Full text of DOI:10.1016/S0040-4020(01)00549-X

TETRAHEDRON
Pergamon
Tetrahedron 57 /2001) 6579±6588
Synthesis of 4-alkyl-pyrrolidine-3-carboxylic acid stereoisomers
Rong Ling, I. Victor Ekhato, J. Ronald Rubin and David J. Wustrowp
Departments of Chemistry and Discovery Technologies, P®zer Global Research and Development, Ann Arbor Laboratories,
2800 Plymouth Road, Ann Arbor, MI 48105, USA
Received 20 February2001; revised 7 March 2001; accepted 28 March 2001
AbstractÐAll four possible stereoisomers of the 3-carboxyl-4-isopropyl-pyrrolidine /4) were prepared and their stereochemistrywas
assigned unambiguously. q 2001 Elsevier Science Ltd. All rights reserved.
Pregabalin /1) and gabapentin /2) are active in preclinical
models of epilepsy, and neuropathic pain.1±3 Both
compounds have high af®nityfor the a2d component of
voltage gated ion channels.4 Previous studies have found
that a b-pyrrolidine analog of gabapentin, compound 3, also
showed appreciable binding af®nityfor the a2d subunit
of calcium channels.5 In order to investigate the binding
properties of a series of constrained analogs of pregabalin,
stereocontrolled routes to the four possible stereoisomers of
pyrrolidines 4 were needed. In this paper we describe the
stereocontrolled synthesis and characterization of the four
possible stereoisomers of these 3-carboxy-4-isopropylpyrro-
lidines /Fig. 1).
thelin antagonists 5,6 PLG receptor agonists 6,7 and factor
Xa inhibitors such as 77 /Fig. 2).
The ®eld of enantioselective pyrrolidine synthesis has been
reviewed recently.8 Several strategies have emerged for
the stereocontrolled synthesis of 3-pyrroldine carboxylic
acids.9±15
A radical cyclization strategy has been used to prepare such
pyrrolidine rings as exempli®ed in Scheme 1.9 Cyclization
of the radical derived from phenyl selenide 9 gave pyrroli-
dines 10 with the phenyl and carboxylate groups in a trans
orientation. cis Stereochemistrypredominated across the 3±
4 positions of the pyrrolidine ring. This reaction is note-
worthyin that, it sets the relative stereochemistryof three
contiguous centers with good overall selectivity.
The development of stereoselective synthetic routes to
pyrrolidine 3-carboxylic acids is an important problem
because these compounds, also known as b-proline deriva-
tives, playan important role in medicinal chemistry. They
form the heterocyclic nucleus of a variety of biologically
active compounds. Some recent examples include endo-
Aspartic acid has been used recentlyas the source of chir-
ality for the synthesis of 4-benzyl-3-carboxyl pyrrolidine
derivatives as summarized in Scheme 2.16 The bis benzyl
Figure 1. Pregabalin, gabapentin and pyrrolidine derivatives.
Keywords: 1-3 dipolar cycloaddition; chiral oxazolidinone; b-proline.
Corresponding author. Tel.: 11-734-622-1377; fax: 11-734-622-5165; e-mail: david.wustrow@p®zer.com
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020/01)00549-X

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R. Ling et al. / Tetrahedron 57 /2001) 6579±6588
Figure 2. Examples of biologically active pyrrolidine-3-carboxylic acid derivatives.
Scheme 1. Radical cyclization strategy.
Scheme 2. Chiral pyrrolidine carboxylates derived from aspartate.
Scheme 3. Azomethine ylide approach.
derivative 12 was caused to undergo rearrangement and
Azomethine ylide 22 having a chiral group appended to the
nitrogen underwent 1,3-dipolarcycloaddition that
cyclization to the pyrrolidinium quaternary salt 14 which
was subsequentlyconverted to the desired b-proline deriv-
atives 16a and 16b.
a
proceeded with synthetically useful levels of stereo control.
Reaction of the unsaturated lactone 21 with azomethine
ylide 22 gave the bicyclic derivative 23 with good stereo-
selectivitywhich was ultimatelyconverted to the azabicy-
cloheptane system 24 /Scheme 4).21
1,3-Dipolar cycloaddition reactions between unsaturated
esters and azomethine ylides have been recognized as an
17
ef®cient wayto construct pyrrolidines in general
and 3-
carboxy pyrrolidine ring systems in particular.18±20 This
strategy was recently employed in the synthesis of an inter-
mediate for pyrrolidine 3 /Scheme 3).5 Reaction of form-
aldehyde with N-benzyl glycine derivative 17 results in the
in situ formation of azomethine ylide 18 which reacts with
Knoevenagle product 19 giving the pyrrolidine ester 20.
