Asymmetric synthesis of di- and trisubstituted pyrrolidinones via zirconium-mediated intramolecular coupling of N-3-alkenyl carbamates

Article abstract of DOI:10.1016/j.tetasy.2007.01.026

N-3-Alkenyl carbamates, which are readily available in enantiomerically pure form, undergo a stereoselective intramolecular coupling under the effect of a Cp₂ZrCl₂/2n-BuLi reagent. The influence of the carbamate structure on the ster

Full text of DOI:10.1016/j.tetasy.2007.01.026

Tetrahedron: Asymmetry 18 (2007) 424–434
Asymmetric synthesis of di- and trisubstituted pyrrolidinones
via zirconium-mediated intramolecular coupling
of N-3-alkenyl carbamates
*
´
Clement Denhez, Jean-Luc Vasse, Dominique Harakat and Jan Szymoniak
Re´actions Se´lectives et Applications, CNRS (UMR 6519) and Universite´ de Reims, 51687 Reims Cedex 2, France
Received 2 January 2007; accepted 22 January 2007
Available online 21 February 2007
Abstract—N-3-Alkenyl carbamates, which are readily available in enantiomerically pure form, undergo a stereoselective intramolecular
coupling under the effect of a Cp2ZrCl2/2n-BuLi reagent. The influence of the carbamate structure on the stereoselectivity was tested. The
reaction gives an easy access to various di- and trisubstituted enantiopure pyrrolidinones.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
[Zr]
R
R
R
N
Cp2Zr(H)Cl
Cp2ZrCl2,
Lewis acid
OH
N
O
The pyrrolidine and pyrrolidinone moieties are present in
many biologically active molecules, both naturally occur-
ring and synthetic.1 Therefore, the development of efficient
and stereoselective methods for the synthesis of such nitro-
gen heterocycles is an important task. In addition to the C–
N bond-forming cyclization reactions,2 C–C bond-forming
reactions have recently emerged as an interesting alterna-
tive for building five-membered nitrogen-heterocycles.3
Among them, zirconium-mediated intramolecular coupling
reactions4 have been employed. We described a new dia-
stereoselective synthesis of 2-substituted pyrrolidines from
N-allyl oxazolidines via a tandem hydrozirconation–Lewis
acid-mediated ring-closure sequence (Scheme 1, Eq. a).5
Taguchi et al. found access to the pyrrolidinone ring system
via a Zr(II)-mediated intramolecular coupling reaction
starting from N-homoallyl carbamates (Scheme 1, Eq.
b).6 Interestingly, a possible functionalization of the pyrro-
lidinone side chain emphasizes the synthetic potential of
this reaction.7
Eq. a
Eq. b
N
O
N
Ph
Ph
Yields 31-62%
d.e. 55-84%
Ph
E
Zr
E+
n-BuLi (2 equiv)
O
O
O
N
Bn
OR
N
Bn
OR
Bn
E = H,D,I
R = t-Bu, Bn
Scheme 1. Access to pyrrolidines and pyrrolidinones via zirconium-
mediated alkene activation.
aminal, the pyrrolidinone synthesis involves a C–Zr bond
formation as the stereodetermining step. This offers the
possibility of developing the asymmetric variant of the
reaction. Herein, we report an efficient and diastereoselec-
tive zirconium-mediated synthesis of di- and trisubstituted
pyrrolidinones (c-lactams) from enantiomerically pure
N-3-alkenyl carbamates.
Although these two reactions employed the same strategy
(i.e., the formal conversion of an alkene into a nucleophilic
entity followed by a ring-closure step), the stereogenic cen-
ters are created at different stages. In contrast to the pyrrol-
idine synthesis, for which the configuration of the
stereogenic center declined from the configuration of the
2. Results and discussion
Since the required enantiomerically pure side chain can
easily be obtained via diastereoselective allylation of amino
*
Corresponding author. E-mail: jan.szymoniak@univ-reims.fr
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.01.026

C. Denhez et al. / Tetrahedron: Asymmetry 18 (2007) 424–434
Table 1. Synthesis of disubstituted pyrrolidinones
425
alcohol-derived imines, we first synthesized carbamates de-
rived from phenylglycinol. In fact, an efficient final depro-
tection of such a chiral auxiliary is already known.8 We
also thought that the presence of an additional stereogenic
center might influence the stereoselectivity of the cycliza-
tion (Scheme 2). Following this retrosynthetic approach,
the pyrrolidinone skeleton results from zirconium-medi-
ated intramolecular coupling reaction. The stereochemistry
at the C3 atom in pyrrolidinone derives from the stereo-
defined zirconacyclopropane, which in turn is generated
through the facial discrimination of the C@C double bond,
under the effect of the proximal stereogenic centers (C1
and/or C2) of the nitrogen side chain of a carbamate. As
indicated, such carbamates could be obtained simply.
R'
O
R
R
R'
1) Cp2ZrCl2,
OH
n-BuLi (2 equiv)
N
N
O
2) H2O
O
2a-h
1a-h
Entry
R
R0
Compound
dr
1
2
3
4
Ph
Ph
Ph
2a (78%)
2b (75%)
2c (73%)
2d (74%)
2e (78%)
2f (78%)
2g (78%)
2h (46%)
1.4:1
1.2:1
3:1
1.3:1
1.4:1
2:1
2-Fur
2-(1-Me–Pyr)
2-MeO–C6H4
i-Pr
Ph
Ph
Ph
H
5
6a
7a
8a
Ph
2-MeO–C6H4
Ph–CH@CH
H
H
2:1
6:1
M
a Reaction carried out in the racemic series.
E
Zr
O
R1
O
COCl2
OH
R1
O
The diastereoselectivity was improved in these cases but
remained moderate. Additionally, compound 2h was
obtained solely from carbamate 1h bearing two alkene
chains with a different degree of substitution (entry 8). As
an example of deprotection, the chiral auxiliary was
removed from diastereomerically pure 2a to afford the
R1
Ph
N
N
N
PG
R1
N
PG
OR
O
Ph
Readily removable
chiral auxiliary
Scheme 2. Retrosynthetic approach.
corresponding
idinone trans-3 (Scheme 4).
enantiopure
3-methyl-5-phenylpyrrol-
Carbamates 1a–e were first prepared by employing readily
available (R)-2-phenylglycinol. The reaction of phenylgly-
cinol-derived imines with allylbromide and zinc in the pres-
ence of CeCl3Æ7H2O provided the corresponding amino
alcohols in good yields, and in good to excellent diastereo-
selectivities.9 Subsequent treatment with triphosgen, in the
presence of pyridine and a catalytic amount of DMAP,
gave the corresponding carbamates 1a–e in almost quanti-
tative yields10 (Scheme 3).
Ph
Ph
Ph
H
N
1) SOCl2, CH2Cl2
OH
N
2) -a- DBU, CH3CN
O
O
-b- HCl (5M)
65 %
trans-3
2a
Scheme 4. Removal of the chiral auxiliary.
R
O
1) Zn, allyl bromide,
Ph
Ph
.
CeCl3 7H2O, THF
OH
In a recent paper, Taguchi reported that a high level of dia-
stereoselectivity could be achieved in the ester transfer cou-
pling reaction using t-butyloxy N-tosyl carbamate. In
contrast, no selectivity was obtained when employing the
benzyloxy analogue.7 We assumed that in our case, the
low stereoselectivity originated from an inefficient discrim-
ination of the carbonyl group, supposed to stereodirect the
zirconocene approach. Therefore, a most suitable environ-
ment around the carbamate has been envisioned, by
increasing the steric bulkiness at the O atom. This was
ensured by using non-cyclic carbamates 4a–l as starting
materials (Table 2).
N
N
2) triphosgene, py.,
DMAP cat., CH2Cl2
O
R
1a-e
Scheme 3. Synthesis of carbamates 1a–e.
These diversely substituted carbamates were submitted to
the zirconium-mediated alkene–carbamate coupling reac-
tion under modified Taguchi conditions (see Section 4).
As shown in Table 1, the reaction proceeded smoothly with
carbamates bearing aromatic (entries 1 and 4), heteroaro-
matic (entries 2 and 3), and alkyl R groups (entry 5) to
afford the corresponding pyrrolidinones in good yields.
However, a poor stereoselectivity (dr = 1.2:1–3:1) was
observed in these reactions. The major diastereomer could
be isolated in a pure form by column chromatography in
most cases.
Accordingly, compounds 4a–l were synthesized from the
corresponding imines by alkylation and Boc protection.
Compounds 4a–l were subjected to the reaction conditions
as previously described, and the results are shown in Table
2. The stereochemical outcome of the reaction has been
demonstrated to depend strongly on the adjustment of
the nitrogen- and oxygen-carbamate groups (R2 and R3).
Whereas a total lack of diastereoselectivity was observed
when combining two small or two large groups (entries
1–3), good diastereomeric ratios, in favor of the cis-iso-
mer,11 were obtained when combining a small and a large
To estimate the influence of the carbamate substituent
(R0 = Ph) upon the stereochemical outcome of the
reaction, the same reaction sequence was applied to the
substrates containing a substituent-free (R0 = H) ethanol-
amine-derived carbamate moiety (Table 1, entries 6–8).

426
C. Denhez et al. / Tetrahedron: Asymmetry 18 (2007) 424–434
Table 2. Synthesis of disubstituted carbamates 5
t-Bu
O
O
R1
Bn
Bn
R1
R1
t-Bu
Ph
O
R2
N
O
O
N
O
R2
O
N
O
1) Cp2ZrCl2,
N
H
N
R1
n-BuLi (2 equiv)
I
OR3
O
R1
2) H2O
4a-l
5a-l
R1
R2
R3
Compound
dr
[Zr]
Entry
t-Bu
O
Bn
R1
1a
Ph
Ph
Ph
Ph
Ph
Ph
PMP
Bn
tBu
Et
5a (72%)
5b (67%)
5b (68%)
5d (71%)
5b (72%)
5f (69%)
5g (70%)
5h (68%)
5i (73%)
5j (67%)
5k (72%)
5l (57%)
1.2:1
1:1
1.2:1
8:1
7.5:1
7:1
8:1
5.6:1
8:1
8:1
8:1
6:1
Ph
O
Zr
O
Bn
N
N
2a
O
H
N
3a
Bn
Bn
4a
nPr
Bn
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
R1
R1
IV
III
II
5a
6a
PMB
Bn
PMB
Bn
Bn
Bn
Scheme 6. Proposed stereochemical rationale.
7a
4-MeO–C6H4
2-MeO–C6H4
2-Furyl
4-F–C6H4
i-Pr
8a
9a
zirconium complex from the more accessible face of the
carbonyl as shown in complex II. Thus, the alkene–carb-
amate coupling reaction affords bicyclic intermediate III,
precursor of lactam IV.
10a
11a
12b
n-C5H11
Bn
PMP = 4-methoxyphenyl, PMB = 4-methoxybenzyl.
a Reaction carried out in the racemic series.
The reaction was next extended to the synthesis of trisubsti-
tuted pyrrolidinones. Starting carbamates 7 with an
additional substituent at the allylic position (Ph or Me at
Cb–N) were synthesized in two steps from the (R)-2-phen-
ylglycinol-derived imines (Scheme 7). The amino alcohol
precursors were obtained by cerium trichloride-catalyzed
allylzinc bromide addition to the corresponding imine in
good yield, but with a different level of asymmetric induc-
tion.12 However, they could be isolated in a pure diastereo-
merical form after separation by column chromatography.
Further condensation with triphosgene quantitatively
afforded the desired carbamates 7 (Scheme 7). Addition-
ally, opened carbamate 7e was synthesized from amino
alcohol 6e by Pb(OAc)4 treatment, followed by NaBH4
reduction of the resulting imine and Boc protection.
b Reaction carried out by using the enantiomerically pure substrate.
group (entries 4–6). 1,3-Disubstituted pyrrolidinones 5g–l
were consequently obtained with good diastereoselectivi-
ties, when using carbamates with t-BuO group together
with a small N-group (entries 7–12). An efficient stereo-
selective synthesis of 1,3-disubstituted pyrrolidinones
would be thus ensured by the suitable tuning of N- and
O- protecting groups. The products can be easily deprotected
when using carbamates with N-PMB group (Section 4).
Finally, when using carbamate 4m with a non-terminal
C@C double bond, pyrrolidinone 5m was obtained in
56% yield as a 3.5:1 mixture of diastereomers (Scheme 5).
