Asymmetric Synthesis of α,β-Unsaturated δ-Lactones through Copper(I)-Catalyzed Direct Vinylogous Aldol Reaction

Article abstract of DOI:10.1021/jacs.8b07929

A simple methodology for the asymmetric synthesis of chiral α,β-unsaturated δ-lactones was achieved by copper(I)-catalyzed direct vinylogous aldol reaction (DVAR) of β,γ-unsaturated esters and various aldehydes, including aromatic aldehydes, heteroaromatic aldehydes, α,β-unsaturated aldehydes, and aliphatic aldehydes. For aromatic and heteroaromatic aldehydes, a one-pot reaction consisting of DVAR, isomerization of the unsaturated carbon-carbon double bond from (E)-form to (Z)-form, and subsequent intramolecular transesterification was required to get the lactones in moderate to high yields with high enantioselectivity. For α,β-unsaturated and aliphatic aldehydes, the DVAR proceeded directly to afford the lactones in moderate yields with high enantioselectivity. In the DVAR, various functional groups were well tolerated. Moreover, the methodology was nicely applicable to the aldehyde group distributed in natural products, derivatives of natural product, and derivatives of drug molecules (atomoxetine and naproxen). The mechanism studies revealed that α-addition was reversible and not favored, which accounted for the excellent regioselectivity in the DVAR. The copper(I)-dienolate species generated through deprotonation was proposed to form an equilibrium with an allylcopper(I) species, which reacted with aldehydes to afford the DVAR products through a catalytic asymmetric allylation of aldehydes. Finally, the robustness of the present reaction was demonstrated by a gram-scale reaction, and the utility of the present methodology was showcased by the formal asymmetric synthesis of ezetimibe and fostriecin.

Full text of DOI:10.1021/jacs.8b07929

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Article
Asymmetric Synthesis of #,#-Unsaturated #-Lactones through
Copper(I)-Catalyzed Direct Vinylogous Aldol Reaction
Hai-Jun Zhang, and Liang Yin
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 29 Aug 2018
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Journal of the American Chemical Society
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Asymmetric Synthesis of α,β-Unsaturated δ-Lactones through Cop-
per(I)-Catalyzed Direct Vinylogous Aldol Reaction
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HaiꢀJun Zhang, Liang Yin*
CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai
Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling
Road, Shanghai 200032, China
Supporting Information Placeholder
ABSTRACT: A simple methodology for the asymmetric synthesis of chiral α,βꢀunsaturated δꢀlactones was achieved by copper(I)ꢀcatalyzed direct
vinylogous aldol reaction (DVAR) of β,γꢀunsaturated esters and various aldehydes, including aromatic aldehydes, heteroaromatic aldehydes, α,βꢀ
unsaturated aldehydes and aliphatic aldehydes. As for aromatic and heteroaromatic aldehydes, a oneꢀpot reaction consisting of DVAR, isomerizaꢀ
tion of the unsaturated carbonꢀcarbon double bond from (E)ꢀform to (Z)ꢀform and subsequent intramolecular transesterification was required to get
the lactones in moderate to high yields with high enantioselectivity. As for α,βꢀunsaturated and aliphatic aldehydes, the DVAR proceeded directly
to afford the lactones in moderate yields with high enantioselectivity. In the DVAR, various functional groups were well tolerated. Moreover, the
methodology was nicely applicable to the aldehyde group distributed in natural products, derivatives of natural product and derivatives of drug
molecules (Atomoxetine and Naproxen). The mechanism studies revealed that αꢀaddition was reversible and not favored, which accounted for the
excellent regioselectivity in the DVAR. The copper(I)ꢀdienolate species generated through deprotonation was proposed to form an equilibrium
with an allyl copper(I) species, which reacted with aldehydes to afford the DVAR products through a catalytic asymmetric allylation of aldehydes.
Finally, the robustness of the present reaction was demonstrated by a gramꢀscale reaction and the utility of the present methodology was showcased
by the formal asymmetric synthesis of ezetimibe and fostriecin.
yama hypervinylogous aldol reaction of aldehydes.16 In 2011, List
INTRODUCTION
group also developed an efficient asymmetric MVAR by using a
chiral disulfonimide as the catalyst.17 However, the MVAR of aliphatꢀ
The asymmetric vinylogous aldol reaction (VAR) is one of the
most powerful reactions in stereoselective construction of δꢀ
hydroxylated α,βꢀunsaturated carbonyl compounds,1,2 which are preꢀ
cursors in the synthesis of chiral α,βꢀunsaturated δꢀlactones and relatꢀ
ed polyketide networks.3 Chiral α,βꢀunsaturated δꢀlactone moiety is a
prevalent structure unit in natural products,4 which plays an essential
role in the biological activity, due to its potential to act as a Michael
acceptor in the presence of protein functional groups.5 Moreover,
chiral α,βꢀunsaturated δꢀlactones served as versatile synthetic interꢀ
mediates towards total synthesis of natural products with various
biological activities and synthesis of pharmaceutically active artificial
molecules.6 Due to the significance of optically active α,βꢀ
unsaturated δꢀlactones, there is a growing interest in the asymmetric
construction of such compounds and thus various strategies were
employed to construct chiral α,βꢀunsaturated δꢀlactones.4,7 However,
multiple steps were generally required to achieve the asymmetric
synthesis of such molecules.4 Therefore, convenient and stepꢀ
economical synthetic methods are highly desired.
ic aldehydes suffered from unsatisfactory yields and enantioselectivity.
