Enantioselective iridium-catalyzed allylic alkylation of racemic branched alkyl-substituted allylic acetates with malonates

Article abstract of DOI:10.1021/acs.orglett.0c04309

The regio- and enantioselective allylic substitution of branched alkyl-substituted allylic acetates employing malonates has been achieved through a process that calls for Krische's πallyliridium C,O-benzoate catalyst. The protocol reported herein can be applied to a diverse set of branched alkyl substrates that are generally not well tolerated in the other two types of Ir-catalyzed allylation.

Full text of DOI:10.1021/acs.orglett.0c04309

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Letter
Enantioselective Iridium-Catalyzed Allylic Alkylation of Racemic
Branched Alkyl-Substituted Allylic Acetates with Malonates
Tian-Yuan Zhang,§ Yi Deng,§ Kun Wei, and Yu-Rong Yang*
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ABSTRACT: The regio- and enantioselective allylic substitution
of branched alkyl-substituted allylic acetates employing malonates
has been achieved through a process that calls for Krische’s π-
allyliridium C,O-benzoate catalyst. The protocol reported herein
can be applied to a diverse set of branched alkyl substrates that are
generally not well tolerated in the other two types of Ir-catalyzed
allylation.
ince 1997, much research has been oriented toward the
development of iridium-catalyzed asymmetric allylic
S
substitution reactions and the use of chiral adducts as key
intermediates for the synthesis of value-added molecules or
complex natural products. Pursuant to the original inves-
tigations1 of Takeuchi and Helmchen, respectively, in 1997
and comprehensive studies by Helmchen, Hartwig, Carreira,
You, Alexakis, Stoltz, and many others over the ensuing years, a
broad range of nucleophiles and reaction modes can now be
accommodated in highly regio- and enantioselective allylic
substitution.2
During the last two decades, two main categories of the
iridium-catalyzed allylic substitution have arisen (Figure 1).2e
In type-I reactions, linear allylic esters are frequently used as
substrates under basic conditions. In type-II reactions, mostly
developed by Carreira,3 environmentally friendly branched
allylic alcohols can be employed under acidic conditions.
These important methods overcome a limitation associated
with Pd-catalyzed variants, which have the propensity to
promote nucleophilic attack at the less substituted allylic
terminus, leading to achiral linear products.4 Nonetheless, it
has become evident that aryl-substituted allylic substrates are
more commonly used than alkyl-substituted substrates in these
two types of asymmetric iridium-catalyzed allylic substitution.
For instance, although widely studied, sodium malonates have
seldom been seen in the branched alkyl-substituted allylic
substrates under type-I conditions due to the low enantiose-
lectivity.5 Furthermore, according to our recent report,6 the
analogous substitution of branched alkyl alcohols with
malonates using type-II catalysts was not successful because
of the disappointedly low yield (Figure 1).7 In general, the
branched substrates are much easier to prepare than the linear
ones, and there have been many reports of aryl-substituted
branched substrates. Therefore, developing general and
Figure 1. Three types of iridium catalysts and their applications in the
allylic alkylation of branched alkyl-substituted allylic derivatives with
malonates.
practical methodologies for the Ir-catalyzed allylic substitution
of branched alkyl-substituted substrates with various nucleo-
philes is an important task. Currently, this is still a continuing
challenge, even for the classic nucleophiles such as malonates.
Received: December 30, 2020
Published: January 22, 2021
https://dx.doi.org/10.1021/acs.orglett.0c04309
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1086−1089
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a
In 2018 and 2019, Krische and coauthors at Genentech
made a breakthrough in this regard, reporting the interesting
Ir-catalyzed asymmetric amination of branched alkyl-substi-
tuted allylic acetates.8 In contrast with the above two iridium
catalyst systems, the authors applied π-allyliridium C,O-
benzoates as the catalysts, which are neutral, stable to air,
water, and silica gel column chromatography, and previously
well known by the Krische group to catalyze allyl-acetate-
mediated carbonyl allylation.9 This new category of iridium
catalysts, named type-III catalysts by Krische et al., can
overcome the weakness in the substrate scope for allylic
amination for which aryl or heteroaryl groups were normally
needed. Inspired by Krische’s encouraging results, we
wondered if a carbon nucleophile could be employed in a
similar catalyst system. If so, it would be an ideal solution to
the longstanding problem discussed in the preceding para-
graph. Reported herein are our efforts through which racemic
branched alkyl-substituted allylic acetates have been found to
react with malonates catalyzed by Krische’s catalysts for the
first time, giving the chiral adducts in high yields with high
regio- and enantioselectivities.
