Diastereoselective Syntheses of Chroman Spiroketals via [4 + 2] Cycloaddition of Enol Ethers and o-Quinone Methides

Abstract

A variety of chroman spiroketals are synthesized via inverse-demand [4 + 2] cycloaddition of enol ethers and ortho-quinone methides (o-QMs). Low temperature o-QM generation in situ allows for the kinetic, diastereoselective construction of these motifs, providing entry to a number of unusual chroman spiroketal natural products.Aliphatic spiroketals are a common substructure of natural products isolated in a large variety from both marine and terrestrial sources. 1 Studies aimed at understanding the origins of their conformational preference have resulted in the general assumption that the spiroketal carbon corresponds to the thermodynamically most stable isomer as determined by stereoelectronic influences. Hence, the biosynthesis of these fluxional natural products usually results in the construction of the most stable diastereomer or a mixture that reflects energy differences between respective diastereomers.For some time, we have speculated that a rare subset consisting of chroman spiroketals (1, 2 2 ,3 and 3 ,4 Figure 1) may possess features that refute this basic tenet and require a kinetic assembly. These uniquely robust chroman spiroketal scaffolds have caused us to consider new methods for their construction.Some time ago, we developed a method that enables the controlled, low-temperature generation of o-quinone methides (o-QMs) (Figure 2, I). 5 The process, which is driven by the relative stability of sequential anions formed along the cascade, begins by formation of an alkoxide. This species intercepts a neighboring carbonyl of a phenolic carbonate and thus liberates a phenoxide that subsequently undergoes β-elimination of a carboxylate and thereby forms a reactive o-QM species, which captures the first nucleophile that it subsequently encounters. This is a useful method for o-QM generation because, since the reactive o-QM intermediate is generated at low temperature in low concentrations, it subsequently participates in very precise, kinetically controlled reactions. 6 Using this procedure, we demonstrated the first examples of diastereoselective o-QM cycloadditions and found that the inverse demand [4 + 2] significantly favors an endo transition state with electron-rich alkenes. 7 In further experiments, we showed that chiral enol ethers containing remote stereocenters, such as those derived from (1S,2R)-2-phenyl-cyclohexanol, will participate in diastereoselective cycloadditions to yield the corresponding chroman acetals with an R configuration (Figure 2, II) NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript R 1 , R 2 , and R 3 substituents should also participate in cycloadditions with similar diastereoselectivity (Figure 2, III). Detailed analysis of our proposed transition state allowed us to further speculate that substituents R 1 and R 3 would have a pronounced effect on the stereochemical outcome, whereas the R 2 residue would not, allowing it to be tolerated on the same face as the reaction. Therefore, we began to examine model systems that might eventually be ...

New strategies for natural products containing chroman spiroketals

“…On the basis of these findings, we speculated that exocyclic enol ethers would participate in this o -QMDA reaction to furnish chroman spiroketals [10]. Unlike conventional ketalizations that furnish only the thermodynamic diastereomer, the stereochemical outcome of our reaction would be governed by the geometry of the enol ether starting material in relation to the intervening transition state.…”

“…10). The reaction provided compound 33 with the desired chroman spiroketal [10b]. For the actual synthesis, we needed to incorporate the octyl residue onto the o -QM coupling partner.…”

Synthesis of 5,6- and 6,6-Spirocyclic Compounds

“…Unfortunately, the corresponding 5,6-spiroacetals could not be accessed using this method due to the difficulty in obtaining the requisite enol ether 318, which under methylenation conditions Scheme 77 Belmont et al's HDA approach to mono(benzannulated) spiroacetals [163] isomerized to the endocyclic isomer exclusively. Similarly, Pettus and coworkers [154] were only able to obtain bis(benzannulated) spiroacetal 320 in poor yield when using enol ether 318 as the dienophile. However, when the enol ether 322 (which is less prone to isomerization) is submitted to the same conditions, paecilospirone-like spiroacetal 323 is obtained in moderate yield.…”

“…The first of these methods, reported by Pettus et al [154], generates an o-QM from 277 at low temperature via a t-BuMgCl initiated cascasde [155], which can then undergo a reverse electron demand-HDA (Scheme 72). A contemporaneous report from Bray [156] made use of a similar strategy, where the o-QM is generated from precursor 281 using i-PrMgCl.…”

“…Scheme 78 HDA approaches toward bis(benzannulated) spiroacetals [154,164] Scheme 79 Xie et al's vinyl sulfoxide-based HDA approach toward bis(benzannulated) spiroacetals [165] Following the HDA, elimination of the sulfoxide occurs under the reaction conditions to afford the 5,6-spiroacetals 326 in good yield.…”