Synthesis of (+)-(R)-5-hydroxy-6-hydroxymethyl-7-methoxy-8-methylflavanone

Article abstract of DOI:10.1016/S0957-4166(99)00266-9

The synthesis of (+)-(R)-5-hydroxy-6-hydroxymethyl-7-methoxy-8-methylflavanone is described. A new chromylation method of β-ketosulfoxide 9 leading to the Michael acceptor 12 has been developed. Dilithium tetra-chlorocuprate was shown to be a very efficie

Full text of DOI:10.1016/S0957-4166(99)00266-9

Pergamon
Tetrahedron: Asymmetry 10 (1999) 2739–2747
Synthesis of (+)-(R)-5-hydroxy-6-hydroxymethyl-7-methoxy-
8-methylflavanone
Guy Solladié,a,∗ Nicolai Gehrold a and Jean Maignan b
aLaboratoire de Stéréochimie Associé au CNRS, Université Louis Pasteur, ECPM, 25 rue Becquerel, F-67087 Strasbourg,
France
bLaboratoires de Recherche de la société L’Oréal, 1 av. E. Schueller, F-93601 Aulnay sous Bois, France
Received 7 June 1999; accepted 28 June 1999
Abstract
The synthesis of (+)-(R)-5-hydroxy-6-hydroxymethyl-7-methoxy-8-methylflavanone is described. A new chro-
mylation method of β-ketosulfoxide 9 leading to the Michael acceptor 12 has been developed. Dilithium tetra-
chlorocuprate was shown to be a very efficient catalyst for the conjugate addition reaction of phenyl magnesium
bromide to the α,β-unsaturated sulfoxide 12. The instability of the obtained adducts 10 represents a limitation in
terms of yield. It was confirmed that the natural flavanone leridol does not possess the structure of title compound
1. © 1999 Elsevier Science Ltd. All rights reserved.
In the course of our studies directed towards biomimetic syntheses of natural flavanones,1 we have been
faced with the preparation of (+)-(R)-1 in enantiomerically pure form, a structure which was erroneously
assigned to natural leridol.1,2
Recently, Wallace3 reported the synthesis of enantiomerically pure (S)-2-methylchroman-4-one 2
based on the following procedure: transformation of methyl salicylate into the corresponding β-
ketosulfoxide, formylation and cyclodehydration to sulfinylchromone and finally diastereoselective
conjugate addition of lithium dimethyl cuprate giving one diastereomer in 24% isolated yield after
chromatographic separation. After desulfurization and partial reduction of the carbonyl with aluminium
amalgam, a PDC oxidation gave (−)-(S)-chromanone 2 in 59% yield (Scheme 1). Without separation of
the diastereomeric intermediates, Wallace3 obtained the cuprate adduct 2 in 88% ee and 65% yield (for
the last three steps).
∗
Corresponding author. Fax: 33 3 88 13 69 49; e-mail: solladie@chimie.u-strasbg.fr
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00266-9

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Scheme 1.
Direct application of this method to the synthesis of compound 1 very quickly raised several problems.
2,4,6-Trimethoxytoluene 3 was orthometallated with the complex base of Schlosser (a mixture of t-
BuOK and n-BuLi)4 and quenched with ethyl carbonate to obtain the ester 4 in 65% yield (Scheme 2).
Monodemethylation with BBr3 in dichloromethane gave a mixture of ethyl 6-hydroxy-2,4-dimethoxy-
3-methylbenzoate (33% isolated yield) and ethyl 2-hydroxy-4,6-dimethoxy-3-methylbenzoate 5 (45%
isolated yield) which was separated by chromatography and identified by NOE experiments. Unfortuna-
tely, all the attempts to obtain the corresponding β-ketosulfoxide by reaction of the ester 5 with an excess
of methyl p-tolylsulfoxide anion failed, probably because of steric hindrance and ester deactivation by
the aromatic oxygens.
Scheme 2.
The strategy was modified and the required β-ketosulfoxide 9 was prepared via the aldehyde 7 which
was synthesized by Vilsmeier–Haack formylation of trimethoxytoluene5 and regioselective demethyla-
tion with AlCl3 (Scheme 3). Yields were much higher than those obtained for the ester 5.
