Published papers

Total synthesis of sphingofungin E (1) is described. Overman rearrangement of an allylic trichloroacetimidate derived from diacetone-d-glucose generated tetra-substituted carbon with nitrogen, and subsequent Wittig olefination afforded the highly functionalized part in sphingofungin E (4) stereoselectively. Coupling reaction of 4 with the C12 hydrophobic part, followed by further manipulation, completed the total synthesis.

Total synthesis starting from aldohexoses of naturally occurring α-substituted α-amino acids, (+)-myriocin (1) and (−)-sphingofungin E (2), is described. Overman rearrangement of allylic trichloroacetimidate 6E derived from D-mannose effectively generated the tetrasubstituted carbon with nitrogen, and subsequent Wittig olefination afforded the highly functionalized moiety 3 of myriocin stereoselectively. Sulfone-mediated coupling reaction of the allyl bromide 3 with C12 hydrophobic part 4 successfully constructed the carbon framework possessing E-olefin 28. Removal of the sulfone and protecting groups completed the chiral and stereoselective total synthesis of (+)-myriocin (1). A similar transformation starting from D-glucose also accomplished the total synthesis of (−)-sphingofungin E (2).

The stereoselective total synthesis of myriocin 1 from D-mannose is described; the carbon framework with three contiguous chiral centers including a tetra-substituted carbon with nitrogen was effectively constructed using Overman rearrangement as the key reaction.

The total synthesis of mycestericin A (1) and its 14-epimer 34 is described herein. The Overman rearrangement of an allylic trichloroacetimidate derived from l-tartrate generated a tetra-substituted carbon with nitrogen and subsequent stereoselective transformations afforded the highly functionalized left-half segment, vinyl iodide. Cross-coupling of the vinyl iodide with a chiral organometallic species synthesized from d-tartrate under the Negishi or Suzuki–Miyaura coupling conditions, followed by deprotection, completed the total synthesis of 1. The 14-epimer of mycestericin A was also synthesized, and a comparison of [α]D values of peracetyl γ-lactone derivatives of mycestericin A and its 14-epimer as well as degradation studies of 1 and 34 fully confirmed the proposed absolute structure of mycestericin A.

The first total synthesis of mycestericin A (1) starting from tartrates is described. The Overman rearrangement of an allylic trichloroacetimidate generated a tetra-substituted carbon with nitrogen, and subsequent stereoselective transformations afforded the highly functionalized vinyl iodide. The cross-coupling of the vinyl iodide with a chiral organozinc species under Negishi conditions, followed by deprotection, completed the total synthesis of 1.

The stereoselective total synthesis of (+)-vittatine 1 and (+)-haemanthamine 2 starting from d-glucose is described. The cyclohexene ring in 1 was prepared in an optically active form from d-glucose using Ferrier's carbocyclization reaction, and the critical quaternary carbon was stereoselectively generated via chirality transfer by the Claisen rearrangement of cyclohexenol 6. The hexahydroindole skeleton was effectively constructed by the intramolecular aminomercuration–demercuration of 14, followed by Chugaev reaction to provide 16. Finally, Pictet–Spengler reaction completed the first chiral synthesis of (+)-vittatine 1. On the other hand, the α-hydroxylation of the ester 5 stereoselectively proceeded to give α-hydroxy ester 19, to which was introduced an amino function to provide 4. A similar transformation of 4, as employed in the synthesis of vittatine, furnished (+)-haemanthamine 2.

© 2018 The Chemical Society of Japan. A stereoselective synthesis of kaitocephalin is described. The central strategy is based on chirality transfer reactions of three secondary alcohols derived from L-arabinose. The Overman rearrangement of an α,β-unsaturated ester, and intramolecular anti-type S N 2¤ reaction constructed a β-hydroxy-α,α-disubstituted amino acid moiety. The third chirality transfer reaction is the Ichikawa rearrangement. These stereoselective reactions successfully established the three contiguous stereocenters embedded in kaitocephalin.

