Asymmetric reaction tandem cycloaddition

Dell C. P. Cycloaddition in Synthesis Contemporary Organic Synthesis 1997 4 87 Keywords natural products, metal catalyzed, asymmetric reactions, Ionic reactions, transannular reactions, tethered reactions, tandem reactions, benzo-qulnones, quinodimethanes, hefero-Dlels-Alder reactions... 

In summary, we have accomplished the first asynunetric total synthesis of crinipellin A along with the formal total synthesis of crinipellin B. The very unique tetraquinane core structure of crinipellins was constructed efficiently through a tandem cycloaddition reaction via TMM diyl. The absolute stereochemistry of crinipellins was also confirmed through our asymmetric total synthesis. 

Denmark advanced a strategy that involves tandem cycloaddition sequences with nitronates for the asymmetric synthesis of alkaloids [73, 74). A camphor-derived auxiliary permits the preparation of chiral enol ethers (cf. 68) as the reacting partners. A noteworthy example of the complex structures that could be generated by use of 68 is illustrated in Scheme 18.15. A hetero-Diels-Alder reaction between 68 and nitronate 67 generated 69 as a 96 4 mixture of endo/exo diastereomers. The adduct then participated in an intramolecular dipolar cycloaddition at elevated temperatures to yield cycloadduct 70 as a single diastereomer (90%). The tricyclic target 72 was obtained in 88 % yield after reductive removal of the chiral auxiliary and lactam formation [74]. 

This strategy was used to synthesize spirocyclopenteneoxindoles, as well as stereodefined cyclopentenes. Likewise, Hu reported a [3 -f 2] annulation reaction of 2-atylideneindane-l,3-diones with MBH carbonates that proceeded smoothly in the presence of a multifunctional thiourea-phosphine catalysts to produce the corresponding quaternary carbon centered spirocyclic cyclopentenes. A phosphine-triggered tandem [3 + 4] annulation reaction between MBH carbonates and 1,4-diheteroatom dinucleophiles was described, which provided access to saturated seven-membered 1,4-heterocycles. Analogously, MBH carbonates were used as C3 synthons in asymmetric [3 + 2] annulation reactions for the asymmetric synthesis of 3-spirocyclopentene-2-oxindoles. Another kind of annulation reaction for the construction of highly functionalized stereodefined cyclopentene skeletons involved a Rauhut-Currier Domino Reaction. Finally, an efficient asymmetric [3 + 2] cycloaddition reaction between MBH carbonates of isatins and... 

In recent years, the importance of aliphatic nitro compounds has greatly increased, due to the discovery of new selective transformations. These topics are discussed in the following chapters Stereoselective Henry reaction (chapter 3.3), Asymmetric Micheal additions (chapter 4.4), use of nitroalkenes as heterodienes in tandem [4+2]/[3+2] cycloadditions (chapter 8) and radical denitration (chapter 7.2). These reactions discovered in recent years constitute important tools in organic synthesis. They are discussed in more detail than the conventional reactions such as the Nef reaction, reduction to amines, synthesis of nitro sugars, alkylation and acylation (chapter 5). Concerning aromatic nitro chemistry, the preparation of substituted aromatic compounds via the SNAr reaction and nucleophilic aromatic substitution of hydrogen (VNS) are discussed (chapter 9). Preparation of heterocycles such as indoles, are covered (chapter 10). 

Whereas it is easy to foresee expanded application of nitronate cycloadditions in synthesis, important challenges still remain. For example, the potential of these reactions would benefit from the development of catalysts to accelerate the process. Moreover, asymmetric catalysis has only recently been successful in dipolar cycloaddition chemistry and would have a great impact here. Another important avenue would be the invention of new tandem processes that allow for the creation of nitronates from different precursors in the presence of dipolarophiles. 

