A practical route to both enantiomers of bicyclo[3.3.0]oct-2-en-7-one and their use for the synthesis of key trisubstituted cyclopentanes

Article abstract of DOI:10.1016/j.tet.2008.01.134

We describe new methodology for the synthesis of both enantiomers of 7,7-dichlorobicyclo[3.2.0]hep-2-en-6-one and conversion of these compounds into stereochemically defined bicyclo[3.3.0]oct-2-en-7-ones and thence trisubstituted cyclopentanes. These are key intermediates for the synthesis of prostanoids, brefeldin and other cyclopentane-containing natural products.

Full text of DOI:10.1016/j.tet.2008.01.134

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3534e3540
www.elsevier.com/locate/tet
A practical route to both enantiomers of bicyclo[3.3.0]oct-2-en-7-one
and their use for the synthesis of key trisubstituted cyclopentanes
*
David Cousin, John Mann
School of Chemistry, Queen’s University Belfast, David Keir Building, Stranmillis Road, Belfast BT9 5AG, UK
Received 1 November 2007; received in revised form 16 January 2008; accepted 31 January 2008
Available online 6 February 2008
Celebrating the 80th birthday of Professor E.J. Corey who first prepared brefeldin A in 1976
Abstract
We describe new methodology for the synthesis of both enantiomers of 7,7-dichlorobicyclo[3.2.0]hep-2-en-6-one and conversion of these
compounds into stereochemically defined bicyclo[3.3.0]oct-2-en-7-ones and thence trisubstituted cyclopentanes. These are key intermediates
for the synthesis of prostanoids, brefeldin and other cyclopentane-containing natural products.
Ó 2008 Elsevier Ltd. All rights reserved.
CO2H
1. Introduction
OH
The cyclopentane ring is a commonly encountered constit-
uent of many biologically important compounds, e.g., carbacy-
clin 1 and brefeldin A 2 (from Penicillium decumbens), which
are two examples of compounds that have been the targets of
innumerable synthetic endeavours. The chiral bicyclo[3.2.0]-
hept-2-en-6-one 3 has often been used for the synthesis of
prostanoids and could, in principle, also be useful for elabora-
tion into brefeldin A (Scheme 1). In this paper we provide full
details of a new practical route for the synthesis of a range of
other chiral intermediates that could be used for the synthesis
of these natural products and other cyclopentane-containing
natural products.
H
H
OH
Me
H
H
O
O
OH
OH
Carbacyclin 1
(+) brefeldin A 2
O
H
H
(+) bicyclo[3.2.0]hept -2-en-6-one 3
Scheme 1. Structures of carbacyclin 1, (þ) brefeldin A 2 and bicyclo[3.2.0]-
hept-2-en-6-one 3.
2. Results and discussion
enzymes,3 but we wondered whether the dichloroketone might
be a viable substrate for a classical resolution via diastereoiso-
mers, and this indeed proved to be the case (Scheme 2). After
stereoselective reduction of this ketone with sodium borohy-
dride the resultant alcohol 5 was converted into the diastereoiso-
meric camphanate esters 6a,b by reaction with (ꢀ)-camphanoyl
chloride, and these could be efficiently separated using flash
chromatography (Fig. 1). The yield of the mixture of diastereo-
isomers was 96% and the yields of the discrete diastereoisomers
after chromatography were ca. 40% each on the gram scale.
The cycloaddition of dichloroketene to cyclopentadiene is
a tried and tested route for the synthesis of 7,7-dichlorobicy-
clo[3.2.0]hept-2-en-6-one 4 and this compound is then usually
reduced to the requisite ketone 3 using zinc and acetic acid.
Resolution of this bicyclic ketone has been achieved using
fermenting Baker’s yeast,1 porcine pancreatic lipase,2 and other
* Corresponding author. Tel.: þ44 02890975221.
E-mail address: j.mann@qub.ac.uk (J. Mann).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.134

D. Cousin, J. Mann / Tetrahedron 64 (2008) 3534e3540
3535
O
H
H
O
O
Cl
Cl
H
HO
H
Cl
Cl
H
O
Cl
Cl
H
O
H
d)
H
e)
a)
H
O
Cl
Cl
H
HO
H
Cl
Cl
H
(-) 6a
(-) 5a
(+) 4a
H
c)
b)
O
H
H
O
O
Cl
Cl
H
O
Cl
Cl
H
HO
H
Cl
Cl
H
4 racemate
5 racemate
O
H
H
(-) 4b
(+) 5b
(+) 6b
Scheme 2. Resolution of 7,7-dichlorobiyclo[3.2.0]hept-2-en-6-one 4 via the diastereoisomeric camphanate esters 6a and 6b; (a) dichloroacetyl chloride, Et3N,
hexane, rt, overnight, 85%; (b) NaBH4, MeOH, 0 ꢁC to rt, 1 h 30 min , 65%; (c) (1S)camphanic acid chloride, DCM, DMAP, 0 ꢁC to rt, overnight, 37% for
6a, 39% for 6b; (d) LiAlH4, THF, 0 ꢁC to rt, overnight, 60/63%; (e) (COCl)2, DMSO, Et3N, DCM, ꢀ78 ꢁC to rt, 1 h 10 min, 71/77%.
Reduction of these with lithium aluminium hydride provided
the discrete enantiomers of 7,7-dichlorobicyclo[3.2.0]hept-2-
en-6-ol 5a,b with [a]D ꢀ137 and þ139, and thence using Swern
oxidation to produce the original ketone now as pure enantio-
mers 4a,b with [a]D þ84 and ꢀ81. Roberts and co-workers
have reported resolution of 5a,b using 3a,20b-hydroxysteroid
dehydrogenase (from Streptomyces hydrogenas)4 and recorded
an [a]D of ꢀ155 for enantiomer 5a. Our method thus provides
a complementary gram scale and non-enzymatic route to these
important compounds.
