A new approach to 2,2-disubstituted chromenes and tetrahydroquinolines through intramolecular cyclization of chiral 3,4-epoxy alcohols

Article abstract of DOI:10.1016/j.tet.2004.03.010

An efficient route to chiral chromene and tetrahydroquinoline ring models 3 and 4 was developed by means of the vanadium epoxidation of chiral homoallylic alcohols 12 and 19 followed by an intramolecular epoxide opening of 3,4-epoxy alcohols 14 and 20. Th

Full text of DOI:10.1016/j.tet.2004.03.010

Tetrahedron 60 (2004) 4037–4049
A new approach to 2,2-disubstituted chromenes and
tetrahydroquinolines through intramolecular cyclization of chiral
3,4-epoxy alcohols
*
Jean-Yves Goujon, Franc¸oise Zammattio, Jean-Mathieu Chretien and Isabelle Beaudet
´
` ´ `
Laboratoire de Synthese Organique, UMR CNRS 6513 and FR CNRS 2465, Faculte des Sciences et des Techniques, 2 rue de la Houssiniere,
BP 92208, 44322 Nantes Cedex 03, France
Received 29 October 2003; revised 9 February 2004; accepted 3 March 2004
Abstract—An efficient route to chiral chromene and tetrahydroquinoline ring models 3 and 4 was developed by means of the vanadium
epoxidation of chiral homoallylic alcohols 12 and 19 followed by an intramolecular epoxide opening of 3,4-epoxy alcohols 14 and 20. The
configuration of all compounds was confirmed using NMR analysis.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2-hydroxymethyl-2-methyl-2H-chromenes 3 and to another
class of heterocycles, 2-hydroxymethyl-2-methyl-1,2,3,4-
tetrahydroquinolin-4-ols 4 (Fig. 2).
O and N-Heterocyclic compounds have attracted consider-
able attention because of their functionality in pharma-
ceutical chemistry. In particular, synthesis of benzo-fused O
and N-heterocyclic compounds such as chromenes1 and
tetrahydroquinolines2 is very important because they are
found in a variety of natural products, which exert a broad
range of bioactivities (e.g., antioxydants,3 enzyme
inhibitors,4 antitumor agents,5 antibiotic agents6). Numer-
ous publications7 described the preparation of these
important classes of heterocycles. However, it remains a
great challenge to establish stereogenic quaternary carbon
on both chromene and tetrahydroquinoline ring systems.
Only a few publications8 have described an access to these
types of compounds and have been directed to specific
molecules such as, for example, cordiachromene9 1 or
virantmycin6f,g 2 (Fig. 1).
Figure 2.
2. Results and discussion
2.1. Retrosynthetic analysis
A retrosynthetic analysis of target molecule 3 is delineated
in Scheme 1. The formation of 2H-chromene moiety can be
achieved by a ring closure of key chiral epoxide 6 under
acidic conditions. This ring closure through path a (6-exo-
tet) is a more favored process than path b (7-endo-tet)
following Baldwin’s rules.11 Key intermediate 6 is based on
a 3,4-epoxy-3-methyl-1-(2-subtituted phenyl)butan-1-ol
subunit. The desired oxirane function can be introduced
by a stereoselective epoxidation of protected homoallylic
alcohol 7 with vanadium (IV)/tert-butylhydroperoxide as
oxidants. Required homoallylic alcohol 7 can be
synthesized by asymmetric allylation of either various
substituted 2-hydroxybenzaldehyde 8 with (þ) or (2)-b-
methallyldiisopinocampheylborane 9. Homoallylic alcohols
can also be obtained by asymmetric reduction of ketone 10
Figure 1.
In a previous article, we described an efficient three-step
procedure for the synthesis of substituted 2-hydroxymethyl-
2-methyl-2H-chromenes.10 Herein, we wish to report the
extension of our versatile procedure to optically active
Keywords: Chromene; Tetrahydroquinoline; 2H-1-Benzopyrane.
*
Corresponding author. Tel.: þ33-2-5112-5419; fax: þ33-2-5112-5402;
e-mail address: zammattio@chimie.univ-nantes.fr
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.03.010

4038
J.-Y. Goujon et al. / Tetrahedron 60 (2004) 4037–4049
using CBS-oxazaborolidine. This strategy will be applied to
nitrogen analogues to form target tetrahydroquinoline 4.
quantitative yields and ee values ranging from 85 to 95%
(Table 1).
Scheme 3. Reagents and conditions: (a) TBDMSCl, imidazole, DMF, rt;
(b) 2-methylpropenylmagnesium chloride, THF, 50 8C, 3 h; (c) DMP,
DCM, 0 8C, 1 h; (d) (R) or (S)-CBS oxazaborolidine, catecholborane,
toluene, 260 8C; (e) TBHP, VO(acac)2, DCM, 210 8C, 5 h; (f) (i) TBAF,
THF, 0 8C; (ii) CSA (4 mol%), toluene, reflux, 16 h.
Scheme 1. Retrosynthetic analysis of 2,2-disubstituted chromenes 3.
2.2. Asymmetric synthesis of 2,2-disubstituted
chromenes 3
The next step was the stereoselective epoxidation of chiral
homoallylic alcohols 12a-c by the usual and cheap
procedure using tert-butylhydroperoxide (TBHP) and a
catalytic amount of vanadylacetylacetonate (VO(acac)2).14
In each case, epoxyalcohols 14a-c were obtained in both
good yields and diastereoselectivities (Table 1, Scheme 3).
Subsequent O-silyldeprotection of 14a-c with TBAF
followed by the ring closure in refluxing toluene with a
catalytic amount of camphor sulfonic acid (CSA) (4 mol%)
gave directly chromenes 3a-c, as reported in a recent
paper.10 It should be noted that the overall process permitted
synthesis of chromenes with good yields, but in all cases
with a loss of optical purity (based on the ee value of starting
epoxyalcohols 14a-c (Table 2, entries 1–4). This result
could be interpreted by a lack of selectivity during the
cyclization step under acidic conditions or by a possible
racemization via a retro-Claisen rearrangement, which has
already been observed on such compounds upon exposure to
light irradiation.15
As depicted in Scheme 2, the reaction of salicylaldehyde
with tert-butyldimethylsilylchloride (TBDMS-Cl) and
imidazole in DMF afforded the corresponding 2-OTBS
benzaldehyde 11a in excellent yield. Brown’s asymmetric
allylation12 (method A) of compounds 11a with
b-methallyldiisopinocampheylborane 9, prepared from
(þ) or (2)-b-chlorodiisopinocampheylborane ((þ) or (2)-
Ipc2BCl) and 2-methylpropenylmagnesium chloride,
afforded corresponding chiral homoallylic alcohols (þ) or
(2)-12a in good yields and 80% ee (best value, Table 1).
Scheme 2. Reagents and conditions: (a) TBDMSCl, imidazole, DMF, rt;
(b) (þ) or (2)-methallyldiisopinocampheylborane 9, THF, 278 8C, 2 h.
In order to rationalize this result, we have first studied
nucleophile centres which should be involved into the
intramolecular cyclization reaction. According to Baldwin’s
rules, two pathways are favored. Scheme 4 presents the
structures of the possible intermediates corresponding to
this intramolecular cyclization reaction. For 6-exo-tet and
4-exo-tet favored cyclization reactions, which, respectively,
involve one or two Walden inversion, two stereoisomers
related to (þ) or (2)-3a can be formed. These two
competitive ring closures could explain the observed loss
of optical purity for chromenes 3.
Accordingly, an improvement in ee values was necessary,
so we turned our attention to a synthesis of enantiopure
compounds 12a-c, based on asymmetric reduction of
corresponding ketones 13a-c using (R) or (S)-CBS-oxa-
zaborolidines13 as chiral reducing agents (method B in
Table 1, Scheme 3). b,g-Unsaturated ketones 13a-c were
obtained by treatment of compounds 11a-c with an excess
of 2-methylpropenylmagnesium chloride followed by
oxidation with Dess–Martin periodinane (DMP). Enantio-
selective reduction of b,g-unsaturated ketones 13a-c with
(R) or (S)-CBS-oxazaborolidine reagent and catecholborane
at 260 8C led to homoallylic alcohols 12a-c with
Alternatively, the hypothesis of a racemization reaction has

J.-Y. Goujon et al. / Tetrahedron 60 (2004) 4037–4049
4039
Table 1. Allylation and epoxidation reactions
Entry
1
Aldehydes
Method
Ad
Alcohols
Yields (%)a (ee)b
79 (80%)
Epoxides
Yields (%)a (de)c
72 (84%)e
11a
11a
11b
11c
18
Bf
(þ)-(R)-12a
75 (93%)
74 (80%)
(þ)-(1R,3S)-14a
(2)-(1S,3R)-14a
(2)-(1S,3R)-14b
(2)-(1S,3R)-14c
(þ)-(1S,3R)-20
(2)-(1R,3S)-20
2
3
4
5
Ag
72 (86%)e
73 (84%)e
70 (82%)e
89 (82%)
96 (84%)
Bh
Bh
(2)-(S)-12a
(2)-(S)-12b
(2)-(S)-12c
(þ)-(S)-19
(2)-(R)-19
72 (95%)
70 (90%)
Bh
Ag
Ad
75 (85%)
84 (82%)
80 (84%)
6
18
a
Isolated yields.
Enantiomeric excess were determined by HPLC.
Diastereomeric excess determined by 1H NMR spectroscopy.
Reaction carried out with methallyldiisopinocampheylborane 9 prepared from (þ)-DIPCl.
Diastereomeric excess of epoxidation reaction with compounds 12 prepared by method B.
Reaction carried out with (S)-CBS oxazaborolidine.
b
c
d
e
f
g
h
Reaction carried out with methallyldiisopinocampheylborane 9 prepared from (2)-DIPCl.
Reaction carried out with (R)-CBS oxazaborolidine.
also been taken in account. Exposure of chiral chromene
179b to the same experimental conditions used for the
cyclization of 14 (refluxed toluene, CSA 4 mol%) led to a
decrease in the optical activity of 17 (Scheme 5). Half-life
for racemization of 17 is around 96 h. This result gave an
important information about the rate of racemization of
2,2-dialkylchromene via a thermally induced retro-Claisen
rearrangement.
Scheme 4. Hypothetical mechanism for the formation of chromenes 3.

