Regio- and diastereoselective synthesis of 5-trans-substituted and 5,5-disubstituted 2-pyrrolidinones derived from (S)-malic acid

Article abstract of DOI:10.1016/S0957-4166(02)00508-6

5-trans-Substituted 2-pyrrolidinones 6a, 6c and 6d and 5,5-disubstituted 2-pyrrolidinones 6e-k were regio- and diastereoselectively formed through the addition of organolithium species to imides 1a,b derived from malic acid, followed by addition of triethylsilane, allyltributyltin or TMSCN to the N-acyliminium ions formed in situ from the corresponding 5-hydroxy lactams. A short and diastereoselective synthesis of non-natural amino acid trans-4-hydroxy-D-proline is reported.

Full text of DOI:10.1016/S0957-4166(02)00508-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1973–1980
Regio- and diastereoselective synthesis of 5-trans-substituted and
5,5-disubstituted 2-pyrrolidinones derived from (S)-malic acid
Cristina M. Schuch and Ronaldo A. Pilli*
Instituto de Qu´ımica, UNICAMP, PO Box 6154, Campinas, SP 13083-970, Brazil
Received 11 April 2002; accepted 19 August 2002
Abstract—5-trans-Substituted 2-pyrrolidinones 6a, 6c and 6d and 5,5-disubstituted 2-pyrrolidinones 6e–k were regio- and
diastereoselectively formed through the addition of organolithium species to imides 1a,b derived from malic acid, followed by
addition of triethylsilane, allyltributyltin or TMSCN to the N-acyliminium ions formed in situ from the corresponding 5-hydroxy
lactams. A short and diastereoselective synthesis of non-natural amino acid trans-4-hydroxy-D-proline is reported. © 2002
Elsevier Science Ltd. All rights reserved.
1. Introduction
In contrast to the addition of organolithium reagents to
imides derived from tartaric acid which afforded the
corresponding a-hydroxy lactams,6 the addition of
organolithium species to chiral imides 1a and 1b led to
the isolation of a complex mixture of products. Fortu-
Construction of molecules with quaternary stereocen-
ters is a subject of ongoing interest1,2 and in the domain
of nitrogenated compounds few methods are available
to prepare compounds containing four different non-
hydrogen substituents at the a-nitrogen position of 5-
and 6-membered nitrogen heterocycles.3–5 Recently, we
reported on the formation of quaternary stereocenters
through the sequential addition of organolithium
reagents and allyltributyltin to the carbonyl group of
C2-symmetric imides derived from tartaric acid.6
nately, the utilization of n-butyllithium and methyl-
7,8
lithium in the presence of CeCl3
promoted the
smooth nucleophilic addition to imides 1a and 1b.
Surprisingly, the addition occurred mainly or exclu-
sively at C-5 as revealed after conversion of 5-hydroxy
lactams 2 and 3 to the corresponding lactams 6 and 7,
in contrast to the regiochemistry observed in the addi-
tion of Grignard reagents14 and in the reduction of the
corresponding imides derived from malic acid with
metallic hydrides where C-2 addition was observed.15
The formation of lactams 2a–c and 3a–c was achieved
when imides 1a,b were treated in THF at −78°C with
pre-formed organocerium species (prepared after treat-
ing a suspension of 2.6 equiv. of anhydrous CeCl3 in
THF with 2.0 equiv. of methylithium or n-butylithium
at −42°C), followed by another 2.0 equiv. of the
organolithium reagent (Scheme 1). Without the addi-
tion of an extra amount of the organolithium reagent
the addition of the organometallic species did not pro-
ceed. The addition of triethylsilane, allyltributyltin and
trimethylsilyl cyanide to the corresponding N-
acyliminium ions 4a–c and 5a–c formed in situ after
treatment of the corresponding 5-hydroxy lactams with
BF3·OEt2 resulted in the isolation of 5-trans-alkyl sub-
stituted 2-pyrrolidinones 6a and 6c and 5-alkyl-5-substi-
tuted 2-pyrrolidinones 6e–h as the major isomers (Table
1).
Herein, we report the results of the addition of methyl
and n-butyllithium, in the presence of CeCl3,7,8 and
a-alkoxymethyllithium reagents9,10 to imides 1a and 1b
derived from malic acid and the transformation of the
resulting 5-hydroxy quaternary lactams 2a–e and 3a–e
to 5-trans-substituted and 5,5-disubstituted 2-pyrrolidi-
nones (Scheme 1). Our results include a short and
diastereoselective synthesis of non-natural and amino
acid trans-4-hydroxy- -proline from imide 1a derived
D
from malic acid.11,12
2. Results and discussion
Imides 1a and 1b were readily obtained from (S)-malic
acid in 74 and 76% yields, respectively, after five steps.13
* Corresponding author. Fax: 55 19 37883023; e-mail: pilli@
iqm.unicamp.br
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00508-6

1974
C. M. Schuch, R. A. Pilli / Tetrahedron: Asymmetry 13 (2002) 1973–1980
The regiochemistry of the addition was determined
after the reduction of the mixture of hydroxy lactams
2a–c and 3a–c with triethylsilane/BF3·OEt2 and inspec-
tion of the corresponding homonuclear correlation
spectra (1H–1H COSY): a correlation between the
hydrogen at the newly formed stereogenic center in the
major regioisomer and the hydrogens at C-4 unambigu-
ously established the addition at C-5 carbonyl group.
benzyloxymethyllithium proceeded smoothly and with-
out the need for CeCl3 when DMPU was employed as
co-solvent affording a mixture of regioisomeric 5-
hydroxy lactams 2e and 3e in 80% yield and as a 3:1
mixture of regioisomers, as determined after their
reduction with triethylsilane/BF3·OEt2 to the corre-
sponding lactams 6d and 7b (Scheme 1). The major
regioisomer 6d (67% d.e.) was isolated after column
chromatography and its stereochemistry was estab-
1
The ratio of regioisomers formed was established by H
NMR and capilliary gas chromatography: a 2.7:1
regioisomeric ratio was assigned to the addition of
methyllithium/CeCl3 to 1a after reduction with triethyl-
silane/BF3·OEt2 of the corresponding 5-hydroxy lactam
(Table 1, entries 1, 5 and 6) while the exclusive forma-
tion of 2b and 2c was observed as a result of the
regioselective butyllithium/CeCl3 addition to the car-
bonyl group at C-5 of imides 1a and 1b (Table 1,
entries 2, 3, 7 and 8).
