Copper(I)-Catalyzed Enantioselective Addition of Enynes to Ketones

Article abstract of DOI:10.1021/jacs.7b01254

A copper(I)-catalyzed enantioselective addition of enynes to ketones was developed. The method allows facile construction of enantiomerically enriched tertiary alcohols using skipped enynes as stable hydrocarbon pronucleophiles. The combination of a soft

Full text of DOI:10.1021/jacs.7b01254

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Communication
Copper(I)-Catalyzed Enantioselective Addition of Enynes to Ketones
Xiao-Feng Wei, Xiao-Wei Xie, Yohei Shimizu, and Motomu Kanai
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b01254 • Publication Date (Web): 20 Mar 2017
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Copper(I)-Catalyzed Enantioselective Addition of Enynes to Ketones
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Xiao-Feng Wei,† Xiao-Wei Xie,† Yohei Shimizu,*,† Motomu Kanai*,†,§
†Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
§ERATO, Japan Science Technology Agency, Kanai Life Science Catalysis Project, Hongo, Bunkyo-ku, Tokyo 113-0033,
Japan
Supporting Information Placeholder
activated ketones has been developed,7 and asymmetric addition
ABSTRACT: A copper(I)-catalyzed enantioselective addition of
enynes to ketones was developed. The method allows facile con-
of C(sp3)-nucleophiles has remained unexplored. Herein we report
a copper-catalyzed asymmetric addition of enynes to ketones
under proton transfer conditions (Scheme 1d). The reaction does
not require stoichiometric amounts of bases and additives, and
proceeds with good functional group tolerance.
struction of enantiomerically-enriched tertiary alcohols using
skipped enynes as stable hydrocarbon pronucleophiles. The com-
bination of a soft copper(I)-conjugated Brønsted base catalyst
with a chiral diphosphine ligand, (S,S)-Ph-BPE, enabled chemose-
lective deprotonation of the skipped enynes in the presence of
ketones bearing intrinsically more acidic -protons. The catalyti-
cally-generated chiral allylcopper species enantio-, diastereo-,
regio-, and chemo-selectively reacted with ketones, thereby
demonstrating excellent substrate generality with functional group
tolerance. The skipped enyne moieties of the pronucleophiles
were exclusively converted to cis-conjugated enynes, which will
eventually allow for further versatile transformations.
Scheme 1. Catalytic Asymmetric Coupling of Hydrocarbons
with Ketones.
Catalytic asymmetric nucleophilic addition of hydrocarbons to
ketones is a fundamentally important transformation, producing
enantiomerically-enriched tertiary alcohols, which are a frequent-
ly encountered structural motif in biologically active natural
products and pharmaceuticals.1 The general requirement of pre-
formed reactive organometallic reagents along with the generation
of stoichiometric amounts of metal salts waste, however, often
limit the overall synthetic efficiency and functional group toler-
ance. Transition metal-catalyzed asymmetric reductive coupling
of stable hydrocarbons with ketones has led to considerable effort
to override the limitations of preformed organometallic reagents.
The pioneering work of Jamison disclosed nickel-catalyzed
asymmetric alkenylation of ketones using BEt3 as a terminal re-
ductant, which circumvents the prior preparation of reactive or-
ganometallic reagents (Scheme 1a).2 Lam realized a copper-
catalyzed asymmetric addition of C(sp3)-nucleophiles derived
from alkenylazaarenes using PhSiH3 as a reductant (Scheme 1b).3
Related copper catalysis was further applied to conjugated enyne
pronucleophiles by Buchwald for asymmetric propargylation of
ketones.4 A more atom-economical hydrogenative approach using
a rhodium or iridium catalyst was reported by Krische (Scheme
1c),5 although the approach is limited to activated ketones (such
as -keto esters) or heteroaromatic ketones.