In the catalytic asymmetric aldol reaction with linear metal dienoꢀ
lates generated through deprotonation, αꢀaddition occurred preferenꢀ
tially.18 For example, in 2018, Shibasaki and Kumagai reported two
direct asymmetric aldol reactions of β,γꢀunsaturated thioamides and
β,γꢀunsaturated acetamide in the presence of copper(I) catalyst.18b,18c
In these two cases, regioꢀ and enantioselectivity were excellent and
diastereoselective were high in most substrates. However, only a
small quantity of VAR products (γꢀadducts) were obtained. While in
the case of linear copper(I)ꢀdienolates generated through transmetaꢀ
lation with dienolsilanes, γꢀaddition dominated the reaction with aldeꢀ
hydes, which was a catalytic asymmetric MVAR reported by Camꢀ
pagne group (Scheme 1b).19 In this reaction, linear products were
symbiotically produced with α,βꢀunsaturated δꢀlactones. In the viewꢀ
point of the atom economy,20 it is highly desirable to obtain lactones
only (or mainly) with high enantioselectivity. Moreover, Krische
reported a conceptually different but very effective method to generꢀ
ate the linear metal dienolate, starting from a γꢀOBoc ethyl crotonate
(Scheme 1c).21 A series of vinylogous aldol products was produced in
good to excellent regioselectivity with high to excellent enantioselecꢀ
tivity.
In the catalytic asymmetric VAR with cyclic nucleophiles, no matꢀ
ter what dienolsilanes,8 metal dienolates9 or dienolates generated with
organocatalysts10 were employed, VAR afforded γꢀadduct exclusively.
However, in the VAR with linear nucleophiles, linear dienolsilanes
were generally employed due to its natural tendency to favor the γꢀ
addition,3d,3f,11 and such VAR was recognized as the Mukaiyama
vinylogous aldol reaction (MVAR).12,13 Prominent examples were
uncovered by Denmark group (Scheme 1a).14 Lewis base activation of
Lewis acids,15 which was developed by professor Denmark, enabled
highly regioꢀ and enantioselective MVARs. Unfortunately, stoichioꢀ
metric SiCl4 was indispensable and resulted in stoichiometric silicon
waste. Later, Curti, Zanardi, Casiraghi and coworkers successfully
applied this catalytic system to very challenging asymmetric Mukaiꢀ
Scheme 1. Prior Arts in VAR and Our Work
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Journal of the American Chemical Society
Page 2 of 10
(a) Denmark's Catalytic Asymmetric MVAR
through deprotonation. However, due to the relatively high pKa value
of γꢀprotons in crotonate, it is very difficult to perform its deprotonaꢀ
tion with organic base. Therefore, β,γꢀunsaturated ester was utilized
instead to form the copper(I)ꢀdienolate complex more easily with
organic base in the presence of copper(I) complex due to the lower
pKa value of αꢀprotons.24 We embarked on the investigation of
DVAR by using benzyl β,γꢀunsaturated ester (1a) and benzaldehyde
(2a) as the model substrates (Table 1).
1
2
3
4
5
6
7
8
OTBS
OR
OH
O
O
organo-catalysis
ref 14a
+
SiCl4 +
R'
H
R'
OR
(b) Campagne's Catalytic Asymmetric MVAR
O
[Cu]-Tol-BINAP
ref 19e
OTMS
OR
O
OH
O
+
O
R'
H
R'
OR
R'
mixtures generated
(c) Krische's Catalytic Asymmetric VAR
Table 1. Optimization of DVAR of β,γ-Unsaturated esters and
Benzaldehyde Catalyzed by Copper(I)-Bisphosphine Complexa
OH
O
O
O
iridium-catalysis
ref 21
9
+
BocO
R'
OEt
OEt
R'
H
Cu(CH3CN)4PF6 (5 mol %)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ligand
base
(5 mol %)
(5 mol %)
O
(d) Jiang's Catalytic Asymmetric DVAR
O
O
OH
O
+
O
HO
O
THF (0.1 M), T oC, 12 h
OR
Ph
H
Ph
OR
3aa/3ba (LP)
R
organo-catalysis
ref 22c
Ph
4a (CP)
O
+
R'
O
R'
O
O
1
2a
R
N
N
total yieldb LP/CPb ee (LP)c ee (CP)c
R"
R"
entry
1
R
ligand
base
T
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
-20
(e) Shibasaki and Kumagai's Catalytic Asymmetric DVAR
97
96
<5
0
Bn (1a) (R)-BINAP
Barton's Base
Barton's Base
Barton's Base
Barton's Base
Barton's Base
Barton's Base
Barton's Base
Barton's Base
1/1
1/0.9
-
-8%
-7%
-
82%
86%
-
OH
2
Bn (1a) (R)-TOL-BINAP
Bn (1a) (R)-SEGPHOS
Bn (1a) (R,R)-QUINOXP*
Bn (1a) (R)-QUINAP
[Cu]-Ph-BPE-base
O
side products
from -adduct
CN
+
R'
3
R'
H
R' = aryl, vinyl
ref 23a
CN
4
-
-
-
mixtures generated
19
69
82
88
98
98
70
96
98
92
20%
11%
39%
-58%
88%
88%
89%
86%
95%
-
5
>20/1
1/1.6
1/1.5
1/1.9
1/2.1
1/1.6
1/0.6
1/1.4
1/1
-
(f) This Work: Catalytic Asymmetric DVAR
6
Bn (1a) (R)-DIFLUORPHOS
Bn (1a) (R,R)-Ph-BPE
Bn (1a) (R,Rp)-TANIAPHOS
90%
-94%
80%
87%
94%
95%
94%
97%
97%
broad substrate scope
high regioselectivity
high enantioselectivity
applicable to organic
synthesis
O
7
[Cu]*, base
O
O
+
O
*
8
OR
R'
H
R'
9
Bn (1a) (R)-DTBM-SEGPHOS Barton's Base
Ph (1b) (R)-DTBM-SEGPHOS Barton's Base
10
11
12
13d
R' = aryl, heteroaryl: DVAR/Isomerization/Intramolecualr transesterification
R' = vinyl, alkyl: DVAR
Ph (1b) (R)-DTBM-SEGPHOS
Ph (1b) (R)-DTBM-SEGPHOS
TEA
TMG
Ph (1b) (R)-DTBM-SEGPHOS Barton's Base
Since MVAR required stoichiometric preformed dienolsilanes,
which were usually unstable and difficult to purify, the direct vinyloꢀ
gous aldol reaction (DVAR) exhibited significant advantages of high
atom economy.20 Therefore, catalytic asymmetric DVAR was exꢀ
plored by many groups in the past decade,22 however, mainly focusing
on the activated ketones. For example, Jiang group reported a DVAR
of allyl ketones and activated ketones, including isatins, trifluoromeꢀ
thyl ketones, αꢀketoesters and αꢀketo phosphonates, catalyzed by
chiral bifunctional organocatalysts (Scheme 1d).22c,22e DVAR of aldeꢀ
hyde was proved to be very challenging. Shibasaki and Kumagai
reported a DVAR of allyl cyanide and aldehydes with a chiral copꢀ
per(I)ꢀcomplex as the catalyst (Scheme 1e).23a However, this method
was not applicable to aromatic aldehydes with electronꢀwithdrawing
groups and aliphatic aldehydes.
