Synthesis of both enantiomers of flavanone and 2-methylchromanone

Article abstract of DOI:10.1002/1522-2675(200210)85:10<3473::AID-HLCA3473>3.0.CO;2-7

An efficient enantiospecific synthesis of the (R)- and (S)-enantiomers of flavanone and 2-methylchromanone is described. The key steps are a C,C-bond formation by ring opening of a chiral epoxide with a dithiane anion, followed by a Mitsunobu cyclization. The products obtained have high enantiomeric purity.

Full text of DOI:10.1002/1522-2675(200210)85:10<3473::AID-HLCA3473>3.0.CO;2-7

Helvetica Chimica Acta Vol. 85 (2002)
3473
Synthesis of Both Enantiomers of Flavanone and 2-Methylchromanone
by Yoshihiro Noda* and Morio Watanabe
Department of Materials Chemistry and Engineering, College of Engineering, Nihon University,
Tamura-machi, Koriyama, Fukushima, 963-8642 Japan
(e-mail: noda@chem.ce.nihon-u.ac.jp)
Dedicated to Professor Dieter Seebach on the occasion of his 65th birthday
An efficient enantiospecific synthesis of the (R)- and (S)-enantiomers of flavanone and 2-methylchro-
manone is described. The key steps are a C,C-bond formation by ring opening of a chiral epoxide with a dithiane
anion, followed by a Mitsunobu cyclization. The products obtained have high enantiomeric purity.
Flavanones (ˆ2,3-dihydro-2-phenyl-4H-1-benzopyran-4-ones) constitute an im-
portant class of the wide group of flavanoids, and 2-methylchromanones (ˆ2,3-
dihydro-2-methyl-4H-1-benzopyran-4-ones) are also found in several biologically
active natural products. A stereogenic center is present in their structures. Notwith-
standing that they are crucial substituents in a number of naturally occurring and
pharmacologically important compounds, there has been no simple and general
method described to obtain optically active flavanones and 2-methylchromanones.
Syntheses of optically active flavanones and 2-methylchromanones have been
reported by four groups: a) Saengchantara and Wallace reported the synthesis of 2-
methylchromanone by the diasteroselective conjugate addition of lithium dimethyl-
cuprate to (S)-3-(p-tolylsulfinyl)chromanone [1]. Recently, they have prepared the
natural products (S)-2,6-dimethylchromanone and LL-D253a [2]. b) Solladie et al. has
applied the Wallace method, i.e., conjugate addition of PhMgBr to (S)-5,7-dimethoxy-
8-methyl-3-(p-tolylsulfinyl) chromenone in the presence of dilithium tetrachlorocup-
rate as an efficient catalyst, to synthesize (‡)-(R)-5-hydroxy-6-(hydroxymethyl)-7-
methoxy-8-methylflavanone [3]. c) Rama Rao et al. reported the synthesis of both
enantiomers of 5,7-dimethoxy-2-methylchromanone and (R)-7-methoxy-2-methyl-
chromanone by inter- and intramolecular Houben-Hoesch reaction [4]. d) Recently,
Hodgetts reported the synthesis of the biologically active natural product (À)-
pinostrobin (ˆ (R)-5-hydroxy-7-methoxyflavanone) [5].

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Helvetica Chimica Acta Vol. 85 (2002)
Here, we describe a novel route to the optically active flavanone and 2-
methylchromanone starting from salicylaldehyde (1) which was converted to dithiane
derivative 2 by BF3-catalyzed reaction with propane-1,3-dithiol in 95% yield [6]
(Scheme). Treatment of 2 with 2 equiv. of BuLi in THF and a commercially available
optically active epoxide, e.g., (‡)-(R)- and (À)-(S)-styrene oxide (3a and 3b, resp.,)
and (‡)-(R)- and (À)-(S)-propylene oxide (3c and 3d, resp.) gave the corresponding
diols 4a (52% yield), 4b (52%), 4c (72%), and 4d (86%). Mitsunobu cyclization [7][8]
of diols 4a 4d by treating with Ph3P and diethyl azodicarboxylate (DEAD) in dry THF
gave 5a (68% yield), 5b (72%), 5c (85%), and 5d (91%), respectively. In this
cyclization, the absolute configuration was converted completely by an Sn2-type
nucleophilic displacement. Each cyclized compound, 5a 5d, was hydrolyzed in
aqueous MeCN with HgCl2 in the presence of CaCO3 [6] to afford the flavanones 6a
(70% yield) and 6b (73%), and 2-methylchromanones 6c (62% yield) and 6d (66%),
respectively.
