Organocatalytic DYKAT of Si-Stereogenic Silanes.

Chiral organosilanes do not exist in nature and are therefore absent from the "chiral pool". As a consequence, synthetic approaches toward enantiopure silanes, stereogenic at silicon, are rather limited. While catalytic asymmetric desymmetrization reactions of symmetric organosilicon compounds have been developed, the utilization of racemic silanes in a dynamic kinetic asymmetric transformation (DYKAT) or dynamic kinetic resolution (DKR) would significantly expand the breadth of accessible Si-stereogenic compounds. We now report a DYKAT of racemic allyl silanes enabled by strong and confined imidodiphosphorimidate (IDPi) catalysts, providing access to Si-stereogenic silyl ethers. The products of this reaction are easily converted into useful enantiopure monohydrosilanes. We propose a spectroscopically and experimentally supported mechanism involving the epimerization of a catalyst-bound intermediate.

Organocatalytic Asymmetric Synthesis of Si-Stereogenic Silyl Ethers.

Functionalized enantiopure organosilanes are important building blocks with applications in various fields of chemistry; nevertheless, asymmetric synthetic methods for their preparation are rare. Here we report the first organocatalytic enantioselective synthesis of tertiary silyl ethers possessing "central chirality" on silicon. The reaction proceeds via a desymmetrizing carbon-carbon bond forming silicon-hydrogen exchange reaction of symmetrical bis(methallyl)silanes with phenols using newly developed imidodiphosphorimidate (IDPi) catalysts. A variety of enantiopure silyl ethers was obtained in high yields with good chemo- and enantioselectivities and could be readily derivatized to several useful chiral silicon compounds, leveraging the olefin functionality and the leaving group nature of the phenoxy substituent.

Direct Stereoconvergent Allylation of Chiral Alkylcopper Nucleophiles with Racemic Allylic Phosphates.

Copper-catalyzed stereoconvergent allylation of chiral sp3 -hybridized carbon nucleophiles with a racemic mixture of acyclic secondary allylic phosphates is reported. In the presence of a copper-catalyst complexed with chiral BenzP* ligand, tandem coupling reaction of vinyl arenes, bis(pinacolato)diboron, and racemic allylic phosphates provided ß-chiral alkylboronates possessing (E)-alkenyl moiety through a direct stereoconvergent allylic coupling with concomitant generation of a C(sp3 )-stereogenic center. A range of vinyl (hetero)arenes and secondary allylic phosphates bearing 1°, 2°, 3° alkyl and phenyl α-substituents were suitable for the reaction, forming products with high enantioselectivities up to 95 % ee. Density functional theory calculations were conducted in detail to elucidate the origin of the observed regioselectivity of borylcupration and stereoconvergent (E)-olefin formation from racemic allylic phosphates.

Asymmetric Synthesis of Borylalkanes via Copper-Catalyzed Enantioselective Hydroallylation.

An efficient synthetic method for preparing enantioenriched secondary borylalkanes has been achieved through a copper-catalyzed regio- and enantioselective hydroallylation of alkenyl boronates and boramides employing hydrosilanes and allylic phosphates. In the presence of a copper catalyst with a chiral Walphos ligand, a range of alkenylboron compounds with an aryl, heteroaryl, or alkyl substituent produced secondary homoallylic alkylboron compounds in good yields and with high enantioselectivities up to 99% ee. The utility of the resulting alkylboronates was demonstrated in an efficient synthesis of (S)-massoialactone.

Down-regulation of microglial activity attenuates axotomized nigral dopaminergic neuronal cell loss.

BACKGROUND: There is growing evidence that inflammatory processes of activated microglia could play an important role in the progression of nerve cell damage in neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease which harbor features of chronic microglial activation, though the precise mechanism is unknown. In this study, we presented in vivo and ex vivo experimental evidences indicating that activated microglia could exacerbate the survival of axotomized dopaminergic neurons and that appropriate inactivation of microglia could be neuroprotective. RESULTS: The transection of medial forebrain bundle (MFB) of a rat induced loss of dopaminergic neurons in a time-dependent manner and accompanied with microglial activation. Along with microglial activation, production of reactive oxygen species (ROS) was upregulated and TH/OX6/hydroethidine triple-immunofluorescence showed that the microglia mainly produced ROS. When the activated microglial cells that were isolated from the substantia nigra of the MFB axotomized animal, were transplanted into the substantia nigra of which MFB had been transected at 7 days ago, the survival rate of axotomized dopaminergic neurons was significantly reduced as compared with sham control. Meanwhile, when the microglial activation was attenuated by administration of tuftsin fragment 1-3 (microglia inhibitory factor) into the lateral ventricle using mini-osmotic pump, the survival rate of axotomized dopaminergic neurons was increased. CONCLUSION: The present study suggests that activated microglia could actively produce and secrete unfavorable toxic substances, such as ROS, which could accelerate dopaminergic neuronal cell loss. So, well-controlled blockade of microglial activation might be neuroprotective in some neuropathological conditions.

