The synthesis of R-3-alkoxy-1-(1′-hydroxyethyl)-4-methoxy-2-(1″-propenyl)benzenes utilizing Corey-Bakshi-Shibata asymmetric reductions

Article abstract of DOI:10.1016/S0040-4020(03)00328-4

Pyrolysis of the 3-O-allyl derivative 7 of isovanillin followed by alkylation of the derived allylphenol 8 afforded a series of benzaldehyde derivatives 9-11 each of which was transformed by initial treatment with methylmagnesium bromide followed by oxida

Full text of DOI:10.1016/S0040-4020(03)00328-4

Tetrahedron 59 (2003) 3175–3182
The synthesis of R-3-alkoxy-1-(10-hydroxyethyl)-4-methoxy-
2-(100-propenyl)benzenes utilizing Corey–Bakshi–Shibata
asymmetric reductions
c
Charles B. de Koning,a Robin G. F. Giles,b Ivan R. Greenc and Nazeem M. Jahed
,
*
aMolecular Sciences Institute, School of Chemistry, University of the Witwatersrand, P.O. Wits 2050, Johannesburg 2050, South Africa
bDepartment of Chemistry, Murdoch University, Murdoch, WA 6150, Australia
cDepartment of Chemistry, University of the Western Cape, Private Bag X17, Bellville 7530, South Africa
Received 27 November 2002; revised 5 February 2003; accepted 28 February 2003
Abstract—Pyrolysis of the 3-O-allyl derivative 7 of isovanillin followed by alkylation of the derived allylphenol 8 afforded a series of
benzaldehyde derivatives 9–11 each of which was transformed by initial treatment with methylmagnesium bromide followed by oxidation of
the corresponding alcohols 0with activated manganese dioxide into a series of ketones 15–17. Palladium(0) catalysed isomerization of the
double bond in the prop-2 -enyl side-chain afforded ketones 36–38 which were subjected to the Corey–Bakshi–Shibata asymmetric
reduction protocol to afford the R-3-alkoxy-1-(10-hydroxyethyl)-4-methoxy-2-(100-propenyl) benzenes 42–44 in yields of approximately 60%
and with ee’s of 75%. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
bond reacted to produce the alcohols 5 and 6, respectively
(Fig. 2).
Methods for the enantioselective reduction of benzylic
carbonyl containing compounds are relatively well
developed. A particularly useful method for achieving
such reductions is by means of the Corey–Bakshi–Shibata
(CBS) reduction.1 This can be done in the presence of
oxazaborolidines e.g. 1 (Fig. 1). However, other methods
such as those developed by Noyori for asymmetric
hydrogenation of ketones with BINAP-ruthenium catalysts
such as 2 are also routinely employed,2 even in industry.3
An argument put forward was that the methoxy group ortho
to the carbonyl substituent of 3 and 4 caused the latter to be
sterically inaccessible to the approach of the hydride from
the well known oxazaborolidine catalyst.9 Alternative
oxazaborolidines derived from a-pinene10,11 were not
favoured due to their larger steric bulk and the low
enantiomeric excess (ee) values of the desired product
alcohols. The bifunctional ligands of Sibi et al.12 were also
unsuccessful due to similar low ee’s of the derived alcohols.
Earlier attempts by us4 to employ the CBS enantioselective
reduction protocol5 – 8 to reduce the ortho allyl aryl
ketones 3 and 4 were unsuccessful since reduction of
the ketone carbonyl group did not occur. Instead the olefin
In two major reviews on enantioselective reductions of
carbonyl groups, it would appear that a,b-enones could be
reduced to the correspondered a,b-enols in good yield and
Figure 1.
Keywords: chiral reductions; benzylic alcohols.
*
Corresponding author. Tel.: þ27-21-959-2262; fax: þ27-21-959-3055;
e-mail: igreen@uwc.ac.za
Figure 2.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00328-4

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C. B. de Koning et al. / Tetrahedron 59 (2003) 3175–3182
Figure 3.
Table 1. Yields of products for the reduction of ketones 15–17
Scheme 1. (i) 1808C/N2. (ii) RBr, K2CO3, DMF, 808C. (iii) MeMgBr, ether
or THF, 258C. (iv) MnO2, benzene, reflux.
Starting material
Product
Yield (%)
Yield (%)
Yield (%)
Yield (%)
with high ee values using borane in conjunction with the
CBS catalyst.1,13 However, no examples resembling our
system or simple examples of ortho allyl aryl ketones were
apparent. Although the reviews indicated that reduction of
moderately sterically crowded carbonyls could tolerate the
above conditions, we decided to reduce the steric environ-
ment of the carbonyl group by moving the ortho-methoxy
group of 1 to the para-position. In addition, the offending
reactive ortho-allyl substituent was converted into the
corresponding styrene. In this paper the enantioselective
CBS reductions on these substrates is described. Prelimi-
nary results have been disclosed in a communication.14
15, R¼Me
16, R¼iPr
17, R¼Bn
18, 5
19, 6
20, 4
21, 7
22, 5
23, 8
24, 26
25, 21
26, 23
27, 21
28, 24
29, 26
the purposes of brevity only the 3,4-dimethoxy analogue 15
will be discussed.
Typically the first product to elute after column chroma-
tography was the saturated ketone 18. A nmax at 1688 cm21
in the IR spectrum supported the presence of the aryl ketone
functional group.17 Support for the propanyl side-chain was
1
clear from the H NMR spectrum by a 3-proton triplet at
0.98 ppm (J¼7.4 Hz), a 2-proton multiplet at 1.55 ppm and
a 2-proton multiplet at 2.99 ppm. Signals at 14.6, 24.6 and
29.8 ppm in the 13C NMR spectrum lent further credence to
the proposed structure.
2. Results and discussion
Pyrolysis of 715 at 1808C for 12 h afforded phenol 8 which
was without isolation immediately treated with 4 mole
equivalents of the appropriate alkyl halide and potassium
carbonate in hot (808C) DMF to afford the ortho-allyl
benzaldehydes 9–11 in yields of 77, 89 and 77%,
respectively.
The next product to elute was assigned the structure 21 and
is based, inter alia, on the following spectral data. A broad
absorption band at 3404 cm21 in the IR spectrum was
assigned to the hydroxyl group. A sharp 3-proton doublet at
1.46 ppm (J¼6.4 Hz) in the 1H NMR spectrum was
assigned to methyl group of the hydroxyethyl group while
the corresponding 1-proton quartet at 5.06 ppm (J¼6.4 Hz)
was assigned to0H-1 of the same side-chain. It is of interest
to note that H-1 of the 3-(20-propenyl) side-chain appeared
as a 2-proton0 ddt at 3.52 ppm (J¼13.0, 5.6, 2.0 Hz) while
the trans H-3 appeared as a ddd at 4.90 ppm (J¼17.0, 2.1,
2.0 Hz) and the cis H-30 appeared as a ddd at 5.03 ppm
(J¼10.2, 2.1, 2.0 Hz).
Each of the benzaldehydes was in turn treated with 1.5 mole
equivalents of freshly prepared methylmagnesium iodide to
produce the racemic alcohols 12–14 in yields of 93, 80, and
89%, respectively. It is interesting to note that when a larger
excess of the Grignard reagent is used the yields are lowered
with a concomitant increase in the production of a
polymeric material. Oxidation of the racemic alcohols
with activated manganese(IV) oxide in boiling benzene16
afforded the corresponding ketones 15–17 in an average
yield of 58% as illustrated in Scheme 1.
Since alcohols 24 and 27 co-eluted, assignments were made
by comparison and quantitative assessments were derived
based on the relative integrations in the 1H NMR spectra. In
order to corroborate the structural assignments to the
alcohols, the mixture was subjected to acetylation18 and
the derived acetates 30 and 33, Figure 4, were separated and
their structural assignments follow from an analysis of their
spectral properties.