More often the chiralityinduced bythis tpye of 3
12
cycloaddition reaction has been controlled by the stereo-
chemistry of the dipolarophile as in the synthesis of tricyclic
lactam 26 /Scheme 5).13
Cycloaddition of azomethine ylides /derived in situ from

R. Ling et al. / Tetrahedron 57 /2001) 6579±6588
6581
Scheme 4. Dipolar cycloaddition reaction controlled by chiral azomethine ylide.
auxiliaries in a number of synthetic processes.22 Recently
theyhave been shown to in¯uence the dipolar cycloaddtion
of azomethine ylides to form 3-pyrrolidine carboxylic acid
templates /Scheme 7).10,14
The initial screening of various four substituted oxazoli-
dinones revealed that the 4-phenyl derivative gave the
best stereoselectivity/entries 1±3). This same auxiliary
has previouslybeen shown to be most effective in directing
1,4-conjugate additions.23 Increasing the size of the alkyl
substituent in the b position of the enoate also led to a
modest increase in the stereoselectivity. A slightly greater
degree of stereoselectivitywas observed when the 1,3-
dipolar cycloaddition reaction was carried out in toluene
than when dichloromethane was used as the solvent.14 In a
subsequent studyit was determined that the 4- t-butyl oxazo-
lidinone induced the opposite sense of relative diastereo-
Scheme 5. Dipolarophile controlled cycloaddition reaction.
N-benzyl-N-methoxymethyl-N-trimethylsilylmethyl amine)
with simple enoate ester chiral auxiliaryderivatives offer an
alternative strategyfor the concise stereoselective construc-
tion of pyrrolidine-3-carboxylic acid derivatives. A number
of chiral auxiliaries have been investigated some of which
are shown below /Scheme 6).
10
control albeit with moderate selectivity/Scheme 8).
The reaction of camphorsultam derived cinamates /Scheme
6, entries 1±3) proceeded in good yield. Good to moderate
diastereoselectivitywas observed depending on the phenyl
group substitution.10±12 The stereoselectivityof the reaction
appeared to be affected bysubstitution on the cinamate
phenyl group. The diastereoselectivity observed using the
furanose derived chiral auxiliarywas lower than that
This reversal in stereoselectivityhas been explained by
differences in the preferred reacting conformation of the
dipolarophile. Reaction of the phenyl substituted oxazoli-
dinone derivative 31f was postulated to proceed mainly
through the U conformer as depicted in Scheme 9. For the
t-butyl oxazolidinone 34, the Z conformation of the
dipolarophile, as shown in Scheme 9, is thought to be the
11
observed with the camphorsultam /Scheme 6, entry4).
10
modestlypreferred conformation for reaction.
Oxazolidinones have also been successfullyused as chiral
Scheme 6. Chiral auxiliarycontrolled 1,3 dipolar cycloaddition reactions.

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R. Ling et al. / Tetrahedron 57 /2001) 6579±6588
Scheme 7. Oxazolidinone chiral auxiliaries.
Scheme 8.
Scheme 9. 1,3 Cycloaddition transition states through the U and Z conformations.
This dependence on dipolarophile conformation in deter-
mining the relative /and therefore absolute) stereochemical
outcome of this process explains whyboth the oxazoli-
dinone and to a lesser extent the ole®n substituent playa
role in determining diastereoselectivity.
in the presence of tri¯uoroacetic acid, provided pyrrolidine
39a as a single diastereomer. In contrast to previous cases,
no minor stereoisomer was observed byproton and 13C
NMR of the crude reaction mixture. The relative and there-
fore absolute stereochemistryof 39a was unambiguously
determined to be 3R4R bysingle crystal X-raydiffraction
/Fig. 3). In this case the reaction proceeds exclusively
through the extended U-conformer of oxazolidinone 38a
as shown in Scheme 11. It is possible that the greater select-
ivityseen in this reaction results from a greater energetic
preference for this conformer due to the more bulkyiso-
propyl group.
With these considerations in mind we undertook the synthe-
sis of 4a and 4b using the 4-phenyl oxazolidinone chiral
auxiliarycontrolled 1,3-dipolar cycloaddition as the key
pyrrolidine forming reaction /Scheme 10). The dipolaro-
phile 38a was easilyprepared bycoupling / E)-enoic acid
36 and /S)-4-phenyl oxazolidinone /37a). Dipolar cycload-
dition of 38a with the azomethine ylide derived from
N-benzyl-N-/methoxymethyl)-trimethylsilylmethylamine
Hydrolysis of 39a with lithium hydroperoxide24 resulted in

R. Ling et al. / Tetrahedron 57 /2001) 6579±6588
6583
Scheme 10. Synthesis of enantiomers 4a and 4b. /a) Oxalyl chloride, DMF, Toluene, rt; /b) NaH, /S)-4-phenyl-2-oxazolidinone /37a), THF, 08C, 98% /two
steps); /c) Me3SiCH2N/Bn)CH2OMe, TFA, Toluene, 08C, 62%; /d) LiOH, H2O2, THF±H2O, rt, 78%; /e) H2, 20%Pd/C, EtOH, 70%. /f) NaH, /S)-4-phenyl-2-
oxazolidinone /37b), THF, 08C, 98% /two steps).
formation of b-aminoacid 40a and the recoveryof the chiral
auxiliary in nearly quantitative yields. Finally the benzyl
group was removed under reductive conditions providing
the R,R pyrrolidine 4a in 70% yield. Similarly, the S,S
enantiomer 4b was obtained byuse of / R)-4-phenyl oxazoli-
dinone /37b) as the chiral auxiliary.
In order to prepare the stereoisomers 4c and 4d via the
cycloaddition strategy, the Z-enoate 44 was required.
