which was taken
on without further purification.
3. Experimental
3.1. General
Starting materials were purchased from commercial sources
and were used without further purification. Dichloro-
methane was distilled from calcium hydride and tetra-
hydrofuran was distilled from sodium benzophenone ketyl.
1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were
Triethylamine (0.84 mL, 6.03 mmol) was added to a
solution of the crude enone 6 (1.16 g, 5.45 mmol) in dry
chloroform (20 mL) under a nitrogen atmosphere and the
reaction mixture was stirred at room temperature for 3 h.
The chloroform was removed in vacuo and the crude
product was purified by flash chromatography (SiO2, 50%
ethyl acetate in hexane) to afford the title compound 10
(0.78 g, 4.62 mmol, 85%) as a white crystalline solid; Rf 0.3
(50% ethyl acetate in hexane); dH (400 MHz, CDCl3) 7.53
(1H, m, CHvCHCvO), 6.25 (1H, m, CHvCHCvO), 5.00
(1H, br. s, NH), 4.91 (1H, br. s, CHNH), 4.15 (2H, q,
J¼7.1 Hz, CH2CH3), 2.86 (1H, dd, J¼18.7, 6.5 Hz, CHH),
2.18 (1H, dd, J¼18.7, 2.4 Hz, CHH), 1.26 (3H, t, J¼7.1 Hz,
CH2CH3); dC (100 MHz, CDCl3) 206.2 (s), 161.7 (d), 155.9
(s), 135.4 (d), 61.4 (t), 51.4 (d), 42.3 (t), 14.5 (q); m/z (CI)
187 ([MNH4]þ, 100%), 170 ([MH]þ, 92), 169 ([M]þ, 14).
Found [MH]þ 170.0814 ([MH]þ C8H12NO3 requires
170.0817).
1
recorded using a Bruker AMX400 spectrometer. H NMR
(300 MHz) and 13C NMR (75 MHz) spectra were recorded
using a Varian Gemini 2000 spectrometer. Optical rotation
measurements were recorded using an Optical Activity,
Polaar 2001 polarimeter at 589 nm and quoted in units of
1021 deg cm2 g21. Flash column chromatography was
performed under moderate pressure using silica gel—ICN
˚
32-63, 60 A. Analytical HPLC measurements were per-
formed on a Gilson HPLC machine using an OD column
and GC measurements were performed on a Shimadzu
GC-14AH machine using a Lipodex E (Macherey-Nagel)
column.
3.1.1. 3-(4-Oxocyclopent-2-enyl)-4-methylphenylsulfonyl
carbamic acid (9).15 p-Tolylsulfonyl isocyanate (2.94 g,
14.9 mmol) was added to a solution of the enone 3 (1.46 g,
14.9 mmol) in dry dichloromethane (10 mL) under a nitrogen
atmosphere and the reaction mixture was stirred at room
temperature for 5 h. The dichloromethane was removed in
vacuo and the crude product was purified by flash chroma-
tography (SiO2, 40% ethyl acetate in hexane) to afford the
compound 5 (1.93 g, 6.54 mmol, 44%) as a light yellow solid;
Rf 0.25 (50% ethyl acetate in hexane); dH (400 MHz, CDCl3)
7.87–7.76 (2H, m, ArH), 7.39–7.32 (3H, m, CHvCHCvO,
ArH), 6.20 (1H, dd, J¼5.6, 1.8 Hz, CHvCHCvO), 4.96 (1H,
d, J¼9.1 Hz, NH), 4.63(1H,m,CHOR), 2.58(1H,dd, J¼18.8,
6.7 Hz, CHH), 2.45 (3H, s, ArCH3), 1.98 (1H, dd, J¼18.8,
2.5 Hz, CHH); dC (100 MHz, CDCl3) 205.3 (s), 160.9 (d),
145.7 (s), 144.3 (s), 137.2 (s), 136.0 (d), 130.1 (d), 127.2 (d),
53.6 (d), 42.1 (t), 21.6 (q).
3.1.3. (4-Oxocyclopent-2-enyl)-carbamic acid phenyl
ester (11). Phenoxycarbonyl isocyanate (1.60 mL,
12.1 mmol) was added to a solution of the enone 3
(1.18 g, 12.0 mmol) in dry dichloromethane (15 mL)
under a nitrogen atmosphere and the reaction mixture was
stirred at room temperature for 24 h. The dichloromethane
was removed in vacuo and the crude product was purified by
flash chromatography (SiO2, 20% ethyl acetate in hexane) to
afford the compound 7 (0.85 g, 3.26 mmol, 27%) as a white
solid; Rf 0.4 (50% ethyl acetate in hexane); dH (400 MHz,
CDCl3) 7.60 (1H, dd, J¼5.7, 2.4 Hz, CHvCHCvO), 7.38
(2H, t, J¼7.9 Hz, ArH), 7.23 (1H, t, J¼7.5 Hz, ArH), 7.14
(2H, m, ArH), 6.30 (1H, dd, J¼5.7, 1.7 Hz, CHvCHCvO),
5.33 (1H, m, NH), 5.07 (1H, m, CHOR), 2.93 (1H, dd,
J¼18.8, 6.8 Hz, CHH), 2.28 (1H, dd, J¼18.8, 2.5 Hz,
CHH); dC (100 MHz, CDCl3) 205.8 (s), 161.2 (d), 154.0 (s),
150.7 (s), 135.8 (d), 129.4 (d), 125.7 (d), 121.4 (d), 120.5
(s), 51.6 (d), 42.0 (t).
A catalytic amount of triethylamine (3–4 drops) was added
to a solution of the enone 5 (148 mg, 0.50 mmol) in dry
chloroform (5 mL) under a nitrogen atmosphere and the
reaction mixture was stirred at room temperature for 4 h.
The chloroform was removed in vacuo and the crude
product was purified by flash chromatography (SiO2, 40%
ethyl acetate in hexane) to afford the title compound 9
(86 mg, 0.34 mmol, 68%) as a white crystalline solid; dH
(400 MHz, CDCl3) 7.75 (2H, d, J¼8.2 Hz, ArH), 7.37 (1H,
dd, J¼5.7, 2.4 Hz, CHvCHCvO), 7.35 (2H, d, J¼8.2 Hz,
ArH), 6.20 (1H, dd, J¼5.7, 1.8 Hz, CHvCHCvO), 4.80
(1H, d, J¼9.2 Hz, NH), 4.60 (1H, m, CHNH), 2.55 (1H, dd,
J¼18.8, 6.7 Hz, CHH), 2.45 (3H, s, ArCH3), 1.95 (1H, dd,
J¼18.8, 2.6 Hz, CHH); dC (100 MHz, CDCl3) 205.1 (s),
160.7 (d), 144.3 (s), 137.3 (s), 136.1 (d), 130.1 (d), 127.2
(d), 53.6 (d), 42.2 (t), 21.6 (q); m/z (CI) 269 ([MNH4]þ,
100%), 252 ([MH]þ, 20). Found [MH]þ 252.0699 ([MH]þ
C12H14NO3S requires 252.0694).
