A new approach to 5-substituted prolines and 2-pyrrolecarboxylates

Article abstract of DOI:10.1055/s-1998-1768

Iodocyclisations of the allylic glycinates 7 lead either to the trans- or cis-2,5-disubstituted proline derivatives 8 or 9, depending on the reaction conditions; subsequent treatment of these with DBU in DMF gives the 2-pyrrolecarboxylates 10 and 13 in excellent yields by a double elimination of hydrogen iodide and toluenesulfinic acid.

Full text of DOI:10.1055/s-1998-1768

July 1998
SYNLETT
731
A New Approach to 5-Substituted Prolines and 2-Pyrrolecarboxylates
a,*
a
b
David W. Knight, Adele L. Redfern and Jeremy Gilmore
a
Chemistry Department, Cardiff University, P. O. Box 912, Cardiff, CF1 3TB, UK
b
Eli Lilly and Co. Ltd., Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey, GU20 6PH, UK
Fax : UK (0)1222 874210; e-mail :- knightdw@cf.ac.uk
Received 1 May 1998
4
Abstract: Iodocyclisations of the allylic glycinates 7 lead either to the
trans- or cis-2,5-disubstituted proline derivatives 8 or 9, depending on
the reaction conditions; subsequent treatment of these with DBU in
DMF gives the 2-pyrrolecarboxylates 10 and 13 in excellent yields by a
double elimination of hydrogen iodide and toluenesulfinic acid.
methyl glycinate 5 (Scheme 2). We chose to exemplify the method
using a phenyl, a 2-furyl and an alkyl substituent. The initial products 6
were isolated in 55-75% yields, following separation of the small
amounts of regioisomers formed by formal S 2' displacement of the
carbonate function. Acid hydrolysis of the imine and N-tosylation then
gave the required (E)-alkenyl glycinates 7.
N
Electrophile-induced cyclisations of unsaturated alcohols and amine
derivatives have been widely used for the synthesis of both five- and
six-membered saturated heterocycles, typically by 5- or 6-exo
1
processes. In a continuation of our studies of the less common,
2
electrophile-induced, 5-endo-trig cyclisations, we have reported that,
when applied to (E)-homoallylic tosylamides 1, these reactions provide
a useful, stereodivergent route to either trans- or cis-2,5-disubstituted-3-
iodopyrrolidines [2 and 3 respectively], depending upon the conditions
3
employed (Scheme 1). Thus, under basic conditions, the 2,5-trans
isomers 2 are obtained, typically in a ratio of ≥15:1, with the minor
isomer having the corresponding 2,5-cis stereochemistry 3. In contrast,
when the cyclisations are carried out in the absence of base, the latter
isomers 3 are the sole products. It would appear that the trans-isomers 2
are the initial kinetic products which, under the acidic conditions [ii]
resulting from hydrogen iodide release during the cyclisation, revert to
the more thermodynamically stable isomers 3. Evidence for this is that
the trans-isomers 2, after isolation, can be smoothly and rapidly
converted into the corresponding cis-isomers 3 by exposure to iodine
Scheme 2
Gratifyingly, exposure of these alkenyl glycinates 7 to iodine in
acetonitrile containing potassium carbonate led to the 2,5-trans-4-
iodoprolines 8 in the reasonable to good isolated yields shown (Scheme
5
3), as single diastereoisomers; traces of other stereoisomers were visible
1
13
in the H and C NMR spectra of the crude products but these were
removed during chromatographic purification.
3
and hydrogen iodide in acetonitrile.
Scheme 1
In this initial work, we only exemplified the cyclisations using relatively
unfunctionalized substrates 1, wherein the substituents were either n-
alkyl or phenyl groups. In order to expand the synthetic potential of this
methodology, it was therefore necessary to investigate whether other,
potentially more reactive, functional groups were compatible with the
cyclisation conditions. The danger in this is that incorporation of such
functionality will inevitably introduce heteroatoms or unsaturation
which could compete with the 5-endo process by more favoured 5- or 6-
exo-trig pathways. In this respect, a methoxycarbonyl group seemed a
likely candidate as this has been found not to participate readily in such
Scheme 3
Similarly, under "acidic" conditions (see above), the corresponding 2,5-
cis diastereoisomers 9 were formed in good yield and as single
5
isomers, presumably via the trans isomers 8. The relatively poor yield
obtained for the 5-furyl derivative 9a was largely due to degradation of
the furan ring by attack of the hydrogen iodide formed during the
cyclisation. This methodology therefore provides a flexible approach to
the 5-substituted proline derivatives 8 and 9 and should be amenable to
the elaboration of chiral, non-racemic products, particularly because the
starting alkenyl glycinates 7 should be available as single enantiomers
from alkylations of one of the many asymmetric glycine enolate
2
cyclisations in general and, if successfully incorporated, would result
in the formation of a range of substituted prolines, as well as providing
additional opportunities for subsequent homologation. Herein, we report
the successful outcome of our initial work in this area, which has also
resulted in the realization of a new pyrrole synthesis.
6
equivalents which are currently available.
The starting alkenyl glycines 7 were prepared by palladium(0)-catalysed
coupling of the allylic carbonates 4 and the benzophenone imine of