Synthesis of 44 has been reported previouslyin the litera-
ture,25,26 however, we adopted a convenient three-step
procedure shown in Scheme 12. Subjecting 3-methyl butyr-
aldehyde /41) to Corey±Fuchs conditions27 gave the dibro-
moole®n 42 which was converted to the acetylene
carboxylate 43. Lindlar hydrogenation of this substrate
gave the desired Z-enoate 44 in good overall yield. All
attempts to append the phenyloxazolidinone chiral auxiliary
to 44 or the corresponding acid resulted in signi®cant double
bond isomerization.
Figure 3. ortep plot of 39a.
Instead, the eneoate 44 was reacted directlywith N-benzyl-
N-/methoxymethyl)-trimethylsilylmethylamine in the pres-
ence of tri¯uoroacetic acid to give the cis di-substituted
pyrrolidine 45 in racemic form /Scheme 13). The benzylic
group was removed byhydrogenation. Resolution of the
Scheme 11. Transition state of the reaction of 38a with an azomethine
ylide.
Scheme 12. Synthesis of cis eneoate. /a) Ph3P,CBr4, CH2Cl2, 2108C, 78%; /b) n-BuLi, EtOCOCl, THF, 92%; /c) H2, Lindlar cat., THF, 86%.

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R. Ling et al. / Tetrahedron 57 /2001) 6579±6588
Scheme 13. Synthesis of cis pyrroldine enantiomers 4c and 4d. /a) Me3SiCH2N/Bn)CH2OMe, TFA, Toluene, 08C, 62%; /b) H2, 20%Pd/C, EtOH, 70%; /c) 2N
NaOH then 6N HCl.
Scheme 14. Synthesis of MPTA derivatives.
ion exchange column chromatographyto provide 4c and 4d,
respectively.
Using complementarymethodologyall four stereoisomers
of constrained pregabalin analogs were prepared with
known relative and absolute stereochemistry. The trans
isomers 4a and 4b were obtained via a highlystereoselec-
tive 1,3-dipolar cycloaddition azomethine ylide reaction.
However, this methodologywas not readilyapplicable to
the preparation of cis isomers 4c and 4d. These compounds
were obtained through resolution with diastereomeric salts
of cycloaddition intermediates. These compounds represent
possible conformations of pregabalin and their enantiomers
which can be used in better understanding the molecular
interaction of pregabalin with its site of action.
Figure 4. ortep plot of 47a.
pyrrolidines 46 was accomplished byfractional crystalliza-
tion of its tartaric acid salts 47a /l-tartaric acid) and 47b
/d-tartaric acid) from methanol. The enantiomeric excesses
of amines 47a and 47b were determined byGC analysis of
the MTPA derivatives 48a and 48b /Scheme 14). Both 47a
and 47b were recrystallized to greater than 98% stereo-
chemcial purity. The absolute con®guration of the of the
pyrrolidine portion of 47a was determined to be 3R4S by
single crystal X-ray crystallography /Fig. 4). The tartaric
acid salt 47a and 47b were converted to the corresponding
free amino esters, which were subjected to hydrolysis and
1. Experimental
1.1. General
1
The structure of all the compounds were con®rmed by H
NMR and in most cases 13C NMR on a Varian Unity
400 MHz spectrometer. Chemical ionization mass spectra
were obtained on a Micromass Trio 2A spectrometer.
Elemental analysis was performed in the Robertson labs.
Where analyses are indicated by the symbols of elements,

R. Ling et al. / Tetrahedron 57 /2001) 6579±6588
6585
the results are within ^0.4% of the theoretical values.
Analytical thin layer chromatography /TLC) was performed
on 0.25 mm Merck silica gel F254 glass plates. Flash
column chromatographywas performed on silica gel /E,
Merck, grade 60, 230±300 mesh). Optical rotations were
measured on a Perkin±Elmer 241 polarimeter at 208C.
[a]D values were given in units of 1021 deg cm2 g21. Melt-
ing points were determined on a Thomas±Hoover capillary
melting point apparatus and are uncorrected.
Jˆ9.0 Hz, 1H, oxazolidinone ring), 5.40 /m, 1H, oxazoli-
dinone ring), 7.18±7.36 /m, 5H, aromatic); 13C NMR
/CDCl3): d 22.46, 23.05, 26.72, 37.00, 44.07, 49.41, 57.48,
57.85, 59.84, 60.54, 69.87, 125.67, 126.80, 128.21, 128.48,
128.65, 129.25, 139.01, 139.05, 153.55, 173.71; MS /CI) m/z
407 /M11)1. Anal. /C25H30N2O3) C, H, N. Exp. 73.75, 7.44,
6.74; Theor. 73.86, 7.44, 6.86.
1.1.3. trans-4-(R)-Isobutylpyrrolidine-3-(R)-carboxylic
acid (4a). To a solution of 1-benzyl-4-/R)-isobutyl-3-/R)-
[40-/S)-phenyl-20-oxazolidinon-30-yl)carbonyl]pyrrolidine
39a /1.37 g, 3.37 mmol) in THF /30 mL) was added a solu-
tion of LiOH /1 M in H2O, 8.44 mmol) and H2O2 /30%,
6.75 mmol) in H2O /10 mL) at 08C slowly. The reaction
mixture was stirred at 08C for 1 h, then diluted with water
/40 mL). Sodium sul®te /0.85 g, 6.75 mmol) was added and
the mixture was extracted with ethyl acetate. The aqueous
phase was adjusted to pH 5.0 with KH2PO4 /1.51 g,
11.1 mmol) and 10% HCl. This solution was extracted
with isopropyl alcohol±methylene chloride /1:3), which
was dried over Na2SO4 and concentrated to afford 0.88 g
of 1-benzyl-4-/R)-isobutylpyrrolidine-3-/R)-carboxylic acid
/40a) which was used without further puri®cation. To a
solution of this carboxylic acid /0.72 g) in ethanol
/55 mL) was added 20% Pd/C /0.11 g) and hydrogenated
at 50 psi for 11 h. The reaction mixture was ®ltered through
a pad of Celite. After the solvent was evaporated at reduced
pressure the crude product was subjected to ion exchange
column /Dowex 50) and recrystallized from methanol±ether
to give 0.33 g /71% yield) of 4a as a white solid.
