Optically Active Flavaglines-Inspired Molecules by a Palladium-Catalyzed Decarboxylative Dearomative Asymmetric Allylic Alkylation

Article abstract of DOI:10.1021/jacs.0c05113

With the aid of a class of newly discovered Trost-type bisphosphine ligands bearing a chiral cycloalkane framework, the Pd-catalyzed decarboxylative dearomative asymmetric allylic alkylation (AAA) of benzofurans was achieved with high efficiency [0.2-1.0 mol% Pd2(dba)3/L], good generality, and high enantioselectivity (>30 examples, 82-99% yield and 90-96% ee). Moreover, a diversity-oriented synthesis (DOS) of previously unreachable flavaglines is disclosed. It features a reliable and scalable sequence of the freshly developed Tsuji-Trost-Stoltz AAA, a Wacker-Grubbs-Stoltz oxidation, an intra-benzoin condensation, and a conjugate addition, which allows the efficient construction of the challenging and compact cyclopenta[b]benzofuran scaffold with contiguous stereocenters. This strategy offers a new avenue for developing flavagline-based drugs.

Full text of DOI:10.1021/jacs.0c05113

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Communication
Optically Active Flavaglines-Inspired Molecules by a Palladium-
Catalyzed Decarboxylative Dearomative Asymmetric Allylic Al-kylation
Meng-Yue Cao, Bin-Jie Ma, Zhi-Qi Lao, Hongliang Wang, Jing Wang, Juan Liu, Kuan
Xing, Yu-Hao Huang, Kang-Ji Gan, Wei Gao, Huaimin Wang, Xin Hong, and Hai-Hua Lu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c05113 • Publication Date (Web): 25 Jun 2020
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Journal of the American Chemical Society
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Optically Active Flavaglines-Inspired Molecules by a Palladium-
Catalyzed Decarboxylative Dearomative Asymmetric Allylic Alkylation
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Meng-Yue Cao,†,§ Bin-Jie Ma,† Zhi-Qi Lao,† H. Wang,§ Jing Wang,† Juan Liu,‡ Kuan Xing,† Yu-Hao
Huang,† Kang-Ji Gan,†,§ Wei Gao,‡ Huaimin Wang,† Xin Hong,§ and Hai-Hua Lu*,†,‡,§
†Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province, School of Science, Westlake
University, 18 Shilongshan Road, Hangzhou 310024, China; Institute of Natural Sciences, Westlake Institute for
Advanced Study, Hangzhou 310024, China
‡Institute of Advanced Synthesis (IAS), Nanjing Tech University, 30 South Puzhu Road, Nanjing 211816, China
§Department of Chemistry, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China
KEYWORDS: Palladium-Catalyzed AAA, Enantioselective Synthesis, Flavaglines, Diversity-Oriented Synthesis (DOS)
ABSTRACT: With the aid of a class of newly discovered Trost-type bisphosphine ligands bearing a chiral cycloalkane
framework, the Pd-catalyzed decarboxylative dearomative asymmetric allylic alkylation (AAA) of benzofurans was achieved
with high efficiency [0.2-1.0 mol% Pd2(dba)3/L], good generality and high enantioselectivity (> 30 examples, 82-99% yield
and 90-96% ee). Moreover, a diversity-oriented synthesis (DOS) of previously unreachable flavaglines is disclosed. It features
a reliable and scalable sequence of the freshly developed Tsuji-Trost-Stoltz AAA, a Wacker-Grubbs-Stoltz oxidation, an intra-
benzoin condensation and a conjugate addition, which allows the efficient construction of the challenging and compact
cyclopenta[b]benzofuran scaffold with contiguous stereocenters. This strategy offers a new avenue for developing flavagline-
based drugs.
A. Representative Natural and non-Natural Bioactive Flavaglines
The palladium-catalyzed asymmetric allylic alkylation
O
O
HO
HO
HO
HO
HO
MeO
HO
OMe
MeO
MeO
(AAA) has become one of the most powerful bond-forming
reactions for accessing biologically relevant molecules in
the realm of enantioselective catalysis.1 Due to its wide
applicability, the mechanism has been thoroughly explored
by preeminent researchers such as Trost, Stoltz, Lloyd-
Jones, etc., through experimental and/or computational
methods.2 We are now cognizant of the fact that the reaction
pathway could vary greatly depending on various
parameters, while chiral ligand plays a vital role in ensuring
a highly enantiomeric transformation. In this context, PHOX
ligands developed independently by Helmchen, Pfaltz and
Williams,3 as well as Trost’s DPPBA-based ligands were
soon revealed as the privileged candidates for AAA.4 Despite
the notable advancement, ligand design for surmounting
highly challenging while practical enantioselective
transformations continues to be a popular research area.
Recently, by incorporating a chiral cyclohexane scaffold into
the PHOX framework, we developed a new class of CyPHOX
ligands,5 which exhibited much better performance in
X
N
H
R1
O
MeO
O
O
MeO
MeO
R2
OMe
OMe
rocaglaol ( ): R1 = H, R2 = OMe
4
6
)
aglafolin
(
): X = OMe
rohinitib (
1
5
rocaglamide ( ): X = NMe2
FL3 ( ): R1 = H, R2 = Br
2
IMD-019064 ( ): R1 = F, R2 = OMe
3
HO
MeO
CO2Me
N
HO
N
MeO
HO
O
Ph
O
OH
O
O
MeO
O
O
OMe
OH
OMe
silvestrol (
OMe
7
8
)
)
aglaroxin C
(
B. This Work:
DOS of Flavaglines by a Pd-Catalyzed Dearomative AAA
R7
R6
R8
R4
O
R5
R3
O
8
Ar
5
1
HO
2
3
8a
8b
3a
7
6
Ar
R1
R2
Ar
R1
O
4a
O
R1
O
flavaglines
9
10
Pd AAA
0.2-1.0 mol%
O
O
O
O
O
NH HN
L
/
Pd2(dba)3
O
Lam's
nickel-catalyzed
desymmetrizing
arylative
R1
Ar
90-96% ee
cyclization than the common PHOX ligands.6 With our
continuing interest in ligand design and asymmetric
synthesis, we herein report the discovery of a new class of
Trost-type bisphosphine ligands bearing chiral cycloalkane
scaffolds, which exhibited excellent performance in the Pd-
PAr2 Ar2
New!
