Other Spirocycles

Marinetti and coworkers have developed the enantioselective [3-1-2] cycloaddition approach between allenoates and exocyclic enones catalyzed by planar ehiral 

Ma and coworkers reported a similar reaction for the synthesis of spiro-3,4-dihydropyranes [44]. The reaction between cyclic p-oxo aldehydes and aromatic p,Y-unsaturated a-ketoesters catalyzed by the cinchona alkaloid derivatives afforded the corresponding spirocyclic compounds in good yields and moderate to good enantioselectivities. 

83 in the presence of a cinchona alkaloid derivative XX. Next, the nucleophilic displacement of Se02Ph by the ester group of the Michael adduct intermediate 

84 occurred in the presence of silica gel. The tert-butyl groups could be easily 

The same research group developed a new strategy for the synthesis of spirocycles by the addition of a-isothiocyanato imides and esters to unsaturated pyrazolones [52], The reaction was catalyzed by bifunctional tertiary amine-thiourea catalysts to afford the corresponding products in good to excellent yields (72-99%) as well as diastereo (up to 20 1 dr) and enantioselectivities (72-99% ee). 

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The spirocyclic zwitterionic A5A/-silicates 77,52 78,53 and 7953 contain two bidentate salicylato(2-) ligands. The chiral zwitterions are built up by two six-membered Si02C3 ring systems that are connected by the silicon spirocenter, whereas all the other spirocyclic A5A/-silicates described in Section III contain two five-membered Si02C2 (III,A to III,D) or Si02CN rings (III,F). 

These reaction conditions using fluorinated solvents have also been applied to the construction of other spirocyclic systems. 

Spirocyclic 4//-pyrans 69a (90ACS833) and 69b were prepared in the same way. In the case of 69b the starting a,)8-unsaturated component was generated in situ from enolacetate 70 (89CB1285). Analogous procedures with HC=COEt were used for the preparation of other spirocyclic products 71 and 72 (89CB1285). 

The products included allgrl substituted derivatives (30, 31) and halogenated species (32, 33). Other spirocyclic compounds were obtained through reaction of phosphazenes with a bis-anilino species. Scheme... 

Asymmetric induction has also been achieved in the cyclization of aliphatic alcohol substrates where the catalyst derived from a spirocyclic ligand differentiates enantiotopic alcohols and alkenes (Equation (114)).416 The catalyst system derived from Pd(TFA)2 and (—)-sparteine has recently been reported for a similar cyclization process (Equation (115)).417 In contrast to the previous cases, molecular oxygen was used as the stoichiometric oxidant, thereby eliminating the reliance on other co-oxidants such as GuCl or/>-benzoquinone. Additional aerobic Wacker-type cyclizations have also been reported employing a Pd(n) system supported by A-heterocyclic carbene (NHC) ligands.401,418... 

The first cyclization of a-hydroxyalkoxyallenes goes back to the pioneering experiments of Brandsma, Hoff and Arens, who found that dihydrofuran derivatives 102 are formed by treatment of 101 with KOtBu in DMSO (Scheme 8.26) [12c], This reaction protocol was successfully applied by others [61, 63, 64, 80-83], for example in the preparation of spiro compound 104 (Eq. 8.19) [83] and in the cyclization of 64 leading to a-amino acid-derived dihydrofurans 105 (Scheme 8.27) [61, 63], Acidic hydrolysis of dihydrofurans furnished 3(2H)-dihydrofuranones, which could be used again as carbonyl components in the repetitive addition of lithiated methoxyal-lene 42. This concept was employed in syntheses of racemic [82] and enantiomeri-cally pure [64] primary helical spirocycles. 

The molecular structure of 124 has been elucidated by an X-ray structural analysis. The central structural motif of 124 is an unsymmetrically substituted six-membered TisOs ring. Two pentamethylcyclopentadienyl ligands are coordinated to one titanium atom, while the other two are free of Cp. They are both part of eight-membered TiSi304 ring systems within the silsesquioxane frameworks. This results in an unusual bis(spirocyclic) inorganic ring system in the molecular structure of 124. 

