Kana Shintani, Haruna Ebisu, Minagi Mukaiyama, Taisei Hatanaka, Takumi Chinen, Daisuke Takao, Yoko Nagumo, Akira Sakakura, Ichiro Hayakawa,* Takeo Usui*
ACS Med. Chem. Lett. 2020, 11 (6), 1125–1129. (Published online: March 30, 2020)
Gatastatin (O7-benzyl glaziovianin A) is a γ-tubulin-specific inhibitor that is used to investigate γ-tubulin function in cells. We have previously reported that the unsubstituted phenyl ring of the O7-benzyl group in gatastatin is important for γ-tubulin inhibition. To obtain further structural information regarding γ-tubulin inhibition, we synthesized several gatastatin derivatives containing a fixed O7-benzyl moiety. Modifications of the B-ring resulted in drastic decrease in cytotoxicity, abnormal spindle formation activity, and inhibition of microtubule (MT) nucleation. In contrast, various O6-alkylated gatastatin derivatives showed potent cytotoxicity, induced abnormal spindle formation, and inhibited MT nucleation. We had previously reported that O6-benzyl glaziovianin A is a potent α/β-tubulin inhibitor; thus, these new results suggest that the O6-position restricts affinity for α/β- and γ-tubulin. Considering that an O7-benzyl group increases specificity for γ-tubulin, more potent and specific γ-tubulin inhibitors can be generated through O6-modifications of gatastatin.
Yuya Araki, Natsumi Miyoshi, Kazuki Morimoto, Takayuki Kudoh, Haruki Mizoguchi, Akira Sakakura*
J. Org. Chem. 2020, 85 (2), 798–805. (Published online: December 18, 2019)
A formal total synthesis of manzacidin B is described. β,β-Disubstituted γ-hydroxy-β-aminoalcohol, the key structure of manzacidin B, is stereoselectively constructed via sequential Henry reactions. By taking advantage of noncovalent interactions, such as intramolecular hydrogen bonding and chelation, we could diastereodivergently control the stereoselectivity of the Henry reaction.
Toward the Synthesis of SB-203207: Construction of Four Contiguous Nitrogen-Containing Stereogenic Centers
Ichiro Hayakawa,* Anna Nagayasu, Akira Sakakura*
J. Org. Chem. 2019, 84 (23), 15614–15623. (Published online: November 8, 2019)
SB-203207 is an altemicidin-type alkaloid that potently inhibits isoleucyl tRNA synthetase activity. Its main structural feature is a hexahydro-6-azaindene framework containing a unique β-hydroxy α,α-disubstituted α-amino acid moiety on the cyclopentane portion. Herein we have established a method for constructing the four contiguous nitrogen-containing stereogenic centers of SB-203207 by using as key steps the stereoselective alkylation of bowl-shaped tricyclic lactone to construct quaternary carbon at C1, the stereoselective hydroboration–oxidation reaction to install the C2 hydroxy group, and the Curtius rearrangement to introduce a nitrogen atom onto the C1 quaternary carbon.
Ichiro Hayakawa,* Ryosuke Nagatani, Masaki Ikeda, Dong-eun Yoo, Keita Saito, Hideo Kigoshi, and Akira Sakakura*
Org. Lett. 2019, 21 (16), 6337–6341. (Published online: July 30, 2019)
The heterocyclic portions of yuzurimine-type alkaloids, such as deoxyyuzurimine and macrodaphnine, were synthesized by using a stereoselective hydroboration−oxidation reaction to install the C20 methyl group, the intramolecular Mitsunobu reaction to construct the E-ring portion, and the intramolecular SN2 reaction to construct the F-ring portion as key steps.
Chihiro Kidou, Haruki Mizoguchi, Tatsuo Nehira, Akira Sakakura*
Synlett 2019, 30 (15), 1835–1839. (Published online: July 30, 2019)
Organoammonium salts of dipeptide-derived chiral triamines or diamines with TfOH catalyzed the enantioselective 1,3-dipolar cycloaddition reactions of α-acyloxyacroleins with nitrones to give the corresponding adducts in good yields (up to 96%) and with high diastereo- and enantioselectivities (up to 89% ee). Although α-( p-methoxybenzoyloxy)acrolein is rather unstable under the reaction conditions, α-(3-pyrroline-1-carbonyloxy)acrolein is stable enough to be smoothly converted into the corresponding adducts with the aid of the chiral organoammonium salt catalysts.