14d,e Ph (1b) (R)-DTBM-SEGPHOS Barton's Base -20
<1/20
a1, 0.2 mmol; 2a, 0.1 mmol. bDetermined by 1H NMR analysis of reaction crude mixture using CH3NO2 as an
internal standard. cDetermined by chiral-stationary-phase HPLC analysis. d48 h. eAfter DVAR, Ph2PMe (0.1
equiv) was added to the reaction mixture in 1 mL toluene, which was stirred at 100 oC for 8 h. Barton's Base =
2-tButyl-1,1,3,3-tetramethylguanidine. TEA = Triethyl amine. TMG = Tetramethyl guanidine.
O
tBu
R
Ph
PPh2
Ph
NMe2
PPh2
R
N
N
P
O
O
PAr2
PAr2
PAr2
PAr2
PPh2
Me
tBu
P
P
Fe
H
N
R
R
P
Ph
Ph
(R,R)-Ph-BPE
Me
O
Ar = Ph,
(R)-BINAP;
Ar = Tol,
(R)-TOL-
BINAP
R
(R,R)-QUINOXP*
(R)-QUINAP
R = H, Ar = Ph, ( )-SEGPHOS;
(R,Rp)-TANIAPHOS
R = F, Ar = Ph, (R)-DIFLUORPHOS;
R = H, Ar = 3,5-tBu2-4-OMe-Ph,
(R)-DTBM-SEGPHOS
In the presence of 5 mol % Cu(CH3CN)4PF6 and (R)ꢀBINAP or
(R)ꢀTOLꢀBINAP, DVAR preceded smoothly to afford a mixture of
linear product (LP, 3aa) and cyclic product (CP, 4a) in excellent
yields (entries 1ꢀ2). However, both ratio of 3aa/4a and enantioselecꢀ
tivity of 3aa were very bad. Surprisingly, (R)ꢀSEGPHOS and (R,R)ꢀ
QUINOXP* were completely ineffective (entries 3ꢀ4). (R)ꢀQUINAP
led to excellent control of the ratio of 3aa/4a. However, both yield
and enantioselectivity of 3aa were very low (entry 5). In the cases of
(R,R)ꢀPhꢀBPE, (R)ꢀDIFLUORPHOS and (R,Rp)ꢀTANIAPHOS, 4a
was produced in high enantioselectivity but with bad control of the
ratio of 3aa/4a and unsatisfactory enantioselectivity of 3aa (entries 6ꢀ
8). (R)ꢀDTBMꢀSEGPHOS was found to be the best, since both 4a and
3aa were obtained in good enantioselectivity (entry 9).
To the best of our knowledge, there is no general method for cataꢀ
lytic asymmetric DVAR of aldehydes (especially aliphatic aldehydes)
with high yield and high regioꢀ, diastereoꢀ and enantioselectivity.
Furthermore, the catalytic asymmetric DVAR with unsaturated esters
as the pronucleophiles, which were very common and versatile interꢀ
mediates in organic synthesis, were not disclosed. The pronucleoꢀ
philes reported in above catalytic asymmetric DVAR were limited to
some special types, such as more reactive unsaturated aldehydes,22a
unsaturated cyclic ketones,22b allyl ketones,22c,22e,22j, and unsaturated
amides derived from oxindoles.22f,22h,22i Herein, we uncover a simple
methodology including copper(I)ꢀcatalyzed asymmetric DVAR of
aldehydes and β,γꢀunsaturated esters, which rapidly leads to an array
of chiral α,βꢀunsaturated δꢀlactones in high regioꢀ and enantioselecꢀ
tivity (Scheme 1f).
