Concise synthesis of (4S,5S)-4,5-(isopropylidenedioxy)-2-cyclopentenone and a novel C2-symmetric ketone

Article abstract of DOI:10.1016/S0957-4166(97)00153-5

A new and concise synthesis of the useful synthetic intermediate 1 is described which also allows access to a novel C₂-symmetric ketone 2. The route relies on the Sharpless asymmetric dihydroxylation of fulvenes.

Full text of DOI:10.1016/S0957-4166(97)00153-5

Tetrahedron: Asymmetry, Vol. 8. No. 10, pp. 1677-1684, 1997
@
1997 Elsevier Science Ltd. All rights reserved.
) Pergamon
~
Printed in Great Britain
0957-4166/97 $1700 + 0.00
PII: S0957-4166(97)00153-5
Concise synthesis of (4S,5S)-4,5-(isopropylidenedioxy)-2-
cyclopentenone and a novel C2-symmetric ketone
Alan Armstrong * and Barry R. Hayter
Department of Chemistry, University of Nottingham, Nottingham NG7 2RD, UK
Abstract: A new and concise synthesis of the useful synthetic intermediate 1 is described
which also allows access to a novel C2-symmetric ketone 2. The route relies on the
Sharpless asymmetric dihydroxylation of fulvenes. (~) 1997 Elsevier Science Ltd
Introduction
Despite having several potential uses in asymmetric synthesis, very few examples of chiral, C2-
symmetrical ketones are known.l As part of our investigations into asymmetric oxidation via chiral
dioxiranes, we wished to examine the ketone 2 as a promoter of the epoxidation of alkenes by Oxone®.2
Ketone 2 is conformationally well defined, and epimerisation cx-to the carbonyl is prevented because
of the high strain inherent in a trans-fused bicyclo[3.3.0] ring system. Moreover, we envisaged that
the presence of ~x-oxygens should increase the susceptibility of the carbonyl to nucleophilic attack,
a strategy that has since proved fruitful for Yang and co-workers) A non-C2-symmetric, fructose-
derived ketone with similar design features to ours has recently been reported to provide excellent
levels of enantioselectivity in the asymmetric epoxidation of trans-disubstituted alkenes.4
We expected that 2 could be accessed via cis-dihydroxylation of enone 1 with subsequent acetonide
protection (Scheme 1). Enone 1 is an important synthetic intermediate, for example in prostaglandin
synthesis, and so several routes have appeared in the literature for its preparation in enantiomerically
pure form.5 For example, D-ribose can be converted into 4 steps into the lactone 3, which reacts
with a lithiated phosphonate to give 1 (Scheme 2).6 In our hands, however, this final step was
extremely unreliable and gave low and variable yields (0-30%). A second reported route from D-
ribose (Scheme 3) also gave low yields (27% in our hands) for the final step.7 Hudlicky has reported a
synthesis of 1 starting from 4, the product of microbial cis-dihydroxylation of toluene (Scheme 4), but
the final ring closure is again reported to be unreliable.8 This problem is reduced if the chlorobenzene
derivative is used instead.9
O
O
o.--
i ~ ' i " ~.....
c ~ -
o
%o
%o
1
2
Scheme 1.
O
~
OCH3
4
stops
LtCHzP(O)(OCH3,1.~
D-nbose
D
•
oxo
Scheme 2.
* Corresponding author. Email: Alan'Armstr°ng@n°ttinghamac'uk
1677

A. ARMSTRONG and B. R. HAYTER
OAe
1678
5
slops
N a O M e , M o O H
~
D-ribose
I
oxo
S c h e m e 3.
b
I
4
S c h e m e 4.
In view of our difficulties in obtaining reasonable quantities of enantiomerically enriched 1 by
literature routes, we developed and report here a reliable new approach which also allowed access to
our initial target, the C2-symmetrical ketone 2.
