Synthesis of various 2H-benzopyran compounds and their kinetic resolution by asymmetric hydrolysis of their racemic acetates mediated by lipases

Article abstract of DOI:10.1016/S0957-4166(00)00176-2

The preparation of 2H-benzopyrans from bromophenols and tertiary allylic alcohols is described. The reaction is characterised by its mildness, good yields and ease of work-up. Kinetic resolution of the latter up to 95% ee was obtained by using enzyme-cata

Full text of DOI:10.1016/S0957-4166(00)00176-2

Tetrahedron: Asymmetry 11 (2000) 2409±2420
Synthesis of various 2H-benzopyran compounds and their
kinetic resolution by asymmetric hydrolysis of their racemic
acetates mediated by lipases
J. Y. Goujon, F. Zammattio* and B. Kirschleger
Á Â Á
Laboratoire de Synthese Organique, CNRS UMR 6513, Faculte des Sciences et des Techniques, 2 rue de la Houssiniere,
44072 Nantes Cedex 03, France
Received 21 April 2000; accepted 5 May 2000
Abstract
The preparation of 2H-benzopyrans from bromophenols and tertiary allylic alcohols is described. The
reaction is characterised by its mildness, good yields and ease of work-up. Kinetic resolution of the latter
up to 95% ee was obtained by using enzyme-catalysed enantioselective hydrolysis. # 2000 Elsevier Science
Ltd. All rights reserved.
1. Introduction
The central role of heterocycles in life sciences and natural product chemistry provides a
constant drive for the development of even more ecient methods for their preparation. Among
them, benzopyran and 3,4-dihydrobenzopyran nuclei are present in many biologically active com-
pounds, such as a-tocopherol or vitamin E,1 levcromakalim,2 cannabichromene3 and ubichromenol
or cordiachromene 1e.4 This latter compound was ®rst isolated from Cordia alliodora, which is a
tropical American tree whose wood is known for its durability in marine use. Moreover, cordia-
chromene exhibits high anti-in¯ammatory activity,5 which seems to be due to a selective inhibition
of cyclooxygenase.5
In the course of our interest concerning the development of new methods for the construction
of benzopyran nuclei, we became interested in the preparation of substituted-3,4-dihydro-
benzopyrans of type 1, 2 and 3 with various R substituents. In addition, we also wanted to study
the in¯uence of relative and absolute stereochemistry of the stereogenic centre on the inhibition of
cyclooxygenase.
* Corresponding author. Fax: 02 51 12 54 12; e-mail: fancoise.zammattio@chimie.univ-nantes.fr
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00176-2

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The most used strategies for the synthesis of 3,4-dihydrobenzopyran nuclei involve a Claisen
rearrangement of propargyl ethers6 or a cyclisation of substituted quinones in re¯uxing pyridine.7
To try to introduce aryl diversity using readily available phenols, we envisaged a particularly
attractive approach, similar to the one reported by Saa,8 based on a palladium-catalysed reaction
of a tertiary allylic alcohol with an ortho-bromophenol. This strategy has been used in order to
circumvent the lack of availability of 2-iodophenols, which are the starting materials in the Saa8
route. Moreover, to explore the scope and limitations of this process as well as its ability to
facilitate the synthesis of various 3,4-dihydrobenzopyran, we systematically investigated the
reaction of various tertiary allylic alcohols with diverse ortho-bromophenols using palladium
acetate as the precatalyst.
In this paper, we are reporting our results concerning syntheses of compounds 1, 2 and 3 and
enzymatic kinetic resolution of 1e and 2b as an alternative for their stereocontrolled construction.
2. Results and discussion
2.1. Synthesis of 2H-1-benzopyran derivatives 1 to 3
Chiral racemic allylic alcohols 9, 10 and 11 were prepared as shown in Scheme 1. The treatment
of 4 with bromine9 in methylene chloride provided the desired 2-bromophenols 5 in high yields.
Heck reaction of 5 with 2 mol equiv. linalool 6 in CH3CN in the presence of CsCO3 (0.5 equiv.)
Scheme 1. Synthesis of compounds 1, 2 and 3

