14 asymmetric allylation reactions

Myers Chem 115 Asymmetric Allylation Reactions Brown Allylation and Crotylation Reactions Enantioselective Allylboration Et2O –78 A 23 °C; O Reviews: H + (–)-Ipc2B R R NaOH, H2O2 Srebnik, M.; Ramachandran, P V Aldrichimica Acta 1987, 20, R Roush, W R In Comprehensive Organic Synthesis, Trost, B M.; Fleming, I., Eds., Pergamon Press: New York, 1991, Vol 2, pp 1-53 Synthesis of B-Allyldiisopinocampheylborane H 3C CH3 CH3 CH3 CH3 = (1R)-(+)-_-Pinene 91.3% ee H3B•S(CH3)2 THF, °C h,72% 72 h, 72% BH BH (–)-Ipc2BH CH3OH, h °C, 100% yield (%) ee (%)a ee (%)b CH3 74 93 •99 n-C3H7 71 86 - n-C4H9 72 87 96 t-C4H9 88 83 •99 C 6H 81 96 96 aAllylboration carried out without filtration of Mg salts bAllylboration carried out at –100 °C under Mg-salt free conditions 98.9% ee OH • The reaction is quite general; the stereochemistry of the addition is the same in all cases examined • Lower reaction temperatures (0 A –78 A –100 °C) lead to increased enantioselectivity CH3 BB CH3 MgBr 98.9% ee BOCH33 BOCH –78 A 25 °C 25 °C, h 98.9% ee • Only Mg-salt free reagent can be used at –100 °C because the reactive borane is sequestered by ate complex formation with CH3OMgBr at this temperature • Allylboration of aldehydes is essentially instantaneous at –78 or –100 °C in the absence of Mg salts • Prolonged incubation at °C affords enantiomerically enriched Ipc2BH This is due to equilibration of tetraisopinocampheyldiborane with _-pinene and triisopinocampheyldiborane; the symmetrical dimer crystallizes preferentially H 3C H 3C • Both enantiomers of _-pinene are commercially available and inexpensive.(Aldrich: (1R)-(+)-_-pinene, 91% ee, $100/500mL; (1S)-(–)-_-pinene, 87% ee, $42/100mL) • B-Allyldiisopinocampheylborane can be prepared and used in situ after filtration of the magnesium salts produced during its formation Brown, H C.; Desai, M C.; Jadhav, P K J Org Chem 1982, 47, 5065-5069 Brown, H C.; Singaram, B J Org Chem 1984, 49, 945-947 Jadhav, P K.; Bhat, K S.; Perumal, P T.; Brown, H C J Org Chem 1986, 51, 432-439 H H H H H CH3 H B O H3C H CH3 CH3 • Allylation of aldehydes proceeds through a chair-like TS where R occupies an equatorial position and the aldehyde facial selectivity derives from minimization of steric interactions between the axial Ipc ligand and the allyl group R H Brown, H C.; Jadhav, P K J Am Chem Soc 1983, 105, 2092-2093 Brown, H C.; Bhat, K S J Am Chem Soc 1986, 108, 5919-5923 Racherla, U S.; Brown, H C J Org Chem 1991, 56, 401-404 M Movassaghi Diastereoselective Allylboration of Chiral, _-Substituted Aldehydes Asymmetric Isoprenylation of Aldehydes (+)-Ipc2BH + • CH3 THF CH3 –25 °C, h (+)-Ipc2B • The diastereofacial selectivity of the B-allyldiisopinocampheylborane reagent typically overrides any facial preference of the aldehyde for nucleophilic attack CH3 CH3 • Hydroboration of allenes is an efficient method for preparing B-prenyldiisopinocamphenylboranes B-allyldiisopinocamphenylboranes O allylboration H3C (+)-Ipc2B CH3 CH3 RCHO, Et2O –78 °C, 12 h; NaOH, H2O2 R yield (%) ee (%) CH3 73 91 n-C4H9 79 92 CH2=CH 70 95 (CH3)2C=CH 85 OH H OH H 3C + Et2O, –78 °C H3C 81% R H3C CH3 O H 3C H3C (–)-Ipc2BCH2CH=CH2 (+)-Ipc2BCH2CH=CH2 MATCHED: MISMATCHED: 96 OH H3C allylboration H : : 96 95 OH H 3C Et2O, –78 °C OBz H3C (92% de) (90% de) OH H3C + OBz OBz 80% Brown, H C.; Jadhav, P K Tetrahedron Lett 1984, 25, 1215-1218 Jadhav, P K.; Bhat, K S.; Perumal, P T.; Brown, H C J Org Chem 1986, 51, 432-439 MISMATCHED: Methallylation of Aldehydes CH3 (+)-Ipc2BOCH3 + Li (–)-Ipc2BCH2CH=CH2 (+)-Ipc2BCH2CH=CH2 MATCHED: Et2O CH3 (+)-Ipc2B –78 °C, h R CH3 RCHO, Et2O –78 °C, 12 h; NaOH, H2O2 yield (%) 56 OH CH3 R n-C3H7 54 90 n-C4H9 56 91 t-C4H9 55 90 CH2=CH 57 92 96 (88% de) (92% de) • Although the stereochemical outcome of the allylboration of aldehydes using B-allyldiisopinocampheylborane is typically reagent controlled, this selectivity may be challenged with certain substrates: ee (%) 90 : : 94 O H 3C H Ph OH allylboration Et2O, –78 °C OH + H 3C H 3C Ph Ph 72% MISMATCHED: MATCHED: (–)-Ipc2BCH2CH=CH2 (+)-Ipc2BCH2CH=CH2 67 : : 33 98 (34% de) (96% de) • The yields for methallylation of aldehydes are generally lower than in simple allylation reactions Brown, H C.; Jadhav, P K.; Perumal, P T Tetrahedron Lett 1984, 25, 5111-5114 Jadhav, P K.; Bhat, K S.; Perumal, P T.; Brown, H C J Org Chem 1986, 51, 432-439 Brown, H C.; Bhat, K S.; Randad, R S J Org Chem 1987, 52, 319-320 Brown, H C.; Bhat, K S.; Randad, R S J Org Chem 1989, 54, 1570-1576 M Movassaghi Chair TS's Produce syn Adducts from (Z)-Crotylboranes and anti Adducts from (E)Crotylboranes (Z)-Crotylboranes CH3 H3C (–)-Ipc2BOCH3 n-BuLi, KOt-Bu H3C K CH THF –45 °C CH3 OCH3 – B K –78 °C + CH3 BF3•OEt2 –78 °C H3C H H H H B H Ipc "(Z)-crotylborane" H3C H H3C H H CH3 H B O H3C H B CH3 B aldehyde NaOH, H2O2 yield (%) A:B CH3 ee (%) "syn adduct" H3C H CH3 R CH3 A CH3 CH3 O H3C R CH3 R RCHO –78 °C; OH + R CH3 CH3 H H OH OH OH CH3 – CH3CHO 75 + CH3CHO 72 – C2H5CHO 70 + C2H5CHO 78 – CH2=CHCHO 63 95:5 90 – C6H5CHO 72 94:6 88 R CH3 CH3 95:5 4:96 95:5 4:96 90 92 90 92 R H "(E)-crotylborane" "anti adduct" • The crotylboranes are used immediately after decomplexation of methoxide from the ate complex by BF3•OEt2 at –78 °C to avoid crotyl isomerization "Superbases" for Organic Synthesis • These adducts can be viewed as protected aldol products; "deprotection" is brought about by dihydroxylation/periodate cleavage or by ozonolysis Brown, H C.; Bhat, K S J Am Chem Soc 1986, 108, 293-294 Brown, H C.; Bhat, K S J Am Chem Soc 1986, 108, 5919-5923 Roush, W R In Comprehensive Organic Synthesis, Trost, B M.; Fleming, I., Eds., Pergamon Press: New York, 1991, Vol 2, pp 1-53 • The "superbase" prepared by mixing n-butyllithium and potassium t-butoxide (1:1) can metalate hydrocarbons of low acidity, in particular olefins • Allylic methyl groups are much more readily metalated than allylic methylene or methine centers • cis-2-alkenes generally react faster than their trans-isomers K R2 • The large atomic radius of potassium favors !3-bonding in allyl, crotyl and prenyl derivatives: R1 R1, R2 = H, CH3 Schlosser, M Pure & Appl Chem 1988, 60, 1627-1634 Schlosser, M.; Stahle, M Angew Chem., Int Ed Engl 1980, 19, 487-489 M Movassaghi (E)-Crotylboranes H3C CH3 Diastereo- and Enantioselective vic-Diol Synthesis n-BuLi, KOt-Bu CH3 THF –45 °C CH3 OCH3 – B (–)-Ipc2BOCH3 K –78 °C K CH3 (–)-Ipc2BOCH3 s-BuLi OCH3 + THF, –78 °C Li OCH3 CH3 OCH3 Li + – B BF3•OEt2 –78 °C OH + R B R CH3 C CH3 D Ipc aldehyde yield (%) – CH3CHO 78 + CH3CHO 76 – C2H5CHO 70 + C2H5CHO 69 – CH2=CHCHO 65 – C6H5CHO 79 NaOH, H2O2 C:D 95:5 BF3•OEt2 –78 °C CH3 RCHO –78 °C; OH ee (%) CH3 CH3 O B OH NH2 B RCHO, –78 °C; + R + R OCH3 E (crystalline) CH3 OH OCH3 F • Treatment of the crude product mixture with ethanolamine allows for easy removal of the reagent by-product as a crystalline adduct; this is an alternative to oxidative work-up 90 Ipc aldehyde yield (%) E:F ee (%) 90 – CH3CHO 57 95:5 90 92 + CH3CHO 59 95:5 90 – C2H5CHO 65 94:6 88 + C2H5CHO 68 – CH2=CHCHO 63 94:6 88 – C6H5CHO 72 95:5 90 95:5 4:96 OCH3 HOCH2CH2NH2 