cis-Selective synthesis of 2,5-disubstituted pyrrolidines

Article abstract of DOI:10.1016/j.tetlet.2003.12.021

A concise approach to cis-2,5-disubstituted pyrrolidines is reported, which relies upon N-tert-butoxycarbonylmethyl substitution in a substrate derived from pyroglutamic acid. The method is especially noteworthy since a significant improvement in the cond

Full text of DOI:10.1016/j.tetlet.2003.12.021

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1125–1127
cis-Selective synthesis of 2,5-disubstituted pyrrolidines
Syed Raziullah Hussaini and Mark G. Moloney*
The Department of Chemistry, Dyson Perrins Laboratory, The University of Oxford, South Parks Road, Oxford OX1 3QY, UK
Received 17 October 2003; revised 27 November 2003; accepted 5 December 2003
Abstract—A concise approach to cis-2,5-disubstituted pyrrolidines is reported, which relies upon N-tert-butoxycarbonylmethyl
substitution in a substrate derived from pyroglutamic acid. The method is especially noteworthy since a significant improvement in
the conditions for a key LawessonÕs reaction have been established. Regioselective enolate generation and alkylation permits
extension of the C-5 side chain.
Ó 2003 Elsevier Ltd. All rights reserved.
We recently reported that trans-disubstituted pyrrol-
idines are available by a short sequence from pyroglu-
tamic acid ethyl ester 1a;1 thus, conversion to the
thiolactam 1b followed by Eschenmoser sulfur contrac-
tion2 to give enamine 1c and catalytic reduction under
forcing conditions gave the corresponding 2,5-disubsti-
tuted pyrrolidine 2a as a mixture of diastereomers in
excellent yield (Scheme 1). Attempted protection of the
amine functionality with an alkyl substituent proved to
be problematic, but after N-benzoyl protection,
achieved under mild conditions (BzCl, py, 4 h, rt), to
give 2b, regioselective generation of either the C-6 eno-
late (NaH) or the C-2 enolate (excess LDA), led to
adducts 3a and 4 in good yields exclusively as the trans-
adducts. Subsequent alkylation of 3a provided access to
2,5-disubstituted product 3b; this sequence permits
EtO2C
CO2Et
EtO2C
N
v
R2
Bz
R1
3a R1 = Me, Bn; R2 = H
3b R1 = Me, R2 = Bn
iii
EtO2C
iv
6
5
2
vi
CO2 Et
CO2Et
X
N
H
N
R
EtO2C
1a X = O
1b X = S
1c X = C(CO2Et)2
vii
CO2Et
i
ii
2a R = H
2b R = COPh
EtO2C
N
Me
Bz
EtO2C
4
1c only
viii
ix
EtO2C
EtO2C
EtO2C
EtO2C
CO2 Et
CO2 Et
N
N
COPh
COPh
6
5
Scheme 1. Reagents and conditions: (i) LawessonÕs reagent, CH2Cl2, rt; (ii) BrCH(CO2Et)2, NaHCO3; (iii) H2 (4.5 atm), PtO2, TFA, AcOH, 48 h; (iv)
PhCOCl, py; (v) NaH, then MeI, THF or PhCH2Br/DMF; (vi) LDA then PhCH2Br; (vii) LDA (2 equiv) then MeI; (viii) PhCOCl, Et3N, DMAP,
CH2Cl2, 2 days, reflux; (ix) H2 (5 atm), 10% Pd/C, EtOH, CH2Cl2, 24 h.
Keywords: Pyrrolidines; Thionation; LawessonÕs reagent.
* Corresponding author. Tel.: +44-1865-275656; fax: +44-1865-275674; e-mail: mark.moloney@chem.ox.ac.uk
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.021

