A Catalytic Asymmetric Synthesis of a Spirofused Azetidinone as a Cholesterol Absorption Inhibitor

Full text of DOI:10.1021/jo9704366

6412
J . Org. Chem. 1997, 62, 6412-6414
Sch em e 1
A Ca ta lytic Asym m etr ic Syn th esis of a
Sp ir ofu sed Azetid in on e a s a Ch olester ol
Absor p tion In h ibitor
Guangzhong Wu* and Wanda Tormos
Chemical Process Research and Development,
Schering-Plough Research Institute, 2015 Galloping Hill
Road, Kenilworth, New J ersey 07033
Received March 10, 1997
In tr od u ction
The recent discovery of potent cholesterol absorption
inhibition by a class of azetidinone compounds exempli-
fied by 1 and 2 has stimulated significant synthetic
interest in developing asymmetric processes.1-3 To date,
all approaches to these type of azetidinones have em-
ployed chiral auxiliary-based chemistry.1-4 While recy-
cling of these auxiliaries is possible, the tedious process-
ing and yield losses make it inefficient. Clearly, a
catalytic process would be much more cost-effective. A
multikilogram requirement of 2 prompted this effort, and
we wish to report both a catalytic asymmetric synthesis
of 2 and a novel selective hydrogenative debenzylation.
After initial screening, 3a 6 was found to give the best
result and was selected for the studies. A one-step
procedure was developed to afford 3 in 87% yield.
Catalyst 3a is formed in situ by reaction with BH3‚THF
(Scheme 1).
Our initial attempts at the chiral aldol reaction af-
forded a poor selectivity of 55:45 (S:R). After distillation
of both the solvent and the silyl enol ether 4, the S:R
ratio improved to 78:22 when 0.4 equiv of 3a was used.
During process development, we identified two more
critical factors that control the enantioselectivity: (1) the
best ratio of BH3‚THF to 3 is 0.9 and (2) slow addition of
the aldehyde is necessary. Under the optimized condi-
tions, the S:R ratio improved from 78:22 to 95.5:4.5.
Although this reaction required 0.4 equiv of catalyst,
87% of it was readily recovered. Thus, concentration of
the organic layer resulted in 5 as a crystalline solid,
enhancing the ee from 90% to 94%. Acidification of the
aqueous layer, followed by extraction with t-BuOMe, led
to the recovery of 3 in 87% yield. There was no loss of
enantioselectivity after nine consecutive recycles on a
kilogram scale. After recovery, the net consumption of
3 in each run was only 5 mol %.
The addition of 4-ClC6H4MgBr took place from both
faces of the carbonyl group in ketone 6, producing a
diastereomeric mixture of 7 and 7a with a disappointing
ratio of 83:17. Moreover, there were a lot of impurities
in the reaction mixture. We suspected that the complex
reaction was the result of enolization which could be
minimized by reverse addition. Indeed, the reaction
proceeded to >98% completion when the ketone 6 was
added dropwise to 1.5 equiv of the Grignard reagent.
Further studies indicated that the higher the reaction
temperature the better the diastereoselectivity. The best
result was obtained when the reaction was carried out
in toluene at 80 °C as shown in Table 1.
Resu lts a n d Discu ssion
The synthetic strategy was to construct the desired
chiral center via an aldol condensation followed by
amination and cyclization.3d Catalysts employed for the
Mukaiyama-type aldol condensation can be divided into
two major categories: amino acid derivatives4 and arti-
ficially designed chiral ligands such as the binaphthol-
titanium complexes.5 We have chosen the former type
of catalyst because such ligands are readily available.
(1) (a) 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. (b)
McKittrick, B. A.; Dugar, S.; Clader, J . W.; Davis, H., J r.; Czarniecki,
M. Bioorg. Med. Chem. Lett. 1996, 6, 1947. (c) Dugar, S.; Clader, J .
W.; Chan, T. M.; Davis, H., J r. J . Med. Chem. 1995, 38, 4875.