Achiral ester-substituted nitrones as well as chiral nitrones can be employed in diastereoselective asymmetric versions of tandem transesterification/[3 + 21-cycloaddition reactions, as shown in Scheme 11.54 (174). High diastereoselectivity and excellent chemical yields have been observed in the reaction with a (Z)-allylic alcohol having a chiral center at the a-position in the presence of a catalytic amount of TiCl4- On the other hand, the reaction with an ( )-allylic alcohol having a chiral center at the a-position, under similar conditions, affords very low selectivities. Tamura et al. has solved this problem with a double chiral induction method. Thus, high diastereoselectivity has been attained by use of a chiral nitrone. 

A large number of catalytic asymmetric MCR are based on deoxo-bisubstitution reactions of carbonyl compounds such as the Mannich and Strecker reactions in which an oxo-group is displaced by two new cr-bonds, one to a nitrogen atom and one to a carbon atom. Other examples of deoxo-bisubstitutions include tandem processes that involve an initial Knoevenagel condensation followed by either a nucleophilic or a cycloaddition. These processes are characterized by the conversion of a C O-K-bond into two new C-C-cr-bonds and have been termed carba-acetalizations. 

The use of the zinc complex of the BINOL ligand 946 in the hDA reaction between Danishefsky s diene 947 and aldehydes proceeds in excellent yield and enantioselectivity to afford dihydropyran-4-ones 948 (Equation 370, Table 45) <2002OL4349>. An asymmetric diethyl zinc addition can occur in tandem with the cycloaddition reaction between Danishefsky s diene 947 and isophthalaldehyde using a related catalyst 949 (Equation 371) <20030L1091, 2005T9465>. 

The condensation of an imine with a Reformatsky-type reagent and tandem reactions can result in asymmetric induction.3-207-484 87 The reaction of a ketene with an electron-rich alkene results in a [2+2] cycloaddition, although other systems can also be used,488 90 The stereochemistry of the adduct is cis, and functionalized ketenes can also be used. The ketene can be generated in situ (Scheme 26.21).491... 

The choice of Lewis acid promoter for these reactions can change the sense of asymmetric induction. " For example, tandem [4 + 2]/ [3 + 2] cycloadditions (eq 4) mediated by Ti(0-i-Pr)2Cl2, followed by hydrogenolysis afforded tricyclic (-)-a-hydroxy lactam [(-)-8] in 98% ee. When mediated by methyl-aluminum-bis(2,6-diphenylphenoxide) (MAPh), the same reaction gave (+ )-8 in 93% ee. Importantly, the observed selectivity is not chiral auxiliary dependent. Rather, it is attributed to a highly endo selective cycloaddition in the case of Ti compared to high exo selectivity in the case of MAPh. 

Tandem pericyclic reactions are a powerful strategy for construction of complex, polycyclic compounds. In recent years tandem [4 + 2]/[3 + 2] chemistry of nitro-alkenes and nitronates has been developed by Denmark et al. as a general approach to functionalized pyrrolidine-containing structures [118]. Within the subclass of inter [4 -I- 2]/intra [3 + 2] cycloadditions, they have documented the fused mode (/3-tether, Eq. 77), spiro mode (a-tether, Eq. 78), and bridged mode (a-tether, Eq. 79 or /3-tether, Eq. 80) constructions. These are highly stereoselective processes in the presence of Lewis acid such as SnCU and are amenable to asymmetric modification by use of chiral vinyl ethers. Finally, the nitroso acetals are readily transformed, by hydroge-nolysis, into polycyclic, a-hydroxypyrrolidinones, 4-aminocyclohexanones, and cyclo-pentylamines. 

The isoquinuclidine ring system is readily accessible through various synthetic routes. The most widely used approach to the construction of the ISQ ring system is through Diels-Alder or 4+2 cycloaddition reactions. Dihydropyridines (DHPs) or 1,3-cyclohexadienes are most commonly employed as diene components and various dienophiles have been employed based on the substitution pattern of the final desired product. Intramolecular cyclizations, tandem-Michael addition/aldolizations or cyclization via tricyclic aziridines or perhydro / -aminobenzoic acid derivatives have also been reported. Several synthetic routes employing asymmetric or chiral synthetic approaches have also been reported. Most recently, solution-phase parallel synthesis of ISQ derivatives using several of these approaches has been reported [49,50,51]. 

