2-Hydroxy-1,2,2-triphenylethyl Acetate1

(R)

[95061-47-5]  · C22H20O3  · 2-Hydroxy-1,2,2-triphenylethyl Acetate  · (MW 332.42) (S)

[95061-51-1]

(enantiopure acetate for stereoselective aldol addition of the dilithioenolate to aldehydes to give chiral nonracemic b-hydroxy acids)

Alternate Name: HYTRA.

Physical Data: mp 239 °C (toluene); (R) [a]20D (c = 1, pyridine) +215° to +217°; (S) [a]20D (c = 1, pyridine) -214° to -216°.

Solubility: sol pyridine, boiling toluene; slightly sol THF, chloroform, cold toluene.

Form Supplied in: white solid; both isomers are commercially available.

Stereoselective Aldol Reactions.

The (R)- and (S)-2-hydroxy-1,2,2-triphenylethyl acetates (HYTRA) offer a simple solution for a stereoselective aldol addition of a-unsubstituted enolates. When a suspension of HYTRA is treated in THF with 2 equiv of Lithium Diisopropylamide, a clear solution 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 (R)-3-hydroxy-4-methylpentanoic acid in 86-94% ee but also liberates the optically pure auxiliary reagent (R)-1,2,2-triphenylethane-1,2-diol, which can be removed and reused (eq 1).2,3

The diastereoselectivity has been enhanced by a transmetalation of the lithium enolate with Magnesium Bromide or Magnesium Iodide prior to the addition of benzaldehyde (eq 2).3-5

On the other hand, enantiomeric excesses up to 94% are reached even at -78 °C, provided that Lithium Hexamethyldisilazide (LHMDS) (3 equiv) is used for deprotonation instead of LDA (2 equiv) (eq 3).6

Predictable lk-topicity [i.e. (R)-enolate attacks predominantly the re-face of the carbonyl group whereas the (S)-reagent approaches predominantly from the si-face] has been observed in all additions of doubly deprotonated HYTRA to achiral as well as to enantiomerically pure aldehydes.7,8 The aldol reaction of HYTRA has been used for the syntheses of natural products such as shikonin and alkannin,9 D- and L-digitoxose (1),10 FK506,11 statin (2)8 and analogs,12 detoxinine (3)13 and tetrahydrolipstatin (4).14 Besides compactin and mevinolin (5),15 a series of nonnatural HMG-CoA reductase inhibitors which serve as hypocholesterolemic agents have been synthesized by this method.6,16 Peptide isosters,17 deoxy- and aminodeoxyfuranosides,18 3-amino-2-hydroxybutanoic acid (GABOB) (6)19 and intermediates for the preparation of antidepressants20 are available as well.

Related Reagents.

Boron Triiodide; (R)-2-t-Butyl-6-methyl-4H-1,3-dioxin-4-one; (S)-4-Benzyl-2-oxazolidinone; (R,R)-1,2-Diphenyl-1,2-diaminoethane N,N-Bis[3,5-bis(trifluoromethyl)benzenesulfonamide]; trans-2,5-Bis(methoxymethyl)pyrrolidine; Chloro(cyclopentadienyl)bis[3-O-(1,2:5,6-di-O-isopropylidene-a-D-glucofuranosyl)]titanium; 10-Dicyclohexylsulfonamidoisoborneol; Diisopinocampheylboron Trifluoromethanesulfonate; a-Methyltoluene-2,a-sultam; 1,1,2-Triphenyl-1,2-ethanediol.


