Stereocontrolled synthesis of C-arylglycosides applied to the south west fragment of the antibiotic kendomycin

Article abstract of DOI:10.1055/s-2002-35990

A nine step synthesis of the southwest fragment 3 of the antibiotic kendomycin (1) is reported. The tetrahydropyran ring is prepared in a highly stereocontrolled and efficient sequence. The key step concerns an anti-aldol reaction using chiral ketone 10. C-Aryl glycoside 3 exhibits atropisomerism and the relative configuration around its tetrahydropyran ring was established by NOE experiments.

Full text of DOI:10.1055/s-2002-35990

2766
PAPER
Stereocontrolled Synthesis of C-Arylglycosides Applied to the South West
Fragment of the Antibiotic Kendomycin
Synthesis of
C-
Arylgly
a
coside
s
A
p
r
plied to
i
S
ou
a
th
W
est Fragmen
M
t
of the Antibiotic
K
en
.
domycin B. Marques, Stefan Pichlmair, Harry J. Martin, Johann Mulzer*
Institut für Organische Chemie der Universität Wien, Währingerstr. 38, 1090 Wien, Austria
Fax +43(1)427752189; E-mail: johann.mulzer@univie.ac.at
Received 8 August 2002; revised 25 September 2002
than five stereogenic centers along with a fully substituted
highly oxygenated aryl ring.
Abstract: A nine step synthesis of the southwest fragment 3 of the
antibiotic kendomycin (1) is reported. The tetrahydropyran ring is
prepared in a highly stereocontrolled and efficient sequence. The
key step concerns an anti-aldol reaction using chiral ketone 10. C-
Aryl glycoside 3 exhibits atropisomerism and the relative configu-
ration around its tetrahydropyran ring was established by NOE ex-
periments.
The synthesis started from the known ester 4,3 which after
bromination, subsequent hydrolysis, methylation and
formylation led to aldehyde 75 and dichloro compound 6
(which can be converted into 7 in an overall yield of 89%).
In our first approach, aldehyde 7 was added to the known
ketone 86 using anti-aldol conditions [(c-C6H11)2BCl–
Et3N],7 leading to the anti-aldol product 9 with 86% yield
and a low diastereoselectivity (1.5:1) (Scheme 2). Since
the diastereoselectivity of this aldol addition was even
worse than the one in our first approach3 it was necessary
to develop a new, and hopefully more stereocontrolled
route.
Key words: total synthesis, natural products, aldol reactions, gly-
cosides, atropisomerism, antibiotics
Kendomycin [(–)-TAN 2162] (1), a polyketide produced
from various Streptomyces species, was recently reported
as a potent endothelin receptor antagonist and anti-
osteoporotic compound.1 Recently antibacterial activity
and cytotoxic properties were also described.2 This struc-
turally unique polyketide features a quinone methide
chromophore connected to a highly substituted tetrahy-
dropyran ring with an aliphatic ansa chain. The remark-
able pharmacological activity as well as the unique
molecular architecture encouraged us to study the synthe-
sis of 1.
As presented in an earlier report,3 our synthetic plan
(Scheme 1) is centered around a ring closing metathesis
for macrocyclization (C13/C14) of intermediate 2 as a late
step in the sequence. Further disconnection of intermedi-
ate 2 gives 3 as a precursor of 1. In this paper we describe
a stereocontrolled synthesis of key fragment 3, which
structurally represents a C-aryl glycoside4 with no less
Thus, we used Evans aldol methodology with chiral -
keto imide 108 as the aldol donor. Enolization of 10 and
reaction with aldehyde 7 afforded the anti-aldol aduct 11
in 97% yield and high diastereoselectivity (ds > 98%)
(Scheme 3). Subsequent anti-selective reduction with
Me4NBH(OAc)3 gave diol 12 with ds 90:10. On treatment
with a catalytic amount of DBU and in situ protection with
TPSCl, lactone 13 was obtained. The introduction of the
upper aliphatic chain was achieved via addition of allyl-
magnesium bromide to 13 to form the corresponding lac-
tol, which was, without any further purification, reduced
to tetrahydropyran 3 with Et3SiH in the presence of SnCl4.
As a side product of the reduction desilylated product 14
(27% yield) was formed which was reprotected to give 3
in a combined yield of 90%.
13
14
Me
Me
Me
Me
OH
Me
OR2
Me
R1O
Me
HO
O
Br
Me
O
O
O
OMe
Me
O
R1O
Me
MeO
Me
HO
Me
Me
RO
Me
OMe
O
OR
Kendomycin (1)
2
3
Scheme 1 Retrosynthetic plan of Kendomycin (1)
Synthesis 2002, No. 18, Print: 19 12 2002.
