Enantioselective synthetic method for 3-hydroxyflavanones: An approach to (2R,3R)-3',4'-O-dimethyltaxifolin

Article abstract of DOI:10.1016/S0040-4039(00)01382-4

A new enantioselective synthetic method for (2R,3R)-3-hydroxyflavanone (1a) was developed via asymmetric dihydroxylation (ADH) and intramolecular Mitsunobu reaction as key reactions and the application to synthesis of (2R,3R)-3',4'-O-dimethyltaxifolin (1b) is described. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01382-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7925–7928
Enantioselective synthetic method for 3-hydroxyflavanones:
an approach to (2R,3R)-3%,4%-O-dimethyltaxifolin
Sang-sup Jew,* Hyun-ah Kim, So-young Bae, Jeong-hoon Kim and Hyeung-geun Park*
College of Pharmacy, Seoul National University, Seoul 151-742, South Korea
Received 5 July 2000; revised 7 August 2000; accepted 10 August 2000
Abstract
A new enantioselective synthetic method for (2R,3R)-3-hydroxyflavanone (1a) was developed via
asymmetric dihydroxylation (ADH) and intramolecular Mitsunobu reaction as key reactions and the
application to synthesis of (2R,3R)-3%,4%-O-dimethyltaxifolin (1b) is described. © 2000 Elsevier Science
Ltd. All rights reserved.
Keywords: 3-hydroxyflavanone; asymmetric dihydroxylation; intramolecular Mitsunobu reaction; (2R,3R)-3%,4%-O-
dimethyltaxifolin.
3-Hydroxyflavanone type natural products which are widely distributed in the plant kingdom
show considerable and various biological activities.1 Among them, Silybin and Taxifolin show
strong hepatoprotective effect due to their strong antioxidant effect.2
Two chiral centers exist at C(2) and C(3) in 3-hydroxyflavanone and the absolute configura-
tions of the majority of naturally occurring 3-hydroxyflavanones are 2R and 3R. Onda (57–62%
ee)3 and Ferreira (20–92% ee)4 reported the enantioselective synthesis of 3-hydroxyflavanone
derivatives by using catalytic asymmetric epoxidation, but the stereoselectivity is relatively lower
than the practical level. In this paper, a highly enantioselective synthetic method (99% ee) for
optically pure (2R,3R)-3-hydroxyflavanones by using catalytic asymmetric dihydroxylation5 and
an intramolecular Mitsunobu reaction6 as key reactions and the application to the synthesis of
(2R,3R)-3%,4%-O-dimethyltaxifolin are described.
* Corresponding authors. Fax: +82-2-872-9129; e-mail: ssjew@plaza.snu.ac.kr
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01382-4

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(2R,3R)-3-Hydroxyflavanones (1a,b) were retrosynthesized via three key steps; asymmetric
dihydroxylation of methyl cinnamates (4a,b), addition of aryllithium (2a,b) to chiral dihydroxy-
aldehydes (3a,b), and intramolecular Mitsunobu reaction as shown in Scheme 1.
Scheme 1.
Sharpless asymmetric dihydroxylations of 4a and 4b with AD-mix-a7 gave highly optically
pure diols, 5a (80, 99% ee) and 5b (89, 99% ee), respectively (Scheme 2). The enantiomeric excess
1
was determined by the analysis of H NMR of the diastereomeric Mosher’s esters of 5a and 5b.8
The absolute configurations of C(2) and C(3) in 5a were assigned as 2R,3S by comparison with
the literature data.9 In the case of 5b, the absolute configuration was tentatively assigned as
2R,3S from enantioselectivity mnemonic of ADH reactions (Table 1).5
Scheme 2. Reaction conditions: (i) AD-mix-a (1.4 g/mmol), methanesulfonamide (1.0 equiv.), t-BuOH–H2O (1:1)
soln., 18–24 h. 5a (80%), 5b (89%), (ii) MOMCl (9–10 equiv.), (i-Pr)2NEt (2.5 equiv.), CH2Cl2, rt, 8–10 h, 6a (95%),
6b (92%), (iii) DIBAL-H (1.3 equiv.), toluene, −78°C, 1.5 h, 7a (69%), 7b (83%), (iv) 2a (1.0 equiv.), THF, −78°C, 5
min then 5a (0.78 equiv.), −78°C to rt, 1.5 h, 8a (50%); 2b (1.2 equiv.), THF, 50°C, 20 min, 5b (1.0 equiv.), −50°C
,
to rt, 30 min, 8b (65%), (v) NMO (1.5 equiv.), TPAP (0.2 equiv.), 4 A molecular sieve, CH2Cl2, rt, 1.5–2 h, CH2Cl2,
9a (92%), 9b (90%), (vi) 2% HCl in MeOH, 40°C, 2 h, 10a (31%), 10b (41%), (vii) PPh3 (1.5 equiv.), DEAD (1.5
equiv.), THF, rt, 40 min, 1a (54%), 1b (51%)

