Chroman spiroacetals

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. 

SCHEME 4 Our initial proposal for the synthesis of chroman spiroacetals. 

SCHEME 5 Three-component coupling reactirm for the synthesis of amino-substituted chroman spiroacetals. 

SCHEME 6 Diastereoselective synthesis of oxygen-substituted chroman spiroacetals. 

SCHEME 8 Proof of concept. Silver-catalyzed synthesis of a chroman spiroacetal similar to... 

To quickly assess the viability of our proposed key reaction, we explored a model system employing readily available alkynol 15c and salicylaldehyde derivative 23a. In this simplified case, we intentionally selected an alkynol without stereogenic centers and a simplified version of the required aldehyde. As previously mentioned, it was our intention that the same metal catalyst would activate the alkyne of both reagents 15 and 23. After a short optimization study, it was found that this model reaction proceeded in the presence of 5 mol% of silver triflate (AgOTf) to give the desired polycyclic chroman spiroacetal derivative 24a basically in a quantitative yield as a single diastereoisomer (Scheme 8). It should be noted that this reaction proceeds without the need of an excess of either of the starting materials 15c or 23a. 

In summary, starting with the discovery of a new catalytic method for the synthesis of chroman spiroacetals, we have been able to synthesize the relatively complex natural product ( )-berkelic acid. Thus, a topic (the multicomponent catalytic coupling reactions) that initially did not promise any short-term... 

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... 

In their successful synthesis of racemic y-rubromycin 58 [170], highly functionalized chroman 333 and naphthoquinone 332 underwent oxidative [3+2]-cycloaddition (Scheme 81). The o- and p-quinone spiroacetals 334 and 335 were obtained as a 1 2 mixture in 58 % yield. Fortuitously, the demethylation conditions also catalyzed isomerization of 334, converting the mixture of quinones to ( )-y-rubromycin 58 in moderate yield. 

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