Spiroacetal enol ethers

Attempts to selectively arylate [6,6]-spiroacetal enol ethers at the 2-position under palladium-mediated arylation conditions gave the double-Heck product, while reaction with benzenesulfinic acid resulted in rearrangement to the corresponding 5-phenylsulfonyl-3,4,5,6-tetrahydrochromans (Scheme 140). ... 

In the Asteraceae, acetylenes are widely distributed and structurally very diverse, including aliphatic acetylenes, acetylenic thiophenes, aromatics, isocoumarins and spiroacetal enol ethers (Table 5.1 and Figures 5.3,5.4 and 5.5). 

Spiroacetal enol ethers are characteristic of the tribe Anthemideae of the Asteraceae, and it is therefore not surprising that the acetylenes isolated from the utilized parts of Chrysanthemum coronarium (garland chrysanthemum) and Matricaria chamomilla... 

Figure 5.4 Aromatic isocoumarin and spiroacetal enol ether acetylenes isolated from the utilized parts of food plants from the tribe Anthemideae (Asteraceae).

Figure 5.5 The possible biosynthesis of spiroacetal enol ethers isolated from the utilized parts of food plants of the tribe Anthemideae (Asteraceae). [O] = oxidation, [H = reduction, — [H] = dehydrogenation (oxidation followed by the loss of water), [CH3SH] = addition of CH3SH or the biochemical equivalent to CH3SH.

The cyclofunctionalization of cycloalkenyl systems where the chain containing the nucleophilic functionality is attached at one end of the double bond leads to spirocyclic structures. Cyclizations of cyclic and acyclic enol ethers to generate spiroacetals are shown in equations (66)168 and (67).169 These reactions generate the thermodynamically more stable products based on anomeric and steric factors.170 Spiroacetal products have also been obtained using isoxazolines as the nucleophilic functionality (cf. Table 14).l4lb Studies of steric and stereoelectronic control in selenoetherification reactions which form spirocyclic tetrahydrofurans have been reported.38 An interesting example of stereoelectronic control in the formation of a spirocyclic lactone has been reported in a recent mevinolin synthesis (equation 68).171... 

A versatile approach to spiro-oxacycles is the use of cyclic a-methylene enol ethers employed by us in an efficient and short enantioselective total synthesis of the mycotoxin talaromycin B (see Sect. 7.1). Later Pale and Vogel [148] employed the same protocol for the preparation of spiroacetals 2-145 using e.g. acrolein 2-78, methyl vinyl ketone and 2-pentenal, respectively with the enol ether 2-143 (Fig. 2-39). In most cases the yields were only modest, however, reaction of 2-143 and 2-78 in benzene in the presence of the mild Lewis acid ZnCl2 gave 2-145 in 70% yield as a single adduct. 

The cydization of the hydroxy enol ether 5, performed with trifluoroacetic acid in benzene, leads to a single spiroacetal 6. On the other hand, when treated with acetic acid in benzene, 5 gives an equimolar mixture of spiroacetals 6 and 7. It is worth mentioning, however, that on treatment with trifluoroacetic acid this mixture leads exclusively to 6. These results show that the cydization, performed with either acetic acid/benzene or trifluoroacetic acid/benzene, proceeds under kinetic or thermodynamic control, respectively152. 

The reaction is effective with electron-rich carbonyls such as trimethylsilyl esters and thioesters, as Table 20 indicates. Lactones ate substrates for alkylidenation however, hydroxy ketones are formed as side products, and yields are lower than with alkyl esters. Amides are also effective, but form the ( )-isomer predominantly. This method has been applied to the synthesis of precursors to spiroacetals (499) by Kocienski (equation 115). ° The reaction was found to be compatible with THP-protected hy- oxy groups, aromatic and branched substituents, and alkene functionality, although complex substitution leads to varying rates of reaction for alkylidenation. Kocienski and coworkers found the intramolecular reaction to be problematic. As with the CrCb chemistry, this reaction cannot be used with a disubstituted dibromoalkane to form the tetrasubstituted enol ether. Attempts were made to apply this reaction to alkene formation by reaction with aldehydes and ketones, but unfortunately the (Z) ( )-ratio of the alkenes formed is virtu ly 1 1. ... 

Analogous treatment of the unsaturated ester 207 using 1,1-dibromoethane in this case cleanly produced the dihydropyran 208 in high yield on a gram scale (Scheme 2.73) [41bj. Cydic enol ether 208 was then efficiently advanced to a spiroacetal, which corresponds to the core structure of the bioactive polyketide spirofungin A. 

An efficient strategy for the eonstruction of endocyclic enol ethers (35) based on the Suzuki-Miyaura eoupling of the enol phosphate (33) and the alkylborane (34) followed by the ring-closing metathesis (RCM), has been described by Fuwa and Sasaki (Scheme 8). This methodology has been successfully applied in the synthesis of a variety of spiroacetals, including the cytotoxic marine metabolites attenols A and B. 

