The 5-exo-trig radical cyclization reaction under reductive and oxidative conditions in the synthesis of optically pure GABA derivatives

Article abstract of DOI:10.1016/j.tet.2004.09.053

Free radical precursors 4a and 4b were synthesized and treated under reductive or oxidative conditions to obtain the corresponding optically pure pyrrolidinones 5-8, which were subsequently transformed into corresponding optically pure GABA derivatives 9-11. When reductive radical conditions (4a→7 and 8) were used, a Ph_1-5 migration product 14 was obtained; presumably depending upon the specific conformation of the rotamer precursor and also 14 was found to be a kinetic product.

Full text of DOI:10.1016/j.tet.2004.09.053

Tetrahedron 60 (2004) 10809–10815
The 5-exo-trig radical cyclization reaction under reductive and
oxidative conditions in the synthesis of optically pure GABA
derivatives
*
Veronica Rodrıguez, Mario Sanchez, Leticia Quintero and Fernando Sartillo-Piscil
*
´
´
´
´ ´ ´ ´
Centro de Investigacion de la Facultad de Ciencias Quımicas, Benemerita Universidad Autonoma de Puebla, 14 Sur Esq. San Claudio,
´
San Manuel, 72570, Puebla Mexico
Received 17 July 2004; revised 16 September 2004; accepted 16 September 2004
Available online 2 October 2004
Abstract—Free radical precursors 4a and 4b were synthesized and treated under reductive or oxidative conditions to obtain the
corresponding optically pure pyrrolidinones 5–8, which were subsequently transformed into corresponding optically pure GABA derivatives
9–11. When reductive radical conditions (4a/7 and 8) were used, a Ph1–5 migration product 14 was obtained; presumably depending upon
the specific conformation of the rotamer precursor and also 14 was found to be a kinetic product.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
construction of the corresponding 4-substituted pyrrolidi-
nones (5–8). Then, by removing of the chiral auxiliary
followed by an aqueous hydrolysis, the corresponding
optically pure GABA derivatives b-substituted will be
obtained (9–12, Scheme 1).
g-Aminobutyric acid (GABA) is the most important
inhibitory neurotransmitter in the mammalian central
nervous system.1 The GABA derivatives have been subject
to further biological studies and they have showed an
extensive spectrum of biological activity.2 Some of the most
important GABA derivatives are Gabapentin (1),3
Vigabatrin (2),4 and Baclofen (3)5 which not only have
been introduced as anticonvulsant agents but recently have
shown to be a potential treatment for neurogenic pain6
(see Fig. 1).
2. Results and discussion
The synthesis of radical precursors 4a and 4b commences
with an allylation reaction of (S)-a-methylbenzylamine
followed by N-acylation reaction with bromoacetylbromide
to afford 4a. The exposure of 4a to potassium ethylxanthate
leads the formation of the radical precursor 4b (Scheme 2).
Additionally some derivatives of Gabapentin 1 (with alkyl
groups or sulfur atom into the cyclohexane ring framework)
have been synthesized and tested, and same biological
activity compared to Gabepentin itself has been observed.7
Thus, developing of novel synthetic routes for the synthesis
of the compounds above represents an active synthetic
challenge.
The 5-exo radical cyclization was achieved by dropwise
addition of tributyltin hydride and catalytic amounts of
AIBN to 4a in benzene at reflux when the separable
pyrrolidinones 7 (43%), 8 (38%) were obtained, and a
Ph1,5-migration product 14 (11%) was also obtained, and
very small amount of the reduction product (w3%, not
showed) was detected (see Scheme 3).
In this regard, this work describes a novel and accessible
route for the synthesis of optically pure GABA derivatives
b-substituted. The key of this work is the use of the (S)-a-
methylbenzylamine as chiral auxiliary,8 and the well-
studied 5-exo-trig radical cyclization9 as strategy for the
Keywords: 5-exo Radical cyclization; Reductive and oxidative conditions;
GABA derivatives; Ar1,5-migracion.
* Corresponding authors. Tel.: C52 2222 295500x7387; fax: C52 2222
454293 (F.S.-P.); e-mail: fsarpis@siu.buap.mx
Figure 1. Some GABA derivatives with pharmacological activity.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.09.053

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10810
Scheme 1. Synthetic strategy for the synthesis of optically pure GABA derivatives.
