J. CHEM. SOC. PERKIN TRANS. I 1989 841 Approaches to the '1,6,8-Trioxadispiro4.1.5.3pentadec-l3-en-I5-01 Ring System of Salinomycin and Related Polyether Antibiotics Philip Kocienski", Yagamare Fall, and Richard WhitbyDepartment of Chemistry, The University, Southampton, SO9 5NH The acid-catalysed rearrangement of 2,5-dialkyl-2,5-dioxy-2,5-dihydrofurans (9) and (15) are key steps common to two alternative approaches to the dispiroacetal ring system of salinomycin and related polyether antibiotics. ~~~~~~~ ~~ The 1,6,8-trioxadispiro4.1.5.3pentadec-l3-enering system is a structural feature common to the polyether antibiotics salino-mycin, narasin, noboritomycin, and CP 44,661.' Recent synthetic approaches to salinomycin (1) have exploited the addition of carbanions to 6-valerolactones followed by cyclis-ation to generate the unsaturated central ring., We now report two alternative approaches to the 1,6,8-trioxadispiro4.1.5.3-pentadec-13-en-15-01ring system (2) in which a key step is the acid-catalysed rearrangement of a 2,5-dialkyl-2,5-dioxy-2,5-dihydrofuran intermediate.The first approach required the spirocyclic butenolide (6) which was prepared as shown in Scheme 1. Metallation of the HO The structures and conformations of the spiroacetals (10) and (11) were established by n.m.r. studies? (Tables 1-3). 2D COSY and C-H correlation experiments in both C6D6 and CDCl,, together with coupling constants, allowed the assign-ment of most of the I3C and 'H resonances. The stereo-chemistry of the protons around the tetrahydrofuran ring and the relative stereochemistry of the anomeric centres at C-5 and C-7 were assigned with the aid of n.0.e.difference experiments. Thus for spiroacetal (10) in C6D6, irradiation of the methyl resonance at 6 1.48 caused enhancement of 12e-H and 1la-H on the tetrahydropyran ring establishing it as Me' with the stereochemistry shown. Enhancement of the protons at 6 1.998 OH-. . Iiii 02 "1. TBDMSO -0 Me0 Go-(6) Scheme 1. Reagents: i, Bu'Li/THF, -70 OC, 1 h; ii, CO,; iii, 10 H,S0,-Et20, 0 "C, 1 h; iv, HF/MeCN, 20 "C, 2 h methoxyallene (3)3 followed by carboxylation gave the inter-mediate (4) which underwent stereoselective protonation4 and cyclisation to give the butenolide (5).Subsequent hydrolysis and cyclisation to the spirocyclic butenolide (6) was best achieved using 40aqueous HF in acetonitrile.' Addition (Scheme 2) of the butenolide (6) to 2 equiv. of the lithiated dihydrofuran (8)6 at -60 "C followed by aqueous work-up and treatment of the crude reaction mixture with acid gave a complex mixture from which the dispiroacetals (10) and (11) (1: 1) were isolated in 15 combined yield after column chromatography on silica gel eluting with Et,O-hexanes (1 :4). and 2.286 was also observed establishing these as 3-H' and 4-H'. By comparison irradiation of the 6 1.370 methyl resonance gave n.0.e. enhancements only of the signals at 6 1.878 (3-H) and 6 3.002 (4-H). The structure was further supported by a small n.0.e.enhancement of 4-H' on irradiation of 9a-H, t 'H, COSY, and n.0.e. difference experiments were recorded at 360 MHz on a Bruker AM-360 spectrometer. 13C and C-H correlation experiments were carried out on a JEOL GX-270 machine at 270 MHz (proton) and 65 MHz (carbon). 