Palladium-Catalyzed Asymmetric Allylic Alkylation of 3-Substituted 1 H-Indoles and Tryptophan Derivatives with Vinylcyclopropanes

Article abstract of DOI:10.1021/jacs.8b03656

Vinylcyclopropanes (VCPs) are known to generate 1,3-dipoles with a palladium catalyst that initially serve as nucleophiles to undergo [3 + 2] cycloadditions with electron-deficient olefins. In this report, we reverse this reactivity and drive the 1,3-dipoles to serve as electrophiles by employing 3-alkylated indoles as nucleophiles. This represents the first use of VCPs for the completely atom-economic functionalization of 3-substituted 1H-indoles and tryptophan derivatives via a Pd-catalyzed asymmetric allylic alkylation (Pd-AAA). Excellent yields and high chemo-, regio-, and enantioselectivities have been realized, providing various indolenine and indoline products. The method is amenable to gram scale and works efficiently with tryptophan derivatives that contain a diketopiperazine or diketomorpholine ring, allowing us to synthesize mollenine A in a rapid and ligand-controlled fashion. The obtained indolenine products bear an imine, an internal olefin, and a malonate motif, giving multiple sites with diverse reactivities for product diversification. Complicated polycyclic skeletons can be conveniently constructed by leveraging this unique juxtaposition of functional groups.

Full text of DOI:10.1021/jacs.8b03656

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Article
Palladium-Catalyzed Asymmetric Allylic Alkylation of 3-Substituted-1H-
Indoles and Tryptophan Derivatives with Vinylcyclopropanes
Barry M. Trost, Wen-Ju Bai, Christoph Hohn, Yu Bai, and James J Cregg
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 11 May 2018
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Page 1 of 9
Journal of the American Chemical Society
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Palladium-Catalyzed Asymmetric Allylic Alkylation of 3-
Substituted-1H-Indoles and Tryptophan Derivatives with Vinylcy-
clopropanes
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9
0
‡
‡
Barry M. Trost,* Wen-Ju Bai, Christoph Hohn, Yu Bai, James J. Cregg
Department of Chemistry, Stanford University, Stanford, California 94305-5080, United States
ABSTRACT: Vinylcyclopropanes (VCPs) are known to generate 1,3-dipoles with a palladium catalyst that initially serve as nu-
cleophiles to undergo [3 + 2] cycloadditions with electron-deficient olefins. In this report, we reverse this reactivity and drive the
1,3-dipoles to serve as electrophiles by employing 3-alkylated indoles as nucleophiles. This represents the first use of VCPs for the
completely atom-economic functionalization of 3-substituted-1H-indoles and tryptophan derivatives via a Pd-catalyzed asymmetric
allylic alkylation (Pd-AAA). Excellent yields and high chemo-, regio- and enantioselectivities have been realized, providing vari-
ous indolenine and indoline products. The method is amenable to gram scale, and works efficiently with tryptophan derivatives that
contain a diketopiperazine or diketomorpholine ring, allowing us to synthesize mollenine A in a rapid and ligand-controlled fash-
ion. The obtained indolenine products bear an imine, an internal olefin, and a malonate motif, giving multiple sites with diverse
reactivities for product diversification. Complicated polycyclic skeletons can be conveniently constructed by leveraging this unique
juxtaposition of functional groups.
5
a
7
INTRODUCTION
doles, among which the Pd-AAA of 3-substituted-1H-
1
indoles represents an efficient way to achieve this goal.
Naturally occurring indole alkaloids display a broad range of
2
anticancer, antibacterial, and antifungal properties (Figure 1).
For example, borreverine is strongly active against Gram-
positive bacteria. As a result, these molecules provide an
attractive platform for structure-activity relationship studies
Trost (2006)
R2
2
R
3
R1
Pd (dba) •CHCl , L*
+
2
3
3
R1
R1
X
OH
or
84-95% yield, 80:20 to 95:5 er
Ar
N
H
9-BBN-(C
6
H
13
)
N
N
H
4
and lead compound discovery in drug development. Their
Ar
indoline cores usually fuse with other hetero- or carbocyclic
backbones, creating marvelous structural complexity and di-
versity (Figure 1, highlighted in red).
You (2014, 2015)
1
X
R
XH
R
1
X
or
N
H
[Ir(COD)Cl]
2
, L*
R1
N
+
Ar
OR
Ar
additives
40-85% yield
96:4 to >99:1 er
R = OCO Me
N
H
R = H or OCO Me
2
71-97% yield
92:8 to 99:1 er
O
R = H
CO2Me Me
2
Me
Me
O
NHMe
Me
HN
Figure 2. Previous partners for transition metal catalyzed asym-
metric allylation of 3-substituted indoles are limited to allylic
alcohols and carbonates.
