Enantioselective synthesis of (-)-(R)-cordiachromene and (-)-(R)-dictyochromenol utilizing intramolecular SNAr reaction

Article abstract of DOI:10.1002/hlca.201200312

A simple and efficient enantioselective synthesis of chromene, (-)-(R)-cordiachromene (1), and (-)-(R)-dictyochromenol (2) has been accomplished. This convergent synthesis utilizes intramolecular S_NAr reaction for the formation of chroman ring,

Full text of DOI:10.1002/hlca.201200312

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Helvetica Chimica Acta – Vol. 95 (2012)
Enantioselective Synthesis of (ꢀ)-(R)-Cordiachromene and (ꢀ)-(R)-
Dictyochromenol Utilizing Intramolecular SNAr Reaction
by Yoshihiro Noda* and Misato Yasuda
Department of Chemical Biology and Applied Chemistry, 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 75th birthday
A simple and efficient enantioselective synthesis of chromene, (ꢀ)-(R)-cordiachromene (1), and
(ꢀ)-(R)-dictyochromenol (2) has been accomplished. This convergent synthesis utilizes intramolecular
SNAr reaction for the formation of chroman ring, and Seebachꢀs method of ꢁself-reproduction of chiralityꢀ
should establish the (R)-configuration of the C(2) side chain as key steps.
Introduction. – Chromenes (benzopyrans) are most ubiquitous heterocyclic
building blocks in both natural products and synthetic compounds with important
biological activities.
Cordiachromene (¼2-methyl-2-(4-methylpent-3-en-1-yl)-2H-chromen-6-ol; 1) was
first isolated from the American tree Cordia alliodora in 1977 by Manners and Jurd [1]
and later from Aplidium constellatum [2], Aplidium antillens [3], and Aplidium
multiplicantium [4]. This chromene 1 displays antibacterial activity against Staph-
ylococcus aureus [3] and anti-inflammatry activity [5].
The short synthesis of racemic 1 using a Claisen rearrangement of propargyl ether
has been reported [6]. The asymmetric total synthesis of 1 has been achieved by
utilizing the Sharpless enantioselective epoxidation [7] and lipase-catalyzed kinetic
resolution of racemic acetates [8]. Recently, Takenaka et al. [9] have reported the
synthesis of 1 by an enantioselective 6-endo-trig Wacker-type cyclization of hydro-
quinone and geraniol in two steps.
Dictyochromenol (¼2-[(3E)-4,8-dimethylnona-3,7-dien-1-yl]-2-methyl-2H-chro-
men-6-ol; 2) was first isolated from brown alga Dictyopteris undulata in 1984 by Dave
et al. [10] and later from Piper tricuspe [11]. This chromene 2 shows antifeedant [10],
antimalarial [11], and antioxidant [11] activities.
The asymmetric total synthesis of 2 has been achieved by utilizing lipase catalyzed
kinetic resolution of racemic acetates [9], and synthesis of both enantiomers by
Sharpless enantioselective epoxidation in 2002 by Aoki et al. [12].
ꢂ 2012 Verlag Helvetica Chimica Acta AG, Zꢃrich

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In this article, we report a new approach to the enantioselective total synthesis of
(ꢀ)-(R)-1 and (ꢀ)-(R)-2. Our strategy for the synthesis of (ꢀ)-(R)-1 and (ꢀ)-(R)-2,
outlined in Scheme 1, relies on the two key reactions. We envisioned that chromene ring
system could be effectively prepared using the enantioselective intramolecular SNAr
(aromatic nucleophilic substitution) reaction methodology [13], developed in our
labolatory [14]. The Seebachꢀs method [15] of ꢁself-reproduction of chiralityꢀ should
then establish the (R)-configuration at C(2) of chromene.
Scheme 1. Retrosynthetic Analysis for the Preparation of 1 and 2
Results and Discussion. – To establish the configuration at C(2) of the chromene,
the Seebachꢀs method of ꢁself-reproduction of chiralityꢀ using (2R,5R)-2-(tert-butyl)-5-
methyl-1,3-dioxolan-4-one (8; Scheme 2) was employed. Compound 8 was obtained
from the condensation of pivalaldehyde and (S)-lactic acid in pentane in high yield.
The dioxolanone 8 was treated with lithium diisopropylamide (LDA) in THF and
alkylated with homoprenyl iodides 9a or 9b, which had been synthesized according to
[16]. The substituted dioxolanones 7a or 7b were reduced to the diols 10a and 10b,
respectively, with LiAlH4 in absolute Et2O. The ring closure to the epoxides 6a and 6b
was carried out applying a phase transfer-catalyzed one-pot procedure [17]: a soln. of
Scheme 2
a) LDA, THF, 5-iodo-2-methylpent-2-ene or (E)-9-iodo-2,6-dimethylnonane-2,6-diene (9a or 9b, resp.),
ꢀ 788 to r.t. b) LiAlH4, Et2O, ꢀ 788 to r.t. c) TEBA, TsCl, CH2Cl2/50% NaOH aq.