All three ketones 15–17 behaved analogously under the
standard conditions of enantioselective reduction using the
CBS catalyst and diborane dimethyl sulphide complex.12,13
Very careful chromatographic separation of the products
of the reaction revealed that apart from minor amounts
of starting material each ketone afforded a similar range of
three different undesired products (Fig. 3 and Table 1). For

C. B. de Koning et al. / Tetrahedron 59 (2003) 3175–3182
3177
NMR spectra since each H and C signal of the dimer could
be identified and appeared as two sets of signals at slightly
different d values. Thus in dimer 39 there are inter alia two
3-proton triplets at 1.04 and 1.08 ppm (J¼7.2 Hz) for H-30
of the propano side-chain, two 3-proton doublets at 1.52 and
1.63 ppm (J¼6.6 Hz) for H-200 of the hydroxyethyl side-
chain, two 1-proton multiplets at 2.43 and 2.62 ppm for H-10
of the propano side-chain and four 3-proton singlets at 3.82,
3.84, 3.85 and 3.86 ppm for the methoxy groups. Interest-
ingly the two hydroxy groups were evident as D2O
exchangeable signals at 4.28 and 4.38 ppm.
Figure 4.
As shown in Table 1 low yields (,7%) of the desired chiral
alcohols 21–23, were obtained and therefore, alternative
routes were investigated in order to enhance the enantio-
selective reduction of the ketone function of 15–17.
The next products to elute were assigned as the desired
chiral alcohols 42–44 (,60%). In the case of 42 a strong
molecular ion at m/z 222 in the mass spectrum supported the
expected molecular formula while in the IR spectrum a
strong band at 3407 cm21 confirmed the hydroxyl function-
ality. The following signals in the 1H NMR spectrum
support the assigned structure viz. a 3-proton doublet
at 1.46 ppm (J¼6.4 Hz) coupled to a 1-proton quartet
at 5.13 ppm (J¼6.4 Hz) supported the presence of the
10-hydroxyethyl side-chain. A 3-proton dd at 1.92 ppm
(J¼6.4, 1.8 Hz) was assigned to the H-300, while a 1-proton
dq at 6.00 ppm (J¼16.0, 6.4 Hz) was assigned to the trans
H-200 and a 1-proton dq at 6.400ppm (J¼16.0, 1.8 Hz) was
assigned to H-100 of the trans 1 -propenyl side-chain.
An analysis of the results in Figure 3 and Table 1 clearly
indicates that the steric demand and possible electrophilic
nature of the carbonyl in question for approach by the
hydride from the oxazaborolidine catalyst is not still
possible. It is suggested that the steric environment and
electronic nature of the carbonyl group would be improved
by moving the allyl double bond. Consequently, ketones
15–17 were treated with palladium dichloride bisaceto-
nitrile19 which cause0d the double bond in the side-chain to
isomerize from the 2 - to the 10-position thereby, producing
ketones 36–38 in yields of 90%. Clear evidence for the
1
trans geometry of the double bond was evident in the H
NMR spectrum in which H-30 appeared as a 3-proton dd at
,1.88 ppm (J¼6.7, 1.8 Hz), H-20 appeared as a 1-proton dq
at ,5.85 ppm (J¼16.0, 6.7 Hz) while H-10 appeared as a
1-proton dq at ,6.70 ppm (J¼16.0, 1.8 Hz), Scheme 2.
Three techniques were used to determine the enantiomeric
excesses of the chiral alcohols 42–44. In the classical
Mosher ester methodology20,21 it was found that the esters
hydrolysed during chromatographic purification. However
by employing the acid chloride methodology22 the Mosher
esters were stable. The methoxy signal of the Mosher ester
moiety was used to determine the ee the R enantiomer being
assigned at d 3.55 while the S enantiomer being assigned at
d 3.48. In the case of 19F NMR spectroscopy23 a 19F probe
was used and the R and S enantiomers were assigned at
80.63 and 80.68 ppm, respectively. Excellent corroboration
was obtained by the use of tris[3-heptafluoro-propylhydro-
methoxy methylene-(þ)-camphorate], Eu(hfc)3 in which
the doublets for H-5 separated and were assigned as follows:
42 (R, 8.11; S, 8.02); 43 (R, 7.41; S, 7.77); and 44 (R, 8.09; S,
8.01), respectively.
Consequently, ketones 36–38 were subjected to the same
enantioselective reduction protocol described earlier and in
all cases two products were isolated. The first product
(,18%), which interestingly had a similar RF to the starting
material, was assigned the dimeric diastereoisomeric
structures 39–41, respectively for the three analogues of
the series. A strong absorption band at 3434 cm21 in the IR
spectrum demonstrated the presence of the hydroxyl groups.
The mass spectra did not show the required molecular ion
but rather evidence of the fragmentation pattern of the
dimer. However, clear evidence for the diastereoisotopic
nature of the molecule was provided by both the 1H and 13
C
Further attempts to increase the enantiomeric excess of the
chiral reductions using catecol–borane as reducing agent24
did not lead to clean products and was not investigated
further. Investigations of the temperature range25 for the
chiral reduction, demonstrated that 258C was in fact the
optimum temperature for the reduction.
In conclusion a method has been established fo0r the
asymmetric reduction of 4-methoxy-3-alkyloxy-2-(1 -pro-
penyl)acetophenones using the CBS oxazaborolidine cata-
lyst to form the corresponding (R)-alcohols in yields of 60%
and with ee values of 75%.
3. Experimental
3.1. General
Scheme 2. (i) PdCl2(CH3CN)2, CH2Cl2, 358C, 72 h, 81–94%;
(ii) BH3(CH3)2S, THF, CBS catalyst, 258C, 30 min, 55–61%, 74–75% ee.
1H and 13C NMR Spectra were recorded using a Varian

3178
C. B. de Koning et al. / Tetrahedron 59 (2003) 3175–3182
200 MHz spectrometer at 208C in deuterochloroform and J
values are given in Hz. Infrared spectra were measured as
Nujol mulls or as thin films on a Perkin–Elmer FT-IR 1000
PC spectrometer. Melting points were recorded on a
Fischer–John apparatus and are uncorrected. C and H
Analyses were performed on a Carlo Erba NA 1500
Nitrogen analyser and GC-MS spectra were recorded on a
Finnigan–Matt GCQ instrument. Column chromatography
was carried out using Merck Kieselgel 60 (70–230 mesh) as
dry columns. Hexane refers to that fraction boiling between
60–758C. The residue obtained upon workup refers to
material obtained from the dried (MgSO4) organic extract
after filtration and solvent removal.
137.3 (£2), 137.5, 140.7, 146.2, 157.8, and 191.2. (Found:
C, 76.7; H, 6.3%; Mþ 282. Calcd for C18H18O3: C, 76.6; H,
6.4%; M 282).