(2) (a) Burnett, D. A.; Caplen, M. A.; Davis, H. R.; Burrier, R. E.;
Clader, J . W. J . Med. Chem. 1994, 37, 1733. (b) Burnett, D. A.
Tetrahedron Lett. 1994, 35. 7339. (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.
(3) (a) Thiruvengadam, T. K.; Tann, C. H.; Lee, J .; McAllister, T.;
Sudhakar, A. US Patent 5306817, 1994; Chem. Abstr. 1994, 112,
157423e. (b) Chen, L.; Zaks, A.; Chacklamanil, S.; Dugar, S. J . Org.
Chem. Soc. 1996, 61, 8341. (c) For a review see: Georg, G. I. The
Organic Chemistry of â-Lactams; VCH: New York, 1993. (d) Shirai,
F.; Nakai, T. Tetrahedron Lett. 1988, 29, 6461.
(4) (a) Corey, E. J .; Cywin, C. L.; Roper, T. D. Tetrahedron Lett. 1992,
33, 6907. (b) Corey, E. J .; Loh, T.-P. J . Am. Chem. Soc. 1991, 113, 8966.
(c) Parmee, E. R.; Tempkin, O.; Masamune, S. J . Am. Chem. Soc. 1991,
113, 9365. (d) Kiyooka, S.-i.; Kaneko, Y.; Kume, K.-I. Tetrahedron Lett.
1992, 33, 4927. (e) Kobayashi, S.; Horibe, M. J . Am. Chem. Soc. 1994,
116, 9805.
(5) (a) Sodeoka, M.; Ohrai, K.; Shibasaki, M. J . Org. Chem. 1995,
60, 2648. (b) Carreira, E. M.; Singer, R. A.; Lee, W. J . Am. Chem. Soc.
1994, 116, 8837. (c) Mikami, K.; Terada, M.; Nakai, T. J . Am. Chem.
Soc. 1989, 111, 1940.
Pd/C-catalyzed debenzylation of compound 7 generated
an unacceptable 4.7% (HPLC area normalization) of the
deschloro impurity. Initially, we circumvented this
problem by exchanging the benzyl group for TBDMS
prior to the Grignard addition and learned that 0.6% of
the deschloro impurity arose from the Grignard reagent.
We thought that the dechlorination could have been
taking place via a palladium oxidative insertion into the
C-Cl bond followed by a hydrogenative reduction and
speculated that addition of a Lewis acid might slow down
the insertion. To our delight, the dechlorination pathway
(6) Kiyooka, S.; Kaneko, Y.; Komura, M.; Matsuo, H.; Nakano, M.
J . Org. Chem. 1991, 56, 2276.
S0022-3263(97)00436-2 CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 18, 1997 6413
Ta ble 1
tion in the presence of a catalytic amount of BnNEt3Cl,
generated the â-lactam ring in 59% overall yield. Addi-
tion of 4-ClC6H4MgBr to ketone 6 in toluene followed by
the novel selective debenzylation produced 2 in 99.5%
chemical purity and 99.5% ee. This process was scaled
up smoothly and produced 1.5 kg of 2.
In summary, we have invented a catalytic enantio- and
diastereoselective synthesis of 2 which has proven robust
enough for large scale use. We have also discovered a
novel selective debenzylation mediated by ZnBr2.
entry
solvent
Et2O/THF
t-BuOMe/toluene
t-BuOMe/toluene
temp (°C)
7:7a
1
2
3
-20
50
80
83:17
93:7
94:6
Exp er im en ta l Section
All reactions were carried out under nitrogen. 1H and 13C
NMR spectra (300 or 400 MHz) were recorded in CDCl3 and
referred to TMS unless otherwise noted. All starting materials
were purchased commercially, and 4-BnOC6H4CHO was recrys-
tallized from toluene.
