Asymmetric allylic C-H oxidation for the synthesis of chromans

Article abstract of DOI:10.1021/jacs.5b08477

An enantioselective intramolecular allylic C-H oxidation to generate optically active chromans has been accomplished under the cooperative catalysis of a palladium complex of chiral phosphoramidite ligand and 2-fluorobenzoic acid. Mechanistic studies suggest that this reaction commences with a Pd-catalyzed allylic C-H activation event and then undergoes asymmetric allylic alkoxylation. The synthetic significance of the method has been embodied by concisely building up a key chiral intermediate to access (+)-diversonol.

Full text of DOI:10.1021/jacs.5b08477

Communication
Asymmetric Allylic C-H Oxidation for the Synthesis of Chromans
Pu-Sheng Wang, Peng Liu, Yu-Jia Zhai, Hua-Chen Lin, Zhi-Yong Han, and Liu-Zhu Gong
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 24 Sep 2015
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Asymmetric Allylic C−H Oxidation for the Synthesis of Chromans
Pu-Sheng Wang†, Peng Liu†, Yu-Jia Zhai†, Hua-Chen Lin†, Zhi-Yong Han†, Liu-Zhu Gong*†‡
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† Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and Technology
of China, Hefei, 230026, China
‡ Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), China
Supporting Information
allylic substitution processes.9 However, the construction of
chiral chroman frameworks via direct inert C−H oxidation
ABSTRACT: An enantioselective intramolecular allylic C−H
oxidation to generate optically active chromans has been
strategy has not been reported, yet.10 In the last decade, highly
accomplished under the cooperative catalysis of a palladium
effective allylic C−H oxidation has been established as one of
complex of chiral phosphoramidite ligand and 2-fluorobenzoic
more appealing synthetic alternatives for fine chemical
acid. Mechanistic studies suggest that this reaction commences
synthesis, in comparison with conventional procedures.11
with a Pd-catalyzed allylic C−H activation event and then
Although
a
successful
application
of
chiral
undergoes asymmetric allylic alkoxylation. The synthetic
significance of the method has been embodied by concisely
building up a key chiral intermediate to access (+)-diversonol.
bisoxazoline/copper complexes in asymmetric allylic C−H
oxidation has achieved high levels of enantioselectivity
(Scheme 1a), the efficiency of these systems is limited to
cyclic olefins.12 Recently, White and coworkers found that the
combined use of a palladium complex and a chiral Lewis acid
was able to significantly enhance the efficiency of asymmetric
allylic C−H oxidation of terminal olefins, but with a moderate
enantioselectivity (Scheme 1b).13 Soon after the discovery of
phosphine ligand promoted Pd-catalyzed allylic C-H
alkylations,14 Trost and coworkers established an asymmetric
allylic C−H alkylation by using chiral phosphoramidite
ligands to control stereochemistry.15 Very recently, our group
accomplished the first enantioselective α-allylation of
aldehydes with terminal alkenes by combining chiral
counteranion catalysis and Pd-catalyzed allylic C−H
activation.16 Herein, we will present an asymmetric allylic
C−H oxidation for asymmetric synthesis of various chromans
enabled by cooperative catalysis of chiral palladium complex
and achiral Brønsted acid (Scheme 1c), allowing for a concise
enantioselective formal synthesis of (+)-diversonol.
Chiral chroman core moiety is widely distributed in numerous
naturally occurring compounds, many of which exhibit
significant biological properties (Figure 1).1 For example,
Vitamin E is a well-known fat-soluble vitamin and important
intramembrane antioxidant that prevents the propagation of
free radical damage in biological membranes.2 Another
example is tetrahydroxanthenone, which is a fast growing
class of mycotoxins with interesting biological activities.3
Among them is diversonol, which is a fungal metabolite and
has been isolated from different fungi such as Penicillium
diversum and Microdiplodia sp.4 Although the bioactivity of
diversonol seems unclear so far, the related dimeric secalonic
acids can exhibit antibacterial, cytostatic, and anti-HIV
properties.5 Therefore, the total synthesis of diversonol has
continuously drawn the attention of chemical community.6
Scheme 1. Asymmetric Allylic C−H Oxidation Reactions
Figure 1. Representative natural products bearing chiral
chroman core moiety
For the synthesis of the chiral chroman motifs, a variety of
enantioselective approaches have been described.7 For years, a
great deal of attention has focused on asymmetric synthesis
that relies on transition metal-catalyzed Wacker-type8 or
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which further demonstrated that this Pd-catalyzed allylic C−H
oxidation process was dramatically accelerated by the
Brønsted acid and phosphoramidite ligand.