Scheme 2. Transformation of LP to CP through Isomerization of
the Unsaturated Carbon-Carbon Double Bond and Subsequent
Intramolecular Transesterification
RESULTS AND DISCUSSION
1. Optimization of Reaction Conditions. The most direct method
to set up a catalytic asymmetric DVAR employed α,βꢀunsaturated
ester (crotonate) as the precursor for the generation of metalꢀdienolate
2 / 10
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Further screening of the ester moiety revealed that phenyl ester was
superior to benzyl ester (entry 10). Screening of organic bases was
fruitless (entries 11ꢀ12). The reaction with Barton’s Base performed
at ꢀ20 C led to a mixture of 3ba and 4a in 98% total yield with 95%
1
2
3
4
5
6
7
8
o
ee for 3ba and 97% ee for 4a (entry 13). We were very lucky to note
that the absolute configuration of the stereogenic carbon centers in
3ba and 4a were identical, which allows the possibility to transform
3ba to 4a in oneꢀpot reaction manner with maintained high enantioseꢀ
lectivity for 4a. Since the isomerization of (Z)ꢀα,βꢀunsaturated ketone
to (E)ꢀα,βꢀunsaturated ketone was reported in literature,25 we tried to
isomerize (E)ꢀLP to (Z)ꢀLP, which would give 4a after intramolecular
transesterification. Several phosphines were screened and Ph2PMe
was identified as the best in terms of reaction efficiency. For example,
3ba of 88% ee was subjected to the THF solution of 25 mol %
Ph2PMe. After the mixture was heated at 60 oC for 10 h, 4a of 88% ee
was obtained in 85% yield (Scheme 2). Then, we performed the oneꢀ
pot reaction consisting of DVAR/isomerization/intramolecular transꢀ
esterification. As shown in Table 1, entry 14, the oneꢀpot reaction led
to 4a predominantly in 92% yield with 97% ee.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Unfortunately, as for aliphatic aldehydes, such as hexanꢀ1ꢀal (5a),
(R)ꢀDTBMꢀSEGPHOS was not the most suitable ligand as lactone 6a
was obtained in significantly low yield with 81% ee and αꢀadduct was
obtained mainly.26 Then, screening of the ester moiety was performed
with 5a.26 It was found that 4ꢀbutenoic acid ester of 3ꢀphenylpropꢀ2ꢀ
ynꢀ1ꢀol led to 6a in highest yield together with good enantioselectiviꢀ
ty. Subsequently, screening of the chiral bisphosphine ligands were
carried out. Common commercially available ligands, such as (R)ꢀ
BINAP, (R)ꢀTOLꢀBINAP, (R)ꢀDIFLUORPHOS and (R,Rp)ꢀ
TANIAPHOS, were not suitable as αꢀadduct was generated domiꢀ
nantly. Fortunately, (R,R)ꢀPhꢀBPE was identified as the best ligand as
the 6a was observed in 59% yield with 90% ee.27 With (R,R)ꢀPhꢀBPE
as the ligand, further screening of the ester moiety revealed that 4ꢀ
butenoic acid ester of butꢀ2ꢀynꢀ1ꢀol was the most suitable substrate as
it is more easily accessed and 6a was obtained in 71% yield with 90%
ee.27 Further screening of copper source and base identified mesityꢀ
lcopper(I)18b,18c,28 as the best copper catalyst in terms of the yield of
6a.29 Since LP showed significantly lower ee than 6a and they owned
opposite absolute configuration, the isomerization/intramolecular
transesterification sequence was not employed to increase the yield of
6a (for details, see SI).
2. Investigation of the Substrate Scope. The substrate scope of
aromatic and heteroaromatic aldehydes was evaluated under the optiꢀ
mized reaction conditions (Table 2). As for the benzaldehydes bearing
paraꢀsubstituent, both electronꢀdonating groups, such as methyl (4b),
tertꢀbutyl (4c), methoxyl (4d) and methylthio (4e), and electronꢀ
withdrawing groups, such as fluoride (4f), chloride (4g), bromide (4h),
iodide (4i), phenyl (4j), and BPin (4k), were well tolerated. orthoꢀ
Methylꢀbenzaldehyde was also competent substrate to afford lactone
4l in 91% yield with 96% ee although the orthoꢀmethyl may lead to
increased steric hindrance and potentially result in lower yield. The
metaꢀmethyl on the benzaldehyde did not disturb both the reactivity
and enantioselectivity (4m). 3,4ꢀDimethoxyl benzaldehyde reacted
with 1b to generate the corresponding lactone (4n) in moderate yield
with excellent enantioselectivity.
Heteroaromatic aldehydes, such as furanꢀ2ꢀcarbaldehyde, thioꢀ
pheneꢀ2ꢀcarbaldehyde, furanꢀ3ꢀcarbaldehyde and thiopheneꢀ3ꢀ
carbaldehyde, were acceptable substrates to give the lactones (4oꢀ4r)
in moderate yields with excellent enantioselectivity. 2ꢀ
Naphthaldehyde was an excellent substrate as the corresponding lacꢀ
tone (4s) was isolated in 85% yield with 97% ee. It is noteworthy that
aldehydes containing nitrogen heterocycle, such as NꢀBocꢀindole and
carbazole, were applicable in the present oneꢀpot reaction. The correꢀ
sponding lactones (4tꢀ4u) were isolated in good yields with high
enantioselectivity. The absolute configurations of 4a, 4f and 4j were
determined to be R by comparing their optical rotation values with
reported data. The absolute configurations in other aromatic products
were deduced by analogy.
Table 3. Substrate Scope of Aliphatic Aldehydesa
Table 2. Substrate Scope of Aromatic and Heteroaromatic Alde-
hydesa
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Page 4 of 10
mesitylcopper(I) (5 mol %)
1. (R,R)-Ph-BPE (5 mol %)
Table 4. DVAR of the Aldehyde Group Distributed in Natural
Products, Natural Product Derivatives and a Derivative of Drug
Molecule Atomoxetinea
O
O
O
5
1
2
3
4
5
6
7
8
+
O
OR
Alk
H
1. THF (0.2 M), rt, 12 h
Alk
R = CH2C CCH3
1c
mesitylcopper(I) (5 mol %)
1. ligand (5 mol %)
O
6
O
O
7
+
O
OR
R
H
1. THF (0.2 M), rt, 12 h
R = nC5H11, 68%, 90% ee
R
6a,
O
R = CH2C CCH3
6b,R = nC7H15, 67%, 89% ee
O
6c, R = nC11H23, 68%, 90% ee
6h,R = Ph, 70%, 86% ee
6i,
1c
8 or 9
O
i
R = CH3, 67%, 85% ee
6d,
R = Pr, 72%, 96% ee
O
6e, R = cyclopropyl, 78%, 95% ee
R = cyclopentyl, 74%, 97% ee
R
ligand = (R,R)-Ph-BPE
6f,
R
6g,R = cyclohexyl, 72%, 97% ee
O
O
O
O
9
O
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
O
6k, R = OTBS, 65%, 90% ee
6l,
R = SO2Ph, 58%, 90% ee
O
N
6m, R = Cl, 60%, 91% ee
6n, R = CO2Me, 62%, 89% ee
8c, 70%, >20/1 drb
R
O
O
8a, 72%, 13/1 dr
8b, 58%, 16/1 dr
6j, 63%, 87% ee
O
O
O
O
O
N
O
O
O
O
6o, 54%, 89% ee
6p, 59%, 90% ee
8d, 62%, 7/1 drb
8e, 62%, 13/1 drb
O
O
O
O
O
O
O
O
O
TBSO
O
O
O
O
H
H
6q, 62%, 89% ee
6r, 65%, 91% ee
6s, 57%, >20/1 dr
H
H
H
H
TBSO
O
a1c
5
chiral-
H
H
8g, 61%, >20/1 dr
, 0.6 mmol; , 0.4 mmol. Isolated yield reported. Enantioselectivity determined by
stationary-phase HPLC analysis. Diastereoselectivity determined by 1H NMR analysis of the
reaction crude mixture.
