Unexpected formation of optically active 4-substituted 5-hydroxy-γ- lactams by organocatalyzed reaction of 3-substituted cyclobutanones with nitrosobenzene

Article abstract of DOI:10.1055/s-0030-1259084

An organocatalyzed enantioselective desymmetrization reaction for converting 3-substituted cyclobutanones into 4-substituted 5-hydroxy-γ- lactams is presented. This involves a ring-expanding O-nitroso aldol-cyclization domino sequence. This synthetic prot

Full text of DOI:10.1055/s-0030-1259084

LETTER
89
Unexpected Formation of Optically Active 4-Substituted 5-Hydroxy-g-
lactams by Organocatalyzed Reaction of 3-Substituted Cyclobutanones with
Nitrosobenzene
Formation of
a
O
r
ptically
a
A
ctive 4-
S
n
ubstituted 5-
c
H
ydroxy-
g
e
-
lactam
s
sca Capitta,a,b Angelo Frongia,*a Jean Ollivier,b Pier Paolo Piras,*a Francesco Seccia
Dipartimento di Scienze Chimiche, Università di Cagliari, Complesso Universitario di Monserrato, S.S. 554, Bivio per Sestu, 09042
Monserrato (Cagliari), Italy
Fax +39(070)6754388; E-mail: angelo.frongia@gmail.com; E-mail: pppiras@unica.it
UMR 8182, Laboratoire de Synthèse Organique et Méthodologie, ICMMO, Université Paris-Sud 11, 91405 Orsay Cedex, France
b
Received 7 September 2010
O
Abstract: An organocatalyzed enantioselective desymmetrization
reaction for converting 3-substituted cyclobutanones into 4-substi-
tuted 5-hydroxy-g-lactams is presented. This involves a ring-
expanding O-nitroso aldol–cyclization domino sequence. This syn-
thetic protocol provides access to five-membered ring systems in
good yields with the generation of two new stereogenic centers.
X
*
R
previous works:
X = O (Baeyer–Villiger)
X = NR (Beckmann, Schmidt)
O
asymmetric ring
H
expansion
Key words: rearrangements, ring expansion, ketones, organocatal-
ysis
H
R
1
O
Cyclobutanones reveal interesting characteristics such as
high electrophilicity and ring strain which make them
good substrates for ring-transformation reactions. Func-
tionalized cyclobutanones have been the subject of studies
which describe their reactivity with nucleophiles to in-
duce ring opening, ring contraction, and ring expansion.1
X
* *
R
OH
this paper:
X = NPh
Scheme 1
Synthetically important ring-expansion reactions include
those that add the elements of carbon, oxygen, or nitrogen
to an existing carbocyclic unit.2 These reactions can be
viewed as the formal insertion of a group into a carbon–
carbon single bond. When a prochiral cyclobutanone such
as 1 is employed in such a reaction, the potential of carry-
ing out asymmetric ring-expansion chemistry arises
(Scheme 1).
O
*
*
ONHPh
O
O
Cl
2
+
Asymmetric Baeyer–Villiger processes using enzymatic,3
metal-promoted,4 and organocatalyzed5 reactions or
Beckmann6 and Schmidt reactions2e have received the
greatest share of attention in this regard.
L-proline
N
CHCl3, 0 °C
O
N
Ph
Cl
50%
1a
Following our involvement in the chemistry of small car-
bocylic derivatives,7 we were intrigued by the possibility
of preparing optically active 2,3-disubstituted cyclo-
butanones by an enantio- and diastereoselective
organocatalytic8 desymmetrization of 3-substituted
prochiral cyclobutanones.
OH
Cl
3a/3a' = 88:12
Scheme 2 Attempted synthesis of a-aminoxylated cyclobutanone 2
During this research, initially we decided to examine the
reaction of suitable prochiral cyclobutanones 1 with ni-
trosobenzene in the presence of different organocatalysts9
(Scheme 2).