P
R1
O
Ar
low catalyst loading
excellent outcome
> 30 examples
O
11
L15
ent-
: Ar = 4-CH3-C6H4
L16
12
good scalablility
or
Figure 1. A Diversity-Oriented Synthesis (DOS) Approach to
Flavaglines by A Palladium-Catalyzed AAA.
catalyzed
decarboxylative
dearomative
AAA
of
benzofurans,7,8 Furthermore, the success of this AAA
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enabled a diversity-oriented synthesis (DOS) of unprece-
delivered the desired allylation product 10a by using PHOX
and CyPHOX ligands (Table 1, entries 1-9), and best results
were obtained with tert-Butyl PHOX L5 (entry 4, 62% ee).16
To our disappointment, our CyPHOX ligands showed poor
performance in this AAA (entries 6-9). Considering
completely different transition states involved in the
palladium-catalyzed AAA with PHOX ligands2h and Trost’s
bisphosphine ligands,2a-g we thus prepared Trost-type
ligands L11-L14 incorporating our chiral cyclohexane
scaffold (see SI for synthesis), and evaluated their
performance in this AAA. To our delight, among these four
new ligands, the best chirality matched one L12 offered a
significant improvement with an ee of 65% compared with
the original Trost ligand L1 (20% ee). Based upon previous
pioneering mechanistic investigations,2a-g we reckoned that,
in addition to the traditional Wall-Flap effect, the chiral
cycloalkane scaffold of L12 might play a role of further
enhancing selectivity through its interaction with the
nucleophile during the bond-forming step, as the π-allyl
moiety involved is deeply embraced in the chiral pocket.17
As one more tunable element introduced into the Trost
Modular Ligand (TML) series, chances of success are
supposed to increase. Thus, a series of this new class of
ligands were prepared and evaluated in this AAA. L15 was
soon found to give best results for benzofuran 12a (entry
15, 79% ee).18 More intriguingly, decreasing the loading of
the catalyst from 2.5 mol% to 0.2 mol% has a negligible
influence on the enantiomeric outcome of this AAA (entry
19, 80% ee). Furthermore, the reaction proceeded with very
good efficiency even at -20 °C with 0.2 mol%
Pd2(dba)3/L15, and best results were thus obtained (entry
20, 89% yield and 92% ee).
dented flavaglines (Figure 1).9
1
2
3
4
5
6
7
8
Flavaglines (rocaglates), characterized by a densely
functionalized cyclopenta[b]benzofuran scaffold with
contiguous
stereocenters
(including
two
vicinal
tetrasubstituted carbons, Figure 1A),10 were found to exhibit
a notably wide array of biological properties, and of
particular interest is their selective cytotoxicity towards a
broad spectrum of cancer cell lines over normal cell lines.
This activity is now believed to be due to their ability to
target prohibitins (PHBs) 1 and 2 as well as translation
initiation factor eIF4A.11,12 For these reasons, flavaglines
have long been the focus of numerous synthetic studies,13
and drug development.14 However, to the best of our
knowledge, a general strategy, suitable for manipulation at
C3a and C3 beyond dominant aryl groups (Figure 1B), and to
overcome the critical issues such as substrate dependence,
reliability and optical outcome associated with existing
synthetic methods, remains a significant challenge. By close
analysis of flavaglines (Figure 1B), we envisioned that an
asymmetric diversity-oriented synthesis (DOS) synthesis
should be viable through a two-stage diversification design:
1) the palladium-catalyzed AAA of benzofuran-3(2H)-ones
11 or its benzofuran derivatives 12; and 2) classic conjugate
additions or other alkene functionalizations of the tricyclic
intermediates 9 derived from AAA products 10, although
establishing all the required stereocenters on such a highly
compact and strained scaffold will be a formidable task.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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With these considerations in mind, we started to
investigate the Pd-catalyzed AAA. Initially, the direct AAA of
11 was tested, but it proved unsuccessful.15 To our delight,
the mild and neutral Tsuji-Trost-Stoltz AAA of 12a cleanly
Table 1. Ligand Development and Optimization for the Palladium-Catalyzed AAA.a
entry Ligand
X
Y
yield (%)b ee (%)c
O
X mol% Pd2(dba)3.CHCl3
Ligand
O
O
Y mol%
THF, -20 o
O
1
L1
5
10
10
10
10
10
10
10
10
10
2.5
2.5
2.5
2.5
2.5
2.5
2.5
0.2
0.2
61
80
84
95
78
88
81
86
83
89
90
87
87
85
89
88
91
89
2
C
Bn
O
Bn
2
L2
5
13
46
62
4
O
12a
10a
3
L3
5
4
L4
5
L1
L2
L3
L4
L5
: R = Ph, R' = Ph
: R = Ph, R' = Bn
: R = Ph, R' = i-Pr
: R = Ph, R' = t-Bu
O
O
O
5
L5
5
P
N
P
N
P
N
Ph
Ph
Ph
Ph
R
R
: R = c-Hex, R' = t-Bu
t-Bu
t-Bu
6
L6
5
8
R'
L6
L7
7
L7
5
3
O
O
O
O
8
L8
5
4
NH HN
P
N
P
N
Ph
Ph
Ph
Ph
9
L9
5
7
PPh2 Ph2
P
t-Bu
t-Bu
10
11
12
13
14
15
16
19
20
L10
L11
L12
L13
L14
L15
L16
L15
L15
2.5
2.5
2.5
2.5
2.5
2.5
2.5
0.2
0.2
-20d
40
65
-60d,e
11e
79e
72e
80e
92
L8
L9
L10
O
: (S,S)-Trost ligand
O
O
O
O
O
NH HN
NH HN
NH HN
PPh2 Ph2
L11
P
PPh2 Ph2
L12
P
PPh2 Ph2
L13
P
Ar
Ar
O
O
O
O
O
O
NH HN
NH HN
NH HN
PPh2 Ph2
P
PAr2 Ar2
P
PPh2 Ph2
L14
P
L15
L16
: Ar = 1-naphthyl
: Ar = 4-CH3-C6H4-
aUnless otherwise noted, the reactions were carried out with 12 (0.5 mmol), X mol% Pd2(dba)3·CHCl3 and Y mol% ligand (L) in
THF at -20 °C. bIsolated Yield. cDetermined by Chiral HPLC. dReverse sequence of peaks by HPLC. eRun at RT.
