Zinc Acetate Catalyzed Enantioselective Reductive Aldol Reaction of Ketones

Article abstract of DOI:10.1002/adsc.201901457

A highly enantioselective method for the synthesis of β-hydroxy esters via reductive aldol reaction of acrylates with aryl and heteroaromatic ketones is described. In situ generated catalyst composed of zinc acetate and chiral diamine afforded enantioenri

Full text of DOI:10.1002/adsc.201901457

Title: Zinc Acetate-Catalyzed Enantioselective Reductive Aldol
Reaction of Ketones
Authors: Izabela Węglarz, Marcin Szewczyk, and Jacek Mlynarski
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10.1002/adsc.201901457
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Zinc Acetate Catalyzed Enantioselective Reductive Aldol
Reaction of Ketones
Izabela Węglarz,a Marcin Szewczyk,b Jacek Mlynarskia,*
a
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland;
Fax: (+48)-22-632-66-81; phone: (+48)-22-632-2322; e-mail: jacek.mlynarski@gmail.com (homepage:
www.jacekmlynarski.pl)
Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A highly enantioselective method for the
synthesis of β-hydroxy esters via reductive aldol reaction
of acrylates with aryl and heteroaromatic ketones is
described. In situ generated catalyst composed of zinc
acetate and chiral diamine afforded enantioenriched
tertiary alcohols in high yields and with excellent
enantioselectivity (up to 91% ee). This is also the first
successful application of the zinc hydride reagent in
stereoselective reductive aldol reactions of ketones.
efficient protocols based on copper(I) complexes have
been then developed.[8] Riant[8b] and Fukuzawa[8c]
elaborated catalytic method for the highly
stereoselective construction of stereogenic quaternary
carbon centers through domino conjugated
reduction/aldol reaction of methyl acrylate with
various alkyl aryl ketones promoted by Cu-ferrophos
and taniaphos complexes. The alternative approach to
asymmetric copper(I)-catalyzed reductive aldol-type
reaction of acrylates with ketones was showed by
Nishiyama.[9] Although the use of a chiral rhodium-
bis(oxazolinylphenyl) catalyst proceeded highly
enantioselective (57-98% ee), the substrate scope was
mainly limited to few examples of aliphatic ketones.[9]
In all these examples copper complexes have been
documented as the catalyst of choice. These findings
fit the overall supremacy of copper in the reduction
reactions. For a long time copper continues to
dominate the catalytic chemistry of the coinage metal
hydrides[10] and copper hydrides were best known as
reagents or as catalytic intermediates in selective
reduction chemistry. While broad array of structures of
hydride complexes of copper (and also silver, and gold
– so called coinage metals) inspired recent advances in
synthesis and catalysis, application of zinc hydride
intermediate is far less documented. This paper support
our thesis that zinc complexes can also promote the
asymmetric reductive aldol reaction and zinc may be
also used in the catalytic processes in which coinage
metal hydrides act as intermediates.
Keywords: asymmetric synthesis; aldol reaction; zinc;
hydrosilylation; ketones
The asymmetric reductive aldol reaction of carbonyl
compounds with α,β-unsaturated esters provides a
convenient and efficient way to optically active β-
hydroxy esters, which are valuable building blocks in
organic synthesis.[1] Resulting chiral secondary and
tertiary alcohols prepared from aldehydes and ketones
are an important class of organic compounds which
have found wide applications in both academia and
industry.[2] Therefore, numerous catalytic strategies
towards asymmetric reductive aldol reaction of
carbonyl compounds have already been developed.[3]
While transition metal-catalyzed enantioselective
variant of the reductive aldol addition reaction with
aldehydes promoted by the combination of Rh-,[4]
Co-,[5] or Cu-based complexes[6] with silanes is well
established, only limited success has been achieved in
asymmetric addition to ketones, mostly restricted to
intramolecular reaction.[3b,7] Therefore, further
development in this area deserves continuous attention.