Scheme
i) Propane-1,3-dithiol, BF3 ¥ Et2O, CHCl3, r.t. ii) 2 equiv. BuLi, epoxides ((‡)-(R)-styrene oxide (3a), (À)-(S)-
styrene oxide (3b), (‡)-(R)-propylene oxide (3c), (À)-(S)-propylene oxide (3d)) THF, À 188. iii) PPh3, diethyl
azodicarboxylate (DEAD), THF, r.t. iv) HgCl2, CaCO3, MeCN/H2O, r.t.
Our samples of (‡)-(R)-6a (m.p. 778 (hexane/CH2Cl2), [a]2D2 ˆ ‡62.8 (c ˆ 0.5,
CHCl3)), (À)-(S)-6b (m.p. 77 788 (hexane/CH2Cl2), [a]2D2 ˆ À63.6 (c ˆ 0.5,
CHCl3))1), and 2-methylchromanones (À)-(S)-6c (m.p. 43 448 (hexane/CH2Cl2),
[a]2D1 ˆ À46.78 (c ˆ 1.4, CHCl3)), (‡)-(R)-6d (m.p. 43 448 (hexane/CH2Cl2), [a]1D9
ˆ
‡47.9 (c ˆ 0.8, CHCl3))2), were shown to be of high enantiomeric purity (flavanone
(‡)-(R)-6a: 95% ee, (À)-(S)-6b: 97% ee, 2-methylchromanone (À)-(S)-6c: 97% ee,
1
)
Reported data for (‡)-(R)- and (À)-(S)-flavanone [9]: m.p. 778, [a]D ˆ ‡67.2 (c ˆ 0.35, CHCl3), and m.p.
76 778, [a]D ˆ À64.4 (c ˆ 0.35, CHCl3), resp.; [10]: m.p. 768 (petroleum ether), [a]2D5 ˆ ‡52 (c ˆ 0.75,
CHCl3), and m.p. 77 788 (petroleum ether), [a]2D5 ˆ À53.5 (c ˆ 2.27, CHCl3), resp.; [11]: m.p. 72 748,
[a]D ˆ ‡12.48 (benzene), and m.p. 75 768, [a]D ˆ À9.358 (benzene), resp.
)
Reported data for (À)-(S)-2-methylchromanone m.p. 39 408, [a]2D2 ˆÀ 50 ‡À 48 (c ˆ 2, CHCl3), reference
[1], (‡)-(R)-[a]D ˆ‡ 518 (c ˆ 1, CHCl3), reference [5].
2

Helvetica Chimica Acta Vol. 85 (2002)
3475
(‡)-(R)-6d: 99% ee) by HPLC analysis under optimized conditions for racemic
standard on a chiral stationary phase (Sumichiral OA-7000).
In conclusion, we have developed a general and efficient synthesis of optically
active flavanone and 2-methylchromanone of high enantiomeric purity from readily
available starting materials. The method presented may be generally applicable to the
synthesis of natural products.
We thankProf. Y. Fujimoto and Dr. M. Makino, College of Pharmacy, Nihon University, for mass spectra.
Experimental Part
General. M.p.: Yanako MP-500D melting-point apparatus; uncorrected. Prep. TLC: Kieselgel GF 254.
Column chromatography (CC): silica gel (Merck, Kieselgel 60, 70 230 mesh). Specific rotations: JASCO DIP-
360 polarimeter, CHCl3 as solvent; concentration in g/100 ml. IR Spectra: Perkin-Elmer Paragon 1000 FT-IR
spectrometer, in CHCl3 soln. 1H- and 13C-NMR spectra: Hitachi R3000 (300- (1H) or 75-MHz (13C)) instrument;
all spectra were recorded with TMS as internal standard in CDCl3 as solvent. MS: at 70 eV with a JEOL GC
mate instrument. Solvent systems used are shown in parentheses. Anh. MgSO4 was employed to dry extracts.
