A facile asymmetric synthesis of 1,2,3-substituted indenes

Full text of DOI:10.1021/jo9819638

J . Org. Chem. 1999, 64, 1733-1737
1733
(Scheme 1). The desired unsaturated imide substrate 3
was prepared by addition of the lithium salt of (S)-4-
phenyloxazolidinone (2) to (E)-pentenoyl chloride. Addi-
tion of the aryl cuprate derived from 3-[bis(trimethylsilyl)-
amino]phenylmagnesium chloride8 to 3 then gave Michael
adduct 4 as a single diastereomer after bisbenzylation
and recrystallization.9 Introduction of an acetyl group to
4 was accomplished via formation of the potassium
enolate of 4 with potassium bis(trimethylsilyl)amide,
followed by treatment of that enolate with MgBr2‚OEt2
and subsequent addition of acetyl chloride to yield 5 as
a single diastereomer.10a Assignment of the absolute
stereochemistry of both asymmetric centers was based
on literature precedent.11,12 Synthesis of indene 6 was
completed via the facile cyclization of methyl ketone 5
in the presence of titanium tetrachloride and a tertiary
amine, and the chiral auxiliary was readily cleaved with
lithium peroxide to produce 1. Both the cyclization and
oxazolidinone cleavage steps proceeded without racem-
ization of the C-1 stereogenic center.13
We examined this intriguing and quite facile cycliza-
tion of the methyl ketone to the indene nucleus in some
detail. Our standard cyclization conditions required
treatment of 5 with 1.0 M TiCl4 in CH2Cl2 (1 equiv),
followed by addition of diisopropylethylamine (1.2 equiv)
at low temperatures. The reaction mixture was then
warmed to ambient temperature to effect complete cy-
clization. After 1.5 h at -15 °C, conversion was 15%. In
the same time period at 0 °C, conversion proceeded to
52%, and at ambient temperatures, 60% conversion was
realized. HPLC studies of quenched aliquots from the
reaction mixture showed complete consumption of start-
ing material after 3.75 h at ambient temperature. The
only product from this reaction was the desired indene,
and when conversion was not complete, only starting
material was recovered.
A F a cile Asym m etr ic Syn th esis of
1,2,3-Su bstitu ted In d en es
Karen R. Romines,*,† Kristine D. Lovasz,
Stephen A. Mizsak, J eanette K. Morris, Eric P. Seest,
Fusen Han, J ohn Tulinsky, Thomas M. J udge, and
Ronald B. Gammill‡
Structural, Analytical, and Medicinal Chemistry Research,
Pharmacia & Upjohn, Kalamazoo, MI, 49001
Received September 29, 1998
In tr od u ction
The indene nucleus has been known for many years,1
and highly substituted indenes have recently been pre-
pared by numerous methods. These include manganese-
mediated cyclization of aryl ketones and acetylenes,2
rearrangement of arylcyclopropenes,3 sigmatropic4 or
free-radical5 cyclization of phenylvinyl derivatives, and
Lewis acid mediated cyclization of R-oxoketenedithio-
acetal/phenyl Grignard adducts.6 These methods, how-
ever, do not allow for stereocontrol of a C-1 stereogenic
center. Asymmetric indenes have previously been pre-
pared using resolution strategies.7 Recently, we have
developed an efficient asymmetric synthesis of 1,2,3-
substituted indenes (1) from readily available R,â-
unsaturated acids. Our strategy involved the use of a
chiral imide derivative, which through standard protocols
enabled us to selectively form the C-1 stereogenic center
of the indene nucleus.
The relative stereochemistry of the two centers estab-
lished by the cuprate addition and the acylation steps
was crucial. Cyclization did not occur when the substit-
uents of the methyl ketone at C-2 and C-3 were syn to
one another. For example, in the case of methyl ketone
8,10a even after stirring at room temperature for 20 h
Resu lts a n d Discu ssion
Our indene synthesis begins by establishing the asym-
metric center at what will become the C-1 position via
an organocuprate addition to an unsaturated imide
(8) Purchased from Aldrich Chemical Co.
† Current address: Glaxo Wellcome, Five Moore Drive, Research
Triangle Park, NC 27709. E-mail: krr92858@glaxowellcome.com.
‡ Current address: Central Research Division, Pfizer, Inc., Eastern
Point Road, Groton, CT 06340
(1) Heller, H. G. In Aromatic Compounds with Two Fused Carbocy-
clic Ring Systems: Benzocyclopropene, Benzocyclobutene, and Indene
and their Derivatives, 2nd ed.; Correy, S., Ansell, M. F., Eds.; Rodd’s
Chemistry of Carbon Compounds; Elsevier: Amsterdam, The Neth-
erlands, 1978; Vol. 3, Issue G.
(9) For reviews, see: (a) Rossiter, B. E.; Swinge, N. M. Chem. Rev.
1992, 92, 771. (b) Nicolas, E.; Russell, K. C.; Hruby, V. J . J . Org. Chem.
1993, 58, 766.