Art Id.1437-210X,E;2002,0,18,2766,2770,ftx,en;T09202SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

PAPER
Synthesis of C-Arylglycosides Applied to the South West Fragment of the Antibiotic Kendomycin
2767
In the case of the secondary alcohol 14, separation of the
atropisomers by means of chromatographic separation
1
and crystallisation was not successful. Also H NOE ex-
periments were carried out to assign the configuration of
the tetrahydropyran ring in 3 (Figure 1). The interaction of
1-H with 3-H and 5-H, and interaction of 4-Me with 2-H,
as well as the coupling constant J1,2 of 9.6 Hz corroborated
the configuration attributed to 3.
NOE
Me
R
4
H
5
O
H
TPSO
Ar
2
H
3
1
H
Me
H
NOE
NOE
Scheme 2 Reagents and conditions: a) NBS (1.3 equiv), MeCN, r.t.,
3 h, 97%; b) KOH (2 equiv), MeOH, H2O, r.t., 1.5 h, 99%; c) Me2SO4
(2.4 equiv), K2CO3 (2.9 equiv), acetone, r.t., 17 h, 93%; d)
CHCl2OMe (1.4 equiv), SnCl4 (1.3 equiv), 0 °C, 7.5 h, 72%; e) DMF–
NaOH (1 N) (1:1), 2 h, 100 °C, 72%; f) (c-C6H11)2BCl (1.5 equiv),
Et3N (2 equiv), 8 (1.5 equiv), Et2O, –78 °C, 86%, dr 1.5:1.
Figure 1 Assignment of the stereochemistry of 3 – NOE experi-
ments
All moisture sensitive reactions were carried out under argon. An-
hyd solvents were obtained as follows: THF distilled from sodium–
benzophenone ketyl; Et2O distilled from LiAlH4; acetone, CH2Cl2
and DMF distilled from P2O5; Et3N distilled from CaH2. All other
solvents were HPLC grade. Column chromatography was per-
formed with Merck silica gel (0.04–0.63 m, 240–400 mesh) under
low pressure. TLC was carried out with E. Merck silica gel 60-F254
plates. Mps were determined on a Leica Galen III apparatus and are
uncorrected. IR spectra were recorded using a Perkin–Elmer 1600
Series FTIR spectrometer and are reported in wave numbers (cm–1).
Optical rotations were measured on a P 341 Perkin–Elmer polarim-
eter. NMR spectra were recorded on either a Bruker Avance DPX
250 MHz, or a Bruker Avance DRX 600 MHz spectrometer. Unless
otherwise stated, all NMR spectra were measured in CDCl3 solu-
tions and referenced to the residual CHCl3 signal (1H, = 7.26; 13C,
O
O
OH
O
Br
O
O
O
OMe
Me
a
O
N
O
N
Me
MeO
Me
Me Me
Bn
Bn
OMe
10
11
O
OH OH
O
Br
OMe
Me
b
c
O
N
Me
Me
MeO
Bn
OMe
= 77.0). All H and 13C shifts are given in ppm (s = singlet;
12
1
d = doublet; t = triplet; q = quadruplet; m = multiplet; br s = broad
signal). Coupling constants J are given in Hz; assignments of proton
resonances were confirmed, when possible, by selective homonu-
clear decoupling experiments or by correlated spectroscopy. Mass
spectra were measured on a Micro mass, trio 200 Fisions Instru-
ments. HRMS were performed with a Finnigan MAT 8230 with a
resolution of 10000. Elemental analyses were recorded on a Perkin–
Elmer-240-Elementaranalyser.
O
Me
TPSO
Me
RO
O
Br
d
O
Br
OMe
Me
OMe
Me
Me
MeO
Me
MeO
OMe
OMe
Propionic Acid 5-Bromo-2,4-dimethoxy-3-methylphenyl Ester
(5)
14 (R = H)
(R = TPS)
13
c
3
NBS (1.07 g, 6.03 mmol) was added to a solution of 4 (1.00 g, 4.46
mmol) in absolute MeCN (20 mL) and stirred for 3 h. The solvent
was removed by evaporation and the residue was treated with of
CCl4 (20 mL), whereby the precipitate was removed by filtration
and the mother liquid was concentrated and dried in vacuum.
Scheme 3 Reagents and Conditions: a) (c-C6H11)2BCl (1.6 equiv),
NEt2Me (1.8 equiv), Et2O, 0 °C, 2 h, add 7, –78 to 0 °C over 2 h, 97%,
ds > 98%; b) (Me)4NBH(OAc)3 (3 equiv), MeCN–HOAc (1:1),
–40 °C to r.t., 3.5 h, 63%, ds 90:10; c) DBU (0.05 equiv), CH2Cl2, r.t.,
1.5 h; imidazole (1.2 equiv), TPSCl (1.1 equiv), r.t., overnight, 65%
(over two steps); d) CH2=CHCH2MgBr (3 equiv), THF, –78 °C, 2.5
h; Et3SiH (10 equiv), SnCl4 (1 equiv), –78 °C to –25 °C, 3 h, 60%
(over 2 steps).
