Diastereoselective synthesis of the acid part of a new muscarinic M3 receptor antagonist

Article abstract of DOI:10.1016/S0040-4020(00)00961-3

Diastereoselective synthesis of (2R)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid 1, an important component of a novel muscarinic M₃ receptor antagonist 3, was achieved via Michael addition of an enolate of chiral dioxolane 4 to (-)-dicyclopentadiene 9 in 90% de as a key step. The desired Michael adduct 10, which was easily isolated by recrystallization of a mixture of diastereomers, was submitted to retrograde Diels-Alder reaction. Subsequent hydrogenation of the resultant enone 12 gave the key intermediate 5 in 91% chemical yield from 10. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00961-3

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 9901±9907
Diastereoselective Synthesis of the Acid Part of a New Muscarinic
M3 Receptor Antagonist
*
Morihiro Mitsuya, Yoshio Ogino, Norikazu Ohtake and Toshiaki Mase
*
Banyu Tsukuba Research Institute in collaboration with Merck Research Laboratories, Okubo-3, Tsukuba 300-2611, Ibaraki, Japan
Received 18 September 2000; accepted 10 October 2000
AbstractÐDiastereoselective synthesis of (2R)-2-[(1R)-3,3-di¯uorocyclopentyl]-2-hydroxy-2-phenylacetic acid 1, an important component
of a novel muscarinic M3 receptor antagonist 3, was achieved via Michael addition of an enolate of chiral dioxolane 4 to (2)-dicyclopenta-
diene 9 in 90% de as a key step. The desired Michael adduct 10, which was easily isolated by recrystallization of a mixture of diastereomers,
was submitted to retrograde Diels±Alder reaction. Subsequent hydrogenation of the resultant enone 12 gave the key intermediate 5 in 91%
chemical yield from 10. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
fragment 1 and an 4-amino-1-(aminopyridylmethyl)-
piperidine moiety 2 connected through an amide bond
(Fig. 1). The original synthesis of this acid 1 included
Michael addition of an enolate of 42 to 2-cyclopenten-1-
one and subsequent chromatographic separation of the
diasteromeric mixture of Michael adducts (5:6ˆ1.2:1) to
Compound 3 is a long-acting, orally active muscarinic
receptor antagonist with 190-fold selectivity for M3 over
M2 receptors.1 This compound is now being developed for
the treatment of urinary tract disorders such as urinary
incontinence (UI) and respiratory disorders such as chronic
obstructive pulmonary disease (COPD).
obtain the key intermediate
5
(Scheme 1).3,4 We
considered it desirable to produce 5 diastereoselectively to
streamline the synthesis of 1. In this paper, we describe a
synthesis of 1 involving a diastereoselective preparation
of 5.
The muscarinic M3 receptor antagonist 3 consists of a
unique chiral di¯uorinated cyclopentylphenylacetic acid
Figure 1.
Scheme 1. Conditions: (a) LDA, 2-cyclopenten-1-one, THF, 2788C. (b) DAST, CHCl3, 708C. (c) NaOH, MeOH, rt.
Keywords: muscarinic receptor; antagonist; Michael addition; enolate.
* Corresponding authors. Tel.: 181-298-77-2000; fax: 181-298-77-2029; e-mail: mituyamr@banyu.co.jp
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00961-3

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M. Mitsuya et al. / Tetrahedron 56 (2000) 9901±9907
Figure 2.
Scheme 2. Conditions: (a) LDA, 2-cyclopenten-1-one, THF, 2708C, then TMSCl. (b) Pd(OAc)2, p-benzoquinone, CH3CN, rt.
Table 1. 1,4-Reduction of 7
some of the reported methods for 1,4-reduction of 7
including DIBAL±CuI,6 [(Ph3P)CuH]6±PhSiH3,7 and
Ph2SiH2±Pd(Ph3P)4±ZnCl2 systems did not lead to the
8
desired diastereoselectivity. These results indicated that
the chirality on the 1,3-dioxolan-4-one moiety may not
affect the diastereoselective reduction of the double bond.
Next, we investigated the use of a chirally derived 2-cyclo-
penten-1-one [e.g. (2)-9] as a Michael acceptor in place
of 2-cyclopenten-1-one to obtain 5 stereoselectively. (2)-
Tricyclo[5,2,1,02,6]deca-4,8-dien-3-one (2)-99 has been
used as a chiral cyclopentenone equivalent for the enantio-
selective syntheses of various natural products such as (1)-
equilenin and (2)-physostigmine.10 In the previously
reported examples, Michael addition of a naphtyl Grignard
reagent (2.4 equiv.) to (2)-9 in the presence of CuI
(1.2 equiv.) was reported to produce the exo-adduct
exclusively,10 however the conjugate addition of an enolate
to this substrate has not been reported.