lished after its conversion to trans-4-hydroxy-D-proline
as discussed below. The addition of allyltributyltin and
TMSCN to N-acyliminium ions 4d–e and 5d–e led to
the isolation of compounds 6i–k and 7e–g as 3:1 mix-
tures of regioisomers. After separation by column chro-
matography, compounds 6i–k were obtained as single
diastereoisomers. Interestingly, compounds 6d, 7b and
6k, 7g were isolated as the deprotected primary alcohol
due to the loss of the PMB protecting group probably
by the action of Lewis acid species present in the
reaction medium. The stereochemistry of the major
product in each case is depicted in Table 1.
The addition of benzyloxymethyllithium16 and p-
methoxybenzyloxymethyllithium17 to imides 1a and 1b
was examined next. The reaction of 1a with p-methoxy-
Scheme 1. Reagents and conditions: (a) R1Li (R1=alkyl, 2.0 equiv.), CeCl3 (1.3 equiv.), THF, −78°C, 1 h or POCH2Li (P=PMB
or Bn) (3.0 equiv.), DMPU (8.7 equiv.), THF, −78°C, 1 h; (b) Et3SiH (4.0 equiv.) or allylSnBu3 (3.0 equiv.) or TMSCN (3.0
equiv.), BF3·OEt2 (2.0 equiv.), CH2Cl2, −78 to 0°C, 3 h.
Table 1. Addition of triethylsilane, allyltributyltin and TMSCN to 5-hydroxylactams 2a–e/3a–e
Entry
Major regioisomer
Minor regioisomer
Ratio 6:7
P
R1
R2
Yield (%)a
55
d.e. (%)b
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
6g
6h
6i
7a
–
–
7b
7c
7d
–
2.7:1
100:0
100:0
3:1
2.7:1
2.7:1
100:0
100:0
3:1
TBDMS
TBDMS
Bn
TBDMS
TBDMS
TBDMS
Bn
Me
H
H
H
H
Allyl
CN
Allyl
CN
40
–
\95
67
41
64
76
87
\95
\95
\95
c
nBu
nBu
CH2OH
Me
Me
nBu
nBu
CH2OBn Allyl
CH2OBn CN
CH2OH
–
51
63
53
50
55
52
64
55
68
–
Bn
9
10
11
7e
7f
7g
TBDMS
TBDMS
TBDMS
6j
6k
3:1
3:1
CN
a Yields (6+7, two steps) are reported after purification of the crude mixture by column chromatography on silica gel.
b Diastereoisomeric ratio of the major regioisomer determined by 1H NMR (300 MHz).
c Unsaturated lactam 8 isolated in 61% yield after column chromatography as a single stereoisomer (double bond configuration not determined).

C. M. Schuch, R. A. Pilli / Tetrahedron: Asymmetry 13 (2002) 1973–1980
1975
We were unable to isolate the product containing the
quaternary stereocenter from the addition of nucleo-
philes to N-acyliminium ion 4b (entry 2). Unsaturated
lactam 8 (61% yield) was isolated instead as a single
isomer (stereochemistry not determined) as the result of
elimination of the labile hydroxyl group of the tertiary
hydroxy lactam, under Lewis acid conditions (Scheme
2). Surprisingly, hydrogenation of 8 afforded lactam 9
(88% yield) as a single stereoisomer. The cis relation-
ship between the -OTBS group and the n-butyl side
signal while no increment was observed in the H-3
signal of 6b upon irradiation of H-5.
5,5-Disubstituted 2-pyrrolidinones 6e–k and 7c–g were
isolated in 50–68% combined yield from imides 1a or 1b
and 41–87% diastereoisomeric excess, except for 6i–k
(entries 9–11), which were isolated as single
diastereoisomers. NOE experiments (Fig. 1) carried out
with the major stereoisomer 6e and with the major and
minor isomers of 6f suggested the cis addition of the
nucleophile (allyltributyltin and TMSCN, respectively).
Additionally, the stereochemistry of the major product
6g was unambiguously assigned after its conversion to
the corresponding bicyclic derivative 10 (Scheme 3).
The same stereochemical outcome was assigned to the
major stereoisomers 6h–k by inference.
1
chain in 9 was established upon comparing its H and
13C NMR spectra with those of 6b, prepared from 6c
after hydrogenolysis and protection of the secondary
hydroxy group with TBDMSCl. NOESY experiments
carried out with 6b and 9 confirmed our assignment:
irradiation at H-5 in 9 led to 0.8% increment in the H-3
Scheme 2.
Figure 1. Some selected NOE correlations observed in 6f.
Scheme 3. Reagents and conditions: (a) i. O3/O2, MeOH, −78°C, 2 h; ii. DMS, rt, 12 h; (b) NaClO2, NaH2PO4, tert-BuOH,
2-methyl-2-butene, rt, 1 h; (c) Pd/C 10%, H2 (15 bar), AcOEt, rt, 5 h; (d) p-TsOH, toluene, reflux, 1.5 h (25% overall yield).

