Kinetic Resolution of Neopentylic Secondary Alcohols by Cu-H-Catalyzed Enantioselective Silylation with Hydrosilanes

Article abstract of DOI:10.1021/acs.orglett.0c03943

A nonenzymatic kinetic resolution of sterically congested alcohols having a quaternary carbon atom in the β-position is reported. The catalyst system CuCl/NaOtBu/(R,R)-Ph-BPE together with a 3,5-xylyl-substituted tertiary hydrosilane enable enantioselective silylation of the hydroxy group. Several alcohols are obtained with good to excellent selectivity factors, and there are no other known straightforward methods to access these motifs.

Full text of DOI:10.1021/acs.orglett.0c03943

pubs.acs.org/OrgLett
Letter
Kinetic Resolution of Neopentylic Secondary Alcohols by Cu−H-
Catalyzed Enantioselective Silylation with Hydrosilanes
Zaneta Papadopulu and Martin Oestreich*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c03943
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A nonenzymatic kinetic resolution of sterically
congested alcohols having a quaternary carbon atom in the β-
position is reported. The catalyst system CuCl/NaOtBu/(R,R)-Ph-
BPE together with a 3,5-xylyl-substituted tertiary hydrosilane
enable enantioselective silylation of the hydroxy group. Several
alcohols are obtained with good to excellent selectivity factors, and
there are no other known straightforward methods to access these
motifs.
ver the past ten years, nonenzymatic kinetic resolution1
(KR) of alcohols by enantioselective silylation developed
Scheme 1. Kinetic Resolution of Secondary Alcohols by
Enantioselective Cu−H-Catalyzed Dehydrogenative Si−O
Coupling
O
into a useful methodology.2 Several procedures are now
available, either relying on chlorosilanes and various chiral
nitrogen Lewis bases as catalysts3,4 or on hydrosilanes and
chiral copper complexes with (R,R)-Ph-BPE as ligand.5,6 With
regard to secondary substrates, the majority comprises benzylic
alcohols.3,5,6 There are just a few exceptions such as the KR of
α-hydroxy lactones and lactams7 by Wiskur and α-hydroxy
oxime ethers8 by us. The KR of aliphatic alcohols is far less
efficient.3c,5a For example, the Cu−H-catalyzed enantioselec-
tive silylation of benzylic secondary alcohols with nBu3SiH
using CuCl/NaOtBu/(R,R)-Ph-BPE as the catalyst system is
broadly applicable (Scheme 1, top)5a and can even be applied
in the related dynamic kinetic resolution (DKR, not shown).9
Conversely, the same setup gives an inferior result in the KR of
an alkyl-substituted secondary alcohol (s = 9.62; Scheme 1,
bottom); for comparison, the selectivity factor10 s for 1-
phenylethanol is 14.6.5a Starting from this initial situation, we
decided to explore the effect of increased steric demand of one
of the substituents, hoping that this would allow for better
discrimination of the enantiomers. More precisely, secondary
alcohols with an all-carbon-substituted quaternary carbon atom
in the β-position caught our attention (Scheme 1, bottom).