In 2006, Shibasaki and co-workers reported a
While an example of the chiral Rh complex in
presence of zinc salt has been presented by Ando in
2014, the role of Et2Zn was limited only to generation
of rhodium hydride complex.[11] Previously, we
elaborated expedient protocols for the asymmetric
hydrosilylation of prochiral ketones and imines by
using readily available chiral Zn(OAc)2 complexes in
situ forming zinc hydride as an active intermediate.[12]
This prompted us to predict that the chiral zinc hydride
complex may be a cheaper and easy formed equivalent
of Cu-based catalysts. Here, we describe the first
breakthrough in the intermolecular enantioselective
reductive aldol reaction of α,β-unsaturated esters to
ketones.[8a] Application of CuF complex with chiral
diphosphine ligands and triethoxysilane (TES),
resulted in a low yield and low enantioselectivity (up
to 30% ee) for the reaction between acetophenone and
methyl acrylate.[8a] Following this achievement, a few
1
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10.1002/adsc.201901457
Advanced Synthesis & Catalysis
example of a highly efficient and enantioselective zinc
Data collected in Table 1 indicate that slightly
acetate-catalyzed reductive aldol reaction of broad changing the (R,R)-diamine ligand structure had
range of aryl and heteroaromatic ketones with α,β- immense impact on the reaction enantioselectivity.
unsaturated esters.
Figure 1. Structures of diamine ligands used in this study.
From among tested benzyl derivatives of DPEDA
(L2L8, entries 410), only ligand L8 bearing four
bulky tert-butyl groups at the meta positions resulted
in moderate yield and promising enantioselectivity (up
to 48% ee for anti-isomer 3a). While the
diastereoselectivity of this reaction was poor, the
chemoselectivity was acceptable in all examples and
the minor product 4a formed in very low yield.
Having the best type of ligand in hand, several
commercially available Lewis acids were tested and
results are also collected in Table 1. Metal salts
screening demonstrated that only Zn(OAc)2 and zinc
propionate (entry 12) effectively promotes this
reaction, while the iron(II)- and copper(II) complexes
turned out to be entirely inactive in the asymmetric
reductive aldol reaction (Table 1, entry 13). Other zinc
salts as zinc triflate (entry 12) or zinc chloride were
identified as not promising catalyst precursors.
Catalyst composed of diethylzinc with ligand L8 have
also been unreactive under conditions described in
Table 1. Despite the fact that the diastereoselectivity of
this reaction was in favor of syn-3a, the promising
attempt of the chiral Zn(OAc)2 catalyst based on the
After initial study, we found that Zn(OAc)2 was
the most promising zinc salt in a model reaction of
acetophenone (1a) with methyl acrylate (2a) in
presence of TES as a reducing agent. After confirming
the efficiency of the non-chiral N,N,N’,N’-
tetramethylethylenediamine (TMEDA, Figure 1, L1)
in reaction (Table 1, entries 13), many chiral ligand
based on (R,R)-diphenylethylenediamine (DPEDA,
Figure 1, L2 L8) have been prepared and screened in
reductive aldol reaction of acetophenone.
Table 1. Initial screening of diamine ligands in asymmetric
reductive aldol reaction between acetophenone and methyl ligand L8 encouraged us to pursue further optimization
acrylate.[a]
of the reaction conditions. Although changing solvent
from THF to m-xylene gave a higher yield of the newly
Table 2. Asymmetric reductive aldol reaction between
acetophenone and methyl acrylate under various
conditions.[a]
Yield (%)[b]
ee (%)[d]
Entry Ligand
dr[c]
ee (%)[d]
T
(C)
Time
(h)
Cat.
(mol%)
Yield
(%)[b]
dr[c]
3a
4a
syn anti
Entry
syn
anti
1
2[e]
3[f]
4
63
84
95
70
68
75
54
73
54
55
48
trace
0
25
15
trace
24
31
15
33
trace
23
21
18
1.6 : 1
2.0 : 1
2.2 : 1
1.3 : 1
2.5 : 1
1.7 : 1
3.8 : 1
1.8 : 1
2.7 : 1
1.6 : 1
1.8:1
-
rac rac
rac rac
rac rac
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
L8
L8
L8
1[e]
2[f]
3[g]
4
5
6
7
8
9
10
11
rt
rt
rt
rt
4
24
24
24
24
24
48
48
48
72
48
72
72
72
48
5
5
5
5
5
55
72
67
68
68
76
trace
21
46
40
1.6:1
1.3:1
1.7:1
1.4:1
1.3:1
1.2:1
-
1.9:1
1.8:1
1.4:1
1.4:1
1.6:1
1.4:1
1.8:1
22
22
29
26
24
26
-
16
23
16
6
48
56
46
58
62
66
-
80
77
78
82
78
76
77
14
15
10
9
8
9
22
15
-
16
12
15
16
10
16
48
35
-
5
6
7
8
4
5
5
-30
-30
-30
-30
-30
10
10
15
15
15
15
20
9
10
11[g]
12[h]
13[i]
73
63
69
75
32
trace
12[f] -30
13[h] -30
14
10
20
22
-
-
-
[a] Reactions were carried out by stirring Zn(OAc)2 (5 mol%)
with L1L8 diamine ligands (5 mol%) in THF (1 mL) at
room temperature for 24 h, containing TES (1.0 mmol),
acetophenone 1a (0.5 mmol) and methyl acrylate 2a (0.6
-30
[a]
Reactions were performed with Zn(OAc)2 (520 mol%)
and chiral L8-ligand (520 mol%) in m-xylene (1 mL) at the
specified time and temperature, containing TES (1.0 mmol),
acetophenone 1a (0.5 mmol) and methyl acrylate 2a (0.6
[b]
mmol) unless otherwise stated. Isolated yield after silica
[c]
1
gel chromatography.