Miyuki Terazaki, Kei-ichi Shiomoto, Haruki Mizoguchi, Akira Sakakura*
Org. Lett. 2019, 21 (7), 2073–2076. (Published online: March 12, 2019)
Thioureas bearing electron-deficient aryl groups show high catalytic activity in the biomimetic bromocyclization of geranyl derivatives. The reaction of geranyl derivatives with N-bromosuccinimide (NBS) proceeds rapidly in CH2Cl2 to give the corresponding bromocyclization products in high yields as a ca. 1:1 mixture of endo- and exo-isomers. The reactivity of geranyl derivatives highly depends on the terminal substituent: electron-donating substituents increase the reactivity, while electron-withdrawing substituents decrease the reactivity.
Yutaro Niwa, Mayu Miyake, Ichiro Hayakawa, Akira Sakakura*
Chem. Commun. 2019, 55 (27), 3923–3926. (Published online: March 5, 2019)
A catalytic enantioselective Hosomi–Sakurai reaction of α-ketoesters has been developed. A copper(II) complex with a chiral bis(oxazoline) ligand bearing methanesulfonamide groups shows excellent catalytic activity to give α,α-disubstituted α-hydroxyesters in high yields with high enantioselectivities. This is the first successful method for the catalytic enantioselective 1,2-addition of α-ketoesters with allylic silanes.
Haruka Okamoto, Kohei Toh, Takuya Mochizuki, Hidefumi Nakatsuji, Akira Sakakura,* Manabu Hatano,* Kazuaki Ishihara*
Synthesis 2018, 50 (23), 4577–4590. (Published online: Aug 22, 2018)
Chiral BINOL-derived pyrophosphoric acid catalysts were developed and used for the regio- and enantioselective aza-Friedel–Crafts reaction of phenols with aldimines. ortho/ para-Directing phenols could react at the para-position selectively with moderate to good enantioselectivities. Moreover, the gram-scale transformation of a product into the key intermediate for the antifungal agent ( R)-bifonazole was demonstrated.
Manabu Hatano, Haruka Okamoto, Taro Kawakami, Kohei Toh, Hidefumi Nakatsuji, Akira Sakakura,* Kazuaki Ishihara*
Chem. Sci. 2018, 9 (30), 6361–6367. (Published online: June 25, 2018)
Chiral C2- and C1-symmetric BINOL-derived bis(phosphoric acid) catalysts, which have OP(=O)(OH)2/OP(=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.
Ichiro Hayakawa,* Yuji Yamanaka, Koichi Mitsudo, Hiromi Ota, Akira Sakakura*
Heterocycles 2017, 94 (12), 2299–2306. (Published online: Oct 26, 2017)
The reaction of silyl dienol ether of γ-pyrone with dimethyl acetylenedicarboxylate (DMAD) gives the regioselective insertion product in 66% yield. This DMAD-insertion reaction is thought to include a three-step sequence: (1) thermal [2+2]-type cycloaddition reaction of silyl dienol ether of γ-pyrone with DMAD, (2) ring-opening electrocyclic reaction of the cyclobutene skeleton, and (3) hydrolysis of the silyl dienol ether. The present reaction proceeds under mild conditions without any catalysts or heating. In addition, the [2+2]-type cycloaddition reaction proceeds regioselectively at the C3–C4 double bond in the silyl dienol ether of γ-pyrone.
Takayuki Kudoh, Yuya Araki, Natsumi Miyoshi, Mizuho Tanioka, and Akira Sakakura*
Asian J. Org. Chem. 2017, 6 (12), 1760–1763. (Published online: Oct 19, 2017)
β,β-Disubstituted β-amino alcohols has been synthesized in a diastereodivergent manner from chiral secondary nitroalkanes as starting materials. In this key Henry reaction, the use of different protecting groups resulted in the diastereoselective construction of the tetrasubstituted carbon stereocenter with different configuration. Based on this methodology, a total synthesis of manzacidins A and C has been achieved.
Takayuki Kudoh, Syo Fujisawa, Megumi Kitamura, Akira Sakakura*
Synlett 2017, 28 (16), 2189–2193. (Published online: July 6, 2017)
The intramolecular dehydro-Diels–Alder reaction of 1-indolyl-1,6-heptadiynes proceeds smoothly under rather mild heating conditions to give substituted carbazoles in moderate to good yields. The reaction of 7-aryl-1-indolyl-1,6-heptadiynes under heating gives the corresponding carbazoles chemoselectively in high yields, whereas the reaction under basic conditions gives naphthalenes as major products.
Reinvestigation of the Biomimetic Cyclization of 3,5-Diketoesters: Application to the Total Synthesis of Cyercene A, an α-Methoxy-γ-Pyrone-Containing Polypropionate
Kai Onda, Ichiro Hayakawa, Akira Sakakura*
Synlett 2017, 28 (13), 1596–1600. (Published online: Apr 26, 2017)
The biomimetic cyclization of 3,5-diketoesters was reinvestigated for the synthesis of α-methoxy-γ-pyrones. 3,5-Diketoesters were selectively synthesized via the aldol reaction of commercially available methyl 2-methyl-3-oxopentanoate with an aldehyde followed by the oxidation with AZADOL® and PhI(OAc)2. The DBU-promoted intramolecular transesterification of 3,5-diketoesters showed excellent reactivity in MeOH, to give the corresponding γ-hydroxy-α-pyrones in high yields under mild reaction conditions. Based on the present cyclization scheme, the total synthesis of cyercene A was achieved.
