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Highly Diastereoselective Heterogeneously Catalyzed Hydrogenation of Enamines for the Synthesis of Chiral ß-Amino Acid Derivatives

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Highly Diastereoselective Heterogeneously Catalyzed Hydrogenation of Enamines for the Synthesis of Chiral ß-Amino Acid Derivatives
  Highly Diastereoselective Heterogeneously Catalyzed Hydrogenation ofEnamines for the Synthesis of Chiral   -Amino Acid Derivatives Norihiro Ikemoto,* David M. Tellers,* Spencer D. Dreher, Jinchu Liu, Angie Huang, Nelo R. Rivera,*Eugenia Njolito, Yi Hsiao, J. Christopher McWilliams, J. Michael Williams, Joseph D. Armstrong, III,Yongkui Sun, David J. Mathre, Edward J. J. Grabowski, and Richard D. Tillyer  Department of Process Research and the Catalysis and Reaction Disco V  ery and De V  elopment Lab, Merck and Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065-0900 Received October 1, 2003; E-mail: norihiro_ikemoto@merck.com Enantiopure   -amino acids and their derivatives are componentsof a variety of important natural products and targets for pharma-ceutical research. 1 A useful method for preparing compounds of this class in high enantioselectivity involves enantioselectivehydrogenation of the corresponding  N  -acyl protected dehydro-   -amino acid derivative (enamine) using a homogeneous chiralcatalyst. 2 However, this method typically requires prior separationof the (  Z  )- and (  E  )-enamine isomers from generally poorly selectivemixtures to obtain this high enantioselectivity. 3 Also, removal of the  N  -acyl protecting group to access free   -aminoesters and amidesafter hydrogenation is difficult. An alternative route is the hetero-geneous diastereoselective hydrogenation of chiral enamines pro-duced from   -ketoesters and chiral benzylamines followed byhydrogenolysis of the benzyl group. The limited examples of auxiliary-based hydrogenation methods appearing in the literatureproceed with low to moderate selectivity ( < 80% de). 4 Despite this,the heterogeneous approach offers numerous advantages: ease inseparation of product from catalyst, low catalyst cost, catalyst reuse/ recovery, and facile catalytic deprotection. Consequently, there isstill a great impetus to develop asymmetric processes which employheterogeneous catalysts. Toward this end, we have developed adiastereoselective heterogeneous catalytic system that convertsenamines derived from   -ketoesters and amides and chiral phe-nylglycine amide (PGA) to   -amino acid derivatives in up to 99%de (200:1 selectivity). This approach has been applied to a varietyof PGA-enamines affording stereoselectivities that are the highestever reported for heterogeneous catalysts and are comparable tothose of the best homogeneous catalysts.We chose to explore the utility of the new chiral amine, ( S  )-phenylglycine amide (PGA) (Table 1), as a chiral auxiliary. 5 Weanticipated that the carboxamide functionality on phenylglycineamide would serve as an additional point of coordination with theheterogeneous catalyst to give a more ordered hydrogenationtransition state leading to higher diastereoselectivity. The ( S  )-PGA-enamine esters and amides ( 2a - k , Table 1) were prepared bystirring the corresponding   -ketoesters and amides with ( S  )-PGAin methanol or 2-propanol in the presence of catalytic amounts of acetic acid. 6 In all examples studied, only the (  Z  )-enamine isomercrystallized allowing isolation of the enamine in high geometricalpurity. The ORTEP diagram of   2b  confirms the (  Z  )-enaminegeometry (Figure 1). Of note is the hydrogen bond between the   -enamine proton and the carbonyl functionalities of the carboxa-mide and methyl ester, which helps to stabilize the  Z  -isomer inpreference to the  E  -isomer.With a convenient method for preparing the PGA-derivedenamines, we next sought to identify a heterogeneous catalyst.Preliminary screening indicated that platinum oxide (PtO 2 , Adam’scatalyst) in THF was the most active and selective catalyst for thishydrogenation. 7 A practical hydrogen pressure of 90 psi was usedat 22  ° C. Initially, the reaction was slow using 10 mol % PtO 2 (entry 1, Table 1). Acetic acid is often used to acceleratehydrogenations catalyzed by PtO 2  either by activating the catalystby dissolving surface bound alkali metals 8 or by preventingdeactivation of the catalyst by the product amine. 