A practical access to highly enantiomerically pure flavanones by catalytic asymmetric transfer hydrogenation

Article abstract of DOI:10.1002/anie.201306500

A surprisingly selective, non-enzymatic kinetic resolution of readily available, racemic β-chiral ketones enabled the title process, which was applied to a rapid synthesis of several bioactive flavanones in virtually enantiopure form (see scheme; MOM=methoxymethyl, Ts=p-toluenesulfonyl). Copyright

Full text of DOI:10.1002/anie.201306500

Angewandte
Chemie
DOI: 10.1002/anie.201306500
Kinetic Resolution
A Practical Access to Highly Enantiomerically Pure Flavanones by
Catalytic Asymmetric Transfer Hydrogenation
Marie-Kristin Lemke, Pia Schwab, Petra Fischer, Sandra Tischer, Morris Witt,
Laurence Noehringer, Victor Rogachev, Anne Jꢀger, Olga Kataeva, Roland Frçhlich, and
Peter Metz*
Dedicated to Dr. habil. Helmuth Tietz on the occasion of his 65th birthday
Flavonoids constitute the largest share of secondary metab-
olites occurring in higher plants. A subgroup of these natural
products, the flavanones (1), features a variety of useful
bioactivities such as antifungal, antibacterial, and antiviral
effects (Scheme 1).[1] Particularly prenylated derivatives show
pronounced physiological activities.[2] The naturally occurring
effects. Amongst others,[7] the licorice constituent (S)-4
inhibits the cancer target isoprenylcysteine carboxyl methyl-
transferase[8a] and shows potent activity against Staphylococ-
cus aureus and Mycobacterium smegmatis.[8b]
While many flavanones can be isolated from plants, only
the naturally occurring enantiomers are available in this way
and often only with low efficiency. The enantioselective
synthesis of flavanones has been explored more intensely in
recent years,[9,10] but additional studies, which provide prac-
tical access to highly enantiomerically pure flavanones, are
still very desirable. Here we report such a procedure[11] that
gives rise to both enantiomers quickly and efficiently through
the non-enzymatic kinetic resolution[12] of easily available
racemic flavanone derivatives. The starting point for the
development of this process was the discovery that the
racemic b-chiral ketone rac-5a[4] derived in only three steps
from naringenin (2) can be subjected to a surprisingly[13]
selective asymmetric transfer hydrogenation[14] to give (S)-
5a and (2R,4R)-6a under suitable conditions (Scheme 2).
Scheme 1. Basic structure of flavanones (1), naringenin (2), 8-prenyl-
naringenin (3), and glabrol (4).
(2S) enantiomer of 8-prenylnaringenin (3), also known as
sophoraflavanon B,[3] is currently the strongest phytoestrogen
known[4,5] and additionally exhibits further interesting bio-
logical properties.[6] Similarly, the less oxygenated prenylated
flavanone glabrol (4) displays a range of interesting biological
Scheme 2. Kinetic resolution (KR) of rac-7,4’-O,O-diacetyl-8-prenyl-
naringenin (rac-5a) by asymmetric reduction.
[*] Dr. M.-K. Lemke, Dr. P. Schwab, Dr. P. Fischer, Dr. S. Tischer,
Dipl.-Chem. M. Witt, M. Sc. L. Noehringer, Dr. V. Rogachev,
Dipl.-Lebensmittelchem. A. Jꢀger,[+] Dr. O. Kataeva,[+] Prof. Dr. P. Metz
Fachrichtung Chemie und Lebensmittelchemie
Initially, the kinetic resolution of rac-5a was investigated
using a number of chiral metal–diamine complexes (I–IV,
Scheme 3)[15] in a mixture of formic acid and triethylamine
(Table 1). The chiral complexes (I–IV) were generated in situ
from a suitable metal precursor and the monotosylated
diamine ligand and transformed into the catalytically active
metal hydride under the reaction conditions of transfer
hydrogenation. Only rhodium(III) complex III[15b–f] provided
very good yields and excellent enantiomeric excesses for both
products. When the (R,R)-diamine ligand was used, the (R)
enantiomer was transfer hydrogenated highly selectively even
with only 0.5 mol% of III, and a mixture of the nonconverted
ketone (S)-5a[16] and the alcohol (2R,4R)-6a was obtained
which was readily separated by flash chromatography. An
increase of the catalyst loading to 2 mol% III yielded (S)-5a
Organische Chemie I, Technische Universitꢀt Dresden
Bergstrasse 66, 01069 Dresden (Germany)
E-mail: peter.metz@chemie.tu-dresden.de
Homepage: http://www.chm.tu-dresden.de/oc1/
Dr. V. Rogachev
Tomsk Polytechnic University
Tomsk (Russia)
Dr. R. Frçhlich[+]
Organisch-Chemisches Institut
Westfꢀlische Wilhelms-Universitꢀt Mꢁnster (Germany)
[+] X-ray diffraction analysis
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201306500.
