Effect of the U-Shaped Cavity of Conformationally Flexible Chiral Lewis-Acidic Boron-Based Catalysts in Multiselective Diels-Alder Reactions.

The effect of the U-shaped cavity of conformationally flexible chiral Lewis acidic boron-based catalysts in multiselective Diels-Alder reactions was investigated. The U-shaped catalysts can recognize substituents at the terminal acetylene moiety of propynal based on steric factors and can also recognize alkyne and alkene substrates based on the match/mismatch between the catalysts and substrates. Moreover, even in a mixture of different catalysts and substrates, the desired competitive reactions can proceed multiselectively. This proof-of-concept study should contribute to the development of artificial enzyme-like catalysis in vitro.

Boron Trifluoride-Mediated Domino Dehydration/Electrophilic Cyclization of Silylalkynols Leading to 2,3-Fused Tricyclic Benzofulvenes.

A BF3-mediated domino dehydration/electrophilic cyclization of silylalkynols to form 2,3-fused tricyclic benzofulvenes was achieved. In the latter step, in situ generated BF3·OH2 enables the electrophilic activation of alkynes. The predominant Z-selectivity of the reaction is also discussed.

Dearomative Intramolecular Diels-Alder/Sulfur Extrusion Reaction of Thiophenes with Alkynes Using peri-Substituted Naphthalene as a Tether.

Dearomative intramolecular Diels-Alder/sulfur extrusion reaction of thiophenes with alkynes successfully afforded fluoranthenes in moderate to excellent yields. The proximity of both reactive sites fixed at the peri-position of naphthalene would play an important role in the progress of this reaction. Tri(o-tolyl)phosphine effectively suppressed the side reactions as a sulfur scavenger.

Chiral Macrocyclic Catalysts for the Enantioselective Addition of Lithium Acetylides to Ketones.

Alkynyl addition to carbonyl compounds is a valuable synthetic method for the preparation of versatile chiral alcohols that are widely found in pharmaceuticals and natural products. Although a variety of enantioselective variations have been reported, alkynyl addition to simple ketones remains an unmet challenge due to their low reactivity and difficult enantiofacial discrimination. Here, we report a method for the catalytic enantioselective addition of lithium acetylide to a variety of ketones using macrocyclic lithium binaphtholates as catalysts. These reactions generally suffer from facile aggregation of lithium species, which leads to less active and selective catalysts. The macrocyclic structure designed in this study prevents such aggregation, affording a monomeric and highly active catalyst that can furnish enantioenriched tertiary alcohols from a variety of ketones within 5-30 min. Moreover, the confined cavity and lipophilicity of the macrocycle confer substrate specificity on the system, demonstrating a multiselectivity similar to that of enzymatic reactions. Thus, these findings offer new insights into the rational design of small-molecule artificial enzymes that exhibit high levels of reactivity and multiselectivity.

Multiselective Diels-Alder Reaction of α-Arylacroleins Catalyzed by Boron Tribromide-Assisted Chiral Phosphoric Acids.

A multiselective Diels-Alder (DA) reaction of α-arylacroleins with cyclopentadiene using BBr3-assisted chiral BINOL-derived phosphoric acid catalysts has been developed. This unusual exo- and enantioselective DA reaction can be multicontrolled by the chiral cavity of the in situ-formed acid-base cooperative catalysts, in particular, suppressing the competitive hetero Diels-Alder (HDA) reaction effectively.

Insight into the Mechanism of the Acylation of Alcohols with Acid Anhydrides Catalyzed by Phosphoric Acid Derivatives.