Triethylamine (0.23 mL, 1.65 mmol) was added to a
solution of the enone 7 (0.41 g, 1.57 mmol) in dry chloro-
form (10 mL) under a nitrogen atmosphere and the reaction
mixture was stirred at room temperature for 4 h. The solvent
was removed in vacuo to afford the title compound 11
(0.32 g, 1.47 mmol, 94%) as a copper coloured solid; Rf 0.4
(50% ethyl acetate in hexane); mp 111–112 8C (EtOAc/
hexane); dH (400 MHz, CDCl3) 7.58 (1H, dd, J¼5.6,
2.4 Hz, CHvCHCvO), 7.40–7.33 (2H, m, ArH),
7.247.19 (1H, m, ArH), 7.15–7.10 (2H, m, ArH), 6.29
(1H, dd, J¼5.6, 1.8 Hz, CHvCHCvO), 5.28 (1H, br. s,
NH), 5.09–5.01 (1H, m, CHNH), 2.91 (1H, dd, J¼18.6,
6.8 Hz, CHH), 2.27 (1H, dd, J¼18.6, 2.2 Hz, CHH); dC
(100 MHz, CDCl3) 205.7 (s), 161.1 (d), 153.9 (s), 150.7 (s),

J. Dauvergne et al. / Tetrahedron 60 (2004) 2559–2567
2563
135.8 (d), 129.4 (d), 125.7 (d), 121.4 (d), 51.6 (d), 42.0 (t);
m/z (CI) 235 ([MNH4]þ, 100%), 218 ([MH]þ, 16), 217
([M]þ, 0.3). Found [MH]þ 218.0824 ([MH]þ C12H12NO3
requires 218.0817).
15 (0.70 g, 3.55 mmol) in a 7:1 mixture of acetonitrile and
water (24 mL). The suspension was stirred for 10 min at
room temperature, then sodium borohydride (0.07 g,
1.85 mmol) was added and the suspension was heated
under reflux for 3 h. Upon completion of reaction, the
mixture was allowed to cool to room temperature, filtered
through a celitew plug, and evaporated to dryness to give a
dark oil. Flash chromatography (SiO2, 50% ethyl acetate in
petrol) gave the alcohol 16 (0.46 g, 2.31 mmol, 65%) as a
colourless oil; dH (400 MHz, CDCl3) 6.02–5.96 (1H, m,
CHvCH), 5.85 (1H, dd, J¼5.5, 1.2 Hz, CHvCH), 4.82–
4.67 (2H, m), 4.47–4.39 (1H, m), 2.75 (1H, dt, J¼14.4,
7.7 Hz, CHH), 2.63–2.57 (1H, m, CHH), 1.56–1.50 (1H,
m, OH), 1.45 (9H, s, CO2C(CH3)3); dC (100 MHz, CDCl3)
155.2 (s), 136.1 (d), 134.2 (d), 79.6 (s), 75.3 (d), 55.0 (d),
41.5 (t), 28.4 (q); m/z (CI). Found [MH]þ 200.1285 ([MH]þ
C10H18NO3 requires 200.1287).
3.1.4. 2-Chloro-N-(4-oxocyclopent-2-enyl)-acetamide
(12). Chloroacetyl isocyanate (0.84 g, 9.86 mmol) was
added to a solution of the enone 3 (0.96 g, 9.80 mmol) in
dry dichloromethane (10 mL) under a nitrogen atmosphere
and the reaction mixture was stirred at room temperature for
20 h. The dichloromethane was removed in vacuo and the
crude product was purified by flash chromatography (SiO2,
20% ethyl acetate in hexane) to afford the title compound 12
(0.68 g, 3.92 mmol, 40%) as a white solid; Rf 0.5 (ethyl
acetate); mp 99–100 8C (EtOAc/hexane); dH (400 MHz,
CDCl3) 7.53 (1H, dd, J¼5.6, 2.4 Hz, CHvCHCvO), 6.71
(1H, s, NH), 6.33 (1H, dd, J¼5.6, 1.8 Hz, CHvCHCvO),
5.31–5.23 (1H, m, CHNH), 4.09 (2H, s, CH2Cl), 2.91 (1H,
dd, J¼18.8, 6.8 Hz, CHH), 2.22 (1H, dd, J¼18.8, 2.7 Hz,
CHH); dC (100 MHz, CDCl3) 205.5 (s), 165.8 (s), 160.6 (d),
136.2 (d), 50.0 (d), 42.4 (t), 41.7 (t); m/z (CI) 191
([MNH4]þ, 100%), 174 ([MH]þ, 39), 173 ([M]þ, 3.7).
Found [MH]þ 174.0321 ([MH]þ C7H9NO2Cl requires
174.0322).
Method B. Disodium hydrogen phosphate (42.3 g, 0.30 mol)
was added to a solution of the bicycle 15 (16.9 g,
85.7 mmol) in ethanol (230 mL). After cooling to 0 8C,
freshly prepared and pulverised sodium amalgam (150 g,
5% sodium, 0.33 mol) was added in one portion
(CAUTION: EXOTHERM). However, after stirring for
1 h at 0 8C some starting material remained, so further
amalgam (50 g, 0.11 mol) was added. Further stirring at
0 8C for 30 min allowed full consumption of starting
material, so the reaction mixture was then filtered through
a celitew plug. The filtrate was then diluted with water
(350 mL) and extracted with dichloromethane (3£100 mL).
The combined organic extracts were then dried over
anhydrous magnesium sulfate, and evaporated in vacuo to
give the alcohol 16 (12.7 g, 63.7 mmol, 74%) as a pale
yellow oil of suitable purity to be taken on and with identical
data to the material prepared via the previous method.
3.1.5. 2-Oxa-3-azabicyclo[2.2.1]hept-5-ene-3-carboxylic
acid tert-butyl ester (15).6 Water (5 mL) and sodium
carbonate (23.9 g, 0.23 mol) were added to a suspension of
hydroxylamine hydrochloride (24.0 g, 0.35 mol) in diethyl
ether (150 mL). The suspension was stirred at room
temperature for 1 h, then cooled to 0 8C. Subsequently, a
solution of di-tert-butyl dicarbonate (50.2 g, 0.23 mol) in
diethyl ether (50 mL) was added dropwise over 30 min and
the suspension was allowed to warm up to room
temperature, then stirred for 3 h. Upon completion of
reaction, the mixture was filtered and washed with ether
(2£100 mL). The filtrate was evaporated to dryness to yield
a colourless oil. Upon addition of cyclohexane, compound
14 was crystallised as colourless needles (27.2 g, 0.20 mol,
89%, 2 crops).
