Enantio- and diastereoselective synthesis of 2,5-disubstituted pyrrolidines through a multicomponent Ugi reaction and their transformation into bicyclic scaffolds

Article abstract of DOI:10.1016/j.tetlet.2004.07.015

2,5-Disubstituted pyrrolidines 2a,b have been prepared from L-glutamic acid by a diastereoselective Ugi condensation on pyrroline 1. Intermediates 2a,b have been converted into diastereomeric bicyclic lactones 3a,b. A new enantio- and diastereoselective synthesis of 2,5-disubstituted pyrrolidines through a multicomponent approach has been developed, using highly reactive pyrrolines 4 as preformed cyclic imines. The pyrrolidines obtained using protected aspartic acid as acid component in the Ugi condensation have been transformed into two epimeric bicyclic lactones 18, 19, which may find an application as external reverse turn inducers.

Full text of DOI:10.1016/j.tetlet.2004.07.015

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6637–6640
Enantio- and diastereoselective synthesis of 2,5-disubstituted
pyrrolidines through a multicomponent Ugi reaction and
their transformation into bicyclic scaffolds
Luca Banfi, Andrea Basso, Giuseppe Guanti and Renata Riva*
Dipartimento di Chimica e Chimica Industriale, Via Dodecaneso 31, I-16146 Genova, Italy
Received 14 May 2004; revised 14 June 2004; accepted 5 July 2004
Available online 22 July 2004
Abstract—A new enantio- and diastereoselective synthesis of 2,5-disubstituted pyrrolidines through a multicomponent approach has
been developed, using highly reactive pyrrolines 4 as preformed cyclic imines. The pyrrolidines obtained using protected aspartic
acid as acid component in the Ugi condensation have been transformed into two epimeric bicyclic lactones 18, 19, which may find
an application as external reverse turn inducers.
Ó 2004 Elsevier Ltd. All rights reserved.
Recently, the replacement of natural amino acids in pep-
tides with non-proteinogenic derivatives has become an
important goal in synthetic organic chemistry. In parti-
cular the synthesis of peptidomimetics that mimic natural
dipeptides is very attractive, since these motifs, if charac-
terized by a suitable conformation, can induce a reverse
turn in an oligopeptidic chain connected to them.1 This
fact is of great importance for the synthesis of ligands of
receptors, such as the integrins, involved in many dis-
eases connected with cell-adhesion processes, like angio-
genesis and tumor metastasis.2 We recently reported the
synthesis of a new semi-rigid derivative, having the char-
acteristics of Ôexternal reverse turn scaffoldÕ,3 employing
an Ugi four component (4CR) reaction, followed by a
highly stereoselective ring closing metathesis.4 Within
the same project we explored also the possibility of syn-
thesizing a novel family of epimeric bicyclic scaffolds
through a highly convergent strategy, exploiting the
Ugi condensation of chiral pyrrolines, followed by an
appropriate cyclization. These derivatives may behave
as reverse turn inducers, in line with previous results ob-
tained with other bicylic lactams.5
2),6 to be used as common intermediates for the prepa-
ration of a small library of epimeric 2,5-disubstitued
pyrrolidines 2, 3 (Scheme 1). Among several recently re-
ported methods for the synthesis of pyrrolines,7,8 we
choose, for the preparation of 4a,b, the strategy involv-
ing the formation of the heterocyclic ring as the last step,
through a Staudinger Aza–Wittig reaction.7 We started
therefore from diprotected triol 5, readily obtained from
L-glutamic acid by a known procedure (Scheme 2).9 Fur-
ther elaboration of 5 required an independent manipula-
tion of the three alcoholic functionalities: among the
primary hydroxy groups only one is conserved in a pro-
tected form in the pyrrolines 4a,b, while the other one
had to be oxidized to an aldehyde to give 9a,b. The ste-
reospecific transformation of the secondary hydroxy
group into an azide was performed in excellent yield
by a nucleophilic displacement.10 This synthesis allowed
the preparation of two pyrrolines through a non-race-
mizing sequence11 in an excellent overall yield [59%
(4a) and 54% (4b) from 5].
For our purposes we first studied the enantioselective
synthesis of monosubstituted pyrrolines 4a,b (Scheme
Keywords: Multicomponent Ugi reaction; Pyrrolines; Reverse turn
inducer.
*
Corresponding author. Tel.: +39-0103536126; fax: +39-
0103536118; e-mail: riva@chimica.unige.it
Scheme 1.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.015