Although the Ar1–5-migration is a well recorded free radical
process (neophyl rearrangement),10 we believe that in this
particular case the slow rotation of the amide bond may
contribute to the rearrangement. By a simple inspection of
the 1H NMR spectra of 4a at room temperature, a pair of set
sharp peaks were observed, indicating the existence of a
mixture of E/Z rotamers in a ratio of 3:1, favoring to Z
rotamer11–13 (see Scheme 4).
In this sense, we found interesting to study the dynamic
nature of the Ph1–5-migration product. Thus, it was observed
by adding catalytic amounts of selenol (0.2 equiv as
diphenyl diselenide)14 that the yield of the Ph1–5 migration
product 14 was increased (from 11% with Bu3SnH to 18%
with PhSeH). On the other hand, by using a much poorer
hydrogen donor like tris(trimethyl)silyl silane (TTMSS), the
formation of 14 was inhibited. These results suggest a
thermodynamic and kinetic process in the C4D4E
equilibriums, in which 14 seems to be a kinetic product:
only a very fast hydrogen donor like selenol can be capable
to capture the radical E.15 On the other hand, in the presence
of the slow hydrogen donor there is not chance to capture
the short half-life time radical E, and the reaction course
goes back to the formation of the pyrrolidinones 7 and 8 (see
Scheme 6).16 It is important to mention that the ratio of the
pyrrolidinones was not changed by using different hydrogen
donor.
Geometrically speaking, the formation of pyrrolidinones 7
and 8 is achieved when the Z-4a rotamer is present and the
Ph1–5-migration product 14 when the E-4a rotamer is highly
populated or the rotation of the amide bond is quite slow. In
order to support this hypothesis, we synthesized the radical
precursor 15, expecting with the increment of the molecular
polarity (NH bond) a rapid rotation of the amide bond and
reducing the half-time of the E rotamer which presumably is
the responsible for the formation of the Ph1–5 migration
product 16 (see Scheme 5).
On the other hand, the 5-exo-radical cyclization for xanthate
4b under pseudo-catalytic oxidizing conditions afforded the
pyrrolidinones 5 and 6, (Scheme 7). This very well-known
chain radical process17 allows forming a carbon–sulfur bond
that eventually will afford to optically pure 3-mercapto-
methyl-g-aminoacids 9 and 10. As it was mentioned before,
the incorporation of the sulfur atom in the structure of
the GABA derivatives increase significantly the pharmaco-
logical activity.7
The 1H NMR spectra of the compound 15 at room
temperature did show a single set of sharp peaks, indicating
a single rotamer or a very rapid interconversion between
both rotamers E-15 and Z-15. Thus, treating to the radical
precursor 15 under the same conditions as 4a, the reduction
product 15 was only observed, and no even traces of the
Ph1–5 migration product 16 were detected.
Although 4b showed the same conformational behavior as
4a, no evidence for the formation of the Ph1–5-migration
Scheme 3. Synthesis of pyrrolidinones 7 and 8 by 5-exo trig radical
cyclization of 4a under reductive conditions.
Scheme 2. Synthesis of the radical precursors 4a and 4b.

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Scheme 4. Dependence of the free radical reaction course upon the conformation of the rotamers.
Scheme 5. Rapid equilibrium between E-15 and Z-15 rotamers.
Scheme 6. Dynamic nature of the Ph1,5-migration product.
product G was found. The reasonsfor the failure might be due
to the direct oxidation of the radical E by DLP into cationic
specie,18 which is transformed into byproducts like enamines
or its corresponding hydrolysis products; but unfortunately
none of them were observed or isolated. It might be also due
to the slow addition of the radical E to the thiocarbonyl of the
starting material 4b (propagation step), so the radical E can
not be trapped by xanthate group leading the equilibriums
toward the formation of the pyrrolidinones 5 and 6 only, this
supports the theory of only a very fast hydrogen donor like
selenol can be capable to capture the radical E.