This motif can be accessed by reduction of α,α-disubstituted
(α-tertiary alkyl) ketones11 and 1,2-addition of carbon
nucleophiles to congate aldehydes,12 respectively. Aside from
a few exceptions such as a dedicated study by Wills and co-
workers,11b these reactions have largely been limited to
pinacolone and pivaldehyde as carbonyl compounds. In this
paper, we report the KR of a broad range of neopentylic
secondary alcohols by making use of our Cu−H-catalyzed
silylation strategy5,9 (Scheme 1, bottom).13
conversion was observed. We had already expected such
alcohol silylations to be slow,9 and this was further confirmed
when nBu3SiH (2a) was replaced with less hindered
Me2PhSiH (2b). Full conversion was obtained after 6 days,
Received: November 29, 2020
Starting from the above KR of an aliphatic alcohol (s = 9.62;
Scheme 1, bottom), we subjected the neopentylic alcohol 1a to
the same reaction conditions (Table 1, entry 1). No
© XXXX The Authors. Published by
American Chemical Society
https://dx.doi.org/10.1021/acs.orglett.0c03943
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
a
Table 1. Hydrosilane Screening
Scheme 2. Substrate Scope I: Screening of Various
a
Neopentylic Secondary Alcohols
b
c
c
conv
ee of 1a ee of 3a
entry
hydrosilane 2
(%)
time
(%)
(%)
s
1
2
3
4
5
nBu3SiH (2a)
Me2PhSiH (2b)
MePh2SiH (2c)
Ph3SiH (2d)
nr
52
d
62
62
20 d
6 d
24 h
24 h
6 d
51
48
4.6
17
92
10
55
1.4
11
ArMe2SiH (2e)
a
Unless otherwise noted, reactions were performed on a 0.2 mmol
b
scale and monitored by 1H NMR spectroscopy. Conversion was
determined by HPLC analysis and calculated according to conversion
= eeunreacted alcohol/(eesilyl ether + eeunreacted alcohol). Enantiomeric excesses
c
a
were determined by HPLC analysis on chiral stationary phases (after
cleavage of the silyl ether). Decomposition during purification. Ar =
See caption of Table 1 for details.
d
3,5-Me2C6H3. nr = no reaction.
with an s value of 11, reaching 41% conversion after 10 days
(not shown; see the Supporting Information for details).
The success with spirocyclic 10a prompted us to investigate
a subset of benzannulated congeners (10b−d, Scheme 3).
Three different ring sizes were probed, and six-membered 10c
and seven-membered 10d converted into the corresponding
silyl ethers 11ce and 11de with superb selectivity factors of 72
and 67, respectively.15 However, 10d was far less reactive than
10c (days vs hours). The silylation of five-membered 10b
furnished a complex reaction mixture. The only difference
between 10c and 8 (see Scheme 2) is the rigid indan-2,2-diyl
unit instead of two flexible benzyl substituents yet their
reaction outcomes are markedly different: s = 72 (12 h) vs s =
11 (6 days). The cyclic alcohol structure was in fact not
needed for an efficient KR with the indane backbone installed.
Compound 4c, a benzannulated version of rather poor
substrate 4a (see Scheme 2), underwent the KR with high
efficacy (s = 66 vs s = 10). The absolute configuration of (R)-
4c was assigned by X-ray diffraction and is in agreement with
the asymmetric induction of the CuCl/NaOtBu/(R,R)-Ph-
BPE catalyst system in the KR of other alcohols.15 With that
important structural feature, even an ethyl (as in 4d) and a
phenyl (as in 4e) group were now compatible; the s values
decreased significantly but were still decent in comparison with
previous results (cf. 3a and 3b as well as ref 5a). The
functional-group tolerance is generally excellent for this copper
catalysis,5,8,9 and we examined a few substrates derived from 4c
with an electronically and sterically modified aryl group (4f−n,
Scheme 3). Their KR yielded consistently high selectivity
factors, and the reaction time was always 20 h. Substrate 4i
with an o-methoxy group was an exception, requiring more
than one month to reach 37% conversion; the s value of 171
was very high though. No such influence was seen for 4n with
an o,o-dichloro-substituted aryl ring. Importantly, the aryl
substituent in 4 can be replaced by an ester group as in 12 (s =
27; gray box, Scheme 3). A larger ring size as in 4o was also
possible (s = 18); 4o is a benzannulated version of 4b (s = 19;
Scheme 2).
and the silyl ether 3ab and the slow-reacting enantiomer of 1a
were isolated in 51% ee and 48% ee, respectively (entry 2).
With s = 4.6, the efficiency was modest. Both MePh2SiH (2c)
and Ph3SiH (2d) did react within 24 h, but 1a/3ac
decomposed (entry 3) and 1a/3ad formed with hardly any
resolution (entry 4). In one of our early studies on catalyst-
controlled Si−O coupling,14 we had screened a broad range of
aryl-substituted hydrosilanes of types ArMe2SiH and
Ar2MeSiH. A 3,5-xylyl group as Ar had given particularly
good results, and we therefore tested ArMe2SiH (2e) with Ar =
3,5-Me2C6H3 in our model reaction. While the reaction was
again slow, the selectivity factor greatly improved (s = 11);
unreacted 1a was isolated with 92% ee along with the silyl
ether 3ae with 55% ee (entry 5).