Yield: 1.32 g (97%) (without purification); slightly yellow oil; Rf
0.59 (SiO2; hexane–EtOAc, 3:1).
1H NMR (400 MHz, CDCl3): = 7.03 (s, 1 H, ArH), 3.72 (s, 3 H,
OMe), 3.67 (s, 3 H, OMe), 2.53 (q, J = 7.6 Hz, 2 H, CH2), 2.18 (s,
3 H, ArMe), 1.20 (t, J = 7.6 Hz, 3 H, MeCH2).
13C NMR (100 MHz, CDCl3): = 172.8, 154.2, 150.6, 140.9, 128.1,
124.6, 111.5, 61.1, 60.8, 27.9, 10.7, 9.5.
Lactone 13 and compounds 3 and 14 form mixtures of at-
ropisomers, as a consequence of the hindered rotation
around the arylic sp2–sp3 bond. This issue was observed in
the tetrahydropyran ring system previously synthesized.3
MS (EI, 70 eV): m/z = 302 (11) [M]+, 246 (100) [M – CH3CH2CO]+,
231 (42) [M – CH3 – CH3CH2CO]+.
Synthesis 2002, No. 18, 2766–2770 ISSN 0039-7881 © Thieme Stuttgart · New York

2768
M. M. B. Marques et al.
PAPER
HRMS (60 °C, 70 eV): m/z calcd for C12H15O4Br: 302.0154; found:
Compound 6
302.0163.
Rf 0.40 (SiO2; hexane–EtOAc, 6:1).
Anal. Calcd for C12H15BrO4: C, 47.54; H, 4.99. Found: C, 47.70; H,
5.01.
1H NMR (400 MHz, CDCl3): = 7.45–7.3 (br s, 1 H CHCl2Ar),
3.87 (s, 6 H, OMe), 3.78 (s, 3 H, OMe), 2.30 (s, 3 H, ArMe).
The bromide 5 from the reaction above (486 mg, 1.60 mmol) was
dissolved in MeOH (1 mL) under argon atmosphere, cooled to 0 °C
and KOH (183 mg, 3.20 mmol) dissolved in MeOH (1 mL) was
added. After 1.5 h, HCl (2 N, 8 mL) and Et2O (6 mL) were added
and the aq layer was extracted with Et2O (4 20 mL). The com-
bined organic layers were dried (MgSO4), filtered, evaporated and
dried under high vacuum.
13C NMR (100 MHz, CDCl3): = 149.73, 149.20, 139.53, 125.20,
118.64, 115.78, 61.45, 61.02, 60.94, 60.72, 10.61.
MS (EI, 70 eV): m/z = 343 (65) [M]+, 325 (60) [M – CH3]+, 309 (56)
[M – Cl]+, 394 (31) [M – Cl – CH3].
Anal. Calcd for C11H13BrCl2O3: C, 38.40; H, 3.81. Found: C, 38.34;
H, 3.79.
Yield: 393 mg (99%); slightly yellow oil.
Spectroscopic data are consistent with those in ref.9
5-Benzyloxy-1-(2-bromo-3,5,6-trimethoxy-4-methylphenyl)-1-
hydroxy-2,4-dimethylpentan-3-one (9)
BCl(C6H11)2 (1.27 mmol; 1.28 mL, 1.0 M in hexane) and Et3N (0.24
mL, 1.70 mmol) was stirred in anhyd Et2O (3 mL) at –78 °C for 15
min. Afterwards ketone 8 (200 mg, 0.85 mmol) was added in 0.5
mL of Et2O within 5 minutes and the temperature was allowed to
warm up to –35 °C within 1.5 h. The temperature was kept at
–35 °C for another 1.5 h until aldehyde 7 (367 mg, 1.27 mmol) was
added in Et2O (0.8 mL) at –81 °C within 30 min. After 18 h stirring
at –78 °C the reaction was quenched with KH2PO4 buffer (20 mL,
1 M, pH 7.0) and extracted with Et2O (3 20 mL). The organic
phase was dried (Na2SO4), filtered and the solvent was evaporated.
The crude product was stirred with NaBO3 (391 mg, 2.54 mmol) in
H2O–THF (1:1; 3.6 mL) for 15 h to cleave the boron complex. The
mixture was diluted with H2O (5 mL) and extracted with Et2O
(3 15 mL). The organic layer was dried (Na2SO4), filtered and the
solvent was evaporated. The residue was purified by column chro-
matography (silica gel; hexane–EtOAc, 5:1) to give 9 as a mixture
of diastereomers (60:40).