J. Y. Goujon et al. / Tetrahedron: Asymmetry 11 (2000) 2409±2420
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and 5 mol% of Pd(OAc)2 at 100ꢀC for 3 h gave the corresponding allylic alcohols 9 in satisfactory
yields (Table 1: entries 1±4). These results show that the Heck coupling reaction works well with
2-bromophenols bearing electron withdrawing or donating groups. On the other hand, it is
noteworthy that the same conditions could be applied to the preparation of analogues 10 and 11
(Table 1: entries 5 and 6) from the nerolidol 7 or the geranyl linalool 8, respectively.
Table 1
Heck reaction of bromophenols 5 with allylic alcohols 6, 7 and 8
Finally, conversion of 9, 10 and 11 to the corresponding 2H-1-benzopyrans 1, 2 and 3 was
simply achieved in quantitative yields by heating pure 9, 10 or 11 at 120ꢀC, under vacuum for 30
min.
2.2. Kinetic resolution of 1e and 2b
With the desired 1a and 2a in hand, we turned our attention to their kinetic resolution as an
alternative to their asymmetric synthesis. With this aim, removal of the benzyl-protecting group
was ®rst undertaken. The Lewis acid deprotection10 of 1a and 2a a€orded compounds 1e and 2b
(Table 2) which served as key starting materials for our enzymatic resolution. Then, three lipases
were tested for the enantioselective hydrolysis of racemic acetate (þ)-12 generated from 1e (Table 2).
As shown by the results listed in Table 2, the lipase from Candida cylindracea (CCL) was found to
be the most e€ective one, even if (+)-12 and (^)-12 were not resolved with the same eciency,
leaving the enantiopure acetate (^)-12 in satisfactory chemical yield and enantiomeric excess
(Table 2: entry 2). Acetate (^)-12 gave 2H-1-benzopyran (^)-1e in quantitative yield on K2CO3
mediated methanolysis. With the success of this kinetic resolution, we applied this methodology to
the trans racemic acetate (þ)-13 generated from the trans (þ)-2b (Table 2). Subsequently, enzymatic
hydrolysis and methanolysis of the pure trans enantiomer (^)-13 a€orded the corresponding trans
2H-1-benzopyran (^)-2b (>98% ee) in 20% yield (Table 2: entry 4). The hydrolysis of substrates
was followed by HPLC analysis. As an example, the HPLC analysis of a sample of acetate 12 is
reported in Figs. 1 and 2.
2.3. Absolute con®guration of 1e and 2b
Since optically active 2H-1-benzopyrans 1e, 2b, 12 and 13 have never been described, we could
not, at this stage of our study, assign the absolute con®guration of the stereogenic centre (C2).
Nevertheless, the (S) preference observed with lipase AY in the case of enantioselective hydrolysis
of (RS)-tocol acetate,11 which is very similar to substrates (RS)-12 and (RS)-13, supports the
hypothesis that these latter substrates could be hydrolysed with the same enantioselectivity. To

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Table 2
Lipase-catalysed kinetic resolution of 2H-1-benzopyran acetates (þ)-12 and 13
Figure 1. HPLC analysis of racemic acetate 12

J. Y. Goujon et al. / Tetrahedron: Asymmetry 11 (2000) 2409±2420
2413
Figure 2. HPLC analysis of hydrolysis reaction mixture containing (^)-12 and (þ)-1e (Chiralcel OD-H, hexane:propan-
2-ol, 95:5, ¯ow 0.5 ml/min, l 254 nm)
con®rm the enantiopreference of lipases AY and CCL, kinetic resolution of racemic acetate 15, of
which both the relative and absolute con®guration of each enantiomer were known,12b was carried
out. Racemic acetate 15 was prepared as reported12a and submitted to lipase hydrolysis. From the
reaction mixture, recovered (+)-15 could be isolated in 15% yield and 70% ee (Scheme 2). The
con®guration of the pure enantiomer (+)-15 was unequivocally established as (R) by comparison
of its speci®c rotation with that of an authentic sample of (R)-(+)-15.12b This result con®rmed the
(S) enantiopreference of the enzyme and allows us to assign the (R) con®guration at C2 for (^)-12
and (^)-13 as well as for (^)-1e and (^)-2b.
Scheme 2. Lipase-catalysed kinetic resolution of (RS)-15. (a) Ac2O, DMAP, Et3N, CH2Cl2, 25ꢀC; (b) lipase CCL, IPE/
H2O

