Diastereodivergent synthesis of the C9-cyclopentanone chiral building blocks

Article abstract of DOI:10.1055/s-2000-8235

Diastereodivergent synthesis the C9-cyclopentanone chiral building block, serving as the non-tryptamine moiety of the Corynanthe type indole alkaloids and the related natural products, and its diastereomer has been developed from racemic norcamphor by employing lipase-mediated resolution via an allylic acetate intermediate having a bicyclo[3.2.1]octane framework. A potential of the latter diastereomer has been demonstrated by its conversion into (-)-semburin, a monoterpene isolated from Swertia japonica previously and obtained from the C9-block.

Full text of DOI:10.1055/s-2000-8235

PAPER
1825
Diastereodivergent Synthesis of the C9-Cyclopentanone Chiral Building
Blocks
Hiroshi Nagata, Mitsuhiro Kawamura, Kunio Ogasawara*
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan
Fax +81(22)217-6845; E-mail: konol@mail.cc.tohoku.ac.jp
Received 23 June 2000; revised 24 July 2000
ly related compound2 starting from (+)-norcamphor [(+)-
1] through the C9-cyclopentanone intermediate (+)-2 af-
ter diastereocontrolled introduction of a vinyl functional-
ity (Scheme 1). Although the conversion of the key C9-
Abstract: Diastereodivergent synthesis the C9-cyclopentanone
chiral building block, serving as the non-tryptamine moiety of the
Corynanthe type indole alkaloids and the related natural products,
and its diastereomer has been developed from racemic norcamphor
by employing lipase-mediated resolution via an allylic acetate inter- block (+)-2 into the target molecules shown could be effi-
mediate having a bicyclo[3.2.1]octane framework. A potential of
the latter diastereomer has been demonstrated by its conversion into
(-)-semburin, a monoterpene isolated from Swertia japonica previ-
which still remain unsolved. One is the acquisition of the
ously and obtained from the C9-block.
ciently carried out without difficulty, the synthesis of the
block (+)-2 itself was accompanied by two difficulties
block 2 in both enantiomeric forms. In the above synthe-
Key words: lipase-mediated kinetic resolution, enantioconvergent
ses, we used (+)-norcamphor [(+)-1] generated by the ox-
synthesis, diastereoconvergent synthesis, enantiodivergent synthe-
idation of (+)-norborneol.3 Since (+)-norborneol
sis, diastereodivergent synthesis, chiral building block, ring expan-
precursor is practically produced through a reiterative li-
sion
pase-mediated kinetic resolution with loss of the (-)-
enantiomer, the enantiomeric (-)-norcamphor [(-)-1],
therefore, could not be obtained which prevents the prep-
aration of the enantiomeric C9-block (-)-2. The other one
is the lability of the stereochemistry of the second stereo-
Recently we have disclosed an unified enantiocontrolled
route to the Corynanthe type indole alkaloids1 and its bio-
genetically related natural products as well as a structural-
genic center introduced at the vicinal carbon to the carbo-
N
N
N
H
N
H
H
H
H
*
*
H
H
H
HO
HO
(–)-antirhine 3
(+)-isocorynantheol 4
OBn
*
CO2H
CO2H
H
*
O
O
N
H
H
*
(–)-kainic acid 8
(+)-norcamphor 1
(+)-C9-block 2
N
H
N
H
N
H
HO
H
*
H
O
O
OMe
*
*
N
H
H
H
H
(+)-uleine 6
(–)-quinine 7
(–)-semburine 5
Scheme 1
Scheme 1
Synthesis 2000, No. 13, 1825–1834 ISSN 0039-7881 © Thieme Stuttgart · New York

1826
H. Nagata et al.
PAPER
nyl functionality under basic conditions. This makes Resolution of (±)-12 under transesterification conditions
preservation of the newly introduced stereogenic center was first investigated. The reaction was found to proceed
extremely difficult though the introduction itself may be when (±)-12 was treated with vinyl acetate in tert-butyl
carried out in a diastereocontrolled manner on the basis of methyl ether in the presence of an immobilized lipase [Li-
the inherent convex-face selectivity of the intermediate pase PS (Pseudomonas sp., Amano)] which furnished the
lactone having a biased bicyclo[3.2.1]octane framework. enantiomerically enriched acetate (-)-13 in 47% yield
This stereochemical lability also prevents the diastereodi- leaving the enantiomerically enriched alcohol (+)-12 in
vergent synthesis of the diastereomer of the C9-block 2 at 40% recovery yield after three days at room temperature.
the second stereogenic center. In oder to circumvent these Moreover, the same reaction proceeded within two days
two difficulties, we explored an alternative procedure be- to give (-)-13 in 48% yield and (+)-12 in 46% recovery
ing capable of producing the building block 2 and its dias- yield when a different immobilized lipase, Chirazyme
tereomer in both enantiomerically pure forms by L-2 (Candida antarctica, Roche), was used in place of Li-
employing a different methodology. We report here an al- pase PS. However, as the enantiomeric excess of the prod-
ternative synthesis of the C9-block 2 and its diastereomer ucts were still less than satisfactory for practical use, 85%
29 in both enantiomeric forms in a diastereocontrolled ee for the former and ~81% ee for the latter, we gave up
manner from racemic norcamphor [(±)-1] by a sequence the transesterification method in the present study.
involving ring-expansion to the enone system, lipase-me-
diated kinetic resolution of an allylic acetate intermediate,
On the other hand, when the racemic acetate (±)-13 was
treated under hydrolysis conditions in a mixture of phos-
and the non-epimerizable introduction of second stereo-
phate buffer and acetone (10:1) in the presence of the
genic center.4
same Lipase PS, the enantiopure alcohol (-)-12 was ob-
Thus, racemic norcamphor (±)-1 was first transformed tained in 46% yield leaving the highly enantioenriched ac-
into the silyl enol ether5 9 which was then converted into etate (>95% ee) (+)-13 in 50% yield though it took
the enone6 (±)-11 having a bicyclo[3.2.1]octenone frame- 2 weeks at room temperature. Moreover, we found that
work via the cyclopropane 10 by sequential Simmons- the same reaction could be carried out in much shorter
Smith reaction and oxidative ring-expansion.7 The enone time using Chirazyme L-2 to give the alcohol6 (-)-12 and
(±)-11 was transformed into the endo-allyl alcohol6,8 (±)- the acetate6 (+)-13 both in enantiomerically pure forms in
12 which was further transformed into the allyl acetate6 yields of 39% and 40%, respectively, within two days in
(±)-13, both to be used as substrates for lipase-mediated the same phosphate buffer-acetone (10:1) solution. We
resolution. The reduction of 11 proceeded in a completely used the hydrolysis products thus obtained for practical
diastereoselective manner owing to the inherent convex- purpose. The enantiopure products obtained were next
face selectivity exerted by its bicyclo[3.2.1]enone back- transformed into the enone6 11. Thus, the alcohol 12 was
ground (Scheme 2).
oxidized under Dess-Martin conditions9 to afford the
enantiopure enone 11, while the acetate 13 was converted
O
Et2Zn
CH2I2
OTMS
OR
FeCl3
DIBAL
TMS-Cl
(±)-1
CH2Cl2
(85%)
DMF
(93%)
Et3N
Et2O
OTMS
Ac2O
Et3N
DMAP
CH2Cl2
(±)-11
(±)-10
(±)-9
(±)-12 : R=H
(±)-13 : R=Ac
(97%)
Scheme 2
O
Et2Zn
CH2I2
OTMS
OR
FeCl3
DIBAL
CH2Cl2
(85%)
TMS-Cl
Et3N
(±)-1
DMF
(93%)
Et2O
OTMS
Ac2O
Et3N
DMAP
CH2Cl2
(±)-11
(±)-10
(±)-9
(±)-12 : R=H
(±)-13 : R=Ac
(97%)
Reagents and conditions: a) for 12: vinyl acetate, t-BuOMe, Lipase PS or Chirazyme L-2; b) for 13: phosphate buffer-acetone (10:1), Chira-
zyme L-2
Scheme 3
Synthesis 2000, No. 13, 1825–1834 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Diastereodivergent Synthesis of the C9-Cyclopentanone Chiral Building Blocks
1827
into the enantiopure enone 11 by sequential alkaline meth-
anolysis and Dess-Martin oxidation (Scheme 3).
