Enantioselective functionalization of allylic C-H bonds following a strategy of functionalization and diversification

Article abstract of DOI:10.1021/ja409995w

We report the enantioselective functionalization of allylic C-H bonds in terminal alkenes by a strategy involving the installation of a temporary functional group at the terminal carbon atom by C-H bond functionalization, followed by the catalytic diversification of this intermediate with a broad scope of reagents. The method consists of a one-pot sequence of palladium-catalyzed allylic C-H bond oxidation under neutral conditions to form linear allyl benzoates, followed by iridium-catalyzed allylic substitution. This overall transformation forms a variety of chiral products containing a new C-N, C-O, C-S, or C-C bond at the allylic position in good yield with a high branched-to-linear selectivity and excellent enantioselectivity (ee ≤97%). The broad scope of the overall process results from separating the oxidation and functionalization steps; by doing so, the scope of nucleophile encompasses those sensitive to direct oxidative functionalization. The high enantioselectivity of the overall process is achieved by developing an allylic oxidation that occurs without acid to form the linear isomer with high selectivity. These allylic functionalization processes are amenable to an iterative sequence leading to (1,n)-functionalized products with catalyst-controlled diastereo- and enantioselectivity. The utility of the method in the synthesis of biologically active molecules has been demonstrated.

Full text of DOI:10.1021/ja409995w

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Article
Enantioselective Functionalization of Allylic C-H Bonds
Following a Strategy of Functionalization and Diversification
Ankit Sharma, and John F. Hartwig
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 24 Oct 2013
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Enantioselective Functionalization of Allylic C-H Bonds Fol-
lowing a Strategy of Functionalization and Diversification
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Ankit Sharma and John F. Hartwig*
Department of Chemistry, University of California, Berkeley, California 94720, United States
ABSTRACT: We report the enantioselective functionalization of allylic C-H bonds in terminal alkenes by a strategy
involving the installation of a temporary functional group at the terminal carbon atom by C-H bond functionalization,
followed by diversification of this intermediate with a broad scope of reagents. The method consists of a one-pot se-
quence of palladium-catalyzed allylic C-H bond oxidation under neutral conditions to form linear allyl benzoates, fol-
lowed by iridium-catalyzed allylic substitution. This overall transformation forms a variety of chiral products containing
a new C-N, C-O, C-S or C-C bond at the allylic position in good yield with high branched-to-linear selectivity and excel-
lent enantioselectivity (ee ≤ 97%). The broad scope of the overall process results from separating the oxidation and
functionalization steps; by doing so, the scope of nucleophile encompasses those sensitive to direct oxidative functional-
ization. The high enantioselectivity of the overall process is achieved by developing an allylic oxidation that occurs with-
out acid to form the linear isomer with high selectivity. These allylic functionalization processes are amenable to an it-
erative sequence leading to (1,n)-functionalized products with catalyst-controlled diastereo- and enantioselectivity. The
utility of the method in the synthesis of biologically active molecules has been demonstrated.
Introduction
ate that can be converted to biaryls, alkylarenes,
haloarenes, arylamines, aryl ethers, aryl nitriles, and
fluoroalkylarenes, among other products.2k,5b,6
The stereochemical complexity of medicinally important
compounds is increasing, and recent studies have sug-
gested that compounds containing increased numbers of
sp3 carbon centers are more successful through clinical
trials.1 Although C-H bond functionalization reactions
have the potential to alter the strategies by which these
compounds are prepared,2 a major challenge encoun-
tered when developing C-H bond functionalization reac-
tions is the control of absolute and relative stereochemis-
try.2m,3
We sought to develop a related strategy for enantioselec-
tive functionalizations of aliphatic C-H bonds. To devel-
op a general strategy for enantioselective C-H bond func-
tionalization reactions, the introduction of various car-
bon and heteroatom nucleophiles must be accomplished
with control of the configuration - both absolute and rel-
ative – of any new stereogenic center generated by the C-
H bond functionalization reaction.