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Table 2. Scope of the Palladium-Catalyzed Decarboxylative Dearomative AAA.a
1
2
3
4
5
6
7
8
9
O
O
O
O
0.2 mol% Pd2(dba)3
L15
O
0.2 mol%
THF, -20 o
O
NH HN
C
Ar
R1
R1
PAr2 Ar2P
O
Ar
O
12
10
L15
: Ar = 4-CH3-C6H4-
representative examples
O
O
O
O
10a (
10b (
10c (
10d (
10e (
O
O
X = O, R = H ): 89% y, 92% ee
X = NAc, R = H ): 89% y, 82% ee
X = O, R = CO2Me): 99% y, 91% ee
X = O, R = CN): 91% y, 90% ee
X = O, R = CF3): 92% y, 90% ee
b
O
O
O
X
O
O
Me
Me
X
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
10f
(X = O, R = F): 92% y, 90% ee
10g
(X = O, R = Cl): 93% y, 90% ee
OMe
c
10h (
X = O, R = OMe): 99% y, 91% ee
Me
c
R
10i (
X = O, R = NHBoc): 88% y, 90% ee
10j
10k
(X = Me): 97% y, 92% ee
10m
10n
91% y, 91% ee
10o
98% y, 96% ee
99% y, 91% eec
10l (X = Br): 82% y, 93% eec
95% y, 92% ee
O
O
O
O
O
OMe
O
O
O
MeO
O
O
O
O
O
O
R
X
R
N
Ph
Ph
Me
c
10s
10w
98% y, 91% ee
10v
10p
10q
10r
10t
10u
(X = O): 95% y, 90% ee
(X = S): 94% y, 92% ee
c
94% y, 90% ee
99% y, 90% eec
97% y, 90% eec
91% y, 90% eec
99% y, 91% ee
10v-10c': R = 1-naphthyl
O
OMe
O
O
O
O
O
O
N
O
R
O
O
X
O
R
N
O
MeO
O
Ph
O
R
Ph
O
X
Ph
R'
e
10x
10y
10z
(X = OMe): 99% y, 91% ee
c
d
10a'
10d'
98% y, 91% ee
10e'
10f'
90% y, 90% ee
10b'
10g'
(X = OMe): 98% y, 90% ee
(X = Br): 99% y, 92% ee
(R' = OMe): 83% y, 90% ee
(X = Br): 98% y, 94% ee
(X = F): 98% y, 94% ee
98% y, 90% ee
10c'
98% y, 94% ee
10h' (R' = H): 92% y, 90% eef
d
aUnless otherwise noted, the reactions were carried out with 12 (0.5 mmol) and 0.2 mol% Pd2(dba)3/L15 in THF at -20 °C. bWith
1.0 mol% Pd2(dba)3/L16 and 4 Å MS in THF at -20 °C. cWith 0.4 mol% Pd2(dba)3/15 in THF at -40 °C. dWith 0.4 mol% Pd2(dba)3/L15
in THF at -5 °C. eWith 1.0 mol% Pd2(dba)3/L16 and 4 Å MS in THF at -50 °C. With 1.0 mol% Pd2(dba)3/L16 and 4 Å MS in THF at -
f
45 °C.
With best conditions in hand, we then evaluated the
scope of this Pd-catalyzed AAA (Table 2). A series of
benzofurans (12a, 12c-u) with various different alkyl
substituent at C3a position were first evaluated under the
established optimal conditions. In the presence of 0.2 or 0.4
mol % of Pd2(dba)3/L15, all reactions proceeded smoothly
to provide the desired products in excellent yields (82-
99%) with excellent enantioselectivities (90-96% ee),
regardless of their steric or electronic properties. More
importantly, variations of the benzofuran core (10v-10h’),
notably even with a heterocyclic ring pyridine, had no
obvious influence on the reaction efficiency, and excellent
results were preserved with low catalyst loading as well
(90-99% yields, 90-94% ee). It is worth to note that L16
evolved to be the best option for benzofurans containing
aryl substituents at C3a position (10g’ and 10h’), and
additive 4Å molecular sieves are found essential for
obtaining high enantioselectivities.19 Furthermore, indole
12b could also be applied in this AAA to produce the desired
allylation product 10b with good results (89% yield, 81%
ee).20
Scheme 1. Diversity-Oriented Synthesis of Flavaglines.a
20 mol%
N
BF4
O
O
CHO
O
N
C6F5
14
HO
15
N
multi-gram scale
gram scale
PdCl2(PhCN)2
CuCl2.2H2
NaOAc, THF
(80% y)
multi-gram scale
Bn
O
O
10 mol% Pd(OAc)2
O
Bn
(75% y)
AgNO2, O2
TFA, O2, DMSO
(92% y)
13
t-BuOH/MeNO2
1. SmI2, THF; 2. SO3.Py, Et3N-DMSO
O
O
(50% y, 2 steps)
HO
Br2, Et3
DCM
N
3a
Bn
O
10a
ent-
(4.97 g)
(98% y)
O
Bn
9a
0.2 mol%
multi-gram
gram scale
CuBr.SMe2
i-PrMgBr
scale
L15
O
Pd2(dba)3/ent-
16
(90% y)
THF, -20 o
C
94% y, 91% ee
HO
HO
O
O
HO
Me4NBH(OAc)3
3
O
Me
Me
CH3CN-HOAc
O
O
Bn
Bn
Me
(85% y)
Bn
O
Me
18: rocaglaol-type
17a
12a
DMF
gram scale
2
unprecedented
MMC,
1.
1. Pd(OAc)2, O2
2. 10% Pd/C, H2
(60% y, 2 steps)
then
TMSCHN
O
O
HO
HO
1. DMAP, Me2NH
CO2Me
HO
NMe2
Me
toluene
O
Me
2. Me4NBH(OAc)3
CH3CN-HOAc
(53% y, 3 steps)
HO
O
Bn
O
Bn
Me
Me
: rocaglamide-type
Me
20
19
O
Bn
This AAA is quite practical, as ent-10a could be obtained
on a multigram scale without a decrease in efficiency by
means of ent-L15 (94% yield, 91% ee).21 This allowed us to
evaluate our DOS design for flavagline synthesis (Scheme
1). The Wacker-oxidation of ent-10a by the Grubbs-Stoltz
protocol provided aldehyde 13 on a multigram scale,22 and
the subsequent cyclization was achieved either by a
literature-based two-step operation (50%, 2 steps),12 or in
one step by N-heterocyclic carbene (NHC) catalysis (80%)
affording 15 bearing the cyclopenta[b]benzofuran core in
Me
17a
3-epi-
flavaglines
O
same as for
HO
O
HO
HO
18 & 20
HO
NMe2
Me
Me
Bn
O
Bn
Me
21
: rocaglaol-type
Me
22
: rocaglamide-type
aSee the Supporting Information for detailed procedures
and characterization data. Key for the X-ray of structure of
16 and 22: C, gray; H, white; N, blue; O, red; Br, green.