Having the optically pure pyrrolidinones (5–8) in our hands,
the assignment of the absolute configuration at C4 was
carried out by simple chemical correlation. Birch debenzy-
lation of pyrrolidinone 8 afforded pyrrolidinone 18, which
was identical with the sample reported by Meyers and
Snyder,19 except the magnitude of the [a]D (observed
[a]DZK20.3 (c 1, CHCl3), reported by Meyers and Snyder
[a]DZK6.5 (c 0.26, CH2Cl2), see Scheme 8). The optical
purity of 18 was determined by HPLC analysis in a chiral
stationary phase of Chiralcel OD, hexane/2-propanol (93:7)
as eluent.
Scheme 7. Synthesis of pyrrolidinones 5 and 6 by 5-exo radical cyclization oxidative of 4a under oxidative conditions.

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10812
Scheme 8. Determination of the absolute stereochemistry at C4 for 8 and 6 by chemical correlation.
Confirmation of the absolute stereochemistry for xanthates
5 and 6 was achieved by reductive removal of the xanthate
group from 6 with tributyltin hydride and AIBN, (see
Scheme 6).
phenylethyl)pyrrolidin-2-ones 20 and 21. Then, a Birch
debenzylation-acid hydrolysis in one pot produced to the
optically pure (R) and (S)-4-amino-3-(mercaptomethyl)
butanoic acids R-9 and S-10, (see Scheme 9).
Finally, pyrrolidinones 7 and 8 were separately debenzy-
lated followed by an alkaline hydrolysis with NaOH
yielding the corresponding (R) and (S)-3-methyl-4-amino-
butyric acids R-11 and S-12.20 On the other hand,
pyrrolidinones 5 and 6 were separately hydrolyzed under
controlled conditions by adding aqueous NaOH to obtain
the corresponding (R) and (S)-4-(mercaptomethyl)-1-((S)-1-
3. Conclusion
A practical procedure for the synthesis of optically pure
GABA derivatives is reported. As the result of the use of
reductive free radical conditions in the 5-exo-trig cycliza-
tion reaction for the construction of the pyrrolidinones
Scheme 9. Synthesis of optically pure GABA derivatives.

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10813
framework, a Ph1–5-migration product was observed, which
presumably depends upon the conformation of the amide
rotamer precursor, and it also showed to be a kinetic
product. Besides, another use of the beneficial catalytic
effect of the selenol in the free radical reactions is reported,
in this case in the Ph1–5-migration reaction.
JZ6.8 Hz), 5.71 (m, 1H), 7.23 (m, 5H); 13C NMR
(100 MHz, CDCl3) d: 18.6, 26.6, 45.5, 56.5, 116.2, 126.4,
127.6, 128.5, 133.5, 139.7, 166.8; IR (CCl4) 3029
; Anal. Calcd for
C13H16BrNO: C, 55.33; H, 5.72. Found: C, 55.12; H, 5.81.
(CH]CH2), 1646 (C]O) cmK1
4.1.3. (S)-N-Allyl-2-ethylxanthate-N-(phenylethyl)aceta-
mide 4b. Radical precursor 4a (1.11 g, 3.93 mmol) was
treated with potassium ethylxanthate (0.95 g, 5.9 mmol) in
30 mL of acetone at 0 8C for 2 h. Evaporated under reduced
pressure, and the residue was purified by column chroma-
tography through silica gel (5:1, hexane/ethyl acetate) to
give 1.2 g (89%) of 4b as colorless oil; [a]DZK165.3 (c 1,
CHCl3); NMR data is reported as a mixture of E/Z rotamers:
1H NMR (400 MHz, CDCl3) d: 1.39 (t, 6H, JZ7.2 Hz), 1.51
(d, 3H, JZ7.2 Hz), 1.67 (d, 3H, JZ6.8 Hz), 3.49 (dd, 1H,
JZ15.2, 6.0 Hz), 3.71 (dd, 1H, JZ18.0, 5.2 Hz), 3.87 (dd,
1H, JZ18.0, 5.2 Hz), 4.02 (d, 1H, JZ16.0 Hz), 4.10 (dd,
1H, JZ15.2, 6.0 Hz), 4.12 (d, 1H, JZ16.0 Hz), 4.23 (q, 1H,
JZ15.6 Hz), 4.62 (q, 4H, JZ7.2 Hz), 4.98 (dd, 2H, JZ
11.2, 4.0 Hz), 5.13 (dd, 2H, JZ14.0, 2.4 Hz), 5.25 (q, 1H,
JZ7.2 Hz), 5.60 (m, 1H), 5.72 (m, 1H), 6.06 (q, 1H, JZ
7.2 Hz), 7.18–7.32 (m, 10H); 13C NMR (100 MHz, CDCl3)
d: 13.8, 16.5, 18.2, 40.0, 40.2, 46.0, 46.3, 51.9, 56.1, 70.3,
70.4, 116.3, 117.0, 126.5, 127.3, 127.3, 127.6, 128.2, 128.5,
134.0, 134.3, 139.9, 167.0, 213.7; IR (CCl4) 1667 (C]O),
1235 (C]S) cmK1; Anal. Calcd for C16H21NO2S2: C,
59.41; H, 6.54. Found: C, 59.53; H, 6.72.
