Pd-Catalyzed Decarboxylative Olefination: Stereoselective Synthesis of Polysubstituted Butadienes and Macrocyclic P-glycoprotein Inhibitors

Article abstract of DOI:10.1021/jacs.0c00078

The efficient and stereoselective synthesis of polysubstituted butadienes, especially the multifunctional butadienes, represents a great challenge in organic synthesis. Herein, we wish to report a distinctive Pd(0) carbene-initiated decarboxylative olefination approach that enables the direct coupling of diazo esters with vinylethylene carbonates (VECs), vinyl oxazolidinones, or vinyl benzoxazinones to afford alcohol-, amine-, or aniline-containing 1,3-dienes in moderate to high yields and with excellent stereoselectivity. This protocol features operational simplicity, mild reaction conditions, a broad substrate scope, and gram-scalability. Notably, a structurally unique allylic Pd(II) intermediate was isolated and characterized. DFT calculation and control experiments demonstrated that a rare Pd(0) carbene intermediate could be involved in this reaction. Moreover, the polysubstituted butadienes as novel building blocks were unprecedentedly assembled into macrocycles, which efficiently inhibited the P-glycoprotein and dramatically reversed multidrug resistance in cancer cells by 190-fold.

Full text of DOI:10.1021/jacs.0c00078

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Article
Pd-Catalyzed Decarboxylative Olefination: Stereoselective Synthesis
of Polysubstituted Butadienes and Bioactive Macrocyclic Inhibitors
Bichao Song, Peipei Xie, Yingzi Li, Jiping Hao, Lu Wang, Xiangyang Chen, Zhongliang
Xu, Haitian Quan, Li-guang Lou, Yuanzhi Xia, K. N. Houk, and Weibo Yang
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 30 Apr 2020
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Pd-Catalyzed Decarboxylative Olefination: Stereoselective
Synthesis of Polysubstituted Butadienes and Bioactive Macrocyclic
Inhibitors
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Bichao Song,1,4 Peipei Xie,2 Yingzi Li,3 Jiping Hao1, Lu Wang,1 Xiangyang Chen,3 Zhongliang Xu,1,4
Haitian, Quan,4 Liguang, Lou,4 Yuanzhi Xia,2* K. N. Houk,3* and Weibo Yang1,4,5*
1 Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM),
Chinese Academy of Sciences, Shanghai, China
2College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, China
3Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
4University of Chinese Academy of Sciences, Beijing 100049, China
5Key Laboratory for Functional Material, Educational Department of Liaoning Province, University of Science and Technology Liaoning,
Anshan 114051, China
KEYWORDS. Pd(0) carbene, decarboxylation, olefination, 1,3-dienes, macrocyclic inhibitors.
ABSTRACT: The efficient and stereoselective synthesis of polysubstituted butadienes, especially the multifunctional butadienes,
represents a great challenge in organic synthesis. Herein, we wish to report a distinctive Pd(0) carbene-initiated decarboxylative
olefination approach that enables the direct coupling of diazo esters with vinylethylene carbonates (VECs), vinyl oxazolidinones, or
vinyl benzoxazinones to afford alcohols, amines, or anilines-containing 1,3-dienes in moderate to high yields and with excellent
stereoselectivity. This protocol features operational simplicity, mild reaction conditions, a broad substrate scope, and gram-scalability.
Notably, a structurally unique allylic Pd(II) intermediate was isolated and characterized. DFT calculation and control experiments
demonstrated that a rare Pd(0) carbene intermediate could be involved in this reaction. Moreover, the polysubstituted butadienes as
novel building blocks were unprecedentedly assembled into macrocycles, which efficiently inhibited the P-glycoprotein (P-gp) and
dramatically reversed multidrug resistance in cancer cell with 190 folds.
O
INTRODUCTION
O
OH
O
O
O
OH
H
O
The Pd-catalyzed cross coupling reaction between electrophiles
and diazo compounds has emerged as a versatile and reliable
tool for olefination via subsequent Pd(0) oxidative addition of
C-X (X = carbon, nitrogen, halides, et al) bond, migratory
insertion and β-hydride elimination.1 In this context, the
hypothesis of Pd(II) carbene pathway has been widely accepted
and investigated1 (Scheme 2a). In contrast, an alternative Pd(0)
carbene manifold has comparatively been underexploited in this
field, although it could hold great promise for the development
of novel transformations. The distinction between these two
pathways is the sequence of diazo decomposition which is
determined by the activation energy. Undoubtedly, deep
understanding of the Pd carbene pathway and design of Pd
carbene trappings have become two overarching goals to the
continuing development of carbene cross coupling chemistry.
H
O
H
N
O
O
O
O
Homopetasinic acid
H
O
H
OH
OH
N
O
N
O
O
OH OH
O
S
OH
OH
O
Inhibitor of protease plasmepsin-1/2
Thuggacin A
O
O
OH
O
Tautomycetin D-3
OH
O
OH
O
OH
O
OH
O
Alcohols, amines or anilines-containing 1,3-dienes are
structural motifs in a wide range of natural products6 and
biologically active molecules7 (Scheme 1). Moreover, these
1,3-dienes could serve as versatile handles for further complex
molecule elaboration8 owing to their multifunctional groups and
ease of manipulation, such as construction of macrocyclic
Scheme 1. Natural products and pharmaceutical molecules with
alcohol or ether-containing 1,3-dienes
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compounds, and they have received much attention from the
synthetic community9, 10
might become the preferable pathway rather than
.
decarboxylative olefination, as it has been very recently
demonstrated by Xiao and Lu12. b) Although Pd-catalyzed
cycloadditions and allylic substitutions of VECs or vinyl
benzoxazinones have been well-established12, 13, 14, studies on
Pd-catalyzed carbene coupling reactions of VECs remain
underdeveloped, particularly, the DFT calculations of Pd(II) or
Pd(0) carbene formation is still uncovered to date. c) There are
some other methods having been reported to construct the 1,3-
diene structure. But they need one configuration-confirmed
double bond in the reactant10. Different from those methods,
two double bonds in our product are newly formed during the
reaction, which makes it more difficult to control
stereoselectivity of 1,3-dienes.
Recently, Loh and Xu recently reported Pd-catalyzed oxidative
cross coupling which can provide trisubstituted (2E,4Z)-
configurated alcohols-containing 1,3-dienes10d (Scheme 2b).
However, the construction of more bulky tetrasubstituted
(2E,4E)-configurated alcohols and amines-containing 1,3-
dienes was not successful. Thus, from the sustainable synthesis
and new drug discovery viewpoints, a general and simple
method for rapidly assemble structurally diverse and alcohols,
amines, or anilines-containing 1,3-dienes is desirable.