Addition of methyl p-tolylsulfoxide anion to the phenolate of the aldehyde 7 afforded a diastereomeric
mixture (60/40) of the crude and almost pure β-hydroxysulfoxide 8 which was oxidized with MnO2
to the corresponding β-ketosulfoxide 9. Compound 9 was obtained from the commercial 3 in excellent
yields and without any chromatographic purification.
Reaction of the β-ketosulfoxide 9 with benzaldehyde in the presence of pyrrolidine should give
the sulfinylflavanone 10 via a Knoevenagel condensation followed by a cyclization step. However, we
isolated only the flavone 11 formed by spontaneous syn elimination of p-tolylsulfenic acid (Scheme 4).
This reaction was already reported for the attempted synthesis of trans-3-(phenylsulfinyl)flavanone by
m-CPBA oxidation of the corresponding sulfide. In contrast, the isomer having the sulfinyl and phenyl
groups cis was stable and could be obtained in a good yield.6 In our case, no sulfinylflavanone 10 could
be isolated, probably due to a rapid interconversion of the four possible diastereomers under the reaction
conditions.

G. Solladié et al. / Tetrahedron: Asymmetry 10 (1999) 2739–2747
2741
Scheme 3.
Scheme 4.
Direct formylation–cyclodehydration of 9 under the conditions of Allan–Robinson proposed by
Wallace3 (acetic formic anhydride, sodium formate, reflux 3 h) gave the sulfinylchromen-4-one 12 in
only 22% yield. We finally obtained a yield of 72% by using in situ formed N-formylimidazole7 as
formylating agent. The reaction of the dianion of 9 and the imidazolide carried out between −40°C and
room temperature gave a mixture of the chromone 12 and a not fully identified intermediate which was
transformed into 12 by treatment with silica gel in dichloromethane (Scheme 5). The described conditions
represent a new general method for preparation of 3-substituted chromones of type 12.
Scheme 5.
Addition of lithium diphenyl cuprate, phenyl magnesium bromide or phenyl lithium to the chromone
12 gave only traces of addition product 10 and its elimination product 11. We finally solved this
problem by adding the phenylmagnesium bromide in the presence of a catalytic amount of lithium
tetrachlorocuprate, a compound used till now only for Würtz type coupling reactions.8 Under these
conditions, a very clean reaction was observed, leading immediately after work-up to a mixture of
three diastereomers of 10 and to 11 in the ratio 5:2:2:2, the main diastereomer being 10A which was
isolated by chromatography in 45% yield. The relative stereochemistry of 10A was not clear from the

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G. Solladié et al. / Tetrahedron: Asymmetry 10 (1999) 2739–2747
coupling constant (J2,3=2 Hz). Isomers 10B and 10C could not be separated by chromatography, but
they showed very different stabilities. Isomer 10C disappeared almost completely within 24 h, while
isomer 10B seemed to be stable at room temperature in CDCl3. On this basis, it is reasonable to attribute
the trans stereochemistry to 10C and cis to 10B. Stability of 10A was between those of 10B and 10C.
The main isomer 10A could be 2,3-trans or 2,3-cis, the latter suffering from slow epimerization to 2,3-
trans and rapid elimination of p-tolylsulfenic acid. Due to its low stability, 10A was desulfurized as
quickly as possible. The yield with aluminium amalgam was only 45% because some decomposition
occurred before running the reaction. The flavanone 13 was identified as (+)-(R)-dimethylcryptostrobin,
enantiomer of a known natural product (Scheme 6).9
Scheme 6.
Finally 13 was regioselectively demethylated with aluminium chloride and hydroxymethylated with
formaldehyde, a reaction sequence already used in racemic form 1, to obtain the flavanone (+)-(R)-1
(Scheme 7).
Scheme 7.
The (+)-enantiomer of 1 exhibited all the characteristics of racemic 11 showing particularly a different
melting point (98–100°C) with respect to natural leridol (139–140°C).2 This is good confirmation that
natural leridol does not have the structure 1. The enantiomerically pure flavanone (+)-(R)-1 could be
synthesized in nine steps with an overall yield of 6.1% starting from trimethoxytoluene 3.