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Helvetica Chimica Acta – Vol. 95 (2012)
the diols 10a and 10b, respectively, in CH2Cl2 was vigolously stirred for 15 min with
TsCl, benzyl(triethyl)ammonium chloride (TEBA), and 50% NaOH aqueous solution
(Scheme 2).
The sulfide 13 was prepared from 2-fluoro-5-methoxybenzaldehyde (11). The
aldehyde 11 was reduced with NaBH4 in MeOH to give the alcohol 12. Compound 12
was then treated with PhSSPh and Bu3P in pyridine to give 13 in 86% yield for two steps
(Scheme 3).
Scheme 3
a) NaBH4, MeOH, 08. b) PhSSPh, Bu3P, pyridine.
The lithium salt, prepared from 13 with BuLi, was treated with epoxides 6a and 6b
in THF (ꢀ 788) to give the tertiary alcohols 14a and 14b, respectively (Scheme 4).
Cyclization reaction was carried out with tBuOK in THF to furnish 15a and 15b (55 and
69%, resp.). The chroman system was formed through an intramolecular aromatic
nucleophilic substitution reaction (SNAr). In this cyclization, the absolute configu-
ration of C(2) was retained. In this type of nucleophilic attacks, F is used to be the best
leaving group.
Scheme 4
a) BuLi, THF, 6a or 6b, ꢀ 788. b) tBuOK, THF, reflux. c) mCPBA, CH2Cl2, 08. d) CaCO3, toluene, reflux.
e) EtSNa, DMF, reflux.
Oxidation of sulfides 15a and 15b with m-chloroperbenzoic acid (mCPBA) in
CH2Cl2 yielded sulfoxides 16a and 16b, respectively. Without purification, 16a and 16b
with a b-H-atom readily underwent syn-elimination on pyrolysis to form chromenes
17a and 17b, respectively. Finally, conversion of the methyl ether to alcohol in the
methoxy-cordiachromene 17a and methoxy-dictyochromenol 17b with NaSEt in DMF
furnished the (ꢀ)-(R)-cordiachromene (1) and (ꢀ)-(R)-dictyochromenol (2). All the

Helvetica Chimica Acta – Vol. 95 (2012)
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intermediate compounds, including (ꢀ)-(R)-1, and (ꢀ)-(R)-2, were fully characterized
by 1H- and 13C-NMR, IR, and MS data. Comparison of our physical and spectroscopic
data with those published in [7], [12] confirmed our successful synthesis of (ꢀ)-(R)-
cordiachromene (1; [a]2D2 ¼ ꢀ110.7 (c ¼ 0.65, CHCl3), [7]: antipode: [a]2D0 ¼ þ101.6
(c ¼ 0.83, CHCl3)), and (ꢀ)-(R)-dictyochromenol (2; [a]2D1 ¼ ꢀ86.5 (c ¼ 0.38, CHCl3),
[12]: [a]2D0 ¼ ꢀ82.4 (c ¼ 0.83, CHCl3)).
Conclusions. – We have developed an efficient enantioselective protocol for the
synthesis of (ꢀ)-(R)-cordiachromene (1) and (ꢀ)-(R)-dictyochromenol (2) by employ-
ing intramolecular SNAr reaction and Seebachꢀs method of ꢁself-reproduction of
chiralityꢀ as the key reaction steps.
Experimental Part
General. Anh. MgSO4 was employed to dry extracts. Prep. TLC: Kieselgel GF 254. Column
chromatography (CC): silica gel (SiO2, Kieselgel 60, 70 – 230 mesh; Merck). 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 and CDCl3 as solvent. MS: at
70 eV with a JEOL GC mate instrument.
(2R,5S)-2-(tert-Butyl)-5-methyl-5-(4-methylpent-3-en-1-yl)-1,3-dioxolan-4-one (7a). BuLi (5.6 ml,
9.45 mmol; 1.6m in hexane) was added to a stirred cold (ꢀ 788) soln. of 1.3 g (10 mmol) of iPr2NH in 20 ml
of dry THF. After 1 h, 995 mg (6.3 mmol) of dioxolanone 8, dissolved in 4 ml of THF, was added
dropwise. After stirring for 30 min, 1.6 g (7.6 mmol) of homoprenyl iodide 5-iodo-2-methylpent-2-ene
(9a) in 3 ml of THF was added, and the mixture was allowed to warm to r.t. during 20 h. Sat. NH4Cl soln.