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Scheme 2. Profile of Pd carbene formation and our designs
Herein, we report the first Pd-catalyzed decarboxylative
olefination reaction of vinylethylene carbonates and analogs
with donor/acceptor carbenes. Accordingly, this palladium-
catalyzed transformation enables a highly stereoselective,
expeditious synthesis of E-configurated alcohols, amines, and
anilines-containing 1,3-dienes. Moreover, the polysubstituted
butadienes as novel building blocks were successfully
assembled into bioactive macrocycles for the first time.
a) Profile of Pd carbene formation
N2
R2
X
PdII
R2
X
R1
Well-established
No report
Pd (0)
X
Pd(II)
R1
X
PdII
R2
X
N2
Pd(0)
R2
Pd (0)
R2
R1
R1
R1
b) Previous work synthesis of alcohols-containing 1,3-diene
OH
OH
COOR
Pd (II)
amines, aniline-containing 1,3-dienes were not reported
Loh and Xu's work
COOR
Ph
Ph
RESULTS AND DISCUSSION
This work: c) Pd-catalyzed decarboxylative olefination
To examine the feasibility of this reaction, vinylethylene
carbonates (1a) and methyl 2-diazo-2-phenylacetate (2a) were
used as model substrates. The elegant work of Kleij13 and
Zhang14 showed that phosphine ligands are highly effective for
Pd-catalyzed cross coupling of vinylethylene carbonates. We
first investigated the effect of different phosphine ligands by
choosing [Pd2(dba)3]·CHCl3 (5 mol%) as the catalyst and DMF
as solvent at 60 º C (see the Supporting Information). As
described there, screenings of Pd(0) catalysts, diphosphorus
ligands and additives showed that the phosphorus ligands are
not required, but tert-butyl ammonium bromide (TBAB) is
adequate. The optimal condition is using [Pd2(dba)3]·CHCl3
(2.5 mol%) as Pd source, TBAB (100 mol%) in DMF at 60 ºC.
E
E
R2 R1
R4
Pd(II) carbene pathway
Pd(0) carbene pathway
X
O
O
XH
R3
O
N
O
R3
N2
R2
Ts
Pd(0)
R1
R2
R1
Pd(0)
HN
Ts
R4
X = O, NNos, NTs
counteranion
counteranion
Challenge II:
Challenge III:
Challenge I:
Decarboxylative olefination
& [1+n] cycloaddition
Pd(0) carbene
& Pd(II) carbene
Z & E
Stereoselectivity
Chemoselectivity
DFT calculation
KBV200
120
100
80
60
40
20
0
VNR
Macrocycles
P-gp inhibitor
Vinorelbine+13a
VNR+10 M 14a
VNR+10 M 15a
VNR+10 M 13a
NH2
Ph
Ph
IC50 3.9 nm (193 folds)
NH2
1
2
3
4
-20
Log [nM]
O
With the optimal conditions in hand, we evaluated various
vinylethylene carbonates in the Pd-catalyzed decarboxylative
olefination reactions with methyl 2-diazo-2-phenylacetate (2a)
(Table 1). The newly developed protocol gave excellent
stereoselectivities in most of the cases, with E/Z ratios more
than 94:6 and moderate to very good isolated yields. Functional
groups on the rings such as cyano (1c), ester (1d),
trifluoromethyl (1e), methoxyl (1g), and methyl (1i) were
tolerated well, furnishing the desired products in moderate to
good yields. A useful brominated arene was converted (1b),
thereby providing a versatile
Stimulated by those pioneering studies on Pd-catalyzed carbene
coupling reactions and our previous works in the Pd-catalyzed
allylic transformations11, we envisioned that vinylethylene
carbonates, vinyl oxazolidinones or vinyl benzoxazinones
could be applied as new Pd-carbene trappings. If successful,
such a protocol would not only provide a unique opportunity to
learn more about Pd(0) or Pd(II) carbeniond reaction pathway
but also represent a powerful technique for accessing our
multifunctional groups-containing 1,3-dienes targets. However,
there are three challenging issues to be addressed in these
scenarios: a) Pd-catalyzed chemoselective [1+n] cycloaddition
Table 1. Substrate scope for Pd-catalyzed synthesis of tetrasubstituted E-configurated alcohols and amines-containing 1,3-dienes
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Allylic alcohols
3
4
5
6
OH
OH
TBAB (100 mol%)
N2
O
R2
[Pd (dba) ] CHCl3 (2.5 mol%)
•
2
3
Ph
O
O
+
R2
R3
Ph
DMF, 60 oC, 2 hrs
R1
O
R1
O
O
O
O
O
R3
4b - 4j
1a - 1o
2a - 2j
3a - 3o
7
8
9
OH
OH
OH
OH
OH
OH
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O
CH3
O
CH3
O
CH3
O
CH3
O
CH3
O
O
CH3
O
O
O
O
F
O
F3C
Br
NC
MeOOC
3a
78%
3b
76%
3c
74%
3d
68%
3e
65%
3f
87%
(2E,4E)/(2Z,4Z) = 94:6
(2E,4E)/(2Z,4Z) = 94:6
(2E,4E)/(2Z,4Z) = 94:6
(2E,4E)/(2Z,4Z) = 92:8
(2E,4E)/(2Z,4Z) = 96:4
(2E,4E)/(2Z,4Z) = 95:5
OH
OH
OH
OH
OH
OH
O
O
CH3
O
O
CH3
O
CH3
O
O
CH3
O
O
CH3
O
O
CH3
O
CH3
O
F
H3C
CH3
BnO
3g
74%
3h
3i
3j
72%
3k
86%
3l
67%
80%
80%
(2E,4E)/(2Z,4Z) = 96:4
(2E,4E)/(2Z,4Z) = 94:6
(2E,4E)/(2Z,4Z) = 94:6
(2E,4E)/(2Z,4Z) = 97:3
(2E,4E)/(2Z,4Z) = 95:5
(2E,4E)/(2Z,4Z) = 93:7
OH
OH
OH
O
OH
OH
OH
O
O
CH3
O
CH3
OBn
O
O
CH3
O
CH3
O
O
O
O
Cl
Cl
O
CH3
3m
72%
3n
43%
3o
59%
4b
73%
4c
56%
4d
44%
(2E,4E)/(2Z,4Z) = 94:6
(2E,4E)/(2Z,4Z) >99:1
(2E,4E)/(2Z,4Z) = 89:11
(2E,4E)/(2Z,4Z) = 96:4
(2E,4E)/(2Z,4Z) = 95:5
(2E,4E)/(2Z,4Z) = 95:5
F
Cl
OH
OH
OH
OH
OH
OH
Cl
O
CH3
O
CH3
O
CH3
O
CH3
O
CH3
O
CH3
O
O
O
O
O
O
4e
68%
4f
74%
4g
85%
