Aza-Cope rearrangement cationic

Cartion-cartxin bond formation via tandem Mannich condensation, cationic aza-Cope rearrangement of homoaHylarrunes, leading to pyrolidmes... 

The mechanism involves conversion of V-homoallylamine 116a to imine 117a via a Lewis acid-catalyzed cationic aza-Cope rearrangement (equation 61). Various Lewis acids were tested with yields ranging from 40-99% with high diastereoselectivities. 

In an elegant approach to gelsemine [238] based on a similar strategy the cationic aza-Cope rearrangement was superseded by a simple Mannich reaction because the twistane skeleton is more highly strained. However, the desired transformation is achievable using the anionic version. 

The use of a cationic aza-Cope rearrangement in concert with a Mannich cyclization has also been applied to the total synthesis of enantiomerically pure (—)-crinine (359) (205). In the event, nucleophilic opening of cyclopentenoxide with the aluminum amide that was formed on reaction of (/ )-a-methylbenzyl-amine and trimethylaluminum gave the amino alcohol 485 together with its (15,25) diastereomer. Although there was essentially no asymmetric induction in this process, the diastereomeric amino alcohols were readily separated by chromatography, and the overall procedure therefore constitutes an efficient means for the preparation of enantiomerically pure 2-amino alcohols from epoxides. When the hydrochloride salt derived from 485 was treated with paraformaldehyde and potassium cyanide, the amino nitrile 486 was formed. Subsequent Swem oxida-... 

Overman, L. E. Kakimoto, M. Okazaki, M. E. Meier, G. P. Carbon-carbon bond formation under mild conditions via tandem cationic aza-Cope rearrangement-Mannich reactions. 

This reaction exhibits strong analogy with the silver-promoted cationic aza-Cope rearrangement described by Overman et al. As a new route toward alkaloids, these authors showed thatcyanomethylamines carrying unsaturated chain led to pyrrolidine or piperidine derivatives on treatment with silver salts depending on the substituent (Scheme 3.38) 59 60... 

On the basis of this rearrangement, an efficient synthetic route to pyrrolidines such as (46) was developed by Overman, starting from oxazolidine (42), via hydroxylated homoallylic imines such as (43 Scheme 22).Mechanistically, the formation of (46) may explained as a tandem-type combination of a cationic aza-Cope rearrangement with a subsequent Maimich cyclization (route a) or, alternatively, as an alkene-iminium ion cyclization/pinacolic rearrangement sequence (route b). 

The tandem cationic aza-Cope rearrangement followed by a Mannich cyclization was applied in the synthesis of the novel tricyclic core structure of the powerful immunosupressant FR901483 in the laboratory of K. Brummond. Their approach was the first synthetic example in which this tandem reaction passes through a bridgehead iminium ion. 

Jacobsen, E. J., Levin, J., Overman, L. E. Synthesis applications of cationic aza-Cope rearrangements. Part 18. Scope and mechanism of tandem cationic aza-Cope rearrangement-Mannich cyclization reactions. J. Am. Chem. Soc. 1988, 110, 4329-4336. 

Brummond, K. M., Lu, J. Tandem Cationic aza-Cope Rearrangement-Mannich Cyclization Approach to the Core Structure of FR901483 via a Bridgehead Iminium Ion. Org. Lett. 2001, 3,1347-1349. 

Recently, cyclizations of the isomeric unsaturated carbamates (141) and (142) have been investigated (equation 107). These fundamental reactions are not as regio- and stereo-selective as similar cyclizations starting from cyclic A -acyliminium ions (equations 25 and 26). The loss of stereoselectivity might have to do with the occurrence of cationic aza-Cope rearrangements in combination with chair-chair interconversions (equation 108). Normal cyclization of (142) occurs via conformation (145) and should lead to (144). If sigmatropic rearrangement competes with normal cyclization, (146) arises, but this conformation still leads to (144). Only after chair-chair interconversion to (147) and subsequent cyclization, (143) is formed. Via the same mechanism (141) can produce the abnormal product (144). 

The occurrence of a fast cationic aza-Cope reairangement has been proven in the case of vinylsilane cyclizations (equation 109). Enantiomerically pure ethoxycarbamate (148) cyclizes under the influence of BF3-Et20 to a I I mixture of racemic tetrahydropyridines (149) and (150). Thus, the equilibration of iminium ions (151) and (152), attended with racemization (equation 110), occurs much faster than ir-cy-clization. Because allylsilanes are more nucleophilic than vinylsilanes, ir-cyclization probably takes place from (152). The fast rate of cyclization of allylsilanes is apparent from the cyclization via (140), where cationic aza-Cope rearrangement cannot compete (equation 105). 

Homoallylic amines containing an allylic hydroxy group rearrange in the presence of an aldehyde and an acid catalyst to yield 3-acylpyrrolidines. If the starting amino alcohol is cyclic, this transformation provides a pyrrolidine-annulated product, in which the initial ring is expanded by one member. The mechanism has been proposed to proceed via a tandem cationic aza-Cope rearrangement/Mannich cyclization1134. 

Brummond s synthesis through the tandem cationic aza-Cope rearrangement-Mannich cyclization reaction... 

Brummond s approach to FR901483 involves compound V, which can be accessed in a very efficient manner using a tandem cationic aza-Cope rearrangement/Mannich cyclization strategy. The complete retrosynthetic analysis leads to three relatively simple starting materials (Scheme 25). 

Cationic aza-Cope rearrangement. Doubly allylic ammonium salts may be induced to undergo sigmatropic rearrangement after equilibration to the allyl vinyl ammonium isomers. Hydrolysis of the resulting iminium ions leads to xS-unsatu-rated carbonyl compounds. 

Overman and co-workers continue to report new applications of their tandem cationic aza-Cope rearrangement-Mannich cyclization route to nitrogen heterocyclic systems. Perhaps the nicest illus-... 

Other academic groups have used the Overman pyrrolidine synthesis en route to complex alkaloids and other medicinally relevant compounds. The Brummond group at the University of Pittsburgh has reported the formal synthesis of (-)-FR901483 (48), an immunosuppressant isolated by researchers at Fujisawa Pharmaceuticals. In this report, Brummond incorporated a tandem cationic aza-Cope rearrangement/Mannich cyclization that proceeds via a bridgehead iminium ion. Treatment of intermediate 44... 

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