Enantioselective Rh-Catalyzed Anti-Markovnikov Hydroformylation of 1,1-Disubstituted Allylic Alcohols and Amines: An Efficient Route to Chiral Lactones and Lactams

Article abstract of DOI:10.1021/acscatal.9b02667

Rh-catalyzed highly enantioselective anti-Markovnikov hydroformylation of 1,1-disubstituted allylic alcohols and amines has been achieved. By using a chiral hybrid phosphorus ligand, a series of challenging 1,1-disubstituted allylic alcohols and amines we

Full text of DOI:10.1021/acscatal.9b02667

Letter
Cite This: ACS Catal. 2019, 9, 8529−8533
pubs.acs.org/acscatalysis
Enantioselective Rh-Catalyzed Anti-Markovnikov Hydroformylation
of 1,1-Disubstituted Allylic Alcohols and Amines: An Efficient Route
to Chiral Lactones and Lactams
†
,∇
†,∇
†
,†,§
and Xumu Zhang*,‡,†
Cai You, Shuailong Li, Xiuxiu Li, Hui Lv,*
†Key Laboratory of Biomedical Polymers of Ministry of Education & College of Chemistry and Molecular Sciences, Wuhan
University, Wuhan, Hubei 430072, People’s Republic of China
‡
Grubbs Institute and Department of Chemistry, Southern University of Science and Technology, Shenzhen, Guangdong 518000,
People’s Republic of China
§
Engineering Research Center of Organosilicon Compounds & Materials, Ministry of Education, Sauvage Center for Molecular
Sciences, College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, China
*
S Supporting Information
ABSTRACT: Rh-catalyzed highly enantioselective anti-Markovnikov
hydroformylation of 1,1-disubstituted allylic alcohols and amines has
been achieved. By using a chiral hybrid phosphorus ligand, a series of
challenging 1,1-disubstituted allylic alcohols and amines were transformed
to valuable chiral lactones and lactams with good yields and high
enantioselectivities (up to 90% yield and 93% enantiomeric excess (ee))
under very mild reaction conditions (50 °C, CO/H = 2.5/2.5 bar).
2
Furthermore, gram-scale reaction and diverse synthetic transformations
have also been achieved, demonstrating the wide synthetic utility of this
methodology.
KEYWORDS: enantioselectivity, hydroformylation, rhodium, lactone, lactam
symmetric hydroformylation (AHF) of alkenes represents
an atom-economic route for the preparation of chiral
In a synthetic sense, AHF of allylic alcohols and amines,
A
followed by oxidation or reduction, provides a concise method
to valuable lactones, lactams, furanidines, and pyrrolidines,
which occur in many natural products and are common motifs
in many biologically active compounds. However, AHF of
allylic alcohols and amines has been rarely investigated,
because of the challenge involved in controling the
enantioselectvity. For example, in the AHF of allylic alcohols,
the hydroxyl group was expected to benefit for the stereo-
induction, because of the weak coordination with Rh.
aldehydes, which are important intermediates for drugs and
1
synthetic chemicals. Over the past decades, intensive efforts
have been devoted to this field and a series of chiral
2
phosphorus ligands, including Binaphos, bis-
3
4
5
6
(
diazaphospholane) (BDP), YanPhos, Bobphos, Ph-BPE,
7 8
Chiraphite, and other chiral phosphorus ligands, have been
developed for this asymmetric transformation. Although
practical levels of regioselectivity and enantioselectivity can
be obtained in AHF of some alkenes, the substrate scope is still
narrow and mainly limited to monosubstituted and 1,2-
disubstituted olefins. Because the adverse effect of steric
hindrance on CC bond coordination with a metal center,
Nevertheless, the results of AHF of 1,2-disubstituted allylic
1g,11
alcohols,
1,1-disubstituted allylic alcohols (see the
Supporting Information) and the structurally similar aliphatic
alkenes under the same reaction conditions demostrate that
the hydroxyl group was actually deleterious to enantioselecti-
1
,1-disubstituted alkenes generally show low reactivity in AHF.