3.1.4. 3,4-Dimethoxy-1-(10-hydroxyethyl)-2-prop-20-
enylbenzene 12. To a freshly prepared solution of methyl
magnesium bromide [from magnesium turnings (730 mg;
30 mmol) and methyl iodide (4.26 g; 30 mmol) in ether
(40 mL)] was added dropwise a solution of aldehyde 9
(4.12 g; 20 mmol) in ether (40 mL) at 208C. After being
stirred an additional 40 min, the solution was treated with
saturated aqueous ammonium chloride to destroy excess
Grignard reagent. The residue obtained upon ether extrac-
tion was chromatographed using EtOAc/hexane (1:4)
initially and later (2:3) as eluent to afford the alcohol 12
(4.4 g; 93%) as a yellow oil. nmax 3404 cm21; dH 1.46 (3H,
d, J¼6.4 Hz, CH(OH)CH3), 1.58 (1H, bs, D2O exchange-
able, OH), 3.52 (2H, ddt, J¼13.0, 5.6, 2.0 Hz, CH2CHvCH2),
3.80 (3H, s, OCH3), 3.86 (3H, s, OCH3), 4.90 (1H, ddd,
J¼17.0, 2.1, 1.9 Hz, trans CH2CHvCH2), 5.03 (1H, ddd,
J¼10.2, 2.1, 1.9 Hz, cis CH2CHvCH2), 5.06 (1H, q,
J¼6.4 Hz, CH3CHOH), 6.00 (1H, m, CH2CHvCH2),
6.86 (1H, d, J¼8.2 Hz, H-5), and 7.24 (1H, d, J¼8.2 Hz,
H-6); dC 24.3, 29.7, 55.7, 60.9, 66.2, 110.8, 115.3, 121.0,
130.7, 137.2, 137.9, 147.1, and 152.1. (Found: C, 70.0; H,
8.1%; Mþ 222. Calcd for C13H18O3: C, 70.2; H, 8.2%; M
222).
3.1.1. 3,4-Dimethoxy-2-prop-20-enylbenzaldehyde 9.
Aldehyde 715 (8.01 g; 41.7 mmol) was pyrolysed at 1808C
(oil bath) under nitrogen for 12 h to afford the corresponding
phenol 8 which without isolation was dissolved in
dimethylformamide (80 mL) and treated with methyl iodide
(23.7 g; 166 mmol) and potassium carbonate (23 g;
166 mmol) and vigorously stirred at 808C for 24 h. The
cooled reaction mixture was filtered and the filtrate was
treated with water (600 mL) and the resulting solution was
extracted with ether (4£150 mL). The residue obtained
upon workup was chromatographed using EtOAc/
hexane (1:4) as eluent to afford the aldehyde 9 (6.64 g;
77%) as a yellow oil. nmax 1686 cm21; dH 3.81 (3H, s,
OCH3), 3.86 (2H, dt, J¼5.8, 1.8 Hz, –CH2CHvCH2),
3.93 (3H, s, OCH3), 4.91 (1H, dq, J¼17.4, 1.8 Hz, trans
–CH2CHvCH2), 5.01 (1H, dq, J¼10.2, 1.8 Hz, cis
–CH2CHvCH2), 6.00 (1H, m, CH2CHvCH2), 6.92 (1H,
d, J¼8.6 Hz, H-5), 7.64 (1H, d, J¼8.6 Hz, H-6), and 10.05
(1H, s, CHO); dC 28.7, 55.8, 61.0, 110.0, 115.8, 128.1,
129.2, 136.3, 137.3, 147.4, 157.7, and 191.1. (Found: C,
69.7; H, 6.6%, Mþ 206. Calcd for C12H14O3: C, 69.9; H,
6.9%; M 206).
3.1.5. 3-Isopropoxy-4-methoxy-1-(10-hydroxyethyl)-2-
prop-20-enylbenzene 13. Conversion of aldehyde 10 by
an analogous protocol described for 12 afforded alcohol 13
(4.01 g; 80%) as a yellow oil. nmax 3396 cm21; dH 1.24 and
1.27 [each 3H, each d, J¼6.2 Hz, CH(CH3)2], 1.44 [3H, d,
J¼6.4 Hz, CH3CH(OH)], 1.75 (1H, bs, D2O exchangeable,
OH), 3.54 (2H, ddt, J¼16.4, 5.8, 1.8 Hz, CH2CHvCH2),
3.82 (3H, s, OCH3), 4.49 [1H, septet, J¼6.2 Hz, CH(CH3)2],
4.95 (1H, ddd, J¼17.2, 1.9, 1.7 Hz, trans CH2CHvCH2],
5.00 (1H, ddd, J¼10.4, 1.9, 1.7 Hz, cis CH2CHvCH2),
5.08 [1H, q, J¼6.4 Hz, CH3CH(OH)], 5.95 (1H, m,
CH2CHvCH2), 6.83 (1H, d, J¼8.6 Hz, H-5), and 7.22
(1H, d, J¼8.6 Hz, H-6); dC 22.6 (£2), 24.3, 30.2, 55.7, 66.1,
74.7, 110.7, 115.1, 120.4, 131.1, 137.3, 137.9, 144.8, and
152.1. (Found: C, 71.8; H, 8.9%; Mþ 250. Calcd for
C15H22O3: C, 71.9; H, 8.9%; M 250).
3.1.2. 3-Isopropoxy-4-methoxy-2-prop-20-enylbenzalde-
hyde 10. Aldehyde 7 was similarly converted using
isopropyl bromide into the corresponding aldehyde 10
(7.20 g; 90%) as a yellow oil. nmax 1686 cm21; dH 1.28 [6H,
d J¼6.2 Hz, CH(CH3)2], 3.88 (2H, dt, J¼5.8, 1.6 Hz,
CH2CHvCH2), 3.90 (3H, s, OCH3), 4.56 (1H, septet, J¼
6.2 Hz, CH(CH3)2), 4.88 (1H, ddd, J¼17.2, 1.7, 1.5 Hz,
trans CH2CHvCH2), 5.02 (1H, ddd, J¼10.2, 1.7, 1.5 Hz,
cis CH2CHvCH2), 6.00 (1H, m, CH2CHvCH2), 6.90 (1H,
d, J¼8.6 Hz, H-5), 7.61 (1H, d, J¼8.6 Hz, H-6), and 10.07
(1H, s, CHO); dC 22.5 (£2), 29.0; 55.7, 75.0, 109.7, 115.7,
128.2 (£2), 136.6, 137.3, 145.1, 157.8 and 191.3. (Found: C,
71.7; H, 7.7%; Mþ 234. Calcd for C14H18O3: C, 71.8; H,
7.8; M 234).
3.1.6. 3-Benzyloxy-4-methoxy-1-(10-hydroxyethyl)-2-
prop-20-enylbenzene 14. Conversion of aldehyde 11 by
an analogous protocol described for 12 afforded alcohol
14 (5.28 g; 89%) as a yellow oil. nmax 3384 cm21; dH 1.46
[3H, d, J¼6.4 Hz, CH3CH(OH)], 1.68 (1H, bs, D2O
exchangeable, OH), 3.51 (2H, ddt, J¼14.2, 5.8, 1.8 Hz,
CH2CHvCH2), 3.88 (3H, s, OCH3), 4.88 (1H, ddd, J¼17.2,
1.9, 1.7 Hz, trans CH2CHvCH2), 4.98 (2H, s, CH2Ph), 5.03
(1H, ddd, J¼10.2, 1.9, 1.7 Hz, cis CH2CHvCH2), 5.06 [1H,
q, J¼6.4 Hz, CH3CH(OH)], 5.97 (1H, m, CH2CHvCH2),
6.91 (1H, d, J¼8.6 Hz, H-5), 7.31 (1H, d, J¼8.6 Hz, H-6),
and 7.40 (5H, m, Ph); dC 24.3, 29.9, 55.8, 66.2, 74.8, 110.9,
115.3, 121.1, 127.9, 128.1 (£2), 128.5 (£2), 131.0, 137.9,
137.3, 138.1, 145.0, and 152.2. (Found: C, 76.3; H, 7.5%;
3.1.3. 3-Benzyloxy-4-methoxy-2-prop-20-enylbenzalde-
hyde 11. Aldehyde 8 was similarly converted using benzyl
bromide into the corresponding aldehyde 11 (9.05 g; 77%)
as a yellow oil. nmax 1686 cm21; dH 3.85 (2H, dt, J¼5.6,
1.8 Hz, CH2CHvCH2), 3.97 (3H, s, OCH3), 4.89 (1H,
ddd, J¼17.6, 1.9, 1.7 Hz, trans CH2CHvCH2), 4.98 (2H,
s, CH2Ph), 5.02 (1H, ddd, J¼10.2, 1.9, 1.7 Hz, cis
CH2CHvCH2), 6.00 (1H, m, CH2CHvCH2), 6.96 (1H,
d, J¼8.6 Hz, H-5), 7.37 (5H, m, Aryl-H), 7.67 (1H, d,
J¼8.6 Hz, H-6), and 10.06 (1H, s, CHO); dC 28.9, 56.0,
75.0, 110.0, 115.9, 128.2 (£2), 128.6 (£2), 129.2, 136.7,
M
þ 298. Calcd for C19H22O3: C, 76.5; H, 7.45%; M 298).