To catalytically generate reactive organocopper species via
deprotonation of hydrocarbons, we first evaluated whether a soft-
soft interaction between copper(I) catalyst and C-C multiple
bonds could acidify adjacent C(sp3)-H protons.8,9 Thus, skipped
enynes were selected as pronucleophiles to maximize the interac-
tion with the copper(I) catalyst, where a C-C double bond as well
as a triple bond can coordinate to the copper(I) catalyst (Scheme
1d: A). Allylcopper species B generated through deprotonation
would attack ketones via six-membered transition state C.10 The
A redox-neutral asymmetric coupling reaction between hydro-
carbon pronucleophiles and ketones under proton transfer condi-
tions is an ideal approach that does not require stoichiometric
amounts of bases and additives. Difficulties in deprotonating hy-
drocarbons to generate organometallic reagents, however, have
hampered the development of such reactions.6 Only a combination
of relatively acidic terminal alkynes (C(sp)-pronucleophiles) and
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products, conjugated enynes, are an important structural motif due
reaction mixture,14 revealed that only (S,S)-Ph-BPE (L4) exhibit-
to their synthetic versatility and prevalence in biologically rele-
vant molecules.11 Previously reported methods using skipped
enynes as pronucleophiles in organic synthesis, however, required
harsh conditions. Medlik utilized a stoichiometric amount of
MeLi for selective monometalation of skipped enynes followed
by alkylation at the methylene position.12 Later, Yamaguchi de-
veloped a GaCl3-promoted ethynylation reaction of skipped
enynes using silylchloroacetylenes as electrophiles.13 Although
ethynylation can proceed with a catalytic amount of GaCl3, the
high temperature (150 oC) required in the presence of a strong
Lewis acid sharply limits the functional group tolerance.
ed moderate reactivity and excellent enantioselectivity and
trans/cis-selectivity (entry 5). Neither a possible regio-isomer via
internal addition nor the trans-isomer was observed. Use of
AgClO4, instead of CuClO4(MeCN)4, led to lower reactivity and
enantioselectivity (entry 6). While other copper(I) sources, such
as CuCl (entry 7) and CuOAc (entry 8), produced only a trace
amount of the product, mesitylcopper (MesCu) without additional
base was identified to be the optimal choice (entry 9). Decreasing
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the temperature to -30 C further improved the enantioselectivity
to 97% ee (entry 10) without a significant loss of catalyst activity.
The catalyst loading could be reduced to 5 mol% and the product
was obtained still in high yield with comparable enantioselectivity
(entry 11).
Table 1. Optimization of Copper(I)-Catalyzed Asymmetric
Addition of Enyne to Ketone.a
Having established the optimal conditions, we next examined
the substrate scope (Table 2). With 1a as a pronucleophile, ketone
electrophiles were evaluated first (2a-2r). Products were obtained
in high yield and with excellent enantioselectivity for aryl ketones
containing electron-donating groups or halogen substituents at the
para position (3ab, 3ac, and 3ad). Substrates with a substitution
at the ortho or meta position were less reactive than other aryl
ketones. Using Mg(OiPr)2 as a cocatalyst,15 however, 3ae and 3af
were produced in good yield with excellent enantioselectivity. A
ketone with a bulky naphthyl group was also applicable (3ag:
74% yield, 88% ee). Additionally, heteroaryl ketones, which po-
tentially inhibit the reaction by coordinating to the copper catalyst,
were competent (3ah and 3ai). On the other hand, a ketone with a
strong electron-withdrawing group, p-nitroacetophenone, was
totally unreactive probably due to great acidity of the α-protons of
the ketone, hampering deprotonation of 1a.16
Enones (2j and 2k) also served as appropriate electrophiles:
potential byproducts derived from 1,4-addition of the allylcopper
nucleophile to enones were not detected in either case. Moreover,
an aliphatic ketone (2l) was applicable, resulting in satisfactory
yield, albeit with moderate enantioselectivity (3al). The reaction
was effective not only for methyl ketones but also for longer chain
ketones, in which it is more difficult to differentiate the steric
factors between the two substituents of the carbonyl group. Pro-
piophenone (2m), cyclic α-tetralone (2n) and 1-benzosuberone
(2o) underwent the asymmetric carbonyl addition with high yield
and satisfactory enantioselectivity. Moreover, ketones bearing
functional groups were also competent. A siloxy group (2p) and
an ester group (2q) were unaffected under the reaction conditions.
