The Stereoselective Synthesis of 2-Substituted 3-Azabicyclo[3.2.0]heptanes by Intramolecular [2+2]-Photocycloaddition Reactions

Abstract

The stereoselective synthesis of the 3-azabicyclo[3.2.0]heptanes 6, 12, 13, 17, 22, 23 and 24 by an intramolecular [2+2]-photocycloaddition is described. The product yield was good to excellent in almost all cases studied (65-87%) except for a single example (21 → 24) in which a low yield was recorded (22%). The facial diastereoselectivity of the reaction is high if a-branched N,Ndiallylamines are employed as starting materials which either bear a comparably bulky a-substituent (25) or the a-substituent of which is connected to the nitrogen atom via an oxazolidinone ring (16, 19, 20, 21). These diallylamines were readily prepared from methionine and it was shown that their preparation proceeded free of racemization. The photocycloaddition could be conducted in two ways. The more general method is based on the Cu-catalyzed reaction which was carried out with Cu(OTf) 2 in diethyl ether and is applicable to essentially all substrates under scrutiny. The N-cinnamyl substituted substrates 5, 11, 16 and 25 which possess a comparably low lying T 1 state reacted well in a triplet-sensitized process employing acetophenone as the sensitizer and acetone as the solvent.

Photochemistry of Cyclobutanes: Synthesis and Reactivity

“…Perfect facial diastereoselection is exhibited in the more rigid diene 23. Its irradiation under the same conditions as in the previous examples affords 24 with a selectivity of >95:<5 28,29 . Dimerization of more complex styrenes has been reported in the crystalline phase.…”

Synthesis of 3‐Azabicyclo[3.2.0]heptane‐Derived Building Blocks via [3+2] Cycloaddition

“…Several approaches to the construction of 3‐azabicyclo[3.2.0]heptane core are described in the literature, mostly being represented by intra‐ and intermolecular [2+2]cycloaddition reactions. Each of these methods usually require the use of transition‐metal catalysis or UV irradiation, except for the case of intramolecular cycloaddition of keteniminium salts,, thus typically being limited in substrate scope.…”

Visible Light‐Mediated Synthesis of Enantiopure γ‐Cyclobutane Amino and 3‐(Aminomethyl)‐5‐phenylpentanoic Acids

“…This method could also be applied to 1,3-dienes. [16] More recently, Mykhailiuk and coworkers irradiated N-benzyl-substituted amide-linked dienes at 366 nm in the presence of acetophenone as photosensitizer in order to build up 3-azabicylo[3.2.0] heptanes, which are attractive building blocks for drug discovery. In contrast to this metal-based photocatalytic process, also flavin derivatives can serve as triplet sensitizer for this reaction type, [13] being demonstrated for the cyclization of nitrogen-and sulfurcontaining aryl dienes to the corresponding arylbicyclo[3.2.0]heptanes 4.…”

“…The electron-rich heterocycles thiophene and furan on the carbonyl side also accelerate the [2 + 2] photocycloaddition with respect to the phenyl substituent (entry 8,12,13). [16] In the case of the ester-linked derivative 5 j, an increase in the reaction temperature to 80 8C was necessary, nevertheless, the cyclobutane 6 j was only obtained in a yield of 29% (entry 16). The [2 + 2] cycloaddition of substrates with two aromatic substituents (entry 1-4, 16) resulted in a diastereomeric mixture, from which a minor compound could not be isolated and thus its stereochemistry cannot be assigned with certainty.…”

“…An elegant example of utilizing UV light for the triplet-sensitized intramolecular [2 + 2] photocycloaddition was later reported by Bach et al, who described the stereoselective preparation of 3-azabicyclo[3.2.0]heptanes from N,N-diallylamines with acetophenone as the sensitizer. [16] More recently, Mykhailiuk and coworkers irradiated N-benzyl-substituted amide-linked dienes at 366 nm in the presence of acetophenone as photosensitizer in order to build up 3-azabicylo[3.2.0] heptanes, which are attractive building blocks for drug discovery. [17] Having the synthesis of novel cyclobutane containing amino acids in mind, we investigated the extension of the iridium-based triplet sensitized reaction to amide linked dienes 5 (Scheme 1).…”