The first stereocontrolled synthesis of isoflavanones

Article abstract of DOI:10.1016/S0040-4039(00)01464-7

The first asymmetric synthesis of isoflavanones has been performed employing a stereocontrolled aldol reaction between an (S,S)-(+)-pseudoephedrine arylacetamide and para-formaldehyde as the key step. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01464-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8297–8300
The first stereocontrolled synthesis of isoflavanones
Jose L. Vicario, Dolores Bad´ıa,* Esther Dom´ınguez, Mo´nica Rodr´ıguez and Luisa Carrillo
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, Universidad del Pa´ıs Vasco, PO Box 644,
48080 Bilbao, Spain
Received 28 July 2000; accepted 1 September 2000
Abstract
The first asymmetric synthesis of isoflavanones has been performed employing a stereocontrolled aldol
reaction between an (S,S)-(+)-pseudoephedrine arylacetamide and para-formaldehyde as the key step.
© 2000 Elsevier Science Ltd. All rights reserved.
Keywords: asymmetric synthesis; flavanoids; isoflavanoids.
Isoflavanoids represent a large group of naturally occurring secondary metabolites displaying
a wide array of physiological activities.1 Among them, the isoflavanones are a relatively small
group of compounds which have shown interesting antifungal2 and antibacterial3 activities and
behave as potent phytoalexins.4 A chiral centre is present in their structure, and therefore the
design of synthetic procedures should allow their synthesis in a stereocontrolled way. To date,
only the asymmetric syntheses of close derivatives like isoflavans,5 pterocarpans6 or isoflavanols7
have been carried out but no asymmetric synthesis of isoflavanones have been reported.
In the context of our research in the field of asymmetric synthesis of natural products,8 we
have developed a procedure to obtain isoflavanone derivatives in a stereocontrolled way
according to the retro-synthetic approach shown in Scheme 1. Following this sequence, the
chiral centre present in the final molecule will be formed by an asymmetric aldol reaction
between an (S,S)-(+)-pseudoephedrine-based arylacetamide derivative and formaldehyde under
1
O
8
O
HO
7
6
2
OH
Ph
R2
R2
A
B
N
3
4
CO2H
R1
R1
R1
5
O
O
Scheme 1.
* Corresponding author. E-mail: qopbaurm@lg.ehu.es
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01464-7

8298
a protocol developed previously by us.9 Later, the B ring will be introduced in the form of a
phenol ether and finally, after the chiral auxiliary is removed, the A ring will be formed by an
intramolecular acylation process building up the skeleton of the target heterocycle. This
preparative approach to accessing this kind of heterocycle is novel in this group of substances.
The arylacetamides 1, prepared by a previously reported procedure,10 were submitted to
deprotonation by 2 equiv. of LDA in THF at −78°C (Scheme 2) and the formed dianion was
reacted with para-formaldehyde (4 equiv.) at −105°C yielding the corresponding b-hydroxy-
amides in good yields and only one of the two possible diastereomers was formed, as indicated
by HPLC analysis under the optimised conditions for a 1:1 mixture of both epimers (see Table
1). According to a previously reported mechanism for the asymmetric aldol reactions of
(S,S)-(+)-pseudoephedrine amides,9 the configuration of the newly created chiral centre was
assigned as S.
HO
OH
Ph
OH
Ph
R1
R2
(i)
R1
R2
N
N
O
O
R3
R3
1a-c
2a-c
Scheme 2. Reagents and conditions: (i) 1. LDA, THF, −78°C; 2. HCHO, THF, −105°C
Table 1
Asymmetric aldol reaction between arylacetamides 1a–c and HCHO
Product
R1
R2
R3
d.e. (%)a
Yield
2a
2b
2c
OCH3
OCH3
OCH2O
OCH3
OCH3
OCH2O
H
OCH3
H
\99
\99
\99
85
81
86
a Determined by HPLC (Chiralcel OD, hexane/iso-propanol 70:30, flow rate 1.00 mL/min).
We then proceeded to introduce the isoflavanone B ring via phenol ether formation, which
was performed by nucleophilic displacement of the hydroxylic function by a phenolic alcohol
under Mitsunobu conditions.11 Thus after 12 h of reaction of amides 2a–c with 2 equiv. of
phenol and di-isopropyl azodicarboxylate (DIAD) in THF at rt, in the presence of excess PPh3,
the starting material was completely consumed. However, attempts to isolate the reaction
product were unsuccessful due to the presence of large amounts of PPh3ꢀO. Therefore, the crude
reaction mixture was subjected to acid hydrolysis (4 M H2SO4/dioxane, reflux) and, after a
previous standard acid–base work-up treatment followed by flash column chromatography
purification, the corresponding acids 3a–d were obtained in moderate overall yield. The chiral
auxiliary (S,S)-(+)-pseudoephedrine was recovered from the work-up of the basic extracts but as
its phenol ether derivative, which indicated that both hydroxylic functions of the amides 2a–c
were converted to the respective phenol ethers during the Mitsunobu reaction.
Finally, in the last step of the synthesis, these acids were converted into the final heterocycles
by intramolecular Friedel–Crafts acylation (see Scheme 3) yielding the isoflavanones 4a–d in
good yields (see Table 2) and only as one detectable enantiomer, as indicated by chiral HPLC
analysis under optimised conditions for a racemic standard.12

