Enals annulations

The formation of the c -annulated hexahydrothioxanthene (34) from thiophenol and hept-6-enals may also result from a [ +2] cycloaddition, although the minor stereoisomers probably arise from a cationic non-concerted cyclisation <96SL396>. 

Nair and co-workers have extended the use of enals for homoenolate generation to allow ring annulation with enones [13], Cyclopentene formation is achieved via... 

We attempted the key intramolecular oxa-[3 + 3] annulation reaction of diketo-enal 8 under high-dilution conditions at room temperature using piperidinium acetate salt in THF. We were delighted upon the discovery of the formation of the desired... 

Homoenolates generated catalytically with NHCs can also be employed for C-C and C-N bond formation. Bode and Glorias have independently accomplished the diastereoselective synthesis of y-butyrolactones by annulation of enals and aldehydes [121, 122]. Bode and co-workers envisioned that increasing the steric bulk of the acyl anion equivalent would allow reactivity at the homoenolate position. While trying to suppress the competing benzoin and enal dimerization the authors comment on the steric importance of the catalyst. Thiazolium pre-catalyst 173 proved unsuccessful at inducing annulation. A-mesityl substituted imidazolium salt 200 was found to provide up to 87% yield and moderate diastereoselectivities (Scheme 34). 

In an extension to the above methodology, a sequential 1,2-addition, dehydration, and in situ ring closure via a 67t-electron electrocyclic cyclization has been described in the context of the pharmacologically relevant natural products warfarin A, the arisugacins, merulidial, and isovelleral (Scheme 20) <2005CAR1287>. Carbohydrate-derived a,3-unsaturated enals were coupled with 4-hydroxycoumarin 188 and 4-hydroxy-6-methylpyran-2//-one 191 in the presence of proline catalysts to provide pyrone-annulated products of types 190 and 192. Stereoselective electrocyclic ring closure was observed only when hydroxyl functionality (at any of R -k ) on the enal was acyl protected. 

General Procedure for the Catalytic Annulation of Enals and Aldehydes [90] (p. 334)... 

He M, Bode JW (2005) Catalytic synthesis of y-lactams via direct annulations of enals and N-sulfonylimines. Qrg Lett 7 3131-3134 He M, Struble JR, Bode JW (2006) Highly enantioselective azadiene Diels-Alder reactions catalyzed by chiral N-heterocyclic carbenes. J Am Chem Soc 128 8418-8420... 

Sohn SS, Rosen EL, Bode JW (2004) N-Heterocyclic carbene-catalyzed generation of homoenolates y-butyrolactones by direct annulations of enals and aldehydes. J Am Chem Soc 126 14370-14371... 

He M, Bode JW (2005) Catalytic synthesis of y-lactams via direct annulations of enals and A-sulfonylimines. Qrg Lett 7 3131-3134... 

Conjugate additions. Enals undergo selective allylation with diallylcerium chloride in the presence of ATPH. Regioselective Robinson annulations can be initiated by the conjugated addition of lithium enolates to enones. - Remarkably, silyllithium reagents add to the p-position of aromatic carbonyl compounds in the presence of ATPH. ... 

Finally, the enantioselective bicyclo-P-lactam formation, via direct annulation of enals and unsaturated N-solfonyl ketimines using N-mesityl-substituted triazolium chloride (in the presence of bases in organic solvents) as pre-catalyst, has been investigated by W. Bode et al. [98]. 

Once you understand the mechanisms, concentrate on the synthetic applications of the process. Focus on the carbon-carbon bond-forming examples, with particular emphasis on the Michael addition, the 1,4-addition of enolates to enones or enals. The combination Michael addition-aldol condensation provides a powerful means of synthesis of six-membered rings, the Robinson annulation. Don t worry about all these people s names learn the retrosynthetic analysis for compounds containing six-membered rings. 

Pseudosugars are yet another class of stable carbohydrate isosteres which are resistant to both chemical and enzymatic hydrolysis at the pseudoanomeric center. Understandably, for the construction of highly functionalized carbocycle the natural choice would be to take advantage of chiral templates to install the chirality endowed on their periphery. A novel [3 + 3]-annulation reaction was planned by a Michael-Wittig reaction between a chiral enal and yUde in which the chirality of the cyclohexane could be drawn from the y-chiral hydroxy group of the enal. 

The Saigo group disclosed the first highly enantioselective self-annulation of enals catalyzed by the cyclophane-type chiral NHC to afford y-butyro-lactones (91-99% ee for the trans isomers). a,a,a-Trifluoroacetophenone... 

Scheme 7.36 NHC-catalyzed asymmetric self-annulation of enals reported by Saigo.

Scheme 7.37 NHC-catalyzed asymmetric cross-annulation of enals and a-keto-phosphonates reported by Cheong and Schiedt.

Seheme 7.38 NHC-catalyzed as)mimetric cross-annulation of aromatic enals and isatins reported by Ye. 

Scheme 7.39 NHC-catal) ed asymmetric cross-annulation of enals and isatins reported by Scheldt.

Scheme 7.40 NHC-catalyzed cross-annulation of p,p-disubstituted enals and isatins reported by Glorius.

In 2008, the Bode group documented a highly enantioselective cis-cyclopentene-forming annulation of enals and -4-oxo-2-butenoate using a chiral triazolium salt. A cascade sequence involving a catalytic, asymmetric... 

Scheme 7.51 NHC-catalyzed cross-annulation of enals with l-acyl-2-aryldiazenes reported by Scheldt.

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