Synthesis of a Diels-Alder precursor for the Elisabethin A skeleton

Article abstract of DOI:10.1055/s-2002-33919

A synthesis of a precursor 2 for the Elisabethin A skeleton is reported. Containing a masked quinone and a (E,Z)-diene sub-unit, it has the required elements for the envisaged intramolecular Diels-Alder reaction to form the tricyclic system of Elisabethin A. Starting from methylresorcinol, the sequence involves the preparation of an arylacetic acid, which was α-alkylated by a chiral building block. Subsequent HWE reaction and cis-selective Wittig olefination furnished the diene with the desired geometry.

Full text of DOI:10.1055/s-2002-33919

PAPER
1857
Synthesis of a Diels–Alder Precursor for the Elisabethin A Skeleton
P
recursor for th
h
e
Elisabethin
i
A
Ske
l
leton o J. Heckrodt, Johann Mulzer*
Institut für Organische Chemie der Universität Wien, Währingerstr. 38, 1090 Wien, Austria
Fax +43(1)427752189; E-mail: johann.mulzer@univie.ac.at
Received 25 April 2002; revised 21 June 2002
Abstract: A synthesis of a precursor 2 for the Elisabethin A skele-
ton is reported. Containing a masked quinone and a (E,Z)-diene sub-
unit, it has the required elements for the envisaged intramolecular
Diels–Alder reaction to form the tricyclic system of Elisabethin A.
Starting from methylresorcinol, the sequence involves the prepara-
tion of an arylacetic acid, which was -alkylated by a chiral building
block. Subsequent HWE reaction and cis-selective Wittig olefina-
tion furnished the diene with the desired geometry.
Key words: total synthesis, natural products, alkylations, Wittig re-
actions, stereoselectivity
Elisabethin A (1) is a marine diterpenoid, which was iso-
lated in 1998 from the chemically rich Caribbean gorgon-
ian Pseudopterogorgia elisabethae (Octocorallia).1 It acts
as a highly bioactive terpenoid secondary metabolite.
Studies to assess the biological properties of this com-
pound are currently underway. The structure of Elisabe-
thin A is representative for previously undescribed natural
products possessing a novel carbon skeleton.2
The retrosynthetic disconnection is shown in Scheme 1.
We planned to introduce the required olefinic unit (C10–
C11) in a late stage of the synthesis. Further disconnection
implies an intramolecular Diels–Alder reaction of an
(E,Z)-diene to a p-benzoquinone. The precursor for the
key step is molecule 2, which contains a masked quinone.
Compound 2 is derived from arylacetic acid 3a, which has
to be -alkylated with iodide 4. In our first approach we
converted 3a into the Evans oxazolidinone derivative 3b
to achieve a highly diastereocontrolled alkylation.
Scheme 1 Retrosynthetic disconnection
however this new route gives better yields than the de-
scribed syntheses.3
Regioselective introduction of a chloromethyl group via
Blanc reaction furnished 11 in 94% yield. Subsequent
conversion to the nitrile using TMSCN/TBAF at room
temperature afforded 12,4 which was hydrolysed under
basic conditions to yield the arylacetic acid 3a
(Scheme 3). Conversion into 3b was achieved via the
mixed anhydride, whereas the chloride did not react.
The synthesis of 3a and 3b started with methylresorcinol
(5), which was acetylated by a Friedel–Crafts type reac-
tion with acetic anhydride and BF3 OEt2 as Lewis acid.
During the subsequent attempt to protect both hydroxy
groups as methyl ethers it turned out, that under mild con-
ditions selective methylation of the p-hydroxy group is
possible in high yield (>90%). This is due to the fact that
the o-hydroxy group is more hindered and a strong hydro-
The chiral alkylation agent for 3a/b was synthesised as
shown in Scheme 4. PMB-protection of the hydroxy
group of the commercially available (R)-(–)-3-hydroxy-2-
methylpropionic acid ester 13 followed by reduction of
the methyl ester with LiAlH4 gave the alcohol 14, that was
converted into the iodide 4 by an Appel reaction
(Scheme 4). Compound 4 is known, however, no synthet-
ic procedures nor spectroscopic data are available; the
synthesis outlined below surpasses, by far, the yield de-
scribed in literature (60% overall compared with 46%).5
1
gen bond to the ketone exists (sharp signal in the H
NMR). This result might be useful for an orthogonal pro-
tecting group strategy. Under more drastic conditions
dimethylated compound 8 was obtained in 95% yield.
Bayer–Villiger oxidation with MCPBA gave the desired
ester, which was hydrolysed and methylated to yield tri-
methoxytoluene 10 (Scheme 2). Compound 10 is known,
In the next operation, it turned out that deprotonated 3b
would not react with iodide 4. Obviously, the bulky ox-
azolidinone moiety shielded the -position so efficiently
that the access of the alkylating agent was prevented. To
Synthesis 2002, No. 13, Print: 20 09 2002.
Art Id.1437-210X,E;2002,0,13,1857,1866,ftx,en;T05102SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1858
T. J. Heckrodt, J. Mulzer
PAPER
Scheme 4 Reagents and conditions: a) PMB-TCAI (2.0 equiv),
CSA (0.1 equiv), CH2Cl2, 14 h, r.t., 84%; b) LiAlH4 (2.5 equiv), Et2O,
18 h, r.t., 97%; c) Im (2.5 equiv), Ph3P (2.5 equiv), I2 (2.0 equiv), ben-
zene, 3 h, r.t., 73% (Im = imidazole, PMB-TCAI p-methoxybenzyltri-
chloroacetimidate, CSA = camphorsulfonic acid).
Scheme 2 Reagents and conditions: a) Ac2O (1.1 equiv), BF3 Et2O
(2.4 equiv), 80 °C, 6 h, 99% (recrystalised from H2O–MeOH); b)
K2CO3 (4.0 equiv), Me2SO4 (4.0 equiv), acetone, 14 h, r.t., 90%
(with 1.0 equiv/1.0 equiv >95%); c) K2CO3 (2.0 equiv), Me2SO4
(2.0 equiv), acetone, 48 h, reflux, 95%; d) MCPBA (2.0 equiv),
TosOH H2O (0.03 equiv), CH2Cl2, 14 h, r.t., 63%; e) KOH (2.0
equiv), MeOH–H2O, 3 h, reflux, 98%; f) K2CO3 (2.0 equiv), Me2SO4
(2.0 equiv), acetone, 14 h, r.t., 91% (MCPBA = m-chloroperbenzoic
acid, TosOH = p-toluenesulfonic acid).
Scheme 5 Reagents and conditions: a) Bu2BOTf (1.2 equiv), Et3N
(1.3 equiv), then add 15 (1.0 equiv), CH2Cl2, 6 h, –78 °C 0 °C, 74%,
91% de; b) MesCl (5.0 equiv), Et3N (1.5 equiv), DMAP (0.2 equiv),
CH2Cl2, 6 h, r.t.; c) LiAlH4 (2.5 equiv), Et2O, 10 h, r.t.
Thus, we returned to the free acid 3a. Treatment with two
equivalents of BuLi resulted in the formation of the deep
red dianion, which was alkylated with iodide 4
(Scheme 6). The -alkylation proceeded with acceptable
yield, leading to the formation of two diastereomers 18a/
1
b in a ratio of 66:34, as determined from the H NMR
spectrum. As the isolation of acids 18a/b was difficult, the
crude product mixture was reduced either with LiAlH4 or
Me2S BH3 to the corresponding alcohols 19a/b with 62%
overall yield (Scheme 6). Without separation, compounds
19a/b were protected as TBS-ethers and the PMB-protect-
ing group was cleaved with DDQ to yield alcohols 20a/b.
Subsequent Swern oxidation furnished the aldehydes 21a/
b quantitatively without any racemization. To introduce
the first double bond, a Horner–Wadsworth–Emmons re-
action was carried out to give the desired amides 23a/b in
92% total yield (diastereomeric mixture) and excellent
trans-selectivity (>95:5). At this stage of the synthesis it
was possible to separate the diastereomers completely by
normal flash chromatography. The major isomer 23a was
isolated in 57% yield and reduced to the aldehyde 24 with
Scheme 3 Reagents and conditions: a) HCHO 37% (5.0 equiv),
HCl 32% (3.0 equiv), HCl gas, 1 h, 70 °C, 94%; b) TMSCN (1.5
equiv), TBAF (1.5 equiv), MeCN, 10 h, r.t., 81%; c) NaOH (2.0
equiv), H2O, 8 h, reflux, 100%; d) PivCl (1.1 equiv), Et3N (1.3
equiv), Evans oxazolidinone (1.2 equiv), THF, 10 h, –78 °C r.t.,
90% (PivCl = pivaloyl chloride, TBAF = tetrabutylammonium fluo-
ride, TMSCN = trimethylsilyl cyanide).
remedy this situation we envisaged an aldol addition of 3b
and the known aldehyde 15,6 with ensuing removal of the
superfluous hydroxyl function via deoxygenation. In fact,
the aldol addition did stereoselectively furnish adduct 16.
All attempts, however, to convert 16 into 17 were unsuc-
cessful (Scheme 5).
Synthesis 2002, No. 13, 1857–1866 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of a Diels–Alder Precursor for the Elisabethin A Skeleton
1859
three equivalents of DIBAL-H in 98% yield. (Z)-Selective with K2CO3 in methanol the desired lactol 26 was formed
Wittig reaction of 24 with Ph3P=CHCH3 furnished the de- as a 45:55 mixture of anomers. To simplify the NMR
sired key intermediate 2 (Scheme 6).
spectra for the required NOE experiments of the cyclic
compound, the anomeric center was destroyed by oxida-
tion to the lactone 27 (along with elimination product 28)
using Dess–Martin periodinane (Scheme 7).
Scheme 7 Assignment of the stereochemistry. Reagents and condi-
tions: a) (COCl)2 (2.0 equiv), DMSO (4.0 equiv), Et3N (6.0 equiv),
CH2Cl2, –78 °C r.t.; b) TBAF (2.0 equiv), THF, r.t., 1 h; c) K2CO3
(2.0 equiv), MeOH, reflux, 2.5 h, 89% over 3 steps; d) DMP (5.0
equiv), NaHCO3 (20.0 equiv), CH2Cl2, r.t., 1 h, 92% (27 + 28, 1:1)
(TBAF = tetrabutylammonium fluoride, DMP = Dess–Martin peri-
odinane).