It is also noteworthy that a substrate bearing a protic NH func-
tional group (2r) produced chiral tertiary alcohols with high enan-
tioselectivity.17
We then examined the scope of skipped enyne pronucleo-
philes. In addition to the phenyl-substituted enyne (1a), the termi-
nal substituents of enynes can cover a p-nitrophenyl group (1b),
an indole moiety (1c), an aliphatic substituent (1d), a silicon sub-
stituent (1e), and a conjugated diyne (1f), which showed broad
adaptability for facile construction of an array of compounds con-
taining a variety of conjugated enyne moieties. The protic func-
tional groups on the pronucleophile side were also amenable to
the reaction, affording the products with satisfactory enantioselec-
tivity (3ga and 3ha).
aGeneral reaction conditions: 1a (0.15 mmol), 2a (0.1 mmol),
MesCu (0.01 mmol), and ligand (0.01 mmol) were reacted in THF
o
1
(200 µL) at -20 C for 4 h. Yields were determined by H NMR
analysis of the crude mixture using 1,3,5-trimethylbenzene as an
internal standard. bWithout KOtBu. c-30 oC. d5 mol% catalyst
loading. eReaction time was 6 h.
The conjugated enyne-containing tertiary alcohol products of-
fer multiple possibilities for further transformations.18,19 Repre-
sentative examples are shown in Scheme 2. Hydrogenation of the
enyne moiety of 3ar produced 4, which is difficult to access in an
enantiomerically enriched form by other methods, in 91% yield.
The conjugated enyne moiety could be regio- and stereo-
selectively transformed to the cis-diene moiety under palladium-
catalyzed hydrosilylation conditions to give 5 in high yield.20
These transformations proceeded without any epimerization.
Based on the above-mentioned working hypothesis, we initiat-
ed our investigation using acetophenone (2a) and 1-phenyl-4-
penten-1-yne (1a; 1.5 equiv) as substrates (Table 1). The use of 10
mol% KOtBu in the absence of a copper(I) catalyst was complete-
ly ineffective (entry 1). Examination of a variety of chiral ligands
using CuClO4(MeCN)4 as a copper source in combination with
KOtBu (10 mol%), generating chiral CuOtBu complexes in the
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Table 2. Substrate Scope of Copper(I)-Catalyzed Asymmetric Addition of Conjugated Enynes to Ketones.a
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aGeneral reaction conditions: 1a (0.15 mmol), 2a (0.1 mmol), MesCu (0.01 mmol), and (S,S)-Ph-BPE (0.01 mmol) were reacted in THF
(200 µL) at -30 oC. b-45 oC. c0.2 equiv of Mg(OiPr)2 was added. dReaction time was 12 h. e0.5 equiv of Cs2CO3 was added. f-40 oC. g-10 oC.
j
h0.4 equiv of Mg(OiPr)2 was added. i500 µL of THF was used as solvent. 20 mol% of MesCu/(S,S)-Ph-BPE was used.
In summary, we developed the first catalytic enantioselective
C-C bond-forming reaction via in situ generation of nucleophilic
organometallic species through deprotonation of the non-acidic
C(sp3)-H bond of hydrocarbons without adjacent electron-
withdrawing groups.21 The catalytically generated chiral al-
lylcopper(I) species exhibited high nucleophilicity, enantioselec-
tivity, and functional group-tolerance even in the presence of
protic functional groups. The products containing unique conju-
gated cis-enyne moieties22 serve as versatile building blocks in
organic synthesis. Studies toward switching the cis/trans stereo-
selectivity and regio-selectivity of this method to further diversify
the product structures are on-going in our laboratory.
Scheme 2. Transformation of the Products.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
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Since 1a was recovered without isomerization in 95% yield after the reac-
tion, deprotonation of 1a was not likely to proceed when p-
nitroacetophenone was present.
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Experimental details and characterization data (PDF)
AUTHOR INFORMATION
Corresponding Author
y-shimizu@mol.f.u-tokyo.ac.jp
kanai@mol.f.u-tokyo.ac.jp
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Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported in part by ERATO from JST (MK) and
Grant-in-Aid for Scientific Research (C) from JSPS (YS).
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