HYTRA

A similar case of enolatc-controlled stereochemistry is found in aldol additions of the chiral acetate 2-hydroxy-2.2-triphenylethyl acetate (HYTRA) when both enantiomers of double deprotonated (R)- and (S)-HYTRA are combined with an enantiomerically pure aldehyde, e.g., (7 )-3-benzyloxybutanal. As in the case of achiral aldehydes, the deprotonated (tf)-HYTRA also attacks (independent of the chirality of the substrate) mainly from the /te-side to give predominantly the t/nii-carboxylic acid after hydrolysis. On the other hand, the (S)-reagcnt attacks the (/ )-aldebyde preferably from the. S7-side to give. s wz-carboxylic acids with comparable selectivity 6... 

R)-(+)-1,1,2-Triphenyl-1,2-ethanediol is available from methyl3 and ethyl4 (R)-(-)-mandelate by treatment with phenylmagnesium bromide. The synthesis of (R)-(+)-2-hydroxy-1,2,2-triphenylethyl acetate [(R)-HYTRA] has been reported previously by the submitters.5 6 (S)-(-)-2-Hydroxy-1,2,2-triphenylethyl acetate is available according to this procedure starting from the enantiomeric methyl (S)-(+)-mandelate or (S)-(+)-... 

STEREOSELECTIVE ALDOL REACTION OF DOUBLY DEPROTONATED (RM+)-2-HYDROXY-1,2,2-TRIPHENYLETHYL ACETATE (HYTRA) (R)-3-HYDROXY-4-METHYLPENTANOIC ACID (Pentanoic acid, 3-hydroxy-4-methyl-, (R)-)... 

The addition of doubly deprotonated HYTRA to achiral4 5 as well as to enantiomerically pure aldehydes enables one to obtain non-racemic (3-hydroxycarboxylic acids. Thus, the method provides a practical solution for the stereoselective aldoi addition of a-unsubstituted enolates, a long-standing synthetic problem.7 As opposed to some other chiral acetate reagents,7 both enantiomers of HYTRA are readily available. Furthermore, the chiral auxiliary reagent, 1,1,2-triphenyl-1,2-ethanediol, can be recovered easily. Aldol additions of HYTRA have been used in syntheses of natural products and biological active compounds, and some of those applications are given in Table I. (The chiral center, introduced by a stereoselective aldol addition with HYTRA, is marked by an asterisk.)... 

NATURAL PRODUCTS AND BIOLOGICALLY ACTIVE ANALOGUES PREPARED BY STEREOSELECTIVE ALDOL ADDITON OF DOUBLY DEPROTONATED (R)- AND (S)-HYTRA... 

R)- and (S)-HYTRA are commercially available from Merck AG, D-Darmstadt. 

Preparation of (R)-(+)-3-hydroxy-4-methylpentanoic acid has been reported previously by the submitters.5 Alternative syntheses of (R)-(+)- or (S)-(-)-3-hydroxy-4-methylpentanoic acid rely on aidoi reactions of chiral ketone, ester, or amide enolates,2 8 10 and Lewis-acid mediated additions of chiral silyl ketene acetals to Isobutyraldehyde.3 11 Since both enantiomers of HYTRA are readily available this method enables one to prepare (S)-3-hydroxy-4-methylpentanoic acid as well. 

R)-(+)-2-Hydroxy-1,2,2-triphenylethyl acetate [(R)-HYTRA], To a mechanically stirred solution of (R)-(+)-1,1,2-triphenyl-1,2-ethanediol (35.0 g. 0.121 mol, Note 1) and acetic anhydride (17.1 mL, 0.181 mol, 1.5 eq, Note 2) in anhydrous acetonitrile (500 mL, Note 3) at room temperature under nitrogen is added a solution of scandium(lll) trifluoromethanesulfonate (1.23 g, 2.5 mmol, 2 mol%, Note 4) in anhydrous acetonitrile (125 mL) over approximately 35 min (Note 5). After about 8 min a white precipitate begins to appear, and the resulting mixture is stirred at room temperature under nitrogen for a total of 3 hr. The solid is filtered, washed with acetonitrile (2 x 25 mL), and dried under vacuum at 40°C overnight to afford (R)-(+)-2-hydroxy-1,2,2-triphenylethyl acetate (35.42 g, 0.107 mol, 88%) as a white solid (Note 6). 