(10) (a) A full account of this work, which was initially described in
ref 10b, is currently under revision and will appear shortly. (b) J udge,
T. M.; Phillips, G.; Morris, J . K.; Lovasz, K. D.; Romines, K. R.; Luke,
G. P.; Tulinsky, J .; Tustin, J . M.; Chrusciel, R. A.; Dolak, L. A.; Mizsak,
S. A.; Watt, W.; Morris, J .; Vander Velde, S. L.; Strohbach, J . W.;
Gammill, R. B. J . Am. Chem. Soc. 1997, 119, 3627.
(2) (a) Liebeskind, L. S.; Gasdaska, J . R.; McCallum, J . S. J . Org.
Chem. 1989, 54, 669. (b) Robinson, N. P.; Main, L.; Nicholson, B. K. J .
Organomet. Chem. 1989, 364, C37. (c) Cambie, R. C.; Metzler, M. R.;
Rutledge, P. S.; Woodgate, P. D. J . Organomet. Chem. 1992, 429, 41.
(3) (a) Padwa, A.; Blacklock, T. J .; Getman, D.; Hatanaka, N. J . Am.
Chem. Soc. 1977, 99, 2344. (b) Semmelhack, M. F.; Ho, S.; Cohen, D.;
Steigerwald, M.; Lee, M. C.; Lee, G.; Gilbert, A. M.; Wulff, W. D.; Ball,
R. G. J . Am. Chem. Soc. 1994, 116, 7108.
(4) Gassman, P. G.; Ray, J . A.; Wenthold, P. G.; Mickelson, J . W. J .
Org. Chem. 1991, 56, 5143.
(5) Yamamura, K.; Miyake, H.; Seta, A. Bull. Chem. Soc. J pn. 1986,
59, 3699.
(11) (a) Nicholas, E.; Dharanipragada, R.; Toth, G.; Hruby, V. J .
Tetrahedron Lett. 1989, 30, 6845. (b) Qian, X.; Russell, K. D.; Boteju,
L. W.; Hruby, V. J . Tetrahedron Lett. 1995, 51, 1033.
(12) Evans, D. A.; Urpi, F.; Somers, T. C.; Clark, J . S.; Bilodeau, M.
T. J . Am. Chem. Soc. 1990, 112, 8215.
(13) To evaluate the stability of the stereogenic center of 6 and 1
(R1 ) Et, R2 ) Me), the enantiomers of these compounds were prepared
from (R)-4-phenyloxazolidinone, which is the enantiomer of 2 (Scheme
1). Analytical chiral HPLC indicated that 6, 1 (R1 ) Et, R2 ) Me), and
their enantiomers were of >99% ee. Compounds 6 (tR 18.51 min) and
its enantiomer 22 (tR 22.20 min) were analyzed using a 0.46 × 25 cm
Whelk-O column (elution of 0.5 mL/min with EtOH, detection at 380
(6) Singh, G.; Ila, H.; J unjappa, H. Synthesis 1986, 744.
(7) For example, see: (a) Weidler, A.-M.; Bergson, G Acta Chem.
Scand. 1964, 18, 1483. (b) Hussenius, A.; Matsson, O.; Bergson, G. J .
Chem. Soc., Perkin Trans. 2 1989, 851.
nm). Compounds 1 (R1 ) Et, R2 ) Me) (tR 16.78 min) and its
enantiomer 23 (tR 14.70 min) were analyzed using a 0.46 × 25 cm
Chiralcel OD-H column (elution of 0.5 mL/min with 5% 2-propanol/
0.5% acetic acid/heptane, detection at 353 nm).
10.1021/jo9819638 CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/18/1999

1734 J . Org. Chem., Vol. 64, No. 5, 1999
Notes
Sch em e 1a
recovered â-keto ester 10; however, the ratio of diaster-
eomers in the recovered â-keto ester was reversed to
1:2.5. This result indicated a very substantial rate
difference between cyclization of the major diastereomer
from the acylation, in which the substituents at C-2 and
C-3 are anti, and cyclization of the minor diastereomer,
in which the C-2 and C-3 substituents are syn.
We also investigated the electronic influence of the
substituent on the aryl ring. Initially, we used a methyl
ketone with a p-N,N-bisbenzyl group which introduces a
convenient site for further chemistry. To explore the role
of the para substituent, we synthesized substrates with
an electronically neutral group (H, 12a ), an electron-
withdrawing group (F, 12b), or a mildly electron donating
group (OMe, 12c) at the para position (eq 2). When
submitted to our standard protocol, all of these substrates
failed to produce the cyclization products, and only
starting materials were recovered. These results il-
lustrate the significant electronic contributions of the
para-substituted amino group.
Sch em e 2a
One feature of this new synthetic route is the ability
to modify the C-1 substituent of the indene. We chose to
acylate the chiral oxazolidinones to give 13a ,b so that
the C-1 substituent could be installed via condensation
of 13a ,b with the appropriate aldehyde (Scheme 3). In
all cases, Michael addition and bis-benzylation proceeded
smoothly. For the cyclopropyl derivative 15c, the acyla-
tion and cyclization steps then produced indene 18. It
was interesting to note that use of a tert-butyl substituent
precluded C-acylation. The only product observed with
15a was the O-acylated derivative 16a . Use of a benzyl
oxazolidinone as the chiral source did not sufficiently
relieve the steric strain to alter the course of the acylation
step, and 16b was the only product observed.
under the standard reaction conditions, there was no
evidence of conversion to indene (NMR, HPLC, MS, or
TLC) (eq 1). A similar result was also noted with the
â-keto ester 10, which was prepared from the imide 9a 10b
(Scheme 2). First, the chiral auxiliary was converted to
the methyl ester 9b.14 In the subsequent acylation step,
the existing stereogenic center exerted some stereochem-
ical influence and the â-keto ester 10 was formed as a
3.25:1 mixture of diastereomers. Treatment of this mix-
ture with TiCl4 and Hunig’s base yielded indene 11 and
A potentially important feature of this methodology
was the ability to modify the C-3 substituent of the
(14) Seebach, D.; Hungerbu¨hler, E.; Naef, R.; Schnurrenberger, P.;
Weidmann, B.; Zu¨ger, M. Synthesis 1982, 138.

