MSU LIBRARIES M w RETURNING MATERIALS: Place in book drop to remove this checkout from your record. FINES wil] be Charged if book is returned after the date Stamped be1ow. STUDIES AND APPLICATIONS OF FURAN OXIDATIONS BY Peter D. Williams A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 1982 ABSTRACT STUDIES AND APPLICATIONS OF FURAN OXIDATIONS BY Peter D. Williams The oxidation of alkylfurans using m-chloroperoxyben- zoic acid (MCPBA) was investigated. In methylene chloride solution, 2,5-dialkylfurans were oxidized by one equivalent of MCPBA to give cis-l,4—enediones in high yield. The initial enedione product derived from 2-n-buty1furan rearranged in the presence of acid to give 5-n-butyl—2- (3H)furanone in good yield. Further oxidation occurred with more highly substituted alkylfurans. For example, 2,3,5-trimethylfuran consumed two equivalents of MCPBA to give (Z)-4-acetoxy-3-methyl-3-buten—2-one, along with a minor amount of 3,4-epoxy-3—methy1hexane-2,S-dione. The mono-oxidation product, (Z)-3-methyl-3-hexene-2,S-dione, gave the same product mixture upon treatment with MCPBA, suggesting that the second oxidation occurs via a regio- selective Baeyer-Villiger mechanism. Oxidation of alkylfurans using MCPBA in methanol gave 2,5—dimethoxy—2,5- dihydrofuran derivatives in high yield. Furan oxidation methodology was employed as the key step in a model study for the construction of the Peter D. Williams 2,9-dioxabicyclo[3.3.1]nonane ring system of the antibiotic, tirandamycin. Thus, oxidation of 2-(l,3-dihydroxypropyl)- 3,5-dimethylfuran with MCPBA followed by the addition of a catalytic amount of aqueous p-toluenesulfonic acid gave l,7-dimethyl-2,9-dioxabicyclo[3.3.1]non—7-en-6-one in high yield. Selective oxidation of the furan nucleus in substrates possessing a 3,5-hexadienyl side chain enabled the synthesis of several 3,8,lO-undecatriene—2,S-diones, whose thermal chemistry provided hydrindenone products via intramolecular Diels-Alder cyclization. The effect of enedione (dienophile) double bond geometry and substitution upon the exo/endo cyclization selectivity was examined. The synthesis of macrocyclic polyketones was realized by oxidation of furan-containing macrocycles.l Thus, the cyclic tetramer obtained from the condensation of furan and acetone was oxidized by bromine in acetic acid or MCPBA to give trans- and cis-enedione—functionalized macrocycles. The cyclic furan-acetone hexamer was oxidized using MCPBA to the fully ring-opened dodecaketone derivative. A new furan macrocycle, 1,1,15,15-tetramethyl[l.3.1.3](2,5)- furanophane, was synthesized and then oxidized by MCPBA to the corresponding 24-membered macrocyclic octaketone. 1. Williams, P.D.; LeGoff, E. J. Org. Chem. (1981) :2, 4143. To my parents; without their love and support thlS work could never have begun, and to my wife, Theresa; without her love and companionship this work could never have been so happily ended. ACKNOWLEGEMENT It is with great pleasure that I acknowledge the guidance, support, and friendship of Professor Eugene LeGoff. His willingness to share chemical insight at both the blackboard and bench levels has made the art of chemical research infinitely more comprehensible, and the interest and support he has shown for me has made my experience as a graduate student infinitely more meaningful. I would also like to thank the organic faculty for their contribution to my graduate education, especially Drs. Farnum, Reusch, and Tanis for their many helpful discussions. Financial support from the SOHIO and Dow Corporations during the last two years of my stay at Michigan State is gratefully acknowledged; it is an honor to have received these Fellowship awards. ii TABLE OF CONTENTS LIST OF TABLES. . . . . . . . . 'LIST OF FIGURES. . . . . . . . INTRODUCTION. . . . . . . . Scheme 1. . . . . Scheme 2. . . . . Scheme 3. . . . . Scheme 4. . . Scheme 5. . . Scheme 6. . . . Scheme 7. . . . Scheme 8. . . . Scheme 9. . . . . . . Scheme 10. . . . . . Scheme 11. . . . . . Scheme 12. . . . . . . . . . Scheme 13. . . . . . . . . . A. Oxidation of Simple Furans: Considerations. . . . . . Scheme 14. . . . . . . . . . Scheme 15. . . . . . . . . . Scheme 16. . . . . . . . Scheme 17. . . . . . . . Scheme 18. . . . . . . . . . Scheme 19. . . . . . . . . . Scheme 20. . . . . . . . B. Tirandamycin Model Study. Retrosynthetic Scheme 1. . . iii PAGE viii P' X \OCDQO‘mhbJWNl—‘H H +4 H n u3+4 16 .16 .19 .20 .21 .25 .27 .29 34 .35 Scheme 21. . . . . . . . . . . . . . . . . . Scheme 22. . . . . . . . . . . . . . . . . Scheme 23. . . . . . . . . . . . . . . . . C. Intramolecular Diels-Alder Reactions. Scheme 24. . . . . . . . . . . . . . . . . . Scheme 25. . . . . . . . . . . . . . . . . . Scheme 26. . . . . . . . . . . . . . . . . Scheme 27. . . . . . . . . . . . . . . . . Scheme 28. . . . . . . . . . . . . . . . . D. Synthesis of Macrocyclic Polyketones. . Scheme 29. . . . . . . . . . . . . . . . Scheme 30. . . . . . . . . . . . . . . . . . Scheme 31. . . . . . . . . . . . . . . . . . Scheme 32. . . . . . . . . . . . . . . . . Scheme 33. . . . . . . . . . . . . . . . . Scheme 34. . . . . . . . . . . . . . . . . EXPERIMENTAL. . . . . . . . . . . . . . . . General Methods. . . . . . . . . . . . . . cis-3-Hexene-2,5-dione (37), cis-B-octene- 2,5-dione (39a), cis-enedionediester 41a, bis-spiroketal 4}, and tetracyclic dione 29. General Procedure. . . . . . . . . . . . . cis-B-Hexene-2,5-dione (3]). . . . . . . . cis-3-Octene-2,5-dione (39a). . . . . . cis-Enedionediester 41a. . . . . . . . . bis-Spiroketal 4}. . . . . . . . . . . . . Tetracyclic dione 29. . . . . . . . . . . Isomerization of 39a to trans-3-octene-2,5- dione (31b). . . . . . . . . . . . . . . trans-Enedionediester 41b. . . . . . . . cis-4-Oxo-2-pentenal (43). . . . . . . . . cis-4-Oxo—2-octenal (48). . . . . . . . 5-n-Buty1-2(3H)-furanone (4?) . . . . . . Oxidation of menthofuran (58) to enol lactone 59. . . . . . . . IV. . . . . . . iv PAGE .39 .40 .45 50 .51 .53 .55 .57 .59 84 .87 .90 .94 .98 100 103 104 104 105 105 106 .106 106 107 107 108 108 109 .110 .110 .111 Oxidation of tetramethylfuran (60) to enol acetate 61. . . . . . . . . . . . . . . . . . Oxidation of 2,3,5-trimethylfuran (62) using 1 equivalent of MCPBA to (Z)-3-methyl-3-hexene- 2, S-dione (63a). . . . . . . . . . . . . . . . Isomerization of 63a to (E)— —3-methyl- -3- hexene- 2, 5— dione (63b). . . . . . . . . . . . . . . . Oxidation of 2, 3, 5- -trimethy1furan (62) using 2 equivalents of MCPBA to (Z)- -4- -acetoxy- 3- methy1-3- buten- 2-one 64a and epoxyketone 65. . Isomerization of 64a to trans- enol acetate 64b. 0 O I O O O O O O O O O O O O O O O O O O Oxidation of (Z)-3-methyl-3-hexene-2,S-dione (63a) using MCPBA to 64a and 65. . . . . . . . Oxidation of 2, 4- -dimethy1furan (68) using 2 equivalents of MCPBA. . . . . . . . . . . . . 2-Methyl-2,5-dimethoxy-2,S-dihydrofuran (46), 2-n-butyl—2,5- dimethoxy— 2, 5- -dihydrofuran (73), spiroketal 72, 2, 5— —dimethyl- -2, 5- -dimethoxy— $2 5- dihydrofuran~ (74), 2, 4- -dimethyl- -2, 5- -dimethoxy- 2, 5- -dihydrofuran (76), 2,3,5-trimethyl-2,5- dimethoxy-Z,5-dihydrofuran (76), 2,5-dimethoxy- L 5- -dihydromenthofuran (77), 2, 3, 4, 5— tetra— methyl- -2, S— —dimethoxy-2, 5— —dihydrofuran (78), and tetracyclic dione 20.. . . . . . . . . . . General Procedure. . . . . . . . . . . . . . 2-Methy1-2,5-dimethoxy-2,S-dihydrofuran (46). . 2-n-Butyl-2,5-dimethoxy-2,5-dihydrofuran (73). Spiroketal 72. . . . . . . . . . . . . . . . . 2,5-Dimethyl-2,5-dimethoxy-2,S-dihydrofuran (74). . . . . . . . . . . . . . . . . . . . . . 2,4-Dimethyl-2,5-dimethoxy-2,S-dihydrofuran (75). . . . . . . . . . . . . . . . . . . . . . 2,3,5-Trimethyl-2,5-dimethoxyl-2,S-dihydro- furan (76). . . . . . . . . . . . . . . . . . 2 ,S-Dimethoxy-Z, 5-dihydromenthofuran (77). . . 2, 3, 4, 5- Tetramethyl- 2, 5- -dimethoxy- -2, 5- -dihydro- furan (78). . . . . . . . . . . . . . . . . Tetracyclic dione 20.. . . . . . . . . . . . 3, 5-Dimethylfuran-2-carboxa1dehyde (88). . . . PAGE .112 112 . 113 114 . 115 . 115 .116 .117 . 117 .118 118 119 .119 .119 .120 . 120 .121 .121 121 PAGE Ethyl 3-(3,5-dimethy1-2-fury1)-3-hydroxy- propanoate (89). . . . . . . . . . . . . . . . . 123 2-(1,3-dihydroxypropy1)-3,5—dimethy1furan (99). . . . . . . . . . . . . . . . . . . . . . .124 3,3-bis(3,5-Dimethy1-2-furyl)-1-propanol (93). . 125 1,7-Dimethy1-2,9-dioxabicyclo[3.3.1]non-7-en- 6-one (2}). . . . . . . . . . . . . . . . . . . .126 3-(S-Methyl-Z-furyl)propanal (96a). . . . . . . .127 Ethyl 5-(S-methyl-Z-furyl)-2—pentenoate (96a). . 128 S-Methyl-Z-(5-hydroxy-3-pentenyl)furan (92a). . .129 5-(5-Methyl-2-fury1)-2(E)-pentena1 (96a). . . . .130 2-(3(E),S-hexadienyl)-5-methylfuran (99a). . . . 131 3-(3,5-Dimethyl-2-furyl)propanal (96b): . . . . .133 Ethyl 5-(3,5-dimethyl-2-furyl)-2-pentenoate (96b). . . . . . . . . . . . . . . . . . . . . 133 3, 5- -Dimethy1- 2-(5- hydroxy- 3-penteny1)furan (97b). . . . . . . . . . . . . . . . . . . . . 134 5-(3,5- Dimethyl-Z-fury1)-2(E)-pentena1 (98b). . .134 3,5-Dimethyl—2—(3(E),5-hexadienyl)furan (99b). . 135 3(Z),8(E),lO-Undecatriene-2,5-dione (103). . . . 135 4-Methy1-3(Z),8(E),10-undecatriene-2,5- dione (IQS). . . . . . . . . . . . . . . . . . . 137 3(E), 8(E), 10- Undecatriene- 2, 5- dione (1Q5) via PCC oxidation. . . . . . . . . . . . . . . . 138 3(E),8(E),lO-Undecatriene-Z,5-dione (1Q5) via pyridine isomerization of cis-enedione (1Q3).. . . . . . . . . . . . . . . . . . . . . 140 Attempted isomerization of cis- -enedione 1Q5 using DBU: 2, 5- -dimethyl- -4- -hydroxy- -5- (2, 4- pentadienyl)- -2- -cyclopentenone (1Q7). . . . . . . 140 Isomerization of cis- -enedione 1Q5 using triethylamine: 4-methy1- 3(E), 8(E), 10- undecatriene- 2, 5— dione (1Q9) and 4-methylidene— 8,10(E)-undecadiene-2,5-dione (1Q8) . . . . . . 141 Intramolecular Diels-Alder cyclization of 1Q3 to hydrindenones 110a and llOb. . . . . . . . . .143 Epimerization of trans- fused hydrindenone 110a to cis- -fused lllb. . . . . . . . . . . . . . . . 144 Intramolecular Diels-Alder cyclization of 1Q6 to hydrindenones 111a and lllb. . . . . . . . . .144 vi Intramolecular Diels-Alder cyclization of 105 to hydrindenones 112a and 112b. . . . . . Intramolecular Diels-Alder cyclization of 109 to hydrindenones 113a and 113b. . . . . . Condensation of 1g3 with acetone to give linear nonamer 127. . . . . . . . . . . . Formylation of linear nonamer 127 to dialdehyde 128. . . . . . . . .~. . . . . . . Di-ring-opened trans-enedione 129. . . . . . Dibromo-trans-enedione 130. . . . . . . . Saturated tetraketone 131. . . . . . . . . . Tetra-ring-opened octaketone 132. . . . . . Hexa-ring-opened dodecaketone 133. . . . . . Saturated octaketone 134. . . .~. . . . . . . Saturated dodecaketone 135. . . . . . . . . . Tri-ring-opened hexaketone 136. . . . . . . . Saturated hexaketone 137. . . . . . . . . . Di-ring-opened cis-enediones 138 and 139. Di-ring-opened trans-enediones~129 and~141. Saturated tetraketone 140. . . . . . . . . . 2,2-bis[5-(3-Oxopropyl)-2-fury1]propane (112). 2,2-bis[5-(3-Hydroxypropy1)-2-fury1]propane (143). . . . . . . . . . . . . . . . . . . . 2,2-bis[5-(3-Bromopropy1)-2-fury1]propane (144). . . . . . . . . . . . . . . . . . . 2,2-bis{5-[3-(2-Furyl)propy1]-2-fury1} propane (145). . . . . . . . . . . . . . . 1,1,15,15-Tetramethy1-[1. 3.1.3](2,5)furano- phane (146). . . . . . . . . . . . . . . Tetra- -ring— opened cis-enedione 147. APPENDIX. 0 O O O O O O O O O O O O 0 LIST OF REFERENCES. . . . . . . . . . . . . vii PAGE .145 .146 .149 .150 151 .152 153 .154 155 .155 .156 .157 .158 .158 .160 161 161 162 163 .164 165 .166 . 167 227 TABLE LIST OF TABLES Results from the oxidation of 2,5- dialkylfurans using MCPBA. . . . . . . . Oxidation of furans by MCPBA in methanol. High field 1 13 H NMR assignments for 91. C NMR chemical shifts of hydrindenones 110a, 110b, 111a, and lllb. . . . . . . Chemical shifts of the Cl carbonyl carbon in the cis- and trans-fused hydrindenone pairs llOa,b-llBa,b. . . . . . . . . . . . Electronic absorption spectra for cis- and trans-enediones. . . . . . . . . . . . . . viii PAGE 17 .32 .48 .69 74 . 97 FIGURE 1 10 LIST OF FIGURES Oxidation of diol 99 with MCPBA; 250 MHz 1H NMR spectrum after 15 minutes. . . . . . . Oxidation of diol 90 with MCPBA; 250 MHz 1H NMR spectrum after 2 hours. . . . . . . . Oxidation of diol 90 with MCPBA; 250 MHz 1H NMR spectrum after 12 hours. . . . . . . . Expanded regions in the 250 MHz 1H NMR spectrum of 91. Methyl and enone resonances have been omitted. See Table 3 for accompanying chemical shifts and coupling constantS. . . . . . . . . . . . . . . . . . Ziegler's tirandamycin model. . . . . . . . . DeShong's tirandamycin model. . . . . . . . . Studies by White and Sheldon on the IMDA reactions of sorbyl mesaconates and citraconates. . . . . . . . . . . . . . . . . Chemical shifts, coupling constants, and conformations of hydrindenones 110a and llOb. . . . . . . . . . . . . . . . . . . . Epimerization of 110a. Chemical shifts, coupling constants, and conformations of hydrindenone lllb. . . . . . . . . . . . . . Epimerizations of trans-fused bicyclo- [4.3.0] systems to cis-fused isomers. . . . . ix PAGE 42 44 .47 49 49 6O 62 .64 66 FIGURE 11 12 13 14 15 16 17 18 19 20 21 22 PAGE Chemical shift and coupling constant data for hydrindenone 111a. . . . . . . . . . . . .67 Comparison of selected spectral properties of hydrindenones 112a and 112b with related compounds. . . . . . . . . . . . . . .71 Chemical shifts, coupling constants, and conformations for hydrindenones 113a and 113b. O O O O O O O O O O O O O O O O O O 0 O 73 Observations on the cyclization of cis- and trans-decatrienoates. . . . . . . . . . . 75 IMDA reactions of internally activated trienes which gave predominantly cis- hydrindenes. . . . . . . . . . . . . . . . . .76 Exo and endo transition states for the IMDA reactions of 1,6,8-nonatrienes. . . . . .76 Exo and endo transition states for trienes 103 and 106. O O O C O O O C O I O O O O O O .79 Non-synchronous exo and endo transition states for triene 105. . . . . . . . . . . . .81 Exo and endo transition states for triene 109. . . . . . . . . . . . . . . . . . 83 ORTEP representation of di-ring-opened trans-enedione 129 with the acetic acid dimers omitted for clarity. . . . . . . . . . 91 "Top View" of di-ring-opened trans- enedione 129 showing the orientation of the acetic acid dimers. . . . . . . . . . . . 93 ORTEP representation of tetra-ring- opened octaketone 132. . . . . . . . . . . . .96 FIGURE A1 A2 A3 A4 A5 A6 A7 A8 A9 A10 A11 A12 A13 A14 A15 PAGE 60 MHz 1H NMR spectrum of cis-B-hexene- 2,5-dione (37). . . . . . . . . . . . . . . .167 60 MHz 1H NMR spectrum of cis-4-oxo-2- Pentenal (45). . . . . . . . . . . . . . . . 167 250 MHz 1H NMR spectrum of cis-3- octene-2,5-dione (39a). . . . . . . . . . . .168 1 250 MHz H NMR spectrum of cis-enedione- diester 41a. . . . . . . . . . . . . . . . . 169 250 MHz 1H NMR spectrum of bis-spiro- ketal 43. . . . . . . . . . . . . . . . . . .170 250 MHz 1H NMR spectrum of tetracyclic dione 20. . . . . . . . . . . . . . . . . . .171 250 MHz 1H NMR spectrum of trans-3- octene-2,5-dione (39b). . . . . . . . . . . .172 250 MHz 1H NMR spectrum of trans-enedione- diester 41b. . . . . . . . . . . . . . . . . 173 250 MHz 1H NMR spectrum of cis-4-oxo-2- octenal (48). . . . . . . . . . . . . . . . .174 250 MHz 1H NMR spectrum of S-n-butyl-Z- (3H)furanone (49). . . . . . . . . . . . . 175 60 MHz 1H NMR spectrum of S-n-butyl— 2(3H)furanone (49). . . . . . . . . . . . .176 60 MHz 1H NMR spectrum of enol lactone 59. . 176 250 MHz 1H NMR spectrum of (Z)-3-methy1— 3-hexene-2,5-dione (63a). . . . . . . . . . .177 250 MHz 1H NMR spectrum of (Z)-4- acetoxy-3-methyl-3-butene-2-one (64a). . . . 178 60 MHz 1H NMR spectrum of 2-methy1—2,5- dimethoxy-2,5-dihydrofuran (46). . . . . . ..l79 xi FIGURE A16 A17 A18 A19 A20 A21 A22 A23 A24 A25 A26 A27 A28 A29 PAGE 60 MHz 1H NMR spectrum of spiroketal 72. . . 179 60 MHz 1H NMR spectrum of 2,5-dimethyl- 2,5-dimethoxy-2,5-dihydrofuran (74). . . . . 180 60 MHz 1H NMR spectrum of 2,4-dimethy1- 2,5-dimethoxy-2,5-dihydrofuran (75). . . . . 180 60 MHz 1H NMR spectrum of 2,3,5-trimethy1- 2,5-dimethoxy-2,S-dihydrofuran (76). . . . . 181 60 MHz 1H NMR spectrum of 2,3,4,5- tetramethy1-2,S-dimethoxy-Z,S-dihydro- furan (78). . . . . . . . . . . . . . . . . .181 60 MHz 1H NMR spectrum of 2,5-dimethoxy- 2,5—dihydromenthofuran (77). . . . . . . . . 182 60 MHz 1H NMR spectrum of 3,5-dimethyl- furan-Z-carboxaldehyde (88). . . . . . . . . 182 60 MHz 1H NMR spectrum of ethyl 3-(3,5- dimethyl-Z-furyl)—3-hydroxypropanoate (89). .183 60 MHz 1H NMR spectrum of 1,7-dimethy1- 2,9-dioxabicyclo[3.3.1]non-7-ene-6-one (91). C O O O O O O I O O O I C C C O O O O .183 250 MHz 1H NMR spectrum of 2-(1,3- dihydroxypropyl)-3,5-dimethy1furan (90). . . 184 250 MHz 1H NMR spectrum of 3,3-bis(3,5- dimethyl-Z-furyl)-1-propanol (92). . . . . . 185 250 MHz 1H NMR spectrum of 1,7—dimethy1- 2,9-dioxabicyclo[3.3.1]non-7-en-6-one (91). .186 60 MHz 1H NMR spectrum of 3-(5-methyl- 2-fury1)propana1 (95a). . . . . . . . . . . .187 60 MHz 1H NMR spectrum of 3-(3,5-dimethy1- 2—furyl)propana1 (95b). . . . . . . . . . . .187 xii FIGURE PAGE A30 60 MHz 1H NMR spectrum of ethyl 5—(5- methyl-Z-furyl)-2-pentenoate (96a). . . . . .188 1 A31 60 MHz H NMR spectrum of ethyl 5-(3,5- dimethyl-Z-furyl)-2-pentenoate (96b). . . . .188 A32 60 MHz 1 (5-hydroxy-3-penteny1)furan (97a). . . . . . 189 l H NMR spectrum of S-methyl-Z— A33 60 MHz H NMR sepctrum of 3,5-dimethyl-2- (5-hydroxy-3-pentenyl)furan (97b). . . . . . 189 A34 250 MHz 1H NMR spectrum of 5-(5-methy1- 2-fury1)-2(E)-pentena1 (98a). . . . . . . . .190 A35 250 MHz 1H NMR spectrum of 5-(3,5- dimethyl-Z-fury1)-2(E)-pentenal (98b). . . . 191 A36 250 MHz 1H NMR spectrum of 2-(3(E),5- hexadienyl)-5-methylfuran (99a). . . . . . . 192 A37 250 MHz 1H NMR spectrum of 3,5-dimethy1-2- (3(E),5-hexadieny1)furan (99b). . . . . . . .193 A38 250 MHz 1H NMR spectrum of 3(Z),8(E),10- undecatriene-2,5-dione (103). . . . . . . . .194 A39 250 MHz 1H NMR spectrum of 4-methy1-3(Z),- 8(E),10-undecatriene-2,5-dione (105). . . . .195 A40 250 MHz 1H NMR spectrum of 3(E),8(E),10- undecatriene-2,5-dione (106). . . . . . . . .196 A41 250 MHz 1H NMR spectrum of 4-methyl-3(E),- 8(E),10-undecatriene-2,S-dione (109). . . . .197 A42 Expansion in the 250 MHz 1H NMR spectrum of 109. . . . . . . . . . . . . . . . . . . .198 A43 250 MHz 1H NMR spectrum of 2,4-dimethy1-4- hydroxy-S-(2,4-pentadieny1)—2-cyclopente- none (107). . . . . . . . . . . . . . . . . .199 xiii FIGURE PAGE A44 250 MHz 1H NMR spectrum of 4-methy1idene- 8(E),10-undecadiene-2,S-dione (108) as a mixture with triene 105. . . . . . . . . . . 200 A45 Expansion in the 250 MHz 1H NMR spectrum of 108. . . . . . . . . . . . . . . . . . . .201 A46 250 MHz 1H NMR spectrum of cis-fused hydrindenone 110b. . . . . . . . . . . . . . 202 A47 250 MHz 1H NMR spectrum of llOb plus Eu(fod)3. . . . . . . . . . . . . . . . . . .203 A48 250 MHz 1 hydrindenone 110a and epimer, cis-fused hydrindenone 111b. . . . . . . . . . . . . . 204 1 H NMR spectrum of trans-fused A49 250 MHz cis—fused hydrindenones 111a and lllb. . . . 205 A50 Expansion in the 250 MHz 1H NMR spectrum of hydrindenones 111a and lllb. . . . . . . .206 1 H NMR spectrum of trans- and A51 250 MHz cis-fused hydrindenones 112a and 112b. . . . 207 A52 Expansion in the 250 MHz 1H NMR spectrum of hydrindenones 112a and 112b. . . . . . . .208 A53 250 MHz 1H NMR spectrum of trans-fused hydrindenone 113a (contains a minor H NMR spectrum of trans- and amount of cis-fused 113b). . . . . . . . . . 209 A54 Expansion in the 250 MHz 1H NMR spectrum of hydrindenone 113a. . . . . . . . . . . . .210 A55 250 MHz 1H NMR spectrum of trans- and cis- fused hydrindenones 113a and 113b. . . . . . 211 A56 Expansion in the 250 MHz 1H NMR spectrum of hydrindenones 113a and 113b. . . . . . . .212 xiv FIGURE A57 A58 A59 A60 A61 A62 A63 A64 A65 A66 A67 A68 A69 A70 A71 60 MHz 1H NMR spectrum of linear furan- acetone nonamer 127. . . . . . . . . . 1 250 MHz H NMR spectrum of linear furan- acetone nonamer dialdehyde 128. . . . . 60 MHz 1 trans-enedione 129. . . . . . . . . . . 60 MHz 1H NMR spectrum of saturated tetraketone 131. . . . . . . . . . . . . 1 H NMR spectrum of di-ring-opened 60 MHz opened octaketone 132. . . . . . . . . . 1 H NMR spectrum of tetra-ring— 60 MHz octaketone 134. . . . . . . . . . . . . 60 MHz 1H NMR spectrum of hexa—ring- H NMR Spectrum of saturated opened dodecaketone 133. . . . . . . . 60 MHz 1H NMR spectrum of saturated dodecaketone 135. . . . . . . . . . . . 60 MHz 1 opened hexaketone 136, 60 MHz 1H NMR spectrum of tri-ring- H NMR spectrum of tri-ring- opened hexaketone 136 plus Eu(fod)3. 60 MHz 1 hexaketone 137. 1 H NMR spectrum of saturated 60 MHz opened cis-enedione 138. . . . . . . . . 60 MHz 1H NMR spectrum of di-ring- H NMR spectrum of di-ring- opened cis-enedione 139. 60 MHz1 opened trans—enedione 141. . l H NMR spectrum of di-ring- 60 MHz tetraketone 140. . . . . . . . . . . . . H NMR spectrum of saturated XV PAGE 213 .214 .215 215 216 .216 217 .217 218 218 .219 , 219 220 . 220 221 FIGURE PAGE 1 A72 60 MHz H NMR spectrum of dibromo-trans- enedione 130. . . . . . . . . . . . . . . . .221 A73 60 MHz 1H NMR spectrum of 2,2-bis[5-(3- oxopropyl)-2-fury1]propane (142). . . . . . .222 A74 60 MHz 1H NMR spectrum of 2,2-bis[5-(3- hydroxypropyl)-2-fury1]propane (143). . . . .222 1 A75 60 MHz H NMR spectrum of 2,2-bis[5-(3- bromopropyl)-2-fury1]propane (144). . . . . .223 A76 60 MHz 1H NMR spectrum of 2,2—bis{5-[3— (2-fury1)propy1]-2-furyl}propane (145). . . .223 A77 250 MHz 1H NMR spectrum of 2,5-bis{5-[3- (2-fury1)propy1]-2-fury1}propane (145). . . .224 A78 250 MHz 1H NMR spectrum of 1,1,15,15- tetramethyl-[1.3.1.3](2,5)-furanophane (146). . . . . . . . . . . . . . . . . . . . 225 A79 250 MHz 1 opened cis-enedione (147). . . . . . . . . . 226 H NMR spectrum of tetra-ring- xvi INTRODUCTION The use of furan compounds in organic synthesis has been extensive. - Owing to the enol-like structure of furan, an important aspect of its chemistry has been concerned with transformations to 1,4-dicarbony1 compounds. As shown in Scheme 1, both hydrolytic and oxidative pathways are conceptually available, from which saturated and unsaturated 1,4-dicarbony1 products, respectively, may be obtained. Direct hydrolysis of the furan ring has Scheme 1 0' H 0” met with varied success because of the limited stability of the product to the reaction conditions. In many cases, however, this method has been successfully applied. For example, the first two equations in Scheme 2 illustrate the use of furans as masked 1,4-diketones in annulation sequences.3b’4'5 The third equation is an interesting example of a "glycolytic" method which produces the 1,4-diketone in protected form as a bis-ketal.6 Scheme 2 cat. H280“ O - o HOAc-HZO CHZR OH / 1.. ————-——-4> C“: Q ‘CHzR (50$) 0 Chg CH3 cone. HCl CH CH cone. H01 3 r.t. CH30H. rfx ;D’ (100%) HOCHZCHZOH I ) TsOH (3HJ Br ’ CH3 Br 0.. 7 90% O O \__l Perhaps the most widely employed method for the oxidation of furans is that of Clauson-Kaas,1'7 in which the furan is treated with bromine in a buffered methanolic solution. The product 2,5-dimethoxy-2,5— dihydrofuran 1 (see Scheme 3) is thought to arise from 1,4 addition of bromine to the furan nucleus, followed by methanolysis. This transformation can also be accomplished electrochemically, and reviews of these two Scheme 3 Br — / \ 2 R R . R O ’ {k 4 RQR Br Br Br NHuBr CHBOH CHBOH, a- -HBr — CHBOH R R 'HBI' R — R #2): .1 [ {03:} CH, OCH, Br CH, 1 methods have appeared.l’8 The oxidation products 1 serve as a convenient source of cis- and trans-enediones, depending on the conditions of hydrolysis (see Scheme 4).9 Scheme 4 H0140 fl ’ CH, CH, / H20 0 0 “3,53?” Me 0 Chile \ cone. HCl 0 I. CH3)K//\(CH3 0* cis-Enediones have been employed in hydroxycyclopentenone annulation sequences10 as illustrated by the transformation of furan 2 to the useful intermediate for prostaglandin synthesis, 3 10a Achmatowicz and associates have developed a very convenient entry to pyranose carbohydrates and higher-carbon sugars using a furan oxidation/hydrolysis R R .r’ ,r C) I? / \ 1) Brz. CHBOH _ Na2C03 / 1D ~4> CH' 2) Amberlite H 0 0 CH3 HO 2 resin (H+) 3 R = 40112500231; sequence.11 The 2,5-dia1koxy-2,5-dihydrofurans derived from furfuryl alcohols give upon mild acid hydrolysis pyranone hemiacetals 4,11a which have been elaborated in a stereocontrolled manner to numerous sugar derivatives (see Scheme 5). Oxidation of furfuryl alcohols to y-pyrones Scheme 5 + R / \ Brz .... H H30 0 I! ‘rib l2----i>(3 _____ (”4 01130}! MeO OH OMe 2 pyranose carbohydrates has also been reported.12 Thus, an efficient, one-pot synthesis of maltol 6 was realized by the oxidation of 5 using two equivalents of aqueous chlorine (see Scheme 6).12C The first oxidation occurs on the furan ring to give, after in situ hydrolysis, pyranone hemiacetal 5a. Consumption of the remaining equivalent of hypohalous acid and dehydration gives chloro-enone 5b, from which maltol is obtained upon heating. Scheme 6 CH, H001 H CH 3011-1120 1“ _6_ (70%) Another method for the oxidation of furans which has received considerable attention uses singlet oxygen. Thus, 13 or chemically14 generated singlet oxygen photochemically adds to furans in a [4+2] cycloaddition process to give endoperoxides (9.9. 