Mechanistic Details of Asymmetric Bromocyclization with BINAP Monoxide: Identification of Chiral Proton-Bridged Bisphosphine Oxide Complex and Its Application to Parallel Kinetic Resolution.

The mechanism of our previously reported catalytic asymmetric bromocyclization reactions using 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) monoxide was examined in detail by the means of control experiments, NMR studies, X-ray structure analysis, and CryoSpray electrospray ionization mass spectrometry (ESI-MS) analysis. The chiral BINAP monoxide was transformed to a key catalyst precursor, proton-bridged bisphosphine oxide complex (POHOP·Br), in the presence of N-bromosuccinimide (NBS) and contaminating water. The thus-formed POHOP further reacts with NBS to afford BINAP dioxide and molecular bromine (Br2) simultaneously in equimolar amounts. While the resulting Br2 is activated by NBS to form a more reactive brominating reagent (Br2─NBS), BINAP dioxide serves as a bifunctional catalyst, acting as both a Lewis base that reacts with Br2─NBS to form a chiral brominating agent (P═O+─Br) and also as a Brønsted base for the activation of the substrate. By taking advantage of this novel concerted Lewis/Brønsted base catalysis by BINAP dioxide, we achieved the first regio- and chemodivergent parallel kinetic resolutions (PKRs) of racemic unsymmetrical bisallylic amides via bromocyclization.

Rigorous control of vesicle-forming lipid pKa by fluorine-conjugated bioisosteres for gene-silencing with siRNA.

While the influence of pKa provided by amine-containing materials in siRNA delivery vectors for use in gene-silencing has been widely studied, there are little reports in which amine pKa is controlled rigorously by using bioisosteres and its effect on gene-silencing. Here, we report that amine pKa could be rigorously controlled by replacement of hydrogen atom(s) with fluorine atom(s). A series of mono- and di-amine lipids with a different number of fluorine atoms were synthesized. The pKa of the polyamine lipids was shifted to a lower value with an increase in the number of fluorine atoms. The optimal pKa for high gene-silencing efficiency varied according to the number of amine residues in the polyamine lipid. Whereas the endosomal escape ability of mono-amine lipid-containing lipid vesicles (LVs) depended on the pKa, that of all tested di-amine lipid-containing LVs showed equal membrane-destabilizing activity. LVs showing moderately weak interactions with siRNA facilitated cytoplasmic release of siRNA, resulting in strong gene-silencing. These findings indicate that appropriate amine pKa engineering depending on the number of amines is important for the induction of effective RNA interference.

Regio- and chemoselective Csp3-H arylation of benzylamines by single electron transfer/hydrogen atom transfer synergistic catalysis.

We present a highly regio- and chemoselective Csp3-H arylation of benzylamines mediated by synergy of single electron transfer (SET) and hydrogen atom transfer (HAT) catalysis. Under well precedented SET catalysis alone, the arylation reaction of N,N-dimethylbenzylamine proceeded via aminium radical cation formation and selectively targeted the N-methyl group. In contrast, addition of PhC(O)SH as a HAT catalyst precursor completely switched the regioselectivity to Csp3-H arylation at the N-benzylic position. Measurement of oxidation potentials indicated that the conjugate base of PhC(O)SH is oxidized in preference to the substrate amine. The discovery of the thiocarboxylate as a novel HAT catalyst allowed for the selective generation of the sulfur-centered radical, so that the N-benzyl selectivity was achieved by overriding the inherent N-methyl and/or N-methylene selectivity under SET catalysis conditions. While visible light-driven α-C-H functionalization of amines has mostly been demonstrated with aniline derivatives and tetrahydroisoquinolines (THIQs), our method is applicable to a variety of primary, secondary and tertiary benzylamines for efficient N-benzylic C-H arylation. Functional group tolerance was high, and various 1,1-diarylmethylamines, including an α,α,α-trisubstituted amine, were obtained in good to excellent yield (up to 98%). Importantly, the reaction is applicable to late-stage functionalization of pharmaceuticals.

Photofluorination of Aliphatic C-H Bonds Promoted by the Phthalimide Group.

Aliphatic C-H fluorination of phthalimide derivatives with Selectfluor was investigated under photoirradiation conditions. The reaction did not require any additive or catalyst and afforded C-H fluorinated products in moderate to good yields. It is likely that the reaction site depends on the C-H bond energy, and this may be the reason for the good to high regioselectivity.