Ta ble 2
8-Ca r beth oxy-1,3-d ioxa sp ir o[1.4]d eca n e (8). A mixture
of 307.5 g (1.968 mol) of ethyl 4-oxocyclohexanecarboxylate, 131.7
mL (2.362 mol) of ethylene glycol, and 3.74 g (19.68 mmol) of
4-MeC6H4SO3H in a 2-L flask was heated at reflux. Water
produced was removed via azeotropic distillation. When the
reaction slowed, 75 mL of toluene was added and the distillation
was continued for about 4 h. The cooled reaction mixture was
added slowly to 450 mL of ice cold saturated NaHCO3 solution
and extracted three times with 300 mL of EtOAc. The combined
extract was washed with brine, dried with MgSO4, and concen-
trated. The residue was distilled at 115-125 °C/0.3 mmHg to
give 319.0 g (81%) of 8. HRMS 215.1283 (M+ + H), calcd for
entry
ZnBr2
HOAc
Des-Cl, %
Des-OH, %
1
2
3
0
0
0
4.7
7.1
0.6
2.6
3.3
2.0
2 drops
0
0.6 equiv
Sch em e 2
C
11H19O4 215.1292. 1H NMR δ 4.13 (q, J ) 7.0 Hz, 2H), 3.96 (s,
4H), 2.4-2.3 (m, 1H), 2.0-1.9 (m, 2H), 1.9-1.75 (m, 4H), 1.65-
1.5 (m, 2H), 1.26 (t, J ) 7.0 Hz, 3H); IR (neat) 2940 (s), 2840
(s),1730 (s) cm-1
.
8-[E t h o x y (t r im e t h y ls ilo x y )m e t h y lid e n e ]-1,3-d io x a -
sp ir o[1.5]d eca n e (4). To 23.3 mL (166 mmol) of i-Pr2NH and
130 mL of THF in a dry 1-L three-necked flask equipped with a
mechanical stirrer was added dropwise at -20 °C 104 mL (166
mmol) of 1.6 M n-BuLi/hexane. After 30 min at -20 °C, a
solution of 29.6 g (138 mmol) 8 in 30 mL of THF was added,
and the resulting mixture was stirred at -20 °C for 1 h. To the
above enolate at -20 °C was added dropwise 26.3 mL (207 mmol)
of TMSCl. The resulting mixture was stirred at -20 °C for 30
min and allowed to warm to rt for 1 h. After removal of THF,
the residue was transferred into a smaller flask via a Schlenk
filter and distilled at 87-92 °C/0.3 mmHg to give 38.9 g (94%)
of 4. HRMS 285.1512 (M+ - 1), calcd for C14H27O4 285.1522.
1H NMR δ 3.89 (s, 4H), 3.71 (q, J ) 7.0 Hz, 2H),2.25-2.20 (m,
2H), 2.19-2.10 (m, 2H), 1.48-1.40 (m, 4H), 1.15 (t, J ) 7.0 Hz,
3H), 0.13 (s, 9H).
(1S)-8-[4-(Ben zyloxy)p h en yl]-1-(h yd r oxym eth yl)-1-ca r -
beth oxy-1,3-d ioxa sp ir o[1.5]d eca n e (5). To 1.23 g (4.0 mmol)
of 3 in 5 mL of at 5 °C was added dropwise 4.0 mL (4.0 mmol)
of 1.0 M BH3‚THF. The resulting mixture was stirred at 5 °C
for 10 min and cooled to -78 °C. To the reaction mixture were
added sequentially 3.15 g (11.0 mmol) of silyl enol ether 4 and
a solution of 2.12 g (10.0 mmol) 4-BnOC6H4CHO in 4 mL EtCN
over 2 h using a syringe pump. After stirring at -78 °C for 1 h,
the reaction was poured into 50 mL of ice cold saturated
NaHCO3 and extracted three times with 50 mL of EtOAc. The
combined extract was washed four times with NaHCO3 and
concentrated to a small volume. To the residue was added 7
mL (7.0 mmol) of 1.0 M n-Bu4NF in THF. After stirring at rt
for 1 h, the mixture was extracted with toluene. The combined
extract was washed, dried over MgSO4, and concentrated. The
precipitate was filtered and dried at 55 °C to give 3.85 g (90%)
is completely blocked when ZnBr2 is used. For compari-
son, organic acids such as HOAc do not prevent the
dechlorination as shown in entry 2 of Table 2. In
addition, ZnBr2 does not increase the des-OH impurity.