We continued with this setup (see Table 1, entry 5) and
tested several structural motifs (Scheme 2). Ethyl instead of
methyl at the carbinol carbon atom brought about a dramatic
decrease of the reaction rate (weeks vs days), and the
selectivity factor collapsed9 (11 for 1a/3ae vs 2.7 for 1b/3be;
top). Further structural changes to methyl-substituted 1a led to
4a and 4b. Both were more reactive than 1a (hours vs days),
and the KR was better for 4b/5be and in the same range for
4a/5ae (top). To investigate the effect of more rigidity, we
subjected three representative cyclohexanol derivatives to the
standard procedure (bottom).3c,5a Two of these highly
hindered cyclic alcohols, 6 and 8, required days for full
conversion, and the enantioselection was again comparable to
that achieved with acyclic 1a and 4a,b. Spirocyclic 10a (gray
box) stood out both in terms of reactivity (hours) and
efficiency (s = 31). (R)-10a was one of the alcohols prepared
in high enantiomeric excess by asymmetric transfer hydro-
genation by Wills and co-workers,11b and the absolute
configurations of (R)-10a and (S)-11ae were assigned on
that basis. For completion, we inspected the KR of a strictly
aliphatic alcohol; 1-(adamantan-1-yl)ethan-1-ol reacted slowly
B
https://dx.doi.org/10.1021/acs.orglett.0c03943
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
a
Scheme 3. Substrate Scope II: Variations at the Indane
Motif
Scheme 4. Attempted Dynamic Kinetic Resolution
a
a
See caption of Table 1 for details. Conversion was determined by
GLC analysis.
methodology to neopentylic alcohols failed because the
racemization of sterically hindered alcohols does not work
with Ru-CNN (e.g., 10c → 11ce; Scheme 4). We cannot
generalize this for the alcohols covered in this study but
racemization is for sure greatly slowed down. We had already
made a similar observation with o,o-disubstituted benzylic
alcohols.9
In summary, this work demonstrates that the enantiose-
lective Cu−H-catalyzed silylation of alcohols for their
nonenzymatic KR can be applied to congested neopentylic
alcohols. These alcohols cannot be made easily by other
asymmetric methods,11b including Cu−H-catalyzed enantiose-
lective hydrosilylation of the corresponding ketones.17 By this,
alcohols having a quaternary carbon atom in the β-position
have become accessible with good efficiency.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03943.
General procedures, experimental details, character-
ization, and spectral data for all new compounds and
crystal data and structural refinement for compound
(R)-4c (PDF)
Accession Codes
CCDC 2042256 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Martin Oestreich − Institut für Chemie, Technische
Universität Berlin, 10623 Berlin, Germany; orcid.org/
0000-0002-1487-9218; Email: martin.oestreich@tu-
berlin.de
a
See caption of Table 1 for details.
Author
Zaneta Papadopulu − Institut für Chemie, Technische
Universität Berlin, 10623 Berlin, Germany; orcid.org/
0000-0003-3444-6820
Our laboratory recently introduced a dynamic kinetic
resolution of mainly benzylic alcohols based on the
enantioselective Cu−H-catalyzed dehydrogenative Si−O cou-
pling.9 An orthogonal combination of the chiral copper
precatalyst CuCl/NaOtBu/(R,R)-Ph-BPE and Baratta’s bifunc-
tional ruthenium pincer complex Ru-CNN16 (gray box,
Scheme 4) allowed for rapid alcohol racemization without
interfering with the resolving system. Extension of this
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03943
Notes
The authors declare no competing financial interest.