1, Scheme 7), the thermal and chemical transformations of which have provided a number of interest- ing products. For example, the endoperoxide derived from 2,5-dimethy1furan undergoes nucleOphilic ring opening in methanol solution to hydroperoxide 8, and deoxygenation by triphenylphosphine to give trans-3-hexene-2,5-dione 5 (see Scheme 7).1 The endoperoxides of unsymmetrically substituted alkylfurans undergo regiospecific ring Opening in alcoholic media as exemplified by hydroperoxide 9, which is derived from the endoperoxide of 2-methy1furan.15a Treatment of hydroperoxides which possess an a-hydrogen with base or lead tetraacetate gives y-alkoxybutenolides such as 10.16 Replacement of the hydroperoxy group to 6 Scheme 7 02 CH, 0313011 _ /\ __.. 34,, H, CH3 CH3 / O o2 CHBOH mfg-3 b[flblo]—-——O cH, (DH CH3 0 CH 9 Pb(0Ac)u cat. V205 or OH- CHBOH o 3 CH: CH #00" 10 a} give Clauson-Kaas-type products (9.9., 11) occurs readily in methanol solution containing catalytic quantities of 17 vanadium pentoxide. The former transformation has found application in the conversion of certain furanoeremophilanes to the corresponding butenolides (e.g., 13-+13).18 In certain cases, depending on the nature of the the substitutents on the furan ring, the endoperoxides undergo a Baeyer-Villiger-like rearrangement in non- nucleophilic solvents to give y-oxo-a,8-unsaturated H,C CH H CH, 1 CH, H0 0 . CH on 3 , \ 2 3 | 9 OH O OCH, 1.351 1.2 H,C OAC CH, ACO CH / O 1.3 0 .4020 OCH, Pyridine esters (e.g., 14 and 16, Scheme 8).19 Butenolides 15 and 17 Scheme 8 1 _ / \ °2 ~10'c _ CH,OMe———>- o .1 WOW —.H ,, OCH,OMe c14013 61.0 0 o 14 -6o'c CHJOH. rfx CH 9&0 15 ~ CHA' 102 n ”3°“ CH — a o SnMe; ——>CH, o o OSiMe,——-> O C) CClu H o'c L6 1.7 10 ___ 2 @910 4 Etogo EtOH {9 were formed upon exposure of the primary photoproducts to methanol. Analogous y-alkoxybutenolides, e.g., 18, can be obtained directly from the photosensitized oxygenation of several furan derivatives in alcoholic solvents.20 The reaction of furanocyclophane 19 with singlet oxygen was found to be solvent dependent (see 21a,b Scheme 9). In methanol, polycyclic dione 29 was obtained (presumably via the intramolecular Diels-Alder Scheme 9 pathway shown), whereas in methylene chloride, the bis-endoperoxide 19a rearranged thermally to give the novel tetra-epoxide 21. Analogous to this latter rearrangement, the endoperoxides derived from furans 23a and 23b undergo R co,cn, 1 R CK’CFI 02 CHO CH’ 3°°° 2 3 I \ sh 3 2 / $ CH, CH, 0 CH3 CH3 R CH, figmb 2.3a,b a. R!B H b, R8 COZCH3 valence isomerization to the bis-epoxides 23a,b in high yield.22 Recently, the use of chromium(VI) reagents for furan oxidations has been investigated. Thus, as shown in Scheme 10,pyridinium chlorochromate (PCC) oxidizes 23a 2,5—dia1kylfurans to trans-enediones 22, 5-methyl—2— furyl-carbinols to pyranone hemiacetals 23,23b and S-bromo- 23c 2—furyl—carbinols to hydroxybutenolides 24. These Scheme 10 0' CH3 0 R —> CH3 / R /\ PCC CH, R 4 10H a} PCC _ H BHJZ;E)\r,R 4’ ofiz;;)(jifli OH a; OH reactions are thought to proceed via 1,4-addition of theactive Cr(VI) species to give a cyclic chromate ester such as 25. Heterolytic reorganization then affords a cis-enedicarbonyl compound which is subject to intramolecu- lar capture in the case of 2} and 24, or isomerization in the case of 22. It is interesting to note that using 10 PCC -————. ._. IV’JQ:;EL‘11 " '!\\r<:EEEE:>1’¢J‘._____..'r‘—<“.Ri O\ /o 00 \\Cr// 611’! \‘cn 25 PCC supported on alumina, furfuryl alcohol was oxidized to furfural in high yield.24 It is not known whether this difference in oxidation selectivity is a result of the modified reagent, or if there is a particular requirement within the substrate, e.g., alkyl substitution, which facilitates ring cleavage. Oxidation of furans with osmium tetroxide has recently been investigated using a catalytic procedure in which potassium chlorate is used to regenerate the oxidant. 2-5-Dimethylfuran was oxidized to the mesa form of 25 3,4-dihydroxyhexane-2,5-dione 26, in accordance with 26 earlier findings by Clauson-Kaas. The structure of I \ cat . 0304 0 9H CH: CH) 4 CH3 2 equiv. K0103 H20 (70%) CH, osmium tetroxide-furan adducts in pyridine solution have recently been elucidated by proton NMR.27 These findings indicate that furan, 2-methylfuran, and 2,5-dimethylfuran form cyclic osmate esters 23, the result of 1,4-addition. ll 0304 pyridine R _ R A » 7<3>r R. (J I! R= H. CH3 0\ /0 //°s\\ O C) 27 In pyridine, 2:1 osmium-furan adducts were not observed for these substrates. Thus, from these and other28 obServations, it is likely that the formation of mesa-26 is the result of sequential oxidations by osmium tetroxide in which the second equivalent acts upon the double bond of dihydrofuran 26a (see Scheme 11). Scheme 11 l \ 080“ C“ H, KClOa — CH, CH, —.. o __, Cflflm 9°» H (M4 x0103 CH, o /, CH, f CH, CH. O '0304 Ho OH 26 ~ Until recently, the reactions of furans with peroxy- acids had not been extensively investigated. Clauson-Kaas 12 examined the oxidation of furan with peracetic and perbenzoic acids29 and isolated the bis-phenylhydrazone of malealdehyde in yields never exceeding 20%. Other products from these reactions were not reported. In a series of papers, Lutz and co-workers studied oxidations of tetraarylfurans and noted unusual "cis effects" in cis-diaroylstilbenes. Tetraphenylfuran, for example, was reported to give cis-enedione 28 upon oxidation with . Ph Ph Ph Ph 30033 RCO Ph — 3" Ph \ Ph / \ 4;» ‘""$ Ph ——————9» Ph 0 Ph R: CH O O 0 Ph 3 Y or P11 2‘8 i9 0 peracetic or perbenzoic acid (among other oxidizing agents).3 Further oxidation of ci3-28 (but not trans-28) gave enol benzoate 29. More recently, a Canadian research group at Ayerest has been interested in synthesizing new cardiotonic agents related to the cardenolide family of steroids (e.g., digitoxigenin 39, R=H) in which the DI BAL 0 13 31 C17 butenolide moiety has been modified. Their approach involved oxidation reactions of furyl steroid 30a. Oxida- 31b with tion of a model compound, 3-isopropylfuran, peracetic acid gave hydroxybutenolide 31, whereas oxidation with aqueous N-bromosuccinimide (NBS) gave a different butenolide, 32. Analogous results were obtained with steroid 39a, although the peracid procedure gave a poor NBS dioxane-HZO 1;.» ~ / (60%) O EXCESS ,, (50%) 0 o 0” yield (16%). A mechanistic interpretation was not given for the peracid oxidation; however, comment was made on a the NBS oxidation (see Scheme 12).31 Attack Of electro- philic bromine at the less hindered C5 d-position (and Scheme 12 R R R H —¢3 -HBr r 1. ——. 4:1 ——~ m... OBr OH Br OH H9 2.2a 33" l4 electronically less nucleophilic32) produces bromohydrin 33a, which loses HBr to give enol 33b. Protonation at the C5 a—position produces the observed butenolide. A plausible mechanism for the peracetic acid oxidation is given in Scheme 13. As will become apparent from the Scheme 13 R R R 01130031! A H20 CH3003H ~H+ R R -CHBCOZH J!” _ 0 0H ‘———- “4,245, OH results in the first section of this thesis, the initial products from the peracid oxidation of furans are cis- enediones. Thus, it is likely that malealdehyde derivative zla is an unstable intermediate which, under the aqueous acidic reaction conditions, can exist as hydrate llb. Solvolysis at the less hindered and more electrOphilic C5 a-position using a second equivalent of peracid gives peroxyester 31c which can eliminate acetic acid as shown to provide the hydroxybutenolide product. The mechanism 15 of the second oxidation in this sequence finds analogy with a known procedure in which aldehyde acetals are oxidized to esters (e.g., 3§-*3§).33 The Ayerest group CH3C03H cut/V cu(0|3u)2 » cry/V60,“ (73%) 33 34 ~ ~ has also investigated the oxidation of furfuryl alcohols with m-chloroperoxybenzoic acid (MCPBA) and obtained 34 pyranone hemiacetals 35 in good yield, certain derivatives of which were found to possess significant antimicrobial activity.34b In these reactions, the intermediate 0 R. R. MC PBA _ R . R; R‘ -———————a»l4 ” Ra <9 . O 0 Fl H O OH 2.5 15a cis-enedione 3§a undergoes rapid cyclization to give exclusively hemiacetal products. In this thesis, the oxidation of alkylfurans with MCPBA is examined. In the first section, the scope of the reaction is explored using simple furan substrates and various reaction conditions. The subsequent sections deal with specific applications of furan oxidations which demonstrate the utility of this method in organic synthesis. 16 A. OXIDATION OF SIMPLE FURANS: GENERAL CONSIDERATIONS Although a number of methods have been developed for the oxidation of furan compounds, a direct, high yield route to geometrically pure cis-enediones from 2,5-dialkyl- furans has not been reported.35 The most commonly employed method for this transformation is a two-step procedure in which the furan is first oxidized to the 2,5-dialkoxy- 2,5—dihydrofuran derivative and then hydrolyzed under mildly 9,10,36 acidic conditions (see Scheme 14). We have found that this transformation can be accomplished directly using m-chloroperoxybenzoic acid (hereafter abbreviated as MCPBA). Scheme 14 Br2.Cl-130H$ “07(1):“ 0 "_‘ CH, CH, U+ The reaction is simple, rapid, and provides exclusively cis-enediones in high yield. Examples are given in Table 1. In the first three entries, the cis-enedione double bond geometry was assigned on the basis of the upfield chemical shift of the olefinic protons (ca. 6.1-6.3 ppm). For 17 Table 1. Results from the oxidation of 2,5-dia1kylfurans using MCPBA. substrate product yield / \ fl 99% cuch. °"’ o A’ °"’ 2Q 2? H“ CH — 96% c 3 0 CH3 3 o 0/ CH3 3.53 3.9a / \ '— IEtO,C:((:l-l2 o CH2)‘CO,Et EtO,C(CHz‘ / "95023 97% 39 12a HWQ/VH @039 87% 43 {t3 88% instance, the olefinic proton resonances of cis-B-hexene-2,5- dione (33) and its trans isomer fall at 6.18 and 6.72 ppm, respectively.9b Conclusive evidence for the cis configuration in 39a and {la was obtained by preparation of their respective trans isomers. Thus, isomerization of 39a in pyridine (presumably via an addition-elimination mechanism in which the more thermodynamically stable trans 18 isomer dominates the equilibrium) gave 39b in nearly quantitative yield. Diester 40 was oxidized using pyridinium chlorochromate23a to the trans-enedione 41b in 60% yield. 6. 3 ppm H 3 6.67 PPm m 0 H pyridine / CH: O 0 CH3 4 CH’MOKVCH: 2,921 19b 0) PCC 9.0 * EtOzC((:H,))\//\((c”2).,602Et CHZCI2 4 O in: Facile intramolecular ketalization occurs upon MCPBA oxidation of diol 13, giving bis-spiroketal {3 as a 1:1 mixture of diasteriomers.37 No open chain products were observed. Furanocyclophane I? was smoothly oxidized by one equivalent of MCPBA to give the intramolecular Diels-Alder adduct 19, identical in all respects with the physical properties reported by Wasserman21a and Katz21b (mp, 1H and 13C NMR, IR) for the product obtained upon photosensitized oxygenation of 19 in methanol (cf. Scheme 9). Attempts at preparation of the unsaturated tetraketone {3 from 19 using two equivalents of peracid failed, and gave instead low yields of an uncharacterized mixture. The mechanism of the MCPBA oxidation is thought to occur via initial attack of the electrophilic peracid 19 2 equiv. MCPBA oxygen at an a-position on the furan ring as shown in Scheme 15. The precise electronic events which follow are not clear; possibilities are as follows. The Scheme 15 R :22: R . (0 ° a) r Y H (J (a) 8. (b) ,__ 65 0" >049 ° ° Ar \H AI’COZ ‘H ' §o .......... (e) I; l1./”-‘$ l? \9/5 Al'COzH developing positive charge in the furan ring might be stabilized by the incipient carboxylate anion to the extent that 1,4-addition is achieved (path a). Alterna- tively, covalent attachment of the carboxylate may never occur, resulting in the formation of an ion pair (path b). 20 The peracid might function as in the oxidation of alkenes to give a furan epoxide (path c). While the studies performed here do not conclusively distinguish between these alternatives, it is clear that all of the intermedi- ates in Scheme 15 can produce the observed cis—enedione product by the appropriate reorganization of electrons. Oxidation of 2-substituted furans with MCPBA gave the anticipated cis-Y-oxo-a,B-unsaturated enals {6 and {g (see Scheme 16), albeit in rather low yields. The cis olefin geometry was established by comparison of the proton NMR spectral data with literature values.9b’36 Scheme 16 MC PBA CH Cl 2 2 CHflHO (40%) “3 $0 / is / GHQ 1) MCPBA m101 - \ 2 2 4 CH: (78%) CH, 2) CH CH CH 3 9.6 MCPBA CH 22Cl / 2+ CHM—\CHO (38%) / Cva/~\v/z;:§ \1) MCPBA CH 2201 117,04“ (7% o C) 2) CF 3CO ‘21-!$ ~9 21 Loss of product in these reactions had evidently occurred during the aqueous bicarbonate workup as concluded from the following observations. cis-Enal {6 could be "trapped" upon methanolic quench to give the ketalized derivative 46 in 78% isolated yield. The crude reaction mixture from the oxidation of 2-n-butylfuran ({2) with MCPBA in chloroform-d1 solution was examined by 250 MHz 1H NMR and revealed the presence of cis-enal {B and m-chlorobenzoic acid as the only products. Upon standing at room tempera- ture for 24 hours, however, a second product began to appear at the expense of QB. This new product exhibited narrow multiplets at 5.11 and 3.18 ppm, in addition to butyl group resonances at higher field, data consistent with 2(3H)—furanone {9. Lactone formation is thought to occur via the protonated species {Ba (see Scheme 17), which Scheme 17 + -H —— () 993%”; /\ R (”4 R C) 13H — 433a \H (b) 1:8 R= n-Bu \Rfiékbr' 2 can either lose a ring proton and tautomerize (path a), or undergo a 1,2-hydride shift with concomitant loss of 22 the OH proton (path b). The rate of butenolide formation was greatly enhanced by the addition of a catalytic amount of trifluoroacetic acid to the crude reaction mixture. Thus, in a one-pot procedure, 2—n-butylfuran was oxidized to B,Y-unsaturated butenolide {9 in 74% yield after flash column chromatography. Lactonic products have been observed previously from the hydrolysis of 2,S-dialkoxy—Z,S-dihydrofurans 9b,36,38 For which are unsubstituted at one a-position. instance, Hirsch and Eastman38 were unable to isolate enedione products from the hydrolysis of 50, the Clauson- Kaas oxidation product of menthofuran. Instead there was CH3 CH3 H CH3 ” *bo ” ' CH3 9 O 'I" O CH: O (34%) CH. ° CH. OCH, H 50 ,. 51a (1:3) 53b p obtained a 1:3 mixture of butenolides 31a and 31b, respec- tively, presumably via a mechanism similar to the one given in Scheme 17. Recently, it has been reported that 2-trimethylsilylfurans are oxidized by peracetic acid to B,Y-unsaturated lactones.39 This is thought to occur via rearrangement of an intermediate silylepoxide 52a as shown below. Protiodesilation of the resulting a—trimethylsilyl lactone 33b under the mildly acidic conditions produces the observed product. This method does not seem to offer A . 011300311 / O \ SIMe3 R O SIMe3 4 R O SiMe3—_—" R ‘39 52 52a / SMMH much advantage for the synthesis of butenolides d} where R=alkyl, compared to the more direct method reported here. However, the use of trimethylsilylfurans a? would appear to be useful when acid sensitive side chains are present. These authors also maintained that oxidation of 2—n— hexylfuran with MCPBA or peracetic acid gave intractable mixtures.39 Concurrent with the work in this thesis, the MCPBA oxidation of two more highly substituted furans was reported. Thus, tri- and tetrasubstituted furans §5 and §§ rapidly consumed two equivalents of MCPBA to give 40 di-oxidized products §§ and Q], respectively. The kinetics of these reactions are such that the products of CH, H3 2 equiv. C) 0 MCPBA 5.3} o 2 equiv. / \ . O o MCPBA 0 24 mono-oxidation could not be isolated; use of only one equivalent of MCPBA gave a 50:50 mixture of starting material and di-oxidized product. These findings are in agreement with the results obtained here using similarly substituted substrates. Thus, menthofuran (SS), prepared by the method of Morel and Verkade,41 gave enol lactone S? in high yield. The cis arrangement about the enol double bond in S9 was not rigorously established, CH, ”3 2 equiv. CH3 / .l \ 4 0 HO CH, 0 MCPBA 52 0 29 CH, CH l1 3 C 3 2equiv. CH3 \ CH3 + other 4 products C“: H: MCPBA O YCH’ 60 §} 0 but was inferred on the basis of enol lactone 57, whose structure was established by single-crystal X-ray analy- 40 and from the observations in subsequent oxidation sis, experiments (vide infra). Tetramethylfuran (Q9), on the other hand, was not oxidized cleanly to only one product. Spectroscopic evidence (1H and 13C NMR, IR, MS) suggests that the major product from this reaction is enol acetate d}, although the inability to obtain this material in reasonably pure form precluded definitive characterization. As noted before, use of only one equivalent of MCPBA with 25 S? and Q9 generated mixtures of starting material and di- oxidized products, indicating that the second equivalent of peracid is consumed more rapidly than the first. As shown in Scheme 18, the kinetics of oxidation of 2,3,5-trimethylfuran (62) are such that cis-enedione @3a was obtained in nearly quantitative yield in the reaction with one equivalent of MCPBA. The cis configura- tion of 63a was confirmed by its partial isomerization to Scheme 18 CH H /3\ 3x CH, o MCPBA — CH CH3 CH3 #CH3 0 0/] CH3—-. 3NCH3 C) ég §9a 63b MCPBA 2 equiv. MCPBA CH, CH, O °”= \ H“ A CH O CH, + 3 \\o 0// CH3 * / 6‘”- Her 65 CHv\w,l\‘/x) CH (g§.6:1) \ Y ’ ‘0 C) Ha éflb trans-enedione §§b after standing in CDCl3 solution at room temperature for ca. 2 months. Using two equivalents of MCPBA, Q? was oxidized to enol acetate fifa and a minor amount of epoxyketone SS. The cis arrangement in dfa was demonstrated by acid—catalyzed equilibration, which gave 64a and its trans isomer 64b as a 1:1 mixture. These 26 isomers were distinguished on the basis of the chemical shift of vinyl proton Ha (7.71 and 8.24 ppm, respectively). The di-oxidized product mixture d4a/§§ was also obtained upon oxidation of enedione Sga with one equivalent of MCPBA, thus implicating the intermediacy of enediones in the oxidation of substrates 54, SE, fig, and d9. This conclusion is supported by the observation that oxygen— 1abelled Sf gives enol lactone S] having the label equally distributed between the ketone and lactone carbonyl oxygens.42 The second oxidation which occurs in the higher substituted substrates is thought to occur via a Baeyer— Villiger rearrangement. Also, because of the regiospecifi- city observed in the case of the unsymmetrical substrates SS and Q2, it is clear that peracid addition to the intermediate enedione must be subject to some sort of steric and/or electronic control. In Scheme 19, two possible peracid adducts A and B are shown. It is postulated that addition of the peracid to the intermediate 43 with respect to enedione qga is the rate-limiting step the second oxidation process, and that the energy of the transition state for peracid addition is sensitive to electronic factors as depicted in the charge-separated transition states A* and B*. Thus, path a in Scheme 19 is favored because of the increased electronic stability . . . . . i of the cation (protonated enedione) 1n tran51tion state A relative to the cation in transition state B*. Notice, too, 27 Scheme 19 CH, CHflCHs O 0 -MC BA CH3 CH3 3: C) (A') 63a " (b) MCPBA CH, B CH3 ] [ 3 OH Arco? CW1, (B) GEEQCHJ I 9 OH ArgO O .141an CH3 C H3 W “W” ° 0 §§ (not observed) “:A 1 CH 0/, CH, 3 \\o 65 ~ 28 that the unfavorable eclipsing interaction of the vicinal methyl groups in B* is absent in A*. Peroxyester A can then rearrange with preferential migration of the sp2 carbon to the electron-deficient oxygen, thereby producing enol acetate 64a. Close examination of the 250 MHz 1H NMR spectrum of crude 64a did not reveal the presence 44 which would have of the regioisomeric enol acetate d9, resulted from oxidation path b. The minor product, SS, might result from a Michael addition of the peracid to the intermediate enedione to give peroxyester A' (see Scheme 19). Displacement at the electrophilic oxygen center using the enol n bond would then produce the observed product. That electronic effects dominate in the addition of the peracid to the intermediate enedione may readily be inferred from the oxidation of SS (see Scheme 20). Thus, oxidation products derived from peroxyester B, the adduct which should be preferred on steric grounds, were not observed. Rather, the increased electronic stability associated with transition state A* lowers the energy of this pathway such that enol lactone S? is the only observed product. This mode of addition might be likened to the regiospecific ring opening of unsymmetrical furan endoperoxides by methanol (cf. 12-*12a in the Introduction). 29 Scheme 20 ./ CHO (:Fh () (a) MCPBA CH, (b) MCPBA (B) -MC BA / OCHO .O:CH CH, ’ CH3 (not observed) (3 30 An interesting deviation from this reactivity pattern should be noted in the oxidation of lindestrene (66) to B,Y-unsaturated lactone 67 using perbenzoic acid.45 Evidently, this peracid is not effective at bringing about the facile Baeyer-Villiger oxidation as observed in the MCPBA oxidation of similarly substituted menthofuran (6g). Although these authors had no comment on the oxidation, it is suggested here that lactone 67 is the result of a very facile acid-catalyzed rearrangement of an intermediate enedione as described previously in Scheme 17. 2,4-Dimethylfuran 66 was oxidized using one and two equivalents of MCPBA, and in both cases a rather complex product mixture was obtained in comparatively low isolated yield. From the reaction using two equivalents of peracid, the major products appeared to be enol acetate 69 and enol formate 79 by 1H NMR analysis of the crude mixture. These results indicate that the Baeyer-Villiger oxidation had not occurred with the regiospecificity observed earlier. Separation of this reaction mixture was not attempted, so the structural assignments should be considered tentative. The reaction mixture obtained using one equivalent of 31 10.1 ppm 7.98 ppm CH, CH,‘/v/ “fl 2equiv. : ‘ r/kCHO CH3WCH, 3 0 new chO 0 OCHO 6g (58%) O i9 (a. 2.1) Z9 1 MCPBA proved even more complex as evidenced by H NMR; in addition to a multitude of other products (9.9., the proton—decoupled 13C NMR spectrum of this mixture exhibited in excess of 70 signalsl), varying amounts of the apparently di—oxidized 69 were detected, indicating that a second oxidation must proceed at a comparable rate. In contrast, 2,5-dimethylfuran (16) did not undergo a second, Baeyer- Villiger oxidation in the presence of excess peracid, even when more forcing conditions were used (e.g., heating and/or addition of acid catalysts). These experiments demonstrate the sensitivity of the reaction to differences in furan substitution, a factor which seems to play a major role in determining the mode, regioselectivity, and velocity of oxidation. The oxidation of furans using MCPBA in methanol was also examined. As can be seen from the results in Table 2, all of the substrates tested, with the exception of 1?, underwent smooth oxidation to give 2,5-dimethoxy-2,5- dihydrofuran derivatives. Further oxidation did not occur 32 Table 2. Oxidation of furans by MCPBA in methanol. substrate product yield / 95% CHQ 1+6 “’5 cu, ~ CH I \ 1+ WOO HM ..7 73 CH 92% C 0 fl 3 CH, CH, HOW Z} '73 dime", 82% / \ 6 - CH, CH, 3 Z? CH O H: 97% CH, H, CH, CH, ,6 68 75 c 89% c”: 0 ~ " CHH’ CH, CH, cu, / \ 6 " 90% CH: CH. 63 1 CH 0 H, CH, H, CH3 ”3 | \ 58 Z] I CH, 9% CH, 0 ~ c": o OCH, CH, CH, “‘3 c“: U» 6'9 78 “g-k“: 93% CH3 "8 ~ 0 CH, H, 20 90% O O 33 in the more highly substituted furans as observed previously in methylene chloride. The formation of intramolecular Diels-Alder adduct 89 from furanocyclo- phane I9 is noteworthy, as oxidation using the methanolic bromine method provided the expected methoxylated product 79 in 85% yield.46 These observations suggest that in ~ OH MeO OMe BrZ' CH3 "' ' (85%) ' " MeO OMe the MCPBA-CH OH oxidations, the immediate precursor to 3 the 2,5-dimethoxy-2,5—dihydrofuran product is a cis-enedione. In the case of 19, intramolecular Diels-Alder reaction occurs faster than ketalization. This interpretation is supported by the result that cis-3-hexene-2,5-dione (33) gives 2,5-dimethyl-2,5-dimethoxy-2,5-dihydrofuran (73) in nearly quantitative yield when treated with m-chlorobenzoic acid in methanol. The MCPBA-CH3OH oxidation method seems to be of synthetic importance in view of the poor yields obtained from the oxidation of the more highly substituted furans (e.g., tetramethylfuran, 77) using methanolic . 