1. Experimental
1.1. General remarks
1H and 13C NMR spectra were recorded on a Bruker AC-200 spectrometer at 200 and 50 MHz,
respectively. Chemical shifts δ were in ppm relative to solvent signal (residual proton signal for
proton spectra or carbon signal for carbon spectra). IR spectra: Perkin–Elmer 257 spectrophotometer
in cm−1. Melting points: Reichert uncorrected. Elemental analysis: Microanalytical Service of CNRS
of Strasbourg. Optical rotations: Perkin–Elmer 241 MC polarimeter between 20 and 23°C. Analytical
TLC: precoated Merck silica gel 60F-254 glass plates; detection by UV (λ=254 nm or 365 nm) and/or
visualization by spray reagents (ethanolic vanillin/H2SO4, p-anisaldehyde/H2SO4 or phosphomolybdic
acid). Preparative (column) chromatography: silica gel Geduran Si 60 (40–63 µm; 70–230 mesh) from

G. Solladié et al. / Tetrahedron: Asymmetry 10 (1999) 2739–2747
2743
E. Merck. Work-up: organic solutions were dried using magnesium sulfate monohydrate (MgSO4·H2O),
filtered over sintered glass and concentrated by rotary evaporation at water aspirator pressure, unless
otherwise stated.
1.2. Ethyl 2,4,6-trimethoxy-3-methylbenzoate 4
A 1.5 M solution of n-butyllithium in hexane (1.46 ml, 2.19 mmol, 2.0 equiv.) was slowly added to a
stirred suspension of t-BuOK (246 mg, 2.19 mmol, 2.0 equiv.) in THF (7 ml) at −78°C. To this mixture
was added a solution of 2,4,6-trimethoxytoluene 3 (200 mg, 1.10 mmol, 1.0 equiv.) in THF (2 ml). After
30 min, diethyl carbonate (0.63 ml, 2.19 mmol, 2.0 equiv.) was added dropwise. The solution was stirred
for 30 min before being quenched with water (10 ml). The two phases were separated and the aqueous
phase was extracted with ether (3×20 ml). The combined organic phases were washed with brine (20
ml), dried, filtered and concentrated. The crude product was purified on silica gel to give 182 mg (yield
65%) of 4. Rf=0.22 (hexane:AcOEt, 4:1); 1H NMR (CDCl3): δ 1.37 (t, 3H, J=7 Hz, CH3 ester), 2.08 (s,
3H, 3-Me), 3.80, 3.82, 3.84 (3s, 9H, 3×OMe), 4.37 (q, 2H, CH2 ester), 6.24 (s, 1H, H-5).
1.3. Ethyl 2-hydroxy-4,6-dimethoxy-3-methylbenzoate 5
To a solution of benzoate 4 (100 mg, 0.393 mmol, 1.0 equiv.) in CH2Cl2 (1 ml) was added a 1 M
solution of boron tribromide (0.39 mg, 0.39 mmol, 1.0 equiv.) in CH2Cl2 at −78°C. The solution was
stirred for 1 h before being quenched with water (5 ml). Ethyl acetate was added and the emulsion was
broken by adding brine and 10% hydrochloric acid. The two phases were separated and the aqueous
phase was extracted with ethyl acetate (3×5 ml). The combined organic phases were dried, filtered and
concentrated. The crude product was purified on silica gel to give 42 mg (yield 45%) of 5 as well as
1
31 mg (yield 33%) of its 6-hydroxy isomer. Rf=0.32 (hexane:AcOEt, 4:1); H NMR (CDCl3): δ 1.40
(t, 3H, J=7 Hz, CH3 ester), 2.02 (s, 3H, 3-Me), 3.85, 3.86 (2s, 6H, 2×OMe), 4.38 (q, 2H, J=7 Hz,
CH2 ester), 5.99 (s, 1H, H-5), 11.94 (s, 1H, 2-OH); ethyl 6-hydroxy-2,4-dimethoxy-3-methylbenzoate:
Rf=0.44 (hexane:AcOEt, 4:1); 1H NMR (CDCl3): δ 1.43 (t, 3H, J=7 Hz, CH3 ester), 2.04 (s, 3H, 3-Me),
3.71, 3.83 (2s, 6H, 2×OMe), 4.42 (q, 2H, J=7 Hz, CH2 ester), 6.27 (s, 1H, H-5), 11.70 (s, 1H, 6-OH).
