Asymmetric Deprotonation

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1 ( )-sparteine i-pr, t 2, -98 C 84% ee Asymmetric Deprotonation gands, Bases, and Applications CF 3 TMS t-bu TMSCl, MPA TF, -100 C t-bu 93% ee Fe (i-pr) 2 1. n-bu ( )-sparteine t 2, -78 C 2. 2 PCl P 2 Fe (i-pr) 2 90% ee David bner Stoltz Group terature Presentation March 28, 2005

2 nantioselective Deprotonation eaction Pathways retention b - a M b electrophile ' ' inversion b a b base ' possible anion inversion retention a ' - b a M electrophile ' ' inversion a '

3 nantioselective Deprotonation eaction Pathways retention b - a M b electrophile ' ' inversion b a b base ' possible anion inversion retention a ' - b a M electrophile ' ' inversion a '

4 nantioselective Deprotonation What Will T Be Covered retention b - a M b electrophile ' ' inversion b a b base ' possible anion inversion retention a ' - b a M electrophile ' ' inversion a ' Great Chemistry ot Covered Today: - Chiral Auxiliary-Directed Deprotonation - nantioselective Additions of Achiral Anions to Chiral or omochiral lectrophiles Aldols Carbolithiations Achiral Alkyllithium Additions to lectrophiles - nantioselective eactions of acemic or quilibrating Anions Deprotonation Adjacent to S, P, Se, (usually) Wittig earrangements

nantioselective Deprotonation I. meso-ketone Deprotonations II. meso-poxide Deprotonations a. -Deprotonation b. -Deprotonation III. Deprotonation Adjacent to eteroatoms a.

Koga Tokyo Ketones D. odgson xford poxides. Simpkins ottingham Ketones and Aromatics D. oppe Muenster eteroatoms: M. Majewski Saskatchewan Ketones P.

3, pp 39-76, JAI Press, London: 1998. 2. Waldmann, "nantioselective Deprotonation and Protonation," in rganic Synthesis ighlights II,. Waldmann, ed. pp 19-28, VC, Weinheim: 1995. 3. rganolithiums in nantioselective Synthesis, D.

, Perkin Trans. 1, 1998, 1439-1457. 5. oppe and ense, "nantioselective Synthesis with thium/( )-Sparteine Carbanion Pairs," Angew. Chem. Int. d. ngl. 1997, 36, 2282-2313. 6.

Cox and Simpkins, "Asymmetric Synthesis Using omochiral thium Amide Bases," Tetrahedron: Asymmetry, 1991, 2 (1), 1-26. 8.

5 nantioselective Deprotonation I. meso-ketone Deprotonations II. meso-poxide Deprotonations a. -Deprotonation b. -Deprotonation III. Deprotonation Adjacent to eteroatoms a. : Alkyl and Allylic Systems b. : Alkyl, Benzylic, and Allylic Systems IV. ther nantioselective Deprotonations a. limination of X b. Aromatic thiation utline and Key Players K. Koga Tokyo Ketones D. odgson xford poxides. Simpkins ottingham Ketones and Aromatics D. oppe Muenster eteroatoms: M. Majewski Saskatchewan Ketones P. Beak Illinois, Urbana-Champaign eteroatoms: General eviews: 1. Majewski, "nantioselective Deprotonation of Cyclic Ketones," in Advances in Asymmetric Synthesis, Vol. 3, pp 39-76, JAI Press, London: Waldmann, "nantioselective Deprotonation and Protonation," in rganic Synthesis ighlights II,. Waldmann, ed. pp 19-28, VC, Weinheim: rganolithiums in nantioselective Synthesis, D. odgson, ed. Springer, ew York: (Whole book is good, especially pp ) 4. 'Brien, "ecent Advances in Asymmetric Synthesis Using Chiral thium Amide Bases," J. Chem. Soc., Perkin Trans. 1, 1998, oppe and ense, "nantioselective Synthesis with thium/( )-Sparteine Carbanion Pairs," Angew. Chem. Int. d. ngl. 1997, 36, odgson, Gibbs, and Lee, "nantioselective Desymmetrisation of Achiral poxides," Tetrahedron, 1996, 52 (46), Cox and Simpkins, "Asymmetric Synthesis Using omochiral thium Amide Bases," Tetrahedron: Asymmetry, 1991, 2 (1), ames, "ecent Developments in nantioselective Deprotonation Mediated by Sub-Stoichiometric Quantities of Chiral Bases," ur. J. rg. Chem., 2002, Beak, Basu, Gallagher, Park and Thayumanavan, "egioselective, Diastereoselective, and nantioselective thiation-substitution Sequences: eaction Pathways and Synthetic Applicaitons," Acc. Chem. es. 1996, 29,

6 Asymmetric Deprotonation of meso Cyclic Ketones General Considerations -amide Base (Additives) Protons Differentiated by Chiral Base L n '' ' L n ' '' + -amide Base (Additives)?

