Desymmetrization construction of chiral lactones by synergistic Cu(II) complex and organic base

Article abstract of DOI:10.1016/j.tetlet.2020.152106

A highly enantioselective construction of quaternary carbon center has been realized by the desymmetrization strategy. Chiral enol lactones with up to 95% ee could be synthesized from prochiral dialkynoic acid under the catalysis of synergistic chiral Cu(II) complex and chiral (DHQ)₂-PHAL base.

Full text of DOI:10.1016/j.tetlet.2020.152106

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Desymmetrization construction of chiral lactones by synergistic Cu(II) com‐
plex and organic base
Murad Ali, Changkun Li
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S0040-4039(20)30557-8
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Reference:
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TETL 152106
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Please cite this article as: Ali, M., Li, C., Desymmetrization construction of chiral lactones by synergistic Cu(II)
complex and organic base, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.152106
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Desymmetrization Construction of Chiral Lactones
by Synergistic Cu(II) Complex and Organic Base
Murad Ali, Changkun Li
Leave this area blank for abstract info.
nPr nPr
cat. Cu(II)
O
COOH
L
cat.
R
O
O
cat. chiral base
O
N
N
R
L
Ph
Ph
Desymmetrization enabled by synergistic up 97% yield
chiral Cu(II) complex and organic base
up to 95% ee

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Desymmetrization construction of chiral lactones by synergistic Cu(II) complex and
organic base
Murad Alia, Changkun Lia 
a Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Chemistry and Chemical Engineering, Frontiers Science Center for
Transformative Molecules, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
———
ARTICLE INFO
ABSTRACT
 Corresponding author. e-mail: chkli@sjtu.edu.cn
Article history:
Received
Received in revised form
Accepted
A highly enantioselective construction of quaternary carbon center has been realized by the
desymmetrization strategy. Chiral enol lactones with up to 95% ee could be synthesized from
prochiral dialkynoic acid under the catalysis of synergistic chiral Cu(II) complex and chiral
(DHQ)2-PHAL base.
Available online
2020 Elsevier Ltd. All rights reserved.
Keywords:
desymmetrization
all-carbon quaternary center
copper
lactone
synergistic catalysis
Asymmetric construction of all-carbon quaternary carbon
stereocenters is a challenging task in organic synthesis [1].
Desymmetrization conversion of only one between the two
possible reaction sites in the prochiral substrates provides a
successful strategy to build quaternary-carbon-containing chiral
molecules [2]. Prochiral bisalkynes were frequently utilized for
the versatile transformation of the triple bonds. Different types of
reactions, such as hydroacylation [3], azide-alkyne cycloaddition
[4], hydro-functionalization [5], were realized desymmetrically.
In 2013, Hennecke reported the asymmetric bromolactonization
of diynoic acid with chiral base (DHQD)2-PHAL to prepare
lactones with alkenyl bromide (Scheme 1) [6]. The
enantioselectivity of lactone from terminal diynoic acid could be
further improved to 88% with monomeric Cinchona alkaloid
based catalyst [7]. The atom-economic direct lactonization could
be catalyzed by many transition metals, such as Au, Pd, Ru, Rh,
Ir, Cu, Co and others [8]. However, the asymmetric version is
still far from optimal, due to the long distance between the
reaction site and the prochiral stereocenter. Sridharan and Sasai
developed a Pd(OAc)2/(R)-SDP-catalyzed lactonization and low
enantiomeric excess could be obtained for terminal diynoic acid
[9]. Herein, we present the high enantioselective
desymmetrization construction of chiral enol lactones by
synergistic transition-metal catalysis and organocatalysis [10].
Up to 95% ee was obtained when catalytic amount of chiral
Cu(II)/Box complex and chiral (DHQ)2-PHAL were applied.
a
) Hennecke, chiral base, bromolactonization
O
Ph
COOH
1.2 equiv. NBS
10 mol% chiral base
O
Ph
H
Br
up to 88% ee
b
) Sridharan and Sasai, Pd(OAc)2/chiral ligand
O
Ph COOH
10 mol% Pd(OAc)2
PPh2
PPh2
12 mol% (R)-SDP
*
O
Ph
H
H
(R)-SDP
93% yield, 13% ee
c
) This work: Synergistic catalysis by Cu(II)/Box and chiral base
10 mol% Cu(ClO4) 6H2O
n-Pr n-Pr
O
COOH
L
12 mol%
R
O
O
12 mol% (DHQ)2PHAL
O
N
N
R
L
Ph
Ph
up 97% yield
up to 95% ee
Et
N
Et
N
N
N
O
O
H
H
MeO
OMe
(DHQ)2PHAL
N
N
Scheme 1. Quaternary Carbon Centers Construction from Prochiral
Dialkynes by Desymmetrical Lactonization.
We commenced the study with phenyl substituted terminal
diynoic acid 1a as the model substrate (Table 1). When Cu(OTf)2
and Box ligand L1 were used, lactone 2a was isolated with
92%yield and 42% ee (entry 1). Ligands with t-butyl and benzyl
groups on the oxazoline rings were less selective than L1 (entries
2 and 3). Keeping the phenyl on the oxazoline rings, the size
effect of the ligand backbone was further examined. Lower

