An effective method for the synthesis of 13C-labeled polyprenylhydroxybenzoic acids

Article abstract of DOI:10.1055/s-2005-861863

The synthesis of side-chain ¹³C-labeled geranylgeranyl-4- hydroxybenzoic acids and geranylgeranyl-3,4-dihydroxybenzoic acids is described. The synthesis starts from O-protected methyl hydroxyiodobenzoates, which are transformed into Grignard re

Full text of DOI:10.1055/s-2005-861863

FEATURE ARTICLE
1019
An Effective Method for the Synthesis of 13C-Labeled Polyprenylhydroxy-
benzoic Acids
13
M
C-Labeled Polypreny
a
lhydroxybe
r
nzoic
A
c
t
ids in Lang,1 Wolfgang Steglich*
Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstr. 5–13 (F), 81377 München, Germany
Fax +49(89)218077756; E-mail: wolfgang.steglich@cup.uni-muenchen.de
Received 12 January 2005
stead of the corresponding ester derivatives. In these cases
additional protection/deprotection steps, as well as chang-
es of the oxidation state, are required.
Abstract: The synthesis of side-chain 13C-labeled geranylgeranyl-
4-hydroxybenzoic acids and geranylgeranyl-3,4-dihydroxybenzoic
acids is described. The synthesis starts from O-protected methyl hy-
droxyiodobenzoates, which are transformed into Grignard reagents
by low-temperature iodine–magnesium exchange according to
Knochel’s procedure. Copper catalyzed cross-coupling with labeled
geranylgeranyl bromide followed by deprotection affords the prod-
ucts with good yields and full retention of stereochemistry.
In recent years, important progress in Grignard methodol-
ogy has been contributed by Knochel and coworkers.13
They demonstrated that halogen–magnesium exchange in
(hetero)aryl or alkenyl halides can be performed with i-
PrMgBr at low temperatures, thereby avoiding reaction of
the resulting Grignard reagents with sensitive functional-
ities such as amide, cyano, halogen, or carboxylic ester
groups. We believed that this technique would allow us to
introduce the valuable 13C-labeled side chain into iodo-
benzoic acid derivatives at a later stage of the synthesis.
The preparation of the desired O-protected hydroxyiodo-
benzoates is depicted in Scheme 1.
Key words: allylations, copper, coupling, Grignard reactions, or-
ganometallic reagents
In the course of our studies on the biosynthesis of mero-
terpenoids from larger fungi, we required side-chain 13C-
labeled polyprenylhydroxybenzoic acids for feeding ex-
periments. Unfortunately, known methods for the poly-
prenylation of hydroxybenzoic acids appeared to be
unsuitable for the preparation of the valuable isotope-la-
beled compounds due to lack of generality, unreliable
yields or loss of stereochemical integrity in the side chain.
In this publication we describe an effective method for the
introduction of polyprenyl side chains into hydroxyben-
zoic acids that circumvents these problems.
In the synthesis of iodoester 2, methyl 4-hydroxybenzoate
was treated with NaI and chloramine-T14 and the resulting
The Claisen alkylation2 of 4-alkoxycarbonylphenolates
with (poly)prenyl bromides3 represents the most common
method for the synthesis of 4-hydroxy-3-(poly)prenylben-
zoic acids. The reported yields, however, are generally
low, covering a range between 7%3b and 37%.3c Recently,
Wessjohann4 developed an enzymatic method for the
transfer of polyprenyl pyrophosphates to the meta-posi-
tion of 4-hydroxy- and 4-aminobenzoic acids using a pre-
nyltransferase isolated from an overproducing strain of E.
coli.
The syntheses of (2¢E,6¢E)-3-farnesyl-4-hydroxybenzoic
acid and 3-farnesyl-4,5-dihydroxybenzoic acid were ac-
complished by the Stille coupling.5 This methodology,
however, suffers from the problem of removing toxic6a
traces of organotin compounds.6b In the course of the
Stille coupling of methyl 4,5-diacetoxy-3-[(tri-n-bu-
tyl)stannyl]benzoate with polyprenyl bromides, we also
observed the formation of a 3:1 E/Z mixture at C-2¢.7–10
Methods based on the formation of lithiated intermediates
use silyl-protected benzyl alcohols11 or oxazolines12 in-
Scheme 1 Reagents and conditions: (a) MOMCl, i-Pr2NEt, CH2Cl2
or DMF, r.t.; (b) I2, KOH, MeOH, 0 °C; (c) LTMDA, –20 °C; then n-
BuLi (excess), –20 °C; then 1,2-diiodoethane, –40 °C → r.t.; (d)
NaClO2, 2-methyl-2-butene, NaH2PO4, t-BuOH, H2O, r.t.; (e) MeI,
DBU, DMF, r.t.
SYNTHESIS 2005, No. 6, pp 1019–1027
x
x
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x
x
.2
0
0
5
Advanced online publication: 09.03.2005
DOI: 10.1055/s-2005-861863; Art ID: Z01205SS
© Georg Thieme Verlag Stuttgart · New York

1020
M. Lang, W. Steglich
FEATURE ARTICLE
iodo derivative 1 was converted into the methoxymethyl oxidized with sodium chlorite in the presence of 2-meth-
(MOM) ether 2.15
yl-2-butene.21 Treatment of the resulting carboxylic acid
with MeI and 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU)22 afforded the desired ester 11.
The synthesis of ester 5 started from 4,5-dihydroxy-3-io-
dobenzoic acid (3),16 which can be easily prepared by
demethylation of 5-iodovanillin with BBr3. Protection of
3 with MOM chloride15 and oxidation of the resulting di-
ether 4 with iodine and KOH in MeOH17 afforded 5 in ex-
cellent yield.
For the synthesis of regioisomer 8, 3,4-dihydroxybenzal-
dehyde was methoxymethylated15 and the resulting di-
ether 6 was treated with the lithium salt of N,N,N¢-
trimethylethylenediamine (LTMDA).18 Ortho-lithiation
with n-butyl lithium followed by treatment with 1,2-diio-
doethane afforded a mixture of 2-iodo-3,4-bis(meth-
oxymethoxy)benzaldehyde (7) and its 6-iodo isomer in
63% and 3% yield, respectively. This reflects the cooper-
ative anion stabilizing effect of the neighboring a-amino
alkoxide18 and methoxymethyl19 groups favoring the pre-
dominant formation of the 2-iodo isomer. Alkaline iodine
oxidation17 of the crude aldehyde mixture and chromato-
graphic purification of the product yielded the methyl es-
ter 8.
Scheme 2 Reagents and conditions: (a) Me2SO4 (excess), 155 °C to
165 °C;25 (b) See ref.24; (c) See ref.23; (d) PPh3, CBr4, CH2Cl2, 0 °C, 2
h. The atom numbering indicates the system used for NMR assign-
ments of all geranylgeranyl compounds.
(2E,6E,10E)-[1-13C]Geranylgeraniol (13) was prepared
from (2E,6E)-farnesyl bromide and ethyl [1-13C]aceto-
acetate (12) applying the four-step procedure of
Schmalz23 (Scheme 2). Compound 12 was obtained by
acetylation24 of ethyl [1-13C]acetate, which was in turn
prepared by alkylation of sodium [1-13C]acetate with di-
ethyl sulfate.25 For the conversion of polyprenyl alcohols
Methyl 2-iodo-4-(triisopropylsilyloxy)benzoate (11) was
prepared from aldehyde 9.20 Treatment of 9 with LTMDA
and n-BuLi,18 followed by addition of 1,2-diiodoethane
yielded exclusively the 2-iodo derivative 10, which was
Biographical Sketches
Martin Lang was born in 1972 in diploma in 1997. He received his currently working as a medicinal
Weilheim, Germany. He studied PhD under the guidance of Prof. chemist at 4SC AG, Martinsried.
chemistry in Munich and obtained his Wolfgang Steglich in 2002 and is
Wolfgang Steglich was born in 1933 bilitation in München in 1965 and pyrrole alkaloids and the chemistry
in Kamenz/Sachsen. He studied held chairs of Organic Chemistry at of peptides. He introduced DMAP as
chemistry at the TU Berlin and re- the TU Berlin (1971–1975), Univer- a nucleophilic catalyst in organic
ceived his PhD at the TU München sity of Bonn (1975–1991), and Uni- synthesis and was involved in the de-
under the guidance of Prof. Friedrich versity of München (emeritus status velopment of strobilurins as a major
Weygand. During his postdoctoral since 2001). His major topic of inter- class of fungicides. He has served as
studies with Sir Derek H. R. Barton est is the chemistry of natural prod- an editor of several journals and the
at the Imperial College London, he ucts, especially the isolation, Römpp Encyclopedia ‘Natural Prod-
worked on the biosynthesis of mor- synthesis and biosynthesis of fungal ucts’.
phine alkaloids. He finished his ha- metabolites, the synthesis of marine
Synthesis 2005, No. 6, 1019–1027 © Thieme Stuttgart · New York

FEATURE ARTICLE
13C-Labeled Polyprenylhydroxybenzoic Acids
1021
to the corresponding bromides (e.g. 14), the Appel were cleaved with 0.5 M HCl in i-PrOH34 to yield 20 and
reaction26 was preferred over the use of PBr3.27
23, respectively. Acetal hydrolysis of 16 required both
higher HCl concentration and prolonged reaction time.