92 4:96 OCH3 –78 °C • The crotylboranes are used immediately after decomplexation of methoxide from the ate complex by BF3•OEt2 at –78 °C to avoid crotyl isomerization 4:96 96:4 5:95 92 92 90 • Other vinyl ethers may be used, such as methoxymethyl vinyl ether (affording the MOM-protected vic-diol) Brown, H C.; Bhat, K S J Am Chem Soc 1986, 108, 293-294 Brown, H C.; Bhat, K S J Am Chem Soc 1986, 108, 5919-5923 Brown, H C.; Jadhav, P K.; Bhat, K S J Am Chem Soc 1988, 110, 1535-1538 M Movassaghi Preparation of (E)- and (Z)-Crotylboronate Reagents Roush Allylation and Crotylation Reactions Roush, W R In Comprehensive Organic Synthesis, Trost, B M.; Fleming, I., Eds., Pergamon Press: New York, 1991, Vol 2, pp 1-53 Roush, W R.; Palkowitz, A D.; Ando, K J Am Chem Soc 1990, 112, 6348-6359 Roush, W R.; Halterman, R L J Am Chem Soc 1986, 108, 294-296 O B • The stability of allylboronate reagents permits their purification by distillation Allyl diisopinocamphenyl reagents cannot be distilled + O THF –78 A –25 °C 45 toluene CO2i-Pr yield (%) ee (%) n-C9H19CHO 86 79 c-C6H11CHO 77 78 C6H5CHO 78 71 HR FAVORED R CH3 O CO2i-Pr •99% Z 70-75 % H O R OR H H O B O O H OH OR DISFAVORED OH + R R –78 °C, 4Å-MS CH3 R reagent yield (%) n-C9H19 90 n-C9H19 70 c-C6H11 94 c-C6H11 90 TBSOCH2CH2 71 TBSOCH2CH2 68 aee CH3 anti:syn 95:5 1:>99 >99:1 2:98 •98:2 2:•98 ee (%)a 86 77 86 83 85 72 of major diastereomer OH OH R 1N HCl, Et2O DIPT, MgSO4 (R,R)-2 or (R,R)-3 toluene O H OR H H H 3C K O B • Essentially identical results are obtained with a range of commercially available tartrate esters (CH3, Et, i-Pr) O O O B O O B(Oi-Pr)3 –78 °C • Competition experiments have shown that (E)-crotylboronates react faster with aldehydes than the corresponding (Z)-isomers Proposed Origin of Selectivity in Tartarate DerivedAllylboronate AllylboronateAdditions Additions Tartrate Derived H 70-75 % • Tartrate modified (E)- and (Z)-Crotylboronates can be stored for several months at –20 °C in Tartrate-modified neat form or in solution with little noticeable deterioration R –78 °C, 4Å-MS aldehyde OR H H •98% E OH • Enantioselectivities are typically moderate • 4Å-MS are necessary to achieve the highest levels of selectivity O Pr CO2i-Pr O • Crotylboronates are configurationally stable at or slightly above room temperature CO2i-Pr H H3C 1N HCl, Et2O DIPT, MgSO4 n-BuLi, KOt-Bu CH3 CH3 R THF –78 A –50 °C 15 H 3C O B CO2i-Pr 77% O B n-BuLi, KOt-Bu CO2i-Pr B(Oi-Pr)3 –78 °C CO2i-Pr O 2N HCl, Et2O (+)-DIPT, MgSO4 O CH3 CO2i-Pr B(OCH3)3 Et2O, –78 °C MgBr H 3C K R • The favored transition state is believed to minimize unfavorable lone-pair lone-pair lone pair-lone pair interactions Roush, W R.; Walts, A E.; Hoong, L K J Am Chem Soc 1985, 107, 8186-8190 Roush, W R.; Ando, K.; Powers, D B.; Palkowitz, A D.; Halterman, R L J Am Chem Soc 1990, 112, 6339-6348 Roush, W R.; Palkowitz, A D.; Palmer, M A J J Org Chem 1987, 52, 316-318 M Movassaghi (–)-Bafilomycin A1: Reaction of Tartrate-Derived Allyl- or Crotylboronates with Chiral Aldehydes MATCHED: CO2i-Pr CO2i-Pr CH3 OTBS OHC O B + CH3 CO2i-Pr O OTBS OH 71%, 78% de MISMATCHED: CO2i-Pr CH3 O B OTBDPS + OHC O MATCHED: + H 3C CH3 OTBS OHC + O B H 3C O CO2i-Pr MATCHED H 3C OTBDPS + O B H 3C O CO2i-Pr + OHC (R,R)-2 OPMB CH3 (S,S)-2 (S,S)-1, Toluene –78 °C TBSOTf MISMATCHED 85%, •96% de (R,R)-1, Toluene (R,R)-2 –78 °C, h 92%, 70% de OTBS DMPO OTBS OH H 3C OPMB CH3 CH3 CO2i-Pr CH3 O B CH3 CH3 OH 80%, 94% de MISMATCHED: CO2i-Pr DMP = 3,4-dimethoxyphenyl CO2i-Pr CH3 CO2i-Pr O (S,S)-2 OTBDPS OH 72%, 74% de OHC CHO H 3C CH3 