Novel preparation of (-)-4-hydroxycyclohex-2-enone: Reaction of 4-hydroxycyclohex-2-enone and 4-hydroxycyclopent-2-enone with some thiols

Article abstract of DOI:10.1016/j.tetasy.2006.01.002

A new route to (R)-4-hydroxycyclohex-2-enone from cyclohexanedione monoketal (27% yield) commences with reaction of the ketal with nitrosobenzene catalysed by l-proline. 4-Hydroxycyclohex-2-enone and 4-hydroxycyclopent-2-enone react with thiols to afford

Full text of DOI:10.1016/j.tetasy.2006.01.002

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 17 (2006) 355–362
Novel preparation of (À)-4-hydroxycyclohex-2-enone: reaction
of 4-hydroxycyclohex-2-enone and 4-hydroxycyclopent-2-enone
with some thiols
Jamie F. Bickley,a Paul Evans,b Alastair Meek,a Ben S. Morgana and Stanley M. Robertsc,*
aDepartment of Chemistry, Liverpool University, Liverpool L69 7ZD, United Kingdom
bDepartment of Chemistry, Trinity College, Dublin 2, Ireland
cCoEBio3, University of Manchester, Faraday Building, Manchester M60 1QD, United Kingdom
Received 17 November 2005; accepted 4 January 2006
Available online 20 February 2006
Abstract—A new route to (R)-4-hydroxycyclohex-2-enone from cyclohexanedione monoketal (27% yield) commences with reaction
of the ketal with nitrosobenzene catalysed by L-proline. 4-Hydroxycyclohex-2-enone and 4-hydroxycyclopent-2-enone react with thi-
ols to afford the corresponding syn-disubstituted cycloalkanones.
ꢀ 2006 Published by Elsevier Ltd.
1. Introduction
O
O
For some time, we and others have been interested in the
use of 4-substituted cycloalk-2-enones in synthetic
organic chemistry.1 Within this broad series of com-
pounds, 4-tert-butyldimethylsilyloxycyclopent-2-enone
1 is the best known example, particularly in connection
with Noyori’s three component synthesis of prostaglan-
dins.2 More recently, silyl compound 1 has been shown
to exhibit startling biological activity in its own right;
for instance it shows significant inhibition of the impor-
tant gene-signalling agent NF kappa B.3
OR
OH
3
t
1 R = SiMe2 Bu
2 R = H
Figure 1.
2. Results and discussion
Addition of benzylthiol to silyl compound 1 gave a sin-
gle diastereomer of the adduct 45 (Scheme 1) as expected
and as described previously.6
Enone 1 undergoes a Michael-type 1,4-conjugate addi-
tion reactions with nucleophiles, such as cuprate
reagents and thiols. The bulky silyloxy group directs the
incoming nucleophile to the opposite face of the electro-
philic enone unit. Herein we report the addition of thiols
to the parent compound 4-hydroxycyclopent-2-enone 2.
Reduction of adduct 4 using sodium borohydride under
Luche conditions was not very selective, affording the
¨
1
diastereomers 5 and 6 in a ratio 4:3 (by H NMR), sep-
arable by column chromatography. Deprotection of the
major isomer 5 under standard conditions furnished diol
7, the structure of which was confirmed by X-ray crys-
tallography (Fig. 2).7 Similarly, compound 6 was depro-
tected to give a sample of diol 8.
4-Hydroxycyclohex-2-enone 3 (and its derivatives) have
also been utilised extensively as synthetic building
blocks in organic chemistry.4 In the latter section of this
paper, we describe a new route to the optically active
hydroxy ketone 3 (Fig. 1).
Reaction of 4-hydroxycyclopent-2-enone 2 with benzyl
thiol in dichloromethane containing a catalytic amount
of triethylamine gave a single product.6 However, con-
ducting the same reaction in the absence of triethylamine
*
Corresponding author. Tel.: +44 (0)161 306 4501; fax: +44 (0)161
306 5101; e-mail addresses: Stanley.Roberts@manchester.ac.uk;
smrsm@liverpool.ac.uk
0957-4166/$ - see front matter ꢀ 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2006.01.002

356
J. F. Bickley et al. / Tetrahedron: Asymmetry 17 (2006) 355–362
O
O
OH
OH
O
O
O
i
i
ii
+
+
C-4
OH
C-4
OR
C-4
OH
OR
BnS
BnS
OR
BnS
OR
OH
( )-2
BnS
BnS
9
10
4
6
5
t
1 R = SiMe2 Bu
ii
ii
iii
iii
OH
OH
OH
OH
OH
OH
iii
+
OH
BnS
OH
BnS
OH BnS
OH
BnS
OH
BnS
OH
12
11
7
7
8
8
Scheme 1. Reagents and conditions: (i) BnSH (1 equiv), Et3N
(0.1 equiv), DCM, rt, 91%; (ii) NaBH4 (1 equiv), CeCl3Æ7H2O
(0.5 equiv), MeOH, 99%; (iii) TBAF (1 equiv), DCM, 98%.
Scheme 2. Reagents and conditions: (i) (a) BnSH (1 equiv), DCM,
Et3N (0.1 equiv), rt, 9 91%, (b) BnSH (1 equiv), DMSO, rt, 10 59% (9
24% as the faster eluting diastereomer); (ii) NaBH4 (1 equiv),
CeCl3Æ7H2O (0.5 equiv), MeOH, 99%; (iii) Raney nickel (1 equiv),
EtOH, 90%.
OH
O
i
i
BnS
BnS
OH
OH
BnS
BnS
OH
OH
13
9
O
OH
Figure 2.