Under these conditions, however, a significant amount of
material underwent HCl addition to the terminal double
bond;35 this could not be prevented by addition of 20
equivalents of 2-methyl-2-butene. The problem was final-
ly solved by deprotecting 16 with p-toluenesulfonic acid
in i-PrOH at 60 °C.
With the four aryl iodides 2, 5, 8, and 11 at hand, we were
able to show that the iodine–magnesium exchange under
Knochel’s conditions13 was complete after 0.5 h at –20 °C
without affecting the ester group.28 Not surprisingly, the
coupling of the Grignard compounds with polyprenyl bro-
mides required catalysis.
Dilithium tetrachlorocuprate(II)29 is a frequently used cat-
alyst in the reaction of Grignard reagents with electro-
philes.30 The catalytically active species is most likely a
copper(I) derivative31 formed in situ on reduction of the
copper(II) complex by the organomagnesium compound.
In cases of intramolecular stabilization of the Grignard re-
agent by chelating substituents, e.g. MOM ethers, this re-
duction is reported to be seriously hampered, resulting in
reduced coupling yields.32 This can be prevented by the
use of dilithium trichlorocuprate(I) instead of the cop-
per(II) salt.32 Accordingly, we used the copper(I)
complex33 as a catalyst and good coupling yields with ger-
anyl bromide were obtained. Later, however, no signifi-
cant difference between the copper(I) complex and
dilithium tetrachlorocuprate(II) was noted. The latter is
commercially available and can be stored in THF solu-
tion. With both copper catalysts, a (SN2) substitution oc-
curred exclusively, and no g (SN2¢) substitution product
was detectable by NMR. E/Z isomerization of the 2¢-dou-
ble bond in the polyprenyl chain was negligible, and the
coupling yields with geranylgeranyl bromide (14) were
generally in the range of 70%–88%. With respect to the
valuable isotope-labeled side chain, a slight excess (1.2
equivalents) of aryl iodide was employed.
In conclusion, we have developed a reliable method for
the synthesis of stereo- and regiochemically defined poly-
prenylhydroxybenzoic acids. These compounds are not
only potential biosynthetic precursors of meroterpenoids
from larger fungi,36 but are also intermediates in the bio-
synthesis of ubiquinones.37 They have been isolated from
several plants, fungi and marine sponges38 and include ac-
ids 17,38f–j 20,38j,k and 23,38j,k whose syntheses are reported
for the first time. Their NMR and IR spectra are in good
agreement with the literature data.38k In addition, our new
method offers easy access to many other compounds of
this type. To the best of our knowledge, 4-hydroxybenzoic
acids carrying a polyprenyl residue at C-2 have not been
prepared before.
Melting points (uncorrected): Büchi SMP 535 apparatus. IR spec-
tra: Perkin-Elmer FT-IR Spectrum 1000. Abbreviations: s, strong;
m, medium; w, weak; sh, shoulder; br, broad. Mass spectra (EI, 70
eV): Finnigan MAT 90 and Finnigan MAT 95Q. High-resolution
mass spectra (EI, 70 eV): Finnigan MAT 95Q. NMR spectra: Bru-
ker ARX 300 and Bruker AMX 600. The spectra were recorded in
CDCl3 or acetone-d6 using the residual solvent peak as an internal
standard (CDCl3, dH = 7.26 and dC = 77.10; acetone-d6, dH = 2.04
and dC = 29.80). For atom numbering within geranylgeranyl chains,
†
see Scheme 2. Interchangeable NMR assignments are labeled by
The methyl ester and silyl ether groups of 24 were cleaved
with LiOH to afford hydroxy acid 25. Standard hydrolysis
of the corresponding esters furnished the crude acids 16,
19, and 22, respectively. The MOM groups of 19 and 22
and ‡ or separated by /. Elemental analyses were carried out by the
Microanalytical Laboratory of the Department Chemie, Universität
München. TLC: Silica gel F254 (Merck). Flash chromatography
(FC): Merck Kieselgel 60 (0.040–0.063 mm). Solvents for chroma-
Scheme 3 Reagents and conditions: (a) i-PrMgBr, –20 °C; then Li2CuCl4 (4 mol%), 14; (b) LiOH, MeOH, H2O, 100 °C; (c) p-TsOH (1 equiv,
0.1 M), i-PrOH, 60 °C, approx. 6 h; (d) AcCl (5 equiv, 0.5 M), i-PrOH, r.t., approx. 5 h.
Synthesis 2005, No. 6, 1019–1027 © Thieme Stuttgart · New York

1022
M. Lang, W. Steglich
FEATURE ARTICLE
tography were distilled before use. THF was distilled under Ar from
Na/benzophenone. CH2Cl2 was distilled under Ar from Sicapent
(Merck). Dry DMF was purchased from Fluka.
crude 3 which was suspended in anhyd CH2Cl2 (15 mL) and treated
with a 6 M solution of MOMCl in EtOAc15b (2.5 mL, 15 mmol) and
i-PrNEt2 (2.9 mL, 17.5 mmol). The mixture was stirred for 5 h at r.t.,
then treated with 2 N NH4OH (30 mL) and extracted with Et2O (3 ×
40 mL). The combined organic phases were washed with brine,
dried (Na2SO4), and concentrated in vacuo. FC (hexanes–EtOAc,
5:2) afforded 4 as a colorless oil (1.60 g, 4.53 mmol, 91%).
n-BuLi was purchased as a solution in hexanes (Aldrich) and the ac-
tual concentration was determined using diphenylacetic acid.39
Li2CuCl4 (0.2 M solution in THF) was obtained from Aldrich. Al-
ternatively, the solution was prepared from dry LiCl und CuCl2.29
Geraniol was purchased from Fluka, (2E,6E)-farnesol from Ald-
rich. For every substitution pattern of the polyprenylhydroxybenzo-
ic acids, the geranyl, (2¢E,6¢E,10¢E)-geranylgeranyl, and
(2¢E,6¢E,10¢E)-[1-13C]geranylgeranyl derivatives were synthesized.
Only the data of the labeled geranylgeranyl compounds are given.
1H NMR (300 MHz, CDCl3): d = 3.50 (s, 3 H, OCH2OCH3), 3.66 (s,
3 H, OCH2OCH3), 5.24 (s, 2 H, OCH2OCH3), 5.31 (s, 2 H,
OCH2OCH3), 7.62 (d, 1 H, 4J = 1.9 Hz, 6-H), 7.95 (d, 1 H, 4J = 1.9
Hz, 2-H), 9.81 (s, 1 H, CHO).
13C NMR (75 MHz, CDCl3): d = 56.6 (OCH2OCH3), 58.6
(OCH2OCH3), 92.7 (C-3), 95.3 (OCH2OCH3), 99.1 (OCH2OCH3),
116.3 (C-6), 134.0 (C-1), 135.1 (C-2), 149.9/151.7 (C-4, C-5),
189.5 (CHO).
Air and moisture sensitive compounds were handled under argon
using standard Schlenk techniques.
Methyl 4-Hydroxy-3-iodobenzoate (1)
To a solution of methyl 4-hydroxybenzoate (1.52 g, 10 mmol) and
NaI (1.80 g, 12 mmol) in MeCN (30 mL) was added within 10 min
chloramine-T trihydrate (3.38 g, 12 mmol). The mixture was stirred
for 1.5 h at r.t., then slightly acidified with 2 N HCl and concentrat-
ed in vacuo. H2O (30 mL) was added and the resulting mixture was
extracted with EtOAc (3 × 40 mL). The combined organic layers
were washed with aq Na2S2O3 and brine, dried (Na2SO4), and con-
centrated in vacuo. Flash chromatography (FC) (hexanes–EtOAc,
3:1) afforded a colorless solid (2.47 g) consisting of 8.3 mmol of 1
Methyl 3-Iodo-4,5-bis(methoxymethoxy)benzoate (5)
To a solution of 4 (1.17 g, 3.33 mmol) in MeOH (40 mL) at 0 °C
was added a cold solution of KOH (0.49 g, 8.65 mmol) in MeOH
(11 mL), followed by rapid addition of a cold solution of iodine
(1.10 g, 4.33 mmol) in MeOH (11 mL). The mixture was treated
with sat. aq NH4Cl (30 mL) and sat. aq Na2S2O3 (10 mL) and then
extracted with EtOAc (3 × 40 mL). The combined extracts were
washed with H2O and brine, dried (Na2SO4), and concentrated. FC
(hexanes–EtOAc, 5:1) afforded 5 as a yellowish oil (1.20 g, 3.13
mmol, 94%).
1
(83% yield) and 1.1 mmol of starting material (determined by H
NMR).40
1H NMR (300 MHz, CDCl3): d = 3.49 (s, 3 H, OCH2OCH3), 3.65 (s,
3 H, OCH2OCH3), 3.88 (s, 3 H, CO2CH3), 5.22 (s, 2 H,
OCH2OCH3), 5.27 (s, 2 H, OCH2OCH3), 7.76 (d, 1 H, 4J = 2.0 Hz,
6-H), 8.14 (d, 1 H, 4J = 2.0 Hz, 2-H).
1H NMR (300 MHz, acetone-d6): d = 3.83 (s, 3 H), 7.02 (d, 1 H,
3J = 8.5 Hz), 7.87 (dd, 1 H, 3J = 8.5 Hz, 4J = 2.1 Hz), 8.34 (d, 1 H,
4J = 2.1 Hz).