(30 ml) was added, and the mixture was extracted with Et2O (3 ꢁ 30 ml). The combined org. phase
washed with H2O and brine, dried, and filtered. Evaporation and purification by CC (Et2O/hexane 1:10)
afforded 787 mg (52%) of 7a. Colorless liquid. [a]2D6 ¼ þ38.3 (c ¼ 0.65, CHCl3); [15b]: [a]D20 ¼ þ30.2 (c ¼
2.40, CHCl3). 1H-NMR (300 MHz): 0.96 (s, tBu); 1.44 (s, Me); 1.61 (s, Me); 1.68 (s, Me); 1.72 – 1.79 (m,
CH2); 2.0 – 2.2 (m, CH2); 5.18 (s, CH). 13C-NMR (75 MHz): 17.7; 22.3; 22.7; 23.3; 25.6; 34.6; 36.3; 79.8;
108.5; 122.7; 132.7; 175.7.
(2R,5S)-2-(tert-Butyl)-5-[(3E)-4,8-dimethylnona-3,7-dien-1-yl]-5-methyl-1,3-dioxolan-4-one (7b).
From 1.5 g of 8 (9.5 mmol) and 3.17 g of (E)-9-iodo-2,6-dimethylnonane-2,6-diene (9b, 11.4 mmol),
1.23 g (42%) of 7b was obtained. Colorless liquid. [a]2D4 ¼ þ33.3 (c ¼ 0.49, CHCl3). 1H-NMR (300 MHz):
t
0.96 (s, Bu); 1.43 (s, Me); 1.60 (br. s, Me); 1.63 (br. s, Me); 1.69 (br. s, Me); 2.0 (br. t, J ¼ 7.2, CH2);
2.0 – 2.2 (m, CH2); 2.6 – 2.7 (m, 2 CH2); 5.10 (br., 2 CH); 5.18 (s, CH). 13C-NMR (75 MHz): 15.7; 17.7;
21.6; 22.7; 23.4; 25.7; 27.0; 34.6; 35.6; 39.3; 79.9; 108.4; 123.0; 124.0; 131.3; 133.4; 133.8; 175.8.
(2R)-2,6-Dimethylhept-5-ene-1,2-diol (10a). Compound 7a 1.5 g (6.25 mmol) in 10 ml of dry THF
was added dropwise to a mixture of LiAlH4 (430 mg, 11.3 mmol) and 20 ml of THF under Ar at ꢀ 788.
The mixture was allowed to warm to r.t. during 20 h. at 08, and 1 ml H2O was added. The precipitate was
filtered. The org. layer was dried and evaporated. The residue purified by CC (Et2O/hexane 8 :1) to give
918 mg (93%) of 10a. Colorless liquid. [a]2D1 ¼ ꢀ1.49 (c ¼ 1.05, CHCl3); [15b]: [a]2D0 ¼ þ1.7 (c ¼ 2.76,
CHCl3). 1H-NMR (300 MHz): 1.17 (s, Me); 1.47 – 1.57 (m, CH2); 1.62 (br. s, Me); 1.68 (s, Me); 2.04 (br. q,
J ¼ 7, CH2); 2.85 (br., 2 OH); 3.39 (d, J ¼ 11, CH); 3.46 (d, J ¼ 11, CH); 5.11 (br. t, J ¼ 7, CH ) . 13C-NMR
(75 MHz): 17.6; 22.4; 23.0; 25.7; 38.4; 69.6; 73.1; 124.1; 131.8.
(2R,5E)-2,6,10-Trimethylundeca-5,9-diene-1,2-diol (10b). From 1.5 g (4.87 mmol) of 7b, 1.06 g
(96%) of 10b was obtained. Colorless liquid. [a]2D3 ¼ ꢀ0.41 (c ¼ 0.70, CHCl3). 1H-NMR (300 MHz): 1.16
(s, Me); 1.48 (s, Me); 1.62 (br. s, Me); 1.68 (s, Me); 1.9 – 2.0 (m, 2 CH2); 2.0 – 2.07 (m, 2 CH2); 2.97 (br., 2
OH); 3.38 (d, J ¼ 11, CH); 3.45 (d, J ¼ 11, CH); 5.12 (br., 2 CH). 13C-NMR (75 MHz): 15.8; 17.7; 22.3;
23.0; 25.7; 26.9; 38.3; 39.6; 69.6; 73.0; 123.2; 124.1; 131.2; 134.8.