10
8
gave rise to a second, minor product while the propor-
tion of this minor product was substantially increased
when the enone was reacted with the thiol using dimeth-
ylsulfoxide as the solvent. The 13C NMR spectra of the
two adducts formed from enone 2 were compared to
the ‘standard’ anti-adduct 4. The signal assigned to C-4
in compound 4 was observed at 74.9 ppm. The equiva-
lent signal from the major adduct derived from the com-
bination of compound 2 and benzylthiol appeared at
68.4 ppm; the minor adduct showed a signal in the 13C
NMR spectrum at 74.2 ppm. Thus it began to appear
that the major adduct may in fact be the syn-adduct 9
while the minor adduct may be the anti-adduct 10. Fur-
ther transformations of the adducts confirmed this pos-
tulate. Thus the reduction of the minor adduct with
NaBH4 and cerium(III) chloride gave a mixture of diols
7 (53%) and 8 (43%). In contrast, the major syn-adduct
gave a different diol 11 as the sole product. Desulfuriza-
tion confirmed the relative orientation of the two hydro-
xy groups in the latter compound through the formation
of the known meso-diol 128 (Scheme 2). In order to con-
firm this hypothesis and to extend the synthetic utility of
this sequence the reduction of 9 under Evans’ conditions9
was considered. Pleasingly under these conditions reduc-
tion of 9 furnished the remaining diastereomer 13 selec-
tively (Scheme 3).
Scheme 3. Reagents and conditions: (i) NMe4(OAc)3BH (5 equiv),
AcOH (10 equiv), CH3CN, 0 ꢁC, 48 h, 86–91%.
in each instance (de >95%). In all cases, the 13C NMR
signal for C-4 appeared in the range 68.3–68.5 ppm
and consequently the products 14–16 were assigned the
syn-configuration. Under these standard conditions,
however, reaction of compound 2 with 2-naphthylthiol
produced the syn-adduct 17 (C-4 signal at 68.95) and
the anti-adduct 18 (C-4 signal at 73.1) in the ratio ca.
1:1, possibly reflecting the reversibility of the conjugate
addition in this instance (Scheme 4). The ratios of 17
and 18 were ca. 1:1 and ca. 1:2 when the reaction was
conducted in DCM/Et3N and DMSO, respectively.
O
O
O
i
C-4
OH
C-4
OH
OH
( )-2
RS
RS
14 R = C12H24
15 R = CH2-C6H4Cl
16 R = cyclopentyl
17 (syn) and 18 (anti) R = 2-naphthyl
The reaction of hydroxy ketone 2 with dodecylthiol, or
para-chlorobenzylthiol or cyclopentylthiol in dichloro-
methane containing triethylamine gave a single adduct
Scheme 4. Reagents and conditions: (i) RSH (1 equiv), Et3N
(0.1 equiv), DCM, rt.

J. F. Bickley et al. / Tetrahedron: Asymmetry 17 (2006) 355–362
357
catalytic copper sulfate to produce diol 22. A one-pot
deketalisation/elimination cascade produced (R)-4-
hydroxycyclohex-2-enone (R)-3 in 69% yield and
93.9% ee. We have shown in an earlier paper that
4-hydroxycyclohex-2-enone reacts with benzylthiol to
produce the syn-3-benzylthia-4-hydroxycyclohexanone
as part of an alternative process to provide optically
active 4-hydroxycyclohex-2-enone, optionally isolated
as the TBS protected compound 25 (Scheme 6).6
O
O
OH
ONHPh
ii
ONHPh
i
O
O
O
O
O
O
19
20
21
iii
OH
OH
3. Conclusion
OH
iv
A new route to optically active 4-hydroxycyclohex-2-
enone (27% from 19, Scheme 5) is competitive to an
earlier route to this building block that we recently
reported (15% from 3, Scheme 6). Contrary to our early
expectations,6 4-hydroxycyclopent-2-enone 2 reacts with
thiols in a relatively nonpolar solvent (DCM) to give the
syn-adducts predominantly or exclusively. Presumably
the thiol/thiolate is encouraged to approach the enone
moiety from the more hindered face by hydrogen bond-
ing to the OH group and to the best of our knowledge
this type of ‘directed’ conjugate addition has not been
reported previously. In a polar solvent, such as dimeth-
ylsulfoxide, the key intermolecular interaction is reduced
or even eliminated. The substitution pattern is impor-
tant in connection with the conversion of optically
active 4-hydroxycyclopent-2-enone 2 into optically
active 4-benzylthiacyclopent-2-enone 26 (Scheme 7).6
O
O
O
(R)-3
22
Scheme 5. Reagents and conditions: (i) PhNO, L-Pro (30 mol %),
DMF; (ii) NaBH4 (2.1 equiv), CeCl3Æ7H2O (2.1 equiv), MeOH; (iii)
CuSO4 (30 mol %), MeOH; (yield 40% for three steps); (iv) 2 M
HCl(aq), THF/H2O (1:1), 69%.
Our new approach to the formation of optically active 4-
hydroxycyclohex-2-enone 3 commenced with oxidation
of the mono-ketal 19 using nitrosobenzene with L-pro-
line as the catalyst as described previously (Scheme
5).10 The resultant optically active hydroxylamine 20
}
was reduced to afford a single alcohol 21 using Luche
conditions. The resulting alcohol 21 was treated with
O
O
O
O
i
ii
+
BnS
BnS
BnS
OH
OH
OH
OAc
( )-3
( )-23
(+)-23
(-)-24
iii
O
iv
O
OTBS
(-)-25
OTBS
(+)-25
Scheme 6. Reagents and conditions: (i) BnSH (1 equiv), Et3N (0.1 equiv), DCM, rt; (ii) Novozym 435, vinyl acetate (5 equiv), DIPE, 30 ꢁC; (iii)
TBSCl (3 equiv) DBU (4 equiv), DCM, rt, 16 h; (iv) (a) NaIO4 (1 equiv), MeOH/H2O (1:1), 0 ꢁC > rt, 16 h, (b) toluene, D 16 h, (c) K2CO3 (1 equiv),
MeOH, rt, 2 h, (d) TBSCl (1.1 equiv), DBU (1.2 equiv), rt, 16 h.
O
O
O
O
i
ii
BnS
( )-9
OH
BnS
OH
BnS
BnS
(S)-26
(R)-26
(3R, 4S)-9
Scheme 7. Reagents and conditions: (i) (a) Novozym 435, vinyl acetate (5 equiv), DIPE, 30 ꢁC, (b) Et3N (0.1 equiv) 30 min; (ii) Ac2O, Et3N, DCM,
rt.

