Trans-2,5-Disubstituted pyrrolidines: Rapid stereocontrolled access from sulfones

Article abstract of DOI:10.1039/b611583g

A direct method for the reliable synthesis of trans-2,5-distributed pyrrolidines from pyroglutamic acid that was conducted at scale and without chromatographic purification of key intermediates was investigated. An analogous reaction involving the partial reduction of succinimides and displacement of the resulting lactol with benzenesulfinic acid yields sulfonyl pyrrolidinones. It was found that a highly diastereoselective and general approach to 2,5-difunctionalized pyrrolidines could be achieved by applying this strategy to the pyroglutamate system. The four step synthesis required no chromatographic purification of intermediates, where the product sulfone was readily purified by recrystallization and the sequence proceeded in 52% overall yield. The results show that such an approach would be of great importance for the preparation of substituted pyrrolidines in natural product systems.

Full text of DOI:10.1039/b611583g

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www.rsc.org/obc | Organic & Biomolecular Chemistry
trans-2,5-Disubstituted pyrrolidines: rapid stereocontrolled access
from sulfones
Mark G. Moloney,*a,b Terry Panchala,b and Richard Pikea,b
Received 10th August 2006, Accepted 19th September 2006
First published as an Advance Article on the web 3rd October 2006
DOI: 10.1039/b611583g
A direct and versatile route for the reliable synthesis of
trans-2,5-disubstituted pyrrolidines from pyroglutamic acid
is reported, which can be conducted at scale and without
chromatographic purification of key intermediates.
2,5-Disubstituted pyrrolidines are of widespread occurrence
amongst natural products and considerable importance in a
variety of contexts, and much effort has been expended on
the development of suitable synthetic methodology to access
them,1,2 and some recent developments expand the opportunities
in that regard.3–5 The synthesis of these compounds by elaboration
of pyroglutamic acid 1a has been achieved using a variety of
approaches, but common difficulties have been operational com-
plexity, scalability, generality, or control of diastereoselectivity.6–12
Scheme 1
at the newly introduced chiral centre. However, because of the
The first report of diastereoselective access to cis- and trans-
2,5-disubstituted pyrrolidines using pyroglutamate was made
by Rapoport.13 Subsequent to this, more general approaches,
based upon nucleophilic additions to N-acyliminium species, also
readily available from pyroglutamate, became available, but these
principally gave access to mixtures of diastereomeric products,11,14
although careful choice of conditions did enable high levels of
trans-diastereocontrol; organocuprates15 and the use of bicyclic
systems10 were found to be particularly useful in that regard.
Other methods of attaining high trans-selectivity involve cyclisa-
tions of suitable substrates derived from pyroglutamate,16–20 more
recently by Pd(0)-mediated coupling21 and sequential lithiation of
N-Boc pyrrolidine.22 Cis-selective synthesis of 2,5-disubstituted
pyrrolidines is generally achieved by reduction of a suitable
monosubstituted system,4,6,8,9,23–26 but has also been reported to
be possible by nucleophilic additions to N-acyliminium species; in
this case, the diastereoselectivity was found to critically depend
on the nature of the nitrogen protecting groups and the ring
substituents.27
potential simplicity of this overall approach, and the utility of
the products, it was of interest to us to optimise this chemistry
as far as possible. The difficulties appeared to derive from the
order of the manipulations on pyroglutamic acid 1a; for maximum
effectiveness, the Eschenmoser sulfide contraction proceeds best
with (doubly activated) bromomalonates, but this in turn generates
a highly deactivated enamine product 1b that is both difficult to
reduce in the first instance, and then prone to epimerisation once
reduced.
