Unsaturated macrocyclic lactone synthesisviacatalytic ring-closing metathesis 1

摘要

J. Chem. Soc. Perkin Trans. 1 1997 2869 Unsaturated macrocyclic lactone synthesis via catalytic ring-closing metathesis 1 Konstantinos E. Litinas * and Basil E. Salteris Laboratory of Organic Chemistry Aristotle University of Thessaloniki 54006 Thessaloniki Greece Ring-closing metathesis (RCM) of the terminal diene esters 2a,b with the Ru catalyst 1 results in the formation of the 20- 21-membered macrolactones 3a,b in high yields. RCM of the diene oleate esters 4a,b with 1 gives the 19- 20-membered macrolactones 5a,b in good yields while an analogous reaction of the diene ‚,„-unsaturated ester 6a gives the 13-membered lactone 7a in low yield. Macrocyclic lactones are important components of naturally occurring compounds,2,3 many of them insects pheromones.4 They possess a range of significant biological activity,5 (e.g.antibiotic,3e,6 antifungal,5c antitumour cytostatic,7 oestrogenic and anabolic 2a,5c) as well as being used as fragrances.8 There are several multi-step syntheses of these compounds in moderate to high yields,5 which include the following ring enlargement of smaller rings,9 lactonization of w-hydroxycarboxylic acids 10 with different reagents CC bond formation by intramolecular addition of enolate ion with Pd0 catalyst,11a intramolecular diacetylene ester coupling,11b by intramolecular Wittig 11c or Horner–Emmons11d reactions and by olefin metathesis using WCl6–Me4Sn12a or WCl6–Cp2TiMe2 12b,c or WOCl4–Cp2- TiMe2 12c as catalysts. Recent progress in the development of well-defined metathesis catalysts with a single component has extended the use of olefin metathesis 13 in polymer chemistry through ring-opening metathesis polymerization (ROMP),14 in organic synthesis 15,16 and in natural products synthesis.17 Ring-closing metathesis (RCM) of dienes,15 especially with the very efficient Ru catalyst 1,13b,18 is a general method for the construction of unsaturated carbocycles and heterocycles (Scheme 1).In continuation of our efforts 19 to synthesize 6- and 7- membered unsaturated lactones we report here our results for the preparation of 19- 20- 21- 13- and 14-membered macrolactones from RCM of acyclic diene esters with the Ru catalyst 1 (Schemes 2–4). All diene esters were prepared from commercially available materials (Scheme 5) by simple esterifi- cation. Dec-9-enyl undec-10-enoate 2a prepared in 78 yield by esterification of dec-9-enol with undec-10-enoic acid in the presence of conc.H2SO4 as catalyst in refluxing benzene for 5 h in a Dean–Stark trap was heated with a benzene solution of the catalyst 1 (1.7 mol) at 60 8C for 24 h under an argon atmosphere. Purification of the crude product by column chromatography gave the 20-membered macrolactone 3a (83) together with the first-eluted unchanged ester 2a (13). Compound 3a extracted in two fractions was a mixture of Z- and E-isomers (ratio 57 43 as indicated by GC analysis). The first fraction Z/E (80 20) by GC showed in the IR spectrum more intense absorption for cis- (720 cm21) than for trans- (965 cm21) Scheme 1 (X) (CH2)n R1 R2 (CH2)n (X) R1 P(Cy)3 Ru P(Cy)3 Ph Ph Cl Cl 1–5 mol X = O NR CH2; n = 1,2,3,4 1 isomer in comparison to the IR spectrum of the second fraction Z/E (40 60) by GC.An analogous reaction (Scheme 2) of the diene ester 2b (prepared in 94 yield by esterification for 5 h of the corresponding alcohol and acid) with a benzene solution of 1 (4 mol) gave after purification by PTLC unchanged ester 2b (8) and the 21-membered unsaturated lactone 3b (82). This lactone (eluted as two fractions) was also a mixture of Z- and E-isomers (IR absorptions 720 and 965 cm21 respectively) in a total ratio of 60 40 (by GC). In the first fraction the ratio was 73 27 (GC) and in the second 43 57. The 1H NMR spectrum of the first fraction showed signals at d 4.10 (t 2 H J 5.9 CO2CH2) and 5.31–5.36 (m 2 H CH CH) for the Z-isomer whilst the second fraction showed two triplets at 4.10 (J 5.9 CO2CH2) and 4.11 (J 5.5 CO2CH2) for the Z- and E-isomers respectively and a multiplet at 5.30–5.38 (CH CH) for both isomers.The 13C NMR spectrum of the first fraction showed signals at 173.9 ppm (COO) 130.9 and 130.6 (CH CH-) 64.0 (COOCH2-) and 34.5 ppm (CH2COO) for the Z- isomer as indicated from the more intense signals of the spectrum and that of the second spectrum showed similar signals together with others at 174.0 130.1 130.0 64.2 and 34.8 ppm for the E-isomer. The lactone 3b has previously been prepared 12c by Tsuji and Hashigushi (12 yield) by olefin metathesis of the same ester 2b with WOCl4 (20 mol)–Cp2TiMe2 (24 mol). Such macrolactonization gives from commercially available materials large-ring compounds in high yields by a simple twostep procedure. RCM of dec-9-enyl oleate 4a (prepared in 79 yield from esterification of dec-9-enol and oleic acid) with the catalyst 1 (0.8 mol) (Scheme 3) gave after column chromatography the 19-membered unsaturated lactone 5a (65).The lactone 5a was obtained as an inseparable (by GC) mixture of Z- and E-isomers (IR absorption at 720 and 965 cm21). This lactone was prepared 12c earlier (18 yield) from RCM of dec-9-enyl oleate with WCl6 (20 mol)–Cp2TiMe2 (24 mol). The ester 4b (prepared in 96 yield from undec-10-enol and oleic acid) with 1 (2 mol; Scheme 3) gave the 20-membered ring lactone 5b (63) together with unchanged starting ester Scheme 2 Reagents and conditions 1 (1.7 4 mol) C6H6 60 8C 24 h C (CH2)8 O (CH2)n O 2a,b 2,3a n = 8 (83) b n = 9 (82) O C O (CH2)8 (CH2)n 3a,b 2870 J. Chem. Soc. Perkin Trans. 1 1997 (14).This lactone eluted in two fractions as a mixture of Z- and E-isomers in a total ratio of 61 39 (by GC). In the first fraction the ratio was 71 29 (GC) while in the second it was 42 58 (GC). Thus in RCM the oleate esters give lower yields than the undec-10-enoate esters probably because of steric hindrance by the non-9-enyl moiety in the former. This behaviour is in accord with previous observations that 1 is more effective with terminal dienes.15b RCM of dec-9-enyl (E)-hex-3-enoate 6a prepared in 84 yield from esterification of dec-9-enol and (E)-hex-3-enoic acid with a benzene solution of 1 (1.5 mol) gave after column chromatography first unchanged 6a (66) followed by the known4c,f 13-membered lactone 7a (6) and then a complex mixture. The lactone 7a is an aggregation pheromone of the flat grain beetle Cryptolestes pusillus.4f Attempted preparation of the 14-membered lactone 7b from the diene ester 6b prepared in 95 yield from undec-10-enol and (E)-hex-3-enoic acid and 1 (1.5 mol) gave only a complex mixture eluted after unchanged 6b (68).The low yield in the preparation of the 13- membered lactone 7a could be attributed to the possible unproductive complexation of Ru with the b,g-double bond of the hex-3-enoate and the ester carbonyl and to steric hindrance of the propenyl ester moiety. In conclusion RCM of diene esters is an excellent method for macrolactone formation especially for terminal alkenes. The yield of this reaction is decreased with increasing steric hindrance and the possible complexation of the double bond the Ru atom and the ester carbonyl.Parallel work appeared very recently in the literature 20 in Scheme 3 Reagents and conditions 1 (0.8 2 mol) C6H6 60 8C 24 h C (CH2)7 O (CH2)n O O C O (CH2)7 (CH2)n (CH2)7CH3 4a,b 5a,b 4,5a n = 8 (65) b n = 9 (63) Scheme 4 Reagents and conditions 1 (1.5 mol) C6H6 60 8C 24 h O C O (CH2)n O (CH2)n C O 6a,b 7a,b 6,7a n = 8 (6) b n = 9 Scheme 5 Reagents and conditions i C6H6 reflux (Dean–Stark trap) Cat. conc. H2SO4 5 h Yields 78–96 (CH2)8 CO2H HO(CH2)n (CH2)8 CO2 (CH2)n + i n = 8,9 (CH2)7CO2H (CH2)7CH3 + HO(CH2)n i n = 8,9 (CH2)7CO2 (CH2)7CH3 (CH2)n 2a,b 4a,b COOH + HO(CH2)n i n = 8,9 COO (CH2)n 6a,b which the 21-membered lactone 3b was synthesized (71 yield; 82 in our preparation) by using the catalyst 1 (4 mol) and the ester 2b in dichloromethane solution.Experimental IR spectra were run as films on a Perkin–Elmer 1310 spectrophotometer. 