9 asymmetric alkylation of enolates

Myers Asymmetric Alkylation of Enolates • An early milestone in the use of a chiral auxiliary for asymmetric alkylation: Cl H2N OH HO C6H5 OEt • Application to iterative assembly of 1,3,n-substituted carbon chains by Evans et al in synthesis of ionomycin: O KOt-Bu, CH3I NH2 • Strongly nucleophilic prolinol amide enolates react with "-branched alkyl halides C6H5 CH3 CH3 N CH3O OH O LDA; EtI 2-Oxazolines as carboxyl equivalents C6H5 O HO CH3 N Ph CH3 CH3 Ph I CH3 dr 97 : CH3 N CH3O 84% CH2CH3 N OH O KH, LDA; O 3-6 N HCl CH3 Chem 115 83% CH2CH3 aq HCl, 100 °C; latent aldehyde NaOH 78% ee 91% O Meyers, A I.; Knaus, G.; Kamata, K.; Ford, M E J Am Chem Soc 1976, 98, 567-576 SO2Ph TDSO Ph HO CH3 CH3 CH3 CH3 • Prolinol amide enolates provided an important advance: PhSO2 OH CH3CH2COCl NH OH O N Et3N 16 14 CH3 OTBDPS CH3 CH3 • 3° amides form Z-enolates selectively LDA (S)-2-Pyrrolidinemethanol 12 O OLi OLi CH3 N H H H CH3 CH3 O HO CH3 CH2C6H5 N HCl, ! BnBr N 92% CH3 CH2C6H5 Evans, D A.; Takacs, J M.; Tetrahedron Lett 1980, 21, 4233 Sonnet, P.; Heath, R R J Org Chem 1980, 45, 3137 75% yield, 76% de O OH OH Ca OH 16 OH O CH3 CH3 CH3 14 O O O O 12 CH3 CH3 CH3 CH3 CH3 Ionomycin Calcium Complex Evans, D A.; Dow, R L.; Shih, T L.; Takacs, J M.; Zahler, R J Am Chem Soc 1990, 112, 5290-5313 Evans Oxazolidinone Auxiliaries in Asymmetric Synthesis: Alkylations Myers Chem 115 Evans Oxazolidinone Auxiliaries in Asymmetric Synthesis: Alkylations Acylation provides imides, closer to esters than amides in terms of acidity, enolate nucleophilicity and cleavage chemistry: As originally introduced, two enantio-complimentary reagents: O O NH n-BuLi, THF, –78˚C; O NH O CH3 (4R, 5S)-(+)-4-Methyl-5-phenyl-2-oxazolidinone Evans, D A.; Ennis, M D.; Mathre, D J J Am Chem Soc 1982, 104, 1737-1739 O O NH CH2CH3 N PrCOCl, 80-90% CH3 H3C Evans, D A.; Bartroli, J.: Shih, T L J Am Chem Soc 1981, 103, 2127-2129 Z-Enolates are formed with very high selectivity Chelated geometry presumed in ground and transition states: O O O O O H3C Several oxazolidinones are now commercially available, in both enantiomeric forms: O NH CH3 CH3 H3C (S)-(!)-4-Isopropyl-2-oxazolidinone O O O O CH2CH3 N NH O LDA, THF O Li O CH2CH3 N –78 ˚C CH3 CH3 H3C H3C BnBr, –78 ˚C (S)-(!)-4-Benzyl-2-oxazolidinone (S)-(+)-4-Benzyl-2-oxazolidinone O O O O 92% O NH O NH O CH2CH3 N Bn CH3 H3C (S)-(!)-4-Phenyl-2-oxazolidinone (S)-(+)-4-Phenyl-2-oxazolidinone O O O O O NH >99:1 O NH N CH3 CH3 CH3 O O CH2CH3 LDA; BnBr 78% O O CH2CH3 N Bn CH3 >99:1 H3C (4S,5R)-(!)