5
6
Table 1. Optimization of Reaction Conditionsa
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8
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Figure 2. Chiral phosphoramidite ligands used in this study
yield
b
ee
b
c
entry
B-H
1
L*
E/Z
(%)
6
(%)
0
Our previous work on asymmetric allylic C−H alkylation16
prompted us to initially apply cooperative catalysis of a
palladium complex and a chiral Brønsted acid to the synthesis
of the desired chiral chromans using the substrate 1a bearing
1
(PhO)2PO2H
AcOH
BzOH
OFBA
OFBA
OFBA
OFBA
OFBA
OFBA
OFBA
--
4:1
20:1
36:1
20:1
18:1
16:1
16:1
16:1
7:1
1a L1
1a L1
1a L1
1a L1
1a L2
1a L3
1a L4
1a L5
2
44
18
3
26
59
7
1,4-diene
moiety,
however,
poor
to
moderate
4
21
84
83
85
87
85
88
48
--
enantioselectivities were obtained after several trials (Table
S1).17 Alternatively, we decided to employ the combination of
palladium complexes of bulky chiral ligands (Figure 2) and
Brønsted acids to circumvent the challenge in stereochemical
control.18 Although the use of chiral phosphoric acids still led
to unsatisfactory enantioselectivity, an inspiring phenomenon
that the counteranions of palladium complexes exerted
obvious impact on the catalytic activity was found (Table
S1),17 and thereby prompted us to investigate the effect of
achiral Brønsted acid co-catalysts (Table 1, entries 1-4). To
our delight, the use of 2-fluorobenzoic acid as the organic
co-catalyst was able to promote the efficiency and
enantioselectivity of the reaction (entry 4). Then, various
chiral BINOL derived phosphoramidites L2−5 were evaluated.
It was identified that the introduction of highly
electron-deficient 4-nitrobenzyl substitution to 3,3’-positions
of the BINOL moiety was able to greatly enhance the
enantioselectivity (entry 5). Fine tuning of amine moiety on
phosphoramidite ligands found that the presence of sterically
less demanding and more electronically deficient substituents
on the benzyl group were beneficial to the control of
enantioselectivity (entries 6−8). The highest enantioselectivity
was obtained upon using a chiral phosphoramidite ligand
incorporated with an electronically rich aryl substituent on
amine moiety (entry 8). Interestingly, the olefin geometry of
the substrate showed obvious impact on the reaction. In
comparison with E-isomer, Z-isomer underwent the allylic
alkoxylation with higher E/Z selectivity and slightly enhanced
enantioselectivity (entries 9−10), which to some extent
implied the proposed allylic substitution process, as the
Wacker-type approach should give thermodynamically
controlled similar E/Z selectivity via β-H elimination event,
basically unconnected with the olefin geometry after the initial
nucleopalladation,19 while E/Z selectivity of the allylic
alkoxylation showed obvious correlation with the olefin
geometry.9b Although the reaction was also able to proceed
smoothly in the absence of 2-fluorobenzoic acid (OFBA), a
much diminished enantioselectivity was obtained (entry 11),
implying that the Brønsted acid played an important role in the
control of stereoselectivity. Notably, the absence of
phosphoramidite ligand L5 was unable to give the desired
product 2a with nearly quantitative recovery of 1a (entry 12),
5
97
6
95
7
94
95(92d)
90d
87d
70d
8
9
E-1a
L5
10
11
12
Z-1a
20:1
28:1
--
L5
Z-1a
L5
Z-1a
OFBA
trace
--
aReaction conditions: 1a (0.1 mmol, E/Z = 1:1.2), Pd(dba)2 (5
mol%), L (7.5 mol%), B-H (10 mol%), DMBQ (1.2 equiv),
MTBE (1 mL), 45 oC, 12 h, under Ar. bBased on 1H-NMR
analysis of the crude reaction mixture using benzyl benzoate as
an internal standard. cDetermined by HPLC. dIsolated yield.
OFBA = 2-fluorobenzoic acid. MTBE = methyl tert-butyl ether.
