Matthew D. Shair Friday, November 15, 2002 Chemistry 206 Advanced Organic Chemistry Handout 25A The Asymmetric Baylis-Hillman Reaction An Evans Group Afternoon Seminar Jake Janey March 29th, 2001 EWG + cat. base XH EWG X R R' R R' * EWG – Chem 206 J. Janey The Asymmetric Baylis-Hillman Reaction Leading References:Langer, P. Angew. Chem. Int. Ed. Engl. 2000 , 39 , 3049-3052. Ciganek, E. Org. React. 1997 , 51 , 201-350. Basavaiah, D.; et. al . Tetrahedron , 1996 , 52 , 8001-8062. Drewes, S. E.; Roos, G. H. P. Tetrahedron , 1988 , 44 , 4653-4670. An Evans Group Afternoon Seminar Jake Janey March 29th, 2001 EWG + cat. base XH EWG X RR ' R R' * EWG – Baylis-Hillman Reaction Scope R 1 X EWG R 2 X = O, NTs, NCO 2 R, NPPh 2 , NSO 2 Ph R 1 = alkyl, aryl R 2 = H, alkyl, EWG EWG = CO 2 R, CN, POEt 2 , CHO, COR, SO 2 Ph, SO 3 Ph + cat. base EWG R 1 R 2 XH R OH EWG Rh(I), H 2 R EWG OH An anti propionate aldol equivalent... N N N N OH cat. bases: 3-hydroxyquinuclidine (3-QDL) DABCO quinuclidine n -Bu 3 P: Early Synthetic Examples CO 2 Et MeCHO 5% DABCO 25 °C, 7d Me OH CO 2 Et 94% yield HO 2 C Me Me CO 2 H OH Me + Drewes, S. E. J. Chem. Soc., Perkin Trans. 1 1982 , 2079-2083. 10 years after the Baylis-Hillman German patent...used in a C 10 integerrinecic acid synthesis: Shortly thereafter, a more extensive, published study: CO 2 Me RCHO 15% DABCO 25 °C, 0.5 to 7d R OH CO 2 Me 94% yield + Hoffmann, H. M. R.; Rabe, J. Angew. Chem. Int. Ed. Engl. 1983 , 22 , 795-797. ? All reactions run neat in a sealed tube with 1.5-2 equivalents of acrylate. R = alkyl or aromatic 25A-01 11/9/01 1:06 PM Chem 206 The Asymmetric Baylis-Hillman Reaction EWG R 3 N + EWG R 3 N – + R'CHO EWG R 3 N O R' + EWG R' OH NR 3 H H EWG H α O + R' NR 3 H H H α EWG + O E2 elimination... initially formed eliminates ? rate = K obs [aldehyde][alkene][amine] ? pseudo-second order if [amine] ≈ constant ? addition to aldehyde is r.d.s. because the dipole is increased by further charge seperation? acrylonitrile and methyl acrylate studied? enolate geometry not considered? ethereal solvent inhibits reaction whereas alcohols (especially diols) accelerate reaction? huge volume of activation: ? V ? of -79 cm 3 mol -1 (the Diels-Alder is -35 cm 3 mol -1 ) found by plotting ln k obs vs. P. 5000 bar increases rate by 1.1 x 10 6 ? Reaction is reversible (i.e. a Grob type fragmentation), thus mechanism could be ternary, with no discrete enolate intermediate (supported by ? V ? and temperature effects). Hill, J. S.; Isaacs, N. S. J. Phys. Org. Chem. 1990 , 3 , 285-288. Kaye, P. T.; Bode, M. L. Tetrahedron Lett. 1991 , 32 , 5611-5614. :B –– – E1cB is also possible Evidence for an Intermediate OO O 1 eq DABCO CH 2 Cl 2 , r.t., 2.5 h OO N N + Cl X-ray 81% yield Coumarin Salt Drewes:"...the counter ion was chloride (presumably originating from the dichloromethane...)