3.1.7. (4-Oxocyclopent-2-enyl)-carbamic acid tert-butyl
˚
ester (13). Method A. 4 A powdered, activated, molecular
sieves (0.50 g) and pyridinium chlorochromate (0.60 g,
2.78 mmol) were successively added to a solution of the
alcohol 16 (0.46 g, 2.31 mmol) in anhydrous dichloro-
methane (20 mL). The suspension was stirred for 2 h at
room temperature. Upon completion of reaction, the
mixture was filtered over a short silica gel column (50%
ethyl acetate in petrol) to give the ketone 13 (0.38 g,
1.93 mmol, 83%) as a white solid; dH (400 MHz, CDCl3)
7.51 (1H, m, CHvCHCvO), 6.21 (1H, dd, J¼5.7, 0.7 Hz,
CHvCHCvO), 4.94 (2H, m, NHþCHNH), 2.83 (1H, m,
CHH), 2.17 (1H, m, CHH), 1.45 (9H, s, CO2C(CH3)3); dC
(100 MHz, CDCl3) 206.9 (s), 162.6 (d), 155.5 (s), 135.5 (d),
80.6 (s), 51.5 (d), 42.7 (t), 28.7 (q); m/z (EI). Found [M]þ
197.1057 ([M]þ C10H15NO3 requires 197.1052).
Tetra-n-butylammonium periodate (2.0 g, 4.67 mmol) was
added to a solution of freshly cracked cyclopentadiene
(0.46 g, 6.97 mmol) in dichloromethane (15 mL). tert-
Butyl-N-hydroxycarbamate 14 (0.62 g, 4.67 mmol) was
added portionwise over 5 min and the solution was stirred
for 1 h at room temperature. Upon completion of reaction,
the organic solution was washed successively with sodium
thiosulfate (10% aq. soln., 2£50 mL) and sodium hydrogen
carbonate (sat’d. aq., 80 mL), then dried over anhydrous
magnesium sulfate, filtered and concentrated to give a crude
black oil. Flash chromatography (SiO2, 20% ethyl acetate in
petrol) gave the bicyclic adduct 15 (0.73 g, 3.71 mmol,
79%) as a yellow oil, which solidified upon standing in the
freezer; dH (400 MHz, CDCl3) 6.41 (2H, m, CHvCH), 5.20
(1H, m, CHNBoc), 4.98 (1H, m, CHON), 1.98 (1H, dt,
J¼8.5, 1.9 Hz, CHH), 1.73 (1H, m, CHH), 1.46 (9H, s,
CO2C(CH3)3); dC (100 MHz, CDCl3) 158.6 (s), 134.1 (d),
132.9 (d), 83.5 (d), 81.8 (s), 65.0 (d), 48.1 (t), 28.2 (q).
Method B. TEMPO (91 mg, 0.58 mmol) and periodic acid
(14.6 g, 64.0 mmol) were successively added to a solution
of the alcohol 16 (11.5 g, 57.7 mmol) in dichloromethane
(250 mL). The suspension was stirred for 2.5 h at room
temperature. The reaction mixture was poured onto sodium
thiosulfate (sat’d. aq., 300 mL) (CAUTION: EXOTHERM),
the phases separated and the aqueous phase extracted with
dichloromethane (3£500 mL). The combined organic
extracts were then dried over anhydrous magnesium sulfate,
and evaporated in vacuo to give the ketone 13 (11.0 g,
3.1.6. (4-Hydroxycyclopent-2-enyl)-carbamic acid tert-
butyl ester (16). Method A.6 Molybdenum hexacarbonyl
(1.46 g, 5.53 mmol) was added to a solution of the bicycle

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J. Dauvergne et al. / Tetrahedron 60 (2004) 2559–2567
55.8 mmol, 97%) as a white solid of suitable purity to be
taken on and with identical data to the material prepared via
the previous method.
3.1.11. (2R,4S)-Acetic acid 4-tert-butoxycarbonylamino-
cyclopent-2-enyl ester ((2)-17). A solution of acetyl
chloride (0.53 mL, 7.45 mmol) in anhydrous dichloro-
methane (10 mL) was added slowly to a solution of the
enriched alcohol (2)-16 (1.13 g, 5.68 mmol) in a mixture
of pyridine (10 mL) and anhydrous dichloromethane
(10 mL), cooled to 0 8C. The mixture was stirred overnight
at 0 8C. Upon completion of reaction, the mixture was
evaporated and diluted with ethyl acetate (200 mL), then
washed with citric acid (10% aq. soln., 200 mL). The
aqueous layer was then extracted with ethyl acetate
(150 mL). The combined organic layers were washed with
brine (200 mL), dried over anhydrous magnesium sulfate,
filtered and evaporated to give a yellow oil. Flash
chromatography (SiO2, 50% ethyl acetate in petrol) gave
the optically enriched acetate (2)-17 (1.15 g, 4.77 mmol,
84%) as a yellow oil, which showed identical spectro-
scopic data to its enantiomer (þ)-17 as described in
Section 3.1.8.
3.1.8. (2S,4R)-Acetic acid 4-tert-butoxycarbonylamino-
cyclopent-2-enyl ester ((1)-17) and (2S,4R)-(4-hydro-
xycyclopent-2-enyl)-carbamic acid tert-butyl ester ((2)-
16).10 Vinyl acetate (7.0 mL, 76 mmol) and PS-C II Amano
lipase (1.51 g) were successively added to a solution of the
racemic alcohol (^)-16 (1.51 g, 7.59 mmol) in anhydrous
dichloromethane (40 mL) and the slurry was stirred for 72 h
at 35 8C. The mixture was filtered and evaporated to dryness
to give a yellow oil. Flash chromatography (SiO2, 50% ethyl
acetate in petrol) gave the optically active acetate (þ)-17
(0.76 g, 3.15 mmol, 42%) and the optically enriched alcohol
(2)-16 (0.82 g, 4.12 mmol, 55% recovery). Crystallisation
from petroleum ether afforded the optically active acetate
(þ)-17 (0.64 g) as white orthorhombic crystals, whose
stereochemistry was elucidated by obtaining an X-ray
structure; dH (400 MHz, CDCl3) 5.97 (1H, d, J¼5.6 Hz,
CHvCH), 5.92 (1H, d, J¼5.6 Hz, CHvCH), 5.54–5.48
(1H, m, CHOAc), 4.66 (2H, br. s, NHþCHNH), 2.81 (1H,
dt, J¼14.5, 7.3 Hz, CHH), 2.02 (3H, s, O2CCH3), 1.51 (1H,
dt, J¼14.5, 4.0 Hz, CHH), 1.44 (9H, s, CO2C(CH3)3); dC
(100 MHz, CDCl3) 170.5 (s), 155.0 (s), 136.9 (d), 132.0 (d),
79.5 (s), 77.4 (d), 54.3 (d), 38.6 (t), 28.3 (q), 21.1 (q); m/z
(CI) 242 ([MH]þ, 15%), 182 ([MH2AcOH]þ, 34), 142
([MH22CO2C(CH3)3]þ, 77), 126 ([MH2NHBoc]þ, 100).
