Takeo Kawabata

Novel syntheses of the carbapenem key intermediates, (3R,4R)-4-acetoxy-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-2-azetidinone and (3S,4R)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-carboxymethyl-2-azetidinone, from (S)-ethyl lactate

Abstract Two types of the carbapenem key intermediates (4 and 6) have been efficiently synthesized from inexpensive (S)-ethyl lactate (7). Thus, (S)-2-benzyloxypropanal readily obtainable from 7 was condensed with di-p-anisylmethylamine to give the chiral imine. The [2+2]-cycloaddition reaction of diketene with the imine underwent in a highly stereoselective manner, yielding the desired 3,4-trans-3-acetyl-β-lactam (13a) as a major product (diastereoselectivity 7∼10:1). This was elaborated to 4 and 6 in 9 and 6 steps, respectively.

Preparation and properties of chiral 4-pyrrolidinopyridine (PPY) analogues with dual functional side chains

Abstract Chiral 4-pyrrolidinopyridine analogues 8 – 13 with two distinct functional side chains at C(2) and C(4) of the pyrrolidine ring were prepared from 4-hydroxy- l -proline. We examined desymmetrization of meso -1,3-cyclohexanediol through enantioselective acylation using these catalysts and found that introduction of a C(4)-side chain was effective for improving both the chemo- and enantioselectivity of acylation.

Powdered KOH in DMSO: an efficient base for asymmetric cyclization via memory of chirality at ambient temperature.

Enolate chemistry has been extensively used for stereoselective C-C bond formation, in which metal amide bases are frequently employed in strictly anhydrous solvents at low temperatures. However, we found that asymmetric intramolecular C-C bond formation via axially chiral enolate intermediates proceeded in up to 99% ee at 20 degrees C using powdered KOH in dry or wet DMSO as a base. The enantioselectivity was even higher than that of the corresponding reactions with potassium hexamethyldisilazide in DMF at -60 degrees C. The racemization barrier of the axially chiral enolate intermediate was estimated to be approximately 15.5 kcal/mol. On the basis of the barrier, the chiral enolate intermediate was supposed to undergo cyclization within approximately 10(-3) sec at 20 degrees C after it is generated to give the product in >or=99% ee. Thus, enolates generated with powdered KOH in DMSO were expected to be extremely reactive.

A novel and efficient synthesis of the key intermediate of 1β-methylcarbapenem antibiotics employing [ 2+2 ]-cycloaddition reaction of diketene with a chiral imine

Abstract The key intermediate (2) of 1β-methylcarbapenems was efficiently synthesized from ( S )-methyl 3-hydroxy-2-methyl-propionate (( S )-5) in ten steps and 30 % overall yield. Thus, ( S )-3-benzyloxy-2-methylpropanal readily obtainable from ( S )-5, was condensed with di- p -anisylmethylamine to afford the chiral imine. The [2+2]-cycloaddition reaction of diketene with the imine was found to proceed in a highly diastereoselective manner, giving the desired 3,4- trans -3-acetyl-β-lactam (max. diastereoselectivity 11-15:1). This was readily elaborated to 2 by five sequential operations.

Asymmetric α-arylation of amino acid derivatives by clayden rearrangement of ester enolates via memory of chirality

A method for asymmetric α-arylation of amino acid derivatives has been developed. The arylation was performed by Clayden rearrangement of ester enolates via memory of chirality to give hydantoins with an aryl-substituted tetrasubstituted carbon with up to 99% ee.

Total Synthesis of Ellagitannins through Regioselective Sequential Functionalization of Unprotected Glucose

Short total syntheses of natural glycosides (ellagitannins) were performed through sequential and regioselective functionalization of the hydroxy groups of unprotected glucose. The key reactions are β-selective glycosidation of a gallic acid derivative by using unprotected glucose as a glycosyl donor and catalyst-controlled regioselective introduction of a galloyl group into the inherently less reactive hydroxy group of the glucoside.

A novel and efficient synthesis of the key intermediate of 1β-methylcarbapenem antibiotics from (s)-methyl 3-hydroxy-2-methylpropionate

Abstract A highly efficient synthesis of the key intermediate 2 of 1β-methylcarbapenems was accomplished in 10 steps and 30% overall yield starting from commercially available ( S )-methyl 3-hydroxy-2-methylpropionate. The explored synthetic scheme features the addition reaction of diketene with a chiral imine as a key diastereoselective step.

Direct asymmetric intramolecular alkylation of beta-alkoxy-alpha-amino esters via memory of chirality.

The intramolecular alpha-alkylation of beta-alkoxy-alpha-amino esters derived from L-serine proceeded predominantly over beta-elimination. When beta-alkoxy-alpha-amino esters were treated with powdered CsOH in DMSO at 20 degrees C, alpha-alkoxymethyl cyclic amino esters were obtained in up to 94% ee. Optically active THF amino acids were synthesized for the first time by the present method.

Synthesis of spiro compounds through tandem oxidative coupling and a framework rearrangement reaction.

A highly efficient oxidative coupling of 2-naphthols and a rearrangement tandem reaction to afford unique spiro compounds in the presence of FeCl(3).6H(2)O in up to 88% yield have been developed.

Axially Chiral Binaphthyl Surrogates with an Inner N-H-N Hydrogen Bond

Novel chiral binaphtyl surrogates with an inner hydrogen bond have been created. The NH appears at 13.0-13.3 ppm in thier (1)H NMR spectrum, indicating extremely strong hydrogen bonding. Enantiomers of these compounds were stable at ambient temperature and separable by HPLC with a chiral stationary phase. The half-lives of racemization of the enantiomer are in the range 3 months to 2 years at 20 degrees C, and the barriers for racemization are in the range 27.0 to 28.2 kcal/mol. An X-ray crystal analysis of the compound (R = CHPh(2)) shows that the pseudonaphthyl skeleton including CN...HN is almost completely planar and the dihedral angle between the pseudonaphthalene and naphthalene rings is 128 degrees .