Results and discussion
Our route (Scheme 5) starts with the fulvene 5, obtained by condensation of cyclopentadiene with
an aliphatic aldehyde. 10 Our first experiments utilised the octaldehyde-derived fulvene 5a. As reported
by Sharpless,11 asymmetric dihydroxylation of 5a in the presence of the (DHQD)2PHAL ligand
selectively occurs on the ring olefin anti- to the exocyclic alkene substituent, and subsequent acetonide
protection of 6a gives 7a. Sharpless reports that this dihydroxylation proceeds with 80% ee.ll We
now wished to examine a second dihydroxylation of compounds of type 7 in the hope that this would
offer a general and enantioselective approach to polyhydroxylated cyclopentane derivatives, including
2. We hoped that second dihydroxylation of 7a would be regioselective for either of the two olefins:
both of the possible resulting diols would be synthetically useful (vide infra). In the event, osmylation
of 7a in the presence of an achiral ligand (quinuclidine) gave an inseparable 48:52 mixture of 8a and
9a according to 1H NMR analysis of the crude reaction mixture (67% yield). Acid-catalysed reaction
of this mixture with 2,2-dimethoxypropane effected selective protection of 8a, allowing separation
of 10a from unreacted 9a. The configuration of the exocyclic diol in 9a is assigned based on the
assumption that dihydroxylation of 7a occurred predominantly on the less hindered, convex face of
the bicyclic system.
As we had anticipated, both 9a and 10a proved synthetically useful. Periodate cleavage of diol
9a gave the known enone 1. Based on comparison of its optical rotation to the literature value, our
material had 78% ee, which is in good agreement with the enantiomeric excess of 80% reported by
Sharpless for the asymmetric dihydroxylation of 7a.l 1
Despite several attempts, we were unable to effect dihydroxylation of enone 1 and so we examined
10a as a potential precursor of our target C2-symmetrical ketone 2. We were pleased to find that
ozonolysis of 10a with reductive work-up (triphenylphosphine) gave 2, presumed to have 78% ee.
We next examined asymmetric dihydroxylation of 7a in the presence of the chiral ligands
(DHQD)2PHAL and (DHQ)2PHAL, constituents of the commercial AD-mixes.12 As well as poten-
tially providing products with higher enantiomeric excess, it was hoped that this might improve the
regioselectivity of the dihydroxylation in favour of one of the two alkenes. In the event, however,
dihydroxylation of 7a in the presence of (DHQ)2PHAL proceeded with no significant change in ratio
of 8a to 9a (46:54). Conversion to the enone 1 and bisacetonide 10a by the procedures described
above and measurement of their optical rotation indicated that there had been no improvement in
enantiomeric excess over the use of quinuclidine as ligand. Similarly, when (DHQD)2PHAL was used
as ligand, there was little change in ratio of 8a to 9a (48:52) and no improvement of the enantiomeric

(4S,5S)-4,5-(isopropylidenedioxy)-2-cyclopentenone
1679
HO
R
HO . , . , @R
b
a
•
/
HO
5
g
7
8
a
b
R = n-heptyl
R = tea-butyl
g
t°
l
O
~>~°".,~['~
0 '""
y
%
0
2
"
f
O . , ' " J ~ O
°-¢.
11
10
Scheme 5. Reagents and Conditions: For compounds a (R=n-heptyl): (a) K2Os(OH)4, (DHQD)2PHAL, K3Fe(CN)6,
K2CO3, CH3SO2NH2, tBuOH, H20 then Na2SO3, 36%; (b) 2,2-Dimethoxypropane, pTsOH, CH2C12, 93%; (c) K2Os(OH)4,
quinuclidine, K3Fe(CN)6, K2CO3, CH3SO2NH2, tBuOH, H20 then Na2SO3; (d) 2,2-Dimethoxypropane, pTsOH, CH2CI2;
(e) NalO4, THF/H20, 18% over 3 steps from 7a; (f) 03 then Ph3P, 15% over 3 steps from 7a
For compounds b (R=tert-butyl): (a) K2Os(OH)4, (DHQD)2PHAL, K3Fe(CN)6, K2CO3, CH3SO2NH2, tBuOH, H20
then Na2SO3, 40%; (b) 2,2-Dimethoxypropane, pTsOH, CH2CI2. 85%; (c) K2Os(OH)4, quinuclidine, K3Fe(CN)6, K2CO3,
CH3SO2NH2, tBuOH, H20 then Na2SO3 (38% of 8a, 31% of 9a); (d) 2,2-Dimethoxypropane, pTsOH, CH2C12. 100%;
(e) NalO4, THF/H20, 60%: (f) 03 then Me2S. 42%.
excess of 1 or 10a. These results suggest that the influence of the chiral dihydroxylation system is
low relative to that of the inherent chirality of 7a.