Chirazyme L-2
PdCl2(MeCN)2
(7 mol%)
OH
(+)-13
+
OAc
In order to make use of both enantiomers of the enone 11
as the single enantiomer, (+)-11 was first treated with al-
kaline hydrogen peroxide to give diastereoselectively the
exo-epoxide (+)-14 which, on treatment with hydrazine,
gave the exo-alcohol (-)-15 epimeric to the endo-alcohol
(-)-12. Diastereoselective generation of (-)-15 also con-
firmed the convex-face selectivity exerted by (+)-11 in the
epoxidation. On oxidation under Dess-Martin conditions,
(-)-15 afforded the inverted enone (-)-11. Although we
did not carry out the same reaction using the enantiomer
(-)-11, the present conversion constitutes its inversion in
a formal sense5a (Scheme 4).
(–)-12
0.1 M phosphate buffer
(42% : >99% ee)
(+)-13
O
O
+
(6%)
(+)-16
(37% : >99% ee)
(+)-11
Scheme 5
Stimulated by the finding of Williams and co-workers10
that a certain racemic 2-substituted cyclohex-3-enyl ace-
tate was resolved dynamically under lipase-mediated hy-
drolysis conditions in the presence of a palladium catalyst
to give rise to a single enantiomeric 2-substituted cyclo-
hex-3-enol, we also examined the dynamic resolution of
the racemic endo-acetate (±)-13 under the same lipase-
palladium-mediated conditions, as 13 has the same sym-
metric element to those Williams and co-workers had
used with respect to its cyclohexenyl acetate system. The
expected dynamic resolution did not take place, but in-
stead, concomitant resolution of the racemate (±)-13 and
oxidation of the resulting resolved alcohol (+)-12 oc-
curred under these conditions in the presence of No-
vozyme and a palladium catalyst [PdCl2(MeCN)2, 7
mol%] to give the enone (+)-11 and the acetate (+)-13 in
yields of 37% and 42%, respectively, both in enantiomer-
ically pure forms11 accompanied with 7% yield of the
enantiopure ketone (+)-16. When Lipase PS was used in
place of Novozyme, the reaction proceeded very slow and
a complex mixture was generated. Although actual mech-
anism generating two oxidation products from the allyl al-
cohol (+)-12 was uncertain, it is apparently due to the
presence of palladium catalyst and oxygen in the medium,
while a similar palladium-mediated oxidation of allylic al-
cohols has been reported12 (Scheme 5).
and diisopropyl sulfide in THF, furnished diastereoselec-
tively the ketone 17 with generation of a tertiary stereo-
genic center as a single stereoisomer, though a minor
amount of the unreacted starting enone could not be sepa-
rated. In contrast to the previous electrophilic diastereo-
controlled construction of a new tertiary stereogenic
center at the vicinal carbon to the carbonyl functionality,
the present introduction by a nucleophilic 1,4-addition did
not bring about epimerization, though both of the proce-
dures rely their stereocontrol on the inherent convex-face
selectivity exerted by their biased bicyclo[3.2.1]octane
framework, respectively. The ketone 17, without separa-
tion, was next treated with m-chloroperbenzoic acid to
give the single lactone (+)-18 via a regioselective Baey-
er-Villiger pathway after separation of the contaminated
enone (-)-11. To obtain the the C9-block (-)-2, the lac-
tone (+)-18 was first reduced with lithium aluminum hy-
dride to give the diol (+)-19. Applying Oshima
conditions14 reported for chemoselective oxidation of sec-
ondary alcohols, the diol (+)-19 was treated with a catalyt-
ic amount of cerium(IV) ammonium nitrate (CAN) in the
presence of sodium bromate to furnish cleanly the keto al-
cohol (-)-20 leaving the primary hydroxy functionality
intact. Finally, dehydration of (-)-20 was carried out un-
der Grieco conditions15 to give the C9-cyclopentanone
building block1 (-)-2 via the selenide 21. Thus, the first
acquisition of the enantiomer (-)-2, which could not be
obtained previously, as well as an alternative acquisition
of (+)-2 in a formal sense, has been made with overcom-
ing the second difficulty. Overall yield of (-)-2 from the
enone (-)-11 was 21% in 6 steps (Scheme 6).
Having overcome the first difficulty, we next tackled the
second problem in the utilization of the enantiopure enone
11 thus obtained. To obtain the C9-building block (-)-2,
the enantiomer which was not so-far been prepared, one
carbon unit was introduced to (-)-11 as a benzyloxymeth-
yl functionality by diastereoselective 1,4-addition. Thus,
treatment of (-)-11 with a cuprate,13 generated in situ
from benzyl tributylstannylmethyl ether and butyllithium
in the presence of a copper(I)-dimethyl sulfide complex
O
O
OH
O
Dess-Martin
oxidation
30% H2O2
NH2NH2-H2O
AcOH(cat.)
1N NaOH
MeOH
(97%)
O
(81%)
MeOH
(72%)
(–)-11
(–)-15
(+)-14
(+)-11
Scheme 4
Synthesis 2000, No. 13, 1825–1834 ISSN 0039-7881 © Thieme Stuttgart · New York

1828
H. Nagata et al.
PAPER
OBn
OBn
OBn
H
Bu3SnCH2OBn
BuLi
LiAlH4
HO
H
m-CPBA
CH2Cl2
OH
(–)-11
O
H
THF
CuBr·Me2S
i-Pr2S
THF
O
O
(93%)
(+)-19
(57% from 11)
(+)-18
17
OBn
OBn
H
H
H
O
30% H2O2
THF
CAN
O
X
NaBrO3
H
aq. MeCN
(57% from 20)
(–)-2
(–)-20 : X=OH
(68%) o-(NO2)C6H4SeCN
Bu3P
THF
21 : X=SeC6H4(NO2)-o
Scheme 6
As we have solved the second problem for the construc- the same conditions14 as for (-)-20 furnished the keto al-
tion of a new stereogenic center in the C9-block 2 without cohol (-)-27 without affecting the primary hydroxy
epimerization, we next examined the introduction of a ter- group. This compound, after transformation into the se-
tiary stereogenic center in an alternative way so as to con- lenide 28, afforded the C9-cyclopentanone (+)-29, the di-
struct the diastereomer of the C9-block (-)-2 starting with astereomer of the C9-block1 (+)-2. Overall yield of (+)-29
the enantiomeric enone (+)-11. Treatment of (+)-11 with the from the enone (+)-11 was 23% in 8 steps. Thus, dia-
a carbanion generated in situ from benzyl tributylstannyl- stereocontrolled route to both enantiomers of the C9-
methyl ether and butyllithium in THF16 afforded the ter- building block 2 and its diasteromer 29 has been estab-
tiary alcohol (+)-22, diastereoselectively, by an lished at this stage in a formal sence (Scheme 7).