13C NMR (75 MHz, acetone-d6): d = 51.7, 83.2, 114.9, 123.9, 131.6,
141.2, 161.0, 165.1.
13C NMR (75 MHz, CDCl3): d = 52.4 (CO2CH3), 56.6
(OCH2OCH3), 58.5 (OCH2OCH3), 92.0 (C-3), 95.3 (OCH2OCH3),
99.0 (OCH2OCH3), 117.8 (C-6), 127.6 (C-1), 134.1 (C-2), 149.1/
150.5 (C-4, C-5), 165.2 (CO2CH3).
Methyl 3-Iodo-4-(methoxymethoxy)benzoate (2)
To a solution of 1 (2.40 g, containing 8.1 mmol of 1 and 1.1 mmol
of methyl 4-hydroxybenzoate) in CH2Cl2 (15 mL) were added i-
PrNEt2 (3.7 mL, 22.5 mmol) and a 6 M solution of MOMCl in
EtOAc15b (2.5 mL, 15 mmol). The mixture was stirred at r.t. until the
reaction was complete (5 h). 2 N NH4OH (30 mL) was added and
the resulting mixture was extracted with Et2O (3 × 40 mL). The
combined organic phases were washed with brine and dried
(Na2SO4). After removal of the solvent in vacuo, FC (hexanes–
EtOAc, 7:1) afforded a colorless solid (2.42 g) containing 6.9 mmol
of 2 (83% yield) and 1.0 mmol of methyl 4-(methoxymethoxy)ben-
zoate (determined by 1H NMR).40
MS: m/z (%) = 382 (8) [M]+, 351 (1), 306 (100), 275 (12), 255 (2),
179 (2), 45 (62) [C2H5O]+.
Anal. Calcd for C12H15IO6: C, 37.72; H, 3.96; I, 33.21. Found: C,
37.79; H, 3.95; I, 33.17.
3,4-Bis(methoxymethoxy)benzaldehyde (6)
To 3,4-dihydroxybenzaldehyde (3.94 g, 28.5 mmol) in anhyd DMF
(30 mL) was added a 6 M solution of MOMCl in EtOAc15b (19 mL,
0.11 mol), followed by i-PrNEt2 (29 mL, 0.17 mol). After stirring
for 5 h at r.t., 2 N NH4OH (30 mL) was added and the mixture was
extracted with Et2O (3 × 40 mL). The combined organic phases
were washed with brine, dried (Na2SO4), and concentrated. FC
(hexanes–EtOAc, 5:2) afforded 6 as a colorless solid (5.36 g, 23.7
mmol, 83%), mp 58 °C (Lit.41 60 °C).
1H NMR (300 MHz, CDCl3): d = 3.50 (s, 3 H, OCH2OCH3), 3.88 (s,
3 H, CO2CH3), 5.29 (s, 2 H, OCH2OCH3), 7.07 (d, 1 H, 3J = 8.6 Hz,
3
4
5-H), 7.96 (dd, 1 H, J = 8.6 Hz, J = 2.1 Hz, 6-H), 8.45 (d, 1 H,
4J = 2.1 Hz, 2-H).
Anal. Calcd for C11H14O5: C, 58.40; H, 6.24. Found: C, 58.31; H,
6.18.
13C NMR (75 MHz, CDCl3): d = 52.2 (CO2CH3), 56.7
(OCH2OCH3), 86.3 (C-3), 94.8 (OCH2OCH3), 113.5 (C-5‡), 125.3
(C-1), 131.4/141.1 (C-2‡, C-6‡), 159.6 (C-4), 165.5 (CO2CH3).
2-Iodo-3,4-bis(methoxymethoxy)benzaldehyde (7)
GC/MS: m/z (%) = 322 (28) [M]+, 292 (5), 291 (11), 261 (6), 45
(100) [C2H5O]+.
In a dry, argon-flushed Schlenk flask equipped with a gas inlet and
rubber septum, N,N,N¢-trimethylethylenediamine (0.57 mL, 4.4
mmol) was dissolved in anhyd THF (10 mL), and a solution of n-
BuLi (4.2 mmol) in hexanes was added dropwise at 0 °C. After stir-
ring for 15 min at r.t., the mixture was cooled to –20 °C, and a so-
lution of 6 (0.91 g, 4.00 mmol) in anhyd THF (3 mL) was added
slowly. The mixture was stirred for an additional 0.5 h at –20 °C and
then treated with n-BuLi (12 mmol). After stirring at –20 °C for 3
h, the solution was cooled to –40 °C, and a solution of 1,2-diiodo-
ethane (5.1 g, 18 mmol) in anhyd THF (5 mL) was added (caution:
gas development). After 5 min, the cooling bath was removed and
the mixture was allowed to reach r.t. After the addition of sat. aq
NH4Cl (30 mL) followed by sat. aq Na2S2O3 (10 mL), the solution
3-Iodo-4,5-bis(methoxymethoxy)benzaldehyde (4)
To a stirred suspension of 5-iodovanillin (1.39 g, 5.00 mmol) in dry
CH2Cl2 (10 mL), BBr3 (1.20 mL, 12.5 mmol) was added at 0 °C un-
der argon. The ice bath was removed and the mixture was stirred for
4 h at r.t. After cooling to 0 °C, MeOH (10 mL) was added slowly
and the solution was subsequently refluxed for 0.5 h under an argon
atmosphere. The volatiles were distilled off, and H2O (30 mL) was
added to the obtained residue. The mixture was extracted with
EtOAc (3 × 40 mL), and the combined organic phases were washed
with brine and dried (Na2SO4). Concentration in vacuo yielded
Synthesis 2005, No. 6, 1019–1027 © Thieme Stuttgart · New York

FEATURE ARTICLE
13C-Labeled Polyprenylhydroxybenzoic Acids
1023
was extracted with Et2O (3 × 40 mL). The combined organic phases
were washed with brine, dried (Na2SO4), and concentrated. FC
(hexanes–EtOAc, 3:1) afforded 7 as a yellowish solid (0.88 g, 2.51
mmol, 63%); mp 55–57 °C.
13C NMR (75 MHz, CDCl3): d = 12.7 {s, Si[CH(CH3)2]3}, 17.9 (s,
6 CH3), 102.1 (C-2), 120.1 (C-5‡), 128.9 (C-1), 131.5 (C-3‡), 131.7
(C-6‡), 161.8 (C-4), 194.5 (CHO).
HRMS: m/z calcd for C16H25IO2Si: 404.0669; found 404.0662.
1H NMR (300 MHz, acetone-d6): d = 3.49 (s, 3 H, OCH2OCH3),
3.65 (s, 3 H, OCH2OCH3), 5.23 (s, 2 H, OCH2OCH3), 5.39 (s, 2 H,
OCH2OCH3), 7.32 (d, 1 H, 3J = 8.6 Hz)/7.62 (d, 1 H, 3J = 8.6 Hz)
(5-H, 6-H), 10.00 (s, 1 H, CHO).
Methyl 2-Iodo-4-(triisopropylsilyloxy)benzoate (11)
To aldehyde 10 (0.765 g, 1.89 mmol) were added t-BuOH (38 mL),
2-methyl-2-butene (19 mL), and a solution of NaH2PO4·2H2O (2.07
g, 13.3 mmol) in H2O (5 mL). The mixture was stirred vigorously,
and a solution of NaClO2 (80% purity; 2.14 g, 18.9 mmol) in H2O
(5 mL) was added dropwise. After stirring for 0.5 h at r.t., H2O (40
mL) was added and the mixture was extracted with EtOAc (3 × 50
mL). The combined organic phases were washed with water and
concentrated. The residue was agitated with CHCl3 and filtered
through glass wool. Concentration of the filtrate afforded the free
acid as a colorless solid (0.770 g, 1.83 mmol, 97%). The crude acid
(0.763 g, 1.82 mmol) was dissolved in dry DMF (3.5 mL) and treat-
ed with DBU (0.34 mL, 2.27 mmol) and MeI (0.17 mL, 2.72 mmol).
After stirring for 3 h at r.t., H2O was added and the mixture was ex-
tracted with Et2O (3 × 40 mL). The combined extracts were washed
with brine and concentrated. FC (hexanes–CHCl3, 1:1) afforded 11
as a colorless oil (0.682 g, 1.57 mmol, 86%).
13C NMR (75 MHz, acetone-d6): d = 56.8 (OCH2OCH3), 58.7
(OCH2OCH3), 95.7 (OCH2OCH3), 99.8 (OCH2OCH3), 100.6 (C-2),
116.3 (C-5), 127.4 (C-6), 131.1 (C-1), 147.4/155.7 (C-3, C-4),
195.0 (CHO).
Anal. Calcd for C11H13IO5: C, 37.52; H, 3.72; I, 36.04. Found: C,
37.28; H, 3.51; I, 35.96.42
Methyl 2-Iodo-3,4-bis(methoxymethoxy)benzoate (8)
To a solution of 7 (0.400 g, 1.14 mmol) in MeOH (15 mL) was add-
ed at 0 °C a cold solution of KOH (0.195 g, 2.96 mmol) in MeOH
(3.5 mL), followed by rapid addition of a cold solution of I2 (0.375
g, 1.48 mmol) in MeOH (3.5 mL). After stirring for 1 h at 0 °C, the
addition of KOH and I2 was repeated, and the stirring was continued
at 0 °C until the reaction was complete (2 h). After the addition of
sat. aq NH4Cl (30 mL) and sat. aq Na2S2O3 (10 mL), the mixture
was extracted with Et2O (3 × 40 mL). The combined organic phases
were washed with brine, dried (Na2SO4), and concentrated. FC
(CHCl3–acetone, 40:1) afforded pure 8 as a colorless oil [0.416 g,
1.09 mmol, 96%; Rf (TLC) = 0.32] and methyl 2-iodo-4,5-
bis(methoxymethoxy)benzoate (0.01 g, 3%, Rf = 0.37).