1.4. 2,4,6-Trimethoxy-3-methylbenzaldehyde 610
To a solution of 2,4,6-trimethoxytoluene 3 (5.0 g, 27.4 mmol, 1.0 equiv.) in DMF (15 ml) was slowly
added freshly distilled POCl3 (3.0 ml, 32.2 mmol, 1.17 equiv.) at 0°C. The mixture was allowed to reach
room temperature and the solution was stirred for a further 2 h before being poured into ice and water
(40 ml). Next day the fine white needles were filtered, washed with water and dried overnight at reduced
pressure to give 5.221 g (yield 90%) of 6. The filtrate was extracted with ethyl acetate (3×15 ml). The
extracts were dried, filtered and concentrated to give a further 534 mg (yield 9%) of 6. Total yield: 99%.
1
Rf=0.17 (hexane:AcOEt, 2:1); mp=79–82°C (lit.10: 84°C); H NMR (CDCl3): δ 2.05 (s, 3H, 3-CH3),
3.77, 3.89, 3.90 (3s, 9H, 3×OMe), 6.23 (s, 1H, H-5), 10.31 (s, 1H, CHO).
1.5. 2-Hydroxy-4,6-dimethoxy-3-methylbenzaldehyde 7
A mixture of aldehyde 6 (5.75 g, 27.3 mmol, 1.0 equiv.) and aluminium trichloride (5.56 g, 41.7 mmol,
1.52 equiv.) was heated at reflux in benzene (50 ml) for 15 h. After cooling, the supernatant was discarded
and the residual viscous oil was dried in vacuo before being hydrolyzed with water (30 ml) and conc.

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hydrochloric acid (30 ml). Dichloromethane (200 ml) was added, the two phases were separated and the
aqueous phase containing a yellow-orange precipitate was stirred overnight with CH2Cl2 (50 ml). The
two phases were separated and the aqueous phase was extracted with CH2Cl2 (3×30 ml). The combined
organic phases were washed with a saturated NaHCO3 solution (40 ml) and brine (40 ml). They were
1
dried, filtered and concentrated to give 4.90 g (yield 91%) of 7 as a solid (virtually pure in H NMR)
which could be crystallized from ethanol (125 ml) to yield yellowish flakes. Rf=0.34 (hexane:AcOEt,
2:1); mp=168–169°C (lit.11: 168–169°C); 1H NMR (CDCl3): δ 1.99 (s, 3H, 3-CH3), 3.89, 3.91 (2s, 6H,
2×OMe), 5.94 (s, 1H, H-5), 10.14 (s, 1H, CHO), 12.44 (s, 1H, 2-OH).
1.6. (RS)-1-(2-Hydroxy-4,6-dimethoxy-3-methylphenyl)-2-(p-tolylsulfinyl)ethanol 8
Two identical solutions of LDA in THF/hexane (approx. 50 ml, 18.6 mmol, 1.1 equiv.) were prepared.
(+)-(R)-Methyl p-tolylsulfoxide12 (2.604 g, 16.88 mmol, 1.02 equiv.) dissolved in THF (15 ml) was
added to the first solution of LDA at −10°C (solution A). The second solution of LDA was cannulated to
a suspension of aldehyde 7 (3.25 g, 16.56 mmol, 1.0 equiv.) in THF (30 ml) at −40°C. The suspension
became white and the temperature was allowed to reach 0°C for approx. 1 h (suspension B). Solution
A was then cannulated to suspension B at −40°C. The precipitate dissolved during addition and the
obtained clear yellow solution was stirred for 1 h while allowing the temperature to reach −25°C. The
reaction was quenched with 1 M hydrochloric acid (60 ml) and the pH was adjusted to 2–3. The two
phases were separated and the aqueous phase was extracted with ethyl acetate (3×25 ml). The combined
organic phases were washed with brine (50 ml), dried, filtered and concentrated. The oily brown crude
product was re-evaporated with CH2Cl2 (20 ml) to give 5.90 g (mass yield 100%) of 8 as a whitish solid.
