Enantioselective Total Syntheses of Several Bioactive Natural Products Based on the Development of Practical Asymmetric Catalysis

Abstract

I present herewith enantioselective total syntheses of several bioactive natural products, such as (؊)-strychnine, (؉)-decursin, (؊)-cryptocaryolone diacetate, (؊)-fluoxetine, and aeruginosin 298-A, based on practical asymmetric catalyses (Michael reaction, epoxidation, and phase-transfer reaction) that I developed with coworkers in Prof. Shibasaki's group over the past 5 years. In the first part of this review, I discuss the great improvement of catalyst efficiency in an ALB-catalyzed asymmetric Michael reaction of malonate and application to the pre-manufacturing scale (greater than kilogram scale) and enantioselective total synthesis of (؊)-strychnine with the development of novel domino cyclization. To broaden the substrate generality of the Michael reaction, we developed a highly stable, storable, and reusable La-O-linked-BINOL complex. Further extension of the reaction using b b-keto ester as a Michael donor was achieved with the development of a La-NR-linked-BINOL complex, thereby improving indole alkaloid syntheses. In the second section, I discuss enantioselective total synthesis of (؉)-decursin using catalytic asymmetric epoxidation. To achieve the synthesis, we developed a new La-BINOL-Ph 3 As‫؍‬O (1 : 1 : 1) complex catalyst system, which has much higher reactivity and broader substrate generality than the previously developed catalyst systems. This allowed us to achieve catalytic asymmetric epoxidation of a a,b b-unsaturated carboxylic acid derivatives with high enantioselectivity and broad substrate generality for the first time by changing the lanthanide metal and reaction conditions. Among them, catalytic asymmetric epoxidation of a a,b b-unsaturated morpholinyl amides is quite useful in terms of synthetic utility of the corresponding a a,b b-epoxy morpholinyl amides. Highly catalyst-controlled enantio-or diastereoselective epoxidation of the a a,b b-unsaturated morpholinyl amides, coupled with diastereoselective reduction of b b-hydroxy ketones, enabled the synthesis of all possible stereoisomers of 1,3-polyol arrays with successful enantioselective total synthesis of several 1,3-polyol natural products, such as (؊)-cryptocaryolone diacetate. In addition, the development of a new regioselective epoxide-opening reaction of a a,b b-epoxy amides to the corresponding a a-and b b-hydroxy amides enhanced the usefulness of the present epoxidation and was applied to the enantioselective total synthesis of (؊)-fluoxetine. In the final section, I report the development of a new asymmetric two-center organocatalyst (TaDiAS) and its application to the enantioselective synthesis of aeruginosin 298-A and its analogues. Because of the remarkable structural diversity of TaDiAS, a practical asymmetric phase-transfer reaction with broad substrate generality was achieved. As a result, we succeeded in developing a highly versatile synthetic method for aeruginosin 298-A and its analogues. Inhibitory activity studies of the compounds against the serine protease trypsin provided preliminary information about their str...

EMCA and DEEM as Michael Reagents Used in Organic Synthesis

“…Recently, one of the most important variants of Michel reaction are those, which enable to control the stereoselectivity, especially enantioselectivity [36][37][38][39][40][41][42][43]. Generally, there are two approaches to obtain asymmetric induction in Michael reaction [36].…”

Layered Double Hydroxide Nanomaterials Encapsulating Angelica gigas Nakai Extract for Potential Anticancer Nanomedicine

“…Herbal medicine containing diverse bio-active phytochemicals have long been utilized ( Kesarwani and Gupta, 2013 ; Baumann, 2014 ). Recently, medicinal researchers have tried to find out therapeutic single component ( Lim et al, 2001 ); however, several studies suggested that whole extract rather than single component is advantageous in therapies as complicated components stimulate multiple targets, induce synergetic effect and act as bio-enhancers ( Hu et al, 2009 ). Therefore, improved drug efficacy could be envisaged with the less-purified extract ( Lee et al, 2009 ; Rasoanaivo et al, 2011 ).…”

Targeted Engineering of Cyclooctat‐9‐en‐7‐ol Synthase: A Stereospecific Access to Two New Non‐natural Fusicoccane‐Type Diterpenes

“…However, a stereoselective assembly of the carbon macrocycles is challenging because it involves multiple synthesis steps, which results in racemic intermediates and/or low yields. [22,25] In addition, chemical synthesis approaches are often associated with the generation of toxic side streams, which prohibit sustainable production methods. [23,24] In contrast, our biocatalytic approach, which uses targeted engineering of diterpene cyclases, provides an environ-mentally friendly, single-step route for a stereochemical assembly of structurally complex carbon macrocycles.…”

“…[19] Therefore, despite new synthetic concepts in organic chemistry, the production of new bioactive diterpenes remains time and cost intensive and is also associated with the production of toxic waste streams. [3,[19][20][21][22][23][24][25][20][21][22][23][24][25][26][27] In contrast to a classical total synthesis approach, terpene cyclase-based biocatalysis offers a highly stereospecific, single-step route for the biosynthesis of complex macrocycles with potentially high yields and no toxic side streams. [1][2][3] Herein, we have set out to create new diterpene olefinic macrocycles by engineering the CotB2 template.…”