(2E,4E)/(2Z,4Z) = 93:7
4h
78%
(2E,4E)/(2Z,4Z) = 97:3
4i
69%
4j
74%
(2E,4E)/(2Z,4Z) = 92:8
(2E,4E)/(2Z,4Z) = 95:5
(2E,4E)/(2Z,4Z) = 96:4
(2E,4E)/(2Z,4Z) = 93:7
Allylic amines
HN R4
R4
N
N2
TBAB (100 mol%)
[Pd (dba) ] CHCl3 (2.5 mol%)
•
2
3
R2
O
+
R2
R3
R1
O
DMF, r.t. 12 hrs
O
O
O
R1
O
R3
5a-g
2a-c
6a-i
NHNs
NHNs
NHNs
NHNs
NHTs
NHNs
O
O
O
O
O
O
O
O
O
O
O
O
F
Cl
O
6a
51%
6b
64%
6c
6d
57%
6e
60%
6f
78%
50%
(2E,4E)/(2Z,4Z) = 97:3
(2E,4E)/(2Z,4Z) = 93:7
(2E,4E)/(2Z,4Z) = 93:7
(2E,4E)/(2Z,4Z) = 96:4
(2E,4E)/(2Z,4Z) = 94:6
(2E,4E)/(2Z,4Z) = 96:4
NHTs
NHNs
NHNs
OH
O
O
O
O
O
O
Ph
O
6g
76%
6h
41%
6i
37%
(2E,4E)/(2Z,4Z) = 92:8
O
CH3
O
(2E,4E)/(2Z,4Z) = 95:5
(2E,4E)/(2Z,4Z) = 96:4
Reaction conditions: vinylethylene carbonates/ vinyloxazolidin-2-ones (0.1 mmol), diazo compounds 2 (0.2 mmol), Pd catalyst (5
mol%), TBAB (0.1 mmol), DMF (1 mL). The ratio of E/Z was determined by 1H NMR analysis of the crude product using CH2Br2
as an internal standard. All the yields are isolated yields.
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handle for subsequent chemical transformations. Additionally,
the process was not hampered by ortho substitution (1j).
Furthermore, the phenyl ring was successfully replaced by 2-
naphthyl, without an obvious erosive effect on reaction
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efficiency and stereoselectivity (1m). Switching aryl to
We then extended our strategy to the cross coupling of
3
4
5
6
7
8
9
hydrogen was also compatible with this reaction, generating
almost sole isomer albeit with 46% yield (1n).Even the
disubstituted aryl was also amenable to the standard conditions
and the expected product was formed with satisfactory yield 59%
(1o).
vinyloxazolidin-2-ones with diazo compounds. The direct
coupling reaction proceeds smoothly to afford the conjugated
allylic amines in moderate to good yields and high
stereoselectivities at room temperature. Those vinyloxazolidin-
2-ones bearing electron-donating or electron withdrawing
phenyl substituents successfully participated in the reaction,
giving the corresponding products in moderate to good yields
with E/Z stereoselectivities ranging from 92:8 to 97:3 in Table
1. Both the Tosyl and the Nosyl protecting groups were
compatible in this reaction. However, the unprotected substrate
failed to yield the expected product, possibly due to strong
coordination to Pd catalyst.
The diazo compound scope was also investigated. As illustrated
in Table 1, phenyl containing either electron-donating or
electron-withdrawing groups were efficiently accommodated to
yield conjugated allylic alcohols in moderate to good yields and
with high stereoselectivities.
10
11
12
13
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32
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36
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42
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44
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50
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53
54
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57
58
59
60
Table 2. Substrate scope for Pd-catalyzed synthesis of trisubstituted E-configurated aniline-containing 1,3-dienes
Allylic anilines
COOMe
R1
N2
[Pd (dba) ] CHCl3 (2.5 mol%)
•
2
3
Ts NH
O
O
+
R1
DMF, 40 oC, 2 - 4 hrs
R2
N
O
O
Ts
7a-c
R2
8a-h
2a-n
8a
COOMe
Ts NH
COOMe
COOMe
F
COOMe
COOMe
Ts NH
Ts NH
Ts NH
Ts NH
F
8a
77%
8b
65%
8c
66%
8d
74%
8e
75%
(2E,4E)/(2Z,4Z) > 95:5
(2E,4E)/(2Z,4Z) > 95:5
(2E,4E)/(2Z,4Z) > 95:5
(2E,4E)/(2Z,4Z) > 95:5
(2E,4E)/(2Z,4Z) > 95:5
COOMe
COOMe
COOMe
COOMe
COOMe
Ts NH
Ts NH
Ts NH
Ts NH
Ts NH
O
Cl
8f
73%
8ga
57%
8h
65%
8i
49%
8j
65%
(2E,4E)/(2Z,4Z) > 95:5
(2E,4E)/(2Z,4Z) > 95:5
(2E,4E)/(2Z,4Z) > 95:5
(2E,4E)/(2Z,4Z) > 95:5
(2E,4E)/(2Z,4Z) > 95:5
COOMe
COOMe
COOMe
COOMe
COOMe
F
CH3
F
Ts NH
Ts NH
Ts NH
Ts NH
Ts NH
Cl
Cl
8ka
54%
8la
72%
8m
60%
8n
71%
8o
54%
(2E,4E)/(2Z,4Z) > 95:5
(2E,4E)/(2Z,4Z) > 95:5
(2E,4E)/(2Z,4Z) > 95:5
(2E,4E)/(2Z,4Z) > 95:5
(2E,4E)/(2Z,4Z) > 95:5
a: The reaction was carried out overnight.
Reaction conditions: 2H-benzo[d][1,3]oxazin-2-ones (0.05 mmol), diazo compounds 2 (0.1 mmol), Pd catalyst (5 mol%), DMF (0.5
mL). All the yields are isolated yields.
This protocol is also compatible with the construction of the
trisubstituted E-configurated multifunctional aniline-containing
1,3-dienes, when we changed the vinyloxazolidin-2-ones into
vinyl benzoxazinones. This decarboxylative olefination is
distinctive from Xiao and Lu’s recent work, in which they
described an intriguing Pd-catalyzed [4+2] cycloaddition of
vinyl benzoxazinones with diazo ketone under visible light
photoactivation condition12b. As shown in Table 2, various
para-, meta-, or ortho-substituents on the substituted diazo
esters could be well-tolerated to provide the desired products in
moderate to good yields and exclusive E-configurated isomer.
