Spirocyclopropanation

Mioskowski et al. have demonstrated a route to spirocyclopropanes. As an example, treatment of epoxide 100 with n-BuLi in pentane stereoselectively gave tricyclic alcohol 101, albeit in only 47% yield (Scheme 5.21) [29]. With a related substrate, epoxide 102 stereoselectively gave dicydopropane 103 on treatment with PhLi uniquely, the product was isolable after column chromatography in 74% yield [35]. As was also seen with attempts to perform C-H insertion reactions in a non-transannular sense, one should note that steps were taken to minimize the formation of olefin products, either by the use of a base with low nudeophilicity (LTM P) and/or by slow addition of the base to a dilute solution (10-3 m in the case of 102) of the epoxide. 

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>. 

Since it is well known that cyclopropane rings are better electron donors than dimethylmethylene groups, especially towards electron-deficient or electron-attracting centers [9,10], in macrocycles such as 48 it would be expected that the spirocyclopropane rings rather than the dimethylmethylene groups in [nlpericyclines would more efficiently transmit the electronic interaction between the triple bonds (Fig. 2). 

Scheme 26. Acyclic oligoynes for the preparation of permethylated and spirocyclopropanated expanded [n]rotanes...

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

The most remarkable structural features of the planar cyclic mixed trisethyne-monobutadiyne pentaacetylenes 181 and 62 are their drastically bowed diyne moieties [18]. The acetylenic carbon atoms deviate from linearity by an average of 11.7° in 181 and even 13.4° in 62. The internal C-C-C angle is smaller for 181 (103.8°) than for 62 (109.2°). The disparity of the C-C bond lengths in the spirocyclopropane moieties of 62 is analogous to those observed in the expanded [n]rotanes 165-168. 

The fact that only ethylene and tetramethylethylene are evolved from exp-[8]rotane 168 and permethyl-exp-[6]rotane 173 upon thermal decomposition leads to the conclusion that the spirocyclopropane moieties in these expanded [n]rotanes fragment only externally and leave carbene moieties behind. Indeed, the MALDI-TOF mass spectra of several exp-[ ]rotanes show fragment ions with M minus 28. Thus, if this fragmentation in an exp-[n]rotane were to continue n times, a cyclic C carbon cluster would be left over. So far, however, a fragment ion with m/z = 480 corresponding to 182 has not been recorded in the mass spectrum of exp-[8]rotane 168 and it remains to be seen whether a Cgo cluster 183 will be detected in the mass spectrum of exp-[12]rotane 171 (Scheme 35). 

The MALDI-TOF mass spectra of the Cso-fullerene-annelated [3]- and [4]rotanes 127 and 128 also demonstrated that these molecules fragment at the spirocyclopropane units with successive loss of the fullerene moieties. Unfortunately, however, the peaks for cyclo-Ci and cyclo-C2o carbon clusters were not observed [38]. 

Another domino Michael addition/SN sequence has been elaborated by the group of de Meijere. It was discovered that upon basic treatment of 2-chloro-2-cyclopropyl-idenacetates 2-168 with carboxamides 2-169 in MeCN, 4-spirocyclopropane-anne-lated oxazoline-5-carboxylates 2-172 are formed (Scheme 2.40) [91]. As intermediates, the carbanion 2-170 and 2-171 can be proposed. 

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]. 

The two articles in this current volume describe recent developments with small ring compounds which have not teen compiled in such a context before. T. Hirao discusses selective transformations initiated by transition derivatives in the construction of functionally substituted five-, six- and seven-membered rings as well as open-chair compounds. Cycloadditions onto methylene- and alkylidene-cyclopropane derivatives, described by A. Goti, F. M. Cordero and A. Brandi, not only yield products with spirocyclopropane moieties which can be desirable as such or as potential mimics of gem-dimethyl groupings, but also intermediates which can undergo further transformations with ring-opening of the cyclopropane units. 

The cycloadditions of nitrones to alkylidenecyclopropanes are, by far, the most studied reactions of this class. The first example reported in the literature refers to the cycloaddition of ZV-(phenylaminooxoethylidene)aniline iV-oxide (249) to 2,2-dimethylmethylenecyclopropane (250). The authors report about the formation of a single 5-spirocyclopropane fused regioisomer 251 (Scheme 41) [63]. 

The impulse to the study of these cycloadditions came from the discovery that 5-spirocyclopropane isoxazolidines (or isoxazolines) undergo a thermal rearrangement resulting in the production of selectively substituted tetrahydro-(or dihydro) pyrid-4-ones (Scheme 42) [64], In particular, cyclic nitrones gave ultimately N-bridgehead bicyclic ketones, molecular skeleton of many alkaloid families [65]. 

The unexpected regiochemical outcome of the cycloaddition gave rise to a complete study of the factors influencing the regioselectivity, inasmuch as 4-spirocyclopropane isoxazolidines are unable to undergo the useful thermal rearrangement. 

Aryl or alkyl substituents on the exocyclic double bond steer the regioselec-tivity towards the formation of isoxazolidine-4-spirocyclopropanes 274-276 (Table 22, entries 1-3). A complete reversal of regioselectivity to 277-279 was observed in the reactions of methoxycarbonyl substituted methylenecyclo-... 

A positive feature of the reaction is that nitrile oxides are more regioselective, in cycloadditions to methylenecyclopropanes, compared to nitrones. Only traces (up to 5%) of the 4-spirocyclopropane regioisomers are generally observed with methylenecyclopropanes unsubstituted on the exocyclic double bond. The yields are only moderate, but higher with more stable nitrile oxides (Table 27, entries 5, 6, 10-12). 

The unstable 2-cyclopropylidene-l,3-cycloalkanediones 34a,c,d were trapped in situ by isocyanides 391 to give [4 + 1] cycloadducts under mild reactions conditions to afford 3-spirocyclopropane furans or pyrroles (Table 32) [95]. In the case of 34a, the primary cycloaddition products 392 and 394 decomposed very easily to give the stable pyrrolidindiones 393 and 395, respectively, as a single stereoisomer, upon addition of methanol (entries 1-2). Compounds 34c and 34d gave the expected adducts in moderate to good yields (Table 32, entries 3-7). 

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