穴田 仁洋

A concise and direct cyanation of secondary and tertiary benzylic and allylic alcohols catalyzed by Brønsted acid has been developed using trimethylsilyl cyanide (TMSCN) as a cyanide source and 1,1,1,3,3,3‐hexafluoro‐2‐propanol (HFIP) as a solvent. The present transition metal‐free catalytic process is operationally simple to perform under “open‐flask” conditions and it is applicable to the preparation of a number of α‐arylacetonitriles as well as late‐stage material transformations. The effectiveness of the present protocol was further demonstrated by the first enantioselective synthesis and determination of the absolute configuration of verimol F.

Divergent synthesis of multi-substituted phenanthrenes based on an internal redox reaction/ring expansion sequence was achieved.

We have developed a sequential hydride shift process involving a [1,8]-hydride shift. When cinnamylidene malonates having a biphenyl core were treated with 30 mol% Yb(OTf)3 and 10 mol% iPr2NEt, the desired sequential [1,8]-[1,5]-hydride shift process proceeded smoothly to afford synthetically challenging nine-membered carbocycle-fused piperidine derivatives in good chemical yields (up to 77%). Notably, the desired nine-membered carbocycles could not be obtained by a single [1,8]-hydride shift/cyclization process, suggesting that the employment of the sequential system is crucial to achieving the reaction. (Figure presented.).

This article highlights our recent studies on chiral dirhodium(II) complex-catalyzed asymmetric hetero-Diels–Alder (HDA) reactions. Rh2(S-BPTPI)4, a dirhodium(II) carboxamidate complex which incorporates (S)-3-(benzene-fused-phthalimido)-2-piperidinonate as bridging ligands, has been identified as a highly efficient Lewis acid catalyst for endo-selective and enantioselective HDA reactions of aldehydes with electron-rich 1,3-butadienes such as Danishefsky-type dienes, monooxygenated dienes, Rawal’s dienes and 2-aza-3-silyloxy-1,3-butadienes.

The first total synthesis of brasilicardins A and C, novel diterpenoid saccharide amine acid hybrid metabolites with unique immunosuppressive activity, is described. The key step is a Diels-Alder/reductive angular methylation sequence capitalizing on a trans-fused bicyclic alpha-cyano-alpha,beta-enone as its precursor to construct the 8,10-dimethyltrans/syn/trans,perhydrophenanthierie skeleton. Other notable features include an,anti selective aldol reaction, a stereocontrolled glycosylation of a C2 alcohol, and a one-pot, two-step global deprotection sequence that did not damage these sensitive molecules.

A novel indole-2,3-epoxide equivalent, 2-hydroxyindbline-3-triethylammonium bromide, was found, to be a convenient reagent for formal C3-electrophilic reactions of indoles with various nudeophiles. By taking advantage of the nudeophilie character of the oxygen of the 2-hydroxyindo-line the interrupted retro-Claisen interrupted Feist - Benary reactions, with 1,3-dicarbonyl compounds Were efficiently achieved.

Catalytic enantioselective desymmetrization of meso-aziridines with fluoromalonates is described. Optimization studies revealed that the appropriate combination of Bronsted basic metal and Lewis acidic metal is important for promoting the reaction using fluoromalonates. A heterodinuclear Gd(OiPr)(3)/Y(OTf)(3)/Schiff base = 1:1:1 was the best catalyst, and ring-opening adducts, synthetic precursors for alpha-fluoro-gamma-amino acids, were obtained in 98%similar to 17% yield and >99.5%similar to 99% ee. Transformation of the ring-opening adduct into alpha-fluoro-gamma-lactam was also demonstrated.

The first diastereo- and enantioselective construction of bridged bicyclic ring systems by an intramolecular C-H insertion reaction is described. With dirhodium(II) tetrakis[N-phthaloyl-(S)-tert-leucinate], Rh2(S-PTTL)4, the C-H insertion of alpha-alkyl-alpha-diazoesters containing an ethylene ketal moiety at the gamma-position provided methyl 6,7-dioxabicyclo[2.2.1]heptane-3-carboxylate derivatives with up to 95% ee and perfect diastereoselectivity.

