One-pot reactions: Enantiomerically pure bicyclo[5.3.1]undecanes; Synthesis of a taxoid compound

Article abstract of DOI:10.1016/j.tet.2004.06.094

Reaction of C-2 substituted cyclohexenone with an enantiomerically pure α-bromopentenoate leads to enantiopure tricyclooctane, which can be transformed into a taxoid like compound having the typical bicyclo[5.3.1] undecane skeleton. Graphical Abstract

Full text of DOI:10.1016/j.tet.2004.06.094

Tetrahedron 60 (2004) 8137–8141
One-pot reactions: enantiomerically pure
bicyclo[5.3.1]undecanes; synthesis of a taxoid compound
†
Hans-Jurgen Gutke, Norbert A. Braun and Dietrich Spitzner
‡
*
¨
¨ ¨
Institut fur Chemie, Abt. Bioorganische Chemie, Universitat Hohenheim, Garbenstasse 30, D-70599 Stuttgart, Germany
Received 29 April 2004; revised 3 June 2004; accepted 17 June 2004
Available online 20 July 2004
Dedicated to Professor Armin de Meijere on the occasion of his 65th birthday
Abstract—Reaction of C-2 substituted cyclohexenone with an enantiomerically pure a-bromopentenoate leads to enantiopure
tricyclooctane, which can be transformed into a taxoid like compound having the typical bicyclo[5.3.1]undecane skeleton.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
knowledge, they have not been used until now for the
synthesis of a bicyclo[5.3.1]undecane ring system. We will
present in this paper a straightforward way to generate such
a skeleton in enantiopure form.
Search and synthesis of new microtubule stabilizing agents
is still of high interest for cancer research.1 Only a few
natural products, possessing these exceptional molecular
properties, have been identified so far.2 By far the most
widespread and extensively investigated class are taxoids.3
The bicyclo[5.3.1]undecane skeleton is the key structural
feature of taxoid compounds,4 for example paclitaxel (Z
Taxolw) (1)5,6 or aromatic C-ring analogous like 27 (Fig. 1).
2. Results and discussions
We first investigated the alkylation of the enantiomerically
pure bicyclo[3.2.1]octane 4 (Scheme 1), which was
obtained from tricyclo[3.2.1.02,7]octane 3 by hydrogenoly-
tic cleavage of the benzyl ether function and consecutive
ring-opening of the push–pull cyclopropane moiety.11
Alkylation of bicyclo[3.2.1]octane 4 with 2-bromobenzyl
bromide (5) occurred regioselectively at C-3 to give
exclusively bicycle 7, but not the desired C-7 alkylated
Retrosynthetic analysis (Fig. 2) of a taxoid skeleton A with
an attached aromatic C-ring similar to 2 leads via the
tricyclic fragment B to a bicyclo[3.2.1]octane8,9 C and
benzyl halide D. Synthon C is available by ring opening of
the push–pull substituted cyclopropane moiety10 of tricy-
clo[3.2.1.02,7]octane E, which can be synthesized in
enantiopure form by using an anionically induced Domino
reaction.11,12
‘One pot’ syntheses or domino reactions13,14 have been used
many times to increase the preparation efficiency of
complex natural products.15,16 Tricyclo[3.2.1.02,7]octanes
are useful and flexible building blocks for a variety of
carbon skeletons,17,18 however, to the best of our
Keywords: Domino reaction; Taxoids; Diastereoselective synthesis; Ring
closure.
* Corresponding author. Tel.: C49-711-459-2812; fax: C49-711-459-
3703; e-mail: spitzner@uni-hohenheim.de
† Present address: Sympore GmbH, Paul-Ehrlich-Strasse 15, D-72076
Tu¨bingen, Germany.
‡ Present address: Symrise GmbH and Co. KG, Research and Develop-
ment, Mu¨hlenfeldstrasse 1, D-37603 Holzminden, Germany.
Figure 1. Paclitaxel and analog.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.094

8138
H.-J. Gutke et al. / Tetrahedron 60 (2004) 8137–8141
Scheme 2. (a) Et3OBF4, CH2Cl2, 79%; (b) BnOH, p-TsOH, toluene, 84%.
Michael acceptor 1111,22 to form diastereoselectively
tricyclo[3.2.1.02,7]octane 12 (d.e.R95%) in 51% yield.
Figure 2. Retrosynthetic analysis.
