Total synthesis asymmetric protonation

Enyne cycloisomerizations can also be exploited to annulate a cyclopentane onto an existing ring system. An example drawn from Trost and co-workers asymmetric total synthesis of picrotoxinin (119) is the conversion of bridged bicyclic intermediate 117 into tricycle 118 (Scheme 6-20) [46]. The optimal cyclization conditions in this case were unusual, requiring an internal proton delivery and a bidentate phosphine. A related example is the conversion of 120 to 121, which was the pivotal step in Trost s synthesis of (—)-dendrobine (122) [47]. An all-carbon tether is not required, as is exemplified by the conversion of 123 to 124 in the total synthesis of ( )-phyllanthocin (125) [48]. Note that in-situ reduction of the o-palladium species prior to /5-hydride elimination has occuined in this latter-example. The enyne disconnection in the synthesis of ( )-phyllanthocin was... 

In this chapter, the enantioselective protonation of preformed and a-stabilized carbanions is disclosed. A second part is devoted to the asymmetric protonation of enolate species obtained in situ through a first chemical transformation with activated double bonds (i.e., ketenes or Michael acceptors). Herein, among all the advances made using these two main approaches, methodologies that have been used in total synthesis of natural and pharmacologically active products are emphasized. 

The first method using the j-BuLi-sparteine aggregate was successfully applied to the asymmetric protonation of 2-(l-phenylethyl)pyridine 5 to afford (S)-5 in good yield with 50% ee. The 4-aryl-tetrahydroisoquinoline backbone 6, which is of considerable interest because of its presence in several natural or bioactive products such as sertraline or nomifensine, was obtained in good yield with 88% ee. Although the backbone of bioactive compounds was synthesized in an asymmetric fashion, the total synthesis of the corresponding drugs or natural products has not yet been achieved to date. 

Recently, Levacher and co-workers reported on the total synthesis of two natural homoisoflavones using their asymmetric protonation protocol as a key step. Their concept focused on the use of chiral ammonium fluoride as a chiral ion pair to generate a naked enolate or a hypervalent silicate species, which might be trapped in an asymmetric concerted fashion by the proton coming from the chiral counter anion (Figure 31.1). 

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