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Helvetica Chimica Acta – Vol. 95 (2012)
(2R)-2-Methyl-2-(4-methylpent-3-en-1-yl)oxirane (6a). The mixture of 900 mg (5.7 mmol) of 10a,
50 mg (0.2 mmol) of benzyl(triethyl)ammonium chloride in CH2Cl2 (30 ml) and 5 ml of 50% NaOH
soln. was vigorously stirred at r.t. for 15 min. At 08, a soln. of 1.2 g (6.3 mmol) of TsCl in 1 ml of CH2Cl2
was added. The mixture was allowed to warm up to r.t. for 2 h. The two layers were separated, and the
org. layer was washed with H2O. The org. layer dried and evaporated. The residue was distilled (80 – 908
bath temp./15 Torr) and afforded 694 mg of 6a (87%). Colorless liquid. [a]2D5 ¼ ꢀ11.3 (c ¼ 0.52, CHCl3);
1
[15b]: [a]2D0 ¼ ꢀ7.6 (c ¼ 2.33, CHCl3). IR (CHCl3): 3671, 2969, 2858, 1672, 1451, 1390, 1234. H-NMR
(300 MHz): 1.33 (s, Me); 1.5 – 1.6 (m, CH2); 1.62 (s, Me); 1.69 (s, Me); 2.08 (q, J ¼ 7.5, CH2); 2.58 (d, J ¼
5.1, CH); 2.63 (d, J ¼ 5.1, CH); 5.10 (br. t, J ¼ 5.7 CH). 13C-NMR (75 MHz): 17.6; 20.9; 23.8; 25.7; 36.8;
53.9; 56.9; 123.5; 131.9.
(2R)-2-[(3E)-4,8-Dimethylnona-3,7-dien-1-yl]-2-methyloxirane (6b). From 1.0 g (4.2 mmol) of 10b,
782 mg (85%) of 6b was obtained. Colorless liquid. [a]2D5 ¼ ꢀ6.7 (c ¼ 0.41, CHCl3). IR (CHCl3): 3670,
3041, 2969, 2928, 1668, 1449, 1380, 1234. 1H-NMR (300 MHz): 1.31 (s, Me); 1.48 – 1.56 (m, CH2); 1.59 (s,
Me); 1.60 (s, Me); 1.67 (s, Me); 1.95 – 2.18 (m, 3 CH2); 2.54 (d, J ¼ 4.5, CH); 2.65 (d, J ¼ 4.5, CH); 5.09 (br.
q, J ¼ 6.6, 2 CH). 13C-NMR (75 MHz): 15.8; 17.5; 20.8; 23.6; 25.5; 26.4; 36.6; 39.5; 53.7; 56.6; 123.3; 124.0;
131.0; 135.2.
1-Fluoro-4-methoxy-2-[(phenylsulfanyl)methyl]benzene (13). 2-Fluoro-5-methoxybenzaldehyde
(11; 1.0 g, 6.49 mmol) in 10 ml of MeOH was added to a mixture of 296 mg (7.79 mmol) of NaBH4
and 5 ml of MeOH. The mixture was stirred at r.t. for 10 min. H2O (10 ml) was added, and the mixture
was extracted with Et2O (3 ꢁ 30 ml). The combined org. phase washed with sat. NaCl soln. (30 ml), dried
and filtered. Evaporation gave 12 (986 mg).
To a soln. of 986 mg (6.3 mmol) of 2-fluoro-5-methoxybenzenemethanol (12) in 5 ml of pyridine
were added 1.9 g (7.58 mmol) of Bu3P and 1.65 g (7.85 mmol) of PhSSPh in 5 ml of pyridine, and the
mixture was stirred 20 min at r.t. The mixture was diluted with H2O (30 ml). The combined Et2O extracts
were dried and evaporated. Purification by CC (Et2O/hexane 1:20) afforded 13 (1.3 g, 86%; two steps).
Colorless liquid. IR (CHCl3): 3062, 3007, 2938, 1584, 1501, 1282, 1037. 1H-NMR (300 MHz): 3.66 (s,
MeO); 4.07 (s, CH2); 6.67 – 6.73 (m, HꢀC(4), HꢀC(6)); 6.91 (t, J ¼ 8.7, HꢀC(3)); 7.18 – 7.26 (m, 3 arom.
H); 7.31 – 7.34 (m, 2 arom. H). 13C-NMR (75 MHz): 32.3; 32.3; 55.6; 114.0; 115.1; 115.6; 115.9; 125.2;
125.4; 126.7; 128.8; 130.5; 135.5; 153.4; 155.3; 156.6. EI-MS: 250 (10), 249 (28), 248 (56), 140 (30), 139
(100), 109 (42), 96 (28), 83 (17). HR-MS: 248.0671 (Mþ, C14H13FOSþ; calc. 248.0671).
