Simple and efficient access to the left-hand segment of azinomycins

摘要

J. CHEM. SOC. PERKIN TRANS. 1 1992 Simple and Efficient Access to the Left-hand Segment of Azinomycins Kozo Shishido,' Tomoki Omodani and Masayuki Shibuya Faculty of Pharmaceutical Sciences, University of Tokushima, Sho-machi 7, Tokushima 770, Japan A practical synthesis of the epoxy carboxylic acid 4, the left-hand segment of azinomycins, and its conversion into the naturally occurring amide 3 have been achieved enantioselectively. Azinomycin A 1and B 2, antitumour antibiotics, were isolated from the culture broth of strain Streptomyces griseofuscus S42227 by Nagaoka et al.' along with the biologically inactive amide 3, which is the common structural unit of azinomycins. Although the synthesis of the left-hand segment of these antibiotics, such as the amide 32 or the carboxylic acid 4,j has already beem established, no concise route has so far been reported.Therefore, we embarked upon the development of a practical synthetic route to 3 and 4, which would serve as key components in the total synthesis, and now report a simple and efficient synthesis of these compounds starting from the Schreiber's epoxy alcohol 6. 6H 1; AzinomyanA,X=CH2 2; Aziicyin B,X = C=CH(OH) 3; R=NH2 4; R=OH Fig. 1 According to the protocol of Schreiber? the Sharpless asym- metric epoxidation of diisopropenyl carbinol 5 using D-( -)-diisopropyl tartrate provided the epoxy alcohol 6 in 69% yield. Esterification with 3-methoxy-5-methylnaphthalene-l-carboxylic acid5 with the aid of DCC provided the ester 7,tt which was treated with a catalytic amount of osmium tetroxide and sodium metaperiodate to give the methyl ketone 8 in 86% overall yield from 6.Since attempted haloform reaction for the requisite conversion of the methyl ketone moiety in 8 into the carboxyl group was unsuccessful, we chose the following two- step sequence. Thus, treatment of 8 with lithium hexamethyl- disilazide in the presence of HMPA followed by the addition of t All new compounds gave spectral data (IR, NMR, MS) in accord with their assigned structures, and atisfactory combustion analyses or an accurate mass measurement. 1Selected spectral data. For 7: [.ID +31.1 (c 0.39, CHCl,); v,(CHC13)/cm-' 1719; S,(270 MHz, CDCl,) 1.41 (3 H, s), 1.89 (3 H, br s), 2.60-2.73 (4 H, m), 2.97 (1 H, d, J4.9), 3.97 (3 H, s), 5.10 (1 H, br s), 5.20 (1 H, br s), 5.42 (1 H, s), 7.35 (2 H, m), 7.45 (1 H, d, J2.6), 7.81 (1 H, d, J 2.6) and 8.61 (1 H, m); m/z 326 (M') (Found M+,326.1506.C2oH22O4 requires M,326.1517). methyl chloroformate afforded quantitatively the enol carbo- nate 9, which was then exposed to the conditions of Lemieux-Johnson oxidation to provide the required carboxylic acid 4,s identical with the sample jeprepared previously, in 62% yield. It should be noted that the conversion of 9 into 4 took a prolonged reaction time (255 h) because of steric hindrance. With a key compound in hand, we next explored both the conditions for coupling of 4 with an appropriate amine and the conversion of the amide thus prepared into 3, since mild and practical methods for these transformations have not been established so far.For these objectives, we chose p-methoxybenzylamine as an amine component. The amide formation was best carried out using benzotriazolyloxytri(pyrrolidiny1)phosphonium hexa-fluorophosphate (PYBOP")~ and 1-hydroxybenzotriazole (HOBT) in the presence of triethylamine to give the p-methoxybenzylamide 10 in 69% yield. Finally, treatment of 10 with DDQ' afforded the amide 3(81% yield) {m.p. 153-154 "C, lit2 m.p. 153-154 "C; [.ID +45.27 (c 0.31, MeOH), lit.Ib; [a]D +48.0 (c 0.33, MeOH), lit.2; [.ID +47.5" (c 0.32, MeOH)}, the characteristics of which were identical with those of authentic material I5 6 OMe I OM9 10 Scbeme 1 Reagents and Conditions: i, D-( -)-diisopropyl tartrate, Bu'OOH, Ti(OPr'),, CH,Cl,, -2O"C, 16 h, 69%; ii, 3-methoxy-5- methylnaphthalene-1-carboxylicacid, DCC, CDMAP, CH,Cl,, room temp., 5 h, 94%; iii, NalO,, OsO,, Et,O-H,O (1 :l), for 7, room temp., 42 h, 92%, for 9, room temp., 255 h, 62y; iv, LiHMDS, HMPA, ClCO,Me, THF, -78 "C-room temp., 1 h, lWA; v, pmethoxybenzylamine, PyBOP, HOBT, Et3N, DMF, room temp., 0.5 h, 69%; vi, DDQ, CH2Clz-HzO (18: l), 0 "C,4 h, 81%.In summary, we have described a simple and efficient synthesis of the epoxy carboxylic acid 4 and its conversion into the naturally occurring amide 3 in an enantiomerically pure form. 0 [.ID+2.76 (c 1.08, EtOH). We correct the value of the optical rotation reported in ref.3a. fT [uJD Values in units of 10-' deg cm2 g-'. The synthetic route developed here will be of significant value for the convergent total synthesis of azinomycins. Experimental Preparation of the Arnide 10.-To a stirred solution of a mixture of the carboxylic acid 4 (80 mg, 0.24 mmol) and p-methoxybenzylamine (37 mg, 0.27 mmol) in dimethyl-formamide (2.0 ml) was successively added PyBOP* (141 mg, 0.27 mmol), HOBT (41 mg, 0.27 mmol) and triethylamine (54 mg, 0.53 mmol) at 0 "C. After the mixture had been stirred at room temperature for 0.5 h, benzene (10 cm3) and ethyl acetate (20 cm3) were added and the resulting diluted solution was successively washed with 5% aqueous (aq.) hydrochloric acid, water, saturated aq. sodium hydrogen carbonate and saturated brine.The organic phase was dried (MgS04) and concentrated to give a residue which was chromatographed on silica gel with hexane-ethyl acetate (7: 3, v/v) as eluent to afford the amide 10 (75 mg, 69%)as colourless prisms, m.p. 1 15-1 17 "C; [a]D +30.6 (c 0.56, CHCl,); v,,,(CHCl,)/cm-' 3434, 1729 and 1692; 6,(270 MHz, CDCl,) 1.53 (3 H, s), 2.67 (3 H, s), 2.76 (1 H, d, J4.5*), * J Values in Hz. J. CHEM. SOC. PERKIN TRANS. 1 1992 2.99 (1 H, d, J4.5), 3.77 (3 H, s), 3.96 (3 H, s), 4.45 (2 H, t, J5.1), 5.26 (1 H, s), 6.43 (1 H,'br t, J4.3), 6.83 (2 H, d, J 8.7) and 7.21 (2 H, d, J 8.7); m/z 449 (M') (Found: M', 449.1810. C2,H2,N0, requires M, 449.1838). References 1 K. Nagaoka, M. Matsumoto, J. Oono. K. Yokoi, S. Ishizaki and T. Nakashima, J. Antibiot., 1986,39,1527; K. Yokoi, K. Nagaoka and T. Nakashima, Chem. Pharm. Bull., 1986,34,4554. 2 M. Shibuya and H. Terauchi, Tetrahedron Lett., 1987,28,2619. 3 (a)K. Ando, T. Yamada and M. Shibuya, Heterocycles, 1989,29,2209; (b) P. England, K-H. Chun, E. J. Moran and R. W. Armstrong, Tetrahedron Lett., 1990,31,2669. 4 S. L. Schreiber, T. S. Schreiber and D. B. Smith, J. Am. Chem. SOC., 1987,109,1525. 5 M. Shibuya, Tetrahedron Lett., 1983,24, 1175. 6 J. Coste, D. Le-Nguyen and B. Castro, Tetrahedron Lett., 1990, 31, 205. 7 Y. Oikawa, T. Yoshioka and 0.Yonemitsu, Tetrahedron Lett., 1982, 23. 885. Paper 2/03076D Received 10th June 1992 Accepted 23rd June 1992