Enantioselective synthesis of chromenes

Article abstract of DOI:10.1016/S0040-4039(02)02614-X

A concise approach for the synthesis of optically active chromenes is reported. The process described herein involves, as the key steps, a Sharpless-epoxidation, a selective deoxygenation, and a ring-closing metathesis.

Full text of DOI:10.1016/S0040-4039(02)02614-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 435–437
Enantioselective synthesis of chromenes
Christophe Hardouin, Lise Burgaud, Alain Valleix and Eric Doris*
CEA/Saclay, Service de Marquage Mole´culaire et de Chimie Bioorganique, De´partement de Biologie Joliot-Curie,
91191 Gif sur Yvette Cedex, France
Received 6 November 2002; revised 15 November 2002; accepted 18 November 2002
Abstract—A concise approach for the synthesis of optically active chromenes is reported. The process described herein involves,
as the key steps, a Sharpless-epoxidation, a selective deoxygenation, and a ring-closing metathesis. © 2002 Elsevier Science Ltd.
All rights reserved.
The chromene ring system has a central position in
various classes of naturally occurring products.1 Fur-
thermore, many bio-active compounds (e.g. antioxi-
dants,2 enzyme inhibitors3) incorporate this key
heterocycle. However, whilst the synthesis of racemic
chromenes is well documented,4 the methods available
for the preparation of optically active species remain
limited.5,13 We describe in this paper our approach for
the enantioselective synthesis of chromenes. Our gen-
eral strategy is depicted in Scheme 1 and involved the
synthesis, as starting material, of some chiral epoxy-
alcohols 4 and o-vinyl phenols 2.
the other hand, the starting epoxyalcohols 4 were
synthesised by (+)-diisopropyltartrate/Ti(OiPr)4/t-
BuOOH-mediated Sharpless-kinetic resolution of vari-
ously substituted allylic alcohols 3.7 This afforded
optically active alcohols 4 in good yield and with ee
values ranging from 74 to 96% (see Table 1). Subse-
quent Mitsunobu reaction8 with o-vinyl phenols 2 pro-
vided epoxy-ethers 5. During this process, the epoxide
served also as protecting group of the double bond,
thus avoiding the well established SN2% side reaction.9
The epoxy-ethers 5 were then smoothly deoxygenated
by Cp2TiCl10 to regenerate the olefinic system of 6. The
low-valent titaniumIII complex was readily prepared by
in situ reduction of Cp2TiCl2 by activated zinc.11
Finally, the ring closure step was cleanly performed in
nearly quantitative yield by metathesis (RCM)12 using
The latter compounds were prepared by Stille-olefina-
tion of the corresponding a-halogeno-phenol 1 using
tributylvinyltin and Pd2(dba)3·CHCl3 as catalyst.6 On
Scheme 1.
Keywords: chromene; metathesis; Sharpless-epoxidation; titanium.
* Corresponding author. E-mail: eric.doris@cea.fr
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02614-X

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C. Hardouin et al. / Tetrahedron Letters 44 (2003) 435–437
Table 1. Examples of chromene synthesis
desk light (200 W), chromene 7d fully photoracemised
in hexane within 30 h. This light-induced racemisation
has already been observed by others13 and could be
attributed to a retro-Claisen rearrangement (Scheme 3).
In conclusion, we demonstrated that chromenes are
readily accessible in their optically active form starting
from the corresponding o-vinyl-phenol and Sharpless-
derived a-hydroxy-epoxide. Coupling, deoxygenation
and RCM furnishes chiral chromenes in overall satis-
factory yield and good enantiomeric purity.14
Scheme 2.
References
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starting alcohols 4). However, upon irradiation with a

