Angewandte
Chemie
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%.
Angew. Chem. Int. Ed. 2013, 52, 11651 –11655
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim