The synthesis of isochroman-4-ols and isochroman-3-ols: Models for naturally occurring benzo[g]isochromanols

Article abstract of DOI:10.1016/S0040-4020(01)00963-2

The synthesis of isochromanes containing hydroxy substituents at the 4- and 3-positions has been achieved. The key step for the synthesis of the isochroman-4-ols entailed an oxidative mercury mediated ring closure of 2-(prop-1-enyl)phenylmethanol derivati

Full text of DOI:10.1016/S0040-4020(01)00963-2

TETRAHEDRON
Pergamon
Tetrahedron 57 02001) 9623±9634
The synthesis of isochroman-4-ols and isochroman-3-ols:
models for naturally occurring benzo[g]isochromanols
a,p
Charles B. de Koning, Ivan R. Green, Joseph P. Michael and Jose R. Oliveira
b
a
a
Â
aMolecular Sciences Institute, School of Chemistry, University of the Witwatersrand, P.O. Wits 2050, South Africa
bDepartment of Chemistry, University of the Western Cape, Bellville 7535, South Africa
Received 8 June 2001; revised 21 August 2001; accepted 13 September 2001
AbstractÐThe synthesis of isochromanes containing hydroxy substituents at the 4- and 3-positions has been achieved. The key step for the
synthesis of the isochroman-4-ols entailed an oxidative mercury mediated ring closure of 2-0prop-1-enyl)phenylmethanol derivatives, while
in the synthesis of the isochroman-3-ols the key step involved ozonolysis of 2-0prop-2-enyl)phenylmethanol derivatives. q 2001 Elsevier
Science Ltd. All rights reserved.
1. Introduction
C-3 also show biological activity, and it is probable that
this results from them functioning as bioreductive alkylating
agents. Compounds that fall into this class include fusarubin
45 and marticin 56 0Fig. 1).
Moore1 has postulated that many quinones are biologically
active because they are able to act as bioreductive alkylating
agents. Examples include the naturally occurring naphtho-
quinone nanaomycin D 1,2 as well as compounds such as
granaticin B 23 and griseusin A 3.4 Not only do these
compounds contain a naphthoquinone skeleton, but they
all have oxygen substituents at the C-4 position, a feature
that is believed to be important for these compounds to
behave as bioreductive alkylating agents.1 Benzo[g]iso-
chromane quinones possessing an oxygen substituent at
To date, a number of methods have been developed for the
construction of isochromanes and benzo[g]isochromane
systems containing an oxygen substituent at the 4- or
3-position.7 In this paper, we report on two different
approaches to the synthesis of both 4- and 3-isochromanols,
6±11. Part of this work has been reported as a communi-
cation8 0Fig. 2).
Figure 1.
Keywords: isochromanols; cyclization; mercury and compounds; oxygen.
Corresponding author. Tel.: 127-11-716-6724; fax: 127-11-339-7967; e-mail: dekoning@aurum.chem.wits.ac.za
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020001)00 963-2

9624
C. B. de Koning et al. / Tetrahedron 57 *2001) 9623±9634
Figure 2.
1
2. Results and discussion
296.1615 0C15H24O5 requires 296.1624) and the H NMR
spectrum showed, inter alia, a singlet at d 1.34 integrating
for nine protons. It was clear that oxidation had taken place
at C-1 as a singlet was now observed at d 6.19 while the two
signals at C-4 were still present as a doublet of doublets at d
1.42 and 2.32. The orientation of the newly introduced
substituent at C-1 is unclear but it is believed to adopt a
pseudoaxial position. By contrast, treatment of 13 with
oxygen and with simultaneous irradiation from a 250
W-mercury lamp through a quartz ®lter afforded the lactone
16 in low yield. Both of these reactions could be useful for
the synthesis of natural products containing an isocoumarin
nucleus, but these products were not desirable for our
purposes.
2.1. Synthesis of isochroman-4-ols
It has been demonstrated9 that treatment of alcohol 12 with
potassium t-butoxide in DMF affords the isochromane 13.
As a starting point for this work it was thought that 13 could
be hydroxylated to the required product 14, as precedent
exists in the corresponding benzo[g]isochromane series.10
However, attempts by a variety of methods11 failed to
produce the required hydroxylated isochromane 14 from
13 and only led to the recovery of starting material or
gave an intractable mixture of products. As shown in
Scheme 1 two of the attempted methods afforded charac-
terizable, but undesired products. Treatment of isochromane
13 with t-butyl hydroperoxide and chromium0VI) oxide12
yielded the hydroperoxide 15 in 68% yield. The high reso-
lution mass spectrum showed a molecular ion at m/z
We next chose to examine oxidative ring closures on
the related styrene precursor 17, the synthesis of which is
shown in Scheme 2. Treatment of ester 189 with potassium
t
Scheme 1. Reagents and conditions: 0i) KOBut, DMF, 608C, 10min, 82%; 0ii) CrO 3, CH2Cl2, BuOOH, 12 h, 68%; 0iii) O2, CHCl3, hn, 1 h, 20%.
Scheme 2. Reagents and conditions: 0i) KOBut, DMF, rt, 15 min, 99%; 0ii) LiAlH4, Et2O, 12 h, 98%; 0iii) Hg0OAc)2, THF, 15 min; 0iv) NaBH4, DMF, O2,
86%; 0v) PCC, CH2Cl2, 74%; 0vi) LiAlH4, Et2O, 80%; 0vii) AgO, HNO3, dioxane, 89%.

C. B. de Koning et al. / Tetrahedron 57 *2001) 9623±9634
9625
Scheme 3. Reagents and conditions: 0i) 21!22, AcOH/TFAA, CH2Cl2, 67%; 21!23, DMF, POCl3, toluene, 2 h, 95%; 0ii) 22!24, 0a) 1708C, 0b) 0MeO)2SO2,
i
K2CO3, Me2CO, 95%; 23!25, 0a) DMF, re¯ux, 0b) PrBr, K2CO3, Me2CO, 97%; 0iii) 24!26, LiAlH4, Et2O, 74%; 25!27, LiAlH4, Et2O, 99%; 0iv) 26
28, PdCl20MeCN)2, 98%; 27!29 and 30 KOBut, DMF, rt, 15 min, 79% 29 and 15% 30.
t-butoxide in DMF at room temperature gave 19 almost
exclusively as the trans-styrene 099% as estimated by H
oxidized with silver0II) oxide14 to afford the ®rst desired
quinone 6, in 89% yield.
1
1
NMR spectroscopy). The H NMR spectrum showed, inter
alia, a doublet of quartets at d 6.47 0Jˆ16.0and 1.7 Hz),
assigned to the benzylic proton. Reduction of 19 with
lithium aluminium hydride afforded the desired styrene 17
in 98% yield. The stage was now set to attempt oxidative
ring closures. Optimum conditions involved treatment of
alcohol 17 in THF with 1.1 mol equiv. of mercury0II)
acetate.13 This was followed by removal of the THF and
reduction of the intermediate acetoxymercuri-isochromane
with sodium borohydride in an oxygenated solution of
DMF. The desired products 14a and 14b 0ratio: 1:1) were
obtained as a mixture of diastereoisomers in a combined
yield of 86%. The mixture of products 14 could be oxidized
to ketone 20 using pyridinum chlorochromate in CH2Cl2 in
74% yield. This ketone was subsequently reduced with
lithium aluminium hydride to afford isochroman-4-ol 14b
More highly substituted analogs of 6 were prepared from
allyl ether 21, the synthesis of which we have recently
described.15 Treatment of 21 with tri¯uoroacetic acid in
the presence of acetic acid afforded the acetophenone 22
in 67% yield,15 as shown in Scheme 3. Alternatively,
exposure of 21 to POCl3 and DMF afforded aldehyde 23
in 95% yield. Claisen rearrangements of 22 and 23 afforded
phenols that were not isolated but directly protected as the
methyl ether 2416 and as the isopropyl ether 25, respectively.
Each product was then reduced in turn with lithium
aluminium hydride to afford the desired alcohols 2615 and
27 in good yield. Exposure of 26 to palladium0II) chloride±
bisacetonitrile17 gave 28. Careful treatment of 27 with
potassium t-butoxide in DMF for 15 min provided 29, as a
2:1 mixture of trans- and cis-isomers, together with a small
amount of 30.
1
as a single diastereoisomer. The H NMR spectrum clearly
showed the syn relationship between H-3 and H-4 with a
coupling constant of 1.8 Hz. Isochromane 14b was then
As shown in Scheme 4, treatment of 28 with mercury0II)
Scheme 4. Reagents and conditions: 0i) Hg0OAc)2, THF, 15 min; 0ii) NaBH4, NaBr, DMF, O2, 23% 31a and 22% 31b; 0iii) Hg0OAc)2, THF, 15 min;
0iv) NaBH4, DMF, O2, 26% 32a, 22% 32b, 4% 33 and 25% 30.

9626
C. B. de Koning et al. / Tetrahedron 57 *2001) 9623±9634
NMR spectroscopy that product 10 had been formed since
apart from the obvious signals two doublets of doublets at d
2.65 and 2.94 0Jˆ17.1 and 5.2 Hz and Jˆ17.1 and 3.7 Hz),
assigned to 4-H, were present. The doublet of doublet of
doublets at d 5.300 Jˆ5.2, 4.2 and 3.7 Hz) was assigned to
H-3, also indicating coupling to the hydroxy proton. The 1H
NMR spectrum of 34 showed no signals in the aromatic
region, but it was clear that the hydroxy pyran ring system
was still present. The high-resolution mass spectrum
showed the required molecular ion at 216.0629 0C9H12O6
requires 216.0634).
Scheme 5. Reagents and conditions: 0i) O3, MeOH, 2408C, 0b) Zn, AcOH,
53%; with longer exposure to O3 formation of 34 was noted.
acetate, sodium borohydride and oxygen in DMF afforded a
racemic mixture of cis-1,3-dimethyl and trans-1,3-dimethyl
isochroman-4-ols 31a and 31b, respectively 045% combined
yield, in an approximate ratio of 1:1). The coupling
constants derived from the 1H NMR spectrum of 31a
showed that H-3 and H-4 were anti to each other
0Jˆ8.6 Hz) while in isochromanol 31b the same two
protons were syn to each other 0Jˆ1.7 Hz). Under the
same conditions, alcohol 29 was converted into 32a and
32b 0combined yield 48%, in an approximate ratio of 1:1)
together with isochromane 30 and what is believed to
be isochromene 33. The formation of 30 is ascribed to
inef®cient oxygenation during the reaction, while 33 could
be formed by loss of water from either 32a or 32b. Oxi-
dation of 31b, 32a and 32b with silver0II) oxide afforded
quinones 8, 9 and 7, respectively.
The next objective was to attempt the same reaction on the
methallyl equivalent 35 in order to access the 3-methyl-
isochroman-3-ol skeleton 11 of fusarubin 5. Treatment of
2,5-dihydroxybenzoic acid with 1.8 mol equiv. of potas-
sium carbonate and excess methallyl chloride afforded the
desired bismethallylated compound 36 in 50% yield and the
monomethallylated compound 37 in 36% yield 0Scheme 6).
These were easily separated by chromatography. Unfortu-
nately, we were unable to improve the yield of 36 further.
Compound 36 was heated at 1808C for 18 h, after which the
intermediate hydroquinone 38 was immediately protected
by treatment with dimethyl sulfate and potassium carbonate
in boiling acetone to give the bis0methyl ether) 39 in 33%
over two steps. Finally, ester 39 was reduced with lithium
aluminium hydride to give 35. Exposure of alkene 35 to
ozone with careful monitoring every 15 s followed by
quenching the reaction with excess dimethyl sul®de
afforded the desired isochroman-3-ol 11 in 81% yield.
Two doublets at d 2.67 and 2.91 0Jˆ17.2 Hz) were present
in the 1H NMR spectrum and were assigned to H-4. A three-
proton singlet at d 1.53 for the additional methyl group at
C-3 was also evident. A minor product of this reaction
018%) was the isochromene 40. Again it was clear from
2.2. Synthesis of isochroman-3-ols
While working on the synthesis of isochroman-4-ols it came
to our attention that a simple and quick entry to the synthesis
of isochroman-3-ols could be accomplished by treatment
of 12 with ozone, which would give the corresponding
aldehyde. The aldehyde would be in equilibrium with hemi-
acetal 10, which contains the isochroman-3-ol skeleton
0Scheme 5). In principle, this route could be applied to the
synthesis of naturally occurring compounds such as marticin
4 and fusarubin 5. Treatment of alcohol 12 with ozone
for approximately 2 min followed by treatment with zinc
in acetic acid afforded the desired isochroman-3-ol 10
in an optimized yield of 53%. The reaction time for the
ozonolysis was critical, as exposure of the substrate 12 for
longer periods led to the formation of substantial amounts of
34, showing that electron-rich aromatic rings are also
1
the H NMR spectrum that this product had formed as a
one-proton signal at d 5.79 assigned to the benzylic styryl
proton was observed. By comparison, attempts to make 11
by Wacker oxidation18 of alcohol 12 with a catalytic amount
of palladium0II) chloride and copper0II) chloride in DMF
gave, at best, the desired hemiacetal 11 in 29% yield, with
the major product being isochromene 40 050%).
In summary, two novel methods have been developed for
the synthesis of isochroman-4-ols and isochroman-3-ols. At
1
susceptible to oxidation with ozone. It was clear from H
Scheme 6. Reagents and conditions: 0i) 0a) 1808C, 0b) 0MeO)2SO2, Me2CO, K2CO3, 33%; 0ii) LiAlH4, Et2O, 90%; 0iii) 0a) From 35, O3, MeOH, 2408C,
0b) Me2S, 81% 11 and 18% 40.

