Efficient synthesis of the structural core of tetracyclines by a palladium-catalyzed domino Tsuji-Trost-Heck-Mizoroki reaction

Article abstract of DOI:10.1002/chem.200701676

The Pd-catalyzed domino Tsuji-Trost-Heck-Mizoroki reactions of compounds 18, 27, and 34, respectively, each containing an allyl acetate and a halogen aryl moiety, lead to the formation of hexahydronaphthacenes 2 and 3 and octahy-droanthracene 4 in 62-81 % yield. The octahydroanthracene and hexahydronaphthacene motifs are found in many natural products, for example, the tetracycline antibiotics.

Full text of DOI:10.1002/chem.200701676

FULL PAPER
DOI: 10.1002/chem.200701676
Efficient Synthesis of the Structural Core of Tetracyclines by a Palladium-
Catalyzed Domino Tsuji–Trost–Heck–Mizoroki Reaction
Lutz F. Tietze,* Thomas Redert, Hubertus P. Bell, Sascha Hellkamp, and
Laura M. Levy[a]
Dedicated to Professor Karl Heinz Dçtz on the occasion of his 65th birthday
Abstract: The Pd-catalyzed domino Tsuji–Trost–Heck–Mizoroki reactions of com-
pounds 18, 27, and 34, respectively, each containing an allyl acetate and a halogen
aryl moiety, lead to the formation of hexahydronaphthacenes 2 and 3 and octahy-
droanthracene 4 in 62–81% yield. The octahydroanthracene and hexahydronaph-
thacene motifs are found in many natural products, for example, the tetracycline
antibiotics.
Keywords:
domino reactions
palladium · tetracyclines
antibiotics
·
·
·
metathesis
Introduction
Domino reactions[1–3] represent one of the most efficient and
ecologically favorable methods for the formation of diverse
complex scaffolds of carbon- and heteroatom-containing
non-natural and natural compounds. Nearly all known
chemical transformations can be used in domino processes,
in which the combination of transition-metal-catalyzed reac-
tions is of special interest. In particular, Pd-catalyzed trans-
formations, such as the Heck–Mizoroki reaction,[4–6] the
Tsuji–Trost reaction,[7–9] and the Wacker oxidation[10] have
found wide application in synthesis. We have recently devel-
oped an enantioselective domino Wacker–Heck–Mizoroki
reaction for the synthesis of vitamin E[11] and have used a
combination of a Tsuji–Trost and a Heck–Mizoroki reaction
for the enantioselective preparation of the antileukemic
pentacyclic alkaloid cephalotaxine.[12–15] Herein we describe,
as a newapplication of a domino Tsuji–Trost–Heck–Mizoro-
ki reaction, the synthesis of 2, which presents the structural
core of tetracyclines such as 1. These natural products repre-
sent a very important group of antibiotics.[16] In addition, we
have also prepared hexahydronaphthacene 3 and octahy-
droanthracene 4 by using this method.
Results and Discussion
Domino reactions of two or more Pd-catalyzed reactions re-
quire careful adjustment of the reactivity of the different re-
active functionalities to allowa successive process. We had
already shown that an allyl acetate moiety is more reactive
than an aryl iodide or aryl bromide containing an electron-
donating substituent in the aromatic system.[17] In the syn-
thesis of 2, we, therefore, used compound 18 as the starting
material for the domino process; this compound corre-
sponds to the general compound 6 in the retrosynthesis de-
picted in Scheme 1. Substrate 18, necessary for the prepara-
tion of 2 via 5, can easily be obtained from the b-keto ester
[a] Prof. Dr. L. F. Tietze, Dipl.-Chem. T. Redert, Dr. H. P. Bell,
Dr. S. Hellkamp, Dr. L. M. Levy
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität Gçttingen
Tammannstrasse 2, 37077 Gçttingen (Germany)
Fax : (+49)551-399476
E-mail: ltietze@gwdg.de
Chem. Eur. J. 2008, 14, 2527 – 2535
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2527

hydroxy group, by using [PdCl2(PPh3)2], allyl tributyltin, and
G
triphenylphosphine in DMF again under microwave condi-
tions (1508C, 15 min) to afford 3-allyl-4-hydroxymethyl-2,6-
dimethoxybenzoic acid methyl ester in almost quantitative
yield.[23] Higher temperatures led to readdition and elimina-
tion of the palladium species and resulted in isomerization
of the allylic moiety into a vinylic moiety. To transform the
hydroxy group back into the benzyl bromide group necessa-
ry for the subsequent SN-coupling reaction with b-keto ester
10, an Appel reaction[24] with tetrabromomethane and tri-
phenylphosphine was used to afford 3-allyl-4-bromomethyl-
benzoate 14 in 91% yield (Scheme 3).
The SN coupling between b-keto ester 10 and benzyl bro-
mide 14 (Scheme 4) was accomplished in 74% yield by
Scheme 1. Retrosynthetic analysis of hexahydronaphthacene 2.
10 and the benzyl bromide 14. The b-keto ester 10
(Scheme 2) was synthesized from the known 2-iodo-3-me-
thoxybenzaldehyde[18] by an aldol reaction with acetic acid
methyl ester by using LDA in THF at ꢀ788C to give 9 in
98% yield followed by an oxidation of the secondary hy-
droxy group with Dess–Martin periodinane in 87% yield.
For the synthesis of benzyl bromide 14 (Scheme 3), the
known 3-bromo-2,6-dimethoxy-4-methyl benzoic acid
methyl ester[19,20] (11) was treated with NBS and AIBN in
CCl4 to give 12 as the product of the radical bromination in
62% yield.[21] As a benzylic bromide is more reactive than
an aryl bromide in a Stille reaction, which we intended to
use for the introduction of the allyl moiety, we had to trans-
form the benzyl bromide into a benzyl alcohol; this was
done by using CaCO3/H2O under microwave irradiation at
1508C to give 13 in 98% yield within 30 min.[22] The Stille
reaction could nowbe performed without protection of the
Scheme 4. Synthesis of hexahydronaphthacene 2. Mes: mesityl; Cy: cyclo-
hexyl; dppe: 1,2-bis(diphenylphosphino)ethane.
using sodium methoxide in MeOH as a base in the presence
of NaI under microwave irradiation (1308C, 10 min). The
necessary allyl acetate moiety was finally introduced by a
cross-metathesis of 15 and 1,4-diacetoxybutene (17) in the
presence of the second-generation Grubbs catalyst 16
(6.5 mol%; Scheme 4). The desired product, 18, containing
an E-configured allyl acetate moiety was obtained in 61%
yield as the only product. We have also tried to prepare 18
by the reaction of 10 with a benzyl bromide of type 14 al-
ready containing the allyl acetate moiety. However, only de-
composed material was obtained when the conditions de-
scribed for the substitution reaction were used. The final re-
action for the synthesis of tetracene 2 was the domino
Tsuji–Trost–Heck–Mizoroki reaction, which was carried out
in a preheated oil bath at 1108C for 2 h with sodium hy-
Scheme 2. Synthesis of b-keto ester 10. LDA: lithium diisopropylamide;
DMP: Dess–Martin periodinane.
dride, Pd(OAc)2, dppe, and K2CO3 to give the desired hexa-
G
hydronaphthacene 2 in 65% yield as a 1.6:1 mixture of iso-
mers. The microwave-assisted transformation at 1008C for
10 min, employing the same solvent and catalytic system,
led to 2 in only 59% yield, showing that microwave-assisted
reactions are not always superior.
Scheme 3. Synthesis of benzyl bromide 14. NBS: N-bromosuccinimide;
AIBN: 2,2’-azobis(2-methylpropionitrile); All: allyl.
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Chem. Eur. J. 2008, 14, 2527 – 2535

Synthesis of the Tetracycline Structural Core
FULL PAPER
For the synthesis of the hexahydronaphthacene 3, com-
pound 27 was used as the substrate in the domino process to
give the desired product in 62% yield by employing
Pd(OAc)2, triphenylphosphine, tetrabutylammonium chlo-
N
ride, and K2CO3 in DMF for 4 h at 808C (Scheme 5). Com-
pound 27 was prepared by an aldol reaction of 24 with 25
followed by an oxidation, with an overall yield of only 31%.
The lowyield is mainly due to difficulties in the oxidation of
26. We have tried several different reagents and reaction
conditions. However, the only oxidant which gave reasona-
ble yields was TPAP in the presence of NMO.
Scheme 6. Synthesis of octahydroanthracene 4. THP: tetrahydropyranyl.
with acetic acid methyl ester. However, the SN-coupling re-
action of 29 and 31 with sodium hydride in DMF afforded
the undesired O-alkylated product in 57% yield. Luckily,
deprotonation of 31 with sodium methoxide in methanol for
1 h at room temperature followed by addition of heptenyl
bromide 29 and an excess of sodium iodide yielded the de-
sired alkylated b-keto ester 32 in a yield of 62%. The THP-
acetal moiety in 32 was cleaved by using a catalytic amount
of p-toluenesulfonic acid monohydrate to give alcohol 33,
and the necessary allylic acetate 34 was prepared from 33 by
using Ac2O and catalytic amounts of DMAP in dichlorome-
thane, with 75% yield over the two steps. For the domino
Tsuji–Trost–Heck–Mizoroki reaction, 34 was deprotonated
by using sodium hydride in DMF and transformed into the
octahydroanthracene 4 by employing the same reaction con-
ditions as those described for the synthesis of 2. Here, the
use of a microwave reactor gave superior results; thus, 4 was
obtained in 81% yield as a 8.1:1 mixture of diastereomers.
In addition, 10% of the isomerized product, 35, was formed.
Scheme 5. Synthesis of hexahydronaphthacene 3. TIPS: triisopropylsilyl;
DMAP: 4-dimethylaminopyridine; IBX: 2-iodoxybenzoic acid; DMSO:
dimethylsulfoxide; TPAP: tetrapropylammonium perruthenate; NMO: 4-
methylmorpholine N-oxide.
Compound 25 was prepared according to a published pro-
cedure[17] and 24 was obtained by the reaction of known
compound 19[25–29] with vinyl magnesium bromide, protec-
tion of the primary hydroxy group with TIPSCl, and forma-
tion of the allyl acetate by using acetic anhydride to give 22
via 20 and 21. This is followed by cleavage of the TIPS
ether and the oxidation of the formed primary hydroxy
group to afford aldehyde 24 via 23. The overall yield of the
five-step synthesis of 24 from 19 is 49%.