1H NMR (300 MHz, CDCl3): d = 1.06–1.13 {m, 18 H,
Si[CH(CH3)2]3}, 1.19–1.34 {m, 3 H, Si[CH(CH3)2]3}, 3.88 (s, 3 H,
CO2CH3), 6.86 (dd, 1 H, 3J = 8.6 Hz, 4J = 2.4 Hz, 5-H), 7.53 (d, 1
H, 4J = 2.4 Hz, 3-H), 7.79 (d, 1 H, 3J = 8.6 Hz, 6-H).
13C NMR (75 MHz, CDCl3): d = 12.7 {s, Si[CH(CH3)2]3}, 17.9 {s,
Si[CH(CH3)2]3}, 52.2 (CO2CH3), 95.4 (C-2), 119.1 (C-5‡), 126.6
(C-1), 132.5 (C-3‡), 133.2 (C-6‡), 159.2 (C-4), 166.2 (CO2CH3).
1H NMR (300 MHz, CDCl3): d = 3.48 (s, 3 H, OCH2OCH3), 3.68 (s,
3 H, OCH2OCH3), 3.89 (s, 3 H, CO2CH3), 5.17 (s, 2 H,
OCH2OCH3), 5.33 (s, 2 H, OCH2OCH3), 7.13 (d, 1 H, 3J = 8.6 Hz)/
7.52 (d, 1 H, 3J = 8.6 Hz) (5-H, 6-H).
MS: m/z (%) = 435 (5) [M + 1]+, 434 (24) [M]+, 403 (5), 392 (22),
391 (100) [M – CH(CH3)2]+, 364 (6), 363 (33), 336 (7), 335 (52),
321 (17), 305 (5), 264 (5), 222 (3), 221 (3), 167 (5), 152 (5).
13C NMR (75 MHz, CDCl3): d = 52.4 (CO2CH3), 56.5
(OCH2OCH3), 58.6 (OCH2OCH3), 94.7 (C-2), 95.0 (OCH2OCH3),
99.1 (OCH2OCH3), 115.2 (C-5), 127.5 (C-6), 130.0 (C-1), 147.1/
152.3 (C-3, C-4), 166.8 (CO2CH3).
Anal. Calcd for C17H27IO3Si: C, 47.01; H, 6.27; I, 29.21. Found: C,
47.13; H, 6.36; I, 29.18.
Ethyl [1-13C]Acetoacetate (12)
12 was prepared from ethyl [1-13C]acetate25b according to Lit.24; bp
65 °C/18 mbar. Yield 60% to 65%.
MS: m/z (%) = 383 (2) [M + 1]+, 382 (15) [M]+, 351 (3), 337 (2),
307 (10), 306 (100), 275 (33), 255 (15), 179 (7), 45 (32) [C2H5O]+.
3
1H NMR (300 MHz, CDCl3): d = 1.28 (t, 3 H, JHH = 7.1 Hz,
HRMS: m/z calcd for C12H15IO6: 381.9913; found: 381.9898.
2
OCH2CH3), 2.27 (s, 3 H, 4-H), 3.44 (d, 2 H, JCH = 7.3 Hz, 2-H),
4.20 (qd, 2 H, 3JHH = 7.2 Hz, 3JCH = 3.2 Hz, 13CO2CH2CH3), 4.97 (s,
~0.06 H, 2-H, enol tautomer).
4-(Triisopropylsilyloxy)benzaldehyde (9)
Following the standard procedure,43 4-hydroxybenzaldehyde (1.22
g, 10 mmol) was reacted with TIPSCl (2.12 g, 11 mmol), NEt3 (1.67
mL, 12 mmol), and DMAP (0.12 g, 1 mmol) in CH2Cl2 (20 mL). Af-
ter workup, FC (hexanes–EtOAc, 15:1) afforded 9 as a colorless oil
(2.68 g, 9.64 mmol, 96%).
3
13C NMR (75 MHz, CDCl3): d = 14.2 (d, JCC = 2.1 Hz,
13CO2CH2CH3), 30.2 (C-4), 50.2 (d, 1JCC = 58.4 Hz, C-2), 61.5 (d,
2JCC = 2.3 Hz, 13CO2CH2CH3), 167.2 (13C-1), 172.7 (13C-1, enol
tautomer), 200.7 (d, 2JCC = 2.4 Hz, C-3).
2-Iodo-4-(triisopropylsilyloxy)benzaldehyde (10)
(2E,6E,10E)-[1-13C]Geranylgeraniol (13)
13 was synthesized from 12 and (2E,6E)-farnesyl bromide as de-
scribed in the literature.23
In a dry, argon-flushed Schlenk flask equipped with a gas inlet and
rubber septum, N,N,N¢-trimethylethylenediamine (0.56 mL, 4.40
mmol) was dissolved in anhyd THF (10 mL). At 0 °C, n-BuLi (4.20
mmol) in hexanes was added and the solution was stirred for 15 min
at the same temperature. The mixture was cooled to –20 °C and
treated slowly with a solution of 9 (1.11 g, 4.00 mmol) in anhyd
THF (3 mL). After 0.5 h, n-BuLi (12 mmol) was added and the so-
lution was stirred for 15 h at –20 °C. Then the mixture was cooled
to –40 °C and treated with a solution of 1,2-diiodoethane (5.1 g, 18
mmol) in anhyd THF (5 mL). Workup as described for compound 7
and FC (hexanes–EtOAc, 25:1) yielded 10 as a yellow oil (1.29 g,
3.20 mmol, 80%).
1H NMR (300 MHz, CDCl3): d = 1.1 (s, br, 1 H, OH), 1.60 (s, 9 H,
18-H, 19-H, 20-H), 1.68 (s, 6 H, 16-H, 17-H), 1.90–2.18 (m, 12 H,
1
4-H, 5-H, 8-H, 9-H, 12-H, 13-H), 4.15 (dd, 2 H, JCH = 142 Hz,
3JHH = 7.0 Hz, 1-H), 5.06–5.15 (m, 3 H, 6-H, 10-H, 14-H), 5.38–
5.46 (m, 1 H, 2-H).
13C NMR (75 MHz, CDCl3): d = 16.1 (s, 2 CH3, C-18, C-19), 16.4
(C-17), 17.8 (C-20), 25.8 (C-16), 26.4 (C-5), 26.7 (C-9), 26.8 (C-
13), 39.6 (C-4), 39.76/39.80 (C-8, C-12), 59.5 (13C-1), 123.4 (d,
1JCC = 47.5 Hz, C-2), 123.9/124.3/124.5 (C-6, C-10, C-14), 131.3
(C-15), 135.0/135.5 (C-7, C-11), 139.9 (C-3).
1H NMR (300 MHz, CDCl3): d = 1.07–1.13 (m, 18 H, 6 CH3), 1.21–
1.36 {m, 3 H, Si[CH(CH3)2]3}, 6.93 (ddd, 1 H, 3J = 8.6 Hz, 4J = 2.3
Hz, 5J = 0.8 Hz, 5-H), 7.44 (d, 1 H, 4J = 2.3 Hz, 3-H), 7.79 (d, 1 H,
3J = 8.6 Hz, 6-H), 9.92 (d, 1 H, 5J = 0.8 Hz, CHO).
(2E,6E,10E)-[1-13C]Geranylgeranyl bromide (14)
To (2E,6E,10E)-[1-13C]geranylgeraniol (13, 0.291 g, 1.00 mmol) in
anhyd CH2Cl2 (1 mL) was added PPh3 (0.289 g, 1.1 mmol). The
Synthesis 2005, No. 6, 1019–1027 © Thieme Stuttgart · New York

1024
M. Lang, W. Steglich
FEATURE ARTICLE
1
(OCH2OCH3), 112.9 (C-5), 121.8 (d, JCC = 43.7 Hz, C-2¢), 123.3
(d, JCC = 2.9 Hz, C-1), 124.2/124.3/124.5 (C-6¢, C-10¢, C-14¢),
129.2 (C-2‡), 130.8 (d, 3JCC = 43.7 Hz, C-3), 131.24 (C-6‡), 131.28
(C-15¢), 134.9/135.2/136.7 (C-3¢, C-7¢, C-11¢), 158.7 (C-4), 167.1
(CO2CH3).
mixture was cooled to 0 °C, treated with CBr4 (0.398 g, 1.2 mmol)
in one portion, and stirred in the dark for 2 h at 0 °C. Then the sol-
vent was removed in vacuo at r.t., sat. aq NaHCO3 solution (20 mL)
was added, and the aqueous phase was extracted with Et2O (3 × 20
mL). The combined organic phases were washed with H2O and
brine, dried (Na2SO4), and concentrated at r.t. The residue was dis-
solved in n-hexane (5 mL) and the flask stored at 4 °C in the dark
for several hours. After removal of the precipitated PPh3O by filtra-
tion and washing the filter cake with cold n-hexane, the solvent was
partly removed. The flask was stored at –20 °C overnight and the
precipitate was filtered off again. When necessary, the hexane pre-
cipitation was repeated several times. After concentration at r.t. and
drying under vacuum, crude 14 was obtained as a slightly brownish
oil (0.322 g, 0.91 mmol, 91%). The product was used without fur-
ther purification and can be stored at –20 °C for several weeks with-
out decomposition.
