7-Spirocyclopropyl

It is worth mentioning here that the spirocyclopropyl-substituted oxazoline-5-car-boxylates 2-172, as well as the corresponding thiazoline-4-carboxylates, can be transformed into cyclopropyl-substituted amino acids, which might act as potential enzyme inhibitors [93] and interesting building blocks for peptidomimetics [94]. 

Scheme 2.161. Synthesis of spirocyclopropyl ether involving a SET process.

The group ofWalborsky probably has described one of the first true anionic/radi-cal domino process in their synthesis of the spirocyclopropyl ether 2-733 starting from the tertiary allylic bromide 2-730 (Scheme 2.161) [369]. The first step is a Michael addition with methoxide which led to the malonate anion 2-731. It follows a displacement of the tertiary bromide and a subsequent ring closure which is thought to involve a SET from the anionic center to the carbon-bromine anti bonding orbital to produce the diradical 2-732 and a bromide anion. An obvious alternative Sn2 halide displacement was excluded due to steric reasons and the ease with which the reaction proceeded. 

The JV-benzyl aziridines 69, 92-95 which differ only in the nature of the norbomane bridge (CH2, spirocyclopropyl, isopropylidene, oxygen, substituted nitrogen) (Scheme 14), have been prepared and reacted with each of the corresponding benzonorbomadienes 36-40 from which they were derived. All 25 reactions were conducted to produce 14 of the possible 15 different... 

Addition of carbenes to Jt-electron excessive aromatic compounds, or those which possess a high degree of bond fixation, is well established. Dihalocarbenes react with naphthalenes with ring expansion to produce benztropylium systems (Scheme 7.8). Loss of hydrogen halide from the initially formed product leads to an alkene which reacts with a second equivalent of the carbene to yield the spirocyclopropyl derivatives in high yield (>95%) [14, 50]. Insertion into the alkyl side chain (see Section 7.2) also occurs, but to a lesser extent [14]. Not unexpectedly, dichlorocarbene adds to phenanthrenes across the 9,10-bond [9, 10, 14], but it is remarkable that the three possible isomeric spiro compounds could be isolated (in an overall yield of 0.05% ) from the corresponding reaction with toluene [14]. 

These authors also showed that the indolizidine skeleton can be prepared from cyclopropyl dipolarophiles (Scheme 1.16). The cycloaddition of alkyhdenecyclo-propanes 67 with various nitrones (e.g., 68) afforded the expected isoxazolidine adducts 69 and 70, commonly forming the C(5) substituted adducts 70 (97,105-108) predominantly but not exclusively (109-111). Thermally induced rearrangement of the spirocyclopropyl isoxazolidine adduct 70 afforded the piperidinones 71 (107,108). These authors propose reaction via initial N—O bond homolysis of 70 to diradical 72 followed by ring expansion through relief of the cyclopropyl ring strain forming the carbonyl of a second diradical intermediate 73, which cyclizes to afford the isolated piperidinone 71. 

The intermolecular cycloaddition route to spirocyclopropyl isoxazolidines and their subsequent rearrangement, used so widely by Brandi and co-workers (372-375) (Schemes 1.16 and 1.17, Section 1.5), has also been achieved in an intramolecular sense (Scheme 1.72). Cycloaddition of the alkenyl nitrone reagents (333a-c) afforded bicyclic isoxazolidinyl adducts 334, which rearranged under thermolysis in analogous fashion to the earlier work to give piperidinones (335) via... 

Kinder et al. (123,124) utilized a similar approach to the illudins, more specifically to illudin analogs such as 241 that retain efficacy against various cell lines, but are less toxic. The analog design involves a spirocyclopropyl cyclohexane that contains two electrophilic moieties (Scheme 4.63). Some of the analogs formed are as active as adriamycin against several human tumor cell lines. 

It was, therefore, not possible to observe the secondary 3-spirocyclopropyl-2-norbomyl cation 96101. 

The quaternary carbons of the tertiary cations 97 have chemical shifts of <5 l3C 69.2,61.1 and 58.8 for the Me, Ph and cyclopropyl substituted ions, respectively, which shows that progressively less charge is delocalized into the spirocyclopropyl ring going from methyl to phenyl to cyclopropyl. Consequently, the order of the stabilizing effects of the substituents on the cationic center is cyclopropyl > Ph > Me. 

Comparison of Cl and C6 l3C chemical shifts showed that the ff-participation from the 2-norbomyl ring is significantly reduced in the 2-methyl analogue, whereas in the cyclopropyl and phenyl analogues it has essentially vanished. The STO-3G calculated structures show that the spirocyclopropyl participation is mainly from the exo-C—C bond. The l3C NMR studies of these cations adequately accounted for the vanishingly low values of solvolytic keJkenio rate constants, and show that 3-spirocyclopropyl groups effectively compete with the Cl—C6 ff-bond participation in the 2-norbomyl cation framework. 

The formation of cyclopropane derivatives by photolysis of diazoalkanes in the presence of alkenes is believed to occur by photolytic decomposition of the diazoalkane to yield the carbene, followed by addition of this carbene to the alkene. Cycloaddition of this type has been reported in furan, dihydrofuran, and thiophene.198 Thus, photolysis of ethyl diazoacetate in thiophene yields the bicyclic sulfur heterocycle (215). Alternatively, photolysis of 3-diazo-l-methyl-oxindole (216) in cyclohexene leads to the formation of two isomers which are thought to have the spirocyclopropyl structure (217) photolysis in ethanol yields 3-ethoxy-1-methyloxindole.194... 

The composition of 2-C-spirocyclopropyl-2-deoxy-L-arabinose was found64 (by l3C-n.m.r. spectroscopy) to be pyranoses, furanoses and acyclic forms in the ratios of 10.6 2.9 1.0. This is, actually, not a sugar having a fused ring but one with a spiro structure. The proportion of the acyclic form is surprising apparently the spiro arrangement introduces strain into both the pyranose and the furanose forms. 

Figure 10. Spirocyclopropyl substituted derivatives of 1,r-bicyclopropylidene (title compounds).

The 3-spirocyclopropyl-2-cyclopropyl-2-norbornyl cation 97, R = C-C3H5 is stable even up to -20 °C, whereas the phenyl and methyl analogues rearranged to the allylic cations 98 at -70 °C and -90 °C, respectively (equation 58). 

---