2-(1,3-Dithian-2-yl)phenol (2). Salicylaldehyde (ˆ2-hydroxybenzaldehyde, 1; 4.88 g, 40 mmol), propane-
1,3-dithiol (4.83 g, 45 mmol), and BF3 ¥ Et2O (2.00 g, 14 mmol) were stirred in CHCl3 (100 ml) at 258 for 10 h;
10% NaHCO3 (50 ml) was added, and the mixture was extracted with CH2Cl2 (3 Â 50 ml). The combined org.
phase washed with sat. NaCl soln. (100 ml), dried (MgSO4), and filtered. Evaporation gave a yellow solid, which
was recrystallized (hexane/CH2Cl2) to give 2 (8.05 g, 95%). M.p. 138 1398 (hexane/CH2Cl2), IR (CHCl3): 3590,
3425, 3007, 1578, 1487, 1277, 1227, 1170. 1H-NMR (300 MHz): 1.9 2.2 (m, 2 H, dithiane); 3.0 (m, 4 H, dithiane);
5.42 (s, HÀC(4)); 6.04 (br. s, OH); 6.8 7.4 (m, 4 arom. H). 13C-NMR (75 MHz): 24.8; 31.6; 47.2; 117.2; 120.7;
123.6; 129.0; 130.0; 154.3. EI-MS: 124 (15), 123 (20), 122 (100), 147 (32), 139 (25), 138 (100), 137 (93), 105 (19).
HR-MS: 212.03356 (C10H12OS2; calc. 212.03295).
C,C-Bond Formation by Ring Opening of a Chiral Epoxide with 2. General Procedure. Addition of 3.55 ml
(5.7 mmol) of a 1.6m BuLi soln. in hexane to 482 mg (2.27 mmol) of 2 in 20 ml of anh. THF at À188 and stirring
for 3 h. To a soln. of dithiane anion were added 546 mg (4.55 mmol) of styrene oxide in 5 ml of anh. THF and,
after stirring for 3 h, sat. NH4Cl soln. was added, and the mixture was extracted with Et2O (3 Â 50 ml). The org.
layer was dried and evaporated, and the residue purified by CC and prep. TLC to give the alcohol.
2-[(S)-2-(2-Hydroxy-2-phenylethyl)-1,3-dithian-2-yl]phenol (4a). From 492 mg (2.27 mmol) of 2 and
546 mg (4.55 mmol) of (‡)-(R)-styrene oxide (3a), 392 mg (52%) of 4a was obtained. Colorless liquid. [a]D22
ˆ
À4.0 (c ˆ 0.8, CHCl3). IR (CHCl3): 3474, 3195, 3008, 2911, 1605, 1573, 1477, 1457, 1423, 1282, 1226, 1193, 1047,
908. 1H-NMR (300 MHz): 2.0 (m, 2 H, dithiane); 2.34 2.6 (m, CH2); 3.0 (m, 4 H, dithiane); 4.84 (d, J ˆ 8.7,
CHOH); 6.98 (m, 2 arom. H); 7.22 (m, 6 arom. H); 7.93 (m, 1 arom. H); 8.63 (s, OH). 13C-NMR (75 MHz):
24.2; 27.7; 28.0; 51.5; 57.0; 70.7; 119.3; 120.6; 123.3; 125.5; 127.3; 128.3; 130.2; 131.5; 143.7; 155.9. EI-MS: 332
(27), 224 (75), 225 (83), 211 (22), 152 (61), 151 (48), 137 (21), 119 (100), 107 (28), 105 (35), 91 (37), 79 (30), 78
(27). HR-MS: 332.08984 (C18H20O2S2; calc. 332.09046).
2-[(R)-2-(2-Hydroxy-2-phenylethyl)-1,3-dithian-2-yl]phenol (4b). From 469 mg (2.21 mmol) of 2 and
530 mg (4.42 mmol) (À)-(S)-styrene oxide (3b), 382 mg (52%) of 4b was obtained. Colorless liquid. [a]D22
‡3.7 (c ˆ 0.8, CHCl3).
ˆ
2-[(R)-2-(2-Hydroxypropyl)-1,3-dithian-2-yl]phenol (4c). From 759 mg (3.58 mmol) of 2 and 415 mg
(7.2 mmol) (‡)-(R)-propylene oxide (3c), 696 mg (72%) of 4c was obtained. Colorless liquid. [a]2D2 ˆ ‡6.3 (c ˆ
1.3, CHCl3). IR (CHCl3): 3197, 3008, 2911, 1605, 1573, 1477, 1456, 1423, 1281, 1225, 1152, 1047. 1H-NMR
(300 MHz): 1.09 (d, J ˆ 6, Me); 1.95 2.05 (m, 2 H, dithiane); 2.06 2.17 (m, CH2); 2.85 (m, 4 H, dithiane); 4.0
(br., CHOH); 6.95 (m, 2 arom. H); 7.27 (t, J ˆ 7.5, 1 arom. H); 7.90 (d, J ˆ 7.5, 1 arom. H); 8.61 (s, OH).