Me
N
O
H
N
H
N
H
N
N
N
H
H
H
Me
Me
Aspidophylline A
reversing drug resistance
in resistant KB cells
N
H
NMe
Me
Pseudophrynamine A
potential neurotoxin
Borreverine
antibacterial
In 2005, Tamaru reported a C3-selective palladium-
catalyzed allylation of 1H-indoles using allylic alcohols, in
8
N
H
N
H
R1
3
R HN
O
which the borane reagent facilitated the ionizations of allylic
Et
O
9
O
alcohols and thus promoted the catalytic process. Subse-
N
H
N
H
N
H
H
R2
quently, we developed the first catalytic asymmetric version of
this transformation to obtain chiral indolenines and indolines
bearing C3 quaternary stereocenters (Figure 2). Allyl car-
Aspidospermidine
respiratory stimulant
diuretic
CO2Me
Vindolinine
antihyperglycaemic, antifungal
Physovenine analogs
cholinesterase inhibitors
10
bonates proved to be another type of effective reagents for the
Figure 1. Bioactive molecules containing an indoline motif.
1
1
Pd-AAA of 3-substituted indoles. Recently, You investigat-
ed the iridium-catalyzed intermolecular AAA of 3-substituted-
As many indoline-containing alkaloids possess C3 quater-
nary stereocenters, developing catalytic asymmetric methods
12
1H-indoles using cinnamyl alcohols and carbonates. In spite
5
to build these chiral centers is significant. To address this
of these advances, the allylation partners for the asymmetric
C3-functionalization of 3-substituted indoles have so far been
limited to allylic alcohols and carbonates. Therefore, we were
eager to see if the transition metal catalyzed AAA of 3-
substituted indoles could be expanded to include other reaction
partners as electrophiles so as to access indolenine/indoline
synthetic challenge, early methods used an indirect approach
of enantioselective preparation of 3,3-disubstituted oxindoles
followed by further elaboration to the corresponding in-
6
dolines. More recent efforts have focused on tandem C3-
functionalization/cyclization reactions of 3-substituted in-
1
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 9
Lewis acid-directed
branched regioselectivity
branched products
products bearing functionalized C3-allylic motifs for further
synthetic elaborations.
[
3 + 2]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
R
EWG
EWG
Lewis
acids
R
To achieve this goal, we turned our attention to vinylcy-
clopropanes (VCPs). We previously used them in the pres-
ence of a palladium catalyst to generate 1,3-dipoles, which
initially served as nucleophiles to attack electron-deficient
olefins followed by an intramolecular electrophilic cyclization
EWG
EWG
EWG
EWG
R
N
N H
R = non-nucleophile tether
H
N
H
Pd-directed
EWG
EWG
linear regioselectivity
R = alkyl
Pd-AAA
Nu
13
mixed products
N
to give the formal [3 + 2] products (Figure 3). However,
using VCPs in a Pd-AAA reaction, which drives 1,3-dipoles to
serve as electrophiles rather than nucleophiles, has not been
EWG
EWG
Nu = N, O, C
linear products
R = nucleophile tether
competing
intramolecular cyclization
14
realized before this work. We wondered whether this chal-
lenge might be addressed by carefully choosing a reaction
partner such as a 3-substituted indole. The strained C-C bond
of the cyclopropane serves as a leaving group in this new ver-
sion of transition metal catalyzed allylic alkylation, which is
different from the previous cases using allylic alcohols or car-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
no competing
intramolecular
cyclization
Nu
N
Nu = N, O, C
R = nucleophile tether
Figure 4. Lewis acids and palladium render different regioselec-
tivity of the π-allyl cation within the 1,3-dipole.
9
-12
bonates
and represents a completely atom economic ap-
15
proach. More impressively, the obtained indolenine products
would bear an imine, an internal olefin, and a 1,3-dicarbonyl
motif, providing multiple sites with diverse reactivities for
product diversification.
Herein we report an asymmetric allylic alkylation using
VCPs as electrophiles in which 3-substituted-1H-indoles and
tryptophan derivatives are functionalized with high chemo-,
regio-, and enantioselectivity and complete atom economy.
R
EWG
EWG
EWG
EWG
EWG
R
EWG
RESULTS AND DISCUSSION
use as a
nucleophile
[
3 + 2]
We initiated our studies using commercially available 3-
methyl-1H-indole 1a and readily prepared VCP derivative 2a
(Table 1). Simply subjecting the two compounds to 5 mol%
of Pd (dba) •CHCl and 15 mol% of anthracene-derived Trost
ligand L in DCM at 4 °C for 16 h did not produce any detect-
able allylation product (entry 1). To our delight, the addition
EWG
EWG
PdL*
[
PdL*]
EWG
EWG
EWG
EWG
Pd-AAA
R
R
2
3
3
use as an
electrophile
1
N
HN
R = alkyl
multiple sites
diverse reactivities
for product diversification
of 1.2 eq BEt gave the linear allylation product 3a in a mod-
3
erate 76:24 er (entry 2). Neither branched nor N-allylation
products were observed, suggesting that the triethylborane was
at least partially responsible for both reactivity and chemose-
lectivity. We reasoned that the borane reagent, being tightly
bound to the indole nitrogen during the allylation step, not
only increased the nucleophilicity of the indole and according-
ly promoted the reactivity, but also prevented the N-allylation
Figure 3. VCPs solely serve as electrophiles in Pd-AAA of 3-
alkylated-1H-indoles.
Potential problems arising from the proposed Pd-AAA of
3
-alkylated-1H-indoles would include chemo-, regio-, and
16
enantioselectivity. As both N and C3 can undergo allylation,
we need to shut down the N-allylation process. With regard to
the regioselectivity of attack on the π-allyl cation, the indole
may attack the terminal position to give a linear product, or the
internal position to yield the corresponding branched product.