-4-Methyl-5-phenyl-2-oxazolidinone (R)-(+)-4-Phenyl-2-oxazolidinone Evans, D A.; Ennis, M D.; Mathre, D J J Am Chem Soc 1982, 104, 1737-1739 • Less reactive (non-allylic/benzylic) electrophiles require use of sodium enolates or triflate as leaving group: O O O CH3 N O NaN(TMS)2, THF O –78 ˚C; EtI O O CH3 N CH3 N O Exercise: Why are the products configurationally stable? O O O CH3 LDA, THF, –78 ˚C; O N CH3 EtCOCl CH3 88% H3C O Et 53% CH3 • Highly diastereoselective acylation of imide enolates is possible: CH3 CH3 H3C 94 : Evans, D A.; Ennis, M D.; Mathre, D J J Am Chem Soc 1982, 104, 1737-1739 Evans, D A.; Ennis, M D.; Mathre, D J J Am Chem Soc 1982, 104, 1737-1739 O O • Diastereoselective hydroxylation has been demonstrated: O O CH3 N O LDA, –78 ˚C; O CH3 CH3 O O O SO2Ph N (±) 1.5 equiv O N CH3 O O CH3 CH3 CH3 CF3SO3 • note selective enolization of imide over ester NaN(TMS)2 (1 equiv), THF, –78 ˚C CH3 LDA, –78 ˚C; • sodium enolate required OCH3 N 95% de 68% Decicco, C P.; Grover, P J Am Chem Soc 1996, 61, 3534-3541 CH3 • Auxiliary cleaved with Mg(OMe)2 with little to no epimerization 96 : pure isomer: 68% yield Evans, D A.; Morissey, M M.; Dorow, R L J Am Chem Soc 1985, 107, 4346-4348 see also: Williams, D R.; McGill, J M J Org Chem 1990, 55, 3447-3459 • Asymmetric azidation provides a route to !-amino acid derivatives: • Titanium enolates provide a route for diastereoselective SN1-like coupling reactions: O O O N Bn CH3 O TiCl4, (i-Pr)2NEt; (CH3O)3CH 95% O O O N Bn O CH3 CH(OCH3)2 99 : Evans, D A.; Urpi, F.; Somers, T C.; Clark, J S.; Bilodeau, M T J Am Chem Soc 1990, 112, 8215-8216 O O N t-Bu KHMDS, TrisylN3, –78 ˚C; HOAc, –78"0 ºC 90% O O t-Bu N N3 >99 : Trisyl = 2,4,6-triisopropylbenzenesulfonyl Evans, D A.; Britton, T C.; Ellman, J A.; Dorow, R L J Am Chem Soc 1990, 112, 4011-4030 CH3 Alkylation of Pseudoephenamine and Pseudoephedrine Amides: CH3 NHCH3 • Enolates are formed using 1.95–2.2 equiv LDA NHCH3 OH • Alkylations are highly diastereoselective OH (R,R)-(–)-Pseudoephedrine • LiCl (~6 equiv) promotes a rapid, clean reaction (S,S)-(+)-Pseudoephedrine • Pseudoephedrine is a commodity chemical, manufactured on multi-ton scale/annum Its use is highly regulated in many countries Mnemonic: R O N OH CH3 NHCH3 NHCH3 OH (S,S)-(–)-Pseudoephenamine R1 1,4-syn R = CH3 or Ph • Epoxides approach from the opposite enolate π-face • Use of pseudoephenamine is not restricted; it appears to be a superior auxiliary in many instances O R3 Morales, M.R.; Mellem, K.T.; Myers, A.G Angew Chem Int Ed., 2012, 51, 4568–4571 Preparation of Pseudoephedrine and Pseudoephenamine Amides: O R1 O R2 R1 X N NHCH3 OH CH OH O N OH CH3 R2 R2X R = CH3 or Ph OH (R,R)-(+)-Pseudoephenamine