1,2-addition. This was oxidized with pyridinium
To demonstrate a potential of the newly obtained C9-ke-
chlorochromate5b (PCC) to give the b-substituted enone
tone (+)-29, the diastereomer of (+)-2, its conversion into
(-)-23. As expected 1,4-reduction using a complex17 gen-
erated in situ from diisobutylaluminum hydride (DIBAL)
and copper(I) iodide in THF containing hexamethylphos-
phorus triamide (HMPA) proceeded diastereoselectively
from the convex-face to give the ketone (-)-24, the dia-
stereomer of the ketone (+)-18. Baeyer-Villiger oxida-
tion of (-)-24 with m-chloroperbenzoic acid took place
regioselectively to give the single lactone (+)-25 which af-
forded the diol (-)-26 on reduction with lithium alumi-
num hydride. Chemoselective oxididation of (-)-26 under
(-)-sembrin18 (5), a monoterpene principle of Swertia
japonica which has been previously obtained from (+)-2,
was examined on the basis of its functionality and stereo-
chemical background. Thus, (+)-29 was first transformed
into the a-diketone monothioketal (+)-30 by reaction with
trimethylene dithiotosylate19 via the enamine intermedi-
ate,20 whose benzyl ether was cleaved at this stage with
boron tribromide1 to give the primary alcohol 31. Cleav-
age of the a-diketone monothioketal functionality of (+)-
OBn
OBn
m-CPBA
OBn
OBn
DIBAL
PCC
Bu3SnCH2OBn
OH
O
(+)-11
CH2Cl2
(93%)
CuI
HMPA
THF
(96%)
O
O
CH2Cl2
(97%)
O
BuLi
THF
(66%)
(–)-24
(+)-22
(–)-23
(+)-25
OBn
OBn
OBn
H
H
H
30% H2O2
THF
LiAlH4
THF
O
O
HO
H
CAN
X
OH
H
H
NaBrO3
aq. MeCN
(71%)
H
(94%)
(–)-27 : X=OH
28 : X=SeC6H4(NO2)-o
o-(NO2)C6H4SeCN
(–)-26
(60% from 27)
(+)-29
Bu3P
THF
Scheme 7
Synthesis 2000, No. 13, 1825–1834 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Diastereodivergent Synthesis of the C9-Cyclopentanone Chiral Building Blocks
1829
31 with potassium hydroxide in tert-butyl alcohol21 fol-
lowed by acid treatment furnished the d-lactone (+)-32
which was reduced to give the diol (+)-33. Finally, the
dithiane moiety of (+)-33 was hydrolysed22 to give (-)-
semburin (5) after acidic workup with concomitant cy-
clization under the conditions. The product obtained was
identical with that obtained from norcamphor [(+)-1] via
the diastereomeric C9-building block1 (+)-2. We have,
thus, completed a synthesis of (-)-semburin (5) from both
enantiomers of the enone 11 in the diastereo- and enantio-
convergent manner in a formal sense (Scheme 8).
Bicyclo[3.2.1]oct-3-en-2-one [(±)-11] from (±)-Norcamphor
[(±)-1]
To a stirred solution of FeCl3 (23.2 g, 173.98 mmol) in DMF
(140 mL) was added the cyclopropane 10 (prepared from racemic
norcamphor [(±)-1] by the reported procedure5) (15.5 g, 79.08
mmol) in DMF (50 mL) at 0 °C and the stirring was continued for
12 h at r.t. The reaction was quenched by addition of H2O (100 mL)
and was extracted with Et2O (3 × 500 mL). The extract was washed
with brine (30 mL), dried (MgSO4), evaporated under reduced pres-
sure, and chromatographed (SiO2, 400 g, eluent: Et2O/hexane, 1:1
v/v) to give the enone (±)-11 as a colorless oil (9.01 g, 93%).
IR (film): n = 1679 cm-1.
1H NMR (300 MHz, CDCl3): d = 1.49-1.78 (m, 3 H), 1.91-2.21
(m, 3 H), 2.87-2.97 (m, 2 H), 5.84 (dd, 1 H, J = 9.8, 1.9 Hz), 7.26
(ddd, 1 H, J = 9.8, 6.8, 1.6 Hz).
In conclusion, we have overcome two difficulties which
have been encountered previously in the exploitation of
(+)-norcamphor, only practically accessible enantiomer at
present, for the diastereocontrolled synthesis of the
Corynanthe indole alkaloids and the related natural prod-
ucts. The first problem, acquisition of the key C9-chiral
block in both enantiomeric forms, has been solved by con-
verting racemic norcamphor into the enantiopure enone
having a bicyclo[3.2.1]octane framework by employing
lipase-mediated resolution. The second problem, preser-
vation of the labile stereogenic center, has been solved by
introducing a new stereogenic center by diastereoselec-
tive 1,4-addition at the nonenolizable carbonyl b-position
on the basis of the inherent convex-face selectivity exert-
ed by a bicyclo[3.2.1]octane background of the substrate
enone. Not only an alternative route to the C9-chiral block
through a more enzyme-discriminable allylic acetate in-
termediate was established, but a route to its enantiomer
and its diastereomer which are so far unable to obtain
13C NMR (75 MHz, CDCl3): d = 24.4 (t), 29.3 (t), 37.8 (d), 40.2 (t),
50.0 (d), 127.4 (d), 157.0 (d), 204.0 (s).
MS: m/z = 122 (M+), 81 (100%).
HRMS: m/z Calcd for C8H10O 122.0732. Found 122.0693.
endo-Bicyclo[3.2.1]oct-3-en-2-ol [(±)-12]
To a stirred solution of (±)-11 (2.00 g, 16.39 mmol) in CH2Cl2
(60 mL) was added DIBAL (1.5 M in toluene, 13.1 mL, 19.67
mmol) at -78 °C and the stirring was continued for 1 h at the same
temperature. The reaction was quenched by addition of H2O (13
mL) and the mixture was filtered through a Celite pad. The filtrate
was dried (MgSO4), evaporated under reduced pressure, and chro-
matographed (SiO2, 80 g, eluent: Et2O/hexane, 1:1 v/v) to give the
racemic allyl alcohol (±)-12 (1.73 g, 85%).
IR (film): n = 3302 cm-1.
1H NMR (300 MHz, CDCl3): d = 1.53-1.71 (m, 5 H), 1.79-1.83
(m, 1 H), 2.40-2.44 (m, 2 H), 4.56 (s, 1 H), 5.30 (dd, 1 H, J = 9.9,
from (+)-norcamphor was also achieved. Moreover, we 3.3 Hz), 5.97 (ddd, 1 H, J = 10.0, 6.3, 3.3 Hz).
MS: m/z = 124 (M+), 83 (100%).
have demonstrated a potential of the presently obtained
diastereomer by converting it into (-)-sembrin which has
so far been obtained from (+)-norcamphor.
HRMS: m/z Calcd for C8H12O 124.0888. Found 124.0852.
Preparation of 4-Acetoxybicyclo[3.2.1]oct-2-ene [(±)-13]
A mixture of (±)-12 (1.70 g, 13.71 mmol), Et3N (5.3 mL, 41.13
mmol), 4-(N,N-dimethylamino)pyridine (16.7 mg, 1.4 mmol), and
Ac2O (2.1 mmol, 20.57 mmol) was stirred at r.t. for 10 h. The mix-
ture was diluted with Et2O (200 mL) and washed with brine
(20 mL), dried (MgSO4), evaporated under reduced pressure. The
residue was chromatographed (SiO2, eluent: Et2O/hexane, 1:3 v/v)
to give the racemic allyl acetate (±)-13 as a colorless oil (2.20 g,
97%).
Melting points are uncorrected. IR spectra were recorded on a JAS-
CO-IR-700 spectrometer. 1H NMR spectra were recorded on a
Gemini 2000 (300 MHz) spectrometer. Mass spectra were recorded
on a Jenol JMS-DX 303 instrument. Enantiomeric purities were de-
termined on a Gilson Model-307 instrument equipped with a col-
umn with a chiral stationary phase. Optical rotations were measured
with a JASCO-DIP-370 digital polarimeter.
IR (film): n = 1738 cm-1.
OBn
O
O
HO HO
H
H
H
H
O
O
pyrrolidine
MeI
aq. MeCN
O
H
LAH
KOH, t-BuOH
benzene, reflux
H
S
H
H
S
S
(+)-29
S
S
then
aq. HCl
(85%)
THF
(89%)
then
then
PPTS
benzene
S
H
CH2(CH2STs)2
Et3N
MeCN
(74%)
(+)-33
(+)-32
(–)-semburin 5
(41%)
(+)-30 : R=Bn
BBr3
CH2Cl2
(80%)
(+)-31 : R=H
Scheme 8
Synthesis 2000, No. 13, 1825–1834 ISSN 0039-7881 © Thieme Stuttgart · New York

1830
H. Nagata et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 1.60-2.01 (m, 6 H), 2.06 (s, 3 H),
2.40-2.41 (m, 1 H), 2.56-2.58 (m, 1 H), 5.25 (dd, 1 H, J = 9.6, 2.4
Hz), 5.57 (ddd, 1 H, J = 9.6, 6.2, 3.0 Hz).
