Synthesis of chiral chromanols: Via a RuPHOX-Ru catalyzed asymmetric hydrogenation of chromones

Article abstract of DOI:10.1039/c8cc07787h

Chiral chromanols and their derivatives have been synthesized via a RuPHOX-Ru catalyzed asymmetric hydrogenation of chromones in high yields, >20:1 drs and with up to 99.9% ee. Control experiments show that the reaction undergoes two sequential asymmetric hydrogenation steps of the CC and CO double bonds. The reaction could be performed on a gram-scale with a relatively low catalyst loading (up to 1000 S/C), and the resulting products can be transformed to several biologically active compounds.

Full text of DOI:10.1039/c8cc07787h

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Synthesis of chiral chromanols via a RuPHOX–Ru
catalyzed asymmetric hydrogenation of
chromones†
Cite this:DOI: 10.1039/c8cc07787h
Received 28th September 2018,
Accepted 13th November 2018
Yujie Ma,a Jing Li,a Jianxun Ye,a Delong Liu *a and Wanbin Zhang
ab
DOI: 10.1039/c8cc07787h
rsc.li/chemcomm
Chiral chromanols and their derivatives have been synthesized via a
RuPHOX–Ru catalyzed asymmetric hydrogenation of chromones in
high yields, 420: 1 drs and with up to 99.9% ee. Control experiments
show that the reaction undergoes two sequential asymmetric hydro-
Q
Q
genation steps of the C C and C O double bonds. The reaction
could be performed on a gram-scale with a relatively low catalyst
loading (up to 1000 S/C), and the resulting products can be trans-
formed to several biologically active compounds.
The chromanoid structural motif is found in numerous well-
known natural products, drug candidates and biologically active
molecules.1 The subgroups of chromanoids, that is chroma-
nones and chromanols, also exhibit antidiabetic, antibacterial,
Fig. 1 Chiral chromanols and their derivatives.
antioxidant, antiestrogenic activities.2 They can most likely be direct synthesis of chiral chromanols and their flavanol analo-
selected as alternative chiral counterparts of chromones for the gues (Scheme 1).4 Wang et al. established an efficient chiral
development of new drugs which may possess a broader spec- BINOL-Ti(Oi-Pr)4-catalyzed reaction of tertiary enamides with
trum of biological activities. Therefore, the development of these salicylaldehydes under mild conditions to afford diverse
chiral subgroup motifs via an efficient synthetic procedure is 4-chromanol derivatives in high yields with excellent enantio- and
worthwhile.
diastereoselectivity.4a Metz et al. reported a kinetic resolution of
From the viewpoint of convenient derivatization, the direct racemic flavanones with a Rh(III) complex catalyzed asymmetric
synthesis of chiral chromanols is interesting because the transfer hydrogenation, producing chiral flavanones and flavanols
hydroxyl group can either partake in asymmetric nucleophilic in high yields and with excellent enantioselectivities.4b Ashley,
substitution for the preparation of other drugs and drug candi- Sherer and coworkers discovered a unique combination of a base-
dates, be oxidized to chromanones or reduced to chromanes catalyzed b-epimerization and ruthenium-catalyzed asymmetric
(Fig. 1, up). Chiral chromanols themselves and their derivatives transfer hydrogenation that enables the facile reductive dynamic
are all useful skeletons, existing in many natural products kinetic resolution of b-substituted chromanones.4c In 2013, the
(Fig. 1, down). Current methodologies mainly afford chiral Glorius group developed an asymmetric hydrogenation of
chromanones through the asymmetric hydrogenation of 2-substituted flavones and chromones using a chiral ruthenium–
chromones.3 Only a handful of examples have focused on the NHC complex, leading to the formation of chiral flavanones,
flavanols, chromanones, and chromanols.4d Full conversion and
excellent enantioselevtivities, but low diastereoselectivities, were
obtained under high hydrogen pressure (120–150 bar). The asym-
metric hydrogenation of chromanones is one of the most efficient
methods for the synthesis of chiral chromanols because of its high
efficiency, environmental friendliness, and low economic cost.5
Therefore, an efficient asymmetric hydrogenation of chromones
for the direct synthesis of chiral chromanols with excellent
diastereoselectivities is highly desired.
a Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs,
School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road,
Shanghai 200240, P. R. China. E-mail: dlliu@sjtu.edu.cn; Fax: +86 21 34207246;
Tel: +86 21 34207176
b School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University,
800 Dongchuan Road, Shanghai 200240, P. R. China
† Electronic supplementary information (ESI) available. CCDC 1870462 and
1870445. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c8cc07787h
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Thus, the optimal reaction conditions were found to be the
following: using Na2CO3 as a suitable base in MeOH under
20 bar hydrogen pressure at room temperature over 12 h.
With the optimized reaction conditions in hand, substrates
bearing different 2-position and aryl substituents were then
investigated (Table 1). First, substrates 2 with different alkyl
substituents at the 2-position were examined and the desired
products were obtained in high yields and almost 499% ee
(2a–2f). When an electron-donating Me group was present at the
7 and 8-position, high yields and excellent enantioselectivities
were still obtained (2g and 2h). The counterparts of 2h bearing
different alkyl groups at the 2-position were examined and
excellent asymmetric behaviors were observed (2i–2m). When
an Me group was replaced by other electron-donating groups,
e.g. Et and MeO, the desired products were still obtained in
quantitative yields and 96–99% ees (2n–2t). Replacing the
electron-donating substituents with electron-withdrawing groups
such as Cl or F had little effect on the reaction, with the corre-
sponding products being obtained with more than 98% ee in
many cases (2u–2ab). Finally, a substrate lacking a 2-substituent
was examined. To our delight, the desired product 2ac was
obtained in 99% yield and with 99% ee.
To examine the efficiency of the catalyst system, a gram-scale
hydrogenation of 1a (1.87 g) was carried out with a low catalyst
Table 1 Scope of substratesa
Scheme 1 Asymmetric synthesis of chiral chromanols.
We have previously reported the development of a readily
accessible ruthenocenyl phosphino-oxazoline–ruthenium complex
(RuPHOX–Ru) bearing dual catalytic centers, which has shown
promising catalytic activity in many asymmetric reactions.6,7
Specifically, this complex has been employed as a chiral catalyst
for the asymmetric hydrogenation of various CQC and CQO
double bonds, providing the corresponding products in up to
99% yield and 99.9% ee.7 Encouraged by these promising
results, we herein report the efficient and mild RuPHOX–Ru
catalyzed asymmetric hydrogenation of chromones for the direct
synthesis of chiral chromanols (Scheme 1).
Initially, the RuPHOX–Ru catalyzed asymmetric hydrogena-
tion of 2-methyl-4H-chromen-4-one (chromone 1a) was carried
out in the presence of Cs2CO3 under a certain hydrogen pressure
in different solvents at room temperature. It was found that the
a
Using the optimal reaction conditions shown in Table S2 (entry 2,
best results were obtained when 20 bar hydrogen pressure was ESI); ees were determined by chiral HPLC analysis of 2 using an OD-H
1
used in either MeOH or toluene as a solvent.8 Subsequently, we
chose both MeOH and toluene as the solvents to examine the
and AS-H column; Drs were determined by H NMR with 420 : 1 in all
cases; the absolute configurations of 2 were determined by analogy
according to 2a which was determined by the X-ray diffraction of its
impact of different bases on the reaction (Table S2, ESI†).8 single crystal and is shown in Table S2 (ESI).8,9
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Table 2 Screening of reaction timea
loading of 0.1 mol% (S/C = 1000) with modified reaction condi-
tions under 50 bar H2 at room temperature over 12 h. The
desired product 2a was obtained in 99% yield and with 96% ee.8
Chiral chromanols 2 are important building block and can be