Found [MH]þ 242.1394 ([MH]þ C12H20NO4 requires
242.1392).
PS-C II Amano lipase (1.15 g) was added to an emulsion of
the enriched acetate (2)-17 (1.15 g, 4.77 mmol) in a
mixture of acetone (20 mL) and phosphate buffer
(c¼0.1 M, pH¼7.4, 20 mL). The slurry was stirred for
54 h at 35 8C. The mixture was filtered and evaporated to
dryness to give a yellow oil. Flash chromatography (SiO2,
50% ethyl acetate in petrol) gave in the order of elution, the
optically active acetate (2)-17 (0.84 g, 3.49 mmol, 73%
recovery), and the optically enriched alcohol (þ)-16
(0.19 g, 0.95 mmol, 20%).
3.1.9. (2R,4S)-(4-Hydroxycyclopent-2-enyl)-carbamic
acid tert-butyl ester ((1)-16). Lithium hydroxide mono-
hydrate (0.17 g, 4.05 mmol) was added to a solution of the
optically active acetate (þ)-17 (0.64 g, 2.66 mmol) in 75%
aqueous ethanol (40 mL). The solution was stirred for 4 h at
room temperature. Upon completion of reaction, the
mixture was partitioned between water (40 mL) and ethyl
acetate (40 mL), and the aqueous layer was further extracted
with ethyl acetate (2£30 mL). The combined organic layers
were washed successively with sodium hydrogen carbonate
(sat’d. aq., 40 mL), water (40 mL) and brine (40 mL), then
dried over anhydrous magnesium sulfate and evaporated to
give the optically active alcohol (þ)-16 (0.50 g, 2.51 mmol,
95%) as a light yellow oil, which solidified upon standing at
room temperature; [a]D¼þ64.0 (c 1.0, CHCl3); and gave
identical data to the racemic material described in Section
3.1.6.
3.1.12. (2S,4R)-(4-Hydroxycyclopent-2-enyl)-carbamic
acid tert-butyl ester ((2)-16). Lithium hydroxide mono-
hydrate (0.22 g, 5.24 mmol) was added to a solution of the
optically active acetate (2)-17 (0.84 g, 3.49 mmol) in 75%
aqueous ethanol (48 mL). The solution was stirred overnight
at room temperature. Upon completion of reaction, the
mixture was partitioned between water (50 mL) and ethyl
acetate (50 mL), and the aqueous layer was further extracted
with ethyl acetate (2£50 mL). The combined organic layers
were washed successively with sodium hydrogen carbonate
(sat’d. aq., 50 mL), water (50 mL) and brine (50 mL), then
dried over anhydrous magnesium sulfate and evaporated to
give the optically active alcohol (2)-16 (0.70 g, 100%) as a
light yellow oil, which solidified upon standing at room
temperature; [a]D¼267.0 (c 1.0, CHCl3); and gave
identical data to the racemic material described in Section
3.1.6.
3.1.10. (2R)-(4-Oxocyclopent-2-enyl)-carbamic acid tert-
˚
butyl ester ((1)-13). 4 A powdered, activated, molecular
3.1.13. (2S)-(4-Oxocyclopent-2-enyl)-carbamic acid tert-
˚
butyl ester ((2)-13). 4 A powdered, activated, molecular
sieves (0.50 g) and pyridinium chlorochromate (0.65 g,
3.02 mmol) were successively added to a solution of the
optically active alcohol (þ)-16 (0.50 g, 2.54 mmol) in
anhydrous dichloromethane (20 mL). The suspension was
stirred for 1.5 h at room temperature. Upon completion of
reaction, the mixture was filtered over a short silica gel
column (50% ethyl acetate in petrol) to give the optically
active cyclopentenone (þ)-13 (0.40 g, 2.03 mmol, 80%) as
a white solid; ee¼92% (determined by chiral GC (Lipodex;
140 8C; tR (þ)-13¼19.0 min)); [a]D¼þ71.0 (c 1.0, CHCl3);
which gave identical data to the racemic material described
in Section 3.1.7.
sieves (0.75 g) and pyridinium chlorochromate (0.91 g,
4.22 mmol) were successively added to a solution of the
optically active alcohol (2)-16 (0.70 g, 3.52 mmol) in
anhydrous dichloromethane (30 mL). The suspension was
stirred for 1 h at room temperature. Upon completion of
reaction, the mixture was filtered over a short silica gel
column (50% ethyl acetate in petrol) to give the optically
active cyclopentenone (2)-13 (0.55 g, 2.79 mmol, 79%) as
a white solid; ee¼99% (determined by chiral GC (Lipodex;
140 8C; tR (2)-13¼18.4 min)); [a]D¼272.0 (c 1.0, CHCl3);
which gave identical data to the racemic material described
in Section 3.1.7.

J. Dauvergne et al. / Tetrahedron 60 (2004) 2559–2567
2565
3.1.14. (2RS,4SR)-Acetic acid 4-tert-butoxycarbonyl-
aminocyclopent-2-enyl ester ((6)-17). 1,10-Bis(diphenyl-
phosphino)ferrocene (1.43 g, 2.28 mmol), tris(dibenzyl-
ideneacetone)dipalladium (554 mg, 0.61 mmol) and
anhydrous, oxygen-free tetrahydrofuran (90 mL) were
added to dry reaction vessel, under an atmosphere of
nitrogen, to give a very dark purple solution. After stirring
for 20 min at room temperature, the solution turned dark
orange/brown. Di-tert-butyl iminodicarboxylate (22.4 g,
0.10 mol) and the meso-diacetate 18 (19.0 g, 0.10 mol)
were added and the resulting mixture was quickly degassed
by placing under reduced pressure, then backfilling with
nitrogen. N, O-Bis(trimethylsilyl)acetamide (21.0 g,
0.10 mol) was then added and a further 3 degassing cycles
carried out. The resulting solution was heated to 50 8C for
12 h, when tlc analysis showed the reaction to be complete.
