Intramolecular 3+21 cycloaddition aldol reaction

Deslongchamps and coworkers [26] used a combination of a transannular Diels-Alder cycloaddition and an intramolecular aldol reaction in the synthesis of the unnatural enantiomer of a derivative of the (+)-aphidicolin (4-74), which is a diterpe-noic tetraol isolated from the fungus Cephalosporium aphidicolia. This compound is an inhibitor of DNA polymerase, and is also known to act against the herpes simplex type I virus. In addition, it slows down eukaryotic cell proliferation, which makes it an interesting target as an anticancer agent... 

A total synthesis of functionalized 8,14-seco steroids with five- and six-membered D rings has been developed (467). The synthesis is based on the transformation of (S)-carvone into a steroidal AB ring moiety with a side chain at C(9), which allows the creation of a nitrile oxide at this position. The nitrile oxides are coupled with cyclic enones or enol derivatives of 1,3-diketones, and reductive cleavage of the obtained cycloadducts give the desired products. The formation of a twelve-membered ring compound has been reported in the cycloaddition of one of the nitrile oxides with cyclopentenone and as the result of an intramolecular ene reaction, followed by retro-aldol reaction. 

In order to gain more insight into this proposed mechanism, Montgomery and co-workers tried to isolate the intermediate metallacycle. This effort has also led to the development of a new [2 + 2 + 2]-reaction.226 It has been found that the presence of bipyridine (bpy) or tetramethylethylenediamine (TMEDA) makes the isolation of the desired metallacycles possible, and these metallacycles are characterized by X-ray analysis (Scheme 56).227 Besides important mechanistic implications for enyne isomerizations or intramolecular [4 + 2]-cycloadditions,228 the TMEDA-stabilized seven-membered nickel enolates 224 have been further trapped in aldol reactions, opening an access to complex polycyclic compounds and notably triquinanes. Thus, up to three rings can be generated in the intramolecular version of the reaction, for example, spirocycle 223 was obtained in 49% yield as a single diastereomer from dialdehyde 222 (Scheme 56).229... 

Chiral Auxiliary for Asymmetric Induction. Numerous derivatives of (—)-8-phenylmenthol have been utilized for asymmetric induction studies. These include inter- and intramolecular Diels-Alder reactions, dihydroxylations, and intramolecular ene reactions of a,p-unsaturated 8-phenylmenthol esters. These reactions usually proceed in moderate to good yield with high diastereofacial selectivity. a-Keto esters of 8-phenylmenthol (see 8-Phenylmenthyl Pyruvate) have been used for asymmetric addition to the keto group, as well as for asymmetric [2 -F 2] photoadditions and nucleophilic alkylation. Ene reactions of a-imino esters of 8-phenylmenthol with alkenes provide a direct route to a-amino acids of high optical purity. Vinyl and butadienyl ethers of 8-phenylmenthol have been prepared and the diastereofacial selectivity of nitrone and Diels-Alder cycloadditions, respectively, have been evaluated. a-Anions of 8-phenylmenthol esters also show significant diastereofacial selectivity in aldol condensations and enantiose-lective alkene formation by reaction of achiral ketones with 8-phenylmenthyl phosphonoacetate gives de up to 90%. ... 

Copper-catalysed Michael addition followed by an aldol reaction with formaldehyde, gives a 1 1 mixture of diastereoisomers of the aldol 86 that can be eliminated to the enone 83. The resulting efficient photochemical cycloaddition gives ketone 82 with total regioselectivity probably because it is intramolecular. 

Scheme 7.2 Some reaction types which are characterized by large, negative volumes of activation (a) Diels-Alder and other cycloaddition reactions, including heterocyclic and intramolecular examples (b) ionogenic reactions, such as Menshutkin quaterniza-tions (c) additions to double bonds, for example, aldol reactions, Wittig reactions and, chiral-borane reductions (in the last type of reaction, pressure both accelerates the reduction and retards decomposition of the Alpine borane to achiral 9-BBN) (d) sequential...

Snider s approach through 1,3-dipolar cycloaddition and intramolecular aldol reactions... 

Many examples of guanidine base-promoted nitro aldol reactions [1] and their application to the synthesis of natural products have been reported. Ishikawa et al. synthesized (- -)-cyclophelhtol (14), an a-glucosidase inhibitor and also a potential inhibitor of HIV, via the intramolecular 1,3-dipolar cycloaddition reaction of silylnitronate 13. In this synthesis, nitroalcohol 12 was prepared by the reaction of aldehyde 11 with nitromethane in the presence of TMG (3) as a 2 1 diastereomeric mixture [2] (Scheme 7.1). 

The oxazolinone 107, a new recoverable chiral auxiliary that gives a high level of asymmetric induction in model aldol reactions and Diels-Alder cycloadditions (in which the reactant is connected to the auxiliary by -acylation), has been synthesized from L-gulonic acid. The key step in its synthesis was the thermal intramolecular nitiene insertion shown in Scheme 21. The formation of oxazolinethiones on hydrolysis of isothiocyanato-sugar derivatives is covered in detail in Chapter 9, section 3.3. Base-catalysed reaction of StS-O-isopropylidene-D-xylofuranosylamine with P-isothiocyanato-alkanals led to tricyclic derivatives such as 108, considered as cyclonucleoside analogues. ... 

The catalytic cycle of this NHC-catalyzed reaction originates by the addition of the NHC to the vinylketene 39, which in turn was created from the acyl chloride 43 in basic media, to afford the diene A as an intermediate (Scheme 17). The diene A and ketone 47 are subjected to hetero—Diels—Alder (HDA) cycloaddition reaction or undergoes a stepwise vinylogous aldol reaction with intramolecular cyclization to afford the zwitterionic B. The breakdown of zwitterionic B gives the dihydropyra-none 48 and recreates the NHC catalyst (Scheme 17) (2011MI1943). 

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. ... 

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