The furanyl substituted diazo ester worked out smoothly to
produce 8i in a synthetically useful yield. In addition, two
typical vinyl benzoxazinones partners also efficiently engaged
in this olefination regardless of the electronic properties on the
substrates to deliver (8j-8o) in good isolated yield. Generally,
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our method could only produce 1,4-diaryldienes except one
example 3n.
afford a conjugated aldehyde 9a, which is an important building
block to construct luminescent materials. In addition, 3a was
successfully converted into high conjugated allylic amine 10a
by Mitsunobu reaction. And the selective epoxidation of the
carbon-carbon double bond was also achieved, giving the
desired product 11a in 93%. Furthermore, a symmetrical
conjugated allylic diol could be prepared by the reduction of 3a
with DIBAL-H in a good yield (Figure 16 in SI).
The synthetic value of this catalytic system was next
demonstrated through a large-scale reaction and the product
derivatizations. The gram scale reaction of 1a and 2a afforded
the conjugated allylic alcohols 3a with excellent E/Z
stereoselectivities (95:5) and very good isolated yield (79%,
Figure 16 in SI). The selective oxidation of hydroxyl moiety of
3a by treatment with Dess-Martin Periodinane (DMP) can
10
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12
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60
Scheme 3. Construction of novel macrocycles and their bioactivity on reversing P-gp mediated multidrug resistance in cancer cell using
(2E, 4E) 1,3-diene building blocks
Ns
Ph
Ns
Ph
Fmoc
NH
OH
O
NH
NH
N
(a)
(d)
(b)
(c)
Ph
O
Ph
Ph
Ph
Ph
Ph
Ph
O
OH
O
Ph
OH
O
O
O
O
O
O
3a
10a
S22
S21
6a
Fmoc
Ph
O
O
Fmoc
NH
NH
NH
NH
Ph
(e)
(f)
(g)
Ph
Ph
Ph
NH
Fmoc
Ph
Ph
Ph
NH OBn
O
NH NH
O
OH
NH OBn
O
O
O
O
O
S22
S23
S24
13a
O
O
HN
O
HN
NH
KBV200
120
100
80
60
40
20
0
N
VNR
Ph
N
VNR+10 M 14a
VNR+10 M 15a
VNR+10 M 13a
Ph
Ph
NH NH
O
Ph
Ph
O
Ph
NH NH
O
NH
1
2
3
4
O
-20
Log [nM]
O
13a
14a
Vinorelbine+
IC50 4.7 nm (157 folds)
15a
Vinorelbine+
IC50 66.6 nm (11 folds)
Vinorelbine
control IC50 747 nm
13a
Vinorelbine+
IC50 3.9 nm (193 folds)
14a
15a
Reaction conditions: (a) DEAD, PPh3, PhthNH, THF, 0 oC to r.t. 6 h, 67%. (b) 6N HCl aq., AcOH, 140 oC, 48 h; Fmoc-OSu, NaHCO3,
H2O/Acetone, r.t., 12 h, 44%. (c) NaOH, MeOH/H2O, 80 oC, 2 h, 43 %. (d) 2-mercaptoacetic acid, K2CO3, MeOH, r.t., 5 h; Fmoc-OSu,
NaHCO3, H2O/Acetone, r.t., 12 h, 74%. (e) benzyl valinate, EDCI, HOBt, DCM, r.t., 12 h, 37%. (f) DBU, DCM, 1 h; 12-((((9H-fluoren-9-
yl)methoxy)carbonyl)amino)dodecanoic acid, EDCI, HOBt, DCM, r.t., 4 h, 29%. (g) NaOH, MeOH/H2O, r.t. 12 h; EDCI, HOBt, DCM,
r.t., 4 h, 24%.
Interestingly, we found that the structure from our method could
be used as building blocks in drug discovery as well. As
mentioned above, the 1,3-dienes are important structural motifs
found in a number of biologically active natural products,
particularly in macrocycles. Encouraged by this fact, we
attempted to construct 1,3-diene-supported macrocycles by
using 3a or 6a as a building block. With five steps, three novel
macrocycles were efficiently assembled (Scheme 3). To explore
whether these 1,3-diene-supported macrocycles could
successfully transfer pharmacologically relevant features or not,
these collected compounds (13a, 14a, 15a) on reversing MDR15
to chemotherapeutic agents were evaluated using human oral
epidermoid carcinoma KB, and their drug resistant counterparts
KBV200 cells with P-gp overexpression. To our delight, both
13a and 14a exhibited excellent potency with an IC50 of 3.9 nm
and 4.7 nm, respectively. Moreover, they could restore the
sensitivities of KBV200 cells to cytotoxic agent vinorelbine
with 193 fold-reversals and 157 fold reversals, respectively.
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Undoubtedly, these promising results highlighted that our
formation of Pd(0)-carbene intermediate IN3 via diazo
3
4
5
protocol is unique and potentials in lead compounds discovery.
And we believe our structure will have more wide applications
in drug discovery area of other diseases.
decomposition of 2a (Figure 4).
Figure 2. Kinetics experiments of TBAB
6
7
8
9
Figure 1. Isomerization experiments between E isomer and Z
isomer
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OH
OH
O
standard conditions
O
O
O
3a
3a'
Table 3. Effect of counteranions for the reaction
(2퐸, 4퐸)
entry
catalyst
additive
yield
(2퐸, 4퐸) + (2푍, 4푍)
1
2
[Pd2(dba)3]·CHCl3
[Pd2(dba)3]·CHCl3
-
49%
78%
80.8% ± 1.2%
TBAB
93.7% ± 0.7%
To investigate the initiation of the reaction, a series of control
experiments were carried out (Figure 3). First, we separately
submitted VEC (1a) and diazo ester (2a) to the standard
conditions, but using stoichiometric [Pd2(dba)3]·CHCl3.
Although no conversion took place for 1a in the absence of
diazo ester 2a, oxidative addition of Pd (0) with 1a could occur
and form a reversible Pd(II) intermediate (Eq. 1). Interestingly,
a complete conversion of 2a and dba ligand exchange were
observed from NMR analysis. Meanwhile, methyl 2-oxo-2-
phenylacetate, an oxidation product of carbene, was separated
3
4
5
6
[Pd2(dba)3]·CHCl3
[Pd2(dba)3]·CHCl3
Pd2(dba)3
TEABa
TMABb
TBAB
-
68%
68%
71%
14%
90.9% ± 0.7%
89.1% ± 1.9%
92.2% ± 1.2%
80.8% ± 5.2%
Pd2(dba)3
a) Tetraethylammonium bromide (TEAB); b) Tetramethylammonium
bromide (TMAB)
1
and identified by H NMR (Eq. 2). Combining a catalytic
amount of 2a (20%) with stoichiometric 1a and
[Pd2(dba)3]·CHCl3 gave the olefination product 3a in 40%
NMR yield (Eq. 3).Those results above showed that the reaction
could be initiated by Pd (0) carbene intermediate generated
from direct diazo decomposition of 2a, but we couldn’t clearly
exclude the Pd(II) carbene intermediate pathway initiated from
oxidative addition of Pd (0) with VECs.