9a bromine. 34 B. TIRANDAMYCIN MODEL STUDY The occurrence of a 2,9-dioxabicyclo[3.3.1]nonane ring system in the antibiotic tirandamycin (89),47 presents an excellent opportunity to employ furan oxidation methodol- ogy (see Retrosynthetic Scheme 1). Tirandamycin belongs to the 3-acyl tetramic acid family of antibiotics and displays, in addition to antibiotic activity, inhibitory activity against bacterial DNA-directed RNA polymerase.48 This latter activity contrasts sharply with that of the simpler 3-acyl tetramic acids, and it has been suggested that the presence of the 2,9-dioxabicyclo[3.3.1]nonane moiety in 89 might be responsible for the additional activity.49 Recently, tirandamycic acid (81, R=H), a degradation product of tirandamycin, has been synthesized in optically active form by Ireland and co-workers.50 The bicyclic portion of 8} was constructed in a multistep sequence starting from a glycal derived from D-glucose, and the dienoate side chain was subsequently elaborated by consecutive Wittig condensations from enone aldehyde 8? (22:0). Importantly, the Ireland synthesis established that base-catalyzed epoxidation of the bicyclic enone proceeds in a selective fashion to give the desired epoxyketone diasteriomer. The latter stages of the synthetic plan depicted in Retrosynthetic Scheme 1 thus parallel the Ireland approach. 35 Retrosynthetic Scheme 1 (b) CH, :2) /\ 2'“ E“: CH3 GOHCMCHZZ OR 8.5 (a)‘<::j CH, CH, 0 CH0 6kCH0 6kCH0 36 The formal hydrolysis product of 83, however, reveals the presence of an enedione moiety and thus suggests the furan precursor, 83. It is known through the work of 34a lla 23a Lefebvre, Achmatowicz, and Piancatelli that furfuryl alcohols upon oxidation yield pyranone hemiacetals (i.e., cyclization of an intermediate hydroxyenedione occurs spontaneously) and thus it is anticipated that MCPBA oxidation of furan 8} would provide pyranone 83a. Participation of the C3 hydroxyl, then, in an acid (or Lewis acid) catalyzed closure at C1 would produce the bicyclic enone 83. Electronic considerations for the moment notwithstanding, closure at C1 should be facilitated from a conformational standpoint, as the substituents at C3 and C4 would occupy pseudo-equatorial positions in the transition state leading to the desired dioxane ring formation. Other modes of ring closure, i.e., Michael addition at C8 or hemiketal formation at C6' might be competitive, especially when one considers the electronic consequences of carbonium ion formation at C1 relative to C8 and C6 of the enone moiety. In this regard, it should 11a be noted that Achmatowicz and co-workers have been successful in the preparation of methyl glycosides 6a 37 from the corresponding pyranosuloses 85. The above— mentioned problems, however, were encountered to varying degrees when other more standard glycosidation methods were 'employed. Noteworthy to this discussion, too, is the O O O R BFB'OEtZ or R R = CHZOH I 4 I 4 l O O O SnC 14 O H cm OCHB) 3 0M9 é; §§a Q? intramolecular cyclization observed for substrate 85 (R=CH20H) to bicyclic enone 86 (ca. 25% yield) under the indicated reaction conditions. Finally, there exists the possibility that the acidic conditions required for ring closure might induce epimerization at C pyrylium salt 87.51 The oxygenated side chain of furan 8} in Retrosyn— thetic Scheme 1 might be constructed by either of two pathways. The more linear route depicted in path a utilizes a sequential, stereoselective aldol approach, an area in which there has recently been great progress.52 38 The desired stereochemistry in 83 requires that the first condensation between the furyl aldehyde and propanal enolate equivalent proceeds with erythro selectivity,53 and that the second propanal enolate equivalent must add in a Cram's rule sense (chelation controlled) with three 53 selectivity. An added feature of path A is that optically active 8} might be prepared using the recently devised chiral enolate methodology of Evans54 or Masamune.55 Path b, the more convergent approach, necessitates a Cram's rule addition (steric) of an a-metallated furan to (optically active) aldehyde 8}. With an approach to tirandamycin as described above, one which differs significantly from the Ireland strategy in the method for construction of the 2,9-dioxabicyclo- [3.3.1]nonane portion of the molecule, a model system was sought in order to assess the feasibility of a furan oxidation approach. 3,5-Dimethylfuran-Z-carboxaldehyde 88 (see Scheme 21) was already available from previous work, and can be prepared in multigram quantities by Vilsmeier— Haak formylation of 2,4-dimethylfuran. Condensation of the lithium enolate of ethyl acetate, prepared by deprotonation using lithium diisopropylamide, with aldehyde 88 at -78°C provided aldol 89 in excellent yield. Used directly in the next step, crude 89 was reduced by lithium aluminum hydride to diol 89 in nearly quantitative yield. From its NMR spectra, crude 9O 39 Scheme 21 CH: CH, DMF-POCl 3 . /\ CH; CH, CHO (87%) 8? LiCHZCOZEt (96%) CH3 LAH CH, (99%) I \ E I \ CH3 CH3 0 COzEt OH OH OH 9.9 ,9 1) MCPBA, CH2012 0'0. 15 min 2) 0.10 equiv. TsOH, H20 (90%) appeared to be at least 95% pure and gave only one spot on TLC. Additionally, Biol 99, proved to be quite sensitive to acidic conditions and decomposed when subjected to flash column chromatography. The major decomposition product thus obtained was identified as 83 from its spectral properties. A likely mechanism for the formation of 82 is given in Scheme 22. Although well known in pyrrole chemistry for the formation of dipyrrylmethanes,56 40 Scheme 22 8'0 0 12 l \ 29 9.. ——vcn, o 0 10H - HOCHZCHZCHO —H+ it is only recently that this type of self-condensation has been reported using furan compounds.57 It was realized from the outset that the methyl substitution in model compound 89 is incorrect; tiranda- mycin requires a 4,5-dimethyl substitition pattern on the furan ring. However, because of the ease with which certain trisubstituted furans undergo a second, more 40 it was at this stage rapid Baeyer-Villiger oxidation, deemed more important to determine the effect, if any, of trisubstitution per se on the course of the peracid oxidation. Initial attempts at oxidation of 89 (1.1 equiv. MCPBA, CH2C12, 0°C->RT) in which the reaction was worked up after relatively short time periods (1—2 h) were discouraging in that low yields of complex product mixtures were obtained. However, when the reaction progress was monitored by TLC (SiOz, ether), it was found that within 41 10 minutes after addition of the peracid, all of the starting material had been consumed and converted to a single, less polar product. After 1-2 hours, when the reaction mixture had warmed to room temperature, TLC analysis indicated the presence of several less polar intermediates. After stirring at room temperature overnight, virtually all of these intermediates had disappeared, leaving only one UV-active component at high Rf. The reaction progress could also be conveniently monitored by l H NMR, and the spectra of the product mixtures which resulted after reaction times of 15 minutes, 2 hours, and 12 hours are shown in Figures 1, 2, and 3, respectively. The spectrum in Figure 1, during which time there was observed only one spot by TLC, is consistent with the anticipated pyranone hemiketal 83 (see Scheme 23). It is suggested that the occurrence of 83 as only one diasteriomer (inferred from 1H NMR and TLC) is due to an anomeric effect described by Achmatowicz and co-workers in their studies of related pyranosulose systems;11a hence 83 is tentatively formulated here as the a anomer. The spectrum in Figure 2 exhibits a plethora of methyl group resonances at high field, as well as regions of uninterpretable overlapping multiplets in the alkene and alcohol a-CH regions. To account for this complexity, one might assume that pyranone hemiacetal 83 after standing at room temperature in the presence of the 42 .mwuocfle ma umuwm Esuuommm mzz m o w H N m t++brlririr+ Nmz omm “ammo: snug om Hoes mo coHumCon .H museum V m @ —+f>kkt¥¥FtL>bt¥+tFErr j a} j ' VF 'II tribr- :11 q 11“: 11 r L IIPI F In} Ilr 1 I I} Phi)? I}; {I ’i .14 ‘11 4411 1:111“ 1111 43 [r O b .muson m Hmuwm Esuuommm mzz m was omm “dmmuz spas om HOHU mo coaumpflxo .N ousmflm H p N n v m w h FLLFrFLPCPLFHCPPLCHFHPLHPH+LHH+HF‘bLyLrLLbFLLLPPFCFPLCHFFELHLHFFF‘H}HF k 44 .muso: NH uwumw ssuuommm mzz m was omm Nmmmoz spas mw Hoflp mo coflumpflxo .m wusmwm H O p N a v m o i); 933:1 4 1115341 1‘1 45 Scheme 23 CH, / \ O CH, 0 CH, 29 (M4 /’ *f" cry C) O 2?b(10%) 105(87%) 54 The products were readily identified from their 250 MHz 1H NMR spectra. From the isolated yields indicated in Scheme 25, it is clear that a furan-selective oxidation is operative. The yield of the desired triene 100 was 70% based on consumed starting material, and the relative rate of furan vs. diene oxidation for %?a was ca. 9.5:1. Oxidation of 03b under the same reaction conditions (Scheme 25) gave only two products, recovered starting material (10%) and triene 105 (96% yield based on consumed starting material). No products resulting from diene oxidation were isolated. Evidently the additional methyl group in 29b increases the electron density on the furan nucleus such that an even more selective reaction by the electrophilic peracid takes place. To examine the influence of the dienophile double bond geometry on the exo/endo cyclization selectivity of the ensuing IMDA reactions, the trans-enedione isomers of 103 and 105 were sought. The previously mentioned oxidation procedure of Piancatelli was thus applied to %?a (see Scheme 26). Oxidation with PCC (5—6 equiv., CHZClZ, r.t. for 20 h, then reflux for 6 h) gave a multi-component product mixture which was separated by flash column chroma- tography. In this manner, only a moderate yield of the desired trans-enedione 106 was obtained (30% based on consumed starting material). Other products identified from this mixture were the hydrindenones llOb and lllb. ~ 55 Scheme 26 PCC O I C”: / a CH3 / \ | 0 29a 126(27%) CH, 0 o + 9. + + 2.9a(10%) 1$Qb(7%) 111b(6%) __ pyridine a) 106(l+o%) CH3 0 o /l 133 + 110a + 110b + 111b The presence of the latter two products was detected by TLC early in the reaction, concurrent with the formation of trans-enedione 106. This observation, in addition to the much faster rate of cyclization of 103 compared to 106 (vide infra) leads to the conclusion that hydrindenones llOb and lllb are derived from the initially formed cis- enedione 103, which undergoes IMDA cyclization (and epimerization in the case of lllb) competitive with 56 isomerization to trans-106. The experiment in which cis-enedione 59a was cleanly isomerized to trans-enedione %?b by pyridine (see Section A) suggested that 103 might be isomerized in an analogous fashion (see Scheme 26). Treatment of 103 with a large excess of pyridine (CHC13, r.t., 18 h) gave trans-enedione 106 in ca. 40% yield after flash column chromatography. The presence of hydrindenones l§a, 10b, and 19b (2:1:1, respectively), which constituted ca. 40% of the reaction mixture, indicated that this procedure also suffers from competetitve IMDA cyclization. The isomerization of cis-enedione 105 was also investigated; however, neither pyridine nor 4-N,N-dimethyl— aminopyridine (DMAP) were effective in bringing about this transformation (see Scheme 27). On the other hand, the more basic amine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), catalyzed a rapid internal condensation (1.2 equiv. DBU, CHC13, r.t., 3-5 min) to give cyclopentenone 107 in good yield. Satisfactory results could only be obtained using triethylamine. Thus, reaction of 105 with a large excess of triethylamine (CHC13, r.t., 8 h) gave an equilibrium mixture of three compounds, 105, 108, and 109 in a ratio of l:1.8:l.2, respectively. Fortuitously, the desired trans-enedione 109 was easily separated by flash column chromatography from the more polar cis-enedione 105 and deconjugated isomer 108, which eluted as a completely inseparable mixture. The latter mixture, however, could be 57 Scheme 27 CPL _ pyridine ) no reaction CH3 0 O / I or DMAP 1.95 DBU C) CH, 1’ I EtBN CH, 12? OH 0 CH3 I 125 + CH, / \ EtBN 109 O 125 + 128 or 129 + O CH, I CH, \ 198 recycled by treatment with triethylamine as before to provide more 109. That 109 is the product of an equilibrium- controlled process was demonstrated by re-establishment of the original three-component mixture upon exposure to triethylamine (see Scheme 27). With the two pairs of cis- and trans-enedione IMDA precursors on hand, investigations were then set forth to determine their relative rates of cyclization and 58 exo/endo cyclization selectivities. Cyclizations were performed in refluxing chloroform-dl (bp=6l°C) or toluene- d8 (bp=lll°C) and the reaction progress was monitored by 250 MHz 1H NMR. Integration of appropriately resolved product and starting material resonances from aliquots withdrawn at measured intervals provided half-life data. The cyclizations of trienes 103, 105, and 106 proceded at convenient rates in refluxing chloroform-d1, whereas negligible cyclization had occurred with substrate 109 after 6 hours in this solvent, and therefore the higher boiling toluene-d was used instead. The half-life data 8 given in Scheme 28 indicate that the methyl substituted trienes undergo cyclization more slowly than their unsubstituted counterparts, not a surprising result in terms of steric considerations. Also, the half-life data indicate that, for a given dienophile substitution, the cis-enediones cyclize faster than the corresponding trans isomers. A similar rate effect has been observed by 62 in their studies on the IMDA reactions White and Sheldon of trienes which also possess dienophile l,2-diactivation (see Figure 7). Stereochemical assignments for the product hydrindenones shown in Scheme 28 were made on spectrosc0pic considerations (250 MHz 1 13 H NMR and 62.9 MHz C NMR), using as a guide the growing body of data available from related studies. Thus, triene 103, which undergoes facile cyclization (ether, r.t., 3 days; or CHC13, reflux, 4.5 h), gave 59 Scheme 28 CH 0 t1/2 (61°C) - 30 min 3 0 123 Wm ” o. (925) H 11.03 1£0b 196 . a/b= 63: 3? (82%) O t1/2 (61.0) = 9 h 3 CH,O 125 .. MW e. (87%) 112a 112b CH, 0 t1/2 (111'C)> 15 h CH,O 129 A 8/b= 50 a 50 (67$) 9. 1i3b 60 C H302C o . ‘\~ 130 C CH3 24 h only product. 40% CH, 0 CH,O,CMO/\//\IL CH 130.0. 5 days 3 60% conversion Figure 7. Studies by White and Sheldon on the IMDA reactions of sorbyl mesaconates and citraconates. 61 two hydrindenones in equal amounts as determined by integration in the 1H NMR spectrum of the crude product mixture. Separation of the two products was effected by flash column chromatography, thus enabling unambiguous assignment of the resonances peculiar to each. Assignment of the less polar isomer as trans-fused 110a and the more polar, crystalline product as the cis-fused isomer llOb rests upon the following spectroscopic observations. The J7a-3a values for llOa and 110b, as determined by decoupling experiments in which H-7 was selectively irradiated, are 13.6 and 7.7 Hz, respectively (see Figure 3). On the basis of dihedral angle considerations, the trans-diaxial arrangement of H-7a and H—3a in the conformationally restricted trans-fused isomer 110a is expected to give rise to greater coupling compared to cis-fused 110b, which has available to it conformations in which the H-C7a-C3a-H dihedral angle ranges from 00 to ca. 40°. Diagnostic, too, is the 1.2 ppm upfield chemical shift of H-7a in 110a compared with the same proton in 110b. Examination of molecular models of 110a indicates that H-7a, by virtue of the trans ring fusion, is rather rigidly held in a pseudo-axial position, which places it nearly perpendicular to the C1 carbonyl C-O bond axis and hence out of the strongly deshielding region associated with this functional group.63 Additionally, the trans ring fusion in 110a holds H-7a in a region of moderate ~ 62 3.35 ppm. ddd. 2.55 ppm. ddd 337.11, 3.7, 3.7 Hz J=10.8, 6.5, 3.5 Hz 1.98 ppm. ddd. J= 13.6. 3.7. 1.2 Hz 3-16 ppm, ddm, J: 7'79 305 Hz Mi: ~ H y 9 CH3 110a H 0 110b P1 CH, 0 Figure 8. Chemical shifts, coupling constants, and conformations of hydrindenones 110a and 110b. ~ 63 shielding over the c4-c5 double bond.64 The cis-fused isomer 110b, on the other hand, has conformations available to it in which H-7a is nearly coplanar with the C1 carbonyl C-O bond axis and well away from the shielding region of the C4-C5 double bond. Consistent with the presumed cis arrangement of H-7 and H-7a in cycloadducts 110a and llOb (which requires a gauche-like arrangement of these protons in the various conformers) are the J values of 3.7 and 7-7a 3.5 Hz, respectively. The origin of the additional 1.2 Hz splitting of H-7a in 110a could not be conclusively determined by decoupling experiments. Long range coupling via the well known "W conformation" is not possible in the trans—fused hydrindenone ring system; however, it does seem possible as judged by examination of molecular models that splitting of H-7a by the pseudo-axial proton at C2 (see Figure 8) could occur by a mechanism in which long range coupling takes place via mutual overlap of the C-H 65 0 bonds with the n p orbital of the C carbonyl carbon. 1 Chemical evidence for the trans fusion in 110a was provided by its slow epimerization at room temperature in the absence of acid or base to give a new hydrindenone (as an inseparable mixture with 110a), whose structure was determined to be cis—fused 111b based on the following spectroscopic evidence. The new J7a-3a value as determined by irradiation of H-7 was found to be 7.3 Hz (see Figure 9) and, consistent with previous observations, H-7a in the new isomer resonates at 0.8 ppm downfield of the 64 3.10 ppm, ddd. J=7.2. 3-5. 3-5 Hz 2.77 ppm. ddd. J=7-3. 3.5. 0-9 Hz 110a 111b N II' Figure 9. Epimerization of 110a. Chemical shifts, coupling constants, and conformations of hydrindenone lllb. 65 corresponding proton in the original epimer. The rather small J7-7a value of 3.5 Hz suggests that the conformation of 111b in solution does not resemble ii (see Figure 9) because of the trans-diaxial arrangement of H—7 and H-7a in the latter. The slow epimerization of llOa to its cis-fused epimer is not surprising in light of similar observations by other workers. For example, in the base-catalyzed equilibration of l—hydrindanone using triethylamine, House and Rasmusson66 found a ca. 3:1 preference for the cis-fused isomer. Ichihara and co-workers described the acid67a and base67b catalyzed epimerization of trans- coronafacic acid 114a to the cis-fused isomer 114b, the latter being the naturally occurring stereoisomer found in the phytotoxin, coronatine 115 (see Figure 10). Lactone 116a, a product of IMDA cyclization from a study by White and Sheldon,62 was epimerized to its cis-fused epimer, ll6b (see Figure 10). The spectral data shown in Figure 10 for the 116a,b epimeric pair concur nicely with the spectroscopic arguments in the foregoing discussion. Cyclization of triene 106 required longer reaction times than 103 (see Scheme 28),and examination of the crude product mixture by 1H NMR indicated the presence of two cycloadducts in a ratio of 63:37. A small amount of diene polymerization had occurred as inferred from a broad singlet at 6.8 ppm (the chemical shift region for trans-enedione vinyl protons) and a somewhat lower yield of 66 COOH t 3.19 ppm. d, J= 14 Hz 4.05 ppm, d, J= 9 Hz MCOch, NaOCH 3 ’II 4 CHBOH 116a 116b Figure 10. Epimerizations of trans-fused bicyclo[4.3.0] systems to cis-fused isomers. 67 chromatographed cycloadducts. The mixture of hydrindenones proved to be inseparable by flash column chromatography, and therefore structural assignments had to be made using the mixture. The minor isomer showed resonances in the proton and 13 C NMR identical to those of 111b, the epimerization product of 110a described above. By default, then, the structure of the new hydrindenone must be trans- fused llla (see Figure 11). The diagnostic J value 7a-3a for 111a, however, could not be assessed in this case 2.85 ppm. ddd. J= 10.3, 10.3. 6.8 Hz 0 Figure 11. Chemical shift and coupling constant data for hydrindenone 111a. because the upfield—shifted H-7a was obscured by other high field resonances. Supportive of the stereochemical assignment, though, is the J value of 10.3 Hz (which 7-7a could not be verified by decoupling experiments since the positions of H-7a and the protons at C6 were unknown), consistent with a trans-diaxial arrangement of these protons. Also, the upfield chemical shift of H-7 in 111a (2.85 ppm) relative to the same proton in trans- fused llOa (3.35 ppm) is a demonstration that H-7 in the former occupies a pseudo-axial position and is out of the 68 strongly deshielding region of the nearby C carbonyl 1 group. The 13C NMR spectra of the two trans—fused hydrinde- nones 110a and 111a show striking similarities, as do the spectra of the two cis—fused epimers llOb and 111b (see Table 4). Although it is still quite early to be making generalizations, it appears that the chemical shift of the Cl carbonyl carbon might be of diagnostic value to aid in the differentiation between cis- and trans-fused hydrindenones. Of the two carbonyl resonances for each compound, the upfield signal is ascribed to the acetyl carbonyl carbon (cyclohexyl methyl ketone exhibits a resonance at 210.7 ppm68 ). Thus, from the values given in Table 4, it can be seen that the Cl carbonyl carbons of the trans—fused hydrindenones exhibit chemical shifts upfield of those in the cis-fused isomers. It is tempting to speculate that the difference in chemical shift is strain related; construction of molecular models clearly indicates that the trans-fused ring system is more strained. If the strain is manifested as a deformation of bond angles in the cyclopentanone portion of the molecule, then a slight change in hybridization at C might be responsible l for the chemical shift differences. Triene 105 cyclized cleanly to give an inseparable mixture of two products in the ratio of 83:17 as determined from the crude product mixture by integration of the 69 l|u|l‘)|. "ls‘ll‘llll‘l ee.o~a me.mo~ mm.- mo.em He.e~ mm.em em.mm em.ee mm.me om.m~e Hm.mem QHHH mo.m~H me.mo~ mo.m~ HH.HN em.e~ ms.em ee.em me.me mm.me ee.mma mm.eem hone HN.HNH em.oem em.em me.m~ mm.om He.em me.mm oe.ee mm.mm om.m~e oa.ee~ mafia Hm.emH m~.mom He.e~ em.e~ me.m~ mm.mm mm.mm He.ee He.em Hm.mma m~.eem moae Hmcuo UHU onu pcsomfioo .nHmH 6:8 .meme .nome .mome mmeocmeeehesn mo memenm Hmermeo mzz o .e magma 70 angular methyl group signals. The major product was assigned a trans ring fusion based on the upfield chemical shift of its angular methyl group (0.89 ppm), a characteristic feature for trans—hydrindenones which 69’71 Values of has been noted by several other workers. 