1126
S. R. Hussaini, M. G. Moloney / Tetrahedron Letters 45 (2004) 1125–1127
regioselective manipulation of the C-2 and/or the C-5
positions independently. The observed trans-stereo-
selectivity was postulated to be due to a ring opening–
ring closing equilibration process, assisted by the
good leaving group character of the N-benzoyl group,
leading to the thermodynamically most favourable
outcome; a similar equilibration has been reported in
closely related substrates.3 We report here that two
simple modifications of this procedure significantly
improve the efficiency of this process, and cleanly pro-
vide access to the corresponding cis-2,5-disubstituted
series.
converted to enamine 1c in quantitative yield under
standard Eschenmoser coupling conditions.
With enamine 1c reliably in hand, we found that reversal
of the order of steps iii and iv of the sequence shown in
Scheme 1 leading to the intermediate benzamide 2b
permitted reduction under milder conditions and con-
sequent isolation of the cis-isomer. Thus, protection of
the enamine function11 of 1c under forcing conditions
(BzCl, Et3N, DCM, DMAP, 2 days at reflux) gave the
N-benzoyl derivative 5 in 41% yield, and this was sus-
ceptible to reduction under significantly milder condi-
tions than enamine 1c (10% Pd/C, H2, 5 atm, 24 h,
EtOH/DCM 10:1) to give pyrrolidine 6 as a 9:1 mixture
of cis:trans-isomers in 79% yield. However, since we had
earlier found1 that alkylation of cis-6 (prepared by a
different route) gave only the corresponding trans-
products after enolate generation, due to the same facile
ring opening–ring closing equilibration alluded to
above, this compound was of limited synthetic utility
for our purpose.
The key step of the sequence is activation of the lactam
carbonyl of pyroglutamic acid ethyl ester 1a as the
thiocarbonyl derivative 1b, achieved using either P2S5 or
LawessonÕs reagent; although both methods are known
and have been used, the former requires heterogeneous
reaction conditions4;5 and the latter6 seems to be highly
solvent dependent. The latter reaction has routinely
been conducted in refluxing anhydrous toluene,7 but we
found that the use of such conditions for the conversion
of pyroglutamic acid 1a to thiopyroglutamic acid 1b
gave modest yields (50%) and, more significantly, a
product, which required more than one chromato-
graphic purification in order to obtain material of good
enough quality to be used in subsequent steps. The
solvents DME6 and more recently, anhydrous THF at
room temperature, giving a 90% yield of thiolactam 1b8
have been used, although we found that scale-up of this
reaction led to a large reduction of yield (21%) and a
requirement for multiple chromatographic purifications.
Significantly, we have found that the conversion of
lactam 1a to thiopyroglutamic acid 1b in commercially
available HPLC-grade dichloromethane at room tem-
perature for only 1.5 h gives excellent yields of the cor-
responding product, which was readily purified by a
single chromatographic step (0.1 g scale, 78%; 12 g scale,
82%); moreover, the reaction can be conducted on crude
ester 1a.9 We believe that the efficiency of this procedure
can be attributed to the greater solubility of LawessonsÕs
reagent in DCM compared to other solvents, and the
use of room temperature conditions, which avoids the
formation of a phosphorus impurity reported previously
by Lawesson and co-workers, which is difficult to
remove.6 These milder conditions are likely to extend
the already recognised synthetic applications of Lawes-
sonÕs reagent.7 These preparative difficulties had been
addressed earlier by the use of BelleauÕs reagent10 but
this approach suffers from the fact that the reagent is not
commercially available. Thiolactam 1b could be readily
Since the crucial equilibration process leading to the
trans-product seemed likely to depend on the N-benzoyl
leaving groups of 2b and 6, we expected that this path-
way could be effectively blocked by careful choice of the
amine protecting group. However, protection of the
amine group of compounds like 1c and 2a is difficult,
due to the hindered nature of the amine function, and
attempts at introducing N-Me or N-Bn groups into 2a
by standard alkylation-type approaches gave recovered
starting material, and attempted reductive amination
with benzaldehyde gave no identifiable material.
Deprotonation of amine 2a (cis:trans ¼ 1:2) with
LiHMDS at 0 °C followed by reaction with tert-butyl
bromoacetate gave the desired adduct 7 in 50% yield, as
the cis-isomer exclusively (Scheme 2); this isomer is
likely to be favoured since an all trans arrangement of
contiguous substituted ring positions is possible. Sig-
nificantly, this tertiary amine could be readily purified
by chromatography on silica, unlike related compounds,
which required distillation.12 Noteworthy was that the
1H NMR spectrum of this compound at room temper-
ature gave well resolved signals, unlike the N-benzoyl
protected series,1 which required VT analysis at 373 K to
give useful spectra, and its stereochemical assignment
was based on careful NOE analysis at room temperature
(Fig. 1). Simple molecular modeling calculations
(ChemDraw with MM2 parameters) suggested that the
2,5-cis-isomer was more stable than the corresponding
2,5-trans-isomer by 4.8 kJ molꢀ1, and that the preferred
EtO2C
ii
i
CO2Et
EtO2C
EtO2C
2a
5
2
EtO2C
N
CO2Et
N
CH2 CO2 t-Bu
R
CH2 CO2 t-Bu
8a R = Et (32%)
8b R = Bn (36%)
7
Scheme 2. Reagents and conditions: (i) LiHMDS (1.5 equiv), 0 °C, THF then BrCH2CO2t-Bu (50%); (ii) NaH and EtOTf/CH2Cl2 or PhCH2Br/
DMF.