358
J. F. Bickley et al. / Tetrahedron: Asymmetry 17 (2006) 355–362
In contrast to our earlier report, the lipase-mediated
kinetic resolution of the benzylthiol adduct 9 derived
from racemic 4-hydroxycyclopent-2-enone 2 produces
(4S)-benzylthiacyclopent-2-enone (S)-26 and (3R,4S)-3-
benzylthia-4-hydroxycyclopentanone (3R,4S)-9. Treat-
ment of the latter compound with acetic anhydride
and triethylamine affords (4R)-benzylthiacyclopent-2-
enone (R)-26.
4.17–4.25 (1H, m, CHOH), 7.24–7.36 (5H, m, ArH).
13C NMR (100 MHz, CDCl3) 138.4 (C), 129.2 (CH),
129.0 (CH), 127.8 (CH), 72.7 (CHOH), 72.0 (CHOH),
50.2 (CHS), 42.6 (CH2), 41.0 (CH2), 36.8 (CH2). IR mmax
(neat, cmÀ1) 3451, 3030, 2970, 2932. HRMS calcd for
C12H17O2S (CI+NH3) requires 225.09494; found
225.09514.
4.3. ( )-anti-3-Benzylthio-4-hydroxycyclopentanone 10
4. Experimental
In a dry 10 mL round-bottomed flask, a solution of
benzyl mercaptan (188 mg, 1.53 mmol, 1 equiv) in anhy-
drous dimethyl sulfoxide (4 mL) was added to a solution
of enone 2 (150 mg, 1.53 mmol, 1 equiv) in anhydrous
dimethyl sulfoxide (5 mL). The reaction mixture was
stirred under argon at room temperature for 16 h. To
the reaction mixture were added dichloromethane
(40 mL) and water (40 mL). The biphasic solution was
then partitioned. The aqueous layer was further
extracted with dichloromethane (3 · 30 mL.). The organic
extractions were combined and dried over magnesium
sulfate and filtered. The filtrate was absorbed onto silica
and purified by column chromatography (% MeOH in
CH2Cl2, Rf = 0.29) to give ketone 10 (59%) as a clear
4.1. ( )-syn-3-Benzylthio-4-hydroxycyclopentanone 9
In a dry 250 mL round-bottomed flask, a solution of
benzyl mercaptan (6.95 g, 56 mol equiv) in anhydrous
dichloromethane (5 mL) and triethylamine (0.52 g,
5.6 mmol, 0.1 equiv) was added to a solution of enone
2 (5.0 g, 56 mmol, 1 equiv) in anhydrous dichlorometh-
ane (120 mL). The reaction mixture was stirred under
argon at room temperature for 16 h. Solvent was
removed in vacuo and the resultant residue purified by
column chromatography (1% MeOH in CH2Cl2,
Rf = 0.42) to afford the title compound (92%) as a white
1
solid mp 50–52 ꢁC. H NMR (400 MHz, CDCl3) d 2.18
oil. ( )-syn-3-Benzylthio-4-hydroxycyclopentanone 9
(1H, ddd, J = 1.5, 12.0, 18.5 Hz, CHAHB), 2.27 (1H, dd,
J = 4.5, 18.5 Hz, CHAHB), 2.39 (1H, ddd, J = 1.0, 8.0,
18.5 Hz, CHAHB), 2.50 (1H, dd, J = 1.25, 18.5 Hz,
CHAHB), 2.70 (1H, s, OH), 3.28 (1H, ddd, J = 3.5,
8.25, 11.75 Hz, CHS), 3.76 (1H, d, J = 13.75 Hz,
CHAHB), 3.82 (1H, d, J = 13.75 Hz, CHAHB), 4.16
(1H, apparent t, J = 3.85 Hz, CHOH) 7.25–7.36 (5H,
m, ArH). 13C NMR (100 MHz, CDCl3) 213.4 (C@O),
137.7 (C), 128.9 (CH), 128.6 (CH), 127.7 (CH), 68.0
(CHOH), 47.1 (CHS), 46.5 (CH2), 40.3 (CH2), 35.5
(CH2). IR mmax (neat, cmÀ1) 3478, 3055, 2985, 2921,
2305, 1748, 1602, 1264, 735. HRMS calcd for
C12H18NO2S (CI, MNH4+) requires 240.1058; found
240.1058. Anal. Calcd for C12H14O2S: C, 64.86; H,
6.31. Found: C, 64.60; H, 6.31.
(24%) was the faster eluting diastereomer. 1H NMR
(400 MHz, CDCl3) d 2.13–2.27 (2H, m, 2 · CHAHB),
2.69–2.78 (2H, m, 2 · CHAHB), 3.13–3.19 (1H, m,
CHS), 3.79 (1H, d, J = 13.75 Hz, CHAHB), 3.87 (1H,
d, J = 13.75 Hz, CHAHB), 4.32–4.38 (1H, m apparent
q, J = 4.75 Hz, CHOH), 7.32–7.56 (5H, m, ArH) 13C
NMR (100 MHz, CDCl3) 214.1 (C@O), 138.1 (C),
129.2 (CH), 128.6 (CH), 127.8 (CH), 74.2 (CHOH),
47.9 (CHS), 46.0 (CH2), 43.8 (CH2), 36.5 (CH2). HRMS
calcd for C12H18NO2S (CI, MNH4+) requires 240.1058;
found 240.1050.
4.4. (3S,4S)-3-(Benzylthio)-4-(tert-butyldimethylsilyloxy)
cyclopentanone 4
In a dry 50 mL round-bottomed flask, a solution of ben-
zyl mercaptan (1.22 g, 9.8 mmol, 1 equiv) in anhydrous
dichloromethane (5 mL) and triethylamine (49 mg,
0.98 mmol, 0.1 equiv) was added to a solution of enone
1 (2.08 g, 9.8 mmol, 1 equiv) in anhydrous dichloro-
methane (20 mL). The reaction mixture was stirred
under argon at room temperature for 16 h. Solvent
was removed in vacuo and the resultant residue purified
by column chromatography (19:1, n-hexane/ethyl
acetate, Rf = 0.33) to provide compound 4 (88%) as a
4.2. (1R,3S,4R)-4-(Benzylthio)cyclopentane-1,3-diol 11
In a dry 250 mL round-bottomed flask, a solution of 9
(50 mg, 0.23 mmol, 1 equiv) methanol (4 mL) and cerium
trichloride heptahydrate (84 mg, 0.23 mmol, 1 equiv) was
stirred at À78 ꢁC. To this solution sodium borohydride
(8.5 mg, 0.23 mmol, 1 equiv) was added portionwise.