842 J. CHEM. SOC. PERKIN TRANS. I 1989 Table 1. I3C N.m.r. data for dispiroacetal products' GCb/p.p.m. Ar -l Carbon (10) (11) (16y (17)' (19)' (20)' (22)' (21)' (23)' 2 85.14 85.24 84.39 83.77 84.53 83.74 83.53 84.34 84.13 3 37.77 37.90 37.14 36.87 36.93 37.29 37.22 37.36 37.30 4 35.25 34.89 36.41 36.16 36.44 36.19 36.11 35.39 35.85 5 106.12 104.95 105.69 104.04 104.99 109.52 107.19 108.37 106.46 7 95.22 93.51 93.48 93.94 93.48 96.49 96.58 95.37 96.06 9 61.64 61.66 62.18 61.84 61.49 62.31 62.28 61.88 61.76 10 25.04 25.20 25.18 25.05 25.19 25.22 25.15 25.11 25.15 11 18.89 18.50 18.47 18.28 18.88 18.48 18.32 18.96 18.76 12 34.79 36.07 35.62 35.43 35.76 30.36 31.23 35.31 35.70 13 149.78 148.84 131.06 132.10 135.90 131.35 132.36 131.17 134.02 14 125.87 125.57 129.62 122.45 122.60 129.35 126.37 129.83 124.83 15 190.44 190.94 66.07 68.47 68.33 67.67 69.28 65.87 67.52 Me 27.95 27.98 28.95 28.72 28.95 30.00 29.68 29.27 29.27 Me' 29.04 28.95 28.09 27.76 28.09 28.58 28.19 28.35 28.16 CH,CO 21.19 21.29 21.19 21.32 CH,CO 170.83 170.73 170.16 170.88 a Recorded on a JEOL GX-270 spectrometer.Relative to CDCI,. The relative assignment of C-3, C-4, C-12, Me and Me' may be interchanged. r 1 +14 (10) (11) Scheme 2.Reagents: i, Bu'Li/THF, -20 "C, 30 min; ii, add (6)at -60 "C; iii, camphorsulphonic acid-CH,Cl,, 20 "C, 2 h 60 '1. * ButMe2Si0 But MezSiOF(12) "" OH (14) Scheme 3. Reagents: i, Bu'LiITHF, -70 "C to 0 "C; ii, add lactone (13), -70 "C; iii, Br,-MeOH-Et,O, -35 "C, 1 h followed by addition of NH, (g); iv, HF-MeCN J. CHEM. SOC. PERKTNTRANS. I 1989 ~ ~~ Table 2. Selected 'H n.m.r. data for dispiroacetal products' GHb/p.p.m. AI-bsol; (10)' (lo* (11)" (Wd (17)' (19)' (22)' (23)' 3-H 1.878 1.902 1.941 1.95 3-H' 1.998 2.036 2.009 2.05 4-H 3.002 '2.610 3.122 2.775 4-H' 2.286 2.193 2.196 2.02 9e-H 3.802 3.745 3.849 3.750 3.59 3.658 3.71 3.68 9a-H 4.228 4.037 4.297 4.102 3.94 4.046 4.003 4.02 1 Oe-H 1.42 1.6 1.48 1.68 1Oa-H 1.63 1.6 1.62 1.68 1 le-H 1.65 1.6 1.58 1.68 1la-H 2.09 1.94 2.085 1.92 12e-H 2.44 2.18 1.67 1.68 12a-H 1.58 1.62 1.54 1.68 13-H 6.54 6.68 6.47 6.75 5.584 5.983 5.663 5.809 14-H 6.14 6.10 6.15 6.14 5.700 6.057 5.7 15 5.870 15-H 5.245 4.869 5.332 5.2 18 Me 1.370 1.232 1.396 1.232 1.146 1.188 1.198 1.229 Me' 1.482 1.419 1.232 1.460 1.342 1.408 1.454 1.439 Ac 2.053 2.074 2.102 2.118 a Recorded on a Bruker AM 360 spectrometer.Relative to Me,Si. 'CDCI,. C,D,. Table 3. J(HH) for the dispiroacetals (lo),(ll),and (19). H on the tetrahydropyran ring. Irradiation of this methyl group also gave weak enhancements of the protons at 6 2.02 and 2.05 J/Hz allowing their assignment as 3-H' and 4-H'. Small n.0.e. amp; enhancements of the same protons were also observed on Coupling (10) (11) (19) irradiation of 9a-H.By comparison, irradiation of the methyl resoLTance at 6 1.232 gave n.0.e. enhancements of the signals at 3-3' 12.0 11.8 6 1.95 (3-H) and 6 2.775 (4-H) only. Thus (10)has the same 3-4 8.2 8.1 relative stereochemistry at the spiroacetal centres as (8-0)-3 -4' 4.5 5.6 deoxy- 17-epi-saIinomy~in,~ whereas (1 1) has the same relative 3 '-4 9.5 8.6 stereochemistry as salinomycin.' 3'-4' 7.5 7.6 A second approach to the spiroacetals (10)and (11) based on 4'-4' 13.2 13.0 the Achmatowicz pyranone synthesisg,'* (Scheme 3) was much 9a-9e 11.1 11.1 more efficient. Lithiation of the furan (12)followed by reaction 9a- 10a 11.8 12.6 with the lactone (13)gave the 2-acylfuran (14)in 60 yield.The 9e-10a 4.9 4.8 key step in the sequence was the oxidation of the furan (14)with9a-1Oe 3.4 2.6 bromine in methanol to give the 2,5-dialkyl-2,5-dioxy-2,5-9e- 1 Oe 1.9 1.8 dihydrofuran intermediate (15) which rearranged to a 1:19e-1 le 1.9 0.5 mixture of the dispiroacetals (10) and (11) in 88 yield on1 Oa- 10e treatment with 40 aqueous HF in MeCN." 10a-lla 12.9 13.0 Reduction of the enone (11) (Scheme 4) with a variety of 10a-lle reducing agents gave exclusively the allylic alcohol (16)with the 1Oe-lla 3.9 3.9 wrong stereochemistry at C-15. Unfortunately, the inversion of 10e-lle this centre via the Mitsunobu procedure gave poor yields (ca.10e-12e 1.6 8) of the p-nitrobenzoate ester (18) with recovered starting I la-1 le 12.9 13.0 material accounting for the bulk of the reaction products.1la-12a 12.9 13.0 Hydrolysis of (18) gave the desired allylic alcohol (2)as an acid- lla-12e 3.9 