To the best of our knowledge, this is a novel selective
debenzylation.7
With the development delineated above, we were able
to complete the catalytic enantio- and diastereoselective
synthesis of 2 as shown in Scheme 2. Thus, enolization
of ester 8 with LDA, followed by trapping with TMSCl,
gave silyl enol ether 4 in 94% yield. A catalytic chiral
aldol reaction followed by n-Bu4NF deprotection afforded
the hydroxy ester 5 in 95% ee. Amination of 5 was
achieved in high yield with 4-FC6H4NH2 by using Me3Al.8
Conversion of the hydroxy function into a leaving group
with (EtO)2P(O)Cl,3 followed by NaOH-promoted cycliza-
of 5 with a 91% ee. [R]22.6 ) +10.7° (c 0.52, EtOH). Mp 83-85
D
°C. HRMS 449.1940 (M+ + Na), calcd for C25H30O6Na 449.1942.
1H NMR δ 7.40-7.25 (m, 5H), 7.07 (d, J ) 8.7 Hz, 2H), 6.85 (d,
J ) 8.7 Hz, 2H),4.99 (s, 2H), 4.61 (s, 1H), 4.15-4.0 (m, 2H), 3.85
(s, 4H), 2.91 (bs, 1H), 2.3-2.2 (m, 1H), 2.0-1.9 (m, 1H), 1.7-1.4
(m, 6H), 1.14 (t, J ) 7.1 Hz, 3H). 13C NMR δ 175.2, 158.7, 137.2,
1330., 128.9, 128.5, 127.8, 114.5, 108.7, 79.6, 70.3, 64.6, 61.2,
52.3, 32.3, 32.2, 29.2, 27.8, 14.4. IR (KBr, Nujol) 3480 (m), 2920
(s), 1720 (m) cm-1. Anal. Calcd for C25H30O6: C, 70.39, H, 7.09.
Found: C, 70.07, H, 7.14.
(7) (a) Rylander, P. N. Catalytic Hydrogenation in Organic Synthe-
ses; Academic Press: New York, 1979. (b) Augustine, R. L. Catalytic
Hydrogenation; Marcel Dekker: New York, 1965. (c) A manuscript on
ZnBr2-mediated selective hydrogenation is in preparation.
(8) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977,
4171.

6414 J . Org. Chem., Vol. 62, No. 18, 1997
Notes
N-(2-Na p h th a len esu lfon yl)-D-va lin e (3). To a mixture of
400.0 g (3.414 mol) of D-valine, 3 L of water, 380 mL of THF,
and 1190 mL (8.572 mol) of TEA in a 12-L three-necked flask
with a mechanical stirrer was added dropwise at 5-10 °C a
solution of 774 g (3.414 mol) of 2-naphthalenesulfonyl chloride
in 800 mL of THF. The mixture was allowed to warm to rt and
stirred for 2 h. After evaporation of THF, the reaction was
poured into 4 L of 3 N HCl and extracted with t-BuOMe.
