Synthesis of 1,2-dithiolane analogues of leucine for potential use in peptide chemistry.

Article abstract of DOI:10.1021/ol0255458

[reaction: see text]1,2-Dithiolanes present several points of interest for both peptide and medicinal chemistry, yet no chiral alpha-amino acids containing this five-membered heterocyclic system are available. We report here the first synthesis of N- and C-protected derivative of (S)-2-amino-3-(1,2-dithiolan-4-yl)propionic acid (Adp) and its 1,3-dithiolic form.

Full text of DOI:10.1021/ol0255458

ORGANIC
LETTERS
2002
Vol. 4, No. 7
1139-1142
Synthesis of 1,2-Dithiolane Analogues of
Leucine for Potential Use in Peptide
Chemistry
Enrico Morera, Francesco Pinnen,† and Gino Lucente*
Dipartimento di Studi Farmaceutici and Centro di Studio per la Chimica del Farmaco
del CNR, UniVersita` degli Studi di Roma “La Sapienza”, P.le A. Moro 5,
00185 Roma, Italy, and Dipartimento di Scienze del Farmaco,
UniVersita` G. D’Annunzio, Via dei Vestini, 66100 Chieti, Italy
gino.lucente@uniroma1.it
Received January 11, 2002
ABSTRACT
1,2-Dithiolanes present several points of interest for both peptide and medicinal chemistry, yet no chiral r-amino acids containing this five-
membered heterocyclic system are available. We report here the first synthesis of N- and C-protected derivative of (S)-2-amino-3-(1,2-dithiolan-
4-yl)propionic acid (Adp) and its 1,3-dithiolic form.
Proteinogenic R-amino acids represent an exceptionally rich
source of chiral building blocks and synthons to be used in
both organic and medicinal chemistry.1 Nonproteinogenic and
synthetic amino acids are, however, becoming increasingly
important for the design of peptidomimetics endowed with
improved specific properties.2 It is well-known in fact that,
although native biologically active peptides have a great
potential as therapeutic agents, they need to be modified to
overcome problems connected with metabolic stability,
appropriate bioavailability, and receptor selectivity.
a variety of chemical structures and, when appropriately
inserted into peptide backbones, offer the opportunity to
establish efficient interactions with the biomolecular targets.
In this context, the heterocyclic five-membered ring of 1,2-
dithiolanes should represent an interesting molecular frag-
ment to be introduced into R-amino acid side chains. Due
to the stereoelectronic effects involving the sulfur lone pairs
and the small dihedral angle around the S-S bond,4,5 the
chemical and physical properties of 1,2-dithiolanes, which
represent the oxidized form of 1,3-dithiols, are very distinct
from those of open chain and large ring disulfides; of
particular relevance, in the field of peptidomimetics, are the
fast rate of ring opening by nucleophiles,6,7 the activity as
Among nonproteinogenic R-amino acids, particular atten-
tion is being devoted to models whose side chain bears a
heterocyclic ring system;3 these compounds present in fact
† Chieti University.
(1) (a) Barrett, G. C. Chemistry and Biochemistry of the Amino Acids;
Chapman and Hall: London, 1985. (b) Duthaler, R. O. Tetrahedron 1994,
50, 1539.
(2) (a) Hruby, V. J.; Balse, P. M. Curr. Med. Chem. 2000, 7, 945. (b)
Williams, R. M. Organic Chemistry Series Volume 7: Synthesis of Optically
ActiVe a-Amino Acids; Baldwin, J. E., Magnus, P. D., Eds.: Pergamon
Press: Oxford, 1989.
(3) Adlington, R. M.; Baldwin, J. E.; Catterick, D.; Pritchard, G. J. J.
Chem. Soc., Perkin Trans. 1 2001, 668 and references therein.
(4) (a) Bock, H.; Wagner, G. Angew. Chem., Int. Ed. Engl. 1972, 11,
150. (b) Bock, H.; Stein, U.; Semkov, A. Chem. Ber. 1980, 113, 3208.
(5) (a) Breslow, D. S.; Skolnik, H. Multi-sulfur and Sulfur and Oxygen
Five- and Six-Membered Heterocycles, Part One; The Chemistry of
Heterocyclic Compounds, Vol. 21; Weissberger, A., Ed.; Interscience
Publ.: New York, 1966. (b) Teuber, L. Sulfur Rep. 1990, 9, 257.
10.1021/ol0255458 CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/03/2002

