Spirocyclic rings

Fetter and co-workers reacted the tetrazole-substituted pyrrolidinone 274 with cerium(rv) ammonium nitrate to generate the tricyclic spirocyclic ring system 275 in 60% yield (Equation 75) <1996T10169>. 

It has long been recognized that nitrone cycloadditions may allow access to spirocyclic ring systems. Such systems are inherently difficult to synthesize by conventional methods, yet are a structural component of a number of biologically active natural materials. Two common strategies have emerged for spirocycle generation from exocyclic or endocyclic nitrones (Scheme 1.45). In the exocyclic version, the carbon atom (arrowed) of the nitrone C=N double bond of dipole 209 carries a cyclic substitutent and thus an intermolecular cycloaddition reaction will... 

Mattay et al. used triethylamine as electron donor in tandem fragmentation/cyclization reactions of a-cyclopropylketones (49) [48]. The initial electron transfer to the ketone moiety is followed by subsequent cyclopropylcarbinyl-homoallyl rearrangement yielding a distonic radical anion (50). With an appropriate unsaturated side chain attached to the molecule both annelated and spirocyclic ring systems are accessible in moderate yields. Scheme 26 shows some representative examples. 

Fig. 14.13 Various quinolones substituted by 3-aminomethyl-1 -pyrrolidinyl rings with the aminomethyl group inserted into a fused or spirocyclic ring system.

When the enamine is terminally disubstituted, the photocyclization can lead to the formation of a spirocyclic ring system (equation 3)7,8. This spirocyclization proceeds in good yield both with substituted phenyl rings as well as with furan, thiophene, pyridine or indole heteroaromatic rings. 

Typical examples of bis-cyclization anion capture processes forming fused and spirocyclic rings, triggered by aryliodide species, are shown in Scheme 5.6.16. Thus, enamide 50 reacts with Af-SEM-indolyl stannane in the presence of Pd(0) to afford a 5 1 diastereomer mixture of 51 and 52 in 74% yield, whilst 53 reacts with 2-pyridyltri- -butyltin in the presence of Pd(0) to afford 54a as a single diastereoisomer. ... 

Similar tandem reactions have been utilized to construct all-carbon spirocyclic ring systems. Initially, achiral studies were conducted by Undheim and coworkers using Rh2(OAc)4 (25a) as the catalyst [73, 74], Although they provided proof of concept, the yields were generally low, and multi-step procedures were often necessary to obtain the final products. Additionally, the methodology was not extended to asymmetric catalysis. In 2001, Hashimoto and coworkers optimized conditions by which spirocyclic product 62 could be obtained in one pot from bis-diazo compound 60 in good yield and up to 80% ee with phthalimide catalyst Rh2(5-PTTI.)4 (29a, Scheme 13) [75],... 

Although no four-coordinate Si compounds have been found to have planar geometry, the five-coordinate anion (53), prepared as shown in equation (57), has a geometry at silicon distorted very much away from trigonal bipyramidal towards square pyramidal geometry. The O-Si-0 angles across the spirocyclic ring are about 166° and 143°. The structures of numerous silatranes have been determined and are discussed elsewhere. ... 

One must bear in mind that spirophosphoranes such as [6] may not be truly representative of simple TBP intermediates. Of the stable phosphor-anes that have been studied, many contain spirocyclic rings, the presence of which may cause considerable distortion from TBP geometry (Holmes, 1980a,b). 

Abstract This chapter provides an overview of emerging strategies for the selective introduction of functionality at oxindole C3. Specific emphasis has been devoted toward asymmetric methods for the introduction of C3 quaternary centers and spirocyclic ring systems. The chapter has been divided into two sections oti general methodology for the stereoselective synthesis of oxindoles and spirooxin-doles, respectively. A third section is devoted toward efforts in natural product total synthesis involving oxindole or spirocyclic variants as targets or key intermediates. 

The Trost group has devised a strategy for stereoselective spirocyclic ring installation across 3-alkylidene oxindoles via palladium-catalyzed [3-1-2] cycloaddition with cyano-substituted trimethylenemethane (Scheme 33) [74, 75]. As illustrated, the opposite sense of diastereoselectivity was observed depending on the choice of chiral ligand 125 or 126. Preferential orientation of the benzenoid portion of the oxindole as dictated by the varied steric environments of the naphthyl ring systems on the catalysts has been put forth as a rationale for the observed difference in stereochemical outcomes. Spirooxindoles 127 and 128 were obtained in 92% ee and 99% ee, respectively. A variation of this methodology has been applied in the racemic synthesis of marcfortine B [75]. 

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