(e) Resolution of the Racemic Acetate (±)-13 in the Presence of
Novozyme and PdCl2(MeCN)2
A suspension of (±)-13 (230 mg, 1.39 mmol), Novozyme (230 mg)
and PdCl2(MeCN)2 (18 mg, 0.07 mmol) in phosphate buffer (0.1 M,
9 mL) was stirred at r.t. for 48 h. The mixture was diluted with Et2O
(40 mL) and filtered through a Celite pad. The organic layer was
separated, washed with brine (5 mL), dried (MgSO4), evaporated
under reduced pressure, and chromatographed (SiO2, 10 g, eluent:
Et2O/hexane, 1:5 v/v) to give the acetate (+)-13, the enone (+)-11
and the ketone (+)-16. The spectroscopic data of the enantiopure ac-
etate (+)-13 and the enone (+)-11 thus obtained were identical with
those of the racemates, respectively.
MS: m/z = 166 (M+), 124 (100%).
HRMS: m/z Calcd for C10H14O2 166.0993. Found 166.0990.
Lipase-Meadiated Kinetic Resolution
(a) Resolution of the Racemic Alcohol (±)-12 in the Presence of
Lipase PS
A suspension of (±)-12 (40 mg, 0.32 mmol), vinyl acetate (0.06 mL,
0.64 mmol), and Lipase PS (32 mg) in tert butyl methyl ether
(5.0 mL) was stirred at r.t. for 3 d. After filtration, the mixture was
evaporated under reduced pressure and chromatographed (SiO2, 4
g, eluent: Et2O/hexane, 1:3 v/v) to give the acetate (-)-13 (25 mg,
47%) as a colorless oil and the alcohol (+)-12 (16 mg, 40%) (from
Et2O/hexane, 1:1 v/v eluent) as a colorless oil. Optical purity of the
products were determined by HPLC using a column with a chiral
stationary phase (CHIRALCEL OB, eluent: i-PrOH/hexane, 1:200
v/v) as 85% ee for (-)-13 and 71% ee for (+)-12. Spectroscopic data
are identical with the racemates.
(+)-13
Yield: 96 mg (42%); >99% ee by HPLC; colorless oil; [a]D25 +32.1
(c = 0.8, CHCl3)
(+)-11
Yield: 63 mg (37%); >99% ee by HPLC; colorless oil; [a]D27 +340.5
(c = 0.6, CHCl3).
(+)-16
Yield: 10 mg (6%); mp 58-60 °C; [a]D29 +129.6 (c = 0.3, CHCl3).
IR (film): n = 1717 cm-1.
1H NMR (300 MHz, CDCl3): d = 1.64-2.05 (m, 8 H), 2.15-2.25
(m, 1 H), 2.31-2.46 (m, 2 H), 2.70 (t, 1 H, J = 5.2 Hz).
(b) Resolution of the Racemic Alcohol (±)-12 in the Presence of
Novozyme
A suspension of (±)-12 (160 mg, 1.29 mmol), vinyl acetate
(0.24 mL, 2.58 mmol), and Chirazymel-2 (128 mg) in tert butyl me-
thyl ether (10 mL) was stirred at r.t. for 2 d. After filtration, the mix-
ture was evaporated under reduced pressure and chromatographed
(SiO2, 10 g, eluent: Et2O/hexane, 1:3 v/v) to give the acetate (-)-13
(103 mg, 48%) as a colorless oil and the alcohol (+)-12 (73 mg,
46%) (eluent: Et2O/hexane, 1:1 v/v) as a colorless oil. Optical purity
of the product was determined as above using HPLC as 85% ee for
(-)-13 and 81% ee for (+)-12.
MS: m/z = 124 (M+), 80 (100%).
HRMS: m/z Calcd for C10H14O2 124.0888. Found 124.0868.
The spectral data of (+)-16 including specific rotation value were
identical with those obtained from the enantiopure enone (+)-11 on
catalytic hydrogenation {[a]D28 +127.0 (c = 0.7, CHCl3)}.
Conversion of the Allyl Alcohol (-)-12 into the Enone (+)-11
To a stirred solution of (-)-12 (135 mg, 1.09 mmol) in CH2Cl2
(5 mL) was added the Dess-Martin reagent (554 mg, 1.3 mmol) at
r.t. and the stirring was continued for 5 min at the same temperature.
H2O (10 mL) was added and the mixture was extracted with Et2O
(2 × 20 mL). The extract was washed with sat. aq NaHCO3 solution
(5 mL) and brine (3 mL), dried (MgSO4), evaporated under reduced
pressure, and filtered through a Celite pad. The filtrate was dried
(MgSO4), evaporated under reduced pressure, and chromato-
graphed (SiO2, 5 g, eluent: Et2O/hexane, 1:2 v/v) to give (+)-11 (107
mg, 81%); [a]D28 +362.1 (c = 1.6, CHCl3) (>99% ee by HPLC), as a
colorless oil. Spectroscopic data were indentical with those of
(±)-11.
(c) Resolution of the Racemic Acetate (±)-13 in the Presence of
Lipase PS
A suspension of (±)-13 (100 mg, 0.06 mmol) and Lipase PS (60 mg)
in a mixture of phosphate buffer (0.1 M, 5 mL) and acetone
(0.5 mL) was stirred at r.t. for 2 weeks. The mixture was diluted
with Et2O (20 mL) and filtered through a Celite pad. The organic
layer was washed with brine (5 mL), dried (MgSO4), evaporated un-
der reduced pressure, and chromatographed (SiO2 10g, eluent:
Et2O/hexane, 1:3 v/v) to give the acetate (+)-13 (50 mg, 50%) and
the alcohol (-)-12 (34 mg, 46%), (eluent: Et2O/hexane, 1:1 v/v elu-
ent) both as colorless oils. Optical purity of the products were deter-
mined as above which revealed (+)-13 as 94% ee and (-)-12 as 95%
ee.
Conversion of the Allyl Acetate (+)-13 into the Allyl Alcohol (+)-
12
(d) Resolution of the Racemic Acetate (±)-13 in the Presence of
Novozyme
To a stirred solution of (+)-13 (2.6 mg, 15.66 mmol) in MeOH
(50 mL) was added the K2CO3 (4.3 mg, 31.33 mmol) at r.t. and the
stirring was continued for 1 h. The mixture was diluted with Et2O
(200 mL) and was filtered through a Celile pad. The filtrate was
evaporated under reduced pressure and chromatographed (SiO2,
50 g, eluent: Et2O/hexane, 1:1 v/v) to give enantiopure (+)-12 as a
colorless oil (1.92 g, 98%).
A suspension of (±)-13 (100 mg, 0.60 mmol) and Novozyme
(100 mg) in phosphate buffer (0.1 M, 3 mL) was stirred at r.t. for 48
h. The mixture was diluted with Et2O (20 mL) and filtered through
a Celite pad. The organic layer was washed with brine (5 mL), dried
(MgSO4), evaporated under reduced pressure, and chromato-
graphed (SiO2, 5 g, eluent: Et2O/hexane, 1:5 v/v) to give the acetate
(+)-13 (40 mg, 40%) and the alcohol (-)-12 (29 mg, 39%) (elunet:
Et2O/hexane, 1:2 v/v) both as colorless oils. Optical purity of the
products were determined as above.