The key reaction for an approach to brefeldin A (shown in
Scheme 3) now involved a ring expansion reaction of the (þ)-
enantiomer 4a using diazomethane and this provided the 8,8-di-
chlorobicyclo[3.3.0]oct-2-en-7-one 7a, which could be reduced
with zinc and acetic acid to yield the key bicyclo[3.3.0]oct-
2-en-7-one 8a. This has been reported previously by Kashihara
and co-workers,5 who recorded an [a]D of ꢀ161 while our [a]D
was ꢀ138. We have no explanation for this discrepancy since
our sample was of high purity. However, reduction with lithium
aluminium hydride provided primarily the endo alcohol 9a
(57% isolated yield) together with around 17% of the exo
alcohol, which could be recycled, and the [a]D for compound
9a was ꢀ74, which agreed very well with the value of ꢀ75 re-
corded by Kashihara. Alcohol 9a was protected as its TBDMS-
ether 10 prior to ozonolytic cleavage of the double bond to yield
(after reduction of the ozonide with sodium borohydride) the
trisubstituted cyclopentane 11. Various methods were tried for
selective protection of the alcohols but this was not possible
and the two isomers 12 and 13 were produced after reaction
with tert-butyldiphenylsilyl chloride. The latter was oxidised
Figure 1. X-ray structures of camphanate derivatives 6a and 6b.
O
O
OR
OTBDMS
Cl
O
Cl
Cl
Cl
H
e)
a)
b)
c), d)
H
H
H
H
H
H
H
OH
(+) 4a
(-) 4b
(+) 7a
(-) 7b
(-) 8a
(-) 9a, R=H
(-) 10, R=TBDMS HO
(-) 11
(+) 8b
f)
OTBDMS
OTBDMS
OTBDMS
OTBDMS
OMOM
g)
h)
+
O
H
O
OH
OTBDPS
OH
H
TBDPSO
TBDPSO
(+) 14
TBDPSO
HO
1.8:1
16
(-) 15
(-) 13
(-) 12
Scheme 3. Synthesis of the chiral intermediate 15 for an approach to (þ) brefeldin A. (a) CH2N2, Et2O, 0 ꢁC, 3 h, 74%; (b) Zn, AcOH, 70 ꢁC, 1 h 30 min, 95%; (c)
LiAlH4, THF, 0 ꢁC, 1 h, 57% (þ17% exo isomer); (d) TBDMSOTf, Et3N, DCM, rt, 1 h, quantitative; (e) (1) O3, DCM/MeOH 2:1, ꢀ78 ꢁC; (2) NaBH4, DCM/
MeOH 2:1, 66e77%; (f) (1) NaH, THF, rt, 10 min; (2) TBDPSCl, THf, rt, 20 h, 60%; (g) DesseMartin periodinane, DCM, 1 h 30 min, 90%; (h) DBU, THF,
rt, 4 h, 88%.

3536
D. Cousin, J. Mann / Tetrahedron 64 (2008) 3534e3540
to the aldehyde 14, which could be epimerised with DBU to
yield the key intermediate 15. This has the correct absolute
stereochemistry and appropriate functionality for conversion
into intermediates like 16, which have been used to prepare
brefeldin and analogues via a short synthetic sequence6 involv-
ing an INOC reaction as the key step. These are of considerable
interest due to the fascinating spectrum of biological activities
possessed by the parent natural product and we hope to prepare
a small library of such analogues for biological evaluation.
In summary, we have produced multigram quantities of
both enantiomers of 7,7-dichloro[3.2.0]hept-2-en-6-one via
classical resolution of camphanate esters, and then used these
for the synthesis of a range of stereochemically defined trisub-
stituted cyclopentanes, which have potential for the synthesis
of natural products and related structures.
atomic displacement parameters. Hydrogen was added at
idealised positions, subsequent refinement uses a riding model
with atomic displacement parameters fixed at 1.2 Ueq of the
atom to which they are attached (1.5 Ueq for methyl groups).
2
2
The function minimised for wR2 was S[w(jFoj ꢀjFcj )] with
2
reflection weights wꢀ1¼[s2jFoj þ(g1P)2þg2P] where P¼
2
2
[maxjFoj þ2jFcj ]/3 for all F2. The SAINT1 and SHELXTL2
PC packages were used for data collection, reduction, structure
solution and refinement. Additional material available from the
Cambridge Structural Database includes atomic co-ordinates,
thermal parameters, remaining bond lengths and angles, and
structure factors (CCDC numbers: 646816 and 646817).
3.3. Synthesis of (ꢂ)-7,7-dichlorobicyclo[3.2.0]hept-2-en-6-
one 4
3. Experimental
A solution of triethylamine (21 mL, 149 mmol, 1.1 equiv) in
hexane (250 mL) was added dropwise to a solution of freshly
distilled cyclopentadiene (30 mL, 455 mmol, 3 equiv) and di-
chloroacetyl chloride (14 mL, 145 mmol) in hexane
(450 mL). The mixture was vigorously stirred at room temper-
ature overnight. The precipitate of triethylamine hydrochloride
was removed by filtration and the filtrate was concentrated
under vacuum. The crude product was purified by flash chroma-
tography and 22 g (85%) of (ꢂ)-7,7-dichlorobiyclo [3.2.0]
hept-2-en-6-one 4 was obtained as a yellow oil. Rf: 0.44
(EtOAc/P.E. 1:9); nmax/cmꢀ1: 1806.6 (C]O), 1028, 753
(HC]CH), 730 (CeCl); dH (CDCl3): m (6.04e6.05, 1H, H2),
m (5.79e5.81, 1H, H3), ddd (4.26, 1H, H5, J5/4¼8.7 Hz,
3.1. General
All solvents were dried before use. Dichloromethane and
methanol were either distilled from calcium hydride under ni-
trogen or argon or used after drying on a high pressure alumina
column device (MBRAUN). Tetrahydrofuran was either dried
by distillation in the presence of sodium and benzophenone
or used after drying on a high pressure alumina column device.