Diethyl ether (200 mL) was then added and the mixture was
poured onto ammonium chloride (sat’d., aq., 100 mL). The
phases were then separated and the aqueous phase was
extracted with dichloromethane (3£20 mL). The combined
organic extracts were then dried over anhydrous magnesium
sulfate and evaporated in vacuo. Flash chromatography
(SiO2, 12% ethyl acetate in hexane) gave the mono-
substituted product 19 (31.7 g, 92.8 mmol, 90%) as a
white solid; dH (400 MHz, CDCl3) 5.98 (1H, dt, J¼5.6,
1.7 Hz, CHvCH), 5.82 (1H, dt, J¼5.6, 2.2 Hz, CHvCH),
5.59–5.53 (1H, m, CHOAc), 5.14–5.08 (1H, m, CHN),
2.84 (1H, dt, J¼13.3, 8.0 Hz, CHH), 2.04 (3H, s, O2CCH3),
1.93 (1H, dt, J¼13.3, 6.6 Hz, CHH), 1.49 (18H, s,
N[CO2C(CH3)3]2); which was taken on without further
characterisation.
reaction to be complete. This was then filtered through a
short pad of silica and the filtrate was treated with a solution
of tetrabutylammonium fluoride in tetrahydrofuran and
washed with brine. The organics were then dried over
anhydrous magnesium sulfate and evaporated in vacuo.
Flash chromatography (SiO2, 25% ethyl acetate in hexane)
gave the mono-substituted product 21 (714 mg, 2.39 mmol,
68%) as a white solid; mp 54–55 8C (EtOAc/hexane); dH
(400 MHz, CDCl3) 6.04 (1H, dt, J¼5.4, 2.3 Hz, CHvCH),
5.76 (1H, dd, J¼5.4, 2.3 Hz, CHvCH), 5.09 (1H, app. dq,
J¼9.3, 2.3 Hz, CHN), 4.60 (1H, m, CHOH), 3.53 (1H, br. d,
J¼11.0 Hz, OH), 2.68 (1H, ddd, J¼15.1, 9.3, 7.9 Hz, CHH),
1.85 (1H, dt, J¼15.1, 2.3 Hz, CHH), 1.49 (18H, s,
N[CO2C(CH3)3]2); dC (100 MHz, CDCl3) 153.3 (s), 136.8
(d), 131.4 (d), 82.8 (s), 75.7 (d), 60.2 (d), 38.8 (t), 28.0 (q);
m/z (CI). Found [MNa]þ 322.1642 ([MNa]þ C15H25NO5Na
requires 322.1630). Found: C, 60.4; H, 8.6; N, 4.4,
C15H25NO5 requires C, 60.2; H, 8.4; N, 4.7%.
Trifluoroacetic acid (0.41 g, 3.60 mol) was added to a
solution of this product 21 (0.71 g, 2.37 mmol) in
dichloromethane (12 mL) at 0 8C. The mixture was then
stirred for 20 h. Sodium hydrogen carbonate (sat’d., aq.,
12 mL) was then added, the phases separated and the
aqueous phase extracted with dichloromethane (3£20 mL).
The combined organic extracts were then dried over
anhydrous magnesium sulfate and evaporated in vacuo.
Flash chromatography (SiO2, 50% ethyl acetate in hexane)
gave the mono-Boc product (þ)-16 (452 mg, 2.27 mmol,
96%) as a pale yellow oil; ee¼98% (determined by chiral
HPLC (OD; 5% ethanol in hexane; tR (þ)-16¼8.1 min; tR
(2)-16¼7.3 min)); which gave identical data to the racemic
material prepared by the method in Section 3.1.6.
Trifluoroacetic acid (15.3 g, 0.13 mol) was added to a
solution of this product 19 (31.3 g, 91.7 mmol) in
dichloromethane (450 mL) at 0 8C. The mixture was then
stirred for 20 h. Sodium hydrogen carbonate (sat’d., aq.,
400 mL) was then added, the phases separated and the
aqueous phase extracted with dichloromethane (3£20 mL).
The combined organic extracts were then dried over
anhydrous magnesium sulfate and evaporated in vacuo.
Flash chromatography (SiO2, 25% ethyl acetate in hexane)
gave the mono-Boc product (^)-17 (21.5 g, 89.1 mmol,
97%) as a pale yellow oil, which gave identical data to the
enantiomerically enriched material prepared by the method
in Section 3.1.8.
3.1.16. Toluene-4-sulfonic acid 5,5-dimethyl-4-oxocyclo-
pent-2-enyl ester (22). p-Toluenesulfonyl chloride (477 mg
2.50 mmol) was added to a solution of 4-hydroxy-5,5-
dimethylcyclopent-2-enone (252 mg, 2.00 mmol) and
4-dimethylaminopyridine (366 mg, 3.00 mmol) in dichloro-
methane (6 mL) and the reaction mixture was stirred at
room temperature for 2 h. The solvent was removed in
vacuo and the residue was purified by flash chromatography
(Si2O, dichloromethane) to give the tosylate 22 (500 mg,
1.78 mmol, 89%) as a white solid; mp 74–75 8C (Et2O/
hexane); nmax(film)/cm21 2976, 1727, 1598; dH (400 MHz,
CDCl3) 7.85 (2H, d, J¼8.1 Hz, ArH), 7.40 (2H, d,
J¼8.1 Hz, ArH), 7.28 (1H, dd, J¼6.0, 2.3 Hz,
CHvCHCvO), 6.27 (1H, dd, J¼6.0, 1.4 Hz,
CHvCHCvO), 5.20–5.19 (1H, m, CHOTs), 2.48 (3H, s,
ArCH3), 1.04 (3H, s, CCH3), 1.03 (3H, s, CCH3); dC
(100 MHz, CDCl3) 208.5 (s), 155.5 (d), 145.5 (s), 134.9 (d),
133.3 (s), 130.1 (d), 127.9 (d), 86.2 (d), 47.3 (s), 22.3 (q),
21.7 (q), 20.7 (q); m/z (CI) 298 ([MNH4]þ, 43%). Found
[MNH4]þ 298.1113 ([MNH4]þ C14H20NO4S requires
298.1113). Found: C, 60.0; H, 5.7, C14H16O4S requires C,
60.0; H, 5.8%.