The reaction mixture was stirred for a further 15 min.
Water (10 mL) was added to quench the reaction. The
resultant biphasic solution was extracted with ethyl ace-
tate (4 · 15 mL). The combined organic extractions were
washed with brine (sat.), dried over magnesium sulfate
and filtered. Solvent was removed in vacuo. The residue
was purified by column chromatography (n-hexane/ethyl
acetate, 1:1, Rf = 0.47). Yield = 94%. [a]D = +97.1 (c
1.05, CH2Cl2). 1H NMR (400 MHz, CDCl3) d 1.57
(1H, ddt, J = 2.0, 9.75, 16.75 Hz, CHAHB), 1.74 (1H,
ddd, J = 3.75, 6.5, 14.75 Hz, CHAHB), 2.05–2.15 (1H,
m, CHAHB), 2.48 (1H, ddd, J = 7.0, 10.0, 16.75 Hz,
CHAHB), 2.92 (1H, m, CHS), 2.93 (1H, s, OH), 3.70
(1H, d, J = 13.5 Hz, CHAHB), 3.75 (1H, d, J = 13.5 Hz,
CHAHB), 3.92 (1H, m apparent t, J = 3.5 Hz, CHOH),
1
colourless oil. H NMR (400 MHz, CDCl3) d 0.1 (6H,
2 · s, (CH3)2), 0.87 (9H, s, tert-butyl), 2.06–2.16 (2H,
m, 2 · CHAHB), 2.65 (1H, m, CHAHB), 2.71 (1H, m,
CHAHB), 3.17 (1H, ddd, J = 1.5, 4.25, 8.5 Hz, CHS),
3.74 (1H, d, J = 13.5 Hz, CHAHB), 3.82 (1H, d,
J = 13.5 Hz, CHAHB), 4.32 (1H, ddd, J = 3.0, 6.0,
8.5 Hz, CHOH), 7.20–7.31 (5H, m, ArH). 13C NMR
(100 MHz, CDCl3) 215.0 (C@O), 138.0 (C), 129.1
(CH), 129.0 (CH), 127.7 (CH), 74.9 (CHOH), 48.1
(CHS), 46.6 (CH2), 43.1 (CH2), 36.6 (CH2), 26.0 (tBu),
18.3 (C), À4.4 (2 · CH3). IR mmax (neat, cmÀ1) 3054,
2984, 1747, 1422, 1205, 836. HRMS calcd for
C18H32O2SSiN (CI, MNH4+) requires 354.19232; found

J. F. Bickley et al. / Tetrahedron: Asymmetry 17 (2006) 355–362
359
354.19144. Anal. Calcd for C18H28O2SSi: C, 64.24; H,
8.39. Found: C, 64.10; H, 8.36.
CH2), 3.40 (1H, ddd, J = 3.25, 8.0, 11.25 Hz, CHS),
4.36 (1H, dd apparent t, J = 4.0 Hz, CHOH). 13C
NMR (100 MHz, CDCl3) 214.0 (C@O), 68.3 (CHOH),
48.3 (CHS), 46.9 (CH2), 41.0 (CH2), 32.3 (CH2), 31.4
(CH2), 30.3 (CH2), 30.0 (CH2), 29.95 (CH2), 29.9
(CH2), 29.8 (CH2), 29.7 (CH2), 29.5 (CH2), 29.2
4.5. (1R,3S,4S)-3-(Benzylthio)-4-(tert-butyldimethylsilyl-
oxy)cyclopentanol 5 and (1S,3S,4S)-3-(benzylthio)-4-
(tert-butyldimethylsilyloxy)cyclopentanol 6
(CH2), 23.0 (CH2), 14.5 (CH3). IR mmax (neat, cmÀ1
)
In a dry 50 mL round-bottomed flask, a solution of 4
(500 mg, 1.5 mmol, 1 equiv) and methanol (20 mL),
and cerium trichloride heptahydrate (569 mg, 1.5 mmol,
1 equiv) were stirred at À78 ꢁC. To this solution, sodium
borohydride (57 mg, 1.5 mmol, 1 equiv) was added por-
tionwise. The reaction mixture was stirred for a further
15 min. Water (20 mL) was then added to quench the
reaction. The resultant solution was extracted with ethyl
acetate (4 · 15 mL). The combined organic extractions
were washed with brine (satd), dried over magnesium
sulfate and filtered. Solvent was removed in vacuo. The
residue was purified by column chromatography (0.5%
methanol in CH2Cl2, Rf = 0.47 5 and 0.43 6) to yield
compound 5 (49%) and 6 (38%). Data for compound 5
1H NMR (400 MHz, CDCl3) 5 d 0.1 (6H, 2 · s,
(CH3)2), 0.9 (9H, s, tert-butyl), 1.76–1.87 (2H, m,
2 · CHAHB), 2.11 (1H, dt, J = 5.0, 14.0 Hz, CHAHB),
2.32 (1H, ddt, J = 1.75, 8.25, 14.75 Hz, CHAHB), 3.16
(1H, ddd, 1.75, 5.5, 8.0 Hz, CHS), 3.73 (1H, d,
J = 13.75 Hz, CHAHB), 3.79 (1H, d, J = 13.75 Hz,
CHAHB), 4.20–4.23 (1H, m, CHOTBS), 4.28–4.33 (1H,
m, CHOH), 7.22–7.35 (5H, m, ArH). 13C NMR
(100 MHz, CDCl3) 138.4 (C), 129.2 (CH), 128.9 (CH),
127.5 (CH), 80.6 (CHOH), 73.8 (CHOH), 50.4 (CHS),
43.2 (CH2), 42.8 (CH2), 37.0 (CH2), 25.1 (tBu), 18.2
(C), À4.2 (CH3), À4.4 (CH3). HRMS calcd for
C18H34O2SSiN (CI, M+NH3) requires 356.20798; found
3477, 2926, 2855, 1749, 1466, 1394, 1332, 1283, 1212,
1152, 1009, 909, 733. HRMS calcd for C17H36O2SN
(CI, M+NH3) requires 318.24670; found 318.24718.
