Diastereoselective synthesis of 4-substituted L-prolines by intramolecular radical cyclization of N-aryl sulphonyl-N-allyl 3-bromoalanines: Interesting dependence of selectivity on the nature of sulphonamido groups

Article abstract of DOI:10.1246/cl.2002.710

Enantiopure 4-substituted L-proline derivatives have been prepared via intramolecular radical cyclization of N-aryl sulphonyl-N-allyl-3-bromo-L-alanines in high yields. Surprisingly, the extent of selectivity was found to be primarily dependent on the nat

Full text of DOI:10.1246/cl.2002.710

710
Chemistry Letters 2002
Diastereoselective Synthesis of 4-Substituted L-Prolines by Intramolecular Radical Cyclization
of N-Aryl sulphonyl-N-allyl 3-bromoalanines:Interesting Dependence of Selectivity on the
Nature of Sulphonamido Groups
Amit Basak,Ã Subhendu Sekhar Bag, Kakali Rani Rudra, Jharna Barman, and Sumana Dutta
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
(Received July 3, 2002; CL-020222)
Enantiopure 4-substituted L-proline derivatives have been
prepared via intramolecular radical cyclization of N-aryl
sulphonyl-N-allyl-3-bromo-L-alanines in high yields. Surpris-
ingly, the extent of selectivity was found to be primarily
dependent on the nature of sulphonamido aryl group and could
be as high as 33 : 1 using naphthyl sulphonamide.
excellent to moderate seems not to depend upon the steric bulk of
the ester as revealed in the constancy of product ratio when benzyl
is replaced by diphenyl methyl (example 11a and 11e) both of
which having the N-tosyl group. Replacement of the allyl group
with cinnamyl group predictably lowered the diastereoselectivity
mainly because of the generation of a stabilized radical that
inhibited the equilibriation process for the generation of
thermodynamically more stable product. The most interesting
aspect of this cyclization was the unexpected dependence of
diastereoselectivity on the nature of the sulphonamido aryl group.
In case of the naphthyl sulphonamido having a benzyl ester 11d,
the selectivity went upto around 8 : 1 as compared to 3 : 1 in case
of tosyl. Increasing the steric bulk of the ester in 11k led to even
higher extent of selectivity (33 : 1). Changing the electron
withdrawing character of the sulphonamido aryl also improved
the extent of selectivity, though to a lesser extent. Similar trend
was reflected in case of the cinnamyl system. With naphthyl
sulphonamide, the diastereoselectivity also improved, although
much less dramatically, because of the generation of stable benzyl
radical which hinders the equilibriation between the radicals. The
selectivity did not change by carrying out the reaction at a higher
temperature in refluxing toluene.
Peptide structures containing proline derivatives have
received considerable interest in the area of protein folding1
and drug design.2 Special structural motifs like the ꢀ-turn as well
as the various enzyme inhibitors very often involve proline.
Proline-containing natural products3 with interesting biological
properties is also well known. Thus methods leading to the
synthesis of proline derivatives especially in enantio pure forms
are always important. Out of the several possibilities, stereo-
selective C3–C4 bond formation leading to the heterocyclic ring
of proline from an acyclic intermediate is the one that drew our
attention. Literature survey revealed the excellent contribution by
Padwa et al.4 in the mid eighties on the synthesis of pyrrolidines
via intramolecular radical cyclization. In a closely related study,
Adlington et al.5 synthesized exomethylene proline derivatives
via the cyclization of N-propargyl sulphones. In both the cases the
reaction preferentially followed the kinetically favourable 5-exo
route. However the question of any steric induction during radical
cyclization did not arise in these examples. Parsons et al.6 have
