Indian Journal of Chemistry Vol. 44B, December 2005, pp. 2611-2613

Note

Wolff rearrangement of Nα- Boc-/Z-protected The synthesis of Boc- as well as Z-β-amino acids aminodiazoketones to the corresponding β- was carried out usually by refluxing the mixture of α- diazoketone/ / Na2CO3/ Na2S2O3.5H2O at amino acids under microwave irradiation o 9 11 80 C for 1-3 hr . Leggio et al. made Fmoc-β-amino Kantharaju, Basanagoud S Patil & Vommina V acids by refluxing the corresponding α-diazoketones o Suresh Babu* at 70 C in the presence of silver benzoate for about 1- 3 hr in 50-90% yield. The ultrasound promoted Department of Studies in Chemistry, Central College Campus, Bangalore University, Dr B R Ambedkar Veedhi rearrangement of α-diazoketones at room temperature 12 Bangalore 560 001, India in the presence of silver benzoate took about 30 min E-mail: [email protected] for completion of the rearrangement. On the other + Received 26 March 2004; accepted (revised) 10 December 2004 hand, the use of Ag catalyzed decomposition of α- diazoketones employing three-folds of a tertiary base 1 The Wolff rearrangement of Nα-Boc-/Z-protected amino- was also known . The rearrangement was to be diazoketones in the presence of silver benzoate under microwave carried out for about 3-12 hr. irradiation is described. The reaction is found to be rapid, efficient The present communication deals with the synthesis and complete. It results in the isolation of Boc-/Z- protected-β- amino acids in good purity as well as yield. of Boc- and Z-protected β-amino acids assisted by microwave irradiation. It has been now found that the Keywords: Wolff rearrangement, microwave irradiation, Boc-/Z- Wolff rearrangement of Boc-/Z-protected α-amino- aminodiazoketones, β-amino acids diazoketones can be accomplished in the presence of IPC: Int.Cl.7 C 07 C catalytic amount of silver benzoate using microwave irradiation. The rearrangement was carried out by The construction of peptides comprising the higher exposing the mixture of Boc-/Z-protected α-amino- homologues of α-amino acids like β- and γ-amino diazoketones and catalytic amount of silver benzoate acids results in well-defined secondary structures like in 1,4-dioxane- (2:1) in a beaker to microwaves helices, sheets, turns, which are similar to the well- operating at 2450 MHz frequency at its 60% of power known secondary structures of proteins1-4. The (480W) (Scheme I). The reaction was monitored by homologation of the commercially available TLC and IR. The reaction was found to be completed crystalline, optically pure α-amino acids to β-amino in about 40-60 sec for one mmole proportion of the acids by Arndt-Eistert method5,6 has been starting material. A simple work-up of the reaction accomplished by employing α-aminodiazoketones as mixture has resulted in isolation of all the β-amino the key intermediates. These optically active acids 2a-j in good yield (80-92%) and purity (as substrates have been converted to the corresponding analyzed by RP-HPLC). It was found to be free from β-amino acids by the Wolff rearrangement7 in the racemization. This was confirmed by comparing the 8-11 6 25 presence of water, thermally , photochemically , by determined specific rotations of 2g; [α]D –29.1 (c=1, + 12 25 metal ion (Ag ) catalysis or by using ultrasound . CHCl3) and 2h; [α]D +29.6 (c=1, CHCl3) with the The microwave irradiation technique13, has been reported values16. Thus, the decomposition of Boc-/Z- used to decrease the time necessary to carry out protected α-aminodiazoketones to the corresponding cleaner reactions with higher selectivity and easier β-amino acids can be accomplished under no base work-up. We have demonstrated the utility of conditions employing microwave irradiation. microwave irradiation for of Fmoc- to isocyanates both in Experimental Section solution and solvent free conditions14. A simple, rapid, and efficient route for the preparation of several All the amino acids used, unless otherwise amino acid benzyl ester p-toluenesulfonate and specified has L-configuration. Melting points were hydrochloride salts under microwave irradiation was determined using a Leitz-Wetzler melting point also demonstrated by us15. apparatus and are uncorrected. TLC was carried out 2612 INDIAN J. CHEM., SEC B, DECEMBER 2005

