Kosuke Namba

Hg(OTf)2-catalyzed arylene cyclization.

Novel Hg(OTf) 2-catalyzed arylene cyclization was achieved with highly efficient catalytic turnover (up to 200 times). The reaction takes place via protonation of allylic hydroxyl group by in situ formed TfOH of an organomercuric intermediate to generate a cationic species. Subsequent smooth demercuration regenerates the catalyst.

Hg(OTf)2–BINAPHANE‐Catalyzed Enantioselective Anilino Sulfonamide Allyl Alcohol Cyclization

Direct allylic amination of allylic alcohols with amine nucleophiles to produce water as the only byproduct is one of the most attractive reactions in modern organic synthesis. Therefore, significant resources have been devoted to developing the latent ability of transition-metal reagents with the aim of achieving allylic amination from allylic alcohols in high catalytic turnover. Recently, Shibasaki, Matsunaga, and co-workers reported the direct allylic amination with sulfonamides by using a catalytic amount of Bi ACHTUNGTRENNUNG(OTf)3 and KPF6 under mild reaction conditions. [2b] Although intermolecular allylic aminations are well-established reactions, [PdCl2ACHTUNGTRENNUNG(MeCN)2] has been used exclusively as the catalyst for intramolecular N-cyclization of amino allylic alcohols. Moreover, no catalytic enantioselective cyclization of amino allylic alcohol has been reported thus far. We have developed mercuric triflate [Hg ACHTUNGTRENNUNG(OTf)2] as a key catalyst for organic synthesis by achieving the hydration of terminal alkynes to methyl ketones in high catalytic turnover. Indeed, enyne cyclization, arylyne cyclization, and indole synthesis have been developed based on the significant affinity of HgACHTUNGTRENNUNG(OTf)2 for the alkyne group. Recently the procedure has expanded to include alkene cyclization by the introduction of an allylic hydroxyl moiety as the leaving group, thereby triggering the smooth demercuration step that regenerates the catalyst. The reaction of anilino sulACHTUNGTRENNUNGfon ACHTUNGTRENNUNGamide allyl alcohol 1 with 1 mol% of HgACHTUNGTRENNUNG(OTf)2 was completed within 30 min at room temperature to give 2-vinyl indoline 2 in 99% yield [Eq. (1), Scheme 1]. Because a new chiral center is generated, we decided to perform the reaction in the presence of chiral auxiliaries. We found that BINAPHANE provides effective chiral induction (up to 99% ee) during the conversion of 4 to 5 [Eq. (2)]. Although asymmetric oxymercuration of alkene has already been reported, mercuric salt catalyzed asymmetric reactions are seldom described in the literature.

Silaphenylmercuric Triflate Catalyzed Reactions: Synthesis of a Solid‐Supported Mercuric Salt Catalyst

Let it flow, let it flow: A procedure to generate the first solid-supported mercuric salt, silaphenylmercuric triflate, is described. Silaphenylmercuric triflate showed remarkable catalytic activity for an indole synthesis, furanoyne cyclization, arylyne cyclization, and tandem carbocyclizations. An efficient flow reaction system for indole synthesis and arylyne cyclization is also described (see figure).

Direct synthesis of fluorescent 1,3a,6a-triazapentalene derivatives via click-cyclization-aromatization cascade reaction.

An efficient and versatile method was established for the preparation of 1,3a,6a-triazapentalenes. The 1,3a,6a-triazapentalene skeleton without an additional fused ring system was discovered to be a compact and highly fluorescent chromophore, which exhibited various interesting fluorescent properties such as a noteworthy correlation of luminescent wavelength with the Hammett σ(p) value and a strongly positive solvatofluorochromism.

Toward palau'amine: Hg(OTf)2-catalyzed synthesis of the cyclopentane core.