Insight into the mechanism of a safe, simple, and inexpensive phosphoric acid (H3PO4)-catalyzed acylation of alcohols with acid anhydrides is described. The corresponding in situ-generated diacylated mixed anhydrides, unlike traditionally proposed monoacylated mixed anhydrides, are proposed as the active species. In particular, the diacylated mixed anhydrides act as efficient catalytic acyl transfer reagents rather than as Brønsted acid catalysts simply activating acid anhydrides. Remarkably, highly efficient phosphoric acid (1-3 mol %)-catalyzed acylation of alcohols with acid anhydrides was achieved and a 23 g scale synthesis of an ester was demonstrated. Also, phosphoric acid catalyst was effective for synthetically useful esterification from carboxylic acids, alcohols, and acid anhydride. Moreover, with regard to recent developments in chiral 1,1'-bi-2-naphthol (BINOL)-derived phosphoric acid diester catalysts toward asymmetric kinetic resolution of alcohols by acylation, some phosphate diesters were examined. As a result, a 31P NMR study and a kinetics study strongly supported not only the acid-base cooperative mechanism as previously proposed by other researchers but also the mixed anhydride mechanism as presently proposed by us.

Enantioselective Aza-Friedel-Crafts Reaction of Indoles and Pyrroles Catalyzed by Chiral C1-Symmetric Bis(phosphoric Acid).

A hydrogen bonding network in chiral Brønsted acid catalysts is important for the construction of a chiral cavity and the enhancement of catalytic activity. In this regard, we developed a highly enantioselective aza-Friedel-Crafts reaction of indoles and pyrroles with acyclic α-ketimino esters in the presence of a chiral C1-symmetric BINOL-derived bis(phosphoric acid) catalyst. The desired alkylation products with chiral quaternary carbon centers were obtained in high yields with high enantioselectivities on up to a 1.2-g scale with 0.2 mol % catalyst loading. Interestingly, the absolute configurations of the products from indoles and pyrroles were opposite even with the use of the same chiral catalyst. Moreover, preliminary mechanistic considerations disclosed that a unique hydrogen bonding network with or without π-π interactions among the catalyst and substrates might partially play a pivotal role.

Neuroendocrine Carcinoma of Uterine Cervix: Stereotactic Radiotherapy for Brain Metastasis and Stereotactic Body Radiotherapy for Renal and Pancreatic Metastases.

A case of cervical neuroendocrine carcinoma (NEC) of the uterine cervix (NECUC) was presented. After total hysterectomy with bilateral salpingo-oophorectomy and adjuvant chemotherapy, a left renal tumor and a pancreatic lesion developed and were both diagnosed on pathological examination as metastases from NEC. In addition, a brainstem metastasis causing neurologic signs developed. The brain lesion was treated by stereotactic radiotherapy (SRT) and the renal and pancreatic lesions by stereotactic body radiotherapy (SBRT). Despite control of the renal and pancreatic lesions, multiple small lung metastases developed later. Recurrence and newly developed brain metastases were treated by repeat stereotactic radiosurgery (SRS)/SRT successfully. Chemotherapy was continued and controlled the lung metastases until three and a half years after the initial operation of the uterus.

Stereotactic Radiosurgery and Stereotactic Radiotherapy for Malignant Skull Base Tumors.

The role of stereotactic radiosurgery/stereotactic radiotherapy (SRS/SRT) for malignant skull base tumors was summarized and discussed. The treatment of skull base tumors remains challenging. Their total resection is often difficult. SRS/SRT is one useful treatment option for residual or recurrent tumors after surgical resection in cases of primary skull base tumors. If skull base metastasis and skull base invasion are relatively localized, they can be candidates for SRS/SRT. Low rates of cervical lymph node involvement in early-stage (N0M0, no lymph node involvement or distant metastasis) nasal and paranasal carcinomas (NpNCa) and external auditory canal carcinomas (EACCa) have been reported in the literature. Such cases might be good candidates for SRS/SRT as the initial therapy. We previously reported the results of SRS/SRT for various malignant extra-axial skull base tumors. In addition, treatment results of early-stage head and neck carcinomas were summarized. Those of our data and those of other reported series were reviewed here to clarify the usefulness of SRS/SRT for malignant extra-axial skull base tumors.

Chiral Supramolecular U-Shaped Catalysts Induce the Multiselective Diels-Alder Reaction of Propargyl Aldehyde.

