ldehyde  using suitable organocatalysts would provide an efficient asym- metric synthetic route to INCB08   Scheme . The synthesis of Michael donor via a Suzuki coupling of  Cladribine 4291-63-8 protected pyrazole pinacol borate   and the protected chlorodeazapurine  7  is depicted in Scheme. -Iodo- H – Scheme . Synthesis of Michael Donors and 0 pyrazole  8  or -bromo- H -pyrazole  9  was treated with ethyl vinyl ether 0  to give the protected pyrazoles and respectively. Halogen-magnesium exchange of or followed by addition of boratea orb afforded the pyrazole pinacol borate in good yield. Treatment of compound  with

NaH and -trimethylsilylethoxyethyl chloride SEM-Cl,   afforded the SEM-protected 7 in 89% 8 a Gandelman, M.; Jacobsen, E. N. Angew. Chem., Int. Ed. 00 ,  Cladribine Antimetabolites inhibitor Zalatan, D. N.; Lerchner, A. M.; Jacobsen, E. N. J. Am. Chem. Soc. 00 ,7 ,. c Myers, J.; Jacobsen, E. N. J. Am. Chem. Soc.999 , , 899. d Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 00 , ,78. e Yamagiwa, N.; Qin, H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 00 ,7 ,9. f Shibasaki, M.; Kanai, M. Aldrichim. Acta 00 , 9 , . g Hii, K. K. Pure Appl. Chem. 00 , 78 ,  . 9 Horstmann, T. E.; Guerin, D. J.; Miller, S. L. Angew. Chem., Int. Ed. 000 , 9 , . b Guerin, D. J.; Miller, S. L. J. Am. Chem. Soc. 00 ,  , . c Jarvo, E. R.; Miller, S. L. Tetrahedron 00 , 8 , 8 . 0 Chen, Y. K.; Yoshida, M.; MacMillan, D. W. C. J. Am. Chem. Soc. 00 ,8 , 98 .  Dine´r, P.; Nielsen, M.; Marigo, M.; Jørgensen, K. A.

Angew. Chem., Int. Ed. 007 ,  ,98 . 000 yield. Suzuki coupling of 7 with pyrazole pinacol borate furnished intermediate which was hydrolyzed in situ to give the key Michael donor in 8% yield for two steps. The POM-protected Michael donor 0 was similarly pre- pared. Treatment of the sodium anion of compound  with pivaloyloxymethyl chloride POM-Cl,7  afforded inter- mediate8 in 9% yield. Suzuki coupling of8 and afforded 0 in 9% yield via9 . On the basis of the mechanism proposed by Jørgenson, it was conceivable that the enantioselectivity could be improved by the modulation of steric hindrance of the Cladribine organocatalyst. Catalyst  R -  was purchased from a com- mercial source and catalysts  R -  and  R – were synthesized according to literature procedures see experimental details in the Supporting Information. Wittig olefination of cyclopentanecarbaldehyde    pro- vided  as shown in Scheme . The olefin  was shown by H NMR to be exclusively in the  E  configuration. However, it was contaminated with about% of the dienal

The impurity a could be removed by preparative HPLC but not by silica gel flash chromatography. As a control experiment, pure dienal a was reacted with . Very low conversion to the corresponding Michael adduct was observed less than0% over  h under the same conditions as described in entry, Table . This suggested the dienal impurity a would not have a significant influence on the asymmetric aza-Michael addition. Since an excess amount of the Michael acceptor  was used in the reactions, for practical considerations,  was used without further purification in this study. With Michael donors  and 0 , Michael acceptor  , and organocatalysts  R -  ,  R -  , and  R -  , in hand, the stage was set for the asymmetric aza- Michael reaction. The effects of solvent, acid additive, temperature, and loading of catalyst  R -  on the enantioselectivity and yield of the aza-Michael addition of to the acceptor  are shown in Table. The reactions proceeded faster and gave adduct  R -  in higher yields and ee in toluene and Chemical element entries  and  than those in polar solvents, such as THF and,-dioxane entries 7 and 8. Acid additives, such as benzoic acid and -nitrobenzoic acid, accelerated the reaction entries  and vs 9. Lower reaction temper