The pyrrole-imidazole alkaloids, which comprise a large family of natural products,1 have received a great deal of attention due to their potent biological activities and tremendous structural diversity. Palau’amine (1a) was originally isolated from a sponge, Stylotella agminata, in 1993 by Scheuer as a novel class of the pyrrole-imidazole alkaloid.2 Since the initial disclosure of its proposed structure (1a), palau’amine (1) has been an attractive synthetic target because of its intriguing molecular architecture and significant biological properties such as antifungal, antitumor, and immunosuppressive activities. However, according to several groups, the originally proposed structure 1a was recently revised as 1b, which possesses the indicated the trans-D/E ring junction and the β-chlorine substituent.3, 5e, 5g The noteworthy structural features of palau’amine include: two guanidine moieties, fused polycyclic system with a spiro cycle, complex all carbon substituted cyclopentane ring, nitrogen-substituted quaternary carbon center, and eight contiguous stereogenic centers. Not surprisingly, many attempts to synthesize palau’amine and related natural products have been reported so far, 4, 5 and the first total synthesis of the related natural products axinellamines A and B (2) was recently accomplished.6 However, a total synthesis of palau’amine itself has not yet been reported. Efficient construction of the complex cyclopentane core with the correct stereochemistry at each carbon center, including a quaternary carbon center, is definitely one of the most difficult synthetic challenges for the synthesis of palau’ amine. Herein, we describe an efficient synthesis of the cyclopentane core of palau’amine by the application of a highly efficient novel Hg(OTf)2-catalyzed reaction developed in our laboratory.7 In 2008, the Hg(OTf)2-catalyzed alkyne cyclization reactions were expanded to the alkene cyclization reactions by using allylic alcohol or vinyl methyl ether substrates that, after cyclization, undergo a smooth proto-demercuration to give the cyclized products and the regenerated Hg(OTf)2 catalyst.8 For instance, Hg(OTf)2-catalyzed cyclization of N-tosylanilino allylic alcohol 3 provided 2-vinylindolines 4 in high yield (Scheme 1).8b Thus, the cyclization of cyclopentylidene alcohol 5 is expected to give 6 by constructing a quaternary carbon center that corresponds to the C16 of palau’amine. However, the catalytic cyclization of amide 5 is also possible to give the O-cyclized product 7 in preference to the N-cyclized product 6. Indeed, we confirmed this was the case. The conventional methods for N-selective cyclization are limited by the cumbersome substrate modifications, the addition of strong Lewis acids and/or strong base, or the formation of N-radical. 9 Moreover, the catalytic conditions for generating such a quaternary carbon center have not yet to be determined. Therefore, we designed an acylhydrazide 8 as a simple modification of primary amides for Hg(OTf)2-cataylized cyclization. The vinyl lactum 9, prepared by the Hg(OTf)2-catalyzed cyclization of 8, could be an excellent precursor to construct cyclopentane core 10 by introducing two CH2-N groups (Scheme 1). Scheme 1 Hg(OTf)2-Catalyzed Cyclization of Allylic Alcohol and Synthetic Design of Palau’amine Cyclopentane Core 10. Commercially available 2-cyclopentene-1-one 10 was employed as the starting material. A Morita-Baylis-Hillman reaction of 10 with a commercial preparation of (tert-butyldimethylsilyloxy)-acetaldehyde afforded 11 in 70% yield. 11 was subsequently converted to 13 by a sequential operation of acetylation, a Luche reduction, 10 and a TBS protection. The acetate 13 were then obtained as a 2: 1 diastereomeric mixture, setting the stage for an Ireland-Claisen rearrangement.11, 12 After the treatment of 13 with LHMDS/TBSCl/HMPA in THF at −78 °C, refluxing in toluene induced the desired Ireland-Claisen rearrangement to afford the cyclopentylidene carboxylic acid 15 via 14 in good yield. Next, we attempted to prepare an acylhydrazide by the coupling of 15 with N-tosylhydrazide by the combined action of EDCI and DMAP in dichloromethane. Surprisingly, the nitrogen masked with a tosyl group participated in the condensation to give a 2: 1 diastereomeric mixture of 16 in 68% overall yield after four steps from 13. Presumably, the nucleophilicity of the more basic primary amine was attenuated by protonation with the HCl derived from the used EDCI-HCl salt.13 The double bond geometry of 15 was determined to be Z by the NOE experiment of its amide derivative (Scheme 2). The TBS groups were cleaved under mild acidic conditions to give diol 17. Scheme 2 Synthesis of Hydrazide 17 Reaction of 17 with 2 mol % of Hg(OTf)2 took place smoothly in nitromethane at room temperature to afford 18α and 18β in 84% yield as a separable 1:2 diastereomeric mixture. The lactone 19 was not detected (Sheme 3). Stereochemical outcome at the ring junction was completely controlled to cis regardless of the stereocenter of the secondary alcohol at C17. The structures of 18α and 18β were unambiguously confirmed by an X-ray diffraction study and NOE studies (see supporting information). 14 We thus established that the Hg(OTf)2-catalyzed protocol efficiently mediates N-selective cyclizations of amide carbony moieties, which is very difficult to achieve using conventional methodologies.15 Having prepared a sufficient amount of N-cyclized product 18, we attempted to construct the cyclopentane core of palau’amine. The SO3·pyridine oxidation of the mixture of 18α and 18β gave a single ketone 20 in quantitative yield.16 Direct oxidation of 20 to enone 22, using IBX,17 and selenium dioxide, or enolate oxidation using selenium halide, sulfinimidoyl chloride,18 and NBS, were unsuccessful. Although the preparation of the silyl enol ether was not straightforward, a combination of TMSI and hexamethyldisilazane in dichloromethane was found to give trimethylsilylenolether 21 in quantitative yield.19, 20 Saegusa-Ito oxidation of 21 provided enone 22 in good yield.21 Morita-Baylis-Hillman reaction of 22 with formaldehyde gave alcohol 23 in excellent yield. Subsequent 1, 4-addition of nitromethane in the presence of a catalytic amount of a 1, 1, 3, 3-tetramethylguanidine (TMG) afforded the desired 1, 4-adduct 24.22 We found that 24 was readily converted to the exomethylene product by dehydration during a column chromatography purification on silica gel. Therefore, the crude 24 was directly subjected to reduction with NaBH4 to give 25. The stereochemistry of 25 was confirmed to be as we planned for our palau’amine synthesis by an NOE experiment. Finally, the primary alcohol of 25 was converted to azide 26 that is the targeted cyclopentene core of palau’amine. The structure of 26 was unequivocally established by an X-ray diffraction study (Scheme 6 and supporting information). 23 In summary, we have established an efficient route to the cyclopentane 26, which corresponds to our E ring synthetic intermediate of palau’ amine by the application of novel Hg(OTf)2-catalyzed cyclization. Furthermore, a selective N-cyclization protocol of acylhydrazide for catalytic construction of a quaternary carbon center was also developed. Throughout this investigation, Hg(OTf)2 was shown to be a powerful catalyst for the construction of complex carbon frameworks of the type found in natural products. Total synthesis of palau’amine, one of the most challenging synthetic targets in the last decade, is currently underway in our laboratory.

