Asymmetric synthesis of substituted 2-azaspiro[3.5]nonan-1-ones: An enantioselective synthesis of the cholesterol absorption inhibitor (+)-SCH 54016

Full text of DOI:10.1021/jo961096b

J . Org. Chem. 1996, 61, 8341-8343
8341
Asym m etr ic Syn th esis of Su bstitu ted
2-Aza sp ir o[3.5]n on a n -1-on es: An
En a n tioselective Syn th esis of th e
Ch olester ol Absor p tion In h ibitor (+)-SCH
54016
Lian-Yong Chen,* Aleksey Zaks,
Samuel Chackalamannil, and Sundeep Dugar*
Schering-Plough Research Institute,
2015 Galloping Hill Road,
Kenilworth, New J ersey, 07033-0539
Received J une 11, 1996
Substituted 2-azaspiro[3.5]nonan-1-ones are potent
cholesterol absorption inhibitors.1 Structure-activity stud-
ies identified (+)-SCH 54016 (1) as one of the most potent
compounds in this series.2 In order to generate multi-
gram quantities of (+)-SCH 54016 for continuing biologi-
cal evaluation, an efficient synthetic route for this class
of compounds had to be developed. An optimal pathway
would not only afford stereochemical control at C-4 of the
2-azetidinone ring, but also lend itself amenable to a
dissymmetric spiroannulation at C-3 providing a trans
relationship between the 4-chlorophenyl moiety and the
carbonyl group, as this is critical for activity.2 Herein,
we report a general highly enantioselective synthetic
route to substituted 2-azaspiro[3.5]nonan-1-ones such as
(+)-SCH 54016 (1).
F igu r e 1.
Sch em e 1
the alkylation of a chiral C-3 unsubstituted 2-azetidinone
A with a chiral bis-electrophile B, where the electrophilic
center X reacts first. The selectivity of this intramolecu-
lar spiro-alkylation would determine the ratio of the cis-
and trans-cyclohexyl diastereomers D and E. By anal-
ogy, reversing the chirality of B or by altering the
reactivity of the centers X and Y should yield the
corresponding diastereomer E, thereby allowing for the
synthesis of either diastereomer. This methodology
should also provide a route for the diastereoselective
synthesis of various regioisomers of D or E with the use
of the appropriate bis-electrophile.
The synthesis of a 2-azaspiro[3.4]octan-1-one, by the
bis-alkylation of a C-3 unsubstituted 2-azetidinone with
1,5-diiodopentane, has been reported before.3f All at-
tempts at the synthesis of 6 via the alkylation of 2 with
3 were unsuccessful (Scheme 1).5 Subsequent attempts
at alkylation of 2 with 4 or 5 were also unsuccessful;
however, the enolate of 2 could be methylated with
iodomethane.6 Further investigation revealed that at
temperatures below -30 °C the electrophiles 3-5 were
unreactive; warming the reaction above -30 °C, however,
resulted in the decomposition of the enolate of 2.6 In
contrast, the alkylation of monosubstituted 2-azetidinone
7 with 5 proceeded smoothly to yield the disubstituted
2-azetidinone 8 as a single diastereomer where the
phenylpropyl side chain was trans to the C-4 aryl moiety.7
Several synthetic routes to substituted 2-azaspiro[3.5]-
nonan-1-ones have been reported.3 However, none of
these provide control of the stereochemistry of substit-
uents at the cyclohexyl ring. Due to steric constraints,
C-4 substituted 2-azetidinone enolates predominantly
yield the C-3,4-trans-diastereomer upon reaction with
electrophiles.4 This propensity of 2-azetidinone enolates
could be exploited to achieve the diastereomeric control
of substituents on the cyclohexyl ring of 2-azaspiro[3.5]-
nonan-1-ones. Thus, the intramolecular alkylation of C,
Figure 1, should result in the formation of D, with the
electrophilic center Y approaching the enolate of C trans
to the C-4 substituent. C should be readily available by
(1) Dugar, S.; Clader, J .; Chan, T.-M; Davis, H., J r. J . Med. Chem.
1995, 38, 4875.
(2) Dugar, S. et al. Manuscript to be submitted to J . Med. Chem.
(3) (a) Mullen, G. B.; Georgiev, V. S. Heterocycles 1986, 24, 3441.