R1
O
R1
R
R
R
R2
R2
ii)
Ph
i)
Ph Ph
N
N
H
N
Bn
1) Cp2ZrCl2,
N
OH
OH
O
N
Boc
n-BuLi (2 equiv)
R1
6
O
7
7a : R = Ph, R1 = Ph, R2 = Me
Ph
2) H2O
56%
5m
Ph
4m
7b : R = Ph, R1 = CH2OBn, R2 = Ph
7c : R = H, R1 = Ph, R2 = Ph
d.r. = 3.5 : 1
7d : R = Ph, R1 = i-Pr, R2 = Ph
Scheme 5.
Ph
O
To account for the observed selectivity when using t-butyl-
oxy carbamates 4d–l, we first assumed that the presence of
two differently sized substituents (Bn and the homoallyl
chain) at the nitrogen atom would preferentially orientate
the carbonyl toward the largest homoallyl fragment
(Scheme 6). Moreover, it is likely that the R1 group adopts
a pseudo-axial position with respect to the carbamate plan.
Therefore, to minimize the steric interactions, and acting as
a relay, the flexible protecting group would be located
at the opposite side from both the phenyl group and the
t-butyloxy group as depicted in conformer I. Accordingly,
the bulky t-butyloxy group would cloud selectively one face
of the carbonyl moiety, enhancing the approach of the
O
Ph
Ph
N
i)
Ph
Ph
iii), iv)
N
H
N
OH
O
OH
Boc
7e
6e
Scheme 7. Synthesis of carbamates 7. Reagents and conditions: (i)
R2CH@CH–CH2Br, Zn, CeCl3Æ7H2O, Zn, THF; (ii) (Cl3CO)2CO, cat.
DMAP, pyridine, CH2Cl2; (iii) (a) Pb(OAc)4, CH2Cl2, MeOH, (b) NaBH4;
(iv) Boc2O, CH2Cl2.
The intramolecular alkene–carbamate coupling reactions
were performed as previously described and the results

C. Denhez et al. / Tetrahedron: Asymmetry 18 (2007) 424–434
427
are shown in Table 3. The trisubstituted pyrrolidinones
4.2. (R)-2-[(R)-1-(1-Methyl-1H-pyrrol-2-yl)but-3-enyl-
amino]-2-phenylethanol
were obtained from both opened (7e) and cyclic (7a–d) car-
bamates in good yields and diastereoselectivities. Aryl, het-
eroaryl, and alkyl groups can be present on the Ca–N atom
of the carbamate leading to pyrrolidinones 8a–e.
To a mixture of (R)-2-[(1-methyl-1H-pyrrol-2-yl)methyl-
eneamino]-2-phenylethanol (1.14 g, 5 mmol), zinc dust
(0.82 g, 12.5 mmol), and CeCl3Æ7H2O (0.19 g, 0.5 mmol) in
THF (20 mL), was added dropwise allylbromide (1.3 mL,
12.5 mmol) at 0 ꢁC. The resulting mixture was stirred for
2 h and quenched with water (20 mL). The layers were
separated and the aqueous layer extracted with Et2O
(3 · 20 mL). The organic layers were combined, dried over
Na2SO4, filtered, and concentrated. The residue was purified
by column chromatography on silica gel using a mixture of
Table 3. Synthesis of trisubstituted pyrrolidinones 8
O
O
1) Cp2ZrCl2,
n-BuLi (2 equiv)
Ph
Ph
Ph
Bn
N
N
2) H2O
52%
Boc
7e
petroleum ether/AcOEt as solvent to give the title com-
25
O
pound as a pale yellow oil. ½aꢀD ¼ ꢁ44:5 (c 0.9, CH2Cl2);
8e
1H NMR (250 MHz, CDCl3): d 7.29 (m, 5H), 6.48 (t, 1H,
J = 2.2 Hz), 6.05 (m, 2H), 5.71 (tdd, 1H, J = 7.0, 10.2,
17.1 Hz), 5.04 (dm, 1H, J = 17.1 Hz), 5.01 (dm, 1H,
J = 10.2 Hz), 3.90 (dd, 1H, J = 4.6, 7.9 Hz), 3.76 (dd,
1H, J = 6.0, 7.3 Hz), 3.66 (d, 1H, J = 4.6 Hz), 3.51 (dd,
1H, J = 8.0, 10.7 Hz), 3.37 (s, 3H), 2.43–2.63 (m, 2H); 13C
NMR (62.5 MHz, CDCl3): d 141.0, 135.1, 134.2, 128.6,
127.6, 127.3, 121.9, 117.2, 106.7, 106.3, 66.0, 61.1, 51.5,
39.2, 33.7; IR (film) mmax: 3371, 2926, 2867, 1634, 1053,
701; 3330, 2927, 1491, 1453, 703 cmꢁ1; HRMS-ESI: m/z
[M+H]+ calcd for C17H23N2O: 271.1810; found: 271.1812.
d.r. 4.5:1
R1
R1
R
R
1) Cp2ZrCl2,
R2
n-BuLi (2 equiv)
OH
N
N
R2
2) H2O
O
O
7a-d
O
8a-d
Entry
R
R1
R2
Compound
dr
9:1
10:1
12:1
10:1
1
2
3
4
Ph
Ph
H
Ph
CH2OBn
Ph
Me
Ph
Ph
Ph
8a (65%)
8b (68%)
8c (71%)
8d (53%)
4.3. General procedure for the preparation of carbamates
1a–h (procedure A)
Ph
i-Pr
A solution of triphosgeneꢂ (148 mg, 1 mmol) in CH2Cl2
(2 mL) was added dropwise to a solution of amino alcohol
(2 mmol) and pyridine (0.18 mL, 2 mmol) in CH2Cl2
(3 mL) at 0 ꢁC. The resulting mixture was stirred for 2 h
at rt and diluted with CH2Cl2 (10 mL). The organic layer
was washed with an aqueous solution of HCl (1 M,
5 mL), dried over MgSO4, and concentrated under vac-
uum. The residue was purified by column chromatography
on silica gel using a mixture of petroleum ether/AcOEt as
solvent to give the corresponding carbamate.
3. Conclusion
In conclusion, we have described an efficient and straight-
forward synthesis of optically active di- and trisubstituted
pyrrolidinones via a zirconium-mediated alkene–carba-
mate intramolecular coupling reaction. This reaction is
quite general and gives access to diversely substituted pyrrol-
idines, which are valuable building blocks. Acyclic carba-
mates have been shown to be more appropriate than the
cyclic ones to prepare disubstituted pyrrolidinones in a
highly stereoselective way. Cyclic carbamates derived from
an amino alcohol can be used for the stereoselective prep-
aration of trisubstituted pyrrolidinones. The easy prepara-
tion of starting materials and versatile utility of substituted
pyrrolidinones, render this method attractive in organic
synthesis.
4.3.1. (R)-4-Phenyl-3-[(R)-1-phenylbut-3-enyl]oxazolidin-2-
25
one 1a. Yellow oil; ½aꢀD ¼ ꢁ11:0 (c 1.2, CH2Cl2);
1H NMR (250 MHz, CDCl3): d 7.28 (m, 6H), 7.13
(m, 4H), 5.67 (tdd, 1H, J = 6.2, 10.2, 16.8 Hz), 5.01 (t,
1H, J = 8.0 Hz), 4.91 (dm, 1H, J = 10.2 Hz), 4.86 (dm,
1H, J = 16.8 Hz), 4.34 (dd, 1H, J = 8.0, 9.0 Hz), 4.23
(dd, 1H, J = 6.5, 7.8 Hz), 4.07 (dd, 1H, J = 6.5, 8.0 Hz),
2.25 (m, 2H); 13C NMR (62.5 MHz, CDCl3): d 174.5,
139.3, 137.5, 134.5, 129.0, 128.9, 128.5, 128.4, 128.1,
127.7, 117.6, 70.2, 58.8, 58.3, 35.7; IR (film): mmax 1725,
14.05, 1235, 1045, 925, 705 cmꢁ1; HRMS-ESI: m/z
[M+H]+ calcd for C19H20NO2: 294.1494; found: 294.1493.
4. Experimental
4.1. General
All reactions were conducted under an atmosphere of
argon using standard Schlenk techniques. Prior to use,
tetrahydrofuran and Et2O were distilled under argon from
sodium benzophenone ketyl, NEt3, CH3CN, and CH2Cl2
were distilled under argon from CaH2. Reagents (Aldrich)
were used as received. 1H and 13C NMR spectra were
recorded in CDCl3 on a Brucker AC-250. Mass spectra
were recorded on a Micromass Q-TOF micro MS
spectrometer.
4.3.2. (R)-3-[(R)-1-(Furan-2-yl)but-3-enyl]-4-phenyloxazol-
25
idin-2-one 1b. Red oil; ½aꢀD ¼ ꢁ8:5 (c 1, CH2Cl2);
1H NMR (250 MHz, CDCl3): d 7.36 (dd, 1H, J = 1.0,
1.8 Hz), 7.38 (m, 3H), 7.27 (m, 2H), 6.29 (dd, 1H,
J = 2.1, 3.2 Hz), 6.08 (d, 1H, J = 3.2 Hz), 5.55 (tdd, 1H,
J = 6.7, 10.2, 17.2 Hz), 5.06 (t, 1H, J = 7.9 Hz), 5.01 (dm,
1H, J = 10.2 Hz), 4.44 (t, 1H, J = 6.9 Hz), 4.28 (dd, 1H,
J = 6.7, 8.7 Hz), 4.05 (dd, 1H, J = 7.0, 8.2 Hz), 2.11 (m,

428
C. Denhez et al. / Tetrahedron: Asymmetry 18 (2007) 424–434
2H); 13C NMR (62.5 MHz, CDCl3): d 158.4, 151.3, 142.3,
9.2 Hz), 5.18 (dm, 1H, J = 17.5 Hz), 5.08 (dm, 1H,
J = 10.7 Hz), 4.15–4.30 (m, 2H), 3.84 (s, 3H), 3.54 (td,
1H, J = 6.1, 8.4 Hz), 3.22 (td, 1H, J = 6.9, 8.4 Hz), 2.78
(m, 2H); 13C NMR (62.5 MHz, CDCl3): d 157.8, 157.5,
134.7, 129.2, 128.0, 126.3, 120.2, 117.5, 110.8, 61.8, 55.4,
51.1, 41.5, 34.9; IR (film): mmax 2920, 1745, 1492, 1421,
139.1, 133.7, 128.9, 128.5, 127.5, 117.6, 110.0, 109.0, 70.1,
58.8, 52.7, 35.3; IR (film) m: 2933, 1710, 1640, 1439 cmꢁ1
;
HRMS-ESI: m/z [M+Na]+ calcd for C17H17NO3:
306.1116; found: 306.1111.
4.3.3.
(R)-3-[(R)-1-(1-Methyl-1H-pyrrol-2-yl)but-3-enyl]-
1248 cmꢁ1
;
HRMS-ESI: m/z [M+Na]+ calcd for
25
4-phenyloxazolidin-2-one 1c. Yellow oil; ½aꢀD ¼ ꢁ15:5 (c
1, CH2Cl2); 1H NMR (250 MHz, CDCl3): d 7.35 (m,
3H), 7.25 (m, 2H), 6.68 (dd, 1H, J = 1.7, 2.8 Hz), 6.09
(dd, 1H, J = 2.8, 3.5 Hz), 5.88 (dd, 1H, J = 1.7, 3.5 Hz),
5.70 (dddd, 1H, J = 6.0, 7.0, 10.5, 17.0 Hz), 4.99 (dm,
1H, J = 17.0 Hz), 4.88 (dm, 1H, J = 10.5 Hz), 4.48 (t,
1H, J = 11.3 Hz), 4.17 (dd, 1H, J = 2.7, 6.5 Hz), 4.12
(dd, 1H, J = 2.2, 6.7 Hz), 3.60 (s, 3H), 2.22–2.02 (m, 2H);
13C NMR (62.5 MHz, CDCl3): d 181.0, 158.2, 139.9,
134.5, 129.0, 128.7, 127.8, 123.2, 117.5, 109.6, 106.7, 70.4,
57.7, 50.8, 36.9, 33.9; IR (film): mmax 1750, 1404, 1218,
1423, 701 cmꢁ1; HRMS-ESI: m/z [M+Na]+ calcd for
C18H20N2O2: 319.1422; found: 319.1425.
C14H17NO2Na: 270.1006; found: 270.1008.
