Synthesis of optically active 5-substituted-2-pyrrolidinone derivatives having atropisomeric structure and 3,5-cis-selective reaction of their enolates with electrophiles

Article abstract of DOI:10.1021/jo991578y

Optically pure forms (≥98% ee) of N-(o-tert-butylphenyl)-5- (methoxymethyl)-2-pyrrolidinone having atropisomerism and N-(o-tert- butyldiphenylsiloxyphenyl)-5-(methoxymethyl)-2-pyrrolidinone having an atropisomerism-like structure were prepared from ortho-substituted aniline derivatives and (S)-5-(methoxymethyl)butyrolactone in a stereoselective manner. The reactions of Li-enolates from these lactams with various electrophiles and subsequent dearylation of the products gave 3,5-cis- disubstituted-2-pyrrolidinone derivatives.

Full text of DOI:10.1021/jo991578y

1108
J . Org. Chem. 2000, 65, 1108-1114
Syn th esis of Op tica lly Active 5-Su bstitu ted -2-p yr r olid in on e
Der iva tives Ha vin g Atr op isom er ic Str u ctu r e a n d 3,5-Cis-Selective
Rea ction of Th eir En ola tes w ith Electr op h iles
Masao Fujita, Osamu Kitagawa, Yoichiro Yamada, Hirotaka Izawa, Hiroshi Hasegawa, and
Takeo Taguchi*
Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-03, J apan
Received October 11, 1999
Optically pure forms (g98% ee) of N-(o-tert-butylphenyl)-5-(methoxymethyl)-2-pyrrolidinone having
atropisomerism and N-(o-tert-butyldiphenylsiloxyphenyl)-5-(methoxymethyl)-2-pyrrolidinone having
an atropisomerism-like structure were prepared from ortho-substituted aniline derivatives and (S)-
5-(methoxymethyl)butyrolactone in a stereoselective manner. The reactions of Li-enolates from these
lactams with various electrophiles and subsequent dearylation of the products gave 3,5-cis-
disubstituted-2-pyrrolidinone derivatives.
Sch em e 1
In tr od u ction
N-Substituted anilide derivatives bearing a large sub-
stituent such as a tert-Bu group at the ortho-position are
known to resist racemization and have atropisomerism
due to the high rotation barrier of the N-Ar bond.1,2a
Although the application of such atropisomeric anilide
derivatives to stereoselective reaction has been reported
initially by Curran, followed by several other groups,
these compounds could not be applied to asymmetric
reaction because of the use of the racemic or achiral
forms.2 As an evolution of atropisomeric anilide chemis-
try, we have recently succeeded in the first synthesis of
the amide (+)-1 and the imide (+)-2 with high optical
purity and definite absolute configuration, and the
development of an asymmetric Diels-Alder reaction
using (+)-1 and (+)-2 (Scheme 1).3,4 In relation to this
work, we have investigated further utilization of such
optically active atropisomeric amides.
Sch em e 2
glutamic acid, have been widely used as a key step for
the asymmetric synthesis of alkaloids and biologically
active compounds.5 In these reactions, trans-3,5-disub-
stituted-2-pyrolidinone derivatives are generally obtained
as a major product, because the attack of an electrophile
to lactam enolate preferentially occurs from the opposite
site of a substituent at the C-5 position (Scheme 2).6 On
the other hand, 3,5-cis-selective reactions with 5-substi-
tuted-2-pyrrolidinone enolates have not been reported so
far, aside from a few exceptional cases.7
The reactions of chiral 2-pyrrolidinone enolates with
various electrophiles, in particular, the diastereoselective
reactions with optically active 5-substituted-2-pyrrolidi-
none enolates which can be easily derived from pyro-
* To whom correspondence should be addressed. Fax and tel:
81-426-76-3257. e-mail: kitagawa@ps.toyaku.ac.jp or taguchi@
ps.toyaku.ac.jp.
(1) (a) Kashima, C.; Katoh, A.; J . Chem. Soc., Perkin Trans. 1 1980,
1599. (b) Roussel, C.; Adjimi, M.; Chemlal, A.; Djafri, A. J . Org. Chem.
1988, 53, 5076.
(2) (a) Curran, D. P.; Qi, H.; Geib, S. J .; DeMello, N. C. J . Am. Chem.
Soc. 1994, 116, 3131-3132. (b) Kishikawa, K.; Tsuru, I.; Kohmoto, S.;
Yamamoto, M.; Yamada, K. Chem Lett. 1994, 1605. (c) Hughes, A. D.;
Price, D. A.; Shishkin, O.; Simpkins, N. S. Tetrahedron Lett. 1996, 37,
7607. (d) Clayden, J .; Angew. Chem., Int. Ed. Engl. 1997, 36, 949.
(3) (a) Kitagawa, O.; Izawa, H.; Taguchi, T.; Shiro, M. Tetrahedron
Lett. 1997, 38, 4447. (b) Kitagawa, O.; Izawa, H.; Sato, K.; Dobashi,
A.; Taguchi, T.; Shiro, M. J . Org. Chem. 1998, 63, 2634.
(4) Recently, Simpkins et al. also reported the synthesis of optically
active N-(o-tert-butylphenyl)propanamide (93% ee) in accordance with
our optical resolution method (ref 2). (a) Hughes, A. D.; Simpkins, N.
S. Synlett 1998, 967. (b) Hughes, A. D.; Price, D. A.; Simpkins, N. S.
J . Chem. Soc., Perkin Trans. 1 1999, 1295. On the other hand, the
synthesis of optically pure forms of atropisomeric amides and imides
through the optical resolution using chiral chromatography has been
reported by two groups, while the absolute configuration of these
atropisomeric compounds has not yet been determined. (c) Curran, D.
P.; Hale, G. R.; Geib, S. J .; Balog, A.; Cass, Q. B.; Degani, A. L. G.;
Hernandes, M. Z.; Freitas, L. C. G. Tetrahedron: Asymmetry 1997, 8,
3955. (d) Kondo, K.; Fujita, H.; Suzuki, T.; Murakami, Y. Tetrahedron
Lett. 1999, 40, 5577.