." OOH + Cl O OOH + OMe O 1 eq DABCOCH 2 Cl 2 , 0 °C OO N N + Cl Or... 40% yield Drewes, S. E.; et. al. Syn. Comm. 1993 , 23 , 2807-2815. H H H – – Effects of Acrylate Ester Substituent CO 2 R + 13% DABCO neat, r.t 1.3 eq 1.0 eq Ph OH O OR PhCHO R Me Et Bn n -C 10 H 21 t -Bu 2-adamantyl CH 2 CH 2 F CH 2 CH 2 Br CH 2 CF 3 CH 2 CH 2 OMe CH 2 CH 2 NMe 2 (CH 2 ) 6 Cl time (days) 672 146562 32 15 h 48 15 yield (%) 89798875654081 NR 588982 NR Caubere, P.; et. al. Tetrahedron 1992 , 48 , 6371-6384. ? For aryl substituted benzyl ethers, no clear relation between σ values and reactivity was observed.? Trends hold for furfural.? The products undergo retro Baylis-Hillman, i.e. the reaction is reversible. J. Janey 25A-02 11/9/01 1:07 PM Chem 206 The Asymmetric Baylis-Hillman Reaction Bases for Catalysis N N DABCO 2.97, 8.82 (2.97, 8.93) N Quinuclidine 10.9 (9.80) N 3-Hydroxyquinuclidine (3-QDL) 9.5 (~8.5) OH >> > > N 3-Acetoxyquinuclidine OAc N 3-Quinuclidone 6.9 O or O OR N O H ...or could accelerateprotonation ofintermediate, as anyalcohol additivewill acceleratereaction NMe 2 NMe 2 Proton sponge 12.0 (7.50) N N DBU (~12) Sterics also important: Me 2 NH > Me 2 NEt > MeNEt 2 > NEt 3 10.75 (9.00) Many, many phosphines screened...the winner: n -Bu 3 P ~9 P P unreactive ? n -Bu 3 P is only a slightly better catalyst than DABCO. pK a H 2 O (DMSO) – > > Temperature Effects CO 2 Me MeCHO + 0.1 mol% DABCO 2M in dioxane Me OH CO 2 Me 25 °C 1 week0 °C 8 hours! 74% yield ? Reaction is accelerated for a wide variety of aldehydes when conducted at 0 °C? Temperature effect not seen with acrylonitrile (cannot form enolate)? Author concludes that one enolate must react faster than another (i.e. a kinetic versus a thermodynamic enolate). NR 3 O OMe O R 3 N + + – E CO 2 Me R 3 N + Z Which enolate is more stable and which is more reactive? Leahy, J. W.; Rafel, S. J. Org. Chem. 1997 , 62 , 1521-1522. – OMe Enolate Geometry NR 3 O OMe O R 3 N + + – E R 3 N + Z Thermodynamic Kinetic ? less charge seperation? less reactive ? more charge separation? less stable? enolate twists out of plane by PM3 O OMe R 3 N + OO M e O NR 3 MeO σ * 4 π e - HOMO + MeO NR 3 O σ * + better conjugation into σ * OMe – – – J. Janey 25A-03 11/9/01 1:07 PM Chem 206 The Asymmetric Baylis-Hillman Reaction Salt Additive CO 2 Me PhCHO + 5% DABCO Et 2 O, 0 °C, 20 h Ph OH CO 2 Me LiClO 4 (mol%)05 105070 100200500 y ield (%) trace 124063 72 (81) a 2512 trace 1.2 eq 1.0 eq a 15 mol% DABCO was used. ? Ether was found to be optimal from solvent screening.? General for a variety of alkenes and aldehydes. O R 3 N + Li ClO 4Stablize