The NOE between H-2 and H-4 indicated that lactone 27
possesses the shown stereochemistry 2S,4S and therefore
the main product of the -alkylation (3a 18a/b) has to be
the desired 2R,4S-isomer.
In conclusion, a facile route to diastereomerically pure
Elisabethin A precursor 2 was developed. Particularly
noteworthy in this sequence is the high C-nucleophilicity
of the dianion which even reacts smoothly with poor elec-
trophiles such as iodide 4. Evans alkylations are of very
limited applicability in these cases.
Scheme 6 Reagents and conditions: a) BuLi (2.0 equiv), then add
4, THF, 0 °C, 5 h; b) Me2S BH3 (1.5 equiv), THF, –40 °C r.t., 18 h,
62% over 2 steps; c) Im (2.5 equiv), TBSCl (1.2 equiv), DMF, r.t., 24
h, 95%; d) DDQ (1.5 equiv), CH2Cl2/H2O (18:1), 3 h, r.t., 69%; e)
(COCl)2 (2.0 equiv), DMSO (4.0 equiv), Et3N (6.0 equiv), CH2Cl2,
–78 °C r.t., 99%; f) 22 (1.3 equiv), NaH (1.3 equiv) then 21a/b (1.0
equiv), THF, 4 h, 0 °C r.t., 92%; g) DIBAL-H (3.0 equiv), THF, 1
h, –78 °C, 98%; h) CH3CH2Ph3P+Br– (1.5 equiv), NaHMDS (1.5
equiv), THF, 14 h, –78 °C
r.t., 73% (DDQ = 2,3-dichloro-5,6-di-
All moisture sensitive reactions were carried out under Argon. An-
hyd solvents were obtained as follows: THF distilled from sodium/
benzophenone ketyl; Et2O distilled from LiAlH4; acetone, CH2Cl2
and DMF distilled from P2O5; Et3N distilled from CaH2. All other
solvents were HPLC grade. Column chromatography was per-
formed with Merck silica gel (0.040–0.63 m, 240–400 mesh) un-
der low pressure of 5–10 psi. TLC was carried out with E. Merck
silica gel 60-F254 plates. Mps were determined on a Leica Galen III
apparatus and are uncorrected. IR spectra were recorded using a
Perkin-Elmer 1600 Series FTIR spectrometer and are reported in
wave numbers (cm–1). Optical rotations were measured on a P 341
cyano-1,4-benzoquinone, DIBAL-H = diisobutylaluminum hydride,
NaHMDS = sodium bis(trimethylsilyl)amide, PMB = p-methoxy-
benzyl, TBS = tert-butyldimethylsilyl).
To assign the configuration of the major -alkylation
product 18a, the minor diastereomer 20b was converted
into lactone 27 according to Scheme 7. Swern oxidation
furnished the enantiopure aldehyde, which was deprotect-
ed with TBAF to give hydroxy aldehyde 25. Upon heating
Synthesis 2002, No. 13, 1857–1866 ISSN 0039-7881 © Thieme Stuttgart · New York

1860
T. J. Heckrodt, J. Mulzer
PAPER
Perkin-Elmer polarimeter. NMR spectra were recorded on either a
Bruker Avance DPX 250 MHz, a Bruker Avance DRX 400 MHz or
a Bruker Avance DRX 600 MHz spectrometer. Unless otherwise
stated, all NMR spectra were measured in CDCl3 solutions and ref-
erenced to the residual CHCl3 signal (1H, = 7.26; 13C, = 77.0).
MS (EI, 70 eV): m/z (%) = 178 (57, [M]+), 163 (100, [M – CH3]+),
120 (69), 87 (46).
HRMS (60 °C, 70 eV): m/z calcd for C9H10O3: 178.0994; found:
178.0998.
1
All H and 13C shifts are given in ppm (s = singlet, d = doublet,
1-(2,4-Dimethoxy-3-methylphenyl)ethanone (8)
t = triplet, q = quadruplet, quin = quintet, sex = sextet, sep = septet,
oct = octet, m = multiplet, br s = broad signal). Coupling constants
J are given in Hz; assignments of proton resonances were con-
firmed, when possible, by selective homonuclear decoupling exper-
iments or correlated spectroscopy. Mass spectra were measured on
a Micro Mass, Trio 200 Fisions Instrument. High resolution mass
spectra (HRMS) were taken with a Finnigan MAT 8230 with a res-
olution of 10000. Elemental analyses were recorded on a Perkin-
Elmer-240-Elementaranalyser.
K2CO3 (191 g, 1.38 mol) was added to a solution of phenol 7 (111.7
g, 620 mmol) in acetone (500 mL). Within 15 min, Me2SO4 (174 g,
1.38 mol) was added dropwise and the mixture was kept under re-
flux for 2 d. The K2CO3 was filtered off, H2O (500 mL) was added,
the mixture was extracted with Et2O (3 400 mL), the Et2O layer
was dried (Na2SO4) and concentrated. Finally the Me2SO4 was dis-
tilled off (1.8 mbar/47 °C) to give 114.5 g (95%) of the dimethylat-
ed compound 8 as a brown oil; Rf 0.52 (SiO2, hexane–EtOAc, 6:4).
1H NMR (250 MHz, CDCl3): = 7.54 (d, J = 8.7 Hz, 1 H, ArH),
6.59 (d, J = 8.7 Hz, 1 H, ArH), 3.79 (s, 3 H, OCH3), 3.67 (s, 3 H,
OCH3), 2.54 (s, 3 H, CH3CO), 2.09 (s, 3 H, ArCH3).
1-(2,4-Dihydroxy-3-methylphenyl)ethanone (6)
To a solution of BF3 Et2 (247 g, 1.74 mol) under argon (in a flask
equipped with reflux condenser, dropping funnel and argon-tap)
was added methylresorcinol (Aldrich 90%, 5; 100 g, 725 mmol).
This suspension was warmed to 70 °C until a red, clear solution was
obtained. This solution was allowed to cool down to r.t. and Ac2O
(Fluka 95%, 85.8 g, 798 mmol) was added dropwise to the solution
over a period of 1 h. To keep the reaction under control the mixture
was occasionally cooled with a water/ice bath. After the addition
was complete, the mixture was heated for 6 h at 80 °C whereby the
clear, red solution turned into a orange-yellow suspension, with the
Et2O, liberated from the boron-complex, floating on the top. After
cooling down to r.t., ice water (500 mL) was added and the water
layer was extracted with Et2O (4 100 mL). The Et2O was removed
under reduced pressure to give yellow crystals, which were recrys-
tallised from a large volume ( 5 L) of boiling H2O/MeOH. The pre-
cipitate was filtered off, washed with H2O and dried in high
vacuum; 119.2 g (99%) of colourless crystals were obtained; Rf
0.21 (SiO2, hexane–EtOAc, 7:3); mp 120–122 °C (Lit.7 mp 124–
125 °C).
13C NMR (62.9 MHz, CDCl3): = 198.4, 161.9, 159.1, 128.7,
125.2, 119.9, 105.6, 61.5, 55.4, 29.9, 8.6.
MS (EI, 70 eV): m/z (%) = 194 (22, [M]+), 178 (100, [M – CH3]+),
136 (12, [M – CH3 – CH3CO]+), 91 (12).
HRMS (20 °C, 70 eV): m/z calcd for C11H14O3: 194.0943; found:
194.0937.
Acetic Acid 2,4-Dimethoxy-3-methylphenyl Ester (9)
The acetophenone 8 (114.5 g, 590 mmol) was dissolved in CH2Cl2
(700 mL) together with p-toluenesulfonic acid hydrate (3.00 g, 15.0
mmol). Under vigorous stirring m-chloroperbenzoic acid (Fluka
70%, 291 g, 1.18 mmol) was added carefully in small portions over
a long period ( 1 h). (CAUTION! Changing the order of addition
or a too rapid addition might result in a sudden exothermic reac-
tion). The colour of the solution changed from green over yellow to
orange; the powder funnel was replaced by a reflux condenser. Af-
ter 20 min, a strong evolution of heat was observed and the CH2Cl2
started to reflux. The mixture was stirred for another 15 h at r.t., then
aq sat. NaHCO3 solution (500 mL) was added and extracted with
CH2Cl2 (3 300 mL). Solvents were removed from the combined
organic layers and the crystalline residue was shaken with aq sat.
NHCO3 solution (5 500 mL) to remove 3-chlorobenzoic acid. Af-
ter decanting, the residue was dissolved in Et2O, passed through
MgSO4 and the solvent was evaporated. Subsequent column chro-
matography (hexane–EtOAc, 8:2) furnished 78.1 g (63%) of the de-
sired ester 9; Rf 0.53 (SiO2, hexane–EtOAc, 6:4).
1H NMR (250 MHz, MeOD): = 13.02 (s, 1 H, OH), 7.46 (d,
J = 8.8 Hz, 1 H, ArH), 6.34 (d, J = 8.8 Hz, 1 H, ArH), 4.95 (br s, 1
H, OH), 2.46 (s, 3 H, CH3CO), 2.02 (s, 3 H, ArCH3).
13C NMR (62.9 MHz, MeOD): = 204.3, 163.9, 163.8, 131.0,
113.9, 112.2, 107.9, 26.1, 7.6.
MS (EI, 70 eV): m/z (%) = 166 (40, [M]+), 161 (100, [M – CH3]+).
HRMS (60 °C, 70 eV): m/z calcd for C9H10O3: 166.0630; found:
166.0632.
1H NMR (250 MHz, CDCl3): = 6.86 (d, J = 8.9 Hz, 1 H, ArH),
6.59 (d, J = 8.9 Hz, 1 H, ArH), 3.80, 3.75 (2 s, each 3 H, OCH3),
2.32 (s, 3 H, CH3CO), 2.17 (s, 3 H, ArCH3).
13C NMR (62.9 MHz, CDCl3): = 169.5, 156.3, 150.4, 137.5,
121.0, 119.6, 105.5, 61.7, 55.6, 20.6, 9.0.
1-(2-Hydroxy-4-methoxy-3-methylphenyl)ethanone (7)
Compound 6 (114.9 g, 691 mmol) was dissolved in acetone (1 L).