In a final attempt to improve the regioselectivity of dihydroxylation of 7, the route was repeated
starting from the ten-butyl fulvene 5b. While no improvement in regioselectivity or enantioselectivity
of dihydroxylation was observed (78% yield of a 55:45 mixture of 8b:9b using OSO4, quinuclidine),
the two diols 8b and 9b were now separable by flash chromatography. Based on determination of their
specific rotation, both products had 84% ee. A single recrystallisation from ether-petrol improved the
ee of 8b to 93% and that of 9b to 91%, again based on optical rotation measurements. Additional
recrystallisation would doubtless have further increased the optical purities.
Periodate cleavage of 9b did not occur at room temperature, but was cleanly effected upon heating to
55°C. Enone 1 was thus obtained in 60% yield. Acetonide protection of 8b afforded 10b. Ozonolysis
of 10b was lower yielding than for 10a, and the product ratio was found to be dependent upon the
work-up procedure. Use of triphenylphosphine as reducing agent afforded a complex mixture of which
the lactone 11 (37%) was the major component. Quenching with dimethylsulfide as an alternative
again gave 11 as the major product (49%), but also provided the desired ketone 2 (42%).
In conclusion, we have developed a concise and reliable route to the synthetically useful enone
1, as well as the novel C2-symmetrical ketone 2, both in enantiomerically enriched form. We have
found our route to 1 to be more amenable to the preparation of quantities of 1 than those already in
the literature: an additional advantage is that it should be possible to obtain the other enantiomer of
1 by using the AD-mix-0t reagent in the dihydroxylation of 5.]1 The second dihydroxylation of the
fulvene-derived acetonides 7 also offers a potential approach to other polyhydroxylated cyclopentane
derivatives. Applications of the novel C2-symmetrical ketone 2 in asymmetric synthesis are under
investigation and will be reported elsewhere.
Experimental
General details
NMR spectra were recorded on Jeol GX 270, Jeol EX 270, Jeol EX 400, Bruker AM 400 or
Bruker DRX 500 spectrometers. J values are measured in Hertz and are quoted to the nearest 0.5 Hz.
Multiplicities in 13C spectra were determined by DEPT experiments. Infra red spectra were recorded on

1680
A. ARMSTRONG and B R. HAYTER
a Perkin-Elmer 1605 FT-IR spectrometer. Microanalyses were performed in the School of Chemistry,
University of Bath, and the Department of Chemistry, University of Nottingham. Melting points were
recorded on a Kofler hot stage apparatus and are uncorrected. Optical rotations were recorded on a
JASCO DIP-310 spectrometer. Flash column chromatography was performed using Matrex silica Si.
Where appropriate the silica was neutrafsed by flushing it once with a 1% solution of triethylamine.
Petrol refers to light petroleum b.p. 40-60°C.
n-Heptylfulvene 5a
To a stirred solution of freshly cracked cyclopentadiene (20 ml, 0.244 tool) and octyl aldehyde (24
ml, 0.15 mol) in methanol (170 ml) was added pyrrolidine (20 ml, 0.24 mol). After 30 minutes acetic
acid (15 ml, 0.26 tool) was added dropwise. The solution was stirred for 10 minutes, water (50 ml)
was added, and the mixture was extracted three times with ether. The combined organic extracts were
washed with brine, dried over MgSO4, fltered and the solvent removed under reduced pressure to
give a yellow oil. Flash column chromatography (petrol) yielded 5a (20.4 g, 77%) as a yellow oil,
Vmax (film)/cm-1 2925, 1649, 1474, 1380; 8H (270 MHz, CDCI3) 6.57-6.41 (4H, m), 6.23-6.19 (1H,
m), 2.57-2.49 (2H, dt, J 7.5, 7.5), 1.55-1.48 (2H, m), 1.43-1.28 (SH, m), 0.88 (3H, t, J 6.5).
(1 R, 2S, 5E)-5- Octy'lidene-cyclopen t-3- ene- 1,2-diol 6aI!
To a stirred biphasic mixture of water (225 ml) and ten-butanol (225 ml) was added potassium
osmate dihydrate (343 rag, 0.93 mmol), potassium ferricyanide (48 g, 0.18 mol), (DHQD)2PHAL
(1.13 g, 1.50 mmol), potassium carbonate (25 g, 0.18 tool) and methane sulfonamide (11 g, 0.12
mol). After 15 minutes fulvene 5a (10.2 g, 0.06 mol) was added, and the reaction mixture stirred for
a further 22 hours. Sodium sulfite (84 g, 0.59 tool) was added and the mixture stirred for a further 15
minutes before extracting three times into ethyl acetate. The combined organic extracts were washed
with 2M KOH, dried over MgSO4, filtered, and the solvent removed under reduced pressure. Flash
column chromatography (40% ether-petrol) gave diol 6a (4.34 g, 36%) as a colourless solid, [e~]to9
+63.7 (c 1.1, EtOH); 8H (270 MHz, CDCI3) 6.55 (IH, d, J 6.0), 6.05 (1H, dt, J 6.0, 1.5), 5.57 (1H,
dt, J 6.5, 1.5), 4.59 (1H, m), 4.46 (1H, t, J 6.5), 2.37 (1H, d, J 6.5), 2.27 (1H, d, J 7.5), 2.16 (2H, dt,
J 7.5, 7.5), 1.42-1.20 (10H, m), 0.88 (3H, t, J 7.0).