13C-NMR (75 MHz): 24.3; 24.7; 28.0; 28.4; 51.2; 57.3; 65.0; 120.0; 121.0; 123.8; 130.6; 131.8; 156.4. MS: 270 (96),
211 (28), 195 (35), 178 (28), 163 (100), 152 (45), 151 (46), 145 (22), 137 (30), 91 (58). HR-MS: 270.07477
(C13H18O2S2; calc. 270.07481).
2-[(S)-2-(2-Hydroxypropyl)-1,3-dithian-2-yl]phenol (4d). From 759 mg (3.58 mmol) of 2 and 415 mg
(7.2 mmol) (À)-(S)-propylene oxide (3d), 831 mg (86%) of 4d was obtained. Colorless liquid. [a]2D2 ˆ À6.6 (c ˆ
1.2, CHCl3).

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Helvetica Chimica Acta Vol. 85 (2002)
Mitsunobu Cyclization. General Procedure. To a soln. of 957 mg (3.65 mmol) Ph3P in 10 ml of anh. THF
was added at r.t. 1.6 g (1.66 mmol) of diethyl azodicarboxylate (DEAD), and, after stirring 1 h, the mixture was
added to 303 mg (0.91 mmol) of 4a. After 2 h, the reaction was monitored by TLC, then the mixture was diluted
with H2O (30 ml) and extracted with Et2O (3 Â 50 ml). The combined Et2O extracts were dried and evaporated.
Purification (TLC) and recrystallization (hexane/CH2Cl2) afforded the cyclized compound 5a.
(R)-2,3-Dihydro-2-phenylspiro[4H-[1]benzopyran-4,2'-[1,3]dithiane] (5a). From 303 mg (0.91 mmol) of
4a, 195 mg (68%) of 5a was obtained. M.p. 147 1488 (hexane/CH2Cl2). [a]2D2 ˆ À63.5 (c ˆ 0.6, CHCl3). IR
(CHCl3): 3010, 1606, 1578, 1480, 1453, 1220, 1041, 916. 1H-NMR (300 MHz): 1.98 2.2 (m, 2 H, dithiane); 2.5
2.6 (m, CH2(3)); 2.6 2.8 (m, 2 H, dithiane); 3.05 3.15 (m, 2 H, dithiane); 5.32 (d, J ˆ 10.2, HÀC(2)); 6.8 7.8
(m, 9 arom. H). 13C-NMR (75 MHz): 24.7; 27.8; 27.9; 43.8; 48.5; 75.5; 117.3; 121.0; 123.6; 126.4; 128.2; 128.6;
129.6; 129.7; 140.3; 154.7. EI-MS: 332 (27), 224 (75), 225 (83), 211 (22), 152 (61), 151 (48), 137 (21), 119 (100),
107 (28), 105 (35), 91 (37), 79 (30), 78 (27). HR-MS: 332.09046 (C18H20O2S2; calc. 332.09046).
(S)-2,3-Dihydro-2-phenylspiro[4H-[1]benzopyran-4,2'-[1,3]dithiane] (5b). From 214 mg (0.64 mmol) of
4b, 148 mg (73%) of 5b was obtained. M.p. 147 1488 (hexane/CH2Cl2). [a]2D2 ˆ ‡61.1 (c ˆ 0.6, CHCl3).
(S)-2,3-Dihydro-2-methylspiro[4H-[1]benzopyran-4,2'-[1,3]dithiane] (5c). From 620 mg (2.3 mmol) of 4c,
492 mg (85%) of 5c was obtained. M.p. 118 1198 (hexane/CH2Cl2). [a]2D3 ˆ À167.5 (c ˆ 1.4, CHCl3). IR
(CHCl3): 3008, 2979, 2908, 1579, 1480, 1455, 1279, 1230, 1125, 1069. 1H-NMR (300 MHz): 1.46 (d, J ˆ 6.6, Me);
1.95 (m, CH2(3)); 2.6 2.8 (m, 2 H, dithiane); 2.8 3.0 (m, 2 H, dithiane); 4.42 (m, HÀC(2)); 6.80 (d, J ˆ 8.1,
1 arom. H); 6.92 (t, J ˆ 7.5, 1 arom. H); 7.19 (t, J ˆ 7.5, 1 arom. H); 7.82 (d, J ˆ 8.1, 1 arom. H). 13C-NMR
(75 MHz): 20.7; 24.7; 27.8; 27.9; 42.9; 48.2; 69.6; 117.0; 120.6; 123.6; 129.6; 129.7; 154.8. EI-MS: 253 (17), 252
(85), 237 (43), 179 (24), 178 (100), 177 (45), 163 (58), 145 (66), 131 (15). HR-MS: 252.06412 (C13H16OS2; calc.