The preliminary reaction of 1a with nitrosobenzene (3.0
equiv) in the presence of 30% L-proline gave, instead of
the expected a-aminoxylated cyclobutanone 2, good
yields (50%) of the a-hydroxy-g-lactam 3 as a mixture of
two diastereomers 3a/3a¢ (dr = 88:12), that we consid-
ered, at this stage, to be a trans/cis mixture (44% and 70%
ee, respectively) of a single regioisomer.
SYNLETT 2011, No. 1, pp 0089–0093
x
x.
x
x.
2
0
1
1
Advanced online publication: 07.12.2010
DOI: 10.1055/s-0030-1259084; Art ID: D24110ST
© Georg Thieme Verlag Stuttgart · New York

90
F. Capitta et al.
LETTER
Table 1 Optimization Studiesa
O
O
catalyst (20 mol%)
solvent
O
N
and
N
N
O
OH
OH
Cl
Cl
1a
3a
3a'
Cl
OH
N
O
O
N
N
Ph
COOH
N
N
N
N
H
COOH
HN SO2Ph
HN
IV
H
HN
III
H
H
H2N
Ph
I
II
V
OH
Entry
1e
2f
Catalyst
I
Solvent
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
toluene
CHCl3
CH2Cl2
DMSO
DMF
Temp (°C)
Yield (%)b
ee trans (%)c
dr (%)d trans/cis
0
50
65
40
30
–
44
50
52
>99
–
88:12
I
0
70:30
3
II
0
>99:<1
4
II
–10
–20
0
>99:<1
5
II
–
6
III
III
IV
IV
IV
IV
IV
V
–
–
–
7
0
–
–
–
8
0
55
30
0
58
60
–
>99:<1
9
0
>99:<1
10
11
12
13
r.t.
0
–
–
–
–
0
–
toluene
CHCl3
0
0
–
0
0
–
a Unless otherwise noted, all the reactions were carried out with 3.0 equiv of nitrosobenzene relative to prochiral cyclobutanone and 20 mol%
of catalyst at 0 °C for 96 h.
b Yield of isolated product (sum of diastereomers).
c Determined by chiral HPLC analysis.
d Determined by 1H NMR spectroscopic analysis of the crude reaction mixture.
e 30 mol% of L-proline was used.
f The reaction was carried out by slow addition (48 h) of nitrosobenzene to 5 equiv of cyclobutanone 1 in the presence of 30 mol% of L-proline.
This was an unprecedented result and its importance was Among the catalysts probed, I and IV were the best pro-
further increased by the fact that 2-pyrrolidinones and moters of the process (Table 1, entries 2 and 8) in terms of
their derivatives are very interesting compounds for the both chemical yield and stereoselectivity. As the use of
pharmaceutical industry.10 Moreover the 5-hydroxy- other solvents as well as reaction temperatures was not ad-
substituted 2-pyrrolidinones show several versatile vantageous, we extended this reaction to different cyclo-
applications11 and are also the precursors of the highly re- butanones 1b–g using CHCl3 as a solvent at 0 °C, and the
active cyclic a-acyliminium ion.12
results are summarized in Table 2.
Intrigued by this preliminary result, we sought to establish The reaction can be rationalized by assuming the mecha-
reaction conditions that would give improvement in yield nism shown in Scheme 3, based on a catalytic cycle
and stereoselectivity.
through a cascade reaction initiated by an O-nitroso aldol–
cyclization domino reaction resulting in a cyclobutyl ring
expansion.
The reaction of cyclobutanone 1a and nitrosobenzene was
investigated as a model and the effect of a number of
known catalysts I–V, different solvents, and reaction con- Chiral L-proline catalyzes the diastereospecific in situ
ditions were examined with the results summarized in generation of enamine A from cyclobutanone 1. Subse-
Table 1.
quent nucleophilic addition to nitrosobenzene furnishes
Synlett 2011, No. 1, 89–93 © Thieme Stuttgart · New York

LETTER
Formation of Optically Active 4-Substituted 5-Hydroxy-g-lactams
91
HOOC
PhNO
O
N
– H2O
enamine
catalysis
–OOC
R
1
R
A
N+
O
R
NH
N
H
COOH
B
cyclization
H2O
O
N
–OOC
–OOC
+
R
OH
N
N
3
b
N
O+
N
a
path a
R
H
H
R
OH
C
ring
expansion
path b
H2O
N
N
N+
O
COO–
OH
R
OH
R
4
Scheme 3 Proposed catalytic cycle of the domino organocatalytic asymmetric synthesis of g-lactams 3 (only the trans-isomer is shown)
the a-aminoxylated cyclobutyl iminium intermediate B.