R LDA, LiCl R1 OLi R2 R1 R2 X Yield (%) mp (ºC) Ph CH3 EtCO2 88 188–191 Ph Et n-PrCO2 83 133–135 Ph Bn Cl 80 147–149 Ph n-Bu R'CH2CO2 70 88–90 CH3 CH3 CH3O* 89 114–115 CH3 Ph Cl 88 145–146 CH3 Cl Cl 90 79–81 CH3 i-Pr Cl 92 73–74 CH3 3-pyridyl (H3C)3CCO2 97 117.5–118.5 H H R1 N H3C OLi R2 H R3X • Askin et al reported this type of selectivity reversal for epoxide electrophiles with prolinol amide enolates and proposed that the Li cation coordinates and directs the epoxide opening: OBn I OTBS H OLi OLi N R H OBn *Even unactivated esters react (under basic conditions), presumbly by transesterification followed by intramolecular O!N Acyl Transfer Myers, A G.; Yang, B H.; Chen, H.; McKinstry, L.: Kopecky, D J.; Gleason, J L J Am Chem Soc 1997, 119, 6496-6511 Morales, M.R.; Mellem, K.T.; Myers, A.G Angew Chem Int Ed., 2012, 51, 4568–4571 Myers, A G.; McKinstry, L J Org Chem 1996, 61, 2428 O Askin, D.; Volante, R P.; Ryan, K M.; Reamer, R A.; Shinkai, I Tetrahedron Lett 1988, 29, 4245 Kevin Mellem Reduction of Alkylation Products: Diastereoselective Alkylation Reactions: R1 O • Lithium amidotrihydroborate (LiH2NBH3 (LAB)), prepared by deprotonation (LDA) of commercial, crystalline ammonia-borane complex, provides primary alcohols: R1 LDA, LiCl R2 N OH CH3 O N OH CH3 R3 R3X R2 CH3 O R1 R2 R3X temp (˚C) crude (isol) de (%) isol yield (%) Ph CH3 BnBr 90 (≥99) 85 Ph CH3 EtI 88 (96) 96 Ph n-Bu CH3I 90 (96) 84 Ph Bn n-BuI –78 ≥99 (≥99) 99 CH3 CH3 BrCH2CO2t-Bu –78 94 (96) 78 CH3 Ph EtI 96 (≥99) 92 CH3 i-Pr BnBr 98 (≥99) 83 CH3 t-Bu BnBr 98 (≥99) 84 Cl BnBr –45 90 (≥99) 88 CH3 LAB, THF OTIPS N OH CH3 CH3 CH3 OTIPS HO 23 ˚C, h CH3 CH3 98% 98% de 97% ee Myers, A G.; Yang, B H.; Kopecky, D J Tetrahedron Lett 1996, 37, 3623 Myers, A G.; Yang, B H.; Chen, H.; Kopecky, D J Synlett 1997, 5, 457 • Semi-reduction with Brown's lithium triethoxyaluminium hydride provides aldehydes directly but it can be complicated by low yields, epimerization of the "-stereocenter, and formation of a stable aminal intermediate: CH3 O N OH CH3 Bn n-Bu O LiAlH(OEt)3 hexanes-THF, ˚C Bn 82% 97% ee ≥99% de Hydrolysis of Alkylation Products: • Occurs under acidic or basic conditions Both methods likely involve initial N!O acyl transfer • Strongly acidic conditions are required, but are well tolerated by many simple substrates n-Bu H Myers, A G.; Yang, B H.; Chen, H.; McKinstry, L.; Kopecky, D J.; Gleason, J L J Am Chem Soc 1997, 119, 6496-6511 Brown, H C.; Tsukamoto, A J Am Chem Soc 1964, 86, 1089 Addition of Alkyllithium Reagents to form Ketones: O Bn N OH CH3 n-Bu O H2SO4, dioxane reflux Bn HO 93% O O n-Bu 97% ee ≥99% de • Alkaline