Asymmetric Linear-Selective Hydroformylation of 1,1-Dialkyl Olefins Assisted by a Steric-Auxiliary Strategy

Article abstract of DOI:10.1021/acs.orglett.0c01550

Asymmetric hydroformylation of 1,2-dialkyl olefins was reported. In order to increase the enantiomeric induction, steric auxiliary sulfonyl groups were introduced. Using a Rh/Yanphos complex as catalyst, chiral aldehydes were obtained with high enantiosel

Full text of DOI:10.1021/acs.orglett.0c01550

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Letter
Asymmetric Linear-Selective Hydroformylation of 1,1-Dialkyl Olefins
Assisted by a Steric-Auxiliary Strategy
Dequan Zhang, Cai You, Xiuxiu Li, Jialin Wen,* and Xumu Zhang*
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ABSTRACT: Asymmetric hydroformylation of 1,2-dialkyl olefins was reported. In order to increase the enantiomeric induction,
steric auxiliary sulfonyl groups were introduced. Using a Rh/Yanphos complex as catalyst, chiral aldehydes were obtained with high
enantioselectivities under mild pressure. The easily removable auxiliary made this method a powerful tool in the preparation of
important enantiopure building blocks.
ince hydroformylation reaction was accidentally discovered
resulting in a relatively poor chiral environment due to a long
Sby Roelen in 1938, this chemical transformation has distance for chiral induction; and (3) multiple reaction sites
become one of the most important chemical processes.1,2 Each
created by carbon monoxide dissociation. In addition, the
steric properties of the two C1 substituents are not large
enough to discriminate, which has been a notorious problem
for other asymmetric transformations such as hydrogena-
tion16,17 and epoxidation.18
year, millions of tons of oxo products are produced in the
world. The value-added products, aldehydes, are extremely
importance intermediates for chemical industries.3 The
enantioselective version (asymmetric hydroformylation,
AHF) has been regarded as the most straightforward approach
to obtain chiral aldehydes from olefins.4 However, the
development of AHF has proceeded much slower compared
to other stereoselective transformation reactions.5 It is
challenging, since chemists must balance between chemo-
selectivity, regioselectivity, and enantioselectivity in a single
reaction.6,7 One of the key factors for achieving these
selectivities is believed to be the chiral phosphorus-containing
ligand.8,9 Unfortunately, the development of ligands for AHF
has been relatively slow compared to ligands for asymmetric
hydrogenation: only a few chiral ligands, such as BINA-
PHOS10,11 and BDP,12,13 have been successfully applied in
AHF with high enantioselectivity (>90% ee).
1,1-Disubstituted olefins are an interesting type of substrate
for AHF. The regioselectivity is roughly a result of substrate
control.14 Apart from the cases with electron-withdrawing
substituents, 1,1-disubstituted olefins normally undergo anti-
Markovnikov addition which forms linear aldehydes (Keule-
mans’ empirical rule,15 a quaternary carbon is avoided). A β-
chiral center is therefore generated in this reaction. From our
perspective, the challenges of AHF are attributed to such
factors as (1) lack of secondary interaction to facilitate
enantiomeric control, leaving steric effect alone being
responsible; (2) a five-coordinate trigonal bipyramid geometry
Gratefully, our group has developed a family of phosphine-
amidophosphite chiral bidentate ligands (Yanphos19,20) which
could be successfully applied in AHF of unfunctionalized 1,1-
disubstituted olefins.21−23 After coordination to Yanphos with
an equatorial−axial pattern, the rhodium reactive species could
form an ideal chiral pocket for 1,1-disubstituted olefins14,22
(for the philosophy of ligand design, see Figure 1). Although
aryl-alkyl olefins could be hydroformylated with high
enantioselectivities, dialkyl substrates are still an unsolved
challenge.24−27 We envisioned that an easily removed auxiliary
might be a practical compromise for the AHF of 1,1-dialkyl
olefins. The steric auxiliary should meet such criteria as (1)
readily available for synthesis, (2) easy to remove after
reaction, and (3) being chemically inert. We rationalized that
sulfonyl groups might the ideal auxiliary,28 as 1.3-benzodithiole
tetraoxide plays a role as an important synthon in organic
synthesis29 (Scheme 1).
Received: May 6, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01550
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
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Letter
Scheme 2. Reaction Scope for AHF of 1,1-Dialkyl Olefins
Figure 1. Philosophy in ligand design and analysis for enantio-
induction.
Scheme 1. Rh-Catalyzed AHF of 1,1-Disubstituted Olefins
Our study commenced by optimization of the reaction
conditions for AHF of disulfonyl substrate 1a. N-Bn-Yanphos
showed superiority in the screening of chiral ligands (see
Supporting Information): other commonly used phosphorus-
containing bidentate ligands faded in either reactivity or
enantioselectivity. Reducing the reaction temperature led to a
decrease in yield but an increase in ee value (Table 1, entries 2
not bring significant changes in either yield or enantioselec-
tivity. While heteroatoms (2g, 2n) did not influence the
outcomes of the hydroformylation reaction, many types of
functionalities, such as silyl group (2m), ether (2s), ester (2o),
and amine (2p), were compatible with the catalytic system. A
coordinating sulfur atom did not make the reaction sluggish
(2t). In addition, trisubstituted alkene did not undergo
hydroformylation or hydrogenation under the reaction
conditions (2h). Switching the other alkyl group from methyl
to a longer alkyl group showed limited differences (2q, 2r).
In order to demonstrate the role of steric auxiliary in the
enantiomeric induction in the Rh/Yanphos catalyzed AHF, a
control experiment was conducted (Scheme 3). Without the
Table 1. Condition Optimization for AHF of Dialkyl Olefin
a
1a
entry
T (°C)
CO/H2 (atm)
t (h)
conv.
yield
ee
1
2
3
4
5
6
100
90
80
80
80
80
80
80
5/5
5/5
5/5
2.5/2.5
2.5/2.5
2.5/2.5
2.5/2.5
2.5/2.5
48
48
48
48
48
72
72
120
48%
42%
21%
43%
76%
91%
93%
N.D.
48%
42%
20%
41%
76%
90%
93%
80%
84%
88%
90%
90%
90%
90%
91%
90%
b
b
c
7
8
Scheme 3. Control Experiment To Demonstrate the Role of
Steric Auxiliary
d
a
Conditions: 1a/Rh(acac)(CO)2/ligand = 50/1/2, [1a] = 0.25 M, 1
mL of toluene; the conversion was analyzed by 1H NMR of the crude
product; ee was determined by HPLC on a chiral stationary phase.
b
c
d
[1a] = 2.0 M. [1a] = 3.0 M. 1.2 mmol of 1a, 1% Rh catalyst
loading; N.D. = not determined.
and 3). Lowering the pressure of synthetic gas promoted the
production of hydroformylation product. Both elongating the
reaction time and increasing the concentration of the reaction
mixture resulted in a higher yield. To our delight, no
hydrogenation product or branched aldehyde was observed
in the crude products. Disulfonyl substrate 1a was hydro-
formylated at 80 °C with a yield of 93% and 91% ee. When
elongating the reaction time, the catalyst loading could be
lowered to 1% with no significant change in enantioselectivity
(entry 8).
With the optimized conditions, the reaction scope was
investigated (Scheme 2). With the disulfonyl auxiliary, dialkyl
olefins could undergo hydroformylation smoothly with high
enantioselectivities. The size of alkyl groups (blue color) did
two sulfonyl groups, the ee value for 1k was dramatically
decreased from 97% to 62% (1u). A rough calculation
indicated that the auxiliaries create an extra energy difference
of ∼1.6 kcal/mol30 in the two diastereomeric pathways which
renders a pair of enantiomers.
In order to demonstrate the potential application in the
construction of chiral building blocks, various elaborations on
the chiral disulfonyl chiral aldehydes were conducted. The
auxiliary survived in chemical transformations such as
reduction, oxidation, and reductive amination (Scheme 4).
The auxiliary sulfonyl group could be easily removed with an
B
https://dx.doi.org/10.1021/acs.orglett.0c01550
Org. Lett. XXXX, XXX, XXX−XXX

