Stereoselective Organic Synthesis

Transcription

1 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 , India tel: (+91) (40) e mail: prabhata@ilsresearch.org website:

2 Day 1 Basic Principles in Stereochemistry and Asymmetric Synthesis 2

3 utline Chiral Drugs Chirality in ature omenclature Chirality in Cyclic and Acyclic Systems Enantiomers vs Diastereomers ature Chiral Pool Examples of Diastereo- and Enantio-selective Synthesis 3

4 Thalidomide Children (1950s) 4

5 Thalidomide Drug (1950s) Use models here 5

6 6

7 Achiral bjects (Symmetrical) 7

8 Chiral bjects (Asymmetric) 8

9 Proteins 9

10 atural Proteins from L-Amino Acids Use models here Tripeptide Sequence natural amino acids (for side chain modifications) 10

11 Use models here 11

12 sp3 Geometry Use models here 12

13 Asymmetric sp3 Geometry Use models here Why Chirality is Important? 13

14 Why Chirality is Important? Use models here 14

15 Use models here 15

16 Molecular Recognition Small molecule Protein (or other Biomolecule) Receptor Interactions DA/RA Protein Interactions Protein Protein Interactions Carbohydrate/Glycoprotein Protein interactions 16

17 Enantiomers of Carvone Use models here 17

18 The Cahn-Ingold-Prelog Rule for R/S Assignment of Enantiomers 1. Identify the stereogenic centers (most commonly an sp 3 C with 4 different groups attached) 2. Assign the priority to each group (high = 1, low = 4) based on atomic number of the atom attached to the stereogenic center 3. Position the lowest priority group away as if you were looking along the C-(4) sigma bond. If you are using a model, grasp the group in your fist 4. For the other 3 groups, determine the direction of high to low priority (1 to 3) 5. If this is clockwise, then the center is R (Latin: rectus = right) 6. If this is counter clockwise, then it is S (Latin: sinister = left) 18

19 R/S omenclature C 2 C 2 C S C 2 C 2 C R

20 R/S omenclature C 2 C 2 C C 2 C 2 C 20

21 Absolute Configuration Assignment Use models here 21

22 Enantiomers vs Diastereomers Diastereomers: Stereoisomers that are not mirror images mirror Use models here 2 S S R R 2 2 R R A B C 2 S S 2 S R 2 R S 22

23 Fischer Projection The Fischer projection, devised by ermann Emil Fischer in 1891, is a two-dimensional representation of a three-dimensional organic molecule by projection. All bonds are depicted as horizontal or vertical lines. The carbon chain is depicted vertically, with carbon atoms represented by the center of crossing lines. The orientation of the carbon chain is so that the C1 carbon is at the top. 23

24 ld (Fischer) Vs ew Way of Drawing Structures Use models here 24

25 Use models here 25

26 Cis and Trans Terminology in Cyclic Systems Use models here 26

27 Enantiomers and Diastereomers in Cyclic Systems Use models here 27

28 Six m Ring Conformation 6 Use models here 28

29 An Example of Stereoselective Reduction Use models here 29

30 An Example of Stereoselective Carbon ucleophile Attack Asymmetric Quaternary Center Use models here 30

31 Facial Selectivity Use models here 31

32 Chiral Products from Amino Acids 2 C 2 C C C 2 C 2 C 2 C C C C C 2 2 Use models here C 32

33 Artificial Amino Acids- Going Beyond ature! R 1 β amino acids γ amino acid 2 C R 1 R 1 C C C R 1 work from Arya Lab etero Michael Reaction P 1 C C P 2 C 2 S 2Cyclization P 1 P 1 P 2 Use models here 33

34 Artificial Amino Acids- Going Beyond ature! β amino acids Use models here 34

35 Atropisomerism Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers. The word atropisomer is derived from the Greek a which means not and tropos which translates as turn. The name was coined by Kuhn in 1933, but atropisomerism was first detected in 6,6 -dinitro-2,2 - diphenic acid by Cristie in

36 Examples of Atropisomerism Use models here 36

37 Atropsiomersim: Stereoselective Synthesis Example 37

38 Show Vancomycin model atropisomerism 38

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40 DA 40

41 ligonucleotides - B 5' 3' 2' P 5' 3' 2' P - B - B 5' 3' 2' P - 5' 3' P 2' B 2 2 A G 2 C U T Use models here 41

42 Carbohydrate-Protein Interactions 42

43 Sci Am Jan 1993, 82-89

44 Cell Surface Carbohydrate - Protein Interactions 44

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46 Carbohydrates as Drugs (Carbohydrate Mimics as Drugs) 46