also developed a radical cyclization route to various pyrrolidi-
nones. Pandey et al.7 synthesized pyrrolidines by a PET promoted
cyclization. However the diastereoselectivity in both methods
was not satisfactory. To our knowledge, intramolecular cycliza-
tion of N-allyl-N-aryl sulphonyl alanines8 that would lead to
homochiral 4-substituted L-prolines have not been tried. In this
paper we provide a number of such examples. We also reveal a
novel approach of increasing the diastereoselectivity to an
extraordinarily high level.
Our initial attempt to prepare the iodo alanine derivative 10a
that would have been a better radical precursor under mild
condition was not successful because of its extreme sensitivity
towards ꢀ-elimination. This has compelled us to prepare the
bromo alanines 11a–11k from the corresponding serine deriva-
tives 9a–9k via reaction with PPh3 and carbon tetrabromide
(Scheme 1).9 The bromo derivatives were stable and can be stored
in the refrigerator without any elimination. On being subjected to
tin hydride mediated radical generating conditions10 (Bu3SnH,
AIBN, benzene, reflux) 11a–11k underwent smooth intramole-
cular cyclization to generate the proline derivatives 5a–5k and
6a–6k in yields of over 80%. The results shown in Table 1
revealed exclusive 5-exo addition11 with predominant formation
of the trans isomer.12 The diastereoselectivity which varied from
Scheme 1.
The predominant formation of the trans isomer could be
explained on the basis of a chair-like conformation13 for the
transition states leading to the diastereomers (Scheme 2). The TS
‘‘A’’ leading to the trans isomer has both the ester and the
sulphonamido in the pseudo equatorial configuration. Formation
of the cis isomer involves a TS ‘‘B’’ in which the ester is in the
pseudo axial orientation. The energy difference between the two
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
711
Table 1. Cyclization of Various Bromides 11a–11k
sulphonamides.
Thus we have demonstrated forthe first time the remote effect
of a sulphonamido group in controlling the selectivity of radical
cyclization leading to the formation of proline derivatives. By
fine-tuning the nature of sulphonyl aryl, the selectivity could be
increased to a very high level. This should offer a new general
strategy towards synthesis of enantiomerically pure 4-substituted
proline derivatives.
SSB and KR thank Council of Scientific and Industrial
Research for Research Fellowships. SD thanks Jawaharlal Nehru
Centre for Advanced Research, Bangalore, India for a summer
fellowship.
Entry Substituents
Substrate Products Total
and their percent
ratio
yield
80
1
2
R=H, R1=Bn
Ar=p-Tolyl
R=H, R1=Bn
Ar=p-
Nitrophenyl
11a
11b
5a & 6a
3 : 1
5b & 6b
4 : 1
83
85
3
R=H, R1=Bn
Ar=p-
Chlorophenyl
11c
5c & 6c
4 : 1
References and Notes
4
5
R=H, R1=Bn
Ar=2-Naphthyl
11d
11e
5d & 6d
8 : 1
85
82
1
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R=H,
R1=CHPh2
Ar=p-Tolyl
R=Ph, R1=Bn,
Ar=p-Tolyl
5e & 6e
3 : 1
6
7
11f
5f & 6f
1:7 : 1
85
90
R=Ph,
R1=CHPh2
Ar=p-Tolyl
R=Ph, R1=Bn
Ar=2-Naphthyl
11g
5g & 6g
2 : 1
2
3
R. B. Silverman, ‘‘Organic Chemistry of Drug Design and
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8
9
11h
11i
5h & 6h
2:5 : 1
87
88
R=Ph,
R1=CHPh2
Ar=2-Naphthyl
5i & 6i
3:5 : 1
4
5
6
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10
11
R=Ph,
11j
5j & 6j
2:5 : 1
90
96
R1=CHPh2
Ar=p-
Nitrophenyl
R=H,
R1=CHPh2
Ar=2-Naphthyl
11k
5k & 6k
33 : 1
7
8
G. Pandey, G. D. Reddy, and G. Kumaraswamy, Tetrahedron,
50, 8185 (1994).
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9
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12 The configurations were determined from NOE and coupling
constants.
13 A. L. J. Beckwith, T. Lawrence, and K. S. Serelis, J.Chem.
Soc., Chem.Commun. , 1980, 484.
Scheme 2.
TS is dependent upon the steric bulk or electronic nature of the