To this orange solution was added K2CO3 (382 g, 2.76 mol) to give
a weak red solution. Over a period of 15 min, Me2SO4 was added
dropwise whereby the colour changed to citrus yellow. The solution
was stirred for 17 h at r.t., then the K2CO3 was filtered off and ap-
proximately half of the solvent was removed under reduced pres-
sure. H2O (500 mL) was added and the mixture was extracted with
Et2O (3 400 mL). The combined organic layers were dried
(MgSO4) and concentrated under reduced pressure. The Me2SO4
was distilled off under vacuum (1.8 mbar/47 °C) to give 7 as a red
oil (111.7 g, 90%). Higher yields (>95%) of the monomethylated
product are accessible if one uses 1 equiv of K2CO3 and 1 equiv of
Me2SO4; Rf 0.58 (SiO2, hexane–EtOAc, 6:4).
1H NMR (250 MHz, CDCl3): = 12.64 (s, 1 H, OH), 7.55 (d,
J = 8.9 Hz, 1 H, ArH), 6.41 (d, J = 8.9 Hz, 1 H, ArH), 3.86 (s, 3 H,
OCH3), 2.53 (s, 3 H, CH3CO), 2.06 (s, 3 H, ArCH3).
13C NMR (62.9 MHz, CDCl3): = 202.8, 163.4, 161.8, 129.7,
113.9, 113.2, 101.7, 55.6, 26.1, 7.3.
MS (EI, 70 eV): m/z (%) = 210 (12, [M]+), 168 (100, [M –
C2H2O]+), 153 (60), 125 (16).
HRMS (20 °C, 70 eV): m/z calcd for C11H14O4: 210.0892; found:
210.0889.
1,2,4-Trimethoxy-3-methylbenzene (10)
A solution of KOH (32.3 g, 576 mmol) in MeOH–H2O (200 mL,
9:1) was added dropwise to a solution of ester 9 (60.5 g, 288 mmol)
in MeOH (200 mL) at r.t. The solution was then refluxed for 3 h and
after cooling, as much as possible of the MeOH was removed under
reduced pressure. After the addition of H2O (50 mL), the solution
was acidified with HCl (16%) and more H2O was added, as long as
all precipitated salts were dissolved. Extraction with Et2O (5 100
mL), drying (Na2SO4) and evaporation of the solvent gave a brown
crude oil, which was flashed through a short column of silica gel
(hexane–EtOAc, 9:1). 2,4-Dimethoxy-3-methylphenol was ob-
Synthesis 2002, No. 13, 1857–1866 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of a Diels–Alder Precursor for the Elisabethin A Skeleton
1861
tained as pale yellow oil in 98% (47.5 g) yield; Rf 0.48 (SiO2, hex-
ane–EtOAc, 6:4).
(2,4,5-Trimethoxy-3-methylphenyl)acetonitrile (12)
To a solution of 11 (12.4 g, 53.0 mmol) in MeCN (500 mL) was
added TMSCN (8.05 g, 79.5 mmol) and) and TBAF (1 M in THF,
79.5 mL, 79.5 mmol). The clear, slightly yellow solution was stirred
at r.t. for 10 h, then the solvent was removed under reduced pressure
to give a yellow syrup, which was subjected straight to column
chromatography (hexane–EtOAc, 9:1). The desired nitrile 12 was
obtained as a colourless, crystalline solid in 81% (9.49 g) yield after
evaporation of solvents; Rf 0.18 (SiO2, hexane–EtOAc, 8/2), mp
64–66 °C.
1H NMR (250 MHz, CDCl3): = 6.74 (s, 1 H, ArH), 3.82, 3.77,
3.70 (3 s, each 3 H, OCH3), 3.68 (s, 2 H, CH2CN), 2.19 (s, 3 H,
ArCH3).
13C NMR (62.9 MHz, CDCl3): = 150.0, 149.3, 147.9, 125.7,
125.7, 118.1, 118.0, 109.8, 60.6, 60.0, 55.8, 18.1, 9.4.
2,4-Dimethoxy-3-methylphenol
1H NMR (250 MHz, CDCl3): = 6.76 (d, J = 8.9 Hz, 1 H, ArH),
6.53 (d, J = 8.9 Hz, 1 H, ArH), 5.51 (br s, 1 H, OH), 3.77 (s, 6 H,
OCH3), 2.18 (s, 3 H, ArCH3).
13C NMR (62.9 MHz, CDCl3): = 151.8, 145.9, 142.9, 128.9,
111.7, 106.7, 60.7, 55.9, 9.2.
MS (EI, 70 eV): m/z (%) = 168 (100, [M]+), 153 (65, [M – CH3]+),
125 (49, [M – CH3 – CO]+), 110 (14), 107 (13), 85 (25), 84 (37).
HRMS (50 °C, 70 eV): m/z calcd for C9H12O3 168.0786; found
168.0790.
The phenol (41.67 g, 247 mmol) from the above reaction was dis-
solved in anhyd acetone (300 mL), and K2CO3 (68.3 g, 494 mmol)
and Me2SO4 (62.2 g, 494 mmol) were added to this yellow suspen-
sion. The mixture was stirred for 20 h at r.t., then refluxed for 2 h to
convert traces of starting material to the methyl ether. The suspen-
sion was passed through a plug of MgSO4 to remove the salts and
then concentrated in vacuo. The excess of Me2SO4 was removed by
distillation (1.8 mbar/47 °C), then the product was distilled ( 0.5
mbar/75–80 °C). Upon standing the trimethoxytoluene 10 crystal-
lised as a colourless solid; Rf 0.44 (SiO2, hexane–EtOAc, 8:2); mp
32–33 °C (Lit.3 mp 30–31 °C).
MS (EI, 70 eV): m/z = 221 (72, [M]+), 207 (12, [M – N]+), 206 (100,
[M – CH3]+), 178 (20, [M – CH3 – CO]+), 85 (29), 83 (48).
HRMS (30 °C, 70 eV): m/z calcd for C12H15NO3: 221.1052; found:
221.1058.
Anal. Calcd for C12H15O3N: C, 65.14; H, 6.83; N, 6.33. Found: C,
65.17; H, 6.95; N, 6.36.
(2,4,5-Trimethoxy-3-methylphenyl)acetic Acid (3a)
To the nitrile 12 (8.54 g, 38.5 mmol) was added a solution of NaOH
(3.08 g, 77 mmol) in H2O (9.3 mL) to give a milky-white suspen-
sion. This mixture was kept under reflux for 8 h, whereby the
progress of the hydrolysis was monitored by indicator paper sitting
on the top of the reflux condenser (liberation of NH3). After a few
hours the suspension turned into a clear, slightly yellow solution.
Finally the solution was acidified with H2SO4 (20%, 15 mL), the
precipitated acid was filtered and washed with H2O. The mother li-
quor was extracted with CHCl3, the organic layer was combined
with the precipitate and solvents were removed in vacuo. After dry-
ing in high vacuum for 16 h, the acid was isolated in 100% (9.23
g) yield as colourless crystals; Rf 0.13 (SiO2, hexane–EtOAc, 8:2);
mp 258–260 °C.
1H NMR (250 MHz, CDCl3): = 6.64 (s, 1 H, ArH), 6.32 (br s, 1 H,
CO2H), 3.82, 3.79, 3.70 (3 s, each 3 H, OCH3), 3.65 (s, 2 H,
CH2CO2H), 2.22 (s, 3 H, ArCH3).
13C NMR (62.9 MHz, CDCl3): = 176.6, 150.6, 149.3, 147.5,
125.6, 121.5, 111.4, 60.8, 60.2, 55.9, 35.6, 9.7.
10
1H NMR (250 MHz, CDCl3): = 6.69 (d, J = 8.9 Hz, 1 H, ArH),
6.53 (d, J = 8.9 Hz, 1 H, ArH), 3.81, 3.80, 3.78 (3 s, each 3 H,
OCH3), 2.17 (s, 3 H, ArCH3).
13C NMR (62.9 MHz, CDCl3): = 152.4, 148.1, 147.1, 121.0,
108.5, 105.1, 60.2, 56.1, 55.7, 8.8.
MS (EI, 70 eV): m/z (%) = 182 (100, [M]+), 167 (78, [M – CH3]+),
152 (18, [M – CH3 – CH3]+), 139 (43, [M – CH3 – CO]+), 124 (25),
107 (14), 91 (12), 85 (10), 83 (15), 53 (12).
HRMS (20 °C, 70 eV): m/z calcd for C10H14O3: 182.0943; found:
182.0940.
1-Chloromethyl-2,4,5-trimethoxy-3-methylbenzene (11)
Trimethoxytoluene 10 (33.2 g, 182 mmol) was placed in a flask to-
gether with HCHO (Apoka 37%, 63.7 mL, 910 mmol) and HCl
(Riedel de Häen 32%, 63.7 mL, 558 mmol). Over a period of 1 h 15
min HCl gas (prepared by dropping H2SO4 to NaCl) was passed
through the mixture; during this procedure a strong heat tone (60–
80 °C) was observed and the colour changed from salmon pink to
pale orange. Finally the reaction product was poured on ice/water
and extracted with Et2O (5 50 mL), the Et2O layer was dried
(MgSO4) and the solvent was evaporated under reduced pressure.
The product was isolated in 94% (39.52 g) yield as colourless crys-
tals; Rf 0.48 (SiO2, hexane–EtOAc, 8:2); mp 33–35 °C (Lit.3 mp
39–40 °C).
MS (EI, 70 eV): m/z (%) = 241 (15, [M + H]+), 240 (100, [M]+), 225
(11, [M – CH3]+), 221 (13, [M – H3O]+), 207 (12), 206 (16), 196
(10), 195 (40, [M – CHO2]+), 181 (67), 165 (17), 138 (12), 137 (10).
HRMS (70 °C, 70 eV): m/z calcd for C12H16O5: 240.0998; found:
240.1003.
Anal. Calcd for C12H16O5: C, 59.99; H, 6.71. Found: C, 59.82; H,
6.79.
1H NMR (250 MHz, CDCl3): = 6.77 (s, 1 H, ArH), 4.63 (s, 2 H,
CH2Cl), 3.83, 3.79, 3.77 (3 s, each 3 H, OCH3), 2.21 (s, 3 H,
ArCH3).
13C NMR (62.9 MHz, CDCl3): = 150.8, 149.3, 148.4, 125.7,
125.4, 110.9, 61.4, 60.1, 55.8, 41.5, 9.4.
