Spiro annulations

The syntheses of stemodin and stemodinone, structural relatives of aphidicolin, were accomplished using the A/B double annulation and B/C spiro annulation processes developed for the assembly of aphidicolin. 

For 10 years, attention has been focused on the intramolecular additions ofallylic and alkynyl-silanes to enones. In early studies, a variety of Lewis acids were tested and reaction conditions were optimized to make this reaction a powerful tool in the synthesis of spiro-annulated, and 1,2-fused ring systems, which can be utilized in the total synthesis of natural products34,35. 

An optically active spiro-annulated compound with excellent stereocontrol over the quaternary spirocenter is obtained from 5 which is prepared from 2-benzyloxycyclohexanone225,226. 

The general approach has been followed for the de novo synthesis of a multitude of differently substituted, unsaturated [112,113] or regiospedfically labeled sugars [102,114]. Unusual branched-chain (42), (43)) and spiro-annulated sugars (45), (46)) have been synthesized from the corresponding aldehyde precursors... 

The availability of cyclopentenones from butanolides allows the lactone annulation to facilitate the synthesis of cyclopentyl natural and unnatural products. An example that highlights the latter is dodecahedrane (178) for which 179 constitutes a critical synthetic intermediate 136,137). Lateral fusion of cyclopentenones as present in 179 can arise by acid induced reorganization and dehydration of 180. While a variety of routes can be envisioned to convert a ketone such as 182 into 180, none worked satisfactorily137 On the other hand, the cyclobutanone spiro-annulation approach via 181 proceeds in 64 % overall yield. Thus, the total carbon cource of dodecahedrane derives from two building blocks — cyclopentadiene and the cyclopropyl sulfonium ylide. 

B. Li, Y. Qiu, L. Wang, and Y. Gao, Spiro-annulated compound as stable and high efficiency blue host light emitter, Jpn. J. Appl. Phys., 9 5599-5601 (2002). 

Under analogous conditions, the 3-cyanomethylene-2-indolones 213 react with barbituric acid and its derivatives 191 with the formation of spiro-annulated pyranopyrimidines 223 (88JIC202, 90H(31)31)... 

A large series of spiro-annulated pyranopyrazoles were synthesized in base-catalyzed three-component reactions (08JCO741, 09JCC)914). 

Ketene dithioacetal 237, obtained from acetylacetone, can serve as the initial reactant for the synthesis of aminopyran 238, spiro-annulated with oxazolidine (00SC1269) (Scheme 91). 

The key structure of antimicrobial marine natural product, araplysillin-I (28), which was isolated from Psammaplysilla arabica, was synthesized by spiro-annulation of o-phenolic oxime-amide (147) with PIDA [104] (Scheme 18). 

When the photolyses were performed in methanol as solvent the styrene radical cations were trapped by methanol in an a ti-Markovnikov fashion and the resulting biradicals combined to give macrocyclic lactones in moderate to good yields. Spiro-annulated products were formed by irradiation of the corresponding indenyl-substituted starting materials in methanol [167]. The yields for the heterocyclic products were excellent even for the 13-membered representative (86 %). 

Fused and spiro-annulated cyclopentenes of type 1 and 3 were prepared in moderate to good yields by the application of the flow pyrolysis technique." " ... 

Spiro-annulated compounds 6a,b (Figure 16.14) exhibited much higher binding affinities. nor-Derivative (+)-6a bound at = 53.1 nM with a 10-fold higher affinity than its enantiomer (A" = 533 nM). Introduction of the N-methyl substituent resulted in a significant improvement. 

Ullrich, T., Krich, S., Binder, D., Mereiter, K., Anderson, D. J., Meyer, M. D., Pyerin, M. Conformationally constrained nicotines poly-cycHc, bridged, and spiro-annulated analogues as novel hgands for the nicotinic acetylcholine receptor. J. Med. Chem. 2002,45(18), 4047 054. 

Spiro-annulated 2,5-cyclohexadienones have been obtained by the oxidation of 4-phenylphenols with phenyliodosodiacetate. Thus 1-(4-hydroxyphenyl)-2- 3-methoxyphenyl)ethane in acetonitrile afforded the 1-spirotetralin compound illustrated upon refluxing with the reagent during 4 hours (ref.32). Unsubstituted, 4-methoxy and 3,4-dimethoxyphenyl analogues have also been synthesised. 

Intramolecular nitrile oxide addition to the 2,3-double bond of thiophene has been used to synthesize several spiro-annulated heterocycles <88S342>. 

In a separate investigation by Porco, Jr. and coworkers, the isatin derivative 134 (R = H) was converted to spirooxindole pyran 141 in 13 1 dr and 99% ee by means of a Prins-type cyclization involving homoaUyhc alcohol 140 [79]. The diastereos-electivity of the transformation has been proposed to arise from a preferred chairlike transition state with the benzenoid ring of oxindole in a pseudoequatorial orientation. Spirooxindole oxepenes also were prepared via diastereoselective spiro-annulation of isatins with bis-homoallyhc alcohols. 

In an approach to the gastrin receptor antagonist (+)-AG-041, the Iwabuchi group has prepared the nitrogen-substituted spirocycle 153 by means of an oxidative intermolecular aza-spiro-annulation (Scheme 38) [82], Accordingly, indole 151 was treated with dirhodium catalyst 152 in the presence of PHl(OAc)2 and MgO to afford spirocycle 153 in 70% yield and 96% ee. The deuterium labeling was necessary for successful implementation of the spirocyclization. 

Synthesis and properties of quinolines spiro annulated at heterocyclic fragment 05JHC39. 

W.Y. Huang, S.Y. Huang, Sterically encumbered lluorene-based poly(arylene ether)s containing spiro-annulated substituents on the main chain. Macromolecules 43 (24) (2010) 10355-10365. 

Trost et al. reported an efficient method for synthesis of plumericin (67), allamcin (68), and antileukemic allamandin (69), applying a biomimetic strategy. The requisite key intermediates were synthesized using the concept of spiro-annulation and stereocontrolled geminal alkylation. Their strategy required 9, 13, and 14 steps from bicyclic ketone (70) for synthesis of allamcin, plumericin, and allamandin, respectively. The bicyclic ketone was synthesized from cycloocta-1,3-diene in three steps. The synthetic route is outlined in Scheme 97.3 [101]. 

A general spiro-annulation procedure (Scheme 4) involves reaction between cyclic anhydrides and bis(bromomagnesio)alkanes. For simple, symmetrical anhydrides, the yields of lactones are between 63 and 86%. Clearly, this method will be largely limited to symmetrical anhydrides. However, a further dimension... 

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