1H NMR spectra were recorded on a Bruker 300 AM (300 MHz) spectrometer with CDCl3 as a solvent with SiMe4 as internal standard. J Values are given in Hz. 13C NMR spectra were obtained at 75.5 MHz in CDCl3 solutions with SiMe4 as internal reference. Mass spectra were determined on a VG-250 spectrometer (70 eV). GC analyses were performed with a SS column packed with 20 Carbowax 20 M (3.78 g) on Chromosorb W AW DMCS 60/80 mesh (10 ft × 1/8 in). The acids and alcohols used were commercial products of Aldrich Chem. Co. Inc. The Ru catalyst 1 was prepared according to a published procedure.18 Benzene was distilled under argon atmosphere with benzophenone ketyl and was degassed before use under anhydrous conditions.Catalyst and solvent transfers in the reaction flask were made under argon atmosphere by using a glove bag. All reactions were carried out under an argon atmosphere. General procedure for the synthesis of the diene esters 2a,b 4a,b and 6a,b The acid (0.02 mol) was added in a benzene (30 cm3) solution of the alcohol (0.03 mol) followed by 5 drops of conc. H2SO4. After the mixture had been heated under reflux in a Dean–Stark trap for 5 h most of the benzene was removed and the residue was poured onto Et2O (25 cm3) and washed with water (15 cm3). The aqueous layer was separated and extracted with Et2O (15 cm3) and the combined organic layer and extracts were washed with 5 aqueous NaHCO3 (20 cm3) and with water (cm3) dried (Na2SO4) and concentrated under reduced pressure.Column chromatography silica gel No 60 Merck hexane–dichloromethane (4 1) of the residue gave at first the corresponding diene ester followed by a small amount of unchanged alcohol. Dec-9-enyl undec-10-enoate 2a. This ester (78) was a colourless oil; nmax/cm21 3070 2920 2840 1730 1632 1460 1170 990 910 740 and 720; dH 1.21–1.43 (m 20H) 1.55–1.7 (m 4H) 1.98–2.1 (m 4H) 2.29 (t J 7.5 2H) 4.05 (t J 6.7 2H) 4.9–5.03 (m 4H) and 5.76–5.88 (m 2H); dC 25.0 25.9 28.6 28.8 28.9 29.0 29.05 29.1 29.15 29.2 29.25 29.3 29.4 33.75 34.4 64.3 114.1 139.1 and 173.9; m/z () 322 (57) 304 (9) 184 (54) 166 (62) 138 (77) 110 (74) 96 (88) 83 (94) and 55 (100) (Found C 78.4; H 11.8. C21H38O2 requires C 78.2; H 11.9). Undec-10-enyl undec-10-enoate 2b. The title ester (94) as a colourless oil;12c nmax/cm21 3060 2920 2840 1730 1630 1460 1170 990 900 and 725; dH 1.22–1.45 (m 22H) 1.56–1.69 (m 4H) 1.98–2.08 (m 4H) 2.29 (t J 7.5 2H) 4.05 (t J 6.7 2H) 4.88–5.05 (m 4H) and 5.72–5.88 (m 2H); dC 24.9 25.8 28.6 28.65 28.7 28.8 28.9 28.95 29.0 29.1 29.2 29.25 29.3 29.5 33.6 34.2 64.1 114.0 138.8 and 173.4; m/z () 336 (50) 318 (7) 184 (55) 166 (62) 152 (69) 124 (71) 110 (75) 96 (90) 82 (95) and 55 (100).Dec-9-enyl oleate 4a. This ester (79) was a colourless oil; nmax/cm21 3060 2980 2920 2840 1730 1635 1460 1170 990 910 and 725; dH 0.88 (t J 6.6 3H) 1.18–1.42 (m 30H) 1.54– 1.68 (m 4H) 1.94–2.01 (m 6H) 2.29 (t J 7.5 2H) 4.05 (t J 6.7 2H) 4.90–5.05 (m 2H) 5.27–5.43 (m 2H) and 5.73–5.87 (m 1H); dC 14.0 22.6 25.0 25.9 27.1 27.2 28.6 28.9 28.95 29.0 29.1 29.15 29.2 29.3 29.4 29.5 29.55 29.65 29.7 31.9 33.7 34.3 64.3 114.1 129.7 129.9 139.0 and 173.8; m/z () 420 (53) 392 (12) 283 (33) 264 (67) 222 (35) 138 (84) 97 (86) 83 (93) and 55 (100) (Found C 79.8; H 12.6.C28H52O2 requires C 79.9; H 12.45). Undec-10-enyl oleate 4b. The title ester (96) was a colourless oil; nmax/cm21 3060 2985 2910 2840 1730 1635 1460 1170 990 910 and 725; dH 0.88 (t J 6.6 3H) 1.20–1.40 (m, J. Chem. Soc. Perkin Trans. 1 1997 2871 32H) 1.55–1.68 (m 4H) 1.95–2.09 (m 6H) 2.29 (t J 7.5 2H) 4.05 (t J 6.7 2H) 4.90–5.05 (m 2H) 5.30–5.42 (m 2H) and 5.75–5.88 (m 1H); dC 14.0 22.6 25.0 25.9 27.1 27.2 28.6 28.9 28.95 29.0 29.1 29.2 29.25 29.3 29.35 29.4 29.5 29.6 29.65 29.7 31.9 33.75 34.3 64.3 114.1 129.7 129.9 139.05 and 173.8; m/z () 434 (46) 406 (10) 283 (28) 264 (66) 222 (37) 152 (77) 97 (88) 83 (91) and 55 (100) (Found C 79.9; H 12.2.C29H54O2 requires C 80.1; H 12.5). Dec-9-enyl (E)-hex-3-enoate 6a. This ester (84) was a colourless oil; nmax/cm21 3060 3020 2920 2840 1730 1630 1460 1160 990 965 and 910; dH 0.96 (t J 7.5 3H) 1.22–1.42 (m 10H) 1.55–1.67 (m 2H) 1.98–2.10 (m 4H) 2.99 (d J 6.2 2H) 4.04 (t J 6.7 2H) 4.87–5.03 (m 2H) 5.43–5.63 (m 2H) and 5.72–5.86 (m 1H); dC 13.5 25.5 26.0 28.7 29.0 29.1 29.3 29.4 33.9 38.2 64.7 114.2 120.9 136.2 139.1 and 172.5; m/z () 252 (46) 251 (32) 224 (6) 138 (70) 114 (79) 97 (83) 83 (85) and 55 (100) (Found C 76.4; H 11.0. C16H28O2 requires C 76.1; H 11.2). Undec-10-enyl (E)-hex-3-enoate 6b. The title ester (95) was a colourless oil; nmax/cm21 3060 3020 2915 2840 1730 1630 1460 1160 990 965 and 910; dH 0.98 (t J 7.5 3H) 1.20–1.44 (m 12H) 1.55–1.68 (m 2H) 1.98–2.11 (m 4H) 3.02 (d J 6.0 2H) 4.07 (t J 6.7 2H) 4.90–5.03 (m 2H) 5.45–5.66 (m 2H) and 5.74–5.88 (m 1H); dC 13.4 25.5 25.8 28.5 28.9 29.0 29.2 29.3 29.4 33.7 38.1 64.5 114.1 120.7 136.2 139.2 and 172.3; m/z () 266 (60) 265 (48) 238 (11) 152 (76) 124 (61) 114 (94) 97 (94) 83 (100) and 55 (96) (Found C 76.7; H 11.4.C17H30O2 requires C 76.6; H 11.35). Representative procedure for the synthesis of macrolactones Nonadec-10-en-19-olide 3a. Ruthenium catalyst 1 (9.3 mg 0.01 mmol) was dissolved in a three-necked flask in benzene (80 cm3) in a glove bag at room temperature. The diene ester 2a (191 mg 0.593 mmol) was added to the resulting light orange–brown solution via a syringe under argon atmosphere and the mixture was then heated at 60 8C for 24 h.After cooling the mixture was quenched by exposure to air and concentrated under reduced pressure. The residue was separated by column chromatography silica gel No 60 Merck hexane– dichloromethane (2 1 to 1 2) to give after elution of unchanged 2a (25 mg 13) the olide 3a as a colourless oil in two fractions first fraction 60 mg Z/E (80 20 by GC); second fraction 85 mg Z/E (40 60 by GC); total 145 mg 83 yield Z/E (57 43); nmax/cm21 3050 2920 2840 1730 1460 1165 965 w (weak) for first and m (medium) for second fraction 735 and 720 (m for both fractions); dH 1.20–1.42 (m 20H) 1.55– 1.70 (m 4H) 1.96–2.08 (m 4H) 2.315 (t J 6.9 CH2CO2) and 2.33 (t J 6.6 CH2CO2) 4.10 (t J 6.2 CO2CH2) and 4.12 (t J 5.9 CO2CH2) and 5.26–5.41 (m 2H); dC 24.9 25.1 26.0 26.2 26.4 26.5 27.3 27.35 27.5 27.55 28.1 28.15 28.4 28.45 28.5 28.6 28.65 28.75 28.8 28.9 29.0 29.1 29.2 29.3 29.4 29.45 31.7 31.8 34.1 34.75 64.2 64.25 130.0 130.05 130.6 130.7 174.0 and 174.05; m/z () 294 (20) 276 (10) 149 (46) 137 (47) 123 (84) 109 (95) 95 (99) 81 (99) and 55 (100) (Found C 77.4; H 11.5.C19H34O2 requires C 77.5; H 11.65). Eicos-10-en-20-olide 3b. Addition of the diene 2b (130 mg 0.387 mmol) to a benzene solution of the Ru catalyst 1 (15 mg 0.016 mmol) according to the above described procedure gave after separation of the resulting mixture by PTLC silica gel hexane–CH2Cl2 (1:2) unchanged 2b (10 mg 8) and the olide 3b as a colourless oil 12c in two fractions first fraction 55 mg Z/E (73 27 by GC); second fraction 42 mg Z/E (43 57 by GC); total 97 mg 82 yield Z/E (60 40); nmax/cm21 3070 2920 2840 1730 1460 1170 965 (m for both fractions) 735sh and 720 (m for first and w for second fraction); dH(first fraction) 1.22–1.41 (m 22H) 1.55–1.70 (m 4H) 1.93–2.06 (m 4H) 2.31 (t J 6.7 2H) 4.10 (t J 5.9 2H) and 5.31–5.36 (m 2H); dH- (second fraction) 1.22–1.41 (m 22H) 1.55–1.70 (m 4H) 1.93– 2.06 (m 4H) 2.31 (t J 6.7 2H) 4.10 (t J 5.9 CO2CH2) and 4.12 (t J 5.5 CO2CH2) and 5.30–5.38 (m 2H); dC 25.2 25.75 25.8 26.0 26.15 26.5 26.6 27.7 27.9 27.95 28.3 28.4 28.45 28.5 28.55 28.65 28.7 28.8 28.9 29.0 29.1 29.15 29.2 29.35 29.4 29.45 29.5 29.55 31.7 31.95 34.5 34.8 64.0 64.2 130.0 130.1 130.6 130.9 173.9 and 174.0; m/z () 308 (22) 290 (8) 110 (86) 96 (84) 82 (100) 55 (79) and 54 (85).Octadec-9-en-18-olide 5a. Reaction of the diene 4a (244 mg 0.581 mmol) with the catalyst 1 (4.25 mg 0.0046 mmol) gave after purification by column chromatography and after the elution of the unchanged ester 4a (64 mg 26) the olide 5a as a colourless oil 12c (106 mg 65) not separated by GC; nmax/cm21 3060 2920 2850 1730 1460 1170 965 730sh and 720; dH 1.18–1.45 (m 18H) 1.56–1.70 (m 4H) 1.96–2.09 (m 4H) 2.31 (t J 6.8 2H) 4.11 (t J 5.4 2H) and 5.25–5.40 (m 2H); dC 25.3 25.9 26.1 26.3 26.35 27.1 27.2 27.8 27.9 28.1 28.6 28.8 28.85 28.9 28.95 29.05 29.1 29.15 29.2 29.3 29.4 29.5 29.6 29.65 32.0 32.1 34.9 35.0 64.2 64.6 130.1 130.3 130.6 130.8 174.0 and 174.1; m/z () 280 (62) 262 (28) 252 (12) 149 (30) 137 (48) 123 (6) 109 (68) 95 (78) 82 (88) and 55 (100).Nonadec-9-en-19-olide 5b. Reaction of the diene 4b (174 mg 0.4 mmol) with the catalyst 1 (7.3 mg 0.079 mmol) gave after elution of the unchanged 4b (25 mg 14) the olide 5b as a colourless oil in two fractions first fraction 48 mg Z/E (71:29 by GC); second fraction 26 mg Z/E (42 58 by GC); total 74 mg 63 yield Z/E (61 39); nmax/cm21 3060 2910 2840 1730 1460 1170 965 735sh and 720; dH 1.55–1.45 (m 20H) 1.55– 1.70 (m 4H) 1.92–2.10 (m 4H) 2.32 (t J 6.7 2H) 4.12 (t J 6.1 2H) and 5.25–5.40 (m 2H); dC 24.9 25.3 25.4 25.5 25.9 26.5 27.0 27.4 27.9 28.0 28.05 28.1 28.2 28.4 28.5 28.6 28.7 28.8 28.9 29.05 29.1 29.3 29.4 29.5 29.55 29.7 31.6 32.3 34.6 34.8 63.8 64.1 129.9 130.0 130.6 130.9 173.85 and 173.9; m/z () 294 (13) 276 (6) 149 (62) 123 (60) 109 (91) 95 (98) 81 (100) 55 (99) (Found C 77.3; H 11.6.C19H34O2 requires C 77.5; H 11.65). Dodec-3-en-12-olide 7a. Reaction of the diene 6a (167 mg 0.663 mmol) with 1 (9 mg 0.0097 mmol) gave after separation by column chromatography the unchanged ester 6a (110 mg 66) followed by the olide 7a as colourless oil 4c,f (8 mg 6) dH 1.22–1.46 (m 10H) 1.55–1.66 (m 2H) 1.98–2.11 (m 2H) 3.01 (d J 6.1) 4.08 (t J 5.0) and 5.52–5.95 (m 2H); m/z () 196 (8) 149 (34) 137 (52) 123 (67) 110 (79) 96 (94) 82 (96) and 55 (100).Finally a complex mixture (27 mg) was eluted. Attempted preparation of tridec-3-en-13-olide 7b. Reaction of the diene 6b (151 mg 0.568 mmol) with 1 (8 mg 0.0086 mmol) gave after separation by column chromatography unchanged 6b (103 mg 68) followed by a complex mixture (25 mg). Acknowledgements We gratefully acknowledge the generous gift of the Ru catalyst 1 by Prof. R. H. Grubbs (California Institute of Technology). References 1 Preliminary communication K.E. Litinas and B. E. Salteris presented at the 17th Hellenic Chemical Congress Patra 1996 Abstrs. p. 144. 2 (a) R. H. 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Perkin Trans. 1 1997 2869 Unsaturated macrocyclic lactone synthesis via catalytic ring-closing metathesis 1 Konstantinos E.Litinas * and Basil E. Salteris Laboratory of Organic Chemistry Aristotle University of Thessaloniki 54006 Thessaloniki Greece Ring-closing metathesis (RCM) of the terminal diene esters 2a,b with the Ru catalyst 1 results in the formation of the 20- 21-membered macrolactones 3a,b in high yields. RCM of the diene oleate esters 4a,b with 1 gives the 19- 20-membered macrolactones 5a,b in good yields while an analogous reaction of the diene ‚,„-unsaturated ester 6a gives the 13-membered lactone 7a in low yield. Macrocyclic lactones are important components of naturally occurring compounds,2,3 many of them insects pheromones.4 They possess a range of significant biological activity,5 (e.g.antibiotic,3e,6 antifungal,5c antitumour cytostatic,7 oestrogenic and anabolic 2a,5c) as well as being used as fragrances.8 There are several multi-step syntheses of these compounds in moderate to high yields,5 which include the following ring enlargement of smaller rings,9 lactonization of w-hydroxycarboxylic acids 10 with different reagents CC bond formation by intramolecular addition of enolate ion with Pd0 catalyst,11a intramolecular diacetylene ester coupling,11b by intramolecular Wittig 11c or Horner–Emmons11d reactions and by olefin metathesis using WCl6–Me4Sn12a or WCl6–Cp2TiMe2 12b,c or WOCl4–Cp2- TiMe2 12c as catalysts. Recent progress in the development of well-defined metathesis catalysts with a single component has extended the use of olefin metathesis 13 in polymer chemistry through ring-opening metathesis polymerization (ROMP),14 in organic synthesis 15,16 and in natural products synthesis.17 Ring-closing metathesis (RCM) of dienes,15 especially with the very efficient Ru catalyst 1,13b,18 is a general method for the construction of unsaturated carbocycles and heterocycles (Scheme 1).In continuation of our efforts 19 to synthesize 6- and 7- membered unsaturated lactones we report here our results for the preparation of 19- 20- 21- 13- and 14-membered macrolactones from RCM of acyclic diene esters with the Ru catalyst 1 (Schemes 2–4). All diene esters were prepared from commercially available materials (Scheme 5) by simple esterifi- cation. Dec-9-enyl undec-10-enoate 2a prepared in 78 yield by esterification of dec-9-enol with undec-10-enoic acid in the presence of conc.H2SO4 as catalyst in refluxing benzene for 5 h in a Dean–Stark trap was heated with a benzene solution of the catalyst 1 (1.7 mol) at 60 8C for 24 h under an argon atmosphere. Purification of the crude product by column chromatography gave