Rh-Catalyzed Asymmetric Hydrogenation of β-Branched Enol Esters for the Synthesis of β-Chiral Primary Alcohols

Article abstract of DOI:10.1021/acs.orglett.7b03469

An asymmetric hydrogenation of β-branched enol esters has been developed for the first time, providing a new route for the synthesis of β-chiral primary alcohols. Using a (S)-SKP-Rh complex bearing a large bite angle and enol ester substrates possessing an O-fomyl directing group, the desired products were obtained in quantitative yields and with excellent enantioselectivities.

Full text of DOI:10.1021/acs.orglett.7b03469

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rh-Catalyzed Asymmetric Hydrogenation of β‑Branched Enol Esters
for the Synthesis of β‑Chiral Primary Alcohols
Chong Liu,† Jing Yuan,† Jian Zhang,‡ Zhihui Wang,‡ Zhenfeng Zhang,*,‡ and Wanbin Zhang*,†,‡
†Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Chemistry and Chemical Engineering, and ‡School
of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
S
* Supporting Information
ABSTRACT: An asymmetric hydrogenation of β-branched enol
esters has been developed for the first time, providing a new route for
the synthesis of β-chiral primary alcohols. Using a (S)-SKP-Rh
complex bearing a large bite angle and enol ester substrates
possessing an O-fomyl directing group, the desired products were
obtained in quantitative yields and with excellent enantioselectivities.
hiral alcohols are versatile intermediates for the synthesis of
various important pharmaceuticals and bioactive com-
Scheme 1. Three Asymmetric Hydrogenations for the
Synthesis of β-Chiral Primary Alcohols
C
pounds, either directly or in the form of esters and ethers.
Therefore, numerous methodologies have been developed for
the asymmetric catalytic synthesis of chiral alcohols. However,
most of these reports concern the construction of chiral
secondary and tertiary alcohols, while the preparation of chiral
primary alcohols has been less studied. Enzyme-catalyzed
(dynamic) acylative kinetic resolution of racemic β-branched
primary alcohols1 and dynamic reductive kinetic resolution of
racemic α-branched aldehydes2 are the most attractive method-
ologies for the synthesis of such compounds with satisfactory
enantioselectivities. Two indirect methods, asymmetric hydro-
boration/oxidation of 1,1-disubstituted alkenes3 and asymmetric
carboalumination/or carboboration/oxidation of 1-substituted
alkenes,4 have also been developed. However, several problems
associated with these processes, such as low efficiency, high
catalyst loading, complex reaction system, or large amounts of
byproduct, render them impractical. Since its discovery,
asymmetric hydrogenation (AH) has been considered to be a
practical process because of its high efficiency, environmental
friendliness, and low economic cost.5 According to retrosynthetic
analyses, one can conclude that there are three routes of
asymmetric hydrogenations for the synthesis of β-chiral primary
alcohols (Scheme 1). One route involves the asymmetric
hydrogenation of racemic α-branched aldehydes via dynamic
kinetic resolution which has been developed independently by
Zhou’s and List’s groups.6 Using a catalytic system of
bisphosphine-Ru-diamine, high enantioselectivities were ob-
tained for substrates bearing bulky α-alkyl substituents. However,
high hydrogen pressure (20−50 atm) and a strong base (usually
t-BuOK) are required to complete the reaction. A second route
involves the asymmetric hydrogenation of β-branched allylic
alcohols or esters which has been primarily studied by
synthesis of β-chiral primary alcohols via the asymmetric
hydrogenation of β-branched enol esters. To the best of our
knowledge, the asymmetric hydrogenation of enol esters bearing
an α-branched substituent has been widely studied,8 but no
report has been published concerning the asymmetric hydro-
genation of enol esters bearing only a β-branched substituent
(Figure 1), probably due to the difficulties in preparing pure
substrates with only a Z- or E-configuration and developing
active catalytic systems with good stereocontrol.
The initial hydrogenation reactions were conducted on the
model substrate (E)-2-phenylprop-1-en-1-yl acetate (1a-Me)
which was synthesized by acetylation of 2-phenylpropanal. In
order to utilize the directing effect of the acetyl group, rhodium
complexes with the ability to chelate to enol esters were chosen.