Conclusion
Finally, we also prepared octahydroanthracenes 4 and 35
by the Pd-catalyzed domino process by using the procedure
developed for the synthesis of 2, which is more reliable and
gives better yields than the method used for the preparation
of 3 (Scheme 6). As starting materials we employed the Z-
alkene 29, obtained from the THP-protected bromoheptynyl
alcohol[30,31] 28 by hydrogenation in the presence of P2-
nickel catalyst, and the b-keto ester 31, which is accessible
by a Claisen ester condensation from 2-bromobenzoate 30
The domino Tsuji–Trost–Heck–Mizoroki reaction is a pow-
erful tool for the efficient preparation of substituted octahy-
droanthracenes and hexahydronaphthacenes. Further inves-
tigations will focus on the total synthesis of natural tetracy-
clines.
Chem. Eur. J. 2008, 14, 2527 – 2535
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2529

L. F. Tietze et al.
2H; CH2, ketone), 5.32 (s, 1H; 2-H, enol), 6.88 (dd, J=1.4, 8.0 Hz, 1H;
6’-H, enol), 6.89 (dd, J=1.6, 8.4 Hz, 1H; 6’-H, ketone), 6.96 (dd, J=1.6,
8.4 Hz, 1H; 4’-H, ketone), 6.97 (dd, J=1.4, 8.0 Hz, 1H; 4’-H, enol), 7.31
(t, J=8.0 Hz, 1H; 5’-H, enol), 7.35 (t, J=8.4 Hz, 1H; 5’-H, ketone),
12.3 ppm (s, 1H; OH, enol); 13C NMR (75.5 MHz, CDCl3): d=48.41 (C-
2), 51.55 (COOCH3, enol), 52.48 (COOCH3, ketone), 56.71 (OCH3,
ketone, enol), 83.40 (C-2’, ketone), 92.61 (C-2, enol), 111.8 (C-4’, enol),
112.5 (C-4’, ketone), 120.1 (C-6’, enol), 121.9 (C-6’, ketone), 129.4 (C-5’,
enol), 129.8 (C-5’, ketone), 141.9 (C-1’, enol), 146.1 (C-1’, ketone), 158.3
(C-3’, ketone), 167.0 (C-3’, enol), 172.8 (C-3, enol), 174.6 (C-1, ketone),
197.2 ppm (C-3, ketone); UV (MeOH): lmax (lg e)=203.0 (4.415),
223.0 nm (4.145); IR (KBr): n˜ =2953, 1747, 1654, 1579, 1564, 1464, 1441,
1421, 1389, 1293, 1256, 1212, 1182, 1117, 1095, 1048, 1008, 943, 890, 817,
786, 741, 715, 608, 421 cmꢀ1; MS (EI, 70 eV): m/z (%): 334 (14) [M]+,
261 (48) [MꢀCH2CO2CH3]+, 207 (100) [MꢀI]+; HRMS: calcd for
[M+H+], [M+NH4+], and [M+Na+]: 334.97748, 352.00403, 356.95942;
found: 334.97748, 352.00395, 356.95930.
Experimental Section
General: Reactions were carried out under argon in flame-dried glass-
ware. All solvents were dried according to standard laboratory methods.
If indicated, solvents were degassed by argon being bubbled through the
solvent for an appropriate period of time. All reagents obtained from
commercial sources were used without further purification. Reactions
under microwave irradiation were carried out in a SmithCreator micro-
wave reactor from Personal Chemistry. Thin-layer chromatography
(TLC) was performed on precoated (0.25 mm) silica gel SIL G/UV254
plates from Machery–Nagel. UV/Vis spectra were recorded with
a
Perkin–Elmer Lambda 2 instrument. IR spectra were recorded with sam-
ples in KBr pellets or as films between NaCl plates by using a Bruker
Vector 22 instrument. 1H and 13C NMR spectra were recorded with
Varian Mercury 200, Mercury 300, Unity-300, Unity Inova-500, and Unity
Inova-600 spectrometers with TMS or the indicated solvent as an internal
standard. For NMR spectra of compounds exhibiting a keto–enol equilib-
rium, the assignment of the resonances to the keto or enol form of the
compounds is based on the different integration of the peaks in the
3-Bromo-4-bromomethyl-2,6-dimethoxybenzoic acid methyl ester (12): A
catalytic amount of a,a’-bisazoisobutyronitrile was added several times
to a stirred solution of 11 (8.14 g, 28.2 mmol, 1.00 equiv) and NBS
(5.01 g, 28.2 mmol, 1.00 equiv) in CCl4 (560 mL), and the reaction mix-
ture was heated under reflux conditions for 18 h. The mixture was fil-
tered, and the solvent was removed under reduced pressure to give 12 as
a light-yellowsolid in 62% yield after flash chromatography (EtOAc/pe-
troleum ether 1:99!5:95!10:90). Rf =0.58 (petroleum ether/EtOAc
7:3); 1H NMR (300 MHz, CDCl3): d=3.85 (s, 3H; 6-OCH3), 3.89 (s, 3H;
COOCH3), 3.92 (s, 3H; 2-OCH3), 4.59 (s, 2H; CH2), 6.83 ppm (s, 1H; 5-
H); 13C NMR (75.5 MHz, CDCl3): d=33.23 (CH2), 52.75 (COOCH3),
56.28 (6-OCH3), 62.29 (2-OCH3), 109.4 (C-5), 110.6 (C-4), 119.8 (C-3),
140.1 (C-6), 155.2 (C-2), 156.1 (C-1), 165.4 ppm (COOCH3); UV
(MeOH): lmax (lg e)=210.5 (4.462), 298.0 nm (3.362); IR (KBr): 2945,
2852, 1733, 1597, 1563, 1466, 1447, 1435, 1390, 1331, 1278, 1214, 1105,
1039, 976, 950, 921, 882, 852, 834, 779, 694, 663, 617, 579, 556 cmꢀ1; MS
(EI, 70 eV): m/z (%): 370 (6) [M]+, 368 (16) [M]+, 366 (6) [M]+, 290
(58) [MꢀBr+H]+, 289 (32) [MꢀBr]+, 288 (59) [MꢀBr+H]+, 287 (25)
[MꢀBr]+, 259 (98) [MꢀBrꢀ2Me]+, 257 (100) [MꢀBrꢀ2Me]+, 244 (22)
[MꢀBrꢀ3Me]+, 242 (22) [MꢀBrꢀ3Me]+; HRMS: calcd for [M]+:
365.9102; found: 365.9111.
1H NMR spectra. MS were recorded by using
TSQ 7000, LCQ instrument. HRMS were recorded with
a
Finnigan MAT 95,
Bruker
a
APEX IV spectrometer equipped with a Bruker Apollo source and a
Cole–Parmer syringe pump (74900 series). Melting points (m.p.) were de-
termined with a Mettler FP61 instrument and are uncorrected.
3-Hydroxy-3-(2-iodo-3-methoxyphenyl)propionic acid methyl ester (9):
nBuLi (40.4 mL, 101 mmol, 1.50 equiv) was added dropwise to a stirred
solution of diisopropyl amine (14.3 mL, 10.2 g, 101 mmol, 1.50 equiv) in
dry THF at ꢀ788C, and the mixture was stirred at room temperature for
a further 30 min. The mixture was then recooled to ꢀ788C and a solution
of acetic acid methyl ester (8.04 mL, 7.48 g, 101 mmol, 1.50 equiv) in dry
THF (20.0 mL) was added dropwise. After the mixture had been stirred
for 30 min,
a
solution of 2-iodo-3-methoxybenzaldehyde[18] (17.6 g,
67.3 mmol, 1.00 equiv) in dry THF (30.0 mL) was added, and the stirring
was continued for 1 h at ꢀ788C. After addition of saturated aq. NH4Cl
(50 mL), the reaction mixture was warmed to room temperature, diluted
with Et2O (200 mL), and washed with water (2”300 mL). The aqueous
phase was extracted with Et2O (4”200 mL), the combined organic ex-
tracts were washed with brine (500 mL), dried over Na2SO4, and the sol-
vent was removed under reduced pressure to give 9 as a white solid in
98% yield. Rf =0.23 (petroleum ether/EtOAc 8:2); 1H NMR (200 MHz,
CDCl3): d=2.53 (dd, J=9.9, 16.6 Hz, 1H; 2-HA), 2.89 (dd, J=2.6,
16.6 Hz, 1H; 2-HB), 3.43 (d, J=3.2 Hz, 1H; OH), 3.76 (s, 3H;
COOCH3), 3.90 (s, 3H; OCH3), 5.42 (dt, J=2.6, 9.9 Hz, 1H; CHOH),
6.77 (dd, J=1.4, 7.8 Hz, 1H; 4’-H), 7.21 (dd, J=1.4, 7.8 Hz, 1H; 6’-H),
7.34 ppm (t, J=7.8 Hz, 1H; 5’-H); 13C NMR (50.3 MHz, CDCl3): d=
41.33 (C-2), 52.00 (COOCH3), 56.55 ((C-3’)OCH3), 73.94 (C-3), 89.35 (C-
2’), 110.1 (C-4’), 119.3 (C-6’), 129.6 (C-5’), 146.2 (C-1’), 157.6 (C-3’),
172.8 ppm (C-1); UV (MeOH): lmax (lg e)=205.0 (4.544), 278.0 (3.441),
285.0 nm (3.442); IR (KBr): n˜ =3467, 2978, 2948, 2842, 1944, 1716, 1586,
1566, 1464, 1443, 1429, 1417, 1364, 1330, 1280, 1245, 1223, 1172, 1080,
3-Bromo-4-hydroxymethyl-2,6-dimethoxybenzoic acid methyl ester (13):
A microwave tube was charged with 12 (368 mg, 1.00 mmol, 1.00 equiv),
calcium carbonate (300 mg, 3.00 mmol, 3.00 equiv), and a 1,4-dioxane/
water mixture (1:1 v/v, 5 mL), then the tube was sealed and heated in the
microwave reactor for 30 min at 1508C. The reaction mixture was diluted
with water (50 mL) and the aqueous phase was extracted with CH2Cl2
(3”50 mL). The combined organic extracts were dried over Na2SO4 and
the solvent was removed under reduced pressure to give 13 as a white
solid in 98% yield after flash chromatography (EtOAc/petroleum ether
1:99!3:7). Rf =0.25 (petroleum ether/EtOAc 7:3); 1H NMR (200 MHz,
CDCl3): d=2.45 (t, J=6.3 Hz, 1H; OH), 3.82 (s, 3H; 6-OCH3), 3.87 (s,
3H; COOCH3), 3.92 (s, 3H; 2-OCH3), 4.71 (d, J=6.3 Hz, 2H; CH2OH),
6.91 ppm (s, 1H; 5-H); 13C NMR (50.3 MHz, CDCl3): d=52.69
(C(O)OCH3), 56.19 (6-OCH3), 62.21 (2-OCH3), 64.75 (CH2OH), 106.4
(C-5), 107.1 (C-3), 118.1 (C-1), 143.7 (C-4), 154.4 (C-6), 165.4 (C-2),
166.0 ppm (C(O)O); UV (MeOH): lmax (lg e)=202.5 (4.486), 204.5
(4.521), 286.0 nm (3.296); IR (KBr): n˜ =3462, 3098, 2952, 2850, 1717,
1594, 1563, 1453, 1428, 1395, 1353, 1322, 1269, 1200, 1177, 1112, 1084,
1024, 982, 973, 942, 911, 845, 795, 757, 692, 676, 624, 592, 481 cmꢀ1; MS
(ESI): m/z (%): 635 (20) [2M+Na]+, 633 (46) [2M+Na]+, 631 (22)
[2M+Na]+, 329 (64) [M+Na]+, 327 (67) [M+Na]+.
1055, 1013, 984, 924, 891, 877, 786, 725, 712, 649, 598, 558, 518, 469 cmꢀ1
;
MS (EI, 70 eV): m/z (%): 336 (32) [M]+, 263 (42) [MꢀCH2CO2CH3]+,
209 (100) [MꢀI]+, 136 (29) [MꢀCH2CO2CH3ꢀI]+, 135 (49)
[MꢀCH2CO2CH3ꢀIꢀH]+, 108 (32) [PhOCH3]+.
3-(2-Iodo-3-methoxyphenyl)-3-oxopropionic acid methyl ester (10):
Dess–Martin periodinane (3.28 g, 7.74 mmol, 1.30 equiv) was added to a
stirred solution of 9 (2.00 g, 5.95 mmol, 1.00 equiv) in CH2Cl2 (30.0 mL)
at room temperature, and the mixture was stirred for a further 2.5 h. Sa-
turated aq. NaHCO3 (5 mL) and saturated aq. Na2S2O3 (5 mL) were
added simultaneously, and the mixture was stirred for an additional hour.
The organic phase was washed with 1n NaOH (50 mL); the aqueous
phase was acidified with 2n HCl and extracted with Et2O (5”50 mL).
The combined organic extracts were washed with brine, dried over
MgSO4, and concentrated under reduced pressure to give 10 as a white
solid in 87% yield after flash chromatography (EtOAc/pentane 1:99!
5:95). Rf =0.45 (petroleum ether/EtOAc 7:3); 1H NMR (300 MHz,
CDCl3): d=3.75 (s, 3H; COOCH3, ketone), 3.82 (s, 3H; COOCH3,
enol), 3.91 (s, 3H; 3-OCH3, enol), 3.92 (s, 3H; 3-OCH3, ketone), 4.00 (s,
3-Allyl-4-bromomethyl-2,6-dimethoxybenzoic acid methyl ester (14):
3-Allyl-4-hydroxymethyl-2,6-dimethoxybenzoic acid methyl ester: In a mi-
crowave tube, 13 (420 mg, 1.14 mmol, 1.00 equiv), [PdCl2(PPh3)2] (42 mg,
A
60 mmol, 5.0 mol%), and triphenylphosphine (29 mg, 0.11 mmol,
10 mol%) were dissolved in degassed DMF (5.0 mL) under an argon at-
mosphere. Allyl tributyltin (387 mL, 414 mg, 1.25 mmol, 1.10 equiv) was
added and the reaction mixture was heated to 1608C for 10 min in the
microwave reactor. The reaction mixture was cooled and diluted with
water (20 mL). The aqueous phase was extracted with Et2O (5”20 mL),
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Chem. Eur. J. 2008, 14, 2527 – 2535

Synthesis of the Tetracycline Structural Core
FULL PAPER
the combined organic fractions were dried over Na2SO4, and the solvent
was removed under reduced pressure to give the title compound as a col-
orless oil in quantitative yield after flash chromatography (EtOAc/pen-
tane 3:7!2:3). Rf =0.26 (pentane/EtOAc 1:1); 1H NMR (200 MHz,
CDCl3): d=2.10 (t, J=6.0 Hz, 1H; OH), 3.38 (dt, J=1.7, 5.4 Hz, 2H;
CH2CH=CH2), 3.76 (s, 3H; 2-OCH3), 3.82 (s, 3H; 6-OCH3), 3.92 (s, 3H;
COOCH3), 4.65 (d, J=6.0 Hz, 2H; CH2OH), 4.88 (dd, J=1.7, 18.2 Hz,
1H; CH=CHHtrans), 5.02 (dd, J=1.7, 10.3 Hz, 1H; CH=CHHcis), 5.86–
6.05 (ddt, J=5.4, 10.3, 18.2 Hz, 1H; CH2CH=CH2), 6.88 ppm (s, 1H; 5-
H); 13C NMR (50.3 MHz, CDCl3): d=29.08 (CH2CH=CH2), 52.47
(COOCH3), 55.96 (6-OCH3), 62.42 (CH2OH), 62.76 (2-OCH3), 106.0 (C-
5), 115.2 (CH2CH=CH2), 116.9 (C-1), 122.1 (C-3), 137.0 (CH2CH=CH2),
143.4 (C-4), 155.7 (C-6), 156.2 (C-2), 167.1 ppm (COOCH3).
12.92 ppm (s, 1H; OH, enol); 13C NMR (75.5 MHz, CDCl3): d=29.11
((C-1’’)-CH2, enol), 29.34 (CH2CH=CH2, enol), 29.64 (CH2CH=CH2,
ketone), 31.26 ((C-1’’)-CH2, ketone), 52.03 ((C-4’’)-OCH3, enol), 52.50
((C-4’’)-OCH3, ketone), 52.47 ((C-1)-OCH3, enol), 52.61 ((C-1)-OCH3,
ketone), 55.99 ((C-5’’)-OCH3, ketone), 56.20 ((C-5’’)-OCH3, enol), 56.60
((C-3’’)-OCH3, enol), 56.68 ((C-3’’)-OCH3, ketone), 58.84 (C-2, ketone),
62.67 ((C-3’)-OCH3, ketone), 62.76 ((C-3’)-OCH3, enol), 83.96 (C-2’,
ketone), 88.10 (C-2’, enol), 99.70 (C-2, enol), 106.1 (C-6’’, enol), 108.8 (C-
6’’, ketone), 111.2 (C-4’, enol), 112.4 (C-4’, ketone), 114.7 (CH=CH2,
enol), 115.3 (CH=CH2, ketone), 115.6 (C-4’’, enol), 116.6 (C4’’, ketone),
119.9 (C-6’, ketone), 121.1 (C-6’, enol), 122.8 (C-2’’, enol), 123.6 (C-2’’,
ketone), 129.6 (C-5’), 135.9 (CH=CH2, enol), 136.8 (CH=CH2, ketone),
140.9 (C-1’’, ketone), 140.9 (C-1’’, enol), 141.3 (C-1’, enol), 146.0 (C-1’,
ketone), 155.2 (C-3’, enol), 155.3 (C-5’’, ketone), 156.0 (C-5’’, enol), 156.4
(C-3’’, ketone), 158.4 (C-3’’, enol), 158.5 (C-3’, ketone), 167.1 (C-1, enol),
168.8 (COOCH3, ketone), 171.3 (C-3, enol), 173.1 (COOCH3, enol),
173.7 (C-1, ketone), 198.4 ppm (C-3, ketone); UV (MeOH): lmax (lg e)=
202.0 (4.733), 204.0 nm (4.730); IR (MeOH): n˜ =2950, 1733, 1650, 1604,
1577, 1464, 1435, 1420, 1404, 1352, 1268, 1203, 1149, 1107, 1002, 916, 850,
3-Allyl-4-bromomethyl-2,6-dimethoxybenzoic acid methyl ester (14): A so-
lution of triphenylphosphine (2.03 g, 7.73 mmol, 1.25 equiv) in CH2Cl2
(16.0 mL) was added to a solution of 3-allyl-4-hydroxymethyl-2,6-dime-
thoxybenzoic acid methyl ester (1.65 g, 6.18 mmol, 1.00 equiv) and tetra-
bromomethane (2.56 g, 7.73 mmol, 1.25 equiv) in CH2Cl2 (27.0 mL) at
08C. The reaction mixture was allowed to warm to room temperature
and was stirred for 1.5 h. The solvent was removed under reduced pres-
sure, the residue was taken up in Et2O (50 mL), the solution was filtered,
and the solids were washed in portions with Et2O (150 mL). The com-
bined organic filtrates were concentrated under reduced pressure to give
14 as a colorless oil in 91% yield after flash chromatography (EtOAc/pe-
troleum ether 1:9). Rf =0.66 (pentane/EtOAc 4:1); 1H NMR (200 MHz,
CDCl3): d=3.51 (dt, J=1.7, 5.4 Hz, 2H; CH2CH=CH2), 3.77 (s, 3H; 6-
OCH3), 3.82 (s, 3H; 2-OCH3), 3.92 (s, 3H; COOCH3), 4.45 (s, 2H;
CH2Br), 4.89 (dd, J=1.6, 17.2 Hz, 1H; CH=CHHtrans), 5.04 (dd, J=1.6,
10.1 Hz, 1H; CH=CHHcis), 5.91–6.10 (ddt, J=5.4, 10.1, 17.2 Hz, 1H;
CH=CH2), 6.72 ppm (s, 1H; 5-H); 13C NMR (50.3 MHz, CDCl3): d=
29.29 ((C-3)CH2), 30.91 (CH2Br), 52.51 (COOCH3), 56.04 (6-OCH3),
62.78 (2-OCH3), 109.8 (C-5), 115.4 (CH=CH2), 118.5 (C-1), 124.3 (C-3),
136.6 (CH=CH2), 139.8 (C-4), 155.6 (C-6), 156.7 (C-2), 166.6 ppm
(COOCH3); UV (MeOH): lmax (lg e)=212.0 (4.503), 244.5 (3.876),
296.5 nm (3.490); IR (neat): n˜ =2948, 1733, 1637, 1604, 1575, 1484, 1462,
1433, 1404, 1327, 1273, 1195, 1157, 1103, 1011, 919, 845, 804 cmꢀ1; MS
(EI, 70 eV): m/z (%): 330 (97) [M]+, 328 (100) [M]+, 299 (25)
[MꢀOCH3]+, 297 (25) [MꢀOCH3]+, 249 (74) [MꢀBr]+, 217 (65)
788, 732 cmꢀ1
;
MS (ESI): m/z (%): 582 (14) [M+H]+, 541 (10)
[MꢀCH2CH=CH2+H]+,
261
(31)
[C8H6IO2+H]+,
248
(100)
[C14H17O4ꢀH]+, 217 (14) [C13H13O3]+, 135 (16) [C8H6O2+H]+; HRMS:
calcd for [M+H]+: 583.082; found: 583.082.