Likewise, a major challenge facing the development of C-
H bond functionalization reactions is limited reaction
scope. Reactions involving both catalyzed and uncata-
lyzed alkyl, aryl and acyl substitution reactions occur
with broad scope and are used, therefore, widely in me-
dicinal chemistry to build or embellish the core of biolog-
ically active compound.4 Yet the same broad scope does
not apply to C-H bond functionalization reactions. The
functionalization of an aryl C-H bond located ortho to a
strong directing group does occur with a range of rea-
gents and oxidants,2c,2l,5 but the functionalization of oth-
er classes of C-H bonds do not.
Iridium-catalyzed allylic substitution has become one of
the most general reactions that form new carbon-carbon
or carbon-heteroatom bonds with control of the absolute
configuration of an aliphatic stereocenter.7 In this reac-
tion many types of carbon, nitrogen, oxygen, and sulfur
nucleophiles react with an allylic electrophile to form
products in which the configuration of the new stereo-
center is controlled by the catalyst, rather than existing
stereogenic centers in the substrate.7e,8
If the electrophile for such substitution reactions could
be prepared by a C-H bond oxidation process that is
compatible with the substitution reaction, then a strategy
for the synthesis of common structural types by C-H ac-
tivation would result (Figure 1, B). However, the devel-
opment of such a method for C-H bond oxidation is chal-
lenging. As described in more detail below, such a reac-
tion most form linear allylic esters with high linear-to-
branched selectivity under neutral conditions without
excess of oxidant, and such allylic oxidation reactions are
unknown. Published conditions for allylic oxidation are
incompatible with most catalysts for subsequent trans-
formations of the oxidation products.
One approach to create a C-H bond functionalization
that occurs with broad scope is to combine one C-H bond
functionalization reaction with a subsequent step that
creates diversity from the initial product of C-H bond
functionalization (Figure 1, A). For greatest efficiency,
the C-H bond functionalization and subsequent trans-
formation should be conducted in the same reaction ves-
sel without purification of the intermediate. The strength
of this approach is illustrated by the borylation of aro-
matic C-H bonds. In this case, one reliable, iridium-
catalyzed C-H borylation reaction leads to an intermedi-
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Page 2 of 8
(A) General Strategy for C-H bond Functionalization
iridium catalyst in the second step. Third, the allylic ester
1
2
3
4
5
6
7
8
must be generated in a neutral medium if a second cata-
lyst is to be added to convert the oxidation product to a
range of different products. The iridium catalyst for
asymmetric allylic substitution (1, Figure 1, B) is not sta-
ble to acidic media. This issue is a particular concern
because most oxidation processes are conducted in acid-
ic medium, and palladium-catalyzed allylic oxidations
that have been published recently with oxygen or qui-
none as the oxidant require acid for converting the oxy-
gen to hydrogen peroxide or the quinone to the hydro-
quinone. Thus, we first needed to develop a highly selec-
tive catalyst for allylic oxidation to form the terminal
allylic ester with high selectivity without excess of oxi-
dant under neutral conditions.
reliable reaction
Cat.
+
H
TG
R FG
R
R
TG
Oxidant
FG= Functional group
TG= Easily transformable
temporary functional group
(B) Strategy for Allylic C-H bond Functionalization
O
P
O
Nu
*
OBz
1
Ir
cat. 1
Cat.
R
N
R
Oxidant
Nu.
R
Nu = Nucleophile
Ph
Ph
9
O
= (R)-BINOL
O
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(C) Strategy for (1,n)-Functionalization
Nu1
Nu1 Nu2
Nu1
R
R
R
(1,n)-Functionalization
R
n
n
Homologation
C-H Bond
Functionalization
A. Development of an allylic oxidation under
neutral conditions to form linear products. With
these challenges in mind, our initial studies focused on
developing conditions for allylic oxidation to form linear
allylic esters under conditions lacking acid or oxidant
that would interfere with the allylic substitution process.