3.9 sensitive oil which was characterised as its acetate ester (19).1 le-12a 3.6 The reduction product (20)of the enone (10) provided a1 le-12e 1.6 more efficient albeit roundabout route to (2).Reduction of the I2a- 12e 12.5 enone (10)was stereoselective giving an inseparable mixture of 13-14 10.2 10.4 10.1 the allylic alcohols (20) and (21) (9:1 respectively) in 8513-15 0.0 yield. These were converted into the corresponding acetates 14-15 5.4 (22)and (23)in the usual way and then easily separated by column chromatography on silica gel eluting with hexane-ether (3 :1).The crystalline acetate (22)isomerised on treatment with enhancements of 9e-H and lla-H also being observed. The a catalytic amount of camphorsulphonic acid in CH,Cl, at abnormally lowfield position of 12e-H S 2.18 in CDCI, room temperature for 2 h to give a separable mixture of the compared with 6 1.68 for isomer (ll) is due to its close acetate (19) and recovered (22) (2:3 respectively) in 97 proximity to the tetrahydrofuran ring oxygen. yield. The composition of the reaction mixture at equilibrium In isomer (11)the most dramatic n.0.e. enhancement was was (17):(19):(22):(23) = 12:30:38:20. Similar isomerisation observed between the methyl group (6 1.460 in CDCl,) and 9a- studies on the alcohol (16)resulted in initial partial conversion 844 J.CHEM. SOC. PERKIN TRANS. I 1989 II (11) (16) R = Hlsquo;71 * (18) = pNBrdquo;_iv Ill (17) R = Ac (2) R =H m.p. 83 -85OC ( EtZO -hexane) (19) R = AC m.p. 64-65OC (Et,O -hexane) + 9: 1 qj5lsquo;ldquo;OR (10) 71iii (20) R = H (21) R=H lsquo;71iii (22) R = AC (23)R = Ac m.p. 65-66OC( Et,O -hexane) Scheme 4. Reagents: i, NaBH,, CeC1,- MeOH, -70 ldquo;C; ii, diethyl azodicarboxylate, p-nitrobenzoic acid-benzene; iii, Ac20-pyridine; iv, KOH MeOH into (21) before decomposition set in. These results show that epimerisation of the allylic anomeric centre at C-7 is faster than isomerisation of the C-5 centre. In conclusion we have developed an efficient synthesis of the 1,6,8-trioxadispiro4. 1.5.31pentadec- 1 3-en-1 5-01 ring system which should be readily applicable to the synthesis of salinomycin and related polyether antibiotics.Acknowledgements we thank the S.E.R.C. for financial support, This is a contribution from the Southampton University Institute of Biomolecular Science. References 1 D. E. Cane, W. D. Celmer, and J. W. Westley, J. Am. Chem SOC.,1983, 105. 3594 and references therein. 2 Y. Kishi, S. Hatakeyama, and M. D. Lewis, lsquo;Frontiers of Chemistry,rsquo; ed. K. J. Laidler, Pergamon, Oxford, 1982, p. 287; K. Horita, S. Nagato, Y. Oikawa, and 0.Yonemitsu, Tetrahedron Lett., 1987,28, 3253; R. Baker and M. A. Brimble, J. Chem. Soc., Perkin Trans. 1, 1988, 125 and references therein. 3 R. Whitby and P. Kocienski, J. Chem. SOC.,Chem. Commun., 1987, 906. 4 F.Derguini and G. Linstrumelle, Tetrahedron Lett., 1984,255763. 5 E. W. Collington, H. Finch, and I. J. Smith, Tetrahedron Loit., 1985, 26,68 1. 6 J. Huet, Bull. Soc. Chirn. Fr., 1964, 2677. 7 J. W. Westley, J. F. Blount, R. H. Evans, and C. Liu, J. Antibiotics, 1977, 30, 610; R. Baker, M. A. Brimble, and J. A. Robinson, Tetrahedron Lett., 1985,26,2115. 8 H. Kinashi, N. Otake, H. Yonehara, s. Sato, and y. Saito, Tetrahedron Lett., 1973, 4955. 9 0.Achmatowicz, P. Bukowski, B. Szechner, Z. Zwierzchowska, and A. Zamojski, Tetralzedron, 1971,27, 1973. 10 0.Achmatowicz, in lsquo;Organic Synthesis Today and Tomorrow,rsquo; ed. B. M. Trost, Pergamon, Oxford, 1981, p. 307. 11 For a relatedIapplication of the Achmatowicz pyranone rearrangement to the synthesis of a spiroacetal ring system see P. DeShong, R. E. Waltermire, and H. L. Ammon, J. Am. Chem. Soc., 1988,110,1901. Received 26th September 1988; Paper 8/03746I (cCopyright 1989 by The Royal Society of Chemistry
展开▼