3.1.7. Acetyl-3,4-dimethoxy-2-prop-20-enylbenzene 15.
Alcohol 12 (2.16 g; 9.3 mmol) in benzene (150 mL) was

C. B. de Koning et al. / Tetrahedron 59 (2003) 3175–3182
3179
treated with activated manganese dioxide (21.6 g)15 and the
resulting mixture vigorously stirred and heated under reflux
under nitrogen for 40 min. The warm mixture was filtered
through Celitew and the residue obtained upon workup was
chromatographed using EtOAc/hexane (1:4) as eluent to
yield the ketone 15 (1.22 g; 57%) as a bright yellow oil. nmax
1684 cm21; dH 2.52 (3H, s, CH3CO), 3.76 (2H, dt, J¼6.0,
1.8 Hz, CH2CHvCH2), 3.80 (3H, s, OCH3), 3.91 (3H,
s, OCH3), 4.94 (1H, ddd, J¼17.0, 1.9, 1.7 Hz, trans
CH2CHvCH2), 4.95 (1H, ddd, J¼10.2, 1.9, 1.7 Hz, cis
CH2CHvCH2), 6.00 (1H, m, CH2CHvCH2), 6.80 (1H,
d, J¼8.8 Hz, H-5), and 7.50 (1H, d, J¼8.8 Hz, H-6);
dC 29.6, 30.4, 55.8, 60.9, 109.1, 114.9, 126.8, 131.5,
135.0, 137.8, 148.0, 155.7 and 200.5. (Found: C, 70.9; H,
7.2%; Mþ 220. Calcd for C13H16O3: C, 70.9; H, 7.3%; M
220).
15 (22 mg; 3%) identified by spectral comparison to pure
ketone 15.
3.2.1. 1-Acetyl-3,4-dimethoxy-2-propylbenzene 18. (38 mg;
5%) as an oil. nmax 1688 cm21; dH 0.98 (3H, t, J¼7.4 Hz,
H-30), 1.55 (2H, m, H-20), 2.54 (3H, s, CH3CO), 2.90 (2H,
m, H-10), 3.81 and 3.91 (each 3H, s, OCH3), 6.78 (1H, d,
J¼8.8 Hz, H-5), and 7.48 (1H, d, J¼8.8 Hz, H-6); dC 14.6,
24.6, 28.6, 29.8, 55.8, 60.9, 108.6, 126.8, 131.5, 138.4,
147.8, 155.5, and 200.7. (Found: C, 70.15; H, 8.3%; Mþ
222. Calcd for C13H18O3: C, 70.2; H, 8.2%; M 222).
Alcohol 21 (51 mg; 7%) as an oil. nmax 3404 cm21; dH 1.46
(3H, d, J¼6.3 Hz, CH3CHOH), 1.58 (1H, bs, D2O
exchangeable, OH), 3.52 (2H, ddt, J¼13.0, 5.6, 2.0 Hz,
CH2CHvCH2), 3.80 and 3.86 (each 3H, s, OCH3), 4.90
(1H, ddd, J¼17.0, 2.1, 1.9 Hz, trans CH2CHvCH2), 5.03
(1H, ddd, J¼10.2, 2.1, 1.9 Hz, cis CH2CHvCH2), 5.06 (1H,
q, J¼6.4 Hz, CH2CHOH), 6.00 (1H, m, CH2CHvCH2),
6.86 (1H, d, J¼8.8 Hz, H-5), and 7.24 (1H, d, J¼8.8 Hz,
H-6); dC 24.3, 29.7, 55.7, 60.9, 66.2, 110.8, 115.3, 121.0,
130.7, 137.2, 137.9, 147.1 and 152.1. (Found: C, 70.1; H,
8.2%; Mþ 222. Calcd for C13H18O3: C, 70.2; H, 8.2%; M
222).
3.1.8. Acetyl-3-isopropoxy-4-methoxy-2-prop-20-enyl-
benzene 16. Oxidation of alcohol 13 under the same
conditions as 12 afforded ketone 16 (60%) as a bright yellow
oil. nmax 1688 cm21; dH 1.27 [6H, d, J¼6.4 Hz, CH(CH3)2],
2.51 (3H, s, CH3CO), 3.80 (2H, dt, J¼6.0, 1.8 Hz,
CH2CHvCH2), 3.87 (3H, s, OCH3), 4.50 [1H, septet,
J¼6.4 Hz, CH(CH3)2], 4.93 (1H, ddd, J¼17.0, 1.9, 1.7 Hz,
trans CH2CHvCH2), 4.95 (1H, ddd, J¼10.2, 1.9, 1.7 Hz,
cis CH2CHvCH2), 5.91 (1H, m, CH2CHvCH2), 6.78
(1H, d, J¼8.8 Hz, H-5), and 7.44 (1H, J¼8.8 Hz, H-6); dC
22.6 (£2), 29.7, 30.6, 55.7, 75.0, 108.8, 114.9, 126.0,
131.9, 135.2, 137.6, 145.6, 155.7, and 201.0. (Found: C,
72.4; H, 8.2%; Mþ 248. Calcd for C15H20O3: C, 72.5; H,
8.1%; M 248).
3.2.2. 1-Acetyl-2-(30-hydroxypropyl)-3,4-dimethoxyben-
zene 24. (205 mg; 26%) as an oil. nmax 3348 and
1680 cm21; dH 1.81 (2H, m, H-20), 2.56 (3H, s, CH3CO),
3.03 (2H, t, J¼6.2 Hz, H-10), 3.54 (2H, t, J¼6.0 Hz, H-30),
3.83 and 3.92 (each 3H, s, OCH3), 6.82 (1H, d, J¼8.8 Hz,
H-5), and 7.50 (1H, d, J¼8.8 Hz, H-6).
3.1.9. Acetyl-3-benzyloxy-4-methoxy-2-prop-20-enylben-
zene 17. Oxidation of alcohol 14 under the same conditions
as 12 afforded ketone 17 (58%) as a bright yellow oil. nmax
1684 cm21; dH 2.54 (3H, s, CH3CO), 3.78 (2H, dt, J¼5.8,
1.8 Hz, CH2CHvCH2), 3.93 (3H, s, OCH3), 4.93 (1H, ddd,
J¼18.6, 1.9, 1.7 Hz, trans CH2CHvCH2), 4.95 (1H, ddd,
J¼10.1, 1.9, 1.7 Hz, cis CH2CHvCH2), 4.96 (2H, s,
CH2Ph), 5.98 (1H, m, CH2CHvCH2), 6.85 (1H, d, J¼
8.6 Hz, H-5), 7.41 (5H, m, Ph), and 7.53 (1H, d, J¼8.6 Hz,
H-6); dC 29.6, 30.6, 55.8, 78.4, 109.1, 115.0, 127.0, 128.1
(£3), 128.6 (£2), 131.7, 137.8, 135.3, 146.8, 147.1, 155.8,
and 200.6. (Found: C, 76.9; H, 6.65%; Mþ 296. Calcd for
C19H22O3: C, 77.0; H, 6.8%; M 296).