Prior methods for allylic acetoxylation based on early
reports from Tsuji9 and Akermark,10 form linear prod-
ucts, but most of these reactions are conducted with ex-
cess of acid (often as solvent) or oxidant, or both.11
Figure 1. General Strategy for Aliphatic or Allylic C-H bond
Functionalization
However, if such a combination of oxidation and asym-
metric substitution were developed, then an opportunity
would be created to use a sequence of allylic functionali-
zation and homologation reactions to form diols, amino
alcohols, and diamines, as well as products with a new
alkyl or sulfur-containing group. In these reactions the
functionality and configurations would be programmed
by the identity of the reagent and configuration of the
catalyst. This strategy is depicted in Figure 1, (C). The
new functional groups could be located at nearly any
position along an alkyl chain.
To avoid these acidic conditions with excess oxidant, we
investigated the reactions of alkenes with peresters,
which would serve as the oxidant and could create an
appropriate leaving group for the allylic substitution re-
action. Copper-catalyzed allylic oxidation with peresters,
such as tert-butyl perbenzoate (also known as the
Kharasch-Sosnovsky reaction) has been studied exten-
sively.12 However, this reaction forms branched allylic
esters as the major isomer and, therefore, is not suitable
for the envisioned allylic functionalization sequence.
We report the discovery of a sequence comprising C-H
bond oxidation and asymmetric allylic substitution. The
two steps involve a palladium-catalyzed oxidation of al-
kenes under neutral conditions to form linear allylic ben-
zoates, and iridium-catalyzed allylic substitution to form
products containing new C-O, C-N, C-C and C-S bonds
with control over absolute and relative configuration of
the stereogenic centers in the product. In contrast to re-
cently published asymmetric allylic functionalizations,3o
the reactants in our process are common nucleophiles
lacking protecting groups and substituents that modu-
late their reactivity. This process forms products contain-
ing new functionalities at stereogenic centers located 1,3-
, 1,4-, 1,5- or even further removed from each other, and
the absolute and relative configuration of all new stereo-
centers are fully controlled by the catalytic process. In
addition to creating new building blocks from simple
alkenes, this work introduces a strategy for aliphatic sub-
strates to combine C-H bond functionalization with di-
versification of the intermediate through reliable catalyt-
ic chemistry.
3g,12b,12c,13
Palladium catalysts also have been used in
combination with peresters for oxidation reactions,14 but
this combination has not been used for the oxidation of
allylic C-H bonds. Thus we sought to develop a palladi-
um catalyzed C-H oxidation with tert-butyl perbenzoate
as the oxidant and source of the benzoate group that
would form the linear allylic ester.
The combination of Pd(OAc)2 and bidentate nitrogen
ligands were tested as catalyst for the benzoylation of 1-
decene with tert-butylperbenzoate (Chart 1). The activity
and regioselectivity was highest in neat alkene with a 2:1
ratio of alkene to oxidant. Reactions conducted with pal-
ladium complexes of tert-butylbipyridine (L1), phenan-
throline (L2), 1,10-phenanthroline-5,6-dione (L3) and
2,2'-bipyrimidine (L4) provided low yields of oxidation
product 2a (7%, 5%, 0% and 11% respectively). The lig-
and 4,5-diazafluorenone (L5) was reported by Stahl to
form the products of allylic oxidation with O2 as reagent
in acetic acid with good linear-to-branched selectivity.11a
Thus, we tested this catalyst system for the reaction with
tert-butyl perbenzoate as oxidant. Important for the im-
plementation of the functionalization and diversification
strategy, this reaction occurred in 70% yield, with a 15:1
linear-to-branched ratio.
Results and Discussion
The development of a process involving the combination
of palladium-catalyzed allylic oxidation and iridium-
catalyzed allylic substitution of the oxidation product
confronts several challenges that would be met by devel-
opment of novel conditions for allylic C-H oxidation.
