Cycloaddition precursor reaction

The total synthesis of biotin (1) described in this chapter provides an impressive example of the intramolecular nitrone-olefin [3+2] cycloaddition reaction. Aiming for a practical process, the Hoff-mann-La Roche group utilized relatively simple and inexpensive starting materials, and ingeniously controlled the crucial [3+2] cycloaddition reaction to give only one stereoisomer by confining the cycloaddition precursor to a ten-membered ring. 

Dauben s group utilized the same retrosynthetic disconnections, but chose to add more functionality to the cycloaddition precursor. From a simple frawi-disubstituted cyclopentane, Dauben used an aldol reaction of a cyclopropylvinyl aldehyde to prepare the cycloaddition precursor. The diazo-substituted (3-ketoester was completed using a Roskamp-Padwa coupling followed by diazo-transfer. Addition of rhodium acetate to the diazo substituted p-ketoester 179 led to an excellent 86% yield of the correct diastereomer (Scheme 4.42). 

Another attractive method for E ring formation featured an intramolecular [2+3]cycloaddition of an azide moiety, emanating from the indole 3-position via a two-carbon linker, to, now, an electron-rich version of the C15-C16 double bond.19 The cycloaddition precursor 10 was made via 9, in turn assembled by regioselective cocylization of protected methoxyacetylene (Scheme 5). In a puzzling turn of events, thermolysis of the azide product in toluene at moderate temperature (to minimize nitrene formation) and in low concentration (to suppress intermolecular reactions) produced the two oxidized pentacyclic products 11 and 12 in a 2 1 ratio. Performing the reaction in a more polar solvent (DMF, 80 °C, 7 d) altered the ratio to 5 1.20... 

The various heterocyclic ligands just described are easily cleaved from the respective molybdenum centers either by reaction with sulfur or through ligand exchange with l,2-bis(diphenylphosphino)ethane (Scheme 17).44a The Diels-Alder cycloaddition is successfully expanded to transient 1-phospha-1,3-diene complexes such as 25 and suitable dienophiles. As illustrated in Scheme 12, the isomeric 1,2-dihydrophosphetes (e.g., 26) are their masked stable precursors. Reaction of 26 with dimethyl acetylenedicarboxy-late or with benzaldehyde furnishes the Diels-Alder adducts of transient 25, compound 71, as a mixture of two isomers, and isomerically pure 72.44b (See Scheme 18.)... 

Photochemically induced [2 + 2] cycloaddition is of extraordinary importance in organic synthesis,as this is a method ideally suited for the preparation of sterically congested compounds. The reaction may occur by a concerted mechanism allowed by rules of orbital symmetry, or, more often, via a biradical pathway. For preparative purposes, the most widely exploited is the enone-alkene photochemical [2 + 2] cycloaddition. This reaction proceeds with high regioselectivity, although its stereoselectivity might be low. The first example of the utilization of this reaction for the synthesis of a natural compound, a-cariophyllene 385, was described by Corey (Scheme 2.129). Adduct 386, formed as a mixture of stereoisomers in high yield from simple precursors, was further transformed via the tricyclic intermediate 387 into the... 

The total synthesis of (+)-cyclophellitol containing a fully oxygenated cyclohexane ring was accomplished by T. Ishikawa and co-workers. The synthetic strategy was based on the intramolecular silyl nitronate [3+2] cycloaddition reaction. The cycloaddition precursor was prepared by the Henry reaction starting from a D-glucose-derived aldehyde. 

In the laboratory of S.F. Martin, a biomimetic approach toward the total synthesis of ( )-strychnine was developed by using tandem vinylogous Mannich addition and HDA reaction to construct the pentacyclic heteroyohimboid core of the natural product.The commercially available 4,9-dihydro-3/-/-P-carboline was first converted to the corresponding A/-acylium ion and then reacted with 1-trimethylsilyloxybutadiene in a vinyiogous Mannich reaction. The resulting cycloaddition precursor readily underwent the expected HDA reaction in 85% yield. 

Apart from the utilization of aryl- and vinyl-diazoacetates that can achieve the moderate to high chemo-, regio-, and enantioselectivity in intermolecular asymmetric C—H bond insertion reactions, Af-sulfonyl-l,2,3-triazole 11 was found to be able to function as an alternative carbene precursor for diverse transformations (Scheme 1.4). One advantage for using the N-sulfonyl-1,2,3-triazole is that it could be easily prepared by the Cu -catalyzed azide-alkyne cycloaddition (CuAAC) reaction, and in some cases, delicately designed reactions can be conducted in a one-pot procedure starting from alkynes and sulfonyl azides. Moreover, since there exists an inherent equilibrium... 

Direct Wittig reaction of Ph PCHCOn,Me with the four unsubstituted D-aldopentoses followed by acetylation provides convenient preparative access to acyclic seven-carbon trans-2.3-unsaturated sugar derivatives. These products served as dienophiles for a detailed comparative study in Diels—Alder cycloaddition with cyclopentadiene. Related syntheses afforded analogous cis-dienophiles. Cycloaddition under uncatalyzed thermal conditions gave mixtures of the four possible stereoisomeric norbornene adducts. The endo, exo ratios, and diastereofacial selectivities of the adducts were determined by NMR spectroscopy and by chemical transformations, supplemented by selected X-ray crystallographic analyses. Different distributions of isomers were encountered when a Lewis acid was used to catalyze the cycloaddition. The reaction can be controlled to provide preparative access to selected isomers and thus constitutes a versatile method for chirality transfer from the precursor sugar to four new asymmetric centers in a carbocyclic framework. 