(5) (a) Thottathil, J . K.; Moniot, J . L.; Mueller, R. H.; Wong, M. K.
Y.; Kissick, T. P. J . Org. Chem. 1986, 51, 3140. (b) Ohta, T.; Hosoi, A.;
Nozoe, S. Tetrahedron Lett. 1988, 29, 329. (c) Baldwin, J . E.; Miranda,
T.; Moloney, M. G.; Hokelek, T. Tetrahedron 1989, 45, 7459. (d) Hon,
Y.; Chang, Y.; Gong, M. Heterocycles 1990, 31, 191. (e) Baldwin, J . E.;
Moloney, M. G.; Shim, S. B. Tetrahedron Lett. 1991, 32, 1379. (f)
Armstrong, R. W.; DeMattei, J . A. Tetrahedron Lett. 1991, 32, 5749.
(g) Langlois, N.; Rojas, A.; Tetrahedron Lett. 1993, 34, 2477. (h)
Ezquerra, J .; Pedregal, C.; Rubio, A.; Yruretagoyena, B.; Escribano,
A.; Sanchez-Ferrando, F. Tetrahedron 1993, 49, 8665. (i) Nagasaka,
T.; Imai, T. Chem. Pharm. Bull. 1995, 43, 1081. (j) Charrier, J . D.;
Duffy, J . E. S.; Hitchcock, P. B.; Young, D. W. Tetrahedron Lett. 1998,
39, 2199. (k) Zhang, R.; Brownewell, F.; Madalengoitia, J . S. Tetrahe-
dron Lett. 1999, 40, 2707. For review: (l) Na`jera, C.; Yus, M.
Tetrahedron: Asymmetry 1999, 10, 2245. See also ref 6b.
(6) Papers in relation to the origin of 3,5-trans-selectivity: (a)
Seebach, D.; Maetzke, T.; Petter, W.; Klotzer, B.; Plattner, D. A. J .
Am. Chem. Soc. 1991, 113, 1781. (b) Meyers, A. I.; Seefeld, M. A.; Bruce,
A. L.; Blake, J . F. J . Am. Chem. Soc. 1997, 119, 4565. (c) Ando, K.;
Green, N. S.; Li, Y.; Houk, K. N. J . Am. Chem. Soc. 1999, 121, 5334.
10.1021/jo991578y CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/03/2000

Optically Active 5-Substituted-2-pyrrolidinones
J . Org. Chem., Vol. 65, No. 4, 2000 1109
Sch em e 3
Sch em e 5
Sch em e 4
stereomer on the basis of a chiral carbon and atropisom-
erism could not be detected by the NMR spectrum.
Furthermore, since optical purity of 3 was estimated to
be g98% ee by HPLC analysis using a chiral column, the
aminocyclization, giving rise to 3, should proceed with
an almost complete chirality transfer both to the chiral
carbon at the 5-position in an inversion manner and to
an axially chiral moiety from the chiral carbon of 4.
The diastereomeric lactam 3′ was found to be formed
through the protonation of the enolate prepared from
lactam 3. That is, when the Li-enolate 3A prepared by
treating 3 with LDA in THF was gradually warmed from
-78 °C to room temperature and then protonated by HCl,
a mixture of lactam 3 and 3′ was obtained in a ratio of
2.7:1 (Scheme 5). The isomerization due to the free
rotation around the N-Ar bond was not observed on
treating with LDA for 20 min at -95 °C, while the
treatment for 20 min at -78 °C resulted in a mixture of
3 and 3′ in a ratio of 40:1 (Scheme 5). The isomerization
to 3′ from 3 through the enolate formation may be due
to the sp3 character of the nitrogen atom in the enolate.
The free rotation around the N-Ar bond in the enolate
3A was assumed to easily occur even at low temperature
because of the sp3 character of the nitrogen atom.9 In
addition, a molecular model study of the enolate indicates
that steric repulsion between the tert-butyl and meth-
oxymethy groups in enolate 3A′ considerably diminishes
in comparison with that in lactam 3′ having an sp2
nitrogen atom. Thus, the decrease in the gap of the
thermodynamic stability between enolates 3A and 3A′
may result in the partial isomerization to 3A′ from 3A.
Lactam 3′ could not be separated in diastereomerically
pure form because of the relatively rapid isomerization
We expected that in the reaction of the enolate from
the atropisomeric lactam having a trans-relationship
between an ortho-substituent (R1) and an alkoxymethyl
group at the C-5 position, an electrophile may preferen-
tially attack from the opposite site of the ortho-substitu-
ent close to the reaction center; thereby, cis-3,5-disub-
stituted-2-pyrrolidinone may be obtained as a major
product after removal of the Ar group (Scheme 3). In this
paper, we report stereoselective synthesis of 5-substituted-
2-pyrrolidinone derivatives having atropisomerism or an
atropisomerism-like structure, and 3,5-cis-selective reac-
tions of Li-enolates from these lactams with various
electrophiles.8 Furthermore, interesting features of these
atropisomeric lactams are also described.
Resu lts a n d Discu ssion
St er eoselect ive Syn t h esis of N-(o-ter t-b u t yl-
p h en yl)-5-(m eth oxym eth yl)-2-p yr r olid in on e Ha vin g
Atr op isom er ism a n d Its Rea ction w ith Som e Elec-
tr op h iles. As an optically active 5-substituted-2-pyrro-
ridinone derivative having atropisomerism, N-(o-tert-
butylphenyl)-5-(methoxymethyl)-2-pyrrolidinone 3 which
can be easily derived from commercially available (S)-5-
(hydroxymethyl)butyrolactone and o-tert-butylaniline,
was chosen. The synthesis of lactam 3 is shown in
Scheme 4; mesylation and subsquent aminocyclization
reaction of γ-hydroxyamide 4 which was prepared in a
good yield from (S)-5-(methoxymethyl)butyrolactone and
o-tert-butylaniline, gave the desired lactam 3 in 87%
yield. The lactam 3 obtained through the aminocycliza-
tion was a single isomer and the existence of a dia-
(7) Moderate 3.5-cis-selectivity (cis/trans ) 5) has been observed in
the reaction of bicyclic lactam enolate with a small electrophile such
as MeI, while under the same conditions, the reaction with other
electrophiles such as allyl bromide and benzyl bromide proceeded in a
nonselective manner or with low 3,5-trans-selectivity. See refs 5f, 5j,
and 5k.