Run
Condition
H2, Pd±C, EtOAc
H2, Pd±C, EtOH
Ratio of 5 and 6a Yield (%)
1
2
3
4
5
6
7
1:1.2
1:1.4
1:1.3
1.2:1
1:1.2
1:1.2
1.1:1
99
97
89
88
76
73
72
H2, Pd±C, THF
H2, Rh±Al2O3, EtOAc
Cul, DIBAL, THF±HMPA
[(Ph3P)CuH]6, PhSiH3, benzene
Ph2SiH2, Pd(PPh3)4, ZnCl2,
CHCl3
a Determined by 1H NMR of the crude reaction mixture.
Results and Discussion
We thus investigated the conjugate addition of the corre-
sponding enolate of 4 to the chiral enone (2)-9, paying
particular attention to the stoichiometry of the substrate
and reagent (Scheme 3). After some experimentation, we
found favorable reaction conditions: the lithium enolate of
the dioxolane 4 generated by LDA was reacted with
1.1 equiv. of (2)-9 at 2708C to give Michael adducts 10
and 11 in a ratio of 8:1.11 Importantly, the desired compound
10 was isolated exclusively (.99% de) by recrystallization
of the mixture from hexane±EtOAc in 72% yield from 4.
The stereochemical structure of 10 was elucidated by NOE
experiments.12 The minor isomer 11 was also assigned to be
a 5S-epimer of 10 by the NOE experiments,12 indicating that
the newly generated asymmetric carbon at the tricyclic
ketone moiety was completely stereocontrolled as expected.
Retro-synthetic analysis of 1 suggested two potentially
feasible approaches for the diastereoselective synthesis of
the key intermediate 5; (1) diastereoselective hydrogenation
of enone 7, and (2) diastereoselective Michael addition of an
enolate of 4 to a cyclopentenone derivative with chiral
auxiliaries (Fig. 2).
We ®rst attempted the diastereoselective 1,4-reduction of 7,
which was prepared in 61% yield from 4 by palladium
catalyzed oxidation5 of enol trimethylsilane 8 (Scheme 2).
Catalytic hydrogenation of 7 with 10% Pd±C or Rhodium
on alumina under a hydrogen atmosphere proceeded in a
non-selective manner to give a mixture of 5 and 6 in a
ratio of 1.2:1,1:1.4 (Table 1). In addition, application of

M. Mitsuya et al. / Tetrahedron 56 (2000) 9901±9907
9903
Scheme 3. Conditions: (a) LDA, THF, 2708C, then (2)-9. (b) 1758C, 1,2-dichlorobenzene. (c) H2, Pd±C, EtOAc.
It has been reported that chiral or achiral amines aggregating
with lithium enolates enhance the selectivity and rate of the
corresponding addition reactions.13 Therefore, the effects of
additives on Michael addition of the lithium enolate of 4
were examined in an attempt to increase diastereoselectivity
(Table 2). Among the additives tested, tetramethylethylene-
diamine (TMEDA) gave the best selectivity (10:11ˆ20:1).
This ®nding suggests that TMEDA coordinating to the
enolate may block the undesirable access of (2)-9 from
the Si face as well as the tert-butyl group, although the
structure of this type of aggregate remains unclear.13
Subsequently, the retrograde Diels±Alder reaction of 10
was accomplished at 1758C in 1,2-dichlorobenzene to
produce an enone 12 in 92% yield without any decomposi-
tion. The enone 12 was hydrogenated with a catalytic
amount of 10% Pd on carbon under a hydrogen atmosphere
to yield 5 in 99% yield. Conversion of 5 to 1 was accom-
plished by di¯uorination of the ketone moiety using DAST
followed by hydrolysis under basic condition as reported
previously.1 The absolute stereochemical structure of 1
was unambiguously determined to be (2R,10R) by the
X-ray analysis of its (S)-phenetylamine salt (Fig. 3).
Table 2. Michael addition of 4 to (2)-9
Conclusion
In summary, we investigated improved synthetic methods
for the preparation of 1, focusing on the diastereoselective
synthesis of 5. As a result, we found that the Michael
reaction of an enolate of 4 with a (2)-tricyclo[5,2,1,02,6]-
deca-4,8-dien-3-one (2)-9 proceeded diastereoselectively
to yield 10 in 90% de, which was easily converted to the
key intermediate 5 in excellent yield. This method may
enable us to provide multi-hundred grams of 1 from 4
without chromatographic separation.