Table 1. Optimization of Reaction Parameters
b
c
entry
R
catalyst
base
yield (%)
er
1
2
3
4
5
6
7
8
Ac
Boc
PO(OEt)2
cat-1
cat-1
cat-1
cat-1
cat-2
cat-3
cat-4
cat-5
cat-1
cat-1
cat-1
cat-1
cat-1
cat-1
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
94
91
89
20
58
36
85
94
97:3
91:9
95:5
96:4
54:46
88:12
88:12
89:11
94:6
97:3
92:8
N.D.
N.D.
96:4
Bz
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
9
32
39
65
10
11
12
13
LiOt-Bu
NaOAc
KOAc
N.R.
N.R.
90
d
14
KOAc
Our studies commenced with an exploration of the efficacy
of the leaving groups, bases, and catalysts prepared with
different ligands10 on the yield and the enantioselectivity of the
model reaction between allylic esters 1a−d and dimethyl
malonate (2). As shown in Table 1, with (R)-Ir-Tol-BINAP as
the iridium catalyst (5 mol %) in the presence of Cs2CO3 as
the base additive and DME as the solvent, the tested acetate 1a
underwent a clean reaction at 50 °C with dimethyl malonate to
give chiral adduct 3a in 94% yield with 97:3 er (entry 1).
Interestingly, an undesired linear product was not observed.
Before achieving the above optimized conditions, we had
conducted an in-depth survey of the reaction parameters. (For
the detailed optimization, see the SI.) Changing acetate to
other better leaving groups such as carbonate, phosphate, and
benzoate led to lower yields (entries 2−4). To examine the
effects of the catalysts, four more ligands were used to prepare
catalysts 2−5. To our knowledge, catalyst 2 is unprece-
dented.11 When the newly designed (R)-Ir-SDP was employed,
surprisingly, no enantioselectivity was observed (entry 5).
When (R)-Ir-H8-BINAP, (R)-Ir-SEGPHOS, and (R)-Ir-DM-
BINAP were used, less satisfactory results compared with those
of (R)-Ir-Tol-BINAP were obtained with respect to the yield
and enantioselectivity (entries 6−8). Other bases such as
K2CO3, K3PO4, and LiOt-Bu proved to be less efficient in
terms of the lower yields. If weaker bases were used, then no
reaction was observed (entries 9−13). To illustrate the utility
of this methodology, the reaction was scaled up from 0.1 to 1.0
mmol, and the outcome was still excellent (entry 14). The
absolute configuration of 3a was assigned through a
comparison of its optical rotation to the reported value.5b
Having found reaction conditions that resulted in an
excellent outcome, we set out to investigate the scope of the
electrophilic component. As shown in Scheme 1, a diverse
array of alkyl-substituted allylic acetates was examined. The
branched allylic acetates incorporating α-benzyl, α-methyl, and
α-propyl moieties, respectively, were efficiently converted into
chiral malonates 3b−3d. Those substrates containing cyclo-
alkyl substitutes were tolerated, affording adducts 3e−3g in
high yields with high enantioselectivities. Other functionalities
such as PMB ether, TBDPS ether, Ts-protected amine, and
alkene can also be included in the alkyl chain (3h−3l). When
chiral allylic acetate made from (S)-citronellal was attacked by
a
b
Reactions performed on a 0.1 mmol scale. Isolated yields.