4.7. ( )-syn-3-(4-Chlorobenzylthio)-4-hydroxycyclopen-
tanone 15
Enone 2 (1.0 g, 10.2 mmol, 1 equiv) was reacted with
para-chlorobenzyl thiol (1.62 g, 10.2 mmol, 1 equiv) as
described above. Purification by column chromatogra-
phy (1% MeOH in CH2Cl2, Rf = 0.25) gave the title
compound 14 as a yellow oil (84%). 1H NMR
(400 MHz, CDCl3) d 2.19 (1H, ddd, J = 1.0, 11.75,
18.5 Hz, CHAHB), 2.29 (1H, dd, J = 4.5, 18.5 Hz,
CHAHB), 2.40 (1H, ddd, J = 1.0, 8.25, 18.5 Hz,
CHAHB), 2.52 (1H, dd, J = 1.0, 18.5 Hz, CHAHB),
3.27 (1H, ddd, J = 3.25, 8.0, 11.75 Hz, CHS), 3.73
(1H, d, J = 13.75 Hz, CHAHB), 3.79 (1H, d,
J = 13.75 Hz, CHAHB), 4.19–4.23 (1H, m, CHOH),
7.26–7.38 (4H, m, ArH). 13C NMR (100 MHz, CDCl3)
213.1 (C@O), 139.6 (C), 136.1 (C-Hal), 129.9 (CH),
129.4 (CH), 129.0 (CH), 128.8 (CH), 68.1 (CHOH),
47.0 (CHS), 46.5 (CH2), 40.3 (CH2), 34.7 (CH2). IR
mmax (neat, cmÀ1) 3425.6, 3054.9, 2951.4, 1679.2,
1491.7, 744.0. HRMS calcd for C12H17ClO2SN (CI,
M+NH3) requires 274.06686; found 274.06746.
1
356.20704. Data for compound 6 H NMR (400 MHz,
4.8. ( )-syn-3-(Cyclopentylthio)-4-hydroxycyclopenta-
none 16
CDCl3) d 0.1 (6H, 2 · s, (CH3)2), 0.9 (9H, s, tert-butyl),
1.52 (1H, ddd apparent dt, J = 5.0, 14.25 Hz, CHAHB),
1.81 (1H, m, CHACHB), 1.92–1.99 (1H, m, CHACHB),
2.40 (1H, dt, 1H, J = 7.25, 14.25 Hz, CHAHB), 2.80
(1H, ddd, J = 4.5, 6.0, 10.5 Hz, CHS), 3.72 (1H, d,
J = 13.25 Hz, CHAHB), 3.78 (1H, d, J = 13.25 Hz,
CHACHB), 4.18–4.23 (1H, m, CHOTBS), 4.32 (1H,
dddd, J = 2.5, 4.5, 6.5, 14.25 Hz, CHOH), 7.15–7.30
(5H, m, ArH). 13C NMR (100 MHz, CDCl3) 137.2 (C),
127.8 (CH), 127.5 (CH), 126.0 (CH), 77.5 (CHOH),
70.5 (CHOH), 49.0 (CHS), 43.8 (CH2), 39.6 (CH2),
35.3 (CH2), 24.8 (tBu), 16.9 (C), À5.6 (CH3), À5.7
(CH3). IR mmax (neat, cmÀ1) 3416, 2928, 2856, 1361,
1256, 836. HRMS calcd for C18H34O2SSiN (CI,
M+NH3) requires 356.20798; found 356.20686.
Enone 2 (500 mg, 5.1 mmol, 1 equiv) was reacted with
cyclopentyl thiol (521 mg, 5.1 mmol, 1 equiv) as
described above. Purification by column chromatogra-
phy (n-hexane/ethyl acetate, 1:1 Rf = 0.25) gave the title
compound 15 as a clear oil (90%).1H NMR (400 MHz,
CDCl3) d 1.48–1.67 (4H, m, 2 · CH2), 1.73–1.84 (2H,
m, CH2), 2.02–2.12 (2H, m, CH2), 2.20 (1H, ddd,
J = 1.25, 12.0, 18.5 Hz, CHAHB), 2.38 (1H, dd, 4.5,
18.5 Hz, CHAHB), 2.50 (1H, ddd, J = 0.75, 8.25,
18.5 Hz, CHAHB), 2.60 (1H, dd, J = 1.5, 18.5 Hz,
CHAHB), 1.98 (1H, s, OH), 3.14–3.22 (1H, m apparent
quint, J = 7.25 Hz, CHS), 3.47 (1H, ddd, J = 3.5, 8.25,
12.0 Hz, CHS), 4.36–4.40 (1H,
m
apparent t,
J = 4.0 Hz, CHOH). 13C NMR (100 MHz, CDCl3)
214.0 (C@O), 68.4 (CHOH), 47.7 (CHS), 46.6 (CH2),
43.2 (CHS), 40.6 (CH2), 39.3 (CH2), 34.3 (CH2), 24.6
(CH2). IR mmax (neat, cmÀ1) 3464, 2960, 1747. HRMS
calcd for C10H20O2SN (CI, M+NH3) requires
218.12148; found 218.12136. Anal. Calcd for
C10H16O2S: C, 59.96; H, 8.05. Found: C, 60.01; H, 8.05.