enolate? Kobayashi, S.; Kawamura, M. Tetrahedron Lett. 1999 , 40 , 1539-1542. – OMe Lewis Acid Catalysis CO 2 t -Bu PhCHO + 1 eq DABCO MeCN , r.t., 1 d Ph OH CO 2 t -Bu ligand none (+)BINOL (+)diethyl tartrate (+)diisopropyl tartrate (+)TMTDA (+)hydrobenzoin (+)triphenylethanediol (+)TADDOL ethylene glycoltriethanolamine salen box N -methylephedrine Sc(OTf) 3 3.39.45.23.54.13.53.22.93.3 4.652.31 3.6 2.87 Yb(OTf) 3 3.6 14.4 9.79.58.0 16.2 5.24.56.35.8 Eu(OTf) 3 3.5 12.8 5.54.63.65.82.23.85.23.2 La(OTf) 3 4.7 14.6 7.38.14.05.35.94.7 10.8 4.04.4 5 mol% ligand, 5 mol% metal Relative Reaction Rates ? no enantioselectivity observed? DABCO loading dropped to <10 mol% with (+)-BINOL? rac -BINOL showed no rate acceleration Aggarwal, V. K.; et. al. Chem. Commun. 1996 , 2713-2714. Aggarwal, V. K.; et. al. J. Org. Chem. 1998 , 63 , 7183-7189. J. Janey 25A-04 11/9/01 1:07 PM Chem 206 The Asymmetric Baylis-Hillman Reaction Possible Stereoisomers H α O R' H H H NR 3 + O MeO H α O H R' H H NR 3 + O MeO H α O R' H + OMe O H H R 3 N H α O H R' + OMe O H H R 3 N CO 2 Me H α O R' H H H NR 3 + CO 2 Me H α O H R' H H NR 3 + CO 2 Me H α O R' H + H H R 3 N CO 2 Me H α O H R' + H H R 3 N H R 3 N H H α MeO 2 C H R 3 N H H α MeO 2 C H H NR 3 H α CO 2 Me H H NR 3 H α CO 2 Me R' H OH R' OH H R' HO H R' H HO R' CO 2 Me OH R' CO 2 Me OH ++ + + 120 ° rotationthen E2 elim. Assumptions:? E enolate formed ? E2 favored over E1 pathway? -NR 3 + is orthogonal to π face (stereoelectronics) –– – – –– – – J. Janey 25A-05 11/9/01 1:08 PM Chem 206 The Asymmetric Baylis-Hillman Reaction E/Z Selectivity with Crotononitrile CN Me PhCHO Ph Me CN OH Ph CN OH Me r.t. ++ EZ Solvent neatTHF CHCl 3 CH 3 CN MeOH E/Z ratio 1.2 : 11.4 : 11.5 : 13.1 : 1 4 : 1 5 mol% DABCO, 8 kbar, 17 h, solvent 50 vol% Base DABCO 3-QDL NEt 3 E/Z ratio 1 : 12 : 14 : 1 10 mol% base, 8 kbar,17 h, CHCl 3 50 vol% 1 eq 1 eq 5 mol% DABCO,17 h, solvent 50 vol% Rozendaal, E. L. M.; Voss, B. M. W.; Scheeren, H. W. Tetrahedron 1993 , 49 , 6931-6936. ? E and Z crotononitrile is easily isomerized under the reaction conditions.? Products did not undergo retro-Baylis-Hillman. J. Janey 25A-06 11/9/01 1:08 PM Chem 206 The Asymmetric Baylis-Hillman Reaction Possible Stereoisomers for Methylcrotonate H α O H R' Me H NR 3 + O MeO H α O H R' H Me NR 3 + O MeO CO 2 Me H α O H R' Me H NR 3 + CO 2 Me H α O H R' H Me NR 3 + Me R 3 N H H α MeO 2 C H R 3 N Me H α MeO 2 C R' OH H R' OH H ++ H α O R' H H Me NR 3 + O MeO H α O R' H Me H NR 3 + O MeO CO 2 Me H α O R' H H Me NR 3 + CO 2 Me H α O R' H Me H NR 3 + H R 3 N Me H α MeO 2 C Me R 3 N H H α MeO 2 C R' H OH R' H OH ++ NR 3 H Me H α MeO 2 C NR 3 Me H H α MeO 2 C R' OH H R' OH H NR 3 Me H H α MeO 2 C NR 3 H Me H α MeO 2 C R' H OH R' H OH ++ + + R' CO 