Cycloaddition precursor cyclobutanes

Intramolecular [2 + 2 + 2] cycloadditions belong to the same type of valence isomerization as those of 1,5-unsaturated compounds to cyclobutanes.70 The cobalt-mediated cyclization of l-en-5-ynes stereoselectively converts enediynes directly to bicyclo[4.2.0]hexa-l,3-dienes, as single diastereomers, when a stoichiometric amount of dicarbonyl(cyclopentadienyl)cobalt is used. This cyclization90 has a high efficiency (92%). An example is the synthesis of the protoilludane framework 23 from the enediyne precursor 22.71... 

During the synthesis of the Woodward reseipine precursor (17 Scheme 4), Peariman used the protected acylacetal (13) to control the stereochemistry of an intramolecular photocherrucal cycloaddition to (14). The strategy for opening the cyclobutane ring employed the Baeyer-Villiger reaction to convert the... 

Cyclobutanes may be converted to alkenes thermally, the reverse of the [2 + 2] cycloaddition reaction. These retroaddition or cycloreversion reactions have important synthetic applications and offer further insights into the chemical behavior of the 1,4-diradical intermediates involved they may proceed to product alkenes or collapse to starting material with loss of stereochemistry. Both observations are readily accommodated by the diradical mechanism. Generation of 1,4-tetramethylene diradicals in other ways, such as from cyclic diazo precursors, results in formation of both alkenes and cyclobutanes, with stereochemical details consistent with kinetically competitive bond rotations before the diradical gives cyclobutanes or alkenes. From the tetraalkyl-substituted systems (5) and (6), cyclobutane products are formed with very high retention stereospecificity,while the diradicals generated from the azo precursors (7) and (8) lead to alkene and cyclobutane products with some loss of stereochemical definition. ... 

Formation of the ester cyclization precursor 92 was readily achieved as a 1 1 mixture of diastereoisomers and, upon irradiation, afforded a 1 1 mixture of cyclobutanes 93 differing only in the stereochemistry of the silyloxy substituent. The tether had therefore controlled both the regio- and stereoselectivity of the cycloaddition event. Subsequent manipulations afforded the desired natural product (Scheme 10-30). 

The fused cyclobutane derivatives produced via the above cycloaddition reactions have been utilized as synthetic precursors for the preparation of indole-2-acetonitriles (Scheme 6) [23]. First, the acetyl-substituted cyclobutanes 28 were converted to the cyclobutanone derivatives 29, which were in turn treated with hydroxylamine to provide the corresponding oximes. Beckmann fission of oximes 30 in the presence of thionyl chloride then produced the l-benzoylindole-2-aceto-nitrile derivatives 31 in good yield. 

A particularly good route to four-membered rings is via a (2-i-2]-cycloaddition. With a suitably functionalized precursor, this is a good method for preparing amino-cyclobutane amino acids. Reaction of enamine 7319 (derived from isobutyraldehyde)... 

Variations on the theme of [2 + 2]cycloaddition reactions as a route to cyclobutanes continue to be developed. 1,2-Diynylcyclobutanes (29) can be prepared by triplet-sensitized photochemical dimerization of the corresponding enynes in general, this method cannot be used for the efficient synthesis of more highly substituted cyclobutanes. Similar photochemical methods have also been used to prepare a range of substituted ci5-l,2-diaminocyclobutanes (30), and the tricyclic compounds (31), which can serve as precursors to the tricyclo[4.2.0.0 ]octanes (32) via the Wolff rearrangement. ... 

Synthesis of a Polysubstituted Bicyclobutane - To broaden our collection ot bicyclobutane monomers, we have e qplored the utility of zwitterionic cycloaddition reactions to synthesize the required cyclobutane precursors. Such reactions of electron-rich olefins with electron-poor olefins were studied by Brannock and coworkers (19). To obtain substituents at the proper locations on the cyclobutane ring, we used trisubstituted electrophilic olefins (20) in the following reaction sequence ... 

The first models for asymmetric induction in [2 + 2] cycloadditions are ketimines derived from precursors such as (25), which react with both cyclic and acyclic alkenes to give adducts with high enantiomeric excesses. Full details have been reported on the regio- and stereo-specificity of the addition of dichloroketene to 1-substituted cyclohexenes. Methyl (phenylthiomethyl)-ketene (26) provides a further example of a ketene which, after cycloaddition to cyclopentadiene, undergoes facile opening of the cyclobutane that is thus formed to provide vicinally substituted cyclopentene derivatives. ... 

Irradiation of cyclohexene in the presence of CuOTf produces the dimers 14 (49%) and 15 (8%), along with the cyclohexylcyclohexene 16 (24%) (Scheme 5)T The stereochemical outcome in Cu(I)-catalyzed dimerization of cyclohexene may be the result of cis-tram isomerization on irradiation of the initially formed Cu(I)-cyclohexene complex to the trans-cyclohexene-CuOTf complex 13, followed by a concerted ground state 2 + 2 cycloaddition of the highly strained tram-cyclohexene to another cyclohexene. Cycloheptene, on the other hand, produces the aU tra s-fused trimer 17 (Scheme 6) as the sole product. A 1 3 CuOTf-trans-cycloheptene complex has been proposed to be the precursor of this product. No dimerization reaction has been observed for cyclooctene and acychc olefins.However, mixed photocycloaddition occurs with cyclooctene if the other olefin is sufficiently reactive. Thus, cyclooctene adds to norbornene to produce the cyclobutane derivative 18 in 40% yield. GDdimerization was also observed when a mixture of cyclohexene and cycloheptene was irradiated in the presence of CuOTf to yield the adduct 19 (Scheme 6). ... 

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