Enantioselective Construction of Tertiary C-O Bond via Allylic Substitution of Vinylethylene Carbonates with Water and Alcohols

Article abstract of DOI:10.1021/jacs.7b04759

An efficient method for the enantioselective construction of tertiary C-O bond via asymmetric allylic substitution of racemic vinylethylene carbonates with water and alcohols has been developed. Under the cooperative catalysis system of an in situ generated chiral palladium complex and boron reagent in mild conditions, the process allowed rapid access to valuable tertiary alcohols and ethers in high yields with complete regioselectivities and high enantioselectivities. This protocol represented the first example of direct enantioselective formation of a tertiary C-O bond with water as an oxygen donor. The synthetic utilities of the process have been demonstrated by the elaboration of the products into key intermediates of biologically relevant agents, and chiral tertiary cyclic ethers could also be provided through the sequential reactions of the allylic etherification and ring-closing metathesis.

Full text of DOI:10.1021/jacs.7b04759

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Article
Enantioselective Construction of Tertiary C-O Bond via Allylic
Substitution of Vinylethylene Carbonates with Water and Alcohols
Ajmal Khan, Sardaraz Khan, Ijaz Khan, Can Zhao, Yuxue Mao, Yan Chen, and Yong Jian Zhang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b04759 • Publication Date (Web): 20 Jul 2017
Downloaded from http://pubs.acs.org on July 20, 2017
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Journal of the American Chemical Society
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Enantioselective Construction of Tertiary C-O Bond via Allylic Sub-
stitution of Vinylethylene Carbonates with Water and Alcohols
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Ajmal Khan, Sardaraz Khan, Ijaz Khan, Can Zhao, Yuxue Mao, Yan Chen, Yong Jian Zhang*
School of Chemistry and Chemical Engineering, and Shanghai Key Laboratory of Electrical Insulation and Thermal Aging,
Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
Asymmetric catalysis, asymmetric allylic substitution, chiral tertiary alcohols, cooperative catalysis
ABSTRACT: An efficient method for the enantioselective construction of tertiary CꢀO bond via asymmetric allylic substitution of
racemic vinylethylene carbonates with water and alcohols has been developed. Under the cooperative catalysis system of an in situ
generated chiral palladium complex and boron reagent in mild conditions, the process allowed rapid access to valuable tertiary alꢀ
cohols and ethers in high yields with complete regioselectivities and high enantioselectivities. This protocol represented the first
example of direct enantioselective formation of tertiary CꢀO bond with water as an oxygen donor. The synthetic utilities of the proꢀ
cess have been demonstrated by the elaboration of the products into key intermediates of biologically relevant agents, and chiral
tertiary cyclic ethers could also be provided through the sequential reactions of the allylic etherification and ringꢀclosing metathesis.
to substrates of 2ꢀalkyl substituted 2ꢀvinyloxirans. For vinyl
epoxides, isoprene oxide can be readily made from abundant
INTRODUCTION
Chiral tertiary alcohols and ethers are ubiquitous in mediciꢀ
nally relevant agents and biologically active natural products.1
Consequently, catalytic asymmetric synthesis of these skeleꢀ
tons from readily available precursors is a prominent objective
in modern organic synthesis. A most common approach to
chiral tertiary alcohols is an asymmetric addition of organomeꢀ
tallic reagents to ketones.1a However, high asymmetric inducꢀ
tion of the process invariably relies on the steric difference
between the substituents bearing the carbonyl group. When the
steric difference is small, the enantioselectivity is often low.
Tertiary alcohols and ethers are also produced by asymmetric
dihydroxylation2 and epoxidation3 of 1,1ꢀdisubstituted alkenes.
However, the enantioselectivity of the process is also chalꢀ
lenged on the enantiofacial discrimination between the two
substituents flanking the carbonꢀcarbon double bond. Agꢀ
garwal and coꢀworkers reported an efficient method for the
synthesis of tertiary alcohols from chiral secondary alcohols
via stereospecific 1,2ꢀmetallate rearrangement of boronate
complexes with broad substrate scope.4 Although some other
approaches to chiral tertiary alcohols and ethers have sporadiꢀ
cally been reported,5,6 the development of efficient methods
for enantioselective construction of tertiary CꢀO bond is still
highly appealing.