Conversion of the Allyl Alcohol (+)-12 into the Enone (-)-11
To a stirred solution of (+)-12 (1.8 mg, 14.75 mmol) in CH2Cl2
(50 mL) was added the Dess-Martin reagent (18.8 g, 44.26 mmol)
at r.t. After 1 h, the mixture was diluted with H2O (50 mL) and Et2O
(300 mL), and washed successively with sat.aq NaHCO3 solution
(50 mL) and brine (30 mL), dried (MgSO4), evaporated under re-
duced presure, and chromatographed (SiO2, 50 g, eluent: Et2O/hex-
ane, 1:2 v/v) to give (-)-11 (1.48 g, 82%); [a]D22 -339.0 (c = 1.6,
CHCl3); >99% ee by HPLC.
(+)-13
[a]D25 +32.1 (c = 0.8, CHCl3); >99% ee.
(-)-12
[a]D29 -10.8 (c = 0.6, CHCl3); >99% ee.
Synthesis 2000, No. 13, 1825–1834 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Diastereodivergent Synthesis of the C9-Cyclopentanone Chiral Building Blocks
1831
(+)-(1R,5S,6S)-5-Benzyloxymethyl-2-oxabicyclo[4.2.1]nonan-3-
one (18)
IR (film): n = 3450, 1725 cm-1.
1H NMR (300 MHz, CDCl3): d = 1.46-1.93 (m, 6 H), 2.05-2.44
(m, 5 H), 2.57 (br s, 1 H), 3.49 (dd, 1 H, J = 9.0, 3.0 Hz), 3.56 (dd,
1 H, J = 9.0, 3.3 Hz), 3.62-3.74 (m, 2 H), 4.53 (d, 2 H, J = 2.2 Hz),
7.26-7.40 (m, 5 H).
To a stirred solution of Bu3SnCH2OBn (588 mg, 1.43 mmol) in
THF (5.0 mL) was added BuLi (1.56 M in hexane, 0.92 mL,
1.43 mmol) was added at -78 °C and, after 10 min, CuBr◊Me2S
(316 mg, 1.54 mmol) and i-Pr2S (1.5 mL) in THF (2.5 mL), were
added and the stirring was continued for 20 min at the same temper-
ature. To this mixture was added the enone (+)-11 (125 mg, 1.03
mmol) in THF, then after 5 min, BF3◊Et2O (0.19 mL, 1.54 mmol)
and the stirring was continued for 30 min at 0 °C. The reaction was
quenched by the addition of sat. aq NH4Cl solution (10 mL) and ex-
tracted with Et2O (3 × 20 mL). The extract was washed with brine
(5 mL), dried (MgSO4), evaporated under reduced pressure, and
chromatographed (SiO2, 10 g, eluent: Et2O/hexane, 1:2 v/v) to give
the ketone 17 as a mixture containing a minor amount of the starting
enone (-)-11 which was used for the next reaction. The mixture was
dissolved in CH2Cl2 (5.0 mL) and was treated with m-CPBA (70%,
379 mg, 1.54 mmol) with stirring at 0 °C and the stirring was con-
tinued for 12 h at the same temperature. The reaction was quenched
by addition of 5% aq Na2SO3 solution (5 mL) and the mixture was
diluted with EtOAc (20 mL). The organic layer was separated,
washed successively with 10% aq NaOH solution (5 mL) and brine
(5 mL) dried (MgSO4), evaporated under reduced pressure, and
chromatographed (SiO2, 10 g, eluent: EtOAc/hexane, 1:2 v/v) to
give the lactone 18 (152 mg, 57%); as a colorless oil; [a]D28 +6.7 (c
= 1.2, CHCl3).
MS: m/z = 263 (M+ + 1), 91 (100%).
HRMS: m/z Calcd for C16H23O3 263.1646. Found 263.1695.
(-)-(3S)-3-[(1S)-2-Benzyloxy-1-vinylethyl]cyclopentan-1-one
[(-)-2]
A solution of (-)-20 (95 mg, 0.36 mmol) in THF (2 mL) was stirred
with o-nitrophenyl selenocyanate (99 mg, 0.44 mmol) and Bu3P
(0.1 mL, 0.44 mmol) at r.t. for 30 min. After evaporation of the sol-
vent under reduced pressure, the residue was dissolved in THF
(3 mL) and the solution was treated with 30% H2O2 (0.3 mL) at 0 °C
with stirring and the stirring was continued for 2 h at r.t. The mix-
ture was extracted with Et2O (20 mL) and the extract was washed
successively with H2O (10 mL) and brine (5 mL), dried (MgSO4),
evaporated under reduced pressure, and chromatographed (SiO2,
10 g, eluent: Et2O/hexane, 5:1 v/v) to give (-)-2 (51 mg, 57%);
[a]D27 -111.7 (c = 0.5, CHCl3) {Lit.1a [a]D28 +112.3 (c = 2.0, CHCl3)
for the enantiomer}, as a colorless oil which, except for the sign of
the optical rotation, was identical in all respects with an authentic
material obtained from norcamphor [(+)-1].
IR (film): n = 1717 cm-1.
(+)-(1R,2S,5R)-2-Benzyloxymethylbicyclo[3.2.1]oct-3-en-2-ol
(22)
1H NMR (300 MHz, CDCl3): d = 1.58-1.76 (m, 2 H), 1.85-2.08
(m, 4 H), 2.16-2.32 (m, 1 H), 2.63 (dd, 1 H, J = 14.8, 4.7 Hz), 2.76
(dd, 1 H, J = 14.3, 4.7 Hz), 3.45 (d, 1 H, J = 7.5 Hz), 4.52 (d, 2 H,
J = 11.8 Hz), 4.82 (t, 1 H, J = 6.6 Hz), 7.26-7.38 (m, 5 H).
To a stirred solution of Bu3SnCH2OBn (1.34 g, 3.28 mmol) in THF
(20 mL) was added BuLi (1.58 mL, 2.46 mmol) at -78 °C and the
mixture was stirred at the same temperature for 20 min. To this
stirred mixture was then added (+)-11 (200 mg, 1.639 mmol) in
THF (5 mL) at -78 °C and the mixture was stirred at the same tem-
perature for 10 min. The mixture was diluted with Et2O (20 mL) and
washed successively with H2O (10 mL) and brine (5 mL), dried
(MgSO4), evaporated under reduced pressure, and chromato-
graphed (SiO2, 20g, eluent: Et2O/hexane, 1:5 v/v) to give the tertia-
ry alcohol 23 (264 mg, 66%) as a colorless oil; [a]D23 +90.5 (c = 1.3
CHCl3).
MS: m/z = 260 (M+), 91 (100%).
HRMS: m/z Calcd for C16H20O3 260.1411. Found 260.1410.
(+)-(1R,3S)-3-[(1S)-1-Benzyloxymethyl-3-hydoroxypropyl]cy-
clopentan-1-ol (19)
To a stirred solution of the lactone (+)-18 (152 mg, 0.59 mmol) in
THF (4.0 mL) was added LiAlH4 (33 mg, 0.88 mmol) at 0 °C. After
10 min the reaction was quenched by addition of 35% NH4OH
(3 mL) and the mixture was diluted with CHCl3 (20 mL) and filtered
through a Celite pad. The filtrate was dried (MgSO4), evaporated
under reduced pressure, and chromatographed (SiO2, 5 g, eluent:
CHCl3/MeOH, 10:1 v/v) to give the diol 19 (143 mg, 93%); as a col-
orless oil; [a]D29 +7.8 (c = 1.2, CHCl3).
IR (film): n = 3452 cm-1.
1H NMR (300 MHz, CDCl3): d = 1.39-1.48 (m, 1 H), 1.56-1.82
(m, 5 H), 2.15-2.24 (m, 1 H), 2.38-2.45 (m, 2 H), 3.38 (d, 1 H,
J = 9.0 Hz), 3.56 (d, 1 H, J = 9.0 Hz), 4.57 (d, 1 H, J = 4.4 Hz),
5.21 (dd, 1 H, J = 9.6, 1.9 Hz), 6.01 (ddd, 1 H, J = 9.9, 6.4, 1.4 Hz),
7.26-7.40 (m, 5 H).