Concentration of the solvent gave 910.0 g (87%) of 3 as a white
solid. Mp 170-172 °C, (lit.6 170-172 °C), whose spectra data
were identical to those reported.6
ClFNO3 541.1816. 7. 1H NMR δ 7.50-7.20 (m, 8H), 7.00 (d, J
) 8.6 Hz, 2H), 6.93 (t, J ) 8.6 Hz, 2H), 5.04 (s, 2H), 4.86 (s,
1H), 2.60-2.50 (m, 1H), 2.16 (td, J ) 13.8, 4.3 Hz, 1H), 2.05-
1.90 (m, 3H), 1.63 (dm, J ) 13.8 Hz, 1H), 1.32 (dm, J ) 14.3 Hz,
1H), 1.10 (td, J ) 13,8, 4.3 Hz, 1H). 13C NMR δ 171.2, 160.4,
159.3, 158.0, 147.4, 133.0, 128.9, 128.7, 128.5, 128.4, 127.9, 127.3,
126.2, 119.0, 118.9, 117.0, 116.2, 116.0, 115.5, 71.8, 70.4, 66.5,
59.3, 35.9, 33.7, 28.3, 22.2; IR (KBr, Nujol) 3410 (w), 2920 (s),
1730 (m) cm-1. 7a . 1H NMR δ 7.47 (dd, J ) 6.8, 1.9 Hz, 2H),
7.44-7.21 (m, 9H), 7.15 (d, J ) 8.5 Hz, 2H), 6.96 (d, J ) 8.9 Hz,
2H), 7.00-6.95 (m, 2H),2.53 (td, J ) 13.4, 4.0 Hz, 1 H), 2.42 (td,
J )13.4, 4.3 Hz, 1 H), 2.36 (td, J ) 13.1, 3.7 Hz, 1 H), 2.16 (dm,
J ) 13.4, 1 H), 1.81 (dm, J )14.0 Hz, 1 H), 1.67-1.49 (m, 3 H),
1.39 (td, J ) 13.4, 4.0 Hz, 1 H). 13C NMR δ 170.8, 160.5, 158.8,
157.3, 147.1, 136.7, 134.1, 134.1, 132.7, 128.6, 128.4, 128.1, 127.9,
127.5, 126.7, 126.0, 118.6, 118.5, 116.0, 115.7, 115.0, 72.5, 70.1,
65.3, 58.4, 36.0, 35.9, 29.2, 24.8. IR (KBr, Nujol) 3450 (w), 2920
(1S)-4-[4-(Ben zyloxy)p h en yl]-4-(h yd r oxym eth yl)-4-[[(4-
flu or op h en yl)a m in o]ca r bon yl]cycloh exa n -1-on e (9). To a
dry 2-L three-necked flask with a mechanical stirrer were added
41.3 mL (436 mmol) of 4-FC6H4NH2, 120 mL of CH2Cl2, and 218
mL (436 mmol) of 2.0 M Me3Al in toluene. After agitating at rt
for 30 min, a solution of 46.7 g (109 mmol) of 5 in 110 mL of
CH2Cl2 was added dropwise, and the resulting mixture was
heated at 50-55 °C for 2 d. The cooled reaction mixture was
added dropwise to a solution of 700 mL of 3 N HCl and 400 mL
of toluene. The mixture was extracted two times with 400 mL
of EtOAc and washed with 300 mL of 3 N HCl. After concentra-
tion of the solvent, the residue was dissolved in 250 mL of THF,
followed by addition of 300 mL of 3 N HCl, and the mixture was
stirred at rt for 3 d. After removal of THF, the crude product
was filtered and slurried with saturated NaHCO3 to give 40.9 g
of 9. Recrystallization from EtOAc/hexane gave an analytical
sample. Mp 173-175 °C. HRMS 448.1924 (M+ + H), calcd for
(s), 2820 (s), 1730 (m) cm-1
.
(3R)-7-(4-Ch lor op h en yl)-2-(4-flu or op h en yl)-3-(4-h yd r ox-
yp h en yl)-2-a za sp ir o[3.5]n on a n -1-on e (2). To a 2-L Pyrex
pressure bottle were added 35.0 g of 10% Pd/C, 350.0 g (ca. 645
mmol) of crude 7, and 87.0 g (387 mmol) of ZnBr2. The bottle
was sealed, evacuated, and purged with nitrogen three times.