3.1.15. (2R,4S)-(4-Hydroxycyclopent-2-enyl)-carbamic
acid tert-butyl ester ((1)-16). 1,10-Bis(diphenylphos-
phino)ferrocene (80 mg, 0.14 mmol), tris(dibenzylidene-
acetone)dipalladium (32 mg, 35 mmol) and anhydrous,
oxygen-free tetrahydrofuran (4 mL) were added to dry
reaction vessel, under an atmosphere of nitrogen, to give a
very dark purple solution. After stirring for 15 min at room
temperature, the solution turned dark orange/brown. This
solution was added, via cannula, to a solution of di-tert-
butyl iminodicarboxylate (0.75 g, 3.45 mmol) and the
mono-acetate 20 (0.50 g, 3.42 mmol) in anhydrous, oxygen-
free tetrahydrofuran (4 mL) and the resulting mixture was
quickly degassed by placing under reduced pressure, then
backfilling with nitrogen. N, O-Bis(trimethylsilyl)acetamide
(0.84 g, 4.14 mmol) was then added and a further 2
degassing cycles carried out. The resulting solution was
heated to 45 8C for 3 h, when tlc analysis showed the
3.1.17. 4-(Benzylmethylamino)-5,5-dimethylcyclopent-2-
enone (23). Benzyl methylamine (34 mL, 0.26 mmol) was
added to a solution of tosylate 22 (33 mg, 0.12 mmol) in
ethanol (12 mL) and the reaction was heated at reflux for
48 h. The reaction was allowed to cool and the solvent
removed in vacuo. The crude product was dissolved in

2566
J. Dauvergne et al. / Tetrahedron 60 (2004) 2559–2567
diethyl ether (10 mL) and NaHCO3 (sat’d., aq., 10 mL)
added. The layers were separated and the aqueous layer was
extracted with diethyl ether (3£5 mL). The combined
organic layers were dried over anhydrous magnesium
sulfate and evaporated in vacuo. Flash chromatography
(SiO2, 10% ethyl acetate in hexane) gave the title compound
23 (20 mg, 87 mmol, 74%) as a colourless oil; nmax(film)/
cm21 1712; dH (400 MHz, CDCl3) 7.66 (1H, dd, J¼6.0,
2.4 Hz, CHvCHCvO), 7.37–7.25 (5H, m, ArH), 6.24 (1H,
dd, J¼6.0, 1.9 Hz, CHvCHCvO), 3.72 (2H, s, CH2Ar),
3.62 (1H, t, J¼2.2 Hz, CHN), 2.30 (3H, s, NCH3), 1.19 (3H,
s, CCH3), 1.08 (3H, s, CCH3); dC (100 MHz, CDCl3) 213.1
(s), 160.6 (d), 139.4 (s), 132.8 (d), 128.4 (d), 128.3 (d),
127.1 (d), 74.3 (d), 60.2 (t), 48.2 (s), 40.3 (q), 26.4 (q), 20.1
(q); m/z (CI) 230 ([MH]þ, 100%). Found [MH]þ 230.1553
([MH]þ C15H20NO requires 230.1545).
3.1.20. 4-Hexylsulfanyl-5,5-dimethylcyclopent-2-enone
(26), trans-2,2-dimethyl-4-hexylsulfanyl-3-O-para-
toluenesulfonylcyclopentanone (28) and cis-2,2-
dimethyl-4-hexylsulfanyl-3-O-para-toluenesulfonyl-
cyclopentanone (30). A solution of DBU (0.16 mL,
1.07 mmol) and hexanethiol (0.15 mL, 1.07 mmol) in dry
tetrahydrofuran (1 mL) was added to a solution of tosylate
22 (300 mg, 1.07 mmol) in dry tetrahydrofuran (2 mL). The
reaction mixture was stirred for 1 min before solvent was
removed at 0 8C. Flash chromatography of the residue
(SiO2, 2%, then 5% ethyl acetate in hexane) afforded the
enone 26 (104 mg, 0.46 mmol, 43%) as a yellow viscous oil;
n
max(film)/cm21 1709; dH (300 MHz, CDCl3) 7.50 (1H, dd,
J¼5.8, 2.5 Hz, CHvCHCvO), 6.16 (1H, dd, J¼5.8,
1.9 Hz, CHvCHCvO), 3.66 (1H, dd, J¼2.5, 1.9 Hz,
CHS), 2.57 (2H, t, J¼7.4 Hz, SCH2), 1.64–1.55 (2H, m,
SCH2CH2), 1.47–1.20 (6H, m, (CH2)3CH3), 1.18 (3H, s,
CCH3), 1.16 (3H, s, CCH3), 0.90 (3H, t, J¼6.7 Hz,
CH2CH3); dC (75 MHz, CDCl3) 215.5 (s), 161.2 (d), 131.0
(d), 57.6 (d), 47.6 (s), 32.4 (t), 31.4 (t), 29.7 (t), 28.5 (t), 25.2
(t), 22.5 (q), 22.2 (q), 13.9 (q); m/z (EI) 226 ([M]þ, 5%), 109
([M2SC6H13]þ, 100). Found [M]þ 226.1392 ([M]þ
C13H22OS requires 226.1391); then the trans-3,4-disubsti-
tuted cyclopentanone 28 (98 mg, 0.25 mmol, 23%) as a
white solid; mp 34–35 8C (EtOAc/hexane); nmax(film)/
cm21 1747; dH (300 MHz, CDCl3) 7.88–7.84 (2H, m,
ArH), 7.40–7.35 (2H, m, ArH), 4.75 (1H, d, J¼6.0 Hz,
CHOTs), 3.35 (1H, m, CHS), 2.92 (1H, dd, J¼19.2, 9.0 Hz,
CHHCvO), 2.52–2.40 (5H, m, SCH2, ArCH3), 2.29 (1H,
dd, J¼19.2, 8.1 Hz, CHHCvO), 1.57–1.41 (2H, m,
SCH2CH2), 1.40–1.21 (6H, m, (CH2)3CH3), 1.20 (3H, s,
CCH3), 1.00 (3H, s, CCH3), 0.89 (3H, t, J¼6.9 Hz,
CH2CH3); dC (75 MHz, CDCl3) 215.3 (s), 145.2 (s), 134.0
(s), 129.9 (d), 128.1 (d), 90.6 (d), 49.9 (s), 42.8 (d), 42.0 (t),
31.8 (t), 31.3 (t), 29.3 (t), 28.4 (t), 23.4 (t), 22.4 (q), 21.5 (q),
19.2 (q), 13.9 (q). Found: C, 60.3; H, 7.7, C20H30O4S2
requires C, 60.3; H, 7.6%; and finally, the corresponding
cis-iosmer 30 (90 mg, 0.23 mmol, 21%) as a white solid; mp
37–38 8C (diethyl ether/hexane); nmax(film)/cm21 1746; dH
(300 MHz, CDCl3) 7.88–7.84 (2H, m, ArH), 7.35–7.32
(2H, m, ArH), 5.00 (1H, d, J¼4.4 Hz, CHOTs), 3.56–3.48
(1H, m, CHS), 2.69 (1H, dd, J¼18.7, 8.1 Hz, CHHCvO),
2.53–2.37 (6H, m, SCH2, ArCH3, CHHCvO), 1.55–1.41
(2H, m, SCH2CH2), 1.40–1.20 (6H, m, (CH2)3CH3), 1.10
(3H, s, CCH3), 1.07 (3H, s, CCH3), 0.89 (3H, t, J¼6.8 Hz,
CH2CH3); dC (75 MHz, CDCl3) 215.9 (s), 144.9 (s), 134.2
(s), 129.6 (d), 128.2 (d), 88.4 (d), 51.0 (s), 42.5 (d), 42.0 (t),
32.0 (t), 31.4 (t), 29.4 (t), 28.5 (t), 23.6 (t), 22.5 (q), 21.6 (q),
19.4 (q), 14.0 (q); m/z (EI) 398 ([M]þ, 8%), 226
([M2TsOH]þ, 24), 171 ([TsO]þ, 33), 155 ([Ts]þ, 29),
109 ([M2TsOHSC6H13]þ, 27). Found [M]þ 398.1582
([M]þ C20H30O4S2 requires 398.1586). Found: C, 60.4; H,
7.6, C20H30O4S2 requires C, 60.3; H, 7.6%.