MS (EI, 70 eV): m/z (%) = 232 {23, [M(37Cl)]+}, 230 {71,
[M(35Cl)]+}, 215 {20, [M – CH3]+}, 195 {100, [M – 37Cl– 35Cl]+},
165 (39), 152 (13), 150 (23), 137 (12), 105 (17), 91 (11), 77 (13).
(R)-4-Benzyl-3-[2-(2,4,5-trimethoxy-3-methylphenyl)acetyl]ox-
azolidin-2-one (3b)
To a solution of 3a (4.71 g, 19.6 mmol) in anhyd THF (200 mL) was
added Et3N (2.58 g, 25.5 mmol) and pivaloyl chloride (2.6 g, 21.6
mmol) at –78 °C. The milky-white mixture was allowed to warm to
0 °C over a period of 2 h. After cooling down again to –78 °C, a sus-
pension of (R)-4-benzyl-2-oxazolidinone (4.16 g, 23.5 mmol),
deprotonated with BuLi (2.5 M in hexane, 9.5 mL, 23.5 mmol) in
anhyd THF at –78 °C/30 min, was transferred via canula to the
mixed anhydride at –78 °C. The mixture was allowed to warm to r.t.
overnight ( 14 h), then quenched with aq NH4Cl (130 mL). After
extraction with Et2O (3 150 mL) and removal of solvents under
reduced pressure, the remaining crude oil was further purified by
column chromatography on silica gel using hexane–EtOAc (6:4) as
HRMS (20 °C, 70 eV): m/z calcd for C11H1535ClO3: 230.0710;
found: 230.0707.
Synthesis 2002, No. 13, 1857–1866 ISSN 0039-7881 © Thieme Stuttgart · New York

1862
T. J. Heckrodt, J. Mulzer
PAPER
eluent. Compound 3b was obtained as a clear, highly viscous oil in
90% (7.05 g) yield; Rf 0.39 (SiO2, hexane–EtOAc, 1:1); [ ]D
+48.5 (c 1.00, CH2Cl2).
OCH3), 3.62–3.55 (m, 2 H, CH2OH), 3.52 (dd, J = 4.7, 8.9 Hz, 1 H,
MeCHCH2O), 3.39 (dd, J =& nbsp;8.0, 8.9 Hz, 1 H, MeCHCH2O),
2.53 (br s, 1 H, OH), 2.21–1.97 (m, 1 H, MeCH), 0.87 (d, J = 7.1
Hz, 3 H, CHCH3).
13C NMR (100.6 MHz, CDCl3): = 159.3, 130.2, 129.3, 113.9,
75.2, 73.1, 67.9, 55.3, 35.6, 13.5.
20
1H NMR (250 MHz, CDCl3): = 7.39–7.15 (m, 5 H, C6H5), 6.62 (s,
1 H, ArH), 4.78–4.63 (m, 1 H, NCH), 4.26 (s, 2 H, ArCH2), 4.24–
4.20 (m, 2 H, OCH2), 3.83, 3.81, 3.69 (3 s, each 3 H, OCH3), 3.34
(dd, J = 2.1, 14.2 Hz, 1 H, PhCH2), 2.79 (dd, J = 8.6, 14.2 Hz, 1 H,
PhCH2), 2.24 (s, 3 H, ArCH3).
13C NMR (100.6 MHz, CDCl3): = 171.4, 153.6, 151.0, 149.1,
147.4, 135.3, 129.4, 128.9, 127.3, 125.5, 121.8, 111.9, 66.3, 60.7,
60.2, 55.9, 55.5, 37.8, 37.1, 8.8.
MS (EI, 70 eV): m/z (%) = 210 (6, [M]+), 138 (20), 137 (63, [M –
HOCH2CH(CH3)CH2]+), 122 (13), 121 (100, [M
HOCH2CHMeCH2O]+), 109 (16), 77 (13).
–
HRMS (50 °C, 70 eV): m/z calcd for C12H18O3: 210.1256; found:
210.1252.
MS (EI, 70 eV): m/z (%) = 399 (23, [M]+), 223 (23), 222 (100), 207
(37), 195 (15), 149 (12).
Anal. Calcd for C12H18O3: C, 74.60; H, 10.11. Found: C, 74.68; H,
10.21.
HRMS (120 °C, 70 eV): m/z calcd for C22H25NO6 399.1682; found
399.1675.
(S)-(–)-1-(3-Iodo-2-methylpropoxymethyl)-4-methoxybenzene
(4)
Anal. Calcd for C22H25NO6: C, 66.15; H, 6.31; N, 3.51. Found: C,
66.32; H, 6.18; N, 3.72.
To a solution of alcohol 14 (5.79 g, 27.7 mmol) in anhyd benzene
(240 mL) was added imidazole (4.71 g, 69.2 mmol), Ph3P (18.1 g,
69.2 mmol) and I2 (14.1 g, 55.3 mmol) at 0 °C. After 5 min, the
cooling bath was removed and the reaction mixture was stirred for
3 h at r.t. whereby the colour changed from brown to bright yellow.
Then the reaction was quenched by the addition of a aq sat. Na2S2O3
solution (200 mL), the liquid phases were decanted and the solid
residue was extracted with Et2O (3 40 mL). The combined organ-
ic layers were washed once with aq sat. Na2S2O3 solution and brine.
After drying (MgSO4), solvents were evaporated to give 20.5 g of a
white solid, which was dissolved under heating in a minimum
amount of a 4:1 mixture of hexane–Et2O. This solution was kept in
the freezer at –40 °C for several hours, then the precipitated white
solid (Ph3PO/PPh3) was filtered off, solvents were removed and the
residue was further purified by column chromatography on silica
gel, eluting with hexane–EtOAc (15:1). Finally 6.49 g (73%) of the
iodide 4 was obtained as a colourless oil; Rf 0.59 (SiO2, hexane–
EtOAc, 7:3); [ ]D20 –13.5 (c 1.15, CH2Cl2).
(S)-(–)-3-(4-Methoxybenzyloxy)-2-methylpropan-1-ol (14)
To a solution of 13 (7.15 g, 60.5 mmol) in CH2Cl2 (30 mL) was add-
ed dropwise a solution of p-methoxybenzyltrichloroacetimidate
(34.2 g, 121 mmol, prepared from p-methoxybenzyl alcohol and
trichloroacetonitrile8) in anhyd CH2Cl2 (75 mL). After cooling to
–5 °C, camphorsulfonic acid (1.41 g, 6.05 mmol) was added and the
milky-cloudy mixture was stirred for 30 h at r.t. Then the suspen-
sion was filtered through a silica gel/Celite plug, to remove the pre-
cipitated trichloroacetamide. The silica gel/Celite plug was washed
twice with hexane–CH2Cl2 (100 mL, 2:1), the combined filtrates
were concentrated in vacuo and purified by silica gel column chro-
matography using hexane–EtOAc (10:1) as eluent. The PMB-pro-
tected derivative of compound 13 was isolated in 84% (12.1 g) yield
as a colourless oil; Rf 0.48 (SiO2, hexane–EtOAc, 8:2); [ ]D20 –12.5
(c 1.00, CH2Cl2).
PMB-Protected Derivative of Compound 13
1H NMR (250 MHz, CDCl3): = 7.26 (d, J = 8.6 Hz, 2 H, ArH),
6.88 (d, J = 8.6 Hz, 2 H, ArH), 4.44 (s, 2 H, ArCH2), 3.81 (s, 3 H,
OCH3), 3.39–3.23 (m, 4 H, CH2I and MeCHCH2O), 1.76 (m, 1 H,
MeCH), 0.98 (d, J = 6.6 Hz, 3 H, CHCH3).
13C NMR (62.9 MHz, CDCl3): = 159.2, 130.4, 129.2, 113.8, 73.9,
72.9, 67.9, 55.3, 35.2, 17.7, 13.9.
1H NMR (250 MHz, CDCl3): = 7.23 (d, J = 8.6 Hz, 2 H, ArH),
6.86 (d, J = 8.6 Hz, 2 H, ArH), 4.44 (s, 2 H, ArCH2), 3.79, 3.68 (2
s, each 3 H, OCH3), 3.63 (dd, J = 7.3, 9.1 Hz, 1 H, MeCHCH2O),
3.45 (dd, J = 5.9, 9.1 Hz, 1 H, MeCHCH2O), 2.76 (m, 1 H, MeCH),
1.16 (d, J = 7.3 Hz, 3 H, CHCH3).
13C NMR (100.6 MHz, CDCl3): = 175.3, 159.2, 129.7, 129.4,
114.3, 72.8, 71.7, 55.4, 51.7, 40.2, 14.0.
MS (EI, 70 eV): m/z (%) = 238 (12, [M]+), 138 (14), 137 (100, [M
– MeO2CHCH3]+), 122 (15), 121 (96, [M – MeO2CHCH3O]+), 109
(13), 78 (10), 77 (14).
MS (EI, 70 eV): m/z (%) = 320 (20, [M]+), 122 (11), 121 (100,
[CH2C6H4OMe-4]+).
HRMS (50 °C, 70 eV): m/z calcd for C12H17O2I 320.0273; found
320.0268.
Anal. Calcd for C12H18O3: C, 45.02; H, 5.35. Found: C, 45.18; H,
5.19.
HRMS (20 °C, 70 eV): m/z calcd for C13H18O4: 238.1205; found:
238.1212.
To a suspension of LiAlH4 (3.18 g, 83.8 mmol) in anhyd Et2O (50
mL) was added slowly a solution of the PMB-protected derivative
of the Roche alcohol 13 (7.96 g, 33.4 mmol) from the above reac-
tion, in anhyd Et2O (50 mL). The mixture was stirred for 18 h at r.t.,
then carefully quenched under cooling with H2O ( 5.5 mL) until gas
development stopped, followed by the addition aq 1 N NaOH ( 25
mL) until all grey LiAlH4 was converted into white Al(OH)3. The
precipitated salts were filtered off, H2O (100 mL) was added to the
filtrate and extracted with Et2O (3 50 mL). Finally the combined
organic layers were passed through a plug of MgSO4 and the solvent
was evaporated under reduced pressure to give 6.79 g (97%) of the
desired alcohol 14 as a colourless oil; Rf 0.18 (SiO2, hexane–
EtOAc, 7:3); [ ]D20 –10.8 (c 1.20, CH2Cl2).