the 20-membered macrolactone 3a (83) together with the first-eluted unchanged ester 2a (13). Compound 3a extracted in two fractions was a mixture of Z- and E-isomers (ratio 57 43 as indicated by GC analysis). The first fraction Z/E (80 20) by GC showed in the IR spectrum more intense absorption for cis- (720 cm21) than for trans- (965 cm21) Scheme 1 (X) (CH2)n R1 R2 (CH2)n (X) R1 P(Cy)3 Ru P(Cy)3 Ph Ph Cl Cl 1–5 mol X = O NR CH2; n = 1,2,3,4 1 isomer in comparison to the IR spectrum of the second fraction Z/E (40 60) by GC.An analogous reaction (Scheme 2) of the diene ester 2b (prepared in 94 yield by esterification for 5 h of the corresponding alcohol and acid) with a benzene solution of 1 (4 mol) gave after purification by PTLC unchanged ester 2b (8) and the 21-membered unsaturated lactone 3b (82). This lactone (eluted as two fractions) was also a mixture of Z- and E-isomers (IR absorptions 720 and 965 cm21 respectively) in a total ratio of 60 40 (by GC). In the first fraction the ratio was 73 27 (GC) and in the second 43 57. The 1H NMR spectrum of the first fraction showed signals at d 4.10 (t 2 H J 5.9 CO2CH2) and 5.31–5.36 (m 2 H CH CH) for the Z-isomer whilst the second fraction showed two triplets at 4.10 (J 5.9 CO2CH2) and 4.11 (J 5.5 CO2CH2) for the Z- and E-isomers respectively and a multiplet at 5.30–5.38 (CH CH) for both isomers.The 13C NMR spectrum of the first fraction showed signals at 173.9 ppm (COO) 130.9 and 130.6 (CH CH-) 64.0 (COOCH2-) and 34.5 ppm (CH2COO) for the Z- isomer as indicated from the more intense signals of the spectrum and that of the second spectrum showed similar signals together with others at 174.0 130.1 130.0 64.2 and 34.8 ppm for the E-isomer. The lactone 3b has previously been prepared 12c by Tsuji and Hashigushi (12 yield) by olefin metathesis of the same ester 2b with WOCl4 (20 mol)–Cp2TiMe2 (24 mol). Such macrolactonization gives from commercially available materials large-ring compounds in high yields by a simple twostep procedure. RCM of dec-9-enyl oleate 4a (prepared in 79 yield from esterification of dec-9-enol and oleic acid) with the catalyst 1 (0.8 mol) (Scheme 3) gave after column chromatography the 19-membered unsaturated lactone 5a (65).The lactone 5a was obtained as an inseparable (by GC) mixture of Z- and E-isomers (IR absorption at 720 and 965 cm21). This lactone was prepared 12c earlier (18 yield) from RCM of dec-9-enyl oleate with WCl6 (20 mol)–Cp2TiMe2 (24 mol). The ester 4b (prepared in 96 yield from undec-10-enol and oleic acid) with 1 (2 mol; Scheme 3) gave the 20-membered ring lactone 5b (63) together with unchanged starting ester Scheme 2 Reagents and conditions 1 (1.7 4 mol) C6H6 60 8C 24 h C (CH2)8 O (CH2)n O 2a,b 2,3a n = 8 (83) b n = 9 (82) O C O (CH2)8 (CH2)n 3a,b 2870 J. Chem. Soc. Perkin Trans. 1 1997 (14). This lactone eluted in two fractions as a mixture of Z- and E-isomers in a total ratio of 61 39 (by GC).In the first fraction the ratio was 71 29 (GC) while in the second it was 42 58 (GC). Thus in RCM the oleate esters give lower yields than the undec-10-enoate esters probably because of steric hindrance by the non-9-enyl moiety in the former. This behaviour is in accord with previous observations that 1 is more effective with terminal dienes.15b RCM of dec-9-enyl (E)-hex-3-enoate 6a prepared in 84 yield from esterification of dec-9-enol and (E)-hex-3-enoic acid with a benzene solution of 1 (1.5 mol) gave after column chromatography first unchanged 6a (66) followed by the known4c,f 13-membered lactone 7a (6) and then a complex mixture. The lactone 7a is an aggregation pheromone of the flat grain beetle Cryptolestes pusillus.4f Attempted preparation of the 14-membered lactone 7b from the diene ester 6b prepared in 95 yield from undec-10-enol and (E)-hex-3-enoic acid and 1 (1.5 mol) gave only a complex mixture eluted after unchanged 6b (68).The low yield in the preparation of the 13- membered lactone 7a could be attributed to the possible unproductive complexation of Ru with the b,g-double bond of the hex-3-enoate and the ester carbonyl and to steric hindrance of the propenyl ester moiety. In conclusion RCM of diene esters is an excellent method for macrolactone formation especially for terminal alkenes. The yield of this reaction is decreased with increasing steric hindrance and the possible complexation of the double bond the Ru atom and the ester carbonyl.Parallel work appeared very recently in the literature 20 in Scheme 3 Reagents and conditions 1 (0.8 2 mol) C6H6 60 8C 24 h C (CH2)7 O (CH2)n O O C O (CH2)7 (CH2)n (CH2)7CH3 4a,b 5a,b 4,5a n = 8 (65) b n = 9 (63) Scheme 4 Reagents and conditions 1 (1.5 mol) C6H6 60 8C 24 h O C O (CH2)n O (CH2)n C O 6a,b 7a,b 6,7a n = 8 (6) b n = 9 Scheme 5 Reagents and conditions i C6H6 reflux (Dean–Stark trap) Cat. conc. H2SO4 5 h Yields 78–96 (CH2)8 CO2H HO(CH2)n (CH2)8 CO2 (CH2)n + i n = 8,9 (CH2)7CO2H (CH2)7CH3 + HO(CH2)n i n = 8,9 (CH2)7CO2 (CH2)7CH3 (CH2)n 2a,b 4a,b COOH + HO(CH2)n i n = 8,9 COO (CH2)n 6a,b which the 21-membered lactone 3b was synthesized (71 yield; 82 in our preparation) by using the catalyst 1 (4 mol) and the ester 2b in dichloromethane solution. Experimental IR spectra were run as films on a Perkin–Elmer 1310 spectrophotometer.1H NMR spectra were recorded on a Bruker 300 AM (300 MHz) spectrometer with CDCl3 as a solvent with SiMe4 as internal standard. J Values are given in Hz. 13C NMR spectra were obtained at 75.5 MHz in CDCl3 solutions with SiMe4 as internal reference. Mass spectra were determined on a VG-250 spectrometer (70 eV). GC analyses were performed with a SS column packed with 20 Carbowax 20 M (3.78 g) on Chromosorb W AW DMCS 60/80 mesh (10 ft × 1/8 in). The acids and alcohols used were commercial products of Aldrich Chem. Co. Inc. The Ru catalyst 1 was prepared according to a published procedure.18 Benzene was distilled under argon atmosphere with benzophenone ketyl and was degassed before use under anhydrous conditions. Catalyst and solvent transfers in the reaction flask were made under argon atmosphere by using a glove bag.All reactions were carried out under an argon atmosphere. General procedure for the synthesis of the diene esters 2a,b 4a,b and 6a,b The acid (0.02 mol) was added in a benzene (30 cm3) solution of the alcohol (0.03 mol) followed by 5 drops of conc. H2SO4. After the mixture had been heated under reflux in a Dean–Stark trap for 5 h most of the benzene was removed and the residue was poured onto Et2O (25 cm3) and washed with water (15 cm3). The aqueous layer was separated and extracted with Et2O (15 cm3) and the combined organic layer and extracts were washed with 5 aqueous NaHCO3 (20 cm3) and with water (cm3) dried (Na2SO4) and concentrated under reduced pressure. Column chromatography silica gel No 60 Merck hexane–dichloromethane (4 1) of the residue gave at first the corresponding diene ester followed by a small amount of unchanged alcohol.Dec-9-enyl undec-10-enoate 2a. This ester (78) was a colourless oil; nmax/cm21 