4040
J.-Y. Goujon et al. / Tetrahedron 60 (2004) 4037–4049
From all these results, it seems that both the thermally
induced racemization and the two possible ring closure
pathways might limit stereoselectivity of this intramolecular
cyclization reaction accounting for poor optical purity of
chromenes 3.
protected as a sulfonamide. Compound 18 was easily
transformed to homoallylic alcohols 19 (80,ee,86%)
which were then converted to corresponding epoxyalcohols
20 using the same experimental conditions as above for the
preparation of 14a-c (Scheme 6, Table 1). It is noteworthy
that in order to increase the ee of compounds 19, we
attempted, without any success, asymmetric reduction of the
corresponding ketone.17 At this stage in our synthetic
strategy, behavior of 20 in the intramolecular epoxide
opening sequence was investigated using conditions
described by Morimoto et al.6f,g Treatment of 20 with
trifluoroacetic acid in toluene at room temperature for 16 h
expectedly provided desired 1,2,3,4-tetrahydroquinolin-4-ol
4 as the exclusive product of cyclization reaction. Moreover,
2.3. Asymmetric synthesis of 2,2-disubstituted-1,2,3,4-
tetrahydroquinolin-4-ols 4
Tos-protected aminobenzaldehyde 18 was readily available
in high yield by a two-step sequence on multigram scale
from commercially available 2-aminobenzyl alcohol. After
oxidation with manganese dioxide in dichloromethane to
the corresponding aldehyde,16 the amino group was
Scheme 5. Racemization of 17.
Table 2. Synthesis of chromene 3a-c and tetrahydroquinoline 4
Entry
1
Epoxides
Alcohols
Yields (%)a (ee)
80 (46%)b
(þ)-(1R,3S)-14a
(2)-(1S,3R)-14a
(2)-(1S,3R)-14b
(2)-(1S,3R)-14c
(þ)-3a
(2)-3a
(2)-3b
(2)-3c
2
3
4
5
80 (44%)b
75 (43%)b
68 (35%)b
45
(þ)-trans-4: (88%)c
(þ)-cis-4: (40%)c
(þ)-(1S,3R)-20
(2)-(1R,3S)-20
(þ)-trans-(2R,4S)-4
(2)-trans-(2S,4R)-4
(þ)-cis-(2S,4S)-4
(2)-cis-(2R,4R)-4
6
58
(2)-trans-4: (94%)c
(2)-cis-4: (63%)c
a
Isolated overall yields.
Enantiomeric excesses determined by HPLC on a chiral column.
Enantiomeric excesses determined by HPLC on a chiral column after isolation of each diastereomer by flash chromatography.
b
c

J.-Y. Goujon et al. / Tetrahedron 60 (2004) 4037–4049
4041
stereogenic centre created during epoxidation and conse-
quently, the absolute configuration at C3. With this idea in
mind, we envisaged the conversion of epoxy alcohols to
their corresponding six-membered acetonides in order to
study their conformational properties by NMR
spectroscopy. In order to simplify this study, the synthetic
sequence described in Scheme 7 was carried out with epoxy
alcohol 22 instead of more complex epoxy alcohols 14.
Thus, epoxy alcohol 22 was prepared in two steps starting
from benzaldehyde and 2-methylpropenylmagnesium
chloride followed by oxidation of the resultant product
with tert-butylhydroperoxide (TBHP) and a catalytic
amount of vanadylacetylacetonate (VO(acac)2). According
to these experimental conditions, 22 was obtained in
good yield as a 80:20 mixture of diastereomers. Then, 22
was converted to acetonide 26 in a four-step sequence
involving protection of the secondary alcohol, regio-
selective addition of phenyllithium, O-silyl deprotection
and acetalization.
Scheme 6. Reagents and conditions: (a) MnO2, DCM, rt; (b) acid p-toluene
sulfonyl chloride, DCM, pyridine, rt; (c) (þ) or (2)-methallyldiisopino-
campheylborane 9, THF, 278 8C, 2 h; (d) TBHP, VO(acac)2, DCM, 25 8C,
5 h; (e) 2 equiv. of TFA, toluene, rt, 16 h.
it should be pointed out that compound 4 was obtained as a
mixture of diastereomers (50:50) which were easily
separated by column chromatography to furnish dia-
stereomerically pure tetrahydroquinolines (þ)-cis-4 and
(þ)-trans-4 from (þ)-20 and (2)-cis-4 and (2)-trans-4
from (2)-20 in good overall yields (Table 2, entries 5 and
6). As for chromene’s series, the loss of stereoselectivity in
the last step might be explained by assuming that the two
favored mechanisms are competitive.
In addition, the enantiomeric excess in which these
heterocycles 4 were obtained, was determined by chiral
HPLC showing that little or no racemization occurred at C1
during the process from 20 to tetrahydroquinoline 4
(Table 2).
Scheme 7. Reagents and conditions: (a) 2-methylpropenylmagnesium
chloride, THF, 50 8C, 3 h; (b) TBHP, VO(acac)2, DCM, 0 8C, 8 h; (c)
TBDMSCl, imidazole, DMF, rt; (d) PhLi, BF3·Et2O, THF, 278 8C; (e)
TBAF, THF, rt; (f) CSA, DMP, rt.
2.4. Determination of relative and absolute configuration
of the products
The relative configuration of 26 was determined by 13C
NMR analysis as shown in Figure 3.
2.4.1. Determination of absolute configuration of 3,4-
epoxy alcohols 14. While the oxidative reaction of
homoallylic alcohols using vanadium (IV)14 as a catalyst
often gave epoxy alcohols with both good yields and
diastereoselectivities, our major intention was to establish
the relative configuration between C1 and new C3
The chemical shifts of the methyl of the acetal for major
compound 26 were in accord with a 1,3-syn stereo-
chemistry.18 These results confirmed the syn stereo-
selectivity of the epoxidation with vanadium (IV)14 as a
catalyst.
Figure 3. 13C NMR analysis of epoxides.

4042
J.-Y. Goujon et al. / Tetrahedron 60 (2004) 4037–4049
2.4.2. Determination of absolute configuration of tetra-
hydroquinolines 4. The configurational assignment of
compounds 4 was effected by NOESY experiments. As
summarized in Figure 4, NOESY spectra clearly showed a
significant NOE cor0responding to the dipolar interactions
between H4 and H2 for compounds (2)-trans-4 and (þ)-
trans-4 when either H4 or H20 were irradiated. This suggests
a cis configuration between them for trans-4. On the other
hand, the0 absence of a NOE enhancement on H4 for cis-4
when H2 was irradiated suggests a trans configuration of
the latters. This result was confirmed by a NOE enhance-
ment of H4 by irradiation of CH3 even if it is difficult to
evaluate because of interactions between H4 and H3 in the
same time (same chemical shifts for H3 and CH3).
Therefore, the determined cis configuration between H4
and H20 of trans-4 confirms (2R,4S) and (2S,4R) absolute
configuration of the stereogenic centres of (þ)-trans-4 and
(2)-trans-4. The cis configuration between H4 and CH3 of
cis-4 allows us to assign (2S,4S) and (2R,4R) absolute
configuration of stereogenic centres of (þ)-cis-4 and (2)-
cis-4 compounds.
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 polari-
meter. Melting points were determined on a C. REICHERT
microscope apparatus and were uncorrected. Elemental
analysis were carried out by CNRS Analysis Laboratory,
Vernaison, France, on a Perkin–Elmer 2400 C, H, N
elemental analyser.
4.2. Chemicals
Every starting material was obtained from commercial
suppliers and used without further purification. Dichloro-
methane, ethylacetate were dried by distillation over P2O5.
Diethylether, THF, benzene and toluene were distilled from
sodium.
4.3. General procedure for formation of silylether 11a-c
To a solution of phenol derivative (3.5 mmol), imidazole
(1 g, 14.8 mmol) in DMF (10 mL) was added tert-
butyldimethylsilyl chloride (810 mg, 5.4 mmol). The reac-
tion was heated 20 h at 80 8C, then 50 mL of water and
50 mL of EtOAc were added. The aqueous layer was
extracted with EtOAc (3£40 mL), the combined organic
layers were washed with brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (9:1, petroleum ether/EtOAc)
to give the silylether 11a-c.
4.3.1. 2-tert-Butyldimethylsilyloxybenzaldehyde 11a.
Compound 11a was obtained from salicyladehyde as a
colorless oil (740 mg, 90% yield); 1H NMR (200 MHz,
CDCl3): dH 0.26 (s, 6H, 2SiCH3), 1.01 (s, 9H, 3CH3), 6.85–
7.82 (m, 4H, Har), 10.45 (s, 1H, CHO); 13C NMR
(50.3 MHz, CDCl3): dC 24.3, 22.9, 18.3, 25.6 (3C),
120.1, 121.4, 127.1, 128.2, 135.6, 158.3, 190.1; IR (film)
n 2956, 2931, 2859, 1689, 1599, 1479, 1254 cm21; MS-CI
m/z (relative intensity) 237 (Mþ1, 100), 221 (30), 179 (28).
Figure 4. NOE correlation observed in cis- and trans-4.
3. Conclusion
4.3.2. 4-Methoxy-2-tert-butyldimethylsilyloxybenzalde-
hyde 11b. Compound 11b was obtained from 2-hydroxy-
5-methoxybenzaldehyde (456 mg, 3.0 mmol) as a colorless
In summary, we successfully extended our method for the
stereoselective synthesis of chromene and tetrahydroquino-
line rings. If the synthetic utility of the method was limited
because of racemization of chromenes, the diastereomeric
mixtures of tetrahydroquinolines were easily separated by
column chromatography and the absolute configuration of
diastereomers was thus assigned.
1
oil (718 mg, 90% yield); H NMR (200 MHz, CDCl3): dH
0.24 (s, 6H, 2SiCH3), 1.01 (s, 9H, 3CH3), 3.80 (s, 3H, OMe),
6.80–7.28 (m, 3H, Har), 10.41 (s, 1H, CHO); 13C NMR
(50.3 MHz, CDCl3): dC 24.4 (2C), 18.3, 25.6 (3C), 55.7,
109.5, 121.6, 123.9, 127.1, 153.4, 154.0, 190.0; IR (film) n
2956, 2931, 2886,2858,1683,1489 cm21;MS-EIm/z(relative
intensity) 266 (Mþ, 0), 251 (1), 209 (100), 191 (12), 166 (19).
4. Experimental
4.1. Apparatus
4.3.3. 2,5-Di-tert-butyldimethylsilyloxybenzaldehyde
11c. Compound 11c was obtained from 2,5-dihydroxy-
benzaldehyde (420 mg, 3.0 mmol) as a colorless oil
(660 mg, 90% yield); 1H NMR (200 MHz, CDCl3): dH
0.16 (s, 6H, 2CH3), 0.23 (s, 6H, 2CH3), 0.96 (s, 9H, 3CH3),
1.00 (s, 9H, 3CH3), 6.72–7.25 (m, 3H, Har), 10.37 (s, 1H,
CHO); 13C NMR (50.3 MHz, CDCl3): dC 24.5 (2C), 24.4
(2C), 18.1, 18.3, 25.6 (6C), 117.6, 121.1, 127.4, 127.9,
149.8, 153.4, 189.9; IR (film) n 2956, 2931, 2859, 1689,
1488 cm21; MS-CI m/z (relative intensity) 367 (Mþ1, 100),
308 (11).
1H and 13C NMR spectra were recorded on Bruker AC 200
and Bruker AMX 400 spectrometers in CDCl3 as the solvent
and TMS as the internal standard; chemical shifts (d) are
expressed in ppm and coupling constants (J) in Hertz. IR
spectra were recorded on a Bruker vector 22 spectrometer.
Mass spectra (m/e (% base peak)) were recorded on HP
5889A spectrometer in EI mode (70 eV) or in CI mode (with
CH4 or NH3 as reacting gas). For high performance liquid