The phenol from above (45.8 g, 0.19 mol) was dissolved in anhyd
acetone and dimethyl sulfate (43.9 mL, 0.46 mol), and K2CO3 (76.8
g, 0.56 mol) was added. The reaction mixture was stirred for 17 h,
then the K2CO3 was filtered off and the acetone was evaporated.
The yellow oil was dissolved in Et2O (500 mL), and ammonia
(25%; 500 mL) was added. After 10 min stirring the aq layer was
extracted with Et2O (3 200 mL) and the combined organic layers
were washed with H2O (300 mL), HCl (1 N; 300 mL), sat. aq NaCl
(300 mL). The organic layer was dried (MgSO4), filtered, and evap-
orated under reduced pressure. The methylated product was isolated
without any further purification.
Yield: 45.0 g (93%); yellow oil.
Spectroscopic data are consistent with those in ref.10
2-Bromo-3,5,6-trimethoxy-4-methylbenzaldehyde (7) and 1-
Bromo-2-dichloromethyl-3,4,6-trimethoxy-5-methylbenzene
(6)
Yield: 391 mg (88%).
The methylated bromide from the previous reaction (3.00 g 11.5
mmol) and dichloromethyl methyl ether (1.43 mL, 15.8 mmol) was
dissolved in anhyd CH2Cl2 at 0 °C. Tin tetrachloride (14.9 mmol,
14.9 mL of a 1 M solution in CH2Cl2) was added slowly within 20
min. The reaction mixture was stirred for 7.5 h, then CH2Cl2 (60
mL) and ice (30 g) were added, and the mixture was stirred for 1.5
h while it was allowed to warm up to r.t. The mixture was extracted
with Et2O (3 50 mL), washed with sat. aq NaCl, dried (MgSO4),
filtered and evaporated to give a black oil which was purified by
column chromatography (silica gel; hexane–EtOAc, 15:1) to give
the aldehyde 7 (2.02 g, 61%) and 1-bromo-2-dichloromethyl-3,4,6-
trimethoxy-5-methylbenzene (6) (1.19 g, 30%) as a byproduct.
Compound 6 (1.19 g, 3.46 mmol) was hydrolysed to the desired al-
dehyde in DMF–aq NaOH (1 N) (1:1; 15 mL) for 2 h at 100 °C. Af-
ter cooling down to r.t., the mixture was diluted with H2O (50 mL)
and extracted with Et2O (3 30 mL). The combined organic layers
were dried (MgSO4), filtered and evaporated. After column chro-
matography more aldehyde 5 [725 mg (72%)] could be obtained.
Separation by HPLC of the desired major product delivered an an-
alytically pure sample.
Rf 0.13 (SiO2, hexane–EtOAc, 5:1); [ ]D20 + 0.2 (c 1.53 CHCl3).
1H NMR (400 MHz, CDCl3): = 7.15 (d, J = 8.2 Hz, 2 H, ArH),
6.78 (d, J = 8.2 Hz, 2 H, ArH), 5.43 (t, J = 9.3 Hz, 1 H, ArCHOH),
4.39 (d, J = 11.5 Hz, 1 H, ArCHHO), 4.34 (d, J = 11.5 Hz, 1 H,
ArCHHO), 3.84 (s, 3 H, OMe), 3.72 (s, 3 H, OMe), 3.71 (s, 3 H,
OMe), 3.68 (s, 3 H, OMe), 3.61 (t, J = 8.3, 1 H, OH), 3.30–3.50 m,
3 H, OCH2CHMe and CHMe), 3.02 (q, J = 6.8, 1 H, CHMe), 2.17
(s, 3 H, ArCH3), 1.07 (d, J = 7.1, 1 H, CHMe), 0.82 (d, J = 6.8, 1 H,
CHMe).
13C (100 MHz, CDCl3): = 216.42, 159.58, 151.84, 149.34, 130.55,
129.64, 127.21, 114.14, 73.42, 72.43, 61.47, 60.67, 60.36, 55.64,
47.22, 15.66, 14.10, 13.85, 10.53.
MS (EI, 70 eV): m/z = 525 (0.2) [M]+, 508 (15) [M – OH]+, 427 (4),
372 (55), 288 (84), 236 (33), 121 (100) [MeOPhCH2]+.
HRMS (60 °C, 70 eV): m/z calcd for C25H31O679Br: 506.1304;
found: 506.1321.
Aldehyde 7
Rf 0.33 (SiO2; hexane–EtOAc, 6:1).
Anal. Calcd for C24H31BrO6: C, 58.19; H, 6.31. Found: C, 58.35; H,
6.30.
1H NMR (400 MHz, CDCl3): = 10.35 (s, 1 H, CHO), 6.82 (s, 1 H,
ArH), 2.89 (s, 3 H, OMe), 2.86 (s, 3 H, OMe), 2.84 (s, 3 H, OMe),
2.20 (s, 3 H, ArMe).