4.3.8. 3-[(E)-1-Phenylhexa-1,5-dien-3-yl]oxazolidin-2-one
1h. Yellow oil; 1H NMR (250 MHz, CDCl3): d 7.40–
7.25 (m, 5H), 6.58 (dd, 1H, J = 1.2, 16.0 Hz), 6.16 (dd,
1H, J = 6.5, 16.0 Hz), 5.82 (tdd, 1H, J = 6.0, 10.0,
17.0 Hz), 5.18 (dm, 1H, J = 17.0 Hz), 5.13 (dm, 1H,
J = 10.0 Hz), 4.65 (td, 1H, J = 6.5, 8.8 Hz), 4.33 (t app,
1H, J = 8.0 Hz), 3.53 (t app, 1H, J = 7.8 Hz), 2.55 (ddm,
1H, J = 6.5, 14.2 Hz), 2.46 (ddm, 1H, J = 8.7, 14.2 Hz);
13C NMR (62.5 MHz, CDCl3): d 133.9, 132.7, 128.6,
128.0, 126.4, 126.0, 117.9, 62.0, 54.1, 40.4, 36.2, 2C are
missing; IR (film): mmax 2917, 1742, 1425, 1254 cmꢁ1
;
HRMS-ESI: m/z [M+Na]+ calcd for C15H17NO2Na:
4.3.4. (R)-3-[(R)-1-(2-Methoxyphenyl)but-3-enyl]-4-phenyl-
266.1157; found: 266.1154.
25
oxazolidin-2-one 1d. Yellow oil; ½aꢀD ¼ ꢁ19 (c 0.8,
1
CH2Cl2); H NMR (250 MHz, CDCl3): d 7.32 (m, 4H),
4.4. General procedure for the preparation of pyrrolidinones
2a–h (procedure B)
7.08 (m, 2H), 6.96 (t, 1H, J = 7.0 Hz), 6.90 (d, 2H,
J = 8.5 Hz), 5.78 (tdd, 1H, J = 6.5, 10.0, 17.2 Hz), 5.33
(dd, 1H, J = 7.5, 9.0 Hz), 5.02 (dm, 1H, J = 10.0 Hz),
4.96 (dm, 1H, J = 17.0 Hz), 4.40 (t, 1H, J = 8.2 Hz), 4.03
(dt, 1H, J = 7.6 Hz), 3.80 (s, 3H), 2.32 (m, 2H); 13C
NMR (62.5 MHz, CDCl3): d 158.7, 157.6, 139.6, 135.0,
129.3, 128.8, 128.7, 128.6, 127.7, 125.1, 119.9, 117.4,
110.2, 70.0, 59.1, 55.4, 52.5, 36.2; IR (film): mmax 1755,
1490, 1450 cmꢁ1; HRMS-ESI: m/z [M+Na]+ calcd for
C20H22NO3: 324.1600; found: 324.1597.
To a solution of Cp2ZrCl2 (292 mg, 1 mmol) in THF
(5 mL) was added dropwise a solution of n-BuLi (1.6 in
hexane, 1.25 mL, 2 mmol) at ꢁ78 ꢁC under Ar. The result-
ing solution was stirred at ꢁ78 ꢁC for 30 min, then a solu-
tion of carbamates 1, 4, or 7 (1 mmol) in THF (2 mL) was
added dropwise at this temperature. The reaction was
slowly warmed to room temperature, and then stirred for
6 h. The reaction was quenched by adding an aqueous solu-
tion of HCl (1 M, 2 mL). The aqueous layer was extracted
with AcOEt (3 · 5 mL). The organic layers were combined,
dried over MgSO4, and concentrated under vacuum. The
residue was purified by column chromatography on silica
gel using a mixture of petroleum ether/AcOEt as solvent
to give the corresponding pyrrolidinone.
4.3.5.
(R)-3-[(R)-2-Methylhex-5-en-3-yl]-4-phenyloxazol-
25
1
idin-2-one 1e. Yellow oil; ½aꢀD ¼ ꢁ14 (c 0.8, CH2Cl2); H
NMR (250 MHz, CDCl3): d 7.38 (m, 5H), 5.76 (tdd, 1H,
J = 6.0, 10.2, 17.0 Hz), 5.04 (dm, 1H, J = 10.2 Hz), 4.96
(dm, 1H, J = 17.2 Hz), 4.75 (dd, 1H, J = 7.0, 9.0 Hz),
4.58 (t, 1H, J = 8.7 Hz), 4.23 (dd, 1H, J = 6.7, 8.7 Hz),
3.07 (dt, 1H, J = 4.0, 10.2 Hz), 2.12 (m, 2H), 0.88 (d, 3H,
J = 6.7 Hz), 0.81 (d, 3H, J = 6.7 Hz); 13C NMR
(62.5 MHz, CDCl3): d 151.9, 138.7, 135.6, 129.1, 128.9,
128.2, 117.4, 69.8, 61.3, 60.7, 34.7, 29.8, 20.6, 20.4; IR (film):
mmax 1745, 1410, 1220 cmꢁ1; HRMS-ESI: m/z [M+Na]+
calcd for C16H21NO2Na: 282.1470; found: 282.1471.
4.4.1. (3S,5R)-1-[(R)-2-Hydroxy-1-phenylethyl]-3-methyl-5-
phenylpyrrolidin-2-one 2a. Major diastereomer: White
25
1
solid; ½aꢀD ¼ ꢁ22:5 (c 1.1, CH2Cl2); mp 106 ꢁC H NMR
(250 MHz, CDCl3): d 7.28 (m, 6H), 7.10 (m, 4H), 5.22
(dd, 1H, J = 6.0, 8.3 Hz), 4.28 (dd, 1H, J = 3.1, 8.5 Hz),
3.86–3.62 (m, 2H), 2.89 (m, 1H), 2.75 (br m, 1H), 2.15–
1.86 (m, 2H), 1.24 (d, 3H, J = 7.1 Hz); 13C NMR
(62.5 MHz, CDCl3): d 179.6, 142.2, 136.3, 128.7, 128.5,
128.3, 128.0 (2C), 126.4, 63.1, 60.3, 59.5, 38.1, 35.4, 16.3;
HRMS-ESI: m/z [M+H]+ calcd for C19H22NO2:
296.1651; found: 296.1644; Anal. Calcd for C19H21NO2:
C, 77.26; H, 7.17; N, 4.74. Found: C, 77.38; H, 7.26; N,
4.63.
4.3.6. 3-(1-Phenylbut-3-enyl)oxazolidin-2-one 1f. Yellow
oil; 1H NMR (250 MHz, CDCl3): d 7.35 (m, 5H), 5.82
(dddd, 1H, J = 6.0, 7.5, 10.2, 17.3 Hz), 5.24–5.08 (m,
2H), 4.34–4.16 (m, 2H), 3.50 (ddd, 1H, J = 6.5, 8.2,
9.0 Hz), 3.20 (ddd, 1H, J = 7.5, 8.2, 9.0 Hz), 2.85–2.64
(m, 2H); 13C NMR (62.5 MHz, CDCl3): d 158.2, 138.1,
134.1, 128.7, 128.0, 127.4, 117.8, 61.9, 55.6, 40.0, 34.7; IR
(film): mmax 2918, 1733, 1423, 1252, 703 cmꢁ1; HRMS-
ESI: m/z [M+Na]+ calcd for C13H15NO2Na: 240.1000;
found: 240.0998.
4.4.2.
5-(Furan-2-yl)-1-[(R)-2-hydroxy-1-phenylethyl]-3-
methylpyrrolidin-2-one 2b. Red oil; major diastereomer
(3S,5R): 1H NMR (250 MHz, CDCl3): d 7.28 (m, 4H),
7.15 (m, 2H), 6.25 (dd, 1H, J = 1.8, 3.2 Hz), 6.07 (d, 1H,
J = 0.7, 3.2 Hz), 5.17 (dd, 1H, J = 6.5, 7.5 Hz), 4.34 (dd,
1H, J = 2.8, 8.7 Hz), 3.77 (m, 2H), 2.99 (qdd, 1H,
J = 7.1, 8.5, 9.5 Hz), 2.28 (ddd, 1H, J = 2.8, 8.2,
4.3.7.
3-[1-(2-Methoxyphenyl)but-3-enyl]oxazolidin-2-one
1
1g. Yellow oil; H NMR (250 MHz, CDCl3): d 7.30 (m,
2H), 6.92 (m, 2H), 5.82 (m, 1H), 5.35 (dd, 1H, J = 6.5,

C. Denhez et al. / Tetrahedron: Asymmetry 18 (2007) 424–434
429
12.6 Hz), 1.89 (ddd, 1H, J = 8.7, 9.5, 12.6 Hz), 1.26 (d, 3H,
J = 7.1 Hz); 13C NMR (62.5 MHz, CDCl3): d 178.9, 153.7,
142.4, 136.2, 128.6, 128.5, 128.0, 127.8, 110.4, 107.6, 62.6,
59.2, 53.1, 35.9, 34.7, 16.1; IR (film): mmax 3402, 2971,
2933, 2876, 1677, 1454, 1418, 1251, 1062, 1012, 749,
ESI: m/z [M+H]+ calcd for C13H18NO2: 220.1338; found:
220.1342.
4.4.7. 1-(2-Hydroxyethyl)-5-(2-methoxyphenyl)-3-methyl-
1
pyrrolidin-2-one 2g. Yellow oil; major isomer: H NMR:
699 cmꢁ1
;
HRMS-ESI: m/z [M+H]+ calcd for
d 7.28 (dt, 1H, J = 1.9, 7.5 Hz), 6.97 (m, 3H), 5.04 (dd,
1H, J = 4.8, 6.7 Hz), 3.72–3.58 (m, 3H), 3.01 (m, 2H),
2.66 (hex, 1H, J = 7.8 Hz), 2.13 (m, 2H), 1.23 (d, 3H,
J = 7.1 Hz); 13C NMR (62.5 MHz, CDCl3): d 180.2,
156.9, 128.8, 128.4, 126.1, 120.5, 110.7, 61.1, 56.4, 55.3,
45.6, 36.0, 35.1, 16.2; IR (film): mmax 3403, 2965, 2933,
1668, 1491, 1463, 1243, 755 cmꢁ1; MS-ESI: m/z [M+H]+:
249.
C17H20NO3: 286.1443; found: 286.1448.
4.4.3. 1-[(R)-2-Hydroxy-1-phenylethyl]-3-methyl-5-(1-meth-
yl-1H-pyrrol-2-yl)pyrrolidin-2-one 2c. Yellow oil; major
diastereomer (3S,5R): 1H NMR (250 MHz, CDCl3): d
7.30 (m, 3H), 7.11 (m, 2H), 6.49 (dd, 1H, J = 2.0,
2.7 Hz), 6.10 (dd, 1H, J = 2.0, 3.7 Hz), 6.05 (dd, 1H,
J = 2.7, 3.5 Hz), 5.20 (dd, 1H, J = 5.2, 8.0 Hz), 4.39 (dd,
1H, J = 3.2, 8.5 Hz), 3.98 (ddd, 1H, J = 6.2, 8.0,
11.5 Hz), 3.85 (td, 1H, J = 5.0, 11.5 Hz), 3.09 (s, 3H),
2.90 (qt, 1H, J = 7.0, 8.5 Hz), 2.73 (br t, 1H, J = 5.7 Hz),
2.14 (ddd, 1H, J = 3.0, 8.2, 12.5 Hz), 1.90 (td, 1H,
J = 8.7, 12.5 Hz), 1.25 (d, 3H, J = 7.0 Hz); 13C NMR
(62.5 MHz, CDCl3): d 179.1, 136.5, 131.7, 128.6, 128.3,
128.0, 122.9, 107.3, 63.2, 59.0, 52.2, 36.4, 35.2, 33.6, 16.1;
IR (film): mmax 3411, 2967, 1674, 753, 702 cmꢁ1; HRMS-
ESI: m/z [M+Na]+ calcd for C18H22N2O2: 321.1579;
found: 321.1573.
