A new approach to the synthesis of dipeptides with unnatural amino acids using organozinc chemistry

摘要

J. CHEM. SOC. PERKZN TRANS.1 1995 A new approach to the synthesis of dipeptides with unnatural amino acids using organozinc chemistry Michael J. Dunn, Sylvie Gomez and Richard F. W. Jackson * Department of Chemistry, Bedson Building, The Uniuersity of Newcastle, Newcastle upon Tyne NEl 7RU, UK Dipeptides which incorporate an iodoalanine unit at either the N-or C-terminus can be converted into the corresponding organozinc reagents upon treatment with activated zinc. The C-terminal dipeptide organozinc reagents undergo palladium-catalysed reaction with electrophiles to give dipeptides incorporating non-proteinogenic amino acids without loss of stereochemical purity. The N-terminal organozinc reagents are less synthetically useful. The serine-derived organozinc reagent 1 is an effective reagent for the preparation of enantiomerically pure a-amino acids, 1 M=Rh 2 M=ZZn(NC)Ch either using palladium catalysis or by transmetallation to the zinc/copper reagent 2 followed by reaction with electro- philes.' These results establish that a carbon-zinc bond at the P-position of an amino acid is kinetically stable to a significant extent both to protonolysis by the acidic NH group and to p-elimination with loss of the carbamate anion.We now report that it is also possible to incorporate a carbon-zinc bond in the side-chain of simple dipeptides, and that reaction of these intermediates with electrophiles leads to stereoisomerically pure modified dipeptides. Previous approaches to the modification of peptides by carbon-carbon bond formation have not permitted complete control of stereochemistry, since they have almost always relied on diastereoselective processes.3-10 As our initial starting material we chose to prepare the dipeptide 3b, incorporating a P-iodoalanine unit at the N-terminus. The immediate precursor to the dipeptide 3b, the chloro derivative 3a, was prepared by coupling N-Boc-P-chloroalanine with alanine methyl ester using dicyclohexyl- carbodiimide and 1-hydroxybenzotriazole in dichloromethane (90). Treatment of the dipeptide 3a with sodium iodide in acetone proceeded slowly at 40"C to give the required iodide 3b. Use of more vigorous conditions (acetone at reflux) leads to significant amounts of the dehydropeptide 4 (Scheme 1).X. 3 4 'La X=CI b X=I c x=Izn Scheme 1 15 d Reagents and conditions: i, NaI (3 equiv.), acetone, 40"C, Reaction of the iodide 3b with activated zinc," followed by addition of 2-furoyl chloride and catalytic palladium(o), resulted in a low yield (12) of the desired peptide 5a (as a single stereoisomer), together with significant amounts of Bw-Ala- Ala-OMe. Since these results implied that the organozinc reagent 3c was unstable towards proton-transfer, the iodide 3b was treated with activated zinc in the presence of iodobenzene and catalytic Pd'. In this case a small amount of Boc-Phe-Ala- OMe 5b was isolated (lo),together with the starting iodide 3b (50) (Scheme 2), suggesting that the reaction of zinc with 3b was being inhibited.0 Me 3b X=IiOiiG50 X=2-kyl iuI7Sb X=Ph Scheme 2 Reagents andconditions: i, Zn*, THF, 35 "C Cprepared from zinc dust by treatment with 1,2dibromoethane (5 molx), and then chlorotrimethylsilant (3 molx), in THF; ii, 2-furoyl chloride, Pd,(dba), (2.5 molx), PPh3 (10 molx); iii, Zn*, THF, PhI, Pd,(dba), (2.5 molx), P(u-tol), (10 molx), 50 "C,4 h Given these rather disappointing results, we turned to the C-terminal iodide 6b, isomeric with the iodide 3b. The necessary precursor, the chloride 6a, was prepared by coupling of N-Bw protected alanine with P-chloroalanine methyl ester (70)."*12Transformation of 6a into 6b by treatment with sodium iodide in acetone proceeded slowly (15 days) at 35"C (75).As we had already obseivedduring the preparation of 3b, use of more vigorous conditions led to the formation of the dehydropeptide 7 (Scheme 3). Treatment of the iodide 6b with a X=CIiiicb X=I 7 Scbeme3 Reagents and conditions: i, Bu'OCOCI (1.1 equiv.), Et,N (1.1 equiv.), THF, -15 "C, 1 h; ii, Ala(FCl)-OMe (1 equiv.) and Et3N (1.1 equiv.) in DMF,-15 "C, 1.5 h, then room temp., 2 d; iii, NaI (5 equiv.), acetone, 35 OC, 15 d 1640 J. CHEM. soc. PERKIN TRANS. I 1995 Table 1 Preparation from the dipeptide 6bof the C-terminal modified dipeptides 9a-g Electrophile Catalyst Temp. (T/OC) PhCOCl 4-BrC6H,COCI PhI 2-FurylCOCl 4-02NC6H41 4-BrCamp;I 1-1odonaphthalene