Cycloheptanes, cycloaddition

A review of intramolecular 4 + 3-cycloadditions of allyl cations has been presented.277 The 4 + 3-cycloaddition reaction of C(2)-substituted furans with 1,3-dimethyloxyallyl cations show high endo diastereoselectivity and a cis dia-stereospecificity.278 The tandem Peterson olefination/[4 + 3]-cycloaddition of tertiary alcohols (149) in the presence of filran and Lewis acids (TiCLt) furnishes cycloheptanes (150) in modest yields (Scheme 57).279 (Trimethylsilyl)methyl allylic sulfones (151) were used to investigate the scope and limitations of intramolecular 4 + 3-cycloadditions of allylic sulfones (Scheme 58).280 Lewis acid-catalysed 4 + 3-... 

From another viewpoint, the value of the arene-alkene meta cycloaddition arises from its capacity to produce a cycloadduct (66 equation 14) with three new rings and up to six new stereocenters, an impressive feat even when compared with the highly regarded Diels-Alder cycloaddition. Moreover, the cycloadduct can be used in the synthesis of a variety of commonly encountei structural types including cyclopentanes, cycloheptanes, bicyclo[3.2.1]octanes and bicyclo[3.3.0]octanes. While fr uently overlooked in some discussions of reaction classification, the overall processes leading to cycloheptanes, bi-cyclo[3.2.1]octanes and bicyclo[3.3.0]octanes are clearly classifiable as [5C + 2C], [3C + 2C] and [3C + 2C] cycloadditions, respectively. Examples of these types will be given in the following section. 

A single example is known for a palladium(0)-catalyzed cotrimerization reaction involving two molecules of an alkene and a methylenecyclopropane molecule, leading to the formation of a seven-membered-ring product.The reaction is limited to unsubstituted allene and, along with the cyclotrimer, l,3,5-tris(methylene)cycloheptane (3), 1,3-bis(methylene)cyclopen-tane (2), the product of a [3 + 2] cycloaddition, is also obtained. The product ratio 2/3 is markedly dependent on the catalyst composition. Additionally, the allene trimer, 1,2,4-tris(methyl-ene)cyclohexane (4), and the methylenecyclopropane homodimer, 5-methylenespiro[2.4]hep-tane (5), are formed. 

In another example, a [3+2] cycloaddition leads to the concomitant formation of a highly substituted cycloheptane (Eq. 48)7 ... 

Recently, Cdrdova and co-workers revealed a regiospecific, highly chemo-, diastereo-, and enantioselective one-pot organocatalytic domino reaction of a, 3-unsaturated aldehydes 269, aromatic aldehydes 106, and phenylhydroxyamine 265, providing cycloheptane derivatives 270, Scheme 3.86 [109]. The tandemmulti-component [2+3]/[3 + 2] cycloaddition afforded six new bonds and five new... 

Some natural products outside the carbohydrate field - particularly those with highly hydroxylated cyclohexane ring components - have been subject to synthetic studies which are dependent on the mercury-based rearrangement reaction the alkaloid (+)-lycoricidine (30) [12] and the cycloheptane-based (+)-calystegine 62(31) which stimulates growth of nitrogen-fixing Rhizobia [29] are examples, and compound 32 which offers novel access to the anthracyclinone components of anthracyclin anti-cancer compounds, has been produced by cycloaddition of a naphthalene-based o-xylylene to a 2,3-unsaturated hex-4-uloside followed by carbocyclization of the product by use of the mercuration procedure [30]. Studies on HMG-CoA reductase inhibitors like compactin have afforded the tetra-carbon-substituted 33 made from a hex-5-enopyranoside with deoxy-branch chains at C-2, C-3 and C-4 [31]. 

The application of the TBCP furan cycloaddition chemistry to the platen-simycin system highlights the ability to directly access the oxa-bridged core foxmd in these natural products. In a second application, we describe how opening of the oxa-bridge can lead to the highly substituted cycloheptane ring found in the marine natural product frondosin A. 

A variety of synthetic studies focused on clinical CNS candidate 1 are described. The original medicinal chemistry route (Scheme 1) is described, and issues which precluded its scale-up are discussed. An Ullman route to 2-fluoro-4-methoxyaniline (Scheme 4) was developed to avoid a non-selective nitration reaction. The first GMP bulk canpaign utilized a ring expansion strategy via a dichloroketene [2+2] cycloaddition (Scheme 6) to prepare cycloheptane-1,3-dione. While effective on laboratory scale, several issues arose upon scale-up the mechanistic basis for these issues was determined to be competition between desilylation and dechlorination of dichlorocyclobutanone 22 (Scheme 11). These issues led us to develop a third synthesis of 1, in which c3reloheptane-1,3-dione is avoided. Two variants of this Friedel-Crafts strategy are described (Schemes 13 and 14). 

The Influence of Dienophile Structure on Reactivity and Stereoselectivity in Tandem Cycloadditions of 1,3,4-0xadiazoles The best dienophiles for the tandem cycloadditions of 1,3,4-oxadiazoles are electron-rich, unhindered, and strained alkenes. These components are used in excess because they also serve as the dipolarophiles in the next step. The yields are often moderate, probably, due to the harsh reaction conditions. Thus, cyclopentene reacts with oxadiazole 440 (Scheme 16.88) to provide the oxabi-cycloheptane derivative 443 in 33% yield [167a]. The product configuration has been established as synlanti with respect to the oxygen atom bridge. It is not clear which of the two steps ([4 + 2] or [3 - - 2]) produced which relationship. Ethylene has also been used as the dienophile in the earliest report. 

Siloxyallyl cations are comparatively reactive and electrophilic, and their cycloadditions proceed under mild reaction conditions and at low temperatures, being sufficiently reactive to be trapped by dienes. These conditions can accommodate various preexisting functionalities in the substrate molecule and thus exhibit a good potential and compatibility to be adapted to building cycloheptane substructures in complex natural product syntheses. These advantages merit the arguable extra step to prepare the enolsilanes for [4+3] cycloaddition reactions. 

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