Synthetic analogues of the antibiotic pestalone

Article abstract of DOI:10.1016/S0040-4020(03)01136-0

The first synthetic study towards the natural product pestalone (1) is described culminating in the preparation of selected n-1 analogues. Pestalone is a chlorinated and prenylated benzophenone antibiotic, which is of interest due to a strong activity aga

Full text of DOI:10.1016/S0040-4020(03)01136-0

Tetrahedron 59 (2003) 7345–7355
Synthetic analogues of the antibiotic pestalone
†
Florian Kaiser and Hans-Gunther Schmalz
*
¨
¨ ¨ ¨ ¨
Institut fur Organische Chemie, Universitat zu Koln, Greinstrasse 4, D-50939 Koln, Germany
Received 2 June 2003; revised 22 July 2003; accepted 22 July 2003
Abstract—The first synthetic study towards the natural product pestalone (1) is described culminating in the preparation of selected n21
analogues. Pestalone is a chlorinated and prenylated benzophenone antibiotic, which is of interest due to a strong activity against methicillin-
resistant staphylococcus aureus strains (MRSA). Key step of the synthesis is the nucleophilic addition of a highly functionalized aryllithium
building block to a 2-prenylated 3,5-dialkoxy-benzaldehyde followed by oxidation. For the introduction of the prenyl sidechain by aryl-allyl
coupling, different procedures were evaluated, among them the Stille reaction and a nickel p-allyl complex coupling.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
infectious diseases. Pestalone was obtained from the mixed
fermentation of a marine derived deuteromycete of the
genus Pestalotia together with a marine bacterium. The
structure of 1 was established by NMR analysis and X-ray
diffraction. The new compound shows a structure which
significantly differs to that of other natural products,6 mostly
because the two rings have a substitution pattern different
from each other. While the aromatic ring B with its
dichloroorcine structure shows similarities with the fungal
metabolites geodin and erdin7 and many lichen xanthones,8
the A-ring of the benzophenone with its prenyl and formyl
o-substituents is somewhat related to fungal and plant-
derived benzophenones9 and xanthones. Among the family
of the benzophenone natural products, the tetra-ortho-
substituted benzophenones form only a small subgroup,
with the PKA inhibitor balanol10 and the G6Pase inhibitor
mumbaistatin11 being the most prominent members. As
known for other natural benzophenones, it can be assumed
that pestalone is biosynthetically derived from oxidative
cleavage of a corresponding anthracenone generated by
either a mixed shikimate-acetate or a pure polyketide
pathway with subsequent prenylation and chlorination.
Today several classes of antibiotics are clinically used to
fight infectious diseases, for example the b-lactames,
glycopeptides, tetracyclines, macrolides, rifamycines and
quinolones. However, due to the emergence of resistance to
antimicrobial agents1 and the fact that time for resistance to
develop against new drugs if often short, the search for new
antibiotics2 remains an important goal for medicinal
chemistry. Especially the introduction of completely new
classes of antibiotics (for example the oxazolidinone
linezolid3) are important. Recently, Fenical and coworkers
discovered a new marine natural product, the prenylated and
chlorinated tetra-ortho-substituted benzophenone4 pesta-
lone5 (1) (Fig. 1). Pestalone showed potent antibacterial
activity against methicillin-resistant Staphylococcus aureus
(MIC¼37 ng/mL) and vancomycin-resistant Enterococcus
faecium (MIC¼78 ng/mL). Thus, pestalone was recom-
mended to be evaluated in advanced animal models of
The biological activity of pestalone (1) makes it an
interesting target for total synthesis. A short and flexible
synthetic approach to this new antibiotic lead structure
would also pave the way for the synthesis of (possibly
simplified) analogs, which could then be screened in order
to study structure activity relationships and possibly to
identify new useful antimicrobials.
Figure 1. Structure of pestalalone (1).
Keywords: pestalone; benzophenones; antibiotics; synthesis; natural
products.
Despite the seemingly simple appearance (pestalone carries
no stereochemical information and has a molecular weight
of only 440), pestalone (1) features several challenging
structural elements, namely the densely functionalized
aromatic core (11 out of the 12 aromatic carbons are
*
Corresponding author. Tel.: þ49-2214703063; fax: þ49-2214703064;
e-mail: schmalz@uni-koeln.de
Present address: The Scripps Research Institute, 10550 North Torrey
Pines Road, La Jolla, California 92037, USA.
†
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)01136-0

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F. Kaiser, H.-G. Schmalz / Tetrahedron 59 (2003) 7345–7355
Scheme 2. Synthesis of the B-ring building block (a) SOCl2, CHCl3/CH3-
CN 5:1, rt, 3 h, 90%; (b) Br2, CH3CN, 08C, 3 h, 99%; (c) DIPEA, MOMCl,
CH2Cl2, rt, overnight, 46% of 9, 31% of 8; (d) 6N HCl, THF, rt, 12 h, 99%;
(e) NaH, Me2SO4, DMF, rt, overnight, 97%.
benzophenone coupling. The preparation of the B-ring
precursor 10 (Scheme 2) began with the literature-known
double chlorination of orcinol 5 using sulfuryl chloride.14
Optimization of the solvent system greatly increased the
selectivity of the reaction, and in a 5:1 mixture of
chloroform/acetonitrile, dichloroorcinol 6 was obtained in
90% yield. Subsequent bromination of the last free aromatic
position using bromine in acetonitrile gave the bromide 715
almost quantitatively. The following desymmetrisation by
mono-protection of the diphenol gave mono MOM-
protected 8 only in 31% together with 46% of the
Scheme 1. Retrosynthetic analysis for pestalone and simplified analogs.
substituted), the possible acid-labile o-prenylphenol-sub-
structure and, most importantly, the sterically crowded
benzophenone. Beside the anionic homo-Fries rearrange-
ment,12 the nucleophilic carbonyl-addition of a lithiated
arene to a benzaldehyde followed by oxidation is the most
important method for the setup of such hindered benzo-
phenones.13 For our synthetic study towards pestalone and
analogs we intended to utilize the latter method (Scheme 1)
by reacting a benzaldehyde of type 2 with an aryllithium-
nucleophile generated from a bromide 3. The attachment of
the prenyl sidechain should be achieved by an organo-
metallic reaction, using either alkylation of an aryl cuprate,
a Pd-catalyzed Stille cross- coupling or, alternatively, a
nickel-(p-allyl) complex as a coupling reagent.
The final CC bond connection, i.e. the introduction of the
formyl group, could possibly be achieved by an electro-
philic aromatic substitution reaction (Vilsmeier or a related
formylation) in a late stage of the synthesis; this would be
especially attractive due to the fact that the key nucleophilic
coupling of the two aromatic segments would be facilitated
with only three ortho-substituents. Alternatively, an anionic
formylation or Pd-catalyzed carbonylation starting from a
suitable benzophenone halide could be considered. In the
beginning of the project, the order and the exact timing for
the three CC bond formations was not obvious. In any case,
the two aromatic building blocks should be prepared from
the (commercial) symmetric resorcine derivatives 4 and 5.
Scheme 3. Synthesis of the A-ring building block (a) Br2, CHCl3/CH3CN
6:1, rt, 5 h, 96%; (b) DIPEA, MOMCl, CH3CN, rt, overnight, 95%;
(c) LiAlH4, THF, rt, 24 h, 91%; (d) imidazole, DMAP, TBSCl, CH2Cl2, rt,
overnight, 87%; (e) (i) t-BuLi, THF, 2788C, (ii) CuCN·2LiCl, 2158C, 1 h,
(iii) prenyl bromide, HMPT, 2788C rt, overnight, (iv) TBAF, THF, rt, 8 h,
60% (2 steps); (f) IBX, DMSO, rt, 5 h, 91%; (g) (COCl)2, DMSO, NEt3,
CH2Cl2, 2788C rt, overnight, 95%; (h) see Table 1.