(8) Preliminary communication of this work: Fujita, M.; Kitagawa,
O.; Izawa, H.; Dobashi, A.; Fukaya, H.; Taguchi, T. Tetrahedron Lett.
1999, 40, 1949.
F igu r e 1. Chem 3D drawing of 3 obtained by X-ray analysis.

1110 J . Org. Chem., Vol. 65, No. 4, 2000
Fujita et al.
Sch em e 6
Sch em e 8
Sch em e 9
Sch em e 7
to 3 at room temperature. The mixture of 3 and 3′ in a
ratio of 1:2.7 obtained by MPLC separation was com-
pletely converted to 3 after 4 days at room temperature
(tentatively t1/2 ) 14 h at ca. 25 °C). This result should
suggest that 3′ having a cis-relationship between the
o-tert-butyl and methoxymethyl groups easily isomerizes
to the more stable 3 having a trans-relationship. Indeed,
the X-ray crystal structure of 3 indicates that the o-tert-
butyl and methoxymethyl groups are in a trans-relation-
ship with a large torsion angle (76.4°) between the amide
and tert-butylphenyl groups (Figure 1).
N-phenyl-5-(methoxymethyl)-2-pyrrolidinone 7 with Davis-
reagent under the same conditions proceeded with low
3,5-trans-selectivity (cis/trans ) 1/1.7, Scheme 7).10
For the removal of the tert-butylphenyl part from
product 5a , although several methods such as RuO4-
oxidation, ozonolysis, and Birch reduction were at-
tempted, none has been successful. Accordingly, we
further investigated the synthesis of an atropisomeric
lactam having a removable aryl group and its 3,5-cis-
selective reaction.
The reactions of enolate 3A from lactam 3 with some
electrophiles were investigated (Scheme 6). All the reac-
tions were performed within 20 min at -95 °C to prevent
the rotation around the N-Ar bond. Lithium tetra-
methylpiperidide (Li-TMP) was the most effective as a
base, and the use of other bases such as LDA, n-BuLi, or
(Me3Si)2NNa resulted in a considerable decrease in the
chemical yields of products 5. As expected, the reactions
with benzyl bromide and Davis-reagent proceeded with
high 3,5-cis-selectivity to give 3,5-disubstituted lactams
5a (cis/ trans ) 10) and 5b (cis/ trans ) 15), respectiv-
ely.10-12 Although a decrease in the selectivity was
observed, the reaction with allyl bromide also gave 3,5-
cis-lactam 5c (cis/trans ) 4) as a major product.10,12 The
contribution of an atropisomerism in these cis-selective
reactions should be obvious, because the reaction of
St er eoselect ive Syn t h esis of N-(o-ter t-Bu t yld i-
p h en ylsiloxyp h en yl)-5-(m eth oxym eth yl)-2-p yr r oli-
d in on e Ha vin g a n Atr op isom er ism -Lik e Str u ctu r e
a n d Its Rea ction w ith Som e Electr op h iles. As an
atropisomeric lactam possessing an aryl group may be
easily removed by CAN-oxidation,13 we devised N-(o-tert-
butyldiphenylsiloxyphenyl)-5-(methoxymethyl)-2-pyrro-
lidinone 11. Lactam 11 was prepared in a good yield in
accordance with Scheme 8. Mesylation of γ-hydroxyamide
9 prepared from (S)-5-(methoxymethyl)butyrolactone and
o-benzyloxyaniline, and subsequent aminocyclization of
the mesylate gave lactam 10 in a good yield. 10 was
converted to lactam 11 by hydrogenation followed by tert-
butyldiphenylsilylation. The ee of lactam 11 was found
to be g98% ee by HPLC analysis using a chiral column.
To confirm the existence of atropisomerism in the
lactams 10 and 11, similar to the case of N-(o-tert-
butylphenyl)-lactam 3 (Scheme 5), the isomerization
through the enolate formation was examined, but the
generation of atropisomers of 10 and 11 could not be
detected (Scheme 9). The X-ray crystral structure of the
lactam 11 indicates cis-relationship between the meth-
(9) It has been reported that nitrogen of amide Li-enolates is
completely tetrahedralized. (a) Laube, T.; Dunitz, J . D. Seebach, D.
Helv. Chim. Acta 1985, 68, 1373. (b) Bauer, W.; Laube, T.; Seebach,
D. Chem. Ber. 1985, 118, 764.
(10) The stereochemistries of the products were determined on the
basis of NOE experiments.
(11) The stereochemistries of cis- and trans-5b were determined
after conversion to benzoate 6b, because cis- and trans-6b can be easily
separated in comparison with cis- and trans-5b (Scheme 6).
(12) The diastereomer ratio was determined by 300 MHz 1H NMR.
(13) Yamazaki, N.; Ito, T.; Kibayashi, C. Synlett 1999, 37.

Optically Active 5-Substituted-2-pyrrolidinones
J . Org. Chem., Vol. 65, No. 4, 2000 1111
Sch em e 11
Sch em e 12
F igu r e 2. Chem 3D drawing of 11 obtained by X-ray analysis.
Hydrogen atoms have been omitted for clarity.
Sch em e 10
Sch em e 13
3A, increase in the cis-selectivity was observed (cis/trans
) 14), while in the reaction with Davis-reagent and allyl
bromide, a slight decrease in the cis-selectivity was
resulted (cis/trans ) 10 and 3.2, respectively).10 The
diastereomer ratios in the reactions were determined
after conversion to phenol derivatives 13.12,14 The result
shown in Scheme 10 may indicate that a major conformer
of Li-enolate from 11 is 11A having a trans-relationship
between the methoxymethyl and TBDPSO groups (and
not 11A′), and the electrophiles preferentially attack from
the opposite side of the TBDPSO group in 11A (Scheme
11). These results obtained here indicated that for the
achievement of 3,5-cis-selectivity, the existence of stable
atropisomerism such as lactam 3 is not always required.