CO2i-Pr O B DMPO CH3 CH3 CH3 CH3 O CO2i-Pr OTBDPS OH 85%, 76% de MATCHED: CO2i-Pr CH3 OHC OTBS O B + CH3 CH3 O CO2i-Pr OH 71%, 90% de CH3 MISMATCHED: TESOTBSO OH OH B(OH)2 H3C CH3 O B OTBDPS + CO2i-Pr CH3 Pd(PPh3)4, TlOH THF, 23 °C, 30 65% KOH, 1,4-dioxane; 2,4,6-trichlorobenzoyl chloride, i-Pr2NEt, THF; DMAP, toluene, reflux 52% OTBS OH 28% de • All reactions were performed in toluene at –78 °C in the presence of 4Å-MS CH3O O O TBSO Roush, W R.; Walts, A E.; Hoong, L K J Am Chem Soc 1985, 107, 8186-8190 Roush, W R.; Palkowitz, A D.; Palmer, M A J J Org Chem 1987, 52, 316-318 CH3 CH3 CH3 CH3 OCH3 CH3 OCH3 CH3 CH3 O CO2CH3 I + CO2i-Pr CH3 OHC OTBS CH3 CH3 OTES O H 3C H 3C CH3 CH3 OCH3 CH3 M Movassaghi CH3O TBSO H 3C OTES O O TBSO O + H CH3 CH3 O OH OH Catalytic, Enantioselective Addition of Allylsilanes to Aldehydes H 3C H 3C CH3 OCH3 CH3 CH3 CH3 (S)-(–)-BINOL CH3 O TMSCl, Et3N, LHMDS CH2Cl2, –78 °C, 30 1, BF3•OEt2, –78 °C, 30 R H + Si(CH3)3 (S)-(–)-BINOL (20 mol%) TiF4 (10 mol%) CH2Cl2, CH3CN, °C OH R Bu4NF, THF aldehyde time (h) yield (%) ee (%) 85% CHO 90 94 20 93 84 91 94 20 92 93 20 81a 74 PhCHO 85 80 c-C6H11CHO 72 60 PhCH2CH2CHO 69 61 H3C CH3 CH3O TBSO H 3C O OH OTBSO CH3 CH3 OTES O H 3C CH3 CH3 OCH3 CH3 CH3 (CH3)3CCHO CHO Ph CH3 TASF, DMF, H2O 23 °C, h TASF = [(CH3)2N]3S[(CH3)3SiF2] CHO TIPSO H3C CH3 O O 93% H 3C H 3C HO CH3 O CH3O O OH O CH3 CH3 OH H 3C aBased HO CHO CH3 CH3 CH3 OCH3 CH3 on 25% recovered aldehyde • Allyltrimethylsilane initially reacts with the HF produced during catalyst preparation to give propene and (CH3)3SiF (–)-Bafilomycin A1 • It is important that the reaction be conducted in the presence of small amounts of CH3CN to solubilize the polymeric TiF4 Scheidt, K A.; Tasaka, A.; Bannister, T D.; Wendt, M D.; Roush, W R Angew Chem., Int Ed Engl 1999, 38, 1652-1655 Roush, W R.; Bannister, T D Tetrahedron Lett 1992, 33, 3587-3590 • _,_-Disubstituted aldehydes afford the highest enantioselectivities Gauthier, D R Jr.; Carreira, E M Angew Chem., Int Ed Engl 1996, 35, 2363-2365 M Movassaghi Enantioselective Allylation Using a Stoichiometric Chiral Controller Group Catalytic, Enantioselective Addition of Allyltin Reagents to Aldehydes O R1 R2 Sn(n-Bu)3 H + CF33 CF (S)-(–)-BINOL (10 mol%) Ti(Oi-Pr)4 (10 mol%) 4Å-MS F3C F Ph OH R2 FF33CC R1 CH2Cl2, –20 °C Ph CF CF33 S N B N S O O O Br O R1 C 6H R2 time (h) H 70 yield (%) ee (%) 88 95 R2 Sn(n-Bu)3 C 6H CH3 60 75 91 c-C6H11 H 70 66 94 c-C6H11 CH3 48 50 84 (E)-C6H5CH=CH H 70 42 89 (E)-C6H5CH=CH CH3 12 68 87 PhCHO C6H5CH2CH2 H 70 93 96 C6H5CH2CH2 CH3 40 97 98 i-C3H7 H 70 89 96 furyl H 70 73 96 furyl CH3 12 99 99 p-CH3OC6H4 CH3 48 61 93 p-CH3OC6H4CH2OCH2 H 70 81 96 BnOCH2 H 60 84 95 • Addition occurs to the re face of the aldehyde with the catalyst prepared from (R)-(+)-BINOL 1, PhCH3 23 °C HO H R2 R1 R1CHO –78 °C aldehyde yield (%) ee (%) H 92 96 PhCHO Cl 80 90 c-C6H11CHO H 84 92 c-C6H11CHO Cl 76 88 R2 • Reagent is produced from the corresponding (R,R)-bis-sulfonamide by reaction with BBr3 in CH2Cl2 • Transmetallation of allyltin reagents with the chiral B-bromoboron B-Bromoboron reagent in toluene is complete in 3-20 h • This procedure allows for the efficient asymmetric methallylation of aldehydes, typically a difficult transformation • The (R,R)-bis-sulfonamide can be recovered from the reaction mixture Keck, G E.; Krishnamurthy, D Org Syn 1998, 75, 12-18 Corey, E J.; Kim, S S Tetrahedron Lett 1990, 31, 3715-3718 Keck, G E.; Tarbet, K H.; Geraci, L S J Am Chem Soc 1993, 115, 8467-8468 Keck, G E.; Krishnamurthy, D.; Grier, M C J Org