A much more common approach to 2,5-difunctionalised pyrro-
lidines in the literature is initial partial reduction of pyrog-
lutamate to an intermediate lactol 4a, followed by displace-
ment with methanol to give aminal 4b (Scheme 2).14 Reaction
of 4b with organometallic nucleophiles yields 2,5-disubstituted
pyrrolidines, but the stereocontrol is largely dependent on the
We recently reported that both cis- and trans-2,5-disubstituted
pyrrolidines were available from pyroglutamic acid 1a, by applica-
tion of an Eschenmoser sulfide contraction28 to give an enamine
intermediate 1b, followed by reduction (Scheme 1); depending on
the nature of the R group, either cis- and trans-2,5-disubstituted
pyrrolidines 3a or 3b could be accessed.29,30 However, although an
effective sequence, this methodological approach was limited by
the difficulty of the reduction of the enamine 1b, which typically
required Adams catalyst and high pressure, and the formation of
an activated b-aminoester moiety 2 that was particularly suscep-
tible to retro-conjugate addition, leading to facile epimerisation
Scheme 2 Reagents and conditions: (i) 3 equiv. EtOH, cat. H2SO4, toluene,
reflux, overnight, 94%; (ii) 1.1 equiv. Boc2O, 0.1 equiv. DMAP, 1.5 equiv.
Et3N, DCM, rt, overnight, 97%; (iii) 1 equiv. LiBEt3H, THF, −78 ◦C,
1 h, product not isolated; (iv) 1 equiv. PhSO2H, 3 equiv. CaCl2, DCM, rt,
overnight, 57%.
aThe Department of Chemistry, Chemistry Research Laboratory, The
University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK
bGlaxoSmithKline Research & Development Ltd, New Frontiers Science
Park, Third Avenue, Harlow, Essex, CM19 5AW, UK
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Table 1 Reaction of sulfone 6 with organometallic reagents according to Scheme 3
R
Conditionsa
Product 7 or 8 (yield, %)
Product 9 (yield, %)
Ph-
m-MeOC6H4-
H2C CH-
H2C CHCH2-
PhCH CH-
A
A
A
C
A
A
A
A
B
7a (93)
7b (72)
7c (28)
7d (39)
7e (15)
7f (76)
7g (68)
7h (76)
8a (39)
8b (38)
9a (34)
9b (68)
—
=
=
—
—
=
PhC≡C-
9c (70, 68b)
—
MEMOCH2C≡C-
TBDPSOCH2C≡C-
t-BuO2CCH2-
9d (45)
—
—
t-BuO2CCH(Me)-
B
a Conditions A (RMgBr, ZnBr2, rt, THF); B (RZnBr, reflux, overnight); C (RMgBr, ZnCl2, rt, CH2Cl2, THF). b Direct conversion of 6 → 7f → 8c without
isolation of intermediates.
nature of the nucleophile, the N-protecting group and other
ring substituents.27 An analogous reaction involving the partial
reduction of succinimides and displacement of the resulting
lactol with benzenesulfinic acid yields sulfonyl pyrrolidinones,
which undergo selective nucleophilic displacement of the sulfone
with Grignard reagents and zinc bromide.38 This method is
versatile, and applicable to a range of organometallic nucleophiles,
but since the reaction appears to proceed through an SN1-like
mechanism, the diastereoselectivity is principally dependent on the
substrate. It therefore seemed to us that a highly diastereoselective
and general approach to 2,5-difunctionalised pyrrolidines could
be achieved by applying this strategy to the pyroglutamate
system.
Conversion of pyroglutamic acid 5a to its ester 5b, N-BOC
protection to 5c and reduction to the hemiaminal intermediate 4a
followed the literature protocol.14 Displacement of the hydroxyl
group with benzenesulfinic acid gave the crystalline product 6
in 57% yield (Scheme 2);31 the presence of the BOC protection
is essential for the stability of this compound. NOESY analysis
did not give correlation between H-2 and H-5, as expected for
a trans-relationship,32 and this assignment was easily confirmed
by single-crystal X-ray analysis.33 Significantly, this four-step
synthesis from commercially available pyroglutamic acid requires
no chromatographic purification of intermediates, the product
sulfone is readily purified by recrystallisation, and the sequence
proceeds in 52% overall yield. The reaction has been successfully
run on a thirty-gram scale.
