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Literature Report

Reporter: Xijian Li

Supervisor: Yong Huang

Date: 2012-12-17

Mohr, J. T., Hong, A. Y. Stoltz, B. M. Nature Chemistry, 2009, 1, 359

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Enantioselective H-atom transfer

Enantioselective protonation by a chiral

Enantioselective protonation by a chiral proton donor

Enantioselective protonation in enzymatic systems

Introduction

Contents

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Brian M. Stoltz

• B.S. Indiana University of Pennsylvania 1993• M.S. Yale University (John Wood), 1996• Ph.D. Yale University (John Wood), 1997• NIH Postdoctoral Fellow Harvard University (E. J. Corey) 1998-2000

Degrees

Research Interests

Introduction

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Introduction

HOOC R2

EWG R1

H R2

EWG R1

Decarboxylation of malonates

EWG = COOR, COOH, CN, COR

Addition of NuH to ketenesR1 R2

CO

NuHNu

OR1

H R2

Conjugated additon of NuH

R1

OR2

NuHR1

OR2

H Nu

R1

OH

R3

R2R1

OR2

H R3

Tautomerisation of enols

AHR1

OTMS

R3

R2

Protonation of silyl enolates

Scheme 1: Main strategies investigated in enantioselective protonation

Enantioselective transfer of a proton presents unusual challenges —manipulating a very small atom and avoiding product racemization at a particularly labile stereocentre.

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Introduction

Important factors in achieving enantioselective protonation

1. Kinetic processes

2. Match the pKa of the proton donor and the product

3. Prevent background reaction

4. Stereochemistry of the substrate

5. Mechanistic details of enantioselective protonations

OH NPh

OLi

1

2THF, PhCH3

-78 C

OLi

OH

PhN

3

OH

42 equiv. 2, 97% e.e.0.5 equiv. 2, 83% e.e.

Figure 1: Enantioselective tautomerization of an isolated enol

Fehr, C. Angew. Chem. Int. Ed. 2007, 46, 7119

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Enantioselective H-atom transfer

Enantioselective protonation by a chiral

Enantioselective protonation by a chiral proton donor

Enantioselective protonation in enzymatic systems

Introduction

Contents

7

Enantioselective protonation in enzymatic systems

Decarboxylases and esterases have proved to be two popular classes of natural enzymes for the construction of α-stereocentres adjacent to ketones.

Esterases release latent enolates from prochiral substrates whereas decarboxylases generate enolates in situ from malonic acid derivatives

Matoishi, K., Ueda, M., Miyamoto, K., Ohta, H. J. Mol. Catal. B. 2004. 27, 161

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Enantioselective protonation in enzymatic systems

H3CO

H3C

CH2OHCO2H

H3CO

CH3

CHOH

Rhodococcus sp. KU1314Glycine/NaOH buffer

H2O61% yield

H3CO

H3C

CHOCO2H

- CO2

H3CO

H3C

CO2HH

H3CO

CH3

H

OEnantioselective

protonation O

7 8

9 10 (R)-11

Figure 3: Enzymatic oxidation/decarboxylation/protonation/oxidation cascade74% e.e.

Miyamoto, K., Hirokawa, S., Ohta, H. J. Mol. Catal. B: Enzym. 2007, 46, 14Matsumoto, K., Tsutsumi, S., Ihori, T., Ohta, H. J. Am. Chem. Soc. 1990, 112, 9614Hirata, T., Shimoda, K., Kawano, T. Tetrahedron 2000, 11, 1063

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Enantioselective protonation in enzymatic systems

Advantage of enzymatic enantioselective protonation:

1. Environmental-friendly

2. Also give high yield and high e.e.

3. Demonstrate many of the key controlling elements necessary for successful enantioselective protonation

Shortage of enzymatic enantioselective protonation: Enzymatic reactions can not provide a general solution to the synthesis of enantioenriched protonation products

1. The difficulty of enzyme modification to give the unnatural antipode of product

2. The need for buffers to help stabilize enzymes or cells

3. Substrate scope is limited due to the specificity of substrate recognition

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Approaches for non-enzymatic enantioselective protonation

1. The use of a chiral proton donor and/or the generation of a chiral proton acceptor intermediate

2. Catalytic generation of a chiral metal–enolate complex in situ

3. Coupling of a catalytic chiral proton donor to a stoichiometric achiral proton source (In this case, a specific order of thermodynamic acidity of the reaction components must be used : stoichiometric proton source > catalytic chiral protonating agent > product)

4. An accompanying balance of kinetic rates of proton transfer between all of thesecomponents must also be achieved to allow a reasonable rate of protonation through the catalysed pathway while avoiding undesired background reaction between the prochiral proton acceptor and the stoichiometric achiral proton donor.

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Enantioselective H-atom transfer

Enantioselective protonation by a chiral

Enantioselective protonation by a chiral proton donor

Enantioselective protonation in enzymatic systems

Introduction

Contents

12

Enantioselective protonation by a chiral proton donor

Kim, B. M., Kim, H., Kim, W., Im, K. Y., Park, J. K. J. Org. Chem. 2004, 69, 5104Amere, M., Lasne, M.-C., Rouden, J. Org. Lett. 2007, 9, 2621

A π–π-stacking interaction between the substrate and proton source was proposed as the chiral controlling interaction during the protonation event

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Enantioselective protonation by a chiral proton donor

N

(R)-24(5 mol)%

25PhH, 60 C(87% yield)20

NH

PO

OOO

H

NH

PO

OOO

H

21 22

NH

H

H

H

8:1 trans:cistrans-23, 94% e.e.

cis-23, 99% e.e.