3070 2920 2840 1730 1632 1460 1170 990 910 740 and 720; dH 1.21–1.43 (m 20H) 1.55–1.7 (m 4H) 1.98–2.1 (m 4H) 2.29 (t J 7.5 2H) 4.05 (t J 6.7 2H) 4.9–5.03 (m 4H) and 5.76–5.88 (m 2H); dC 25.0 25.9 28.6 28.8 28.9 29.0 29.05 29.1 29.15 29.2 29.25 29.3 29.4 33.75 34.4 64.3 114.1 139.1 and 173.9; m/z () 322 (57) 304 (9) 184 (54) 166 (62) 138 (77) 110 (74) 96 (88) 83 (94) and 55 (100) (Found C 78.4; H 11.8. C21H38O2 requires C 78.2; H 11.9). Undec-10-enyl undec-10-enoate 2b. The title ester (94) as a colourless oil;12c nmax/cm21 3060 2920 2840 1730 1630 1460 1170 990 900 and 725; dH 1.22–1.45 (m 22H) 1.56–1.69 (m 4H) 1.98–2.08 (m 4H) 2.29 (t J 7.5 2H) 4.05 (t J 6.7 2H) 4.88–5.05 (m 4H) and 5.72–5.88 (m 2H); dC 24.9 25.8 28.6 28.65 28.7 28.8 28.9 28.95 29.0 29.1 29.2 29.25 29.3 29.5 33.6 34.2 64.1 114.0 138.8 and 173.4; m/z () 336 (50) 318 (7) 184 (55) 166 (62) 152 (69) 124 (71) 110 (75) 96 (90) 82 (95) and 55 (100).Dec-9-enyl oleate 4a. This ester (79) was a colourless oil; nmax/cm21 3060 2980 2920 2840 1730 1635 1460 1170 990 910 and 725; dH 0.88 (t J 6.6 3H) 1.18–1.42 (m 30H) 1.54– 1.68 (m 4H) 1.94–2.01 (m 6H) 2.29 (t J 7.5 2H) 4.05 (t J 6.7 2H) 4.90–5.05 (m 2H) 5.27–5.43 (m 2H) and 5.73–5.87 (m 1H); dC 14.0 22.6 25.0 25.9 27.1 27.2 28.6 28.9 28.95 29.0 29.1 29.15 29.2 29.3 29.4 29.5 29.55 29.65 29.7 31.9 33.7 34.3 64.3 114.1 129.7 129.9 139.0 and 173.8; m/z () 420 (53) 392 (12) 283 (33) 264 (67) 222 (35) 138 (84) 97 (86) 83 (93) and 55 (100) (Found C 79.8; H 12.6.C28H52O2 requires C 79.9; H 12.45). Undec-10-enyl oleate 4b. The title ester (96) was a colourless oil; nmax/cm21 3060 2985 2910 2840 1730 1635 1460 1170 990 910 and 725; dH 0.88 (t J 6.6 3H) 1.20–1.40 (m, J. Chem. Soc. Perkin Trans. 1 1997 2871 32H) 1.55–1.68 (m 4H) 1.95–2.09 (m 6H) 2.29 (t J 7.5 2H) 4.05 (t J 6.7 2H) 4.90–5.05 (m 2H) 5.30–5.42 (m 2H) and 5.75–5.88 (m 1H); dC 14.0 22.6 25.0 25.9 27.1 27.2 28.6 28.9 28.95 29.0 29.1 29.2 29.25 29.3 29.35 29.4 29.5 29.6 29.65 29.7 31.9 33.75 34.3 64.3 114.1 129.7 129.9 139.05 and 173.8; m/z () 434 (46) 406 (10) 283 (28) 264 (66) 222 (37) 152 (77) 97 (88) 83 (91) and 55 (100) (Found C 79.9; H 12.2.C29H54O2 requires C 80.1; H 12.5). Dec-9-enyl (E)-hex-3-enoate 6a. This ester (84) was a colourless oil; nmax/cm21 3060 3020 2920 2840 1730 1630 1460 1160 990 965 and 910; dH 0.96 (t J 7.5 3H) 1.22–1.42 (m 10H) 1.55–1.67 (m 2H) 1.98–2.10 (m 4H) 2.99 (d J 6.2 2H) 4.04 (t J 6.7 2H) 4.87–5.03 (m 2H) 5.43–5.63 (m 2H) and 5.72–5.86 (m 1H); dC 13.5 25.5 26.0 28.7 29.0 29.1 29.3 29.4 33.9 38.2 64.7 114.2 120.9 136.2 139.1 and 172.5; m/z () 252 (46) 251 (32) 224 (6) 138 (70) 114 (79) 97 (83) 83 (85) and 55 (100) (Found C 76.4; H 11.0. C16H28O2 requires C 76.1; H 11.2). Undec-10-enyl (E)-hex-3-enoate 6b. The title ester (95) was a colourless oil; nmax/cm21 3060 3020 2915 2840 1730 1630 1460 1160 990 965 and 910; dH 0.98 (t J 7.5 3H) 1.20–1.44 (m 12H) 1.55–1.68 (m 2H) 1.98–2.11 (m 4H) 3.02 (d J 6.0 2H) 4.07 (t J 6.7 2H) 4.90–5.03 (m 2H) 5.45–5.66 (m 2H) and 5.74–5.88 (m 1H); dC 13.4 25.5 25.8 28.5 28.9 29.0 29.2 29.3 29.4 33.7 38.1 64.5 114.1 120.7 136.2 139.2 and 172.3; m/z () 266 (60) 265 (48) 238 (11) 152 (76) 124 (61) 114 (94) 97 (94) 83 (100) and 55 (96) (Found C 76.7; H 11.4.C17H30O2 requires C 76.6; H 11.35). Representative procedure for the synthesis of macrolactones Nonadec-10-en-19-olide 3a. Ruthenium catalyst 1 (9.3 mg 0.01 mmol) was dissolved in a three-necked flask in benzene (80 cm3) in a glove bag at room temperature. The diene ester 2a (191 mg 0.593 mmol) was added to the resulting light orange–brown solution via a syringe under argon atmosphere and the mixture was then heated at 60 8C for 24 h. After cooling the mixture was quenched by exposure to air and concentrated under reduced pressure.The residue was separated by column chromatography silica gel No 60 Merck hexane– dichloromethane (2 1 to 1 2) to give after elution of unchanged 2a (25 mg 13) the olide 3a as a colourless oil in two fractions first fraction 60 mg Z/E (80 20 by GC); second fraction 85 mg Z/E (40 60 by GC); total 145 mg 83 yield Z/E (57 43); nmax/cm21 3050 2920 2840 1730 1460 1165 965 w (weak) for first and m (medium) for second fraction 735 and 720 (m for both fractions); dH 1.20–1.42 (m 20H) 1.55– 1.70 (m 4H) 1.96–2.08 (m 4H) 2.315 (t J 6.9 CH2CO2) and 2.33 (t J 6.6 CH2CO2) 4.10 (t J 6.2 CO2CH2) and 4.12 (t J 5.9 CO2CH2) and 5.26–5.41 (m 2H); dC 24.9 25.1 26.0 26.2 26.4 26.5 27.3 27.35 27.5 27.55 28.1 28.15 28.4 28.45 28.5 28.6 28.65 28.75 28.8 28.9 29.0 29.1 29.2 29.3 29.4 29.45 31.7 31.8 34.1 34.75 64.2 64.25 130.0 130.05 130.6 130.7 174.0 and 174.05; m/z () 294 (20) 276 (10) 149 (46) 137 (47) 123 (84) 109 (95) 95 (99) 81 (99) and 55 (100) (Found C 77.4; H 11.5.C19H34O2 requires C 77.5; H 11.65). Eicos-10-en-20-olide 3b. Addition of the diene 2b (130 mg 0.387 mmol) to a benzene solution of the Ru catalyst 1 (15 mg 0.016 mmol) according to the above described procedure gave after separation of the resulting mixture by PTLC silica gel hexane–CH2Cl2 (1:2) unchanged 2b (10 mg 8) and the olide 3b as a colourless oil 12c in two fractions first fraction 55 mg Z/E (73 27 by GC); second fraction 42 mg Z/E (43 57 by GC); total 97 mg 82 yield Z/E (60 40); nmax/cm21 3070 2920 2840 1730 1460 1170 965 (m for both fractions) 735sh and 720 (m for first and w for second fraction); dH(first fraction) 1.22–1.41 (m 22H) 1.55–1.70 (m 4H) 1.93–2.06 (m 4H) 2.31 (t J 6.7 2H) 4.10 (t J 5.9 2H) and 5.31–5.36 (m 2H); dH- (second fraction) 1.22–1.41 (m 22H) 1.55–1.70 (m 4H) 1.93– 2.06 (m 4H) 2.31 (t J 6.7 2H) 4.10 (t J 5.9 CO2CH2) and 4.12 (t J 5.5 CO2CH2) and 5.30–5.38 (m 2H); dC 25.2 25.75 25.8 26.0 26.15 26.5 26.6 27.7 27.9 27.95 28.3 28.4 28.45 28.5 28.55 28.65 28.7 28.8 28.9 29.0 29.1 29.15 29.2 29.35 29.4 29.45 29.5 29.55 31.7 31.95 34.5 34.8 64.0 64.2 130.0 130.1 130.6 130.9 173.9 and 174.0; m/z () 308 (22) 290 (8) 110 (86) 96 (84) 82 (100) 55 (79) and 54 (85).Octadec-9-en-18-olide 5a. Reaction of the diene 4a (244 mg 0.581 mmol) with the catalyst 1 (4.25 mg 0.0046 mmol) gave after purification by column chromatography and after the elution of the unchanged ester 4a (64 mg 26) the olide 5a as a colourless oil 12c (106 mg 65) not separated by GC; nmax/cm21 3060 2920 2850 1730 1460 1170 965 730sh and 720; dH 1.18–1.45 (m 18H) 1.56–1.70 (m 4H) 1.96–2.09 (m 4H) 2.31 (t J 6.8 2H) 4.11 (t J 5.4 2H) and 5.25–5.40 (m 2H); dC 25.3 25.9 26.1 26.3 26.35 27.1 27.2 27.8 27.9 28.1 28.6 28.8 28.85 28.9 28.95 29.05 29.1 29.15 29.2 29.3 29.4 29.5 29.6 29.65 32.0 32.1 34.9 35.0 64.2 64.6 130.1 130.3 130.6 130.8 174.0 and 174.1; m/z () 280 (62) 262 (28) 252 (12) 149 (30) 137 (48) 123 (6) 109 (68) 95 (78) 82 (88) and 55 (100).Nonadec-9-en-19-olide 5b. Reaction of the diene 4b (174 mg 0.4 mmol) with the catalyst 1 (7.3 mg 0.079 mmol) gave after elution of the unchanged 4b (25 mg 14) the olide 5b as a colourless oil in two fractions first fraction 48 mg Z/E (71:29 by GC); second fraction 26 mg Z/E (42 58 by GC); total 74 mg 63 yield Z/E (61 