An enantioselective approach to cytotoxic norcalamenenes via electron-transfer-driven benzylic umpolung of an arene tricarbonyl chromium complex

Article abstract of DOI:10.1055/s-2003-41030

An efficient enantioselective total synthesis of (R)-1-isopropenyl-6-methoxy-7-methyl-1,2,3,4-tetrahydronaphthalene, the dehydro-analog of the cytotoxic norsesquiterpene (R)-7-demethyl-2-methoxycalamenene, was achieved in seven steps starting from 6-methoxytetralone. The synthesis exploits the specific reactivity and stereochemistry of planar chiral η⁶-arene-Cr(CO)₃ complexes. In a key step, a Cr(CO)₃-complexed benzylic anion, regioselectively generated by means of electron- transfer-driven benzylic umpolung, is diastereoselectively alkylated with acetyl chloride.

Full text of DOI:10.1055/s-2003-41030

PAPER
1851
An Enantioselective Approach to Cytotoxic Norcalamenenes via Electron-
Transfer-Driven Benzylic Umpolung of an Arene Tricarbonyl Chromium
Complex
An
E
nantioselectiv
a
e
A
pproach
n
toCytotoxi
s
c
N
orcala
-
menenesGünther Schmalz,* Oliver Kiehl, Ursula Korell, Johann Lex
Institut für Organische Chemie, Universität zu Köln, Greinstrasse 4, 50939 Köln, Germany
Fax +49(221)4703064; E-mail: Schmalz@uni-koeln.de.
Received 13 June 2003; revised 3 July 2003
Dedicated to Professor Wolfgang Steglich on the occasion of his 70th birthday.
probe and demonstrate the power of arenechromium
chemistry.6 We disclose here a short and highly selective
synthesis of 2, which makes use of a methodology devel-
oped in this laboratory, i.e. the benzylic umpolung of
Abstract: An efficient enantioselective total synthesis of (R)-1-iso-
propenyl-6-methoxy-7-methyl-1,2,3,4-tetrahydronaphthalene, the
dehydro-analog of the cytotoxic norsesquiterpene (R)-7-demethyl-
2-methoxycalamenene, was achieved in seven steps starting from 6-
methoxytetralone. The synthesis exploits the specific reactivity and arene-Cr(CO)3 complexes.7
stereochemistry of planar chiral 6-arene-Cr(CO)3 complexes. In a
As a precursor for the synthesis of 1 and 2 we considered
key step, a Cr(CO)3-complexed benzylic anion, regioselectively
generated by means of electron- transfer-driven benzylic umpolung,
is diastereoselectively alkylated with acetyl chloride.
the chromium complex 3 as a suitable candidate, which
would allow aromatic methylation in the position ortho to
the methoxy group. The diastereoselective introduction of
the isopropenyl side chain could then be imagined by
benzylic alkylation of the planar chiral anionic complex 4
from the less hindered face of the ligand. This intermedi-
ate 4 represents a Cr(CO)3-stabilized benzylic anion8,9
which cannot be prepared by regioselective deprotonation
Key words: arene complexes, asymmetric synthesis, chromium,
electron-transfer, natural products
The demethyl calamenene 1 and some related norsesqui-
terpenes were isolated by Bohlmann et al. from the plant
Heterotheca grandiflora in 1979.1 Three syntheses of rac-
1 using standard methodology have been published.2 The
main challenge for synthetic chemistry posed by such
compounds, however, is the control of the absolute con-
figuration of the benzylic stereocenter. The only enantio-
selective synthesis of 1 and its dehydro analogue 2
(Figure 1) was reported in 1995 by Tietze and Raschke.3
These authors also identified 1 as a potent cytotoxic agent
against cells of the human bronchial adenocarcinoma A
549. The Tietze synthesis utilizes an elegant enantioselec-
tive (silane terminated) Heck reaction4 as the key step and
reaches the target molecule in eleven steps starting from
3-(3-methoxyphenyl)propanol.
of the substituted tetralin-Cr(CO)3 derivative
5
(Scheme 1).10 Nevertheless, it seemed feasible to generate
4 from the chiral (nonracemic) ethoxy substituted com-
plex 6 by treating it with a single electron reducing agent
according to our method for the benzylic umpolung of
such complexes.7
1/2
OMe
Cr(CO)3
5
OMe
OMe
OEt
Cr(CO)3
Cr(CO)3
3
4
OMe
Cr(CO)3
6
OMe
OMe
Scheme 1 Retrosynthetic Analysis
1
2
Figure 1 Structures of the cytotoxic nor-sequiterpene 1 and its de-
hydro-analog 2
Our synthesis (Scheme 2) started from the commercially
available ketone 7, which was first converted to the tetra-
lol 8 by enantioselective borane reduction (CBS reduc-
tion)11 in the presence of the oxazaborolidine catalyst 12
[prepared from (S)- , -diphenylprolinol and methylbo-
ronic acid]. Dichloromethane proved to be the solvent of
choice in this case giving the product 8 in 96% yield and
an enantiomeric purity of 94% ee.12 Less satisfying results
(89% ee, 85% yield) were obtained in THF as the solvent
commonly used in such reactions. Diastereoselective
complexation of 8 was achieved, even on multigram scale,
In the course of our program aimed at the use of planar
chiral arene-Cr(CO)3 complexes as synthetic building
blocks,5 we were interested in developing an efficient al-
ternative access to 1 and related compounds in order to
Synthesis 2003, No. 12, Print: 02 09 2003. Web: 13 08 2003.