In addition, in contrast to AHF of monosubstituted and 1,2-
disubstituted alkenes with the formation of α-chiral branched
aldehydes, AHF of 1,1-disubstituted alkenes to furnish β-chiral
1g
12
3b
vity. The Nozaki group and the Landis group have
reported the Rh-catalyzed asymmetric hydroformylation of
cinnamyl alcohol, respectively. Recently, our group has
achieved the AHF of 1,2-disubstituted protected allylic
9
linear aldehydes (as indicated by Keulemans’ empirical rule)
has proven to be a great challenge, because of the poor
4
e
1g
amines. In contrast to the success in AHF of 1,2-
enantioselectivity. To date, there have been only a few
successful examples (>90% enantiomeric excess (ee)) on AHF
8b,10
of 1,1-disubstituted alkenes have been achieved.
Thus,
Received: June 25, 2019
Revised: August 16, 2019
expansion of the substrate scope and widening of the
application of asymmetric hydroformylation is very desirable.
©
XXXX American Chemical Society
8529
DOI: 10.1021/acscatal.9b02667
ACS Catal. 2019, 9, 8529−8533

ACS Catalysis
Letter
a
disubstituted allylic alcohols and amines, the results in AHF of
Scheme 2. Evaluation of Chiral Ligands
1,1-disubstituted allylic alcohols and amines seem lackluster.
Because of the difficulty in controlling enantioselectivity and
the inherently poor reactivity of 1,1-disubstituted allylic
alcohols and amines, AHF of these substrates has been a
challenge. In 1997, the Nozaki group reported the first but
single example in AHF of 1,1-disubstituted allylic alcohols with
12
only 12% ee and 37% yield (see Scheme 1a). Herein, we
Scheme 1. Asymmetric Hydroformylation of 1,1-
Disubstituted Allylic Alcohols and Amines
report the Rh-catalyzed AHF of the very challenging 1,1-
disubstituted allylic alcohols and amines, and high yields (up to
9
5%) with good to excellent enantioselectivities (up to 93%
a
Reaction conditions: 1a (0.2 mmol), Rh(acac)(CO) (4 mol %),
2
ee) are achieved with our developed chiral ligand under very
ligand (12 mol %), CO (5 bar), H (5 bar), toluene (1 mL), 60 °C, 48
2
mild conditions (50 °C, CO/H = 2.5/2.5 bar).
h. Oxidation conditions: Pyridinium chlorochromate (PCC) (0.4
mmol), sodium acetate trihydrate (0.4 mmol), SiO2 (100 mg),
2
We initiated our studies by examining the asymmetric
hydroformylation of the 1,1-disubstituted allylic alcohol 1
CH Cl (5 mL), 25 °C, overnight. Conversions were determined by
2 2
1
(
Scheme 2). Chiral ligands that have good performance in the
H NMR analysis. Enantiomeric excesses (ee) were determined by
HPLC analysis using a chiral stationary phase.
AHF or asymmetric hydrogenation (AH), such as (S,S)-Ph-
BPE, (Rc,Sp)-DuanPhos, (R,R)-QuinoxP*, (S,S)-Me-DuPhos,
(
S)-BINAP, (S,S)-SegPhos, XuPhos, (S,R)-YanPhos, were
1,1-disubstituted allylic alcohols could be transformed to the
chiral lactones with high ee values and good to excellent yields
(see Scheme 3). Various functional groups, such as methyl
(2b), isopropyl (2c), tertiary butyl (2d) phenyl (2e), methoxyl
(2f), trifluoromethyl (2g), esters (2h), and halides (2i and 2j),
at the para position of the phenyl group, were well-tolerated in
this reaction. In addition, the substrate with meta-substitution
on the phenyl group also worked smoothly, delivering target
product with high ee value (2k). As the steric hindrance
increased, substrate with a substitution on the ortho position of
benzene ring showed slightly low reactivity, but high yield with
high enantioselectivities were obtained at higher temperature
(2l). Moreover, substrates with 3,4-disubstituted groups and
3,5-disubstituted groups could be accommodated, as exempli-
fied by 2m−2o and 2p, respectively. Furthermore, naphthyl,
furyl, benzofuryl and benzothienyl substrates were also
compatible with this transformation, affording chiral lactones
2q, 2r, 2s, and 2t in good yields with high ee values.
