Synthesis of Enantiopure 1-Azabicyclo[3.2.2]nonanes via Stereoselective Capture of Chiral Carbocations

Abstract

[reaction: see text] A new class of doubly functionalized and enantiomerically pure 1-azabicyclo[3.2.2]nonanes derived from quincorine and quincoridine is described. 2,5-Disubstituted quinuclidines with a C9-mesyloxy group were easily transformed into the corresponding halides upon treatment with lithium salts. Subsequent silver salt-mediated ring expansion stereoselectively furnished the title azabicyclics. Chiral carbocations which are configurationally stable and nonplanar are postulated to account for the striking stereoselectivity of the capture of external nucleophile. 5-Ethynyl-2-iodomethylquinuclidines afford the alpha-benzoyloxy amines rather than alpha-methoxy amines, even in MeOH.

Chemistry of Bridged Lactams and Related Heterocycles

“…423 Treatment of β-amino iodides 366 and 369 with methanol in the presence of AgOBz resulted in stereoselective rearrangement to α-amino ethers via bridged iminium ions. Other silver salts proved less efficient in promoting the reaction or led to partial epimerization of the desired products.…”

Crystal structure of (1S,2R,5R,6R)-2-methoxy-6-(16-nitrophenylethynyl)-1-azabicyclo[3.2.2]nonane, C17H20N2O3

“…The mechanism of the rearrangement involves a 1,2-nucleophilic shift with generation of a strained non-planar iminium-ion and a stereoselective nucleophilic capture by the solvent. Likewise, silver salt-mediated ring enlargement of halogenated Quincorine® and Quincoridine® derivatives offers a short and stereoselective route to novel substituted l-azabicyclo[3.2.2]nonanes containing four stereogenic centres [7]. In view of the high synthetic and therapeutic potential of 5-substituted quinuclidine derivatives we prepared (1 S,2/?,5fl,6fl)-2-methoxy-6-( 16-nitrophenylethynyl)-1 -azabicyclo[3.2.2]nonane and present its crystal structure.…”

Recent Advances inCinchonaAlkaloid Chemistry

“…in refluxing dioxane (Scheme 7). [15] The NϪC8ϪC9ϪO backbone conformation allowing free access to C9 from the rear is usually only a minor rotamer, and S N 2 displacements may be sluggish. Bidentate interaction with excess Li ϩ in solvent dioxane (but not in THF), however, is believed to change the rotameric equilibrium and to ''open up'' C9 to backside attack.…”

“…The situation appears to parallel that in some carbohydrates, in which S N 2 displacements on 1,2-alkoxy halides can also be recalcitrant. [14,15] Fluorides 12-F and 13-F and corresponding amines have been prepared by standard methods. [14,16] Interestingly, fluorine derivative 12-F is highly volatile and has a characteristic odour.…”

“…More recently, the ''first Cinchona cage expansion'' has also been accomplished for quincorine and quincoridine (Scheme 23). [15] There are substantial barriers to flipping of the tight 3-carbon bridges, with the limits of the Bredt rule being tested. The rearrangement proceeds stereoselectively under mild S N 1-like conditions and tolerates additional functionality such as carbonyl and ester groups, as well as terminal alkynes.…”