Herpes simplex virus type 1 (HSV-1) is a causative agent for a variety of diseases. Although antiherpetic drugs such as acyclovir have been developed to inhibit virus replication through interaction with DNA kinases, their continuous administration leads to an increase in the frequency of drug-resistant HSV-1, which is an important clinical issue that requires urgent solution. Recently, we reported that the sialylated O-linked sugar T antigen (sTn) and its attached peptide region (O-glycosylated sTn peptide) derived from the HSV-1 glycoprotein B (gB) protein inhibited HSV-1 infection by specifically targeting paired immunoglobulin-like type 2 receptor alpha (PILR alpha) in vitro. In this study, to further identify novel inhibitors of gB-mediated HSV-1 infection in vitro, we established a cell-based fusion assay for rapid drug screening. Chinese hamster ovary (CHO) cells were transfected with expression plasmids for HSV-1 gB, gD, gH, and gL, and T7 RNA polymerase, and were designated as the effector cells. The CHO-K1 cells stably expressing PILRa were transfected with the expression plasmid for firefly luciferase under the T7 promoter, and were designated as the target cells. The effector and target cells were co-cultured, and luminescence was measured when both cells were successfully fused. Importantly, we found that cell-to-cell fusion was specifically inhibited by O-glycosylated sTn peptide in a dose dependent manner. Our results suggested that this virus-free cell-based fusion assay system could be a useful and promising approach to identify novel inhibitors of gB-mediated HSV-1 infection, and will aid in the development of antiviral therapeutic strategies for HSV-1-associated diseases.

An asymmetric total synthesis of the guaiane sesquiterpene (-)-englerin A, a potent and selective inhibitor of the growth of renal cancer cell lines, was accomplished. The basis of the approach is a highly diastereo- and enantioselective carbonyl ylide cycloaddition with an ethyl vinyl ether dipolarophile under catalysis by dirhodium(II) tetrakis[N-tetrachlorophthaloyl-(S)-tert-leucinate], [Rh-2(S-TCPTTL)(4)], to construct the oxabicyclo[3.2.1]octane framework with concomitant introduction of the oxygen substituent at C9 on the exo-face. Another notable feature of the synthesis is ruthenium tetraoxide-catalyzed chemoselective oxidative conversion of C9 ethyl ether to C9 acetate.

© 2015 Elsevier Ltd. An asymmetric synthesis of (-)-E-δ-viniferin, a trans-resveratrol dimer natural product containing a dihydrobenzofuran ring, has been achieved by exploiting a Rh(II)-catalyzed intramolecular C-H insertion reaction of a diaryldiazomethane derivative as a key step. The C-H insertion under catalysis by dirhodium(II) tetrakis[N-tetrafluorophthaloyl-(S)-tert-leucinate], Rh<inf>2</inf>(S-TFPTTL)<inf>4</inf>, provided the 2,3-diaryl-2,3-dihydrobenzofuran core structure with perfect cis diastereoselectivity and 96%ee.

© 2015 Elsevier Ltd. All rights reserved. The first catalytic asymmetric intramolecular 1,6-C-H insertion reaction of α-diazo esters is described. With dirhodium(II) tetrakis[N-phthaloyl-(S)-tert-leucinate], Rh<inf>2</inf>(S-PTTL)<inf>4</inf>, the C-H insertion proceeded in a chemoselective manner to give 2-alkenyltetrahydropyran-3-carboxylates with up to 95% ee and perfect cis diastereoselectivity.

The first catalytic asymmetric hetero-Diels-Alder (HDA) reaction between 3-tert-butyldimethylsilyloxy-1-dimethylamino-1,3-pentadiene (4-methyl-substituted Rawal's diene) and aldehydes is described. With 3 mol % of dirhodium(II) tetrakis[N-benzene-fused-phthaloy1-(S)-piperidinonatel, Rh-2((S)-BPTPI)(4), the cycloaddition reaction proceeded exclusively in an endo fashion and gave, after a novel sequential treatment with dimethyl acetylenedicarboxylate and acetyl chloride, the corresponding 2,3-cis-disubstituted dihydropyranones with up to 98% ee and perfect diastereoselectivity. The utility of this catalytic protocol was demonstrated by an asymmetric synthesis of the (-)-cis-aerangis lactone. (C) 2013 Elsevier Ltd. All rights reserved.