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Journal of the American Chemical Society
gram quantities. It is interesting to note, this intra-benzoin
Page 4 of 7
features two diversification stages that allows access to
flavaglines that are unreachable by previous synthetic
methods. The first stage highlights the significance of the
palladium-catalyzed asymmetric allylic alkylation (AAA).
With the newly discovered class of Trost-type bisphosphine
ligands incorporating a chiral cycloalkane framework, the
Pd-catalyzed decarboxylative dearomative AAA of
benzofurans was achieved with high efficiency [0.2-1.0
mol% Pd2(dba)3/L], good generality and high
enantioselectivity. Studies to understand the exact effect of
the chiral cycloalkane scaffold in this new class of Trost-
type ligands as well as in our previous CyPHOX ligands are
necessary and underway.
1
2
3
4
5
6
7
8
cyclization proved nontrivial, and only NHC catalyst 14 was
ultimately found to be optimal for 13 to provide the desired
intramolecular selectivity over the intermolecular benzoin
condensation.23,24 Next, a direct oxidative dehydrogenation
by Stahl’s protocol gave enone 9a.25 At this stage, the
absolute configuration was unambiguously determined by
X-ray crystallographic analysis of the mono-brominated
enone product 16 derived from 9a. For the second phase of
diversification, we used readily available Grignard reagents
as nucleophiles for conjugate addition with 9a and expected
that the nucleophilic addition from the convex face would
provide the stereochemistry at C3, matching that of natural
products. To our surprise, only product 17a from addition
to the concave face was obtained with isopropyl cuprate.26
From 17a, rocaglaol-type and rocaglamide-type flavaglines
(18 and 20, respectively) were prepared in one or three
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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40
41
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43
44
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ASSOCIATED CONTENT
Supporting Information. Experimental procedures, and
characterization data for all the products. The Supporting
Information is available free of charge on the ACS Publications
website.
simple
operations
(reduction
or
Stiles
carboxylation/transamination/reduction),
respectively.
Meanwhile, 3-epi-17b could be accessed in good isolated
yield from a two-step oxidation-reduction process (60%, 2
steps) though the diastereoselectivity was moderate (2:1
dr). This result highlights the difficulties associated with
this highly compact and strained scaffold, and two more
flavaglines (21 and 22) were secured proving our DOS
design of flavaglines efficacious.27
AUTHOR INFORMATION
Corresponding Author
*luhaihua@westlake.edu.cn
Author Contributions
All authors have given approval to the final version of the
manuscript.
To shed some light on the concave selectivity and the
hydrogenation result, we then further conducted some
experimental studies with a series of (±)-9 (Scheme 2).
Notes
The authors declare no competing financial interests.
Scheme 2.
O
O
ACKNOWLEDGMENT
R2
R2
HO
CuBr.SMe2
R3MgBr
HO
8b
We are grateful to the National Natural Science Foundation of
China (NNSFC, 21772090) and the 1000 Youth Talents
Program of China for support of this research. We thank Prof.
Tian Qin at UT Southwestern for their helpful discussions, and
the Instrumentation and Service Center for Physical Sciences at
Westlake University for help with measurement and data
interpretation.
THF, -78 o
C
3a
3a
R3
R1
R1
R2
R2
O
O
(R1 = Bn, R2 = H, R3 = i-Pr): 90% y, > 19:1 d.r.
(R1 = Bn, R2 = H, R3 = Et): 90% y, > 19:1 d.r.
(R1 = Bn, R2 = H, R3 = Me): 91% y, > 19:1 d.r.
(R1 = Bn, R2 = H, R3 = Ph): 87% y, > 19:1 d.r.
(R1 = Ph, R2 = OMe, R3 = Ph): 62% y, > 19:1 d.r.
+
( )-
9a-b
+
17a
17b
17c
17d
17e
( )-
+
( )-
+
( )-
+
( )-
+
( )-
O
O
17b
17b
[(+)-
[( )-3-epi-
: 38% y]
: 22% y]
(*dr = 1.9:1)
HO
HO
+
+
1. CuBr.SMe2
EtMgBr
2.10% Pd/C, H2
or TBAF
1. CuBr.SMe2
ABBREVIATIONS
Et
Et
EtMgBr
2. 20 mol% DMAP
toluene-H2O, 90 o
O
O
+
Bn
Bn
AAA = asymmetric allylic alkylation; NHC = N-heterocyclic
carbene; RT = room temperature; dba = dibenzylideneacetone;
Bn = benzyl; y = yield; ee = enantiomeric excess. MMC (Stiles
reagent) = methoxymagnesium methyl carbonate.
+
17b
17b
( )-
3-epi-( )-
C
O
O
CO2Me
2
RO
+
+
17b]
3-epi-( )-
HO
[
17b:
R
*dr ( )-
Bn
4.9:1
3.5:1
8b
TBS
O
O
Bn
Bn
9e
* Determined by crude NMR
+
( )-
+
( )-
9c-d
REFERENCES
Firstly, regardless of alkyl or aryl cuprates, only concave
addition products were obtained with (±)-9a or (±)-9b.
Secondly, diastereoselectivities were observed when the
tertiary alcohol at C8b was protected, with the more steric
TBS giving a best 3.5:1 dr, although concave products
predominated regardless of chelating and non-chelating
groups. Moreover, an introduction of ester group at C2
further increased the diastereoselectivity [concerning (±)-
3-epi-17b]. These results suggest that the steric bias
between the concave and convex faces is subtle in this
case.28 This also explains why the hydrogenation afforded a
moderate diastereoselectivity, as hydrogen is much smaller
than the cuprates.
(1) For selected excellent reviews, see: (a) Trost, B. M.; Schultz,
J. E. Palladium-Catalyzed Asymmetric Allylic Alkylation Strategies
for the Synthesis of Acyclic Tetrasubstituted Stereocenters.
Synthesis, 2019, 1-30. (b) Pritchett, B. P.; Stoltz, B. M.
