Tohru Fukuyama

2- and 4-Nitrobenzenesulfonamides: Exceptionally versatile means for preparation of secondary amines and protection of amines

Abstract 2- and 4-Nitrobenzenesulfonamides, readily prepared from primary amines, undergo smooth alkylation by Mitsunobu reaction or by conventional methods to give N-alkylated sulfonamides in near quantitative yields. These sulfonamides could be deprotected readily via Meisenheimer complexes upon treatment with thiolates in DMF at room temperature, giving secondary amines in high yields.

2,4-Dinitrobenzenesulfonamides: A simple and practical method for the preparation of a variety of secondary amines and diamines

Abstract 2,4-Dinitrobenzenesulfonamides, readily prepared from primary amines and 2,4-dinitrobenzenesulfonyl chloride, can be alkylated by the Mitsunobu reaction or by the conventional methods to give N , N -disubstituted sulfonamides in excellent yields. Since 2,4-dinitrobenzenesulfonamides can be removed without deprotecting 2-nitrobenzenesulfonamides, a wide variety of diamines could be prepared by the combined use of these protecting/activating groups.

Sulindac Sulfide Is a Noncompetitive γ-Secretase Inhibitor That Preferentially Reduces Aβ42 Generation

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been known to reduce risk for Alzheimers disease. In addition to the anti-inflammatory effects of NSAIDs to block cylooxygenase, it has been shown recently that a subset of NSAIDs selectively inhibits the secretion of highly amyloidogenic Aβ42 from cultured cells, although the molecular target(s) of NSAIDs in reducing the activity of γ-secretase for Aβ42 generation (γ42-secretase) still remain unknown. Here we show that sulindac sulfide (SSide) directly acts on γ-secretase and preferentially inhibits the γ42-secretase activity derived from the 3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonate-solubilized membrane fractions of HeLa cells, in an in vitroγ-secretase assay using recombinant amyloid β precursor protein C100 as a substrate. SSide also inhibits activities for the generation of Aβ40 as well as for Notch intracellular domain at higher concentrations. Notably, SSide displayed linear noncompetitive inhibition profiles for γ42-secretase in vitro. Our data suggest that SSide is a direct inhibitor of γ-secretase that preferentially affects the γ42-secretase activity.

p-Anisyl group: A versatile protecting group for primary alcohols

Abstract A primary alcohol can be protected as a highly stable p-anisyl ether, which undergoes mild oxidative deprotection by ceric ammonium nitrate.

C-terminal Fragment of Presenilin Is the Molecular Target of a Dipeptidic γ-Secretase-specific Inhibitor DAPT (N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-Butyl Ester)

γ-Secretase is a multimeric membrane protein complex composed of presenilin (PS), nicastrin, Aph-1 and, Pen-2 that is responsible for the intramembrane proteolysis of various type I transmembrane proteins, including amyloid β-precursor protein and Notch. The direct labeling of PS polypeptides by transition-state analogue γ-secretase inhibitors suggested that PS represents the catalytic center of γ-secretase. Here we show that one of the major γ-secretase inhibitors of dipeptidic type, N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT), targets the C-terminal fragment of PS, especially the transmembrane domain 7 or more C-terminal region, by designing and synthesizing DAP-BpB (N-[N-(3,5-difluorophenacetyl)-l-alanyl]-(S)-phenylglycine-4-(4-(8-biotinamido)octylamino)benzoyl)benzyl)methylamide), a photoactivable DAPT derivative. We also found that DAP-BpB selectively binds to the high molecular weight γ-secretase complex in an activity-dependent manner. Photolabeling of PS by DAP-BpB is completely blocked by DAPT or its structural relatives (e.g. Compound E) as well as by arylsulfonamides. In contrast, transition-state analogue inhibitor L-685,458 or α-helical peptidic inhibitor attenuated the photolabeling of PS1 only at higher concentrations. These data illustrate the DAPT binding site as a novel functional domain within the PS C-terminal fragment that is distinct from the catalytic site or the substrate binding site.

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.

Total Synthesis of (+)-Haplophytine†

Despite the many impressive accomplishments in the field of total synthesis in recent years, a number of natural products have proven stubbornly resistant to its advances. Among them is haplophytine (1, Scheme 1a), which has only very recently succumbed to synthesis following the elegant work of Fukuyama, Tokuyama and co-workers. Haplophytine was first isolated by Snyder and co-workers in 1952, and identified as the principle bioactive component of the wild flower Haplophyton cimicidum, valued for centuries by the Aztecs and subsequent settlers of Central America for its insecticidal properties. A heterodimeric indole alkaloid, haplophytine features a particularly complex polycyclic array of ten rings, six stereocenters (five of which are quaternary) and a highly congested carbon carbon bond adjoining the two distinct halves of the molecule. The tetracyclic left-hand domain features a unique bridged ketone structure, while the righthand domain consists of the naturally occurring aspidosperma alkaloid, aspidophytine (2, Scheme 1b). A complete appreciation of haplophytine s molecular structure was only reached some 21 years subsequent to its isolation, following extensive chemical degradation, spectroscopic, and X-ray crystallographic studies from the groups of Cava, Yates, and Zacharias, which included identification of the dihydrobromide derivative 3 (Scheme 1a). As depicted, this compound is formed through a unique acid-mediated skeletal rearrangement of the left-hand domain involving the 1,2-shift of an aminal C N bond. Under basic conditions, however, this process can be reversed such as to return haplophytine through a complementary semi-pinacol type mechanism. As