Hexane was used after drying on a high pressure alumina col-
umn device. P.E. refers to the fraction of petroleum ether boil-
ing range 60e80 ꢁC. Thin layer chromatography was used to
monitor reactions using PolygramÒ SIL G/UV254 precoated
plastic sheets with a 0.2 mm layer of silica gel containing fluo-
rescent indicator UV254. Plates were visualised using a 254 nm
UV lamp and potassium permanganate stain. Flash column
chromatography was carried out using SorbsilÒ (or Fluoro-
chemÒ) C60 silica gel (40e60 mesh) with the eluent or the gra-
dient of eluents reported. NMR spectra were recorded using
Bruker Avance300 or Bruker DRX500 spectrometers. Samples
were dissolved in CDCl3 with tetramethylsilane as a reference.
IR spectra were recorded using a PerkineElmer RXI FT-IR
system spectrometer. Samples were dissolved in chloroform
with the indicated concentration and optical rotations were
recorded at 20 ꢁC on a PerkineElmer model 341 polarimeter.
Mass spectra were recorded on a VG Autospec spectrometer
and were carried out by Analytical Services, Queen’s Univer-
sity of Belfast. Melting points were recorded on a Stuart melt-
ing point apparatus and are uncorrected.
0
J5/1¼7.5 Hz, J5/4 ¼1.1 Hz), m (4.06e4.08, 1H, H1), m (2.79e
0
2.84, 1H, H4equatorial), ddddd (2.57, 1H, H4axial, J4/4 ¼17.5 Hz,
4
J4/5¼8.7 Hz, J4/1wJ4/2wJ4/3w2.1 Hz); dC (CDCl3): 197.8
(C6), 136.8 (C2), 128.8 (C3), 88.0 (C7), 59.6 (C1), 58.6 (C5),
35.2 (C4); m/z (EIMS): 181 (MHþ (37Cl), 6), 180 (Mþ (37Cl),
7), 179 (MHþ (35Cl, 37Cl), 16), 178 (Mþ (35Cl, 37Cl), 35), 177
(MHþ (35Cl), 27), 176 (Mþ (35Cl), 55), 150 (43), 149 (37),
148 (66), 147 (44), 143 (MþꢀCl (35Cl), 32), 141 (MþꢀCl
(37Cl), 100), 140 (51); C7H6Cl2O requires 175.9795, found:
175.9792.
3.4. Synthesis of (ꢂ)-7,7-dichlorobicyclo[3.2.0]hept-2-en-6-
ol 5
A solution of the dichloroketone 4 (15 g, 84.3 mmol) in
methanol (400 mL) was cooled to 0 ꢁC before addition of small
portions of sodium borohydride (7.97 g, 210.7 mmol,
2.5 equiv). The mixture was stirred at room temperature for
1 h 30 min, and 1 M HCl was added until the white precipitate
formed was dissolved. The solution was concentrated under vac-
uum and the residue was extracted with EtOAc. The combined
organic extracts were washed with brine and dried with
MgSO4. After evaporation of the solvent and purification by
flash chromatography (EtOAc/P.E. 1:9), 9.72 g (65%) of endo-
dichloro-alcohol 5 was obtained as a colourless oil. Rf: 0.33
(EtOAc/P.E. 1:9); nmax/cmꢀ1: 3437 (br), 1117 (CeOeC), 769,
3.2. X-ray crystallography7
Single crystal X-ray crystallographic data were collected us-
ing a Bruker SMART diffractometer with graphite monochro-
mated Mo Ka radiation. The crystal stability was monitored
and there was no significant decay (ꢂ1%). Data were collected
at low temperature ca. 153 K. Omega/phi scans were employed
for data collection and Lorentz and polarisation corrections
were applied. The structures were solved by direct methods
and all non-hydrogen atoms were refined with anisotropic
723 (CeCl); dH (CDCl3): m (6.06e6.09, 1H, H2
3), m
or
(5.77e5.79, 1H, H2 or 3), ddd (4.53, 1H, H6, J6/OH¼9.5 Hz,

D. Cousin, J. Mann / Tetrahedron 64 (2008) 3534e3540
3537
3J5/6¼7.5 Hz, 4J6/1¼3.3 Hz), m (3.92e3.93, 1H, H1), dddd (qd
2.3 Hz), m (2.39e2.55, 3H, H4equatorial, H4axial and H15equatorial),
m (2.05e2.09, 1H, H15axial), ddd (1.93, 1H, H14equatorial
J1¼13.2 Hz, J2¼10.5 Hz, J3¼4.5 Hz), m (1.68e1.72, 1H,
14axial), s (1.12, 3H, CH3), s (1.10, 3H, CH3), s (1.01, 3H,
0
like) (3.41, 1H, H5, J5/1wJ5/6wJ5/4¼8.0 Hz, J5/4 ¼1.5 Hz), m
,
0
(2.65e2.68, 1H, H4 ), m (2.39e2.45, 1H, H4), d (2.28, 2.30,
1H, OH, J¼9.5 Hz); dC (CDCl3): 138 (C2 or 3), 131 (C2 or 3),
91 (C7), 81 (C5), 65 (C1), 38 (C6), 32 (C4). Note: no mass spec-
trum could be obtained with this compound, i.e., EI, CI, electro-
spray, FAB did not give the expected mass. In the best case, the
mass obtained in CI corresponded to a dimeric compound.