1
Rf=0.53 (AcOEt; anisaldehyde: blue; the diastereomeric mixture gave a single spot in TLC); H NMR
(CDCl3): the spectrum indicated the presence of two diastereomers (83%) in a 60:40 ratio, as well as
those of aldehyde 7 (7%) and starting sulfoxide (10%). Yield of crude product was thus estimated to be
92%. Major isomer: δ 1.99 (s, 3H, 30-CH3), 2.47 (s, 3H, CH3 p-Tol), 2.59 (dd, 1H, JAB=14 Hz, J1,2=1.5
Hz, H-2B), 3.40 (s, 3H, OMe), 3.65 (dd, 1H, JAB=14 Hz, J1,2=10.5 Hz, H-2A), 3.74 (s, 3H, OMe), 5.65
(m, 1H, H-1), 5.83 (m, 2H, 1-OH and H-50), 7.48 (A2B2, 4H, J=8 Hz, ∆ν=26.5 Hz, ArH), 9.58 (s, 1H,
20-OH); minor isomer: δ 1.99 (s, 3H, 30-CH3), 2.41 (s, 3H, CH3 p-Tol), 2.90 (dd, 1H, J1,2=2.5 Hz, H-
2B), 3.28 (dd, 1H, H-2A), 3.79 (s, 3H, OMe), 3.81 (s, 3H, OMe), 5.83 (m, 1H, 1-OH), 5.99 (s, 1H, H-50),
6.05 (m, 1H, H-1), 7.43 (A2B2, 4H, J=8 Hz, ∆ν=45 Hz, ArH), 9.44 (s, 1H, 20-OH); the other coupling
constants could not be determined.
1.7. (−)-(RS)-1-(2-Hydroxy-4,6-dimethoxy-3-methylphenyl)-2-(p-tolylsulfinyl)ethanone 9
A mixture of crude hydroxysulfoxide 8 (3.75 g, 10.7 mmol, 1.0 equiv.) and MnO2 (Fluka 63548
activated at 120°C; 6.12 g, 70 mmol, 6.6 equiv.) in CH2Cl2 (30 ml) was stirred at room temperature for
48 h. A second portion of MnO2 (4.0 g, 46 mmol, 4.3 equiv.) was added and the mixture was stirred for a
further 20 h. The reagent was separated by filtration over sintered glass (porosity 4) and well washed with
CH2Cl2. The filtrate was reduced to 50 ml on the rotary evaporator and washed with 0.3 M hydrochloric
acid (10 ml), a saturated NaHCO3 solution (10 ml) and brine (10 ml). The organic phase was dried,
filtered and concentrated to give 3.37 g (90%) of crude product. The crude product was crystallized from
ethyl acetate (76 ml) to give 2.482 g (yield 67.6%) of 9 as fine yellow needles. The residue of the mother
liquor was purified by chromatography on silica gel to give a further 435 mg (11.8%) of 9. Overall yield:
79% based on aldehyde 7. Rf=0.30 (AcOEt; anisaldehyde: orange red); mp=170–172°C; [α]D=−44 (c
1.0; CHCl3); the optical rotations of the chromatographed and crystallized products, respectively, were

G. Solladié et al. / Tetrahedron: Asymmetry 10 (1999) 2739–2747
2745
1
identical. H NMR (CDCl3): δ 1.98 (s, 3H, 30-CH3), 2.40 (s, 3H, Me p-Tol), 3.90 (s, 3H, OMe), 3.92
(s, 3H, OMe), 4.54 (AB, 2H, J=14 Hz, ∆ν=85 Hz, H-2), 5.94 (s, 1H, H-50), 7.43 (A2B2, 4H, J=8 Hz,
∆ν=53 Hz, ArH), 13.17 (s, 1H, 20-OH); 13C NMR (CDCl3): δ 7.2 (50-Me), 21.5 (Me p-Tol), 55.7, 55.8
(OMe), 72.2 (C-2), 86.0 (C-50), 105.6, 106.2 (C-10, C-30), 124.5, 130.0 (Cart), 141.0, 141.9 (Carq), 161.3,
163.9, 164.8 (C-20, C-40, C-60), 194.2 (C-1); IR (CHCl3): νmax (cm−1) 3960, 3920, 2990, 2400, 1630,
1600, 1495, 1470, 1410, 1290, 1145, 1090, 1035, 1015, 940. Anal. calcd for C18H20O5S: C, 62.05; H,
5.79. Found: C, 62.14; H, 5.62.
1.8. 5,7-Dimethoxy-8-methylflavone 11
To a solution of ketosulfoxide 9 (55 mg, 0.158 mmol, 1.0 equiv.) in CH2Cl2 (2 ml) was added 0.4
ml of a solution prepared from benzaldehyde (1.0 ml, 9.8 mmol), pyrrolidine (0.1 ml, 1.2 mmol) and
CH2Cl2 (4 ml). The solution was stirred for 22 h before being evaporated to dryness. A mixture of
hexane:AcOEt (1:1, 5 ml) was added and the solid product was filtered to give 27 mg (yield 58%) of 11.
