Synthesis of a constrained tricyclic scaffold based on trans-4-hydroxy-L- proline

Article abstract of DOI:10.1016/j.tetlet.2005.09.021

Drug discovery research has taken advantage of peptidomimetic chemistry in order to achieve new leads possessing structural and functional characteristics of bioactive peptides together with enhanced metabolic resistance towards proteases. Herein is repor

Full text of DOI:10.1016/j.tetlet.2005.09.021

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7813–7816
Synthesis of a constrained tricyclic scaffold based
on trans-4-hydroxy-L-proline
Andrea Trabocchi, Massimo Rolla, Gloria Menchi and Antonio Guarna*
`
Dipartimento di Chimica Organica ‘Ugo Schiff’, Universita degli Studi di Firenze, Polo Scientifico di Sesto Fiorentino,
Via della Lastruccia 13, I-50019 Sesto Fiorentino (FI), Italy
Received 18 July 2005; revised 5 September 2005; accepted 6 September 2005
Available online 23 September 2005
Abstract—Drug discovery research has taken advantage of peptidomimetic chemistry in order to achieve new leads possessing struc-
tural and functional characteristics of bioactive peptides together with enhanced metabolic resistance towards proteases. Herein is
reported the synthesis of a tricyclic peptidomimetic scaffold derived from the combination of trans-4-hydroxy-L-proline and tartaric
acid derivatives by means of amidation and acid trans-acetalisation reactions. Further manipulations of the hydroxylic function on
the pyrrolidine ring gave access to a new set of amino acid scaffolds possessing high rigidity and a fixed arrangement of the func-
tional groups.
Ó 2005 Elsevier Ltd. All rights reserved.
In recent years, drug discovery has focused on bioactive
peptides as therapeutics. The severe pharmacological
limitations such as poor absorption and low oral bio-
availability have led researchers to develop the concept
of Ôpeptidomimetic chemistryÕ,1–5 which allowed one to
generate compounds able to preserve peptide-like activ-
ity and to increase resistance towards proteases. Many
templates have been developed so far, and unnatural
amino acids proved to be of great interest as new build-
ing blocks for the development of peptidomimetics pos-
sessing enhanced diversity and structural constraints.
same heterocyclic core. The key step to obtain the bicy-
clic scaffold is an acid-catalysed trans-acetalisation of a
1,2-diol moiety with a free or protected aldehyde func-
tion. In particular, a masked aldehyde as an acetal
allowed to achieve final compounds in higher amounts
due to easier access and relatively cheaper chemistry.9
trans-4-Hydroxy-proline has been widely used for the
generation of new-proline-based compounds,13–15 and
the three functional groups on the pyrrolidine ring have
been also used for the generation of combinatorial
libraries on solid support.16 According to the general
retrosynthetic path to achieve BTAa scaffolds, conden-
sation of amino aldehydes derived from a-amino acids
with tartaric acid derivatives could give access to bicyclic
compounds having a carboxylic group at position 7 and
a secondary amino group at position 3.6 On the con-
trary, by using the secondary a-amino acid proline, a
tertiary amide bond and an additional cycle in the 6,8-
dioxa-3-azabicyclo[3.2.1]octane template are intro-
duced, thus increasing the conformational rigidity,
though losing the possibility of functionalising the ami-
no group at position 3. Thus, 4-substituted proline was
chosen in order to keep two functional groups in the
scaffold architecture, with a well-defined topology and
an increased distance between them. Moreover, com-
pound 2 was chosen in order to reduce the synthesis of
the scaffold to two steps, namely amidation and acid
catalysed trans-acetalisation (Fig. 1).
Following our interests, in generating constrained scaf-
folds for peptidomimetic design, we focused our atten-
tion towards polycyclic structures carrying functional
groups in a well-defined topological arrangement. In
particular, we explored the chemistry of a 6,8-dioxa-3-
azabicyclo[3.2.1]octane scaffold,6 which proved to act as
a constrained scaffold for the generation of rigid amino
acids,6–10 and for asymmetric synthesis.11,12 Different
synthetic strategies using sugar or tartaric acid deriva-
tives with amino acid derivatives allowed us to obtain
different sub-classes of scaffolds named BTKa (bicycles
from tartaric acid and keto amines)8 and BTAa (bicycles
from tartaric acid and amino acids),9,10 based on the
Keywords: Peptidomimetics; Drug design; Peptides; Amino acids.
*
Corresponding author. Tel.: +39 055 457 3481; fax: +39 055 457
3569; e-mail: antonio.guarna@unifi.it
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.021

