1.3- Dipolar cycloaddition reactions natural products

Ever since Huisgen s seminal studies [4, 15, 25], a wide variety of 1,3-dipoles have found widespread synthetic use [22, 23, 28-34]. Selected examples of common dipoles are depicted in Figure 18.2. In contrast to the developments seen with other transformations, the evolution of dipolar cycloaddition reactions has largely occurred in its strategic applications in complex molecule synthesis. The discussion that follows therefore focuses on classic applications of dipolar cycloadditions in natural products total syntheses. The diastereoselective dipolar cycloadditions of allylic and homoallylic alcohols with nitrile oxides presented at the end of this section constitute a general synthetic method to gain access to chiral polyketide fragments. 

The importance of the 1,3-dipolar cycloaddition reaction for the synthesis of five-membered heterocycles arises from the many possible dipole/dipolarophile combinations. Five-membered heterocycles are often found as structural subunits of natural products. Furthermore an intramolecular variant makes possible the formation of more complex structures from relatively simple starting materials. For example the tricyclic compound 10 is formed from 9 by an intramolecular cycloaddition in 80% yield ... 

A.1.3. Syntheses of Natural Products and Related Compounds 1,3-Dipolar cycloaddition reactions of nitrile oxides in the synthesis of natural products and their analogs has been the subject of a recent review (458). 

For reviews dealing with stereoselective 1,3-dipolar cycloaddition reactions, see (a) Martin JN, Jones RCF. In The Chemistry of Heterocyclic Compounds Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products, Padwa A, Pearson WH (Eds.), John Wiley Sons, New-York, Vol. 59, ch. 1, 1-81, 2002 ... 

The general method, that has been widely used for the synthesis of perhydropyrrolo[1,2-6]isoxazoles, is based on a cycloaddition reaction of cyclic nitrones with dipolarophiles. The nitrone is easily available by oxidation of the corresponding hydroxylamine with mercuric chloride. The cycloaddition of nitrone to dipolarophiles is highly regioselective and stereoselective and have been often applied in the total synthesis of natural products <20010L1367, 2004BML3967, 2005JOC3157>. As one representative example of dipolar cycloaddition, reaction... 

The rhodium( 11)-catalyzed formation of 1,3-dipoles has played a major role in facilitating the use of the dipolar cycloaddition reaction in modern organic synthesis. This is apparent from the increasing number of applications of this chemistry for the construction of heterocyclic and natural product ring systems. This chapter initially focuses on those aspects of rhodium(II) catalysis that control dipole formation and reactivity, and concludes with a sampling of the myriad examples that exist in the Hterature today. 

Since the discovery of triazole formation from phenyl azide and dimethyl acetylenedicarboxylate in 1893, synthetic applications of azides as 1,3-dipoles for the construction of heterocychc frameworks and core structures of natural products have progressed steadily. As the 1,3-dipolar cycloaddition of azides was comprehensively reviewed in the 1984 edition of this book (2), in this chapter we recount developments of 1,3-dipolar cycloaddition reactions of azides from 1984 to 2000, with an emphasis on the synthesis of not only heterocycles but also complex natural products, intermediates, and analogues. 

The reader was given a taste of the power of isomiinchnone dipolar cycloaddition chemistry in Section 10.2.1. As discussed by Potts (1) and Gingrich and Baum (10), the isomiinchnone ring system—a masked carbonyl dipole—is exceptionally reactive as a 1,3-dipole in 1,3-dipolar cycloaddition reactions. In the intervening years since these two excellent reviews the major research efforts in isomiinchnone chemistry have entailed synthetic applications to specific targets such as alkaloids and other natural and unnatural products. 

The application of intramolecular dipolar cycloaddition reactions to the synthesis of complex natural products has recently come to be recognized as a very powerful synthetic tool, one equally akin to the intramolecular Diels-Alder reaction in its potential scope of application.69 This is particularly the case with nitrile oxides and the 1NOC reaction has been extensively utilized in total synthesis.70 The intramolecular nitrile oxide cycloaddition (INOC) generally displays exceptional regio- and stereo-chemical control which undoubtedly accounts for the popularity of this reaction. Internal cycloadditions of nitrile oxides have been found to offer a powerful solution to many problems in complex natural product synthesis.48 For example, Confalone and coworkers have utilized the INOC reaction for the stereospecific synthesis of the key amino alcohol (60), which was converted in five subsequent steps to ( )-biotin (61 Scheme 14).71... 