(3R)-1-(2-Fluoro-5-methoxyphenyl)-3,7-dimethyl-1-(phenylsulfanyl)oct-6-en-3-ol (14a). To a stirred
soln. of 13 (400 mg, 1.61 mmol) in dry THF (8 ml) was added BuLi (2.4 mmol; 1.6m in hexane; 1.5 ml) at
ꢀ 788 under Ar. The mixture was stirred for 2 h, and a soln. of 6a (248 mg, 1.77 mmol) in dry THF (2 ml)
was added dropwise with stirring. The mixture allowed to warm to r.t. for 20 h. The reaction was
quenched with sat. NH4Cl soln. (20 ml), and the mixture was extracted with Et2O (3 ꢁ 30 ml), dried, and
evaporated. The crude product was purified by CC (Et2O/hexane 1:2) to afford 14a (606 mg, 97%).
Colorless liquid. IR (CHCl3): 3595, 3504, 3060, 3006, 2968, 1584, 1499, 1198, 1037. 1H-NMR (300 MHz):
1.16 (s, Me); 1.45 – 1.55 (m, CH2); 1.58 (s, Me); 1.67 (s, Me); 1.88 – 2.0 (m, CH2); 2.15 (d, J ¼ 6.6, CH2);
3.72 (s, MeO); 4.73 (dd, J ¼ 9, 6.6, CH); 5.04 (br., CH); 6.62 – 6.72 (m, HꢀC(4)); 6.82 – 6.89 (m, HꢀC(3),
HꢀC(6)); 7.2 – 7.3 (m, 5 arom. H). 13C-NMR (75 MHz): 17.6; 17.7; 22.5; 22.7; 25.7; 26.6; 27.2; 41.6; 41.7;
42.8; 46.3; 46.4; 55.7; 113.6; 113.7; 115.6; 116.0; 124.0; 124.1; 127.5; 128.7; 131.8; 132.6; 132.6; 133.9; 133.9;
152.6; 155.6; 155.6. EI-MS: 388 (9), 370 (10), 278 (12), 260 (30), 247 (20), 152 (58), 109 (100) 69 (84).
HR-MS: 388.1878 (Mþ, C23H29FO2Sþ; calc. 388.1872).
(3R,6E)-1-(2-Fluoro-5-methoxyphenyl)-3,7,11-trimethyl-1-(phenylsulfanyl)dodeca-6,10-dien-3-ol
(14b). From 400 mg (1.61 mmol) of 13 and 366 mg (1.76 mmol) of 6b, 705 mg (96%) of 14b was
1
obtained. Colorless liquid. IR (CHCl3): 3590, 3492, 3061, 3007, 2970, 1584, 1498, 1199, 1036. H-NMR
(300 MHz): 1.16 (s, Me); 1.45 – 1.55 (m, CH2); 1.58 (s, 2 Me); 1.68 (s, Me); 1.85 – 2.18 (m, 3 CH2); 2.15 (d,
J ¼ 6.6, CH2); 3.72 (s, MeO); 4.73 (dd, J ¼ 9, 6.6, CH); 5.07 (br., 2 CH); 6.64 – 6.67 (m, HꢀC(4));
6.82 – 6.88 (m, HꢀC(3), HꢀC(6)); 7.2 – 7.3 (m, 5 arom. H). 13C-NMR (75 MHz): 16.0; 16.1; 17.7; 22.4;
22.6; 25.7; 26.6; 27.2; 39.6; 41.6; 41.7; 41.7; 42.8; 46.3; 46.4; 55.7; 72.7; 72.9; 113.5; 113.6; 113.7; 115.6;
116.0; 123.9; 124.0; 124.1; 127.5; 128.7; 130.7; 131.8; 132.5; 132.6; 133.9; 133.9; 136.3; 155.6; 155.6. EI-MS:
456 (5), 438 (15), 328 (28), 247 (60), 177 (40), 152 (35), 149 (40), 109 (38) 69 (100). HR-MS: 456.2500
(Mþ, C28H37FO2Sþ; calc. 456.2498).