An investigation of the displacement of the sulfone residue
was then made; we found that displacement of the phenylsulfone
residue was most readily achieved on a scale up to 1.5 mmol
using a mixture of Grignard reagents† with zinc halide salts
to give products 7a–h, or less efficiently with Reformatsky
reagents, to give aminoesters 8a,b (Table 1).31 This reaction was
entirely chemoselective for the phenylsulfonyl residue, and the
trans-2,5-disubstituted products were obtained exclusively after
chromatography. Unfortunately these were not crystalline, and
direct stereochemical assignment was therefore not possible, since
NOESY analysis was not a reliable method, as discussed above.
Removal of the BOC group from compounds 7a, 7b, 7f and 7h with
TFA readily gave products 9a–d and simultaneously permitted
stereochemical assignment. NOE analysis of 9a showed only a very
weak direct enhancement of H-2 and H-5, irradiation of H-5 gave
enhancements to all of H-4a, H-4band H-3a, and irradiation of H-
2 gave enhancements to all of H-3a, H-3b and H-4b; this is consis-
tent with trans-2,5-stereochemistry, and by implication trans-2,5-
stereochemistry of the BOC-protected pyrrolidine 7a (Scheme 3).34
The relative stereochemistry of the compounds 7b, 7f and 7h were
assigned in a similar manner. This trans-stereochemical outcome
could be explained by initial elimination of the sulfone residue
by assistance from the adjacent ester to generate an iminium ion,
followed by subsequent nucleophilic attack which occurs anti to
the C-2 ester substituent (Scheme 3); this nicely complements the
route selective for the cis-isomer reported by Langlois.8,9 Evidence
for the straightforward formation of the required intermediate
Scheme 3
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acyliminium ion (Scheme 3) comes from the X-ray analysis of 6,
in which the distance from the oxygen of the ester carbonyl to the
23 A. J. Mota and N. Langlois, Tetrahedron Lett., 2003, 44, 1141–1143.
24 H. Li, T. Sakamoto and Y. Kikugawa, Tetrahedron Lett., 1997, 38,
6677–6680.
25 R. Lin, J. Castells and H. Rapoport, J. Org. Chem., 1998, 63, 4069–4078.
26 D. E. Davies, P. M. Doyle, R. D. Farrant, R. D. Hill, P. B. Hitchcock,
P. N. Sanderson and D. W. Young, Tetrahedron Lett., 2003, 44, 8887–
8891.
27 T. Shono, T. Fujita and Y. Matsumara, Chem. Lett., 1991, 81–84.
28 M. C. Elliott and S. V. Wordingham, SYNLETT, 2006, 1162–1170.
29 S. R. Hussaini and M. G. Moloney, Org. Biomol. Chem., 2003, 1, 1838–
1841.
˚
C-5 carbon is only 3.30 A, thereby facilitating neighbouring group
participation.
This sequence can be operated without isolation of interme-
diates; thus, conversion of sulfone 6 to acetylene 7f immediately
followed by deprotection (TFA) gave a 68% yield of product 9c.
A novel method providing exclusive access to trans-2,5-
disubstituted pyrrolidines from pyroglutamic acid which can be
operated at scale via a crystalline intermediate and with no chro-
matographic purification has been established. We anticipate that
this approach will be of synthetic importance for the preparation
of similarly substituted pyrrolidines in natural product systems.
30 S. R. Hussaini and M. G. Moloney, Tetrahedron Lett., 2004, 45, 1125–
1127.