Run
Additive
Ratio of 10 and 11 Yield (%)a
1
2
3
4
None
TMEDA
8:1
72
74
66
70
20:1
10:1
11:1
Pentamethyldiethylenetriamine
Hexamethyltriethylenetetramine
a Isolated yields after recrystallization.
Experimental
Melting points were determined with a Yanaco MP micro-
melting point apparatus and were not corrected. Proton
NMR spectra were obtained on a Varian Gemini-300
with tetramethylsilane as an internal standard. Mass
spectrometry was performed with a JEOL JMS-SX 102A.
Optical rotations were measured with a Jasco DIP-370
polarimeter. TLC was done with Merck Kieselgel F254
pre-coated plates. Silica gel (SiO2) column chromatography
was carried out on Wako gel C-300.
(2R,5R)-2-tert-Butyl-5-(3-oxo-1-cyclopentenyl)-5-
phenyl-1,3-dioxolan-4-one (7)
To a solution of (2R,5R)-2-tert-butyl-5-phenyl-1,3-dioxo-
lan-4-one2 4 (3.18 g, 14.5 mmol) in THF (150 mL) was
dropwise added 1.50 M of lithium diisopropylamide
mono-(tetrahydrofuran)
in
cyclohexane
(11.0 mL,
Figure 3. ORTEP drawing (50% ellipsoid) of 1.

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M. Mitsuya et al. / Tetrahedron 56 (2000) 9901±9907
16.5 mmol) at 2708C, and the mixture was stirred at the
same temperature for 30 min. To the mixture was added a
solution of 2-cyclopenten-1-one (1.40 g, 17.1 mmol) in
THF (5 mL) for 10 min, maintaining the temperature
below 2658C. After the mixture was stirred for 1 h at
2708C, chlorotrimethylsilane (2.20 mL, 17.3 mmol) was
added and the resulting mixture was allowed to warm to
2408C for 2 h. The reaction was quenched by the addition
of saturated aqueous NH4Cl solution at 2408C. The mixture
was warmed to room temperature, diluted with H2O and
extracted with EtOAc. The organic layer was washed with
H2O and brine, dried over MgSO4 and concentrated under
reduced pressure to give crude 8. To a solution of crude 8
(6.01 g) in CH3CN (150 mL) was added p-benzoquinone
(1.90 g, 17.6 mmol) and palladium acetate (3.30 g,
14.7 mmol) at room temperature. The mixture was stirred
for 24 h, concentrated to a small volume and diluted with
Et2O. The insoluble matter was ®ltered off through a pad of
Celite. The ®ltrate was concentrated under reduced pressure
and the residue (7:its 5S-isomerˆ9:1) was puri®ed by silica
gel column chromatography (hexane±EtOAc, 20:1±10:1
elution) to give a mixture of 7 and its 5S-isomer (30:1,
3.50 g). This mixture was further recrystallized to afford 7
(2.65 g, 61%, .98% de) as a white solid: mp 92±948C
chromatography (hexane±EtOAc, 20:1±10:1 elution) to
give a mixture of 5 and 6 (50 mg, 76%).
Reduction of 7 with [(Ph
3P)CuH]6 and PhSiH3
To a suspension of [(Ph3P)CuH]6 (5.0 mg, 0.0025 mmol) in
toluene (1.0 mL) were added phenylsilane (0.060 mL,
0.49 mmol) and 7 (95 mg, 0.32 mmol) at room temperature.
After stirring for 43 h, the mixture was diluted with Et2O.
The organic layer was washed with saturated aqueous
NH4Cl solution, saturated aqueous NaHCO3 solution and
brine, dried over MgSO4 and concentrated under reduced
pressure. The residue (5:6ˆ1:1.2) was puri®ed by silica gel
column chromatography (hexane±EtOAc, 20:1±10:1
elution) to give a mixture of 5 and 6 (70 mg, 73%).
Pd-catalyzed reduction of 7 with Ph2SiH2 and ZnCl2
To a solution of 7 (98 mg, 0.33 mmol) in CHCl3 (2.0 mL)
were successively added diphenylsilane (125 mg,
0.49 mmol), zinc chloride (20 mg, 0.15 mmol) and
Pd(Ph3P)4 (10 mg, 0.0087 mmol) at room temperature.
After stirring for 46 h, the mixture was washed with satu-
rated aqueous NaHCO3 solution and dried over MgSO4.