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(2R,4R)-6 were isolated in good yields with excellent
enantiomeric excesses. Besides acyl groups, also ethers and
acetals are well tolerated, whereas silyl ethers are partially
cleaved under these conditions. Control of conversion is not
required, since the reaction stops completely after transfer
hydrogenation of one enantiomer. While a loading of 2 mol%
of III is usually sufficient to obtain almost enantiomerically
pure products, in part significantly reduced catalyst loadings
can be used depending on the substrate. Thus, kinetic
resolution of rac-5g[17] with only 0.2 mol% of III provided
the flavanone derivative (S)-5g with 99% ee, and for the
preparation of (S)-5b[18] with 95% ee the loading could even
be lowered to 0.1 mol% III. Only for the highly enantiose-
lective synthesis of the anti-inflammatory[19a] and molluscici-
dal[19b] naringenin trimethyl ether (S)-5h as well as the methyl
ether (S)-5i a higher catalyst loading was necessary.
Scheme 3. Chiral metal–diamine complexes I–IV. Ts=tosyl=p-toluene-
sulfonyl.
Table 1: Asymmetric reduction of rac-5a to give ketone (S)-5a and
alcohol (2R,4R)-6a (see Scheme 2).[a,b]
NOESY measurements of the resulting alcohols 6 showed
that only the cis diastereomers were formed, which was also
confirmed by X-ray analysis[16] of the compounds (2R,4R)-6 f,
(2R,4R)-6h, and (2R,4R)-6i. The absolute configuration of
the acetylated flavanones (S)-5a,b,c,f was determined by
deacylation to give (S)-8-prenylnaringenin ((S)-3), (S)-na-
ringenin ((S)-2), and (S)-6-(1,1-dimethylallyl)naringenin,
respectively, while the absolute configuration of (S)-5i was
established by crystal structure analysis[16] of (2R,4R)-6i using
anomalous X-ray diffraction. For the flavanone derivatives
(S)-5d,e,g,h, the absolute configuration was assigned in
analogy to the five entries mentioned above and by applica-
tion of the transition-state model in Scheme 4. This model is
based on the attractive CH–p interactions between the
methyl groups of the pentamethylcyclopentadienyl (Cp*)
ligand and the aromatic part of the substrate ketone as well as
on the simultaneous transfer of the rhodium hydride and the
syn NH proton to the carbonyl group.[20] A geometry like that
sketched in Scheme 4 for the unreactive (S)-flavanone
enantiomer leads to a destabilizing interaction between the
tosyl group of the rhodium complex and the aromatic
substituent at C-2 of the flavanone, which does not occur in
Cat.
[mol%]
(S)-5a
(2R,4R)-6a
[d]
I
I
II
II
III
III
IV
IV
2[c]
5[e]
2
5
0.5
2
56%, 64% ee
traces[f]
–
73%, 7% ee
72%, 15% ee
82%, 16% ee
50%, 97% ee
43%, ꢀ99% ee
89%, 14% ee
49%, 70% ee
13%, –[f]
18%, –[f]
45%, ꢀ99% ee
41%, ꢀ95% ee[g]
[d]
2
–
5[h]
48%, 79% ee
[a] HCO2H/Et3N, EtOAc, 2 h, RT. [b] Enantiomeric excess (ee) deter-
mined by HPLC on a chiral stationary phase. [c] 10 h. [d] Not isolated.
[e] 14 h. [f] ee value not determined. [g] After oxidation to give (R)-5a
determined by optical rotation. [h] 19 h.
even with ꢀ 99% ee. Under analogous conditions, rutheni-
um(II) complex I[15a,d,e] showed only low enantioselectivity,
and iridium(III) complex II[15b–e] was much less reactive than
III. Likewise, switching from rhodium(III) catalyst III to
IV[15b] resulted in decreased reactivity and selectivity.
With rhodium(III) catalyst III, a variety of flavanone
derivatives (rac-5a–i) can be subjected to efficient kinetic
resolution (Table 2). Both the ketones (S)-5 and the alcohols
Table 2: Asymmetric transfer hydrogenation of flavanone derivatives rac-5 with rhodium(III) catalyst III.
rac-5
R1
R2
R3
R4
R5
[mol%]
(R,R)-III
(S)-5
yield [%][a]
(2R,4R)-6
yield [%][a]
ee [%][b]
ee [%][b]
a
b
c
d
e
f
g
h[e]
i
prenyl
H
prenyl
prenyl
H
H
H
H
Me
H
H
H
H
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Me
Me
H
H
Ac
MOM
MOM
H
H
Me
Me
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Me
Me
0.5
0.1
1
2
2
50
47
44
41
42
48
47
48
48
97
95
ꢀ99
ꢀ99
97
45
45
–
44
47
47
50
48
47
ꢀ99
ꢀ99
–
ꢀ99
H
98
1,1-dimethylallyl
prenyl
H
2
ꢀ99
ꢀ95[c]
[d]
0.2
10
10
99
–
98
99
ꢀ99
H
ꢀ95[c]
[a] Yield of isolated product. [b] Determined by HPLC on a chiral stationary phase. [c] After oxidation to give (R)-5 determined by optical rotation.
