Azabicyclo octane nucleophile

The majority of transformations carried out at ring substituents of bicyclic azetidinones were described in Section 5.12.3.3.2 for azetidinones related to cephalosporins and penicillins. Nucleophilic displacement reactions of 7-halo-l-azabicyclo[4.2.0]octan-8-ones with thallium phthalimide and hydrazine have been reported (76ACS(B)318). 

If the internal nucleophile is an alkenic group, then 5,6-dihydropyridine (Scheme 18) " or 1-pyrroline (Scheme 19) rings are produced. In a recent development of the latter process, the diol (44) follows the same sequence to yield the carbenium ion (45 R = Bn). However, this now cyclizes onto the aromatic group originating from the nitrile component and produces the tetrahydrobenz indole (46) in good yield, with the conventional pyrroline structure (47) now being only a minor product. Compound (46), present as a tautomeric mixture, was rapidly autoxidized to (48 Scheme 20). A further unusual variant of this process is the production of small quantities of the 3-azabicyclo[3.3.0]octanes (49) and (50) from Ritter reaction of l-vinylbicyclo(2.1.1]hexane (equation 32). ... 

Synthetic access to quinidine positions other than C2 and C3 is more challenging. Treatment of quinine in superacid, for example, delivers a tricyclic derivative 96 via nucleophilic ring closure between the C9 OH oxygen and a carbocation at C5 (Scheme 12.27). However, cyclization occurs only subsequent to a rearrangement of the azabicyclo[2.2.2]octane unit into a thermodynamically more stable [3.2.1]-system [65]. 

Subsequently, the same authors found that the structiual analogue bieyeUe azetidine derivative 166, having a silylated alcohol on the lateral ehain, showed increased reactivity in a similar transformation, albeit with low enantioselec-tivity (ee-value up to 26%), indicating that azabicyclo[3.2.0]heptane is more nucleophilic than azabicyclo[3.3.0]octane since the same MBH reaction with catalyst 163 was significantly slower (Scheme 2.81). This enhancement in catalytic activity can probably be attributed to increased pyramidalization of the nitrogen atom imposed by the four-membered ring. ... 

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