Enantioselective Synthesis of Chiral Cyclopent-2-enones by Nickel-Catalyzed Desymmetrization of Malonate Esters

Article abstract of DOI:10.1002/anie.201805578

The enantioselective synthesis of highly functionalized chiral cyclopent-2-enones by the reaction of alkynyl malonate esters with arylboronic acids is described. These desymmetrizing arylative cyclizations are catalyzed by a chiral phosphinooxazoline/nickel complex, and cyclization is enabled by the reversible E/Z isomerization of alkenylnickel species. The general methodology is also applicable to the synthesis of 1,6-dihydropyridin-3(2H)-ones.

Full text of DOI:10.1002/anie.201805578

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Accepted Article
Title: Enantioselective Synthesis of Chiral Cyclopent-2-enones by
Nickel-Catalyzed Desymmetrization of Malonate Esters
Authors: Somnath Narayan Karad, Heena Panchal, Christopher
Clarke, William Lewis, and Hon Wai Lam
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201805578
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10.1002/anie.201805578
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Enantioselective Synthesis of Chiral Cyclopent-2-enones by
Nickel-Catalyzed Desymmetrization of Malonate Esters
Somnath Narayan Karad, Heena Panchal, Christopher Clarke, William Lewis, and Hon Wai Lam*
Abstract: The enantioselective synthesis of highly functionalized
chiral cyclopent-2-enones by the reaction of alkynyl malonate esters
with arylboronic acids is described. These desymmetrizing arylative
cyclizations are catalyzed by a chiral phosphinooxazoline–nickel
complex, and cyclization is enabled by the reversible E/Z
isomerization of alkenylnickel species. The general methodology is
also applicable to the synthesis of 1,6-dihydropyridin-3(2H)-ones.
Chiral cyclopent-2-enones are versatile building blocks for
synthesis[1] and are present in many biologically active natural
products[1] such as (+)-achalensolide,[ 2 ] phorbol,[ 3 ] and (–)-
kjellmanianone[4] (Figure 1). In view of their broad significance,
various methods have been developed for the de novo
construction of enantiomerically enriched chiral cyclopent-2-
enones,[1, 5 – 7 ] such as Pauson-Khand reactions,[5] Nazarov
cyclizations,[6] and several other approaches.[7] However, given
the wide structural diversity of chiral cyclopent-2-enones in
target compounds, the development of new strategies to these
structures continues to be highly valuable.
Scheme 1. Proposed synthesis of chiral cyclopent-2-enones.
well as in the combretocyclopentenones 5[12b] and related
compounds,[12c] which exhibit antitumor activity. Moreover, there
are few asymmetric methods for the de novo construction of
cyclopent-2-enones with a quaternary stereocenter at the 5-
position (as in 3).[5k,6g] Although our previous work on
enantioselective nickel-catalyzed arylative cyclizations of alkynyl
electrophiles showed that ketones[8a] and activated alkenes[8a,b]
are competent reaction partners for alkenylnickel species, the
ability of less electrophilic esters to undergo analogous
cyclizations was less certain. Herein, we report the successful
implementation of this strategy. Not only can this methodology
produce highly functionalized, enantiomerically enriched chiral
cyclopent-2-enones, 1,6-dihydropyridin-3(2H)-ones are also
accessible.
Figure 1. Natural products containing cyclopent-2-enones.
We envisaged that chiral cyclopent-2-enones might be
prepared by the enantioselective nickel-catalyzed reaction of
alkynyl malonate esters 1 with arylboronic acids (Scheme 1).
