Formal Asymmetric Synthesis of a Cholesterol Absorption Inhibitor Bearing a 2-Azaspiro[3.5]nonan-1-one Moiety

Full text of DOI:10.1021/jo990933h

9282
J . Org. Chem. 1999, 64, 9282-9285
We describe herein a short-step, catalytic asymmetric
F or m a l Asym m etr ic Syn th esis of a
Ch olester ol Absor p tion In h ibitor Bea r in g a
2-Aza sp ir o[3.5]n on a n -1-on e Moiety
synthesis of substituted 2-azaspiro[3.5]nonan-1-one 8, the
key intermediate for Sch 58053 1.9
Takeshi Kambara and Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences, Kyoto
University, Yoshida, Sakyo-ku, Kyoto 606-8501, J apan
Received J une 8, 1999
In tr od u ction
Azetidin-2-one has been known as the central motif of
the so-called â-lactam antibiotics.1 The recent discovery
of potent cholesterol absorption inhibition (CAI) by a class
of azetidinones renewed interest in this class of com-
pounds.2 Subsequent work by the Schering-Plough group
led to the further discovery that conformationally fixed
spiro-fused azetidin-2-ones 1 and 2 also displayed potent
CAI activity.3 These efforts have stimulated significant
synthetic interest in developing asymmetric processes.4
The approaches to these types of azetidinones have
employed chiral auxiliary- and chiral pool-based chem-
istry.5,6 A recently reported brilliant exception for the
construction of (R)-azetidin-2-one was the catalytic asym-
metric aldol strategy followed by amination and cycliza-
tion.7 Clearly, a catalytic and short-step asymmetric
condensation process of an enolate with an imine would
be much more effective to afford directly the desired
azetidin-2-one. We have been engaged in the catalytic
asymmetric condensation of a lithium ester enolate with
an imine employing an external chiral ligand strategy.8
Resu lts a n d Discu ssion
The synthetic strategy was to construct the spiro-fused
azetidinone with the desired chiral center via an ester
enolate-imine condensation. Our methodology employed
for the condensation can be divided into two categories.
One uses a ternary complex reagent that is comprised of
a lithium ester enolate, a lithium amide, and a chiral
ligand 5,8,10 and the other uses a binary complex11 of a
lithium ester enolate with the chiral ligands 5 or 10. We
examined both methodologies because such reagents are
highly effective and readily available.
Our initial attempt at the asymmetric condensation of
4-fluoroaniline imine of 4-benzyloxybenzaldehyde 4 with
the ternary reagent of lithium ester enolate 3,8,10 gener-
ated from 2 equiv of 2-methyl-1-(methylethyl)propyl
2-methylpropanoate, 2.6 equiv of dimethyl ether ligand
5,12 and 4.4 equiv of LDA in toluene, produced only a
trace amount of the desired azetidinone 6. Since the
addition product was observed by TLC, the cyclization
was considered to have suffered from an excess of lithium
amide or lithium enolate. This problem was solved by
addition of 1 equiv of methanol to quench the excess of
lithium amide or lithium enolate prior to warming up
for cyclization. Thus, after the reaction of the ternary
complex of 3 with 4 was conducted at -60 °C for 8 h,
methanol was added. The reaction mixture was allowed
to warm to 10 °C over 2 h to afford 6 in 84% yield. The
selectivity was determined to be 90% ee by a chiral
stationary-phase HPLC.13
(1) Lukacs, G.; Ohno, M. Eds, Recent Progress in the Chemical
Synthesis of Antibiotics; Springer-Verlag: Berlin, 1990.
(2) (a) Burnett, D. A.; Caplen, M. A.; Davis, H. R., J r.; Burrier, R.
E.; Clader, J . W. J . Med. Chem. 1994, 37, 1733-1736. (b) Salisbury,
B. G.; Davis, H. R.; Burrier, R.; Burnett, D. A.; Boykow, G.; Caplen,
M. A.; Clemmons, A. L.; Compton, D. S.; Hoos, L. M.; McGregor, D.
G.; Schnitzer-Polokoff, R.; Smith, A. A.; Weig, B. C.; Zilli, D. L.; Clader,
J . W.; Sybertz. E. J . Atherosclerosis 1995, 115, 45.
(3) Dugar, S.; Clader, J .; Chan, T.-M.; Davis, H., J r. J . Med. Chem.