The effect of the TBDPSO group as an ortho-substitu-
ent should be noteworthy, because the benzylation of the
enolates from the lactams 10 and 14 possessing benzyl-
oxy and triphenylsiloxy groups proceeded with low 3,5-
trans- and 3,5-cis-selectivies (cis/trans ) 1/1.5 and 2.7),
respectively (Scheme 12). In the reaction of o-trityloxy
derivative 15, although moderate 3,5-cis-selectivity was
observed (cis/trans ) 5), a considerable decrease in the
chemical yield was resulted (57%).
oxymethyl and tert-butyldiphenylsiloxy (TBDPSO) groups
(Figure 2). In contrast, a conformer having a trans-
relationship between the methoxymethyl and TBDPSO
groups was found to preferentially occur in solution by
NOE experiment (Scheme 9). That is, in CDCl3, a strong
NOE was observed between Ha at the 5-position and the
tert-butyl hydrogen of the TBDPS group, while no NOE
was observed between Hb of the methoxymethyl group
and the tert-butyl hydrogen (Scheme 9). These results
strongly suggest that the free rotation around N-Ar bond
of lactam 11 easily occurs at room temperature. On the
other hand, if the preference of the trans-confomer which
was observed in solution of lactam 11 is also applicable
to the case of Li-enolate 11A, 3,5-cis-selective reaction
with electrophiles may be possible.
Indeed, the reaction of Li-enolate 11A prepared from
Li-TMP and 11 with some electrophiles proceeded with
moderate to high cis-selectivity to give 3,5-disubstituted
lactam 12 in good yields (Scheme 10). In the reaction with
benzyl bromide, in comparison with the case of enolate
(14) Separation of the cis- and trans-13 was easily carried out in
comparison with that of cis- and trans-12.

1112 J . Org. Chem., Vol. 65, No. 4, 2000
Fujita et al.
saturated aqueous NaHCO3 solution and brine, dried over
MgSO4, and evaporated to dryness. Purification of the residue
by column chromatography (hexane/AcOEt ) 3) gave lactam
3 (2.28 g, 87%). The ee of 3 was determined by HPLC analysis
using a CHIRALPAK AD column [25 cm × 0.46 cm i.d.; 10%
i-PrOH in hexane; flow rate, 0.5 mL/min; (+)-3; tR ) 13.0 min,
The removal of the Ar group from the products cis-13a
and cis-13b was effectively achieved by CAN oxidation
(Scheme 13).15 These dearylations proceeded without any
epimerization to give NH lactams cis-16a and cis-16b,
respectively.
In conclusion, we have succeeded in the development
of the stereoselective synthesis of N-(o-tert-butylphenyl)-
5-(methoxymethyl)-2-pyrrolidinone having atropisomer-
ism and N-(o-tert-butyldiphenylsiloxyphenyl)-5-(meth-
oxymethyl)-2-pyrrolidinone having an atropisomerism-
like structure, and the 3,5-cis-selective reaction of their
Li-enolates with some electrophiles. The present reaction
should be noted not only as a synthetic method for 3,5-
cis-disubstituted-2-pyrrolidinone derivatives but also as
a new concept for stereoselective reaction.
(-)-3; tR ) 15.0 min]. 3: white solid; mp 93-94.5 °C; [R]D
)
+9.0 (CHCl3, c ) 1.0); IR (KBr) 3448, 2961, 1685 cm-1; 1H NMR
(CDCl3) δ: 7.53 (1H, dd, J ) 2.0, 7.6 Hz), 7.20-7.32 (2H, m),
7.01 (1H, dd, J ) 2.0, 7.6 Hz), 3.89 (1H, m), 3.44 (1H, dd, J )
3.5, 9.9 Hz), 3.35 (3H, s), 3.31 (1H, dd, J ) 2.3, 9.9 Hz), 2.68
(1H, m), 2.25-2.45 (2H, m), 2.16 (1H, m), 1.38 (9H, s); 13C NMR
(CDCl3) δ: 176.5, 148.1, 134.8, 132.0, 128.3, 128.1, 126.6, 72.2,
61.7, 58.6, 35.4, 31.5, 30.2, 22.4. MS (m/z) 262 (M+ + 1). Anal.
Calcd for C16H22NO2: C, 73.53; H, 8.87; N, 5.36. Found: C,
73.65; H, 8.84; N, 5.42.
(5R)-1-(o-ter t-b u t ylp h en yl)-5-(m et h oxym et h yl)-2-p yr -
r olid in on e (3′). To a solution of lactam 3 (78 mg, 0.3 mmol)
in THF (3 mL) was added 0.3 M THF solution of lithium
diisopropylamide (1.1 mL, 0.33 mmol) under an argon atmo-
sphere at -78 °C, and then the reaction mixture was stirred
for 15 h at -78 °C to room temperature. The mixture was
poured into 10% HCl and extracted with AcOEt. The AcOEt
extracts were washed with brine, dried over MgSO4, and
evaporated to dryness. Purification of the residue by column
chromatography (hexane/AcOEt ) 1) and subsequent MPLC
(hexane/AcOEt ) 2) gave a mixture (76 mg, 97%) of 3 and 3′
in a ratio of 1:2.6. 3′: 1H NMR (CDCl3) δ 7.56 (1H, dd, J )
1.8, 7.7 Hz), 7.17-7.30 (2H, m), 7.00 (1H, dd, J ) 2.0, 7.7 Hz),
4.16 (1H, m), 3.38-3.48 (2H, m), 3.24 (3H, s), 2.30-2.58 (3H,
m), 2.21 (1H, m); 13C NMR (CDCl3) δ: 176.8, 148.1, 135.4,
129.9, 127.5, 127.4, 126.7, 73.0, 62.4, 58.6, 36.3, 32.0, 31.0, 23.2.