1.1.1. 3-[(E)-3-Isobutylpropenoyl]-4-(S)-phenyl-2-oxazo-
lidinone (38a). To a solution of /E)-5-methyl-hex-2-enoic
acid /36) /3.2 g, 25 mmol) in toluene /20 mL) was added
oxalyl chloride /4.4 mL, 50 mmol) slowly at 08C under N2
followed byone drop of DMF. The mixture was stirred at
228C for 1 h. The volatiles were removed under reduced
pressure to give the desired acid chloride which was used
without further puri®cation. To a solution of NaH /0.84 g,
21 mmol) in THF /30 mL) was added a solution of /S)-/2)-
4-phenyl-2-oxazolidinone /37a) /3.4 g, 21 mmol) in THF
/10 mL) at 08C. The mixture was stirred at 228C for 1 h.
The crude acid chloride was then introduced while main-
taining the temperature at 08C. The mixture was stirred at
08C for 1 h and then at 228C for an additional 12 h. The
reaction was quenched with 1N HCl aqueous solution,
extracted with CHCl3, then dried over Na2SO4. After the
solvent was evaporated at reduced pressure the crude
product was subjected to column chromatography/silica
gel, hexanes±etherˆ2:1) to give 6.25 g /100% yield) of
1
38a as a white solid. mp 84±858C; H NMR /CDCl3): d
1
0.81 /d, Jˆ6.8 Hz, 6H, CH/CH3)2), 1.68±1.78 /m, 1H,
CH2CH/CH3)2), 2.11±2.14 /m, 2H, CH2CH/CH3)2), 4.24±
4.27 /m, 1H, oxazolidinone ring), 4.65±4.72 /t, Jˆ8.8 Hz,
1H, oxazolidinone ring), 5.44±5.48 /m, 1H, oxazolidinone
ring), 7.02±7.09 /m, 1H, vinyl), 7.23±7.28 /m, 1H, vinyl),
7.31±7.38 /m, 5H, aromatic); 13C NMR /CDCl3): d 22.35,
22.39, 27.88, 41.82, 57.77, 69.92, 121.11, 125.95, 128.63,
129.16, 139.14, 151.10, 153.70, 164.56; MS /CI) m/z 274
/M11)1. Anal. /C16H19NO3) C, H, N. Exp. 70.02, 7.00,
5.26; Theor. 70.31, 7.01, 5.12.
[a]Dˆ144.88; mp 236±2398C; H NMR /CD3OD): d 0.89
/m, 6H, CH3), 1.26 /m, 1H, CH2CH/CH3)2), 1.51 /m, 1H,
CH2CH/CH3)2), 1.60 /m, 1H, CH2CH/CH3)2), 2.52 /m, 2H,
pyrrolidine ring), 2.78 /m, 1H, pyrrolidine ring), 3.37 /m,
2H, pyrrolidine ring), 3.44 /m, 1H, pyrrolidine ring); 13C
NMR /CD3OD): d 21.07, 22.07, 26.29, 40.81, 41.83,
48.39, 50.11, 51.78, 177.47; MS /CI) m/z 172 /M11)1.
Anal. /C9H17NO2) C, H, N. Exp. 62.85, 10.20, 8.09;
Theor. 63.13, 10.01, 8.18.
1.1.4. 3-[(E)-3-Isobutylpropenoyl]-4-(R)-phenyl-2-oxazo-
lidinone (38b). To a solution of /E)-5-methyl-hex-2-enoic
acid /36) /1.77 g, 13.8 mmol) in toluene /20 mL) was added
oxalyl chloride /2.4 mL, 27.6 mmol) slowly at 08C under N2
followed byone drop of DMF. The mixture was stirred at
228C for 1 h. The volatiles were removed under reduced
pressure to give the desired acid chloride which was used
without further puri®cation. To a solution of NaH /0.37 g,
9.2 mmol) in THF /30 mL) was added a solution of /R)-/2)-
4-phenyl-2-oxazolidinone /37b) /1.5 g, 9.2 mmol) in THF
/10 mL) at 08C. The mixture was stirred at 228C for 1 h. The
crude acid chloride was then introduced while maintaining
the temperature at 08C. The mixture was stirred at 08C for
1 h and then at 228C for an additional 12 h. The reaction was
quenched with 1N HCl aqueous solution, extracted with
CHCl3, then dried over Na2SO4. After the solvent was
evaporated at reduced pressure the crude product was
subjected to column chromatography/silica gel, hexanes±
acetoneˆ3:1) to give 2.5 g /100% yield) of 38b as a white
solid. mp 84±858C; 1H NMR /CDCl3): d 0.81 /d, Jˆ6.8 Hz,
6H, CH/CH3)2), 1.68±1.78 /m, 1H, CH2CH/CH3)2), 2.11±
2.14 /m, 2H,CH2CH/CH3)2), 4.24±4.27 /m, 1H, oxazoli-
dinone ring), 4.65±4.72 /t, Jˆ8.8 Hz, 1H, oxazolidinone
1.1.2.