By using Li-10b as starting material only a minor amount
(%9%) of the corresponding tricycle was obtained.
product 6. The structure of 7 was determined by NOESY
(vicinity of 3-H and 7-H) and H,1H-COSY. This structure
1
The characteristic bicyclo[5.3.1]undecane skeleton of
taxoids can be synthesized in only three steps from tricycle
12 (Scheme 3). Formation of the carbon–carbon bond
between the carbonyl and the aromatic ring could be
performed either by using a radical reaction23 or halogen–
metal exchange. Lithiation with tert-butyllithium at K
110 8C gave tertiary alcohol 13, which was used as a crude
product for the next step. Protonation of 13 followed by
dehydration and ring opening of the push–pull substituted
cyclopropane unit yielded olefin 14. Under these conditions,
the dioxolane moiety was not hydrolyzed. Both structure
confirmation of 14 and determination of the absolute
configuration were done by X-ray analysis.24 Ozonolysis
of the double bond of olefin 14 at K95 8C and work-up with
dimethylsulfide yielded triketone 15, which can be further
transformed into different paclitaxel analogous. The oxi-
dative cleavage of a double bond in a bicyclo[3.2.1]octane
system to form a bicyclo[5.3.1]undecane has been applied
previously25,26 and it is a common tactic in the synthesis of
medium and large ring systems.27 In our case, the
enantiopure taxoid skeleton 15 possessing the opposite
absolute configuration of the naturally occurring taxanes
was formed in only four steps in 24% overall yield starting
from easily available precursors.
is in agreement with the corresponding PC-MODEL
calculation.19 Obviously, the 6-membered ring ketone
possesses a higher reactivity.
One could envision an alternative way to generate 6 by
kinetically controlled alkylation at C-720,21 of tricycle 3
with bromide 5. However, this transformation led to tricycle
8 in only poor yield (%8%). The kinetic acidity of such a
strained carbocylic ketone is dramatically diminished both
by an ethoxy and a benzyloxy group.20
We turned our interest to introduce the aromatic moiety at
C-7 by a rather straightforward manner. Our synthesis
commenced from the C-2 substituted enones 10, which were
prepared from dione 9 (Scheme 2).
The kinetically controlled generated lithium dienolate Li-
10a reacted smoothly with the enantiomerically pure
In summary, enantiopure tricyclo[3.2.1.02,7]octanes are
flexible building blocks for a variety of carbon skeletons
including bicyclo[5.3.1]undecanes. Moreover, we could
show that the diastereoselectivity of the domino reaction
with Michael acceptors of type 11 is not influenced by a C-2
substitution of enone 10, however, the yield of this reaction
strongly depends on the C-3 substituent of enone 10.28
3. Experimental
3.1. General
All reagents were commercial products (Fluka, Aldrich or
Lancaster) and used as received. THF and toluene were
freshly distilled from sodium/benzophenone. All other
solvents were distilled prior to use. Diisopropylamine was
distilled from CaH2. n-Butyl-lithium was obtained as
solution in hexane from Chemetall, Frankfurt, Germany,
and titrated prior to use. LDA was freshly prepared from
diisopropylamine and n-butyllithium. Reactions involving
Scheme 1. (a) Pd/C, H2, EtOAc, 80%; (b) LDA, 5, THF, 6: 0%, 7: 47%
(d.e.O95%); (c) LDA, 5, THF, ca. 8%; BrBnZ2-bromobenzyl.

H.-J. Gutke et al. / Tetrahedron 60 (2004) 8137–8141
8139
Scheme 3. (a) LDA, THF, 51%; (b) tert-BuLi, THF; (c) 15% HCl, CH2Cl2, 59% (over 2 steps); (d) O3, MeOH, K95 8C, Me2S, 81%.
air and/or moisture sensitive reagents were conducted under
an atmosphere of argon, and the glassware was oven dried
(140 8C) and purged with argon. All reactions were
monitored by analytical TLC (silica gel 60 F254), Merck,
Darmstadt, Germany. Preparative column chromatography:
silica gel 60 (63–200 mm), Macherey and Nagel, Du¨ren,
Germany. NMR: UnityINOVA Varian 300 spectrometer (1H:
300 MHz; 13C: 75.48 MHz) in CDCl3 if not otherwise stated
with TMS as internal standard; chemical shifts (d) in ppm
and coupling constants (J) in Hz. IR: Perkin–Elmer Paragon
1000 FT-IR spectrometer; wave number (n) in cmK1. MS:
Finnigan MAT 8200 in EI mode (70 eV); data in m/z (%).