8.5 and 1.8 Hz for the coupling of H-7 with the vicinal C6 protons imply a pseudo-axial orientation of the acetyl group at C7, and thus the major product was formulated as 29a (see Figure 12). The minor product was therefore assigned structure 112b, the product of endo cyclization. Comparison of the spectral data for 112a and 112b with 69 shown in Figure 12 lends the related compounds 117a,b further credence to these structural assignments. Cyclization of triene 109 required much higher temperatures as noted previously. After 15 hours at 111°C, the reaction was only 35-40% complete as judged by 1H NMR. The mixture was therefore transferred to a re-sealable tube and heated at 195°C in the presence of methylene blue for an additional 8 hours. The 1H NMR spectrum of the crude product mixture thus obtained revealed the presence of a 1:1 mixture of two new hydrindenones as the major products, ca. 10% of a 5:1 mixture of hydrindenones 112a and 112b (the same relative ratio as obtained from 105), and less than 5% of the deconjugated triene 108. The presence of the latter three products suggests that 109 had undergone thermal isomerization to give 105 and 108, the same products 3.01 ppm, dd. J8 8.5. 1.8 Hz 0 /0.89 ppm H CH, 2.94 ppm. dd. J"3 7.5, 1.9 Hz / 0.90 ppm Figure 12. 71 2.87 ppm. dd. JII 5.8, 5.2 Hz O /1.114 ppm H H 112b 2.74 ppm, dd, J= 5-9. 5.9 Hz 1.21 ppm \\ Meo,c H CH, 0 H 1,1. 7b Comparison of selected spectral properties of hydrindenones 112a and 112b with related compounds. 72 obtained from base-catalyzed isomerization (see Scheme 27). At the temperature required for isomerization, 105 should undergo relatively rapid IMDA cyclization to give the 112a,b mixture (vide supra). Triene 108, on the other hand, appears to be unreactive under these conditions. A partial separation of the two new hydrindenone isomers was achieved by flash column chromatography, providing the less polar 113a in greater than 90% purity and 113b as a ca. 3:1 mixture with 113a. The similarity in chemical shift of the angular methyl groups in these isomers prevented an unambiguous assessment of their ring fusion stereochemistries, and hence H-7 was used as a stereochemical probe. Trans-fused 113a exhibited coupling constants for this proton of 10.7 and 6.6 Hz, values consistent with a pseudo-axial orientation of H-7 (see Figure 13). The conformationally more flexible cis- fused 113b, on the other hand, exhibited values of 6.4 and 4.0 Hz. Roush69 has reported similar values (9.7, 7.8 Hz and 5.5, 5.5 Hz) for hydrindenones analogous to 113a and 113b wherein the acetyl group at C is replaced by 7 carbomethoxyl. As noted previously in the "nor" series, the Cl carbonyl carbon resonances of the trans-fused hydrindenones 112a and 113a appear upfield of the Cl resonances of the cis-fused isomers 112b and 113b (see Table 5). From these data, it would appear that the Cl resonance is 73 3.0a ppm, dd, 2.99 ppm, dd, J8 6.9, 4.0 Hz J8 10.7, 6.6 Hz Figure 13. Chemical shifts, coupling constants, and conformations for hydrindenones 113a and 113b. 74 Table 5. Chemical shifts of the Cl carbon in the cis- and trans-fused carbonyl hydrindenone pairs llOa,b—113a,b. trans-fused cis-fused compound (a series) (b series) 110 214.25 ppm 217.95 ppm 111 214.10 ppm 219.51 ppm li2 217.92 ppm 222.51 ppm 113 217.45 ppm 221.45 ppm indeed of diagnostic value in the assignment of cis- and trans-hydrind-4-en—1—ones of similar constitution. The exo/endo cyclization selectivities observed for the trienes in this investigation (see Scheme 28) are not easily rationalized using the generalizations and conclusions put forth in related IMDA studies. From the work of 69:70 62'71_73 it has become apparent that Roush and others, the exa/endo selectivities in the thermal cyclization of trienes which give hydrindene products (i.e., three atoms in the chain connecting the diene and dienophile) are not dominated by classical secondary orbital overlap. Instead, rather subtle non-bonded interactions which develop along the reaction coordinate, as the diene and dienophile approach one another, have helped to rationalize the results in many cases. For example, Roush7O studied the cyclization of trienes 118a and 118b (see Figure 14) and found that the geometry of the dienophile did not alter to significant extent the ratio of cis- and trans—fused 75 COzMe Meo,c \ 150'c, 24 h I + . trans/.Ci_s= 60 s 40 ,/ H 118a C02Me T gone 3 \ 1eo’c. 5h ' 'é , a may 65: 35 I/ H ‘. 118b ; Figure 14. Observations on the cyclization of cis- and trans-decatrienoates. products as might have been expected on the basis of secondary orbital effects. Rather, from these and many other examples it has been demonstrated that trienes which possess terminally activated dienophiles cyclize selectively to give trans-hydrindenes as major products. On the other hand, trienes which contain internally placed activating groups have been found to give predominantly cis-hydrindene products (see Figure 15). Thus, terminally activated trienes prefer transition state A in which the connecting chain adopts an era orientation with respect to the diene (see Figure 16), while internally activated trienes prefer transition state B in which the connecting chain is endo. It has been proposed by several groups62'69’70'72’73 that these selectivities are the 76 CH3 CH,o (J \ 19o‘c. 13 h | $ 9. trans/c188 3o. 70 ,,r H CH0 OCH,Ph CHO OCHzph \ 150‘s. 16 h 1:5 = so was — v H Figure 15. IMDA reactions of internally activated trienes which give predominantly cis hydrindenes. Figure 16. Exo and endo transition states for the IMDA reactions of 1,6,8-nonatrienes. r--._-_-_c. .- -.“l‘o ..‘3 fl-IfiH‘--‘.__fi 77 result of a "concerted but non-synchronous" mechanism wherein bond formation between one pair of carbon atoms precedes bond formation at the other termini. Using 74,75 frontier molecular orbital theory as a guide, the following conclusions regarding the observed selectivities were formulated. For the IMDA cyclizations involving terminally activated dienophiles, the LUMO coefficient at C2 should be greater in magnitude than the coefficient 3 75,76 at C1' and therefore bonding between C2 and C6 should be initiated first. In this situation, the steric '_'-‘ --' 7 ..l. I lfi’lq \r interactions involving the chain linking the diene and dienophile develop at an early stage of the reaction, as the five—membered ring is forming, and become a dominant factor in the course of the reaction. The exo transition state A is thus favored under these circumstances because of the non-bonded interactions which develop in transition state B between the C hydrogen and the C methylene 7 3 group in the connecting chain. For trienes which possess internally activated dienophiles, C bears the larger 1 LUMO coefficient and thus bond formation between C1 and C9 precedes bond formation between C2 and C6. In this case, the steric and/or electronic features which disfavor transition state A relative to transition state B are not as clear, although Roush69 has suggested that close approach between Cl and C9 is best accomodated in a skewed, cis-fused transition state. On the basis of the foregoing discussion, one might anticipate that the exo/endo 78 cyclization selectivity for substrates possessing dienophile l,2-diactivation, as in the present study, should be governed by an even more complex interplay of steric and electronic effects. As a general remark concerning both exo and endo cyclization modes for the substrates studied here, it is apparent from molecular models that when a product—like boat arrangement of diene and dienophile is attained, the internal C5 carbonyl group is tilted out of planarity with the dienophile double bond by about 30-40° due to torsional forces within the connecting chain. The restricted n orbial overlap is expected to cause a slight decrease in magnitude of the LUMO coefficient at C3 (for numbering,see Figure 17). Thus, in the absence of other steric factors, it is presumed that there would exist a moderate polarization of the dienophile double bond such that the substrates might behave as weak terminally activated trienes. Also, it is anticipated that the presence of an sp2 hybridized center in the connecting chain (i.e., the C5 carbonyl group) is going to considerably lessen the previously noted unfavorable non-bonded interactions associated with the endo transition state. Molecular models indicate that the position of the C carbonyl group in an 5 endo transition state is not well-suited for effective secondary orbital overlap and hence, stabilization of the ‘1 2' .10". .u‘._o'.uu-—.1.-.~h—fin t- ...___.. 79 g 9: CH, ‘\ 0 7:1. 9 D Figure 17. Exo and endo transition states for trienes 123 and 106. endo transition state by this interaction is not expected to be a dominating feature. Noteworthy for substrate 103 in Scheme 28 is the comparatively low temperature at which cyclization takes place. Other examples in the literature which exhibit this rapid a cyclization rate to give bicyclic[4.3.0] systems all employ an activated alkyne as the dieno- phile.62’69 In the absence of steric factors, i.e., diene and/or dienophile substitution, ci8-1,2-diactivation as in 103 seems to contribute strongly towards lowering the dienophile LUMO energy, a situation not unlike that in the potent dienophile, maleic anhydride. 1 . a". - ‘ 80 The lack of selectivity in the cyclization of 103 is thought to be the result of competetive stabilizing and destabilizing forces present in endo transition state B (see Figure 17) which contribute towards its total energy in such a way as to make the two cycliza- tion modes comparable in energy. Thus, relative to exo transition state A, the endo transition state is destabilized because of non-bonded interactions experienced between the diene and connecting chain. But because the desta- bilization is attenuated due to the presence of the C5 carbonyl group, secondary orbital overlap using the terminal acetyl group becomes a competetive factor in determining transition state energy, and thus stabilization is also experienced in this cyclization mode. Compatible with these arguments is the moderate selectivity observed in the cyclization of trans-enedione 106. In this case, secondary orbital overlap by the terminal acetyl group would serve to stabilize transition state C, while non- bonded interactions due to an endo orientation of the connecting chain destabilize transition state 2; The stabilizing and destabilzing forces thus conspire to create a selectivity for the trans-fused product 111a, as observed. The magnitude of the forces under considera- tion must be quite small, though, as the energy difference between transition states E and 2 is only ca. 0.35 kcal/mole. The presence of the methyl group in cis-enedione 105 noticeably perturbs the relative energies of the exo and 81 endo transition states as evidenced by the reasonably high selectivity for the trans-fused product 112a (see Scheme 28). Electronically, substitution of a methyl group at C4 should serve to further polarize the dienophile double bond in such a way as to increase the LUMO coeffi- 75’76 Thus, it is expected that cycloaddition cient at C4. might occur in a comparatively less synchronous manner, with bond formation between C4 and C8 significantly preceding bond formation between C3 and C11. Representa- tions of non—synchronous transition states for 105 are given in Figure 18. From a comparison of the top views A and B, it appears that the incipient angular methyl group experiences an additional non-bonded interaction in CH3 1H 3L CH, \ CH, H g! Figure 18. Non—synchronous exo and endo transition states for triene 105. 82 transition state A (the one which leads to the major product) due to its proximal approach with H-9 of the diene. However, in transition state B, the terminal acetyl group lies over the diene, and it is suspected that because of the larger distance separating C3 and C in this 11 presumedly non-synchronous transition state (depicted by A' and B'), secondary orbital overlap between the C2 T carbonyl group and diene in endo transition state 2' is i going to be severely weakened. Therefore the diene will g perceive the terminal acetyl group only in a steric sense, 2 an interaction of considerably less importance in exo ' transition state A'. The effect of the methyl group in trans-enedione 109 should not be one which further polarizes the dienophile 1'3 strain double bond. Rather, it is expected that A produced by the peri arrangement of the methyl group and C2 carbonyl oxygen would result in a slight disruption of n orbital overlap between the latter and the dienophile double bond. Therefore, it is expected that the LUMO coefficient at C4 should not differ significantly from the unsubstituted dienophile double bond of 106. Presuma- bly it is the inhibition of conjugation of BREE carbonyl groups with the dienophile double bond during IMDA cyclization which accounts for the much higher cyclization temperatures in this case. The lack of cyclization selectivity is thought to be the result of opposing forces in both exo and endo transition states. Thus, transition 83 lb 1!!! Figure 19. Exo and endo transition states for triene 109. state A in Figure 19 is destabilized by steric interactions between the methyl group and C hydrogen, but lacks the 9 less favorable endo orientation of the connecting chain. In transition state B, these steric consequences are reversed. The contribution of the terminal acetyl group towards the total energy of each transition state is less clear; i.e., the terminal acetyl group does not seem to exert a dominating steric effect to destabilize transition state A nor does secondary orbital overlap strongly stabilize it. In retrospect, it is apparent that the cyclizations of the four trienes in this study are not dominated by one strong steric or electronic effect. In order to examine more clearly the effect of dienophile l,2- diactivation, it would be necessary to "insulate" the electronics of the dienophile from the torsional effects which develop in the connecting chain as the transition state geometry is reached. It might therefore be 84 informative to examine IMDA cyclizations of substrates in which the diene and dienophile are separated by a greater number of atoms. As mentioned earlier, flexibility in the alkadienylfuran synthesis would . enable an easy entry to these other systems. Finally, it should be noted that the cyclization selectivities observed in the present study contrast sharply with the results of White and Sheldon,62 who examined the IMDA reactions of trienes possessing dienophile l,2-diester activation (see Figure 7, for example) and found a high selectivity for trans-fused products in all cases. It is speculated that the lower reaction temperature employed in the present study (with the exception of 109) allows secondary orbital effects to compete with the steric factors which seem to dominate in the IMDA reactions performed at higher temperatures.77 D. SYNTHESIS OF MACROCYCLIC POLYKETONES Macrocyclic chemistry has grown enormously since the pioneering studies of large-ring hydrocarbons, ketones, and lactones conducted by Ruzicka78 during the first half of this century. Since then, macrocyclic compounds have attracted an interdisciplinary range of interest owing to their diverse physical and chemical properties.79’80 Spawned by the discovery of the crown ethers in 1967 by Petersen,81 there has been a great deal of interest in the design and synthesis of macrocyclic polydentate 85 ligands which can selectively complex metal ions, a phenomenon of considerable importance from both a chemical and biological point of view (e.g. phase transfer 82a 82b catalysis and ion transport across lipid membranes ). Most of the synthetic efforts to date have focused on the incorporation of polyether functionality in the various topological arrangements (e.g., coronands, cryptands, podands, and spherand583). The incorporation -m- _q-' of a donor oxygen atom in the form of a carbonyl group, however, has received much less attention, even though .- a m- *‘“~ it is known that ester carbonyl oxygens can ligate i effectively as in the K+ ion complex of the dodeca- depsipeptide, valinomycin.84 Several groups have reported synthesis of macrocycles 85-87 and it is not containing 1,3-diketone units, surprising that the B-diketonates derived therefrom have shown good metal ion binding properties. Hexaketone 119, for example, has been shown to be a specific host 2+ . . . . . for UO2 , an ion whose coordination sphere lS quasz- H O 1.19, enol form CH, 5, planar hexacoordinate. Other complexes have been observed for oxo-crown ethers of the type 120 (m==6,8,9; n==3) with K+ (Zeise's salt) in chloroform solution,88 although 86 it was not mentioned in this communication what effect, if any, the carbonyl groups had upon the complexing ability of these compounds. 120 m=6,8,9 n=3 m CH, 0 0 Because of the limited number of methods available for the synthesis of macrocyclic polyketones,89 we wanted to explore the chemistry of the known furan macrocycles 121 and 126 (see Scheme 29), with the hope that furan ring-opening reactions would enable the production of polyketone derivatives. Thus, condensation of furan with excess acetone in ethanolic aqueous HCl produces the cyclic furan-acetone cyclic tetramer 12190 in 22-29% yield. The survival of this product under the strongly acidic reaction conditions can be attributed to the fact that 121 precipitates from the reaction medium as it is formed, thereby minimizing side reactions such as hydrolysis and/or polymerization. The ease of preparation and ready availability of starting materials enables the production of 121 in relatively large quantities (up to 70 grams per run), an attractive feature for the starting point in an exploratory project! Under a different set of reaction conditions in which 90a furan is used in excess, condensation with acetone 87 Scheme 29 (;;> 7. ,zji\\ EtOH H01 EtOH ~e ,8 ‘\ / (CH3 )2 c= 0 (CH 3)2°‘° HCl(g) HCl(aq ) /\ /\ /\ 7 137 (CH3 ) 2c= o H01(g) DMF—POCl 3 V 88 gives the linear products 122, 123, and 124 (see Scheme 29). Using the two—step procedure worked out by Kobuke and co-workers,91 linear "trimer" 123 can be converted to the cyclic hexamer 126. The successful condensation of two molecules of 123 with acetone to give linear hexamer 125, with no further oligimerization, relies on the insolubility of 125 in the aqueous ethanolic medium. In an attempt to simplify the two-step conversion of 123 to 126, anhydrous reaction conditions were employed (i.e., HCl gas was used instead of aqueous HCl) with the hope that cyclization to 126 would occur via a soluble linear hexamer. After stirring for several hours, the reaction mixture yielded a thick precipitate. Analysis of this material by proton NMR indicated the presence of furan a-protons, a clear indication that cyclization had not occurred. Formylation of this linear oligimer gave a dialdehyde whose 250 MHz 1 H NMR spectrum exhibited four different methyl group signals of equal intensity, data consistent with an oligiomeric structure containing nine furan rings. The products from the condensation and subsequent formylation reaction are thus formulated as 127 and 128, respectively (see Scheme 29). Although the anhydrous reaction conditions employed in the condensation did not meet the requirements for a "one—pot" conversion of 123 to 126, the procedure does constitute a relatively efficient method for the controlled oligimerization of 123. 89 Initial attempts at oxidizing cyclic tetramer 121 were performed using the methanolic bromine method of Clauson-Kaas.7 Thus, a suspension of 121 and sodium acetate in methanol decolorized a solution of methanolic bromine (2.5 equivalents) which was added dropwise to 121 over a period of about three hours. The methoxylated derivative of 121 was isolated and then hydrolyzed using a variety of acidic conditions to give large amounts of a viscous yellow oil, and a small amount of a bright yellow crystalline product whose yield was never much greater than 10%. A more efficient method for the production of this compound was found which involves the dropwise addition of 2.5 equivalents of bromine to a well—stirred suspension of finely divided 121 in moist acetic acid. In this way, yields ranging from 65—74% were obtained. The presence of a carbonyl stretching frequency in the infrared spectrum at 1695 cm.1 and a molecular ion peak at m/e 464 in the mass spectrum indicated that this material must be a di-ring—opened derivative of 121, and from the 1H and 13C NMR spectra, it was clear that the more symmetrical of the two possible di-ring-opened regioisomers was obtained. Because of the downfield chemical shift of the olefinic protons (6.95 ppm) in the proton NMR spectrum, it was concluded that oxidative ring-opening had proceeded to give trans-enedione functionalization, not a surprising result in view of the rather acidic conditions of the reaction.96 90 Thus, the structure of this compound was formulated as di-ring-opened trans—enedione 129 (see Scheme 30). Verification of the trans-enedione configuration in 129 was provided by single-crystal X—ray analysis (see Figure 20).92 An inclusion compound was formed upon Scheme 30 2.5 equiv. Brz *’8 HOAC-HZO 139 . Zn 4.0 equiv. Brz H0Ac-H20 "0A0 Zn, HOAC 91 Figure 20. ORTEP representation of di-ring-opened trans-enedione 129 with the acetic acid dimers omitted for clarity. 92 recrystallization of 129 from acetic acid, with a host-guest ratio of 1:4 as determined by integration in the proton NMR spectrum of the adduct. From the X-ray analysis, it was found that acetic acid dimers93 were located in the intermolecular cavities of the host lattice, with the mean plane of each acetic acid dimer being perpendicular to the mean plane of host 129 (see Figure 21). Isolation of only the more symmetrical of the two possible di—ring-opened regioisomers from the bromine- acetic acid oxidation procedure is attributed to the fact that 129 is rather insoluble in acetic acid and precipitates from the reaction mixture as it is formed, thus protecting it from further oxidation and/or degradation. It is suspected that a lesser amount of the "1,2" di-ring— opened regioisomer is also produced, but is destroyed because it does not precipitate from the strongly acidic reaction medium. Attempts at effecting further ring- Opening of 121 using 4.0 equivalents of bromine in acetic acid failed, and gave instead the dibromo-trans-enedione 120 (see Scheme 30), in addition to greatly diminished yields of 129. The bromine adduct 130 and trans-enedione 129 were shown to be related by the reduction of each using zinc in acetic acid to the same product, saturated tetraketone.131 Attention was then turned to oxidations using MCPBA. Treatment of cyclic tetramer 121 in hot chloroform with 4.2 equivalents of MCPBA gave excellent yields of the 93 .mHmEHC pflwm oaumom wnu mo coaumucmfiuo on» mcHBOQm mma macapmcmlmssse COGOQOIOCHHIHU mo =3mfl> QOBs .HN musmflm 94 fully ring-opened octaketone 132 (see Scheme 31). The symmetry of this product is evident from its uncomplicated 1H and 13C NMR spectra (2 and 4 signals, respectively). In accordance with the cis-enedione double bond configura— tion in 132, the olefinic protons resonate 0.47 ppm upfield of those in the macrocyclic trans-enedione 129. Scheme 31 4.2 equiv. 1 2 1 ,... MC PBA 1’36 1.3.2 134 6.3 equiv. ~ MC PBA 95 Likewise, treatment of the cyclic furan-acetone hexamer 136 with 6.3 equivalents of MCPBA resulted in oxidation of all six furans to give the dodecaketone 133 in good yield. Once again, the high degree of symmetry and cis-enedione functionalization in 133 is evident from the 1H and 13C NMR spectra. Single-crystal X-ray analysis of tetra-ring-opened octaketone 132 was performed (see Figure 22),92 verifying the degree of oxidation and configuration of enedione double bonds. An interesting conformational feature depicted in the stereostructure of 132 (see Figure 22) is the significant deviation from planarity of one of the carbonyl groups with the remainder of the enone grouping in each of the cis-enedione moieties, a situation which must arise because of unfavorable non— bonded interactions between the carbonyl oxygens in a coplanar arrangement. In contrast, the stereostructure of di-ring-opened trans-enedione 139 (see Figures 21 and 22) reveals an entirely coplanar arrangement of the atoms which comprise each of the trans-enedione units. The difference in geometry, and hence degree of n orbital overlap,of the cis- and trans-enedione moieties results in markedly different UV-vis spectra for 139 and 132 in that the more extended trans-enedione chromophore in 139 absorbs at longer wavelengths than the twisted cis-enedione chromOphore in 132. This tendency has also been noted for 9b simple cis- and trans-enediones (see Table 6). Hydro- genation of the enedione double bonds in 132 and 133 96 Figure 22. ORTEP representation of tetra-ring-opened octaketone 132. 