Enantioselective Synthesis of Nelfinavir via Asymmetric Bromocyclization of Bisallylic Amide.

We describe a concise enantioselective synthesis of the HIV-protease inhibitor nelfinavir (1) via a new route in which the key step is construction of the central optically active 1,2-amino alcohol framework via asymmetric bromocyclization of bisallylic amide with N-bromosuccinimide in the presence of a catalytic amount of ( S)-BINAP or ( S)-BINAP monoxide. The remaining alkene and bromo functionalities were used to install the requisite thioether and chiral perhydroisoquinoline units, respectively.

Dianionic Phase-Transfer Catalyst for Asymmetric Fluoro-cyclization.

Inspired by the dicationic nature of the electrophilic fluorinating reagent, Selectfluor (1), we rationally designed a series of dicarboxylic acid precatalysts (2), which, when deprotonated, act as anionic phase-transfer catalysts for asymmetric fluorination of alkenes. Among them, 2a having the shortest linker moiety efficiently catalyzed unprecedented 6-endo-fluoro-cyclization of various allylic amides, affording fluorinated dihydrooxazine compounds with high enantioselectivity (up to 99% ee). In addition to cyclic substrates, acyclic trisubstituted alkenes underwent the reaction with good diastereoselectivity, whereas low diastereoselectivity was observed for linear disubstituted alkenes. Results suggest that the reaction proceeds via a fluoro-carbocation intermediate.

Desymmetrization of Bisallylic Amides through Catalytic Enantioselective Bromocyclization with BINAP Monoxide.

We report the first desymmetrization of bisallylic amides by enantioselective bromocyclization with BINAP monoxide as a catalyst. Depending upon the substitution pattern of the alkene moieties, densely functionalized, optically active oxazoline or dihydrooxazine compounds were obtained in a highly stereoselective manner. The remaining alkene moiety was subjected to various functional group manipulations to afford a diverse array of chiral molecules with multiple stereogenic centers.

Benzylic C-H Trifluoromethylation via Photoenol.

Photoenols generated in situ from ortho-methyl-substituted phenylketones such as benzophenones and acetophenones were trifluoromethylated with Togni reagent without any additive or catalyst. This trifluoromethylation reaction proceeded smoothly under photoirradiation conditions (365 nm). Various functional groups were tolerant of the reaction conditions. Interestingly, the trifluoromethyl group was exclusively introduced at the ortho-benzylic position. Mechanistic studies suggested that this reaction proceeds via formation of a photoenol, not via a radical pathway.

Difunctionalization of Alkenes Using 1-Chloro-1,2-benziodoxol-3-(1H)-one.

Difunctionalization of alkenes with 1-chloro-1,2-benziodoxol-3-(1H)-one (1) was investigated. Various additional nucleophiles were tested, and oxychlorination, dichlorination, azidochlorination, chlorothiocyanation, and iodoesterfication were demonstrated. The oxychlorination product was obtained efficiently when the reaction was operated in water. Dichlorination occurred in the presence of a Lewis basic promoter, such as 4-phenylpyridine N-oxide, as an additive. The reaction with in situ-generated azido anion afforded azidochlorinated compounds with a chlorine atom at the terminal position, while the reaction with trimethylsilyl isothiocyanate produced chlorothiocyanation adducts with a chlorine atom at the benzylic position. On the other hand, when 1 was treated with tetra-n-butylammonium iodide prior to the addition of alkenes, only iodoesterification occurred selectively. These mild reactions enable convenient site-selective difunctionalizations of substrates having two alkene moieties. NMR experiments suggested that the electrophilic reactive species in each reaction varied depending on the nature of the added nucleophile.

Highly Enantioselective Bromocyclization of Allylic Amides with a P/P=O Double-Site Lewis Base Catalyst.

The enantioselective bromocyclization of allylic amides catalyzed by phosphorus-containing Lewis bases was examined in detail. A series of control experiments and NMR studies showed that a partially oxidized bis-phosphine generated in situ serves as the actual enantioselective catalyst. The reaction mechanism involves distinct roles of two Lewis basic sites, P and P=O, with P+ Br serving as a fine-tuning element for substrate fixation in the chiral environment, and P+ OBr as the Br+ transfer agent to the olefin. Catalyst loading could be reduced to as little as 1 mol %, and the reaction affords enantioenriched oxazolines with up to >99.5 % ee.

