Rapid diastereocontrolled synthesis of 2,2,5-trisubstituted pyrrolidines

Article abstract of DOI:10.1039/b811642c

2,2,5-Trisubstituted pyrrolidines are available from allylic pyroglutamates by Ireland-Claisen ester rearrangement followed by Eschenmoser sulfide contraction and reduction in a highly diastereoselective and efficient sequence. Some of the products from this sequence exhibit activity against S. aureus, but are much less active against E. coli. The Royal Society of Chemistry 2008.

Full text of DOI:10.1039/b811642c

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Rapid diastereocontrolled synthesis of 2,2,5-trisubstituted pyrrolidines†
Nandkishkor Chandan and Mark G. Moloney*
Received 9th July 2008, Accepted 31st July 2008
First published as an Advance Article on the web 5th September 2008
DOI: 10.1039/b811642c
2,2,5-Trisubstituted pyrrolidines are available from allylic
pyroglutamates by Ireland–Claisen ester rearrangement fol-
lowed by Eschenmoser sulfide contraction and reduction in a
highly diastereoselective and efficient sequence. Some of the
products from this sequence exhibit activity against S. aureus,
but are much less active against E. coli.
We recently reported that 2,5-disubstituted pyrrolidines were avail-
able from pyroglutamic acid 1a, by application of an Eschenmoser
sulfide contraction1 to give an enamine intermediate 1b followed
by reduction (Scheme 1); depending on the nature of the R
group, either cis- or trans-2,5-disubstituted pyrrolidines 2 could
be accessed.2,3 We have also shown that trans-2,5-disubstituted
Scheme 1
pyrrolidines 4 are readily available by Grignard displacement of
the sulfone 3,4 but interestingly using both of these methods,
further manipulation of either the C-2 or C-6 positions via enolate
formation proved to be problematic, probably on steric grounds.
The development of stereoselective approaches to functionalised
pyrrolidines is a topic of considerable interest in the context
of natural product and small molecule synthesis, and medicinal
chemistry.5–7 Of interest to us were the recent reports of the
application of Ireland–Claisen ester rearrangements on furyl8,9
and pyrrolidinyl10,11 substrates, and we wondered if this approach
might provide rapid access to 2,2,5-trisubstituted pyrrolidine
derivatives from pyroglutamic acid. Such a substitution pattern
occurs in a range of natural products, including brevianamide
C,12 fusarin,6 azaspirene,13,14 lepadiformine,15 and kaitocephalin.16
We report here the successful application of this strategy for the
preparation of 2,2,5-trisubstituted pyrrolidines using a short and
high yielding sequence, which is highly diastereoselective.
methanol gave the methyl esters 8a–c in high yield, and conversion
of these lactams 8a–c to thiolactams 9a–c with Lawesson’s reagent
and reaction with diethyl bromomalonate–sodium bicarbonate to
effect an Eschenmoser sulfide contraction1 gave enamines 10a–c in
excellent yield, which could be reduced to the 2,2,5-trisubstituted
pyrrolidine system using sodium cyanoborohydride or sodium
borohydride–ruthenium trichloride giving vinyl lactams 11a–c or
propyl lactam 12 respectively in good yield. Pyrrolidines 11b and
11c were obtained as single diastereomers, but 11a as a 4 : 1 ratio of
cis-/trans- diastereomers. Noteworthy is the reduction of the vinyl
double bond in the latter case;21 this borohydride-type reduction of
enamines compares very favourably with the diastereoselectivity
of our earlier approaches2,3,22 but is significantly superior in terms
Table 1 Bioactivity of lactams against S. aureus and E. coli (hole plate
bioassay) at 4 mg ml-1
Esterification of pyroglutamic acid 5 under acidic or DCC con-
ditions conveniently gave the allylic esters 6a–c in excellent yield
(Scheme 2), and rearrangement using Kazmaier’s conditions11
efficiently gave the rearranged products 7a–c again in high yield;
this reaction was highly diastereoselective, giving 7a, 7b and 7c as
single diastereomers. Interestingly, the Claisen rearrangement only
occurred in the presence of the quinine ligand, but in its absence,
unreacted starting material was recovered from the reaction.17 The
relative stereochemistry of the new stereocentres of 7b and 7c was
established by single crystal X-ray analysis (Fig. 1, ESI†)18 and
found to be syn- in both cases, consistent with a chair transition
state in which the phenyl and methyl substituents respectively
occupy an equatorial position,19 an outcome which has been
reported in a related system.20 Esterification of the acid with acidic
Activity/mma (relative potency%b)
Substrate
S. aureus
E. coli
7a
7b
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
14 (3.8)
Inactive
15 (5.9)
16 (7.9)
16 (8.2)
15 (8.7)
14 (6.3)
14 (6.6)
12 (5.9)
15 (0.024)
16 (0.031)
16 (0.042)
Inactive
14 (0.024)
15 (0.037)
Inactive
14 (0.026)
16 (0.047)
13 (0.033)
15 (0.049)
14 (0.051)
12 (0.029)
12 (0.030)
14 (0.050)
7c
8a
8b
8c
9a
9b
9c
10a
10b
10c
11a
11b
11c
The Department of Chemistry, Chemistry Research Laboratory, The Univer-
sity of Oxford, 12 Mansfield Road, Oxford, UK OX1 3TA
a Zone size (mm) measured from hole plate bioassay at 4 mg ml-1 (7 :
3 DMSO–H2O).29 b Expressed as zone size per mg ml-1, relative to
cephalosporin C standard.