31 Preparation of 6: Lactam 5c (13.7 g, 53.4 mmol) in dry THF (550 ml)
under N2 was cooled to −78 ◦C, and lithium triethylborohydride
solution (53.4 ml, 1.0 M in THF) slowly added such that the
temperature was maintained below −65 ◦C. The mixture was left for
1 h and quenched by addition of sat. aq. NaHCO3 solution (70 ml)
followed by hydrogen peroxide (35% w/w) (27 ml). The mixture was
allowed to warm to rt and stirred for 30 min. The solvent was removed
in vacuo and the solid residue was extracted with DCM (3 × 200 ml)
and the solution filtered. The combined organic layers were dried over
MgSO4 and concentrated in vacuo to give crude 4a which was used
immediately without further purification. Crude 4a, benzenesulfinic
acid (7.59 g, 53.4 mmol) and calcium chloride (17.8 g, 160 mmol) were
suspended in DCM (690 ml) and stirred at rt under N2 overnight.
Water (345 ml) was added and the mixture was extracted with DCM
(3 × 345 ml). The combined organic phases were dried over MgSO4
and concentrated in vacuo to yield the crude product as a yellow solid.
The solid was purified by recrystallisation from diethyl ether to give
the product as a white crystalline solid (10.1 g, 49%). [a]2D2 = −56.3 (c
1.00, CH2Cl2); mp 122–124 ◦C (diethyl ether); dH (C6D6, 400 MHz) (2
rotamers) 1.00 (3H, 2 × t, J 7.1, OCH2CH3), 1.23 and 1.25 (3H and 6H,
2 × s, C(CH3)3), 1.58–1.70 (1H, m, C(3)H), 2.02–2.24 (1H, m, C(4)H),
2.53–2.95 (2H, m, C(3)H and C(4)H), 3.84–4.04 (2H, m, OCH2), 4.45
and 4.67 (0.7H and 0.3H, 2 × d, J 9.1, C(2)H), 5.20 and 5.40 (0.3H and
0.7H, 2 × d, J 8.1, C(5)H), 7.00–7.16 (3H, m, ArH), 7.87–8.04 (2H, m,
ArH); dC (C6D6, 100 MHz) (2 rotamers) 14.0, 14.1 (OCH2CH3), 24.8,
26.4 (C(3)), 27.7, 37.8 (C(CH3)3), 28.2, 29.7 (C(4)), 61.0 (OCH2), 60.9,
61.1 (C(2)), 78.6, 79.1 (C(5)), 80.8, 81.3 (C(CH3)3), 127.8, 127.9, 128.0,
128.2, 128.8, 129.2, 129.8, 133.3, 133.5 (Ar(C)), 138.9 (q, Ar(C)), 152.9,
153.4 (CO2C(CH3)3), 172.1, 172.3 (CO2CH2CH3); m/z (EI) 789 (2M
+ Na+, 75%), 442 (M + MeCN + NH4+, 100%), 406 (M + Na+, 15%);
HRMS (M + Na+) calculated 406.1300, found 406.1309. Preparation
of pyrrolidine 7f: Isopropylmagnesium chloride solution (1.3 ml, 2.0 M
in diethyl ether) was added to a solution of phenylacetylene (0.29 ml,
2.58 mmol) in dry THF (5 ml) under N2 at 0 ◦C so that the temperature
did not exceed 25 ◦C. After, the addition was complete, the mixture was
warmed to rt and left for 1 h. A solution of anhydrous zinc bromide
(0.580 g, 2.58 mmol) in dry THF (5 ml) was added to the mixture
and stirred for 30 min. A solution of sulfone 6 (0.494 g, 1.29 mmol)
in dry THF (10 ml) was added to the mixture and the reaction was
left overnight. The reaction was quenched by addition of sat. aq.
