ature gave  R -  in slightly higher enantioselectivity entry vs . Higher loading of  R -  at 0 mol% did not improve the yield or enantioselectivity entry vs; vs. An excess of acceptor  to donor gave higher yield of  R -  entry vs. The Michael addition of and  was slower ca. 0% conversion over h with sterically hindered catalysts  R -  or  R -  at 0 ° C as compared to that with  R -  . Therefore, reactions of and  using  R -  or  R -  were carried out at room Nelarabine temperature Table . The use of larger excess of   equiv resulted in higher yield entries and 7 vs. Using  equiv of the  , we compared the reaction of pure  a Reyes, E.; Jiang, H.; Milelli, A.; Elsner, P.; Hazell, R. G.; Jørgensen

K. A. Angew. Chem., Int. Ed. 007 ,  , 90. b Gotoh, H.; Hayashi, Y. Org. Lett. 007 , 9 , 89 .  Jacobi, P. A.; Kravitz, J. I.; Zheng, W. J. Org. Chem.99 , 0 , 7 . Org. Lett., Vol., No. 9, 009  faster reactions as illustrated by benzoic acids substituted Table. Reactions of using  R -  a with electron withdrawing fluoro-entries ,  or nitro- groups entries, ,  compared to Nelarabine 121032-29-9 benzoic acid entry t time yield ee . Interestingly, further increase in acidity from -ni- entrye solvent PhMe PhMe PhH PhCF  PhCl cyclohex THF dioxane PhMe PhH PhMe PhH PhMe PhMe PhMe additive trobenzoic acid entry to dinitrobenzoic acids entry ,  resulted in lower enantioselectivities. Applying the optimized conditions entry, Table , adduct  R -  was obtained in 8% yield at 89% ee.  R -  was treated with aqueous ammonia to give the corresponding imine which was subsequently oxidized by iodine to provide the nitrile  R -  in 8% yield. The SEM protection group in  R -  was removed using LiBF  and aqueous ammonia to give INCB08   in 8% yield.

The enantiomeric purity was maintained during this reaction. Using the optimized conditions for the reaction between and  , we conducted the aza-Michael addition of the POM-protected 0 to aldehyde  Scheme  and Table . a 0. mmol scale with equiv of and. equiv of aldehyde  in the presence of0 mol % of organocatalyst  R -  and0 mol % of acid buy Nelarabine additive in . mL of solvent. b Isolated yields. c Determined by chiral HPLC analysis of the corresponding nitrile  R -  , conditions: Chiralcel OD-H . × 0 mm,  µ m particle size; mL/min; rt; 0 nm; mobile phase,0% v/v ethanol and 90% v/v hexanes. d Organocatalyst 0 mol %  R -  was used. e . equiv and equiv of aldehyde  used. Table . Reactions of using . The ee of the adducts were identical and yields were similar, confirming the low reactivity of the impurity a . Under identical reaction conditions entries,,7, sterically hindered catalysts  R -  and  R -  gave higher enantioselectivity 88% ee and 90% ee respectively than  R -  8% ee. The use of stronger acid additives gave Org. Lett., Vol., No. 9, 009 a with equiv of 0 and  equiv of aldehyde  in the presence of  -0 mol % of organocatalyst and  -0 mol % of -nitrobenzoic acid. b Isolated yields. c Determined by chiral HPLC analysis Chiralcel OD-H of corre- sponding nitrile  R – 8 , same conditions as described in Table. d Pure aldehyde  contained no a  was used.

Due to the low solubility of 0 in toluene, lower yield and slower reactions entries,  were observed as compared 00 Reaction condition: unless specified, all reactions were carried out on Reaction condition: all reactions were carried out on 0. mmol scale Reaction condition: all reactions were carried out on 0. mmol scale  mercury BIOBUSINESS BRIEFS D E A L WAT C H Dipping into Incyte’s JAK-pot Incyte has entered into two large licensing deals for their JAK/JAK inhibitors INCB800 and INCB8. In late December 009, the worldwide rights to INCB800, which is in mid-stage trials for rheumatoid arthritis, w