Cyclization modes complexes

According to the Baldwin rule, the exo cyclization mode is favored in intramolecular reactions of alkynyloxiranes with alcohols to afford cyclic ethers. However, the unfavorable endo cyclization mode is observed by the complexation. Thus exclusive endo cyclization of epoxide complex 146 takes place regioselectively to give 147, without forming the five-membered ether 148 by exo mode reaction [37]. 

This observation is not related to traces of base or acid from the silver salts used since control experiments mled out this possibility. It was known from the literature that the 5-exo-dig versus 6-endo-dig cyclization mode could depend on the nature of the carbonyl group,56 57 of the alkyne substituent,58 59 and of the nature60 61 and oxidation state62 of the metallic source used. Also, work from Yamamoto25 demonstrated the importance of both a- and Jt-Lewis acidity properties of silver(I) complexes. Therefore, depending on the silver salt used, two mechanistic pathways were proposed (pathways A and B, Scheme 5.15). 

Gordon and Danishefsky [112] used the reaction of a chromium Fischer car-bene complex 164 with a cycloalkine 163 to build the naphthoquinone core 165 (Dotz reaction, review [113]), a procedure often used for synthesis of the linearly condensed anthracyclinones (e.g., [114]). The quinone ketone 165 has nucleophilic and electrophilic centers correctly positioned to furnish a ben-zo[fl]anthraquinone. However, treatment with NaH or Triton B gave the spiro-compounds 166 as a mixture of two stereoisomers. These products evidently arose from Michael addition of the ketone enolate to the naphthoquinone double bond. But the weaker base DBU induced cyclization at ambient temperature to the benzo[a]anthraquinone 167 in 65% yield (Scheme 42). The primary aldol adduct apparently eliminated water and the resulting dihydrobenzo[a]anthraquinone aromatized under basic conditions in the presence of air. This is an instructive example of the influence of the base on the cyclization mode. 

Scheme 26. Exo-endo dig cyclization modes involving nucleophilic attack of the arene upon the metal-alkyne n complex.

As part of our investigation of the hydroarylation of alkynes (or alkenylation of arenes) catalyzed by electrophilic transition metal complexes, our group reported the intra- and intermolecular reaction of indoles with alkynes catalyzed by gold (see Ref. [118, 133] in Chap. 1). Thus, alkynyUndole III-l cycUzes readily in the presence of a cationic gold(I) complex to give azepino[4,5-h]indole derivative III-2, whereas the use of AuCls leads to indoloazocine III-3 by a S-endo-dig process, this cyclization mode has not been observed in other hydroarylation of alkynes (Scheme 4.7). Under certain forcing conditions, aUenes and tetracyclic compounds were also obtained (see Refs. [118, 133] in Chap. 1). 

Aldol Reactions.— Baldwin has extended the nomenclature for classifying ring-closures to include intramolecular aldol reactions. Observations of the modes of cyclization of polyketonic substrates have shown that, for example, 6-(enolendo)-exo-trig cyclizations are indeed favoured whereas the five-membered version is disfavoured (Scheme 50). Such generalizations may prove powerful aids to recognition of likely pathways that cyclizations may follow when a multitude of cyclization modes are formally possible, and to the evaluation of the likelihood of success in aldol reactions by which complex cyclic targets are prepared. 

Like GDP in monoterpenes, FDP in sesquiterpenes can give rise to linear or cyclic compounds. Due to the increased complexity of FDP translated to the length of the side chain and the multiple unsaturation compared to GDP, the number of possible cyclization modes is also increased and a large number of mono-, bi-, and tricyclic diverse structures can be formed catalyzed by specific enzymes collectively termed as... 

The close relationship of cyclization modes existed in sesquiterpene biosynthetic machinery, with those presented by the metal-catalyzed cycloisomerizations, justify the vast amount of reports on total synthesis of sesquiterpenes, in which the utilization of enyne or diene cycloisomerizations are the key components of their synthetic strategy. This chapter is intended to cover only selected examples on the topic. Special concern is given on covering catalyzed reactions, which are triggering different cyclization modes, only for the construction of sesqniterpene core strnctnres. Assuredly, cycloisomerization reactions are powerfnl tools in providing also other classes of secondary metabolites, as complex terpenoids and alkaloids, in which the readers are referred to more general reviews on the topic [26,30]. 

The formation of the tricarbonylchromium-complexed fulvene 81 from the 3-dimethylamino-3-(2 -trimethylsilyloxy-2 -propyl)propenylidene complex 80 and 1-pentyne also constitutes a formal [3+2] cycloaddition, although the mechanism is still obscure (Scheme 17) [76]. The rf-complex 81 must arise after an initial alkyne insertion, followed by cyclization, 1,2-shift of the dimethylamino group, and subsequent elimination of the trimethylsilyloxy moiety. Particularly conspicuous here are the alkyne insertion with opposite regioselectivity as compared to that in the Dotz reaction, and the migration of the dimethylamino functionality, which must occur by an intra- or intermo-lecular process. The mode of formation of the cyclopenta[Z ]pyran by-product 82 will be discussed in the next section. 