antioxidant and free-radical scavengers,8 and the efficient
metal-ion coordinating properties.9 It should be remembered
here that the 1,2-dithiolane ring system represents the key
structural feature on which the reactivity of relevant bio-
molecules such as that of lipoic acid (1, Figure 1), the
Scheme 1
Figure 1. Structure of 1,2-dithiolane derivatives: naturally oc-
curring R-enantiomer of 1,2-dithiolane-3-pentanoic acid (lipoic acid,
1); 4-amino-1,2-dithiolan-4-carboxylic acid (Adt, 2); (S)-2-amino-
3-(1,2-dithiolan-4-yl)-propionic acid (Adp, 3).
essential cofactor in the oxidative decarboxylation of R-
ketoacids, is based.9,10
An alternative approach (see Scheme 2), which follows
in part the route previously used to prepare (S)-5,5′-
dihydroxyleucine,14 was then adopted.
On the basis of the above-reported considerations and by
considering the absence of information on the chemistry of
peptidomimetics incorporating 1,2-dithiolane heterocyclics,
we recently began a research program centered on the study
of this topic. The CR,R-tetrasubstituted and achiral residue
of 4-amino-1,2-dithiolane-4-carboxylic acid (Adt, 2) was
chosen as an initial model and the conformational and bio-
chemical consequences of its insertion into bioactive oligo-
peptides have been described.11,12 As a continuation of these
studies we report here the stereocontrolled synthesis of the
N- and C-protected derivatives of (S)-2-amino-3-(1,2-dithi-
olan-4-yl)propionic acid (Adp, 3) and its 1,3-dithiolic form
14. The Adp molecule represents the first example of chiral
an R-amino acid containing a cyclic disulfide in its side chain.
The use of the malonic precursor, obtained from (S)-
pyroglutamic acid or (S)-serine derivatives, as depicted in
Scheme 1, was initially considered a suitable approach to
prepare 3. However, the regioselective reduction of this
compound was found to be sluggish and gave complex
reaction mixtures. Difficulties during the reduction of N-
protected γ-carboxy glutamyl derivatives analogous to that
reported in Scheme 1 have already been noted by Dubois et
al.13 and are attributable, at least in part, to the participation
of the urethane NH and formation of pyrrolidine derivatives.
tert-Butyl (S)-N-tert-butoxycarbonylpyroglutamate 6 was
used as the starting material.15 This was converted in high
yield into the enaminone 7 by using tert-butoxy-bis(dim-
ethylamino)methane (Bredereck’s reagent).16 The NaBH3-
CN reduction of the intermediate aldehyde 8, obtained by
acidic hydrolysis of 7, at a pH value between 3.5 and 4.0,
afforded a diastereoisomeric mixture of cis and trans alcohols
9 with improvement of the yield and shortening of the
reaction time as compared with the original protocol.14 The
mixture of the alcohols was then hydrolyzed using aqueous
LiOH in THF, and the resulting hydroxy acid 10 was