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L. Banfi et al. / Tetrahedron Letters 45 (2004) 6637–6640
1–2h. The yields ranged from moderate to excellent (Ta-
ble 1). On the other hand the diastereomeric ratio was in
all cases only moderate. Surprisingly, when the bulkier
trityl O-protecting group was employed, the reaction
was nearly not stereoselective at all (entry 2).
The relative configuration was unambiguously demon-
strated, in the case of 2, 3f, by converting them into sym-
metric triamides 12 and 13 (Scheme 3). Compound 12,
deriving from the prevailing diastereoisomer, showed
itself to be optically active {[a]D +6.0 (c 0.68, EtOH)},
demonstrating therefore a trans relationship of the sub-
stituents in the parent compound 2f. On the contrary,
the epimer, derived from 3f, showed, as expected, no
optical activity, being a meso compound.
Although we do not have yet a definite proof for the rel-
ative stereochemistry of the other adducts, we can rea-
sonably assume that, especially for compounds 2 and
3a,g,h,i, all deriving from the same pyrroline and the
same isocyanide, the major stereoisomer has a trans rel-
ative configuration as well. It is highly unlikely, indeed,
that the nature of the carboxylic component can have
such a great influence on the stereoselection as to reverse
the stereoselectivity.15 It should be noted that the single
previous example of Ugi condensation with chiral
pyrrolines13 afforded preferentially the cis isomers. The
stereogenic centre was however placed in a different
position. On the other hand, Ugi reaction with other
cyclic imines14 afforded usually the trans isomer as
major product.
Scheme 2. Reagents and conditions: (a) Ac2O, Py, rt; (b) AcOH, H2O,
rt; (c) t-BuMe2SiCl, imidazole, DMAP, THF, rt; (d) trityl chloride, Py,
CH2Cl2, rt; (e) (i) MsCl, Et3N, CH2Cl2, ꢀ30°C; (ii) NaN3, DMF,
65°C; (f) KOH, MeOH, 0°C; (g) (COCl)2, DMSO, Et3N,
ꢀ78°C!ꢀ50°C; (h) PPh3, THF, 50°C.
With compounds 4a,b in hand we turned our attention
on the Ugi multicomponent reaction (Scheme 3).12 Only
one example of Ugi reaction employing pyrrolines was
previously reported13 and, in general, only few examples
involving cyclic imines are known.14 Pyrrolines 4a,b
showed a high degree of reactivity and, under standard
conditions, the reaction was usually complete within
Finally, we demonstrated that the Ugi reaction did not
cause racemization on the stereocentre of 4. Using
L- and D-Fmoc-Ala as acid component (entries 7 and
8) only two different diastereoisomers were identified
by HPLC analysis.
Compounds 2, 3i, obtained using a N-protected bifunc-
tional amino acid (aspartic acid in this case), showed the
opportunity for the first synthetic application of these
derivatives, which is summarized in Scheme 4.
For preparative purposes we separated the two epimers
after removal of the silyl ether. We then independently
submitted hydroxymethyl pyrrolidines 14 and 15 to the
cleavage of the ester moiety under hydrogenolytic condi-
tions. The final step, that is, the formation of an eight-
membered lactone, was realized using PyBop [(benzo-
triazolyl-1-oxy)tripyrrolidinophosphonium hexafluoro-
phosphate] as condensing agent under high dilution
conditions. In this case only the bicyclic lactones 18, 19
were isolated in excellent overall yield.16
The size of the lactone/lactam ring can of course be
decided before performing the Ugi reaction, just by a
correct choice of the diacid. Moreover, the two pro-
tected functionalities of 2, 3i can be elaborated in a dif-
ferent fashion, in order to create bicyclic derivatives1
with different structures (Scheme 1). The presence of a
protected amine and of an amide functionality bonded
to these scaffolds allows the introduction of amino acid
units in order to assemble various acyclic or cyclic pep-
Scheme 3. Reagents and conditions: (a) HF, CH3CN, 0°C, then
separation of the alcohols and independent transformation on both;
(b) (i) Jones oxidation; (ii) benzyl amine, 2,4,6-collidine, HATU [(O-(7-
azabenzotriazol-1-yl)-N,N,N0,N0-tetramethyluronium hexafluorophos-
phate], DMF/CH2Cl2, rt.