Enders described a fascinating organocatalytic one-pot asymmetric synthesis of tricyclic compounds using a triple-cascade/Diels-Alder reaction sequence. Combination of dieneal 110 with enal 111 and nitro alkene 112 in the presence of a chiral amine catalyst results in a Michael/Michael/aldol condensation sequence to yield cycloaddition precursor 113. Cooling the reaction mixture and addition of a Lewis acid promotes the desired intramolecular Diels-Alder reaction to selectively afford the highly functionalized tricyclic target 114. ... 

Nitrogen-containing heterocycles are also available via intramolecular hetero Diels-Alder reactions. Williams employed an aza diene to prepare a complex polycyclic synthetic intermediate in his synthesis of versicolamide B. Boger reported a tandem intramolecular hetero Diels-Alder/l,3-dipolar cycloaddition sequence for the synthesis of vindorosine. Cycloaddition precursor 137 undergoes an inverse electron demand Diels-Alder reaction to yield 138. This compound decomposes via a retro dipolar cycloaddition to generate nitrogen gas and a 1,3-dipole that completes the cascade by reacting with the indole alkene to afford 139. Seven more steps enable the completion of vindorosine. ... 

S2Sa. Since the imine 525b was not a precursor of the cyclazine 524, it was concluded that C-S bond breaking must precede C-C and C-N bond formation, as would be the case if 3,5-didehydroimidazo[l,5-a]pyridine (525c) were an intermediate. An alternative explanation involving a [2-h8] cycloaddition of the reactants followed by elimination of lithium thioethoxide was also considered, however, but has not yet been disproven. Precedent for such cycloaddition-elimination reactions exists in the closely related pyrrocoline system. ... 

One application of this reaction was in the synthesis of yohimban 11.17 (Scheme 11.6). The cycloaddition precursor 11.14 could be easily built up from tryptamine 11.13 and the cyclization employed a nickel/phosphite catalyst system. Selective reduction of the less-hindered alkene, protio-desilylation and a Bischler-Napieralski reaction gave the desired pentacyclic system 11.16. Reduction of the remaining alkene gave yohimban 11.17... 

Mention should also be made of the modular synthesis of block copolymers by the so-called cKck chemistry, designed for instance by Opsteen and van Hest [68]. These authors prepared a large variety of block copolymers via a high yield 1,3-dipolar cycloaddition coupling reaction of terminal azide and alkyne precursor blocks as illustrated in the following scheme ... 

From the chiral epoxide 56, the TMM cycloaddition precursor 55 for construction of the tetraquinane stmcture was prepared in a straightforward manner. Oxidation of epoxy alcohol 56 by the Swem protocol followed by treatment with Bestmann-Ohira reagent (E) produced alkyne 70. Iron-catalyzed Sisr2 -type reaction of 70 afforded an allene moiety as a diastereo-meric mixture in a 1 1 ratio and this mixture was used in the next step without the separation of isomers. Allenyl alcohol 71 was protected as a TBDPS ether to give 0-silylated allene 72. Deprotection of the acetal of 72 was delicate as the allenyl moiety was not stable under acidic condition. Fortunately, treatment of 72 with p-toluenesulfonic acid monohydrate in presence of formaldehyde afforded aldehyde 73, and subsequent treatment with p-toluene sulfonyUiyrazide furnished the precursor 55 for the tandem cycloaddition reaction (Scheme 21). 

The model studies demonstrated that an exo-(tether)-[4-1-2] cycloaddition on the a-unsubstimted nitroalkene, and the construction of the piperidine ring are possible. In the next stage of the synthesis the elements needed to create rings A, D, E, and F were installed in a suitable precursor. Thus, enantiopure nitroalkene (S)-165 (prepared as a 5/1 mixture of nitroalkene isomers, Scheme 16.83) [47, 147] undergoes tandem, double-intramolecular [4 + 2]/[3- -2] cycloaddition in the presence of SnCLj to provide an inseparable mixture of nitroso acetals 167. Assuming that the substrate does not isomerize prior to the [4 + 2] cycloaddition, the reaction proceeds via the cnt/o-(tether)-transi-tion stmcture. Calculations suggest that the reaction is... 

The use of preformed enolsilane derivatives for generating oxyallyl cation species not only allows reactions to proceed at higher rates and lower temperatures, but also provides cycloaddition precursors of a controlled constitution and defined enol ether geometry, which would impact the reaction stereochemical outcome. The generation and cycloaddition of a lithium oxyallyl from dichloroketone 12 results in all four possible diastereomeric cycloadducts... 

Acylisocyanates or isothiocyanates undergo cycloaddition with 5-hydroxy-THISs under so mild conditions that isolation of the initial adducts becomes possible (23). In cycloaddition reactions the 5-hydroxy-THISs can be replaced by their precursors (23). 

Miscellaneous Reactions. Some hydantoin derivatives can serve as precursors of carbonium—immonium electrophiles (57). 5-Alkoxyhydantoins are useful precursors of dienophiles (17), which undergo Diels-Alder cycloadditions under thermal conditions or in the presence of acid catalysis (58). The pyridine ring of Streptonigrine has been constmcted on the basis of this reaction (59). 

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