The Rearrangement Route to 3-CH₂X-2-azabicyclo[2.1.1]hexanes. Substituent Control of Neighboring Group Participation

Abstract

The stereocontrolled synthesis of a functionalized 3-hydroxymethyl-2-azabicyclo[2.1.1]hexane synthon for a variety of methano-bridged pyrrolidines has been effected. The key step in an electrophilic addition-rearrangement route uses a 3-nosyloxymethyl group in the 2-azabicyclo[2.2.0]hex-5-ene precursor in order to suppress unwanted competitive oxygen neighboring group participation. [reaction: see text]

Regioselective and Diastereoselective Amination of Polybenzyl Ethers Using Chlorosulfonyl Isocyanate: Total Syntheses of 1,4-Dideoxy-1,4-imino-d-arabinitol and (−)-Lentiginosine

“…The diastereoselectivity of these reactions can be explained by the neighboring group effect, in which the NHCbz group orientation retains the original configuration in benzyl ether via a double inversion of the configuration, as shown in Figure . The reduced diastereoselectivities of 8 and 9 may have been caused by the increased steric repulsion between the two bulky substituents in transition state B.…”

Second-Chance Rearrangement Route to Novel 5(6)-Syn,anti-difunctional 2-Azabicyclo[2.1.1]hexanes

“…Attack of the nucleophile occurs at C 1 in 5- exo -bromoaziridinium ions. See refs a, b,c, and 6. Although the ion iii has a larger LUMO at C 1 , there is a bromine atom steric effect for nucleophilic attack at C 6 not present in 9 .…”

“…The 2-azabicyclo[2.1.1]hexane ring system 1 has now been generated by photochemical, ring closure, and rearrangement routes, but there is a paucity of methods for introducing useful hydroxyl or halide functionality into the methanobridges of 1 . A three-step rearrangement route introduces 5- anti -bromo-6- anti -hydroxy groups as in 2 , but this bromonium ion pathway does not allow for direct introduction of 5(6)-syn substituents …”

“…The nine-step cyclobutane ring closure route of Huet et al. has enabled a 5- syn -phenylselenyl group to be introduced as in 3 ,1d but this group lacks the synthetic utility of a hydroxyl group or the biological utility of a fluoride. As part of our efforts to prepare fluoro- and hydroxy-substituted methanoprolines , and to generate methanopyrrolidine synthons for library generation, we desired an efficient stereocontrolled method for introducing these functional groups into the methano bridges of azabicycle 1 in stereochemically defined syn and anti orientations.…”

Chlorosulfonyl Isocyanate Reactions with N-(Alkoxycarbonyl)-2-azabicyclo[2.2.0]hex- 5-enes. Regiospecific Two-Atom Insertion Pathways

“…N -(Alkoxycarbonyl)-2-azabicyclo[2.2.0]hex-5-enes 1 , readily synthesized from pyridines via 1,2-dihydropyridines, , have now been shown to be useful substrates for a variety of novel monocyclic, − fused ring, − and bridged 7-9 nitrogen heterocycles. The reactions of azabicycles 1 at the olefin position have been found to show a large dependence on the folded nature of its structure and to be strongly influenced by the neighboring nitrogen.…”