IR (film): n = 3370 cm-1.
MS: m/z = 244 (M+), 91 (100%).
1H NMR (300 MHz, CDCl3): d = 1.18-1.29 (m, 1 H), 1.38-1.96
(m, 9 H), 2.06-2.18 (m, 1 H), 3.40 (dd, 1 H, J = 9.3, 5.8 Hz), 3.55
(dd, 1 H, J = 9.3, 5.8 Hz), 3.58-3.74 (m, 2 H), 4.24-4.32 (m, 1 H),
4.51 (d, 2 H, J = 2.5 Hz), 7.25-7.39 (m, 5 H).
HRMS: m/z Calcd for C16H20O2 244.1462. Found 244.1486.
(-)-(1R,5S)-4-Benzyloxymethylbicyclo[3.2.1]oct-3-en-2-one
(23)
MS: m/z = 264 (M+), 91 (100%).
To a stirred solution of 22 (490 mg, 2.01 mmol) in CH2Cl2 (15 mL)
was added PCC (866 mg, 4.02 mmol) at r.t. and the stirring was con-
tinued for 3 h at the same temperature. The mixture was diluted with
Et2O (50 mL) and filtered through a Celite-pad, evaporated under
reduced pressure, and chromatographed (SiO2, 40 g, eluent: Et2O/
hexane, 1:1 v/v) to give the enone 23 (470 mg, 97%) as a colorless
oil; [a]D28 -138.5 (c = 2.1, CHCl3).
HRMS: m/z Calcd for C16H24O3 264.1724. Found 264.1718.
(-)-(3S)-3-[(1S)-1-Benzyloxymethyl-3-hydroxypropyl]cyclo-
pentan-1-one (20)
To a stirred solution of the diol (+)-19 (143 mg, 0.54 mmol) in aq
MeCN (25%, 6.5 mL) were added sequentially, NaBrO3 (82 mg,
0.54 mmol) and (NH4)2Ce(NO2)6 (CAN, 30 mg, 0.05 mmol) at r.t.
and the mixture was refluxed for 1 h. After cooling, the mixture was
extracted with EtOAc (20 mL) and the extract was washed succes-
sively with sat. aq NaHCO3 solution (5 mL) and brine (3 mL), dried
(MgSO4), evaprorated under reduced pressure and chromato-
graphed (SiO2, 10g, eluent: EtOAc/hexane, 1:1 v/v) to give the keto
IR (film): n = 1658 cm-1.
1H NMR (300 MHz, CDCl3): d = 1.53-1.70 (m, 3 H), 1.91-2.05
(m, 2 H), 2.07-2.19 (m, 1 H), 2.73 (t, 1 H, J = 5.0 Hz), 2.94 (t, 1 H,
J = 5.5 Hz), 4.09 (dd, 1 H, J = 15.9, 1.7 Hz), 4.26 (dd, 1 H,
J = 16.2, 1.9 Hz), 4.56 (d, 2 H, J = 3.3 Hz), 5.83 (s, 1 H), 7.25-7.40
(m, 5 H).
29
alcohol 20 (95 mg, 68%) as a colorless oil; [a]D -97.9 (c = 1.2,
CHCl3).
MS: m/z = 242 (M+), 91 (100%).
Synthesis 2000, No. 13, 1825–1834 ISSN 0039-7881 © Thieme Stuttgart · New York

1832
H. Nagata et al.
PAPER
HRMS: m/z Calcd for C16H18O2 242.1306. Found 242.1307.
(-)-(3S)-3-[(1R)-1-Benzyloxymethyl-3-hydroxypropyl]cyclo-
pentan-1-one (27)
To a stirred solution of the diol 26 (141 mg, 0.53 mmol) in aq MeCN
(25%, 7 mL) was added NaBrO3 (81 mg, 0.53 mmol) and
(NH4)2Ce(NO2)6 (29 mg, 0.06 mmol) at r.t. and the mixture was re-
fluxed for 1 h. After cooling, the mixture was extracted with EtOAC
(20 mL) and the extract was washed with sat. aq NaHCO3 solution
(5 mL) and brine (3 mL), dried (MgSO4), evaporated under reduced
pressure, and chromatographed (SiO2, 10g, eluent: EtOAc/hexane,
1:1 v/v) to give the ketol 27 (100 mg, 71%) as a colorless oil; [a]D
-95.2 (c = 0.9, CHCl3),.
IR (film): n = 3430, 1739 cm-1.
1H NMR (300 MHz, CDCl3): d = 1.47-1.56 (m, 1 H), 1.58-1.93
(m, 4 H), 2.05-2.40 (m, 5 H), 2.60 (br s, 1 H), 3.42 (dd, 1 H, J = 9.3,
3.3 Hz), 3.53 (dd, 1 H, J = 9.3, 3.0 Hz), 3.64-3.76 (m, 2 H), 4.50
(d, 1 H, J = 3.6 Hz), 7.26-7.40 (m, 5 H).
(-)-(1R,4R,5S)-4-Benzyloxymethylbicyclo[3.2.1]octan-2-one
(24)
To a stirred suspension of CuI (2.25 g, 11.84 mmol) and HMPA
(17.5 mL) in THF (50 mL) was added DIBAL (15.8 mL,
23.68 mmol) at -78 °C and the stirring was continued for 30 min at
the same temperature. Then, the enone 23 (1.91 g, 7.89 mmol) in
THF (20 mL) was added at the same temperature. After raising the
temperature to -20 °C, the mixture was further stirred for 2 h at the
same temperature and diluted with Et2O (100 mL), washed succes-
sively with H2O (20 mL) and brine (10 mL), dried (MgSO4), evap-
orated under reduced pressure, chromatographed (SiO2, 80g, eluent:
Et2O/hexane, 1:4 v/v) to give the ketone 24 (1.84 g, 96%) as a col-
orless oil; [a]D25 -46.9 (c = 0.9, CHCl3).
25
IR (film): n = 1712 cm-1.
1H NMR (300 MHz, CDCl3): d = 1.56-1.66 (m, 1 H), 1.72-2.01
(m, 6 H), 2.16-2.29 (m, 2 H), 2.50 (br s, 1 H), 2.70 (t, 1 H, J = 5.2
Hz), 3.30 (dd, 1 H, J = 9.3, 5.5 Hz), 3.42 (dd, 1 H, J = 9.3, 5.5 Hz),
4.51 (d, 2 H, J = 2.7 Hz), 7.22-7.40 (m, 5 H).
MS: m/z = 262 (M+), 91 (100%).
HRMS: m/z Calcd. for C16H22O3 262.1568. Found 262.1555.
(+)-(3S)-3-[(1R)-2-Benzyloxy-1-vinylethyl]cyclopentan-1-one
(29)
MS: m/z = 244 (M+), 91 (100%).
HRMS: m/z Calcd for C16H20O2 244.1462. Found 244.1443.
A solution of (-)-27 (282 mg, 1.08 mmol) in THF (7 mL) was
stirred with o-nitrophenyl selenocyanate (733 mg, 3.23 mmol) and
Bu3P (0.80 mL, 3.23 mmol) at r.t. for 30 min. After evaporation of
the solvent under reduced pressure, the residue was treated with
30% H2O2 (2.0 mL) at 0 °C with stirring and the stirring was con-
tinued for 2 h at r.t. The mixture was extracted with Et2O (30 mL)
and the extract was washed successively with H2O (5 mL) and brine
(3 mL), dried (MgSO4), evaporated under reduced pressure, and
chromatographed (SiO2, 30 g, eluent: Et2O/hexane, 5:1 v/v) to give
(+)-29 (158 mg, 60%) as a colorless oil; [a]D +0.9 (c = 1.1,
CHCl3),.
IR (film): n = 1728 cm-1.