The Diels-Alder reaction, which is a traditional [4 + 2] cycloaddition with two carbon-carbon bond formations, is one of the most powerful tools to synthesize versatile and unique six-membered rings. We show that chiral supramolecular U-shaped boron Lewis acid catalysts promote the unprecedented multiselective Diels-Alder reaction of propargyl aldehyde with cyclic dienes. Independent from the substrate control, enantio-, endo/exo-, π-facial-, regio-, site-, and substrate-selectivities could be controlled by the present U-shaped catalysts. The obtained reaction products could access the concise synthesis of chiral diene ligands and a key intermediate of (+)-sarkomycin. The results presented here might partially contribute to the development of artificial enzyme-like supramolecular catalysts for multiselective reactions, which will be able to target organic compounds that have thus far eluded synthesis.

Enantioselective aza-Friedel-Crafts reaction of furan with α-ketimino esters induced by a conjugated double hydrogen bond network of chiral bis(phosphoric acid) catalysts.

Chiral C 2- and C 1-symmetric BINOL-derived bis(phosphoric acid) catalysts, which have OP([double bond, length as m-dash]O)(OH)2/OP([double bond, length as m-dash]O)(OH)(OR) moieties at the 2,2'-positions, were developed and used for the enantioselective aza-Friedel-Crafts reaction of 2-methoxyfuran with α-ketimino esters for the first time. The intramolecular conjugated double hydrogen bond network is a key to increasing the Brønsted acidity and preventing deactivation of the catalysts. Highly functionalized α-amino acid derivatives with a chiral quaternary carbon center could be transformed into versatile optically active N- and O-heterocycles and an α-aryl-substituted serine.

Synthesis of 1,1'-Spirobiindane-7,7'-Disulfonic Acid and Disulfonimide: Application for Catalytic Asymmetric Aminalization.

1,1'-Spirobiindane-7,7'-disulfonic acid (SPISA) and 1,1'-spirobiindane-7,7'-disulfonimide were synthesized from 1,1'-spirobiindane-7,7'-diol (SPINOL) in 4 steps using a Pd-catalyzed Newman-Kwart rearrangement as a key step. These new catalysts possessing a rigid spirocyclic backbone were evaluated in a catalytic asymmetric aminalization reaction, and SPISA/iPr2 NEt exhibited high enantioselectivity, demonstrating the utility of SPISA as a chiral Brønsted acid catalyst.

Boron Tribromide-Assisted Chiral Phosphoric Acid Catalysts for Enantioselective [2+2] Cycloaddition.

BBr3 -assisted chiral phosphoric acid catalysts for enantioselective [2+2] cycloaddition were developed. The reactions of phenyl vinyl sulfide with α-substituted acroleins proceeded, and the corresponding [2+2] cycloadducts were obtained with high enantioselectivity. In particular, the [2+2] cycloadduct obtained from methacrolein is a synthetically useful optically active cyclobutane, which could be transformed to a key intermediate for (+)-frontalin, a pheromone of Asian elephants.

Enantioselective Cycloaddition of Styrenes with Aldimines Catalyzed by a Chiral Magnesium Potassium Binaphthyldisulfonate Cluster as a Chiral Brønsted Acid Catalyst.

A chiral magnesium potassium binaphthyldisulfonate cluster, as a chiral Brønsted acid catalyst, was shown to catalyze an enantioselective cycloaddition of styrenes with aldimines for the first time. The strong Brønsted acidity of the catalyst precursors, which might dissolve drying agents and take up the leached Mg2+ and K+, serendipitously led to good enantioselectivity. Mechanistic aspects were supported by X-ray and ESI-MS analysis of the catalyst and a kinetics study of the reaction. Useful transformations to optically active 1,3-amino alcohols on a gram scale were also demonstrated.

Regioselective 1,4- and 1,6-Conjugate Additions of Grignard Reagent-Derived Organozinc(II)ates to Polyconjugated Esters.

Regioselective synthetic methods were developed for 1,4- and 1,6-conjugate additions of Grignard reagent-derived organozinc(II)ates to malonate-derived polyconjugated esters. By taking advantage of the tight ion-pair control of organozinc(II)ates, it was possible to switch between 1,4- and 1,6-conjugate additions by introducing a terminal ethoxy moiety in the conjugation.