Art Id.1437-210X,E;2003,0,12,1851,1855,ftx,en;T05103SS.pdf.
DOI: 10.1055/s-2003-41030
© Georg Thieme Verlag Stuttgart · New York

1852
H.-G. Schmalz et al.
PAPER
by refluxing it with Cr(CO)6 in a 1:1 mixture of dibutyl
ether and heptane containing small amounts of THF.13
The diastereoselectivity was greater than 90% as deter-
mined by HPLC from the crude reaction mixture. After re-
moving the significantly more polar (undesired) exo-
diastereomer by flash chromatography, the pure crystal-
line endo-complex 9 was obtained in 84% yield. Reaction
of 9 with ethyl iodide and powdered KOH in DMSO14 af-
forded the desired ether 6, the key intermediate for the
planned benzylic alkylation.
+ 1e-
-OEt-
AcCl
+ 1e-
6
10
OMe
OMe
Cr(CO)3
Cr(CO)3
4 (18 VE)
13 (17 VE)
Scheme 3 Electron-transfer-driven formation of the benzylic anion
4
Having succeeded in preparing the benzylic acylated te-
tralin derivative 10 in a highly regio- and diastereoselec-
tive manner, methylenation of 10 employing the method
of Lombardo (CH2Br2, Zn, TiCl4)16 afforded complex 3 in
76% yield. Remarkably, the time required for the prepara-
tion of the reagent was reduced considerably by using ul-
trasound (4 h at 0 °C versus 3 d at 5 °C in the original
procedure). The regioselective introduction of the methyl
group at C-3 was then achieved by ortho-lithiation of 3
with n-butyllithium and subsequent addition of methyl io-
dide. After chromatographic separation of the bis-methyl-
ated by-product 14 (ca. 15%) and recrystallization in
order to remove small amounts (ca. 5%) of the undesired
regioisomer 15 (Figure 2), the pure complex 11 was ob-
tained in 71% yield.
OH
O
OH
b
a
OMe
OMe
OMe
Cr(CO)3
9
7
8
(94% ee)
c
O
OEt
e
d
OMe
OMe
OMe
Cr(CO)3
Cr(CO)3
Cr(CO)3
3
10
6
f
Ph
H
Ph
g
O
N
OMe
OMe
B
OMe
OMe
Cr(CO)3
Cr(CO)3
Cr(CO)3
12
2
11
(99% ee)
14
15
Figure 2 By-products 14 and 15 formed during the preparation of
11
Scheme 2 Reagents and conditions: (a) 12 (30 mol%), BH3·DMS
(1.5 equiv), CH2Cl2, r.t., 3 h, 96%; (b) Cr(CO)6 (1.5 equiv), Bu2O–n-
heptane–THF (10:10:1), reflux, 42 h, 84%; (c) KOH (4 equiv), EtI (2
equiv), DMSO, r.t., 3 h, recryst., 74%; (d) LiDBB (excess), THF, –78
Complex 11 showed an enantiomeric purity of 99% ee as
determined by HPLC.12 Obviously, an enantiomeric en-
richment had occurred during recrystallization at the stage
of 6 or 11. The relative and absolute configuration of com-
plex 11 was confirmed by X-ray crystal structure analysis
(Figure 3), which shows the molecule preferring a
pseudochair conformation with the isopropenyl side chain
in a pseudo-equatorial position.17
–40 °C, 1 h, AcCl (3 equiv), –40 °C
Zn, CH2Br2, THF, CH2Cl2, 0 °C, 15 min, r.t., 4 h, 76%; (f) n-BuLi
(1.2 equiv), –70 –25 °C, 1.5 h, –45 °C, MeI (2.2 equiv),
r.t., 2.5 h, 61%; (e) TiCl4,
–20 °C, 40 min, r.t., 70 min, recryst., 71%; (g) sunlight, air, Et2O, 6 h,
97%
Following the standard protocol developed before,7 com-
pound 6 was first reacted with an excess (4 equiv) of lith-
ium 4,4 -di-tert-butylbiphenyl (LiDBB)15 at –78 °C, and
the resulting anion 4 was trapped with acetyl chloride to
give exclusively the exo-acetylated product 10 in 61%
yield.