Enantioselective Palladium-Catalyzed Allylic Alkylation Reactions
in the Synthesis of Aspidosperma and Structurally Related
Monoterpene Indole Alkaloids. Nat. Prod. Rep. 2018, 35, 559-574.
(c) Weaver, J. D.; Recio, III, A.; Grenning, A. J.; Tunge, J. A. Transition
Metal-Catalyzed Decarboxylative Allylation and Benzylation
Reactions. Chem. Rev. 2011, 111, 1846-1913. (d) Lu, Z.; Ma, S.
Metal-catalyzed Enantioselective Allylation in Asymmetric
Synthesis. Angew. Chem. Int. Ed. 2008, 47, 258-297. (d) Trost, B.
M.;Crawley, M. L. Asymmetric Transition-Metal-Catalyzed Allylic
Alkylations: Applications in Total Synthesis. Chem. Rev. 2003, 103,
2921-2943.
In summary, a new blueprint for flavagline-based drug
development was established by DOS design. This strategy
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(2) (a) Racys, D. T.; Eastoe, J.; Norrby, P. O.; Grillo, I.; Rogers, S.
Zhang, X.-M.; Xu X.-Y.; Yuan, W.-C. Organocatalyzed Dearomative
Cycloaddition of 2‑Nitrobenzofurans and Isatin-Derived Morita-
Baylis-Hillman Carbonates: Highly Stereoselective Construction of
Cyclopenta[b]benzofuran Scaffolds. Org. Lett. 2019, 21, 660-664.
(f) Yang, X.-H.; Li, J. P.; Wang, D.-C.; Xie, M. S.; Qu, G.-R.; Guo, H.-M.
Enantioselective Dearomative [3+2] Cycloaddition of 2-
Nitrobenzofurans with Aldehyde-derived Morita–Baylis–Hillman
Carbonates. Chem. Commun. 2019, 55, 9144-9147. (g) Wang, H.-M.;
Zhang, J.-Y.; Tu Y.-S.; Zhang, J.-L. Phosphine-Catalyzed
Enantioselective Dearomative [3+2]-Cycloaddition of 3-
Nitroindoles and 2-Nitrobenzofurans. Angew. Chem. Int. Ed. 2019,
58, 5422-5426.
(8) For selected notable examples of previous synthetic
methods (frequently an ester group at C3a position required), see:
(a) Pirrung, M. C.; Werner, J. A. Intramolecular generation and
[2,3]-sigmatropic rearrangement of oxonium ylides. J. Am. Chem.
Soc. 1986, 108, 6060-6062. (b) Fu, J.; Shang, H.; Wang, Z.; Chang, L.;
Shao, W.; Yang, Z.; Tang, Y. Gold-Catalyzed Rearrangement of Allylic
Oxonium Ylides: Efficient Synthesis of Highly Functionalized
Dihydrofuran-3-ones. Angew. Chem. Int. Ed. 2013, 52, 4198-4202.
(c) Z.-S. Chen, X.-Y. Huang, L.-H. Chen, J.-M. Gao, K. Ji, Rh(II)/Pd(0)
Dual Catalysis: Regiodivergent Transformations of Alkylic
Oxonium Ylides. ACS Catal. 2017, 7, 7902-7907. (d) Liu, W.; Ali, S.
Z.; Ammann, S. E.; White, M. C. Asymmetric Allylic C−H Alkylation
via Palladium(II)/cis-ArSOX Catalysis. J. Am. Chem. Soc. 2018, 140,
10658-10662. (e) Liu, Y.-J.; Ding, Y.-L.; Niu, S.-S.; Ma, J. -T.; Cheng, Y.
E.; Lloyd-Jones, G. C. Pd- η3-C6H9 Complexes of the Trost Modular
Ligand: High Nuclearity Columnar Aggregation Controlled by
Concentration, Solvent and Counterion. Chem. Sci. 2015, 6, 5793-
5801. (b) Butts, C. P.; Filali, E.; Lloyd-Jones, G. C.; Norrby, P. O.; Sale,
D. A.; Schramm, Y. Structure-Based Rationale for Selectivity in the
Asymmetric Allylic Alkylation of Cycloalkenyl Esters Employing
the Trost 'Standard Ligand' (TSL): Isolation, Analysis and
Alkylation of the Monomeric form of the Cationic η3-Cyclohexenyl
Complex [(η3-c-C6H9)Pd(TSL)]+. J. Am. Chem. Soc. 2009, 131, 9945-
9957. (c) Lloyd-Jones, G. C.; Stephen, S. C.; Fairlamb, I. J. S.;
Martorell, A.; Dominguez, B.; Tomlin, P. M.; Murray, M.; Fernandez,
J. M.; Jeffery, J. C.; Riis-Johannessen, T.; Guerziz, T. Coordination of
the Trost Modular Ligand to Palladium Allyl Fragments: Oligomers,
Monomers and Memory Effects in Catalysis. Pure Appl. Chem. 2004,
76, 589-601. (d) Bai, D. C.; Yu, F. L.; Wang, W. Y.; Chen, D.; Li, H.; Liu,
Q. R.; Ding, C. H.; Chen, B.; Hou, X. L.Palladium/N-Heterocyclic
Carbene Catalysed Regio and Diastereoselective Reaction of
Ketones with Allyl Reagents via Inner-Sphere Mechanism. Nat.
Commun. 2015, 7, 1-11. (e) Keith, J. A.; Behenna, D. C.; Sherden, N.;
Mohr, J. T.; Ma, S.; Marinescu, S. C.; Nielsen, R. J.; Oxgaard, J.; Stoltz,
B. M.; Goddard, W. A. The Reaction Mechanism of the
Enantioselective Tsuji Allylation: Inner-Sphere and Outer-Sphere
Pathways, Internal Rearrangements, and Asymmetric C-C Bond
Formation. J. Am. Chem. Soc. 2012, 134, 19050-19060, (f) Trost, B.
M.; Toste, F. D. Regio- and Enantioselective Allylic Alkylation of an
Unsymmetrical Substrate: A Working Model. J. Am. Chem. Soc.
1999, 121, 4545-4554. (g) Trost, B. M.; Machacek, M. R.; Aponick,
A. Predicting the Stereochemistry of Diphenylphosphino Benzoic
Acid (DPPBA)-Based Palladium-Catalyzed Asymmetric Allylic
Alkylation Reactions: A Working Model. Acc. Chem. Res. 2006, 39,
747-760, and references therein. (h) Steinhagen, H.; Reggelin, M.;
Helmchen, G. Palladium-Catalyzed Allylic Alkylation with
Phosphinoaryldihydrooxazole Ligands: First Evidence and NMR
Spectroscopic Structure Determination of a Primary Olefin-Pd0
Complex. Angew. Chem. Int. Ed. 1997, 36, 2108-2110.