7 Chiral thium Amides Used in Ketone Deprotonations nly a Few of the Many! CF 3 Me Me CF 3 t-bu

8 Prochiral 4-Substituted Cyclohexanones nantioselective Deprotonation of Simple Substrates -amide TMSCl TMS -amide TMSCl TMS MPA TF, -100 C t-bu TF t-bu CF 3 % Yield % ee Temp ( C) Quench Cl (equiv) % ee Me Internal 0 69 i-pr Internal xternal 0 23 t-bu xternal Koga, et. al. Tetrahedron 1997, 53, Simpkins, et. al. J. Chem. Soc., Perkin Trans , 3113

9 Tropinone Derivatives Different Conditions and lectrophiles Lead to a Variety of Products Cl, TF, -78 C t-bu C Me 2 CC 95% ee Me 2 C ClC 2 Bn Bn 2 C Majewski, et. al. Tetrahedron Lett. 1994, 35, 3653 Tetrahedron Lett. 1995, 36, 5465

10 ther Prochiral Cyclic Substrates Similar gands Yield Good ee's with a Variety of lectrophiles TS TMS C 2 Me 67% 92% ee 84% ee TMS 72% 91% ee 97% ee 81% 71% ee TMS 60% ee t-bu Bn 96% 84% ee TMS t-bu TMS n n = 3: >99% ee n = 5: 95% ee 62% 85% ee TMS TBS 90% 90% ee TMS 95% 83% ee TMS

11 Catalytic Asymmetric Ketone Deprotonations arly fforts Lead to Moderate Selectivity 1. Base, TF, -78 C MPA (2.4 equiv) 2. TMSCl TMS CF equiv CF equiv 2.4 equiv 1.5 equiv DABC Stoichiometric, 1 h % Yield % ee Catalytic, 1.5 h % Yield % ee Me i-pr t-bu Koga, et. al. Tetrahedron 1997, 53, 1698

12 Chiral Magnesium Amides in Ketone Deprotonation Less eactive Alternative to thium Amides 2 Mg TMS i-pr i-pr Mg 2 i-pr TMS i-pr MPA (0.5 equiv), TMSCl TF, -78 C, 6 h MPA (0.5 equiv) TMSCl, TF % Conv. % ee Temp ( C) Time (h) % Conv. % ee Me >99 n-pr i-pr rt t-bu i-pr (±)- i-pr 2 Mg MPA (0.5 equiv), TMSCl TF, -40 C, 67 h TMS i-pr i-pr i-pr i-pr + 66%, 62% ee 34%, 88% ee Kerr, enderson, et. al. Tetrahedron, 2002, 58, 4573

13 Deprotonation of poxides arly Surprising esults t 2 t 2, -10 C Proposed Mechanism: :B 95% Cope and Tiffany, J. Am. Chem. Soc. 1951, 73, 4158 t 2 t 2, C % 55-60% 10-15% :B :B Cope, et. al. J. Am. Chem. Soc. 1958, 80, 2849

14 Deprotonation of poxides arly Surprising esults t 2 t 2, -10 C Proposed Mechanism: :B 95% Cope and Tiffany, J. Am. Chem. Soc. 1951, 73, 4158 t 2 t 2, C % 55-60% 10-15% :B :B Cope, et. al. J. Am. Chem. Soc. 1958, 80, 2849

15 Deprotonation of poxides arly Surprising esults t 2 t 2, -10 C Proposed Mechanism: :B 95% Cope and Tiffany, J. Am. Chem. Soc. 1951, 73, 4158 t 2 t 2, C % 55-60% 10-15% :B :B Cope, et. al. J. Am. Chem. Soc. 1958, 80, 2849