Determined by chiral HPLC analysis. Reaction conducted on a 1.0
c
d
mmol scale.
dibenzyl malonate promoted by catalysts (R)-Ir-Tol-BINAP
and (S)-Ir-Tol-BINAP, respectively, both of their yields and
diastereoselectivities were high enough to efficiently provide
diastereomers 3m and 3n. Finally, a complex steroid allylic
acetate prepared from lithocholic acid was tested, and the
outcome was very satisfactory (3o). In all cases studied, the
undesired linear constitutional isomers were not formed. The
absolute stereochemistry of adducts 3b−3o was assigned by
analogy to adduct 3a. It is noteworthy that the π-allyl
enantiofacial selectivity of this allylic alkylation is the same as
that observed in the corresponding allylic aminations.8
In summary, an Ir-catalyzed highly regio- and enantiose-
lective allylic substitution of branched allylic acetates bearing
alkyl groups with malonates has been developed. The readily
available π-allyliridium C,O-benzoates, which are well known
to catalyze nucleophilic carbonyl allylation and have only
recently been discovered by Krische and coworkers to catalyze
electrophilic allylic amination, have been proven to catalyze
allylic substitution on branched alkyl acetate with malonates,
asymmetrically forming a new C−C bond.12,13 We believe that
this method will broaden access to diverse chiral carbogenic
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Letter
a
https://pubs.acs.org/10.1021/acs.orglett.0c04309
Scheme 1. Electrophile Substrate Scope
Author Contributions
§T.-Y.Z. and Y.D. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the Key Research Program
of the Frontier Sciences of the CAS (grant no. QYZDB-SSW-
SMC026) and the National Natural Science Foundation of
China (21971249).
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■
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c04309.
Full characterization, spectral data, HPLC analysis, and
experimental procedures (PDF)
(6) Meng, C.-Y.; Liang, X.; Wei, K.; Yang, Y.-R. Org. Lett. 2019, 21,
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AUTHOR INFORMATION
Corresponding Author
■
Yu-Rong Yang − State Key Laboratory of Phytochemistry and
Plant Resources in West China, Kunming Institute of Botany,
Chinese Academy of Sciences, Kunming 650201, China;
orcid.org/0000-0001-6874-109X; Email: yangyurong@
mail.kib.ac.cn
Authors
Tian-Yuan Zhang − State Key Laboratory of Phytochemistry
and Plant Resources in West China, Kunming Institute of
Botany, Chinese Academy of Sciences, Kunming 650201,
China; University of Chinese Academy of Sciences, Beijing
100049, China
Yi Deng − State Key Laboratory of Phytochemistry and Plant
Resources in West China, Kunming Institute of Botany,
Chinese Academy of Sciences, Kunming 650201, China;
University of Chinese Academy of Sciences, Beijing 100049,
China
(11) Kim, I. S.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc. 2008,
130, 14891.
(12) Currently, one limitation of this method is the modest
enantiopurity for the aryl-substituted branched substrate, albeit in
high yield; see the SI.
(13) During the revisions, we briefly conducted more experiments
for this method using a ketoester, diketone, and substituted malonate
Kun Wei − State Key Laboratory of Phytochemistry and Plant
Resources in West China, Kunming Institute of Botany,
Chinese Academy of Sciences, Kunming 650201, China
Complete contact information is available at:
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Letter
as the nucleophiles. Except for the diketone, namely, acetylacetone,
with no reaction, the reactions gave good results; see the SI.
(14) For selected examples of the strategic utilization of the Ir-
catalyzed asymmetric allylation in total synthesis by us, see: (a) Jiang,
S.-Z.; Zeng, X.-Y.; Liang, X.; Lei, T.; Wei, K.; Yang, Y.-R. Angew.
Chem., Int. Ed. 2016, 55, 4044. (b) Liang, X.; Jiang, S.-Z.; Wei, K.;
Yang, Y.-R. J. Am. Chem. Soc. 2016, 138, 2560. (c) Liang, X.; Zhang,
T.-Y.; Zeng, X.-Y.; Zheng, Y.; Wei, K.; Yang, Y.-R. J. Am. Chem. Soc.
2017, 139, 3364. (d) Liang, X.; Zhang, T.-Y.; Meng, C.-Y.; Li, X.-D.;
Wei, K.; Yang, Y.-R. Org. Lett. 2018, 20, 4575.
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