2 Me OH Me R' CO 2 Me OH R' CO 2 Me OH R' CO 2 Me OH Me Me Me Assumptions:? E enolate formed ? E2 favored over E1 pathway, only after rotation of ammonium to anti conformation? -NR 3 + is orthogonal to π face (stereoelectronics)? only one π face of enolate considered, thus there are an additional 4 stereoisomers possible ? starting geometry of methylcrotonate and in situ isomerization not considered? retro-Baylis-Hillman not considered –– – – –– –– J. Janey 25A-07 11/9/01 1:09 PM Chem 206 The Asymmetric Baylis-Hillman Reaction Camphorsultam Acrylate Baylis-Hillman S N O O O RCHO, 10% DABCOCH 2 Cl 2 , 0 °C, 12 h O O O R R R Me Et n -Pr i -Pr PhCH 2 CH 2 AcOCH 2 (CH 3 ) 2 CHCH 2 Ph yield (%) 85987033686867 0 ee (%) >99>99>99>99>99>99>99 MeOH, CSA (85%) MeO 2 C OH R = Et Me Rh(I), H 2 (85%) MeO 2 C Me OH Me Leahy, J. W.; et. al. J. Am. Chem Soc. 1997 , 119 , 4317-4318. Camphorsultam Acrylate Mechanism S N O O O NR 3 + S N O O NR 3 O + Dipole minimized RCHO O X c N NR 3 H H R O + X c N O R O R 3 N+ X c N O NR 3 OR OR + O O O NR 3 R R + O O O R R Author's model: – – – – – αααα -Branched Aldehydes: Modest Felkin-Anh Selection R 1 R 2 CHCHO + CO 2 Me r.t CO 2 Me R 2 OH R 1 CO 2 Me R 2 OH R 1 + anti syn R 2 MeMeMePhn -Pr MeMe ConditionsDABCO, 4 d3-QDL, 1.5 dDABCO, 6 dDABCO, 10 d3-QDL, 60 dDABCO, 55 dDABCO, 7 dDABCO, 3.5 dDABCO, 11 d yield (%) 556042423062802843 anti:syn 70:3072:2870:3037:6335:6569:3126:7446:5489:11 ? Varying the amount of catalyst only affects the rate, not selectivity.? Anti and syn drawn incorrectly in review, should be reversed. R 1 MeOCH 2 O MeOCH 2 O BnOCH 2 O MeOCH 2 O MeNHCO 2 t -Bu N -Phthalimidyl -N(CO 2 t -Bu)C(Me) 2 OCH 2 - -OC(Me) 2 OCH 2 - O N H H Me H t -BuO 2 C syn selective Ciganek, E. Org. React. 1997 , 51 , 217-218. J. Janey 25A-08 11/9/01 1:09 PM Chem 206 The Asymmetric Baylis-Hillman Reaction Chiral Aldehydes: Chromium Auxiliary Cr(CO) 3 OH R 50% DABCO neat, r.t. CO 2 Me + Cr(CO) 3 R MeO 2 C H OH h ν , air CH 3 CN OH CO 2 Me R aldehyde racracracrac S -(+) S -(+) R OMe Cl F Me OMe Cl time (h) 93 67 5893 8 yield (%) 878992908597 dr >98:2>98:2 92:8 84:16>98:2>98:2 ? dr determined by 200 MHz 1 H NMR ? N -Tosyl arylimine chromium complex also reacts excess Kundig, P. E.; et. al. Tetrahedron Lett. 1993 , 34 , 7049-7052. Chiral Phosphine Catalysts CO 2 Et O OH CO 2 Et 18 mol% (-)-CAMP neat, r.t., 10 d 75% yield (40% isolated) 14% ee (-)-CAMP = POMe Me 62% ee Frater, G.; e t . al. Tetrahedron Lett. 1992 , 33 , 1045-1048. NC H O CO 2 Me + CO 2 Me OH N 10 mol% cat. neat, r.t. 9-94 h 18-83% yield 2-19% ee cat. = P R R'OR'O R Ph R = Me and R' = H gave highest reactivity Zhang, X.; et. al. J. Org. Chem. 2000 , 65 , 3489-3496. The High Point of Chiral Phosphine Catalysts N N CHO CO 2 R 2 N N OH CO 2 R 2 R 1 R 1 + 20 mol% ( S )-BINAP CHCl 3 , r.t. 3-14 d 2.4 eq R 1 HHH MeMe R 2 i -PrEt MeMeMe time (d) 434 14 3 yield (%) 8 12241826 ee (%)9 254437 30 a a Tol-BINAP was used ? other phosphines screened gave ~racemic products:DIOP, NORPHOS, BPPFOH, and MOP Soai, K.; et. al. Chem. Commun. 