97 Table 6. Electronic absorption spectra for cis- and trans-enediones. compound (solvent) UV-vis ; Amax’ nm(log 8) di-ring-opened trans-enedione 139 382(3.25), 304(3.67), 232(4.52) (CH3CN) tetra-ring-opened cis-enedione 132 shoulder atr~290(2.9), 212(4.4) cis-3-hexene-2,5-dione9b 284(2.00), 22l(3.58) (ethanol) 9b trans-3-hexene-2,5-dione 328(1.8), 227(4.15) (ethanol) gave the crystalline macrocyclic polyketones 134 and 135, respectively. By varying the stoichiometry of MCPBA in the oxidation of tetramer 131, several other enedione-functionalized macrocycles were obtained (see Scheme 32). Thus, treatment of 131 with 3.1 equivalents of MCPBA gave a mixture of tri-ring-opened hexaketone 136 and a small amount of tetra-ring-opened 132, which were readily separated by flash column chromatography to give pure 136 in 60% yield. Hydrogenation of the enedione double bonds in 136 gave the saturated hexaketone 137 in good yield. Using 2.2 equiva- lents of MCPBA, a three—component mixture resulted which, after separation by flash column chromatography, gave the di—ring-Opened regioisomers 138 and 139 in yields of 32% 12} 98 Scheme 32 2.2 equiv. MCPBA 129 Zn, HOAC 136 99 and 36%, respectively, in addition to 17% of tri-ring- opened 136. In accordance with the anticipated cis- enedione configuration, the olefinic protons in di-ring- opened 138 resonate at 0.95 ppm upfield from those in trans-enedione 139; moreover, reduction of the enedione double bonds in 138 using zinc in acetic acid gave 131, the same product as obtained from 139. Hydrogenation of the regioisomeric di-ring-opened 139 gave a different saturated tetraketone derivative, 140. In another experiment using 2.0 equivalents of MCPBA, a small amount of concentrated aqueous HCl was added to the crude reaction mixture, causing isomerization of the initially formed cis-enedione products. The two products which survived the acidic conditions were the regioisomeric di-ring-opened trans-enediones 139 and 141, isolated in .41% and 19% yield, respectively (see Scheme 33). That 141 differs from 139 only in the configuration about the enedione double bonds was demonstrated by catalytic hydro- genation of the former to give saturated tetraketone 140, the same product as obtained from 139. Attempts at isomerization of cis-enediones 132 and 136 using either acids (e.g., conc. HCl in chloroform, conc. HCl in acetic acid, acetic acid and heating) or base (e.g., pyridine, triethylamine in chloroform) gave complex mixtures of intractable products. The results from these studies leave little doubt that furan-containing macrocycles can serve as a convenient 100 Scheme 33 1) 2.0 equiv. MCPBA 2) conc. HCl 131 131 1330 source of polyketo macrocycles via oxidative transformations using MCPBA.94 Attack of the peracid does not seem to be particularly sensitive to the rather hindered environment of the furan rings in 131 and 136 as evidenced by the efficacy of peracid ring-opening to give the fully oxidized polyketo derivatives 132 and 133. Preliminary investigations on the ability of several of the polyketo macrocycles prepared here (129, 131, 132, 134, and 135) to complex cesium ion have given 101 negative results.95 Problems were encountered with the reactivity of several of these compounds when tetrahydro- furan solutions containing cesium octanoate were made up. It seems likely that the carboxylate anion might function as a relatively strong base under the anhydrous conditions with the highly electropositive cesium counterion. Thus, the saturated polyketones 131, 134, and 135 would be subject to intra- and intermolecular condensation reactions, and the unsaturated polyketones 139 and 132 could add the carboxylate anion in a Michael fashion. Investigations of the complexation of polyketo macrocycles with other metal ions have not yet been pursued. One of the major concerns regarding the macrocyclic polyketones discussed thus far is the presence of a tertiary center adjacent to each carbonyl group. If the carbonyl oxygen is to function as a ligand, then it is anticipated that an adjacent gem-dimethyl group would only serve to destabilize complex formation in a steric sense as the metal ion approaches the ligand (on the other hand, one might argue that an adjacent tertiary center would also retard undesired addition reactions to the carbonyl group, as well as preclude enolization in that direction). Also, it is possible that conforma— tional mobility in the polyketo macrocycles discussed above is somewhat restricted because of the many gem-dimethyl groups,96 and thus, it might be difficult - ..0" rd“ :1? 'm III I - ”Hf-_\. 102 for the molecule to assume a conformation required for complexation. In order to overcome some of these inherent problems, synthesis of the extended furan macrocycle 146 was undertaken (see Scheme 34). Acid-catalyzed addition of acrolein97 to 2,2- difurylpropane90a (excess acrolein, catalytic p-touluene- sulfonic acid, THF, reflux, 6 h) gave dialdehyde 142 in 43% yield after column chromatography. Reduction to diol 133 (excess NaBH4, methanol, -10°C to 0°C, 1 h; 98%) followed by bromination98 (4.4 equiv. CBr4, 4.6 equiv. Ph3P, ether, r.t., 4 h; 81%) gave dibromide 144 in 79% yield from 142. Treatment of 144 with 4 equivalents of 2-1ithiofuran99 (THF-hexane, -78°C to r.t., 12 h; 85%) gave the linear furan compound 135 which was cyclized in dilute solution (6.3 equiv. 2,2-dimethoxypropane, 4.2 equiv. p-toluenesulfonic acid, benzene, 60°C, 20 h) to give l,1,15,15-tetramethyl-[l.3.1.3]furanophane 136 in 47% yield after column chromatography. Incorporation of the trimethylene bridges is expected to endow 146 with much more conformational mobility as compared to the isomeric tetramer 131. Additionally, relief of steric impedance about the furan rings in 146 might enable the production of other large-ring compounds via cycloaddition reactions.100 For the present, however, 146 was oxidized with 4.2 equivalents of MCPBA to give the 24-membered ring octaketone 147 in 48% yield. The chemistry of this compound, including possibilities for metal ion complexa- tion, have not yet been investigated. .103 Scheme 34 / I CH2=CHCH0 C) TsOH, THF 132 1) NaBHu 7 It 11:5 11:3 , X8 OH 134 , X8 Br TsOH (CH3)ZC(0C}-13)2 136 127 I 1.....- -_....._ EXPERIMENTAL General Methods All melting points were determined using a Thomas- F Hoover capillary melting point apparatus and are uncorrected. ) Unless otherwise noted, all NMR spectra were obtained in chloroform-dl solution with the chemical shifts reported } in parts per million downfield from tetramethylsilane internal standard. Proton NMR spectra were obtained on Varian T-60 and Bruker WM—250 Spectrometers at 60 MHz and 250 MHz, respectively. Carbon-13 NMR spectra (proton- decoupled) were obtained on Varian CFT-20 and Bruker WM-250 spectrometers at 20 MHz and 62.9 MHz, respectively. Unless otherwise noted, NMR data are reported at 60 MHz for proton spectra and 20 MHz for carbon-13 spectra. Infrared spectra (IR) were obtained on a Perkin-Elmer 237 grating spectropho- tometer and were calibrated using the polystyrene 1601 cm.-1 peak. Ultraviolet and visible spectra (UV-vis) were recorded on a Cary 219 spectrOphotometer in acetonitrile solution (MCB-Omni Solv spectral grade) using matched quartz cells. Mass spectra (MS) were obtained on a Finnigan 4000instrument at 70 eV or, when noted, using ionized methane (CI). Combus— tion analyses were performed at Guelph Chemical Laboratories, Ltd., Spang Microanalytical Laboratory, and Galbraith 104 105 Laboratories, Inc. Flash column chromatography refers to the method of Still, Kahn, and Mitra,101 using Whatman LPS-2 silica gel (37-53 um). For regular column chromato- graphy, "Silica Gel 60" (EM cat. #7734, 70-230 mesh) was employed. Thin layer chromatography (TLC) was performed using Machery-Nagel "Polygram SIL N-HR/UV254" 0.2 mm pre-coated silica gel plates. Technical grade m-chlorOper- oxybenzoic acid (MCPBA) was used as obtained from Aldrich Chemical Company (80-90%; the amounts used were calculated “1:! 1+“. ~*~n- ml! 5- ‘--- assuming 85% by weight peroxy acid). Dry ether, benzene, and tetrahydrofuran (THF) were obtained by distillation from potassium-benzophenone under an atmosphere of nitrogen. Dry methylene chloride was obtained by passage through a column of alumina (Woelm B, Akt. I). cis—3-Hexene-2,5-dione (3]), cis-3-octene-2,5-dione (39a), cis-enedionediester 41a, bis-spiroketal 43, and tetracyclic dione 29_ General Procedure: To a magnetically stirred solution of the furan compound (10 mmol) in methylene chloride or chloroform (50 mL) at 0°C was added MCPBA (11 mmol) in one portion. The reaction mixture was stirred at 0°C for 1-2 h and then at room temperature for an additional 1—3 h. The resulting milky- white suspension was extracted with saturated aqueous filtered, NaHCO3 (3><75 mL), dried over anhydrous NaZSO4, 106 and the solvent was removed under reduced pressure. The products thus obtained were essentially pure as evidenced by TLC (SiOz, ether) and NMR. Purification methods (if any), yields, and spectral data are given below. cis-3-Hexene-2,5-dione (3719a’b Obtained as a very pale yellow liquid, 99%. 1H NMR: 66.18 (s, 2H), 2.18 (s, 6H); 130 NMR: 200.11, 135.32, 1 .. It 29.27 ppm; 33 (neat): 1698, 1616 cm 1. cis-3—Octene-2,5—dione (3931 . ;_ Obtained as a very pale yellow liquid, 96%. 250 MHz 1H NMR: 06.33 (AB quartet, J==11.9 Hz, 2H), 2.54 (t, J==7.0 HZ, 2H), 2.30 (s, 3H), 1.66 (sextet, J==7.0 Hz, 2H), 0.95 (t, J==7.0 Hz, 3H); 62.9 MHz 130 NMR: 202.72, 200.72, 136.12, 135.32, 44.46, 29.73, 16.97, 13.61 ppm; 33 (neat): 1695, 1615 cm'l; Hg (CI): m/e==141 (M+l, base peak). cis-Enedionediester 413 Obtained as a very pale yellow oil which was passed through a short column of silica gel (ether eluent) to remove the last traces of MCPBA. Yie1d==97%. 250 MHz 1H NMR: 06.34 (s, 2H), 4.12 (q, J==7 Hz, 4H), 2.58 107 (hr t, J==7 Hz, 4H), 2.32 (br t, J==7 Hz, 4H), 1.67 (m, 8H), 1.26 (t, J==7 Hz, 6H); 62.9 MHz 130 NMR: 202.25, 173.35, 135.71, 60.25, 42.08, 34.08, 24.38, 22.91, 1 14.26 ppm; 35 (neat): 1725, 1690 cm- ; M3: m/e==340 (parent), 165 (base peak). bis-Spiroketal 43:7 Obtained as a colorless liquid which was passed through a short alumina column (Woelm N, Akt. 1; methylene chloride eluent) to remove last traces of MCPBA. Yield==87%. An analytical sample was prepared by distillation using a molecular still; bp==110-120°C (bath temp.), ca. 20 mm Hg 37 l (lit. bp==89-90°C, 2 mm). 250 MHz H NMR: 65.93, 5.92 (25, 4H), 4.08 (m, 4H), 3.85 (q of m, J==6.7 Hz, 4H), 2.2-1.9 (m, 16H); 62.9 MHz 13C NMR: 132.94, 132.64, 117.15, 116.26, 68.63, 68.36, 36.84, 36.46, 24.99, 24.88 ppm; 35 (neat): broad, intense bands at 1075 and 980 cm—1; M3: m/e = 182 (parent), 110 (base peak). Anal. Calcd for C10H14O3: C, 65.91; H, 7.19 Found: C, 65.42; H, 7.60 21a,b Tetracyclic dione 29 Obtained as a white crystalline solid. Yield==88%. Recrystallized from ethanol, mp==188-189°C (lit.21a ~J—n -fi.’ m :u .'¢-'..- mfi‘p-fl 108 mp==186-187°C). 250 MHz 1H NMR: 66.52 (s, 2H), 2.52 (s, 2H), 2.75-2.35 (m, 8H); 13c NMR: 211.62, 136.89, 95.94, 56.24, 38.19, 24.58 ppm; 13 (Nujol): 1745 cm’l; M3: m/e==204 (parent), 108 (base peak). Isomerization of 39a to trans-3-octene-2,5-dione (39bl ~ To a 5 mm NMR tube containing a solution of 39a (ca. 50 mg) in CDCl3 (ca. 0.5 mL) was added 2 drops of pyridine- d The progress of the reaction was monitored by 5. 250 MHz 1H NMR, and after 8 h, 39a had completely isomerized. The trans-enedione product was not isolated. 250 MHz 1H NMR (ca. 10% pyridine-d5 in CDC13): 06.67 (AB quartet, J==16.5 Hz, 2H), 2.48 (t, J==7.3 Hz, 2H), 2.20 (s, 3H), 1.50 (sextet, J==7.3 Hz, 2H), 0.78 (t, J==7.3 Hz, 3H). trans-Enedionediester 41b To a solution of 1.0 g of furandiester 49 (3.1 mmol) in dry methylene chloride (30 mL) at 0°C under an atmosphere of nitrogen was added 4.0 g of pyridinium chlorochromate (18 mmol) in one portion. The mixture was stirred for 1 h at 0°C and then for 24 h at room temperature. A condenser was attached and the dark mixture was refluxed for 8 h. Ether (60 mL) was added to the cooled reaction mixture and the resulting suspension was filtered throughaa 109 glass frit packed with Florisil. The gummy black residue remaining in the flask was rinsed several times with ether and filtered. The filtrate solvents were removed under reduced pressure and the semi-solid residue was flash chromatographed using 30% ether—hexane to give 0.63 g of 43b (60%) as shiny white flakes, mp=54-56°C. 250 MHz 1H NMR: 66.88 (s, 2H), 4.13 (q, J=7.2 Hz, 4H), 2.68 (t, J==7.1 Hz, 4H), 2.32 (t, J==7.1 Hz, 4H), 1.65 (m, 8H), 1.26 (t, J8=7.2 Hz, 6H); 13 (Nujol): 1725, ca. 1690 (shoulder) cm‘l; Lag: m/e=340 (parent), 226 (base peak). ..._.._- cis-4-Oxo-2-pentenal (4§)9b To a solution of 1.00 g of 2-methylfuran (12.2 mmol) in 45 mL of methylene chloride at 0°C was added 2.7 g of MCPBA (13 mmol) in one portion. The mixture was stirred for 2 h at 0°C and then for 1 h at room temperature. The resulting bright yellow suspension was extracted with saturated aqueous NaHCO3 (3><50 mL). The aqueous washings were combined, saturated with NaCl, and extracted with methylene chloride (2><35 mL). The organic phases were combined, dried over anhydrous NaZSO4, filtered, and the solvent was removed under reduced pressure to give 0.48 g of the title compound (40%) as a bright yellow liquid. The product decomposed over a period of days when stored at room temperature as a neat liquid or in 110 solution. 1H NMR: 610.08 (d, J=7 Hz, 1H), 7.0 (d, J==12 Hz, 1H), 6.12 (dd, J==7, 12 Hz, 1H), 2.38 (5, 3h). cis-4-Oxo-2-octenal (4 36 ~)_ The procedure was followed as in 45 above; 0.50 g of 2-n-butylfuran (4]) gave 0.21 g of the title compound (38%) as a bright yellow liquid, which decomposed as noted for 45 above. 250 MHz 1H NMR: 610.23 (d, J=7 Hz, 1H), 7.96 (d, J==12 Hz, 1H), 6.19 (dd, J==7, 12 Hz, 1H), 2.62 (t, J==7.2 Hz, 2H), 1.65 (pentet, J==7.2 Hz, 2H), 1.37 (sextet, J==7.2 Hz, 2H), 0.94 (t, J==7.2 Hz, 3H). 5-n-Butyl-2(3H)-furanone (49L To a solution of 752 mg of 2—n-buty1-furan (6.06 mmol) in 60 mL of methylene chloride at 0°C was added 1.35 g of MCPBA (6.6 mmol) in one portion. The mixture was stirred for 2 h at 0°C, and then for l h at room temperature. After adding 30 mL more methylene chloride (which dissolved all of the m-chlorobenzoic acid precipitate), the solution was cooled to 0°C and 2 drops of trifluoroacetic acid were added, causing a noticeable lightening of the bright yellow solution. After 8 h at 0°C, the solution was extracted with saturated aqueous NaHCO3 (3><50 mL), dried over anhydrous NaZSO4, filtered, and the solvent was removed under reduced pressure to give 0.72 g of a very pale I-” ‘5- . r- o m.) J lll yellow oil. Examination of this material by proton NMR indicated that butenolide 49 was the major product. Purification by flash column chromatography (40% ether- hexane) gave 627 mg of the title compound as a colorless liquid. Upon standing at room temperature as a neat liquid under an atmosphere of nitrogen, 49 decomposed to a viscous oil after ca. two weeks. 250 MHz 1H NMR: 05.11 (tt, J==2.4, 1.2 Hz, 1H), 3-18 (dt, J==2.4, 2.4 Hz, 2H), 2.30 (tm, J==7.3 Hz, 2H), 1.54 (pentet of m, J'~7.3 Hz, 2H), 1.37 (sextet of m, Jz~7.3 Hz, 2H), 0.92 (t, J==7.3 Hz, 3H); 62.9 MHz 13C NMR: 176.93, 157.47, 98.16, 33.96, 27.99, 27.91, 22.14, 13.70 ppm; 13 (neat): 1795, 1680 cm'l; M3: m/e==l40 (parent), 96 (base peak). Oxidation of menthofuran (58) to enol lactone 59_ Freshly distilled menthofuraH£L(l.00 g; 6.67 mmol) dissolved in 65 mL of methylene chloride was cooled to 0°C. To this solution was added 2.84 g of MCPBA (14.0 mmol) in one portion. After stirring at 0°C for 1 h, the white suspension was extracted with saturated aqueous NaHCO3 (3><75 mL), dried over anhydrous Na2S04, filtered and the solvent was removed under reduced pressure to give 1.18 g of 59 (97%) as a colorless oil. 1H NMR: 610.00 (5, 1H), 1.75 (s, 3H), 1.10 (d, J==7 Hz, 3H), 1.2-3.0 (m, 7H); 13C NMR: 191.05, 170.79, 165.49, 124.93, 42.12, 34.45, 31.27, 31.01, 23.05, 10.42 ppm; £3 (neat): 1770, 112 1680, 1645 cm'l; Hg: m/e==182 (parent), 85 (base peak). Oxidation of tetramethylfuran (60) to enol acetate 61_ Tetramethylfuran (520 mg; 4.19 mmol) dissolved in chloroform (30 mL) was cooled to 0°C. To this solution was added 1.79 g of MCPBA (8.8 mmol) in one portion. After stirring at 0°C for 3 h and then at room temperature for and additional 9 h, the white suspension was extracted with saturated aqueous NaHCO3 (3><50 mL), dried over anhydrous NaZSO4, filtered, and the solvent was removed under reduced pressure to give 652 mg of a colorless liquid (99%). Spectral data and TLC analysis (8102, 1:1 ether-hexane) indicated the presence of more than one product. The major component, as analyzed in the crude product mixture, exhibited spectral properties consistent with enol acetate 6,.1- 111.151.1113: 62-17 (s.~6 H). 1.83 (S;~3H),1.53 (s,~3h); £3§_Efl3: 205.04, 168.14, 133.13(?), 124.13, 26.59, 20.71, 14.59, 13.51 ppm; £3 (neat): 1760, 1720, 1655 cm'l; M3: m/e==156 (parent, rel. intensity==l.2%), 114 (M-42, rel. intensity==25.2%), 99 (rel. intensity==49.5%), 43 (base peak). Oxidation of 2,3,5-trimethylfuran (62) using 1 equivalent of MCPBA to (Z)-3-methyl-3-hexene-2,5-dione (63 ) ~— A solution of 2,3,5-trimethylfuran (503 mg; 4.57 mmol) in methylene chloride (30 mL) was cooled to 0°C, when 113 0.97 g of MCPBA (4.8 mmol) was added in one portion. The solution was stirred at 0°C for l h, and then at room temperature for 0.5 h. The resulting white suSpension was extracted with saturated aqueous NaHCO3 containing a small amount of Na25203 (2><50 mL), dried over anhydrous Na 80 filtered, and the solvent was removed under reduced 2 4' pressure to give 570 mg of the title compound (99%) as a colorless liquid. In several runs, a small amount (ca. 5%) of di-oxidized product 64a was also observed. Separation of this minor by-product by flash column chromatography (40% ether-hexanes) was not possible. 250 MHz 1H NMR: 66.11 (q, J=1.5 Hz, 1H), 2.28 (s, 3H), 2.22 (s, 3H), 1.98 (d, J=1.5 Hz, 3H); 62.9 MHz 130 NMR: 206.84, 196.75, 155.67, 124.36, 29.99, 28.02, 20.ll ppm; £5 (neat) 1695, 1620 cm-1; Mé‘ m/e==126 (parent), 111 (base peak). Isomerization of 63a to (E)-3-methyl-3-hexene-2,S-dione (639) A solution of 63a (ca. 150 mg) in CDC13(ca. 2 mL) was allowed to stand at room temperature for approximately 2 months. After this time period, the proton NMR spectrum was run again, showing 63a as a mixture with a second compound in a ratio of ca. 2:1, respectively. The new compound was not isolated, but exhibited the following in the 250 MHz 1H NMR: 66.91 (q, J=1.5 Hz, 1H), 2.40 (s, 3H), 2.36 (s, 3H), 2.13 (d, J==1.5 Hz, 3H). 114 Oxidation of 2,3,5-trimethylfuran (62) using 2 equivalents of MCPBA to (Z)-4-acetoxy-3-methyl-3-buten-2-one 64a and epoxyketone 65_ To a solution of 600 mg of 2,3,5-trimethylfuran 62 (5.45 mmol) in 45 mL of methylene chloride at 0°C was added 2.41 g of MCPBA (11.9 mmol) in one portion. The mixture was stirred for 12 h, allowing the cooling bath to warm to room temperature. The resulting white suspension was extracted with saturated aqueous NaHCO3 containing a small amount of Na25203 (3><40 mL), dried over anhydrous Na2504, pressure to give 689 mg of a clear, colorless liquid (89%). filtered, and the solvent was removed under reduced Analysis of the proton NMR spectrum of this mixture indicated the presence of the 64a as the major product, along with a second componet whose relative abundance varied from run to run, ranging from 0-15%. Flash column chromatography (40% ether-hexanes) enabled purification of 64a, although the minor component could not be isolated (presumably because of decomposition on the column). The chromatographed major product was distilled using a molecular still, bp==85-95°C (bath temp.) at ca. 20 mm Hg to give pure 64a. 250 MHz 1H NMR: 67.71 (q, J==1.5 Hz, 1H), 2.48 (s, 3H), 2.27 (S, 3H), 1.75 (d, J==1.5 Hz, 3H); 62.9 MHz 13C NMR: 198.08, 166.49, 139.91, 124.39, 31.73, 18.73, 14.50 ppm; 33 (neat): 1775, 1720, 1670, 1650 cm’l; gg (CI): m/e==143 (M+l, base peak). The minor component, 115 analyzed as a mixture with 64a, had spectral characteristics 1H NMR: 63.65 consistent with epoxyketone 65. 250 MHz (5, 1H), 2.26 (s, 3H), 2.24 (s, 3H), 1.59 (s, 3H), 62.9 MHz 13C NMR: 204.84, 201.81, 66.93, 64.84, 28.23, 27.41, 20.85 ppm. Isomerization of 64a to trans-enol acetate 64b A solution of crude 64a (ca. 150 mg) in CDCl3 (ca. 2 mL) containing m-chlorobenzoic acid (ca. 20 mol% by 1H NMR) was allowed to stand at room temperature for approximately 1 month. After this time period, the proton NMR spectrum was run again, showing 64a as a ca. 1:1 mixture with 64b (a moderate amount of decomposition had also occurred,as evidenced by the rather complex absorptions in the methyl group region). The trans isomer was not isolated, but exhibited the following resonances in the 250 MHz 1H NMR: 68.24 (q. J==1.5 Hz, 1H), 2.33 (S, 3H), 2.29 (s, 3H), 1.81 (d, J==1.5 Hz, 3H). Oxidation of (Z)-3-methyl-3-hexene-2,5-dione (63a) using MCPBA to 64a and 65_ To a solution of chromatographed 63a (110 mg; 0.87 mmol) in chloroform-d1 (10 mL) at 0°C was added 195 mg of MCPBA (0.97 mmol) in one portion. The mixture was 116 stirred for 13 h, allowing the cooling bath to warm to room temperature. An aliquot was withdrawn (ca. 0.5 mL) and diluted with enough CDCl3 such that the m-chlorobenzoic acid precipitate had completely dissolved. Analysis by 250 MHz 1 H NMR revealed the presence of the di-oxidized products 64a and 65 in a ratio of ca. 4:1. The aliquot was combined with the reaction mixture and the resulting solution was extracted with saturated aqueous NaHCO3 containing a small amount of NaZSZOB (3><25 mL), dried over anhydrous NaZSO4, filtered, and the solvent was removed under reduced pressure to give 92 mg of a colorless liquid (74%). Analysis of the product mixture by 250 MHz 1 H NMR showed 64a as the major component, with less than 5% of 65 present (loss of the latter product had evidently occurred during the aqueous work-up). Oxidation of 2,4-dimethylfuran (68) using 2 equivalents Of MCPBA To a solution of 1.50 g of 2,4-dimethylfuran41 (15.6 mmol) in 75 mL of methylene chloride at 0°C was added 6.66 g of MCPBA (32.8 mmol) in one portion. The mixture was stirred for 2 h at 0°C, and then for 0.5 h at room temperature. The white suspension was extracted with saturated aqueous NaHCO3 (3><100 mL), dried over anhydrous Na2804, filtered, and the solvent was removed under reduced pressure to give 0.85 g of a colorless 117 liquid (43%). Analysis of this material by proton NMR indicated the presence of several products. The major component appeared to be (Z)—3-acetoxy-2-methy1propenal (69) based on the following resonances in the 1H NMR: 610.1 (s, 1H), 7.83 (q, J==1.5 Hz, 1H), 2.25 (s,'~3H), 1.67 (d, J==1.5 Hz,’~3H). Suggestive of the regioisomeric Baeyer— Villiger product, 79, was another set of resonances; 67.98 (s, 1H), 6.85 (q, J==1.5 Hz, 1H), 2.10 (s,—~3H), 1.87 (d, J==1.5 Hz,'~3 H). Separation of this mixture was not attempted, and therefore the structural assignments presented here must be considered tentative. 2-Methyl-2,5-dimethoxy-2,5-dihydrofuran (66), 2-n-butyl-2,5- dimethoxy-Z,5—dihydrofuran (73), spiroketal 72, 2,5-dimethy1- 2,5-dimethoxy-2,5-dihydrofuran (74), 2,4-dimethyl-2,5- dimethoxy-Z,5-dihydrofuran (75), 2,3,5-trimethyl-2,5- dimethoxy-Z,5-dihydrofuran (76), 2,5-dimethoxy-2,5-dihydro- menthofuran (72), 2,3,4,5-tetramethyl-2,S-dimethoxy-Z,5- dihydrofuran (78), and tetracyclic dione 20_ General Procedure: The furan compound (10 mmol) was dissolved in reagent grade methanol (SO—75 mL) and cooled to 0°C in an ice bath, when MCPBA (12 mmol) was added in one portion. Stirring was continued at 0°C for 1—2 h, and then at room temperature for an additional 1 h. The volume was condensed under reduced pressure at room temperature to ca. one-half the 118 original volume, chloroform (50-75 mL) was added, followed by extraction using saturated aqueous NaHCO3 (100 mL), 5% aqueous Na25203 (50 mL), again with NaHCO3 (75 mL), and then with saturated aqueous NaCl. The organic phase was dried over anhydrous NaZSO4, filtered, and the solvent was removed under reduced pressure. Yields, purification methods (if any), and spectral properties are given below. 2-Methyl-2,5-dimethoxy-2,S-dihydrofuran (46_)_9'a'b Obtained as a colorless liquid in 95% yield. 