Helvetica Chimica Acta – Vol. 95 (2012)
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(2R)-3,4-Dihydro-6-methoxy-2-methyl-2-(4-methylpent-3-en-1-yl)-4-(phenylsulfanyl)-2H-chromene
t
(15a). To a soln. of BuOK (638 mg, 5.7 mmol) in dry THF (20 ml) was added dropwise 14a (220 mg,
0.57 mmol) in THF (10 ml) at r.t. under Ar. Then, the mixture was refluxed for 15 h. The reaction was
quenched with sat. NH4Cl soln., and the mixture extracted with Et2O (3 ꢁ 20 ml). The org. layer was
washed with H2O and brine, and dried. The solvent was evaporated, and the residue was purified by CC
(Et2O/hexane 1:10) to afford 115 mg (55%) 15a and recovered 14a (18 mg). Colorless liquid. IR: 3007,
2934, 1614, 1582, 1492, 1465, 1379, 1225, 1039. 1H-NMR (300 MHz): 1.19 (s, 1.5 H of Me); 1.34 (s, 1.5 H of
Me); 1.53 (s, 1.5 H of Me); 1.62 (s, 1.5 H of Me); 1.64 (s, 1.5 H of Me); 1.66 (s, 1.5 H of Me); 1.5 – 1.7 (m,
CH2); 1.9 – 2.2 (m, CH2); 3.74 (s, Me); 4.43 (m, CH); 5.0 (br. t, J ¼ 6, 0.5 H of CH); 5.1 (br. t, J ¼ 6, 0.5 H
of CH); 6.73 (s, HꢀC(7), HꢀC( 8 )) ; 7.2 – 7.4 ( m, 6 arom. H). 13C-NMR (75 MHz): 17.5; 17.6; 22.1; 22.3;
22.6; 25.6; 25.7; 26.0; 36.7; 39.1; 39.7; 41.4; 41.7; 55.6; 76.3; 113.1; 115.4; 118.3; 121.7; 123.7; 124.0; 127.1;
127.2; 128.9; 131.6; 131.7; 131.8; 132.1; 134.5; 134.6; 147.6; 147.8; 153.0; 153.1. EI-MS: 368 (28), 259 (94),
203 (95), 177 (100), 137 (45), 109 (33). HR-MS: 368.1804 (Mþ, C23H28O2Sþ; calc. 368.1810).
(2R)-2-[(3E)-4,8-Dimethylnona-3,7-dien-1-yl]-3,4-dihydro-6-methoxy-2-methyl-4-(phenylsulfanyl)-
2H-chromene (15b). From 700 mg (1.54 mmol) of 14b, 461 mg (69%) of 15b and recovered 14b (253 mg)
were obtained. Colorless liquid. IR: 3060, 3007, 2970, 2931, 1614, 1582, 1491, 1465, 1379, 1225, 1040.
1H-NMR (300 MHz): 1.20 (s, 1.5 H of Me); 1.35 (s, 1.5 H of Me); 1.57 (s, 1.5 H of Me); 1.59 (s, 1.5 H of
Me); 1.65 (s, Me); 1.67 (s, 1.5 H of Me); 1.69 (s, 1.5 H of Me); 1.5 – 1.7 (m, CH2); 1.9 – 2.2 (m, 3 CH2); 3.75
(s, Me); 4.39 – 4.45 (m, CH); 5.0 (br. t, J ¼ 6, 0.5 H of CH); 5.1 (br. t, J ¼ 6, 0.5 H of CH); 6.73 (s, HꢀC(7),
HꢀC( 8 )) ; 7.2 – 7.4 ( m, 6 arom. H). 13C-NMR (75 MHz): 15.9; 16.0; 17.7; 17.7; 22.0; 22.3; 22.6; 22.6; 25.7;
25.7; 26.1; 26.6; 26.7; 36.7; 39.1; 39.6; 39.6; 41.4; 41.7; 55.7; 76.3; 113.1; 115.4; 115.5; 118.3; 121.7; 123.5;
123.8; 124.1; 124.2; 127.2; 127.3; 129.0; 131.3; 131.3; 131.8; 132.1; 134.4; 134.5; 135.2; 135.4; 147.6; 147.8;
152.9; 153.0. EI-MS: 436 (9), 326 (25), 175 (100), 137 (13), 110 (20). HR-MS: 436.2440 (Mþ, C28H36O2Sþ;
calc. 436.2436).
(2R)-6-Methoxy-2-methyl-2-(4-methylpent-3-en-1-yl)-2H-chromene (17a). To a soln. of mCPBA
(80%; 72 mg, 0.34 mmol) in CH2Cl2 (5 ml) was added 15a (116 mg, 0.32 mmol) in CH2Cl2 at 08 under Ar.
The mixture was stirred for 10 min. The reaction was quenched with 5 ml 10% Na2S2O3 soln., and the
mixture was extracted with CH2Cl2 (3 ꢁ 5 ml). The combined org. soln. was washed with sat. NaHCO3
soln. and brine, and dried. The solvent was evaporated to afford 16a. Without purification, 16a in 2 ml of
toluene containing 10 mg of CaCO3 was heated for 30 min at 1108 under Ar. The mixture was filtered.
