\z )t ! ) J-) - tf \A Reprinted from the Journal of the American Chemical Society,1989, I11,627. Copyright 6l lggg Liitt. American Chemical Societyand reprinted by permission of the copvright owDer. Rabbit MuscleAldolase as a Catalyst in OrganicSynthesisr Mark D. Bednarski,2 Ethan S. Simon,3 Norbert Bischofberger,a Wolf-Dieter Fessner, Mahn-Joo Kim, Watson kes,S Tohru Saito, Herbert Waldmann,5 and George M. Whitesidesr Contributionfrom the Department of Chemistrl', Haruard Uniuersity, ' | ' . Cambridge, Massachusetts 021 38. Receiredlv{arch4, ],988 Abst6ct: p-Fructosc-1,6-bisphosphate aldolase from rabbit muscle (RA\tA, EC 4.1.2 l3) is a synthetically uscfulcatalyst for the stcreoselective aldolcbndensation between dihydroxyacetone phosphate (DHAP, l) and aldehl'des having a rangc of structurcs. This paper dcmonstratcs that more than 50aldehydcs [in addition to its natural substratc, >glyccraldehyde 3-phcPFtc' G-3-P (2)l arc iu6strates for RAMA. Unhindered aliphatic, a-heteroarom-substrtuted, and difierentially protectcd.alkory andamino aldehydes aresubstitutes;sterically hindercd aliphatic and a,6-unsaturated aldehydes arenot. Aromatic aldehydcs areeither poot "t substrates or theydo not react.Phosphorylated aldehydcs react more rapidly thanthcirunphosphorylated counterparts, and aldehydes substituted in thea position with an electroncgative group react morerapidll' thanunsubstitutcd aliphatic aldehydes. Pcrmissible variations in ttiestructure of the DHAP moiety' are much morerestricted; only two-I,3' dihydroxy-2-butanone 3-phosphate (68)and 1,4-dihydroxy-3-butanone-l-phosphonate (69)-of I I DHAP analogues tcstcd weicsubstrates for RA\{A. neVn is stable under tirereattion conditions used in synthetic applications: it withstands organic cosolvents (up to 207o D\1SO or EIOH); it canbe uscd in immobilized iorm, in soluble form,or enclosed withina mcmbranc; it is also air-stable. Synthcscs of 5,6-dideoxy-D-threo-2-hexulose l-phosphate (82),5-O-methyl-D-fructose (85),o-xylulcc (8t), and peracetylatedvglycero-o-altru2-octulose (91) on scales of 4 mmol-l moldemonstrate practical applicationgf thit catalytic synthetic methodoiogy. In a limited srudy of kinetic diastereoselectivity, RAMA exhibits useiul selectivity in tyo cascsl *itir (*)-glyccraldchydc 3-phosphate [2; 20:'lratio, the majorisomer being >fructose 1,6-bisphosphate (3)] andwilh (+)-2-(benzyloxyipropanal [19; 3:t raiio,tiri majorisomer being (S,S,R)-5-(benzyloxy)-3,4-dihydroxy'l-(phosphon*xl)' h.*"n-i-on. igtlj 'When 1+j-f -hydroxybuunal (lm) reacs with DHRP, high thermodynamic diasterecelectivity was sbccnrcd: the ratioof the two stcrcoisomers (ror to lo{) is 97:3 andthe majorisomer is 5,?-didcoxy-t-gluco2-heptulopyrance l'phcpbatc (103). The development of methods for stereoselective formationof carbon-carbonbonds using the aldol reaction is a current focus of effort in organic synthesis.?-12 Many successful strategies using (l) Supportcd by thc NIH, Grant GM 30367. The Nlv{R instrumenLation \vassupportcd in part by thc National ScienccFoundation, ChcmicalIn- strurnentation Program (Grant CHE 84-10774). (2) Amcrican Cancer Socicty PostdoctoralFellow, Grant PF-2762, I 986-l 987. (3) DuPont Fellow 1985-198?. (4) Postdoctoral Fcllow of Ciba-Gcigy and thc Government of Austria. (5) Natural Science and Engineering Rescarch Council of Canada, Pre- doctoral Traincc. (6) Postdoctoral Fcllow of thc Dcutsche Forscbungsgemcinschaft, I 9E5-l986. (7) Stocochcmlstry of Organic and Bioorganic Transformaliorui Barl- m8nn, W., Sharplcss, K. 8., Eds.; VCH: Ncw York, 1987. , (t) Braun,M. Anger+,, Chcm.,Int. Ed. Engl.19E1,26,24. (9) Rccta M. T. Angew. Chcm, Int. Ed. Engl. 19t4, 23, 556. (10) Asynnctrlc Syruheli.r; Morrison, J.D., Ed.; Acadcmic: Ncw York, l9E3;Vol. 2 and 3. (ll) 'lsynmctrlc Rcactiorc and Prxcsses ln Chcmistry. Elicl, L., Otsuka, S., Eds.; ACS Sympoium Scrics185; Amcrican Chcmical Socicty: Wash' ington,DC, 19E2. chiral auxiliaries have been reported.lF2l In principle, howe;e:' a catalytic asymmetric aldol reaction requiring minimal cffor: to prepare the catalyst would be preferable to methods rcquiring a stoichiometric equivalent of a chirotopic auxiliary. hevious re- ports22 describe three nonbiological catalysts-Zn(II) compleres Q2) Arganic Syntlesis Today and Tomorror4 Trost, B. M' Hutchils:r:. C. R., Eds.;Pergamon: New York, 1981. : (13) Evans, D' A.; Nclson, J. V.;Tahr, T' R. Iop. Sterapr'lu'nr. 19t1 /J' l. l. (21)Mukaiyama, T. Org.React. (,v'f') 19t2,28,20r. o l g8q American Chemical Societv noo?-?R61 lP,S lt 5 r r -06?7S01 so/0