C. B. de Koning et al. / Tetrahedron 57 *2001) 9623±9634
9627
present we are in the process of developing these methods
for the synthesis of naturally occurring compounds con-
taining this structural motif, viz. nanaomycin D 1 and
fusarubin 4.
methoxy-3-methylisochroman 13 0196 mg, 0.94 mmol)
was dissolved in dry chloroform 015 cm3) in a quartz vessel.
Oxygen was bubbled through the solution, which was
irradiated with light from a 250W-mercury lamp for 1 h.
The reaction mixture was then washed with a 10% aqueous
hydrochloric acid solution and then with a 15% aqueous
sodium hydroxide solution. The separated organic phase
was dried with anhydrous magnesium sulfate, ®ltered and
the solvent evaporated under reduced pressure. Chroma-
tography 0eluant 40% ethyl acetate/hexane) afforded 5,8-
dimethoxy-3-methylisocoumarin 16 as a yellow solid
042 mg, 20%). Mp 67±698C 0lit.19 69±708C); IR 0CHCl3):
3. Experimental
3.1. General
1H and 13C NMR spectra were recorded either on a Bruker
AC-200, or on a Bruker DRX-400 spectrometer at the
frequency indicated. DEPT, CH-correlated and HMBC
spectra were run on some samples to enable complete
assignments of all the signals. NMR spectral assignments
with the same superscript may be interchanged. J-Values
are given in Hz. Infra-red spectra were recorded on either
a Bruker IFS 25 Fourier Transform spectrometer, or on a
Bruker Vector 22 Fourier Transform spectrometer. Mass
spectra were recorded on a Kratos MS 9/50, VG 70E MS
or a VG 70SEQ mass spectrometer. Elemental analysis
was performed on a Perkin±Elmer 2400 CHN Elemental
Analyser. Macherey±Nagel Kieselgel 600particle size
0.063±0.200 mm) was used for conventional silica gel
chromatography, and Macherey±Nagel Kieselgel 60
0particle size 0.040±0.063 mm) was used for preparative
¯ash chromatography. All solvents used for reactions and
chromatography was distilled prior to use.
1
nmaxˆ1720cm 21 0s, CvO), 16100m, C vC); H NMR
0200 MHz): dHˆ1.49 03H, d, Jˆ6.3 Hz, 3-CH3), 2.57 01H,
ddd, Jˆ16.9, 11.7 and 0.6 Hz, 4-HaHb), 3.15 01H, dd, Jˆ
16.9 and 2.9 Hz, 4-HaHb), 3.82 03H, s, OCH3), 3.9003H, s,
OCH3), 4.5001H, dqd, Jˆ11.7, 6.3 and 2.9 Hz, 3-H), 6.86
01H, d, Jˆ9.1 Hz, 6-H)a, 7.04 01H, d, Jˆ9.1 Hz, 7-H)a.
3.1.3. trans-Prop-2-enyl 3,6-dimethoxy-2-1prop-1-enyl)-
benzoate 19. Prop-2-enyl 3,6-dimethoxy-2-0prop-2-enyl)-
benzoate 189 01.223 g, 4.67 mmol) was dissolved in DMF
045 cm3). Potassium t-butoxide 01.05 g, 9.36 mmol) was
added to the stirred solution. The yellow solution turned
black after 2 min. The reaction was stirred for 15 min at
room temperature under a nitrogen atmosphere. The
reaction was quenched with water 0100 cm3) and the
aqueous phase was thoroughly extracted with diethyl ether
05£40cm 3). The combined organic layers were dried with
magnesium sulfate, ®ltered and concentrated under reduced
pressure. Column chromatography 0eluant 10% ethyl
acetate/hexane) afforded trans-prop-2-enyl 3,6-dimethoxy-
2-0prop-1-enyl)benzoate 0with traces of the cis product) 19
as a yellow oil 01.211 g, 99%). Rfˆ0.33 015% EtOAc/hex-
ane); IR 0®lm): nmaxˆ1734 cm21 0s, CvO), 1648 and 1591
3.1.1. 1-t-Butylperoxy-5,8-dimethoxy-3-methylisochro-
mane 15. A 25 cm3 round-bottomed ¯ask was charged
with chromium trioxide 08.9 mg, 0.09 mmol), dichloro-
methane 05 cm3) and t-butyl hydroperoxide 070% in
t-BuOH, 1.0cm 3, 0.937 g, 7.3 mmol). The mixture was
allowed to stir for 2 min before 5,8-dimethoxy-3-methyl-
isochroman 139 0230mg, 1.11 mmol) was added, and
stirring was continued at ambient temperature under an air
atmosphere for 12 h. The reaction was then quenched with
water 05 cm3) and extracted with dichloromethane
04£20cm 3). The organic layer was dried with anhydrous
magnesium sulfate, ®ltered and the solvent removed under
reduced pressure. Chromatography of the residue 0eluant
5% ethyl acetate/hexane) to remove traces of starting
material afforded 1-t-butylperoxy-5,8-dimethoxy-3-methyl-
isochroman 15 as clear to off-white crystals 0233 mg, 68%).
Rf 0.58 020% EtOAc/hexane); mp 75±778C; IR 0CHCl3):
nmaxˆ1590cm 21 0m, CvC), 1020 0s, C±O); 1H NMR
0200 MHz): dHˆ1.34 [9H, s, OOC0CH3)3], 1.42 03H, d,
Jˆ6.3 Hz, 3-CH3), 2.32 01H, dd, Jˆ17.5 and 11.5 Hz,
4-HaHb), 2.78 01H, dd, Jˆ17.5 and 3.6 Hz, 4-HaHb), 3.77
03H, s, OCH3), 3.8003H, s, OCH 3), 4.41 01H, dqd, Jˆ11.5,
6.3 and 3.6 Hz, 3-H), 6.19 01H, s, 1-H), 6.68 01H, d,
Jˆ8.9 Hz, 7-H)a, 6.77 01H, d, Jˆ8.9 Hz, 6-H)a; 13C NMR
050MHz): dCˆ21.3 03-CH3), 26.5 [OOC0CH3)3], 29.7
0C-4), 55.6 0OCH3), 55.6 0OCH3), 62.2 0C-3), 80.5
[OOC0CH3)3], 96.6 0C-1), 108.0 0C-7)a, 110.4 0C-6)a,
120.0 0C-8a)b, 126.2 0C-4a)b, 150.5 0C-8)c, 151.4 0C-5)c;
MS 0EI): m/z 0%): 296 0M1, 2), 222 011), 208 012), 207
0100), 192 010), 179 013), 58 019), 43 019), 32 076), 28
098); HRMS calcd for C16H24O5 M 296.1624, found
296.1615.
1
0m, CvC); H NMR 0400 MHz): dHˆ1.84 [3H, dd, Jˆ6.6
and 1.7 Hz, vCH0CH3)], 3.77 03H, s, OCH3), 3.77 03H, s,
OCH3),4.7902H,ddd,Jˆ5.8,1.4and1.4 Hz,COOCH2CHv),
5.26 01H, ddd, Jˆ10.4, 2.8 and 1.4 Hz, vCHaHb), 5.4001H,
ddd, Jˆ17.2, 2.8 and 1.4 Hz, vCHaHb), 5.99 01H, ddt,
Jˆ17.2, 10.4 and 5.8 Hz, COOCH2CHv), 6.16 [1H, dq,
Jˆ16.0and 6.6 Hz, vCH0CH3)], 6.4001H, dq, Jˆ16.0
and 1.7 Hz, ArCHv), 6.73 01H, d, Jˆ9.0Hz, 5-H) a, 6.84
01H, d, Jˆ9.0Hz, 4-H) a; 13C NMR 0100 MHz): dCˆ19.2
[vCH0CH3)], 56.00OCH 3), 56.3 0OCH3), 65.7
0COOCH2CHv), 109.9 0vCH2)a, 112.1 0C-5)a, 118.5
0C-4)a, 123.9 0C-2)b, 124.1 [vCH0CH3)], 125.9 0C-1)b,
131.5 0ArCHv)c, 131.9 0COOCH2CHv)c, 150.1 0C-6)d,
151.5 0C-3)d, 167.7 0CO); MS 0EI): m/z 0%): 263 0M11,
14), 262 0M1, 82), 221 0100), 205 039), 193 054), 178 020),
150025), 149 021), 91 011), 41 015); HRMS calcd for
C15H18O4 M 262.1205, found 262.1208.
3.1.4.
trans-[3,6-Dimethoxy-2-1prop-1-enyl)phenyl]-
methanol 17a and cis-[3,6-dimethoxy-2-1prop-1-enyl)-
phenyl]methanol 17b. Prop-2-enyl 3,6-dimethoxy-2-
0prop-1-enyl)benzoate 19 02.79 g, 10.5 mmol) in dry diethyl
ether 040cm 3) was added to a stirred suspension of lithium
aluminium hydride 00.80 g, 21 mmol) in dry diethyl ether
040cm 3). The reaction was stirred under a nitrogen atmos-
phere for 12 h. The reaction mixture was successively
treated with water 00.8 cm3), aqueous sodium hydroxide
015%, 0.8 cm3) and water 02.4 cm3). The aqueous phase
3.1.2. 5,8-Dimethoxy-3-methylisocoumarin 16. 5,8-Di-