Structural element responsible for the Fe(III)-phytosiderophore specific transport by HvYS1 transporter in barley.

Hordeum vulgare L. yellow stripe 1 (HvYS1) is a selective transporter for Fe(III)–phytosiderophores, involved in primary iron acquisition from soils in barley roots. In contrast, Zea mays yellow stripe 1 (ZmYS1) in maize possesses broad substrate specificity, despite a high homology with HvYS1. Here we revealed, by assessing the transport activity of a series of HvYS1–ZmYS1 chimeras, that the outer membrane loop between the sixth and seventh transmembrane regions is essential for substrate specificity. Circular dichroism spectra indicated that a synthetic peptide corresponding to the loop of HvYS1 forms an α‐helix in solution, whereas that of ZmYS1 is flexible. We propose that the structural difference at this particular loop determines the substrate specificity of the HvYS1 transporter.

Novel and efficient transformation of α-amino nitrile to α-imino and α-amide nitriles in asymmetric Strecker synthesis

Abstract Oxidation of α-amino nitrile 4 with ozone gave rise to a mixture of α-imino nitrile 5 and a novel fragmentation product of 6 in one-step. The mixture was converted to a variety of α-substituted α-amino acids 7 in high yields, which enabled the asymmetric transferring Strecker synthesis to be a widely useful method.

One-Pot Synthesis of Highly Fluorescent 2,5-Disubstituted-1,3a,6a-triazapentalene

A one-pot synthetic method was established for the preparation of 2,5-disubstituted-1,3a,6a-triazapentalenes. The fluorescence observation of the synthetic 2,5-disubstituted-1,3a,6a-triazapentalenes revealed that the introduction of a substituent at the C5 position allowed a substantial change in the fluorescence quantum yield with little effect on the fluorescence wavelength.

Hg(OTf)2-catalyzed vinylogous semi-pinacol rearrangement leading to 1,4-dihydroquinolines.

An efficient method for the construction of dihydroquinoline derivatives possessing a quaternary carbon center is developed by an application of Hg(OTf)(2)-catalyzed vinylogous semi-pinacol-type rearrangement. The reaction was found to be specifically catalyzed by mercury salt and to proceed via a bicyclic aminal.

One-Pot Synthesis of Tri- and Tetrasubstituted Pyridines by Sequential Ring-Opening/Cyclization/Oxidation of N-Arylmethyl 3-Aziridinylpropiolate Esters†

A novel strategy for the one-pot synthesis of substituted pyridines from N-arylmethyl 3-aziridinylpropiolate esters is described. The method employs a three-step procedure including the formation of allenyl imines, phosphine-catalyzed cyclization, and subsequent oxidation of the dihydropyridines. Depending on the reaction conditions of the final oxidation step, tri- and tetrasubstituted pyridines can be selectively produced.