Highly Selective and Catalytic Generation of Acyclic Quaternary Carbon Stereocenters via Functionalization of 1,3-Dienes with CO2

Article abstract of DOI:10.1021/jacs.9b09721

The catalytic asymmetric functionalization of readily available 1,3-dienes is highly important, but current examples are mostly limited to the construction of tertiary chiral centers. The asymmetric generation of acyclic products containing all-carbon quaternary stereocenters from substituted 1,3-dienes represents a more challenging, but highly desirable, synthetic process for which there are very few examples. Herein, we report the highly selective copper-catalyzed generation of chiral all-carbon acyclic quaternary stereocenters via functionalization of 1,3-dienes with CO₂. A variety of readily available 1,1-disubstituted 1,3-dienes, as well as a 1,3,5-triene, undergo reductive hydroxymethylation with high chemo-, regio-, E/Z-, and enantioselectivities. The reported method features good functional group tolerance, is readily scaled up to at least 5 mmol of starting diene, and generates chiral products that are useful building blocks for further derivatization. Systemic mechanistic investigations using density functional theory calculations were performed and provided the first theoretical investigation for an asymmetric transformation involving CO₂. These computational results indicate that the 1,2-hydrocupration of 1,3-diene proceeds with high π-facial selectivity to generate an (S)-allylcopper intermediate, which further induces the chirality of the quaternary carbon center in the final product. The 1,4-addition of an internal allylcopper complex, which differs from previous reports involving terminal allylmetallic intermediates, to CO₂ kinetically determines the E/Z- and regioselectivity. The rapid reduction of a copper carboxylate intermediate to the corresponding silyl-ether in the presence of Me(MeO)₂SiH provides the exergonic impetus and leads to chemoselective hydroxymethylation rather than carboxylation. These results provide new insights for guiding further development of asymmetric C-C bond formations with CO₂

Full text of DOI:10.1021/jacs.9b09721

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Article
Highly Selective and Catalytic Generation of Acyclic Quaternary
Carbon Stereocenters via Functionalization of 1,3-Dienes with CO2
Xiao-Wang Chen, Lei Zhu, Yong-Yuan Gui, Ke Jing, Yuan-
Xu Jiang, Zhi-Yu Bo, Yu Lan, Jing Li, and Da-Gang Yu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b09721 • Publication Date (Web): 08 Nov 2019
Downloaded from pubs.acs.org on November 8, 2019
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Journal of the American Chemical Society
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Highly Selective and Catalytic Generation of Acyclic Quaternary Carbon
Stereocenters via Functionalization of 1,3-Dienes with CO2
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Xiao-Wang Chen,† Lei Zhu,‡ Yong-Yuan Gui,†,§ Ke Jing,† Yuan-Xu Jiang,† Zhi-Yu Bo,† Yu Lan,*,‡,#
Jing Li,† Da-Gang Yu*,†,¶
† Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University,
Chengdu 610064, P. R. China
‡ School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400030, P. R. China
§ College of Chemistry and Materials Science, Sichuan Normal University, Chengdu 610068, P. R. China
# College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, P. R. China
¶ Beijing National Laboratory for Molecular Sciences, Beijing 100190, P. R. China
Supporting Information Placeholder
ABSTRACT: The catalytic asymmetric functionalization of readily available 1,3-dienes is highly important, but current examples
are mostly limited to the construction of tertiary chiral centers. The asymmetric generation of acyclic products containing all-carbon
quaternary stereocenters from substituted 1,3-dienes represents a more challenging, but highly desirable, synthetic process for
which there are very few examples. Herein, we report the highly selective copper-catalyzed generation of chiral all-carbon acyclic
quaternary stereocenters via functionalization of 1,3-dienes with CO2. A variety of readily available 1,1-disubstituted 1,3-dienes, as
well as a 1,3,5-triene, undergo reductive hydroxymethylation with high chemo-, regio-, E/Z-, and enantioselectivities. The reported
method features good functional group tolerance, is readily scaled up to at least 5 mmol of starting diene, and generates chiral
products that are useful building blocks for further derivatization. Systemic mechanistic investigations using density functional
theory calculations were performed and provided the first theoretical investigation for an asymmetric transformation involving CO2.
These computational results indicate that the 1,2-hydrocupration of 1,3-diene proceeds with high π-facial selectivity to generate an
(S)-allylcopper intermediate, which further induces the chirality of the quaternary carbon center in the final product. The 1,4-
addition of an internal allylcopper complex, which differs from previous reports involving terminal allylmetallic intermediates, to
CO2 kinetically determines the E/Z- and regioselectivity. The rapid reduction of a copper carboxylate intermediate to the
corresponding silyl-ether in the presence of Me(MeO)2SiH provides the exergonic impetus and leads to chemoselective
hydroxymethylation rather than carboxylation. These results provide new insights for guiding further development of asymmetric
C−C bond formations with CO2.