1995, 38, 4875-4877.
(4) For the reviews, see: (a) Georg, G. I. The Organic Chemistry of
â-Lactams VCH: New York, 1993. (b) Williams, R. M. Synthesis Of
Optically Active R-Amino Acids; Pergamon Press: New York, 1989.
(c) Seyden-Penne, J . Chiral Auxiliaries and Ligands in Asymmetric
Synthesis; J ohn Wiley and Sons: New York, 1995.
(5) (a) Shirai, F.; Nakai, T. Tetrahedron Lett. 1988, 29, 6461-6464.
(b) Burnett, D. A. Tetrahedron Lett. 1994, 35. 7339-7342. (b) Dugar,
S.; Clader, J . W.; Chan, T. M.; Davis, H. R., J r. J . Med. Chem. 1995,
38, 4875-4877. (c) Browne, M.; Burnett, D. A.; Caplen, M. A.; Chen,
L.-y.; Clader, J . W.; Domalski, M.; Dugar, S.; Pushpavanam, P.; Sher,
R.; Vaccaro, W.; Viziano, M.; Zhao, H. Tetrahedron Lett. 1995, 36,
2555-2558. (d) McKittrick, B. A.; Dugar, S.; Crader, J . W.; Davis, H.
R., J r.; Czarniecki, M. Bioorg. Med. Chem. Lett. 1996, 6, 1947-1950.
(e) Clader, J . W.; Burnett, D. A.; Caplen, M. A.; Domalski, M. S.; Dugar,
S.; Vaccaro, W.; Sher, R.; Browne, M. E.; Zhao, H.; Burrier, R. E.;
Salisbury, B.; Davis, H. R., J r. J . Med. Chem. 1996, 39, 3684-3693.
(6) Synthesis of spiro-fused azetidinone: (a) Wittig, G.; Hesse, A.
Liebigs Ann. Chem. 1976, 500-510. (b) Spurr, P. R.; Hamon, D. P. G.
J . Am. Chem. Soc. 1983, 105, 4734-4739. (c) Ikeda, M.; Uchino, T.;
Ishibashi, H.; Tamura, Y.; Kido, M. J . Chem. Soc., Chem. Commun.
1984, 758-759. (d) Mullen, G. B.; Georgiev, V. S. Heterocycles 1986,
24, 3441-3446. (e) Ishibashi, H.; Nakamura, N.; Tatsunori, S.;
Takeuchi, M.; Ikeda, M. Tetrahedron Lett. 1991, 32, 1725-1728. (f)
Le Blanc, S.; Pete, J .-P.; Piva, O. Tetrahedron Lett. 1992, 33, 1993-
1996. (g) Fujisawa, T.; Ukaji, Y.; Noro, T.; Date, K.; Shimizu, M.
Tetrahedron 1992, 48, 5629-5638. (h) Toda, F.; Miyamoto, H.; Takeda,
K.; Matsugawa, R.; Maruyama, N. J . Org. Chem. 1993, 58, 6208-6211.
(i) Chen, L.; Zaks, A.; Chacklamanil, S.; Dugar, S. J . Org. Chem. 1996,
61, 8341-8343.
Encouraged by the high enantioselectivity, we then
examined the condensation reaction of a lithium ester
enolate 7 bearing the requisite protected 4-oxocyclohexyl
moiety. The reaction of 7a with 4 was conducted under
the ternary complex reagent conditions, 7a -5-lithium
(8) Fujieda, H.; Kanai, M.; Kambara, T.; Iida, A.; Tomioka, K. J .
Am. Chem. Soc. 1997, 119, 2060-2061.
(9) After submission of our paper, a diastereo- and enantioselective
synthesis of cholesterol absorption inhibitors has been reported. Wu,
G.; Wong, Y.; Chen, X.; Ding, Z. J . Org. Chem. 1999, 64, 3714-3718.
(10) Kambara, T.; Hussein, M. A.; Fujieda, H.; Iida, A.; Tomioka,
K. Tetrahedron Lett. 1998, 39, 9055-9058.
(11) (a) Tomioka, K.; Fujieda, H.; Hayashi, S.; Hussein, M. A.;
Kambara, T.; Nomura, Y.; Kanai, M.; Koga, K. Chem. Commun. 1999,
715-716. (b) Kambara, T.; Tomioka, K. Chem. Pharm. Bull. 1999, 47,
720-721.