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A. Trabocchi et al. / Tetrahedron Letters 46 (2005) 7813–7816
alkylation with benzyl bromide in 86% yield.17 Reduc-
tion of the ester function of 7 by means of NaBH4 affor-
ded the corresponding protected amino alcohol 8, which
was subjected to Swern oxidation to give aldehyde 9.
Treatment of 9 with a methanolic solution of HCl,
obtained by reaction of MeOH with acetyl chloride,
allowed us to achieve directly the final amino acetal 2
in 75% yield after two steps, as a consequence of simul-
taneous acetalisation and Boc-deprotection.
Figure 1.
With the amino acetal 2 in hand, the synthetic route to
the polycyclic scaffold consisted in a two-step process,
that is, amide bond formation and acid-catalysed intra-
molecular cyclisation, as showed in Scheme 2. Amide
bond formation was achieved using PyBrOP as the car-
boxylic acid activator, giving product 10 in 62% yield
after purification. Interestingly, the coupling of monoes-
ter 3 with trans-4-(O-benzyloxy)-prolinol, corresponding
to the Boc-deprotected derivative of 8, did not produce
the related amide in satisfactory yield (30%), and an
ester by-product was observed as main product, as a
consequence of the reaction of the primary hydroxyl
group instead of the secondary amine. Thus, it was
hypothesised that there was an interaction between the
hydroxyl and the amine group resulting in the deactiva-
tion of the latter, hence disfavouring the reaction with
the tartaric acid derivative. Intramolecular cyclisation
was carried out in refluxing toluene and in the presence
of acid silica gel, (prepared by slow addition of concen-
trated sulfuric acid to a suspension of silica gel in dichlo-
romethane, followed by solvent evaporation),6 giving 11
in 67% yield. It was found optimal to increase the reac-
tion time to an hour, instead of the few minutes required
for other BTAa compounds, as a consequence of the
increased constraint of the final compound carrying an
additional cycle. Compound 11 showed both the proton
at C-4 and the hydroxyl function in endo configuration
relatively to the six-membered ring. On the contrary,
the reaction of amino acetal 2 with monoester derivative
(S,S)-3 of D-tartaric acid gave access to the diastereo-
meric scaffold 13, having both the proton at C-4 and
Scheme 1.
Amino acetal 2 was obtained from trans-4-hydroxy-L-
proline in six steps according to Scheme 1.
Fisher esterification of 4 produced compound 5, which
was successively converted to the Boc-protected amino
ester 6. Subsequent protection of the hydroxyl group
was accomplished by treatment with NaH, followed by
Scheme 2.

A. Trabocchi et al. / Tetrahedron Letters 46 (2005) 7813–7816
7815
the hydroxyl function oriented in exo with respect to the
six-membered ring (Scheme 2). In this case, acid-cataly-
sed cyclisation of 12 to give 13 occurred with high diffi-
culty, giving the desired product in a yield lower (11%)
than that for the diastereomeric 11.
The stability of the new polycyclic system bearing an
acetal moiety was assessed by treating 11 for several
hours in refluxing toluene. It showed complete resistance
towards epimerisation on heating, although partial deg-
radation was observed. Moreover, compound 11 in a
CDCl3 solution containing 1% TFA showed complete
stability towards epimerisation and ring opening, even
upon addition of small quantities of water. Successively,
in order to test the versatility of the tricyclic scaffold, the
hydroxyl group on the pyrrolidine ring was further pro-
cessed in order to achieve a new constrained amino acid.
Thus, the benzyl group of 11 was removed by hydrogen-
olysis to give the corresponding hydroxy ester 1. Sur-
prisingly, epimerisation at the C-2 stereocentre was
observed, giving 1 and 14 as a 1:1 mixture of diastereo-
isomers (Scheme 3).
Figure 2. X-ray structure of compound 1.
any NOE effect between 2-H and 4-H of the tricyclic sys-
tem, whereas an intense NOE interaction was observed
for the isomer 14.
Interestingly, the X-ray analysis of compound 1 showed
the preferred syn orientation of the carbonyl group of
the ester at C-9 with respect to the C-9–O-10 bond in
the solid state. This is in contrast to the preferred anti
orientation observed from molecular modelling calcula-
tions for other BTAa scaffolds.6 Moreover, the mea-
sured distance between the carbonylic carbon atom of
the ester group at C-9 and the oxygen at C-4 was
Structural determination of these two isomers was
achieved by X-ray analysis of 118 (Fig. 2) and by NOE
experiments (Scheme 3). Compound 1 did not show
˚
7.247 A, corresponding approximatively to the length
of a tripeptide sequence.
Successively, two strategies were explored for the syn-
thesis of a new tricyclic amino acid (Scheme 4). Initially,
compound 1 was reacted with tosyl chloride to give 15 in
46% yield, which was successively treated with NaN3, to
give the amino acid precursor 16. Final hydrogenolysis
with catalytic Pd/C afforded the target amino acid 19.
Alternatively, the hydroxyl group of 1 was transformed
to the corresponding triflate 17, which was treated with
benzylamine to give the resulting N-benzyl amino acid
18 in 24% yield over two steps.
In conclusion, a new tricyclic scaffold was synthesised
Scheme 3.
from trans-4-hydroxy-L-proline and tartaric acid deriva-
Scheme 4.

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A. Trabocchi et al. / Tetrahedron Letters 46 (2005) 7813–7816
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Acknowledgements
`
The authors wish to thank Universita degli Studi di
Firenze and COFIN 2004–2005 for financial support,
and Ente Cassa di Risparmio di Firenze for granting
the 400 MHz NMR instrument. Dr. Cristina Faggi is
kindly acknowledged for X-ray analysis, and Mr. Mau-
rizio Passaponti and Ms. Brunella Innocenti for techni-
cal assistance.
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Supplementary data
Experimental procedures and characterisation data for
compounds 1, 2, 11 and 13–19. Supplementary data
associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2005.09.021.
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References and notes
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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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