2. Results and discussion
Our approach started with the preparation of suitable
functionalized aromatic building blocks for the anticipated

F. Kaiser, H.-G. Schmalz / Tetrahedron 59 (2003) 7345–7355
7347
Table 1. Introduction of the prenyl sidechain via Pd- or Ni-mediated coupling reactions (Scheme 3)
Entry
Complex
Reaction conditions
Yield
1
2
3
4
5
6
18
18
18
18
19
19
Pd(Ph)4 (0.1 equiv.), CsF, DMF, 708C, 20 h
22%
40%
38%
68%
35%
Traces
Pd2dba3 (0.05 equiv.), As(Ph)3 (0.2 equiv.), CsF, NMO, 708C, 20 h
Pd2dba3 (0.05 equiv.), As(Ph)3 (0.2 equiv.), CsF, NMO, 208C, 48 h
Pd2dba3 (0.05 equiv.), P(tBu)3 (0.2 equiv.), CsF, NMO, 708C, 20 h
19 (3 equiv.), DMF, 508C, 10 h
19 (3 equiv.), benzene, hn, N-methy-limidazole, 208C, 20 h
di-alkylated compound 9. However, due to the fact that 9
and all mixture fractions could be quantitatively recycled by
deprotection using 6N HCl in THF, the yield of 8 based on
recovered starting material was almost 85%.
alcohol 15 in 60% yield (two steps).20 Subsequent IBX-
oxidation21 furnished the benzaldehyde 16 (Scheme 3).
A different procedure for aromatic prenylation, which has
become popular in the recent past, is the Pd-catalyzed Stille
cross-coupling22,23 of a prenylstannane with an aryl-halide.
In contrast to most other allylmetallic reagents, the
3,3-disubstituted allylstannanes tend to react without allylic
inversion or rearrangement in coupling reactions. First,
alcohol 13 was oxidized to the corresponding benzaldehyde
17 under Swern conditions24 in order to reduce the electron-
richness of the arylbromide for the following coupling
reaction. The Stille reaction between 17 and prenyl
tributyltin (18)25 was attempted under various conditions
(Table 1). Soon it became obvious that the anticipated cross
coupling between the o,o-disubstituted bromide and the tin
reagent proceeds only sluggishly and was hampered by long
reaction times and unproductive side reactions. While
PdCl2dppf, Pd(Ph)4 or PdCl2/P(o-tol)3 proved to be less
successful (in terms of conversion and the ratio of coupling
The synthesis of the B-ring building block 10 was
completed by methylation of the remaining phenolic
OH-group of 8 using NaH/dimethyl sulfate (97% yield).
The synthesis of the anticipated A-ring benzaldehydes of
type 2 is shown in Scheme 3. Double halogenation of
3,5-dihydroxymethyl benzoate 4 using bromine in aceto-
nitrile/chloroform gave the symmetric bromide 11. After
MOM-protection of the two phenolic OH groups, treatment
of the o,o-dibromoester 12 with an excess of LiAlH4 led to
ester reduction under simultaneous loss of one of the halides
and cleanly gave the benzylic alcohol 13.16 Compound 13
was the starting point for the preparation of prenylated
benzaldehyde 16.
26
One part of the synthetic project was to test and compare
common methods for the introduction of isoprenoid allyl-
sidechains (like the dimethylallyl group in pestalone) onto
the aromatic nucleus.17 In a first approach, the benzylic
alcohol 13 was protected (TBSCl, imidazole, DMAP, 87%
yield) to give the silyl ether 14.18 After bromine–lithium
exchange using t-BuLi followed by transmetallation with
CuCN·2LiCl,19 the resulting cuprate was treated with
prenylbromide to afford the allylated product, which was
directly desilylated (TBAF) to give the o-prenylbenzylic
product vs. debromination), Pd2dba3/As(Ph)3 in NMO or
DMF gave the coupling product 16, albeit only in a
moderate yield of 40% due to partial degradation, regardless
if the reaction was run for 48 h at rt or 20 h at 708C. CsF was
added as promoter in all the reactions. Application of Fu’s
catalyst system (Pd2dba3/P(tBu)3)27 gave an improved yield
of 68% (NMO, 20 h for 708C). Interestingly, when Fu’s
catalyst was employed at rt, the dehalogenated product was
obtained almost exclusively. Last, we examined the
coupling of bromide 17 with the p-allyl nickel bromide
Scheme 4. Synthesis of the pestalone analogues 22–24 (a) (i) 10, n-BuLi, THF, 2788C, (ii) 16, THF, 2788C rt, overnight, 86%; (b) DMP, CH2Cl2, rt, 3 h,
88%; (c) p-TsOH, MeOH, 608C, 3 h, 50%; (d) CSA, MeOH, rt, 24 h, 91%; (e) Ac2O, pyridine, rt, overnight, 90%.

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F. Kaiser, H.-G. Schmalz / Tetrahedron 59 (2003) 7345–7355
complex 19.28,29 This complex was prepared in situ from
prenyl bromide and Ni(COD)2 and used without isolation.
Coupling under the standard conditions (stirring for 24 h at
608C in DMF) gave the prenylated product 16 only in 35%
yield, while the Schugar-modification30 for the nickel-
promoted allylation (irridation, use of N-methylimidazole as
a ligand in a non-coordinating solvent like benzene)
produced only traces of the product. In summary, the Stille
coupling came out to be the method of choice for the
preparation of the prenylated benzaldehyde 16, which was
synthesized in five steps and an overall yield of more than
50% (Scheme 3).
described herein towards the synthesis of further analogs
and the natural product itself is a subject of current
investigations in these laboratories.
4. Experimental
4.1. General information
Melting points (Mp) were determined in open capillary
tubes measured on a Bu¨chi Melting Point B-545 apparatus
and are uncorrected. 1H and 13C NMR spectra were
recorded on Bruker 250, 300 or 500 MHz instruments and
are referenced to the non-deuterated impurities of the used
solvents (CDCl3, CD3OD, d6-DMSO) as internal standard.
The spectra are reported in ppm using the following
abbreviations to express the multiplicities: s¼singlet;
d¼doublet; t¼triplet; q¼quartet; m¼multiplet; b¼broad.
With both the benzaldehyde 16 and the aryl bromide 10 in
our hands, we next focused on the anticipated nucleophilic
coupling to form the sterically hindered benzophenone.
Bromine–lithium exchange of 10 employing n-BuLi at
2788C followed by reaction with 16 at 2788C!rt cleanly
gave the benzhydrol 20 in 86% yield (Scheme 4).
Subsequent oxidation employing the Dess–Martin period-
inane31 (88% yield) or, alternatively, Jones-reagent32 (87%
yield) furnished the benzophenone 21. As foreseen, the
following deprotection turned out to be challenging: The use
of reagents like 6N HCl, TMSBr or BF3 only resulted in
decomposition or crude product mixtures. Heating of 21
together with p-toluenesulphonic acid in methanol produced
the chromane 22. Under the acidic conditions, complete
deprotection had occured with concomitant cyclization of
the o-prenylphenol system.33 In contrast, use of campfor-
sulfonic acid in methanol at rt33b gave the corresponding
prenyl-benzophenone 23 (deformyl-pestalone).
1
13C chemical shifts were determined using H-decouplet
spectra, the number of protons bound directly was
determined employing the DEPT sequence (q¼CH3;
t¼CH2; d¼CH; s¼quarternary carbon) Some of the assign-
ments are based on 2-dimensional spectra additionally
recorded. IR-spectra were recorded on a Perkin–Elmer
Paragon 1000 FT-IR spectrometer using the ATR-tech-
nique. Gas-chromatography (GC) and low-resolution mass
spectra (EI, 70 eV) were recorded on an Agilent HP 6890
GC-MS system using an Optima 1 MS column with H2 as
carrier-gas (flow 10 psi). Temperature programs are pre-
sented as following: starting temperaturelength of stay [min]
!
[8C/min]!end temperaturelength of stay [min]. Given are the
retention times and the purities calculated from the
uncorrected FID-integrations. High resolution mass spectra
(HRMS) were recorded on a Finnigan MAT 900S (ESI).
Analytical thin-layer chromatography (TLC) was per-
formed on silica coated alumina plates. Flash chroma-
tography was performed on Merck silica gel 60 (230–400
mesh). Reagents were supplied by Aldrich, Merck, Fluka,
Acros and Chemetall and were used without further
purification unless otherwise noted. THF and toluene were
freshly distilled from sodium benzophenone ketyl, and
dichloromethane was distilled from CaH2. Other solvents
(acetonitrile, benzene, hexane, DMF, DMSO) were pur-
chased in HPLC-pure quality and stored under argon over
molecular sieves. Bulk solvents for chromatography and
extraction, such as ethyl acetate, cyclohexane, dichloro-
methane and methyl tertbutyl ether (MTBE), were distilled
prior to use. All reactions with organometallic reagents were
carried out under a positive atmosphere of dry argon in
oven-dried glassware by using Schlenk techniques. Solvents
and solutions were added with syringes through rubber
septa.