J.-Y. Goujon et al. / Tetrahedron 60 (2004) 4037–4049
4043
4.4. Preparation of methallylborane reagents 9
(3£20 mL), the combined organic layers were dried over
MgSO4, and concentrated in vacuo. The residue was
purified by column chromatography (9:1, petroleum ether/
EtOAc).
To a solution of diisopinocampheylborane chloride
(4 equiv.) in anhydrous diethyl ether (20 mL) at 0 8C
under argon was added dropwise a solution of 2-methyl-
propenyl magnesium chloride (1.5 equiv.) in THF. The
reaction mixture was stirred 1 h at 0 8C and 1 h at room
temperature. The formation of methallyldiisopino-
campheylborane 9 is indicated by precipitation of the
magnesium salts. The reagent can be readily isolated as a
clear solution, free of magnesium salts, by passing the
reaction mixture through a filtration chamber.
4.6.1. 3-Methyl-1-(2-tert-butyldimethylsilyloxyphenyl)-
but-3-en-1-ol 12a. Compound 12a was obtained from 11a
as a colorless oil in 98% yield.
4.6.2. 3-Methyl-1-(5-methoxy-2-tert-butyldimethylsilyl-
oxyphenyl)but-3-en-1-ol 12b. Compound 12b was
obtained from 11b as a colorless oil in 97% yield; 1H
NMR (400 MHz, CDCl3): dH 0.24 (s, 3H, SiCH3), 0.25 (s,
3H, SiCH3), 1.01 (s, 9H, 3CH3), 1.81 (s, 3H, CH3), 2.25 (d,
1H, J¼2.8 Hz, OH), 2.31 (dd, 1H, J¼9.6, 14.0 Hz, H2), 2.51
(dd, 1H, J¼3.2, 14.0 Hz, H2), 3.77 (s, 3H, OMe), 4.87 (bs,
1H, H4), 4.92 (bs, 1H, H4), 5.11 (dt, 1H, J¼3.2, 9.6, 2.8 Hz,
H1), 6.66 (dd, 1H, J¼8.8, 2.8 Hz, Har), 6.71 (d, 1H,
J¼8.8 Hz, Har), 7.02 (d, 1H, J¼2.8 Hz, Har); 13C NMR
(50.3 MHz, CDCl3): dC 24.2, 24.0, 18.1, 22.3, 25.8 (3C),
46.2, 55.6, 66.2, 111.7, 113.0, 113.7, 118.7, 135.0, 142.7,
145.9, 153.9; IR (film) n 3472, 3074, 2956, 2931, 2858,
1495 cm21; MS-EI m/z (relative intensity) 322 (Mþ, 1), 267
(24), 209 (39), 195 (36), 75 (44), 73 (100).
4.5. Typical procedure for preparation of homoallylic
alcohols 12a
To the precedent clear filtrate 9 (free of magnesium
salts) was added, dropwise, at 278 8C and under argon, a
solution of compound 11a (1 equiv.) in anhydrous THF
(10 mL). The mixture was stirred for 3 h until TLC
showed complete disappearance of starting material. The
reaction mixture was then hydrolyzed with 1 N HCl
(12 mL) and the organic layer was washed with brine
(20 mL), dried over MgSO4 and concentrated in vacuo. The
crude product was heated 1 h in a Kugelrohr at 100 8C under
5 mbar in order to remove most of isopinocampheol
formed during the reaction. The residue was purified by
column chromatography on silica gel (8:2, petroleum ether/
EtOAc).
4.6.3. 3-Methyl-1-(2,5-di-tert-butyldimethylsilyloxy-
phenyl)but-3-en-1-ol 12c. Compound 12c was obtained
from 11c as a colorless oil in 98% yield; 1H NMR
(400 MHz, CDCl3): dH 0.15 (s, 6H, 2SiCH3), 0.22 (s, 3H,
SiCH3), 0.23 (s, 3H, SiCH3), 0.96 (s, 9H, 3CH3), 0.99 (s,
9H, 3CH3), 1.78 (s, 3H, CH3), 2.24 (bs, 1H, OH), 2.29 (dd,
1H, J¼9.6, 14.0 Hz, H2), 2.47 (dd, 1H, J¼3.2, 14.0 Hz, H2),
4.84 (s, 1H, H4), 4.89 (s, 1H, H4), 5.05 (dd, 1H, J¼3.2,
9.6 Hz, H1), 6.57 (dd, 1H, J¼12.0, 4.0 Hz, Har), 6.62 (d, 1H,
J¼12.0 Hz, Har), 6.89 (d, 1H, J¼4.0 Hz, Har); 13C NMR
(50.3 MHz, CDCl3): dC 24.5 (2C), 24.1, 23.9, 18.1, 18.2,
22.4, 25.7 (6C), 46.2, 66.4, 113.7, 118.1, 118.5, 118.7,
134.9, 142.7, 146.4, 149.6; IR (film) n 3489, 3075, 2956,
2930, 2858, 1488 cm21; MS-CI m/z (relative intensity) 422
(Mþ, 21), 404 (100), 366 (81).
4.5.1. (1)-(1R)-3-Methyl-1-(2-tert-butyldimethylsilyl-
oxyphenyl)but-3-en-1-ol 12a. Compound (þ)-(R)-12a
was obtained from 11a and 9 (prepared with (þ)-DIP-Cl)
as a pale yellow solid in 79% yield; [a]2D0¼þ38.8 (c¼1.2,
acetone); ee¼80%; 1H NMR (400 MHz, CDCl3): dH 0.27 (s,
3H, SiCH3), 0.28 (s, 3H, SiCH3), 1.02 (s, 9H, 3CH3), 1.80
(s, 3H, CH3), 2.27 (d, 1H, J¼3.2 Hz, OH), 2.33 (dd, 1H,
J¼14, 9.6 Hz, H2), 2.52 (dd, 1H, J¼14, 3.2 Hz, H2), 4.86 (s,
1H, H4), 4.92 (s, 1H, H4), 5.15 (dt, 1H, J¼3.2, 3.2, 9.6 Hz,
H1), 6.79 (d, 1H, J¼8.0 Hz, Har), 6.96 (dd, 1H, J¼7.2,
7.6 Hz, Har), 7.13 (ddd, 1H, J¼7.2, 8.0, 1.6 Hz, Har), 7.44
(dd, 1H, J¼7.6, 1.6 Hz, Har); 13C NMR (50.3 MHz, CDCl3):
dC 24.1 (2C), 18.2, 22.4, 25.8 (3C), 46.3, 66.3, 113.7,
118.0, 121.2, 126.7, 127.8, 134.2, 142.8, 152.2; IR (film) n
3424, 2956, 2931, 2859, 1488, 1254 cm21; MS-EI m/z
(relative intensity) 292 (Mþ, 1), 277 (1), 237 (62), 165 (38),
73 (100).
4.7. General procedure for oxidation of homoallylic
alcohol 12a-c with Dess–Martin periodinane (DMP)
To a solution of alcohol 12a-c (1.7 mmol) in DCM (10 mL)
was added at 0 8C Dess–Martin Periodinane (1.06 g,
2.5 mmol). After 1 h, an aqueous solution of NaHCO3
(10%) and Na2S2O3 (10%) was added, the aqueous layer
was extracted with DCM (3£20 mL). The combined organic
layers were dried over MgSO4, and concentrated in vacuo to
give the unstable ketone 13a-c used without further
purification.
4.5.2. (2)-(1S)-3-Methyl-1-(2-tert-butyldimethylsilyloxy-
phenyl)but-3-en-1-ol 12a. Compound (2)-(S)-12a was
obtained from 11a and 9 (prepared with (2)-DIP-Cl) as a
pale yellow solid in 74% yield; [a]2D0¼235.9 (c¼1.3,
acetone); ee¼80%.
4.7.1. 3-Methyl-1-(2-tert-butyldimethylsilyloxyphenyl)-
but-3-en-1-one 13a. Compound 13a was obtained from
4.6. General procedure for the formation of racemic
homoallylic alcohol 12a-c from aldehyde 11a-c
1
12a as a colorless oil in 98% yield; H NMR (200 MHz,
CDCl3): dH 0.24 (s, 6H, 2SiCH3), 0.99 (s, 9H, 3CH3),
1.76 (s, 3H, CH3), 3.70 (s, 2H, H2), 4.78 (s, 1H, H4), 4.90 (s,
1H, H4), 6.82–7.51 (m, 4H, Har); 13C NMR (50.3 MHz,
CDCl3): dC 24.0 (2C), 18.3, 22.8, 25.8 (3C), 51.9, 114.7,
120.1, 121.1, 129.8, 131.5, 132.4, 139.5, 153.9, 201.6; IR
(film) n 2956, 2931, 2887, 2859, 1690, 1479, 1255,
To a solution of 2-methylpropene magnesium chloride
(0.6 M in THF) at 230 8C was added dropwise a solution
of aldehyde 11a-c (2.1 mmol) in THF (10 mL). The
reaction was stirred 1 h at room temperature and then
quenched with a saturated aqueous solution of NH4Cl
(20 mL). The aqueous layer was extracted with EtOAc
910 cm21
.