H
CH3); dC (CDCl3): 178.4 (C9), 166.3 (C12), 137.1 (C2), 129.0
(C3), 91.2 (C7), 87.4 (C10), 80.7 (C6), 65.5 (C1), 55.2 (C13 or
C16), 54.7 (C13 or C16), 36.3 (C5), 32.8 (C4), 31.5 (C15), 29.3
(C14), 17.0 (2Me), 10.0 (Me); m/z (EIMS): 363 (MHþ (37Cl),
7), 361 (MHþ (35Cl, 37Cl), 15), 360 (Mþ (35Cl, 37Cl), 32), 359
(MHþ (35Cl), 52), 343 (6), 341 (9), 315 (9), 313 (14), 295
(24), 293 (36), 249 (9), 247 (14), 182 (15), 181 (40), 153 (75),
137 (25), 135 (34), 125 (78), 109 (45), 97 (50), 83 (83), 66
(100); C17H20Cl2O4 requires 358.0738, found: 358.0735. Crys-
tal data for C17H20Cl2O4 (6a): M¼359.23, orthorhombic, space
3.5. Synthesis of (ꢀ)-endo-(1S)-camphanic acid (1S,5R,6R)-
7,7-dichlorobicyclo[3.2.0]hept-2-en-6-yl ester 6a and (þ)-
endo-(1S)-camphanic acid (1R,5S,6S)-7,7-
dichlorobicyclo[3.2.0]hept-2-en-6-yl ester 6b
˚
˚
˚
Camphanic acid chloride (6 g, 27.7 mmol, 1.1 equiv) was
added to a solution of the alcohol 5 (4.5 g, 25.2 mmol) and
DMAP (28 g, 230 mmol, 9 equiv) in DCM (250 mL) at room
temperature and the mixture was stirred overnight. The mixture
was washed with a saturated solution of NaHCO3 and the aque-
ous layer was extracted with DCM. The combined organic layers
were washed with brine and then dried over MgSO4 and 8.7 g
(96%) of the diastereoisomeric mixture was obtained. The two
diastereoisomers were separated by portions of 3 g by succes-
sive flash chromatography and 3.51 g (39%) of (þ) camphanate
ester 6b and 3.24 g (37%) of (ꢀ) camphanate ester 6a were ob-
tained as white solids. Data for 6b: Rf: 0.25 (EtOAc/P.E. 2:8);
nmax, cmꢀ1: 2968 (alkyl), 1789 (C]O lactone), 1763 (C]O es-
ter), 1261, 1108.5 and 1055 (CeO), 728 (CeCl); dr: 100%; [a]D
þ58.5(c 0.75);mp:122/123 ꢁC; dH (CDCl3): m (6.03e6.07, 1H,
group P212121, a¼6.488(8) A, b¼12.224(15) A, c¼44.23(6) A,
U¼3508(8) A , Z¼8, m¼0.386 mmꢀ1, Rint¼0.1091. A total of
3
˚
25,535 reflections were measured for the angle range
1.8<2q<50 and 6185 independent reflections were used in the
refinement. The final parameters were wR2¼0.2785 and
R1¼0.0999 [I>2sI].
3.6. Synthesis of (ꢀ)-7,7-dichlorobiyclo[3.2.0]hept-2-en-6-ol
5a and (þ)-7,7-dichlorobicyclo[3.2.0]hept-2-en-6-ol 5b
A solution of (ꢀ) camphanate ester 6a (3.3 g, 9.18 mmol)
in THF (10 mL) was added dropwise at 0 ꢁC to a suspension
of lithium aluminium hydride (383 mg, 10.1 mmol, 1.1 equiv)
in THF (20 mL), and the mixture was stirred at room temper-
ature for 18 h. The excess of lithium aluminium hydride and
the complex were decomposed at 0 ꢁC with wet THF. A
2 M sulfuric acid solution was added dropwise and the mixture
was heated at 60 ꢁC for 30 min. The aqueous layer was
extracted with ether and the combined organic layers were
washed with water, brine and dried with MgSO4. After evap-
oration and flash chromatography (EtOAc/P.E. 2:8), 986 mg of
(ꢀ) alcohol 5a (60%) and recovered starting material were
obtained. The same reaction was carried out with the other di-
astereoisomer 6b (4.36 g) and 1.34 g (63%) of (þ) alcohol 5b
was obtained. Same analytical data as 5; 5a: [a]D ꢀ137, (lit.4:
[a]D ꢀ155); 5b: [a]D þ139.6 (c 0.56).
4
H2), m (5.71e5.75, 1H, H3), dd (5.54, 1H, H6, J6/1¼2.8 Hz,
J6/5¼7.9 Hz), m (3.97e4.00, 1H, H1), dddd (qd like) (3.52,
0
1H, H5, J5/4 ¼1.9 Hz, J5/1wJ5/6wJ5/4w8.5 Hz), m (2.59e2.61,
H4equatorial), m (2.43e2.53, 2H, H4axial and H15equatorial), m
(2.00e2.05, 1H, H15axial), m (1.89e1.93, 1H, H14equatorial), m
(1.69, 1H, H14axial), s (1.12, 3H, CH3), s (1.06, 3H, CH3), s
(1.03, 3H, CH3); dC (CDCl3): 178.5 (C9), 166.7 (C12), 137.1
(C2), 129.0 (C3), 91.5 (C7), 87.5 (C10), 81.1 (C6), 65.5 (C1),
55.4 (C13 or C16), 54.7 (C13 or C16), 36.3 (C5), 32.9 (C4), 31.3
(C15), 29.1 (C14), 17.1 and 17.3 (2Me), 10.1 (Me); m/z
(EIMS): 363 (MHþ (37Cl), 6), 361 (MHþ (35Cl, 37Cl), 35),
359 (MHþ (35Cl), 49), 343 (7), 341 (8), 315 (8), 313 (13), 295
(19), 293 (27), 249 (8), 247 (12), 182 (13), 181 (33), 153 (61),
137 (19), 135 (27), 125 (64), 109 (34), 97 (42), 83 (77), 66
(100); C17H20Cl2O4 requires 358.0738, found: 358.0733. Crys-
tal data for C17H20Cl2O4 (6b): M¼359.23, monoclinic, space
3.7. Synthesis of (þ)-(1R,5S)-7,7-dichlorobicyclo[3.2.0]hept-
2-en-6-one 4a and (ꢀ)-(1S,5R)-7,7-dichlorobicyclo-
[3.2.0]hept-2-en-6-one 4b
˚
˚
˚
group P21, a¼12.109(2) A, b¼9.9216(16) A, c¼14.911(3) A,
DMSO (1.1 mL, 15.31 mmol, 3 equiv) in DCM (25 mL)
was stirred at room temperature under argon. After 5 min,
the mixture was cooled to ꢀ78 ꢁC using a dry ice/acetone
bath. Oxalyl chloride (890 mL, 10.2 mmol, 2 equiv) was added
dropwise and the mixture was stirred for 10 min. A solution of
the (ꢀ) alcohol 5a (914 mg, 5.10 mmol) in DCM (7 mL) was
added dropwise and then the mixture was stirred for 30 min.