(12) Shindo M.; Koga K.; Tomioka, K. J . Org. Chem. 1998, 63, 9351-
9357.
(7) Wu, G.; Tormos, W. J . Org. Chem. 1997, 62, 6412-6414.
(13) The absolute configuration of 6 has not yet been determined.
10.1021/jo990933h CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/23/1999

Notes
J . Org. Chem., Vol. 64, No. 25, 1999 9283
using a tridentate chiral aminodiether 10.11a The reaction
of the binary complex of 7g was mediated by a stoichio-
metric amount of 10 at -40 °C for 1 h to give (+)-8h in
90% ee and quantitative yield (entry 10).15 The catalytic
asymmetric reaction was also realized using 20 mol % of
10 at -40 °C for 4 h to give 8h in 81% ee and 86% yield.
It is also important to note that the ligand 10 was
recoverable quantitatively for reuse.
In summary, employing an enolate-imine condensa-
tion process, we have invented a catalytic enantioselec-
tive and direct synthesis of spiro-fused azetidin-2-one (+)-
8h , the established intermediate for cholesterol absorption
inhibitor, Sch 58053 1. We believe that the developed
methodology is applicable to a catalytic asymmetric
construction of a variety of substituted 2-azaspiro[3.5]-
nonan-1-ones of pharmaceutical potency.
cyclohexylisopropylamide (LICA),14 to afford (+)-8h in
74% yield and 62% ee (Table 1, entry 1). Although the
selectivity was unexpectedly low, enantioenrichment was
possible by recrystallization from ethanol to afford 8h in
over 98% ee and 40% overall yield. Unmasking of the
ketal group in 8h in aqueous acetic acid at 90 °C gave
ketone (+)-(R)-9 in 97% yield. Since the two-step and
high-yield conversion of (R)-9 to 1 has been already
reported,7 the present asymmetric synthesis constitutes
the shortest-step formal synthesis of optically active 1.
Exp er im en ta l Section 16
4-(2-Aza-2-(4-flu or oph en yl)vin yl)-1-ben zyloxyben zen e (4).
A mixture of 4-benzyloxybenzaldehyde (21.2 g, 100 mmol) and
4-fluoroaniline (11.1 g, 100 mmol) was stirred at 100 °C for 1 h.
Recrystallization of a brown solid from EtOH afforded 4 as
colorless plates (25.4 g, 84%) of mp 132-133 °C. IR (Nujol):
1600, 1500 cm-1. MS m/z: 305 (M+). Anal. Calcd for C20H16
-
FNO2: C, 78.67; H, 5.28; N, 4.59. Found: C, 78.58; H, 5.48; N,
4.48.
2-Meth yl-1-(m eth yleth yl)pr opyl 2-Meth ylpr opan oate (th e
Ester Cor r esp on d in g to 3). A mixture of isobutyric acid (60
g, 0.68 mol), 2,4-dimethylpentan-3-ol (237 g, 2.04 mol), and
p-toluenesulfonic acid monohydrate (1.22 g, 6.8 mmol) in toluene
(60 mL) was stirred under reflux (with Dean-Stark trap) for 2
d and quenched with saturated NaHCO3. The organic layer was
washed with brine and then dried over Na2SO4. Concentration
followed by distillation (bp 75 °C/15 mmHg) gave the ester as a
colorless oil (68 g, 53%). IR (neat): 1730 cm-1. MS m/z: 186 (M+).
Anal. Calcd for C11H22O2: C, 70.92; H, 11.90. Found: C, 70.65;
H, 11.85.
2-Meth yl-1-(m eth yleth yl)p r op yl 4-Oxocycloh exa n eca r -
boxyla te. A mixture of 4-oxocyclohexanecarboxylic acid17 (3.55
g, 25 mmol), 2-methyl-1-(methylethyl)propanol (3.02 g, 26 mmol),
DCC (6.19 g, 30 mmol), and 4-(dimethylamino)pyridine (0.92 g,
8 mmol) in CHCl3 (25 mL) was stirred at room temperature for
0.5 h. After filtration, the filtrate was concentrated to give an
oil. Chromatography (EtOAc/hexane ) 3/1, then ether) gave the
ester (4.98 g, 83%) as a colorless oil. IR (film): 1720 cm-1. MS
m/z: 240 (M+). Anal. Calcd for C14H24O3: C, 69.96; H, 10.07.