2
Tetrahedron
enantioselectivity was observed when L4 with a smaller
substitutions at the para-position of the phenyl ring was further
checked. Electron-donating MeO and t-Bu groups as well as the
electron-neutral phenyl and 2-naphthyl groups were tolerated
smoothly to give 2e to 2h in high yields and ees. The absolute
configuration of 2h was assigned to S by the single crystal X-ray
diffraction analysis. Carbon-carbon triple and double bonds could
also be introduced into the products 2i and 2j in high yield and
enantioselectivities. Substrates with electron-withdrawing groups
react under the same condition to afford the lactones in high
yields. However, lower enantioselectivities were obtained. A
clear trend was observed among these results. The more electron-
withdrawing the substitution is, the lower enantiomeric excess
could be obtained. 78% to 86% ees were observed for halogen-
substituted 2k to 2m (-para constants [11] for F, Cl and Br are
0.06, 0.23 and 0.23 respectively). The ee of 2n with an electron-
withdrawing CF3 group (-para constant is 0.54) drops to 61%.
Furthermore, only 39% ee was obtained when strong electron-
withdrawing nitro group was introduced (-para constant for
nitro group is 0.78). Finally, heterocyclic diyonic acid with 3-
thiophenyl group also successfully react to afford the expected
cyclopropane group was used (entry 4). While the reaction
applying L5 with bulkier two n-propyl groups lead to 62% ee
(entry 5). Cu(ClO4)2·6H2O was proven to be a better catalyst
precursor than Cu(acac)2 and Cu(MeCN)4PF6 (entries 6-8),
although the solubility of Cu(ClO4)2·6H2O is not good in DCE
and a mixture of DCE and CH3CN in 2 : 1 ratio has to be used as
solvent. Lewis acidic Zn and Y metal salts other than Cu can also
catalyze the reaction, albeit in lower enantioselectivities (entries
9-11). Inspired by the effect of chiral base in the
bromolactonization reaction [6,7], several bases were added as
additive. As we expected, the enantioselectivity increased to 89%
ee when 12 mol% (DHQ)2-PHAL was used (entry 12). The
enantiomeric excess was further improved to 94% when the
o
reaction was run at 0 C (entry 13). Control experiments were
conducted to examine the effect of the chiral base (DHQ)2-
PHAL. 90% of racemic 2a was isolated when (DHQ)2-PHAL
was used without the help of any chiral Box ligand (entry 14).
The other enantiomer of the product was obtained predominantly