9628
C. B. de Koning et al. / Tetrahedron 57 *2001) 9623±9634
was extracted with diethyl ether 03£100 cm3) and the
combined ether layers were dried with anhydrous mag-
nesium sulfate. The residue obtained upon evaporation of
ether under reduced pressure was puri®ed by column
chromatography 0eluant 40% ethyl acetate/hexane) to afford
[3,6-dimethoxy-2-0prop-1-enyl)phenyl]methanol 17a and
17b 02.16 g, 98%) as a yellow oil 068:32 ratio, respectively;
estimated by NMR spectroscopy). Rf 0.38 030% EtOAc/
hexane); IR 0®lm): nmaxˆ3370cm 21 0s, OH), 1640and
13C NMR 0100 MHz): dCˆ18.2 03-CH3), 55.4 0OCH3),
55.6 0OCH3), 63.4 0C-1)a, 68.1 0C-4)a, 74.5 0C-3)a, 108.5
0C-6)b, 108.6 0C-7)b, 125.5 0C-8a)c, 125.8 0C-4a)c, 149.2
0C-8)d, 151.6 0C-5)d; MS 0EI): m/z 0%): 224 0M1, 19), 181
013), 180 0100), 179 011), 165 036), 149 08), 9109), 77 09), 43
09); HRMS: calcd for C12H16O4 M 224.1049, found
224.1036.
Further elution 030% ethyl acetate/hexane) afforded the
03Rp,4Rp)-5,8-dimethoxy-3-methyliso-
1
1600 0m, CvC); H NMR 0200 MHz) 17a: dHˆ1.93 [3H,
cis-diastereomer
dd, Jˆ6.7 and 1.7 Hz, vCH0CH3)], 2.2 01H, br s, OH), 3.78
03H, s, OCH3), 3.84 03H, s, OCH3), 4.77 02H, s, ArCH2OH),
5.98 [1H, dq, Jˆ16.0and 6.7 Hz, vCH0CH3)], 6.47 01H,
dq, Jˆ16.0and 1.7 Hz, ArCH v), 6.72 01H, d, Jˆ9.0Hz,
5-H), 6.78 01H, d, Jˆ9.0Hz, 4-H); 17b: dHˆ1.52 [3H, dd,
Jˆ6.7 and 1.7 Hz, vCH0CH3)], 2.2 01H, br s, OH), 3.77
03H, s, OCH3), 3.86 03H, s, OCH3), 4.67 02H, s, ArCH2OH),
5.98 [1H, dq, Jˆ11.2 and 6.7 Hz, vCH0CH3)], 6.35 01H,
dq, Jˆ11.2 and 1.7 Hz, ArCHv), 6.79 02H, s, 4-H and 5-H);
13C NMR 050MHz) 17a: dCˆ19.1 [vCH0CH3)], 55.7
0OCH3), 56.00OCH 3), 58.3 0ArCH2OH), 108.6 0C-5)a,
110.1 0C-4)a, 124.0[ vCH0CH3)], 127.8 0C-2)b, 128.9
0C-1)b, 132.4 0ArCHv), 151.4 0C-3)c, 152.5 0C-6)c; 17b:
chroman-4-ol 14b as white crystals 0161 mg, 41%). Rf
0.31 030% EtOAc/hexane); mp 68±708C 0white cubes,
hexane); IR 0CHCl3): nmaxˆ3403 cm21 0m, OH), 1605 0m,
1
CvC), 1060 0m, C±O); H NMR 0200 MHz): dHˆ1.43
03H, d, Jˆ6.5 Hz, 3-CH3), 2.12 01H, br s, OH), 3.67 01H,
qd, Jˆ6.5 and 1.8 Hz, 3-H), 3.76 03H, s, OCH3), 3.84 03H, s,
OCH3), 4.55 01H, d, Jˆ16.1 Hz, ArCHaHbO), 4.56 01H, d,
Jˆ1.8 Hz, 4-H), 4.93 01H, d, Jˆ16.1 Hz, ArCHaHbO), 6.72
02H, s, 6-H and 7-H); 13C NMR 050MHz): dCˆ16.7
03-CH3), 55.5 0OCH3), 55.8 0OCH3), 62.7 0C-1)a, 64.9
0C-4)a, 73.8 0C-3)a, 108.3 0C-6)b, 109.1 0C-7)b, 124.7
c
0C-8a)c, 126.00C-4a) , 149.2 0C-8)d, 151.5 0C-5)d; MS
0EI): m/z 0%): 224 0M1, 28), 181 013), 180 0100), 179
054), 165 037), 149 010), 91 012), 77 09), 43 08); HRMS:
calcd for C12H16O4 M 224.1049, found 224.1038.
dCˆ14.6 [vCH0CH3)], 55.6 0OCH3), 56.00OCH ), 58.9
3
0ArCH2OH), 109.1 0C-5)a, 110.0 0C-4)a, 123.8 [vCH
0CH3)], 128.3 0C-2)b, 128.9 0C-1)b, 129.7 0ArCHv), 151.2
0C-3)c, 152.2 0C-6)c; MS 0EI): m/z 0%): 209 0M11, 13), 208
0M1, 100), 179 017), 177 022), 175 030), 165 060), 161 021),
147 018), 121 022), 115 033), 107 020), 105 037), 103 026), 91
061), 77 054); HRMS calcd for C12H16O3 M 208.1099, found
208.1108.
3.1.6. 1^)-5,8-Dimethoxy-3-methylisochroman-4-one 20.
A diastereomeric mixture of 5,8-dimethoxy-3-methyliso-
chroman-4-ols 14a and 14b 0240mg, 1.07 mmol) was
dissolved in dichloromethane 015 cm3) and cooled to
2108C.
A dispersion of pyridinium chlorochromate
01.04 g, 4.80 mmol) and celite 01.04 g) was added to the
solution. The orange suspension was stirred for 12 h, after
which it was ®ltered, the solvent evaporated under reduced
pressure and the residue puri®ed by column chroma-
tography 0eluant 20% ethyl acetate/hexane) to afford 5,8-
dimethoxy-3-methylisochroman-4-one 20 as an off-white
3.1.5. 13Rp,4Sp)-5,8-Dimethoxy-3-methylisochroman-4-ol
14a and 13Rp,4Rp)-5,8-dimethoxy-3-methylisochroman-
4-ol 14b. cis- and trans-[3,6-Dimethoxy-2-0prop-1-enyl)]-
phenylmethanol 17a and 17b 0364 mg, 1.75 mmol) were
dissolved in dry THF 020cm 3). To this was added
mercury0II) acetate 0669 mg, 2.10mmol) and the reaction
mixture was stirred at room temperature under a nitrogen
atmosphere for 15 min. The solvent was evaporated under
reduced pressure; the residue was dissolved in DMF
015 cm3) and transferred into a pressure-equalizing dropping
funnel. Sodium borohydride 0165 mg, 4.37 mmol) was
suspended in DMF 015 cm3), and the suspension was
thoroughly purged with oxygen 020min). To this was
added dropwise over a period of 15 min the mercuric salt
solution in DMF. The gray suspension was stirred for a
further 1 h, at which time the solution was clear, with
droplets of mercury evident at the bottom of the reaction
vessel. 0This does not always occur, and the reaction needs
to be monitored by TLC.) The solvent was removed in
vacuo and the residue subjected to column chromatography
0eluant 10% ethyl acetate/hexane) to afford trans-
diastereomer 03Rp,4Sp)-5,8-dimethoxy-3-methylisochroman-
4-ol 14a as white crystals 0177 mg, 45%). Rf 0.49 030%
EtOAc/hexane); mp 60±618C 0white needles, hexane/
dichloromethane); IR 0CHCl3): nmaxˆ3438 cm21 0m, OH),
solid 0176 mg, 74%). Mp 143±1458C; IR 0CHCl3): nmax
ˆ
1710cm 21 0s, CvO), 1599 0m, CvC), 1032 0m, C±O); 1H
NMR 0200 MHz): dHˆ1.49 03H, d, Jˆ6.6 Hz, 3-CH3), 3.82
03H, s, OCH3), 3.88 03H, s, OCH3), 4.15 01H, qd, Jˆ6.6 and
1.0, 3-H), 4.68 01H, dt, Jˆ16.2 and 1.0Hz, 1- HaHb), 5.09
01H, d, Jˆ16.2 Hz, 1-HaHb), 6.85 01H, d, Jˆ9.1 Hz, 6-H)a,
7.03 01H, d, Jˆ9.1 Hz, 7-H)a; 13C NMR 050MHz): dCˆ
16.00CH ), 55.9 0OCH3), 56.2 0OCH3), 62.8 0C-1), 78.2
3
0C-3), 110.8 0C-6)a, 116.4 0C-7)a, 119.00C-8a) b, 132.4
c
0C-4a)b, 148.00C-8) , 153.9 0C-5)c, 194.9 0C-4); MS 0EI):
m/z 0%): 222 0M1, 85), 178 0100), 177 029), 163 053), 148
021), 121 041), 120041); HRMS calcd for C12H14O4
222.0892, found 222.0881.
M
3.1.7. 13Rp,4Rp)-5,8-Dimethoxy-3-methylisochroman-4-ol
14b. A solution of isochroman-4-one 20 0196 mg, 0.88
mmol) in dry tetrahydrofuran 05 cm3) was added to a
suspension of lithium aluminium hydride 040mg, 1.05
mmol) in dry tetrahydrofuran 05 cm3). The suspension was
stirred at ambient temperature under a nitrogen atmosphere
for 5 h. The reaction mixture was treated successively with
water 00.1 cm3), aqueous sodium hydroxide 015%, 0.1 cm3)
and water 00.3 cm3). The white precipitate was removed by
®ltration, and the solution was concentrated under reduced
pressure. Column chromatography of the residue afforded
03Rp,4Rp)-5,8-dimethoxy-3-methylisochroman-4-ol 14b 0176
1
1604 0m, CvC), 1035 0s, C±O); H NMR 0400 MHz):
dHˆ1.41 03H, d, Jˆ6.2 Hz, 3-CH3), 3.66 01H, dq, Jˆ7.5
and 6.2 Hz, 3-H), 3.74 03H, s, OCH3), 3.83 03H, s, OCH3),
4.59 01H, d, Jˆ16.0Hz, ArC HaHbO), 4.59 01H, d, Jˆ
7.5 Hz, 4-H), 4.8001H, d, Jˆ16.0Hz, ArCH aHbO), 6.67
01H, d, Jˆ8.9 Hz, 6-H)a, 6.72 01H, d, Jˆ8.9 Hz, 7-H)a;