3
MS: m/z (%) = 470 (2) [M + 1]+, 469 (6) [M]+, 438 (2) [M –
OCH3]+, 424 (3) [M – C2H5O]+, 400 (4) [M – C5H9]+, 368 (2), 324
(6), 300 (6), 263 (6), 259 (9), 256 (11), 232 (10), 218 (13), 210 (11),
204 (23), 190 (10), 189 (10), 188 (37), 166 (19), 137 (12), 136 (15),
135 (18), 123 (14), 121 (14), 109 (12), 107 (10), 95 (13), 93 (12), 81
(40) [C6H9]+, 69 (100) [C5H9]+, 45 (83) [C2H5O]+, 41 (19) [C3H5]+.
Anal. Calcd for C30H44O4 (unlabeled compound): C, 76.88; H, 9.46.
Found: C, 76.80; H, 9.43.
Methyl (2¢E,6¢E,10¢E)-3-[1¢-13C]Geranylgeranyl-4,5-bis(meth-
oxymethoxy)benzoate (18)
From 5 (0.138 g, 0.36 mmol) and 14 (0.106 g, 0.30 mmol) according
to the general procedure. FC (hexanes–EtOAc, 7:1) yielded 18 as a
colorless oil (0.119 g, 0.23 mmol, 75%).
1H NMR (300 MHz, CDCl3): d = 1.60 (s, 9 H, 18-H, 19-H, 20-H),
1.68 (s, 3 H, 16-H), 1.73 (s, 3 H, 17-H), 1.93–2.15 (m, 12 H, 4-H,
1
5-H, 8-H, 9-H, 12-H, 13-H), 4.02 (dd, 2 H, JCH = 153 Hz,
3JHH = 8.4 Hz, 2-H), 5.05–5.15 (m, 3 H, 6-H, 10-H, 14-H), 5.48–
5.58 (m, 1 H, 2-H).
IR (KBr):45 2952 (s), 2917 (s), 2852 (m), 1723 (s), 1590 (m), 1484
(m), 1435 (s), 1401 (w), 1383 (w), 1329 (m), 1310 (m), 1298 (m),
1246 (w), 1219 (m), 1195 (m), 1180 (m), 1158 (s), 1094 (m), 1077
(m), 1037 (s), 962 (s), 927 (m), 769 (s), 595 (w, br) cm–1.
13C NMR (75 MHz, CDCl3): d = 16.02/16.08/16.13 (C-17, C-18, C-
19), 17.8 (C-20), 25.8 (C-16), 26.2 (C-5), 26.7/26.9 (C-9, C-13),
29.7 (13C-1), 39.6 (d, 3JCC = 5.0 Hz, C-4), 39.75/39.80 (C-8, C-12),
1H NMR (300 MHz, CDCl3): d = 1.59 (s, 9 H, 18¢-H, 19¢-H, 20¢-H),
1.67 (s, 3 H, 16¢-H), 1.72 (s, 3 H, 17¢-H), 1.91–2.17 (m, 12 H, 4¢-H,
1
120.6 (d, JCC = 47.6 Hz, C-2), 123.5/124.3/124.5 (C-6, C-10, C-
14), 131.3 (C-15), 135.0/135.7 (C-7, C-11), 143.7 (C-3).
1
5¢-H, 8¢-H, 9¢-H, 12¢-H, 13¢-H), 3.44 (dd, 2 H, JCH = 128 Hz,
3JHH = 7.1 Hz, 1¢-H), 3.50 (s, 3 H, OCH2OCH3), 3.58 (s, 3 H,
OCH2OCH3), 3.87 (s, 3 H, CO2CH3), 5.04–5.17 (m, 3 H, 6¢-H, 10¢-
H, 14¢-H), 5.18 (s, 2 H, OCH2OCH3), 5.22 (s, 2 H, OCH2OCH3),
Coupling of the Iodobenzoic Acid Derivatives with Polyprenyl
Bromides; General Procedure
In a dry, argon-flushed Schlenk flask equipped with a gas inlet and
rubber septum, the corresponding aryl iodide (0.6 mmol) was dis-
solved in anhyd THF (3 mL). After cooling to –20 °C, i-PrMgBr44
(0.675 mmol, approx. 1 M in THF) was added dropwise. After stir-
ring for 0.5 h at –20 °C, a 0.2 M solution of Li2CuCl4 (0.1 mL, 0.02
mmol) in THF was added, and the stirring was continued for 10 min
at –20 °C. Then a solution of the appropriate polyprenyl bromide
(0.5 mmol) in anhyd THF (concentration, 0.2 to 0.4 M) was added
dropwise over 30–45 min by means of a syringe pump. After stir-
ring for 1.5 h at –20 °C, the cooling bath was removed and the so-
lution was allowed to warm to r.t. Then sat. aq NH4Cl (15 mL) was
added and the mixture was extracted with Et2O (3 × 20 mL). The
combined organic phases were washed with NH4OH and brine and
dried (Na2SO4). The products were purified by FC.
4
5.27–5.36 (m, 1 H, 2¢-H), 7.57 (dd, 1 H, 3JCH = 4.1 Hz, JHH = 2.0
Hz, 2-H), 7.64 (d, 1 H, 4JHH = 2.0 Hz, 6-H).
13C NMR (75 MHz, CDCl3): d = 16.04/16.06 (C-18¢, C-19¢), 16.3
(d, 3JCC = 3.5 Hz, C-17¢), 17.7 (C-20¢), 25.7 (C-16¢), 26.7 (2 CH2)/
26.8 (1 CH2) (C-5¢, C-9¢, C-13¢), 28.5 (13C-1¢), 39.7–39.9 (m, C-4¢,
C-8¢, C-12¢), 52.1 (CO2CH3), 56.4 (OCH2OCH3), 57.6
(OCH2OCH3), 95.2 (OCH2OCH3), 99.0 (OCH2OCH3), 115.2 (C-
2‡), 121.9 (d, 1JCC = 43.7 Hz, C-2¢), 124.2/124.3/124.5/125.0 (C-6‡,
3
C-6¢, C-10¢, C-14¢), 125.9 (d, JCC = 3.8 Hz, C-1), 131.3 (C-15¢),
1
134.9/135.2 (C-7¢†, C-11¢†), 136.1 (d, JCC = 43.7 Hz, C-3), 137.0
(C-3¢†), 149.0/149.3 (C-4, C-5), 166.7 (CO2CH3).
MS: m/z (%) = 529 (1) [M]+, 498 (2) [M – OCH3]+, 497 (2) [M –
CH3OH]+, 484 (4), 460 (2) [M – C5H9]+, 452 (3), 428 (3), 396 (2),
384 (2), 361 (2), 360 (2), 328 (3), 316 (5), 248 (18), 234 (13), 220
(12), 216 (11), 194 (30), 182 (12), 135 (18), 121 (16), 109 (14), 107
(12), 95 (13), 93 (15), 81 (32) [C6H9]+, 69 (71) [C5H9]+, 45 (100)
[C2H5O]+, 41 (18) [C3H5]+.
Methyl (2¢E,6¢E,10¢E)-3-[1¢-13C]Geranylgeranyl-4-(methoxy-
methoxy)benzoate (15)
From 2 [0.140 g, containing 0.40 mmol of 2 and 0.06 mmol of meth-
yl 4-(methoxymethoxy)benzoate40] and 14 (0.117 g, 0.33 mmol) ac-
cording to the general procedure. FC (hexanes–EtOAc, 12:1)
yielded 15 as a colorless oil (0.129 g, 0.27 mmol, 83%).
Anal. Calcd for C32H48O6 (unlabeled compound): C, 72.69; H, 9.15.
Found: C, 72.50; H, 9.10.
IR (KBr):45 2951 (s, sh), 2917 (s), 2853 (s), 1722 (s), 1606 (m), 1498
(m), 1437 (s), 1383 (w), 1326 (w), 1297 (s), 1266 (s), 1246 (s), 1193
(m), 1155 (s), 1131 (s), 1121 (s), 1080 (s), 999 (s), 925 (m), 832 (w),
771 (s), 658 (w) cm–1.
Methyl (2¢E,6¢E,10¢E)-2-[1¢-13C]Geranylgeranyl-3,4-bis(meth-
oxymethoxy)benzoate (21)
From 8 (0.092 g, 0.24 mmol) and 14 (0.071 g, 0.20 mmol) according
to the general procedure. FC (hexanes–EtOAc, 6:1) yielded 21 as a
colorless oil (83 mg, 0.157 mmol, 78%).
1H NMR (300 MHz, CDCl3): d = 1.60 (s, 9 H, 18¢-H, 19¢-H, 20¢-H),
1.68 (s, 3 H, 16¢-H), 1.73 (s, 3 H, 17¢-H), 1.92–2.17 (m, 12 H, 4¢-H,
IR (KBr):45 2917 (s), 2853 (m), 1723 (s), 1596 (m), 1486 (m), 1435
(s), 1398 (w), 1383 (w), 1263 (s), 1220 (m), 1207 (m), 1192 (m),
1157 (s), 1135 (m), 1090 (m), 1033 (s), 965 (m), 931 (m), 828 (w),
792 (m), 753 (m) cm–1.
