10.1002/anie.201813229
Angewandte Chemie International Edition
COMMUNICATION
MesCu (5 mol%)
Acknowledgements
(R,R)-Ph-BPE (6 mol%)
styrene (1 equiv)
Ph3SiH (2h, 0.5 equiv)
OH
Me
OH
Me
OSiPh3
R1
R1
R1
Me
R2
This
research
was
supported
by
the
Deutsche
+
toluene, 4Å MS
–20 °C
Forschungsgemeinschaft (Oe 249/14-1) and the Fonds der
Chemischen Industrie (predoctoral fellowship to J.S., 2018–
2020). X.D. thanks the China Scholarship Council for
R2
R2
(R)-6a–g
rac-6a–g
(S)-7ah–gh
a
predoctoral fellowship (2014–2018), and M.O. is indebted to the
Einstein Foundation (Berlin) for an endowed professorship.
OH
OH
Me
OH
Me
Me
iPr
BocN
TIPS
6a + 7ah
(w/ ~ 0.5 equiv SiH)
48% conversion (48 h)
(R)-OH: 48%, 89% ee
(S)-SiO: 47%, 97% ee
s = 207
TIPS
6b + 7bh
TIPS
6c + 7ch
(w/ ~ 0.5 equiv SiH)
48% conversion (48 h)
(R)-OH: 50%, 46% ee
(S)-SiO: 46%, n.d.
s = 4.6
6a
6b
6c
Conflict of interest
(w/ ~ 0.5 equiv SiH)[a]
52% conversion (68 h)
(R)-OH: 42%, 96% ee
(S)-SiO: 45%, 88% ee
s = 64
The authors declare no conflict of interest.
OH
OH
Me
OH
Me
Keywords: asymmetric catalysis • copper • dehydrogenative
Me
nBu
coupling • tertiary alcohols • silicon
TIPS
nBu
3 OTBDMS
6f + 7fh
(w/ ~ 0.5 equiv SiH)
52% conversion (48 h)
(R)-OH: 45%, 92% ee
(S)-SiO: 50%, 86% ee
s = 46
[1]
[2]
a) Y.-L. Liu, X.-T. Lin, Adv. Synth. Catal. DOI 10.1002/adsc.201801023;
b) M. Shibasaki, M. Kanai, Chem. Rev. 2008, 108, 2853–2873.
a) V. Bisai, V. K. Singh, Tetrahedron Lett. 2016, 57, 4771–4784; b) T.
Ohshima in Comprehensive Chirality, Vol. 4 (Eds.: E. M. Carreira, H.
Yamamoto), Elsevier, New York, 2012, pp. 355–377; c) B. M. Trost, A.
H. Weiss, Adv. Synth. Catal. 2009, 351, 963–983.
6d
6d + 7dh
6e
6e + 7eh
6f
(w/ ~ 0.55 equiv SiH)
53% conversion (48 h)
(R)-OH: 46%, 24% ee
(S)-SiO: 46%, n.d.
s = 1.9
(w/ ~ 0.5 equiv SiH)
52% conversion (48 h)
(R)-OH: 42%, 94% ee
(S)-SiO: 49%, 87% ee
s = 52
OH
Me
OH
Me
HO Me
[3]
[4]
For selected examples of ligand-accelerated catalysis, see: a) L. Tan,
C.-y. Chen, R. D. Tillyer, E. J. J. Grabowski, P. J. Reider, Angew.
Chem. Int. Ed. 1999, 38, 711–713; Angew. Chem. 1999, 111, 724–727;
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Ichibakase, M. Nakajima, J. Org. Chem. 2014, 79, 4817–4825.
For selected examples of metal-catalyzed alkynylations of unactivated
ketones, see: a) G. Lu, X. Li, X. Jia, W. L. Chan, A. S. C. Chan, Angew.
Chem. Int. Ed. 2003, 42, 5057–5058; Angew. Chem. 2003, 115, 5211–
5212; b) Y. Zhou, R. Wang, Z. Xu, W. Yan, L. Liu, Y. Kang, Z. Han, Org.
Lett. 2004, 6, 4147–4149; c) L. Liu, R. Wang, Y.-F. Kang, C. Chen, Z.-
Q. Xu, Y.-F. Zhou, M. Ni, H.-Q. Cai, M.-Z. Gong, J. Org. Chem. 2005,
70, 1084–1086; d) J.-i. Ito, S. Ubukata, S. Muraoka, H. Nishiyama,
Chem. Eur. J. 2016, 22, 16801–16804; e) A. M. Cook, C. Wolf, Angew.
