Conjugate addition to 3-arylsulfinylchromones as a synthetic route to homochiral 2-substituted chromanones: Scope and limitations

Article abstract of DOI:10.1016/S0040-4020(01)00615-9

A route to homochiral 2-substituted chromanones via the diastereoselective conjugate addition of organocopper reagents to 3-(p-tolylsulfinyl)chromones has been improved and used to prepare 2,6-dimethylchromanone (S)-4 and LL-D253α methyl ether (S)-6. The attempted preparation of a 2-phenylchromanone (flavanone) using this strategy was unsuccessful due to the lability of the intermediate 2-phenyl-3-(p-tolylsulfinyl)chromanone, which underwent sulfoxide elimination at room temperature to give the corresponding 2-phenylchromone (flavone).

Full text of DOI:10.1016/S0040-4020(01)00615-9

TETRAHEDRON
Pergamon
Tetrahedron 57 ,2001) 6793±6804
Conjugate addition to 3-arylsul®nylchromones as a synthetic
route to homochiral 2-substituted chromanones:
scope and limitations
Kevin J. Hodgetts, Konstantina I. Maragkou, Timothy W. Wallacep and Robert C. R. Wootton
Department of Chemistry, School of Sciences, University of Salford, Salford M5 4WT, UK
Received 8 March 2001; revised 9 May 2001; accepted 31 May 2001
AbstractÐA route to homochiral 2-substituted chromanones via the diastereoselective conjugate addition of organocopper reagents to 3-,p-
tolylsul®nyl)chromones has been improved and used to prepare 2,6-dimethylchromanone ,S)-4 and LL-D253a methyl ether ,S)-6. The
attempted preparation of a 2-phenylchromanone ,¯avanone) using this strategy was unsuccessful due to the lability of the intermediate 2-
phenyl-3-,p-tolylsul®nyl)chromanone, which underwent sulfoxide elimination at room temperature to give the corresponding 2-phenylchro-
mone ,¯avone). q 2001 Elsevier Science Ltd. All rights reserved.
The chroman ring system features in a wide variety of
compounds of biological and medicinal interest,1 and new
examples continue to emerge.2 From a synthetic viewpoint,
substituted chroman-4-ones ,2,3-dihydro-4-oxo-4H-1-
benzopyrans)3 are valued both as functional intermediates
and as targets in their own right.4,5 Our interest in such
compounds prompted us to explore a conjugate addition
approach to 2-substituted chromanones,6 and we established
that the treatment of ,S)-3-,p-tolylsul®nyl)chromone 1 with
lithium dimethylcuprate provides the chromanones 2
diastereoselectively, and that their subsequent reductive
desulfurisation generates ,2S)-methylchromanone 3 without
racemisation ,Scheme 1).7
,S)-2,6-dimethylchroman-4-one 4, which has been isolated
from the essential oil produced by natural roots ,and
also from genetically transformed root cultures) of
Leontopodium alpinum ,Edelweiss).8 The second was
,R)-5,7-dimethoxy¯avanone 5, the dimethyl ether of the
uncommon ,1)-antipode of pinocembrin, which was
recently isolated from the pine tree Pseudotsuga
wilsoniana.9 The third target was the methyl ether 6 of the
antibiotic LL-D253a 7, a fungal metabolite isolated from a
culture of Phoma pigmentivora by a group at Lederle.10
The metabolite and methyl derivative were originally
assigned the respective structures 8 and 9, but doubt was
cast on these constitutions by Takahashi et al. following
their isolation of the same metabolite from other micro-
organisms.11 The issue was eventually resolved by
Simpson and coworkers, who synthesised both 7 and 8 in
racemic form.12
We recently applied this methodology to three chromanone
targets with the objective of exploring its scope and limi-
tations, and herein describe our ®ndings. The ®rst target was
Scheme 1. Reagents: ,i) Me2CuLi, Et2O±THF, 278 to 08C; ,ii) Al±Hg, THF±H2O; ,iii) PDC, CH2Cl2.
Keywords: benzopyranone; chromanone; ¯avone; conjugate addition; chiral auxiliary; sulfoxide.
Corresponding author. Fax: 144-0-161-295-5111; e-mail: t.w.wallace@salford.ac.uk
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020,01)00615-9

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K. J. Hodgetts et al. / Tetrahedron 57 (2001) 6793±6804
Scheme 2. Reagents and conditions: ,i) ,R)-,1)-Methyl p-tolyl sulfoxide 11, LDA, THF, 278 to 208C; ,ii) AcOCHO, HCO2Na, toluene, 608C, 3 h;
,iii) Me2CuLi, Et2O±THF, 278 to 08C, then chromatography ,14115, 78%); ,iv) Zn, NH4Cl, THF±H2O, 208C, 3 h.
step had again proceeded with high diastereoselectivity. The
relative stereochemistry of the products 14±17 was assigned
1
by comparison of the H NMR data of the products with
those of the homologues 2 described previously.7 Puri®-
cation of the mixture by ¯ash chromatography gave a
mixture of the trans- and cis-,2S,6)-dimethyl-3-,tolyl-
sul®nyl)chromanones 14 and 15 in 78% overall yield.
The removal of the sulfoxide auxiliary from the mixed
isomers 14 and 15 was initially attempted with aluminium
amalgam, but as before7 this caused some carbonyl reduc-
tion which necessitated a reoxidation with pyridinium
dichromate. This ®nal step of the sequence was much
improved by the use of zinc and ammonium chloride,16
which produced the chromanone ,2)-4 cleanly and in
1
high yield. For the most part the H NMR spectrum of our
material coincided with the reported data,8 but our material
was a crystalline solid ,rather than an oil) with a speci®c
rotation of more than twice that reported. The issue of the
Our approach to the chromanone ,S)-4 was analogous to that
which gave 3, but with two signi®cant re®nements which
made the overall sequence shorter and more ef®cient
,Scheme 2). Firstly, the protection of the starting salicylate
as an ether7 proved unnecessary. Treating methyl 5-methyl-
salicylate 10 with an excess of lithium diisopropylamide
,LDA) followed by the lithium derivative of ,R)-,1)-methyl
p-tolyl sulfoxide 11 gave the desired ketosulfoxide ,R)-12
directly and in good yield. This strategy was used by
homogeneity of the natural material is discussed later.
Our proposed route to the ¯avanone ,R)-5 began with the
acylation of the lithium derivative of the sulfoxide ,R)-11
using methyl 2-hydroxy-4,6-dimethoxybenzoate 1817
,Scheme 3). However, this reaction was rather sluggish,
and gave the ketoester ,R)-19 in only moderate yield
together with unreacted starting materials. We assume, as
Â
13
did Solladie and coworkers, that the two methoxy sub-
Â
Solladie and coworkers in an application of the sulfoxide-
stituents in 18 electronically deactivate the carbonyl
substituent towards nucleophilic attack, and that 2,6-di-
substitution also imposes an adverse steric effect on this
process. The formylation of 19 also required more forcing
conditions, but gave an acceptable yield of the desired
chromone ,S)-,2)-20 as a yellow crystalline solid, mp
151±1528C.
cuprate approach to a ¯avanone,13 and by others for related
enolate anion additions to salicylates.14 The formation of the
chromone 13 was achieved conventionally using acetic
formic anhydride15 and sodium formate. The reaction of
13 with 3 equiv. of lithium dimethylcuprate at 2788C
gave the two desired products 14 [d 1.43 ,d, 2-Me)] and
15 [d 1.90 ,d, 2-Me)] ,$91% of the mixture) and two minor
products, 16 [d 1.86 ,d, 2-Me)] and 17 [d 1.445 ,d, 2-Me)]
,#9% of the mixture) indicating that the conjugate addition
In an attempt to effect the conjugate addition of a phenyl
group to 20, a racemic sample was prepared from ,^)-1118

K. J. Hodgetts et al. / Tetrahedron 57 (2001) 6793±6804
6795
Scheme 3. Reagents and conditions: ,i) ,R)-,1)-11, LDA, THF, 278 to 208C; ,ii) AcOCHO, HCO2Na, 70±808C, 12h; ,iii) PhMgBr, CuBr´SMe 2, Et2O±THF,
278 to 08C; ,iv) room temperature.
as per Scheme 3, and treated with an excess of phenyl-
magnesium bromide and copper,I) bromide±dimethyl
sul®de complex. However, the major product isolated
after conventional work-up and chromatography was
neither of the desired tolylsul®nylchromanones 21 or 22,
but chrysin dimethyl ether 23.19 This would be expected
to arise most readily via the thermal syn-elimination of
p-toluenesulfenic acid from the anticipated major ,trans)
product 21. Such eliminations can be effected at 808C in
the corresponding 2-methyl series,7 but its occurrence at
room temperature or below was unexpected. It appears
that the activation barrier to the elimination process is
signi®cantly lower when the eliminating ,C-2) hydrogen is
1-formylimidazole,22 which was more convenient and
effective than acetic formic anhydride, and provided the
chromone 31 in good yield.
