Enantioselective Syntheses of Aeruginosin 298-A and Its Analogues Using a Catalytic Asymmetric Phase-Transfer Reaction and Epoxidation

Ohshima, Takashi; Gnanadesikan, Vijay; Shibuguchi, Tomoyuki; Fukuta, Yuhei; Nemoto, Tetsuhiro; Shibasaki, Masakatsu

doi:10.1021/ja037290e

Cited by 90 publications

(66 citation statements)

References 11 publications

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“…Based on the structure of aeruginosin 102-A (1b), we also synthesized the D-Tyr analog D-3b (88%, 92% ee) and the D-Phe(4-F) analog D-3c (93%, 94% ee). During the scaling-up of the reaction, we found that after quenching the reaction with water and ether, catalyst 2 was deposited as a white solid and easily recoverable in Ϸ90% yield just by simple decantation (15). This finding suggests that catalyst 2 is extremely stable even under strongly basic conditions in contrast to commonly used Cinchona alkaloid derived catalysts (24)(25)(26)(27).…”

Section: Resultsmentioning

confidence: 88%

“…When using 10 mol % of (S,S)-2a, phase-transfer alkylation of 4 proceeded smoothly to afford a variety of ␣-amino acids (14,15). For the synthesis of 1a (D-Leu portion), methallyl bromide was used as an electrophile to afford D-3a [93%, 91% enantiomeric excess (ee)].…”

Section: Resultsmentioning

confidence: 99%

“…This finding suggests that catalyst 2 is extremely stable even under strongly basic conditions in contrast to commonly used Cinchona alkaloid derived catalysts (24)(25)(26)(27). The recovered catalyst had the same catalyst efficiency (15). Hydrolysis of benzophenone imine of 3 by acid treatment (0.5 M aqueous citric acid) or hydrogenolysis conditions (H 2 , catalyzed by Pd-C, MeOH) afforded the corresponding amino esters 7 in high yield and they were used for the next coupling reaction (vide infra).…”

Section: Resultsmentioning

confidence: 99%

“…Details for the syntheses of aeruginosin 298-A and its analogs are provided in Supporting Materials and Methods, which is published as supporting information on the PNAS web site (see also ref. 15). …”

Section: Methodsmentioning

confidence: 99%

“…To address this issue, we applied asymmetric phase-transfer catalysis (PTC) promoted by two-center catalysts, which were recently developed by our group (14), to the syntheses of 1a as well as its analogs. Here, we report the enantioselective syntheses of aeruginosin 298-A and its analogs (15) by using asymmetric PTC and the catalytic asymmetric epoxidation of an ␣,␤-unsaturated imidazolide, which was also recently developed by our group (16)(17)(18)(19)(20)(21)(22). Moreover, serine protease inhibitory activities of 1a and its analogs were examined, leading to the future discovery of analogs possessing higher and more selective protease inhibitor potencies than those of the natural products.…”

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confidence: 99%

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Enantioselective syntheses and biological studies of aeruginosin 298-A and its analogs: Application of catalytic asymmetric phase-transfer reaction

Fukuta

Ohshima

Gnanadesikan

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Aeruginosin 298-A was isolated from the freshwater cyanobacterium Microcystis aeruginosa (NIES-298) and is an equipotent thrombin and trypsin inhibitor. A variety of analogs were synthesized to gain insight into the structure-activity relations. We developed a versatile synthetic process for aeruginosin 298-A as well as several attractive analogs, in which all stereocenters were controlled by catalytic asymmetric phase-transfer reaction promoted by twocenter asymmetric catalysts and catalytic asymmetric epoxidation promoted by a lanthanide-BINOL complex. Furthermore, serine protease inhibitory activities of aeruginosin 298-A and its analogs were examined. P roteolytic reactions control many important biologic processes; thus, the discovery of new selective proteolysis inhibitors continues to receive significant attention (1). Several serine proteases have been selected as potential therapeutic targets, such as the coagulation enzyme factors Xa, VIIa, and IIa (thrombin) (2) and urokinase-type plasminogen activator (3-5). The catalytic sites of the different serine proteases involved have a highly homologous region (2); therefore, engineering high selectivity would be especially challenging. Cyanobacteria produce several unique biologically active peptides, such as microcystins, microviridin, nodularin, and puwainaphycins. Aeruginosin 298-A (1a) was isolated by Murakami and coworkers from the freshwater cyanobacterium Microcystis aeruginosa (NIES-298) (6) and is an equipotent thrombin and trypsin inhibitor (7) (Fig. 1). Since 1994, Ͼ10 aeruginosins have been isolated by Murakami (6-9), along with microcin SF608, which was isolated by Carmelli and coworker (10). These compounds have a tetrapeptide-like structure including nonstandard ␣-amino acids such as 3-(4-hydroxyphenyl)lactic acid (Hpla) and 2-carboxy-6-hydroxyoctahydroindole (Choi). Of the aeruginosin family, aeruginosin 102-A (1b) is reported to have the highest activity (7,8). More potent analogs in terms of selectivity and activity, however, need to be developed. Although the total synthesis of 1a was reported by Bonjoch et al. (11,12) and Wipf and Methot (13), the development of a highly versatile synthetic method is required to gain insight into the structure-activity relations by the syntheses of a variety of analogs. To address this issue, we applied asymmetric phase-transfer catalysis (PTC) promoted by two-center catalysts, which were recently developed by our group (14), to the syntheses of 1a as well as its analogs. Here, we report the enantioselective syntheses of aeruginosin 298-A and its analogs (15) by using asymmetric PTC and the catalytic asymmetric epoxidation of an ␣,␤-unsaturated imidazolide, which was also recently developed by our group (16)(17)(18)(19)(20)(21)(22). Moreover, serine protease inhibitory activities of 1a and its analogs were examined, leading to the future discovery of analogs possessing higher and more selective protease inhibitor potencies than those of the natural products. The knowledge gained provides important inform...

