Spiro-cyclopropanes, synthesis

A new selective thermal cascade ring-enlargement process of 4-chloro-substituted spiro[cyclopropane-l,5 -isoxazolidines], leading to a new method for the synthesis of the indolizine skeleton, has been reported (see Scheme 17). Apparently, the process is made possible by the presence of a chlorine substituent on the carbon a to the spirocyclopropane ring which facilitates a cyclopropyl-to-cyclobutyl ring enlargement mediated by a polar solvent. 

Meijere et al. [117] group have investigated the direct synthesis of 3-spiro-cyclopropanated p-lactams 184 (Scheme 43) using novel three-component cascade reaction. Earlier, Alberto Brandi and coworkers [118-120] have applied nitrones 181 and bicyclopropylidene 182 to obtain cylcoadducts 183, which were further fragmented under acidic conditions to afford spiro-p-lactams 184. However, this reaction required longer reaction time for the formation of cycloadducts 183. 

Synthesis and properties of nitrogen heterocycles containing a spiro cyclopropane fragment 00UK507. 

Very recently the synthesis of derivatives which incorporated a spiro-cyclopropyl group at N-1 by bridging to C-2 was reported [53]. The fused spiro-cyclopropane ring was obtained through an intramolecular addition of Grignard reagent, as shown in Fig. 20. 

A total synthesis of strychnofoline (277), a bisindole constituted from the union of a tetracyclic oxindole and a tryptamine unit, and previously isolated from S. usambarensis (165), has been recently reported (166). A key feature of the synthesis is the convergent assembly of the tetracyclic core containing the oxindole moiety 276 through the ring-expansion reaction of a spiro[cyclopropan-l,3-oxin-dole] 274 and a cyclic imine 275, as shown in Scheme 21. 

The full details of oxa-bis- and oxa-tris-a/ic-homobenzene syntheses, cw-aza-bis-and cis-aza-tris-a-homobenzene and cis-aza-tris-a-homotropilidene synthesis, and the decomposition of spiro[fluorene-9,3 -indazole] have become available, and there have been a number of routine applications of pyrazoline decomposition for cyclopropane synthesis. ... 

The use of the Simmons-Smith reaction of allenes provides an efficient synthesis of novel spiro cyclopropanes. The use of chiral oxazolidinone-attached allenes 89 afforded chiral spiro[2.2]pentanes 90 and 91 (Scheme 1.48) [82]. 

A second common reaction of sulphonium ylides is Michael addition to ajS-unsaturated carbonyl compounds, giving cyclopropanes. This reaction forms the basis of a cyclopentene synthesis starting from sulphonium allylide (14). Other recent examples include the preparation of spiro[cyclopropane-l,4-A -pyrazolin]-5 -one derivatives (15) and cyclopropyl-ulose (16). Un-... 

Keywords Absolute configuration, Amines, Amino acids, Carbenes, Cascade reactions, 2-chloro-2-cyclopropylideneacetates. Combinatorial libraries. Cycloadditions, Cyclobutenes, Cyclopropanes, Diels-Alder reactions. Heterocycles, Michael additions. Nitrones, Nucleophilic substitutions, Peptidomimetics, Palladium catalysis. Polycycles, Solid phase synthesis, Spiro compounds. Thiols... 

Chmielewski and colleagues reported a Bu3SnH-mediated radical-induced isoxazoli-dine-isoxazolidin-5-one transformation (equation 99)778, while Sulsky and coworkers described conformational switching in the synthesis of a spiro[2H-indol]-3(lH)-ones (e.g. 122) by radical cyclization, an example of which is depicted in equation 100787. In this final example, Takekawa and Shishido described the selective cleavage of substituted cyclopropanes via stannane-induced radical fragmentation, an example of which is illustrated in equation 101791. 

Reductive dehalogenation is an efficient method of synthesis of cyclopropanes spiroannulated to five- and higher-membered carbocycles (i.e. compounds in which spiroannulation does not result in accumulation of extra strain) . The required gem-(dihalomethyl)cycloalkanes are usually prepared by halogenation of the precursor diols (equation 1). The cyclization is most efficiently accomplished in the Zn-alcohol-water system . For example, spiro[2.5]octane 7 was prepared in 91% yield using this procedure. This method is useful even for a one-step preparation of bis-spirocyclopropyl compounds as exemplified in equation 2. However, the application of the reductive dehalogenation method to the synthesis of more strained SPC (i.e. spirohexane or spiropentane) often leads to rearranged products. For example, methylenecyclopentane was the only product obtained from bis(bromomethyl)cyclobutane (equation 3) ... 

Compound 1 did not react with unstimned internal olefins such as tetramethylethylene, /ra s-3-hexene, tram-stilbene, cyclooctene, cyclohexene, or cyclopentene. But imposing strain to the olefinic moiety resulted in a clean silylene transfer to the double bond Norbomene formed with 1 the tricyclic silacyclopropane 6. Whereas 2 did not add to the double bond of 7, methylene cyclopropane 8 could be transformed into spiro[2.2]pentane 9 by reaction with 1. Addition of 2 to bicyclopropylidene allowed the convenient synthesis of dispiro[2.0.2.1]heptane 10 in a quantitative manner. 

With regard to the reagents used in this type of cyclopropanation, 1,2-dibromoethane has been used most frequently. l-Bromo-2-chloroethane, however, may give better yields in some cases. 2-Chloroethylsulfonium iodide is used in the reaction of cyclic ketones to give the spiro derivatives . The use of vinylogous derivatives of 1,2-dihalides allows a synthesis of vinylcyclopropanes (equation 89) . (Chloromethyl)oxirane provides substituted cyclopropylmethanols (equation Oxiranes may also be used in place of... 

In this kind of cyclopropane ring-opening olefins are currently generated by elimination. An approach to spiro-vetivones and a synthesis of indole alkaloids (equation 48) take advantage of this property. 

The reaction between the sodium salt of an a-formylcycloalkanone and the phosphonium cyclopropane has been found to produce spiro compound 605, together with minor amounts of the dihydrofuran 606 (equation 215). This reaction sequence has been used in the synthesis of spirovetivane sesquiterpenes. ... 

---