The high (2E, 4E) stereoselectivity of this Pd-catalyzed-
decarboxylative olefination attracted our attention, we found
that no isomerization of the products was observed under the
standard conditions. The two newly formed double bonds of
1,3-dienes are probably controlled by β-O and β-H eliminations.
(Figure 1). TBAB is much more effective than other less
sterically hindered additives, such as TMAB, TEAB or no
additive, whose the E/Z stereoselectivities have declined(Table
3). Besides the steric effect improving the stereoselectivities,
the fact is that the counteranions, such as bromide, chloride,
have proven to be crucial to improve the reaction yield as well
as the stereoselectivities, which is in consistent with our DFT
calculation (see the following part or Supporting Information).
Moreover, kinetic studies show the reaction initial rate will
decrease as the usage of TBAB increasing (Figure 2), because
excess counter anion Br is harmful for beta-H elimination
(Figure 13 of the Supporting Information).16 And the overall
reaction is nearly zero order in respect to vinylcarbonate 1a
(Figure 3 in SI) which could provide a support for the initial
Due to the instability of Pd (0) carbene intermediate, we
attempted to capture the π-allyl Pd (II) intermediate acting as a
precursor of Pd(II) carbene instead, which we have successfully
isolated in our previous work.11c The π-allyl Pd (II) intermediate
has been stabilized with pyridine ligand (Eq. 4) and fully
1
characterized by H, 13C, and X-ray spectroscopy. With the π-
allyl Pd (II) intermediate in hand, a set of experiments were
conducted to further elucidate the possible pathway of the
reaction. If the π-allyl Pd (II) intermediate, a precursor of Pd(II)
carbene, makes the reaction sluggish, the Pd (II) carbene
pathway could be a less preferable one. Gratifyingly, when the
stoichiometric amount of the π-allyl Pd (II) intermediate was
subjected to the reaction with 2a, the yield and stereoselectivity
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of 3a were profoundly decreased (Eq. 5). Further, in order to
3
eliminate the
4
5
6
Figure 3. Mechanistic experiments
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5
Eq 1.
TBAB (1 eq.)
[Pd2(dba)3]•CHCl3 (1eq.)
DMF, 60 oC, 2 hrs
O
O
O
no reaction was observed.
6
7
1a (1 eq.)
conv. a = 0%
8
9
Eq 2.
NBu4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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34
35
36
37
38
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40
41
42
43
44
45
46
47
48
49
50
51
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53
54
55
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57
58
59
60
Br
TBAB (1 eq.)
[Pd2(dba)3]•CHCl3 (1eq.)
N2
O
O
(dba)Pd
O
O
O
DMF, 60 oC, 2 hrs
O
O
2a (1 eq.)
conv. = 100%
yield = 34%
Proposed intermediate
OH
Eq 3.
TBAB (1 eq.)
O
N2
[Pd2(dba)3] CHCl3 (1eq.)
•
O
O
O
+
DMF, 60 oC, 2 hrs
O
O
O
1a (1 eq.)
2a (0.2 eq.)
conv. = 100%
3a
yield b = 40%
conv. = 77%
a.) conv. = conversion
b.) the yield was calculated on the base of the dosage of diazo compound.
Eq 4.
N
O
O
O
OH
Cl
Pd
O
O
Pd2(dba)3•CHCl3
K2CO3, MeCN, 80 o
Ph
Ph
N
C
1a
X
Yield: 45%
Eq 5.
Ph
OH
OH
dba (1.5 eq.)
TBAB (1 eq.)
N2
Pd
N
Cl
O
+
DMF, 60 oC, 2 hrs
O
O
O
O
X (1 eq.)
2a (2 eq.)
3a, yield = 43%, E/Z 76:24
Eq 6.
Ph
OH
O
N2
TBAB (1 eq.)
O
Pd
N
OH
O
Cl
O
+
+
+
DMF, 60 oC, 2 hrs
O
O
O
O
1a (1 eq.)
2a (2 eq.)
X (0.05 eq.)
3a, yield = 24%, E/Z 82:18
Eq 7.
Ph
OH
dba (0.075 eq.)
TBAB (1 eq.)
O
O
N2
O
Pd
N
OH
O
Cl
+
DMF, 60 oC, 2 hrs
O
O
O
O
1a (1 eq.)
2a (2 eq.)
X (0.05 eq.)
3a, yield = 87%, E/Z 93:7
concerns on the effect of strong coordination between pyridine
and Pd (II) intermediate and keep consistent with the standard
conditions, additional two control experiments were carried out
(Eq. 6 and 7). Notably, the results demonstrated that the
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presence of pyridine ligand might not be the crucial factor to the
On the other hand, the calculated energies show that the
pathway leading to the minor product 3 (2Z,4Z) is less favorable
kinetically (Figure 5), being in good agreement with the
observed stereoselectivity. Other possible competing reactions
are higher in energy and are given in the SI Figure 9.
decrease of yield and stereoselectivity. By contrast, it is more
likely that the Pd(II)-allyl complex is the retarding effect of the
final yield/selectivity. Altogether, we could make a conclusion
that it is more likely for the reaction to be initiated by Pd (0)
carbene intermediate generated from direct diazo
decomposition of 2a instead of the oxidative addition of Pd (0)
to VEC (1a).
Accordingly, the association of reactant complex IN1 with
TMBA forms IN2 favorably, from which the dinitrogen
elimination occurs via TS1 with a barrier of only 16.3 kcal/mol
and gives rise to Pd(0) carbene species IN3 exergonically. After
incorporation of 1a, π complex IN4 is formed slight
exergonically. In the following step, we found the olefin favors
the [2+2] cycloaddition with the Pd=C moiety (via TS2) to form
intermediate IN5 containing a four-membered ring.18 In IN5 the
Pd-C3 and C4-O bonds are anti to each other (Figure 4). We
failed to locate a TS for direct cleavage of the C4-O bond to
form a zwitterionic intermediate. Instead, calculations found
IN5 undergoes the ring expansion rearrangement easily by a
concerted 1,2-oxygen/1,2-palladium migration via TS3 (C3-O
= 2.40 and C4-O = 2.52 Å) to form bicyclic intermediate IN6
(Figure 4). This intermediate is slightly less stable than IN5 and
undergoes the C4-O bond cleavage via TS4 to form ionic
species IN7, which eliminates the CO2 via TS5, giving rise to
intermediate IN8 through an exergonic process. Both steps are
very facile with barriers less than 10 kcal/mol. As determined
by the configuration of IN6, the newly formed double bond in
IN7 adopts the E configuration. IN8 is a homoallylic palladium
complex in which the Pd is intramolecularly coordinated by the
oxygen anion. Prior to the β-H elimination, the incorporation of
another TMAB is necessary to form IN9 via an endergonic
process.19 IN9 has C-H…Pd agostic interaction and undergoes
stereoselective β-H elimination facilely via TS6 (C2-H = 1.73
and C1-Pd = 2.20 Å), generating intermediate IN10 with the
expected stereochemistry of the 1,3-diene moiety. Further
calculations indicate the final product 3a (2E,4E) could be
formed by reductive elimination of the palladium hydride
species (IN10 and IN11).