regioselectively reduced after conversion into the corre-
sponding mixed anhydride and in situ treatment with NaBH4.
The synthesis of the dimesylate 12 was followed by treatment
with potassium thiolacetate to give the bis-mercaptoacetyl
derivative 13 in 85% combined yields. Aqueous alkaline
hydrolysis of 13 at 0 °C afforded the (S)-5,5′-dimercapto-
leucine derivative 1417 whose iodine oxidation furnished
(13) Dubois, J.; Foure`s, C.; Bory, S.; Falcou, S.; Gaudry, M.; Marquet,
A. Tetrahedron 1991, 47, 1001.
(14) August, R. A.; Khan, J. A.; Moody, C. M.; Young, D. W. J. Chem.
Soc., Perkin Trans. 1 1996, 507.
(15) Protection as the N-Boc tert-butyl ester allows a regioselective
hydrolysis during the ring-opening step and preserves the stereochemical
integrity of the R-center (see: August, R. A.; Khan, J. A.; Moody, C. M.;
Young, D. W. Tetrahedron Lett. 1992, 33, 4617).
(6) Concerning nucleophilic reactions at the sulfur atoms, it should be
noted (see: Schmidt, U.; Grafen, P.; Goedde, H. W. Angew. Chem., Int.
Ed. Engl. 1965, 4, 846) that the ground state of the1,2-dithiolane ring system
(valence angle at the S atom, 92°; S-S bond length, 2.1 Å) is much more
similar geometrically to the transition state than is the ground state of an
open chain disulfide (valence angle at S, 107°; S-S distance, 2.05 Å).
(7) Singh, R.; Whitesides, G. M. J. Am. Chem. Soc. 1990, 112, 6304.
(8) (a) Packer, L.; Witt, E. H.; Tritschler, H. J. Free Radical Biol. Med.
1995, 19, 227. (b) Haenen, G. R. M. M.; Bast, A. Biochem. Pharmacol.
1991, 42, 2244.
(9) (a) Sigel, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 389. (b) Lodge,
J. K.; Traber, M. G.; Packer, L. Free Radical Biol. Med. 1998, 25, 287.
(10) Reed, L. J. ComprehensiVe Biochemistry 1966, 14, 99.
(11) Morera, E.; Nalli, M.; Pinnen, F.; Rossi, D.; Lucente, G. Bioorg.
Med. Chem. Lett. 2000, 10, 1585.
(16) Bredereck, H.; Simchen, G.; Rebsdat, S.; Kantlehner, W.; Horn,
P.; Wahl, R.; Hoffmann, H.; Grieshaber, P. Chem. Ber. 1968, 101, 41.
(17) (S)-N-Boc-5,5′-dimercaptoleucine tert-Butyl Ester (14). A solution
of bis-thioacetate derivative 13 (0.135 g, 0.31 mmol) in degassed EtOH (2
mL) was treated with 0.93 mL of aqueous 1 N NaOH at 0 °C for 1 h. The
mixture was neutralized with 2 N HCl and extracted with CH2Cl2. The
organic phase, washed with water, dried, and evaporated at room temper-
ature, gave an oily residue of pure 14 (0.108 g, 99%). [R]D +9° (c ) 2.0;
1
CHCl3); IR (CHCl3) 3434, 2981, 1706, 1501, 1369, 1236, 1153 cm-1; H
NMR (300 MHz, CDCl3) δ 1.24 (m, 1H, SHA), 1.32 (t, 1H, J ) 8.5 Hz,
SHB), 1.44 and 1.47 (2 × s, 18H, 2 × tert-butyl), 1.65 (m, 1H, â-CHA),
1.87 (m, 2H, â-CHB and γ-CH), 2.70 and 2.82 (2 × m, 4H, 2 × CH2S),
(12) Morera, E.; Lucente, G.; Ortar, G.; Nalli, M.; Mazza, F.; Gavuzzo,
E.; Spisani, S. Bioorg. Med. Chem. 2002, 10, 147.
1140
Org. Lett., Vol. 4, No. 7, 2002