8f, 61%, >20/1 dr
ligand = (S,S)-Ph-BPE
O
O
O
The substrate scope of aliphatic aldehydes was studied with 5 mol %
complex of mesitylcopper(I) and (R,R)ꢀPhꢀBPE at room temperature
(Table 3). Linear aliphatic aldehydes reacted with 1c smoothly to give
the lactones (6aꢀ6c) in moderate yields with satisfactory enantioselecꢀ
tivity. It is noteworthy that lactone 6a is a natural product, named as (ꢀ
)ꢀmassoia lactone.30 The αꢀbranched aldehyde, as well as the cycloalꢀ
kyl aldehydes, was also competent substrates to generate the lactones
(6dꢀ6g) in moderate yields and excellent enantioselectivity. In the
cases of α,βꢀunsaturated aldehyde, the corresponding lactones (6hꢀ6i)
were isolated in moderate yields with acceptable enantioselectivity.
Enantiomer of lactone 6h, named as goniothalamin, which exhibited a
broad manifold of biological activities,31 is a known natural product.
O
O
O
ent-8c, 65%, 7/1 drb
O
O
9a, 73%, 11/1 dr
9b, 65%, 11/1 dr
O
N
O
O
O
ent-8d, 69%, >20/1 drb
9e, 62%, 11/1 drb
O
O
O
O
Furthermore, a series of aliphatic aldehydes bearing various funcꢀ
tional groups was evaluated under the optimized reaction conditions.
Phthalimide (6j), TBSꢀether (6k), phenyl sulfone (6l), alkyl chloride
(6m), ester (6n), terminal olefin (6o), internal alkyne (6p) and acetal
(6q) were well tolerated under the present catalytic system. These
versatile functional groups leave the spacious room for further elaboꢀ
ration of the structures in organic synthesis. It is particularly noteworꢀ
thy that a methyl ketone moiety, which may lead to a competitive
aldol reaction with the aldehyde moiety, did not disturb the DVAR in
the present conditions. The corresponding lactone (6r) was isolated in
65% yield with 91% ee. Moreover, a chiral aldehyde containing TBSꢀ
ether of a secondary alcohol was employed in the DVAR. The reacꢀ
tion proceeded nicely to give the corresponding lactone (6s) in excelꢀ
lent stereoselectivty, which would lead to the enantiomer of natural
product euscapholide (antiꢀinflammatory activity)32 through deprotecꢀ
tion of the TBSꢀether moiety. The absolute configurations of 6a, 6b,
6g, 6h and 6s were determined as shown in Table 3 through comparꢀ
ing their optical rotation values with reported data. The absolute conꢀ
figurations in other products were assigned tentatively by analogy.
H
H
H
H
H
H
TBSO
O
H
H
9f, 63%, >20/1 dr
9g, 64%, >20/1 dr
, 0.6 mmol; , 0.4 mmol. Isolated yield reported. Diastereoselctivity determined by 1H
NMR analysis of the reaction crude mixture. bDiastereoselectivity determined by chiral-
stationary-phase HPLC analysis.
a1c
7
The present methodology was successfully extended to chiral natuꢀ
ral products, natural product derivatives and a derivative of drug molꢀ
ecule Atomoxetine, all of which contain an aldehyde moiety (Table 4).
In the presence of 5 mol % mesitylcopper(I) and 5 mol % (R,R)ꢀPhꢀ
BPE or (S,S)ꢀPhꢀBPE, (ꢀ)ꢀperillaldehyde and (ꢀ)ꢀmyrtenal reacted
smoothly with 1c to afforded the lactones (8a, 8b, 9a and 9b) in modꢀ
erate yields with high diastereoselectivity. It is noteworthy that the
copper catalyst derived from (R,R)ꢀPhꢀBPE exhibited slightly better
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asymmetric induction. Both (ꢀ)ꢀcitronellal and (+)ꢀcitronellal were
suitable substrates, which afforded all four enantiomers of the lactone
(8c, 8d, entꢀ8c and entꢀ8d) in moderate yields. However, in the case
of 8d and entꢀ8c, the diastereoselectivity was moderate due to the
unsatisfactory optical purity of commercially available (+)ꢀcitronellal.
Moreover, an aldehyde derived from drug molecule Atomoxetine,
which is used to treat attention deficit hyperactivity disorder, was
applicable under the present reaction conditions. Lactones 8e and 9e
were generated in moderate yields with high diastereoselectivity.
DVAR of two steroidal molecules (7f and 7e) bearing an aldehyde
group, which derived from (+)ꢀlithocholic acid, resulted in lactones
(8f, 8g, 9f and 9g) in good yields with excellent diastereoselectivity.
The stereochemistry of product 9f was determined as shown in Table
4 by Xꢀray diffraction analysis (for details, see SI). The stereochemisꢀ
try of other products was assigned by analogy.