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In conclusion, we have developed a practical and ecient general route to 2H-1-benzopyrans in
quite good yields and up to 95% enantioselectivity by using lipase-mediated kinetic resolution as an
alternative to their asymmetric synthesis.
3. Experimental
3.1. Apparatus
1H and 13C NMR spectra were recorded with Bruker AC 200 and Bruker AMX 400 spectro-
meters in chloroform-d1; chemical shifts are expressed in ppm. IR spectra were recorded on a
Bruker vector 22 spectrometer. Mass spectra (m/e (% base peak)) were recorded on HP 5889A
spectrometer EI (70 eV). For high performance liquid chromatography (HPLC) analysis a Hewlett±
Packard model (HP 1050) equipped with a UV detector (254 nm) and a Chiralcel OD-H column
were employed. Optical rotations were measured on a Perkin±Elmer 341 polarimeter. Melting
points were determined on a C. Reichert microscope apparatus and are uncorrected. Elemental
analyses were carried out on a Perkin±Elmer 2400 C,H,N elemental analyser.
3.2. Chemicals
Dichloromethane and ethyl acetate were dried by distillation over P2O5. Hexane was dried by
distillation over CaCl2. Lipase from Candida rugosa (AY) and porcine pancreas (PPL, type II)
were obtained from Sigma. Lipase from Candida cylindracea (CCL, type VII) was obtained from
Aldrich. Linalool, nerolidol and geranyl-linalool were purchased from Acros. Bromophenols 5
were prepared following classical procedures.9
3.3. General procedure for the preparation of tertiary allylic alcohols 9, 10 and 11
To a solution of 2-bromophenol 5 (3.5 mmol) in acetonitrile (9 ml), CsCO3 (0.7 g, 1.5 mmol),
Pd(OAc)2 (0.03 g, 0.13 mmol) and 1.1 g (7.0 mmol) of linalool were added. The reaction mixture
was stirred under argon at 100ꢀC for 3 h, then diluted with dichloromethane and ®nally washed
with brine. The organic layer was dried (MgSO4), concentrated under vacuum and chromato-
graphed on silica gel, eluting with a 80:20 (v/v) mixture of hexane:EtOAc.
3.3.1. 1-(2-Hydroxy-5-benzyloxyphenyl)-3,7-dimethylocta-1,6-dien-3-ol 9a
Compound 9a was obtained as a brown solid from 5a in 77%; mp 42ꢀC; ꢀH (CDCl3) 1.37 (s,
3H, CH3), 1.57 (s, 3H, CH3), 1.66 (s, 3H, CH3), 1.57±1.69 (m, 2H, CH2), 2.04±2.09 (m, 2H, CH2),
4.98 (s, 2H, OCH2), 5.08±5.15 (m, 1H, ±CHˆ), 6.16±6.24 (d, 1H, J=16.1 Hz, ˆCH±), 6.71 (m,
1H, CarH), 6.79±6.87 (d, 1H, J=16.1 Hz, ˆCH±), 6.96 (m, 2H, CarH), 7.28±7.38 (m, 5H, CarH);
ꢀC (CDCl3) 17.7, 22.9, 25.6, 28.2, 42.5, 70.7, 74.1, 113.2, 115.0, 116.8, 121.8, 124.2, 124.2, 127.5,
127.8, 128.4, 130.7, 132.2, 137.9, 147.5, 152.7; IR 3355, 3033, 2965, 2926, 2856, 1500, 1445, 1196
cm^1; MS (m/e) 352 (M+Á, 0), 334 (14), 251 (100), 91 (20).
3.3.2. 1-(2-Hydroxy-5-methoxyphenyl)-3,7-dimethylocta-1,6-dien-3-ol 9b
Compound 9b was obtained as a white solid from 5b in 78% yield; mp 41ꢀC; ꢀH (CDCl3) 1.37
(s, 3H, CH3), 1.57 (s, 3H, CH3), 1.63 (m, 2H, CH2), 1.65 (s, 3H, CH3), 2.04±2.10 (m, 2H, CH2),