C. B. de Koning et al. / Tetrahedron 57 *2001) 9623±9634
9629
mg, 89%) as white crystals identical in all respects with the
material described above.
3.1.10. 3-Isopropoxy-4,6-dimethoxy-2-1prop-2-enyl)benz-
aldehyde 25. 2,4-Dimethoxy-5-0prop-2-enyloxy)benzalde-
hyde 23 01.120g, 5.05 mmol) was dissolved in DMF
010cm 3) and heated at re¯ux with stirring under a nitrogen
atmosphere for 20h. The solution was allowed to cool and a
further 40cm 3 of DMF was added to the solution. 2-Bromo-
propane 02.4 cm3, 3.1 g, 25.2 mmol) and potassium carbon-
ate 03.49 g, 25.2 mmol) were added and the resulting
suspension was stirred at 808C under a nitrogen atmosphere
for 12 h. The reaction mixture was allowed to cool, ®ltered,
and the solvent removed under reduced pressure. Column
chromatography of the residue afforded 3-isopropoxy-4,6-
dimethoxy-2-0prop-2-enyl)benzaldehyde 25 01.29 g, 97%)
as a yellow oil. Rf 0.60 040% EtOAc/hexane); IR 0®lm):
nmaxˆ2787 cm21 0w, CHO), 1686 0s, CvO); 1H NMR
0400 MHz): dHˆ1.24 [6H, d, Jˆ6.2 Hz, OCH0CH3)2],
3.86 02H, ddd, Jˆ6.0, 1.6 and 1.6 Hz, ArCH2), 3.88 03H,
3.1.8. 13Rp,4Rp)-4-Hydroxy-3-methylisochromane-5,8-
quinone
6.
03Rp,4Rp)-5,8-Dimethoxy-3-methyliso-
chroman-4-ol 14b 0122 mg, 0.54 mmol) was dissolved in
dioxane 06 cm3) and silver0II) oxide 0337 mg, 2.72 mmol)
was added to the solution. Nitric acid 06 M) was added
dropwise to the stirred suspension until all the silver0II)
oxide was consumed, resulting in an orange solution. The
solution was stirred for a further 2 min and quenched with
water 015 cm3). The aqueous phase was extracted with
dichloromethane 03£20cm 3). The combined organic layers
were dried with magnesium sulfate, ®ltered and the solvent
removed under reduced pressure. Column chromatography
of the residue 0eluant 30% ethyl acetate/hexane) afforded
03Rp,4Rp)-4-hydroxy-3-methylisochromane-5,8-quinone
6
094 mg, 89%) as a red±brown solid. Rf 0.50 050% EtOAc/
s, OCH3), 3.9003H, s, OCH ), 4.35 [1H, sept, Jˆ6.2 Hz,
3
hexane); IR 0CHCl3): nmaxˆ3419 cm21 0s, br, OH), 1651
OCH0CH3)2], 4.89±4.97 02H, m, vCH2), 5.91 01H, ddt,
Jˆ17.1, 10.2 and 6.0 Hz, CHvCH2), 6.4001H, s, 5-H),
10.43 01H, s, CHO); 13C NMR 0100 MHz): dCˆ22.3
1
0vs, CvO), 16100w, C vC), 1054 0m, C±O); H NMR
0400 MHz): dHˆ1.4003H, d, Jˆ6.5 Hz, 3-CH3), 2.45 01H,
d, Jˆ6.2 Hz, 4-OH), 3.61 01H, dq, Jˆ6.5 and 2.0Hz, 3-H),
4.34 01H, dd, Jˆ18.9 and 1.8 Hz, ArCHaHb), 4.37 01H, ddd,
[OCH0CH3)2], 30.2 0ArCH2), 55.6 0OCH3), 56.00OCH ),
3
74.8 [OCH0CH3)2], 94.1 0C-5), 114.7 0vCH2), 116.1
0C-1), 137.00 CHvCH2), 137.00C-2), 138.9 0C-3), 158.3
Jˆ6.2, 2.0and 1.8 Hz, 4-H), 4.7001H, d,
Jˆ18.9 Hz,
ArCHaHb), 6.76 01H, d, Jˆ10.2 Hz, 6-H)a, 6.81 01H, d,
Jˆ10.2 Hz, 6-H)a; 13C NMR 0100 MHz): dCˆ16.0
03-CH3), 61.00C-3) a, 63.00C-1) a, 73.5 0C-4), 136.3
0C-4)a, 161.00C-6) , 190.1 0CHO); MS 0EI): m/z 0%): 264
a
0M1, 52), 222 046), 221 063), 207 0100), 193 028), 189 016),
173 034); HRMS calcd for C15H20O4 M 264.1362, found
264.1369.
c
0C-6)b, 136.5 0C-7)b, 139.00C-8a) , 141.1 0C-4a)c, 185.9
0C-8)d, 186.3 0C-5)d; MS 0EI): m/z 0%): 194 0M1, 3),
150 0100), 122 027), 121 022), 95 014), 94 021), 82 010),
66 019); HRMS calcd for C10H10O4 M 194.0579, found
194.0571.
3.1.11.
[3-Isopropoxy-4,6-dimethoxy-2-1prop-2-enyl)-
phenyl]methanol 27. 3-Isopropoxy-4,6-dimethoxy-2-
0prop-2-enyl)benzaldehyde 25 01.453 g, 5.50mmol) was
dissolved in dry diethyl ether 050cm 3) and added to a stirred
suspension of lithium aluminium hydride 0420mg, 11.0
mmol) in dry diethyl ether 020cm 3). The gray suspension
was stirred at ambient temperature, under a nitrogen atmos-
phere, for 12 h. The reaction mixture was treated succes-
sively with water 00.40 cm3), aqueous sodium hydroxide
015%, 0.4 cm3) and water 01.3 cm3), and stirred for
10min. The white precipitate was removed by ®ltration
and the ®ltrate was dried with magnesium sulfate, ®ltered
and concentrated under reduced pressure. Column chroma-
tography of the residue 0eluant 30% ethyl acetate/hexane)
3.1.9. 2,4-Dimethoxy-5-1prop-2-enyloxy)benzaldehyde 23.
2,4-Dimethoxy-1-0prop-2-enyloxy)benzene 2115 05.36 g,
27.63 mmol) was dissolved in dry toluene 07 cm3) and the
solution was cooled to 08C. DMF 04.1 cm3, 4.0g, 55.3
mmol) and phosphorus0V) oxychloride 03.1 cm3, 5.1 g,
33.2 mmol) were added, and the solution was stirred
under a nitrogen atmosphere at 08C for 20min. The yellow
solution was heated at re¯ux for 2 h, turning progressively
to dark yellow, then orange and ®nally black. The solution
was allowed to cool and poured into ice slurry of aqueous
sodium hydroxide 010%, 50 cm3). The aqueous layer
was extracted with dichloromethane 03£100 cm3). The
combined organic extracts were dried with anhydrous
magnesium sulfate, ®ltered and concentrated under reduced
pressure. Puri®cation by column chromatography 0eluant
20% ethyl acetate/hexane) afforded 2,4-dimethoxy-5-
0prop-2-enyloxy)benzaldehyde 23 05.82 g, 95%) as a yellow
solid. Rf 0.37 030% EtOAc/hexane); mp 154±1568C; IR
0®lm): nmaxˆ2854 cm21 0s, CHO), 1657 0m, CvO), 1605
0m, CvC), 1037 0m, C±O); 1H NMR 0200 MHz): dHˆ3.92
03H, s, OCH3), 3.97 03H, s, OCH3), 4.57±4.61 02H, m,
OCH2Cv), 5.26±5.46 02H, m, vCH2), 6.00±6.18 01H, m,
CHvCH2), 6.49 01H, s, 3-H), 7.34 01H, s, 6-H), 10.30 01H,
s, CHO); 13C NMR 050MHz): dCˆ56.1 0OCH3), 56.2
0OCH3), 70.1 0OCH2Cv), 96.00C-3), 111.3 0 vCH2),
117.3 0C-1), 118.4 0C-6), 132.8 0CHvCH2), 142.4 0C-5),
156.2 0C-4)a, 158.7 0C-2)a, 187.9 0CHO); MS 0EI): m/z 0%):
222 0M1, 32), 181 0100), 153 063), 151 0100), 125 09), 110
05), 109 04); HRMS calcd for C12H14O4 M 222.0892, found
222.0894.
afforded
[3-isopropoxy-4,6-dimethoxy-2-0prop-2-enyl)-
phenyl]methanol 27 as a clear oil 01.453 g, 99%). Rf 0.46
040% EtOAc/hexane); IR 0®lm): nmaxˆ3441 cm21 0m, br,
OH), 1637 and 1597 0m, CvC); 1H NMR 0200 MHz): dHˆ
1.25 [6H, d, Jˆ6.2 Hz, OCH0CH3)2], 2.2 01H, br s, OH),
3.58 02H, dt, Jˆ5.7 and 1.8 Hz, ArCH2CHv), 3.85 06H,
2£s, each OCH3), 4.35 [1H, sept, Jˆ6.2 Hz, OCH0CH3)2],
4.63 02H, s, ArCH2OH), 4.87±5.05 02H, ddt, Jˆ17.1, 10.2
and 5.7 Hz, vCH2), 5.97 01H, m, CHvCH2), 6.43 01H, s,
5-H); 13C NMR 050MHz): dCˆ22.5 [OCH0CH3)2], 30.7
0ArCH2CHv), 55.8 02£OCH3), 57.3 0ArCH2OH), 74.7
[OCH0CH3)2], 95.3 0C-5), 115.1 0vCH2), 120.2 0C-1)a,
133.5 0C-2)a, 137.8 0CHvCH2), 138.7 0C-3), 152.9
0C-4)b, 154.4 0C-6)b; MS 0EI): m/z 0%): 266 088), 224
0100), 223 046), 207 025), 191 036), 69 016); HRMS calcd
for C15H22O4 M 266.1518, found 266.1523.
3.1.12. 1-{3,4,6-Trimethoxy-2-[1E)-1-propenyl]phenyl}-
1-ethanol 28. Alcohol 2615 0252 mg, 1.0mmol) in dry
dichloromethane 050cm 3) was treated with palladium0II)