3.2.3. 1-(10-Hydroxyethyl)-2-(300-hydroxypropyl)-3,4-di-
methoxybenzene 27. (167 mg; 21%) an an oil. nmax
3350 cm21; dH 1.49 (3H, d, J¼6.4 Hz, CH3CHOH), 1.81
(2H, m, H-200), 2.82 (2H, m, H-100), 3.54 (2H, t, J¼6.1 Hz,
H-300), 3.83 and 3.92 (each 3H, s, OCH3), 5.10 (1H, q,
J¼6.4 Hz, CH3CHOH), 6.80 (1H, d, J¼8.8 Hz, H-5), and
7.24 (1H, d, J¼8.8 Hz, H-6).
The mixture of alcohols 24 and 27 was acetylated18 and the
acetates were purified by chromatographic separation using
EtOAc/hexane (1:4) as eluent to yield 2-(30-acetoxypropyl)-
1-acetyl-3,4-dimethoxybenzene 30 (217 mg; 90%) as an oil.
n
max 1742 and 1688 cm21; dH 1.86 (2H, m, H-20), 2.06 (3H,
s, CH3COO), 2.54 (3H, s, CH3CO), 3.00 (2H, m, H-10), 3.81
and 3.91 (each 3H, s, OCH3), 4.13 (2H, t, J¼8.6 Hz, H-30),
6.80 (1H, d, J¼8.6 Hz, H-5), and 7.53 (1H, d, J¼8.6 Hz,
H-6); dC 21.0, 23.3, 29.6, 29.8, 55.8, 60.8, 64.8, 108.9,
127.2, 131.1, 137.3, 147.9, 155.7, 171.5, and 200.5. (Found:
64.1; H, 7.1%; Mþ 280. Calcd for C15H20O5: C, 64.3; H,
7.2%, M 280). Further elution afforded 1-(10-acetoxyethyl)-
2-(300-acetoxypropyl)-3,4-dimethoxy-benzene 33 (192 mg;
85%) as an oil. nmax 1752 cm21; 1.51 (3H, d, J¼6.6 Hz,
CH3CHOAc), 1.75 (2H, m, H-200), 2.04 and 2.08 (each
3H, s, CH3COO), 2.75 (2H, m, H-100), 3.82 and 3.85 (each
3H, s, OCH3), 4.13 (2H, t, J¼6.4 Hz, H-300), 6.02 (1H, q,
J¼6.6 Hz, CH3CHOAc), 6.82 (1H, d, J¼8.6 Hz, H-5),
and 7.15 (1H, d, J¼8.6 Hz, H-6); dC 21.0, 21.4, 22.2, 22.7,
29.7, 55.7, 60.7, 64.4, 68.9, 110.6, 121.8, 132.9, 133.3,
147.1, 152.3, 170.5, and 171.5. (Found: C, 62.9; H, 7.4%;
(Mþ-60) 264. Calcd for C17H24O6: C, 63.0; H, 7.4%; M
324).
3.2. The Corey–Bakshi–Shibata (CBS) reduction of
acetyl-3,4-dimethoxy-2-prop-20-enylbenzene 15
To an oven dried 3-necked flask was introduced the CBS
catalyst6 (0.1 mL, 0.05 mmol) under nitrogen at 258C
followed by the dropwise addition of borane/dimethyl
sulphide complex in THF (0.33 mL, 0.33 mmol) and stirring
was continued for 5 min. Ketone 15 (3.31 mmol) in THF
(2.0 mL) was then introduced by syringe through one neck
while additional borane/dimethyl sulphide complex in THF
(1.99 mL; 1.99 mmol) was dripped in simultaneously by
syringe through the other neck over a period of 10 min.
After stirring for an additional 30 min, methanol (1.0 mL)
was added and after stirring for 10 min more, the reaction
mixture was extracted with dichloromethane and the residue
was chromatographed using EtOAc/hexane (1:4) as eluent
to yield the following products in order of elution. Ketone

3180
C. B. de Koning et al. / Tetrahedron 59 (2003) 3175–3182
3.3. The CBS reduction of acetyl-3-isopropoxy-4-
methoxy-2-prop-20-enylbenzene 16
C, 66.3; H, 7.8%; Mþ 308. Calcd for C17H24O5: C, 66.2;
H, 7.9%; M 308). Next to elute from the column was 1-(10-
acetoxyethyl)-2-(300-acetoxypropyl)-3-isopropoxy-4-meth-
By an analogous procedure described above ketone 16
(850 mg; 3.43 mmol) was reduced to give:
oxybenzene 34. (247 mg; 85%) as an oil. nmax 1766 cm21
;
dH 1.27 [6H, d, J¼6.2 Hz, CH(CH3)2], 1.51 (3H, d, J¼
6.6 Hz, CH3CHOAc), 1.86 (2H, m, H-200), 2.05 and 2.08
(each 3H, s, CH3COO), 2.80 (2H, t, J¼6.4 Hz, H-100), 3.82
(3H, s, OCH3), 4.12 (2H, t, J¼6.4 Hz, H-300), 4.52 [1H,
septet, J¼6.2 Hz, CH(CH3)2], 6.08 (1H, q, J¼6.6 Hz,
CH3CHOAc), 6.80 (1H, d, J¼8.6 Hz, H-5), and 7.12 (1H,
d, J¼8.6 Hz, H-6); dC 21.1, 21.5 (£2), 22.3, 22.8, 23.3, 29.3,
55.7, 64.6, 69.1, 74.5, 110.4, 121.2, 132.8, 133.8, 144.8,
152.2, 170.4 and 171.4. (Found: C, 64.6; H, 8.1%; Mþ 352.
Calcd for C19H28O6: C, 64.7; H, 8.0%; M 352).
Ketone 16 (51 mg; 6%) by comparison of spectra.
3.3.1. 1-Acetyl-3-isopropoxy-2-propyl-4-methoxyben-
zene 19. (51 mg; 6%) as an oil. nmax 1686 cm21; dH 0.93
(3H, t, J¼7.4 Hz, H-30), 1.26 [6H, d, J¼6.0 Hz, CH(CH3)2],
1.52 (2H, m, H-20), 2.52 (3H, s, CH3CO), 2.92 (2H, m,
H-10), 3.85 (3H, s, OCH3), 4.46 [1H, septet, J¼6.0 Hz,
CH(CH3)2], 6.71 (1H, d, J¼8.6 Hz, H-5), and 7.42 (1H, d,
J¼8.6 Hz, H-6); dC 12.6, 20.6 (£2), 22.1, 27.0, 27.8, 53.6,
72.9, 106.3, 124.2, 129.7, 136.8, 143.5, 153.6 and 199.1.
(Found: C, 71.8; H, 8.8%; Mþ 250. Calcd for C15H22O3: C,
71.95; H, 8.9%; M 250).
3.4. The CBS reduction of acetyl-3-benzyloxy-4-
methoxy-2-prop-20-enylenzene 17
By an analogous procedure describe above ketone 17
(980 mg; 3.31 mmol) was reduced to give:
3.3.2. 3-Isopropoxy-4-methoxy-1-(10-hydroxyethyl)-2-
prop-200-enylbenzene 22. (43 mg; 5%) as an oil. nmax
3396 cm21; dH 1.24 and 1.27 [each 3H, d, J¼6.2 Hz,
CH(CH3)2], 1.44 (3H, d, J¼6.4 Hz, CH3CHOH), 1.75 (1H,
bs, D2O exchangeable, OH), 3.54 (2H, ddt, J¼16.4, 5.8,
1.8 Hz, CH2CHvCH2), 3.82 (3H, s, OCH3), 4.49 [1H,
septet, J¼6.2 Hz, CH(CH3)2], 4.95 (1H, ddd, J¼17.2, 1.9,
1.7 Hz, trans CH2CHvCH2), 5.00 (1H, ddd, J¼10.4,
1.9, 1.7 Hz, cis CH2CHvCH2), 5.08 (1H, q, J¼6.4 Hz,
CH3CHOH), 5.95 (1H, m, CH2CHvCH2), 6.83 (1H, d,
J¼8.6 Hz, H-5), and 7.22 (1H, d, J¼8.6 Hz, H-6); dC
22.6 (£2), 24.3, 30.2, 55.7, 66.1, 74.7, 110.7, 115.1, 120.4,
131.1, 137.3, 137.9, 144.8, and 152.1. (Found: C, 71.8; H,
8.9%; Mþ 250. Calcd for C15H22O3: C, 71.95; H, 8.9%; M
250).
