Robinson annulation selectivity

As already discussed for aldol and Robinson annulation reactions, proline is also a catalyst for enantioselective Mannich reactions. Proline effectively catalyzes the reactions of aldehydes such as 3-methylbutanal and hexanal with /V-arylimines of ethyl glyoxalate.196 These reactions show 2,3-syn selectivity, although the products with small alkyl groups tend to isomerize to the anti isomer. 

In summary, we have demonstrated the first efficient enantio-selective alkylation via phase transfer catalysis. This alkylation was expanded to include an enantioselective Robinson annulation. The methodology was developed for the preparation of either enantiomer. Finally, our kinetic studies have provided additional mechanistic insight into the chiral PT alkylation. 

The 1,4-conjugate addition of ketones to a, 3-unsaturated ketones, under protic conditions, was reported by Stobbe in 1912 "8a further developments afforded protocols for the synthesis of fused cyclo-hexenones, i.e. Robinson annulation.ll8lwl Robinson also reported that aprotic 1,4-conjugate additions of select reagents, e.g. sodiocyclohexanone with styryl methyl ketone,"9 was preferable to the protic addi-... 

Furthermore the bicyclic starting material could also be constructed by a Robinson annulation on a cyclopentanedione. In this case the final functionality must be achieved by selective reductions of the olefin and ketone functions at appropriate stages in the synthesis. 

The intramolecular interaction between an enolate and a carbonyl electrophile to form a six-membered ring is a well-known and general method (e.g. the Robinson annulation, see Section 2.3.3). This and related cyclization reactions involving interactions between 1,5-dicarbonyl moieties proceeds with high selectivity (A), and the alternative option, the formation of a four-membered ring (B), is much less favorable and rarely observed (Scheme 2.108). The usefulness of this method for the preparation of compounds containing the cyclohexenone moiety is abundantly documented in the literature. 

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. ... 

The Hajos and Wiechert research groups looked at a number of other potential proline based catalysts for their intramolecular Robinson annulation. (. -(-)-Hygrinic acid, Af-methylproline 13, was examined, but only the racemic intermediate ketol product 2 was obtained. In a similar manner, the proline methyl ester 14 also produced the racemic ketol intermediate. No reaction was observed with the piperidine analog 15. The homo-proline analog 16 gave the enantiomeric product. An explanation for this change in selectivity has not been provided yet. Please note that the use of (i )-proline provides the enantiomeric product. 

In analogy to Roush s earlier studies (see Scheme 14) the A-ring was incorporated by a Robinson annulation (176 177) which provided the desired stereochemistry at C-5 and C-6. Reduction then unraveled the bicyclic system to yield the expected precursor for cydization (178). Although attempts to cyclize this tetraol were unsuccessful, simple conversion of the 15-hydroxy group to the acetate (179) allowed for smooth cydization and provided the 13-nortrichothecene (180). After standard elaboration to the hydroxy diene (181) it was found that, in sharp contrast to other oxygenated trichothecenes, peracid oxidation selectively epox-idized the 12,13-double bond. This result allowed for rapid completion of the synthesis yielding the natural antipode of anguidine (9). 

As was pointed out earlier, the gradient theory can be linked easily to a semi-empirical equation of state. The equations of state applied in this study are the Peng-Robinson equation of state and the Associated-Perturbed-Anisotropic-Chain-Theory (APACT). The only effect on the interfacial tensions of pure fluids that is strongly influenced by the selected equation of state is the behavioitr in the near-critical region, since other differences are completely annulled by the fitting procerdure that is applied for the influence parameter. 

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