J. Y. Goujon et al. / Tetrahedron: Asymmetry 11 (2000) 2409±2420
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3.74 (s, 3H, OCH3), 5.10 (m, 1H, ±CHˆ), 6.19±6.23 (d, 1H, J=16.1 Hz, ˆCH±), 6.62±6.65 (m,
1H, CarH), 6.72±6.74 (m, 1H, CarH), 6.82±6.84 (d, 1H, J=16.1 Hz, ˆCH±), 6.87±6.88 (m, 1H,
CarH); ꢀC (CDCl3) 17.6, 22.9, 25.6, 28.0, 42.5, 55.7, 74.0, 111.7, 114.1, 116.9, 121.9, 124.2, 125.1,
131.8, 147.4, 153.4; MS (m/e) 276 (M+Á, 0), 258 (8), 175 (100).
3.3.3. 1-(2-Hydroxy-5-methylphenyl)-3,7-dimethylocta-1,6-dien-3-ol 9c
Compound 9c was obtained as a white solid from 5c in 76% yield; mp 37ꢀC; ꢀH (CDCl3) 1.36
(s, 3H, CH3), 1.55 (s, 3H, CH3), 1.60±1.68 (m, 2H, CH2), 1.65 (s, 3H, CH3), 2.02±2.10 (m, 2H,
CH2), 2.22 (s, 3H, CH3), 5.04±5.08 (m, 1H, ±CHˆ), 6.14±6.22 (d, 1H, J=16.2 Hz, ˆCH±), 6.68±
6.87 (m, 2H, CarH), 6.72±6.79 (d, 1H, J=16.2 Hz, ˆCH±), 7.10±7.11 (m, 1H, CarH); ꢀC (CDCl3)
17.6, 20.4, 22.9, 25.6, 27.9, 42.4, 74.2, 115.9, 122.1, 124.1, 124.1, 127.3, 128.9, 128.9, 131.7, 137.0,
153.4; MS (m/e) 260 (M+Á, 0), 242 (3), 202 (18), 159 (27), 43 (100).
3.3.4. 1-(2-Hydroxy-5-cyanophenyl)-3,7-dimethylocta-1,6-dien-3-ol 9d
Compound 9d was obtained as a yellow oil from 5d in 52% yield; ꢀH (CDCl3) 1.42 (s, 3H,
CH3), 1.57 (s, 3H, CH3), 1.66±1.74 (m, 2H, CH2), 1.74 (s, 3H, CH3), 2.04±2.14 (m, 2H, CH2),
5.07±5.14 (m, 1H, ±CHˆ), 6.26±6.34 (d, 1H, J=16.3 Hz, ˆCH±), 6.79±6.87 (d, 1H, J=16.3 Hz,
ˆCH±), 6.90±6.94 (m, 1H, CarH), 7.30±7.59 (m, 1H, CarH), 7.58 (m, 1H, CarH); ꢀC (CDCl3) 17.6,
22.8, 25.6, 27.8, 42.3, 74.4, 102.3, 116.7, 119.4, 120.6, 123.0, 125.8, 131.2, 132.1, 132.2, 138.7,
158.1; IR 3300, 2971, 2928, 2226, 1601, 1277 cm^1; MS (m/e) 271 (M+Á, 0), 253 (19), 210 (33), 170
(100), 43 (24), 41 (26).
3.3.5. 1-(2-Hydroxy-5-benzyloxyphenyl)-3,7,11-trimethyldodeca-1,6,10-trien-3-ol 10
Compound 10 was obtained as a brown oil from 5a in 65% yield; ꢀH (CDCl3) 1.37 (s, 3H,
CH3), 1.57 (s, 6H, 2CH3), 1.63±1.69 (m, 2H, CH2), 1.66 (s, 3H, CH3), 1.98±2.06 (m, 6H, 3CH2),
4.96 (s, 2H, OCH2), 5.07±5.14 (m, 2H, 2CHˆ), 6.14±6.22 (d, 1H, J=16.1 Hz, ˆCH±), 6.70±6.71
(m, 2H, 2CarH), 6.79±6.87 (d, 1H, J=16.1 Hz, ˆCH±), 6.96 (s, 1H, CarH), 7.31±7.47 (m, 5H,
CarH); ꢀC (CDCl3) 16.0, 17.5, 22.6, 25.6, 26.4, 28.0, 39.6, 42.3, 70.7, 73.9, 113.2, 115.0, 116.8,
121.8, 124.0, 124.2, 125.0, 127.4, 127.8, 128.4, 131.3, 135.2, 137.2, 137.8, 147.5, 152.7; IR 3355,
3032, 2966, 2925, 2856, 1503, 1437, 1196 cm^1; MS (m/e) 420 (M+Á, 0), 402 (19), 251 (100), 91 (50).
3.3.6. 1-(2-Hydroxy-5-benzyloxyphenyl)-3,7,11,15-tetramethylhexdeca-1,6,10,14-tetraen-3-ol 11
Compound 11 was obtained as a brown oil from 5a in 65% yield; ꢀH (CDCl3) 1.36 (s, 3H,
CH3), 1.57 (s, 6H, 2CH3), 1.64 (m, 2H, CH2), 1.66 (s, 6H, 2CH3), 2.02 (m, 10H, 5CH2), 4.96 (s,
2H, OCH2), 5.05 (m, 3H, 3CHˆ), 5.93 (d, 1H, J=13.0 Hz, ˆCH±), 6.36 (m, 2H, 2CarH), 6.44 (d,
1H, J=13.0 Hz, ˆCH±), 6.57 (m, 1H, CarH), 7.31 (m, 5H, CarH); ꢀC (CDCl3) 15.9, 17.6, 22.9,
23.4, 25.6, 25.9, 26.7, 28.1, 31.9, 39.7, 42.5, 70.7, 74.0, 113.2, 115.0, 116.8, 121.8, 124.0, 124.1,
124.9, 124.9, 127.5, 127.8, 128.5, 130.5, 131.5, 135.8, 137.8, 138.6, 147.5, 152.7; IR 3356, 3033,
2965, 2925, 2855, 1499, 1453, 1196 cm^1; MS (m/e) 488 (M+Á, 0), 470 (9), 317 (21), 251 (37), 91
(100), 41 (62).
3.4. General procedure for the cyclisation of tertiary allylic alcohols 9,10 and 11 to 2H-1-benzo-
pyran
The tertiary allylic alcohol was warmed at 120ꢀC under vacuum to obtain the corresponding
pure racemic 2H-1-benzopyran without any further puri®cation.