3.1.18. 5,5-Dimethyl-4-morpholin-4-yl-cyclopent-2-
enone (24). Morpholine (35 mL, 0.40 mmol) was added to
a solution of tosylate 22 (50 mg, 0.18 mmol) in ethanol
(18 mL) and the reaction was heated at reflux for 48 h. The
reaction was allowed to cool and the solvent removed in
vacuo. The crude product was dissolved in diethyl ether
(5 mL) and NaHCO3 (sat’d., aq., 5 mL) added. The layers
were separated and the aqueous layer was extracted with
diethyl ether (2£5 mL). The combined organic layers were
dried over anhydrous magnesium sulfate and evaporated in
vacuo. Flash chromatography (SiO2, 50% ethyl acetate in
hexane) gave the title compound 24 (23 mg, 0.12 mmol,
66%) as a pale orange oil; nmax(film)/cm21 1713; dH
(400 MHz, CDCl3) 7.65 (1H, dd, J¼6.0, 2.4 Hz,
CHvCHCvO), 6.24 (1H, dd, J¼6.0, 1.9 Hz,
CHvCHCvO), 3.75–3.65 (4H, m, 2£CH2), 3.35 (1H, t,
J¼2.2 Hz, CHN), 2.63 (4H, t, J¼4.6 Hz, 2£CH2), 1.15 (3H,
s, CCH3), 1.11 (3H, s, CCH3); dC (100 MHz, CDCl3) 213.0
(s), 159.4 (d), 133.3 (d), 76.1 (d), 67.6 (t), 52.9 (t), 48.3 (s),
26.6 (q), 20.6 (q); m/z (CI) 196 ([MH]þ, 100%). Found
[MH]þ 196.1340 ([MH]þ C11H18NO2 requires 196.1337).
3.1.19. 4-[4-(4-Fluorophenyl)-piperazin-1-yl]-5,5-
dimethylcyclopent-2-enone (25). 1-(4-Fluorophenyl)-
piperazine (83 mg, 0.46 mmol) was added to a solution of
tosylate 22 (60 mg, 0.21 mmol) in ethanol (20 mL) and the
reaction was heated at reflux for 19 h. The reaction was
allowed to cool and the solvent removed in vacuo. The
crude product was dissolved in diethyl ether (5 mL) and
NaHCO3 (sat’d., aq., 5 mL) added. The layers were
separated and the aqueous layer was extracted with diethyl
ether (2£5 mL). The combined organic layers were dried
over anhydrous magnesium sulfate and evaporated in vacuo.
Flash chromatography (SiO2, 25% ethyl acetate in hexane)
gave the title compound 25 (41 mg, 0.14 mmol, 65%) as a
colourless oil; nmax(film)/cm21 1712, 1510, 1236; dH
(400 MHz, CDCl3) 7.68 (1H, dd, J¼6.0, 2.5 Hz,
CHvCHCvO), 6.99–6.93 (2H, m, ArH), 6.89–6.84 (2H,
m, ArH), 6.25 (1H, dd, J¼6.0, 1.8 Hz, CHvCHCvO), 3.44
(1H, t, J¼2.2 Hz, CHN), 3.15–3.06 (4H, m, 2£CH2), 2.83–
2.74 (4H, m, 2£CH2), 1.17 (3H, s, CCH3), 1.13 (3H, s,
CCH3); dC (100 MHz, CDCl3) 213.2 (s), 159.7 (d), 158.8
(s), 148.3 (s), 133.3 (d), 118.3 (d), 115.9 (d), 75.7 (d), 52.2
(t), 51.0 (t), 48.3 (s), 26.8 (q), 20.5 (q); m/z (CI) 289 ([MH]þ,
100%). Found [MH]þ 289.1720 ([MH]þ C17H22FN2O
requires 289.1716).
3.1.21. Conversion of trans-2,2-dimethyl-4-hexyl-
sulfanyl-3-O-p-toluenesulfonyl-cyclopentanone (28) to
4-hexylsulfanyl-5,5-dimethylcyclopent-2-enone (26). A
solution of 28 (15.8 mg, 40 mmol) in dichloromethane
(1 mL) was refluxed for 1 h. The solvent was removed in
vacuo and flash chromatography (SiO2, 2.5% ethyl acetate
in hexane) of the residue afforded enone 26 (8.3 mg,
37 mmol, 93%) as a yellow viscous oil; which showed
identical spectroscopic data to the material obtained by the

J. Dauvergne et al. / Tetrahedron 60 (2004) 2559–2567
2567
procedure described above in Section 3.1.20. Thiol adduct
30 remained unchanged even after prolonged refluxing
(10 h) under the same conditions.
sulfanyl-5,5-dimethylcyclopent-2-enone (27). A solution
of 29 (17 mg, 40 mmol) in dichloromethane (1 mL) was
refluxed for 1 h. The solvent was removed in vacuo and
flash chromatography (SiO2, 2.5% ethyl acetate in hexane)
of the residue afforded enone 27 (9 mg, 35 mmol, 89%) as a
yellow viscous oil; which showed identical spectroscopic
data to the material obtained by the procedure described
above in Section 3.1.22. Thiol adduct 31 remained
unchanged even after prolonged refluxing (10 h) under the
same conditions.
3.1.22. 4-Octylsulfanyl-5,5-dimethylcyclopent-2-enone
(27), trans-2,2-dimethyl-4-octylsulfanyl-3-O-para-tolue-
nesulfonylcyclopentanone (29) and cis-2,2-dimethyl-4-
octylsulfanyl-3-O-para-toluenesulfonylcyclopentanone
(31). A solution of DBU (0.16 mL, 1.07 mmol) and
n-octanethiol (0.19 mL, 1.07 mmol) in dry tetrahydrofuran
(1 mL) was added to a solution of tosylate 22 (300 mg,
1.07 mmol) in dry tetrahydrofuran (2 mL). The reaction
mixture was stirred for 10 min, then evaporated in vacuo.