INTRODUCTION
bearing both a chiral carbon center and a valuable alkene
handle for further functionalization.6 Many groups have
independently developed different catalytic systems to
construct tertiary chirality centers via the efficient and
selective functionalization of 1,3-dienes with various
electrophiles (e.g. aldehydes, ketones, imines) or nucleophiles
(Figure 1, A, left), albeit control of regioselectivity remains a
challenge.7,8,9 The generation of chiral all-carbon quaternary
stereocenters, especially in acyclic products, via the
functionalization of substituted 1,3-dienes remains relatively
challenging (Figure 1, A, right). To date, there is only one
report toward this end; Krische and co-workers realized the
highly selective Ir-catalyzed coupling of 1,3-dienes with
methanol to generate quaternary carbon centers via hydrogen
auto-transfer strategy (Figure 1, B).7e In this tranformation, 2-
substituted 1,3-dienes were utilized as surrogates for the
terminal Ir-allyl complex which attacked the in-situ generated
electrophile formaldehyde (HCHO).10 While this report was a
breakthrough in the field, the utilization of less reactive one-
Chiral all-carbon quaternary stereocenters exist widely in
natural products and drug molecules.1 Nevertheless, the
catalytic construction of chiral all-carbon quaternary
stereocenters bearing diverse functional group handles for
further derivatization via asymmetric C−C bond formation
remains
a
significant challenge,2 especially for the
construction of acyclic quaternary stereocenters.3 Moreover,
most methods for obtaining quaternary stereocenters rely on
the use of fine chemicals. Therefore, the development of more
atom- and step-economic protocols for the generation of chiral
quaternary stereocenters from abundant and inexpensive raw
materials and industrial feedstocks remains in high demand.4
Alkenes are one of the most important chemical feedstocks
that are produced on huge scale in industry. 1,3-Dienes are
particulary attractive in organic synthesis due to their ready
availability and diverse reactivities.5 Very recently, significant
attention has been paid to the asymmetric catalytic
functionalization of 1,3-dienes for the generation of products
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carbon coupling partners in the functionalization of 1,3-dienes Fourth, controlling enantioselectivity will be challenging,
1
2
3
4
5
6
7
8
represents a challenging, but highly desirable prospect.
(A) Asymmetric catalytic functionalization of 1,3-dienes to generate chiral carbon centers
especially when the difference between substituents on the
diene substrate are not significant. 1,1-Dialkyl-substituted 1,3-
dienes, for example, represent highly challenging substrates
and their successful application toward the catalytic
construction of functionalized chiral all-carbon quaternary
stereocenters is extremely rare.
C3
C3
widely
investigated
under
developed
C4
C2
feedstock
1,3-dienes
H
C1
C1
C2
only one
report (ref. 7e)
many reports
(ref. 6-9)
quaternary
challengingly accessible
tertiary
easily accessible
(B) Asymmetric Ir-catalysis with 2-substituted 1,3-dienes and MeOH (Krische)ref. 7e
1
2
R
1
RESULTS AND DISCUSSION
Ir(II)/(R)-PhanePhos (cat.)
CH2OH
+
MeOH
4
4
formal 1,2-addition;
terminal Ir-allyl reacts with
in-situ generated HCHO
R
2
9
3
With such challenges in mind, we initiated our investigation
by using (E)-4-(penta-2,4-dien-2-yl)-1,1'-biphenyl 1a as a
model substrate, 5 mol % Cu(OAc)2 as the precatalyst, and
Me(MeO)2SiH as hydride donor. Additionally, seven
privileged chiral phosphine ligands for CuH chemistry18,19
were examined in cyclohexane (CyH) under 1 atmosphere of
CO2 for 10 h at 60 oC (Table 1, entries 1−7). Following these
conditions, we found that the reaction using (S,S)-Ph-BPE as
ligand (entry 6, L6) generated the desired 1,4-addition
3
(solvent)
R = aryl, c-hexyl
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(C) Asymmetric Cu-catalysis with 1,1-disubstituted 1,3-dienes and CO2 (This work)
Cu(II)/(S,S)-Ph-BPE (cat.)
RS
RS
RL
CH2OH
Me(MeO)2SiH
+
CO2
R
R
RL
1,4-addition;
internal Cu-allyl reacts
with inert CO2
1
3
3
1
2
4
2
4
RL = aryl, alkyl, c-hexenyl
RS = alkyl; R = H, Me
High chemo-, regio-, / -
and enantio-selectivities
(1 atm)
E Z
Figure 1. Asymmetric catalytic functionalization of acyclic
1,3-dienes to generate all-carbon quaternary stereocenters.
Table 1. Reaction Optimizationa
Herein, we report the first highly selective and catalytic
construction of functionalized chiral all-carbon quaternary
stereocenters in acyclic materials via the functionalization of
1,3-dienes with generally inert CO2 (Figure 1, C). A variety of
easily available 1,1-disubsituted 1,3-dienes, including the
challenging 1,1-dialkyl-substituted 1,3-dienes derived from
terpenoids, undergo the Cu-catalyzed reductive hydroxy-
methylation with high chemo-, regio-, E/Z- and enantio-
selectivities.
Me
Me CH2OH
Me CH2OH
Cu(OAc)2 (5 mol%)
Ligand (6 mol%)
+
+
CO2
Me(MeO)2SiH (8 equiv)
solvent (0.2 M), 60 °C, 10 h Ph
(1 atm) then NH4F/MeOH work up
Ph
Ph
1a
2a
2a'
entry
1
L*
L1
L2
L3
L4
L5
L6
L7
L6
L6
L6
L6
L6
—
solvent
Yieldb
84%
79%
77%
84%
trace
74%
57%
66%
62%
52%
54%
N.R.
N.R.
N.R.
eec
CyH
CyH
CyH
CyH
CyH
CyH
CyH
THF
MTBE
EA
72%
-32%
52%
80%
2
3
CO2 is abundant, nontoxic, and recyclable one-carbon
feedstock and it has been widely used toward the synthesis of
diverse value-added compounds.11 It is difficult, however, to
utilize this gas efficiently, especially in asymmetric
transformations, due to its inherent characters. First, the
maximized oxidation state and highly delocalized electronic
structure of CO2 endow it with relative thermodynamical
stability. Second, the nonpolar nature and weak coordination
ability of the gas render it kinetically inert and difficult to
activated by transition-metal complexes. Although different
methods have been reported for catalytic asymmetric C−O
bond formations using CO2,12 only limited successful
examples for the catalytic enantioselective C−C bond
formations from CO2 have been realized, predominantly by
Mori, Marek, Wang and Ding, and our group.13,14,15 As part of
a long-term interest in the utilization of CO2 in organic
transformations,16 we sought to realize a selective generation
of quaternary all-carbon stereocenters through the transition-
metal-catalyzed coupling of readily available 1,1-disubsituted
1,3-dienes with CO2.15,17 If successful, such a transformation
would provide ready access to chiral all-carbon quaternary
stereocenters bearing several functional groups, including an
alkene motif and a oxygen-containing group. There were
several obvious challenges for this proposed transformation.