(b) Ishibashi, H; Nakamura, N.; Tatsunori, S.; Takeuchi, M.; Ikeda,
M. Tetrahedron Lett. 1991, 32, 1725. (c) Ikeda, M.; Uchino, T.;
Ishibashi, H.; Tamura, Y.; Kido M. J . Chem. Soc., Chem. Commun.
1984, 758. (d) Spurr, P. R.; Hamon, D. P. G. J . Amer. Chem. Soc. 1983,
105, 4734. (e) Wittig, G.; Hesse, A. Liebigs Ann. Chem. 1976, 500. (f)
Fujisawa, T.; Ukaji, Y.; Noro, T.; Date. K.; Shimizu, M. Tetrahedron
1992, 48, 5629. (g) Le Blanc, S.; Pete, J .-P.; Piva, O. Tetrahedron Lett.
1992, 33, 1993. (h) Toda, F.; Miyamoto, H.; Takeda, K.; Matsugawa,
R.; Maruyama, N. J . Org. Chem. 1993, 58, 6208.
(5) The alkylation was investigated using the bases LDA, LICA, or
LHMDS in the presence or absence of HMPA.
(6) Browne, M. E.; 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.
(4) Gabe, E.; Lee, F. J . Org. Chem. 1990, 55, 5525. (b) Mash, E. A.;
Sharma, M. K. Tetrahedron 1987, 43, 679.
S0022-3263(96)01096-1 CCC: $12.00 © 1996 American Chemical Society

8342 J . Org. Chem., Vol. 61, No. 23, 1996
Notes
Sch em e 2
Since the synthesis of the C-3 monoalkylated 2-azetidi-
none 6 was not accessible via direct alkylation of 2 an
alternate route, outlined in Scheme 2, was employed.
(R)-3-(4-Chlorophenyl)glutarate monoethyl ester (9),
obtained by R-chymotrypsin-catalyzed hydrolysis of the
corresponding diethyl glutarate (ee ) 97%),8 was selec-
tively reduced.9 The resulting hydroxy acid was cyclized
without purification to give lactone 10 in 68% yield (two
steps). A one-pot process involving first the reduction of
lactone 10 with diisobutylaluminum hydride to the lactol
followed by Horner-Emmons reaction with triethyl
phosphonoacetate gave the hydroxy ester 11 in 75%
yield.10 The alcohol was protected as a silyl ether and
the double bond in 11 reduced with magnesium powder
in methanol to give methyl ester 12.11 Subsequent
hydrolysis to the acid and condensation of the acid
chloride with Evans’s chiral auxiliary (R)-4-phenyl-2-
oxazolidinone gave 13 in 97% yield. Condensation of the
titanium enolate12 of 13 with N-(4-methoxybenzylidene)-
aniline gave 14 which was used without purification.13
Silylation of the aniline with N,O-bis(trimethylsilyl)-
acetamide followed by treatment with tetrabutylammo-
nium fluoride resulted in the cyclization to form the
2-azetidinone ring and simultaneous hydrolysis of the
silyl ether to give 15 in 75% yield.13 The enolate-imine
condensation proceeded with the predicted stereoselec-
tivity as the corresponding cis diastereomer of 15 was
not detectable by 400 MHz 1H-NMR. Azetidinone 15 was
then converted to the corresponding bromide, which
underwent smooth intramolecular alkylation when treated
with lithium diisopropylamide in tetrahydrofuran to give
1 in 83% yield (28% overall from 9) and >99% ee (as
determined by HPLC) after purification on a silica gel
column.14 As expected, the approach of the bromide side
chain occurred trans to the C-4 aryl substituent translat-
ing into a trans relationship between the 4-chlorophenyl
moiety and the 2-azetidinone carbonyl group.
In summary, this investigation has led to an efficient
and highly enantioselective synthesis of (+)-SCH 54016
(1). Though the intermolecular diastereoselective trans
alkylation of C-4 substituted 2-azetidinones is well
documented, to our knowledge this is the first instance
of an unambiguous intramolecular transalkylation of a
2-azetidinone. This route should also serve as a general
method for the asymmetric synthesis of various azaspiro-
[3.5]nonan-1-ones for structure-activity relationship
studies.
Exp er im en ta l Section
Syn th esis of (3R)-(4-Ch lor op h en yl)p en ta n ed ioic Acid
Mon oeth yl Ester (9). Diethyl 3-(4-chlorophenyl)glutarate (19.2
g, 64.4 mmol) was added to a 5 L round-bottomed flask
containing aqueous solution of potassium chloride (2.5 L of a 50
mM solution) and vigorously stirred with an overhead stirrer.