DMBQ = 2,6-dimethyl-1,4-benzoquinone.
Under the optimized conditions, we next explored the
generality of the asymmetric allylic C-H oxidation reaction
(Scheme 2). The installation of different substituents on the
benzene ring was nicely tolerated, giving rise to the desired
chiral chromans 2 in high yields, excellent E/Z selectivity, and
with moderate to good levels of enantioselectivities. Either
electron donating or withdrawing substituent at 4-position of
the benzene ring led to the generation of chromans 2b−g with
good performance, except for 4-acetamide substituted
substrate 1h, which gave slightly lower enantioselectivity.
Especially, the reaction was highly sensitive to the substitution
pattern on the benzene ring, as shown in 1i-j. As such, the
installation of a substituent at either 3- or 5-position led to
much diminished E/Z selectivity and enantioselectivity. To our
delight, the E/Z selectivity could be improved to 30:1 with
slightly improved enantioselectivity by using ligand L6 to
replace L5 in the case of 1j. Notably, 1k was also able to
participate in a clean reaction with ligand L6 to give excellent
E/Z selectivity and enantioselectivity. Moreover, the presence
of bulkier alkyl group adjacent to the internal alkenes (1l-o)
was also compatible with the optimal reaction conditions,
delivering the desired products in good yields and with high
enantioselectivities. However, the presence of a substituent at
the terminal double bond (1p) led to a much slower reaction
2
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under the optimized conditions, while enhanced results could
be obtained by replacing ligand L5 with ligand L7.
E/Z selectivity (Scheme 3b), relatively close to the results
observed for the reaction of 1a (Table 1). More importantly, a
significant intramolecular kinetic isotope effect (KIE, kH/kD =
2.5) was observed for the reaction of D2-1a (Scheme 3c),17
which revealed that the allylic C−H cleavage was the
rate-determining step. All of these results aggregately suggest
that the allylic C-H activation process to generate π-allyl
palladium species turns out to be the initial step of the reaction,
rather than a Wacker-type pathway.8
Scheme 2. Substrate Scopea
Pd(dba)2 (5 mol%)
R2
L5 (7.5 mol%)
3
4
R1
OFBA (10 mol%)
R1
*
R2
O
DMBQ (1.2 eq.)
MTBE, 45 oC, 12 h
under Ar
5
OH
1
R3
R3
2
9
iPr
MeO
Me
10
11
12
13
14
15
16
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O
O
O
Scheme 4. Asymmetric Formal Synthesis of (+)-Diversonol
Me
2b, 81% yield,
Me
Me
2c, 86% yield,
E/Z = 25:1, 90%ee
2d, 88% yield,
E/Z = 27:1, 83%ee
E/Z = 24:1, 85%ee
OMe
OMe
a
tBu
b
F
Cl
61%
13:1 dr
95%
Me
Me
O
Me
O
OH
O
O
O
Me
Me
Me
Me
Me
4
2k, 84%ee
2e, 93% yield,
2f, 84% yield,
E/Z = 15:1, 80%ee
2g, 85% yield,
E/Z = 29:1, 85%ee
OMe
OMe
E/Z = 28:1, 86%ee
AcHN
c
OMe
76%
O
OH
Me
O
O
O
Me
Me
O
Me
O
O
Me
5
Me
O
Me
OMe
2h, 88% yield,
E/Z = 23:1, 75%ee
2j, 68% yield, E/Z = 5:1, 71%ee,
b72% yield, E/Z = 30:1, 72%ee
2i, 82% yield,
E/Z = 18:1, 76%ee
OMe
d
e
OMe
CHO
Me
O
Me
O
6
Me
OH
O
O
O
OH
OH
Me
O
Me
OMe
Me
OMe
OH
O
2k, b87% yield,
2l, 91% yield,
E/Z = 46:1, 89%ee
2m, 93% yield,
E/Z = 35:1, 87%ee
OH
Ref. 6c, 6d
5 steps
E/Z = 23:1, 90%ee
Me
O
Me
Me
O
O
7, 81% for 2 steps
OH
(+)-diversonol
O
O
O
O
Me
Me
95%ee
Bn
iPr
2o, 86% yield,
Reaction conditions: a) 9-BBN (2.0 equiv.), THF, rt, 12h, then
NaOH, H2O2. b) Zr(OtBu)4 (0.5 eq.), D
2p, c71% yield,
2n, 95% yield,
E/Z = 32:1, 88%ee
-
(
-
)
-DIPT (0.6 equiv.),
TBHP (2.0 equiv.), DCM, 0 C, 12 h. c) SO3·Py (6.0 equiv.),
E/Z > 50:1, 66%ee
E/Z > 50:1, 86%ee
o
aReaction conditions: 1 (0.1 mmol), Pd(dba)2 (5 mol%), L5 (7.5
mol%), OFBA (10 mol%), DMBQ (1.2 equiv), MTBE (1.0 mL),
45 C, 12 h, under Ar. L6 was used instead of L5. L7 was used
instead of L5
o
Et3N (10 equiv.), DMSO (40 equiv.), DCM, 0 C, 1 h. d) Pd/C
(5 mol%), H2, EtOAc, rt, 1h. e) PCC (2.0 equiv.), DCM, rt, 1h.
