Development and Implementation of

Enantioselective Diboration of Mono-Substituted

Alkenes via Platinum Catalyst and Sequential

Cross-Coupling

Tanner McDaniel

Michigan State University

19 February 2014

1. Introduction

a) Importance of Chirality and Enantioselectivity

b) Why are Simple Olefins a Good Starting Point?

c) Classical Examples of Enantioselective Reactions

d) Brief History of Diboration

2. Development of Enantioselective Diboration

a) Examples of How to Access 1,2-Diboronates

b) Optimization

3. Mechanistic Investigation

a) Kinetic, Kinetic Isotope Effect, Trapping Experiments

4. Substrate Scope

a) Aliphatic, Aryl, Chiral Substrates

b) Selectivity and Limits of Reaction

5. Sequential Diboration Cross-Coupling (DCC) Reaction

a) Suzuki Coupling Conditions

b) One-pot Synthesis of DCC Products

6. Conclusion

2

3

The Thalidomide Tragedy

1950’s – Over-the-counter drug for:

• Insomnia

• Morning sickness for pregnant women

1961 – Withdrawn from human use world wide

Why?

Effective sedative Birth defects

Kelsey, F. O., J. Dent. Res. 1967, 46, 1199

Kim, J. H.; Scialli, A. R., Toxicol. Sci. 2011, 122, 1

4

Alkenes

• Diverse

• Produced on Large Scales

• Inexpensive

• Functionalization

Substrate Directed Chemical Reactions

5 Hoveyda, A. H.; Evans, D. A.; Fu, G. C., Chem. Rev. 1993, 93, 1307

McKittrick, B. A.; Ganem, B. Tetrahedron Lett. 1985, 26,4895

6

Sharpless

Xu, D.; Crispino, G. A.; Sharpless, K. B., J. Am. Chem.Soc.,1992, 114, 7570.

Sharpless, K. B.; et. al., J. Org. Chem. 1992, 57, 2768

Schlesinger

7

Suzuki

Ceron, P.; Finch, A.; Frey, J.; Kerrigan, J.; Parsons, T.; Urry, G.; Schlesinger, H. I., J. Am. Chem. Soc., 1959, 81, 6368

Miyaura, N.; Suzuki, A., Chem. Rev., 1995, 95, 2457

Ishiyama, T.; Matsuda, N.; Miyaura, N.; Suzuki, A., J. Am. Chem. Soc., 1993, 115, 11018.

8

Suzuki

Smith and Iverson

Miyaura, N.; Suzuki, A., Chem. Rev., 1995, 95, 2457

Ishiyama, T.; Matsuda, N.; Miyaura, N.; Suzuki, A., J. Am. Chem. Soc., 1993, 115, 11018.

Iverson, C. N.; Smith, M. R., J. Am. Chem. Soc., 1995, 117, 4403-4404.

Iverson, C. N.; Smith, M. R., Organometallics 1996, 15, 5155-5165.

9

Smith

Marder

…and many other

by products

Iverson, C. N.; Smith, M. R., Organometallics 1997, 16, 2757-2759. Marder, T. B.; Norman, N. C.; Rice, C. R., Tetrahedron Lett. 1998, 39, 155.

1. Introduction

a) Importance of Chirality and Enantioselectivity

b) Alkenes

c) Classical Examples of Enantioselective Reactions

d) Brief History of Diboration

2. Development of Enantioselective Diboration

a) Examples of How to Access 1,2-Diboronates

b) Optimization

3. Mechanistic Investigation

a) Kinetic, Kinetic Isotope Effect, Trapping Experiments

4. Substrate Scope

a) Aliphatic, Aryl, Chiral Substrates

b) Selectivity and Limits of Reaction

5. Sequential Diboration Cross-Coupling (DCC) Reaction

a) Suzuki Coupling Conditions,

b) One-pot Synthesis of DCC Products

6. Conclusion

10

11

So….why would diboration be useful for asymmetric synthesis?

Morken

12 Morgan, J. B.; Miller, S. P.; Morken, J. P., J. Am. Chem. Soc., 2003, 125, 8702-8703.

Hoveyda

13 Lee, Y.; Jang, H.; Hoveyda, A. H., J. Am. Chem. Soc., 2009, 131, 18234-18235.

Andersson

14 Paptchikhine, A.; Cheruku, P.; Engman, M.; Andersson, P. G., Chem. Commun. , 2009, 5996.

Morken

15 Burks, H. E.; Kliman, L. T.; Morken, J. P., J. Am. Chem. Soc., 2009, 131, 9134-9135.

16

Morken’s Group Approach

Burks, H. E.; Kliman, L. T.; Morken, J. P., J. Am. Chem. Soc., 2009, 131, 9134-9135.