To this mixture was added R-chymotrypsin (7.5 g, from bovine
pancreas, Sigma, type II), and the reaction was maintained at
rt and pH 7.8 by automatic titration with 0.2 M NaOH solution.
After 120 h (at which point 70.8 mmol of NaOH was consumed),
the reaction was stopped by adjusting the pH to 2.25 with 6 N
HCl. The solution was lyophilized, and the residue was ex-
tracted with ethyl acetate (750 mL). The enzyme was removed
by filtration and the ethyl acetate removed under reduced
pressure to give 9 (16.0 g, 97% ee, 92% yield) as a white solid.
1H NMR (400 MHz, CDCl3) 7.26 (2H, d, J ) 9.8 Hz), 7.16 (2H,
d, J ) 9.8 Hz), 4.03 (2H, q, J ) 7 Hz), 3.61 (1H, qt, J ) 7 Hz),
2.80-2.56 (4H, m), 1.15 (3H, t, J ) 7 Hz). Anal. Calcd for C13
15ClO4: C, 57.68; H, 5.59. Found: C, 57.65; H, 6.06.
Syn th esis of (4S)-(4-Ch lor op h en yl)tetr a h yd r o-2H-p y-
-
H
r a n -2-on e (10). To a stirred suspension of LiBH4 (802 mg, 35
mmol) in anhyd DME (20 mL) was added a solution containing
the monoacid ester 9 (4.72 g, 20 mmol) and methanol (1.42 mL,
35 mmol) in DME (60 mL). The reaction mixture was heated
at reflux for 1 h and then allowed to reach rt. The reaction was
quenched with 1 N HCl at 0 °C. The aqueous phase was
extracted with CH2Cl2 (3 × 30 mL), and the combined organic
phases were dried over Na2SO4, filtered, and concd to give a
crude product which was used in the next step without further
purification.
The crude product from the previous step was taken up into
toluene (80 mL) and was heated at reflux for 3.5 h in the
presence of p-toluenesulfonic acid (20 mg) with azeotropic
removal of water. After cooling to rt, the mixture was concd to
dryness to leave a solid. Purification by silica gel chromatog-
raphy (2:1 ethyl acetate/hexane, Rf 0.35) afforded 10 (2.8 g, 76%)
as a white solid. Mp: 81-83 °C. 1H NMR (400 MHZ, CDCl3)
7.33 (2H, J ) 7.5 Hz, d), 7.15 (2H, J ) 7.5 Hz, d), 4.52 (1H, J )
11.5, 4.9, 3.8 Hz, ddd), 4.39 (1H, J ) 11.6, 3.7 Hz, dt), 3.23 (1H,
m), 2.91 (1H, J ) 17.3, 5.9, 1.6 Hz, ddd,), 2.59 (1H, J ) 17.3,
10.6 Hz, dd), 2.17 (1H, m), 2.02 (1H, m); HRMS (M+ + H) calcd
(7) Structure was confirmed by NOE experiments.
(8) Cheˆnevert, R.; Desjardins M. Tetrahedron Lett. 1991, 32, 4249.
(9) Soai, K.; Ookawa, A. J . Org. Chem. 1986, 51, 4000.
(10) Takacs, J .; Helle, M.; Seely, F. Tetrahedron Lett. 1986, 27, 1257.
(11) Youn, I. K.; Yon, G. H.; Pak, C. S. Tetrahedron Lett. 1986, 27,
2409.
(12) Evans, D. A.; Reiger, D. L.; Bilodeau, M. T.; Urpi, F. J . Am.
Chem. Soc. 1991, 113, 1047.
(13) Thiruvengadam, T. K.; Tann, C.-H.; Lee, J .; McAllister, T.;
Sudhakar, A. U.S. Patent 5,306,817, 1994. Thiruvengadam, T. K.;
McAllister, T.; Tann, C.-H. PCT Intl. Appl. WO 95 01,961 (Chem. Abstr.
1995, 123, 9326b).
for C11H11ClO2 210.0448, found: 210.0457. Anal. Calcd for C11
11ClO2: C, 62.72; H, 5.26. Found: C, 62.53; H, 5.20.