Enantioselective Cyanosilylation of Ketones with Lithium(I) Dicyanotrimethylsilicate(IV) Catalyzed by a Chiral Lithium(I) Phosphoryl Phenoxide.

A highly enantioselective cyanosilylation of ketones was developed by using a chiral lithium(I) phosphoryl phenoxide aqua complex as an acid/base cooperative catalyst. The pentacoordinate silicate generated in situ from Me3SiCN/LiCN acts as an extremely reactive cyano reagent. Described is a 30 gram scale reaction and the synthesis of the key precursor to (+)-13-hydroxyisocyclocelabenzine.

Boron Tribromide-Assisted Chiral Phosphoric Acid Catalyst for a Highly Enantioselective Diels-Alder Reaction of 1,2-Dihydropyridines.

BBr3-chiral phosphoric acid complexes are highly effective and practical Lewis acid-assisted Brønsted acid (LBA) catalysts for promoting the enantioselective Diels-Alder (DA) reaction of α-substituted acroleins and α-CF3 acrylate. In particular, the DA reaction of α-substituted acroleins with 1,2-dihydropyridines gave the corresponding optically active isoquinuclidines with high enantioselectivities. Moreover, transformations to the key intermediates of indole alkaloids, catharanthine and allocatharanthine, are demonstrated.

Gamma knife radiosurgery of craniopharyngioma: results of 30 cases treated at Nagoya Radiosurgery Center.

Evaluation of 30 cases of craniopharyngioma treated by Gamma Knife at Nagoya Radiosurgery Center (NRC), Nagoya Kyoritsu Hospital since July, 2004 has been made. The mean volume of the tumor was 2.64 ml, which was treated with the marginal dose of 11.7 Gy. Mean follow-up period was 79.9 months. The effects were evaluated by MRI findings, neuro-endocrine and hypothalamic signs and symptoms, complications and KPS every 3~6 months. As the results, complete remission was obtained in 8, partial remission in 12, no change in 6, progression in 3, in which two died by hypothalamic invasion. Tumor response rate was 68.9% and control rate 87.9%. Actuarial survival was 96% at 5 and 86% at 10 years. However, progression free survival was 76% and 76%, respectively. Using marginal dose of 11.7Gy to a smaller tumor, better control without complications has been obtained. KPS was excellent in 14, good in 9, fair in 2, poor in 1 and unknown in a case. Finally, there were three deaths, where two were died of tumor progression and one by infirmity. The progression of hypothalamic symptoms other than diabetes insipidus were found in two cases. Volume reduction and effective dose setting will be important for the improvement of QOL and survival after combined microsurgery and radiosurgery of craniopharyngioma.

C- and N-Selective Grignard Addition Reactions of α-Aldimino Esters in the Presence or Absence of Zinc(II) Chloride: Synthetic Applications to Optically Active Azacycles.

Highly practical synthetic methods were developed for the C- and N-selective Grignard addition reactions of N-4-MeOC6H4-protected α-aldimino esters in the presence or absence of zinc(II) chloride. Diastereoselective C-alkyl addition, tandem C-alkyl addition-N-alkylation, and some transformations to synthetically useful optically active azacycles were demonstrated.

C-selective and diastereoselective alkyl addition to ß,γ-alkynyl-α-imino esters with zinc(II)ate complexes.

Since umpolung α-imino esters contain three electrophilic centers, regioselective alkyl addition with traditional organometallic reagents has been a serious problem in the practical synthesis of versatile chiral α-amino acid derivatives. An unusual C-alkyl addition to α-imino esters using a Grignard reagent (RMgX)-derived zinc(II)ate was developed. Zinc(II)ate complexes consist of a Lewis acidic [MgX](+) moiety, a nucleophilic [R3 Zn](-) moiety, and 2 [MgX2 ]. Therefore, the ionically separated [R3 Zn](-) selectively attacks the imino carbon atom ,which is most strongly activated by chelation of [MgX](+) . In particular, chiral ß,γ-alkynyl-α-imino esters can strongly promote highly regio- and diastereoselective C-alkylation because of structural considerations, and the corresponding optically active α-quaternary amino acid derivatives are obtained within 5 minutes in high to excellent yields.