4.6. ( )-syn-3-(Dodecylthio)-4-hydroxycyclopentanone 14
Enone 2 (500 mg, 5.1 mmol, 1 equiv) was reacted with
dodecylthiol (1.03 g, 5.1 mmol, 1 equiv) as described
above. Purification by column chromatography (1%
MeOH in CH2Cl2, Rf = 0.25) gave the title compound
1
14 as a white solid (84%). H NMR (400 MHz, CDCl3)
d 0.8 (3H, t, J = 6.75 Hz, CH3), 1.23–1.35 (18H, m,
CH2), 1.36–1.44 (2H, m, CH2), 1.59–1.68 (2H, m,
CH2), 2.19 (1H, ddd, J = 1.4, 11.75, 18.5 Hz, CHAHB),
2.36 (1H, dd, J = 4.5, 18.5 Hz, CHAHB), 2.49 (1H,
ddd, J = 0.8, 8.0, 18.5 Hz, CHAHB), 2.56–2.62 (2H, m,
4.9. ( )-syn-3-Hydroxy-4-(naphthalene-2-ylthio)-
cyclopentanone 17 and 18
Enone 2 (1.0 g, 10.2 mmol, 1 equiv) was reacted with 2-
naphthyl thiol (1.63 g, 10.2 mmol, 1 equiv) as described

360
J. F. Bickley et al. / Tetrahedron: Asymmetry 17 (2006) 355–362
above. Purification by column chromatography (1%
MeOH in CH2Cl2, Rf = 0.27) furnished a mixture of
17 and 18 as a pale, yellow oil (69%). Data for com-
pound 17 1H NMR (400 MHz, CDCl3) d 2.30–2.45
(2H, m, 2 · CHAHB), 2.54–2.65 (2H, m, CHAHB), 2.93
(1H, s, OH) 3.87 (1H, ddd, J = 3.25, 8.0, 11.5 Hz,
CHS), 4.32–4.38 (1H, m, CHOH), 7.48–7.55 (3H, m,
ArH), 7.76–7.84 (3H, m, ArH), 7.94–7.97 (1H, m,
ArH). 13C NMR (100 MHz, CDCl3) 213.5 (C@O),
134.1 (C), 133.0 (C), 131.6 (C), 130.2 (CH), 129.5
(CH), 129.4 (CH), 128.2 (CH), 127.8 (CH), 127.1
(CH), 126.9 (CH), 68.8 (CHOH), 51.4 (CHS), 46.9
(CH2), 40.7 (CH2). IR mmax (neat, cmÀ1) 3444, 1749,
1393, 907, 731. HRMS calcd for C15H18O2SN (CI,
M+NH3) requires 276.10583; found 276.10613.
J = 0.8, 4.25, 6.75, 14.0 Hz, CHAHB), 2.48 (1H, ddd
apparent dt, J = 7.5, 14.25 Hz, CHAHB), 2.81 (1H,
ddd, J = 5.25, 7.50, 13.0 Hz, CHS), 3.78 (1H, d,
J = 13.5 Hz, CHAHB), 3.85 (1H, d, J = 13.5 Hz,
CHAHB), 4.24 (1H, dt, app. q, J = 5.75, 12.0 Hz,
CHOH), 4.37 (1H, dddd, J = 4.25, 4.50, 8.50, 8.75 Hz,
CHOH), 7.21–7.37 (5H, m, ArH). 13C NMR
(100 MHz, CDCl3) 138.7 (C), 129.3 (CH), 129.0 (CH),
127.6 (CH), 78.0 (CHOH), 71.3 (CHOH), 50.4 (CHS),
44.0 (CH2), 41.4 (CH2), 36.4 (CH2). IR mmax (neat,
cmÀ1) 3441, 3054, 2986, 2928, 1422, 1266. HRMS calcd
for C12H20O2SN (CI, MNH4+) requires 242.12148;
found 242.12138.
4.12. (1S,3S,4R)-4-(Benzylthio)cyclopentane-1,3-diol 13
4.10. (1R,3S,4S)-4-(Benzylthio)cyclopentane-1,3-diol 7
In a 25 mL round-bottomed flask, a solution of tetra-
methylammonium triacetoxyborohydride (600 mg,
2.3 mmol, 5 equiv) and acetic acid (0.26 mL, 4.5 mmol,
10 equiv) in 10 mL of acetonitrile was added to a solu-
tion of 9 (100 mg, 0.45 mmol, 1 equiv) in 1 mL of aceto-
nitrile. The reaction mixture was stirred at 0 ꢁC for 48 h
before it was quenched with 3.0 mL of saturated aque-
ous ammonium chloride solution. After effervescence
had ceased, the solution was treated with 3 mL of
1.0 M aqueous sodium/potassium tartrate solution and
stirred for 20 min. The aqueous solution was extracted
with dichloromethane (10 · 5 mL). The combined
organic layers were washed with 5 mL of saturated
aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate, filtered and concentrated in vacuo.
The residue was purified by column chromatography
(n-hexane/ethyl acetate, 1:1, Rf = 0.16) to give the diol
13 as a clear oil. Yield = 86%. [a]D = +57.2 (c 0.66,
CHCl3). 1H NMR (400 MHz, CDCl3) d 1.76 (1H,
apparent dt, J = 4.25, 14.75 Hz, CHAHB), 1.87 (2H,
m, 2 · CHAHB), 2.24 (1H, ddd, J = 2.0, 6.75,
14.75 Hz, CHAHB), 3.32 (1H, m, CHS), 3.71 (1H, d,
J = 13.5 Hz, CHAHB), 3.76 (1H, d, J = 13.5 Hz,
CHAHB), 3.97–4.01 (1H, m, CHOH), 4.44–4.49 (1H,
m, CHOH), 7.28–7.40 (5H, m, ArH). 13C NMR
(100 MHz, CDCl3) 138.6 (C), 129.1 (CH), 129.0 (CH),
127.7 (CH), 71.3 (CHOH), 71.1 (CHOH), 49.7 (CHS),
43.9 (CH2), 40.0 (CH2), 36.7 (CH2). HRMS calcd for
C12H17O2S (CI, MNH4+) requires 225.09494; found
225.09414.