An a-allenic sulfonamide undergoes Pd-catalyzed carbonylative cyclization with iodobenzene, affording a mixture of isomeric heterocycles (Scheme 16.12) [17]. The coupling reaction of an allene with a PhCOPdl species takes place at the allenyl central catrbon to form a 2-acyl-Jt-allylpalladium complex, which is attacked by an internal sulfonamide group in an endo mode, affording a mixture of isomeric heterocycles (Scheme 16.13). 

Over the past 15 years, we developed three procedures for the iron-mediated carbazole synthesis, which differ in the mode of oxidative cyclization arylamine cyclization, quinone imine cyclization, and oxidative cyclization by air (8,10,557,558). The one-pot transformation of the arylamine-substituted tricarbonyl(ri -cyclohexadiene) iron complexes 571 to the 9H-carbazoles 573 proceeds via a sequence of cyclization, aromatization, and demetalation. This iron-mediated arylamine cyclization has been widely applied to the total synthesis of a broad range of 1-oxygenated, 3-oxygenated, and 3,4-dioxygenated carbazole alkaloids (Scheme 5.24). 

In the quinone imine cyclization of iron complexes to carbazoles, the arylamine-substituted tricarbonyl(ri -cyclohexadiene)iron complexes 571 are chemoselectively oxidized to a quinone imine 574 prior to cyclodehydrogenation. This mode of cyclization is particularly applicable for the total synthesis of 3-oxygenated tricyclic carbazole alkaloids (Scheme 5.25). 

However, in the majority of cases, the substrates with substituted double bonds give complex mixtures of products, due to competition of both modes of termination, exo- and //[Pg.421]

The electronic nature of a nitrogen centered radical, dictated by reaction conditions and/or the radical precursor employed, is crucial to the mode of reaction, to the ability to undergo efficient intramolecular cyclizations or intermolecular additions, and to the products isolated from the radical reaction. The types of radicals discussed in this review include neutral aminyl radicals, protonated aminyl radicals (aminium cation radicals), metal complexed aminyl radicals, and amidyl radicals. Sulfonamidyl and urethanyl radicals are known (71S1 78T3241), but they are not within the scope of this chapter. 

In summary, a stereoselective 10-step total synthetic route to the antimalarial sesquiterpene (+)-artemisinin (1) was developed. Crucial elements of the approach included diastereoselective trimethylsilylanion addition to a,p-unsaturated aldehyde 16, and a tandem Claisen ester-enolate rearrangement-dianion alkylation to afford the diastereomerically pure erythro acid 41. Finally, acid 41 was converted in a one-pot procedure involving sequential treatment with ozone followed by wet acidic silica gel to effect a complex process of dioxetane formation, ketal deprotection, and multiple cyclization to the natural product (+)-artemisinin (1). The route was designed for the late incorporation of a carbon-14 label and the production of a variety of analogues for structure-activity-relationship (SAR) studies. We were successful in preparing two millimoles of l4C-l73 which was used for conversion to I4C-arteether for metabolism75 and mode of action studies.76,77... 

To achieve low radical concentrations, most radical reactions are traditionally performed as chain reactions. Atom or group transfer reactions are one of the two basic chain modes. In this process the atom or group X is the chain carrier. A metal complex can promote such chain reactions in two ways. On one hand, the catalyst acts only to initiate the chain process by generating the initial radical 29A from substrate 29 (Fig. 10). This intermediate undergoes the typical radical reactions, such as additions or cyclizations leading to radical 29B, which stabilizes to product 30 by abstracting the group X from 29. A typical example is the use of catalytic amounts of cobalt(II) salts in oxidative radical reactions catalyzed by /V-hydroxyphthalimide (NHPI), which is the chain carrier [102]. 

Metal complexes of heterocyclic compounds display reactivities changed greatly from those of the uncomplexed parent systems. All of the -electron system(s) of the parent heterocycle can be tied up in the complex formation, or part can be left to take part in alkenic reactions. The system may be greatly stabilized in the complex, so that reactions, on a heteroatom, for example, can be performed which the parent compound itself would not survive. Orbital energy levels may be split and symmetries changed, allowing hitherto forbidden reactions to occur. In short, a multitude of new reaction modes can be made possible by using complexes dimerization of azirines with a palladium catalyst serves as a typical example (Scheme 81). A variety of other insertion reactions, dimerizations, intramolecular cyclizations, and intermolecular addition reactions of azirines are promoted by transition metals. 

The pyrrolidinone and piperidinones (Tab. 5.2, n=l and n=2, respectively) had similarly impressive potencies, establishing that such cyclization led to increased potency, and also that inhibition was not extremely sensitive to ring size in this series. As described above, the binding modes observed for the pyrrolidinones (Tab. 5.2, n=l) in the cathepsin K complex crystal structures seem fairly consistent with previous structures observed with acydic compounds bound (Fig. 5.5). Unfortunately the 5- and 6-membered cyclic diaminoketones shared the undesir-... 

Compound 82, containing a deprotonated bridging A-hydroxyglutarimide, was obtained in an unusual hydroxylamine elimination and cyclization reaction upon reaction of lb with glutaroddiydroxamic acid (132). Even four distinct hydroxamate binding modes were observed in a heptanuclear Ni(ll) complex with 2-(dimethylamino)phenylhydroxamic acid (2-dmAphaH), [Ni7(2-dmAphaH-l)2 (2-dmApha)g(H20)2]S04- I5H2O (133). 

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