Biomimetic Total Syntheses of (−)-TAN1251A, (+)-TAN1251B, (+)-TAN1251C, and (+)-TAN1251D

The muscarinic antagonists (−)-TAN1251A (1), (+)-TAN1251B (2), (+)-TAN1251C (3), and (+)-TAN1251D (4) have been synthesized biomimetically by enamine formation from an amino aldehyde to give TAN1251C ketal 18. Oxidation and reduction lead to TAN1251A (1), which has been hydroxylated to give TAN1251B (2). Stereospecific reduction of TAN1251C ketal 18 leads to TAN1251D (4)

Synthesis of the Isoxazolo[4,3,2-<i>de</i>]phenanthridinone Moiety of the Parnafungins

A practical route to the labile tetracyclic isoxazolo[4,3,2-de]phenanthridinone moiety of the antifungal parnafungins has been developed. Zinc reduction of a methyl 2′-hydroxymethyl-2-nitro-3-biphenylcarboxylate, which was prepared by a Suzuki coupling, afforded a benzisoxazolone that was treated with MsCl and base to generate the labile tetracyclic ring system in 37−47% yield. This compound decomposes to the phenanthridine in CDCl3 and the phenanthridine N-oxide in aqueous base

Synthesis of (+)- and (−)-Monanchorin

The optically pure epoxy acetal was converted to the protected guanidino alcohol by reaction with NaN3 in DMF, hydrogenation of the azide, and reaction of the amine with MeSC(NBoc)NHBoc, AgNO3, and Et3N. Treatment of the protected guanidino alcohol with 9:1 CDCl3/TFA afforded monanchorin, whose absolute stereochemistry was assigned as shown

Biomimetic Total Syntheses of (−)-TAN1251A, (+)-TAN1251B, (+)-TAN1251C, and (+)-TAN1251D

The muscarinic antagonists (−)-TAN1251A (1), (+)-TAN1251B (2), (+)-TAN1251C (3), and (+)-TAN1251D (4) have been synthesized biomimetically by enamine formation from an amino aldehyde to give TAN1251C ketal 18. Oxidation and reduction lead to TAN1251A (1), which has been hydroxylated to give TAN1251B (2). Stereospecific reduction of TAN1251C ketal 18 leads to TAN1251D (4)

Total Synthesis of (−)-Fumiquinazolines A, B, C, E, H, and I. Approaches to the Synthesis of Fiscalin A

The first syntheses of (−)-fumiquinazolines A, B, and I, which proceed in 14 steps from protected tryptophan, anthranilic acid, leucine, and alanine in 7% overall yield, are described. Tricycle 30 was formed by a palladium-catalyzed cyclization. Oxidation of 30a with saccharine-derived oxaziridine 21 for fumiquinazolines A and B and oxidation of 30b with dimethyldioxirane for fumiquinazoline I selectively formed the appropriate imidazoindolone stereoisomers. Application of the Ganesan−Mazurkiewicz cyclization completed the syntheses. Efficient 14-step syntheses of (−)-fumiquinazolines C (7) and E (3) and a 15-step synthesis of (−)-fumiquinazoline H (8) using FmocNHCH(CH2SePh)CO2H as a dehydroalanine precursor that spontaneously eliminated benzeneselenol without oxidation under the cyclization conditions are also reported. Model 86 for fiscalins A with the H and OH anti to each other has been prepared, but the procedure that worked for the model failed with the fully functionalized side chain

Syntheses of Chloroisosulochrin and Isosulochrin and Biomimetic Elaboration to Maldoxin, Maldoxone, Dihydromaldoxin, and Dechlorodihydromaldoxin

An efficient synthesis of chloroisosulochrin was accomplished using a novel ortho-selective chlorination of a phenol with sulfuryl chloride and 2,2,6,6-tetramethylpiperidine as the key step. Further elaboration by a biomimetic route converted chloroisosulochrin to dihydromaldoxin, maldoxone (lactone formed by dehydration of dihydromaldoxin), and maldoxin and isosulochrin to dechlorodihydromaldoxin and dechloromaldoxin

Synthesis of the Carbocyclic Skeleton of Abyssomicins C and D

Intramolecular Diels−Alder substrate trienyl methylenebutenolide 5 was prepared in six steps by coupling 3-methoxy-4-methylenebutenolide (6) with trienone keto aldehyde 7. Heating 5 in CHCl3 for 2 d at 70 °C afforded 80% of a single Diels−Alder adduct 4 with the complete carbon skeleton of abyssomicin C. Addition of thiophenoxide to the enone double bond of 4 followed by an intramolecular Michael addition afforded 15 with the abyssomicin D carbon skeleton

Total Synthesis of (−)-Fumiquinazolines A, B, C, E, H, and I. Approaches to the Synthesis of Fiscalin A

The first syntheses of (−)-fumiquinazolines A, B, and I, which proceed in 14 steps from protected tryptophan, anthranilic acid, leucine, and alanine in 7% overall yield, are described. Tricycle 30 was formed by a palladium-catalyzed cyclization. Oxidation of 30a with saccharine-derived oxaziridine 21 for fumiquinazolines A and B and oxidation of 30b with dimethyldioxirane for fumiquinazoline I selectively formed the appropriate imidazoindolone stereoisomers. Application of the Ganesan−Mazurkiewicz cyclization completed the syntheses. Efficient 14-step syntheses of (−)-fumiquinazolines C (7) and E (3) and a 15-step synthesis of (−)-fumiquinazoline H (8) using FmocNHCH(CH2SePh)CO2H as a dehydroalanine precursor that spontaneously eliminated benzeneselenol without oxidation under the cyclization conditions are also reported. Model 86 for fiscalins A with the H and OH anti to each other has been prepared, but the procedure that worked for the model failed with the fully functionalized side chain

Biomimetic Synthesis of the Tetracyclic Core of Berkelic Acid

Acid-catalyzed condensation of 2,6-dihydroxybenzoic acid 3 with ketal aldehyde 14 in methanol at 25 °C, followed by CH2N2 esterification, gave a 4:1:4:1 mixture of diastereomers 15b−18b in 60% yield. Equilibration of this mixture with TFA in CDCl3 provided tetracycle 15b (83% yield) with the complete skeleton of berkelic acid. A similar condensation at 0 °C afforded 15b−18b and a reduction product 19b, which was probably formed by a 1,5-hydride shift

Synthesis of Hexacyclic Parnafungin A and C Models

A convergent, practical route to unstable hexacyclic parnafungin A and C models has been developed. Two iodoxanthones were prepared in four or five steps (33−50% overall yield). Suzuki−Miyaura coupling of the iodoxanthones with excess readily available 3-carbomethoxy-2-nitrophenyl pinacol boronate afforded the hindered highly functionalized 2-arylxanthones (53−58%) in the first key step. In the second key step, zinc reduction gave benzisoxazolinones that were treated with MsCl and then base to generate the unstable hexacyclic parnafungin A (13% overall yield for 8 steps) and C (8% overall yield for 9 steps) models. Analogously to the parnafungins, hexacyclic parnafungin C model decomposes to a phenanthridine with a half-life of 2 d in CDCl3