16 Deprotonation of poxides arly Surprising esults t 2 t 2, -10 C Proposed Mechanism: :B 95% Cope and Tiffany, J. Am. Chem. Soc. 1951, 73, 4158 t 2 t 2, C % 55-60% 10-15% :B :B Cope, et. al. J. Am. Chem. Soc. 1958, 80, 2849

17 Deprotonation of poxides arly Surprising esults t 2 t 2, -10 C Proposed Mechanism: :B 95% Cope and Tiffany, J. Am. Chem. Soc. 1951, 73, 4158 t 2 t 2, C % 55-60% 10-15% :B :B Cope, et. al. J. Am. Chem. Soc. 1958, 80, 2849

18 Asymmetric Deprotonation of poxides Can eactivity Be Controlled? Base Addition lectrophile Trapping lectrocyclic -ing pening 1,2-ydride Shift C- Insertion 2 C- or C=C Insertion eductive Alkylation odgson and Gras, Synthesis, 2002, 12, 1625

19 Asymmetric ß-Deprotonation of poxides Allylic Alcohols Using thium Aminoamide Bases TF, 0 C 77% 79% ee Proposed Selectivity Model: amide TBS TBS, 4 C 92% 90% ee Favored Disfavored C TBS amide C 3, 0 C C TBS 75% 89% ee Asami, et. al. Tetrahedron, 1995, 51, TBS TBS, 0 C 30 h 66% 97% ee Singh, et. al. J. rg. Chem, 1996, 61, 6108

20 Asymmetric ß-Deprotonation of poxides Use of Commercially-Available phedrine-based Aminoalcohols = Bn 91%, 86% ee = C 2 57%, 95% ee Murphy, et. al. J. Chem. Soc., Chem. Commun., 1993, 884 = Me 63%, 99% ee = Bu 67%, 96% ee = BnC 2 76%, 89% ee odgson, et. al. Tetrahedron: Asymmetry, 1996, 7, 407

21 Catalytic Asymmetric xamples ecent Studies Allow Similar Levels of Selectivity amide (20 mol %) LDA, TF, rt + 1 equiv LDA + 6 equiv DBU 12 h, 71%, 75% ee equiv LDA 6 h, 95%, 88% ee Asami, et. al. Tetrahedron: Asymmetry 1994, 5, 793 Tetrahedron Lett. 1997, 38, 6425 n catalyst (5 mol%) LDA (2 equiv) TF/DBU (95:5) 0 C, 24 h n n = 1 91%, 96% ee n = 2 89%, 96% ee n = 3 81%, 78% ee catalyst (20 mol%) LDA (1.25 equiv) TF, 0 C, 15 h 77% 95% ee Andersson, et. al. J. Am. Chem. Soc., 1998, 120, Malhotra, Tetrahedron: Asymmetry, 2003, 14, 645

22 nantioselective -Deprotonation of poxides Transannular C- Insertion With Alkyllithium Diamine Complexes 86% 84% ee ( )-sparteine (2.5 equiv) i-pr (2.4 equiv) t 2, -98 C to rt, 20 h 77% 83% ee 97% 77% ee odgson and Lee, Chem. Commun. 1996, 1015 ( )- -isosparteine (24 mol %) i-pr (2.4 equiv) t 2, -98 C, 40 h t-bu 54%, 89% ee odgson, et. al. J. Chem. Soc., Perkin Trans 1, 2001, 2161

23 More Transannular poxide earrangements eactivity Differences in Bicyclic Systems chiral base ydride Shift amide t 2 0 C to rt ( )-sparteine s-bu pentane -78 C to rt 73%, 49% ee 73%, 52% ee a + b 40%, 32% ee 20%, 38% ee a Shift b Shift b a odgson and Marriott,Tetrahedron: Asymmetry, 1997, 8, 519

24 Trapping of thiated poxides nantioselective poxide Substitution with Various lectrophiles TMS 72%, 74% ee 80%, 76% ee 68%, 77% ee TMSCl C CMe 2 Conditions Sn 3 = Bu; 72%, 74% ee = Me; 65%, 78% ee 3 SnCl tc t 74%, 76% ee s-bu (1.25 equiv) ( )-sparteine (1.3 equiv) t 2, -90 C, 3 h then electrophile (1.5 equiv) -90 C to rt over 5 h tccl tcme 2 t 2 C t t t t 58%, 81% ee 75%, 77% ee 67%, 78% ee odgson, et. al. rg. Biomol. Chem. 2003, 1, 4293