4. Experimental
4.1. General
Instrumental NMR studies were carried out with Varian
mercury 400 and 300 instruments. Internal reference (TMS)
for 1H and 13C. Chemical shifts are stated in parts per
million. COSY, HSQC, and NOESY experiments have been
carried out in order to assign the 1H and 13C spectra
completely. High resolution Mass spectra (FABC ion mode)
were realized on a Jeol JMS-SX102A 10 KV and Elemental
Analysis at Service de Microanalyse I.C.S.N.-C.N.R.S.-
France. IR were carried out with a SHIMADZU FTIR-8400
instrument.
4.1.1. (S)-N-(1-Phenylethyl)prop-2-en-1-amine 13. To a
solution of (S)-(K)-a-methylbenzylamine (3 g, 24.7 mmol)
and sodium carbonate (3.14 g, 29.7 mmol) in 40 mL of dry
acetonitrile at 0 8C was allowed to react for 15 min before to
add allyl iodine (4.9 g, 29.7 mmol) dissolved in 5 mL of
acetonitrile. The reaction mixture was stirred for 4 h at room
temperature before add 30 mL of water, extracted with ethyl
acetate, dried with Na2SO4 and evaporated under reduced
pressure. The residue was purified by column chromato-
graphy (2:1, hexane/ethyl acetate) to give 2.85 g of 13
(72%) as a white solid. MpZ103–104 8C; [a]DZK62.3
(c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) d: 1.38 (d, 3H,
JZ6.4 Hz), 1.75 (b, 1H), 3.12 (m, 2H), 3.82 (q, 1H, JZ
6.4 Hz), 5.09 (d, 1H, JZ10 Hz), 5.15 (d, 1H, JZ17.2 Hz),
5.91 (m, 1H), 7.22–7.37 (m, 5H); 13C NMR (100 MHz,
CDCl3) d: 24.1, 49.9, 57.2, 115.2, 126.1, 126.4, 127.9,
136.5, 144.9. EI-MS m/z 161 (MC).
4.2. The 5-exo-radical cyclization under reductive
condition (Tin method)
(R) and (S)-4-Methyl-1-((S)-1-phenylethyl)pyrrolidin-2-
ones 7 and 8, and N-allyl-N-ethyl-2-phenylacetamide 14.
To a solution of 4a (0.2 g, 0.7 mmol) in 30 mL of benzene at
80 8C was added dropwise (in a period of 1 h) Bu3SnH
(0.21 g, 0.71 mmol) and AIBN (20 mg) dissolved in 30 mL
of benzene. The reaction mixture was allowed to stir for 2 h
before evaporating under reduced pressure. The residue was
purified by column chromatography through silica gel (only
hexanes until tin residues come out, then a system of 4:1,
hexane ethyl acetate is used) to give 60 mg of 7 (43%),
53 mg of 8 (38%), and 16 mg of 14 (12%) all as colorless
oils.
4.1.2. (S)-N-Allyl-2-bromo-N-(phenylethyl)acetamide
4a. To a solution of 13 (1 g, 6.2 mmol) and DMAP
(1.13 g, 9.24 mmol) in 30 mL of dry THF at 0 8C was
allowed to react for 15 min before to add bromoacetyl
bromide (1.5 g, 7.44 mmol) dissolved in 5 mL of dry THF.
