Applications in the Synthesis of Natural Products

Numerous examples of intramolecular Diels-Alder reactions have been repor-ted especially from application in the synthesis of natural products, where stereoselectivity is of particular importance e.g. syntheses of steroids. " ... 

Although the Paterno-Buchi reaction is of high synthetic potential, its use in organic synthesis is still not far developed. In recent years some promising applications in the synthesis of natural products have been reported. The scarce application in synthesis may be due to the non-selective formation of isomeric products that can be difficult to separate—e.g. 6 and 7—as well as to the formation of products by competitive side-reactions such as Norrish type-I- and type-II fragmentations. 

Herein we will focus on the recent development of vinylogous [1] aldol reactions and their application in the synthesis of natural products [2-5]. In particular the synthesis of unsaturated esters through the vinylogous Mukaiyama aldol reaction is of great interest, since it provides rapid access to larger carbon frameworks and allows for a wide variety of transformations of the double bond (dihydroxylation, epoxidation, cuprate addition etc.). 

The Cope rearrangement is of great importance as a synthetic method e.g. for the construction of seven- and eight-membered carbocycles from 1,2-divinylcyclopropanes and 1,2-divinylcyclobutanes respectively (e.g. 11 12), and has found wide application in the synthesis of natural products. The second step of the para-Claisen rearrangement is also a Cope rearrangement reaction. 

Catalytic transformations of alkynes have recently led to tremendous developments of synthetic methods with useful applications in the synthesis of natural products and molecular materials. Among them, the selective activations of terminal alkynes and propargylic alcohols via vinylidene- and allenylidene-metal intermediates play an important role, and have opened new catalytic routes toward anti-Markovnikov additions to terminal alkynes, carbocyclizations or propargylations, in parallel to the production of new types of molecular catalysts. 

Magnesium enolates react with aldehydes and ketones to give aldol products after hydrolysis. The reaction proceeds both regio- and stereoselectively and has found many applications in the synthesis of natural products. 

One of the most useful and widely used applications in the synthesis of natural product derivatives relies on the efficient photoaddition of RS-H onto a double bond (a reaction known as thiol-ene coupling) [55], The reaction exploits the weakness of the S—H bond that can be cleaved homolytically under irradiation (atca. 254nm). The electrophilic sulfur-centered radical attacks a nucleophilic double bond, thus starting a radical chain reaction. 

Multiple cyclo olefinic relays are also suitable substrates to promote cascades of RCM-ROM-RCM reactions [9] (Scheme 16). Thus, W-protected polycyclic amines have been synthesized in moderate to good yields, but an increasing number of cyclopentene relays gave rise to less efficient cascade transformations. This ring rearrangement metathesis (RCM-ROM-RCM) has been extensively reported by Blechert and co-workers for its application in the synthesis of natural products [30-34]. 

The preparation of alkenic alcohols based on rDA processes has found application in the synthesis of natural products. Matsutake alcohol (14a (-)-( )-l-octen-3-ol), an important flavor component of mushrooms, can be prepared in high enantiomeric purity by a method that includes rDA cleavage as a key step. Asymmetric DA addition gave enantiomerically pure adducts that were modified dia-... 

The reaction of activated dienes with aldehydes is emerging as a powerful tool in the synthesis of natural products. This chapter reviews the major contributions that have led to the discovery and use of this reaction in organic synthesis. The first part of the chapter discusses the mechanism of the reaction, the second part describes the use of chiral aldehydes, chiral dienes and chiral catalysts in controlling stereochemistry, and the last section outlines applications in the synthesis of natural products. 

Cycloaddition reactions continue to find application in the synthesis of natural products and related substances containing indole and carbazole rings. Moody has published a summary of syntheses of carbazole alkaloids in which cycloadditions of pyrano[3,4-b]indol-3-ones figure prominently. <94SL681>... 

Palladium-catalyzed a-arylation of carbonyl derivatives and its applications in the synthesis of natural products 05CJO282. 

Some interesting examples of levoglucosenone s application in the synthesis of natural products and rare carbohydrates have been reported (58-81). Indeed, levoglucosenone has been used in the synthesis of (+)-multistriatin (58,72-73), Prelog-Djerassi lactonic acid (58,59) md (-)-a//o-yohimbane (61) The synthesis of indole alkaloid reserpine (61), and serricomin (58), as well as tetrodotoxin (53,62) were also reported from levoglucosenone or its functionalized derivatives and was reviewed earlier by us (1). 

The synthetic utility of DPM-type rearrangements now extends well beyond their application in the synthesis of natural products and biologically active systems. So, for example, dibenzobarrelenes annulated with a pyrrolinium unit (e.g., 142) and including a benzophenone counterion 143 undergo a DPM rearrangement reaction in the solid state, and the product dibenzosemibullvalene 144 serves as a phase-transfer catalyst in alkylation reactions. 

The goal of this book is to cover the principal methods employed to obtain DKR by enzymatic or non-enzymatic methods that have been reported in the last fifteen years and to illustrate the diversity of useful produets that ean be obtained through this powerful coneept. The aim of this book is to demonstrate that some most important achievements, such as organocatalysed DKRs, and enzymatic or non-enzymatic transition metal-catalysed DKRs, have considerably expanded the synthetic scope of the proeess. Moreover, a great number of novel enzymatic DKRs have been developed. The atropose-lective reactions reported by Bringmann et al. and their application in the synthesis of natural products and chiral auxiliaries are also included. ... 

Asymmetric Induction on the Nucleophile The use of the tBu-PHOX ligand led to the first catalytic enantioselective Tsuji allylations of simple alkanone enol derivatives 62. These mild, operationally straightforward and stereoselective reactions described by Stoltz et al. [52] produce chiral cycloalkanones 63 with quaternary stereocenters at the a-position with high enantiopurities and in excellent chemical yields (Scheme 12.31). Mechanistic studies showed the incorporation of an O-bound enolate in the intermediate Pd-allyl complex [53]. Further investigations on the substrate scope led to several applications in the synthesis of natural products [54]. Recently, a similar approach was used to afford enantiopure quaternary lactams 65 that intercept synthetic intermediates previously used in the synthesis of the Aspidospcrma alkaloids quebrachamine and rhazinilam, but that were previously only available by chiral-auxiliary-assisted approaches or as racemic mixtures (Scheme 12.32) [55],... 

The carbometalation reaction has been reviewed recently [28-30]. Negishi has demonstrated that zirconium(TV) complexes catalyze the carboalumination of MesAl to various alkynes and enynes [31]. Also the Zr-catalyzed asymmetric carboalumination of aUcenes (ZACA reaction) [32-34] has found important applications in the synthesis of natural products [35-37]. Especially efficient was the asymmetric synthesis of insect pheromones such as (S. / ./ ,S. / ,S)-4,6,8,10,16,18-hexamethyl-docosane (88) (Scheme 8) [38]. 

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