10
11
12
13
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Notably, except for NHC palladium(0) complex5b-h, other
reactive Pd(0) carbene intermediates5a are rarely reported in
comparison with ubiquitous high valent metal carbene species
such as Pd(II)1, Cu(I)2, Rh(II)3, Ir(I)4 et al.. To further
investigate the reaction mechanism,
a series of DFT
calculations were conducted at the level of (SMD)M06/6-
311+G(d,p)/SDD//M06/6-31G(d)/LANL2DZ, using 4-phenyl-
4-vinyl-1,3-dioxolan-2-one (1a) and methyl 2-diazo-2-
phenylacetate (2a) as the model reactants.17 Calculations found
that if the Pd2(dba)3 was used as the catalyst without any
additive, a very high activation barrier of 36.3 kcal/mol was
calculated for the β-hydrogen elimination step (see SI Figure 8
for details). This prediction correlates well the experimental
observations (Table 3, entry 6). However, in reaction with the
[Pd2(dba)3]·CHCl3 catalyst, the yield of product 3 was increased
to 49%. (Table 3, entry 1), indicating notable promoting effects
of the complexed CHCl3 molecule. Inspired by the results of the
control experiment (Table 3, entry 1 and 6), that the CHCl3
could act as the source of the chloride in intermediate as well as
the intermediate x (Figure 3, Eq. 4) we have reported in our
previous work12c, we proposed that the bromide anion from
TBAB additive may be involved as a ligand to Pd to promote
the reactions. Indeed, when a TMAB, a simplified model for
TBAB, was included in calculations to simulate the effects of
the quaternary ammonium salt additive on the reaction, the
initiation by generation of Pd(0) carbene species was found to
be the most favorable (The other Pd(II) initiation pathway
calculated in the SI Figure 7), from which the observed product
3a (2E,4E) could be formed with reasonable energy values
(Figure 4).
Figure 4. DFT Computed Potential Energy surface and geometric structures for key species for the Pd-Catalyzed Reactions
between 1a and 2a (All hydrogens on NMe4 ion were omitted for clarity; selected distances are
in Å).
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4
N
Gsol
kcal/mol
Ph
O
N
11.3
Ph
(dba)Pd
Br
O
TS1
O
O
MeO2C
Pd
Br
O
N
O
N
NMe4
O
(dba)Pd
NMe4
5
TS1
TS2
6
7
8
0.0
NMe4
Br
Pd
IN1
TMAB
N2
-9.1
H
O
NMe4
Ph
O
NMe4
Ph
TS2
Br
NMe4
Br
Pd
Ph
O
9
H
-5.0
MeO2C
NMe4
Ph
NMe4
Ph
O
Br
Pd
H
Ph
Br
IN2
Pd
Ph
MeO2C
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1
O
H
MeO2C
Pd
Ph
O
Br
O
Ph CO2Me
O
O
1
4
Ph
MeO2C
N
2
O
O
-30.0
TS7
3 O
NMe4
N
4
-31.5
2
3
-31.5
Br
O
TS6
H
TS4
-34.5
(dba)Pd
1a
-36.1
-35.3
TS5
IN9
-19.2
NMe4
Br
NMe4
O
TS3
HO
-20.1
IN3
O
TMAB
Ph
NMe4
Br
IN4
(dba)Pd
Ph
H
H
O
dba
Ph
Ph
Pd
O
Br
-40.6
IN7
Br
Ph CO2Me
Br
CO2Me
-43.2
-40.3
Ph
Pd
O
Br
NMe4
H
O
O
Pd
O
O
-47.0
IN6
CO2
IN11
3(2E,4E)
-42.7
NMe4
O
IN5
NMe4
NMe4
O
Ph
IN10
1
O
Pd
TMAB
O
Br
1
MeO2C
Ph
4
Br
4
O
Ph
Ph
NMe4 Pd 3
Pd
2
2
Ph
Ph
Br
Ph
MeO2C
O
O
-51.2
NMe4
Pd
H
4
3
O
2a dba
+
MeO2C
2
Ph
MeO2C
1
IN8
Br
H
H
3
-67.4
3(2E,4E)
O
O
NMe4
Pd
Ph
MeO2C
NMe4
O
Pd
O
Ph
Ph
1
-78.5
Ph
Br
IN12
MeO2C
4
2
IN2
3
Ph
Ph
H
MeO2C
2
4
3
1
3
2
4
3
2
4
Pd
1
Pd
1
Pd
TS2
TS3
TS4
4
Pd
3
2
2
4
1
2
3
4
3
1
Pd
1
Pd
TS6
IN5
IN8
Due to the endergonicity for regeneration of IN2 from IN12
(11.1 kcal/mol), the overall activation barrier for the reaction
should be 27.4 kcal/mol, as determined by the energy change
for the process IN12→IN2→TS1. This is the highest barrier for
the whole reaction, indicating the dinitrogen elimination via
TS1 is the rate-determining step of the reaction. In addition, β-
H elimination process is from TS6 to IN10 (Figure 4), for which
the syn-coplanar of Pd-C-C-H are necessary as well as a TMAB
dissociating from catalyst to afford an empty orbital of Pd. If
excess counter anion Br is contained, the formation of a
coordination-saturated Pd complex (given in Figure 13 of the
Supporting Information), instead of IN9, will make the
elimination process sluggish, in agreement with the kinetic
experiment in respect to TBAB.16
To generate the minor product 3a (2Z,4Z), a less stable
conformer IN5’ could be firstly formed by rotation of the C-C
single bond connecting the two rings in IN5 (Figure 5). From
IN5’ the cleavage of C4-O and C3-Pd bonds occurs concertedly
to form a nine-membered ring intermediate IN6’, in which the
newly formed C-C double bond adopts Z configuration. In the
following step, the decarboxylation occurs via TS4’ to generate
IN7’. Finally, the β-H elimination is completed by an
intramolecular hydrogen transfer from C2 to O via TS5’ to
afford product complex IN8’ exergonically18, and the diene
moiety has a 2Z,4Z configuration. In this pathway, the TS5’ has
a highest relative free energy of -28.7 kcal/mol, being 1.3
kcal/mol higher than that of TS7 on the major pathway. This
indicates the formation of 3a (2Z,4Z) is less favorable, as both
steps from TS5’ and TS7 are highly exergonic and
irreversible.17 Thus, the DFT results suggested that the
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stereochemical outcome of the whole reaction is actually
Based on the previous reports1, 13, 14, computational results and
2
3
4
5
6
7
8
9
determined by TS7 and TS5’ in the last step.