Mp (uncorrected): Bu¨chi melting-point apparatus. [a]D:
Perkin–Elmer polarimeter 241 with concentrations (c)
expressed in g/100 mL. Elemental analyses were obtained
9.0 Hz, 1H, 40-H), 4.29 (dd, JZ5.7, 8.8 Hz, 1H, 50-H), 7.08
(m, 1H), 7.20–7.23 (m, 2H), 7.52 (d, JZ7.8 Hz, 1H). 13C:
25.54 and 26.62 [q, C(CH3)2], 27.98 [q, C(CH3)3], 28.98 (t,
C-4), 35.47 (t, CH2C6H4Br), 44.05 (d, C-3), 47.64 (t, C-7),
50.05 (d, C-5), 50.07 (d, C-8), 63.65 (s, C-1), 70.57 (t, C-50),
73.37 (d, C-40), 82.67 [s, C(CH3)3], 108.26 (s, C-20), 124.69
(s, H4C5CBr), 127.45, 128.28, 131.57 and 133.00 (d,
C6H4Br), 137.97 (s, C6H4Br), 168.79 (s, COO), 205.82 (s,
C-2), 212.38 (s, C-6). IR (KBr): 3070, 2990, 2940, 2890,
1740, 1710 (C]O), 1565, 1475, 1305, 1285. MS: 506/508
(1) [M]C, 491/493 (1) [MKCH3]C, 57 (100) [C4H9]C.
APCI-MS (neg.): 505/507 (100) [MKH]K, 449/451 (84),
79/81 (86) [Br]K. UV (MeOH): lmax (log 3)Z212 nm
(4.045), 266 nm (2.740). CD (MeOH): lmax (Q/D3)Z
295 nm (K7602/K2.30), 303.5 nm (K7421/K2.25).
[a]2D3ZK13.18 (cZ1.23, CHCl3). C25H31O6Br (507.42):
calcd C 59.18, H 6.16, Br 15.75; found C 58.97, H 6.25, Br
15.62.
¨
from Mikroanalytisches Laboratorium, Universitat Stutt-
gart, Germany.
3.1.1. tert-Butyl (1R,3R,5S,8R,40S)-3-(2-bromobenzyl)-8-
(20,20-dimethyl-10,30-dioxolan-40-yl)-2,6-dioxobicy-
clo[3.2.1]octane-1-carboxylate (7). A solution of bicycle
411 (0.47 g, 1.40 mmol) in THF (5 mL) was slowly added
via syringe at K78 8C to LDA (3.08 mmol) in THF
(15 mL). Stirring was continued for 30 min and then 2-
bromobenzyl bromide (5) (0.35 g, 1.40 mmol) in THF
(5 mL) was added. The reaction mixture was stirred at
K78 8C for additional 30 min, slowly warmed to room
temperature and quenched with sat. aqueous NH4Cl
(15 mL). The reaction mixture was extracted with Et2O,
the combined extracts dried (MgSO4) and concentrated. The
residue was chromatographed (silica gel, Et2O/petroleum
etherZ1C1) to give 0.33 g (47%) of bicycle 7 (d.e.R95%,
3.1.2. 2-(2-Bromobenzyl)-1,3-cyclohexandione (9). Bro-
mide 5 (7.50 g, 30 mmol) was liquified in a water bath and a
solution of 1,3-cyclohexandione (3.36 g, 30 mmol) and
KOH (2.02 g, 36 mmol) in H2O (9 mL) was added under
vigorous stirring. The suspension was stirred for 5 days at
room temperature in the dark and continuously adjusted to
pH 12 with aqueous 20% KOH. Then 1 M NaOH (100 mL)
was added and the reaction mixture extracted twice with
Et2O. The organic layer was discarded and the aqueous
phase acidified under cooling with 2 M HCl to pHZ1. The
precipitate was filtered off, rinsed with H2O, dried under
high vacuum and finally recrystallized from Et2O to yield
5.42 g (64%)29,30 of dione 9. Colorless crystals, mp 189–
1
determined by H NMR of the crude reaction mixture).