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3.4.1. 6-Benzyloxy-2-methyl-2-(4-methylpent-3-enyl)-2H-1-benzopyran 1a
Compound 1a was obtained from 9a as a brown oil in 95% yield; ꢀH (CDCl3) 1.36 (s, 3H,
CH3), 1.56 (s, 3H, CH3), 1.64 (s, 3H, CH3), 1.61±1.71 (m, 2H, CH2), 2.11±2.19 (m, 2H, CH2), 4.98
(s, 2H, CH2), 5.04±5.13 (m, 1H, ±CHˆ), 5.54±5.59 (d, 1H, J=9.9 Hz, ˆCH±), 6.26±6.31 (d, 1H,
J=9.9 Hz, ˆCH±), 6.61±6.73 (m, 3H, CarH), 7.28±7.42 (m, 5H, CarH); ꢀC (CDCl3) 12.5, 14.7,
20.5, 20.9, 35.8, 65.4, 72.9, 107.6, 110.1, 111.4, 116.6, 117.7, 119.0, 122.3, 122.4, 123.3, 125.6,
126.4, 132.2, 142.1, 147.7; IR 3033, 2968, 2924, 2856, 1489, 1267, 1225 cm^1; MS (m/e) 334 (M+Á, 11);
251 (100); 91 (38); anal. calcd for C23H26O2: C, 82.60; H, 7.84; O, 9.57. Found: C, 82.51; H, 7.80.
3.4.2. 6-Methoxy-2-methyl-2-(4-methylpent-3-enyl)-2H-1-benzopyran 1b
Compound 1b was obtained from 9b as a brown oil in 92% yield; ꢀH (CDCl3) 1.36 (s, 3H,
CH3), 1.61 (s, 3H, CH3), 1.65±1.73 (m, 2H, CH2), 1.69 (s, 3H, CH3), 2.04±2.16 (m, 2H, CH2), 3.73
(s, 3H, OCH3), 5.04±5.13 (m, 1H, ±CHˆ), 5.55±5.60 (d, 1H, J=9.9 Hz, ˆCH±), 6.27±6.32 (d, 1H,
J=9.9 Hz, ˆCH±), 6.52±6.72 (m, 3H, CarH); ꢀC (CDCl3) 17.5, 22.7, 25.6, 26.0, 40.9, 55.6, 78.0,
111.5, 114.1, 116.5, 121.7, 122.8, 124.1, 130.1, 131.5, 146.9, 153.5; IR 2968, 2925, 2856, 1492,
1266, 1226, 1198, 1041 cm^1; MS (m/e) 258 (M+Á, 10); 175 (100); 41 (9); anal. calcd for C17H22O2:
C, 79.03; H, 8.58; O, 12.39. Found: C, 79.00; H, 8.48.
3.4.3. 2,6-Dimethyl-2-(4-methylpent-3-enyl)-2H-1-benzopyran 1c
Compound 1c was obtained from 9c as a yellow oil in 95% yield; ꢀH (CDCl3) 1.37 (s, 3H,
CH3), 1.57 (s, 3H, CH3), 1.58±1.74 (m, 2H, CH2), 1.66 (s, 3H, CH3), 2.00±2.13 (m, 2H, CH2), 2.23
(s, 3H, CH3), 5.09±5.12 (m, 1H, ±CHˆ), 5.51±5.56 (d, 1H, J=9.9 Hz, ˆCH±), 6.28±6.32 (d, 1H,
J=9.9 Hz, ˆCH±), 6.64±6.90 (m, 3H, CarH); ꢀC (CDCl3) 17.6, 20.4, 22.7, 25.6, 26.3, 41.1, 78.2,
115.8, 120.8, 122.8, 124.1, 126.7, 129.4, 129.5, 129.7, 131.5, 150.9; IR 2969, 2923, 2860, 1492, 1256
cm^1; MS (m/e) 243 (M+Á, 2), 159 (100), 41 (14); anal. calcd for C17H22O: C, 84.25; H, 9.15; O,
6.60. Found: C, 84.14; H, 9.11.
3.4.4. 6-Cyano-2-methyl-2-(4-methylpent-3-enyl)-2H-1-benzopyran 1d
Compound 1d was obtained from 9d as a yellow oil in 94% yield; ꢀH (CDCl3) 1.33 (s, 3H,
CH3), 1.47 (s, 3H, CH3), 1.56 (s, 3H, CH3), 1.58±1.66 (m, 2H, CH2), 1.95±2.06 (m, 2H, CH2),
4.95±5.03 (m, 1H, ±CHˆ), 5.54±5.59 (d, 1H, J=10.1 Hz, ˆCH±), 6.21±6.26 (d, 1H, J=10.1 Hz,
ˆCH±), 6.67±6.71 (d, 1H, J=8.4 Hz, CarH), 7.13±7.14 (d, 1H, J=2.0 Hz, CarH), 7.25±7.30 (dd,
1H, J=8.4 Hz, J=2.0 Hz, CarH); ꢀC (CDCl3) 17.6, 22.5, 25.5, 27.0, 41.2, 80.2, 103.4, 116.8, 121.1,
121.4, 123.4, 130.0, 131.0, 131.9, 146.9, 133.2, 157.0; IR 3301, 2971, 2927, 2857, 2226, 1601, 1487,
1276 cm^1; MS (m/e) 253 (M+Á, 13); 170 (100); 41 (22); anal. calcd for C17H19NO: C, 80.60; H,
7.56; N, 5.53; O, 6.32. Found: C, 80.49; H, 7.58; N, 5.45.
3.4.5. 6-Benzyloxy-2-methyl-2-(4,8-dimethylnona-3,7-dienyl)-2H-1-benzopyran 2a
Compound 2a was obtained from 10 as a brown oil in 90% yield; ꢀH (CDCl3) 1.36 (s, 3H,
CH3), 1.56 (s, 3H, 1CH3), 1.66 (s, 6H, 2CH3), 1.66±1.75 (m, 2H, CH2), 1.89±2.09 (m, 6H, 3CH2),
4.98 (s, 2H, CH2), 5.06±5.13 (m, 2H, 2CHˆ), 5.54±5.59 (d, 1H, J=9.8 Hz, ˆCH±), 6.26±6.31 (d,
1H, J=9.8 Hz, ˆCH±), 6.6±6.71 (m, 3H, CarH), 7.36±7.40 (m, 5H, CarH); ꢀC (CDCl3) 16.0, 17.6,
22.7, 23.3, 25.6, 26.4, 31.8, 39.6, 70.6, 78.0, 112.5, 115.2, 116.5, 122.8, 124.0, 125.0, 127.4, 127.5,
128.4, 130.6, 132.1, 135.5, 137.0, 145.9, 153.3; IR 3034, 2966, 2924, 2856, 1489, 1222 cm^1; MS
(m/e) 402 (M+Á, 12); 251 (100); 91 (21); anal. calcd for C28H34O2: C, 83.54; H, 8.51; O, 7.95.
Found C 83.45; H, 8.48.