Chem 1993, 58, 6543-6544 M Movassaghi Diastereoselective Allyltitanation of Chiral Aldehydes Enantioselective Allyltitanation of Aldehydes Ph Ph O HO HO CH3 + Ti Cl CH3 Cl Cl O Ph Ph (R,R)-TADDOL Et3N, Et2O 23 °C Ph Cl or cyclohexane, reflux Ti O O Ph Ph O Ph Ph O O Ph Ph Ph Ph R O O Ph M Ti O O R M = Li, MgX CH3 CH3 Ph Cl Ti O O Ph Ph O O M R1 Ph Ti O O R1 Et2O, °C CH3 CH3 Ph Ph R1 R2 ee (%) H H H CH3 Ph (CH3)3Si EtO CH3 (CH3)3Si Ph (CH3)2CH CH2=CH Ph Ph Ph Ph CH3(CH2)8 CH3(CH2)8 95 97 95 98 97 •98 95 •98 •98 H3C H3C : 95 • Exceptionally high reagent selectivity is observed in the mismatched allylation of (R)-2-phenylbutyraldehyde (90% de) (cf., (–)-Ipc2BCH2CH=CH2: 34% de) Ph O R2CHO, –74 °C CHO O H3C yield (%) 97 •98 •98 75 •98 •98 93 88 79 89 54 68 77 86 69 • (E)-Crotyltitanation of aldehydes affords anti products, presumably by a chair-like TS + O N H3C Boc CH3 R2 O NH4F, H2O CH3 O CH3 de (%) OH OH CH3 CH3 OH Ph OH Ph + O Ph Ph 0.5 OH Ph MISMATCHED reagent Ph H3C : 99.5 H H3C • (E)-Crotyltitanium reagents are produced from (E)- or (Z)-crotyl anion precursors Ph H3C TiCpL(R,R) 91-94% 91–94% Ph + MATCHED • The chiral diol is readily available in both enantiomeric forms from the corresponding tartrate esters • Complex formation is driven to completion by neutralization of HCl with Et3N, or by removal of HCl by heating • The complex may be used in crude form, as prepared in solution, or the complex may be crystallized and isolated Ti O Cl O 91–94% 91-94% OH Ph H H3C CH3 CH3 O OH TiCpL(R,R) R1 N CH3 O H3C Boc N Boc CH3 yield TiCpL(R,R) 93 98.1 1.9 TiCpL(S,S) 95 0.5 99.5 TiCp(Oi-Pr)2 89 37.3 62.7 MgCl 86 55.1 44.9 OH CHO O H 3C H 3C TiCpL(R,R) N CH3 Boc 93% O N CH3 CH3 Boc a single diastereomer H3 C Hafner, A.; Duthaler, R O; Marti, R.; Rihs, G.; Rothe-Streit, P.; Schwarzenbach, F J Am Chem Soc 1992, 114, 2321-2336 Duthaler, R O.; Hafner, A.; Riediker, M Pure & Appl Chem 1990, 62, 631-642 M Movassaghi Myers Chem 115 Asymmetric Allylation Reactions Proposed Catalytic Cycle: Krische Allylation and Crotylation Reactions: Hassan, A.; Krische, M J Org Proc Res Devel 2011, 15, 1236 Han, S B.; Kim, I S.; Krische, M J Chem Commun 2009, 7278 OAc General Allylation Reaction: OAc [Ir(cod)Cl]2 (2.5 mol %) (R)-BINAP (5 mol %) OH + R R = aryl, alkyl m-NO2BzOH (10 mol %) Cs2CO3 (20 mol %) THF, 100 °C NO2 O P P IrIr O R OAc + R H R = aryl, alkyl m-NO2BzOH (10 mol %) Cs2CO3 (20 mol %) i-PrOH (200 mol %) THF, 100 °C OH III P P NO2 Ir CH3 + R = aryl, alkyl 4-CN-3-NO2BzOH (10 mol %) Cs2CO3 (20 mol %) THF, 90 °C O O OH R CH3 65-73% yield 86-97% ee 4:1 to 8:1 dr OAc CH3 [Ir(cod)Cl2] (2.5 mol %) (S)-SEGPHOS (5 mol %) O + H R R = aryl, alkyl OH O O O O I NO2 Ir Base P P H H P P NO2 III Ir O R III NO2 Ir O H H R • The Ir catalyst (generated in situ) undergoes addition to aldehyde via a 6-membered chair-like transition state to generate the IrIII alkoxide This does not undergo further dehydrogenation as the olefin is thought to occupy a coordination site, blocking !-hydride elimination • Ligand exchange with the reactant alcohol (or isopropanol) generates the homoallylic alcohol • The Ir alkoxide undergoes !