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Technology, Shenzhen 518055, China; orcid.org/0000-
0001-5700-0608; Email: zhangxm@sustech.edu.cn
Scheme 4. Elaboration of the AHF Product to Prepared
Chiral Building Blocks
Authors
Dequan Zhang − Shenzhen Grubbs Institute and Department of
Chemistry, Shenzhen Key Laboratory of Small Molecule Drug
Discovery and Synthesis, Southern University of Science and
Technology, Shenzhen 518055, China
Cai You − Shenzhen Grubbs Institute and Department of
Chemistry, Shenzhen Key Laboratory of Small Molecule Drug
Discovery and Synthesis, Southern University of Science and
Technology, Shenzhen 518055, China
Xiuxiu Li − Shenzhen Grubbs Institute and Department of
Chemistry, Shenzhen Key Laboratory of Small Molecule Drug
Discovery and Synthesis, Southern University of Science and
Technology, Shenzhen 518055, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01550
excess amount of magnesium in methanol afterward. Chiral
alcohol, acid, and amine could be obtained with high yields
after the sequential two steps. Gratefully, no epimerization was
observed. Chiral building blocks 3a−3c were obtained with
overall 22%−25% yields after this sequence from the C1
synthon 1.3-benzodithiole tetraoxide. These transformations
demonstrated the potential application of this synthetic
strategy in the manufacturing of chiral compounds.
In summary, we reported a method to prepare chiral
aldehydes with a β-chiral center based on the AHF of 1,1-
disalkyl olefins. In order to increase enantioselectivity, the
strategy of steric auxiliary was introduced. Using a Rh/Yanphos
complex as catalyst, chiral aldehydes were obtained with high
enantioselectivities and various functionalities were compatible
in the catalytic system. The sulfonyl groups which could be
readily available in the synthetic route could be removed after
the reaction. This method renders a powerful tool to convert
terminal olefins to value-added chiral building blocks.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (21672094), Shenzhen Nobel
Prize Scientists Laboratory Project (C17783101), and the
Science, Technology and Innovation Commission of Shenzhen
(KQTD20150717103157174, ZDSYS20190902093215877).
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
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Accession Codes
CCDC 1993523 contains the supplementary crystallographic
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AUTHOR INFORMATION
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