P-hydroxy amides

As previously explored by Bode, other a-reducible substrates, such as a,P-epoxy aldehyde and aziridinylaldehyde, are competent partners for redox reactions. (Scheme 33) [109], Various amines are compatible nucleophiles in this methodology in which P-hydroxy amides are furnished in good yield and excellent diastereose-lectivity. A similar reaction manifold was discovered concurrently by Bode and co-workers using imidazole as co-catalyst [117],... 

Thionyl chloride (SOCI2) has often been used as a dehydrating agent for primary, secondary, as well as tertiary p-hydroxy amides. With primary hydroxyl amides, the intermediate p-chloro amide can usually be isolated, which will then... 

TABLE 8.4. OXAZOLINES FROM SECONDARY AND TERTIARY p-HYDROXY AMIDES AND SOCI,... 

The reaction of the p-hydroxy amides with SOCI2 can be solvent sensitive. For example, during the semisynthesis of pachtaxel from baccatin 111, the reaction of hydroxybenzamide 16 with SOCI2 in benzene gave a mixture of isomeric 2-oxo-1,2,3-oxathiazohdines 17a and 17b together with a small amount of the trans-oxazoline 18a. If a polar solvent is used, 18a is formed as the exclusive product. ... 

Wuts and co-workers recently reported that the Vilsmeier reagent is superior to thionyl chloride for the cyclodehydration of primary and secondary p-hydroxy amides to prepare oxazolines, in particular, for oxazoline 18b, which is used in Taxol synthesis (Scheme 8.10). Some other examples are shown in Table 8.5 (Fig. 8.3). As expected, inversion of configuration at the alcohol bearing carbon atom is observed. Of the examples examined, serine afforded low yields due to the formation of dehydroalanine. The reaction is conveniently carried out in pyridine at room temperature. p-Chloro amides are also formed, which can be converted to the oxazoline with DBU, generally using the same mixture without isolation. The... 

TABLE 8.5. OXAZOLINES FROM P-HYDROXY AMIDES USING VILSMEIER REAGENT"... 

TABLE 8.6. OXAZOLINES FROM URETHANE-PROTECTED TERTIARY P-HYDROXY AMIDES"... 

Conversion of the hydroxyl group of a p-hydroxy amide to a mesylate, triilate, ° ° or an acetate ° ° followed by intramolecular displacement of the leaving group is a commonly employed strategy for oxazoline formation. Some examples from the recent literature are hsted in Table Oxazolines... 

Burgess reagent has also been used to effect cyclodehydration of p-hydroxy amides to oxazolines. Representative examples are shown in Table The advantage of this reagent is that the cyclodehydration is performed under essentially neutral and mild conditions, typically in THF at room temperamre or reflux. 

The Mitsunobu reaction has also been applied successfully for the preparation of oxazolines from p-hydroxy amides. This method provides an alternative to the Burgess reagent. Some recent examples are listed in Table... 

TABLE 8.10. OXAZOLINES VIA THE MITSUNOBU REACTION OF P-HYDROXY AMIDES... 

Bis-(2-methoxyethyl)aminosulfur trioxide (Deoxo-Fluor) has also been used in place of DAST. Deoxo-Fluor may have the advantage of increased thermal stability. A comparison of the two reagents for the cyclization of several peptidyl p-hydroxy amides has been reported (Table 8.13). 

TABLE 8.12. OXAZOLINES EROM P-HYDROXY AMIDES USING DAST... 

The preparation of oxazolines from p-hydroxy amides and SOCI2 via the corresponding p-chloro amides under basic conditions is well known and has been discussed earlier. Potassium fluoride on alumina has been reported as a mild alternative to the aqueous or alcoholic bases that are commonly used. The reaction is typically carried out in acetonitrile or tetramethylene sulfone and moderate to good yields of oxazolines and oxazines can be obtained as shown in Scheme 8.29. 