9630
C. B. de Koning et al. / Tetrahedron 57 *2001) 9623±9634
chloride bisacetonitrile 015 mg) and stirred under argon at
258C for 3 h. Removal of the palladium salt by ¯ash
chromatography 0eluant 20% ethyl acetate/hexane) afforded
the trans-conjugated alcohol 28 0248 mg, 98%) as a low
melting semi-solid. Rf 0.40 020% EtOAc/hexane); IR
vCHCH3), 6.36±6.51 02H, m, ArCHv and 5-H); 29b:
dHˆ1.19 [6H, d, Jˆ6.2 Hz, OCH0CH3)2], 1.54 03H, dd,
Jˆ6.8 and 1.7 Hz, vCHCH3), 2.3 01H, br s, OH), 3.85
03H, s, OCH3), 3.86 03H, s, OCH3), 4.15 [1H, sept, Jˆ
6.2 Hz, OCH0CH3)2], 4.6002H, s, ArC H2OH), 5.9001H,
dq, Jˆ11.3 and 6.8 Hz, vCHCH3), 6.36±6.51 02H, m,
ArCHv and 5-H); 13C NMR 0100 MHz) 29a: dCˆ18.9
0vCHCH3), 22.3 [OCH0CH3)2], 55.8 0OCH3)a, 55.9
0OCH3)a, 57.8 0ArCH2OH)a, 75.0[O CH0CH3)2], 95.4
0C-5), 119.1 0C-4), 124.9 0vCHCH3), 132.3 0ArCHv),
134.5 0C-3), 138.5 0C-2), 152.8 0C-1)b, 154.5 0C-6)b; 29b:
dCˆ14.9 0vCHCH3), 22.3 [OCH0CH3)2], 55.7 0OCH3)a,
55.8 0OCH3)a, 58.2 0ArCH2OH)a, 75.1 [OCH0CH3)2], 95.5
0C-5), 119.4 0C-4), 124.4 0vCHCH3), 129.4 0ArCHv),
132.5 0C-3), 138.3 0C-2), 152.9 0C-1)b, 154.1 0C-6)b; MS
0EI): m/z 0%): 266 082), 224 087), 223 037), 209 020), 207
033), 206 042), 205 087), 191 0100), 181 050), 177 022), 175
040), 161 021), 91 025), 77 032), 65 020), 43 044), 41 050);
HRMS calcd for C15H22O4 M 266.1518, found 266.1512.
1
0nujol); nmaxˆ3536 cm21 0m, OH), 1594 0s, CvC); H
NMR 0400 MHz): dHˆ1.52 [3H, d, Jˆ6.6 Hz, ArCH0CH3)],
1.92 [3H, dd, Jˆ6.5, and 1.8 Hz, vCH0CH3)], 2.3 01H, br s,
OH), 3.68 03H, s, OCH3), 3.88 03H, s, OCH3), 3.9003H, s,
OCH3), 5.05 [1H, m, CH0OH)], 5.79 01H, dq, Jˆ16.0, 1 and
6.5 Hz, vCHCH3), 6.4001H, dq, Jˆ16.0and 1.8 Hz,
1ArCHv), 6.48 01H, s, 6-H); 13C NMR 0100 MHz): dCˆ
19.00CH CH3), 23.9 0vCHCH3), 55.7 0OCH3), 56.1
0OCH3), 60.2 0OCH3), 67.3 [CH0OH)], 96.6 0C-6), 123.5
0C-2), 124.00 vCHCH3), 132.2 0ArCHv), 140.8 0C-4)a,
a
151.6 0C-1)a, 154.00C-5) ; MS 0EI): m/z 0%): 252 0100),
234 015), 219 040), 207 045), 91 020), 77 015), 43 050);
0Calcd for C14H20O4: C, 66.7; H, 7.9%. Found: C, 66.6, H,
7.7%).
3.1.13. trans-[3-Isopropoxy-4,6-dimethoxy-2-1prop-1-enyl)-
phenyl]methanol 29a, cis-[3-isopropoxy-4,6-dimethoxy-
2-1prop-1-enyl)phenyl]methanol 29b and 1^)-5-isopro-
poxy-6,8-dimethoxy-3-methylisochromane 30. [3-Isopro-
poxy-4,6-dimethoxy-2-0prop-2-enyl)phenyl]methanol 27
0521 mg, 1.96 mmol) was dissolved in DMF 025 cm3).
Potassium t-butoxide 0220mg, 1.96 mmol) was added and
the resulting black solution was stirred under a nitrogen
atmosphere, at ambient temperature for 15 min. The reac-
tion mixture was quenched with water 030cm 3) and
thoroughly extracted with diethyl ether. The combined
ether extracts were dried with magnesium sulfate, ®ltered
and concentrated under reduced pressure. Column chroma-
tography of the residue 0eluant 10% ethyl acetate/hexane)
3.1.14. 11Rp,3Sp,4Rp)-5,6,8-Trimethoxy-1,3-dimethyl-3,4-
dihydro-1H-isochroman-4-ol 31a and 11Rp,3Rp,4Rp)-
5,6,8-trimethoxy-1,3-dimethyl-3,4-dihydro-1H-isochro-
man-4-ol 31b. Alcohol 28 0280mg, 1.11 mmol) in THF
025 cm3) was treated with mercury0II) acetate 0424 mg,
1.33 mmol) at 258C and stirred for 30min, after which
time sodium bromide 0136 mg, 1.33 mmol) in hot methanol
010cm 3, 508C) was added and stirring was continued for an
additional 30min. Removal of the solvents by rotary
evaporation at 408C gave a residue which was dissolved
in DMF 025 cm3). This was added dropwise to a slurry of
sodium borohydride 084 mg, 2.22 mmol) in DMF 012 cm3)
into which dry oxygen had previously been bubbled for
5 min. Passage of oxygen was continued for an additional
3 h after addition. Removal of the solvent at 508C under
reduced pressure afforded a gray semi-solid which was
mixed with water 040cm 3) and the resulting suspension
was extracted with dichloromethane and the residue
obtained was subjected to chromatography 0eluant 30%
ethyl acetate/hexane) to yield pyran 31a 065 mg, 22%) as
white crystals; mp 111±1128C 0hexane), Rf 0.45 030%
EtOAc/hexane); IR 0nujol): nmaxˆ3512 cm21 0m, OH),
afforded
0^)-5-isopropoxy-6,8-dimethoxy-3-methyliso-
chroman 30 as white crystals 078 mg, 15%). Rf 0.76 030%
EtOAc/hexane); IR 0CHCl3); nmaxˆ1610cm 21 0m, CvC),
11200s, C±O); 1H NMR 0400 MHz): dHˆ1.25 [3H, d,
Jˆ6.2 Hz, OCH0CH3)a0CH3)b], 1.26 03H, d, Jˆ6.2 Hz,
OCH0CH3)a0CH3)b], 1.35 03H, d, Jˆ6.2 Hz, 3-CH3), 2.39
01H, dd, Jˆ16.8 and 10.6 Hz, 4-CHaHb), 2.85 01H, ddd,
Jˆ16.8, 2.9 and 1.1 Hz, 4-CHaHb), 3.62±3.67 01H, dddd,
Jˆ10.6, 6.2, 2.9 and 1.1 Hz, 3-H), 3.77 03H, s, OCH3), 3.83
03H, s, OCH3), 4.36 [1H, sept, Jˆ6.2 Hz, OCH0CH3)2], 4.57
01H, ddd, Jˆ15.4, 1.1 and 1.1 Hz, 1-CHaHb), 4.86 01H, d,
Jˆ15.4 Hz, 1-CHaHb), 6.35 01H, s, 7-H); 13C NMR 0100
MHz): dCˆ21.6 03-CH3), 22.5 [OCH0CH3)a0CH3)b], 22.6
[OCH0CH3)a0CH3)b], 31.4 0C-4), 55.4 0OCH3), 56.1
0OCH3), 64.2 0C-1), 70.2 [OCH0CH3)2], 74.2 0C-3), 94.7
0C-7), 115.6 0C-8a)a, 129.4 0C-4a)a, 137.9 0C-5), 151.1
0C-6), 151.2 0C-8).
1
1604 0s, CvC); H NMR 0400 MHz) dHˆ1.45 03H, d, Jˆ
6.2 Hz, 3-CH3), 1.49 03H, d, Jˆ6.6 Hz, 1-CH3), 3.44 01H,
dq, Jˆ8.6 and 6.2 Hz, pseudoaxial 3-H), 3.8003H, s,
OCH3), 3.9006H, s, 2 £OCH3), 4.58 01H, d, Jˆ8.6 Hz,
pseudoaxial 4-H), 4.59 01H, s, D2O exchangeable, pseudo-
equatorial 4-OH), 4.85 01H, dq, Jˆ6.6 and 1.0Hz, pseudo-
axial 1-H), 6.46 01H, s, 7-H); 13C NMR 0100 MHz) dCˆ18.6
03-CH3), 21.7 01-CH3), 55.6 0OCH3), 56.1 0OCH3), 61.1
0OCH3), 69.6 0C-4), 71.1 0C-1), 73.5 0C-3), 96.6 0C-7),
121.2 0C-8a)a, 132.8 0C-4a)a, 140.5 0C-5), 151.1 0C-6)b,
152.4 0C-8)b; MS 0EI): m/z 0%): 268 0100), 250 010), 235
095), 209 050), 191 030); 0Calcd for C14H20O5: C, 62.7; H,
7.5%. Found: C, 62.5; H, 7.6%).
Further elution 030% ethyl acetate/hexane) yielded trans-[3-
isopropoxy-4,6-dimethoxy-2-0prop-1-enyl)phenyl]methanol
29a and cis-[3-isopropoxy-4,6-dimethoxy-2-0prop-1-enyl)-
phenyl]methanol 29b 064:36, respectively, by NMR ratio,
79%) as a yellow oil. Rf 0.42 040% EtOAc/hexane); IR
0®lm): nmaxˆ3491 cm21 0m, br, OH), 1588 0s, CvC),
11100s, C±O); 1H NMR 0400 MHz) 29a: dHˆ1.22 [6H, d,
Jˆ6.2 Hz, OCH0CH3)2], 1.91 03H, dd, Jˆ6.5 and 1.8 Hz,
vCHCH3), 2.3 01H, br s, OH), 3.83 03H, s, OCH3), 3.84
03H, s, OCH3), 4.22 [1H, sept, Jˆ6.2 Hz, OCH0CH3)2], 4.68
02H, s, ArCH2OH), 6.04 01H, dq, Jˆ16.0and 6.5 Hz,
Further elution afforded isochromanol 31b 078 mg, 26%) as
white crystals; mp 100±1018C 0hexane), Rf 0.45 030%
EtOAc/hexane); IR 0nujol): nmaxˆ3458 cm21 0m, OH),
1
1616 0m, CvC); H NMR 0400 MHz) dHˆ1.4003H, d,
Jˆ6.2 Hz, 3-CH3), 1.47 03H, d, Jˆ6.6 Hz, 1-CH3), 1.8
01H, br s, D2O exchangeable, pseudoequatorial 4-OH),
3.8003H, s, OCH 3), 3.89 03H, s, OCH3), 3.9003H, s,