47 DA Proteins Linear Biopolymers 47

48 Complexity in Carbohydrates Use models here 48

49 D-Glucose Carbohydrates Sawhorth Fischer β α Use models here 49

50 D-Glucose Carbohydrates D-Galactose Use models here 50

51 L-Glucose in ature (!) Use models here 51

52 Common atural Monosaccharides 52

53 Two Examples of Disaccharides 1 3 Use models here

54 Branched Biopolymers 54

55 Enzymatic and Chemical Glycosylations 55

56 Disaccharides 56

57 -Linked Glycopeptides Use models here 57

58 -Linked Glycopeptides -linked -linked Use models here 58

59 Three Case Studies in Stereocontrolled rganic Synthesis 59

60 Artificial Amino Acids- Going Beyond ature! R 1 β amino acids γ amino acid 2 C R 1 R 1 C C C R 1 work from Arya Lab etero Michael Reaction P 1 C C P 2 C 2 S 2Cyclization P 1 P 1 P 2 Use models here 60

61 Artificial Amino Acids- Going Beyond ature! Arya et al J. Comb. Chem. 2004, 6, Prakesch et al J. Comb. Chem., 2006, 8,

62 Enantioselective Synthesis of Tetrahydroaminoquinoline Scaffold CEt 2 1. MEMCl, DIPEA, 95% 2 CEt 2 C 2D MR- ESY 1. Zn/Ac, 90% 2. LDA, TF, 80% MEM 2. Wittig, 90% 3. Sharpless Aminohydroxylation, 70% BzC MEM BzC MEM C 2 - and C 4 - ne favored CEt CBz ee >92% MEM MEM M BzC Et MEM BzC Teoc 1 2 CEt 4 3 TBS Alloc + M Use models here disf avored 2 CEt Prakesch et al J. Comb. Chem., 2006, 8,

63 An Unprecedented, Stereocontrolled Aza Michael! R 3 R 3 P CR 1 C 2 Et P CR 1 C 2 Et R 2 R 2 R 3 R 3 P 1 P 1 CEt R 1 C R 2 CEt R 1 C R 2 Use models here Prakesch et al J. Comb. Chem., 2006, 8,

64 An Unprecedented, Stereocontrolled Aza Michael! 2D MR- ESY Use models here ne between -3 and -7

65 Enantioenriched Aminoindoline Scaffold 1. MEMCl, DIPEA, 97% 2. (Et) 2 P()C 2 CEt, 2 a, 92% MEM 1. LB, 85% 2. BzCl, py, 88% C 3. Sharpless Aminohydroxylation, 79% 2 CEt CBz 3. TsCl, DMAP, 90% MEM enantioenriched, ee >95% Ts 1. 2, Lindlar cat 1. TeocCl, py, 98% 2 CBz Bz 2. K 2 C 3,TF 75%, 2 steps MEM CBz Bz 2. 2,Pd/C, 3. AllocCl, py, 85% rthogonal Protecting Groups Teoc anchoring site for SPS MEM Alloc Bz for building skeletal diversity Gan, Reddy, Quevillon, Couve-Bonnaire and Arya Angew. Chem. Int. Ed. 2005, 44,

66 Stereocontrolled Aza Michael piperidine >95% MEM Alloc CEt Gan, Reddy, Quevillon, Couve-Bonnaire and Arya Angew. Chem. Int. Ed. 2005, 44,

67 A Tandem Approach to btain Polycyclic Architectures Angew. Chem. Int. Ed. 2005, 44,

68 Masataka and Fukumoto Angew. Chem. Int. Ed. Engl. 1993, 32, Literature Examples

69 Model Study Ph CEt Et 3, TBSTf, DCM -78 o Ctort (68%) 20% Et 2 C Ph + 20% Et 2 C Ph + Et 2 C Ph 8% 20% Ph C 2 Et Brochu, Prakesch, Enright, Leek and Arya J. Comb. Chem. 2008, 10,

70 Lewis Acid Study X-Ray SM: starting material TBS/TES/TMS reactions with TBSTf/TESTf/TMSTf Solvent system, 3:1, EtAc:exane Use models here Brochu, Prakesch, Enright, Leek and Arya J. Comb. Chem. 2008, 10,

71 MR Analysis Brochu, Prakesch, Enright, Leek and Arya J. Comb. Chem. 2008, 10, =E 2 1 a b 7 8 a b 4 Ph C 2 Et - SQC clearly demonstrated the presence of group - Stereochemistry was determined by MR/ESY analysis =E a 1 2 b 7 8 a b 4 C 2 Et

72 Proposed Transition States Et 2 C R LA R C 2 Et LA R C 2 Et Et 2 C R Et 2 C Favored R R LA C 2 Et R LA C 2 Et Et 2 C R

73 Proposed Transition States Et 2 C R Et 2 C R Et 2 C R Et 2 C R R Et LA Et LA R R LA Et LA Et R Favored

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