Published papers

© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Full details of a stereodivergent hydroboration of allenes are reported. While hydroboration of an allene with 9-BBN provided a thermodynamically stable (E)-allylic alcohol after oxidative work-up, the reaction of an identical allene with HB(Sia)2 (disiamylborane) formed a (Z)-allylic alcohol as the kinetic product. The developed conditions allowed for the synthesis of trisubstituted olefins in a highly stereoselective fashion, which is known to be challenging. The method was also applied to the stereodivergent synthesis of structural motifs such as skipped dienes and allylbenzenes, which are often embedded in biologically active natural products.

© 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.

© 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 SN2¤ 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.

Copyright © 2018 American Chemical Society. An iridium-catalyzed reductive nucleophilic addition to secondary amides is reported. After the iridium-catalyzed reduction, the resulting imines can undergo the Strecker reaction, the Mannich reaction, allylation, and [3 + 2]-cycloaddition. The method shows high chemoselectivity in the presence of other functional groups such as methyl ester.

© 2018 The Royal Society of Chemistry. Nucleophilic addition to amides has been recognized as a promising transformation for total synthesis of complex alkaloids. Amides can accept two different organometallic reagents through the nucleophilic addition, which enables it to serve as a stable surrogate of multi-substituted amines. However, the nucleophilic addition has been overlooked for a long time due to three main reasons: low electrophilicity of amide carbonyls, potential hydrolysis of the reaction intermediate and excess addition of an organometallic reagent. This mini review focuses on the recent progress of total synthesis of complex alkaloids based on the nucleophilic additions to N-alkoxyamides, tertiary amides and secondary amides.

© 2019 The Chemical Society of Japan. This article describes the development of an iridium-catalyzed reductive nucleophilic addition to tertiary amides. A conspicuous feature of this reaction is its high amide-selectivity via two processes: i) chemoselective hydrosilylation of amide carbonyls with Vaska’s complex [IrCl(CO)(PPh3)2] and (Me2HSi)2O, and ii) subsequent addition of a variety of mild nucleophiles to the resulting electrophilic iminium ions by the assistance of an acid. The reaction takes place in the presence of a variety of functional groups such as ester and nitro groups.

© 2019 The Japan Institute of Heterocyclic Chemistry – Stereoselective total synthesis of (–)-zephyranthine 1 based on the chiral pool approach starting from D-arabinose is described. The three consecutive chiral centers in (–)-zephyranthine were effectively constructed by the sequential [3,3] sigmatropic rearrangements (Claisen, Overman, and Claisen rearrangements) with chirality transfer of the hydroxy groups in D-arabinose.

© 2019 The Chemical Society of Japan. All rights reserved. The full details of a unified total synthesis of madangamine alkaloids are disclosed. Our central strategy is based on the construction of a common ABCE-tetracyclic system, followed by the late-stage installation of various D-rings. The common intermediate is assembled through N-acyliminium cyclization of a propargylsilane, and formation of the (Z,Z)-skipped diene. Stereoselective synthesis of the (Z,Z)-skipped diene is especially challenging, and is accomplished by the combination of Z-selective hydroboration of the 1,1-disubstituted allene and subsequent Migita-Kosugi-Stille coupling. Macrocyclic alkylation enables the late-stage variation of the D-rings on the common tetracyclic intermediate, resulting in the collective total syntheses of madangamines AE. The synthetic madangamine alkaloids exhibited inhibitory activities against a variety of human cancer cell lines.

A five-step total synthesis of (±)-aspidospermidine (1) based on a lactam strategy is reported. Our synthesis features an iridium-catalyzed reductive Michael addition/[3+2] cycloaddition cascade to give a tricyclic ketone intermediate from a simple lactam via an azomethine ylide. The developed strategy enables easily available lactams to be used as stable surrogates of multisubstituted amines and would be applicable to a unified total synthesis of complex Aspidosperma alkaloids.

Madangamines are marine natural products isolated from Xestospongia ingens, and madangamine A–E with a different D-ring structure have been reported. We have reported that madangamine A has strong anti-proliferative activity against various human cancer cell lines. In this study, to clarify the anti-proliferative activity of madangamine A, we searched for molecular target of the madangamine A in human cells. Treatment with madangamine A increased the levels of LC3-II and p62, autophagy-related proteins, concomitant with growth inhibition. Moreover, madangamine A resulted in lysosome enlargement and increase in lysosomal pH, which are same phenomena observed in chloroquine-treated cells. These results suggest that madangamine A is a novel lysosome inhibitor, and the anti-proliferative activity of madangamine A is due to the inhibition of lysosome function.

All-nitrogenated sugars (ANSs), in which all hydroxy groups in a carbohydrate are replaced with amino groups, are anticipated to be privileged structures with useful biological activities. However, ANS synthesis has been challenging due to the difficulty in the installation of multi-amino groups. We report herein the development of a concise synthetic route to peracetylated ANSs in seven steps from commercially available monosaccharides. The key to success is the use of the sequential Overman rearrangement, which enables formal simultaneous substitution of four or five hydroxy groups in monosaccharides with amino groups. A variety of ANSs are available through the same reaction sequence starting from different initial monosaccharides by chirality transfer of secondary alcohols. Transformations of the resulting peracetylated ANSs such as glycosylation and deacetylation are also demonstrated. Biological studies reveal that ANS-modified cholesterol show cytotoxicity against human cancer cell lines, whereas each ANS and cholesterol have no cytotoxicity.