Flash chromatography of the residue (SiO2, 2%, then 5%
ethyl acetate in hexane) afforded the enone 27 (0.11 g,
0.43 mmol, 40%) as a yellow viscous oil; nmax(film)/cm21
1709; dH (300 MHz, CDCl3) 7.50 (1H, dd, J¼5.8, 2.5 Hz,
CHvCHCvO), 6.15 (1H, dd, J¼5.8, 1.9 Hz,
CHvCHCvO), 3.66 (1H, dd, J¼2.5, 1.9 Hz, CHS), 2.56
(2H, t, J¼7.4 Hz, SCH2), 1.67–1.55 (2H, m, SCH2CH2),
1.45–1.20 (10H, m, (CH2)5CH3), 1.18 (3H, s, CCH3), 1.16
(3H, s, CCH3), 0.88 (3H, t, J¼6.7 Hz, CH2CH3); dC
(75 MHz, CDCl3) 212.6 (s), 161.3 (d), 131.1 (d), 57.6 (d),
47.5 (s), 32.3 (t), 31.7 (t), 29.7 (t), 29.1 (t), 29.0 (t), 28.8 (t),
25.2 (t), 22.5 (q), 22.1 (q), 13.9 (q); m/z (EI) 254 ([M]þ,
2%), 109 ([M2SC8H17]þ, 100). Found [M]þ 254.1703
([M]þ C15H26OS requires 254.1704); then the trans-3,4-
disubstituted cyclopentanone 29 (0.12 g, 0.28 mmol, 26%)
as a white solid; mp 58–59 8C (EtOAc/hexane); nmax(film)/
cm21 1748; dH (300 MHz, CDCl3) 7.88–7.84 (2H, m,
ArH), 7.39–7.35 (2H, m, ArH), 4.75 (1H, d, J¼6.0 Hz,
CHOTs), 3.35 (1H, m, CHS), 2.92 (1H, dd, J¼19.1, 9.0 Hz,
CHHCvO), 2.60–2.40 (5H, m, SCH2, ArCH3), 2.30 (1H,
dd, J¼19.1, 8.0 Hz, CHHCvO), 1.60–1.41 (2H, m,
SCH2CH2), 1.40–1.21 (10H, m, (CH2)5CH3), 1.20 (3H, s,
CCH3), 1.00 (3H, s, CCH3), 0.89 (3H, t, J¼6.7 Hz,
CH2CH3); dC (75 MHz, CDCl3) 215.2 (s), 145.1 (s), 133.9
(s), 129.9 (d), 128.1 (d), 90.6 (d), 49.9 (s), 42.8 (d), 42.0 (t),
31.9 (t), 31.8 (t), 29.4 (t), 29.1 (t), 28.8 (t), 23.5 (t), 22.6 (q),
21.6 (q), 19.2 (q), 14.0 (q). Found: C, 61.8; H, 8.1,
C22H34O4S2 requires C, 61.9; H, 8.0%; and finally, the
corresponding cis-iosmer 31 (96 mg, 0.23 mmol, 21%) as
a white solid; mp 50–51 8C (diethyl ether/hexane);
Acknowledgements
Charterhouse Therapeutics, Oxford and Stylacats, Liverpool
are thanked for the funding of this work, as are the DTI for
funding via a SMART award (to J. D, A. M. H and P. J. M).
References and notes
1. (a) Kim, K.-H.; Miller, M. J. Tetrahedron Lett. 2003, 44, 4571.
(b) Zhang, D.; Miller, M. J. J. Org. Chem. 1998, 63, 755.
2. A number of reports explain the synthesis of 1-hydroxy-4-aza-
cyclopent-2-enones by various approaches (see Refs. below),
but there are few reports of the synthesis of 4-aza-cyclopent-2-
enones.
3. Rossi, A.; Elia, G.; Santoro, M. G. J. Biol. Chem. 1996, 271,
32192.
4. Harris, C. J. J. Chem. Soc., Perkin Trans. 1 1980, 2497.
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Lett. 1996, 37, 3799.
7. A number of approaches to the diastereoselective [4þ2]
cycloaddition with RpNvO have been disclosed using a chiral
auxiliary on the nitrogen, see: (a) Zhang, D.; Su¨ling, C.;
Miller, M. J. J. Org. Chem. 1998, 63, 885. (b) Gouverneur, V.;
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8. Smith, C. R.; Justice, D.; Malpass, J. R. Tetrahedron 1993, 49,
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9. Kim, S. S.; Nehru, K. Synlett 2002, 616.
n
max(film)/cm21 1747; dH (300 MHz, CDCl3) 7.87–7.84
(2H, m, ArH), 7.36–7.32 (2H, m, ArH), 5.00 (1H, d,
J¼4.3 Hz, CHOTs), 3.56–3.48 (1H, m, CHS), 2.68 (1H, dd,
J¼18.7, 8.1 Hz, CHHCvO), 2.53–2.37 (6H, m, SCH2,
ArCH3, CHHCvO), 1.60–1.41 (2H, m, SCH2CH2), 1.40–
1.18 (10H, m, (CH2)5CH3), 1.10 (3H, s, CCH3), 1.07 (3H, s,
CCH3), 0.89 (3H, t, J¼6.7 Hz, CH2CH3); dC (75 MHz,
CDCl3) 215.9 (s), 144.9 (s), 134.2 (s), 129.6 (d), 128.2 (d),
88.4 (d), 51.0 (s), 42.5 (d), 42.0 (t), 32.1 (t), 31.8 (t), 29.5 (t),
29.2 (t), 28.9 (t), 23.7 (t), 22.6 (q), 21.6 (q), 19.5 (q), 14.0
(q); m/z (EI) 426 ([M]þ, 5%), 254 ([M2TsOH]þ, 7), 155
([Ts]þ, 28), 109 ([M2TsOHSC8H17]þ, 46). Found [M]þ
426.1895 ([M]þ C22H34O4S2 requires 426.1899). Found: C,
61.9; H, 8.1, C22H34O4S2 requires C, 61.9; H, 8.0%.
10. Mulvihill, M. J.; Gage, J. L.; Miller, M. J. J. Org. Chem. 1998,
63, 3357.
˚
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Chem. 1988, 53, 3845.
12. A number of enzymes have been studied with electric eel
acetylcholinesterase Pseudomonas cepacia lipase and
Candida antarctica lipase B being the most effective, see:
Johnson, C. J.; Bis, S. J. Tetrahedron Lett. 1992, 33, 7287.
13. (a) Deardorff, D. R.; Linde, R. G., II; Martin, A. M.; Shulman,
M. J. J. Org. Chem. 1989, 54, 2759. (b) Koga, M.; Schneller,
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14. Miyaoka, H.; Sagawa, S.; Nagaoka, H.; Yamada, Y.
Tetrahedron: Asymmetry 1995, 6, 587.
3.1.23. Conversion of trans-2,2-dimethyl-4-octylsulfanyl-
3-O-p-toluenesulfonyl-cyclopentanone (29) to 4-octyl-
15. Ranganathan, D.; Ranganathan, S.; Rao, C. B.; Raman, K.
Tetrahedron 1981, 37, 629.