4.4.8. (E)-1-(2-Hydroxyethyl)-3-methyl-5-styrylpyrrolidin-2-
1
one 2h. Yellow oil; major isomer: H NMR (250 MHz,
CDCl3): d 7.40–7.26 (m, 5H), 6.54 (d, 1H, J = 15.8 Hz),
6.04 (dd, 1H, J = 8.6, 15.8 Hz), 4.25 (dt, 1H, J = 3.8,
8.2 Hz), 3.73 (t, 1H, J = 5.1 Hz), 3.60 (m, 1H), 3.22 (td,
1H, J = 4.0, 14.8 Hz), 2.67 (hex, 1H, J = 7.6 Hz), 2.13
(ddd, 1H, J = 3.9, 8.5, 12.8 Hz), 2.00 (dt, 1H, J = 4.5,
8.0 Hz), 1.24 (d, 3H, J = 7.2 Hz); 13C NMR (62.5 MHz,
CDCl3): d 179.2, 135.7, 134.2, 132.8, 128.6, 128.1, 126.5,
61.2, 60.4, 44.7, 35.4, 34.8, 16.3; IR (film): mmax 3389,
2967, 2932, 1668, 1456, 753 cmꢁ1; MS-ESI: m/z [M+H]+:
245.
4.4.4. (3S,5R)-1-[(R)-2-Hydroxy-1-phenylethyl]-5-(2-methoxy-
phenyl)-3-methylpyrrolidin-2-one 2d. Major diastereo-
25
1
mer: Yellow oil; ½aꢀD ¼ þ46 (c 1.2, CH2Cl2); H NMR: d
7.23 (m, 4H), 7.08 (m, 3H), 6.86 (t, 1H, J = 7.4 Hz), 6.77
(d, 1H, J = 8.0 Hz), 5.09 (dd, 1H, J = 5.2, 7.7 Hz), 5.64
(d, 1H, J = 7.0 Hz), 3.82 (m, 2H), 3.70 (s, 3H), 2.98–2.80
(m, 2H), 2.12 (dd, 1H, J = 10.0, 12.7 Hz), 1.95 (dt, 1H,
J = 9.2, 12.7 Hz), 1.25 (d, 3H, J = 7.0 Hz); 13C NMR
(62.5 MHz, CDCl3): d 180.1, 156.6, 136.6, 129.6, 129.1,
128.6, 128.3, 127.7, 120.4, 110.7, 63.6, 60.1, 55.1, 36.2,
35.8, 16.7, 2C are missing; IR (film): mmax 3403, 2963,
2932, 1668, 1492, 1464, 1244, 1026, 755 cmꢁ1; HRMS-
ESI: m/z [M+H]+ calcd for C20H24NO3: 326.1756; found:
326.1753.
4.5. (3S,5R)-3-Methyl-5-phenylpyrrolidin-2-one trans-3
A solution of 2a (210 mg, 0.71 mmol) and thionyl chloride
(165 mg, 1.4 mmol) in CH2Cl2 (3 mL) was stirred at rt for
2 h. The solvent and the excess of thionyl chloride was
removed under vacuum. The residue was dissolved in
CH3CN (3 mL) and DBU (0.34 mL, 2.3 mmol) was added
and the resulting mixture stirred overnight. The solvent
was removed under vacuum and the residue dissolved in
CH2Cl2 (2 mL). A solution of HCl (5 M, 0.8 mL) was
added and the resulting mixture stirred vigorously for
30 min at rt. The layers were separated and the aqueous
layer was extracted with CH2Cl2 (3 · 3 mL). The organic
layers were combined, dried over Na2SO4, and concen-
trated to give the lactam 3-trans, as white needles, after col-
umn chromatography on silica gel using a mixture of
petroleum ether/AcOEt as solvent. Mp 139 ꢁC,
4.4.5. (3S,5R)-1-[(R)-2-Hydroxy-1-phenylethyl]-5-isopropyl-
3-methylpyrrolidin-2-one 2e. Major diastereomer: Yellow
25
1
oil; ½aꢀD ¼ þ24:5 (c 0.3, CH2Cl2); H NMR (250 MHz,
CDCl3): d 7.34 (m, 5H), 4.69 (dd, 1H, J = 4.4, 7.6 Hz),
4.23 (td, 1H, J = 7.9, 11.2 Hz), 4.08 (td, 1H, J = 3.7,
11.2 Hz), 3.87 (dd, 1H, J = 4.3, 7.7 Hz), 3.33 (dm, 1H,
J = 9.2 Hz), 2.62 (m, 1H), 2.06 (dd, 1H, J = 10.5,
11.4 Hz), 1.82 (m, 1H), 1.60 (td, 1H, J = 9.5, 12.2 Hz),
1.23 (d, 3H, J = 7.1 Hz), 0.77 (d, 3H, J = 6.9 Hz), 0.61
(d, 3H, J = 6.7 Hz); 13C NMR (62.5 MHz, CDCl3): d
179.7, 137.6, 128.6, 128.0, 127.7, 64.9, 64.6, 62.5, 36.9,
30.3, 27.8, 19.2, 17.3, 14.5; IR (film): mmax 3395, 2963,
25
1
½aꢀD ¼ þ39 (c 0.5, CH2Cl2); H NMR (250 MHz, CDCl3):
d 7.30 (m, 5H), 6.95, (br s, 1H), 4.73 (dd, 1H, J = 5.9,
6.3 Hz), 2.61 (hex, 1H, J = 7.2 Hz), 2.21 (m, 2H), 1.23 (d,
3H, J = 7.2 Hz).
4.6. General procedure for the preparation of carbamates
4a–l
1661, 1451, 1065, 755, 701 cmꢁ1
;
HRMS-ESI: m/z
To a solution of amine and DMAP (12 mg, 0.1 mmol) in
CH2Cl2 (3 mL) was added dropwise a solution of (Boc)2O
(275 mg, 1.25 mmol) in CH2Cl2 (2 mL) at rt. The reaction
mixture was then stirred for 4 h at rt and quenched by add-
ing water (2 mL). The aqueous layer was extracted with
dichloromethane (3 · 5 mL), the organic layers were com-
bined, dried over Na2SO4, filtered, and concentrated under
vacuum. The residue was purified by column chromatogra-
phy on silica gel using a mixture of petroleum ether/AcOEt
as eluant to give the corresponding carbamate 4.
[M+H]+ calcd for C16H24NO2: 262.1807; found: 262.1804.
4.4.6. 1-(2-Hydroxyethyl)-3-methyl-5-phenylpyrrolidin-2-one
2f. Yellow oil; major isomer: 1H NMR (250 MHz,
CDCl3): d 7.27 (m, 3H), 7.10 (dd, 2H, J = 2.0, 8.1 Hz),
4.65 (t, 1H, J = 6.1 Hz), 3.58 (m, 4H), 2.88 (m, 1H), 2.65
(m, 1H), 2.09 (m, 2H), 1.18 (d, 3H, J = 7.2 Hz); 13C
NMR (62.5 MHz, CDCl3): d 161.5, 140.8, 128.9, 127.9,
127.1, 126.2, 61.6, 60.7, 44.9, 37.3, 35.2, 16.3; HRMS-

430
C. Denhez et al. / Tetrahedron: Asymmetry 18 (2007) 424–434
4.6.1. tert-Butyl 4-methoxyphenyl(1-phenylbut-3-enyl)carb-
amate 4a. Yellow oil; 1H NMR (250 MHz, CDCl3): d
7.27 (m, 3H), 7.20 (m, 2H), 6.70 (m, 4H), 5.88 (dddd,
J = 6.1, 6.7, 10.2, 17.1 Hz, 1H), 5.71 (dd, J = 6.9, 9.0 Hz,
1H), 5.19 (dm, J = 17.1 Hz, 1H), 5.14 (dm, J = 10.2 Hz,
1H), 3.75 (s, 3H), 2.68 (m, 2H), 1.38 (s, 9H); 13C NMR
(62.5 MHz, CDCl3): d 27.3, 35.0, 55.2, 60.8, 84.3, 113.6,
117.9, 128.0, 128.2, 128.5, 130.4, 134.3, 138.4, 147.8,
149.8, 159.1; IR (film): mmax 2980, 1775, 1733, 1512, 1219,
4.6.7. tert-Butyl benzyl[1-(furan-2-yl)but-3-enyl]carbamate
4i. Yellow oil; H NMR (250 MHz, CDCl3): d 7.00–7.26
1
(br m, 6H), 6.26–6.04 (br m, 2H), 5.81–5.50 (br m, 1.5H),
5.20–4.92 (br m, 2.5H), 4.31 (br m, 1H), 4.17 (d,
J = 15.8 Hz, 1H), 2.57 (br s, 2H), 1.47–1.33 (s, 9H); 13C
NMR (62.5 MHz, CDCl3): d 155.6, 153.1, 141.6, 139.4,
134.1, 127.7, 126.5, 126.2, 117.3, 109.8, 79.8, 52.4, 46.9,
35.5, 28.1; IR (film): mmax 2977, 2931, 1699, 1454, 1164,
735 cmꢁ1; MS-ESI: m/z [M+H]+: 327.
1148 cmꢁ1
.
4.6.8. tert-Butyl benzyl[1-(4-fluorophenyl)but-3-enyl]carb-
1
4.6.2. tert-Butyl
1-phenylbut-3-enyl(propyl)carbamate
amate 4j. Yellow oil; H NMR (250 MHz, CDCl3): d 7.10
1
4d. Yellow oil; H NMR (250 MHz, CDCl3): d 7.30 (m,
5H), 5.82 (tdd, 1H, J = 6.7, 10.2, 17.1 Hz), 5.71 (br m,
1H), 5.19 (dd, 1H, J = 1.4, 17.1 Hz), 5.06 (dm, 1H,
J = 10.2 Hz), 2.88 (m, 2H), 2.72 (m, 2H), 1.38 (s, 9H),
1.20 (br m, 2H), 0.68 (t, 3H, J = 7.4 Hz); 13C NMR
(62.5 MHz, CDCl3): d 155.9, 140.5, 135.1, 128.1, 127.7,
127.1, 117.0, 79.2, 35.5, 28.4, 22.6, 11.4, 1C is missing;
MS-ESI: m/z [M+H]+: 289.
(m, 5H), 6.96 (br m, 2H), 6.83 (t, 2H, J = 7.7 Hz), 5.60 (br
m, 1H), 5.28 (br m, 1H), 4.92 (br m, 2H), 4.20 (br m, 1H),
4.02 (d, 1H, J = 15.7 Hz), 2.54 (m, 2H), 1.30 (s, 9H); 13C
NMR (62.5 MHz, CDCl3): d 161.9 (d, J = 245 Hz), 155.9,
137.5 (d, J = 225 Hz), 134.8, 129.7, 127.9, 127.2, 126.6,
117.3, 114.9 (d, J = 21 Hz), 80.0, 57.9, 47.4, 35.9, 28.2; IR
(film): mmax 2977, 2930, 1685, 1511, 1226, 1157 cmꢁ1;19F
NMR: d ꢁ115.3 (br m); MS-ESI: m/z [M+H]+: 355.
4.6.3.
tert-Butyl
benzyl(1-phenylbut-3-enyl)carbamate
4.6.9. tert-Butyl benzyl(2-methylhex-5-en-3-yl)carbamate
4k. Yellow oil; obtained as a mixture of two rotamers:
1H NMR (250 MHz, CDCl3): d 7.26 (m, 5H), 5.66 (m,
0.5H), 5.51 (m, 0.5H), 4.99–4.85 (m, 2H), 4.35 (s, 1H),
4.24 (s, 1H), 3.77 (br m, 0.5H), 2.34 (br m, 0.5H), 1.84
(br m, 1H), 1.50 (s, 4.5H), 1.36 (s, 4.5H), 0.90 (br m,
3H), 0.81 (d, J = 6.2 Hz, 1.5H), 0.71 (d, J = 5.1 Hz,
1.5H); 13C NMR (62.5 MHz, CDCl3): d 156.5, 156.0,
139.6, 139.1, 135.9, 135.8, 128. 4, 127.9, 127.8, 127.4,
126.6, 126.4, 116.1 (2C), 79.3, 79.1, 64.2, 62.8, 48.5, 48.4,
35.5, 34.8, 31.4, 30.9, 28.3, 28.1, 20.6 (2C), 20.2, 20.0; IR
(film): mmax 2975, 2873, 1684, 1365, 1166, 701 cmꢁ1; MS-
ESI: m/z [M+H]+: 301.