Asymmetric synthesis of γ-chiral borylalkanes via sequential reduction/hydroboration using a single copper catalyst.

The synthesis of γ-chiral borylalkanes through copper-catalyzed enantioselective SN2'-reduction of γ,γ-disubstituted allylic substrates and subsequent hydroboration was reported. A copper-DTBM-Segphos catalyst produced a range of γ-chiral alkylboronates from easily accessible allylic acetate or benzoate with high enantioselectivities up to 99% ee. Furthermore, selective organic transformations of the resulting γ-chiral alkylboronates generated the corresponding γ-chiral alcohol, arene and amine compounds.

Asymmetric Synthesis of 1,2-Dihydronaphthalene-1-ols via Copper-Catalyzed Intramolecular Reductive Cyclization.

We describe a copper-catalyzed intramolecular reductive cyclization of easily accessible benz-tethered 1,3-dienes containing a ketone moiety. This process provided biologically active 1,2-dihydronaphthalene-1-ol derivatives in good yields with excellent enantio- and diastereoselectivity. Mechanistic investigations using density functional theory revealed that (Z)- and (E)-allylcopper intermediates formed in situ from the diene and copper catalyst undergo isomerization and selective intramolecular allylation of the (E)-allylcopper form of the major product through a six-membered boatlike transition state. The resulting products were further transformed to fully saturated naphthalene-1-ols by reactions of the olefin moiety.

Asymmetric synthesis of α-chiral ß-hydroxy allenes: copper-catalyzed γ-selective borylative coupling of vinyl arenes and propargyl phosphates.

Copper-catalyzed enantioselective coupling of vinyl arenes with bis(pinacolato)diboron (B2pin2) and propargylic phosphates is presented. The protocol affords a facile route to enantioenriched α-branched allenes with a versatile pinacolboronate group at the ß-position with high enantioselectivity up to 98 : 2 er. In the presence of a copper catalyst complexed with a chiral bisphosphine ligand, catalytic assembly of α-chiral ß-hydroxy allenes was accomplished through highly selective γ-addition of a borylalkyl copper species to propargyl substrates, followed by oxidation. Catalyst-controlled divergent cyclization reactions of the resulting allenes led to concise syntheses of enantioenriched dihydropyran and dihydrofuran rings without any loss of chiral purity.

Copper-Catalyzed Synthesis of Tetrasubstituted Enynylboronates via Chemo-, Regio-, and Stereoselective Borylalkynylation.

An efficient, catalytic method for accessing tetrasubstituted enynylboronates has been established via copper-catalyzed chemo-, regio-, and stereoselective borylalkynylation of internal alkynes. In this protocol, a range of symmetrical and unsymmetrical internal alkynes with aryl, heteroaryl, and alkyl substituents afforded fully substituted enynylboron compounds in good yields and with high levels of regio- and stereoselectivity, up to a ratio of >20:1. The enynylboron products could be further utilized in transforming the C-B bond into C-C bonds by coupling reactions.

Copper-Catalyzed Asymmetric Borylallylation of Vinyl Arenes.

A copper-catalyzed, enantioselective method for the borylallylation of vinyl arenes is reported. The reaction produces enantioenriched and functionalized organoboron compounds by sequentially incorporating boryl and allyl groups onto the C═C bond of vinyl arenes. Copper-catalyzed borylative coupling of vinyl arenes with allyl phosphates successfully proceeds in a regio- and enantioselective manner in the absence of a palladium cocatalyst.

SAR Studies of Indole-5-propanoic Acid Derivatives To Develop Novel GPR40 Agonists.

G-protein coupled receptor 40 (GPR40) has been considered to be an attractive drug target for the treatment of type 2 diabetes because of its role in free fatty acids-mediated enhancement of glucose-stimulated insulin secretion (GSIS) from pancreatic ß-cells. A series of indole-5-propanoic acid compounds were synthesized, and their GPR40 agonistic activities were evaluated by nuclear factor of activated T-cells reporter assay and GSIS assay in the MIN-6 insulinoma cells. Three compounds, 8h (EC50 = 58.6 nM), 8i (EC50 = 37.8 nM), and 8o (EC50 = 9.4 nM), were identified as potent GPR40 agonists with good GSIS effects.