-hydride elimination to produce the IrIII hydride Dissociation of the aldehyde produces an IrIII hydride which undergoes deprotonation by the base to provide the IrI anion • Oxidative addition of allyl acetate to regenerates "-allyl IrIII catalyst (S)-SEGPHOS O R O P P PPh2 PPh2 O OH R R O R NO2 O General Crotylation Reaction: [Ir(cod)Cl2] (2.5 mol %) (S)-SEGPHOS (5 mol %) H OAc III Ir R Hexa-Coordinate 18 Electron Complex R O 55-80% yield 90-93% ee P P O H R • Couplings of primary alcohols or aldehydes with allyl acetate utilizing Ir catalysts generate allylation products without the use of stoichiometric allyl-metal(oid) reagents OH NO2 III Ir AcO– TMBTP = 2,2',5,5'-Tetramethyl-4,4'-bis(diphenylphoshino)-3,3'-bithiophene OAc O O O P P O O O 55-80% yield 90-93% ee [Ir(cod)Cl2] (2.5 mol %) (–)-TMBTP (5 mol %) [Ir(cod)Cl]2 AcOH OH (X-Ray) O m-NO2BzOH III 4-CN-3-NO2BzOH (10 mol %) Cs2CO3 (20 mol %) i-PrOH (200 mol %) THF, 90 °C OH R • To use aldehydes as substrates in lieu of an alcohol, the use of a terminal reductant (isopropanol) is necessary for the catalytic cycle to proceed • Enantioselectivites are high for both alcohol and aldehyde reactants CH3 66-82% yield 96-98% ee 6:1 to 13:1 dr Kim, I S.; Ngai, M, -Y.; Krische, M J J Am Chem Soc 2008, 130, 6340-6341 Kim, I S.; Nagi, M -Y.; Krische, M J J Am Chem Soc 2008, 130, 14891-14899 Anne-Marie Schmitt, Fan Liu 10 Myers Chem 115 Asymmetric Allylation Reactions Stereochemical Model in Asymmetric Crotolation Reactions: • Couplings of aldehydes display higher diastereoselectivities than with alcohols, as higher concentrations of aldehyde promote rapid capture of the kinetically formed trans-crotyl iridium complex H R' R' R [Ir] O [Ir] O H R Bis Allylation and Crotylation of Glycols OAc [Ir(cod)Cl]2 (5 mol %) (S)-Cl,MeO-BIPHEP (10 mol %) OH OH Cs2CO3 (40 mol %) 4-Cl-3-NO2-BzOH (20 mol %) Dioxane (0.2 M) 90 °C H H • Kinetically formed trans-crotyl iridium complex generates the anti diastereomer • Equilibration to the cis-crotyl iridium complex causes erosion in diastereoselectivity OH OH 70%, >30:1 dr >99% ee • Equivalent bis aldehyde counterparts are unstable or unknown Kim, I S.; Han, S B.; Krische, M J J Am Chem Soc 2009, 131, 2514–2520 O Other allyl donors have been used with alcohols and aldehydes as reactants: Ph2 Ir P P Ph2 O O O Allyl Donor Products Generated OH OBz R OBz OH OH O R = aryl, alkyl 58-74% Yield 93-99% ee R O O OH OH OBz R = aryl, alkyl 57-80% Yield 87-99% ee R CF3 CF3 OH OH CN OH OH R = aryl, alkyl 62-77% Yield 96-99% ee O O OAc NO2 CH3 CH3 CH3 CH3 CH3 THF:H2O (4:1, 1.6 M) K3PO4 (100 mol %) 70 °C pseudo-C2 symmetric 62%, >6:1 dr >99% ee • Predominantly of 16 possible stereoisomers was formed • Chromatographic isolation of the pre-formed iridium catalyst allows crotylations to be run at lower temperatures Application to the Total Synthesis of Roxaticin • Catalyst Generation: OH OH OBz R = aryl, alkyl 58-78% Yield 90-99% ee R SiMe3 SiMe3 [Ir(cod)Cl]2 O (R)-Cl,MeO-BIPHEP O Cl OAc NO2 Cs2CO3 Dioxane, 110 °C Cl OCH3 Ph2 Ir P P Ph2 OCH3 Cl O Cl NO2 (R)-I Generated in situ O O EtO OBoc EtO OH R R = aryl, alkyl 58-79% Yield 92-99% ee Han, S B.; Han, H Krische, M J J Am Chem Soc 2010, 132, 1760–1761 Zhang, Y J.; Yang, J H.; Kim, S H.; Krische, M J J Am Chem Soc 2010, 132, 4562–4563 Gao, X.; Zhang, Y J.; Krische, M J Angew Chem Int Ed 2011, 50, 4173–4175 Han, S B.; Gao, X.; Krische, M J J Am Chem Soc 2010, 132, 9153–9156 Hassan, A.; Zbieg, J R.; Krische, M J Angew Chem Int Ed 2011, 50, 3493–3496 O O OH [Ir(cod)Cl]2 OAc O (S)-SEGPHOS Cs2CO3 CN THF, 80 °C NO2 92% (isolated via precipitation) Ph2 P Ir P Ph2 O O O O (S)-II NC NO2 Anne-Marie Schmitt, Fan Liu 11 Myers Chem 115 Asymmetric Allylation Reactions Application to the Synthesis of Roxaticin, continued OH OH OAc Allylation of Epimerizable Aldehydes from the Alcohol Oxidation Level: • Allylation of !