First, the in-situ generated organometallic intermediate must
be able to react with relatively inert CO2, which is less reactive
than other electrophiles commonly used for such reactions.7
Second, the coordinative ability of CO2 to transition metals is
low, resulting in high energy barriers for nucleophilic attack.
Third, the 1,3-diene substrates contain multiple reactive sites,
presenting a challenge to realizing high regioselectivity. To
generate quaternary stereocenters from 1,1-disubstituted 1,3-
dienes, CO2 must be incorporated onto the more conjested
position instead of the less hindered position, an event which
is highly challenging and not favored thermodynamically.
4
d
5
—
6
96%
74%
96%
96%
95%
62%
7
8
9
10
11
12e
13f
14g
DMF
CyH
CyH
CyH
d
—
d
—
d
L6
—
O
PCy2
Me
PAr2
PAr2
PAr2
PAr2
PPh2
PPh2
Ar2
P
O
O
MeO
MeO
Fe
O
Ar = 3,5-tBu-4-MeOC6H2
(R)-DTBM-SEGPHOS
L1
Ar = 3,5-MeC6H3
(S)-XylBINAP
L2
Ar = 3,5-tBu-4-MeOC6H2
Josiphos SL-J007-1
L4
(R)-MeO-BIPHEP
L3
Me
Ph
Ph
P
P
Me
P
Me
O
O
Ph
P
Ph
PPh2 Ph2
P
Me
(R,R,R)-(+)-PH-SKP
(S,S)-Ph-BPE
(R,R)-Me-DUPHOS
L5
L6
L7
aConditions: diene 1a (0.5 mmol), copper precatalyst (5
mol %), chiral ligand (6 mol %), Me(MeO)2SiH (8 equiv) in
solvent (2.5 mL) at 60 °C for 10 h. The yields of pure 1,4-
b
addition product (2a) after column chromatography
purification on silica gel; all regioisomeric ratios of 1,4-
addition (2a)/1,2-addition (2a’) were >95:5, as determined by
1H NMR analysis of the crude reaction mixtures.
cEnantiomeric excess (ee) was determined by chiral HPLC
analysis. dNot determined. eWithout Cu-catalyst. Without
f
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Me
Cu(OAc)2 (5 mol%)
(S,S)-Ph-BPE (6 mol%)
Me CH2OH
ligand. gWithout silane. N.R. = No reaction. PMHS =
polymethylhydrosiloxane.
+
CO2
(eq. 1)
Me(MeO)2SiH (8 equiv)
CyH (0.2 M), 60 °C, 10 h
then NH4F/MeOH work up
1
Ph
Ph
1ak
2ak
, 84% yield
95% ee
, E/Z = 4:1
(1 atm)
2
3
4
5
6
7
8
9
product 2a (1,4-addition : 1,2-addition > 95:5) in 74% isolated
yield and 96% ee (entry 6). The minor 1,2-addition product 2a’,
which is generated when the 1,3-diene reacts with CO2 at the
less hindered position, was only detected in less than 5%,
based on NMR analysis of the crude reaction mixtures.20 Other
chiral ligands, such as (R)-DTBM-SEGPHOS L1 (entry 1) and
Josiphos ligand L4 (entry 4), provided higher yields at the cost
of lower enantioselectivities. Therefore, we chose L6 as the
ligand to further test different solvents (entries 8-11). Ethers
tetrahydrofuran (THF) and methyl t-butyl ether (MTBE), as
well as ethyl acetate (EA) also could promote the reaction
(entries 8-10) with high enantioselectivity, albeit with lower
yields versus CyH. Polar solvents, such as N,N-
dimethylformamide (DMF), were not suitable for this reaction,
resulting in a significant drop in the ee value (entry 11).
Systematic investigation of the silane hydride sources and
copper precatalysts (See SI for detail) did not improve the
yield. Lastly, control experiments demonstrated that the
catalyst, ligand, and silane all were essential to this
transformation (entries 12-14). The structure and absolute
stereochemistry of (S)-2a were assigned by single crystal X-
ray diffraction analysis of the corresponding 4-bromobenzoate
ester (CCDC 1911002).21
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Table 2. Substrate Scope of 1-Aryl-Substituted Acyclic 1,3-
Dienesa
Cu(OAc)2 (5 mol%)
CH2OH
After identifying suitable reaction conditions, we tested a
wide range of 1-aryl-1-methyl-substituted 1,3-dienes to
evaluate the substrate scope of this transformation (Table 2).
Dienes with either electron-donating groups (EDGs), such as
methyl (1d, 1j), methoxy (1f, 1k), methylsulfide (1g), and
morpholine (1h) groups, or electron-withdrawing groups
(EWGs), such as trifluoromethoxy (1e), esters (1o), and
trifluoromethyl (1i, 1n) groups, at the meta and para positions
of the benzene ring reacted smoothly to give the desired
products 2 in moderate to good yields (from 53% to 82%) and
moderate to excellent enantioselectivities (up to 98% ee).
Various functional groups were tolerated in this reaction,
including carbon−halogen (F, Cl, Br) bonds, ethers, thioethers,
esters, and amines. Moreover, the transformation was not
sensitive to steric hindrance. The hydroxy-methylations of 2-
tolyl (1p) and 2-chloro-substituted dienes (1q) both performed
well to afford the desired products in good yields and excellent
enantioselectivities. Additionally, 1-naphthyl (1s) and 2-
naphthyl-substituted (1r) dienes exhibited good reactivity.
Further surveys of the substrate scope showed that 1,3-dienes
bearing polysubstituted benzenes (1t-1w) also delivered the
corresponding products with excellent control of
enantioselectivity (up to >99.5% ee). Other types of
substituents on the 1,3-dienes were also investigated.
Exchanging the methyl group with more hindered groups,
such as ethyl (1x-1aa), n-butyl (1ab), and i-butyl (1ac), did
not have a negative impact on the overall transformations.