The facile conversion of 6 under the conditions described
can be understood in terms of the electron-transfer (ET)-
driven process shown in Scheme 3. After the initial trans-
fer of an electron from the single electron reducing agent
LiDBB and loss of the ethoxy anion, a 17 VE (valence
electron) radical intermediate 13 is formed. This is rapidly
reduced by a second ET to the more stable anionic 18 VE
species 4, from which the product 10 arises by benzylic
exo-acylation as a sole diastereomer.
Figure 3 Structure of complex 11 in the crystalline state
Synthesis 2003, No. 12, 1851–1855 © Thieme Stuttgart · New York

PAPER
An Enantioselective Approach to Cytotoxic Norcalamenenes
1853
of 8 as a colorless oil (94% ee as determined by HPLC). HPLC: iso-
propyl alcohol–hexane (20:80), UV-detection at 256 nm; tr (ent-
8) = 12.5 min, tr (8) = 14.4 min; [ ]589 –23.3, [ ]578 –24.4, [ ]546
–28.1, [ ]436 –52.3.
1H NMR (400 MHz, CDCl3): = 1.68–1.82 (1 H, m), 1.88–2.02 (3
H, m), 2.46–2.55 (1 H, m), 2.56–2.66 (1 H, m), 3.79 (3 H, s), 4.72
(1 H, br s), 6.63 (1 H, d, J = 3.0 Hz); 6.77 (1 H, dd, J = 3.0, 8.5 Hz);
7.33 (1 H, d, J = 8.5 Hz).
Simple exposure of an etheral solution of 11 to sunlight
and air finally led to compound 2 in 97% yield, which ex-
hibited identical characteristic properties as the sample re-
ported by Tietze and coworkers.
In conclusion, we have synthesized the target compound
2 in a short and efficient reaction sequence exploiting both
chemical and stereochemical properties of arene-Cr(CO)3
complexes. Starting from a central chiral compound 8 the
absolute stereochemical information is transferred in the
complexation step to the planar chiral metal complex sub-
structure, from which it is transferred back during the ben-
zylic alkylation to a lasting chiralilty center. Thus, this
synthesis represents another example for the concept of
(1R,4aS)-Tricarbonyl-[ 6-(6-methoxy-1,2,3,4-tetrahydronaph-
thalene-1-ol)]chromium(0) (9)
A flame dried Schlenk flask equipped with a reflux condenser and
a mercury bubbler was charged with 6-methoxytetralol (8; 1.99 g,
11.2 mmol), Cr(CO)6 (3.70 g, 16.8 mmol), anhyd dibutyl ether (65
mL) and anhyd n-heptane (65 mL). The apparatus was evacuated
self-regeneration of a stereocenter.18 The synthesis re- and flushed with argon several times before adding anhyd THF (6.5
mL). The mixture was refluxed under stirring for 42 h and then al-
lowed to cool to r.t. under argon. After filtration and concentration
in vacuo, the crude product was purified by flash chromatography
(CH2Cl2) to yield pure 9 as a yellow crystalline solid (2.97 g, 84%);
quires only seven steps for the conversion of 6-methoxy-
tetralone (7) to the target molecule 2 in ca. 20% overall
yield. It demonstrates the usefulness of the electron-trans-
fer-driven umpolung of Cr(CO)3-complexed benzylic
mp 101 °C; [ ]589 –20.9, [ ]578 –23.9, [ ]546 –35.1 (c = 0.33,
ethers for the regioselective generation of a Cr(CO)3-com-
plexed benzylic anion. As both carbon substituents at the
tetralin core are introduced by alkylation, it should be pos-
sible to use the same strategy for the preparation of a
broad range of structurally related compounds with differ-
ent side chains.19
CHCl3).
IR: 3436, 3091, 2944, 2870, 1951, 1862, 1541, 1475, 1458, 1439,
1393, 1271, 1235, 1151, 1112, 1069, 1044, 1022, 999, 971, 845,
687, 671 cm–1.
1H NMR (400 MHz, CDCl3): = 1.65–1.74 (2 H, m), 1.92–2.02 (2
H, m), 2.60–2.68 (1 H, m), 2.76–2.86 (1 H, m), 3.74 (3 H, s), 4.83–
4.44 (1 H, m), 4.94 (1 H, d, J = 2.5 Hz), 5.04 (1 H, dd, J = 2.5, 7.0
Hz), 5.91 (1 H, d, J = 7.0 Hz).