1976
C. M. Schuch, R. A. Pilli / Tetrahedron: Asymmetry 13 (2002) 1973–1980
phenyl ring would preferentially be positioned at the
opposite side of the 5-membered ring with respect to
the oxygenated substituent at C-3, thus directing the cis
approach of the nucleophile.24 Such a conformational
bias is related to the relay effect invoked by some
authors to explain the countersteric sense of addition
observed in the alkylation of 5- and 6-membered nitro-
gen heterocycles bearing a stereogenic center a to the
nitrogen atom.25–28
The sense of regiochemistry observed in the addition of
alkyllithium/CeCl3 and a-alkoxymethyllithium/DMPU
to imides 1a,b derived from malic acid was rather
surprising as it contrasts with the preferential addition
to the C-2 carbonyl observed in the addition of Grig-
nard reagents14 and in the reduction of the correspond-
ing imides derived from malic acid with metallic
hydrides.11,12,15 The need for CeCl3 in the reactions
involving methyllithium and n-butyllithium might be
associated with the higher basicity of these organo-
lithium reagents as compared to the corresponding
benzyloxymethyl and p-methoxybenzyloxymethyl spe-
cies. The use of organocerium reagents was pioneered
by Imamoto and co-workers.7 Their structure in solu-
tion is difficult to establish but it is recognized that they
are less basic than the corresponding organolithium or
Grignard reagents, adding with high 1,2-regioselectivity
to a,b-unsaturated carbonyl compounds.7,8,18 Addition-
ally, cerium(III) species can coordinate to Lewis basic
atoms and the coordination of the organocerium spe-
cies to the more sterically available and more electron-
rich C-5 carbonyl group accounts for the
regiochemistry observed (entries 2, 3 and 7, 8, Table 1).
3. Conclusion
The BF3·OEt2-promoted reduction of 5-hydroxy lac-
tams 2a–e and 3a–e, prepared by the regioselective
addition of alkyl lithium/CeCl3 or a-alkoxy
methylithium to imides 1a and 1b, occurred cis to the
3-protected alkoxy group to afford 5-trans-substituted
2-pyrrolidinones 6a–d and 7a–b with moderate to good
diastereoisomeric excess (44–67%), except for 6c where
a single regio- and diastereoisomer was formed (d.e.
>95%).
In a similar way, 5,5-disubstituted 2-pyrrolidinones 6e–
k, 7c–g were prepared in 50–68% yields after two steps
and 41–>95% diastereoisomeric excess employing allyl-
tributyltin and TMSCN as carbon nucleophiles. The
relative stereochemistry of the major pyrrolidinones
To rigorously establish the stereochemistry of 6d, we
carried out its conversion to the known non-natural
amino acid trans-4-hydroxy-D-proline, a useful precur-
sor of neuroexcitatory kainoid analogues, which is usu-
1
was assigned by H NMR spectroscopy (NOE studies)
ally obtained from the expensive cis-4-hydroxy-
D
-proline via Mitsunobu reaction.19,20 Reduction of the
and through the conversion of compound 6g to the
bicyclic derivative 10 and 6d to trans-4-hydroxy-D-pro-
carbonyl group with BH3·SMe2 led to the isolation of
prolinol derivative 11 in quantitative yield (Scheme 4),
which was submitted to Jones oxidation, followed by
the deprotection of the silyl ether and of the N-benzyl
groups. After chromatographic separation in Dowex
line, which was prepared in six steps and 33% overall
yield from the (S)-malic acid imide 1a.
In summary, we have disclosed the unusual stereochem-
ical outcome of the addition of methyl and n-
cationic exchange resin, trans-4-hydroxy-D-proline was
butylithium/CeCl3,
benzyloxymethyllithium
and
obtained in 52% overall yield ([h]D +42.5 (c 1.0, 1N
p-methoxybenzyloxymethyllithium to cyclic imides
derived from (S)-malic acid, which provides a stereose-
lective access to 3,5-disubstituted- and 3,5,5-trisubsti-
tuted pyrrolidine derivatives.
HCl); lit:21 [h]D −46.4 (c 1.0, 1N HCl) for trans-4-
hydroxy-L-proline).
We observed that the stereochemical course of the
addition of nucleophiles to 5-substituted N-
acyliminium ions derived from (S)-malic acid was pref-
erentially cis to the protected alkoxy group at the C3
stereogenic center. Seebach and Renaud22 have also
observed a similar stereochemical behavior in the syn-
4. Experimental
4.1. General
thesis of 2,4-cis-substituted pyrrolidines.23 Allylic A1,3
-
interactions involving the substituent a to the nitrogen
atom and the N-benzyl group may determine the pref-
erential conformation of the phenyl group in the inter-
mediate N-acyl iminium ion. In such a scenario the
All solvents and reagents were purchased from com-
mercial suppliers and used as received, unless otherwise
indicated. Imides 1a and 1b were synthesized from
(S)-(−)-malic acid, as indicated in Ref. 12, in 74 and
Scheme 4. Reagents and conditions: (a) BH3·SMe2, THF, rt, 3 h, quant.; (b) Jones’ reagent 2.6 M (2.0 equiv.), 0°C to rt, 1 h; (c)
40% HF/MeCN (1:9), 1 h; (d) H2, Pd(OH)2/C, MeOH, 1 h; Dowex 5W 8×200 (52%, four steps).

C. M. Schuch, R. A. Pilli / Tetrahedron: Asymmetry 13 (2002) 1973–1980
1977
76% overall yield, respectively. Commercial solutions of
nBuLi (2.5 M in hexane) and MeLi (1.0 M in ether)
were employed. Tetrahydrofuran (THF) and toluene
the imide, the reaction was quenched with NH4Cl (1.0
mL) and the mixture was allowed to stir for 10 min at
room temperature, when it was diluted with CHCl3 (10
mL), and washed with brine (5.0 mL). The organic
phase was dried over MgSO4, filtered, and the solvent
was removed under reduced pressure. Purification of
the resultant oil by column chromatography on silica
gel 230–400 mesh (27% EtOAc/hexane, v/v) afforded
the a-hydroxylactams 2d–e and 3d–e as colorless crys-
tals (0.70 mmol) in 78% yield, as a mixture of regio-
and diastereoisomers.
were
distilled
from
Na-benzophenone
ketyl.
Dichloromethane and 1,3-dimethyl-3,4,5,6-tetrahydro-
2-pyrimidinone (DMPU) were distilled from calcium
hydride. Cerium trichloride heptahydrate was dried
under reduced pressure (2 mm/Hg) at 120°C for 5 h
immediately before use. All reactions were performed
under a positive argon pressure. The normal processing
of organic extracts consisted of drying over MgSO4,
1
filtration and concentration in a rotary evaporator. H
and 13C NMR data were recorded in CDCl3 (except
where indicated otherwise) on Varian Gemini 300,
Bruker AC 300P (7.05 T) or Varian Inova (11.7 T).