This intermediate undergoes intramolecular nucleophilic
1,2-addition followed by rearrangement of the bicyclic in-
termediate C, either into the 5-hydroxy-g-lactam 3 by mi-
gration of the more substituted terminus (path a) or into
the 3-hydroxy-g-lactam 4 by migration of the less substi-
tuted terminus (path b).13
O
O
PCC
N
CH2Cl2
N
60%
OH
O
3f/3f' = 67:33
(Table 2, entry 5)
5
40% ee
On the basis of this mechanism we could be dealing either
with two geometric isomers of a single regioisomer or
with two regioisomers with the same geometry. To solve
the above-mentioned uncertainty we carried out the oxi-
dation of the inseparable mixture of diastereomers 3f and
3f¢ (Scheme 4).
O
N
O
Lit.15
O
1) NaBH4
Baclofen
2) H2SO4
75%
OH
The fact that we obtained only the product 5 (ee = 40%)
was taken as a conclusive evidence that mixture 3f/3f¢ was
a trans/cis mixture of a single regioisomer (5-hydroxy-g-
lactams).
Cl
Cl
3a/3a' = 70:30
(Table 1, entry 2)
6
23% ee
The geometry of compounds 3a–g and 3a¢–g¢ was as-
signed on the basis of the value of the coupling constants
for C4–H and C5–H as well as by comparison with litera-
ture data.14
Scheme 4 Reactions of two g-lactams 3 to assign their relative and
absolute configurations. Only the prevailing stereochemistry is
shown.
On the other hand, the absolute stereochemistry of the ma-
jor isomer of compounds 3a–g could be assigned by anal-
ogy with that assigned to 3a/3a¢ after its conversion into
the (R)-lactone 6 (ee = 23%) that is a known precursor15 of
the amino acid Baclofen (Scheme 4).
Synlett 2011, No. 1, 89–93 © Thieme Stuttgart · New York

92
F. Capitta et al.
LETTER
References and Notes
Table 2 Asymmetric Synthesis of 4-Substituted 5-Hydroxy-g-lac-
tams 3a
(1) (a) Namsylo, J. C.; Kaufmann, D. E. Chem. Rev. 2003, 103,
1485. (b) Lee-Ruff, E.; Mladenova, G. Chem. Rev. 2003,
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Cyclobutanes; Rappoport, Z.; Liebman, J. F., Eds.; J. Wiley
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Liebman, J. F., Eds.; J. Wiley and Sons: Chichester/New
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(2) (a) Aubé, J.; Wang, Y.; Hammond, M.; Tanol, M.;
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2001, 66, 733. (d) Paneghetti, C.; Gavagnin, R.; Pinna, F.;
Strukul, G. Organometallics 1999, 18, 5057.
O
O
catalyst
CHCl3, 0 °C
O
and
N
N
N
O
R
R
OH
R
OH
1b–g
3b–g
3b'–g'
Entry R (product)
Catalyst Yieldb
ee trans dr(%)d
(%)c trans/cis
1
2
Ph (3b/3b¢)
4-BrC6H4 (3c/3c¢)
I
IV
40
45
20
30
95:5
79:21
I
IV
57
20
27
4
73:27
>99:<1
(e) Sahasrabudhe, K.; Gracias, V.; Furness, K.; Smith, B. T.;
Katz, C. E.; Reddy, D. S.; Aubé, J. J. Am. Chem. Soc. 2003,
125, 7914. (f) Trost, B. M.; Xie, J. J. Am. Chem. Soc. 2008,
130, 6231. (g) Fenster, E.; Smith, B. T.; Gracias, V.;
Milligan, G. L.; Aubé, J. J. Org. Chem. 2008, 73, 201.
