Organic synthesis cyclization

Transition-metal-catalyzed intramolecular cycloisomerization is one of the most useful carbocyclization reactions, and specifically, the Rh-catalyzed cycloisomerization of 1,6-enynes provides a powerful tool in organic synthesis. Cyclization of l,6-en5me 452 catalyzed by Wilkinson s catalyst gave 1-exo-methylene-2-cyclohexene 453 via a 6-exo-trig mode in 83% yield (Scheme 2-50). Terminal substitution on the alkene moiety dramatically suppressed the cyclization, and substitution of the terminal alkyne moiety was detrimental to the reaction as well. 

On the basis of the examples addressed thus far, it is clear that radical reactions can accomplish manifold transformations in organic synthesis. One of the outstanding achievements of synthetic radical chemistry is the development of synthetic strategies based on controlled, tandem radical cyclizations. The efficiency of such strategies is exemplified in the substantial and elegant synthetic work of D. P. Curran and his group.54 The remainder of this chapter will address the concise total syntheses of ( )-hirsutene [( )-1]55 and ( )-A9(12)-capnellene [( )-2]56 by the Curran group. 

As expected, some sequences also occur where a domino anionic/pericyclic process is followed by another bond-forming reaction. An example of this is an anionic/per-icyclic/anionic sequence such as the domino iminium ion formation/aza-Cope/ imino aldol (Mannich) process, which has often been used in organic synthesis, especially to construct the pyrrolidine framework. The group of Brummond [450] has recently used this approach to synthesize the core structure 2-885 of the immunosuppressant FR 901483 (2-886) [451] (Scheme 2.197). The process is most likely initiated by the acid-catalyzed formation of the iminium ion 2-882. There follows an aza-Cope rearrangement to produce 2-883, which cyclizes under formation of the aldehyde 2-884. As this compound is rather unstable, it was transformed into the stable acetal 2-885. The proposed intermediate 2-880 is quite unusual as it does not obey Bredf s rule. Recently, this approach was used successfully for a formal total synthesis of FR 901483 2-886 [452]. 

TMC ATRA reactions can also be conducted intramolecularly when alkyl halide and alkene functionalities are part of the same molecule. Intramolecular TMC ATRA or atom transfer radical cyclization (ATRC) is a very attractive synthetic tool because it enables the synthesis of functionalized ring systems that can be used as starting materials for the preparation of complex organic molecules [10,11], Furthermore, halide functionality in the resulting product can be very beneficial because it can be easily reduced, eliminated, displaced, converted to a Grignard reagent, or if desired serve as a further radical precursor. The use of copper-mediated ATRC in organic synthesis has been reviewed recently and some illustrative examples are shown in Scheme 3 [10,11,31,32,33],... 

Few other examples of such reaction sequences have been described to date. Oh has reported the palladium-catalyzed reductive cyclizations of 1,6-enynes in the presence of formic acid or triethylsilane via an alkylpalladium intermediate and its application to organic synthesis. Palladium complexes also catalyze the conversion of a range of enynes to cyclic 6,7-unsaturated carboxylic acids in the presence of CO.260... 

When the TMS group is absent and if the reaction is carried out in methanol, a platinum(ll)-catalyzed alkoxycy-clization takes place (Scheme 87).308 This cyclization catalyzed by Pt(ll) was found to be mechanistically similar to the carbohydroxypalladation reported by Genet.309 310 This process has intrinsic importance in organic synthesis since it allows the simultaneous and generally stereoselective formation of a C-O and a C-C bond to occur from an enyne system. This reaction has been applied for the synthesis of a key intermediate of podophyllotoxin.311... 

Allylic amination is important for the solid-phase organic synthesis.15 The solid-phase allylic aminations are devised into the G-N bond formation on solid support and the deprotection of allyl ethers. As a novel deprotection method, the palladium-catalyzed cyclization-cleavage strategy was reported by Brown et al. (Equation (4)).15a,15b The solid-phase synthesis of several pyrrolidines 70 was achieved by using palladium-catalyzed nucleophilic cleavage of allylic linkages of 69. 