C
https://dx.doi.org/10.1021/acs.orglett.0c03943
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
2006, 128, 4940−4941. See also: (b) Iseki, K.; Mizuno, S.; Kuroki,
Y.; Kobayashi, Y. Asymmetric Allylation with Chiral Formamide
Catalysts. Tetrahedron 1999, 55, 977−988.
(13) For an enzymatic KR of 1-tert-butyl- and 1-adamantyl-
substituted ethanol derivatives by acylation, see: Hatzakis, N. S.;
Smonou, I. Asymmetric transesterification of secondary alcohols
catalyzed by feruloyl esterase from Humicola insolens. Bioorg. Chem.
2005, 33, 325−337.
ACKNOWLEDGMENTS
■
This research was supported by the Deutsche Forschungsge-
meinschaft (Oe 249/14-1). M.O. is indebted to the Einstein
Foundation Berlin for an endowed professorship. We are
grateful to Dr. Elisabeth Irran (TU Berlin) for the X-ray crystal
structure analysis.
(14) Weickgenannt, A.; Mewald, M.; Muesmann, T. W. T.;
Oestreich, M. Catalytic Asymmetric Si−O Coupling of Simple
Achiral Silanes and Chiral Donor-Functionalized Alcohols. Angew.
Chem., Int. Ed. 2010, 49, 2223−2226.
REFERENCES
■
(1) Vedejs, E.; Jure, M. Efficiency in Nonenzymatic Kinetic
Resolution. Angew. Chem., Int. Ed. 2005, 44, 3974−4001.
(2) (a) Hoveyda, A. H.; Snapper, M. L. Enantioselective Synthesis of
Silyl Ethers Through Catalytic Si−O Bond Formation. In Organo-
silicon Chemistry: Novel Approaches and Reactions; Hiyama, T.,
Oestreich, M., Eds.; Wiley-VCH: Weinheim, 2019; pp 459−493.
(b) Seliger, J.; Oestreich, M. Making the Silylation of Alcohols Chiral:
Asymmetric Protection of Hydroxy Groups. Chem. - Eur. J. 2019, 25,
9358−9365. (c) Xu, L.-W.; Chen, Y.; Lu, Y. Catalytic Silylations of
Alcohols: Turning Simple Protecting-Group Strategies into Powerful
Enantioselective Synthetic Methods. Angew. Chem., Int. Ed. 2015, 54,
9456−9466.
(15) (R)-10c was also prepared by Wills and co-workers,11b and the
CuCl/NaOtBu/(R,R)-Ph-BPE catalyst system again kinetically selects
the (S)-configured alcohol to afford (S)-11ce with (R)-10c as the
slow-reacting enantiomer.
(16) Baratta, W.; Chelucci, G.; Gladiali, S.; Siega, K.; Toniutti, M.;
Zanette, M.; Zangrando, E.; Rigo, P. Ruthenium(II) Terdentate CNN
Complexes: Superlative Catalysts for the Hydrogen-Transfer Reduc-
tion of Ketones by Reversible Insertion of a Carbonyl Group into the
Ru−H Bond. Angew. Chem., Int. Ed. 2005, 44, 6214−6219.
(17) For an unsuccessful application of enantioselective Cu−H-
catalyzed hydrosilylation of pinacolone, see: Junge, K.; Wendt, B.;
Addis, D.; Zhou, S.; Das, S.; Beller, M. Copper-Catalyzed
Enantioselective Hydrosilylation of Ketones by Using Monodentate
Binaphthophosphepine Ligands. Chem. - Eur. J. 2010, 16, 68−73.
(3) (a) Isobe, T.; Fukuda, K.; Araki, Y.; Ishikawa, T. Modified
guanidines as chiral superbases: the first example of asymmetric
silylation of secondary alcohols. Chem. Commun. 2001, 243−244.
(b) Sheppard, C. I.; Taylor, J. L.; Wiskur, S. L. Silylation-Based
Kinetic Resolution of Monofunctional Secondary Alcohols. Org. Lett.
2011, 13, 3794−3797. (c) Wang, L.; Akhani, R. K.; Wiskur, S. L.