The first catalytic asymmetric carbonyl ylide cycloaddition with arylallenes is described. With dirhodium(ii) tetrakis[N-tetrachlorophthaloyl-(S) -tert-leucinate], Rh2(S-TCPTTL)4, the cycloaddition of carbonyl ylides derived from diazoketoesters with arylallenes proceeded in a fully chemo- and regioselective manner to give highly functionalized 8-oxabicyclo[3.2.1]octanes with up to 99% ee and perfect exo diastereoselectivity.© 2013 The Royal Society of Chemistry.

ムチン型糖タンパク質はO-結合型糖タンパク質とも呼ばれ、ペプチド鎖のセリンあるいはスレオニン残基にN-アセチルガラクトサミンがa-グリコシド結合したT_N-antigenという共通構造をもつことが知られている。多くのムチン型糖タンパク質は糖鎖の非還元末端にシアル酸が結合しており、癌化を含め細胞の分化・増殖、免疫応答に深く関与するばかりでなく、ホルモン、細菌やウイルスのレセプターとしても機能している¹⁾。 最近、荒瀬らは単純ヘルペスウイルス（HSV）がもつglycoprotein B（gB）と、ヒトのpaired Ig-like type 2 receptor a（PILRa）という細胞表面分子が会合することによりHSV感染が成立することを報告した²⁾。またごく最近、前仲らはgBの一部である糖ペプチド1がgBとPILRaとの会合を阻害することを見出した³⁾（図1）。 これまで我々の研究室では、糖供与体の脱離基がグリコシル化反応の成否に支配的な役割を果たすという考えのもとに含リン脱離基を組み込んだ糖供与体を用いる高立体選択的グリコシル化反応の開発を行ってきた⁴⁾。今回、我々は含リン脱離基法を機軸とするa-選択的グリコシル化反応の開発を行うとともに、ムチン型糖ペプチドコア構造および新規作用機序に基づく抗ヘルペス活性をもつシアル酸含有糖ペプチド1とその類縁体の合成を行ったので報告する。 1. 合成計画 我々の合成計画をスキーム1に示した。我々は4,6位水酸基をベンジリデンアセタール、3位水酸基をアセチル基あるいはクロロアセチル基で保護したガラクトシルジフェニルホスファートを糖供与体として用いるセリンあるいはスレオニン誘導体のグリコシル化反応を行い、得られたグリコシドをカセットとして用いる合成計画を立てた。すなわち、クロロアセチル基を脱保護して得られるアルコールのグリコシル化反応を行いムチン型糖ペプチドコア5構造を合成し、ベンジリデンアセタールを除去して得られるジオールに対してグリコシル化することでムチン型糖ペプチドコア7構造およびシアリルT_N-antigenへと導く。さらに得られたシアリルT_N-antigenに対して種々の官能基変換を行いペプチド固相合成に適用することで、シアル酸含有糖ペプチド1が合成できると考えた。 2. ジフェニルホスファートを糖供与体とするa-選択的グリコシル化反応とムチン型糖ペプチドコアの合成 ムチン型糖ペプチドの合成に適用実績が多い保護様式である、4,6位水酸基をベンジリデンアセタール保護した糖供与体2を用いて、セリン誘導体3のグリコシル化反応を検討した。反応剤および溶媒の検討を行ったところ、THF/エーテル混合溶媒中TMSOTfを作用させることで、高収率かつ高立体選択的に目的のa-グリコシドが得られた（表1, entry 1）。糖供与体をスレオニン誘導体6としても良好な収率と高いa-選択性でグリコシドが得られた（entry 2）。また、3位水酸基を緩和な条件で脱保護可能なクロロアセチル基で保護した糖供与体5を用いる3および6のグリコシル化反応も良好な結果を与えた（entries 3, 4）。 (View PDFfor the rest of the abstract.)