3-(4-Acetoxybut-2-enyl)-4-[3-(2-iodo-3-methoxyphenyl)-2-methoxycar-
bonyl-3-oxopropyl)-2,6-dimethoxybenzoic acid methyl ester (18):
A
round-bottomed flask was charged with second-generation Grubbs cata-
lyst 16 (11 mg, 13 mmol, 6.5 mol%), a solution of 15 (117 mg, 201 mmol,
1.00 equiv) in dry CH2Cl2 (2.5 mL), and (Z)-acetic acid 4-acetoxy-but-2-
enyl ester (17) (116 mg, 673 mmol, 3.35 equiv). The flask was sealed and
heated to 508C for 25 h. The reaction mixture was cooled to room tem-
perature and then concentrated under reduced pressure to give 16 as a
gray oil in 61% yield after flash chromatography (EtOAc/petroleum
ether 3:7). Rf =0.08–0.22 (pentane/EtOAc 7:3). 1H NMR (500 MHz,
CDCl3): d=1.99 (s, 3H; CH3, ketone), 2.01 (s, 3H; CH3, enol), 3.22 (d,
J=5.4 Hz, 2H; CH2CH=CH2, enol), 3.29 (dd, J=6.4, 8.6 Hz, 2H; (C-1’’)-
CH2, ketone), 3.62, 3.69, 3.73, 3.75, 3.80, 3.89, 3.91 (7”s, 10”3H; 2”
COOCH3, ketone, 3”OCH3, ketone, 2”COOCH3, enol, 3”OCH3, enol),
4.32 (d, J=6.4 Hz, 2H; OCH2CH=CH2, enol), 4.43 (d, J=6.7 Hz, 1H; 2-
H, ketone), 4.45 (d, J=6.0 Hz, 2H; OCH2CH=CH2, ketone), 5.21 (dt, J=
6.4, 15.3 Hz, 1H; OCH2CH=CH, enol), 5.33 (dt, J=6.0, 15.6 Hz, 1H;
OCH2CH=CH, ketone), 5.67 (dt, J=5.1, 15.3 Hz, 1H; OCH2CH=CH,
enol), 5.84 (dt, J=5.1, 15.6 Hz, 1H; OCH2CH=CH, ketone), 6.52 (s, 1H;
6’’-H, enol), 6.60 (s, 1H; 6’’-H, ketone), 6.74 (d, J=7.6 Hz, 1H; 4’-H,
enol), 6.75 (d, J=7.6 Hz, 1H; 4’-H, ketone), 6.80 (d, J=8.3 Hz, 1H; 6’-H,
enol), 6.88 (d, J=8.3 Hz, 1H; 6’-H, ketone), 7.24 (t, J=7.6 Hz, 1H; 5’-H,
enol), 7.33 (t, J=7.6 Hz, 1H; 5’-H, ketone), 12.92 ppm (s, 1H; OH,
enol); 13C NMR (75.5 MHz, CDCl3): d=20.90 (CH3, ketone), 20.93 (CH3,
enol), 27.77 (ArCH2CH=CHCH2, enol), 28.31 (ArCH2CH=CHCH2,
ketone), 29.52 (ArCH2, enol), 31.25 (ArCH2, ketone), 52.06, 52.48, 52.50,
52.60 (4”COOCH3), 55.98 ((C-5’’)-OCH3, ketone), 56.18 ((C-5’’)-OCH3,
enol), 56.54 ((C-3’)-OCH3, enol), 56.65 ((C-3’)-OCH3, ketone), 58.76 (C-
2, ketone), 62.54 ((C-3’’)-OCH3, enol), 62.65 ((C-3’’)-OCH3, ketone),
64.64 (OCH2CH=CH, enol), 64.70 (OCH2CH=CH, ketone), 83.89 (C-2’,
ketone), 87.99 (C-2’, enol), 99.52 (C-2, enol), 106.1 (C-6’’, enol), 108.8 (C-
6’’, ketone), 111.2 (C-6’, enol), 112.4 (C-6’, ketone), 115.6 (C-2’’, enol),
116.6 (C-2’’, ketone), 119.9 (C-4’, ketone), 121.9 (C-4’, enol), 122.6 (C-4’’,
enol), 123.4 (C-4’’, ketone), 124.2 (OCH2CH=CH, enol), 124.7
(OCH2CH=CH, ketone), 129.5 (C-5’, enol), 129.6 (C-5’, ketone), 133.2
(ArCH2CH=CH, enol), 133.9 (ArCH2CH=CH, ketone), 140.7 (C-1’’,
ketone), 141.2 (C-1’’, enol), 143.2 (C-1’, ketone), 146.0 (C-1’, enol), 155.4,
155.4, 155.9, 156.5, 158.4, 158.4 (C-3’, C-3’’, C-5’’, keto, enol), 167.0
(CH3C(O), ketone), 167.2 (CH3C(O), enol), 168.7 ((C-1)-COOCH3,
ketone), 171.0 (C-3, enol), 170.7 ((C-1)-COOCH3, enol), 173.3 ((C-4’’)-
COOCH3, ketone), 173.6 ((C-4’’)-COOCH3, enol), 198.4 ppm (C-3,
ketone); UV (MeOH): lmax (lg e)=204.0 (4.730), 279.0 nm (3.882); IR
(neat): n˜ =3425, 2950, 1735, 1651, 1604, 1577, 1464, 1437, 1421, 1406,
1362, 1267, 1201, 1149, 1106, 1023, 966, 789, 736, 702, 605 cmꢀ1; MS
(ESI): m/z (%): 677 (52) [M+Na]+, 653 (100) [MꢀH]ꢀ; HRMS: calcd for
[C13H13O3]+,
203
(43)
[MꢀBrꢀOCH3ꢀCH3]+,
190
(32)
[MꢀBrꢀCO2Me]+, 189 (22) [MꢀBrꢀCO2CH3ꢀH]+; HRMS: calcd for
[M+H+]: 329.03885; found: 329.03837.
3-Allyl-4-[3-(2-iodo-3-methoxyphenyl)-2-methoxycarbonyl-3-oxopropyl]-
2,6-dimethoxybenzoic acid methyl ester (15): A solution of 10 (250 mg,
748 mmol, 1.00 equiv) in dry MeOH (0.8 mL) was added dropwise to a
stirred solution of NaOMe (30% solution in MeOH, 148 mg, 823 mmol,
1.10 equiv) in dry MeOH (0.8 mL) at room temperature, and stirring of
the mixture was continued for 1 h. After addition of NaI (123 mg,
823 mmol, 1.10 equiv) to the mixture, a solution of 14 (271 mg, 823 mmol,
1.10 equiv) in dry MeOH (0.8 mL) was added dropwise, and the resulting
solution was heated in the microwave reactor at 1308C for 10 min. The
cooled reaction mixture was diluted with water (6.0 mL) and the aqueous
phase was extracted with CH2Cl2 (5”6.0 mL). The combined organic ex-
tracts were washed with brine, dried over Na2SO4, and concentrated
under reduced pressure to give 15 as an orange oil in 74% yield after
flash chromatography (EtOAc/pentane 2:8). Rf =0.22–0.36 (pentane/
EtOAc 7:3); 1H NMR (300 MHz, CDCl3): d=3.22 (dd, J=0.8, 5.3 Hz,
2H; CH2CH=CH2, enol), 3.31 (dd, J=6.3, 8.4 Hz, 2H; C1’’-CH2, ketone),
3.39 (m, 2H; CH2CH=CH2, ketone), 3.63, 3.70, 3.73, 3.75, 3.76, 3.81, 3.89,
3.91 (8”s, 10”3H; 2”COOCH3, ketone, 3”OCH3, ketone, 2”
COOCH3, enol, 3”OCH3, enol), 4.46 (dd, J=6.3, 8.4 Hz, 1H, 2-H;
ketone), 4.61 (dd, J=1.9, 17.1 Hz, 1H; CH=CHHtrans, enol), 4.77 (dd, J=
1.9, 10.3 Hz, 1H; CH=CHHcis, enol), 4.82 (dd, J=1.9, 17.1 Hz, 1H; CH=
CHHtrans, ketone), 5.00 (dd, J=1.9, 10.1 Hz, 1H; CH=CHHcis, ketone),
5.68–5.81 (ddt, J=5.3, 10.0, 17.1 Hz, 1H; CH=CH2, enol), 5.85–5.98 (ddt,
J=5.7, 9.9, 17.1 Hz, 1H; CH=CH2, ketone), 6.52 (s, 1H, 6’’-H, enol), 6.61
(s, 1H; 6’’-H, ketone), 6.74 (dd, J=1.3, 7.4 Hz, 1H; 6’-H, enol), 6.75 (dd,
J=1.3, 7.6 Hz, 1H; 6’-H, ketone), 6.79 (dd, J=1.5, 8.4 Hz, 1H; 4’-H,
enol), 6.89 (dd, J=1.2, 8.4 Hz, 1H; 4’-H, ketone), 7.24 (dd, J=7.6,
8.4 Hz, 1H; 5’-H, enol), 7.33 (dd, J=7.8, 8.4 Hz, 1H; 5’-H, ketone),
Chem. Eur. J. 2008, 14, 2527 – 2535
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2531

L. F. Tietze et al.
[M+NH4]+ and [M+Na]+: 672.13002, 677.08541; found: 672.13002,
677.08541.
dry THF (40 mL) at ꢀ788C. Stirring of the mixture was continued for
2 h, then the reaction mixture was warmed to room temperature. The
mixture was washed with saturated aq. NH4Cl (50 mL) and 2m HCl
(50 mL), then the aqueous phase was extracted with Et2O (5”60 mL).
