Conformations disubstituted enols

In acyclic systems, the enolate conformation comes into play. p,(3-Disubstituted enolates prefer a conformation with the hydrogen eclipsed with the enolate double bond. In unfunctionalized enolates, alkylation usually takes place anti to the larger substituent, but with very modest stereoselectivity. 

The prototype of the disubstituted enols and thiols, whatever the position of substituents, is V in fig. 11, with 8 electrons, in which the only bonding MOs are the low-lying 7Tiand 7r2 orbitals. The bonding contribution along the C-0 (resp. C-S) bond is thus very weak in fluorine compounds. For instance, starting from syn conformation, the rotational barrier is very weak in trans FHC=CFOH. Its anti conformer is stabilized by interaction e. All three anti fluorine molecules are slightly distorted. 

The deprotonation of C-3 substituted l,4-benzodiazepin-2-ones with JCHMDS afforded an enantiopure, conformationally chiral enolate with a relatively bulky N — I substituent, which provided a sufficient barrier to enolate racemization. In contrast, LHMDS proved to be ineffective in this transformation, and KHMDS served as an operationally simpler alternative to a mixed base consisting of LDA/n-BuLi. At —100 °C a simultaneous addition of KHMDS and an excess of benzyl bromide to the substrate provided the alkylated product in 75% ee (78% yield). However, the simultaneous addition could not be carried out with a more reactive benzyl iodide. Ultimately, the best result was achieved in a stepwise addition mode, when the deprotonation with KHMDS (20 min) at — 109°C (THF-HMPA) was followed by the addition of an excess of benzyl iodide affording the 3,3-disubstituted benzodiazepine in 97% ee (93% yield) (eq 68). ... 

It seems obvious that the same mechanism could also apply to the cyclopropanation of the fran,s-crotonic ester (Figure 9.3, bottom). A Michael addition of the S ylide would then convert it directly into the ester enolate B. This species would cyclize exclusively to the fratw-disubstituted cyclopropane exactly as when it is produced from the cis-crotonic ester in two steps via the conformer A. 

Besides stereoselective alkylations of glycine-derived enolates, enantioselective construction of chiral quaternary carbon centers from a-amino acids is one of the most challenging topics in current organic synthesis , since nonproteinogenic a,a-disubstituted amino acids often show a remarkable influence on the conformation of peptides. Moreover, they can act as enzyme inhibitors or as building blocks for the synthesis of a wide range of natural products . 

Alkylations of P-substituted 6-lactone enolates occur anti to the substituent with high dia-stereoselectivity unless bulky groups are present at the a-position. " Then, conformational effects may lead to a reversal of the diastereofacial differentiation. Other 8-lactone enolates are alkylated with poor diastereoselectivity unless they are cu-disubstituted at the 7- and 6-positions. Still and Galynker have shown that remote substituents may exert a considerable amount of asymmetric induction in mediumring lactone enolate alkylations. The remote substituent can determine which of the lower energy conformations of the enolate are available for alkylation. ... 

The elimination pathway of stereochemically defined / -halovinyl ketones has been investigated using triethylamine leading to the formation of allenyl ketones and propargyl ketones. A preferential a-vinyl enolization of ( )- -chlorovinyl ketones has been observed where a nonplanar s-cis conformation is proposed as a dominant conformation as opposed to a planar s-cis conformation of (Z)- -chlorovinyl ketones. The synthetic utility of the elimination reaction of j5-chlorovinyl ketones was further demonstrated for a one-pot synthesis of 2,5-disubstituted ftirans in the presence of 1 mol % CuCl (Scheme 2). 

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