The addition of lithium dimethylcuprate to the chromone
31, carried out as before, yielded a mixture of products
1
which was analysed by H NMR spectroscopy. The major
component was assigned the 2R-trans structure 32 on the
basis of characteristic signals [dH ,300 MHz) 1.32,3H, d,
Jˆ6.5 Hz, 2-Me), 2.31 ,3H, s, 400-Me), 3.42,1H, d, Jˆ2Hz,
3-H), 5.31 ,1H, dq, Jˆ2, 6.5 Hz, 2-H)] which were analo-
gous to those of 14. A second isomer, assigned the 2R-cis
structure 33, was also evident [dH ,300 MHz) 1.67 ,3H, d,
Jˆ6.5 Hz, 2-Me)], but neither of the minor ,2S) isomers
could be distinguished. Reductive desulfurisation16 of the
crude mixture, followed by chromatography, gave the
chromanone ,1)-34 as a crystalline solid, mp 101±1038C.
The values for the speci®c rotation of this material before
and after recrystallisation were consistent with a minimum
of 90% diastereoselectivity in the cuprate addition step. The
transformation of ,1)-34 into the target molecule was
accomplished via Lemieux±Johnson cleavage23 of the
side-chain to obtain the aldehyde 35, followed by boro-
hydride reduction, which gave ,R)-,1)-6 as a colourless
Â
benzylic. Solladie also encountered this facile elimination in
a similar system,13 and it represents a signi®cant limitation
to the effectiveness of the sulfoxide±cuprate methodology
as a route to ¯avanones. However, it does offer a direct route
from 3-,arylsul®nyl)chromones to ¯avones, as exempli®ed
by the copper,I)-assisted addition of phenylmagnesium
bromide to the sulfoxide ,^)-1, which provided the parent
system 24 in 91% yield.
Our attempts to prepare the LL-D253a derivative ,R)-6
began with the heat-induced Claisen rearrangement20 of
the allyl ether 25 to the salicylate 26, which proceeded
almost quantitatively and established the requisite aromatic
substitution pattern ,Scheme 4). However, the reaction of
the ester 26 with the lithium derivative of methyl p-tolyl
sulfoxide 11 gave, at best, only a trace of the desired product
27 after several attempts, and it appeared that the deacti-
vating electronic and steric effects ®rst encountered with the
ester 18 were now prohibitive. Fortunately the correspond-
ing aldehyde 29, prepared from the allylphenol 2821 by
Vilsmeier formylation, proved more reactive towards the
sulfoxide nucleophile and the chromone precursor 27 was
accessible in moderate overall yield via sulfoxide addition,
producing the mixed alcohols 30, followed by oxidation
with manganese dioxide. Following a protocol developed
1
crystalline solid whose properties ,mp, H NMR spectrum)
corresponded to those previously described.10 An exception
to this was the speci®c rotation, which had the correct sign
but was considerably higher than the published value ,see
Scheme 4). Such a discrepancy was observed with the
simpler analogue ,S)-,2)-4, and invites some speculation
as to the optical purity of the materials isolated from natural
sources. There are various reasons why chiral compounds of
biosynthetic origin might not be enantiomerically pure,24
but for chromanones such as 4 and 6 there is the possibility
of partial racemisation via the reversible ,retro-Michael)
elimination of the pyran oxygen, either in vivo or during
isolation. The conditions under which this process can be
induced ,or avoided) have been discussed.25
for use in a similar context by Solladie et al.,13 formylation
Â
of 27 was in this instance effected using in situ-generated
The sluggish reaction of the lithiated sulfoxide 11 with the

6796
K. J. Hodgetts et al. / Tetrahedron 57 (2001) 6793±6804
Scheme 4. Reagents and conditions: ,i) 2158C, 12h ,98%); ,ii) LDA, THF±DMPU, , S)-,2)-11, 278 to 208C ,trace); ,iii) POCl3, DMF, MeCN, 0±208C, 7 h
,83%); ,iv) LDA, THF, ,S)-,2)-11, 278 to 208C, then MnO2, CH2Cl2, 2 08C, 48 h ,57%); ,v) LDA, THF, 1-formylimidazole, 278 to 208C, 18 h, then SiO2,
CH2Cl2, 2 08C, 16 h ,73%); ,vi) Me2CuLi, Et2O±THF, 278 to 2108C, HOAc quench; ,vii) Zn, NH4Cl, THF±H2O, 208C, 3 h ,54% over two steps); ,viii) cat.
OsO4, NaIO4, THF±water, 208C, 3 h, then NaBH4, THF, 20 min ,53% over two steps).
Scheme 5.

K. J. Hodgetts et al. / Tetrahedron 57 (2001) 6793±6804
6797
Scheme 6. Reagents: ,i) LDA, CuI, THF, 2788C, then room temperature, 2h ,42%, ee 66 ^9% R); ,ii) KH, THF, 2788C, then room temperature, 3 h ,31%, ee
23^6% S).
ester 26, circumvented using the aldehyde 29, prompted us
to examine another potential route to intermediate keto-
sulfoxides. Some time ago we established that this type of
molecule is accessible via the sul®nylation of ketone
enolates.26 Thus, reacting the acetophenones 36 and 3727
with sodium hydride and ethyl p-toluenesul®nate ,^)-3828
gave fair yields of the corresponding ketosulfoxides 39
,48%) and 40 ,55%), together with unreacted starting
material in each case ,Scheme 5).
ether) 5 was unsuccessful due to the thermal instability of
the intermediate 2-phenyl-3-,p-tolylsul®nyl)chromanone
21, which underwent sulfoxide elimination at room
temperature to give the corresponding 2-phenylchromone
,¯avone) 23.
1. Experimental
1.1. General
In seeking to extend this approach to homochiral targets, we
attempted to prepare ,R)-12 from the acetophenone 41 using
,2)-menthyl ,S)-p-toluenesul®nate 42 as the sul®nylating
species. Two different conditions were used, but in each
case the procedure was neither ef®cient nor stereoselective.
With LDA in the presence of copper,I) iodide, the sul®nyl-
ation proceeded in 42% yield, but although polarimetry
indicated a net inversion at sulfur this was only partial.
With potassium hydride as the base both the yield and the
stereoselectivity were lower, the outcome this time being
net retention at sulfur. Extending the reaction times of these
sul®nylations did not signi®cantly change the yield or
stereoselectivity ,Scheme 6).
All compounds are racemic unless their names are preceded
by stereochemical descriptors. Melting points were deter-
mined using an Electrothermal apparatus and are uncor-
rected. Unless otherwise stated, IR spectra were of neat
thin ®lms on NaCl plates, recorded on a Perkin±Elmer
1710FT spectrometer. NMR spectra were measured on
Varian Gemini-300 ,1H at 300 MHz), Bruker AC300
spectrometer ,1H at 300 MHz, 13C at 75 MHz), or Varian
Unity-400 ,1H at 400 MHz) instruments for solutions in
deuteriochloroform with tetramethylsilane as the internal
standard; coupling constants ,J values) are quoted to the
nearest 0.5 Hz. Mass spectra were measured on Finnegan
4500 or Micromass Trio 2000 ,low resolution) and Kratos
Concept 1S ,high resolution) instruments using the ammo-
nia CI method unless stated. Data for most peaks with an
intensity of less than 20% of that of the base peak are
omitted. Optical rotations were measured at 589 nm using
AA-10 and AA-100 polarimeters ,Optical Activity Ltd.).
The divergent mechanistic pathways which would account
for these results remain obscure, but there are precedents.
Sul®nylation of the sodium enolate of cyclohexanone with
methyl p-toluenesul®nate proceeds with inversion at sulfur,
whereas with the corresponding lithium enolate the net
result is retention; the stereoselectivity is only partial ,ca.
10%) in each case.29 In the present case one possibility is the
involvement of other potential sul®nylating species derived
from 42, e.g. the aryl sul®nate ,R)-43 or enol sul®nate 44,
which could mediate the formation of ,S)-12 via two succes-
sive inversions at sulfur. The intramolecular transformation
of 43 into ,S)-12, essentially a sulfur variant of the Baker±
Venkataraman rearrangement,30 is another intriguing possi-
bility which we are currently investigating.
Starting materials and solvents were routinely puri®ed by
conventional techniques31 and most reactions were carried
out under nitrogen or argon. Organic solutions were dried
using anhydrous magnesium sulfate and concentrated by
rotary evaporation. Analytical thin layer chromatography
,TLC) was carried out on Camlab Polygram SIL G/UV254
plates. The chromatograms were visualised by the use of
UV light or the following developing agents; ethanolic
vanillin or potassium permanganate. Unless otherwise
indicated, preparative ,column) chromatography was
carried out on 60H silica gel ,Merck 9385) or basic alumina
using the ¯ash technique.32 Compositions of solvent
mixtures are quoted as ratios of volume. `Petroleum' refers
to a light petroleum fraction, bp 40±608C, unless otherwise
stated.