R H R H Silver benzoate, O CHN2 1,4-dioxane-water C X N C X N OH H M.W., 40-60 sec. H O 1a-j 2a-j X= Boc-/Z- group Compd X R Compd X R

a Boc CH3 f Z CH3

b Boc CH(CH3)2 g /h Z (CH2)2CH3

c/d Boc CH(CH3)CH2CH3 i Z CH2C6H5

e Boc CH2C6H5 j Z C6H5

Scheme I  Synthesis of Nα-Boc-/Z-protected β-amino acids on precoated silica gel plates using the solvent water (2 × 20 mL), dried over anhyd. Na2SO4 and systems: (i) chloroform-- (45:2:1) evaporated to obtain Nα-Boc-/Z-β-amino acids 2a-j. and (ii) chloroform-methanol (9:1) and the Rf values N-(t-Butyloxycarbonyl)-β-homoalanine 2a: Yield o 25 are designated as Rf A and Rf B, respectively. Optical 86%; m.p. 98-99 C; Rf A 0.62;Rf B 0.72; [α]D rotations were measured with an automatic AA-10 – 18.1 (c=1, CHCl3). Anal. Calcd. for C9H17NO4: C, polarimeter. IR spectra were recorded on a Nicolet 53.45; H, 8.47; N, 6.92. Found: C, 53.24; H, 8.50; N, model impact 400D FT-IR spectrometer (KBr pellets, 6.52%. IR: 1698 cm-1 (CO of urethane); 1H NMR -1 30 cm resolution). Elemental analysis was carried (CDCl3): δ 1.2 (3H, d), 1.33 (9H, s), 2.4 (2H, d), 4.01 out by Perkin-Elmer Analyzer and the samples were (1H, m), 5.25 (1H, br) and 8.4 (1H, br). dried for 24 hr under vacuum before analysis. N-(t-Butyloxycarbonyl)-β-homovaline 2b: Yield Analytical reverse phase RP-HPLC was performed o 25 87%; m.p. 65-66 C; Rf A 0.61; Rf B 0.70; [α]D with a LC-3000 system using a C-18 –20.2 (c=1, CHCl ). Anal. Calcd. for C H NO C, o 3 11 21 4: Bondapak column (3.9 × 300 mm, 10 A spherical) 57.37; H, 9.19; N, 6.08. Found: C, 56.80; H, 9.34; N, using as the eluent acetonitrile-0.1% trifluroacetic 5.82%. IR: 1690 cm-1 (CO of urethane); 1H NMR acid and water [65:35.isocratic, flow rate: 0.7 1 (CDCl3): δ 0.94 (6H, d), 1.32 (9H, s), 1.72 (1H, m), mL/min, monitoring at 220 nm]. H NMR spectra 2.5 (2H, d), 4.20 (1H, m), 5.4 (1H, br) and 8.3 (1H, were recorded on a Bruker AMX-400 MHz br). spectrometer. LG domestic microwave oven MS N-(t-Butyloxycarbonyl)-β-homoisoleucine 2c: 194W operating at 2450 MHz frequency at its 60% o Yield 82%; m.p. 85-86 C; Rf A 0.58; Rf B 0.64; power (480W) was used. Boc- as well as Z-α- [α] 25 – 24.0 (c=1, CHCl ). Anal. Calcd. for aminodiazoketones has been prepared by the reported D 3 17 C12H23NO4: C, 58.99; H, 9.48; N, 5.73. Found: C, procedure . 58.92; H, 9.36; N, 5.84%. IR: 1690 cm-1 (CO of α 1 General procedure for preparation of N - urethane); H NMR (CDCl3): δ 0.93 (6H, d), 1.33 protected β-amino acids 2a-j. A suspension of Nα- (11H, m), 1.5 (1H, m), 2.38 (2H, d), 3.70 (1H, m), Boc-/Z-aminoacyldiazomethane (1 mmole), silver 5.42 (1H, br) and 8.4 (1H, br). benzoate (2 mg, 0.08 mmole) in 1,4-dioxane (10 mL) N-(t-Butyloxycarbonyl)-D-β-homoisoleucine 2d: o 25 and water (5 mL) was irradiated to microwaves till the Yield 80%; m.p. 87 C; Rf A 0.60; Rf B 0.68; [α]D completion of the rearrangement. The remaining + 24.8 (c=1, CHCl3). Anal. Calcd. for C12H23NO4: C, solvent was filtered and evaporated under reduced 58.99; H, 9.48; N, 5.73. Found: C, 58.92; H, 9.36; N, pressure. The resulting residue was redissolved in 5.84%. IR: 1690 cm-1 (CO of urethane); 1H NMR 10% aqueous sodium carbonate solution (20 mL). It (CDCl3): δ 0.93 (6H, d), 1.32 (11H, m), 1.5 (1H, m), was washed with ether (2 × 30 mL) and acidified to 2.38 (2H, d), 3.70 (1H, m), 5.42 (1H, br) and 8.4 pH 2 using 10% HCl (or citric acid in case of Boc- (1H, br). derivatives) and extracted using ethyl acetate (3 × 25 N - (t-Butyloxycarbonyl) - β-homophenylalanine o mL). The combined organic layer was washed with 2e: Yield 90%; m.p. 68-70 C; Rf A 0.61; Rf B 0.68; NOTES 2613