Found: C, 69.98; H, 10.08.
1-Eth ylpr opyl 4-Oxocycloh exan ecar boxylate. By the same
procedure for the above ester, the ester was obtained in 83%
yield as a colorless oil of bp 150 °C (2.5 mmHg). IR (film): 1720
cm-1. MS m/z: 212 (M+). Anal. Calcd for C12H20O3: C, 67.89; H,
9.50. Found: C, 67.74; H, 9.76.
2-Meth yl-1-(m eth yleth yl)p r op yl 1,4-Dioxa sp ir o[4.5]d ec-
a n e-8-ca r boxyla te (th e Keta l Cor r esp on d in g to 7a ). Ac-
cording to the reported procedure for ethyl 1,4-dioxaspiro[4.5]-
decane-8-carboxylate,7 the ketal was obtained in 98% yield as
an oil of bp 160 °C (0.9 mmHg). IR (film): 1725 cm-1. MS m/z:
284 (M+). Anal. Calcd for C16H28O4: C, 67.57; H, 9.92. Found:
C, 67.34; H, 9.83.
2-Meth yl-1-(m eth yleth yl)p r op yl 1,4-Dith ia sp ir o[4.5]d ec-
a n e-8-ca r boxyla te (th e Th iok eta l Cor r esp on d in g to 7c). By
the same procedure for the ethyl ester below, the ketone (120
mg, 0.5 mmol) was converted into the ketal (97%) as an oil of
Although the enantioselective formal total synthesis
of 1 was completed with the development delineated
above, further efforts were continued to improve the
efficiency of the condensation reaction. Thus, the reaction
of a ternary complex of 7b, generated from the ethyl
ester, gave 8h in 47% ee (entry 2). The corresponding
binary complex of 7b, generated from 2 equiv of the ester,
2.2 equiv of LICA, and 2.6 equiv of 5, gave only 38% ee.
Then, we changed the ethylenedioxy ketal protection to
the ethylenedithio group. The reaction of the ternary
complex of 7c gave 8i in a much poorer selectivity of 53%
ee (entry 4). The ternary and binary complexes of the
corresponding ethyl ester enolate 7d also were not good
enolate reagents, giving 37% ee and 27% ee (entries 5
and 6). Good selectivity was attained using the ternary
complex of 7e having a trimethlenedioxy protection to
afford 8j in 71% ee (entry 7). The reactions using 7f were
not satisfactory, giving 8j in 52% ee and 36% ee (entries
8 and 9). The absolute configurations of (+)-8i,j were also
determined by converting to (+)-(R)-9.
(15) The ternary complex of 10 did not afford satisfactory selectivity.
(16) Purification was carried out using silica gel column chroma-
tography unless otherwise noted.
(17) (a) Hardegger, E.; Plattner, P. A.; Blank, F. Helv. Chim. Acta
1944, 27, 793-800. (b) Kusuma, T.; Sugasawa, S. Tetrahedron 1958,
3, 175-177. (c) Sanchez, I. H.; Ortega, A.; Garcia, G.; Larraza, M. I.;
Flores, H. J . Synth. Commun. 1985, 15, 141-149. (d) Cauletti, C.; Maio,
G. D. Tetrahedron 1986, 42, 3677-3682.
Although the results obtained above using a chiral
diether ligand 5 were unsatisfactory, we were able to
establish the highly enantioselective condensation of 7g
(14) Use of LDA did not exceed the selectivity obtained by use of
LICA.

9284 J . Org. Chem., Vol. 64, No. 25, 1999
Ta ble 1. Asym m etr ic Con d en sa tion of 7 w ith 4 Med ia ted by 5 a n d 10 Givin g 8a
Notes
ee/%
entry
7
R4
R5
ligand
LICA/equivb
T/°C (time/h)
8
yield/%
1
2
3
4
5
6
7
8
9
a
b
b
c
d
d
e
f
O(CH2)2O
O(CH2)2O
O(CH2)2O
S(CH2)2S
S(CH2)2S
S(CH2)2S
O(CH2)3O
O(CH2)3O
O(CH2)3O
O(CH2)2O
i-Pr2CH
Et
Et
i-Pr2CH
Et
Et
i-Pr2CH
Et
Et
5
5
5
5
5
5
5
5
5
1.2
1.2
0
1.2
1.2
0
1.2
1.2
0
-60 (15), 0 (0.5)c
-60 (15)
h
h
h
i
i
i
j
j
j
h
74
37
99
61
47
70
75
71
98
99
62
47
38
53
37
27
71
52
36
90
-70 to 0 (2)
-20 (2)
-60 (20)
-15 (2)
-40 (2), 0 (0.5)c
-60 (20)
f
g
-15 (2)
-40 (1)
10
Et2CH
10
0
a
b
The reaction was conducted using 2 equiv of 7 and 2.6 equiv of 5 or 10. The equivalency to 7. c Methanol (1 equiv) was added before
warming to 0 °C for cyclization.