© 2018 The Chemical Society of Japan. The development of a two-step synthesis for β-hydroxy-α,α- disubstituted amino acid derivatives from cyclic orthoamide is reported. The first step is the orthoamide-type Overman rearrangement of an α,β-unsaturated ester to give a sterically hindered α,α-disubstituted amidoester. The α,β-unsaturated ester is known to be a challenging substrate in the conventional Overman rearrangement due to the competitive aza-Michael reaction. However, suppression of the aza-Michael reaction is realized by two factors; 1) the high reaction temperature, and 2) an alkyl substituent at the α-position. The second step is stereodivergent intramolecular SN2′ reaction for the installation of a hydroxy group at the β-position. Either syn- or anti-type SN2′ reaction is possible by simply changing the reaction conditions. The developed method can provide all four possible stereoisomers of the β-hydroxy-α,α-disubstituted amino acid, and is successfully applied to the total synthesis of sphingofungin F.

The collective synthesis of pentacyclic stemoamide-type alkaloids is recognized as a daunting task despite high demand for a comprehensive biological profiling of these natural products. In this Letter, we report a unified synthesis of seven pentacyclic alkaloids and two unnatural derivatives. The keys to success are (1) the chemoselective assembly of four five-membered building blocks, (2) the direct oxidation of pyrrolidine natural products to pyrrole derivatives, and (3) the stereodivergent construction of totally E- or Z-substituted butenolides.

The total synthesis of paclitaxel (Taxol) is described. Double Rubottom oxidation of the bis(silyl enol ether) derived from a tricarbocyclic diketone effectively installed a bridgehead olefin and C-5/C-13 hydroxy groups in a one-step operation. The novel Ag-promoted oxetane formation smoothly constructed the tetracyclic framework of paclitaxel.

The totally substituted butenolide including two tetrasubstituted olefins is a distinct structural motif seen in Stemona alkaloids, but efficient methods for its synthesis are not well developed. As an ongoing program aimed at the collective total synthesis of the stemoamide group, we report a stereodivergent method to give either (E)-or (Z)-totally substituted butenolide from the same intermediate. While the AgOTf-mediated elimination via the E1-type mechanism results in the formation of the kinetic (Z)-tetrasubstituted olefin, the subsequent TfOH-mediated isomerization gives the thermodynamic (E)-tetrasubstituted olefin. The pyrrole ring is another important structure found in Stemona alkaloids. The direct oxidation of pyrrolidine rings with MnO2 and careful purification give the pyrrole groups without isomerization of the stereocenter in the lactone group. These two methods enable us to synthesize a series of stemoamide-type alkaloids including tricyclic, tetracyclic and pentacyclic frameworks. The anti-inflammatory activities by inhibition of iNOS expression in macrophage cell line RAW264.7 indicate that the most potent anti-inflammatory compounds without cytotoxicity are protostemonines, which consist of pentacyclic frameworks including the totally substituted butenolide.

Water-insoluble natural colored compounds adsorbed or chemically bound on cellulosic fabrics were bleached effectively at room temperature by a selective photolysis of the colored compounds using various excimer lasers (ArF, KrF, XeCl, XeF), a low-pressure mercury lamp, and a black-light fluorescent lamp in the presence of aqueous solutions of various reducing reagents. Sodium borohydride gave the best efficiency on the bleaching when KrF, XeCl, XeF excimer lasers or a low-pressure mercury lamp were used as light sources and the efficiency of the bleaching was found to be comparable to that of the conventional thermal bleaching processes.

Water-insoluble natural colored compounds adsorbed or chemically bound on cellulosic fabrics were bleached effectively by a selective photolysis of the colored compounds using various excimer lasers (KrF, XeCl, XeF), a low-pressure mercury lamp, and a black-light fluorescent lamp in the presence of sodium peroxocarbonate or mixtures of sodium carbonate and hydrogen peroxide aqueous solutions at room temperature. The efficiency of the photochemical bleaching was found to be comparable to that of the commercial thermal bleaching processes when a XeF excimer laser or a black-light fluorescent lamp were used as light sources.

In the title compound, C16H19NO3, the pyrrolidine ring is in a twist conformation. The dihedral angle between the di­hydro­furan ring [maximum deviation = 0.0016 (11) Å] and the phenyl ring is 47.22 (8)°. In the crystal, mol­ecules are linked by weak C—H⋯O hydrogen bonds, forming helical chains along the b-axis direction. The chains are further linked by C—H⋯π inter­actions to constitute a three-dimensional architecture.