25 [α]D – 18.0 (c=1, CHCl3). Anal. Calcd. for C, 68.44; H, 5.74; N, 4.95. Found: C, 68.23; H, 5.68; -1 1 C15H21NO4: C, 64.04; H, 7.92; N, 5.18. Found: C, N, 4.67%. IR : 1702 cm (CO of urethane); H NMR -1 64.73; H, 7.60; N, 5.03%. IR: 1700 cm (CO of (CDCl3): δ 2.5 (2H, d), 4.2 (1H, m), 5.01 (2H, s), 5.46 1 urethane); H NMR (CDCl3): δ 1.38 (9H, s), 2.38 (2H, (1H, br) and 7.15-7.45 (10H, s). d), 2.72 (2H, d), 4.01 (1H, m), 5.0 (1H, m), 7.3 (5H, s) and 8.3 (1H, br). Acknowledgement N-Benzyloxycarbonyl-β-homoalanine 2f: Yield Authors thank the Department of Science and o 25 84%; m.p. 121-122 C; Rf A 0.60;Rf B 0.69; [α]D Technology, Govt. of India for financial assistance. – 19.8 (c=1, CHCl3). Anal. Calcd. for C12H15NO4: C, Authors also thank Professor Fred Naider, City 61.00; H, 6.39; N, 5.92. Found: C, 61.27; H, 6.23; N, University of New York, New York for useful -1 1 5.87%. IR: 1700 cm (CO of urethane); H NMR discussions. One of the authors (KR) thanks the (CDCl3): δ 1.2 (3H, d), 2.4 (2H, d), 3.6 (1H, m), 5.1 CSIR, New Delhi for the award of a SRF. (2H, s), 5.4 (1H, br), 7.15-7.35 (5H, s) and 8.4 (1H, br). References N – Benzyloxycarbonyl - β-homonorvaline 2g: o 1 Seebach D, Overhand M, Kuhnle F N M, Martinoni B, Oberer Yield 80%; m.p. 82-83 C; Rf A 0.63; Rf B 0.67; L, Hommel V & Widmer H, Helv Chim Acta, 79, 1996, 913. 25 [α]D –29.1 (c=1, CHCl3). Anal. Calcd. for 2 Seebach D, Abele S, Gademann K & Jaun B, Angew Chem, C14H19NO4: C, 63.38; H, 7.22; N, 5.28. Found: C, 111, 1999, 1700. 63.18; H, 7.18; N, 5.18%. IR: 1690 cm-1 (CO of 3 Abele S, Seiler P & Seebach D, Helv Chim Acta, 82, 1999, 1 1159. urethane); H NMR (CDCl3): δ 1.1-1.3 (7H, m), 2.6 (2H, d), 3.9 (1H, d), 5.15 (2H, s), 5.8 (1H, br) and 7.2 4 Gellman S H, Acc Chem Res, 31, 1998, 173. 5 Ye T & McKervey M A, Chem Rev, 94, 1994, 1091. (5H, m). 