Colorless crystals, mp 102–104 8C (petroleum ether). H:
1
1
191 8C (Et2O). H (CD3OD): 1.92 (tt, J1ZJ2Z6.4 Hz, 2H,
5-H), 2.38 (t, JZ6.4 Hz, 4H, 4-H and 6-H), 3.52 (s, 2H,
CH2C6H4Br), 6.84 (dd, JZ1.7, 7.7 Hz, 1H, C6H4Br), 6.88
and 7.04 (ddd, J1Z1.7, J2ZJ3Z7.7 Hz, 2H, C6H4Br), 7.38
(dd, JZ1.7, 7.7 Hz, 1H, C6H4Br). IR (KBr): 3060, 2970,
2940, 2600 (C]COH), 1640 (C]O), 1565, 1470, 1455,
1415, 1370, 1280, 1230, 1195, 1155, 1105, 1080, 1025, 930,
865, 810, 755, 680, 670, 610.
1.32 and 1.38 [s, each 3H, C(CH3)2], 1.49 [s, 9H, C(CH3)3],
1.87 (dddd, JZ1.6, 3.6, 8.4, 13.4 Hz, 1H, 4-H), 2.13 (ddd,
JZ3.4, 12.0, 13.4 Hz, 1H, 4-H), 2.69 (dd, JZ8.6, 13.9 Hz,
1H, CH2C6H4Br), 2.71 (d, JZ19.5 Hz, 1H, 7-H), 2.77 (m,
1H, 8-H), 2.78 (d, JZ19.5 Hz, 1H, 7-H), 2.85–2.96 (m, 2H,
3-H and 5-H), 3.48 (dd, JZ4.7, 13.9 Hz, 1H, CH2C6H4Br),
3.84 (dd, JZ7.3, 8.8 Hz, 1H, 50-H), 4.07 (ddd, JZ5.7, 7.3,

8140
H.-J. Gutke et al. / Tetrahedron 60 (2004) 8137–8141
3.1.3. 2-(2-Bromobenzyl)-3-ethoxy-cyclohex-2-en-1-one
(10a). To a suspension of dione 9 (12.5 g, 44.5 mmol) in
anhydrous CH2Cl2 (120 mL) was added triethyloxonium
tetrafluoroborate (11.4 g, 60.0 mmol). The mixture was
stirred for 3 days at room temperature and then slowly
poured under vigorous stirring into sat. aqueous NaHCO3.
The reaction mixture was extracted with CH2Cl2, the
combined extracts dried (Na2SO4) and concentrated. The
product was suspended in Et2O (250 mL) and the precipitate
(dione 9) filtered off and rinsed with Et2O. The filtrate was
concentrated under vacuum, precipitated in a refrigerator
from petroleum ether/Et2O (3C1), filtered off and dried
under vacuum to obtain 10.8 g (79%) of enone 10a.
within 20 min at K80 8C. After 30 min a solution of
bromoester 1111,21 (1.62 g, 5.80 mmol) in THF (20 mL) was
added via a syringe pump within 5 h at K80 8C. The
reaction mixture was allowed to warm to room temperature
overnight. Sat. aqueous NH4Cl was added and the mixture
extracted with Et2O. The combined organic phases were
washed with brine (2!20 mL), dried (Na2SO4) and
concentrated under vacuum. The residue was chromato-
graphed (silica gel, ether/petroleum ether, 2C1) to yield
1.40 g (51%) of 12 (d.e.R95%, determined by 1H NMR of
the crude reaction mixture). Colorless crystals, mp 96–
98 8C. 1H (C6D6): 0.71 (t, JZ7.2 Hz, 3H, CH2CH3), 1.01 (t,
JZ7.0 Hz, 3H, CH2CH3), 1.32 and 1.34 (s, each 3H, CH3),
1.25–1.50 (m, 1H, 4-H), 1.73–1.86 (m, 1H, 4-H), 2.05–2.19
(m, 2H, 3-H), 2.55 (m, 1H, 5-H), 2.83 (dd, JZ5.7, 9.0 Hz,
1H, 8-H), 3.21 (q, JZ7.0 Hz, 2H, OCH2), 3.49–3.71 (m,
2H, OCH2), 3.65 and 3.77 (d, JZ17.1 Hz, 1H, CH2Ph), 3.89
(dd, JZ7.5, 8.4 Hz, 1H, 50-H), 4.21 (m, 1H, 40-H), 4.32 (dd,
JZ5.7, 8.4 Hz, 1H, 50-H), 6.60 (t, JZ8.1 Hz, 1H, Ph–H),
6.98 (t, JZ8.1 Hz, 1H, Ph–H), 7.17 (d, JZ8.1 Hz, 1H, Ph–