conditions work well with many substrates, but not those susceptible to facile epimerization ("-aryl) CH3 O n-Bu N OH CH3 CH3 ≥99% de 93% –78 ! ˚C 95% ≥97% de CH3 n-Bu ≥95% ee O n-Bu4NOH, t-BuOH, H2O reflux N OH CH3 CH3 n-BuLi (2.4 eq), Et2O HO n-Bu O CH3 97% ee Myers, A G.; Yang, B H.; Chen, H.; McKinstry, L.; Kopecky, D J.; Gleason, J L J Am Chem Soc 1997, 119, 6496-6511 Morales, M.R.; Mellem, K.T.; Myers, A.G Angew Chem Int Ed., 2012, 51, 4568–4571 O CH3 N OH CH3 n-Bu ≥96% de PhLi (2.4 eq), Et2O –78 ! ˚C 96% CH3 Ph n-Bu ≥93% ee Kevin Mellem Application to the Iterative Synthesis of 1,3,n-Substituted Carbon Chains: >199:1 >199:1 CH3 H O (EtCO)2O, Et3N N OH CH3 CH3 X!+ 95% O LDA, LiCl; BnBr 90% LAB Bn X!+ 90% CH3 I CH3 PPh3, I2, Im Bn CH3 98% Bn O O LAB LDA, LiCl, Bn X!+ 95% 97% CH3 CH3 CH3 CH3 LDA, LiCl, ent-1 95% 93% LDA, LiCl, ent-1 X!" LAB 142:1 O CH3 CH3 CH3 LAB 93% CH3 CH3 CH3 "matched" 91% LAB 66:1 Bn CH3 CH3 CH3 60% yield, steps 94.1% final de HO Bn X!" "mismatched" 70:1 HO 199:1 X!+ CH3 CH3 CH3 93% 58% yield, steps 95.7% final de 94% Bn "mismatched" CH3 CH3 CH3 93% O Bn "matched" Bn LDA, LiCl, ent-1 66:1 O CH3 CH3 CH3 HO LDA, LiCl, 96% O LAB 97% CH3 CH3 70 : X!+ PPh3, I2, Im Bn I 142 : Bn CH3 CH3 "mismatched" CH3 CH3 LDA, LiCl, Bn HO 96% CH3 CH3 Bn I 97% LAB Bn X!" "matched" PPh3, I2, Im 55 : 58 : >99:1 >99:1 HO Bn HO 89% 199:1 Bn CH3 CH3 CH3 56% yield, steps 92.6% final de HO Bn CH3 CH3 CH3 57% yield, steps 94.7% final de Myers, A G.; Yang, B H.; Chen, H.; Kopecky, D J Synlett 1997, 5, 457-459 Construction of Quaternary Centers R1 R LDA, LiCl O N CH3 OH CH3 CH3 THF ºC Matched R = CH3 or Ph OLi X"+ O BnBr CH3 CH3 X"+ DMPU –40 ºC Z-enolate CH3 H3C Bn 95%, 9.9:1 dr R2 R2 Ph Ph O N R2 OH CH3R3 CH3 R3X, DMPU OH CH3 CH3 R1 R1 LDA, LiCl, ºC N • Pseudoephenamine and pseudoephedrine can be used to direct the formation of quaternary centers by two methods: enolization–alkylation or conjugate addition–alkylation Enolization–Alkylation: O R3X temp (˚C) crude dr isol yield (%) CH3 BnBr –40!0 ≥19:1 85 CH3 allylBr –40!0 ≥19:1 99 ≥19:1 87 Ph n-Pr BnBr –40!0 Ph Ph allylBr –40!0 ≥19:1 82 CH3 Ph EtI –40 6.2:1 87 BnBr –40 19:1 90 CH3 vinyl Conjugate Addition–Alkylation: R LDA, LiCl O N CH3 OH CH3 CH3 THF ºC Mismatched OLi X"+ CH3 CH3 E-enolate O BnBr X"+ DMPU –40 ºC Bn CH3 CH3 89%, 5.2:1 dr R = CH3 or Ph O N OH CH3 CH3 CH3Li (1.0 eq), LiCl, THF –78 ºC t-BuLi –78!