L. Banfi et al. / Tetrahedron Letters 45 (2004) 6637–6640
6639
Table 1. Ugi reaction of pyrrolines 4
Entrya
R1
R2–CO2H
R3
Products
Yield% (2+3)
Dr (2:3)
1
2
3
4
5
6
7
8
9
Bn
Bn
n-C3H7–CO2H
n-C3H7–CO2H
Ph–CO2H
SiMe2t-Bu
Trityl
2, 3a
2, 3b
2, 3c
2, 3d
2, 3e
2, 3f
2, 3g
2, 3h
2, 3i
45
68:32b
53:47c
53:47e,f
64:36b
63:37b
68:32e
64:36e
65:35e
66:34e
70
CH2CO2t-Bu
SiMe2t-Bu
SiMe2t-Bu
SiMe2t-Bu
SiMe2t-Bu
SiMe2t-Bu
SiMe2t-Bu
SiMe2t-Bu
62d
44d
46d
60
n-Bu
t-Bu
Bn
Ph–CO2H
Ph–CO2H
CH2@CH(CH2)2–CO2H
Fmoc-L-Ala
Bn
Bn
80
69
Fmoc-D-Ala
Boc-L-Asp(OBn)
Bn
85
a All the reactions were carried out in MeOH (0.30M) at rt for 1–2h.
b By GC–MS.
c By weight.
d Yield from 9a.
e By HPLC.
f Determined after SiMe2t-Bu removal (n-Bu4NF, THF, rt, 69%).
1001–1004; Belvisi, L.; Caporale, A.; Colombo, M.;
Manzoni, L.; Potenza, D.; Pisano, C. Helv. Chim. Acta
2002, 85, 4353–4368.
6. All new compounds were fully characterized by 1H and
13C NMR, IR, GC–MS (when possible) and [a]D.
7. Mulzer, J.; Meier, A.; Buschmann, J.; Luger, P. Synthesis,
1996, 123–132.
8. Xia, Q.; Ganem, B. Tetrahedron Lett. 2002, 43, 1597–1598.
9. Larcheveque, M.; Lalande, J. Tetrahedron 1984, 40,
1061–1065; Gringore, O. H.; Rouessac, F. P. Org. Synth.
1985, 63, 121–126.
10. In our case the displacement, promoted by sodium azide
on the mesylate, worked well, contrary to a previous
report on similar compounds,7 and we obtained a com-
plete conversion of 7a,b into 8a,b in excellent yields.
Moreover this two-step sequence is safer than the one-step
Mitsunobu reaction involving hydrazoic acid used by the
same authors to overcome the decomposition of the
mesylate.
Scheme 4. Reagents and conditions: (a) HF, CH3CN, 0°C; (b) (i) H2,
Pd/C, EtOH, rt; (ii) PyBOP, Et3N, CH2Cl2 2mM, reflux.
tidomimetics. Studies in these fields are still under inves-
tigation in our group and will be reported in due course.
11. This was proved by NMR analysis of both diastereomeric
MosherÕs esters of 7a.
12. Ugi, I.; Steinbruckner, C. Angew. Chem. 1960, 72,
¨
267–268; Ugi, I. Angew. Chem., Int. Ed. Engl. 1982, 21,
810–819; Do¨mling, A.; Ugi, A. Angew. Chem., Int. Ed.
2000, 39, 3168–3210.
Acknowledgements
´
13. Flanagan, D. M.; Joullie, M. M. Synth. Commun. 1989,
19, 1–12; Bowers, M. M.; Carroll, P.; Joullie, M. M. J.
Chem. Soc., Perkin Trans 1 1989, 857–865.
14. Hatam, M.; Tehranfar, D.; Martens, J. Synthesis 1994,
619–623; Gro¨ger, H.; Hatam, M.; Martens, J. Tetrahedron
