Controlled generation of three contiguous stereocentres in the Michael addition of 1-pyrrolidinocyclohexene to (E)-(1-methyl-2-oxoindolin-3-ylidene)acetophenone

Article abstract of DOI:10.1002/1099-0690(200205)2002:10<1702::AID-EJOC1702>3.0.CO;2-9

Addition of 1-pyrrolidinocyclohexene to (E)-(1-methyl-2-oxoindolin-3-ylidene)acetophenone followed by acid hydrolysis was diastereoselectively controlled to give (±)-7a (3R*,1′S*,2′S*) or (±)-7b (3S*,1′R*,2′S*), the structures of which were supported by ¹H NMR spectroscopic data and corroborated by X-ray diffraction analysis. The change in configuration at the C-2′ centre greatly affected the geometries of the two diastereomers, both in solid and in solution, An explanation of the observed diastereoselectivity is provided. An approach to the N-methylwelwitindolinone C skeleton from 7b as a starting material, by insertion of a rhodium carbenoid into the C(4)-H indole position, was abandoned because of the initial experimental results, which are also described. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200205)2002:10<1702::AID-EJOC1702>3.0.CO;2-9

FULL PAPER
Controlled Generation of Three Contiguous Stereocentres in the Michael
Addition of 1-Pyrrolidinocyclohexene to (E)-(1-Methyl-2-oxoindolin-
3-ylidene)acetophenone
[a]
[b]
[b]
´
´
´
´
Pilar Lopez-Alvarado, Santiago Garcıa-Granda, Carmen Alvarez-Rua, and
[a]
˜
Carmen Avendano*
Keywords: Diastereoselectivity / Michael additions / Structure elucidation / X-ray diffraction
Addition of 1-pyrrolidinocyclohexene to (E)-(1-methyl-2-
oxoindolin-3-ylidene)acetophenone followed by acid hydro-
lysis was diastereoselectively controlled to give ( )-7a (3R*
tion of the observed diastereoselectivity is provided. An ap-
proach to the N-methylwelwitindolinone C skeleton from 7b
as a starting material, by insertion of a rhodium carbenoid
,1ЈS*,2ЈS*) or ( )-7b (3S*,1ЈR*,2ЈS*), the structures of which into the C(4)−H indole position, was abandoned because of
were supported by 1H NMR spectroscopic data and corrobor- the initial experimental results, which are also described.
ated by X-ray diffraction analysis. The change in configura-
tion at the C-2Ј centre greatly affected the geometries of the
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
two diastereomers, both in solid and in solution. An explana- 2002)
Introduction
Certain indole alkaloid natural products and analogous
fully synthetic compounds are very active agents for re-
versal of multiple drug resistance (MDR) in cancer chemo-
therapy, a problem frequently related to overexpression of
P-glycoprotein (P-170), which makes tumour cells resistant
not only to the initial chemotherapeutic agent, but also to
Figure 1. Welwistatin (1) and a synthetic intermediate (2)
other clinically useful drugs.[1,2] One of these natural MDR
reversal agents, isolated from a variety of blue-green algae,
is N-methylwelwitindolinone C isothiocyanate (welwistatin,
1),[3] which has an unusual indole ring-containing structure.
It reverses resistance towards vinblastine, taxol, actinomy-
cin D, daunomycin and colchicine at concentrations of
about 10Ϫ7 , far below its cytotoxicity values.[4]
Among the few published reports of attempted syntheses
of welwistatin, formation of the seven-membered C-ring
spanning C-3 and C-4 of the oxindole system has been en-
visaged by preparation of the cyclohexanone intermediate
2, with the desired absolute stereochemistry, through the
use of (R,R)-hydrobenzoin as a chiral auxiliary (Fig-
ure 1).[5,6]
Other approaches have focused on insertion of the chlo-
roolefin and isothiocyanate functions in the final steps, and
have established the utility of rhodium carbenoids derived
from diazomethyl ketones to achieve the insertion of the
methylene carbon atom into the C(4)ϪH indole position.[7]
This methodology was applied to 3 by the use of
Rh2(TFA)4 and Montmorillonite K10 as catalyst to give 4
after oxidation to an α-diketone and regioselective diazotiz-
ation. Subsequent coupling of the corresponding rhodium
carbenoid with allylic alcohols and further manipulation
gave the welwistatin skeleton precursor 5 (Scheme 1).[8]
Other intramolecular cyclizations of a C(3)-side chain of
indole derivatives onto the C(4)-position to make a cyclo-
hepta[c,d]indole system are also known.[9]
[a]
´
´
´
Departamento de Quımica Organica y Farmaceutica, Facultad
de Farmacia, Universidad Complutense
28040 Madrid, Spain
In this context, we planned the synthesis of the indole
derivative 7 as a model compound with which to study the
accessibility of compound 8 through a diazo transfer reac-
tion on the 4Ј-formyl or 4Ј-benzoyl β-diketones. This diazo
ketone could enable direct introduction of welwistatin C-D
Fax: (internat.) ϩ 34Ϫ91/394 18 22
E-mail: avendano@farm.ucm.es
[b]
´
´
´
Departamento de Quımica Fısica y Analıtica. Facultad de
´
Quımica. Universidad de Oviedo
33006 Oviedo, Spain
1702
 WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0510Ϫ1702 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2002, 1702Ϫ1707

Controlled Generation of Three Contiguous Stereocentres
FULL PAPER
a 1.7:1 mixture of two cyclopentanone ‘‘isomers’’. The only
basis for the identification of the two isomers in both en-
1
amines and ketones were the differences found in some H
NMR signals in the crude adducts (enamines recorded at
low temperature) and ketones.