13C NMR (100 MHz, CDCl3): = 190.73, 152.90, 152.39, 133.75,
129.25, 127.37, 113.83, 62.61, 60.90, 60.86, 11.18.
(2R,4S,5R)-1-[(4R)-Benzyl-2-oxo-oxazolidin-3-yl]-5-(2-bromo-
3,5,6-trimethoxy-4-methylphenyl)-5-hydroxy-2,4-dimethylpen-
tane-1,3-dione (11)
MS (EI, 70 eV): m/z = 290 (100) [M]+, 275 (66) [M – CH3]+, 260
B(C6H11)2Cl (4.44 mL, 4.44 mmol, 1 M in hexane) was added to a
solution of ketone 10 (1.00 g, 3.46 mmol) in anhyd Et2O (24 mL)
under argon at 0 °C. Then NEtMe2 (0.48 mL, 5.00 mmol) was add-
ed slowly and the mixture was stirred for 2 h at 0 °C. The slightly
yellow suspension thus formed was cooled to –78 °C and a solution
of 2-bromo-3,5,6-trimethoxy-4-methylbenzaldehyde (7) (0.80 g,
2.77 mmol) in anhyd Et2O (2.4 mL) was added via canula. The re-
sulting mixture was allowed to warm up to 0 °C over 2 h and was
(14), [M – 2 CH3] 247 (25) [M – CH3 – CHO]+.
HRMS (20 °C, 70 eV): m/z calcd for C11H13O479Br: 288.9997;
found: 288.0005.
Anal. Calcd for C11H13BrO4: C, 45.70; H, 4.53. Found: C, 45.62; H,
4.52.
Synthesis 2002, No. 18, 2766–2770 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of C-Arylglycosides Applied to the South West Fragment of the Antibiotic Kendomycin
2769
quenched by the addition of aq NaHCO3 (5%; 50 mL). The mixture
was stirred for 10 min and then diluted with CH2Cl2 (50 mL). The
layers were separated and the aq layer washed with CH2Cl2 (2 50
mL). The organic layers were collected, dried (MgSO4), filtered and
the solvent was removed under reduced pressure. The residue was
purified by column chromatography (silica gel; hexane–EtOAc,
gradient 9:1 2:1). Aldol adduct 11 was obtained as a white foam.
HRMS (200 °C, 70 eV): m/z calcd for C27H34O8N79Br: 581.1453;
found: 581.1465.
Anal. Calcd for C27H34BrNO8: C, 55.87; H, 5.90; N, 2.42. Found: C,
55.99; H, 5.88; N, 2.41.
(5S,3R,4R,6R)-6-(2-Bromo-3,5,6-trimethoxy-4-methylphenyl)-
3,5-dimethyl-4-triphenylsilanyloxytetrahydropyran-2-one (13)
DBU (8.46 L, 0.06 mmol) was added to a solution of the diol (12)
(0.71 mg, 1.22 mmol) in CH2Cl2 (16 mL) under argon. The resulting
mixture was stirred at r.t. for 1.5 h until the starting material was
consumed. Imidazole (100 mg, 1.47 mmol) and chlorotriphenylsi-
lane (406 mg, 1.37 mmol) were added and the reaction mixture was
stirred at r.t. overnight. The reaction was quenched by addition of
sat. aq NH4Cl (30 mL) and the aq layer was washed with CH2Cl2
(3 30 mL). The organic layers were collected, dried (MgSO4), fil-
tered and the solvent was evaporated at reduced pressure. The re-
maining crude oil was purified by column chromatography (silica
gel; hexane–EtOAc, 5:1) to give lactone 13 after crystallisation
from hexane–Et2O as a mixture of atropisomers (1: 0.66). Only the
major atropisomer was assigned.
Yield: 1.54 g (97%); ds = 98%; Rf 0.10 (SiO2; hexane–EtOAc, 5:1);
[ ]D20 –107.0 (c 1.73 CH2Cl2).
1H NMR (400 MHz, CDCl3): = 7.36–7.20 (m, 5 H, ArH), 5.49 (t,
1 H, J = 9.3 Hz, CHOH), 5.11 (q, 1 H, J = 7.0 Hz, COCCH3HCO),
4.78–4.71 (m, 1 H, NCH), 4.28 (t, 1 H, J = 9.0 Hz, OCH2CHN),
4.21 (dd, 1 H, J = 2.5, 8.8 Hz, OCH2CHN), 3.96 (s, 3 H, ArOMe),
3.79 (s, 3 H, ArOMe), 3.74 (s, 3 H, ArOMe), 3.64–3.62 (m, 1 H,
COCHCH3CHOH), 3.32 (dd, 1 H, J = 3.2, 13.3 Hz, CH2Ph), 2.81
(dd, 1 H, J = 9.5, 13.3 Hz, CH2Ph), 2.23 (s, 3 H, ArMe), 1.54 (d, 3
H, J = 7.0 Hz, COCH3CO), 0.93 (d,
COCH3CHOH).