Chemical shifts are reported in ppm (l relative to
4.2.3. BF3·OEt2-mediated reduction of a-hydroxy lac-
tams 2a–e with Et3SiH. To a solution of hydroxylac-
tams 2a–e/3a–e (0.35 mmol) in CH2Cl2 (3.5 mL), under
an argon atmosphere at −78°C, was added Et3SiH (0.20
mL, 1.4 mmol) followed by dropwise addition of
BF3·OEt2 (80 mL, 0.70 mmol). Stirring was continued
for 15 min at −78°C, followed by 3 h at 0°C. The
reaction was quenched with H2O (1.0 mL) and
extracted with CH2Cl2 (2×5.0 mL). The organic phase
was washed with brine (5.0 mL), dried over MgSO4,
and the solvent was removed under reduced pressure.
Purification by column chromatography on silica gel
(25–50% EtOAc/hexane, v/v) afforded pyrrolidinones
6a–d and 7a–b (Table 1).
1
(CH3)4Si for H and CDCl3 for 13C NMR. Coupling
constants J are reported in Hz. IR spectra were
obtained on Nicolet Impact 410 FT (film and KBr).
High resolution mass spectra (HRMS) were measured
on a VG Autospec-Micromass spectrometer. Chro-
matographic separations were performed using 70–230
or 230–400 mesh (E. Merck) silica gel. Thin-layer chro-
matography was carried out on Macherey–Nagel pre-
coated silica plates (0.25 mm layer thickness). GC
analyses were performed with
a HP-5890 chro-
matograph with a HP-5 (30 m×0.53 mm×1.3 mm)
column. Optical rotation measures were measured with
a Polamat A polarimeter.
4.2.3.1. (3S,5S)-3-[(tert-Butyldimethylsilyl)oxy]-1-ben-
zyl-5-methyl-2-pyrrolidinone, 6a. Colorless oil; 55%
yield as a 2.7:1 mixture of regioisomers 6a (40% d.e.)
and 7a (d.e. not determined). Data for the major isomer
4.2. Synthesis of 5-trans-substituted and 5,5-disubsti-
tuted 2-pyrrolidinones
1
6a: H NMR (300 MHz): l 0.20 (s, 3H); 0.22 (s, 3H);
0.95 (s, 9H); 1.15 (d, J=6.2, 3H); 1.90 (ddd, J=4.4, 7.0
and 13.0, 1H); 2.06 (ddd, J=5.5, 7.0 and 13.0, 1H);
3.59 (m, 1H); 3.98 (d, J=15.0, 1H); 4.43 (t, J=7.0,
1H); 4.99 (d, J=15.0, 1H); 7.29 (m, 5H). 13C NMR
(75.5 MHz): l −5.1, −4.5, 18.3, 19.3, 25.7, 37.7, 43.9,
49.6, 70.4, 127.4, 127.9, 128.6, 136.3, 173.4. IR (film,
cm−1): 3072, 3030, 2968, 2920, 1668, 1442. HRMS
C18H29NO2Si (M+, calcd): 319.19676 (M+, found):
319.19656.
4.2.1. General procedure for the addition of alkyllithium
to imides 1a and 1b in the presence of CeCl3: synthesis of
a-hydroxylactams 2a–c and 3a–c. Anhydrous CeCl3 (1.3
mmol) was cooled to room temperature under an argon
atmosphere, THF (2.0 mL) was added and the mixture
was maintained under sonication for 30 min to obtain a
homogeneous suspension which was cooled to −42°C.
A solution of the alkyllithium reagent (1.0 mmol) was
added and the color of the suspension immediately
changed to pale yellow. The mixture was vigorously
stirred for 40 min and cooled to −78°C. A solution of
imide 1a or 1b (0.50 mmol) in THF (1.0 mL) was added
dropwise followed by addition of the alkyllithium (1.0
mmol). After complete consumption of the imide (TLC
monitoring), the reaction was quenched with NH4Cl
(1.0 mL) and the mixture was allowed to stir 10 min at
rt, when it was diluted with CHCl3 (10 mL), and
washed with brine (5.0 mL). The organic phase was
dried over MgSO4, filtered, and the solvent was
removed under reduced pressure. The resultant oil was
employed in the next step without further purification.
4.2.3.2.
(3S,5S)-3-Benzyloxy-1-benzyl-5-n-butyl-2-
pyrrolidinone, 6c. Colorless oil, 51% yield (single
1
regioisomer and d.e. >95%). H NMR (300 MHz): l
0.85 (t, J=7.0, 3H); 1.19 (m, 4H); 1.64 (m, 2H); 1.98
(ddd, J=4.4; 7.7 and 13.2, 1H); 2.08 (ddd, J=5.6; 7.7
and 13.2, 1H); 3.48 (m, 1H); 3.95 (d, J=15.0, 1H); 4.21
(t, J=7.7, 1H); 4.77 (d, J=12.0, 1H); 5.02 (d, J=15.0,
1H); 5.04 (d, J=12.0, 1H); 7.31 (m, 10H). 13C NMR
(75.5 MHz): l 13.9, 22.5, 26.6, 32.3, 32.6, 44.0, 54.2,
72.0, 75.3, 127.5, 127.7, 127.9, 128.1, 128.4, 128.7,
136.1, 138.0, 172.9. IR (film, cm−1): 3077, 3030, 2940,
2864, 1695. HRMS C22H27NO2 (M+−C7H7, calcd):
246.14940 (M+−C7H7, found): 246.15358.
4.2.2. General procedure for the addition of a-
alkoxymethyllithium to imides 1a and 1b: synthesis of
a-hydroxylactams 2d–e. To a solution of p-methoxyben-
zyloxymethyllithium or benzyloxymethyllithium16 (2.7
mmol) at −78°C, under an argon atmosphere, was
added a solution of imide 1a or 1b (0.9 mmol) in THF
(2.0 mL) and DMPU (7.8 mmol). The mixture was
stirred at −78°C for 1 h. After complete consumption of
4.2.3.3.