Gen er a l P r oced u r e for th e Rea ction of En ola te fr om
3 w ith Electr op h iles. To a solution of lactam 3 (130.5 mg,
0.5 mmol) in THF (5 mL) was added 0.3 M THF solution of
lithium 2,2,6,6-tetramethylpiperidide (1.8 mL, 0.55 mmol)
under an argon atmosphere at -95 °C (hexane-liq N2). After
the mixture was stirred for 5 min, benzyl bromide (0.06 mL,
0.5 mmol) was added, and then the reaction mixture was
stirred for 5 min at -95 °C. The mixture was poured into 10%
HCl and extracted with AcOEt. The AcOEt extracts were
washed with brine, dried over MgSO4, and evaporated to
dryness. Purification of the residue by column chromatography
(hexane/AcOEt ) 3) and subsequent MPLC (hexane/AcOEt )
3) gave cis-5a (156 mg, 89%, less polar) and trans-5a (15 mg,
9%, more polar).
Exp er im en ta l Section
Melting points are uncorrected. 1H and 13C NMR spectra
were recorded on a 300-MHz spectrometer. In H and 13C NMR
1
spectra, chemical shifts were expressed in δ (ppm) downfield
from CHCl3 (7.26 ppm) and CDCl3 (77.0 ppm), respectively.
Mass spectra were recorded by electron impact or chemical
ionization. Column chromatography was performed on silica
gel, Wakogel C-200 (75-150 µm). Medium-pressure liquid
chromatography (MPLC) was performed on a 30 × 4 cm i.d.
prepacked column (silica gel, 50 µm) with a UV detector.
Sta r tin g Ma ter ia l. (S)-5-(Methoxymethyl)butyrolactone
was prepared from commercially available (S)-5-(hydroxy-
methyl)butyrolactone in accordance with reported proce-
dures.16
(4S)-N-(o-ter t-Bu tylp h en yl)-4-h yd r oxy-5-m eth oxyp en -
ta n a m id e (4). To a solution of (S)-5-(methoxymethyl)butyro-
lactone (2.34 g, 18 mmol) in toluene (50 mL) was added 0.98
M hexane solution of Me3Al (22 mL, 21.6 mmol) under an
argon atmosphere at room temperature. After being stirred
for 10 min at room temperature, o-tert-butylaniline (2.8 mL,
18 mmol) was added, and then the reaction mixture was
refluxed for 1 h. The mixture was carefully treated with 10%
HCl and extracted with AcOEt. The AcOEt extracts were
washed with brine, dried over MgSO4, and evaporated to
dryness. Purification of the residue by column chromatography
(hexane/AcOEt ) 1) gave 4 (4.02 g, 80%). 4: white solid; mp
75-77 °C; [R]D ) -5.5 (CHCl3, c ) 1.0); IR (KBr) 3466, 3241,
1651 cm-1; 1H NMR (CDCl3) δ: 7.54 (1H, d, J ) 7.8 Hz), 7.39
(1H, d, J ) 7.8 Hz), 7.38 (1H, br s), 7.13-7.26 (2H, m), 3.91
(1H, m), 3.44 (1H, dd, J ) 3.9, 9.6 Hz), 3.40 (3H, s), 3.32 (1H,
dd, J ) 7.0, 9.6 Hz), 2.94 (1H, d, J ) 3.3 Hz), 2.61 (2H, t, J )
6.9 Hz), 1.99 (1H, m), 1.81 (1H, m) 1.41 (9H, s); 13C NMR
(CDCl3) δ: 172.0, 143.2, 134.9, 129.0, 126.5, 126.5, 126.4, 76.7,
69.5, 58.9, 34.5, 33.4, 30.6, 28.5. MS (m/z) 279 (M+). Anal. Calcd
for C16H25NO3: C, 68.78; H, 9.02; N, 5.01. Found: C, 68.89;
H, 8.97; N, 5.11.
(5R)-1-(o-ter t-Bu tylp h en yl)-5-(m eth oxym eth yl)-2-p yr -
r olid in on e (3). To a solution of amide 4 (2.79 g, 10 mmol)
and Et3N (2.1 mL, 15 mmol) in CH2Cl2 (50 mL) was added
MsCl (0.9 mL, 12 mmol) under an argon atmosphere at 0 °C.
After being stirred for 30 min at 0 °C, the mixture was poured
into saturated aqueous NaHCO3 solution and extracted with
Et2O. The Et2O extracts were washed with brine, dried over
MgSO4, and evaporated to dryness. Purification of the residue
by column chromatography (hexane/AcOEt ) 1) gave the
mesylate. To a solution of the mesylate in toluene (80 mL) was
added tert-BuOK (2.24 g, 20 mmol) under an argon atmosphere
at room temperature, and then the reaction mixture was
stirred for 3 h at room temperature. The mixture was poured
into saturated aqueous KHSO4 solution and extracted with
AcOEt. The AcOEt extracts were successively washed with
(3R,5R) a n d (3S,5R)-1-(o-ter t-Bu t ylp h en yl)-5-(m et h -
oxym eth yl)-3-p h en ylm eth yl-2-p yr r olid in on e (cis-5a a n d
tr a n s-5a ). cis-5a : colorless oil; [R]D ) -9.0 (CHCl3, c ) 1.11);
1
IR (KBr) 2958, 1694 cm-1; H NMR (CDCl3) δ: 7.54 (1H, dd,
J ) 1.7, 7.9 Hz), 7.20-7.38 (7H, m), 6.99 (1H, dd, J ) 1.7, 7.9
Hz), 3.92 (1H, m), 3.33 (1H, d, J ) 10.8 Hz), 3.27 (3H, s), 3.14
(1H, dd, J ) 2.9, 9.8 Hz), 3.06 (1H, dd, J ) 4.1, 9.8 Hz), 2.89
(1H, dd, J ) 10.7, 10.8 Hz), 2.83 (1H, m), 2.29 (1H, ddd, J )
8.5, 9.7, 13.3 Hz), 1.91 (1H, ddd, J ) 5.4, 6.7, 13.3 Hz), 1.36
(9H, s); 13C NMR (CDCl3) δ: 176.8, 148.0, 140.0, 134.4, 132.4,
129.0, 128.8, 128.6, 128.2, 126.6, 126.0, 71.6, 59.6, 58.4, 42.8,
36.9, 35.6, 31.7, 27.1. MS (m/z) 351 (M+); HRMS calcd for
C23H29NO2 351.2198, found 351.2211. trans-5a : white solid; mp
108-109 °C; [R]D ) +41.0 (CHCl3, c ) 0.50); IR (KBr) 2953,
1686 cm-1; 1H NMR (CDCl3) δ: 7.52 (1H, dd, J ) 1.9, 7.7 Hz)
7.20-7.34 (7H, m), 7.00 (1H, dd, J ) 1.9, 7.7 Hz), 3.74 (1H,
m), 3.41 (1H, dd, J ) 3.5, 9.9 Hz), 3.38 (1H, dd, J ) 3.0, 13.7
Hz), 3.31 (3H, s), 3.25 (1H, dd, J ) 2.3, 9.9 Hz), 3.11 (1H, m),
2.62 (1H, dd, J ) 10.4, 13.7 Hz), 2.01-2.22 (2H, m), 1.34 (9H,
s); 13C NMR (CDCl3) δ: 177.2, 148.1, 139.4, 135.2, 131.9, 128.9,
128.3, 128.1, 128.1, 126.6, 125.9, 72.0, 60.1, 58.5, 42.5, 37.3,
35.5, 31.6, 29.5. MS (m/z) 351 (M+). Anal. Calcd for C23H29
-
NO2: C, 78.59; H, 8.32; N, 3.99. Found: C, 78.56; H, 8.22; N,
4.04.
