Abstract:The structure of azaprophen, which was originally assigned by 1H NMR analysis, was confirmed by X-ray crystallography. A comparison of 13C NMR isotropic chemical shift data for azaprophen in the solid state and in CDCl3 and DMSO-d6 solution was used to correlate solution and solid-state conformation as determined by the X-ray data. The data suggested that the solid-state and solution conformation of azaprophen were similar. The observed solid-state structure was also compared to low-energy conformations identi… Show more
“…We have recently examined the photocycloaddition of the corresponding 1,5-dienes, that is, 5 , and we report herein that these substrates lead to a general synthesis of azabicyclo[3,2,1]octanones, 8 , via the “crossed” photoadduct, 6 . The widespread distribution of the azabicyclo[3,2,1]octanone ring system in molecules of nature, that is, sarain A, 9 , securinine, 10 , and hetisine, 11 , and the importance of this ring system in medicinal chemistry for the development of analgesics and muscarinic antagonists suggests that the photochemistry of 5 should be of comparable utility to that of 1 . …”
“…We have recently examined the photocycloaddition of the corresponding 1,5-dienes, that is, 5 , and we report herein that these substrates lead to a general synthesis of azabicyclo[3,2,1]octanones, 8 , via the “crossed” photoadduct, 6 . The widespread distribution of the azabicyclo[3,2,1]octanone ring system in molecules of nature, that is, sarain A, 9 , securinine, 10 , and hetisine, 11 , and the importance of this ring system in medicinal chemistry for the development of analgesics and muscarinic antagonists suggests that the photochemistry of 5 should be of comparable utility to that of 1 . …”
“…As one important class of bridged bicyclic nitrogen scaffolds, the 6‐azabicyclo[3.2.1]octane ring system is frequently observed in naturally occurring and synthetic small molecules, and it is considered a privileged scaffold for drug discovery (Scheme 1c) [6] . Although a number of synthetic strategies have been developed for synthesizing molecules containing this type of ring system, [7] only four synthetic approaches [7g, l, q, r] have been developed to access 6‐azabicyclo[3.2.1]octan‐3‐ones, which can serve as the synthetic intermediates for accessing bioactive natural products and drug candidates, including azaprophen, [8] actinobolamine, [7e] and cocaine analogues [6] (Scheme 1c). Despite their elegant design, these chemical synthetic methods suffer from either multistep synthesis with low efficiency or complex starting materials, and limited substrate scope (Scheme 1d) [7g, l, q, r] .…”
Herein we report that ene reductases (EREDs) can facilitate an unprecedented intramolecular β-CÀ H functionalization reaction for the synthesis of bridged bicyclic nitrogen heterocycles containing the 6azabicyclo[3.2.1]octane scaffold. To streamline the synthesis of these privileged motifs, we developed a gramscale one-pot chemoenzymatic cascade by combining iridium photocatalysis with EREDs, using readily available N-phenylglycines and cyclohexenones that can be obtained from biomass. Further derivatization using enzymatic or chemical methods can convert 6azabicyclo[3.2.1]octan-3-one into 6-azabicyclo-[3.2.1]octan-3α-ols, which can be potentially utilized for the synthesis of azaprophen and its analogues for drug discovery. Mechanistic studies revealed the reaction requires oxygen, presumably to produce oxidized flavin, which can selectively dehydrogenate the 3-substituted cyclohexanone derivatives to form the α,β-unsaturated ketone, which subsequently undergoes spontaneous intramolecular aza-Michael addition under basic conditions.
“…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. [ 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.…”
In an approach to the biologically important 6-azabicyclo[3.2.1]octane ring system, the scope of the tandem 4-exo-trig carbamoyl radical cyclization—dithiocarbamate group transfer reaction to ring-fused β-lactams is evaluated. β-Lactams fused to five-, six-, and seven-membered rings are prepared in good to excellent yield, and with moderate to complete control at the newly formed dithiocarbamate stereocentre. No cyclization is observed with an additional methyl substituent on the terminus of the double bond. Elimination of the dithiocarbamate group gives α,β- or β,γ-unsaturated lactams depending on both the methodology employed (base-mediated or thermal) and the nature of the carbocycle fused to the β-lactam. Fused β-lactam diols, obtained from catalytic OsO4-mediated dihydroxylation of α,β-unsaturated β-lactams, undergo semipinacol rearrangement via the corresponding cyclic sulfite or phosphorane to give keto-bridged bicyclic amides by exclusive N-acyl group migration. A monocyclic β-lactam diol undergoes Appel reaction at a primary alcohol in preference to semipinacol rearrangement. Preliminary investigations into the chemo- and stereoselective manipulation of the two carbonyl groups present in a representative 7,8-dioxo-6-azabicyclo[3.2.1]octane rearrangement product are also reported.
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