1
2
3
4
5
6
7
8
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
N-Heterocyclic
Carbene/Palladium
Cascade
Catalysis:
Construction of 2,2-Disubstitiuted Benzofuranones from the
Reaction of 3-(2-Formylphenoxy)propenoates with Allylic Esters.
J. Org. Chem. 2018, 83, 4, 1913–1923.
(9) For selected excellent reviews on drug discovery by
diversity-oriented synthesis: (a) Target-Oriented and Diversity-
Oriented Organic Synthesis in Drug Discovery. Science 2000, 287,
1964-1969. (b) Schreiber, S. L. Organic Chemistry: Molecular
Diversity by Design. Nature 2009, 457, 153-154. (c) Wilson, R. M.;
Danishefsky, S. J. Small Molecule Natural Products in the Discovery
of Therapeutic Agents:ꢀ The Synthesis Connection. J. Org. Chem.
2006, 71, 8329-8351. For selected examples: (d) Peters, D. S.;
Romesberg, F. E.; Baran, P. S. Scalable Access to Arylomycins via C–
H Functionalization Logic. J. Am. Chem. Soc. 2018, 140, 2072-2075.
(e) Nicolaou, K. C.; Rhoades, D.; Kumar, S. M. Total Syntheses of
Thailanstatins A-C, Spliceostatin D, and Analogues Thereof.
Stereodivergent Synthesis of Tetrasubstituted Dihydro- and
Tetrahydropyrans and Design, Synthesis, Biological Evaluation,
and Discovery of Potent Antitumor Agents. J. Am. Chem. Soc. 2018,
140, 8303-8320. (f) Murphy, S. K.; Zeng, M.; Herzon, S. B. A Modular
and Enantioselective Synthesis of the Pleuromutilin Antibiotics.
Science 2017, 356, 956-959. (g) Morton, D.; Leach, S.: Cordier, C.;
Warriner, S.; Nelson, A. Synthesis of Natural-Product-Like
Molecules with Over Eighty Distinct Scaffolds. Angew. Chem. Int. Ed.
2008, 48, 104-109. (h) Charest, M. G.; Lerner, C. D.; Brubaker, J. D.;
Siegel, D. R.; Myers, A. G. A Convergent Enantioselective Route to
Structurally Diverse 6-Deoxytetracycline Antibiotics. Science,
2005, 308, 395-398.
(10) Proksch, P.; Edrada, R.; Ebel, R.; Bohnenstengel, F.;
Nugroho, B. Chemistry and Biological Activity of Rocaglamide
Derivatives and Related Compounds in Aglaia Species (Meliaceae).
Curr. Org. Chem. 2001, 5, 923-938, and references therein.
(11) (a) Thuaud, F.; Bernard, Y.; Türkeri, G.; Dirr, R.; Aubert, G.;
Cresteil, T.; Baguet, A.; Tomasetto, C.; Svitkin, Y.; Sonenberg, N.;
Nebigil, C.G.; Désaubry, L. Synthetic analogue of rocaglaol displays
a potent and selective cytotoxicity in cancer cells: involvement of
apoptosis inducing factor and caspase-12. J. Med. Chem. 2009, 52,
5176-5187. (b) Thuaud, F.; Ribeiro, N.; Gaiddon, C.; Cresteil, T.;
Désaubry, L. Novel flavaglines displaying improved cytotoxicity. J.
Med. Chem. 2011, 54, 411-415.
(3) (a) Sprinz, J.; Helmchen, G. Phosphinoaryl- and
Phosphinoalkyloxazolines as New Chiral Ligands for
Enantioselective Catalysis: Very High Enantioselectivity in
Palladium Catalyzed Allylic Substitutions. Tetrahedron Lett. 1993,
34, 1769–1772. (b) von Matt, P.; Pfaltz, A. Chiral
Phosphinoaryldihydrooxazoles as Ligands in Asymmetric
Catalysis: Pd-Catalyzed Allylic Substitution, Angew. Chem. Int. Ed.
1993, 32, 566–568. (c) Dawson, G. J.; Frost, C. G.; Williams, J.M.J.;
Coote, S. J. Asymmetric Palladium Catalysed Allylic Substitution
using Phosphorus Containing Oxazoline Ligands. Tetrahedron Lett.
1993, 34, 3149–3150.
(4) Uli, K. (Ed.) Transition Metal Catalyzed Enantioselective
Allylic Substitution in Organic Synthesis. Springer, 2012.
(5) Cao, M.-Y.; Xu, Z.-M.; Gao, W.; Liu, J.; Tan, F.; Lu, H.-H. Catalytic
Asymmetric Synthesis of
a New Class of CyPHOX Ligands,
Tetrahedron 2019, 75, 3282-3291.
(6) Karad, S. N.; Panchal, H.; Clarke, C.; Lewis, W.; Lam, H. W.
Enantioselective Synthesis of Chiral Cyclopent-2-enones by Nickel-
Catalyzed Desymmetrization of Malonate Esters. Angew. Chem. Int.
Ed. 2018, 57, 9122-9125,
(7) For selected reviews on dearomative chemistry, see: (a)
Roche, S. P.; Porco, J. A. Dearomatization Strategies in the Synthesis
of Complex Natural Products. Angew. Chem. Int. Ed. 2011, 50, 4068-
4093. (b) Zhuo, C.-X.; Zheng, C.; You, S.-L. Transition-Metal-
Catalyzed Asymmetric Allylic Dearomatization Reactions. Acc.
Chem. Res. 2014, 47, 2558-2573. (c) S. You (Ed.), Asymmetric
Dearomatization Reactions, 2016. Known asymmetric
dearomative chemistry of benzofurans are focused on
cycloaddition of highly electron-deficient 2-nitrobenzofurans, for
recent examples: (d) Cheng, Q.; Zhang, H.-J.; Yue, W.-J.; You, S.-L.