When the synthesis of compound 7 was planned, we ex-
pected some diastereoselective control in the formation of
the stereogenic centres at C-3, C-1Ј, and C-2Ј, given the
rigidity imposed by the intramolecular stabilization of the
zwitterion intermediate I.[11] Addition of 1-pyrrolidino-1-
cyclohexene to a cooled suspension of 6[12] in light petro-
leum ether took place with a change from the original red
colour to yellow. After a preliminary study, we found that
if this suspension was maintained at 0 °C for 17 hours and
the pale yellow precipitate (IIa)[13] was filtered and hydro-
lysed, we obtained a single product (7a, 55%) that was dif-
ferent to the one obtained if the suspension was kept for
the same time at 25 °C and the dark yellow filtrate (IIb)[13]
was similarly hydrolysed (room temperature, H2O/HOAc)
(7b, 64%).
Scheme 1
rings under dirhodium tetraacetate catalysis conditions to
give 9 (Scheme 2). Here we report the synthesis of 7 through
conjugate addition of 1-pyrrolidinocyclohexene to (E)-(1-
methyl-2-oxoindolin-3-ylidene)acetophenone (6), the geo-
metry of the stereogenic centres thus formed, and initial
attempts to obtain 8 by activation of the cyclohexanone α-
position.
Spectroscopic studies (1H NMR, CDCl3) showed that the
H(2Ј)-proton in (Ϯ)-7a was deshielded relative to the same
proton in (Ϯ)-7b, and comparison of the J3-1Ј values in the
two
isomers
showed
that
the
torsion
angle
H(3)ϪC(3)ϪC(1Ј)ϪH(1Ј) had to be close to 90° in 7b (Fig-
ure 2). Furthermore, NOE experiments showed that the
cyclohexane ring approached the indole system in 7b (cf.
the NOE between the H(4) and the H(2Ј)-protons), while
this position was adopted by the phenyl ring in 7a [cf. the
NOE between the H(4) and the H(2ЈЈ)-protons]. This geo-
metry explained the chemical shift of the H(2Ј)-proton in
7a, because of the anisotropic effect of the close C(2)ϭO
carbonyl group. All 1H NMR spectroscopic data supported
an unlike (u) stereochemistry for the C(3) and C(1Ј)-ste-
reocentres in both diastereoisomers, but a like (l) stereo-
chemistry for the C(1Ј) and C(2Ј)-stereocentres in 7a, which
was unlike (u) in 7b.
Scheme 2
Results and Discussion
Figure 2. Selected NOEs of compounds 7a and 7b
The addition of 1-pyrrolidinocyclopentene to compound
6[10] and the hydrolytic cleavage of the reaction products
was reported by Tacconi, without attention being paid to
X-ray diffraction analysis of crystals of (Ϯ)-7a (meth-
the stereochemistry.[11] In that case, ‘‘at least two isomers’’, anol) and (Ϯ)-7b (diethyl ether) confirmed the (3R*,1ЈS*
assumed to be the more and the less substituted enamine, ,2ЈS*) configuration for 7a and the (3S*,1ЈR*,2ЈS*) config-
were formed in the first step and, after acid hydrolysis, gave uration in 7b (Figures 3 and 4)[14]
.
Eur. J. Org. Chem. 2002, 1702Ϫ1707
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P. Lo pez-Alvarado, S. Garcıa-Granda, C. Alvarez-Rua, C. Avendan˜o
FULL PAPER
Figure 3. Perspective view of (Ϯ)-7a with crystallographic num-
bering
Scheme 3
derivative 8 through the regioselective acylation of the
C(4Ј)-position[16Ϫ18] seemed possible because, in a prelimin-
ary experiment, the desired enolate could be trapped as the
trimethylsilyl derivative 10. However, attempts at acylation
revealed many difficulties due to the reactivity of the H-1Ј,
H-2Ј, and H-3 protons (Scheme 4). For instance, the at-
tempted benzoylation of 7b (LHMDS, benzoyl chloride)
Figure 4. Perspective view of (Ϯ)-7b with crystallographic
numbering
It seems reasonable that a like stereochemistry in the C-
1Ј and C-2Ј stereocentres of the zwitterionic intermediate
I[15] should permit its intramolecular stabilization, with less
steric interaction than with the unlike stereochemistry
(Scheme 3). At low temperature, this intermediate should
give enamine IIa through elimination of the less hindered
H(7Ј)-proton. In consequence, the hydrolysis product 7a
should have the same relative configuration as zwitterion I.
At 25 °C, I would give the more substituted enamine IIb
through elimination of the H(2Ј)-proton, and the stereo-
chemistry of the hydrolysis here would be controlled to give
the all unlike product 7b.