o
b
c
Finally, we attempted to apply this new method to the
enantioselective synthesis of (+)-diversonol (Scheme 4). It is
noteworthy that the more easily accessible E/Z-isomeric
mixture of 1k was able to undergo a scale-up reaction to give
Scheme 3. Experiments for Mechanistic Studies
2k in
a
high yield and with synthetically useful
enantioselectivity in the presence of 2 mol% of chiral
palladium complex.17 Regioselective hydroboration of 2k with
9-borabicyclo[3.3.1]nonane (9-BBN) and followed by an
oxidation with hydrogen peroxide in the presence of sodium
hydroxide was able to give homoallylic alcohol 4 in an almost
perfect yield. After various conditions were examined for the
diastereoselective epoxidation of 4, a modified Onaka’s
Zr(OtBu)4–DIPT–TBHP system was found to give satisfactory
diastereomeric ratio of 13:1.20 The conversion of 5 to
γ-hydroxyl unsaturated aldehyde
6 was established by
β-elimination reaction of the corresponding epoxide aldehyde
intermediate21 under the standard Parikh–Doering oxidation
conditions.22 The hydrogenation of 6 catalyzed by Pd/C under
H2 atmosphere gave rise to the corresponding hemiacetal
intermediate, which was oxidized by PCC to furnish the
chroman lactone 5 with 95%ee, which was actually a key
intermediate for the total synthesis of (+)-diversonol by
following procedures reported by Nicolaou6c and Bräse.6d All
of the spectroscopic data of the synthetic chroman lactone 5
was in complete agreement with those reported previously.6d,17
Then, a series of parallel reactions (Scheme 3) were
conducted to identify the allylic C-H activation pathway. The
control reaction using 2-(3-methylpent-3-en-1-yl)phenol (1q)
under the optimized conditions (Scheme 3a) failed to afford
the desired product and the starting material was nearly
quantitatively recovered, implying that the Wacker-type
reaction is impossible to occur and might thereby be ruled out
as a pathway. In contrast, a typical Pd-catalyzed allylic
alkoxylation of 3 in the presence of ligand L5 resulted in 15:1
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Zahoor, A.; Hussain, H.; Ahmed, I.; Ahmad, V. U.; Padula, D.;
In conclusion, an enantioselective intramolecular allylic
C−H oxidation reaction has been established under the
cooperative catalysis of a chiral palladium complex and
2-fluorobenzoic acid, allowing for an efficient synthesis of
chromans in high yields and with high levels of
enantioselectivity. Mechanistic studies suggest that the
reaction proceeds via an initial counteranion-assisted
Pd-catalyzed allylic C−H activation and followed by an allylic
alkoxylation, rather than a formal Wacker-type cyclization.
More significantly, this method has provided a new efficient
synthetic route to the key chiral intermediate for the synthesis
of (+)-diversonol.
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ASSOCIATED CONTENT
Supporting Information. Complete experimental procedures and
characterization data for the prepared compounds. This material is
available free of charge via the internet at http://pubs.acs.org
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AUTHOR INFORMATION
Corresponding Author
gonglz@ustc.edu.cn
ACKNOWLEDGMENT
We are grateful for financial support from MOST (973 project
2015CB856600), NSFC (21232007, 21302177), and the
Fundamental Research Funds for the Central Universities
(WK2060190041).
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