39); nmax/cm21 3060 2910 2840 1730 1460 1170 965 735sh and 720; dH 1.55–1.45 (m 20H) 1.55– 1.70 (m 4H) 1.92–2.10 (m 4H) 2.32 (t J 6.7 2H) 4.12 (t J 6.1 2H) and 5.25–5.40 (m 2H); dC 24.9 25.3 25.4 25.5 25.9 26.5 27.0 27.4 27.9 28.0 28.05 28.1 28.2 28.4 28.5 28.6 28.7 28.8 28.9 29.05 29.1 29.3 29.4 29.5 29.55 29.7 31.6 32.3 34.6 34.8 63.8 64.1 129.9 130.0 130.6 130.9 173.85 and 173.9; m/z () 294 (13) 276 (6) 149 (62) 123 (60) 109 (91) 95 (98) 81 (100) 55 (99) (Found C 77.3; H 11.6.C19H34O2 requires C 77.5; H 11.65). Dodec-3-en-12-olide 7a. Reaction of the diene 6a (167 mg 0.663 mmol) with 1 (9 mg 0.0097 mmol) gave after separation by column chromatography the unchanged ester 6a (110 mg 66) followed by the olide 7a as colourless oil 4c,f (8 mg 6) dH 1.22–1.46 (m 10H) 1.55–1.66 (m 2H) 1.98–2.11 (m 2H) 3.01 (d J 6.1) 4.08 (t J 5.0) and 5.52–5.95 (m 2H); m/z () 196 (8) 149 (34) 137 (52) 123 (67) 110 (79) 96 (94) 82 (96) and 55 (100).Finally a complex mixture (27 mg) was eluted. Attempted preparation of tridec-3-en-13-olide 7b. Reaction of the diene 6b (151 mg 0.568 mmol) with 1 (8 mg 0.0086 mmol) gave after separation by column chromatography unchanged 6b (103 mg 68) followed by a complex mixture (25 mg). Acknowledgements We gratefully acknowledge the generous gift of the Ru catalyst 1 by Prof. R. H. Grubbs (California Institute of Technology). References 1 Preliminary communication K.E. Litinas and B. E. Salteris presented at the 17th Hellenic Chemical Congress Patra 1996 Abstrs. p. 144. 2 (a) R. H. Thomson The Chemistry of Natural Products Blackie Glasgow 1986 p. 119; (b) W. B. Turner and D. C. Aldridge Fungal Metabolites II Academic Press London 1983 p. 176; (c) K. Nakanishi T. Goto S. Ito S. Natori and S. Nozoe Natural Products Chemistry Academic Press New York 1974 vol. 2 p. 299. 3 (a) M. Kerschbaum Ber. Deutsch. Chem. Ges. 1927 60B 902; (b) H. Brockmann and W. Henkel Naturwissenschaften 1950 37 138; (c) J. Taskinen and L. Nykanen Acta Chem. Scand. Ser. B 1975 29 757; (d) K. Hanson J. A. O’Neill T. J. Simpson and C. L. Willis J. Chem. Soc. Perkin Trans. 1 1994 2493; (e) A. J. Carnell G. Casy G. Gorins A. Kompany-Saeid R. McCague H. F. Olivo S. M. Roberts and A.J. Willets J. Chem. Soc. Perkin Trans. 1 1994 3431; ( f ) S. D. Rychnovsky and K. Hwang J. Org. Chem. 1994 59 5414. 4 (a) T. Hamada K. Daikai R. Irie and T. Katsuki Tetrahedron Asymmetry 1995 6 2441; (b) G. H. Vecchio and A. C. 2872 J. Chem. Soc. Perkin Trans. 1 1997 Oehlschlager J. Org. Chem. 1994 59 4853; (c) C. D. J. 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Tamm Angew. Chem. Int. Ed. Engl. 1973 12 370; S. B. Carter Endeavour 1972 31 77. 8 S. Abe T. Eto and Y. Tsujito Cosmet. Perfum. 1973 88 67; B. D. Mookherjee and R. A. Wilson in Fragrance Chemistry ed. E. T. Theimer Academic Press Orlando 1982 p.443; P. Kraft and W. Tochtermann Liebigs Ann. Chem. 1994 1161. 9 E. J. Corey D. J. Brunelle and K. C. Nicolaou J. Am. Chem. Soc. 1977 99 7359; L. Ruzicka and M. Stoll Helv. Chim. Acta 1928 11 1159. 10 M. Stoll and A. Rouve Helv. Chim. Acta 1934 17 1283; K. Steliou and M.-A. Poupart J. Am. Chem. Soc. 1983 105 7130; E. J. Corey and K. C. Nicolaou J. Am. Chem. Soc. 1974 96 5614; T. Kurihara Y. Nakajima and O. Mitsunobu Tetrahedron Lett. 1976 2455; G. Voss and H. Gerlach Helv. Chim. Acta 1983 66 2994; J. Inanaga K. Hirata H. Saeki T. Katsuki and M. Yamaguchi Bull. Chem. Soc. Jpn. 1979 52 1989. 11 (a) B. M. Trost and T. R. Verhoeven J. Am. Chem. Soc. 1977 99 3867; (b) B. M. Trost S. Matsubara and J. J. Caringi J. Am. Chem. Soc. 1989 111 8745; (c) H. J. Bestmann and R. Schobert Angew. Chem.Int. Ed. Engl. 1983 22 780; (d) G. E. Keck A. Paslani and S. F. McHardy J. Org. Chem. 1994 59 3113. 12 (a) D. Villemin Tetrahedron Lett. 1980 21 1715; (b) J. Tsuji and S. Hashiguchi Tetrahedron Lett. 1980 21 2955; (c) J. Tsuji and S. Hashiguchi J. Organometal. Chem. 1981 218 69. 13 (a) K. J. Ivin Olefin Metathesis Academic Press New York 1983; (b) R. H. Grubbs and S. H. Pine in Comprehensive Organic Synthesis ed. B. M. Trost Pergamon New York 1991 vol. 5 ch. 9.3; (c) R. H. Grubbs S. J. Miller and G. C. Fu Acc. Chem. Res. 1995 28 446; (d) H. G. Schmalz Angew. Chem. 1995 107 1981. 14 B. M. Novak and R. H. Grubbs J. Am. Chem. Soc. 1988 110 960; B. M. Novak and R. H. Grubbs J. Am. Chem. Soc. 1988 110 7542; R. H. Grubbs and W. Tumas Science 1989 243 907; G. C. Bazan E. Khosravi R. R.Schrock W. J. Feast V. C. Gibson M. B. O’Regan J. K. Thomas and W. M. Davis J. Am. Chem. Soc. 1990 112 8378; G. C. Bazan J. K. Oskam H. C. Cho L. Y. Park and R. R. Schrock J. Am. Chem. Soc. 1991 113 6899; B. M. Novak W. Risse and R. H. Grubbs Adv. Polym. Sci. 1992 102 47; M. A. Hillmyer C. Lepetit D. V. McGrath B. M. Novak and R. H. Grubbs Macromolecules 1992 25 3345; S. T. Nguyen L. K. Johnson and R. H. Grubbs J. Am. Chem. Soc. 1992 114 3974; R. R. Schrock in Ring Opening Polymerization ed. D. J. Brunnel Hawer Munich 1993 p. 129; S. T. Nguyen and R. H. Grubbs J. Am. Chem. Soc. 1993 115 9858; P. E. Schwab M. B. France R. H. Grubbs and J. W. Ziller Angew. Chem. Int. Ed. Engl. 1995 34 2039; C. Fraser and R. H. Grubbs Macromolecules 1995 28 7248; A. W. Stumpf E. Saive A. Demonceau and A.F. Noels J. Chem. Soc. Chem. Commun. 1995 1127; M. D. Lynn S. Kanaoka and R. H. Grubbs J. Am. Chem. Soc. 1996 118 784. 15 (a) G. C. Fu and R. H. Grubbs J. Am. Chem. Soc. 1992 114 5426; (b) G. C. Fu and R. H. Grubbs J. Am. Chem. Soc. 1992 114 7324; (c) G. C. Fu and R. H. Grubbs J. Am. Chem. Soc. 1993 115 3800; (d) G. C. Fu S. T. Nguyen and R. H. Grubbs J. Am. Chem. Soc. 1993 115 9856; (e) O. Fujimura G. C. Fu and R. H. Grubbs J. Org. Chem. 1994 59 4029; ( f) S. Kim N. Bowden and R. H. Grubbs J. Am. Chem. Soc. 1994 116 1081; (g) S. J. Miller S. Kim Z. Chen and R. H. Grubbs J. Am. Chem. Soc. 1995 117 2108; (h) S. J. Miller and R. H. Grubbs J. Am. Chem. Soc. 1995 117 5855; (i) C. M. Huwe O. C. Kiehl and S. Blechert Synlett 1996 65; ( j) O. Fujimura and R. H. Grubbs J. Am. Chem. Soc.1996 118 2499; (k) S. Kim W. J. Zuercher N. B. Bowden and R. H. Grubbs J. Org. Chem. 1996 61 1073. 16 O. Fujimura G. C. Fu P. W. K. Rothemund and R. H. Grubbs J. Am. Chem. Soc. 1995 117 2355; R. R. Schrock J. S. Murdzek G. C. Bazan J. Robbins M. DiMare and M. O’Regan J. Am. Chem. Soc. 1990 112 3875; R. R. Schrock R. T. DePue J. Feldman C. J. Schowerien J. C. Dewan and A. H. Liu J. Am. Chem. Soc. 1988 110 1423; A. Aguero J. Kress and J. A. Osborn J. Chem. Soc. Chem. Commun. 1985 793; J. Couturier C. Paillet M. Leconte J. M. Basset and K. Weiss Angew. Chem. Int. Ed. Engl. 1992 31 628. 17 B. C. Borer S. Deerenberg H. Bierangel and U. K. Pandit Tetrahedron Lett. 1994 35 3191; S. F. Martin Y. Liao H.-J. Chen M. Patzel and M. N. Ramser Tetrahedron Lett. 1994 35 6005; S. A. Wagman and S.F. Martin Tetrahedron Lett. 1995 36 1169; A. F. Houri Z. Xu D. A. Cogan and A. H. Hoveyda J. Am. Chem. Soc. 1995 117 2943; P. Bertinato E. J. Sorensen D. Meng and S. J. Danishefsky J. Org. Chem. 1996 61 8000; K. C. Nicolaou Yen He D. Vourloumis H. Vallberg and Z. Yang Angew. Chem. Int. Ed. Engl. 1996 35 2399. 