Stereoselective rganic Synthesis Prabhat Arya Professor and Leader, Chemical Biology Program Dean, Academic Affairs, Institute of Life Sciences (An Associate Institute of University of yderabad Supported by Dr. Reddy s) University of yderabad Campus Gachibowli, yderabad 500046, India Adjunct Professor, Biochemistry, McGill University mber, ttawa Institute of Systems Biology tel: (+91) (40) 6657 1500 e mail: prabhata@ilsresearch.org website: http://www.ilsresearch.org 1
Day 2 Stereo- and Enantio-selective Carbon- Carbon and Carbon-etero Atom Bond Forming Reactions Using Asymmetric Carbanion Chemistry 2
utline Enol ethers: kinetic and thermodynamic Enolates in cyclic systems: outside and inside the ring Acyclic enolates Stereo- and enantio-controlled aldol reaction Stereo- and enantio-controlled carbon-hetero atom bond formation using enolates Lewis acid-mediated stereo- and enantio-controlled allylsilane/stannane reactions Aldol reaction: reagent-based stereocontrol Enantioselective synthesis of Swinholide A (Paterson) 3
Enolate Chemistry 4
Carbanions R 1 R2 R 1 R2 R 4 R 3 R 4 R 3 R 2 R 1 R 2 R 1 R 2 R 1 CR 1 R 2 R 1 N 2 R 2 R 1 CN 2 5
Kinetic vs Thermodynamic Enol Ethers R 3 R 1 base - R 3 R 1 + - R 3 R 1 R 2 R 2 R 2 R 1,R 2,R 3 alkyl groups kinetic thermodynamic Kinetic enolate - fast, irreversible hydrogen removal - enolate at less substitution - low temperature, aprotic solvents Thermodynamic enolate - slow, reversible due to steric crowd - enolate at high substition - stable due to hyperconjugation N 3 Si N Si 3 Li Li non-nucleophilic bulky bases 2 C 2 C 2 C 6
Enolates Inside and utside the Cyclic Structures 7
Five mbered Ring Endocyclic Enolate Alkylation Inside the ring 1,2 asymmetric induction Li R-Br R C 6 13 60% C 6 13 + Ph Ph Ph Li Br Ph Ph 96% 60% Ph LDA Et-I Ph Ph Ph Li 1,3 asymmetric induction Ph Ph Ph 8
Endocyclic Enolate Alkylation Six mbered Ring 1,3 asymmetric induction + (large) (small) Ph - Cl Ph Ph Ph - Ph 9
Chair Conformation Six mbered Ring Flipped Chair NMR ne Studies! Use models here 10
- Endocyclic Enolate Alkylation + Br Six mbered Ring - Br 11
Endocyclic Enolate Alkylation Six mbered Ring - Br + major minor El + - - El + 12
Endocyclic Enolate Alkylation Decalones Axial attack dr >95:5 dr >95:5 Erik Carreira and Lisbet Kvaerno, Book Chapter 3 Classics in Stereoselective Synthesis, Wiley-VC, 2007 Equatorial attack 13
Endocyclic Enolate Alkylation Trans and Cis Decalins Use models here 14
Endocyclic Enolate Alkylation Decalones 15
Exocyclic Enolate Alkylation 1,2 asymmetric induction Et Et - Et Et El El exocyclic enolate 3 2 M 1 Et 1,3 allylic strain Et M Use models here 16
Exocyclic Enolate Alkylation 4 7 2 2 2 2 17
Exocyclic Enolate Alkylation 1,3 asymmetric induction - Et o o Use models here 18
Exocyclic Enolate Alkylation M M Use models here 19
Exocyclic Enolate Alkylation - - equatorial attack (major) - NMR ne studies C C axial attack (minor) Et C C Use models here 20
Exocyclic Enolate Alkylation CN t CN C C CN CN C - 21
Exocyclic Enolate Alkylation Use models here 22
Enolates in Acyclic Systems 23
Acyclic Enolates: Regio and Stereochemistry A A + A (kinetic conditions) LDA,TF, -78 o C (Z:E, 3:7) A + Z:E, 98:2 A + Z:E, 98:2 24
The Proposed Transition States Use models here 25
Examples of Allylic Strain Effect Ph 3 C Ph 3 C 1,3- Allylic Strain X Ph 3 C Nu Nu Ph 3 C Nu 26
Intramolecular 1,3 Asymmetric Induction Chelation Effect : etero atom at β- position Li Li Li Li R 1 Et R 1 Et R 1 Et 1 Re + Re- R 1 El Et 1,2- anti (- and El) 27
Intramolecular 1,3 Asymmetric Induction Chelation Effect : etero atom at β- position Li Li Li Li R 1 Et R 1 Et R 1 Et 1 Si + Si- R 1 El Et 1,2- anti ( and El) 28
Another Example of Intramolecular Asymmetric Induction R 1 N R 1 Li Li Li R 1 N N Li + + Si R 1 N R 1 N El El Ask for the synthesis route to obtain the starting material 29
R 1 N R 1 Li N R 1 Li N Re + R 1 N El Major diastereomer 30
Stereo- and Enantio-selective Aldol Reaction 31
Facial Selectivity 2 1 re 2 1 2 1 si- 1 re 2 1 2 David Evans et al, J Am Chem Soc, 6120 (1979) 32
Aldol Reaction: Basic Principles Major Isomer Zimmerman-Traxler Transition State Model Use models here 33