-
(14) The %ee was determined on a Chiralcel OD column (95:5,
hexane/2-propanol).
H

Notes
Syn th esis of Eth yl (5S)-(4-Ch lor op h en yl)-7-h yd r oxy-2-
J . Org. Chem., Vol. 61, No. 23, 1996 8343
cooled to -25 °C, was added a solution of titanium tetrachloride
(9.5 mL/1.0 M in CH2Cl2, 9.5 mmol). After the mixture was
stirred at this temperature for 10 min, diisopropylethylamine
(3.0 mL, 17.2 mmol) was added and the mixture was stirred at
-25 °C for another 30 min followed by slow addition of a solution
of N-(4-methoxybenzylidene)aniline (3.7 g, 17.2 mmol) in CH2-
Cl2 (40 mL). The mixture was stirred at -25 °C for an additional
1 h and quenched with 2 N sulfuric acid (150 mL) at 0 °C. The
mixture was diluted with ethyl acetate (400 mL) and stirred at
0 °C until a clear separation of the two phases resulted. The
aqueous phase was separated and extracted with CH2Cl2 (3 ×
80 mL). The combined organic phases were dried over Na2SO4,
filtered, and concd to give 14 as a greenish solid.
The crude product mixture was dissolved in hot toluene (70
mL) at 90 °C. N,O-bis(trimethylsilyl)acetamide (5.1 g, 6.5 mmol)
was added to this solution and the reaction mixture stirred at
90 °C for 1 h followed by addition of tetra-n-butylammonium
fluoride (5.0 g, 19.1 mmol). The mixture was heated at 90 °C
for an additional 2 h and then allowed to cool to rt. The reaction
mixture was quenched with 10% KHSO4 and extracted with
ethyl acetate (3 × 70 mL). The organic phase was dried over
Na2SO4 , filtered, and concd. Purification by silica gel chroma-
tography (1:1 ethyl acetate/hexane, Rf 0.25) afforded 15 (1.8 g,
75%). 1H NMR (400 MHz, CDCl3) 6.99-7.45 (13H, m), 5.20 (1H,
bs), 4.51(1H, d, J ) 2.3 Hz), 3.80 (3H, s), 3.56 (1H, m), 3.42 (1H,
m), 2.99 (1H, dt, J ) 2.3, 8.3 Hz), 2.77 (1H, m), 1.70-1.97 (6H,
m). HRMS (M+ + H) calcd for C27H29ClNO3 450.1836, found
450.1826.
Syn th esis of (3R)-7-(4-Ch lor op h en yl)-4-(4-m eth oxyp h en -
yl)-2-p h en yl-2-a za sp ir o[3.5]n on a n -1-on e (1). To a mixture
of alcohol 15 (218 mg,0.4 mmol) and carbon tetrabromide (380
mg, 1.1 mmol) in CH2Cl2 (10 mL) at 0 °C was added triphen-
ylphosphine (300 mg, 1.1 mmol). The cooling bath was removed,
and the mixture was stirred for 1.5 h as it warmed to rt. It was
then diluted with hexane (10 mL, and the precipitate was filtered
through Celite. The filtrate was concd and the crude product
mixture was purified on a silica gel column (1:3 ethyl acetate/
hexane, Rf 0.30) to give 3-[5-bromo-3-(4-chlorophenyl)pentyl]-4-
(4-methoxyphenyl)-1-phenyl-2-azetidinone (256 mg, 100%) as a
colorless oil. 1H NMR (400 MHz, CDCl3) 6.99-7.30 (13H, m),
4.52 (1H, d, J ) 2.4 Hz), 3.80 (3H, s), 3.30 (1H, m), 3.05 (1H,
m), 3.00 (1H, dt, J ) 2.4, 8.3 Hz), 2.80 (1H, m), 1.65-1.20 (6H,
m).
h ep ten oa te (11). To a stirred solution of triethyl phospho-
noacetate (2.15 mL, 10.6 mmol) in 50 mL anhyd THF was added
a solution of n-butyllithium (6.9 mL, 11.0 mmol; 1.6 M in hexane)
at -78 °C. The mixture was stirred at this temperature for 30
min, and then the lactone 10 (2.1 g, 10.0 mmol) dissolved in
anhyd THF (10 mL) was added dropwise. The resulting mixture
was stirred at -78 °C for 10 min. DIBALH (10.0 mL, 10.0 mmol;
1.0 M in toluene) was added at the rate of 1 mL/min by a syringe
pump. The cooling bath was removed, and the mixture was
stirred at rt overnight. The mixture was quenched with aqueous
10% KHSO4 solution (70 mL), the aqueous phase was extracted
with CH2Cl2 (3 × 50 mL). The combined organic phases were
dried over Na2SO4, filtered, and concd to give the crude product.