1H NMR: 65.83 (br s, 2H), 5.65, 5.37 (2s, 1H), 3.43, 3.33 (23, 3H), 3.13, 3.08 (25, 3H), 1.53, 1.47 (25, BB); £3 (neat): broad, intense bands between 1095—960 cm'l; gs (CI): m/e==113 (M-31, base peak). 2-n-Butyl-2,5-dimethoxy-2,5-dihydrofuran (73L36 Obtained as a very pale yellow liquid in 92% yield. 1H NMR: 65.83 (AB quartet, J==6 Hz, 2H), 5.63, 5.35 (2 br s, 1H), 3.43, 3.37 (25, 3H), 3.13, 3.05 (25, 3H), 1.77 (m, 2H), 1.33 (m, 4H), 0.89 (t, 3H); £3 (neat): broad, intense 1 bands between 1100-980 cm’ ; Hg (CI): m/e==155 (M-31, base peak). 119 , 102 Spiroketal 72_ Obtained as a colorless liquid after passage through a short column of alumina (Woelm N, Akt. l; chloroform eluent) in 82% yield. 1H NMR: 65.87 (s, 2H), 5.66, 5.50 (23, 1H), 4.00 (m, 2H), 3.30 (s, 3H), 2.00 (m, 4H); 62.9 MHz 13C NMR: 134.11, 134.02, 130.64, 130.08, 118.32, 116.66, 107.62, 106.38, 68.66, 68.54, 54.34, 53.19, 36.93, 36.17, 24.88 ppm; 13 (neat): broad, intense bands between 1100-950 cm-l; HS: m/e==155 (M-l), 125 (M-3l, base peak). 2,5-Dimethyl—2,5—dimethoxy-2,5-dihydrofuran (74L9a,b Obtained as a colorless liquid in 97% yield. 1H NMR: 65.78 (s, 2H), 3.25, 3.15 (25, 6H), 1.55, 1.47 (28, 6H); 13 (neat): broad, intense bands between 1070-1010 cm—l; HS (CI): m/e==127 (M-31, base peak). 9b 2,4-Qimethyl-2,5-dimethoxy—2,S-dihydrofuran (75) Yields and purity were variable. A persistent by- product appeared to be 2-methoxy-3,5-dimethylfuran from the peaks in the proton NMR at 65.57 (br s, 1H), 3.75 (s, 3H), and 2.08 (d, J'vl Hz, 3H). The other methyl resonance was obscured (1it.9b values: 65.62, 3.78, 2.12, 1.79). The formation of this product has been observed previously in the electrochemical oxidation of 2,4-dimethylfuran.9b 120 The best yield obtained was 89%, in which case the purity of 75 was ca. 88% as judged by the proton NMR spectrum of the crude product. 1H NMR: 65.40 (br s, 1H), 5.13 (br s, 1H), 3.43, 3.32 (25, 3H), 3.12, 3.05 (25, 3H), 1.77 (2 overlapping narrow doublets, 3H), 1.50, 1.47 (25, 3H); 13C NMR: 139.5, 128.0, 127.6, 111.0, 109.1, 108.8, 108.3, 55.6, 49.9, 26.03, 11.5, 11.3 ppm. 2,3,5-Trimethyl-2,5-dimethoxy—2,5-dihydrofuran (76L l Obtained as a colorless liquid in 90% yield. H NMR: 65.50 (q, Jr~1.5 Hz, 1H), 3.27, 3.23, 3.18, 3.12 (45, 6H), 1.73 (d, J'~1.5 Hz, 3H), 1.53, 1.50 (25, 3H), 1.43, 1.40 (25, 3H); 62.9 MHZ 13C NMR: 141.62, 141.47, 127.86, 127.80, 112.21, 111.01, 109.92, 49.99, 49.90, 49.64, 24.47, 24.32, 23.47, 23.35, 11.23 ppm; Hg; m/e==l4l (M—31, base peak), 157 (M-15). 2,5-Dimethoxy-2,5-dihydromenthofuran (77L38 Obtained as a colorless liquid in 94% yield. 1H NMR: 65.52, 5.07 (2 br s, 1H), 3.43, 3.33 (2s, 3H), 3.05, 2.98 (2s, 3H), 1.67 (s, 3H), 0.88 (d, J==6 Hz, 3H), 2.5-1.0 (m); 13c NMR: 135.88, 135.35, 128.63, 128.17, 112.14, 110.46, 109.52, 108.54, 55.75, 53.89, 49.11, 48.62, 46.86, 46.58, 34.67, 29.41, 22.89, 21.31, 9.27, 8.90 ppm; 13 (neat): 121 1 strong, broad bands between 1175-925 cm” ; Hg (c1): m/e==212 (parent), 181 (M-3l), 153 (base peak). 2,3,4,5-Tetramethyl-2,5-dimethoxy-2,S-dihydrofuran (78L Obtained as a colorless liquid in 93% yield. 1H NMR: 63.18, 3.05 (25, 6H), 1.62 (s, 6H), 1.48, 1.37 (23, 6H); 13C NMR: 132.21, 111.19, 109.88. 49.34. 49.14, 22.93. 22.76, 8.78 ppm; 13 (neat): strong, broad bands between 1200-880 cm'l; Hg; m/e==l7l (M-lS, base peak), 155 (M-3l). 21a,b Tetracyclic dione 20 Obtained as a white crystalline solid in 90% yield. After recrystallization from ethanol, 20 had mp==188-189°C 21 (lit. a mp==186-187°C). Spectral data appeared earlier in this section. 3,5-Dimethylfuran-Z-carboxaldehyde (88) To a flame-dried 250 mL three-necked round-bottomed flask equipped with a nitrogen inlet/bubbler atop a reflux condenser, a mechanical stirrer, and a 50 mL pressure- equalized addition funnel was added 9.7 mL of dry dimethyl- formamide (d==0.994 g/mL; 125 mmol). After cooling to -10°C using an ice-salt bath, 10.7 mL of phosphorus oxychloride (115 mmol) was added dropwise over a period 122 of 10 min. A small amount of dimethylformamide (ca. 2 mL) was used to rinse the residual phosphorus oxychloride from the addition funnel into the flask, and the resulting solution was stirred at -10°C to 0°C for 1.5 h, during which time the imminium salt precipitated as a heavy white solid. Dry methylene chloride (30 mL) was added, the cooling bath was removed, and the mixture was stirred until the solid had dissolved. After cooling the solution to 0°C, 10.00 g of 2,4-dimethy1furan41 (104 mmol) in 20 mL of dry methylene chloride was added over a period of 45 min, during which time the reaction took on a reddish-brown color. Stirring was continued for 4 h, allowing the cooling bath to warm to room temperature, followed by heating at reflux for 3 h. A solution of 20 g of sodium acetate (240 mmol) in 100 mL of water was then added to the cooled (0°C) reaction mixture, and stirring was continued at room temperature for 18 h. The two-phase mixture was poured into a separatory funnel, the layers were separated, and the aqueous phase was saturated with NaCl and extracted with chloroform (4><40 mL). The organic extracts and mother liquor were combined and washed with saturated aqueous NaHCO3 (2><50 mL; caution, foamingl), saturated aqueous NaCl (1><50 mL), dried over anhydrous NaZSO4, and filtered. The solvents were removed under reduced pressure, giving 12.4 g of a dark liquid which was distilled under vacuum using a short path distillation apparatus. The title compound was obtained as a very pale 123 yellow liquid (11.2 g; 87%), bp==34-37°C at 0.10 mm Hg. 1H NMR: 69.53 (s, 1H), 6.05 (s, 1H), 2.33 (s, 6H). Ethyl 3-(3,5-dimethyl-2-furyl)-3-hydroxypropanoate (69L To an ice cold solution of 2.73 mL of diisopropylamine (d==0.722 g/mL; 19.5 mmol) in 20 mL of anhydrous THF under a nitrogen atmosphere was added 12.0 mL of n-butyl- lithium in hexane (1.55 M; 18.6 mmol). The resulting solution was stirred for 15 min at 0°C and then cooled to -78°C. Ethyl acetate (1.73 mL, d==0.902 g/mL; 17.7 mmol) was introduced dropwise via syringe over a period of 3 min, and stirring at -78°C was Continued for 30 min. A solution of 2.00 g of 3,5-dimethy1furan-2-carboxaldehyde, 88, (16.1 mmol) in 10 mL of anhydrous THF was added through an addition funnel as rapidly as possible and stirring at ~78°C was continued for 2 min. The reaction was quenched at -78°C by the rapid addition of 10 mL of water. The cooling bath was removed, and after warming to room temperature, the mixture was transferred to a separatory funnel and the reaction flash was rinsed with ether (2><20 mL). The layers were separated and the organic phase was washed with 1% HCl (2><20 mL). The combined aqueous washings were extracted with ether (2><20 mL) and the organic phases were combined and washed with saturated aqueous NaHCO3 (2><30 mL), saturated aqueous NaCl (l><30 mL), dried over anhydrous MgSO and filtered. 4! 124 Removal of the solvents under reduced pressure gave 3.28 g of the title aldol (96%) as a very pale yellow oil. This material was sufficiently pure as evidenced bylfi£2(SiOZ, 1 13 ether), H and C NMR for use in the next step without further purification. 250 MHz 1H NMR: 65.77 (s, 1H), 5.10 (dd, J==4.3, 8.9 Hz, 1H), 4.17 (q, J==7.0 Hz, 2H), 3.2 (V br S, 1H; OE), 3.00 (dd, J==8.9, 16.2 Hz, 1H), 2.69 (dd, J==4.3, 16.2 Hz, 1H), 2.21 (s, 3H), 1.99 (S, 3H), 1.26 (t, J==7.0 Hz, 3H); 62.9 MHz 13C NMR: 172.09, 150.86, 147.54, 117.61, 109.28, 62.23, 60.73, 40.21, 14.15, 13.39, 9.66 ppm; £3 (neat): 3450, 1730, 1630, 1575 cm—1; HS: m/e==212 (parent), 125 (base peak). 2-(1,3-Dihydroxypropyl)-3,5-dimethylfuran (90L To a suspension of 0.61 g of lithium aluminum hydride (15.9 mmol) in 25 mL of anhydrous THF at 0°C under an atmosphere of nitrogen was added dropwise over a period of 30 min a solution of 3.00 g of aldol 89 (14.2 mmol) in 10 mL of anhydrous THF. The cooling bath was allowed to warm to room temperature and stirring was continued for 24 h. After cooling to 0°C, the reaction was quenched by the successive dropwise addition of 0.60 mL of water, 0.60 mL of 15% aqueous NaOH, and 2.4 mL of water. After stirring at room temperature for 3 h, the granular grey suspension was suction filtered through Celite and washed with ether (3><15 mL). The filtrate was dried over 125 anhydrous NaZSO filtered, and the solvents were removed 4, under reduced pressure to give 2.42 g of the title diol (99%) as a dense, colorless oil. Analysis of the product by TLC (SiOZ, ether; Rf==0.22, I2 visualiztion), 1H NMR, and 13C NMR indicated the presence of only one component. Purification by silica gel column chromatography was accompanied by decomposition and loss of material (see :TKI below). Accordingly, the crude product was used directly in the next step. Storage of diol 99 for extended periods of time without decomposition was best accomplished in 1 ether solution at -20°C. 250 MHz H NMR (CDCl + D20): 3 65.78, (S, 1H), 4.89 (dd, J==4.5, 9.0 Hz, 1H), 3.9-3.7 (m, 2H), 2.22 (d, J==0.9 Hz, 3H), ~2.2 (m, 1H),’”l.95 (m, 1H), 1.98 (s, 3H); 62.9 MHz 13C NMR: 150.62, 148.88, 117.00, 109.21, 64.78, 60.63, 37.46, 13.41, 9.67 ppm; 1 15 (neat): 3350, 1635, 1575 cm“ ; 5% (c1): m/e==153 (M—l7, base peak). 3,3-bis(3,5-Dimethy1-2-furyl)-l-propanol (92) In an attempted purification of diol 99 by flash column chromatography (ether eluent), a second, less polar component co-eluted with the desired diol product. The new product was obtained in pure form by re-chroma- tographing the fractions containing the mixture. In this way, 320 mg of 92 was obtained as a white crystalline solid (mp==86-87°C) from 1.08 g of diol 90 originally 126 chromatographed. 250 MHz 1H NMR: 65.72 (m, 1H), 4.22 (t, J==7.9 Hz, 1H), 3.58 (t, J==6.1 Hz, 2H), 2.25 (dt, J==7.9, 6.1 Hz, 2H), 2.21 (d, J==0.9 Hz, 3H), 1.86 (s, 3H); 33 (Nujol): 3250, 1635, 1575 cm‘l; 99: m/e==248 (parent),203 (base peak). 1,7-Dimethyl-2,9-dioxabicyclo[3.3.1]non—7—en-6-one (91) To a magnetically stirred solution of 1.00 g of 2—(1,3-dihydroxypropyl)-3,5-dimethylfuran 99 (5.88 mmol) in 60 mL of methylene chloride at 0°C was added 1.31 g of MCPBA (6.47 mmol) in one portion. Stirring at 0°C was continued for 15 min, after which time 5.9 mL of 0.10 N aqueous p-toluenesulfonic acid solution (0.59 mmol) was added. The cooling bath was removed and the reaction progress was monitored by TLC (SiOZ, ether, anisaldehyde- sulfuric acid visualization) for disappearance of the more polar intermediates at R = 0.18 and 0.24, and appearance f of the product (UV-active) at Rf==0.69. After 6 h, the reaction was complete, and work-up involved washing the organic solution with saturated aqueous NaHCO3 containing ca. 1% Na28203 (3><30 mL), drying over anhydrous NaZSO4, and filtering. Removal of the solvent under reduced pressure gave 0.95 g of bicyclic enone 9} (96%) as a colorless liquid. Examination of the crude material by TLC (SiOz, ether, anisaldehyde-sulfuric acid visualization) indicated the presence of trace impurities at low Rf, 127 1H NMR spectrum, the impurities were and in the 250 MHz observed as several very small methyl resonances in the region from 1.0-1.8 ppm. After passage through a short column of silica gel (50% ether-hexane eluent) and evaporation of the solvents under reduced pressure, 0.89 g of the title compound (90%) was obtained as a colorless liquid. An analytical sample was prepared by distillation using a molecular still, bp==85-90°C (bath temp.) at ca. 20 mm Hg. 250 MHz 1H NMR: 65.41 (q, J==1.5 Hz, 1H), 4.36 (ddd, J==6.2, 1.1, 1.1 Hz, 1H), 3.99 (ddd, J==12.1, 13.3, 3.0 Hz, 1H), 3.86 (dddd, J==12.1, 6.2, 1.1, 1.1 Hz, 1H), 2.38 (dddd, J==13.3, 13.3, 6.2, 6.2 Hz, 1H), 1.92 (d, J==1.5 Hz, 3H), 1.53 (dddd, J==13.2, 3.0, 1.1, 1.1 Hz, 1H), 1.52 (s, 3H); 62.9 MHz 130 NMR: 197.69, 140.47, 137.12, 94.45, 74.95, 58.55, 27.61, 26.96, 13.85 ppm; I3 (neat): 1690, 1640 cm-1; fig m/e==168 (parent), 43 (base peak). Anal. Calcd for C9H1203: C, 64.27 H, 7.19 Found: C, 63.56 H, 7.04 3-(5-Methyl-2-fury1)propanal (9“_L A solution containing 19.0 g of 2-methylfuran (232 mmol), 20.7 g of acrolein (371 mmol), and 30 mL of glacial acetic acid in 120 mL of THF was refluxed for 6.5 h under an atmosphere of nitrogen. The cooled reaction mixture was filtered with suction through Celite (to remove the 128 particulate acrolein stabilizer which causes emulsions during the aqueous washings) and the filtrate was transferred to a separatory funnel along with 100 mL of ether. After successive washings with water (2><75 mL), saturated aqueous NaHCO3 (2><75 mL; caution, foamingl), and saturated aqueous NaCl (l><50 mL), the organic phase was dried over anhydrous M9504, filtered, and the solvents were removed under reduced pressure to give an orange— brown oil. Vacuum distillation of this material gave 21.8 g (68%) of the title compound, bp==34-36°c (0.10 mm Hg). 1H NMR: 69.67 (t, J==1 Hz, 1H), 5.78 (br s, 2H), 2.80 (m, 4H), 2.20 (s, 3H); 62.9 MHz 130 NMR: 201.08, 152.09, 150.82, 106.18, 106.07, 42.05, 20.91, 13.41 ppm; £3 (neat): 1725, 1610, 1565 cm’l; 99; m/e==138 (parent), 95 (base peak). Ethyl 5-(5-methyl-2-furyl)-2-pentenoate (963i A solution containing 6.00 g of aldehyde 99a (43.4 mmol) and 16.64 g of carbethoxymethylenetriphenylphos— phorane (47.8 mmol) in 150 mL of THF was stirred at room temperature for 12 h. The semi-solid which was obtained after evaporating the solvent under reduced pressure was suspended in 125 mL of ice-cold 1:1 ether-hexanes and suction filtered. The filtrate solvents were then removed under reduced pressure affording a pale yellow liquid, 129 from which the last traces of triphenylphosphine oxide were removed by passage through a short column (silica gel, ether). In this way, 8.86 g (99%) of the title compound was obtained. 1H NMR: 66.88 (dt, J==l6.6 Hz, 1H), 5.92 (dt, J==l6.1 Hz, 1H), 5.93 (br s, 2H), 4.12 (q, J==7 Hz, 2H), 2.60 (m, 4H), 2.22 (s, 3H), 1.25 (t, J=7 Hz, 3H); 62.9 MHz 13c NMR: 166.44, 152.59, 150.59, 147.59, 122.09, 106.07, 105.98, 60.13, 30.76, 26.73, 14.26, 13.41 ppm; g9: m/e==208 (parent), 95 (base peak). 5-Methyl-2—(5-hydroxy—3-pentenyl)furan (973L A solution of 8.40 g of ester 96a (40.4 mmol) in 35 mL of anhydrous ether was added dropwise to a solution of 60 mL of 25% diisobutylaluminum hydride in toluene (1.5 M, 89.8 mmol) at 0°C under an atmosphere of nitrogen. After the addition was complete (10 min), the cooling bath was removed and stirring was continued for 1.5 h. Excess hydride was destroyed by the cautious dropwise addition of methanol (5 mL), and the reaction mixture was slowly poured into 200 mL of ice-cold 2N HCl. The organic phase was separated and the aqueous phase extracted with ether (2><60 mL). The organic phases were combined and washed successively with 1N HCL (1><50 mL), saturated aqueous NaHCO3 (1><50 mL), saturated aqueous NaCl (l><50 mL), dried over anhydrous MgSO4, and filtered. Removal of the solvents under reduced pressure gave 6.23 g (94%) of 130 the title compound. The purity of this material was sufficient for use in the next step. 1H NMR: 65.77 (s, 2H), 5.60 (m, 2H), 3.98 (br d, J==3 Hz, 2H), 2.5-2.8 (m, 4H), 2.21 (s, 3H); 62.9 MHz 13C NMR: 153.61, 150.32, 131.74, 129.91, 105.83, 105.62, 63.52, 30.76, 27.82, 13.44 ppm; fig: m/e==l66 (parent), 95 (base peak). 5-(5-Methyl—2-furyl)-2(E)-pentenal (98g) A solution of 6.00 g of allylic alcohol 93a (36.1 mmol) in 15 mL of dry methylene chloride was added to a suspension of 14.15 g of pyridinium chlorochromate (65.8 mmol) in 45 mL of dry methylene chloride at 0°C under an atmosphere of nitrogen. fter the addition was complete (3 min), the cooling bath was removed and the progress of the reaction was monitored by TLC (SiOZ, 1:1 ether-hexane) for disappearance of starting material (Rf alcohol==0.28, Rf aldehyde==0.46). When the reaction was complete (1.5-2.0 h), the dark mixture was diluted with 200 mL of ether and filtered through a fritted funnel packed with Florisil (bottom layer) and Celite (top layer). The remaining black salts were broken up, slurried in ether, and filtered. The filtrate solvents were removed under reduced pressure leaving a pale yellow- green liquid (4.45 g) which was purified by column chromatography (silica gel, 25% ether-hexanes) to give 4.04 g (68%) of the title compound as a very pale yellow 131 liquid. 250 MHz 1H NMR: 69.52 (d, J==7.8 Hz, 1H), 6.86 (dt, J==15.4, 6.4 Hz, 1H), 6.15 (ddt, J==15.4, 7.8, 1.3 Hz, 1H), 5.88 (AB q, J==3.0 Hz, 2H), 2.80 (br t, J==6.8 Hz, 2H), 2.68 (m, 2H), 2.24 (d, J==1.0 Hz, 3H); 62.9 MHz 13C NMR: 193.78, 156.79, 152.06, 150.88, 133.50, 106.36, 105.98, 31.20, 26.49, 13.47 ppm; 15 (neat): 1690, 1635, 1565 cm-1; E§=HV%3= 164 (parent), 95 (base peak). 2-(3(E),5-Hexadienyl)-5-methylfuran (993L To a rapidly stirred suspension of 10.45 g of (methyl)triphenylphosphonium bromide (29.2 mmol) in 85 mL of anhydrous THF at 0°C under a nitrogen atmosphere was added 17.3 mL of n-butyllithium in hexane (1.55 M, 26.8 mmol) dropwise over a period of 5 min, and the resulting yellow-orange solution was stirred for 2 h, allowing the cooling bath to warm to room temperature. The solution was then re-cooled to -10°C using an ice- salt bath, when a solution of 4.00 g of enal 99a (24.4 mmol) in 25 mL of anhydrous THF was introduced dropwise over a period of 15 min. Stirring was continued at -10°C for 45 min and then, after removing the cooling bath, at room temperature for an additional 45 min. Excess ylid was destroyed by the dropwise addition of glacial acetic acid, until the color of the ylid had dissipated. Pentane (125 mL) was added, and the supernatant liquid was decanted from the gummy precipitate into a 1000-mL 132 Erlenmeyer flask containing 300 mL of pentane. The gummy residue was washed twice with 1:1 pentane-ether (75 mL) and the combined organic phases were cooled at -20°C overnight. The resulting cloudy suspension was filtered through Celite into a lOOO-mL round-bottomed flask and the solvents were distilled at atmospheric pressure through a 30 cm Vigreaux column until the volume had been reduced to ca. 20 mL. The remaining liquid was then passed through a short column of silica gel using 10% ether- pentane. The product was collected in one large fraction (250 mL) and the solvents were removed by distillation at atmospheric pressure. The remaining pale yellow liquid was vacuum distilled to give 3.20 g (81%) of diene 99a as a colorless liquid, bp==34-37°c (0.18 mm Hg). 250 MHz 1H NMR: 66.29 (dt, J==16.9, 10.3 Hz, 1H), 6.08 (ddm, J==15.0, 10.3 Hz, 1H), 5.83 (AB q, J==2.9 Hz, 2H), 5.71, (dt, J==15.0, 7.0 Hz, 1H), 5.09 (dm, J==16.9 Hz, 1H), 4.96 (dm, J==10.3 Hz, 1H), 2.67 (t, J==7.2 Hz, 2H), 2.41 (q, J==7.1 Hz, 2H), 2.24 (d, J==0.8 Hz, 3H); 62.9 MHz 130 NMR: 153.64, 150.26, 137.18, 133.77, 131.74, 115.18, 105.89, 105.65, 31.17, 27.91, 13.44 ppm; ;§_(neat): 1640, 1600, 1560 cm’l; gg; m/e==162 (parent), 95 (base peak). 133 3-(3,S-Dimethyl-Z-furyl)propanal (952i The procedure was followed as for 95a, using 6.00 g of 2,4-dimethylfuran. There was obtained 5.89 g (62%) of the title compound after distillation, bp==45- 47°C (0.10 mm Hg). 1H NMR: 69.67 (t, J==l Hz, 1H), 5.65 (S, 1H), 2.75 (m, 4H), 2.17 (S, 3H), 1.88 (s, 3H); 62.9 MHz 13c NMR: 201.61, 149.73, 146.79, 115.21, 108.96, 42.52, 18.76, 13.38, 9.76 ppm; £3 (neat); 1720, 1635, 1575 cm-1; £9: m/e==152 (parent), 109 (base peak). Ethyl 5-(3,5-dimethy1-2—fury1)—2—pentenoate (9621 The procedure was followed as for 96a, using 5.50 g of aldehyde 99b. There was obtained 7.88 g (98%) of the title compound as a colorless liquid. 1H NMR: 66.88 (dt, J==15.5, 6.5 Hz, 1H), 5.75 (dm, J==15.5 Hz, 1H), 5.65 (s, 1H), 4.15 (q, J==7 Hz, 2H), 2.58 (m, 4H), 2.17 (s, 3H), 1.87 (s, 3H), 1.25 (t, J==7 Hz, 3H); 62.9 MHz 13C NMR: 166.58, 147.94, 149.53, 147.44, 121.89, 115.09, 108.77, 60.16, 14.29, 31.35, 24.70, 13.41, 9.82 ppm; 35 (neat): 1720, 1650, 1575 cm’l; fig; m/e==222 (parent), 109 (base peak). 134 3,5-Dimethyl-2-(5-hydroxy-3-pentenyl)furan (92b) The procedure was followed as for 92a, using 7.50 g of ester 99b. There was obtained 5.83 g (96%) of the title compound as a colorless oil. 1H NMR: 65.63 (s, 1H), 5.56 (m, 2H), 3.98 (br d, J==3 Hz, 2H), 2.7-2.3 (m, 5H, including OH), 2.17 (s, 3H), 1.87 (s, 3H); 62.9 MHz 13C NMR: 149.20, 148.47, 131.94, 129.77, 114.62, 108.71, 63.52, 31.41, 25.82, 13.41, 9.82 ppm; ;3_(neat): 3300, 1665, 1635, 1575 cm‘l; gg: m/e==l80 (parent), 109 (base peak). 5-(3,5-Dimethyl-2—furyl)-2(E)-pentenal (982L The procedure was followed as for 99a, using 5.50 g of allylic alcohol 92b. There was obtained 3.15 g (58%) of the title compound as a pale yellow oil. 250 MHz 1H NMR: 69.49 (d, J==8.l Hz, 1H), 6.84 (dt, J==15.8, 6.7 Hz, 1H), 6.12 (ddt, J==15.8, 8.1, 1.4 Hz, 1H), 5.74 (s, 1H), 2.75-2.6 (m, 4H), 2.20 (d, J==0.9 Hz, 3H), 1.89 (s, 3H); 62.9 MHz 13C NMR: 193.75, 157.17, 149.65, 146.97, 133.38, 115.33, 115.33, 108.86, 31.76, 24.41, 13.38, 9.79 ppm; 13 (neat): 1685, 1635, 1575 cm'l; 99: m/e==178 (parent), 109 (base peak). 135 3,5-Dimethyl-2-(3(E),5-hexadienyl)furan (9 ) ~——— The procedure was followed as for 99a, using 3.00 g of enal 99b. There was obtained 2.61 g (88%) of the title compound, bp==47-50°C (0.10 mm Hg). 250 MHz 1H NMR: 66.28 (dt, J=l7.l, 10.1 Hz, 1H), 6.06 (ddm, J==10.2, 15.0 Hz, 1H), 5.71 (S, 1H), 5.69 (dt, J==15.0, 7.0 Hz, 1H) 5.07 (dm, J==17.l HZ, 1H), 4.95 (dm, J==10.1 Hz, 1H), 2.59 (br t, J==6.7 HZ, 2H), 2.35 (br q, J==7.0 Hz, 2H), 2.19 (d, J==0.9 HZ, 3H), 1.87 (8, 3H); 62.9 MHZ 13C NMR: 149.20, 148.44, 137.24, 134.09, 131.50, 115.06, 114.62, 108.68, 31.79, 25.88, 13.41, 9.79 ppm; 13 (neat): 1650, 1595, 1575 cm'l; 119: m/e=176 (parent), 109 (base peak). 3(Z),8(E),10-Undecatriene-2,5-dione (1031 To a solution of 720 mg of furyl diene 99a (4.44 mmol) in 30 mL of methylene chloride at -10°C (ice-salt bath) was added 811 mg of MCPBA (4.00 mmol) in one portion. After being stirred 1.5 h at -10°C, and then for 0.5 h at room temperature, the mixture was extracted with saturated aqueous NaHCO3 (3><40 mL), dried over anhydrous NaZSO4, and filtered. The solvent was removed under reduced pressure to give 740 mg of a light yellow oil. Analysis of this material by TLC (SiOZ, 40% ether-hexane, anisaldehyde—sulfuric acid spray visualization) indicated the presence of at 136 least five components (R ==0.68, 0.54, 0.48, 0.21, 0.11). f Separation of this mixture was accomplished by flash column chromatography (40% ether-hexane eluent) to give the following products, in order of their elution: starting furan 99a (96 mg, 13%); epoxyfurans 191 and 192 (only partially separated; combined mass==26 mg, 3.8% based on consumed starting material); the title compound 193 (478 mg, 70% based on consumed starting material); and di-oxidized epoxyenedione 194 (29 mg; 3.9% based on recovered starting material). The desired enedione product 193 was obtained as a pale yellow liquid which underwent intramolecular Diels-Alder cyclization upon storage at room temperature as a neat liquid or in solution. 250 MHz 1H NMR: 66.32 (s, 2H), 6.29 (ddd, J==16.8, 10.6, 10.6 Hz, 1H), 6.09 (ddm, J==14.9, 10.6 Hz, 1H), 5.70 (dt, J==14.9, 7.2 Hz, 1H), 5.11 (dm, J==16.8 Hz, 1H), 4.99 (dm, J==10.6 Hz, 1H), 2.65 (t, J==7.4 Hz, 2H), 2.43 (br q, J;~7.2 Hz, 2H), 2.39 (s, 3H); 62.9 MHz 130 NMR: 201.84, 200.28, 136.91, 135.91, 135.53, 132.80, 131.97, 115.59, 41.84, 29.73, 26.41 ppm; £3 (neat): 1690, 1600 cm-1; fig: m/e 178 (parent), 98 (base peak). Spectral data for epoxyfuran 191. 250 MHz 1H NMR: 65.87 (AB q, J==3.2 Hz, 2H), 5.57 (ddd, J==17.1, 9.6, 7.2 Hz, 1H), 5.43 (dd, J==17.1, 2.1 Hz, 1H), 5.25 (ddm, J==9.6, 2.1 Hz, 1H), 3.09 (dd, J==7.2, 2.1 Hz, 1H); 2.90 (ddd, J==6.0, 5.3, 2.1 Hz, 1H), 2.78-2.70 (m, 2H), 2.25 (br S, 3H), 1.95—1.85 (m, 2H). 137 Spectral data for epoxyfuran 102. 250 MHz 1H NMR: 65.99 (dt, J==15.7, 6.8 Hz, 1H), 5.85 (AB q, J==2.9 Hz, 2H), 5.20 (ddt, J==15.7, 8.2, 1.5 Hz, 1H), 3.32 (ddd, J==8.2, 4.1, 2.8 Hz, 1H), 2.94 (dd, J==5.1, 4.1 Hz, 1H), 2.67 (t, J==7.2 Hz, 2H), 2.64 (dd, J==5.1, 2.7 Hz, 1H), 2.40 (gm, J;~7.2 Hz, 2H), 2.25 (br s, 3H). Spectral data for epoxyenedione 104. 250 MHz 1H NMR: 66.34 (5, 2H), 5.58 (ddd, J==16.9, 9.5, 6.9 Hz, 1H); 5.46 (dd, J==16.9, 2.3 Hz, 1H), 5.27 (ddm, J==9.5, 2.3 Hz, 1H), 3.15 (dd, J==6.9, 2.1 Hz, 1H), 2.94 (ddd, J==7.0, 4.4, 2.1 Hz), 2.71 (t, J==7.1 Hz, 2H), 2.30 (s, 3H); 2.11 (dtd, J==14.6, 7.1, 4.4 Hz, 1H), 1.88 (dq, J==14.6, 7.1 Hz, 1H); 62.9 MHz 13C NMR: 201.63 (second carbonyl resonance not observed), 135.82, 135.68, 135.47, 119.21, 59.25, 58.87, 38.26, 29.76, 25.73 ppm; £5 (neat): 1690, 1605 cm‘l; PE: m/e=l94 (parent), 82 (base peak). 