(3S,5R)-3-[(tert-Butyldimethylsilyl)oxy]-1-
benzyl-5-hydroxymethyl-2-pyrrolidinone, 6d. Colorless
oil, 63% yield as a 3:1 mixture of regioisomers 6d (67%
d.e.)and 7b (d.e. not determined). Major isomer 6d was
isolated by column chromatography on silica gel (40%
EtOAc/hexane, v/v). 1H NMR (300 MHz, C6D6): l
0.41 (s, 3H); 0.52 (s, 3H); 1.17 (s, 9H); 1.85 (m, 1H);
2.29 (m, 1H); 3.12 (m, 3H); 3.65 (dd, J=2.2 and 12.1,

1978
C. M. Schuch, R. A. Pilli / Tetrahedron: Asymmetry 13 (2002) 1973–1980
1H); 4.03 (d, J=15.0, 1H); 4.88 (t, J=7.7, 1H); 5.20 (d,
J=15.0, 1H); 7.19 (m, 5H). 13C NMR (125.7 MHz): l
−5.1, −4.5, 18.3, 25.8, 33.2, 44.8, 55.9, 61.7, 70.5, 127.7;
128.0; 128.8; 136.3; 174.8. IR (film, cm−1): 3408 (broad),
3030, 2960, 2929, 2856, 1693. HRMS C18H29NO3Si
(M+−C4H9, calcd): 278.12125 (found, M+−C4H9):
278.12122. [h]D −143.6 (c 3.6, EtOAc).
4H); 1.49 (m, 1H); 1.78 (m, 1H); 2.56 (dd, J=7.3 and
14.2, 1H); 2.73 (m, 2H); 2.90 (dd, J=7.8 and 16.8, 1H);
4.18 (t, J=7.3, 1H); 4.37 (d, J=15.4, 1H); 4.64 (d,
J=11.7, 1H); 4.82 (d, J=11.7, 1H); 4.85 (d, J=15.4,
1H); 5.19 (dd, J=1.5 and 17.1, 1H); 5.22 (d, J=10.2,
1H); 6.00 (m, 1H); 7.40 (m, 10H). 13C NMR (75.5
MHz): l 13.8, 22.9, 25.6, 36.9, 38.2, 38.3, 43.5, 69.7,
71.5, 77.0, 119.0, 127.1, 127.5, 127.8, 128.0, 128.3,
128.4, 133.7, 137.6, 138.4; 173.2. IR (film, cm−1): 3064,
3030, 2954, 2870, 1693. HRMS C25H31NO2 (M++1,
calcd): 378.24330 (M++1, found): 378.24335.
4.2.4. General procedure for the synthesis of 5,5-disubsti-
tuted pyrrolidinones 6e–k and 7c–g. To a solution of
a-hydroxylactam 2a–e and 3a–e (0.50 mmol) in CH2Cl2
(5.0 mL), under an argon atmosphere at −78°C, was
added allyltributyltin (0.46 mL, 1.5 mmol) or TMSCN
(0.20 mL, 1.5 mmol) followed by BF3·OEt2 (0.13 mL,
1.0 mmol) dropwise. Stirring was continued for 15 min
at −78°C, followed by 3 h at 0°C. The reaction was
quenched with a 10% aq. KF solution (2.0 mL) and
allowed to stir for 1 h at room temperature. The
mixture was diluted with CH2Cl2 (10 mL) and washed
with brine (5.0 mL), dried over MgSO4, and the solvent
was removed under reduced pressure. Purification by
column chromatography on silica gel (30–50% EtOAc/
hexane, v/v) afforded 5,5-disubstituted pyrrolidinones
6e–k and 7c–g (Table 1).
4.2.4.4.
(3S,5S)-3-Benzyloxy-1-benzyl-5-cyano-5-n-
butyl-2-pyrrolidinone, 6h. Colorless oil, 52% yield as a
single regioisomer (87% d.e.). Data for the major iso-
1
mer 6h: H NMR (300 MHz): l 0.81 (t, J=7.0, 3H);
1.12–1.69 (m, 5H); 1.92 (m, 1H); 2.06 (dd, J=8.4 and
13.5, 1H); 2.75 (dd, J=8.1 and 13.5, 1H); 4.35 (dd,
J=8.1 and 8.4, 1H); 4.38 (d, J=15.4, 1H); 4.79 (d,
J=15.4, 1H); 4.83 (d, J=11.7, 1H); 5.11 (d, J=11.7,
1H); 7.40 (m, 10H). 13C NMR (75.5 MHz): l 13.5, 22.1,
25.5, 37.9, 37.9, 44.9, 58.9, 72.7, 73.3, 119.1, 127.9,
127.9, 128.0, 128.1, 128.5, 128.7, 136.2, 137.1, 173.1. IR
(film, cm−1): 3062, 3030, 2956, 2931, 2871, 1716. HRMS
C23H26N2O2 (M+−C7H7, calcd): 271.14465 (M+−C7H7,
found): 271.14462.
4.2.4.1.
(3S,5R)-3-[(tert-Butyldimethylsilyl)oxy]-1-
benzyl-5-allyl-5-methyl-2-pyrrolidinone, 6e. Colorless oil,
53% yield as a 2.7:1 mixture of regioisomers 6e (41%
d.e.) and 7c (d.e. not determined). Major isomer 6e was
isolated by column chromatography on silica gel (30%
4.2.4.5.
(3S,5R)-3-[(tert-Butyldimethylsilyl)oxy]-1-
6i.
benzyl-5-allyl-5-benzyloxymethyl-2-pyrrolidinone,
Colorless oil, 64% yield as a 3:1 mixture of regioisomers
6i (>95% d.e.) and 7e (d.e. not determined). Data for 6i:
1H NMR (300 MHz): l 0.07 (s, 3H); 0.10 (s, 3H); 0.85
(s, 9H); 1.25 (m, 2H) 2.25 (m, 2H); 2.95 (d, J=9.5, 1H);
3.09 (d, J=9.5, 1H); 3.92 (d, J=11.7, 1H); 4.03 (d,
J=11.7, 1H); 4.12 (d, J=15.4, 1H); 4.57 (t, J=8.1,
1H); 4.69 (d, J=15.4, 1H); 5.06 (m, 2H); 5.56 (m, 1H);
7.19 (m, 10H). 13C NMR (75.5 MHz): l −5.2, −4.6,
17.4, 25.8, 27.7, 38.9, 43.2, 63.2, 70.0, 72.7, 73.6, 119.7,
127.2, 127.6, 128.0, 128.1, 128.3, 128.4, 131.8, 137.9,
138.5, 175.1. IR (film, cm−1): 3064, 3030, 2954, 2930,
2856, 1699, 1651. HRMS C28H39NO3Si (M+−C4H9,
calcd): 408.19950; (found, M+−C4H9): 408.19944.