feedstock, isoprene. However, 2ꢀvinyloxiranes bearing diverse
2ꢀsubstituents are not readily accessible by the epoxidation
process because the corresponding 2ꢀsubstituted butadiene
compounds are not easy to access. Although 2ꢀsubstituted 2ꢀ
vinyloxiranes can be synthesized from the corresponding αꢀ
halogenated ketones,10b this type of epoxides is somewhat
unstable.11 Most recently, we have developed vinylethylene
carbonates (VECs) as more stable and readily available subꢀ
strate for Pdꢀ
Scheme 1. Regioꢀ and Enantioselective Allylic Substitution
of VECs with Water and Alcohols
Transition metalꢀcatalyzed asymmetric allylic substitution
with Oꢀnucleophiles is one of the most powerful methods for
the enantioselective construction of CꢀO bond.7 Although the
transformation has well been developed to provide chiral secꢀ
ondary allylic ethers, regioselective construction of tertiary Cꢀ
O bond via allylic substitution of 1,1ꢀ or 3,3ꢀdisubstituted alꢀ
lylic donors remains a significant challenge.8,9 An elegant exꢀ
ample of forming tertiary allylic ethers with high regioꢀ and
enantioselectivity has been developed under Pdꢀcatalyzed alꢀ
lylic substitution of vinyl epoxides with alcohols using trialꢀ
kylborane as a coꢀcatalyst.10 However, this method is limited
catalyzed asymmetric decarboxylative cycloaddition with unꢀ
saturated electrophiles to construct functionalized heterocycles
with quaternary stereocenters in high efficiencies.12ꢀ14
Based on our continuous efforts to develop efficient methods
for the enantioselective construction of quaternary stereocenꢀ
ters, we are interested in asymmetric allylic substitution of
VECs with water15 in anticipation of the direct construction of
chiral tertiary alcohols. Despite water is one of the most abunꢀ
dant, safe, environmentally benign and costꢀefficient reꢀ
sources, however, direct construction of CꢀO bond for the
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production of chiral alcohols using water as an oxygen donor
Page 2 of 10
remains elusive.16,17 To the best of our knowledge, correspondꢀ
ing protocols for enantioselective construction of tertiary CꢀO
bond with water are unknown. Two challenging issues should
be solved for the process including how to promote nucleoꢀ
philicity of water and how to control regioselectivity to form
tertiary CꢀO bond. Inspired by an earlier report by Trost and
coꢀworkers of allylic etherification of isoprene oxide,9a we
envisioned that the process with boron reagent as a coꢀcatalyst
could solve these problems.18 We hypothesized that VECs
could undergo the decarboxylative process to afford the zwitꢀ
terionic πꢀallylpalladium intermediate A, which with boron
reagent would form boronate complex B. The intermediate B
could capture water to give key intermediate C. This species
would subsequently undergo nucleophilic addition regioselecꢀ
tively to form desired tertiary alcohols (Scheme 1). Herein we
report the realization of this idea and present asymmetric alꢀ
lylic substitution of VECs with water under cooperative catalꢀ
ysis system of palladium and boron reagent, a practical apꢀ
proach which allows rapid access to valuable chiral tertiary
1,2ꢀdiols in high yields with complete regioselectivities and
high level of enantioselectivities. The synthetic strategy is also
suitable for the allylic etherification of VECs with alcohols to
afford tertiary ethers with high efficiencies. The chiral tertiary
cyclic ethers could also be provided through the sequential
reactions of the allylic etherification and ringꢀclosing metatheꢀ
sis.
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60
enꢀ ligand
try
boron reagent
solvent
yield
(%)b
ee
(%)c
ꢀ
1
(R)ꢀL1
ꢀ
THF
ꢀ
2
(R)ꢀL1
BEt3
THF
73
73
90
90
84
90
84
83
82
62
32
66
96
ꢀ
68
77
60
77
78
82
79
78
70
83
ꢀ57
ꢀ77
95
ꢀ
3
(R)ꢀL1
B(2ꢀPhꢀethyl)3
BCy3
THF
4
(R)ꢀL1
THF
5
(R)ꢀL1
B(OH)3
THF
6
(R)ꢀL1
B(OMe)3
THF
7
(R)ꢀL1
PhB(OH)2
2ꢀMeC6H4B(OH)2
4ꢀMeC6H4B(OH)2
4ꢀCF3C6H4B(OH)2
C6F5B(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
THF
8
(R)ꢀL1
THF
9
(R)ꢀL1
THF
RESULTS AND DISCUSSION
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21
22
23
24
25
26
27
(R)ꢀL1
THF
Enantioselective construction of tertiary alcohols via alꢀ
lylic substitution of VECs with water. Initially, we tried the
reaction of PhꢀVEC 1a as a model substrate with water using
the catalyst generated in situ from the Pd2(dba)3ꢁCHCl3 and
Feringa’s phosphoramidite19 (R)ꢀL1 as a ligand in THF at 40
oC. However, the reaction did not proceed at all, and 1a was
recovered in practically quantitative yield (Table 1, entry 1).
