4252 J. Am. Chem. SOC. 1985, 107, 4252-4259 mL and DMF and saturated with methylamine gas at 0 OC. The vessel was sealed and agitated for 1 day. The polymer was washed successively in dioxane, ethanol, 2 N NaOH/i-PrOH (l:l), water (until eluate neu- tral), ethanol, and ether. After drying in vacuo, the polymer (3.7 g/3.8 mequiv of amino groups/l g of dry weight) was suspended in a mixture of water (1.5 mL), ethanol (0.5 mL), triethylamine (7 mL), and 4- chloropyridine hydrochloride (4.7 g) in a glass pressure vessel, sealed and heated for 4 days at 140 OC. The polymer was washed as before, and unreacted amino groups were blocked by acetylation (acetic anhydride in CH2C12, then base wash). The washed DMAP polymer was dried at 150 OC in vacuo until constant weight. Incorporation of pyridine groups was determined by potentiometric chloride titration of the hydrochloride salt bound to the polymer: 2.53 mequiv/g compared to 3.15 mequiv/g prior to acetylation. Polymeric l-Acyl-4-(diaUtylamino)pyridinium Chlorides. In a typical experiment, the anhydrous 4-(dialkylamino)pyridine polymer was swelled in methylene chloride (freshly distilled from P205 under argon) and treated with excess benzoyl chloride at 0 OC. The polymer was filtered and washed with methylene chloride under anhydrous conditions until the washings contained negligible amounts of benzoyl chloride-by the silver nitrate test in alcohol (less than 0.1% of total pyridine groups as indicated by GC). The polymer was dried under vacuum at room tem- perature and was stable at -10 OC for several months. After treatment with a primary (e.g., benzyl) amine in methylene chloride, a pure amide was recovered by filtration and acid/base wash. The amount of amide corresponded to 0.8 mequiv/g of acyl substitution on the polymer. Anhydrous manipulation as above and those involving transfer be- tween two polymers were most conveniently carried out by using a cir- culating system described in Figure 1, containing Teflon columns (1-4- (10) Warshawsky, A,; Deshe, A.; Rossey, G.; Patchornik, A. React. Polym. 1984, 2, 301. mL volume) joined to the solvent distillation apparatus, waste, and vacuum pump via Teflon tubing. In summary, we have shown for the first time the possibility to per- form highly efficient condensation reactions, by transferring polymer- bound electrophiles (Le., active esters) via a mediator (shadchan) to polymer-bound nucleophiles (i.e., amines). We have also shown the possibility of on-line monitoring which is relevant for automation. The mediator methodology developed here is believed not to be limited to acylation and related processes but to be expandable to other chemical processes that involve the creation of activated intermediates. These possibilities are currently under investigation. Acknowledgment. We thank the Etta P. Schiff Trust and the Bantrell Fund for financial support. This work is dedicated to Prof. Arieh Berger on the 10th anniversary of his death. Registry No. Boc-Phe-OH, 13734-34-4; Boc-Gly-OH, 4530-20-5; Boc-Tyr(0Bz)-OH, 21 30-96-3; Boc-Tyr(OBz-2,6-CI)-OH, 40298-7 1-3; Boc-Phe-Leu-OCH,, 64152-76-7; H2NPhe-Leu-OH, 3303-55-7; H,NAla-Leu-OH, 3303-34-2; H2NGly-Phe-Leu-OH, 15373-56-5; H,NGly-Gly-Phe-Leu-OH, 60254-83-3; Boc-Tyr(0Bz)-Gly-Gly-Che- Leu-OCH,, 63631-33-4; H2NTyr-Gly-Gly-Phe-Leu-OH, 58822-25-6; HOCHZPh, 100-51-6; HOC6Hd-p-NO2, 100-02-7; HSC6H4-p-NO2, 1849-36-1; PhCOOH, 65-85-0; CH,COOH, 64-19-7; HZNCHzPh, 100- 46-9; CH,C02CH2Ph, 140-11-4; PhCO2C6Hd-p-NO2, 959-22-8; PhCOSC6H4-p-NO2, 1219-32-5; CH,CO,COPh, 2819-08-1; PhCOF, 455-32-3; i-BuOCONHCH,Ph, 69805-82-9; P-~OSYI-NHCH~P~, 1576- 37-0; methylamine, 74-89-5; 4-chloropyridine hydrochloride, 7379-35-3; benzoyl chloride, 98-88-4; menthol, 89-78-1; menthol benzoate, 612-33-9; benzoic anhydride, 93-97-0; 1-methylethyl 2-chlorophenyl dimethyl- phosphoramidate, 96227-79-1; 2-chlorophenyl methyl 1-methylethyl phosphorate, 96227-80-4. General Method of Diastereo- and Enantioselective Synthesis of P-Hydroxy-a-amino Acids by Condensation of Aldehydes and Ketones with Glycine Yuri N. Belokon',* Alexander G. Bulychev, Sergei V. Vitt, Yuri T. Struchkov, Andrei S. Batsanov, Tatiana V. Timofeeva, Vladimir A. Tsyryapkin, Michail C. Ryzhov, Ludmila A. Lysova, Vladimir I. Bakhmutov, and Vassili M. Belikov Contribution from Nesmeyanov Institute of Organo-Element Compounds, Academy of Sciences of the U.S.S.R., Moscow, U.S.S.R. Received September 18, 1984 Abstract: The condensation of formaldehyde with a Ni(I1) complex of glycine Schiff base with (S)-2-[N-(benzylprolyl)- aminolacetophenone (1) or (S)-2-[N-(benzylprolyl)amino]benzophenone (2) in CH30H at 25 OC in the presence of Et3N yields (S)-Ser with an enantiomeric excess (ee) of 80-98%. The same reaction gives rise to (R)-Ser with an ee greater than 80% in the presence of more than 0.2 N CH,ONa, a-(hydroxymethy1)serine being formed in negligible quantities. The reaction of benzaldehyde, 3,4-(methylenedioxy)benzaldehyde, and acetaldehyde with these Gly complexes in 0.2 N CH30Na at 25 OC yields P-hydroxy-a-amino acids: (R)-P-phenylserine, (R)-3,4-(methylenedioxy)-P-phenylserine, and (R)-threonine, respectively, with a threo/allo ratio ranging from 1O:l up to over 50:l and ee more than 80%. Condensation with acetone yields (R)-P- hydroxyvaline with an enantiomeric purity of 70%. The enantiomerically pure P-hydroxy-a-amino acids can be obtained from pure diastereomers, isolated by chromatography on silica or Toyopearl HW-60. The initial reagents 1 and 2 were recovered with 60-98% yield. The stereochemical mechanism of the reaction is discussed. P-Hydroxy-a-amino acids (3) represent an important group of natural products. In spite of the recent progress in the field of titular,* convenient preparative methods for chemical enantios- Scheme I P ? OH asymmetric synthesis of amino acids in general' and 3 in par- elective synthesis of threo-3 are still not available. -M-N --M--N 0-c I ).HZ + RCHO - Y-JH-lH R /' I\ (1) Kagan, H. B.; Fiaud, J. C. Top. Srereochem. 1978, 10, 175-193. ApSimon, J. W.; Seguin, R. P. Tetrahedron 1979, 35, 2797-2842. Bosnich, B.; Fryzuk, M. D. Top. Stereochem. 1981, 12, 119-154. Halpern, J. Science (Washington, D.C.) 1982, 217, 401-407. Mosher, H. S.; Morrison, J. D. Science (Washington, D.C.) 1983, 221, 1013-1019. (2) Nakatsuka, T,; ~i~~, T,; Mukaiyama, T. them, hit,