The first example of dirhodium(II) complex-catalyzed asymmetric intermolecular C-H insertion with α-alkyl-α-diazoesters is described. The reaction of 1,4-cyclohexadiene with 2,4-dimethyl-3-pentyl α-alkyl-α-diazoacetates under catalysis by dirhodium(II) tetrakis[N-phthaloyl-(S)-tert-leucinate], Rh2(S-PTTL)4, or dirhodium(II) tetrakis[N-tetrafluorophthaloyl-(S)-tert-leucinate], Rh2(S-TFPTTL)4, gave the corresponding C-H insertion products with enantioselectivities of up to 86% ee, albeit in low to modest yields. © 2012 The Japan Institute of Heterocyclic Chemistry.

The immobilization of dirhodium(II) tetrakis[N-tetrafluorophthaloyl-(S)-tert-leucinate], [Rh-2(S-TFPTTL)(4)], has been accomplished by co-polymerization of a dirhodium(II) complex-containing monomer with styrene and 1,6-bis(4-vinylbenzyloxy) hexane as a flexible cross-linker. The polymer-supported chiral fluorinated dirhodium(II) complex catalyzed the amination of silyl enol ethers with [N-(2-nitrophenylsulfonyl)imino]phenyliodinane (NsN=IPh) to provide alpha-amino ketones in high yields with high levels of enantioselectivity and could be used up to 20 times as the catalyst readily withstood stirring in the presence of the solid reactant.

The first catalytic asymmetric hetero-Diels-Alder reaction between 2-aza-3-silyloxy-1,3-butadienes and aldehydes is described. With dirhodium(II) tetrakis[N-benzene-fused-phthaloyl-(S)-piperidinonate], Rh-2(S-BPTPI)(4), the cycloaddition reaction proceeded exclusively in an endo mode to give all-cis-substituted 1,3-oxazinan-4-ones in high yields with up to 98% ee.

The first successful example of a catalytic asymmetric cyclopropanation with α-diazopropionates is described. The cyclopropanation reaction of 1-aryl-substituted and related conjugated alkenes with tert-butyl α-diazopropionate has been achieved by catalysis with dirhodium(II) tetrakis[N-tetrabromophthaloyl-(S)-tert-leucinate], Rh2(S-TBPTTL) 4, providing the corresponding cyclopropane products containing a quarternary stereogenic center in good to high yields and with high diastereo- and enantioselectivities (trans:cis = 90:10 to >99:1, 81-93% ee). © 2011 Elsevier Ltd. All rights reserved.

Two rhodium(II) ions work together: [Rh2(S-tbpttl)4] is an exceptionally effective catalyst for enantioselective cyclopropenation reactions of 1-alkynes with α-alkyl-α-diazoacetates (see scheme). Cyclopropenation is preferred over alkene formation through a 1,2-hydride shift. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A new route to the diarylheptanoid diospongins A and B was developed. The key step is a novel, one-pot, sequential dirhodium(II) tetrakis[(S)-3-(benzo-fused phthalimido)-2-piperidinonate] [Rh-2(S-BPTPI)(4)] catalyzed enantioselective hetero-Diels-Alder/TMSOTf-catalyzed Mukaiyama-Michael reaction process. The sign of the optical rotation of natural diospongin B was determined to be (+) and not (-) as was originally reported.

A catalytic asymmetric synthesis of descurainin has been achieved by incorporating an enantioselective 1,3-dipolar cycloaddition, a stereoselective alkene hydrogenation, an oxidation with Fremy's salt and a regioselective demethylation with NbCl5 as the key step. The 1,3-dipolar cycloaddition of a carbonyl ylide derived from tert-butyl 2-diazo-5-formyl-3-oxopetanoate with 4-hydroxy-3-methoxyphenylacetylene in the presence of dirhodium(II) tetrakis[N-tetrachlorophthaloyl-(R)-tert-leucinate], Rh-2(R-TCPTTL)(4), provided an 8-oxabicyclo[3.2.1]octane skeleton in 95% ee. (C) 2010 Elsevier Ltd. All rights reserved.

The reaction of a six-membered cyclic formyl-carbonyl ylide derived from alpha-diazo-beta-ketoester with phenylacetylene derivatives under the catalysis of dirhodium(II) tetrakis[N-tetra-chlorophthaloyl-(S)-tert-leucinate], Rh-2(S-TCPTTL)4, provides cycloadducts containing an 8-oxabicyclo[3.2.1]octane ring system in up to 97% cc. This represents the first example of an enantioselective 1,3-dipolar cycloaddition of a cyclic formyl-carbonyl ylide. Using this catalytic process, an asymmetric synthesis of endo-6-aryl-8-oxabicyclo[3.2.1]oct-3-en-2-one natural product 1 from Ligusticum chuanxing Hort. has been achieved.