(-54% ee) when ent-L5 (the other enantiomer of L5) and
(DHQ)2-PHAL were used (entry 15).
10 mol% Cu(ClO4)2 6H2O
Table 1
O
COOH
L5
12 mol%
R
12 mol% (DHQ)2PHAL
Optimization of the Cu(II)/Box and (DHQ)2-PHAL Co-catalyzed
Lactonization of Terminal Diynoic Acida
O
DCE : CH3CN, 0 oC, 18 h
R
O
Ph COOH
O
1
2
10 mol% Cat.
L*
12 mol%
O
Ph
DCE, rt, 24 h
O
O
O
O
2a
1a,
0.2 mmol
O
O
O
Me
Me
Me Me
nPr nPr
Me
1
L1
L2
L3
O
N
O
, R = Ph
O
O
O
O
2a
2b
2c
2d
, 92%, 94% ee
, 96%, 95% ee
, 96%, 95% ee
, 90%, 13% ee
1
t
, R = Bu
N
N
N
N
N
gram scale
1
, R = Bn
R1
R1
Ph
Ph
Ph
Ph
L5
L4
O
O
O
O
O
entry
1
2
catalyst
yield (%)b
92
ee (%)c
42
26
2
ligand
L1
L2
O
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
tBu
MeO
2e
Ph
94
90
3
L3
, 97%, 94% ee
2g
, 94%, 88% ee
2f
, 97%,93% ee
4
5
6d
7
8
9
10
11
12d,e
13d,e,f
14d,e
15d,e,f
Cu(OTf)2
Cu(OTf)2
Cu(ClO4)2·6H2O
Cu(acac)2
Cu(CH3CN)4PF6
Zn(OTf)2
Zn(BF4)2
Y(OTf)3
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
L4
L5
L5
L5
L5
L5
L5
L5
59
93
97
91
90
94
87
85
93
93
90
95
30
62
66
47
61
30
35
13
89
94
0
O
O
O
O
Ph
2h
, 93%, 91% ee
2i
, 97%, 86% ee
L5
L5
-
O
O
O
O
O
O
O
O
F
Br
Cl
ent-L5
-54
a Conditions: 0.2 mmol of 1a in DCE (2.0 mL).
bIsolated yield.
2j
, 93%, 94% ee 2k
2l
, 96%, 81% ee
, 96%, 86% ee
2m
, 96%, 78% ee
cThe enantiomeric excess of 2a was determined by HPLC with a
chiral column.
O
O
O
O
O
dA mixture of DCE and CH3CN in 2 : 1 ratio was used as solvent.
e12 mol% of (DHQ)2-PHAL was added, 12 h.
fReaction was run at 0 oC, 18 h.
S
O
O2N
F3C
2n
, 96%, 61% ee
2o
, 95%, 39% ee
2p
, 93%, 65% ee
With the optimized condition in hand, we examined the scope
of the Cu(II)/Box and (DHQ)2-PHAL co-catalyzed lactonization
(Scheme 2). Firstly, the synthesis of 2a could be conducted in 1
gram scale without erosion of the enantioselectivity. Methyl
groups at para- or meta-position of the phenyl ring have
neglectable effect to the enantioselectivities of the lactones (2b
and 2c). On the contrast, only 13% ee was obtained in 2d with an
ortho-methyl substituted phenyl group. The electronic effect of
Scheme 2. Scope for Cu(II)/Box and (DHQ)2-PHAL Co-catalyzed
Lactonization.
product 2p in high yield with modest enantioselectivity (65% ee).
To gain more insight into reaction mechanism, some control
experiments were conducted (scheme 3). Deuterium labelled
diynoic acid 1a-D was tested under standard reaction condition