Previous studies using a Lewis acid catalyst showed that
branched selectivity was dominant as indoles attacked the
18
and therefore benefited the chemoselectivity. Unlike Lewis
acid catalysts, the palladium catalyst enabled the indole 1a to
react at the terminal position of the 1,3-dipole, leading to ex-
clusive formation of the linear product 3a. This result con-
firmed our initial idea that a transition metal could be used to
tune the regioselectivity of the 1,3-dipoles generated from
VCP derivatives. Ligand examination revealed that using
stilbene-derived Trost ligand L afforded a pleasing 95:5 enan-
tiomeric ratio (entries 3-5). Switching to coordinating sol-
vents like THF or MeCN was detrimental to the reactivity
17
internal position of the π-allyl cation (Figure 4). An interest-
ing question arises if the C3-alkyl substituent of the indole is
tethered to a nucleophile, since the pendant nucleophile and
the nucleophilic site of the 1,3-dipole could compete for addi-
tion to the imine intermediate. This will especially become an
issue if the two nucleophiles have similar nucleophilicity,
leading to mixed product formation. Indeed, reactions be-
tween VCPs and indoles bearing a C3-pendant nucleophile are
scarce seen. By using a palladium catalyst, we envisioned that
this problem would be alleviated since the Pd-directed linear
regioselectivity would give an imine intermediate that pre-
cludes competing intramolecular cyclization due to the E-
olefin geometry. As a result, indoles bearing a pendant C3-
nucleophile would be able to react with VCPs in a Pd-AAA
fashion, cleanly providing the linear tricyclic indoline prod-
ucts.
4
(
entries 6-7), whereas using a nonpolar solvent like toluene
gave full conversion (entry 8). Eventually, we found that us-
ing chloroform slightly boosted the er to 96:4 (entry 9). Alt-
hough the more bulky 9-BBN-(C H ) marginally advanced
the er, further increasing the steric size of the borane reagent
dramatically impeded the reaction (entries 10-11). We chose
triethylborane as it is commercially available as a solution in
hexanes. Halving the catalyst loading maintained the full con-
version and 96:4 er, and further decreasing the amount did not
significantly affect the results (entries 12-13). Using 0.2 eq of
6
13
BEt still gave 75% conversion, suggesting that the role of the
3
borane reagent was catalytic (entry 14).
a
Table 1. Optimization of the Reaction Conditions.
2
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Page 3 of 9
Journal of the American Chemical Society
CO2Me
CO2Me
CO Me
2
1
2
3
4
5
6
7
8
9
CO Me
2
Me
Pd2(dba)3•CHCl3 (x mol%)
MeO2C CO2Me
1
2
3
4
5
a
b
c
93
90
91
96
92
96:4
99:1
97:3
96:4
95:5
L* (y mol%)
Me
Me
+
N
H
borane, solvent
4 °C, 16h
1
a
2a
3a
N
N
CO2Me
CO2Me
O
O
O
O
Me
N
H
N
H
NH HN
F
Me
PPh2 Ph2P
PPh2 Ph2P
N
(R,R)-L1
(R,R)-L2
CO2Me
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ph
Ph
CO2Me
Ph
O
O
O
O
NH HN
NH HN
F
N
PPh2 Ph2P
PPh2 Ph2P
CO2Me
CO2Me
(
R,R)-L3
(R,R)-L4
d
e
b
c
entry
lig.
L1
L1
L2
L3
L4
L4
L4
L4
x/y
borane
none
BEt3
BEt3
BEt3
BEt3
BEt3
BEt3
BEt3
solv
DCM
DCM
DCM
DCM
DCM
THF
conv.
<5%
full
full
full
er
nd
1
2
3
4
5
6
7
8
9
5/15
5/15
5/15
5/15
5/15
5/15
5/15
5/15
5/15
O
N
Me
76:24
92:8
94:6
95:5
90:10
95:5
93:7
96:4
CO Me
2
CO2Me
full
MeO
66%
85%
full
O
N Me
MeCN
Tol
a
Reaction Conditions: 0.20 mmol of 1, 2.5 mol% of
Pd (dba) •CHCl , 7.5 mol% of L , 0.24 mmol of BEt and 2a, in
2
3
3
4
3
L4
BEt3
CHCl3
full
b
c
CHCl at 4 °C for 16h. Isolated yield. Determined by HPLC on a
3
9
-BBN-
1
1
0
1
L4
5/15
5/15
CHCl3
full
97:3
nd
chiral stationary phase.