Extremely sterically demanding Br0nsted acid catalyst 13 indeed efficiently catalyzed the asymmetric conversion of small and further unfunctionalized hydroxy enol ether substrates. Various spiroacetals were obtained with high enantios-electivity independent of the ring size of the enol ether by the formation of either 6- or 5-membered rings (Table 4) [57]. Catalyst 13 also enabled the first catalytic asymmetric synthesis of the natural product olean (entry 2). AU these small spiroacetals in Table 4 are core stmcmres of many natural products [6-8]. 

The main stereoselective MBFTs for the synthesis of spirocyclic acetals or aminals involve the activation of a C-C triple bond to form an intermediate cyclic enol ether. The method disclosed above for the synthesis of a-heteroatom-substituted spirocen-ter (see Section 9.3.3, Scheme 9.18) [34] was next extended by the same authors to the synthesis of spiroacetals. They simply used salicyladehyde as starting aldehyde, but the transformation was not diastereoselective anymore [43]. This problem of stereoselectivity was recently solved by Gong and coworkers, who employed a gold(I)/chiral Brpnsted acid catalysis to do so [44], The chroman spiroacetals were obtained in excellent yields (67-97%) and with high stereoselectivities (up to 95% ee, up to 25 1 dr) (Scheme 9.24). This reaction resulted in the formation of three new single bonds and two stereogenic centers. 

Synthesis of the C9-C28 spiroacetal fragment of didemnaketal B was achieved using a similar strategy. Suzuki-Miyaura coupling of an alkyl borate (derived from iodide 102 and B-methoxy-BBN) to the phosphate 103 afforded endocyclic enol ether 104. Spirocyclization took place after cleavage of the silyl ethers with subsequent treatment with mild acid (PFTS), affording the doubly anomerically stabilized spiroacetal 105 in high yield. 

Alternatively, an exocyclic enol ether may be used for the synthesis of spiroacetals, the spirocyclization once again taking place via generation of an oxonium ion intermediate (Scheme 34). 

An alternative method for the synthesis of spiroacetals involves cyclization of a pendant alcohol to an exocyclic enol ether. A recent example of an acid-catalyzed cyclization of an exocyclic enol ether has been reported by Goekjian et al. [79] in their synthesis of the cytotoxic marine metabolite bistramide A, 72 (Scheme 35). Lactone 137 and benzothiazole 138 were coupled in a modified Julia-Koscienski olefination [80] to give the requisite exocyclic enol ether 139 subsequent treatment with catalytic PTSA in dichloromethane afforded the spiroacetal 140 in good yield over two steps. 

Classically, treatment of an endocyclic enol ether with an electrophilic halide reagent such as iV-bromo- or A[-iodosuccinimide [72,113-117], or organoselenium reagents (PhSeX) [118-122], affords electrophUe-substituted spiroacetals (Scheme 53). The halide is then removed using reductive methods or used for further elaboration of the spiroacetal toward the target molecule. 

Shair et al. [123] have used an electrophilic spirocychzation in their synthesis of cephalostatin 1 (Scheme 54). The spiroacetal of the western half, 228, was obtained by treatment of the endocyclic enol ether 226 with PhSeBr, giving the mono-anomeric spiroacetal 227 in excellent yield. Transformation to the desired doubly anomeric spiroacetal 228 was achieved by reductive removal of the bromide, followed by epimerization with CSA. 

The hetero-Diels-Alder reaction (HDA) has been used extensively for the construction of spiroacetals [4], notably in the synthesis of the reveromycins [150-153]. In particular, the recent development of mild methods for the generation of ort/to-quinone methides (o-QM) in the presence of sensitive five-membered exocyclic enol ethers has revealed an alternative route to benzannulated... 

Treatment of spicifemin-inspired alkynol 307 and pulvilloric acid-inspired fragment 306 with AgSbFs resulted in cycloisomerization of 307 to enol ether 309 formation of o-QM 308 from 306 and subsequent HDA of 308 and 309 to give an inseparable mixture of spiroacetal 311 as the major component, along with a mixture of four other diastereomers in an approximate ratio of 6 4. Careful regioselective demethylation to the free acid allowed separation of the diastereomers, and berkelic acid 96 was therefore obtained in 46 % after one recycle. 

The application of a HDA strategy for the synthesis of bis(benzannulated) spiroacetals as exemplihed by the rabromycin family of natural products has also attracted attention. An initial report [164] of the HDA between an o-QM and chroman-derived enol ethers 315 required high temperature and pressure to afford... 

The cycloisomerization/cycloaddition cascade approach has been extended to bis (benzannulated) 5,6-spiroacetals recently by Xue et al. [166] (Scheme 80). Thus, Cu (I)-catalyzed cycloisomerization of aUcynol 327 gives the enol ether 329, which then undergoes HDA with the o-QM 330, generated in situ from 328 under flie thermal reaction conditions. The bis(benzannulated) spiroacetals 331 were obtained in good yield and selectivity (dr >20 1), favoring the doubly anomeric configuration. 

An alternative cycloaddition approach to bis(benzannulated) spiroacetals has been explored by Pettus and coworkers in their synthesis of Y-rubromycin 58. Based on the [3+2]-cycloaddition of an enol ether with a p-diketone-derived zwitterion [167], early studies on simple substrates afforded the 5,6-spiroacetal in moderate yield [168, 169]. 

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