Aldol Stereochemical Assignments

In numerous complex aldol adducts it is not always possible to extract the relevant vicinal proton coupling constants. Heathcock and co-workers have recently noted that for the -hydroxy ketones and esters that exist in the preferred hydrogen-bonded conformations A and A, NMR spectroscopy may be conveniently employed to assign stereochemistry (13). 

Vicinal Coupling Constants for Diastereomeric Aldol Adducts Versus Ligand Variables Ri, R2, and R3 (CDCI3) 

It has been well established that either kinetic or thermodynamic principles can be employed in the aldol process to define product stereochemistry. When conditions are chosen such that the condensation process is rendered reversible, the more stable threo metal aldolate complex 3 with diequatorial substituents Rj and R3 is usually the dominant diastereomer observed (2,5,14). 

In a frequently cited investigation, House studied the condensations of a variety of metal enolates with aldehydes under conditions of thermodynamic control (14). In the cyclohexanone enolate-benzaldehyde condensation (eq. [5]), it was observed that the zinc enolate (14°C, 5 min) afforded a 5 1 ratio of aldol adducts 5T and 

Entry Ri Metal Half-Life [atr(°C)] Product Ratio 12E 12T[at 7X°C)] 

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When 2-lithio-2-(trimethylsilyl)-l,3-dithiane,9 formed by deprotonation of 9 with an alkyllithium base, is combined with iodide 8, the desired carbon-carbon bond forming reaction takes place smoothly and gives intermediate 7 in 70-80% yield (Scheme 2). Treatment of 7 with lithium diisopropylamide (LDA) results in the formation of a lactam enolate which is subsequently employed in an intermolecular aldol condensation with acetaldehyde (6). The union of intermediates 6 and 7 in this manner provides a 1 1 mixture of diastereomeric trans aldol adducts 16 and 17, epimeric at C-8, in 97 % total yield. Although stereochemical assignments could be made for both aldol isomers, the development of an alternative, more stereoselective route for the synthesis of the desired aldol adduct (16) was pursued. Thus, enolization of /Mactam 7 with LDA, as before, followed by acylation of the lactam enolate carbon atom with A-acetylimidazole, provides intermediate 18 in 82% yield. Alternatively, intermediate 18 could be prepared in 88% yield, through oxidation of the 1 1 mixture of diastereomeric aldol adducts 16 and 17 with trifluoroacetic anhydride (TFAA) in... 

The kinetic enolization of esters with amide bases such as lithium diisopropylamide (LDA) and the resultant aldol condensations with representative aldehydes have been investigated by several groups (2,32,33). The enolate stereochemical assignments were determined by silylation in direct analogy to studies reported by Ireland (34). The preponderance of (E )-enolate observed with LDA (THF) in these... 

The syn-configuration of the resulting aldols 4i and 42 can be deduced from the coupling constants in the H-NMR spectra (4.5 Hz), and the absolute stereochemical assignments were made by degradative removal of the hydroxyl group and correlation of the resulting a-substituted carboxylic acids. 

Please note that in the original article [136] the incorrect (lS)-cQnfiguration was assigned to the polyhydroxy-lated pyrroUzidines. Based on this assignment, the aldol reaction was thought to proceed with low diastere-oselectivity. The correct stereochemical assignment was unequivocally established in a later study [112]. Therefore, RhuA was fully stereoselective in the aldol addition of DHAP to N-Cbz-prolinal derivatives. 

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