1
5¢-H, 8¢-H, 9¢-H, 12¢-H, 13¢-H), 3.37 (dd, 2 H, JCH = 127.5 Hz,
3JHH = 7.2 Hz, 1¢-H), 3.48 (s, 3 H, OCH2OCH3), 3.87 (s, 3 H,
CO2CH3), 5.05–5.16 (m, 3 H, 6¢-H, 10¢-H, 14¢-H), 5.25 (s, 2 H,
OCH2OCH3), 5.27–5.36 (m, 1 H, 2¢-H), 7.07 (app. d, 1 H, 3J = 9.2
Hz, 5-H), 7.83–7.88 (m, 2 H, 2-H, 6-H).
1H NMR (600 MHz, CDCl3): d = 1.57 (s, 3 H)/1.58 (s, 3 H)/1.59 (s,
3 H) (18¢-H, 19¢-H, 20¢-H), 1.67 (s, 3 H, 16¢-H), 1.75 (s, 3 H, 17¢-
H), 1.92–1.99 (m, 6 H)/2.00–2.08 (m, 6 H) (4¢-H, 5¢-H, 8¢-H, 9¢-H,
12¢-H, 13¢-H), 3.49 (s, 3 H, OCH2OCH3), 3.60 (s, 3 H, OCH2OCH3),
13C NMR (75 MHz, CDCl3): d = 16.1 (s, 2 CH3, C-18¢, C-19¢), 16.3
(d, 3JCC = 3.8 Hz, C-17¢), 17.7 (C-20¢), 25.7 (C-16¢), 26.7 (2 CH2)/
26.8 (1 CH2) (C-5¢, C-9¢, C-13¢), 28.7 (13C-1¢), 39.7–40.0 (m, 3 CH2,
C-4¢, C-8¢, C-12¢), 51.9 (CO2CH3), 56.2 (OCH2OCH3), 94.1
1
3
3.81 (dd, 2 H, JCH = 129 Hz, JHH = 6.3 Hz, 1¢-H), 3.83 (s, 3 H,
CO2CH3), 5.05–5.11 (m, 3 H, 6¢-H, 10¢-H, 14¢-H), 5.08 (s, 2 H,
Synthesis 2005, No. 6, 1019–1027 © Thieme Stuttgart · New York

FEATURE ARTICLE
13C-Labeled Polyprenylhydroxybenzoic Acids
1025
OCH2OCH3), 5.11–5.16 (m, 1 H, 2¢-H), 5.23 (s, 2 H, OCH2OCH3),
7.01 (d, 1 H, 3J = 8.7 Hz)/7.60 (d, 1 H, 3J = 8.7 Hz) (5-H, 6-H).
(2¢E,6¢E,10¢E)-3-[1¢-13C]Geranylgeranyl-4-hydroxybenzoic
Acid (17)
Hydrolysis of 15 (118 mg, 0.251 mmol) according to the general
procedure afforded crude acid 16 as a colorless oil (113 mg, 0.248
mmol, 99%). 16 (63.2 mg, 0.139 mmol) was dissolved in i-PrOH
(1.4 mL), and after addition of p-TsOH·H2O (26 mg, 0.14 mmol) the
solution was stirred at 60 °C until TLC indicated completion (6 h).
Then H2O (15 mL) was added and the product was extracted with
EtOAc (3 × 20 mL). The combined organic layers were washed with
H2O and concentrated. FC (CHCl3–MeOH, 12:1) yielded 17 as a
colorless, waxy solid (50.0 mg, 0.121 mmol, 87%).
13C NMR (75 MHz, CDCl3): d = 16.0 (s, 2 CH3, C-18¢, C-19¢), 16.5
(d, 4JCC = 3.8 Hz, C-17¢), 17.7 (C-20¢), 25.7 (C-16¢), 26.1 (13C-1¢),
26.71/26.80/26.83 (C-5¢, C-9¢, C-13¢), 39.7–39.9 (m, 3 CH2, C-4¢,
C-8¢, C-12¢), 51.9 (CO2CH3), 56.4 (OCH2OCH3), 57.7
(OCH2OCH3), 94.8 (OCH2OCH3), 99.3 (OCH2OCH3), 112.7 (C-
5‡), 123.3 (d, 1JCC = 42.9 Hz, C-2¢), 124.28/124.35/124.48 (C-6¢, C-
10¢, C-14¢), 124.7 (C-1), 127.5 (C-6‡), 131.3 (C-15¢), 134.9/135.0/
1
135.4 (C-3¢, C-7¢, C-11¢), 138.6 (d, JCC = 42.9 Hz, C-2), 144.9/
152.9 (C-3, C-4), 167.9 (CO2CH3).
IR (KBr):45 3387 (s, br), 2967 (s), 2922 (s), 2855 (s), 2664 (m), 2544
(m), 1682 (s), 1603 (s), 1506 (w), 1444 (m), 1410 (m), 1383 (m),
1276 (s), 1219 (m), 1172 (m), 1128 (m), 1096 (m), 928 (w), 833
(m), 774 (m), 636 (m) cm–1.
MS: m/z (%) = 530 (1) [M + 1]+, 529 (2) [M]+, 485 (2), 484 (7) [M –
C2H5O]+, 452 (2), 428 (2), 392 (3), 360 (5), 334 (5), 328 (4), 316 (6),
284 (7), 278 (8), 264 (15), 248 (35), 234 (20), 220 (26), 216 (27),
194 (17), 121 (23), 95 (16), 81 (34) [C6H9]+, 69 (82) [C5H9]+, 45
(100) [C2H5O]+, 41 (17) [C3H5]+.
1H NMR (300 MHz, CDCl3): d = 1.60 (s, 9 H, 18¢-H, 19¢-H, 20¢-H),
1.68 (s, 3 H, 16¢-H), 1.80 (s, 3 H, 17¢-H), 1.91–2.21 (m, 12 H, 4¢-H,
Anal. Calcd for C32H48O6 (unlabeled compound): C, 72.69; H, 9.15.
Found: C, 72.50; H, 9.28.
1
5¢-H, 8¢-H, 9¢-H, 12¢-H, 13¢-H), 3.42 (dd, 2 H, JCH = 127 Hz,
3JHH = 7.1 Hz, 1¢-H), 5.04–5.16 (m, 3 H, 6¢-H, 10¢-H, 14¢-H), 5.29–
5.39 (m, 1 H, 2¢-H), 6.85 (d, 1 H, 3JHH = 9.0 Hz, 5-H), 7.88–7.93 (m,
2 H, 2-H, 6-H).
Methyl (2¢E,6¢E,10¢E)-2-[1¢-13C]Geranylgeranyl-4-(triisopro-
pylsilyloxy)benzoate (24)
From 11 (0.209 g, 0.48 mmol) and 14 (0.142 g, 0.40 mmol) accord-
ing to the general procedure. FC (hexanes–CHCl3, 1:1) yielded 24
as a colorless oil (0.186 g, 0.32 mmol, 81%).
13C NMR (75 MHz, CDCl3): d = 16.08/16.15 (C-18¢, C-19¢), 16.4
(d, 3JCC = 3.5 Hz, C-17¢), 17.8 (C-20¢), 25.8 (C-16¢), 26.5/26.7/26.9
(C-5¢, C-9¢, C-13¢), 29.8 (13C-1¢), 39.6–39.9 (m, C-4¢, C-8¢, C-12¢),
115.9 (C-5), 120.9 (d, JCC = 42.3 Hz, C-2¢), 121.8 (s, br, C-1),
1
123.6/ 124.3/124.5 (C-6¢, C-10¢, C-14¢), 126.9 (d, JCC = 44.3 Hz,
C-3), 130.6 (C-2‡), 131.3 (C-15¢), 132.7 (C-6‡), 135.0/135.8 (C-7¢,
C-11¢), 139.6 (C-3¢), 159.6 (C-4), 172.2 (CO2H).
1
IR (KBr):45 2946 (s), 2926 (s), 2868 (s), 1722 (s), 1601 (s), 1566
(m), 1494 (m), 1463 (m), 1434 (s), 1384 (m), 1298 (s), 1249 (s),
1271 (s), 1189 (m), 1124 (s), 1080 (m), 990 (s), 883 (s), 838 (s), 800
(m), 779 (m), 701 (m, sh), 688 (s), 664 (m), 650 (m, sh), 598 (w, br),
451 (w) cm–1.
MS: m/z (%) = 412 (2) [M + 1]+, 411 (8) [M]+, 368 (2), 342 (10)
[M – C5H9]+, 287 (4), 259 (7), 232 (6), 218 (6), 205 (12), 204 (13),
192 (10), 190 (13), 162 (15), 152 (56), 137 (19), 136 (27), 135 (26),
123 (24), 121 (19), 109 (20), 107 (18), 95 (21), 93 (21), 81 (55)
[C6H9]+, 69 (100) [C5H9]+, 55 (12), 41 (31) [C3H5]+.