4044
J.-Y. Goujon et al. / Tetrahedron 60 (2004) 4037–4049
4.7.2. 3-Methyl-1-(5-methoxy-2-tert-butyldimethylsilyl-
oxyphenyl)but-3-en-1-one 13b. Compound 13b was
obtained from 12b as a colorless oil in 97% yield;
1H NMR (200 MHz, CDCl3): dH 0.22 (s, 6H, 2SiCH3),
0.99 (s, 9H, 3CH3), 1.77 (s, 3H, CH3), 3.72 (s, 2H, H2),
3.77 (s, 3H, OMe), 4.79 (bs, 1H, H4), 4.91 (bs, 1H,
H4), 6.76–7.03 (m, 3H, Har); 13C NMR (50.3 MHz,
CDCl3): dC 24.1 (2C), 18.3, 22.8, 25.8 (3C), 51.8,
55.6, 113.2, 114.7, 119.1, 121.2, 131.5, 139.6, 147.8,
153.6, 201.2; IR (film) n 2956, 2931, 2859, 1684,
4.9. Representative procedure for epoxidation of chiral
homoallylic alcohols 12a-c and 19 with vanadium (IV)
and tert-butylhydroperoxide
To a blue solution of homoallylic alcohol and vanadyl
acetylacetonate (0.05 equiv.) in anhydrous dichloro-
methane, was added, at 25 8C under argon, tert-butyl
hydroperoxide (5.5 M in nonane, 2 equiv.). The resulting
red-brown solution was stirred at 25 8C for 3–5 h. Then,
the reaction mixture was poured into 10% aqueous Na2S2O3
and extracted with dichloromethane. The combined organic
layers were washed with brine, dried over MgSO4 and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (7:3, petroleum ether/EtOAc)
to provide 14 and 20 as a mixture of diastereomers.
1490 cm21
.
4.7.3. 3-Methyl-1-(2,5-di-tert-butyldimethylsilyloxy-
phenyl)but-3-en-1-one 13c. Compound 13c was obtained
from 12c as a colorless oil in 96% yield; 1H NMR
(200 MHz, CDCl3): dH 0.15 (s, 6H, 2SiCH3), 0.20 (s, 6H,
2SiCH3), 0.96 (s, 9H, 3CH3), 0.97 (s, 9H, 3CH3), 1.75 (s,
3H, CH3), 3.67 (s, 2H, H2), 4.77 (s, 1H, H4), 4.89 (s, 1H,
H4), 6.78–6.96 (m, 3H, Har); 13C NMR (50.3 MHz, CDCl3):
dC 24.5 (2C), 24.1 (2C), 18.1, 18.7, 22.8, 25.6 (3C), 25.8
(3C), 51.9, 114.7, 120.3, 120.7, 123.9, 131.8, 139.7, 148.1,
149.5, 202.5; IR (film) n 2956, 2930, 2886, 2859, 1692,
4.9.1. (2)-(1S,3R)-3,4-Epoxy-3-methyl-1-(2-tert-butyl-
dimethylsilyloxyphenyl)butan-1-ol 14a. Compound (2)-
14a was obtained from (2)-12a as a colorless oil in 72%
yield; [a]2D0¼246.2 (c¼0.75, acetone); de¼86%; major
isomer 1H NMR (400 MHz, CDCl3): dH 0.28 (s, 6H,
2SiCH3), 1.02 (s, 9H, 3CH3), 1.46 (s, 3H, CH3), 1.74 (dd,
1H, J¼14.4, 10.0 Hz, H2), 2.16 (dd, 1H, J¼14.4, 3.2 Hz,
H2), 2.59–2.65 (2d, 2H, J¼4.8 Hz, H4), 2.98 (d, 1H,
J¼3.6 Hz, OH), 5.31 (dt, 1H, J¼3.2, 3.6, 10.0 Hz, H1),
6.65–6.71 (m, 2H, Har), 7.01–7.05 (m, 2H, Har); 13C NMR
(100.62 MHz, CDCl3): dC 24.0 (2C), 18.3, 21.2 25.8 (3C),
43.7, 53.7, 56.3, 66.6, 118.1, 121.3, 126.8, 127.9, 134.3,
1485, 1257, 909 cm21
.
4.8. General procedure for enantioselective reduction of
ketone 13a-c with CBS-oxazaborolidine
To a solution of ketone 13a-c (1.7 mmol) and CBS-
oxazaborolidine (0.17 mmol, 1 M in toluene) in anhydrous
toluene (10 mL) at 260 8C under argon was added
catecholborane (3.7 mmol, 1 M in THF). The reaction was
stirred 16 h at this temperature and quenched with water
(10 mL). The aqueous layer was extracted with EtOAc
(3£10 mL), the combined organic layers were washed
successively with an aqueous solution of NaHCO3 (10%,
10 mL), an aqueous solution of HCl (1 N, 10 mL) and brine
(10 mL). The organic layer was dried over MgSO4, and
concentrated in vacuo. The residue was purified by column
chromatography.
1
151.9; minor isomer H NMR (400 MHz, CDCl3): dH 0.25
(s, 6H, 2SiCH3), 1.01 (s, 9H, 3CH3), 1.38 (s, 3H, CH3), 1.90
(dd, 1H, J¼14.8, 10.4 Hz, H2), 2.23 (dd, 1H, J¼14.8,
2.4 Hz, H2), 2.70 (d, 1H, J¼4.0 Hz, H4), 3.05 (d, 1H,
J¼4.0 Hz, H4), 3.25 (d, 1H, J¼2.4 Hz, OH), 5.31 (dt, 1H,
J¼2.4, 2.4, 10.4 Hz, H1), 6.65–7.05 (m, 4H, Har); 13C NMR
(100.62 MHz, CDCl3): dC 24.3 (2C), 18.3, 22.6 25.7 (3C),
42.0, 52.9, 57.2, 65.9, 117.9, 121.3, 126.6, 127.9, 134.0,
151.9; IR (film) n 3457, 2956, 2930, 2859, 1488,
1254 cm21; MS-CI m/z (relative intensity) 308 (Mþ,80),
291 (100).
4.8.1. (2)-(1S)-3-Methyl-1-(2-tert-butyldimethylsilyloxy-
phenyl)but-3-en-1-ol 12a. Compound (2)-12a was
obtained by reduction of 13a using (R)-CBS-oxazaboro-
lidine as a colorless oil in 72% yield; [a]2D0¼244.3 (c¼1,
acetone); ee¼95%.
4.9.2. (1)-(1R,3S)-3,4-Epoxy-3-methyl-1-(2-tert-butyl-
dimethylsilyloxyphenyl)butan-1-ol 14a. Compound (þ)-
14a was obtained from (þ)-12a as a colorless oil in 72%
yield; [a]2D0¼þ44.2 (c¼1.1, acetone); de¼84%.
4.9.3. (2)-(1S,3R)-3,4-Epoxy-3-methyl-1-(5-methoxy-2-
tert-butyldimethylsilyloxyphenyl)butan-1-ol 14b. Com-
pound (2)-14b was obtained from (2)-12b as a colorless oil
in 73% yield; [a]2D0¼242.7 (c¼1.1, acetone); de¼84%;
major isomer 1H NMR (400 MHz, CDCl3): dH 0.25 (s, 6H,
2SiCH3), 1.01 (s, 9H, 3CH3), 1.47 (s, 3H, CH3), 1.68 (dd,
1H, J¼14.8, 10.0 Hz, H2), 2.17 (dd, 1H, J¼14.8, 2.8 Hz,
H2), 2.60–2.66 (2d, 2H, J¼4.8 Hz, H4), 3.01 (d, 1H,
J¼3.2 Hz, OH), 3.76 (s, 3H, OMe), 5.28 (dt, 1H, J¼3.2, 2.8,
10.0 Hz, H1), 6.65–6.71 (m, 2H, 2Har), 7.01–7.05 (m, 1H,
Har); 13C NMR (100.62 MHz, CDCl3): dC 24.0 (2C), 18.3,
21.2, 25.6 (3C), 43.8, 53.7, 55.6, 56.3, 66.7, 111.7, 113.3,
118.8, 135.2, 145.6, 154.1; minor isomer 1H NMR
(400 MHz, CDCl3): dH 0.22 (s, 6H, 2SiCH3), 0.97 (s, 9H,
3CH3), 1.38 (s, 3H, CH3), 1.90 (dd, 1H, J¼14.8, 10.4 Hz,
H2), 2.23 (dd, 1H, J¼14.8, 2.4 Hz, H2), 2.71 (d, 1H,
J¼4.0 Hz, H4), 2.07 (d, 1H, J¼4.0 Hz, H4), 3.31 (d, 1H,
J¼2.4 Hz, OH), 3.77 (s, 3H, OMe), 5.02 (dt, 1H, J¼2.4, 2.4,
4.8.2. (1)-(1R)-3-Methyl-1-(2-tert-butyldimethylsilyl-
oxyphenyl)but-3-en-1-ol 12a. Compound (þ)-12a was
obtained by reduction of 13a using (S)-CBS-oxazaboro-
lidine as a colorless oil in 75% yield; [a]2D0¼þ43.8 (c¼1.1,
acetone); ee¼93%.
4.8.3. (2)-(1S)-3-Methyl-1-(5-methoxy-2-tert-butyl-
dimethylsilyloxyphenyl)but-3-en-1-ol 12b. Compound
(2)-12b was obtained by reduction of 13b using (R)-
CBS-oxazaborolidine as a colorless oil in 70% yield;
[a]2D0¼240.7 (c¼0.8, acetone); ee¼90%.
4.8.4. (2)-(1S)-3-Methyl-1-(2,5-di-tert-butyldimethyl-
silyloxyphenyl)but-3-en-1-ol 12c. Compound (2)-12c
was obtained by reduction of 13c using (R)-CBS-oxaza-
borolidine as a colorless oil in 75% yield; [a]2D0¼238.7
(c¼0.8, acetone); ee¼84%.