Platinum Catalyzed Diboration

Morken

17 Kliman, L. T.; Mlynarski, S. N.; Morken, J. P., J. Am. Chem. Soc., 2009, 131, 13210.

Ligand

18

Entry Ligand R solvent Yield (%) er

1 L1 H tol 24 80:20

2 L2 Me THF 84 95:05

3 L3 Me tol 81 92:08

4 L4 Et tol 83 96:04

5 L5 i-Pr THF 82 97:03

6 L6 i-Pr tol 84 97:03

7 L7 t-Bu tol 74 90:10

Coombs, J. R.; Haeffner, F.; Kliman, L. T.; Morken, J. P. J. Am. Chem. Soc., 2013, 135, 11222.

Catalyst Loading and Metal-Ligand Ratio

19

entry Pt(dba)3

(mol %)

(R,R)-L4

(mol %)

[octene]

(M)

Time

(h)

yield

(%)

er

1 3.0 6.0 0.1 3 89 97:3

2 0.5 1.0 1.0 11 88 96:4

3 0.2 0.4 1.0 28 60 96:4

4 3.0 3.6 0.1 1 88 98:2

5 1.0 1.2 1.0 3 82 97:3

6 3.0 3.0 0.1 3 75 86:14

7 1.0 1.0 1.0 3 66 94:6

8 1.0 0.75 1.0 3 39 80:20

9 1.0 0.5 1.0 3 30 64:36

Coombs, J. R.; Haeffner, F.; Kliman, L. T.; Morken, J. P. J. Am. Chem. Soc., 2013, 135, 11222

20

Diboration vs Oxidation Step

Coombs, J. R.; Haeffner, F.; Kliman, L. T.; Morken, J. P. J. Am. Chem. Soc., 2013, 135, 11222

1. Introduction

a) Importance of Chirality and Enantioselectivity

b) Alkenes

c) Classical Examples of Enantioselective Reactions

d) Brief History of Diboration

2. Development of Enantioselective Diboration

a) Examples of How to Access 1,2-Diboronates

b) Optimization

3. Mechanistic Investigation

a) Kinetic, Kinetic Isotope Effect, Trapping Experiments

4. Substrate Scope

a) Aliphatic, Aryl, Chiral Substrates

b) Selectivity and Limits of Reaction

5. Sequential Diboration Cross-Coupling (DCC) Reaction

a) Suzuki Coupling Conditions,

b) One-pot Synthesis of DCC Products

6. Conclusion

21

22

General Mechanism

Olefin Coordination

Migratory Insertion

Reductive Elimination

Oxidative Addition

?

Coombs, J. R.; Haeffner, F.; Kliman, L. T.; Morken, J. P. J. Am. Chem. Soc., 2013, 135, 11222.

Iverson, C. N.; Smith, M. R., Organometallics 1996, 15, 5155.

Lesley, G.; Nguyen, P.; Taylor, N. J.; Marder, T. B.; Scott, A. J.; Clegg, W.; Norman, N. C. Organometallics 1996, 15, 5137.

.

Reaction Rate vs Substrate Concentrations

23

Alkene B2(pin)2 Pt(dba)3 Ligand

1.0 M 1.05 M 1 mol% 1.2 mol%

1.5 M 1.5 M 1 mol% 1.2 mol%

[Substrates]

Red line

Blue line

*Alkene = 1-tetradecene

Close to zero-order

Coombs, J. R.; Haeffner, F.; Kliman, L. T.; Morken, J. P. J. Am. Chem. Soc., 2013, 135, 11222.

Reaction Rate vs Catalyst Concentration

24

Alkene B2(pin)2 Pt(dba)3 Ligand

1.0 M 1.05 M 1 mol% 1.2 mol%

1.0 M 1.05 M 2 mol% 2.4 mol%

[Substrates]

Red line

Blue line

*Alkene = 1-tetradecene

1st order

Coombs, J. R.; Haeffner, F.; Kliman, L. T.; Morken, J. P. J. Am. Chem. Soc., 2013, 135, 11222

Proposed Mechanism

25

?

1 2

3 4

How to get near zero order for substrates?

Reversible

alkene

binding

3 → 4 = Rate Determining Step

RDS

Or

4 → 1 = Rate Determining Step

RDS

Coombs, J. R.; Haeffner, F.; Kliman, L. T.; Morken, J. P. J. Am. Chem. Soc., 2013, 135, 11222

Iverson, C. N.; Smith, M. R., Organometallics 1996, 15, 5155.

Lesley, G.; Nguyen, P.; Taylor, N. J.; Marder, T. B.; Scott, A. J.; Clegg, W.; Norman, N. C., Organometallics 1996, 15, 5137.

.