C. Hardouin et al. / Tetrahedron Letters 44 (2003) 435–437
437
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17.7 Hz, 1H), 6.21 (d, J=2.4 Hz, 1H), 6.46 (dd, J=2.4
and 8.5 Hz, 1H), 6.98 (d, J=9.1 Hz, 2H), 7.04 (dd,
J=11.2 and 17.7 Hz, 1H), 7.27 (d, J=8.6 Hz, 2H), 7.31
(d, J=9.1 Hz, 2H), 7.39 (d, J=8.5 Hz, 1H), 7.66 (d,
J=8.6 Hz, 2H). 13C NMR (CDCl3) l 21.6, 44.6, 54.6,
55.1, 80.8, 101.4, 106.1, 112.4, 120.5, 122.7, 127.2, 127.8,
128.3, 129.7, 131.0, 132.1, 136.1, 145.4, 149.4, 155.3,
160.0. MS (CI/NH3), 470 (M+18, 100). Synthesis of
allylic-ether 6d: To a mixture of Cp2TiCl2 (0.065 g, 2.2
equiv.) and powdered Zn (0.040 g, 5.1 equiv.) in a
flame-dried flask was added 1 mL of THF. The solution
was degassed under vacuum and purged with nitrogen
(this operation was repeated three times). The hetero-
geneous solution was stirred vigorously for 45 min at rt.
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epoxy-ether 5d (0.055 g, 0.12 mmol, 1 equiv.) in 1 mL of
THF. The solution was degassed under vacuum and
purged with nitrogen (this operation was repeated three
times). After 30 min, the mixture was filtered over paper
and quenched with H2O. The aqueous layer was
extracted three times with Et2O. The combined organic
layers were dried over Na2SO4, filtered, and concentrated
under reduced pressure. The crude product was purified
by chromatography over silica (hexane/EtOAc: 85/15) to
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1
give allylic-ether 6d (96% ee, oil, 0.027 g, 51% yield). H
NMR (CDCl3) l 2.43 (s, 3H), 3.71 (s, 3H), 5.14 (dd,
J=1.3 and 11.2 Hz, 1H), 5.23–5.35 (m, 2H), 5.56–5.65
(m, 2H), 5.96 (m, 1H), 6.32 (d, J=2.4 Hz, 1H), 6.47 (dd,
J=2.4 and 8.5 Hz, 1H), 6.96 (d, J=8.6 Hz, 2H), 7.01
(dd, J=11.2 and 17.7 Hz, 1H), 7.28 (d, J=8.4 Hz, 2H),
7.32 (d, J=8.6 Hz, 2H), 7.40 (d, J=8.5 Hz, 1H), 7.67 (d,
J=8.4 Hz, 2H). 13C NMR (CDCl3) l 21.7, 55.3, 80.7,
101.8, 105.9, 112.3, 117.0, 120.8, 122, 6, 127.1, 127.8,
128.5, 129.7, 131.2, 132.4, 137.3, 139.0, 145.3, 149.1,
155.6, 160.2. MS (CI/NH3), 454 (M+18, 100). [h]2D5 +12 (c
0.16, CH2Cl2). Synthesis of chromene 7d: To a solution of
diene 6d (0.013 g, 0.03 mmol, 1 equiv.) in CH2Cl2 (1 mL)
was added 8 (0.001 g, 0.04 equiv.). The reaction mixture
was stirred at rt overnight in the dark and the solvent was
evaporated under reduced pressure. The crude product
was purified by chromatography over silica (hexane/
EtOAc: 4/1) to give the chromene 7d (94% ee, oil, 0.012
12. Chang, S.; Grubbs, R. H. J. Org. Chem. 1998, 63,
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14. A typical experimental procedure is given for the synthesis
of chromene 7d: Synthesis of epoxy-ether 5d: To a solu-
tion of epoxy-alcohol 4d (96% ee, 0.069 g, 0.21 mmol, 1
equiv.) in 2 mL of THF was added, at 0°C, vinyl-phenol
2d (0.035 g, 1.1 equiv.), PPh3 (0.060 g, 1.1 equiv.) and
DEAD (35 mL, 1.1 equiv.). The reaction was stirred at rt
for 16 h and the solvent was evaporated under reduced
pressure. The crude product was purified by chromatog-
raphy over silica (hexane/EtOAc: 4/1) to give epoxy-ether
1
g, 97% yield). H NMR (CDCl3) l 2.42 (s, 3H), 3.72 (s,
3H), 5.58 (dd, J=3.3 and 10.0 Hz, 1H), 5.81 (m, 1H),
6.34 (d, J=2.4 Hz, 1H), 6.41 (dd, J=2.4 and 8.3 Hz,
1H), 6.46 (dd, J=1.8 and 9.9 Hz, 1H), 6.89 (d, J=7.9
Hz, 1H), 6.95 (d, J=8.5 Hz, 2H), 7.28 (d, J=8.0 Hz,
2H), 7.34 (d, J=8.5 Hz, 2H), 7.68 (d, J=8.0 Hz, 2H). 13
C
NMR (CDCl3) l 21.6, 55.2, 76.2, 101.8, 107.0, 114.4,
121.2, 122.4, 123.9, 127.3, 128.2, 128.4, 129.7, 132.3,
139.8, 145.4, 149.3, 154.0, 160.9. MS (CI/NH3), 409
(M+1, 100). HRMS calcd for C23H20O5S (M)+ 408.1031,
found 408.1066. IR (neat): 866, 1153, 1177, 1198, 1373,
1503, 1598, 1615, 1738, 2937.
1
5d (oil, 0.06 g, 66% yield). H NMR (CDCl3) l 2.43 (s,
3H), 2.69 (dd, J=2.6 and 4.5 Hz, 1H), 2.83 (t, J=4.5 Hz,
1H), 3.36 (m, 1H), 3.67 (s, 3H), 4.89 (d, J=5.8 Hz, 1H),
5.17 (dd, J=1.3 and 11.2 Hz, 1H), 5.64 (dd, J=1.3 and