(
C H )
6
13
Sia B-
2
L4
CHCl3
<10%
We next moved onto substrates bearing a pendant nucleo-
phile that could intercept the formed imines under the reaction
conditions to generate varied tricyclic skeletons. Employing
our previously established standard conditions, tryptophol 1f
efficiently delivered the anticipated furoindoline 3f in 93%
yield with 96:4 er (Table 3, entry 1). This result confirmed
our prior assumption that using a palladium catalyst would
enable indoles bearing a pendant C3-nucleophile to cleanly
react with VCPs, while employing a Lewis acid might have
generated mixed products. Replacing the solvent with DCM,
using 9-BBN-(C H ) as borane reagent, warming up the reac-
(C H )
6
13
12
L4
L4
L4
2.5/7.5
1/3
2.5/7.5
BEt3
BEt3
BEt3
CHCl3
CHCl3
CHCl3
full
full
75%
96:4
94:6
nd
1
3
d
1
4
a
Reaction Conditions: 0.20 mmol of 1a,
x
mol% of
Pd (dba) •CHCl , y mol% of L, 0.24 mmol of BEt and 2a, in
various solvent at 4 °C for 16h. Determined by H NMR analysis.
Determined by HPLC on a chiral stationary phase. Reaction was
2
3
3
3
b
1
c
d
performed with 0.2 eq of BEt3.
With the optimized conditions in hand, we started to ex-
plore the scope of this transformation using 3-alkylated 1H-
indoles 1a-e (Table 2). High yields were obtained in all cases.
Substrates bearing electron-withdrawing or -donating groups
all smoothly delivered the corresponding 3,3-disubstituted
indolenines, with enantiomeric ratio ranging from 95:5 to
6
13
tion to ambient temperature, or lowering the catalyst loading
did not considerably change the yield or enantioselectivity
(entries 2-5).
a
Table 3. Optimization with Tryptophol 1f.
CO2Me
9
9:1. These indolenine products 3a-e are exceptional accep-
standard conditions
CO2Me
tors for various nucleophiles, as we demonstrated later when
derivatizing these products. Additionally, indoles containing a
carbonyl functional group were also tolerated (entries 4-5),
which provided an extra handle to elaborate the products.
Pd2(dba)3•CHCl3 (2.5 mol%)
L4 (7.5 mol%)
OH MeO2C CO2Me
+
N
H
O
BEt3 (1.2 eq)
3
1
f
2a
CHCl , 4 °C, 16h
N
H
H
3f
deviation from
standard conditions
none
DCM as solvent
reaction at rt
b
c
Table 2. Scope of C3-allylation of 3-Subsituted-1H-
entry
yield
er
a
indoles.
1
2
3
4
93
88
91
91
96:4
96:4
94:6
97:3
CO2Me
CO2Me
R2
Pd2(dba)3•CHCl3 (2.5 mol%)
L4 (7.5 mol%)
MeO2C CO2Me
R2
9-BBN-(C
mol% of Pd
3 mol% of L
4
6
H
13) as the borane
R1
+
1
2
(dba) •CHCl3 and
3
N
H
BEt3 (1.2 eq)
3
R1
5
88
94:6
2a
CHCl , 4 °C, 16h
1
N
3
a
Standard Conditions: 0.20 mmol of 1f, 2.5 mol% of
Pd (dba) •CHCl , 7.5 mol% of L , 0.24 mmol of BEt and 2a, in
b
c
entry
3
product structure
yield
er
2
3
3
4
3
b
c
CHCl at 4 °C for 16h. Isolated yield. Determined by HPLC on a
3
chiral stationary phase.
3
ACS Paragon Plus Environment

Journal of the American Chemical Society
The scope of this tandem C3-allylation/cyclization process
Page 4 of 9
CO2Me
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
was then investigated (Table 4). Electron-deficient tryp-
tophols afforded better enantioselectivity compared to elec-
tron-rich ones, but in all cases >92:8 er was realized (entries 1-
CO Me
7
l
88
91:9
MeO
Me
F
O
5
). Homologating the C3-alcoholic chain of the indoles deliv-
ered the corresponding cis-[4,3,0]-N,O-tricyclic products 3l-n
in 87-90 yields with enantiomeric ratios from 86:14 to 98:2
N H
H
2
CO Me
CO2Me
(
entries 7-9). Using tryptamine derivatives afforded pyr-
roloindolines 3o-p with outstanding enantioselectivity (entries
0-11). It is worth noting that N-Ts and N-Boc protected tryp-
8
9
m
n
o
87
90
80
85
80
86:14
98:2
96:4
95:5
94:6
O
1
N
H
H
tamines work equally well for this transformation. The malo-
nate-containing side chain could also effectively trap the ini-
tially formed indolenines, providing the respective indolines
featuring five- or six-membered carbocycle (entries 12-13).
Lastly, VCP derivatives bearing sterically more hindered ester
groups were tested. These bulky ester groups not only better
guide the enantioselectivity, but also offer an opportunity for
ester cleavage using other conditions if necessary (entries 14-
CO2Me
CO2Me
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
N
H
H
CO2Me
CO2Me
1
5).
10
NTs
Table 4. Scope of Tandem C3-allylation/Cyclizations of 3-
N
H
H
a
Substituted-1H-indoles.