The crude product was crystallized from ethanol (1.4 ml) to give fine white needles. Rf≈0.05 (AcOEt;
1
anisaldehyde: yellow); mp=228–229°C (lit.13: 230–232°C); H NMR (CDCl3): δ 2.33 (s, 3H, 8-Me),
3.95, 4.00 (2s, 6H, 2×OMe), 6.42 (s, 1H, H-6), 6.67 (s, 1H, H-2), 7.5 (m, 3H, ArH), 7.9 (m, 2H, ArH);
13C NMR (CDCl3): δ 8.2 (8-Me), 55.9, 56.5 (OMe), 91.5 (C-6), 106.2, 108.4 (C-8, C-10), 126.0 (C-20,
C-60), 129.1 (C-30, C-50), 131.2 (C-40), 132.0 (C-10), 156.7, 159.1, 160.5, 161.4 (C-2, C-5, C-7, C-9),
178.4 (C-4).
1.9. (−)-(SS)-5,7-Dimethoxy-8-methyl-3-(p-tolylsulfinyl)chromen-4-one 12
A solution of LDA (14.9 mmol, 2.6 equiv.) was cannulated to a suspension of ketosulfoxide 9 (2.00 g,
5.75 mmol, 1.0 equiv.) in THF (25 ml) at −40°C, giving an orange solution. The temperature was then
allowed to reach −20°C (solution A). At the same time, 1-formyl-1H-imidazole was prepared in situ at
room temperature by adding formic acid (0.47 ml, 12.3 mmol, 2.13 equiv.; in 5 ml of THF) to a solution
of 1,10-carbonyldiimidazole (2.01 g, 12.4 mmol, 2.16 equiv.) in THF (15 ml) (solution B). Solution B
was added to solution A at −60°C and the mixture was allowed to reach room temperature. The solution
was stirred overnight before being quenched with 1 M sulfuric acid (15 ml). The organic solvents were
evaporated and the residue was taken up with CH2Cl2 and washed with brine. The organic phase was
dried, filtered and concentrated. The crude product was dissolved in CH2Cl2 (35 ml) and stirred in the
presence of silica gel (6 g) until disappearance of the intermediate product (2 h). This mixture was
poured onto a filled column of silica gel/CH2Cl2 and eluted with CH2Cl2:AcOEt (3:1) to give 1.490 g
(yield 72%) of 12. The product could be crystallized from AcOEt (25 ml) and CH2Cl2 (10 ml). Rf=0.42
(CH2Cl2:AcOEt, 1:1); Rf (intermediate product)=0.27 (CH2Cl2:AcOEt, 1:1); mp=223–225°C (fine white
needles); [α]D=−300 (c 1.0; CHCl3); 1H NMR (CDCl3): δ 2.19 (s, 3H, 8-CH3), 2.35 (s, 3H, Me p-Tol),
3.92, 3.93 (2s, 6H, 2×OMe), 6.37 (s, 1H, H-6), 7.51 (AB, 4H, J=8 Hz, ∆ν=108 Hz), 8.24 (s, 1H, H-2);
13C NMR (CDCl3): δ 7.8 (8-Me), 21.5 (Me p-Tol), 56.0, 56.4 (OMe), 92.0 (C-6), 106.5, 108.3 (C-8,
C-10), 125.7, 129.9 (Cart), 129.6 (C-3), 140.6, 142.0 (Carq), 152.8 (C-2), 156.8, 159.4, 162.1 (C-5, C-7,
C-9), 173.2 (C-4); IR (CHCl3): νmax (cm−1) 3690, 3620, 2990, 2400, 1645, 1610, 1585, 1500, 1470,
1435, 1395, 1340, 1315, 1270, 1145, 1125, 1080, 1035, 1015, 950, 920. Anal. calcd for C19H18O5S: C,
63.67; H, 5.06. Found: C, 63.69; H, 4.81.