(3R,5R) a n d (3S,5R)-1-(o-ter t-Bu tylp h en yl)-3-(ben zoyl-
oxy)-5-(m et h oxym et h yl)-2-p yr r olid in on e (cis-6b a n d
tr a n s-6b). cis-5b and trans-5b were prepared through the
reaction of Li-enolate from 3 (130.5 mg, 0.5 mmol) with Davis-
reagent (144 mg, 0.55 mmol) in accordance with general
(15) Kronenthal, D. R.; Han, C. Y.; Taylor, M. K. J . Org. Chem. 1982,
47, 2765.
(16) Nemoto, H.; Nagai, M.; Fukumoto, K.; Kametani, T. J . Org.
Chem. 1985, 50, 2764.

Optically Active 5-Substituted-2-pyrrolidinones
J . Org. Chem., Vol. 65, No. 4, 2000 1113
procedure. Purification by column chromatography (hexane/
AcOEt ) 1) gave a mixture of cis-5b and trans-5b (90 mg, 65%)
in a ratio of 15:1. To a solution of 5b (90 mg, 0.32 mmol) and
Et3N (0.07 mL, 0.48 mmol) in CH2Cl2 (3 mL) was added
benzoyl chloride (0.04 mL, 0.38 mmol) at room temperature,
and then the reaction mixture was stirred for 1 h. The mixture
was poured into 10% HCl and extracted with AcOEt. The
AcOEt extracts were washed with brine, dried over MgSO4,
and evaporated to dryness. Purification of the residue by
column chromatography (hexane/AcOEt ) 3) and subsequent
MPLC (hexane/AcOEt ) 3) gave cis-6b (112 mg, 92%, less
polar) and trans-6b (7 mg, 6%, more polar). cis-6b: white solid;
mp 114-116 °C; [R]D ) -33.5 (CHCl3, c ) 1.02); IR (KBr) 2960,
1730, 1708 cm-1; 1H NMR (CDCl3) δ: 8.12-8.20 (2H, m) 7.55-
7.62 (2H, m), 7.43-7.49 (2H, m), 7.24-7.38 (2H, m), 7.19 (1H,
dd, J ) 1.7, 7.7 Hz), 5.57 (1H, dd, J ) 7.2, 9.0 Hz), 4.07 (1H,
m), 3.35 (1H, dd, J ) 3.9, 10.1 Hz), 3.30 (1H, dd, J ) 3.2, 10.1
Hz), 3.26 (3H, s), 2.89 (1H, ddd, J ) 7.5, 9.1, 13.6 Hz), 2.31
(1H, ddd, J ) 6.1, 7.2, 13.6 Hz), 1.38 (9H, s); 13C NMR (CDCl3)
δ: 171.0, 166.1, 148.0, 133.6, 133.2, 132.6, 130.0, 129.5, 128.9,
128.8, 128.3, 126.9, 71.0, 70.7, 58.7, 58.6, 35.8, 31.9, 29.5. MS
(m/z) 381 (M+). Anal. Calcd for C23H27NO4: C, 72.42; H, 7.14;
N, 3.67. Found: C, 72.48; H, 7.32; N, 3.73. trans-6b: white
solid; mp 192-194 °C; [R]D ) -27.3 (CHCl3, c ) 0.33); IR (KBr)
for 3 h at room temperature. The mixture was poured into
saturated aqueous KHSO4 solution and extracted with AcOEt.
The AcOEt extracts were washed with brine, dried over
MgSO4, and evaporated to dryness. Purification of the residue
by column chromatography (hexane/AcOEt ) 7) gave lactam
11 (2.62 g, 92%). The ee of 11 was determined by HPLC
analysis using a CHIRALPAK AD column [25 cm × 0.46 cm
i.d.; 5% i-PrOH in hexane; flow rate, 1.0 mL/min; (+)-11; tR
)
9.0 min, (-)-11; tR ) 11.5 min]. 11: white solid; mp 116-117
°C; [R]D ) +69.4 (CHCl3, c ) 1.02); IR (KBr) 2933, 1681 cm-1
;
1H NMR (CDCl3) δ: 7.74 (2H, dd, J ) 1.5, 7.7 Hz), 7.72 (2H,
dd, J ) 1.7, 7.7 Hz), 7.31-7.47 (6H, m), 7.20 (1H, m), 6.80-
6.92 (2H, m), 6.48 (1H, d, J ) 1.5, 7.7 Hz), 4.30 (1H, m), 3.39
(2H, d, J ) 3.9 Hz), 3.31 (3H, s), 2.70 (1H, ddd, J ) 7.3, 10.1,
17.1 Hz), 2.54 (1H, ddd, J ) 5.5, 9.9, 17.1 Hz), 2.36 (1H, m),
2.16 (1H, m), 1.06 (9H, s); 13C NMR (CDCl3) δ: 175.3, 151.5,
135.4, 135.2, 132.3, 131.3, 130.2, 130.2, 130.0, 128.4, 127.8,
127.8, 127.4, 121.3, 120.0, 73.0, 59.6, 58.9, 30.5, 26.3, 22.2, 19.2.