1998 , 1271-1272. J. Janey 25A-09 11/9/01 1:09 PM Chem 206 The Asymmetric Baylis-Hillman Reaction Naturally Occurring Alkaloids as Chiral Catalysts CN OH CN Me MeCHO + ? mol% cat. 9 kbar, 25-60 °C 0-81% yield 3-17% ee ? (-)-quinine, (1 R ,2 S ) N -methylephedrine, S -(-)-nicotine, S -(-)- N -methylprolinol screened ? (-)-menthyl acrylate ester gave 100% de with aromatic aldehydes and DABCO under high P Isaacs, N. S.; et. al. Tetrahedron: Asymm. 1991 , 2 , 969-972. O Me RCHO + 10 mol% quinidine CH 2 Cl 2 , r.t. 20 h R OH O Me R n -Pr n -C 9 H 19 i -Pr c -hex Pressure 3 kbar 10 kbar 3 kbar3 kbar ee (%) 18313745 40-50% yield ? 3-QDL, quinine, cinchonine, cinchonidine, O -acetyl quinidine, N -methylprolinol, N -methylephedrine also screened ? ee is highly pressure dependent, optimized pressure is shown in table Marko, I. E.; Giles, P. R.; Hindley, N. J. Tetrahedron 1997 , 53 , 1015-1024. N N MeO O H O H H H H Me O + R H N N MeO O H O R H H H Me O + H H RM e O OH minor RM e O OH major Model For Quinidine Catalyst Author's model: ? C α hydrogens control π face of the aldehyde ? bulky R should enhance selectivity, a trend that they say is "...clearly visible."? H-bonding plays a "clear role" as O -acyl quinidine gives no enantioselectivity αα Marko, I. E.; Giles, P. R.; Hindley, N. J. Tetrahedron 1997 , 53 , 1015-1024. N N MeO O H H + H α O – H O H R Alternative: H H Me major – – J. Janey 25A-10 11/9/01 1:10 PM Chem 206 The Asymmetric Baylis-Hillman Reaction C 2 Symmetric DABCO Catalyst CHO Me O O 2 N O 2 N O Me OH 15 mol% cat. 1% Hydroquinone 5-10 kbar, THF, 30 °C + N N OR cat. = R Bn TBDPS TIPS Ph Mesityl 1-naphthyl 1-anthranyl 1-napththoyl N -Cbz-Gly time (h) 121228162816241724 yield (%) 452333606766 9 6863 ee (%) 473419351642111521 ? racemic alcohol product can be easily resolved by kineticresolution with Sharpless asymmetric epoxidation? other chiral DABCO's made, but not tested... N N N N N N Ph Ph Hirama, M.; et. al. Tetrahedron: Asymm. 1995 , 6 , 1241-1244. H H OR Ph H H Ph Ph Ph H H H H Chiral Pyrrolizidine Catalyst Me O Ar O Me OH 10 mol% cat. 1 eq NaBF 4 CH 3 CN, -40 °C, 0.5-3 d + N O 2 N HO H H cat. = ArCHO Ar 2-NO 2 2-F 2-Cl2-Br 3-NO 2 2-pyridyl3-pyridyl 4-quinolinyl 4-NO 2 yield (%) 713158635183936317 ee (%) 676372713721497039 N + O Me NO 2 O H O R H Na + N + O Me NO 2 O H Na + OR H favored disfavored Author's model: Barrett, A. G. M.; et. al. Chem. Commun. 