C. B. de Koning et al. / Tetrahedron 57 *2001) 9623±9634
9631
OCH3), 4.05 01H, dq, Jˆ6.2 and 1.7 Hz, pseudoaxial 3-H),
4.53 01H, d, Jˆ1.7 Hz, pseudoequatorial 4-H), 5.04 01H, q,
Jˆ6.6 Hz, 1-H), 6.48 01H, s, 7-H); 13C NMR 0100 MHz)
dCˆ16.9 03-CH3), 18.3 01-CH3), 55.6 0OCH3), 56.2
0OCH3), 61.6 0OCH3), 62.9 0C-4), 66.3 0C-1), 68.4 0C-3),
96.6 0C-7), 119.7 0C-8a)a, 130.8 0C-4a)a, 140.7 0C-5), 151.5
0C-6 and C-8); MS 0EI): m/z 0%): 268 0100), 250 030), 235
095), 209 050), 191 040); 0Calcd for C14H20O5: C, 62.7; H,
7.5%. Found: C, 62.5; H, 7.3%).
The last set of fractions 0eluant 30% ethyl acetate/hexane)
afforded 03Sp,4Sp)-5-isopropoxy-6,8-dimethoxy-3-methyl-
isochroman-4-ol 32b as a white solid 091 mg, 20%). Rf
0.32 030% EtOAc/hexane); IR 0CHCl3): nmaxˆ3400 cm21
1
0m, br, OH), 1602 0s, CvC), 1070 0s, C±O); H NMR
0400 MHz): dHˆ1.22 [3H, d, Jˆ6.2 Hz, OCH
0CH3)a0CH3)b], 1.38 03H, d, Jˆ6.2 Hz, OCH0CH3)a0CH3)b],
1.42 03H, d, Jˆ6.4 Hz, 3-CH3), 2.3 01H, br s, OH), 3.65 01H,
dq, Jˆ6.4 and 1.5 Hz, 3-H), 3.78 03H, s, OCH3), 3.85 03H, s,
OCH3), 4.51 01H, d, Jˆ15.6 Hz, PhCHaHbO), 4.56 01H, d,
Jˆ1.5 Hz, 4-H), 4.63 [1H, sept, Jˆ6.2 Hz, OCH0CH3)2],
4.86 01H, d, Jˆ15.6 Hz, PhCHaHbO), 6.45 01H, s, 7-H);
13C NMR 0100 MHz): dCˆ16.7 [OCH0CH3)a0CH3)b], 22.1
[OCH0CH3)a0CH3)b], 22.3 03-CH3), 55.4 0OCH3), 56.1
0OCH3), 63.4 0C-4), 64.4 0C-1), 73.7 0C-3), 74.8 [OCH
0CH3)2], 96.6 0C-7), 115.2 0C-8a)a, 131.3 0C-4a)a, 139.4
3.1.15. 13Rp,4Sp)-5-Isopropoxy-6,8-dimethoxy-3-methyli-
sochroman-4-ol 32a, 13Rp,4Rp)-5-isopropoxy-6,8-dimeth-
oxy-3-methylisochroman-4-ol 32b, 1^)-5-isopropoxy-
6,8-dimethoxy-3-methylisochromane 30 and 5-isopro-
poxy-6,8-dimethoxy-3-methylisochromene 33. A mixture
of cis- and trans-[3-isopropoxy-4,6-dimethoxy-2-0prop-1-
enyl)phenyl]methanol 29 0431 mg, 1.62 mmol) was dis-
solved in dry THF 020cm 3). Mercury0II) acetate 0620mg,
1.94 mmol) was added to the solution and the reaction
mixture was stirred at room temperature under a nitrogen
atmosphere for 15 min. The solvent was evaporated under
reduced pressure; the residue was dissolved in DMF
015 cm3) and transferred into a pressure-equalizing dropping
funnel. Sodium borohydride 0123 mg, 3.24 mmol) was
suspended in DMF and the solution was purged thoroughly
with oxygen 020min). The mercuric salt solution in DMF
was added dropwise over a period of 15 min. The gray
suspension was stirred for a further 1 h, at which time the
solution was clear, with droplets of mercury evident at the
bottom of the reaction vessel. 0This does not always occur
and the reaction needs to be monitored by TLC.) The
solvent was removed in vacuo and the residue subjected
to column chromatography 0eluant 10% ethyl acetate/
hexane) to afford an inseparable mixture of 0^)-5-isopro-
poxy-6,8-dimethoxy-3-methylisochromane 30 and 5-iso-
propoxy-6,8-dimethoxy-3-methylisochromene 33 [125 mg,
25%) and 016 mg, 4%), respectively, by NMR spectroscopy
ratio], as a white solid. The signals for 30 could be identi®ed
by comparison to authentic material. The signals for
isochromene 33 could not be fully assigned owing to the
small quantity of 33 present in the mixture, but were
distinguished by analogy with isochromene 40.
b
0C-5), 151.00C-6) , 151.4 0C-8)b; MS 0EI): m/z 0%): 282
0M1, 25), 222 0100), 196 027), 195 083), 181 018), 180 030),
179 077); HRMS calcd for C15H22O5 M 282.1467, found
282.1469.
3.1.16. 11Rp,3Rp,4Sp)-4-Hydroxy-6-methoxy-1,3-dimethyl-
isochromane-5,8-dione 8. To a solution of isochromanol
31b 026 mg, 0.097 mmol) in acetonitrile 02 cm3) was
added water 00.7 cm3). The mixture was added dropwise
to cerium0IV) ammonium nitrate 0106 mg, 0.20 mmol) in
water 01.0cm 3). Stirring was continued for an additional
3
20min, after which water 030cm ) was added and the
yellow emulsion was extracted with dichloromethane. The
residue obtained after evaporation of the solvent under
reduced pressure was subjected to chromatography 0eluant
40% ethyl acetate/hexane) to yield quinone 8 as a solid; mp
134±1368C. Rf 0.30 040% EtOAc/hexane); IR 0nujol):
nmaxˆ3350cm 21 0br m, OH), 1668 0s, CvC), 16400s,
1
CvC); H NMR 0400 MHz): dHˆ1.37 03H, d, Jˆ6.2 Hz,
3-CH3), 1.45 03H, d, Jˆ6.6 Hz, 1-CH3), 3.83 03H, s,
6-OCH3), 3.94 01H, dq, Jˆ6.6 and 2.1 Hz, pseudoaxial
3-H), 4.38 01H, d, Jˆ2.1 Hz, pseudoequatorial 4-H), 4.87
01H, q, Jˆ6.2 Hz, 1-H), 5.91 01H, s, 7-H); 13C NMR
0100 MHz): dCˆ16.1 03-CH3), 18.1 01-CH3), 56.3 0OCH3),
61.00C-3), 66.6 0C-1), 67.2 0C-4), 170.7 0C-7), 137.0
0C-8a)a, 145.2 0C-4a)a, 158.4 0C-6), 181.2 08-CO)b, 186.1
05-CO); HRMS calcd for C12H14O5 M 238.0842, found
238.0838. 0Calc. for C12H14O5: C, 60.5; H, 5.9%. Found:
C, 60.7; H, 5.7%).
Further elution 020% ethyl acetate/hexane) afforded
03Rp,4Sp)-5-isopropoxy-6,8-dimethoxy-3-methylisochroman-
4-ol 32a 0109 mg, 24%) as a white solid. Rf 0.56 030%
EtOAc/hexane); IR 0CHCl3): nmaxˆ3400 cm21 0m, br,
OH), 16100s, C vC), 1035 0s, C±O); 1H NMR 0400
MHz): dHˆ1.23 03H, d, Jˆ6.2 Hz, 3-CH3), 1.40[3H, d,
Jˆ6.2 Hz, OCH0CH3)a0CH3)b], 1.42 03H, d, Jˆ6.2 Hz,
OCH0CH3)a0CH3)b], 3.56 01H, dq, Jˆ7.8 and 6.2 Hz,
3-H), 3.78 03H, s, OCH3), 3.85 03H, s, OCH3), 4.5001H,
s, OH), 4.55 01H, dd, Jˆ15.4 and 1.0Hz, PhC HaHbO), 4.58
01H, dd, Jˆ7.8 and 1.0Hz, 4-H), 4.55±4.59 [obscured by
signals at 4.55 and 4.58, 1H, OCH0CH3)2], 4.77 01H, d,
Jˆ15.4 Hz, PhCHaHbO), 6.41 01H, s, 7-H); 13C NMR
0100 MHz): dCˆ18.3 [OCH0CH3)a0CH3)b], 22.1 03-CH3),
3.1.17.
13Rp,4Rp)-4-Hydroxy-6-methoxy-3-methyliso-
chromane-5,8-quinone 7. 03Rp,4Sp)-5-Isopropoxy-6,8-
dimethoxy-3-methylisochroman-4-ol 32b 052 mg, 0.184
mmol) was dissolved in dioxane 05 cm3). Silver0II) oxide
0114 mg, 0.925 mmol) was added to the solution. Nitric acid
06 M) was added dropwise to the suspension until all the
silver0II) oxide had been consumed and an orange solution
resulted. The reaction mixture was quenched with water
010cm 3) and extracted with dichloromethane 03£10cm 3).
The combined extracts were dried with magnesium sulfate,
®ltered and concentrated under reduced pressure. Column
chromatography of the residue afforded 03Rp,4Rp)-4-
hydroxy-6-methoxy-3-methylisochroman-5,8-quinone 7 as
an orange±brown solid 015 mg, 37%). Rf 0.43 050%
22.9 [OCH0CH3)a0CH3)b], 55.4 0OCH3), 56.00OCH ), 63.8
3
0C-1), 69.6 0C-4), 74.6 0C-3), 75.3 [OCH0CH3)2], 95.9
0C-7), 116.1 0C-8a)a, 131.6 0C-4a)a, 138.3 0C-5), 150.9
0C-6)b, 151.2 0C-8)b; MS 0EI): m/z 0%): 222 0M1, 100),
196 030), 195 032), 181 015), 180 032), 179 084), 151 013);
HRMS calcd for C15H22O5 M 282.1467, found 282.1456.
1
EtOAc/hexane); H NMR 0200 MHz): dHˆ1.4003H, d,
Jˆ6.2 Hz, 3-CH3), 1.8 01H, br s, 4-OH), 3.56 01H, dq, Jˆ
7.6 and 6.2 Hz, 3-H), 3.84 03H, s, OCH3), 4.43 01H, dd,

9632
C. B. de Koning et al. / Tetrahedron 57 *2001) 9623±9634
Jˆ19.8 and 2.7 Hz, 1-HaHb), 4.43 0overlaps with signal at
4.43, 1H, ddd, Jˆ7.6, 2.7 and 2.4 Hz, 4-H), 4.64 01H, dd,
Jˆ19.8 and 2.4 Hz, 1-HaHb), 5.9001H, 2, 7-H); MS 0EI):
m/z 0%): 224 0M1, 8), 181 023), 180 0100), 179 020), 152
028), 149 019), 122 025), 85 022), 83 033), 81 021), 71 077),
69 079), 59 057), 58 029), 57 038), 56 021), 55 053), 53 021),
45 034), 43 074); HRMS calcd for C11H12O5 M 224.0685,
found 224.0673.
55.4 0OCH3), 55.6 0OCH3), 60.3 0C-1), 92.1 0C-3), 107.1
0C-7)a, 107.9 0C-6)a, 121.2 0C-8a)b, 123.5 0C-4a)b, 149.1
1
0C-8)c, 151.2 0C-5)c; MS 0EI): m/z 0%): 211 08), 2100M
,
69), 192 03), 177 04), 164 0100), 149 061), 134 06), 121 015),
91 018), 87 015), 74 025); HRMS calcd for C11H14O4 M
210.0892, found 210.0890.
Method B. [3,6-Dimethoxy-2-0prop-2-enyl)]phenylmetha-
nol 12 0412 mg, 1.98 mmol) was dissolved in methanol
020cm 3) and cooled to 2408C. Oxygen containing ozone
was passed through the solution for 5 min, after which
ozone was no longer absorbed, as indicated by the liberation
of iodine from a solution of potassium iodide at the reactor
exit. Glacial acetic acid 03 cm3) and zinc dust 00.2 g) were
added and the solution was warmed to ambient temperature.
The mixture was ®ltered with suction and the methanol
removed under reduced pressure. Water 010cm 3) was
added and the aqueous layer was extracted with dichloro-
methane 03£10cm 3). The organic layer was dried with
anhydrous magnesium sulfate, ®ltered and the solvent
removed under reduced pressure. Chromatography 0eluant
20% ethyl acetate/hexane) afforded 5,8-dimethoxyiso-
chroman-3-ol 10 0176 mg, 42%) as white crystals. Further
elution 020% ethyl acetate/hexane) afforded dimethyl 3,6-
dihydro-2-hydroxy-2H-pyran-4,5-dicarboxylate 34 045 mg,
10%) as a yellow oil. IR 0®lm): nmaxˆ3436 cm21 0w, br,
OH), 1728 0vs, CvO), 1604 0w, CvC), 1060 and 1044
3.1.18.
13Rp,4Sp)-4-Hydroxy-6-methoxy-3-methyliso-
chromane-5,8-quinone 9. 03Rp,4Rp)-5-Isopropoxy-6,8-
dimethoxy-3-methylisochroman-4-ol 32a 0100 mg, 0.354
mmol) was dissolved in dioxane 05 cm3). Silver0II) oxide
0219 mg, 1.77 mmol) was added to the solution. Nitric acid
06 M) was added dropwise to the suspension until all the
silver0II) oxide had been consumed and an orange solution
resulted. The reaction mixture was quenched with water
010cm 3) and extracted with dichloromethane 03£10cm 3).
The combined extracts were dried with magnesium sulfate,
®ltered and concentrated under reduced pressure. Column
chromatography of the residue afforded 03Rp,4Sp)-4-
hydroxy-6-methoxy-3-methylisochromane-5,8-quinone
9
as an orange±red solid 055 mg, 69%). Rf 0.33 050%
EtOAc/hexane); 1H NMR 0200 MHz): dHˆ1.39 03H, d,
Jˆ6.4 Hz, 3-CH3), 2.42 01H, br s, 4-OH), 3.59 01H, dq,
Jˆ6.4 and 1.9 Hz, 3-H), 3.85 03H, s, OCH3), 4.34 01H,
dd, Jˆ19.1 and 1.7 Hz, 1-HaHb), 4.400overlaps with signal
at 4.34, 1H, dd, Jˆ1.9 and 1.7 Hz, 4-H), 4.72 01H, d,
Jˆ19.1 Hz, 1-HaHb), 5.96 01H, 7-H); 13C NMR 050MHz):
dCˆ15.9 03-CH3), 56.4 0OCH3), 60.8 0C-1), 63.2 0C-4), 73.6
0C-3), 107.2 0C-7), 137.3 0C-8a)a, 141.8 0C-4a)a, 158.7
0C-6), 180.6 0C-8)b, 186.1 0C-5)b; MS 0EI): m/z 0%): 224
0M1, 1), 180 0100), 165 018), 152 018), 122 022), 95 040), 69
049); HRMS calcd for C11H12O5 M 224.0685, found
224.0677.
1
0C±O); H NMR 0200 MHz): dHˆ2.42 01H, ddd, Jˆ18.2,
6.1 and 3.0Hz, 3- HaHb), 2.66 01H, ddd, Jˆ18.2, 6.9 and
3.0Hz, 3-H aHb), ,3.7 0obscured, 1H, m, OH), 3.78 03H,
s, OCH3), 3.8003H, s, OCH ), 4.36 01H, ddd, Jˆ17.3, 3.0
3
and 3.0Hz, 6- HaHb), 4.55 01H, ddd, Jˆ17.3, 3.0and 3.0Hz,
6-HaHb), 5.27 01H, dd, Jˆ6.9 and 6.1 Hz, 2-H); 13C NMR
050MHz): dCˆ31.6 0C-3), 52.3 0OCH3) 52.5 0OCH3), 60.2
0C-6), 90.2 0C-2), 131.6 0C-5)a, 132.2 0C-4)a, 165.6 0CO),
167.3 0CO); MS 0EI): m/z 0%): 216 0M1), 185 028), 184
023), 155 050), 152 025), 140 024), 139 090), 127 024), 123
027), 112 022), 111 041), 83 054), 59 048), 53 036), 43 029),
41 023), 39 021), 28 046); HRMS calcd for C9H12O6 M
216.0634, found 216.0629.
3.1.19. 5,8-Dimethoxyisochroman-3-ol 10 and dimethyl
3,6-dihydro-2-hydroxy-2H-pyran-4,5-dicarboxylate 34.
Method A. [3,6-Dimethoxy-2-0prop-2-enyl)]phenylmetha-
nol 12 0206 mg, 0.99 mmol) was dissolved in methanol
010cm 3) and cooled to 2408C. Oxygen containing ozone
was passed through the solution for periods of 15 s, and the
reaction was monitored by TLC each time. When TLC
indicated that total conversion of starting material had
occurred 0,2 min), glacial acetic acid 01.5 cm3) and zinc
dust 00.1 g) were added and the solution was warmed to
ambient temperature. The mixture was ®ltered with suction
and the methanol removed under reduced pressure. Water
010cm 3) was added and the aqueous layer was extracted
with dichloromethane 03£10cm 3). The organic layer was
separated dried with anhydrous magnesium sulfate, ®ltered
and the solvent removed under reduced pressure. Chroma-
tography 0eluant 20% ethyl acetate/hexane) afforded
5,8-dimethoxyisochroman-3-ol 10 0222 mg, 53%) as white
crystals. Mp 115±1178C 0hexane/CH2Cl2); IR 0CHCl3):
nmaxˆ3500 cm21 0m, br, OH), 16200m, C vC), 1040 0w,
C±O); 1H NMR 0200 MHz): dHˆ2.65 01H, dd, Jˆ17.1 and
5.2 Hz, 4-HaHb), 2.94 01H, dd, Jˆ17.1 and 3.7 Hz, 4-HaHb),
3.27 01H, d, Jˆ4.2 Hz, 3-OH), 3.75 03H, s, OCH3), 3.76
03H, s, OCH3), 4.73 01H, d, Jˆ15.9 Hz, 1-HaHb), 4.94
01H, d, Jˆ15.9 Hz, 1-HaHb), 5.3001H, ddd, Jˆ5.1, 4.2
and 3.7 Hz, 3-H), 6.62 01H, d, Jˆ8.9 Hz, 7-H)a, 6.67 01H,
d, Jˆ8.9 Hz, 6-H)a; 13C NMR 050MHz): dCˆ29.2 0C-4),
3.1.20. 2-Methylprop-2-enyl 2-hydroxy-5-12-methyl-
prop-2-enyloxy)benzoate 36 and 2-methylprop-2-enyl
2,5-dihydroxybenzoate 37. 2,5-Dihydroxybenzoic acid
03.83 g, 35.8 mmol) was dissolved in distilled acetone
0300 cm3). 3-Chloro-2-methylpropene 0methallyl chloride)
010.6 cm3, 9.72 g, 107.3 mmol, 3 equiv.), potassium carbo-
nate 08.91 g, 64.5 mmol) and potassium iodide 0594 mg,
3.58 mmol) were added to the solution. The resulting
mixture was heated at re¯ux, with stirring, under a nitrogen
atmosphere for 12 h. The reaction mixture was ®ltered and
the solvent removed under reduced pressure. The residue
was puri®ed by column chromatography 0eluant 2.5%
ethyl acetate/hexane) to afford 2-methylprop-2-enyl
2-hydroxy-5-02-methylprop-2-enyloxy)benzoate 36 04.69 g,
50%) as a yellow oil. Rf 0.84 030% EtOAc/hexane); IR
0CHCl3): nmaxˆ3223 cm21 0w, br, OH), 1686 0s, CO),
1
1617 0s, CvC), 1084 0m, C±O); H NMR 0200 MHz):
dHˆ1.82 [3H, s, COOCH2C0CH3)v]a, 1.84 [3H, s,
OCH2C0CH3)v]a, 4.39 [2H, s, OCH2C0CH3)v], 4.76 [2H,
s, COOCH2C0CH3)v], 4.99±5.09 04H, m, 2£vCH2), 6.91
01H, d, Jˆ9.1 Hz, 3-H), 7.11 01H, dd, Jˆ9.1 and 3.1 Hz,
4-H), 7.37 01H, d, Jˆ3.1 Hz, 6-H), 10.37 01 H, s, OH, D2O