1-Benzyl-4-(R)-isobutyl-3-(R)-[40-(S)-phenyl-20-
oxazolidinon-30-yl]carbonyl pyrrolidine (39a). To a stirred
solution of 3-[/E)-3-isobutylpropenoyl]-4-/S)-phenyl-2-
oxazolidinone /38a) /1.50 g, 5.50 mmol) in toluene /20 mL)
was added N-benzyl-N-/methoxymethyl) trimethylsilyl-
methylamine /1.56 g, 6.60 mmol) at 08C under N2. After
20 min, a solution of TFA /1 M in CH2Cl2, 0.55 mmol) was
added slowlyat 0 8C. The mixture was stirred at 08C for
30 min and then at 228C for an additional 12 h. The reaction
was quenched with H2O, extracted with CHCl3, then dried
over MgSO4. The solvent was evaporated to dryness, and
the oilyresidue was subjected to column chromatography
/silica gel, hexanes±etherˆ2:1) to give 1.37 g /62% yield)
of 39a as a white solid which was subjected to recrystalli-
zation in ether±hexanes to provided crystalline needled. Mp
34±358C; 1H NMR /CDCl3): d 0.84±0.86 /m, 6H,
CH/CH3)2), 1.26±1.29 /m, 2H, CH2CH/CH3)2), 1.42±1.47
/m, 1H, CH2CH/CH3)2), 2.08 /t, Jˆ7.3 Hz, 1H, pyrrolidine
ring), 2.62 /dd, Jˆ9.8 Hz, 4.6 Hz, 1H, pyrrolidine ring),
2.83±2.94 /m, 3H, pyrrolidine ring), 3.37±3.67 /ABq,
Jˆ13.0 Hz, 2H, CH2Ph), 3.68±3.72 /m, 1H, pyrrolidine
ring), 4.16±4.19 /m, 1H, oxazolidinone ring), 4.63 /t,

6586
R. Ling et al. / Tetrahedron 57 /2001) 6579±6588
ring), 5.44±5.48 /m, 1H, oxazolidinone ring), 7.02±7.09 /m,
1H, vinyl), 7.23±7.28 /m, 1H, vinyl), 7.31±7.38 /m, 5H,
aromatic); 13C NMR /CDCl3): d 22.35, 22.39, 27.88,
41.82, 57.77, 69.92, 121.11, 125.95, 128.63, 129.16,
139.14, 151.10, 153.70, 164.56; MS /CI) m/z 274
/M11)1. Anal. /C16H19NO3) C, H, N. Exp. 70.20, 7.05,
5.15; Theor. 70.31, 7.01, 5.12.
3.44 /m, 1H, pyrrolidine ring); 13C NMR /CD3OD): d
21.07, 22.07, 26.29, 40.81, 41.83, 48.39, 50.11, 51.78,
177.47; MS /CI) m/z 172 /M11)1. Anal. /C9H17NO2) C,
H, N. Exp. 62.96, 9.89, 7.98; Theor. 63.13, 10.01, 8.18.
1.1.7. 1,1-Dibromo-4-methyl-1-pentene (42). To a stirred
solution of carbon tetrabromide /30 g, 90.93 mmol) in
dichloromethane /400 mL) at 2108C was added triphenyl-
phosphine /60 g, 229 mmol) in portions. The internal
temperature of the reaction vessel was kept below 58C
during the addition, and it was stirred for an additional
30 min at this temperature after the addition was completed.
To this mixture was slowlyadded a solution of isovaler-
aldehyde /41) /9.4 mL, 87.6 mmol) in methylene chloride
/40 mL). The reaction was stirred for 3 h during which time
the temperature did not rise above 58C. After the solvent
was removed on a rotaryevaporator, pentane /600 mL) was
added to the residue. The solid which separated was
removed by®ltration. Evaporation of the solvent from the
®ltrate gave a light oil which was chromatographed on a
silica gel column. The pure compound was eluted with pet
ether to afford 1,1-dibromo-4methyl-pent-1-ene /42) as an
1.1.5. 1-Benzyl-4-(S)-isobutyl-3-(S)-[40-(R)-phenyl-20-
oxazolidinon-30-yl]carbonyl pyrrolidine (39b). To a stirred
solution of 3-[/E)-3-isobutylpropenoyl]-4-/R)-phenyl-2-
oxazolidinone /38b) /1.50 g, 5.50 mmol) in toluene /20 mL)
was added N-benzyl-N-/methoxymethyl) trimethylsilyl-
methylamine /1.56 g, 6.60 mmol) at 08C under N2. After
20 min, a solution of TFA /1 M in CH2Cl2, 0.55 mmol) was
added slowlyat 0 8C. The mixture was stirred at 08C for
30 min and then at 228C for an additional 12 h. The reaction
was quenched with H2O, extracted with CHCl3, then dried
over MgSO4. The solvent was evaporated to dryness, and
the oilyresidue was subjected to column chromatography
/silica gel, hexanes±etherˆ2:1) to give 1.45 g /65% yield)
1
of 39b as a white solid. mp 33±358C; H NMR /CDCl3): d
1
0.84±0.86 /m, 6H, CH/CH3)2), 1.26±1.29 /m, 2H,
CH2CH/CH3)2), 1.42±1.47 /m, 1H, CH2CH/CH3)2), 2.08 /t,
Jˆ7.3 Hz, 1H, pyrrolidine ring), 2.62 /dd, Jˆ9.8 Hz, 4.6 Hz,
1H, pyrrolidine ring), 2.83±2.94 /m, 3H, pyrrolidine ring),
3.37±3.67 /ABq, Jˆ13.0 Hz, 2H, CH2Ph), 3.68±3.72 /m,
1H, pyrrolidine ring), 4.16±4.19 /m, 1H, oxazolidinone
ring), 4.63 /t, Jˆ9.0 Hz, 1H, oxazolidinone ring), 5.40 /m,
1H, oxazolidinone ring), 7.18±7.36 /m, 5H, aromatic); 13C
NMR /CDCl3): d 22.46, 23.05, 26.72, 37.00, 44.07, 49.41,
57.48, 57.85, 59.84, 60.54, 69.87, 125.67, 126.80, 128.21,
128.48, 128.65, 129.25, 139.01, 139.05, 153.55, 173.71; MS
/CI) m/z 407 /M11)1. Anal. /C25H30N2O3) C, H, N. Exp.
