Syntheses of Biologically Active Natural Products and Leading Compounds for New Pharmaceuticals Employing Effective Construction of a Polycyclic Skeleton

Abstract

IntroductionWhen various functional groups exist on a polycyclic skeleton, the three-dimensional relationships of the functional groups are restricted and a specific biological activity would be expected due to the rigid conformation (Chart 1). Therefore the development of an efficient method for the construction of polycyclic ring systems is highly desirable, particularly in the field of medicinal chemistry. Cascade reactions 2-7) forming a number of bonds in one operation are useful for the creation of polycyclic compounds. Many stereogenic centers can be created at the same time. A reduction in the number of reaction steps save reagents and energy and reduce waste. Therefore cascade reactions are important from the economic and green chemistry points of view. In this context, we have been studying cascade reactions under various reaction conditions, such as pericyclic, polar, radical, and transition metal-catalyzed reaction conditions. Cascade Reaction under Polar Conditions 2.1. Double Michael ReactionThe bicyclo[2.2.2]octane skeleton is a framework of several natural products. We encountered difficulty in the stereoselective synthesis of the corresponding polycyclic systems using the intramolecular Diels-Alder reaction.8) The problem was solved by employing the intramolecular double Michael reaction, as shown in Chart 2. The treatment of cyclohexenones 1 and 3 with an a,b-unsaturated ester side chain at the 6 or 5 position with LiN(TMS) 2 provided the polycyclic bridged compounds 2 and 4 in highly stereoselective manners, respectively. 9,10) The objective products were produced via ideal transition states, fixed by the coordination with lithium ion.As a typical example of the application of this methodology, the synthesis of (Ϯ)-culumorin (13) 11) is shown in Chart Cascade reactions are useful methods for the construction of polycyclic skeletons, which are important cores for biological activities. A variety of cascade reactions carried out under multiple reaction conditions, such as pericyclic, polar, radical, and transition metal-catalyzed reaction conditions, have been investigated. Culmorin, pentalenene, pentalenic acid, deoxypentalenic acid, longiborneol, cedrandiol, 8,14-cedranoxide, atisirene, atisine, and estrane-type steroids were synthesized via the intramolecular double Michael reaction. Aza double Michael reaction was applied to the syntheses of tylophorine, epilupinine, tacamonine, and paroxetine. Furthermore, sequential Michael and aldol reactions were performed in both intramolecular and intermolecular manners, leading to the formation of polycyclic compounds fused to a four-membered ring. Synthesis of paesslerin A utilizing a multicomponent cascade reaction revealed an error in the proposed structure. Unique cascade reactions carried out under radical and transition metal-catalyzed reaction conditions were also investigated. With the combination of several cascade reactions, serofendic acids and methyl 7b b-hydroxykaurenoate, both of which have neuroprotective activity, were synthesized in a...

Chemical synthesis of culmorin metabolites and their biologic role in culmorin and acetyl-culmorin treated wheat cells

“…Several strategies for the synthesis of CUL and its core structure have been reported. [30][31][32][33] The acetylation of CUL affording 8-acetyl-and 11-acetylculmorin (11-AcCUL 2, Fig. 1a) was described very recently by Bahadoor et al 20 Besides this, no further synthetic modifications or derivatizations have been described.…”

Recent Advance of Domino Michael Reaction in Natural Product Synthesis

“…In the initial studies on domino Michael reactions, kinetic enolates generated by strong bases such as LDA were mainly used to initiate the domino reactions. 6,56,57 In these reactions, the ketone enolate underwent Michael reactions intermolecularly or intramolecularly, and the new enolate generated on the Michael acceptor underwent subsequent Michael reactions intramolecularly to give thermodynamically stable cyclic compounds. In the reactions using strong bases, aldehydes and αβ-unsaturated aldehydes could not be used as Michael donors or Michael acceptors due to the highly electrophilic nature of the formyl groups.…”

“…Among a variety of basic reactions as a candidate for a domino reaction as a key step for natural product syntheses, a Michael reaction has been utilized often, [5][6][7] because the species generated on the Michael acceptor has an ability to achieve a next Michael reaction furthermore. Since both a Michael donor and an acceptor are installed in a product without loss of atoms, a Michael reaction is superior in atomeconomy, 8 which provides an additional merit for a domino process.…”

“…A Michael reaction is a thermodynamically controlled reaction. In order to shift the equilibrium into thermodynamically stable product and to push the domino Michael reaction forward, several reaction systems were designed, among which kinetically controlled carbanion species were utilized to initiate the domino Michael reactions, [5][6][7] whereas, the use of a strong base such as a stoichiometric amount of lithium diisopropylamide (LDA) to generate a kinetically controlled carbanion for the initiation of the first Michael reaction is not suitable for the reactions of a labile Michael acceptor such as an αβ-unsaturated aldehyde. However, recent developments in the chemistry of organocatalysts 9,10 changed the game, in which an unmodified aldehyde as well as an unmodified αβ-unsaturated aldehyde can be applicable as a Michael donor and a Michael acceptor, respectively, to extend substrate scope.…”

Advances and Applications in Organocatalytic Asymmetric aza‐Michael Addition

“…[2] In particular, the Michael addition of nitrogen-based nucleophiles to a,b-unsaturated carbonyl systems, also termed the aza-Michael reaction, represents an especially interesting variant since it is a versatile method for constructing a new CÀN bond and constitutes; an important step in the synthesis of bioactive natural compounds. [3] During the past decade, a number of elegant organocatalysts have been developed for enantiocontrol in a large variety of reactions. Accordingly, the organocatalytic asymmetric aza-Michael addition has been a very active field of research, the previous progress of which has also been the subject to some excellent reviews.…”