C. B. de Koning et al. / Tetrahedron 57 *2001) 9623±9634
9633
exchangeable); 13C NMR 050MHz): dCˆ19.3 [OCH2C
0CH3)v]a, 19.4 [COOCH2C0CH3)v]a, 68.3 [COOCH2C
0CH3)v], 72.5 [OCH2C0CH3)v], 111.9 0C-1), 112.9
[COOCH2C0CH3)vCH2]b, 113.4 [OCH2C0CH3)vCH2]b,
113.5 0C-6), 118.4 0C-3), 124.5 0C-4), 139.3 [COOCH2C
m/z 0%): 2900M 1, 58), 235 069), 219 037), 191 022), 176
037), 149 0100), 57 032), 55 027); HRMS calcd for C17H22O4
M 290.1518, found 290.1519.
3.1.22. [3,6-Dimethoxy-2-12-methylprop-2-enyl)phenyl]-
methanol 35. 2-Methylprop-2-enyl 3,6-dimethoxy-2-02-
methylprop-2-enyl)benzoate 39 0430mg, 1.64 mmol) was
dissolved in dry diethyl ether 020cm 3). A suspension of
lithium aluminium hydride 0250mg, 6.58 mmol) in diethyl
ether 020cm 3) was added to the solution. The gray suspen-
sion was stirred at ambient temperature under a nitrogen
atmosphere for 16 h. The reaction mixture was successively
treated with water 00.25 cm3), aqueous sodium hydroxide
015%, 0.25 cm3) and water 00.25 cm3). The white precipitate
was ®ltered off, and the solution was dried with anhydrous
magnesium sulfate, ®ltered and concentrated under reduced
pressure. Column chromatography of the residue 0eluant
20% ethyl acetate/hexane) afforded [3,6-dimethoxy-2-02-
methylprop-2-enyl)phenyl]methanol 35 as a clear oil
0327 mg, 90%). Rf 0.41 030% EtOAc/hexane); IR 0®lm):
nmaxˆ3420cm 21 0s, br, OH), 1640and 1600m, C vC),
d
0CH3)v]c, 140.8 [OCH2C0CH3)v]c, 151.00C-5) , 156.2
0C-2)d, 169.4 0CO); MS 0EI): m/z 0%): 262 0M1, 24), 207
014), 135 013), 135 012), 55 0100); HRMS calcd for
C15H18O4 M 262.1205, found 262.1205. Further elution
0eluant 30% ethyl acetate/hexane) led to the isolation of
2-methylprop-2-enyl 2,5-dihydroxybenzoate 37 02.68 g,
36%) as white plates. Rf 0.56 030% EtOAc/hexane); mp
45±478C; IR 0CHCl3): nmaxˆ3397 cm21 0s, OH) and 3250
0br shoulder, OH), 1686 0s, CO), 1622 0m, CvC); 1H NMR
0200 MHz): dH 1.82 [3H, s, COOCH2C0CH3)v], 4.74 [2H,
d, Jˆ0.5 Hz, COOCH2C0CH3)v], 4.96±5.07 02H, m,
vCH2), 6.1 01H, br s, 5-OH, D2O exchangeable), 6.87
01H, d, Jˆ8.9 Hz, 3-H), 7.03 01H, dd, Jˆ8.9 and 3.0Hz,
4-H), 7.34 01H, d, Jˆ3.0Hz, 6-H), 10.36 01H, s, 2-O H, D2O
exchangeable); 13C NMR 0100 MHz): dCˆ19.3 [OCH2C
0CH3)v]a, 68.5 [COOCH2C0CH3)v], 112.2 0C-1), 113.6
[COOCH2C0CH3)vCH2]b, 114.8 0C-6)b, 118.4 0C-3),
124.2 0C-4), 139.1 [COOCH2C0CH3)v], 147.9 0C-5)d,
155.5 0C-2)d, 169.4 0CO); MS 0EI): m/z 0%): 208 0M1,
46), 137 047), 136 0100), 108 012), 81 012), 55 065), 53
012), 52 012); HRMS calcd for C11H12O4 M 208.0736,
found 208.0749.
1
1060 0m, C±O); H NMR 0200 MHz): dHˆ1.79 [3H, t,
Jˆ0.6 Hz, ArCH2C0CH3)v], 2.6 01H, br s, OH), 3.46
[2H, s, ArCH2C0CH3)v], 3.73 03H, s, OCH3), 3.76 03H, s,
OCH3), 4.33±4.34 01H, m, vCHaHb), 4.63 02H, s,
ArCH2OH), 4.71±4.74 01H, m, vCHaHb), 6.72 01H, d,
Jˆ9.0Hz, 4-H), 6.79 01H, d, Jˆ9.0Hz, 5-H); 13C NMR
050MHz): dCˆ22.9 [ArCH2C0CH3)v], 33.1 [ArCH2C
3.1.21. 2-Methylprop-2-enyl 3,6-dimethoxy-2-12-methyl-
prop-2-enyl)benzoate 39. 2-Methylprop-2-enyl 2-hydroxy-
5-02-methylprop-2-enyloxy)benzoate 36 01.286 g, 4.91
mmol) was heated in the absence of solvent at 1808C
under a nitrogen atmosphere for 18 h. After cooling, acetone
040cm 3) was added. Dimethyl sulfate 02.3 cm3, 3.09 g,
24.5 mmol) and potassium carbonate 03.39 g, 24.5 mmol)
were added to the black solution. The reaction mixture
was heated at re¯ux under a nitrogen atmosphere for 18 h.
After cooling and ®ltration, the solvent was removed under
reduced pressure. The residue was dissolved in diethyl ether
050cm 3) and successively washed with aqueous ammonia
025%, 3£50cm 3), dilute hydrochloric acid 02£50cm 3) and
water 050cm 3). The ether layer was dried with anhydrous
magnesium sulfate, ®ltered and concentrated under reduced
pressure. Column chromatography of the residue afforded 2-
methylprop-2-enyl 3,6-dimethoxy-2-02-methylprop-2-enyl)-
benzoate 39 as a yellow oil 0430mg, 33%). IR 0®lm):
nmaxˆ1734 cm21 0s, COO), 1657 and 16070w, CvC),
0CH3)v], 55.5 0OCH3)a, 56.00OCH )a, 57.2 0ArCH2OH)a,
3
108.7 0vCH2)b, 110.0 0C-4)b, 110.5 0C-5)b, 128.1 0C-1)c,
c
129.00C-2) , 145.5 [ArCH2C0CH3)v], 151.8 0C-3)d, 152.1
0C-6)d; MS 0EI): m/z 0%): 222 0M1, 100), 204 018), 189 054),
179 022), 175 015), 174 014), 173 014), 149 012), 91 015), 77
012), 43 012); HRMS calcd for C13H18O3 M 222.1256, found
222.1259.
3.1.23. 5,8-Dimethoxy-3-methylisochroman-3-ol 11 and
5,8-dimethoxy-3-methylisochromene 40. Method A. [3,6-
Dimethoxy-2-02-methylprop-2-enyl)phenyl]methanol 35
0227 mg, 1.02 mmol) was dissolved in methanol 020 cm3)
and cooled to -408C. Oxygen containing ozone was passed
through the solution for approximately 1 min, after which
ozone was no longer absorbed, as indicated by the liberation
of iodine from a solution of potassium iodide at the reactor
exit. Dimethyl sul®de 00.15 cm3, 127 mg, 2.04 mmol) was
added; the solution was warmed to ambient temperature and
stirred for 30min. The reaction mixture was concentrated
under reduced pressure. The residue was subjected to
column chromatography 0eluant 5% ethyl acetate/hexane)
to afford 5,8-dimethoxy-3-methylisochromene 40 as white
crystals 038 mg, 0.184 mmol, 18%). Rf 0.65 020% EtOAc/
hexane); mp 52±538C 0hexane/CH2Cl2); IR 0CHCl3):
nmaxˆ1610cm 21 0m, CvC), 1599 0w, CvC), 1039 0m,
1
1074 0s, C±O); H NMR 0200 MHz): dHˆ1.71 [3H, d,
Jˆ0.5 Hz, COOCH2C0CH3)v], 1.79 [3H, s, ArCH2C
0CH3)v], 3.35 [2H, s, ArCH2C0CH3)ˆ], 3.75 03H, s,
OCH3), 3.76 03H, s, OCH3), 4.46±4.47 [1H, m, ArCH2-
C0CH3)vCHaHb], 4.69 [2H, s, COOCH2C0CH3)v] 4.69±
4.73 [overlaps with signal at 4.69, 1H, m, ArCH2-
C0CH3)vCHaHb], 4.94±4.96 [1H, m, COOCH2C0CH3)v
CHaHb], 5.08±5.09 [1H, m, COOCH2C0CH3)vCHaHb],
6.75 01H, d, Jˆ9.0Hz, 4-H), 6.85 01H, d, Jˆ9.0Hz, 5-H);
13C NMR 050MHz): dCˆ19.4 [COOCH2C0CH3)v], 22.7
[ArCH2C0CH3)v], 34.5 [ArCH2C0CH3)v], 56.1 0OCH3),
56.2 0OCH3), 68.4 [COOCH2C0CH3)v], 109.7 [ArCH2C
0CH3)vCH2], 110.7 [COOCH2C0CH3)vCH2], 112.3
0C-4)a, 113.5 0C-5)a, 125.5 0C-1)b, 127.00C-2) b, 139.7
[COOCH2C0CH3)v], 143.6 [ArCH2C0CH3)v], 150.2
0C-3)c, 151.8 0C-6)c, 167.4 [COOCH2C0CH3)v]; MS 0EI):
1
C±O); H NMR 0400 MHz): dHˆ1.85 03H, d, Jˆ0.9 Hz,
3-CH3), 3.66 03H, s, OCH3), 3.68 03H, s, OCH3), 5.04
02H, s, ArCH2O), 5.79 01H, d, Jˆ0.9 Hz, 4-H), 6.50 01H,
d, Jˆ8.9 Hz, 7-H)a, 6.58 01H, d, Jˆ8.9 Hz, 6-H)a; 13C NMR
0100 MHz): dCˆ19.7 03-CH3), 55.7 0OCH3), 56.00OCH ),
3
63.4 0C-1), 95.3 0C-4), 108.0 0C-6)a, 110.0 0C-7)a, 115.8
0C-4a)b, 122.1 0C-8a)b, 146.7 0C-3)c, 148.8 0C-5)c, 154.7
0C-8)c; MS 0EI): m/z 0%): 206 0M1, 100), 205 029), 191
072), 176 010); HRMS calcd for C12H14O3 M 206.0943,
found 206.0946.