The reaction mixture was warmed up to room temperature
and allowed to stir for 2 h before to add 20 mL of water,
extracted with ethyl acetate, dried with Na2SO4 and
evaporated under reduced pressure. The residue was
purified by column chromatography through silica gel
(5:1, hexane/ethyl acetate) to give 1.53 g (88%) of 13 as
colorless oil; [a]DZK157.5 (c 1.7, CHCl3); NMR data is
given separately for each rotamer: Z-4a 1H NMR (400 MHz,
CDCl3) d: 1.50 (d, 3H, JZ7.2 Hz), 3.64 (dd, 1H, JZ18.0,
4.8 Hz), 3.82 (dd, 1H, JZ18.0, 4.8 Hz), 3.84 (d, 1H, JZ
10.8 Hz), 3.89 (d, 1H, JZ10.8 Hz), 5.01 (m, 2H), 5.60 (m,
1H), 6.00 (q, 1H, JZ7.2 Hz), 7.25 (m, 5H); 13C NMR
(100 MHz, CDCl3) d: 16.3, 27.2, 46.2, 51.6, 116.4, 127.2,
127.6, 128.3, 134.6, 139.8, 167.2; E-4a 1H NMR (400 MHz,
CDCl3) d: 1.67 (d, 3H, JZ6.8 Hz), 3.44 (dd, 1H, JZ16.0,
6.4 Hz), 3.89 (d, 1H, JZ10.0 Hz), 3.99 (d, 1H, JZ10.0 Hz),
4.05 (dd, 1H, JZ16.0, 5.2 Hz), 5.00 (m, 2H), 5.17 (q, 1H,
4.2.1. (R)-4-Methyl-1-((S)-1-phenylethyl)pyrrolidin-2-
1
one 7. [a]DZK93.3 (c 1, CHCl3); H NMR (400 MHz,
CDCl3) d: 0.96 (d, 3H, JZ7.2 Hz), 1.51 (d, 3H, JZ7.2 Hz),
2.02 (dd, 1H, JZ16.4, 6.4 Hz), 2.37 (m, 1H), 2.50 (dd, 1H,
JZ9.6, 5.6 Hz), 2.59 (dd, 1H, JZ16.8, 8.4 Hz), 3.41 (dd,
1H, JZ9.6, 7.6 Hz), 5.50 (q, 1H, JZ7.2 Hz), 7.29 (m, 5H);
13C NMR (100 MHz, CDCl3) d: 16.1, 19.6, 26.3, 39.7, 48.6,
49.3, 126.8, 127.1, 128.2, 139.8, 173.6; IR (CCl4) 1677
(C]O) cmK1; FABS m/z 204.1381 (MCH)C (Calcd for
C13H17NO2O4: 204.1389).
4.2.2. (S)-4-Methyl-1-((S)-1-phenylethyl)pyrrolidin-2-
1
one 8. [a]DZK120 (c 1, CHCl3); H NMR (400 MHz,
CDCl3) d: 1.08 (d, 3H. JZ6.8 Hz), 1.50 (d, 3H, JZ7.6 Hz),
2.10 (dd, 1H, JZ16.4, 7.2 Hz), 2.30 (m, 1H), 2.57 (dd, 1H,
JZ16.8, 8.8 Hz), 2.87 (dd, 1H, JZ9.2, 6.0 Hz), 3.01 (t, 1H,
JZ8.2 Hz), 5.48 (q, 1H, JZ7.2 Hz), 7.29 (m, 5H); 13C
NMR (100 MHz, CDCl3) d: 16.1, 19.5, 26.5, 39.7, 48.6,

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10814
49.5, 126.7, 127.1, 128.2, 139.9, 173.6; IR (CCl4) 1681
(C]O) cmK1; FABS m/z 204.1383 (MCH)C (Calcd for
C13H17NO: 204.1389).
d: 1.13 (d, 3H, JZ6.4 Hz), 1.95 (dd, 1H, JZ16.8, 7.2 Hz),
2.45(dd, 1H, JZ16.4, 8.8 Hz), 2.53(m, 1H), 2.96(dd, 1H, JZ
9.6, 6.0 Hz), 3.51 (ddd, 1H, JZ8.4, 8.0, 1.2 Hz), 4.25 (b, 1H);
13C NMR (100 MHz, CDCl3) d: 19.6, 29.4, 38.5, 49.6, 178.5.