18 Preparation and characterization of catalyst 1 S. T. Nguyen L. K. Johnson R. H. Grubbs and J. W. Ziller J. Am. Chem. Soc. 1992 114 3974; S. T. Nguyen R. H. Grubbs and J. W. Ziller J. Am. Chem. Soc. 1993 115 9858. 19 G. C. Fu R. H. Grubbs K. E. Litinas and S. T. Nguyen unpublished results. 20 A. Furstner and K. Langemann J. Org. Chem. 1996 61 3942. Paper 7/02353G Received 7th April 1997 Accepted 29th May 1997 J. Chem. Soc. Perkin Trans. 1 1997 2869 Unsaturated macrocyclic lactone synthesis via catalytic ring-closing metathesis 1 Konstantinos E.Litinas * and Basil E. Salteris Laboratory of Organic Chemistry Aristotle University of Thessaloniki 54006 Thessaloniki Greece Ring-closing metathesis (RCM) of the terminal diene esters 2a,b with the Ru catalyst 1 results in the formation of the 20- 21-membered macrolactones 3a,b in high yields. RCM of the diene oleate esters 4a,b with 1 gives the 19- 20-membered macrolactones 5a,b in good yields while an analogous reaction of the diene ‚,„-unsaturated ester 6a gives the 13-membered lactone 7a in low yield. Macrocyclic lactones are important components of naturally occurring compounds,2,3 many of them insects pheromones.4 They possess a range of significant biological activity,5 (e.g. antibiotic,3e,6 antifungal,5c antitumour cytostatic,7 oestrogenic and anabolic 2a,5c) as well as being used as fragrances.8 There are several multi-step syntheses of these compounds in moderate to high yields,5 which include the following ring enlargement of smaller rings,9 lactonization of w-hydroxycarboxylic acids 10 with different reagents CC bond formation by intramolecular addition of enolate ion with Pd0 catalyst,11a intramolecular diacetylene ester coupling,11b by intramolecular Wittig 11c or Horner–Emmons11d reactions and by olefin metathesis using WCl6–Me4Sn12a or WCl6–Cp2TiMe2 12b,c or WOCl4–Cp2- TiMe2 12c as catalysts.Recent progress in the development of well-defined metathesis catalysts with a single component has extended the use of olefin metathesis 13 in polymer chemistry through ring-opening metathesis polymerization (ROMP),14 in organic synthesis 15,16 and in natural products synthesis.17 Ring-closing metathesis (RCM) of dienes,15 especially with the very efficient Ru catalyst 1,13b,18 is a general method for the construction of unsaturated carbocycles and heterocycles (Scheme 1).In continuation of our efforts 19 to synthesize 6- and 7- membered unsaturated lactones we report here our results for the preparation of 19- 20- 21- 13- and 14-membered macrolactones from RCM of acyclic diene esters with the Ru catalyst 1 (Schemes 2–4). All diene esters were prepared from commercially available materials (Scheme 5) by simple esterifi- cation. Dec-9-enyl undec-10-enoate 2a prepared in 78 yield by esterification of dec-9-enol with undec-10-enoic acid in the presence of conc.H2SO4 as catalyst in refluxing benzene for 5 h in a Dean–Stark trap was heated with a benzene solution of the catalyst 1 (1.7 mol) at 60 8C for 24 h under an argon atmosphere. Purification of the crude product by column chromatography gave the 20-membered macrolactone 3a (83) together with the first-eluted unchanged ester 2a (13). Compound 3a extracted in two fractions was a mixture of Z- and E-isomers (ratio 57 43 as indicated by GC analysis). The first fraction Z/E (80 20) by GC showed in the IR spectrum more intense absorption for cis- (720 cm21) than for trans- (965 cm21) Scheme 1 (X) (CH2)n R1 R2 (CH2)n (X) R1 P(Cy)3 Ru P(Cy)3 Ph Ph Cl Cl 1–5 mol X = O NR CH2; n = 1,2,3,4 1 isomer in comparison to the IR spectrum of the second fraction Z/E (40 60) by GC.An analogous reaction (Scheme 2) of the diene ester 2b (prepared in 94 yield by esterification for 5 h of the corresponding alcohol and acid) with a benzene solution of 1 (4 mol) gave after purification by PTLC unchanged ester 2b (8) and the 21-membered unsaturated lactone 3b (82). This lactone (eluted as two fractions) was also a mixture of Z- and E-isomers (IR absorptions 720 and 965 cm21 respectively) in a total ratio of 60 40 (by GC). In the first fraction the ratio was 73 27 (GC) and in the second 43 57. The 1H NMR spectrum of the first fraction showed signals at d 4.10 (t 2 H J 5.9 CO2CH2) and 5.31–5.36 (m 2 H CH CH) for the Z-isomer whilst the second fraction showed two triplets at 4.10 (J 5.9 CO2CH2) and 4.11 (J 5.5 CO2CH2) for the Z- and E-isomers respectively and a multiplet at 5.30–5.38 (CH CH) for both isomers.The 13C NMR spectrum of the first fraction showed signals at 173.9 ppm (COO) 130.9 and 130.6 (CH CH-) 64.0 (COOCH2-) and 34.5 ppm (CH2COO) for the Z- isomer as indicated from the more intense signals of the spectrum and that of the second spectrum showed similar signals together with others at 174.0 130.1 130.0 64.2 and 34.8 ppm for the E-isomer. The lactone 3b has previously been prepared 12c by Tsuji and Hashigushi (12 yield) by olefin metathesis of the same ester 2b with WOCl4 (20 mol)–Cp2TiMe2 (24 mol). Such macrolactonization gives from commercially available materials large-ring compounds in high yields by a simple twostep procedure. RCM of dec-9-enyl oleate 4a (prepared in 79 yield from esterification of dec-9-enol and oleic acid) with the catalyst 1 (0.8 mol) (Scheme 3) gave after column chromatography the 19-membered unsaturated lactone 5a (65).The lactone 5a was obtained as an inseparable (by GC) mixture of Z- and E-isomers (IR absorption at 720 and 965 cm21). This lactone was prepared 12c earlier (18 yield) from RCM of dec-9-enyl oleate with WCl6 (20 mol)–Cp2TiMe2 (24 mol). The ester 4b (prepared in 96 yield from undec-10-enol and oleic acid) with 1 (2 mol; Scheme 3) gave the 20-membered ring lactone 5b (63) together with unchanged starting ester Scheme 2 Reagents and conditions 1 (1.7 4 mol) C6H6 60 8C 24 h C (CH2)8 O (CH2)n O 2a,b 2,3a n = 8 (83) b n = 9 (82) O C O (CH2)8 (CH2)n 3a,b 2870 J. Chem. Soc. Perkin Trans. 