Ketone 17 (39 mg; 4%) identified by spectral comparisons.
3.4.1. 1-Acetyl-3-benzyloxy-2-propyl-4-methoxybenzene
20. (39 mg; 4%) as an oil. nmax 1677 cm21; dH 0.95 (3H, t,
J¼7.4 Hz, H-30), 1.54 (2H, m, H-20), 2.56 (3H, s, CH3CO),
2.92 (2H, t, J¼8.8 Hz, H-10), 3.93 (3H, s, OCH3), 4.98
(2H, s, OCH2Ph), 6.81 (1H, d, J¼8.6 Hz, H-5), 7.41 (5H, m,
aryl-H) and 7.49 (1H, d, J¼8.6 Hz, H-6); dC 14.5, 24.5,
28.9, 29.7, 55.7, 74.8, 108.6, 127.0, 127.9 (£3), 128.2 (£2),
130.9, 131.4, 138.6, 146.7, 155.6 and 200.6. (Found: C,
76.4; H, 7.55%; Mþ 298. Calcd for C19H22O3: C, 76.5; H,
7.45%; M 298).
3.4.2. 3-Benzyloxy-4-methoxy-1-(10-hydroxyethyl)-2-
prop-200-enylbenzene 23. (79 mg; 8%) as an oil. nmax
3384 cm21; dH 1.46 (3H, d, J¼6.4 Hz, CH3CHOH), 1.68
(1H, bs, D2O exchangeable, OH), 3.51 (2H, ddt, J¼14.2,
5.8, 1.8 Hz, CH2CHvCH2), 3.88 (3H, s, OCH3), 4.88 (1H,
ddd, J¼17.2, 1.9, 1.7 Hz, trans CH2CHvCH2), 4.98 (2H,
s, CH2Ph), 5.03 (1H, ddd, J¼10.2, 1.9, 1.7 Hz, cis
CH2CHvCH2), 5.06 (1H, q, J¼6.4 Hz, CH3CHOH), 5.97
(1H, m, CH2CHvCH2), 6.91 (1H, d, J¼8.6 Hz, H-5), 7.31
(1H, d, J¼8.6 Hz, H-6), and 7.40 (5H, m, aryl-H); dC 24.3,
29.9, 55.8, 66.2, 74.8, 110.9, 115.3, 121.1, 127.9, 128.1
(£2), 128.5 (£2), 131.0, 137.3, 137.9, 138.1, 145.0 and
152.2. (Found: C, 76.3; H, 7.5%; Mþ 298. Calcd for
C19H22O3: C, 76.5; H, 7.45%; M 298).
3.3.3. 1-Acetyl-2-(30-hydroxypropyl)-3-isopropoxy-4-
methoxybenzene 25. (163 mg; 21%) as an oil. nmax 3346
and 1682 cm21; dH 1.28 [6H, d, J¼6.2 Hz, CH(CH3)2], 1.83
(2H, m, H-20), 2.56 (3H, s, CH3CO), 3.10 (2H, t, J¼6.2 Hz,
H-10), 3.46 (2H, t, J¼6.2 Hz, H-30), 3.89 (3H, s, OCH3), 4.50
[1H, septet, J¼6.2 Hz, CH(CH3)2], 6.80 (1H, d, J¼8.6 Hz,
H-5), and 7.54 (1H, d, J¼8.6 Hz, H-6).
3.3.4. 1-(10-Hydroxyethyl)-2-(300-hydroxypropyl)-3-iso-
propoxy-4-methoxybenzene 28. (188 mg; 24%) as an oil.
nmax 3345 cm21; dH 1.25 [6H, d, J¼6.2 Hz, CH(CH3)2],
1.45 (3H, d, J¼6.4 Hz, CH3CHOH), 1.75 (2H, m, H-200),
2.83 (2H, t, J¼6.2 Hz, H-100), 3.43 (2H, t, J¼6.0 Hz, H-300),
3.81 (3H, s, OCH3), 4.50 [1H, septet, J¼6.2 Hz, CH(CH3)2],
6.79 (1H, d, J¼8.6 Hz, H-5), and 7.21 (1H, d, J¼8.6 Hz,
H-6).
3.4.3. 1-Acetyl-2-(30-hydroxypropyl)-3-benzyloxy-4-
methoxybenzene 26. (239 mg; 23%) as an oil. dH 1.83
(2H, m, H-20), 2.57 (3H, s, CH3CO), 3.03 (2H, t, J¼6.0 Hz,
H-10), 3.48 (2H, t, J¼6.0 Hz, H-30), 3.95 (3H, s, OCH3), 4.98
(2H, s, CH2Ph), 6.85 (1H, d, J¼8.6 Hz, H-5), 7.39 (5H, m,
aryl-H), and 7.55 (1H, d, J¼8.6 Hz, H-6).
3.4.4. 1-(10-Hydroxyethyl)-2-(300-hydroxypropyl)-3-ben-
zyloxy-4-methoxybenzene 29. (272 mg; 26%) as an oil.
dH 1.49 (3H, d, J¼6.4 Hz, CH3CHOH), 1.81 (2H, m, H-200),
2.79 (2H, t, J¼6.0 Hz, H-100), 3.47 (2H, t, J¼6.0 Hz, H-300),
3.89 (3H, s, OCH3), 4.98 (2H, s, CH2Ph), 5.10 (1H, d,
J¼6.4 Hz, CHCHOH), 6.87 (1H, d, J¼8.8 Hz, H-5), 7.28
(1H, d, J¼8.8 Hz, H-6), and 7.41 (5H, m, aryl-H).
The above mixture of alcohols 25 and 28 (351 mg) was
acetylated and the acetates were purified as described earlier
to yield 2-(30-acetoxypropyl)-1-acetyl-3-isopropoxy-4-
methoxy-benzene 31 (188 mg; 85%) as an oil. nmax 1734
and 1688 cm21; dH 1.27 [6H, d, J¼6.2 Hz, CH(CH3)2], 1.89
(2H, m, H-20), 2.06 (3H, s, CH3COO), 2.55 (3H, s, CH3CO),
3.08 (2H, t, J¼8.5 Hz, H-10), 3.88 (3H, s, OCH3), 4.10 (2H,
t, H-30), 4.56 [1H, septet, J¼6.2 Hz, CH(CH3)2), 6.77 (1H,
d, J¼8.8 Hz, 5-H), and 7.49 (1H, d, J¼8.8 Hz, H-6); dC
21.2, 22.7 (£2), 23.8, 29.5, 29.7, 55.7, 64.9, 74.8, 108.7,
126.5, 131.2, 137.6, 145.5, 155.6, 171.4 and 200.3. (Found:

C. B. de Koning et al. / Tetrahedron 59 (2003) 3175–3182
3181
The mixture of alcohols 26 and 29 (511 mg) was acetyl-
ated to yield the pure acetates as described earlier. 2-(30-
Acetoxypropyl)-1-acetyl-3-benzyloxy-4-methoxybenzene
32 (238 mg; 88%) as an oil. nmax 1750 and 1684 cm21; dH
1.89 (2H, m, H-20), 1.96 (3H, s, CH3COO), 2.55 (3H, s,
CH3CO), 3.08 (2H, t, J¼7.8 Hz, H-10), 3.93 (3H, s, OCH3),
4.08 (2H, t, J¼6.6 Hz, H-30), 4.97 (2H, s, CH2Ph), 6.84 (1H,
d, J¼8.6 Hz, H-5), 7.39 (5H, m, aryl-H), and 7.56 (1H, d,
J¼8.6 Hz, H-6); dC 20.9, 23.6, 29.5, 29.7, 55.8, 64.7, 74.6,
108.9, 127.4, 128.0 (£3), 128.5 (£2), 131.1, 135.7, 137.7,
146.7, 155.7, 171.4 and 200.1. (Found: C, 70.7; H, 6.7%;
Mþ-60¼296. Calcd for C21H24O5: C, 70.8; H, 6.8%; M 356).