The intramolecular 1,3-dipolar cycloaddition reaction of azides has become an increasingly useful process for the construction of natural products and molecules of theoretical interest.192 193 For example, 2-substituted azido enone (238) was prepared from the corresponding bromide by treatment with sodium azide. Thermolysis of this material afforded aziridinyl ketone (240) presumably via a transient dipolar cycloadduct (239).193 Ketone (240) was subsequently converted to an intermediate previously used to prepare histrionicotoxin (241 Scheme 56). 

SCS-MP2 and the new perturbative B2-PLYP density functional methods provide accurate reaction barriers and outperform MP2 and B3-LYP methods when applied to the 1,3-dipolar cycloaddition reactions of ethylene and acetylene.39 Phosphepine has been shown to catalyse the asymmetric 3 + 2-cycloaddition of allenes with a variety of enones (e.g. chalcones) to produce highly functionalized cyclopentenes with good enantiomeric excess.40 The AuPPh3SbF6 complex catalysed the intramolecular 3 + 2- cycloaddition of unactivated arenyne- (or enyne)-yne functionalities under ambient conditions.41 A review of the use of Rh(I)-catalysed 3 + 2-cycloadditions of diaryl-and arylalkyl-cyclopropenones and aryl-, heteroaryl-, and dialkyl-substituted alkynes to synthesise cyclopentadienones for use in the synthesis of natural products, polymers, dendrimers, and antigen-presenting scaffolds has been presented.42... 

A variety of elegant experiments serve to highlight the nature of the subtle factors which control dia-stereofaciad selectivity in dipolar cycloaddition reactions between optically active nitrones, of the type illustrated, and electron-rich dipolarophiles. In general, facial selectivity is found to be influenced by the nature of the substituent on nitrogen and by the presence of a second stereogenic center. As illustrated, selectivities ranging from zero to complete have been observed (Scheme 22). Notice also the preference for formation of the endo transition state derived product. 

Many examples of guanidine base-promoted nitro aldol reactions [1] and their application to the synthesis of natural products have been reported. Ishikawa et al. synthesized (- -)-cyclophelhtol (14), an a-glucosidase inhibitor and also a potential inhibitor of HIV, via the intramolecular 1,3-dipolar cycloaddition reaction of silylnitronate 13. In this synthesis, nitroalcohol 12 was prepared by the reaction of aldehyde 11 with nitromethane in the presence of TMG (3) as a 2 1 diastereomeric mixture [2] (Scheme 7.1). 

Ciufolini and co-workers demonstrated the use of 1,3-dipolar azide-olefin cycloaddition reactions in the total synthesis of ( )-FR66979 (52) [25], an antitiunor agent which is structurally related to the mitomycins [26]. Thus, the triazoline 50 was obtained as a single diastereomer by smooth cycloaddition of the activated double bond and the dipole in 49 by heating in toluene. Brief photolysis of 50 provided aziridine 51, which fragmented to 52 (Scheme 8B). Other intramolecular azide-alkene cycloaddition in natural product synthesis is illustrated by a munber of examples [27-32]. 

Herein, a comparison is presented of the chemical differences that exist among the 1,3-dipolar cycloaddition reactions of acychc or cyclic carbonyl ylides with the major classes of dipolarophiles. It is hoped that this work will provide a useful reference and stimulate further efforts in this sphere, which has further potential for varied synthetic applications towards heterocycles and natural products. 

The use of Rh(II) catalysts for the formation of 1,3-dipoles from diazo compounds via rhodium-carbenoids has facilitated the use of the dipolar cycloaddition reaction in key steps in the preparation of natural products. The synthesis of aspidosperma alkaloids 227 and their derivatives is important because these alkaloids contain the highly functionalized vindoline nucleus which is found in... 

The concept of (3 -I- 2)-dipolar cycloadditions, pioneered by Rolf Huisgen, dates back to the early 1960s [19]. Over the years, this reaction has found widespread utility in heterocyclic chemistry, natural product synthesis and medicinal chemistry [20-22]. These elegant chemical transformations facilitate the construction of products with high complexity where two new tj-bonds are formed in a single step. In a typical (3 -I- 2)-dipolar cycloaddition reaction, a 1,3-dipole reacts with a... 

The imidazole core is a common moiety in a variety of natural products and pharmacologically active compounds such as the commercially available drugs etomidate, cimet-idine, omeprazole, and lansoprazole. In view of developing an easy and clean protocol for the synthesis of small libraries of imidazole derivatives, Yli-Kauhaluoma and coworkers have recently elaborated a microwave-assisted protocol based on the 1,3-dipolar cycloaddition reaction of l-(isocyanomethylsulfonyl)-4-methylbenzene (TOSMIC) with suitably functionalized imines immobilized on solid support (Scheme 8.7). 

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