Enantioselective Nickel-Catalyzed anti-Arylmetallative Cyclizations onto Acyclic Ketones

Article abstract of DOI:10.1002/chem.202100143

Domino reactions involving nickel-catalyzed additions of (hetero)arylboronic acids to alkynes, followed by cyclization of the alkenylnickel intermediates onto tethered acyclic ketones to give chiral tertiary-alcohol-containing products in high enantioselectivities, are described. The reversible E/Z isomerization of the alkenylnickel intermediates enables overall anti-arylmetallative cyclization to occur. The ring system of the products are substructures of certain diarylindolizidine alkaloids.

Full text of DOI:10.1002/chem.202100143

Communication
doi.org/10.1002/chem.202100143
Chemistry—A European Journal
&
Catalysis
Enantioselective Nickel-Catalyzed anti-Arylmetallative Cyclizations
onto Acyclic Ketones
Harley Green,[a, b] Stephen P. Argent,[b] and Hon Wai Lam*[a, b]
often enables unique transformations not available to other
Abstract: Domino reactions involving nickel-catalyzed ad-
metal catalysts.
ditions of (hetero)arylboronic acids to alkynes, followed by
Our first contribution to this field included a study of enan-
cyclization of the alkenylnickel intermediates onto teth-
tioselective nickel-catalyzed desymmetrizations of cyclic 1,3-di-
ered acyclic ketones to give chiral tertiary-alcohol-contain-
ketones, which give fused bicycles in high diastereo- and enan-
ing products in high enantioselectivities, are described.
tioselectivities (Scheme 1A).[3a] Although effective, the ability to
The reversible E/Z isomerization of the alkenylnickel inter-
use acyclic ketones in non-desymmetrizing cyclizations would
mediates enables overall anti-arylmetallative cyclization to
also be valuable to significantly broaden the substrate scope
occur. The ring system of the products are substructures
and provide simpler, non-fused products. However, acyclic ke-
of certain diarylindolizidine alkaloids.
tones are potentially less reactive than cyclic 1,3-diketones be-
cause of their greater conformational flexibility, and because
they lack the activation from the second ketone through its
Stereogenic cyclic tertiary alcohols are important structural
units that feature prominently in biologically active natural
products and therapeutic compounds. Accordingly, new meth-
ods for the enantioselective construction of these units pro-
vide valuable tools for target synthesis. Of the strategies avail-
able, the catalytic asymmetric addition of carbon nucleophiles
to ketones ranks highly in directness, versatility, and overall
synthetic efficiency.[1] One subset of these reactions are metal-
catalyzed domino sequences initiated by the addition of an ar-
ylboron reagent to an alkyne, followed by enantioselective cyc-
lization of the resulting alkenylmetal species onto a tethered
ketone, which are applicable to the synthesis of diverse carbo-
and heterocycles.[2] Recently, nickel-catalyzed variants of these
reactions have been developed in which reversible E/Z isomeri-
zation of the alkenylnickel intermediates is essential for cycliza-
tion.[3] Application of this general method to achiral products
has also been reported,[4] and other related nickel-catalyzed
processes have also appeared.[5–7] In addition to nickel being
much less expensive than comparable rhodium- or palladium-
catalyzed reactions,[2] the diverse reactivity of nickel catalysis[5]
electron-withdrawing effect as well as the electronic repulsion
caused by having aligned dipoles. Two individual examples of
non-asymmetric nickel-catalyzed arylative cyclizations onto
acyclic ketones have been reported recently,[6d] but to our
knowledge, corresponding enantioselective processes have yet
to be described.
Herein, we describe the successful use of acyclic dialkyl and
alkyl-aryl ketones in these reactions in the enantioselective
preparation of aza- and carbocyclic tertiary alcohols
[a] H. Green, Prof. H. W. Lam
The GlaxoSmithKline Carbon Neutral Laboratories for
Sustainable Chemistry, University of Nottingham
Jubilee Campus, Triumph Road, Nottingham, NG7 2TU (UK)
E-mail: hon.lam@nottingham.ac.uk
Homepage: http://www.nottingham.ac.uk/~pczhl/
[b] H. Green, Dr. S. P. Argent, Prof. H. W. Lam
School of Chemistry, University of Nottingham
University Park, Nottingham, NG7 2RD (UK)
Supporting information and the ORCID identification numbers for the
authors of this article can be found under:
https://doi.org/10.1002/chem.202100143.
