Tandem sequence

The cyclopropane ring is an important structural motif in a great number of natural products and biologically active agents. In addition, eyclopropyl derivatives also constitute valuable synthetic building blocks in organic synthesis. Consequently, a number of efforts have been made to develop efficient synthetie methods of ehiral eyelopropanes. Among them, asymmetric 

This ehapter illustrates how much asymmetric nickel catalysis has contributed to the development of novel enantioselective domino, multicomponent, and tandem sequential reactions. It updates the major progress in the field of enantioselective two- and multicomponent domino reactions as well as tandem sequences promoted by chiral nickel catalysts, covering the literature since the beginning of 2004. It well illustrates the power of these 

Cowen and S. J. Miller, Ghem. Soc. Rev., 2009,38,3102-3116, Special Issue on Rapid formation of molecular complexity in organic synthesis. 

Shintani and T. Hayashi, in Modern Organonickel Chemistry, ed. Y. Tamaru, Wiley-VCH, Weinheim, 2005, pp. 240-272. 

Perlmutter, in Conjugate Addition Reactions in Organic Synthesis, Per-gamon Press, Oxford, 1992 (b) M. P. Sibi and S. Manyem, Tetrahedron, 2000, 56, 8033-8061 (c) M. Kanai and M. Shibasaki, in Catalytic Asymmetric Synthesis, 2nd edn, Wiley, New York, 2000, p. 569 (d) N. Krause and A. Hoffmann-Roder, Synthesis, 2001,171-196. 

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Although nitrile oxide cycloadditions have been extensively investigated, cycloadditions of silyl nitronates, synthetic equivalent of nitrile oxides in their reactions with olefins, have not received similar attention. Since we found that the initial cycloadducts, hl-silyloxyisoxazolidines, are formed with high degree of stereoselectivity and can be easily transformed into isoxazolines upon treatment with acid or TBAF, intramolecular silylnitronate-olefin cycloadditions (ISOC) have emerged as a superior alternative to their corresponding INOC reactions [43]. Furthermore, adaptability of ISOC reactions to one-pot tandem sequences involving 1,4-addition and ISOC as the key steps has recently been demonstrated [44]. 

One-pot tandem sequences involving 1,4-addition and ISOC as the key steps have been developed for the construction of N and 0 heterocycles as well as of carbocycles [44]. In this sequence, the nitronate arising from 1,4-addition to an a, -unsaturated nitro alkene is trapped kinetically using trimethyl silyl chloride (TMSCl). The resulting silyl nitronate underwent a facile intramolecular 1,3-dipolar cycloaddition with the unsaturated tether (e.g.. Schemes 20-22). 

Chapter 10 considers the role of reactive intermediates—carbocations, carbenes, and radicals—in synthesis. The carbocation reactions covered include the carbonyl-ene reaction, polyolefin cyclization, and carbocation rearrangements. In the carbene section, addition (cyclopropanation) and insertion reactions are emphasized. Recent development of catalysts that provide both selectivity and enantioselectivity are discussed, and both intermolecular and intramolecular (cyclization) addition reactions of radicals are dealt with. The use of atom transfer steps and tandem sequences in synthesis is also illustrated. 

Abstract This review presents a description of the C-C bond-forming reactions that have emerged in the field of titanocene mediated or catalyzed epoxide opening over the last 5 years or so. The powerful tandem sequences for polycylization will be especially emphasized. 

Scheme 33 Oltra s and Cuerva s tandem sequence featuring a 7-endo cyclization...

The vinyl metal intermediate arising from intermolecular nucleophilic addition of an oxygen nucleophile to a metal-alkyne complex has been harnessed for further transformations prior to protonation. An example is the ruthenium-catalyzed benzannulation of 1,5-enedyines that occurs through a tandem sequence involving hydroalk-oxylation, carbometallation, and protonation (Equation (82)).293... 

Grubbs has reported a similar tandem olefin metathesis-carbonyl olelination process for the preparation of cyclic olefins [31]. In this case, treatment of a keto-olefin with the molybdenum alkylidene 1 at 20°C generates an intermediate alkylidene complex. Under these conditions, competing intermolecular olelination does not occur. However, intramolecular carbonyl olelination of the initially formed alkylidene complex can occur and this results in the formation of a cyclic olefin. This tandem sequence is illustrated by the transformation of keto-olefins... 

Preliminary investigations in this area involved treatment of olefinic ester 125 with a large excess (4 equiv) of the Tebbe reagent 93 (Scheme 18) [34a]. After 20 min at 25°C, the mixture was heated at reflux for 5 h. This resulted in the formation of tricyclic enol ether 127 in 71% overall yield. If only 1.3 equiv of Tebbe reagent 93 was employed and the reaction stopped after 20 min at 25°C,the olefinic enol ether 126 could be isolated in 77% yield. The proposed intermediacy of diene 126 in the initial tandem sequence was validated by its subsequent conversion into the cyclic enol ether 127 under the original reaction conditions [34a],... 

Scheme 15 Radical tandem sequence for tetrahydrofuran formation...

In summary, according to the computational analysis it should be possible to realize the desired overall tandem sequence in the absence of alternative radical pathways with lower energies of activation. The formation of the... 

In many of the reactions the allenes are only intermediates in such tandem sequences [540-542] or the starting materials generated in situ [543-545]. 