CO Me
2
CO2R
CO2R
CO2Me
1
1
p
q
XH
Pd2(dba)3•CHCl3 (2.5 mol%)
L4 (7.5 mol%)
RO2C CO2R
R1
entry
1
NBoc
+
N
H
N
H
H
BEt3 (1.2 eq)
3
X
1
2
CHCl , 4 °C, 16h
N
H
H
3
CO Me
2
b
c
3
product structure
yield
er
CO2Me
CO2Me
d
12
13
MeO
CO2Me
CO Me
2
N
H
H CO2Me
f
93
96:4
92:8
92:8
96:4
94:6
92:8
CO2Me
CO2Me
O
N
H
H
CO2Me
CO2Me
d
r
s
t
82
93
90
95:5
97:3
98:2
MeO
CO2Me
N
H
H CO Me
2
3
4
5
6
g
h
i
83
89
95
89
92
2
Me
O
CO2Bn
CO2Bn
N
H
H
CO2Me
CO2Me
1
1
4
O
N
H
H
MeO
O
CO2CH2tBu
CO2CH2tBu
N
H
H
CO2Me
CO2Me
5
O
N
H
H
F
Cl
Br
O
a
Reaction Conditions: 0.20 mmol of 1, 2.5 mol% of
Pd (dba) •CHCl , 7.5 mol% of L , 0.24 mmol of BEt and 2, in
N
H
H
2
3
3
4
3
CO2Me
CO2Me
b
c
CHCl at 4 °C for 16h. Isolated yield. Determined by HPLC on a
chiral stationary phase. The cyclization onto the imine interme-
diate smoothly occurred by addition of ethanolamine to the crude
indolenine products.
3
d
j
O
N
H
H
To demonstrate the scalability and practicality of this new-
ly developed method, the reaction was performed using one
gram of the N-Boc protected tryptamine 1p with decreased
catalyst loading (eq. 1). To our delight, employing 2 mol%
CO2Me
CO2Me
k
O
palladium catalyst and 6 mol% of the Trost ligand L provided
the pyrroloindoline 3p in 89% isolated yield and 95:5 er.
4
N
H
H
4
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Journal of the American Chemical Society
CO2Me
Scheme 1. Pd-AAA of the N-Boc-L-Tryptophan Methyl
1
2
3
4
5
6
7
8
9
CO2Me
NBoc
Ester Using a VCP.
NHBoc
MeO2C CO2Me
Pd2(dba)3•CHCl3 (2 mol%)
L4 (6 mol%)
CO2Me
N
+
(
eq. 1)
H
1
p
BEt3 (1.2 eq)
CHCl3, 4 °C, 16h
CO2Me
2
1
gram
3.8 mmol)
N
H
H
Pd2(dba)3•CHCl3 (2.5 mol%)
L4 (7.5 mol%)
2a
CO Me
(
3p
1.57 g (3.4 mmol)
9%, 95:5 er
(1.2 eq)
8
NBoc
2
a, BEt3 (1.2 eq)
CO2Me
NHBoc
CHCl3, 4 °C, 16h
N
H
5
Tryptophan-originated alkaloids are ubiquitous in nature,
mostly as diketopiperazines (DKPs) or diketomorpholines
(DKMs) (Figure 5, highlighted in red). Early efforts to con-
struct these natural products usually employed an indirect ap-
proach through diastereoselective seleno- or halocyclization of
tryptophan derivatives followed by Stille coupling to install
the desired allyl motifs. More recently, Tamaru showed that
a Pd-catalyzed allylation of L-tryptophan methyl ester using
triethylborane exclusively provided the endo-pyrroloindoline
product while Carreira found that a Ir-catalyzed reverse
prenylation of the same starting material led to the preferential
formation of the exo-pyrroloindoline product, both in a dia-
stereoselective manner. Later, Stark reported the first and
only diastereodivergent reverse prenylation of tryptophan de-
rivatives, in which the borane reagents mysteriously played a
H
single diastereomer, 95%
N
4
CO Me
2
19
H
Pd2(dba)3•CHCl3 (2.5 mol%)
ent-L4 (7.5 mol%)
CO2Me
CO2Me
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2a, BEt3 (1.2 eq)
CHCl3, 4 °C, 16h
NBoc
N
H
H
6
>30:1 dr
95%
2
0
We next turned our attention to the DKP-containing tryp-
2
3
8
tophan derivative 7 (Schemes 2). This cyclic dipeptide un-
derwent the desired asymmetric allylation with slightly in-
creased catalyst loading to provide the corresponding pentacy-
clic products 8 and 9 in high yield. The ligand effectively
controlled the product formation during this transformation.
Interestingly, the obtained products could further participate in
a cross-metathesis reaction with 2-methylbut-2-ene to deliver
the corresponding prenylated products 10 and 11 that are
known precursors for the cell cycle inhibitor tryprostatin B.
21
2
4
2
2
key role in determining the exo- and endo-selectivity.
A
ligand-controlled enantioselective allylation of tryptophan
derivatives can hypothetically provide convenient access to
either exo- or endo-selective pyrroloindoles, but the pre-
existing chirality of the starting material might display a
2
5
Scheme 2. Pd-AAA of the Cyclo(L-Trp-L-Pro) (DKP motif)
Using a VCP.
match-mismatch effect with the chiral ligand and consequently
Me
Me
12b
hamper the exo- or endo-selectivity.
Building upon the en-
couraging results of asymmetric allylation of 3-substituted-
H-indoles using VCPs, we were curious to examine the more
challenging tryptophan derivatives, in the hope of accessing
pyrroloindoline products with the corresponding exo- and en-
do-selectivity being well controlled by the chiral ligands.