syn/anti ratio determined by H
[b]
NMR spectroscopy. [d] Determined by chiral HPLC analysis.
mmol) unless otherwise stated. Isolated yield after silica
[c]
1
[e] Catalyst loading: 10 mol%. [f] Reaction carried out at 4 C
gel chromatography.
syn/anti ratio determined by H
NMR spectroscopy. [d] Determined by chiral HPLC analysis.
[g]
for 48 h with 10 mol% of catalyst loading. Zn(OCOEt)2,
THF, [f] toluene,[g] DCM and [h] THF/m-xylene (6:1) were
[e]
[h] Zn(OTf)2, [i] Fe(OAc)2 orFe(OTf)2 or Cu(OTf)2 were used
instead of Zn(OAc)2.
used instead of m-xylene.
2
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10.1002/adsc.201901457
Advanced Synthesis & Catalysis
formed anti-3a product, still the relatively low level of investigations revealed that the position of the
enantioselectivity left much to be desired (Table 2, substituent attached to the aromatic ring has a decisive
entry 1 vs. 4).
influence on the reaction enantioselectivity. Substrates
Further investigations showed that conditions possessing groups placed in the meta position gave
such as temperature and catalyst loading have a higher ee (7491%), whereas the para-substituted
significant impact on the control of the reaction products formed with slightly lower selectivities for
stereoselectivity. Based on the initial screening each cases (up to 81% ee). Moreover, the switch of
performed at room temperature, cooling down to 4 C electron-withdrawing groups (3g3i) by electron-
increased the ee to 66% (Table 2, entry 5). However, donating groups (3b3f) on acetophenone significantly
we noticed that reaction performed below 0 C was increased both the ee and yield of the corresponding
unfortunately unsuccessful in the case of 5 mol% of the anti-products. Interestingly, the presence of alkyl
catalyst (Table 2, entry 7). Considering further substituents on the meta position afforded the desired
improvement of the reaction enantioselectivity, the products (3b, 3d) with excellent enantioselective
optimal amount of employed catalyst was evaluated in control (around 91% ee), whereas replacing by a
low reaction temperature. We found that increasing the strongly activating group decreased both yield and
catalyst loading was required to reactions proceed, and enantioselectivity of 3e to 78% ee. The replacement of
played a crucial role in asymmetric induction and the relatively small methyl group by the tert-butyl
reaction efficiency. To our delight, higher catalyst group in the ester fragment led to significantly lower
loading (10 mol%) resulted in formation of desired level of enantioselectivity (51% ee) of the
anti-3a with a high level of enantioselectivity to 80% corresponding 3j. In addition to the above-mentioned
ee, albeit the efficiency suffered (Table 2, entry 8). A substrates, attempts to the reaction of 3’-
satisfactory yield up to 73% was obtained without loss nitroacetophenone (3o) were unsuccessful and gave
of ee by employing 15 mol% of the catalyst loading only trace of desired product. Aryl ketones bearing the
and prolonged reaction time to 72 h (Table 2, entry 11). nitro groups are known to be problematic in
Interestingly, further loading (20 mol%), resulted in a hydrosilylations, as shown for instance by
slight decrease of the zinc-complex activity.