Specifically, nickel-catalyzed syn-addition of an arylboronic acid
to the alkyne of 1 would give alkenylnickel species (Z)-2, which
possesses the incorrect stereochemistry for cyclization onto one
of the esters. However, reversible E/Z isomerization[8,9] of (Z)-2
would give alkenylnickel species (E)-2, which could now attack
an ester in an enantioselective desymmetrization[10] to give 2,3-
diaryl cyclopent-2-enones 3.[11] The 2,3-diaryl cyclopent-2-enone
scaffold is present in the highly potent COX-2 inhibitor 4,[12a] as
Table 1. Evaluation of reaction conditions[a]
[]
Dr. S. N. Karad, H. Panchal, C. Clarke, Prof. H. W. Lam
The GlaxoSmithKline Carbon Neutral Laboratories for Sustainable
Chemistry, University of Nottingham, Jubilee Campus, Triumph
Road, Nottingham, NG7 2TU (UK)
Entry
Ligand
L1
Temp (°C)
NMR yield [%][b]
ee [%][c]
91
1
2
3
4
5
6
100
80
80
80
80
80
98
99
94
84
49
61
L1
94
E-mail: hon.lam@nottingham.ac.uk
Homepage: http://www.nottingham.ac.uk/~pczhl/
L2
–81[d]
–94[d]
88
L3
Dr. S. N. Karad, H. Panchal, C. Clarke, Dr. W. Lewis, Prof. H. W.
Lam
L4
L5
–78[d]
School of Chemistry, University of Nottingham, University Park,
Nottingham, NG7 2RD (UK)
[a] Reactions were conducted with 0.05 mmol of 1a in TFE (0.5 mL).
[b] Determined by 1H NMR analysis using 1,4-dimethoxybenzene as an
internal standard. [c] Determined by HPLC analysis on a chiral stationary
phase. [d] These reactions gave ent-3aa as the major enantiomer.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
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Our initial experiments revealed that substrates 1 containing
the substituent at the 2-position of substrates 1 can be altered to
a phenyl group (3ba), mono- and disubstituted benzenes with
electron-donating or electron-withdrawing substiutents (3ca–3ga,
3ka, and 3la), and a 2-naphthyl group (3ha). Ethoxy (3ma),
benzyloxy (3na), 3-thienylmethoxy (3oa), and anilino groups
(3pa) at this position are also tolerated. The reaction is
compatible with various other (hetero)aryl groups at the alkyne,
such as 4-methoxyphenyl (3ia), 3-methylphenyl (3ja), 4-
chlorophenyl (3ka), and 2-thienyl (3la). In a few cases, reaction
at 100 °C (3ca, 3ka, and 3la) or use of a 20 mol% catalyst
loading (3ma and 3oa) were required for complete consumption
of the starting material.
ethyl esters are insufficiently reactive under
a range of
conditions that are effective in our nickel-catalyzed anti-
carbometallative cyclizations described previously.[8] However,
the more electrophilic bis(2,2,2-trifluoroethyl) malonate 1a
reacted successfully with PhB(OH)2 (2.0 equiv) in the presence
of 10 mol% each of Ni(OAc)2·4H2O and various chiral P,N-
ligands L1–L5 in 2,2,2-trifluoroethanol (TFE) to give cyclopent-2-
enone 3aa (Table 1). At 100 °C, (R)-Ph-PHOX (L1) gave 3aa in
98% yield (by 1H NMR analysis) and 91% ee (entry 1).[ 13 ]
Reducing the temperature to 80 °C improved the
enantioselectivity to 94% ee with no loss of yield (entry 2). Other
phosphinooxazolines L2–L5 are effective at 80 °C (entries 3–5),
but with the exception of L3 (entry 4), the yields and
enantioselectivities are appreciably lower than with L1.
The scope of this process with respect to the alkynyl
bis(2,2,2-trifluoroethyl) malonate was then explored using L1 as
the chiral ligand in reactions with PhB(OH)2, which gave
cyclopent-2-enones 3aa–3pa in 46–98% yield and 77–94% ee
(Scheme 2). As well as a 2-thienyl group (3aa, 3ia, and 3ja),
The process is not limited to aryl groups at the alkyne, as
shown by the reaction of 1,3-enyne 6 to give cyclopent-2-enone
7 in 76% yield and 80% ee [Eq. (1)]. (R)-Ph-PHOX (L1) is less
effective for substrates with alkyl groups at the 2-position. For
Scheme 2. Scope of the alkynyl bis(2,2,2-trifluoroethyl) malonate. Reactions
were conducted with 0.30 mmol of 1a–1o in TFE (3 mL). Yields are of isolated
products. Enantiomeric excesses were determined by HPLC analysis on a
chiral stationary phase. [a] Conducted at 100 °C. [b] Conducted with 20 mol%
each of Ni(OAc)2·4H2O and L1.