1 1997 (14). This lactone eluted in two fractions as a mixture of Z- and E-isomers in a total ratio of 61 39 (by GC).In the first fraction the ratio was 71 29 (GC) while in the second it was 42 58 (GC). Thus in RCM the oleate esters give lower yields than the undec-10-enoate esters probably because of steric hindrance by the non-9-enyl moiety in the former. This behaviour is in accord with previous observations that 1 is more effective with terminal dienes.15b RCM of dec-9-enyl (E)-hex-3-enoate 6a prepared in 84 yield from esterification of dec-9-enol and (E)-hex-3-enoic acid with a benzene solution of 1 (1.5 mol) gave after column chromatography first unchanged 6a (66) followed by the known4c,f 13-membered lactone 7a (6) and then a complex mixture. The lactone 7a is an aggregation pheromone of the flat grain beetle Cryptolestes pusillus.4f Attempted preparation of the 14-membered lactone 7b from the diene ester 6b prepared in 95 yield from undec-10-enol and (E)-hex-3-enoic acid and 1 (1.5 mol) gave only a complex mixture eluted after unchanged 6b (68).The low yield in the preparation of the 13- membered lactone 7a could be attributed to the possible unproductive complexation of Ru with the b,g-double bond of the hex-3-enoate and the ester carbonyl and to steric hindrance of the propenyl ester moiety. In conclusion RCM of diene esters is an excellent method for macrolactone formation especially for terminal alkenes. The yield of this reaction is decreased with increasing steric hindrance and the possible complexation of the double bond the Ru atom and the ester carbonyl. Parallel work appeared very recently in the literature 20 in Scheme 3 Reagents and conditions 1 (0.8 2 mol) C6H6 60 8C 24 h C (CH2)7 O (CH2)n O O C O (CH2)7 (CH2)n (CH2)7CH3 4a,b 5a,b 4,5a n = 8 (65) b n = 9 (63) Scheme 4 Reagents and conditions 1 (1.5 mol) C6H6 60 8C 24 h O C O (CH2)n O (CH2)n C O 6a,b 7a,b 6,7a n = 8 (6) b n = 9 Scheme 5 Reagents and conditions i C6H6 reflux (Dean–Stark trap) Cat.conc. H2SO4 5 h Yields 78–96 (CH2)8 CO2H HO(CH2)n (CH2)8 CO2 (CH2)n + i n = 8,9 (CH2)7CO2H (CH2)7CH3 + HO(CH2)n i n = 8,9 (CH2)7CO2 (CH2)7CH3 (CH2)n 2a,b 4a,b COOH + HO(CH2)n i n = 8,9 COO (CH2)n 6a,b which the 21-membered lactone 3b was synthesized (71 yield; 82 in our preparation) by using the catalyst 1 (4 mol) and the ester 2b in dichloromethane solution. Experimental IR spectra were run as films on a Perkin–Elmer 1310 spectrophotometer.1H NMR spectra were recorded on a Bruker 300 AM (300 MHz) spectrometer with CDCl3 as a solvent with SiMe4 as internal standard. J Values are given in Hz. 13C NMR spectra were obtained at 75.5 MHz in CDCl3 solutions with SiMe4 as internal reference. Mass spectra were determined on a VG-250 spectrometer (70 eV). GC analyses were performed with a SS column packed with 20 Carbowax 20 M (3.78 g) on Chromosorb W AW DMCS 60/80 mesh (10 ft × 1/8 in). The acids and alcohols used were commercial products of Aldrich Chem. Co. Inc. The Ru catalyst 1 was prepared according to a published procedure.18 Benzene was distilled under argon atmosphere with benzophenone ketyl and was degassed before use under anhydrous conditions. Catalyst and solvent transfers in the reaction flask were made under argon atmosphere by using a glove bag.All reactions were carried out under an argon atmosphere. General procedure for the synthesis of the diene esters 2a,b 4a,b and 6a,b The acid (0.02 mol) was added in a benzene (30 cm3) solution of the alcohol (0.03 mol) followed by 5 drops of conc. H2SO4. After the mixture had been heated under reflux in a Dean–Stark trap for 5 h most of the benzene was removed and the residue was poured onto Et2O (25 cm3) and washed with water (15 cm3). The aqueous layer was separated and extracted with Et2O (15 cm3) and the combined organic layer and extracts were washed with 5 aqueous NaHCO3 (20 cm3) and with water (cm3) dried (Na2SO4) and concentrated under reduced pressure. Column chromatography silica gel No 60 Merck hexane–dichloromethane (4 1) of the residue gave at first the corresponding diene ester followed by a small amount of unchanged alcohol.Dec-9-enyl undec-10-enoate 2a. This ester (78) was a colourless oil; nmax/cm21 3070 2920 2840 1730 1632 1460 1170 990 910 740 and 720; dH 1.21–1.43 (m 20H) 1.55–1.7 (m 4H) 1.98–2.1 (m 4H) 2.29 (t J 7.5 2H) 4.05 (t J 6.7 2H) 4.9–5.03 (m 4H) and 5.76–5.88 (m 2H); dC 25.0 25.9 28.6 28.8 28.9 29.0 29.05 29.1 29.15 29.2 29.25 29.3 29.4 33.75 34.4 64.3 114.1 139.1 and 173.9; m/z () 322 (57) 304 (9) 184 (54) 166 (62) 138 (77) 110 (74) 96 (88) 83 (94) and 55 (100) (Found C 78.4; H 11.8. C21H38O2 requires C 78.2; H 11.9). Undec-10-enyl undec-10-enoate 2b. The title ester (94) as a colourless oil;12c nmax/cm21 3060 2920 2840 1730 1630 1460 1170 990 900 and 725; dH 1.22–1.45 (m 22H) 1.56–1.69 (m 4H) 1.98–2.08 (m 4H) 2.29 (t J 7.5 2H) 4.05 (t J 6.7 2H) 4.88–5.05 (m 4H) and 5.72–5.88 (m 2H); dC 24.9 25.8 28.6 28.65 28.7 28.8 28.9 28.95 29.0 29.1 29.2 29.25 29.3 29.5 33.6 34.2 64.1 114.0 138.8 and 173.4; m/z () 336 (50) 318 (7) 184 (55) 166 (62) 152 (69) 124 (71) 110 (75) 96 (90) 82 (95) and 55 (100).Dec-9-enyl oleate 4a. This ester (79) was a colourless oil; nmax/cm21 3060 2980 2920 2840 1730 1635 1460 1170 990 910 and 725; dH 0.88 (t J 6.6 3H) 1.18–1.42 (m 30H) 1.54– 1.68 (m 4H) 1.94–2.01 (m 6H) 2.29 (t J 7.5 2H) 4.05 (t J 6.7 2H) 4.90–5.05 (m 2H) 5.27–5.43 (m 2H) and 5.73–5.87 (m 1H); dC 14.0 22.6 25.0 25.9 27.1 27.2 28.6 28.9 28.95 29.0 29.1 29.15 29.2 29.3 29.4 29.5 29.55 29.65 29.7 31.9 33.7 34.3 64.3 114.1 129.7 129.9 139.0 and 173.8; m/z () 420 (53) 392 (12) 283 (33) 264 (67) 222 (35) 138 (84) 97 (86) 83 (93) and 55 (100) (Found C 79.8; H 12.6.C28H52O2 requires C 79.9; H 12.45). Undec-10-enyl oleate 4b. The title ester (96) was a colourless oil; nmax/cm21 3060 2985 2910 2840 1730 1635 1460 1170 990 910 and 725; dH 0.88 (t J 6.6 3H) 1.20–1.40 (m, J. Chem. Soc. Perkin Trans. 1 1997 2871 32H) 1.55–1.68 (m 4H) 1.95–2.09 (m 6H) 2.29 (t J 7.5 2H) 4.05 (t J 6.7 2H) 4.90–5.05 (m 2H) 5.30–5.42 (m 2H) and 5.75–5.88 (m 1H); dC 14.0 22.6 25.0 25.9 27.1 27.2 28.6 28.9 28.95 29.0 29.1 29.2 29.25 29.3 29.35 29.4 29.5 29.6 29.65 29.7 31.9 33.75 34.3 64.3 114.1 129.7 129.9 139.05 and 173.8; m/z () 434 (46) 406 (10) 283 (28) 264 (66) 222 (37) 152 (77) 97 (88) 83 (91) and 55 (100) (Found C 79.9; H 12.2.C29H54O2 requires C 80.1; H 12.5). Dec-9-enyl (E)-hex-3-enoate 6a. This ester (84) was a colourless oil; nmax/cm21 3060 3020 2920 2840 1730 1630 1460 1160 990 965 and 910; dH 0.96 (t J 7.5 3H) 1.22–1.42 (m 10H) 1.55–1.67 (m 2H) 1.98–2.10 (m 4H) 2.99 (d J 6.2 2H) 4.04 (t J 6.7 2H) 4.87–5.03 (m 2H) 5.43–5.63 (m 2H) and 5.72–5.86 (m 1H); dC 13.5 25.5 26.0 28.7 29.0 29.1 29.3 29.4 33.9 38.2 64.7 114.2 120.9 136.2 139.1 and 172.5; m/z () 252 (46) 251 (32) 224 (6) 138 (70) 114 (79) 97 (83) 83 (85) and 55 (100) (Found C 76.4; H 11.0. C16H28O2 requires C 76.1; H 11.2). Undec-10-enyl (E)-hex-3-enoate 6b. The title ester (95) was a colourless oil; nmax/cm21 3060 3020 2915 2840 1730 1630 1460 1160 990 965 and 910; dH 0.98 (t J 7.5 3H) 1.20–1.44 (m 12H) 1.55–1.68 (m 2H) 1.98–2.11 (m 4H) 3.02 (d J 6.0 2H) 4.07 (t J 6.7 2H) 4.90–5.03 (m 2H) 5.45–5.66 (m 2H) and 5.74–5.88 (m 1H); dC 13.4 25.5 25.8 28.5 28.9 29.0 29.2 29.3 29.4 33.7 38.1 64.5 114.1 120.7 136.2 139.2 and 172.3; m/z () 266 (60) 265 (48) 238 (11) 152 (76) 124 (61) 114 (94) 97 (94) 83 (100) and 55 (96) (Found C 76.7; H 11.4.C17H30O2 requires C 76.6; H 11.35). Representative procedure for the synthesis of macrolactones Nonadec-10-en-19-olide 3a. Ruthenium catalyst 1 (9.3 mg 0.01 mmol) was dissolved in a three-necked flask in benzene (80 cm3) in a glove bag at room temperature. The diene ester 2a (191 mg 0.593 mmol) was added to the resulting light orange–brown solution via a syringe under argon atmosphere and the mixture was then heated at 60 8C for 24 h. After cooling the mixture was quenched by exposure to air and concentrated under reduced pressure.The residue was separated by column chromatography silica gel No 60