Our attempts to prepare the natural product itself from the
deformyl derivative 23 were not successful, so far. The
anticipated introduction of the formyl group by a SEAr
reaction failed under a variety of conditions: The classical
Vilsmeier formylation,34 dichloro-methylation using TiCl4
or SnCl4/CHCl2OMe,35 or the Casiraghi formylation36 only
resulted in either no conversion of 23 or complete
decomposition of the starting material at higher tempera-
tures. Likewise, formylation attempts employing the MOM-
protected derivative 21 or the acetylated compound 24 did
not lead to success.
3. Conclusion
In this article, we described the first synthetic studies
towards the highly substituted benzophenone antibiotic
pestalone. While having elaborated an efficient access to
deformyl-derivatives thus demonstrating the power of the
selected approach, we could identify the final formylation
as a surprisingly difficult task. Nevertheless, a series of
selected n21 analogues of the natural product have been
synthesized, which will be used for preliminary SAR
studies.
4.1.1. 2,6-Dichloro-3,5-dihydroxytoluene (6). 12.41 g
(100 mmol) of orcinol 5 was dissolved in a mixture of
450 mL of chloroform and 100 mL of acetonitrile. At 08C a
solution of 16.2 mL (200 mmol) of sulfuryl chloride in
50 mL of chloroform was added dropwise over 30 min.
After stirring for further 3 h at rt, 50 mL of a 1 M aqueous
solution of NaOH was added. After stirring for 15 min, the
mixture was acidified with 200 mL of 1 M aqueous HCl,
and the phases were separated. The aqueous layer was
extracted with dichloromethane (3£200 mL). The combined
To open an entry to the natural product itself (and other
o-formylated benzophenone derivatives), prenylated benz-
aldehydes of type 16 bearing a second o-substituent, either
a protected benzylic alcohol, an ester or, alternatively, a
halide may be used as building blocks in the central
carbonyl addition step. The extension of the approach

F. Kaiser, H.-G. Schmalz / Tetrahedron 59 (2003) 7345–7355
7349
organic layers were washed with brine and dried over
MgSO4. After evaporation of the solvent, the residue, a
white-yellow solid, was purified by flash chromatography
(400 g of silica, cyclohexane/ethyl acetate 4:1) to give
17.37 g (90 mmol, 90%) of dichloroorcinol 6 as a white
crystalline solid. The compound showed analytical data in
accordance to those described in literature.13d Mp: 1708C
(lit. 170.5–1718C). TLC (cyclohexane/ethyl acetate 5:1)
Rf¼0.18. 1H NMR (250 MHz, d6-DMSO): d [ppm]¼2.33 (s,
3H, C7), 3.39 (br s, 2H, OH), 6.55 (s, 1H, C4). 13C NMR
(63 MHz, d6-DMSO): d [ppm]¼17.7 (q, C7), 101.6 (d, C4),
111.1 (s, C2/C6), 134.4 (s, C1), 152.1 (s, C3/C5). HR-MS
(EI): calcd 191.9745 for C7H6O2Cl2, found 191.975. Anal.
calcd for C7H6O2Cl2: C 43.56; H 3.13; found: C 43.60; H
3.14.
addition of 200 mL of a saturated NH4Cl solution, the
phases were separated, and the aqueous layer was extracted
with dichloromethane (3£200 mL). The combined organic
layers were washed with a saturated CuSO4 solution and
brine and dried over MgSO4. After evaporation of the
solvent, the resulting brown oil was purified by flash
chromatography to give 13.34 g (37 mmol, 46%) of 2,6-di-
chloro-4-bromo-3,5-dimethoxymethoxytoluene (9) as a
white-yellow crystalline solid and 7.89 g (25 mmol,
31%) of 2,6-dichloro-4-bromo-3-methoxymethoxy-5-
hydroxy-toluene (8) as a white crystalline solid. Analytical
data of 9. Mp: 86–888C. TLC (cyclohexane/dichloro-
methane 1:1) R ¼0.3. IR (ATR) n [cm21]¼2951 (w),
˜
f
2826 (w), 1446 (w), 1414 (m), 1368 (s), 1328 (w), 1209 (m),
1159 (s), 1096 (m), 1042 (s), 1008 (s), 897 (s), 763 (m). 1H
NMR (250 MHz, CDCl3): d [ppm]¼2.45 (s, 3H, H at C7),
3.67 (s, 2£3H, CH3 of C3-OMOM, C5-OMOM), 5.12
(s, 2£2H, CH2 of C3-OMOM, C5-OMOM). 13C NMR
(63 MHz, CDCl3): d [ppm]¼18.5 (q, C7), 58.5 (q, CH3 of
C3-OMOM, C5-OMOM), 99.4 (t, CH2 of C3-OMOM,
C5-OMOM), 112.6 (s, C4), 125.9 (s, C2, C6), 135.6 (s, C1),
150.0 (s, C3, C5). GC-MS (Optima 1 MS, 10 psi,
5082![258C/min]!300810): tRet¼9.94 min, 95% purity.
MS (EI): (the peaks showed the typical isotopic pattern
of a momobromo-dichloro compound) 360 (8, [Mþ]), 329
(1–2, [M2OCH3]þ), 300 (2), 191 (5), 145 (5), 111 (3), 87
(3), 75 (6), 63 (4), 45 (100). HR-MS (EI): calcd 357.9374
for C11H13O4BrCl2, found 357.937. Analytical data of 8.
Mp: 110–1128C. TLC (cyclohexane/dichloromethane 1:1)
4.1.2. 2,6-Dichloro-4-bromo-3,5-dihydroxytoluene (7).
8.98 g (46.5 mmol) of 6 was dissolved in 300 mL of
acetonitrile. At 08C a solution of 2.5 mL (48.8 mmol) of
bromine in 50 mL of acetonitrile was added dropwise over a
period of 30 min, and the resulting mixture was stirred
for 2 h at 08C. After full conversion was ensured by
GC-analysis, 200 mL of a saturated Na2S2O3 solution was
added. After addition of 100 mL of ethyl acetate and
subsequent phase separation, the aqueous layer was
extracted with ethyl acetate (3£200 mL). The combined
organic layers were washed with brine and dried over
MgSO4. The solution was concentrated to 100 mL and
passed through a pad of silica. After evaporation of the
solvent, the resulting fawn solid was washed with hexane
and dried in vacuo to give 12.517 g (46 mmol, 99%) of
bromine 7 as a white crystalline solid. The compound
showed analytical data in accordance to those described in
literature.13d Mp: 1078C (lit. 107–1088C). TLC (cyclo-
R ¼0.1. IR (ATR) n [cm21]¼3336 (br, s), 2978 (w), 1558
˜
f
(m), 1452 (m), 1432 (s), 1388 (s), 1347 (s), 1276 (s), 1205
(s), 1157 (s), 1099 (m), 1076 (s), 1017 (m), 934 (s), 913 (s),
1
753 (s), 733 (m). H NMR (250 MHz, CDCl3): d [ppm]¼
2.43 (s, 3H, H at C7), 3.69 (s, 3H, CH3 of C3-OMOM), 5.14
(s, 2H, CH2 of C3-OMOM), 6.00 (s, 1H, C5-OH). 13C NMR
(63 MHz, CDCl3): d [ppm]¼18.2 (q, C7), 58.4 (q, CH3 of
C3-OMOM), 99.6 (t, CH2 of C3-OMOM), 104.1 (s, C4),
117.3, 121.2 (each s, C3, C5), 134.9 (s, C1), 148.1, 149.8
(each s, C3, C5). GC-MS (Optima 1 MS, 10 psi,
5082![258C/min]!300810): tRet¼9.44 min, 95% purity.
MS (EI): (the peaks showed the typical isotopic pattern of
a momobromo-dichloro compound) 316 (19, [M]þ), 286
(7), 272 (4), 243 (5), 206 (3), 179 (5), 162 (6), 127 (5), 111
(5), 87 (5), 63 (7), 45 (100). HR-MS (EI): calcd 313.9112
for C9H9O3BrCl2, found 313.911.
hexane/dichloromethane 1:1) Rf¼0.25. IR (ATR)
n
˜
[cm21]¼3570 (m), 3470 (s), 3270 (br, m), 1724 (w), 1613
(w), 1575 (m), 1444 (s), 1425 (s), 1404 (s), 1362 (m), 1309
(s), 1206 (s), 1086 (s), 1017 (w), 739 (s), 713 (m), 662 (m).
1H NMR (250 MHz, CDCl3): d [ppm]¼2.35 (s, 3H, C7),
9.85 (br s, OH). 13C NMR (63 MHz, CDCl3): d [ppm]¼18.2
(q, C7), 100.1 (s, C4), 113.5 (s, C2, C6), 133.1 (s, C1),
149.5 (s, C3, C5). GC-MS (Optima 1 MS, 10 psi,
5082![258C/min]!300810): tRet¼9.95 min, 96% purity.