Asymmetric N-H insertion of phenyldiazoacetates with anilines catalyzed cooperatively by achiral dirhodium(II) carboxylates and cinchona alkaloids is described. A new catalytic system of dirhodium(II) tetrakis(triphenylacetate), Rh(2)(TPA)(4), and dihydrocinchonine provides phenylglycine derivatives in up to 71% ee.

The Mukaiyama aldol reaction of silyl ketene acetals with aldehydes has been effected by using commercially available 4 angstrom molecular sieves (4 angstrom MS) as a promoter. Various silyl ketene acetals and silyl enol ethers have been shown to be effective nucleophiles for this reaction. For the first time, it has been found that 4 angstrom MS can promote the Mukaiyama Michael addition reactions of silyl ketene acetals to alpha,beta-enones.

Dirhodium(II) tetrakis[N-tetrafluorophthaloyl-(S)-tert-leucinate], Rh-2(S-TFPTTL)(4), is an exceptionally efficient catalyst for enantioselective tandem cyclic oxonium ylide formation and [2.3]-sigmatropic rearrangement from alpha-diazo-beta-ketoester bearing cyclic allylic acetal functionality, providing the 2,8-dioxabicyclo[3.2.1]octane core structure of zaragozic acids in up to 93% ee.

The reaction of silyl cool ethers derived from cyclohexanone with 1(4-nitropheylsulfonyl)imino|phenyliodinane (pNsN=IPh) catalyzed by dirhodium(II) tetrakis[N-tetrachlorophthaloyl-(S)-tert-leucinate] Rh(2)(S-TCPTTL)(4), provides, after desilylation, N-pNs-protected (S)-beta-aminocyclohexanone in Lip to 72% ee. This represents the first example of the insertion of nitrene species into ail allylic C-H bond of silyl enol ethers. Using this process, a new catalytic asymmetric route to an advanced intermediate in Overman's synthesis of the montanine-type Amaryllidaceae alkaloid (-)-pancracine has been developed. The key steps involve (a) a one-pot Rh(2)(R-TCPTTI_)(4)-catalyzed sequential 1,4-hhydrosilylation/enantio-selective C-H amination of 2-cyclohexen-1-one, (b) N-alkylation and subsequent intramolecular Mukaiyama aldol reaction/dehydration, and (c) a regio- and steieocontrolled reductive deoxygenation of bicyclic enone 27 with migration of the double bond to create the C1/C11a double bond and the stereogenic center at Cl I of 3-arylhexahydroindole 31. (C) 2008 Elsevier Ltd. All right,. reserved.

The first example of a chiral Lewis acid-catalyzed enantioselective hetero-Diels-Alder (HDA) reaction between 1-dimethylamino-3-silyloxy-1,3-butadiene (Rawal's diene) and aldehydes is described. The cycloaddition reaction under the influence of 1 mol% of dirhodium(II) tetrakis[N-benzene-fused-phthaloyl-(S)-piperidinonate], Rh(2)(S-BPTPI)(4), proceeded cleanly and gave, after treatment with acetyl chloride, the corresponding dihydropyranones in up to 99% ee.

A catalytic asymmetric synthesis of (-)-ritodrine hydrochloride was achieved, incorporating an enantioselective amination of (Z)-silyl enol ether derived from 4-benzyloxypropiophenone with [(2-nitrophenylsulfonyl)imino]phenyliodinane (NsN=IPh) and a chelation-controlled reduction of the ketone carbonyl group with Zn(BH4)(2) as the key steps. The use of dirhodium(II) tetrakis[tetrafluoroplithaloyl-(S)-tert-leucinate] as a catalyst produced the targeted a-amino ketone in 94% yield with 91 % ee.