Triethylamine (2.84 mL, 20.4 mmol, 4 equiv) was added and
the mixture was stirred for 10 min at ꢀ78 ꢁC, then 30 min at
room temperature. Water, followed by DCM was added and
the aqueous layer was extracted with DCM. The combined or-
ganic layers were washed with brine and dried with MgSO4.
b¼103.640(7), U¼1741.0(6) A , Z¼4, m¼0.389 mmꢀ1
,
3
˚
Rint¼0.0305. A total of 20,188 reflections were measured for
the angle range 1.8<2q<57 and 7749 independent reflections
were used in the refinement. The final parameters were
wR2¼0.1441 and R1¼0.0578 [I>2sI]. Data for 6a: Rf: 0.20
(EtOAc/P.E. 2:8); nmax, cmꢀ1: 2970 (alkyl), 1791 (C]O lac-
tone), 1762 (C]O ester), 1261, 1107.1 and 1055.2 (CeO),
722.5 (CeCl); dr: 100%; [a]D ꢀ78.5 (c 0.61); mp: 82/84 ꢁC;
dH (CDCl3): m (6.04e6.07, 1H, H2), m (5.72e5.75, 1H, H3),
4
dd (5.56, 1H, H6, J6/1¼2.9 Hz, J6/5¼7.7 Hz), m (3.97e4.01,
0
1H, H1), dddd (3.51, 1H, H5, J5/6wJ5/1wJ5/4¼7.7 Hz, J5/4
¼

3538
D. Cousin, J. Mann / Tetrahedron 64 (2008) 3534e3540
After evaporation of the solvents and flash chromatography
(EtOAc/P.E. 1:9), 691 mg (77%) of (þ) ketone 4a was obtained
as a yellow oil. The same reaction was carried out with the other
enantiomer 5b (1.30 g) and 0.92 g (71%) of the (ꢀ) ketone 4b
was obtained. Same analytical data as 4; [a]D þ83.9 (c 0.79) for
4a, [a]D ꢀ81 (c 0.75) for 4b.
removed under vacuum and 272 mg (95%) of the ketone 8a
was obtained as a colourless oil. The product was used without
further purification. The same reaction was carried out with the
other enantiomer 7b (600 mg) and 338 mg of ketone 8b was ob-
tained as a colourless oil. Rf: 0.28 (EtOAc/P.E. 2:8); nmax, cmꢀ1
:
2924, 2850 (CeH), 1742 (C]O), 1402, 1258, 1159, 1027, 723;
dH (CDCl3): m (5.73e5.75, 1H, H2), m (5.62e5.63, 1H, H3), m
(3.41e3.42, 1H, H1), m (2.93e3.00, 1H, H5), ddddd (2.70, 1H,
0
3.8. Synthesis of (þ)-(1R,5S)-8,8-dichlorobicyclo[3.3.0]oct-
2-en-7-one 7a and (ꢀ)-(1S,5R)-8,8-dichlorobicyclo-
[3.3.0]oct-2-en-7-one 7b
H
4axial, J4/4 ¼16.5 Hz, J4/5¼7.6 Hz, 4J4/1wJ4/2wJ4/3w2.5 Hz),
m (2.44e2.53, 2H, H6axial and H8axial), m (2.20e2.27, 2H,
0
H4equatorial and H8equatorial), ddd (2.00, 1H, H6equatorial, J6/6
¼
A solution of KOH (6.1 g, 108.9 mmol, 30 equiv) in water/
ethanol (11/12 mL) was heated to 65 ꢁC without stirring. A so-
lution of Diazald (7.3 g, 36.3 mmol, 10 equiv) in ether
(65 mL) was added dropwise so that the reflux rate of addition
equalled the reflux rate of distillation. After complete addition,
the distillation was maintained until the distillate became col-
ourless. The resulting solution of diazomethane was poured
into a solution of the ketone 4a (610 mg, 3.40 mmol) in ether
(7 mL), and the mixture was stirred at 0 ꢁC for 3 h. The reac-
tion was quenched with acetic acid until disappearance of the
yellow colour. The solvent was removed under vacuum and
the crude mixture was purified by flash chromatography
(EtOAc/P.E. 1:9), and 480 mg (74%) of 8,8-dichlorobicy-
clo[3.3.0]oct-2-en-7-one 7a were obtained as a colourless
oil. The same reaction was carried out with the other enantio-
mer 4b (900 mg) and 700 mg (78%) of (ꢀ) dichloroketone 7b
was obtained as a colourless oil. Rf: 0.36 (EtOAc/P.E. 1:9);
nmax, cmꢀ1: 2917 (CeH), 1766 (C]O), 1139, 804, 774.; dH
(CDCl3): m (5.94e5.95, 1H, H2 or 3), m (5.69e5.70, 1H, H2
or 3), m (3.90, 1H, H1), m (3.10e3.14, 1H, H5), dd (3.03,
19.0 Hz, J6/5¼7.5 Hz, J3¼1.5 Hz); dC (CDCl3): 220.6 (C7),
134.5 (C2), 130.8 (C3), 46.7 (C1), 45.3 (C6), 43.0 (C8), 40.5
(C4), 37.4 (C5); [a]D ꢀ137.5 (c 0.96) for 8a, [a]D þ132.2
(c 0.99) for 8b (lit.5: [a]D ꢀ160.5).