4-Benzyl-3-[3-hydroxy-5-(4-methoxybenzyloxy)-4-methyl-2-
(2,4,5-trimethoxy-3-methylphenyl)pentanoyl]oxazolidin-2-one
(16)
Compound 3b (5.14 g, 12.9 mmol) was dissolved in anhyd CH2Cl2
(11 mL), then Et3N (1.69 g, 16.7 mmol) and Bu2BOTf (4.24 g, 15.5
mmol, freshly prepared9) were added at 0 °C. The clear yellow-or-
ange solution was stirred for 3.5 h at 0 °C, cooled to –78 °C and al-
dehyde 156 (4.26 g, 12.9 mmol), dissolved in anhyd CH2Cl2 (11
mL), was transferred via syringe into the flask. The solution was al-
lowed to warm to 0 °C over a period of 6 h. To quench the reaction
pH 7 buffer (15 mL) was added, followed by the addition of MeOH
(20 mL) and a 2:1 mixture of MeOH–H2O2 (43 mL) and this solu-
tion was stirred for 1 h at r.t. Finally most of the solvents were evap-
orated under reduced pressure and the residue was extracted with
Et2O (3 30 mL). The combined organic layers were dried
(MgSO4), solvents were evaporated and the crude oil was further
purified by column chromatography eluting with hexane–EtOAc
14
1H NMR (250 MHz, CDCl3): = 7.25 (d, J = 8.8 Hz, 2 H, ArH),
6.88 (d, J = 8.8 Hz, 2 H, ArH), 4.45 (s, 2 H, ArCH2), 3.80 (s, 3 H,
Synthesis 2002, No. 13, 1857–1866 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of a Diels–Alder Precursor for the Elisabethin A Skeleton
1863
(7:3). The desired adduct 16 was isolated in 74% (4.64 g, clear oil)
yield as a single diastereomer. The diastereomeric excess of the re-
action was 91%, as determined from the 1H NMR spectrum of the
MS (EI, 70 eV): m/z (%) = 432 (10, [M]+), 320 (9, [M – H –
CH2C6H4OMe-4]+), 294 (16), 265 (24), 212 (11), 211 (23), 209
(23), 196 (14), 195 (37), 183 (19), 129 (26), 121 (100,
[CH2C6H4OMe-4]+).
20
crude product; Rf 0.47 (SiO2, hexane–EtOAc, 6:4); [ ]D +31.6
(c 1.00, CHCl3).
HRMS (100 °C, 70 eV): m/z calcd for C24H32O7: 432.2148; found:
1H NMR (250 MHz, CDCl3): = 7.39–7.15 (m, 7 H, C6H5 and
CH2C6H4OMe-4), 6.92 (s, 1 H, ArH), 6.88 (d, J = 8.4 Hz, 2 H,
CH2C6H4OMe-4), 5.70 (d, J = 10.8 Hz, 1 H, ArCH), 4.68 (mc, 1 H,
NCH), 4.44 (dd, J = 2.4, 10.8 Hz, 1 H, ArCHCH), 4.38 (s, 2 H,
CH2C6H4OMe-4), 4.07–3.98 (m, 2 H, OCH2CHN), 3.82 (s, 3 H,
CH2C6H4OCH3-4), 3.72 (s, 9 H, 3 OCH3), 3.20, 3.11 (2 mc, each 1
H, OCH2CHMe), 3.06 (dd, J = 1.9, 9.4 Hz, 1 H, PhCH2), 2.53 (dd,
J = 6.4, 9.4 Hz, 1 H, PhCH2), 2.18 (s, 3 H, ArCH3), 1.96–1.86 (m, 1
H, CHMe), 1.05 (d, J = 6.6 Hz, 3 H,CHCH3).
13C NMR (62.9 MHz, CDCl3): = 173.2, 159.6, 153.1, 152.4,
149.7, 147.9, 144.6, 135.3, 133.4, 129.2, 128.8, 127.6, 126.1, 123.9,
109.8, 87.1, 74.7, 67.6, 66.0, 61.7, 60.8, 56.4, 55.3, 46.6, 37.7, 37.5,
21.4, 14.6, 10.8, 10.6.
432.2145.
Anal. Calcd for C24H32O7: C, 66.65; H, 7.46. Found: C, 66.48; H,
7.52.
The crude product (0.904 g, 2.08 mmol) from the above reaction
was dissolved anhyd THF (10 mL) and cooled to –40 °C. DMS BH3
(0.2 mL, 3.12 mmol) was added via syringe and the mixture was al-
lowed to warm slowly to r.t. whereby the colour turned from orange
into yellow. After stirring for 18 h, a mixture of EtOAc–AcOH (10
mL, 1:1) was added carefully under icebath cooling, then the solu-
tion was neutralised with a aq sat. NaHCO3 solution (25 mL) and
extracted with EtOAc (3 25 mL). The combined organic layers
were passed through a plug of MgSO4 and the solvents were evap-
orated. The remaining yellow oil was further purified by column
chromatography on silica gel using hexane–EtOAc (6:4) as eluent.
The desired alcohols 19a/b were obtained in 62% (542 mg, clear
oil) yield over the two steps; Rf 0.32 (for both isomers, SiO2, hex-
ane–EtOAc, 1:1).
MS (EI, 70 eV): m/z (%) = 607 (6, [M]+), 486, (21), 399 (45), 330
(18), 121 (100).
HRMS (50 °C, 70 eV): m/z calcd for C34H41O9N: 607.2781; found:
607.2792.
Anal. Calcd for C34H41O9N: C, 67.20; H, 6.80; N, 2.30. Found: C,
67.48; H, 6.97; N, 2.01.
19a/b
1H NMR (250 MHz, CDCl3): (major isomer) = 7.16 (d, J = 8.4
Hz, 2 H, CH2C6H4OMe-4), 6.80 (d, J = 8.4 Hz, 2 H, CH2C6H4OMe-
4), 6.56 (s, 1 H, ArH), 4.29 (s, 2 H, OCH2C6H4OMe-4), 3.73, 3.71,
3.67, 3.62 (4 s, each 3 H, OCH3), 3.69–3.58 (m, 2 H, CH2OH), 3.41–
3.22 (m, 2 H, CH2OPMB), 3.22–3.14 (m, 1 H, ArCH), 2.59 (br s, 1
H, OH), 2.18 (s, 3 H, ArCH3), 1.88–1.66 (m, 1 H, ArCHCH2), 1.66–
1.52 (m, 1 H, CHMe), 1.49–1.24 (m, 1 H, ArCHCH2), 0.92 (d,
J = 6.6 Hz, 3 H, CHCH3). (minor isomer) = 7.20 (d, J = 8.4 Hz, 2
H, CH2C6H4OMe-4), 6.82 (d, J = 8.4 Hz, 2 H, CH2C6H4OMe-4),
6.58 (s, 1 H, ArH), 4.36 (s, 2 H, OCH2C6H4OMe-4), 3.75, 3.73,
3.71, 3.59 (4 s, each 3 H, OCH3), 3.69–3.58 (m, 2 H, CH2OH), 3.41–
3.22 (m, 2 H, CH2OPMB), 3.22–3.14 (m, 1 H, ArCH), 2.59 (br s, 1
H, OH), 2.18 (s, 3 H, ArCH3), 1.88–1.66 (m, 1 H, ArCHCH2), 1.66–
1.52 (m, 1 H, CHMe), 1.49–1.24 (m, 1 H, ArCHCH2), 0.92 (d,
J = 6.6 Hz, 3 H, CHCH3).
(4S)-5-(4-Methoxybenzyloxy)-4-methyl-2-(2,4,5-trimethoxy-3-
methylphenyl)pentan-1-ol (19a/b)
The arylacetic acid 3a (500 mg, 2.08 mmol) was dissolved in anhyd
THF (4 mL) and treated with BuLi (1.66 mL, 2.5 M in hexane, 4.16
mmol) at 0 °C. To the deep red dianion was added the iodide 4, dis-
solved in anhyd THF (1 mL), whereby the colour changed to yel-
low. The mixture was stirred for another 5 h at 0 °C, then quenched
with aq sat. NH4Cl solution (5 mL). After evaporation of the sol-
vents, H2O (10 mL) was added and the suspension was slightly acid-
ified with aq 1 N HCl. Extraction with CHCl3 (3 10 mL) afforded
0.931 g of the crude product 18a/b, after removal of solvents. For
analytical purpose, a small sample was purified by column chroma-
tography on silica gel (hexane–EtOAc, 5:5). The ratio of the dia-
stereomers was 66:34, determined by signal integration (ArH and
CH2C6H4OMe) of the 1H NMR spectrum; Rf 0.25 (for both isomers,
SiO2, hexane–EtOAc, 2:8).
13C NMR (62.9 MHz, CDCl3): (major isomer) = 158.7, 151.0,
149.1, 145.8, 130.4, 129.7, 128.6, 124.6, 113.3, 107.9, 75.6, 72.1,
67.5, 60.7, 59.6, 55.4, 54.7, 37.6, 35.4, 30.5, 16.6, 9.4. (minor iso-
mer) = 158.6, 150.6, 149.0, 145.9, 130.7, 129.7, 128.6, 124.7,
113.3, 107.9, 74.7, 72.2, 66.7, 60.7, 59.6, 55.4, 54.7, 37.5, 35.9,
31.0, 17.7, 9.4.
MS (EI, 70 eV): m/z (%) = 418 (24, [M]+), 282 (18, [M – O –
CH2C6H4OMe-4]+), 279 (13), 267 (14), 251 (23), 222 (16), 195
(43), 137 (15), 122 (15), 121 (100, [CH2C6H4OMe-4]+), 85 (13).
18a/b
1H NMR (400 MHz, CDCl3): (major isomer) = 7.13 (d, J = 8.6
Hz, 2 H, CH2C6H4OMe-4), 6.76 (d, J = 8.6 Hz, 2 H, CH2C6H4OMe-
4), 6.63 (s, 1 H, ArH), 4.28 (s, 2 H, OCH2C6H4OMe-4), 4.15–4.06
(m, 1 H, ArCHCO2H), 3.73, 3.70, 3.69, 3.60 (4 s, each 3 H, OCH3),
3.25–3.16 (m, 2 H, CH2OPMB), 2.12 (s, 3 H, ArCH3), 1.91–1.82
(m, 1 H, ArCHCH2), 1.79–1.70 (m, 1 H, ArCHCH2), 1.62–1.51 (m,
1 H, CHMe), 086 (d, J = 6.6 Hz, 3 H, CHCH3). (minor isomer)
= 7.16 (d, J = 8.6 Hz, 2 H, CH2C6H4OMe-4), 6.77 (d, J = 8.6 Hz, 2
H, CH2C6H4OMe-4), 6.65 (s, 1 H, ArH), 4.32 (s, 2 H,
OCH2C6H4OMe-4), 4.15–4.06 (m, 1 H, ArCHCO2), 3.75, 3.71,
3.69, 3.66 (4 s, each 3 H, OCH3), 3.25–3.16 (m, 2 H, CH2OPMB),
2.12 (s, 3 H, ArCH3), 1.91–1.82 (m, 1 H, ArCHCH2), 1.70–1.64 (m,
1 H, ArCHCH2), 1.43–1.35 (m, 1 H, CHMe), 0.87 (d, J = 6.6 Hz, 3
H, CHCH3).