3.4.5. 1-(10-Acetoxyethyl)-2-(300-acetoxypropyl)-3-benzyl-
oxy-4-methoxybenzene 35. (294 mg; 85%) as an oil. nmax
1734cm21; dH 1.52 (3H, d, J¼6.6 Hz, CH3CHOAc), 1.86
(2H, m, H-200), 2.00 and 2.06 (each 3H, s, CH3COO), 2.75
(2H, t, J¼7.0 Hz, H-100), 3.88 (3H, s, OCH3), 4.06 (2H, t,
J¼7.0 Hz, H-300), 5.01 (2H, s, CH2Ph), 6.08 (1H, q, J¼
6.6 Hz, CH3CHOAc), 6.85 (1H, d, J¼8.6 Hz, H-5), 7.11
(1H, d, J¼8.6 Hz, H-6), and 7.39 (5H, m, aryl-H); dC 20.9,
21.4, 22.1, 23.0, 29.6, 55.7, 64.3, 68.9, 74.7, 110.6, 121.9,
127.9 (£3), 128.5 (£2), 132.9, 133.5, 138.1, 145.0, 152.4,
170.4, and 171.4. (Found: C, 79.5; H, 7.8%; Mþ-60¼340.
Calcd for C23H28O6: C, 79.5; H, 7.9%; M 400).
(£3), 128.5 (£2), 133.0, 133.5, 133.8, 137.5, 145.3, 155.1,
and 203.3. (Found: C, 76.8; H, 6.9%; Mþ 296. Calcd for
C19H22O3: C, 77.00; H, 6.8%; M 296).
3.4.9. (R)-3,4-Dimethoxy-1-(10-hydroxyethyl)-2-prop-100-
enylbenzene 42. The residue obtained from the CBS-
catalysed enantiomeric reduction of ketone 36 (1.00 g;
4.55 mmol) as described earlier was chromatographed using
EtOAc/hexane (1:4) as eluent to yield firstly the dimeric
diastereoisomer 39 (365 mg; 18%) as a viscous oil. nmax
3434 cm21; dH 1.04 and 1.08 (each 3H, t, J¼7.2 Hz, H-30),
1.52 and 1.63 [each 3H, d, J¼6.6 Hz, CH3CH(OH)], 1.82
(4H, m, H-20), 2.43 and 2.62 (each 1H, m, H-10), 3.82, 3.84,
3.85, and 3.86 (each 3H, s, OCH3), 4.28 and 4.38 (each 1H,
bs, D2O exchangeable, OH), 5.20 [2H, q, J¼6.6 Hz,
CH(OH)CH3], 6.75 (3H, m, 2£H-5 and H-6) and 6.93
(1H, d, J¼8.8 Hz, H-6); dC 14.1, 14.3, 22.5, 23.8, 27.3, 27.6,
55.6, 55.7, 60.5, 60.7, 70.1 (£2), 73.9 (£2), 109.3, 110.2,
119.3, 120.4, 133.1, 133.4, 133.6, 134.8, 146.8, 147.4, 154.4
and 155.0. (Found: C, 70.0; H, 8.6%. Calcd for C26H38O6:
C, 69.9; H, 8.6%). Further elution afforded the R-alcohol 42
(590 mg; 59%) as an oil. nmax 3407 cm21; dH 1.46 (3H, d,
J¼6.4 Hz, CH3CHOH), 1.64 (1H, bs, D2O exchangeable,
OH), 1.92 (3H, dd, J¼6.4, 1.8 Hz, H-300), 3.72 and 3.86
(each 3H, s, OCH3), 5.13 (1H, q, J¼6.4 Hz, CH3CHOH),
6.00 (1H, dq, J¼16.0, 6.4 Hz, H-200), 6.42 (1H, dq, J¼16.0,
1.8 Hz, H-100), 6.82 (1H, d, J¼8.6 Hz, H-5), and 7.26 (1H, d,
J¼8.6 Hz, H-6); dC 19.4, 24.4, 55.9, 60.2, 66.4, 111.0,
120.7, 123.5, 131.2, 132.3, 136.7, 146.5, and 151.5. [a]D¼
þ32.28 (c¼0.785, CH2Cl2); ee via Mosher ester 75% and
via Eu(hfc)3 reagent 75%. (Found: C, 70.2; H, 8.1%; Mþ
222. Calcd for C13H18O3: C, 70.2; H, 8.2%; M 222).
3.4.6. Acetyl-3,4-dimethoxy-2-prop-10-enylbenzene 36.
Acetyl-3,4-dimethoxy-2-prop-20-enylbenzene 15 (1.00 g;
4.45 mmol) in dichloromethane (50 mL) was treated with
palladium dichloride bis-acetonitrile (100 mg) and the
mixture stirred under gentle reflux for 72 h. Flash
chromatography using EtOAc/hexane (1:9) as eluent
afforded the conjugated product 36 (940 mg; 94%) as a
yellow oil. nmax 1684 cm21; dH 1.90 (3H, dd, J¼6.6, 1.8 Hz,
H-30), 2.41 (3H, s, CH3CO), 3.75 and 3.89 (each 3H, s,
OCH3), 5.85 (1H, dq, J¼16.0, 6.6 Hz, H-20), 6.73 (1H, dq,
J¼16.0, 1.8 Hz, H-10), 6.82 (1H, d, J¼8.6 Hz, H-5), and
7.25 (1H, d, J¼8.6 Hz, H-6); dC 19.3, 30.6, 55.9, 60.3,
110.0, 124.7, 124.8, 132.4, 133.4, 133.8, 146.5, 154.9, and
203.4. (Found: C, 70.8; H, 7.4%; Mþ 220. Calcd for
C13H16O3: C, 70.9; H, 7.3%; M 220).