H), 7.40 (d, JZ8.1 Hz, 1H, Ph–H). 13C (C6D6): 13.65 and
15.41 (q, CH2CH3), 20.34 (t, C-4), 21.68 (t, C-3), 26.06 and
26.74 (q, CH3), 27.87 (t, 7-CH2), 43.48 (s, C-7), 43.89 (d, C-
5/C-8), 44.50 (d, C-8/C-5), 50.54 (s, C-1), 60.91 (t, OCH2),
63.92 and 70.43 (t, OCH2), 75.46 (s, C-2), 76.12 (d, C-50),
108.28 (s, C-20), 125.56 (s, Ph–C), 127.31, 127.40, 128.73,
132.68 (d, Ph–C), 139.09 (s, Ph–C), 167.99 (s, CO2Et),
207.07 (s, C-6). IR (KBr): 2990, 1720, 1700, 1520, 1490,
1380, 1270, 1250, 1070, 880, 760. MS: 508/506 (6) [M]C,
493/491 (5) [MKCH3]C, 427 (8) [MKBr]C, 369 (33), 169
(19), 101 (45), 43 (100). C25H31BrO6 (507.4): calcd C
59.18, H 6.16; found C 59.19, H 6.21. [a]20ZC46.94 (cZ
1.0, MeOH).
1
Colorless crystals, mp 79–81 8C. H: 1.22 (t, JZ7.0 Hz,
3H, CH3), 2.05 (m, 2H, 5-H), 2.44 (t, JZ7.0 Hz, 2H, 4-H/6-
H), 2.63 (t, JZ7.0 Hz, 2H, 6-H/4-H), 3.76 (s, 2H, CH2Ph),
4.02 (q, JZ7.0 Hz, 2H, OCH2), 6.96–7.04 (m, 2H, Ph–H),
7.15–7.20 (m, 1H, Ph–H), 7.52 (m, 1H, Ph–H). 13C: 15.05
(q, CH3), 20.87 (t, C-5), 25.42 (t, C-4/C-6), 28.14 (t, C-6/C-
4), 36.30 (t, CH2Ph), 63.72 (t, OCH2), 117.34 (s, C-2),
124.62 (s, Ph–C), 126.77, 126.85, 129.11, 132.13 (d, Ph–C),
140.40 (s, Ph–C), 173.27 (s, C-3), 197.81 (s, C-1). IR (KBr):
2960, 1630 (C]O), 1610 (C]C), 1380, 1240, 1200, 1050,
760. MS: 229 (94) [MKBr]C, 201 (100), 171 (14), 115 (20),
54 (20). C15H17BrO2 (309.2): calcd C 58.27, H 5.54; found
C 58.14, H 5.58.
3.1.4. 3-Benzyloxy-2-(2-bromobenzyl)-cyclohex-2-en-1-
one (10b). Benzyl alcohol (1.62 g, 15 mmol) and a catalytic
amount of p-TsOH were added to a solution of dione 9
(3.37 g, 12 mmol) in toluene (100 mL). The mixture was
˚
heated to reflux at a Dean–Stark trap charged with 3A
molecular sieves until the disappearance of the starting
material (TLC: Et2O/petroleum etherZ4C1). The reaction
mixture was neutralized with sat. aqueous NaHCO3, the
organic phase separated and the aqueous phase extracted
with Et2O. The combined and dried (MgSO4) organic
phases were concentrated and the residue chromatographed
(silica gel, Et2O/petroleum etherZ4C1) to yield 3.74 g
3.1.6. Ethyl (1S,2S,6S,7S,10R,11R,40S)-benzo[4,5]-6-
hydroxy-11-(20,20-dimethyl-10,30-dioxolan-40-yl)-tetracy-
clo[5.3.1.02,6.02,10]undecane-1-carboxylate (13). To a
solution of tricycle 12 (2.46 g, 4.85 mmol) in THF
(120 mL) was added tert-butyllithium in pentane (6.7 mL,
10.0 mmol, 1.5 M) within 10 min at K115 8C. The reaction
mixture was kept at this temperature for 2 h, warmed to
K45 8C within 1 h and quenched with sat. aqueous NH4Cl
(30 mL). The reaction mixture was extracted with Et2O, the
combined organic phases dried (Na2SO4) and concentrated
to yield alcohol 13 as a pale yellow oil, which was used
directly without further purification.