As our expected, the reaction using a catalytic amount of triꢀ
ethylborane (20 mol%) under otherwise identical conditions
with entry 1 afforded the desired tertiary 1,2ꢀdiol 2a as the
only regioisomer, albeit with moderate enantiomeric excess
(ee) (68% ee, entry 2). We next found that the reaction could
perform well with various boron sources, such as tri(2ꢀ
phenylethyl)borane (entry 3), tricyclohexylborane (entry 4),
boric acid (entry 5), trimethyl borate (entry 6) and phenylꢀ
boronic acid (entry 7). We didn’t find any
(R)ꢀL1
THF
(S,S,S)ꢀL2
(S,R,R)ꢀL3
(R)ꢀL4
THF
THF
THF
(R,R,R)ꢀL5
(S,R,R)ꢀL6
(R)ꢀBINAP
(S)ꢀSegphos
Trost ligand
(R)ꢀL4
THF
THF
26
62
18
ꢀ
ꢀ50
ꢀ20
20
ꢀ
THF
THF
THF
toluene
CH2Cl2
dioxane
Et2O
CyH
81
88
92
87
61
90
95
89
92
76
92
94
84
91
79
50
(R)ꢀL4
(R)ꢀL4
(R)ꢀL4
Table 1. Optimizations of Catalytic System for Allylic Subꢀ
stitution of PhꢀVEC 1a with Watera
(R)ꢀL4
(R)ꢀL4
acetone
CH3CN
H2O
(R)ꢀL4
(R)ꢀL4
a
Reaction conditions: Pd2(dba)3ꢁCHCl3 (2.5 mol%), ligand (10
mol%), boron source (20 mol%), 1a (0.2 mmol), water (2.0
mmol), solvent (1.0 mL), 40 C, 16 hours. b Isolated yields. Deꢀ
termined by HPLC using a Chiralcel ADꢀH column. The absolute
configuration was confirmed by the comparison of the sign of
optical rotation with that of reported in literature.22
o
c
Table 2. Asymmetric Allylic Substitution of VECs 1 with
Watera
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for the reaction, even though the enantioselectivities were
1
2
3
slightly decreased. Notably, the reaction performed well in
water as solvent to afford the product 2a in high yield, but the
enantioselectivity decreased remarkably (entry 27).
4
5
6
7
8
9
With these optimized conditions in hand (entry 14, Table 1),
the generality of the protocol was evaluated with different
VECs 1 (Table 2). Significantly, a wide range of substituted
phenylꢀVECs having different electronic and steric properties
was tolerated under the reaction conditions to convert into the
corresponding tertiary 1,2ꢀdiols 2aꢀ2l in high yields with comꢀ
plete regioselectivities and high level of enantioselectivities.
The reaction of VECs bearing naphthyl group also proceeded
smoothly to afford 1,2ꢀdiols 2m and 2n in high yields with
excellent enantioselectivities. The process also worked well
for VECs with versatile furan and thiophene moieties to furꢀ
nish corresponding tertiary 1,2ꢀdiols 2o and 2p in high yield
with good enantioselectivities.
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57
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59
60
Table 3. Optimization of Catalytic System for Allylic Subꢀ
stitution of VEC 1q with Watera
enꢀ
try
ligand
boron reaꢀ T (oC) yield
ee (%)c
gent
(%)b
82
52
50
45
41
ꢀ
1
2
3
4
5
6
7
8
9d
(R)ꢀL4
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
BEt3
40
20
20
20
20
20
20
20
20
20
ꢀ30
ꢀ57
ꢀ12
89
8
(R)ꢀL4
(R)ꢀL1
(S,S,S)ꢀL2
(S,R,R)ꢀL3
(R,R,R)ꢀL5
(S,R,R)ꢀL6
(S,S,S)ꢀL2
(S,S,S)ꢀL2
(S,S,S)ꢀL2
ꢀ
ꢀ
ꢀ
53
43
63
97
>99
>99
BEt3
10e
a
BEt3
a
Reaction conditions: Pd2(dba)3ꢁCHCl3 (2.5 mol%), (R)ꢀL4
(10 mol%), phenylboronic acid (20 mol%), 1 (0.2 mmol), waꢀ
Reaction conditions: Pd2(dba)3ꢁCHCl3 (2.5 mol%), ligand
o
ter (2.0 mmol), THF (1.0 mL), 40 C, 16 hours. Yields are of
isolated materials. The enantioselectivities were determined by
HPLC using chiral stationary phase.
(10 mol%), boron source (20 mol%), 1q (0.2 mmol), water
b
c
(2.0 mmol), THF (1.0 mL), 16 hours. Isolated yields. Deꢀ
d
termined by HPLC using a Chiralcel ADꢀH column. The
reaction was performed with 10 mol% of Et3B. The reaction
e
methoxylated product when using trimethyl borate or allylꢀ
phenyl coupling product when using phenylboronic acid.20
These results demonstrated that boron is a useful coꢀcatalyst
for the process. The reaction with phenylboronic acid gave
best enantioselectivity (82% ee). Further screening of substiꢀ
tuted phenylboronic acids with different steric and electronic
properties, the reaction efficiency did not improve (entries 8ꢀ
11). To our delight, through the examination of different
phosphoramidite ligands (entries 12ꢀ16), we found that the
reaction with the combination of Pd2(dba)3ꢁCHCl3 (2.5 mol%),
a Zhou’s ligand21 (R)ꢀL4 (10 mol%) and phenylboronic acid
was performed with 10 mol% of Et3B for 24 hours.