NMR spectra were recorded on Bruker AM 270, AM 400, AM 500
spectrometers. Proton chemical shifts are reported in ppm ( ) rela-
tive to the solvent reference (CDCl3, = 7.24). Data are reported as
follows: chemical shift (multiplicity [singlet (s), doublet (d), triplet
(t), quartet (q), multiplet (m), broad (br) and pseudo ( )], coupling
constants [Hz], integration). Carbon chemical shifts are reported in
ppm ( ) relative to the solvent resonance as the internal standard
(CDCl3, = 77.0). Multiplicities were determined via DEPT and
are given as follows: q (CH3), t (CH2), d (CH), s (quaternary car-
bons). IR spectra were recorded on a Nicolet Magna FT-IR using
the ATR technique (attenuated total reflectance). Mass spectra were
obtained on a Finnigan MAT 95 ST spectrometer (70 eV). Enantio-
meric purities were determined by analytical HPLC using Daicel
Chiracel OJ column on a Merck-Hitachi HPLC system with pump
L 6200 and UV detector L 4000. Optical rotations were measured
on Perkin-Elmer 241 polarimeter at 20 °C, concentrations (c) are
given in g/100 mL. Preparative thin layer chromatography (PTLC)
was carried out using a chromatotron Harrison Research 7924 T on
glass plates coated with 1–4 mm layers of silica gel containing gyp-
sum (Merck PF 60F 254). The sonochemical transformation was
carried out using a Branson Sonifier 250 apparatus.
13C NMR (67.7 MHz, CDCl3): = 18.7 (t), 28.2 (t), 32.2 (t), 55.6
(q), 65.6 (d), 77.9 (d), 76.9 (d), 94.5 (d), 107.9 (s), 113.6 (s), 142.7
(s), 233.2 (s).
MS (DIPMS: 90 °C): m/z (%) = 314 ([M]+, 28), 258 (9), 230 (28,
[M]+ – 3 CO), 228 (19), 212 (17), 210 (28), 162 (12), 161 (100), 149
(10), 148 (11), 111 (11), 109 (10), 97 (16).
HRMS: m/z calcd for C14H14CrO5: 314.0246; found: 314.0241.
(1R,4aS)-Tricarbonyl[ 6-(1-ethoxy-6-methoxy-1,2,3,4-tetrahy-
dronaphthalene)]chromium(0) (6)
Powdered KOH (1.45 g, 25.9 mmol) and complex 9 (2.0 g, 6.47
mmol) were suspended in anhyd DMSO (15 mL) and the mixture
was stirred for 15 min at r.t. to give a brownish solution. The mix-
ture was then cooled to 15 °C and EtI (1 mL, 12.9 mmol) was added.
After 4 h at r.t., TLC control indicated complete conversion of 9.
The mixture was partitioned between H2O and t-butyl methyl ether
(MTBE) and the aqueous phase was extracted several times with
MTBE. The combined organic layers were washed with H2O and
brine, dried (MgSO4) and the solvent was removed under reduced
pressure. The resulting yellow solid was recrystallized from
MTBE–hexane. An additional crop of pure 6 was obtained from the
mother liquor after PTLC (hexane–EtOAc, 5:1). Complex 6 was
obtained as a yellow solid (combined yield: 1.64 g, 74%); mp
132 °C; [ ]589 –25.9, [ ]546 –39.5 (c = 0.495, CHCl3).
(1R)-6-Methoxy-1,2,3,4-tetrahydronaphthalene-1-ol (8)
In a flame dried Schlenk flask equipped with a pressure equalizing
dropping funnel (charged with 40 mL of 4 Å molecular sieves, and
topped with a reflux condenser), a solution of (S)-diphenylprolinol
(861 mg, 3.4 mmol) and methylboronic acid (204 mg, 2.00 mmol)
in anhyd toluene (96 mL) was refluxed for 15 h under argon. After
removal of the solvent, the residue (the oxazaborolidine 12) was
dried in vacuo and then dissolved in anhyd CH2Cl2 (10 mL). Then,
a 2 M solution of BH3·SMe2 (8.5 mL) was added and the mixture
was stirred for 15 min before a solution of 6-methoxytetralone (7;
2.00 g, 11.35 mmol) in anhyd CH2Cl2 (9 mL) was added via a sy-
ringe pump over a period of 2 h. After stirring for 1 h at r.t., MeOH
(ca. 15 mL) was added carefully (gas evolution) and all the solvents
were evaporated in vacuo. The crude product was purified by flash
chromatography (EtOAc– cyclohexane, 1:1) to yield 1.939 g (96%)
IR: 2975, 2943, 2869, 1951, 1863, 1541, 1475, 1440, 1394, 1270,
1150, 1114, 1023, 671 cm–1.
1H NMR (400 MHz, CDCl3): = 1.29 (3 H, t, J = 7.0 Hz), 1.56–1.70
(2 H, m), 1.88–2.02 (2 H, m), 2.56–2.64 (1 H, m), 2.76–2.86 (1 H,
m), 3.49 (1 H, m), 3.71 (3 H, s), 3.76 (1 H, m), 4.08 (1 H, br dd,
J = 5.0, 7.0 Hz), 4.86 (1 H, d, J = 2.0), 5.01 (1 H, dd, J = 2.0, 7.5
Hz), 5.80 (1 H, d, J = 7.5 Hz).