our preliminarily mechanistic experiments, a plausible reaction
mechanism for the formation of tetrasubstituted E -configurated
1,3-dienes containing alcohols illustrated in Figure 6. The
palladium (0) carbene intermediate IN2 is initially formed
through N2 emission of diazo ester 2a. The intermediate IN3
then reacts with vinylethylene carbonate 1a to generate 4-
Figure 5. DFT Computed Potential Energy surface for the
formation of 3a (2Z, 4Z) from IN5.
NMe4
Br
O
Ph
O
NMe4
O
O
Ph
MeO2C
H
-28.7
Pd
TS5'
H
-30.6
Pd Br
Ph
MeO2C
membered palladacycle intermediate IN5 via a [2+2]
Ph
H
TS3'
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13
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intermolecular cycloaddition. Subsequently, the intermediate
IN5 takes place a ring expansion and a 1,2-oxygen migration to
afford intermediate IN6, which then undergoes the C-O bond
cleavage and CO2 elimination, followed by β-H elimination to
give intermediate IN10. Finally, protonation of intermediate
IN10 yields the major geometric isomer 3a (E) and reductive
elimination of HPdBr regenerates the active Pd(0) for the next
catalytic cycle. Alternatively, intermediate IN5 could form 7-
membered palladacycle intermediate IN7’, which eventually
provides the minor geometric isomer 3a (Z).
O
NMe4
Ph
O
O
Pd
Br
Ph
CO2Me
-43.1
-44.7
TS4'
-47.0
IN5
IN5'
-48.6
-51.8
IN7'
O
IN6'
O
O
NMe4
-63.7
IN8'
NMe4
O
4
Br
NMe4 Pd
Br
NMe4
3
Ph
O
Ph
O
Ph
4
O
Ph
H
Pd
Pd
Ph
CO2Me
Br
Pd
Br
2
Ph
MeO2C
1
MeO2C
Ph
1
3
Ph
CO2Me
OH
2
Figure 6. Proposed mechanism for the formation of tetrasubstituted conjugated E or Z-configurated 1,3-dienes containing alcohols.
The mechanism for the formation of (2E, 4E) product
The mechanism for the formation of (2Z, 4Z) product
OH
Ph
Ph
HO
(2Z,4Z)
(2E,4E)
Ph
CO2Me
MeO2C
Ph
NBu4
3a (E)
3a (Z)
NBu4
Br
Pd
O
Br
Ph
TBAB
OH
H
Pd
Ph
Ph
MeO2C
Pd(dba)
O
+
NBu4
Br
CO2Me
Ph
N2
Ph
TBAB
IN10
IN8'
O
H
H
Pd
O
Br
Ph CO2Me
NBu4
2a
N2
NBu4
IN9
Br
O
TBAB
NBu4
Br
Ph
O
(dba)Pd
O
Pd
Ph
NBu4
Br
CO2Me
Pd
O
IN3
O
Ph
Ph
IN7'
O
MeO2C
O
H
Ph
IN8
dba
1a
O
O
CO2
Br
Pd
O
CO2
O
O
Br
Ph
MeO2C
NBu4
Ph
MeO2C
Ph
O
NBu4
Pd
Ph
H
O
O
Ph
Ph
Pd
O
Br
NBu4
O
Pd
Br
H
IN5
Ph
MeO2C
O
IN7
O
CO2Me
Ph
IN6'
NBu4
IN6
In summary, we have developed an unprecedented Pd-catalyzed
highly stereoselective decarboxylative olefination of VECs and
CONCLUSIONS
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5
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Quaternary Carbon Centers. Angew. Chem. Int. Ed. 2012, 51, 1370-
1374.
(2) (a) Zhang, H.; Wu, G. J.; Yi, H.; Sun, T.; Wang, B.; Zhang, Y.;
Dong, G. B.; Wang, J. B. Copper(I)-Catalyzed Chemoselective
Coupling of Cyclopropanols with Diazoesters: Ring-Opening C-C
Bond Formations. Angew. Chem. Int. Ed. 2017, 56, 3945-3950. (b)
Zhou, L.; Ma, J.; Zhang, Y.; Wang, J. B. Copper-catalyzed cascade
analogs with donor/acceptor carbenes by a Pd(0) carbene
pathway. This strategy provides a practical, user-friendly, and
operationally simple protocol for the synthesis of
polysubstituted multifunctional E-configurated 1,3-dienes.
Remarkably, our privileged structures 1,3-dienes were
successfully incorporated into macrocycles which could fight
P-gp-mediated multidrug resistance (MDR) in cancer
chemotherapy with 190 fold-reversals. Finally, the mechanism
was better understood by combination of control experiments
and DFT calculations, which provided in depth insights into the
counterion effect and stereochemistry of the transformation.
More mechanistic investigations about Pd(0) carbene and
extensions of this chemistry are underway in our laboratory.
coupling/cyclization of terminal alkynes with diazoacetates:
a
straightforward route for trisubstituted furans. Tetrahedron Lett. 2011,
52, 5484-5487. (c) Park, E. J.; Kim, S. H.; Chang, S. Copper-Catalyzed
Reaction of α-Aryldiazoesters with Terminal Alkynes: A Formal [3 +
2] Cycloaddition Route Leading to Indene Derivatives. J. Am. Chem.
Soc. 2008, 130, 17268-17269. (d) Zhao, X.; Wu, G.; Zhang, Y.; Wang,
J. B. Copper-Catalyzed Direct Benzylation or Allylation of 1,3-Azoles
with N-Tosylhydrazones. J. Am. Chem. Soc. 2011, 133, 3296-3299.
(3) (a)Tsoi, Y.-K.; Zhou, Z.; Yu, W.-Y. Rhodium-Catalyzed Cross-
Coupling Reaction of Arylboronates and Diazoesters and Tandem
Alkylation Reaction for the Synthesis of Quaternary α, α-Heterodiaryl
Carboxylic Esters. Org. Lett. 2011, 13, 5370–5373. (b) Wang, H.;
Guptill, D. M.; Alvarez, A. V.; Musaev, D. G.; Davies, H. M. Rhodium-
catalyzed enantioselective cyclopropanation of electron-deficient
alkenes. Chem. Sci. 2013, 4, 2844-2850. (c) Davies, H. M.; Manning,
J. R. Catalytic C-H functionalization by metal carbene and nitrenoid
insertion. Nature 2008, 451, 417-424.