Chem. Int. Ed. 2016, 55, 2929–2933; Angew. Chem. 2016, 128, 2982–
2986; f) Y. Zheng, Y. Tan, K. Harms, M. Marsch, R. Riedel, L. Zhang, E.
Meggers, J. Am. Chem. Soc. 2017, 139, 4322–4325.
nBu
6g + 7gh
(w/ ~ 0.5 equiv SiH)
51% conversion (48 h)
(R)-OH: 46%, 24% ee
(S)-SiO: 48%, 22% ee
s = 1.9
nBu
8 + 10h
6g
8
9
9 + 11h
(w/ ~ 0.65 equiv SiH)[b]
59% conversion (18 h)
(R,E)-OH: 36%, 79% ee
(S,E)-SiO: 51%, 54% ee
s = 7.7
(w/ ~ 0.5 equiv SiH)[b]
52% conversion (18 h)
(R)-OH: 46%, 37% ee
(S)-SiO: 50%, 33% ee
s = 2.8
Scheme 5. Kinetic resolution of dialkyl-substituted propargylic alcohols. [a]
Performed at °C. [b] Performed at room temperature. Boc tert-
butoxycarbonyl.[19,20b,21]
0
=
In summary, we disclosed the first kinetic resolution of
tertiary alcohols by means of an enantioselective silylation.
Commercially available MesCu/(R,R)-Ph-BPE is used as the
catalyst system in combination with Ph3SiH (2h) as the resolving
reagent. Under these conditions, a variety of unbiased tertiary
aryl,alkyl-substituted as well as dialkyl-substituted propargylic
alcohols have been resolved with good to excellent selectivities.
From the different substitution patterns investigated, several
trends regarding the effect on the selectivity emerge (Figure 1).
The synthetic utility of this method was further demonstrated by
a gram-scale experiment.
[5]
For enantioselective additions to ynones, see: a) S. Lou, P. N. Moquist,
S. E. Schaus, J. Am. Chem. Soc. 2006, 128, 12660–12661 (allylation;
one example); b) D. K. Friel, M. L. Snapper, A. H. Hoveyda, J. Am.
Chem. Soc. 2008, 130, 9942–9951 (with pyridyl as directing group); c)
H. Kawai, K. Tachi, E. Tokunaga, M. Shiro, N. Shibata, Org. Lett. 2010,
12, 5104–5107 (trifluoromethylation only).
[6]
[7]
[8]
For substrate-controlled strategies, see: a) M. I. Antczak, F. Cai, J. M.
Ready, Org. Lett. 2011, 13, 184–187; b) R. I. Rodríguez, E. Ramírez, F.
Yuste, R. Sánchez-Obregón, J. Alemán, J. Org. Chem. 2018, 83,
1940–1947.
a) E. Vedejs, M. Jure, Angew. Chem. Int. Ed. 2005, 44, 3974–4001;
Angew. Chem. 2005, 117, 4040–4069; b) H. B. Kagan, J. C. Fiaud in
Topics in Stereochemistry, Vol. 18 (Eds.: E. L. Eliel, S. H. Wilen), Wiley,
New York, 1988, pp. 249–330.
The field of enzymatic kinetic resolution to furnish enantioenriched
tertiary alcohols was especially advanced by Bornscheuer and co-
workers. For an authoritative review, see: a) R. Kourist, P. Domínguez
de María, U. T. Bornscheuer, ChemBioChem 2008, 9, 491–498; for
original work, see for example: b) S. Bartsch, R. Kourist, U. T.
Bornscheuer, Angew. Chem. Int. Ed. 2008, 47, 1508–1511; Angew.
Chem. 2008, 120, 1531–1534.
[9]
For selected examples of non-enzymatic kinetic resolutions furnishing
tertiary alcohols, see: a) E. R. Jarvo, C. A. Evans, G. T. Copeland, S. J.
Miller, J. Org. Chem. 2001, 66, 5522–5527; b) T. G. Driver, J. R. Harris,
K. A. Woerpel, J. Am. Chem. Soc. 2007, 129, 3836–3837; c) R.
Shintani, K. Takatsu, T. Hayashi, Org. Lett. 2008, 10, 1191–1193; d) B.
Karatas, S. Rendler, R. Fröhlich, M. Oestreich, Org. Biomol. Chem.
2008, 6, 1435–1440; e) Z. Li, V. Boyarskikh, J. H. Hansen, J.
Figure 1. Summarized substituent effects on the selectivity. EWG = electron-
withdrawing group, EDG = electron-donating group.
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