Evaporation of the solvent gave the crude residue
(5:6ˆ1.1:1), which was puri®ed by silica gel column chro-
matography (hexane±EtOAc, 20:1±10:1 elution) to afford a
mixture of 5 and 6 (71 mg, 72%).
1
(hexane±EtOAc); H NMR (CDCl3) d 1.03 (9H, s), 2.40±
2.50 (2H, m), 2.57±2.36 (2H, m), 5.29 (1H, s), 6.44 (1H, m),
7.35±7.50 (3H, m), 7.57±7.71 (2H, m); IR (KBr, cm21
)
1794, 1709; FAB-MS m/z 301 (M1H)1; Anal. calcd for
C18H20O4: C, 71.98; H, 6.71. Found: C, 71.84; H, 6.66;
[a]2D0ˆ286.3 (c 1.0, CHCl3).
(2)-(1R,2R,3S,6R,7S)-Tricyclo[5.2.1.02,6]deca-4,8-dien-
3-one [(2)-9]
General procedure for catalytic hydrogenation of 7
This was prepared according to the method reported in the
literature.9a mp 76±778C (hexane); [a]2D5ˆ2157.3 (c 1.0,
CHCl3); [lit.9c: mp 768C (hexane); [a]3D0ˆ2158.5 (c 1.0,
CHCl3)].
To a solution of 7 (51 mg, 0.17 mmol) in EtOH (2 mL) was
added 10% palladium on carbon (15 mg, 0.014 mmol), and
the mixture was hydrogenated under atmospheric pressure
for 2 h. After ®ltration of the catalyst, the ®ltrate was
concentrated under reduced pressure. After the selectivity
(2R,5R)-2-tert-Butyl-5-[(1R,2R,3S,6R,7S)-5-oxotricyclo-
[5.2.1.02,6]dec-8-en-3-yl]-5-phenyl-1,3-dioxolan-4-one
(10) and (2R,5S)-2-tert-butyl-5-[(1R,2R,3S,6R,7S)-5-
oxotricyclo[5.2.1.02,6]dec-8-en-3-yl]-5-phenyl-1,3-
dioxolan-4-one (11)
1
ratio of the crude material was determined by H NMR
(5:6ˆ1:1.4), the crude material was puri®ed by silica gel
column chromatography (hexane±EtOAc, 20:1±10:1
elution) to give a mixture of 5 and 6 (50 mg, 97%). The
1H NMR and MS spectra of 5 and 6 were identical to the
reported data.4
To a solution of 4 (21.2 g, 96.5 mmol) in THF (700 mL) was
dropwise added 1.50 M of lithium diisopropylamide mono-
(tetrahydrofuran) in cyclohexane (75.0 mL, 113 mmol) at
2708C, and the mixture was stirred at the same temperature
for 30 min. To the mixture was added a solution of
(1S,2R,6R,7R)-tricyclo[5.2.1.02,6]dec-4,8-dien-3-one (2)-9
(15.4 g, 106 mmol) in THF (200 mL), while maintaining
the temperature below 2658C, and the resulting mixture
was stirred for 1.5 h at 2708C. The reaction was quenched
by the addition of saturated aqueous NH4Cl solution, and the
mixture was warmed to room temperature, diluted with H2O
and extracted with EtOAc. The organic layer was washed
with H2O and brine, dried over MgSO4 and concentrated
under reduced pressure. The residual solid (10:11ˆ8:1)
was crystallized from hexane±EtOAc to afford 10 (25.5 g,
72%, .98% de) as a white solid: mp 178±1808C (hexane±
Other catalytic hydrogenation reactions (run 2±4) were
conducted according to this procedure. The yields and
selectivity ratios are given in Table 1.
Reduction of 7 with CuI±DIBAL
To a suspension of CuI (200 mg, 1.05 mmol) in THF±
HMPA (4:1, 1.0 mL) was added 1.0 M of diisobutyl
aluminum hydride in toluene (1.0 mL, 1.0 mmol) at
2788C. After the mixture was stirred for 1 h at the same
temperature, 7 (65 mg, 0.22 mmol) was added, and the
resulting mixture was allowed to warm to 2308C for 1 h.