Notes
J . Org. Chem., Vol. 64, No. 5, 1999 1735
Sch em e 3a
Sch em e 4a
Con clu sion s
We have developed a simple and efficient asymmetric
route to prepare highly substituted indenes. Our chiral
sources are the readily available phenyloxazolidinones,
and the stereogenic center is efficiently prepared via a
Michael addition to a chiral imide. Ambient temperatures
and Lewis acid conditions provide an attractive, mild
procedure for the cyclization to indene. Both the cycliza-
tion and subsequent removal of the chiral auxiliary take
place without corruption of the stereogenic center. This
procedure also provides flexibility for indene substitution,
particularly at the C-3 position. Furthermore, this route
can be readily modified to yield 1-aminoindans.
Exp er im en ta l Section
indene. By simply choosing different acid chlorides,
indenes with different C-3 substituents can be synthe-
sized. For example, treatment of the enolate of â-ketoim-
ide 4 with benzoyl chloride afforded the phenyl ketone
intermediate in good yield (eq 3). Cyclization under
standard conditions then readily gave the 3-phenyl
indene derivative 19.
Melting points are uncorrected. NMR spectra were recorded
using tetramethylsilane as an internal standard. Flash chro-
matography was performed on 230-400 mesh silica gel 60.
(4S)-3-[[(1S)-6-[Bis(ph en ylm eth yl)am in o]-1-eth yl-3-m eth -
yl-1H-in d en -2-yl]ca r bon yl]-4-p h en yl-2-oxa zolid in on e (6). A
solution of 510a,16 (0.200 g, 0.357 mmol) in CH2Cl2 (3 mL) was
cooled to -78 °C, and titanium tetrachloride (0.36 mL of a 1.0
M solution in CH2Cl2, 0.357 mmol) was added dropwise. Diiso-
propylethylamine (0.075 mL, 0.428 mmol) was added, and the
resulting mixture was stirred at -78 °C for 80 min and then
allowed to warm to room temperature over 3.5 h. The mixture
was quenched with half-saturated NH4Cl (aq, 3 mL) and
partitioned between CH2Cl2 and water. The aqueous layer was
extracted with three portions of CH2Cl2. The combined organic
layers were washed with saturated NaHCO3 (aq), water, and
brine, dried over MgSO4, filtered, and concentrated in vacuo to
give 0.182 g of crude material. Column chromatography on silica
gel (elution with 50-80% CH2Cl2/hexanes) afforded 0.123 g
(63%) of the title compound as a yellow solid: mp 159-162 °C;
1
[R]25 (c 1.0, CHCl3) -148; H NMR (300 MHz, CDCl3) δ 7.45-
D
7.20 (m, 16 H), 6.75 (br s, 1 H), 6.69 (dd, J ) 2.2, 8.4 Hz, 1 H),
5.64 (t, J ) 8.9 Hz, 1 H), 4.73-4.67 (m, 5 H), 4.31 (t, J ) 8.9 Hz,
1 H), 4.07 (br s, 1 H), 2.31 (s, 3 H), 1.79-1.70 (m, 2 H), 0.38 (br
A variation of the C-3 substitution step allowed us to
extend our strategy to the preparation of 3-aminoindanes.
Treatment of ketoimide 9a at -78 °C with TiCl4, Hunig’s
base, and the Vilsmeier reagent provided the novel
aminoindans 20a and 20b in a 2:1 ratio (Scheme 4).15
Interestingly, use of Vilsmeier reagent to form indans
was not sterically limited. Using the tert-butyl intermedi-
ate 15a , we readily obtained 21a and 21b.
(15) NMR spectra indicated the diastereomers were epimeric at the
C-1 position (NMe2 substituent). An X-ray crystal structure was
obtained of 20a to assign the absolute stereochemistry based on the
known configuration of the C-3 ethyl substituent.
(16) Synthesis and characterization of the enantiomers of com-
pounds 3-5 have been previously described in ref 10b.

1736 J . Org. Chem., Vol. 64, No. 5, 1999
Notes
s, 3 H) ppm; 13C NMR (75 MHz, CDCl3) δ 165.9, 153.5, 150.3,
149.9, 138.2, 137.6, 134.1, 132.7, 129.1, 128.8, 128.7, 127.4, 127.1,
126.7, 122.3, 111.4, 107.5, 69.4, 58.9, 54.6, 50.5, 23.4, 13.0, 8.8
ppm; IR (mull) 1778, 1655 cm-1; MS (EI) m/ z 542 (M+•). Anal.