NH4Cl (15 ml) and water (15 ml). The organic layer was separated
and the aqueous layer was extracted with EtOAc (3 × 25 ml). The
combined organic layers were dried over brine (50 ml) and MgSO4,
and concentrated in vacuo to give the crude product. The product was
purified by silica gel flash column chromatography [10 : 90 EtOAc–
petrol (40–60)], which gave the pure product as a colourless liquid
(0.34 g, 76%). Rf = 0.54 [40 : 60 EtOAc–petrol (40–60)]; [a]2D2 = −151
(c 0.50, CH2Cl2); dH (CDCl3, 400 MHz) (2 rotamers) 1.23–1.30 (3H, m,
OCH2CH3), 1.43 and 1.50 (4.5H and 4.5H, 2 × s, C(CH3)3), 2.00–2.10
(2H, m, C(3)Ha and C(4)Hb), 2.22–2.34 (1H, m, C(4)Ha), 2.43–2.60 (1H,
m, C(3)Hb), 4.06–4.23 (2H, m, OCH2CH3), 4.34 and 4.44 (0.5H and
0.5H, 2 × d, J 8.8, C(2)H), 4.83 and 4.95 (0.5H and 0.5H, 2 × d, J 7.8,
C(5)H), 7.24–7.43 (5H, m, ArH); dC (CDCl3, 100 MHz) (2 rotamers)
14.1, 14.3 (OCH2CH3), 28.3, 28.4 (C(CH3)3), 28.6, 29.7 (C(3)), 31.3,
31.9 (C(4)), 49.3, 49.5 (C(5)), 58.7, 59.1 (C(2)), 61.0, 61.1 (OCH2CH3),
80.4 (C(CH3)3), 81.8, 82.0 (C(7)), 89.2, 89.4 (C(6)), 123.0 (q, Ar(C)),
128.0, 128.1, 128.3, 131.5, 131.8 (Ar(C)), 153.1, 153.8 (CO2C(CH3)3),
172.5, 172.8 (CO2CH2CH3); m/z (EI) 402 (M + MeCN + NH4+, 100%),
366 (M + Na+, 2%); HRMS (M + H+) calculated 344.1862, found
344.1859.
Acknowledgements
RP gratefully acknowledges CASE studentship support from the
EPSRC and GSK (Harlow). We thank Dr Andrew Cowley for
the crystallographic analysis. We gratefully acknowledge the use
of the EPSRC Chemical Database Service at Daresbury.35
Notes and references
†
Grignard reagents were chosen on the basis of their potential for
side chain extension, but alkyl Grignard cases are equally satisfactory;
octylmagnesium gave the corresponding product 7 in 65% yield.
1 M. Pichon and B. Figadere, Tetrahedron, 1996, 7, 927–964.
2 P.-Q. Huang, Synlett, 2006, 1133–1149.
3 L. Banfi, A. Basso, G. Guanti and R. Riva, Tetrahedron, 2006, 62,
4331–4341.
4 F. A. Davis, M. Song and A. Augustine, J. Org. Chem., 2006, 71, 2779–
2786.
5 L. Banfi, A. Basso, G. Guanti and R. Riva, Tetrahedron Lett., 2004, 45,
6637–6640.
6 J. B. Brenneman, R. Machauer and S. F. Martin, Tetrahedron, 2004, 60,
7301–7314.
7 A. C. Rudolph, R. Machauer and S. F. Martin, Tetrahedron Lett., 2004,
45, 4895–4898.
8 J. B. Brenneman and S. F. Martin, Org. Lett., 2004, 6, 1329–1331.
9 A. J. Mota, A. Chiaroni and N. Langlois, Eur. J. Org. Chem.,
2003, 4187–4198. For a recent in-depth discussion of stereocontrol
in acyliminium reactions, see:; T. Shinada, M. Hamada, M. Kawasaki
and Y. Ohfune, Heterocycles, 2005, 66, 511–525.
10 H. Dhimane, C. Vanucci-Bacque, L. Hamon and G. Lhommet,
Eur. J. Org. Chem., 1998, 1955–1963.
