A Tandem Horner−Emmons Olefination−Conjugate Addition Approach to the Synthesis of 1,5-Disubstituted-6-azabicyclo[3.2.1]octanes Based on the AE Ring Structure of the Norditerpenoid Alkaloid Methyllycaconitine

Abstract

A novel Horner-Emmons olefination conjugate addition reaction of N-acetylamides to form 1,5-disubstituted-6-azabicyclo[3.2.1]octanes with two bridgehead quarternary carbon centers is reported. This reaction is a key step in an approach to the synthesis of small ring analogues based on the AE ring structure of the Delphinium norditerpenoid, methyllycaconitine (MLA) (1). Initially, 3-(hydroxymethyl)cyclohex-2-en-1-one (10) was selected as the starting material to these structures, but its generation proved inefficient. In contrast, the synthesis of 3-[(phenylthio)methyl]cyclohex-2-en-1-one (6) and 3-(1,3-dithian-2-yl)cyclohex-2-en-1-one (11) proceeded in good yield. Subsequent hydrocyanation, ketalization, reduction, acetylation, deprotection of the acetal, and Horner-Emmons olefination-conjugate addition reaction to form 1-[(phenylthio)methyl]-5-[(ethoxycarbonyl)methyl]-6-acetamido-6-azabicyclo[3.2.1]octane (28), 1-(1,3-dithian-2-yl)-5-[(ethoxycarbonyl)methyl]-6-acetyl-6-azabicyclo[3.2.1]octane (29), respectively, are reported, as well as for readily available 3-methylcyclohex-2-en-1-one (12). Studies on the Pummerer rearrangement of 28 and subsequent desulfurization and reduction to form an hydroxymethyl-substituted azabicyclo[3.2.1.]octane (40) and then selective protection to form a protected hydroxyethyl N-ethyl (hydroxymethyl)azabicyclo[3.2.1]octane (3) are also described.

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

“…[ 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. [ 19 ]…”

Bicyclic β-amino acids

“…266 The syntheses commenced from cyclohexenone derivatives 624 -626, which were transformed into aminoketone derivatives 627 -629 using quite standard reactions (Scheme 154). Upon HornerWadsworth -Emmons olefination conditions, cyclization occurred to give the bicyclic amino acid derivatives 630 -632.…”

A Review of Advances in the Synthesis of Analogues of the Delphinium ­Alkaloid Methyllycaconitine

“…Addition of the N-methylsuccinimido anthranilate moiety was achieved in the same manner as described in the partial synthesis above (Scheme 1) to afford the MLA analogue 37c in 65% yield. Potter and co-workers 54 reported the synthesis of a substituted-6-azabicyclo[3.2.1] octane (49), an AE ring analogue with the E ring contracted to a 5-membered system (Figure 10). Commercially available 3-ethoxycyclohex-2-en-1-one (50) was treated with thioanisole, 1,4-diazabicyclo[2.2.2]octane (DABCO) and n-butyllithium in THF followed by acid hydrolysis to afford the enone 51 in 67% yield (Scheme 10).…”