ꢀ 2021 The Authors. Published by Wiley-VCH GmbH. This is an open access
article under the terms of the Creative Commons Attribution License, which
permits use, distribution and reproduction in any medium, provided the
original work is properly cited.
Scheme 1. Enantioselective nickel-catalyzed arylative cyclizations onto ke-
tones.
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Chemistry—A European Journal
(Scheme 1B). Most of the products contain the 4,5-diaryl-
1,2,3,6-tetrahydropyridine ring system, which appears in indoli-
zidine natural products such as (À)-phyllosteminine,[8] (À)-sep-
ticine,[9] and (À)-fistulopsine A[10] (Scheme 1C).
up to 99% ee.[11] Small quantities of minor arylative cyclization
products 3, resulting from initial phenylnickelation of the
alkyne with the regioselectivity opposite to that required for
the formation of the major products 2, were also observed by
1H NMR spectroscopy, but with the exception of the reaction
producing 2k and 3k, these were not isolated. A range of aro-
matic ketones are tolerated in these reactions, with substrates
containing phenyl (2a), 4-chlorophenyl (2b), (3-trifluorometh-
yl)phenyl (2c), or 2-methylphenyl ketones (2d) readily under-
going arylative cyclization. Simple dialkyl ketones are also com-
petent electrophiles, with ketones containing methyl (2e, 2 f,
2i, and 2j), ethyl (2k), isopropyl (2g), or methyl propanoate
(2h) groups reacting successfully. Regarding the alkynyl sub-
stituent, the process is tolerant of phenyl (2a-2h), (4-
carbomethoxy)phenyl (2i), and 3-methoxyphenyl groups (2j).
A substrate with a vinyl group on the alkyne also reacted
smoothly, but the enantiomeric excess of the resulting product
2k (45% ee) was lower than in the other cases. Replacing the
This investigation began with the reaction of PhB(OH)2 with
acyclic substrates 1, which contain an alkyne tethered to a
ketone through a sulfonamide (Table 1). Chiral phosphine-oxa-
zoline (PHOX) ligands have proven to be excellent ligands in
related studies[3] and we found (S)-tBu-PHOX (L1) to be highly
effective in these reactions. Heating a mixture of the substrate
1 and PhB(OH)2 (2.0 equiv) in the presence of 10 mol% each of
Ni(OAc)2·4H2O and L1 in TFE (2,2,2-trifluoroethanol) at 60 or
808C for 24 h provided azacycles 2a-2k in 44–90% yield and
Table 1. Scope of alkynyl-tethered ketones.[a]
para-toluenesulfonamide with
a
4-nitrophenylsulfonamide
group is also possible (2 f), which has implications for subse-
quent product manipulation because 4-nitrophenylsulfonyl
groups are more readily deprotected than tosyl groups.
Next, different boronic acids were investigated in reactions
with substrate 1 f, and we were pleased to observe that aryla-
tive cyclization products 2l-2p were obtained in up to 79%
yield and uniformly high enantioselectivities (98% to >99%
ee, Table 2). Various substituted phenylboronic acids are com-
patible with this process including, notably, 3-hydroxyphenyl-
boronic acid (2m). 2-Naphthylboronic acid (2o) and 3-thienyl-
boronic acid (2p) also readily underwent the reaction.
Table 2. Scope of boronic acids.[a]
[a] Reactions were conducted using 0.30 mmol of 1 in TFE (3 mL). Yields
are of isolated products. Values in parentheses refer to the ratio of 2:3 as
1
determined by H NMR analysis of the crude reactions. Unless stated oth-
[a] Reactions were conducted using 0.30 mmol of 1 f in TFE (3 mL). Yields
are of isolated products. Values in parentheses refer to the ratio of 2:3 as
determined by H NMR analysis of the crude reactions. Unless stated oth-
erwise, the minor isomers 3 were not evident in the isolated products.
Enantiomeric excesses were determined by HPLC analysis on a chiral sta-
tionary phase.
erwise, the minor isomers 3 were not evident in the isolated products.