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1.10. (2R,SS)-5,7-Dimethoxy-8-methyl-3-(p-tolylsulfinyl)flavanone 10A
The sulfoxide 12 (385 mg, 1.08 mmol, 1.0 equiv.) was dissolved in a minimum of THF (20 ml) and
a 0.1 M solution of Li2CuCl4 in THF (2.2 ml, 0.22 mmol, 0.2 equiv.) was added at −72°C. The formed
white precipitate dissolved during the slow addition of a solution of 1 M PhMgBr in THF (2.2 ml, 0.22
mmol, 2.0 equiv.). The solution was stirred for 1 h between −72 and −40°C before being quenched
with a saturated NH4Cl solution. The two phases were separated and the aqueous phase was extracted
with ethyl acetate (3×10 ml). The combined organic phases were washed with brine, dried, filtered and
concentrated. The crude product was chromatographed on demetalated silica gel to give 211 mg (yield
1
45%) of 10A. Rf=0.57 (CH2Cl2:AcOEt, 1:1); H NMR (CDCl3): δ 2.14 (s, 3H, 8-Me), 2.41 (s, 3H,
Me p-Tol), 3.84, 3.91 (2s, 6H, 2×OMe), 3.94 (d, 1H, J2,3=2 Hz, H-3), 6.07 (s, 1H, H-6), 6.36 (d, 1H,
J
2,3=2 Hz, H-2), 7.2–7.5 (m, 9H, ArH); 13C NMR (CDCl3): δ 8.0 (8-Me), 21.7 (Me p-Tol), 55.8 and
56.0 (OMe), 75.7 and 77.3 (C-2, C-3), 88.5 (C-6), 106.4, 106.5 (C-8, C-10), 125.0, 126.0, 128.3, 128.8,
130.0 (Cart), 136.6, 138.4, 142.5 (Carq), 158.9, 160.4, 164.7 (C-5, C-7, C-9), 180.6 (C-4). Isomers 10B
1
and 10C: Rf=0.42 (CH2Cl2:AcOEt, 1:1); H NMR (CDCl3): 10B characteristic signals: δ 3.79 (d, 1H,
J=2.5 Hz, H-3), 5.85 (d, 1H, J=2.5 Hz, H-2), 6.16 (s, 1H, H-6); 10C characteristic signals: δ 5.91 (s, 1H,
H-6), 6.20 (d, H-2).
1.11. (+)-(R)-5,7-Dimethoxy-8-methylflavanone (dimethylcryptostrobin) 13
Aluminium amalgam (Al/Hg) (90 mg, 3.3 mmol, 9.4 equiv.) was added to a stirred solution of
sulfinylflavanone 10A (155 mg, 0.355 mol, 1.0 equiv.) in THF:H2O (9:1, 15 ml) at −5°C. The solution
was stirred for 35 min before being filtered over sintered glass. The precipitate was washed with THF
(3×10 ml), water (5 ml) and brine (10 ml) were added and the product was extracted with ethyl acetate
(3×10 ml). The combined organic phases were dried, filtered and concentrated. The crude product was
chromatographed on silica gel to give 47.5 mg (yield 45%) of 13. Mp=139–141°c (lit.9: 141–142°C for
1
the (S)-isomer); [α]D=+37.5 (c 0.93; EtOH); lit.9: [α]D=−37.1 (c 0.38; EtOH) for the (S)-isomer; H
NMR (CDCl3): δ 2.04 (s, 3H, 8-Me), 2.89 (ABX, 2H, JAB=16.5 Hz, JAX=12 Hz, JBX=4 Hz, ∆ν=22.5
Hz, H-3), 3.89 and 3.92 (2s, 6H, 2×OMe), 5.38 (dd, ABX, 1H, JAX=12 Hz, JBX=4 Hz, H-2), 6.11 (s, 1H,
H-6), 7.3–7.5 (m, 5H, ArH); 13C NMR (CDCl3): δ 7.9 (8-Me), 45.8 (C-3), 55.7 and 56.1 (OMe), 78.5
(C-2), 88.5 (C-6), 106.0, 106.3 (C-8, C-10), 125.9 (C-20, C-60), 128.4 (C-40), 128.7 (C-30, C-50), 139.4
(C-10), 160.6, 161.2, 163.6 (C-5, C-7, C-9), 190.0 (C-4).