The reaction was quenched by the addition of 0.5N HCl, and
the mixture was extracted with EtOAc. The organic layer
was washed with 0.5N HCl, H2O and brine, dried over
MgSO4 and concentrated under reduced pressure. The
residue (5:6ˆ1:1.2) was puri®ed by silica gel column
1
EtOAc); H NMR (CDCl3) d 0.91 (9H, s), 1.44 (1H, brd,
Jˆ8.7 Hz), 1.58 (1H, brd, Jˆ8.7 Hz), 1.87 (1H, dd, Jˆ9.3,
18.6 Hz), 2.25 (1H, dd, Jˆ6.9, 18.6 Hz), 2.43 (1H, m), 2.90
(1H, m), 2.93±3.02 (2H, m), 3.17 (1H, m), 5.46 (1H, s),

M. Mitsuya et al. / Tetrahedron 56 (2000) 9901±9907
9905
6.10±6.20 (2H, m), 7.29±7.41 (3H, m), 7.62 (2H, brd,
Jˆ8.3 Hz); The NOEs between d 1.87 (Hb) and d 2.43
(Ha), d 2.43 (Ha) and d 6.10±6.20 (He), d 2.43 (Ha) and d
7.62 (Hd), d 2.90 (Hf) and d 5.46 (Hc) were observed. IR
(KBr, cm21) 1788, 1734; FAB-MS m/z 367 (M1H)1; Anal.
calcd for C23H26O4: C, 75.38; H, 7.15. Found: C, 75.43; H,
7.14; [a]2D0ˆ265.8 (c 1.0, CHCl3).
further crystallized from hexane to give 12 (9.5 g, 31%) as
a second crop: mp 93±948C (hexane±EtOAc); H NMR
1
(CDCl3) d 0.94 (9H, s), 2.16 (1H, dd, Jˆ6.6, 18.9 Hz),
2.33 (1H, dd, Jˆ2.7, 18.9 Hz), 3.71 (1H, m), 5.21 (1H, s),
6.38 (1H, dd, Jˆ1.8, 5.7 Hz), 7.31±7.49 (3H, m), 7.61±7.76
(3H, m); IR (KBr, cm21) 1792, 1709; FAB-MS m/z 301
(M1H)1; Anal. calcd for C18H20O4: C, 71.98; H, 6.71.
Found: C, 71.79; H, 6.55; [a]2D0ˆ294.2 (c 1.0, CHCl3).
For elucidation of the structure of the minor isomer (11), the
mother liquid was concentrated, puri®ed by silica gel
column chromatography (hexane±EtOAc, 20:1 elution),
and recrystallized to afford 11 (2.90 g, 8%) as a white
crystalline solid: mp 131±1328C (hexane±EtOAc); 1H
NMR (CDCl3) d 1.03 (9H, s), 1.28 (1H, brd, Jˆ9.6 Hz),
1.40 (1H, brd, Jˆ9.6 Hz), 2.20 (1H, dd, Jˆ9.6, 18.6 Hz),
2.23 (1H, m), 2.38 (1H, dd, Jˆ6.3, 18.6 Hz), 2.51 (1H, m),
2.80 (1H, m), 2.94 (1H, m), 3.13 (1H, m), 5.11 (1H, s), 6.06
(1H, m), 6.13 (1H, m), 7.36±7.50 (3H, m), 7.56 (2H, brd,
Jˆ8.3); The NOEs between d 2.20 (Hb) and d 2.51 (Ha), d
2.51 (Ha) and d 6.06 (He), d 2.51 (Ha) and d 7.56 (Hd), d
(2R,5R)-2-tert-Butyl-5-[(1R)-3-oxocyclopentyl]-5-phenyl-
1,3-dioxolan-4-one (5)4
To a solution of 12 (19.1 g, 64.2 mmol) in EtOAc (700 mL)
was added 10% palladium on carbon (2.02 g, 1.90 mmol),
and the mixture was hydrogenated under atmospheric pres-
sure for 2 h. After ®ltration of the catalyst, the ®ltrate was
concentrated under reduced pressure. The resultant solid
was washed with hexane and dried to afford 5 (16.8 g,
87%). The ®ltrate was concentrated and puri®ed by silica
gel column chromatography (hexane±EtOAc, 20:1±10:1
elution) to give an additional 5 (2.40 g, 12%).
5.11 (Hc) and d 7.56 (Hd) were observed. IR (KBr, cm21
)
1789, 1738; FAB-MS m/z 367 (M1H)1; Anal. calcd for
C23H26O4: C, 75.38; H, 7.15. Found: C, 75.39; H, 7.28;
[a]2D0ˆ2176.4 (c 1.0, CHCl3).