Next, we investigated the Rh-catalyzed asymmetric hydro-
formylation of more-challenging 1,1-disubstituted allylic
amines (Scheme 4). In contrast with the AHF of 1,1-
disubstituted allylic alcohols, lower yields, and ee values were
obtained in the AHF of these acetyl protected allylic amines, as
summarized in Scheme 4. Even so, six valuable chiral lactams
were obtained with good ee values, albeit with moderate yields.
Moreover, we found that different substituents on the phenyl
group, such as methyl (4b), methoxyl (4c), trifluoromethyl
tested, but the low conversions and low ee values revealed
the dual challenges of achieving high levels of reactivity and
enantioselectivity for 1,1-disubstituted allylic alcohols in
asymmetric hydroformylation.
Next, we tested a series of (S,S)-YanPhos. (S,S)-Ph-
YanPhos, and (S,S)-Xyl-YanPhos, which showed high con-
versions albeit with low ee values, which gave us a promising
lead. By changing the meta-substituents on the phenyl group
from methyl to tert-butyl ((S,S)-DTB-YanPhos), we obtained
full conversion with 73% ee. We envisioned that further
increasing the steric hindrance on the phosphine part of the
ligand could improve the differentiation of the two prochiral
faces of 1a. To test this hypothesis, we prepared a novel
analogue, (S,S)-DTBM-YanPhos, which bears an additional
paramethoxy substituent. To our delight, this ligand afforded
full conversion with 81% ee. Subsequently, other reaction
conditions, such as pressure and temperature, were evaluated.
We found that lower reaction temperature led to higher
enantioselectivity, albeit with lower conversion. Decreasing the
syngas pressure resulted in higher conversion, and the
enantioselectivity remained the same. Finally, the complete
conversion was achieved under 5 bar CO/H (1:1) at 50 °C,
2
affording the desired product with full conversion (87%
isolated yield) and 90% ee.
Under the optimal conditions, the substrate scope and
generality of this reaction were evaluated. In most cases, the
8
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DOI: 10.1021/acscatal.9b02667
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ACS Catalysis
Letter
Scheme 3. Asymmetric Hydroformylation of 1,1-
Disubstituted Allylic Alcohols*
Scheme 4. Asymmetric Hydroformylation of 1,1-
Disubstituted Allylic Amines
a
a
Reaction conditions: 3 (0.2 mmol), Rh(acac)(CO)2 (4 mol %),
S,S)-DTBM-YanPhos (12 mol %), CO (2.5 bar), H2 (2.5 bar),
(
toluene (1 mL), 50 °C, 48 h. Oxidation conditions: pyridinium
chlorochromate (PCC) (0.4 mmol), sodium acetate trihydrate (0.4
mmol), SiO (100 mg), CH Cl (5 mL), 25 °C, overnight. Isolated
2
2
2
yields. Enantiomeric excess (ee) values were determined by HPLC
analysis using a chiral stationary.
Scheme 5. Synthetic Transformations
*
Reaction conditions: 1 (0.2 mmol), Rh(acac)(CO) (4 mol %),
2
(
S,S)-DTBM-YanPhos (12 mol %), CO (2.5 bar), H2 (2.5 bar),
toluene (1 mL), 50 °C, 48 h. Oxidation conditions: Pyridinium
chlorochromate (PCC) (0.4 mmol), sodium acetate trihydrate (0.4
mmol), SiO (100 mg), CH Cl (5 mL), 25 °C, overnight. Isolated
yields. Enantiomeric excesses (ee) were determined by HPLC analysis
using a chiral stationary. 70 °C, 72 h.
