Spirocyclopropanes, synthesis

The cycloadducts formed from the Diels-Alder reaction of 3-amino-5-chloro-2(17/)-pyrazinones with methyl acrylate in toluene are subject to two alternative modes of ring transformation yielding either methyl 6-cyano-l,2-dihydro-2-oxo-4-pyridinecarboxylates or the corresponding 3-amino-6-cyano-l,2,5,6-tetrahydro-2-oxo-4-pyridinecarboxylates. From the latter compounds, 3-amino-2-pyridones can be generated through subsequent loss of HCN <96 JOC(61)304>. Synthesis of 3-spirocyclopropane-4-pyridone and furo[2,3-c]pyridine derivatives can be achieved by the thermal rearrangement of nitrone and nitrile oxide cycloadducts of bicyclopropylidene <96JCX (61)1665>. 

Scheme 31. Attempted synthesis of spirocyclopropanated butadiyne-expanded [n]rotanes from the acyclic precursors 150 and 151...

In their synthesis of spirocyclopropanated oxazolines (see Section 2.1), the de Meijere group obtained initially unexpected cyclobutene-annelated pyrimidones 2-569 by reaction of the cyclopropylidene derivative 2-567 with the amidines 2-568. In this fourfold anionic transformation a Michael addition takes place to furnish 2-570, which is followed by an isomerization affording cyclobutenecarboxylates 2-572 and a final lactamization (Scheme 2.128) [294]. 

Recent research deals with stereoselective 1,3-dipolar cycloadditions of nitrones for the syntheses of alkaloids and aza heterocycles asymmetric synthesis of biologically active compounds such as glycosidase inhibitors, sugar mimetics, /3-lactams, and amino acids synthesis of peptido-mimetics and peptides chemistry of spirocyclopropane heterocycles synthesis of organic materials for molecular recognition and photochemical applications. 

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. 

Scheme 13. Convergent synthesis of spirocyclopropanated bicyclopropylidenes 55-57 and 61 via repetitive application of the Kulinkovich reaction [14]...

So-called domino or cascade reactions have become more and more important for the efficient synthesis of complex organic molecules [1211. In this respect methyl 2-chloro-2-cyclopropylideneacetate (1-Me) has been used as a dieno-phile to trap cyclic dienes which were produced by intramolecular Heck reactions in Diels-Alder cycloadditions. Thus, the spirocyclopropanated functionalized bicyclo[4.3.0lnonenes 248,250 (Fig. 11) were obtained from the bromo-diene 247 or enynes 249 in 56-83% yield (Scheme 71) [122,1231. 

A review of neighbouring-group effects in natural products includes steroidal examples. The 19-acetoxy-5a-bromo-6-oxo-steroids (228) fragment with base to give the 6-oxo-A -compounds (229) which are regarded as potentially useful intermediates in prostanoid synthesis.The preparation and properties of the 6-spirocyclopropane (230) have been reported. Attempts to cleave the cyclopropane symmetrically were unsuccessful although other cleavages are discussed. ... 

The formation of spirocyclopropanes from the reaction of diazodiphenylmethane and ( )-8-phenylmenthyl esters of acrylic acid and methyl fumarate occurred with a modest level of diastereofacial selectivity (136). In contrast, diastereoselectivities of 90 10 were achieved in the cycloadditions of diazo(trimethylsilyl)methane with acrylamides 65 derived from camphor sultam as the chiral auxiliary (137) (Scheme 8.16). Interestingly, the initial cycloadducts 66 afforded the nonconjugated A -pyrazolines 67 on protodesilylation the latter were converted into optically active azaproline derivatives 68. In a related manner, acrylamide 69 was converted into A -pyrazolines 70a,b (138). The major diastereoisomer 70a was used to synthesize indolizidine 71. The key step in this synthesis involves the hydrogenolytic cleavage of the pyrazoline ring. 

Sulfur ylides are among the most interesting carbon nucleophiles and their synthetic importance has been recently reviewed.One especially interesting use of these ylides is their application to the synthesis of cyclopropane derivatives using unsaturated oxazolones. For example, stabilized sulfur yhdes react with unsaturated oxazolones 629 via a Michael reaction to give oxazolone spirocyclopropanes 630 as shown in Scheme 7.202 and Table 7.46 (Fig. 7.57), whereas the less stabilized sulfur ylides give ring-opened products 631 as the major compounds (Scheme 7.202). ... 

In addition to insertion into p-C—H bonds, cyclopropylidenes can undergo other reactions such as alkylation (c/. Section 4.7.3.2), dimerization, insertion into C—H bonds of the ether solvent (equation 60)183 or reaction with alkenes to afford spirocyclopropanes (equation 61).184 Addition of stoichiometric amounts of Bu OK has been shown to promote the reactions of lithium carbenoids, even at -83 C, with THF to give the insertion product (equation 62).185 Addition to alkenes is also promoted under these conditions. Intramolecular addition of the carbenoid to double bonds has been exploited in the synthesis of spirotricyclic compounds (equation 63).186... 

Scheme 40 Synthesis of 3-spirocyclopropanated 2-azetidinones by a cascade three-component reaction...

Scheme 18 Synthesis of 3-benzylated a- and P-anomeric benzylspiro[2]-deoxy-(D,L)-arabino-hexopyranoside-2,l,-cydopropanes 60 via spirocyclopropane-annelated dihy-dropyrans 59 [53]...

The synthesis of functionalized 7,7-dialkyl-7,8-dihydropterins and a 7-spirocyclopropane derivative have been performed to find new types of inhibitors for 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase and dihydrofolate reductase <85JCS(Pl)2133, 85JCS(P1)2145, 89JCS(P1)1297>. An informative review on the chemical and biological reactions of reduced pterins is also available <84MI 718-08). 

Vasella, A, Waldraff, C A A, Glycosylidene carbenes. Part 3. Synthesis of spirocyclopropanes, Helv. Chim. Acta, 74, 585-593, 1991. 

Guijar, M K, Kumar, P, Rao, B V, Stereocontrolled synthesis of spirocyclopropane sugars and their application to asymmetric formation of tertiary chiral centres a route to 2,2 -diaIkylated pyranose subunit (C-18-C-23) of lasonolide A, Tetrahedron Lett., il, 8617-8620, 1996. 

Due to a growing interest in poly-spirocyclopropanes (triangulanes), a general approach to their synthesis has been developed. It consists of the addition of chlorofmethyl)-carbene to an alkene, the dehydrochlorination of the product 1-chloro-l-methylcyclopropane to a methylenecyclopropane, which is then submitted to cyclopropanation. The chloro(methyl)spiroalkanes 2 have been prepared utilizing this approach. 

Synthesis of pyridine derivatives by rearrangement of isoxazolidone-5-spirocyclopropanes resulting from dipolar addition to methylenecyclopropanes. 

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