(3S,4R,5E)-3,4-( Isopropylidenedio©,)- 5-octylidenecyc lopentene 7a
To a solution of 6a (4.67 g, 22.2 mmol) in dichloromethane (100 ml) at -5°C was added 2,2-
dimethoxypropane (8 ml, 65 mmol) and para-toluenesulfonic acid (10 mg, 0.06 mmol). The reaction
mixture was allowed to warm to room temperature while stirring for 3 hours. The solvent was removed
and the residue purified by flash column chromatography (10% ether-petrol) to yield 7a (5.15 g, 93%)
as a colourless oil, [e~]~9 +114.0 (c 1.14, CHC13); Vmax (film)/cm -j 2926, 2855, 1457, 1369, 1262,
1235, 1206, 1156, 1051; 8H (270 MHz, CDC13) 6.46 (1H, d, J 6.0), 6.03 (1H, d, J 6.0), 5.66 (1H, t,
J 7.5), 5.11 (1H, d, J 6.0), 4.88 (IH, d, J 6.0), 2.17 (2H, dr, J 7.5, 7.5), 1.41 (3H, s), 1.39 (3H, s),
1.20-1.35 (10H, m), 0.87 (3H, t, J 6.5); •C (67.9 MHz, CDCI3) 142.0 (s), 134.6 (d), 131.4 (d), 127.6
(d), 111.0 (s), 82.8 (d), 79.7 (d), 31.8 (t), 29.5 (t), 29.23 (t), 29.18 (t), 29.12 (t), 27.4 (q), 25.9 (q),
22.6 (t), 14.4 (q); m/z (FAB+) 250 (M+, 5%), 235 (M-CH3, 30), 193 (M~C3HsO, 100%); (Found:
M÷, 250.1926. C16H2602 requires 250.1933).
(1R,2IL3R,4R)-l,2:3,4-bis-(lsopropylidenedioxy)-5-oco, lidenecyclopentane lOa and (4S,5S)-4,5-
(isopropylidenedioxy)-2-cyclopentenone 1
To a biphasic mixture of ten-butanol (11 ml) and water (11 ml) was added potassium osmate
dihydrate (8 rag, 0.02 mmoi), quinuclidine (3.6 rag, 0.05 retool), potassium ferricyanide (1.29 g, 6.42
mmol), potassium carbonate (0.89 g, 6.42 mmol) and methane sulfonamide (204 rag, 4.28 mmol).
The mixture was stirred at room temperature for 15 minutes and 7a (536 mg, 2.14 mmol) added.
The reaction mixture was stirred for 40 hours and sodium sulfite (2 g, 15.8 mmol) added. After a
further 15 minutes, the mixture was extracted into ethyl acetate, dried over MgSO4, filtered, and the

(4S.5S)-4,5-(isopropylidenedioxy)-2-cyclopentenone
1681
solvent removed under reduced pressure. Flash column chromatography (50% ether-petrol) yielded
an inseparable mixture of diols 8a and 9a as a colourless solid (405 mg, 67%; 8a:9a=42:58 by IH
NMR) which was reacted on without further purification.