1H NMR (300 MHz, CDCl3): d = 1.42-1.58 (m, 1 H), 2.12-2.18
(m, 2 H), 2.20-2.40 (m, 4 H), 3.48 (d, 1 H, J = 4.7 Hz), 4.51 (s, 2
H), 5.12 (dd, 1 H, J = 17.0, 1.7 Hz), 5.16 (dd, 1 H, J = 10.7, 1.9 Hz),
5.75 (ddd, 1 H, J = 17.0, 10.4, 8.5 Hz), 7.26-7.39 (m, 5 H).
(+)-(1R,5R,6S)-5-Benzyloxymethyloxabicyclo[4.2.1]nonan-3-
one (25)
To a stirred solution of (-)-24 (649 mg, 2.66 mmol) in CH2Cl2
(20 mL) was added m-chloroperbenzoic acid (70%, 1.06 g, 6.65
mmol) at 0 °C and the stirring was continued for 12 h at the same
temperature. The reaction wad quenched by addition of 5% aq
Na2S2O3 solution (5 mL) and the mixture was diluted with EtOAc
(50 mL). The organic layer was separated, washed successively
with 10% aq NaOH (5 mL) and brine (5mL), dried (MgSO4), evap-
orated under reduced pressure, and chromatographed (SiO2, 60g,
eluent: EtOAc/hexane, 1:2 v/v) to give the lactone 25 (641 mg,
93%) as a colorless oil; [a]D34 +33.2 (c = 1.4, CHCl3).
31
IR (film): n = 1717 cm-1.
1H NMR (300 MHz, CDCl3): d = 1.59-1.74 (m, 1 H), 1.76-1.82
(m, 1 H), 1.84-2.40 (m, 4 H), 2.18-2.35 (m, 2 H), 2.55 (t, 1 H,
J = 6.6 Hz), 2.71 (m, 1 H), 3.30 (dd, 1 H, J = 9.3, 7.7 Hz), 3.36 (dd,
1 H, J = 9.3, 7.7 Hz), 4.50 (s, 1 H), 4.85 (t, 1 H, J = 6.7 Hz), 7.26-
7.40 (m, 5 H).
MS: m/z = 244 (M+), 91 (100%).
HRMS: m/z Calcd for C16H20O2 244.1462. Found 244.1463.
(+)-(4R)-4-[(1R)-2-Benzyloxy-1-vinylethyl]-2,2-propanedithio-
cyclopentan-1-one (30)
MS: m/z = 260 (M+), 91 (100%).
HRMS: m/z Calcd for C16H20O3 260.1411. Found 260.1379.
A solution of (+)-29 (420 mg, 1.72 mmol) and pyrrolidine (0.72 mL,
8.61 mmol) in benzene (20 mL) was refluxed with removal of water
using a Dean-Stark apparatus. After 1 h, the benzene was replaced
by MeCN (12 mL) after evaporation under reduced prossure and to
this mixture were added trimethylene dithiotosylate (716 mg,
1.72 mmol) and Et3N (0.72 mL, 5.16 mmol) and the mixture was re-
fluxed for 1 h. The mixture was diluted with Et2O (50 mL) and
washed successively with H2O (20 mL) and brine (10 mL), dried
(MgSO4), evaporated under reduced pressure, and chromato-
graphed (SiO2, 100 g, eluent: Et2O/ hexane, 1:5 v/v) to give
the a-diketone monothioketal 30 (442 mg, 74%) as a pale yellow
oil; [a]D31 +53.4 (c = 0.6, CHCl3),.
(-)-(1R,3S)-3-[(1R)-1-Benzyloxymethyl-3·hydroxypropyl]cy-
clopentan-1-ol (26)
To a stirred solution of the lactone (+)-25 (641 mg, 2.47 mmol) in
THF (20 mL) was added LiAlH4 (140 mg, 3.70 mmol) at 0 °C. After
10 min, the reaction was quenched by the addition of 35% NH4OH
(5 mL) and the mixture was diluted with CHCl3 (20 mL) and filtered
through a Celite pad. The filtrate was dried (MgSO4), evaporated
under reduced pressure, and chromatographed (SiO2, 30g, eluent:
CHCl3/MeOH, 10:1 v/v) to give the diol 26 (614 mg, 94 %) as a col-
orless oil; [a]D27 -4.5 (c = 1.6, CHCl3).
IR (film): n = 1723 cm-1.
IR (film): n = 3342 cm-1.
1H NMR (300 MHz, CDCl3): d = 1.64 (dd, 1 H, J = 15.0, 11.3 Hz),
1.87 (tq, 1 H, J = 13.5, 3.1 Hz), 2.08-2.32 (m, 4 H), 2.43-2.72 (m,
4 H), 3.14 (dt, 1 H, J = 13.4, 2.2 Hz), 3.43 (d, 2 H, J = 5.8 Hz), 3.89
(dt, 1 H, J = 13.5, 2.0 Hz), 4.49 (s, 2 H), 5.12 (d, 1 H, J = 17.0 Hz),
5.16 (d, 1 H, J = 10.2 Hz), 5.68 (dt, 1 H, J = 17.0, 10.1 Hz), 7.26-
7.39 (m, 5 H).
1H NMR (300 MHz, CDCl3): d = 1.16-1.28 (m, 1 H), 1.40-1.86
(m, 9 H), 2.04-2.18 (m, 1 H), 2.86 (br s, 1 H), 3.46 (dd, 1 H, J = 9.1,
6.6 Hz), 3.54 (dd, 1 H, J = 9.3, 6.0 Hz), 3.58-3.74 (m, 2 H), 4.23-
4.32 (m, 1 H), 4.51 (d, 2 H, J = 2.5 Hz), 7.26-7.39 (m, 5 H).
MS: m/z = 264 (M+), 91 (100%).
HRMS: m/z Calcd for C16H24O3 264.1724. Found 264.1705.
MS: m/z = 348 (M+), 257 (100%).
Synthesis 2000, No. 13, 1825–1834 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Diastereodivergent Synthesis of the C9-Cyclopentanone Chiral Building Blocks
1833
HRMS: m/z Calcd for C19H24O2S2 348.1216. Found 348.1245.
(-)-Semburin (5)
A solution of the diol (+)-33 (60 mg, 0.23 mmol) and MeI (0.48 mL,
6.9 mmol) in aq MeCN (10%, 5.5 mL) was stirred at r.t. for 12 h.
The mixture was diluted with Et2O (20 mL) and treated with aq 5%
Na2S2O3 solution (2 mL). The organic layer was separated and was
washed with brine (3 mL), dried (MgSO4) and evaporated under re-
duced pressure to give a hemiacetal mixture. The mixture was then
dissolved in benzene (3.0 mL) and refluxed for 5 h in the presence
of pyridinim p-toluenesulfonate (PPTS, 6 mg, 0.02 mmol). After
cooling the mixture was diluted with Et2O (20 mL) and the solution
was washed successively with sat. aq NaHCO3 solution (5 mL) and
brine (3 mL), dried (MgSO4), evaporated under reduced pressure,
and chromatographed (SiO2, 5 g, eluent: EtOAc/hexane, 1:5 v/v) to
give (-)-semburin (5) (14.4 mg, 41%) as a colorless oil; [a]D29 -2.7
(c = 0.1, CHCl3) {Lit. [a]D25 -2.0 (c = 0.1, CHCl3)}. Spectroscopic
data were identical in all respects with those of an authentic material
obtained from (+)-norcamphor [(+)-1].
(+)-(4R)-4-[(1R)-2-Hydroxy-1-vinylethyl]-2,2-propanedithiocy-
clopentan-1-one (31)
To a stirred solution of (+)-30 (410 mg, 1.18 mmol) in CH2Cl2
(15 mL) was added BBr3 (1 M in CH2Cl2, 3.5 mL, 3.53 mmol) at
-78 °C and, after 10 min, the mixture was quenched by addition of
sat. aq NaHCO3 solution (5 mL) and extracted with Et2O (30 mL).