The combined organic extracts were washed with brine and dried over
Na2SO4, and the solvent was removed under reduced pressure to give 20
as a colorless oil in 84% yield after flash chromatography (EtOAc/pen-
tane 1:2). Rf =0.13 (pentane/EtOAc 3:1); 1H NMR (200 MHz, CDCl3):
d=2.91 (d, J=6.4 Hz, 2H; 1-H2), 3.27 (s, 2H; 2”OH), 4.33 (ddd, J=
6.4 Hz, 1H; 2-H), 4.51 (d, J=12.0 Hz, 1H; CH2OH), 4.75 (d, J=12.0 Hz,
1H; CH2OH), 5.17 (d, J=10.4 Hz, 1H; 4-Hcis), 5.30 (d, J=17.2 Hz, 1H;
4-Htrans), 5.99 (ddd, J=6.4, 10.4, 17.2 Hz, 1H; 3-H), 7.18–7.38 ppm (m,
4H; Ar-H); 13C NMR (50.3 MHz, CDCl3): d=39.7 (C-1), 63.0 (CH2OH),
73.7 (C-2), 114.8 (C-4), 126.8, 128.3, 130.0, 130.5 (C-3’, C-4’, C-5’, C-6’),
137.1, 139.3 (C-1’, C-2’), 140.5 ppm (C-3); IR (neat): n˜ =3315, 2920, 2876,
1452, 1425, 1002, 750 cmꢀ1; MS (200 eV, DCI): m/z (%): 196 (100)
[M+NH4]+, 374 (12) [2M+NH4]+.
1,3,10-Trimethoxy-11-methylene-6-oxo-(5,5a,6,11,11a,12-hexahydronaph-
thacene)-2,5a-dicarboxylic acid dimethyl ester (2):
Conventional heating: NaH (60% in mineral oil, 7 mg, 0.16 mmol,
1.1 equiv) was added in one portion to
a solution of 18 (95 mg,
0.14 mmol, 1.0 equiv) in degassed DMF (0.9 mL) at 08C, and the mixture
was warmed to room temperature and stirred for 20 min (solution A). In
a separate flask, a solution of Pd(OAc)2 (7 mg, 14 mmol, 0.10 equiv) and
T
dppe (12 mg, 29 mmol, 0.20 equiv) in degassed DMF (0.58 mL) was
stirred for 30 min at room temperature (solution B). Solution A was
added dropwise through a syringe to solution B, and the combined mix-
ture was stirred for 10 min at room temperature. KOAc (28 mg,
0.29 mmol, 2.00 equiv) was then added, and the reaction mixture was
stirred for 2 h in a preheated oil bath at 1108C. The reaction mixture was
cooled to room temperature and concentrated to give 2 as a yellowoil in
65% yield after flash chromatography (EtOAc/petroleum ether 2:8).
1-(2-Triisopropylsilanyloxymethylphenyl)-but-3-en-2-ol
(21): TIPSCl
Microwave heating: NaH (60% in mineral oil, 10 mg, 0.26 mmol,
(1.21 mL, 1.10 g, 5.72 mmol, 1.20 equiv) was added dropwise to a stirred
solution of 20 (0.850 g, 4.77 mmol, 1.00 equiv) and imidazole (0.820 g,
11.9 mmol, 2.50 equiv) in DMF (27 mL) at ꢀ108C. The solution was
stirred for 3 h at ꢀ108C and then allowed to warm to room temperature.
The reaction mixture was diluted with water (100 mL) and extracted with
CH2Cl2 (3”50 mL). The combined organic extracts were washed with
brine and dried over Na2SO4. After removal of the volatiles and flash
chromatography (EtOAc/pentane 1:9), 21 was obtained as a colorless oil
in 98% yield. Rf =0.30 (pentane/EtOAc 10:1); 1H NMR (200 MHz,
1.1 equiv) was added in one portion to
0.232 mmol, 1.00 equiv) in degassed DMF (0.93 mL) at 08C, and the mix-
ture was warmed to room temperature and stirred for 20 min (solu-
tion A). In a separate flask, a solution of Pd(OAc)2 (11 mg, 23 mmol,
0.10 equiv) and dppe (19 mg, 47 mmol, 0.20 equiv) in degassed DMF
(0.58 mL) was stirred for 30 min at room temperature (solution B). Solu-
tion A was added dropwise through a syringe to solution B, and the com-
bined mixture was stirred for 10 min at room temperature. KOAc (46 mg,
0.47 mmol, 2.00 equiv) was added, and the reaction mixture was stirred in
the microwave reactor for 10 min at 1008C. The reaction mixture was
cooled to room temperature and concentrated to give 2 as a yellowoil in
59% yield after flash chromatography (EtOAc/petroleum ether 2:8).
a solution of 18 (152 mg,
A
CDCl3): d=1.05–1.25 (m, 21H; Si(iPr)3), 2.71–2.99 (m, 3H; 1-H2, OH),
A
4.35 (m, 1H; 2-H), 4.78 (d, J=12.3 Hz, 1H; CH2OTIPS), 4.91 (d, J=
12.3 Hz, 1H; CH2OTIPS), 5.13 (d, J=10.4 Hz, 1H; 4-Hcis), 5.29 (d, J=
17.2 Hz, 1H; 4-Htrans), 5.97 (ddd, J=17.0, 10.3, 5.6 Hz, 1H; 3-H), 7.18–
7.38 ppm (m, 4H; Ar-H); 13C NMR (50.3 MHz, CDCl3): d=11.9 (3”
Compound 2: As the assignment of the NMR peaks to the cis and trans
isomers is not possible, the isomers are distinguished by h for the major
isomer and m for the minor isomer. Rf =0.58 (pentane/EtOAc 1:1);
1H NMR (500 MHz, CDCl3): d=2.70 (dd, J=9.0, 18.0 Hz, 1H; 12-Ha,
m), 2.85 (dd, J=12.8, 15.8 Hz, 1H; 12-Ha, h), 2.92 (dd, J=6.3, 18.0 Hz,
1H; 12-Hb, m), 3.00 (d, J=4.2, 12.8 Hz, 1H; 11a-H, h), 3.07 (d, J=
17.9 Hz, 1H; 5-Ha, h), 3.19 (dd, J=4.2, 16.0 Hz, 1H; 12-Hb, h), 3.20 (d,
J=16.9 Hz, 1H; 5-Ha, m), 2.51, 3.81, 3.83, 3.92, 3.93 (5”s, 5”3H, OCH3
or CO2CH3, h), 3.55 (dd, J=6.3, 8.9 Hz, 1H; 11a-H, m), 3.65, 3.67, 3.79,
3.89, 3.91 (5”s, 5”3H, OCH3 or CO2CH3, m), 3.69 (d, J=17.9 Hz, 1H;
5-Hb, h), 5.56 (s, 1H; 11-CHHb, h), 5.69 (d, J=0.9 Hz, 1H; 11-CHHb, h),
6.19 (d, J=1.4 Hz, 1H; 11-CHHa, m), 6.29 (d, J=0.9 Hz, 1H; 11-CHHa,
h), 6.49 (s, 1H; 4-H, m), 6.55 (s, 1H; 4-H, h), 7.17 (dd, J=1,0, 8.2 Hz,
1H; 9-H, m), 7.20 (dd, J=1.1, 8.2 Hz, 1H; 9-H, h), 7.33 (dd, J=8.0 Hz,
1H; 8-H, m), 7.37 (dd, J=8.0 Hz, 1H; 8-H, m), 7.70 (dd, J=1.0, 7.8 Hz,
1H; 7-H, m), 7.79 ppm (dd, J=1.1, 7.8 Hz, 1H; 7-H, h); 13C NMR
(125.7 MHz, CDCl3): d=23.60 (C-12, h), 24.85 (C-12, m), 32.49 (C-5, m),
35.64 (C-5, h), 43.42 (C-11a, h), 46.25 (C-11a, m), 52.02, 52.41 ((C-5a)-
COOCH3, (C-2)-COOCH3, h), 52.39, 52.70 ((C-5a)-COOCH3, (C-2)-
COOCH3, m), 55.84, 55.91 ((C-3)-OCH3, (C-10)-OCH3, m), 55.92, 55.96
((C-3)-OCH3, (C-10)-OCH3, h), 57.71 (C-5a, h), 58.63 (C-5a, m), 61.16
((C-1)-OCH3, m), 61.49 ((C-1)-OCH3, h), 106.5 (C-4, m), 106.62 (C-4, h),
115.4 (C-2, h), 115.6 (C-2, m), 116.5 (C-9, h), 116.6 (C-9, m), 117.1 ((C-
11)-CH2, h), 119.1 (C-12a, m), 119.7 (C-12a, h), 120.0 ((C-11)-CH2, m),
120.0 (C-7, m), 120.4 (C-7, h), 127.1 (C-10a, m), 128.3 (C-8, m), 128.5 (C-
8, h), 130.8 (C-10a, h), 131.6 (C-6a, m), 131.7 (C-6a, h), 137.1 (C-4a, m),
137.4 (C-4a, h), 137.7 (C-11, m), 137.9 (C-11, h), 155.2, 155.3, 155.4 (C-1,
C-3, h, m), 156.5 (C-10, h), 157.5 (C-10, m), 167.0 ((C-2)-COOCH3, m),
167.1 ((C-2)-COOCH3, h), 170.0 ((C-5a)-COOCH3, h), 172.1 ((C-5a)-
COOCH3, m), 194.1 (C-6, m), 195.4 ppm (C-6; h); UV (MeOH): lmax (lg
e)=204.0 (4.730), 279.0 nm (3.882); IR (neat): n˜ =2950, 1735, 1684, 1608,
1589, 1465, 1411, 1270, 1212, 1157, 1105, 764 cmꢀ1; MS (ESI): m/z (%):
950 (55) [2M+NH4]+, 467 (100) [M+H]+, 435 (60) [MꢀOCH3]+;
HRMS: calcd for [M+H]+, [MꢀOCH3]+: 467.17004, 435.14438; found:
467.17027, 435.14396.