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3.4.6. 6-Benzyloxy-2-methyl-2-(4,8,12-trimethyltrideca-3,7,11-trienyl)-2H-1-benzopyran 3
Compound 3 was obtained from 11 as a brown oil in 88% yield; ꢀH (CDCl3) 1.33 (s, 3H, CH3),
1.56 (s, 6H, 2CH3), 1.66 (s, 6H, 2CH3), 1.66±1.75 (m, 2H, CH2), 1.94±2.06 (m, 10H, 5CH2), 4.96
(s, 2H, CH2), 5.09±5.11 (m, 3H, 3CHˆ), 5.55±5.58 (d, 1H, J=9.8 Hz, ˆCH±), 6.26±6.28 (d, 1H,
J=9.8 Hz, ˆCH±), 6.59±6.70 (m, 3H, CarH), 7.32±7.40 (m, 5H, CarH); ꢀC (CDCl3) 15.9, 17.5,
22.0, 23.3, 25.6, 26.0, 26.2, 26.6, 31.8, 39.6, 41.1, 70.6, 77.9, 112.6, 115.2, 116.5, 121.2, 122.8,
123.9, 124.3, 124.9, 127.3, 127.7, 128.3, 130.6, 131.0, 134.9, 135.6, 137.4, 147.1, 152.7; IR 3033,
2965, 2924, 2856, 1489, 1452, 1224 cm^1; MS (m/e) 470 (M+Á, 8), 251 (100), 91 (24); anal. calcd for
C33H42O2: C, 84.21; H, 8.99; O, 6.80. Found: C, 84.15; H, 8.89.
3.5. General procedure for debenzylation of 2H-1-benzopyran
To a solution of benzylated compound (2 mmol), EtSH (6 ml) in diethylether, was added AlCl3
(6 mmol) at ^30ꢀC. After stirring for 30 min, the reaction mixture was poured into water and
extracted with diethylether. The organic layer was washed with brine, dried (MgSO4), ®ltered,
concentrated under vacuum and chromatographed on silica gel, eluting with a 80:20 (v/v) mixture
of hexane:EtOAc.
3.5.1. 6-Hydroxy-2-methyl-2-(4-methylpent-3-enyl)-2H-1-benzopyran 1e (cordiachromene)
Compound 1e was obtained from 1a as a brown oil in 82% yield; ꢀH (CDCl3) 1.35 (s, 3H,
CH3), 1.57 (s, 3H, 1CH3), 1.65 (s, 3H, CH3), 1.66±2.06 (m, 4H, 2CH2), 4.75 (s, 1H, OH), 5.08 (m,
1H, CHˆ), 5.60±5.65 (d, 1H, J=9.8 Hz, ˆCH±), 6.28±6.33 (d, 1H, J=9.8 Hz, ˆCH±), 6.62±6.71
(m, 3H, CarH); ꢀC (CDCl3) 17.5, 22.5, 25.5, 25.8, 40.7, 78.0, 112.8, 115.6, 121.8, 122.5, 124.0,
130.8, 131.5, 146.7, 149.1; IR 3394, 3017, 2971, 2920, 2853, 1620, 1580, 1490, 1455, 1221 cm^1;
MS (m/e) 244 (M+Á, 41), 161 (100); anal. calcd for C16H20O2: C, 78.65; H, 8.25; O, 13.10. Found:
C, 78.56; H, 8.33.
3.5.2. 6-Hydroxy-2-methyl-2-(4,8-dimethylnona-3,7-dienyl)-2H-1-benzopyran 2b (dictyochromenol)
Compound 2b was obtained from 2a as a brown oil in 80% yield; ꢀH (CDCl3) 1.37 (s, 3H,
CH3), 1.58 (s, 6H, 2CH3), 1.67 (s, 3H, CH3), 1.68±2.10 (m, 8H, 4CH2), 4.56 (s, 1H, OH), 5.00±
5.15 (m, 2H, 2CHˆ), 5.54±5.59 (d, 1H, J=9.9 Hz, ˆCH±), 6.22±6.27 (d, 1H, J=9.9 Hz, ˆCH±),
6.47±6.62 (m, 3H, CarH); ꢀC (CDCl3) 16.3, 18.0, 22.9, 26.0, 26.3, 27.0, 40.0, 41.2, 78.5, 113.2,
115.7, 117.0, 115.6, 122.3, 124.3, 124.6, 131.3, 132.6, 135.6, 147.2, 149.6; IR 3350, 2966, 2923,
2855, 1590, 1495, 1240 cm^1; MS (m/e) 312 (M+Á, 41), 203 (100), 161 (70); anal. calcd for
C21H28O2: C, 80.73; H, 9.03; O, 10.24. Found C 80.65; H, 8.96.
3.6. 6-Acetoxy-2-methyl-2-(4-methylpent-3-enyl)-2H-1-benzopyran 12
To a solution of 1e (490 mg, 2 mmol), Et3N (0.35 ml, 2.5 mmol), and DMAP (12 mg, 0.1
mmol) in dichloromethane (6 ml) was added acetic anhydride (0.24 ml, 2.5 mmol) dropwise. The
reaction mixture was stirred for 3 h at room temperature. The reaction was then diluted with
brine, and the organic layer was washed with 1N HCl, 10% NaHCO3, and dried (MgSO4). The
solvent was removed under vacuum, yielding 550 mg (96%) of 12 as a brown oil; ꢀH (CDCl3) 1.37
(s, 3H, CH3), 1.57 (s, 3H, 1CH3), 1.66 (s, 3H, CH3), 1.68±2.06 (m, 4H, 2CH2), 2.25 (s, 3H,
CH3CO), 5.09 (m, 1H, CHˆ), 5.55±5.60 (d, 1H, J=9.8 Hz, ˆCH±), 6.26±6.30 (d, 1H, J=9.8 Hz,
ˆCH±), 6.68±6.77 (m, 3H, CarH); ꢀC (CDCl3) 17.5, 20.9, 22.7, 25.6, 26.4, 41.2, 78.7, 116.4, 119.0,

