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

Abstract

Zeit zum Lampenwechsel: Ein Alkyldithiocarbamat, selbst das Produkt der lichtinduzierten Gruppentransfercyclisierung eines Carbamoylradikals, geht einen zweiten lichtvermittelten Radikalprozess ein, der durch eine andere Lichtquelle ausgelöst wird. Diese Reaktionen, die über das gleiche Cyclohexenylradikal verlaufen, sind Schlüsselschritte in einer neuen asymmetrischen Synthese des Alkaloids Aphanorphin. TEMPO = 2,2,6,6‐Tetramethyl‐1‐piperidinoxylradikal.

Carbamoyl Radical‐Mediated Synthesis and Semipinacol Rearrangement of β‐Lactam Diols

“…[ 6 ] In related research we have employed the regioselective cyclization of carbamoyl dithiocarbamate 5 to synthesize the bridged 6-azabicyclo[3.2.1]octane ring system 6 of aphanorphine, an alkaloid isolated from a blue–green algae. [ 7 ]…”

“…The 6-azabicyclo[3.2.1]octane ring system is found within a range of synthetic[ 8 ]–[ 10 ] and naturally occurring,[ 7 , 11 ]–[ 18 ] biologically active compounds (Figure 1 ). The former include 7 (“azaprophen”), a synthetic muscarinic anatagonist,[ 9 ] and 8 , a synthetic cocaine analogue and inhibitor of dopamine reuptake.…”

“…The former include 7 (“azaprophen”), a synthetic muscarinic anatagonist,[ 9 ] and 8 , a synthetic cocaine analogue and inhibitor of dopamine reuptake. [ 10 ] Representative natural products containing the 6-azabicyclo[3.2.1]octane ring system include aphanorphine,[ 7 , 11 ] members of the Securinega alkaloids, for example securinine,[ 12 ] actinobolamine,[ 13 ] members of the hetisine alkaloids, for example nominine,[ 14 ] lyconadin A,[ 15 ] peduncularine,[ 16 ] calyciphilline D[ 17 ] and sarain A. [ 18 ] Hence this ring system has been the focus of intense synthetic interest, with a number of approaches reported in addition to those applied in target synthesis.…”

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“…[6] In related research we have employed the regioselective cyclization of carbamoyl dithiocarbamate 5 to synthesize the bridged 6azabicyclo[3.2.1]octane ring system 6 of aphanorphine, an alkaloid isolated from a blue-green algae. [7] The 6-azabicyclo[3.2.1]octane ring system is found within a range of synthetic [8][9][10] and naturally occurring, [7,[11][12][13][14][15][16][17][18] biologically active compounds ( Figure 1). The former include 7 ("azaprophen"), a synthetic muscarinic anatagonist, [9] and 8, a synthet-ic cocaine analogue and inhibitor of dopamine reuptake.…”

“…The former include 7 ("azaprophen"), a synthetic muscarinic anatagonist, [9] and 8, a synthet-ic cocaine analogue and inhibitor of dopamine reuptake. [10] Representative natural products containing the 6-azabicyclo-[3.2.1]octane ring system include aphanorphine, [7,11] members of the Securinega alkaloids, for example securinine, [12] actinobolamine, [13] members of the hetisine alkaloids, for example nominine, [14] lyconadin A, [15] peduncularine, [16] calyciphilline D [17] and sarain A. [18] Hence this ring system has been the focus of intense synthetic interest, with a number of approaches reported in addition to those applied in target synthesis.…”