The generality of these observations is supported by the data in Scheme 8. In the case of the reactions of monosubstituted l-(l-alkynyl)cyclopropanols 15, 5-substituted cyclopentenones 17 are obtained with complete selectivity when trans-15 are used as substrates. On the other hand, 4-substituted cyclopentenones 16 are obtained with good to high regioselectivity by employing ferf-butyl-dimethylsilyl ethers of cis-l5 as substrates. Furthermore, 5,5-disubstituted cyclopentenones 20 including a spirocyclic derivative are obtained selectively starting from 2,2-disubstituted l-(l-alkynyl)cyclopropanols 18. 

Spirocyclic C-aryl glycosides are central structural skeletons of papulacandins that constitute a family of novel antifungal antibiotics isolated from a strain of Papularia sphaerosperna. They have shown potent in vitro antifungal activity against Candida albicans, Candida tropicalis, Pneumocystis carinii, among other microorganisms [110],... 

Several examples of direct ring phosphorus interaction with transition metals are now known [279-287]. For example, reaction of N3P3CI6 with Na2Fe2(CO)g affords a novel spirocyclic diiron octa carbonyl derivative (Scheme 25) [282, 283]. The diiron spiro derivative acts as a template for the construction of several transition metal clusters. Some of the other examples where ring phosphorus atom is involved in interaction with transition metals are summarized in Scheme 25. The ring phosphorus atoms in hydrido phos-phazenes, N3P3R4R H also coordinates to transition metals. This has been discussed in an earlier section (vide supra). 

Two additional synthetic routes to ( )-j8-vetivone (350) have been developed. In one of these a suitably substituted spirocyclic system [cf. (349)] is constructed by addition of Me2CuLi to the fulvene derivative (348)/ Subsequent functional group modification (cf. Scheme 32) provides ( )-j8 -vetivone (350). In the other total synthesis d the well-known intramolecular alkylation of para-substituted phenols has been used to produce a spirocyclic intermediate (353) which can be converted into ( )-/3-vetivone (350) (cf. Scheme 33). 

Cycloadditions with other symmetrical acetylenes were carried out by using thiocarbonyl (5)-methylide (69) (159). Interestingly, no reaction was observed when acetylene dicarboxamide was used. The reaction of 69 with cyclooctyne resulted in the formation of cycloadduct 103 (Scheme 5.38). Interestingly, the spirocyclic 2,5-dihydrothiophenes of type 103 or 104 undergo acid-catalyzed ring opening upon treatment with silica gel or trifluoroacetic acid to give thiophenes 105 and 106, respectively. 

Other examples of spirocyclic 2-amino-4(5//)-oxazolones have been prepared and evaluated for their CNS activity and as potential antiviral agents. " In these reports, cyclization of the appropriate ot-hydroxy ester with guanidine afforded the novel analogues 93, albeit in low-to-modest yields. Representative examples are shown in Table 6.4 (Fig. 6.10). 

On the other hand, Wyeth-Ayerst chemists ° encountered limitations with this methodology during their syntheses of spirocyclic 2,4-oxazolidinediones derived from isoindole (Scheme 6.55). For example, reaction of 246 with chlorosulfonyl isocyanate followed by cyclization with potassium terf-butoxide afforded poor to modest yields of 247 when R was a substituted benzyl group. Cyclization of 246 using ethyl chloroformate (ECF), triethylamine and 4-(dimethylamino)pyridine (DMAP) in refluxing tetrahydrofuran (THF) gave 247 in only 29% yield when R was methyl and failed completely if R was an isopropyl group. However,... 

Ketol 146, on the other hand, was formed after the reaction of spirocyclic 4//-pyran 147 with methanolic hydrogen chloride.191... 

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