Browsing by Subject "ACC"

The direct addition of enolizable aldehydes and sulfonyl imines to α-halo thioesters to produce β-hydroxy/amino thioesters enabled by reductive soft enolization is reported. The transformation is operationally simple and efficient and has the unusual feature of giving high syn-selectivity, which is the opposite of that produced for the aldol addition with (thio)esters under conventional conditions. This method is tolerant to aldehydes and imines that not only contain acidic α-protons, but also towards electrophiles containing other acidic protons and base-sensitive functional groups. Moreover, excellent diastereoselectivity is achieved when a chiral non-racemic α-hydroxy aldehyde derivative is used. Using MgI₂ and Ph₃P, this method gives a wide range of aldol and Mannich products in good yields with high syn-diastereoselectivity. The products obtained from the reductive aldol and Mannich reactions are synthetically important intermediates in both polyketide and β-lactam synthesis, respectively, and can be readily derivatized to form many carbonyl derivatives through known manipulation of the thioester moiety.

Also, herein the asymmetric synthesis of (+)-mefloquine, a potent anti-malarial compound, is described. The synthesis is based on a key enantioselective Darzens reaction between a chiral α-chloro-N-amino cyclic carbamate (ACC) hydrazone and a quinoline-based aldehyde. This is a novel methodology developed by our lab, which gives a highly enantioenriched epoxide that can be further functionalized to give both enantiomers of mefloquine.

In the first part of this dissertation, the first asymmetric anti selective aldol addition of a ketone-derived donor that is independent of the structure of the ketone is described. This transformation is facilitated by the use of chiral N-amino cyclic carbamate (ACC) auxiliaries. Under certain conditions, this transformation not only exhibits near perfect anti selectivity and enantioselectivity but also does so via thermodynamic control. Simple manipulation of the reaction conditions allows for the O-benzylation of the prepared aldol products and the subsequent removal of the ACC auxiliary to give the β-benzyloxy ketone. Both symmetric and asymmetric ketones can be utilized, and aldol products that would otherwise be difficult if not impossible to prepare via conventional methods are able to be prepared.

The second part of this dissertation describes the asymmetric total synthesis of (+)- and (-)-mefloquine hydrochloride, a potent antimalarial compound. The synthesis is based on an ACC-mediated asymmetric Darzens reaction between an α-chloro ketone and a quinoline-based aldehyde. This novel methodology gives a highly enantioenriched epoxide that can be further functionalized to prepare both enantiomers of the antimalarial drug.