4-Methyl-3(Z),8(E),10-undecatriene-2,5-dione (199L To a solution of 750 mg of furyl diene 99b (4.26 mmol) in 35 mL of methylene chloride at 0°C was added 779 mg MCPBA (3.84 mmol) in one portion. After being stirred for l h at 0°C, and then for 0.5 h at room temperature, the mixture was extracted with saturated aqueous NaHCO3 (3><40 mL), dried over anhydrous NaZSO4, and filtered. Evaporation of the solvent under reduced pressure gave 138 787 mg of a colorless oil. Analysis of this material by TLC (SiOZ, 50% ether-hexane, anisaldehyde-sulfuric acid spray visualization) indicated the presence of only two components, Rf==0.69 and 0.31. Separation of this mixture by flash column chromatography (30% ethyl acetate-hexane eluent) gave 74 mg of starting furan 99b (10%), and 710 mg of the title compound (95% based on consumed starting material) as a pale yellow liquid. 250 MHz 1H NMR: 66.29 (ddd, J=l6.8, 10.1, 10.1 Hz), 6.10 (q, J==1.8 Hz, 1H), 6.08 (Splitting obscured, 1H), 5.74 (dt, J==15.0, 6.8 Hz, 1H), 5.09 (dm, J==16.8 Hz, 1H), 4.96 (dm, J==10.l Hz, 1H), 2.61 (m, 2H), 2.48 (br q, J'~6.8 Hz, 2H), 2.19 (s, 3H), 1.96 (d, J==1.8 Hz, 3H); 62.9 MHz 13C NMR: 208.10, 196.64, 155.79, 137.03, 133.32, 131.77, 124.68, 115.33, 39.93, 29.96, 26.35, 20.44 ppm; £3 (neat): 1690, 1615 cm-1; 33: parent ion not observed, m/e==112 (M-80, base peak). 3(E),8(E),lO—Undecatriene-2,5-dione (195) via PCC oxidation A solution of furyl diene 99a (1.00 g; 6.17 mmol) in 3 mL of dry methylene chloride was added dropwise over a period of ca. 1 min to a suspension of pyridinium chlorochromate (7.95 g; 37 mmol) in 20 mL of dry methylene chloride at 0°C under an atmosphere of nitrogen. After 15 min, the cooling bath was removed and the mixture was stirred for 20 h at room temperature, and then for 6 h at 139 reflux. Ether (75 mL) was added to the cooled reaction mixture, and the resulting suspension was suction filtered through a glass frit packed with Florisil. The black salts remaining in the reaction flask were broken up in ether and filtered. The filtrate solvents were removed under reduced pressure to give 632 mg of a pale yellow oil. Analysis of this material by TLC (SiOz, 1:1 ether-hexane, anisaldehyde-sulfuric acid spray visualiza- tion) indicated the presence of at least four components (Rf==0.70, 0.37, 0.31, 0.26). Separation of this mixture by flash column chromatography (30% ethyl acetate- hexane eluent) gave the following products, in order of their elution: starting furan 99a (100 mg, 10%); the title compound 196 (296 mg, 30% based on consumed starting material); hydrindenone l£1b (84 mg,8.5% based on consumed starting material); and hydrindenone l£0b (89 mg, 9% based on consumed starting material). The desired triene 196 was obtained as a pale greenish-yellow waxy solid (mp~30°C). 250 MHz 1H NMR: 66.83 (s, 2H), 6.29 (ddd, J==16.9, 10.2, 10.2 Hz, 1H), 6.09 (ddm J==15.4, 10.2 Hz, 1H), 5.69 (dt, J==15.4, 7.1 Hz, 1H), 5.12 (dm, J==16.9 Hz, 1H), 5.00 (dm, J==10.2 Hz, 1H), 2.78 (t, J==7.6 Hz, 2H), 2.44 (br q, J'~7.2 Hz, 2H), 2.37 (s, 3H); 62.9 MHZ 13C NMR: 199.52, 198.22, 137.06, 136.97, 136.77, 132.35, 132.24, 115.89, 40.76, 28.20, 26.47 ppm; £3 (neat): 1685, 1620 cm-1; 33: parent ion not observed, m/e==135 (M-43), 43 (base peak). 140 3(E),8(E),10-Undecatriene-2,5-dione (105) via pyridine isomerization of dis-enedione (103) To a solution of freshly chromtographed dis-enedione 193 (212 mg; 1.19 mmol) in chloroform (3 mL) was added an equal volume of pyridine. The mixture was checked periodically by TLC (8102, 1:1 ether-hexane) for disap- pearance of starting material (Rf== 0.27) and appearance of product (Rf==0.38). After 18 h, the solvents were removed in vacuo and the residue was flash chromatographed (30% ethyl acetate-hexane eluent) to give, in order of elution: 84 mg of the title compound (40%); hydrindenones l£0a and l£lb as an inseparable mixture (43 mg, 20%); and hydrindenone llOb (41 mg, 19%). Attempted isomerization of dis-enedione 105 using DBU: 2,4-dimethyl-4-hydroxy-5-(2,4—pentadienyl)-2-cyclo- pentenone (lOZL To a solution of dis-enediones 105 (192 mg; 1.00 mmol) in chloroform-d (5 mL) was added 1,8—diazabicyclo- l [5.4.0]undec-7-ene (0.15 g; 1.0 mmol). The reaction progress was followed by proton NMR, and after 5 min, all of the starting material had been consumed. The reaction mixture was diluted with methylene chloride (20 mL) and extracted with 1% aqueous HCl (2><20 mL), saturated aqueous NaHCO3 (1><20 mL), dried over anhydrous NaZSO4, and filtered. 141 Evaporation of the solvents under reduced pressure gave a pale brown oil which was passed through a short column of silica gel (40% ether-hexane eluent) to give 138 mg of the title compound (72%) as a colorless oil. 250 MHz 1H NMR: 67.03 (q, J==1.5 Hz, 1H), 6.33 (ddd, J==16.8, 10.1, 10.1 Hz, 1H), 6.19 (ddm, J==15.0, 10.1 Hz, 1H), 5.85 (ddd, J==15.0, 7.6, 5.8 Hz, 1H), 5.12 (dm, J==16.8 Hz, 1H), 5.00 (dm, J==lO.l Hz, 1H), 2.67 (ddd, J==15.3, 5.8, 4.6 Hz, 1H), 2.62 (br s, 1H; 03), 2.54 (dd, J==9.5, 4.6 Hz, 1H), 2.19 (ddd, J==15.3, 9.5, 7.6 Hz, 1H), 1.76 (d, J==1.5 Hz, 3H), 1.36 (s, 3H); 62.9 MHz 13C NMR: 206.28, 159.55, 139.85, 136.94, 132.77, 132.47, 115.62, 58.75, 28.91, 24.58, 9.82 ppm. Isomerization of dis-enedione 105 using triethylamine: 4-methyl-3(E),8(E),lO-undecatriene-2,S-dione (199) and 4-methylidene-8,10(E)-undecadiene-2,S-dione (199£ To a solution of 405 mg of dis-enedione 195 (2.11 mmol) in 6 mL of chloroform was added 3 mL of triethylamine. After 8 h at room temperature, the solvents were removed under reduced pressure to give a pale brown oil. Analysis of this mixture by proton NMR (250 MHz) revealed the presence of the starting dis-enedione 195 along with the trans isomer 199 and deconjugated isomer 198 in a ratio of l:l.2:l.8, respectively. Analysis of this mixture by TLC (SiOz, 40% ether-hexane) showed two UV-active spots at 142 Rf==0.38 and 0.26. Flash column chromatography (40% ether-hexane eluent) provided 118 mg of trans-enedione 199 (29%) and 277 mg of a 1:1.8 mixture of dis-enedione 195 and deconjugated isomer 198. The latter two compounds were totally inseparable by column chromatography. The desired trans-enedione 199 was obtained as a colorless liquid and exhibited the following spectral properties. 250 MHz 1H NMR: 66.84 (q, J==1.5 Hz, 1H), 6.29 (ddd, J==17.1, 10.3, 10.3 Hz, 1H), 6.09 (ddm, J==15.0, 10.3 Hz, 1H), 5.70 (dt, J==15.0, 7.0 Hz, 1H), 5.12 (dm, J==17.1 Hz, 1H), 5.00 (dm, J==10.3 Hz, 1H), 2.82 (t, J==7.0 Hz, 2H), 2.42 (br q, J;~7.0 Hz, 1H), 2.34 (s, 3H), 2.16 (d, J==1.5 Hz, 3H); 62.9 MHz 13C NMR: 201.93, 199.63, 147.26, 136.82, 132.77, 132.15, 130.83, 115.80, 37.96, 32.05, 26.94, 13.64 ppm; £3 (neat): 1685, 1615 cm-1; 33 m/e==l92 (parent), 43 (base peak). Spectral data for 198 (analyzed as a mixture with 105). 250 MHz 1H NMR: 66.18 (s, 1H) and 5.86 (t, J==l.l Hz, 1H) are due to the methylidene group (the diene resonances were obscured by similar resonances in 105), 3.38 (S, W ==2.1 Hz, 2H), 2.83 (t, J==7.3 Hz, 5 2H), 2.39 (br q, J'~7.1 Hz, 2H), 2.18 (s, 3H); 62.9 MHz iig_flfl3: 205.25, 199.90, 142.79, 136.94, 133.21, 131.80, 127.33, 115.48, 45.90, 36.61, 29.82, 27.02 ppm. 143 Intramolecular Diels-Alder cyclization of 103 to ~ hydrindenones 110a and 1193 A solution of triene 103 (425 mg; 2.39 mmol) in chloroform (20 mL) was refluxed for 4.5 h, after which time TLC analysis (SiOz, 30% ethyl acetate-hexane, anisalde- hyde-sulfuric acid spray visualization) indicated that all of the starting material (Rf==0.47) had been consumed, leaving two closely spaced spots at Rf==0.23 and 0.30. The solvent was removed under reduced pressure and the residue was flash chromatographed (25% ethyl acetate- hexane eluent) to give, in order of their elution, 197 mg of trans-fused hydrindeone l£0a (46%) and 194 mg of cis- fused hydrindenone l£0b (46%). The latter product solidified upon removal of the solvent, and was recrystal- lized from methylene chloride-hexane (1:10) to give 1£0b as white needles, mp==84-85°C. Spectral data for cis-fused hydrindenone llOb: 250 MHz 1H NMR: 65.80 (doublet of pentets (dddd), J==10.0, ~2.5 Hz, 1H), 5.60 (dm, J==10.0 Hz, 1H), 3.16 (ddm, J==7.7, 3.5 Hz, 1H),;v3.12 (m, overlaps with signal at 63.16, 1H), 2.55 (ddd, J==10.8, 6.1, 3.5 Hz, 1H), 2.26 ‘3 (s, 3H), 1.95 (m); 62.9 MHz 1”C NMR: 217.95, 208.75, 129.44, 128.03, 49.99, 45.49, 37.64, 34.73, 27.67, 27.17, 23.08 ppm; £3 (Nujol): 1725, 1700 cm-l; 33: m/e==l78 (parent), 43 (base peak). 144 Spectral data for trans-fused hydrindenone l£0a: 250 MHz 1H NMR: 65.88 (dq (dddd), J==10.2,;~2.0 Hz, 1H), 5.66 (dddd, J==10.2, 3.9, 3.2, 3.2 Hz, 1H), 3.35 (ddd, J==7.4, 3.7, 3.7 Hz, 1H), 2.16 (S, 3H), 1.98 (ddd, J==13.6, 3.7, 1.2 Hz, 1H), 1.50 (m); 62.9 MHz 13c NMR: 214.25, 208.25, 129.91, 126.91, 54.61, 44.11, 38.32, 35. 96, 29.49, 27.94, 26.47 ppm. Epimerization of trans-fused hydrindenone 110a to cis- fused 1£13 Upon standing at room temperature for two weeks in methylene chloride, a sample of l£0a epimerized to give a ca. 1:1 mixture of 1£0a and trans—fused l£lb. These two products could not be separated by flash column chroma- tography. Spectral data for lllb, as analyzed from the mixture, are as follows. 250 MHz 1H NMR: 65.73 (doublet of pentets (dddd), J==10.2,:~2.4 Hz 1H), 5.59 (dm, J==10.2 Hz, 1H), 3.10 (ddd, J==7.2, 3.5, 3.5 Hz, 1H), 3.02 (m, 1H), 2.77 (ddd, J==7.3, 3.5, 0.9 Hz, 1H), 2.20 (s, 3H); 62.9 MHz 13C NMR: 219.51, 209.43, 129.50, 126.44, 48.52, 44.87, 35.26, 34.35, 27.67, 27.05, 22.82 ppm. Intramolecular Diels-Alder cyclization of 106 to hydrinde- nones 111a and 1£13 A solution of triene 196 (110 mg; 0.62 mmol) in chloroform (6 mL) was refluxed for 36 h, after which time 145 TLC analysis (SiOZ, 1:1 ether—hexane, anisaldehyde-sulfuric acid spray visualization) indicated that the starting material (Rf==0.44) had been completely consumed. The solvent was removed under reduced pressure, and the residue was flash chromatographed (35% ether-hexane eluent) to give 90 mg of hydrindenones l£la and 1£1b (82%) as an inseparable mixture. From integration in the proton NMR, these products were obtained in a ratio of 1.7:1, respec— tively. Spectral data for cis-fused l£lb were given in the previous experiment. Spectral data for trans-fused hydrindenone l£la, as analyzed from the mixture, are as follows. 250 MHz 1H NMR: 65.89 (dm, J==10.3 Hz, 1H), 5.69 (dm, J==10.3 Hz, 1H), 2.85 (ddd, J==10.3, 10.3, 6.8 Hz, 1H), 2.32 (s, 3H), 1.63 (m); 62.9 MHz 13C NMR: 214.10, 210.87, 55.28, 46.46, 39.76, 37.17, 30.26, 29.76, 26.29 ppm. Intramolecular Diels-Alder cyclization of 105 to hydrindenones l£2a and 1133 A solution of triene 195 (183 mg; 0.95 mmol) in chloroform (8 mL) was refluxed for 54 h, after which time TLC analysis (SiO 40% ether-hexane,'anisaldehyde‘SUIfuriC 2! acid spray visualization) indicated that the starting material had been completely consumed. The solvent was removed under reduced pressure and the residue was flash chromatographed (30% ether-hexane eluent) to give 159 mg 146 of hydrindenones l£2a and l£2b (87%) as an inseparable mixture. As determined from integration of the angular methyl groups in the proton NMR spectrum, l£2a and l£2b were obtained in a ratio of 4.9:1, respectively. The difference in relative abundance of the two products made possible assignments in the 13C NMR spectrum on the basis of signal intensities, except where noted by an asterisk (*). Spectral data for trans-fused hydrindenone l£2a. 250 MHz 1H NMR: 65.75 (d q (dddd), J==10.0,;~2.4 Hz, 1H), 5.61 (d q (dddd), J==10.0,'~3.3 Hz, 1H), 3.01 (dd, J==8.5, 1.8 Hz, 1H), 3.10 (m, 1H), 2.18 (S, 3H), 0.89 (s, 3H); 62.9 MHz 130 NMR: 217.92, 209.31, 127.56, 125.15, 50.93, 49.11*, 38.40, 36.58, 30.26, 26.02, 22.52, 15.70 ppm. Spectral data for dis-fused hydrindenone l£2b. 250 MHz 1H NMR: the olefinic resonances are obscured by those of 112a, 62.87 (dd, J==5.8, 5.2 Hz, 1H), 2.13 (S, 3H), 1.14 (S, 3H); 62.9 MHz 13C NMR: 222.51, 209.19, 131.24, 122.65, 55.19*, 47.34, 44.73*, 37.51, 28.05, 26.20, 24.90, 24.20 ppm. Intramolecular Diels-Alder cyclization of 199 to hydrindenones 1£3a and l£3§ A solution of triene 109 (212 mg; 1.10 mmol) in chloroform-dl (8 mL) was refluxed for 6 h, when an aliquot 147 was withdrawn and examined by 250 MHz 1H NMR. The spectrum revealed that no reaction had taken place. The aliquot was combined with the reaction mixture and the solvent was removed in vacuo. Toluene-d8 (5 mL) was added, and the mixture was refluxed. Aliquots were removed after 4 h and 15 h, the latter indicating that cyclization was only ca. 35% complete. Small resonances at 0.89 and 1.14 ppm (relative ratio==5:1, respectively) indicated the presence of the hydrindenone mixture l£2a,b derived from dis-enedione 195. The reaction mixture was allowed to cool and then transferred to a re-sealable high pressure reaction vessel along with 15 mg of methylene blue as a radical inhibitor.72 After flushing the system with nitrogen, the vessel was sealed and immersed into a silicon oil bath at 195°C for 8 h. After cooling to room temperature, the vessel was opened, the contents transferred to a round-bottomed flask, and the solvent was removed under reduced pressure. The residue was analyzed by 250 MHz 1 H NMR, which indicated the presence of a 50:50 mixture of hydrindenones 1£3a and l£3b, ca. 10% of the l£2a,b hydrindenone pair, less than 5% of the deconjugated triene 198, and a small amount of starting material. Separation of these products was effected by flash column chromatography (35% ether-hexane eluent) to give, in order of their elution, 7 mg of starting material 199 (3.3%), 43 mg of a ca. 10:1 mixture of 113a-113b (20%), 99 mg of a ca. 1:2.5 mixture of 113a-113b (47%), and 18 mg 148 of a mixture of triene 108 and hydrindenones 112a,b (8.5% combined yield). Spectral data for trans-fused hydrindenone 113a. 250 MHz 1H NMR: 65.69 (m, 2H), 2.99 (dd, J==10.7, 6.6 Hz, 1H), 2.36 (s, 3H), 0.99 (s, 3H); 62.9 MHz i:g_§§§; 217.28, 210.75, 127.94, 126.18, 51.25, 50.81, 45.46, 35.70, 32.85, 28.17, 22.38, 9.15 ppm. Spectral data for cis-fused hydrindenone 113b. 250 MHz 1H NMR: 05.69 (m, 2H), 3.04 (dd, J==6.4, 4.0 Hz, 1H), 2.88 (m, 1H), 2.17 (s, 3H), 1.03 (s, 3H); 62.9 MHz 130 NMR: 221.45, 209.13, 130.59, 124.36, 49.55. 48.28. 42.43, 34.17, 30.64, 25.38, 24.49, 19.41 ppm. 149 Condensation of 123 with acetone to give linear nonamer 127_ Trimer 123 (15.0 g; 52.8 mmol) was suspended in 125 mL of absolute ethanol. Gaseous HC1 was bubbled into the mixture for ca. 6 min, which generated enough heat to dissolve all of the starting material. Then, with mechanical stirring, a solution of acetone (4.0 g; 68 mmol) in 20 mL of absolute ethanol was added dropwise over a period of ca. 10 min. After being stirred at room temperature for another 10 min, a white precipitate began to form. Stirring was continued for 15 h, and then the mixture was allowed to stand for 20 h at room temperature, during which time the suspension had become very thick. The precipitate was collected by suction filtration, dissolved in methylene chloride (200 mL), and washed with saturated aqueous NaHCO3 (2><100 mL) and saturated aqueous NaCl (1><100 mL). The resulting greenish solution was dried over anhydrous NaZSO4, filtered, and condensed in vacuo to ca. 30 mL, with precipitation. Ethanol (100 mL) was added and the suspension was cooled at -30°C for 2 h. Suction filtration gave 10.2 g of the title compound as an off-white amorphous solid (83%), mp==107-ll2°C. This material was not purified further. A second crop (1.7 g) of a white crystalline material was obtained. Proton NMR analysis indicated that it was the cyclic hexamer 126 (10%), mp=179-181°c (111:.91 Spectral properties of nonamer 127. 1H NMR: 57.17 mp = 182° C). 150 (m, 2H), 6.12 (m, 2H), 5.82 (dm, J==3 Hz, 2H), 5.68 (m, 14H), 15.5 (s, 48H). Formylation of linear nonamer 127 to dialdehyde 128_ To 1.0 mL of dry dimethylformamide at 0°C was added 0.88 mL of phosphorus oxychloride (d==l.645 g/mL; 9.4 mmol) dropwise over a period of ca. 3 min. The mixture was stirred at 0°C for 1 h, during which time the solution had solidified. Dry l,2-dichloroethane (10 mL) was added and the mixture was stirred at room temperature until all of the iminium salt had dissolved. The colorless solution was cooled to 0°C, when a solution of 127 (4.0 g; 4.3 mmol) in 20 mL of dry l,2-dichloroethane was added dropwise over a period of 0.5 h. After the reddish brown reaction mixture had been stirred at room temperature for 8 h, a solution of 10 g of sodium acetate in 50 mL of water was added, and the resulting two-phase mixture was stirred at room temperature overnight. The layers were separated and the aqueous phase was extracted with chloroform (2><25 mL). The combined organic phases were washed with water (1><25 mL), saturated aqueous NaHCO3 (2><25 mL), saturated aqueous NaCl (l><25 mL), dried over anhydrous Na2S04, and filtered. Removal of the solvent under reduced pressure gave 3.94 g of a pale yellow solid which was recrystallized from a minimum amount of ethanol to give 3.41 g of dialdehyde 128 (80%) as a very pale yellow amorphous solid, mp==123-125°C. 151 250 MHz 1H NMR: 09.53 (s, 2H), 7.10 (d, J==3.4 Hz, 2H), 6.07 (d, J==3.4 Hz, 2H), 5.98 (d, J==3.4 Hz, 2H), 5.86 (d, J==3.4 Hz, 2H), 5.79 (m, 10H), 1.66 (s, 3H), 1.57 (s, 3H), 1.56 (s, 3H), 1.55 (s, 3H); £3 (Nujol): 1680, 1550, 1510 cm-1; g8: m/e==988 (parent), 245 (base peak). Di-ring-opened trans-enedione 129_ A magnetically stirred, lOOO-mL round-bottomed flask was charged with 5.00 g of finely powdered tetramer 121 (11.6 mmol), 650 mL of glacial acetic acid and 20 mL of distilled water. Added dropwise to the vigorously stirred suspension was a solution of 4.64 g of bromine (29.0 mmol) in 100 mL of glacial acetic acid over a period of 3 h, during which time the suspension had taken on a bright yellow color. Stirring was continued for an additional hour, and the crude product was collected by suction filtration and washed with methanol. Recrystalli- zation from chloroform to remove the acetic acid from the crude product gave 3.97 g of 129 as small bright yellow cubes, mp==276-278°c (dec). 1H NMR: 66.95 (s, 4H), 6.10 (s, 4H), 1.40 (s, 24H); 13C NMR: 194.39, 156.43, 132.47, 107.51, 48.53, 22.03 ppm; £3 (Nujol): 1698, 1540 cm”1; UV—vis: 382 nm (log s==3.25), 304 (3.67), 232 (4.52); fig: m/e==464 (parent), 150 (base peak). Anal. Calcd for C H O C, 72.39; H, 6.94 32 6‘ Found: C, 72.88; H, 6.90 28 152 Dibromo-trans-enedione 130_ ~ The procedure was followed as for 129 above, except that 7.42 g of bromine (4.0 equivalents) were used. The addition took 2.5 h, and the reaction mixture was allowed to stand overnight. The crude product was collected by suction filtration, and the proton NMR spectrum of this material showed a mixture of 129, 130, and acetic acid. The bright yellow solid was suspended in 50 mL of ethyl acetate with warming on a steam bath to dissolve 130 (129 is insoluble). The remaining solids were removed by filtration, and the filtrate was taken to dryness in vacuo. The resulting oily yellow solid was cooled in ethanol at -30°C overnight and the product was collected by suction filtration to give 2.90 g of 130 (40%). Recrys- tallization from chloroform-ethanol (1:4) gave 130 as long, fine yellow needles, mp=247-248°c (dec.). 1H NMR: 67.08 (s, 2H), 6.13 (s, 4H), 4.87 (s, 2H), 1.53 (s, 6H), 1.48 (s, 6H), 1.43 (s, 12H); 130 NMR: 199.79, 196.56, 155.27, 155.06, 133.02, 108.71, 108.35, 48.97, 48.49, 39.85, 22.68, 22.40, 22.14, 22.03 ppm; 13 (Nujol): 1710, 1675, 1530 cm’l; UV-vis: 388 nm (log s=3.03), 311 (3.47), 224 (4.32); ES (CI): m/e==625 (M+l; base peak). Anal. Calcd for C28H323r206: Found: C, 52.89; H, 5.11 C, 53.86; H, 5.17 153 Saturated tetraketone 131_ Reduction of 129, 131, and 138 using zinc in acetic acid gave a nearly quantitative yield of 131. A typical procedure is as follows. In a 250—mL Erlenmeyer flask was placed 1.00 g of di-ring-opened trans-enedione 129 (2.16 mmol) and 75 mL of glacial acetic acid. The mixture was brought to a boil on a hot plate to dissolve 129, removed from the heat for ca. 1 min, and with swirling, 2.0 g of zinc dust was added. The bright yellow solution was decolorized within seconds after addition of the zinc, indicating that the reaction was complete. After cooling to room temperature, the excess zinc and zinc salts were removed by suction filtration through celite and washed thoroughly with chloroform. The colorless filtrate was poured into two volumes of water, the layers were separated, and the aqueous phase was extracted with chloroform (2><30 mL). The combined organic phases were washed with water (l><50 mL), saturated aqueous NaHCO3 (2><50 mL), saturated aqueous NaCl (l><50 mL), dried over anhydrous Na2804, and filtered. Removal of the solvent under reduced pressure left a white crystalline solid. Cold ethanol was added and the crystals were collected by suction filtration to give 1.00 g of saturated tetraketone 131 (99%). Recrystallization from chloroform-ethanol (1:3) gave 131 as small white cubes, mp=269-270°c. 18 NMR: 66.03 (s, 4H), 2.40 (s, 8H), 1.40 (s, 24H); 13C NMR: 154 209.26, 157.44, 106.38, 48.70, 30.88, 22.94 ppm; 13 (Nujol): 1706, 1600, 1550 om’l; g8: m/e==468 (parent), 135 (base peak). Anal. Cacd for C28H36O6: C, 71.77; H, 7.74 Found: C, 72.20; H, 7.79 Tetra-ring-opened octaketone 132_ Tetramer 121 (1.00 g; 2.31 mmol) in 75 mL of chloroform was brought to a boil. The solution was removed from the heat and allowed to cool to 55-60°c, when 1.97 g of MCPBA (9.70 mmol) was added in one portion. After being stirred overnight at room temperature, the pale greenish yellow solution was extracted with saturated aqueous NaHCO3 (3><50 mL), dried over anhydrous NaZSO4, and filtered. The solution was concentrated in vacuo to ca. 15 mL, when ethanol (40 mL) was added. Cooling for several hours at 0°C gave white crystals which were collected by suction filtration to afford 0.99 g of the product (87%), mp==208-210°c (dec.). 1H NMR: 66.48 (s, 8H), 1.40 (s, 24H); 130 NMR: 200.50, 133.91, 59.77, 21.79 ppm; £3 (Nujol): 1711, 1698, 1684, 1615, 1600 cm-1; UV-vis: shoulder at 290 nm (log e==2.9), 212 (4.4); HS (CI): m/e==497 (M+1), 125 (base peak). Anal. Calcd for C28H3208: C, 67.73; H, 6.50 Found: C, 68.18; H, 6.47 155 Hexa-ring-opened dodecaketone 133_ To a solution of 0.50 g of cyclic hexamer 126 (0.77 mmol) in 35 mL of chloroform was added 0.99 g of MCPBA (4.9 mmol) in one portion. After being stirred at room temperature overnight, the pale greenish yellow solution was extracted with saturated aqueous NaHCO3 (3><40 mL), dried over anhydrous NaZSO4, and filtered. Removal of the solvent under reduced pressure gave a pale greenish yellow solid which was broken up in ethanol and cooled at —30°C for several hours. Collection of the crude product by suction filtration gave 0.49 g (85%). Recrystal- lization from chloroform-ethanol (1:4) gave 0.43 g of 133 as fluffy pale greenish yellow needles, mp==173-174°C. 1H NMR: 66.47 (s, 12H), 1.40 (s, 36H); 13c NMR: 201.08, 135.17, 60.44, 20.93 ppm; 13 (Nujol): 1685, 1630 om'l; UV-vis: shoulder at 295 nm (log €==3.0), 223 (4.42); ES (CI): m/e==745 (M+l; base peak). 102 Anal. Calcd for (C42H48012)2°CHC13. C, 63.45, H, 6.08 Found: C, 63.16; H, 6.13 Saturated octaketone 134_ A suspension of 0.50 g of tetra-ring-opened octaketone 132 (1.0 mmol), 60 mg of 10% palladium on carbon, and 60 mL of ethyl acetate was shaken under 50 psi of hydrogen in a Parr apparatus for 3 h. The catalyst was removed by 156 filtration and washed with chloroform. The filtrate was evaporated under reduced pressure, and the resulting oily solid was suspended in 20 mL of ethanol and cooled to -30°C overnight. Collection of the product by suction filtration gave 0.40 g of the product (78%) as a white crystalline solid. Recrystallization from chloroform-ethanol (1:4) 1 gave 134 as long white needles, mp==187-188°C. H NMR: 02.70 (S, 16H), 1.35 (S, 24H); 13C NMR: 207.78, 62.71, 32.72, 20.79 ppm; 13 (Nujol): 1702 om'l; gs (c1): m/e==501 (M+1), 126 (base peak). Anal. Calcd for C28H4008: C, 66.65; H, 7.99 Found: C, 66.21; H, 8.05 Saturated dodecaketone 135_ The procedure was used as in 134 above; 0.20 g of hexa-ring—opened 133 (0.27 mmol) and 10 mg of catalyst in 25 mL of ethyl acetate gave 0.13 g of 135 (65%) after recrystallization from chloroform-ethanol (1:4) as white 1 needles, mp==186-187°C. H NMR: 02.65 (s, 24H), 1.37 (s, 36H); 130 NMR: 208.12, 61.74, 32.20, 21.45 ppm; IR (Nujol): 1698 cm-1; HS: a molecular ion could not be detected using electron impact or chemical ionization; m/e==126 (base peak). Anal. Calcd for C H O C, 66.65; H, 7.99 60 12‘ 'Found: c, 66.40; H, 8.11 42 157 Tri-ring-opened hexaketone 136_ To a solution of 1.00 g of tetramer 121 (2.31 mmol) dissolved in 45 mL of chloroform was added 1.45 g of MCPBA (7.14 mmol) in one portion. After being stirred for 4.5 h at room temperature, the mixture was washed with saturated aqueous NaHCO (3><50 mL), dried over anhydrous NaZSO4, 3 and filtered. Removal of the solvent under reduced pressure gave an oily greenish yellow solid whose proton NMR spectrum showed a mixture of 136 and tetra- ring opened 132. TLC analysis (SiOZ, 4:1 chloroform- ethyl acetate, UV visualization) gave two spots at Rf==45 and 0.35. Separation of this mixture by flash column chromatography (4:1 chloroform-ethyl acetate eluent) gave 0.67 g of pure tri—ring-opened hexaketone 136. The tetra-ring-opened product 132 had evidently decomposed on the column. Recrystallization of 136 from chloroform- ethanol (1:5) gave the product as small, pale greenish yellow prisms, mp=186-187°c (dec.). 