Myers Asymmetric Alkylation of Enolates Chem 115 • An early milestone in the use of a chiral auxiliary for asymmetric alkylation: • Strongly nucleophilic prolinol amide enolates react with "-branched alkyl halides. OEt • Application to iterative assembly of 1,3,n-substituted carbon chains by Evans et al. in Cl C H OH CH3 6 5 synthesis of ionomycin: H2N O HO C6H5 CH3 KOt-Bu, CH3I NH2 N CH3O OH OH LDA; EtI O KH, LDA; O CH 2-Oxazolines as N 3 N Ph carboxyl equivalents C6H5 I Ph CH3 CH3 O 3-6 N HCl O CH3 dr 97 : 3 CH3 CH HO N 3 CH CH 84% CH3O 83% latent aldehyde aq. HCl, 100 °C; 2 3 CH2CH3 NaOH 78% ee 91% O SO Ph Meyers, A. I.; Knaus, G.; Kamata, K.; Ford, M. E. J. Am. Chem. Soc. 1976, 98, 567-576. TDSO 2 HO Ph CH3 CH3 CH3 CH3 • Prolinol amide enolates provided an important advance: PhSO2 16 OH OH 14 12 O OTBDPS CH3CH2COCl CH CH CH NH N 3 3 3 Et N • 3° amides 3 form Z-enolates H (S)-2-Pyrrolidinemethanol 2 LDA selectively H CH3 CH3 OLi O O OLi CH3 OH CH3 CH OH N 3 CH3 Ca H OH O 16 O O O OH BnBr 14 12 O O 1 N HCl, ! CH3 CH3 CH3 CH3 CH3 CH CH3 75% yield, 76% de HO 3 N 92% CH C H CH2C6H5 2 6 5 Ionomycin Calcium Complex Evans, D. A.; Takacs, J. M.; Tetrahedron Lett. 1980, 21, 4233. Evans, D. A.; Dow, R. L.; Shih, T. L.; Takacs, J. M.; Zahler, R. J. Am. Chem. Soc. Sonnet, P.; Heath, R. R. J. Org. Chem. 1980, 45, 3137. 1990, 112, 5290-5313. 1 Myers Evans Oxazolidinone Auxiliaries in Asymmetric Synthesis: Alkylations Chem 115 Evans Oxazolidinone Auxiliaries in Asymmetric Synthesis: Alkylations Acylation provides imides, closer to esters than amides in terms of acidity, As originally introduced, two enantio-complimentary reagents: enolate nucleophilicity and cleavage chemistry: O O O O O n-BuLi, THF, –78˚C; CH CH O N 2 3 O NH O NH O NH PrCOCl, 80-90% CH3 CH3 CH3 CH3 H C H3C H3C 3 (S)-(!)-4-Isopropyl-2-oxazolidinone (4R, 5S)-(+)-4-Methyl-5-phenyl-2-oxazolidinone Evans, D. A.; Bartroli, J.: Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127-2129. Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am Chem. Soc. 1982, 104, 1737-1739. Z-Enolates are formed with very high selectivity. Chelated geometry presumed in ground and transition states: Several oxazolidinones are now commercially available, in both enantiomeric forms: Li O O O O CH2CH3 LDA, THF CH CH O O O N O N 2 3 –78 ˚C O NH O NH CH 3 CH3 H C 3 H3C BnBr, –78 ˚C (S)-(!)-4-Benzyl-2-oxazolidinone (S)-(+)-4-Benzyl-2-oxazolidinone 92% O O O O CH2CH3 O NH O NH O N Bn CH3 H3C >99:1 (S)-(!)-4-Phenyl-2-oxazolidinone (S)-(+)-4-Phenyl-2-oxazolidinone O O O O CH2CH3 LDA; BnBr CH2CH3 O O O N O N Bn 78% O NH O NH CH3 CH3 >99:1 CH3 CH3 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. 2 • Less reactive (non-allylic/benzylic) electrophiles require use of sodium enolates or triflate as • Highly diastereoselective acylation of imide enolates is possible: leaving group: Exercise: Why are the products configurationally stable? O O O O O O O O O NaN(TMS) , THF 2 LDA, THF, –78 ˚C; CH3 CH CH3 CH3 O N O N 3 O N O N –78 ˚C; EtI CH Et EtCOCl 3 CH3 53% CH3 CH CH3 3 88% H3C H3C 94 : 6 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. • Diastereoselective hydroxylation has been demonstrated: O O O O O • sodium enolate required CH3 O N OCH3 O N LDA, –78 ˚C; • note selective enolization of imide <5% alkylation over ester CH3 I CH3 NaN(TMS)2 (1 equiv), THF, –78 ˚C CH3 O SO Ph N 2 (±) 1.5 equiv LDA, –78 ˚C; O O O N CH 3 O O O CH3 CH3 CF3SO3 CH3 O N OCH3 • Auxiliary cleaved with Mg(OMe)2 CH3 OH with little to no epimerization >95% de CH 68% 3 96 : 4 pure isomer: 68% yield Decicco, C. P.; Grover, P. J. Am. Chem. Soc. 1996, 61, 3534-3541. 