To the sealed bottle was added through a cannula 1100 mL of
EtOH. The mixture was hydrogenated at 50 psi for 16 h, filtered
through a pad of Celite, and concentrated. The residue was
dissolved in 1 L of EtOAc, poured slowly into 1 L of ice cold
saturated NaHCO3, extracted two times with 300 mL of EtOAc.
The combined extract was washed with saturated NH4Cl and
brine, dried over MgSO4, and concentrated. Addition of 1 L of
CH2Cl2 precipitated 178.0 g (63% over two steps) of 2. Mp 235-
236 °C. [R]25D ) +50.9° (c 0.42, MeOH). 1H NMR (DMSO-d6) δ
9.57 (s, 1H), 7.40-7.15 (m, 10H), 6.80 (d, J ) 8.5 Hz, 2H), 5.14
(s, 1H), 5.04 (s, 1H), 2.30 (td, J ) 12.8, 3.5 Hz, 1H), 2.05 (td, J
) 13.6 Hz, 3.5 Hz, 1H), 1.96 (td, J ) 13.6, 3.9 Hz, 1H), 1.87
(dm, J ) 13.6 Hz, 1H), 1.72 (dm, J ) 13.6 Hz, 1H), 1.48 (dm, J
) 13.6 Hz, 1H), 1.13 (dm, J ) 12.8 Hz, 1H), 0.84 (td, J ) 13.6,
3.5 Hz, 1H). 13C NMR (DMSO-d6) δ 170.6, 158.1 (d, J ) 240
Hz), 157.4, 149.4, 134.1 (d, J ) 2.3 Hz), 130.9, 130.0, 126.6, 125.4,
118.6 (d, J ) 8.0 Hz), 116.0 (d, J ) 23 Hz),115.6, 70.2, 64.9,
58.5, 34.8, 33.4, 27.5, 21.7. IR (KBr, Nujol) 3420 (m), 3180 (m),
2920 (s) 1730 (s) cm-1. Anal. Calcd for C26H23ClFNO3: C, 69.10;
H, 5.13; N, 3.10; Cl, 7.86; F, 4.21. Found: C, 69.16; H, 5.42; N,
3.19; Cl, 7.75; F, 4.30. Chiral HPLC: 99.5% ee. Desch lor o.
Mp 216-218 °C. HRMS 417.1743 (M+), calcd for C26H24FNO3
417.1740. 1H NMR δ 7.34-7.18 (m, 9H), 69.3-6.86 (m, 4H),
6.76 (bs, 1H), 4.84 (s, 1H), 2.56-2.49 (m, 1H), 2.17-1.88 (m,
4H), 1.60-1.56 (m, 1H), 1.29-1.11 (m, 2H). 13C NMR (DMSO-
d6) δ 170.7, 159.3, 157.4, 156.9, 150.4, 134.12, 134.10, 128.0,
126.3, 125.4, 124.5, 118.7, 118.6, 116.1, 115.9, 115.6, 70.4, 65.0,
58.6, 35.0, 33.4, 27.6, 21.7. IR (KBr, Nujol) 3350, 2920, 1725
C
27H27FNO4 448.1920. 1H NMR δ 8.88 (s, 1H), 7.48 (dd, J )
8.9, 4.8 Hz, 2H), 7.40-7.30 (m, 5H), 7.13 (d, J ) 8.6 Hz, 2H),
7.04 (t, J ) 8.6 Hz, 2H), 6.87 (d, J ) 8.6 Hz, 2H), 5.00 (s, 2H),
4.56 (s, 1H), 3.16 (bs, 1H), 2.85-2.75 (m, 1H), 2.75-2.65 (m,
1H), 2.45-2.32 (m, 2H), 2.27 (dm, J ) 15.8 Hz, 1H), 2.15-2.05
(m, 1H), 1.93 (td, J ) 13.4, 5.3 Hz, 1H), 1.55 (td, J ) 13.4, 5.3
Hz, 1H). 13C NMR (DMSO-d6) δ 210.6, 171.5, 159.7, 157.4, 156.5,
137.0, 135.1, 133.7, 128.2, 128.2, 127.7, 127.5, 122.5, 122.4, 115.1,
114.8, 113.6, 76.2, 69.0, 51.4, 37.7, 37.6, 29.5, 29.1. IR (KBr,
Nujol) 3280 (m), 2920 (m), 1700 (s), 1640 (s) cm-1
.