25 Deprotonation Adjacent to eteroatoms A eturn to eaction Pathways retention b - a M b electrophile X X inversion b a b base X = (usually) X = S, P, Se, etc. retention a X - b a M electrophile X X inversion a X Asymmetric Deprotonation Adjacent to eteroatoms X =, = Alkyl X = C=C''', = Aryl, Alkyl X =, = Alkyl, Aryl, Allyl

26 Deprotonation Adjacent to xygen Alkyl Carbamates S Cby 1. s-bu ( )-sparteine 2. lectrophile Cby Cby = Me Cby Cby Bn 2 Cby Me % Yield % ee % Yield % ee % Yield % ee D 86 > 96 3 C(C 2 ) C 2 Me 56 > 95 PbMe C 2 C=C Bu 3 Sn 70 > 95 Me 3 Si 70 > 95 Cby 85 > 95 Me 72 > 95 Fe Cby TBS Cby Cby Cby P 2 SnBu 3 C 2 Me 80% > 95% ee 85% > 95% ee 80% > 95% ee oppe, et. al. Angew. Chem., Int. d. ngl. 1990, 29, 1422 Angew. Chem., Int. d. ngl. 1992, 31, 1505 Synthesis 1999, 1573 rg. Lett. 2002, 4, 2189

27 Asymmetric Deprotonation of Alkyl Carbamates (i-pr) 2 Intramolecular eactions s-bu ( )-sparteine t 2-78 C to rt (i-pr) 2 46% 96% ee -78 C to rt (i-pr) 2 (i-pr) 2 Tomooka, Shimizu, Inoue, Shibata,l akai, Chem. Lett. 1999, 759 Cby Cby s-bu ( )-sparteine t 2, -78 C Cby Cby (sparteine) Cby = TMSCl or ZnCl 2 TBSTf or BF 3 t 2 Cby Cby > 95% ee 74% ee oppe, et. al. Synlett 1994, 1034

28 Silyl Alkenyl Carbamates Configurationally Stable Allyllithiums TMS Cbx n-bu ( )-sparteine C 3, -78 C (i-pr) 2 TMS electrophile TMS Cbx Cbx = (i-pr) 2 = TMS Cbx ' ' ' ' TMS Cbx TMS TMS TMS Cbx Cbx Cbx % Yield % ee Me 3 Si Bu 3 Sn Sn MeC() t-buc() % Yield % ee Me 3 Si Bu 3 Sn Sn % Yield % ee MeC() t-buc() Me 2 C cc oppe, et. al. rg. Lett. 2004, 6, 783

29 nantioselective omoaldols Metal xchange to Ti Leads to a ighly Diastereoselective Process TMS Cbx n-bu ( )-sparteine C 3, -78 C (i-pr) 2 TMS TiCl(t 2 ) 3 TMS Ti(t 2 ) 3 Cbx Cbx = (i-pr) 2 'C ' TMS Cbx ' TMS ' TMS Me Cbx Cbx ' % Yield % ee ' % Yield % ee C 3 (C 2 ) C 3 (C 2 ) (C 3 ) 2 C (C 3 ) 2 C (C 3 ) 3 C (C 3 ) 3 C cc cc C BrC oppe, et. al. rg. Lett. 2004, 6, 783

30 Deprotonation Adjacent to itrogen Alkyl Carbamates evisited S s-bu ( )-sparteine electrophile S t 2, -78 C t-bu % Yield % ee Me % 0-88% ee Coldham, et. al. rg. Lett. 2001, 3, 3799 Me 3 Si Bu 3 Sn C Beak, et. al. J. Am. Chem. Soc. 1994, 116, % 94-98% ee Beak, et. al. J. rg. Chem. 1997, 62, CuC Cl 2. alkenyl iodide % 86-90% ee Dieter, et. al. J. Am. Chem. Soc. 2001, 123, 5132

31 Benzylic Carbamates Configurationally Stable Benzyllithiums Possible Most Benzylic Deprotonations: Configurationally Unstable Anions X chiral base X M* enantioselective electrophile substitution X X = Ar: nantiomeric Anions Do ot Interconvert at Low Temp! Ar chiral base enantioselective deprotonation Ar M* electrophile substitution Ar Me 1. n-bu ( )-sparteine 2. Tf 3. CA % Yield % ee Me t Allyl Bn Beak, et. al. J. Am. Chem. Soc. 1996, 118, 3757

