Carbo-spirocyclization

Nachtsheim and co-workers utilized phenolic benzamido-acrylates of type 124 to construct carbo-spirocycles 125 [88]. They relied on the use of BTI in propionitrile at 90°C to activate the phenols toward the anticipated dearomative spirocyclization, hoping that the carbon-based enamide nucleophilic unit would be the major actor of this intramolecular event. However, the yields of the desired products hardly passed beyond 50%, notably because an unexpected competitive oxo-spirocyclization took place to furnish the 8-spirolactone 126 (Fig. 31). The yield of 126 could even be optimized up to 70% by performing the reaction with the isopropyl ester 124c (i.e., R=i-Pr) in TFE at 0°C in the presence of TFA (2 equiv.). These conditions completely shut down the formation of the corresponding spirolactam 125 [88]. The use of other X -iodane reagents, such as DIB and Koser s HTIB reagent, was also attempted, but BTI turned out to be by far the best reagent for this oxo-spirocyclization. 

In a related study, Yu and co-workers had also selected the use of BTI over that of DIB to convert 4-hydroxyphenyl Af-phenylbenzamides such as 127a into oxindolic spirocyclohexa-2,5-dienones such as 128a (Fig. 32) [89]. These authors 

30 Zhang s synthesis of p-lactamic and pyrrolidonic spirocyclohexa-2,5-dienones 

33 Du-Zhao s synthesis of cyclohexa-2,4-dienonyl spirooxindoles and Gong s catalytic asymmetric variant 

Another interesting case of carbo-spirocyclization of phenolic substrates is that reported by Chabaud and GuUlou on the conversion of para-hydroxy acetanilides of type 133 into 1,2-aza/carbo-dispirodienones 134, using BTI in TFE at 0°C (Fig. 34) [92]. This is the first example of a synthesis of 1,2-dispirodienones via a X -iodane-mediated phenol dearomatization. 

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In the same vein, Canesi s group also reported a method to prepare spiro[5.5] undecanyl ring systems 150 from phenols 147 para-tethered to a free alkyne moiety [98]. The phenoxenium ions 148 undergo carbo-spirocyclization into the vinyl cations 149, which are then trapped by solvent-derived nucleophiles to furnish the spirobicycles 150 in good yields (Fig. 37) [98]. 

Another domino application of an oxidative carbo-spirocyclization and an aza-Michael addition was developed by She and co-workers to construct the core skeleton of the Amaryllidaceae alkaloids tazettine and 6a-epipretazettine. In 2013, they disclosed their approach that requires the phenolic amide 185 as key precursor of the intended carbo-spirocyclization [112]. Both DIB and BTI were first used to mediate this oxidative para-para phenolic coupling reaction, but the more electrophilic Kita s p-oxoBTI reagent (see Fig. 4) in TFE gave higher yields. The addition of potassium hydroxide in the reaction mixture then promoted the aza-Michael addition to furnish the known tazettinone intermediate 187 in 72% yield as a single diastereomer (Fig. 46) [112]. 

For their 2010 synthesis of the immunosuppressive polyketides dalesconols A and B [143], Snyder and co-workers developed an outstanding one-pot cascade to forge the bicyclo[5.3.0]decanyl core of these targets from the judiciously functionalized and protected precursors 276. The ultimate addition of DIB in TFE at low temperature served to transform in situ the phenols 277 into the five-membered carbo-spirocyclic cyclohexa-2,5-dienone intermediates 278, which were then efficiently converted into dalesconols A and B (Fig. 67) [143]. 

The synthesis of spirocyclic and fused unusual (3-lactam derivatives has been discussed. The 2-azetidinone skeleton has been extensively used as a template on which to build the carbo(hetero)cyclic structure joined to the four-membered ring, using the chirality and functionalization of the (3-lactam ring as a stereocontrolling element. In many cases the compounds described in this chapter were included because of an interesting synthesis or structure, although limited biological data were found. 

Fig. 31 Nachtsheim s dearomative carbo- and oxo-spirocyclizations from phenolic benzamido-acrylates...

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