The chiral synthesis of (+)-saxitoxin and its derivatives is described. Two consecutive carbon-nitrogen bonds at C-5 and C-6 in saxitoxin were effectively installed by the sequential Overman rearrangement of an allylic vicinal diol derived from d-malic acid. The bicyclic guanidine unit was constructed by the intramolecular aminal formation of an acyclic bis-guanidine derivative possessing a ketone carbonyl at C-4. From the bicyclic aminal intermediate, (+)-saxitoxin, (+)-decarbamoyl-β-saxitoxinol [(+)-dc-β-saxitoxinol], and the unnatural skeletal isomer, (-)-iso-dc-saxitoxinol, were synthesized.

Skipped dienes (1,4-dienes) are widely distributed in a variety of biologically active natural products. The synthesis of these skipped dienes is a relatively undeveloped area compared with that of conjugated dienes (1,3-dienes) due to the sp3-hybridized carbon between two olefins. Especially, development of methods to meet both high stereoselectivity and convergency is highly challenging. This review focuses on recent advances in the synthesis of skipped dienes in the total synthesis of complex natural products, which are classified into three classes; a) skipped dienes comprised of two disubstituted olefins, b) skipped dienes including trisubstituted olefin(s), and c) 3-methyl skipped dienes.

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.

© 2018 Oishi et al. The title compound, C17 H23 NO4 ·H2 O, is an epimer of the natural tetracyclic alkaloid isosaxorumamide which consists of a fused 5-7-5 tricyclic core and a dihydrofuranone substituent. The terminal dihydrofuran ring is essentially planar with a maximum deviation of 0.0273(14)Å from the mean plane and oxolane, azepane and pyrrolidine rings in the tricyclic ring system adopt twist, twist-chair and envelope forms, respectively. In the crystal, the amide and water molecules are linked by O - H...O hydrogen bonds, forming a tape structure running along the b-axis direction. The tapes are further connected by C - H...O interactions into a three-dimensional architecture.

© 2018 International Union of Crystallography. All rights reserved. In the title compound, C 20 H 27 NO 6 , the amide moiety is essentially planar, with a maximum deviation of 0.073(3)Å, and one of the N-methyl groups shows rotational disorder. The five-membered 1,3-dioxolane ring adopts an envelope form, with the C atom bonded to the olefin side chain as the flap, which deviates from the mean plane through the other four atoms by 0.564(7)Å. The 1,3-dioxole ring fused to the benzene ring adopts a flattened envelope form, with the C atom between the two O atoms as the flap, which deviates from the mean plane through the other four atoms by 0.215(7)Å. The C-C=C-C olefin moiety is essentially planar and makes a dihedral angle of 87.1(3)° with the benzene ring. An intramolecular O-H O hydrogen bond supports the molecular conformation, enclosing an S(11) graph-set motif. In the crystal, intermolecular C-H O hydrogen bonding links the molecules into a tape running along the b axis. Furthermore, other weak C-H;O hydrogen bonds and a C-Hπ interaction connect the tapes into a sheet structure parallel to (100).

© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim An approach to cyclic nitrones from N-hydroxylactam derivatives is documented. The nucleophilic addition of an organolithium reagent to an N-OSEM [SEM=2-(trimethylsilyl)ethoxymethyl] lactam forms a five-membered chelated intermediate, which undergoes both elimination and deprotection to give a fully substituted nitrone in a one-pot process. When combined with the N-oxidation of easily available chiral lactams, this method becomes especially useful for the quick synthesis of chiral nitrones in enantio-pure form, enabling the concise total synthesis of cylindricine C.

© 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.

© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim A copper-catalyzed electrophilic amidation of aryltrifluoroborates with use of N-methoxyamides is reported. The reaction shows high functional group compatibility derived from two distinct features: 1) the high stability of the N-methoxyamides and 2) the nonbasic mild conditions in the presence of LiCl. The developed method can also be applied to the synthesis of enamides, which are widely distributed in natural products. Preliminary mechanistic studies suggest that the initial step is the transmetalation of the aryltrifluoroborate by the assistance of LiCl, and the resulting aryl copper intermediate provides the anilide through non-SN2 oxidative addition to the N-methoxyamide and subsequent reductive elimination.

© 2019 The Chemical Society of Japan. Synthesis of the western polyene fragment of corallopyronin A is documented. The α-hydroxy skipped diene structure is stereoselectively synthesized by our method consisting of enantioselective allenylation of an aldehyde, hydroboration of the resulting 1, 1-disubstituted allene and Migita-Kosugi-Stille coupling. The developed approach could become a general platform for α-hydroxy skipped dienes embedded in a number of biologically active natural products because all eight stereoisomers of the α-hydroxy skipped diene are potentially available from the same aldehyde through these three stereodivergent reactions.