In summary, a route to homochiral 2-substituted chroma-
nones based on the diastereoselective conjugate addition of
organocopper reagents to 3-,p-tolylsul®nyl)chromones has
been re®ned and used to prepare ,S)-2,6-dimethylchroma-
none 4 and LL-D253a methyl ether 6. An application of the
strategy to 5,7-dimethoxy¯avanone ,pinocembrin dimethyl
1.1.1. (R)-1-(2-Hydroxy-5-methylphenyl)-2-(4-methyl-
phenylsul®nyl)ethanone (1)-12. A solution of LDA was
prepared by adding n-butyllithium in hexane ,1.6 M,
11.25 ml, 18 mmol) dropwise to a stirred solution of diiso-
propylamine ,1.84 g, 2.55 ml, 18.2 mmol) in THF ,15 ml)
under nitrogen at 08C. The solution was stirred for 0.25 h at

6798
K. J. Hodgetts et al. / Tetrahedron 57 (2001) 6793±6804
08C prior to use. Meanwhile two separate reaction ¯asks, A
and B, were set up. Flask A contained a stirred solution of
,R)-,1)-methyl p-tolyl sulfoxide ,1.0 g, 6.48 mmol) in THF
,5 ml) at 2788C. Flask B contained a stirred solution of
methyl 2-hydroxy-5-methylbenzoate ,1.08 g, 6.50 mmol)
in THF ,5 ml) at 2788C. To ¯ask A was added a portion
,10 ml, ca. 6.8 mmol) of the LDA solution, while to ¯ask B
was added a portion ,5 ml, ca. 3.43 mmol) of the LDA
solution. After 10 min the solution in ¯ask B was added to
¯ask A, and the resulting mixture was stirred for 0.5 h and
then allowed to reach 08C over 0.5 h. The reaction mixture
was then quenched by the addition of 3 M hydrochloric acid
,10 ml), extracted with ethyl acetate ,3£30 ml), and the
extract washed with brine ,25 ml) and dried. Evaporation
gave a yellow solid which was crystallised from ethanol to
obtain the title compound ,1)-12 ,1.70 g, 91%) as a colour-
less solid, mp 1288C ,Found: C, 67.10; H, 5.49; S, 11.29.
C16H16O3S requires C, 66.64; H, 5.59; S, 11.12%) ,M1H1,
were washed with brine ,20 ml), dried and evaporated [the
400 MHz NMR spectrum of the residue indicated that the
product consisted of 14 ,dH 1.43), 15 ,dH 1.90), 16 ,dH 1.86)
and 17 ,dH 1.445) ,ratio 72:19:6:3 by NMR), assignments
being made on the basis of analogy with the previous
study7]. Flash chromatography ,elution with ether±hexane
2:1) gave the mixed ,2S)-isomers 14 and 15 ,245 mg, 78%)
as a mixture ,ratio 5:1 by 400 MHz 1H NMR spectroscopy).
The ,2S)-trans isomer 14 had dH ,400 MHz) 1.43 ,3H, d,
Jˆ6.7 Hz, 2-Me), 2.30±2.45 ,obscured 2£3H, s, 6-Me,
40-Me), 3.49 ,1H, d, Jˆ2.4 Hz, 3-H), 5.46 ,1H, dq, Jˆ
2.4, 6.7 Hz, 2-H), 6.93 ,2H, d, Jˆ8.5 Hz, 8-H), 7.25±7.55
,5H, m, Ar0H4 and 7-H) and 7.95 ,1H, br. s, 5-H). The
,2S)-cis isomer 15 had characteristic signals at dH
,400 MHz) 1.90 ,3H, d, Jˆ6.7 Hz, 2-Me), 3.39 ,1H, d, Jˆ
2.5 Hz, 3-H) and 4.89 ,dq, Jˆ2.5, 6.7 Hz, 2-H). The ,2R)-cis
isomer 16 had characteristic signals at dH ,400 MHz) 1.86
,3H, d, Jˆ6.7 Hz, 2-Me), 3.85 ,1H, d, Jˆ2.5 Hz, 3-H) and
4.95 ,dq, Jˆ2.5, 6.7 Hz, 2-H). The ,2R)-trans isomer 17 was
assigned signals at dH ,400 MHz) 1.445 ,3H, d, Jˆ6.7 Hz,
2-Me), 3.85 ,1H, d, Jˆ 2.5 Hz, 3-H) and 5.15 ,dq, Jˆ2.5,
6.7 Hz, 2-H).
22
289.0901. C16H17O3S requires 289.0898); [a]D ˆ1141^7
,c 1.0, CHCl3); nmax 3400±2900 br, 1637 ,CvO), 1615,
1591, 1489, 1338, 1298, 1250, 1211, 1169, 1085, 1050
,S±O), 1015, 992, 813 cm21; dH ,300 MHz) 2.26 ,3H, s,
5-Me), 2.40 ,3H, s, 40-Me), 4.23 ,1H, d, Jˆ15 Hz, SCH),
4.52,1H, d, Jˆ15 Hz, SCH), 6.87 ,1H, d, Jˆ8 Hz, 3-H),
7.25±7.35 ,4H, m, 4-H, 6-H, 30-H, 50-H), 7.55 ,2H, d, Jˆ
8 Hz, 20-H, 60-H), 11.57 ,1H, s, OH); m/z ,peaks $10%) 306
,trace), 289 ,3), 152 ,12), 151 ,100).
1.1.4. (S)-2,3-Dihydro-2,6-dimethyl-4H-1-benzopyran-4-
one (2)-4. To a vigorously stirred solution of 14115
,157 mg, 0.50 mmol) in THF ,7 ml) and saturated aqueous
ammonium chloride ,7 ml) at room temperature was added
activated zinc powder ,2g, 30 mmol). 16 After 3 h the
mixture was ®ltered through Celitew and washed on the
®lter with ethyl acetate. The ®ltrate was partitioned and
the aquous phase extracted with more ethyl acetate
,2£30 ml). The combined organic phase was washed with
saturated aqueous sodium hydrogen carbonate ,10 ml),
dried and evaporated. Flash chromatography of the residue
,elution with ether±hexane 1:9) gave the title compound
,2)-4 ,78 mg, 89%) as a colourless solid, mp 768C ,lit.8
oil) ,Found: C, 75.17; H, 6.74. C11H12O2 requires C, 74.98;
1.1.2.
(S)-6-Methyl-3-(4-methylphenylsul®nyl)-4H-1-
benzopyran-4-one (2)-13. A mixture of the sulfoxide
,R)-,1)-12 ,884 mg, 3.07 mmol), acetic±formic anhy-
dride15 ,5.77 g, 65.5 mmol), and anhydrous sodium formate
,4.5 g, 66.2mmol) in toluene ,10 ml) was heated to 60 8C for
3 h and then allowed to cool to room temperature. The
resulting yellow solid was partitioned between ethyl acetate
,30 ml) and water ,30 ml), and the aqueous phase extracted
with more ethyl acetate ,30 ml). The combined organic
extract was washed with brine ,30 ml), dried and evaporated
to obtain the title compound ,2)-13 ,890 mg, 97%) as a
colourless solid, mp 1748C ,EtOH) ,Found: C, 68.51; H,
4.67; S, 11.01. C17H14O3S requires C, 68.44; H, 4.73; S,
20
H, 6.86%); [a]D ˆ268^4 ,c 1.0, MeOH); nmax ,FT, neat)
1683, 1621, 1576, 1492, 1456, 1420, 1357, 1294, 1229,
1175, 1146, 1031, 949, 890, 867, 823, 791 cm21; dH ,300
MHz) 1.48 ,3H, d, Jˆ6 Hz, 2-Me), 2.28 ,3H, s, 6-Me),
2.60±2.70 ,2H, m, 3-H2), 4.47±4.59 ,1H, m, 2-H), 6.85
,1H, d, Jˆ8.5 Hz, 8-H), 7.26 ,1H, br. d, Jˆ8.5 Hz, 7-H)
and 7.65 ,1H, br. s, 5-H); dC ,75 MHz) observed [lit.8]
20.38 [18.32] ,6-Me), 20.98 [19.80] ,2-Me), 44.67 [42.6]
,C-3), 74.23 [72.3] ,C-2), 117.65 [114.5] ,C-8), 120.43
[118.6] ,C-4a), 126.52 [124.4] ,C-5), 130.63 [128.8]
,C-6), 137.05 [134.5] ,C-7), 159.78 [155.7] ,C-8a), 192.74
[190.9] ,C-4); m/z ,peaks $10%) 194 ,28), 178 ,11), 177
,100); m/z ,EI, peaks $20%) 177 ,28), 176 ,90), 135 ,24),
134 ,100), 51 ,30), 49 ,83), 47 ,21).