1H NMR: 66.22 (AB quartet, J==11.5 Hz, 4H), 6.53 (s, 2H), 6.12 (s, 2H), 1.43 (s, 12H), 1.38 (s, 12H); 13C NMR: 203.11, 202.33, 199.53, 157.15, 139.82, 134.81, 128.80, 106.81, 60.78, 47.86, 22.33, 22.01 ppm; 13 (Nujol): 1685, 1600, 1550 cm-1; ES: m/e==480 (parent), 149 (base peak). Anal. Calcd for C H O C, 69.98; H, 6.71 32 7‘ Found: C, 69.93; H, 6.85 28 158 Saturated hexaketone 137_ The procedure was used as for 134 above, using 165 mg of tri-ring-opened 136 (0.344 mmol), 10 mg of palladium on carbon, and 20 mL of ethyl acetate. After removing the solvent under reduced pressure, the colorless oil was crystallized by cooling in hexane-benzene (3:1) at -30°C for 24 h. The product was collected by suction filtration to give 117 mg of 137 (70%) as very small white prisms, mp-143-144°c. 1H NMR:‘ 65.97 (s, 2H), 2.55 (s, 4H), 2.48 (s, 8H), 1.38 (s, 12H), 1.33 (s, 12H); IR (Nujol): 1700, 1540 cm'l; MS: m/e==486 (parent), 135 (base peak). Anal. Calcd for C C, 69.11; H, 7.87 28H3807‘ Found: C, 68.78; H, 8.02 Di-ring-opened cis-enediones 138 and 139_ To a solution of tetramer 121 (0.70 g; 1.6 mmol) in 45 mL of chloroform at 0°C was added 0.73 g of MCPBA (3.6 mmol) in one portion. After being stirred for l h at 0°C and 2 h at room temperature, the mixture was washed with saturated aqueous NaHCO3 (3><50 mL), dried over anhydrous NaZSO4, and filtered. Removal of the solvent under reduced pressure gave a pale greenish yellow solid which was broken up in ethanol (10 mL) and cooled to 0°C for 1 h. Suction filtration afforded 0.64 g of a solid 159 which, by TLC analysis (Sioz, 8:1 chloroform-ethyl acetate, UV visualization), consisted of three components, Rf==0.62, 0.52, and 0.37. Separation of the mixture by flash column chromatography (10% ethyl acetate-chloroform eluent) gave, in order of thier elution, 0.24 g of di— ring-opened 138 (32%), 0.26g of di-ring-opened 139 (36%) and 0.15 g of tri-ring-opened 136 (19%). The di-ring- opened tetraketones were each recrystallized from chloroform-ethanol (1:6), giving 0.19 g of 138 as tiny pale yellow prisms, mp==211-212°c, and 0.20 g of 139 as pale greenish yellow plates, mp==165-166°C. Spectral data for 138. 1H NMR: 66.00 (s, 4H), 5.97 (s, 4H), 1.45 (s, 24H); 13c NMR: 202.26, 156.88, 134.13, 106.95, 48.19, 23.08 ppm; £3 (Nujol): 1700, 1610, 1600, 1550 om’l; UV-vis: shoulder at 333 nm (log s==3.0), 277 (3.53), 221 (4.41); 33: m/e==464 (parent), 150 (base peak). Anal. Calcd for C28H3206: C, 72.39; H, 6.94 Found: C, 72.29; H, 6.98 Spectral data for 139. 1H NMR: 05.95 (AB quartet, J==12 Hz, 4H), 5.87 (AB quartet, J==3 Hz, 4H), 1.58 (s, 6H), 1.52 (s, 12H), 1.18 (s, 6H); £3 (Nujol): 1695, 1680, 1605, 1540 om’l; UV-vis: shoulder at 332 nm (log e==2.8), shoulder at 290 (3.1), 221 (4.32); 33: m/e==464 (parent), 150 base peak). Anal. Calcd for C28H3206: C, 72.39; H, 6.94 Found: C, 72.50; H, 7.04 160 Di-ringfopened trans-enediones 139 and 131. To a solution of tetramer 131 (2.00 g; 4.63 mmol) in 150 mL of chloroform was added 1.88 g of MCPBA (9.26 mmol) in one portion. After being stirred for 45 min at room temperature, 1 mL of concentrated HC1 was added, causing a deepening of the initially pale greenish yellow solution. After being stirred for an additional 2 h, the solution was washed with saturated aqueous NaHCO3 (3><100 mL), dried over anhydrous NaZSO and filtered. 4: The volume was concentrated to ca. 20 mL under reduced pressure, when 50 mL of ethanol was added. After cooling at 0°C for several hours, the bright yellow precipitate which resulted was collected by suction filtration to give 0.88 g of 139 (41%), identified by its proton NMR spectrum and melting point. The orange-yellow filtrate was taken to dryness in vacuo, leaving an oil. Ethanol (25 mL) was added, and the solution was cooled to —30°C for 12 h to give a second crop of crystals. Suction filtration gave 0.41 g of 131 (19%) as yellow-orange prisms, mp==159-160°C. 1H NMR: 06.72 (AB quartet, J==16 Hz, 4H), 6.00 (AB quartet, J==3.2 Hz, 4H), 1.52 (s, 6H), 1.40 (s, 12H), 1.33 (s, 6H); 13C NMR: 197.95, 197.41, 159.93, 153.98, 133.84, 132.91, 107.36, 105.09, 61.34, 48.38, 36.81, 25.31, 22.18, 20.71 ppm; 13 (Nujol): 1700, 1680, 1615, 1600, 1550 cm’l; UV-vis: 382 nm (log = 303), 306 (3.38), 233 (4.47); Hg: m/e==464 (parent), 161 150 (base peak). Anal. Calcd for C28H3206: C, 72.39; H, 6.94 Found: C, 72.22; H, 6.91 Saturated tetraketone l40_ The procedure was used as for 134 above, using either 139 or 111. trans-Enedione 111 (150 mg; 0.323 mmol) in 25 mL of ethyl acetate with 10 mg of palladium on carbon gave 111 mg of the title compound (74%) as white needles from ethanol, mp=162-163°c. 1H NMR: 65.88 (s, 4H), 2.45 (m, 8H), 1.52 (S, 6H), 1.40 (s, 12H), 1.27 (s, 6H); £3 (Nujol): 1695, 1550 cm’l; 33: m/e=468 (parent), 150 (base peak). Anal. Calcd for C H O C, 71.77; H, 7.74 36 6‘ Found: C, 71.32; H, 7.79 28 2,2-bis[5-(3-Oxopropyl)-2-fury1]propane (1123 A solution containing 4.00 g of 2,2—bis(2-fury1)- propane 122 (22.7 mmol), 6.36 g of acrolein (114 mmol), and 0.15 g of p-toluenesulfonic acid hydrate (0.79 mmol) in 50 mL of THF was refluxed under an atmosphere of nitrogen. The reaction was monitored by TLC (SiOZ; 20% ether-hexanes, anisaldehyde—sulfuric acid spray visualization) until the starting material (Rf==0.79) had disappeared (6-7 h). The cooled reaction mixture 162 was filtered through Celite to remove the acrolein stabilizer, transferred to a separatory funnel containing an equal volume of ether, and then washed successively with saturated aqueous NaHCO3 (2><75 mL) and saturated aqueous NaCl (l><50 mL). After drying the organic phase over anhydrous MgSO4 and filtering, the organic solvents were removed under reduced pressure and the resulting thick brown oil was chromatographed (8102; 50% ether- hexane eluent) to give 2.82 g of the title compound (43%) as a viscous, pale orange oil. 1H NMR: 09.70 (t, J'~1.5 Hz, 2H), 5.88 (s, 4H), 3.0-2.5 (m, 8H), 1.60 (s, 6H); g§z m/e==2.88 (parent), 273 (base peak). 2,2-bis[5—(3-Hydroxypropyl)-2-fury1]propane (133i A solution of 2.50 g of dialdehyde 142 (8.68 mmol) in 35 mL of methanol was cooled to -10°C using an ice- salt bath, and 0.75 g of NaBH (20 mmol) was added in 4 small portions over a period of 5 min. After being stirred at -10°C for l h, the reaction mixture was poured into water (100 mL) and extracted with methylene chloride (4><30 mL). The extracts were dried over anhydrous NaSO filtered, and the solvents were removed under 4! reduced pressure to give 2.48 g of the crude diol (98%) as a viscous oil which was used without purification in the next step. 1H NMR: 05.82 (s, 4H), 3.53 (t, J==7 Hz, 4H),'~3.15 (br s, 2H; OH), 2.62 (t, J==7 Hz, 4H), 1.80 163 (pentet, J==7 Hz, 4H), 1.57 (s, 6H); Hg: m/e==292 (parent), 277 (base peak). 2,2-bis[5—(3-Bromopropy1)-2-furyl]propane (1143 To a well-stirred solution of 2.00 g of the crude diol 113 (6.85 mmol) and 10.0 g of carbon tetrabromide (30.1 mmol) in 150 mL of anhydrous ether at room tempera- ture was added 8.25 g of triphenylphosphine (31.5 mmol) in one portion. The progress of the reaction was monitored by TLC ($102; 30% ether-hexanes, anisaldehyde-sulfuric acid spray visualization) for the disappearance of starting material (Rf==0.20) and intermediate monobromide (Rf ==0.40),and appearance of product (Rf==0.6), which required 3-4 h. An equal volume of hexane was added to the reaction mixture and the flocculent white precipitate was removed by suction filtration and washed with hexane. The filtrate solvents were removed under reduced pressure and the resulting oil was chromatographed (Si02; 15% ether-hexane eluent) to give 2.30 g of the title compound (81%) as a colorless liquid. 1H NMR: 05.87 (br s, 4H), 3.38 (t, J==7 Hz, 4H), 2.73 (t, J==7 Hz, 4H), 2.12 (pentet, J==7 Hz, 4H), 1.57 (s, 6H); Hg: m/e==418 (parent), 403 (base peak). 164 2,2—bi8{5-[3-(2-Furyl)propylJ-Z-furyl}pr0pane (1133 To a solution of 1.46 mL of distilled, dry furan (20.1 mmol) in 35 mL of anhydrous THF at -78°C under nitrogen atmosphere was added 20.6 mL of n-butyllithium in hexane (0.95 M; 19.6 mmol). The solution was stirred at -78°c for 2 h, warmed to -20° to -3o°c for 1 h, and then re-cooled to -78°C. Dibromide 114 (2.00 g; 4.78 mmol) in 15 mL of anhydrous THF was added dropwise over a period of 15 min. The cooling bath was allowed to warm to room temperature (ca. 4 h) and stirring was continued overnight. The reaction mixture was poured into an equal volume of water, the layers were separated, and the aqueous phase was extracted with ether (2><30 mL). The combined organic phases were then washed with 1% HC1, (l><30 mL), saturated aqueous NaHCO3 (l><50 mL), and saturated aqueous NaCl (l><50 mL), dried over anhydrous M980 and filtered. Removal of the solvents under 4’ reduced pressure gave 1.72 g of a pale orange-brown oil which was purified by flash column chromatography (10% ether-hexane eluent) to give 1.57 g of the title compound (85%) as a colorless oil. 250 MHz 1H NMR: 07.29 (dd, J==1.8, 0.9 Hz, 2H), 6.27 (dd, J==3.1, 1.8 Hz, 2H), 5.98 (dd, J==3.1, 0.9 Hz, 2H), 5.87 (AB quartet, J==3.l Hz, 4H), 2.65 (t, J==7.6 Hz, 4H), 2.61 (t, J==7.6 Hz, 4H), 1.94 (pentet, J =7.6 Hz, 4H), 1.59 (s, 6H); 62.9 MHz 13c NMR: 158.73, 155.85, 154.14, 140.85, 110.09, 105.36, 105.04, 165 104.33, 37.43, 27.44, 27.35, 26.61, 26.47 ppm; fig: m/e==392 (parent), 377 (base peak). 1,1,15,lS-Tetramethyl-[1.3.l.3](2,5)furanophane (1163 A solution containing 150 mg of the open-chain sub- strate 135 (0.383 mmol), 0.25 g of 2,2-dimethoxypropane (2.4 mmol), 0.30 g of p—toluenesulfonic acid hydrate (1.6 mmol), and 70 mL of anhydrous benzene was stirred at 60°C (bath temperature) under a nitrogen atmosphere for 20 h. An equal volume of ether was added and the solution was washed with saturated aqueous NaHCO3 (2><30 mL) and saturated aqueous NaCl (l><30 mL). The organic phase was dried over anhydrous M9804, filtered, and the solvents were removed under reduced pressure, leaving a dark brown oil. Flash column chromatography (20% benzene-hexane eluent) gave 78 mg of the title compound (47%) as a white solid. Recrystallization from benzene-hexane (1:4) gave 136 as white flakes, mp==113-114°c. 250 MHz 1H NMR: 65.96 (d, J==3.2 Hz, 4H), 5.82 (dt, J==3.2,'~0.5 Hz, 4H), 2.46 (t, J==7.6 Hz, 8H), 1.73 (pentet of multiplets, J==7.6 Hz, 4H), 1.56 (s, 12H); 62.9 MHz 13c NMR: 158.82, 154.59, 104.86, 103.54, (quaternary carbon signal not observed), 27.64, 26.96, 26.26 ppm; 33: m/e==432 (parent), 417 (base peak). 166 Tetra-ring-opened dis-enedione l4Z_ To a solution of 65 mg of furanophane 136 (0.150 mmol) in 15 mL of chloroform was added 128 mg of MCPBA (0.632 mmol in one portion. After being stirred for 3 h at room temperature, the solution was washed with saturated aqueous NaHCO3 (3><30 mL), dried over anhydrous NaZSO4, and filtered. Removal of the solvent under reduced pressure gave 74 mg of a solid which was recrystallized from chloroform-ethanol (1:5) to give 36 mg of 126 (48%) as tiny neeldes, mp=172-173°c. 250 MHz 1H NMR: 66.48 (AB quartet, J==ll.9 Hz, 8H), 2.67 (t, J==6.4 Hz, 8H), 1.95 (pentet, J==6.4 Hz, 4H), 1.38 (s, 12H); 35 (Nujol): 1685, 1600 cm_l; Hg: m/e==496 (parent), 107 (base peak). APPENDIX .' l9. 167 9 I 0 5 I CHflCH f ' o o/ 3 LP v 'v CH2C|z i J 3 1 J 1 1 J 1 11 1-1 . J 11T1114141441.3.111..11111111-.3I..-.1.111l 0 7: cc 3: n~-' a. J: In ‘1 Figure A1. 60 MHz 1H NMR spectrum of cis-B-hexene- 2,5—dione (37). L L L L id L L ) L L 2".th— 4 L L— T L —J L L L v.4 L "I-h— Figure A2. 60 MHz 1H NMR spectrum of cis-4-oxo-2— pentenal (4g). 168 .Amme ocoflplm.mlmcwu001mumwb mo Eouuomdm mzz ma um: omm .md mhsmflm o r N a v m o p p PH+rLrLFV :+>r¥**Lr_r+rLlr>+LP*+LL*LLFHLLF+1F1PH+F+*LFF r*+**rhrlr*bllr ******* :3 1 1. 1P1? 169 1? (711 4% \\ .mmw Hoummflpmcofloocmlmwo mo Eduuommm mzz ma NEE omm .v< ousmflm _. N n v m \\II) . JWL 170 2 .mv Hmuwxouflmmlmwb mo Esuuommm mzz m Nmz omm H O r N n v m .m< oudmflm ML 931 1:) 117 731131.113 O O J 71 171 .mw mcoflo OHHoxomuuou mo Esupoomm mzz m Nmz omm H .oa musmflm o _. N t n @ .1 J N TL 172 .Anmwv mcoflplm.mlmcwuooumlm:ogp mo Esuuowmm mzz m um: omm .>< whomem H o H. N n v m o x. F—r***r**br** +H»+L*+**i—rr+>r}*r*+h*FHF}???.P._>¥¥>HH+H>F>}*¥}>*HHH*>*H>HPPAFL Jail) 173 .Qflw Hmummflpmcoflpocolmrosp mo Eouuommm mzz ma NEE omm .md muomflm o p N n v m o N tFP>PLL*PL¥br>P+1PL7>¥L—rL*1PFLbr**>_‘+}LL>>F*FLL+LFLLLHFF>L’1P¥>PLHE1LI11F‘ J - Jfl) .O c ta N Ov 174 .Ame HmcmuoonmloxOIvlmwo mo Esuuommm mzz EH Nmz omm .m< mysmfih FLLLFEEEL .WIVLLFLLWLLFLL-LLHLL Ls fl .11.)- ( 1- .1) a W o..6(V\/\/£o _ (g 4. secu©6 175 o \I\ .Amvv wcocmuSmAmmvmleusnlrlm mo Esuuowmm mzz m mm: 0mm .OH< wpsmHm H v o 7s: H 3:333 ..Q>> 176 003 Figure All. 60 MHz 1H NMR spectrum of 5—n-butyl- 2(3H)furanone (49). dfid “3 non} CH3 HO i 0 (i O 1 “MA, A— A ——4_3_ __L l J l 1 1 . 1 1 J 11.1 111 ] --J..111J113 1111-1- 1 l 1 Figure A12. 60 MHz H NMR spectrum of enol lactone 59. 177 O -Flr .Ammwv ocoHUIm.mlmcoxonIMIngumEIMIANV mo Esnuoomm mzz m H NmE 0mm .mH¢ ousmHm P N n v m m P L » FL » FL » L F LL r b L t-F-LFLLLLLL-LFLIFLLIL LYFIrFlftnrk-L (VLF .f-F-L .3 -J D J1) 178 .Amme mcolmlmcouDQIMIHmnuoelmwaouQUMIvnANV mo Esuuommm mzz mH um: omm .de ousmHm O p N n v m m .{IF hhh » PHLIFHFFPNFFPFHFHFFHFFPFC?FFFLPHLrFFLFPFirFFFFFEl—vtllrlrttlr-%:t 1? 1.3ij- - - N w *HFPFF PFFHLPFFPPFFFFFIH ‘ o -4 179 _ 1' cityQ‘ocm g! 1 HF ———- ~-——-—-— 1. ~— . -—--cu——_ CHIC); L 11:30 J 1 . 1 1 J - g‘a I A A J J I A J J Jj 44 2 A l A A 4‘ A I *4 l L A A H j A 2 1. A I A n j.- :. . ’( c ‘. ”v ‘ o, I . Figure A15. 60 MHz 1H NMR spectrum of 2-methyl-2,5- dimethoxy-Z,5-dihydrofuran (46). ““3 Figure A16. 60 MHz 1H NMR spectrum of spiroketal 7g. 180 CH:?¥C;:k§:}h f—- r—— CH; CH, : ' .. I l a | v I y: l7 r t -i W A A 4‘ AA ' v— _1 l A l A A J A A A A Aj A A4 A 1 A4 A A I A A A A 1 A 7: '.. ”v ' a (a. . A __l___ A A 4 A I A A AA A I A A A A .1— Figure A17. 60 MHz 1H NMR spectrum of 2,5-dimethyl- 2,S-dimethoxy—Z,S-dihydrofuran (74). CW3 CH‘CH (J .— __—— _- .- .—-.._.—— Figure A18. 60 MHz 1H NMR spectrum of 2,4-dimethyl- 2,5-dimethoxy-2,5-dihydrofuran (Z§). 181 CH cu, L4 ;_‘ Lfl/J 4 J . 1 . J A 11 A 1 A 1 #giAi.IA-A IA A‘IA-..jAAAAIAAAAI.AAALgAT Figure A19. 60 MHz 1H NMR spectrum of 2,3,5-trimethyl- 2,5-dimethoxy-2,S-dihydrofuran (76). CH H, cu, ° cu, /‘/ 1 ___/—~* JJ, 1 JAN H—Jr 1 I A‘Aiy-uj-{1juui1:11.133‘1‘jBJ-Ui1111 1 Figure A20. 60 MHz H NMR spectrum of 2,3,4,5- tetramethyl-Z,S-dimethoxy—Z,S—dihydofuran (78). 182 1P 1 1% Figure A21. 60 MHz 1H NMR spectrum of 2,5-dimethoxy- 2,5-dihydromenthofuran (2]). CHACHO 11'" n emu, - 1 AJ A_A l I l .. ‘. 5. A j 1 AL A AA Figure A22. 60 MHz 1H NMR spectrum of 3,5-dimethylfuran- 2-carboxaldehyde (88). 183 H ! CH3 0 c02Et ' I V f/f r1 s j s J A A J A_A l - AI - .1 1 '- A 11‘ WAAJAIJAAAjAAJAIAAAAIAAATAA-7.IAAAA 7c 0 ' a; :I: 2: < _ at. Figure A23. 60 MHz 1H NMR spectrum of ethyl 3—(3,5- dimethyl-Z-furyl)-3-hydroxypropanoate (89). Figure A24. 60 MHz 1H NMR spectrum of 1,7-dimethyl- 2,9-dioxabicyclo[3.3.1]non-7-ene-6-one (91). 184 .823 amusmasnumeflwum.mnAasmoumsxoucssflcum.avum mo asuuommm mzz mH um: omm .m~< musmflm . a n v m o 1:~:+++F::+»~+ »L:»L+1+~1:++L111+_:::+FL+1L~L+111FLLL- :7 1% . \ 143?? R 11-. 10 IO N Au n:u o._ + I \ n:o 185 .Ame HocmmoumnauAasuswumnaxspmeflwum.mvassum.m mo asuuommm mzz m an: omm .o~¢ mucous H *wr**rr+r*+~*+r*****ymkrbrkbrbrbr*m+xbr*rlr+xr**w.rPberxP+PP»M++P*r**+rw*ryt 1i 5 ? J 3:1 is :__ e \u1 186 o |>y h hr + .P * x? P * by L! Ill) -flH.m.m_oao>oflnmxofloum.muflsnumaflwus.fl mo asuuommm mzz m _. a} 11, \_V by + + L P .r .P F P j N F L! P V x? hr } * hr * by . Awe mcouoémééoa H was omm .n~< musmgm +£111L+ *‘P + FLV+ILFL+* P1Plr+ * o 1* if L! \DVFL 1r *111 187 oWsd. 7 1 ‘00“; l p l -. I u l _1_A J A A J l A A1] IAJ 1111.11A. I 11L I 1' n L an ac n- c J: 2 c 1‘ Figure A28. 60 MHz 1H NMR spectrum of 3-(5—methyl- 2-furyl)propanal (Qéa). f WIN” f Figure A29. 60 MHz 1H NMR spectrum of 3-(3,5-dimethyl- 2-furyl)propanal (Q§b). 188 Figure A30. 60 MHz 1H NMR spectrum of ethyl S-(S- methyl-Z-furyl)~2—pentenoate (an). CH, n / H o COZEt W u M Figure A31. 60 MHz 1H NMR spectrum of ethyl 5-(3,5- dimethyl-Z-furyl)-2-pentenoate (96b). 189 1 _1 A A I A A A l A A J A AJ— A A AAIAA.AIAAAAJAAAAWAAAAJAAAA[AAA.JAAAA].AAAIJ . n, o; 1 b u. :2 c Figure A32. 60 MHz 1H NMR spectrum of S-methyl-Z- (5-hydroxy-3-pentenyl)furan (22a). ca, r/ M I \ CH; 0 / CHZOH H Figure A33. 60 MHz 1H NMR spectrum of 3,5-dimethyl-2- (S-hydroxy-B-pentenyl)furan (32b). 190 .Amme HmcwnchIAmvNIAH>HSMImlahnumEImVIm m0 Eduuommm mzz : N32 omN .vmd musmflm H 0 b ”PPrFPFKPPl-Vhrhr‘,>bhbrbr** HFLPrKFPK-r} ..u.:u n 98; :o 191 .Anmwv HmcmuammuAmvNIAHsH:MIN-H>numaflwum.mvum mo asuuomam mzz m p N n v a um: 0mm .mm¢ mucosa @ h o 0:0 :11 192 .Ammwc amusmassumEIm-Afiscmflcmxmnum.Amvmvum mo asuuommm mzz mg was omm .om< musmflm PPLFFFFFKPFFPFPLP F*P\PBILPFrHFPPLPPPPFPWPFFPerPFFHPIF|Pb 1% JADE fa 193 .Anme amusmAHscwmexmzum.Amvmcumaasnumeflwum.m mo ennuommm mzz : mm: omm .sm< museum H O p N n v m o h J? J 194 .AmmHv wCOHUIm.mlmcmHuumomGCDIOH.Amvm.ANVm mo Esuuowmm mzz m H was omm .mma musmflm PPP:F1PPPPHFPL1*L1PP*¥IHPVP*FFP*L¥H#PPFFFPPPMPPFF**1P#*FPPPLPPV .1114 142<fi|fi||1441t15§44wi|u 195 .Ammav wcoflnum.m ImcmHHumowpcsloH.Amvm.ANvmuH>£umE|v mo Esuuommm mzz m Nmz omm .mm< wusmHm J a)# H 3 0.. _'*”p””_”p’b’"’—Pppp_rp”~’p"~’*"h”’P—>’p’_”>’_’"’-rppr’—}"’_p>hr’_”’>P”>’_”b" I PDP>P A. A. . A“VI<“»/(\)/%WIKV\.:u :iu 196 .I‘ r‘l‘lnltn\ u.‘ and... . A. . , ,.\¢.\. .Gm: mcoflwum.mnmcmfluumomwcsuoa.Amvm.Amvm Mo Esuuommm mzz ma um: omm .oe< wusmflm a n v o h *+r+*~*+*+*11+*b>>1er¥++¥~k1k1+8811 PLPbr>*Lrubr**—r+brLKP**+xP1—r*1 F A J of. LP>>PF+*P*\_*+>>_*>P* Ilgfifis \JJéi. :4<fi::1:||l:4 O n O s.» «.0 s. u‘ 5 11 w: 197 o Amway mcoflwum.m IwcmHuuwompcsloH.Amvm.Amvmlecmelv mo Esuuowmm mzz mH NEE omm .qu musmHm _. N m m o h \P}*1+KPLLV*PVLF}¥L**>PLLFF?V*Pby +*LPF+*+L PL**++>r+F*LrL+r1rt>FLV+LPL1L7LrL*LrP*1P 4 J) 1533331 41 198 . . . — r5! .-lngo. ,.|9«“,..1«I1‘~.~...tlall: :- .Aaem magmas mmmv mma mo esuuommm mzz m um: omm may cg coflmcmmxm .mem musmflm H m m r**+P*b*+b**PFF++*Pr>>*F?xPxP>P>P>FFri?>>P**rrhxr*P*P**PFP>tLPl—757LLVPLberrrK—rerrP*lPP*Prbxr+L-rlrbbhP*P*PP*PFFF*PP+++FL¥L _ 3 iwfij 199 “an .. D . .1 - u:.. 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K 202 .QOMH wcocmchuU>£ pwmswlmwu wo Esupowmm mzz m Nmz 0mm .wvd wusmHm H N a v m o h PPPPPLP%PPPF\PFPFPFPrhpPPFPPIrFFLFLFP+PL1FkLFLF8LPFFFPFLFFLPPPPFF m.N Gd 0..» 0.0 203 maneuvsm mafia Amv< m so .m mm my noma mo 5: uommw mzz ma um: omm .nq¢ m :sm .m h J? 7411\11 \2 204 2 .QHNH mcocmchHp>£ pmmSMImwm .HmEHmm paw mOHH mcocmchH©>£ pmmDMImssxu mo Enuuommm mzz mH um: omm .mv¢ wusmflm L*PF**#+¥L¥*1PKFL**rrLr1—r1rLr .. N n v _ Lrlb1r1—r1r*¥1r\rbrb*+L11L*Lr*1r*11—r**kr+brbrby*¥ :1 Ill;3(\dfillll 6.0 a.» 06 ' 205 .nHHH cam MHMH mmcocmchuU>£ UmmDMImwu 0cm larva» mo Esuuommm mzz mH um: omm .mv< musmHm N n v m o H *F P » *LL* *‘rLr PFL++ P P er** ***¥L1LL1LV*1P* r*1+*r*‘rb*y+**++**1—71 1% 206 Ucm mHMH mmcocmwcflu©>z mo Esuuommw mzz m n P P D \P Ly — xbr + r I? L L? IrLr L P r l? [r * + L? r * LL‘I)‘. + L r P + * L7 * + .Amqa musmflm mmmv nHmH H was omm may CH coamcmmxm .om< muswfim 0 p * * L E 0.0 Q 207 .nNmH can MNMH mwcocmwcfluwxn Ummswlmwu Ucm surcgu mo Esuuommm mzz ma NEE omm .Hmd musmflm o p N n w p +L¥++L+L+»»»rL+++_>L»++»»r»»r++++++»p p»»p++¥ a .0 + .0 OnIU 6IO o ”:o A. o_ ”:o 208 .Aamm musmflm wmmv nmmfi mam mNmH mmcocmwcfluc>n mo Esuuommm mzz m Nmz omm wnu CH Goflmcmmxm .mm¢ musmflm H QN Wm 06 PrrFrprLbfipbrFr¥r*FLrbrr+P>PPxPKFPPP¥FFV*¥PL*F*P*P¥¥P**+Fk—rbrb}*gfrpr+k_rrr>+P*Prrp++rrb+ md afi 209 2 .AanH ommsmumwo mo unseen nocfle m mchucoov MMHH mcocmccHH©>5 meDMImrdau mo Esuuommm mzz m Nmz omm .mm¢ musmHm o r N LLF}¥}L¥L¥L*F¥+*¥LLL+¥xFLLLPLLrL*L LLLLFLLL‘ H ~¥¥LL>>LLLW¥DF>LF>F¥ J 0 FL 210 mmmv mmmH mcocmwcHummn mo Eduuommm mzz m }L>>P+P>>FbFFLVF}?¥LP>>>FM .Amm< musmflm H Nmz omm may CH COHmcmmxm .vm¢ musmHm n *bLFhFFFLbVbbrtbeP¥FxPP¥L¥>b>bePKPLxPPKP>>hPP>b_>*+*L_FL>PFFL 211 MmmH mmcocmwcHH©>£ wmmSMImwu cam Im269u mo Esuuommm mzz m *rm>>F*irL+L\Pb?>D>F*F’mrbL}’p*L?m}brb>bb‘>b7>b>>>>?bfl>¥¥*>k>b¥b .nmma mam H mm: omm J]; 3:7 .mm¢ musmHm 212 .Amm¢ musmflm mmmv nmma cam ammH mmcocmwcHuwmn mo Esuuowmm mzz m um: omm may CH conchxm .mm< wusmHm H r*h>bLPb>4>>rFL>F+F+**FM***L_P>¥Fx—L>FKPFL*¥LP\PLbFF*>bPPFFLL~}L\PLFV*L»%L**PM*+*FLFPb 213 .an HmEmco: mcouwomacmu5m umwcHH mo Esuuommm mzz mH um: om .bmfl musmHm ~ .— OI. 214 .mmH mcmzmvHMHU HwEmcoc wcoumUMICMHSM umwcHH mo Ezyuommm mzz m H mm: omm .mm< musmflm . N m . m 4 H P’b‘kaLLLrberLb [*Fbpfit *Lbbhb‘Pb_*+P>b>*L+_7>tb_bbbrb P>*>bbP>F LFPDL— ‘Jaa ; 1 H a .5 . . H L“ as a 215 A. AL:-—-.‘——\ Figure A59. 60 MHz 1H NMR spectrum of di-ring- opened trans-enedione 129. Figure A60. 60 MHz 1H NMR spectrum of saturated tetraketone 121. 216 Figure A61. Figure A62. 60 MHz 1H NMR spectrum of tetra-ring- opened octaketone 132. fl 3 . f‘ H De f‘ 60 MHz 1H NMR spectrum of saturated octaketone 134. 217 -—1 —v—-.-.—_ Figure A63. 60 MHz 1H NMR spectrum of hexa-ring- opened dodecaketone 123. _1 A A l a A l A A l . 4 J _A A J A . A ‘ I A A 4 A j A A A A 1 A #4 4 I A 4+; ] J A . A j A L 42 a. 4‘; 0» 7c 0. a.» ‘ Figure 64. 60 MHz 1H NMR spectrum of saturated dodecaketone 12d. 218 UL ‘ F A 4*; J J A A A 4 A A AA ‘ l A A A A l A L A l A A A A l A AA A A J A A A l A A A l A A A A A 1 A A_A A_l A A A A j A A A A l A A A A 1 A A AA A I L A A A J A A A A l A A A A u n u u a... W a u u u 0 Figure A65. 60 MHz 1H NMR spectrum of tri-ring- opened hexaketone 136. L U M L - A'A'A L l A 1 A A l A A l A A J A A J A A J A A 1 A A Al A A 1 A A 1 A A A A j A A A A l A A A A l J A A A I A A A A —I A A A A l A A A A l A A u u u u on... m u :o M 2_o lo 0 Figure A66. 60 MHz 1H NMR spectrum of tri-ring- opened hexaketone 126 plus Eu(fod)3. 219 Figure A67. 60 MHz 1H NMR spectrum of saturated hexaketone 137. k— J: * r ' A‘Jk‘i A A A A A A A A . A A +414 A A A IA AAA 1AA AAJ AA AAIA A A A I J A A IA A A AAAA 14 IO ’0 0.. IO h ll: 40 I. 20 ID Figure A68. 60 MHz 1H NMR spectrum of di-ring- opened cis-enedione 128. 220 Figure A69. 60 MHz 1H NMR spectrum of di—ring- opened cis-enedione 139. Figure A70. 60 MHz 1H NMR spectrum of di-ring- opened trans-enedione 141. 221 Figure A71. 60 MHz 1H NMR spectrum of saturated tetraketone 140. 1 enedione 120. Figure A72. 60 MHz H NMR spectrum of dibromo-trans- 222 OH HO l L y u L. L Figure A73. 60 MHz 1H NMR spectrum of 2,2-bis[5- (3-oxopropyl)-2-furyl]propane (142). Figure A74. 60 MHz 1H NMR spectrum of 2,2-bis[S-(3- hydroxypropyl)-2-fury1]propane (143). 223 Figure A75. 60 MHz 1H NMR spectrum of 2,2-bis[5-(3- bromopropyl)-2-furyl]propane (134). Figure A76. 60 MHz 1H NMR spectrum of 2,2-bis{5-[3- (2-fury1)propyl]-2-furyl}propane (145). 224 SIREkb-U .«43d Wk p .. 9h .Amev mammoum thawuswlmlfla>moumAamusmlmvImHumwmwpumim mo Esuuommm mzz ma um: omm .nwfi musmflm v m o h it—rlLvlrlLrlLllrE- FLclr Linkilrlrbi L: j J: 1%.! N n FLIFIrLILIrl— LrLulrlrkIrlkLllranIrLft } 225 .AmWHV mcmcmocmusw u . . . . I » umsmuumuuma.ma.fi.a mo Enuuomdm mzz m was omm .mn< magmas Ammzmamdfin H p N n v m @ rL7+ IJJ \ 226 .ANWHV mcofipwcmlmwu wmchOImcflulmuumu wo Esuuommm mzz ma Nmz omm .mhfl musmflm — *L_Prb*b>?.PW»P>PL>b>Fbr>>bFFhbbbr$>pxPFFb>>—}FPbLP>waKP>LPLhLb>b P» L (Isis i m 31... a \ LIST OF REFERENCES 10. 11. LIST OF REFERENCES For a review of the syntheses and applications of 2,5-diacyloxy- and 2,5-dialkoxy-2,5—dihydrofurans in organic synthesis see, Elming, N. 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