Benzylic C-H trifluoromethylation of phenol derivatives.

Phenol derivatives were trifluoromethylated using copper/Togni reagent. In dimethylformamide, the benzylic C-H bond at the para position of the hydroxyl group was selectively substituted with a CF3 group. In contrast, aromatic C-H trifluoromethylation occurred in alcoholic solvents. Practical utility of the reactions was demonstrated by application to the synthesis of a potent enoyl-acyl carrier protein reductase (FabI) inhibitor.

Asymmetric Fluorolactonization with a Bifunctional Hydroxyl Carboxylate Catalyst.

We report the first successful example of a highly enantioselective fluorolactonization with an electrophilic fluorinating reagent, Selectfluor(®), in the presence of a novel bifunctional organocatalyst. The catalyst design includes a carboxylate anion functioning as a phase-transfer agent and a benzyl alcohol unit to capture the substrate through hydrogen bonding. Fluorinated isobenzofuranones were obtained in good yields with up to 94% ee (97:3 er). On the basis of mechanistic studies, we propose a unique reaction mechanism with potential for further applications.

Catalytic asymmetric mannich-type reaction of N-alkylidene-α-aminoacetonitrile with ketimines.

Optically active vicinal diamines are versatile chiral building blocks in organic synthesis. A soft Lewis acid/hard Brønsted base cooperative catalyst allows for an efficient stereoselective coupling of N-alkylidene-α-aminoacetonitrile and ketimines to access this class of compounds bearing consecutive tetra- and trisubstituted stereogenic centers. The strategic use of a soft Lewis basic thiophosphinoyl group for ketimines is the key to promoting the reaction, and aliphatic ketimines serve as suitable substrates with as little as 3 mol % catalyst loading.

Enantioselective bromocyclization of allylic amides catalyzed by BINAP derivatives.

A highly enantioselective bromocyclization of allylic amides with N-bromosuccinimide (NBS) was developed with DTBM-BINAP as a catalyst, affording chiral oxazolines with a tetrasubstituted carbon center in high yield with up to 99% ee. By utilizing the bromo substituent as a handle, the obtained compounds were converted to synthetically useful chiral building blocks.

Direct catalytic asymmetric addition of acetonitrile to N-thiophosphinoylimines.

Direct catalytic addition of acetonitrile pronucleophiles to thiophosphinoylimines is described. Soft Lewis acid-hard Brønsted base cooperative catalysis is crucial to promote this elusive carbon-carbon bond-forming reaction in an enantioselective fashion.

Streamlined catalytic asymmetric synthesis of atorvastatin.

An efficient enantioselective synthetic route to atorvastatin was developed based on a direct catalytic asymmetric aldol reaction. The expensive chiral ligand used in the initial aldol reaction was readily recovered (91 %) and reused. Implementation of an oxy-Michael reaction for the construction of the syn-1,3-diol unit eliminated several redundant steps, allowing for rapid access to the common intermediate in six steps.

Anti-selective direct catalytic asymmetric aldol reaction of thiolactams.

An anti-selective direct catalytic asymmetric aldol reaction of thiolactam is described. A soft Lewis acid/hard Brønsted base cooperative catalyst comprised of mesitylcopper/(R,R)-Ph-BPE exhibited high catalytic performance to produce an anti-aldol product with high stereoselectivity. The highly chemoselective nature of the present catalysis allows for the use of enolizable aldehydes as aldol acceptors. The diverse transformations of the thiolactam moiety highlight the synthetic utility of the present anti-aldol protocol.

Catalytic asymmetric conjugate addition of alpha-cyanoketones for the construction of a quaternary stereogenic center.

The catalytic asymmetric conjugate addition of alpha-cyanoketone pronucleophiles to vinyl ketones promoted by a Y/1 catalyst is described. High enantioselectivity was observed for a range of aromatic vinyl ketones, providing 1,5-dicarbonyl compounds bearing an all-carbon quaternary stereogenic center. The product was successfully converted to a spiro-piperidine entity and a bicyclo[3.3.0]octane framework through either the reduction of nitrile or intramolecular pinacol coupling.