J.-Y. Goujon et al. / Tetrahedron 60 (2004) 4037–4049
4045
10.4 Hz, H1), 6.65–7.05 (m, 3H, Har); 13C NMR
(100.62 MHz, CDCl3): dC 24.0 (2C), 18.3, 22.7, 25.9
(3C), 41.8, 52.8, 55.6, 57.3, 66.0, 111.7, 113.3, 118.6, 134.8,
(relative intensity) 176 (Mþ, 3), 145 (100), 115 (13), 91 (5).
Anal. Calcd for C11H12O2: C, 74.98; H, 6.86. Found C,
74.82; H, 6.91.
145.5, 154.1; IR (film) n 3473, 2930, 2858, 1495 cm21
;
MS-CI m/z (relative intensity) 338 (Mþ, 62), 321 (M217,
100).
4.10.2. (1)-2-Hydroxymethyl-2-methyl-2H-1-benzo-
pyran 3a. Compound (þ)-3a was obtained from (þ)-14a
as a colorless oil in 80% yield; [a]2D0¼þ13.0 (c¼0.5,
acetone); ee¼46%.
4.9.4. (2)-(1S,3R)-3,4-Epoxy-3-methyl-1-(2,5-di-tert-
butyldimethylsilyloxyphenyl)butan-1-ol 14c. Compound
(2)-14c was obtained from (2)-12c as a colorless oil in
70% yield; [a]2D0¼239.1 (c¼1.0, acetone); de¼82%; major
isomer 1H NMR (400 MHz, CDCl3): dH 0.16 (s, 6H,
2SiCH3), 0.24 (s, 6H, 2SiCH3), 0.96 (s, 9H, 3CH3), 1.01 (s,
9H, 3CH3), 1.45 (s, 3H, CH3), 1.72 (dd, 1H, J¼14.4,
10.0 Hz, H2), 2.13 (dd, 1H, J¼14.4, 3.2 Hz, H2), 2.58–2.65
(2d, 2H, J¼4.8 Hz, H4), 2.91 (d, 1H, J¼3.2 Hz, OH), 5.21
(dt, 1H, J¼3.2, 3.2, 10.0 Hz, H1), 6.58 (dd, 1H, J¼8.8,
2.8 Hz, Har), 6.63 (d, 1H, J¼8.8 Hz, Har), 6.90 (d, 1H,
J¼2.8 Hz, Har); 13C NMR (100.62 MHz, CDCl3): dC 24.5
(2C), 24.0 (2C), 18.1, 18.3, 21.3, 25.7 (3C), 25.9 (3C), 43.8,
53.7, 56.3, 66.7, 118.2, 118.8, 118.9, 135.1, 146.1, 151.9;
minor isomer 1H NMR (400 MHz, CDCl3): dH 0.16 (s, 6H,
2SiCH3), 0.23 (s, 6H, 2SiCH3), 0.96 (s, 9H, 3CH3), 0.98 (s,
9H, 3CH3), 1.38 (s, 3H, CH3), 1.85 (dd, 1H, J¼14.8,
10.0 Hz, H2), 2.21 (dd, 1H, J¼14.8, 2.4 Hz, H2), 2.69 (d,
1H, J¼4.0 Hz, H4), 3.03 (d, 1H, J¼4.0 Hz, H4), 3.20 (d, 1H,
J¼2.4 Hz, OH), 4.99 (dt, 1H, J¼2.4, 2.4, 10.0 Hz, H1),
6.57–6.94 (m, 3H, Har); 13C NMR (100.62 MHz, CDCl3):
dC 24.3 (2C), 24.1 (2C), 18.1, 18.3, 22.7, 25.7 (3C),
25.9 (3C), 41.9, 52.9, 57.2, 66.0, 118.2, 118.8, 118.9,
134.8, 146.1, 151.8; IR (film) 3470, 2930, 2858,
1488 cm21; MS-CI m/z (relative intensity) 438 (Mþ, 54),
421 (100).
4.10.3. (2)-2-Hydroxymethyl-6-methoxy-2-methyl-2H-
1-benzopyran 3b. Compound (2)-3b was obtained from
(2)-14b as a colorless oil in 75% yield; [a]2D0¼210.2
(c¼0.4, acetone); ee¼43%; 1H NMR (200 MHz, CDCl3): d
1.35 (s, 3H, CH3), 2.03 (bs, 1H, OH), 3.58 (d, 1H,
0
0
J¼11.8 Hz, H1 ), 3.67 (d, 1H, J¼11.8 Hz, H1 ), 3.75 (s,
3H, OCH3), 5.62 (d, 1H, J¼10.0 Hz, H3), 6.42 (d, 1H,
J¼10.0 Hz, H4), 6.56 (d, 1H, J¼2.8 Hz, Har), 6.67 (dd,
1H, J¼2.8, 8.8 Hz, Har), 6.73 (d, 1H, J¼8.8 Hz, Har); 13C
NMR (50.3 MHz, CDCl3): d 22.3, 55.7, 68.5, 79.0, 111.8,
114.5, 116.7, 121.5, 124.9, 127.9, 146.2, 154.0; IR (film)
n 3432, 2932, 2834, 1492, 1040 cm21; MS-EI m/z
(relative intensity) 206 (Mþ, 5), 175 (100), 132 (18);
anal.calcd for C12H14O3: C, 69.88; H, 6.86. Found C, 69.95;
H, 6.80.
4.10.4. (2)-2-Hydroxymethyl-6-hydroxy-2-methyl-2H-
1-benzopyran 3c. Compound (2)-3c was obtained from
(2)-14c as a colorless oil in 68% yield; [a]2D0¼27.6 (c¼0.3,
acetone); ee¼35%; 1H NMR (200 MHz, CDCl3): d 1.35 (s,
0
3H, CH3), 3.58 (d, 1H, J¼11.6 Hz, H1 ), 3.68 (d, 1H,
0
J¼11.6 Hz, H1 ), 5.61 (d, 1H, J¼9.6 Hz, H3), 6.38 (d, 1H,
J¼9.6 Hz, H4), 6.50 (d, 1H, J¼2.8 Hz, Har), 6.59 (dd, 1H,
J¼2.8, 8.4 Hz, Har), 6.68 (d, 1H, J¼8.4 Hz, Har); 13C NMR
(50.3 MHz, CDCl3): d 22.3, 68.4, 79.3, 111.8, 114.8, 116.4,
121.5, 124.2, 127.8, 146.6, 154.2; IR (film) n 3432, 2932,
2834, 1492, 1040 cm21; MS-CI m/z (relative intensity) 210
(Mþ18, 100), 192 (Mþ, 51). Anal. Calcd for C11H12O3: C,
68.74; H, 6.29. Found C, 68.82; H, 6.36.
4.10. General procedure for formation of 2H-1-benzo-
pyran 3a-c
To a solution of epoxide 14a-c (0.26 mmol) in THF (2 mL)
was added at 0 8C TBAF (1 M in THF, 0.31 mmol). The
reaction was stirred 1 h at room temperature and then
hydrolyzed with a saturated aqueous solution of NH4Cl
(2 mL). The aqueous layer was extracted with EtOAc
(3£10 mL), the organic layers were washed with brine
(30 mL) and dried over MgSO4, and concentrated in vacuo.
The residue was dissolved in toluene (2 mL) and a catalytic
amount of CSA (4 mol%) was added and the reaction was
heated at 80 8C for 16 h. After cooling, a saturated aqueous
solution of NaHCO3 (1 mL) was added, the combined
organic layer was dried over MgSO4, and concentrated in
vacuo. The residue was purified by column chromatography
(8:2, petroleum ether/EtOAc) to give the 2H-1-benzopyran
3a-c.
4.11. 2-Tosylaminobenzaldehyde 18
To a solution of 2-aminobenzaldehyde (2.8 g, 23.3 mmol)
and pyridine (4.1 mL, 51.3 mmol) in anhydrous dichloro-
methane (30 mL) was added, dropwise at room temperature
under argon, a solution of para-toluenesulfonyl chloride
(4.8 g, 25.6 mmol) in dry dichloromethane (20 mL). The
resulting mixture was stirred for 20 h, poured into water
(80 mL) and extracted with dichloromethane (3£50 mL).
The combined organic layers were washed with saturated
aqueous CuSO4 (100 mL), brine (100 mL) and dried over
MgSO4. After concentration in vacuo the crude residue was
triturated with a mixture of 8:2 petroleum ether/ethyl acetate
(20 mL), filtered over celite, concentrated under vacuum
and purified by column chromatography on silica gel (8:2,
petroleum ether/EtOAc) to provide 18 (4.48 g, 70%) as a
pale yellow solid; mp 128 8C; 1H NMR (200 MHz, CDCl3)
dH 2.36 (s, 3H, CH3), 7.12–7.26 (m, 4H, Har), 7.51–7.79
4.10.1. (2)-2-Hydroxymethyl-2-methyl-2H-1-benzo-
pyran 3a. Compound (2)-3a was obtained from (2)-14a
as a colorless oil in 80% yield; [a]2D0¼213.4 (c¼0.4,
acetone); ee¼44%; 1H NMR (200 MHz, CDCl3): d 1.36 (s,
0
3H, CH3), 2.03 (bs, 1H, OH), 3.59 (d, 1H, J¼11.6 Hz, H1 ),
(m, 4H, Har), 9.82 (s, 1H, CHO), 10.80 (s, 1H, NHTs); 13
C
0
3.68 (d, 1H, J¼11.6 Hz, H1 ), 5.56 (d, 1H, J¼9.9 Hz, H3),
6.45 (d, 1H, J¼9.9 Hz, H4), 6.76–7.15 (m, 4H, Har); 13C
NMR (50.3 MHz, CDCl3): d 22.6, 68.7, 79.2, 116.1, 120.8,
121.1, 124.7, 126.6, 126.7, 129.3, 153.9; IR (film) n 3396,
2972, 2927, 1486, 1240, 1053, 773 cm21; MS-EI m/z
NMR (50.3 MHz, CDCl3): dC 21.4, 117.7, 121.7, 122.9,
127.1 (2C), 129.7 (2C), 135.7, 136.0, 136.2, 139.1, 144.1,
195.0; IR (KBr) n 1662, 1602, 1493 cm21; MS-EI m/z
(relative intensity) 275 (Mþ, 10), 120 (100), 91 (50), 65
(33), 39 (12).