OO

PO

OH

SiPh3

SiPh3(R)-24

NH

O

OHH

O

O

25

A. Rueping's quinoline reduction/protonation

Rueping, M., Theissmann, T., Raja, S., Bats, J. W. Adv. Synth. Catal. 2008, 350, 1001Yanagisawa, A., Touge, T. & Arai, T. Angew. Chem. Int. Ed. 2005, 44, 1546

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Enantioselective protonation by a chiral proton donor

Cheon, C. H., Yamamoto, H. J. Am. Chem. Soc. 2008, 130, 9246Beck, E. M., Hyde, A. M., Jacobsen, E. N. Org. Lett., 2011, 13, 4260Dai, X., Nakai, T., Romero, J. A. C., Fu, G. C. Angew. Chem. Int. Ed. 2007, 46, 4367

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Enantioselective protonation by a chiral proton donor

O

CN+

Cl CNAlkaloid derived

catalyst (10 mol%)

Toluene95-99 % yield

O

Using 48:(R,S)-45, 93% e.e., 20:1 d.r.Using 49:(S,R)-45, 96% e.e., 20:1 d.r.Using 50:(S,S)-45, 93% e.e., 20:1 d.r.

CN

CN

Cl

N

O

HO

NN

OR

OH

49, R = 9- phenanthryl

N N

N

O

HN NH

S

CF3

CF3

H

43 44

48 50

F. Deng's conjugate addition/protonation

N O

OOPhSH, 50 (1 mol%)

Toluene, r.t.N O

OO

PhS

46 4790% e.e.

G. Singh's conjugate addition/protonation

Wang, Y., Liu, X., Deng, L. J. Am. Chem. Soc. 2006, 128, 3928Rana, N. K., Singh, V. K. Org. Lett. 2011, 13, 6520

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Enantioselective H-atom transfer

Enantioselective protonation by a chiral

Enantioselective protonation by a chiral proton donor

Enantioselective protonation in enzymatic systems

Introduction

Contents

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18Reynolds, N. T., Rovis, T. J. Am. Chem. Soc. 2005, 127, 16406Yamamoto, E., Nagai, A., Hamasaki, A., Tokunaga, M. Chem. Eur. J. 2011, 26, 7178

O

OCl

Pr

Q+OH-O

Pr

+QH+

OPr

N

ON RO

H

H+

N

ON O

H

R

Figure 8: The use of PTC to generate proton accepter

or

55 58

56 57

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NHBoc

CO2t-Bu

Rh(cod)2 PF6 (3 mol%)(S)-BINAP (6.6 mol%)

PhBF3K2-methoxyphenol

toluene, 110 C(70% yield)

Ph

NHBoc

t-BuOO

RhPh

NHBocRh

t-BuOO

-hydrideelimination

Ph

N

CO2t-Bu

Boc

RhH Hydride

transfer H NBoc

RhH H NHBoc

Ph PhCO2t-Bu CO2t-Bu

A. Reaction pathway consisting of -hydride elimination, H-transfer, and protonation

59 60 61

62 63 (R)-6495% e.e.

ON

O O

CH3

OO

N NO

Ph Ph(R, R)-66 (33 mol%)

Zn(NTf2)2 (30 mol%)NMP, 4 MS, DCM, -30 C

(98% yield)

ON

O O

CH3

ZnN N

Conjugateaddition

then enolateprotonation O

N

O ON

H CH365 67 (S)-68

93% e.e.

B. Friedel-Crafts-type conjugate addition followed by enantioselective protonation

Figure 9: Conjugate addition/protonation sequences catalysed by chiral metal complexesNavarre, L., Martinez, R., Genet, J.-P., Darses, S. J. Am. Chem. Soc. 2008, 130, 6159Sibi, M. P., Coulomb, J., Stanley, L. M. Angew. Chem. Int. Ed. 2008, 47, 9913

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OO

i-Pr

NO

N N

O

Sc(OTf)3

(1S, 2R)-70(10 mol%)

3 MS, CH3CN, 0 C(88% yield)

OO

i-Pr

Sc

4electrocyclization

O

H

OSc

-H O

OSc

+HO

OH

A. Trauner's Nazarov cyclization/enantioselective protonation

69 71

72 73 (S)-7495% e.e.

Liang, G., Trauner, D. J. Am. Chem. Soc. 2004, 126, 9544Marinescu, S. C., Nishimata, T., Mohr, J. T., Stoltz, B. M. Org. Lett. 2008, 10, 1039

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Enantioselective H-atom transfer

Enantioselective protonation by a chiral

Enantioselective protonation by a chiral proton donor

Enantioselective protonation in enzymatic systems

Introduction

Contents

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Enantioselective H-atom transfer

Sibi, M. P., Patil, K. Angew. Chem. Int. Ed. 2004, 43, 1235

Mg·bis(oxazoline) complexes effectively promoted radical conjugate addition to form the enolate followed by enantioselective quenching of the radical intermediate by H-atom transfer

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Conclusion

Introduced several enantioselective enzymatic protonation reactions and it’s advantage and shortage

Introduced a lot of techniques for achieving enantioselective protonation in laboratories

The current level of mechanistic understanding in nearly all of the enantioselective protonation reactions reported to date remains relatively immature.

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