2
2
2
a
(
4d), and halides (4e and 4f), have a very small effect on yields
and enantioselectivities in this transformation.
With the scope of the transformation established, we sought
to demonstrate the potential utility of this protocol and several
transformations were conducted, as summarized in Scheme 5.
First, upon decreasing the catalyst loading to 1 mol %, the
asymmetric reaction was conducted on a gram scale, affording
the desired hemiacetal 5 in good yield with excellent
enantioselectivity, albeit with a low diastereomeric ratio (dr)
(
Scheme 5a). The hemiacetal 5 was subsequently subjected to
a series of useful organic transformations (Scheme 5b).
Treatment of the hemiacetal 5 to PCC oxidation conditions
provided the chiral lactone 2p in 92% isolated yield with 90%
ee. In addition, 5 was treated with triethylsilane and BF ·OEt
3
2
to furnish 6a in good yield without any loss of enantiopurity.
Also, 2,4-disubstituted furan 6b was formed in high yield with
high diastereoselectivity and enantioselectivity by the treat-
ment of allyltrimethyl silane in the presence of BF ·OEt .
3
2
Reduction of hemiacetal 5 with NaBH yielded chiral diol 6c in
4
almost quantitative yield with 90% ee. Furthermore, starting
1
3
14
from 2a and 2j, Phenibut and Baclofen can be synthesized
15
readily, following published literature procedures.
lective Rh-catalyzed anti-Markovnikov hydroformylation of
challenging 1,1-disubstituted allylic alcohols and amines was
achieved under mild conditions and a wide range of chiral
In summary, by employing our developed chiral hybrid
phosphorus ligand (S,S)-DTBM-YanPhos, highly enantiose-
8
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ACS Catalysis
Letter
lactones and lactams, which are important intermediates in
organic synthesis, were obtained in good yields with high ee
values. Furthermore, several synthetic transformations were
conducted, demonstrating the high synthetic utility of the
current reaction. The practicality of this asymmetric trans-
formation was further enhanced by the gram-scale reaction.
Further exploration into the chiral ligand design, substrate
scope, mechanism, and applications of asymmetric hydro-
formylation is underway in our laboratory.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.9b02667.
■
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Experimental procedures and compound characteriza-
tion (PDF)
AUTHOR INFORMATION
Corresponding Authors
E-mail: huilv@whu.edu.cn (H. Lv).
E-mail: zhangxm@sustc.edu.cn (X. Zhang).
■
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Hui Lv: 0000-0003-1378-1945
Xumu Zhang: 0000-0001-5700-0608
Author Contributions
∇
These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
6
511−6514. (e) Chen, C.; Jin, S.; Zhang, Z.; Wei, B.; Wang, H.;
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Zhang, K.; Lv, H.; Dong, X. Q.; Zhang, X. Rhodium/Yanphos-
Catalyzed Asymmetric Interrupted Intramolecular Hydroaminome-
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We would like to thank National Natural Science Foundation
of China (Grant Nos. 21871212, 21432007, and 21672094),
the Natural Science Foundation of Hubei Province (No.
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38, 9017−9020. (f) You, C.; Li, X.; Yang, Y.; Yang, Y.-S.; Tan, X.; Li,
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and Enantioselective Rhodium-Catalyzed Hydroformylation. Nat.
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018CFB430), Science and Technology Innovation Commit-
tee of Shenzhen (No. JSGG20160608140847864), Shenzhen
Nobel Prize Scientists Laboratory Project (No. C17213101),
and SZDRC Discipline Construction Program for financial
support.
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DOI: 10.1021/acscatal.9b02667
ACS Catal. 2019, 9, 8529−8533