22
10.75%); [a]D ˆ2352^11 ,c 2.0, CHCl3); nmax 1636,
1617, 1605, 1484, 1298, 1125, 1084, 1044 ,S±O), 813,
786 cm21; dH ,400 MHz) 2.36 ,3H, s, 5-Me), 2.42 ,3H, s,
40-Me), 7.27 ,2H, d, Jˆ8 Hz, 30-H, 50-H), 7.41 ,1H, d, Jˆ
8.5 Hz, 8-H), 7.51 ,1H, dd, Jˆ2.5, 8.5 Hz, 7-H), 7.78 ,2H, d,
Jˆ8 Hz, 20-H, 60-H), 7.89 ,1H, br. s, 5-H), 8.39 ,1H, s, 2-H);
m/z ,peaks $20%) 316 ,6), 299 ,70), 283 ,74), 163 ,24), 161
,100), 58 ,46).
1.1.3. Conjugate addition of lithium dimethylcuprate to
the chromone (S)-(2)-13. 2,3-Dihydro-2,6-dimethyl-3-
,4-methylphenylsul®nyl)-4H-1-benzopyran-4-ones 14±17.
To a stirred solution of lithium dimethylcuprate, prepared
from copper,I) iodide ,0.95 g, 5 mmol) in ether ,20 ml) and
methyllithium ,1.5 M; 6.7 ml, 10 mmol) at 08C under
nitrogen, was added dropwise at 2788C a solution of
,S)-,2)-13 ,0.298 g, 1.0 mmol) in THF ,10 ml). After 2 h
at 2788C the mixture was allowed to warm up to 08C over
ca. 1 h and then quenched by the addition of saturated
aqueous ammonium chloride ,30 ml). The organic layer
was separated and the aqueous layer was extracted with
ethyl acetate ,3£20 ml). The combined organic phases
1.1.5. (R)-1-(2-Hydroxy-4,6-dimethoxyphenyl)-2-(4-methyl-
phenylsul®nyl)ethanone (2)-19. To a stirred solution of
diisopropylamine ,1.3 ml, 0.94 g, 9.28 mmol) in THF
,5 ml) under argon at 2788C was added dropwise n-butyl-
lithium ,1.3 M; 7.2ml, 9.36 mmol). After 20 min a solution
of ,R)-,1)-methyl p-tolyl sulfoxide 11 ,0.90 g, 5.84 mmol)
in THF ,5 ml) was added dropwise to the stirred solution.
The reaction mixture was stirred at 2788C for a further
0.5 h, at which point a solution of methyl 2-hydroxy-4,6-
dimethoxybenzoate 1817 ,1.6 g, 7.54 mmol) in THF ,15 ml)
and n-butyllithium ,1.3 M; 5.8 ml, 7.54 mmol) was added

K. J. Hodgetts et al. / Tetrahedron 57 (2001) 6793±6804
6799
dropwise. After 1 h at 2788C, the reaction mixture was
allowed to return to room temperature over 2h and
quenched by addition of 2M HCl ,15 ml). The mixture
was extracted with DCM ,5£25 ml), and the combined
extracts were washed with water ,2£20 ml), saturated aq.
sodium hydrogen carbonate ,20 ml) and brine ,20 ml), and
then dried and evaporated. Flash chromatography of the
residual yellow oil, eluting with DCM±petroleum ,6:1),
followed by crystallisation from ethanol, gave the title
compound ,2)-19 ,1.13 g, 58%) as pale yellow crystals,
mp 107±1098C ,M1H1, 335.0957. C17H19O5S requires
1260, 1099, 1018, 798 cm21; dH ,300 MHz) 3.89 ,3H, s,
OMe), 3.93 ,3H, s, OMe), 6.35 ,1H, d, Jˆ2Hz, 6-H),
6.55 ,1H, d, Jˆ2Hz, 8-H), 6.66 ,1H, s, 3-H), 7.45±7.50
,3H, m, 30,40,50-H), 7.83±7.87 ,2H, m, 20,60-H) [lit.19 dH
3.93 ,s), 3.97 ,s), 6.39 ,d, Jˆ2Hz), 6.59 ,d, Jˆ2Hz), 6.70
,s), 7.52,m), 7.90 ,m)]; m/z ,CI) 283 ,M1H1, 100%); Rf
,DCM±ethyl acetate 4:1) 0.25. The chromatography also
yielded a portion of unreacted starting material 20 ,15 mg,
25%).
1.1.8. 2-Phenyl-4H-1-benzopyran-4-one 24. A solution of
the chromone ,^)-17 ,200 mg, 0.70 mmol) and copper,I)
bromide±dimethyl sul®de complex ,576 mg, 2.80 mmol)
in THF ,20 ml) under argon was cooled to 2788C and
treated dropwise with a solution of phenylmagnesium
bromide in THF ,1.0 M, 2.8 ml, 2.8 mmol). The resulting
mixture was stirred at 2788C for 1.5 h and at 08C for 1 h,
after which the reaction was quenched by the addition of
saturated aq. ammonium chloride ,15 ml). The mixture was
extracted with ethyl acetate ,3£40 ml). The combined
organics were washed with 2M HCl ,40 ml), water
,40 ml), and brine ,40 ml), dried and evaporated to a yellow
oil. Flash chromatography, eluting with petroleum±ethyl
acetate ,2:1) gave 2-phenyl-4H-1-benzopyran-4-one 24
,143 mg, 91%) as a colourless solid, mp 98±998C, which
was identical ,TLC, IR, 1H NMR) with a commercial
sample.33
20
335.0953); [a]D ˆ230^2 ,c 1.0, CHCl3); nmax ,Nujol)
1615, 1591, 1284, 1219, 1199, 1153, 1125, 1048, 842,
810 cm21; dH ,300 MHz) 2.38 ,3H, s, Me), 3.81 ,3H, s,
OMe), 3.84 ,3H, s, OMe), 4.31 and 4.70 ,each 1H, d,
Jˆ14 Hz, CH2), 5.89 ,1H, d, Jˆ2Hz, 3-H), 6.03 ,1H, d,
Jˆ2 Hz, 5-H), 7.28 ,2H, d, Jˆ8 Hz, 30,50-H), 7.55 ,2H, d,
1
Jˆ8 Hz, 20,60-H), 13.24 ,1H, s, OH); m/z 352,M 1NH4
,
16%), 336 ,16), 335 ,M1H1, 100), 294 ,60), 197 ,25); Rf
,DCM±ethyl acetate 4:1) 0.40 ,brown with vanillin).
The chromatography also yielded portions of unreacted
sulfoxide 11 ,0.2 g, 22%) and ester 18 ,0.7 g).
1.1.6. (S)-5,7-Dimethoxy-3-(4-methylphenylsul®nyl)-4H-
1-benzopyran-4-one (2)-20. A mixture of the sulfoxide
,2)-19 ,800 mg, 2.39 mmol), acetic±formic anhydride
,4.16 g, 47 mmol), and anhydrous sodium formate ,3.25 g,
48 mmol) was heated to 70±808C for 12h and then allowed
to cool to room temperature. Water ,30 ml) was added and
the mixture was extracted with dichloromethane ,3£20 ml).
The combined extracts were washed with water ,3£20 ml)
and brine ,20 ml), dried, and evaporated. Flash chroma-
tography of the residual yellow oil, eluting with ethyl
acetate±petroleum ,1:1), followed by crystallisation from
ethyl acetate, gave the title compound ,2)-20 ,552mg,
67%) as yellow crystals, mp 151±1528C ,Found: C,
62.38; H, 4.59. C18H16O5S requires C, 62.78; H, 4.68%)
,M1H1, 345.0782. C18H17O5S requires 345.0797);
1.1.9. Methyl 2-allyloxy-4,6-dimethoxybenzoate 25. To a
stirred suspension of methyl 2-hydroxy-4,6-dimethoxy-
benzoate 1817 ,1.00 g, 4.7 mmol) and anhydrous potassium
carbonate ,12g, 87 mmol) in dry acetone ,100 ml) in a
conical ¯ask ®tted with a powerful stirrer and a drying
tube was added allyl bromide ,0.5 ml, 0.70 g, 5.8 mmol).
The mixture was stirred at room temperature for 24 h,
®ltered and the ®ltrate treated with 1 M ammonium
hydroxide ,100 ml). The mixture was extracted with DCM
,3£100 ml) and the combined extract was dried and evapo-
rated to give the crude product as an oil ,0.90 g, 3.6 mmol,
76%) which was dif®cult to purify as it underwent rearran-
gement when distilled ,M1H1, 253.1080. C13H17O5
requires 253.1076); nmax 1729, 1608, 1422, 1267, 1226,
1203, 1161, 1124, 1053, 820 cm21; dH 3.78 ,6H, s,
2£OMe), 3.86 ,3H, s, CO2Me), 4.51 ,2H, dt, Jˆ1.5, 5 Hz,
10-H2), 5.22 ,1H, dq, Jˆ1.5, 10.5 Hz, 30-H), 5.36 ,1H, dq,
Jˆ1.5, 17.5 Hz, 30-H), 5.96 ,1H, overlapping ddt, Jˆ5,
10.5, 17.5 Hz, 20-H), 6.07, 6.08 ,each 1H, d, Jˆ2Hz, 3-H
and 5-H); m/z 253 ,M1H1, 100%).