However, the conditions were not suitable for the reaction of
alkyl substituted VEC 1q, giving the product 2q in 82% yield
with only 30% ee (Table 3, entry 1). Therefore, we tried to
find optimal conditions for the reaction of VEC 1q with water
(Table 3). Firstly, we found that the enantioselectivity could
o
be improved when the reaction temperature reduced to 20 C,
even though the yield is decreased (entry 2). Further screening
of ligand (entries 3ꢀ7), we found that the reaction with Ferinꢀ
ga’s ligand (S,S,S)ꢀL2 gave tertiary diol 2q with 89% ee (entry
4). To our delight, the enantioselectivity could be improved to
97% by the replacement of phenylboronic acid with triethylꢀ
borane (entry 8). The reaction with 10 mol% of triethylborane
gave 2q with almost single enantiomer (entry 9). The yield can
be improved to 63% by prolong the reaction time to 24 hours
(entry 10).
o
(20 mol%) in THF at 40 C gave tertiary 1,2ꢀdiol 2a as a sinꢀ
gle regioisomer in 96% yield with 95% ee (entry 14). Low
enantioselectivities were observed when the reaction with
bisphosphine ligand, BINAP (entry 17) or Segphos (entry 18).
The reaction did not proceed with Trost ligand (entry 19).
Further screening of solvent (entries 20ꢀ27) showed that toluꢀ
ene, 1,4ꢀdioxane, ether and acetone are also suitable solvents
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try
(%)b
92
80
89
88
28
ꢀ
(%)c
80
ꢀ86
ꢀ70
89
65
ꢀ
Table 4. Asymmetric Allylic Substitution of Alkylꢀ
Substituted VECs with Watera
1
2
3
4
5
6
7
8
1
(R)ꢀL1
BEt3
THF
2
(S,S,S)ꢀL2
(S,R,R)ꢀL3
(R)ꢀL4
BEt3
THF
3
BEt3
THF
4
BEt3
THF
5
(R,R,R)ꢀL5
(S,R,R)ꢀL6
(R)ꢀL4
BEt3
THF
6
BEt3
THF
7
BEt3
toluene
CH2Cl2
Et2O
92
72
75
82
36
86
73
48
78
69
62
94
90
63
89
80
86
90
88
85
80
88
83
93
9
8
(R)ꢀL4
BEt3
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
9
(R)ꢀL4
BEt3
10
11
12
13
14
15
16
17
18d
(R)ꢀL4
BEt3
cyclohexane
1,4ꢀdioxane
toluene
toluene
toluene
toluene
toluene
toluene
toluene
(R)ꢀL4
BEt3
(R)ꢀL4
BnBu3
BCy3
BPh3
B(OH)3
B(OMe)3
PhB(OH)2
BEt3
(R)ꢀL4
(R)ꢀL4
(R)ꢀL4
(R)ꢀL4
a Reaction conditions: Pd2(dba)3ꢁCHCl3 (2.5 mol%), (S,S,S)ꢀL2
(10 mol%), triethylborane (10 mol%), 1 (0.2 mmol), water (2.0
(R)ꢀL4
(R)ꢀL4
o
mmol), THF (1.0 mL), 20 C, 24 h. Yields are of isolated materiꢀ
a
Reaction conditions: Pd2(dba)3ꢁCHCl3 (2.5 mol%), ligand (10
als. The ee values were determined by HPLC analysis. The ee
values of 2r, 2t and 2u were determined by HPLC analysis of
their diol monobenzoyl esters. b the reaction was carried out under
the conditions as described in Table 2.
mol%), boron reagent (5 mol%), 1a (0.2 mmol), benzyl alcohol
(3a) (0.22 mmol), solvent (0.1 M), 40 oC, 16 hours. Isolated
b
c
d
yield. Determined by HPLC using chiral stationary phase. The
reaction was performed by the addition of 4 Å molecular sieves
(100 mg).