First the oxidation step must generate the terminal al-
lylic ester with high selectivity. The branched impurity
would reduce the enantioselectivity of the overall process
because iridium-catalyzed allylic substitution of the
branched ester leads to racemic product at full conver-
sion. Second, the oxidant must be completely consumed
in the first step. Remaining oxidant would deactivate the
Reactions conducted with the catalysts formed from
Pd(OAc)2 and derivatives of diazafluorenone ligands L6,
L7 and L8 gave lower yields of 2a than those conducted
with L5. Thus, catalyst derived from Pd(OAc)2 and 4,5-
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diazafluoreneone was used for further studies on the a method to control the diastereoselectivity of the amina-
1
2
3
4
development of asymmetric allylic C-H functionalization
tion of chiral, non-racemic alkenes. For example, the
chiral alkene (ee > 99%) containing a MOM-protected
alcohol (MOM=methoxy methyl) reacted to form the
substitution product 3p in 57% yield with 18:1 diastere-
oselectivity.
with tert-butyl perbenzoate as oxidant.
Chart 1. Effect of Ligands on Palladium Catalyzed ben-
zoylation of Allylic C-H Bondsa
O
5
O
Pd(OAc)2
O
6
7
8
9
Because the oxidation and functionalization steps occur
sequentially, the process occurs with a range of nucleo-
philes that would be incompatible with direct oxidative
functionalization reactions. The data in Chart 2 reveal
the broad scope of this asymmetric allylic functionaliza-
tion process with a variety of nitrogen, oxygen, carbon
and sulfur nucleophiles. For example, the protocol we
developed occurred with alkylamines and nitrogen het-
erocycles to form the allylamine and N-allyl heteroarene
derivatives 3q-3t in good isolated yields with excellent
enantioselectivity. Potassium phthalimide also reacted to
give the corresponding amination product 3u in similar
yield to that obtained with the other nitrogen nucleo-
philes. In addition, sodium dimethyl malonate (carbon-),
sodium phenoxide (oxygen-) and sodium p-
toluenesulfinate (sulfur) nucleophiles reacted to form
products 3v-3x containing new C-C, C-O and C-S bonds
at the stereogenic center.
O
ligand
65 o
O
+
C7H15
C
C7H15
2a
O
O
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tBu
tBu
N
N
N
N
N
N
N
N
N
N
L1, 7%
L2, 5%
L3, 0%
C6H13
L4, 11%
Ph
C6H13
O
N
N
N
N
N
N
N
N
L5, 70%, 15:1
L6, 23%, 11:1
L7, 15%, 12:1
L8, 25%, 10:1
a
Conditions: 5.0 mol% Pd(OAc)2, 5.5 mol% ligand, 1-
decene (0.6 mmol, 2.0 equiv.) and tert-butyl-perbenzoate
(0.3 mmol, 1.0 equiv.), 65 °C. The yields and linear to
branched ratios were determined by GC with dodecane as
internal standard.
C. Short synthesis of biologically active mole-
cules. By exploiting this asymmetric allylic functionali-
zation, we were able to conduct short, asymmetric syn-
theses of two biologically active compounds (-)-(R)-
vigabatrin and (-)-(R)-angustureine from simple com-
mercially available alkenes, in part to assign the absolute
configuration of the functionalization products.
B. Compatibility and scope of the strategy for asymmet-
ric allylic C-H bond functionalization and iridium-
catalyzed amination reactions. If the iridium catalyzed
allylic amination would occur directly on the material
generated from the allylic oxidation, then a simple pro-
cess involving first adding the palladium catalyst and
oxidant, followed by adding the iridium catalyst and nu-
cleophile, would lead to a range of allylic functionaliza-
tion products. To consume the benzoic acid product from
the substitution reactions with neutral nucleophiles, a
base is needed. Thus, we added K3PO4 as base with these
nucleophiles. Under these conditions, the reaction with
aniline as nucleophile resulted in complete conversion of
2a. The final amination product (3a) was isolated in 53%
overall yield for the two steps and 89% ee (Chart 2). The
scope of alkenes that undergo the allylic amination se-
quence is revealed by the data in Chart 2. In addition to
the linear 1-decene, branched terminal alkenes under-
went the asymmetric allylic amination in good yields and
excellent enantioselectivity (3b-3d). The reaction se-
quence was tolerant of a broad range of functional
groups that could undergo further derivatization. Al-
kenes containing ketal and chloride functional groups
were well tolerated, affording the corresponding aro-
matic amines 3e and 3f, respectively. Alkenes containing
silyl ether and benzoate functional groups reacted to af-
ford 1,2 amino alcohol derivatives 3g and 3h respectively.
