A new bicyclic proline-mimetic amino acid

Article abstract of DOI:10.1016/S0040-4039(03)00663-4

A new constrained bicyclic α-amino acid proline-mimetic was developed. The synthesis was achieved starting from derivatives of the chiral pool, thus allowing to prepare analogues of either L- or D-proline by choosing appropriate stereoisomers of serine and α,β-isopropylidene-glycerol derivatives. The scaffolds were prepared as N-Fmoc-amino acid suitable for solid-phase peptide synthesis.

Full text of DOI:10.1016/S0040-4039(03)00663-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3489–3492
A new bicyclic proline-mimetic amino acid
Andrea Trabocchi, Nicoletta Cini, Gloria Menchi and Antonio Guarna*
Dipartimento di Chimica Organica ‘Ugo Schiff’, Universita` degli Studi di Firenze, and Istituto di Chimica dei Composti
Organometallici-CNR, Polo Scientifico di Sesto Fiorentino, Via della Lastruccia 13, Sesto Fiorentino, I-50019 Firenze, Italy
Received 17 February 2003; revised 7 March 2003; accepted 7 March 2003
Abstract—A new constrained bicyclic a-amino acid proline-mimetic was developed. The synthesis was achieved starting from
derivatives of the chiral pool, thus allowing to prepare analogues of either L- or D-proline by choosing appropriate stereoisomers
of serine and a,b-isopropylidene-glycerol derivatives. The scaffolds were prepared as N-Fmoc-amino acid suitable for solid-phase
peptide synthesis. © 2003 Elsevier Science Ltd. All rights reserved.
b-turns are ten-membered ring hydrogen-bonded struc-
tures, which play an important role in proteins for
folding and generating compact structures, and their
structural mimics have been extensively studied.1
Indeed, considerable effort has been focused on devel-
oping conformationally restricted mimics of these struc-
tures, which show particular conformation of backbone
geometry and side-chain orientations, and exhibit
intramolecular hydrogen bonding.2 Among the natu-
rally occurring amino acids, proline is often involved in
the nucleation of reverse turn structures such as b-turns
and b-hairpins. Moreover, the ability of proline to form
cis peptide bonds and undergo cis/trans isomerization is
well known. Depending upon the cis/trans stereochem-
istry of the Xaa-Pro amide bond, proline is involved
either in type I-II or in type VI b-turn. Specifically, cis
geometry of proline amide bond causes peptide back-
bone to fold in a type VI b-turn in which proline
occupies the i+2 position, while type I and type II
b-turns show a structure in which proline is in position
i+1 and generates a trans amide bond with the preced-
ing amino acid in position i. These structural properties
of proline and its derivatives result in characteristic and
unique constraints on the conformational space of pep-
tide sequences containing proline or hydroxyproline.3
Numerous mimetics and analogues of proline have been
developed and applied in the synthesis of biologically
active compounds, with the aim of modulating the
cis/trans ratio of acyl-Pro bonds, constraining the con-
formation of the peptide bond and producing proline-
like reverse turn inducers.2,4
During recent years we have developed a new class of
bicyclic 3-aza-6,8-dioxa-bicyclo[3.2.1]octane scaffolds as
g/d amino acids named BTAa5 and BTKa,6 obtained
from tartaric acid and amino carbonyl derivatives,
which proved to be valuable dipeptide isosteres when
inserted in peptide chains. In particular, compounds
belonging to the 7-endo-BTAa sub-class showed
marked properties as reverse turn inducers in both
cyclic7 and linear8 peptide sequences, acting as mimetics
of i+1-i+2 central dipeptidic sequence of a typical b-
turn motif, in which the rigidity imposed by ten-mem-
bered ring hydrogen bond was retained by the scaffolds
architecture.
With the aim of exploring the capabilities of BTAa
scaffolds to revert the direction of peptide backbone in
another fashion, we developed a new set of bicyclic
compounds named BGS, in which the carboxyl moiety
of 7-endo-BTG is shifted from position 7 to 4, thus
generating a constrained unnatural a-amino acid show-
ing structural features similar to proline (Fig. 1).
In particular, owing to the structural asset of the
bicyclic structure, BGS and BgS amino acids, having R
absolute configuration at C-4, could be considered the
* Corresponding author. Tel.: +39-055-457-3481; fax: +39-055-457-
3569; e-mail: antonio.guarna@unifi.it
Figure 1. Shift of carboxylic function from position 7 to 4.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00663-4