The crude product was purified by silica gel chromatography
(1:1 ethyl acetate/hexane, Rf 0.25) to afford 11 (2.2 g, 75%) as a
colorless oil. 1H NMR (400 MHz, CDCl3) 7.09-7.30 (4H, m), 6.79
(1H, J ) 15.4, 6.9 Hz, td), 5.78 (1H, J ) 15.4 Hz, d), 4.15 (2H,
J ) 7.2 Hz, q), 3.57 (1H, m), 3.42(1H, m), 2.93 (1H, m), 2.50
(2H, m), 1.98 and 1.79 (2H, m), 1.70 (1H,bs), 1.26 (3H, t). [R]23.1
D
) +30.7° (c ) 0.54, MeOH). HRMS (M+ + H) calcd for C15H19
-
ClO3 282.1023, found 282.1031. Anal. Calcd for C15H19ClO3‚
1/4H2O: C, 62.72; H, 6.84. Found: C, 62.85; H, 6.99.
Syn t h esis of Met h yl (5R)-7-[2-[[(1,1-Dim et h ylet h yl)-
diph en ylsilyl]oxy]eth yl]-5-(4-ch lor oph en yl)h eptan oate (12).
The alcohol ester 11 (2.1 g, 7.4 mmol), tert-butyldiphenylsilyl
chloride (2.3 g, 8.1 mmol), triethylamine (1.3 mL, 8.9 mmol),
and DMAP (catalytic) were dissolved in 50 mL of anhyd CH2Cl2
and stirred at rt for 15 h (precipitation observed after 15 min).
The mixture was quenched with 10% KHSO4 (40 mL), and the
aqueous phase was extracted with of CH2Cl2 (2 × 50 mL). The
combined organic phases were dried over Na2SO4 and concd to
leave 3.9 g (100%) of crude product as a clear oil which was used
without purification. 1H NMR (400 MHz, CDCl3) 7.00-7.60
(14H, m), 6.79 (1H, J ) 15.4, 6.9 Hz, td), 5.74 (1H, J ) 15.4 Hz,
d), 4.15 (2H, J ) 7.2 Hz, q), 3.55 (1H, m), 3.42 (1H, m), 3.00
(1H, m), 2.45 (2H, m), 1.98 and 1.71 (2H, m), 1.26 (3H, t), 1.01
(9H, s).
To a solution of the crude R,â-unsaturated ester (3.8 g, 7.3
mmol) in methanol (100 mL) was added magnesium powder (1.8
g, 73 mmol) in portions over a period of 1.5 h. The mixture was
stirred at rt for an additional 0.5 h and then concd. The residue
was taken up into ethyl acetate (200 mL), filtered, and concd.
Purification of the crude product mixture by silica gel chroma-
tography (9:1 ethyl acetate/hexane, Rf 0.5) afforded 12 (3.7 g,
97%) as colorless oil. 1H NMR (400 MHz, CDCl3) 7.00-7.60
(14H, m), 3.61 (3H, s), 3.51 (1H, m), 3.42 (1H, m), 2.79 (1H, m),
2.22 (2H, J ) 7.2 Hz, t), 1.90 and 1.69 (2H, m), 1.40-1.60 (4H,
To a solution of diisopropylamine (0.34 mL, 2.6 mmol) in
anhyd THF (15 mL) cooled in an acetone/dry ice bath was added
n-butyllithium (1.6 mL/1.6 M in hexane, 2.6 mmol). The reaction
mixture was stirred at -78 °C for 0.5 h followed by the addition
of 3-[5-bromo-3-(4-chlorophenyl)pentyl]-4-(4-methoxyphenyl)-1-
phenyl-2-azetidinone (740 mg, 1.3 mmol) as a solution in anhyd
THF (20 mL). The mixture was stirred at -78 °C for an
additional 0.5 h, and the cooling bath was removed. The
progress of cyclization was monitored by silica gel TLC (1:9, ethyl
acetate/hexane, Rf 0.35) until completion (1.5-3.5 h.). The
mixture was quenched with 10% KHSO4 (50 mL) and extracted
with ethyl acetate (3 × 60 mL). The organic phase was dried
over magnesium sulfate, filtered, and concd. Purification by
silica gel chromatography (1:9 ethyl acetate/hexane) afforded 420
mg (83%) 1 as a white solid: mp 174-176 °C. 1H NMR (400
MHz, CDCl3) 6.99-7.30 (13H, m), 4.52 (1H, d, J ) 2.4 Hz), 3.80
(3H, s), 3.30 (1H, m), 3.05 (1H, m), 3.00 (1H, dt, J ) 2.4, 8.3
Hz), 2.80 (1H, m), 1.65-1.20 (6H, m). HRMS (M+ + H) calcd
m), 1.01 (9H, s). [R]23.1 ) +4.5° (c ) 0.60, MeOH).