(3) (a) Mazzini, C.; Lebreton, J.; Alphand, V.; Furstoss, R.
Tetrahedron Lett. 1997, 38, 1195. (b) Resende, P.; Almeida,
W.; Coelho, F. Tetrahedron: Asymmetry 1999, 10, 2113.
(4) Malkov, A. V.; Friscourt, F.; Bell, M.; Swarbrick, M. E.;
Kocovsky, P. J. Org. Chem. 2008, 73, 3996.
3
4
4-MeC6H4 (3d/3d¢) IV
30
40
77:23
PhCH2CH2 (3e/3e¢)
I
IV
65
40
51
42
93:7
94:6
5
6
C6H13 (3f/3f¢)
I
IV
60
40
38
60
67:33
99:1
c-Hex (3g/3g¢)
I
IV
48
41
37
56
85:15
72:28
(5) (a) Murahashi, S.-I.; Ono, S.; Imada, Y. Angew. Chem. Int.
Ed. 2002, 41, 2366. (b) Xu, S.; Wang, Z.; Zhang, X.; Zhang,
X.; Ding, K. Angew. Chem. Int. Ed. 2008, 47, 2840.
(6) Aubé, J.; Wang, Y.; Ghosh, S.; Langhans, K. L. Synth.
Commun. 1991, 21, 693.
(7) (a) Bernard, A. M.; Frongia, A.; Guillot, R.; Piras, P. P.;
Secci, F.; Spiga, M. Org. Lett. 2007, 9, 541. (b) Frongia,
A.; Ollivier, J.; Piras, P. P.; Secci, F. Synthesis 2007, 999.
(c) Frongia, A.; Girard, C.; Ollivier, J.; Piras, P. P.; Secci, F.
Synlett 2008, 2823. (d) Alberti, G.; Bernard, A. M.; Floris,
C.; Frongia, A.; Piras, P. P.; Secci, F.; Spiga, M. Org.
Biomol. Chem. 2009, 7, 3512.
(8) For some recent reviews on organocatalysis, see:
(a) Erkkila, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007,
107, 5416. (b) Mukherjee, S.; Yang, J. W.; Hoffmann, S.;
List, B. Chem. Rev. 2007, 107, 5471. (c) Dalko, P. I.
Enantioselective Organocatalysis; Wiley-VCH: Weinheim,
2007. (d) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli,
G. Angew. Chem. Int. Ed. 2008, 47, 6138; Angew. Chem.
2008, 120, 6232.
(9) For references to important direct and enantioselective
organocatalytic a-oxidation of aldehydes and ketones
literature, see: (a) Brown, S. P.; Brochu, M. P.; Sinz, C. J.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 10808.
(b) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji, M.
Tetrahedron Lett. 2003, 44, 8293. (c) Momiyama, N.; Torii,
H.; Saito, S.; Yamamoto, H. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5374. (d) Hayashi, Y.; Yamaguchi, J.; Sumiya,
T.; Shoji, M. Angew. Chem. Int. Ed. 2004, 43, 1112.
(e) Bogevig, A.; Sundén, H.; Cordova, A. Angew. Chem. Int.
Ed. 2004, 43, 1109. (f) Hayashi, Y.; Yamaguchi, J.; Sumiya,
T.; Hibino, K.; Shoji, M. J. Org. Chem. 2004, 69, 5966.
(g) Ramachary, D.; Barbas, C. F. I. I. I. Org. Lett. 2005, 7,
1577.
a The reactions were carried out in CHCl3, with 3.0 equiv of ni-
trosobenzene relative to prochiral cyclobutanone and 20 mol% of cat-
alyst IV or by slow addition (48 h) of nitrosobenzene to 5 equiv of
cyclobutanone 1 in the presence of 30 mol% of L-proline, at 0 °C for
96 h.
b Yield of isolated product (sum of diastereomers).
c Determined by chiral HPLC analysis.
d Determined by 1H NMR spectroscopic analysis of the crude reaction
mixture.