SiCH
C
G
(C-2), 114.3 (C-4), 126.5, 127.5, 127.9, 130.2 (C-3’, C-4’, C-5’, C-6’), 135.9,
139.0 (C-1’, C-2’), 140.7 ppm (C-3); IR (neat): n˜ =3406, 2943, 2866, 1463,
1067, 883, 682 cmꢀ1; MS (200 eV, DCI): m/z (%): 335 (80) [M+H]+, 352
(100) [M+NH4]+, 687 (28) [2M+NH4]+.
Acetic acid 1-(2-triisopropylsilanylmethylphenyl)allyl ester (22): Ac2O
(10.2 g, 9.43 mL, 99.8 mmol, 5.00 equiv) was added dropwise to a stirred
solution of 21 (6.67 g, 20.0 mmol, 1.00 equiv) and a catalytic amount of
DMAP in pyridine (19 mL). After the reaction had been stirred for 4 h,
MeOH (40 mL) was added and the mixture was stirred again for 1 h. The
reaction mixture was diluted with water (20 mL) and extracted with Et2O
(3”40 mL). The combined organic fractions were washed with brine and
dried over Na2SO4, then the solvent was evaporated under reduced pres-
sure to give 22 as a colorless oil in 85% yield after flash chromatography
(EtOAc/pentane 1:19). Rf =0.59 (pentane/EtOAc 10:1); 1H NMR
(200 MHz, CDCl3): d=1.06–1.27 (m, 21H; Si(iPr)3), 2.01 (s, 3H;
U
COCH3), 2.95 (m, 2H; 1-H2), 4.90 (s, 2H; CH2OTIPS), 5.16 (d, J=
10.5 Hz, 1H; 4-Hcis), 5.21 (d, J=17.2 Hz, 1H; 4-Htrans), 5.50 (q, J=6.7 Hz,
1H; 2-H), 5.84 (ddd, J=17.2, 10.5, 6.2 Hz, 1H; 3-H), 7.12–7.30, 7.48–
7.56 ppm (m, 4H; Ar-H); 13C NMR (50.3 MHz, CDCl3): d=12.0 (3”
SiCH
A
(CH2OTIPS), 74.6 (C-2), 116.7 (C-4), 126.7, 126.8, 130.1, 133.7 (C-3’, C-
4’, C-5’, C-6’), 135.9, 139.6 (C-1’, C-2’), 139.6 (C-3), 169.1 ppm (COCH3);
IR (neat): n˜ =2943, 2866, 1743, 1463, 1236, 1083, 1066, 882, 683 cmꢀ1; MS
(200 eV, DCI): m/z (%): 377 (50) [M+H]+, 394 (100) [M+NH4]+, 771 (6)
[2M+NH4]+.
Acetic acid 1-(2-hydroxymethylphenyl)allyl ester (23): Bu4NF (16.1 g,
51.0 mmol, 3.00 equiv) was added to a stirred solution of 22 (6.40 g,
17.0 mmol, 1.00 equiv) in THF at 08C, and stirring of the mixture was
continued for 20 min. The reaction mixture was then diluted with water
(100 mL) and extracted with Et2O (5”70 mL). The combined organic ex-
tracts were washed with brine and dried over Na2SO4, then the solvent
was evaporated under reduced pressure to give 23 as a colorless oil in
99% yield after flash chromatography (EtOAc/pentane 1:3). Rf =0.43
(pentane/EtOAc 3:1); 1H NMR (200 MHz, CDCl3): d=1.96 (s, 3H;
COCH3), 2.78 (brs, 1H; OH), 2.99 (m, 2H; 1-H2), 4.90 (d, J=5 Hz, 2H;
1-(2-Hydroxymethylphenyl)but-3-en-2-ol (20): Vinyl magnesium bromide
(1m solution in THF, 20.0 mL, 20.0 mmol, 3.00 equiv) was added drop-
wise to a stirred solution of lactol 19 (1.00 g, 6.66 mmol, 1.00 equiv) in
2532
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 2527 – 2535

Synthesis of the Tetracycline Structural Core
FULL PAPER
CH2OH), 5.16 (d, J=10.5 Hz, 1H; 4-Hcis), 5.21 (d, J=17.2 Hz, 1H; 4-
Rf =0.37 (pentane/EtOAc 3:1); 1H NMR (200 MHz, CDCl3): d=1.98 (s,
3H; COCH3), 3.17 (dd, J=13.7, 8.3 Hz, 1H; 4-Ha), 3.41 (dd, J=13.7,
5.0 Hz, 1H; 4-Hb), 3.64 (s, 0.6H; 8-H2 ketone), 3.82 (s, 3H; OCH3), 5.16
(brd, J=10.4 Hz, 1H; 1-Hcis), 5.22 (brd, J=17.1 Hz, 1H; 1-Htrans), 5.63
(m, 1H; 3-H), 5.87 (ddd, J=16.9, 10.5, 6.1 Hz, 1H; 2-H), 6.04 (s, 0.7H; 8-
H enol), 6.72–7.88 (m, 7H; Ar-H), 15.8 ppm (brs, 0.7H; OH enol); UV
(CH3CN): lmax (lg e)=308.5 nm (2.16); IR (neat): n˜ =2938, 1739, 1565,
1461, 1424, 1025 cmꢀ1; MS (70 eV, EI): m/z (%): 261 (100) [25ꢀCH3]+,
432 (17) [MꢀOAc]+, 492 (1) [M]+.
H
trans), 5.48 (q, J=6.7 Hz, 1H; 2-H), 5.85 (ddd, J=17.2, 10.5, 6.2 Hz, 1H;
3-H), 7.13–7.38 ppm (m, 4H; Ar-H); 13C NMR (50.3 MHz, CDCl3): d=
20.8 (COCH3), 37.1 (C-1), 62.6 (CH2OH), 75.0 (C-2), 116.8 (C-4), 126.8,
127.4, 128.6, 130.6 (C-3’, C-4’, C-5’, C-6’), 134.8, 139.1 (C-1’, C-2’), 135.5
(C-3), 170.2 ppm (COCH3); IR (neat): n˜ =3419, 2933, 1737, 1373, 1240,
1022 cmꢀ1; MS (200 eV, DCI): m/z (%): 238 (29) [M+NH4]+, 458 (100)
[2M+NH4]+.
Acetic acid 1-(2-formylbenzyl)allyl ester (24): Molecular sieves (4 Š,
5.0 g) and IBX (9.90 g, 35.4 mmol, 2.00 equiv) were added to a stirred so-
lution of 23 (3.90 g, 17.7 mmol, 1.00 equiv) in DMSO (400 mL), and the
reaction mixture was shaken at room temperature for 3 h, before being
diluted at ꢀ108C with cold brine (ꢀ108C) and filtered. The filtrate was
extracted with Et2O (5”80 mL) and the solids were extracted by using a
Soxhlet apparatus (100 mL Et2O, 10 h). The combined organic extracts
were washed with brine and dried over Na2SO4, then the solvents were
evaporated under reduced pressure to give 24 as a colorless oil in 71%
yield after flash chromatography (EtOAc/pentane 1:3). Rf =0.63 (pen-
6-Hydroxy-4-methoxy-12-methylene-(5,5a,6,11,11a,12-hexahydronaph-
thacene)-5-one (3): Bu4NCl (11.1 mg, 40.6 mmol, 2.00 equiv), K2CO3
(5.50 mg, 40.6 mmol, 2.00 equiv), Pd(OAc)2 (4.50 mg, 20.3 mmol,
G
1.00 equiv), and PPh3 (10.5 mg, 40.6 mmol, 2.00 equiv) were added to a
solution of 27 (10.0 mg, 20.3 mmol, 1.00 equiv) in DMF (2.0 mL), and the
mixture was stirred for 4 h at 808C. The reaction was then quenched by
the addition of saturated aq. NH4Cl (5.0 mL), and the aqueous phase was
extracted with Et2O (3”25 mL). The combined organic fractions were
washed with brine and dried over Na2SO4, then the solvents were evapo-
rated under reduced pressure to give 3 as a yellowoil in 62% yield after
flash chromatography (acetone/pentane 1:10). Rf =0.33 (pentane/EtOAc
3:1); 1H NMR (200 MHz, CDCl3): d=2.63 (d, J=8.9 Hz, 2H; 11-H2),
3.22–3.31 (m, 1H; 11a-H), 3.38 (s, 3H; OCH3), 4.88 (d, J=2.7 Hz, 1H;
13-Ha), 5.28 (s, J=2.7 Hz, 1H; 13-Hb), 6.80–7.40 (m, 7H; Ar-H),
17.99 ppm (s, 1H; OH); MS (70 eV, EI): m/z (%): 304 (100) [M]+, 289
(27) [MꢀCH3]+.
1
tane/EtOAc 3:1); H NMR (200 MHz, CDCl3): d=1.94 (s, 3H; COCH3),
3.23 (dd, J=13.5, 8.5 Hz, 1H; 1-Ha), 3.49 (dd, J=13.5, 5.2 Hz, 1H; 1-Hb),
5.17 (d, J=10.5 Hz, 1H; 4-Hcis), 5.23 (d, J=17.3 Hz, 1H; 4-Htrans), 5.46
(m, 1H; 2-H), 5.87 (ddd, J=17.3, 10.5, 6.1 Hz, 1H; 3-H), 7.28 (dd, J=
7.4, 1.5 Hz, 1H; 3’-H), 7.41 (dt, J=7.4, 1.5 Hz, 1H; 5’-H), 7.51 (dt, J=
7.4, 1.5 Hz, 1H; 4’-H), 7.83 (dd, J=7.4, 1.5 Hz, 1H; 6’-H), 10.23 ppm (s,
1H; CHO); 13C NMR (50.3 MHz, CDCl3): d=20.8 (COCH3), 37.0 (C-1),
74.6 (C-2), 116.8 (C-4), 127.2, 132.1, 132.4, 133.3 (C-3’, C-4’, C-5’, C-6’),
134.2, 139.1 (C-1’, C-2’), 135.5 (C-3), 169.7 (COCH3), 192.5 ppm (CHO);
IR (neat): n˜ =3073, 3021, 2989, 2934, 2866, 2839, 2744, 1739, 1697, 1600,
1372, 1237, 1022, 759 cmꢀ1; MS (200 eV, DCI): m/z (%): 236 (100)
[M+NH4]+, 454 (9) [2M+NH4]+.