6 Wolfgang Kirmse, Eur J Org Chem, 2002, 2193. N-Benzyloxycarbonyl-D-β-homonorvaline 2h: 7 Gill G B, The Wolff rearrnagement in Comprehensive o Yield 82%; m.p. 83-85 C; Rf A 0.61; Rf B 0.69; Organic Synthesis, Vol 3, edited by G Pattenden, (Pergamon 25 Press, New York), 1991, 887. [α]D +29.6 (c=1, CHCl3). Anal. Calcd. for 8 Baldwin S E & Aube J, Tetrahedron Lett, 28, 1987, 179. C14H19NO4: C, 63.38; H, 7.22; N, 5.28. Found: C, 63.18; H, 7.12; N, 5.08%. IR: 1692 cm-1 (CO of 9 Plucinska K & Liberek B, Tetrahedron, 43, 1987, 179. 1 10 Ellmerer, Muller E P, Brossner D, Mastouh N & Tako A, urethane); H NMR (CDCl3): δ 1.2-1.5 (7H, m), 2.45 Helv Chim Acta, 81, 1998, 59. (2H, d), 3.8 (1H, d), 5.17 (2H, s), 5.6 (1H, br) and 7.2 11 Leggio A, Liguori A, Procopio A & Sindona G, J Chem Soc (5H, m). Perkin Trans 1, 1997, 1969. N-Benzyloxycarbonyl-β-homophenylalanine 2i: 12 Muller A, Vogt C & Sewald N, Synthesis, 1998, 837. o Yield 86%; m.p. 84-85 C; Rf A 0.60; Rf B 0.68; 13 Varma R S, Advances in Green Chemistry: Chemical [α] 25–36.2 (c=1, CHCl ). Anal. Calcd. for synthesis using microwave irradiation, edited by M K D 3 Sumitra, Astra Zeneca Research Foundation India; Special C18H19NO4: C, 69.21; H, 6.13; N, 4.48. Found: C, Publication No. 008, Bangalore, 2002. -1 69.63; H, 6.47; N, 4.32%. IR: 1698 cm (CO of 14 Patil B S, Vasanthakumar G-R & Suresh Babu V V, J Org 1 urethane); H NMR (CDCl3): δ 2.55 (2H, d), 2.71 Chem, 68, 2003, 7274. (2H, d), 4.24 (1H, br), 5.08 (2H, s), 5.28 (1H, m) and 15 Vasanthakumar G-R, Patil B S & Suresh Babu V V, Lett in 7.15-7.38 (10H, m). Peptide Science, 9, 2002, 207. N-Benzyloxycarbonyl-β-homophenylglycine 2j: 16 Ananda K, Gopi H N & Suresh Babu V V, J Peptide Res, 55, o 2000, 289. Yield 80%; m.p., 86-88 C; Rf A 0.63; Rf B 0.74; 17 Vasanthakumar G-R, Patil B S & Suresh Babu V V, J Chem 25 [α]D –18.5 (c=1, CHCl3). Anal. Calcd. for C17H17NO4: Soc Perkin Trans 1, 2002, 2087.