1
EtOAc/hexane, v/v). H NMR (500 MHz): l 0.18 (s,
3H); 0.22 (s, 3H); 0.95 (s, 9H); 1.01 (s, 3H); 1.97 (dd,
J=7.8 and 12.9, 1H); 2.01 (dd, J=6.8 and 12.9, 1H);
2.29 (m, 2H); 4.37 (d, J=15.4, 1H); 4.42 (dd, J=6.8
and 7.8, 1H); 4.52 (d, J=15.4, 1H); 5.07 (ddd, J=1.5;
2.0 and 17.2, 1H); 5.10 (ddd, J=1.5; 2.0 and 10.1, 1H);
5.66 (m, 1H); 7.30 (m, 5H). 13C NMR (75.5 MHz): l
−5.1, −4.4, 18.3, 25.4, 25.8, 41.6, 43.1, 44.9, 60.7, 70.1,
119.2, 127.1, 127.9, 128.4, 132.7, 138.5, 173.7. IR (film,
cm−1): 3076, 3028, 2930, 2854, 1699. HRMS
C21H33NO2Si (M+−C4H9, calcd): 302.15763 (M+−C4H9,
found): 302.15765. [h]D −25.9 (c 1.5, CHCl3).
4.2.4.2. (3S,5S)-3-[(tert-Butyldimethylsilyl)oxy]-1-ben-
zyl-5-cyano-5-methyl-2-pyrrolidinone, 6f. Colorless solid,
50% yield as a 2.7:1 mixture of regioisomers 6f (64%
d.e.) and 7d (d.e. not determined). Major isomer 6f was
isolated by column chromatography on silica gel (40%
EtOAc/hexane, v/v). Mp 70–71°C. 1H NMR (500
MHz): l 0.11 (s, 3H); 0.15 (s, 3H); 0.85 (s, 9H); 1.43 (s,
3H); 1.92 (dd, J=8.3 and 12.9, 1H); 2.74 (dd, J=7.8
and 12.9, 1H); 4.30 (d, J=15.4, 1H); 4.43 (dd, J=7.8
and 8.3, 1H); 4.67 (d, J=15.4, 1H); 7.24 (m, 5H). 13C
NMR (75.5 MHz): l −5.5, −5.3, 18.2, 25.6, 26.1, 43.0,
44.7, 54.3, 69.1, 119.6, 127.9, 128.1, 128.7, 136.3, 173.3.
IR (film, cm−1): 3032, 2929, 2856, 2233, 1716. HRMS
C19H28N2O2Si (M+−C4H9, calcd): 287.12158 (M+−C4H9,
found): 287.12152. [h]D −51.1 (c 1.8, CH2Cl2).
4.2.4.6. (3S,5S)-3-[(tert-Butyldimethylsilyl)oxy]-1-ben-
zyl-5-cyano-5-benzyloxymethyl-2-pyrrolidinone, 6j. Col-
orless oil, 55% yield as a 3:1 mixture of regioisomers 6j
(>95% d.e.) and 7f (d.e. not determined). Data for 6j:
1H NMR (300 MHz): l 0.20 (s, 3H); 0.23 (s, 3H); 0.94
(s, 9H); 2.21 (dd, J=7.7 and 13.2, 1H); 2.72 (dd, J=7.7
and 13.2, 1H); 3.43 (s, 2H); 4.29 (d, J=12.1, 1H); 4.32
(d, J=12.1, 1H); 4.40 (d, J=15.4, 1H); 4.52 (t, J=7.7,
1H); 4.81 (d, J=15.4, 1H); 7.29 (m, 10H). 13C NMR
(75.5 MHz): l −5.2, −4.5, 18.2, 25.7, 38.2, 45.5, 58.5,
68.8, 72.1, 73.5, 118.1, 127.8, 127.9, 128.1, 128.5, 128.5,
128.5, 136.4, 136.4, 173.6. IR (film, cm−1): 3061, 3031,
2952, 2927, 2856, 1724. HRMS C26H34N2O3Si (M+−
C4H9, calcd): 393.16345; found (M+−C4H9): 393.16344.
4.2.4.7. (3S,5S)-3-[(tert-Butyldimethylsilyl)oxy]-1-ben-
zyl-5-cyano-5-hydroxymethyl-2-pyrrolidinone, 6k. Color-
less oil, 68% yield as a 3:1 mixture of regioisomers 6k
(>95% d.e.) and 7g (d.e. not determined). Data for 6k:
1H NMR (300 MHz): l 0.20 (s, 3H); 0.23 (s, 3H); 0.94
4.2.4.3.
(3S,5R)-3-Benzyloxy-1-benzyl-5-allyl-5-n-
butyl-2-pyrrolidinone, 6g. Colorless oil, 55% yield, single
regioisomer (76% d.e.). Data for the major isomer 6g:
1H NMR (300 MHz): l 0.90 (t, J=7.1, 3H); 1.11 (m,

C. M. Schuch, R. A. Pilli / Tetrahedron: Asymmetry 13 (2002) 1973–1980
1979
(s, 9H); 1.71 (t, J=7.0, 1H); 2.31 (dd, J=7.7 and 13.5,
1H); 2.67 (dd, J=7.7 and 13.5, 1H); 3.56 (dd, J=7.0
and 12.1, 1H); 3.70 (dd, J=5.9 and 12.1, 1H); 4.20 (d,
J=15.4, 1H); 4.52 (t, J=7.7, 1H); 4.99 (d, J=15.4,
1H); 7.35 (m, 5H). 13C NMR (75.5 MHz): l −5.2, −4.5,
18.2, 25.7, 37.0, 45.3, 60.1, 64.3, 68.7, 117.8, 128.0,
128.4, 129.2, 136.4, 173.8. IR (film, cm−1): 3419 (broad);
2954, 2931, 2856, 1714. HRMS C19H28N2O3Si (M+−
C4H9, calcd): 303.11649 (found, M+−C4H9): 303.11641.
organic phase was dried over MgSO4 and the solvent
was evaporated under reduced pressure. The crude oil
was dissolved in 2.0 mL of EtOAc, 25 mg of 10% Pd/C
was added and a hydrogen atmosphere (15 bar) was
admitted into the system, maintaining the mixture
under magnetic stirring at room temperature for 5 h.