13C NMR (67.7 MHz, CDCl3): = 15.3 (q), 18.8 (t), 27.7 (t), 28.1
(t), 55.5 (q), 64.6 (t), 72.5 (d), 76.2 (d), 76.4 (d), 94.2 (d), 105.2 (s),
112.1 (s), 142.9 (s), 233.9 (s).
Synthesis 2003, No. 12, 1851–1855 © Thieme Stuttgart · New York

1854
H.-G. Schmalz et al.
PAPER
IR: 2942, 1952, 1862, 1541, 1474, 1261, 1150, 1023, 671 cm–1.
1H NMR (400 MHz, CDCl3): = 1.54–1.64 (1 H, m), 1.67 (3 H, s),
1.75–1.88 (3 H, m), 3.24 (1 H, dd, J = 9.0, 7.0 Hz), 3.69 (3 H, s),
4.70 (1 H, s), 4.92 (1 H, s), 4.99 (1 H, d, J = 2.0 Hz), 5.12 (1 H, dd,
J = 7.0, 2.0 Hz), 5.58 (1 H, d, J = 7.0 Hz).
13C NMR (67.7 MHz, CDCl3): = 19.5 (q), 19.7 (t), 27.2 (t), 29.0
(t), 45.3 (d), 55.5 (q), 77.8 (d), 78.5 (d), 95.9 (d), 103.9 (s), 111.5
(s), 114.8 (t), 142.4 (s), 147.2 (s), 233.8 (s).
MS: m/z (%) = 342 (45), 286 (20), 258 (58), 256 (39), 214 (100),
212 (98), 197 (12), 162 (10), 161 (85), 115 (10), 91 (10), 69 (14), 52
(96).
HRMS: m/z calcd for C16H18CrO5: 342.0559; found: 342.0555.
(1S,4aS)-Tricarbonyl[ 6-(1-acetyl-6-methoxy-1,2,3,4-tetrahy-
dronaphthalene)]chromium(0) (10)
An argon flushed Schlenk flask was charged with di-tert-butylbi-
phenyl (309 mg, 1.16 mmol) in anhyd THF (15 mL). The stirred so-
lution was cooled in an ice–water bath before lithium metal (16 mg,
2.32 mmol, freshly cleaned by immersing into acetone for a few
seconds and subsequently polishing the surface under cyclohexane)
were added. Within a few min a deep blue-green color appeared and
rapid stirring was continued for another 3–4 h at 0 °C. The mixture
was filtered under argon through a Schlenk frit and cooled to
–78 °C. Then, a solution of 6 (100 mg, 0.29 mmol) in anhyd THF (5
mL) was added all at once by means of a gas-tight syringe. The re-
sulting mixture was stirred for about 1 h while warming from –78 to
–40 °C, before it was transferred through a cannula to a stirred so-
lution of freshly distilled acetyl chloride (0.062 mL, 0.87 mmol) in
THF (5 mL) cooled to –40 °C. After stirring for 30 min at the same
temperature, the cooling bath was removed and stirring was contin-
ued for 2.5 h at r.t. The reaction mixture was partitioned between
MTBE (20 mL) and H2O (25 mL) and the aqueous layer was ex-
tracted with MTBE (2 × 30 mL). The combined organic layers were
washed with brine and dried (MgSO4). The solvent was removed
under reduced pressure and the residue was purified by flash chro-
matography (hexane–EtOAc, 3:1) to yield 10 (60 mg, 61%) as a yel-
low solid; mp 128 °C (dec.); [ ]589 +96.7, [ ]546 +118.2 (c = 0.295,
CHCl3).
MS: m/z (%) = 338 ([M]+, 16), 254 ([M]+ – 3 CO, 100), 161 (17), 91
(16), 71 (13), 58 (22), 43 (65).
HRMS: m/z calcd for C17H18CrO4: 338.0610; found: 338.0612.
(1R,4aS)-Tricarbonyl[ 6-(1-isopropenyl-6-methoxy-7-methyl-
1,2,3,4-tetrahydronaphthalene)]chromium(0) (11)
A solution of 3 (100 mg, 0.294 mmol) in anhyd THF (5 mL) was
cooled to –70 °C before a 1.58 M solution of n-BuLi in hexane
(0.225 mL, 0.355 mmol) was added by a syringe. The mixture was
allowed to warm up to –25 °C over a period of 90 min before it was
cooled to –45 °C and MeI was added. After allowing the mixture to
warm up to –20 °C within 40 min, the cooling bath was removed
and the stirring was continued for 70 min at r.t. After dilution with
MTBE (30 mL), H2O (10 mL) was added. The aqueous phase was
extracted with MTBE (2 × 40 mL) and the combined organic phases
were washed with brine (2 × 30 ml) and dried (MgSO4). The solvent
was distilled off under reduced pressure and the resulting yellow oil
was purified by PTLC using hexane–CH2Cl2 (3:1) to yield a 93:7
mixture of 11 and its isomer 15 (detected by 1H NMR spectrosco-
py). Recrystallization yielded pure 11 (88 mg, 71%) as a yellow sol-
id; mp 104 °C; [ ]589 +249.7, [ ]54620 +307.7, (c = 0.1, CHCl3).