Dienes with more rigid cyclic backbones, such as indane (1ad)
and tetralene (1ae), as well as the ferrocene-substituted 1,3-
diene 1ag, were all acceptable substrates. It is worth noting
that several dienes bearing heterocycles, such as benzodioxole
(1af), thiophene (1ah) and indole (1aj), reacted well under the
reaction conditions to provide the corresponding homoallylic
alcohols with good to excellent enantioselectivities (up to 99%
ee) and moderate to good yields (from 51% to 81%). The
substrate 1ai bearing a pyridyl group, which is known to be
strong competitive ligand for copper catalysts, also showed
good reactivity to produce 2ai in 67% isolated yield and 91%
ee. While most substrates investigated were (E)-dienes, (Z)-
diene 1a’’ also was subjected to the reaction conditions and
(S,S)-Ph-BPE (6 mol%)
+
CO2
Me(MeO)2SiH (8 equiv)
CyH (0.2 M), 60 °C, 10 h
then NH4F/MeOH work up
Ar
Ar
1a-1aj
2a-2aj
(1 atm)
Me CH2OH
Me CH2OH
Me CH2OH
R
R
R
2a,
S
2j
2k
2l
2m
2n
2o
2p
2q
R = Ph(E), ( ) 74% yield, 96% ee
, R = Me, 82% yield, 96% ee
, R = OMe, 73% yield, 94% ee
, R = Cl, 65% yield, 92% ee
, R = Br, 53% yield, 96% ee
, R = CF3, 63% yield, 77% ee
, R = CO2Me, 53% yield, 96% ee
Me CH2OH
, R = Me, 65% yield, 94% ee
, R = Cl, 78% yield, 94% ee
2a''
R
, R = Ph(Z), ( ) 90% yield, -94% ee
2b
2c
2d
2e
, R = F, 79% yield, 93% ee
, R = H, 62% yield, 97% ee
, R = Me, 79% yield, 94% ee
, R = OCF3, 62% yield, 94% ee
, R = OMe, 81% yield, 96% ee
Me CH2OH
2f
2g
2h
, R = SMe, 73% yield, 94% ee
, R = morpholine, 80% yield, 98% ee
, R = CF3, 70% yield, 98% ee
2r
2s
, 71% yield
97% ee
, 85% yield
88% ee
2i
Me CH2OH
F
Me CH2OH
Me CH2OH
Br
MeO
MeO
F
F
2t
2v
, 60% yield
>99.5% ee
, 78% yield
96% ee
2u
, 68% yield
90% ee
Me CH2OH
Me
CH2OH
MeO
MeO
Me
CH2OH
MeO
OMe
2w
2x
, 74% yield
98% ee
, 74% yield
94% ee
2y,
95.5% ee
71% yield
Me
F
Me
CH2OH
CH2OH
Me
CH2OH
MeO
Cl
2aa,
66% yield
97% ee
2z,
62% yield
98% ee
2ab
, 85% yield
96% ee
OMe
Me
Me
CH2OH
CH2OH
CH2OH
2ac
2ad
2ae
, 74% yield
, 77% yield
93% ee
, 67% yield
98% ee
97.5% ee
Me CH2OH
S
Me CH2OH
Me
O
Fe
CH2OH
O
2af
, 81% yield
99% ee
2ag
91% ee
2ah
, 67% yield
81% ee
, 56% yield
Me CH2OH
Me CH2OH
BocN
2aj
MeO
2ai
N
2a
, 67% yield
91% ee
, 51% yield
91% ee
X-ray for 4-bromobenzoate ester of
CCDC 1911002
afforded 2a’’, with
a configuration of the quaternary
aThe reactions were performed on a 0.5 mmol scale. The
yields of pure 1,4-addition products were obtained by column
chromatography purification on silica gel; all regioisomeric
ratios of 1,4-addition/1,2-addition were >95:5. Enantiomeric
excesses were determined by HPLC analysis on a chiral
stationary phase.
stereocenter opposite to that observed from corresponding (E)-
diene 1a. Presumably, this resulted from a change in the steric
hindrance between the substrate and the catalyst during the
hydrocupration step compared with (E)-1a. We also
investigated the reactivity of 1,1,4-trisubstituted 1,3-diene
(1ak), which yielded 2ak in 84% yield and 95% ee (eq. 1).
This successful result demonstrates that the reaction
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Me CH2OH
Me
conditions tolerate diverse substitution modes on the 1,3-diene
Cu(OAc)2 (5 mol%)
(S,S)-Ph-BPE (6 mol%)
1
2
3
4
5
6
7
8
(eq. 2)
substrates. Notably, almost all these reactions afforded the
corresponding products with >95:5 regioselectivity and >98:2
E/Z-selectivity of the resultant double bond. The absolute
stereochemistry of products 2b-2ak were assigned by analogy
to the single crystal X-ray diffraction analysis of the 4-
bromobenzoate ester of 2a (CCDC 1911002).
+
CO2
Me(MeO)2SiH (8 equiv)
CyH (0.2 M), 60 °C, 10 h
then NH4F/MeOH work up
3l
(1 atm)
4l
, 83% yield; E/Z > 98:2
86% ee
to high yields, good E/Z-selectivity and excellent
enantioselectivity. The sterically encumbered benzhydryl-
substituted 1,3-diene 3f also demonstrated high reactivity to
afford 4f in outstanding yield (90%), enantioselectivity
(>99%), and E/Z selectivity (>98:2). Notably, 1,3-dienes
bearing two more flexible substituents with less steric
distinction (3g-3j) could also be applied to this reaction and
the products were provided with good enantioselectivity.
Moreover, the 1,3-diene 3k bearing a bulky adamantyl moiety
performed well in the reaction with high chemo-, E/Z- and
enantioselectivity. To our delight, when a 1,3,5-triene 3l was
applied to our reaction conditions, the desired product 4l was
obtained in good yield, regio-, E/Z- and enantio-selectivity (eq.