A solution of the mixture of diols prepared above (405 rag, 1.42 mmol) in dichloromethane (15
ml) was cooled to -5°C in an ice-salt bath and 2,2-dimethoxypropane (791al, 0.64 retool) and para-
toluenesulfonic acid (5 rag) added. The reaction was stirred at -5°C for 4 hours, being monitored by
taking aliquots and measuring the disappearance of the peak at 4.9 and the appearance of peaks at 5.04
and 5.12 ppm in the IH NMR spectrum. The reaction mixture was absorbed onto silica and purified
by flash column chromatography. Elution with 5% ether-petrol gave 10a (105 mg, 15% from 7a) as
a colourless oil, Rf 0.86 in 50% ether-petrol; [o~]~° +96.4 (c 1.16, CHC13) @ ca. 78% ee. (Found
C, 70.4; H, 9.95. C19H3204 requires C, 70.3; H; 9.95%); Vmax (film)/cm -I 2986, 2927, 2855, 1456,
1379, 1370, 1238, 1161, 1067; 6H (400 MHz, CDCI3) 5.88 (IH, t, J 7.5), 5.20 (IH, d, J 6.0), 4.98
(IH, d, J 5.5), 4.53 (1H, d, J 6.0), 4.48 (1H, d, J 5.5), 2.28-2.21 (2H, m), 1.40 (3H, s), 1.39 (3H, s),
1.33 (3H, s), 1.32 (3H, s), 1.32-1.25 (10H, m), 0.88 (3H, t, J 7.0); 6c (67.9 MHz, CDCI3) 139.7 (s),
135.4 (d), 111.2 (s), 110.9 (s), 82.8 (d), 82.6 (d), 81.6 (d), 78.7 (d), 31.8 (t), 29.22 (t), 29.17 (t), 29.11
(t), 29.0 (t), 27.4 (q), 27.0 (q), 25.6 (q), 25.0 (q), 22.6 (t), 14.1 (q); m/z (FAB) 325 (MH+, 12%), 323
((M+-I), 15), 309 (M+-CH3, 44), 209 (MH+-2×acetone, 100).
Elution with 50% ether-petrol gave 9a (210 mg), Rf 0.2 in 50% ether-petrol, contaminated with
ca. 15% of 8a. This was reacted on without further purification. NMR data for 9a: 6H (270 MHz,
CDCI3) 6.02 (IH, dd, J 6.0, 2.0), 5.76 (IH, d, J 6.0), 5.28 (IH, dd, J 6.0, 2.0), 4.54 (1H, d, J 6.0),
3.80-3.60 (1H, m), 3.00 (1H, s), 2.81 (IH, d, J 4.0), 1.61-1.28 (18H, m), 0.88 (3H, t, J 7.0); 6C (67.9
MHz, CDCI3) 136.3 (d), 135.0 (d), 113.5 (s), 87.8 (d), 87.8 (s), 84.3 (d), 74.1 (d), 32.2 (t), 30.3 (t),
30.0 (t), 29.6 (t), 27.3 (q), 26.5 (t), 25.7 (q), 23.0 (t), 14.4 (q).
To a stirred solution of the impure 9a obtained above ( 180 mg) in tetrahydrofuran ( 10 ml) and water
(2.5 ml) was added sodium periodate (280 mg, 1.31 mmol). After 18 hours the reaction mixture was
extracted into ethyl acetate, washed with saturated sodium thiosulfate solution, saturated NaHCO3
solution and brine, dried over MgSO4, filtered, and the solvent removed under reduced pressure. Flash
column chromatography (25% EtOAc in petrol) gave 1 (50 mg, 18% from 7a) as a colourless solid,
[oc] 2° +55.9 (c 1,107, CHC13) (lit.5c [o~]~5 +71.3 (c 0.92, CHCI3)). This suggests that the asymmetric
dihydroxylation of 5a proceeded with 78% ee. ~iH (270 MHz, CDC13) 7.60 (IH, dd, J 6.0, 2.0), 6.20
(IH, d, J 6.0), 5.25 (1H, dd, J 5.5, 2.0), 4.45 (IH, d, J 5.5), 1.40 (6H, s).
(2S,3S, 4S,5S)-2,3:4,5-bis-( Isopropylidenenediox3,)cyclopentanone 2
10a (84 mg, 0.26 mmol) was dissolved in dichloromethane (5 ml) and the solution cooled to -78°C.
Ozone-enriched 02 was bubbled through the solution until a deep blue colour persisted, followed
by a stream of 02 until the blue colour disappeared. Triphenylphosphine (250 mg, 0.95 mmol) was
added, and the reaction was stirred for 30 minutes while allowing to warm to room temperature. The
solvent was removed under reduced pressure. Flash column chromatography (25% ether-petrol) gave
2 (58 mg, 98%) as a white solid, m.p. 72-80°C. [o~]~° +124.3 (c 0.63, CHCI3) @ ca. 78% ee; Vmax
(film)/cm -l 2986, 1780, 1375, 1212, 1150, 1060; 8H (270 MHz, CDCI3) 4.68 (2H, d, J 5.0), 4.58
(2H, d, J 5.0), 1.41 (6H, s), 1.36 (6H, s); 5C (67.9 MHz, CDCI3) 208.5 (s), 113.0 (s), 77.8 (d), 77.5 (d),
26.6 (q), 24.6 (q); m/z (EI) 228 (M+, 6%), 213 (M+-CH3, 8%), 100 (100%); Found: M+, 228.0998.