–40 ºC OLi X#– t-Bu CH3 Kummer, D A.; Chain, W J.; Morales, M R.; Quiroga, O.; Myers, A G J Am Chem Soc 2008, 130, 13231–13233 Br –40 ºC Mnemonic: O X#– O N O LDA, LiCl R1 OH CH3 H CH3 R2X, DMPU t-Bu H3C N R1 85%, ≥19:1 dr OH CH3 R2 CH3 • Even bulky organolithium reagents such as tert-buyllithium are suitable reagents for this transformation Retention of stereochemistry Morales, M R.; Mellem, K T.; Myers, A G Angew Chem Int Ed., 2012, 51, 4568–4571 E Reyes, J L Vicario, L Carrillo, D Badia, A Iza, U Uria, Org Lett 2006, 8, 2535–2538 Kevin Mellem Myers Asymmetric Alkylation of Enolates R1 CH3Li, LiCl, –78 ºC R3Li, –78" –40 ºC O N OH CH3 R2 O R1 R3 N R R OH CH3 R4X, –40 ºC Chem 115 Addition of alkyllithium reagents to form ketones: CH3 O N CH3 Bn CH3 OH CH3 R1 R2 R3 R4X crude dr isol yield (%) Ph CH3 n-Bu BnBr ≥19:1 75 Ph CH3 Ph AllylBr ≥19:1 80 Ph Et t-Bu CH3I ≥19:1 79 CH3I Ph n-pentyl t-Bu ≥19:1 76 CH3 CH3 n-Bu allylBr 11.1:1 72 CH3 CH3 t-Bu allylBr 12.5:1 98 CH3 Et t-Bu CH3I 9.1:1 99 CH3 Et Ph CH3I 19:1 89 O CH3Li, HMPA Et2O –78"0 ºC H3C Bn CH3 CH3 93% Reduction to form aldehydes: Ph CH3 O Tf2O, pyr CH3 N Ph Bn OH CH3 CH2Cl2, ºC O H3C N CH3 TfO H3C Ph Bn oxazolinium triflate Red-Al THF, ºC; then HCl-TFA Transformations of !-quaternary pseudoephenamine and pseudoephedrine amides 90 % (two steps) O Hydrolysis of !-quaternary alkylation products: CH3 H CH3 O N CH3 Bn CH3 OH CH3 O n-Bu4NOH H2O/dioxane 115 ºC Ph HO Bn CH3 CH3 Bn LAB reduction to form primary alcohols: 94% Kummer, D A.; Chain, W J.; Morales, M R.; Quiroga, O.; Myers, A G J Am Chem Soc 2008, 130, 13231–13233 O LAB t-Bu N OH CH3 H3C CH3 THF, 60 ºC HO t-Bu CH3 98% H3C Kevin Mellem Myers Asymmetric Alkylation of Enolates • Enders chiral hydrazone methodology: • Helmchen camphor-derived auxiliaries: H3C CH3 SO2Ph N OH CH3 CH3 Chem 115 H3C CH3SO2Ph N O CH3 CH3 CH3 CH3 O CH3 O H CH2OCH3 84% 94% ee O H3C CH3 LICA, THF –78 ˚C BnBr (95%); LiAlH4 CH2Ph HO N N t-BuLi, –78 ˚C; BOMCl,–-100 ˚C; aq CuCl2 er 94 : CH3 O CH2OCH2Ph O O H3C CH3 (S)-(+)-1-Amino-2-(methoxymethyl) pyrrolidine [SAMP-Hydrazone] Enders, D In Asymmetric Synthesis; Morrison, J D.; Academic Press: New York, 1984; Vol 3, Chapter Enders, D.; Hundertmark, T.; Lazny, R Syn Comm 1999, 29, 27-33 Schmierier, R.; Grotemeier, G.; Helmchen, G.; Selim, A Angew Chem., Int Ed Engl 1981, 20, 207-208 • Oppolzer camphorsultam auxiliaries in asymmetric alkylation: H3C CH3 NaH; NH H3C • An alternative oxazolidinone-based auxiliary allows !