In summary we have developed an organocatalyzed de-
symmetrization of 3-substituted cyclobutanones using as
electrophile nitrosobenzene that led to the discovery of the
first direct organocatalyzed enantioselective ‘ring-
expanding O-nitroso aldol–cyclization domino reaction’.
Two are the focal points of this reaction sequence: a) for
the first time, we could successfully combine enamine or-
ganocatalysis with a cyclization–ring-expansion-termi-
nated reaction in a tandem sequence,16 b) the fundamental
role of the strained cyclobutyl ring that easily expands to
create the pyrrolidinone derivatives. This is a powerful
approach for the generation of these optically active nitro-
gen-containing molecules.17
Despite the moderate enantioselectivities, our results add
new knowledge because the mechanistic model proposed
represents an extension for existing concepts in the chem-
istry of cyclobutanes and enamine catalysis. Further ef-
forts will be spent on evaluating the scope of this
processes and the improvement of stereochemistry.
(10) Brabandt, W. V.; De Kimpe, N. J. Org. Chem. 2005, 70,
3369.
(11) (a) Kakeya, H.; Takahashi, I.; Okada, G.; Isono, K.; Osada,
H. J. Antibiot. 1995, 48, 733. (b) Winterfeldt, E. Synthesis
1975, 617.
Acknowledgment
Financial support from the MIUR, Rome, and by the University of
Cagliari (National Project ‘Stereoselezione in Sintesi Organica,
Metodologie ed Applicazioni’) and from CINMPIS is gratefully
acknowledged.
(12) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56,
3817.
Synlett 2011, No. 1, 89–93 © Thieme Stuttgart · New York

LETTER
Formation of Optically Active 4-Substituted 5-Hydroxy-g-lactams
93
(13) A reviewer proposed a plausible alternative mechanism for
the tandem asymmetric formation of g-lactams 3 from the
intermediate C. He suggests that a fragmentation of N–O
bond (in the bicyclic intermediate C) could occur to give a
nitrogen cation, stabilized by resonance into the phenyl
group, prior to migration.
(14) For coupling constant value of trans-substituted g-lactams,
see: (a) Kar, G. K.; Roy, B. C.; Das Adhikari, S.; Ray, J. K.;
Brahma, N. K. Bioorg. Med. Chem. 1998, 6, 2397. (b) Kar,
G. K.; Chatterjee, B. G.; Ray, J. K. Synth. Commun. 1993,
23, 1953. (c) For coupling constant value of cis-substituted
g-lactams, see: Ghosh, M.; Kar, G. K.; Ray, J. K.; Chatterjee,
B. G. Synth. Commun. 1983, 13, 667.
(15) (a) Mazzini, C.; Lebreton, J.; Alphand, V.; Furstoss, R.
Tetrahedron Lett. 1997, 38, 1195. (b) Resende, P.; Almeida,
W.; Coelho, F. Tetrahedron: Asymmetry 1999, 10, 2113.
(16) (a) Enders, D.; Grondal, C.; Huttl, M. R. M. Angew. Chem.
Int. Ed. 2007, 46, 1570. (b) Tietze, L. F.; Brasche, G.;
Gericke, K. M. Domino Reactions in Organic Synthesis
Wiley–VCH: Weinheim, 2006;. (c) Yu, X.; Wang, W. Org.
Biomol. Chem. 2008, 6, 2037. (d) Guillena, G.; Ramón, D.
J.; Yus, M. Tetrahedron: Asymmetry 2007, 18, 693.
(17) General Procedure (Using Catalyst I)
(m, 20 H). 13C NMR (75 MHz, CDCl3): d = 37.1, 38.6, 48.5,
48.8, 92.4, 103.5, 114.6, 118.8, 120.1, 124.9, 125.5, 127.0,
127.2, 127.6, 127.8, 128.5, 128.6, 129.0, 129.1, 129.3,
139.3, 139.5, 170.3, 170.8. MS: m/z (%, the same for the two
diastereomers) = 235 (100) [M+ – 18], 206 (100), 115 (20),
104 (48), 77 (57), 63 (7), 51 (16). The ee was determined to
be 20% ee for the trans-diastereomer by chiral-phase HPLC
using a Daicel Chiralcel OJ column (hexane–i-PrOH =
90:10, flow rate 1.2 mL/min, l = 254 nm): tR(major) =
30.8 min; tR(minor) = 36.6 min.
