Satoshi Yokoshima

A novel ketone synthesis by a palladium-catalyzed reaction of thiol esters and organozinc reagents

Abstract A variety of ketones have been prepared by a palladium-catalyzed reaction of ethanethiol esters with organozinc reagents. Various functional groups, including esters, ketones, aromatic halides and aldehydes, tolerate the reaction conditions. The reaction can also be applied to the synthesis of α-amino ketones using the corresponding L-α-amino thiol esters without racemization.

Total Synthesis of Ecteinascidin 743

The total synthesis of ecteinascidin 743 (1), an extremely potent antitumor agent, has been accomplished. The synthesis features Ugis 4CC reaction, intramolecular Heck reaction, phenol-aldehyde cyclization, and acid-induced intramolecular sulfide formation.

BACE1 Activity Is Modulated by Cell-Associated Sphingosine-1-Phosphate

Sphingosine kinase (SphK) 1 and 2 phosphorylate sphingosine to generate sphingosine-1-phosphate (S1P), a pluripotent lipophilic mediator implicated in a variety of cellular events. Here we show that the activity of β-site APP cleaving enzyme-1 (BACE1), the rate-limiting enzyme for amyloid-β peptide (Aβ) production, is modulated by S1P in mouse neurons. Treatment by SphK inhibitor, RNA interference knockdown of SphK, or overexpression of S1P degrading enzymes decreased BACE1 activity, which reduced Aβ production. S1P specifically bound to full-length BACE1 and increased its proteolytic activity, suggesting that cellular S1P directly modulates BACE1 activity. Notably, the relative activity of SphK2 was upregulated in the brains of patients with Alzheimers disease. The unique modulatory effect of cellular S1P on BACE1 activity is a novel potential therapeutic target for Alzheimers disease.

Total Synthesis of (−)-Mersicarpine

The total synthesis of (-)-mersicarpine was achieved in 10 steps from a known ketoester. Our synthesis features an Eschenmoser-Tanabe-type fragmentation to synthesize an alkyne unit containing a quaternary carbon center, a facile construction of the indole skeleton via a combination of a Sonogashira coupling and a gold(III) catalyzed cyclization, as well as a one-pot process to arrange the cyclic imine and the hemiaminal moieties. Our synthesis unambiguously confirmed the reported structure of (-)-mersicarpine including the absolute configuration.

Phenylpiperidine‐type γ‐secretase modulators target the transmembrane domain 1 of presenilin 1

Amyloid‐β peptide ending at the 42nd residue (Aβ42) is implicated in the pathogenesis of Alzheimers disease (AD). Small compounds that exhibit selective lowering effects on Aβ42 production are termed γ‐secretase modulators (GSMs) and are deemed as promising therapeutic agents against AD, although the molecular target as well as the mechanism of action remains controversial. Here, we show that a phenylpiperidine‐type compound GSM‐1 directly targets the transmembrane domain (TMD) 1 of presenilin 1 (PS1) by photoaffinity labelling experiments combined with limited digestion. Binding of GSM‐1 affected the structure of the initial substrate binding and the catalytic sites of the γ‐secretase, thereby decreasing production of Aβ42, possibly by enhancing its conversion to Aβ38. These data indicate an allosteric action of GSM‐1 by directly binding to the TMD1 of PS1, pinpointing the target structure of the phenylpiperidine‐type GSMs.

Concise total synthesis of (+)-lyconadin A.

The total synthesis of lyconadin A from (R)-5-methylcyclohex-2-enone was accomplished. Our synthesis features the facile construction of a highly fused tetracyclic compound through a combination of an aza-Prins reaction and an electrocyclic ring opening. Transformation of the bromoalkene moiety in the tetracycle could be achieved by either a vinylogous Pummerer rearrangement or the formation and subsequent isomerization of the nitrosoalkene to furnish an α,β-unsaturated ketone, from which the pyridone ring was constructed.

Total synthesis of gelsemoxonine.

The first total synthesis of gelsemoxonine (1) has been accomplished. Divinylcyclopropane-cycloheptadiene rearrangement of the highly functionalized substrate was successfully applied to assemble the spiro-quaternary carbon center connected to the bicyclic seven-membered core structure. A one-pot isomerization reaction of the α,β-unsaturated aldehyde to the saturated ester via the TMSCN-DBU reagent combination allowed a facile diastereoselective introduction of the latent nitrogen functionality of the unique azetidine moiety.

Total Syntheses of Lyconadins A–C

The total synthesis of the Lycopodium alkaloid lyconadin A was accomplished and it was applied to the total syntheses of the related congeners, lyconadins B and C. Lyconadin A has attracted attention as a challenging target for total synthesis due to the unprecedented pentacyclic skeleton. Our synthesis of lyconadin A features a facile construction of the highly fused tetracyclic skeleton through a combination of an aza-Prins reaction and an electrocyclic ring opening, followed by formation of a C-N bond. Transformation of the bromoalkene moiety of the tetracycle to a key enone intermediate was extensively investigated, and three methods via sulfide, oxime, or azide intermediates were established. A pyridone ring was constructed from the key enone intermediate to complete the synthesis of lyconadin A. A dihydropyridone ring could also be formed from the same enone intermediate, leading to a synthesis of lyconadin B. Establishment of the conditions for an electrocyclic ring opening without formation of the C-N bond resulted in completion of the total synthesis of lyconadin C.

Total Synthesis of Huperzine Q

The total synthesis of huperzine Q was accomplished. The synthesis features the construction of the cis-hydrindane skeleton via a Diels-Alder reaction and a ring contraction reaction of an epoxyketone.

Allosteric regulation of γ-secretase activity by a phenylimidazole-type γ-secretase modulator

Significance For mechanism-based development of treatment for Alzheimer’s disease (AD), the precise molecular mechanism of γ-secretase modulators (GSMs), which have been extensively developed as possible therapeutic reagents, is required. Here, we analyzed the mode of actions of phenylimidazole-type GSMs using a chemical biology approach and systematic mutagenesis. We provide the first structural model, to our knowledge, that binding of the phenylimidazole-type GSMs at the luminal loop of presenilin induces a conformational change of the catalytic center to reduce toxic amyloid-β species selectively. Our results may facilitate the effective development of AD therapeutics. γ-Secretase is an intramembrane-cleaving protease responsible for the generation of amyloid-β (Aβ) peptides. Recently, a series of compounds called γ-secretase modulators (GSMs) has been shown to decrease the levels of long toxic Aβ species (i.e., Aβ42), with a concomitant elevation of the production of shorter Aβ species. In this study, we show that a phenylimidazole-type GSM allosterically induces conformational changes in the catalytic site of γ-secretase to augment the proteolytic activity. Analyses using the photoaffinity labeling technique and systematic mutational studies revealed that the phenylimidazole-type GSM targets a previously unidentified extracellular binding pocket within the N-terminal fragment of presenilin (PS). Collectively, we provide a model for the mechanism of action of the phenylimidazole-type GSM in which binding at the luminal side of PS induces a conformational change in the catalytic center of γ-secretase to modulate Aβ production.