[d] Not determined. [e] At 08C, 20 h reaction time. Prenyl=3-methyl-2-butenyl, MOM=methoxymethyl.
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the flavanone derivative (R)-5a. Similarly, oxidation with
tetrapropylammonium perruthenate and N-methylmorpho-
line N-oxide[24] afforded (R)-5a without racemization; how-
ever, the yield was slightly lower (64%). Deacetylation of
diacetate (S)-5a to give the flavanone (S)-8-prenylnaringenin
((S)-3) with potassium carbonate in methanol[4] caused
significant racemization. Gratifyingly, this transformation
succeeded by transesterification with butanol in the presence
of catalytic amounts of a lipase from Pseudomonas sp.
(Roche) at room temperature without stereochemical erosion
in high yield. Alternatively, transesterification with methanol
catalyzed by the Verkade base 10[25] (10 mol%) at 408C could
be performed, after which (S)-3 was isolated in 89% yield
with 92% ee. This non-enzymatic deblocking was further
optimized for diacetate (R)-5a and led with only minimal
racemization to (R)-8-prenylnaringenin ((R)-3).
Our approach to (S)- and (R)-glabrol (4) is shown in
Scheme 7. Racemic 4[26] was prepared from commercially
available liquiritigenin (rac-11)[27] by formation of the double
isoprenyl ether through reaction with carbonate 13[28] fol-
lowed by a highly regioselective europium(III)-catalyzed[4,29]
twofold Claisen rearrangement preferably under microwave
irradiation. Formation of diacetate rac-14 set the stage for the
crucial asymmetric transfer hydrogenation, which proceeded
with excellent enantioselectivity using catalyst III. As yet
another alternative deblocking procedure that minimizes
racemization, sodium perborate[30] in methanol converted (S)-
14 to the natural product (S)-glabrol ((S)-4),[7a,31] while the
Scheme 4. Unfavorable Ts$Ar interaction in the transition state of the
asymmetric transfer hydrogenation of the unreactive (S)-flavanone
enantiomer with the catalytically active species from III.
the transition state of the asymmetric transfer hydrogenation
of the reactive (R) enantiomer.
The model depicted in Scheme 4 implies that less
substituted flavanones should also undergo a highly enantio-
selective reduction. Indeed, the simple flavanone rac-7
reacted with perfect discrimination between the two enan-
tiomers as well to give ketone (S)-7[21] and alcohol (2R,4R)-
8
9
[22] in virtually enantiopure form (Scheme 5). In contrast, rac-
[23] lacking the aryl ketone moiety showed no conversion.
Scheme 6 illustrates the application of the highly enantio-
selective asymmetric transfer hydrogenation of rac-5a with
rhodium(III) complex III to the synthesis of (S)- and (R)-8-
prenylnaringenin (3). Oxidation with activated manganese
dioxide[10h,22] smoothly converted the alcohol (2R,4R)-6a to
Scheme 5. Asymmetric transfer hydrogenation of substrates rac-7 and
rac-9. a) 1 mol% III, HCO2H/Et3N, CH2Cl2, 24 h, RT, 47% (S)-7, 43%
(2R,4R)-8.
Scheme 7. Enantioselective synthesis of (S)- and (R)-glabrol (4). a) 13,
1 mol% [Pd(PPh3)4], THF, 08C to RT, 100%; b) 5 mol% [Eu(fod)3],
toluene, 2 h, 1008C, microwave irradiation (300 W), 81% or 5 mol%
[Eu(fod)3], toluene, 24 h, 1008C, 67%; c) Ac2O, Et3N, CH2Cl2, 08C to
RT, 97%; d) 1 mol% III, HCO2H/Et3N, CH2Cl2, 24 h, RT, 46% (S)-14
(ꢀ99% ee), 44% (2R,4R)-15 (ꢀ99% ee); e) NaBO3·4H2O, MeOH, RT,
47% (S)-4, 57% (R)-4; f) 15 mol% TPAP, NMO, MS 4 ꢂ, CH2Cl2, RT,
98%. fod=6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionate,
TPAP=tetrapropylammonium perruthenate, NMO=N-methylmorpho-
line N-oxide, MS=molecular sieves.
Scheme 6. Enantioselective synthesis of (S)- and (R)-8-prenylnarin-
genin (3). a) Pseudomonas sp. lipase, THF, BuOH, RT, 96%; b) MnO2,
CH2Cl2, RT, 74%; c) 5 mol% 10, MeOH, 408C, 64%.
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Received: July 25, 2013
Published online: September 11, 2013
Keywords: asymmetric catalysis · flavonoids · glabrol ·
.
kinetic resolution · natural products
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