Yamamoto and co-workers reported the use of scandium(lll) triflate as an esterification catalyst when acetic anhydride was used as the acetate source.5 6 While they only reported on monoalcohols (1°, 2°, and 3°) on a small scale, the submitters modified the Yamamoto procedure to suit the submitters reaction with the 1,1,2-triphenyl-1,2-ethanediol. As detailed above, the current procedure provides a yield of the HYTRA acetate that is comparable to the procedure reported by Braun and coworkers,2 1 but via simple, direct filtration for the reaction mixture. 

In a more recent approach (Scheme 11), Schin-zer solved the problem of the C4-C5 retro-aldol reaction with Braun s (S)-HYTRA (51) [44] by replacing the keto group in /(-ketoaldehyde 49 with a C=C double bond cf. 52, derived in four steps from ethyl-2-bromo-Ao-butyrate and 3-pentanone in 13% overall yield). The thus formed intermediate 53 is later deprotected and cleaved oxidatively to give the desired C5 ketone 7 in 52 % yield and 96 % ee from aldehyde 52 [22]. 

Stereoselective Aldol Reactions. The (R)- and (S)-2-hydroxy-1,2,2-triphenylethyl acetates (HYTRA) offer a simple soludon for a stereoselecdve aldol addition of a-unsubstituted enolates. When a suspension of HYTRA is treated in THF with 2 equiv of Lithium Diisopropylamide, a clear soludon of the enolate forms (eq 1). Subsequent dilution with 2-methylbutane followed by the addition of 2-methylpropanal affords predominantly the (R,R)-diastereomeric adduct. Alkaline hydrolysis not only delivers (/ )-3-hydroxy-4-methylpentanoic acid in 86-94% ee but also liberates the optically pure auxiliary reagent (/ )-1,2,2-triphenylethane-1,2-diol, which can be removed and reused (eq 1). - ... 

Braun s enantiomerically pure acetate 95 ((7 )- HYTRA ) [81] can be converted to the lithium enolate 96. Subsequent addition to acrolein predominantly gives VR, >R)-91... 

SCHEME 13.40 Diastereoselective aldol reaction with (/ )- HYTRA . 

D-Digitoxose, a component of cardiac glycosides found in Digitalis purpurea and other higher plants, can be prepared following a similar method starting from ethyl (7 )-lactate and (7 )-HYTRA [83] (Scheme 13.41). 

Braun s enantiomerically pure acetate 105 ((7 )- HYTRA ) [245] can be converted to the lithium enolate 106. Subsequent addition to acrolein predominantly gives (Ti ,3i )-107 (diastereoselectivity 92 8). Alkaline hydrolysis of (Ti ,3i )-107 provides (i )-108 with 83% ee (O Scheme 49). On treatment of (R)-108 with (.5)-1-phenylethylamine and recrystallization. 

K)-108 is isolated in 42% overall yield and > 99% ee. This compound has been converted into 109 by iodolactonization. It is a precursor of all kinds of 2-deoxyfuranosides [246], D-Digitoxose, a component of cardiac glycosides found in Digitalis purpurea and other higher plants, can be prepared following a similar method starting from ethyl (i )-lactate (111) and (i )-HYTRA (O Scheme 50) [247],... 

HMPA, HMPT HOAt HOBt HYTRA IBX Im hexamethylphosphoramide l-hydroxy-7-azabenzotriazole 1 -hydroxybenzotriazole (7 )-(+)-2-hydroxy-l,2,2-triphenylethyl acetate o-iodoxybenzoic acid Imidazolyl... 

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