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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
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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
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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
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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
19
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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