73.60, 7.41, 6.69; Theor. 73.86, 7.44, 6.86.
oil /16.5 g, 78%). H NMR /CDCl3): d 0.89 /d, 6H), 1.70
/m, 1H), 1.95 /triplet, 2H), 6.38 /triplet, 1H).
1.1.8. 5-Methyl-hex-2-ynoic acid ethyl ester (43). 1,1-
Dibromo-4-methyl-pent-1-ene /42) /40 g 165.9 mmol) was
dissolved in dryTHF /120 mL) and the solution was cooled
to 2788C. To the stirred solution was added n-butyllithium
/1.6 M sol., in hexanes, 190 mL, 305 mmol) in a dropwise
manner. After 1 h, ethyl chloroformate /15 mL, 154.5 mmol)
was added and the reaction was stirred at ambient tempera-
ture overnight. The reaction was carefullypoured into water
and extracted with ether /3£250 mL), dried over mag-
nesium sulfate and the solvents were evaporated under
reduced pressure. The resulting light oil was ¯ash chromato-
graphed on silica gel using 10% ether in pet ether as the
eluant to afford 5-methyl-hex-2-ynoic acid ethyl ester /43)
1.1.6. trans-4-(S)-Isobutylpyrrolidine-3-(S)-carboxylic
acid (4b). To a solution of 1-benzyl-4-/S)-isobutyl-3-/S)-
[40-/R)-phenyl-20-oxazolidinon-30-yl)carbonyl]pyrrolidine
/39b) /1.44 g, 3.56 mmol) in THF /30 mL) was added a
solution of LiOH /1 M in H2O, 8.89 mmol) and H2O2
/30%, 7.11 mmol) in H2O /10 mL) at 08C slowly. The reac-
tion mixture was stirred at 08C for 1 h, then diluted with
water /40 mL). Sodium sul®te /0.89 g, 7.11 mmol) was
added and the mixture was extracted with ethyl acetate.
The aqueous phase was adjusted to pH 5.0 with KH2PO4
/1.59 g, 11.7 mmol) and 10% HCl. This solution was
extracted with isopropyl alcohol±methylene chloride
/1:3), which was dried over Na2SO4 and concentrated to
afford 0.93 g of 1-benzyl-4-/S)-isobutylpyrrolidine-3-/S)-
carboxylic acid /40b) which was used without further puri-
®cation. To a solution of this carboxylic acid /0.94 g) in
ethanol /55 mL) was added 20% Pd/C /0.21 g) and hydro-
genated at 50 psi for 11 h. The reaction mixture was ®ltered
through a pad of Celite. After the solvent was evaporated at
reduced pressure the crude product was subjected to ion
exchange column /Dowex 50) and recrystallized from
methanol±ether to give 0.43 g /70% yield) of 4b as a
white solid. [a]Dˆ245.88; mp 251±2548C; 1H NMR
1
/23.6 g, 92%). H NMR /CDCl3): d 0.94 /d, 6H), 1.24 /t,
3H), 1.85 /m, 1H), 2.16 /d, 2H), 4.14 /m, 2H).