9634
C. B. de Koning et al. / Tetrahedron 57 *2001) 9623±9634
7. For a partial review see: 0a) Brimble, M. A.; Nairn, M. R.;
Prabaharan, H. Tetrahedron 2000, 56, 1937±1992. For some
selected examples of mainly 4-oxygenated isochromanes see:
0b) Tatsuta, K.; Akimoto, K.; Annaka, M.; Ohno, Y.;
Kinoshita, M. Bull. Chem. Soc. Jpn 1985, 58, 1699±1706.
0c) Freskos, J. N.; Swenton, J. S. J. Chem. Soc., Chem.
Commun. 1985, 658±659. 0d) Elsworth, J. F.; Giles, R. G. F.;
Green, I. R.; Ramdohr, J. E.; Yorke, S. C. J. Chem. Soc.,
Perkin Trans. 1 1988, 2469±2476. 0e) Brimble, M. A.;
Phythian, S. J. Tetrahedron Lett. 1993, 34, 5813±5814.
0f) Kraus, G. A.; Li, J.; Gorden, M. S.; Jensen, J. H. J. Am.
Chem. Soc. 1993, 115, 5859±5860. 0g) Winters, M. P.;
Stranberg, M.; Moore, H. W. J. Org. Chem. 1994, 59,
7572±7574. 0h) Kraus, G. A.; Li, J.; Gorden, M. S.; Jensen,
J. H. J. Org. Chem. 1994, 59, 2219±2222. 0i) Brimble, M. A.;
Lynds, S. M. J. Chem. Soc., Perkin Trans. 1 1994, 493±496.
0j) Kraus, G. A.; Li, J.; Gorden, M. S.; Jensen, J. H. J. Org.
Chem. 1995, 60, 1154±1159. 0k) Giles, R. G. F.; Joll, C. A.
Tetrahedron Lett. 1995, 36, 1125±1127. 0l) Deshpande, P. P.;
Price, K. N.; Baker, D. C. Bioorg. Med. Chem. Lett. 1995, 5,
1059±1060. 0m) Brimble, M. A.; Phythian, S. J.; Prabaharan,
H. J. Chem. Soc., Perkin Trans. 1 1995, 2855±2860.
0n) Swenton, J. S.; Freskos, J. N.; Dalidowicz, P.; Kerns,
M. L. J. Org. Chem. 1996, 61, 459±464. 0o) Masquelin, T.;
Hengartner, U.; Streith, J. Helv. Chim. Acta 1997, 80, 43±58.
0p) Brimble, M. A.; Neville, D.; Duncalf, L. J. Tetrahedron
Lett. 1998, 39, 5647±5650. 0q) Brimble, M. A.; Nairn, M. R.;
Park, J. Org. Lett. 1999, 1, 1459±1462. 0r) Giles, R. G. F.;
Green, I. R.; Gruchlik, Y.; Oosthuizen, F. J. Aust. J. Chem.
2000, 53, 341±347 and references therein.
Further elution 020% ethyl acetate/hexane) afforded
5,8-dimethoxy-3-methylisochroman-3-ol 11 as a white
needles 0185 mg, 81%). Rfˆ0.38 030% EtOAc/hexane);
mp 107±1098C; IR 0®lm): nmaxˆ3470cm 21 0m, br, OH),
1
1615 0m, CvC), 1070 0w, C±O); H NMR 0200 MHz):
dHˆ1.55 03H, s, 3-CH3), 2.67 01H, d, Jˆ17.2 Hz,
4-HaHb), 2.91 01H, d, Jˆ17.2 Hz, 4-HaHb), 2.92 01H, s,
3-OH), 3.74 03H, s, OCH3), 3.75 03H, s, OCH3), 4.78 02H,
s, ArCH2O), 6.59 01H, d, Jˆ9.0Hz, 7-H) a, 6.64 01H, d,
Jˆ9.0Hz, 6-H) a; 13C NMR 050MHz): dCˆ23.003-CH ),
3
28.8 0C-4), 55.3 0OCH3), 55.5 0OCH3), 58.8 0C-1), 94.3
0C-3), 106.9 0C-7)a, 107.6 0C-6)a, 121.3 0C-8a)b, 123.0
0C-4a)b, 149.1 0C-8)c, 151.1 0C-5)c; MS 0EI): m/z 0%): 224
0M1, 39), 207 05), 206 06), 191 05), 181 06), 164 0100), 149
061), 91 021), 77 018), 65 010); HRMS calcd for C12H14O3 M
224.1049, found 224.1051.
Method B. [3,6-Dimethoxy-2-0prop-2-enyl)]phenylmetha-
nol 12 0160mg, 0.77 mmol) was dissolved in a water/
DMF mixture 01:1, 3 cm3). Palladium0II) chloride 014 mg,
0.08 mmol) and copper0II) chloride 0103 mg, 0.77 mmol)
were added to the solution. Oxygen was bubbled through
the reaction mixture, which was stirred at ambient tempera-
ture for 2 h. The reaction mixture was ®ltered, concentrated
under reduced pressure and the residue was subjected to
column chromatography 0eluant 5% ethyl acetate/hexane)
to afford 5,8-dimethoxy-3-methylisochromene 40 as white
crystals 079 mg, 50%). Further elution 020% ethyl acetate/
hexane) afforded 5,8-dimethoxy-3-methylisochroman-3-ol
11 as a yellow oil 050mg, 29%); characterization as above.
8. de Koning, C. B.; Green, I. R.; Michael, J. P.; Oliveira, J. R.
Tetrahedron Lett. 1997, 38, 5055±5056.
9. Green, I. R.; Hugo, V. I.; Oosthuisen, F. J.; van Eeden, N.;
Giles, R. G. F. S. Afr. J. Chem. 1995, 48, 15±22.
Acknowledgements
10. 0a) Giles, R. G. F.; Green, I. R.; Hugo, V. I.; Mitchell, P. R. K.
J. Chem. Soc., Chem. Commun. 1983, 51±52. 0b) Elsworth,
J. F.; Giles, R. G. F.; Green, I. R.; Ramdohr, J. E.; Yorke, S. C.
J. Chem. Soc., Perkin Trans. 1 1988, 2469±2476.
11. See for example 0a) Organic Synthesis by Oxidation with
Metal Compounds, Mijs, W. J., de Jonge, C. R. H. I., Eds.;
Plenum: New York, 1986. 0b) Bulman Page, P. C.; McCarthy,
T. J. Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 7, pp. 83±
117.
We wish to thank C. F. Broli, C. W. van der Westhuyzen
and L. Li for preparing some of the initial starting materials.
This work was supported by ®nancial aid provided by
the Foundation for Research Development, Pretoria 0now
the National Research Foundation), the University of the
Witwatersrand and the University of the Western Cape.
Mrs S. Heiss of this University and Dr P. Boshoff 0Cape
Technikon) are thanked for recording NMR spectra and
mass spectra, respectively.
12. 0a) Muzart, J.; Ajjou, A. N. J. Mol. Catal. 1991, 66, 155±161.
0b) Muzart, J.; Ajjou, A. N. Synth. Commun. 1993, 23, 2113±
2118.
References
13. Hill, C. L.; Whitesides, G. M. J. Am. Chem. Soc. 1974, 96,
870±875.
1. 0a) Moore, H. W. Science 1977, 197, 527±532. 0b) Moore,
H. W.; Czerniak, R. Med. Res. Rev. 1981, 1, 249±280.
2. 0a) Thomson, R. H. Naturally Occurring Quinones III, Recent
Advances; Chapman & Hall: London, 1987; p. 273 and
references therein. 0b) Omura, S.; Tanaka, H.; Okada, Y.;
Marumo, H. J. Chem. Soc., Chem. Commun. 1976, 320±321.
3. Draeger, G.; Park, S.-H.; Floss, H. G. J. Am. Chem. Soc. 1999,
121, 2611±2612 and references therein.
14. Snyder, C. D.; Rapoport, H. J. Am. Chem. Soc. 1972, 94, 227±
231.
15. de Koning, C. B.; Michael, J. P.; van Otterlo, W. A. L. J. Chem.
Soc., Perkin Trans. 1 2000, 799±811.
16. Green, I. R.; de Koning, C. B.; Hugo, V. I. S. Afr. J. Chem.
1999, 52, 112±119.
17. Giles, R. G. F.; Lee Son, V. R.; Sargent, M. V. Aust. J. Chem.
1990, 43, 777±781.
18. Tsuji, J. Synthesis 1984, 369±384.
4. Brimble, M. A.; Nairn, M. R.; Park, J. S. O. J. Chem. Soc.,
Perkin Trans. 1 2000, 697±709 and references therein.
5. 0a) Parisot, D.; Devys, M.; Barbier, M. Microbois 1990, 64,
31±47. 0b) Medentsev, A. G.; Akimenko, V. K. Phyto-
chemistry 1998, 47, 935±959.
19. Harwood, L. M. J. Chem. Soc., Perkin Trans. 1 1984, 2577±
2582.
6. Thomson, R. H. Naturally Occurring Quinones III, Recent
Advances; Chapman & Hall: London, 1987; p. 276 and
references therein.