Facile Synthesis of r,r-Diisobutylglycine and Anchoring Its Derivatives onto PAL-PEG-PS Resin Yanwen Fu, Marcus A. Etienne, and Robert P. Hammer* Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana 70803
[email protected] Received June 23, 2003
Abstract: R,R-Diisobutylglycine has been synthesized using a Pd-mediated dialkylation of ethyl nitroacetate as a key first step. The free RRAA is NR-protected and has been applied to the assembly of conformationally constrained peptide analogues. Mixed anhydrides from BOP-Cl and FmocRRAA-OH are used for anchoring RRAAs onto a trialkoxybenzyl linker on PEG-PS grafted support, upon which a β-strand mimic with difficult sequence is assembled in a superior quality.
There is an increased interest in the synthesis and use of symmetrically R,R-disubstituted amino acids (RRAAs) in controlling peptide secondary structures.1,2 Recent approaches to RRAAs via alkylation of R-nitroacetate3 and Ni-Schiff base complex4 allow practical preparation of a variety of RRAAs in good chemical yields. However, highly hindered RRAAs that possess branched side chains, such as R,R-diisobutylglycine 3a (Dibg),5 have not been readily synthesized.6,7 Though Dibg was traditionally prepared via the Bucherer-Bergs method,8 there were major flaws associated with this approach due to the high resistance to the formation and hydrolysis of the hydantoin, which in turn gave a very low overall yield of the desired product. In our effort to assemble a number of β-strand mimics containing Dibg and other RRAAs, we needed to develop a practical method for preparing a large quantity of protected Dibg that is suitable for solidphase peptide synthesis. Herein we report an efficient * To whom correspondence should be addressed. Tel: (225) 5784025. Fax: (225) 578-3458. (1) For recent reviews on use of RRAAs in peptide design, see: (a) Toniolo, C.; Crisma, M.; Formaggio, F.; Peggion, C. Biopolymers 2001, 60, 396-419. (b) Wysong, C. L.; Yokum, T. S.; McLaughlin, M. L.; Hammer, R. P. Chemtech 1997, 27, 26-33. (2) For a recent review on synthesis of RRAAs, see: Kotha, S. Acc. Chem. Res. 2003, 36, 342-351. (3) Fu, Y.; Hammarstro¨m, L. G. J.; Miller, T. J.; Fronczek, F. R.; McLaughlin, M. L.; Hammer, R. P. J. Org. Chem. 2001, 66, 71187124. (4) Ellis, T. K.; Martin, C. H.; Ueki, H.; Soloshonok, V. A. Tetrahedron Lett. 2003, 44, 1063-1066. (5) Abbrevations: Aib, R-aminoisobutyric acid; Api, 4-aminopiperidine-4-carboxylic acid; BOP-Cl, bis(2-oxo-3-oxazolidinyl)phosphinic chloride; Dbzg, R,R-dibenzylglycine; DCE, 1,2-dichloroethane; Dibg, R,R-diisobutylglycine; DIEA, N,N-diisopropylethylamine; Dpg, R,Rdipropylglycine; Fmoc, 9-fluorenylmethoxycarbonyl; HATU, O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; HOAt, hydroxy-7-azabenzotriazole; MALDI-MS, matrix-assisted laser desorption ionization mass spectrometry; PAL, 5-(4-aminomethyl-3,5dimethoxyphenoxy)valeric acid; PEG-PS, poly(ethylene glycol)polystyrene graft; PyAOP, 7-azabenzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluoro-phosphate; SPPS, solid-phase peptide synthesis; TPS, triisopropylsilane; Z, benzyloxycarbonyl.