MS (EI): (the peaks showed the typical isotopic pattern of
a monobromo-dichloro compound) 274 (46, [M]þ), 272
(100, [M]þ), 270 (61, [M]þ), 254 (4, [M2H2O]þ), 239 (14,
[M2Cl]þ), 237 (57, [M2Cl]þ), 235 (44, [M2Cl]þ), 219 (4,
[M2Cl–H2O]þ), 207 (3), 192 (9, [M2Br]þ), 179 (3), 157
(8, [M2Br–Cl]þ), 145 (6), 127 (8), 99 (10), 87 (8), 73 (10),
63 (15), 51 (6), 39 (7). HR-MS (EI): calcd 269.8850 for
C7H5O2BrCl2, found 269.885. Anal. calcd for C7H5O2BrCl2
C 30.92; H 1.85; found: C 30.74; H 1.90.
4.2. Recovery of 2,6-dichloro-4-bromo-3,5-dihydroxy-
toluene (7) from 2,6-dichloro-4-bromo-3,5-dimethoxy-
methoxytoluene (9)
15.83 g (44 mmol) of 9 was dissolved in 200 mL of THF.
50 mL of a 6N HCl solution was added, and the resulting
solution was stirred for 12 h at rt. After addition of each
100 mL of water and ethyl acetate the phases were
separated. The aqueous layer was extracted with ethyl
acetate (3£100 mL). The combined organic layers
were washed with brine and dried over MgSO4. After
the solution was passed through a pad of silica, the
solvent was evaporated to give 11.85 g (43.6 mmol, 99%) of
7 as a white solid which was free of impurities (GC, 1H NMR).
4.1.3. 2,6-Dichloro-4-bromo-3-methoxymethoxy-5-
hydroxytoluene (8) and 2,6-dichloro-4-bromo-3,5-
dimethoxymethoxytoluene (9). 21.91 g (80.5 mmol) of 7
was dissolved in 600 mL of dry dichloromethane under
argon. At 08C 18.3 mL (105 mmol) of diisopropylethyl-
amine (DIPEA) was added. After 30 min 8.6 mL
(113 mmol) of MOMCl [CAUTION: Due to the carcino-
genity of MOMCl all operations involving this reagent
should be performed in a well working fume hood!] was
added, and the solution was stirred overnight at rt. After
4.2.1. 2,6-Dichloro-4-bromo-3-methoxymethoxy-5-meth-
oxytoluene (10). 1.19 g of a 60% dispersion of sodium

7350
F. Kaiser, H.-G. Schmalz / Tetrahedron 59 (2003) 7345–7355
hydride in oil were placed in a flask under argon. After
washing with dry hexane, the NaH was suspended in 60 mL
of dry DMF. The cooled (08C) suspension was slowly
treated with a solution of 7.12 g (22.8 mmol) of phenol 8 in
40 mL of dry DMF. After the emission of hydrogen had
ceased, the mixture was stirred for 1 h at rt. The cooled
(08C) reaction mixture was treated with 4.3 mL (45.6 mmol)
of dimethylsulfate. Stirring was continued overnight at rt,
before 200 mL of an ice cold NH4Cl solution was added.
The mixture was extracted with MTBE (4£100 mL). The
combined organic layers were washed with brine and dried
over MgSO4. After evaporation of the solvent, the residue
was purified by flash-chromatography (200 g of silica,
cyclohexane/ethyl acetate 15:1) to give 7.39 g (22.2 mmol,
97%) of 10 as a white solid with a low melting point. Mp:
20–258C. TLC (cyclohexane/ethyl acetate 3:1) Rf¼0.2. IR
267 (11, [M2COOCH3]þ), 246 (10, [M2Br]þ), 230 (6),
215 (19), 188 (25), 186 (25), 168 (9), 160 (8), 137 (12), 129
(11), 123 (4), 109 (5), 93 (4), 78 (8), 69 (25), 62 (5), 50 (20).
HR-MS (EI): calcd 326.8646 for C8H6O4Br2, found
326.864. Anal. calcd for C8H6O4Br2: C 29.48; H 1.86;
found: C 29.36; H 1.88.
4.2.3. 2,6-Dibromo-3,5-dimethoxymethoxymethyl benzo-
ate (12). 34.00 g (104 mmol) of 11 was dissolved in each
250 mL of dichloromethane and acetonitrile under argon.
The solution was cooled to 08C, and 54.5 mL (312 mmol) of
diisopropyl-ethylamine was added dropwise via syringe.
After 30 min 24.7 mL (325 mmol) of MOMCl [CAUTION:
Due to the carcinogenity of MOMCl all operations
involving this reagent should be performed in a well
working fume hood!] was added via syringe, and the
resulting solution was stirred at rt overnight. After addition
of 200 mL of saturated NH4Cl solution the flask was opened
and the mixture was stirred for 1 h. After phase separation
the aqueous layer was extracted with ethyl acetate
(3£200 mL). After concentration, the combined organic
layer was washed with K2CO3 solution and brine and dried
over MgSO4. The solution was passed through a pad of
silica, and the solvent was evaporated to give 40.70 g
(98.3 mmol, 95%) of a yellow oil which solidified upon
standing. Mp: 62–638C. TLC (cyclohexane/dichloro-
(ATR) n [cm21]¼2931 (m), 1542 (w), 1448 (m), 1412 (m),
˜
1369 (s), 1328 (m), 1209 (m), 1159 (s), 1067 (s), 1011 (s),
945 (s), 901 (s), 756 (m), 713 (m). H NMR (300 MHz,
1
CDCl3): d [ppm]¼2.45 (s, 3H, H an C7), 3.69 (s, 3H, CH3 of
C3-OMOM), 3.85 (s, 3H, CH3 at C5-OMe), 5.13 (s, 2H,
CH2 of C3-OMOM). 13C NMR (75 MHz, CDCl3): d
[ppm]¼18.3 (q, C7), 58.4 (q, CH3 of C3-OMOM), 60.5
(q, CH3 of C5-OMe), 99.6 (t, CH2 of C3-OMOM), 112.2 s,
C4), 125.7, 125.9 (each s, C2, C6), 135.6 (s, C1), 150.0,
152.7 (each s, C3, C5). GC-MS (Optima 1 MS, 10 psi,
5082![258C/min]!300810): tRet¼9.3 min, 96% purity. MS
(EI): (the peaks showed the typical isotopic pattern of a
momobromo-dichloro compound) 330 (12, [M]þ), 300 (8),
285 (2), 257 (4), 242 (4), 189 (3), 133 (3), 111 (3), 75 (3), 45
(100). HR-MS (EI): calcd 327.9268 for C10H11O3BrCl2,
found 327.927. Anal. calcd for C10H11O3BrCl2: C 36.40; H
3.36; found: C 36.15; H 3.34.
methane 1:2) R ¼0.15. IR (ATR) n [cm21]¼2950 (m),
˜
f
1737 (s), 1571 (s), 1434 (s), 1397 (m), 1324 (s), 1220 (s),
1149 (s), 1087 (s), 1009 (s), 957 (s), 918 (s), 876 (s), 788
1
(m), 700 (m). H NMR (250 MHz, CDCl3): d [ppm]¼3.47
(s, 2£3H, CH3 of C3-OMOM, C5-OMOM), 3.96 (s, 3H,
CH3 of C7 (O)OMe), 5.21 (s, 2£2H, CH2 of C3-OMOM,
C5-OMOM), 7.04 (s, H at C4). 13C NMR (63 MHz, CDCl3):
d [ppm]¼53.1 (q, CH3 of C7OOMe), 56.6 (q, 2C, CH3 of
C3-OMOM, C5-OMOM), 95.4 (t, 2C, CH2 of C3-OMOM,
C5-OMOM), 102.4 (s, 2C, C2, C6), 104.7 (d, C4), 139.2 (s,
C1), 153.9 (s, 2C, C3, C5), 166.4 (s, C7). GC-MS (Optima 1
MS, 10 psi, 5082![258C/min]!300810): tRet¼11.78 min,
96% purity. MS (EI): (the peaks showed the typical isotopic
pattern of a dibromo compound) 414 (13, [M]þ), 383 (5,
[M2OCH3]þ), 354 (2), 336 (3), 29 (3), 140 (4), 77 (3), 61
(3), 45 (100). HR-MS (EI): calcd 413.9137 for
C12H14O6Br2, found 413.914.
4.2.2. 2,6-Dibromo-3,5-dihydroxymethyl benzoate (11).