O
H
CO Me
2
N
2
MeO C
1
N
N H
H
Pd
2
(dba)
3 mol%)
(9 mol%)
3
•CHCl
3
O
H
O
1
0, 93%
Grubbs-II
(
H
N
Me Me
Me
L
4
N
H
DCM, 45 °C
O
O
H
2a, BEt3 (2.0 eq)
CHCl , 4 °C, 16h
N
H
3
N
H
H
Me
O
Me
Me
Me
O
HN
8, >10:1 dr, 91%
H
N
O
H
N
H
NH Me
Me
CO Me
7
2
N
N
Pd
2
(dba)
(3 mol%)
ent-L (9 mol%)
3
•CHCl
3
MeO
2
C
N
Me
N H
H
O
4
N
Me
H
O
O
H
Me Me
Me
Nocardioazine B
Brevicompanine B
2a, BEt3 (2.0 eq)
CHCl , 4 °C, 16h
Grubbs-II
DCM, 45 °C
3
N
Me
Me
Me
Me
H
N
Me Mollenine A
H
N
H
H
O
N
NFY88-P
Me
O
H
N
O
9, >10:1 dr, 89%
O
Me
O
Me
Me
N
N
N
H
H
H
O
N
11, 90%
N
H
H
N
H
H
O
O
Our motivation to examine the DKM-containing trypto-
phan derivative 13 arose from the desire to quickly access and
verify the absolute stereochemistry of mollenine A using our
newly established method (Scheme 3). Chan recently reported
the first total synthesis of this molecule in 9 steps and 11.4%
overall yield, using the aforementioned indirect approach of
diastereoselective bromo-cyclization of N1-Boc-protected 4
followed by a Stille allylation and olefin cross-metathesis to
DKP (diketopiperazine)
DKM (diketomorpholine)
Figure 5. Bioactive molecules bearing DKP and DKM motifs.
We first studied the Pd-catalyzed asymmetric allylation of
commercial N-Boc-L-tryptophan methyl ester 4 with VCP
derivative 2a using triethylborane and stilbene-derived Trost
ligand L4 [(R,R)] (Scheme 1). To our delight, the exo-
pyrroloindoline product 5 was obtained as a single diastere-
26
install the prenyl moiety. During the preparation of this
manuscript, Ishikawa realized the synthesis of mollenine A in
three steps and 16.5% overall yield through a direct yet uncon-
omer in 95% yield. Switching to ent-L [(S,S)] led to exclu-
4
sive formation of the endo-selective product 6. In stark con-
trast, using DPPF as a ligand delivered a 1:1 mixture of prod-
ucts 5 and 6. These outcomes suggested that the product dis-
tribution during the Pd-AAA was guided by the chiral ligand.
Accordingly, no match-mismatch effect was seen, which is
different from prior observations in the iridium-catalyzed sys-
trolled prenylation of D-tryptophan ethyl ester under strong
27
acidic conditions.
The desired prenylated intermediate was
obtained in 22% yield along with six side products. As a re-
sult, we believed that our ligand-controlled allylation process
would provide a better approach to synthesize mollenine A.
Starting from L-tryptophan drivative 4 and (S)-2-hydroxy-4-
methylpentanoic acid (HMA) 12, the DKM 13 was prepared in
1
2b
tem using a cinnamyl carbonate as the electrophile.
5
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Journal of the American Chemical Society
Page 6 of 9
2
8
30
7
0% yield in one pot. Subjecting this material to the allyla-
3 2
thylsilyl)acetylide in the presence of BF •Et O and propargyl
3
1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
tion conditions using ligand L [(R,R)] and ent-L [(S,S)] pro-
4
4
bromide/In under sonication diastereoselectively installed
the corresponding alkynyl and propargyl motifs, providing the
indolines 17 and 18 both in >90% yield and >20:1 dr. Both
the obtained indolines could participate in a Pauson-Khand
vided the tetracyclic pyrroloindolines 14 and 15 respectively
in high yields and >10:1 dr, showcasing the ligand control for
the transformation. Subsequent olefin cross-metathesis pro-
vided mollenine A (revised structure) as well as the enantio-
mer of its proposed structure. This allowed us to verify the
absolute configuration of mollenine A and also establish the
absolute stereochemistry of the Pd-AAA products 14 and 15.
The three-pot synthesis enabled us to obtain the mollenine A
in an impressive 60% overall yield, demonstrating the utility
of our method to build DKP- and DKM-containing natural
products.
3
2
reaction to deliver the respective 6,5,5,5- and 6,5,6,5-
tetracyclic compounds 19 and 20 with good control of dia-
stereoselectivity. In addition, the Ru-catalyzed alkene-alkyne
coupling of indoline 17 provided the tricyclic 1,4-diene 21 in
84% yield and >20:1 dr, whose stereochemistry was deter-
mined by NOE analysis. These powerful transformations take
advantage of the newly furnished imine and allyl motifs,
demonstrating the benefits of functionalizing C3-substituted-
1H indoles via Pd-AAA. Using VCPs for this tranformation
also introduces a malonate group, which can serve as an excel-
lent nucleophile for additional product decorations. For in-
stance, propargylation of indoline 17 using propargyl bromide
and NaH provided the enediyne 22, which smoothly under-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 3. Pd-AAA of the Cyclo(L-Trp-S-HMA) (DKM
motif) Using a VCP; Total Synthesis of Mollenine A.
