Asymmetric Synthesis of Benzylic Quaternary Carbon Center via an Enzymatic Reaction

Concise Route to (–)‐ and (+)‐Aphanorphine

“…This discrepancy is notable since many of the formal syntheses reported for (–)‐aphanorphine are based on the preparation of this O ‐methyl intermediate 8 . To confirm the absolute stereochemistry, the synthesis of (–)‐aphanorphine ( 1 ) was completed by treatment of compound 8 with BBr 3 according to a reported procedure 16. The optical rotation exhibited by compound 1 {[ α ] D 20 = –23.3 ( c = 0.23, MeOH)} is in agreement with data reported in the literature {[ α ] D 20 = –24.0 ( c = 0.33, MeOH)16 and [ α ] D 20 = –23.6 ( c = 0.20, MeOH)17} for natural (–)‐aphanorphine.…”

“…To confirm the absolute stereochemistry, the synthesis of (–)‐aphanorphine ( 1 ) was completed by treatment of compound 8 with BBr 3 according to a reported procedure 16. The optical rotation exhibited by compound 1 {[ α ] D 20 = –23.3 ( c = 0.23, MeOH)} is in agreement with data reported in the literature {[ α ] D 20 = –24.0 ( c = 0.33, MeOH)16 and [ α ] D 20 = –23.6 ( c = 0.20, MeOH)17} for natural (–)‐aphanorphine. Importantly, since all the stereochemical information in the natural product is introduced in the α‐aminoallylation reaction, this result confirms the stereochemical outcome we proposed for this reaction 11…”

Lipase-catalyzed resolution of primary alcohol containing quaternary chiral carbon

“…There are many reports on the enzymatic kinetic resolution of secondary alcohols or primary alcohols containing secondary chiral carbon. But there are not many reports about resolution of quatemary chiral carbon (Canet et al, 1992;Fade1 and Arzel, 1995;Honda and Hallinan, 1995;Shiotani et al, 1996). Therefore,we have studied the best conditions for the resolution of compound (2) and (3).…”

Formal Synthesis of (−)‐Aphanorphine Using Sequential Photomediated Radical Reactions of Dithiocarbamates

“…Aphanorphine ( 1 ), an alkaloid isolated from the freshwater blue‐green alga Aphanizomenon flos‐aquae ,1 has attracted considerable attention from the synthetic community owing to its structural similarity to natural and non‐natural analgesics such as morphine, eptazocine, and pentazocine (Scheme ) 2. Approaches to aphanorphine developed to date have all relied on the formation of the B or C ring to complete the C ‐norbenzomorphan skeleton, typically exploiting the rigidity of the bridged tricyclic 3‐benzazepine structure to set the second stereocenter from a preexisting quaternary benzylic stereocenter at C1,2a–d,i,k or from an α‐branched amine at C4 2n,o,r,t–v,x,y. In this communication we present a complementary strategy for the synthesis of aphanorphine which is characterized by the late‐stage incorporation of the aromatic A ring, and formation of the pyrrolidine C ring through a novel carbon–carbon bond‐forming reaction.…”

“…The resulting lactam 19 had an optical rotation consistent with that reported in the literature,2v and its preparation constitutes a formal total synthesis of (−)‐aphanorphine ( 1 ). Conversion of 19 to the natural product has previously been accomplished in two steps—reduction of the amide to the amine using LiAlH 4 in 87–93 % yield,2o,v,w followed by O‐demethylation using BBr 3 in yields ranging from 61–88 % 2a,b,i,k,o,x…”