1
(84%) of enone 10b. Waxy yellow solid. H: 2.00 (tt, J1Z
J2Z6.2 Hz, 2H, 5-H), 2.40 (m, JZ6.2 Hz, 2H, 6-H), 2.60 (t,
JZ6.2 Hz, 2H, 4-H), 3.79 (s, 2H, CH2C6H4Br), 5.05 (s, 2H,
OCH2C6H5), 6.96–7.16 (m, 4H, C6H4Br and C6H5), 7.26–
7.31 (m, 3H, C6H4Br and C6H5), 7.36 and 7.49 (m, 1H,
C6H4Br, each). 13C: 20.83 (t, C-5), 25.60 (t, C-4), 28.22 (t,
CH2C6H4Br), 36.22 (t, C-6), 69.34 (t, OCH2C6H5), 117.99
(s, C-2), 124.78 (s, CBr), 126.63, 126.91, 126.97, 128.08,
128.58, 129.06, 132.25 (d, C6H4Br and C6H5), 136.14 (s,
C6H5), 140.15 (s, C6H4Br), 172.80 (s, C-3), 197.81 (s, C-1).
IR (film): 3060, 3040, 2950, 2890, 1645 (C]O), 1610
(C]C), 1500, 1470, 1455, 1440, 1370, 1240, 1190, 1115,
1085, 1045, 1035, 975, 930, 875, 845, 755, 710. MS: 326/
328 (3), 291 (48) [MKBr]C, 200 (19) [MKC7H7]C, 199
(72), 108 (12), 92 (20), 91 (100) [C7H7]C, 65 (16). APCI-
MS: 371/373 (100) [MCH]C, 91 (8) [C7H7]C. C20H19O2Br
(371.27): calcd C 64.70, H 5.16, Br 21.52; found C 64.99, H
5.37, Br 21.44.
3.1.7. Ethyl (1S,7R,11R,40S)-benzo[4,5]-11-(20,20-
dimethyl-10,30-dioxolan-40-yl)-10-oxotricyclo[5.3.1.02,6
]
undec-2(6)-ene-1-carboxylate (14). Crude alcohol 13 was
dissolved in CH2Cl2 (80 mL) and treated with 15% HCl
(2 mL) for 1 h. The reaction mixture was alkalinized with
sat. aqueous NaHCO3 (30 mL). The organic layer was
separated and the aqueous phase extracted with CH2Cl2.
The combined organic phases were dried (Na2SO4),
concentrated and chromatographed (silica gel, petroleum
ether/Et2OZ4C1) to give 1.09 g (59%) of ketone 14.
Colorless oil, that solidified upon standing at 0 8C, mp 82–
85 8C. 1H (C6D6): 0.99 (t, JZ7.3 Hz, 3H, OCH2CH3), 1.35
and 1.42 (s, each 3H, CH3), 1.38–1.60 (m, 1H, 8-H), 1.82
(dd, JZ10.0, 17.5 Hz, 1H, 9-H), 2.03 (dd, JZ7.5, 17.5 Hz,
1H, 9-H), 2.28–2.41 (m, 1H, 8-H), 3.14 (dd, JZ4.1,
10.0 Hz, 1H, 11-H) 3.14 and 3.36 (d, JZ23.2 Hz, each
3.1.5. Ethyl (1S,2R,5S,7S,8R,40S)-7-(2-bromobenzyl)-8-
(20,20-dimethyl-10,30-dioxolan-40-yl)-2-ethoxy-6-oxotricy-
clo[3.2.1.02,7]octane-1-carboxylate (12). To LDA
(5.8 mmol) in THF (100 mL) was added under stirring a
solution of enone 10a (1.67 g, 5.40 mmol) in THF (50 mL)

H.-J. Gutke et al. / Tetrahedron 60 (2004) 8137–8141
8141
1H, 3-H), 3.43 (sbr, 1H, 7-H), 4.03 (q, JZ7.3 Hz, 2H,
References and notes
OCH2), 4.04 (dd, JZ7.8, 8.8 Hz, 1H, 50-H), 4.34 (m, 1H, 40-
H), 4.53 (dd, JZ5.6, 8.8 Hz, 1H, 50-H), 7.07–7.28 (m, 4H,
Ph–H). 13C (C6D6): 14.14 (q, CH2CH3), 22.52 (t, C-8),
25.97 and 26.86 (q, CH3), 35.68 (t, C-9), 38.03 (d, C-11),
60.13 (d, C-7), 61.05 (t, CH2CH3), 69.77 (s, C-1), 71.14 (t,
C-50), 74.23 (d, C-40), 108.15 (s, C-20), 119.97, 124.88,
125.56, 126.81 (d, Ph–C), 140.01 and 147.93 (s, Ph–C),
147.97 (s, C-6), 153.31 (s, C-2), 168.84 (s, CO2Et), 202.27
(s, C-10). IR (KBr): 3000, 1740 (C]O), 1710 (C]O),
1470, 1380, 1260, 1070, 880, 740. MS: 382 (12) [M]C, 367
(24) [MKCH3]C, 324 (77), 238 (24), 165 (25), 43 (100).