The C-H bond functionalization sequence was also suita-
ble for the synthesis of the chiral 1,2 diamine 3i. Func-
tional groups containing weakly acidic protons, such as
sulfones, esters and amides, were also tolerated, and the
sequence provided functionalized alkenes 3j-3l. Finally,
allylarenes bearing electron-donating or electron-
withdrawing groups formed the corresponding amines in
good yields with excellent regioselectivity and stereose-
lectivity (3m-3o).
Scheme 1. Synthesis of biologically active molecules
NH3Cl
O
O
N
C-H ftna
b
c
HO2C
50%, er 95:5
MeO2C
3
MeO2C
4
55%, er 95:5
(−)-(R)-Vigabatrin
I
NH
C-H ftna
ref 9a
C4H9
C4H9
N
57%, er 94:6
(−)-(R)-Angustureine
o
a C-H ftn: Pd(OAc)2/L5 (5 mol%), 65 C, 8 h; 1 (5 mol%),
K3PO4 (1.5 equiv), nucleophile (2 equiv); b 10 M NaOH, 12 h;
c NaBH4, H2O:EtOH.
(-)-(R)-vigabatrin was synthesized from unsaturated
ester 4 using the (R, R, R)-1 enantiomer of the catalyst,
followed by basic workup and removal of phthalimide
protecting group (Scheme 1). Similarly, (-)-(R)-
angustureine was synthesized from 1-octene using 2-
iodoaniline as nucleophile and (R, R, R)-1 as catalyst.
The N-allylamine product was subjected to the previous-
ly reported sequence of hydroboration, intramolecular
Suzuki-Miyaura cross-coupling, and alkylation to pro-
vide (-)-angustureine.8a The relative configuration of the
product and iridium catalyst shows that the allylic sub-
stitution step of the functionalization sequence occurs
with the same stereoselectivity as previously reported
substitutions of allylic carbonates.7c,15
Because the iridium catalyst controls the configuration of
the new stereocenter, 7e,8 the allylic substitution provides
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Previously reported mechanistic studies from our group onto the allyl ligand from the side opposite to the metal
on iridium catalyzed allylic substitution reactions7d,16
have shown that the reaction occurs by a highly diastere-
oselective oxidative addition of an allylic benzoate to an
iridium complex 1, followed by attack of the nucleophile
for all of the nucleophiles in the current study. This nu-
cleophilic attack is a faster than the η3-η1-η3 isomeriza-
tion of the allyl complex.
