1. Theoretical Investigation of Mechanisms and Stereoselectivities of Synthetic Organic Reactions

Transcription

1 1. Theoretical Investigation of Mechanisms and Stereoselectivities of Synthetic Organic Reactions 2. Copper Catalyzed One-Pot Synthesis of Multisubstituted Quinolinones Hao Wang Denmark Group Presentation January 28, 2014

2 PROJECTS SUMMARY Quantitative calculations to understand the mechanisms and stereoselectivities of asymmetric reactions (B3LYP/6-31G*) Alkylations Dihydroxylations Allylborations One-pot synthesis of polyheterocycles

3 1. Steric Control of Stereoselectivities in α- and β-alkylation of Azulenone Intermediates in a Guanacastepene A Synthesis Wang, H.; Michalak, K.; Michalak, M.; Jimenez-Oses, G.; Wicha, J.; Houk. K. N. J. Org. Chem. 2010, 75,

4 Guanacastepene A 1. Natural product isolated from an unidentified fungus growing on the tree. 2. Antibacterial activity 3. Linearly fused 5,7,6-tricyclic ring system, five stereo centers involving two quaternary chiral centers.

5 Retrosynthesis C8 Hydroazulenone Stereoselective control methylation from α-face Mihirbaran M.; Danishefsky S. J. J. Org. Chem., 2005, 70,

6 Opposite stereoselec,vi,es Michalak, K.; Michalak, M.; Wicha, J. in preparation.

7 Conformations of enolate A Chair-like: (0.0) Boat-like: (1.6)

8 Transition structures for methylation on chair-like enolate A α a0ack 1α ΔG = 1.8 kcal/mol β a0ack 1β ΔG = 0.0 kcal/mol

9 Transition structures for methylation on chair-like enolate A α a0ack 1α ΔG = 1.8 kcal/mol Pred: 91% de Exp: 80% de β a0ack 1β ΔG = 0.0 kcal/mol

10 Conformations of enolate B Boat- like conforma,on

11 Transition structures for methylation on boat-like enolate B α a0ack 2α ΔG = 0.0 kcal/mol β a0ack 2β ΔG = 5.2 kcal/mol

12 Transition structures for methylation on boat-like enolate B α a0ack 2α ΔG = 0.0 kcal/mol Pred: >99% de Exp: >99% de β a0ack 2β ΔG = 5.2 kcal/mol

13 Substrate control Enolate B Enolate A

14 Conclusion The diastereoselectivities observed experimentally in azulenone enolates alkylation originate from the steric interactions between the alkylation reagent and the substrate, controlling of stereoselectivities can be achieved by conformation manipulation of the substrates.

15 2. Torsional Control of Stereoselectivities of Dihydroxylation in the Chromodorolide A Synthesis Wang, H.; Kohler, P.; Overman, L. E.; Houk, K. N. J. Am. Chem. Soc. 2012, 134,

16 Dihydroxylation stereoselectivities X-ray of reactant (Bn) Concave face: more hindered Chromodorolide A Convex face: less hindered Prof Overman, UC Irvine

17 Related Examples Torsional control Torsional strain occurs when vicinal bonds are placed in an eclipsed conformation instead of the more stable staggered conformation. Cheong, P. H.; Yun, H.; Danishefsky, S. J.; Houk, K. N. Org. Lett. 2006, 8,

18 Torsional Control of Stereoselectivities: Electrophilic Additions and Cycloadditions to Alkenes Favored Disfavored

19 Torsional Control of Stereoselectivities: Electrophilic Additions and Cycloadditions to Alkenes Favored Disfavored Exo Endo Cycloadditions of phenyl azide to exo (left) and endo (right) faces of norbornene Lopez, S. A.; Houk, K. N. J. Org. Chem. 2013, 78, Wang, H.; Houk, K. N. Chem. Sci. 2014, 5, 462.

