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The total synthesis of saxitoxin Strategies Tactics Org. Synth. 1989, 2, 191.

A review with 44 refs.

Total synthesis of (+)- and (-)-norsecurinine Tetrahedron Lett. 1989, 30, 7173.

(-)-Norsecurinine (I) was prepd. in a stereospecific fashion beginning with the acetylenic oxazole II. Diels-Alder cyclization of II afforded the furanoketone III, which was transformed in five steps to the butenolide mesylate IV. Transannular alkylation of IV then afforded I. In identical fashion, ent-II gave (+)-norsecurinine.

Enynones in organic synthesis. II. An electron transfer mediated synthesis of methylenecyclopentenones Tetrahedron Lett. 1988, 29, 6869.

Electrocyclization of enynones to methylenecyclopentenones is markedly accelerated by phenols and catechols having a low oxidn. potential. Thus, (PhCH2)2C:CHCOC.tplbond.CMe was heated at 125.degree. in EtCHClCH2Cl in the presence of NaHCO3 and 4-Me3CC6H3(OH)2-1,2 to give 97% of a mixt. of (E)- and (Z)-benzylethylidenephenylcyclopentenones I.

Thiazoles in organic synthesis. Novel syntheses of menthanes and eremophilanes Tetrahedron 1988, 44, 3327.

Acetylenic thiazoles, e.g. I, of proper design were shown to undergo an intramol. Diels-Alder reaction leading to fused-ring thiophene derivs., e.g. II. When appropriately substituted, these latter materials can be readily converted to terpenes of the methane, e.g., III; and eremophilane, e.g. IV, class by Raney-Ni desulfurization.

A novel synthesis of pyrromethenones Tetrahedron Lett. 1988, 29, 4823.

Pyrromethenones I [R = H, CO2Me; R1 = R2 = H; R1R2 = (CH2)4] were prepd. by acylation of N-aminopyrroles II with HO2CCH2CH2C.tplbond.CCO2Me followed by sequential 5-exo-dig cyclization and 3,5-sigmatropic shift.

Enynones in organic synthesis. I. Spiroannulation by tandem oxy-Cope rearrangement-electrocyclic ring closure Tetrahedron Lett. 1988, 29, 6865.

Bisacetylenic alcs. e.g. I (R = Me, Ph, R1 = H) of proper design undergo a facile oxy-Cope rearrangement to afford mixts. of E- and Z-enynones e.g., II. These latter compds. afford methylenecyclopentanones, e.g., III, upon enolization and electrocyclic ring closure.

Enynones in organic synthesis. III. A novel synthesis of phenols Tetrahedron Lett. 1988, 29, 6873.

Enynones are converted to phenols by an acid catalyzed process which can be controlled to give either of 2 regioisomeric series of products. Thus, enynones I (n = 1, 2; R = H, Me) were treated with collidine para-toluenesulfonate in the presence of isopropenyl acetate, to give phenols II (same n, R).

Stereospecific total syntheses of 7.alpha.- and 7.beta.-eremophilane-6-one and 7.alpha.- and 7.beta.-eremophilane Tetrahedron Lett. 1987, 28, 2937.

The title compds. I (RR1 = O, R = R1 = H, resp.) were prepd. in a highly efficient fashion by a route involving an intramol. Diels-Alder reaction of an acetylenic thiazole followed by reductive modification of the resulting fused-ring thiophene.

Total synthesis of (.+-.)-paniculide A Tetrahedron 1987, 43, 5475.

Paniculide A precursor (I) was prepd. from 3-methylglutaric anhydride utilizing as the key step an intramol. Diels-Alder reaction of an acetylenic oxazole to give a 2-methoxyfuran. Acid hydrolysis then provided the requisite butenolide ring characteristic of the paniculides.

The azomethine imine route to guanidines. Total synthesis of (.+-.)-saxitoxin Croat. Chem. Acta. 1986, 59, 267.

Azomethine imines may be readily generated through the interaction of aldehyde acetals with carboxylic acid hydrazides. These reactions are most highly favored in polar aprotic solvents and acid catalysis is required. With suitably functionalized hydrazides these substances undergo a facile intramol. addn. to give fused-ring pyrazolidine derivs. (.+-.)-Saxitonin, the paralytic agent of the Alaska butter clam, Saxidomas giganteus, was synthesized in a totally stereospecific fashion through a sequence involving as the key steps the intramol. 1,3-dipolar addn. of an azomethine imine to a 2-imidazolone, reductive cleavage of the resulting pyrazolidine ring, followed by intramol. acylation, and elaboration of a bis-pseudourea to the requisite guanidine functionality.

Bisheteroannulation. 6. The first example of a Diels-Alder reaction involving a thiazole ring with an acetylenic dienophile. Geometrical control of reaction pathway Heterocycles1984, 22, 281.

Acetylenic thiazoles I (R = CO2Me, R1 = OH, R2 = H, R1R2 = O; R = Me, CH2OMe, R1R2 = O) were subjected to a range of cyclization conditions. I (R = CO2Me, R1 = OH, R2 = H, R1R2 = O) were heated (refluxing in PhEt) to give 55-60% annulated thiazole II. I (R = Me, R1R2 = O) decompd. slowly to polar products in several days in refluxing PhEt. I (R = CH2OMe, R1R2 = O), in the presence of catalytic methylene blue underwent intramol. Diels-Alder to give 60% thiophene III with loss of MeCN.

Bis heteroannulation. 7. Total syntheses of (.+-.)-gnididione and (.+-.)-isognididione J. Am. Chem. Soc. 1984, 106, 3041.