3.10. Synthesis of (ꢀ)-(1R,5S,7S)-bicyclo[3.3.0]oct-2-ene-7-
ol 9a and (þ)-(1S,5R,7R)-bicyclo[3.3.0]oct-2-ene-7-ol 9b
A solution of the ketone 8a (240 mg, 2.00 mmol) in dry
THF (6 mL) was added to a 1 M solution of lithium alumin-
ium hydride (2.2 mL, 2.2 mmol, 1.1 equiv) in THF (4 mL) at
0 ꢁC. The mixture was stirred for 1 h and 85 mL of water
was added dropwise, followed by the addition of 85 mL of
a 15% NaOH solution. The mixture was stirred for 5 min, wa-
ter was added (250 mL) and the mixture was heated at reflux
for 30 min. The white precipitate was filtered and the solution
was concentrated under vacuum. The crude product was puri-
fied by flash chromatography and 136 mg of (ꢀ) alcohol 9a
(57%) and 40 mg (17%) of the exo isomer were obtained as
colourless oils. Similarly, 8b was converted into 9b. Data for
compound 9a: Rf: 0.25 (EtOAc/P.E. 2:8); nmax, cmꢀ1: 3342
(OH), 2931e2849 (CeH), 1085e1060 (CeO); dH (CDCl3):
m (5.76e5.79, 1H, H2), m (5.64e5.67, 1H, H3), m (4.19e
4.21, 1H, H7), m (3.19e3.20, 1H, H1), m (2.69e2.74, 2H,
H5 and H4axial), m (2.26e2.31, 1H, H4equatorial), m (2.18, 1H,
0
0
0
1H, H6 , J6/6 ¼19.5 Hz, J6 /5¼10.3 Hz), m (2.75e2.80, 1H,
0
H4), br d (2.30e2.33, 1H, H4 , J¼17 Hz), dd (2.00, 1H, H6,
0
J6/6 ¼19.5 Hz, J5/6¼5.3 Hz); dC (CDCl3): 201.6 (C7), 135.0
(C2), 128.7 (C3), 87.6 (C8), 64.5 (C1), 41.3 (C4), 38.9 (C6),
33.9 (C5); m/z (EIMS): 194 (Mþ (37Cl), 8), 192 (Mþ (35Cl,
37Cl), 37), 190 (Mþ (35Cl), 52), 179 (10), 177 (17), 169
(13), 161 (17), 157 (32), 155 (83), 149 (52), 147 (27), 141
(21), 127 (33), 125 (44), 119 (19), 115 (26), 113 (48), 105
(21), 91 (65), 89 (18), 85 (26), 79 (58), 78 (100), 72 (42),
66 (19), 64 (63), 62 (30), 59 (16); C8H8Cl2O requires
189.9952, found: 189.9956; [a]D þ1.27 (c 1.11) for 7a, [a]D
ꢀ1.28 (c 1.25) for 7b.
H6axial), m (1.99e2.01, 1H, H8axial), br s (1.77, 1H, OH), m
(1.56e1.58, 1H, H8equatorial), m (1.48e1.49, 1H, H6equatorial);
dC (CDCl3): 136.6 (C2), 129.4 (C3), 75.5 (C7), 49.8 (C1),
44.6 (C6), 41.5 (C4), 41.1 (C8), 38.5 (C5); [a]D ꢀ73.6 (c
0.75) for 9a, [a]D þ73.8 (c 0.70) for 9b (lit.5: [a]D ꢀ75.4).
3.11. Synthesis (ꢀ)-(1R,5S,7S)-bicyclo[3.3.0]oct-2-ene-7-
oxy-tert-butyldimethylsilane 10
3.9. Synthesis of (ꢀ)-(1R,5S)-bicyclo[3.3.0]oct-2-en-7-one 8a
and (þ)-(1S,5R)-bicyclo[3.3.0]oct-2-en-7-one 8b
tert-Butyldimethylsilyl-trifluoromethanesulfonate (340 mL,
1.47 mmol, 1.4 equiv) was added dropwise at 0 ꢁC to a solution
of the alcohol 9a (130 mg, 1.05 mmol) in DCM/Et3N (5.5 mL,
350 mL, 2.52 mmol, 2.4 equiv). The mixture was stirred at
room temperature for 2 h. Water was added and the organic
layer was extracted with DCM. The combined organic layers
were washed with brine and dried with MgSO4. The product
was purified by flash chromatography (EtOAc/P.E. 2:8) and
250 mg (quantitative) of silyl ether 10 was obtained as
A solution of the dichloroketone 7a (450 mg, 2.35 mmol) in
acetic acid (2 mL) was added dropwise to a suspension of zinc
powder (924 mg, 14.1 mmol, 6 equiv) in acetic acid (1.5 mL).
An exothermic reaction occurred. After complete addition,
the mixture was heated to 70 ꢁC for 1 h 30 min. The mixture
was cooled to room temperature and ether was added. After fil-
tration over Celite, the pad was washed with ether and water,
and the aqueous layer was extracted with ether. The combined
organic layers were washed with 2 M Na2CO3 until pH 7,
then with brine. After drying with MgSO4, the solvent was
a pale yellow oil. Rf: 0.79 (EtOAc/P.E. 2:8); nmax, cmꢀ1
:
2929, 2857 (CeH), 1255 (SieMe), 1112 (SieO), 836
(SieO), 774; [a]D ꢀ38.8 (c 0.69); dH (CDCl3): m (5.66e5.67,

D. Cousin, J. Mann / Tetrahedron 64 (2008) 3534e3540
3539
1H, H2), m (5.56e5.57, 1H, H3), m (4.06e4.15, 1H, H7), m
(3.01e3.03, 1H, H1), m (2.52e2.61, 2H, H5 and H4axial), m
(2.06e2.21, 3H, H4equatorial, H6axial, H8axial), m (1.28e1.35,
2H, H8equatorial, H6equatorial), s (0.89, 9H, (CH3)3), s (0.05e
0.07, 3Hþ3H, CH3); dC (CDCl3): 135.1 (C2), 128.1 (C3),
74.6 (C7), 48.2, (C1), 43.7 (C6), 41.2 (C4), 40.2, (C8), 37.9
(C5), 26.1e26.3 (t-Bu), 18.5 (CMe3), ꢀ2.53, ꢀ4.36 (Me2);
m/z (EIMS): 239 (MHþ), 206 (25), 192 (9), 190 (10), 181
(8), 177 (19), 164 (29), 153 (26), 152 (33), 150 (38), 141
(20), 140 (33), 139 (43), 138 (37); C14H27OSi (MHþ) requires
239.1831, found: 239.1826.