1.12. (+)-(R)-5-Hydroxy-7-methoxy-8-methylflavanone 14
A mixture of 13 (46 mg, 0.154 mmol, 1.0 equiv.) and anhydrous aluminium chloride (75 mg, 0.56
mmol, 3.6 equiv.) in acetonitrile (2.5 ml) was refluxed for 2 h. After standing at room temperature for
2 h the mixture was poured on ice. The volume was reduced by evaporation and 3 M hydrochloric acid
(5 ml) was added. The aqueous phase was extracted with ethyl acetate (3×5 ml). The combined organic
phases were washed with brine (5 ml), dried, filtered and concentrated. The crude product was purified on
silica gel to give the title compound 14 (33 mg, yield 75%). Rf=0.57 (hexane:AcOEt. 3:1, anisaldehyde:
orange); mp=143–145°C (lit.14: mp=143°C); [α]D=+67 (c 0.54; CHCl3); 1H NMR (CDCl3): δ 2.01 (s,
3H, 8-Me), 2.94 (ABX, 2H, JAB=17 Hz, JAX=12.5 Hz, JBX=3.5 Hz, ∆ν=35.5 Hz, H-3), 3.86 (s, 3H,
OMe), 5.42 (dd, ABX, 1H, JAX=12.5 Hz, JBX=3.5 Hz, H-2), 6.10 (s, 1H, H-6), 7.3–7.5 (m, 5H, ArH),
12.12 (s, 1H, chelated ArOH); 13C NMR (CDCl3): δ 7.7 (8-Me), 43.5 (C-3), 56.0 (7-OMe), 78.6 (C-2),

G. Solladié et al. / Tetrahedron: Asymmetry 10 (1999) 2739–2747
2747
92.3 (C-6), 102.9, 105.0 (C-8, C-10), 126.0 (C-20, C-60), 128.6 (C-40), 128.9 (C-30, C-50), 139.1 (C-10),
158.9, 162.5, 166.1 (C-5, C-7, C-9), 196.3 (C-4).
1.13. (+)-(R)-5-Hydroxy-6-hydroxymethyl-7-methoxy-8-methylflavanone 1
To a solution of flavanone 14 (26 mg, 0.091 mmol, 1.0 equiv.) in glacial acetic acid (4 ml) were
successively added formalin 37 wt% (0.3 ml, ∼3.8 mmol, 40 equiv.) and concentrated hydrochloric acid
(0.3 ml) at room temperature. The mixture was stirred for 4 h before being quenched with water (20
ml). The aqueous phase was extracted with ethyl acetate (4×10 ml). The combined organic phases were
washed with a saturated NaHCO3 solution (10 ml), dried, filtered and concentrated. The crude product
was purified on silica gel to give 20.5 mg (yield 71%) of 1 as a white solid. Rf=0.43 (hexane:AcOEt,
1
1:1, vanillin: red); mp=98–100°C; [α]D=+29 (c 0.2; CHCl3); H NMR (CDCl3): δ 2.10 (s, 3H, 8-Me),
2.34 (t, 1H, J=6.5 Hz, OH), 2.98 (ABX, 2H, JAB=17 Hz, JAX=12 Hz, JBX=3.5 Hz, ∆ν=35 Hz, H-3),
3.85 (s, 3H, OMe), 4.73 (d, 2H, J=6.5 Hz, 6-CH2O), 5.45 (dd, ABX, 1H, JAX=12 Hz, JBX=3.5 Hz, H-2),
7.39–7.50 (m, 5H, ArH), 12.15 (s, 1H, chelated ArOH); 13C NMR (CDCl3): δ 8.6 (8-Me), 43.5 (C-3),
54.5 (6-CH2O), 62.0 (7-OMe), 78.8 (C-2), 105.0, 110.3 (C-8, C-10), 114.7 (C-6), 126.0 (C-20, C-60),
128.8 (C-40), 128.9 (C-30, C-50), 138.6 (C-10), 159.8 (magnetic equivalence) and 165.7 (C-5, C-7, C-9),
197.5 (C-4).
Acknowledgements
We gratefully acknowledge L’Oréal for financial support as well as for a scholarship to N.G.
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