IR: 2945, 1951, 1859, 1711, 1544, 1480, 1359, 1267, 1155, 1023,
673 cm–1.
IR: 2941, 2863, 1949, 1862, 1644, 1545, 1481, 1264, 1104, 1023,
900, 673 cm–1.
1H NMR (400 MHz, CDCl3): = 1.65–1.76 (1 H, m), 1.82–1.92 (2
H, m), 2.08–2.16 (1 H, m), 2.26 (3 H, s), 2.63–2.79 (2 H, m), 3.59
(1 H, t, J = 6.5 Hz), 3.71 (3 H, s), 5.02 (1 H, d, J = 2.5 Hz), 5.13 (1
H, dd, J = 7.0, 2.5 Hz), 5.37 (1 H, d, J = 7.0 Hz).
1H NMR (400 MHz, CDCl3): = 1.55–1.64 (1 H, m), 1.68 (3 H, s),
1.70–1.86 (3 H, m), 2.10 (3 H, s), 2.63 (2 H, t, J = 6.0 Hz), 3.29
(1 H, dd, J = 8.0, 5.0 Hz), 3.70 (3 H, s), 4.70 (1 H, d, J = 1.5 Hz),
4.94 (1 H, dd, J = 1.5, 1.5 Hz), 4.98 (1 H, s), 5.48 (1 H, s).
13C NMR (67.7 MHz, CDCl3): = 19.3 (t), 25.6 (t), 28.0 (t), 28.5
(q), 51.1 (d), 55.6 (q), 78.0 (d), 78.2 (d), 96.3 (d), 99.3 (s), 111.2 (s),
142.8 (s), 208.8 (s), 233.9 (s).
13C NMR (67.7 MHz, CDCl3): = 15.8 (q), 19.6 (q), 19.8 (t), 27.2
(t), 28.7 (t), 45.2 (d), 55.9 (q), 75.9 (d), 97.6 (s), 97.7 (d), 104.3 (s),
109.2 (s), 114.7 (t), 140.6 (s), 147.6 (s), 234.2 (s).
MS: m/z (%) = 352 ([M]+, 12), 286 (100), 216 (19), 201 (16), 175
(38), 173 (17), 128 (14), 115 (17).
MS: m/z (%) = 340 (24), 257 (32), 256 (100), 210 (10), 161 (73).
HRMS: m/z calcd for C16H16CrO5: 340.0403; found: 340.0407.
HRMS: m/z calcd for C18H20CrO4: 352.0767; found: 352.0765.
(1R,4aS)-Tricarbonyl[ 6-(1-isopropenyl-6-methoxy-1,2,3,4-tet-
rahydronaphthalene)]chromium(0) (3)
(1R,4aS)-Tricarbonyl[ 6-(1-isopropenyl-5,7-dimethyl-6-meth-
oxy-1,2,3,4-tetrahydronaphthalene)]chromium(0) (14)
This compound was obtained as a by-product in the preparation of
11.
1H NMR (400 MHz, CDCl3): = 1.60–1.76 (2 H, m), 1.69 (3 H, s),
1.76–1.91 (2 H, m), 2.20 (3 H, s), 2.22 (3 H, s), 2.48 (1 H, dt, Jd = 17
Hz, Jt = 6.5 Hz), 2.63 (1 H, dt, Jd = 17 Hz, Jt = 6 Hz), 3.36 (1 H, t,
J = 6.5 Hz), 3.72 (3 H, s), 4.63 (1 H, d, J = 1 Hz), 4.94 (1 H, dd,
J1 = 1 Hz, J2 = 1 Hz), 5.09 (1 H, s).
A suspension of activated zinc powder (2.90 g, 44.3 mmol) and
CH2Br2 (2.477 g, 14.25 mmol) in anhyd THF (30 mL) was cooled
to –40 °C and TiCl4 (1.25 mL) was added slowly. After 5 min (the
color had changed to grayish green), an ultrasound horn was intro-
duced into the solution under a continuous stream of argon. The sus-
pension was then sonicated for 4.5 h while being constantly cooled
in an ice–water bath. The resulting suspension (Lombardo reagent)
was ready for use, but it could be stored at –20 °C for at least several
days. To a stirred mixture of the Lombardo reagent (4 mL) and an-
hyd CH2Cl2 (5 mL) was added slowly a solution of 10 (200 mg,
0.588 mmol) in anhyd CH2Cl2 (4 mL) at 0 °C via a syringe. After
5 min at 0 °C, the reaction mixture was warmed up to r.t., and stir-
ring was continued for 4 h before sat. aq NaHCO3 (4 mL) was added
carefully. The aqueous layer was extracted with MTBE (2 × 10
mL), the combined organic layers were washed with brine (2 × 10
mL) and dried (MgSO4). The solvents were removed under reduced
pressure and the residue was purified by PTLC (hexane–EtOAc,
10:1) to yield 3 (152 mg, 76%) as a yellow oil; [ ]589 +140.0,
[ ]546 +174.5 (c = 0.225, CHCl3).
