15 ellman auxiliary

Myers Synthesis of Chiral Amines by Asymmetric Additions to tert-Butylsulfinimines (Ellman Auxiliary) Chem 115 tert-Butylsulfinamide: Recent Reviews: Robak, M T.; Herbage, M A.; Ellman, J A Chem Rev 2010, 110, 3600–3740 • The advantages of tert-butylsulfinamide over related arenesulfinamides include ease of substrate synthesis, enhanced stereoselectivity, and reduction in side-reactions (e.g., addition at sulfur) Ferreira, F.; Botuha, C.; Chemla, F.; Pérez-Luna, A Chem Soc Rev 2009, 38, 1162–1186 Zhou, P.; Chen B.-C.; Davis, F A Tetrahedron 2004, 60, 8003–8030 • Both enantiomers are readily available at reasonable prices (99:1 CH3 i-Pr MgBr 93% >95:5 H C9H19 MgBr 77% 91:9 H3 C Cogan, D A.; Liu, G.; Ellman, J Tetrahedron 1999, 55, 8883 Bertrand, M B.; Wolfe, J P Org Lett 2006, 8, 2353 H N + R In (4 equiv) Br t-Bu S O O O N R1 R2 TiLn O CH3 R1 R2 yield (%) dr i-Pr H 85 98 : 3-pyr H 70 95 : i-Pr CH3 85 99 : CH3 89 98 : O t-Bu NaBr (saturated aqueous) H3CO O S O NH R t-Bu S R1 O N + R3 R2 OR5 R4 LDA (2.1 equiv); ClTi(Oi-Pr)3 (2 equiv) THF, #78 °C t-Bu R3 S O yield dr 3,4-(MeO)2-Ph 81% 98:2 90% 95:5 3-furyl S t-Bu R1 R2 R4 R1 O O N R2 TiLn O R5 O 2-pyridyl 73% 95:5 i-Pr 82% 96:4 R1 R2 R3 H i-Bu H H CH3 H CH3 Ph CH3 CH3 CH3 Ph R4 S t-Bu R1 R2 R3 R4 R5 yield (%) dr CH3 CH3 85 96 : : : PMB PMB 70 89 : : : CH3 86 99 : CH3 65 99 : -(CH2)5- HN R5O • The allylindium species, generated in situ, is an effective nucleophile in aqueous solution R HN • The use of "-subsituted esters as enolate precursors allows for the stereoselective synthesis of tri- and even tetrasubstituted !-amino acid derivatives O S THF, #78 °C Ph Allylation of Imines in Aqueous Solution t-Bu OCH3 R2 R1 R1 + LDA (2.1 equiv); ClTi(Oi-Pr)3 (2 equiv) Tang, T P.; Ellman, J A J Org Chem 1999, 64, 12–13 Sun, X.-W.; Liu, M.; Xu, M.-H.; Lin, G.-Q Org Lett 2008, 10, 1259 Tang, T P.; Ellman, J A J Org Chem 2002, 67, 7819–7832 Jonathan William Medley, Daniel Schmitt Myers Synthesis of Chiral Amines by Asymmetric Additions to tert-Butylsulfinimines (Ellman Auxiliary) Additions to Enantioenriched Sulfinimines in the Pharmaceutical Industry: H3C O F H2N O H N MgBr TMS O Br CH2Cl2, THF –78 °C N S H3C H3C CH3 O HN Cbz N S O F 80% H F F N F F TMS O 10% HCl (aq) MeOH O Cbz N NH2 •HCl CH3 CH3 p-TsOH, MgSO4 PhMe, 23 °C t-Bu Ti(Oi-Pr)4, THF, 60 °C Br N S H2N F Chem 115 85:15 dr, (65%, dr = 99.8:0.2 after crystallization) BrMg F CH2Cl2, –70 °C >55% over steps er = : steps • An addition to a tert-butanesulfinimine was used in the synthesis of a !-secretase inhibitor for the treatment of Alzheimer's Disease • The stereochemistry of Grignard addition is consistent with the standard chelated chair-like transition state • No chromatography was necessary over steps O O N O S Probst, G et al J Med Chem 2013, 56, 5261–5274 t-Bu O S O NH2 MgSO4, PhMe O t-Bu S N H O CH3 NH2 H N O LpxC inhibitor CH3 H3C H HCl (aq), 23 °C NaOH workup F HN N CH3 CH3 S O O F 72% F F F DPP4 Inhibitor F • Synthesis of a DPP4 inhibitor for the treatment of diabetes • The imine addition proceeded with lower diastereoselectivity in ethereal solvents NO2 O CH3 OEt N (1.10 kg) H3C O N O N O S H3C J Org Chem 2008, 73, 9016–9021 O OEt NH2 O • The synthesis of an LpxC inhibitor for the treatment of bacterial infectious diseases employed a nitronate anion as