3 H, J = 7.0 Hz,
13C NMR (100 MHz, CDCl3): = 210.0, 170.6, 154.2, 151.8, 149.3,
135.4, 129.8, 129.4, 129.3, 127.8, 127.6, 127.3, 66.7, 61.5, 60.6,
60.4, 53.1, 52.8, 38.3, 15.0, 13.8, 10.5.
Yield: 522 mg (65%); colourless crystals; mp 69–70 °C; Rf 0.31
(SiO2; hexane–EtOAc, 5:1).
MS (EI, 70 eV): m/z = 579 (3) [M]+, 400 (67) [M
–
1H NMR (400 MHz, CDCl3): = 7.68–7.64 (m, 6 H, ArH), 7.46–
7.35 (m, 9 H, ArH), 5.39 (d, 1 H, J = 11.1 Hz, CHAr), 3.84 (s, 3 H,
ArOMe), 3.83 (s, 3 H, ArOMe), 3.72 (s, 3 H, ArOMe), 3.60–3.55
(m, 1 H, CHOTPS), 3.00–2.94 (m, 1 H, CHCH3CHAr), 2.83–2.75
(m, 1 H, COCHMe), 2.23 (s, 3 H, ArMe), 1.25 (d, 3 H, J = 7.3 Hz,
CHMeCO), 0.70 (d, 3 H, J = 7.0 Hz, CHMeCHAr).
13C NMR (100 MHz, CDCl3): = 136.0, 135.9, 135.3, 134.4, 134.3,
130.6, 130.5, 128.3, 128.2, 82.8, 78.2, 61.5, 60.6, 60.3, 45.5, 40.6,
15.4, 15.0, 10.6.
BnCHNHCOOCH2 + H]+, 290 (100) [ArCHOH + H]+, 92 (93)
[Bn]+.
HRMS (170 °C, 70 eV): m/z calcd for C27H32O8N79Br: 579.1345;
found: 579.1332.
Anal. Calcd for C27H32BrNO8: C, 56.06; H, 5.58; N, 2.42. Found: C,
56.22; H, 5.60; N, 2.42.
(2R,3R,4R,5R)-{(4R)-Benzyl-3-[5-(2-bromo-3,5,6-trimethoxy-4-
methylphenyl)-3,5-dihydroxy-2,4-dimethylpentanoyl]oxazoli-
din-2-one} (12)
MS (EI, 70 eV): m/z = 660 (11) [M]+, 259 (32) [TPS]+, 199 (92), 96
(100).
A solution of (CH3)4NBH(OCOCH3)3 (1.60 g, 6.08 mmol) in
MeCN–HOAc (1:1; 1.5 mL) was slowly added via canula to a solu-
tion of 11 (1.20 g, 2.07 mmol) in MeCN–HOAc (1:1; 7 mL) at –
40 °C. After the addition, the temperature was allowed to warm up
to –20 °C within 2 h. Then the bath was replaced by an ice bath and
the temperature was slowly warmed up to r.t. within 1.5 h. Then the
reaction was diluted with CH2Cl2 (50 mL) and quenched by addition
of sat. aq Na/K-tartrate (50 mL), while stirring vigorously. Then
solid NaHCO3 was added until the gas evolution was over. The re-
sulting mixture was stirred overnight at r.t., then the layers were
separated and the aq layer was washed with CH2Cl2 (3 50 mL).
The organic layers were dried (MgSO4), filtered and the solvent was
removed under reduced pressure to give a colourless oil that was pu-
rified by column chromatography (silica gel; hexane–EtOAc, 1:1)
to give compound 12.
HRMS (240 °C, 70 eV): m/z calcd for C35H37O6Si79Br: 660.1543;
found: 660.1427.
Anal. Calcd for C35H37BrO6Si: C, 63.53; H, 5.64. Found: C, 63.64;
H, 5.65.
