Asymmetric Synthesis of 2,3-Disubstituted Cyclic Ketones by Enantioselective Conjugate Radical Additions

Article abstract of DOI:10.1002/hlca.201900223

Enantioselective conjugate radical addition to 2-acyloxymethyl cycloalkenones proceeds in high yield with outstanding diastereoselectivity and excellent enantioselectivity using chiral salen Lewis acids. The process provides access to 2,3-disubstituted cycloalkanones, a structural motif present in natural products.

Full text of DOI:10.1002/hlca.201900223

DOI: 10.1002/hlca.201900223
FULL PAPER
Asymmetric Synthesis of 2,3-Disubstituted Cyclic Ketones by
Enantioselective Conjugate Radical Additions
a
a
Sukanya Nad and Mukund P. Sibi*
a
Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND 58108–6050, USA,
e-mail: Mukund.Sibi@ndsu.edu
Happy 60th birthday to Philippe Renaud, a great scientist and a dear friend
Enantioselective conjugate radical addition to 2-acyloxymethyl cycloalkenones proceeds in high yield with
outstanding diastereoselectivity and excellent enantioselectivity using chiral salen Lewis acids. The process
provides access to 2,3-disubstituted cycloalkanones, a structural motif present in natural products.
Keywords: enantioselectivity, chiral Lewis acids, radical reactions, conjugate additions, cyclic ketones.
as penienone, penihydrone, and prostaglandins.[26–30]
There are many examples in the literature which
Introduction
Enantioselective radical chemistry continues to attract report enantioselective addition/trapping experiments
[1]
interest from the synthetic community.
Radical with cycloalkenones using ionic chemistry to provide
reactions are well suited for the installation of multiple 2,3-disubstituted cycloalkanones. These reactions
stereocenters in a single operation.[ Enantioselective show selectivities across the spectrum in addition/
2,3]
[
31–38]
conjugate radical additions have been extensively trapping experiments.
Reactions with 2-substi-
investigated using substrates capable of bidentate tuted cyclohexenones generally proceed with modest
coordination.[
4–18]
In contrast, stereoselective reactions enantio- and/or diastereoselectivity.[39–42] In contrast,
with single point binding substrates are more chal- there are only scattered examples of radical additions
lenging and only a few examples of reactions proceed- to enones in the literature with most of these trans-
ing with high selectivity have been reported.[
19–22]
We formations in racemic fashion.
[43–46]
In this his work we
have previously shown that γ-pyranones possessing a report highly efficient and enantioselective conjugate
fixed s-trans enone geometry undergo highly selective radical additions to 2-hydroxymethyl-cycloalkenones,
conjugate radical additions.[ Furthermore, we have precursors that are readily available from Baylis-Hill-
also completed a study on enantioselective radical man reactions, to yield 2,3-disubstituted cyclopenta-
additions to α-alkylidene ketones with a fixed s-cis nones and hexanones in high yield and selectivity.
enone geometry.[ Recently, we reported on enantio- Furthermore, we also show that the nature of the
selective conjugate radical additions to α-arylidene Lewis acid activator plays an important role in the
ketones and lactones also possessing a fixed s-cis stereochemical outcome of the reaction.
23]
24]
[
25]
enone geometry.
We have been interested in
further extending this chemistry to s-trans configured
cyclic enones. The methodology has the potential for
accessing 2,3-disubstituted cyclic ketones. This is a
Results and Discussion
substitution pattern present in natural products such We began our investigation by examining the effec-
tiveness of conjugate radical addition to cyclohexe-
none 1 (Scheme 1). A variety of chiral Lewis acids were
Supporting information for this article is available on the evaluated with very limited success with respect to ee
WWW under https://doi.org/10.1002/hlca.201900223
of the conjugate addition product (<40%). Conjugate
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Helv. Chim. Acta 2019, 102, e1900223
Table 1. Conjugate radical addition to 2-alkoxymethyl-2-cyclohexenones.
Entry
R
mol-% CLA
Time [h]
Yield [%][a]
dr[b]
ee [%][c]
1
2
3
4
H (8a)
100
50
50
4
1
1
2
Trace
90
95
–
PhÀ CH (8b)
99:1
99:1
99:1
68
73
83
2
4-MeOÀ C H À CH (8c)
6
4
2
4-MeOÀ C H À CO (8d)
50
98
6
4
[
a]
Yield of isolated product. [b] Determined by NMR. The minor isomer could not be detected. [c] Determined by chiral HPLC.
radical additions to 2- substituted-cyclohexenones 4 tigate conjugate radical additions to readily accessible
[
49]
and 5 were also evaluated in an effort to prepare 2,3- substrate 8. In these experiments, conjugate radical
disubstituted cyclic ketones. However, these com- addition is followed by diastereoselective H-atom
[
50–52]
pounds proved to be very unreactive under a variety transfer.