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Section: Resultsmentioning

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Enantioselective syntheses and biological studies of aeruginosin 298-A and its analogs: Application of catalytic asymmetric phase-transfer reaction

Fukuta

Ohshima

Gnanadesikan

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Asymmetric Epoxidation of Electron‐Deficient Alkenes

Porter

Skidmore

2009

Organic Reactions

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Asymmetric epoxidation reactions have the distinction of being among the first enantioselective transformations to be widely sued in organic synthesis. The Sharpless asymmetric epoxidation is arguably one of the most important methods for the synthesis of enantiomerically enriched intermediates uses en route to a wide range of synthetic targets. To date most examples have employed electrophilic oxidizing agents and are thus applicable to electron‐neutral or electron‐rich double bonds. On the other hand alkenes substituted with electron‐withdrawing groups often react inefficiently with electrophilic oxidizing agents; such alkanes are more readily epoxidized using nucleophilic oxidants. The Weitz‐Scheffer epoxidation of alpha,beta‐unsaturated ketones to the corresponding epoxy ketones using basic hydrogen peroxide is the classical nucleophilic epoxidation reaction. This chapter considers the more general case of the conversion of an electron deficient alkene into the corresponding epoxide in an enantioselective fashion. Only methods based on chiral reagents or catalysts are covered. This review covers the literature to the end of 2005.

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The Catalytic, Enantioselective Michael Reaction

et al. 2016

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The catalytic enantioselective Michael reaction is the conjugate addition of a resonance‐stabilized carbanion to an electron‐poor olefin (an αβ‐unsaturated carbonyl compound or a related derivative) mediated by substoichiometric amounts of a chiral catalyst that enables stereocontrol in the newly generated stereocenter(s). This reaction allows the direct enantioselective construction of substituted 1,5‐dicarbonyl compounds or related architectures through the appropriate selection of the enolizable carbonyl compound employed as pronucleophile and the Michael acceptor. A variety of catalyst architectures have been described that make it possible to carry out this reaction with superior levels of chemical efficiency and high enantio‐ and stereocontrol, and also under conditions that tolerate a wide variety of functional groups. Both transition metal catalysis and organocatalysis have been employed as methodological approaches for carrying out this reaction in an enantioselective manner. This chapter describes different catalytic systems and methods developed for achieving enantioselective Michael reactions through the end of 2012, including a detailed mechanistic explanation of the different generic modes of substrate activation operating with each type of catalyst and their associated stereochemical aspects. The intention is to provide researchers interested in applying this methodology to their own synthetic strategies with a suitable starting point for identifying an efficient synthetic approach. In addition, the preparation of selected catalysts that are excellent for a particular pairing of substrates in this reaction, together with practical experimental protocols are described and some examples in which these methodologies have been applied to total synthesis have been included. This chapter is limited exclusively to those examples in which the final Michael addition product is obtained after protonation of the conjugate addition intermediate and therefore, tandem, domino, or cascade processes initiated by Michael reactions lie outside the scope of this work. Supplemental references are provided for articles published after the 2012 cut‐off date through the first half of 2015.

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Enantioselective Syntheses of Aeruginosin 298-A and Its Analogues Using a Catalytic Asymmetric Phase-Transfer Reaction and Epoxidation

Cited by 90 publications

References 11 publications

Enantioselective syntheses and biological studies of aeruginosin 298-A and its analogs: Application of catalytic asymmetric phase-transfer reaction

Enantioselective syntheses and biological studies of aeruginosin 298-A and its analogs: Application of catalytic asymmetric phase-transfer reaction

Asymmetric Epoxidation of Electron‐Deficient Alkenes

The Catalytic, Enantioselective Michael Reaction

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