4046
J.-Y. Goujon et al. / Tetrahedron 60 (2004) 4037–4049
4.12. Preparation of chiral homoallylic alcohols 19
into water (20 mL) and extracted with diethyl ether
(3£20 mL). The combined organic layers were washed
with brine (30 mL), dried over MgSO4 and concentrated in
vacuo. The residue was purified by column chromatography
on silica gel (7:3, petroleum ether/EtOAc) to provide two
diastereomers.
Homoallylic alcohols 19 were prepared according to
Section 4.5.
4.12.1. (2)-(R)-Methyl-1-(2-tosylaminophenyl)but-3-en-
1-ol (2)-19. Compound (2)-(R)-19 was obtained from 18
and 9 (prepared with (þ)-DIP-Cl) as a pale yellow solid in
80% yield: mp 79 8C; [a]2D0¼216.7 (c¼1.0, acetone);
ee¼84%; 1H NMR (200 MHz, CDCl3) dH 1.69 (s, 3H,
CH3), 2.19 (dd, 1H, J¼4, 14 Hz, H2), 2.28 (dd, 1H, J¼10,
14 Hz, H2), 2.37 (s, 3H, CH3), 2.56 (bs, 1H, OH), 4.68 (dd,
1H, J¼10, 4 Hz, H1), 4.75 (s, 1H, H4), 4.92 (s, 1H, H4),
7.02–7.72 (m, 8H, Har), 8.57 (s, 1H, NH); 13C NMR
(50.3 MHz, CDCl3) dC 21.4, 22.0, 45.1, 71.3, 114.6, 121.7,
124.4, 127.0 (2C), 127.5, 128.4, 129.5 (2C), 132.0, 135.8,
4.14.1. (2)-trans-(2S,4R)-2-(Hydroxymethyl)-2-methyl-
1-tosyl-1,2,3,4-tetrahydroquinolin-4-ol (2)-4. Compound
(2)-trans-(2S,4R)-4 was obtained from (2)-(1R,3S)-20
(220 mg, 0.63 mmol) as a colorless oil (64 mg, 29%);
[a]2D0¼23.0 (c¼0.5, acetone); ee¼94%; 1H NMR
(400 MHz, CDCl3) dH 1.43 (s, 3H, CH3), 1.83 (dd, 1H,
J¼13, 11 Hz, H3), 2.14 (dd, 1H, J¼13, 5 Hz, H3), 2.35 (s,
3H, CH3), 3.90 (s, 2H, CH2), 5.02 (dd, 1H, J¼11, 5 Hz, H4),
6.98–7.70 (m, 8H, Har); 13C NMR (100.62 MHz, CDCl3) dC
21.5, 25.0, 47.3, 78.2, 80.1, 80.3, 121.6, 124.4, 127.0 (2C),
127.1, 128.5, 129.6 (2C), 130.4, 136.0, 137.2, 143.6; IR
(film) n 3492, 3254, 2967, 2928, 2880, 1592, 1499, 1453,
1334, 1159 cm21; MS-EI m/z (relative intensity) 347 (Mþ,
3), 274 (17), 192 (25), 174 (80), 144 (42), 118 (100), 117
(43), 91 (72), 65 (36), 39 (16); MS-CI m/z (relative
intensity) 365 (MþNH3, 18), 348 (MHþ, 100), 330 (61),
291 (37), 274 (69), 144 (21). Anal. Calcd for C18H21O4NS:
C, 62.18; H, 6.04; S, 9.21; N, 4.03. Found: C, 62.90; H, 6.34;
S, 9.25; N, 4.05.
136.9, 141.3, 143.6; IR(KBr)n 3491, 3239, 2922, 1159 cm21
MS-EI m/z (relative intensity) 276 (35), 91 (100), 65 (35).
;
4.12.2. (1)-(S)-Methyl-1-(2-tosylaminophenyl)but-3-en-
1-ol (1)-19. Compound (þ)-(S)-19 was obtained from 18
and 9 (prepared with (2)-DIP-Cl) as a pale yellow solid in
84% yield: mp 79 8C; [a]2D0¼þ17.0 (c¼1.0, acetone);
ee¼82%.
4.13. Preparation of epoxide 20
Epoxides 20 were prepared according to Section 4.9.
4.14.2. (2)-cis-(2R,4R)-2-(Hydroxymethyl)-2-methyl-1-
tosyl-1,2,3,4-tetrahydroquinolin-4-ol (2)-4. Compound
(2)-cis-(2R,4R)-4 was obtained from (2)-(1R,3S)-20
(220 mg, 0.63 mmol) as a white solid (64 mg, 29%);
[a]2D0¼24.0 (c¼0.2, acetone); ee¼63%; 1H NMR
(400 MHz, CDCl3) dH 1.52 (s, 3H, CH3), 1.5–1.6 (m, 4H,
H3, CH3), 1.89 (dd, 1H, J¼14, 6 Hz, H3), 2.01 (d, 1H,
4.13.1. (2)-(1R,3S)-3,4-Epoxy-3-methyl-1-(2-tosyl-
amino-phenyl)butan-1-ol (2)-20. Compound (2)-
(1R,3S)-20 was obtained from (2)-(R)-19 (250 mg,
754 mmol) as a colorless oil (252 mg, 96%); [a]2D0¼213.9
1
(c¼0.6, acetone); de¼84%; H NMR (200 MHz, CDCl3);
major isomer dH 1.33 (s, 3H, CH3), 1.72 (dd, 1H, J¼9.4,
14.6 Hz, H2), 1.86 (dd, 1H, J¼3.5, 14.6 Hz, H2), 2.38 (s,
3H, CH3), 2.57 (d, 1H, J¼4.6 Hz, H4), 2.61 (d, 1H,
J¼4.6 Hz, H4), 3.70 (bs, 1H, OH), 4.99 (dd, 1H, J¼3.5,
J¼6 Hz, OH), 2.40 (s, 3H, CH3), 2.85 (bt, 1H, J¼6 Hz, OH),
0
3.52 (dd, 1H, J¼12, 6 Hz, H2 ), 3.63 (dd, 1H, J¼12, 6 Hz,
0
H2 ), 4.54 (dd, 1H, J¼12, 6 Hz, H4), 7.21–7.34 (m, 8H, Har);
IR (KBr) n 3300, 3024, 2957, 2925, 2852, 1599, 1481,
1454, 1350, 1159, 1090 cm21; MS-EI m/z (relative
intensity) 347 (1), 316 (20), 155 (12), 144 (100), 91 (41),
77 (13), 65 (19). Anal. Calcd for C18H21O4NS: C, 62.18; H,
6.04; S, 9.21; N, 4.03. Found: C, 63.20; H, 6.38; S, 9.15; N,
4.05.
9.4 Hz, H1), 6.99–7.72 (m, 8H, Har), 8.67 (s, 1H, NH); 13
C
NMR (50.3 MHz, CDCl3) dC 21.1, 21.4, 42.2, 54.3, 56.2,
71.6, 122.0, 124.6, 127.1 (2C), 127.3, 128.5, 129.6 (2C),
132.7, 135.8, 137.1, 143.6; minor isomer (meaningful
signals) dH 2.73 (d, 1H, J¼3.7 Hz, H4), 3.04 (d, 1H,
J¼3.7 Hz, H4), 4.67 (dd, 1H, J¼3.5, 9.4 Hz, H1); 13C
NMR (50.3 MHz, CDCl3) dC 40.3, 52.2, 57.4, 71.3;
IR (film) n 3474, 3239, 2925, 1161 cm21; MS-EI m/z
(relative intensity) 248 (8), 192 (25), 174 (20), 132 (100),
91 (24); MS-CI m/z (relative intensity) 364 (100), 347
(95).
4.14.3. (1)-trans-(2R,4S)-2-(Hydroxymethyl)-2-methyl-
1-tosyl-1,2,3,4-tetrahydroquinolin-4-ol (1)-4. Compound
(þ)-trans-(2R,4S)-4 was obtained from (þ)-(1S,3R)-20
(300 mg, 0.86 mmol) as a colorless oil (68 mg, 23%);
[a]2D0¼þ2.8 (c¼0.3, acetone); ee¼88%. Anal. Calcd for
C18H21O4NS: C, 62.18; H, 6.04; S, 9.21; N, 4.03. Found: C,
62.19; H, 6.05; S, 9.21; N, 4.03.
4.13.2. (1)-(1S,3R)-3,4-Epoxy-3-methyl-1-(2-tosyl-
aminophenyl)butan-1ol (1)-20. Compound (þ)-(1S,3R)-
20 was obtained from (þ)-(S)-19 (600 mg, 1.81 mmol) as a
colorless oil (560 mg, 89%); [a]2D0¼þ10.8 (c¼1.0,
acetone); de¼82%.
4.14.4. (1)-cis-(2S,4S)-2-(Hydroxymethyl)-2-methyl-1-
tosyl-1,2,3,4-tetrahydroquinolin-4-ol (1)-4. Compound
(þ)-cis-(2S,4S)-4 was obtained from (þ)-(1S,3R)-20
(300 mg, 0.86 mmol) as a white solid (66 mg, 22%);
[a]2D0¼þ2.0 (c¼0.2, acetone); ee¼40%. Anal. Calcd for
C18H21O4NS: C, 62.18; H, 6.04; S, 9.21; N, 4.03. Found: C,
62.20; H, 6.04; S, 9.21; N, 4.08.
4.14. Typical procedure for formation of compounds 4
To a solution of epoxide 20 in anhydrous toluene (25 mL) at
room temperature under argon was added slowly trifluoro-
acetic acid (2 equiv.) and the solution was stirred for 16 h.
The reaction mixture was then quenched with saturated
aqueous NaHCO3 (4 mL). The resulting mixture was poured
4.15. Formation of the acetonide
4.15.1. 3-Methyl-1-phenylbut-3-en-1-ol 21. To a solution