Calcd for C36H34N2O3: C, 79.68; H, 6.32; N, 5.16. Found: C,
79.67; H, 6.47; N, 5.20.
prepared from 10 and 0.185 g (43%) of starting material was
recovered. Physical characteristics for 11: mp 104-106 °C; [R]25
D
(c 0.9, CHCl3) -40; 1H NMR (CDCl3) δ 7.35-7.24 (m, 11 H),
6.84-6.75 (m, 2 H), 4.71 (s, 4 H), 3.79 (s, 3 H), 3.67 (br s, 1 H),
2.45 (s, 3 H), 1.99-1.89 (m, 2 H), 0.41 (t, J ) 7 Hz, 3 H) ppm;
13C NMR (CDCl3) δ 166.5, 152.3, 150.5, 149.9, 138.4, 134.5,
129.2, 128.7, 127.1, 126.8, 121.9, 111.6, 108.1, 54.9, 50.6, 50.2,
24.0, 12.6, 8.6 ppm; IR (mull) 1689 cm -1; UV λmax 359 (ꢀ 26100,
MeOH); MS (EI) m/z 411 (M+•). Anal. Calcd for C28H29NO2: C,
81.72; H, 7.10; N, 3.40. Found: C, 81.49; H, 7.12; N, 3.52.
(4S)-4-P h en yl-3-[(3R)-3-ph en ylpen tan oyl]-1,3-oxazolidin -
2-on e (24a ). A solution of CuBr‚Me2S (2.01 g, 9.78 mmol) in 18
mL of THF was cooled to -50 °C, and phenylmagnesium bromide
(9.8 mL of a 1.0 M solution, 9.78 mmol) was added dropwise
over 15 min. The reaction mixture was stirred an additional 30
min at ca. -20 °C. The reaction mixture was then placed in an
ice bath, and a solution of 310a,16 (1.999 g, 8.15 mmol) in 6 mL of
THF was added dropwise over 9 min. The resulting mixture was
stirred at 0 °C for 35 min and then quenched with 50 mL of
saturated NH4Cl (aq, pH ) 8). Extraction with 100 mL of ether
gave an organic layer which was washed with three 50-mL
portions of NH4Cl (saturated aq, pH ) 8), washed with water,
dried over MgSO4, filtered, and concentrated to give 2.662 g of
yellow solid. Crystallization from Et2O afforded 1.845 g (70%)
(1S)-6-[Bis(p h en ylm et h yl)a m in o]-1-et h yl-3-m et h yl-1H -
in d en e-2-ca r boxylic Acid (1, R1 ) Et, R2 ) Me). A solution
of 6 (0.486 g, 0.90 mmol) in THF (10 mL) was diluted with water
(5 mL) and cooled to 0 °C in an ice bath. Hydrogen peroxide
(1.5 mL of a 30% aqueous solution, 13.4 mmol) and lithium
hydroxide (5.6 mL of a 0.8 M aqueous solution, 4.5 mmol) were
added dropwise, and the resulting mixture was stirred at
ambient temperature for 19 h. The reaction mixture was then
cooled to 0 °C, quenched with Na2SO3 (10.3 mL of a 1.3 M
solution, 13.4 mmol), and extracted with two 50-mL portions of
EtOAc. The combined organic layers were dried over MgSO4,
filtered, and concentrated to give 0.605 g of yellow oil. Column
chromatography on 35 g silica gel (elution with 10-30% EtOAc/
hexanes) yielded 0.186 g (53%) of the title compound as a yellow
1
foam: [R]25 (c 0.9, CHCl3) +86; H NMR (300 MHz, CDCl3) δ
D
7.38-7.29 (m, 11 H), 6.85 (s, 1 H), 6.76 (d, J ) 10.1 Hz, 1 H),
4.74 (br s, 4 H), 3.73 (br s, 1 H), 2.53 (s, 3 H), 2.16-2.06 (m, 1
H), 2.01-1.92 (m, 1 H), 0.47 (t, J ) 7.3 Hz, 3 H) ppm; 13C NMR
(75 MHz, CDCl3) δ 171.6, 155.4, 151.1, 150.1, 138.2, 134.2, 128.8,
128.2, 127.1, 126.7, 122.4, 111.3, 107.7, 54.6, 49.9, 23.7, 12.9,
8.5 ppm; IR (drift) 2961, 1652 cm-1; MS (EI) m/z 397 (M+•);
HRMS (EI) calcd 397.2042, found 397.2044. Anal. Calcd for
C27H27NO2: C, 81.58; H, 6.85; N, 3.52. Found: C, 81.21; H, 6.87;
N, 3.56.
of the title compound as white crystals: mp 68-70 °C; [R]25 (c
D
0.9, CHCl3) +60; 1H NMR (300 MHz, CDCl3) δ 7.27 (m, 8 H),
6.98-6.95 (m, 2 H), 5.36 (dd, J ) 4.0, 8.8 Hz, 1 H), 4.62 (t, J )
8.8 Hz, 1 H), 4.15 (dd, J ) 4.0, 8.8 Hz, 1 H), 3.57-3.48 (m, 1 H),
3.13-3.06 (m, 2 H), 1.70-1.55 (m, 2 H), 0.76 (t, J ) 7.3 Hz, 3
H) ppm; 13C NMR (300 MHz, CDCl3) δ 171.6, 153.5, 143.5, 138.5,
128.9, 128.2, 127.6, 126.2, 125.3, 69.7, 57.4, 43.5, 41.3, 29.1, 11.7
ppm; IR (mull) 1788, 1697 cm -1; MS (EI) m/z 323 (M+•). Anal.