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 O t-Bu t-Bu O N KHMDS, TrisylN3, –78 ˚C; O N O O O O TiCl4, (i-Pr)2NEt; N CH3 CH HOAc, –78"0 ºC 3 O N O N 3 (CH3O)3CH 90% CH(OCH3)2 >99 : 1 Bn 95% Bn 99 : 1 Trisyl = 2,4,6-triisopropylbenzenesulfonyl Evans, D. A.; Urpi, F.; Somers, T. C.; Clark, J. S.; Bilodeau, M. T. J. Am. Chem. Soc. 1990, 112, 8215-8216. Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J. Am. Chem. Soc. 1990, 112, 4011-4030. 3 Alkylation of Pseudoephenamine and Pseudoephedrine Amides: CH3 CH3 • Enolates are formed using 1.95–2.2 equiv LDA. NHCH3 NHCH3 OH OH • Alkylations are highly diastereoselective. (R,R)-(–)-Pseudoephedrine (S,S)-(+)-Pseudoephedrine • LiCl (~6 equiv) promotes a rapid, clean reaction. • Pseudoephedrine is a commodity chemical, manufactured on multi-ton scale/annum. Its use Mnemonic: is highly regulated in many countries. R O 1. LDA, LiCl R O R R 1,4-syn N 1 N 1 2. R2X OH CH3 OH CH3 R2 NHCH3 NHCH3 R = CH or Ph R = CH or Ph OH OH 3 3 (R,R)-(+)-Pseudoephenamine (S,S)-(–)-Pseudoephenamine • 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 Morales, M.R.; Mellem, K.T.; Myers, A.G. Angew. Chem. Int. Ed., 2012, 51, 4568–4571. R3 Preparation of Pseudoephedrine and Pseudoephenamine Amides: O OLi R1 R2 R1 O H H X OLi R N 2 R N NHCH3 1 R2 H C OH OH CH3 3 H R1 R2 X Yield (%) mp (ºC) Ph CH EtCO 88 188–191 3 2 R X 3 OBn Ph Et n-PrCO2 83 133–135 Ph Bn Cl 80 147–149 I • Askin et al. reported this type of selectivity reversal for Ph n-Bu R'CH CO 70 88–90 OTBS 2 2 epoxide electrophiles with prolinol amide enolates and H OLi CH3 CH3 CH3O* 89 114–115 proposed that the Li cation coordinates and directs the CH3 Ph Cl 88 145–146 epoxide opening: OLi N CH3 Cl Cl 90 79–81 R H CH3 i-Pr Cl 92 73–74 CH3 3-pyridyl (H3C)3CCO2 97 117.5–118.5 OBn *Even unactivated esters react (under basic conditions), presumbly by transesterification O followed by intramolecular O!N Acyl Transfer Myers, A. G.; McKinstry, L. J. Org. Chem. 1996, 61, 2428. Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.: Kopecky, D. J.; Gleason, J. L. Askin, D.; Volante, R. P.; Ryan, K. M.; Reamer, R. A.; Shinkai, I. Tetrahedron Lett. J. Am. Chem. Soc. 1997, 119, 6496-6511. 1988, 29, 4245. Morales, M.R.; Mellem, K.T.; Myers, A.G. Angew. Chem. Int. Ed., 2012, 51, 4568–4571. Kevin Mellem 4 Reduction of Alkylation Products: Diastereoselective Alkylation Reactions: • Lithium amidotrihydroborate (LiH2NBH3 (LAB)), prepared by deprotonation (LDA) of commercial, crystalline ammonia-borane complex, provides primary alcohols: R1 O 1. LDA, LiCl R1 O R2 R2 CH O N N 3 LAB, THF OTIPS 2. R3X OTIPS HO OH CH3 OH CH3 R3 N 23 ˚C, 1 h CH3 CH3 OH CH3 CH3 CH3 R1 R2 R3X temp (˚C) crude (isol) de (%) isol yield (%) 98% 98% de 97% ee Ph CH3 BnBr 0 90 (≥99) 85 Ph CH3 EtI 0 88 (96) 96 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. Ph n-Bu CH3I 0 90 (96) 84 Ph Bn n-BuI –78 ≥99 (≥99) 99 • Semi-reduction with Brown's lithium triethoxyaluminium hydride provides aldehydes directly CH3 CH3 BrCH2CO2t-Bu –78 94 (96) 78 but it can be complicated by low yields, epimerization of the "-stereocenter, and formation of CH3 Ph EtI 0 96 (≥99) 92 a stable aminal intermediate: CH3 i-Pr BnBr 0 98 (≥99) 83 CH O O CH3 t-Bu BnBr 0 98 (≥99) 84 3 LiAlH(OEt)3 n-Bu n-Bu CH3 Cl BnBr –45 90 (≥99) 88 N H hexanes-THF, 0 ˚C OH CH3 Bn Bn 82% ≥99% de 97% ee Hydrolysis of Alkylation Products: • Occurs under acidic or basic conditions. Both methods likely involve initial N!O acyl Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.; Gleason, J. L. J. Am. transfer. Chem. Soc. 1997, 119, 6496-6511. • Strongly acidic conditions are required, but are well tolerated by many simple substrates.