Akira Sakakura, Kazuaki Ishihara
In e-EROS (Encyclopedia of Reagents for Organic Synthesis); Wiley, 2017, Chapter April 2017, pp. 1–4. (Published online: Apr 10, 2017)
Ichiro Hayakawa,* Shuya Shioda, Takumi Chinen, Taisei Hatanaka, Haruna Ebisu, Akira Sakakura, Takeo Usui,* Hideo Kigoshi*
Bioorg. Med. Chem. 2016, 24 (21), 5639–5645. (Published online: Oct 11, 2016)
We have discovered O6-benzyl glaziovianin A, which showed stronger inhibition of microtubule polymerization ( IC50 = 2.1 μM) than known α,β-tubulin inhibitors, such as colchicine and glaziovianin A. Also, we performed competition binding experiments of O6-benzyl glaziovianin A and revealed that O6-benzyl glaziovianin A binds to the colchicine binding site with high affinity. It is interesting that glaziovianin A derivatives change their mode of action in benzylation at the O6 (α,β-tubulin inhibitor) or O7 (γ-tubulin-specific inhibitor) position.
Takayuki Kudoh,* Seiji Isoyama, Sachiko Kagimoto, Katsutoshi Kurihara, Akira Sakakura*
Tetrahedron Lett. 2016, 57 (42), 4693–4696. (Published online: Sept 16, 2016)
A simple procedure for the synthesis of chiral 3,5-disubstituted piperazinones is described. The aza-Michael addition of α-amino esters to β-substituted nitroalkenes in an organic/aqueous biphasic solvent system followed by reduction of a nitro group with zinc nanopowder in acidic media and intramolecular ester-amide exchange under heating conditions gives piperazinones in good overall yields. This novel three-step process can provide a short access to a variety of chiral 3,5-disubstituted piperazinones simply by changing the combination of starting nitroalkenes and α-amino esters. This process can be applied to the concise synthesis of the piperazinone-containing natural product 6’,6’’-didebromo- cis-3,4-dihydrohamacanthin B.
Yasuhiro Sawamura, Yoshihiro Ogura, Hidefumi Nakatsuji, Akira Sakakura* and Kazuki Ishihara*
Chem. Commun. 2016, 52 (36), 6068–6071. (Published online: Mar 18, 2016)
Chiral phosphite-urea bifunctional catalysts have been developed for the first enantioselective bromocyclization of 2-geranylphenols with N-bromophthalimide (NBP). The chiral triaryl phosphite moiety activates NBP to generate a bromophosphonium ion. On the other hand, the urea moiety interacts with a hydroxyl group of the substrate through hydrogen bonding interactions. Enantioselectivity is effectively induced through two-point attractive interactions between the catalyst and substrate.
Akira Sakakura* and Kazuaki Ishihara*
Chem. Rec. 2015, 15 (4), 728–742. (Published online: July 6, 2015)
Electrophilic cyclizations of unactivated alkenes play highly important roles in the synthesis of useful building blocks. This account describes our contributions to the rational design of monofunctionalized chiral Lewis base catalysts for enantioselective iodo- and protocyclizations. For the stereoselective promotion of electrophilic bromocyclizations, nucleophilic phosphite–urea cooperative catalysts have been designed.
Masahiro Hori, Akira Sakakura,* Kazuaki Ishihara*
J. Am. Chem. Soc. 2014, 136 (38), 13198–13201. (Published online: Sept 16, 2014)
We developed 1,3-dipolar cycloadditions of azomethine imines with propioloylpyrazoles catalyzed by a chiral copper(II) complex of 3-(2-naphthyl)-l-alanine amide. The asymmetric environment created by intramolecular π–cation interaction and the N-alkyl group of the chiral ligand gives the corresponding adducts in high yields with excellent enantioselectivity. This is the first successful method for the catalytic enantioselective 1,3-dipolar cycloaddition of azomethine imines with internal alkyne derivatives to give fully substituted pyrazolines.
This paper was highlighted in Synfacts 2014, 10 (12), 1288.