32 More Benzylic Carbamates Applications and lectrophiles Ar 1. n-bu ( )-sparteine 2. Michael Acceptor Ar Ar = p-mec 6 4 Ar = : 72%, 94% ee = Me: 63%, 94% ee Ar n n = 1: 86%, >99:1 dr, 92% ee n = 2: 82%, >99:1 dr, 92% ee C C Ar 91%, 92:8 dr, 90% ee Beak, et. al. J. Am. Chem. Soc. 1997, 119, J. rg. Chem. 1999, 64, 2996 Cl Ar s-bu ( )-sparteine C 3, -78 C Ar Ar % Yield % ee aphthyl thienyl furyl Beak, et. al. J. Am. Chem. Soc. 1996, 118, 715

33 thium Amides in Benzylic Deprotonation Cyclization of Arylamides Leads to Isoindolones -78 to 0 C Me Me Me 1. 4 Cl, 2 2. Cl, 2 88%, 81% ee C 2 C 2 ( )-kainic acid 2 C C 2 C 2 ( )-isodomoic acid C Clayden, et. al. Tetrahedron 2002, 58, 4727 J. Am. Chem. Soc. 2005, 127, 2412

34 nantioselective -Allylcarbamate Deprotonation Ar n-bu ( )-sparteine Ar electrophile Ar Ar = p-mec 6 4 % Yield % ee Me Bn Allyl i-bu 73%, >94% ee 98:2 dr Ar t 2 C t 2 C 86%, 96% ee 94:6 dr Ar C C Cy 80%, 88% ee 63:44 dr Ar Ar 1. n-bu ( )-sparteine 2. Carbonyl or Michael Acceptor ' Ar '' ' '' Ar 77%, 98% ee Ar Ar 80%, 86% ee 90:10 dr Me Ar 62%, 96% ee 80:20 dr 80%, 92% ee 89:11 dr Ar Beak, et. al. J. Am. Chem. Soc. 1996, 118, J. Am. Chem. Soc. 2001, 123, 1004

35 nantioselective Synthesis by Loss of X Chiral Amides Lead to nantioenriched Alkenes X Tf t 2, -70 C X X = 44% ee X = (C 2 ) 2 99% ee Sakai, et. al. Tetrahedron Lett. 1987, 28, 6489 = Me 80% ee Cl 2 C TF, -78 C 2 C = t-bu 82% ee Me Me 75% ee Cl C 2 TF, -78 C C 2 Duhamel, et. al. Tetrahedron: Asymmetry, 1990, 1, 347

36 More nantioselective Loss of X Chiral Alkoxides Allow Catalytic eactions Br Br Me 2 (10 mol %) Me (4 mol %) K, TF -80 C, 72 h Br t-bu % Yield % ee n-pr i-pr p-mec >98 78 >98 p- 2 C 6 4 K + - p-c Br Br Me 2 Me K 10 mol % 4 mol % 2.5 equiv Br MeK 2 Me 2 Duhamel, et. al. J. rg. Chem., 1998, 63, 5541

37 nantioselective thiation of Aromatics Generation of Planar Chirality with thium Amide Bases Fe P 2 TMSCl, TF -78 C Fe P 2 TMS 95% 54% ee Simpkins and Price, Tetrahedron Lett., 1995, 36, 6135 Me Me Me Cl, TF -78 C, 15 min C 67% 65% ee Cr(C) 3 Cr(C) 3 Cr(C) 3 Simpkins, et. al. J. Chem. Soc., Perkin Trans 1, 1997, 401

38 nantioselective thiation of Aromatics Generation of Planar Chirality with Alkyllithium / Sparteine % Yield % ee Fe (i-pr) 2 1. n-bu ( )-sparteine t 2, -78 C 2. electrophile Fe (i-pr) 2 TMS Me C() I P B() Snieckus, et. al. J. Am. Chem. Soc., 1996, 118, 685 Me 2 Me 2 t-bu C 3, -78 C 2 PCl 85% 75% ee P 2 Cr(C) 3 Cr(C) 3 Cr(C) 3 Uemura, et. al. Tetrahedron: Asymmetry, 1994, 5, 1427

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