Spirocyclic ring system

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. 

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],... 

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. 

Various types of domino reactions have been reported in the recent past. The sequential or cascade combination of an olefin metathesis with an intramolecular Heck reaction provides access to various bicycUc spirocyclic ring systems in good yields. Recently, a one-pot metathesis-Heck cascade was employed in the constraction of various ring systems (Scheme 57). " ... 

Fused and spirocyclic ring systems are present in many natural products and drug molecules. An approach to these systems was developed by [2 + 2] cycloaddition between 2,3-dihydrofurans and ketenes generated from ali-cyclic acid chlorides (14TL7240).This approach allows the construction of complex-fused, spirocyclic cyclobutanone frameworks in simple operations, even on a large scale (20 mol). 

An intramolecular aza-Piancatelli rearrangement that constructs a fully substituted carbon centre bearing a nitrogen atom and a spirocyclic ring system in a single operation has been catalysed by dysprosium (Ill)triflate. The azaspirocycles are formed exclusively as the irons diastereomer, consistent with a electrocyclization (Scheme 99). ... 

Arene-metal complexes have again featured in approaches to spirocyclic ring systems. Thus, Semmelhack s group has extended their studies of chromium hexacarbonyl complexes of anisoles to effect new total syntheses of the spiro-sesquiterpenes, acorenone (169) and acorenone B (170) (Scheme 25), In... 

---