Synthesis of Chiral Pyrazolines via Chiral π-Cation Catalysis
Hidefumi Nakatsuji, Yasuhiro Sawamura, Akira Sakakura,* Kazuaki Ishihara*
Angew. Chem. Int. Ed. 2014, 53 (27), 6974–6977. (Published online: 19 May 2014)
Active duty: Chiral triaryl phosphates promote the enantioselective iodolactonization of 4-substituted 4-pentenoic acids to give the corresponding iodolactones in high yields with high enantioselectivity (see scheme). N-Chlorophthalimide (NCP) is employed as a Lewis acidic activator and oxidant of I2 for the present iodolactonization. In combination with 1.5 equivalents of NCP, only 0.5 equivalents of I2 are sufficient for generating the iodinating reagent.
This paper was highlighted in Synfacts 2014 , 10 (8), 0874.
Enantioselective Iodolactonization by Cooperative Activation
Yuki Matsumura, Takahiro Suzuki, Akira Sakakura,* Kazuaki Ishihara *
Angew. Chem. Int. Ed. 2014, 53 (24), 6131–6134. (Published online: 29 Apr 2014)
New on the block: The first diastereo‐ and enantioselective title reaction of β,γ‐unsaturated α‐ketoesters with allylsilanes is described. Chiral copper(II) catalysts successfully activate the β,γ‐unsaturated α‐ketoesters and promote the reaction with allylsilanes with excellent enantioselectivities. This process represents a new entry to chiral oxanes, which are useful building blocks. Tf=trifluoromethanesulfonyl.
5.9 Intermolecular Diels–Alder Reactions
Kazuaki Ishihaira, Akira Sakakura
In Comprehensive Organic Synthesis, 2nd Edition, Vol. 5, Gary A. Molander and Paul Knochel (eds.), Oxford: Elsevier; 2014, pp. 351–408.
5.10 Hetero-Diels–Alder Reactions
Kazuaki Ishihaira, Akira Sakakura
In Comprehensive Organic Synthesis, 2nd Edition, Vol. 5, Gary A. Molander and Paul Knochel (eds.), Oxford: Elsevier; 2014, pp. 409–465.
Yasuhiro Sawamura, Hidefumi Nakatsuji, Matsujiro Akakura, Akira Sakakura,* Kazuaki Ishihara*
Chirality 2014, 26 (7), 356–360. (Published online: 07 Feb 2014)
Nucleophilic phosphite-urea cooperative catalysts are highly efficient for the bromonium-induced cyclization of 2-geranylphenols. Phosphite- N,N’-dimethylurea catalysts also show moderate activity, probably due to the steric effect of their bent conformation.
Yasuhiro Sawamura, Hidefumi Nakatsuji, Akira Sakakura* and Kazuaki Ishihara*
Chem. Sci. 2013, 4 (11), 4181–4186. (Published online: 02 Aug 2013)
Nucleophilic phosphite-urea cooperative high-turnover catalysts have been designed for the highly selective bromocyclization of homogeranylarenes. The introduction of a urea moiety and bulky aryl groups in the catalyst inhibits decomposition of the catalyst and the generation of byproducts. Only 0.5 mol% of the catalyst successfully promotes the bromocyclization of 4-homogeranyltoluene to give the desired product in 96% yield.
Yoshihiro Ogura, Matsujiro Akakura, Akira Sakakura,* Kazuaki Ishihara*
Angew. Chem. Int. Ed. 2013, 52 (32), 8299–8303. (Published online: 03 July 2013)
Teaming up to make it happen: In the title reaction, the Lewis basic site of the catalyst activated ethyl cyanoformate, and the deep and flexible Brønsted acidic cavity stabilized and selectively recognized the key reaction intermediate to promote asymmetric acylation (see scheme).
Risa Yamashita, Akira Sakakura,* Kazuaki Ishihara*
Org. Lett. 2013, 15 (14), 3654–3657. (Published online: 26 June 2013)
Primary alkylboronic acids such as methylboronic acid and butylboronic acid are highly active catalysts for the dehydrative amide condensation of α-hydroxycarboxylic acids. The catalytic activities of these primary alkylboronic acids are much higher than those of the previously reported arylboronic acids. The present method was easily applied to a large-scale synthesis, and 14 g of an amide was obtained in a single reaction.
Masayuki Sakuma, Akira Sakakura,* Kazuaki Ishihara*
Org. Lett. 2013, 15 (11), 2838–2841. (published online: May 15, 2013)
Chiral phosphoniumsalts induce the kinetic resolution of racemicR-substituted unsaturated carboxylic acids through asymmetric protolactonization. Both the lactones and the recovered carboxylic acids are obtained with high enantioselectivities and high S (= kfast/kslow) values . Asymmetric protolactonization also leads to the desymmetrization of achiral carboxylic acids. Notably, chiral phosphonous acid diester not only induced the enantioselectivity but also promoted protolactonization.
This paper was highlighted in Synfacts 2013, 9 (8), 894.
Kinetic Resolution of Unsaturated Carboxylic Acids via Protolactonization