HRMS (130 °C, 70 eV): m/z calcd for C24H34O6: 418.2355; found:
418.2362.
Anal. Calcd for C24H34O6: C, 68.88; H, 8.19. Found: C, 68.81; H,
8.32.
(2S)-5-(tert-Butyldimethylsilyloxy)-2-methyl-4-(trimethoxyme-
thylphenyl)pentan-1-ol (20a/b)
To a solution of the alcohols 19a/b (1.51 g, 3.59 mmol) in anhyd
DMF (4 mL) was added imidazole (612 mg, 8.99 mmol) and TBSCl
(650 mg, 4.32 mmol). This mixture was stirred at r.t. for 1 d, then
diluted with toluene (15 mL) and washed with H2O (4 15 mL).
The combined aqueous layers were extracted with toluene–Et2O
(1:1, 2 ). The organic layers were combined and passed through a
plug of MgSO4. Removal of solvents in vacuo gave 1.82 g (95%) of
TBS-protected 19a/b as a brown crude oil; Rf 0.69 (for both iso-
mers, SiO2, hexane–EtOAc, 6:4).
13C NMR (62.9 MHz, CDCl3): (major isomer) = 180.2, 159.0,
150.5, 149.4, 147.1, 130.6, 129.1, 126.4, 125.3, 113.6, 108.5, 75.4,
72.5, 61.2, 60.1, 55.9, 55.2, 41.3, 36.9, 31.1, 17.0, 9.7. (minor iso-
mer) = 179.9, 159.0, 150.1, 149.3, 147.0, 130.5, 129.0, 127.0,
125.4, 113.7, 108.6, 74.9, 72.3, 61.1, 60.1, 55.8, 55.2, 41.2, 37.2,
31.5, 17.2, 9.7.
Synthesis 2002, No. 13, 1857–1866 ISSN 0039-7881 © Thieme Stuttgart · New York

1864
T. J. Heckrodt, J. Mulzer
PAPER
TBS-Protected 19a/b
HRMS (60 °C, 70 eV): m/z calcd for C22H40O5Si: 412.2645; found:
1H NMR (400 MHz, CDCl3): (major isomer) = 7.24 (d, J = 8.4
Hz, 2 H, CH2C6H4OMe-4), 6.87 (d, J = 8.4 Hz, 2 H, CH2C6H4OMe-
4), 6.67 (s, 1 H, ArH), 4.37 (s, 2 H, OCH2C6H4OMe-4), 3.81, 3.79,
3.75, 3.71 (4 s, each 3 H, OCH3), 3.81–3.65 (m, 2 H, CH2OTBS),
3.46–3.32 (m, 2 H, CH2OPMB), 3.32–3.21 (m, 1 H, ArCH), 2.26 (s,
3 H, ArCH3), 2.02–1.75 (m, 1 H, ArCHCH2), 1.70–1.52 (m, 1 H,
CHMe), 1.49–1.30 (m, 1 H, ArCHCH2), 0.99 (d, J = 6.8 Hz, 3 H,
CHCH3), 0.90 [s, 9 H, OSiC(CH3)3], 0.03 [s, 6 H, OSi(CH3)2].
(minor isomer) = 7.28 (d, J = 8.4 Hz, 2 H, CH2C6H4OMe-4), 6.88
(d, J = 8.4 Hz, 2 H, CH2C6H4OMe-4), 6.69 (s, 1 H, ArH), 4.43 (s, 2
H, OCH2C6H4OMe-4), 3.84, 3.81, 3.79, 3.66 (4 s, each 3 H, OCH3),
3.81–3.65 (m, 2 H, CH2OTBS), 3.46–3.32 (m, 2 H, CH2OPMB),
3.32–3.21 (m, 1 H, ArCH), 2.26 (s, 3 H, ArCH3), 2.02–1.75 (m, 1
H, ArCHCH2), 1.70–1.52 (m, 1 H, CHMe), 1.49–1.30 (m, 1 H,
ArCHCH2), 0.99 (d, J = 6.8 Hz, 3 H, CHCH3), 0.88 [s, 9 H,
OSiC(CH3)3], 0.01 [s, 6 H, OSi(CH3)2].
412.2653.
Anal. Calcd for C22H40O5Si: C, 64.04; H, 9.77. Found: C, 64.31; H,
9.59.
(2S)-5-(tert-Butyldimethylsilyloxy)-2-methyl-4-(trimethoxyme-
thylphenyl)pentanal (21a/b)
To a solution of oxalyl chloride (0.671 g, 5.29 mmol) in anhyd
CH2Cl2 (6 mL) under argon cooled to –78 °C was added DMSO
(0.826 g, 10.6 mmol), dissolved in anhyd CH2Cl2 (2.5 mL). After
stirring for 30 min, the alcohols 20a/b (1.09 g, 2.64 mmol), dis-
solved in anhyd CH2Cl2 (3 mL), were transferred via syringe into
the flask. The stirring was continued for 1 h, then Et3N (1.61 g,
15.86 mmol) was added to the mixture. After 10 min, the dry-ice
Dewar vessel was removed and the cloudy solution was allowed to
warm to r.t. The resulting orange solution was washed with H2O (20
mL), aq sat. NH4Cl solution (20 mL), H2O (20 mL), aq sat. NaHCO3
solution (20 mL), H2O (20 mL) and finally with brine (20 mL). The
organic phase was passed through a plug of MgSO4 and the solvent
was removed in vacuo to yield 1.07 g (99%) of aldehyde 20 as a
light brown oil; Rf 0.56 (for both isomers, SiO2, hexane–EtOAc,
7:3).
1H NMR (250 MHz, CDCl3): (major isomer) = 9.53 (d, J = 1.6
Hz, 1 H, CHO), 6.60 (s, 1 H, ArH), 3.81, 3.78, 3.67 (3 s, each 3 H,
OCH3), 3.79–3.65 (m, 2 H, TBSOCH2), 3.39–3.23 (m, 1 H, ArCH),
2.41–2.25 (m, 1 H, CHMe), 2.20 (s, 3 H, ArCH3), 2.07–1.92 (m, 1
H, CH2CHMe), 1.80–1.67 (m, 1 H, CH2CHMe), 1.13 (d, J = 7.1, 1
H, CHCH3), 0.85 [s, 9 H, SiC(CH3)3], –0.01 [s, 6 H, Si(CH3)2].
(minor isomer) = 9.63 (d, J = 1.6 Hz, 1 H, CHO), 6.62 (s, 1 H,
ArH), 3.82, 3.78, 3.63 (3 s, each 3 H, OCH3), 3.79–3.65 (m, 2 H,
TBSOCH2), 3.39–3.23 (m, 1 H, ArCH), 2.41–2.25 (m, 1 H, CHMe),
2.21 (s, 3 H, ArCH3), 2.07–1.92 (m, 1 H, CH2CHMe), 1.80–1.67
(m, 1 H, CH2CHMe), 1.04 (d, J = 6.9 Hz, 3 H, CHCH3), 0.85 [s, 9
H, SiC(CH3)3], –0.01 [s, 6 H, Si(CH3)2].
13C NMR (62.9 MHz, CDCl3): (major isomer) = 158.8, 151.1,
148.9, 145.9, 131.5, 130.7, 128.7, 124.5, 113.4, 108.6, 75.9, 72.2,
68.0, 60.8, 59.8, 55.6, 54.8, 37.5, 35.4, 30.7, 25.7, 18.1, 16.8, 9.5,
–5.7. (minor isomer) = 158.8, 150.7, 148.8, 145.9, 131.5, 130.4,
128.7, 124.6, 113.4, 108.6, 74.9, 72.3, 67.3, 60.7, 59.8, 55.8, 54.8,
37.6, 35.9, 31.2, 25.7, 18.0, 16.8, 9.5, –5.6.
MS (EI, 70 eV): m/z (%) = 532 (4, [M]+), 135 (23), 121 (100,
[CH2C6H4OMe-4]+), 82 (10), 73 (10).
HRMS (110 °C, 70 eV): m/z calcd for C30H48O6Si: 532.3220;
found: 532.3233.
20a/b
To a solution of TBS-protected alcohols 19a/b (2.23 g, 4.19 mmol)
from the above reaction in a mixture of CH2Cl2/H2O (18:1, 19 mL)
was added DDQ (1.43 g, 6.29 mmol). The reaction mixture turned
into black and the stirring was continued for 3 h at r.t. Then the pre-
cipitated DDQH was filtered off, the organic phase was washed
with aq sat. NH4Cl solution (2 20 mL) and with H2O (1 20 mL).
The aqueous layers were extracted with CH2Cl2 (3 25 mL), the
combined organic phases were passed through a plug of MgSO4 and
concentrated in vacuo to give the crude product as a blue-black oil.
To remove the anisaldehyde, the crude product was further purified
by column chromatography eluting with hexane–EtOAc (8:2). Al-
cohols 20a/b were obtained in 69% yield (1.19 g) as a colourless oil.
It was possible to isolate small quantities of diastereomeric pure
material (first and last fractions); Rf 0.44 (major isomer, SiO2, hex-
ane–EtOAc, 6:4); Rf 0.39 (minor isomer, SiO2, hexane–EtOAc,
6:4).
13C NMR (62.9 MHz, CDCl3): (major isomer) = 205.1, 149.3,
146.8, 145.9, 129.7, 125.2, 108.7, 67.6, 61.2, 60.2, 56.1, 44.3, 37.6,
32.7, 25.8, 18.2, 14.4, 9.7, –5.5. (minor isomer) = 204.9, 149.2,
146.6, 145.7, 130.5, 125.2, 108.5, 67.4, 61.1, 60.2, 56.1, 44.3, 37.8,
33.5, 25.8, 18.2, 13.4, 9.7, –5.5.