Aldol Reaction: Basic Principles Contd. Major Isomer Use models here 34
Aldol Reaction: Basic Principles contd. Minor Isomer Use models here 35
Chiral Auxiliary Approach to btain Enantioenriched Aldol Products N s nbu 2 BTf, i-pr 2 NEt Bu Bu B N s or Bu Bu B N s z- E- base base - - A 1,3 strain R 2 N R 1 A 1,3 strain R 2 N R 1 David Evans et al, J Am Chem Soc, 6120 (1979) and 2127 (1981) Use models here 36
Chiral Auxiliary Approach to btain Enantioenriched Aldol Products David Evans et al, J Am Chem Soc, 6120 (1979) and 2127 (1981) Use models here 37
N R A Bu B N z- Bu B R 1 N + R 1 N A: Bu 2 BTf, i-pr 2 NEt B: R 1 C Major minor R 1 N Bu B Bu N Bu B Bu favored R 1 unfavored 38
Crimmins Approach to Aldol Bn N S s TiCl 4 (2 equiv) i-pr 2 NEt Ln Ti N Bn S R 1 C R 1 N Bn S R 1 Bn N S Ti Cl favored Cl Cl Crimmins et al, J Am Chem Soc, 7883 (1997) Use models here 39
Chiral Auxiliary Removal! Enatioenriched Products 40
Chiral Auxilary Approach to Stereoselective C-N, C- C-Br and C-F Bond Formation 41
Evans Chiral Auxiliary Approach to Stereoselective C-N Bond Formation David Evans et al, J Am Chem Soc, 6365 (1986); 4011 (1990) and 6881 (1987) 42
Scott Gilbertson et al, J Am Chem Soc, 4481 (1994) 43
Arya et al, J rg Chem, 4817 (1998) 44
Chiral Auxiliary-based Approach to Stereoselective C- Bond Formation Ph N PhS 2 N Ph Ph N Ph N attack Ph M N N Ph M attack Use models here Davis et al, Tetrahedron Letts, 3539 (1985) 45
Chiral Auxiliary-based Approach to Stereoselective C- Bond Formation David Evans et al J Am Chem Soc, 4346 (1985) For detailed review on Davis reagent see Chem Rev vol 96, 835-875 (1996) 46
Chiral Auxiliary-based Approach to Stereoselective C-F Bond Formation Davis et al, Teterahedron Letts, 1153 (1992) 47
Chiral Auxiliary-based Approach to Stereoselective Acylation David Evans et al, J Am Chem Soc 1154 (1984) 48
1,2 Asymmetric Induction 49
1,2 Asymmetric Induction Use models here 50
Chiral Auxiliary-based Tandem Michael/Bromination Synthetic route for the starting compound ruby et al, Tetrahedron Letts, 2561 (1993) 51
Aldol Reaction: Substrate Control with Chiral Carbonyl Compounds Taken from Book: Classics in Stereoselective Synthesis, Chapter 4 52
Use models here Cram Model Felkin-Anh Model favored disfavored Taken from Book: Classics in Stereoselective Synthesis, Chapter 4 53
Use models here Felkin-Anh Model Nu disfavored favored Nu Taken from Book: Classics in Stereoselective Synthesis, Chapter 4 54
Polar Substituent at β-position Acyclic control 1,3-anti Use models here Taken from Book: Classics in Stereoselective Synthesis, Chapter 4 55
Polar Substituent at β-position favored Acyclic control Nu Nu Taken from Book: Classics in Stereoselective Synthesis, Chapter 4 56
Aldol Reaction: Reagent-based Control Taken from Book: Classics in Stereoselective Synthesis, Chapter 4 57
Ian Paterson Approach Taken from Book: Classics in Stereoselective Synthesis, Chapter 4 58
Ian Paterson Approach Taken from Book: Classics in Stereoselective Synthesis, Chapter 4 59
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Ian Paterson Approach c-c 6 11 Bn (c- 11 C 6 ) 2 BCl Et 3 N Bn + - B Cl c-c 6 11 Bn c-c 6 11 B c-c 6 11 Use models here C Bn dr anti c-c 6 11 B Bn c-c 6 11 Taken from Book: Classics in Stereoselective Synthesis, Chapter 4 61
Ian Paterson Approach Use models here Taken from Book: Classics in Stereoselective Synthesis, Chapter 4 62
Ian Paterson Approach Use models here Taken from Book: Classics in Stereoselective Synthesis, Chapter 4 63
Synthesis achieved by Ian Paterson team Taken from the Book: Classics in Total Synthesis Part II, Wiley-VC KC Nicolaou and Scott A Snyder 64
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Asymmetric Synthesis, Vol 3 Stereodifferentiating Addition Reactions, Part B Edited by J. D. Morrison Chapter 1: Stereoselective Alkylation Reactions of Chiral tal Enolates by David A. Evans Classics in Stereoselective Synthesis, Wiley-VC, 2009 Erick M. Carreira and Lisbet Kvaerno Classics in Total Synthesis Part II, Wiley-VC KC Nicolaou and Scott A Snyder Advances in Asymmetric Enolate thodology Tetrahderdon (Tetrahedron Report No 514) vol 56, 917-947 (2000) by P. Arya and. Qin 73