Palladium-Catalyzed Highly Stereoselective Dearomative [3 + 2]
Cycloaddition of Nitrobenzofurans. Chem. 2017, 3, 428-436. (e)
Zhao, J.-Q.; Yang, L.; Zhou, X.-J.; You, Y.; Wang, Z.-H.; Zhou, M.-Q.;
(12) (a) G. Polier, J. Neumann, F. Thuaud, N. Ribeiro, C. Gelhaus,
H. Schmidt, M. Giaisi, R. Kohler, W. W. Muller, P. Proksch, M. Leippe,
O. Janssen, L. Désaubry, P. H. Krammer, M. Li-Weber, Chem. Biol.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 7
2012, 19, 1093-1104. (b) H. Sadlish, G. Galicia-Vazquez, C. G. Paris,
(17) A plausible reaction transition state (TS) was proposed in
SI to explain the enantioface selection. Detailed mechanistic
studies are underway.
T. Aust, B. Bhullar, L. Chang, S. B. Helliwell, D. Hoepfner, B. Knapp,
R. Riedl, S. Roggo, S. Schuierer, C. Studer, J. A. Porco, J. Pelletier, N.
R. Movva, ACS Chem. Biol. 2013, 8, 1519-1527. (c) Santagata, M. L.
Mendillo, Y.-c. Tang, A. Subramanian, C. C. Perley, S. P. Roche, B.
Wong, R. Narayan, H. Kwon, M. Koeva, A. Amon, T. R. Golub, J. A.
Porco Jr., L. Whitesell, S. Lindquist, Science 2013, 341, 1238303. (d)
A. L. Wolfe, K. Singh, Y. Zhong, P. Drewe, V. K. Rajasekhar, V. R.
Sanghvi, K. J. Mavrakis, M. Jiang, J. E. Roderick, J. Van der Meulen, J.
H. Schatz, C. M. Rodrigo, C. Zhao, P. Rondou, E. de Stanchina, J.
Teruya-Feldstein, M. A. Kelliher, F. Speleman, J. A. Porco, J. Pelletier,
G. Ratsch, H.-G. Wendel, Nature 2014, 513, 65-70. (e) Iwasaki, S.;
Iwasaki, W.; Takahashi, M.; Sakamoto, A.; Watanabe, C.; Shichino,
Y.; Floor, S. N.; Fujiwara, K.; Mito, M.; Dodo, K.; Sodeoka, M.;
Imataka, H.; Honma, T.; Fukuzawa, K.; Ito, T.; Ingolia, N. T. The
Translation Inhibitor Rocaglamide Targets a Bimolecular Cavity
between eIF4A and Polypurine RNA. Mol. Cell 2019, 73, 738-748.
(13) For a recent excellent overview of flavagline synthesis, see:
(a) Zhao, Q.; Abou-Hamdan, H.; Désaubry, L. Recent Advances in the
Synthesis of Flavaglines, a Family of Potent Bioactive Natural
Compounds Originating from Traditional Chinese Medicine. Eur. J.
Org. Chem. 2016, 5908-5916, and references therein. For
asymmetric syntheses (three protocols), see: (b) Trost, B. M.;
Greenspan, P. D.; Yang, B. V.; Saulnier, M. G. An Unusual Oxidative
Cyclization. A Synthesis and Absolute Stereochemical Assignment
of (−)-Rocaglamide. J. Am. Chem. Soc. 1990, 112, 9022-9024. (c)
Gerard, B.; Sangji, S.; O’Leary, D. J.; Porco, J. A., Jr. Enantioselective
Photocycloaddition Mediated by Chiral Brønsted Acids:
Asymmetric Synthesis of the Rocaglamides. J. Am. Chem. Soc. 2006,
128, 7754-7755. (d) Gerard, B.; Cencic, R.; Pelletier, J.; Porco, J. A.,
Jr. Enantioselective Synthesis of the Complex Rocaglate (−)-
Silvestrol. Angew. Chem., Int. Ed. 2007, 46, 7831-7834. (e)
Lajkiewicz, N. J.; Roche, S. P.; Gerard, B.; Porco, J. A., Jr.
Enantioselective Photocycloaddition of 3-Hydroxyflavones: Total
Syntheses and Absolute Configuration Assignments of (+)-
Ponapensin and (+)-Elliptifoline. J. Am. Chem. Soc. 2012, 134,
13108-13113. (f) Wang, W.; Clay, A.; Krishnan, R.; Lajkiewicz, N. J.;
Brown, L. E.; Sivaguru, J.; Porco, J. A., Jr. Total Syntheses of the
Isomeric Aglain Natural Products Foveoglin A and Perviridisin B:
Selective Excited- State Intramolecular Proton-Transfer
Photocycloaddition. Angew. Chem. Int. Ed. 2017, 56, 14479-14482.
(g) Zhou, Z.; Tius, M. A. Synthesis of Each Enantiomer of
Rocaglamide by Means of a Palladium(0)-Catalyzed Nazarov-Type
Cyclization. Angew. Chem. Int. Ed. 2015, 54, 6037-6040. (h) Zhou,
Z.; Dixon, D. D.; Jolit, A.; Tius, M. A. The Evolution of the Total
Synthesis of Rocaglamide. Chem. Eur. J. 2016, 22, 15929-15936.
(14) For a review, see: Basmadjian, C.; Thuaud, F.; Ribeiro, N.;
Désaubry, L. G. Future Med. Chem. 2013, 5, 2185-2197, and
references therein.
1
2
3
4
5
6
7
8
(18) For a full list of new ligands investigated, as well as
systematic reaction condition optimization of this AAA, please
refer to SI. Thanks to the reviewer’s suggestion, we later found that
a mixed solvent of hexane and THF (v/v 2:1) is a better solvent
choice than THF alone.
(19) For a recent comprehensive review, see: Hong, L.; Sun, W.;
Yang, D.; Li, G.; Wang, R. Additive Effects on Asymmetric Catalysis.
Chem. Rev. 2016, 116, 4006-4123.
(20) The stereochemistry of 10b was not determined. Direct
AAA of indolin-3-ones were known, with a best 75% ee reported
for 10b by Prof. Hou and coworkers: (a) Chen, T. G.; Fang, P.; Hou,
X. L.; Dai, L. X. Palladium-Catalyzed Asymmetric Allylic Alkylation
Reaction of 2-Monosubstituted Indolin-3-ones. Synthesis, 2015,
134-140. (b) Higuchi, K.; Masuda, K.; Koseki, T.; Hatori, M.;
Sakamoto, M.; Kawasaki, T. Asymmetric Alkylation of 2-
Monosubstituted Indolin-3-ones. Heterocycles, 2007, 73, 641-650.