Diastereoselective and Enantioselective Silylation of 2-Arylcyclohex-
anols. Org. Lett. 2015, 17, 2408−2411.
(4) For regiodivergent KR of 1,2-diols, see: (a) Zhao, Y.; Mitra, A.
W.; Hoveyda, A. H.; Snapper, M. L. Kinetic Resolution of 1,2-Diols
through Highly Site- and Enantioselective Catalytic Silylation. Angew.
Chem., Int. Ed. 2007, 46, 8471−8474. (b) Worthy, A. D.; Sun, X.;
Tan, K. L. Site-Selective Catalysis: Toward a Regiodivergent
Resolution of 1,2-Diols. J. Am. Chem. Soc. 2012, 134, 7321−7324.
(5) (a) Dong, X.; Weickgenannt, A.; Oestreich, M. Broad-spectrum
kinetic resolution of alcohols enabled by Cu−H-catalysed dehydro-
genative coupling with hydrosilanes. Nat. Commun. 2017, 8, 15547.
(b) Seliger, J.; Dong, X.; Oestreich, M. Kinetic Resolution of Tertiary
Propargylic Alcohols by Enantioselective Cu−H-Catalyzed Si−O
Coupling. Angew. Chem., Int. Ed. 2019, 58, 1970−1974.
(6) For yet another approach, see: Park, S. Y.; Lee, J.-W.; Song, C. E.
Parts-per-million level loading organocatalysed enantioselective
silylation of alcohols. Nat. Commun. 2015, 6, 7512.
(7) Clark, R. W.; Deaton, T. M.; Zhang, Y.; Moore, M. I.; Wiskur, S.
L. Silylation-Based Kinetic Resolution of α-Hydroxy Lactones and
Lactams. Org. Lett. 2013, 15, 6132−6135.
(8) Dong, X.; Kita, Y.; Oestreich, M. Kinetic Resolution of α-
Hydroxy-Substituted Oxime Ethers by Enantioselective Cu−H-
Catalyzed Si−O Coupling. Angew. Chem., Int. Ed. 2018, 57, 10728−
10731.
(9) Seliger, J.; Oestreich, M. Dynamic Kinetic Resolution of
Alcohols by Enantioselective Silylation Enabled by Two Orthogonal
Transition-Metal Catalysts. Angew. Chem., Int. Ed. 2021, 60, 247−251.
(10) s = ln[(1 − C)(1 − ee)]/ln[1 − C)(1 + ee)] with C =
conversion/100 and ee = eeunreacted alcohol/100. Kagan, H. B.; Fiaud, J.
C. Kinetic Resolution. In Topics in Stereochemistry; Eliel, E. L.; Wilen,
S. H., Eds.; Wiley: New York, 1998; Vol. 18, pp 249−330.
(11) (a) Ohkuma, T.; Sandoval, C. A.; Srinivasan, R.; Lin, Q.; Wei,
Y.; Muniz, K.; Noyori, R. Asymmetric Hydrogenation of tert-Alkyl
̃
Ketones. J. Am. Chem. Soc. 2005, 127, 8288−8289. (b) Soni, R.;
Collinson, J.-M.; Clarkson, G. C.; Wills, M. An Unexpected Directing
Effect in the Asymmetric Transfer Hydrogenation of α,α-Disub-
stituted Ketones. Org. Lett. 2011, 13, 4304−4307. (c) Yamamura, T.;
Nakatsuka, H.; Tanaka, S.; Kitamura, M. Asymmetric Hydrogenation
of tert-Alkyl Ketones: DMSO Effect in Unification of Stereoisomeric
Ruthenium Complexes. Angew. Chem., Int. Ed. 2013, 52, 9313−9315.
(12) (a) Cozzi, P. G.; Kotrusz, P. Highly Enantioselective Addition
of Me2Zn to Aldehydes Catalyzed by ClCr(Salen). J. Am. Chem. Soc.
D
https://dx.doi.org/10.1021/acs.orglett.0c03943
Org. Lett. XXXX, XXX, XXX−XXX