-chiral aldehydes and "-chiral alcohols: the transiently generated aldehyde is prone to epimerization under the reaction conditions: OH OH (R)-I Dioxane, 110 °C OH OTBDPS PPTS , (MeO)2CMe2 CH2Cl2 , 25 °C, 91% 70% Yield, >30:1 dr >99% ee OH OTBDPS O3, CH2Cl2:MeOH –78 °C; NaBH4, 86% OAc Cs2CO3 (20 mol%) 3-NO2-BzOH (10 mol%) THF, 100 °C CH3 H3C CH3 H3C CH3 H3C CH3 O OH O O O O O OH "Second Iteration" (S)-I, Allyl Acetate, 71% TBSCl, imidazole, 85% O3; NaBH4, 85% "Third Iteration" (S)-I, Allyl Acetate, 78% PPTS, (MeO)2CMe2, 93% O3; NaBH4, 78% steps OH O O O O O • Optimized Reaction Conditions: "First Iteration" OH OTBDPS OH OTBDPS HO OAc + CH3 PMBO OAc K3PO4, H2O THF, 70 ºC 85%, dr = 14 : CH3 CH3 (S)-II (10 mol%) CH3 H3C CH3 H3C CH3 H3C CH3 O O O O O O CH3 steps HO PMBO CH3 OH OH OH OH OH CH3 OH HO CH3 O O CH3 CH3 Roxaticin 20 Steps Longest Linear Sequence 29 Total Steps Han, S B.; Hassan, A.; Kim, I S.; Krische, M J J Am Chem Soc 2010, 132, 15559–15561 CH3 CH3 OH OTBDPS CH3 Catalyst (5 mol%) CH3 O CH3 epimerized diastereomer OH H3C CH3 H3C CH3 H3C CH3 O OH OTBDPS H3C CH3 Three interations, total steps O CH3 desired diastereomer dr < : [Ir(cod)Cl]2 (2.5 mol%) (S)-Cl-MeO-BIPHEP (5 mol%) Cs2CO3 (1 equiv), 3,4-(NO2)2-BzOH (10 mol%) H2O (10 equiv) THF (0.4 M), 100 °C, 24 h Catalyst Yield (A : B : C : D) III ent-III 79% (97 : : : 0) 80% (4 : 94 : : 2) CH3 A B OH OTBDPS OH OTBDPS CH3 CH3 D C Cl H3CO H3CO Cl Ph2 P Ir P Ph2 O O O2N • Increased loadings of base improve the yield of A while suppressing III epimerization of the transient !-chiral aldehyde • Water improves the yield of A, possibly by facilitating the exchange between product and reactant alkoxide and by increasing the amount of Cs2CO3 in solution NO2 • The enhanced Lewis acidity at iridium may strengthen the agostic interaction between the iridium center and the carbinol C-H bond, facilitating alcohol dehydrogenation It may also accelerate carbonyl addition with respect to aldehyde epimerization • Inductive electron withdrawal by the 3,4-dinitro benzoate ligand may facilitate deprotonation of the Ir(III) hydride intermediate, allowing for faster catalyst turnover Schmitt, D C.; Dechert-Schmitt, A.-M R.; Krische, M J Org Lett 2012, 14, 6302–6305 Anne-Marie Schmitt, Fan Liu 12 Myers Chem 115 Asymmetric Allylation Reactions Enantioselective Addition to Acylhydrazones: Leighton Silicon Allylation Chemistry: Leighton, J L Aldrichimica Acta 2010, 43, 3–14 Ph Background: • In 2000, Leighton reported an allylation reaction where a Lewis acidic silicon atom is embedded in a strained five-membered ring: H3C H3C N Ph Ac N H O Si N Cl CH3 H3C CH2Cl2, 10 °C, 16h H (5 g) PhCHO (6 equiv) sealed tube, 130 °C O Si Ph N PhCHO PhCH3, 23 °C N H Ph 80%, 98% ee Bz H N H3C N H CHCl3, 23 °C OH Ph Ph t-BuCHO PhCH3, –10 °C HCl 80%, 96% ee H H3C O Si N Cl CH3 78%, 94% ee Bz N N H3C Bz N CH3 HCl, 52% O Si N Cl CH3 Ph Recrystallization Ac N Berger, R.; Rabbat, P M A.; Leighton, J L J Am Chem Soc 2003, 125, 9596–9597 • By incorporating another electronegative element bound to silicon, the reaction takes place at room temperature With a chiral ligand, the reaction becomes enantioselective: Ph H H 88% ee Zacuto, M J.; Leighton, J L J Am Chem Soc 2000, 122, 8587–8588 H3C O H3C Si H3C O Cl H3C N Ac N Ph HCl, 87% CH3 OH H Ph OH H CH3 (5 g) t-Bu H3C O Si N Cl CH3 CHCl3, 40 °C HCl, Et2O Recrystallize Bz H N •HCl H3C N H SmI2, THF Ph H3C NH2 Ph 86% 74%, 98% ee Berger, R.; Duff, K.; Leighton, J L J Am Chem Soc 2004, 126, 5686–5687 Kinnaird, J W A.; Ng, P Y.; Kubota, K.; Wang, X.; Leighton, J L J Am Chem Soc 2002, 124, 7920–7921 Mechanism: Preparation of Allylsilane Ph • Two diastereomers are generated