16.82 g (100 mmol) of 3,5-dihydroxymethyl benzoate (4)
was dissolved in 800 mL of 6:1 mixture of chloroform and
acetonitrile. At rt a solution of 11 mL (215 mmol) of
bromine in 50 mL of chloroform was added dropwise over
30 min, and the resulting solution was stirred for 5 h at rt.
After addition of 200 mL of a saturated Na2S2O3 solution
the phases were separated. The aqueous layer was extracted
with dichloromethane (3£200 mL). The combined organic
layers were washed with brine and dried over MgSO4. After
evaporation of the solvent, the residue was dissolved in
100 mL of ethyl acetate and filtrated through a pad of silica.
The solvent was evaporated to give a yellow oil, which
crystallized overnight at 48C. 31.26 g (97 mmol, 97%) of 11
were obtained as an ocher solid. Mp: 93–948C. TLC
4.2.4. 2-Bromo-3,5-dimethoxymethoxybenzylic alcohol
(13). 4.74 g (125 mmol) of LiAlH4 was suspended in
400 mL of dry THF under argon. At 08C a solution of
20.675 g (50 mmol) of the ester 12 in 100 mL of dry THF
was added slowly via syringe. The resulting mixture was
stirred for 20 h. The flask was cooled to 08C, and acetone
was added carefully to destroy the excess of LiAlH4,
followed by addition of 200 mL of a 10% NaOH solution.
After filtration of the mixture through a sintered funnel and
addition of ethyl acetate, the phases were separated. The
aqueous layer was extracted with ethyl acetate (3£200 mL).
The combined organic layers were concentrated, washed
with brine and dried over MgSO4. The solution was passed
through a pad of silica, and the solvent was evaporated to
give 14.05 g (46 mmol, 91%) of the bromo benzylic alcohol
13 as a white solid. The compound showed analytical data in
accordance to those described in literature.16 Mp: 62–638C.
(cyclohexane/ethyl acetate 2:1) R ¼0.15. IR (ATR) n
˜
f
[cm21]¼3386 (br, s), 2951 (m), 2842 (m), 2709 (m), 2618
(m), 2358 (w), 2339 (w), 2291 (w), 2258 (m), 2141 (w),
1715 (s), 1651 (m), 1579 (s), 1539 (m), 1525 (m), 1512 (m),
1461 (s), 1425 (s), 1368 (s), 1249 (s), 1049 (s), 993 (s), 902
(m), 844 (s), 768 (s), 721 (m). 1H NMR (300 MHz, CDCl3):
d [ppm]¼3.96 (s, 3H, CH3 of C7-OMe), 6.73 (s, 1H, H at
C4). 13C NMR (75 MHz, CDCl3): d [ppm]¼53.3 (q, C8),
98.6 (s, C2, C6), 104.1 (d, C4), 137.0 (s, C1), 153.2 (s,
C3, C5), 166.2 (s, C7). GC-MS (Optima 1 MS, 10 psi,
5082![258C/min]!300810): tRet¼10.36 min, 99% purity.
MS (EI): (the peaks showed the typical isotopic pattern of a
dibromo compound) 328 (43, [M]þ), 326 (88, [M]þ), 324
(47, [M]þ), 297 (50, [M2OCH3]þ), 295 (100), 293 (54),
TLC (cyclohexane/ethyl acetate 2:1) R ¼0.3. IR (ATR) n
˜
f
[cm21]¼3405 (br, s), 2903 (s), 2824 (s), 1585 (s), 1447 (s),

F. Kaiser, H.-G. Schmalz / Tetrahedron 59 (2003) 7345–7355
7351
1396 (s), 1356 (s), 1315 (s), 1211 (s), 1150 (s), 1083 (s), 844
(s). 1H NMR (300 MHz, CDCl3): d [ppm]¼3.44, 3.49 (each
s, 3H, CH3 of C3-OMOM, C5-OMOM), 4.68 (s, 2H, H
at C7), 5.13, 5.20 (each s, 2H, CH2 of C3-OMOM,
(15 mmol) of freshly distilled prenyl bromide was added.
After being stirred fo 1 h at 2788C, the solution was
allowed to slowly come to rt while stirring was continued
overnight. After addition of 20 mL of saturated NH4Cl
solution and subsequent phase separation, the aqueous layer
was extracted with ethyl acetate (3£50 mL). The combined
organic layer was washed with brine and dried over MgSO4.
After evaporation of the solvent, the resulting yellow oil was
placed on top of a silica pad and eluted with cyclohexane/
ethyl acetate 10:1 to give 1.125 g of the prenylated silyl
ether, which was still unpure charged by GC. The crude
product was directly desilylated in the next step without
further purification. TLC (cyclohexane/ethyl acetate 15:1)
Rf¼0.25. GC-MS (Optima 1 MS, 10 psi, 5082![258C/
min]!300810): tRet¼10.55 min, 75% purity. MS (EI): 379
(1, [M2OCH3]þ), 354 (3), 309 (3), 278 (57, [M2
OTBDMS]þ), 263 (17), 247 (5), 233 (18), 217 (10), 202
(15), 187 (8), 89 (12), 69 (21), 45 (100).
4
C5-OMOM), 6.77 (d, 1H, J¼3 Hz, C3 or C5), 6.88 (d,
4
1H, J¼3 Hz, C3 or C5). 13C NMR (75 MHz, CDCl3): d
[ppm]¼ 56.6, 56.9 (each q, CH3 of C3-OMOM,
C5-OMOM), 65.6 (t, C7), 94.9, 95.6 (each t, CH2 of
C3-OMOM, C5-OMOM), 104.5 (d, C4 o. C6), 105.2
(s, C2), 109.7 (d, C4 o. C6), 142.3 (s, C1), 154.8, 157.7
(each s, C3, C5). GC-MS (Optima 1 MS, 10 psi,
5082![258C/min]!300810): tRet¼9.82 min, 99% purity.
MS (EI): 308/306 (13/12, [M]þ), 276/278 (3), 246/248
(4), 232 (2), 212 (3), 77 (4), 63 (5), 45 (100). HR-MS (EI):
calcd 306.0103 for C11H15O5Br, found 306.011.
4.2.5. 2-Bromo-1-[(tert-butyldimethylsilyl)oxymethyl]-
3,5-dimethoxy-methoxybenzene (14). 5.49 g (17.8 mmol)
of the alcohol 13 was dissolved in 180 mL of dry
dichloromethane under argon. After addition of 6.079 g
(89.3 mmol) of imidazole and 110 mg (0.9 mmol) of
DMAP, the resulting solution was cooled to 08C. 5.381 g
(35.7 mmol) of TBSCl was added in portions over a period
of 30 min. The milky reaction mixture was stirred at rt
overnight. After addition of 50 mL of a saturated NH4Cl
solution the layers were separated. The aqueous layer was
extracted with dichloromethane (3£100 mL). The combined
organic layer was washed with a saturated CuSO4 solution
and brine and dried over MgSO4. After evaporation of the
solvent, the residue, a yellow oil, was purified by flash-
chromatography (300 g of silica, cyclohexane/ethyl acetate
10:1) to give 6.53 g (15.5 mmol, 87%) of the silylated
alcohol 14 as a white solid. The compound showed
analytical data in accordance to those described in
literature.18 TLC (cyclohexane/ethyl acetate 10:1) Rf¼0.3.
4.2.7. 2-(3-Methylbut-2-enyl)-3,5-di-(methoxymethoxy)-
benzylic alcohol (15). 1.125 g of the crude silyl ether
(prepared as decribed above) was dissolved in 10 mL of
THF. After addition of 12 mL of a 1 M tetrabutyl-
ammonium fluoride solution in THF, the resulting solution
was stirred for 8 h at rt. Then the reaction mixture was
poured into 20 mL of a saturated NH4Cl solution. The
aqueous mixture was extracted with ethyl acetate
(4£25 mL). The combined organic layer was washed with
brine and dried over MgSO4. After evaporation of the
solvent, the resulting yellow oil was purified by flash-
chromatography (100 g of silica, cyclohexane/ethyl acetate
3:1) to give 531 mg (1.8 mmol, 60% for 2 steps) of benzylic
alcohol 15 as a solidified, colorless oil. TLC (cyclohexane/
ethyl acetate 3:1) R ¼0.2. IR (ATR) n [cm21]¼3422 (br,
˜
f
m), 2955 (m), 2902 (m), 1604 (s), 1587 (s), 1476 (s), 1436
(s), 1397 (s), 1308 (s), 1284 (s), 1214 (s), 1149 (s), 1134 (s),
IR (ATR) n [cm21]¼2948 (s), 2929 (s), 1587 (s), 1469 (m),
˜
1
1447 (s), 1395 (m), 1365 (m), 1316 (s), 1296 (s), 1252 (s),
1143 (s), 1084 (s), 1013 (s), 923 (s), 835 (s), 775 (s). H
1079 (s), 1020 (s), 936 (s), 920 (s), 893 (s), 850 (m). H
4
1
NMR (300 MHz, CDCl3): d [ppm]¼1.65 (d, 3H, J¼2 Hz,
4
NMR (300 MHz, CDCl3): d [ppm]¼0.11 (s, 6H, CH3 of
Si(Me)2tBu), 0.95 (s, 9H, CH3 of Si(Me)2C(CH3)3), 3.45,
3.50 (each s, 3H, CH3 of C3-OMOM, C5-OMOM), 4.75 (s,
2H, H at C7), 5.14, 5.20 (each s, 2H, CH2 of C3-OMOM,
C5-OMOM), 6.70, 6.70 (each d, 1H, 4J¼3 Hz, H at C4, C6).