The crude mixture was filtered on Celite™ and the
solvent was evaporated under reduced pressure. The
crude oil was dissolved in toluene (2.0 mL), transferred
to a sealed flask and 5.0 mg of p-toluenesulphonic acid
was added. The flask was heated to 110°C for 1.5 h.
The mixture was cooled to rt and the solvent was
removed under reduced pressure. Purification of the
crude oil by column chromatography on silica gel (50%
EtOAc/hexane, v/v) afforded bicyclic compound 10 as a
4.2.4.8. (S)-5-Butyliden-3-[-(tert-butyldimethylsilyl)-
oxy]-1-benzyl-2-pyrrolidinone, 8. Colorless oil, 61%
1
yield. H NMR (300 MHz): l 0.12 (s, 3H), 0.13 (s, 3H),
0.73 (t, J=7.3, 3H), 0.87 (s, 9H), 1.22 (dd, J=7.3 and
14.6, 2H), 1.84 (dd, J=7.3 and 14.6, 2H), 2.41 (ddt,
J=1.2, 5.9 and 16.1, 1H), 2.94 (dd, J=8.8 and 16.1,
1H), 4.43 (dd, J=5.9 and 8.8, 1H), 4.54 (d, J=15.4,
1H), 4.56 (m, 1H), 4.61 (d, J=15.4, 1H), 7.13–7.24 (m,
5H). 13C NMR (75.5 MHz): l −5.1, −4.8, 13.5, 18.3,
23.2, 25.8, 28.8, 32.8, 43.7, 69.3, 103.0, 115.0, 127.2,
128.5, 136.1, 174.1. IR (film, cm−1): 2960, 2929, 2856,
1714, 1682. HRMS C21H33NO2Si (M+−C4H9, calcd):
302.15763 (found, M+−C4H9): 302.15759.
1
colorless oil (11 mg) in 25% overall yield. H NMR
(500 MHz): l 0.75 (t, J=7.0, 3H); 0.98 (m, 4H); 1.57
(m, 1H); 1.77 (m, 1H); 2.33 (d, J=18.3, 1H); 2.55 (d,
J=18.3, 1H); 2.73 (dd, J=2.5 and 4.8, 2H); 4.19 (d,
J=15.4, 1H); 4.61 (d, J=15.4, 1H); 4.71 (dd, J=2.5
and 4.8, 1H); 7.23 (m, 5H). 13C NMR (125.5 MHz): l
13.7, 22.5, 25.7, 35.7, 36.9, 38.5, 43.5, 70.1, 80.1, 127.8,
128.0, 128.8, 136.9, 171.8, 173.3. IR (film, cm−1): 2956,
2929, 2872, 1788, 1699. HRMS C17H21NO3 (M+, calcd):
287.15214 (found, M+): 287.15266. [h]D +33.3 (c 0.2,
CHCl3).
4.3. Synthesis of (3S,5R)-3-[tert-butyldimethylsilyl)-
oxy]-1-benzyl-5-n-butyl-2-pyrrolidinone, 9
To a solution of 8 (0.050 g, 0.10 mmol) in ethyl acetate
(2.0 mL) was added 10% Pd/C (10 mg) and the mixture
was stirred under hydrogen (1 atm) for 3 h at rt. The
mixture was filtered over a pad of Celite, the solvent
was removed under reduced pressure and the crude
product was purified by column chromatography to
afford 9 (0.040 g, 0.088 mmol) in 88% yield. Colorless
4.5. Synthesis of trans-4-hydroxy-D-proline
To a solution of 6d (35 mg, 0.10 mmol) in THF (1 mL)
under an argon atmosphere at 0°C, was added dropwise
a solution of BH3·SMe2 complex (10 M, 0.1 mL, 1.0
mmol). The mixture was stirred at rt for 3 h, MeOH
(0.50 mL) was added and the mixture was stirred for 10
min. The solvent was removed under reduced pressure
and then treatment with methanol was repeated twice.
Purification of the crude oil by column chromatogra-
phy on silica gel (8% EtOAc/hexane, v/v) afforded
(2R,4S) - 4 - [(tert - butyldimethylsilyl)oxy] - 2 - hydroxy-
methyl-1-benzyl-pyrrolidine, 11 as a colorless oil (33
1
oil. H NMR (300 MHz): l 0.17 (s, 3H), 0.20 (s, 3H),
0.86 (t, J=7.1, 3H), 0.93 (s, 9H), 1.24 (m, 4H), 1.59 (m,
1H), 1.78 (m, 2H), 2.48 (m, 1H), 3.25 (m, 1H), 4.00 (d,
J=14.9, 1H), 4.31 (t, J=8.0, 1H), 4.97 (d, J=14.9,
1H), 7.30 (m, 5H). 13C NMR (75.5 MHz): l −5.1, −4.5,
13.9, 18.3, 22.6, 25.8, 26.5, 32.8, 35.2, 44.1, 53.3, 70.8,
127.4, 128.0, 128.6, 136.7, 173.8. IR (film, cm−1): 3030,
2966, 2929, 2856, 1705, 1252. HRMS C21H35NO2Si
(M+−C4H9, calcd): 304.17328 (found, M+−C4H9):
304.17303.
