Doephenamine). To apply our new aldol methodology to synthesize chloramphenicol and thiamphenicol, antibiotics that are on the important medicine list published by the Planet Health Organization[16] and play critical roles in the therapy of infectious disease, specifically in developing nations,[17] we investigated reductive cleavage in the auxiliary to generate 2amino-1,3-diols. Remarkably, remedy of aldol adduct eight using the mild reducing agent sodium borohydride (five.0 equiv) in ethanol at 40 provided the 2-amino-1,3-diol 32 in 80 yield (Scheme 4); the auxiliary was recovered quantitatively in pure type. We are conscious of only one prior report of the reduction of tertiary amides (-hydroxy morpholinamides) toAngew Chem Int Ed Engl. Author manuscript; readily available in PMC 2015 April 25.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptSeiple et al.Pagethe corresponding alcohols with sodium borohydride.[18] Reduction of pseudoephedrine and pseudoephenamine amides towards the corresponding primary alcohols has historically been achieved using lithium amidotrihydroborate (LAB),[2b, 3b, 10] a a lot additional reactive hydride donor that we introduced in 1996.[19] Again, we believe that the facile reduction with sodium borohydride we observe is on account of intramolecular N O-acyl transfer followed by reduction on the resulting -amino ester.[20] The synthesis of chloramphenicol was completed by acylation of 32 with methyl dichloroacetate (Scheme 4), supplying the antibiotic in exceptional yield in just 3 measures from (R,R)-pseudoephenamine glycinamide (1) and para-nitrobenzaldehyde. Thiamphenicol was synthesized by an identical 2-step sequence from the aldol adduct 9. In contrast towards the 3-step routes to chloramphenicol and thiamphenicol reported here, the industrial routes to these substances call for six linear steps, which includes a resolution.[21] Commensurate with their value in medicine, chemists have created an extraordinarily diverse array of approaches to synthesize enantiomerically enriched -hydroxy-amino acids. These may possibly be divided into two broad categories: constructive syntheses (as inside the present work) and nonconstructive syntheses.6-(Trifluoromethyl)piperidin-2-one Order The latter include the Sharpless asymmetric aminohydroxylation of particular alkenyl esters,[22] multi-step transformations of Garner aldehyde-type intermediates,[23] asymmetric hydrogenation of 2-amino-ketoesters,[24] too as other techniques.3-Chloro-2-methylbenzaldehyde Order [14f, 25] Constructive syntheses are generally much more powerfully simplifying, for they enable retrosynthetic targeting on the C bond linking the stereogenic, heteroatom-bearing centres.PMID:24635174 The pioneering advances from the Sch lkopf group employing bis-lactim ethers[26] plus the Seebach group employing masked glycine-derived heterocycles[27] as substrates in diastereoselective aldol additions remain critical enabling methodologies. To reveal the parent -hydroxy–amino acids or esters, even so, strongly acidic situations are needed and auxiliary-derived by-products can complicate isolation with the items.[26e, 26f] Evans and Weber developed -isothiocyanato acyl oxazolidinones as substrates in their diastereoselective tin-mediated aldol chemistry,[28] and notable advances have already been recorded by the Willis,[29] Feng,[30] and Seidel[31] groups to transform this process into processes mediated by chiral catalysts. These -isothiocyanate methodologies afford thiocarbamate heterocycles as products, which conveniently serve to protect the amine and alcohol functionalitie.