4e. Yellow oil; 1H NMR (250 MHz, CDCl3): d 7.38–
7.02 (m, 5H), 5.72 (m, 1H), 5.49 (br m, 1H), 5.04–4.97
(m, 2H), 4.31 (br m, 1H), 4.07 (d, 1H, J = 14.9 Hz), 3.76
(s, 3H), 2.65 (dd, 2H, J = 7.0, 7.5 Hz), 1.39 (br s, 9H),
13C NMR (62.5 MHz, CDCl3): d 156.1, 140.0, 139.6,
135.1, 128.3, 128.0, 127.4, 126.5, 117.1, 80.0, 36.0, 28.5,
4C are missing; MS-ESI: m/z [M+H]+: 338.
4.6.4. tert-Butyl 4-methoxybenzyl(1-phenylbut-3-enyl)carb-
amate 4f. Yellow oil; 1H NMR (250 MHz, CDCl3): d 7.28
(m, 5H), 6.98 (br s, 2H), 6.74 (d, J = 8.3 Hz, 2H), 5.71 (tdd,
J = 6.7, 10.3, 17.2 Hz, 1H), 5.36 (br m, 1H), 4.99 (br d,
J = 17.2 Hz, 1H), 4.98 (br d, J = 10.3 Hz, 1H), 4.28 (br s,
1H), 4.00 (d, J = 15.5 Hz, 1H), 3.76 (s, 3H), 2.64 (t,
J = 7.0 Hz, 2H), 1.41 (br s, 9H); 13C NMR: d 158.3,
156.1, 140.1, 135.2, 131.7, 128.8, 128.2, 128.1, 127.3,
117.1, 113.4, 79.9, 58.7, 55.2, 46.9, 35.9, 28.4; IR (film) m:
2977, 2932, 1684, 1513, 1247, 1163 cmꢁ1; MS-ESI: m/z
[M+H]+: 367.
4.6.10. tert-Butyl benzyl(non-1-en-4-yl)carbamate 4l. Yel-
25
1
low oil; ½aꢀ ¼ ꢁ11:9 (c 1, CH2Cl2); H NMR (250 MHz,
CDCl3): dD7.26 (m, 5H), 5.67 (br m, 1H), 4.95 (br m,
2H), 4.37 (br s, 0.9H), 4.26 (br s, 1.1H), 4.14 (br t,
0.55H, J = 6.5 Hz), 3.75 (br s, 0.45H), 2.15 (m, 2H),
1.52–1.08 (br m, 17H), 0.75 (t, J = 6.6 Hz, 3H); 13C
NMR (62.5 MHz, CDCl3): d 154.0, 136.4, 136.2, 128.5,
127.5, 127.0, 117.0, 79.8, 56.6, 47.7, 47.6, 39.0, 38.6, 33.7,
33.1, 32.1, 29.0, 28.8, 26.7, 23.0, 14.4; IR (film): mmax
2983, 2869, 1686, 1361, 1162, 709 cmꢁ1; HRMS-ESI: m/z
[M+H]+ calcd for C21H33NO2: 331.2511; found: 331.2515.
4.6.5. tert-Butyl benzyl(1-(4-methoxyphenyl)but-3-enyl)carb-
amate 4g. Yellow oil; 1H NMR (250 MHz, CDCl3): d
7.20 (m, 5H), 7.06 (br m, 2H), 6.82 (d, 2H, J = 8.5 Hz),
5.84–5.60 (m, 1H), 5.45 (br m, 1H), 4.99 (br d, 1H,
J = 18.2 Hz), 4.97 (br d, 1H, J = 10.1 Hz), 4.30 (br m,
1H), 4.05 (d, 1H, J = 15.8 Hz), 3.75 (s, 3H), 2.61 (dd,
2H, J = 6.7, 7.4 Hz), 1.39 (br s, 9H); 13C NMR: d 158.7,
156.0, 139.6, 135.1, 131.8, 129.2, 127.8, 127.1, 126.4,
116.9, 113.5, 79.7, 57.7, 55.0, 47.0, 36.0, 28.2; IR (film):
mmax 2976, 2932, 1685, 1513, 1250, 1161 cmꢁ1; MS-ESI:
m/z [M+H]+: 367.
4.7. (E)-tert-Butyl 1,4-diphenylbut-3-enyl(4-methoxybenz-
yl)carbamate 4m
A mixture of N-(4-methoxybenzyl)-1-phenylbut-3-en-1-
amine (2.67 g, 10 mmol), iodobenzene (2.45 g, 12 mmol),
and anhydrous NaHCO3 (2.52 g, 30 mmol) and Pd(OAc)2
(224 mg, 1 mmol) in acetonitrile (20 mL) was heated to re-
flux overnight. Water (10 mL) was added and the aqueous
layer extracted with AcOEt (2 · 10 mL). The organic layers
were combined, dried over MgSO4, filtered, and concen-
trated under vacuum. Boc2O (2.6 g, 10 mmol) and DMAP
(50 mg, 0.4 mmol) and CH2Cl2 (20 mL) were added to the
crude mixture, and the reaction was stirred for 4 h at rt.
This solution was washed with an aqueous solution of
HCl (1 M, 5 mL). The aqueous layer was extracted with
4.6.6. tert-Butyl 4-methoxybenzyl[1-(2-methoxyphenyl)but-
3-enyl]carbamate 4h. Yellow oil; 1H NMR (250 MHz,
CDCl3): d 7.30–6.65 (br m, 8H), 5.71 (br m, 1H), 5.49 (br
s, 1H), 4.91–5.04 (br m, 2H), 4.13 (br s, 2H), 3.75 (br s,
3H), 3.73 (br s, 3H), 2.60 (br s, 2H), 1.47 (br s, 9H); 13C
NMR (62.5 MHz, CDCl3): d 158.1, 157.9, 135.6, 132.1,
128.7, 128.4 (br signal), 127.5, 119.8, 116.7, 113.1, 110.2,
55.2, 55.1, 46.8, 28.4; MS-ESI: m/z [M+H]+: 397.

C. Denhez et al. / Tetrahedron: Asymmetry 18 (2007) 424–434
431
AcOEt (2 · 5 mL). The organic layers were combined,
dried over MgSO4, filtered, and concentrated under vac-
uum. The residue was purified by column chromatography
on silica gel using a mixture of petroleum ether/AcOEt as
J = 8.8 Hz), 5.05 (d, 1H, J = 14.4 Hz), 4.25 (dd, 1H,
J = 8.5, 7.1 Hz), 3.78 (s, 3H), 3.44 (d, 1H, J = 14.4 Hz),
2.54 (m, 2H), 1.52 (dt, 1H, J = 12.2, 9.7 Hz), 1.31 (t, 3H,
J = 6.8 Hz); 13C NMR (62.5 MHz, CDCl3): d 177.7,
159.5, 136.5, 132.2, 128.7, 128.6, 128.4, 127.4, 114.2, 59.3,
55.3, 44.3, 38.4, 36.9, 16.4; IR (film): mmax 2964, 2932,
1688, 1513, 1248, 1176, 1033 cmꢁ1; HRMS-ESI: m/z
[M+H]+ calcd for C19H22NO2: 296.1651; found: 296.1646.
1
solvent to give 4m as a yellow oil. H NMR (250 MHz,
CDCl3): d 7.24 (m, 10H), 7.00 (br m, 2H), 6.73 (d, 2H,
J = 8.3 Hz), 6.25 (d, 1H, J = 16.0 Hz), 6.04 (br m, 1H),
5.43 (br m, 1H), 4.31 (br m, 1H), 4.06 (d, 1H,
J = 15.4 Hz), 3.75 (s, 3H), 2.64–2.90 (m, 2H), 1.40 (s,
9H); 13C NMR (62.5 MHz, CDCl3): d 158.3, 156.1, 140.3,
137.4, 132.0, 131.6, 128.5, 128.3 (2C), 127.9, 127.0, 126.9,
126.0, 113.4, 55.1, 47.3, 35.4, 28.3.
4.8.5. (3RS,5RS)-1-Benzyl-5-(4-methoxyphenyl)-3-methyl-
pyrrolidin-2-one 5g. Obtained according to procedure B.
1
Yellow oil; H NMR (250 MHz, CDCl3): d 7.21 (m, 3H),
7.04–6.97 (m, 4H), 6.87 (dd, 2H, J = 8.6, 2.0 Hz), 5.01 (d,
1H, J = 14.5 Hz), 4.20 (t, 1H, J = 6.9 Hz), 3.79 (s, 3H),
3.44 (d, 1H, J = 14.5 Hz), 2.57–2.46 (m, 2H), 1.49 (ddt,
1H, J = 8.5, 8.5, 6.1, 2.1 Hz), 1.30 (d, 3H, J = 6.7 Hz);
13C NMR (62.5 MHz, CDCl3): d 177.7, 159.5, 136.6,
132.2, 128.8, 128.5, 127.4, 114.3, 59.4, 55.3, 44.4, 38.4,
37.0, 16.5; IR (film): mmax 3458, 2932, 2873, 1687, 1513,
4.8. Preparation of pyrrolidinone 5
4.8.1. 1-(4-Methoxyphenyl)-3-methyl-5-phenylpyrrolidin-2-
one 5a. Obtained as a 1.5:1 mixture of diastereomers
according to procedure B. Minor diastereomer: H NMR
1
(250 MHz, CDCl3): d 7.40 (d, 2H, J = 9.0 Hz), 7.32–7.19
(m, 5H), 6.78 (d, 2H, J = 9.0 Hz), 5.12 (dd, 1H, J = 4.0,
6.8 Hz), 3.73 (s, 3H), 2.84 (qt, 1H, J = 7.1, 9.1 Hz), 2.25
(dd, 1H, J = 3.9, 9.1 Hz), 2.23 (d, 1H, J = 9.1 Hz), 1.30
(d, 3H, J = 7.1 Hz); 13C NMR: d 177.0, 156.5, 141.3,
131.8, 128.9, 127.6, 125.8, 123.0, 113.9, 61.9, 55.3, 37.8,
35.7, 15.9. Major diastereomer: 1H NMR: d 7.24–7.19
(m, 7H), 6.74 (d, 2H, J = 9.1 Hz), 5.08 (dd, 1H, J = 6.9,
8.9 Hz), 3.69 (s, 3H), 2.85–2.64 (m, 2H), 1.64 (ddd, 1H,
J = 2.7, 8.5, 17.4 Hz), 1.36 (d, 3H, J = 7.1 Hz); 13C NMR
(62.5 MHz, CDCl3): d 177.2, 156.7, 141.3, 131.0, 128.7,
127.6, 126.6, 124.7, 113.8, 62.2, 55.2, 38.9, 37.5, 16.6; IR
(film): mmax 1694, 1512, 1248 cmꢁ1; HRMS-ESI: m/z
[M+H]+ calcd for C18H20NO2: 282.1494; found: 282.1500.
1248, 1033 cmꢁ1
.
4.8.6. 1-(4-Methoxybenzyl)-5-(2-methoxyphenyl)-3-methyl-
pyrrolidin-2-one 5h. Obtained according to procedure B.
Yellow oil; (3RS,5RS)-isomer: 1H NMR (250 MHz,
CDCl3): d 7.28 (m, 1H), 7.12–6.85 (m, 5H), 6.76 (d,
2H, J = 8.7 Hz), 4.98 (d, 1H, J = 14.4 Hz), 4.73 (t, 1H,
J = 7.0 Hz), 3.77 (s, 3H), 3.72 (s, 3H), 3.48 (d,
1H, J = 14.4 Hz), 2.56 (m, 2H), 1.54 (m, 1H), 1.25
(d, 3H, J = 6.6 Hz); 13C NMR (62.5 MHz, CDCl3): d
177.9, 158.8, 157.3, 130.0, 128.8, 128.5, 120.8, 113.6,
110.9, 55.25, 55.2, 44.0, 36.9, 35.9, 35.8, 16.8, 2C are
missing; IR (film): mmax 2932, 1683, 1513, 1245 cmꢁ1
;
HRMS-ESI: m/z [M+H]+ calcd for C20H24NO3:
4.8.2.
1-Benzyl-3-methyl-5-phenylpyrrolidin-2-one
5b.
326.1756; found: 326.1763.