D
Syn th esis of (4R,5S)-3-[5-(4-Ch lor op h en yl)-7-[[(1,1-d i-
m et h ylet h yl)d ip h en ylsilyl]oxy]-1-oxoh ep t yl]-4-p h en yl-2-
oxa zolid in on e (13). To a stirred solution of ester 12 (6.0 g,
11.8 mmol) in THF (40 mL) was added a solution of LiOH (21
mL of a 1 M solution). The mixture was stirred vigorously at rt
for 2 days and then acidified at 0 °C with 1 N HCl. The mixture
was extracted with CH2Cl2 (3 × 100 mL). The combined organic
phases were dried over magnesium sulfate, filtered, and concd.
The residue was taken up into anhyd toluene (70 mL), and oxalyl
chloride (5.2 mL, 60 mmol) was added. The mixture was stirred
at rt overnight and then was concd to dryness. The crude acid
chloride was dissolved in anhyd CH2Cl2 (40 mL) and was added
dropwise to a stirred solution consisting of (R)-4-phenyl-2-
oxazolidinone (1.87 g, 12 mmol), triethylamine (3.5 mL, 24
mmol), and 4-(dimethylamino)pyridine (catalytic) in CH2Cl2 (60
mL) at -5 °C. After the addition was completed, the mixture
was stirred at rt for 3 h and quenched with 1 N HCl (100 mL).
The aqueous layer was extracted with CH2Cl2 (3 × 100 mL).
The organic phase was dried over Na2SO4, filtered, and concd.
Purification by silica gel chromatography (1:4 ethyl acetate/
hexane, Rf 0.4) afforded 13 (7.0 g, 93%) as a colorless oil. 1H
NMR (400 MHz, CDCl3) 7.60 (2H, d, J ) 6.6 Hz), 7.55 (2H, d, J
) 6.6 Hz), 7.29-7.42 (11H, m), 7.20 (2H, d, J ) 8.3 Hz), 6.99
(2H, d, J ) 8.3 Hz), 5.37 (1H, dd, J ) 1.7, 8.9 Hz), 4.66 (1H, t,
J ) 8.9 Hz), 4.27 (1H, dd, J ) 3.6, 8.9 Hz), 3.50 (1H, m), 3.40
(1H, m), 2.88 (2H, m), 2.75 (1H, m), 1.89 (2H, m), 1.35-1.70 (4H,
m), 1.01 (9H, s).
for C27H27NO2Cl 432.1730, found 432.1734. Anal. Calcd for C27
26ClNO2: C, 75.08; H, 6.07; N, 3.24. Found: C, 75.37; H, 5.94;
N, 3.39. [R]25 ) +60.7° (c ) 0.54, MeOH).
-
H
D
Ack n ow led gm en t. We would like to thank Drs. M.
Browne, D. Burnett, J . Clader, D. Dodds, A. Ganguly,
M. Green, T. K. Thiruvengadam, and W. Vaccaro for
their encouragement, support, and insightful discus-
sions.
Su p p or tin g In for m a tion Ava ila ble: 1H-NMR spectra for
compounds 12, 13, and 15 (3 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
Syn th esis of (3R,4S)-3-[3-(4-Ch lor op h en yl)-5-h yd r oxy-
p en tyl]-4-(4-m eth oxyp h en yl)-1-p h en yl-2-a zetid in on e (15).
To a stirred solution of 13 (5.5 g, 8.6 mmol) in CH2Cl2 (40 mL),
J O961096B