Compound 7b seemed more suitable than 7a as a pre-
cursor of 9 through formation of the C(4)ϪC(4Ј) bond, as
shown in Scheme 2. Activation of 7b to obtain its diazo Scheme 4
1704
Eur. J. Org. Chem. 2002, 1702Ϫ1707

Controlled Generation of Three Contiguous Stereocentres
FULL PAPER
7a. Hydrogen atoms were located in a difference Fourier map for
7b. Geometrical calculations were made with PARST (Nardelli,
1983). The crystallographic plots were made with PLATON (Spek,
2001). All calculations were performed at the University of Oviedo
on the computers of the Scientific Computer Centre and the X-
ray group.
gave the O-acyl derivative 11, while treatment of 10 with
[19]
benzoyl chloride in the presence of TiCl4
produced de-
hydration to give 12 through a PaalϪKnorr-type condensa-
tion. Compound 12 was also formed on attempted activa-
tion of the ketone of 7b with a trifluoroacetyl group
[LHMDS, (F3CCO)2O][20] or with a formyl group under
VilsmeierϪHaack conditions.[21] Formylation under basic Treatment of (E)-(1-Methyl-2-oxoindolin-3-ylidene)acetophenone (6)
conditions (NaOMe, HCO2Et)[22] required large excess of
base (up to 8 equivalents)[23] to give the desired 4Ј-formyl
derivative 13 (mixture of tautomers[24]) in low yield. The
major product of this reaction (up to 50% after prolonged
reaction time) was 14, which must have been formed
through oxidation of the enol tautomer of 13 to give more
extended conjugation. NOE experiments on compound 14,
especially the observed enhancement of the H(4)-proton
after irradiation of H(7Ј)-protons, showed that the C(1Ј)ϭ
with
1-Pyrrolidinocyclohexene:
1-Pyrrolidino-1-cyclohexene
(1.22 mL, 7.60 mmol, 2equiv.) was added to a cooled, stirred sus-
pension of 6[11] (1 g, 3.80 mmol) in petroleum ether (25 mL). Cool-
ing and stirring were maintained until the starting material had
disappeared and a pale yellow precipitate had formed (30 min).
This suspension was maintained at 0 °C for 17 h, and the pale
yellow precipitate was filtered off and washed with cold petroleum
ether (15 mL) to give 1.110 g (70%) of enamine IIa. When the ini-
tial pale yellow mixture was maintained at 25 °C for 17 h, a dark
yellow precipitate was formed. The solid was filtered off and
C(2Ј) bond had Z stereochemistry. At this point, further washed with cold petroleum ether (15 mL) to give 1.237 g (79%) of
enamine IIb.
manipulation of 7b or 14 to obtain their 4Ј-diazo derivatives
was abandoned.
Hydrolytic Cleavage of Enamines IIa and IIb: The solid enamines
IIa or IIb were slowly added to a cooled and stirred mixture of
acetic acid (6 mL) and water (1 mL). The resulting brown solutions
were stirred at 0 °C for 30 min and then for 10 min at room temper-
ature. A further 10 mL of water was added, and the solution was
extracted with dichloromethane (3 ϫ 25 mL). Solid sodium hydro-
gen carbonate was cautiously added, with stirring, to the aqueous
fractions until neutralization was achieved, and they were again
extracted with CH2Cl2 (25 mL). The combined organic layers were
stirred with more solid sodium hydrogen carbonate for 30 min,
dried (Na2SO4), filtered, evaporated under reduced pressure, and
washed with diethyl ether (10 mL), yielding 0.750 g (78% from en-
amine IIa, 55% from 6) of pure compound (Ϯ)-(3R*,1ЈS*,2ЈS*)-7a
or 0.873 g (81% from enamine IIb, 64% from 6) of pure compound
(Ϯ)-(3S*,1ЈR*,2ЈS*)-7b, as white solids.
Conclusion
In conclusion, we have shown that three stereocentres can
be generated in a stereocontrolled fashion and, although
our synthetic approach to the skeleton of N-methylwelwit-
indolinone C through formation of a bond between the
cyclohexanone C(3Ј)-position into the indole C(4)-position
failed, these results are significant in the chemistry of 2-
oxo-1,3-dihydroindole compounds.
Data for 7a: C23H23NO3 (361.4): calcd. C 76.43, H 6.41, N 3.87,
found C 76.13, H 6.14, N 4.04; m.p. 164Ϫ165 °C (methanol); IR
(KBr): ν˜ ϭ 1708, 1678, 1612 cmϪ1; NMR: δH (CDCl3, 250 MHz):
7.90 (dd, J ϭ 7.1, 1.5 Hz, 2 H, H2ЈЈ,6ЈЈ), 7.51 (t, J ϭ 7.3 Hz, 1 H,
H4ЈЈ), 7.39 (t, J ϭ 7.1 Hz, 2 H, H3ЈЈ,5ЈЈ), 7.22 (d, J ϭ 7.4 Hz, 1 H,
H4), 7.12 (t, J ϭ 7.8 Hz, 1 H, H6), 6.82 (m, 1 H, H5), 6.70 (d, J ϭ
7.8 Hz, 1 H, H7), 4.72 (dd, J ϭ 10.0, 3.9 Hz, 1 H, H1Ј), 3.88Ϫ3.77
(m, 1 H, H2Ј), 3.81 (d, J ϭ 3.9 Hz, 1 H, H3), 3.24 (s, 3 H, N-CH3),
2.45Ϫ2.29 (m, 2 H, H4Ј), 2.08Ϫ2.03 (m, 1 H, H5Јax), 1.85Ϫ1.78 (m,
1 H, H7Јax), 1.68Ϫ1.55 (m, 3 H, H5Јeq,6Ј), 1.34Ϫ1.18 (m, 1 H, H7Јeq);
δC (CDCl3, 63 MHz): 212.25 (C3Ј), 201.05 (CO-Ph), 177.01 (C2),
144.52 (C7a), 137.50 (C1ЈЈ), 133.32 (C4ЈЈ), 128.63 (C3ЈЈ,5ЈЈ), 128.31
(C2ЈЈ,6ЈЈ), 127.89 (C6), 126.38 (C3a), 123.75 (C4), 121.61 (C5), 107.83
(C7), 49.34 (C2Ј), 45.61 (C1Ј), 44.37 (C3), 42.42 (C4Ј), 33.97 (C7Ј),
28.78 (C5Ј), 26.10 (CH3), 25.33 (C6Ј).