The synthesis of seven-membered rings from furans and a,a -dibromoketones via oxyallyl intermediates is well known. It was reported that this reaction occurs quite easily when water is used as solvent <97TL8031>. In a study on the influence of steric and electronic effects on a function attached at C-2 of furans in the yield and diastereoselectivity of [4 + 3] cycloaddition reactions with oxyallyl cations it was found that in almost all cases a c/x-diastereospecificity and a high endo diastereoselectivity is obtained <97T11669>. A tandem Peterson olefination-[4 + 3] cycloaddition reaction with furans has been reported <97JOC1578 97TL386l>. For an intramolecular [4 -t- 3] cycloaddition see <97JOC6051>. The first asymmetric [4 + 3]... 

Muthusamy S, Gunanathan C et al (2004) Regioselective synthesis of mono- and bis-decahy-drobenzocarbazoles via tandem reactions of a-diazo ketones. Tetrahedron 60 7885-7897 Nambu H, Hikime M et al (2009) Asymmetric approach to the pentacyclic skeleton of aspidosperma alkaloids via enantioselective intramolecular 1,3-dipolar cycloaddition of carbonyl ylides catalyzed by chiral dirhodium(II) carboxylates. Tetrahedron Lett 50 3675-3678... 

Glucosamine-derived imines 58 were used for the synthesis of carbapenem and carbacephem antibiotics. [2 + 2] Cycloaddition with methoxyacetyl chloride provided diastereomeric S-lactams with low asymmetric induction [56]. Radical cyclization and oxidation reactions of diastereoisomer 59 led to car-bapenems 60 and 61 (Scheme 16) [57]. The same research group continued the transformation of S-lactams derived from o-glucosamine. In particular, a tandem ehmination-conjugate addition performed on 62 provided the second ring of the carbacephem, for example 63 (Scheme 17) [58]. 

The same research group has also demonstrated a catalytic enantioselective tandem carbonyl yhde formation-cycloaddition of the a-diazo-j8-ketoester 91 using 0.5 mol% of Rh2(R-DDBNP)4 95, as catalyst to afford the cycloadduct 93 in good yields (Scheme 28) with up to 90% ee [ 109]. A detailed study on enantioselective reaction using a series of dirhodium tetrakiscar-boxylate and tetrakisbinaphtholphosphate catalysts under different solvent conditions has been described [56]. These studies indicate that dirhodium tetrakisbinaphtholphosphate catalysts are superior to the more commonly used carboxylates and carboxamidates in asymmetric transformations. Typically, the reaction [58] of the nitrophenyl-substituted diazodione 96 and phenyl acetylene in the presence of the binaphthyl catalyst 95 at 0 °C afforded the cycloadduct 97 with 76% ee (Scheme 29). 

P(p-FC6H4)3-catalyzed tandem reaction between ethyl-2,3-butadienoate and nitroalkenes leads to substituted cyclopentenes (Scheme 6.6). The reaction involves a [3-f2] cycloaddition and a subsequent umpolung addition. The asymmetric version of this tandem reaction can be achieved by using chiral phosphine, that is, (/ )-2,2 -bis(diphenylphosphino)-1,1 -binaphthyl (Binap) [8],... 

This synthetic feat relies on an asymmetric Michael/Michael/Henry tandem sequence, resulting in a formal [24-24-2] cycloaddition. The generation of a chiral copper enolate, which undergoes two successive Michael additions on two nitroalkenes followed by ring closure with a Henry reaction, generates the expected adduct in a highly enantio- and diastereoselective manner (Scheme 7.14). 

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