Calcd for C20H21NO3: C, 74.28; H, 6.55; N, 4.33. Found: C, 74.24;
H, 6.69; N, 4.36.
(S)-3-[Bis(p h en ylm eth yl)a m in o]-â-eth ylben zen p r op a n o-
ic Acid Meth yl Ester (9b). Titanium tetrachloride (6.64 mL,
60.4 mmol) was added dropwise to methanol (150 mL) in an ice
bath. The resulting mixture was stirred at ambient temperature
for 2 h, and then 9a 10b (9.5 g, 18.3 mmol) was added. The mixture
was warmed to reflux overnight and then quenched with
saturated NH4Cl (aq) and extracted with EtOAc. The organic
layer was washed with saturated NaHCO3 (aq) and concen-
trated. Column chromatography on 200 g of silica gel (elution
with 5-20% EtOAc/hexanes) gave 5.91 g (83%) of the title
(2R)-1-[(4S)-2-Oxo-4-p h en yl-1,3-oxa zolid in -3-yl]-2-[(1R)-
1-p h en ylp r op yl]-1,3-bu ta n ed ion e (12a ). A solution of MgBr2‚
Et2O (0.661 g, 2.56 mmol) and 24a (0.754 g, 2.33 mmol) in THF
(5 mL) was cooled to -78 °C, and potassium bis(trimethylsilyl)-
amide (7 mL of a 0.5 M solution in toluene, 3.5 mmol) was added
dropwise over 7 min. The resulting mixture was stirred at -78
°C for 30 min, and then a solution of acetyl chloride (0.25 mL,
3.5 mmol) in THF (5 mL) was added dropwise over 3 min. The
reaction mixture was stirred at -78 °C for 20 min and then
allowed to slowly warm to ambient temperature overnight.
The reaction mixture was then quenched with half-saturated
NH4Cl (aq, 5 mL) and extracted with EtOAc (100 mL). The
organic layer was washed with saturated NaHCO3 (aq, 25 mL),
water (25 mL), and brine (10 mL), dried over MgSO4, filtered,
and concentrated to give 1.105 g of yellow solid. Recrystallization
from EtOAc/hexanes gave 0.319 g (37%) of the title compound
as yellow crystals: mp 128-131 °C; [R]25D (c 1.0, CHCl3) +3; 1H
NMR (300 MHz, CDCl3) δ 7.43-7.21 (m, 10 H), 5.48 (dd, J )
3.9, 8.7 Hz, 1 H), 5.14 (d, J ) 10.5 Hz, 1 H), 4.71 (app t, J ) 8.8
Hz, 1 H), 4.25 (dd, J ) 3.9, 8.9 Hz, 1 H), 3.28 (dt, J ) 4.1, 10.5
Hz, 1 H), 1.75-1.68 (m, 2 H), 1.65 (s, 3 H), 0.69 (t, J ) 7.3 Hz,
3 H) ppm; 13C NMR (75 MHz, CDCl3) δ 167.7, 153.7, 140.1, 138.1,
129.1, 128.7, 128.6, 127.0, 125.5, 70.0, 64.4, 57.8, 47.4, 31.0, 26.8,
11.7 ppm; IR (mull) 1789, 1723, 1687 cm -1; MS (EI) m/z 365
(M+•); HRMS (EI) calcd 365.1627, found 365.1604. Anal. Calcd
for C22H23NO4: C, 72.31; H, 6.34; N, 3.83. Found: C, 71.93; H,
6.43; N, 3.99.
compound as an oil: [R]25 (c 0.5, MeOH) +16; 1H NMR (300
D
MHz, CDCl3) δ 7.34-7.30 (m, 4 H), 7.25-7.22 (m, 6 H), 7.09
(app t, J ) 7.8 Hz, 1 H), 6.58 (d, J ) 8.4 Hz, 1 H), 6.53-6.51 (m,
2 H), 4.62 (s, 4 H), 3.57 (s, 3 H), 2.92-2.81 (m, 1 H), 2.51 (d, J
) 7.3 Hz, 2 H), 1.58-1.45 (m, 2 H), 0.69 (t, J ) 7.3 Hz, 3 H)
ppm; IR (liquid) 1738 cm-1; MS (EI) m/z 387 (M+•); HRMS (EI)
calcd for C26H29NO2 387.2198, found 387.2196. Anal. Calcd for
C26H29NO2: C, 80.59; H, 7.54; N, 3.61. Found: C, 80.71; H, 7.69;
N, 3.77.
(âS)-Meth yl r-Acetyl-3-[bis(p h en ylm eth yl)a m in o]-â-eth -
ylben zen ep r op a n oa te (10). A solution of 9b (0.775 g, 2.0
mmol) in THF (5 mL) was cooled to -78 °C, and LDA (1.1 mL
of a 2.0 M solution, 2.2 mmol) was added dropwise over 2 min.