13C NMR (75 MHz, CDCl3): d [ppm]¼25.4 (q, Si(CH3)2),
18.3 (s, SiC), 25.9 (q, SiC(CH3)3), 56.0, 56.4 (q, CH3 of
C3-OMOM, C5-OMOM), 64.8 (t, C7), 94.6, 95.3 (each t,
CH2 of C3-OMOM, C5-OMOM), 103.2 (s, C2), 103.5,
108.5 (each d, C4, C6), 142.6 (s, C1), 153.9, 157.3 (each s,
C3, C5). GC-MS (Optima 1 MS, 10 psi, 5082![258C/min]!
300810): tRet¼10.55 min, 98% purity. MS (EI): 365/636
(6, [M2tBu]þ), 335/333 (5), 318 (1), 303 (5), 239 (6), 209
(4), 179 (3), 137 (4), 89 (15), 73 (6), 45 (100). HR-MS (EI):
calcd 363.0263 for C13H20O5SiBr (M2tBu), found
363.026.
H at C12), 1.76 (d, 3H, J¼2 Hz, H at C11), 3.35 (d, 2H,
3J¼7 Hz, H at C8), 3.45 (s, 2£3H, CH3 of C3-OMOM,
C5-OMOM), 4.62 (s, 2H, H at C7), 5.08 (m, 1H, H at C9),
5.13, 5.15 (each s, 2H, CH2 of C3-OMOM, C5-OMOM),
4
4
6.73 (d, 1H, J¼2.5 Hz, H at C4), 6.78 (d, 1H, J¼2.5 Hz,
H at C6). 13C NMR (75 MHz, CDCl3): d [ppm]¼17.8
(q, C11), 24.3 (t, C8), 25.7 (q, C12), 56.0 (q, 2C, CH3 of
C3-OMOM, C5-OMOM), 63.3 (t, C7), 94.4, 94.6 (each t,
CH2 of C3-OMOM, C5-OMOM), 103.0 (d, C4), 108.8 (d,
C6), 122.3 (s, C2), 123.5 (d, C9), 131.4 (s, C10), 140.8 (s,
C1), 155.9, 156.3 (each s, C3, C5). GC-MS (Optima 1 MS,
10 psi, 5082![258C/min]!300810): tRet¼10.5 min, 99%
purity. MS (EI): 296 (11, [M]þ), 278 (13), 251 (10), 233
(9), 217 (4), 189 (11), 161 (5), 91 (4), 69 (3), 45 (100).
HR-MS (EI): calcd 296.1624 for C16H24O5, found 296.162.
4.2.8. 2-Bromo-3,5-dimethoxymethoxybenzaldehyde
(17). 12.29 g (40 mmol) of alcohol 13 was dissolved in
500 mL of dry dichloromethane. At 2788C 10.4 mL
(160 mmol) of dry DMSO was added, followed by 6.8 mL
(40 mmol) of oxalyl chloride 10 min later. After stirring was
continued at 2788C for 90 min, 27.5 mL (400 mmol) of
triethylamine was added. The reaction mixture was stirred
overnight while the temperature was allowed to slowly
come to rt. After the reaction was quenched by addition of
4.2.6. 1-[tert-Butyldimethylsilyl)oxy]-2-(3-methylbut-2-
enyl)-3,5-dimethoxy-methoxybenzene. 1.264 g (3 mmol)
of the bromide 14 was dissolved in 20 mL of dry THF under
argon. At 2788C, 3.55 mL of t-BuLi (1.7 M solution in
pentane) was added. After 15 min 3 mL of a 1 M solution of
CuCN·2LiCl was added, and the resulting brown solution
was stirred for 1 h at 2158C. After recooling to 2788C,
2.65 mL (15 mmol) of dry HMPA and 5 min later 1.75 mL

7352
F. Kaiser, H.-G. Schmalz / Tetrahedron 59 (2003) 7345–7355
300 mL of brine, the phases were separated. The aqueous
layer was extracted with dichloromethane (3£200 mL). The
combined organic layer was dried over MgSO4, filtrated
through a pad of silica and evaporated. The resulting brown
solid was purified by flash chromatography (400 g of silica,
cyclohexane/ethyl acetate 3:1) to give 11.60 g (38 mmol,
95%) of the benzaldehyde 17 as a yellow crystalline solid.
Mp: 728C. TLC (cyclohexane/ethyl acetate 3:1) Rf¼0.32. IR
bromobenzaldehyde 17, 911 mg (6 mmol) of cesium
fluoride and 92 mg (0.1 mmol) of Pd2dba3 were placed in
a Schlenk flask under argon. 15 mL of NMP was added,
followed by 0.1 mL (0.4 mmol) of P(tBu)3 and 1.440 g
(4 mmol) of prenyltributyl stannane 18. The solution was
degassed, flushed with argon and stirred for 20 h at 708C.
After filtration through a pad of celite, the reaction mixture
was poured into a saturated KF solution (20 mL). The
aqueous mixture was extracted with methyl tertbutyl ether
(3£20 mL). The combined organic layer was washed with
brine, dried over MgSO4 and filtrated through a pad of
silica. After evaporation of the solvent, the residue was
purified by flash chromatography (100 g of silica, 750 mL
of hexane/ether 20:1, then cyclohexane/ethyl acetate 6:1)
to give 398 mg (1.36 mmol, 68%) of the prenylated
benzaldehyde 16 as a pale oil.
(ATR) n [cm21]¼2903 (br, w), 1691 (s), 1583 (s), 1446 (m),
˜
1381 (m), 1282 (s), 1225 (m), 1142 (s), 1084 (s), 1007 (s),
904 (s), 852 (m). 1H NMR (300 MHz, CDCl3): d
[ppm]¼3.38, 3.44 (each s, 3H, CH3 of C3-OMOM,
C5-OMOM), 5.10, 5.18 (each s, 2H, CH2 of C3-OMOM,
4
C5-OMOM), 7.01 (d, 1H, J¼3 Hz, H at C4), 7.18 (d, 1H,
4J¼3 Hz, H at C6). 13C NMR (75 MHz, CDCl3): d
[ppm]¼56.3, 56.5 (each q, CH3 of C3-OMOM,
C5-OMOM), 94.5, 95.3 (each t, CH2 of C3-OMOM,
C5-OMOM), 109.0 (d), 110.4 (s), 110.6 (d), 134.9 (s),
155.0, 157.3 (each s, C3, C5), 191.6 (d, C7). GC-MS
Method C. From 2-bromo-3,5-dimethoxymethoxy-benz-
aldehyde 17 via coupling with the nickel-p-allyl complex
19. In a glovebox, 550 mg (2 mmol) of Ni(COD)2 was
placed in a Schlenk flask under argon. After transfer to a
Schlenk line, 10 mL of dry and degassed benzene was
added. The resulting yellow solution was cooled to 58C, and
a degassed solution of 0.35 mL (3 mmol) of freshly destilled
prenyl bromide in 5 mL of benzene was added dropwise.
The resulting red solution was stirred for 1 h. Then the
benzene was carefully evaporated. The deep red complex
19 was dissolved in 5 mL of dry and degassed DMF.
A degassed solution of 152 mg (0.5 mmol) of bromo
benzaldehyde 17 in 10 mL of dry DMF was added. The
resulting mixture was stirred at 508C, until the solution
had completely changed the color from red to green (10 h).
The mixture was filtered through a pad of celite. After
evaporation of the solvent, the residue was purified by flash
chromatography (20 g of silica, cyclohexane/ethyl acetate
6:1) to give 51 mg (0.17 mmol, 35%) of the prenylated
benzaldehyde 16 as a pale oil.