(R)-4-Methylpyrrolidin-2-one 19 was obtained analogously
to 18 (65%); [a]DZC18.1 (c 1 CHCl3).
4.2.3. N-Allyl-N-ethyl-2-phenylacetamide 14. NMR data
is reported as a mixture of E/Z rotamers: 1H NMR
(400 MHz, CDCl3) d: 1.08 (t, 3H, JZ7.2 Hz), 1.12 (t, 3H,
JZ7.2 Hz), 3.31 (q, 2H, JZ7.2 Hz), 3.40 (q, 2H, JZ
7.2 Hz), 3.67 (s, 3H), 3.73 (s, 3H), 3.86 (dt, 2H, JZ4.8,
2.0 Hz), (d, 2H, JZ6.0 Hz), 5.06–5.22 (m, 4H), 5.72 (m,
2H), 7.27 (m, 10H); 13C NMR (100 MHz, CDCl3) d: 12.6,
13.8, 40.7, 40.8, 42.0, 47.4, 50.0, 116.6, 116.8, 126.6, 126.7,
128.2, 128.6, 128.7, 133.2, 133.5, 135.2, 170.3, 170.7; Anal.
Calcd for C11H15N: C, 81.94; H, 9.38. Found: C, 82.12;
H, 9.24.
4.3.4. (R) and (S)-4-(Mercaptomethyl)-1-((S)-1-phenyl-
ethyl)pyrrolidin-2-ones 20 and 21. Controlled alkaline
hydrolysis: pyrrolidinone 5 (200 mg) were dissolved in
1 mL of ethanol and added 5 mL of an aqueous solution of
NaOH (8 N). The reaction mixture was allowed to stir for
4 h at room temperature, extracted with ethyl acetate, dried
with Na2SO4 and evaporated under reduced pressure; the
residue was purified by column chromatography through
silica gel (2:1, hexane/ethyl acetate) to give 20 (123 mg,
85%). (R)-4-(Mercaptomethyl)-1-((S)-1-phenylethyl)pyrro-
lidin-2-one 20; [a]DZK97.8 (c 1, CHCl3); 1H NMR
(400 MHz, CDCl3) d: 1.48 (d, 3H, JZ7.2 Hz), 2.17 (dd,
1H, JZ16.8, 6.0 Hz), 2.28–2.53 (m, 3H), 2.59 (dd, 1H, JZ
17.2, 8.4 Hz), 2.68 (dd, 1H, JZ10.4, 5.2 Hz), 3.43 (dd, 1H,
JZ10.0, 7.6 Hz), 5.45 (q, 1H, JZ7.2 Hz), 7.25 (m, 5H); 13C
NMR (100 MHz, CDCl3) d: 15.9, 28.4, 34.7, 37.0, 46.5,
48.7, 126.7, 127.2, 128.2, 139.4, 172.6; Anal. Calcd for
C13H17NOS: C, 60.34; H, 7.28. Found: C, 60.30; H, 7.30.
(S)-4-(Mercaptomethyl)-1-((S)-1-phenylethyl)pyrrolidin-2-
one 21 was obtained analogously to 20 (109 mg, 76%);
4.3. The 5-exo-radical cyclization under oxidative
conditions (Xanthate method)
(R) and (S)-4-(Methyl-ethoxythiocarbonil)1-((S)-1-phenyl-
ethyl)pyrrolidin-2-ones 5 and 6. A solution of 4b (0.2 g,
0.61 mmol) and DLP (0.08 g, 0.2 mmol) in 50 mL of
benzene was refluxed for 30 min, then, the reaction mixture
was evaporated under reduced pressure and the residue was
purified by preparative TLC on silica gel (4:1, hexane/ethyl
acetate) yielding 0.82 mg of 5 (41%), and 78 mg of 6 (39%).