1
2
3
4
5
6
7
8
9
3. Insights to the Reaction Mechanism and Proposed Reaction
Pathway. The catalytic asymmetric DVARs of benzaldehyde and 4ꢀ
butenoate 1a and 1b at room temperature are presented in Scheme 5.
When 1a was used, 3aa was generated in 32% yield with 88% ee
while 4a was produced in 66% yield with 87% ee (Scheme 5A). In
the case of 1b, 3ba was obtained in 38% yield with 88% ee while 4a
was obtained in 60% yield with 94% ee. It is interesting to note that
4a (94% ee) showed higher ee than 3ba (88% ee). When we submitꢀ
ted the racemic lactone 4a to the present conditions of DVAR, 4a was
recovered quantitatively without any change in its ee (Scheme 5B).
This observation indicated that the pathway to form 4a was not reꢀ
versible.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Catalytic Asymmetric DVAR via Dynamic Kinetic
Resolution
Scheme 5. Catalytic Asymmetric DVARs of Benzaldehyde with 1a
and 1b (1H NMR Yields Are Given)
DVAR of chiral aldehyde 7h derived from Naproxen, which was
suspicious to racemize under basic conditions, furnished lactone 8h in
1
88% yield with 11/1 dr based on the H NMR analysis of the crude
mixture (Scheme 3A). Fortunately, the diastereoisomers were separatꢀ
ed successfully by column chromatography to deliver pure 8h in 73%
yield with >20/1 dr and 97% ee. When (S,S)ꢀPhꢀBPE was employed
instead of (R,R)ꢀPhꢀBPE, entꢀ8h of 81% ee was produced in 73%
1
yield with 1.8/1 dr based on the H NMR analysis of the crude mixꢀ
ture (Scheme 3B). It was evident that racemization of 7h occurred
under the present basic reaction conditions, which resulted in the
formation of entꢀ8h. We reasoned that if racemic aldehyde 7h was
used, a dynamic kinetic resolution might occur to generate the chiral
lactone 8h. In DVAR of 1c and racꢀ7h, lactone 8h was isolated in 66%
yield with >20/1 dr and 94% ee (Scheme 3C).
However, when racemic 3ba was submitted to the present condiꢀ
tions, 85% 3ba was recovered in 16% ee and 4a was obtained in 15%
yield with 86% ee (Scheme 5C). The reaction of racemic 3aa gave the
similar results, which revealed that the pathway to form 3aa or 3ba
was reversible. More interestingly, the retroꢀDVAR of (R)ꢀ3aa or (R)ꢀ
3ba was favored. Thus, more (S)ꢀ3aa or (S)ꢀ3ba remained in the reacꢀ
tion mixture. These results indicated that a low efficient kinetic resoꢀ
lution possibly existed in the retroꢀDVAR of racemic 3aa or 3ba. The
retroꢀDVAR of 3aa or 3ba occurred to give benzaldehyde and correꢀ
sponding dienolates, which afforded (R)ꢀγꢀadduct with a (Z)ꢀolefin
through the copper(I)ꢀcatalyzed DVAR. Then, (Z,R)ꢀγꢀadduct transꢀ
formed to (R)ꢀ4a through irreversible intramolecular transesterificaꢀ
tion. Since αꢀadduct was not observed in the catalytic asymmetric
DVAR, we tried to explore the reason. In order to get some insights,
we prepared racemic αꢀadduct 10aa according to a reported procedure
with modification.33 Then, it was submitted to the present catalytic
asymmetric reaction conditions (Scheme 5D). Surprisingly, αꢀadduct
Finally, the more easily available crotonates (vs β,γꢀunsaturated esꢀ
ters) were tried under the present reaction conditions. As shown in
Scheme 4, both methyl crotonate and phenyl crotonate were comꢀ
pletely inert in the presence of 5 mol % Cu(CH3CN)4PF6, (R)ꢀDTBMꢀ
SEGPHOS and Barton’s Base. Even by increasing the amount of
Barton’s Base from 5 mol % to 1 equiv, methyl crotonate remained
intact. In the case of phenyl crotonate, only slight decomposition was
observed and no desired VAR products were detected. Clearly, Barꢀ
ton’s Base was not strong enough to achieve the deprotonation proꢀ
cess at the γꢀposition of crotonates.
Scheme 4. DVAR of Methyl Crotonate and Phenyl Crotonate with
Benzaldehyde
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completely consumed. 4a was obtained in 79% yield with 85% ee and
was observed (Scheme 6C). In order to get further insights to the
3aa was obtained in 19% yield with 71% ee. This observation clearly
pointed out that the αꢀaddition of 1 with aromatic aldehydes was
reversible and unfavored in the present basic reaction conditions.
mechanism, the mixed crossꢀover reaction of benzaldehyde and raceꢀ
mic 12ca (dr = 1/1) was performed in the reaction conditions of cataꢀ
lytic asymmetric DVAR with (R)ꢀDTBMꢀSEGPHOS as the ligand
(Scheme 7C). Interestingly, three products were obtained, including
3ca (12% yield, 78% ee), 6a (18% yield, 76% ee) and 4a (56% yield,
83% ee). These results indicated the DVAR of aromatic aldehyde
proceeded preferentially in the presence of aliphatic aldehyde. Moreꢀ
over, it is interesting to note that 4ꢀbutenoic acid ester of butꢀ2ꢀynꢀ1ꢀ
ol (1c) led to more CP (4a) than 4ꢀbutenoic acid ester of phenol (1b)
in the DVAR of aromatic aldehyde with (R)ꢀDTBMꢀSEGPHOS as the
ligand (Scheme 7A vs Scheme 5A). Even in the DVAR of aliphatic
aldehyde 5a and 1c with (R)ꢀDTBMꢀSEGPHOS as the ligand, no LP
(11ca) was generated (Scheme 7B).