With the optimal conditions of the combination of
Enantioselective construction of tertiary ethers via allylic
substitution of VECs with alcohols. After successful realizaꢀ
tion of the asymmetric substitution of VECs with water, we
subsequently turned our attention toward the expansion of this
process with alcohols as nucleophiles to construct tertiary
ethers. Firstly, the studies focused on the allylic substitution of
PhꢀVEC 1a with benzyl alcohol (3a). We began our investigaꢀ
tion by examining the reaction of 1a with 3a in the presence of
triethyl borane (5 mol%) and palladium catalyst bearing difꢀ
Pd2(dba)3ꢁCHCl3 (2.5 mol%), a Feringa’s ligand (S,S,S)ꢀL2 (10
o
mol%) and triethylborane (10 mol%) in THF at 20 C for 24
hours, the generality of the allylic substitution of alkylꢀ
substituted VECs with water was next examined (Table 4). For
alkyl substituted VECs, MeꢀVEC 1r and BnꢀVEC 1s could
convert into the tertiary 1,2ꢀdiols 2r and 2s respectively in
high yields with good enantioselectivities. For the reaction of
long chain substituted VEC 1t, excellent enantioselectivity
(95% ee) was observed, albeit in relatively low yield (62%).
Meaningfully, more functionalized tertiary 1,2ꢀdiols could also
be prepared using this allylic hydroxylation process. Thus,
versatile 1,2ꢀdiols 2uꢀ2w bearing four different functional
groups at one carbon stereogenic center were obtained in good
yields with acceptably high enantioselectivities. Notably, the
reaction condition described in Table 2 for aryl substituted
VECs was more suitable for the reaction of VEC 1v having
benzyloxymethyl group, thus giving the 1,2ꢀdiols 2v in 83%
yield with 98% ee (60% yield and 73% ee was obtained under
the conditions as described in Table 4). Remarkably, for all of
the examples in Table 2 and 4, we didn’t find any correspondꢀ
ing byproducts, which potentially produced from the primary
alcohol of the products 2 acting as nucleophiles to the subꢀ
strates.
o
ferent phosphoramidite ligands in THF at 40 C for 16 h. As
shown in Table 5, the reaction proceeded smoothly with
Zhou’s ligand (R)ꢀL4 gave the desired tertiary ether 4aa in 88%
yield with complete regioselectivity and good enantioselectiviꢀ
ty (89% ee, entry 5). Further screening different solvents, we
found that the reaction efficiency was slightly improved by
using toluene as solvent (entry 7).
Table 6. Asymmetric Allylic Substitution of PhꢀVEC 1a
with Various Alcoholsa
Table 5. Condition Optimizations for the Allylic Substituꢀ
tion of PhꢀVEC 1a with Benzyl Alcohol (3a)a
enꢀ
ligand
boron reagent
solvent
yield
ee
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that the reaction could proceed reasonably with various boron
1
2
3
4
reagents, such as tributylborane, tricyclohexylborane, triꢀ
phenylborane, boric acid, trimethyl borate, and phenylboronic
acid. The reaction could be further improved by the addition
of 4 Å molecular sieves, providing the product 4aa in high
yield (94%) with high enantioselectivity (93% ee, entry 18).
5
6
7
8
9
With the optimized conditions in hand (entry 18, Table 5),
the generality of this allylic etherification process was evaluatꢀ
ed by the reaction of PhꢀVEC 1a with various alcohols 3 (Taꢀ
ble 6). A wide variety of allylic tertiary ethers could be proꢀ
duced in high yields with complete regioselectivities and high
levels of enantioselectivities. The reactions proceeded well
with simple alcohols, such as methanol, ethanol, 2ꢀ
phenylethanol, and cyclohexylmethanol, providing the correꢀ
sponding tertiary ethers 4abꢀ4ae in high yields with good to
high enantioselectivities. Significantly, various functional
groups such as ketoꢀ, cyanoꢀ, esterꢀgroups could be introduced
via the allylic etherification process to afford 4afꢀ4ah in high
yields with good to high enantioselectivities. The reaction
conditions were also suitable for the reaction of 1a with Nꢀboc
protected amino alcohol to afford tertiary ether 4aj in good
efficiency. However, relatively low enantioselectivities were
observed for the reaction with Nꢀbenzoyl and Nꢀtosyl protectꢀ
ed amino alcohols. Nevertheless, the reaction did not proceed
at all with αꢀhydroxy ethyl acetate. The reaction of 1a with 1ꢀ
hexanol bearing terminal chlorine group proceeded well to
furnish corresponding product 4am in high yield with high
enantioselectivity. Various alkenyl and alkynyl moieties could
also be introduced under the optimal conditions, giving correꢀ
sponding tertiary ethers 4anꢀ4at in high yields with good to
high enantioselectivities. The reaction also proceeded well
with 2ꢀnaphthylmethanol, 4ꢀmethoxylꢀ and 4ꢀnitrobenzyl alꢀ
cohols to afford corresponding tertiary ethers 4auꢀ4aw in high
efficiencies. Alcohols with heteroaromatics moieties were also
suitable substrates for the reaction, providing 4ax and 4ay in
high efficiencies. It should be noted that the reaction condiꢀ
tions were not suitable for secondaryꢀ and tertiary alcohols
such as isopropanol and tertꢀbutanol.