1
[a]DZK172 (c 1.1, CHCl3); H NMR (400 MHz, CDCl3)
4.3.1. (R)-4-(methyl-ethoxythiocarbonil)1-((S)-1-phenyl-
1
d: 1.52 (dd, 3H, JZ7.2 Hz), 2.25 (dd, 1H, JZ16.4, 7.2 Hz),
2.39 (m, 1H), 2.60 (m, 3H), 3.12 (m, 2H), 5.51 (c, 1H, JZ
7.2 Hz), 7.30 (m, 5H); 13C NMR (100 MHz, CDCl3) d: 16.2,
28.8, 34.7, 37.2, 46.9, 48.9, 126.8, 127.3, 128.4, 173.0;
Anal. Calcd for C13H17NOS: C, 60.34; H, 7.28. Found: C,
59.98; H, 7.45.
ethyl)pyrrolidin-2-one 5. [a]DZK72.6 (c 1, CHCl3); H
NMR (400 MHz, CDCl3) d: 1.39 (t, 3H, JZ6.8 Hz), 1.51 (d,
3H, JZ7.2 Hz), 2.22 (dd, 1H, JZ16.4, 5.2 Hz), 2.70 (m,
3H), 2.99 (dd, 1H, JZ13.6, 6.8 Hz), 3.14 (dd, 1H, JZ13.8,
6.4 Hz), 3.46 (dd, 1H, JZ12.0, 9.6 Hz), 4.62 (q, 2H, JZ
6.8 Hz), 5.49 (q, 1H, JZ7.2 Hz), 7.26 (m, 5H); 13C NMR
(100 MHz, CDCl3) d: 13.7, 16.0, 30.8, 37.4, 39.6, 47.1,
48.9, 70.2, 127.0, 127.6, 128.6, 139.8, 172.7, 213.8; IR
4.3.5. (R) and (S)-4-Amino-3-(mercaptomethyl)butanoic
acids R-9 and S-10. Birch debenzylation–aqueous hydroly-
sis in one pot, general protocol: Pyrrolidinone 20 (0.230 g,
0.98 mmol) was debenzylated by using the classic Birch
method followed by acidic quenching with 10 mL of an
aqueous solution at10%, and allowed to stir for 30 min at
room temperature, reaction mixture is evaporated under
reduced pressure; residue is crystallized in ethanol to afford
(R)-4-Amino-3-(mercaptomethyl)butanoic acids R-9 as a
with powder (0.125 mg, 86%). MpZ142 8C; [a]DZC32.9
(c 1, CH3OH); 1H NMR (400 MHz, CD3OD) d: 2.22
(dd, 1H, JZ16.8, 5.2 Hz), 2.51 (dd, 1H, JZ17.2, 7.6 Hz),
2.85 (m, 3H), 3.18 (dd, 1H, JZ10.0, 4.4 Hz), 3.55 (dd, 1H,
JZ10.0 6.8 Hz); 13C NMR (100 MHz, CDCl3) d: 34.2, 36.0,
42.2, 47.2, 178.5; IR (KBr) 3226 (OH), 2810 (SH), 1679
(C]O) cmK1; Anal. Calcd for C5H11NO2S: C, 40.25;
H, 7.43. Found: C, 39.98; H, 7.56. (S)-4-Amino-3-
(mercaptomethyl)butanoic acid S-10 was obtained
analogously to R-9 (82%). MpZ142 8C; [a]DZK33.4
(c 1.02, CH3OH); IR (KBr) 3220 (OH), 2778 (SH), 1673
(CCl4) 1687, 1680 (C]O), 1217 (C]S), 1050 (C–S) cmK1
;
FABS m/z 324.1082 (MCH)C (Calcd for C16H21NO2S2:
324.1089).