11 M. V. Chiesa, L. Manzoni and C. Scolastico, Synlett, 1996, 441–443.
12 N. Langlois and A. Rojas, Tetrahedron, 1993, 49, 77–82.
13 K. Shiosaki and H. Rapoport, J. Org. Chem., 1985, 50, 1229–1239;
J. S. Petersen, G. Fels and H. Rapoport, J. Am. Chem. Soc., 1984, 106,
4539–4547.
14 P. W. R. Harris, M. A. Brimble and P. D. Gluckman, Org. Lett., 2003,
5, 1847–1850.
15 I. Collado, J. Ezquerra and C. Pedregal, J. Org. Chem., 1995, 60, 5011–
5015.
16 I. Collado, J. Ezquerra, J. J. Vaquero and C. Pedregal, Tetrahedron Lett.,
1994, 35, 8037–8040.
17 J. Mulzer, F. Schulzchen and J.-W. Bats, Tetrahedron, 2000, 56, 4289–
4298.
18 V. K. Aggarwal, F. Sandrinelli and J. P. H. Charmant, Tetrahedron:
Asymmetry, 2002, 13, 87–93.
19 J. A. Sweet, J. M. Cavallari, W. A. Price, J. W. Ziller and D. V. McGrath,
Tetrahedron: Asymmetry, 1997, 8, 207–211.
20 J. Ezquerra, A. Rubio, C. Pedregal, G. Sanz, J. H. Rodriguez and J. L.
Garcia Ruano, Tetrahedron Lett., 1993, 34, 4989–4992.
21 K. R. Campos, A. Klapars, J. H. Waldman, P. G. Dormer and C. Chen,
J. Am. Chem. Soc., 2006, 128, 3538–3539.
32 This lack of NOE enhancement is not an unequivocal demonstration
of trans-2,5-disubstitution, since our own NOESY analysis of cis- and
22 P. Beak and W. K. Lee, J. Org. Chem., 1993, 58, 1109–1117.
3896 | Org. Biomol. Chem., 2006, 4, 3894–3897
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trans-4b showed no enhancement between H-2 and H-5 in both cases.
However, we have recently reported that stereochemical assignment
in related systems can be more reliably achieved using a VT-NOESY
protocol which eliminates complicating conformational effects, and
in this case the cis-2,5-disubstituted pyrrolidines gave clear NOE(SY)
enhancements between H-2 and H-5, but the trans-2,5-disubstituted
pyrrolidines did not.36 This assignment was confirmed by single crystal
X-ray analysis in several cases.
reference number 615009. For crystallographic data in CIF or other
electronic format see DOI: 10.1039/b611583g.
34 Our proton spectrum for trans-9a was identical to the spectroscopic
data reported for trans-9a; data for cis-9a has also been reported.15
These were assigned by reference to compounds previously reported in
the literature (see ref. 37).
35 D. A. Fletcher, R. F. McMeeking and D. Parkin, J. Chem. Inf. Comput.
Sci., 1996, 36, 746–749.
33 Crystal data and data collection parameters for compound 6:
36 S. R. Hussaini and M. G. Moloney, Org. Biomol. Chem., 2006, 4, 2600–
2615.
C18H25NO6S, M = 383.47, monoclinic, a = 10.6783(3), b = 8.1891(2),
◦
3
˚
˚
c = 11.1365(3) A, b = 98.9319(17) , V = 962.03(4) A , T = 150 K,
space group P21, Z = 2, Dx = 1.324 Mg m−3, l = 0.201 mm−1, 9083
reflections measured, 4183 unique (Rint = 0.039). The final wR(F2) was
0.0340 (all data). The compound was crystallised from EtOAc. CCDC
37 T. Shono, Y. Matsumura, K. Tsubata and K. Uchida, J. Org. Chem.,
1986, 51, 2590–2592.
38 D. S. Brown, P. Clarreau, T. Hansson and S. V. Ley, Tetrahedron, 1991,
47, 1311–1328.
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