Photochemical reduction of a stable enone, flavone (1), was accomplished by excimer laser photolysis using NaBH4 in ethanol, which formed flavanone (2) as a primary product in contrast to the formation of dimers that predominate in conventional photolysis. Flavanone (2) underwent successive thermal reduction with NaBH4 leading to flavanol (3) and photolysis to ethyl salicylate (4), in which the formation of 4 was completely suppressed when a single laser shot was used for the photolysis. The photolysis was conducted using quartz batch reactors having different optical paths and a quartz micro-channel reactor, in combination with KrF and XeCl excimer laser irradiation. This showed a considerable acceleration of the reaction with the micro-channel reactor, and the selectivity of the photoproducts 2, 3, and 4 depended on the optical path of the reactors, the laser wavelengths, the concentration of NaBH4, and the laser repetition rate. An optimal irradiation condition - application of sufficient time interval between the XeCl laser pulses, a low concentration of 1, and high concentration of NaBH4 - showed a considerable increase in the selectivity of 3 by eliminating the formation of 2 and 4.

© 2019 American Chemical Society. The asymmetric total synthesis of fasicularin is reported. The key to success is the use of a chiral N-alkoxyamide to control both reactivity and stereoselectivity. This functional group enables the aza-spirocyclization and the reductive Strecker reaction, which cannot be realized with an ordinary amide. In addition, use of the chiral alkoxy group establishes two consecutive stereocenters in the aza-spirocyclization through remote stereocontrol.

【研究背景】β-ヒドロキシ-α,α-二置換アミノ酸（1）は、スフィンゴファンジンF（2）や(–)-カイトセファリン（3）など生物活性天然物に広く見られる重要な構造モチーフである（Figure 1A）。これまで1の立体選択的な合成法は精力的に開発されてきたが、4種すべての立体異性体を作り分ける合成法は、数例しか報告されていなかった1)。そこで、私達は次のような基本合成戦略を立てた（Figure 1B）。不飽和エステルを有するオルトアミド4のOverman転位によって、1,4-アミドアルコール5を合成する。続いて、分子内SN2'反応を用いてオキサゾリン6または7を立体選択的に合成すれば、β-ヒドロキシ-α,α-二置換アミノ酸の立体選択的な作り分けが実現できると考えた。本発表では不飽和エステルのOverman転位と立体選択的SN2'反応によるβ-ヒドロキシ-α,α-二置換アミノ酸の合成法の開発と、これを用いたスフィンゴファンジンF（2）および(–)-カイトセファリン（3）の不斉合成を報告する。 【不飽和エステルのOverman転位】2,3）Overman転位は立体選択的に、窒素原子を導入する手法として広く利用されているシグマトロピー転位の1つである。Overman転位が不飽和エステル8に対して適用できれば、アミノ酸構造を一挙に構築できる有用な手法となる（8→9→11）。しかし、イミデート9を加熱するとaza-Michael反応（9→10）が進行するため、Overman転位は利用できないと報告されていた4)。そのため、既存の手法では保護体12へと

Our research group has been exploring a lactam strategy for the concise total synthesis of complex alkaloids. In this article, we report full details of the unified total synthesis of stemoamide-type alkaloids by chemoselective assembly of five-membered rings based on the lactam strategy. First, the concise and gram-scale synthesis of tricyclic stemoamide was achieved by vinylogous Michael addition-reduction sequence of an unsaturated γ-lactam with an unsaturated γ-lactone, followed by N-alkylation to form the seven-membered ring. From stemoamide as a common intermediate, chemoselective nucleophilic addition of unsaturated lactone derivatives provides tetracyclic natural products. While stemonine is obtained by an Ir-catalyzed lactam-selective reductive Mannich reaction, saxorumamide and isosaxorumamide are produced through the lactone-selective nucleophilic addition of the lithiated 2-silyl furan. The developed conditions for the lactam-selective nucleophilic reactions are highly general, and were found to be applicable to the total synthesis of pentacyclic stemocochinin and isostemocochinin. The strategy enables the concise and unified total synthesis of tricyclic, tetracyclic and pentacyclic stemoamide-type alkaloids within 12 steps from a commercially available compound.