Dehydrative spirocyclization

Dehydrative spirocyclization of a dihydroxyketone (Scheme 2) leads to the thermodynamically most stable spiroacetal as the major isomer. As discussed earlier, in most cases this also corresponds to the doubly anomericaUy stabilized spiroacetal. 

Cephalosporolides E and F have been synthesized independently by Fernandes and Ingle [46] and Brimble et al. [47]. Both groups used a dehydrative spirocyclization strategy to assemble the spiroacetals in high yield as a mixture of the two epimers (Scheme 3). 

A recent attempt to selectively control the dehydrative spirocyclization of a dihydroxyketone using a chiral-directing element has been reported by Paley et al. [51]. Incorporation of an iron(0)-tricarbonyl diene complex into the dihydroxyketone skeleton was used to direct spirocyclization (Scheme 6). Thus, the unsubstituted spiroacetals 18 and 19 were obtained selectively in high yield from the dehydrative spirocychzation of sulfinyl iron(O) diene complexes 16 and 17, respectively. 

A recent example of the use of dehydrative spirocyclization for the s5mthesis of a heteroannulated spiroacetal natural product is Sudhakar et al. s synthesis of the acortatarins 37 and 38 [54] (Scheme 11). 

Dehydrative spirocyclization of a dihydroxyketone has also been successfully applied to the synthesis of bis(benzannulated) spiroacetals. A recent example is the total synthesis of paecilospirone 46 by Brimble et al. [55] (Scheme 12). 

Scheme 15 Dehydrative spirocyclization in Brimble et al. s synthesis of y-rubromycin [61]...

Dehydrative spirocyclization may also be performed on hemiacetals, whereby treatment with a Br0nsted or Lewis acid gives rise to an oxonium ion intermediate. Subsequent attack of the pendant alcohol thus affords the spiroacetal (Scheme 21). 

Nagorny et al. [75] have used the chiral phosphoric acids (5)-TRIP 120 and its enantiomer to catalyze the asymmetric dehydrative spirocyclization of dihy-dropyrans 122 (Scheme 29). Treatment of the achiral substrates with (S)-TRIP afforded the doubly anomeric 6,6- and 6,7-spiroacetals 123 in excellent yield and selectivity. Conversely, use of (/ )-TRlP as the catalyst afforded the mono-anomeric spiroacetals 124 in high yield and good enantioselectivity. 

The application of this method (Scheme 86) in the syntheses of a variety of spiroacetal natural products has been reviewed recently [175], The mild reaction conditions enable constractimi of spiroacetals from very sensitive substrates that would not withstand more classical spirocyclization strategies (e.g., acid-catalyzed dehydrative spirocyclization). 

Dehydration of a spirocyclic quaternary salt such as 147 gives rise to a 3,4-dihydro-y-carboline (148). This reaction is not, however, of general applicability since both 149 (R = C2H5) and 149 (R = CH2C6H5) yield the fully aromatic carbolinium salt 150 under the same conditions. 

Similarly, 5-lactols and 5-lactones are obtainable from the corresponding homo allylic alcohols. With dehydration, the corresponding dihydropyrans are prepared. Spirocyclic y-butyrolactones of this type and the corresponding 5-lactones are widespread in nature and play a key role as synthetic intermediates. 

Skraup quinoline synthesis, 443 Smiles rearrangement, phenothiazine, 534 Spiroalkylation, 222, 280 Spirocyclization, conjugate addition, 386 Spiroimidazolone formation, 335 Spiropyrazolopiperidine, 375 Stannylation, alkyne, 15 Stereoselective dehydration, 198 Grignard addition, 198, 199 reduction, 129, 226 hydroxyketone, 400 iminoketone beta, 553 oxazaborohydride, 585 transfer chirality, 321 Stilbene formation, self alkylation, 525 Stobbe condensation, benzophenone, 103... 

Polyfluorinated aliphatic aldehydes reacted with 1-phenyl-3-methylpyrazol-5-one, l-phenyl-3-methyl-5-amino (N,N-dimethylaminomethylenamino)pyrazole, and l-phenyl-3-aminopyrazol-5-one at room temperature in the absence of catalyst with formation of 4-(l-hydroxypolyfluoroalkyl)pyrazoles <2000JFC(101)111>. Dehydration of the 4-(l-hydroxypolyfluoroalkyOpyrazoles with morpholinosulfur trifluoride generated 4-polyfluoroalkylidenepyrazoles, which were active dienophiles and reacted with 2,3-dimethylbutadiene and cyclopentadiene forming spirocyclic pyrazole derivatives. 

Dehydrative cycUzation. Intramolecular displacement of a cyclic allylic alcohol can set up spirocyclization. 

A spirocyclic dithiolactone 65 was synthesized in high yield by sulfenyl group-assisted dehydration followed by intramolecular cyclization of P-hydroxy y-(phenylthio) dithioate66 (Scheme 16) [52,53]. 

Attempted reduction of (147) with HI in the presence of red phosphorus in boiling acetic acid for five hours gave almost quantitatively the rearranged spirocyclic aminosulfide (148). The most likely mechanism for this reaction involves the dehydration of (147), the reductive cleavage of the ArCHj SAr bridge, and a subsequent intramolecular cyclization (Scheme 24) <89CCC235>. 

Abstract A large number of marine natural products with bicyclic and/or spirocyclic acetals have been found to date. These compounds are usually biologically active, however, synthetic studies are essential for the structure elucidation and biological application. For spirocyclic acetals in particular, it is necessary to design precursors and to control the process of dehydrative ring-closing acetal formation. Synthetic studies of four types of acetal compounds that represent recent examples are described didemniserinolipid B (6,8-dioxabicyclo[3.2.1]octane), attenols (6,8-dioxabicyclo[3.2.1]octane or l,6-dioxaspiro[4.5]decane), bistramides (l,7-dioxaspiro[5.5]undecane), and pinnatoxins (6,8-dioxabicyclo[3.2.1 ]octane and 1,7,9-trioxadispiro[5.1.5.2]pentadecane)... 

Haak and coworkers in 2015 [78] and 2012 [79] reported monocyclic and bicyclic [3] dendralenes, which were generated via ruthenium-catalyzed cascade transformations. The complex mechanism involves ruthenium(0)-mediated dehydration of the allcyne 124, addition of the nucleophile to an alkenyl ruthenium allenylidene, and cyclization at a ruthenated alkyne to furnish unusual spirocyclic [3] dendralenes 126 and 128 (Scheme 1.17). 

As a consequence the normai fragmentation pattern of the spirocyclic tetrahydrofuranone system is suppressed (see 5.2.5.). The formation of 59 (Fig. 29) proceeds by oxidations of the 3-methyl-2-butenyi side chains in 24, followed by cyclizations, either via intramoiecular dehydration, or via nucleophilic cleavage of the intermediate oxirane ring. No distinction can be made between cis-trans isomers. 

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