2). The absolute configuration of these products 4 were
assigned by analogy to the single crystal X-ray diffraction
analysis of the 4-bromobenzoate ester of 4f (CCDC
1911003).24
Having clearly demonstrated that 1-(hetero)aryl-1,3-dienes
are suitable substrates for our catalytic asymmetric reductive
hydroxymethylation (Table 2), we further challenged the
reaction system by exploring 1,1-dialkyl-substituted 1,3-
dienes to generate quaternary carbon stereocenters.22
Compared to 1-aryl-1-methyl-substituted 1,3-dienes, the
dialkyl-substituted analogues are generally less reactive in
other transformations. Moreover, the in-situ generated allyl
organometallic reagents would be less stable. Moreover, the
relatively insignificant difference between the two alkyl
substituents at the geminal carbon pose a substantial challenge
for realizing excellent enantiofacial discrimination. With these
challenges in mind, we were delighted to observe that an array
of 1,1-dialkyl 1,3-dienes 3 converted efficiently to the desired
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
The well-known acyclic terpenoids geraniol 5m, nerol 5n,
farnesol 5o and solanesol 5p are readily available and widely
used in food processing, cosmetics, and the total synthesis of
natural product and drug molecule synthesis, such as vitamin
A, vitamin K2, coenzyme Q10.25 The precise transformation
of these important polyene feedstocks into to other valuable
compounds has attracted substantial attention. These terpenoid
alcohols were converted by facile oxidation and Wittig
reaction, and the resulting 1,3-dienes (3m-3p) were submitted
to our catalytic asymmetric transformation (Scheme 1). To our
delight, all four terpenoid-derived 1,3-dienes (3m-3p) were
converted into desired products (4m-4p) with high selectivity,
leaving the unconjugated alkene moieties untouched. For
example, the 1,3-diene 3m, a derivative of geraniol 5m, was
transformed efficiently into homoallylic alcohol 4m in 85%
yield and 92% ee. Nerol-derived (Z)-1,3-diene 3n, which has
an opposite olefin stereochemistry compared to other 1,3-
dienes, provided 4n with a slightly lower E/Z- and enantio-
selectivity. Notably, the 1,3-diene 3p, which is derived from
solanesol and possess eight unconjugated double bonds and a
1,3-diene unit, was successfully applied in this reaction to
provide 4p in high yield, chemo-, regio-, E/Z- and
enantioselectivity.
homoallylic alcohols
4
with good to excellent
enantioselectivies when subjected to our general reaction
conditions (Table 3). These results represent the first examples
of challenging 1,1-dialkyl-substituted 1,3-dienes as viable
substrates for the generation of chiral all-carbon quaternary
stereocenters via asymmetric Cu-catalysis.23 Various
functional groups, such as fluoro (4a), bromo (4b), methoxy
(4c), trifluoromethyl (4d), indolyl (4e), piperonyl (4h) and
hydroxy (4i) groups all were well tolerated. The 1-benzyl-1-
methyl 1,3-dienes bearing different functional groups on the
benzene ring (3a-d) underwent the transformation to give the
corresponding alcohols 4 with moderate
Table 3. Substrate Scope of 1,1-Dialkyl-Substituted Acyclic 1,3-
Dienesa
Cu(OAc)2 (5 mol%)
(S,S)-Ph-BPE (6 mol%)
Me
Me CH2OH
Alkyl
+
CO2
Alkyl
Me(MeO)2SiH (8 equiv)
CyH (0.2 M), 60 °C, 10 h
then NH4F/MeOH work up
(1 atm)
3a-3k
4a-4k
Me CH2OH
MeO
F
Me CH2OH
Me CH2OH
MeO
Br
, 64% yield; E/Z = 91:9
97.5% ee
4a
4b
4c
, 77% yield; E/Z = 91:9
,81% yield; E/Z = 91:9
96% ee
94% ee
Me CH2OH
Ph
Me CH2OH
Me CH2OH
Scheme 1. Functionalization of Acyclic Terpenoids-Derived
F3C
BocN
Ph
1,3-Dienea
4d
4e
4f
, 90% yield; E/Z > 98:2
,53% yield; E/Z = 91:9
, 61% yield; E/Z = 91:9
89% ee
96% ee
> 99% ee
Me
Me
Me
Me CH2OH
Me
90%
CH2OH
Me
Me
Me CH2OH
Me CH2OH
Geraniol (5m)
4m
, 85% yield; E/Z = 91:9; 92% ee
Me CH2OH
O
O
HO
3m
Me
Me
4i
, 63% yield; E/Z = 85:15
4g
4h
, 79% yield; E/Z = 86:14
, 77% yield; E/Z = 91:9
Me
Me
Me CH2OH
87.5% ee
89% ee
92% ee
85%
85%
85%
Me
Me
4n
, 63% yield; E/Z = 87.5:12.5; 84.5% ee
CH2OH
Nerol (5n)
Me CH2OH
3n
Me CH2OH
Me
Me
Me
Me
Me
Me CH2OH
Me
CH2OH
CH2OH
4j
4k
4f
, 61% yield; E/Z = 91:9
, 73% yield; E/Z > 98:2
X-ray for 4-bromobenzoate ester of
CCDC 1911003
Me
Me
Me
4o
76% ee
94% ee
Farnesol (5o)
, 87% yield; E/Z = 92.3:7.7; 92% ee
3o
aThe reactions were performed on a 0.5 mmol scale. The
yields of pure 1,4-addition products were obtained by column
chromatography purification on silica gel, all the
regioisomeric ratio of 1,4-addition/1,2-addition is >95:5.
Enantiomeric excesses were determined by HPLC analysis on
Me
Me
Me
Me
Me
Me CH2OH
Me
Me
4p
7
7
Solanesol (5p)
, 80% yield; E/Z = 93.3:6.7; 95% ee
3p
aPerformed on a 0.5 mmol scale and yields of pure 1,4-addition
product were obtained after purification by silica gel column
chromatography; all the regioisomeric ratio of 1,4-addition/1,2-
addition were >95:5. Enantiomeric excesses were determined by
1
a chiral stationary phase. The E/Z ratio was determined by H
NMR spectroscopy of the unpurified mixture.