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J. Y. Goujon et al. / Tetrahedron: Asymmetry 11 (2000) 2409±2420
121.5, 122.2, 123.3, 124.0, 130.5, 131.5, 143.9, 150.7; IR 2966, 2922, 2856, 1763, 1486, 1204 cm^1;
MS (m/e) 286 (M+Á, 7), 203 (100), 161 (94), 69 (6); anal. calcd for C18H22O3: C, 75.50; H, 7.74; O,
16.76. Found: C, 75.09; H, 7.83.
3.7. 6-Acetoxy-2-methyl-2-(4,8-dimethylnona-3,7-dienyl)-2H-1-benzopyran 13
To a solution of 2b (624 mg, 2 mmol), Et3N (0.35 ml, 2.5 mmol), and DMAP (12 mg, 0.1
mmol) in dichloromethane (6 ml) was added acetic anhydride (0.24 ml, 2.5 mmol) dropwise. The
reaction mixture was stirred for 3 h at room temperature. The reaction mixture was then diluted
with brine, and the organic layer was washed with 1N HCl, 10% NaHCO3, and dried (MgSO4).
The solvent was removed under vacuum, yielding 686 mg (97%) of 13 as a brown oil; ꢀH (CDCl3)
1.38 (s, 3H, CH3), 1.56 (s, 3H, CH3), 1.59 (s, 3H, CH3), 1.67 (s, 3H, CH3), 1.68±2.10 (m, 8H,
4CH2), 2.26 (s, 3H, CH3CO), 5.00±5.15 (m, 2H, 2CHˆ), 5.56±5.61 (d, 1H, J=9.9 Hz, ˆCH±),
6.26±6.31 (d, 1H, J=9.9 Hz, ˆCH±), 6.68±6.77 (m, 3H, CarH); ꢀC (CDCl3) 14.9, 21.0, 21.1, 25.6,
26.4, 26.6, 39.6, 41.4, 78.7, 80.2, 116.5, 115.7, 118.9, 121.5, 123.0, 123.1, 123.8, 124.3, 124.6, 135.7,
143.9, 150.7, 169.8; IR 2967, 2924, 2856, 1764, 1486, 1204 cm^1; MS (m/e) 354 (M+Á, 9), 312 (13),
203 (92), 161 (100), 69 (33), 41 (58); anal. calcd for C23H30O3: C, 77.93; H, 8.53; O, 13.54. Found:
C, 77.88; H, 8.48.
3.8. Kinetic resolution of 2H-1-benzopyran acetate (R)-12
Racemic acetate 12 (400 mg, 1.4 mmol) was dissolved in diisopropyl ether (26 ml) saturated
with water and lipase CCL (200 mg) was added. The reaction was followed by HPLC and stopped
at 60% of hydrolysis (reaction time: 1.05 h). Then, the enzyme was ®ltered o€, and the organic
layer was dried (MgSO4), concentrated under vacuum and chromatographed on silica gel, eluting
with a 90:10 (v/v) mixture of hexane:EtOAc to provide R-(^)-12 (60 mg, 0.42 mmol, ee 95%,
[ꢁ]D=^75.7 (c 1.18, acetone)) and (S)-(+)-1e (187 mg, 0.76 mmol, ee 13%, [ꢁ]D=+22.0 (c 1.38,
acetone)).
3.9. Deacetylation of 2H-1-benzopyran acetate 12
Compound R-(^)-12 (50 mg, 0.17 mmol) was dissolved in 2 ml of MeOH and sat. K2CO3 (2 ml)
was added. The reaction mixture was stirred for 4 h until the analysis by TLC revealed complete
disappearance of starting material. The reaction was then acidi®ed with 1N HCl and diluted with
diethyl ether (20 ml). The organic layer was washed with brine, dried (MgSO4), and concentrated
under vacuum, yielding (R)-1e (42.2 mg, 99%) as a pale yellow oil; [ꢁ]D=^109.1 (c 0.95, CHCl3);
ee 95%.
3.10. Kinetic resolution of 2H-1-benzopyran acetate (R)-13
Racemic acetate 13 (1 g, 2.82 mmol) was dissolved in diisopropyl ether (55 ml) saturated with
water and lipase CCL (485 mg) was added. The reaction was followed by HPLC and stopped
at 60% of hydrolysis (reaction time: 1.10 h). Then the enzyme was ®ltered o€, and the organic
layer was dried (MgSO4), concentrated under vacuum and chromatographed on silica gel,
eluting with a 90:10 (v/v) mixture of hexane:EtOAc to provide (R)-13 (200 mg, 0.56 mmol,