nucleophile • The anion resulting from nitronate addition to the imine is sufficiently basic to deprotonate 2nitropropane Therefore, only catalytic LiHMDS is necessary • The stereochemical result is consistent with an open transition state H O H3C 0.4 equiv LiHMDS THF, -20 °C O N H3C OH H2N CH3 NO2 OEt O (370 g) 20% yield over three steps >99% ee AcCl EtOH H3C CH3 O NO2 OEt S t-Bu N H O (1.40 kg) 98:2 dr Fei, Z.; Kong, W.; Wang, H.; Peng, J.; Sun, F.; Yin, Y.; Bajwa, J.; Jiang, X Org Process Res Dev 2012, 16, 1436-1441 CH3 CH3 S H Cl O H3C HN PhMgBr N CH3 CH3 S N O PhMe –20 °C to °C CO2H 2HCl Cl Cl 78% yield, 91:9 dr cetirizine dihydrochloride • Synthesis of an antihistamine sold under the brand name Xyzal The racemic form of this compound is marketed as Zyrtec • A variety of Lewis acid additives were screened, but provided lower diastereoselectivity Pflum, D A.; Krishnamurthy, D.; Han, Z.; Wald, S.; Senanayake, C H Tetrahedron Lett 2002, 43, 923 Jonathan William Medley, Daniel Schmitt Myers Examples in Syntheses of Natural Products: • Ganesan and co-workers employed the addition of a titanium enolate to a sulfinimine in their total syntheses of the marine natural products azumamides A and E O t-Bu S O LDA (2.2 equiv) THF, !78 °C; O N + H3C OPMB H Tce = 2,2,2-trichloroethyl PMBO ClTi(Oi-Pr)3 (4 equiv), TiCl4 O CH3 O i-Pr O NH H N H3C N H O CH3 i-Pr H N CO2Tce H N • Although the methallylation proceeded with only moderate stereoselectivity to afford an inseparable mixture of diastereomers, recrystallization of the amine•HCl salt following ringclosing metathesis, N-methylation, and desulfinylation provided material with excellenet enantiopurity t-Bu CO2Tce HN O N H CH3 O O • In their formal total synthesis of the natural product (!)-aphanorphine, Grainger and Welsh employed an asymmetric methallylation of an enantioenriched tert-butane sulfinimine t-Bu S O N CH3 + MgCl H !48 " 23 °C 95% 83:17 dr CH3 CH3 S CO2Tce Cl NHBoc i-Pr O EDC, HOBT Ph azumamide E CO2H H3C CH3 NH3 92% H H CH3 N O HCl, MeOH t-Bu S N CH3 87%, >98% ee H3C CH3 O NH CH3 Ph O S t-Bu All = allyl O N H HN t-Bu n-BuLi; MeI, 93% Grubbs' II, CH2Cl2, reflux, 94% O N H CH2Cl2, Et2O O AllO AllO S TFA, anisole D-Val-D-Ala-OAll, PyBOP, i-Pr2EtN, CH2Cl2, 66% (2 steps) HCl, EtOAc, i-PrOH Boc-D-Phe, PyBOP i-Pr2EtN, CH2Cl2 53% (2 steps) i-Pr HN O 52% single isomer isolated CO2Tce O Chem 115 Synthesis of Chiral Amines by Asymmetric Additions to tert-Butylsulfinimines (Ellman Auxiliary) NH H N H3C H3C O CH3 N H HN O O Ph CONH2 azumamide A Grainger, R S.; Welsh, E Angew Chem., Int Ed 2007, 46, 5377–5380 Wen, S.; Carey, K L.; Nakao, Y.; Fusetani, N.; Packham, G.; Ganesan, A Org Lett 2007, 9, 1105– 1108 Daniel Schmitt, Jonathan William Medley ... equilibrating mixture of isomers is formed + R1 H t-Bu Chem 115 Synthesis of Chiral Amines by Asymmetric Additions to tert-Butylsulfinimines (Ellman Auxiliary) R1 t-Bu R2 H N + R1 R2MgBr O S NH R1 closed... t-Bu O S R2 NH R1 Jonathan William Medley Myers Chem 115 Synthesis of Chiral Amines by Asymmetric Additions to tert-Butylsulfinimines (Ellman Auxiliary) Use of Ketimine Electrophiles: Additions... Myers Synthesis of Chiral Amines by Asymmetric Additions to tert-Butylsulfinimines (Ellman Auxiliary) Chem 115 Diastereoselective Allylations of Enantioenriched Sulfinimines: Additions of Enolates