3.4.10. (R)-3-Isopropoxy-4-methoxy-1-(10-hydroxy-
ethyl)-2-prop-100-enylbenzene 43. The residue obtained
from the CBS-catalysed enantiomeric reduction of ketone
37 (1.01 g; 4.07 mmol) as described earlier was chromato-
graphed using EtOAc/hexane (1:4) as eluent to yield firstly
the dimeric diastereoisomer 40 (415 mg; 20%) as a viscous
oil. nmax 3428 cm21; dH 0.97 and 1.04 (each 3H, t, J¼
7.2 Hz, H-30), 1.20 and 1.37 [each 6H, d, J¼6.4 Hz,
CH(CH3)2], 1.51 and 1.63 (each 3H, d, J¼6.8 Hz,
CH3CHOH), 1.80 (4H, m, H-20), 2.52 and 2.70 (each 1H,
m, H-10), 3.82 and 3.83 (each 3H, s, OCH3), 4.30 and 4.39
(each 1H, bs, D2O exchangeable, OH), 4.52 [2H, m,
CH(CH3)2], 5.20 (2H, q, J¼6.8 Hz, CH3CHOH), 6.73 (3H,
m, 2£H-5 and H-6), and 6.88 (1H, d, J¼8.8 Hz, H-6); dC
14.0, 14.4, 21.1, 22.2, 22.3, 22.9, 23.0, 23.3, 26.7, 27.8,
55.5, 55.6, 70.2 (£2), 74.0 (£2), 74.1, 74.4, 109.0, 110.0,
118.7, 119.8, 133.1, 133.5, 133.6, 135.4, 144.6, 145.1,
151.4, and 152.1. (Found: C, 71.5, H, 9.2%. Calcd for
C30H46O6: C, 71.7; H, 9.2%). Further elution afforded the
(R)-alcohol 43 (590 mg; 58%) as a pale yellow oil. nmax
3400 cm21; dH 1.22 [6H, d, J¼6.2 Hz, CH(CH3)2], 1.45
(3H, d, J¼6.2 Hz, CH3CHOH), 1.66 (1H, bs, D2O
exchangeable, OH), 1.91 (3H, dd, J¼6.4, 1.6 Hz, H-300),
3.82 (3H, s, OCH3), 4.29 (1H, septet, J¼6.2 Hz, CH(CH3)2],
5.13 (1H, q, J¼6.4 Hz, CH3CHOH), 5.98 (1H, dq, J¼16.0,
6.4 Hz, H-200), 6.41 (1H, dq, J¼16.0, 1.6 Hz, H-100), 6.82
(1H, d, J¼8.6 Hz, H-5), and 7.26 (1H, d, J¼8.6 Hz, H-6); dC
19.2, 22.6 (£2), 24.0, 55.2, 66.5, 75.4, 110.8, 120.2, 124.5,
132.0, 132.2, 136.5, 144.6, and 152.5. [a]D¼þ28.38
(c¼0.755 in CH2Cl2); ee via Mosher ester and Eu(hfc)3
3.4.7. Acetyl-3-isopropoxy-4-methoxy-2-prop-10-enyl-
benzene 37. By an analogous protocol alkene 16 (1.22 g;
4.0 mmol) was isomerised to alkene 37 (989 mg; 81%) as a
yellow oil. nmax 1694 cm21; dH 1.23 [6H, 0 d, J¼6.2 Hz,
CH(CH3)2], 1.88 (3H, dd, J¼6.6, 1.8 Hz, H-3 ), 2.34 (3H, s,
CH3CO), 3.86 (3H, s, OCH3), 4.38 (1H, septet, J¼6.2 Hz,
CH(CH3)2], 5.82 (1H, q, J¼8.8 Hz, H-5), and 7.18 (1H, d,
J¼8.8 Hz, H-6); dC 19.2, 22.6 (£2), 30.7, 55.9, 75.5, 110.0,
124.3, 125.7, 125.9, 128.8, 133.1, 144.6, 155.9, and 203.9.
(Found: C, 72.4; H, 8.2%; Mþ 248. Calcd for C15H20O3: C,
72.5; H, 8.1%; M 248).
3.4.8. Acetyl-3-benzyloxy-4-methoxy-2-prop-10-enylben-
zene 38. Alkene 17 (1.33 g; 4.55 mmol) was isomerised by
an analogous protocol to alkene 38 (1.16 g; 87%) as a
yellow oil. nmax 1684 cm21; dH 1.84 (3H, dd, J¼6.6 Hz,
1.8 Hz, H-30), 2.40 (3H, s, CH3CO), 3.90 (3H, s, OCH3),
4.89 (2H, s, CH2Ph), 5.82 (1H, dq, J¼16.0, 6.6 Hz, H-20),
6.63 (1H, dq, J¼16.0, 1.8 Hz, H-10), 6.84 (1H, d, J¼8.6 Hz,
H-5), 7.28 (1H, d, J¼8.6 Hz, H-6), and 7.37 (5H, m, aryl-
H); dC 19.2, 30.6, 56.0, 74.0, 110.1, 125.1, 128.1, 128.4

3182
C. B. de Koning et al. / Tetrahedron 59 (2003) 3175–3182
was 75%. (Found: C, 71.9; H, 8.9%; Mþ 250. Calcd for
C15H22O3: C, 71.95; H, 8.9%; M 250).
2. (a) Noyori, R.; Ohkuma, T. Angew. Chem. Int. Ed. 2001, 40,
40. (b) Noyori, R.; Yamakawa, M.; Hashiguchi, S. J. Org.
Chem. 2001, 66, 7931.
3.4.11. (R)-3-Benzyloxy-4-methoxy-1-(10-hydroxyethyl)-
2-prop-100-enylbenzene 44. The residue obtained by the
CBS-catalysed enantiomeric reduction of ketone 38
(980 mg; 3.31 mmol) as described earlier was chromato-
graphed using EtOAc/hexane (1:4) as eluent to yield firstly
the dimeric diastereoisomer 41 (370 mg; 19%) as a viscous
oil. nmax 3407 cm21; dH 0.97 and 1.02 (each 3H, t, J¼
7.4 Hz, H-30), 1.53 and 1.64 (each 3H, d, J¼6.6 Hz,
CH3CHOH), 1.62 (4H, m, H-20), 2.44 and 2.60 (each 1H,
m, H-10), 3.88 and 3.89 (each 3H, s, OCH3), 4.38 and 4.40
(each 1H, bs, D2O exchangeable, OH), 5.10 (6H, m,
CH3CHOH and CH2Ph), 6.80 (3H, m, 2£H-5 and H-6), 6.95
(1H, d, J¼8.8 Hz, H-6), and 7.40 (10H, m, aryl-H); dC 14.1,
14.4, 21.5, 24.0, 27.4, 28.0, 55.9, 56.0, 70.1 (£2), 74.0, 74.6,
74.8 (£2), 109.5, 110.4, 119.6, 120.7, 127.8 (£4), 128.5
(£4), 128.6 (£2), 133.5, 133.7 (£2), 133.9, 135.2, 138.2,
145.9, 146.5, 151.6, and 152.2. (Found: C, 76.1; H, 7.7%.
Calcd for C38 H46O6: C, 76.2; H, 7.8%). Further elution
afforded the (R)-alcohol 44 (610 mg; 62%) as a pale yellow
oil. nmax 3396 cm21; dH 1.46 (3H, d, J¼6.2 Hz, CH3CHOH,
1.70 (1H, bs, D2O exchangeable, OH), 1.89 (3H, dd, J¼6.5,
1.8 Hz, H-300), 3.87 (3H, s, OCH3), 4.88 (2H, s, CH2Ph),
5.11 (1H, q, J¼6.2 Hz, CH3CHOH), 5.97 (1H, dq, J¼16.0,
6.5 Hz, H-200), 6.39 (1H, dq, J¼16.0, 1.8 Hz, H-100), 6.87
(1H, d, J¼8.4 Hz, H-5), 7.31 (1H, d, J¼8.4 Hz, H-6), and
7.38 (5H, m, aryl-H); dC 19.2, 24.4, 56.0, 66.5, 74.6, 111.1,
120.8, 123.7, 128.3 (£3), 128.4 (£2), 131.1, 132.4, 136.7,
138.0, 145.5, and 152.1. [a]D¼þ21.98 (c¼0.755, CH2Cl2);
ee via Mosher ester and Eu(hfc)3 was 75%. (Found: C, 76.5;
H, 7.4%; Mþ 298. Calcd for C19H22O3: C, 76.5; H, 7.45%;
M 298).
3. Kumobayashi, H.; Miura, T.; Sayo, N.; Saito, T.; Zhang, X.
Synlett 2001, 1055.
4. Giles, R. G. F.; Green, I. R. Synth. Commun. 1996, 26, 3161.
5. Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc.
1987, 109, 5551.
6. Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, J.-P.; Singh,
V. K. J. Am. Chem. Soc. 1987, 109, 7925.
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10. Masui, M.; Shiori, T. Tetrahedron 1995, 51, 8363.
11. Masui, M.; Shiori, T. Synlett 1996, 49.
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13. Sing, V. K. Synthesis 1992, 605.
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Acknowledgements
This work was supported by the National Research
Foundation, and the Universities of the Western Cape and
Witwatersrand.
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