Takeshi Sugai

Okicamelliaside, a glucoside of ellagic acid with potent anti-degranulation activity, was synthesized from ellagic acid. The regioselectivity, solubility, and high reactivity of the intermediates throughout the synthesis were obtained by the complementary use of triisopropylsilyl (TIPS) and methoxyethoxymethyl (MEM) protective groups on the aglycone skeleton.

A seven-step and scalable synthesis of dihydronorcapsaicin β-D-glucopyranoside, non-pungent and adrenal secretion enhancement activity (diet effect), was accomplished from vanillin. A simple and inexpensive glucosyl donor, acetobromoglucose, was reacted with phenolic hydroxyl group of α-iodovanillin nitrile under basic conditions. Another key step was the lipase-catalyzed coupling reaction of primary amine, which was resulted from the reduction of the glucosylated product, with methyl nonanoate.

On the way to a chemoenzymatic synthesis of a key intermediate for sesquiterpenoids and diterpenoids, 2‐methyl‐2‐(4‐methyl‐3‐oxopentyl)‐1,3‐cyclohexanedione was reduced with the whole cells of yeast biocatalysts. Torulaspora delbrueckii NBRC10921 reduced a cyclic ketone of three carbonyl groups in an enantiofacially selective manner (re‐face attack), but there was poor enantiotopic group selectivity between two carbonyl groups on the cyclohexane ring to yield a mixture of diastereomeric products. Candida floricola IAM13115 reduced mainly the pro‐(R) carbonyl group. In contrast, the reduction proceeded in an enantiofacially poorly selective manner to give another set of diastereomeric products. In both cases, another carbonyl group on the side chain worked as a ‘trapping arm’ of the resulting secondary alcohol. The diastereomeric products were effectively separated as the ‘syn’ or ‘cis’ isomer exclusively exist in the intramolecular hemiacetal structure, while ‘anti’ or ‘trans’ isomer being an equilibrated mixture of cyclic hemiacetal and open‐chain hydroxyketone (ca. 0.7 : 1). Starting separately from the enantiomerically enriched products as above, both enantiomers of the target compound, a key intermediate for terpenoids, were efficiently prepared via stereoselective ring closure under pinacol coupling reaction conditions. Furthermore, a daucane sesquiterpene intermediate, a hydroazulene derivative, was provided after one‐carbon homologation of the six‐membered ring.

Substrate specificity on the reduction of bicyclic diketones with a yeast strain, Torulaspora delbrueckii IFO10921, was investigated. Although this yeast efficiently reduces the isolated carbonyl group involved in the (S)‐enantiomer of Wieland–Miescher ketone with high enantioselectivity (E=126), the introduction of a substituent on the octahydronaphthalene skeleton as well as the structural change into an octahydroindene skeleton retarded the enzymatic reduction and the enantioselectivity fell to E=5–16. Further structural variation into a bicyclo[3.3.0] skeleton led to an exclusive 1,4‐conjugate reduction of the α,β‐unsaturated carbonyl group, and the above results suggested the participation of plural oxidoreductive enzymes in the whole cell. In turn, among the 2,2‐disubstituted cycloalkanediones there were found good substrates to give the corresponding hydroxy ketone equivalents by yeast‐mediated reduction. The products were isolated as cyclic hemiacetals, such as (1S,6S)‐3‐ethyl‐3‐hydroxy‐6‐methyl‐2‐oxabicyclo[4.4.0]decan‐7‐one and (1S,6S)‐3‐hydroxy‐3,6‐dimethyl‐2‐oxabicyclo[4.3.0]nonan‐7‐one. In addition, the reduction worked well with use of an air‐dried, long‐term preservable cell preparation. The subsequent chemical transformation warranted the stereochemistry and the stereochemical purity of the products, which are related to octahydronaphthalenone and octahydroindenone systems that, in turn, are of considerable value as starting materials for terpenoid synthesis.

A heliannane-type sesquiterpene, heliannuol E (1), has been successfully synthesized. The key step was conversion of the electrochemically produced spiro compounds (8, and 18) into the corresponding dihydrobenzopyrans (11, 12, 19, and 20) by a selective ring expansion process.

A short-step route to GlcNAc-Cbz-Asn was developed. Treatment of GlcNAc in sat. aq. NH₄HCO₃ solution and subsequent electorodialytic desalting provided ammonia-free glycosylamine in large quantity. The product was coupled with Cbz-Asn α-isobutyl ester β-fluoride, and finally, the isobutyl ester was deprotected by enzyme-catalyzed hydrolysis under mild conditions.