-alkylation of ketones with excellent stereoselectivities The ease of synthesis and removal of the auxiliary makes it a practical alternative to the traditional RAMP/SAMP methodology: CH3 CH3 H3C CH3 H3C O CH3CH2COCl CH3 N O S O O S O O N H3C (1S)-(–)-2,10-Camphorsultam N O LDA, THF –78 ºC N Br CH3 O 94% N O H3C HMPA, C6H5CH2Br LDA, THF –78 ºC 4-BrC6H4CH2Br 89% 89%, dr = 97 : NaN(TMS)2; H3C HO O O O CH3 CH2C6H5 LiOH, H2O2 O O CH3 CH3 N S O O CH2C6H5 p-TsOH acetone, 23 ºC H3C Br N N Ph Ph Bn H3C 94% Br 97% de Oppolzer, W.; Moretti, R.; Thomi, S Tetrahedron Lett 1989, 30, 5603-5606 Lim, D.; Coltart, D M Angew Chem., Int Ed Engl 2008, 47, 5207–5210 Fan Liu Myers Catalytic Methods for Asymmetric Alkylation • An early, remarkable result from the Merck Process group: H N Br – Chem 115 • Corey and co-workers have developed catalysts that are highly enantioselective: Br " 0.11 g H N+ OH N Cl O CF3 O Cl CH3Cl, C7H8-50% NaOH Cl Cl 20 ºC, 18h, 95% H3CO O CH3 O O H3CO 0.61g N Ph 92% ee N CsOH•H2O, CH2Cl2 Ot-Bu –78 ˚C, 24 h Ph • Although limited to a single example, this provided a dramatic illustration of the potential of chiral phase-transfer catalysis for C-C bond formation Ot-Bu O O O CH3 O O Dolling, U.; David, P.; Grabowski, E J J J Am Chem Soc 1984, 106, 446-447 N Ph O Br Ph CH3 81%, 96% ee 1.5 equiv • The method was adapted by O'Donnell, who had earlier developed a PT method for the synthesis of racemic !-amino acids: Corey, E J.; Xu, F.; Noe, M C J Am Chem Soc 1997, 119, 12414-12415 Cl – H N Phosphazene bases can also be used with the catalyst above, see: O'Donnel, M F.; Delgado, F.; Hostsettler, C.; Schwesinger, R Tetrahedron Lett 1998, 39, 8775-8778 OH N O Ph N O CH2Cl2 - 50% NaOH Ot-Bu Ph 19.2 g (65 mmol) Ot-Bu Ph 25 ˚C, 15 h, 95% Ph N Br 64% ee Cl O OTMS MeLi - LiBr (1 equiv), C7H8, 23 ˚C; Cl crystallization O H2N • Koga and co-workers have developed chiral additives for the asymmetric alkylation of lithium enolates The work has been extended to include examples that employ additives in catalytic amounts: (CH3)2NCH2CH2CH2N(CH3)2 (2 equiv), BnBr (10 equiv), "45 ˚C, 18h 6N HCl, ∆ OH 16.8 g (>99% ee) N H N Ph 6.5 g, >99% ee, 50% overall Cl O' Donnell, M J.; Bennett, W D.; Wu, S J Am Chem Soc 1989, 111, 2353-2355 CH2Ph N CH3 76%, 96% ee CH3 N CH3 0.05 equiv Imai, M.; Hagihara, A.; Kawasaki, H.; Manabe, K.; Koga, K J Am Chem Soc 1994, 116, 8829-8830 10 ... BnBr 90 (? ?99 ) 85 Ph CH3 EtI 88 (96 ) 96 Ph n-Bu CH3I 90 (96 ) 84 Ph Bn n-BuI –78 ? ?99 (? ?99 ) 99 CH3 CH3 BrCH2CO2t-Bu –78 94 (96 ) 78 CH3 Ph EtI 96 (? ?99 ) 92 CH3 i-Pr BnBr 98 (? ?99 ) 83 CH3 t-Bu BnBr 98 ... t-Bu BnBr 98 (? ?99 ) 84 Cl BnBr –45 90 (? ?99 ) 88 CH3 LAB, THF OTIPS N OH CH3 CH3 CH3 OTIPS HO 23 ˚C, h CH3 CH3 98 % 98 % de 97 % ee Myers, A G.; Yang, B H.; Kopecky, D J Tetrahedron Lett 199 6, 37, 3623... 96 % CH3 CH3 Bn I 97 % LAB Bn X!" "matched" PPh3, I2, Im 55 : 58 : >99 :1 >99 :1 HO Bn HO 89% 199 :1 Bn CH3 CH3 CH3 56% yield, steps 92 .6% final de HO Bn CH3 CH3 CH3 57% yield, steps 94 .7% final de