9 Addition of increasing amounts of acetic acid improved the rate (entries 2, 3)but resulted in a progressive decline in selectivity. We discoveredthat acetic acid in the reaction mixture was undesirable because itcatalyzes isomerization to the less selective (  E  )-enamine. 10 Tocircumvent this, we developed a simple procedure involvingwashing the catalyst with acetic acid and thoroughly drying the Table 1.  Diastereoselective Hydrogenation of ( Z  )- 2 entry  2 PtO 2 a (mol %)additive b  (mol %) timeyield c  [conv] e  de (%) f  1  2a  uw (10) 3 h [12%] 922  2a  uw (10) A (100) 3 h [100%] 953  2a  uw (10) A (300) 3 h [100%] 904  2a  aw (10) 3 h [97%] 975  2a  aw (10) B (3) 4 h [96%] 996  2a  aw (10) 8 h 87 (66) d  96 (3  R ) g 7  2b  aw (10) 2 d 94 (82) 97 (3 S  )8  2c  aw (10) 2 d 96 (88) 98 (3  R )9  2d  aw (10) 1 d 97 (94) 98 (3  R , 2 S  )10  2e  aw (2.5) 12 h 99 (98) 99 (3  R )11  2f   aw (2.5) 1 d 96 (88) 97 (3  R )12  2g  aw (50) 2 d [70%] 70 (3 S  ) h 13  2h  aw (50) 3 d 85 (46) 8814  2i  aw (50) 2 d [24%] 7815  2j  aw (10) 2 d 86 (80) 8916  2k  aw (10) 2 d 96 (92) 97 a aw  )  acid washed, uw  )  unwashed.  b A  )  acetic acid, B  ) triethylamine.  c % assay yield.  d  % isolated yield (unoptimized).  e Reactionconversion.  f  Determined by HPLC.  g The absolute configuration determinedafter debenzylation to the free amine by comparing the sign of opticalrotations.  h Assigned from the X-ray structure. Published on Web 02/19/2004 3048  9  J. AM. CHEM. SOC. 2004 ,  126  , 3048 - 3049  10.1021/ja038812t CCC: $27.50 © 2004 American Chemical Society  solid after filtration. 11 Thus, not only is the washed catalyst moreactive than the unwashed catalyst, but it also significantly improvedthe diastereoselectivity in the hydrogenation (entry 1 vs 4). Thiscatalyst still contained a small amount of residual acetic acid thatled to some isomerization and loss in selectivity. Addition of asmall amount of triethylamine, however, neutralized this acid andimproved the selectivity to a very high 99% de with little impacton reaction rate (entry 5).Using the acid washed catalyst, high selectivities were observedwith a wide range of (  Z  )-enamine esters and amides (Table 1). Thealkyl (R 1 ) tri- and tetra-substituted enamines ( 2a - f  ) showed thehighest reactivity and selectivity (97 - 99% de). The relativestereochemistry was the same in all of these examples as indicated. 12 The aryl enamine esters ( 2g , i ) were generally less reactive andselective as compared to the electron-rich aryl enamine ester ( 2h )and aryl enamine amides ( 2j , k ) which displayed higher rates andselectivities.Hydrogenolysis of   3a - f   (H 2 , Pd(OH) 2  /C, methanol, AcOH)readily afforded the free alkyl   -aminoesters and amides with2-phenylacetamide. Hydrogenolysis of the arylamines ( 3g - k ) wasexpected to be problematic under these conditions due to thepresence of competing benzylic sites, and, in fact,  3g  afforded amixture of the desired   -aminoester and a deaminated esterbyproduct (56%). 6 Finally, the diastereoselective hydrogenation anddebenzylation can be performed in one pot by simply adding Pd-(OH) 2  /C after the enamine hydrogenation with platinum oxide.The high diastereoselectivities reported here are remarkableconsidering the structural complexity of Adam’s catalyst 13 and thereduced Pt. The important role that the PGA carboxamide groupplays is evident from the superior selectivities observed with PGA-derived enamines as compared to the R  -methylbenzylamine-derivedenamines 4 and suggests a strong interaction of this group with thecatalyst surface. Invoking the classic Horiuti - Polanyi mechanism, 14 selective binding of the back face of the (  Z  )-enamines  2  to thecatalyst surface, as directed by the coordinating PGA group,followed by hydrogen transfer from the catalyst to the bound faceof   2  affords  3  with the observed stereochemistry. This diastereo-facial discrimination is higher with the (  Z  )-enamines than with the  E  -isomers and is enhanced when activated catalyst is used withless alkali metal impurities present to inhibit hydrogen and substratebinding.To gain further insight into the mechanism of this hydrogenation,a deuterium labeling study was performed. Reaction of   2a  withdeuterium gas (90 psi D 2  for 8 h, acid washed PtO 2 ) afforded  3a with deuterium incorporation at C2 (85%) and C3 (90%) andsignificant deuterium incorporation at the carboxamide NH 2 ( ∼ 60%). These results are consistent with direct reduction of