C23H26O5 (382.5): calcd C 72.23, H 6.85; found C 72.12, H
6.91.
1. Paterson, I.; Florence, G. J. Eur. J. Org. Chem. 2003, 2193–
2208.
2. Cragg, G. M.; Newman, D. J. J. Nat. Prod. 2004, 67, 232–244.
3. Connolly, J. D.; Hill, R. A.; Dictionary of Terpenoids, Vol. 2;
Chapman & Hall: London, 1991 pp 1048–1052.
4. Swindell, C. S. Org. Prep. Proced. Int. 1991, 23, 465–543.
5. Morrissey, S. R. Chem. Eng. News 2003, 81(37), 17–20.
6. Nicolaou, K. C.; Dai, W.-M.; Guy, R. K. Angew. Chem. 1994,
106, 38–69. Angew. Chem. Int. Ed. 1994, 33, 15–44.
7. Nicolaou, K. C.; Claiborne, C. F.; Nantermet, P. G.;
Couladouros, E. A.; Sorensen, E. J. J. Am. Chem. Soc. 1994,
116, 1591–1592.
8. Filippini, M.-H.; Rodriguez, J. Chem. Rev. 1999, 99, 27–76.
9. Trost, B. M.; Hiemstra, H. J. Am. Chem. Soc. 1982, 104, 886–
887.
3.1.8. Ethyl (1S,7R,11R,40S)-benzo[4,5]-11-(20,20-
dimethyl-10,30-dioxolan-40-yl)-2,6,10-trioxobicy-
clo[5.3.1]undecane-1-carboxylate (15). A solution of
alkene 14 (0.35 g, 0.91 mmol) in MeOH (40 mL) was
cooled to K95 8C and treated with ozone until the mixture
remained blue. Dimethylsulfide (15 mL) was added
immediately after completion of the reaction. The reaction
mixture was allowed to warm to room temperature within
2 h. The solvents were evaporated under vacuum and the
residue crystallized at K25 8C from Et2O/petroleum ether
(1C1, 5 mL) to yield 0.31 g (81%) of triketone 14.
10. Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151–1196.
11. Braun, N. A.; Klein, I.; Spitzner, D.; Vogler, B.; Braun, S.;
Borrmann, H.; Simon, A. Liebigs Ann. 1995, 2165–2169.
12. Braun, N. A.; Klein, I.; Spitzner, D.; Vogler, B.; Borrmann, H.;
Simon, A. Tetrahedron Lett. 1995, 36, 3675–3678.
13. Tietze, L. F. Chem. Rev. 1996, 96, 115–136.
14. Brunce, R. A. Tetrahedron 1995, 51, 13103–13159.
15. Spitzner, D.; Rahman, A.-u., Ed.; Sequential Michael-
Additions in the Synthesis of Natural Products Studies in
Natural Products Chemistry, Part E. Elsevier: Amsterdam;
1991. p. 409–431.
