Formal total synthesis of (+)-gephyrotoxin

An efficient formal total synthesis of (+)-gephyrotoxin is described. The key step of our strategy relies on the diastereoselective reduction of a chiral pyrrolidine beta-enamino ester obtained by condensation of ( S)-phenylglycinol on a protected 8-hydroxy-3,6-dioxooctanoate.     

Formal total synthesis of (+)-didemniserinolipid B

The formal total synthesis of (+)-didemniserinolipid B, a marine tunicate possessing a 6,8-dioxabicyclo[3.2.1]octane framework, was accomplished starting from l-(+)-tartaric acid. The key transformations in the synthesis include the elaboration of a γ-hydroxy-amide readily obtained by desymmetrization of tartaric acid bis-amide via the controlled addition of a Grignard reagent followed by stereoselective reduction of the resulting ketone.     

Formal total synthesis of (+)-diepoxin sigma

The highly oxygenated antifungal anticancer natural product (+/-)-diepoxin sigma was prepared in 10 steps and in 15% overall yield from O-methylnaphthazarin. Highlights of the synthetic work include an Ullmann coupling and a possibly biomimetic oxidative spirocyclization for the introduction of the naphthalene ketal as well as the use of a retro-Diels-Alder reaction to unmask the reactive enone moiety in the naphthoquinone bisepoxide ring system. A novel highly bulky chiral binaphthol ligand was developed for a boron-mediated Diels-Alder reaction that constitutes a formal asymmetric total synthesis of (+)-diepoxin sigma.     

Formal total synthesis of (+)-wortmannin using catalytic asymmetric intramolecular aldol condensation reaction

A catalytic process for the synthesis of optically active C4-substituted tetrahydroindandiones using an asymmetric intramolecular aldol condensation reaction was developed. When 30 mol% of phenylalanine and 50 mol% of pyridinium p-toluenesulfonate were used under highly concentrated conditions, a variety of C4-substituted tetrahydroindandiones and octahydronaphthalenediones were obtained in high yield (up to 89% yield) and high enantiomeric excess (up to 94% ee). One of the products was successfully transformed into the key intermediate for the synthesis of the phosphatidylinositol 3-kinase inhibitor wortmannin, achieving formal total synthesis of (+)-wortmannin.     

Formal synthesis of (+)-sorangicin A

The formal synthesis of (+)-sorangicin A was completed by two independent routes. Both approaches feature a cross metathesis reaction to form the C29-C30 bond to arrive at the bicyclic ether/tetrahydropyran fragment. Formation of the C15-C16 olefin to unite the dihydropyran fragment with the rest of the molecule was achieved by either a cross metathesis reaction or a Julia-Kocienski olefination.     

Formal total synthesis of (+)-lysergic acid via zinc(II)-mediated regioselective ring-opening reduction of 2-alkynyl-3-indolyloxirane

Asymmetric formal synthesis of (+)-lysergic acid was achieved with a reductive ring-opening reaction of chiral 2-alkynyl-3-indolyloxirane with NaBH(3)CN as the key step. With Zn(OTf)(2) as an additive, the ring-opening reaction proceeded regioselectively at the 3-position to give the corresponding propargyl alcohol, which was a precursor of the allenic amide for palladium-catalyzed domino cyclization to construct the ergot alkaloid core structure.     

New total synthesis of (+)-cystothiazole A based on palladium-catalyzed cyclization-methoxycarbonylation

Palladium-catalyzed cyclization-methoxycarbonylation of (2R,3S)-3-methylpenta-4-yne-1,2-diol (6) derived from (2R,3S)-epoxy butanoate 7 followed by methylation gave the tetrahydro-2-furylidene acetate (−)-10, which was converted to the left-half aldehyde (+)-3. A Wittig reaction between (+)-4 and the phosphoranylide derived from the bithiazole-type phosphonium iodide 4 using lithium bis(trimethylsilyl)amide afforded the (+)-cystothiazole A (2).     