TABLE 8.2 OXAZOLINES FROM CARBOXYLIC ESTERS AND AMINO ALCOHOLS, 337 TABLE 8.3 OXAZOLINES FROM PRIMARY p-HYDROXY AMIDES AND SOCI2, 340-344... 

TABLE 8.5 OXAZOLINES FROM p-HYDROXY AMIDES USING VILSMEIER REAGENT, 348... 

TABLE 8.13 COMPARISON OF DAST AND DEOXO-FLUOR FOR CYCLIZATION OF PEPTIDYL P-HYDROXY AMIDES, 372... 

Not surprinsingly, the aldol addition of the lithium enolates derived from these systems proved to be unsatisfactory. However, the derived zirkonium enolates in these and related systems have proven to be exceptional 176). The amides (171) and (172), each of which is readily derived from (S)-proline and (S)-valine respectively, exhibit good stereoselectivity with a range of aldehydes. The optical purity of the P-hydroxy amides (173) was very good (>95% e.e.). However, this method has a limitation which has been associated with the acidic conditions that are required to hydrolize these chiral amides (173) to their derived carboxylic acids (174). While... 

Masakatsu Shibasaki of the University of Tokyo has developed effective procedures for the epoxidation of a,P-unsaturated amides with high . He has now reported (Angew. Chem. Int. Ed. 2004, 43y 317) reagents for the selective reduction of the epoxy amide 9 to either the p-hydroxy amide 10 or the a-hydroxy amide 11. 

P-HYDROXY amides (S)-(—)-Menthyl p-tolu-cnesulfinate. (R)-(a-p-Tolylsulfinyl)-N,N-dimethylamide. 

Aldol Reactions. Pseudoephedrine amide enolates have been shown to undergo highly diastereoselective aldol addition reactions, providing enantiomerically enriched p-hydroxy acids, esters, ketones, and their derivatives (Table 11). The optimized procedure for the reaction requires enolization of the pseudoephedrine amide substrate with LDA followed by transmeta-lation with 2 equiv of ZrCp2Cl2 at —78°C and addition of the aldehyde electrophile at — 105°C. It is noteworthy that the reaction did not require the addition of lithium chloride to favor product formation as is necessary in many other pseudoephedrine amide enolate alkylation reactions. The stereochemistry of the alkylation is the same as that observed with alkyl halides and the formation of the 2, i-syn aldol adduct is favored. The tendency of zirconium enolates to form syn aldol products has been previously reported. The p-hydroxy amide products obtained can be readily transformed into the corresponding acids, esters, and ketones as reported with other alkylated pseudoephedrine amides. An asymmetric aldol reaction between an (S,S)-(+)-pseudoephe-drine-based arylacetamide and paraformaldehyde has been used to prepare enantiomerically pure isoflavanones. ... 

A model (1), similar to that proposed for aldol-type condensation of a-sulfinyl esters, has been proposed to predict the chirality of the resulting p-hydroxy amides. 

Simple amide enolates give poor stereoselection as shown by the examples in equation (87).9c-114115 This low degree of simple stereoselection appears to result from differences in the diastereomeric transition states, since A -propionylpyrrolidine gives a single enolate.114 Welch found that the lithium enolates of fluoroacetamides give mixtures of syn and anti aldols, and that the lack of stereoselectivity is due to the fact that enolate mixtures are obtained a typical example is shown in equation (88).116 On the other hand, IV-acyl derivatives of 2,3-dihydro-4//-l,4-benzothiazine and phenothiazine react with a variety of aldehydes to give jy/i-p-hydroxy amides (equations 89-90).117... 

Cerium(III) chloride. 14, 73-77 15, 72-P-Hydroxy amides. Cerium(III) ea than the Li enolates toward ketones and >94% yield of the aldol. 

Wipf and Miller explored a number of reaction conditions for preparing highly functionalized oxazoles required for natural product synthesis. They introduced a mild two-step process (Scheme 1.142) wherein a p-hydroxy amide 520 is oxidized... 

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