(.+-.)-Gnididione and (.+-.)-isognididione I (Z = O, R = .beta.-, .alpha.-Me, resp.) were prepd. via dehydrocyanation-cyclization of the oxazolylcyclopentenone deriv. II (R = .beta.-, .alpha.-Me) and mild acid hydrolysis of I (Z = OCH2CH2O, R = .beta.-, .alpha.-Me, resp.). II were obtained by thermolysis of III stereoisomers, which were prepd. regio- and stereospecifically in many steps from aldehyde IV via addn. reaction with LiCH:CHMe or LiC.tplbond.CMe, oxidn., and Grignard reactions with MeC.tplbond.CBr or MeCH:CHBr.

Total synthesis of (.+-.)-saxitoxin J. Am. Chem. Soc. 1984, 106, 5594.

(.+-.)-Saxitoxin (I), the paralytic agent of the Alaska butter clam Saxidomas gigantus, has been synthesized in a totally stereospecific fashion through a sequence involving as the key steps an intramol. 1,3-dipolar addn. of an azomethine imine to a 2-imidazolone, a reductive cleavage of the resulting pyrazolidine ring followed by intramol. acylation, and elaboration of a bis(pseudourea) to the requisite guanidine functionality.

Bis heteroannulation. 4. Facile syntheses of methylene acids, methylbutenolides, .alpha.-methyl-.gamma.-lactones, and related materials. Total syntheses of (.+-.)-ligularone and (.+-.)-petasalbine J. Am. Chem. Soc. 1984, 106, 5585.

Acetylenic oxazoles undergo an intramol. Diels-Alder reaction leading directly to fused ring furan derivs. With 5-ethoxyoxazoles the corresponding 2-ethoxyfurans are obtained which are useful precursors for a wide variety of natural products. Thus, MeCH(NH2)CO2Et was cyclized with ClCO(CH2)3CO2Me to give I (R = CO2Me) which was reduced to the aldehyde and treated with LiC.tplbond.CCH2OMe to give I [R = C(OH)C.tplbond.CCH2OMe]. The latter was converted in many steps to intermediates II (R1 = OH, R2 = H; R1 = H, R2 = OH) which upon heating eliminated HCN to give racemic petasalbine (III; R3 = OH, R4 = H). Addnl. obtained was liqularone (III; R3R4 = O).

Bis heteroannulation. 8. Total synthesis of (.+-.)-paniculide A Tetrahedron Lett. 1984, 25, 4859.

The hydroxy lactone I, a known intermediate for paniculide A (II), was prepd. in many steps from 3-methylglutaric anhydride.

A mild procedure for the generation of azomethine imines. Stereochemical factors in the intramolecular 1,3-dipolar addition of azomethine imines and a synthetic approach to saxitoxin J. Am. Chem. Soc. 1981, 103, 239.

Azomethine imines may be readily generated through the interaction of aldehyde acetals with carboxylic acid hydrazides. These reactions are most highly favored in polar aprotic solvents, in particular DMF, and acid catalysis is required. With suitably functionalized hydrazides these substances undergo a facile intramol. addn. to give fused-ring pyrazolidine derivs. The stereochem. of these adducts has been conclusively demonstrated by single crystal x-ray anal., and a no. of these derivs. show excellent promise as intermediates for the total synthesis of saxitoxin (I). Thus, 1.82 g II and 1.14 g PhCH(OEt)2 was heated 1 h at 80.degree. in DMF in the presence of 4-MeC6H4SO3H to give 83% III (R = Ph). Similarly prepd. were III (R = p-MeOC6H4, p-MeC6H4, p-O2NC6H4, 2-furyl, 2-thienyl, H).

Bis heteroannulation. 2. Oxazole alcohols from the interaction of lithiomethyl isocyanide with lactones. A novel synthesis of evodone J. Org. Chem. 1981, 46, 2065.

Reaction of cis- and trans-perhydrobenzopyranones I with LiCH2NC gave the corresponding (oxazolylmethyl) cyclohexanemethanols II (R = .alpha.-, .beta.-CH2OH), which underwent oxidn. [(COCl)2] and reaction with LiC.tplbond.CMe followed by (COCl)2 oxidn. to give cis- and trans-II (R = COC.tplbond.CMe), whose facile intramol. Diels-Alder reaction gave the furanosequiterpenes cis- and trans-III, resp. Evodone (IV) was similarly prepd. from tetrahydro-4-methyl-2H-pyran-2-one via treatment with LiCH2NC, oxidn. with (COCl)2, Grignard reaction with MeC.tplbond.CBr, oxidn. with (COCl)2, and cyclization of V.

Bis heteroannulation. 3. Facile synthesis of (.+-.)-ligularone and (.+-.)-petasalbine J. Am. Chem. Soc. 1981, 103, 4611.

(.+-.)-Ligularone (I) and (.+-.)-petasalbin (II) were synthesized regiospecifically via an intramol. Diels-Alder reaction of appropriately substituted acetylenic oxazoles, e. g., III (bis heteroannulation).

Unequivocal synthesis of euglenapterin J. Org. Chem. 1981, 46, 5416.

Euglenapterin (I) was prepd. in an unequivocal fashion as follows. L-Xylose was directly converted to pyrazine 1-oxide (II) by a sequence of steps involving oxidn. to osone, transoximation to give osone aldoxime, and cyclization with H2NCH(CN)CO2Et. II was converted to 2-amino-3-carbamoyl-5-(L-threo-trihydroxypropyl)pyrazine (III) by aminolysis followed by Raney nickel hydrogenation. III cyclized smoothly to I with (Me2N)2C(OEt)2 in DMF at ambient temp.