1H NMR (300 MHz, CDCl3): d = 1.07–1.13 {m, 18 H,
Si[CH(CH3)2]3}, 1.19–1.32 {m, 3 H, Si[CH(CH3)2]3}, 1.60 (s, 9 H,
18¢-H, 19¢-H, 20¢-H), 1.68 (s, 3 H, 16¢-H), 1.70 (s, 3 H, 17¢-H), 1.93–
2.17 (m, 12 H, 4¢-H, 5¢-H, 8¢-H, 9¢-H, 12¢-H, 13¢-H), 3.70 (dd, 2 H,
1JCH = 129 Hz, 3JHH = 7.2 Hz, 1¢-H), 3.85 (s, 3 H, CO2CH3), 5.06–
5.17 (m, 3 H, 6¢-H, 10¢-H, 14¢-H), 5.26–5.36 (m, 1 H, 2¢-H), 6.71
HRMS: m/z calcd for C27H38O3 (unlabeled compound): 410.2821;
found 410.2834.
3
4
(dd, 1 H, JHH = 8.6 Hz, JHH = 2.5 Hz, 5-H), 6.80 (dd, 1 H,
3JCH = 4.7 Hz, JHH = 2.5 Hz, 3-H), 7.83 (dd, 1 H, JHH = 8.6 Hz,
(2¢E,6¢E,10¢E)-3-[1¢-13C]Geranylgeranyl-4,5-dihydroxybenzoic
Acid (20)
4
3
4JCH = 0.7 Hz, 6-H).
18 (137 mg, 0.26 mmol) was hydrolyzed according to the general
procedure to yield acid 19 as a colorless oil (130 mg, 0.25 mmol,
98%). To a solution of crude 19 (83.3 mg, 162 mmol) in i-PrOH (1.6
mL) was added AcCl (57 mL, 0.80 mmol), and the solution was
stirred at r.t. under argon. The reaction was monitored by TLC to
avoid prolonged reaction times. After completion (5 h), H2O (15
mL) was added and the mixture was extracted with EtOAc (3 × 20
mL). The combined organic phases were washed with H2O and con-
centrated. FC (CHCl3–MeOH, 9:1) afforded 20 as a colorless solid
(59 mg, 137 mmol, 84%).
13C NMR (75 MHz, CDCl3): d = 12.8 {s, Si[CH(CH3)2]3}, 16.1 (s,
3
2 CH3, C-18¢, C-19¢), 16.4 (d, JCC = 3.5 Hz, C-17¢), 17.8 (C-20¢),
18.0 {s, Si[CH(CH3)2]3}, 25.8 (C-16¢), 26.7 (1 CH2)/26.9 (2 CH2)
(C-5¢, C-9¢, C-13¢), 32.6 (13C-1¢), 39.7–40.0 (m, C-4¢, C-8¢, C-12¢),
51.7 (CO2CH3), 117.2 (C-5), 121.4 (C-3), 122.0 (C-1), 122.5 (d,
1JCC = 43.5 Hz, C-2¢), 124.26/124.34/124.50 (C-6¢, C-10¢, C-14¢),
131.3 (C-15¢), 132.9 (C-6), 135.0/ 135.1/136.9 (C-3¢, C-7¢, C-11¢),
146.1 (d, 1JCC = 41.7 Hz, C-2), 159.5 (d, 3JCC = 3.8 Hz, C-4), 167.8
(CO2CH3).
MS: m/z (%) = 582 (10) [M + 1]+, 581 (20) [M]+, 538 (6), 512 (11)
[M – C5H9]+, 480 (11), 444 (21), 412 (45), 376 (67), 370 (37), 334
(56), 316 (52), 280 (19), 274 (19), 259 (27), 135 (27), 121 (23), 109
(29), 81 (38) [C6H9]+, 69 (100) [C5H9]+, 41 (31) [C3H5]+.
IR (KBr):45 3433 (s), 3289 (s, br), 2967 (s), 2922 (s), 2854 (s), 1688
(s), 1603 (m), 1444 (s), 1376 (m), 1293 (s), 1234 (s), 1099 (m), 987
(m), 775 (m), 707 (m), 566 (w), 551 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.59 (s, 9 H, 18¢-H, 19¢-H, 20¢-H),
1.68 (s, 3 H, 16¢-H), 1.78 (s, 3 H, 17¢-H), 1.92–2.20 (m, 12 H, 4¢-H,
HRMS: m/z calcd for C37H60O3Si (unlabeled compound): 580.4312;
found 580.4286.
1
5¢-H, 8¢-H, 9¢-H, 12¢-H, 13¢-H), 3.41 (dd, 2 H, JCH = 128 Hz,
3J = 7.1 Hz, 1¢-H), 5.04–5.15 (m, 3 H, 6¢-H, 10¢-H, 14¢-H), 5.30–
5.39 (m, 1 H, 2¢-H), 7.53 (s, 2 H, 2-H, 6-H).
Ester Hydrolysis; General Procedure
A suspension of the corresponding methyl ester (up to 1 mmol) in a
mixture of LiOH·H2O (0.084 g, 2 mmol), H2O (1 mL) and MeOH
(3 mL) was heated to 100 °C until the TLC indicated completion of
the hydrolysis (16, 19, and 22: 4–6 h; 25: 40 h). Then H2O (20 mL)
was added and the mixture was slightly acidified with 2 N HCl (ap-
prox. 1 mL). After extraction of the aq phase with EtOAc (3 × 30
mL), the combined organic phases were washed twice with H2O and
concentrated in vacuo.
13C NMR (75 MHz, CDCl3): d = 16.07/16.14 (C-18¢, C-19¢), 16.3
(d, 3JCC = 2.9 Hz, C-17¢), 17.8 (C-20¢), 25.8 (C-16¢), 26.5/26.7/26.8
(C-5¢, C-9¢, C-13¢), 29.3 (13C-1¢), 39.7–39.9 (m, 3 CH2, C-4¢, C-8¢,
3
C-12¢), 115.1 (C-6), 121.01 (d, JCC = 3.2 Hz, C-1), 121.04 (d,
1JCC = 42.9 Hz, C-2¢), 123.8/124.3/124.5/125.0 (C-2, C-6¢, C-10¢,
1
C-14¢), 127.5 (d, JCC = 43.5 Hz, C-3), 131.4 (C-15¢), 135.1/135.7
(C-7¢, C-11¢), 139.2 (C-3¢), 143.3/147.8 (C-4, C-5), 172.3 (CO2H).
Synthesis 2005, No. 6, 1019–1027 © Thieme Stuttgart · New York

1026
M. Lang, W. Steglich
FEATURE ARTICLE
MS: m/z (%) = 428 (4) [M + 1]+, 427 (12) [M]+, 412 (3) [M – CH3]+,
384 (7), 358 (16) [M – C5H9]+, 276 (10), 259 (16), 248 (12), 234
(11), 223 (14), 221 (17), 208 (23), 206 (33), 204 (23), 168 (89), 149
(18), 137 (28), 136 (32), 135 (35), 123 (36), 121 (31), 109 (32), 107
(21), 95 (29), 93 (24), 81 (68) [C6H9]+, 69 (100) [C5H9]+, 55 (9), 41
(16) [C3H5]+.
H), 6.78 (dd, 1 H, 3JCH = 4.4 Hz, 4JHH = 2.5 Hz, 3-H), 8.01 (d, 1 H,
3J = 8.5 Hz, 6-H).
13C NMR (75 MHz, CDCl3): d = 16.07/16.10 (C-18¢, C-19¢), 16.3
(d, 3JCC = 3.2 Hz, C-17¢), 17.7 (C-20¢), 25.8 (C-16¢), 26.7 (2 CH2)/
26.8 (1 CH2) (C-5¢, C-9¢, C-13¢), 32.8 (13C-1¢), 39.75/39.78 (C-8¢, C-
12¢), 39.9 (d, 3JCC = 4.1 Hz, C-4¢), 112.8/117.1 (C-3, C-5), 120.5 (C-
1), 122.3 (d, 1JCC = 43.5 Hz, C-2¢), 124.2/124.4/124.5 (C-6¢, C-10¢,
C-14¢), 131.4 (C-15¢), 134.5 (C-6), 135.1/135.2 (C-7¢, C-11¢), 137.0
(C-3¢), 148.0 (d, 1JCC = 41.4 Hz, C-2), 159.7 (d, 3JCC = 3.5 Hz, C-4),
172.7 (CO2H).
HRMS: m/z calcd for C27H38O4 (unlabeled compound): 426.2770;
found 426.2744.
(2¢E,6¢E,10¢E)-2-[1¢-13C]Geranylgeranyl-3,4-dihydroxybenzoic
Acid (23)
MS: m/z (%) = 411 (11) [M]+, 298 (5), 259 (3), 256 (3), 214 (6), 189
(10), 162 (23), 161 (20), 160 (17), 148 (12), 147 (11), 146 (13), 137
(11), 136 (13), 135 (17), 123 (12), 121 (18), 108 (27), 107 (20), 95
(19), 93 (19), 81 (48) [C6H9]+, 69 (100) [C5H9]+.
21 (57.6 mg, 109 mmol) was hydrolyzed according to the general
procedure to afford 22 as a colorless, waxy solid (55.1 mg, 107
mmol, 98%). The crude acid (51 mg, 99 mmol) was dissolved in i-
PrOH (1 mL) under argon. Then AcCl (36 mL, 0.5 mmol) was add-
ed, and the solution was stirred at r.t. (TLC monitoring). After com-
pletion of the reaction (5 h), H2O (15 mL) was added and the
mixture was extracted with EtOAc (3 × 20 mL). The combined or-
ganic phases were washed with H2O and concentrated. FC (CHCl3–
MeOH, 10:1) afforded 23 as a brownish, waxy solid (33 mg, 77
mmol, 78%).
HRMS: m/z calcd for C27H38O3 (unlabeled compound): 410.2821;
found 410.2831.
