Evans aldol methodology

The central point of Evans s methodology is the induction of a 7t-enantiotopic facial differentiation through a conformationally rigid highly ordered transition state. Since the dialkylboron enolates of AT-acyl-2-oxazolidinones exhibit excellent syn-diastereoselectivity syn.anti >97 3) when reacted with a variety of aldehydes, Evans [14] studied the aldol condensation with the chiral equivalents 32 and 38. which are synthesised from fS)-valine (35) and the hydrochloride of (15, 2R)-norephedrine (36) (Scheme 9.11), respectively, and presently are commercially available. 

The stereocenters at C(2) and C(3) of 4 were conveniently established with the correct relative and absolute configurations once again through the utilization of the aldol methodology developed by Evans.l 7,20 Thus, reaction of furaldehyde (46) with the boron enolate 47 followed by methanolysis afforded the P-hydroxy ester 48 in enantiomerically pure form. The sequential reaction of 48 with bromine in methanol and then aqueous acid followed by protection of the intermediate anomeric lactols... 

The Evans oxazolidinone methodology is quite versatile and quite apart from its use in aldol reactions (section 5.3.3) lends itself well to the asymmetric synthesis of carboxylic acids substituted in the a-position with oxygen, nitrogen, and carbon.ti l The auxiliary shown is derived from (+)-norephedrine and the opposite enantiomers of the products are available from the valine-derived auxiliary. 

The reliability, scope, and ease of execution of the aldol addition reactions with acyl oxazolidinones have resulted in their extensive use in complex molecule synthesis. In Evans synthesis of the macrolide antibiotic cytovaricin (69), oxazolidinone aldol methodology was utilized to control the installation of eight stereogenic centers (Scheme 4.7) [53]. 

This highly convergent synthesis amply demonstrates the utility of Evans s asymmetric aldol and alkylation methodology for the synthesis of polypropionate-derived natural products. By virtue of the molecular complexity and pronounced lability of cytovaricin, this synthesis ranks among the most outstanding synthetic achievements in the macrolide field. 

D. A. Evans, P. H. Carter, E M. Carreira, J. A. Pmnet, A. B. Charette, M. Lautens Asymmetric Synthesis of Bryosta-tin 2 , Angew. Chem, Int. Ed. Engl. 1998,37,2354-2359. For methodological studies on asymmetric Cu-catalyzed aldol addition, see D. A. Evans, J. Murry, M. C. Koz-lowski C2-Symmetric Cu(II) Complexes as Chiral Lewis Adds. Catalytic Enantiosdective Aldol Additions of Silylketene Acetals to (Benzyloxy)acetaldehyde , J. Am Chem. Soc 1996,118,5814-5815. 

As an extension of their chiral aldol and alkylation technology, Evans and cowotkers have reported a variety of methods for cleaving and replacing Ae chiral oxazolidinone auxiliary once chain construction has been completed. Included in this methodology was the direct transformation of a chiral imide to an lV-methoxy-/V-methylamide through the use of aluminum amides (prepared in situ). ° This reaction has been shown to be rather general for complex substrates (Scheme 2). ... 

Miscellanea A methodology to prepare a-substituted-P-hydroxy acids and esters has been introduced in solid phase based on an Evans oxazolidinone-based linker to produce enantiospecifk aldol condensations (Figure 15.4). Acids and esters were released by treatment with LiOH and H202 in THF (at -20 °C) or NaOMe in THF, respectively [58, 59], Diels-Alder adducts of oxazolidinone-bound crotonates have also been detached with LiOCH2Ph [60],... 

Boron-mediated asymmetric aldol condensation methodology developed by Evans [90] served as an inspiration for preparation of daunosamine starting from chiral oxazoUdinones. It appeared that the choice of chiral auxiUary is quite important for the stereochemical outcome of planned reactions [91]. A successful series of reactions started from N -succinoylation of (R)-3-(l-oxo-3-carbomethoxypropyl)-4-diphenylmethyl)oxazolidin-2-one as a novel chiral auxihary. The chain extension was achieved in aldol condensation with protected lactaldehyde and the key intermediate 132 was converted into the target aminosugar 135, via Curtius rearrangement of carboxyhc acid azide, and reduction of lactone to lactol, as depicted in Scheme 24 [58]. Unexpectedly, boron catalysts were rather ineffective in the aldol condensation step and had to be replaced with more reactive lithiiun enolates (which proved to be non-Evans syn selective). 

In diastereo- and enantiocontrolled aldol addition, the use of enol borinates or enol stannanes has emerged as a standard methodology (Evans or Oppolzer aldol addition) [105]. These intermediates are generated in situ from the parent carbonyl compounds, which typically are auxiliary-substituted amides or esters. The counter ion, which is attached to the enolate, plays a dominant role in the stereochemical outcome. 

---