Experimental Section
All reagents were of commercial quality (Aldrich, Fluka, SDS, Pro-
bus) and were used as received. Solvents (SDS) were dried and
purified by standard techniques. ‘‘Petroleum ether’’ refers to the
fraction boiling at 40Ϫ60 °C. Reactions were monitored by thin
layer chromatography, on aluminium plates coated with silica gel
with fluorescent indicator (MachereyϪNagel Alugram Sil G/
UV254). Separations by flash chromatography were performed on
silica gel (SDS 60 ACC, 230Ϫ40 mesh). Melting points were meas-
ured with a Reichert 723 hot stage microscope, and are uncorrec-
ted. Infrared spectra were recorded on a PerkinϪElmer Paragon
1000 FT-IR spectrophotometer, with all compounds examined in
KBr pellets or as films on a NaCl disk. NMR spectra were ob-
tained on Varian Unity 300 (300 MHz for 1 H, 75 MHz for 13C),
Bruker AC 250 (250 MHz for 1H, 63 MHz for 13C) and Bruker AC
500 (500 MHz for 1 H) spectrometers (Servicio de RMN, Universi-
Data for 7b: . C23H23NO3 (361.4): calcd. C 76.43, H 6.41, N 3.87;
found C 76.24, H 6.64, N 3.83; m.p. 171Ϫ172 °C (diethyl ether);
dad Complutense), with CDCl3 as solvent. Exchangeable assign- IR (KBr): ν˜ ϭ 1711, 1682, 1612 cmϪ1; NMR: δH (CDCl3,
ments are marked with the symbols * and **. Mass spectra were 250 MHz): 8.14 (dd, J ϭ 8.4, 1.3 Hz, 2 H, H2ЈЈ,6ЈЈ), 7.54 (tt, J ϭ
obtained by the Servicio de Espectroscopia, Universidad Complu-
tense. Combustion elemental analyses were determined by the Ser-
7.4, 1.3 Hz, 1 H, H4ЈЈ), 7.46 (tt, J ϭ 8.4, 1.8 Hz, 2 H, H3ЈЈ,5ЈЈ), 7.33
(d, J ϭ 7.6 Hz, 1 H, H4), 7.26 (m 1 H, H6), 6.98 (td, 1 H, J ϭ 7.6,
0.9 Hz, H5), 6.80 (d, J ϭ 7.8 Hz, 1 H, H7), 4.56 (dd, J ϭ 10.6,
2.0 Hz, 1 H, H1Ј), 3.58 (br. s, 1 H, H3), 3.40Ϫ3.24 (m, 1 H, H2Ј),
3.21 (s, 3 H, N-CH3), 2.30Ϫ2.26 (m, 2 H, H4Ј), 2.10Ϫ1.90 (m, 1 H,
H5Јax), 1.66Ϫ1.61 (m, 1 H, H6Ј), 1.57Ϫ1.41 (m, 1 H, H5Јeq),
´
vicio de Microanalisis Elemental, Universidad Complutense. Crys-
tal structures were solved by Direct Methods, using the SHELXS-
97 program (Sheldrick, 1990). Anisotropic least-squares refinement
was carried out with SHELXL-97 (Sheldrick, 1997). All non-hy-
drogen atoms were anisotropically refined. Hydrogen atoms were 1.37Ϫ1.21 (m, 3 H, H6Ј,7Јax,7Јeq); δC (CDCl3, 63 MHz): 211.34 (C3Ј),
geometrically placed and refined riding on their parent atoms for
201.05 (CO-Ph), 175.79 (C2), 143.72 (C7a), 135.71 (C1ЈЈ), 132.90
Eur. J. Org. Chem. 2002, 1702Ϫ1707
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P. Lo pez-Alvarado, S. Garcıa-Granda, C. Alvarez-Rua, C. Avendan˜o
FULL PAPER
(C4ЈЈ), 128.63 and 128.61 (C2ЈЈ,6ЈЈ and C3ЈЈ,5ЈЈ), 128.29 (C6), 124.99
(C4), 124.78 (C3a), 122.50 (C5), 108.08 (C7), 50.46 (C2Ј), 44.72 (C1Ј),
43.99 (C3), 41.90 (C4Ј), 30.45 (C7Ј), 27.82 (C5Ј), 26.40 (CH3),
25.07 (C6Ј).