bp 220 °C (2.5 mmHg). IR (film): 1725 cm-1. MS m/z: 316 (M+).
Anal. Calcd for C16H28O2S2: C, 60.71; H, 8.92. Found: C, 60.66;
H, 8.87.
brine and then dried over Na2SO4. Concentration followed by
chromatography (EtOAc/hexane ) 1/1) gave 8h (176 mg, 74%)
as a pale yellow solid of mp 69-72 °C and [R]25 +24.5 (c 1.00,
D
CHCl3). Ee was determined to be 62% by HPLC (Daicel Chiral-
pak AS, hexane-i-PrOH (2:1), 0.5 mL/min, 250 nm, 13 min
(19%): 19 min (81%)). IR (Nujol): 1740 cm-1. MS m/z: 473 (M+).
Anal. Calcd for C29H28FNO4: C, 73.56;, H, 5.96; N, 2.96. Found:
C, 73.41; H, 5.99;, N, 2.96. The ligand 5 was recovered quanti-
tatively.
E t h yl 1,4-Dit h ia sp ir o[4.5]d eca n e-8-ca r b oxyla t e (t h e
Th ioketal Cor r espon din g to 7d). A mixture of ethyl 4-oxocyclo-
hexanecarboxylate17c (851 mg, 5 mmol), ethanedithiol (629 mg,
7.5 mmol), and boron trifluoride diethyl etherate (5 mmol) in
CH2Cl2 (5 mL) was stirred for 15 min at 0 °C. Concentration
followed by chromatography (EtOAc/hexane ) 1/9) gave the
thioketal (1.16 g, 94%) as a colorless oil of bp 200 °C (6 mmHg).
IR (film): 1730 cm-1. MS m/z: 246 (M+). Anal. Calcd for
C11H18O2S2: C, 53.62; H, 7.36. Found: C, 53.36; H, 7.45.
2-Meth yl-1-(m eth yleth yl)p r op yl 7,11-Dioxa sp ir o[5.5]u n -
d eca n e-3-ca r boxyla te (th e Keta l Cor r esp on d in g to 7e). By
the same procedure for the ketal corresponding to 7a , the ketone
was converted into the ketal (1.73 g, 97%) as an oil of bp 200 °C
(1.5 mmHg). IR (film): 1725 cm-1. MS m/z: 298 (M+). Anal.
Calcd for C17H30O4: C, 68.42; H, 10.13. Found: C, 68.52; H,
10.29.
En a n tioen r ich m en t by Recr ysta lliza tion of (+)-8h . Re-
crystallization of 8h (69.4 mg, 0.15 mmol, 62% ee) from EtOH
(0.8 mL) gave back 8h (37.4 mg, 54%) of mp 66-67 °C and [R]25
+39.3 (c 1.20, CHCl3). Ee was determined to be over 98%.
D
(+)-(R)-2-(4-Flu or oph en yl)-3-(4-ben zyloxy)ph en yl)-2-aza-
sp ir o[3.5]n on a n e-1,7-d ion e ((+)-(R)-9). A solution of (+)-8h
(31.4 mg, 0.07 mmol, 98% ee) in 30% AcOH (3 mL) was stirred
for 36 h at 90 °C. The mixture was diluted with AcOEt, washed
with saturated NaHCO3 and brine, and then dried over Na2-
SO4. Concentration followed by chromatography (ether/hexane
) 2/3) gave (+)-(R)-9 (27.5 mg, 97%) as a white powder of mp
Eth yl 7,11-Dioxa sp ir o[5.5]u n d eca n e-3-ca r boxyla te (th e
Keta l Cor r esp on d in g to 7f). By the same procedure for the
ketal corresponding to 7e, the ketal was obtained in 96% yield
as an oil of bp 190 °C (3 mmHg). IR (film): 1725 cm-1. MS m/z:
228 (M+). Anal. Calcd for C12H20O4: C, 63.14; H, 8.83. Found:
C, 63.39; H, 9.01.