J. Y. Goujon et al. / Tetrahedron: Asymmetry 11 (2000) 2409±2420
2419
ee 98%, [ꢁ]D=^74.3 (c 1.24, CHCl3)) and (S)-(+)-2b (520 mg, 1.6 mmol, ee 18%, [ꢁ]D=+19.0
(c 1.20, CHCl3)).
3.11. Deacetylation of 2H-1-benzopyran acetate 13
Compound (R)-13 (190 mg, 0.53 mmol) was dissolved in 3 ml of MeOH and sat. K2CO3 (3 ml)
were added. The reaction mixture was stirred for 4 h until the analysis by TLC revealed complete
disappearance of starting material. The reaction was then acidi®ed with 1N HCl and diluted with
diethyl ether (30 ml).The organic layer was washed with brine, dried (MgSO4), and concentrated
under vacuum, yielding (R)-2b (164 mg, 98%) as a pale yellow oil; [ꢁ]D=^103.8 (c 1.21, CHCl3);
ee 98%.
3.12. 9-Hydroxy-3-methyl-(4-methylpent-3-enyl)-3H-naphtho[2,1-b]pyran 14
A mixture of 2,7-naphthalenediol (5 g, 31.2 mmol) and citral (4.9 g, 32 mmol) in 4-picoline (10
ml) was heated to re¯ux for 20 h. After cooling to room temperature, the reaction mixture was
diluted with EtOAc (80 ml), and then washed with 1N HCl and brine. The organic layer was
dried (MgSO4), concentrated under vacuum and chromatographed on silica gel, eluting with a
80:20 (v/v) mixture of hexane:EtOAc to provide 14 (8.2 g, 90%) as an orange oil; ꢀH (CDCl3) 1.44
(s, 3H, CH3), 1.58 (s, 3H, 1CH3), 1.66 (s, 3H, CH3), 1.71±1.79 (m, 2H, CH2), 2.13±2.17 (m, 2H,
CH2), 5.08±5.10 (m, 1H, CHˆ), 5.63±5.65 (d, 1H, J=10 Hz, ˆCH±), 6.88±6.90 (d, 1H, J=10 Hz,
ˆCH±), 6.90±7.65(m, 5H, CarH); ꢀC (CDCl3) 17.5, 22.7, 25.6, 40.7, 78.4, 103.9, 112.4, 115.9,
118.5, 124.0, 124.5, 127.9, 129.0, 130.3, 131.6, 151.8, 154.2; IR 3386, 2968, 2924, 2855, 1636, 1210
cm^1; MS (m/e) 294 (M+Á, 12), 211 (100), 41 (5).
3.13. 9-Acetoxy-3-methyl-(4-methylpent-3-enyl)-3H-naphtho[2,1-b]pyran 15
To a solution of 14 (4 g, 13.6 mmol), Et3N (2.4 ml, 17 mmol), and DMAP (81 mg, 0.68 mmol)
in dichloromethane (40 ml) were added dropwise acetic anhydride (1.6 ml, 17 mmol). The reaction
mixture was stirred for 1 h at room temperature. The reaction mixture was then diluted with
brine, the organic layer was washed with 1N HCl, 10% NaHCO3, and dried (MgSO4). The solvent
was removed under vacuum, yielding 4.47 g (98%) of 15 as a yellow oil; ꢀH (CDCl3) 1.43 (s, 3H,
CH3), 1.56 (s, 3H, 1CH3), 1.66 (s, 3H, CH3), 1.67±1.81 (m, 2H, CH2), 2.12±2.15 (m, 2H, CH2),
2.34 (s, 3H, CH3CO), 5.07±5.09 (m, 1H, CHˆ), 5.63±5.65 (d, 1H, J=10 Hz, ˆCH±), 6.90±6.92 (d,
1H, J=10 Hz, ˆCH±), 7.00±7.72 (m, 5H, CarH); ꢀC (CDCl3) 17.6, 21.2, 22.7, 25.6, 26.0, 40.8,
78.5, 112.5, 113.5, 118.3, 118.4, 124.1, 127.0, 128.4, 129.0, 129.9, 131.8, 169.5; IR 2968, 2925,
2856, 1764, 1674, 1206 cm^1; MS (m/e) 336 (M+Á, 12), 253 (100), 211 (75), 43 (12), 41 (14).
3.14. Kinetic resolution of 15
Racemic acetate 15 (900 mg, 2.6 mmol) was dissolved in diisopropyl ether (60 ml) saturated
with water and lipase CCL (1.8 g) was added. The reaction was followed by HPLC and stopped
after 96 h of hydrolysis. Then the enzyme was ®ltered o€, and the organic layer was dried
(MgSO4), concentrated under vacuum and chromatographed on silica gel, eluting with a 90:10 (v/v)
mixture of hexane:EtOAc to provide (R)-(+)-15 (140 mg, mmol, ee 70%, [ꢁ]D=+3.3 (c 1.38,
acetone)) and (S)-(^)-14 (630 mg, mmol, ee 7%, [ꢁ]D =^0.3 (c 1.20, acetone)).

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J. Y. Goujon et al. / Tetrahedron: Asymmetry 11 (2000) 2409±2420
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