The extract was washed successively with sat. aq NaHCO3 solution
(5 mL) and H2O (5 mL), dried (MgSO4), evaporated under reduced
pressure, and chromatographed (SiO2, 20 g, eluent: Et2O/hexane,
1:1 v/v) to give the primary alcohol 31 (242 mg, 80%) as a colorless
needles; mp 77-79 °C; [a]D27 +52.9 (c = 1.8, CHCl3).
IR (film): n = 3438, 1717 cm-1.
1H NMR (300 MHz, CDCl3): d = 1.54 (br s, 1 H), 1.68 (dd, 1 H,
J = 13.7, 11.8 Hz), 1.87 (tq, 1 H, J = 13.4, 3.0 Hz), 2.07-2.24 (m,
4 H), 2.39-2.60 (m, 3 H), 2.73 (ddd, 1 H, J = 18.4, 7.7 1.9 Hz), 3.14
(dt, 1 H, J = 13.2, 2.5 Hz), 3.46-3.54 (m, 1 H), 3.59-3.69 (m, 1 H),
3.89 (dt, 1 H, J = 13.2, 2.5 Hz), 5.20 (d, 1 H, J = 17.0 Hz), 5.25 (d,
1 H, J = 10.4 Hz), 5.62 (dt, 1 H, J = 17.0, 10.0 Hz).
References
(1) (a) Kawamura, M.; Ogasawara, K. Tetrahedron Lett. 1995,
36, 3369.
MS: m/z = 258 (M+), 132 (100%).
(b) Saito, M.; Kawamura, M.; Hiroya, K.; Ogasawara, K.
Chem. Commun. 1997, 765.
HRMS: m/z Calcd for C12H18O2S2 258.0747. Found 258.0729.
(2) Kawamura, M.; Ogasawara, K. Heterocycles 1997, 44, 129.
(3) We used noramphor [(+)-1] prepared from (+)-endo-
norborneol having >95% ee the latter of which was kindly
supplied by Chisso Corporation, Japan.
(+)-(3R,4R)-3-[(1,3-Dithian-2-yl)methyl]-4-vinyl-5-pentanolide
(32)
A solution of (+)-31 (242 mg, 0.94 mmol) in t-BuOH (9.0 mL) was
heated with KOH (194 mg, 3.47 mmol) at 65 °C for 45 min. After
evaporation of the solvent under reduce pressure, the residue was
treated with 1 N HCl (5 mL) and extracted with Et2O (30 mL). The
extract was washed with brine (5 mL), dried (MgSO4), evaporated
under reduced pressure, and chromatographed (SiO2, 10 g, eluent:
Et2O/hexane, 1.1 v/v) to give the lactone 32 (205 mg, 85%) as a col-
orless oil; [a]D25 +28.0 (c = 1.2, CHCl3),.
For an enzyme-mediated resolution of (±)-norborneol see:
Melz, M.; Saccomano, N. A. Tetrahedron Lett. 1992, 33,
1201.
For a catalytic route to both enantiomeric norcamphor, see:
Uozumi, Y.; Lee, S.-Y.; Hayashi, T. Tetrahedron Lett. 1992,
33, 7185.
(4) A part of the present study was reported in a preliminary form,
see:
IR (film): n = 1735 cm-1.
1H NMR (300 MHz, CDCl3): d = 1.51-1.62 (m, 1 H), 1.79-1.95 (m
2 H), 2.02 (ddd, 1 H, J = 14.3, 10.4, 3.9 Hz), 2.14-2.40 (m, 4 H),
2.79-3.00 (m, 5 H), 4.06 (t, 1 H, J = 10.2 Hz), 4.07 (dd, 1 H,
J = 11.2, 3.3 Hz), 4.28 (dd, 1 H, J = 11.6, 3.3 Hz), 5.25 (d, 1 H,
J = 10.0 Hz), 5.29 (d, 1 H, J = 17.3 Hz), 5.58 (ddd, 1 H, J = 17.3,
10.0, 7.9 Hz).
(a) Kawamura, M.; Ogasawara, K. J. Chem. Soc., Chem.
Commun. 1995, 2403.
(b) Nagata, H.; Taniguchi, T.; Kawamura, M.; Ogasawara, K.
Tetrahedron Lett. 1999, 40, 4207.
(5) (a) Patel, V.; Ragauskas, A. J.; Stothers, J. B. Can. J. Chem.
1986, 64, 1440.
(b) Moriarty, R. M.; Vaid, R. K.; Hopkins, T. E.; Vaid, B. K.;
Prakash, O. Tetrahedron Lett. 1990, 31, 197.
(6) Goering, H. L.; Kantner, S. S. J. Org. Chem. 1981, 46, 4605.
(7) Ito, Y.; Fujii, S.; Nakatsuka, M.; Kawamoto, F.; Saegusa, T.
Org. Synth. Coll. Vol. 1988, 6, 327.
(8) Gemal, A. L.; Luche, T. L. J. Am. Chem. Soc. 1981, 103, 5454.
(9) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4156.
Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(10) Allen, J. V.; Williams, J. M. J. Tetrahedron Lett. 1996, 37,
1859.
MS: m/z = 258 (M+), 132 (100%).
HRMS: m/z Calcd for C12H18O2S2 258.0747. Found 258.0770.
(+)-(2R,3R)-3-[(1,3-Dithian-2-yl)methyl]-2-vinylpentane-1,5-
diol (33)
To a stirred solution of the lactone (+)-32 (62 mg, 0.24 mmol) in
THF (3.0 mL) was added LiAlH4 (13.7 mL, 0.36 mmol) at 0 °C and,
after 10 min, the reaction was quenched by the addition of H2O
(5 mL) and the mixture was diluted with EtOAc (20 mL). After fil-
tration through a Celite pad, the filtrate was dried (MgSO4), evapo-
rated under reduced pressure, and chromatographed (SiO2, 5 g,
eluent: EtOAc/hexane, 2:1 v/v) to give the diol 33 (56 mg, 89%) as
a colorless oil; [a]D27 +10.3 (c = 1.3, CHCl3).
See also: Stürmer, R. Angew. Chem. Int. Ed. Engl. 1997, 36,
1173.
Larsson, A. L. E.; Persson, B. A.; Bäckvall, J. -E. Angew.
Chem. Int.Ed. Engl. 1997, 36, 1211.
Jones, M. M.; Williams, J. M. Chem. Commun. 1998, 2519.
(11) Nagata, H.; Ogasawara, K. Tetrahedron Lett. 1999, 40, 6617.
For example, see: Kaneda, K.; Fujii, M.; Morioka, K. J. Org.
Chem. 1996, 61, 4502.
IR (film): n = 3358 cm-1.
1H NMR (300 MHz, CDCl3): d = 1.49-1.70 (m, 3 H), 1.85 (ddd, 1
H, J = 14.3, 10.2, 5.7 Hz), 1.80-2.20 (m, 5 H), 2.28-2.40 (m, 1 H),
2.78-3.00 (m, 4 H), 3.55-3.76 (m, 2 H), 3.71 (t, 1 H, J = 6.6 Hz),
5.16 (dd, 1 H, J = 17.3, 1.9 Hz), 5.22 (dd, 1 H, J = 10.4, 1.9 Hz),
5.63 (ddd, 1 H, J = 17.3, 10.4, 7.7 Hz).
Kaneda, K.; Fujii, Y.; Ebitani, K. Tetrahedron Lett. 1997, 52,
9023.
Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. Tetrahedron
Lett. 1998, 39, 6011.
Hayashi, M.; Yamada, K.; Arikita, O. Tetrahedron Lett. 1999,
40, 1171.
MS: m/z = 262 (M+), 119 (100%).
HRMS: m/z Calcd for C12H22O2S2 262.1060. Found 262.1050.
Synthesis 2000, No. 13, 1825–1834 ISSN 0039-7881 © Thieme Stuttgart · New York

1834
H. Nagata et al.
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1437-210X,E;2000,0,13,1825,1834,ftx,en;F03800SS.pdf
Synthesis 2000, No. 13, 1825–1834 ISSN 0039-7881 © Thieme Stuttgart · New York