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A. Trabocchi et al. / Tetrahedron Letters 44 (2003) 3489–3492
Figure 2. Stereochemical differences of BG(g)S(s) scaffolds depending upon the chirality of starting materials, and structural
analogies with - and -proline amino acids.
D
L
bicyclic analogues of
having C-4 with S absolute configuration, showed simi-
larity with -proline, as shown in Figure 2.
D
-proline, while BGs and Bgs,
Cyclization of the Fmoc-aminoaldehyde proved to be
more difficult than the analogous BTS scaffold, in
which an endocyclic amide was present. In particular,
cyclization conducted in refluxing benzene with H2SO4–
SiO2 catalyst, led to the desired product with poor
yield. On the contrary, when cyclization was performed
at room temperature in pure TFA, a better yield (43%)
was obtained, though not convenient enough for
preparative purposes.
L
BG(g)S(s) molecules displayed different geometrical
presentation of side-chain functions depending on the
stereochemistry of the starting precursors. BGS scaf-
fold, which was prepared from the combination of
D
-a,b-isopropylidene-glycerol and
showed the carboxyl function in 4-exo position, while
BGs compound, obtained from -a,b-isopropylidene-
glycerol and -serine derivatives, displayed the COOH
moiety in 4-endo position (Fig. 2). The corresponding
L-serine derivatives,
D
Moreover, the O-benzyl deprotection showed unex-
pected difficulties. In fact, the benzyl group showed
resistance towards hydrogenolysis in MeOH and EtOH
with Pd/C and Pd(OH)2/C, unless high pressures of
hydrogen were employed. Alternatively, deprotection
was achieved using Lewis acids, and, in particular,
D
enantiomers Bgs and BgS were obtained from
isopropylidene-glycerol derivative.
L-a,b-
The synthesis of BGS scaffold was achieved starting
from
-a,b-isopropylidene-glycerol triflate9 and O-pro-
tected -serinol derivatives (see Scheme 1), and con-
13
FeCl3 proved to be more efficient than TiCl4, while
D
SnCl4 showed no reaction. The main drawback of using
Lewis acids was the low yield, which was found in all
cases to be not higher than 40%.
L
sisted of a coupling step, followed by amine protection
and oxidation of alcohol to aldehyde, to obtain the title
scaffold after acid cyclization.
The need for an efficient strategy to allow the prepara-
tion of a larger amount of final N-protected amino
acids, prompted us to replace O-benzyl-serinol 2b with
a more suitable starting reagent in terms of costs and
compatibility with the synthetic path. In a work of
Meyers et al.,14 an efficient method for the preparation
of O-TBDMS-serinol 2a compounds was described.
Initially, following the information achieved in a previ-
ous work about the preparation of BTS scaffolds,10 we
focused our attention on the synthesis of O-benzyl-pro-
tected BGS amino alcohol, starting from O-benzyl-seri-
nol (2b) and
D-a,b-isopropylidene-glycerol triflate (1)
(Scheme 2). Compound 2b was prepared as reported,11
and 1 was obtained in good yield following the reported
procedure.12 The coupling was achieved in
dichloromethane after overnight stirring at room tem-
perature, thus obtaining the desired amino alcohol
adduct together with 15% of dialkylated product. After
protection of the amine function as Fmoc urethane, the
oxidation step was performed with Dess–Martin perio-
dinane, in agreement with previous consideration about
the tendency of the desired aldehyde to undergo b-elim-
ination to the more stable a,b-unsaturated aldehyde
when Swern conditions were employed.10
Scheme 1. Retrosynthetic approach to BGS scaffold.

A. Trabocchi et al. / Tetrahedron Letters 44 (2003) 3489–3492
3491
Scheme 2. Reagents and conditions: (i) DIPEA, CH2Cl2, rt, overnight; (ii) Fmoc-O-Su, THF, 2,6-lutidine, 0°C, 4 h, then rt,
overnight; (iii) Dess–Martin periodinane, CH2Cl2, rt, 30 min; (iv) TFA, rt, 2 h; (v) FeCl3 2 equiv., CH2Cl2, rt, 30 min; (vi) Jones
reagent, acetone, rt, overnight.
Thus, the silylated amino alcohol was prepared in gram
quantities and coupled with glycerol–triflate derivative 1
(Scheme 2). The alcohol oxidation was performed with
Dess–Martin periodinane using standard work-up with
Na2S2O3–NaHCO3 solution, as no b-elimination to give
corresponding a,b-unsaturated aldehyde was observed.
Finally, acid cyclization with TFA gave BGS scaffold 8
with free OH group, as TBDMS group is known to be
acid sensitive, giving the deprotected scaffold in 63%
yield over two steps. Thus, final N-Fmoc-amino acid 9
was obtained with Jones oxidation in 81% overall yield
(Scheme 2). BGS scaffolds 7–9 showed two rotamers on
1H NMR in about 1:1 ratio, as often observed for
N-Fmoc-BTAa bearing a substituent in 4-exo position.5
cyclization as a consequence of steric restrictions was
known for similar compounds carrying an exocyclic
double bond,10 and in bicyclic scaffolds having a car-
boxylic group shifted from exo to endo position.15 In
particular, cyclization with acid silica in refluxing ben-
zene proved to be difficult and not reproducible on
larger scale, giving BGs scaffold with poor conversion.
When using TFA as a cyclizing agent the final product
was obtained with 40–50% conversion, though after
purification the yield lowered to 11%.16 Jones oxidation
gave final BGs amino acid in lower yield than corre-
sponding BGS isomer, thus confirming the instability of
BGs. Both the amino alcohol and amino acid BGs
scaffolds presented a unique rotamer as a consequence
of steric restriction imposed by carboxyl function in
equatorial position, as already observed in other BTAa
scaffolds.5,8
In the case of BGs, the 4-endo-carboxyl-scaffold was
obtained in lower yield (Scheme 3). The difficult
Scheme 3. Reagents and conditions: (i) DIPEA, CH2Cl2, rt, overnight; (ii) Fmoc-O-Su, 2,6-lutidine, THF, 0°C, 4 h, then rt,
overnight; (iii) Dess–Martin periodinane, CH2Cl2, rt, 30 min; (iv) TFA, rt, 2 h; (v) Jones reagent, acetone, rt, overnight.