(21) (a) Kuttruff, C. A.; Eastgate, M. D.; Baran, P. S. Natural
Product Synthesis in the Age of Scalability. Nat. Prod. Rep. 2014, 31,
419-432. (b) Young, I. S.; Baran, P. S. Protecting-Group-Free
Synthesis as an Opportunity for Invention. Nat. Chem. 2009, 1, 193-
205.
(22) (a) Kim, K. E.; Li, J. M.; Grubbs, R. H.; Stoltz, B. M. Catalytic
Anti-Markovnikov Transformations of Hindered Terminal Alkenes
Enabled by Aldehyde-Selective Wacker-Type Oxidation. J. Am.
Chem. Soc. 2016, 138, 13179-13182. (b) Wickens, Z. K.; Skakuj, K.;
Morandi, B.; Grubbs, R. H. J. Am. Chem. Soc. 2014, 136, 890-893. (c)
Wickens, Z. K.; Morandi, B.; Grubbs, R. H. Angew. Chem., Int. Ed.
2013, 52, 11257-11260.
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
(23) (a) Ema, T.; Akihara, K.; Obayashi, R.; Sakai, T. Construction
of Contiguous Tetrasubstituted Carbon Stereocenters by
Intramolecular Crossed Benzoin Reactions Catalyzed by N-
Heterocyclic Carbene (NHC) Organocatalyst. Adv. Synth. Catal.
2012, 354, 3283-3290, and references therein.
(24) Li, Z.; Li, X.; Cheng, J.-P. An Acidity Scale of Triazolium-Based
NHC Precursors in DMSO. J. Org. Chem. 2017, 82, 9675-9681.
(25) (a) Diao, T. Stahl, S. S. Synthesis of Cyclic Enones via Direct
Palladium-Catalyzed Aerobic Dehydrogenation of Ketones. J. Am.
Chem. Soc. 2011, 133, 14566-14569. For recent reviews on
carbonyl dehydrogenation, see: (b) Turlik, A,; Chen, Y,; Newhouse,
T. R. Dehydrogenation Adjacent to Carbonyls Using Palladium–
Allyl Intermediates. Synlett. 2016, 331-336. (c) Iosub, A. V,; Stahl,
S. S. Palladium-Catalyzed Aerobic Dehydrogenation of Cyclic
Hydrocarbons for the Synthesis of Substituted Aromatics and
Other Unsaturated Products. ACS Catal. 2016, 6, 8201-8213.
(26) For a precedent case: (a) Lopez, S. A.; Pourati, M.; Gais, H.-
J.; Houk, K. N. How Torsional Effects Cause Attack at Sterically
Crowded Concave Faces of Bicyclic Alkenes. J. Org. Chem. 2014, 79,
8304−8312. (b) Rosenstock, B.; Gais, H.-J.; Herrmann, E.; Raabe, G.;
Binger, P.; Freund, A.; Wedemann, P.; Krüger, C.; Linder, H. J. Formal
Asymmetric Synthesis of Pentalenolactone E and Pentalenolactone
F 1. Retrosynthesis and π-Facial Differentiation in Palladium-
Catalyzed and Dipolar [3+2]-Cycloaddition Reactions of Bicyclic
Alkenes: Evidence for Electrostatic Control of Stereoselectivity. Eur.
J. Org. Chem. 1998, 257-273.
(27) A formal synthesis of natural flavagline (±)-rocaglamide 5
was accomplished, while a basic in vitro cytotoxic assay of the new
flavaglines was conducted by using Hela cells (See SI).
(28) The insightful idea of using chelating and non-chelating
groups on the tertiary alcohol was recommended by one of the
referees. In this case, the R group might point to the concave face,
due to its steric interaction with Bn at C3a, thus decrease the steric
bias between the two faces. That is why we then introduced an
etser group at C2. Further studies are underway.
(15) Direct allylation of 11 by phase-transfer catalysis (PTC)
was also investigated, which resulted in a mixture of C-allylation
and O-allylation products. O-Allylation products predominated
when the aromatic ring of 11 bear more electron-withdrawing
groups.
(16) (a) Tsuji, J.; Minami, I. New Synthetic Reactions of Allyl Alkyl
Carbonates, Allyl β-Keto Carboxylates, and Allyl Vinylic Carbonates
Catalyzed by Palladium Complexes. Acc. Chem. Res. 1987, 20, 140-
145, and references therein. (b) Douglas, C. B.; Stoltz, B. M. The
Enantioselective Tsuji Allylation, J. Am. Chem. Soc. 2004, 126,
15044-15045. (c) Behenna, D. C.; Mohr, J. T.; Sherden, N. H.;
Marinescu, S. C.; Harned, A. M.; Tani, K.; Seto, M.; Ma, S.; Novak, Z.;
Krout, M. R.; McFadden, R. M.; Roizen, J. L.; Enquist, J. A.; White, D.
E.; Levine, S. R.; Petrova, K. V.; Iwashita, A.; Virgil, S. C.; Stoltz, B. M.
Chem. Eur. J. 2011, 17, 14199-14223. (d) Trost, B. M.; Xu, J. Regio-
and Enantioselective Pd-catalyzed Allylic Alkylation of Ketones
Through Allyl Enol Carbonates. J. Am. Chem. Soc. 2005, 127, 2846.
(e) Trost, B. M.; Xu, J.; Schmidt, T. Palladium-Catalyzed
Decarboxylative Asymmetric Allylic Alkylation of Enol Carbonates,
J. Am. Chem. Soc. 2009, 131, 18343–18357.
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unprecedented flavaglines
R7
O
HO
R4
HO
1
2
3
4
R6
R5
R3
R8
HO
HO
8
Ar
5
1
NMe2
R or S)
2
3
8a
(R or S)
8b
3a
7
6
(
iPr
iPr
R2
R1
4a
O
O
Bn
O
Bn
rocaglaol-type
rocaglamide-type
flavaglines
protecting-group-free synthesis
5
6
7
8
Pd dearomative AAA
broad scope excellent outcome
0.2-1.0 mol%
O
O
O
O
NH HN
O
L
Pd2(dba)3/
O
PAr2 Ar2
New!
P
Ar
90-96% ee
> 30 examples
R1
R1
O
Ar
9
O
good scalablility
L15
: Ar = 4-CH3-C6H4
L16
12
10
or
10
11
12
13
14
15
16
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