Obtained according to procedure B using 4e as starting
1
material. Yellow oil. Major isomer (3RS,5RS)-: H NMR
4.8.7. (3RS,5RS)-1-Benzyl-5-(furan-2-yl)-3-methylpyrrol-
idin-2-one 5i. Obtained according to procedure B. Yellow
oil; H NMR (250 MHz, CDCl3): d 7.39 (s, 1H), 7.25 (m,
(250 MHz, CDCl3): d 7.36 (d, 2H, J = 7.3 Hz), 7.24 (m,
4H), 7.14 (d, 2H, J = 7.7 Hz), 7.01 (dd, 2H, J = 2.9,
6.4 Hz), 5.08 (d, 1H, J = 14.5 Hz), 4.27 (dd, 1H, J = 8.3,
7.2 Hz), 3.48 (d, 1H, J = 14.5 Hz), 2.67–2.49 (m, 2H),
1.53 (td, 1H, J = 8.4, 5.7 Hz), 1.33 (d, 3H, J = 6.5 Hz);
13C NMR (62.5 MHz, CDCl3): d 178.3, 140.9, 136.8,
129.3, 129.1, 128.9, 128.5, 127.8, 127.7, 126.9, 60.3, 44.9,
38.7, 37.3, 35.7, 16.9; IR (film): mmax 3466, 2930, 1691,
1455, 1241, 700 cmꢁ1; HRMS-ESI: m/z [M+H]+ calcd
for C18H20NO: 266.1545; found: 266.1542.
1
3H), 7.12 (d, 2H, J = 7.3 Hz), 6.34 (td, 1H, J = 1.7,
4.8 Hz), 6.21 (d, 1H, J = 3.1 Hz), 4.94 (d, 1H,
J = 14.7 Hz), 4.43 (dd, 1H, J = 7.1, 8.1 Hz), 3.58 (d, 1H,
J = 14.7 Hz), 2.53 (m, 2H), 1.87 (td, J = 8.7, 12.0 Hz,
1H), 1.34 (d, 3H, J = 6.7 Hz); 13C NMR (62.5 MHz,
CDCl3): d 177.5, 152.4, 143.4, 137.1, 128.9, 128.8, 127.8,
110.7, 109.8, 53.5, 45.1, 36.9, 33.7, 17.0; IR (film): mmax
2973, 2932, 1699 cmꢁ1; HRMS-ESI: m/z [M+H]+ calcd
for C16H18NO2: 256.1338; found: 256.1342.
4.8.3. (3RS,5RS)-3-Methyl-1-propyl-5-phenylpyrrolidin-2-
one 5d. Obtained according to procedure B. Yellow oil;
1H NMR (250 MHz, CDCl3): d 7.22–7.41 (m, 5H), 4.52
(dd, 1H, J = 8.9, 6.6 Hz), 3.59 (dt, 1H) , J = 8.4, 6.0 Hz,
2.53 (m, 3H), 1.32–1.53 (m, 3H), 1.28 (d, 3H, J = 6.8 Hz),
0.78 (t, 3H, J = 7.3 Hz); 13C NMR (62.5 MHz, CDCl3): d
178.0, 141.0, 129.0, 128.2, 127.2, 60.7, 42.3, 38.7, 36.9,
20.1, 16.5, 11.4; IR (film): mmax 2965, 2932, 2874, 1690,
1456, 1418, 702 cmꢁ1; HRMS-ESI: m/z [M+H]+ calcd for
C14H20NO: 218.1545; found: 218.1546.
4.8.8.
(3RS,5RS)-5-(4-Fluorophenyl)-3-methyl-1-phenyl-
pyrrolidin-2-one 5j. Obtained according to procedure B.
Yellow oil; H NMR (250 MHz, CDCl3): d 7.17 (m, 3H),
1
7.09–6.86 (m, 4H), 4.98 (d, 2H, J = 14.4 Hz), 4.18 (dd,
1H, J = 7.0, 8.5 Hz), 3.39 (d, 1H, J = 14.5 Hz), 2.50 (m,
2H), 1.41 (m, 1H), 1.25 (d, 3H, J = 6.6 Hz); 13C NMR
(62.5 MHz, CDCl3): d 178.2, 164.9, 160.9, 136.7, 129.4,
129.0, 127.9, 116.4, 116.1, 59.7, 44.9, 38.8, 37.3, 16.9; 19F
NMR (235 MHz, CDCl3): d ꢁ114.3 (tt, J = 8.2, 5.6 Hz);
IR (film) mmax: 3444, 2931, 1691, 1511, 1407, 1225 cmꢁ1
.
4.8.4. 1-(4-Methoxybenzyl)-3-methyl-5-phenylpyrrolidin-2-
one 5f. Obtained according to procedure B. Yellow oil;
Major isomer (3RS,5RS): H NMR (250 MHz, CDCl3): d
4.8.9. (3RS,5RS)-1-Benzyl-5-isopropyl-3-methylpyrrolidin-
2-one 5k. Obtained according to procedure B. Yellow
oil; H NMR (250 MHz, CDCl3): d 7.25 (m, 5H), 5.12 (d,
1
1
7.35 (m, 4H), 6.95 (d, 2H, J = 8.8 Hz), 6.78 (d, 2H,

432
C. Denhez et al. / Tetrahedron: Asymmetry 18 (2007) 424–434
1H, J = 14.9 Hz), 3.79 (d, 1H, J = 14.9 Hz), 3.33 (ddd, 1H,
J = 3.9, 7.3, 8.8 Hz), 2.47 (qt, 1H, J = 7.1, 9.1 Hz), 2.20–
2.00 (m, 2H), 1.25 (d, 3H, J = 7.1 Hz), 1.25 (m, 1H), 0.81
(d, 3H, J = 6.9 Hz), 0.73 (d, 3H, J = 6.8 Hz); 13C NMR
(62.5 MHz, CDCl3): d 178.7, 137.0, 128.9, 128.5, 127.8,
59.4, 44.5, 36.5, 26.9, 26.8, 18.7, 16.8, 14.2; IR (film): mmax
2962, 2932, 1687, 1454, 1421, 701 cmꢁ1; HRMS-ESI: m/z
[M+H]+ calcd for C15H22NO: 232.1701; found: 232.1705.
42.7, 16.6; IR (film): mmax 3386, 1453, 1028, 758, 700 cmꢁ1
HRMS-ESI: m/z [M+H]+ calcd for C17H23N2O: 281.
;
4.9.2.
(R)-2-[(2R,3R)-1-(Benzyloxy)-3-phenylpent-4-en-2-
ylamino]-2-phenylethanol 6b. Yellow oil; 1H NMR
(250 MHz, CDCl3): d 7.26 (m, 15H), 6.05 (ddd, 1H,
J = 9.5, 10.1, 17.0 Hz), 5.14 (dm, 1H, J = 17.0 Hz), 5.11
(dm, 1H, J = 10.1 Hz), 4.21 (s, 2H), 3.61 (t, 1H,
J = 8.5 Hz), 3.56 (dd, 1H, J = 4.3, 9.2 Hz), 3.44 (m, 2H),
3.27 (dd, 1H, J = 4.2, 9.1 Hz), 3.22 (dd, 1H, J = 4.0,
9.4 Hz), 2.99 (ddd, 1H, J = 3.7, 4.6, 8.3 Hz), 1.79 (br s,
2H); 13C NMR (62.5 MHz, CDCl3): d 142.8, 138.8, 129.0,
128.9, 128.7, 128.5, 128.0, 127.9, 127.4, 126.9, 117.3, 73.4,
70.1, 66.9, 63.9, 60.6, 53.2; IR (film): mmax 3395, 3028,
4.8.10. (3R,5S)-1-Benzyl-3-methyl-5-pentylpyrrolidin-2-one
5l. Obtained according to procedure B. Yellow oil;
25
½aꢀD ¼ ꢁ22:5 (c 0.5, CH2Cl2); 1H NMR (250 MHz,
CDCl3):
d 7.30 (t, 2H, J = 7.1 Hz), 7.26 (t, 1H,
J = 7.1 Hz), 7.21 (d, 2H, J = 6.9 Hz), 4.98 (d, 1H,
J = 15.0 Hz), 3.99 (d, 1H, J = 15.0 Hz), 3.30 (m, 1H),
2.47 (qdd, 1H, J = 7.1, 9.9, 14.1 Hz), 2.35 (ddd, 1H,
J = 6.7, 8.8, 12.4 Hz), 1.26 (d, 3H, J = 7.0 Hz), 1.21 (m,
8H), 0.86 (t, 3H, J = 6.9 Hz); 13C NMR (62.5 MHz,
CDCl3): d 178.3, 137.3, 128.9, 128.3, 127.7, 55.5, 44.6,
36.9, 34.4, 33.8, 32.2, 24.4, 22.9, 17.0, 14.9; IR (film): mmax
2930, 2859, 1688, 1454, 1418, 700 cmꢁ1; HRMS-ESI: m/z
[M+H]+ calcd for C17H26NO: 260.2009; found: 260.2014.
2864, 1495, 1453, 700 cmꢁ1
.
4.9.3. 2-(1,2-Diphenylbut-3-enylamino)ethanol 6c. Yellow
oil; 1H NMR (250 MHz, CDCl3): d 7.18 (m, 5H), 5.71
(ddd, 1H, J = 8.0, 10.2, 17.0 Hz), 4.77 (dm, 1H,
J = 10.2 Hz), 4.64 (dm, 1H, J = 17.0 Hz), 3.79 (d, 1H,
J = 9.2 Hz), 3.46 (dd, 1H, J = 8.3, 8.8 Hz), 3.35–3.17 (m,
2H), 2.41 (dd, 1H, J = 4.7, 12.7 Hz), 2.33 (dd, 1H,
J = 4.7, 12.7 Hz), 2.07 (br s, 2H); 13C NMR (62.5 MHz,
CDCl3): d 141.5, 141.3, 138.6, 128.7, 128.25, 128.2, 128.1,
127.3, 126.8, 116.4, 67.1, 60.8, 57.3, 48.7; IR (film): mmax
4.8.11. (3RS,5RS)-3-Benzyl-1-(4-methoxybenzyl)-5-phenyl-
pyrrolidin-2-one 5m. Obtained according to procedure B.
1
Yellow oil; H NMR (250 MHz, CDCl3): d 7.35–7.15 (m,
3328, 3027, 2921, 1493, 1453, 1055, 756, 701 cmꢁ1
;
10H), 6.94 (d, 2H, J = 8.7 Hz), 6.77 (d, 2H, J = 8.7 Hz),
5.02 (d, 1H, J = 14.3 Hz), 4.20 (dd, 1H, J = 7.3, 8.6 Hz),
3.77 (s, 3H), 3.40 (d, 1H, J = 14.3 Hz), 3.34 (dd, 1H,
J = 9.2, 1.1 Hz), 2.87 (m, 2H), 2.76 (td, 2H, J = 2.8,
9.3 Hz), 2.37 (dt, 1H, J = 7.6, 13.0 Hz), 1.59 (ddd, 1H,
J = 8.9, 9.8, 13.1 Hz); 13C NMR (62.5 MHz, CDCl3): d
176.6, 159.3, 141.0, 139.7, 130.4, 129.5, 129.3, 128.9,
128.5, 127.6, 126.7, 114.2, 60.1, 55.6, 44.4, 44.3, 37.4,
35.6; IR (film): mmax 2931, 1686, 1611, 1512, 1409, 1247,
HRMS-ESI: m/z [M+H]+ calcd for C18H22NO: 268.1701;
found: 268.1709.
4.9.4.
(R)-2-[(3S,4R)-2-Methyl-4-phenylhex-5-en-3-yl-
amino]-2-phenylethanol 6d. Yellow oil; [a]D = ꢁ123 (c
0.5, CH2Cl2); 1H NMR (250 MHz, CDCl3): d 7.34 (m,
8H), 7.15 (dd, 2H, J = 1.8, 7.8 Hz), 5.96 (td, 1H, J = 9.9,
17.0 Hz), 5.09 (dm, 1H, J = 17.0 Hz), 5.06 (dm, 1H,
J = 10.0 Hz), 3.42 (t, 1H, J = 8.9 Hz), 3.35–3.24 (m, 3H),
2.68 (dd, 1H, J = 3.2, 8.2 Hz), 1.84 (hept d, 1H, J = 3.1,
6.9 Hz), 0.85 (d, 3H, J = 6.8 Hz), 0.66 (d, 3H,
J = 6.7 Hz); 13C NMR (62.5 MHz, CDCl3): d 143.6,
141.5, 139.9, 128.5, 128.3, 128.2, 127.7, 127.4, 126.5,
115.5, 66.7, 63.9, 63.2, 55.6, 29.7, 21.0, 15.9.
701 cmꢁ1
;
HRMS-ESI: m/z [M+H]+ calcd for
C25H26NO2: 372.1964; found: 372.1953.