20
[a]D ˆ2203^2 ,c 1.0, CHCl3); nmax ,Nujol) 1642, 1602,
1586, 1277, 1220, 1157, 1077, 1026, 1012, 825 cm21; dH
,300 MHz) 2.33 ,3H, s, Me), 3.85 ,3H, s, OMe), 3.86 ,3H, s,
OMe), 6.33 ,1H, d, Jˆ2.5 Hz, 6-H), 6.46 ,1H, d, Jˆ2.5 Hz,
8-H), 7.23 ,2H, d, Jˆ8 Hz, 30,50-H), 7.77 ,2H, d, Jˆ8 Hz,
20,60-H), 8.17 ,1H, s, 2-H); m/z 345 ,M1H1, 100), 207 ,25);
Rf ,DCM±ethyl acetate 4:1) 0.30 ,yellow with vanillin).
1.1.7. 5,7-Dimethoxy-2-phenyl-4H-1-benzopyran-4-one
23. A solution of the chromone ,^)-20 ,60 mg, 0.17
mmol) and copper,I) bromide±dimethyl sul®de complex
,180 mg, 0.88 mmol) in THF ,10 ml) under argon was
cooled to 2788C and treated dropwise with a solution of
phenylmagnesium bromide in ether ,3.0 M, 0.3 ml,
0.9 mmol). The resulting green mixture was stirred at
2788C for 1.5 h and at 08C for 1 h, after which the reaction
was quenched by the addition of saturated aq. ammonium
chloride ,5 ml). The layers were separated and the aqueous
layer was extracted with ethyl acetate ,3£10 ml). The
combined organics were washed with 2M HCl ,10 ml),
water ,2£15 ml), and brine ,10 ml), dried and evaporated
to a brown oil. Flash chromatography, eluting with DCM±
ethyl acetate ,4:1) gave 5,7-dimethoxy-2-phenyl-4H-1-
benzopyran-4-one 23 ,23 mg, 47%) as a yellow solid, mp
146±1488C ,lit.19 148±1498C); nmax ,Nujol) 1648, 1608,
1.1.10. Methyl 2-hydroxy-3-(prop-2-en-1-yl)-4,6-di-
methoxybenzoate 26. Methyl 2-allyloxy-4,6-dimethoxy-
benzoate 25 ,0.90 g, 3.6 mmol) was degassed by exposure
to a vacuum ,0.01 mmHg) for 0.5 h. The ¯ask was then
¯ushed with argon, ®tted for re¯ux with a short, narrow
air condenser, heated on a Woods metal bath at 2158C for
12h and then allowed to cool. The product could be recrys-
tallised from methanol to give the title compound 26 ,0.88 g,
98%). The analytical sample, obtained by sublimation, had
mp 898C ,Found: C, 62.10; H, 6.31; C13H16O5 requires C,
61.90; H, 6.39%); nmax 3410 br, 1730, 1640, 1613, 1460,
1408, 1278, 1206, 1161, 1121, 996, 952, 909, 814,
780 cm21; dH 3.33 ,2H, dt, Jˆ1.5, 6 Hz, 10-H2), 3.85 ,3H,
s, OMe), 3.86 ,3H, s, OMe), 3.90 ,3H, s, CO2Me),

6800
K. J. Hodgetts et al. / Tetrahedron 57 (2001) 6793±6804
4.90±5.00 ,2H, m, 30-H2), 5.86±5.99 ,1H, m, 20-H), 5.99
,2H, s, 3-H, 5-H), 11.31 ,1H, s, OH) ppm; dC ,75 MHz)
26.58 ,C-10), 52.15 ,ester OMe), 55.51 ,ArOMe), 56.12
,ArOMe), 87.17 ,C-5), 96.69 ,C-1), 107.87 ,C-3), 113.92
,C-30), 136.56 ,C-20), 161.05, 162.15, 162.71 ,C-20, C-40,
C-60), 171.86 ,CvO); m/z 270 ,M1NH41, 8%), 253
,M1H1, 100), 227 ,22), 213 ,35), 195 ,95).
®ltered through a pad of Celitew with the aid of more
DCM. Evaporation of the ®ltrate gave an orange solid
which was washed with ether and collected on a ®lter,
providing the title compound ,1)-27 ,1.650 g, 53%) as a
pale yellow powder. The ether washings were concentrated,
dissolved in ethyl acetate and the solution ®ltered through a
plug of silica gel with the aid of more ethyl acetate. Concen-
tration and trituration with ethanol gave a second crop of
,1)-27 as a yellow solid ,123 mg; total 1.773 g, 57%). The
analytical sample had mp 150±1518C ,EtOH) ,Found: C,
64.39; H, 6.00; S, 8.69. C20H22O5S requires C, 64.15; H,
1.1.11. (S)-1-[2-Hydroxy-4,6-dimethoxy-3-(2-propen-1-
yl)phenyl]-2-(4-methylphenylsul®nyl)ethanone (1)-27.
Method 1. In ¯ask A: To a solution of the ester 26
,242 mg, 1 mmol) in THF ,3 ml) and 1,3-dimethyl-3,4,
5,6-tetrahydro-2,1H)-pyrimidinone ,DMPU) ,1.5 ml),
chilled to 2788C, was added LDA in THF ,1.5 M, 1.0 ml,
1.5 mmol). In ¯ask B: to a solution of ,S)-,2)-methyl
p-tolyl sulfoxide 11 ,200 mg, 1.3 mmol) in THF ,3 ml)
and DMPU ,1.5 ml), chilled to 2788C was added LDA in
THF ,1.5 M, 2.0 ml, 3 mmol). The contents of ¯ask A were
added to ¯ask B at 2788C and the mixture stirred for 0.5 h,
then allowed to rise to room temperature and stirred over-
night. The mixture was quenched with HCl ,2M, 3 ml),
diluted with water ,10 ml) and extracted with ethyl acetate
,3£20 ml). The combined organics were washed with water
,3£30 ml), dried and evaporated. The mixture was freed of
excess DMPU by dissolving the solid in methanol±water
,1:1; 10 ml) and extracting with hexane ,3£10 ml). After
drying and evaporation this yielded a solid ,10 mg) which
TLC and NMR analysis showed to contain a trace of the
desired product 27 [dH 4.31 ,1H, d, Jˆ14 Hz, 2-H), 4.74
,1H, d, Jˆ14 Hz, 2-H)], but mainly the starting ester 26.
30
5.92; S, 8.56%); [a]D ˆ154^2 ,c 1.5, CHCl3); nmax
3392 br, 1620, 1587, 1470, 1413, 1292, 1217, 1141, 1048,
809 cm21; dH 2.38 ,3H, s, 4000-Me), 3.27±3.30 ,2H, m,
100-H2), 3.88 ,3H, s, OMe), 3.91 ,3H, s, OMe), 4.31 ,1H,
d, Jˆ14 Hz, 2-H), 4.74 ,1H, d, Jˆ14 Hz, 2-H), 4.89±4.97
,2H, m, 300-H2), 5.81±5.93 ,1H, m, 200H), 5.94 ,1H, s, 50-H),
7.28 ,2H, d, Jˆ8 Hz, 3000-H, 5000-H), 7.54 ,2H, d, Jˆ8 Hz,
2000-H, 6000-H), 13.15 ,1H, s, OH); dC ,75 MHz) 21.40 ,4000-
Me), 26.19 ,C-100), 55.69 ,2£OMe), 72.06 ,C-2), 86.17
,C-50), 105.76, 108.40 ,C-10, C-30), 114.14 ,C-300 124.45
,C-20, C-6000), 129.83 ,C-3000, C-5000), 136.11 ,C-200), 141.03,
0
141.81 ,C-1000, C-4000), 161.65, 163.80, 164.62,C-2 , C-40,
C-60), 194.17 ,C-1); m/z ,CI) 392,M 1NH41, ,5%), 375
,M1H1, 10), 237 ,100) ,M1H1, 375.1271. C20H23O5S
requires 375.1266); Rf ,EtOAc) 0.46; red with vanillin.
1.1.12. 2-Hydroxy-3-(prop-2-en-1-yl)-4,6-dimethoxybenz-
aldehyde 29. A stirred solution of DMF ,5.0 ml, 4.72g,
65 mmol) in acetonitrile ,20 ml) at room temperature was
treated dropwise with phosphoryl chloride ,5.0 ml, 8.23 g,
54 mmol). After 1 h the solution was cooled to 08C and
treated dropwise with a solution of the phenol 2821
,4.85 g, 25 mmol) in acetonitrile ,20 ml). After the addition,
which took 10 min, the mixture was left for 1 h at 08C and
the ice-bath then removed. The mixture was then stirred at
room temperature for 7 h, and then added slowly to ice ,ca.
