A double Michael route to piperidines and its application towards the synthesis of codeine

Piperidine ring systems are among the most abundant structural sub-units in organic chemistry. Their abundance is clearly obvious from the many natural products, many of which are biologically active, that contain this moiety. We have shown that various 1,5-diacids containing a nitrogen tether undergo double Michael reactions with 3-butyn-2-one to yield highly substituted and functionalized piperidines. When an equatorial ester is present at the 4 position, a second annulation can be performed to yield a trans-perhydroisoquinoline, which makes up the CD ring system in the structure of codeine.; With our methodology, we are able to form two new C-C bonds, two new quaternary centers, and up to three contiguous stereocenters in a single step. We are now applying our double annulation methodology towards the synthesis of (+/-)-codeine.; Codeine and its congeners are some of the most widely used analgesics, and have been tempting targets for synthetic organic chemists for more than 50 years. In the nearly 30 syntheses of the morphine alkaloids, the C(12)--C(13) and C(9)--C(17) bonds of codeine have always been the key formations. We report a synthesis where these two important bonds are already present in the starting materials. Our key steps include a double Michael reaction to form the piperidine (D) ring, a Friedel-Crafts acylation to form the B ring, and a Dieckmann reaction to assemble the C ring.