252.06425).
(R)-2,3-Dihydro-2-methylspiro[4H-[1]-benzopyran-4,2'-[1,3]dithiane] (5d). From 720 mg (2.67 mmol) of
4d, 611 mg (91%) of 5d was obtained. M.p. 116 1178 (hexane/CH2Cl2). [a]2D2 ˆ ‡171.7 (c ˆ 0.1, CHCl3).
Hydrolysis of Dithianes. General Procedure. A suspension of 314 mg (1.16 mmol) of HgCl2, 116 mg
(1.16 mmol) of CaCO3, and 146 mg (0.46 mmol) of 5a in 10 ml of MeCN/H2O 4 :1 were stirred at r.t. After 3 h,
the mixture was filtered off and extracted with CH2Cl2 (3 Â 30 ml). The combined org. layer was dried and
evaporated. Purification (prep. TLC) and recrystallization (hexane/CH2Cl2) afforded flavanone (and 2-
methylchromanone).
(‡)-(R)-Flavanone ( ˆ (‡)-(R)-2,3-Dihydro-2-phenyl-4H-1-benzopyran; 6a). From 146 mg (0.46 mmol) of
5a, 73 mg (70%) of 6a was obtained. M.p. 778 (hexane/CH2Cl2). [a]2D2 ˆ ‡62.8 (c ˆ 0.5, CHCl3). HPLC
(Sumichiral OA-7000 column, 20 mm phosphate buffer (pH 2.0), MeCN/H2O 60 :40): 8.7 min (97.4%), 16.5 min
(2.6%), 95% ee. IR (CHCl3): 3013, 1689, 1606, 1463, 1306, 1228, 1116, 906. 1H-NMR (300 MHz): 3.0
(dd, ABX, J ˆ 17, 13, 2, CH2(3)); 5.48 (dd, ABX, J ˆ 13, 3, HÀC(2)); 7.07 (m, 2 arom. H); 7.3 7.6 (m, 6 ar-
om. H); 7.93 (d, J ˆ 8.1, 1 arom. H). 13C-NMR (75 MHz): 44.7; 79.6; 118.1; 120.9; 121.6; 127.0; 128.7; 128.8;
136.1; 138.7; 161.5; 191.9.
(À)-(S)-Flavanone (ˆ(À)-(S)-2,3-Dihydro-2-phenyl-4H-1-benzopyran; 6b): From 129 mg (0.41 mmol) of
5b, 67 mg (73%) of 6b was obtained. M.p. 77 788 (hexane/CH2Cl2). [a]2D2 ˆ À63.6 (c ˆ 0.5, CHCl3). HPLC:
8.8 min (1.4%), 16.6 min (98.6%), 97% ee.
(À)-(S)-2-Methylchromanone (ˆ(À)-(S)-2,3-Dihydro-2-methyl-4H-1-benzopyran; 6c). From 346 mg
(1.37 mmol) of 5c, 134 mg (62%) of 6c was obtained. M.p. 43 448 (hexane/CH2Cl2). [a]2D1 ˆ À46.7 (c ˆ 1.4,
CHCl3). HPLC (Sumichiral OA-7000 column, 20 mm phosphate buffer (pH 2.0), MeCN/H2O 60 :40): 48.1 min
(1.5%), 51.4 min (98.5%), 97% ee. IR (CHCl3): 3013, 2982, 1693, 1608, 1577, 1473, 1464, 1386, 1349, 1309, 1229,
1153, 1122, 877. 1H-NMR (300 MHz): 1.52 (d, J ˆ 5.7, Me); 2.68 (d, J ˆ 7.5, CH2(3)); 4.59 (dd, J ˆ 7.5, 5.7,
HÀC(2)); 6.9 7.0 (m, 2 arom. H); 7.47 (t, J ˆ 7.5, 1 arom. H); 7.87 (d, J ˆ 7.5, 1 arom. H). 13C-NMR (75 MHz):
21.0; 44.6; 74.2; 117.8; 120.7; 121.1; 126.9; 135.9; 161.6; 192.3.
(‡)-(R)-2-Methylchromanone (ˆ(‡)-(R)-2,3-Dihydro-2-methyl-4H-1-benzopyran; 6d). From 569 mg
(2.26 mmol) of 5d, 241 mg (66%) of 6d was obtained. M.p. 43 448 (hexane/CH2Cl2). [a]1D9 ˆ ‡47.9 (c ˆ 0.8,
CHCl3). HPLC: 48.4 min (99.7%), 51.2 min (0.3%), 99% ee.
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Received May 24, 2002