The reaction mixture was stirred at -78 °C for 5 min and then
transferred via cannula over 10 min to a solution of acetyl
chloride (1.4 mL, 19.7 mmol) in 5 mL of THF at -78 °C. After
an additional 10 min of stirring, the reaction mixture was
allowed to warm to room temperature over 10 min, diluted with
EtOAc, and washed with saturated NaHCO3 (aq) until the
aqueous layer was neutral. The organic layer was then washed
with water and concentrated to give 1.05 g of a greenish oil.
Column chromatography on 100 g of silica gel (elution with
5-30% EtOAc/hexanes) gave 0.67 g (78%) of the title com-
(S)-3-Acetyl-4-p h en yl-2-oxa zolid in on e (13a ). A solution of
(S)-4-phenyl-2-oxazolidinone (10.16 g, 62.2 mmol) in THF (350
mL) was cooled to -78 °C, and n-butyllithium (39 mL of a 1.6
M solution, 62.2 mmol) was added dropwise over 15 min. The
reaction mixture was stirred at -78 °C for an additional 15 min;
then a solution of acetyl chloride (4.9 mL, 68.4 mmol) in THF
(25 mL) was added dropwise over 5 min. The reaction mixture
was then allowed to warm to room temperature and stirred
overnight. The reaction mixture was quenched by pouring into
saturated NH4Cl (aq, 250 mL) and extracted with EtOAc (250
mL). The aqueous layer was extracted with additional EtOAc
(100 mL); then the organic layers were combined, dried over
MgSO4, filtered, and concentrated to give 12.88 g of a white solid.
Recrystallization from EtOAc/hexanes gave 9.436 g (74%) of the
pound: mp 86-103 °C; [R]25 (c 1.1, MeOH) +30; 1H NMR (300
D
MHz, CDCl3) δ 7.28-7.21 (m, 10 H), 7.08 (t, J ) 7.8 Hz, 1 H),
6.80-6.57 (m, 3 H), 4.62 (br s, 4 H), 3.72 (t, J ) 4.1 Hz, 3 H),
3.38 (s, 1 H), 3.28-3.09 (m, 1 H), 2.25 (s, 1 H), 1.78 (s, 1 H),
1.58-1.56 (m, 2 H), 1.55-1.37 (m, 1 H), 0.60-0.55 (m, 3 H) ppm;
13C NMR (75 MHz, CDCl3) δ 202.8, 202.5, 169.3, 168.5, 141.6,
138.6, 129.4, 129.1, 128.6, 128.5, 128.3, 128.2, 127.0, 125.4, 116.5,
113.0, 111.3, 66.6, 66.0, 54.4, 52.4, 52.1, 47.7, 47.3, 29.8, 29.7,
27.4, 26.8, 11.7, 11.5 ppm; IR (mull) 1740, 1714 cm -1; MS (EI)
m/z 429 (M+•). Anal. Calcd for C28H31NO3: C, 78.29; H, 7.27; N,
3.26. Found: C, 78.29; H, 7.33; N, 3.33.
(R)-Meth yl 6-[Bis(p h en ylm eth yl)a m in o]-1-eth yl-3-m eth -
yl-1H-in d en e-2-ca r boxyla te (11). Using the procedure de-
scribed above for 6, 0.141 g (30%) of the title compound was
title compound as white crystals: mp 90-91 °C; [R]25 (c 1.0,
D
1
CHCl3) +56; H NMR (300 MHz, CDCl3) δ 7.39-7.28 (m, 5 H),

Notes
J . Org. Chem., Vol. 64, No. 5, 1999 1737
5.42 (dd, J ) 3.5, 8.7 Hz, 1 H), 4.68 (app t, J ) 8.8 Hz, 1 H),
4.28 (dd, J ) 3.5, 8.9 Hz, 1 H), 2.53 (s, 3 H) ppm; 13C NMR (75
MHz, CDCl3) δ 169.5, 153.7, 138.8, 129.0, 128.6, 125.8, 69.8, 57.2,
23.6 ppm; IR (mull) 1772, 1701 cm-1; MS (EI) m/z 205 (M+•),
162, 161, 145, 132, 119, 105, 104, 91, 77, 51. Anal. Calcd for
C11H11NO3: C, 64.38; H, 5.40; N, 6.82. Found: C, 64.22; H, 5.50;
N, 6.77.
Hz, 1 H), 4.73-4.65 (m, 5 H), 4.07-4.01 (m, 1 H), 2.84 (d, J )
10.7 Hz, 1 H), 2.00 (s, 3 H), 0.40 (s, 9 H) ppm; 13C NMR (75
MHz, DMSO-d6) δ 167.3, 153.8, 147.3, 141.5, 139.2, 138.1, 135.5,
128.7, 128.3, 127.7, 126.8, 126.5, 117.3, 113.4, 110.5, 110.1, 69.4,
58.9, 54.4, 51.4, 33.6, 27.1, 19.9 ppm; IR (mull) 1770 cm -1; MS
(EI) m/z 588 (M+•). Anal. Calcd for C38H40N2O4: C, 77.52; H,
6.85; N, 4.76. Found: C, 77.55; H, 6.81; N, 4.71.