5-Hydroxy-4-phenethyl-1-phenylpyrrolidin-2-one (3e)
Spectral data worked out from the 94:6 inseparable mixture
of two trans- and cis-diastereomers 3e/3e¢. Yield 65%;
orange oil. IR (film): n = 3350, 1660 cm–1. 1H NMR (300
MHz, CDCl3): d = 1.77–2.14 (m, 3 H), 2.36–2.57 (m, 2 H),
2.71 (t, 2 H, J = 7.5 Hz), 3.41 (br s, 1 H), 5.29 (d, 1 H, J = 5.1
Hz), 7.13–7.69 (m, 10 H). 13C NMR (75 MHz, CDCl3): d =
32.9, 36.0, 42.2, 52.3, 102.7, 119.9, 126.1, 128.2, 128.4,
128.5, 128.6, 139.6, 140.9, 170.4. MS: m/z (%, the same for
the two diastereomers) = 263 (31) [M+ – 18], 172 (100), 106
(14), 91 (60), 77 (27), 65 (10), 51 (8). The ee of the trans-
diastereomer was determined to be 51% ee by chiral-phase
HPLC using a Daicel Chiralcel OJ column (hexane–i-
PrOH = 85:15, flow rate 1.0 mL/min, l = 254 nm): tR(major)
= 26.1 min; tR(minor) = 33.6 min.
4-Hexyl-5-hydroxy-1-phenylpyrrolidin-2-one (3f/3f¢)
Spectral data refer to a 67:33 inseparable mixture of two
trans- and cis-diastereomers. Yield 60%; orange oil. IR
(film): n = 3400, 1660 cm–1. 1H NMR (300 MHz, CDCl3):
d = 0.84–1.59 (m, 26 H), 1.92–2.06 (m, 2 H), 2.27–2.63 (m,
4 H), 4.73 (d, 1 H, J = 9.3 Hz), 5.17 (d, 1 H, J = 4.8 Hz), 5.22
(dd, 1 H, J = 6.9, 9.3 Hz), 6.76–7.72 (m, 10 H). 13C NMR (75
MHz, CDCl3): d = 14.0, 22.5, 26.6, 26.8, 29.1, 31.6, 33.0,
33.8, 36.1, 37.3, 42.7, 43.3, 91.4, 102.8, 114.5, 118.6, 119.9,
125.2, 128.5, 129.3, 139.7, 144.1, 170.7, 171.0. MS: m/z (%,
the same for the two diastereomers) = 243 (77) [M+ – 18],
172 (100), 158 (26), 130 (14), 104 (24), 77 (33). The ee was
determined to be 38% ee for the trans-diastereomer and 44%
ee for the cis-diastereomer by chiral-phase HPLC using a
Daicel Chiralcel OJ column (hexane–i-PrOH = 95:5, flow
rate 0.8 mL/min, l = 254 nm): trans-diastereomer: tR(minor)
= 14.3 min(minor); tR(major) = 17.4 min; cis-diastereomer:
tR(major) = 22.2 min; tR(minor) = 26.9 min.
To a CHCl3 (2.7 mL) solution of the prochiral cyclobutanone
1 (3 mmol) and L-proline (0.18 mmol) was added a CHCl3
(0.9 mL) solution of nitrosobenzene (0.6 mmol) over 48 h at
0 °C via syringe pump, and the mixture was stirred for 96 h
at that temperature. The crude reaction mixture was directly
loaded on silica gel column without workup, and pure
products were obtained by flash column chromatography
(silica gel, hexane–Et2O).