Several bisphosphine ligands bearing C2−4 backbones were
́
Andersson, Dieguez and co-workers using a PN−Ir catalytic
system.7 However, only two types of substrates were used in
order to obtain the β-chiral propanols and their acetate
derivatives with 40−98% ee. Considering the limitations of the
aforementioned routes, herein we propose a third route for the
Received: November 8, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03469
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
In order to investigate the effect of the acyl group on the
reaction, we synthesized other substrates and subjected them to
hydrogenation (Table 1). The enantioselectivities gradually
Table 1. Effect of Acyl Groups
a
b
c
entry
R
conv/%
ee/%
1
2
3
4
5
Me
Et
iPr
tBu
H
>99
>99
>99
>99
<10
>99
>99
trace
73
93
90
85
76
nd
97
97
nd
−92
Figure 1. Enol esters for asymmetric hydrogenation.
evaluated. Irrespective of whether or not its chirality is central,
axial, planar, or even P-stereogenic, almost all the commonly
used chiral bisphosphine ligands gave the desired product with
poor conversions (all <10%) and low enantioselectivities
([Rh((R,R)-NorPhos)(cod)]BF4: 9% ee; (R)-BINAP/[Rh-
(nbd)2]BF4: 29% ee; (R,Sp)-JosiPhos/[Rh(nbd)2]BF4: 12% ee;
(R,R)-Me-DuPhos/[Rh(nbd)2]BF4: 45% ee; [Rh((R,R)-
BenzP*)(cod)]SbF6: 30% ee) (the reaction conditions were
the same as those described in Scheme 2). To our surprise, a
d
6
H
de
,
7
8
9
H
df
,
H
dfg
, ,
H
a
Conditions: 1a-R (0.2 mmol), (S)-SKP (1.2 mol %), [Rh(nbd)2]BF4
(1.0 mol %), H2 (1 atm), DCM (2 mL), 25 °C, 5 h, unless otherwise
b
c
noted. The conversions were calculated from 1H NMR spectra. The
d
ee’s were determined by HPLC using chiral columns. [Rh(cod)2]-
SbF6 was used instead of [Rh(nbd)2]BF4. 1 h. (Z)-isomer was used
instead of (E)-isomer. 5 atm.
e
f
Scheme 2. Screen of Ligands
g
decreased when the size of the acyl group increased (entries 1−
4). These results inspired us to explore a new directing group
the O-formyl group. To avoid the difficult separation for the Z-
and E-isomers, a selective synthetic route for the preparation of
the E-isomer has been developed.13 Methyl (E)-3-phenylbut-2-
enoates were selectively synthesized via Horner−Wadsworth−
Emmons reaction using commercially available acetophenones
and subsequently transformed to β,β′-disubstituted-(E)-vinyl
formates via sequential DIBAL-H reduction, MnO2 oxidation,
and Baeyer−Villiger oxidation (see Supporting Information for
details). However, the hydrogenation using the same rhodium
salt with a BF4 anion showed poor activity for this substrate
(entry 5). Therefore, a more active rhodium salt bearing a SbF6
counterion was utilized and gave the desired product in
quantitative conversion and 97% ee under the same reaction
conditions or even in a short reaction time of 1 h (entries 6 and
7). The hydrogenation of the (Z)-isomer (R = H) was also
conducted under 1 atm of hydrogen pressure, but almost no
product was detected (entry 8). When increasing the hydrogen
pressure to 5 atm, the hydrogenated product was obtained with
73% conversion and with an opposite enantioselectivity of 92%
ee (entry 9).
With the optimized reaction conditions in hand, we
investigated the substrate scope of the hydrogenation reaction
catalyzed by the isolated rhodium complex [Rh((S)-SKP)-
(cod)]SbF6 (Scheme 3). All substrates bearing different phenyl
moieties gave their corresponding products 2a−l in satisfactory
yields and excellent enantioselectivities (91−99%), regardless of
the presence of electron-withdrawing or -donating substituents.
The 1- and 2-naphthyl group-substituted substrates showed the
best results giving their corresponding products 2m and 2n with
99% and 97% ee’s, respectively. Furthermore, substrates bearing
an alkyl unit at the β-position furnished their related products
2o−r with excellent results, irrespective of the steric size of the
substituted group.