Enantiomeric excesses were determined by HPLC analysis on a chiral sta-
tionary phase. [b] At 808C. [c] At 608C. [d] Product 2k was obtained as an
inseparable 12:1 mixture together with the minor product 3k in 90%
combined yield.
1
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Further experiments to explore the scope of this process in
the reactions of various other substrates with PhB(OH)2 are
shown in Schemes 2–6. Changing the alkynyl substituent to a
chloride was only moderately successful; substrate 1l reacted
to give chloroalkene-containing tetrahydropyridine 2q in 12%
yield and 71% ee, with the remainder of the material being
predominantly unreacted 1l (Scheme 2). Next, the preparation
of carbocyclic products was attempted by changing the sulfon-
amide connecting the alkyne and the ketone to a malonyl
group. Interestingly, the reaction of substrate 4 did give the
six-membered product 5 in 25% yield and 84% ee, but the cy-
clopent-2-enone 6a resulting from cyclization of the intermedi-
ate alkenylnickel species onto one of the ester groups was also
obtained in 14% yield[12] and 85% ee (Scheme 3). The enantio-
selective formation of cyclopent-2-enones in this manner was
described by our group previously,[3c] and in this case, it ap-
pears that despite the lower electrophilicity of the methyl
esters in 4 compared with the phenyl ketone, the kinetic pref-
erence to form a five-membered ring over a six-membered
ring makes the formation of 6a competitive with 5. An at-
tempt to prepare a five-membered cycloalkanol by the reac-
tion of PhB(OH)2 with substrate 7 was unsuccessful, and gave a
complex mixture of unidentified products (Scheme 4). Howev-
er, it should be noted that the formation of five-membered
rings by anti-carbometallative cyclizations onto cyclic 1,3-dike-
tones was successful in our previous work (see Scheme 1A).[3a]
Attempts to form seven-membered ring products are shown
in Schemes 5 and 6. Substrate 8 reacted with PhB(OH)2 to give
cyclopent-2-enone 6b in 55% yield and 19% ee[13] but no
product resulting from cyclization onto the ketone was ob-
served (Scheme 5). In addition, the reaction of substrate 9 with
PhB(OH)2 led to the trisubstituted alkene (Z)-10 resulting from
alkyne hydroarylation as the only isolable product in 34% yield
(Scheme 6). The identity of the remainder of the material in
this reaction was not clear; although this did not appear to
contain an appreciable quantity of the corresponding E-isomer
of 10, we cannot rule out its presence resulting from E/Z iso-
merization of the alkenylnickel intermediate.
In summary, we have described enantioselective nickel-cata-
lyzed anti-arylmetallative cyclizations of (hetero)arylboronic
acids with substrates containing an alkyne tethered to an acy-
clic ketone, which proceed to give chiral tertiary alcohols with
high enantioselectivities in most cases (often ꢀ99% ee). Com-
pared with a previous study,[3a] this work demonstrates a sub-
stantial increase in scope of ketones that can be used as elec-
trophiles. The products are 4,5-diaryl-1,2,3,6-tetrahydropyri-
dines, a ring system that is seen in certain indolizidine alka-
loids. The formation of carbocyclic products is also possible.[14]
Scheme 5. Attempted formation of a seven-membered carbocycle.
Scheme 2. Reaction of chloroalkyne 1l.
Scheme 6. Attempted formation of a seven-membered azacycle.
Acknowledgements
This work was supported by the Engineering and Physical Sci-
ences Research Council and AstraZeneca [Industrial CASE Stu-
dentship, grant number EP/S513854/1]; the University of Not-
tingham; and GlaxoSmithKline.
Scheme 3. Formation of carbocyclic products 5 and 6a.
Conflict of interest
The authors declare no conflict of interest.
Keywords: asymmetric catalysis · cyclization · isomerization ·
ketones · nickel
Scheme 4. Attempted reaction of substrate 7.
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Manuscript received: January 13, 2021
Accepted manuscript online: February 3, 2021
Balasubramanian, M. Sridhar Reddy, J. Org. Chem. 2018, 83, 15361– Version of record online: March 5, 2021
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