2-(7-Bromo-hept-2-enyloxy)tetrahydropyran (29): A suspension of Ni-
A
with a solution of NaBH4 (95 mg, 2.5 mmol, 0.25 equiv) in dry EtOH
(4.0 mL) and stirred until gas evolution had ceased. Ethylenediamine
(150 mg, 2.50 mmol, 0.250 equiv) and, after 10 min of stirring at room
Acetic acid 1-{2-[1-hydroxy-3-(2-iodo-6-methoxyphenyl)-3-oxopropyl]-
benzyl}allyl ester (26): nBuLi (1.6m solution in hexane, 2.99 mL,
4.72 mmol, 1.00 equiv) was added dropwise to a stirred solution of diiso-
propylamine (573 mg, 0.800 mL, 5.66 mmol, 1.20 equiv) in dry THF
(10 mL) at 08C. After the mixture had been stirred for 1 h, a solution of
25 (1.30 g, 4.72 mmol, 1.00 equiv) was added dropwise. After stirring for
another hour at 08C, the reaction mixture was cooled to ꢀ788C and a so-
lution of 24 (1.03 g, 4.72 mmol, 1.00 equiv) in dry THF (5.0 mL) was
added dropwise. Stirring was continued at ꢀ788C for 1 h and at ꢀ208C
for an additional 30 min, after which the mixture was diluted with satu-
rated aq. NaHCO3 (25 mL) and allowed to warm to room temperature.
The aqueous phase was extracted with CH2Cl2 (4”100 mL), the com-
bined organic extracts were washed with brine and dried over Na2SO4,
and the solvents were evaporated under reduced pressure to give 26 as a
yellowoil in 62% yield after flash chromatography (EtOAc/pentane 1:3).
Rf =0.24 (pentane/EtOAc 3:1); 1H NMR (200 MHz, CDCl3): d=1.93,
1.98 (2”s, 3H; COCH3), 2.91–3.28 (m, 4H; 4-H2, 8-H2), 3.41, 3.46 (2”d,
J=2.2 Hz, 1H; OH), 3.78, 3.80 (2”s, 3H; OCH3), 5.20 (d, J=10.5 Hz,
1H; 1-Hcis), 5.29 (d, J=16.9 Hz, 1H; 1-Htrans), 5.36, 5.46 (2”m, 1H; 3-H),
5.53 (dd, J=7.3, 4.9 Hz, 0.5H; 7-H), 5.58 (dd, J=7.5, 4.3 Hz, 0.5H; 7-H),
5.88 (ddd, J=16.9, 10.5, 6.2 Hz, 1H; 2-H), 6.77 (dd, J=8.4, 5.5 Hz, 1H;
12’-H), 6.92 (dt, J=8.1, 1.5 Hz, 1H; 13’-H), 7.02–7.18 (m, 3H; 6’, 7’, 8’-
H), 7.28 (dd, J=7.9, 1.5 Hz, 1H; 9’-H), 7.43 ppm (brd, J=7.7 Hz, 1H;
14’-H); 13C NMR (50.3 MHz, CDCl3): d=20.9 (OCOCH3), 37.1 (C-4),
51.3 (C-8), 55.8 (OCH3), 65.8 (C-7), 74.8 (C-3), 90.5 (C-15’), 110.6 (C-
12’), 116.9 (C-1), 126.2, 127.2, 127.3, 130.6, 131.1, 131.4 (C-6’, C-7’, C-8’,
C-9’, C-13’, C-14’), 133.6 (C-10’), 135.7, 141.0 (C-5, C-6), 135.9 (C-2),
156.1 (C-11’), 170.0 (OCOCH3), 206.5 ppm (C-9); IR (neat): n˜ =3508,
2940, 1731, 1582, 1565, 1456, 1429, 1258, 1027, 776 cmꢀ1; MS (70 eV, EI):
m/z (%): 261 (100) [25ꢀCH3]+, 434 (4) [MꢀOAc]+, 476 (9) [MꢀH2O]+,
494 (1) [M]+.
temperature,
2-(7-bromohept-2-ynyloxy)tetrahydropyran
(2.75 g,
10.0 mmol, 1.00 equiv) were added. The reaction mixture was stirred at
room temperature under an H2 atmosphere until complete conversion (as
determined by TLC). After the mixture had been stirred with charcoal
for 15 min, the obtained suspension was filtered through a pad of silica
gel and the solvent was removed under reduced pressure to give 29 as a
colorless oil in 89% yield. Rf =0.48 (EtOAc/pentane 1:9); 1H NMR
(200 MHz, CDCl3): d=1.45–1.95 (m, 10H; 5-H2, 6-H2, 3’-H2, 4’-H2, 5’-
H2), 2.12 (td, J=7.1, 6.1 Hz, 2H; 4-H2), 3.40 (t, J=6.6 Hz, 2H; 7-H2),
3.44–3.57 (m, 1H; 6’-HA), 3.80–3.94 (m, 1H; 6’-HB), 3.99–4.10 (m, 1H; 1-
HA), 4.19–4.30 (m, 1H; 1-HB), 4.62 (m, 1H; 2’-H), 5.57 ppm (m, 2H; 2-
H, 3-H); 13C NMR (50.3 MHz, CDCl3): d=19.47 (C4’), 25.41 (C4), 25.94
(C5’), 30.61 (C3’), 32.32 (C5), 33.08 (C6), 62.23 (C1), 62.68 (C6’), 97.98
(C2’), 127.6 (C2), 131.2 ppm (C3); IR (neat): n˜ =3017, 2941, 2870, 2851,
1658, 1453, 1440, 1388, 1352, 1339, 1320, 1298, 1271, 1249, 1201, 1183,
1158, 134, 1118, 1077, 1057, 1026, 973, 905, 870, 815, 677, 647 cmꢀ1; MS
(200 eV, DCI/NH3): m/z (%): 296/294 (21/19), 136 (4), 119 (21), 102
(100).
3-(2-Bromophenyl)-3-oxopropionic acid methyl ester (31): Acetic acid
methyl ester (161 mL, 2.33 mmol, 1.00 equiv) in dry THF (4 mL) was
added dropwise to a suspension of 2-bromobenzoic acid methyl ester (30;
1.00 g, 4.65 mmol, 2.00 equiv) and sodium hydride (139 mg, 4.65 mmol,
2.00 equiv) in dry THF (4 mL). The reaction mixture was stirred for 2 h
at room temperature and then heated under reflux conditions for 24 h.
The solvent was removed under reduced pressure, and the residue taken
up in toluene. This solution was washed with 2n HCl (7 mL) and saturat-
ed aq. NaHCO3 (7 mL). The combined organic phases were dried over
MgSO4 and the solvent was removed under reduced pressure. Compound
31 was obtained as a yellowish oil in 81% yield after flash chromatogra-
phy (EtOAc/pentane 1:9). Rf =0.40 (EtOAc/pentane 1:4); 1H NMR
(200 MHz, CDCl3): d=3.74 (s, 3H; CO2CH3, ketone), 3.81 (s, 3H;
CO2CH3, enol), 4.03 (s, 2H; 2-H2, ketone), 5.47 (s, 1H; 2-H, enol), 7.32
(ddd, J=7.5, 7.5, 1.0 Hz, 1H; 5’-H), 7.42 (dd, J=8.6, 1.0 Hz, 1H; 3’-H),
7.50 (ddd, J=7.5, 7.5, 1.0 Hz, 1H; 4’-H), 7.63 (dd, J=8.0, 1.1 Hz, 1H; 6’-
H), 12.33 ppm (s, 1H; OH, enol); 13C NMR (50.3 MHz, CDCl3): d=48.48
(C-2, ketone), 51.54 (OCH3, enol), 52.44 (OCH3, ketone), 92.85 (C-2,
enol), 119.1 (C-2’, ketone), 120.9 (C-2’, enol), 127.3 (C-5’, enol), 127.5 (C-
5’, ketone), 129.5 (C-6’, enol), 130.2 (C-6’, enol), 131.2 (C-3’, enol), 132.4
Acetic acid 1-{2-[1-hydroxy-3-(2-iodo-6-methoxyphenyl)-3-oxopropenyl]-
benzyl}allyl ester (27): TPAP (80.0 mg, 0.200 mmol, 0.100 equiv) and
NMO (702 mg, 6.06 mmol, 3.00 equiv) were added to a solution of 26
(1.00 g, 2.02 mmol, 1.00 equiv) in CH2Cl2 (20 mL) at room temperature.
The reaction mixture was stirred for 24 h before the solvents were re-
moved under reduced pressure and the residue was purified by prepara-
tive TLC (acetone/pentane 1:10) to give 27 as a yellowoil in 50% yield.
Chem. Eur. J. 2008, 14, 2527 – 2535
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2533

L. F. Tietze et al.
(C-3’, ketone), 133.7 (C-4’, enol), 133.9 (C-4’, ketone), 135.6 (C-1’, enol),
139.8 (C-1’, ketone), 167.2 (C-1, enol), 171.9 (C-3, enol), 172.8 (C-1,
ketone), 195.4 ppm (C-3, ketone); UV (CH3CN): lmax (lg e)=208.0
(4.160), 244.0 nm (3.685); IR (neat): n˜ =1746, 1704, 1651, 1633, 1587,
1564, 1536, 1468, 1446, 1435, 1390, 1326, 1286, 1272, 1249, 1205, 761,
729 cmꢀ1; MS (70 eV, EI): m/z (%): 258/256 (3/3), 225/227 (2/2), 183/185
(38/38), 177 (100), 155/157 (8/8), 69 (8), 50 (4); HRMS: calcd for [M]+:
255.9735; found: 255.9735.