DuPhos analogue bearing a ferrocene backbone ((R,R)-Me-
FcPhos) showed a dramatically improved activity. However, the
enantioselectivity was still not acceptable (Scheme 2). This result
suggested that ligands bearing a large bite angle appear to be
more active in this reaction. A similar trend was also observed in
our previous work concerning the asymmetric hydrogenation of
β-branched allylic alcohols.9 Thus, three chiral bisphosphine
ligands, (R)-PhanePhos,10 (S)-CH2OH-DPPF,11 and (S)-SKP12
possessing a large bite angle, were tested. To our delight, all of
these ligands gave the desired product with complete conversion
and improved enantioselectivities. In particular, (S)-SKP, which
was developed by Ding et al.,12 was found to be the most
promising (Scheme 2). Attempts at hydrogenation of an (E/Z)-
mixture (45/55) under 30 atm of hydrogen pressure only gave a
racemic product (−6% ee), indicating that the (E)- and (Z)-
isomers generate the desired product with opposite enantiose-
lectivity. Further optimization of the reaction conditions, such as
solvent, temperature, and hydrogen pressure, did not provide any
obvious improvement for this reaction (see Table S1 in
Supporting Information). It is noteworthy that this reaction
can go to completion under 1 atm of hydrogen pressure within a
few hours.
To gain insight into the reaction mechanism, a deuterium-
labeling experiment was conducted. The use of D2 instead of H2
B
DOI: 10.1021/acs.orglett.7b03469
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
enantioselectivity (Scheme 4b). Additionally, we examined the
hydrogenation of substrate 1t bearing a heteroaromatic 2-thienyl
group (regarded as a coordinating substituent) and obtained the
hydrogenated product 2t with reduced activity and enantiose-
lectivity (Scheme 4c).
Scheme 3. Substrate Scope
To demonstrate the practicality of this methodology, the
hydrogenated products were transformed to useful bioactive
molecules (Scheme 5). For instance, compound 2h was
Scheme 5. Applications of Hydrogenated Products
hydrolyzed to the corresponding alcohol 3h and then reacted
with mesyl chloride to give a glutamate receptor potentiator 4h.15
The product 2o underwent hydrolysis in aqueous NaOH to give
(S)-2-phenyl-1-butanol (3o), which can be transformed to an
enantiomer of an orally active TAAR1 agonist 4o.16
In conclusion, based on a new strategy that allows access to
substrates as a single E-isomer, and the development of an
efficient system to control the enantioselectivity by using the
bisphosphine ligand bearing a large bite angle and substrates
possessing an O-fomyl directing group, β-branched enol esters
have been hydrogenated for the first time to give β-chiral primary
alcohols quantitatively and with excellent enantioselectivities.
a
Conditions: 1 (0.2 mmol), [Rh((S)-SKP)(cod)]SbF6 (1 mol %)],
DCM (2 mL), H2 (1 atm), 25 °C, 1 h, unless otherwise noted. Isolated
b
yields. The ee’s were determined by HPLC using chiral columns. 6 h.
c
d
e
30 atm, 24 h. Determined after hydrolysis. 40 atm, 24 h.
resulted in deuterium addition to the alkene with no double-
bond-shift occurring (Scheme 4a). This result, combined with
ASSOCIATED CONTENT
* Supporting Information
■
Scheme 4. Mechanism Study
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03469.
Synthetic details for substrates, procedures for hydro-
genation reactions, spectra of NMR and HPLC data
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: wanbin@sjtu.edu.cn.
*E-mail: zhenfeng@sjtu.edu.cn.
ORCID
Zhenfeng Zhang: 0000-0003-3295-6966
Wanbin Zhang: 0000-0002-4788-4195
Notes
the above-mentioned hydrogenation performance of 2a and 2o−
r that no decrease in ee value was observed following an increase
in the size of the alkyl chain, and that the (E)- and (Z)-isomers
generate products with the opposite enantioselectivity, reveals
that the stereoselectivity is predominantly controlled by the
chelating direction of the enol ester to the bisphosphine−
rhodium−dihydride complex, and not because of the diffenence
between the two β-substituents. These results are consistent with
the reported mechanism concerning the asymmetric hydro-
genation of enamides.14 Additional experiments that were also
conducted may support this evidence to some extent. A substrate
with two similar β-aromatic groups (1s) was hydrogenated to
give the desired product 2s with complete conversion and good
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partially supported by National Natural Science
Foundation of China (Nos. 21232004, 21572131, and
21620102003), Shanghai Municipal Education Commission
(No. 201701070002E00030), and Science and Technology
Commission of Shanghai Municipality (No. 15JC1402200). We
thank the Instrumental Analysis Center of Shanghai Jiao Tong
University.
C
DOI: 10.1021/acs.orglett.7b03469
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Paptchikhine, A.; Pam
̀
ies, O.; Andersson, P. G.; Dieg
́
uez, M. Chem. - Eur.
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DOI: 10.1021/acs.orglett.7b03469
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