Activation of 7b by Benzoylation or Formylation
Treatment of 7b with LHMDS and Benzoyl Chloride. Synthesis of
11: A solution of LHMDS (1 , 0.41 mL, 0.41 mmol, 1.5 equiv.)
in THF was added dropwise by cannula at Ϫ20 °C, under an argon
atmosphere, to a solution of 7b (0.1 g, 0.277 mmol) in dry THF
(2 mL). After the mixture had been stirred for 2 min and cooled to
Ϫ78 °C, benzoyl chloride (0.035 mL, 0.304 mmol, 1.1 equiv.) was
added. After 10 min at this temperature, the reaction mixture was
quenched with saturated aqueous NH4Cl (10 mL), extracted with
diethyl ether (2 ϫ 20 mL), dried (Na2SO4), and concentrated under
reduced pressure to give an orange oil. Chromatography (90% pet-
roleum ether/Et2O) yielded 0.112 g (87%) of compound 11 as a
white solid. C30H27NO4 (465.5): calcd. C 77.40, H 5.85, N 3.01,
found C 77.23, H 5.64, N 2.99; m.p. 162Ϫ164 °C. IR (KBr): ν˜ ϭ
1753, 1707, 1683 cmϪ1; NMR: δH (CDCl3, 250 MHz): 8.25 (dd,
X-Ray Experimental and Crystal Data for 7a and 7b[25Ϫ28]
Data for 7a: C23H23NO3, monoclinic, space group P21/n, a ϭ
˚
10.858(7), b ϭ 16.39(1), c ϭ 11.097(6) A, β ϭ 103.17(6) °, V ϭ
3
1923(2) A , Z ϭ 4, Dx ϭ 1.248 Mg·mϪ3
, µ (Mo-Kα) ϭ
˚
0.082 mmϪ1. Crystal dimensions 0.25 ϫ 0.20 ϫ 0.15 mm. λ ϭ
0.71073 A (Mo-Kα radiation, Nonius CAD-4 single crystal dif-
˚
fractometer). Data collection at 293 K, ω-2θ scan mode, 2.2 Ͻ 2θ
Ͻ 26°, h 0 Ǟ 13, k 0 Ǟ 20, l Ϫ13 Ǟ 13. Multiple observations
were averaged, Rmergeϭ 0.1887, resulting in 3772 unique reflections
of which 827 were observed with I Ͼ 2σ(I). The final cycle of full-
matrix, least-squares refinement based on 3772 reflections and 220
parameters converged to a final value of R1[F2Ͼ2σ(F2)] ϭ 0.1294,
wR2 [F2Ͼ2σ(F2)] ϭ 0.4114, R1(F2) ϭ 0.4076, wR2(F2) ϭ 0.5027.
Final difference Fourier maps showed no peaks higher than 0.523
J ϭ 7.2, 1.3 Hz, 2 H, H2ЈЈ,6ЈЈ), 8.00 (d, J ϭ 7.2 Hz, 2 H, H2,6
-
PhCOO-), 7.75 (t, J ϭ 7.9 Hz, 2 H, H3ЈЈ,5ЈЈ), 7.61 (t, J ϭ 7.2 Hz, 2
H, H3,5-PhCOO-), 7.43 (tt, J ϭ 7.4, 2.2 Hz, 1 H, H4-PhCOO-),
7.35Ϫ7.29 (m, 2 H, H4 and H4ЈЈ), 7.22Ϫ7.12 (m, 3 H, H5, H6 and
H7), 4.92 (d, J ϭ 10.6 Hz, 1 H, H1Ј), 3.90Ϫ3.60 (m, 1 H, H2Ј), 3.47
(s, 3 H, N-CH3), 2.52Ϫ2.25 (m, 2 H, H4Ј), 2.09Ϫ2.07 (m, 1 H,
H5Јax), 1.92Ϫ1.87 (m, 1 H, H7Јax), 1.80Ϫ1.72 (m, 1 H, H5Јeq),
1.70Ϫ1.50 (m, 3 H, H6Ј,7Јeq); δC (CDCl3, 63 MHz): 212.73 (C3Ј),
197.46 (CO-Ph), 164.20 (C2-PhCOO-), 140.46 (C7a), 136.66* (C1-
PhCOO-), 134.58 (C4-PhCOO-), 133.10* (C1ЈЈ), 132.29 (C4ЈЈ),
Ϫ3
Ϫ3
˚
˚
e·A nor deeper than Ϫ0.337 e·A
.
Data for 7b: C23H23NO3, monoclinic, space group P21/n, a ϭ
˚
10.5644(1), b ϭ 11.7887(1), c ϭ 15.1836(1) A, β ϭ 95.8795(7) °,
3
V ϭ 1881.03(3) A , Z ϭ 4, Dx ϭ 1.276 Mg·mϪ3, µ(Cu-Kα) ϭ
˚
0.674 mmϪ1. Crystal dimensions 0.35 ϫ 0.35 ϫ 0.25 mm. λ ϭ
˚
1.5418 A (Cu-Kα radiation, Nonius KappaCCD single crystal dif-
130.51 (C2,6-PhCOO-), 128.93, 128.46, and 128.12 (C2ЈЈ,6ЈЈ, C3ЈЈ,5ЈЈ
,
fractometer). Data collection at 200 K, ϕ and ω scans, 4.8 Ͻ 2θ Ͻ
69.8°, h Ϫ12 Ǟ 12, k Ϫ14 Ǟ 14, l Ϫ18 Ǟ 18. Multiple observations
were averaged, Rmergeϭ 0.047, resulting in 3516 unique reflections
of which 3527 were observed with I Ͼ 2σ(I). Final mosaicity was
0.504°. All data completeness was 94%. Intensity Ϫ error ratio for
all reflections was 244.5:5.5. The final cycle of full-matrix, least-
squares refinement based on 3516 reflections and 336 parameters
converged to a final value of R1[F2Ͼ2σ(F2)] ϭ 0.0408, wR2
[F2Ͼ2σ(F2)] ϭ 0.1072, R1(F2) ϭ 0.0431, wR2(F2) ϭ 0.1090. Final
and C3,5-PhCOO-), 127.52 (C3a), 121.58 (C4), 120.14 (C5), 109.07
(C7), 95.39 (C3), 51.54 (C2Ј), 42.90 (C1Ј), 42.19 (C4Ј), 32.02 (C7Ј),
28.57 (CH3), 28.33 (C5Ј), 25.45 (C6Ј). The signals due to C2 and C6
could not be detected.