Scheme 2a
a HClO4 70%, CH3CO2tBu, 76%; (b) (Boc)2O, DMAP, 94%; (c) Bredereck’s reagent, DME, 75 °C, 88%; (d) aqueous 0.2 N HCl, MeOH;
(e) NaBH3CN, 4 h, 56% from 7; (f) aqueous 1 M LiOH, THF, 0 °C, 95%; (g) iBuOCOCl, NMM, THF, -15 °C, then NaBH4 at 0 °C, 79%;
(h) CH3SO2Cl, TEA, CH2Cl2 dry, 0 °C, 94%; (i) CH3COSK, DMF, 91%; (j) aqueous 1 N NaOH, EtOH, 0 °C, 99%; (k) CHCl3, AcONa,
aqueous 0.1 M I2, 98%.
eventually the desired Adp derivative 1518 in almost quan-
titative yield; this latter compound was also obtained by a
one-pot procedure starting from 13 (72%). As expected, and
in accordance with the chemistry of 1,2-dithiolanes,5 the new
R-amino acid derivative 15 can be easily reduced to
regenerate the 5,5′-dimercaptoleucine 14.
Although the Adp derivative 15 contains two tert-butyl
protecting groups, it was possible, by adopting the proce-
dure described by Rapoport et al.,19 to selectively remove
the N-Boc protection in the presence of the tert-butyl
ester; Scheme 3 reports an application of this procedure
together with the synthesis of the dipeptide Z-Phe-Adp-
OtBu.
4.15 (m, 1H, R-CH), 5.09 (d, 1H, J ) 8.4 Hz, NH); 13C NMR (75.43 MHz,
CDCl3) δ 26.3 and 27.0 (2 × CH2S), 27.9 and 28.2 [2 × C(CH3)3], 35.0
(â-CH2), 39.5 (γ-CH), 51.8 (R-CH), 79.7 and 82.0 [2 × C(CH3)3] 155.1
and 171.4 (2 × CO).
Scheme 3a
(18) N-Boc-Adp tert-Butyl Ester (15). An aqueous solution of 0.1 M
iodine was added dropwise at 0 °C to a solution of 14 (0.096 g, 0.273
mmol) and AcONa (0.067 g, 0.820 mmol) in CHCl3 (8 mL) until a persistent
pale yellow color appeared (2.9 mL). The mixture was decolorized with 1
M Na2S2O3 and the organic phase was separated, washed with water, dried,
and evaporated at room temperature. The crude (0.101 g) was cromato-
graphed on silica gel (4 g) using CHCl3 as eluent to give 0.093 g of 15
(98%). Mp 61-61.5 °C (hexane); [R]D +21° (c ) 1.0; CHCl3); IR (CHCl3)
3434, 2982, 1707, 1500, 1369, 1153 cm-1; UV (CHCl3) λmax 332 (152);
1H NMR (300 MHz, CDCl3) δ 1.44 and 1.47 (2 × s, 18H, 2 × tert-butyl),
1.71 (m, 1H, â-CHA), 1.97 (m, 1H, â-CHB) 2.68 (m, 1H, γ-CH), 2.86 and
3.31 (2 × m, 4H, 2 × CH2S), 4.19 (m, 1H, R-CH), 5.10 (d, 1H, J ) 8.1
Hz, NH); 13C NMR (75.43 MHz, CDCl3) δ 27.9 and 28.3 [2 × C(CH3)3],
37.3 (â-CH2), 43.7 and 44.0 (2 × CH2-S), 44.1 (γ-CH), 53.1 (R-CH),
79.8 and 82.2 [2 × C(CH3)3], 155.1 and 171.2 (2 × CO). The Adp derivative
15 could also be prepared by a one-pot procedure: thus, a solution of bis-
dimercaptoacetyl derivative 13 (0.519 g, 1.19 mmol) in EtOH (8 mL) was
treated with 3.56 mL of aqueous 1 N NaOH at 0 °C for 1 h. The mixture
was diluted with CH2Cl2 (60 mL) and then an aqueous solution of 0.1 M
iodine was added dropwise until a persistent pale yellow color appeared.
The mixture was decolorized with 1 M Na2S2O3 and the organic phase
was separated, washed with water, dried, and evaporated at room temper-
ature. The crude (0.385 g) was cromatographed on silica gel (12 g) using
CHCl3 as eluent to give 0.299 g of 15 (72%).
a 1 M HCl in EtOAc, rt, 4 h, 69%; (b) HOBt, EDC, Z-Phe-OH,
TEA, DMF, 79%.
Org. Lett., Vol. 4, No. 7, 2002
1141

In conclusion, we have described the efficient synthesis
of a pair of chiral R-amino acids structurally related to the
natural residue of leucine and characterized by the presence
in its side chain of the 1,2-dithiolane-1,3 dithiol redox
system. By considering the relevant biological role played
by the lipoic-dihydrolipoic acid system as well as the
peculiar reactivity of 1,2-dithiolanes, the incorporation of
these new residues into bioactive peptides should represent
a new and promising approach.
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 12, 13, 16,
and 17. This material is available free of charge via the
Internet at http://pubs.acs.org.
(19) Gibson, F. S.; Bergmeier, S. C.; Rapoport, H. J. Org. Chem. 1994,
59, 3216.
OL0255458
1142
Org. Lett., Vol. 4, No. 7, 2002