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HPLC or SFC analysis on commercial chiral columns. The E/Z
ratio was determined by H NMR spectroscopy of the unpurified
mixture.
regenerated by σ-bond metathesis of IV and silane. Such a
process would also generate the silyl ether V, which would
provide the desired alcohol 2c after reacting with ammonium
fluoride.
1
1
2
3
4
5
6
7
8
9
In order to gain more insight into this process, we
performed density functional theory (DFT) calculations to
investigate several aspects of our proposed reaction
mechanism and gain a theoretical explanation for the observed
high regio-, stereo-, E/Z- and chemoselectivity. The
calculations were performed at the M06-2X/def2-
TZVP/SMD(cyclohexane)// B3LYP/def2-SVP level of
theory.27 As shown in Figure 3, we first investigated the
hydrocupration of 1,3-diene 1c, which might undergo a direct
1,2-hydrocupration or 1,4-hydrocupration followed by a 1,3-
migration. The calculated results suggest that the 1,2-
hydrocupration (via TS1) proceeds preferentially to form a
secondary allylcopper intermediate; the 1,4-hydrocupration
(via TS-1,4) requires 10.3 kcal/mol higher activation free
energy. The relative free energy of the transition state TS1 is
2.4 kcal/mol lower than that of TS1-ent, indicating a high π-
facial selectivity toward generating the (S)-allylcopper
intermediate INT2. Quadrant diagrams analyses (Figure 4)
indicate that steric clashes between the phenyl moiety
proximal to the Cu center and the reactant in TS1-ent can
account for the relatively higher activation free energy.
Meanwhile, the stereoselectively generated (S)-allylcopper
center could be directly translated into the configuration of the
quaternary carbon center in the final product. The calculated
results predict a 96% ee value for final product, which is close
accord with experimental observations (97% ee).
APPLICATIONS
To further demonstrate the potential application of this
methodology, the reaction of 1r was scaled up ten times and the
catalyst loading was lowered to 3 mol %. The target product 2r
was obtained in 62% yield, 96% ee, and >20:1 E/Z selectivity
(Scheme 2A).20 Additionally, we performed representative
derivatizations of product 2a to generate useful building blocks
for organic synthesis (Scheme 2B).7e As α-chiral quaternary
aldehyde and carboxylic acid are important units that widely exist
in natural products, we carried out efficient and selective
oxidations of homoallylic alcohol 2a to the corresponding
quaternary aldehyde 6 and carboxylic acid 7 without erosion of ee.
Moreover, protection of the hydroxyl moiety of 2a with a benzoyl
group followed by oxidative cleavage of the alkene provided the
chiral -hydroxy acid derivative 8 in 55% total yield.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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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
Scheme 2. Scale-Up Reaction and Derivatization of Product
1r
A) Scale-up reaction of
Me
Me CH2OH
Cu(OAc)2 (3 mol%)
(S,S)-Ph-BPE (3.6 mol%)
+
CO2
Me(MeO)2SiH (8 equiv)
CyH (0.2 M), 60 °C, 15 h
then NH4F/MeOH work up
1r
(1 atm)
2r
, 62% yield,
96% ee, E/Z > 20:1
, 5 mmol
2a
B) Derivatization of
Me CHO
Oxalyl chloride (1.2 equiv)
DMSO (2.4 equiv)
Et3N (5 equiv)
DCM (0.05 M), -78 °C - RT
Ph
L*Cu(OAc)2
R3Si-H
6
, 98% yield, 96% ee
Me
Me CH2OH
Ph
Me CH2OSiR3
Ph
NH4F/MeOH
L*Cu-H
Ph
I
Me CH2OH
, 96% ee
Me CO2H
H2CrO4 (3.0 equiv)
acetone (0.1 M), 0 °C - RT
2c
V
1c
R3Si-H
Ph
Ph
2a
7
, 84% yield, 95.5% ee
L*Cu
H
1) DMAP (10 mol%)
BzCl (1.2 equiv)
Et3N (2 equiv)
Me CH2OCuL*
Me
Ph
Me CH2OBz
CO2H
Ph
IV
II
DCM (0.2 M), 0 °C - RT
Me
O
O
2) NaIO4 (8 equiv)
KMnO4 (1 equiv)
tBuOH (0.02 M)
Ph
Ph
*LCu
8
, 55% yield, 95.5% ee
Possible TS
CO2
pH = 7 buffer (0.02 M), RT
R3Si-H
Me CO2CuL*
Ph
III
L*Cu
H
migration
Me CuL*
Me
Ph
H
Ph
MECHANISTIC STUDIES
II
II'
Based on previous reports regarding CuH catalysis and 1,3-
dienes,7l,7n,26 as well as our own observations, we formulated a
possible mechanism for our transformation, as shown in
Figure 2 using 1c as a representative substrate. First, a
complex between the Cu precatalyst and the chiral phosphine
ligand reacts with the silane to form a catalytically-active
chiral L*CuH species I. Then a chiral allylic copper
intermediate II is generated via a highly regio- and
stereoselective 1,2-syn-addition of copper hydride I into 1,3-
diene 1c. Steric repulsion might prevent the energy-disfavored
1,3-migration process to generate the isomeric allylcuprate II’.
A six-membered ring chair-like transition state might be
involved in the nucleophilic addition of II to CO2, forming the
copper carboxylate species III. Silane can further reduce III to
copper alkoxide IV. Finally, the active catalyst I is
Figure 2. Possible mechanism.