C11H1605 requires: M, 228.0998.
(~~L2R~3R~ 4R)-3~ 4-( ~s~pr~pylidenedi~©~)-5-( 2'~2'-dimethy~pr~pylidene )-1~2-~cl~pentanedi~ 8b and
(1R, 1'S• 4S•5S )-•-( •'-hydr•xy•2••2'-dimethylpr•pyl
)-4•5-( is•pr•pylidenedi•xy )-cycl•pent- 2-en•l 9b
(i) Dihydroxylation offulvene 5b11
To a stirred biphasic mixture of water (370 ml) and tert-butanol (370 ml) at room temperature
were added potassium osmate dihydrate (328 mg, 0.89 mmol), potassium ferricyanide (72.8 g, 221
mmol), (DHQD)2PHAL (918 mg, 1.18 mmoi), potassium carbonate (30.6 g, 221 mmol) and methane

1682
A. ARMSTRONG and B. R, HAYTER
sulfonamide (14.2 g, 0.15 tool). After 15 minutes fulvene 5b 10 (10.0 g, 74.5 mmol) was added, and
the reaction mixture stirred for a further 22 hours. Sodium sulfite (112 g, 0.89 mol) was added and the
mixture stirred for a further 15 minutes before extracting three times into ethyl acetate. The combined
organics were washed with 2M KOH, dried over MgSO4, filtered, and the solvent removed under
reduced pressure. Flash column chromatography (40% ether-petrol) gave 6b (5.00 g, 40%) as a pale,
viscous oil which was reacted on without further purification. IH NMR: ~iH (270 MHz, CDCI3) 6.77
(1H, d, J 6.5), 6.07 (IH, d, J 6.0), 5.58 (IH, s), 4.52-4.46 (IH, m), 4.42--4.36 (1H, m), 2.34 (IH, d,
J 7.0), 2.25 (IH, d, J 7.5), 1.14 (9H, s).
(ii) Acetonide protection of 6b
To a solution of 6b (5.00 g, 29.6 retool) in acetone (150 ml) in an ice-salt bath was added 2,2-
dimethoxypropane ( 13 ml, 105 retool) and para-toluenesulfonic acid ( 10 rag, 0.06 mmol). The reaction
was stirred for 1 hour and the solvent removed under reduced pressure. The residue was purified by
flash column chromatography (5% ether-petrol) to yield 7b (5.15 g, 85%) as a colourless oil which
was reacted on without further purification. Vmax (film)/cm I 2957, 1458, 1368, 1205, 1050; 6H (270
MHz, CDC13) 6.67 (1H, d, J6.0), 6.05 (IH, dt, J6.0, 2.0), 5.68 (IH, br s), 5.02 (IH, dd, J5.5, 2.0),
4.84 (1H, d, J5.5), 1.41 (3H, s), 1.39 (3H, s), 1.16 (9H, s); 6c (67.9 MHz, CDC13) 139.4 (s), 138.6
(d), 135.8 (d), 132.2 (d), 110.9 (s), 82.3 (d), 82.0 (d), 34.4 (s), 31.5 (q), 28.0 (q), 26.5 (q).
(iii) Dihydroxylation of 7l,
To a stirred, biphasic mixture of tert-butanol (125 ml) and water (125 ml) was added potassium
osmate dihydrate (37 mg, 0.10 mmol), potassium ferricyanide (24.7 g, 76.2 mmol), quinuclidine (28
mg, 0.26 mmol), potassium carbonate (10.4 g, 74.3 mmol), and methane sulfonamide (2.38 g, 25
mmol). The mixture was stirred for 15 minutes, diene 7b (5.10 g, 25 mmol) was added, and the
reaction was stirred for a further 46 hours. Sodium sulfite (37.5 g, 0.30 mmol) was added, and after a
further 60 minutes the mixture was extracted into ethyl acetate. The combined organics were washed
with 2M KOH solution, dried over MgSO4, filtered, and the solvent removed under reduced pressure.
Flash column chromatography (40% ether-petrol) yielded two compounds. The less polar compound
9b (1.88 g, 31%), Rf 0.3, 50% ether-petrol, was isolated as a colourless solid, m.p. 70-76°C, [o~]~°
+86.5 (c 0.992, MeOH) @ 84% ee. (Found C, 64.2; H, 9.00. CI3H2204 requires C, 64.4; H; 9.15%).