General Procedure (Using Catalyst IV)
In a glass vial equipped with a magnetic stirring bar, to 0.375
mmol of the prochiral cyclobutanone 1, catalyst IV (0.075
mmol, 20 mol%) was added, and the reaction mixture was
stirred at ambient temperature for 10–15 min. To the
reaction mixture nitrosobenzene (1.13 mmol) was added and
stirred at 0 °C for the time indicated in Tables 1 and 2. The
crude reaction mixture was directly loaded on silica gel
column without workup, and pure products were obtained by
flash column chromatography (silica gel, mixture of
hexane–Et2O).
4-(4-Chlorophenyl)-5-hydroxy-1-phenylpyrrolidin-2-
one (3a)
Procedure for the Synthesis of 3-Hexyl-1-phenyl-
pyrrolidine-2,5-dione (5)
Yield 60%; yellow oil. IR (film): n = 3400, 1650 cm–1. 1H
NMR (300 MHz, CDCl3): d = 2.68 (dd, 1 H, J = 4.5, 14.1
Hz), 2.93 (t, 1 H, J = 14.4 Hz), 3.26–3.33 (m, 1 H), 5.48 (d,
1 H, J = 5.4 Hz), 7.18–7.72 (m, 9 H). 13C NMR (75 MHz,
CDCl3): d = 36.9, 47.86, 103.2, 120.0, 125.6, 128.6, 128.7,
129.2, 133.6, 137.6, 139.3, 169.8. MS: m/z (%) = 269 (100)
[M+ – 18], 240 (80), 206 (17), 136 (23), 104 (72). The ee was
determined to be 58% ee by chiral-phase HPLC using a
Daicel Chiralcel OJ column (hexane–i-PrOH = 80:20, flow
rate 1.2 mL/min, l = 254 nm): tR(major) = 12.1 min;
tR(minor) = 14.4 min.
PCC (85.1 mg, 0.395 mmol) was added to a solution of
compounds 3f/3f¢ (dr = 67:33; 70 mg, 0.270 mmol) in
CH2Cl2 (8 mL), the mixture was then stirred at r.t. for 2 h.
The reaction mixture was filtered through a Celite pad,
concentrated to give the crude mixture, which was then
purified by flash column chromatography (hexane–Et2O =
3:1) on silica gel to give the pure pyrrolidine-2,5-dione 5.
Yield 60%; yellow oil. IR (film): n = 1774,1701, 1443, 1376
cm–1. 1H NMR (300 MHz, CDCl3): d = 0.83–1.45 (m, 10 H),
1.58–1.68 (m, 2 H), 1.95–2.03 (m, 1 H), 2.50–2.61 (m, 1 H),
2.91–3.05 (m, 2 H). 13C NMR (75 MHz, CDCl3): d = 14.0,
22.5, 26.6, 28.9, 29.6, 31.51, 31.54, 34.5, 40.0, 126.4, 128.5,
129.1, 131.9, 175.6, 178.9. MS: m/z (%) = 259 (10) [M+],
188 (35), 175 (100), 147 (10), 119 (30), 93 (16), 77 (7), 55
(14). The ee was determined to be 40% ee by chiral-phase
HPLC using a Daicel Chiralcel OJ column (hexane–i-
PrOH = 95:5, flow rate 1.2 mL/min, l = 254 nm): tR(major)
= 41.8 min; tR(minor) = 44.8 min.
5-Hydroxy-1,4-diphenylpyrrolidin-2-one (3b/3b¢)
Spectral data refer to a 95:5 inseparable mixture of two
trans- and cis-diastereomers. Yield 40%; yellow oil. IR
(film): n = 3400, 1650 cm–1. 1H NMR (300 MHz, CDCl3):
d = 2.58–2.66 (m, 1 H), 2.74–2.81 (m, 1 H), 2.90 (t, 1 H,
J = 14.1 Hz), 3.05 (t, 1 H, J = 13.8 Hz), 3.14–3.20 (m, 1 H),
3.23–3.30 (m, 1 H), 4.58 (br s, 1 H), 4.92 (t, 1 H), 5.48 (d, 1
H, J = 5.4 Hz), 5.55 (dd, 1 H, J = 7.05, 9.6 Hz), 6.74–7.73
Synlett 2011, No. 1, 89–93 © Thieme Stuttgart · New York

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