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12
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After the successful realization of the allylic etherification of
PhꢀVEC 1a with various alcohols, the generality of the process
was next examined by the reaction of various substituted
VECs with allylic alcohol (3q). As shown in the Table 7, Varꢀ
ious VECs with substituted phenyl ring bearing different elecꢀ
tronic and steric properties were tolerated under the reaction
conditions to convert into the corresponding tertiary allylic
ethers in high yields with complete regioselectivities and high
level of enantioselectivities. The reaction of VECs bearing
naphthyl group also proceeded smoothly to afford tertiary
allylic ether 4mq in high yield with high enantioselectivity.
The process also worked well for VECs with versatile furan
and thiophene moieties to furnish the corresponding tertiary
allylic ethers 4oq and 4pq in high yields with good enantioseꢀ
lectivities. However, the reaction conditions were less effecꢀ
tive for MeꢀVEC 1r to afford the product 4rq with only 37%
ee. For the etherification of alkylated VEC 1q, moderate enanꢀ
tioselectivity was observed. Notably, more functionalized terꢀ
tiary allylic ether 4vq could also be obtained in high yield with
good enantioselectivity. For all of the examples in Table 6 and
Table 7, the byproducts, which might be formed by the primaꢀ
ry alcohols of the products 4 acting as nucleophiles to VECs,
were not observed.
48
a
Reaction conditions: Pd2(dba)3ꢁCHCl3 (2.5 mol%), (R)ꢀL4
49
50
51
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53
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58
59
60
(10 mol%), triethylborane (5 mol%), 1a (0.2 mmol), alcohols
3 (0.22 mmol), 4 Å molecular sieves (100 mg), toluene (0.1
M), 40 C, 16 hours. Yields are of isolated materials. The ee
values were determined by HPLC using chiral stationary
phase. The absolute configuration was confirmed by the comꢀ
parison of the sign of optical rotation of 4al with that of reꢀ
ported in literature.9b Those of the other products were asꢀ
signed by analogy.
o
Although the reaction efficiency did not improve further by
using other boron reagents (entries 12ꢀ17), it is noteworthy
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Table 7. Asymmetric Allylic Substitution of VECs 1 with
Allyl Alcohol (3q)a
1
2
3
4
5
6
7
8
.
Pd2(dba) 3 CHCl3 (2.5 mol%)
O
O
(R)-L4 (10 mol%)
BEt3 (5 mol%)
O
R
OH
O
+
OH
toluene, 40 oC, 16 h
4 Å MS
3q
4
R
1
MeO
OMe
O
9
MeO
O
O
10
11
12
13
14
15
16
17
18
19
20
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22
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HO
HO
HO
4bq
94% yield, 95% ee
Me
4cq
96% yield, 93% ee
tBu
4xq
94% yield, 99% ee
F
O
O
O
HO
HO
HO
4dq
95% yield, 92% ee
Cl
4eq
95% yield, 96% ee
Br
4yq
Figure 1. Correlation between the enantiopurity of ligand (R)ꢀL4
and the enantioselectivity in the allylic hydroxylation of 1a to 2a.
87% yield, 90% ee
Next, in order to trace the source of the hydroxyl oxygen in
the products of tertiary 1,2ꢀdiols, isotropic labeling experiꢀ
ments were conducted by using H218O instead of H2O. As outꢀ
lined in Scheme 2, the reactions of 1a and 1q with H218O unꢀ
der different two optimized conditions (Table 2 and 4) affordꢀ
ed 18O labeled products 2a’ and 2q’ in 84 and 82 18O% respecꢀ
tively.16d These results demonstrated that the process likely
undergoes key intermediate C and subsequent nucleophilic
addition pathway as proposed in Scheme 1. Thus, the enantiꢀ
oselective allylic substitution of VECs with water could be
achieved under the cooperative catalysis system of palladium
and boron reagent.
O2N
O
O
O
HO
HO
HO
4fq
4gq
87% yield, 94% ee
MeO
4zq
90% yield, 92% ee
O
91% yield, 94% ee
F
OMe
O
F
O
O
O
HO
HO
HO
4iq
4jq
4kq
92% yield, 90% ee
92% yield, 98% ee
84% yield, 90% ee
O
S
O
O
O
Scheme 2. Allylic Substitution of 1a and 1q with H218O
HO
HO
HO
4mq
4oq
4pq
.
Pd2(dba) 3 CHCl (2.5 mol%)
3
94% yield, 92% ee
93% yield, 90% ee
91% yield, 87% ee
O
(R)-L4 (10 mol%)
Ph
H18
HO
O
Ph
PhB(OH)2 (20 mol%)
O
BnO
HO
Me
HO
O
O
O
O
HO
H218O (10 eq.)