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G (kcal/mol)
G (kcal/mol)
O
O
1
O
*LCu
Ph
CuL*
S
O
H
H
2
Ph
30.4
TS-1,4
*LCu
L*Cu
L*Cu
Ph
3
4
5
6
7
8
9
TS3
TS2
TS4
Ph
TS-1,4
5.5
Ph
Ph
22.5
TS1-ent
2.7
TS3
TS1-ent
TS4
CO2
H
2.2
TS2
20.1
TS1
CO2
L*Cu
Ph
1c
-7.0
-11.2
INT4
CuL*
S
TS1
INT2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
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59
60
CuL*
S
0.0
Ph
CuL*
Ph
INT1
S
Ph
Ph
*LCuOOC
-26.3
COOCuL*
L*Cu
H
INT2
-11.2
INT2
R
-28.5
Ph
INT5
S
CuL*
Ph
INT3
R
-12.1
INT2-ent
INT2-ent
Figure 5. Computed energy profiles for the nucleophilic addition
to CO2 to form chiral copper carboxylate species. L* represents
(S,S)-Ph-BPE ligand (L6).
Figure 3. Computed energy profiles for the 1,2- and 1,4-
hydrocupration of diene reactant 1c. L* represents (S,S)-Ph-BPE
(L6).
We also considered the overall regioselectivity of the
transformations and the corresponding results are summarized
in Figure 6. A reversible 1,3-Cu migration of INT2 would
result in benzylcopper intermediate INT6 via transition state
TS5 via a low free energy of 6.2 kcal/mol. Subsequent
addition of benzylcopper INT6 to CO2 could deliver the
formal 1,2-hydrocarboxylation intermediate INT7. The
relative free energy of TS6 is 1.2 kcal/mol higher than that of
TS2, which suggests that the 1,2-addition product should be
detected as a minor product, if at all. These calculated results
corroborate the aforementioned experimental observations.
Subsequent nucleophilic addition of (S)-allylcopper INT2
into CO2 can occur via a six-membered Zimmerman−Traxler-
type transition state (Figure 5).28 The free energy barrier for
addition to CO2 (via TS2) is 13.4 kcal/mol, which indicates
that this process could proceed rapidly compared to the initial
1,2-hydrocupration step. A cyclic transition state such as TS2
would also account for how the chirality of the initially-
formed (S)-allylcopper stereogenic center is completely
delivered to the forming quaternary carbon center in copper
carboxylate INT3. Alternatively, C–C bond rotation in INT2
could afford a isomeric allylcopper species (INT4), which
would undergo addition to CO2 via TS4 to generate (Z)-copper
carboxylate INT5. The calculated 3.3 kcal/mol energetic
discrepancy between TS2 and TS4 suggests that generation of
the (Z)-product is not favored when phenyl-substituted 1,3-
diene 1c is employed.
Calculations regarding the mechanism of the reduction of
the copper carboxylate species INT3 was also performed
(Figure 7). Transmetalation between INT3 and Me(MeO)2SiH
rapidly generates silyl carboxylate INT8 via a six-membered
transition state (TS7) and a free energy barrier of 19.4
kcal/mol. The 1,2-hydrocupration of C=O in silyl carboxylate
INT8 occurs via transition state TS8 with a free energy barrier
of 19.8 kcal/mol leading to the generation of copper alkoxide
intermediate INT9. From INT9 subsequent β-O elimination
leads to the copper siloxide INT10 and aldehyde intermediate
INT11, and the free energy barrier of this step is 9.3 kcal/mol.
The transmetalation between INT10 and silane then leads to
siloxane (SiR3)2O and regeneration of the L*CuH species
INT1. An alternative competitive pathway which involves
transmetalation between INT9 and silane to generate the
corresponding bis(silyl)acetal was also explored (Figure S1).29
Calculated results show that the transmetalation (via TS12) is
unfavorable compared to β-O elimination (via TS9). Further
1,2-hydrocupration of aldehyde intermediate INT11 proceeds
via TS11 with a free energy barrier of 14.7 kcal/mol, affording
copper alkoxide intermediate INT12, from which subsequent
transmetalation regenerates the L*Cu-H species and releases
silyl-ether INT13. Collectively, the calculated results illustrate
that the free energy profile for the reduction of the proposed
copper carboxylate intermediate is an exergonic process.
Additionally, the free energy barriers for 1,2-hydrocupration
of C=O in silyl carboxylate INT8 and aldehyde intermediate
INT11 are lower than that for 1,3-diene 1c, indicating that the
reduction of the copper carboxylate is a rapid process
compared to the initial hydrocarboxylation, thus accounting
II
I
II
I
III
IV III
IV
TS1 (favored)
TS1-ent (disfavored)
Figure 4. Optimized geometries of the 1,2-hydrocupration
transition states.
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for the observed chemoselectivity. Based on the combined
mechanistic studies, we propose the full catalytic cycles outlined
Figure 8, which show more details and new insight on the process
1
2
3
4
5
6
7
8
CONCLUSIONS
for reduction of III to IV.
We have documented a highly selective and catalytic generation
of chiral all-carbon acyclic quaternary stereocenters via
functionalization of 1,3-dienes with CO2. A variety of readily
available 1,1-disubstituted 1,3-dienes and one 1,3,5-triene
undergo reductive hydroxymethylation with high chemo-, regio-,
E/Z- and enantioselectivities. These results represent first time
that challenging 1,1-dialkyl-substituted 1,3-dienes, including four
1,3-dienes derived from terpenoids, were directly converted chiral
all-carbon quaternary stereocenters via asymmetric Cu-catalysis.
This method features good functional group tolerance, facile
scalability, and the installation of useful functionalities that can be
further manipulated to produce valuable chiral building blocks for
organic synthesis. In addition, we systematically explored the
reaction mechanism with DFT calculations to provide the first
theoretical investigation on an asymmetric organic transformation
incorporating CO2. The 1,4-addition of an internal allylcopper
complex, which is mechanistically distinct from previously
reported terminal allylmetallic nucleophiles, into CO2 is a key
step for this reaction. The computational results accurately explain
the origins of the high chemo-, regio-, E/Z- and
enantioselectivities for this process, thus providing new insights
for guiding future developments in the field of asymmetric C−C
bond formation involving CO2.