Treatment of 10 with Benzoyl Chloride and Titanium (IV) Chloride.
Synthesis of 12: A solution of titanium (IV) chloride in dry dichlor-
omethane (0.138 mL, 0.138 mmol, 1 equiv.) was added under an
argon atmosphere to cooled benzoyl chloride (0.023 g, 0.166 mmol,
1.2 equiv.), followed shortly by the dropwise addition of trimethyl-
silyl enol ether 10 (0.060 g, 0.138 mmol) in dry dichloromethane
(0.15 mL). After having been stirred for 1 h at 0 °C, the reaction
mixture was quenched with water (10 mL), extracted with dichloro-
methane (3 ϫ 20 mL), dried (Na2SO4), and concentrated under
reduced pressure to yield 45 mg (95%) of furan 12. C23H21NO2Si
(371.5): calcd. C 80.44, H 6.16, N 4.08, found C 80.12, H 6.17, N
4.00; m.p. 146Ϫ147 °C. IR (KBr): ν˜ ϭ 1716, 1611 cmϪ1; NMR: δH
(CDCl3, 250 MHz): 7.73 (br. s, 2 H, H2ЈЈ,6ЈЈ), 7.40 (t, J ϭ 7.2 Hz, 2
H, H3ЈЈ,5ЈЈ), 7.32Ϫ7.24 (m, 2 H, H4ЈЈ,6), 7.12 (d, J ϭ 7.3 Hz, 1 H,
H4), 7.01 (t, J ϭ 7.3 Hz, 1 H, H5), 6.85 (d, J ϭ 7.7 Hz, 1 H, H7),
4.88 (s, 1 H, H3), 3.27 (s, 3 H, N-CH3), 2.59Ϫ2.54 (m, 2 H, H7Ј),
1.77Ϫ1.66 and 1.50Ϫ1.35 (2 m, 6 H, H4Ј, H5Ј, H6Ј); δC (CDCl3,
63 MHz): 175.94 (C2), 150.62 (C2Ј), 144.02 (C7a), 131.18 (C1ЈЈ),
128.55 (C3ЈЈ,5ЈЈ), 128.34 (C3a), 128.20** (C4ЈЈ), 127.42** (C6), 126.48
(C2ЈЈ,6ЈЈ), 124.48 (C4), 122.63 (C5), 117.88* (C3Ј), 114.79* (C3aЈ),
107.91 (C7), 43.24 (C3), 26.36 (CH3), 23.09, 22.52, 22.48, and 20.22
(C4Ј, C5Ј, C6Ј, C7Ј). The signal due to C7aЈ could not be detected.
MS (EI): 343 [Mϩ].
Ϫ3
˚
difference Fourier maps showed no peaks higher than 0.156 e·A
Ϫ3
˚
nor deeper than Ϫ0.171 e A
.
Preparation of the Trimethylsilyl Derivative 10: A solution of
LHMDS (1 , 10 mL, 10 mmol, 3.6 equiv.) in THF was added
dropwise by cannula at Ϫ20 °C, under an argon atmosphere, to a
solution of 7b (1 g, 2.77 mmol) in dry THF (20 mL). The solution
was stirred for 2 min, and a centrifuged mixture of TMSCl/triethyl-
amine (3.7 mL, 29.1 mmol, 10.5 equiv. of TMSCl and 5.4 mL,
38.8 mmol, 14 equiv. of triethylamine) was added. After 1 h, the
reaction mixture was quenched with water (100 mL), extracted with
diethyl ether (3 ϫ 150 mL), dried (Na2SO4), and concentrated un-
der reduced pressure to give a viscous solid. Petroleum ether
(25 mL) was added, and stirring gradually changed the oily precip-
itate into a crystalline solid, which was filtered off to yield 1.152 g
(96%) of the trimethylsilyl enol ether 10 as a white solid.