The solvent was removed in vacuo, and the residue was purified by TLC (Et2O/hexane 1:20) to afford
17a (56 mg, 69%, over two steps). Colorless liquid. [a]2D4 ¼ ꢀ112.5 (c ¼ 0.58, CHCl3). IR: 3009, 2970,
1
2929, 1578, 1491, 1466, 1268, 1228, 1198. H-NMR (300 MHz): 1.37 (s, Me); 1.59 (s, Me); 1.65 (s, Me);
1.60 – 1.80 (m, CH2); 2.0 – 2.15 (m, CH2); 3.74 (s, Me); 5.08 – 5.12 (m, CH); 5.59 (d, J ¼ 9.5, CH); 6.30 (d,
J ¼ 9.5, CH); 6.53 – 6.71 (m, 3 arom. H). 13C-NMR (75 MHz): 17.6; 22.7; 25.7; 26.0; 40.9; 55.7; 78.0; 111.4;
114.1; 116.5; 121.7; 122.8; 124.1; 130.7; 131.6; 146.9; 153.5.
(2R)-2-[(3E)-4,8-Dimethylnona-3,7-dien-1-yl]-6-methoxy-2-methyl-2H-chromene (17b). From
290 mg (0.67 mmol) of 15b, 17b (145 mg, 67%) was obtained. Colorless liquid. [a]2D1 ¼ 70.6 (c ¼ 0.68,
CHCl3). IR: 3039, 3007, 2969, 2926, 1609, 1578, 1491, 1465, 1267, 1197. 1H-NMR (300 MHz): 1.37 (s, Me);
1.57 (s, Me); 1.58 (s, Me); 1.71 (s, Me); 1.50 – 1.76 (m, CH2); 1.92 – 2.14 (m, 3 CH2); 3.75 (s, Me);
5.07 – 5.13 (m, 2 CH); 5.60 (d, J ¼ 9.8, CH); 6.31 (d, J ¼ 9.8, CH); 6.53 – 6.72 (m, 3 arom. H). 13C-NMR
(75 MHz): 16.0; 17.7; 22.6; 25.7; 26.1; 26.7; 40.0; 40.9; 55.7; 78.1; 111.4; 114.1; 116.5; 121.7; 122.8; 123.9;
124.3; 130.8; 131.3; 135.2; 146.9; 153.5.
(ꢀ)-(R)-Cordiachromene (¼(2R)-2-Methyl-2-(4-methylpent-3-en-1-yl)-2H-chromen-6-ol; 1). Etha-
nethiol (0.05 ml, 0.67 mmol) was added to a suspension of NaH (16 mg, 0.67 mmol) in dry DMF, and the
mixture was stirred 15 min at r.t. Then, 17a (45 mg, 0.17 mmol) was added dropwise. The mixture was
stirred for 6 h at 1408 under Ar. After cooling, the reaction was quenched by addition of 2n HCl (1 ml).
The mixture was extracted with Et2O (3 ꢁ 10 ml). The combined org. phase washed with H2O and brine,
dried and filtered. The solvent was evaporated, and the residue was purified by TLC (Et2O/hexane 1:2)
to afford 13 mg (31%) of 1 and recovered 17a (20 mg). Yellowish liquid. [a]2D2 ¼ ꢀ110.7 (c ¼ 0.65,
CHCl3); [7] antipode: [a]2D0 ¼ þ101.6 (c ¼ 0.83, CHCl3); [4]: [a]D20 ¼ þ2.8 (c ¼ 0.025, CHCl3). IR: 3578,
3384, 3009, 2971, 2927, 1614, 1487, 1456, 1278, 1195. 1H-NMR (300 MHz): 1.36 (s, Me); 1.57 (s, Me); 1.65
(s, Me); 1.58 – 1.75 (m, CH2); 2.0 – 2.15 (m, CH2); 4.7 (br., OH); 5.08 (br. t, J ¼ 3, CH); 5.60 (d, J ¼ 9.8,

1952
Helvetica Chimica Acta – Vol. 95 (2012)
HꢀC(3)); 6.27 (d, J ¼ 9.8, HꢀC(2)); 6.48 (d, J ¼ 2.9, HꢀC(5)); 6.56 (d, J ¼ 8.6, HꢀC(7)); 6.64 (d, J ¼ 8.6,
HꢀC(8)). 13C-NMR (75 MHz): 17.6; 22.7; 25.7; 26.0; 40.9; 78.1; 112.9; 115.4; 116.7; 122.0; 122.6; 124.1;
131.0; 131.7; 147.0; 149.2. EI-MS: 244 (9), 162 (10), 161 (100), 69 (7). HR-MS: 244.1454 (Mþ, C16H20O2þ ;
calc. 244.1463).
