Takayoshi Torii

Dihalomethylation of N-protected phenylalanine esters

Abstract Dihalomethylation of several N-protected amino acid esters gave N-protected α-aminoalkyl-α′-dihalomethylketones, which are useful intermediates for the synthesis of erythro β-amino-α-hydroxycarboxylic acids, in good yield. The dihalomethylketones were successfully converted to N-protected α-aminoalkyl-α′-halomethylketones by selective catalytic hydrogenation.

SYNTHETIC STUDY OF 3′-α-FLUORO-2′,3′-DIDEOXYGUANOSINE

A synthetic method was established for 3′-α-fluoro-2′,3′-dideoxyguanosine 1 from guanosine 2 in 27% overall yield and 6 steps. A byproduct 6a of fluorination was identified by NMR studies, its presence strongly supporting our supposition that the fluorination itself proceeded via a bromonium cation.

A novel l‐isoleucine‐4′‐dioxygenase and l‐isoleucine dihydroxylation cascade in Pantoea ananatis

A unique operon structure has been identified in the genomes of several plant‐ and insect‐associated bacteria. The distinguishing feature of this operon is the presence of tandem hilA and hilB genes encoding dioxygenases belonging to the PF13640 and PF10014 (BsmA) Pfam families, respectively. The genes encoding HilA and HilB from Pantoea ananatis AJ13355 were cloned and expressed in Escherichia coli. The culturing of E. coli cells expressing hilA (E. coli‐HilA) or both hilA and hilB (E. coli‐HilAB) in the presence of l‐isoleucine resulted in the conversion of l‐isoleucine into two novel biogenic compounds: l‐4′‐isoleucine and l‐4,4′‐dihydroxyisoleucine, respectively. In parallel, two novel enzymatic activities were detected in the crude cell lysates of the E. coli‐HilA and E. coli‐HilAB strains: l‐isoleucine, 2‐oxoglutarate: oxygen oxidoreductase (4′‐hydroxylating) (HilA) and l‐4′‐hydroxyisoleucine, 2‐oxoglutarate: oxygen oxidoreductase (4‐hydroxylating) (HilB), respectively. Two hypotheses regarding the physiological significance of C‐4(4′)‐hydroxylation of l‐isoleucine in bacteria are also discussed. According to first hypothesis, the l‐isoleucine dihydroxylation cascade is involved in synthesis of dipeptide antibiotic in P. ananatis. Another unifying hypothesis is that the C‐4(4′)‐hydroxylation of l‐isoleucine in bacteria could result in the synthesis of signal molecules belonging to two classes: 2(5H)‐furanones and analogs of N‐acyl homoserine lactone.

Synthesis of 6-arylthio analogs of 2',3'-dideoxy-3'-fluoroguanosine and their effect against hepatitis B virus replication

A key compound, 2-amino-6-chloro-9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)purine, was prepared from 2-amino-6-chloropurine riboside in 5 steps, then subjected to the nucleophilic displacement with benzenethiols to afford 6-arylthio congeners. These compounds showed a similar anti-HBV effect to that of 2′,3′-dideoxy-3′-fluoroguanosine.

AN ECONOMICAL SYNTHESIS OF FAMCICLOVIR

An economical synthesis of famciclovir from N-2-acetyl-7-benzylguanine by a novel regioselective alkylation with the diester cyclopropane compound was developed.

Synthesis of 2′,3′-Dideoxyinosine via Radical Deoxygenation

A synthetic method for 2 ′,3 ′-dideoxyinosine (ddI) from inosine was established via radical deoxygenation of N1,5 ′-O-diprotected-2 ′,3 ′-bis-S-methyl dithiocarbonate of inosine derivatives. The radical deoxygenation proceeded smoothly to give the desired dideoxy compounds in good yields using 1-ethylpiperidinium hypophosphite and triethylborane. Benzyl or p-methoxybenzyl protection of inosine at the N1, 5 ′-O-positions were effective for the ddI synthesis.

Improved Industrial Syntheses of Penciclovir and Famciclovir Using N2-Acetyl-7-Benzylguanine and a Cyclic Side Chain Precursor

We have established practical synthetic methods for penciclovir (PCV, 1) and famciclovir (FCV, 2) from N2-acetyl-7-benzylguanine (NAc7BnG, 3) and 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (4)—the latter being a more easily prepared cyclic precursor of the diacetate side chain (5) used in the conventional process. The coupling of 4 with 3 proceeded regioselectively at the N9 position of guanine in good yield. The coupling product was then successfully transformed into the known antiviral agents in a short number of steps.