THF, 40 oC, 16 h
2a'
Ph
4rq
4qq
4vq
93% yield
84 18O%
87% yield, 37% ee
97% yield, 61% ee
94% yield, 83% ee
1a
a
Reaction conditions: Pd2(dba)3ꢁCHCl3 (2.5 mol%), (R)ꢀL4 (10
.
Pd2(dba)3 CHCl3 (2.5 mol%)
mol%), triethylborane (5 mol%), 1 (0.2 mmol), allyl alcohol (3l)
(0.22 mmol), 4 Å molecular sieves (100 mg), toluene (0.1 M), 40
oC, 16 hours. Yield of isolated product. The ee values were deꢀ
termined by HPLC using chiral stationary phase.
O
(S,S,S)-L2 (10 mol%)
Ph
H18
HO
O
O
BEt3 (10 mol%)
O
H218O (10 eq.)
THF, 20 oC, 24 h
2q'
1q
57% yield
82 18O%
Mechanistic consideration for the allylic substitution
process. Firstly, to gain insight into the coordination mode of
the phosphoramidite ligand during the catalytic reaction, we
examined the correlation between enantiopurity of ligand (R)ꢀ
L4 with enantioselectivity of the allylic hydroxylation of 1a
under the conditions described in Table 1 (entry 14). As
shown in Figure 1, the enantioselectivity of the reaction is
linearly correlated to the enantiopurity of the ligand (R)ꢀL4
within experimental error. These results implied that the pallaꢀ
dium complex coordinated with one phosphoramidite ligand is
likely to be a true active catalytic species during the reaction.23
Ph
To further gain insight into the reaction pathway, we conꢀ
ducted 11B NMR studies for the allylic etherification reaction
(Figure 2). In control experiments, we found that Et3B could
be converted quantitatively into Et2BOMe and EtB(OMe)2 by
mixing Et3B with methanol in THF (Figure 2a and 2b),24
which was confirmed by comparing it with 11B NMR spectra
of Et2BOMe. Upon mixing Et2BOMe with methanol in THF,
conversion of Et2BOMe into EtB(OMe)2 was also found, but
no signal of B(OMe)3 was observed. Subsequent addition of
NaOMe to the solution, a new broad resonance at 22.02 ppm
was formed (Figure 2e), which is likely to be characteristic of
an –ate complex, Na[EtB(OMe)3].25
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20
a
Reaction conditions: Grubb’s I catalyst (5 mol%), 4 (0.2
mmol), CH2Cl2 (0.1 M), 40 oC, 16 hours. Yields are of isolated
materials. b The reaction was ran by using Grubb’s ǁ catalyst.
Synthetic utility of the allylic substitution process. To
display the synthetic utility of the present allylic hydroxylation
and etherification protocol, we tried to elaborate the products
of tertiary alcohols 2 and tertiary ethers 4 to more valuable
compounds. Firstly, we applied the furnished products 4 to the
convenient synthesis of biologically relevant tertiary cyclic
ethers. As shown in Table 8, ringꢀclosing metathesis of tertiary
ethers 4aqꢀ4as performed well in the presence of Grubbs I or
II catalysts to produce fiveꢀ, sixꢀ and sevenꢀmembered oxoꢀ
heterocycles with high yields. Dihydrofurans with different
functional groups could also be afforded in high yields (86ꢀ
95%). To further demonstrate synthetic utility of the allylic
etherification method, dihydrofuran 8, which would be a key
intermediate for antifungal drug Posaconazole,26 has been
synthesized through sequential reactions of asymmetric allylic
etherification and ringꢀclosing metathesis (Scheme 3). The
reaction of VEC 1k with allylic alcohol 6 was performed
smoothly to furnish desired product 7 in 92% yield with 95%
ee. The tertiary ether 7 underwent ringꢀclosing metathesis with
HoveydaꢀGrubbs 1st generation catalyst to afford the dihydroꢀ
furan 8 in 83% yield.