Scheme 3. Scope of the boronic acid. Reactions were conducted with 0.30
mmol of 1a, 1c, 1i or 1j in TFE (3 mL). Yields are of isolated products.
Enantiomeric excesses were determined by HPLC analysis on
stationary phase. [a] Conducted at 100 °C. [b] Conducted at 120 °C.
a chiral
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example, the cyclization of substrates 1p and 1q (see [Eq. (2)
and (3) for the structures) gave cyclopent-2-enones in 29% ee
and 0% ee, respectively, with L1 as the ligand. However,
somewhat improved results were obtained with (S)-t-Bu-
NeoPHOX (L5),14 which gave ent-3qa and ent-3ra in 59% ee
and 54% ee, respectively [Eq. (2) and (3)].
The reactions of a range of (hetero)arylboronic acids with
representative substrates 1a, 1c, 1i, and 1n are presented in
Scheme 3. Pleasingly, these reactions gave cyclopent-2-enones
in generally good yields (73–92%) and enantioselectivities (80–
94% ee). The process is compatible with arylboronic acids
containing halide (3ab, 3cg, 3ij, 3ik, and 3nm), methyl (3ac,
3ch and 3nm), carboethoxy (3ad), or alkoxy (3cf, 3ij, and 3nl)
substituents. 2-Naphthylboronic acid (3ii) and 3-thienylboronic
acid (3ae) are also effective.
In conclusion, we have reported the enantioselective
synthesis of chiral cyclopent-2-enones by the nickel-catalyzed
desymmetrizing arylative cyclization of alkynyl bis(2,2,2-
trifluoroethyl) malonates with arylboronic acids. The reactions
proceed in good yields and generally high enantioselectivities to
give cyclopent-2-enones containing a fully substituted alkene
and a quaternary stereocenter at the 5-position. This work
further demonstrates the utility of reversible E/Z isomerization of
alkenylnickel species in promoting new domino addition–
cyclizations of alkynyl electrophiles that would otherwise be
impossible.[8,9d,e] Investigation of this reactivity in other contexts
is ongoing and will be reported in due course.
Received:
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The process also works well in gram-scale reactions. For
example, the reaction of 1b (1.38 g, 3.00 mmol) with PhB(OH)2
gave 1.10 g of 3ba (84% yield) in 80% ee [Eq. (4)]. Importantly,
by conducting this reaction a higher concentration of 0.4 M,
rather than at 0.1 M used in the experiments shown in Schemes
2 and 3, the catalyst loading was lowered to 3 mol%.
To demonstrate the synthetic utility of the products, further
transformations of a representative cyclopent-2-enone were
conducted. Trifluoroethyl esters are moderately active acylating
agents[15] and could therefore serve as useful functional handles.
Indeed, heating 3ik with benzylamine (1.5 equiv) in THF at
90 °C smoothly gave amide 8 in 84% yield without affecting the
enone (Scheme 4). A Luche reduction of 8 then gave allylic
alcohol 9 as a single observable diastereomer in 83% yield.
Acknowledgements
This work was supported by the European Union’s Horizon 2020
research and innovation programme [grant number 702386]
through a Marie Skłodowska-Curie Individual Fellowship to
S.N.K.; the Engineering and Physical Sciences Research
Council [grant number EP/M506588/1] through
studentship to C.C.; the University of Nottingham; and
GlaxoSmithKline.
a
PhD
Keywords: asymmetric catalysis
cyclization • isomerization • nickel
•
cyclopent-2-enone
•
[1]
[2]
[3]
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S. N. Karad, H. Panchal, C. Clarke, W.
Lewis, H. W. Lam*
Page No. – Page No.
Enantioselective Synthesis of Chiral
Cyclopent-2-enones by Nickel-Catalyzed
Desymmetrization of Malonate Esters
The enantioselective synthesis of highly functionalized chiral cyclopent-2-enones by
the nickel-catalyzed desymmetrizating arylative cyclization of alkynyl malonate
esters is described. Cyclization is enabled by the reversible E/Z isomerization of
alkenylnickel species.
This article is protected by copyright. All rights reserved.