(5S,3S,4S,6R,2R)-[2-Allyl-6-(2-bromo-3,5,6-trimethoxy-4-me-
thylphenyl)-3,5-dimethyltetrahydropyran-4-yloxy]triphenylsi-
lane (3) and (5S,3S,4S,6R,2R)-2-Allyl-6-(2-bromo-3,5,6-trime-
thoxy-4-methylphenyl)-3,5-dimethyltetrahydropyran-4-ol (14)
Allylmagnesium bromide (0.9 mL; 0.9 mmol, 1 M in Et2O) was
added to a solution of lactone 13 (200 mg, 0.30 mmol) in anhyd
THF (1.8 mL) at –78 °C. After stirring for 2.5 h, the reaction was
quenched by addition of sat. aq NH4Cl (1 mL) and allowed to warm
up to r.t. After extraction with Et2O (3 20 mL) the organic layers
were collected, dried (MgSO4), filtered and the solvent was evapo-
rated at reduced pressure. A crude brown oil (214 mg) was obtained,
which was dissolved in CH2Cl2 (2 mL) under argon atmosphere,
and Et3SiH (0.48 mL, 3.00 mmol) was added. The mixture was
cooled to –78 °C and SnCl4 (40.0 l, 0.34 mmol) was added, where-
by the colour of the mixture changed from colourless to yellow. The
temperature was slowly allowed to warm up to –60 °C within 1 h
and then to –25 °C within 2 h. The reaction was quenched by addi-
tion of H2O (2 mL) and HCl (1 M; 1 mL). The layers were separated
and the aq layer was washed with CH2Cl2 (3 20 mL) and Et2O
(3 20 mL). The organic layers were collected and dried (MgSO4),
filtered and the solvent was evaporated at reduced pressure. The
brown oil collected was purified by column chromatography (silica
gel; hexane–EtOAc, 7:1). Compound 3 was crystallized from hex-
ane–Et2O to give a mixture of atropisomers (1:0.33) along with the
deprotected product 14 which was isolated as a mixture of atropiso-
mers (1:0.35). In both cases only the major atropisomers were as-
signed.
Yield: 754 mg (63%); white foam; ds 88%; Rf 0.43 (SiO2; hexane–
EtOAc, 1:1); [ ]D20 –36.1 (c 1.73 CH2Cl2).
1H NMR (400 MHz, CDCl3): = 7.28 (m, 5 H, PhH), 5.11 [t, 1 H,
J = 10.4 Hz, ArCH(OH)], 4.59–4.54 (m, 1 H, PhCH2CH), 4.43–
4.39 [m, 1 H, CH(Me)C(OH)HCH(Me)], 4.11–4.10 (m, 2 H,
CH2CHCH2Ph), 4.00 [t, 1 H, J = 7.2 Hz, COC(Me)H], 3.86 (s, 3 H,
ArOMe), 3.70 (s, 3 H, ArOMe), 3.66 (s, 3 H, ArOMe), 3.58 (br s, 1
H, OH), 3.18 (dd, 1 H, J = 3.28, 13.3 Hz, CHCH2Ph), 2.48 (dd, 1 H,
J = 9.5, 13.3 Hz, CHCH2Ph), 2.58 (d, 1 H, J = 5.3 Hz, OH), 2.16 (s,
3 H, ArMe), 1.35 (d, 3 H, J = 6.8 Hz, COMeCO), 0.70 (d, 3 H,
J = 7.0 Hz, COMeCHOH).
13C NMR (100 MHz, CDCl3): = 175.4, 151.8, 150.7, 150.2, 147.5,
134.0, 132.3, 128.5, 128.0, 126.4, 125.3, 101.7, 71.1, 68.6, 59.9,
59.2, 58.9, 53.9, 43.5, 40.4, 36.6, 13.6, 9.7, 9.0.
MS (EI, 70 eV): 402 (52) [M – BnCHNHCOOCH2 + H]+, 289 (52)
[ArCHOH]+, 92 (100) [Bn]+.
Synthesis 2002, No. 18, 2766–2770 ISSN 0039-7881 © Thieme Stuttgart · New York

2770
M. M. B. Marques et al.
PAPER
Compound 3
MS (EI, 70 eV): m/z = 429 (100) [M + 1]+, 428 (21) [M]+, 273 (67),
Yield: 125 mg (60%); colourless crystals; mp 124–125 °C; Rf 0.43
(SiO2; hexane–EtOAc, 7:1).
IR (neat): 2962, 2933, 2850, 1456, 1429, 1400, 1375 cm–1.
250 (25), 222 (26).
HRMS (110 °C, 70 eV): m/z calcd for C20H28O579Br: 428.1188;
found: 428.1202.
1H NMR (400 MHz, CDCl3): = 7.68–7.66 (m, 6 H, ArH), 7.44–
7.35 (m, 9 H, ArH), 5.97–5.87 (m, 1 H, CH=CH2), 5.07–4.98 (m, 2
H, CH=CH2), 4.57 (d, 1 H, J = 9.5 Hz, OCHAr), 3.88 (s, 3 H,
ArOMe), 3.86 (s, 3 H, ArOMe), 3.70 (s, 3 H, ArOMe), 3.22–3.07
[m, 2 H, HC(CH2CHCH2) and HCOTPS], 2.71–2.62 (m, 1 H,
CHMeCHAr), 2.47–2.42 (m, 1 H, CH2CH=CH2), 2.31–2.25 (m, 1
H, CH2CH=CH2), 2.22 (s, 3 H, ArMe), 1.87–1.86 [m, 1 H,
Anal. Calcd for C20H29BrNO5: C, 56.95; H, 6.81. Found: C, 56.04;
H, 6.82.