1
2
3
4
5
6
7
8
Scheme 6. Catalytic Asymmetric DVARs of Hexan-1-al with 1c
under Two Different Reaction Conditions (1H NMR Yields Are
Given)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 7. Catalytic Asymmetric Cross-Over DVAR (1H NMR
Yields Are Given)
Based on above experiment observations and literatures,19e,19f
a
plausible reaction pathway is proposed although speculative at this
juncture (Scheme 8). In the presence of copper(I) complex U, deproꢀ
tonation of A by base generates copper(I)ꢀdienolate V, which forms
an equilibrium with allyl copper(I) species W. The aldol reaction of V
with aldehyde B would result in αꢀaddition and finally lead to αꢀ
adduct upon protonation, which was found to be reversible. αꢀ
Addition would be disfavored in the presence of steric hindrance from
the bulky bisphosphine ligand. The competitive allylation of B (γꢀ
addition) with W would furnish copper(I)ꢀalkoxide X and Y through a
formal vinylogous aldol reaction through a sixꢀmembered transition
state. However, the pathway to X and Y is not controlled with selecꢀ
tivity, possibly because that W was not optically pure. Definitely, this
allylation process is reversible in the case of aromatic aldehydes as
demonstrated by above experimental observations. Protonation of Y
with A would lead to linear product C and regenerate copper(I)ꢀ
dienolate V. On the other way, intramolecular transesterification of X
irreversibly generates cyclic product D and releases copper(I) alkoxꢀ
ide/phenoxide, which transforms to copper(I)ꢀdienolate V through
deprotonation with A.
As for aliphatic aldehyde 5a, in the presence of 5 mol % mesityꢀ
lcopper(I)ꢀ(R,R)ꢀBPE, lactone 6a was obtained in 75% yield with 90%
ee while linear product 11ca was observed in 21% yield with 40% ee
(Scheme 6A). It should be noted that 6a had the opposite absolute
configuration to 11ca. In order to explore the reason that only trace αꢀ
adduct was observed, αꢀadduct34 was subjected to the present catalytic
system with mesitylcopper(I)ꢀ(R,R)ꢀBPE. αꢀAdduct 12ca converted to
γꢀadducts completely in 12 h (Scheme 6B). 6a was obtained in 53%
yield with 90% ee and 11ca was generated in 20% yield with 39% ee,
which perfectly matched with the results of the DVAR. Under the
reaction conditions with 5 mol % Cu(CH3CN)4PF6ꢀ(R)ꢀDTBMꢀ
SEGPHOSꢀBarton’s Base, such a tendency was also observed
(Scheme 6E). These experimental observations clearly demonstrated
that the retroꢀaldol reaction of αꢀadduct also occurred in the cases of
aliphatic aldehydes. It should be noted that the DVAR of aliphatic
aldehyde 5a with (R)ꢀDTBMꢀSEGPHOS gave 6a in higher yield
without formation of 11ca than the reaction with (R,R)ꢀPhꢀBPE, albeit
with lower enantioselectivity for 6a (Scheme 6D vs Scheme 6A).
Scheme 8. Proposed Mechanism for the Copper(I)-Catalyzed
Asymmetric DVAR
Furthermore, no change was found in the reaction of racemic 11ca
in the presence of 5 mol % mesitylcopper(I)ꢀ(R,R)ꢀBPE or 20 mol %
Cu(CH3CN)4PF6ꢀ(R)ꢀDTBMꢀSEGPHOSꢀBarton’s Base (Scheme 6F).
When racemic 11ca was subjected to the catalytic system with 20
mol % mesitylcopper(I)ꢀ(R,R)ꢀBPE, a very weak kinetic resolution
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[Cu(I)]-base
O
A
P
Cu(I)
[Cu(I)]
U
*
OR
1
2
3
4
5
P
H
O
B
O
R'
H
O[Cu(I)]
O
OR
copper(I)-dienolate (V)
[Cu(I)]O
R'
O
R'
-adduct
A
D (CP)
OR
base
V
reversible
6
7
Z
O
OH
O
O
OR
R'
OR
8
9
[Cu(I)]
OR
C (LP)
allyl copper(I)
species (W)
H
A
10
11
12
13
14
15
16
O[Cu(I)]
Y
O
O
B
R'
OR
R'
H
R'
O[Cu(I)]
O
OR
X
4. Application of the Present Methodology. The robustness of the
present catalytic asymmetric DVAR was demonstrated by a gramꢀ
scale reaction of paraꢀFꢀbenzaldehyde in the presence of 2 mol %
Cu(CH3CN)4PF6, (R)ꢀDTBMꢀSEGPHOS and Barton’s Base. paraꢀFꢀ
Benzaldehyde (0.993 g) reacted with phenyl 4ꢀbutenoate (1.946 g) to
afford lactone 4g (1.143 g) in 74% yield with 95% ee (Scheme 9).
Interestingly, lactone 4g was an advanced synthetic intermediate toꢀ
ward the synthesis of ezetimibe (Zetia®),6d which is a strong βꢀ
lactamic cholesterol absorption inhibitor and is commercially availaꢀ
ble as a new drug for lowering plasma cholesterol levels. By followꢀ
ing the literature synthetic route,6d ezetimibe could be synthesized
from lactone 4g.
17
18
19
20
21
22
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24
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30
31
32
33
34
35
36
37
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39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The present methodology of DVAR was applied to the formal
asymmetric synthesis of fostriecin (Scheme 10). Commercially availꢀ
able and cheap dimethyl Dꢀmalate (13) was selected as the starting
material. Its partial reduction by borane and sodium borohydride and
subsequent protection of the vicinal diol afforded 14 in 82% yield for
two steps. Reduction of 14 with DIBALꢀH and following Wittigꢀ
olefination with the aldehyde moiety provided 15 in 81% yield for
two steps. The similar synthetic approach from 15 to 16 was realized
in 91% yield for three steps. The reduction of 16 with DIBALꢀH and
succedent Swern oxidation furnished 17 as the starting material for
the key DVAR. The catalytic asymmetric DVAR of 17 gave 18 in 64%
yield with 12/1 diastereoselectivity at room temperature. The total
yield from dimethyl Dꢀmalate to advanced intermediate 18 reached
33%. Then, by following a reported synthetic approach,36 fostriecin
could be accessed.