1
2
3
4
5
6
7
8
Chart 2. Scope of the Alkenes and nucleophiles in the Allylic C-H bond Functionalizationa
Pd(OAc)2
(5 mol%)
PhNH2
K3PO4
OBz
L5 (5.5 mol%)
NHPh
BzO2tBu
+
R
R
65 oC, 6-8 h
1 (5 mol%)
2a-2o
R
1-2 equiv
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60
NHPh
NHPh
NHPh
NHPh
NHPh
NHPh
O
O
Ph
Cl
C7H15
3a, 53%
3d, 70%c
ee 96%
3b, 52%b
ee 90%
3c, 68%
ee 92%
3e, 68%
ee 95%
3f, 60%
ee 88%
ee 89%
O
NHPh
NHPh
O
S
NHPh
NHPh
NHPh
O
N
TBSO
BzO
MeO2C
Tol
3j, 53%c,d
ee 89%
O
3i, 59%c,d,f
ee 90%
3g, 65%
ee 97%
3h, 60%
ee 90%
3k, 58%
ee 88%
O
NHBn
NHPh
NHPh
NHPh
Ph
O
NHPh
O
HN
PMBO
3p, 57%, 18:1d,e
(Et)2N
7
MeO
F
3q, 60%d,e
ee 90%
3l, 52%c,d
ee 87%
3m, 76%d,e
ee 93%
3n, 81%d,e
ee 90%
3o, 77%d,e
ee 95%
S
N
O
O
EtO2C
PMBO
CO2Et
Tol
S
OPh
N
O
NHBn
O
HN
N
TBSO
TBSO
TBSO
TBSO
TBSO
TBSO
3t, 55%d,e,g
ee 90%
3x, 55%d,e,g
ee 90%
3r, 51%
ee 89%
3s, 55%d,e
ee 90%
3u, 57%d,e
ee 85%
3v, 50%d,e
ee 88%
3w, 50%d,e
ee 90%
a
See supporting information for reaction conditions; yields are for isolated products; ee was measured by HPLC, dr is
measured by 1H-NMR spectroscopy (500 MHz). b 3.0 equiv. of alkene was used. c 1.5 equiv. of alkene was used. d The oxidation
step was conducted at 80 oC for 2.5 h. e 1.0 equiv. of alkene was used. f CH2Cl2 was used as solvent in the oxidation step. g Reac-
tion mixture was filtered on silica after palladium catalyzed oxidation step.
D. Iterative C-H bond functionalization: Synthe-
sis of (1,n)-functionalized chiral fragments. To
extend the utility of this process to the introduction of
multiple functional groups with control of absolute and
relative configurations, we developed an iterative se-
quence of C-H bond functionalizations and homologa-
tions to prepare (1,n)-functionalized alkenes (Figure 1,
C). In this sequence, the composition of the new func-
tionality and the configuration of each new stereogenic
center depends on the reagent and configuration of the
catalyst, respectively. Various strategies have been re-
ported for creating (1,2), (1,3) or (1,4) functionalization
in molecules. Prominent examples include addition reac-
tions to alkenes, such as dihydroxylation or halogenation
reactions (1,2-functionalization), aldol reactions, 1,3 di-
polar additions (1,3-functionalization), and metal-
To demonstrate this potential, we converted the simple
PMB-protected but-3-en-1-ol (5) to a wide range of tri-
functional products with controlled functionality and
configuration. These results are summarized in Chart 3.
Mono-functionalized compounds derived from 5 were
prepared by the C-H bond functionalization sequence
described above with tert-butyldimethylsilanol, potassi-
um phthalimide, sodium dimethyl malonate and sodium
4-methylbenzenesulfinate, as the nucleophiles to form
products 3aa-3dd. These products were homologated to
the (1,n,m) alkene intermediates 6a-6g by hydrobora-
tion with 9-BBN followed by Suzuki coupling with n-
bromoalk-1-enes, in excellent yields.
Various trifunctional building blocks (Chart 3, 7a-7j)
containing a (1,3)-, (1,5)-, (1,7)-, and (1,8)-relationship
between two stereogenic centers were then formed from
alkenes (6a-6g) in good yield. The diastereoselectivities
of these reactions were high, and the relative configura-
tions were controlled by the catalyst. For example, both
diastereomers of a silyl protected enantioenriched amino
alcohol (7a and 7b) were prepared using catalyst 1 and
the enantiomer of 1 respectively, with dr values similar
to the er values of the reactions of achiral alkenes.8b,8c
catalyzed
1,4 conjugate
addition
reactions (1,4-
functionalization), respectively. However, no method has
been reported to prepare (1,n)-functionalized molecules
with high diastereoselectivity and enantioselectivity con-
taining a range of installed functional groups and pro-
grammed configurations by C-H bond functionalization.