1998 , 2533-2534. –– J. Janey 25A-11 11/9/01 1:10 PM Chem 206 The Asymmetric Baylis-Hillman Reaction C 2 Symmetric DABCO Catalyst CHO Me O O 2 N O 2 N O Me OH 15 mol% cat. 1% Hydroquinone 5-10 kbar, THF, 30 °C + N N OR cat. = R Bn TBDPS TIPS Ph Mesityl 1-naphthyl 1-anthranyl 1-napththoyl N -Cbz-Gly time (h) 121228162816241724 yield (%) 452333606766 9 6863 ee (%) 473419351642111521 ? racemic alcohol product can be easily resolved by kineticresolution with Sharpless asymmetric epoxidation? other chiral DABCO's made, but not tested... N N N N N N Ph Ph Hirama, M.; et. al. Tetrahedron: Asymm. 1995 , 6 , 1241-1244. H H OR Ph H H Ph Ph Ph H H H H Chiral Pyrrolizidine Catalyst Me O Ar O Me OH 10 mol% cat. 1 eq NaBF 4 CH 3 CN, -40 °C, 0.5-3 d + N O 2 N HO H H cat. = ArCHO Ar 2-NO 2 2-F 2-Cl2-Br 3-NO 2 2-pyridyl3-pyridyl 4-quinolinyl 4-NO 2 yield (%) 713158635183936317 ee (%) 676372713721497039 N + O Me NO 2 O H O R H Na + N + O Me NO 2 O H Na + OR H favored disfavored Author's model: Barrett, A. G. M.; et. al. Chem. Commun. 1998 , 2533-2534. –– J. Janey 25A-12 11/9/01 1:10 PM Chem 206 The Asymmetric Baylis-Hillman Reaction Quinidine Ether Catalyst O O R O O OH 10 mol% cat. DMF , -55 °C, 0.5-3 d + RCHO N O N OH CF 3 CF 3 CF 3CF 3 OO O R R + ester dioxanone R p -NO 2 Ph ( E )-PhCH=CH Et i -Bui -Pr c -Hext -Bu yield (%) 58575040513631 -- ee (%), (config) 91 ( R ) 95 ( R ) 92 ( R ) 97 ( R ) 99 ( R ) 99 ( R ) 99 ( R ) -- R S yield (%) 11 ---- 22182523 -- ee (%), (config) 4 ( R ) ---- 27 ( S ) 18 ( S ) 25 ( S ) 23 ( S ) -- cat. = ? Quinidine and other acyclic derivatives showed no enantioselection and verylow reactivity.? Free hydroxyl on quinoline is essential for enantioselectivity.? Reactions conducted at room temperature showed lower enantioselection.? Racemic ester does not react to give dioxanone under the reaction conditions. Hatakeyama, S.; et. al J. Am. Chem. Soc. 1999 , 121 , 10219-10220. prepared in 65% yield fromquinidine in 85% phosphoricacid and KBr (100 °C, 5 d). Proposed Mechanism: Partial Kinetic Resolution N O N OH O OR' + Et H N O O + Et H CO 2 R' H α R O H H N O N O + Et H CO 2 R' H α H O R H H H H α CO 2 R' Y X O N O R O OR' OH R O OR' OH OO O R R OO O R R RCHO RCHO RCHO RCHO R S S R ? obscures inherent facial selectivity of the catalyst N H O H Et Y = R X = R – – – – J. Janey 25A-13 11/9/01 1:10 PM Chem 206 The Asymmetric Baylis-Hillman Reaction A Model for Facial Selectivity PM3 minimized: C-N bond to enolate constrained to 1.6 ? O R H H O H R H Favored Disfavored ? Catalyst orthogonal to opposite π face of the enolate leads to same major enantiomer after elimination. BINOL as an Additive or Ligand O RCHO + 20 mol% n -Bu 3 P: 10 mol% BINOL THF, r.t. 2-24 h O R OH R n -C 7 H 15 Ph MEMO(CH 2 ) 3 Et PhCH 2 CH 2 yield (%) quant. 