Acknowledgment
Financial support (project P14729-CHE) by the Austrian Science
Fund (FWF) and by Fundação para a Ciência e Tecnologia (SFRH/
PBD/3561/2000) (Lisbon, Portugal) is gratefully acknowledged.
CHMeCH(OTPS)],
0.80
[d,
3
H,
J = 6.3
Hz,
CHMeC(CH2CH=CH2)], 0.60 (d, 3 H, J = 6.3 Hz, CHMeCHAr).
13C NMR (100 MHz, CDCl3): = 153.0, 151.7, 150.3, 136.0, 135.2,
130.9, 130.1, 128.2, 128.1, 126.8, 126.6, 116.6, 115.8, 112.6, 83.2,
79.9, 77.1, 43.1, 41.7,38.0,15.1,14.7,10.5.
References
(1) (a) Funahashi, Y.; Kawamura, N.; Ishimaru, T. Jap. Pat.
08231551 [A2960910], 1996; Chem. Abstr. 1997, 126,
6553. (b) Funahashi, N.; Kawamura, N. Jap. Pat. 08231552
[A2960910], 1996; Chem. Abstr. 1996, 125, 326518.
(c) Su, M. H.; Hosken, M. I.; Hotovec, B. J.; Johnston, T. L.
US Pat. 5728727 [A980317], 1998; Chem. Abstr. 1998, 128,
239489.
(2) (a) Bode, H. B.; Zeeck, A. J. Chem. Soc., Perkin Trans. 1
2000, 323. (b) Bode, H. B.; Zeeck, A. J. Chem. Soc., Perkin
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(3) Martin, H. J.; Drescher, M.; Kählig, H.; Schneider, S.;
Mulzer, J. Angew. Chem. Int. Ed. 2001, 40, 3186.
(4) For a review about how to make C-aryl glycosides, see:
Jaramillo, C.; Knapp, S. Synthesis 1994, 1.
(5) Rieche, A.; Gross, H.; Hoft, E. Chem. Ber. 1960, 93, 88.
(6) Lee, C. S.; Forsyth, C. J. Tetrahedron Lett. 1996, 37, 6449.
(7) Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1.
(8) Evans, D. A.; Ng, H. P.; Clark, J. S.; Rieger, D. L.
Tetrahedron 1992, 48, 2127.
MS (EI, 70 eV): m/z = 686 (17) [M]+, 345 (38) [MeCHCHOTP-
SCHMe]+, 259 (100) [TPS]+, 199 (29).
HRMS (120 °C, 70 eV): m/z calcd for C38H43O5SiBr: 686.2063;
found: 686.2084.
Anal. Calcd for C39H43BrO5: C, 69.74; H, 6.45. Found: C, 69.77; H,
6.45.
Compound 14
Yield: 35.5 mg (27% yield); mp 79–80 °C; Rf 0.19 (SiO2; hexane–
EtOAc, 7:1).
1H NMR (400 MHz, CDCl3): = 6.02–5.99 (m, 1 H, CH=CH2),
5.08–4.99 (m, 2 H, CH=CH2), 4.74 (d, 1 H, J = 10.3 Hz, OCHAr),
3.83 (s, 3 H, ArOMe), 3.81 (s, 3 H, ArMe), 3.75 (s, 3 H, ArOMe),
3.33–3.26 [m, 1 H, CH(CH2CH=CH2)], 3.04–2.97 [m, 1 H,
CH(OH)], 2.64–2.26 (m, 3 H, CHMeCHAr and CH2CH=CH2), 2.23
(s, 3 H, ArMe), 1.06–1.50 [m, 1 H, CHMeCH(OH)], 1.03 [d, 3 H,
J = 6.5 Hz, CHMeC(CH2CH = CH2 )], 0.80 (d, 3 H, J = 6.8 Hz,
CHMeCHAr).
(9) Maruyama, K.; Nagai, N.; Naruta, Y. J. Org. Chem. 1986,
51, 5083.
(10) Carreno, M. C.; Ruano, J. L. G.; Sanz, G.; Toledo, M. A.;
Urbano, A. J. Org. Chem. 1995, 60, 5328.
13C NMR (100 MHz, CDCl3): = 151.4, 150.4, 148.9, 133.9, 130.3,
125.6, 115.4, 114.5, 81.9, 80.1, 78.8, 60.4, 60.0, 59.0, 41.7, 40.4,
36.4, 12.3, 12.1, 9.1.
Synthesis 2002, No. 18, 2766–2770 ISSN 0039-7881 © Thieme Stuttgart · New York