O
G (kcal/mol)
*LCu
O
Ph
L*
Cu
3.4
Ph
TS6
-5.0
9
TS5
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
CO2
-10.4
INT6
CuL*
-11.2
INT2
CuL*
S
S
Ph
Ph
COOCuL*
S
-31.6
Ph
INT7
Figure 6. Computed energy profiles for the nucleophilic addition
to carbon dioxide to form 1,2-hydrocarboxylation product. L*
represents (S,S)-Ph-BPE (L6).
G (kcal/mol)
H
R3SiO
H
Ph
R3Si
CuL*
O
S
O
L*Cu
O
S
Ph
-5.6
COOSiR3
TS7
TS8
-9.1
Ph
H
Ph
S
TS7
R3SiO
L*Cu
S
INT8
HSiR3
O
R3SiO
L*Cu
SiR3
H
-25.4
-25.4
-28.5
Ph
INT11
HSiR3
INT1
H
TS9
INT3
H
S
L*Cu
H
-31.0
-34.7
L*Cu
O
COOCuL*
TS10
INT9
OCuL*
-39.4
INT10
(SiR3)2O
O
S
Ph
-40.4
R3SiO
TS11
S
Ph
S
Ph
L*Cu OSiR3
INT11
-55.1
INT11
INT1
OSiR3
L*Cu
H
-71.9
OCuL*
S
Ph
H
INT12
INT13
S
Ph
HSiR3
-91.3
L*Cu
INT1
Figure 7. Computed energy profiles for sequential reduction of copper carboxylate species. L* represents (S,S)-Ph-BPE (L6).
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L*Cu(OAc)2
Me
1
2
3
4
5
Ph
O
1c
R3Si-H
Me
Ph
OSiR3
Me CuL*
L*Cu-H
INT1
INT8
L*Cu-H
INT1
Ph
6
INT2
L*CuO
Me
H
7
8
9
OSiR3
(R3Si)2O
CO2
Cycle 2
Cycle 1
Ph
INT9
R3Si-H
10
11
12
13
14
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17
18
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57
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59
60
L*Cu-OSiR3
Me CO2CuL*
Ph
L*Cu-H
INT1
INT10
INT3
H
R3Si-H
Me
Ph
O
INT11
Cycle 3
H
H
OH
H
H
H H
NH4F/MeOH
Me
Ph
Me
Ph
OSiR3
Me
Ph
OCuL*
R3Si-H
2c
INT13
INT12
Figure 8. Full catalytic cycles.
T. T. Natural-Products-Inspired Use of the gem-Dimethyl Group in
Medicinal Chemistry. J. Med. Chem. 2018, 61, 2166.
ASSOCIATED CONTENT
Supporting Information
(2) For recent reviews on the catalytic formation of quaternary
stereocenters, see: (a) Quasdorf, K. W.; Overman, L. E. Catalytic
enantioselective synthesis of quaternary carbon stereocenters. Nature
2014, 516, 181. (b) Liu, Y.; Han, S. J.; Liu, W. B.; Stoltz, B. M.
Catalytic enantioselective construction of quaternary stereocenters:
assembly of key building blocks for the synthesis of biologically
active molecules. Acc. Chem. Res. 2015, 48, 740. (c) Zeng, X. P.; Cao,
Z. Y.; Wang, Y. H.; Zhou, F.; Zhou, J. Catalytic Enantioselective
Desymmetrization Reactions to All-Carbon Quaternary Stereocenters.
Chem. Rev. 2016, 116, 7330. (d) Zhu, Y.; Han, J.; Wang, J.; Shibata,
N.; Sodeoka, M.; Soloshonok, V. A.; Coelho, J. A. S.; Toste, F. D.
Modern Approaches for Asymmetric Construction of Carbon-
Fluorine Quaternary Stereogenic Centers: Synthetic Challenges and
Pharmaceutical Needs. Chem. Rev. 2018, 118, 3887. (e) Ping, Y.; Li,
Y.; Zhu, J.; Kong, W. Construction of Quaternary Stereocenters by
Palladium-Catalyzed Carbopalladation-Initiated Cascade Reactions.
Angew. Chem., Int. Ed. 2019, 58, 1562. (f) Xu, P.-W.; Yu, J.-S.; Chen,
C.; Cao, Z.-Y.; Zhou, F.; Zhou, J. Catalytic Enantioselective
Construction of Spiro Quaternary Carbon Stereocenters. ACS Catal.
2019, 9, 1820. (g) Li, C.; Ragab, S. S.; Liu, G.; Tang, W.
Enantioselective formation of quaternary carbon stereocenters in
natural product synthesis: a recent update. Nat. Prod. Rep. 2019, DOI:
10.1039/c9np00039a.
Detailed experimental procedures, spectral data, and analytical
data are available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
Yu Lan: lanyu@cqu.edu.cn
Da-Gang Yu: dgyu@scu.edu.cn
ORCID
Yu Lan: 0000-0002-2328-0020
Da-Gang Yu: 0000-0001-5888-1494
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Financial support provided by the National Natural Science
Foundation of China (21822108, 21822303 and 21772020), the
“973” Project from the MOST of China (2015CB856600), the
“1000-Youth Talents Program”, and the Fundamental Research
Funds for the Central Universities. We also thank the
comprehensive training platform of the Specialized Laboratory in
the College of Chemistry at Sichuan University for compound
testing. We thank Prof. Jason J. Chruma (SCU) for helpful
manuscript revisions.
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Copper-catalysed enantioselective stereodivergent synthesis of amino
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CO2 (1 atm)
Cu(II)/(S,S)-Ph-BPE (cat.)
RS
RS
RL
CH2OH
Me(MeO)2SiH
R
R
RL
RS
O
RL = aryl, alkyl;
RS = alkyl;
RL
O
High chemo-, regio-,
E/Z- and enantio-
selectivities
*LCu
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R = H, Me
R
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