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Table 1
Asymmetric dihydroxylation of methyl cinnamates (4)
asymmetric dihydroxylation
4 ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢁ 5
R2
% Yielda
% eeb
Config.
[h]2D0
a
b
H
OCH3
80
89
99
99
2R,3Sc
2R,3Sd
+10.6
+2.3
a Isolated yields by column chromatography with silica gel.
1
b The enantiomeric excess was determined by the analysis of H NMR of the diastereomeric Mosher’s esters9 of 5a
and 5b.
c The absolute configurations of the diols were determined by comparison of sign of optical rotation of the
enantiomer (2S,3R, lit.9 [h]2D0 −10.7, enantiomerically pure).
d The absolute configurations were tentatively assigned by enantioselectivity mnemonic in ADH reactions.
Protection of the C(2) and C(3) hydroxyl groups of 5a,b with methoxymethylchloride
(MOMCl) and N,N-diisopropylethylamine followed by reduction with diisobutylaluminum
hydride at −78°C gave corresponding aldehydes, 7a,b. Addition of aryllithium 2a,b10 to the
aldehyde 7a,b afforded secondary alcohol 8a,b, respectively. Oxidation of 8a,b with tetra-
propylammonium perruthenate11 and N-methylmorpholine N-oxide produced the corresponding
ketone 9a,b which were deprotected in acidic condition to give pentahydroxyketone 10a,b. 10a
and 10b were submitted to the intramolecular Mitsunobu reaction with triphenylphosphine and
diethyl azodicarboxylate to give 3-hydroxyflavanone 1a ([h]2D3 −25.0, CH2Cl2; lit.3a [h]D12 −12.5,
CH2Cl2; lit.12 [h]D23 −15.9, CH2Cl2; 59% ee) and 3%,4%-O-dimethyltaxifolin 1b ([h]D17 +12.01,
CH3OH), respectively. The absolute configurations of new stereogenic center (C(2)) of 1a,b were
assigned as 2R by the anti-relationship between C(2)H and C(3)H (J=11.5 Hz), which is in
accord with the SN2 mechanism of the Mitsunobu reaction.
In conclusion, highly enantioselective synthetic method for (2R,3R)-3-hydroxyflavanones was
developed via asymmetric dihydroxylation (ADH) and intramolecular Mitsunobu reaction as
key reactions. By this new synthetic method, (2R,3R)-3%,4%-O-dimethyltaxifolin was prepared
from methyl 3,4-dimethoxycinnamate in seven steps (8, 99% ee). We believe that the highly
efficient synthetic method could be applied for the synthesis of other biologically active
(2R,3R)-3-hydroxyflavanone type natural products.
Acknowledgements
This paper was supported by the NON DIRECTED RESEARCH FUND, Korea Research
Foundation, 1996 and the Research Institute of Pharmaceutical Sciences in College of Pharmacy
of Seoul National University.
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