Catalytic Asymmetric Acyl Halide-Aldehyde Cyclocondensation Reactions of Substituted Ketenes

Transcription

1 Catalytic Asymmetric Acyl Halide-Aldehyde Cyclocondensation eactions of Substituted Ketenes Scott G. elson, Cheng Zhu, and Xiaoqiang Shen J. Am. Chem Soc. 2004, 126, Michael C. Myers, Literature Presentation, January 27, 2004

2 The Cyclocondensation eaction Kinetically Complex Processes: 4 Competing eaction Pathways 1. Cyclocondensation 2. Ketene Dimerization 3. Ketene Trimerization 4. Aldehyde Homoaldol Addition Woodward-Hofmann ules Govern Syn Selectivity: [2+2] Cyclocondensation eaction Aluminum (III) Lewis Acid Catalysts: Catalyze Cyclocondensation / Limit ther Pathways 1 st Generation 2 nd Generation (Chiral) Al(SbF 6 ) 3 Al F 3 C 2 S S 2 CF 3 Substituting CH 2 Cl 2 for Benzotrifluoride (BTF): Ammonium Bromide Salts Insoluble in BTF

3 Woodward-Hofmann Implications The orbital requirements for concerted thermal ketene-aldehyde cycloaddition would ensure that substituted ketenes would afford the contrasteric cis-substituted 4- oxetanones, thereby providing the equivalent of a syn-selective propionate aldol. Few Systems et the Geometrical Limits: Most [2π + 2π] Additions Involve Ketenes H 2 or H 1 Supra/Antara Mobius System 4 Electrons Aromatic Allowed HM-Aldehyde LUM-Ketene H 2 = 2 H H 1 1 H Woodward,. B.; Hoffmann,. The conservation of rbital Symmetry; VCH: Weinheim, elson, S. G.; Wan, Z. rg. Lett. 2000, 2,

4 Generation I and II Al (III) Catalysts Empirically Found that Al(SbF 6 ) 3 Catalyzed the AAC eactions mol% Al(SbF 6 ) 3 X H 1.5 equiv. 1.0 equiv. x=cl or Br DIEA, CH 2 Cl 2, -25 o C Al(SbF 6 ) 3 epresents the AlCl 3 :AgSbF 6 Stoichiometry (1:3) Used to Generate the Catalyst elson, S. G.; Wan, Z.; Peelen, T. J.; Spencer, K. L. Tet. Lett. 1999, 40, = 2 =H Bn 2 1 H 2 H H H F 3 C 2 S S 2 CF 3 (CF 3 S 2 ) 2 TEA 90% 3 Al or Et 2 AlCl CH 2 Cl Tf Benzyl amine H 65% Bn Al (III) Triamine Al Chiral Catalyst F 3 C 2 S S 2 CF 3 =Cl or Cernerud, M.; Skrinning, A.; Bergere, I.; Moberg, C. Tetrahedron: Asymmetry 1997, 8, elson, S. G.; Peelen, T. J.; Wan, Z. J. Am. Chem. Soc. 1999, 121,

5 Aluminum (III) Catalyst ole 4-Coordinate Complex Adopting a Trigonal Monopyramidal (tmp) Geometry Balance Between Lewis Acidity of the tal and Lewis Basicity of the Amine Distorted 4-Coordinate Geometry Access Pentacoordiate Species (KEY To eactivity) Bn Al F 3 C 2 S S 2 CF 3 =Cl or C 2 -Symmetric Al (III) Triamine Chiral Catalyst Best Performing Chiral Catalyst elson, S. G.; Kim, B-K.; Peelen, T. J. J. Am. Chem. Soc. 2000, 122, Scott G. elson, Cheng Zhu, and Xiaoqiang Shen J. Am. Chem Soc. 2004, 126,

6 AAC eaction Scope entry 1 2 %ee 9 a syn:anti b,c % yield 9 d a CH 2 CH 2 Ph 90 95:5 71 b (CH 2)8 CHCH :6 77 c CH 2 CH 2 Bn 91 86:14 75 d C 6 H 5 96 >98:2 80 e C CSi :2 76 e f Et CH 2 CH 2 Ph 91 95:5 81 g Et CH 2 CH 2 Bn 91 88:12 83 h Et CH 2 Bn 93 89:11 78 i Et C 6 H 5 94 >98:2 83 j n Pr CH 2 CH 2 Bn 91 91:9 88 k n Pr C 6 H 5 96 >98:2 85 l i Pr C CSi 3 94 >98:2 71 e m i Pr C 6 H 5 96 >98:2 84 CF 3 Al Ar 2 S S 2 CF 3 Second Generation Al (III) Triamine Unsymmetrical Chiral Catalyst a Enantiomeric ratios determined by chiral GLC or HPLC. b Diastereomeric ratios determined by 1 H M of crude product mixtures except for entries b and e (GLC). elative and absolute stereochemical assignments based on prior literature precedent; see ref 2d. d Yields for diastereomerically pure materials except entries g and j (diastereomers were inseparable). e Yield for the amide derived fr om amine -mediated ring opening of the crude?-lactone. c Scott G. elson, Cheng Zhu, and Xiaoqiang Shen J. Am. Chem Soc. 2004, 126,