C26H31NO3Si (433.6): calcd. C 72.05, H 7.21, N 3.23, found 72.11,
H 7.40, N 3.51; m.p. 116Ϫ118 °C; IR (KBr): ν˜ ϭ 1714, 1685, 1612
cmϪ1; NMR: δH (CDCl3, 250 MHz): 7.88 (d, J ϭ 7.3 Hz, 2 H,
H2ЈЈ,6ЈЈ), 7.48Ϫ7.32 (m, 4 H, H4,3ЈЈ,4ЈЈ,5ЈЈ), 7.18 (t, J ϭ 7.8 Hz, 1 H,
H6), 6.88 (m, 1 H, H5), 6.73 (d, J ϭ 7.8 Hz, 1 H, H7), 4.75 (m, 1
H, H4Ј), 4.35 (dd, J ϭ 10.0, 2.5 Hz, 1 H, H1Ј), 3.54 (br. s, 1 H, H3), Attempted Formylation under Vilsmeier؊Haack Conditions. Syn-
3.20 (s, 3 H, N-CH3), 3.20Ϫ3.00 (m, 1 H, H2Ј), 2.00Ϫ1.85 (m, 2 H, thesis of 12: A solution of (chloromethylene)dimethylammonium
H5Ј), 2.65Ϫ1.30 (m, 4 H, H6Ј,7Ј), Ϫ0.13 (s, 9 H, TMS); δC (CDCl3, chloride (39 mg, 0.347 mmol, 1.25 equiv.) in dry dichloromethane
63 MHz): 200.75 (CO-Ph), 176.19 (C2), 151.14 (C3Ј), 144.06 (C7a), (1 mL), was added dropwise by cannula at room temperature, un-
137.27 (C1ЈЈ), 132.27 (C4ЈЈ), 128.46 and 128.11 (C2ЈЈ,6ЈЈ and C3ЈЈ,5ЈЈ),
der an argon atmosphere, to a solution of 7b (0.1 g, 0.277 mmol)
127.81 (C6), 126.31 (C3a), 124.80 (C4), 121.95 (C5), 107.66 (C7), in dry dichloromethane (2 mL). The solution was stirred for 5 h
104.33 (C4Ј), 48.74, 44.57, 39.41, 26.26, 23.98, 21.36 (C1Ј, C2Ј, C3,
and was then quenched with saturated aqueous sodium hydrogen
carbonate (10 mL), extracted with dichloromethane (3 ϫ 50 mL),
C5Ј, C6Ј, C7Ј), 26.20 (CH3), Ϫ0.36 [Si(CH3)].
1706
Eur. J. Org. Chem. 2002, 1702Ϫ1707

Controlled Generation of Three Contiguous Stereocentres
FULL PAPER
dried (Na2SO4), and concentrated under reduced pressure to yield
95 mg (100%) of furan 12.
[1]
[2]
[3]
M. M. Gottesman, I. Pastan, Annu. Rev. Biochem. 1993, 62,
385Ϫ427.
See: M. Wiese, I. K. Pajeva, Current Med. Chem. 2001, 8,
685Ϫ713, and references therein.
Attempted Activation with a Trifluoroacetyl Group (LHMDS,
(F3CCO)2O). Synthesis of 12: A solution of LHMDS (1 , 1 mL,
1 mmol, 3.7 equiv.) in THF was added dropwise by cannula at Ϫ20
°C, under an argon atmosphere, to a solution of 7b (0.1 g,
0.277 mmol) in dry THF (1 mL). After the mixture had been stirred
for 2 min and cooled to Ϫ78 °C, trifluoroacetyl anhydride
(0.156 mL, 1.108 mmol, 4 equiv.) was added. After 10 min at this
temperature, the reaction mixture was quenched with saturated
aqueous NH4Cl (10 mL), extracted with diethyl ether (2 ϫ 20 mL),
dried (Na2SO4), and concentrated under reduced pressure to give
an orange oil. Chromatography (90% petroleum ether/Et2O)
yielded 0.027 g (28%) of 12 and 0.043 g (43%) of recovered start-
ing material.
K. Stratmann, R. E. Moore, R. Bonjouklian, J. B. Deeter, G.
M. L. Patterson, S. Shaffer, C. D. Smith, T. A. Smitka, J. Am.
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´
J. P. Konopelski, J. M. Hottenroth, H. Monzo-Oltra, E. A.
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´
[6]
J. P. Konopelski, H. Deng, K. Schiemann, J. M. Keane, M. M.
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[7]
[8]
E. Wenkert, S. Liu, Synthesis 1992, 323Ϫ327.
J. L. Wood, A. A. Holubec, B. M. Stolz, M. M. Weiss, J. A.
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J. Am. Chem. Soc. 1999, 121, 6326Ϫ6327.
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See: Y. Yokoyama, H. Matsushima, M. Takashima, T. Suzuki,
Y. Murakami, Heterocycles 1997, 46, 133Ϫ136, and references
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G. Tacconi, P. Iadarola, F. Marinone, P. P. Rigghetti, G. Desi-
moni, Tetrahedron. 1975, 31, 1179Ϫ1186.
G. Tacconi, A. Gamba, F. Marinone, G. Desimoni, J. Chem.
Soc. 1976, 1872Ϫ1879.
Formylation under Basic Conditions (MeONa, HCO2Et). Synthesis
of 13 and 14: A solution of 7b (75 mg, 0.208 mmol) in anhydrous
benzene (3 mL) was added dropwise by cannula at room temper-
ature, under an argon atmosphere, to a suspension of sodium me-
thoxide (96 mg, 1.77 mmol, 8.5 equiv.) in the same solvent (1 mL).
The reaction mixture turned dark red and was cooled to 0 °C.
After 10 min, ethyl formate (127 mg, 1.72 mmol, 8.3 equiv.) was
introduced, and stirring was maintained at room temperature for
4 h. Diethyl ether (50 mL) was then added, and the suspension was
washed with water (2 ϫ 25 mL). The ethereal solution was dried
(Na2SO4), and concentrated under reduced pressure to yield 15 mg
(18%) of 13 and 40 mg (50%) of 14. Data for 13 (major tautomer):
NMR: δH (CDCl3, 250 MHz): 13.95 (d, J ϭ 9.8 Hz, 1 H, CHO),
[10]
[11]
[12]
[13]
As was to be expected, the Z isomer of 6 did not react under
the same conditions.