(Optima
1
MS, 10 psi, 5082![258C/min]!300810):
tRet¼10.05 min, 99% purity. MS (EI): (the peaks showed
the typical isotopic pattern of a bromo compound) 306 (10),
274 (2), 63 (59, 45 (100). HR-MS (EI): calcd 303.9946 for
C11H13O5Br, found 303.994. Anal. calcd for C11H13O5Br: C
43.30; H 4.29; found: C 43.45; H 4.19.
4.2.9. 2-(3-Methylbut-2-enyl)-3,5-dimethoxymethoxy-
benzaldehyde (16). Method A. From 2-(3-Methylbut-2-
enyl)-3,5-dimethoxymethoxybenzylic alcohol (15). 125 mg
(0.42 mmol) of benzylic alcohol 15 was dissolved in 4 mL
of dry DMSO. After addition of 178 mg (0.63 mmol) of
IBX, the resulting solution was stirred at rt for 5 h. After
addition of 10 mL of water, the mixture was filtered through
a sintered funnel and subsequently extracted with MTBE
(5£10 mL). The combined organic layer was washed with
brine and dried over MgSO4. After evaporation of the
solvent, the residue was purified by flash chromatography
(10 g of silica, cyclohexane/ethyl acetate 5:1) to give
112 mg (0.38 mmol, 91%) of the benzaldehyde 16 as a
colorless oil. TLC (cyclohexane/ethyl acetate 5:1) Rf¼0.15.
4.2.10. [3,5-Bis-methoxymethoxy-2-(3-methylbut-2-enyl)-
phenyl]-(3,5-dichloro-2-methoxy-6-methoxymethoxy-4-
methyl-phenyl]-methanol (20). 858 mg (2.6 mmol) of
bromide 10 was dissolved in 20 mL of dry THF under
argon. At 2788C 1.69 mL (2.7 mmol) of a 1.6 M solution of
n-BuLi was added, and the resulting solution was stirred for
15 min. A solution of 590 mg (2.0 mmol) of aldehyde 16
in 10 mL of dry THF was added dropwise. The resulting
solution was allowed to slowly warm up to rt while being
stirred overnight. After addition of 20 mL of a saturated
NH4Cl solution, the mixture was extracted with ethyl
acetate (3£30 mL). The combined organic layers were
washed with brine and dried over MgSO4. After evaporation
of the solvent, the residue was purified by flash chroma-
tography (100 g of silica, cyclohexane/ethyl acetate 6:1) to
give 940 mg (1.72 mmol, 86%) of the benzhydrol 20 as a
brown oil. TLC (cyclohexane/ethyl acetate 6:1) Rf¼0.15. IR
IR (ATR) n [cm21]¼2955 (m), 2904 (m), 1687 (s), 1600 (s),
˜
1476 (s), 1449 (m), 1392 (m), 1306 (m), 1277 (s), 1210 (s),
1150 (s), 1137 (s), 1079 (s), 1020 (s), 956 (s), 937 (s), 921
(s), 896 (m), 854 (m). 1H NMR (300 MHz, CDCl3): d
[ppm]¼1.63 (s, 3H, H at C12), 1.74 (s, 3H, H at C11), 3.44,
3.45 (each s, 3H, CH3 of C3-OMOM, C5-OMOM), 3.68 (d,
3
2H, J¼7 Hz, H at C8), 5.08 (m, 1H, H at C9), 5.14, 5.17
(each s, 2H, CH2 of C3-OMOM, C5-OMOM), 7.00 (d, 1H,
4
4J¼2.5 Hz, H at C4), 7.16 (d, 1H, J¼2.5 Hz, H at C6),
10.22 (s, 1H, H at C7). 13C NMR (75 MHz, CDCl3): d
[ppm]¼17.8 (q, C12), 23.0 (t, C8), 25.5 (q, C11), 56.0 (q,
2C, CH3 of C3-OMOM, C5-OMOM), 94.5, 94.6 (each t,
CH2 of C3-OMOM, C5-OMOM), 109.0, 109.2 (each d, C4,
C6), 123.2 (d, C9), 127.8 (s, C2), 131.6 (s, C10), 135.2 (s,
C1), 156.2, 156.2 (each s, C3, C5), 191.5 (s, C7). GC-MS
(Optima
1
MS, 10 psi, 5082![258C/min]!300810):
(ATR) n [cm21]¼3446 (br, m), 2928 (m), 1604 (s), 1448 (s),
˜
tRet¼9.97 min, 98% purity. MS (EI): 294 (25, [M]þ), 279
(7), 251 (10), 236 (3), 217 (7), 202 (5), 189 (5), 175 (6), 161
(4), 115 (5), 91 (4), 77 (5), 45 (100). HR-MS (EI): calcd
294.1467 for C16H22O5, found 294.147.
1379 (s), 1283 (s), 1209 (m), 1150 (s), 1021 (s), 919 (s), 850
1
(m), 780 (w). H NMR (300 MHz, CDCl3): d [ppm]¼1.36
4
4
(d, 3H, J¼1.5 Hz, H at C17), 1.55 (d, 3H, J¼1.5 Hz, H
at C18), 2.45 (s, 3H, H at C19), 2.97/3.12 (each d, 1H,
J¼5.5 Hz, H at C14), 3.37 (s, 3H, CH3 of C3-OMOM), 3.47
(s, 3H, CH3 of C5-OMOM), 3.51 (s, 3H, CH3 of C8-OMe),
3.59 (s, 3H, CH3 of C12-OMOM), 4.25 (m, 1H, H at C15),
Method B. From 2-bromo-3,5-dimethoxymethoxy-benz-
aldehyde (17) via Stille coupling. 611 mg (2 mmol) of the

F. Kaiser, H.-G. Schmalz / Tetrahedron 59 (2003) 7345–7355
7353
3
4.99/5.13 (each d, 1H, J¼5.5 Hz, CH2 of C12-OMOM),
methanon (deformyl-pestalone) (23). 217 mg (0.4 mmol)
of the benzophenone 21 was dissolved in 10 mL of dry
methanol under argon. After addition of 93 mg (0.4 mmol)
of camphorsulphonic acid (CSA), the resulting solution was
stirred for 24 h at rt, until TLC-showed complete conversion
to one final product. After the solvent was evaporated under
reduced pressure, the residue was purified by flash
chromatography (30 g of silica, cyclohexane/ethyl acetate
4:1) to give 150 mg (0.36 mmol, 91%) of the deprotected
benzophenone 23 (deformyl-pestalone). TLC (cyclohexane/
5.10 (s, 2H, CH2 of C3-OMOM), 5.17/5.21 (each d, 1H,
3J¼7 Hz, CH2 of C5-OMOM), 6.29 (s, 1H, H at C13), 6.70
4
4
(d, 1H, J¼2.5 Hz, H at C4), 7.27 (d, 1H, J¼2.5 Hz, H at
C6). 13C NMR (75 MHz, CDCl3): d [ppm]¼18.0 (q, C18),
18.4 (q, C19), 25.2 (t, C14), 25.5 (q, C17), 56.15 (q, CH3 of
C5-OMOM), 56.2 (q, CH3 of C3-OMOM), 58.3 (q, CH3 of
C12-OMOM), 61.6 (q, CH3 of C8-OMe), 67.3 (d, C13),
95.5 (t, CH2 of C3-OMOM), 95.7 (t, CH2 of C5-OMOM),
101.5 (t, CH2 of C12-OMOM), 103.0 (d, C4), 108.8 (d, C6),
122.5 (s, C2), 124.3 (d, C15), 126.2 (s, C9), 126.8 (s, C11),
131.4 (s, C16), 132.5 (s, C7), 137.0 (s, C10), 145.0 (s, C1),
152.3 (s, C12), 155.8 (s, C8), 157.1 (s, C3), 157.15 (s, C5).
GC-MS (Optima 1 MS, 10 psi, 5082![258C/min]!300810):
broad signal, tRet¼13.5–14.4 min, 94% purity. MS (EI):
(the peaks showed the typical isotopic pattern of a dichloro
compound) 544 (5, [M]þ), 526 (15), 481 (38), 458 (15), 413
(22), 405 (25), 369 (16), 339 (15), 263 (11), 233 (22), 219
(27), 189 (20), 149 (27), 115 (22), 91 (42), 69 (100). HR-MS
(EI): calcd 544.1630 for C26H34O8Cl2, found 544.163.