MS (EI, 70 eV): m/z (%) = 410 (39, [M]+), 354 (16), 353 (63, [M –
C3H5O]+), 338 (37), 267 (15), 265 (15), 265 (18), 261 (46), 237 (10),
230 (32), 196 (14), 195 (100), 187 (24), 171 (47).
HRMS (80 °C, 70 eV): m/z calcd for C22H38O5Si: 410.2489; found:
410.2496.
1H NMR (250 MHz, CDCl3): (major isomer) = 6.62 (s, 1 H, ArH),
3.81, 3.77, 3.68 (3 s, each 3 H, OCH3), 3.76–3.62 (m, 2 H, CH2OH),
3.57–3.45 (m, 2 H, CH2OTBS), 3.41–3.28 (m, 1 H, ArCH), 2.21 (s,
3 H, ArCH3), 1.91–1.78 (m, 1 H, ArCHCH2), 1.64–1.47 (m, 1 H,
CHMe), 1.43–1.32 (m, 1 H, ArCHCH2), 0.90 (d, J = 6.7 Hz, 3 H,
CHCH3), 0.83 [s, 9 H, SiC(CH3)3], –0.02 [s, 6 H, Si(CH3)2].
(minor isomer) = 6.65 (s, 1 H, ArH), 3.84, 3.80, 3.71 (3 s, each 3
H, OCH3), 3.76–3.62 (m, 2 H, CH2OH), 3.57–3.45 (m, 2 H,
CH2OTBS), 3.41–3.28 (m, 1 H, ArCH), 2.24 (s, 3 H, ArCH3), 1.91–
1.78 (m, 1 H, ArCHCH2), 1.64–1.47 (m, 1 H, CHMe), 1.32–1.22
(m, 1 H, ArCHCH2), 0.92 (d, J = 6.7 Hz, 3 H, CHCH3), 0.86 [s, 9
H, SiC(CH3)3], –0.01 [s, 6 H, Si(CH3)2].
13C NMR (100.6 MHz, CDCl3): (major isomer) = 150.6, 149.2,
146.2, 131.6, 125.0, 108.5, 68.2, 67.6, 61.2, 60.2, 56.1, 37.6, 36.6,
33.5, 25.8, 18.3, 18.0, 9.7, –5.4, –5.5. (minor isomer) = 150.8,
149.1, 146.4, 131.6, 125.5, 108.5, 69.1, 68.4, 61.2, 60.2, 56.1, 37.6,
36.3, 33.5, 26.2, 18.1, 17.8, 9.7, –5.4, –5.5.
(4S,6R)-(E)-7-(tert-Butyldimethylsilyloxy)-4-methyl-6-(tri-
methoxymethylphenyl)hept-2-enoic Acid Methoxymethyl-
amide (23a)
The diethyl phosphonate 22 (813 mg, 3.40 mmol) was dissolved in
anhyd THF (15 mL) and cooled to 0 °C. NaH (Fluka 60%, 136 mg,
3.40 mmol) was added slowly and the mixture was stirred for 1 h at
0 °C. Then aldehydes 21a/b (1.07 g, 2.62 mmol), dissolved in an-
hyd THF (11 mL), were transferred via syringe to the solution. The
mixture was allowed to warm to r.t. and stirred for another 2.5 h,
then quenched with aq sat. NH4Cl solution (20 mL). After extrac-
tion with Et2O (5 20 mL), drying (MgSO4) and evaporation of sol-
vents, a brown crude oil was obtained, which was further purified
by column chromatography eluting with hexane–EtOAc (7:3). It
was possible to separate the diastereomers; 742 mg (57%, colour-
less oil) of the desired major isomer 23a were isolated along with
456 mg (35%, colourless oil) of the minor isomer 23b, making up a
total yield of 92%; Rf 0.22 (minor isomer, SiO2, hexane–EtOAc,
7:3).
MS (EI, 70 eV): m/z (%) = 412 (8, [M]+), 263 (17), 210 (14), 195
(40), 169 (26), 168 (100), 165 (11), 156 (84), 141 (26), 139 (77),
135 (15), 113 (13), 111 (41), 77 (17), 75 (30).
Synthesis 2002, No. 13, 1857–1866 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
23a
Synthesis of a Diels–Alder Precursor for the Elisabethin A Skeleton
1865
evaporation of solvents in vacuo 525 mg (73%) of the title com-
pound 2 was obtained as a colourless oil; Rf 0.63 (SiO2, hexane–
EtOAc, 8:2); [ ]D20 +43.6 (c 1.05, CHCl3).
20
Rf 0.29 (major isomer, SiO2, hexane–EtOAc, 7:3); [ ]D +57.9
(c 1.00, CHCl3).
1H NMR (250 MHz, CDCl3): = 6.75 (dd, J = 8.4 Hz, 15.5 Hz, 1
H, HCHC=CH), 6.51 (s, 1 H, ArH), 6.20 (d, J = 15.5 Hz, 1 H,
HCHC=CH), 3.70, 3.66, 3.57, 3.51 (4 s, each 3 H, OCH3), 3.62–
3.47 (m, 2 H, TBSOCH2), 3.18–3.08 (m, 1 H, ArCH), 3.11 (s, 3 H,
NCH3), 2.22–2.11 (m, 1 H, CHMe), 2.08 (s, 3 H, ArCH3), 1.82–1.68
(m, 1 H, CH2CHMe), 1.58–1.43 (m, 1 H, CH2CHMe), 0.92 (d,
J = 6.6 Hz, 3 H, CHCH3), 0.72 [s, 9 H, SiC(CH3)3], –0.15 [s, 6 H,
Si(CH3)2].
IR (neat): 2953, 2930, 2856, 2378, 1653, 1091 cm–1.
1H NMR (250 MHz, CDCl3): = 6.62 (s, 1 H, ArH), 6.25 (dd,
J = 10.6 Hz, 15.2 Hz, 1 H, HC=CHCH=CHMe), 5.95 (t, J = 10.6
Hz, 1 H, HC=CHCH=CHMe), 5.51 (dd, J = 8.1 Hz, 15.2 Hz, 1 H,
HC=CHCH=CHMe), 5.36 (m, 1 H, HC=CHCH=CHMe), 3.82,
3.78, 3.64, (3 s, each 3 H, OCH3), 3.73–3.54 (m, 2 H, TBSOCH2),
3.29–3.16 (m, 1 H, ArCH), 2.22 (s, 3 H, ArCH3), 2.18–2.06 (m, 1
H, CHMe), 1.85–1.72 (m, 1 H, CH2CHMe), 1.70 (d, J = 7.1 Hz, 3
H, CH=CHCH3), 1.63–1.51 (m, 1 H, CH2CHMe), 1.01 (d, J = 6.1
Hz, 3 H, CHCH3), 0.85 [s, 9 H, SiC(CH3)3], –0.03 [s, 6 H,
Si(CH3)2].
13C NMR (100.6 MHz, CDCl3): = 166.8, 152.1, 150.8, 148.7,
145.9, 130.4, 124.5, 117.4, 108.6, 67.2, 61.1, 60.6, 59.7, 55.6, 38.5,
37.8, 34.2, 31.9, 25.5, 20.4, 17.8, 9.3, –5.9.
MS (EI, 70 eV): m/z = 496 (11, [M + H]+), 495 (34, [M]+), 439 (28),
438 (100), 208 (11), 195 (21), 73 (23).
13C NMR (100.6 MHz, CDCl3): = 151.2, 148.9, 146.2, 139.8,
131.0, 129.7, 125.5, 125.0, 124.3, 109.1, 67.6, 61.0, 60.1, 56.0,
38.5, 38.2, 34.8, 26.0, 21.5, 18.0, 13.1, 9.7, –5.3.
MS (EI, 70 eV): m/z (%) = 449 (27, [M + H]+), 448 (60, [M]+), 393
(11), 392 (35), 391 (84), 377 (16), 376 (40), 339 (12), 316 (12), 268
(12), 267 (36), 194 (67), 155 (19), 95 (100), 85 (26).
HRMS (110 °C, 70 eV): m/z calcd for C26H45O6NSi: 495.3016;
found: 495.3002.
Anal. Calcd for C26H45O6NSi: C, 62.99; H, 9.15; N, 2.83; Found: C,
62.87; H, 9.03; N, 3.04.
HRMS (60 °C, 70 eV): m/z calcd for C26H44O4Si: 448.3009; found:
(6R,4S)-(E)-7-(tert-Butyldimethylsilyloxy)-4-methyl-6-(tri-
methoxymethylphenyl)hept-2-enal (24)
448.3021.
Anal. Calcd for C26H44O4Si: C, 69.60; H, 9.88; Found: C, 69.71; H,
9.97.
The amid 23a (323 mg, 0.652 mmol) was dissolved in anhyd THF
(5 mL) and cooled to –78 °C. DIBAL-H (1 M in hexane, 1.96 mL,
1.96 mmol) was slowly added via syringe to the solution. The mix-
ture was stirred for 1 h at –78 °C, then carefully quenched with a
mixture of aq 1 M tartaric acid and hexane (1:1, 8 mL). The suspen-
sion was allowed to warm to r.t. and stirred for 1 h. Finally extrac-
tion with Et2O (4 10 mL), drying (MgSO4) and evaporation of
solvents furnished 279 mg (98%) of the aldehyde 24 as a pale yel-
low oil, which was almost pure; Rf 0.54 (SiO2, hexane–EtOAc, 7:3);
[ ]D20 +41.2 (c 1.10, CHCl3).
1H NMR (250 MHz, CDCl3): = 9.48 (d, J = 8.0 Hz, 1 H, CHO),
6.75 (dd, J = 7.5 Hz, 15.7 Hz, 1 H, HC=CHCHO), 6.58 (s, 1 H,
ArH), 6.05 (dd, J = 8.0 Hz, 15.7 Hz, 1 H, HC=CHCHO), 3.82, 3.78,
3.62, (3 s, each 3 H, OCH3), 3.77–3.58 (m, 2 H, TBSOCH2), 3.28–
3.14 (m, 1 H, ArCH), 2.44–2.29 (m, 1 H, CHMe), 2.20 (s, 3 H,
ArCH3), 2.01–1.82 (m, 1 H, CH2CHMe), 1.71–1.58 (m, 1 H,
CH2CHMe), 1.07 (d, J = 6.6 Hz, 3 H, CHCH3), 0.85 [s, 9 H,
SiC(CH3)3], –0.02 [s, 6 H, Si(CH3)2].