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A. Trabocchi et al. / Tetrahedron Letters 44 (2003) 3489–3492
The corresponding enantiomers obtained from
L
-a,b-
Am. Chem. Soc. 1998, 120, 4334–4344; (b) Genin, M. J.;
Johnson, R. L. J. Am. Chem. Soc. 1992, 114, 8778–8783;
(c) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-
G.; Lubell, W. D. Tetrahedron 1997, 53, 12789–12854.
5. Guarna, A.; Guidi, A.; Machetti, F.; Menchi, G.; Occhi-
ato, E. G.; Scarpi, D.; Sisi, S.; Trabocchi, A. J. Org.
Chem. 1999, 64, 7347–7364.
6. Guarna, A.; Bucelli, I.; Machetti, F.; Menchi, G.; Occhi-
ato, E. G.; Scarpi, D.; Trabocchi, A. Tetrahedron 2002,
58, 9865–9870.
7. Scarpi, D.; Occhiato, E. G.; Trabocchi, A.; Leatherbar-
row, R. J.; Brauer, A. B. E.; Nievo, M.; Guarna, A.
Bioorg. Med. Chem. 2001, 9, 1625–1632.
8. Trabocchi, A.; Potenza, D.; Occhiato, E. G.; Guarna, A.
J. Org. Chem. 2002, 67, 7483–7492.
9. The coupling step was also obtained by reductive amina-
isopropylidene-glycerol showed similar behavior, as Bgs
scaffold, being the enantiomer of BGS, belonged to the
matched case, while BgS showed mismatched behavior
in analogy with BGs molecule.
In conclusion, a new strategy for the development of
bicyclic analogues of both
D- and
L-proline was
achieved, obtaining Fmoc-BG(g)S(s) amino acids read-
ily available for SPPS synthesis of new modified reverse
turn peptides. The use of silylated serinol compounds
was found to be more effective in terms of yields, thus
developing a more viable synthetic protocol. The syn-
thesis of BGs or BgS scaffolds, carrying a substituent in
4-endo position proved to be more difficult than the
corresponding 4-exo diastereomer, as a consequence of
difficult cyclization and increased instability of the final
product, thus showing the match/mismatched behavior
of these molecules, depending upon the relative configu-
ration of side chain functionality in position 4 of the
scaffold.
tion with
D
-a,b-isopropylidene-glyceraldehyde using
NaBH(OAc)3 as reducing agent, giving the adduct with
yield comparable to SN2 reaction; the protected aldehyde
was obtained from
D-1,2:5,6-di-O-isopropylidene-manni-
tol by oxidative cleavage with NaIO4, as reported: Earle,
M. J.; Abdur-Rashid, A.; Priestley, N. D. J. Org. Chem.
1996, 61, 5697–5700.
10. Guarna, A.; Cini, N.; Machetti, F.; Menchi, G.; Occhi-
ato, E. G. Eur. J. Org. Chem. 2002, 873–880.
11. Berkowitz, D. B.; Shen, Q.; Maeng, J.-H. Tetrahedron
Lett. 1994, 35, 6445–6448.
Acknowledgements
The authors thank COFIN 2002-2004, and Universita`
degli Studi di Firenze for financial support.
12. Schmidt, R. R.; Moering, U.; Reichrath, M. Chem. Ber.
1982, 115, 39–49.
13. Park, M. H.; Takeda, R.; Nakanishi, K. Tetrahedron
Lett. 1987, 28, 3823–3824.
14. Novachek, K. A.; Meyers, A. I. Tetrahedron Lett. 1996,
37, 1743–1746.
15. Niu, C.; Pettersson, T.; Miller, M. J. J. Org. Chem. 1996,
61, 1014–1022.
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