Substrates = near zero order Catalyst = 1st order

Natural Abundance 13C Kinetic Isotope Effect (KIE)

26 Coombs, J. R.; Haeffner, F.; Kliman, L. T.; Morken, J. P. J. Am. Chem. Soc., 2013, 135, 11222

Singleton, D. A.; Thomas, A. A., J. Am. Chem. Soc., 1995, 117, 9357

Frantz, D. E.; Singleton, D. A.; Snyder, J. P., J. Am. Chem. Soc., 1997, 119, 3383.

(1) 𝑅

𝑅0

= (1 − 𝐹)(1

𝐾𝐼𝐸)−1

(2) 𝐾𝐼𝐸𝐶𝑎𝑙𝑐 = ln(1−𝐹)

ln[ 1−𝐹𝑅

𝑅0]

R = Enriched Integration (Recovered Starting Material)

R0 = “Unreacted” Integration (Original Starting Material)

F = Fractional Conversion of Reactants

KIE = 𝐾12

𝐾13

Singleton’s Method for Measuring Heavy Atom Kinetic Isotope Effect

What if Migratory Insertion is Irreversible?

27

Two Carbons

with 13C KIE !

Coombs, J. R.; Haeffner, F.; Kliman, L. T.; Morken, J. P. J. Am. Chem. Soc., 2013, 135, 11222

Singleton, D. A.; Thomas, A. A., J. Am. Chem. Soc., 1995, 117, 9357.

Frantz, D. E.; Singleton, D. A.; Snyder, J. P., J. Am. Chem. Soc., 1997, 119, 3383.

What if Migratory Insertion is Reversible?

28

One Carbon

with 13C KIE!

Coombs, J. R.; Haeffner, F.; Kliman, L. T.; Morken, J. P. J. Am. Chem. Soc., 2013, 135, 11222

Singleton, D. A.; Thomas, A. A., J. Am. Chem. Soc., 1995, 117, 9357.

Frantz, D. E.; Singleton, D. A.; Snyder, J. P., J. Am. Chem. Soc., 1997, 119, 3383.

Natural Abundance 13C Kinetic Isotope Effect (KIE)

29 Coombs, J. R.; Haeffner, F.; Kliman, L. T.; Morken, J. P. J. Am. Chem. Soc., 2013, 135, 11222

Singleton, D. A.; Thomas, A. A., J. Am. Chem. Soc., 1995, 117, 9357.

Frantz, D. E.; Singleton, D. A.; Snyder, J. P., J. Am. Chem. Soc., 1997, 119, 3383.

KIE = 𝐾12

𝐾13

New Proposed Mechanism Based on 13C KIE

30

Olefin Coordination

Migratory Insertion

Reductive Elimination

Oxidative Addition

Coombs, J. R.; Haeffner, F.; Kliman, L. T.; Morken, J. P. J. Am. Chem. Soc., 2013, 135, 11222

Regioselectivity of Olefin

31

Pt-C Bond Formation on Internal C Pt-C Bond Formation on External C

Coombs, J. R.; Haeffner, F.; Kliman, L. T.; Morken, J. P. J. Am. Chem. Soc., 2013, 135, 11222

Model for Stereoselectivity

32 Coombs, J. R.; Haeffner, F.; Kliman, L. T.; Morken, J. P. J. Am. Chem. Soc., 2013, 135, 11222

(R,R)- L becomes the (R) 1,2-diboronate

(S,S)- L becomes the (S) 1,2-diboronate

1. Introduction

a) Importance of Chirality and Enantioselectivity

b) Alkenes

c) Classical Examples of Enantioselective Reactions

d) Brief History of Diboration

2. Development of Enantioselective Diboration

a) Examples of How to Access 1,2-Diboronates

b) Optimization

3. Mechanistic Investigation

a) Kinetic, Kinetic Isotope Effect, Trapping Experiments

4. Substrate Scope

a) Aliphatic, Aryl, Chiral Substrates

b) Selectivity and Limits of Reaction

5. Sequential Diboration Cross-Coupling (DCC) Reaction

a) Suzuki Coupling Conditions,

b) One-pot Synthesis of DCC Products

6. Conclusion

33

Aliphatic 1-Alkenes

34 Coombs, J. R.; Haeffner, F.; Kliman, L. T.; Morken, J. P. J. Am. Chem. Soc., 2013, 135, 11222

Zhao, H.; Dang, L.; Marder, T. B.; Lin, Z., J. Am. Chem. Soc., 2008, 130, 5586.

Aromatic Alkenes

35 Coombs, J. R.; Haeffner, F.; Kliman, L. T.; Morken, J. P. J. Am. Chem. Soc., 2013, 135, 11222

Chiral Substrates

36

* 3.0% Pt(dba)3 and

3.6% (L4) (R,R or S,S)

was employed at 60 °C

for 12 hour.