The formation of C—C bonds is generally considered to be more important than the formation of C—H bonds. It is therefore not surprising that these reactions have attracted more attention. Of special importance in organic synthesis are 5 -exo cyclizations [17], and the titanocene-mediated reactions are a valuable tool for carrying out these transformations. Three examples are shown in Scheme 12.9. 

The formation of carbon-carbon bonds adjacent to nitrogen is of current interest in organic synthesis. Normally, the cyclization of an a-aminoalkyl... 

Curran2 has reviewed recent applications of the tin hydride method for initiation of radical chain reactions in organic synthesis (191 references). The review covers intermolecular additions of radicals to alkenes (Giese reaction) as well as intramolecular radical cyclizations, including use of vinyl radical cyclization. 

In view of this background, it is the aim of this chapter to organize the fundamentals of radical additions to 1,2-dienes and to present its state of the art in organic synthesis. All aspects of enyne allene cyclizations [19, 20] have been omitted since this topic is addressed in Chapter 20. In order to simplify the mechanistic discussion, the positions and Jt-bonds of allenes have been consistently numbered using the nomenclature outlined in Figure 11.1. 

Cathodic cyclization reactions have supphed and continue to provide a fertile territory for the development and exploration of new reactions and the determination of reaction mechanism. Two areas that appear to merit additional exploration include the application of existing methodology to the synthesis of natural products, and, more significantly, a systematic assessment of the factors associated with the control of both relative and absolute stereochemistry. Until there is a solid foundation to which the non-electrochemist can confidently turn in evaluating the prospects for stereochemical control, it seems somewhat unlikely that electrochemically-based methods will see widespread use in organic synthesis. Fortunately, this comment can be viewed as a challenge and as a problem simply awaiting creative solution. 

For reviews of chemical approaches to radical cyclization reactions see a) Motherwell WB, Crich D (1992) Free radical chain reactions in organic synthesis, Academic Press, London, b) Giese B (1986) Radicals in organic synthesis formation of carbon-carbon bonds, Pergamon, Oxford, and c) Jasperse CP, Curran DP, Fevig TL (1991) Chem Rev 91 1237... 

Although terminal alkynes can easily be converted into vinylidene complexes, vinylidene complexes have not yet been extensively used as intermediates in organic synthesis [150,546,576-578,944]. Some cyclization reactions, which might proceed by transient formation of vinylidenes, are listed in Table 3.23 (see also Sections 2.1.5.1 and 2.2.2). 

The domino cycloaddition-iV-acyliminium ion cyclization cascade has been extensively reviewed. Tandem reactions combining Diels-Alder reactions and sigma-tropic rearrangement reactions in organic synthesis have been extensively reviewed. The tandem Diels-Alder reaction between acetylenedicarboxaldehyde and N,N -dipyrrolylmethane has been extensively studied at the RHT/3-21G and RHF/6-31G levels.The molecular mechanism of the domino Diels-Alder reaction between hexafluorobut-2-yne and A,A -dipyrrolylmethane has been studied using density functional theory. 

Cyclization reactions have boosted the development of free-radical strategies in organic synthesis. The construction of five- and six-membered ring systems has... 

Abstract Bismuth(III) salts are currently considered efficient and ecofriendly reagents and catalysts for the development of new applications in organic synthesis. The preparation of bismuth(III) triflate and its analogues is reviewed as well as some of their applications to the synthesis of bulk chemicals via electrophilic addition and cyclization reactions. The use of bismuth(III) salts in the development of new chemical processes involving steroids and terpenes as substrates is also discussed. 

This chapter is an update (2003 to present) of the main applications of Bi(III) Lewis acids in organic synthesis developed and, in some cases, co-developed, by French and Portuguese research groups. Thus, in this chapter, the preparation of Bi(III) catalysts and their application to chemical transformations ranging from electrophilic addition to cyclization reactions, will be reviewed. The development of new environmentally friendly chemical processes, using Bi(III) reagents and catalysts, with direct application to steroid chemistry and related compounds will also be considered. 

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