9-Methylene-10-oxo-(1,2,3,4,4a,9,9a,10-octahydroanthracene)-4a-carbox-
ylic acid methyl ester (4) and 9-methyl-10-oxo-(1,2,3,4,4a,10-hexahy-
droanthracene)-4a-carboxylic acid methyl ester (35): NaH (60% in min-
eral oil, 11 mg, 0.27 mmol, 1.2 equiv) was added in one portion to a solu-
tion of 34 (92 mg, 0.22 mmol, 1.0 equiv) in DMF (1.6 mL) at 08C, and the
mixture was stirred for 20 min at room temperature (solution A). In a
separate flask, a solution of Pd(OAc)2 (5.4 mg, 24 mmol, 11 mol%) and
T
dppe (20 mg, 49 mmol, 22 mol%) in DMF (0.8 mL) was stirred for 20 min
at room temperature (solution B). KOAc (48 mg, 0.49 mmol, 2.2 equiv)
was added to solution B, then solution A was added dropwise through a
syringe to solution B. The reaction mixture was heated for 10 min at
908C in the microwave reactor and then diluted with saturated aq.
NH4Cl solution. The aqueous phase was extracted with Et2O (3”3 mL).
After removal of all volatiles and chromatography (EtOAc/pentane 1:9),
4 was obtained as a colorless oil (8.1:1 mixture of diastereomers) in 81%
yield; in addition, 35 was isolated in 10% yield.
Compound 4: Rf =0.44, 0.40 (EtOAc/pentane 1:9); 1H NMR (600 MHz,
CDCl3): d=1.34 (m, 1H; 2-HA), 1.68 (m, 1H; 2-HB), 1.77 (m, 2H; 1-HA,
3-HA), 1.93 (m, 2H; 3-HB, 4-HA), 2.23 (m, 1H; 4-HB), 2.54 (m, 1H; 1-
HB), 2.67 (m, 1H; 9a-H), 3.50 (s, 3H; CO2CH3), 5.25 (d, J=2.1 Hz, 1H;
C=CHHA), 5.80 (d, J=2.1 Hz, 1H; C=CHHB), 7.37 (td, J=7.7, 1.2 Hz,
1H; 6-H), 7.52 (td, J=7.3, 1.5 Hz, 1H; 7-H), 7.66 (d, J=7.9 Hz, 1H; 8-
H), 8.03 ppm (dd, J=8.0, 1.3 Hz, 1H; 5-H); 13C NMR (150.8 MHz,
CDCl3): d=21.87 (C-3), 25.08 (C-1), 25.26 (C-2), 31.08 (C-4), 46.40
(C-9a), 51.90 (CO2CH3), 58.67 (C-4a), 110.8 (C=CH2), 124.4 (C-8), 127.9
(C-6), 128.3 (C-5), 130.3 (C-10a), 133.5 (C-7), 141.1 (C-8a), 143.6
(C-9), 170.1 (CO2CH3), 195.5 ppm (C-10); MS (ESI): m/z (%): 563 (37)
[2M++Na], 425 (13), 271 (100) [M+], 211 (25).
Compound 35: Rf =0.36 (EtOAc/pentane 1:9); 1H NMR (200 MHz,
CDCl3): d=1.21–2.09 (m, 6H; 2-H2, 3-H2, 4-H2), 2.21 (s, 3H; 9-CH3),
2.76 (ddt, J=13.7, 3.8, 2.2 Hz, 1H; 1-HA), 3.01 (ddt, J=13.3, 3.1, 1.5 Hz,
1H; 1-HB), 3.64 (s, 3H; CO2CH3), 7.35 (ddd, J=7.1, 7.1, 1.4 Hz, 1H; 6-
H), 7.55 (dd, J=7.9, 1.2 Hz, 1H; 8-H), 7.66 (ddd, J=7.1, 7.1, 1.7 Hz, 1H;
7-H), 8.09 ppm (ddd, J=7.6, 1.5, 0.5 Hz, 1H; 5-H); 13C NMR (75.5 MHz,
CDCl3): d=14.08 (9-CH3), 22.93 (C-3), 28.60 (C-2), 29.90 (C-1), 36.41 (C-
4), 52.76 (CO2CH3), 61.48 (C-4a), 122.0 (C-9), 124.6 (C-5), 126.9 (C-8),
127.2 (C-10a), 127.5 (C-6), 135.0 (C-7), 139.4 (C-9a), 140.4 (C-8a), 169.9
(CO2CH3), 196.4 ppm (C-10).
2-(2-Bromobenzoyl)-9-(tetrahydropyran-2-yloxy)non-7-enoic acid methyl
ester (32):
A solution of the b-keto ester 31 (2.42 g, 9.41 mmol,
1.00 equiv) in MeOH (20 mL) was added dropwise to a stirred solution
of NaOMe (5.4m solution in dry MeOH, 1.74 mL, 9.41 mmol, 1.00 equiv)
in MeOH (20 mL) at 08C, and stirring was continued for 1 h at room
temperature. Compound 29 (3.26 g, 11.8 mmol, 1.25 equiv) and NaI
(1.77 g, 11.8 mmol, 1.25 equiv) were added and the mixture was heated
under reflux conditions for 12 h before being diluted with water (30 mL).
The aqueous phase was extracted with CH2Cl2 (4”20 mL), the combined
organic phases were washed with brine (40 mL), and the volatiles were
removed under reduced pressure to give 32 as a colorless oil in 62%
yield after flash chromatography (EtOAc/pentane 1:9). Rf =0.64 (EtOAc/
pentane 1:4); 1H NMR (200 MHz, CDCl3): d=1.09–2.14 (m, 14H; 3-H2,
4-H2, 5-H2, 6-H2, 3’’-H2, 4’’-H2, 5’’-H2), 3.41–3.58 (m, 1H; 6’’-HA), 3.68 (s;
CO2CH3, ketone), 3.79–3.95 (m, 1H; 6’’-HB), 3.84 (s; CO2CH3, enol),
3.98–4.09 (m, 1H; 9-HA), 4.16–4.28 (m, 1H; 9-HB), 4.23 (t, J=7.1 Hz,
1H; 3-H, ketone), 4.61 (m, 1H; 2’’-H), 5.40–5.63 (m, 2H; 7-H, 8-H),
7.20–7.45 (m, 3H; 4’-H, 5’-H, 6’-H), 7.56–7.65 (m, 1H; 3’-H), 12.65 ppm
(s, 1H; OH, enol); 13C NMR (50.3 MHz, CDCl3): d=19.50 (C-4’’), 25.43
(C-5’’), 26.70 (C-3’’, enol), 27.09 (C-6), 27.18 (C-4), 28.38 (C-3, ketone),
29.26 (C-5), 30.64 (C-3’’), 51.84 (C-2, ketone), 52.38 (CO2CH3, ketone),
57.60 (CO2CH3, enol), 62.22 (C-9), 62.66 (C-6’’), 97.88 (C-2’’), 103.3 (C-2,
enol), 119.0 (C-2’, ketone), 121.4 (C-2’), 125.8 (C-8, enol), 126.2 (C-8,
ketone), 127.2 (C-5’, enol), 127.3 (C-5’, ketone), 128.9 (C-6’, ketone),
129.8 (C-6’, enol), 130.5 (C-7, enol), 131.9 (C-7, ketone), 132.9 (C-3’,
enol), 133.1 (C-3’, ketone), 133.3 (C-4’, enol), 133.8 (C-4’, ketone), 136.0
(C-1’, enol), 140.4 (C-1’, ketone), 169.4 (C-1, enol), 169.7 (C-1 ketone),
198.5 ppm (ArCO, ketone).
2-(2-Bromobenzoyl)-9-hydroxynon-7-enoic acid methyl ester (33): A so-
lution of 32 (1.60 g, 3.54 mmol, 1.00 equiv) and p-toluenesulfonic acid
monohydrate (66 mg, 0.35 mmol, 0.10 equiv) in MeOH (7.0 mL) was
stirred at room temperature until the starting material had been com-
pletely consumed (as determined by TLC). The reaction mixture was di-
luted with saturated aq. NaHCO3 (11 mL), and the aqueous phase was
extracted with CH2Cl2 (3”10 mL). The combined organic phases were
washed with brine and dried over MgSO4, then the solvents were re-
moved under reduced pressure to give 33 as a colorless oil in 82% yield
after flash chromatography (EtOAc/pentane 3:7). Rf =0.31 (EtOAc/pen-
Acknowledgements
This research was supported by the Deutsche Forschungsgemeinschaft.
H.P.B. thanks the Studienstiftung des deutschen Volkes and the Stiftung
Stipendienfonds des Verbandes der Chemischen Industrie for a scholar-
ship. L.M.L. thanks the EC for a Marie Curie scholarship. We thank the
companies Wacker, BASF, and Bayer for generous gifts of chemicals.
1
tane 3:7); H NMR (200 MHz, CDCl3): d=1.05–1.79 (m, 5H; 4-H2, 5-H2,
OH), 1.84–2.18 (m, 4H; 3-H2, 6-H2), 3.68 (s, 3H; OCH3, ketone), 3.85 (s,
3H; OCH3, enol), 4.17 (d, 6.5 Hz, 2H; 9-H2), 4.24 (t, J=7.3 Hz, 1H; 2-H,
ketone), 5.32–5.68 (m, 2H; 7-H, 8-H), 7.21–7.45 (m, 3H; 4’-H, 5’-H, 6’-
H), 7.57–7.66 (m, 1H; 3’-H), 12.64 ppm (s, 1H; OH, enol); 13C NMR
(75.5 MHz, CDCl3): d=26.81 (C-3), 26.85 (C-6), 28.24 (C-4), 29.07 (C-5),
52.47 (OCH3), 57.59 (C-2), 58.53 (C-9), 119.8 (C-2’), 127.4 (C-5’), 128.9
(C-8), 129.0 (C-7), 132.0 (C-6’), 132.4 (C-3’), 133.9 (C-4’), 140.0 (C-1’),
169.8 (C-1), 179.2 ppm (ArCO).
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Received: October 24, 2007
Published online: January 17, 2008
Chem. Eur. J. 2008, 14, 2527 – 2535
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www.chemeurj.org
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