transformed into a number of different biologically active
compounds (Scheme 2). Thus, the oxidation of 2a could be per-
formed to afford the corresponding chromanone product 3 or be
dehydroxylated by Pd/C and H2 to give chromane 4 without any
effect on enantioselectivities (Scheme 2, top). Alternatively, the
hydroxyl of 2a can replaced by o-phthalimide to give 5 with the
opposite configuration via a Mitsunobu reaction in the presence of
PPh3 and DIAD.8,9 5 could be hydrolyzed with hydrazine hydrate to
produce an arthropodicide according to a reported method.10
Similarly, a herbicidal 6 was obtained in 93% yield and with
98% ee via a Mitsunobu reaction with methyl 5-imidazole-
carboxylate (Scheme 2, middle).2c Additionally, the oxidation of
2f using PCC in DCM over 10 min afforded the natural product
flindersiachromanone 7, which can be isolated from the extracts
of the bark of Flindersia laevicarpa (Scheme 2, bottom).2a
Entry
Time/h
1a/3/2ab (%)
1
2
3
4
5
6
7
0.25
0.5
1
2
4
6
12
93.7/4.2/2.1
87.7/6.6/5.7
62.8/16.3/20.9
8.5/6.8/84.7
1.9/2.9/95.2
1.0/2.9/96.1
0/0/100
a
Using the optimal reaction conditions shown in Table S2 (entry 2,
ESI). Determined by 1H NMR.
b
To further verify the above reaction pathway, we prepared
chiral intermediate 3 in 99.9% ee using the abovementioned
method (Scheme 2, top), which was subjected to the asymmetric
hydrogenation using the optimal reaction conditions shown in
Table S2 (ESI†) (entry 2). As expected, the desired product 2a was
obtained in quantitative yield and high diastereoselectivity
(420 : 1 dr) and no erosion in enantioenrichment (99.9% ee,
Scheme 3). Combined with the control experimental results
above, the asymmetric hydrogenation of chromone 1a presumably
undergoes the following sequential steps (Scheme 3): originally,
the CQC double bond, rather than the CQO double bond of 1a,
is reduced, affording the chiral chromanone 3 quickly. Then, the
asymmetric hydrogenation of the CQO double bond of 3 pro-
ceeds to deliver the desired product 2a. It should be noted that the
asymmetric catalytic hydrogenation of 3 proceeds together with a
certain extent of dynamic kinetic resolution process.4c,8
In order to gain a better insight into the reaction process,
a series of control experiments were conducted. The reactions
were quenched at different times (Table 2), and the reaction
mixtures were analysed by 1H NMR spectroscopy. No inter-
mediate 2a0 relating to the hydrogenation of the CQO double
bond was formed; however, an intermediate 3 was observed
corresponding to the hydrogenation of the CQC double bond.
It was obvious that the hydrogenation of CQC double bond is fast
and the amount of 1a decreases sharply (almost disappeared after
4 h, entries 1–5).11 The subsequent hydrogenation of the CQO
double bond of 3 quickly gives the desired product 2a and the
reaction goes to completion within 12 h (entries 6 and 7).
In summary, we have developed a RuPHOX–Ru catalyzed
asymmetric hydrogenation of chromones for the synthesis of
chiral chromanols and their derivatives. Under the optimal
reaction conditions, almost quantitative yields, 420 : 1 drs
and up to 99.9% ees were obtained for all examples. The control
experiments showed that the asymmetric hydrogenation of the
CQC double bond occurs first followed by the reduction of the
CQO double. The reaction could be performed on a gram-scale
with a relatively low catalyst loading (up to 1000 S/C), and the
resulting products can be transformed to several biologically
active compounds.
Scheme 2 Transformation of chromanol and application.
Scheme 3 The possible reaction pathway.
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Foundation of China (No. 21672142, 21472123 and
21620102003) and Shanghai Municipal Education Commission
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Conflicts of interest
There are no conflicts of interest to declare.
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