MS (m/z) 459 (M+). Anal. Calcd for C28H33NO3Si: C, 73.16; H,
7.24; N, 3.05. Found: C, 72.88; H, 7.31; N, 3.06.
(3R,5R) a n d (3S,5R)-1-(o-Hyd r oxyp h en yl)-5-(m eth oxy-
m eth yl)-3-(p h en ylm eth yl)-2-p yr r olid in on e (cis-13a a n d
tr a n s-13a ). cis-12a and trans-12a were prepared through the
reaction of Li-enolate from 11 (230 mg, 0.5 mmol) with benzyl
bromide (0.07 mL, 0.55 mmol) in accordance with general
procedure. Purification by column chromatography (hexane/
AcOEt ) 3) gave a mixture of cis-12a and trans-12a in a ratio
of 14:1 (262 mg, 95.%). 1 M THF solution of TBAF (1 mL, 1
mmol) was added to THF solution of 12a , and the reaction
mixture was stirred for 1 h at room temperature. The mixture
was poured into water and extracted with AcOEt. The AcOEt
extracts were washed with brine, dried over MgSO4, and
evaporated to dryness. Purification of the residue by column
chromatography (hexane/AcOEt ) 1) and subsequent MPLC
(hexane/AcOEt ) 3) gave cis-13a (138 mg, 89%, more polar)
and trans-13a (10 mg, 6%, less polar). cis-13a : white solid;
mp 118-120 °C; [R]D ) +53.9 (CHCl3, c ) 1.09); IR (KBr) 3200,
2971, 1718, 1703 cm-1 1H NMR (CDCl3) δ: 8.08-8.12 (2H,
;
m) 7.53-7.60 (2H, m), 7.40-7.47 (2H, m), 7.25-7.38 (2H, m),
7.02 (1H, dd, J ) 1.8, 7.8 Hz), 5.81 (1H, t, J ) 8.4 Hz), 3.94
(1H, m), 3.52 (1H, dd, J ) 2.4, 10.1 Hz), 3.43 (3H, s), 3.31 (1H,
dd, J ) 1.8, 10.1 Hz), 2.85 (1H, ddd, J ) 1.1, 8.4, 13.0 Hz),
2.34 (1H, ddd, J ) 8.6, 8.8, 13.6 Hz), 1.44 (9H, s); 13C NMR
(CDCl3) δ: 171.8, 166.1, 148.5, 134.6, 133.2, 131.6, 129.9, 129.7,
128.8, 128.7, 128.3, 127.1, 71.4, 71.2, 59.7, 58.9, 35.8, 31.9, 31.8.
MS (m/z) 381 (M+). Anal. Calcd for C23H27NO4: C, 72.42; H,
7.14; N, 3.67. Found: C, 72.36; H, 7.12; N, 3.75.
(4S)-N-(o-(Ben zyloxy)p h en yl)-4-h yd r oxy-5-m et h oxy-
p en ta n a m id e (9). Amide 9 was prepared from (S)-5-(meth-
oxymethyl)butyrolactone (1.90 g, 14.6 mmol) and o-(benzyloxy)-
aniline (2.91 g, 14.6 mmol) in accordance with the procedure
for the synthesis of hydroxyamide 4. Purification by column
chromatography (hexane/AcOEt ) 2) gave 9 (3.70 g, 77%). 9:
white solid; mp 91-92 °C; [R]D ) +3.8 (CHCl3, c ) 1.19); IR
1
2989, 1665 cm-1; H NMR (CDCl3) δ: 7.57 (1H, s), 7.19-7.48
(6H, m), 7.02-7.08 (2H, m), 6.93 (1H, m), 4.17 (1H, m), 3.34
(1H, dd, J ) 3.8, 13.5 Hz), 3.27 (1H, dd, J ) 2.5, 10.1 Hz),
3.22 (3H, s), 3.18 (1H, dd, J ) 4.4, 10.1 Hz), 3.02 (1H, ddt, J
) 3.9, 9.0, 9.5 Hz), 2.86 (1H, dd, J ) 9.9, 13.5 Hz), 2.32 (1H,
ddd, J ) 7.9, 9.5, 13.0 Hz), 1.98 (1H, ddd, J ) 7.4, 9.0, 13.0
Hz); 13C NMR (CDCl3) δ: 177.3, 152.6, 139.1, 128.9, 128.8,
128.3, 126.2, 126.0, 124.6, 120.3, 118.7, 71.1, 58.8, 58.2, 43.4,
37.0, 27.2. MS (m/z) 311 (M+). Anal. Calcd for C19H21NO3: C,
73.29; H, 6.80; N, 4.50. Found: C, 73.26; H, 6.60; N, 4.63. trans-
13a : colorless oil; [R]D ) +218.8 (CHCl3, c ) 1.00); IR (KBr)
3239, 2924, 1665 cm-1; 1H NMR (CDCl3) δ: 7.54 (1H, s), 7.35-
7.18 (6H, m), 7.06 (1H, dd, J ) 1.2, 7.7 Hz), 6.90-6.93 (2H,
m), 3.94 (1H, m), 3.25 (3H, s), 3.11-3.28 (4H, m), 2.85 (1H,
dd, J ) 8.5, 13.4 Hz), 2.25 (1H, ddd, J ) 3.5, 9.0, 13.1 Hz),
2.13 (1H, ddd, J ) 8.2, 8.5, 13.1 Hz); 13C NMR (CDCl3) δ:
171.1, 152.5, 138.7, 129.1, 128.8, 128.4, 126.4, 125.4, 124.8,
120.6, 119.3, 72.0, 59.2, 59.1, 43.4, 37.3, 28.3. MS (m/z) 311
(M+).