† Electronic supplementary information (ESI) available: Thermal ellipsoid
plots for compounds 7a–c. CCDC reference numbers 689197–689199. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/b811642c
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Scheme 2
Fig. 1 Thermal ellipsoid plots (ORTEP-34) at 40% probability level for compounds 7a–c.
of experimental execution, avoiding forcing reductive conditions.23
The establishment of 2,5-relative stereochemistry as that arising
by entry of hydride syn- to the C-2 ester, probably as a result of
steric control, was confirmed by careful nOe analysis (Scheme 2),
which showed that H-5 (multiplet at d3.83) gave a small but
observable nOe to the C-2 methyl ester as did the facially co-
located H-4. H-6 (doublet at d3.35) also gave a weak nOe to
the terminal vinylic hydrogens, as did proR H-4 to the remaining
vinylic hydrogen. Enhancements over this distance were suggestive
of a well-defined conformation in which the bulky C-2 and C-5
substituents adopted a pseudodiequatorial conformation and the
smaller ethoxycarbonyl group a pseudoaxial position, with the
long chain allyl group folded over the molecule; conformations in
simpler a-substituted prolines have recently been determined.24
In view of the known antibacterial activity of pyrrolidine-
and piperidine-containing natural products (such as monomorine,
anisomycin and solenopsine)25–27 and their importance in synthetic
antibiotics,28 bioassays of compounds against S. aureus and E. coli
(hole plate method) at 4 mg ml-1 were made (Table 1); this showed
that compounds 9, 10 and 11 were active against both organisms.
Although only giving weak antibacterial activity against E. coli,
these compounds are much more active against S. aureus, and this
structurally novel template offers a platform suitable for further
optimisation of this starting activity.
We have shown that rapid diastereoselective elaboration of
pyroglutamic acid to 2,2,5-trisubstituted pyrrolidines is possible in
a short, reliable sequence and in good overall yield, and that these
products exhibit antibacterial activity against S. aureus and E. coli.