Adolfsson.[13] We also examined substrates with longer
At the established optimal conditions, the scope of alkyl chain derivatives (3r3t), but products were not
the zinc-catalyzed asymmetric reductive aldol reaction observed, since appear to be more sterically hindered.
with respect to the ketones and unsaturated esters was Application of aliphatic ketones (acetone, butan-2-one,
examined, as presented in Scheme 1. For the range of benzyl methyl ketone) was also not successful,
substrates studies, a variety of aryl and heteroaromatic unfortunately.
ketones participated successfully in the reaction with
Although the reductive aldol reaction of aryl
high enantioselectivities and very good yields. The ketones proceeded in favor of the syn-diastereomer,
Scheme 1. Asymmetric zinc-catalyzed reductive aldol reaction of various ketones with α,β-unsaturated esters.[a], [b], [c], [d]
[a] Reactions were performed with Zn(OAc)2 (15 mol%) and chiral L8-ligand (15 mol%) in m-xylene (1 mL) at 30 C for
[b]
72 h, containing TES (1.0 mmol), aryl or heteroaromatic ketone 1a-t (0.5 mmol) and specified acrylate 2 (0.6 mmol).
Isolated yield after silica gel chromatography. [c] syn/anti ratio is shown in the parentheses and was determined by 1H NMR
spectroscopy. [d] The ee values of anti-isomers were determined by chiral HPLC analysis.
3
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10.1002/adsc.201901457
Advanced Synthesis & Catalysis
Experimental Section
substantially improved diastereocontrol of the reaction
was achieved via the application of heteroaromatic
ketones. As shown in Scheme 1, zinc complex
promoted the reaction of 2-acetylfuran (3k, 3l) in
enantioselective (up to 86% ee) and anti-
diastereoselective manner (dr up to 1.5:1 for anti-3k).
While the actual cause of such reversal is not fully
understood, the similar tendency in terms of dr and ee
was observed for product formation of reaction
between 2-acetylthiophene and methyl acrylate (3m).
Surprisingly, a methyl-group exchange in larger ethyl
group in the acrylate fragment of 3n, resulted in
General procedure for Asymmetric Reductive Aldol
Reaction of Ketones with Acrylates
Under an argon atmosphere at room temperature, Zn(OAc)2
(13.8 mg, 0.075 mmol) and diamine ligand (45.0 mg, 0.075
mmol) were dissolved in anhydrous m-xylene (1 mL) and
stirred for 60 min. Triethoxysilane (0.185 mL, 1.0 mmol)
was then added, the mixture was cooled down to –30 °C and
stirred for additional 5 min. Then, the corresponding ketone
(0.5 mmol) followed by methyl acrylate (0.6 mmol) were
added to the solution. After specified time, the reaction
reversal of diastereoselectivity in favor of syn-isomer mixture was quenched by addition of 5 mL of saturated
K2CO3 in methanol. The resulting mixture was stirred for 30
min, then 10 mL of ethyl acetate was added and the aqueous
layer was extracted three times. The combined organic
layers were washed with brine, then dried over anhydrous
MgSO4. The residue obtained after evaporation of the
solvent under reduced pressure was purified by column
chromatography on silica gel using hexane-ethyl acetate (6:1,
v/v) as eluent. The ee values and dr ratios were then
determined by HPLC methods and NMR spectroscopy. Part
of isolated mixtures of diastereomers were separated by
additional column chromatography on silica gel, eluted with
hexanes-ethyl acetate (9:1, v/v) and the ee values of
particular diastereomers were determined by chiral HPLC
analysis.
once again and decrease in enantioselectivity to 80%
ee. In contrast to reactivity of furan- and thiophene-
type ketones, similar investigation made for pyrrole
(3p) and pyridine (3q) derivatives were unsuccessful.
Finally, we determined an absolute configuration
of isolated anti-β-hydroxy ester 3a by conversion to
described in literature alcohol 7 with a single chiral
center at C-3 position (Scheme 2).[8b,14] Based on
comparison of the optical rotation of reduced (S)-3-
methyl-2-phenyl-butan-2-ol (7) with the literature
value, the absolute configuration of anti-3a was
determined to be (2R,3S).
Acknowledgements
Financial support from the Polish National Science Centre (OPUS
Grant No. NCN 2017/27/B/ST5/01111) is gratefully acknowledged.
Scheme 2. Absolute configuration of anti-3a product.
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5
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Advanced Synthesis & Catalysis
UPDATE
Zinc Acetate Catalyzed Enantioselective Reductive
Aldol Reaction of Ketones
Adv. Synth. Catal. Year, Volume, Page – Page
Izabela Węglarz, Marcin Szewczyk, Jacek
Mlynarski*
6
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