Figure 2. 11B NMR spectra in THF (reference to BF3ꢁOEt2)
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With model studies in hand, the reaction of PhꢀVEC 1a with
methanol was tracked by 11B NMR. Accordingly, two resoꢀ
nances at 54.35 (Et2BOMe) and 32.05 [EtB(OMe)2] ppm were
observed by mixing Et3B (20 mol%) with PhꢀVEC 1a (1
equiv.) and MeOH (1.1 equiv.) in THF (Figure 2f). Subseꢀ
quently, Pd2(dba)3ꢁCHCl3 (5 mol%) and ligand (R)ꢀL4 (20
mol%) were added to the mixture, in which only one signal for
EtB(OMe)2 at 32.02 ppm was observed (Figure 2g). Further
running the reaction for 2 hour (about 30% conversion deterꢀ
mined by TLC), two new resonances at 20.01 and 19.49 ppm
were appeared (Figure 2h). One of the signals (20.01 ppm)
might be attributed to the –ate complex of EtB(OMe)2 with
oxygen anion of zwitterionic πꢀallylpalladium intermediate as
our proposed reaction pathway in Scheme 1. After 1a convertꢀ
ed completely into product 4ab within 12 hours, the resonance
of EtB(OMe)2 remained as a major signal with a resonance at
19.40 ppm, and a new peak at 34.46 ppm was observed (Figꢀ
ure 2i). The resonance at 34.46 and 19.40 ppm might be atꢀ
tributed to the borate generated from transesterification equiꢀ
librium of EtB(OMe)2 and B(OMe)3 with 4ab. These 11B NMR
studies indicated that the real boronꢀcoꢀcatalyst should be
EtB(OR)2, or maybe a mixture of Et2B(OR), EtB(OR)2 or
B(OR)3 in some cases. Thus, the more real reaction pathway in
the asymmetric allylic etherification process is likely that
EtB(OR)2 reacts with allylpalladium intermediate A to generꢀ
ate –ate intermediate, which undergoes nucleophilic addition
to afford product 4 regioselectively. The chiral palladium
complex and EtB(OR)2 are released to the next catalytic cycle.
The synthetic utility of the allylic hydroxylation process was
also demonstrated by the elaboration of tertiary 1,2ꢀdiol 2k
into the corresponding triol 10 (Scheme 4), which is a key
intermediate for the preparation of triazole antifungal agents,27
such as Genaconazole, Ravuconazole, and Albaconazole. The
reaction of 1k with water in 6 mmol scale using (S)ꢀL4 as a
ligand proceeded smoothly to afford (R)ꢀ2k in 92% yield (1.1
g) with 94% ee. Epoxidation of 2k with 3ꢀ
chloroperoxybenzoinc acid (mꢀCPBA) under ꢀ10 oC gave
epoxide 9 in 84% yield with 7:1 of diastereomeric ratio, and
subsequent reduction of the epoxide by the treatment of lithiꢀ
um aluminium hydride afforded triol 10 in 85% yield. The
absolute configuration of triol 10 was confirmed by the comꢀ
parison of 1H NMR data with that of the reported.27
Table 8. Ringꢀclosing Metathesis of 4 to Tertiary Cyclic
Ethers 5a
Scheme 3. Synthesis of a Key Intermediate for Posaconaꢀ
zole
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HPLC chromatographies, H and 13C NMR spectra of the prodꢀ
ucts. This material is available free of charge via the Internet at
http://pubs.acs.org.
1
1
2
3
4
AUTHOR INFORMATION
5
6
7
Corresponding Author
* yjian@sjtu.edu.cn
8
9
Notes
The authors declare no competing financial interests.
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ACKNOWLEDGMENT
This work was supported by the Natural Science Foundation of
China (21572130), China Postdoctoral Science Foundation
(2016M590354), the National Key Basic Research Program of
China (2013CB934102), and Shanghai Jiao Tong University. We
thank the Instrumental Analysis Center of Shanghai Jiao Tong
University for HRMS analysis.
Scheme 4. Synthesis of a Key Intermediate for Triazole
Antifungal Agents
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CONCLUSIONS
In conclusion, we have developed an efficient method for
the enantioselective construction of tertiary CꢀO bond via
asymmetric allylic substitution of VECs with water and alcoꢀ
hols. The process relies on synergistic catalysis system of an
in situ generated chiral palladium complex and boron reagent
to rigorously control the regioꢀ and enantioselectivity, and
allows rapid access to highly functionalized chiral tertiary
alcohols and ethers in high yields with complete regioselecꢀ
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utility of the present process was demonstrated by the syntheꢀ
sis of key intermediates of biologically relevant agents. The
tertiary cyclic ethers with different ring size can also be ofꢀ
fered through the sequential reactions of asymmetric allylic
etherification and ringꢀclosing metathesis with high efficienꢀ
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with other nucleophiles is currently underway in our laboratoꢀ
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ASSOCIATED CONTENT
Supporting Information. Detailed experimental procedures;
characterization data of all of the new compounds; copies of
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Rodríguez, L.; Kuniyil, R.; Martin, E.; EscuderoꢀAdán, E. C.;
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(b) Guo, W.; MartínezꢀRodríguez, L.; Martin, E.; Escuderoꢀ
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2016, 18, 6042. For Pdꢀcatalyzed asymmetric allylic aminaꢀ
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Cai, A.; Guo, W.; MartínezꢀRodríguez, L.; Kleij, A. W. J. Am.
Chem. Soc. 2016, 138, 14194.
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