7 Building Blocks Derived from β-lactones β-lactones are Direct Progenitors of umerous Useful Building Blocks 3 H 4 C Diverse Allenes Aldol Product H β-amino Acids Conjugate Addition Product See eferences Within Presentation

8 Aldol Bond Construction Strategies Typical Aldol Additions Successfully elay Enolate Geometry to the elative Stereochemistry at the Two Stereogenic Centers btain Syn Aldol Adducts Example Stereochemistry elative Woodward-Hofmann Absolute Chiral Lewis Acid elative Enolate Geometry Absolute Chiral xazolidinone Bn Bu 2 BTf, TEA ArCH or TiCl 4, TEA Bn H Ar Syn elson, S. G.; Wan, Z. rg. Lett. 2000, 2, Evans, D. A.; ieger, D. L.; Bilodeau, M. T.; and Urpi, F. J. Am. Chem. Soc. 1991, 113,

9 Asymmetic Conjugate Addition Strategies Prototypical Conjugate Addition eactions Use an Enone Electrophile β-lactones pened with Cu (I) Salts Give Conjugate Addition Products Stereochemistry Based on Chiral Catalyst Stereochemistry Based on Stereocenter (S 2) Example elson, S. G., Wan, Z., Stan, M. A. J. rg. Chem. 2000, 67, Degrado S. J., Mizutani H., Hoveyda A. H. J. Am. Chem. Soc. 2001, 123,

10 β-amino Acid Synthesis Amine-diated S 2 ing pening of β-lactones 10 mol% catalyst a 3 3 Br H 2 Et, CH 2 Cl 2-50 o C 91-97% ee 80-96% yield DMS, 50 o C H H 2, 1. CH 2 2, Et 2 HBoc H 3 Pd/C 2. H 2, Pd/C, Boc 2 = BnCH 2, PhCH 2 CH 2, 2 CHCH 2, various alkyl chains Ser Phe-like Val-like Bn Al III Triamine Catalyst Al F 3 C 2 S S 2 CF 3 elson, S. G., Spencer, K. L., Angew. Chem. Int. Ed. 2000, 39,

11 Allenes from β-lactone Templates Structurally Diverse Allenes are Popular Intermediates for Asymmetric Synthesis S 2` ing pening using Grignard eagents and Cu (I) Catalysts u S 2` chanism Syn Predominates LG u LG Syn Anti 4-Alkynyl-β-Lactones Found to Undergo Sterospecific Anti-1,3-Substitution eactions Minor Amounts of S 2 Lactone ing pened Products When Using Unbranched Grignard eagents Paquette, L. A.; Stirling, C. J. M. Tetrahedron, 1992, 48, S 2` eview Wan, Z.; elson, G. S. J. Am. Chem. Soc. 2000, 122,

12 Stereocontrolled Synthesis of Malyngolide (-)-Malyngolide is a aturally ccurring Antibiotic Both Stereocenters Set in the Initial Asymmetric AAC eaction (a) 10 mol% 1, EtCBr, 2 Et, CH 2 Cl 2, -50 o C. (b) nc9h19mgbr, 10 mol % CuBr, THF, -78 o C. (c) 10 mol%, Ag 3, 5 mol% 2 Et, 80 o C, CH 3 C. (d) H 2, Pd-C. etrosynthesis Step c via H Ag n C9 H 19 C C C Bn C 2 H Four Steps / 54% verall Yield Asymmetric Synthesis Wan, Z.; elson, G. S. J. Am. Chem. Soc. 2000, 122,

13 Summary for Aldehyde Cyclocondensation (AAC) eactions elative Stereochemistry is Set by Woodward-Hoffmann ules: [2+2] Cycloaddition Absolute Stereochemistry is Set by a Chiral Triamine Al (III) Catalyst β-lactones Act As Surrogates For Important Enantioenriched Building Blocks 3 H Can be Used to Prepare 1. Aldol Addition Products 2. Conjugate Addition Products 3. β-amino Acids C Diverse Allenes H Aldol Product 3 4. Diverse Allenes β-amino Acids Conjugate Addition Product (AAC) thodology Could be Used For Large Scale Preparation of Pharmaceutical Precursors if Approach is Competitive and Cost Effective Compared to Current outes