Scheme 9. Application of the Present Catalytic Asymmetric
DVAR in the Formal Asymmetric Synthesis of Ezetimibe
CONCLUSION
In conclusion, a simple methodology for the rapid synthesis of chiꢀ
ral α,βꢀunsaturated δꢀlactones was disclosed by using easily available
starting materials in the presence of copper catalyst. This methodoloꢀ
gy enjoys broad substrate scope, including various aromatic aldehydes,
heteroaromatic aldehydes, α,βꢀunsaturated aldehydes and aliphatic
aldehydes. Interestingly, in the cases of aromatic and heteroaromatic
aldehydes, a oneꢀpot reaction involving DVAR, isomerization of the
unsaturated carbonꢀcarbon double bond from (E)ꢀform to (Z)ꢀform
and subsequent intramolecular transesterification was carried out to
obtain the lactones in good to high yields. Various functional groups,
such as aryl halides (F, Cl, Br, I), methoxyl, methylthio, BPin,
phthalimide, TBSꢀether, sulfone, alkyl chloride, ester, terminal olefin,
internal alkyne, acetal and ketone were well tolerated. Moreover, the
methodology was successfully applied to natural products, natural
product derivatives and derivatives of drug molecules, all of which
contain an aldehyde group. In the proposed mechanism, an allyl copꢀ
per(I) species, which forms an equilibrium with a copper(I)ꢀdienolate
species, was considered as the key intermediate to react with aldeꢀ
hydes to generate the chiral vinylogous products. The retroꢀaldol
reaction of αꢀadducts indicated a reversible and unfavored αꢀaddition
process and was attributed to the reason that perfect regioselectivity
was achieved in the present DVAR. Finally, the present methodology
was applied in the formal asymmetric synthesis of ezetimibe and
fostriecin. Further expansion of the vinylogous pronucleophiles, as
well as application of the present DVAR in the asymmetric synthesis
of complex natural products or medicinal molecules, is currently
ongoing in our laboratory.
Fostriecin, which was a star molecule, exhibited impressive cytoꢀ
toxicity towards a broad spectrum of cancer cell lines, including
breast cancer, ovarian cancer, and leukemia. Therefore, extensive
efforts from the chemical community have been dedicated to its
asymmetric total synthesis.35 Although the phase I clinical trials with
fostriecin were not continued due to its instability and the inconsistent
purity of the samples from natural sources, the endeavors towards its
asymmetric synthesis continued emerging. It is realized that the synꢀ
thetic approaches provide an opportunity for searching potentially
more stable analogues of fostriecin and obtaining sufficient sample
with consistent purity.35 Thus, developing new and efficient synthetic
approaches toward fostriecin are still valuable.
Scheme 10. Application of the Present Catalytic Asymmetric
DVAR in the Formal Asymmetric Synthesis of Fostriecin
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M.; Christmann, M. Synthesis 2002, 2002, 981–1003. (c) Bialy, L.;
ASSOCIATED CONTENT
Supporting Information
Waldmann, H. Chem. Commun. 2003, 1872–1873. (d) Buck, S. B.;
Hardouin, C.; Ichikawa, S.; Soenen, D. R.; Gauss, C.ꢀM.; Hwang, I.;
Swingle, M. R.; Bonness, K. M.; Honkanen, R. E.; Boger, D. L. J.
Am. Chem. Soc. 2003, 125, 15694–15695.
1
2
3
4
5
6
7
8
The Supporting Information is available free of charge on the ACS
Publications website at:
(6) For some selected recent examples, see: (a) Huang, C.; Liu, B. Chem.
Commun. 2010, 46, 5280–5282. (b) Huang, X.; Song, L.; Xu, J.; Zhu,
G.; Liu, B. Angew. Chem., Int. Ed. 2013, 52, 952–955. (c) Melillo,
B.; Smith, A. B., III. Org. Lett. 2013, 15, 2282–2285. (d) Śnieżek,
M.; Stecko, S.; Panfil, I.; Furman, B.; Chmielewski, M. J. Org.
Chem. 2013, 78, 7048–7057. (e) Chen, W.; Yang, X.ꢀD.; Tan, W.ꢀY.;
Zhang, X.ꢀY.; Liao, X.ꢀL.; Zhang, H. Angew. Chem., Int. Ed. 2017,
56, 12327–12331. (f) Xie, C.; Luo, J.; Zhang, Y.; Zhu, L.; Hong, R.
Org. Lett. 2017, 19, 3592–3595.
Crystallographic data for 9f (CIF)
Experimental procedures, Xꢀray diffraction data for 9f, and
spectroscopic data for all new compounds including 1H, 19F,
and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
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(7) For some selected recent examples, see: (a) Kadlčíková, A.; Hrdina,
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Wang, Y.; Zheng, J.; O’Doherty, G. A. Synthesis 2016, 48, 1700–
1710. For two selected interesting synthetic strategies for the syntheꢀ
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*liangyin@sioc.ac.cn
ORCID
Liang Yin: 0000ꢀ0001ꢀ9604ꢀ5198
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We gratefully acknowledge the financial support from the “Thousand
Youth Talents Plan”, the National Natural Science Foundation of
China (No. 21672235 and No. 21871287), the Strategic Priority Reꢀ
search Program of the Chinese Academy of Sciences (No.
XDB20000000), CAS Key Laboratory of Synthetic Chemistry of
Natural Substances and Shanghai Institute of Organic Chemistry. Mr.
JunꢀZhao Xiao from Shanghai Institute of Organic Chemistry is
acknowledged for the check of reproducibility.
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while, LP (11ca) was obtained in 21% yield with 40% ee (Scheme
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