(2R,5R)-2-tert-Butyl-5-[(1S,2S,3R,6S,7R)-5-oxotricyclo-
[5.2.1.02,6]dec-8-en-3-yl]-5-phenyl-1,3-dioxolan-4-one
(13) and (2R,5S)-2-tert-butyl-5-[(1S,2S,3R,6S,7R)-5-
oxotricyclo[5.2.1.02,6]dec-8-en-3-yl]-5-phenyl-1,3-
dioxolan-4-one (14)
Preparation of 10 (Michael addition of 4 to (2)-9 in the
presence of TMEDA)
To a solution of 4 (2.12 g, 9.65 mmol) in THF (70 mL) was
dropwise added 1.50 M of lithium diisopropylamide mono-
(tetrahydrofuran) in cyclohexane (7.45 mL, 11.2 mmol) at
2708C, and the mixture was stirred at the same temperature
for 30 min. Subsequently, tetramethylethylenediamine
(2.10 mL, 13.9 mmol) was added and the mixture was stir-
red at 2708C for 1 h. To the mixture was added a solution of
(2)-9 (1.50 g, 10.3 mmol) in THF (20 mL), maintaining the
temperature below 2658C, and the resulting mixture was
stirred for 1 h at 2708C and allowed to warm to 2258C. The
reaction was quenched by the addition of saturated aqueous
NH4Cl solution, and the mixture was warmed to room
temperature, diluted with H2O and extracted with EtOAc.
The organic layer was washed with H2O and brine, dried
over MgSO4 and concentrated under reduced pressure. The
residual solid (10:11ˆ20:1) was crystallized from hexane±
EtOAc to afford 10 (2.60 g, 74%, .99% de). The diastereo-
meric excess was determined by HPLC analysis (tR of 10:
13.6 min, tR of 11: 15.6 min, DAICEL CHIRALCEL OD-
RH 0.46£15 cm, 0.5 M NaClO4 aq.: CH3CNˆ40:60, ¯ow
rateˆ0.5 ml/min, UV detection 210 nm).
To a solution of 4 (24.6 g, 112 mmol) in THF (800 mL) was
dropwise added 1.50 M of lithium diisopropylamide mono-
(tetrahydrofuran) in cyclohexane (85.0 mL, 128 mmol) at
2708C, and the mixture was stirred at the same temperature
for 30 min. To the mixture was added a solution of
(1R,2S,6S,7S)-tricyclo[5.2.1.02,6]dec-4,8-dien-3-one (1)-9
(17.9 g, 123 mmol) in THF (200 mL), maintaining the
temperature below 2658C, and the mixture was stirred for
2 h at 2708C. The reaction was quenched by the addition of
saturated aqueous NH4Cl solution, and the mixture was
warmed to room temperature, diluted with H2O and
extracted with EtOAc. The organic layer was washed with
H2O and brine, dried over MgSO4 and concentrated under
reduced pressure. The residual solid (13:14ˆ5:1) was
recrystallized to afford 13 (25.1 g, 61%, .98% de) as a
1
white solid: mp 162±1638C (hexane±CHCl3); H NMR
(CDCl3) d 0.92 (9H, s), 1.28 (1H, brd, Jˆ8.1 Hz), 1.40
(1H, brd, Jˆ8.1 Hz), 2.13 (1H, m), 2.25±2.32 (2H, m),
2.42 (1H, m), 2.83 (1H, m), 2.91 (1H, m), 3.10 (1H, m),
5.35 (1H, s), 6.02 (1H, m), 6.12 (1H, m), 7.29±7.48 (3H, m),
7.72 (2H, brd, Jˆ8.3 Hz); The NOEs between d 2.25±2.32
(Hb) and d 5.35 (Hc), d 2.25±2.32 (Hb) and d 2.42 (Ha), d
2.42 (Ha) and d 6.02 (He), d 2.42 (Ha) and d 7.72 (Hd) were
observed. IR (KBr, cm21) 1788, 1743; FAB-MS m/z 367
(M1H)1; Anal. calcd for C23H26O4: C, 75.38; H, 7.15.
Found: C, 75.07; H, 7.03; [a]2D0ˆ184.0 (c 1.0, CHCl3).
Other reactions using additives (run 3±4) were conducted
according to this procedure. The yields and selectivity ratios
are given in Table 2.