3
(eq 1). Only the proton trans to the ester oxygen was partially
transformed into D (20%), which was supported by the NOE
analysis. This result may suggest that an intramolecular anti-
addition of the carboxylic acid to a Cu-activated alkyne
intermediate is involved. When 2-phenylpent-4-ynoic acid 3 was
tested, no any cyclization product was observed and the substrate
was recovered in 95% yield (eq 2). However, 2-methyl-2-
phenylpent-4-ynoic acid rac-4 with a quaternary carbon center
was converted to the lactone 5 in 85% yield, probably due to the
short distance between acid and alkyne group caused by Thorpe-
Ingold effect (eq 3). Finally, 6 with two internal alkynes was
converted to the enol lactone 7 in relatively lower yield and
enantioselectivity, which indicates the terminal alkynes are not
mandatory for the reactivities and the Cu-acetylide formation
might be not involved (eq 4).
with ethyl diazoacetate under CuI successfully afforded 8b in
good yield and ee [12]. Ring opening of the enol lactone by
nucleophilic addition of methanol or dimethylamine to 2a
produces ester 8c and amide 8d respectively under mild reaction
conditions in good yields with small erosion of ee. An all-carbon
quaternary carbon center with three versatile functional groups
(alkyne, ketone and ester or amide) could be constructed with
high enantioselectivities.
Ph
CO2Et
O
O
O
b)
a)
O
8a
O
8b
90%, 94% ee
94%, 95% ee
O
10 mol% Cu(ClO4)2 6H2O
L5
O
Ph COOD
2a
, 94% ee
12 mol%
d)
c)
O
D
COOMe
O
CONMe2
O
Ph
12 mol% (DHQ)2PHAL
(1)
DCE/CH3CN (2 : 1), 0 oC, 18 h
93% yield
H (100%)
8d
(20%)
Me
Me
8c
1a-D
2a-D
92%, 90% ee
92%, 93% ee
Scheme 5. Synthetic Transformation of Enol lactone 2a. aConditions:
a) PhBr (2.5 equiv), Pd(PPh3)2Cl2 (2 mol%), CuI (4 mol%), Et3N (2
equiv), DMF, 50 °C, 12 h. b) N2CHCO2Et (1.1 equiv), CuI (5 mol%),
MeCN, rt, 5 h. c) CH3OH (1 ml, excess), NH(CH3)2 (2 M in THF,
1.1 equiv), 50 oC, 3 h. d) NH(CH3)2 (1 ml, 2 M in THF), rt, 12 h..
Ph
CO2H
standard condition
no reaction
(2)
(3)
3
95% recovered
3
O
Me
Ph
CO2H
Me
O
Ph
standard condition
In conclusion, we have developed a highly enantioselective
synthesis of enol lactones with a quaternary carbon centre. Chiral
enol lactones with up to 95% ee could be synthesized from
prochiral dialkynoic acid under the catalysis of synergistic chiral
Cu(II) complex and chiral (DHQ)2-PHAL base. The reaction
could be conducted in gram scale and the products were easily
transformed to chiral molecules with different functional groups.
The extension of this strategy to other types of reactions from
prochiral bisalkynes is under investigation in our group.
H
5
rac-4
, 85%
Me
O
10 mol% Cu(ClO4)2 6H2O
Ph COOH
L5
12 mol%
12 mol% (DHQ)2PHAL
(4)
DCE/CH3CN (2 : 1), 0 oC, 36 h
O
Ph
Me Me
Me
6
7
, 34%, 78% ee
Scheme 3. Mechanism Studies.
Based on the experiments above and the literature reports, a
tentative mechanism was proposed in Scheme 4. Chiral Cu(II)
complex coordinates with one of the two alkyne groups
selectively under the help of matched chiral organic base, which
is the key step for the desymmetrization process. When R on the
phenyl is a neutral or electron-donating group, a concerted
deprotonation by the chiral base and anti-attack of the carbonyl
oxygen to the Cu-activated alkyne affords the alkenyl Cu
intermediate. Further protonation of the Csp2-Cu bond by the
ammonium salt or the free carboxylic acid delivers the enol
lactone 2 and releases the Cu(II) catalyst. In case R is an
electron-withdrawing group, the acidity of the carboxylic acid
increases and the anti-addition to the alkyne is at least partially
not controlled by the chiral amine, which leads to the low
enantioselectivities observed.
Acknowledgments
This work is supported by National Natural Science Foundation
of China (NSFC) (Grant 21602130) and the starting fund of
Shanghai Jiao Tong University. We thank Xiang Li and Ke Li for
the compound 5 synthesis.
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5


Construction of quaternary carbon
center by the desymmetrization strategy
Chiral enol lactones with up to 95% ee
could be synthesized from prochiral
dialkynoic acid

Synergistic catalysis by chiral Cu(II)
complex and chiral (DHQ)2-PHAL base.