Stereoselective synthesis of gem-dimethyl-5,5-pyrrolidine-trans-lactam (5-oxo-hexahydropyrrolo[3,2-b]pyrrole)

Article abstract of DOI:10.1016/S0040-4039(01)01410-1

The gem-dimethyl-trans-lactam 6 could be prepared by alkylation of the β-methyl isomer 7 but not by alkylation of the α-isomer 5.

Full text of DOI:10.1016/S0040-4039(01)01410-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6933–6935
Stereoselective synthesis of
gem-dimethyl-5,5-pyrrolidine-trans-lactam
(5-oxo-hexahydropyrrolo[3,2-b]pyrrole)
Alan D. Borthwick,* David E. Davies, Anne M. Exall, Andrew M. K. Pennell and
Jemima J. Richards
Department of Medicinal Chemistry CVUO UK, GlaxoSmithKline Research and Development, Medicines Research Centre,
Gunnels Wood Road, Stevenage, Herts. SG1 2NY, UK
Received 17 April 2001; revised 20 July 2001; accepted 27 July 2001
Abstract—The gem-dimethyl-trans-lactam 6 could be prepared by alkylation of the b-methyl isomer 7 but not by alkylation of the
a-isomer 5. © 2001 Elsevier Science Ltd. All rights reserved.
Selectivity for particular serine proteases in the novel,
strained, pyrrolidine-5,5-trans-lactam inhibitors is
determined1 by the substituent adjacent to the acylating
centre of the trans-lactam carbonyl group. We have
investigated2 the alkylation of the pyrrolidine-5,5-trans-
lactam and pyrrolidine-5,5-cis-lactam ring systems with
the aim of introducing a range of substituents into this
position.
tion in the novel, strained, unsubstituted 5,5-trans-lac-
tam ring 4 by alkylation of the corresponding enolate3
to give a series of a-alkyl-5,5-trans-lactams.2 However,
attempts to introduce a second methyl group into the
a-methyl-5,5-trans-lactam 5 to give the gem-dimethyl-
5,5-trans-lactam 6 failed (Scheme 2).
In the corresponding 3-methyl-5,6-trans-fused g-
lactam5 and g-lactone4 systems epimerisation, with
potassium tert-butoxide and stereoselective protonation
of the lithium enolate respectively, gave the correspond-
ing epimers. However, this does not happen with the
more strained pyrrolidine-5,5-trans-lactam or cyclopen-
tane-5,5-trans-lactone6 series ring systems, and neither
deuterium nor a methyl group could be incorporated
into the b-face of the a-substituted ring 5. As the
a-methyl-5,5-trans-lactam 5 was prepared by alkylating
the enolate of the unsubstituted ring 4 from the less
hindered a-face it was reasoned that the gem-dimethyl-
5,5-trans-lactam could be prepared by alkylating the
We have shown2 that methylation of the 5,5-cis-lactam
ring 1 gave the corresponding a-methyl-5,5-cis-lactam 2
where the enolate was alkylated, from the less hindered
convex side of the molecule, on the same face as the
ring-junction protons. Further methylation of 2, pre-
sumably from the less hindered convex side of the
molecule, gave the dimethyl analogue 3 in 63% yield
(Scheme 1).
We have also shown that a range of substituents can be
introduced stereoselectively at the corresponding posi-
Scheme 1. Reagents and conditions: (a) LHMDS (1.1 equiv.)/THF, −78°C, then MeI (2 equiv.).
Keywords: stereoselective alkylation; 5,5-trans-lactam ring pyrrolidines/pyrrolidinones.
* Corresponding author. Fax: +44 (0)1438 763616; e-mail: adb3028@glaxowellcome.co.uk
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01410-1

6934
A. D. Borthwick et al. / Tetrahedron Letters 42 (2001) 6933–6935
Scheme 2. Reagents and conditions: (a) LHMDS (1.3 equiv.), THF, −78°C, 30 min, then titration of excess MeI; (b) LHMDS (1.3
equiv.), THF, −78°C, 30 min, then excess D2O added; (c) LHMDS (1.2 equiv.)/THF, −78°C, 30 min, then (Boc)2O (2.8
equiv.)/THF or (MeOCO)2O, −78°C.
the corresponding overlap of the b-CꢀH bond in the
analogous a-methyl compound 7 is relatively poor
(dihedral angle 51.8°).
b-methyl-5,5-trans-lactam ring
7 from the a-face
(Scheme 2). Protection of 81b with di-tert-butyl or
dimethyl pyrocarbonate gave the protected lactams 77
and 9. Preliminary experiments demonstrated that the
gem-disubstituted analogues 10a and 10b could be pre-
pared by incorporating electrophiles into the a-face of
b-isomer 9. Similarly the required gem-dimethyl ana-
logue 6 was prepared in 72% yield by methylation of
the b-methyl-trans-lactam 7 with methyl iodide.
This stereoelectronic control should be enhanced by
allylic strain effects, whereby an electrophile approach-
ing the enolate from the b-face would experience severe
proximal strain whilst the strain and steric hindrance
for a-face attack would be significantly less.8
Mechanistically, the observed stereoselectivity can be
explained on the basis of the extreme rigidity of the
5,5-trans-lactam system and the consequent great dif-
ference in alignment of the a- and b-CꢀH bonds with
the carbonyl p-system. Molecular modelling (Insight
2000) shows that, in the only energetically accessible
conformation of the trans-lactam 4, the CꢀH bond to
the a-proton is almost parallel to the carbonyl p-system
(dihedral angle 4.3°) whereas that to the b-proton has
far less favourable overlap (dihedral angle 53.5°).
Unlike the corresponding cis-lactam 1 the trans-lactam
ring system 4 is too rigid to allow the flexion necessary
to achieve good overlap between the b-CꢀH and the
carbonyl p-system, so deprotonation and alkylation
occur on the a-face. Likewise, the b-methyl-5,5-trans-
lactam 2 shows excellent overlap of the carbonyl p-sys-
tem with the a-CꢀH bond (dihedral angle 0.2°) while
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