20 Torsional Control of Stereoselectivities: Electrophilic Additions and Cycloadditions to Alkenes β/α ra,o of epoxida,on Favored 1/99 Favored 82/18 50/50 Lucero, M. J.; Houk, K. N. J. Org. Chem.1998, 63, Wang, H.; Houk, K. N. Chem. Sci. 2014, 5,

21 TS analysis kcal/mol

22 Torsional Strain inside TS Staggered kcal/mol Eclipsed

23 Reactant geometry

24 Torsional differences in reactant β- a0ack (Staggered) α- a0ack (Eclipsed)

25 Torsional differences in reactant β- a0ack (Staggered) ΔG = 2.2 kcal/mol α- a0ack (Eclipsed) TSs

26 3. Mechanisms and Stereoselectivity in Chiral Phosphoric Acid-Catalyzed Allylborations Wang, H.; Jain, P.; Antilla, J. C.; Houk., K. N. J. Org. Chem. 2013, 78,

27 Chiral Phosphoric Acid-Catalyzed Allylboration Broad substrate scope: electron-rich and electron-poor aromatic aldehydes, hindered aldehydes, aliphatic aldehydes Mechanisms? Enantioselectivities? Jain, P.; Antilla, J. C. J. Am. Chem. Soc. 2010, 132,

28 Experimental mechanistic studies: Lewis acid Coordination of LA with dioxaborolane oxygens (A) or aldehyde oxygen (B)? Hall, D. G. J. Am. Chem. Soc. 2004, 126,

29 Experimental mechanistic studies: Lewis acid Coordination of LA with dioxaborolane oxygens (A) or aldehyde oxygen (B)? accelera5on with Sc(OTf) 3 No accelera5on with Sc(OTf) 3 Hall, D. G. J. Am. Chem. Soc. 2004, 126,

30 Experimental mechanistic studies: Lewis acid Coordination of LA with dioxaborolane oxygens (A) or aldehyde oxygen (B)? Hall, D. G. J. Am. Chem. Soc. 2004, 126,

31 Different mechanisms proposed Path i: Uncatalyzed Path ii: H- bonding of O 1 Path iii: H- bonding of O 2 Path iv: H- bonding of benzaldehyde

32 Uncatalyzed reaction +

33 Catalyzed reaction TS2: Protona,on of O 1 TS3: Protona,on of O 2 TS4: Protona,on of PhCHO TS2 TS3 TS4 (ΔΔG = 0.0 kcal/mol) (ΔΔG = 3.6 kcal/mol) (ΔΔG = 4.3 kcal/mol) TS2 TS3 TS4 C-C/B-O 2.06 Å/1.47 Å 2.02 Å/1.44 Å 1.60 Å/2.20 Å d B-O :1.47 and 1.44 electrophilicity of boron enhanced d B-O :2.20 B-O(carbonyl) interaction is weakened

34 Phosphoric Acid Catalyzed Allylboration TSs TS5 0.0 TS5 1.4

35 Phosphoric Acid Catalyzed Allylboration TSs TS5 0.0 TS5 1.4 TS6 0.2 TS6 3.2

36 Electrostatic potentials Red: negative ESP Blue: positive ESP Green: neutral

37 Electrostatic potentials TS5 0.0 TS5 1.4 Bottom View

38 Electrostatic potentials TS5 0.0 TS5 1.4 Bottom View TS6 0.2 Top View TS6 3.2

39 Two-Point Binding Models E-Model TS5 0.0 A-Model TS Acidic H of the catalyst forms a H-bond with the boronate oxygen. 2. Electrostatic attractions between the phosphoryl oxygen and relatively positive H s.

40 Enantioselectivities (S)- product minor (R)- product major

41 Diastereomeric allylboration TSs: A-Model TS- rea 0.0 TS- sia 6.1

42 Diastereomeric allylboration TSs: E-Model TS- ree 0.6 TS- sie 2.6

43 Four allylboration TSs E-Model TS- ree 0.6 TS- sie 2.6 A-Model TS- rea 0.0 TS- sia 6.1

44 TSs leading to products E-Model (S)- product minor TS- sie 2.6 A-Model TS- rea 0.0 (R)- product major

45 Summary 1. Activation via H-bonding of the boronate oxygen gives lower activation energy than H-bonding of aldehyde. 2. Boron-oxygen formation is the main reason to accelerate the allylboration reaction. 3. Two different models (A and E) were proposed, the enantioselectivities were governed by the steric interactions in the TSs.