Results from these studies are shown in
1
of conditions. The electron donating alkyl(aryl) group Table 1 . For initial experiments the chiral salen 3, a
on the α-carbon deactivate the β-carbon for efficient single point binding Lewis acid was employed.[
53–57]
nucleophilic radical addition.
Isopropyl radical addition to the parent compound 8a
We have previously shown that acrylate substrates was inefficient under a variety of conditions (Entry 1).
[47]
containing an α-hydroxymethyl and α-amidomethyl The O-benzyl ether (8b) was a better substrate giving
[48]
groups are excellent substrates for conjugate radical the addition product in good yield as a single
addition/enantioselective H-atom transfer reactions. diastereomer and in 68% ee (Entry 2). Conjugate
The respective reactions provide access to addition to the p-methoxybenzyl ether (8c) did not
2
formaldehyde aldols and β -amino acid derivatives in show any improvement in enantioselectivity (Entry 3).
high enantioselectivity. Noting the activation provided The corresponding ester, 4-methoxybenzoate (8d) was
by the hydroxymethyl groups, we decided to inves- an excellent substrate and gave the addition product
as a single diastereomer in 83% ee (Entry 4). These
proof of principle experiments demonstrate that
enantioenriched 2,3-disubstituted cyclohexanones can
be accessed by efficient and highly selective conjugate
radical addition.
In an effort to improve the level of enantioselectiv-
ity in the addition/H-atom transfer protocol, we set
out to investigate the effect of different chiral Lewis
acids using substrate 8d and results from these studies
are presented in Table 2.
Scandium triflate as a Lewis acid was very effective
under racemic conditions producing the product in
high diastereoselectivity (Entry 1). The salen Lewis acid
with a chloride counterion (10) was effective in the
conjugate addition (Entry 2). As noted earlier, the chiral
1
For the synthesis of starting materials, reaction con-
ditions for radical reactions, ee determination, and
Scheme 1. Enantioselective conjugate radical additions to cy- product stereochemical analysis see the Supporting
clohexenones.
Information.
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Helv. Chim. Acta 2019, 102, e1900223
Table 2. Evaluation of chiral Lewis acids.[a]
ligands was investigated (Entries 8–10). The results
from these experiments were quite interesting. Mag-
nesium iodide and 14 as a chiral Lewis acid gave the
addition/trapping product with high diastereoselectiv-
ity, but the product was nearly racemic (Entry 8). In
contrast, magnesium iodide and 15 gave a mixture of
syn and anti isomers with modest ees (Entry 9). The
combination of magnesium perchlorate and 15 proved
to be very effective giving a mixture of syn and anti
isomers in high enantioselectivity (Entry 10). The high
selectivity for both diastereomers suggest that initial
addition occurs with modest selectivity followed by
highly selective matched/mismatched H-atom transfer.
The above experiments with mono- and bidentate
Lewis acids are quite interesting with respect to
requirements for substrate-Lewis acid interactions
which determine the outcome of the stereoselectivity.
Having investigated the effect of the chiral Lewis
acid, we then evaluated the impact of the acyl group
on the enantioselectivity in isopropyl and tert-butyl
radical additions using 3 as a Lewis acid. These results
are presented in Table 3. It is important to note that
the catalyst loading for these experiments is high. This
reflects the modest Lewis acidity of the catalyst and
the steric hinderance at the β-carbon of a relatively
unreactive substrate. Additionally, the high catalyst
loading suggests that catalyst turnover is slow.