To a solution (0 ꢁC) of the silyl ether 5 (150 mg,
0.443 mmol, 1 equiv) in dry tetrahydrofuran (11.6 mL),
was added tetra-n-butylammonium fluoride (TBAF)
(1 M solution in tetrahydrofuran, 1.1 equiv); the result-
ing solution was stirred for 45 min allowing the mixture
to warm to room temperature. The resulting solution
was then diluted with dichloromethane (20 mL) and
quenched with water (5 mL). The organic layer was
extracted with brine (5 mL) and dried over magnesium
sulfate, solvent was removed in vacuo. The crude prod-
uct was purified by flash column chromatography (n-
hexane/ethyl acetate, 3:1 Rf = 0.20) to give the diol 7
1
as a clear oil (87%). [a]D = À39.3 (c 0.89, CHCl3). H
NMR (400 MHz, CDCl3) d 1.68 (1H, ddd, J = 1.25,
5.5, 14.5 Hz, CHAHB), 1.78–1.85 (1H, m, CHAHB),
2.12 (1H, dt, J = 5.25, 14.5 Hz, CHAHB), 2.25 (1H,
ddt, J = 1.75, 8.25, 14.5 Hz, CHAHB), 3.15–3.21 (1H,
m, CHS), 3.75 (1H, d, J = 13.5 Hz, CHAHB), 3.82
(1H, d, J = 13.5 Hz, CHAHB), 4.10–4.15 (1H, m,
CHOH), 4.35–4.40 (1H, m, CHOH), 7.22–7.37 (5H, m,
ArH). 13C NMR (100 MHz, CDCl3) 138.6 (C), 129.3
(CH), 129.0 (CH), 127.5 (CH), 79.9 (CHOH), 73.8
(CHOH), 50.2 (CHS), 42.4 (CH2), 42.3 (CH2), 37.2
(CH2). IR mmax (neat, cmÀ1) 3441, 3054, 2986, 2928,
1422, 1266. HRMS calcd for C12H20O2SN (CI,
MNH4+) requires 242.12148; found 242.12148.
4.11. (1S,3S,4S)-4-(Benzylthio)cyclopentane-1,3-diol 8
To a solution (0 ꢁC) of silyl ether 6 (1 equiv) in dry tet-
rahydrofuran (11.6 mL), was added tetra-n-butylammo-
nium fluoride (TBAF) (1 M solution in tetrahydrofuran,
1.1 equiv) and the resulting solution stirred for 45 min
allowing the mixture to warm to room temperature.
The resulting solution was diluted with dichloromethane
(20 mL) and quenched with water (5 mL). The organic
layer was extracted with brine (5 mL) and dried
over magnesium sulfate, followed by solvent removal
in vacuo. The crude product was purified by flash
column chromatography (n-hexane/ethyl acetate, 3:1,
Rf = 0.17) to give the diol 8 as a clear oil (83%).
[a]D = +40.9 (c 0.44, CHCl3). 1H NMR (400 MHz,
CDCl3) d 1.60 (1H, dddd, J = 0.8, 4.5, 7.0, 14.0 Hz,
CHAHB), 1.90 (1H, m, CHAHB), 2.05 (1H, dddd,
4.13. trans-1,4-Dioxa spiro[4.5]decane-7,8-diol 22
To a 50 mL round-bottomed flask containing a solution
of 1,4-cyclohexanedione monoethyleneketal 19 (1 g,
6.41 mmol) and L-proline (112 mg, 0.96 mmol) in
dimethylformamide (15 mL) at 0 ꢁC was added a solution
of nitrosobenzene (343 mg, 3.2 mmol) in dimethylform-
amide (4 mL) over 15 h by syringe pump. The reaction
mixture was stirred for 2 h. Methanol (8 mL) and cerium
chloride heptahydrate (2.37 g, 7.05 mmol) were added to
the reaction mixture before adding sodium borohydride
(266 mg, 7.05 mmol). The reaction mixture was stirred
for 30 min at 0 ꢁC, before the addition of copper sulfate
pentahydrate (240 mg, 0.96 mmol). The reaction mixture
was stirred for 16 h at 0 ꢁC. Water (10 mL) was added to

J. F. Bickley et al. / Tetrahedron: Asymmetry 17 (2006) 355–362
361
quench the reaction. The resultant biphasic solution was
extracted with ethyl acetate (4 · 20 mL) and the com-
bined organic extracts washed with brine (satd), dried
over magnesium sulfate and filtered. Solvent was
removed in vacuo and the residue purified by column
chromatography (5% methanol in CH2Cl2, Rf = 0.21)
to yield the title compound 22 (40%) as a light brown
oil. [a]D = 0 (c 1, DCM) 1H NMR (400 MHz, CDCl3) d
1.63 (3H, m, 3 · CHAHB), 1.75 (1H, m, CHAHB), 1.93
(1H, m, CHAHB), 2.08 (1H, ddd, J = 2.5, 4.5, 13.0 Hz,
CHAHB), 3.52 (1H, ddd, J = 4.5, 8.3, 13.0 Hz, CHOH),
3.66 (1H, ddd, J = 4.2, 8.0, 12.3, CHOH), 3.95 (4H, m,
OCH2CH2O). 13C NMR (100 MHz, CDCl3) 109.1
(COO), 74.4 (CO), 73.1 (CO), 64.8 (CH2), 64.8 (CH2),
40.5 (CH2), 32.7 (CH2), 28.4 (CH2). IR mmax (neat,
cmÀ1) 3395, 2951, 2891, 1447, 1357, 1102, 1052; HRMS
calcd for C8H15O4 (Cl, MH+) requires 175.09705; found
175.09709.
12.75 Hz, CHAHB), 2.36 (1H, ddd, J = 4.75, 12.75,
17.0 Hz, CHAHB), 2.58 (1H, dtd apparent dt, J = 4.25,
16.75 Hz, CHAHB), 4.53 (1H, dddd, J = 2.0, 2.4, 4.5,
9.0 Hz, CHOTBS), 5.92 (1H, apparent d, J =
10.25 Hz, CHallylic), 6.83 (1H, ddd apparent dt,
J = 2.25, 10.25 Hz, CHallylic). 13C NMR (100 MHz,
CDCl3) 199.2 (C@O), 154.3 (CH), 129.1 (CH), 67.4
(CHOTBS), 35.9 (CH2), 33.3 (CH2), 26.0 (tBu), 18.5
(C), À4.2 (CH3), À4.4 (CH3).