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ASSOCIATED CONTENT
Supporting Information.
Experimental procedures and spectral data for all new compounds
(PDF) are available free of charge via the Internet at
http://pubs.acs.org. X-ray data for compounds 3a, 8a (CIF)
(4) Thomas, B. N.; Moon, P. J.; Yin, S.; Brown, A.; Lundgren, R. J.
Z-Selective iridium-catalyzed cross-coupling of allylic carbonates and
α-diazo esters. Chem. Sci. 2018, 9, 238-244.
AUTHOR INFORMATION
(5) (a)Zhu, Y.; Liu, X.; Dong, S.; Zhou, Y.; Li, W.; Lin, L.; Feng,
X. Asymmetric N-H insertion of secondary and primary anilines under
the catalysis of palladium and chiral guanidine derivatives. Angew.
Chem. Int. Ed. 2014, 53, 1636-1640. (b) Canovese, L.; Visentin, F.;
Levi, C.; Santo, C.; Bertolasi, V., The interaction between heteroditopic
pyridine–nitrogen NHC with novel sulfur NHC ligands in palladium(0)
derivatives: Synthesis and structural characterization of a bis-carbene
palladium(0) olefin complex and formation in solution of an alkene–
Corresponding Author
*yweibo@simm.ac.cn; *houk@chem.ucla.edu; *xyz@wzu.edu.cn
Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the
manuscript.
alkyne mixed intermediate as
a consequence of the ligands
Notes
hemilability. Inorganica Chimica Acta 2012, 390, 105-118. (c)
Warsink, S.; Chang, I. H.; Weigand, J. J.; Hauwert, P.; Chen, J.-T.;
Elsevier, C. J., NHC Ligands with a Secondary Pyrimidyl Donor for
Electron-Rich Palladium(0) Complexes. Organometallics 2010, 29,
4555-4561. (d) Sprengers, J. W.; Wassenaar, J.; Clement, N. D.; Cavell,
K. J.; Elsevier, C. J., Palladium-(N-heterocyclic carbene)
hydrogenation catalysts. Angew. Chem. Int. Ed. 2005, 44, 2026-2029.
(e) Hauwert, P.; Boerleider, R.; Warsink, S.; Weigand, J. J.; Elsevier,
C. J., Mechanism of Pd(NHC)-catalyzed transfer hydrogenation of
alkynes. J. Am. Chem. Soc. 2010, 132, 16900-16910. (f) Hauwert, P.;
Maestri, G.; Sprengers, J. W.; Catellani, M.; Elsevier, C. J., Transfer
semihydrogenation of alkynes catalyzed by a zero-valent palladium N-
heterocyclic carbene complex. Angew. Chem. Int. Ed. 2008, 47, 3223-
3226. (g) Fantasia, S.; Nolan, S. P., A general synthetic route to mixed
NHC-phosphane palladium(0) complexes (NHC = N-heterocyclic
carbene). Chem. Eur. J. 2008, 14, 6987-6993. (h) Clement, N. D.;
Cavell, K. J.; Ooi, L. L., Zerovalent N-heterocyclic carbene complexes
of palladium and nickel dimethyl fumarate: Synthesis, Structure, and
Dynamic Behavior. Organometallics 2006, 25, 4155-4165.
(6) (a) Ersmark, K.; Feierberg, I.; Bjelic, S.; Hamelink, E.; Hackett,
F.; Blackman, M. J.; Hulten, J.; Samuelsson, B.; Aqvist, J.; Hallberg,
A. Potent inhibitors of the Plasmodium falciparum enzymes
plasmepsin I and II devoid of cathepsin D inhibitory activity. J. Med.
Chem. 2004, 47, 110-122. (b) Luo, Y.; Li, W.; Ju, J.; Yuan, Q.; Peters,
N. R.; Hoffmann, F. M.; Huang, S. X.; Bugni, T. S.; Rajski, S.; Osada,
H.; Shen, B. Functional characterization of TtnD and TtnF, unveiling
new insights into tautomycetin biosynthesis. J. Am. Chem. Soc. 2010,
132, 6663-6671. (c) Steinmetz, H.; Irschik, H.; Kunze, B.; Reichenbach,
H.; Hofle, G.; Jansen, R. Thuggacins, Macrolide Antibiotics Active
against Mycobacterium tuberculosis: Isolation from Myxobacteria,
Structure Elucidation, Conformation Analysis and Biosynthesis. Chem.
Eur. J. 2007,13, 5822-5832. (d) Ito, A.; Kumagai, I.; Maruyama, M.;
Maeda, H.; Tonouchi, A.; Nehira, T.; Kimura, K.-i.; Hashimoto, M.
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We gratefully acknowledge 100 talent program of Chinese
Academy of Sciences, NSFC (21702217, 21572163, and
21873074), "1000-Youth Talents Plan", Shanghai-Youth Talent,
National Science & Technology Major Project"Key New Drug
Creation and Manufacturing Program" China (Number:
2018ZX09711002-006), and Shanghai-Technology innovation
Action Plan (18JC1415300), and the National Science Foundation
of the US (CHE-1764328 to KNH) for financial support of this
research.
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(17) Computational results in the main text were obtained with the
chiral center in 2a adopting the R configuration. It should be noted that
the detailed mechanism for reaction with 2a in S configuration is
slightly different from that shown in Figures 4 and 5, that the first
double bond is formed by the syn-elimination of the corresponding IN5
to form the 3 (2E,4E). The diastereoselectivity of the [2+2]
cycloaddition and the conformation analysis of IN5 and IN5’ and the
following elimination TS are given in the Supporting Information.
(18) Analysis of the geometric structures found the TS2 is favorable
with π-π interaction between the two phenyl groups and has less steric
effect than other [2+2] cycloaddition TS, which account for the origin
of diastereoselectivity in IN5. Details are given in Figure 10 in the SI.
(19) Other possible stereoisomers from IN8 and IN7’ are given in
Figure 12 in the SI.
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E
Pd(II) carbene pathway
4
NH
5
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8
Ph
Ph
NH
Pd(0) carbene pathway
O
9
Key step:
Pd-Catalyzed Decarboxylative Olefination
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Vinorelbine+13a
IC50 3.9 nm (193 folds)
Macrocycles
P-gp inhibitor
Modular biomimetic
assembly strategy
14
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