(S)-3-(1-Oxo-4,4-d im eth yl-2-p en ten yl)-4-p h en yl-2-oxa zo-
lid in on e (14a ). A solution of 13a (5.093 g, 24.8 mmol) in
CH2Cl2 (125 mL) was cooled to -78 °C, and TiCl4 (2.9 mL, 26.0
mmol) was added dropwise over 2 min. N,N-Diisopropylethyl-
amine (4.8 mL, 27.3 mmol) was added dropwise over 5 min, and
the resulting mixture was stirred for 40 min at -78 °C. tert-
Butylcarboxaldehyde (2.7 mL, 25.1 mmol) was then added
dropwise over 3 min, and diisopropylethylamine (4.8 mL, 27.3
mmol) was added dropwise over 2 min. The resulting mixture
was allowed to warm to room temperature over 1 h and then
poured into water (100 mL) and stirred for 15 min. The organic
layer was then separated, washed with 1:1 saturated NaHCO3
(aq)/brine (100 mL), dried over MgSO4, filtered, and concentrated
to give 6.922 g of a yellow solid. Recrystallization from EtOH
(4R)-3-{[(1S,2S,3S)-5-(Diben zylam in o)-1-(dim eth ylam in o)-
3-eth yl-2,3-d ih yd r o-1H-in d en -2-yl]ca r bon yl}-4-p h en yl-1,3-
oxa zolid in -2-on e (20a ) a n d (4R)-3-{[(1R,2S,3S)-5-(Diben -
zyla m in o)-1-(d im et h yla m in o)-3-et h yl-2,3-d ih yd r o-1H -in -
d en -2-yl]ca r bon yl}-4-p h en yl-1,3-oxa zolid in -2-on e (20b). A
solution of 9a 10b (2.033 g, 3.92 mmol) in CH2Cl2 (25 mL) was
cooled to -78 °C, and titanium tetrachloride (0.42 mL, 3.92
mmol) was added dropwise. Diisopropylethylamine (0.68 mL,
3.92 mmol) was then added dropwise, and the resulting solution
was stirred at 0 °C for 30 min. The reaction mixture was then
cooled to -78 °C, and (chloromethylene)dimethylammonium
chloride (0.602 g, 4.70 mmol) was added over 4 min. The reaction
mixture was stirred at 0 °C for 3 h, quenched with saturated
NaHCO3 (aq, 150 mL), and extracted with two 150-mL portions
of EtOAc. The combined organic layers were washed with brine,
dried over MgSO4, filtered, and concentrated to give 2.663 g of
a green-yellow oil. Column chromatography on 225 g of silica
gel (elution with 10-30% EtOAc/hexanes) gave 1.137 g (51%)
of 20a as a white foam and 0.580 g (26%) 20b as a pale green
yielded 4.707 g (69%) of the title compound: mp 138-142 °C;
1
[R]25 (c 1.1, CHCl3) +103; H NMR (300 MHz, CDCl3) δ 7.39-
D
7.30 (m, 5 H), 7.19 (d, J ) 15.6 Hz, 1 H), 7.13 (d, J ) 15.6 Hz,
1 H), 5.49 (dd, J ) 3.9, 8.8 Hz, 1 H), 4.69 (t, J ) 8.8 Hz, 1 H),
4.28 (dd, J ) 3.9, 8.8 Hz, 1 H), 1.09 (s, 9 H) ppm; 13C NMR (75
MHz, CDCl3) δ 165.6, 162.1, 154.2, 139.6, 129.6, 129.1, 126.4,
116.1, 70.3, 58.2, 34.8, 29.0 ppm; IR (mull) 1777, 1686, 1633
cm-1; MS (EI) m/z 273 (M+•); HRMS (EI) calcd 273.1365, found
273.1362.
foam. P h ysica l ch a r a cter istics for 20a : [R]25 (c 0.9, CHCl3)
D
-145; 1H NMR (300 MHz, CDCl3) δ 7.45 (dd, J ) 1.5, 6.6 Hz, 2
H), 7.35-7.21 (m, 13 H), 7.01 (d, J ) 9.1 Hz, 1 H), 6.59-6.57
(m, 2 H), 5.52 (dd, J ) 4.0, 8.8 Hz, 1 H), 4.90 (d, J ) 9.2 Hz, 1
H), 4.72 (t, J ) 8.8 Hz, 1 H), 4.61 (s, 4 H), 4.28 (dd, J ) 4.0, 8.8
Hz, 1 H), 4.08 (dd, J ) 4.0, 8.8 Hz, 1 H), 3.81 (ddd, J ) 4.2, 9.2,
9.2 Hz, 1 H), 1.89 (s, 6 H), 1.78-1.71 (m, 1 H), 1.33-1.26 (m, 1
H), 0.76 (t, J ) 7.4 Hz, 3 H) ppm; 13C NMR (75 MHz, CDCl3) δ
171.9, 153.4, 149.6, 147.0, 139.0, 138.6, 128.5, 128.3, 127.9, 127.7,
126.7, 126.3, 125.8, 111.2, 107.7, 69.9, 69.6, 58.0, 55.1, 54.4, 45.4,
42.0, 27.0, 11.2 ppm; IR (mull) 1778, 1702 cm-1; UV λmax 258 (ꢀ