46 4. One- pot, Three- Component Synthesis of Mul,subs,tuted Quinolinones via Cycloaddi,on/C- N Coupling/Cycliza,on/ (C- H Aryla,on) Cascade Reac,on: One single Cu(I) catalyst for mul<ple C- N and C- C bond forma<on Wang, H.; Qian, W-Y; Allen, J. Angew. Chem., Int. Ed. 2013, 52,

47 Copper Mediated Coupling Reactions: The Legacy from a Century ago Drawbacks: Harsh conditions: high temperatures, highly polar solvents, extended reaction time, large amounts of copper Yields are often moderate

48 Renaissance of Copper Mediated Coupling Reactions Since the beginning of the 21 st Century Can we combine two or even three of these different types of reactions in one pot using one single copper catalyst to synthesize novel polyheteroaryl molecules?

49 Merging of cross-coupling and cycloaddition 2-azidoacetamides

50 Proposed copper-mediated, three-component cascade sequence The key is to find the optimal conditions suitable for adding all components and reagents at once and for all elementary transformations to proceed in a organized fashion in one pot.

51 Click reaction accelerated by DMEDA Solvent Yield (%) Toluene 87 Dioxane 94 DMF 88 The reaction was highly exothermic DMEDA is a much better ligand than TEA for click chemistry (The reaction completes in 2 h with TEA in dioxane) Wang, H.; Qian, W-Y; Allen, J. Angew. Chem., Int. Ed. 2013, 52,

52 C-N Coupling/Cyclization: Solvent Screening Solvent Yield (%) Toluene 51 Dioxane 81 DMF 74 Wang, H.; Qian, W-Y; Allen, J. Angew. Chem., Int. Ed. 2013, 52,

53 C-N Coupling/Cyclization: Base Screening Base Yield (%) K 2 CO 3 86 K 3 PO 4 84 Cs 2 CO 3 81 The optimized reaction condition is K 2 CO 3 /Dioxane Wang, H.; Qian, W-Y; Allen, J. Angew. Chem., Int. Ed. 2013, 52,

54 Synthesis of Multisubstituted Quinolinones Wang, H.; Qian, W-Y; Allen, J. Angew. Chem., Int. Ed. 2013, 52,

55 Synthesis of Multisubstituted Quinolinones Electron-rich aryl bromide works well Various functional groups tolerated: acetal, ester, alcohol, amine Wang, H.; Qian, W-Y; Allen, J. Angew. Chem., Int. Ed. 2013, 52,

56 Other Heteroaryl Bromide Substrates Wang, H.; Qian, W-Y; Allen, J. Angew. Chem., Int. Ed. 2013, 52,

57 Secondary Acetamides Cs 2 CO 3 /Toluene gave moderate yield of product formation, longer time is needed Wang, H.; Qian, W-Y; Allen, J. Angew. Chem., Int. Ed. 2013, 52,

58 Carbonyl Functional Group Equivalents Wang, H.; Qian, W-Y; Allen, J. Angew. Chem., Int. Ed. 2013, 52,

59 Intramolecular Direct C-H Arylation Cu catalyzed direct C-H arylation on triazole using weak base and aryl bromide Formation of five bonds (three C-N & two C-C) was achieved via a four-step cascade using one single Cu catalyst Wang, H.; Qian, W-Y; Allen, J. Angew. Chem., Int. Ed. 2013, 52,

60 Summary Copper/diamine catalytic system is efficient for both click reaction and C-N couplings A variety of multisubstituted quinolinones are synthesized using the optimized conditions Cu catalyzed direct C-H arylation on triazole was achieved using weak base and aryl bromide A total of five bonds (three C-N & two C-C) can be formed via a four-step cascade using one single Cu catalyst

61 Labs in Amgen

62 Acknowledgement Prof Ken Houk (supervisor) Dr. Peng Liu Houk group Wenyuan Qian (supervisor) Jennifer Allen Terry Rosen Amgen TD Internship Program