CPd,(dba),l/PPh,CPd2(dba) 3I/PPh3 CPd2(dba)3l/PPh, Pd2(d ba),/P( o-tol), Pd2( d ba),/P( 0-tol), Pd,(dba), J/P(o-tol), Pd2(dba),/P(o-tol), 20 20 20 50 50 65 65 activated zinc under conditions identical with those used earlier for the formation of the zinc reagent 3c led to efficient formation of the corresponding zinc reagent 8, which was characterised in 'H,THF by 'H NMR spectroscopy, and appeared to be significantly more stable than the isomeric zinc reagent 3c.Palladium-catalysed reaction of the zinc reagent 8 with a range of electrophiles, under unoptimised conditions, gave the corresponding dipeptides 9a-g (Scheme 4). Our results are detailed in Table 1. i~6bX = I ..=s X=znI 9 X=E Scheme 4 Reagents and conditions: i, Zn*, THF, 35 "C; ii, electrophile, Pd,(dba), (2.5 molz), phosphine ligand (10 molx), THF As an additional example, Boc-Phe-Ala(.P-I)-OMe 10 was prepared directly (60) from Boc-Phe-Ser-OMe 11 using P(OPh),MeI.This transformation was complete within 0.5 h, which represents a very significant improvement over our previous method. Treatment of the iodide 10with zinc, followed by addition of catalytic Pdo and 44odonitrobenzene, gave Boc-Phe-Phe(4-NO2)-OMe12 (55) (Scheme 5). jcll X=OHii,iiic_lo XZI 12 X Camp;NOz-p Scheme5 Reagems and conditions: i, p(OPh),MeI (2 equiv.), DMF, room temp., 0.5 h; ii, Zn*, THF, 35 "C; iii, 4-IC6H,N02, Pd2(dba), (2.5 molx), P(o-tol), (10 molx), 50 "C, 12 h Experimental Typical experimental procedure: preparation of Boc-Ala-Phe(4-N0amp;OMe 9e A mixture of zinc dust (0.3 g, 4.5 mmol), 1,2-dibromoethane (0.042 g, 20 mm', 0.023 mmol) and dry tetrahydrofuran (0.34 cm') in a dry, nitrogen-purged flask was heated to 65 "C, with stirring, for 5 min with accompanying effervescence.After the flask had been cooled to room temperature, trimethylchloro- silane (6 mm3, 0.05 mmol) was added to it and the contents were sonicated for 30 min.2 After this, the reaction mixture was Time (t/h) Product E Yield () 1 9a PhCO 31 1 1 9b !k 2-FurylCO 4-BrC6H4C0 51 25 2 9d Ph 15 2 9e 4-02NCamp;, 63 2 2 9f 1 -Naphthyl BrC,H, 41 20 warmed to 35 "C, and a solution of Boc-Ala-Ala(P-I)-OMe (0.3 g, 0.75 mmol) in dry tetrahydrofuran (0.75 cm3)was added to it via a syringe. It was then stirred at 35 "C for 30 min until no starting material remained TLC analysis, light petroleum (bp 4amp;60 "C)-ethyl acetate (2 : l).After the reaction mixture had been cooled to room temperature and diluted with dry tetrahydrofuran (5 cm3) and the excess of zinc had settled, the supernatant was carefully removed from the residue via a syringe into a dry, nitrogen-purged flask. The solution of zinc reagent was warmed to 5OoC, and tris(dibenzy1-ideneacetone)dipalladium(o) (0.01 8 g, 0.02 mmol), tri-o-tolyl-phosphine (0.024 g, 0.08 mmol) and 4-iodonitrobenzene (0.249 g, 1.O mmol) were added to it sequentially. After being stirred for 2 h the reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (50 cm3), washed with aqueous hydrochloric acid (0.1 mol drn-,; 25 cm') and water (3 x 25 cm3), dried (MgSO,) and evaporated to give the crude product. Column chromatography of this over silica gel light petroleum (bp 40-60 "Cjethyl acetate, 4 : 11 yielded Boc-Ma-Phe(4-NO2)- OMe 9e (0.184 g, 0.46 mmol, 63).Acknowledgements We thank the EPSRC for a research grant (GR/J24423) and the Commission of the European Union for a Fellowship (S. G.) under the Human Capital and Mobility programme (ERBCHBICT930579). Zeneca and Pfizer are also thanked for additional support. References 1 R. F. W. Jackson, N. Wishart, A. Wood, K. James and M. J. Wythes, J. Org. Chem., 1992,57,3397. 2 M. J. Dunn, R. F. W. Jackson, J. Pietruszka and D. Turner, J. Org. Chem., 1995,60,2210. 3 U. Schmidt, A. Lieberknecht and J. Wild, Synthesis, 1988, 159. 4 R. Polt and D. Seebach, J. Am. Chem. SOC.,1989,111,2622. 5 I. Ojima, T. Komata and X. Qiu, J. Am. Chem. SOC.,1990,112,770. 6 D. Crich and J. W. Davies, Tetrahedron,1989,45, 5641. 7 U. Kazmaier,J. Org. Chem., 1994,59, 6667. 8 H. G. Bossler and D. Seebach, Helv. Chim. Acta, 1994,77, 1 124 and references therein. 9 A. R. Ritter and M. J. Miller, Tetrahedron Lett., 1994,35,9379. 10 M. Jager, K. Polborn and W. Steglich, Tetrahedron Lett., 1995,36, 861. 1 1 P. Knochel and R. D. Singer, Chem. Rev., 1993,93,2117. 12 A. Srinivasan, R. W. Stephenson and R. K. Olsen, J. Org. Chem., 1977,42,2253. 13 J. P. H. Verheyden and J. G. Moffatt, J. Org. Chem., 1970,35,2319. Paper 5/028151 Received 2nd May 1995 Accepted 2nd May 1995