1
Colorless crystals, mp 91–96 8C. H (C6D6): 0.88 (t, JZ
7.5 Hz, 3H, OCH2CH3), 1.13 and 1.14 (s, each 3H, CH3),
1.60–1.75 (m, 1H, 8-H), 2.16–2.30 (m, 1H, 8-H), 2.41–2.54
(m, 1H, 9-H), 2.97 (m, 1H, 9-H), 3.36 (d, JZ4.6 Hz, 1H, 11-
H), 3.43 (dt, JZ3.5, 6.9 Hz, 1H, 7-H), 3.51 and 3.89 (d, JZ
22.0 Hz, each 1H, 3-H), 3.90 (q, JZ7.5 Hz, 2H, OCH2CH3),
3.99 (dd, JZ5.0, 9.6 Hz, 1H, 50-H), 4.25 (dd, JZ6.1,
9.6 Hz, 1H, 50-H), 4.62 (dt, JZ4.8, 6.3 Hz, 1H, 40-H), 6.61–
6.67 (m, 1H, Ph–C), 6.88–6.93 (m, 2H, Ph–H), 7.00–7.05
(m, 1H, Ph–H). 13C (C6D6): 13.77 (q, OCH2CH3), 21.07 (t,
C-8), 24.41 and 26.46 (q, CH3), 36.65 (t, C-9), 44.78 (d, C-
11), 46.47 (t, C-3), 48.40 (d, C-7), 62.32 (t, OCH2CH3),
70.65 (t, C-50), 74.22 (d, C-40), 77.10 (s, C-1), 109.36 (s, C-
20), 127.86, 128.15, 129.88, 130.05 (d, Ph–C), 131.47 (s,
C-5), 139.99 (s, C-6), 166.63 (s, CO2Et), 200.93 (s, C-6),
201.14 (s, C-10), 207.32 (s, C-2). IR (CCl4): 2980, 1725,
1700, 1660, 1460, 1380, 1070, 880. MS: 414 (1) [M]C, 399
(6) [MKCH3]C, 356 (5), 338 (6), 313 (44), 267 (84), 101
(95), 43 (100). C23H26O7 (414.5): calcd C 66.65, H 6.32;
found C 67.04, H 6.37.
16. Hadjiarapoglou, L.; Klein, I.; Spitzner, D.; de Meijere, A.
Synthesis 1996, 525–528.
17. Braun, N. A.; Stumpf, N.; Spitzner, D. Synthesis 1997, 917–
920.
18. Gutke, H.-J.; Oesterreich, K.; Spitzner, D.; Braun, N. A.
Tetrahedron 2001, 57, 997–1003.
19. PC-MODEL, Version 4.0; Serena Software: Bloomington, IN,
USA.
20. de Meijere, A.; Hadjiarapoglou, L.; Gutke, H.-J.; Klein, I.;
Spitzner, D.; Eur J. Org. Chem. 1998, 441–451.
21. Hadjiarapoglou, L.; de Meijere, A.; Seitz, H.-J.; Klein, I.;
Spitzner, D. Tetrahedron Lett. 1994, 35, 3269–3272.
22. Ambrosi, H.-D.; Duczek, W.; Ramm, M.; Gru¨ndemann, E.;
¨
Schulz, B.; Jahnisch, K. Liebigs Ann. Chem. 1994, 1013–1018.
23. Mori, M.; Kaneta, N.; Shibasaki, M. J. Organomet. Chem.
1994, 464, 35–40.
24. Peters, K.; Peters, E. -M.; Gutke, H. -J.; Spitzner, D. Submitted
for publication.
25. Ott, M. M.; Little, R. D. J. Org. Chem. 1997, 62, 1610–1616.
26. Shimada, Y.; Nakamura, M.; Suzuka, T.; Matsui, J.; Tatsumi,
R.; Tsutsumi, K.; Morimoto, T.; Kurosawa, H.; Kakiuchi, K.
Tetrahedron Lett. 2003, 44, 1401–1403.
Acknowledgements
27. Tochtermann, W.; Kraft, P. Synlett 1996, 1029–1035.
28. Braun, N. A.; Bu¨rkle, U.; Feth, M. P.; Klein, I.; Spitzner, D.;
Eur J. Org. Chem. 1998, 1569–1576.
We thank the Deutsche Forschungsgemeinschaft (project:
Sp 198/11-2), Bonn, and Chemetall GmbH, Frankfurt
(Main), for generous gifts of chemicals. N. A. B. thanks
29. Mori, M.; Uozumi, Y.; Shibasaki, M. Heterocycles 1992, 33,
819–830.
¨
¨
the Landesgraduiertenforderung, Baden-Wurttemberg, for a
scholarship.
30. Mori, M.; Uozumi, Y.; Shibasaki, M. J. Org. Chem. 1991, 56,
3486–3493.