1
(KBr) 3449, 2941, 1691 cm-1; H NMR (CDCl3) δ: 8.37 (1H,
dd, J ) 1.5, 7.2 Hz), 8.03 (1H, br s), 7.45-7.35 (5H, m), 7.05-
6.91 (3H, m), 5.11 (2H, s), 3.84 (1H, m), 3.38 (1H, dd, J ) 3.6,
9.5 Hz), 3.37 (3H, s), 3.26 (1H, dd, J ) 7.4, 9.5 Hz), 2.73 (1H,
d, J ) 3.3 Hz), 2.54 (2H, t, J ) 7.0 Hz), 1.90 (1H, m), 1.74
(1H, m); 13C NMR (CDCl3) δ: 171.1, 147.0, 136.2, 128.5, 128.1,
127.7, 127.4, 123.5, 121.2, 120.0, 111.5, 76.6, 70.6, 69.1, 58.8,
33.7, 28.4. MS (m/z) 329 (M+). Anal. Calcd for C19H23NO4: C,
69.28; H, 7.04; N, 4.25. Found: C, 69.35; H, 7.14; N, 4.34.
(5R)-1-(o-(Ben zyloxy)ph en yl)-5-(m eth oxym eth yl)-2-pyr -
r olid in on e (10). Lactam 10 was prepared from amide 9 (2.27
g, 6.9 mmol) in accordance with the procedure for the synthesis
of lactam 3. Purification by column chromatography (hexane/
AcOEt ) 2) gave 10 (1.94 g, 90%). 10: white solid; mp 73-75
°C; [R]D ) +22.8 (CHCl3, c ) 1.28); IR (KBr) 2929, 1695 cm-1
;
1H NMR (CDCl3) δ: 7.20-7.40 (7H, m), 6.98-7.03 (2H, m),
5.08 (2H, s), 4.18 (1H, m), 3.27 (1H, dd, J ) 3.3, 10.0 Hz), 3.25
(1H, dd, J ) 4.7, 10.0 Hz), 3.24 (3H, s), 2.62 (1H, ddd, J ) 7.2,
9.8, 16.9 Hz), 2.44 (1H, ddd, J ) 5.9, 9.7, 16.9 Hz), 2.22 (1H,
dddd, J ) 7.2, 8.2, 9.7, 15.5 Hz), 2.06 (1H, dddd, J ) 4.7, 5.9,
9.8, 15.5 Hz); 13C NMR (CDCl3) δ: 175.5, 154.1, 136.5, 130.0,
128.7, 128.3, 127.7, 126.9, 126.0, 121.0, 113.3, 72.7, 70.2, 59.3,
(3R,5R)-5-(Meth oxym eth yl)-3-(p h en ylm eth yl)-2-p yr r o-
lid in on e (cis-16a ). A solution of cis-13a (342 mg, 1.1 mmol)
in acetonitile (12 mL) was cooled to 0 °C and treated with a
solution of CAN (1.81 g, 3.3 mmol) in water (15 mL) over 3
min. The reaction mixture was stirred at room temperature
for 5 h, and then the mixture was poured into water and
extracted with AcOEt. The AcOEt extracts were successively
washed with saturated aqueous NaHCO3 solution, sodium
sulfite solution, and brine, and dried over MgSO4. The result-
ing solution was filtered through Celite and evaporated to
dryness. Purification of the residue by flash column chroma-
tography (hexane/AcOEt ) 1) gave cis-16a (130 mg, 54%). cis-
16a : white solid; mp 50-52 °C; [R]D ) -138.5 (CHCl3, c )
58.7, 30.4, 22.1. MS (m/z) 311 (M+). Anal. Calcd for C19H21
-
NO3: C, 73.29; H, 6.80; N, 4.50. Found: C, 73.29; H, 6.65; N,
4.59.
(5R)-1-(o-ter t-bu tyld ip h en ylsiloxyp h en yl)-5-(m eth oxy-
m eth yl)-2-p yr r olid in on e (11). To a solution of 10 (1.94 g,
6.2 mmol) in AcOEt (30 mL) was added 10% Pd-C, and then
the reaction mixture was stirred under a hydrogen atmosphere
for 5 h. After removal of Pd-C by filtration and evaporation
of AcOEt, THF (30 mL) and NaH (60%, 298 mg, 7.4 mmol)
were added to the residue. After being stirred for 20 min at
room temperature, tert-butyldiphenylsilyl chloride (1.6 mL, 6.8
mmol) was added, and then the reaction mixture was stirred
0.22); IR (KBr) 3267, 2924, 1694 cm-1 1H NMR (CDCl3) δ:
;
7.15-7.33 (5H, m), 5.98 (1H, br s), 3.72 (1H, m), 3.32 (1H, dd,
J ) 3.5, 13.4 Hz), 3.31 (3H, s), 3.25 (1H, dd, J ) 3.6, 13.4 Hz),
2.98 (1H, dd, J ) 9.0, 9.9 Hz), 2.76 (1H, m), 2.65 (1H, dd, J )
9.9, 13.5 Hz), 2.16 (1H, ddd, J ) 7.1, 8.7, 12.6 Hz), 1.36 (1H,
ddd, J ) 8.5, 9.4, 12.6 Hz); 13C NMR (CDCl3) δ: 178.2, 139.4,

1114 J . Org. Chem., Vol. 65, No. 4, 2000
Fujita et al.
128.9, 128.5, 126.3, 76.7, 59.0, 51.8, 42.8, 36.8, 29.2; MS (m/z)
219 (M+). Anal. Calcd for C13H17NO2: C, 71.20; H, 7.81; N,
6.39. Found: C, 71.03; H, 7.81; N, 6.30.
Su p p or tin g In for m a tion Ava ila ble: Characterization
data and experimental procedures of cis-5c, trans-5c, 7, cis-8,
trans-8, cis-13b, trans-13b, cis-13c, trans-13c, cis-16b, and
X-ray crystal data of 3 and 11. This material is available free
of charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. We gratefully acknowledge the
financial support from Ministry of Education, Science,
Culture and Sports.
J O991578Y