1. (a) Braun, M. AG 1987, 99, 24; AG(E) 1987, 26, 24. (b) Braun, M. In Advances in Carbanion Chemistry; Snieckus, V., Ed.; JAI: Greenwich, CT, 1992, Vol. 1, p 177-247.
2. (a) Braun, M.; Gräf, S.; Herzog, S. OS 1993, 72, 32. (b) Braun, M.; Gräf, S. OS 1993, 72, 38.
3. Braun, M.; Devant, R. TL 1984, 25, 5031.
4. Devant, R.; Mahler, U.; Braun, M. CB 1988, 121, 397.
5. Lynch, J. E.; Volante, R. P.; Wattley, R. V.; Shinkai, I. TL 1987, 28, 1385.
6. Prasad, K.; Chen, K.-M.; Repic, O.; Hardtmann, G. E. TA 1990, 1, 703.
7. Mahler, U.; Devant, R. M.; Braun, M. CB 1988, 121, 2035.
8. Wuts, P. G. M.; Putt, S. R. S 1989, 951.
9. Braun, M.; Bauer, C. LA 1991, 1157.
10. Braun, M; Moritz, J. SL 1991, 750.
11. Mills, S.; Desmond, R.; Reamer, R. A.; Volante, R. P.; Shinkai, I. TL 1988, 29, 281.
12. Devant, R.; Radunz, H. E. TL 1988, 29, 2307.
13. Ewing, W. R.; Harris, B. D.; Bhat, K. L.; Joullié, M. M. T 1986, 42, 2421.
14. Barbier, P.; Schneider, F.; Widmer, U. HCA 1987, 70, 1412.
15. Lynch, J. E.; Shinkai, I.; Volante, R. P. (Merck and Co. Inc.) U.S. Patent 4 611 081, 1986 (CA 1987, 106, 18 119n).
16. (a) Baader, E.; Bartmann, W.; Beck, G.; Below, P.; Bergmann, A.; Jendralla, H.; Kesseler, K.; Wess, G. TL 1989, 30, 5115. (b) Jendralla, H.; Baader, E.; Bartmann, W.; Beck, G.; Bergmann, A.; Granzer, E.; v. Kerekjarto, B.; Kesseler, K.; Krause, R.; Schubert, W.; Wess, G. JMC 1990, 33, 61. (c) Jendralla, H.; Granzer, E.; v. Kerekjarto, B.; Krause, R.; Schacht, U.; Baader, E.; Bartmann, W.; Beck, G.; Bergmann, A.; Kesseler, K.; Wess, G.; Chen, L.-J.; Granata, S.; Herchen, J.; Kleine, H.; Schüssler, H.; Wagner, K. JMC 1991, 34, 2962. (d) Baader, E.; Jendralla, H.; v. Kerekjarto, B.; Beck, G. (Hoechst A.-G.) Eur. Patent Appl. 324 347, 1989 (CA 1990, 112, 21 003z). (e) Roth, B. D.; Blankley, C. J.; Chucholowski, A. W.; Ferguson, E.; Hoefle, M. L.; Ortwine, D. F.; Newton, R. S.; Sekerke, C. S.; Sliskovic, D. R.; Stratton, C. D.; Wilson, M. JMC 1991, 34, 357. (f) Roth, B. D. (Warner-Lambert Co.) Eur. Pat. Appl. 409 281, 1991 (CA 1991, 115, 29 107u). (g) Patel, D. V.; Schmidt, R. J.; Gordon, E. M.; JOC 1992, 57, 7143. (h) Wright, J. J.; Sit, S. Y. (Bristol-Myers Co.) Ger. Offen. 3 805 801, 1988 (CA 1989, 110, 114 836x). (i) Matsuo, M.; Manabe, T.; Okumura, H.; Matsuda, H.; Fujii, N. (Fujisawa Pharmacentical Co., Ltd.) PCT Int. Appl. 91 18 903, 1991 (CA 1992, 116, 151 782w). (k) Natsugari, H.; Ikeda, H. (Takeda Chemical Industries, Ltd.) Eur. Pat. Appl. 424 929, 1991 (CA 1991, 115, 114 373x).
17. (a) Allmendinger, T.; Felder, E.; Hungerbühler, E. TL 1990, 31, 7301. (b) Allmendinger, T.; Hungerbühler, E.; Lattmann, R.; Ofner, S.; Schilling, W.; v. Sprecher, G.; Felder, E. (Ciba-Geigy A.-G.) Eur. Pat. Appl. 353 732, 1990 (CA 1990, 113, 153 046w).
18. Gräf, S.; Braun, M. LA 1993, 1091.
19. Braun, M.; Waldmüller, D. S 1989, 856.
20. Volante, R. P.; Corley, E.; Shinkai, I. (Merck and Co., Inc.) Eur. Pat. Appl. 251 714, 1988 (CA 1988, 108, 150 455q).

Manfred Braun

Heinrich-Heine-Universität, Düsseldorf, Germany



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