Addition to the parent benzoyl compound 8e gave
the addition product in high yield and good selectivity
Entry Lewis acid, ligand
mol-%)
Time Yield
[h]
dr[c] ee
[%][b]
[d]
(
[%]
1
2
3
4
5
6
7
8
9
Sc(OTf) (30%)
10 (50%)
3 (50%)
3 (100%)
11 (50%)
12 (50%)
13 (50%)
0.75 95
1.5 98
1.5 98
1.0 98
1.0 98
>3.0 50
2.0 95
>4.0 65
>4.0 50
99:1
3
99:1 77
99:1 83
99:1 83
99:1 69
99:1 70
99:1 71
(
Entry 1). As noted earlier, isopropyl radical addition to
8d is efficient. The bulkier tert-butyl radical gave the
addition product with slightly higher enantioselectivity
(Entry 2). Reactions using a 2-naphthoyl ester 8f gave
the addition products in good yield and selectivity
MgI , 14 (50%)
99:1
3
2
MgI , 15 (50%)
90:10 31
2
(58)
(Entry 3). The phenylacetic acid ester 8g gave the
1
0
Mg(ClO ) , 15 (50%)
1.0 95
62:38 81
4
2
conjugate addition products with the highest selectiv-
ity in this series (Entry 4). Reactions with 8h were also
effective (Entry 5). Overall, the ester group had reason-
able impact on selectivity with reactions using 8d and
8g being optimal.
(
91)
[
a]
[b]
For experimental details see Supporting Information. Yield
of isolated products. [ Determined by NMR. For reactions with
c]
[d]
9
9:1 selectivity, the minor isomer could not be detected.
Determined by chiral HPLC.
The scope of the radical was evaluated next using
8
d as a substrate and 3 as a Lewis acid. Results from
these experiments are presented in Table 4. Addition
salen with a triflate counterion (3) was excellent as a of primary radicals proceeded with modest chemical
Lewis acid furnishing the product 9d in good yield and efficiency (Entries 1 and 2). Although the diastereose-
selectivity (Entry 3). Increasing the catalyst loading to lectivity was very high, the level of enantioselectivity
1
00 mol% did not result in improvement in selectivity was only modest. As was discussed earlier, acyclic
(Entry 4). Further changes to the counterion led to a secondary (Entry 3) and tertiary radicals (Entry 4) gave
lowering in enantioselectivity (Entries 5 and 6). We addition products in high yield and selectivity. Reac-
then decided to explore bidentate binding Lewis acids tions with cyclic secondary radicals (Entries 5 and 6)
as activators for the reactions. The use of magnesium also gave conjugate addition products with good
salts as a Lewis acid in combination with bisoxazoline selectivity, while the large tertiary radical derived from
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Table 3. Effect of the acyl group on reactivity and selectivity.[a]
R1
R= Pr
i
R= Bu
t
Entry
Yield [%][
b,c]
ee [%][d]
Yield [%]
[b,c]
ee [%][d]
1
2
3
4
5
Ph (8e)
4-MeO-C H (8d)
2-Naphthyl (8f)
Benzyl (8g)
90
98
98
90
95
78
83
85
91
91
88
98
98
85
90
80
89
85
95
89
6
4
2,4,6-Trimethylbenzyl (8h)
[
a]
For experimental details, see Supporting Information. [b] Yield of isolated products. Diastereoselectivity determined by NMR. For
[c]
reactions with 99:1 selectivity, the minor isomer could not be detected. [ Determined by chiral HPLC.
d]
Table 4. Addition of different radicals.[a]
Entry
RÀ I
Prod.
Time [h]
Yield [%][b]
dr[c]
ee [%][d]
1
2
3
4
5
6
7
EtÀ I
9n
9o
9d
9j
9p
9q
9r
>4.0
>4.0
2.0
2.5
2.0
70
65
98
98
98
98
98
99:1
99:1
99:1
99:1
99:1
99:1
99:1
51
49
83
89
77
83
66
PrÀ I
i
PrÀ I
t
BuÀ I
CyclopentylÀ I
CylohexylÀ I
3.0
1.5
1-AdamantylÀ I
[
a]
[b]
[c]
For experimental details, see Supporting Information. Yield of isolated products. Diastereoselectivity determined by NMR. For
reactions with 99:1 selectivity, the minor isomer could not be detected. [ Determined by chiral HPLC.
d]
1
-adamantyl iodide gave the corresponding addition gave the products in high yield and high syn
product with modest ee (Entry 7). These experiments diastereoselectivity. The level of enantioselectivity was
demonstrate that there is reasonable scope for the higher for tert-butyl radical addition than for isopropyl
radical precursors allowing access to a variety of 2,3- radical (Entry 1). Reactions of the phenylacetic acid
disubstituted cyclohexanones.