synthesis of Dibg via Pd-mediated diallylation of R-nitroacetate. Additionally, some of the peptides we are currently making require a hindered RRAA at the C-terminus. Such peptides are difficult to assemble as coupling of the RRAA to the solid support generally affords low yields.9 Thus, we also report here an improved method for anchoring RRAAs onto PAL-PEG-PS resin via mixed anhydrides. We have found R-nitroacetate a very useful synthon for the preparation of RRAAs with and without side chain functionality, where the R,R-dialkylated nitroacetate was produced as a key precursor to the target compound.3 Since direct dialkylation of nitroacetate with branched alkyl halides proved to be nonproductive (Table 1, entry 1), we tried activated allyl halides for the alkylation under different conditions. While allyl iodide gave the diallylated acetate in a moderate yield (Table 1, entry 5), the branched allyl iodide, 3-iodo-2-methylpropene only gave a low yield of the diallylated nitroacetate (Table 1, entry 3), and the major product of this reaction was a mixture of mono-C-allylated and O-allylated derivates. In both cases, allyl bromides only gave trace amount of desired compounds (Table 1, entries 2 and 4). In search for an efficient method for dialkylation of R-nitroacetate with branched allyl halides or it equivalents, we thought that use of “activated” allylic groups as the electrophiles would be a feasible approach. Allylic activation with palladium templates has long been used for alkylation of preformed carbanions.10 The previously reported Pd-catalyzed allylic alkylation of R-substituted nitro carboxylic acids gave quarternary nitro esters in good yields.11,12 Muzart’s group and Lopez’s group reported Pd-mediated alkylation of allyl acetate by nitro (6) While alkylations of the Ni-Schiff base complex with unbranched alkyl halides lead to the formation of RRAAs in high yields, this method has not been extended for the synthesis of branched RRAAs. The alkylation with branched alkyl halides gave predominately mono-alkylated products under attempted conditions. Ellis, T. K.; Martin, C. H.; Tsai, G. M.; Ueki, H.; Soloshonok, V. A. J. Org. Chem. 2003, 68, 6208-6214. (7) Synthetic approaches to Dibg were attempted via condensation of symmetric ketones with PhCH2NH2 or Hofmann degradation of substituted cyanoacetic ester; however, both approaches gave a very low overall yield of the desired product. See: (a) Freitas, A. M.; Maia, H. L. S. Peptide, Proc. Eur. Pept. Symp. 1989, 13-15. (b) Lin, K.-H.; Li, L.; Huang, Y.-T. Science & Technol. China 1948, 1, 5-10. (8) (a) Fu, Y. Artificial Peptides Containing CR, R-disubstituted Amino Acids: Synthesis, Conformational Studies, and Application as β-strand Mimics. Dissertation, Louisiana State University, 2002, pp 22-66. (b) Upham, S. D.; Dermer, T. C. J. Org. Chem. 1957, 22, 799-802. (9) There are only a limited reports on assembling peptides with an RRAA at the C-terminus using SPPS, where typically a less sterically hindered RRAA such as Aib and Api, was coupled onto a resin using Fmoc-RRAA-F in DMF or refluxing CH2Cl2. For examples, see: (a) Wenschuh, H.; Beyermann, M.; Krause, E.; Brudel, M.; Winter, R.; Schu¨mann, M.; Carpino, L. A.; Bienert, M. J. Org. Chem. 1994, 59, 3275-3280. (b) Yokum, T. S.; Gauthier, T. J.; Hammer, R. P.; McLaughlin, M. L. J. Am. Chem. Soc. 1997, 115, 1167-1168. (c) Wysong, C. L.; Yokum, T. S.; Morales, G. A.; Gundry, R. L.; McLaughlin, M. L.; Hammer, R. P. J. Org. Chem. 1996, 61, 7650-7651. (10) For reviews on Pd-catalyzed allylic alkylations, see: (a) Trost, B. M. Acc. Chem. Res. 1996, 29, 355-364. (b) Trost, B. M. Acc. Chem. Res. 1980, 13, 385-393. (c) Trost, B. M., Verhoeven, T. R. J. Am. Chem. Soc. 1980, 102, 4730-4743. (c) Trost, B. M., Verhoeven, T. R. J. Am. Chem. Soc. 1976, 98, 630-632. (11) Fornicola, R. S.; Oblinger, E.; Montgomery, J. J. Org. Chem. 1998, 63, 3528-3529. (12) Lalonde, J. J.; Bergbreiter, D. E.; Wong, C.-H. J. Org. Chem. 1988, 53, 2323-2327. 10.1021/jo034885j CCC: $25.00 © 2003 American Chemical Society
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Published on Web 11/15/2003
TABLE 1. Alkylation of Ethyl Nitroacetate with Allyl Halides and Allyl Acetates entry
electrophile
methoda
reagent
1 2 3 4 5 6 7 8
(CH3)2CHCH2I CH2dC(CH3)CH2Br CH2dC(CH3)CH2I CH2dCHCH2Br CH2dCHCH2I CH2dC(CH3)CH2OAc CH2dC(CH3)CH2OAc CH2dCHCH2OAc
A A A A A B B B
Bu4NI Bu4NBr Bu4NI Bu4NBr Bu4NI Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4
T prod (°C) no. 50 60 60 60 60 50 25 50
1c 1a 1a 1b 1b 1a 1a 1b
yieldb (%) tracec tracec 99% purity).
Acknowledgment. We thank Dr. Dale Treleaven, Dr. Tracy McCarley, and Ms. Martha M. Juban for expert technical support and Dr. Sidney Val for helpful discussions. We also thank the Nebraska Center for Mass Spectrometry for technical assistance. We thank the Louisiana Board of Regents for a graduate fellowship to ME. This work was supported by a grant from the National Institute on Aging (AG 17983) of the National Institutes of Health. Supporting Information Available: Experimental details for 1b, 2a, 3a, 5a, 6a; 1H and 13C NMR spectra for 1a, 2a, 3a, 4a, 5a, and 6a; methods for anchoring Dpg and Dibg onto the resin; MALDI mass spectrum of peptide K7-INH. This material is available free of charge via the Internet at http://pubs.acs.org. JO034885J
J. Org. Chem, Vol. 68, No. 25, 2003 9857