(ꢀ)-(R)-Dictyiochromenol (¼(2R)-2-[(3E)-4,8-Dimethylnona-3,7-dien-1-yl]-2-methyl-2H-chro-
men-6-ol; 2). From 104 mg (0.32 mmol) of 17b, 36 mg (36%) of 2 and recovered 17b (48 mg) were
obtained. Yellowish liquid. [a]2D1 ¼ ꢀ86.5 (c ¼ 0.38, CHCl3); [12]: [a]2D0 ¼ ꢀ82.4 (c ¼ 0.83, CHCl3); [10]:
[a]D20 ¼ þ4; [11]: [a]D29 ¼ þ11 (c ¼ 0.182, CDCl3). IR: 3599, 3386, 3009, 2970, 2926, 1614, 1487, 1455, 1277,
1
1195. H-NMR (300 MHz): 1.37 (s, Me); 1.57 (s, Me); 1.58 (s, Me); 1.67 (s, Me); 1.50 – 1.76 (m, CH2);
1.90 – 2.15 (m, 3 CH2); 4.71 (s, OH); 5.06 – 5.12 (m, CH); 5.60 (d, J ¼ 9.8, HꢀC(3)); 6.27 (d, J ¼ 9.8,
HꢀC(2)); 6.48 (d, J ¼ 2.9, HꢀC(5)); 6.56 (d, J ¼ 8.6, HꢀC(7)); 6.64 (d, J ¼ 8.6, HꢀC(8)). 13C-NMR
(75 MHz): 16.0; 17.7; 22.6; 25.7; 26.0; 26.7; 39.7; 40.8; 78.1; 112.9; 115.4; 116.7; 122.0; 122.6; 123.9; 131.0;
131.4; 135.3; 146.9; 149.2. EI-MS: 312 (12), 162 (10), 161 (100), 69 (9). HR-MS: 312.2087 (Mþ,
C21H28Oþ2 ; calc. 312.2089).
REFERENCES
[1] G. D. Manners, L. Jurd, J. Chem. Soc., Perkin Trans. 1 1977, 405.
[2] N. M. Targett, W. S. Keeran, J. Nat. Prod. 1984, 47, 556.
[3] A. F. Benslimane, Y. F. Pouchus, J. L. Boterff, J. F. Verbist, C. Roussakis, F. Monniot, J. Nat. Prod.
1988, 51, 582.
[4] I. K. Kim, S. K. Park, K. L. Erickson, Magn. Reson. Chem. 1993, 31, 788.
[5] A. F. Benslimane, Y. F. Pouschus, J. F. Verbist, J.-Y. Petit, D. J. Brion, L. Welin, J. Clin. Pharmacol.
1995, 35, 298.
[6] P. H. Kahn, J. Cossy, Tetrahedron Lett. 1999, 40, 8113.
[7] S. Bouzbouz, J.-Y. Goujon, J. Deplanne, B. Kirschleger, Eur. J. Org. Chem. 2000, 3223.
[8] J. Y. Goujon, F. Zammattio, B. Kirschleger, Tetrahedron: Asymmetry 2000, 11, 2409.
[9] K. Takenaka, Y. Tanigaki, M. I. Patil, C. V. L. Rao, S. Takizawa, T. Suzuki, H. Sasai, Tetrahedron:
Asymmetry 2010, 21, 767.
[10] M.-N. Dave, T. Kusumi, M. Ishituka, T. Iwashita, H. Kakisawa, Heterocycles 1984, 22, 2301.
´
[11] A. S. Vega, B. Rojano, S. Blair, C. Segura, B. Figadere, B. Seon, P. Grellier, J. Saez, Pharmacol.
Online 2008, 1, 1.
[12] K. Aoki, M. Takahashi, M. Hashimoto, T. Okuno, K. Kurata, M. Suzuki, Biosci., Biotechnol.,
Biochem. 2002, 66, 1915.
[13] M. B. Smith, J. March, ꢁMarchꢀs Advanced Organic Chemistryꢀ, 5th edn., John Wiley & Sons, New
York, 2001, Chapt. 11.
[14] Y. Noda, Jpn. Kokai Tokkyo Koho, JP 2004026724, 2004.
[15] a) R. Naef, D. Seebach, Liebigs. Ann. Chem. 1983, 1930; b) G. Bojack, H. Bornowski, Tetrahedron
1991, 47, 9179.
[16] Z. Liu, L. Peng, T. Zhang, Y. Li, Synth. Commun. 2001, 31, 2549; P. Kocienski, S. Wadman, K.
Cooper, J. Org. Chem. 1989, 54, 1215.
[17] W. Szeja, Synthesis 1985, 983.
Received June 20, 2012