The authors gratefully thank the University of Genova
and M.I.U.R. (COFIN 02) for financial support, Mr.
Claudio Repetto for his collaboration, Drs. Delia Ber-
toia and Valeria Rocca for performing HPLC analysis
and Prof. Emanuele Magi for HPLC–MS experiments.
´
1995, 51, 7173–7180; Maison, W.; Lutzen, A.; Kosten, M.;
¨
Schlemminger, I.; Westerhoff, O.; Martens, J. J. Chem.
Soc., Perkin Trans 1 1999, 3515–3525; Maison, W.;
Lutzen, A.; Kosten, M.; Schlemminger, I.; Westerhoff,
¨
References and notes
O.; Saak, W.; Martens, J. J. Chem. Soc., Perkin Trans 1
2000, 1867–1871; Schlemminger, I.; Janknecht, H.-H.;
Maison, W.; Saak, W.; Martens, J. Tetrahedron Lett. 2000,
41, 7289–7292.
1. Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.;
Lubell, W. D. Tetrahedron 1997, 53, 12789–12854.
2. Gottschalk, K.-E.; Kessler, H. Angew. Chem., Int. Ed.
2002, 41, 3767–3774; Haubner, R.; Finsinger, D.; Kessler,
H. Angew. Chem., Int. Ed. 1997, 36, 1375–1389.
3. Golebiowski, A.; Jozwik, J.; Klopfenstein, S. R.; Colson,
A. O.; Grieb, A. L.; Russel, A. F.; Rastogi, V. L.; Diven,
C. F.; Portlock, D. E.; Chen, J. J. J. Comb. Chem. 2002, 4,
584–590.
15. The 1H and 13C NMR spectra of compounds 2, 3,
registered at room temperature in d6-DMSO, show the
presence of two rotamers, deriving from restricted rotation
around the N(ring)–CO bond. When registered at 100°C,
the 13C spectra gave only a single set of signals. At the
1
same temperature, the H spectra show usually collapsed
4. Banfi, L.; Basso, A.; Guanti, G.; Riva, R. Tetrahedron
Lett. 2003, 44, 7655–7658.
5. Belvisi, L.; Bernardi, A.; Checchia, A.; Manzoni, L.;
Potenza, D.; Scolastico, C.; Castorina, M.; Cupelli, A.;
Giannini, G.; Carminati, P.; Pisano, C. Org. Lett. 2001, 3,
signals as well, but they were rather broad. Interestingly in
the trans adducts, the NH proton of the major conformer
was always downfield (with a typical difference of 0.3–
0.6ppm and a regular rotamer ratio around 2:1), while in
the cis compounds it fell upfield [with a typical difference

6640
L. Banfi et al. / Tetrahedron Letters 45 (2004) 6637–6640
of 0.2–0.5ppm and a lower (although more varied)
16. The structure of 18, 19 was demonstrated by 1H, 13C
NMR and IR. Moreover an additional support for ruling
out the possibility of dimeric compounds was furnished by
HPLC–MS analysis.
rotamer ratio] (1H NMR at room temperature). This
trend furtherly confirms that the major stereoisomers have
always the same relative configuration.