Vmax (film)/cm -l 3375, 3302, 2949, 1374, 1259, 1056; 5H (270 MHz, CDC13) 6.06 (1H, dt, J 6.0,
1.0), 6.00 (1H, dd, J 6.0, 2.0), 5.23 (IH, ddd, J 5.5, 2.0, 1.0), 4.46 (1H, d, J 5.5), 3.62 (IH, d, J 5.5),
2.89 (1H, s), 2.85 (IH, d, J 5.5), 1.45 (3H, s), 1.36 (3H, s), 1.07 (9H, s); ~iC (67.9 MHz, CDCI3)
137.1 (d), 134.4 (d), 112.0 (s), 89.2 (d), 88.0 (s), 83.3 (d), 79.3 (d), 36.0 (s), 28.3 (q), 27.6 (q), 26.2
(q); m/z (FAB) 243 (MH+, 8%), 185 (MH+-tBu, 100%).
A single recrystallisation (ether/petrol) gave colourless needles (1.29 g, 22%), m.p. 76-78°C, [c~]19
+93.7 (c !.002, MeOH) @ 91% ee. This value of 91% ee was obtained by conversion to enone 1
and comparison of the optical rotation of the resulting sample of 1 to the literature value. The ee
of the unrecrystallised sample of 9b was then estimated by comparing its optical rotation to that of
recrystallised 9b.
The more polar compound 8b (2.27 g, 38%), Rf 0.15 in 50% ether-petrol, was isolated as a colourless
solid m.p. 90-95°C, [o¢]2° +76.6 (c 0.984, MeOH) @ 84% ee; Vmax (film)/cm -! 3350, 2958, 1371,
1207, 1070; •H (270 MHz, CDCI3) 5.90 (IH, t, J 1.5), 4.93 (IH, d, J 6.5), 4.89 (1H, br d, J 4.5),
4.45 (1H, dd, J 6.5, 5.0), 4.06 (1H, br d, J 5.0), 3.25 (IH, d, J 4.5), 2.62 (IH, br s), i.46 (3H, s), 1.41
(3H, s), 1.18 (9H, s); 6C (67.9 MHz, CDCI3) 146.4 (d), 135.2 (s), 112.5 (s), 83.8 (d), 81.8 (d), 78.5
(d), 71.4 (d), 34.0 (s), 30.6 (q), 27.7 (q), 25.7 (q); rrdz (FAB) 265 (MNa+, 8%), 243 (MH+, 15), 185
(MH+-tBu, 26), 167 (M+-tBu-H20, 100%); Found: MH+, 243.1596. C13H2304 requires: 243.1548.
A single recrystallisation from ether/petrol gave colourless plates (1.76 g, 29%), m.p. 100-102°C,
[a]lD9 +84.7 (C 0.990, MeOH) @ 93% ee. This value of 93% ee was obtained by conversion to ketone

(4S,5S)-4,5-(isopropylidenedioxy)-2-cyclopentenone
1683
2 and comparison of the optical rotation of the resulting sample of 2 to that obtained previously. The
ee of the unrecrystallised sample of 8b was then estimated by comparing its optical rotation to that
of recrystallised 8b.
Enone I from diol 9b
To a solution of 9b after recrystallisation (91% ee) (188 mg, 0.78 mmol) in tetrahydrofuran (4 ml)
and water (2 ml) was added NalO4 (332 mg, 1.55 mmol). The solution was heated to 55°C for 18
hours. The resultant suspension was cooled to room temperature, filtered through celite, extracted into
ether. The combined organics were washed with brine, dried over MgSO4, filtered, and the solvent
removed under reduced pressure. Flash column chromatography (25% ether-petrol) gave enone 1 (72
mg, 60%) as a colourless solid, [a] 2° +64.8 (c 1.10, CHC13) @ 91% ee, identical by IH NMR to the
sample prepared previously.
(~R~2IL3~L 4R)~2: 3~4~bis~(~s~pr~py~idenedi~.~)~5-( 2~2~dimethy~pr~pylidene)cycl~pentane lob
To a solution of diol 8b after recrystallisation (93% ee) (1.75 g, 7.22 mmol) in acetone (75 ml)
at 0°C was added 2,2-dimethoxypropane (5 ml, 41 mmol) and para-toluenesulfonic acid (10 rag).