62-67 °C and [R]22.6 +40.5 (c 0.56, EtOH). Ee was determined
D
to be 98% by HPLC (Daicel Chiralpak AS, hexane-i-PrOH (1:
2), 0.5 mL/min, 250 nm, 21 min (1.05%): 36 min (99.0%)). IR
(Nujol): 1740, 1725 cm-1. MS m/z: 429 (M+). Anal. Calcd for
C
27H24FNO3: C, 75.51; H, 5.63; N, 4.42. Found: C, 75.32; H,
5.78; N, 3.26. NMR data were identical with those reported.7
1-Eth ylp r op yl 1,4-Dioxa sp ir o[4.5]d eca n e-8-ca r boxyla te
(th e Keta l Cor r esp on d in g to 7g). By the same procedure for
the ketal corresponding to 7a , the ketal was obtained in 98%
yield. IR (film): 1725 cm-1. MS m/z: 256 (M+). Anal. Calcd for
C14H24O4: C, 65.60; H, 9.44. Found: C, 65.31; H, 9.22.
(+)-1-(4-F lu or op h en yl)-3,3-d im eth yl-4-(4-ben zyloxyp h e-
n yl)a zetid in -2-on e (6). A solution of 2-methyl-1-(methylethyl)-
propyl 2-methylpropanoate (372 mg, 2.0 mmol) and 5 (630 mg,
2.6 mmol) in toluene (3 mL) was added to a solution of LDA
(4.4 mmol) in toluene (4 mL) at -78 °C. After the mixture was
stirred for 20 min at -78 °C, a solution of imine 4 (239 mg, 0.78
mmol) in toluene (6 mL) was added to the solution. After the
mixture was stirred at -60 °C for 8 h, MeOH (0.04 mL, 1 mmol)
was added. The mixture was stirred at 0 °C for 15 min and then
quenched with saturated NH4Cl. The mixture was extracted
with EtOAc. The combined organic layers were washed with
brine and then dried over MgSO4. Concentration followed by
chromatography (EtOAc/hexane ) 1/5) gave 6 (245 mg, 84%) as
Ta ble 1,En tr y 3. The binary complex of 7b (the ester: 429
mg, 2.0 mmol) and 5 (630 mg, 2.6 mmol) in toluene (3 mL) gave
8h (469 mg, 99%, 38% ee) as a colorless solid of mp 55-60 °C
and [R]25 +15.6 (c 1.17, CHCl3).
D
Ta ble 1, en tr y 4: 2-a za -2-(4-flu or op h en yl)-3-(4-(ben zy-
loxy)p h en yl)-8,11-d ith ia d isp ir o[3.2.4.2]tr id eca n -1-on e (8i).
By the same procedure as for 8h (entry 1), 8i was obtained in
61% yield as a pale yellow solid of mp 92-97 °C and [R]25D +7.3
(c 1.02, CHCl3). Ee was determined by HPLC to be 53% (Daicel
Chiralpak AS, hexane-i-PrOH (2:1), 0.5 mL/min, 250 nm, 16
min (23.6%): 29 min (76.4%)). IR (Nujol): 1735 cm-1. MS m/z:
505 (M+). Anal. Calcd for C29H28FNO2S2: C, 68.88; H, 5.58; N,
2.77. Found: C, 68.61; H, 5.63; N, 2.68.
Ta ble 1, en tr y 7: 2-a za -2-(4-flu or op h en yl)-8,12-d ioxa -3-
(4-(ben zyloxy)p h en yl)d isp ir o[3.2.5.2]tetr a d eca n -1-on e (8j).
By the same procedure as for 8h (entry 1), 8j (182 mg, 75%)
was obtained as a pale yellow solid of [R]25 +26.0 (c 1.00,
a solid of [R]25 +75.1 (c 1.40, CHCl3). Ee was determined to be
D
D
CHCl3). Ee was determined to be 71% by HPLC (Daicel Chiral-
pak AS, hexane-i-PrOH (2:1), 0.5 mL/min, 250 nm, 14 min
(14.3%): 22 min (85.7%)). IR (Nujol): 1735 cm-1. MS m/z: 487
(M+). Anal. Calcd for C30H30FNO4: C, 73.90; H, 6.20; N, 2.87.