J.-Y. Goujon et al. / Tetrahedron 60 (2004) 4037–4049
4047
of 2-methylpropene magnesium chloride (0.6 M in THF,
6 mmol) at 230 8C was added dropwise a solution of
benzaldehyde (530 mg, 0.5 mmol) in THF (10 mL). The
reaction was stirred 1 h at room temperature and then
quenched with a saturated aqueous solution of NH4Cl
(20 mL). The aqueous layer was extracted with EtOAc
(2£20 mL), the organic layers were dried over MgSO4, and
concentrated in vacuo. The residue was purified by column
chromatography (9:1, petroleum ether/EtOAc) to give a
colorless oil (794 mg, 98% yield); 1H NMR (200 MHz,
CDCl3): dH 1.78 (s, 3H, CH3), 2.25 (bs, 1H, OH), 2.41 (d,
2H, J¼6.4 Hz, H2), 4.78 (t, 1H, J¼6.4 Hz, H1), 4.81–4.91
(m, 2H, H4), 7.23–7.36 (m, 5H, Har); 13C NMR (50.3 MHz,
CDCl3): dC 22.3, 48.2, 71.3, 114.0, 125.7 (2C), 127.4, 128.3
(2C), 142.3, 144.0; IR (film) n 3396, 3073, 3030, 2969,
2936, 1454, 700 cm21; MS-CI m/z (relative intensity) 180
(Mþ18, 26), 162 (Mþ, 100), 145 (37).
3H, CH3), 2.04 (m, 1H, H2), 2.40 (m, 1H, H2), 2.97 (m, 2H,
H4), 5.21 (m, 1H, H1), 7.63–7.69 (m, 5H, Har); 13C NMR
(50.3 MHz, CDCl3): dC 25.0 (2C), 18.0, 21.3, 25.8 (3C),
48.5, 54.9, 55.3, 72.9, 125.8 (2C), 127.3, 128.1 (2C), 144.9;
IR (film) n 2956, 2929, 2857, 1092, 837 cm21; MS-CI m/z
(relative intensity) 293 (Mþ1, 5), 221 (100), 161 (19), 132
(30).
4.15.4. 2-Methyl-1,4-diphenyl-4-tert-butyldimethylsilyl-
oxybutan-2-ol 24. To a solution of BF3·Et2O (4 mmol), in
THF (4 mL) was added at 278 8C phenyllithium (1.4 M,
2.8 mL, 4.0 mmol). Then, a solution of epoxide 23 (292 mg,
1 mmol) in THF (2 mL) was added quickly and the reaction
was stirred 2 h at 260 8C. The reaction was quenched by
addition of a saturated aqueous solution of NH4Cl (25 mL),
the organic layer was washed with brine, dried over MgSO4,
and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (9:1, petroleum ether/
EtOAc) to give the compound 24 (274 mg, 74% yield) as a
4.15.2. 3,4-Epoxy-3-methyl-1-phenylbutan-1-ol 22. To a
blue solution of homoallylic alcohol 21 (1.3 mmol, 620 mg)
and vanadyl acetylacetonate (131 mmol, 35 mg) in
anhydrous dichloromethane, was added, at 25 8C under
argon, tert-butyl hydroperoxide (5.5 M in nonane, 0.47 mL,
2.6 mmol). The resulting red-brown solution was stirred at
0 8C for 5 h. Then, the reaction mixture was poured into
10% aqueous Na2S2O3 and extracted with dichloromethane.
The combined organic layers were washed with brine, dried
over MgSO4 and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (7:3,
petroleum ether/EtOAc) to provide 22 (180 mg, 78% yield)
1
mixture of diastereoisomers (ratio 8:2); major isomer H
NMR (200 MHz, CDCl3): dH 20.19 (s, 3H, SiCH3), 0.26 (s,
3H, SiCH3), 1.07 (s, 9H, 3CH3), 1.54 (s, 3H, CH3), 1.90 (m,
1H, H3), 2.23 (m, 1H, H3), 2.97 (bs, 2H, H1), 4.60 (bs, 1H,
OH), 5.19 (m, 1H, H4), 7.40–7.51 (m, 10H, Har); 13C NMR
(50.3 MHz, CDCl3): dC 24.1 (2C), 17.8, 25.8 (3C), 28.2,
46.9, 50.2, 72.7, 74.7, 126.1, 127.1 (2C), 127.8 (2C), 128.1
1
(2C), 128.7, 130.7 (2C), 137.7, 144.6; minor isomer H
NMR (200 MHz, CDCl3): dH 20.13 (s, 3H, SiCH3), 0.33 (s,
3H, SiCH3), 1.12 (s, 9H, 3CH3), 1.26 (s, 3H, CH3), 1.84 (m,
1H, H3), 2.27 (m, 1H, H3), 3.05 (d, 1H, J¼13.2 Hz, H1),
3.26 (d, 1H, J¼13.2 Hz, H1), 4.53 (bs, 1H, OH), 5.39 (m,
1H, H4), 7.40–7.51 (m, 10H, Har); 13C NMR (50.3 MHz,
CDCl3): dC 24.9 (2C), 17.8, 25.8 (3C), 28.2, 46.9, 49.1,
72.7, 74.7, 126.4, 127.1 (2C), 127.8 (2C), 128.1 (2C), 128.7,
130.4 (2C), 138.2, 144.6; MS-CI m/z (relative intensity) 388
(Mþ18, 5), 370 (Mþ, 30), 238 (100).
1
as a mixture of diastereomers (ratio 8:2); major isomer H
NMR (200 MHz, CDCl3): dH 1.44 (s, 3H, CH3), 2.00 (m,
2H, H2), 2.60 (m, 2H, H4), 3.05 (bs, 1H, OH), 4.95 (m, 1H,
H1), 7.25–7.35 (m, 5H, Har); 13C NMR (50.3 MHz, CDCl3):
dC 21.2, 45.3, 53.9, 56.2, 71.5, 125.6 (2C), 127.5, 128.4
(2C), 144.0; minor isomer 1H NMR (200 MHz, CDCl3): dH
1.39 (s, 3H, CH3), 2.03 (m, 2H, H2), 2.87 (m, 2H, H4), 3.32
(bs, 1H, OH), 4.74 (m, 1H, H1), 7.25–7.35 (m, 5H, Har); 13
C
4.15.5. 3-Methyl-1,4-diphenylbutan-1,3-diol 25. To a
solution of 24 (290 mg, 0.78 mmol) in THF (2 mL) was
added at 0 8C TBAF (1 M in THF, 0.86 mmol). The reaction
was stirred 1 h at room temperature and then hydrolysed
with a saturated aqueous solution of NH4Cl (2 mL). The
aqueous layer was extracted with EtOAc (3£10 mL), the
organic layers were washed with brine (30 mL) and dried
over MgSO4, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (7:3,
petroleum ether/EtOAc) to give the compound 25 as a white
solid (189 mg, 95% yield) as a mixture of diastereomers
NMR (50.3 MHz, CDCl3): dC 22.6, 43.8, 52.9, 57.1, 71.1,
125.6 (2C), 127.5, 128.4 (2C), 143.6; IR (film) n 3438,
2927, 1071, 760, 701 cm21; MS-CI m/z (relative intensity)
196 (Mþ18, 75), 178 (Mþ, 48), 161 (M217).
4.15.3. 3,4-Epoxy-3-methyl-1-phenyl-1-tert-butyldi-
methylsilyloxybutane 23. To a solution of 22 (620 mg,
3.5 mmol), imidazole (473 mg, 7.0 mmol) in DMF (4 mL)
was added tert-butyldimethylsilyl chloride (780 mg,
5.2 mmol). The reaction was heated 18 h at room tempera-
ture, then 50 mL of water and 50 mL of EtOAc were added.
The aqueous layer was extracted with ethyl acetate
(3£40 mL), the organic layers were washed with brine,
dried over MgSO4, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (9:1,
petroleum ether/EtOAc) to give the compound 23 (880 mg,
86% yield) as a mixture of diastereomers (ratio 8:2); major
isomer 1H NMR (200 MHz, CDCl3): dH 0.17 (s, 3H,
SiCH3), 0.41 (s, 3H, SiCH3), 1.25 (s, 9H, 3CH3), 1.68 (s,
3H, CH3), 2.06 (m, 1H, H2), 2.66 (m, 1H, H2), 2.79 (m, 2H,
H4), 5.14 (m, 1H, H1), 7.63–7.69 (m, 5H, Har); 13C NMR
(50.3 MHz, CDCl3): dC 24.5 (2C), 18.0, 22.2, 25.8 (3C),
47.9, 53.5, 55.1, 72.9, 125.9 (2C), 127.3, 128.1 (2C), 144.9;
minor isomer 1H NMR (200 MHz, CDCl3): dH 0.13 (s, 3H,
SiCH3), 0.37 (s, 3H, SiCH3), 1.25 (s, 9H, 3CH3), 1.79 (s,
1
(ratio 8:2); mp 117 8C; major isomer H NMR (400 MHz,
CDCl3): dH 1.35 (s, 3H, CH3), 1.67 (d, 1H, J¼14.2 Hz, H2),
1.93 (dd, 1H, J¼14.2, 11.0 Hz, H2), 2.73 (d, 1H, J¼13.6 Hz,
H4), 2.78 (d, 1H, J¼13.6 Hz, H4), 3.06 (bs, 1H, OH), 4.05
(bs, 1H, OH), 5.00 (d, 1H, J¼11.0 Hz, H1), 7.16–7.35 (m,
10H, Har); 13C NMR (100.62 MHz, CDCl3): dC 25.3, 48.5,
50.3, 71.8, 73.5, 125.6 (2C), 126.5 (2C), 127.3, 128.1 (2C),
128.3 (2C), 130.5, 136.6, 144.5; minor isomer (meaningful
signals) 1H NMR (200 MHz, CDCl3): dH 1.12 (s, 3H, CH3),
1.85 (m, 2H, H2), 2.84 (d, 1H, J¼13.2 Hz, H4), 3.09 (d, 1H,
J¼13.2 Hz, H4), 3.06 (bs, 1H, OH), 4.05 (bs, 1H, OH), 5.18
(m, 1H, H1), 7.16–7.35 (m, 10H, Har); 13C NMR
(100.62 MHz, CDCl3): dC 28.7, 46.2, 49.1, 71.6, 73.6,
125.5 (2C), 126.4 (2C), 127.3, 128.2 (2C), 128.4 (2C),
130.4, 137.3, 144.6; IR (film) n 3334, 3028, 2971, 2913,