8299
R4
R5
R4
R5
O
O
O
R1
R2
R1
R2
(iii)
(i), (ii)
CO2H
2a-c
R4
R4
R3
R3
3a-d
4a-d
Scheme 3. Reagents and conditions: (i) PPh3, ArOH, DIAD; (ii) 4 M H2SO4/dioxane, reflux; (iii) 1. SOCl2, toluene,
reflux, 2. SnCl4, CH2Cl2, rt
Table 2
The prepared isoflavanones 4a–d
Prod.
R1
R2
R3
R4
R5
Yield
Prod.
e.e. (%)a
Yield
3a
3b
3c
3d
OCH3
OCH3
OCH2O
OCH3
OCH3
OCH3
OCH2O
OCH3
H
OCH3
H
H
H
H
OCH3
OCH3
OCH3
OCH3
H
69
71
68
69
4a
4b
4c
4d
\99
\99
\99
\99
84
86
81
88
H
a Determined by HPLC (Chiralcel OD, hexane/iso-propanol 93:7, flow rate 1.00 mL/min).
In summary, stereoselective synthesis of several isoflavanones has been achieved by employing
the asymmetric aldol reaction of (S,S)-(+)-pseudoephedrine arylacetamides with formaldehyde
as the key step with respect to the formation of the chiral centre. Subsequent transformation
(aryl ether formation, hydrolysis and intramolecular acylation) furnished the target heterocycles
in good yields and excellent optical purities.
Acknowledgements
Financial support from the Basque Government (a fellowship to J.L.V.) and from the Spanish
Direccio´n General de Estudios Superiores (Project PB98-0600) is gratefully acknowledged.
References
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1
12. 4a: Mp 168–170°C (EtOH); [h]2D0 +51.8 (c 0.1, CH2Cl2); H NMR (l, ppm): 3.03 (dd, 1H, J=10.3, 16.4 Hz); 3.19
(dd, 1H, J=6.8, 16.4 Hz); 3.83 (s, 3H); 3.85 (s, 3H); 3.88 (s, 3H); 4.03 (dd, 1H, J=6.8, 10.3 Hz); 6.45–6.79 (m,
5H); 7.18 (s, 1H); 13C NMR (l, ppm): 44.9, 55.5, 55.8, 56.3, 72.4, 103.5, 111.0, 110.4, 111.3, 115.1, 119.6, 130.2,
147.6, 148.4, 152.7, 161.3, 192.4. Relevant data for the rest of isoflavanones 4: 4b: Mp 177–180°C (EtOH), [h]D20
+64.4 (c 0.2, CH2Cl2). 4c: Mp 159–162°C (EtOH), [h]2D0 +58.3 (c 0.2, CH2Cl2). 4d: Mp 163–165°C (EtOH), [h]D20
+54.6 (c 0.2, CH2Cl2).
.
.