theC d C bond as the major hydrogenation pathway 15 rather than viaan initial isomerization to the imine tautomer followed by reductionof the C d N bond. Deuterium incorporation at the carboxamide NH 2 is consistent with coordination of this group to the catalyst surface,possibly via the  π  -orbitals in the conformation seen in the X-raystructure (Figure 1). In this model, the carboxamide binding withthe bulky phenyl group of PGA disposed away from the metalsurface enhances the diastereoface selective binding of the conju-gated enamine system.Thus, a new set of conditions was identified for the preparationof    -aminoesters and amides via heterogeneous catalysis withunprecedented diastereoselectivities and good substrate generality.This approach offers an alternative synthetic strategy to asymmetrichydrogenation methods. Acknowledgment.  We thank Dr. P. Dormer for NMR spec-troscopic analysis, Dr. T. Novak for HRMS data, M. Biba and J.DaSilva for chiral assays, Dr. T. Wang for elemental analysis, andJ. Chilenski for assistance with X-ray data. Supporting Information Available:  Experimental details andcrystallographic data (PDF and CIF). This material is available free of charge via the Internet at http://pubs.acs.org. References (1) See reviews: (a) Abdel-Magid, A. F.; Cohen, J. H.; Maryanoff, C. A. Curr. Med. Chem.  1999 ,  6  , 955. (b) Cole, D. C.  Tetrahedron  1994 ,  50 ,32. (c) Book:  Enantioselecti V  e Synthesis of    -Amino Acids ; Juaristi, E.,Ed.; Wiley-VCH: New York, 1997.(2) (a) Review: Drexler, H.-J.; You, J.; Zhang, S.; Fischer, C.; Baumann,W.; Spannenberg, A.; Heller, D.  Org. Process Res. De V  .  2003 ,  7  , 355.(b) Tang, W.; Wang, W.; Yongxiang, C.; Zhang, X.  Angew. Chem., Int. Ed.  2003 ,  42 , 3509. (c) You, J.; Drexler, H.-J.; Zhang, S.; Fischer, C.;Heller, D.  Angew. Chem., Int. Ed.  2003 ,  42 , 913. (d) Tang, W.; Wu, S.;Zhang, X.  J. Am. Chem. Soc.  2003 ,  125 , 9570. (e) Zhu, G.; Chen, Z.;Zhang, X.  J. Org. Chem .  1999 ,  64 , 6907. (f) Tang, W.; Zhang, X.  Org. Lett  .  2002 ,  4 , 4159. (g) Pen˜a, D.; Minnaard, A. J.; de Vries, J. G.; Feringa,B. L.  J. Am. Chem. Soc .  2002 ,  124 , 14552. (h) Wu, J.; Chen, X.; Guo,R.; Yeung, C.; Chan, A. S. C . J. Org. Chem .  2003 ,  68  , 2490.(3) An example where separation is not required: Zhou, Y.-G.; Tang, W.;Wang, W.-B.; Li, W.; Zhang, X.  J. Am. Chem. Soc .  2002 ,  124 , 4952.(4) (a) Cohen, J. H.; Abdel-Magid, A. F.; Almond, H. R., Jr.; Maryanoff, C.A.  Tetrahedron Lett  .  2002 ,  43 , 1977. (b) Furukawa, M.; Okawara, T.;Noguchi, Y.; Terawaki, Y.  Chem. Pharm. Bull.  1979 ,  27  , 2223. (c)Jolindon, S.; Meul, T. U.S. Patent 4,585,887, 1986. (d) Melillo, D. G.;Cvetovich, R. J.; Ryan, K. M.; Sletzinger, M.  J. Org. Chem.  1986 ,  51 ,1498. (e) Hydride reduction: Cimarelli, C.; Palmieri, G.  J. Org. Chem . 1996 ,  61 , 5557.(5) PGA is a readily available and useful chiral amine source: Van der Sluis,M.; Dalmolen, J.; de Lange, B.; Kaptein, B.; Kellogg, R. M.; Broxterman,Q. B.  Org. Lett  .  2001 ,  3 , 3943.(6) Experimental details are provided in the Supporting Information.(7) Platinum oxide was found to be superior to all catalysts screened (Pt/C,Pt/Al, Pd/C, and Pd/Al) in terms of both rate and selectivity.(8) Keenan, C. W.; Giesemann, B. W.; Smith, H. A.  J. Am. Chem. Soc .  1954 , 76  , 229.(9) Rylander, P. N.  Catalytic Hydrogenation o V  er Platinum Metals ; AcademicPress: London, 1967.(10) Hydrogenation of   2a  as an 82:18 (  Z   /   E  )-mixture afforded only 93% deunder the optimized conditions using acid washed PtO 2 .(11) PtO 2  (Engelhard, 15 g) was stirred 1 h in glacial acetic acid (50 mL) atroom temperature. The catalyst was filtered, rinsed with glacial aceticacid (2 × 10 mL), and dried 1 day in a 50  ° C vacuum oven. Analysis of the acetic acid wash showed significant levels of Na and K ( ∼ 5  µ g each/ mg of PtO 2 ).(12) Using the (  R )-PGA will give the enantiomeric series.(13) Mansour, A. N.; Sayers, D. E.; Cook, J. W., Jr.; Short, D. R.; Shannon,R. D.; Katzer, J. R.  J. Phys. Chem.  1984 ,  88  , 1778.(14) Horiuti, I.; Polanyi, M.  Trans. Faraday Soc .  1934 ,  30 , 1164.(15) Syn-facial delivery of hydrogen is assumed and supported by the observed cis -stereochemistry for  3d . JA038812T Figure 1.  X-ray structure of   2b . C O M M U N I C A T I O N S J. AM. CHEM. SOC.  9  VOL. 126, NO. 10, 2004  3049 View publication statsView publication stats
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