4.9. General procedure for the preparation of amino
alcohol 6
To a mixture of phenylglycinol-derived imine (3 mmol),
zinc dust (0.49 g, 7.5 mmol), and CeCl3Æ7H2O (0.12 g,
0.5 mmol) in THF (15 mL), was added dropwise cinnamyl
or crotylbromide (7.5 mmol) at 0 ꢁC. The resulting mixture
was stirred for 2 h and quenched with water (15 mL). The
layers were separated and the aqueous layer extracted with
Et2O (3 · 10 mL). The organic layers were combined, dried
over Na2SO4, filtered and concentrated. The residue was
purified by column chromatography on silica gel using a
mixture of petroleum ether/AcOEt as solvent to give the
corresponding amino alcohol.
4.9.5.
(R)-2-[(1R,2R)-1-(Furan-2-yl)-2-phenylbut-3-enyl-
25
amino]-2-phenylethanol 6e. Yellow oil; ½aꢀD ¼ ꢁ15 (c 0.5,
1
CH2Cl2); H NMR (250 MHz, CDCl3): d 7.35–7.15 (m,
9H), 7.05 (d, 2H, J = 7.7 Hz), 6.14 (dd, 1H, J = 1.8,
3.1 Hz), 5.97 (ddd, 1H, J = 8.4, 10.4, 18.8 Hz), 5.91 (m,
1H), 5.00 (dm, 1H, J = 10.4 Hz), 4.97 (dm, 1H,
J = 18.8 Hz), 3.96 (d, 1H, J = 8.7 Hz), 3.74 (t, 1H,
J = 8.5 Hz), 3.58 (m, 2H), 3.35 (td, 1H, J = 3.6, 9.3 Hz),
1.99 (br s, 1H); 13C NMR (62.5 MHz, CDCl3): d 154.5,
141.8, 141.5, 141.3, 138.1, 128.7, 128.4, 128.2, 127.3,
127.0, 126.9, 117.0, 109.9, 108.2, 65.3, 62.4, 59.4, 55.2; IR
(film): mmax 3332, 3028, 1453, 1071, 756, 700 cmꢁ1
.
4.9.1. (R)-2-[(1R,2R)-2-Methyl-1-phenylbut-3-enylamino]-2-
25
phenylethanol 6a. Yellow oil; ½aꢀD ¼ ꢁ23 (c 1, CH2Cl2);
4.10. General procedure for the preparation of
pyrrolidinone 7
1H NMR (250 MHz, CDCl3): d 7.30–7.08 (m, 10H), 5.68
(ddd, 1H, J = 7.8, 10.3, 17.3 Hz), 5.04 (dm, 1H,
J = 10.3 Hz), 5.02 (dm, 1H, J = 17.3 Hz), 3.80–3.72 (m,
2H), 3.51 (dd, 1H, J = 7.5, 12.1 Hz), 2.61 (hex, 1H,
J = 6.8 Hz), 2.35 (br s, 2H), 0.96 (d, 3H, J = 6.9 Hz); 13C
NMR (62.5 MHz, CDCl3): d 141.5, 141.3, 140.3, 128.4,
128.0, 127.8, 127.3, 127.0, 126.9, 115.3, 65.0, 64.3, 60.8,
4.10.1. (R)-3-[(1R,2S)-2-Methyl-1-phenylbut-3-enyl]-4-phen-
yloxazolidin-2-one 7a. Obtained according to procedure
25
A. Yellow solid; mp 76 ꢁC; ½aꢀD ¼ ꢁ5:5 (c 1.4, CH2Cl2);
1H NMR (250 MHz, CDCl3): d 7.37 (m, 4H), 7.27 (m,
6H), 5.38 (ddd, 1H, J = 7.6, 10.2, 17.0 Hz), 4.77 (dm, 1H,

C. Denhez et al. / Tetrahedron: Asymmetry 18 (2007) 424–434
433
J = 17.0 Hz), 4.75 (dm, 1H, J = 10.2 Hz), 4.59 (dm, 1H,
J = 11.8 Hz), 4.42 (dd, 1H, J = 8.0, 8.9 Hz), 4.31 (dd,
1H, J = 7.2, 8.9 Hz), 4.11 (dd, 1H, J = 7.2, 8.0 Hz), 2.53
(qdd, 1H, J = 6.5, 7.6, 11.8 Hz), 1.14 (d, 3H, J = 6.5 Hz);
13C NMR (62.5 MHz, CDCl3): d 158.8, 140.6, 138.6,
137.2, 129.6, 129.1, 128.8, 128.2, 128.0, 127.9, 115.2, 70.1,
64.5, 59.8, 38.1, 18.3; IR (film): mmax 2975, 2927, 1748,
1400, 1222, 1059, 707 cmꢁ1; HRMS-ESI: m/z [M+Na]+
calcd for C20H21NO2Na: 330.1470; found: 330.1475.
was extracted with CH2Cl2 (3 · 10 mL). The organic layers
were combined, dried over Na2SO4, filtered, and concen-
trated under vacuum. The residue was dissolved in MeOH
(5 mL) then NaBH4 (35 mg, 0.9 mmol) was added in small
portions at 0 ꢁC. The reaction was stirred for 1 h at rt and
quenched by adding water (10 mL). The aqueous layer was
extracted with Et2O (3 · 15 mL), the organic layers were
combined, dried over Na2SO4, filtered, and concentrated
under vacuum, to give the expected amino alcohol, which
1
was used in the next step without purification: H NMR
4.10.2. (R)-3-[(2R,3R)-1-(Benzyloxy)-3-phenylpent-4-en-2-
yl]-4-phenyloxazolidin-2-one 7b. Obtained according to
(250 MHz, CDCl3): d 7.44–7.20 (m, 7H), 7.11 (dd, 2H,
J = 2.0, 6.7 Hz), 7.03 (dd, 2H, J = 2.0, 7.9 Hz), 6.33 (dd,
1H, J = 1.8, 3.1 Hz), 6.17 (d, J = 3.1 Hz, 1H), 5.84 (ddd,
1H, J = 8.1, 10.3, 17.0 Hz), 4.90 (dm, 1H, J = 10.3 Hz),
4.85 (dm, 1H, J = 17.0 Hz), 3.91 (d, 1H, J = 9.3 Hz), 3.77
(d, 1H, J = 8.4 Hz), 3.69 (d, 1H, J = 13.8 Hz), 3.42 (d,
1H, J = 13.8 Hz), 1.66 (br s, 2H). To a solution of the
crude amine and DMAP (12 mg, 0.1 mmol) in CH2Cl2
(3 mL) was added dropwise a solution of (Boc)2O
(275 mg, 1.25 mmol) in CH2Cl2 (2 mL) at rt. The reaction
mixture was then stirred for 4 h at rt. and quenched by
adding water (2 mL). The aqueous layer was extracted with
dichloromethane (3 · 5 mL), the organic layers were com-
bined, dried over Na2SO4, filtered, and concentrated under
vacuum. The residue was purified by column chromatogra-
25
1
procedure A. Yellow oil; ½aꢀD ¼ ꢁ102 (c 1.3, CH2Cl2); H
NMR (250 MHz, CDCl3): d 7.32 (m, 9H), 7.15 (m, 4H),
7.01 (d, 2H, J = 7.2 Hz), 5.85 (ddd, 1H, J = 7.8, 10.1,
16.9 Hz), 5.06 (dd, 1H, J = 1.3, 16.9 Hz), 4.98 (dd, 1H,
J = 1.3, 10.1 Hz), 4.47 (d, 1H, J = 11.5 Hz), 4.41 (d, 1H,
J = 11.5 Hz), 4.14 (m, 1H), 4.12 (t, 1H, J = 8.4 Hz), 3.81
(t, 1H, J = 8.5 Hz), 3.75–3.63 (m, 4H); 13C NMR d
158.6, 142.0, 138.9, 138.6, 137.7, 129.3, 128.8, 128.6,
128.4, 128.2, 127.6, 117.1, 73.5, 70.8, 69.5, 62.0, 58.3,
50.9; IR (film): mmax 3030, 2907, 2248, 1714, 1418,
1097 cmꢁ1
.
4.10.3. (3SR,4RS,5RS)-3-(1,2-Diphenylbut-3-enyl)oxazoli-
din-2-one 7c. Obtained according to procedure A. Color-
less oil; 1H NMR (250 MHz, CDCl3): d 7.52–7.12
(m, 10H), 5.78 (ddd, 1H, J = 7.3, 10.4, 17.1 Hz), 5.36 (d,
1H, J = 12.1 Hz), 4.93 (dm, 1H, J = 10.4 Hz), 4.88 (dm,
1H, J = 17.1 Hz), 4.14 (ddm, 1H, J = 7.3, 12.1 Hz), 3.98
(ddd, J = 5.1, 8.4, 9.2 Hz, 1H), 3.77 (q, 1H, J = 8.5 Hz),
3.34 (ddd, J = 5.1, 8.0, 9.0 Hz, 1H), 3.23 (dd, 1H,
J = 8.3, 17.4 Hz); 13C NMR (62.5 MHz, CDCl3): d 157.5,
140.0, 138.2, 136.8, 128.75, 128.70, 128.4, 128.1, 127.8,
127.0, 117.2, 77.0, 61.6, 59.7, 50.5, 40.4; IR (film): mmax
phy on silica gel using a mixture of petroleum ether/AcOEt
25
as eluant to give 7e. ½aꢀD ¼ þ62 (c 1.1, CH2Cl2); 4:1 mix-
ture of rotamers, major isomer 1H NMR (250 MHz,
CDCl3): d 1.06 (s, 9H), 4.03 (d, 1H, J = 16.1 Hz), 4.12
(dd, 1H, J = 11.6, 7.2 Hz), 4.34 (d, 1H, J = 16.1 Hz), 4.93
(br d, 1H, J = 10.9 Hz), 4.94 (br d, 1H, J = 16.5 Hz),
5.94–5.80 (m, 2H), 6.26 (br s, 1H), 6.37 (br s, 1H), 6.67
(m, 2H), 6.67 (br m, 2H), 7.29 (m, 7H); 13C NMR
(62.5 MHz, CDCl3): d 155.3, 152.7, 141.7, 140.3, 139.5,
138.6, 128.3 (2C), 127.6, 126.6, 126.3, 126.0, 116.4, 100.1,
109.1, 79.6, 55.6, 51.7, 47.6, 27.9; IR (film): mmax 2977,
1690, 1453, 1403, 1366, 1248, 1165 cmꢁ1; MS-ESI: m/z
[M+H]+: 404.
3031, 2976, 1750, 1458, 1401; 1223, 1059, 706 cmꢁ1
;
HRMS-ESI: m/z [M+H]+ calcd for C19H20NO2:
294.1494; found: 294.1500.
4.10.4. (R)-3-[(3S,4R)-2-Methyl-4-phenylhex-5-en-3-yl]-4-
phenyloxazolidin-2-one 7d. Obtained according to proce-
4.12. Preparation of pyrrolidinones 8
25
dure A. Yellow oil; mp 110 ꢁC; ½aꢀD ¼ ꢁ219 (c 1, CH2Cl2);
4.12.1. (3S,4S,5R)-1-[(R)-2-Hydroxy-1-phenylethyl]-3,4-di-
methyl-5-phenylpyrrolidin-2-one 8a. Obtained according
1H NMR (250 MHz, CDCl3): d 7.32 (m, 8H), 7.12 (m, 2H),
5.96 (ddd, 1H, J = 9.9, 10.0, 16.9 Hz), 5.16 (dm, 1H,
J = 16.9 Hz), 5.02 (dm, 1H, J = 10.0 Hz), 4.19 (t, 1H,
J = 10.1 Hz), 4.01 (dd, 1H, J = 8.0, 13.7 Hz), 3.94 (dd,
1H, J = 7.8, 13.7 Hz), 3.61 (dd, 1H, J = 7.8, 8.0 Hz), 3.15
(dd, 1H, J = 4.1, 10.8 Hz), 2.11 (m, 1H), 0.94 (d, 3H,
J = 7.0 Hz), 0.66 (d, 3H, J = 6.8 Hz); 13C NMR
(62.5 MHz, CDCl3): d 158.1, 142.6, 139.1, 137.8, 129.0,
128.7, 128.6, 128.4, 128.0, 126.8, 116.2, 69.3, 64.4, 63.2,
50.8, 30.6, 21.7, 19.4; HRMS-ESI: m/z [M+H]+ calcd for
C22H26NO2: 336.1964; found: 336.1971.