Although the saturated ketone can be obtained in nearly quantitative yields, the loss of synthetically valuable functionality is unfavorable and can be overcome by a modification of the tandem sequence. The use of the corresponding unsaturated silyl enol ethers in a tandem hydroformyla-tion/Mukaiyama aldol reaction gives the desired aldol adduct with complete... 

Very recently, a tandem sequence consisting of enolboration/hydroform-ylation/aldol reaction has been described [88]. Here configuration of the enol boronate is transferred to the aldol product, allowing good to excellent di-astereoselectivities in the hydroformylation/aldol reaction. With this method, 5-7-membered rings are obtained in excellent yields (Scheme 35). 

The radical produced from the oxidative decarboxylation may also be trapped intramolecularly to form five- and six-membered rings (Scheme 17). The Kolbe protocol avoids the use of the toxic organ-otin reagents that are commonly used in the formation of radicals. Moreover, when alkyltin hydride reagents are used, a C—H bond is formed. The Kolbe reaction protocol, on the other hand, allows the radical formed after cyclization to be captured by a different radical in a coelectrolysis experiment, rather than being reduced. This tandem sequence of events has been exploited in the construction of prostaglandin precursor (70) [37-41]. Here, the cyclized... 

A related amination/rearrangement/cyclization tandem sequence had been introduced by Cossy [49]. Starting from cyclic epoxyketones 224 the reaction with propargylamines 225 caused an oxirane-opening condensation process to generate the enaminoketones 226. Upon heating in toluene to reflux, aza-Claisen rearrangement delivered the intermediate allenyl imines 227, which... 

Various transition metals have been used in redox processes. For example, tandem sequences of cyclization have been initiated from malonate enolates by electron-transfer-induced oxidation with ferricenium ion Cp2pe+ (51) followed by cyclization and either radical or cationic termination (Scheme 41). ° Titanium, in the form of Cp2TiPh, has been used to initiate reductive radical cyclizations to give y- and 5-cyano esters in a 5- or 6-exo manner, respectively (Scheme 42). The Ti(III) reagent coordinates both to the C=0 and CN groups and cyclization proceeds irreversibly without formation of iminyl radical intermediates.The oxidation of benzylic and allylic alcohols in a two-phase system in the presence of r-butyl hydroperoxide, a copper catalyst, and a phase-transfer catalyst has been examined. The reactions were shown to proceed via a heterolytic mechanism however, the oxidations of related active methylene compounds (without the alcohol functionality) were determined to be free-radical processes. 

Reaction at the C atom of nitronate salts is known with a variety of electrophiles, such as aldehydes (Henry reaction) and epoxides (191-193). Thus the incorporation of the nitro moiety and the cyclization event can be combined into a tandem sequence. Addition of the potassium salt of dinitromethane to an a-haloaldehyde affords a nitro aldol product that can then undergo intramolecular O-alkylation to provide the cyclic nitronate (208, Eq. 2.17) (59). This process also has been expanded to a-nitroacetates and unfunctionalized nitroalkanes. Other electrophiles include functionalized a-haloaldehydes (194,195), a-epoxyaldehydes (196), a-haloenones (60), and a-halosulfonium salts (197), (Chart 2.2). In the case of unsubstituted enones, it is reported that the intermediate nitronate salt can undergo formation of a hemiacetal, which can be acetylated in moderate yield (198). 

Polyhalogenated arenes can function as diaryne equivalents via the tandem sequence illustrated in Scheme lO.90-91 The predominant meta addition to aryne (59) can be ascribed to steric hindrance, while in addition to (58) both steric and electronic effects favor the observed regioselectivity. 

A recent modification of these reactions that appears to have significant potential in oiganic synthesis is a tandem sequence of alkyne insertion and cyclopropanation (Scheme 2).11S One particularly impressive, fully intramolecular case is shown in Table 7 (ref. 115). 

The addition of thiyl radicals to alkenes or alkynes to initiate tandem sequences has also been explored. A highly stereo-controlled phenyl thiyl radical addition, 10-endo macrocyclization, termination process has been used to furnish the macrocycle (37) from the dimethylacrylic ester (36).48 In other work the vinyl radical (38) fonned from addition of a thiyl radical to an enyne gives a mixture of the three products (39)-(41) formed either by 6-exo cyclization (39), addition into the aromatic ring followed by trapping with AIBN (40), or rearomatization and fragmentation to give the sulfide (41) (Scheme 15).49... 

A tandem sequence of double [2,3]-sigmatropic rearrangement-six-electron electro-cyclization-4 + 2-cycloaddition has been shown to convert acyclic ene-bis(propargyl alcohols) such as (71), via the corresponding bis-sulfenic ethers such as (72), into anthracene (with an intermolecular final cycloaddition) or phenanthrene or related (with an intramolecular cycloaddition) skeletons. The sequence is illustrated in Scheme 12 for synthesis of a steroid skeleton, estra-l,3,5(10)-trien-17-one (73).81... 

TABLE 12.9. Silver Delivers Only Poor Results in the Tandem Sequence... 

Takasu and coworkers reported the construction of the dodecahydrophenanthrene system (111) through the use of a B SnH-mediated 6-endo, 6-endo, 6-exo cascade process (equation 86)707, while Sha and coworkers described the total synthesis of (+)-paniculatine (112) by a tandem sequence involving a-carbonyl radicals (equation 87)710. 

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