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The chiral alkene prepared from malonate addition was were prepared with similarly high diastereoselectivity (7f
1
2
3
4
further functionalized with the aromatic amine in high
diastereoselectivity (7d). A chiral 1,3 diamine containing
different substituents at nitrogen also formed with high
diastereoselectivity (7e). The 1,3 amino-sulfones, which
could serve as a precursor to amino-sulfone ligands,
and 7g). Alkenes (6e-6g) provided (1,4), (1,5), and (1,6)-
functionalized fragments 7h-7j in excellent diastereo-
and enantioselectivity simply by choosing the appropri-
ate chain length of the 1-bromoalkene.
5
6
7
Chart 3. Iterative C-H Functionalization: Synthesis of (1,n)-Functionalized Alkenes
8
9
10
11
12
13
14
15
16
17
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20
21
22
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O
O
NHPh
Tol
N
O
O
O
N
O
S
PMBO
PMBO
7e, 67%, 18:1b
7f, 53%, 13:1c
RHN
RHN
O
TBSO
N
O
PMBO
TBSO
PMBO
PMBO
6b, 81%a
7i, 65%, 15:1
7h, 63%, 15:1
OTBS
PMBO
TBSO
PMBO
O
3
N
6e, 68%c
O
6f, 63%c
PMBO
TBSO
PMBO
NHPh
3bb, 62%, 88%ee
7a, 68%, 20:1b
OTBS
PMBO
Si
O
PMBO
PMBO
OBz
6a, 85%a
5
PMBO
TBSO
PMBO
NHPh
3aa, 70%, 87%eed
7b, 65%, 17:1c
Me
O
S
CO2Me
MeO2C
PMBO
3cc, 50%, 88%ee
O
O
N
TBSO
PMBO
O
OPMB
OTBS
PMBO
3dd, 53%, 90%eed
7c, 54%, 16:1b
Tol
MeO2C
PMBO
CO2Me
O
S
O
Tol=
R=
6g, 65%c
PMBO
6d, 85%b
6c, 83%a
OMe
OPMB
O
O
OTBS
7j, 66%, 14:1
CO2Me
NHR
Tol
S
NHR
MeO2C
PMBO
PMBO
7g, 65%, 9:1
7d, 65%, 15:1
RHN
a
1
For reaction conditions see supporting information; Overall yields of isolated compounds; dr is measured by H-NMR
spectroscopy (500 MHz). b 1 was used as catalyst in second step. c enantiomer of 1 was used as catalyst in second step. d reac-
tion mixture was filtered over silica prior to iridium catalyzed substitution step.
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This iterative sequence also was followed to prepare chi-
C-H bond oxidation by P450 enzymes18 creates a func-
1
2
3
4
5
6
7
8
ral fragment 8 that was used in the synthesis of spongi-
statin (Scheme 2).17 The 1,3,4 triol derivative 9 was pre-
pared from 5 in excellent diastereo and enantioselectivi-
ty (53%, 15:1, 99% ee). Treatment of 9 with 9-BBN, fol-
lowed by oxidation formed alcohol 10 in 95% yield. By
this iterative method we installed three different protect-
ing groups in triol 9, thus providing selective access to
each hydroxyl functional group for further transfor-
mations. Moreover, the catalyst controlled the configura-
tion of each stereogenic center, thus allowing access to
all possible stereoisomers of this fragment simply by
changing the choice of the enantiomer of the catalyst
without changing the protocol or the starting substrate.
tional group that can be converted to a halogen or can be
used for subsequent Mitsunobu reactions, but the prod-
ucts are formed in a medium that is incompatible with
the second step. The development of additional C-H
bond functionalization reactions that form common syn-
thetic intermediates will be the focus of future studies in
our laboratory.
Representative Procedure for allylic C-H functionaliza-
tion.