1472.0e1428.2, 12,555.6 (CeOeC), 1112, 836, 775, 701
(SieO); dH (CDCl3): m (7.70e7.72, 4H, Ar), m (7.41e7.46,
6H, Ar), m (4.20e4.22, 1H, H4), m (3.57e3.80, 4H, CH2OH,
CH2OTBDPS), m (2.18e2.25, 1H, H1), m (1.97e2.11, 3H,
H2, H3 and H5), m (1.80e1.91, 1H, CH2CH2OTBDPS), m
0
(1.55e1.64, 1H, CH2CH2OTBDPS), m (1.40e1.49, 2H, H3 ,
0
H5 ), s (1.08, 9H, (CH3)3), s (0.88, 9H, (CH3)3), s (0.04e0.05,
3Hþ3H, CH3); dC (CDCl3): 136.0 (Aro), 134.2 (Ari), 129.9
(Arp), 128.0 (Arm), s (73.2, 1C, C4), 65.3 (CH2OH), 62.8
(CH2OTBDPS), 43.3 (C1), 41.7 (C5), 39.2 (C3), 36.9 (C2),
33.5 (CH2CH2OTBDPS), 27.3e26.3 (t-Bu), 19.6e18.4
(C(Me)3), ꢀ4.34, ꢀ4.38 (2s, SiMe2); m/z (CIMS): 513 (MHþ,
100), 275 (25), 257 (75), C30H49O3Si2 (MHþ) requires
513.3220, found: 513.3223; [a]D ꢀ8.96 (c 1.15).
3.12. Synthesis of 2-[(1R,2S,4S)-4-(tert-butyl-dimethyl-
silanyloxy)-2-(tert-butyl-diphenyl-silanyloxymethyl)-
cyclopentyl]-ethanol 12 and {(1S,2R,4S)-4-(tert-butyl-
dimethyl-silanyloxy)-2-[2-(tert-butyl-diphenyl-silanyloxy)-
ethyl]-cyclopentyl}-methanol 13
3.13. Synthesis of (1S,2R,4S)-4-(tert-butyl-dimethyl-
silanyloxy)-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-
cyclopentanecarbaldehyde 14
Ozone was bubbled through a solution of the silyl ether 10
(250 mg, 1.05 mmol) in DCM/MeOH 2:1 (15 mL) at ꢀ78 ꢁC
until a bright blue colour persisted. Solid sodium borohydride
(400 mg, 10.5 mmol, 10 equiv) was added and the mixture
was allowed to warm slowly to room temperature over 3 h.
The solution was concentrated under vacuum and water was
added. The product was extracted with Et2O, and the combined
organic layers were washed with brine, and then dried over
MgSO4. The crude product (colourless oil) (188 mg, 66%)
was pure enough and was used without further purification for
the next step. Sodium hydride (60% dispersion in mineral oil,
20 mg, 0.50 mmol, 2 equiv) was added to a solution of the
diol 11 (68 mg, 0.25 mmol) in THF (2 mL). The resulting mix-
ture was stirred for 10 min before the addition of tert-butyldi-
phenylsilyl chloride (65 mL, 0.25 mmol, 1 equiv), and the
mixture was stirred overnight. The reaction was quenched
with a saturated solution of ammonium chloride and water,
and the product was extracted with Et2O. The combined organic
layers were washed with brine, then dried over MgSO4. The two
regioisomers were separated by flash chromatography (EtOAc/
P.E. 1:9) and 50 mg of the monoprotected diol 13, 27 mg of the
monoprotected diol 12 and recovered starting material were ob-
DesseMartin periodinane (75 mg, 0.175 mmol, 2 equiv)
was added to a solution of the monoprotected diol 13 (45 mg,
0.088 mmol) in DCM (2 mL) at room temperature, and the mix-
ture was stirred for 2 h. The reaction was quenched with a satu-
rated sodium metabisulfite solution and a saturated solution of
sodium hydrogen carbonate. The product was extracted with
DCM and the combined organic layers were washed succes-
sively with water and brine. The extracts were dried over
MgSO4 and the crude product (40 mg, 90%) was used without
purification for the next step. nmax, cmꢀ1: 2930, 2857 (CeH),
1722 (CHO), 1472e1428, 1259 (CeOeC), 776.7e702.3
(SieO); [a]D þ0.27 (c 1.5); dH (CDCl3): d (9.83, 1H, CHO,
J¼4.4 Hz), m (7.66e7.68, 4H, Ar), m (7.41e7.44, 6H, Ar),
m (4.28e4.29, 1H, H4), m (3.65e3.71, 2H, CH2OTBDPS), m
(2.64e2.73, 1H, H1), m (2.32e2.46, 1H, H2), m (2.00e2.16,
0
2H, H3 and H5), m (1.82e1.97, 2H, H5 , CH2CH2OTBDPS),
m (1.62e1.74, 1H, CH2CH2OTBDPS), m (1.40e1.47, 1H,
0
H3 ), s (1.07, 9H, (CH3)3), s (0.89, 9H, (CH3)3), s (0.06e0.07,
3Hþ3H, CH3); dC (CDCl3): 205.7 (CHO), 136.0 (Aro), 134.2
(Ari), 130.0 (Arp), 128.1 (Arm), 73.5 (C4), 63.1 (CH2OTBDPS),
53.3 (C1), 42.1 (C3), 37.8 (C2), 37.3 (C5), 34.5
(CH2CH2OTBDPS), 27.3e26.2 (t-Bu), 19.6e18.4 (C(Me)3),
ꢀ4.4 s (SiMe2); m/z (CIMS): 529 (MHþþNH4þ, 30), 528
(MþþNHþ4 , 64), 512 (MHþ, 39), 511 (Mþ, 80), 497 (40), 453
(18), 433 (33), 391 (53), 321 (36), 301 (30), 255 (100), 216
(16); C30H47O3Si2 (MHþ) requires 511.306178, found:
511.305298.