(2R,5R)-2-tert-Butyl-5-[(1S)-4-oxo-2-cyclopentenyl]-5-
phenyl-1,3-dioxolan-4-one (12)
For elucidation of the structure of the minor isomer (14), the
mother liquid was concentrated, puri®ed by silica gel
column chromatography (hexane±EtOAc, 20:1 elution),
and recrystallized to afford 14 (2.69 g, 7%) as a white crys-
A solution of 11 (36.9 g, 101 mmol) in 1,2-dichlorobenzene
(1.0 L) was heated at 1758C for 8 h with N2-¯ow. The
mixture was cooled to room temperature and the white crys-
tal formed was collected by ®ltration, washed with hexane
and dried to afford 12 (18.6 g, 61%). The ®ltrate was
concentrated under reduced pressure and the residue was
1
talline solid: mp 133±134.58C (hexane±EtOAc); H NMR
(CDCl3) d 1.05 (9H, s), 1.39 (1H, brd, Jˆ8.4 Hz), 1.54 (1H,
brd, Jˆ8.4 Hz), 1.90 (1H, dd, Jˆ10.7, 19.5 Hz), 2.15 (1H,
dd, Jˆ5.7, 19.5 Hz), 2.48 (1H, m), 2.93 (1H, m), 2.97±3.06

9906
M. Mitsuya et al. / Tetrahedron 56 (2000) 9901±9907
(2H, m), 3.19 (1H, m), 5.07 (1H, s), 6.11 (1H, m), 6.21 (1H,
m), 7.30±7.46 (3H, m), 7.47 (2H, brd, Jˆ8.1 Hz); The
NOEs between d 1.05 (Hf) and d 2.93 (Hg), d 1.90 (Hb)
and d 2.48 (Ha), d 2.48 (Ha) and d 6.21 (He), d 2.48 (Ha) and
d 7.47 (Hd), d 5.07 (Hc) and d 7.47 (Hd) were observed. IR
(KBr, cm21) 1794, 1732; FAB-MS m/z 367 (M1H)1; Anal.
calcd for C23H26O4: C, 75.38; H, 7.15. Found: C, 75.34; H,
7.23; [a]2D0ˆ18.4 (c 1.0, CHCl3).
sis Package, Molecular Structure Corporation (1985 and
1992)]. The structure was solved by a direct method. All
non-hydrogen atoms were re®ned anisotropically. Hydro-
gen atoms were included but not re®ned. The ®nal cycle
of full-matrix least-squares re®nement was based on 1276
observed re¯ections [I.3.00s(I)] and 245 variable para-
meters and was converged (largest parameter shift was
0.01 times its esd) with unweighted and weighted agreement
factors of Rˆ0.064 RWˆ0.055. The maximum and mini-
mum peaks on the ®nal difference Fourier map corre-
2
Ê 3
sponded to 0.34 and 20.24 e /A , respectively.
Detailed data have been deposited with the Cambridge
Crystallographic Data Centre (CCDC) as the reference
number 149832.
Acknowledgements
We are grateful to Dr K. Miura and Dr K. Kamata for
X-ray analysis, and to Dr S. Nakajima for the NOE
experiment. We also acknowledge Dr R. P. Volante and
Ms. A. Dobbins, Merck and Co., for critical reading of
this manuscript.
(2R,5R)-2-tert-Butyl-5-[(1S)-3-oxocyclopentyl]-5-phenyl-
1,3-dioxolan-4-one (6)
A solution of 13 (25.1 g, 68.5 mmol) in 1,2-dichlorobenzene
(500 mL) was heated at 1758C for 5 h with N2-¯ow. The
mixture was allowed to cool to room temperature and
concentrated under reduced pressure. The residue was puri-
®ed by silica gel column chromatography (hexane±EtOAc,
10:1 elution) to give (2R,5R)-2-tert-butyl-5-[(1R)-4-oxo-2-
cyclopentenyl]-5-phenyl-1,3-dioxolan-4-one (19.5 g, 95%)
References
1. Mitsuya, M.; Kobayashi, K.; Kawakami, K.; Satoh, A.; Ogino,
Y.; Kakikawa, T.; Ohtake, N.; Kimura, T.; Hirose, H.; Satoh, A.;
Numazawa, T.; Hasegawa, T.; Noguchi, K.; Mase, T. J. Med.
Chem. (in press).
1
as a white solid: mp 122.5±1248C (hexane±EtOAc); H
NMR (CDCl3) d 0.90 (9H, s), 2.27 (1H, dd, Jˆ1.5,
18.9 Hz), 2.49 (1H, dd, Jˆ6.6, 18.9 Hz), 3.67 (1H, m),
5.44 (1H, s), 6.26 (1H, m), 7.30±7.48 (4H, m), 7.60±7.72
(2H, m); IR (KBr, cm21) 1792, 1716; FAB-MS m/z 301
(M1H)1; Anal. calcd for C18H20O4: C, 71.98; H, 6.71.