The elemental analyses of crude enamines IIa (m.p. ϭ 78Ϫ80
°C) and IIb (m.p. ϭ 68Ϫ70 °C) were in accordance with the
calculated values. 1H NMR spectra at low temperature (Ϫ20
°C) were not particularly informative.
CCDC-167761 (7a) and CCDC-167762 (7b) contain the sup-
plementary crystallographic data for this paper. These data can
be obtained free of charge at www. ccdc.cam.ac.uk/conts/re-
trieving. html [or from the Cambridge Crystallographic Data
Centre, 12, Union Road, Cambridge CB2 1EZ, UK; Fax: (in-
ternat.) ϩ44Ϫ1223/336-033; E-mail: deposit@ccdc.cam.ac.uk].
Only one enantiomer is shown.
M. Regitz, Angew. Chem. Int. Ed. Engl. 1967, 6, 733Ϫ749.
B. W. Metcalf, K. Jund, J. P. Burkhart, Tetrahedron Lett. 1980,
21, 15Ϫ18.
D. F. Taber, K. You, Y. Song, J. Org. Chem. 1995, 60,
1093Ϫ1094.
R. E. Tirpak, M. W. Rathke, J. Org. Chem. 1982, 47,
5099Ϫ5102.
R. L. Danheiser, R. F. Miller, R. G. Brisbois, S. Z. Park, J.
Org. Chem. 1986, 55, 1959Ϫ1964.
J. O. Karlsson, T. Frejd, J. Org. Chem. 1983, 48, 1921Ϫ1923.
L. A. Paquette, R. A. Galemmo, Jr., J.-C. Caille, R. S. Valpey,
J. Org. Chem. 1986, 51, 686Ϫ695.
Under these conditions, partial epimerization to 7a was ob-
served. The same treatment of 7a gave a mixture of 7a and 7b.
[14]
7.94 (d, J ϭ 7.2 Hz, 2 H, H2ЈЈ,6ЈЈ), 7.23Ϫ7.15 (m, 4 H, H3ЈЈ,5ЈЈ, H4ЈЈ
,
H6), 7.02Ϫ6.69 (m, 3 H, H4, H5, H7), 4.77 (dd, J ϭ 10.0, 2.4 Hz,
1 H, H1Ј), 4.17 (d, J ϭ 1 0.0 Hz, 1 H, H3), 3.45Ϫ3.35 (m, 1 H,
H2Ј), 3.07 (s, 3 H, N-CH3), 2.74Ϫ2.49, 2.33Ϫ2.14, 2.01Ϫ1.65,
1.51Ϫ1.13 (4 m, 6 H, H5Ј,6Ј,7Ј). The H4Ј-signal could not be clearly
assigned. Data for 14: C24H21NO4 (387.4): calcd. C 74.40, H 5.46,
N 3.61, found C 74.61, H 5.58, N 3.53; m.p. 190Ϫ192 °C. IR (KBr):
ν˜ ϭ 3353, 1725, 1627 cmϪ1; NMR: δH (CDCl3, 250 MHz): 10.10
(s, 1 H, CHO), 7.61Ϫ7.57 (m, 2 H, H2ЈЈ,6ЈЈ), 7.50Ϫ7.39 (m, 3 H,
H3ЈЈ,5ЈЈ and H4ЈЈ), 7.30 (m, 1 H, H6), 6.99 (m, 1 H, H5), 6.83 (d, J ϭ
7.8 Hz, 1 H, H7), 6.64 (d, J ϭ 7.5 Hz, 1 H, H4), 6.47 (br. s, 1 H,
OH), 4.16 (s, 1 H, H3), 3.24 (s, 3 H, N-CH3), 2.40Ϫ2.19 (m, 2 H,
H5Ј), 1.74Ϫ1.70 (m, 2 H, H7Ј), 1.55Ϫ1.50 (m, 2 H, H6Ј); δC (CDCl3,
63 MHz): 188.09 (CHO), 175.24 (C2, C3Ј), 168.35 (CO-Ph), 143.82
(C7a), 138.86* (C4Ј), 137.85* (C2Ј), 132.61 (C1ЈЈ), 129.31 (C4ЈЈ),
128.99 (C6), 128.57 (C3ЈЈ,5ЈЈ), 125.92 (C2ЈЈ,6ЈЈ), 125.20 (C3a), 124.37
(C4), 123.30 (C5), 113.55** (C1Ј), 110.60** (C3Ј), 108.80 (C7), 43.99
(C3), 26.71 (CH3), 22.35 (C7Ј), 21.39 (C6Ј), 19.41 (C5Ј). MS (EI):
387 [Mϩ].
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24] 1H NMR spectroscopic data for the major isomer are given.
Attempts to perform the diazo transfer with tosyl azide only
gave undesired products.
[25]
M. Nardelli, Comput. Chem. 1983, 7, 95Ϫ98.
[26]
G. M. Sheldrick, Acta Crystallogr., Sect. A 1990, 46, 467Ϫ473.
[27]
G. M. Sheldrick, SHELXL-97. University of Göttingen. A
computer program for refinement of crystal structures, 1997.
A. L. Spek. PLATON, a multipurpose crystallographic tool,
[28]
Acknowledgments
Financial support from CICYT (SAF2000-0130) and CICYT
(BQU2000-0219) is gratefully acknowledged.
Utrecht University, Utrecht, The Netherlands, 2001.
Received November 28, 2001
[O01563]
Eur. J. Org. Chem. 2002, 1702Ϫ1707
1707