1
mg, 98%). H NMR (300 MHz, C6D6): l −0.02 (s, 3H);
−0.01 (s, 3H); 0.91 (s, 9H); 1.58 (m, 1H) 2.20 (s, br,
1H); 2.60 (m, 1H); 2.87 (dd, J=5.6 and 11.0, 1H); 3.27
(m, 1H); 3.42 (dd, J=6.1 and 11.0, 1H); 3.84 (dd,
J=2.9 and 12.7, 1H); 3.97 (dd, J=6.1 and 12.7, 1H);
4.13 (s, 2H); 4.61 (m, 1H); 7.23 (m, 5H). 13C NMR
(125.7 MHz): l −5.3, −5.2, 17.7, 25.5, 35.4, 60.4, 65.3,
65.7, 67.8, 68.6, 127.7, 128.6, 133.0, 131.3. IR (film,
cm−1): 3501 (broad), 2952, 2924, 2859, 1471. HRMS
C18H31NO2Si (M+−C4H9, calcd): 321.21241 (found, M+
−C4H9): 321.21240.
4.4. Synthesis of (1S,5S)-5-n-butyl-6-benzyl-2-oxa-6-
azabicyclo-[3.2.1]octan-3,7-dione, 10
A solution of 6g (58 mg, 0.10 mmol, 76% d.e.) in
MeOH (3.0 mL) was treated with O3/O2 stream at
−78°C for 2 h. After argon purging, methyl sulfide (0.2
mL) was added to the colorless solution, stirred
overnight and evaporated to give an oil. The crude
mixture was diluted with tert-BuOH (0.40 mL) and 0.1
mL (0.10 mmol) of 2-methyl-2-butene was added at
0°C. A solution containing NaClO2 (35 mg, 0.40 mmol)
and NaH2PO4 (0.10 g, 0.80 mmol) in water (0.30 mL)
was added dropwise. The mixture was vigorously
stirred for 1 h at room temperature. After the total
consumption of the reagent, NaHSO3 (30 mg) was
added and the stirring was continued for 30 min.
Chloroform was added (3.0 mL) and the aqueous phase
was extracted three times with CHCl3 (2.0 mL). The
To a solution of 11 (50 mg, 0.20 mmol) in acetone (2.0
mL) at 0°C was added a solution of Jones reagent
dropwise (2.6 M, 0.20 mL, 0.40 mmol). The mixture
i
was vigorously stirred at rt for 1 h and then PrOH (0.5
mL) was added. Stirring was continued for 30 min, the
organic phase was separated and the aqueous phase
was extracted with dichloromethane (3×2.0 mL). The
organic phase was dried over MgSO4 and the solvent
was removed under reduced pressure. The crude residue
was dissolved in MeCN (1.0 mL) and five drops of a

1980
C. M. Schuch, R. A. Pilli / Tetrahedron: Asymmetry 13 (2002) 1973–1980
40% aqueous HF solution were added dropwise. The
mixture was stirred for 2 h at rt and the solvent was
removed under reduced pressure. The crude residue was
dissolved in MeOH (1.0 mL), 10% Pd(OH)2/C (5 mg)
was added, a hydrogen atmosphere (2 bar) was admit-
ted into the system and the mixture was stirred for 2 h
at room temperature. The solvent was removed under
reduced pressure and the amino acid was purified in
Dowex 50W×8 resin (200–400 mesh) employing a mix-
ture of H2O/MeOH/NH4OH (1:1:1, v/v/v) as eluent.
11. Bernardi, A.; Micheli, F.; Potenza, D.; Scolastico, C.;
Villa, R. Tetrahedron Lett. 1990, 31, 4949.
12. Koot, W. J.; Hiemstra, H.; Speckamp, W. N. J. Org.
Chem. 1992, 57, 1059.
13. Koot, W. J.; Ginkel, R.; Kranenburg, M.; Hiemstra, H.;
Louwrier, S.; Moolenaar, M. J.; Speckamp, W. N. Tetra-
hedron Lett. 1991, 32, 401.
14. Huang, P. Q.; Wang, S. L.; Ye, J. L.; Ruan, Y. P.;
Huang, Y. Q.; Zheng, H.; Gao, J. X. Tetrahedron 1998,
54, 12547.
15. Pilli, R. A.; Russowsky, D. J. Org. Chem. 1996, 61, 3187.
16. Still, W. C. J. Am. Chem. Soc. 1978, 100, 1481.
17. p-Methoxybenzyloxymethyllithium was prepared in a
similar way as described in Ref. 16.
18. Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima,
T.; Kamiya, Y. J. Am. Chem. Soc. 1989, 111, 4392.
19. Hudlicky, M. J. Fluorine Chem. 1993, 60, 193.
20. Lowe, G.; Vilaivan, J. J. Chem. Soc., Perkin Trans. 1
1997, 539.
21. Kurokawa, N.; Ohfune, Y. Tetrahedron 1993, 49, 6195.
22. Renaud, P.; Seebach, D. Helv. Chim. Acta 1986, 69, 1704.
23. Boto, A.; Herna´ndez, R.; Sua´rez, E. J. Org. Chem. 2000,
65, 4930.
24. Calculations of the relative energies of the anti and syn
conformers of N-acyliminium ions 4b and 4c (ab initio
3-21G, Gaussian 98W) revealed in both cases that the
anti conformation is 0.4–0.5 kcal mol−1 more stable than
the syn conformation and may be the origin of the
nucleophilic attack cis to the alkoxy substituent at C-3.
trans-4-Hydroxy-D-proline (11 mg, 52% overall yield,
1
four steps) as a white solid (mp >250°C, decomp.). H
NMR (D2O, 300 MHz): l 2.15 (ddd, J=4.4, 10.2 and
14.6, 1H); 2.43 (ddt, J=1.8, 8.0 and 14.6, 1H); 3.35 (d,
br, J=12.8, 1H); 3.47 (dd, J=3.7 and 12.8, 1H); 4.34
(dd, J=8.0 and 10.2, 1H); 4.67 (m, 1H). 13C NMR
(125.5 MHz): l 37.1, 52.6, 59.5, 69.7, 173.9. IR (film,
cm−1): 3224 (broad); 2808, 1732, 1402. [h]D +42.5 (c
1.00, 1N HCl); (lit.:21 [h]D −46.4, c 1.0; 1N HCl,
trans-4-hydroxy-
L
-proline).
Acknowledgements
The authors thank FINEP for financial support and
FAPESP and CNPq for fellowships.
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