S. R. Hussaini, M. G. Moloney / Tetrahedron Letters 45 (2004) 1125–1127
1127
H
H
H
H
H
H
H
H
EtO2C
EtO2C
EtO2C
EtO2C
EtO2C
CO2 Et
CO2 Et
N
CO2Et
N
N
H
EtO2C
Ph
H
H
H
H
H
Et
CH2
H
H2C
CH2
CO2 t-Bu
CO2 t-Bu
CO2 t-Bu
7
8b
8a
Figure 1.
conformation was one in which the C-2 and C-5 sub-
stituents were pseudodiaxial and trans to the bulky tert-
butoxycarbonylmethyl substituent. This route is of
significance, since the stereoselective synthesis of cis-
pyrrolidines has been of some recent interest,13;14 in
particular for their conformational controlling proper-
ties,15;16 and the application of N-methoxycarbonyl-
methyl derivatives for intramolecular Dieckmann
cyclisations leading to pyrrolizidine alkaloids has been
reported.3
References and notes
1. Hussaini, S. R.; Moloney, M. G. Org. Biomol. Chem.
2003, 1, 1838–1841.
2. Roth, M.; Dubs, P.; Gotschi, E.; Eschenmoser, A. Helv.
Chim. Acta 1971, 54, 710–734.
3. Rabiczko, J.; Urbabczyk-Lipkowska, Z.; Chmielewski, M.
Tetrahedron 2002, 58, 1433–1441.
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1984, 106, 4539–4547.
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1983, 48, 1439–1444.
Compound 7 proved to be amenable to further manip-
ulation, thus reaction with NaH and ethyl triflate in
CH2Cl2, or benzyl bromide in DMF at room tempera-
ture, gave products 8a,b in 32% (along with 29% of
recovered starting material) and 36%, respectively; the
regioselectivity of this process was evident from careful
NMR spectroscopic analysis and the cis-stereochemistry
was confirmed by NOE analysis (Fig. 1).17 For these
compounds, molecular modeling calculations (Chem-
Draw with MM2 parameters) suggested that the 2,5-
cis-isomers are more stable than the corresponding
2,5-trans-isomers by between 2.0 and 4.5 kJ molꢀ1. We
believe that these modest yields are due to the possibility
of multiple sites for deprotonation in such a densely
functionalised substrate. The importance of heterocyclic
N-alkylcarbonyl derivatives as conformational control-
ling elements in biologically relevant ligands has recently
been reported.18
6. Andersen, T. P.; Rasmussen, P. B.; Thomsen, I.; Lawes-
son, S.-O.; Jorgensen, P.; Lindhardt, P. Liebigs Ann.
Chem. 1986, 269–279.
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9. A solution of the lactam and LawessonÕs reagent
(0.5 equiv) was stirred at room temperature for 1.5 h in
dichloromethane, the solvent removed, and the product
purified by flash chromatography [EtOAc/petrol (40:60)
2:3].
10. Mechelke, M. F.; Meyers, A. I. Tetrahedron Lett. 2000, 41,
4339–4342.
11. For a recent review of the chemistry of enaminones, see:
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3479–3486.
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1141–1143.
15. Wallen, E. A. A.; Christiaans, J. A. M.; Saarinen, T. J.;
Jarho, E. M.; Forsberg, M. M.; Venalainen, J. I.;
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17. The starting material (0.1 g) was dissolved in THF (2 mL)
and LiHMDS (1.5 equiv) added at 0 °C. tert-Butyl bromo-
acetate (2 equiv) in THF (3 mL) was added after 15 min at
0 °C. The reaction was allowed to come to rt, stirred for
7 h and quenched at 0 °C using saturated aqueous ammo-
nium chloride, the organic layer washed with water, brine
and dried over magnesium sulfate. The product was
purified by column chromatography [20% EtOAc, light
petroleum (40:60)].
In conclusion, we have shown that efficient modifica-
tion of the lactam group of pyroglutamic acid and
N-alkylation of cis-2,5-disubstituted pyrrolidines is
possible under mild conditions, and that regioselec-
tive enolate formation and alkylation permits extension
of the appropriate side chain. This neatly comple-
ments our earlier work, which permits access to trans-
2,5-disubstituted pyrrolidines. The application of this
methodology for the synthesis of tetrahydroisoquino-
line alkaloids is under active investigation in our labo-
ratory.
Acknowledgements
We gratefully acknowledge The University of Oxford
(Lady Noon/OUP Fund), St. PeterÕs College Oxford for
a Graduate studentship Award, Lancaster Synthesis for
additional support, and the EPSRC Chemical Database
Service at Daresbury.19
18. Minami, N. K.; Reiner, J. E.; Semple, J. E. Bioorg. Med.
Chem. Lett. 1999, 9, 2625–2628.
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