ester 16b were equally effective giving the addition
Conjugate radical addition to 2-hydroxymethyl products in high yield and good enantioselectivity
cyclopentenones was investigated next. For these (Entry 2). The p-methoxybenzoate ester 16c also gave
experiments, substrates with three different ester the addition products in high yield and good
groups (16a–16c) and three different chiral Lewis selectivity (Entry 3). Use of chiral salen 13 in isopropyl
acids were examined. Results from reactions with radical addition to 16c gave the product in high yield
isopropyl and tert-butyl radicals are presented in but only modest enantioselectivity (Entry 4). Isopropyl
Table 5. Radical addition to 16a using 3 as a Lewis acid radical addition to 16c using a chiral Lewis acid
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Table 5. Addition of different radicals.[a]
R1
Lewis acid
mol-%)
R= Pr
i
R= Bu
t
Entry
(
Yield [%][b][c]
ee [%][d]
Yield [%][b][c]
ee [%][d]
1
2
3
4
5
Phenyl
Benzyl
4-MeO-Phenyl
4-MeO-Phenyl
4-MeO-Phenyl[
3 (50%)
3 (50%)
3 (50%)
13 (50%)
Mg(ClO ) ,
95
90
98
95
98
77
80
79
53
90
90
98
87
84
76
d]
67 (81)
4
2
15 (50%)
[
a]
For experimental details, see Supporting Information. [b] Yield of isolated products. Diastereoselectivity determined by NMR. For
[c]
reactions with 99:1 selectivity, the minor isomer could not be detected. [ Determined by chiral HPLC.
d]
derived from magnesium perchlorate and 15 gave a
mixture of syn and anti isomers in high yield (Entry 5).
As was observed with the six-membered analog, the
syn/anti isomers were again formed with good
enantioselectivity.
The relative configuration for the conjugate addi-
tion products were determined by extensive NOE and
Figure 1. Stereochemical model.
decoupling experiments. The major product has syn
2
configuration . We have not determined the absolute
configuration for the conjugate addition product(s). A
model for conjugate addition to 8d using chiral salen
Conclusions
3
3
is shown in Figure 1 . The initial radical addition is
controlled by the single point binding chiral Lewis acid In conclusion, we have demonstrated that enantiose-
catalyst. The face selectivity in the subsequent H-atom lective conjugate radical addition protocols provide
transfer is determined by the newly formed chiral ready access to syn-2,3-disubstituted cycloalkanones
center with assistance from the still bound catalyst. in excellent chemical yields and high selectivity.
The electron-withdrawing acyloxy group on the α- During the process two stereocenters are established
carbon facilitates nucleophilic radical addition and its with a high degree of selectivity. Furthermore, a
bulk could account for the observed high diastereose- magnesium salt in combination with a bisoxazoline
lectivity. We are currently working on refining our ligand provides both syn and anti isomers with high
model to account for the observed selectivity.
enantioselectivities. Application of the new radical
methodology in the synthesis of natural products is
underway.
Experimental Section
Representative Experiment
2
3
Representative Experimental Procedure for Chiral
Lewis Acid-Catalyzed Conjugate Addition of Radicals
For detailed analysis see the Supporting Information.
The tentative absolute stereochemistry shown is based
on previous work from our laboratory. For stereochemical to 2-Hydroxymethyl Unsaturated Cyclic Ketones. A
models for reactions with chiral salen Lewis acids, see mixture of chiral Lewis acid (0.05 mmol) and 2-
[
23], [24], and [58].
hydroxymethyl unsaturated cyclic ketone (0.1 mmol)
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Helv. Chim. Acta 2019, 102, e1900223
was stirred vigorously in 5.0 mL of dichloromethane at Acknowledgements
room temperature for 45 min, and then cooled at
À 78°C for 20 min. The reaction was initiated by We thank the NIH (NIH-GM-54656) for financial sup-
sequential addition of alkyl halide (0.5 mmol), tribu- port.
tyltin hydride (0.3 mmol), triethylborane (0.4 mmol 1 M
solution in hexane) and oxygen (introduced through
syringe). The reaction was monitored by TLC (hexane/
AcOEt 4:1), and after completion was quenched with
Author Contribution Statement
silica gel, evaporated, washed with hexanes. Finally, S. N. carried out all the experiments and M. P. S. wrote
the silica gel (containing product) was washed with the manuscript.
AcOEt and the crude product (AcOEt layer) was
purified by silica gel chromatography (hexane/AcOEt
4
:1). Racemic standards were prepared using Sc(OTf)3
as a Lewis acid in the absence of a chiral ligand.
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Received September 14, 2019
Accepted October 21, 2019
Enantioselective Transformations: Radical Conjugate Addi-
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© 2019 Wiley-VHCA AG, Zurich, Switzerland