4048
J.-Y. Goujon et al. / Tetrahedron 60 (2004) 4037–4049
700 cm21; MS-CI m/z (relative intensity) 274 (Mþ18, 62),
Roche.. (b) David, M.; Boustie, J.; Peilloux, A.; Poupon, E.;
Amoros, M.; Sauleau, A. Pharm. Sci. 1997, 3, 305–306.
(c) Rao, E. V.; Sridhar, P.; Rao, B. V. L. N.; Ellaiah, P.
Phytochemistry 1999, 50, 1417–1418. (d) Omura, S.;
Nakagawa, A. Tetrahedron Lett. 1981, 22, 2199–2202.
(e) Williamson, N. M.; March, D. R.; Ward, A. D. Tetrahedron
Lett. 1995, 36, 7721–7724. (f) Morimoto, Y.; Shirahama, H.
Tetrahedron 1996, 52, 10631–10652. (g) Morimoto, Y.;
Matsuda, F.; Shirahama, H. Tetrahedron 1996, 52,
10609–10630.
256 (Mþ, 6), 238 (100), 221 (74).
4.15.6. 4-Benzyl-2,2,4-trimethyl-6-phenyl-1,3-dioxa-
cyclohexane 26. To a solution of diol 25 (100 mg,
0.39 mmol) in 2,2-dimethoxypropane (3.5 mL) was added
at rt CSA (2 mol%). After 1 h the reaction was quenched by
addition of a saturated aqueous solution of NaHCO3 (4 mL).
The aqueous layer was extracted with EtOAc (3£10 mL),
the combined organic layers were washed with brine
(30 mL), dried over MgSO4, and concentrated in vacuo.
The residue was purified by column chromatography on
silica gel (9:1, petroleum ether/EtOAc) to give compound
26 as a white solid (106 mg, 92% yield) as a mixture of
diastereomers (ratio 8:2); mp 56 8C; major isomer 1H NMR
(400 MHz, CDCl3): dH 1.41 (s, 3H, CH3), 1.49 (s, 3H, CH3),
1.54 (dd, 1H, J¼2.0, 12.0 Hz, H5), 1.56 (s, 3H, CH3), 1.76
(dd, 1H, J¼11.6, 12.0 Hz, H5), 2.76 (d, 1H, J¼12.0 Hz,
PhCH), 2.81 (d, 1H, J¼12.0 Hz, PhCH), 4.90 (dd, 1H,
J¼2.0, 11.6 Hz, H6), 7.21–7.33 (m, 10H, Har); 13C NMR
(100.62 MHz, CDCl3): dC 25.1, 25.7, 31.9, 41.7, 51.6, 68.0,
73.5, 99.0, 125.9 (2C), 126.2, 127.4, 127.7 (2C), 128.4 (2C),
130.9 (2C), 137.3, 142.5; minor isomer 1H NMR (200 MHz,
CDCl3): dH 1.24 (s, 3H, CH3), 1.49 (s, 3H, CH3), 1.58 (s,
3H, CH3), 1.62–2.10 (m, 2H, H5), 2.90 (d, 1H, J¼13.6 Hz,
PhCH), 3.16 (d, 1H, J¼13.6 Hz, PhCH), 4.84 (m, 1H, H6),
7.21–7.33 (m, 10H, Har); 13C NMR (100.62 MHz, CDCl3):
dC 26.8, 30.4, 31.7, 41.3, 47.5, 68.4, 74.1, 99.0, 125.5 (2C),
126.3, 127.4, 127.9 (2C), 128.4 (2C), 130.6 (2C), 138.0,
142.5; IR (film) n 2990, 2938, 699 cm21; MS-CI m/z
(relative intensity) 314 (Mþ18, 4), 296 (Mþ, 1), 238 (86),
152 (100).
7. (a) Sartori, G.; Casiraghi, G.; Bolzoni, L.; Castani, G. J. Org.
Chem. 1979, 44, 803–805. (b) Talley, J. J. Synthesis 1983,
845–846. (c) Sukbok, C.; Grubbs, R. H. J. Org. Chem. 1998,
63, 864–866. (d) Chauder, B. A.; Kalinin, A. V.; Snieckus, V.
Synthesis 2001, 140–144. (e) Larock, R. C.; Wei, L.;
´
Hightowei, T. R. Synlett 1998, 522–524. (f) Solladie, G.;
Boeffel, G.; Maignan, J. Tetrahedron 1996, 52, 2065–2074.
(g) Chauder, B. A.; Lopes, C. C.; Lopes, R. S. C.; Da Silva,
A. J. M.; Snieckus, V. Synthesis 1998, 279–282. (h) Cruz-
`
Almanza, R.; Perez-Flores, F.; Lemini, C. Heterocycles 1994,
`
37, 759–774. (i) Garcias, X.; Ballester, P.; Saa, J. M.
Tetrahedron Lett. 1991, 32, 7739–7742. (j) Fujita, K. I.;
Yamamoto, K.; Yamaguchi, R. Org. Lett. 2002, 16,
2691–2694. (k) Zigang, L.; Zhang, J.; Li, C. J. Tetrahedron.
Lett. 2003, 44, 153–156. (l) Ma, Y.; Qian, C.; Xic, M.; Sun, J.
J. Org. Chem. 1999, 64, 6462–6467. (m) Qiang, L. G.; Baine,
N. H. J. Org. Chem. 1988, 53, 4218–4222. (n) Makioka, Y.;
Shindo, T.; Taniguchi, Y.; Takaki, K.; Fujiwara, Y. Synthesis
1995, 801–804. (o) Lucchini, V.; Prato, M.; Scrrano, G.;
Stivanello, M.; Valle, G. J. Chem. Soc., Perkin Trans. 2 1992,
259–266. (p) Koichi, N.; Takanori, S. Heterocycles 1993, 35,
1039–1041. (q) Strekowski, L.; Wydra, R. L.; Cegla, M. T.;
Czarny, A.; Harden, D. B.; Patterson, S. E.; Battiste, M. A.;
Coxon, J. M. J. Org. Chem. 1990, 55, 4777–4779.
(r) Spanedda, M. V.; Hoang, V. D.; Crousse, B.; Bonnet-
Acknowledgements
´
Delpon, D.; Begue, J. P. Tetrahedron Lett. 2003, 217–219.
8. Lang, F.; Zewge, D.; Song, Z. J.; Biba, M.; Dormer, P.;
Tschaen, D.; Volante, R. P.; Reider, P. J. Tetrahedron Lett.
2003, 44, 5285–5288.
We are indebted to French Ministry of Education and CNRS
for financial support. We thank Professor Jean-Paul
Quintard for fruitful discussion.
9. (a) Bouzbouz, S.; Goujon, J. Y.; Deplanne, J.; Kirschleger, B.
Eur. J. Org. Chem. 2000, 3223–3228. (b) Goujon, J. Y.;
Zammattio, F.; Kirschleger, B. Tetrahedron: Asymmetry 2000,
11, 2409–2420. (c) Kahn, P.; Cossy, J. Tetrahedron Lett.
1999, 40, 8113–8114.
References and notes
10. Goujon, J. Y.; Zammattio, F.; Pagnoncelli, S.; Boursereau, Y.;
Kirschleger, B. Synlett 2002, 322–324.
1. (a) Nicolaou, K. C.; Pfefferkorn, J. A.; Roecker, A. J.; Cao,
G. Q.; Barluenga, S.; Mitchell, H. J. J. Am. Chem. Soc. 2000,
122, 9939–9953. (b) Elliot, M. C.; William, E. J. Chem. Soc.,
Perkin Trans. 1 2001, 19, 2303–2340.
11. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734–736.
12. (a) Racherla, U. S.; Liao, Y.; Brown, H. C. J. Org. Chem.
1992, 57, 6614–6617. (b) Brown, H. C.; Jadhav, P. K. J. Am.
Chem. Soc. 1983, 105, 2092–2093. (c) Brown, H. C.; Jadhav,
P. K.; Bhat, K. S. J. Am. Chem. Soc. 1985, 107, 2564–2565.
(d) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56,
401–404.
2. Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron 1996,
52, 15031–15070.
3. (a) Kazuo, M.; Kazuya, O.; Hironobu, H. J. Org. Chem. 1989,
54, 557–560. (b) Pryor, W. A.; Strickland, T.; Church, D. F.
J. Am. Chem. Soc. 1988, 110, 2224–2229. (c) Dorey, G.;
Lockhart, B.; Lestage, P.; Casara, P. Bioorg. Med. Chem. Lett.
2000, 10, 935–939.
13. Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37,
1986–2012.
14. Mihelic, E. D.; Daniels, K.; Eickoff, D. J. J. Am. Chem. Soc.
1981, 103, 7690–7692.
4. (a) Ishikawa, T. Heterocycles 2000, 53, 453–473. (b) Resh,
M.; Steigel, A.; Chen, Z.; Bauer, R. J. Nat. Prod. 1998, 61,
347–350.
15. (a) Wipf, P.; Weiner, W. S. J. Org. Chem. 1999, 64,
5321–5324. (b) Oliviera, M. M.; Moustrou, C.; Carvalho,
L. M.; Silva, J. A. C.; Samat, A.; Guglielmetti, R.; Dubest, R.;
Aubart, J.; Oliviera-Campos, A. M. F. Tetrahedron 2002, 58,
1709–1718. (c) Hardouin, C.; Burgaud, L.; Valleix, A.; Doris,
E. Tetrahedron Lett. 2003, 44, 435–437.
5. (a) Caroll, A. R.; Bowden, B. F.; Coll, J. C. Aust. J. Chem.
1993, 46, 1079–1083. (b) Pillai, S. P.; Menon, S. R.; Mitscher,
L. A.; Pillai, C. A.; Shankel, D. M. J. Nat. Prod. 1999, 62,
1358–1362.
6. (a) Masciadri, R. U.S. Patent 5, 773, 446, 1998, Hoffmann La

J.-Y. Goujon et al. / Tetrahedron 60 (2004) 4037–4049
4049
16. Anderson, W. K.; Dalvie, D. K. J. Heterocycl. Chem. 1993, 30,
1533–1536.
31, 945–948. (b) Rychnovsky, S. D.; Rogers, B.; Yang, G.
J. Org. Chem. 1993, 58, 3511–3518. (c) Achmatowicz, B.;
Wicha, J. Tetrahedron: Asymmetry 1993, 4, 399–410.
17. No reaction occurred, starting materials were recovered.
18. (a) Rychnovsky, S. D.; Salitzky, D. J. Tetrahedron Lett. 1990,