Found: C, 72.00; H, 6.76; [a]2D0ˆ1151 (c 1.0, CHCl3).
2. Seebach, D.; Naef, R.; Calderari, G. Tetrahedron 1984, 40,
1313±1324.
3. Mitsuya, M.; Kawakami, K.; Ogino, Y.; Miura, K.; Mase, T.
Bioorg. Med. Chem. Lett. 1999, 9, 2037±2038.
4. Mitsuya, M.; Ogino, Y.; Kawakami, K.; Uchiyama, M.;
Kimura, T.; Numazawa, T.; Hasegawa, T.; Ohtake, N.; Noguchi,
K.; Mase, T. Bioorg. Med. Chem. 2000, 8, 825±832.
5. Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1979, 43, 1011±
1013.
To a solution of (2R,5R)-2-tert-butyl-5-[(1R)-4-oxo-2-
cyclopentenyl]-5-phenyl-1,3-dioxolan-4-one (8.03 g, 26.8
mmol) in EtOAc (300 mL) was added 10% palladium on
carbon (1.05 g, 0.987 mmol) and the mixture was hydro-
genated under atmospheric pressure for 2 h. After ®ltration
of the catalyst, the ®ltrate was concentrated and puri®ed
by silica gel column chromatography (hexane±EtOAc,
20:1±10:1 elution) to give 6 (7.84 g, 97%) as a white
solid.
6. Takano, S.; Kamikubo, T.; Moriya, M.; Ogasawara, K.
Synthesis 1994, 601±604.
7. Lipshutz, B. H.; Keith, J.; Papa, P.; Vivian, R. Tetrahedron Lett.
1998, 39, 4627±4630.
8. Keinian, E.; Greenspoon, N. J. Am. Chem. Soc. 1986, 108,
7314±7325.
X-Ray crystallographic data of the (S)-phenetylamine
salt of 1
9. (a) Takano, S.; Moriya, M.; Tanaka, K.; Ogasawara, K.
Synthesis 1994, 687±688. (b) Tanaka, K.; Ogasawara, K. Synthesis
1995, 1237±1239. (c) Sugahara, T.; Kuroyanagi, Y.; Ogasawara,
K. Synthesis 1996, 1101±1108.
A colorless plate crystal having approximate dimensions of
1.00£0.200£0.080 mm was mounted on a glass ®ber. All
data were collected on a Rigaku AFC7R single crystal
10. (a) Takano, S.; Inomuta, K.; Ogasawara, K. J. Chem. Soc.,
Chem. Commun. 1990, 1544±1546. (b) Takano, S.; Moriya, M.;
Ogasawara, K. J. Org. Chem. 1991, 56, 5982±5984. (c) Ogasawara,
K. Pure Appl. Chem. 1994, 66, 2119±2122.
11. When (1)-4,8-tricyclo[5,2,1,02,6]decadien-3-one (1)-9 was
used in this reaction, the diastereomer 13 was predominantly
produced (13:14ˆ5:1). The adduct 13, isolated in 61% yield by
recrystallization of the mixture, was submitted to retrograde
Diels±Alder reaction. Subsequent hydrogenation gave 6 in 92%
yield from 13.
Ê
diffractometer, using Cu-Ka radiation (lˆ1.5418 A),
v22u scans, to a maximum 2u value of 120.08.
Ê
C21H25F2NO3, Mˆ377.43, monoclinic, aˆ12.430(2) A,
Ê
Ê
Ê 3
bˆ5.743(1) A, cˆ14.608(1) A,Vˆ1006.5(5) A , space
group P21 (#4), Zˆ2, Dcalcˆ1.245 g/cm3, mˆ7.93 cm21. A
total of 1611 re¯ections were collected. All data were
corrected for Lorentz and polar factors. All calculations
were performed using the teXsan [Crystal Structure Analy-

M. Mitsuya et al. / Tetrahedron 56 (2000) 9901±9907
9907
and Hf in 10 were observed. By contrast, the NOEs between Ha and
Hb, Ha and Hd, Ha and He, and Hc and Hd in 11 were observed.
13. (a) Goto, M.; Akimoto, K.; Aoki, K.; Shindo, M.; Koga, K.
Tetrahedron Lett. 1999, 40, 8129±8132. (b) Murakata, M.;
Yasukata, T.; Aoki, T.; Nakajima, M.; Koga, K. Tetrahedron
1998, 54, 2449±2458, and references cited therein.
12. The NOEs between Ha and Hb, Ha and Hd, Ha and He, and Hc