Acknowledgment
The authors would like to thank the Deutsche Forschungsgemein-
schaft (SFB 369) for financial support of this work.
IR (KBr):45 3446 (s), 3292 (s, br), 3140 (s, br), 2966 (s), 2921 (s),
2854 (s), 1682 (s), 1621 (m), 1615 (m), 1584 (s), 1504 (m), 1494
(m), 1446 (m), 1378 (m), 1343 (s), 1296 (s), 1237 (s), 1195 (s), 1148
(m), 1009 (m), 971 (m), 874 (m), 830 (m), 788 (m), 754 (m), 706
(m), 632 (m), 536 (w), 450 (w) cm–1.
References
(1) New address: M. Lang, 4SC AG, Am Klopferspitz 19a,
82152 Martinsried, Germany.
(2) Claisen, L.; Kremers, F.; Roth, F.; Tietze, E. Justus Liebigs
Ann. Chem. 1925, 442, 210.
1H NMR (300 MHz, CDCl3): d = 1.59 (s, 9 H, 18¢-H, 19¢-H, 20¢-H),
1.67 (s, 3 H, 16¢-H), 1.85 (s, 3 H, 17¢-H), 1.90–2.18 (m, 12 H, 4¢-H,
1
5¢-H, 8¢-H, 9¢-H, 12¢-H, 13¢-H), 3.92 (dd, 2 H, JCH = 131 Hz,
3JHH = 6.7 Hz, 1¢-H), 5.01–5.14 (m, 3 H, 6¢-H, 10¢-H, 14¢-H), 5.23–
5.32 (m, 1 H, 2¢-H), 6.82 (d, 1 H, 3J = 8.6 Hz)/7.65 (d, 1 H, 3J = 8.6
Hz) (5-H, 6-H).
(3) (a) Kaczka, E. A.; Shunk, C. H.; Richter, J. W.; Wolf, F. J.;
Gasser, M. M.; Folkers, K. J. Am. Chem. Soc. 1956, 78,
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1821.
13C NMR (75 MHz, CDCl3): d = 16.07/16.16 (C-18¢, C-19¢), 16.4
(d, 3JCC = 3.2 Hz, C-17¢), 17.8 (C-20¢), 25.8 (C-16¢), 26.6 (13C-1¢),
26.8, 39.7–39.9 (m, C-4¢, C-8¢, C-12¢), 112.5 (C-5‡), 120.7 (C-1),
121.7 (d, 1JCC = 41.4 Hz, C-2¢), 123.6/124.2/124.5 (C-6¢, C-10¢, C-
1
14¢), 126.0 (C-6‡), 130.5 (d, JCC = 42.3 Hz, C-2), 131.3 (C-15¢),
135.1/135.9 (C-7¢, C-11¢), 139.3 (C-3¢), 142.7/149.0 (C-3, C-4),
173.0 (CO2H). Two of the three signals of C-5¢, C-9¢, and C-13¢ are
hidden by the 13C-1¢ signal. They appear in the spectrum of the cor-
responding unlabeled compound at d = 26.4, 26.6, 26.8.
MS: m/z (%) = 427 (5) [M + 1]+, 426 (17) [M]+, 411 (3) [M – CH3]+,
383 (7), 357 (17) [M – C5H9]+, 289 (19) [357–C5H8]+, 271 (19), 259
(39), 229 (23), 221 (49), 205 (100), 203 (57), 175 (43), 167 (44),
165 (46), 163 (45), 161 (30), 157 (32), 149 (33), 135 (36), 123 (34),
121 (37), 109 (36), 107 (33), 95 (32), 93 (28), 81 (62) [C6H9]+, 69
(88) [C5H9]+, 41 (19) [C3H5]+.
(5) Shepherd, J. A.; Poon, W. W.; Myles, D. C.; Clarke, C. F.
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Rayez, M.-T.; Roulet, T. C. R. Acad. Sci., Ser. IIc 2001, 641.
(7) Reaction conditions: organotin reagent and electrophile (1:1
stoichiometric ratio), Pd(dba)2 (2.5 mol%), NEt4Cl (10
mol%), THF, 50 °C, 18 h. Yields of coupling products: 60%
to 70%. Residues of organotin compounds could not be
removed satisfactorily despite the fact that fluoride
precipitation was applied prior to chromatography: Leibner,
J. E.; Jacobus, J. J. Org. Chem. 1979, 44, 449.
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Mori, K. Lieb. Ann./Recl. 1997, 825. (c) Takanashi, S.;
Mori, K. Lieb. Ann./Recl. 1997, 1081.
HRMS: m/z calcd for C27H38O4 (unlabeled compound): 426.2770;
found 426.2756.
(2¢E,6¢E,10¢E)-2-[1¢-13C]Geranylgeranyl-4-hydroxybenzoic
Acid (25)
24 (120 mg, 206 mmol) was hydrolyzed according to the general
procedure. FC (CHCl3–MeOH, 10:1) afforded 25 as a colorless,
waxy solid (78 mg, 190 mmol, 92%).
IR (KBr):45 3187 (s, br), 2967 (s), 2919 (s), 2854 (s), 2655 (m), 2548
(m), 1684 (s), 1603 (s), 1576 (s), 1498 (w), 1445 (m), 1407 (m),
1383 (m), 1300 (m), 1236 (s), 1141 (m), 1078 (w), 968 (w), 931 (w),
863 (m), 833 (m), 784 (m), 703 (w), 613 (m) cm–1.
(9) Monoorganostannanes were developed which allow Stille-
type reactions leading to products free of organotin
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with an aryl iodide, however, exclusively SN2¢ substitution
occurred. See: Fouquet, E.; Pereyre, M.; Rodriguez, A. L. J.
Org. Chem. 1997, 62, 5242.
1H NMR (300 MHz, CDCl3): d = 1.60 (s, 9 H, 18¢-H, 19¢-H, 20¢-H),
1.68 (s, 3 H, 16¢-H), 1.71 (s, 3 H, 17¢-H), 1.92–2.18 (m, 12 H, 4¢-H,
1
5¢-H, 8¢-H, 9¢-H, 12¢-H, 13¢-H), 3.78 (dd, 2 H, JCH = 129 Hz,
3JHH = 7.1 Hz, 1¢-H), 5.06–5.18 (m, 3 H, 6¢-H, 10¢-H, 14¢-H), 5.29–
5.38 (m, 1 H, 2¢-H), 6.71 (dd, 1 H, 3JHH = 8.5 Hz, 4JHH = 2.5 Hz, 5-
Synthesis 2005, No. 6, 1019–1027 © Thieme Stuttgart · New York

FEATURE ARTICLE
13C-Labeled Polyprenylhydroxybenzoic Acids
1027
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(39) (a) Kofron, W. G.; Baclawski, L. M. J. Org. Chem. 1976, 41,
1879. (b) 4-Biphenylmethanol may also be used, see:
Juaristi, E.; Martínez-Richa, A.; García-Rivera, A.; Cruz-
Sánchez, J. S. J. Org. Chem. 1983, 48, 2603.
(26) (a) Axelrod, E. H.; Milne, G. M.; van Tamelen, E. E. J. Am.
Chem. Soc. 1970, 92, 2139. (b) See ref. 8b (c) Takagi, R.;
Sasaoka, A.; Nishitani, H.; Kojima, S.; Hiraga, Y.; Ohkata,
K. J. Chem. Soc., Perkin Trans. 1 1998, 925.
(27) Isler, O.; Rüegg, R.; Chopard-dit-Jean, L.; Wagner, H.;
Bernhard, K. Helv. Chim. Acta 1956, 39, 897.
(28) On addition of MeOH, work-up and flash chromatography,
the corresponding dehalogenated compounds were isolated
in nearly quantitative yields.
(40) Methyl 4-hydroxy-3,5-diiodobenzoate was separated from 1
by flash chromatography. Non-iodinated material could be
removed neither from 1 nor from 2. Thus, a mixture of 2 and
methyl 4-(methoxymethoxy)benzoate was employed in the
cross coupling reactions.
(41) Edwards, R. L.; Wilson, D. V. J. Chem. Soc. 1961, 5003.
(42) Impurity: 2-iodo-4,5-bis(methoxymethoxy)benzaldehyde.
(43) Chaudhary, S. K.; Hernandez, O. Tetrahedron Lett. 1979,
20, 99.
(29) Tamura, M.; Kochi, J. Synthesis 1971, 303.
(30) (a) Bertz, S. H.; Fairchild, E. H. In Encyclopedia of Reagents
for Organic Synthesis, Vol. 2; Paquette, L. A., Ed.; John
Wiley & Sons: Chichester, New York, 1995, 1324.
(b) Thompson, A. S. In Encyclopedia of Reagents for
Organic Synthesis, Vol. 3; Paquette, L. A., Ed.; John Wiley
(44) Determination of the concentration: In a dried and argon-
flushed Schlenk flask with gas inlet and rubber septum, an
exactly known amount of menthol (approx. 0.8 mmol) and a
few mg of 1,10-phenanthroline were dissolved in anhyd
THF (2.5 mL). The i-PrMgBr solution was added dropwise
until blue color appeared. See: Watson, S. C.; Eastham, J. F.
J. Organomet. Chem. 1967, 9, 165.
(45) IR data of the corresponding unlabeled compound.
Synthesis 2005, No. 6, 1019–1027 © Thieme Stuttgart · New York