O
CO2Me
OH
Me
Me
O
BOPCl, THF
collidine
HO
NHBoc
HN
Me
+
3
3
N
H
O
then TsOH
tol, reflux
N
H
went a Rh-catalyzed [2 + 2 + 2] reaction to deliver the
,5,5,6,5-pentacyclic product 23 in 75% yield over 2 steps and
4
1
2
Me
O
70%, 13
6
CO2Me
Me
>20:1 dr, the stereochemistry of which was determined by
NOE analysis. The obtained product 23 bears a diene motif
that has the potential to participate in various [4 + 2] reactions
to further increase its structural complexity if needed. These
interesting elaborations demonstrate the rewards of employing
VCP derivatives rather than the previously used allylic alco-
hols or carbonates to functionalize C3-substituted-1H indoles.
Me Me MeO2C
Pd2(dba)3•CHCl3
(3 mol%)
L4 (9 mol%)
Me
O
O
Me
Grubbs-II
Me
O
2
a, BEt3 (2.0 eq)
N
Me
Me
O
DCM, 45 °C
CHCl , 4 °C, 16h
3
N
H
92%
N
Me
O
H
Mollenine A (revised)
pots, 60% overall
N
H
H
O
3
1
4, >10:1 dr, 93%
CO2Me
Me Me
34
MeO2C
Me
The proposed catalytic cycle is depicted in Figure 6. The
Me
Me
palladium(0) catalyst opens the VCP derivative 2a to generate
the zwitterionic π-allylpalladium complex I. Meanwhile, tri-
ethylborane readily binds to the indole 1a to form the complex
II, dramatically increasing the acidity of the indole proton. As
a result, it protonates the malonate anion of I, which conse-
quently shuts down the nucleophilic reactivity of the malonate
site and allows the obtained π-allylpalladium complex III to
solely serve as an electrophile for the following allylation re-
action. The high-energy π-allylpalladium species III might be
stabilized via a possible intramolecular coordination to one of
the ester groups. The newly generated N-indolyltriethylborate
IV regioselectively attacks the complex III at the terminal
O
Pd2(dba)3•CHCl3
(3 mol%)
ent-L4 (9 mol%)
Grubbs-II
O
Me
O
DCM, 45 °C
Me
O
N
Me
90%
2a, BEt3 (2.0 eq)
Me
N
N
H
H
CHCl , 4 °C, 16h
O
3
N H
ent-Mollenine A (proposed)
H
O
3
pots, 57% overall
1
5, >10:1 dr, 92%
To further validate the synthetic utility of our newly de-
veloped method, the obtained indolenine products 3 were
elaborated to complex polycycles via atom-economic addition
processes (Scheme 4). Upon treatment with base, indolenine
3d underwent an intramolecular 1,2-addition to give the tricy-
clic cyclohexanone 16 in 85% yield. Meanwhile, the intermo-
lecular 1,2-additions of indolenine 3b with lithium (trime-
29
Scheme 4. Derivatization of Indolenines 3.
MeO2C
CO Me
H
Me
CO2Me
CO2Me
Me
H
2
CO2Me
Me
[Rh(binap)]BF4
F
Me
F
CO2Me
DCE, rt
N
H
H
22
N
H
H
23, > 20:1 dr
O
75%, 2 steps
NaH
THF, rt
N
H
H
Br
1
6, 85%
from
3d
CO2Me
CO2Me
2
CO Me
Me
Me
KOtBu
CO2Me
CO2Me
H
CO2Me
O
THF, -78 °C
from 3b
TMS
Me
Me
F
F
R2
Li
Co2(CO)8, THF
TMS
N
H
H
N
H
R1
BF3•Et2O
17, 92%
> 20:1 dr
then DMSO
65 °C
H
TMS
N
THF, -78 °C
19, 84%
> 10:1 dr
3
Br
CpRu(CH3CN)3PF6
(10 mol%)
from 3b
DCM, rt
MeO2C
TMS
TMS
Me
In, THF
0 °C, ))
MeO2C
H
Me
4
CO2Me
CO2Me
Me
F
CO2Me
CO2Me
Me
O
21, 84%
> 20:1 dr
Me
F
N
H
Co2(CO)8, THF
H
Me
F
TMS
N
H
H
then DMSO
65 °C
18, 94%
N
H
20, 50% (85% brsm)
H
>
20:1 dr
TMS
7:1 dr
6
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Journal of the American Chemical Society
CO2Me
CO2Me
‡
These authors contributed equally.
MeO2C CO2Me
1
2
3
4
5
6
7
8
9
Me 3a
PdL*
Notes
2a
The authors declare no competing financial interest.
N
ACKNOWLEDGMENT
CO2Me
CO2Me
PdL*
Me
We appreciate the NIH (GM-033049) and the NSF (CHE-
1360634) for their generous support of our programs.