(3S,5S)-3-Methyl-5-(2,4,5-trimethoxy-3-methylphenyl)tetrahy-
dropyran-2-ol (26)
The diastereomeric pure 20b (minor isomer, 19.5 mg, 47.2 mol),
obtained during column chromatography of the diastereomeric mix-
ture of alcohols 20a/b, was oxidised to the aldehyde by Swern oxi-
dation (same procedure as in the step 20a/b 21a/b). The crude
aldehyde (18.6 mg, 45.3 mol) was dissolved in anhyd THF (1 mL)
and TBAF (1 M in hexane, 90.5 L, 90.5 mol) was added via a
Hamilton syringe at r.t. The mixture was stirred for 1 h, then
quenched by the addition of sat. aq NH4Cl (2 mL) solution. After
extraction with Et2O (3 5 mL), the combined organic layers were
passed through a plug of MgSO4 and the solvents were removed un-
der reduced pressure to give the hydroxy aldehyde 25 as a crude oil;
Rf 0.11 (SiO2, hexane–EtOAc, 7:3). The above crude product 25
(29.8 mg, 45 mol) was dissolved in MeOH (1 mL), then K2CO3
(12.3 mg, 89.0 mol) was added and the resulting suspension was
refluxed for 2.5 h. After the addition of H2O (5 mL), the mixture
was extracted with Et2O (3 5 mL), the combined organic layers
were concentrated in vacuo and the residue was further purified by
column chromatography (hexane–EtOAc, 6:4). The lactol 26 was
obtained in 89% (12.5 mg) yield over the three steps as a colourless
oil. The ratio of the two anomers came to 45:55 as determined by
signal integration (ArH and CHCH3) of the 1H NMR spectrum; Rf
0.25 (for both anomers, SiO2, hexane–EtOAc, 6:4).
13C NMR (62.9 MHz, CDCl3): = 193.7, 164.1, 150.9, 149.0,
146.4, 130.5, 130.2, 124.9, 108.5, 67.2, 60.9, 59.9, 55.8, 38.3, 37.7,
34.7, 25.7, 18.9, 18.1, 9.5, –5.6.
MS (EI, 70 eV): m/z (%) = 437 (13, [M + H]+), 436 (39, [M]+), 479
(17, [M – C3H5O]+), 339 (16), 322 (41), 291 (18), 287 (39), 267
(42), 256 (13), 208 (62), 195 (100), 193 (20), 89 (18), 75 (42).
HRMS (100 °C, 70 eV): m/z calcd for C24H40O5Si: 436.2645;
1H NMR (250 MHz, CDCl3): (major anomer) = 6.51 (s, 1 H,
ArH), 4.44 (d, J = 6.6 Hz, CHOH)), 4.11–3.96 (m, 1 H, OCH2),
3.83, 3.78, 3.68 (3 s, each 3 H, OCH3), 3.70–3.55 (m, 1 H, OCH2),
3.41–3.27 (m, 1 H, ArCH), 2.21 (s, 3 H, ArCH3), 1.98–1.88 (m, 1
H, CHMe), 1.79–1.55 (m, 2 H, CH2CHMe), 1.04 (d, J = 6.4 Hz, 3
H, CHCH3), 0.85 [s, 9 H, SiC(CH3)3], –0.03 [s, 6 H, Si(CH3)2].
13C NMR (100.6 MHz, CDCl3): (major anomer) = 151.1, 149.2,
143.8, 124.6, 116.7, 112.2, 98.3, 70.2, 61.9, 58.4, 56.2, 42.9, 39.7,
33.5, 17.8, 10.8.
found: 436.2631.
(2R,4S)-tert-Butyldimethyl-[(5E,7Z)-4-methyl-2-(2,4,5-tri-
methoxy-3-methylphenyl)nona-5,7-dienyloxy]silane (2)
To a suspension of (ethyl)triphenylphosphonium bromide (897 mg,
2.42 mmol) in anhyd THF (11 mL) was added NaHMDS (1 M in
THF, 2.42 mL, 2.42 mmol) at –78 °C, which resulted in the forma-
tion of a deep orange-red solution. The mixture was stirred for 0.5
h at –78 °C, then 0.5 h at 0 °C and cooled again to –78 °C, followed
by the addition of aldehyde 24 (703 mg, 1.61 mmol), dissolved in
anyhd THF (4 mL). The yellow reaction mixture was allowed to
warm slowly to r.t. and stirred for 14 h. A solution of aq sat. NH4Cl
(20 mL) was added, extracted with Et2O (4 15 mL) and solvents
were removed to give a crude oil, which was further purified by col-
umn chromatography eluting with hexane–EtOAc (30:1). After
MS (EI, 70 eV): m/z (%) = 296 (41, [M]+), 247 (28), 201 (64), 182
(100), 167 (18), 139 (27).
HRMS (50 °C, 70 eV): m/z calcd for C16H24O5: 296.1623; found:
296.1629.
Synthesis 2002, No. 13, 1857–1866 ISSN 0039-7881 © Thieme Stuttgart · New York

1866
T. J. Heckrodt, J. Mulzer
PAPER
(3S,5S)-3-Methyl-5-(2,4,5-trimethoxy-3-methylphenyl)tetrahy-
dropyran-2-one (26) and (S)-5-Methyl-3-(2,4,5-trimethoxy-3-
methylphenyl)-3,4-dihydro-2H-pyran (27)
13C NMR (62.9 MHz, CDCl3): = 152.3, 151.1, 144.7, 138.3,
128.3, 116.2, 114.9, 106.1, 69.7, 61.6, 59.7, 55.9, 36.8, 36.1, 18.5,
9.5.
To a slurry made from DMP (89.8 mg, 212 mol), NaHCO3 (71.2
mg, 847 mol) and anhyd CH2Cl2 (1 mL) was added the lactol 26
(12.5 mg, 42.4 mol), dissolved in anhyd CH2Cl2 (0.5 mL). The
mixture was stirred at r.t. for 1 h, then H2O (3 mL) was added and
the mixture was extracted with CH2Cl2 (3 5 mL). The combined
organic phases were passed through a plug of MgSO4 and the sol-
vents were evaporated under reduced pressure. Further purification
by column chromatography gave the desired lactone 27 (6.40 mg,
51%) along with the elimination product 28 (4.80 mg, 41%).
MS (EI, 70 eV): m/z (%) = 278 (100, [M]+), 208 (86), 196 (47), 149
(45), 84 (77).
HRMS (40 °C, 70 eV): m/z calcd for C16H22O4 278.1518; found
278.1523.
Acknowledgement
The authors would like to thank Dr. Valentin S. Enev for helpful
discussions. Thanks are also due to Dr. Hanspeter Kählig for recor-
ding two-dimensional NMR spectra. Financial support by the FWF
(Project P14729-CNE) is gratefully acknowledged.
27
Rf 0.30 (SiO2, hexane–EtOAc, 6:4); [ ]D20 –51.7 (c 0.28, CHCl3).
1H NMR (600 MHz, CDCl3): = 6.57 (s, 1 H, ArH), 4.50 (dd,
J = 2.0 Hz, 5.3 Hz, 1 H, OCOCH2), 4.23 (dd, J = 2.0 Hz, 9.7 Hz, 1
H, OCOCH2), 3.83, 3.79, 3.70 (3 s, each 3 H, OCH3), 3.68–3.62 (m,
1 H, ArCH), 2.73 (sept, J = 6.9 Hz, 1 H, OCCHMe), 2.28–2.23 (m,
1 H, CHMeCH2), 2.22 (s, 3 H, ArCH3), 1.84–1.76 (q, J = 12.7 Hz,
1 H, CHMeCH2), 1.35 (d, J = 6.9 Hz, 1 H, CHCH3).
13C NMR (62.9 MHz, CDCl3): = 177.6, 149.3, 148.4, 143.8,
124.5, 119.7, 107.7, 73.7, 61.4, 60.2, 56.2, 36.1, 35.6, 33.3, 16.9,
9.8.
References
(1) Rodríguez, A. D.; González, E.; Huang, S. D. J. Org. Chem.
1998, 63, 7083.
(2) Rodríguez, A. D.; Ramírez, C.; Rodríguez, I. I.; Barnes, C.
L. J. Org. Chem. 2000, 65, 1390.
(3) Weygand, F.; Vogelbach, K.; Zimmermann, K. Ber. Dtsch.
Chem. Ges. 1947, 80, 391.
(4) Walkup, R. D.; Boatman, P. D.; Kane, R. R.; Cunningham,
R. T. Tetrahedron Lett. 1991, 32, 3937.
(5) Soli, E. D.; Manoso, A. S.; Patterson, M. C.; DeShong, P. J.
Org. Chem. 1999, 64, 3171.
(6) Mulzer, J.; Mantoulidis, A. Tetrahedron Lett. 1996, 37,
9179.
(7) Carter, R. H.; Garson, M. J.; Hill, R. A.; Staunton, J.; Sunter,
D. C. J. Chem. Soc., Perkin Trans. 1 1981, 471.
(8) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O.
Tetrahedron Lett. 1988, 29, 4139.
MS (EI, 70 eV): m/z (%) = 295 (18, [M + H]+), 294 (100, [M]+), 208
(18), 193 (11).
HRMS (80 °C, 70 eV): m/z calcd for C16H22O5: 294.1467; found:
294.1463.
28
Rf 0.48 (SiO2, hexane–EtOAc, 6:4); [ ]D20 –18.1 (c 0.15, CHCl3).
1H NMR (250 MHz, CDCl3): = 6.56 (s, 1 H, ArH), 6.06 (d, J = 3.2
Hz, 1 H, CH=CMe), 3.86, 3.79, 3.69 (3 s, each 3 H, OCH3), 3.82–
3.65 (m, 2 H, OOCH2), 3.42–3.28 (m, 1 H, ArCH), 2.22 (s, 3 H,
ArCH3), 2.16 (d, J = 3.2 Hz, 3 H, CH=CCH3), 1.34–1.13 (m, 1 H,
CH=CMeCH2).
(9) Mukaiyama, T.; Inoue, T. Bull. Chem. Soc. Jpn. 1980, 53,
174.
Synthesis 2002, No. 13, 1857–1866 ISSN 0039-7881 © Thieme Stuttgart · New York