1.1.9. (Z)-5-Methyl-hex-2-enoic acid ethyl ester (44). 5-
Methyl-hex-2-ynoic acid ethyl ester /43) /20.97 g,
136.08 mmol), in a solution of THF /540 mL) and pyridine
/60 mL) was hydrogenated in the presence of 5% PD/BaSO4
/1.10 g) for 3.25 h. The solvent was evaporated and the light
oil was chromatographed over silica gel using 5% ether in
pet. ether as the eluant. An initial fraction of unreacted
acetylene was collected prior to isolation of the pure /Z)-
5-methyl-hex-2-enoic acid ethyl ester /44) /12.0 g, 56%)
1.1.10. cis-1-Benzyl-4-isobutylpyrrolidine-3-carboxylic
acid ethyl ester (45). To a stirred solution of a,b-unsatu-
rated carboxylic acid ethyl ester 44 /1.82 g 11.70 mmol) in
toluene /20 mL) was added N-benzyl-N-/methoxymethyl)
trimethylsilylmethylamine /3.33 g, 14.10 mmol) at 08C
under N2. After 20 min, a solution of TFA /1 M in
CH2Cl2, 1.17 mmol) was added slowlyat 0 8C. The mixture
was stirred at 08C for 30 min and then at 228C for an
additional 12 h. The reaction was quenched with H2O,
extracted with CHCl3, then dried over MgSO4. The solvent
was evaporated to dryness, and the oily residue was subjected
to column chromatography/silica gel, hexanes±ether ˆ6:1)
/CD3OD):
d
0.89 /m, 6H, CH3), 1.26 /m, 1H,
CH2CH/CH3)2), 1.51 /m, 1H, CH2CH/CH3)2), 1.60 /m,
1H, CH2CH/CH3)2), 2.52 /m, 2H, pyrrolidine ring), 2.78
/m, 1H, pyrrolidine ring), 3.37 /m, 2H, pyrrolidine ring),

R. Ling et al. / Tetrahedron 57 /2001) 6579±6588
6587
to give cis-1-benzyl-4-isobutylpyrrolidine-3-carboxylic
acid ethyl ester /45) /1.38 g, 41% yield;) 1H NMR
/CDCl3): d 0.83±0.87 /m, 6H, CH/CH3)2), 1.18±1.29 /m,
5H, CH2CH3 and CH2CH/CH3)2), 1.46±1.49 /m, 1H,
CH2CH/CH3)2), 2.07 /t, Jˆ9.5 Hz, 1H, pyrrolidine ring),
2.56±2.66 /m, 2H, pyrrolidine ring), 3.00±3.13 /m, 2H,
pyrrolidine ring), 3.65 /s, 2H, CH2Ph), 4.10±4.18 /m, 2H,
CH2CH3), 7.25±7.32 /m, 5H, aromatic ring); 13C NMR
/CDCl3): d 15.59, 23.07, 24.83, 27.64, 40.14, 40.23,
47.41, 57.73, 60.69, 61.47, 61.80, 128.19, 129.51, 130.05,
140.44, 175.41; MS /CI) m/z 290 /M11)1. Anal.
/C18H27NO2) C, H, N. Exp. 74.82, 9.48, 4.90; Theor.
74.70, 9.40, 4.84.
1.1.14. cis-4-(R)-Isobutylprrolidine-3-(S)-carboxylic acid,
ethyl ester (S,S)-tartaric acid salt (47b). A 100 mL ¯ask
was charged with enantiomericallyenriched 46 /2.54 g,
12.76 mmol), d-tartaric acid/1.72 g, 11.48 mmol) and
8 mL of MeOH. The mixture was heated to 608C for
10 min and cooled to 258C for crystallization. The crystals
was collected and rinsed with MeOH. Recrystallization in
MeOH afforded 0.8 g of 47b as white needles. [a]25ˆ1378
1
/cˆ0.15, MeOH); mp 172±1738C; H NMR /CD3OD): d
0.91 /m, 6H, CH/CH3)2), 1.27 /m, 5H, CH2CH/CH3)2 and
OCH2CH3), 1.65 /m, 1H, CH2CH/CH3)2), 2.67 /m, 1H,
pyrrolidine ring), 2.97 /t, Jˆ11.2 Hz, 1H, pyrrolidine
ring), 3.23 /m, 2H, pyrrolidine ring), 3.42±3.55 /m, 3H,
pyrrolidine ring), 4.11±4.25 /m, 2H, OCH2CH3), 4.39 /s,
2H, tartaric acid); 13C NMR /CD3OD): d 13.41, 21.58,
21.80, 21.83, 26.35, 37.39, 39.66, 45.85, 48.73, 61.12,
73.07, 172.68, 175.99; Anal. /C15H27NO8) C, H, N. Exp.
51.47, 7.59, 3.83; Theor. 51.57, 7.79, 4.01.
1.1.11. cis-4-(S)-Isobutylprrolidine-3-(R)-carboxylic acid,
ethyl ester (46). cis-1-Benzyl-4-isobutylpyrrolidine-3-
carboxylic acid ethyl ester /45) /2.25 g, 7.78 mmol) in
ethanol /75 mL) and 20% Pd/C /210 mg) was placed
under 50 psi of hydrogen and the reaction proceeded for
5.5 h. The reaction was ®ltered through a pad of celite and
the ®ltrate evaporated to give cis-4-/S)-isobutylprrolidine-3-
/R)-carboxylic acid, ethyl ester /19) as an oil which was
used without further puri®cation.
1.1.15. cis-4-(R)-Isobutylpyrrolidine-3-(S)-carboxylic acid
(4d). To a solution of 47b /0.8 g, 2.29 mmol) in CHCl3
/30 mL) was added 20 mL of NaOH /2N) aqueous solution
and stirred for 10 min. The organic layer was separated and
concentrated. The crude oil was added 6N HCl /20 mL).
