P-Hydroxyamides

Subsequent reduction of the ketone produces either the syn or anft p-hydroxyamides with high diastereoselectivity (eqs 4 and 5). Pyrrolidine-derived a-ketoamides have also been shown to react stereospecifically with reducing agents, as well as with other organometallic reagents. ... 

Some p-hydroxyamides (246) in different diastereomic mixtures were cyclized to tetrahydrofurane derivatives (247) in the presence of Ph-SeCl, and subsequently, their diastereomeric ratios could be determined by Se NMR analysis.Some arylseleninic acids (Ar-SeO2H S = 1200-1276) were optically resolved by chiral columns and their racemization studied. 

The Burgess reagent (54, Figure 3.5.1) is a versatile and mild reagent for the cyclodehydration of P-hydroxyamides or thioamides to produce oxazolines or thiazolines. 

The dehydration of p-hydroxyamides is the most widely used method for the synthesis of oxazolines, and the various reagents used for this conversion will not be discussed further in this section. Instead, the reader should consult Chapter 8 and Chapter 9 in Part B for the synthesis and reactions of oxazolines and chiral bis-oxazohnes for detailed discussions and leading examples. 

Activated manganese dioxide is a closely related oxidant to Ni02 but less commonly used. Meguro, Fujita, and co-workers described oxidation of oxazolines using Mn02 in their synthesis of antidiabetic agents. For example, the serine-derived P-hydroxyamide 21 was cyclized to the oxazoline 22 with polyphosphoric acid. Oxidation of 22 with activated manganese dioxide afforded 2-styryl-4-oxazolecarboxylic acid methyl ester, 23 (Scheme 1.4). 

Esterification of 1584 with 1580 gave 1585 in excellent yield (Scheme 1.403). Sequential deprotection of 1585 unmasked the amino alcohol (not shown), which was subjected to macrolactamization using DPPA to afford the p-hydroxyamide 1586. The synthesis was then completed by cyclization/oxidation of 1586 to install the central oxazole ring of 1587. 

Wipf and co-workers developed an efficient one-pot process to prepare a variety of highly functionalized 2-substituted 4-oxazolecarboxylic acid esters 39. The starting (3-hydroxyamides 1588 were cyclodehydrated using Deoxo-fluor (bis(2-methoxyethyl)aminosulfur trifluoride) or DAST (diethylaminosulfur trifluoride) to afford intermediate oxazolines 38, which were oxidized in situ with B1CCI3/ DBU to afford 39 (Scheme 1.404). DAST was found to be preferable with serine-derived p-hydroxyamides, whereas Deoxo-fluor was more useful for threonine derived p-hydroxyamides. 

The aldol reaction is not restricted to the use of ketone enolates and indeed some of the most important examples in this area use carboxylic esters or amides. Proton abstraction with EDA (or other strong base) at low temperature to give the enolate and addition of the aldehyde or ketone gives a -hydroxyester or p-hydroxyamide product. Likewise the boron or other metal enolates of esters provide alternative methods to effect the aldol reaction. 

Epoxy ketones are selectively reduced with lithium naphthalenide or Cp2TiCl in THF/MeOH ° to the (3-hydroxyketone. Other reduction methods can lead to the epoxy alcohol (see p. ). Reduction of epoxy amides with Sml2 in methanol gave the ot-hydroxyamide. ° ... 

Industrial Synthetic Improvements. One significant modification of the Stembach process is the result of work by Sumitomo chemists in 1975, in which the optical resolution—reduction sequence is replaced with a more efficient asymmetric conversion of the p/eso-cydoacid (13) to the optically pure i7-lactone (17) (Fig. 3) (25). The cydoacid is reacted with the optically active dihydroxyamine [2964-48-9] (23) to quantitativdy yidd the chiral imide [85317-83-5] (24). Diastereoselective reduction of the pro-R-carbonyl using sodium borohydride affords the optically pure hydroxyamide [85317-84-6] (25) after recrystallization. Acid hydrolysis of the amide thenyidds the desired < lactone (17). A similar approach uses rhiral alcohols to form diastereomic half-esters stereosdectivity. These are reduced and directly converted to < lactone (26). In both approaches, the desired diastereomeric half-amide or half-ester is formed in excess, thus avoiding the cosdy resolution step required in the Stembach synthesis. 

Two groups report the addition of metalated benzamides to aldehyde carbonyls. The methods differ in the metal. Lithiated diethylamides must be transmetalated with MgBr2 before addition to the aldehyde, but p-aminoamides react similarly as the lithium derivative. Following addition, the hydroxyamide is hydrolyzed to afford phthalides in moderate overall yield (Scheme 11). 

The metal enolate of (/ )-/V./V-dimethyl-a-(p-tolylsulfinyl)acetamide (92) reacts with an aldehyde to afford a diastereomeric mixture of adduct (93). which undergoes desulfurization with 10% Na(Hg) in MeOH (NaH2P04> to give an optically active 3-hydroxyamide (94). By the use of Li" as a countercation, low to medium levels of enantioselection are achieved. However, the magnesium enolate of (92) realizes a high enantioselectivity, as summarized in Table 4. A rigid chelation model, shown in Scheme 26, is suggested for the transition state of this addition. 

A -Acyl-oxazolidin-2-ones, as 203, are widely used in aldol reactions, however an unprecedented use of the aldol adducts for a stereoselective synthesis of trisubstituted a, 3-unsaturated amides and acids was reported. The yy -aldol adduct 204 underwent clean elimination upon treatment with KHMDS and afforded the E -olefin 205 with a 97% ds. The reaction was wide in scope but with a loss in selectivity using a,P-unsaturated or chiral aldehydes <05OBC2976>. This synthetic approach found immediate application in the synthesis of semiplenamide C 206 <05TL5547>. Oxazolidin-2,4-diones 207, obtained from cyanohydrins, can be easily converted into the corresponding a-hydroxyamides 208 in a reaction that can be accelerated by microwaves <05T7247>. 

Scheme 7.35 Synthesis of a hydroxyamide by using the P-HOBt active ester-forming methodology.

The crystalline mixture of 2.30 g hydroxyamide and its epimer (8.05 mmol) in 65 mL methanol was treated with 0.85 g potassium hydroxide (15.2 mmol) in 15.7 mL 5.25% aqueous NaOCl solution (11.0 mmol). The resulting solution turned yellow and warmed spontaneously to 50°C. After 1 h it was poured into 300 mL brine, and the resulting mixture was extracted five times with chloroform. The dried extracts were evaporated to an oil, which crystallized from ether in colorless needles, 1.51 g tricyclic urethane was obtained, in a yield of 53%, m.p., 147.5-149°C. 

N-(2-Hydroxyethyl)-2-pyrrolidone. See N-Hydroxyethylpyrrolidone N(P-Hydroxyethyl) ricinoleamide Ciassification Hydroxyamide wax Properties Sp.gr. 1.00 m.p. 46 C Uses Lubricant, antistat, mold release agent in plastics, metals, textile coatings slip agent for varnishes and lacquers elec, potting compds. crayons wax blends high-temp, greases Trade Name Synonyms Flexricin 115 t[CasChem... 

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