(3R )-2-(4-F lu o r o p h e n y l)-3-[4-(b e n zy lo x y )p h e n y l]-2-
a za sp ir o[3.5]n on a n e-1,7-d ion e (6.) To a mixture of 39.3 g of
crude 9, 4 g of BnNEt3Cl, and 1.0 L of CH2Cl2 in a 2-L three-
necked flask with a mechanical stirrer were added slowly 232 g
of 50% NaOH and 19 mL (132 mmol) of (EtO)2P(O)Cl over 20
min. The resulting mixture was stirred at rt for 2 h, added
slowly to 2 L of ice cold 3 N HCl, and extracted three times with
500 mL of EtOAc. The combined extract was washed with brine,
dried over MgSO4, and concentrated. Addition of 200 mL of Et2O
to the residue precipitated 23.4 g (59% over two steps) of 6.
[R]22.6 ) +41.6° (c 0.54, EtOH). Mp 127-129 °C. HRMS
D
430.1818 (M+ + H), calcd for C27H25FNO3 430.1805. 1H NMR δ
7.34-7.17 (m, 7H), 7.09 (d, J ) 8.6 Hz, 2H), 6.90-6.96 (m, 4H),
4.95 (s, 2H), 4.80 (s, 1H), 2.80-2.75 (m, 1H), 2.5-2.45 (m, 3H),
2.25-2.15 (m, 1H), 1.95-1.80 (m, 2H), 1.52-1.42 (m, 1H). 13C
NMR δ 209.7, 169.5, 160.5, 159.4, 158.1, 136.7, 133.96, 133.94
128.9, 128.4, 128.1, 127.8, 126.5, 119.0, 118.9, 116.3, 116.1, 115.6,
70.4, 65.2, 58.3, 38.7, 37.9, 32.9, 28.2. IR (KBr, Nujol) 2920 (s),
cm-1
.
Ack n ow led gm en t. We thank the staff of Physical-
Analytical Department for assays. We also thank D.
Schumacher, Bruce Shutts, Michael Mitchell, G. Love,
J . Yang, B. Wang, A. Miller, and D. Moloney for their
support and help.
1735 (m), 1720(m) cm-1
.
(3R)-7-(4-Ch lor op h en yl)-2-(4-flu or op h en yl)-3-[4-(ben zy-
loxy)p h en yl]-2-a za sp ir o[3.5]n on a n -1-on e (7). To 1750 mL
of 1.0 M 4-ClC6H4MgBr/t-BuOMe in a dry 12-L three-necked
flask with a mechanical stirrer was added at 48-52 °C a solution
of 500 g (1.164 mol) of 6 in 2 L of toluene over 1 h. After
agitating for 30 min, the reaction was cooled to rt and added
slowly to 6 L of ice cold 3 N HCl. The mixture was extracted
three times with 3 L of EtOAc. The combined extract was
washed with 3 L of 3 N HCl and brine, dried over MgSO4, and
concentrated to give 567.0 g of crude 7 as a mixture of two
Su p p or tin g In for m a tion Ava ila ble: 1H NMR, 13C NMR,
and IR spectra for 4, 5, 6, 7, 7a , 8, 9, and 2. Also chiral HPLC
chromatograms for 5, 6, 9, and 2 (29 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 for ordering
information.
diastereomers (94:6). HRMS 541.1820 (M+), calcd for C33H29
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J O9704366