4.16. (R)-4-(tert-Butyldimethylsilyloxy)cyclohex-2-enone
(R)-25
To a solution of 1R,2S-246 in MeOH/H2O (1:1) was
added NaIO4 (1 equiv) portionwise at 0 ꢁC and the
resultant mixture was stirred for 16 h. The white slurry
was filtered through a sintered funnel and the filtrate
concentrated in vacuo. The residue was taken up in
dichloromethane (50 mL) and water (50 mL) and
extracted with dichloromethane (5 · 30 mL). The com-
bined organic extracts were washed with brine (30 mL)
and H2O (30 mL), dried over magnesium sulfate and
concentrated in vacuo. The residue was dissolved in tol-
uene and heated to 115 ꢁC for 16 h. The reaction mix-
ture was allowed to cool and concentrated in vacuo.
The residue was dissolved in dichloromethane (50 mL)
and H2O (40 mL) was added. The mixture separated
and the aqueous phase was extracted with dichloro-
methane (4 · 30 mL). The combined organic extracts
were washed with brine (25 mL), dried over magnesium
sulfate and concentrated in vacuo. The resultant residue
(crude 4-acetoxycyclohex-2-enone) was dissolved in
MeOH (20 mL) and cooled to 0 ꢁC. To this mixture
K2CO3 (1 equiv) was added and stirred for 30 min.
Brine (30 mL) and dichloromethane (40 mL) were added
and stirred for 25 min. The biphasic mixture was
extracted with dichloromethane (4 · 25 mL). The com-
bined organic extracts were washed with brine (25 mL)
and H2O (2 · 25 mL), dried over magnesium sulfate, fil-
tered and concentrated in vacuo to furnish 4-hydroxycy-
clohex-2-enone (R)-3 as a brown oil.
4.14. (R)-4-Hydroxycyclohex-2-enone 3
In a 25 mL round-bottomed flask, a solution of 21
(50 mg, 0.29 mmol), 2 M HCl (0.36 mL, 0.73 mmol),
THF (3 mL) and water (3 mL) were stirred at room tem-
perature for 24 h. Ammonium sulfate (satd aq, 25 mL)
was added to quench the reaction. The reaction mixture
was extracted with ethyl acetate (4 · 20 mL). The
combined organic extracts were dried over magnesium
sulfate and filtered. The solvent was removed in vacuo
and the residue was purified by column chromatography
(50% ethyl acetate in n-hexane, Rf = 0.20) to afford the
title compound 3 (69%) as a light yellow oil, ee =
93.6% (chiral GC; Lipodex-C, 100 ꢁC; (S) = 20.10 min,
1
(R) = 20.82 min). [a]D = +94 (c 1.0, DCM). H NMR
(400 MHz, CDCl3) d 2.00 (1H, dddd, J = 1.25, 3.5,
9.5, 12.75 Hz, CHAHB), 2.32–2.44 (2H, m, 2 · CHAHB),
2.59 (1H, dtd, J = 1.0, 4.5, 17.75, CHAHB), 4.59 (1H,
m), 5.97 (1H, ddd, J = 1.0, 2.0, 10.25, CH), 6.92 (1H,
ddd, J = 1.75, 2.5, 10.25, CH). 13C NMR (100 MHz,
CDCl3) 198.9 (C@O), 152.8 (CH), 129.7 (CH), 66.7
(CH), 35.7 (CH2), 32.9 (CH2). IR mmax (neat, cmÀ1
)
3396, 2957, 1698, 1417, 1378, 1132, 1065, 970, 943,
862. HRMS calcd for C6H12O2N (Cl, MNH4+) requires
130.08681; found 130.08660.
A solution of crude (R)-3 (1 equiv) and TBSCl (1 equiv)
in anhydrous dichloromethane (20 mL) was stirred at rt
under argon. DBU (1.1 equiv) was added dropwise over
10 min. After 3 h at rt, the reaction mixture was diluted
with dichloromethane (50 mL) and washed with H2O
(40 mL), 0.1 M HCl (2 · 40 mL), satd NaHCO3
(40 mL) and brine (40 mL), dried over magnesium sul-
fate and concentrated in vacuo. Purification by column
chromatography (n-hexane/ethyl acetate, 19:1) gave
the title compound R-25 in 39% yield (overall),
[a]D = +108.9 (c 2.28, DCM). Data for compound (R)-
25 are consistent with (S)-25 and the literature.
4.15. (S)-4-(tert-Butyldimethylsilyloxy)cyclohex-2-enone
(S)-25
To a stirred solution of (3R,4S)-236 (70 mg, 0.25 mmol,
1 equiv) and TBSCl (75 mg, 0.50 mmol, 2 equiv) in
anhydrous dichloromethane (25 mL) was added DBU
(95 mg, 0.625 mmol, 2.5 equiv) dropwise over 5 min.
The resultant mixture was stirred for a further 16 h at
rt. The reaction mixture was diluted with dichlorometh-
ane (50 mL) and washed with H2O (40 mL), 0.1 M HCl
(2 · 40 mL), satd NaHCO3 (40 mL) and brine (40 mL),
dried over magnesium sulfate and concentrated in
vacuo. Purification by column chromatography (n-hex-
ane/ethyl acetate, 19:1 Rf = 0.16) gave the title com-
pound (S)-25 in 70% yield. [a]D = À109.6 (c 1.46,
Acknowledgements
We thank the Pro-Bio Faraday Partnership for a stu-
dentship to Ben Morgan. We would also like to thank
Mr. Roger Howard for technical assistance with chiral
GC/HPLC analysis.
1
DCM). H NMR (400 MHz, CDCl3) d 0.12 (6H, 2 · s,
t
(CH3)2), 0.92 (9H, s, Bu), 2.01 (1H, tdd, J = 4.25, 9.0,
12.75 Hz, CHAHB), 2.21 (1H, dqd, J = 1.6, 4.75,

362
J. F. Bickley et al. / Tetrahedron: Asymmetry 17 (2006) 355–362
´
´
Figueredo, M.; Font, J.; Garcıa-Garcıa, E.; Rodriguez, S.
Tetrahedron: Asymmetry 2000, 11, 4473; (f) Alibes, R.; De
March, P.; Figueredo, M.; Font, J.; Marjanet, G. Tetra-
hedron: Asymmetry 2004, 15, 1151.
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