Found: C, 73.66; H, 6.32; N, 2.90.
90% by HPLC (Daicel Chiralcel OD-H, hexane-i-PrOH (50:1),
0.5 mL/min, 250 nm, 31 min (95.1%): 36 min (4.9%)). The ligand
5 was recovered quantitatively. IR (Nujol): 1740 cm-1. MS m/z:
375 (M+). Anal. Calcd for C24H22FNO2: C, 76.78; H, 5.91; N, 3.73.
Found: C, 76.48; H, 5.88; N, 3.67.
Deth iok eta liza tion of 8i. To a solution of (+)-8i (40.5 mg,
0.08 mmol, 27% ee) in 75% MeCN was added cerium ammonium
nitrate (350 mg, 0.64 mmol). The pale orange suspension was
stirred for 0.5 h at room temperature and quenched with
saturated NaHCO3. The mixture was extracted with EtOAc. The
organic layers were washed with brine and then dried over Na2-
SO4. Concentration followed by chromatography (EtOAc/hexane
) 2/1) gave (+)-9 (22.2 mg, 65%, 27% ee) as a powder of mp
(+)-(R)-2-Aza -2-(4-flu or op h en yl)-8,11-d ioxa -3-(4-(ben zyl-
oxy)p h en yl)d isp ir o[3.2.4.2]tr id eca n -1-on e (Ta ble 1, En tr y
1, (+)-(R)-8h ). A solution of the ester corresponding to 7a (284
mg, 1.0 mmol) and 5 (315 mg, 1.3 mmol) in toluene (3 mL) was
added to a solution of LICA (2.2 mmol) in toluene (15 mL) at
-78 °C. After being stirred for 20 min at -78 °C, a solution of
4 (153 mg, 0.5 mmol) in toluene (7 mL) was added. After the
mixture was stirred at -60 °C for 20 h, absolute MeOH (0.5
mmol) was added. The mixture was stirred at 0 °C for 15 min
and then quenched with saturated NH4Cl. The mixture was
extracted with EtOAc. The organic layers were washed with
52-56 °C and [R]22.6 +9.3 (c 0.65, EtOH).
D
Dek eta liza tion of 8j. By the same procedure for hydrolysis
of 8a , (+)-8j (73.1 mg, 0.15 mmol, 36% ee) was converted to (+)-9

Notes
J . Org. Chem., Vol. 64, No. 25, 1999 9285
(59.2 mg, 92%, 37% ee) as a powder of mp 62-67 °C and [R]22.6
+14.5 (c 0.57, EtOH).
Ca ta lytic Asym m etr ic Rea ction Usin g 20 Mol % of 10.
By the same procedure above (entry 10) using 20 mol % of 10
(44 mg, 0.15 mmol), 4 (230 mg, 0.75 mmol) was converted into
(+)-8h (306 mg, 86%, 81% ee) as a powder of mp 66-70 °C and
D
Stoich iom etr ic Asym m etr ic Rea ction Usin g 10 (Ta ble
1, en tr y 10). A solution of the ester corresponding to 7g (384
mg, 1.5 mmol) and aminodiether 10 (569 mg, 1.95 mmol) in
toluene (6 mL) was added to a solution of LDA (1.65 mmol) in
toluene (5 mL) at -78 °C. After the mixture was stirred for 1 h,
a solution of 4 (230 mg, 0.75 mmol) in toluene (6 mL) was added.
After the mixture was stirred at -45 °C for 1 h, 5% AcOH (15
mL) was added and the mixture was extracted with EtOAc. The
organic layers were washed with 5% AcOH and brine and then
dried over Na2SO4. Concentration followed by chromatography
(ether/hexane ) 1/5, then ether) gave (+)-8h (357 mg, 99%, 90%
ee) as a powder of mp 65-67 °C and [R]25D +38.0 (c 1.06, CHCl3).
The chiral ligand 10 was recovered quantitatively from the acidic
layer.
[R]25 +34.5 (c 1.08, CHCl3).
D
Ack n ow led gm en t. We gratefully acknowledge fi-
nancial support from J apan Society for Promotion of
Science (RFTF-96P00302) and the Ministry of Educa-
tion, Science, Sports and Culture, J apan.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
peak assignments. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O990933H