13C NMR (100 MHz, CDCl3): = 12.4 (q), 16.2 (q), 19.4 (t), 20.1
(q), 26.3 (t), 26.5 (t), 45.8 (d), 60.3 (q), 93.0 (d), 103.6 (s), 103.9 (s),
106.9 (s), 109.6 (s), 115.0 (t), 137.2 (s), 147.2 (s), 234.4 (s).
(1R)-1-Isopropenyl-6-methoxy-7-methyl-1,2,3,4-tetrahydro-
naphthalene (2)
A solution of 11 (100 mg, 0.284 mmol) in Et2O was exposed to sun-
light and air for 6 h. Filtration over Celite and removal of the solvent
under reduced pressure yielded compound 2 (60 mg, 97%) in virtu-
ally pure form as a colorless oil; [ ]589 –41.1, [ ]578 –43.1, [ ]546
–53.9, [ ]436 –136.9, [ ]356 –291.1 (c = 0.07, CHCl3).
Synthesis 2003, No. 12, 1851–1855 © Thieme Stuttgart · New York

PAPER
An Enantioselective Approach to Cytotoxic Norcalamenenes
1855
IR: 3071, 2927, 2856, 1731, 1643, 1617, 1581, 1506, 1465, 1455,
1402, 1373, 1323, 1303, 1250, 1201, 1154, 1108, 1031, 950, 895,
838, 800, 789 cm–1.
1H NMR (400 MHz, CDCl3): = 1.65 (3 H, s), 1.68–1.96 (4 H, m),
2.17 (3 H, s), 2.70–2.81 (2 H, m), 3.47 (1 H, dd, J = 6.0, 7.0 Hz),
3.82 (3 H, s), 4.70 (1 H, d, J = 1.5 Hz), 4.91 (1 H, d, J = 1.5 Hz),
6.55 (1 H, s), 6.87 (1 H, s).
13C NMR (67.7 MHz, CDCl3): = 15.8 (q), 19.5 (q), 21.5 (t), 28.8
(t), 30.0 (t), 46.8 (d), 55.3 (q), 110.1 (d), 114.0 (t), 124.0 (s), 129.6
(s), 131.1 (d), 135.7 (s), 149.4 (s), 155.9 (s).
MS: (DIPMS: 40 °C): m/z (%) = 216 ([M]+, 61), 201 ([M]+ – CH3,
33), 185 (11), 176 (14), 175 ([M]+ – C3H5, 100), 173 (38), 160 (12),
145 (11), 129 (15), 128 (16), 115 (17), 91 (12).
(8) For reviews on the use of Cr(CO)3-stabilized benzylic anions
in synthesis, see: (a) Davies, S. G.; Coote, S. J.; Goodfellow,
C. L. In Advances in Metal-Organic Chemistry, Vol. 2;
Liebeskind, L. S., Ed.; JAI Press: London, 1989, 1–57.
(b) Davies, S. G.; McCarthy, T. D. In Comprehensive
Organometallic Chemistry II, Vol. 12; Abel, E. W.; Stone, F.
G. A.; Wilkinson, G.; Hegedus, L. S., Eds.; Pergamon: New
York, 1995, 979–1015.
(9) This benzylic anion is best represented by a resonance
structure where the charge is mainly delocalized to the metal
fragment (see Scheme 3). For a discussion of the electronic
structure of Cr(CO)3 complexed benzylic anions, radicals
and anions, see: (a) Pfletschinger, A.; Dargel, T. K.;
Schmalz, H.-G.; Koch, W. Chem. Eur. J. 1999, 5, 537.
(b) See also: Merlic, C. A.; Walsh, J. C.; Tantillo, D. J.;
Houk, K. N. J. Am. Chem. Soc. 1999, 121, 3596.
(10) Even the more acidic arylic hydrogens ortho to the methoxy
group could possibly be protected by silylation, the benzylic
deprotonation would preferentially take place at the
methylene group meta to the methoxy substituent because
the acidity in para position is lower for electronic and
stereoelectronic reasons; see: Volk, T.; Bernicke, D.; Bats, J.
W.; Schmalz, H.-G. Eur. J. Inorg. Chem. 1998, 1883; and
references cited therein.
HRMS: m/z calcd for C15H20O: 216.1514; found: 216.1514.
Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft
(DFG), the Volkswagenstiftung and the Fonds der Chemischen In-
dustrie. Generous gifts of chemicals from Chemetall AG and De-
gussa AG are highly appreciated.
(11) (a) Corey, E. J.; Helal, C. J. Angew. Chem. Int. Ed. 1998, 37,
1987; and references cited therein. (b)Corey, E. J.; Helal, C.
J. Tetrahedron Lett. 1995, 36, 9153.
(12) The enantiomeric excess was determined by HPLC on a
Daicel Chiralcel OJ column (hexane–i-PrOH) using a
racemic sample as reference.
(13) Schmalz, H.-G.; Millies, B.; Bats, J. W.; Dürner, G. Angew.
Chem., Int. Ed. Engl. 1992, 31, 631.
(14) Johnstone, R. A. W.; Rose, M. E. Tetrahedron 1979, 35,
2169.
(15) (a) Freeman, P. K.; Hutchinson, L. J. Org. Chem. 1980, 45,
1924. (b) For the use of LiDBB in arene-Cr(CO)3 chemistry,
see: Siwek, M. J.; Green, J. R. Synlett 1996, 560.
(16) (a) Lombardo, L. Tetrahedron Lett. 1982, 23, 4293.
(b) Lombardo, L. Org. Synth. 1987, 65, 81.
(17) The crystallographic data (excluding structure factors) have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication no. CCDC 154574.
Copies of the data may be obtained from: The Director of the
Cambridge Crystallographic Centre, 12 Union Road, GB-
Cambridge CB2 1EZ, UK; Fax: (+44)1223336033; e-mail:
deposit@ccdc.cam.ac.uk.
References
(1) Bohlmann, F.; Zdero, C.; Robinson, H.; King, R. M.
Phytochemistry 1979, 18, 1675.
(2) (a) Ambade, N. S.; Desai, D. G.; Dhanaji, G.; Mane, R. B.
Indian J. Chem., Sect. B 1981, 20B, 917. (b) Bohlmann, F.;
Giencke, W. Tetrahedron 1983, 39, 443. (c) Kadam, A. J.;
Baraskar, U. K.; Mane, R. B. Indian J. Chem., Sect. B 2000,
39, 822.
(3) (a) Tietze, L. F.; Raschke, T. Synlett 1995, 597. (b) Tietze,
L. F.; Raschke, T. Liebigs Ann. 1996, 1981.
(c) Noltemeyer, M.; Raschke, T.; Tietze, L. F. Acta
Crystallogr., Sect.C 1996, C52, 2256.
(4) (a) Tietze, L. F.; Schimpf, R. Angew. Chem., Int. Ed. Engl.
1994, 33, 1089. (b) Tietze, L. F.; Modi, A. Eur. J. Org.
Chem. 2000, 1959.
(5) Recent work from this laboratory: (a) Dehmel, F.; Lex, J.;
Schmalz, H.-G. Org. Lett. 2002, 4, 3915. (b) Schwarz, O.;
Brun, R.; Bats, J. W.; Schmalz, H.-G. Tetrahedron Lett.
2002, 43, 1009. (c) Dehmel, F.; Schmalz, H.-G. Org. Lett.
2001, 3, 3579. (d) Hörstermann, D. P.; Schmalz, H.-G.;
Kociok-Köhn, G. Tetrahedron 1999, 55, 6905.
(6) Recent overviews: (a) Schmalz, H.-G.; Siegel, S. In
Transition Metals for Organic Synthesis, Vol. 1; Beller, M.;
Bolm, C., Eds.; Wiley-VCH: Weinheim, 1998, 550.
(b) Hegedus, L. S. Transition Metals in the Synthesis of
Complex Organic Molecules, 2nd ed.; University Science
Books: Sausalito CA, 1999, Chap. 10. (c) Kündig, E. P.;
Pache, S. H. In Science of Synthesis (Houben-Weyl), Vol. 2;
Imamoto, T., Ed.; Thieme Verlag: Stuttgart, 2003, 155.
(7) Schmalz, H.-G.; de Koning, C. B.; Bernicke, D.; Siegel, S.;
Pfletschinger, A. Angew. Chem. Int. Ed. 1999, 38, 1620.
(18) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem., Int.
Ed. Engl 1996, 35, 2708.
(19) For previous syntheses of calamenenes using arene
chromium chemistry, see: (a) Schmalz, H.-G.; Arnold, M.;
Hollander, J.; Bats, J. W. Angew. Chem., Int. Ed. Engl. 1994,
33, 109. (b) Schmalz, H.-G.; Hollander, J.; Arnold, M.;
Dürner, G. Tetrahedron Lett. 1993, 34, 6259. (c) Uemura,
M. In Advances in Metal-Organic Chemistry, Vol. 2;
Liebeskind, L. S., Ed.; JAI Press: London, 1991, 195–245.
Synthesis 2003, No. 12, 1851–1855 © Thieme Stuttgart · New York