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SYNLETT
We have also found that these initial products can serve as useful
precursors to 5-substituted-2-pyrrolecarboxylates (Scheme 4). Thus,
when any of the foregoing isomers are exposed to 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) in DMF at 90°C, a double
elimination ensues in less than one hour to give excellent isolated yields
References
(1) Bartlett, P. A. Asymmetric Synthesis, Morrison, J. D., Ed;
Academic Press, Inc., New York, 1983, 3, Ch. 6; Harding, K. E.
Comp. Org. Synth., Trost, B. M.; Fleming, I., Eds., Pergamon
Press, Oxford, 1991, 4, 363; Boivin, T. L. B. Tetrahedron, 1987,
43, 3309; Harmange, J.-C.; Figadere, B. Tetrahedron:Asymm.,
1993, 4, 1711.
5
of the pyrrolecarboxylates 10. The method can also be used to obtain 3-
substituted homologues. Thus, the 3-methylalkenyl glycinate 11,
obtained from (E)-1-phenylbut-1-en-3-ol as a mixture of diastereo-
isomers by the method shown in Scheme 2, was cyclized under acidic
(2) For recent contributions to this area, see Lipshutz, B. H.; Gross, T.
J. Org. Chem., 1995, 60, 3572; Andrey, O.; Ducry, L.; Landais,Y.;
Planchenault, D.; Weber, V. Tetrahedron, 1997, 53, 4339; Chibale,
K.; Warren, S. J. Chem. Soc., Perkin Trans. 1, 1996, 1935; Eames,
J.; Jones, R. V. H.; Warren, S. Tetrahedron Lett., 1996, 37, 4823;
Barks, J. M.; Knight, D. W.; Weingarten, G. G. J. Chem. Soc.,
Chem. Commun., 1994, 719; Barks, J. M.; Knight, D. W.; Seaman,
C. J.; Weingarten, G. G. Tetrahedron Lett., 1994, 35, 7239, and
references therein.
conditions [I , MeCN (Scheme 3)] to give the iodoprolines 12, again as
2
a mixture of stereoisomers. Upon exposure to DBU in hot DMF, these
5
were smoothly converted into a single pyrrolecarboxylate 13, in 70%
isolated yield. Not unreasonably, it appears that, under these conditions,
the elimination processes are insensitive to the relative
stereochemistries of the iodine and the adjacent protons.
(3) Jones, A. D.; Knight, D. W. J. Chem. Soc., Chem. Commun., 1996,
915.
(4) Genet, J.-P.; Juge, S.; Achi, S.; Mallart, S.; Montes, J. R.; Levif,
G. Tetrahedron, 1988, 44, 5263.
(5) Satisfactory spectroscopic and analytical data have been obtained
for all compounds reported herein. The relative stereochemistries
of the iodopyrrolidines 8 and 9 were determined on the basis of
nOe experiments and comparative NMR data and confirmed in
three cases by X-ray analysis, full details of which will be
published elsewhere.
Scheme 4
(6) Williams, R. M. Synthesis of Optically Active α-Amino Acids,
Thus, this method constitutes an alternative strategy for the elaboration
of substituted pyrrolecarboxylates, a topic of considerable recent
Pergamon Press, Oxford, 1989.
7
interest. Overall, the present approach is reminiscent of and
(7) Sundberg, R. J. Comp. Heterocycl. Chem., Katritzky, A. R.; Rees,
C. W., Eds., Pergamon Press, Oxford, 1984, 4, 313; Sundberg, R.
J. Comp. Heterocycl. Chem. II, Katritzky, A. R.; Rees, C. W.;
Scriven, E. F. V., Eds., Elsevier Science Ltd., Oxford, 1996, 2,
119. For some recent contributions, see Katritzky, A. R.; Li, J. J.
Org. Chem., 1996, 61, 1624; Enders, D.; Maassen, R.; Han, S. H.
Annalen, 1996, 1565; Adamczyk, M.; Reddy, R. E. Tetrahedron,
1996, 52, 14689; Yogi, T.; Aoyama, T.; Shioiri, T. Synlett., 1997,
1063.
8
complementary to the Kenner pyrrole synthesis, in that the starting
materials are a glycinate and a three-carbon unit (allylic alcohol and
enone respectively) and the pyrrole is established by a double
elimination, of toluenesulfinic acid and either hydrogen iodide or water
respectively.
Acknowledgements
We thank the EPSRC Mass Spectrometry Service, Swansea University
for the provision of high resolution Mass Spectral data and Eli Lilly and
Co. Ltd. and the EPSRC for financial support.
(8) Terry, W. G.; Jackson, A. H.; Kenner, G. W.; Kornis, G. J. Chem.
Soc., 1965, 4389.