200 g) in a 250 ml beaker. The mixture was stirred for
30 min and then left to stand overnight ,14 h). The aqueous
medium contained a mass of beige needles, together with
some dark resinous material, the majority of which was
stuck to the beaker. The product was collected on a Buchner
funnel and washed well with water. The organic material
was dissolved in DCM ,total 75 ml), dried over anhydrous
magnesium sulfate, ®ltered and evaporated. The residue was
dissolved in a small volume of DCM and the solution
®ltered through a short plug of silica, eluting with more
DCM. The eluate was evaporated to a golden yellow oil
,4.60 g, 83%) that solidi®ed. Crystallisation from ethanol
,25 ml) gave the title compound 29 ,2.82 g, 51%, in two
crops) as cream needles, mp 85±868C ,Found: C, 64.41;
H, 6.19. C12H14O4 requires C, 64.85; H, 6.19%); nmax
,Nujol) 1640, 1618, 1433, 1412, 1298, 1251, 1222, 1204,
1117, 796 cm21; dH ,300 MHz) 3.28 ,2H, d, Jˆ6 Hz,
10-H2), 3.87 ,3H, s, OMe), 3.88 ,3H, s, OMe), 4.90±5.02
,2H, m, 30-H2), 5.82±5.99 ,1H, m, 2 0-H), 5.93 ,1H, s, 5-H),
10.11 ,1H, s, CHO), 10.93 ,1H, s, OH); m/z ,CI) 223
,M1H1, 100%).
Method 2. A solution of LDA was prepared by treating
diisopropylamine ,1.3 ml, 939 mg, 9.28 mmol) in THF
,20 ml) at 25 to 2108C ,ice/acetone bath) with BuLi in
hexane ,1.6 M; 5.8 ml, 9.28 mmol). To this was added a
solution of ,S)-,2)-methyl p-tolyl sulfoxide 11 ,1.30 g,
8.43 mmol) in THF ,10 ml), and the resulting pale yellow
solution was kept at 2108C until required ,solution A). A
second solution of LDA was prepared by treating diiso-
propylamine ,1.3 ml, 939 mg, 9.28 mmol) in THF ,20 ml)
at 25 to 2108C with BuLi in hexane ,1.6 M; 5.8 ml,
9.28 mmol). This solution was transferred via a cannula
into a suspension of the aldehyde 29 ,1.840 g, 8.28 mmol)
in THF ,20 ml) at 2788C. The mixture was stirred at 08C for
1 h ,suspension B). Suspension B was then cooled to 2788
and solution A was added to it via a cannula. The resulting
mixture was stirred for 0.5 h at 2788C and the reaction
vessel then kept in an ice bath at 08C for 1 h, during
which a clear pale yellow solution was formed. The reaction
was then quenched with 1 M hydrochloric acid ,60 ml) and
extracted with ethyl acetate ,3£40 ml). The combined
organic phases were washed with brine ,2£25 ml), dried,
®ltered and concentrated. TLC ,EtOAc) showed the mixed
alcohols 30 as an unresolved spot ,Rf 0.63, UV active, blue±
green with vanillin), together with traces of 11 ,Rf 0.30, UV
active, white with vanillin) and 29 ,Rf 0.71, brown with
vanillin), and an unidenti®ed non-polar by-product ,Rf
0.80, pink with vanillin). The crude products 30 ,max.
8.2794 mmol) and MnO2 ,Aldrich 21,764-6; dried for 2 h
at 1308C/0.1 mmHg; 10.8 g, 124.2 mmol, 15 equiv.) in
DCM ,80 ml) was stirred at room temperature for 48 h.
TLC ,EtOAc) indicated that conversion to the product ,Rf
0.46; red with vanillin) was complete. The solution was
1.1.13. (R)-5,7-Dimethoxy-8-(2-propen-1-yl)-3-(4-methyl-
phenylsul®nyl)-4H-1-benzopyran-4-one (1)-31. A solu-
tion of LDA was prepared by treating diisopropylamine
,1.6 ml, 1.155 g, 11.42mmol) in THF ,25 ml) at 2108C

K. J. Hodgetts et al. / Tetrahedron 57 (2001) 6793±6804
6801
,ice/acetone bath) with BuLi in hexane ,1.6 M; 7.2ml,
11.52mmol). This was added to a suspension of keto-
sulfoxide ,1)-27 ,1.528 g, 4.08 mmol) in THF ,20 ml) at
2788C, giving an orange solution. The solution was then
allowed to warm up to 2108C and was stirred at that
temperature for 10 min ,solution A). Meanwhile, 1-formyl-
1H-imidazole was prepared in situ at room temperature by
adding a solution of formic acid ,0.36 ml, 439 mg,
9.54 mmol) in THF ,4 ml) to a solution of 1,10-carbonyl-
diimidazole ,1.560 g, 9.62mmol) in THF ,15 ml) ,solution
B). Solution A was then cooled back to 2788C, treated with
solution B, and the mixture then allowed to warm up to
room temperature. The solution was stirred overnight
[18 h] and then quenched with 1 M sulfuric acid ,15 ml).
The organic solvents were evaporated and the residue was
taken up with DCM ,150 ml) and washed with brine
,2£50 ml). The organic phase was dried, ®ltered and
was partitioned between water ,40 ml) and ethyl acetate
,40 ml). The organic layer was separated and the water
layer was extracted with ethyl acetate ,2£20 ml). The
combined organic phase was washed with sat. aq. sodium
hydrogen carbonate ,20 ml), and brine ,2£20 ml), dried
1
over anhydrous sodium sulfate and evaporated. The H
NMR spectrum of the residue ,317 mg) suggested that the
major product was ,2R,3R,SS)-32 [dH ,300 MHz) 1.32,3H,
d, Jˆ6.5 Hz, 2-Me), 2.31 ,3H, s, 400Me), 3.25 ,2H, d,
Jˆ6.5 Hz, 10-H2), 3.42,1H, d, Jˆ2Hz, 3-H), 3.79 ,3H, s,
OMe), 3.81 ,3H, s, OMe), 4.80±4.95 ,2H, m, 30-H2), 5.31
,1H, dq, Jˆ2, 6.5 Hz, 2-H), 5.75±5.90 ,1H, m, 20-H), 6.03
,1H, s, 6-H), 7.19 ,2H, d, Jˆ8 Hz, 300H, 500H), 7.35 ,2H, d,
Jˆ8 Hz, 200-H, 600-H)]. A second product was tentatively
identi®ed as ,2R,3S,SS)-33 [dH ,300 MHz) 1.67 ,3H, d,
Jˆ6.5 Hz, 2-Me)]. The ratio 32±33 was approximately
6:1 by NMR. Due to the complexity of the spectrum no
other isomers were quanti®able. Reductive desulfurisation16
was effected as follows: To a vigorously stirred solution of
the above product mixture ,max. 0.695 mmol) in THF
,10 ml) and sat. aq. ammonium chloride ,10 ml) at room
temperature was added activated zinc powder ,3 g,
46 mmol). After 3 h the mixture was ®ltered through
Celitew and washed on the ®lter with ethyl acetate
,30 ml). The ®ltrate was partitioned and the aqueous
phase extracted with more ethyl acetate ,2£30 ml). The
combined organic phase was washed with sat. aq. sodium
hydrogen carbonate ,30 ml), brine ,30 ml), dried and evapo-
rated. Flash chromatography of the residue ,elution with
DCM±ethyl acetate 9:1) gave the title compound ,1)-34
,99 mg, 54% over two steps) as a colourless solid
²
concentrated. The crude product was dissolved in DCM
,70 ml) and stirred in the presence of ¯ash silica ,5 g) for
16 h. The mixture was then poured on to the top of a column
of silica gel±DCM and eluted with DCM±ethyl acetate
,3:1) until a yellow ¯uorescent by-product was about to
emerge. Concentration of the eluate and trituration of the
residual solid ,1.300 g, 83%) with ether gave the title
compound ,1)-31 ,1.147 g, 73%, in two crops) as an
off-white solid. Crystallisation from ethyl acetate gave ¯uffy
white needles, mp 180±1828C ,Found: C, 65.40; H, 5.23; S,
8.64. C21H20O5S requires C, 65.61; H, 5.24; S, 8.34%);
22
[a]D ˆ1258^5 ,c 1.5, chloroform); nmax 1643, 1621,
1598, 1568, 1469, 1386, 1269, 1210, 1128, 1075, 1051,
909, 808 cm21; dH ,300 MHz) 2.31 ,3H, s, 400Me), 3.44
,2H, d, Jˆ6 Hz, 10-H2), 3.88 ,3H, s, OMe), 3.89 ,3H, s,
OMe), 4.88±4.95 ,2H, m, 30-H2), 5.77±5.91 ,1H, m,
20-H), 6.36 ,1H, s, 6-H), 7.21 ,2H, d, Jˆ8 Hz, 300-H,
500H), 7.75 ,2H, d, Jˆ8 Hz, 200H, 600H), 8.18 ,1H, s, 2-H);
dC ,75 MHz) 21.41 ,400-Me), 26.68 ,C-10), 56.03
,OMe), 56.38 ,OMe), 92.28 ,C-6), 108.60, 108.72 ,C-4a,
C-8), 115.04 ,C-30), 125.59 ,C-200, C-600 129.80 ,C-300,
C-500 129.98 ,C-3), 135.26 ,C-20), 140.68, 141.87 ,C-100,
C-400, 152.91 ,C-2), 156.86, 160.07, 162.00 ,C-5, C-7,
C-8a), 173.04 ,C-4); m/z ,CI, peaks .10%) 385 ,M1H1,
11%), 251 ,10), 249 ,57), 248 ,14), 247 ,100); Rf 0.41
,EtOAc).