18900, 95% EtOH); MS (EI) m/z 573 (M+•); HRMS (EI) calcd
573.2991, found 573.2986. Anal. Calcd for C37H39N3O3: C, 77.46;
H, 6.85; N, 7.32. Found: C, 77.33; H, 6.92; N, 7.09. P h ysica l
(4S)-3-[(3S)-3-[3-(Diben zyla m in o)p h en yl]-4,4-d im eth yl-
p en ta n oyl]-4-p h en yl-1,3-oxa zolid in -2-on e] (15a ). Using the
procedure described above for 24a , 4.804 g of (4S)-3-[(3S)-3-(3-
aminophenyl)-4,4-dimethylpentanoyl]-4-phenyl-1,3-oxazolidin-
2-one (25a ) was prepared from 14a . This material was used
immediately without further purification. A solution of 25a (4.8
g), potassium carbonate (3.8 g, 27.8 mmol), and benzyl bromide
(3.3 mL, 27.8 mmol) in acetonitrile (20 mL) was heated to reflux
for 1.25 h. The reaction mixture was then diluted with EtOAc
(100 mL) and washed with two 30-mL portions of water. The
organic layer was dried over MgSO4, filtered, and concentrated
to give 7.295 g of a black oil. Column chromatography on 100 g
of silica gel (elution with 3-20% EtOAc/hexanes) gave 1.068 g
(18% for two steps) of the title compound as an off-white solid:
ch a r a cter istics for 20b: [R]25 (c 1.0, CHCl3) -79; 1H NMR
D
(300 MHz, CDCl3) δ 7.37-7.22 (m, 15 H), 7.02-6.98 (m, 1 H),
6.62 (dd, J ) 2.4, 8.5 Hz, 1 H), 6.45 (d, J ) 2.4 Hz, 1 H), 5.52
(dd, J ) 3.6, 8.8 Hz, 1 H), 4.69 (dd, J ) 8.8, 8.8 Hz, 1 H), 4.63-
4.58 (m, 1 H), 4.61 (s, 4 H), 4.40-4.38 (m, 1 H), 4.34 (dd, J )
3.6, 8.8 Hz, 1 H), 3.29-3.21 (m, 1 H), 2.14 (s, 6 H), 1.79-1.58
(m, 2 H), 0.85 (t, J ) 7.4 Hz, 3 H) ppm; 13C NMR (75 MHz,
CDCl3) δ 176.6, 153.3, 149.6, 144.9, 138.6, 128.9, 128.7, 128.5,
126.7, 126.3, 125.2, 112.0, 107.0, 75.9, 69.2, 58.0, 54.3, 50.4, 46.0,
40.6, 25.9, 10.6 ppm; IR (mull) 1776, 1693 cm-1; UV λmax 258 (ꢀ
18900, 95% EtOH); MS (EI) m/z 573 (M+•); HRMS (EI) calcd
573.2991, found 573.2985. Anal. Calcd for C37H39N3O3: C, 77.46;
H, 6.85; N, 7.32. Found: C, 77.12; H, 6.73; N, 7.06.
mp 156-158 °C; [R]25 (c 1.0, DMSO) +42; 1H NMR (300 MHz,
D
DMSO-d6) δ 7.25-7.19 (m, 10 H), 7.11 (d, J ) 7.2 Hz, 1 H), 7.04-
6.94 (m, 3 H), 6.64-6.58 (m, 3 H), 6.50 (s, 1 H), 6.34 (d, J ) 7.3
Hz, 1 H), 5.36 (dd, J ) 3.5, 8.4 Hz, 1 H), 4.76-4.59 (m, 5 H),
4.07-3.95 (m, 2 H), 2.78-2.65 (m, 2 H), 0.63 (s, 9 H) ppm; 13C
NMR (75 MHz, DMSO-d6) δ 171.6, 153.7, 147.4, 141.3, 139.2,
128.4, 128.3, 127.8, 127.0, 126.5, 124.5, 110.4, 69.8, 56.7, 54.4,
52.2, 33.5, 33.0, 27.6 ppm; IR (mull) 1775, 1714 cm -1; MS (EI)
m/z 546 (M+•). Anal. Calcd for C36H38N2O3: C, 79.09; H, 7.01;
N, 5.12. Found: C, 79.11; H, 7.02; N, 5.08.
(Z,3S)-3-[3-(Diben zyla m in o)p h en yl]-4,4-d im eth yl-1-[(4S)-
2-oxo-4-ph en yl-1,3-oxazolidin -3-yl]-1-pen ten yl Acetate (16a).
Using the procedure described above for 12a , 0.443 g (48%) of
the title compound was prepared from 15a : [R]25D (c 1.0, MeOH)
+6; 1H NMR (300 MHz, DMSO-d6) δ 7.37-7.22 (m, 15 H), 6.88
(app t, J ) 7.8 Hz, 1 H), 6.44 (d, J ) 7.8 Hz, 1 H), 6.30 (s, 1 H),
6.24 (d, J ) 7.8 Hz, 1 H), 5.19-5.12 (m, 1 H), 5.08 (d, J ) 10.7
Su p p or tin g In for m a tion Ava ila ble: Experimental in-
formation for compounds 22 (enantiomer of 6), 23 (enantiomer
of 1, R1 ) Et, R2 ) Me), 12b,c, 14b,c, 15b,c, 16b, 17, 18, 19,
and 21a ,b and X-ray crystal structure of 20a . This material
is available free of charge via the Internet at http://pubs.acs.org.
J O9819638