Tadashi Katoh

Total Synthesis of the Bicyclic Depsipeptide HDAC Inhibitors Spiruchostatins A and B, 5 -epi-Spiruchostatin B, FK228 (FR901228) and Preliminary Evaluation of Their Biological Activity

The bicyclic depsipeptide histone deacetylase (HDAC) inhibitors spiruchostatins A and B, 5-epi-spiruchostatin B and FK228 were efficiently synthesized in a convergent and unified manner. The synthetic method involved the following crucial steps: i) a Julia-Kocienski olefination of a 1,3-propanediol-derived sulfone and a L- or D-malic acid-derived aldehyde to access the most synthetically challenging unit, (3S or 3R,4E)-3-hydroxy-7-mercaptohept-4-enoic acid, present in a D-alanine- or D-valine-containing segment; ii) a condensation of a D-valine-D-cysteine- or D-allo-isoleucine-D-cysteine-containing segment with a D-alanine- or D-valine-containing segment to directly assemble the corresponding seco-acids; and iii) a macrocyclization of a seco-acid using the Shiina method or the Mitsunobu method to construct the requisite 15- or 16-membered macrolactone. The present synthesis has established the C5 stereochemistry of spiruchostatin B. In addition, HDAC inhibitory assay and the cell-growth inhibition analysis of the synthesized depsipeptides determined the order of their potency and revealed some novel aspects of structure-activity relationships. It was also found that unnatural 5-epi-spiruchostatin B shows extremely high selectivity (ca. 1600-fold) for class I HDAC1 (IC(50)=2.4 nM) over class II HDAC6 (IC(50)=3900 nM) with potent cell-growth-inhibitory activity at nanomolar levels of IC(50) values.

Enantioselective Total Synthesis of (−)‐Candelalides A, B and C: Potential Kv1.3 Blocking Immunosuppressive Agents

Novel Kv1.3 blocking immunosuppressants, (-)-candelalides A, B and C, were efficiently synthesized for the first time in a convergent and unified manner starting from (+)-5-methyl-Wieland-Miescher ketone. The synthetic method involved the following key steps: i) a strategic [2,3]-Wittig rearrangement of a stannylmethyl ether to install the stereogenic center at C9 and the exo-methylene function at C8 present in the decalin portion; ii) a straightforward coupling of a trans-decalin portion (BC ring) and a gamma-pyrone moiety through the C16-C3 bond to assemble the requisite carbon framework; and iii) a construction of a characteristic di or tetrahydropyran ring (A ring) by internal nucleophilic ring closure of a hydroxy aldehyde or a hydroxy epoxide. The present total synthesis has fully established the absolute configuration of these natural products.

Ir-catalyzed oxidative desymmetrization of meso-diols.

The catalytic oxidative desymmetrization of meso-diols was realized using a chiral iridium catalyst. In particular, the reaction is effective for the cyclic diols to give the corresponding hydroxy ketones in high chemical yields with high ees. With this reaction as a key step, a short-step synthesis of common intermediate of ottelione and scyphostatin was achieved.

ENANTIOSELECTIVE TOTAL SYNTHESIS OF NOVEL DITERPENOID PYRONES (+)-SESQUICILLIN AND (-)-NALANTHALIDE FROM FUNGAL FERMENTATIONS

We efficiently synthesized (+)-sesquicillin (a glucocorticoid antagonist) and (-)-nalanthalide (a potassium channel Kvl.3 blocker) in a convergent and unified manner starting from (+)-5-methyl-Wieland-Miescher ketone. The synthesis involved the following key steps: (i) a [2,3]-Wittig rearrangement of a stannylmethyl ether to install the stereogenic center at C9 and the exo-methylene functionality at C8 present in the trans-decalin portion, (ii) a coupling reaction of a trans-decalin portion with a γ-pyrone moiety to assemble the requisite whole carbon framework, and (iii) a conversion of a γ-pyrone moiety to an α-pyrone ring to produce (+)-sesquicillin. The present total synthesis has verified the absolute configuration of these natural products.

SPIROCYCLIZATION OF SIX-MEMBERED CYCLIC N-ACYLIMINIUM IONS WITH A CONJUGATED DIENE

Intramolecular spirocyclization of six-membered cyclic N-acyliminium ions with a tethered conjugated diene has been studied. The reaction of an N-acyliminium ion bearing an endocyclic amide carbonyl group led to spirocyclization to give a l-azaspiro[5.5]undecane compound.