25
to procedure B. Yellow oil; ½aꢀD ¼ ꢁ38 (c 0.6, CH2Cl2);
1H NMR (250 MHz, CDCl3): d 7.30 (m, 6H), 7.12 (m,
4H), 5.41 (dd, 1H, J = 8.0, 6.4 Hz), 4.13 (d, 1H,
J = 8.3 Hz), 3.71 (m, 3H), 2.95 (br s, 1H), 2.41 (qd,
J = 6.9, 13.7 Hz, 1H), 2.07 (qdd, 1H, J = 6.9, 8.2,
11.7 Hz), 1.19 (d, 3H, J = 6.9 Hz), 0.54 (d, 3H,
J = 6.8 Hz); 13C NMR (62.5 MHz, CDCl3): d 178.6,
138.3, 136.3, 128.5, 128.4 (3C), 128.0, 127.9, 63.7, 62.95,
62.9, 58.7, 41.9, 41.6, 14.2, 13.7; IR (film): mmax 3438,
29.64, 1454, 1421, 701 cmꢁ1
.
4.11. tert-Butyl benzyl[(1R,2R)-1-(furan-2-yl)-2-phenylbut-
3-enyl]carbamate 7e
4.12.2. (3S,4R,5R)-5-(Benzyloxymethyl)-1-[(R)-2-hydroxy-
1-phenylethyl]-3-methyl-4-phenylpyrrolidin-2-one 8b. Ob-
25
tained according to procedure B. Yellow oil; ½aꢀD ¼ ꢁ60
1
To a solution of Pb(OAc)4 (540 mg,1.2 mmol) in MeOH
(5 mL) was added a solution of 6e (333 mg, 1 mmol) in
CH2Cl2 (5 mL) at 0 ꢁC and the resulting mixture was stir-
red for 1 h. CH2Cl2 (10 mL) was added followed by water
(10 mL). The layers were separated and the aqueous phase
(c 0.6, CH2Cl2); H NMR (250 MHz, CDCl3): d 7.31 (m,
11H), 7.20 (d, 2H, J = 6.9 Hz), 7.11 (d, 2H, J = 7.7 Hz),
5.08 (dd, 1H, J = 4.5, 7.9 Hz), 4.24 (dd, 1H, J = 6.8,
12.0 Hz), 4.19 (m, 1H), 4.12 (dd, 1H, J = 4.6, 12.0 Hz),
3.92 (d, 1H, J = 11.2 Hz), 3.86 (d, 1H, J = 11.2 Hz), 3.52

434
C. Denhez et al. / Tetrahedron: Asymmetry 18 (2007) 424–434
(dm, 1H, J = 7.3 Hz), 3.33–3.29 (m, 2H), 3.18 (dd, 1H,
J = 2.9, 10.4 Hz), 2.86 (d, 1H, J = 10.4 Hz), 1.19 (d, 3H,
J = 6.4 Hz); 13C NMR (62.5 MHz, CDCl3): d 178.8,
137.3, 137.1, 136.5, 128.6, 128.5, 128.4, 128.3, 127.8,
127.7, 127.7, 127.2, 73.1, 68.1, 64.0, 61.9, 60.7, 51.7, 39.8,
14.5; IR (film): mmax 3330, 1490, 1450, 1300, 1050,
References
1. (a) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435–446, and
references cited therein; (b) Daly, J. W.; Spende, T. F.. In
Alkaloids: Chemical and Biological Perspectives; Pelletier, S.
W., Ed.; Wiley: New York, 1986; Vol. 4, Chapter 1.
`
2. For review, see: Pichon, M.; Figadere, B. Tetrahedron:
705 cmꢁ1
.
Asymmetry 1996, 7, 927–964; (a) Davis, F. A.; Song, M.;
Augustine, A. J. Org. Chem. 2006, 71, 2779–2786; (b) Godet,
T.; Bonvin, Y.; Vincent, G.; Merle, D.; Thozet, A.; Ciufolini,
M. A. Org. Lett. 2004, 6, 3281–3284; (c) Raghavan, B.;
Johnson, R. L. J. Org. Chem. 2006, 71, 2151–2154; (d)
Felluga, F.; Pitacco, G.; Prodan, M.; Pricl, S.; Visintin, M.;
Valentin, E. Tetrahedron: Asymmetry 2001, 12, 3241–3249; (e)
Abdel, M.; Harris, B. D.; Maryanoff, C. A. Synlett 1994, 81–
83; (f) Freidinger, R. M.; Perlow, D. S.; Veber, D. F. J. Org.
Chem. 1982, 47, 104–109; (f) Serna, S.; Tellitu, I.; Dominguez,
E.; Moreno, I.; San Martin, R. Org. Lett. 2005, 7, 3073–3076.
4.12.3. 1-(2-Hydroxyethyl)-3-methyl-4,5-diphenylpyrrolidin-
2-one 8c. Obtained according to procedure B. Yellow oil;
1H NMR (250 MHz, CDCl3): d 7.10 (m, 6H), 6.75 (m, 4H),
4.86 (d, 1H, J = 8.2 Hz), 3.80 (m, 3H), 3.61 (dd, 1H,
J = 8.2, 11.7 Hz), 3.37 (br t, 1H J = 4.6 Hz), 3.14 (m,
1H), 2.96 (dd, 1H, J = 6.8, 11.4 Hz), 1.20 (d, 3H,
J = 6.9 Hz); 13C NMR (62.5 MHz, CDCl3): d 178.7,
136.3, 136.0, 128.3, 128.2, 128.0, 127.8, 127.1, 127.0, 67.2,
61.5, 53.8, 46.2, 38.8, 13.8.
´
3. (a) Pedrosa, R.; Andres, C.; Duque-Soladana, J. P.; Mend-
iguchia, P. Eur. J. Org. Chem. 2000, 3727–3730; (b) Bustos,
F.; Gorgojo, J. M.; Suero, R.; Aurrecoechea, J. M. Tetra-
hedron 2002, 58, 6837–6842; (c) Coldham, I.; Hufton, R.
Tetrahedron Lett. 1995, 36, 2157–2160; (d) Quancard, J.;
Labonne, A.; Jacquot, Y.; Chassaing, G.; Lavielle, S.;
Karoyan, P. J. Org. Chem. 2004, 69, 7940–7948; (e) Back,
T. G.; Parvez, M.; Zhai, H. J. Org. Chem. 2003, 68, 9389–
9393; (f) Bryans, J. S.; Chessum, N. E. A.; Parsons, A. F.;
Ghelfi, F. Tetrahedron Lett. 2001, 42, 2901–2905; (g) Zhu, G.;
Zhang, Z. J. Org. Chem. 2005, 70, 3339–3341.
4.12.4. (3S,4S,5R)-1-[(R)-2-Hydroxy-1-phenylethyl]-4-iso-
propyl-3-methyl-5-phenylpyrrolidin-2-one
8d. Obtained
according to procedure B. White solid; mp 150 ꢁC;
25
1
½aꢀD ¼ ꢁ75 (c 0.4, CH2Cl2); H NMR (250 MHz, CDCl3):
d 7.44–7.22 (m, 10H), 4.64 (dd, 1H, J = 4.1, 8.1 Hz), 4.37
(dt, 1H, J = 7.9, 11.3 Hz), 4.09 (td, 1H, J = 3.9, 15.1 Hz),
3.82 (dd, 1H, J = 4.1, 7.8 Hz), 3.65 (dd, 1H, J = 2.1,
8.4 Hz), 3.53 (dd, 1H, J = 8.4, 12.7 Hz), 3.26 (quint, 1H,
J = 6.6 Hz), 1.59 (m, 1H), 1.24 (d, 3H, J = 6.7 Hz), 0.67
(d, 3H, J = 7.2 Hz), 0.37 (d, 3H, J = 7.1 Hz); 13C NMR
(62.5 MHz, CDCl3): d 179.3, 137.8, 136.7, 128.5, 128.5,
128.1, 127.6, 127.1, 70.4, 65.3, 65.0, 52.5, 39.0, 30.5, 19.1,
17.7, 14.7; HRMS-ESI: m/z [M+H]+ calcd for
C22H28NO2: 338.2120; found: 338.2116.
4. (a) For reviews, see: Titanium and Zirconium in Organic
Synthesis; Marek, I., Ed.; Wiley-VCH: Weinheim, 2002; (b)
New Aspects of Zirconium Containing Organic Compounds;
Marek, I., Ed. Topics in Organometallic Chemistry; Springer:
Berlin, 2005; Vol. 10; (c) Metallocenes in Regio- and Stereo-
selective Synthesis; Takahashi, T., Ed.Topics in Organo-
metallic Chemistry; Springer: Berlin, 2005; Vol. 8, (d) Hunter,
R. A.; Macfarlane, D. P. S.; Whitby, R. J. Synlett 2006, 3314–
3318; (e) Owen, D. R.; Whitby, R. J. Synthesis 2003, 2061–
2074; (f) Mori, M.; Kuroda, S.; Zhang, C. S.; Sato, Y. J. Org.
Chem. 1997, 62, 3263–3270; (g) Uesaka, N.; Mori, M.;
Okamura, K.; Date, T. J. Org. Chem. 1994, 59, 4542–4547.
5. Vasse, J.-L.; Joosten, A.; Denhez, C.; Szymoniak, J. Org.
Lett. 2005, 7, 4887–4889.
4.12.5. (3S,4S,5R)-1-Benzyl-5-(2-furyl)-4-phenylpyrrolidin-
2-one 8e. Obtained and isolated according to procedure
B as a mixture 4.5/1 of diastereomers as a pale yellow
25
1
oil; ½aꢀD ¼ ꢁ216 (c 0.3, CH2Cl2); Main isomer: H NMR
(250 MHz, CDCl3): d 7.40–7.10 (m, 9H), 6.91 (dd, 2H,
J = 1.8, 7.2 Hz), 6.15 (dd, 1H, J = 1.6, 3.2 Hz), 5.92 (d,
1H, J = 3.2 Hz), 5.17 (d, 1H, J = 14.8 Hz), 4.55 (d, 1H,
J = 7.2 Hz), 3.63 (d, 1H, J = 14.8 Hz), 3.30–3.14 (m, 2H),
1.26 (d, 3H, J = 6.4 Hz); 13C NMR (62.5 MHz, CDCl3):
d 176.5, 149.9, 142.5, 136.5, 128.7, 128.3, 128.1, 127.9,
127.6, 127.1, 110.1, 109.7, 58.6, 52.6, 45.0, 39.5, 14.2, 1C
is missing; IR (film): mmax 2931, 1696, 1497, 1454, 1232,
755, 700 cmꢁ1; HRMS-ESI: m/z [M+H]+ calcd for
C12H22NO2: 332.1651; found: 332.1655.
6. (a) Ito, H.; Omodera, K.; Takigawa, Y.; Taguchi, T. Org.
Lett. 2002, 4, 1499–1501; (b) Takigawa, Y.; Ito, H.; Omodera,
K.; Ito, M.; Taguchi, T. Tetrahedron 2004, 60, 1385–1392.
7. Takigawa, Y.; Ito, H.; Omodera, K.; Koura, M.; Kai, Y.;
Yoshida, E.; Taguchi, T. Synthesis 2005, 2046–2054.
´ ´
´
8. (a) Dembele, Y. A.; Belaud, C.; Villerias, J. Tetrahedron:
Asymmetry 1992, 3, 511–514; (b) Benningshof, J. C.; Blaauw,
R. H.; Van Ginkel, A. E.; Van Maarseveen, J. H.; Rutles, F.
P. J. T.; Hiemstra, H. J. Chem. Soc., Perkin Trans. 1 2002, 14,
1693–1700.
9. (a) Wu, M.-J.; Pridgen, L. N. Synlett 1990, 636; (b) Wu,
M.-J.; Pridgen, L. N. J. Org. Chem. 1991, 56, 1340.
10. List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am.
Chem. Soc. 2002, 124, 827–833.
11. The cis stereochemistry was assigned after oxidative debenz-
ylation of compound 5f using CAN to afford cis-3.
12. (a) Lee, C.-L. K.; Ling, H. Y.; Loh, T.-P. J. Org. Chem. 2004,
69, 7787–7789; (b) Bazile, T.; Bocoum, A.; Savoia, D.;
Umani-Ronchi, A. J. Org. Chem. 1994, 59, 7766–7773.
Acknowledgment
`
We thank the CNRS and the Ministere de l’Education
Nationale for their financial support.