After 1 hour the solvent was removed under reduced pressure. Flash column chromatography (10%
ether-petrol) gave 10b (2.03 g, 100%) as colourless needles, m.p. 31-32°C. [a] 2° +173.9 (c 0.74,
MeOH) @ 93% ee. (Found C, 67.8; H, 9.45. C16H2604 requires C, 68.1; H, 9.30%); Vmax (film)/cm -1
2955, 1370, 1209, 1162, 1067, 874; 6H (270 MHz, CDC13) 5.83 (1H, t, J 1.5), 5.38 (1H, dt, J 6.0,
1.5), 4.96 (1H, br d, J 5.5), 4.53 (1H, d, J 6.0), 4.41 (1H, dd, J 5.5, 0.5), 1.41 (3H, s), 1.38 (3H, s),
1.33 (3H, s), 1.32 (3H, s), 1.18 (9H, s); 8c (67.9 MHz, CDCl3) 144.8 (d), 136.6 (s), 111.4 (s), 110.5
(s), 82.8 (d), 82.6 (d), 82.3 (d), 78.1 (d), 34.0 (s), 30.4 (q), 27.7 (q), 26.9 (q), 26.1 (q), 24.7 (q); m/z
(EI) 282 (M+, 2%) 267 (M+-CH3, 38), 209 (75%).
Ozonolysis of bis-acetonide lob: preparation of (3S,4S,5S.6R)-3,4:5,6-bis-(isopropylidenedioxy)-
tetrahydropyran-2-one 11 and ketone 2
(a) Reductive workup using triphenylphosphine quench
A solution of 10b (156 mg, 0.55 mmol) in dichloromethane (5 ml) was cooled to -78°C. Ozone
was bubbled through until a deep blue colour was observed, followed by a stream of 02 until the
blue coiour disappeared. Triphenylphosphine (1.0 g, 3.8 mmol) was added, and the solution allowed
to warm to room temperature. The solution was stirred for 18 hours, and the solvent removed under
reduced pressure. Flash column chromatography gave 11 (46 mg, 37%) as a white solid, m.p. 92-94°C,
[a] 2° +24.3 (c 1.058, CHC13) @ 93% ee; Vmax (film)/cm -l 2988, 2922, 2851, 1752, 1456, 1375,
1213, 1157, 1110, 1062, 1012; ~H (500 MHz, CDCI3) 5.92 (1H, d, J 2.5), 4.68 (1H, dd, J5.5, 2.5),
4.56 (1H, d, J 5.5), 4.37 (1H, t, J 2.5), 1.49 (3H, s), !.46 (3H, s), 1.42 (3H, s), 1.40 (3H, s); 8c
(125 MHz, CDC13) 166.2 (s), 112.8 (s), 111.6 (s), 99.1 (d), 74.1 (d), 71.9 (d), 70.5 (d), 27.5 (q),
26.7 (q), 25.6 (q), 25.1 (q); m/z (CI) 243 (M+, 5%), 229 (M+-CH3, 15); Found: M - C H 3+, 229.0712.
C 11H1606 requires: 229.0713.
(b) Reductive workup using dimethylsulfide quench
A solution of 10b (505 mg, 1.79 mmol) in dichloromethane (100 ml) was cooled to -78°C. A
stream of ozone was bubbled through until a deep blue coiour was observed, followed by a stream of
02 until the blue colour disappeared. Dimethylsulfide (5 ml, 68.8 mmol) was added. The solution was
stirred at - 7 8 ° C for 5 minutes, then allowed to warm to room temperature over 2 hours. The solvent
was removed under reduced pressure. Flash column chromatography (10-70% ether-petrol) gave 11
(213 mg, 49%) as a white solid and 2 (170 mg, 42%) as a white solid, rn.p. 74-80°C, [a]~° +133.5
(c 1.025, CHC13) @ 93% ee, identical by IH NMR to the sample prepared previously.

1684
A. ARMSTRONG and B. R. HAYTER
Acknowledgements
We thank the EPSRC, the DTI and a consortium of chemical companies for funding of this work
through the LINK Asymmetric Synthesis Second Core Programme. We are grateful to Dr. G. Potter
(Chiroscience) and Mr. T. Lowdon (Hicksons) for useful discussions. We also thank Prof. K.B.
Sharpless (Scripps) for helpful advice, and Dr. N.J. Turner (Edinburgh) fe: synthetic information and
a sample of the enone 1.
References
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(Received in UK 24 March 1997)