9
To a 4 ml vial containing a magnetic stirbar, Pd(OAc)2
(3.3 mg, 5 mol%) and L5 (3 mg, 5.5 mol%) were added,
followed by 25.0 µL of DCM. The reaction mixture was
then stirred for 15 min at room temperature. The solvent
was then removed under vacuum, and dodacane (25.0
µL) and 1-decene (0.6 or 0.3 mmol) were added followed
by tert-butyl perbenzoate (58.27 mg, 0.3 mmol). The vial
was sealed with a cap containing a PTFE septum and
10
11
12
13
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15
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17
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40
41
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Scheme 2. Synthesis of chiral fragment of
spongistatin
o
1
O
O
then heated at 65 C for 8 h (monitored by H-NMR for
consumption of oxidant). The vial was kept at high vacu-
um for 3-4 h to remove volatile materials and brought
into the glove box. The reaction mixture was dissolved in
0.5 ml of dry toluene. To the resulting solution K3PO4
(95.5 mg, 0.45 mmol) and the aniline (2.0 mmol) were
added, followed by a solution of iridium catalyst 1 (13.0
mg, 5 mol%) in 0.5 ml of dry toluene. The resulting he
reaction mixture was stirred at 25 oC until the linear ben-
zoyl ester was fully consumed, as determined by GC or
TLC. The crude reaction mixture was then treated with 2
ml of EtOAc and extracted with brine. The solvent was
evaporated from the organic layer, and the product was
purified by flash column chromatography on silica gel
eluting with a mixture of hexane and ethyl acetate (99:1).
8-steps
PMBO
OTBS
CH2OH
EtO2C
39%
overall yield
8
OTBS
C-H ftna
PMBO
vinylationb
PMBO
PMBO
PMBO
6a, 85%
3aa, 70%, 87% ee
5
TBSO
OBn
TBSO
OBn
C-H ftna
c
6a
PMBO
CH2OH
10, 95%
9, 53%, 15:1
o
a C-H ftn: Pd(OAc)2/L5 (5 mol%), 65 C, 8 h; 1 (5 mol%),
K3PO4, (1.5 equiv.), 1-phenyl-propyne (10 mol%), nucleo-
b
phile (2 equiv.);
Vinylation: 9-BBN, 10 h, 25 oC;
Pd(dppf)Cl2 (5 mol%), vinyl bromide (3 equiv.), DMF, 50 oC
9-BBN (1.3 equiv., 0.5 M solution in THF), 25 C, 10 h;
c
o
NaBO3, H2O, 24 h.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures and analytical data. This material
is available free of charge via the internet at
http://pubs.acs.org
Conclusion.
In conclusion, a new approach to asymmetric C-H bond
functionalization of allylic C-H bonds in unactivated
terminal alkenes to install a broad range of functional
groups has been developed. This process comprises a
one-pot sequence involving a palladium catalyzed allylic
C-H oxidation system with a perester as both reagent
and oxidant, thereby occurring under neutral conditions,
and an iridium-catalyzed allylic substitution of the prod-
uct that occurs with broad scope and programmed stere-
ochemistry to form the branched, chiral products con-
taining new C-C, C-N, C-O and C-S bonds in high yield
with excellent enantioselectivity (ee up to 97%). An itera-
tive C-H bond functionalization is also reported that can
be used to form a wide range of enantioenriched (1,n)-
functionalized products, including used in the synthesis
of spongistatin, (-)-(R)-vigabatrin and (-)-(R)-
angustureine, from trivial alkene starting materials.
AUTHOR INFORMATION
Corresponding Author
jhartwig@berkeley.edu
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank the NIH (GM-55382 to JFH) and the Swiss Na-
tional Science Foundation (SNSF) (PBGEP2_139830 to AS)
for financial support and Johnson-Matthey for Pd(OAc)2
and [Ir(COD)Cl]2.
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TOC Graphic
1
2
3
Nu1 Nu2
One-pot C-H Bond
Functionalization
Nu1
1. Homologation
R
2. C-H Bond
Functionalization
Pd+ox/Ir + Nu
R
R
n
4
5
up to 18:1 d.r.
up to 99% ee
50-81% yield
up to 97% ee
6
Nu1 and Nu2 = C, O, N, or S nucleophile
7
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