Process Research of (R)-Cyclohexyl Lactic Acid and Related Building Blocks:  A Comparative Study

Abstract

(S)-Cyclohexyl lactic acid is a component of the selective E-selectin inhibitor 2 ((S)-cHexLact-2-O-(3-Galβ(1→3)ddGlc(4→1)αFuc). We describe the evaluation of various synthetic routes to this building block: ( A ) diazotation of phenylalanine followed by phenyl ring hydrogenation; ( B ) phenyl ring hydrogenation of phenyl alanine followed by diazotation; ( C ) acidic hydrolysis of the cyanohydrin derived from phenylacetaldehyde, enantiomeric resolution of the resulting, racemic phenyl lactic acid via diasteromeric salt formation and phenyl ring hydrogenation; ( D ) enantioselective dihydroxylation of a cinnamate ester, followed by hydrogenation of the benzylic hydroxy group and the aromatic nucleus; ( E ) enantioselective biocatalytic reduction of phenylpyruvic acid, followed by phenyl ring hydrogenation. The development of (2R)-2-O-(4-nitrophenyl)sulfonyl-cyclohexyl lactic acid p-bromobenzylester 21 as a buidling block with improved crystallinity and stability is also described.

Total Synthesis of Myxovirescin A1

“…For work up, the aqueous layer was extracted with CH 2 Cl 2 (7 10 mL), the combined organic phases were dried over Na 2 SO 4 and evaporated, and the residue was purified by flash chromatography (pentanes/Et 2 O 2:1) to give product 58 as a colorless liquid (484 mg, 88 %). The a-hydroxyacid segment Benzyl (2S)-2-hydroxypentanoate: nBu 4 NI (1.28 g, 0.347 mmol) and benzyl bromide (4.75 mL, 39.9 mmol) were added to a suspension of acid 68 (4.10 g, 34.7 mmol) [56] and K 2 CO 3 (5.50 g, 39.9 mmol) in acetone (175 mL) and the resulting mixture was stirred under reflux for 24 h. After reaching ambient temperature, all insoluble materials were filtered off through a pad of Celite which was carefully rinsed with acetone, the combined filtrates were evaporated, and the residue was …”

“…In practical terms, it was advantageous that the by-products derived from the minor diastereomer formed in the oxyallylation step could be conveniently removed at this stage. Hydrazinolysis of the phthal-A C H T U N G T R E N N U N G imide in 71 and condensation of the resulting crude amine 72 with the TBDPS-protected 2-hydroxypentanoic acid 70, which is readily available from l-norvaline 67 as shown in Scheme 13, [56] afforded amide 73 without incident. [57] The structure of acid 70 in the solid state is depicted in Figure 3.…”

Biocatalytic Racemization of (Hetero)Aryl‐aliphatic α‐Hydroxycarboxylic Acids by Lactobacillus spp. Proceeds via an Oxidation–Reduction Sequence

“…[9] 3-Phenyllactic acid (1) and several arylsubstituted derivatives thereof are frequently used chiral components of pharmaceuticals, such as rhinovirus protease inhibitors [11] and natural antibiotic agents. [10] The latter compounds are particularly difficult to racemize using conventional methods due to the ease of elimination of H 2 O to form cinnamic acid.…”

“…The latter compounds possess interesting bioactivity themselves or serve as chiral building blocks for the synthesis of numerous pharmaceutical products, such as viral protease and ACE inhibitors. [10] …”

Enantioselective Reduction of 3‐Aryl‐2‐oxo‐propanoic Acids: A Comparison of Enzymatic and Transition‐Metal‐Catalyzed Methods

“…However, substituted phenylalanines have to be synthesized by Pdcatalyzed couplings of functionalized serine derivatives with a suitable aryl-metal species. [11][12][13] More recent alternatives utilize enantioselective catalytic methods such as the asymmetric dihydroxylation of cinnamic acids followed by a hydrogenolytic removal of the benzylic hydroxy group (Figure 1). [14] Oxynitrilase-catalyzed transcyanations represent another strategy to phenyllactic acids albeit the enantioselectivities are not excellent.…”