Dirhodium(II) tetrakis[N-tetrachlorophthaloyl-(S)-tert-leucinate], Rh(2)(S-TCPTTL)(4), is an exceptionally effective catalyst for enantioselective tandem carbonyl ylide formation-cycloaddition reactions of 2-diazo-3,6-diketoesters with arylacetylene, alkoxyacetylene, and styrene dipolarophiles, providing cycloadducts in good to high yields and with enantioselectivities of up to 99% ee as well as with perfect exo diastereoselectivity for styrenes.

The first catalytic enantioselective amination of silylketene acetals with (N-arylsulfonylimino) phenyliodinanes is described. The reaction of silylketene acetals derived from methyl phenylacetates with [N-(2-nitrophenylsulfonyl)imino] phenyliodinane (NsN = IPh) under the catalysis of dirhodium(II) tetrakis[N-tetrachlorophthaloyl-(S)-tert-leucinate], Rh-2(S-TCPTTL)(4), proceeds in benzene at room temperature to give N-(2-nitrophenylsulfonyl) phenylglycine derivatives in high yields and with enantioselectivities of up to 99% ee. (C) 2007 Elsevier Ltd. All rights reserved.

Catalytic asymmetric syntheses of (-)-centrolobine and (-)-de-O-methylcentrolobine have been achieved, incorporating a hetero-Diels-Alder (HDA) reaction between 4-aryl-2-silyloxy-1,3-butadienes and phenylpropargyl aldehyde derivatives as a key step. The HDA reaction using dirhodium(II) tetrakis[(R)-3-(benzene-fused-phthalimido)-2-piperidinonate], Rh-2(R-BPTPI)(4), as a chiral Lewis acid catalyst provides exclusively cis-2,6-disubstituted tetrahydropyran-4-ones in up to 93% ee. (C) 2007 Elsevier Ltd. All rights reserved.

A catalytic asymmetric formal synthesis of diarylheptanoid natural product calyxin L has been achieved by incorporating an enantio- and diastereoselective hetero-Diels-Alder (HDA) reaction, a Suzuki-Miyaura coupling, and a stereocontrolled catalytic hydrogenation of 2,4,6-trisubstituted dihydropyran as the key steps. The HDA reaction between 4-(4-benzyloxyphenyl)-2-triethylsilyloxy-1,3-butadiene and (4-benzenesulfonyloxyphenyl)propynal catalyzed by dirhodium(II) tetrakis[(R)-3-(benzene-fused-phthalimido)-2-piperidinonate], Rh-2(R-BPTPI)(4), provided cis-2,6-disubstituted tetrahydropyran-4-one in 91% yield with 91% ee. (c) 2007 Elsevier Ltd. All rights reserved.

[GRAPHICS] Dirhodium(II) tetrakis[N-tetrafluorophthaloyl-(S)-tert-leucinate], Rh-2(S-FPTTL)(4), is an exceptionally efficient catalyst for enantioselective aminations of silyl enol ethers derived from acyclic ketones or a,beta-enones with [N-(2-nitrophenyisulfonyl)imino]phenyliodinane (NsN=IPh), providing N-(2-nitrophenyisulfonyl)-alpha-amino ketones in high yields and with enantioselectivities of up to 95% ee. The effectiveness of the present catalytic protocol has been demonstrated by an asymmetric formal synthesis of (-)-metazocine.

The enantioselective aziridination of alkenes with [N-(4-nitrophenylsulfonyl)imino]phenyliodinane catalyzed by dirhodium(II) tetrakis[N-tetrachlorophthaloyl-(S)-tert-leucinate], Rh-2(S-TCPTTL)(4), is described. While such enantioselectivities are highly dependent on the properties of the alkenes, 2,2-dimethylchromene was found to be a particularly suitable substrate which can be efficiently transformed into the aziridine product in 98% yield with 94% ee.

The first successful example of the enantioselective intermolecular 1,3-dipolar cycloaddition of a chiral dirhodium(II) catalyst-associated carbonyl ylide with an aromatic aldehyde dipolarophile is described. The tandem carbonyl ylide formation/cycloaddition reactions of l-diazo-5-aryl-2,5-pentanediones with aromatic aldehydes using dirhodium(II) tetrakis[N-benzene-fused-phthaloyl- (S)-valinate] as a catalyst provide exclusively exo cycloadducts in up to 92% ee. © 2007 Wiley-VCH Verlag GmbH & Co. KGaA,.