1
ethyl acetate 4:1) Rf¼0.1. H NMR (300 MHz, CDCl3): d
[ppm]¼1.57 (s, 3H, H at C18), 1.61 (s, 3H, H at C 17), 2.50
(s, 3H, H at C19), 3.18 (d, 2H, J¼6.5 Hz, H at C14), 3.31 (s,
3H, CH3 of C8-OMe), 5.12 (t, 1H, J¼6.5 Hz, H at C15),
5.92 (br s, 1H, C3-OH), 6.18 (s, 1H, C5-OH), 6.23 (d, 1H,
J¼2.5 Hz, H at C6), 6.36 (d, 1H, J¼2.5 Hz, H at C4), 12.15
(s, 1H, C12-OH). 13C NMR (75 MHz, CDCl3): d [ppm]¼
17.7 (q, C18), 19.0 (q, C19), 25.6 (q, C17), 26.1 (t, C14),
61.8 (q, CH3 of C8-OMe), 105.2 (d, C4), 106.2 (d, C6),
115.4 (s, C7), 116.4 (s, C2), 119.0 (s, C11), 119.8 (s, C9),
121.9 (d, C15), 134.8 (s, C16), 142.6 (s, C1), 144.1 (s, C10),
154.3 (s, C5), 155.5 (s, C8), 155.8 (s, C3), 156.5 (s, C12),
201.6 (s, C13). MS (EI): (the peaks showed the typical
isotopic pattern of a dichloro compound) 410 (23, [M]þ),
396 (8), 381 (65), 379 (100), 367 (22), 323 (50), 297 (20),
235 (20), 233 (32), 218 (35), 189 (20), 161 (40), 115 (20), 77
(37), 69 (70), 54 (82). HR-MS (EI): calcd 410.0688 for
C20H20O5Cl2, found 410.069.
4.2.11. [3,5-Bis-methoxymethoxy-2-(3-methylbut-2-enyl)-
phenyl]-(3,5-dichlor-2-methoxy-6-methoxy-methoxy-4-
methyl-phenyl]-methanon (21). 927 mg (1.70 mmol) of
the benzhydrol 20 was dissolved in 15 mL of dry dichloro-
methane. 1.42 g (3.44 mmol) of Dess–Martin periodinane
was added. The resulting orange solution was stirred for 3 h
at rt. Then the reaction mixture was concentrated and
filtered through a pad of celite. After evaporation of the
solvent, the residue was purified by flash chromatography to
give 820 mg (1.50 mmol, 88%) of the benzophenone 21 as a
yellow oil, which slowly solidified upon standing at 48C.
4.2.13. [7-Hydroxy-2,2-dimethyl-chroman-5-yl]-(3,5-di-
chloro-6-methoxy-2-hydroxy-4-methyl-phenyl]-metha-
non (22). 109 mg (0.2 mmol) of the benzophenone 21 was
placed in a flask equipped with a reflux condenser and
dissolved in 5 mL of dry methanol. After addition of 40 mg
(0.2 mmol) of p-toluenesulphonic acid the solution was stirred
at 608C for 3 h. After evaporation of the solvent, the residue
was purified by flash chromatography (10 g of silica,
cyclohexane/ethyl acetate 4:1) to give 40 mg (0.1 mmol,
50%) of the chromane 22 as a yellow crystalline solid. TLC
(cyclohexane/ethyl acetate 4:1) Rf¼0.3. 1H NMR (300 MHz,
CDCl3): d [ppm]¼1.31 (s, 6H, H at C17, C18), 1.72 (t, 2H,
J¼7 Hz, HatC15), 2.53(s, 3H, HatC19),2.62(t, 2H, J¼7 Hz,
H at C14), 3.36 (s, 3H, CH3 of C8-OMe), 6.30 (d, 1H,
J¼2.5 Hz, H at C6), 6.36 (d, 1H, J¼2.5 Hz, H at C4), 11.57 (s,
1H, C12-OH). 13C NMR (75 MHz, CDCl3): d [ppm]¼18.9 (q,
C19), 19.9 (t, C14), 26.6 (q, C17, C18), 32.5 (t, C15), 61.8 (q,
CH3 of C8-OMe), 74.5 (s, C16), 106.3 (d, C4), 106.8 (d, C6),
111.3(s, C2), 115.9(s, C7),118.8(s, C11),119.9(s, C9), 141.6
(s, C1), 143.4 (s, C10), 154.1 (s, C5), 155.1 (s, C3), 155.3 (s,
C8), 155.7 (s, C12), 200.9 (s, C13). MS (EI): (the peaks
showed the typical isotopic pattern of a dichloro compound)
410 (35, [M]þ), 396 (10), 381 (65), 379 (100), 367 (25), 341
(24), 323 (55), 297 (24), 261 (2), 235 (20), 233 (37), 218 (32),
189(24), 177(32), 161(45), 115 (25), 91(27), 77(37), 69(68),
54 (77). HR-MS (EI): calcd 410.0687 for C20H20O5Cl2, found
410.069.
TLC (cyclohexane/ethyl acetate 6:1) R ¼0.2. IR (ATR) n
˜
f
[cm21]¼2954 (m), 2065 (w), 1674 (s), 1600 (s), 1572 (s),
1448 (m), 1371 (s), 1282 (s), 1210 (s), 1152 (s), 1064 (s),
1024 (s), 977 (s), 916 (s). H NMR (300 MHz, CD3OD):
1
d [ppm]¼1.59 (s, 3H, H at C17), 1.55 (s, 3H, H at C18), 2.49
(s, 3H, H at C19), 3.29 (s, 2£3H, CH3 of C3-OMOM,
C5-OMOM), 3.40 (s, 3H, CH3 of C8-OMe), 3.55 (s, 3H,
CH3 of C12-OMOM), 3.61 (d, 2H, J¼6.5 Hz, H at C14),
4.95 (s, 2H, CH2 of C12-OMOM), 4.99 (s, 2H, CH2 of
C3-OMOM), 5.10–5.15 (m, 1H, H at C15), 5.17 (s, 2H,
CH2 of C5-OMOM), 6.72 (d, 1H, 4J¼2.5 Hz, H at C4), 6.97
(d, 1H, 4J¼2.5 Hz, H at C6). 13C NMR (75 MHz, CDCl3): d
[ppm]¼18.5 (q, C18), 18.9 (q, C19), 26.3 (t, C14), 26.3 (q,
C17), 56.5 (q, CH3 of C5-OMOM), 56.7 (q, CH3 of
C3-OMOM), 58.4 (q, CH3 of C12-OMOM), 62.7 (q, CH3
of C8-OMe), 95.9 (t, CH2 of C3-OMOM), 96.0 (t, CH2 of
C5-OMOM), 101.7 (t, CH2 of C12-OMOM), 108.7 (d, C4),
113.8 (d, C6), 124.9 (s, C2), 126.4 (d, C15), 126.8 (s, C9),
131.9 (s, C11), 132.1 (s, C16), 139.5 (s, C7), 140.1 (s, C10),
150.6 (s, C1), 153.8 (s, C12), 157.2 (s, C8), 157.2 (s, C3),
158.2 (s, C5), 195.7 (s, C13). GC-MS (Optima 1 MS, 10 psi,
20082![258C/min]!300810): broad signal, tRet¼7.35–
7.7 min, 99% purity. MS (EI): (the peaks showed the
typical isotopic pattern of a dichloro compound) 542 (3,
[M]þ), 513 (10), 497 (25), 481 (27), 467 (33), 411 (10), 367
(5), 291 (7), 271 (52), 247 (87), 215 (20), 189 (7), 99 (58),
73 (100). HR-MS (EI): calcd 542.1474 for C26H32O8Cl2,
found 542.145.
Acknowledgements
This work was supported by Aventis Pharma GmbH and the
Fonds der Chemischen Industrie. We thank Dr Hans
Schmickler for NMR spectroscopic support and Dr Mathias
4.2.12. [3,5-Bishydroxy-2-(3-methylbut-2-enyl)phenyl]-
(3,5-dichloro-2-methoxy-6-hydroxy-4-methyl-phenyl]-

7354
F. Kaiser, H.-G. Schmalz / Tetrahedron 59 (2003) 7345–7355
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¨
Schafer for MS spectroscopic measurements. Generous
gifts of chemicals from Chemetall AG are also highly
appreciated.
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29. For examples of the p-allyl-nickel halide complex coupling
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¨
(a) Knolker, H.-J.; Baum, E.; Reddy, K. R. Tetrahedron Lett.
¨ ¨
2000, 41, 1171–1174. (b) Knolker, H.-J.; Frohner, W.;
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(c) Horcher, U.; Schwenner, E.; Franck, B. J. Liebigs Ann.
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