Annulation, enantioselective

Tlie constrLiction of carbocydic cotnpoutidi by ring-annulation procedures frequently plays a prominent role in total syntliesis. Tlie tolerance of various functional groups in tlie zinc reagents employed in copper-catalyzed asymmetric 1,4-additions fornis tlie basis for tliree novd catalytic enantioselective annulation metliods discussed bete. 

Scheme 7.25. Annulation methodology a) Hajosh-Parrish version of the Robinson annulation, b) catalytic enantioselective annulation with functionalised organozinc reagents.

Bicyclo[4.3.0]nonenes, thanks to their frequent appearance in natural products, are other important targets for novel annulation methodology. A six-membered ring-annulation to cyclopentenones has yet to be developed, the main reason for this being that, until very recently, the levels of enantioselectivity in catalytic 1,4-additions to 2-cyclopentenone were too low for a synthetically useful procedure. However, a highly enantioselective annulation of a five-membered ring to 2-cyclo-hexenone has been developed (Scheme 7.26) [80]. 

Scheme 7.26. Catalytic enantioselective annulations of five-membered rings.

Scheme 7.27. Catalytic enantioselective annulations using RCM (ring-closing metathesis).

Enantioselective annulation of (A)-2c with l-bromo-4-chlorobutane gives the hexahy-drobenzo[a]quinolizine in good chemical and excellent optical yield12. 

Keller E, Feringa BL. Catalytic enantioselective annulations via 1,4-addition-aldol cyclization of functionalized organozinc reagents. J. Am. Chem. Soc. 1999 121 1104-1105. 

Przezdziecka, A., Stepanenko, W., Wicha, J. Catalytic enantioselective annulation using phenylsulfanylmethyl vinyl ketone. An approach to trans-hydrindane building blocks for ent-vitamin D3 synthesis. Tetrahedron Asymmetry 999, 10,1589-1598. 

The Bode group disclosed NHC-catalyzed highly enantioselective annulations of a,P,P -trisubstituted enals with cyclic sulfonylimines. Mechanistically, it is proposed that the combination of enal and free NHC leads to the formation of the Breslow intermediate, which is oxidized to form the key a,p-unsaturated acyl azolium. Tautomerization between the imine and the enamine occurs readily in the presence of base, and the enamine is intercepted by the key a,p-unsaturated acyl azolium to form a hemiaminal which further engages in a Stork-Hickmott-Stille-type annulation via a tight-ion-pair/aza-Claisen type transition state. Lactam formation follows the protonation of enolate and brings about catalyst turnover to complete the catalytic cycle (Scheme 7.113). 

Rhodium-catalyzed chelation-assisted C—H bond functionalization reactions (enantioselective annulation of aryl imines, dihydropyridine synthesis from imines and ahcynes, one-pot synthesis of pyridines from imines and alkynes, 2-arylpyridine alkylation with imines) 12ACR814. Synthesis of pyridine and dihydropyridine derivatives by regjo- and stereoselective addition to N-activated pyridines 12CRV2642. 

Recently, Enders and coworkers reported the enantioselective annulation of indolin-3-ones with 2-bromoenals to deliver dihydropyranoindol-2-ones 98 in good yields and good to excellent enantiomeric excess values. The mesitylene solvent and the diamine base played important roles in maximising the enantioselectivity (Scheme 20.43). 

Scheme 2.86 Palladium-catal zed enantioselective annulation of allenes.

A synthetically powerful variant of the asymmetric FCA reaction via Michael addition involves cascade processes in which multiple catalytic events occur subsequentially. The approach has been efficiently employed in the synthesis of chromanes and polycyclic analogues via enantioselective annulation reactions. 

The same authors have also used this chiral IV-heterocyclic carbene catalyst in combination with Ti(Oz-Pr)4 to promote a highly diastereo- and enantioselective annulation reaction between a,p-unsaturated aldehydes and enones, which provided the corresponding chiral substituted ds-cyclo-pentenes in good yields and remarkable diastereo- and enantioselectivities of 90% de and 98 to 99% ee, respectively, as shown in Scheme 7.14. ... 

Enantioselective Annulations with NHC-bound Ester Enolate Equivalents... 

Scheme 40,41 N HC-catalyzed enantioselective annulation of enals and enamines via an...

Reaction of a chiral A-heterocyclic carbene catalyst and a,/ -unsaturated aldehyde gives , -unsaturated acyl azolium that participates in enantioselective annulation via a Coates-Claisen rearrangement that invokes the formation of a hemiacetal before a sigmatropic rearrangement to give dihydropyranone products (Scheme 14)7 ... 

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