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aqueous layer was extracted with methylene chloride and the combined
organic phase dried with MgSO4, evaporated under reduced pressure,
and the crude material purified by flashed chromatography, (ethyl
acetate–petroleum ether 1 : 7). 11a: Rf = 0.61 (30% EtOAc : 70%
Acknowledgements
NC gratefully acknowledges receipt of a National Overseas
Scholarship from the Indian Ministry of Social Justice and
Empowerment (GF6-352746), and MGM receipt of EPSRC grant
GR/T20380/01. We gratefully acknowledge the assistance of Dr
A. Knight with the X-ray analyses and the use of the EPSRC
Chemical Database Service at Daresbury.30
20.7
petrol); [a]D = -7.82 (c = 1.15, CHCl3), nmax/cm-1 (neat) 3215(bs),
2979(s), 1731(s), 1200(s); dH(CDCl3, 400 MHz), 1.25–1.26 (6H, t, J =
7.1, 2 ¥ OCH2CH3), 1.64 (1H, m, C4H), 1.82 (1H, m, C4H¢), 2.13 (1H,
=
m, C3H), 2.30 (1H, m, C3H¢), 2.45 (2H, m, CH2CH CH2), 3.30 (1H,
d, J = 9.0, CH(COOEt)2), 3.69 (3H, s, OCH3), 3.79 (1H, m, C5H),
=
4.16–4.20 (4H, q, J = 7.1, 2 ¥ OCH2CH3), 5.04 (2H, m, CH2 CH),
=
5.70 (1H, m, CH CH2); dC(400, CDCl3), 13.6(2 ¥ OCH2CH3), 27.9
=
(C4H2), 32.9 (C3H2), 43.9 (CH2CH CH2), 51.7 (OCH3), 56.1 (C5H),
References
=
58.5 (CH(CO2Et)2), 60.8 (2 ¥ OCH2CH3), 68.7 (C2), 117.4 (CH2 CH),
+
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=
133.2 (CH CH2), 167.6–167.9 (2 ¥ CO2Et), 176.5 (CO2Me); m/z (ES )
328 (M + H+, 100%), 350 (M + Na+, 90%); HRMS (M + H+) accurate
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3215(bs), 2979(s), 1731(s), 1447(s), 1369(bs), 1251(s), 1200(s), 1036(s),
917(s), 862(s); dH(CDCl3, 400 MHz), 0.84 (3H, d, CHCH3), 1.25 (6H,
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1.86 (1H, m, C3H), 1.99 (1H, m, C3H¢), 2.45 (1H, m, CHCH3), 2.89
(1H, bs, NH), 3.25 (1H, d, J = 8.9, CH(COOEt)2), 3.70 (3H, s, OCH3),
3.76 (1H, m, C5H), 4.17 (4H, q, J = 7.1, 2 ¥ OCH2CH3), 5.02 (2H,
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=
=
m, CH2 CH), 5.72 (1H, m, CH CH2); dC (400, CDCl3), 14.3 (2 ¥
OCH2CH3), 16.4 (CH3CH), 28.7 (C4H2), 32.4 (C3H2), 45.8 (CH3CH),
52.4 (OCH3), 56.8 (C5H), 59 (CH(CO2Et)2), 61.5 (2 ¥ OCH2 CH3), 72.1
=
=
(C2), 115.9 (CH2 CH), 140.2 (CH CH2), 168.4–168.7 (2 ¥ CO2Et),
177.7 (CO2Me); m/z (ES+) 342 (M + H+, 100%), 340 (M - H+, 85%), 364
(M + Na+, 97%); HRMS (M + H+) accurate mass 342.1898, C17H28NO6
20.7
requires 342.1911. 11c: Rf = 0.42 (20% EtOAc : 80% petrol), [a]D
=
-13.36 (c = 2.2, CHCl3); nmax/cm-1(neat) 3215(bs), 2981(s), 1732(s),
1369(s), 1200(s), 1030(s), 772(s); dH (CDCl3, 400 MHz), 1.26 (3H, t,
J = 7.1, OCH2CH3), 1.32 (3H, t, J = 7.1, OCH2CH3), 1.64 (1H, m,
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3.35 (1H, d, J = 9.1, CH(CO2Et)2), 3.53 (3H, s, OCH3), 3.61 (1H,
d, CHPh), 3.83 (1H, m, C5H), 4.19 (2H, q, J = 7.1, OCH2CH3),
=
4.28 (2H, q, J = 7.1, OCH2CH3), 5.17 (2H, m, CH2 CH), 6.32 (1H,
=
m, CH CH2), 7.15–7.25 (5H, m, ArH); dC(400, CDCl3), 15.5 (2 ¥
OCH2CH3), 30 (C4H2), 34.3 (C3H2), 53.4 (OCH3), 57.9 (CHPh), 58.3
(C5H), 60.3 (CH(CO2Et)2), 62.6 (2 ¥ OCH2CH3), 74.2 (C2), 118.9
=
=
(CH2 CH), 128–129.5 (ArC), 138.9 (ArC), 142.4 (CH CH2),169.5–
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(M - H+, 100%), 426 (M + Na+, 85%): HRMS (M + H+) accurate mass
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689198 and 689199. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
[fax: +44 (0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk.
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After the reaction mixture was stirred for 36 h, methylene chloride
(20 ml) was added and the solution was washed with 10% NaHCO3, the
3666 | Org. Biomol. Chem., 2008, 6, 3664–3666
This journal is
The Royal Society of Chemistry 2008
©