24
{[a]D ˆ179^2 ,c 2.0, chloroform)}. A sample was
crystallised by dissolving in the minimum of hot ethyl
acetate and adding an excess of petroleum, which gave
pale yellow prisms, mp 101±1038C ,Found: C, 68.86; H,
24
6.87. C15H18O4 requires C, 68.68; H, 6.92%); [a]D
ˆ
183^2 ,c 1.8, chloroform); nmax ,neat) 1672, 1601, 1571,
1465, 1345, 1267, 1214, 1130, 911, 824 cm21; dH
,300 MHz) 1.42,3H, d, Jˆ6.5 Hz, 2-Me), 2.56 ,2H, d, Jˆ
7.5 Hz, 3-H2), 3.25±3.30 ,2H, m, 10-H2), 3.85 ,3H, s, OMe),
3.88 ,3H, s, OMe), 4.44 ,1H, apparent dq, ca. Jˆ7 Hz, 2-H),
4.86±4.98 ,2H, m, 30-H2), 5.78±5.92,1H, m, 2 -H), 6.06
0
,1H, s, 6-H); dC ,75 MHz) 20.68 ,2-Me), 26.79 ,C-10),
45.84 ,C-3), 55.68 ,OMe), 56.03 ,OMe), 73.66 ,C-2),
88.66 ,C-6), 106.12, 108.44 ,C-4a, C-8), 114.06 ,C-30),
136.56 ,C-20), 160.97, 161.46, 163.19 ,C-5, C-7, C-8a),
190.34 ,C-4); m/z ,CI, peaks $10%) 264 ,11%), 263
,M1H1, 100), 160 ,18); Rf ,EtOAc) 0.35 ,red±orange
with vanillin).
1.1.14. (R)-2,3-Dihydro-5,7-dimethoxy-2-methyl-8-(2-pro-
pen-1-yl)-4H-1-benzopyran-4-one (1)-34. To a stirred
solution of lithium dimethylcuprate, prepared from
copper,I) bromide±dimethylsul®de complex ,298 mg,
1.45 mmol) in ether ,8 ml) and methyllithium±lithium
bromide complex ,2.2 M; 1.3 ml, 2.86 mmol) at 08C under
Ar, was added dropwise at 2788C an ice-cold solution of
,R)-,1)-31 ,267 mg, 0.695 mmol) in THF ,10 ml). The
yellow solution was kept at 2788C for 1 h, allowed to
reach 2108C over 1 h, and then cooled back to 2788C
and quenched by the dropwise addition of a solution of
glacial acetic acid ,0.5 ml) in THF ,2ml). The mixture
In repeat of the above sequence, a fraction containing 32
and 33 ,88 mg, 0.22 mmol) was isolated from the cuprate
addition product by ¯ash chromatography ,elution with
DCM±ethyl acetate 9:1). This was dissolved in THF
,4 ml) and treated as described above with sat. aq. ammo-
nium chloride ,4 ml) and zinc powder ,1 g, 15 mmol) for
2h. Isolation as before followed by ¯ash chromatography
,elution with DCM±ethyl acetate 9:1) gave the title
compound ,1)-34 ,43.5 mg, 75%) as a colourless crystal-
line solid.
²
NMR analysis at this stage showed the required product 31 and a signi®-
cant other, possibly a hemiacetal ,i.e. 2-hydroxychromanone) precursor
of 31 [dH ,300 MHz) ,tentative assignments) 3.32,2H, d, Jˆ6 Hz, 10-H2),
5.82,1H, d, Jˆ2.5 Hz, 3-H), 6.07 ,1H, s, 6-H), 6.16 ,1H, d, Jˆ 2.5 Hz,
2-H), 7.08 ,2H, d, Jˆ8 Hz, 300H, 500H), 7.41 ,2H, d, Jˆ8 Hz, 200H, 600H),
8.17 ,1H, s, OH).
1.1.15. (R)-2-(2,3-Dihydro-5,7-dimethoxy-2-methyl-4-oxo-
4H-1-benzopyran-8-yl)ethanol (1)-6. To a solution of the

6802
K. J. Hodgetts et al. / Tetrahedron 57 (2001) 6793±6804
chromanone ,1)-34 ,65 mg, 0.248 mmol) in THF ,4 ml)
and water ,2ml) was added osmium tetroxide ,4% solution
in water, 0.2ml, 0.031 mmol). After the solution had
darkened, NaIO4 ,125 mg, 0.58 mmol) was added and the
mixture was stirred for a further 3 h. The solution was
diluted with water ,20 ml) and extracted with ethyl acetate
,3£20 ml), and the extract was washed with sat. aq. sodium
thiosulfate ,20 ml) and brine ,20 ml). Drying with anhy-
drous sodium sulfate and evaporation gave 35, Rf ,EtOAc)
0.27. A solution, prepared by stirring sodium borohydride
,21 mg, 0.56 mmol) in ethanol ,8 ml) at room temperature
for 10 min, was added dropwise to a stirred solution of the
crude aldehyde 35 prepared as above ,max. 65.5 mg,
0.248 mmol) in dry THF ,7 ml) under Ar. The reaction,
followed by TLC ,elution with ethyl acetate), was complete
after 20 min. The mixture was poured into 0.2 M hydro-
chloric acid ,40 ml) and the solution extracted with DCM
,2£30 ml). The extract was washed with brine ,20 ml), dried
and evaporated, and the residue chromatographed ,elution
with ethyl acetate±DCM 1:1) to obtain the title compound
,1)-6 ,33 mg, 53%), mp 164±1658C ,ethyl acetate);
room temperature under N2 was treated portionwise with
sodium hydride ,0.30 g, 80% oil dispersion, 10 mmol).
The mixture was heated at re¯ux temperature for 4 h and
water ,20 ml) then added. The resulting solution was
neutralised with 3 M hydrochloric acid ,5 ml) and extracted
with ethyl acetate ,3£20 ml). The combined extracts were
washed with water and brine, dried, ®ltered and evaporated.
Chromatography of the residue on silica gel using ether as
eluant gave the title compound 39 ,0.95 g, 48%) and the
unreacted starting material 36 ,0.61 g). The spectra of 39
were identical with those of an authentic sample.7
1.1.18. 1-(2-Phenylmethoxy)phenyl-2-(4-methylphenyl-
sul®nyl)ethanone (^)-40. The preparation of 40 was
carried out as described above for 39, using 20-benzyloxy-
acetophenone 3727 ,1.13 g, 5 mmol), ethyl p-toluene-
sul®nate ,^)-3828 ,0.92g, 5 mmol) and sodium hydride
,0.30 g, 80% oil dispersion, 10 mmol). The title compound
,^)-40 ,1.0 g, 55%) was isolated as colourless needles, mp
111±1138C ,ether±DCM) ,Found: C, 72.75; H, 5.66.
C22H20O3S requires C, 72.50; H, 5.53%); nmax 1650, 1590
and 1040 cm21; dH ,60 MHz) 2.40 ,3H, s, Me), 4.26 ,1H, d,
Jˆ14.5 Hz, 2-H), 4.58 ,1H, d, Jˆ14.5 Hz, 2-H), 5.13 ,2H, s,
OCH2), 6.80±7.95 ,13H, m, ArH); m/z ,EI, peaks $20%)
364 ,M1, 29%), 257 ,33), 229 ,39), 226 ,27), 225 ,75), 224
,31), 223 ,29), 211 ,47), 209 ,31), 140 ,36), 139 ,76), 133
,21), 121 ,60), 120 ,39), 119 ,22), 118 ,32), 105 ,39), 104
,20), 92 ,76), 91 ,100), 90 ,41), 89 ,39), 78 ,21), 77 ,54). A
portion of the starting material 37 was also recovered from
the column.
