Synthesis of l-Octaarginine through Microencapsulated Palladium-Catalyzed Allyl Ester Deprotection

Abstract

Octaarginine has been described as a molecular transporter. We report a useful synthesis of orthogonally protected l-octaarginine by using a method based on a microencapsulated palladium catalyst. Known palladium-based methods for allyl ester deprotection have been modified to facilitate purification of the unprotected intermediates. This improvement in the purification step has also been tested with a variety of allyl α-amino esters and allyl α,β-unsaturated esters.

Key words

peptides - palladium - protecting groups - esters

• References and Notes


For reports on l-Arg homopolymers as molecular carriers for cellular uptake, see:
• 1a Wender PA, Mitchell DJ, Pattabiraman K, Pelkey ET, Steinman L, Rothbard JB. Proc. Natl. Acad. Sci. U.S.A. 2000; 97: 13003
• 1b Lee HL, Dubikovskaya EA, Hwang H, Semyonov AN, Wang H, Jones LR, Twieg RJ, Moerner WE, Wender PA. J. Am. Chem. Soc. 2008; 130: 9364
• 1c Fabbri E, Manicardi A, Tedeschi T, Sforza S, Bianchi N, Brognara E, Finotti A, Breveglieri G, Borgatti M, Corradini R, Marchelli R, Gambari R. ChemMedChem 2011; 6: 2192
• 2 Lindgren M, Hällbrink M, Prochiantz A, Langel Ü. Trends Pharmacol. Sci. 2000; 21: 99
• 3 Wender PA, Jessop TC, Pattabiraman K, Pelkey ET, VanDeusen CL. Org. Lett. 2001; 3: 3229
• 4a Guibe F. Tetrahedron 1998; 54: 2967
• 4b Bräse S, Kirchhoff JH, Köbberling J. Tetrahedron 2003; 59: 885
• 4c Russell AG, Ragoussi ME, Ramalho R, Wharton CW, Carteau D, Bassani DM, Snaith JS. J. Org. Chem. 2010; 75: 4648
• 5a Ramarao C, Ley SV, Smith SC, Shirley IM, DeAlmeida N. Chem. Commun. 2002; 1132
• 5b Ley SV, Ramarao C, Gordon RS, Holmes AB, Morrison AJ, McConvey IF, Shirley IM, Smith SC, Smith MS. Chem. Commun. 2002; 1134
• 5c Bremeyer N, Ley SV, Ramarao C, Shirley IM, Smith SC. Synlett 2002; 1843
• 5d Vickerstaffe E, Warrington BH, Ladlow M, Ley SV. Org. Biomol. Chem. 2003; 1: 2419
• 5e Lee CK. Y, Holmes AB, Ley SV, McConvey IF, Al-Duri B, Leeke GA, Santos RC. D, Seville JP. K. Chem. Commun. 2005; 2175
• 5f Pears DA, Smith SC. Aldrichimica Acta 2005; 38: 23
• 5g Baxendale IR, Griffiths-Jones CM, Ley SV, Tranmer GK. Chem. Eur. J. 2006; 12: 4407
• 6a Sharma AK, Gowdahalli K, Krzeminski J, Amin S. J. Org. Chem. 2007; 72: 8987
• 6b Leeke GA, Santos RC. D, Al-Duri B, Seville JP. K, Smith CJ, Lee CK. Y, Holmes AB, McConvey IF. Org. Process Res. Dev. 2007; 11: 144
• 6c Carpita A, Ribecai A. Tetrahedron Lett. 2009; 50: 204
• 6d Sedelmeier J, Ley SV, Lange H, Baxendale IR. Eur. J. Org. Chem. 2009; 4412
• 6e Kuang YY, Chen FE. Helv. Chim. Acta 2009; 92: 897
• 7a Yu JQ, Wu HC, Ramarao C, Spencer JB, Ley SV. Chem. Commun. 2003; 678
• 7b Ley SV, Mitchell C, Pears D, Ramarao C, Yu JQ, Zhou W. Org. Lett. 2003; 5: 4665
• 7c Ley SV, Stewart-Liddon AJ. P, Pears D, Perni RH, Treacher K. Beilstein J. Org. Chem. 2006; 2: 15
• 7d Quai M, Repetto C, Barbaglia W, Cereda E. Tetrahedron Lett. 2007; 48: 1241
• 7e Kimachi T, Nagata H, Kobayashi Y, Takahashi K, Torii E, Ju-ichi M. Synlett 2011; 365
• 8 Fernandes A, Hensenne P, Mathy B, Guo W, Nysten B, Jonas AM, Riant O. Chem. Eur. J. 2012; 18: 788
• 9 Microencapsulated Palladium Catalyzed Cleavage of Allyl Esters; General Procedure: A suspension of PdEnCat 30 (Aldrich; 0.4 mmol/g loading, 0.05 equiv) in THF–H₂O (9:1, 5 mL) was bubbled with argon for 10 min. After this time, DCHT (0.15 equiv) and the corresponding allyl ester 1 (1.0 equiv, 70 mg) were added under positive pressure. Finally, PhSiH₃ was injected (2.0 equiv), and the mixture was allowed to react for 2 h at r.t. under an argon atmosphere. After this time, the reaction was filtered through Celite and the filtrate was evaporated under reduced pressure. The remaining solid was dissolved with EtOAc (20 mL) and washed with H₂O (3 × 10 mL) and brine (3 × 10 mL). The organic layer was dried (MgSO₄) and evaporated under vacuum. Purification by solid-phase extraction (C18 reverse-phase chromatography, H₂O/MeOH) gave pure carboxylic acids 2 (yields shown in Table 1). Purity was determined by HPLC, ¹H NMR and ¹³C NMR analyses. All the carboxylic acids are commercially available. The recorded ¹H and ¹³C NMR spectra of the synthesized compounds were consistent with those registered for commercial samples.
• 10 Tobiana J, Chidambaram M, Santo A, Sasson Y. Adv. Synth. Catal. 2008; 350: 1230
• 11 Ueki M, Amemiya M. Tetrahedron Lett. 1987; 28: 6617
• 12a El-Faham A, Subirós-Funosas R, Prohens R, Albericio F. Chem. Eur. J. 2009; 15: 9404
• 12b Subirós-Funosas R, Nieto-Rodriguez L, Jensen KJ, Albericio F. J. Pept. Sci. 2013; 19: 408
• 12c Subirós-Funosas R, Prohens R, Barbas R, El-Faham A, Albericio F. Chem. Eur. J. 2009; 15: 9394