tained as colourless oils (60% overall). Data for 13: nmax, cmꢀ1
:
3368 (OH), 2930, 2858 (CeH), 1472e1428, 1257 (CeOeC),
1113e822.0e701 (SieO); dH (CDCl3): m (7.66e7.68, 4H,
Ar), m (7.37e7.42, 6H, Ar), m (4.28e4.29, 1H, H4), m
(3.65e3.71, 4H, CH2OTBDPS, CH2OH), br s (3.33, 1H, OH),
m (2.09e2.16, 1H, H2), m (2.00e2.06, 3H, H1 and H3, H5), m
(1.88e1.94, 1H, CH2CH2OTBDPS), m (1.70e1.76, 1H,
0
0
CH2CH2OTBDPS), br d (1.55, 1H, H3 , J3/3 ¼11.0 Hz), m
0
(1.32e1.37, 1H, H5 ), s (1.05, 9H, (CH3)3), s (0.88, 9H,
3.14. Synthesis of (1R,2R,4S)-4-(tert-butyl-dimethyl-
silanyloxy)-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-
cyclopentanecarbaldehyde 15
(CH3)3), s (0.05e0.6, 3Hþ3H, CH3); dC (CDCl3): 136.0
(Aro), 134.4 (Ari), 129.9 (Arp), 128.0 (Arm), 73.5 (C4), 64.2
(CH2OTBDPS), 64.0 (CH2OH), 43.2 (C2), 43.0 (C3), 41.5
(C5), 38.3 (C1), 33.8 (CH2CH2OTBDPS), 27.3e26.2 (t-Bu),
19.6e18.4 (C(Me)3), ꢀ4.42, ꢀ4.51 (2s, SiMe2); m/z (CIMS):
513 (MHþ), 391 (15), 275 (39); C30H49O3Si2 (MHþ) requires
513.322028, found: 513.322723; [a]D ꢀ0.42 (c 2.15). Data
for 12: nmax, cmꢀ1: 3349.7 (OH), 2930.0, 2857.5 (CeH),
DBU (22 mL, 0.147 mmol, 2.5 equiv) was added to a solution
of the aldehyde 14 (30 mg, 0.059 mmol) in THF (1.5 mL) and
the mixture was stirred for 4 h at room temperature. The reac-
tion was quenched carefully with a 1 M HCl solution until pH
4. The product was extracted with Et2O, and the combined

3540
D. Cousin, J. Mann / Tetrahedron 64 (2008) 3534e3540
organic extracts were washed with NaHCO3, then with brine
and were dried over MgSO4. After evaporation of the solvent,
26 mg of product 15 was obtained (88%) as a colourless oil.
nmax, cmꢀ1: 2957, 2929e2857 (CeH), 1725 (CHO), 1472e
1428, 1259 (CeOeC), 739e702 (SieO); [a]D ꢀ7.68 (c
1.25); dH (CDCl3): d (9.60, 1H, CHO, JCHO/1¼2.8 Hz), m
(7.66e7.68, 4H, Ar), m (7.38e7.40, 6H, Ar), m (4.21e4.23,
1H, H4), m (3.64e3.71, 2H, CH2OTBDPS), dddd (2.68, 1H,
H1, J1wJ2wJ3¼8.5 Hz, J1/CHO¼2.8 Hz), m (2.27e2.31, 1H,
H2), m (2.01e2.07, 1H, H3), m (1.94e1.99, 1H, H5), m
Acknowledgements
D.C. thanks the McClay Trust for a studentship and we
thank Dr. M. Nieuwenhuyzen for the X-Ray structural studies.
References and notes
1. Newton, R. F.; Paton, J.; Reynolds, D. P.; Young, S.; Roberts, S. M.
J. Chem.Soc., Chem. Commun. 1979, 908e909.
2. Cotterill, I. C.; MacFarlane, E. L. A.; Roberts, S. M. J. Chem.Soc., Perkin
Trans. 1 1988, 3387e3391.
0
(1.66e1.84, 3H, CH2CH2OTBDPS, H5 ), m (1.28e1.36, 1H,
3. Dawson, M. J.; Lawrence, G. C.; Lilley, G.; Todd, M.; Noble, D.; Green, S. M.;
Roberts, S. M.; Wallace, T. W.; Newton, R. F.; Carter, M. C.; Hallet, P.; Paton,
J.;Reynolds, D.R.;Young, S.J.Chem. Soc., PerkinTrans. 11983, 2119e2125.
4. Davies, H. G.; Gartenmann, T. C. C.; Leaver, J.; Roberts, S. M.; Turner,
M. K. Tetrahedron Lett. 1986, 27, 1093e1094.
0
H3 ), s (1.04, 9H, (CH3)3), s (0.86, 9H, (CH3)3), s (0.03,
3Hþ3H, CH3); dC (CDCl3): 202.5 (CHO), 135.0 (Aro), 133.8
(Ari), 128.6 (Arp), 126.7 (Arm), 72.1 (C4), 61.5 (CH2OTBDPS),
55.0 (C1), 40.9 (C3), 37.9 (CH2CH2OTBDPS), 35.4 (C5), 34.3
(C2), 25.8e24.8 (t-Bu), 19.1e17.8 (C(Me)3), 0.00 to ꢀ5.8 s
(SiMe2); m/z (CIMS): 529 (MHþþNH4þ, 30), 528
(MþþNHþ4 , 64), 512 (MHþ, 39), 511 (Mþ, 80), 497 (40), 453
(18), 433 (33), 391 (53), 321 (36), 301 (30), 255 (100), 216
(16); C30H47O3Si2 (MHþ) requires 511.306178, found:
511.305298.
5. Kashihara, H.; Suemune, H.; Kawahara, T.; Sakai, K. J. Chem. Soc., Perkin
Trans. 1 1990, 1663e1667.
6. Kim, D.; Lee, J.; Shim, P. J.; Lim, J. I.; Doi, T.; Kim, S. J. Org. Chem.
2002, 67, 772e778.
7. Sheldrick, G. M. SHELXTL: An Integrated System for Data Collection,
Processing, Structure Solution and Refinement; Bruker Analytical X-ray
Systems: Madison, WI, 1998.