upon complexation with pseudoephedrine, which converge on a common complex prior to allyl transfer: Ph OH + H3C NH CH3 Et3N, CH2Cl2 Cl3Si 0–15 °C, 12h (150-g scale) Ph Me Ph Me O Si N Cl CH3 92%, dr = : Ph O O Ph Si N + N H N Cl Me Ph H CH2Cl2, 23 ºC, 15min PhCH3, 23 ºC, 12h 90% H N N Ph Si O O N H Ph H CH3 H CH3 Ph Cl– • A 5-coordinate trigonal bipyramidal silicon species is proposed • The strained silacyclopentane increases the Lewis acidity of silicon • Aldehydes and acylhydrazones react, but not ketones, aldimines, or ketimines Berger, R.; Rabbat, P M A.; Leighton, J L J Am Chem Soc 2003, 125, 9596–9597 Angela Puchlopek-Dermenci, Fan Liu 13 Myers Chem 115 Asymmetric Allylation Reactions A C2-symmetric Chiral Controller for Aldehyde Allylation and Crotylation: Allylation and Crotylation of !-Diketones: • The C2-symmetric N,N'-dialkylcyclohexanediamine silane shown below shows improved selectivites in the allylation and crotylation of aldehydes: • The first example of enantioselective nucleophilic addition to !-diketones was achieved using the C2-symmetric N,N'-dialkylcyclohexanediamine silane reagent: 4-BrC6H4 4-BrC6H4 N Si N Cl + Ph OH CH2Cl2, –10 °C O H 90%, 98% ee N Si N Cl Ph 4-BrC6H4 Br O O OCH3 + Br CHCl3, 23 °C O HO OCH3 89%, 92% ee regioselectivity > 20 : 4-BrC6H4 4-BrC6H4 4-BrC6H4 N Si N Cl CH3 + CH2Cl2, °C O BnO H 83%, 99% ee CH3 + N Si N Cl OH BnO O O Ph CH3 75%, 97% ee dr > 20 : regioselectivity > 20 : 4-BrC6H4 CH3 4-BrC6H4 O HO CH3 CHCl3, 23 °C Ph CH3 Allylation and Crotylation of !-Diketones: OH 4-BrC6H4 N Si N Cl O CH3 + Ph CH2Cl2, °C H O Si Ph 4-BrC6H4 R2 R1 O Si R2 R2 Fast NH O O O (2.09 g) O R1 CH3 + 79%, 97% ee 4-BrC6H4 O NH 90% recovered Si 4-BrC6H4 O R1 Si R1 O R2 R1 Fast O R2 Fast O O Si R1 R2 Kubota, K.; Leighton, J L Angew Chem., Int Ed 2003, 42, 946–948 Hackman, B M.; Lombardi, P J.; Leighton, J L Org Lett 2004, 6, 4375–4377 R2 • Using 2-hydroxybenzene as an activating group, imines can be allylated or crotylated with high selectivity: O HO Ph Me O Si N Cl Me CH3 + R1 HO CH2Cl2, 23 °C N H 74%, 99% ee dr = 96 : Rabbat, P M A.; Valdez, S C.; Leighton, J L Org Lett 2006, 8, 6119–6121 HN CH3 R1 O HO R2 Ar O Si N H Cl– N Ar H H O R1 R2 HO R1 O R2 Ar O Si N H N Ar H H • Four possible diastereomers undergo fast interconversion • Regioselectivity is determined by Curtin-Hammett kinetics Steric interactions are minimized and conjugation is maximized in the lower energy transition state Chalifoux, W A.; Reznik, S K.; Leighton, J L Nature 2012, 487, 86–89 Angela Puchlopek-Dermenci, Fan Liu 14 Myers Chem 115 Asymmetric Allylation Reactions Mechanism: Hoveyda Boron Allylation Chemistry: • The Hoveyda group demonstrated that Cu-complexed C1-symmetric ligands I and II, can effect enantioselective allylation of phosphinoylimines: Ph Ph Mes N Ph Me N BF4 O H + Br N Ar1 N N Ar H3C P Ph N Ph + H H3C O P Ph N Ph Ph H + N P O Ph Ph iPr Mes H3CO B(pin) II H3C CH3 O H3C B H3C O MeOH, THF, –50 °C 92%, 97% ee Ph Mes N O I (5.0 mol%) CuCl (5 mol% ) NaOt-Bu (12 mol%) HN P Ph Ph Ar1 N N Ar Cu O OCH3 Br I (2.5 mol%) CuCl (2.5 mol% ) NaOt-Bu (6 mol%) H3C CH3 O H3C B H3C O H3C CH3 O H3C B H3C O MeOH, THF, –50 °C 61%, 92% ee II (5 mol%) CuCl (5 mol% ) NaOt-Bu (12 mol%) CH3 MeOH, THF, –50 °C 96%, 90% ee CH3OH R O H3C P Ph HN Ph H3C O Ph P NH Ph R H N P O Ph R2 N Cu H3C R N R1 Ph P Ph Ar1 N O R Cu I P Ph Ph B(pin) N BF4 Mes N Ph N N Ar Cu O P Ph Ph Ph Ph • Allylation is driven by the formation of an energetically favorable B–O bond CH3 Ph • Methanol releases the product alkoxide from the NHC–Cu complex