Formal total synthesis of aspergillide A

The formal total synthesis of aspergillide A 1 is described. The cross-metathesis of enone 6 with 6-hepten-2-ol derivative 5 provided E-olefin 15 corresponding to the C₄-C₁₄ backbone of 1. The CBS asymmetric reduction of 15 gave allyl alcohol 16, which was transformed into β-alkoxyacrylate 4 which had a formyl group. SmI₂-induced reductive cyclization of 4 gave a 2,6-syn-2,3-trans THP derivative 3 in good yield. After methoxymethylation of 3, the resulting compound 19 was submitted to desilylation and hydrolysis, to afford Fuwa’s key intermediate 2 for the total synthesis of 1.     

Formal total synthesis of enigmazole A

A stereoselective formal total synthesis of enigmazole A, a marine macrolide isolated from Cinachyrella enigmatica, is described. Lewis acid mediated intramolecular allylation of an α-acetoxy ether, prepared from alcohol and carboxylic acid fragments was carried out to construct the methylene THP ring with high stereoselectivity. The late-stage macrolactonization of the corresponding seco-acid provided a known synthetic intermediate of enigmazole A.     

Formal total synthesis of cyanolide A

Formal total synthesis of cyanolide A, aglycosidic dimeric macrolide is accomplished. The key reactions involved are asymmetric acetate aldol reaction, CBS reduction, and Shiina's lactonization.     

Formal total synthesis of stigmatellin A

An efficient and stereoselective approach for the formal total synthesis of Stigmatellin A has been described. The key steps involved in this synthesis are desymmetrization of the bicyclic olefin to introduce two methyl and two hydroxyl chiral centers, Friedel Crafts acylation, regioselective demethylation, Baker-Venkataraman rearrangement and Grubbs cross metathesis.     

Formal synthesis of (+)-discodermolide

[structure: see text] Herein we report the formal total synthesis of (+)-discodermolide in 21 steps (longest linear sequence) from commercially available Roche ester. This synthesis features the assembly of C(9-18) and C(19-24) fragments via a metal-chelated aldol coupling reaction.     

A total synthesis of (+)-isolaurepan

A versatile and efficient method for the enantioselective synthesis of 2,7-cis-disubstituted oxepane 1c, (+)-isolaurepan, using oxidative resolution of a secondary alcohol and highly diastereoselective Et₃SiH/TMSOTf-promoted reductive cyclization of a hydroxy ketone is described.     

Formal synthesis of (+)-gliocladin C

An asymmetric synthesis of chiral intermediate 15 for (+)-gliocladin C has been accomplished from N-phthaloyl l-tryptophan methyl ester.     

Formal synthesis of (+)-didemniserinolipid B

The formal synthesis of (+)-didemniserinolipid B is achieved using Weinreb reaction, Yadav’s chiral propargyl alcohol protocol and hydrolytic ketal formation as the key steps.     

Formal enantioselective synthesis of (+)-estrone

A formal total synthesis of (+)-estrone (4% overall yield; ca. 12 steps) could be achieved via the Torgov diene. An asymmetric allylic substitution is the key step for the construction of the chiral quaternary carbon center of a synthetic intermediate which was converted in four steps to the Torgov diene. [reaction: see text]     

Formal asymmetric synthesis of (+)-tofacitinib

Tofacitinib is an efficient and selective Janus kinase 3 (JAK3) inhibitor, and is used as an immunosuppressant drug for the treatment of rheumatoid arthritis and transplant patients. Herein we report a concise formal asymmetric synthesis of tofacitinib from homochiral 1,3-dioxolanone 10b, which was elaborated through a highly stereoselective Michael addition followed by solvent-free removal of the chiral auxiliary and ring cyclization to furnish chiral imide 8. The preparation of tofacitinib’s precursor 16 could be obtained after reduction of 8 followed by sequential oxidation, reductive amination and S_NAr reactions.