22
[a]D ˆ156^4 ,c 0.63, methanol); nmax 3500±3200 br,
1650, 1606, 1571, 1471, 1350, 1287, 1212, 1124, 1047,
814 cm21; dH ,300 MHz) 1.44 ,3H, d, Jˆ6.5 Hz, 2-Me),
1.80 ,1H, br s, OH), 2.57 ,2H, apparent d, Jˆ7.5 Hz,
3-H2), 2.86 ,2H, t, Jˆ6.5 Hz, 20-H2), 3.70 ,2H, t, Jˆ
6.5 Hz, 10-H2), 3.86 ,3H, s, OMe), 3.89 ,3H, s, OMe),
4.46 ,1H, apparent sextet, ca. Jˆ7 Hz, 2-H), 6.07 ,1H, s,
6-H); dC ,75 MHz) 20.71 ,20-Me), 26.26 ,C-2), 45.78
,C-30), 55.67 ,OMe), 56.06 ,OMe), 62.49 ,C-1), 73.85
0
,C-20), 88.79 ,C-60), 106.17, 106.92,C-4a , C-80), 161.19,
161.77, 163.59 ,C-50, C-70, C-8a0), 190.00 ,C-40); m/z ,CI)
267 ,M1H1, 100%), 160 ,23); Rf ,EtOAc) 0.22 ,orange
1.1.19. 1-(2-Hydroxy-5-methylphenyl)-2-(4-methylphenyl-
sul®nyl)ethanone 12 from the ketone 41. Using lithium
diisopropylamide and copper(I) iodide. To a stirred solution
of 2-hydroxy-5-methylacetophenone 41 ,50 mg, 0.33
mmol) and CuI ,63 mg, 0.33 mmol) in THF ,3 ml) at
2788C was added a solution of LDA in THF ,0.25 M,
4.0 ml, 1.0 mmol). The mixture was allowed to warm to
room temperature over the course of 0.5 h, then cooled
again to 2788C. A solution of ,1R,2S,5R)-,2)-menthyl
,S)-p-toluenesul®nate 42 ,100 mg, 0.34 mmol) in THF
,3 ml) was slowly added and the mixture was then allowed
to warm to room temperature and stirring continued for 2h.
The mixture was quenched with sat. aq. ammonium chloride
,15 ml) and extracted with ethyl acetate ,3£15 ml). The
extract was washed with water ,2£10 ml) and 0.5 M hydro-
chloric acid ,10 ml), dried and evaporated. The products
were separated on a short silica column, eluting with
ether. Evaporation of the eluate gave a sample of the keto-
sulfoxide 12 ,40 mg, 0.14 mmol, 42%) which was identical
with vanillin). Lit.10 for the methyl ether 6 prepared from
25
LL-D253a 7: mp 165±1668C ,ethyl acetate); [a]D
ˆ
136.0^0.36 ,c 0.545, MeOH); d ,60 MHz) 1.48 ,3H, d,
Jˆca. 7 Hz, 2-Me), 1.85 ,1H, s, OH), 2.51 and 2.63 ,2H,
m, 3-H2), 2.87 ,2H, t, Jˆca. 7 Hz, benzylic CH2), 3.73 ,2H,
t, Jˆca. 7 Hz, CH2OH), 3.89 and 3.90 ,each 3H, s, OMe),
4.50 ,1H, complex quartet, 2-H), 6.12 ,1H, s, ArH).
1.1.16. 1-(2-Phenylmethoxy)phenylethanone 36. A stirred
mixture of 2-hydroxyacetophenone ,2.72 g, 20 mmol),
4-methoxybenzyl chloride ,3.13 g, 20 mmol) and anhydrous
potassium carbonate ,4.14 g, 30 mmol) in acetone ,20 ml)
was heated under re¯ux for 48 h. The solid was removed by
®ltration and the ®ltrate was concentrated and then diluted
with ethyl acetate ,30 ml). The solution was washed succes-
sively with aq. sodium hydroxide ,4 M, 3£30 ml), water and
brine, dried and evaporated. The residue was distilled under
reduced pressure to obtain the title compound 36 ,3.9 g,
76%), bp 190±1958C ,oven temp.) at 0.12mmHg, which
crystallised from ether as colourless needles, mp 67±688C
,Found: C, 75.08; H, 6.43. C16H16O3 requires C, 74.98; H,
6.29%); nmax 1670, 1620, 1600 cm21; dH ,60 MHz) 2.6 ,3H,
s, COMe), 3.8 ,3H, s, OMe), 5.05 ,2H, s, OCH2), 6.8±8.0
,8H, m, ArH); m/z ,EI) 250 ,M1, 2.5%), 122 ,65), 121 ,100),
78 ,49), 77 ,53).
1
,TLC, H NMR) with the material obtained as described
22
earlier and had [a]D ˆ193^8 ,c 0.58, CDCl3). On repeat-
22
ing the above sequence with an increased reaction time of
48 h, the isolated ketosulfoxide 12 ,ca. 40%) had [a]D
174^6 ,c 1.54, CDCl3).
ˆ
Using potassium hydride. To a stirred suspension of KH
,35% dispersion in mineral oil, 160 mg, 1.4 mmol) in
THF ,2.5 ml) under Ar at 2788C was added a solution of
the hydroxyacetophenone 41 ,51 mg, 0.34 mmol) in THF
,2.5 ml). The mixture was stirred for 3 h until the second
colour change ,yellow to yellow±green) was complete. A
solution of ,1R,2S,5R)-,2)-menthyl ,S)-p-toluenesul®nate
1.1.17.
1-(2-(4-Methoxyphenylmethoxy)phenyl-2-(4-
methylphenylsul®nyl)ethanone (^)-39. A stirred solution
of the ketone 36 ,1.36 g, 5.3 mmol) and ethyl p-toluene-
sul®nate ,^)-3828 ,0.92g, 5 mmol) in THF ,20 ml) at

K. J. Hodgetts et al. / Tetrahedron 57 (2001) 6793±6804
6803
Tetrahedron Lett. 1994, 35, 6347±6350. Dauzonne, D.;
Monneret, C. Synthesis 1997, 1305±1308. Gabbutt, C. D.;
Hepworth, J. D.; Urquhart, M. W. J.; Vazquez de Miguel,
L. M. J. Chem. Soc., Perkin Trans. 1 1997, 1819±1824.
Arjona, O.; Garranzo, M.; Mahugo, J.; Maroto, E.; Plumet,
42 ,100 mg, 0.34 mmol) in THF ,3 ml) was added and the
mixture was then allowed to warm to room temperature and
stirring continued for 3 h. The mixture was quenched with
sat. aq. ammonium chloride ,15 ml) and extracted with ethyl
acetate ,3£30 ml). The extract was washed with water
,3£30 ml), dried and evaporated. The products were sepa-
rated on a short silica column, eluting with ether. Evapora-
tion of the eluate gave a sample of the ketosulfoxide 12
Â
J.; Saez, B. Tetrahedron Lett. 1997, 38, 7249±7252.
Woydowski, K.; Ziemer, B.; Liebscher, J. J. Org. Chem.
1999, 64, 3489±3491. Draper, R. W.; Hu, B.; Iyer, R. V.;
Li, X.; Lu, Y.; Rahman, M.; Vater, E. J. Tetrahedron 2000,
56, 1811±1817.
1
,30 mg, 0.10 mmol, 31%) which was identical ,TLC, H
NMR) with the material obtained as described earlier and
22
5. For some recent approaches to chromenes and chromans, see:
North, J. T.; Kronenthal, D. R.; Pullockaran, A. J.; Real, S. D.;
Chen, H. Y. J. Org. Chem. 1995, 60, 3397±3400. Pelter, A.;
Hussain, A.; Smith, G.; Ward, R. S. Tetrahedron 1997, 53,
3879±3916. Johannes, C. W.; Visser, M. S.; Weatherhead,
G. S.; Hoveyda, A. H. J. Am. Chem. Soc. 1998, 120, 8340±
8347. Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1998, 120,
9074±9075 also p. 9400. Jung, M. E.; MacDougall, J. M.
Tetrahedron Lett. 1999, 40, 6339±6342. Hodgetts, K. J.
Tetrahedron Lett. 2000, 41, 8655±8659. Wang, Q.; Finn,
M. G. Org. Lett. 2000, 2, 4063±4065. Torraca, K. E.; Kuwabe,
S.-I.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 12907±
12908.
had [a]D ˆ232^7 ,c 0.5, CDCl3). On repeating the above
22
sequence with an increased reaction time of 18 h, the
isolated ketosulfoxide 12 ,ca. 30%) had [a]D ˆ226^7
,c 0.5, CDCl3).
Acknowledgements
We thank Dr Suthiweth Saengchantara for preliminary
experiments, Mrs Ruth Howard for mass spectra, and Mrs
Laurie Cunliffe, Dr Steve Simpson and Dr Mike Stuckey for
their assistance with NMR measurements. We also wish to
acknowledge the use of the EPSRC's Chemical Database
Service at Daresbury.
6. Saengchantara, S. T.; Wallace, T. W. Tetrahedron 1990, 46,
3029±3036.
7. Saengchantara, S. T.; Wallace, T. W. Tetrahedron 1990, 46,
6553±6564.
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