929891 quant. ? ee were all <10% ? phenol also accelerates reaction? other acrylates also tolerated O + O OH OO Ca 16 mol% 10 mol% n -Bu 3 P: THF, r.t. 7 h Ph CHO Ph 62% yield, 56% ee Ikegami, S.; Yamada, Y. M. A. Tetrahedron Lett. 2000 , 41 , 2165-2169. J. Janey 25A-14 11/9/01 1:11 PM Chem 206 The Asymmetric Baylis-Hillman Reaction A Related Phosphine Catalyzed Reaction ? EtO 2 C + 10 mol% cat.PhCH 3 , 0 °C P Ph i -Pr i -Pr cat. = CO 2 i -Bu CO 2 i -Bu CO 2 Et C O 2 Et CO 2 i -Bu + AB 10 eq CO 2 R PR 3 :PR 3 + CO 2 i -Bu CO 2 i -Bu CO 2 Et C O 2 Et CO 2 i -Bu + R 3 PR 3 P ++ CO 2 i -Bu CO 2 Et C O 2 Et CO 2 i -Bu + R 3 PR 3 P ++ 88% yield100:0 A:B 93% ee :PR 3 P Ph i -Pr EtO 2 C i -BuO 2 C i -Pr Zhang, X.; et. al. J. Am. Chem. Soc. 1997 , 119 , 3836-3837. Lu, X.; et. al. J. Org. Chem. 1995 , 60 , 2906-2908. – – –– –– :PR 3 ? other catalyst and conditions give lower regio- and enantio- selection Phosphine Catalyzed Addition ? RO 2 C + NuH 10 mol% cat. NaOAc/HOAc r.t. PhCH 3 Nu CO 2 R O CO 2 Me R Me Et t -Bu EtEtEt Me O COMe O O COMe O O 2 N CO 2 Et NC yield (%) 80767467833147 ee (%) 73747556484145 product O CO 2 Me CO 2 R O COMe CO 2 Et O O COMe CO 2 Et NO 2 CO 2 Et CO 2 Et CO 2 Me O NC NuH Zhang, X.; et. al. J. Org. Chem. 1998 , 63 , 5631-5635. P Ph Me Me cat. = J. Janey 25A-15 11/9/01 1:11 PM Chem 206 The Asymmetric Baylis-Hillman Reaction Addition Mechanism ? CO 2 R CO 2 R PR 3 :PR 3 + NuH CO 2 R PR 3 + Nu CO 2 R PR 3 + Nu – CO 2 R Nu + cat. :PR 3 HOAc/NaOAc PhCH 3 :PR 3 Author's proposal: H + shift – – Recipe for a Good Catalyst? NR 3 O OR + vs. NR 3 OR O + EZ NR 2 O OR + O R H vs. ? for substituted acrylates, must control enolate π facial selectivity ? chirality on catalyst may also gear ester substituent to influence aldehyde approach NR 2 O OR + O H R Control enolate geometry... Control aldehyde π face... or NR 2 O OR + O H R X NO X OR R 1 R 2 O R H – – – – – – Conclusions ? The Baylis-Hillman reaction provides convenient access to valuable allylic alcohol building blocks which may serve as synthetic equivalents to anti -propionate aldol addition products. ? The basics of the reaction mechanism are understood, but the mechanistic details still remain elusive at best.? Few examples of a general, diastereoselective Baylis-Hillman have been reported and the successful ones are rather limited in scope.? Only one synthetically useful enantioselective, base catalyzed Baylis-Hillman reaction exists. There is no rational design, nor models for asymmetric catalysis.? The asymmetric, catalytic Baylis-Hillman reaction is very promising and attractive methodology, but remains an elusive goal of chiral Lewis base catalysis. J. Janey 25A-16 11/9/01 1:11 PM