Coombs, J. R.; Haeffner, F.; Kliman, L. T.; Morken, J. P. J. Am. Chem. Soc., 2013, 135, 11222

Selectivity

Sharpless

37

Morken

Coombs, J. R.; Haeffner, F.; Kliman, L. T.; Morken, J. P. J. Am. Chem. Soc., 2013, 135, 11222

Xu, D.; Crispino, G. A.; Sharpless, K. B., J. Am. Chem. Soc., 1992, 114, 7570-7571.

Unreactive Substrates

38 Coombs, J. R.; Haeffner, F.; Kliman, L. T.; Morken, J. P. J. Am. Chem. Soc., 2013, 135, 11222

1. Introduction

a) Importance of Chirality and Enantioselectivity

b) Alkenes

c) Classical Examples of Enantioselective Reactions

d) Brief History of Diboration

2. Development of Enantioselective Diboration

a) Examples of How to Access 1,2-Diboronates

b) Optimization

3. Mechanistic Investigation

a) Kinetic, Kinetic Isotope Effect, Trapping Experiments

4. Substrate Scope

a) Aliphatic, Aryl, Chiral Substrates

b) Selectivity and Limits of Reaction

5. Sequential Diboration Cross-Coupling (DCC) Reaction

a) Suzuki Coupling Conditions,

b) One-pot Synthesis of DCC Products

6. Conclusion

39

Why cross-coupling?

40

41

General Reaction

Miyaura, N.; Suzuki, A., Chem. Rev. 1995, 2457, 2483.

Potential Problem

Suzuki

42

Molander

Potential Solution

Molander, G. A.; Canturk, B., Angew. Chem. Int. Ed. 2009, 48, 9240.

Sato, M.; Miyaura, N.; Suzuki, A., Chem. Lett. 1989, 18, 1405

43 Mlynarski, S. N.; Schuster, C. H.; Morken, J. P., Nature 2014, 505, 386.

44

n-octyl 1,2-bis(boronate) versus n-octyl 1-boronate

Why?

Mlynarski, S. N.; Schuster, C. H.; Morken, J. P., Nature 2014, 505, 386.

Plausible Explanations

45

A B

Mlynarski, S. N.; Schuster, C. H.; Morken, J. P., Nature 2014, 505, 386.

Sandrock, D. L.; Jean-Gérard, L.; Chen, C.-y.; Dreher, S. D.; Molander, G. A., J. Am. Chem. Soc. 2010, 132, 17108.

Ridgway, B. H.; Woerpel, K. A., J. Org.Chem. 1998, 63, 458.

Molander

Woerpel

Outer-sphere pathway Inner-sphere pathway

Inversion or Retention

46

Suggests Inner-Sphere Pathway

Mlynarski, S. N.; Schuster, C. H.; Morken, J. P., Nature 2014, 505, 386.

47

Tandem DCC one-pot Synthesis of Chiral Benzylic Alcohols

Mlynarski, S. N.; Schuster, C. H.; Morken, J. P., Nature 2014, 505, 386.

48

Tandem DCC one-pot Synthesis of:

Mlynarski, S. N.; Schuster, C. H.; Morken, J. P., Nature 2014, 505, 386.

49

Tandem DCC one-pot Synthesis of Chiral Homoallylic Alcohols

Mlynarski, S. N.; Schuster, C. H.; Morken, J. P., Nature 2014, 505, 386.

50

Synthesis of (S)-Fenpropimorph

Mlynarski, S. N.; Schuster, C. H.; Morken, J. P., Nature 2014, 505, 386.

51

Synthesis of N-Boc(S)-amphetamine

Mlynarski, S. N.; Schuster, C. H.; Morken, J. P., Nature 2014, 505, 386.

52

Next week on….

1. Introduction

a) Importance of Chirality and Enantioselectivity

b) Alkenes

c) Classical Examples of Enantioselective Reactions

d) Brief History of Diboration

2. Development of Enantioselective Diboration

a) Examples of How to Access 1,2-Diboronates

b) Optimization

3. Mechanistic Investigation

a) Kinetic, Kinetic Isotope Effect, Trapping Experiments

4. Substrate Scope

a) Aliphatic, Aryl, Chiral Substrates

b) Selectivity and Limits of Reaction

5. Sequential Diboration Cross-Coupling (DCC) Reaction

a) Suzuki Coupling Conditions,

b) One-pot Synthesis of DCC Products

6. Conclusion

53

54 Mlynarski, S. N.; Schuster, C. H.; Morken, J. P., Nature 2014, 505, 386.

Coombs, J. R.; Haeffner, F.; Kliman, L. T.; Morken, J. P. J. Am. Chem. Soc., 2013, 135, 11222

Thanks to:

Prof. Aaron Odom

Lab Mates: Amrendra, Ross, Brennan, Cody, Evan, Bailey, Arturo

Special Thanks to:

Elizabeth, Olivia, Yu-Ling, Travis, Kristin

55

Thank you!

56