Me
CO2Me
CO2Me
Me
N
a H
1
N
PdL*
I
V
+
H
BEt3
N
II
REFERENCES
BEt3
Me
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
BEt3
1
2
For recent reviews, see: a) Ishikura, M.; Abe, T.; Choshi, T.;
Hibino, S. Nat. Prod. Rep. 2013, 30, 694. b) Ishikura, M.; Abe,
T.; Choshi, T.; Hibino, S. Nat. Prod. Rep. 2015, 32, 1389.
For isolation of pseudophrynamine A, see: a) Spande, T. F.; Ed-
wards, M. W.; Pannell, L. K.; Daly, J. W.; Erspamer, V.; Melchi-
orri, P. J. Org. Chem. 1988, 53, 1222. For its recent synthesis,
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H.; Erande, R. D.; Dherange, B. D. Org. Lett. 2014, 16, 2764. For
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O.; Hayashi, M.; Koyano, T.; Komiyama, K.; Kam, T. S. J. Nat.
Prod. 2007, 70, 1783. For its recent synthesis, see: f) Zu, L.;
Boal, B. W.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 8877. For
isolation of vindolinine, see: g) Janot, M.-M.; Le Men, J.; Fan, C.
Bull. Soc. Chim. Fr. 1959, 891. For structural studies of aspido-
spermidine, see: h) Biekmann, K.; Spiteller-Friedmann, M.;
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For a recent example, see Wang, C. H.; Alluri, S.; Nikogosyan,
G.; DeCarlo, C.; Monteiro, C.; Mabagos, G.; Feng, H. H.; White,
A. R.; Bartolini, M.; Andrisano, V.; Zhang, L. K.; Ganguly, A. K.
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Angew. Chem., Int. Ed. 2012, 51, 12662. And references therein.
For recent reviews, see: a) Trost, B. M.; Brennan, M. K. Synthesis
IV
CO2Me
CO2Me
H
PdL*
III
Figure 6. Proposed catalytic cycle.
position to deliver the indolenine/palladium complex V and
releases the triethylborane for next association cycle with the
starting indole 1a. As the borane strongly binds to the indole
nitrogen of IV, the N-allylation process is inhibited. Finally,
decomplexation of complex V liberates the product 3a and
then turns over the catalytic cycle.
CONCLUSION
In summary, we have reported the first use of VCP deriva-
tives as electrophiles for the asymmetric allylation of C3-
substituted-1H indoles and tryptophan derivatives. Utilizing
Pd (dba) •CHCl and stilbene-derived Trost ligand L , a broad
3
4
2
3
3
4
range of 3,3-disubstituted- indolenines and indolines has been
prepared in a highly chemo-, regio-, and enantioselective fash-
ion. This completely atom-economic transformation enables
indoles bearing a pendant C3-nucleophile to cleanly react with
VCPs, whereas employing a Lewis acid might be problematic.
The reaction can be performed on gram scale. The stereo-
chemical outcomes of asymmetric functionalizations of tryp-
tophan derivatives are well controlled by the chiral ligands,
allowing us to expeditiously synthesize mollenine A. The
indolenine products can be elaborated to intricate polycyclic
compounds by making use of the newly installed imine and
internal olefin motifs. More importantly, VCPs, like no other
allylation reagents, introduce a nucleophilic malonate substit-
uent through the Pd-AAA, providing an excellent handle for
additional product derivatization.
5
6
2
2
009, 3003. b) Zhou, F.; Liu, Y.-L.; Zhou, J. Adv. Synth. Catal.
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M. J. Am. Chem. Soc. 2009, 131, 9168. d) Trost, B. M.; Malhotra,
S.; Chan. W. H. J. Am. Chem. Soc. 2011, 133, 7328. e) Trost, B.
M.; Xie, J. Sieber, J. D. J. Am. Chem. Soc. 2011, 133, 20611. f)
Mitsunuma, H.; Shibasaki, M.; Kanai, M.; Matsunaga, S. Angew.
Chem., Int. Ed. 2012, 51, 5217.
For recent reviews on Pd-AAA, see: a) Trost, B. M.; Crawley, M.
L. Chem. Rev. 2003, 103, 2921. b) Trost, B. M.; Machacek, M.
R.; Aponick, A. Acc. Chem. Res. 2006, 39, 747. c) Trost, B. M.
and Fandrick, D. R. Aldrichimica Acta 2007, 40, 59.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
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1
0
Experimental details, compound characterization data, and spectra
11
(
PDF)
2
016, 22, 11601. c) Gao, R.-D.; Ding, L.; Zheng, C.; Dai, L.-X.;
You, S.-L. Org. Lett. 2018, 20, 748. For examples of Pd-
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AUTHOR INFORMATION
Corresponding Author
*
bmtrost@stanford.edu
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a) Zhang, X.; You, S.-L. Chem. Sci. 2014, 5, 1059. b) Zhang, X.;
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Author Contributions
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Table of Content
CO2Me
Me
H
F
Me
H
CO2Me
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
use 1,3-dipoles
as electrophiles
R2
CO2Me
CO2Me
R1
N
H
H
PdL*
N
H
CO2Me
CO2R
R2
CO2Me
CO2R
3 4
Pd(0), BEt , L
NBoc
R1
N
H
H
N
Me
O
Pd-directed linear
regioselectivity
Me
Me
O
Me
multiple sites
diverse reactivities
for product diversification
N
H
O
NH
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