4.3.2. (S)-4-(Methyl-ethoxythiocarbonil)1-((S)-1-phenyl-
ethyl)pyrrolidin-2-one 6. [a]DZK85.1 (c 1.3, CHCl3); 1H
NMR (400 MHz, CDCl3) d: 1.40 (t, 3H, JZ7.2 Hz), 1.51 (d,
3H, JZ6.8 Hz), 2.27 (dd, 1H, JZ19.6, 9.6 Hz), 2.61
(m, 2H), 3.0–3.35 (m, 4H), 4.62 (q, 2H, JZ7.2 Hz), 5.48
(q, 1H, JZ6.8 Hz), 7.24 (m, 5H); 13C NMR (100 MHz,
CDCl3) d: 13.7, 16.1, 30.7, 37.3, 39.7, 47.0, 48.8, 70.1,
126.7, 127.2, 128.2, 139.5, 172.2, 213.2; IR (CCl4) 1683
(C]O), 1216 (C]S), 1050 (C–S) cmK1; FABS m/z
324.1082 (MCH)C (Calcd for C16H21NO2S2: 324.1089).
4.3.3. (S) and (R)-4-Methylpyrrolidin-2-ones 18 and 19.19
Birch debenzylation: A solution of 7 (0.140 g, 0.68 mmol) in
15 mL of dry THF was added to a deep blue solution of
Li (0.032 g, 4.5 mmol) in condensed NH3 (ca. 20 mL) at
K70 8C within 10 min. The reaction mixture was allowed to
stir for 1 h at K70 8C before to add NH4Cl (ca. 40 mg), then
neutralized with a diluted solution of HCl, extracted with ethyl
acetate, dried with Na2SO4 and evaporated under reduced
pressure. The residue was purified bycolumnchromatography
through silica gel (hexane/ethyl acetate, 1:1) afforded the
S-18 (45 mg, 67%). (S)-4-Methylpyrrolidin-2-one 18;
(C]O) cmK1
.
4.3.6. (S) and (R)-3-Methyl-4-aminobutyric acids 11 and
12.20 Alkaline hydrolysis: pyrrolidinone S-18 (80 mg,
0.8 mmol) is dissolved in 1 mL of methanol and added
5 mL of an aqueous solution of KOH (8 N). The reaction
mixture is refluxed for 5 h before to add an aqueous solution
of HCl (until get a pH 7), and evaporated under reduced
1
[a]DZK20.3 (c 1.2, CHCl3); H NMR (400 MHz, CDCl3)

´
V. Rodrıguez et al. / Tetrahedron 60 (2004) 10809–10815
10815
Chuang, Ch. -P. ; Lee, J. H.; Liu, S.-T. Tetrahedron 1999, 55,
2273–2288.
pressure, the residue was purified by preparative TLC on
silica gel (ethyl acetate/MeOH 4:1) yielding S-11 (79 mg,
85%); [a]DZC8.1 (c 1, CH3OH); H NMR (400 MHz,
CD3OD) d: 1.04 (d, 3H, JZ6.8 Hz), 2.18 (m, 1H), 2.30
(d, 2H, JZ7.0 Hz), 2.88 (m, 2H); 13C NMR (100 MHz,
CD3OD) d: 17.7, 29.6, 43.3, 45.5, 178.6; IR (KBr) 3431
(OH), 2840 (NHC3 ), 1557 (COOK) cmK1. (R)-3-Methyl-4-
aminobutyric acid 12 was obtained analogously to S-11
(83%); [a]DZK8.3 (c 1, CH3OH).
1
11. The geometry of the E/Z isomers for 4a was easily determined
by applying a computational calculation (Geometry optimiz-
ations for both rotamers were performed with the HF/6-
31G(d,p)12 method using GAUSSIAN 98. The frequencies
were calculated at the same level of theory to confirm that each
stationary point corresponds to a minimum. The optimized
structures at ab initio were used for obtaining energies at a
higher level of theory using the B3LYP/6-311G(d,p)13
method). Above calculation are in agreement with the 1H
NMR spectra, indicating an important intramolecular hydro-
gen bonding between the carbonyl group and Ha (this internal
hydrogen bonding is confirmed by theoretic calculation)
between Ha and carbonyl group in the Z conformation,
causing a downfield shift of almost 1 ppm in compare to the E
rotamer.
Acknowledgements
Financial support from CONACyT (grant number: 35102-
E) is gratefully acknowledged. V.R. Thanks CONACyT for
a graduate scholarship (grant number: 168916). F.S.P. also
´
thanks Benemerita Universidad Autonoma de Puebla
(BUAP) for a PROMEP professorship.
´
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