The reaction mixture was re¯uxed for 12 h. After the
solvent was evaporated at reduced pressure the crude
product was subjected to ion exchange column /Dowex
50) and recrystallized from methanol±ether to 0.32 g
/81% yield) of 4d as a white solid. [a]Dˆ188 /cˆ0.10,
1.1.12. cis-4-(S)-Isobutylprrolidine-3-(R)-carboxylic acid,-
ethyl ester (R,R)-tartaric acid salt (47a). A 250 mL ¯ask
was charged with /^)46 /5.70 g, 28.64 mmol), l-tartaric
acid/3.87 g, 25.77 mmol) and 15 mL of MeOH. The mixture
was heated to 608C for 10 min and cooled to 258C for crystal-
lization. The crystals was collected and rinsed with MeOH.
Recrystallization was done in MeOH. 1.6 g of 47a was
obtained as colorless needles. [a]25ˆ2358 /cˆ0.25,
1
MeOH); mp 2348C /dec); H NMR /CD3OD): d 0.89 /m,
6H, CH3), 1.26 /m, 1H, CH2CH/CH3)2), 1.49 /m, 1H,
CH2CH/CH3)2), 1.64 /m, 1H, CH2CH/CH3)2), 2.52 /m,
2H, pyrrolidine ring), 2.78 /m, 1H, pyrrolidine ring), 3.37
/m, 2H, pyrrolidine ring), 3.44 /m, 1H, pyrrolidine ring); 13C
NMR /D2O): d 21.47, 22.44, 26.02, 37.66, 38.53, 48.39,
48.98, 49.17, 179.29; MS /CI) m/z 172 /M11)1. Anal.
/C9H17NO2) C, H, N. Exp. 63.05, 9.93, 8.10; Theor. 63.13,
10.01, 8.18.
1
MeOH); mp 173±1748C; H NMR /CD3OD): d 0.91 /m,
6H, CH/CH3)2), 1.26 /m, 5H, CH2CH/CH3)2, OCH2CH3),
1.65 /m, 1H, CH2CH/CH3)2), 2.67 /m, 1H, pyrrolidine
ring), 2.97 /t, Jˆ11.0 Hz, 1H, pyrrolidine ring), 3.23 /m,
2H, pyrrolidine ring), 3.42±3.55 /m, 3H, pyrrolidine ring),
4.11±4.25 /m, 2H, OCH2CH3), 4.39 /s, 2H, tartaric acid); 13C
NMR /CD3OD): d 11.81, 19.99, 20.21, 20.23, 24.77, 35.81,
38.07, 44.27, 47.15, 59.53, 71.48, 171.09, 174.39; Anal.
/C15H27NO8) C, H, N. Exp. 51.71, 7.58, 3.97; Theor. 51.57,
7.79, 4.01.
1.2. X-Ray structure of 40a
The compound 40a was crystallized from ethanol solutions.
The crystals are rhombohedral, space group P61, with unit
Ê
cell dimensions aˆbˆcˆ18.43 A. X-Raydiffraction data
were collected at room temperature on a CAD-4 diffracto-
meter. The structure was solved bydirect methods using the
maxus program set and re®ned to Rˆ0.116. An ortep plot
of the re®ned structure is shown in Fig. 3.
1.1.13. cis-4-(S)-Isobutylpyrrolidine-3-(R)-carboxylic acid
(4c). To a solution of 47a /1.25 g, 3.57 mmol) in CHCl3
/30 mL) was added 20 mL of NaOH /2N) aqueous solution
and stirred for 10 min. The organic layer was separated and
concentrated. The crude oil was added 6N HCl /20 mL).
The reaction mixture was re¯uxed for 12 h. After the
solvent was evaporated at reduced pressure the crude
product was subjected to ion exchange column /Dowex
50) and recrystallized from methanol±ether to give 4-alkyl-
pyrrolidine-3-carboxylic acid 0.54 g /88% yield) of 4c as a
white solid. [a]Dˆ298 /cˆ0.11, MeOH); mp 2248C /dec);
1H NMR /CD3OD): d 0.89 /m, 6H, CH3), 1.26 /m, 1H,
CH2CH/CH3)2), 1.49 /m, 1H, CH2CH/CH3)2), 1.64 /m,
1H, CH2CH/CH3)2), 2.52 /m, 2H, pyrrolidine ring), 2.78
/m, 1H, pyrrolidine ring), 3.37 /m, 2H, pyrrolidine ring),
3.44 /m, 1H, pyrrolidine ring); 13C NMR /D2O): d 21.47,
22.43, 26.01, 37.66, 38.54, 48.40, 48.98, 49.18, 179.32; MS
/CI) m/z 172 /M11)1. Anal. /C9H17NO2) C, H, N. Exp.
62.99, 10.02, 8.08; Theor. 63.13, 10.01, 8.18.
1.3. X-Ray structure of 47a
The compound 47a was crystallized from ethanol solutions.
The crystals are monoclinic, space group P21, aˆ7.68
Ê
Ê
Ê
/5) A, bˆ7.67 A, cˆ16.02 A. X-Raydiffraction data were
collected at room temperature on a CAD-4 diffractometer.
The structure was solved bydirect methods using the maxus
program set and re®ned to Rˆ0.118. An ortep plot of the
re®ned structure is shown in Fig. 4.
Acknowledgements
Thanks to Don Johnson and Norm Colbryfor conducting
hydrogenation reactions.

6588
R. Ling et al. / Tetrahedron 57 /2001) 6579±6588
13. Fray, A. H.; Meyers, A. I. J. Org. Chem. 1996, 61, 3362±3374.
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