Intramolecular Diels-Alder reactions with substituted Feringa-butenolides: a dramatic increase in reactivity by double activation

Article abstract of DOI:10.1016/S0957-4166(00)00286-X

A thermal intramolecular endo-selective Diels-Alder reaction with a substituted Feringa-butenolide is described. The structure of the main product is determined by single crystal X-ray analysis. By double activation of the dienophile substructure a dramatic increase in reactivity is reported, which leads to a decrease in reaction temperature by more than 100°C. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00286-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3345–3349
Intramolecular Diels–Alder reactions with substituted
Feringa-butenolides: a dramatic increase in reactivity by
double activation
Ulrich Reiser,a Johann Jaucha,* and Eberhardt Herdtweckb
aInstitut fu¨r Organische Chemie und Biochemie, Technische Universita¨t Mu¨nchen, Lichtenbergstr. 4,
85747 Garching, Germany
bAnorganisch-chemisches Institut, Technische Universita¨t Mu¨nchen, Lichtenbergstr. 4, 85747 Garching, Germany
Received 2 July 2000; accepted 20 July 2000
Abstract
A thermal intramolecular endo-selective Diels–Alder reaction with a substituted Feringa-butenolide is
described. The structure of the main product is determined by single crystal X-ray analysis. By double
activation of the dienophile substructure a dramatic increase in reactivity is reported, which leads to a
decrease in reaction temperature by more than 100°C. © 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
Intramolecular Diels–Alder reactions1 (IMDA reactions) are a powerful tool in natural
product synthesis to construct highly substituted polycyclic carbon skeletons. Most IMDA
reactions use crotonate type dienophile substructures, whereas methacrylate type2 dienophiles
are rarely used in IMDA reactions (Fig. 1).
Figure. 1. Two types of dienophile substructures in IMDA reactions: (a) crotonate type dienophile; (b) methacrylate
type dienophile
* Corresponding author. Tel: +049 89 289 13 289; fax: +049 89 289 13 329; e-mail: jjauch@nucleus.org.chemie.tu-
muenchen.de
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00286-X

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U. Reiser et al. / Tetrahedron: Asymmetry 11 (2000) 3345–3349
Feringa-butenolides were used as dienophiles in intermolecular Diels–Alder reactions3 and as
dipolarophiles in 1,3-dipolar cycloadditions.4 In our project towards the total synthesis of
mniopetals5 we described the first IMDA reaction of the substituted Feringa-butenolide 1, which
contains a methacrylate type dienophile substructure.
2. Results and discussion
When the trienolide 1 is heated at 140°C in xylene for 60 h in a silylated flask, the tricyclic
adduct 2 is obtained in 68% yield along with 3 in 12% yield (2:3 ca. 5.6:1) and a mixture of
unreacted starting material 1 and its epimer 4 (Scheme 1). Silylation of the flask is necessary to
reduce epimerization of 1 catalyzed by the glass surface.
Scheme 1. IMDA reaction of 1
Crystallization of 2 from n-pentane gave crystals suitable for X-ray analysis.6 The corre-
sponding ORTEP-drawing is shown in Fig. 2. The unit cell contains two molecules which differ
in the conformations of the menthyl residue and the OTBDMS group. This probably stems
from packing effects. Additionally, there is a weak hydrogen bond between the secondary
alcohol OH4 and the acetal oxygen O3 (see Fig. 2). The crystallographic data are shown in
Table 1.
To prevent complete epimerization of 1 to 4 during the IMDA reaction, we thought that
activation of the dienophile by an additional electron withdrawing group should lead to an
increased reactivity and therefore to lower reaction temperatures.7 Therefore, we decided to
doubly activate 1 through oxidation8 to the corresponding ketone 5. This was best achieved by
Dess–Martin periodinane9 in the presence of 2,6-lutidine as base to neutralize the acetic acid
liberated during the oxidation. When we carried out this oxidation at room temperature TLC
showed a clean reaction giving 6 in ca. 79–81% yield along with ca. 14% of the corresponding
exo-product after 16 hours. The expected oxo-trienolide 5 could not be detected. Compound 5
cyclizes spontaneously to give 6, identical with the product obtained by oxidation of 2 with
PDC (Scheme 2).

U. Reiser et al. / Tetrahedron: Asymmetry 11 (2000) 3345–3349
3347
Figure. 2. ORTEP-drawing of 2
Table 1
Selected crystallographic data for 2

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U. Reiser et al. / Tetrahedron: Asymmetry 11 (2000) 3345–3349
Scheme 2. IMDA reaction with a double activated Feringa-butenolide
Thus, double activation leads to a dramatic increase in reactivity which results in decrease of
reaction temperature by more than 120°C and a decrease in reaction time. The method described
here is a simple means to accelerate IMDA reactions with methacrylate-type dienophile
substructures which are very sluggish under usual reaction conditions or contain thermally labile
groups.
3. Experimental
Compound 1 (79.7 mg, 0.121 mmol) and 2,6-lutidine (113 ml, 0.968 mmol, 8 equiv.) are
dissolved in dried CH2Cl2 (11 ml) under nitrogen at room temperature. A solution of Dess–
Martin reagent in CH2Cl2 (0.363 mmol, 0.85 ml) is added dropwise and the reaction mixture is
stirred overnight. The reaction is quenched by diluting with diethyl ether and adding saturated
Na2S2O3 solution. The phases are separated and the aqueous layer is extracted with ether. The
combined organic extracts are dried with MgSO4 and the product is purified by flash chromatog-
1
raphy (n-pentane:diethyl ether, 15:1 (v/v)). Yield: 62.9 mg (79%). H NMR (CDCl3, 360 MHz,
l relative to TMS): 7.66 (m, 4H), 7.42 (m, 6H), 6.06 (m, 1H), 5.98 (dt, 9.1 Hz, 3.2 Hz, 1H), 5.30
(d, 2.6 Hz, 1H), 3.90 (m, 2H), 3.50 (dd, 5.8 Hz, 1.9 Hz, 1H), 3.35 (m, 2H), 2.42–2.31 (m, 2H),
2.19 (m, 1H), 2.02 (br. s, 1H), 1.96 (m, 1H), 1.87 (br. d, 12.3 Hz, 1H), 1.70 (m, 1H), 1.59 (s, 3H),
1.41 (s, 3H), 1.09 (s, 9H), 1.02 (s, 3H), 0.81 (d, 7.2 Hz, 3H), 0.80 (d, 6.5 Hz, 3H), 0.64 (d, 7.2
Hz, 3H), 1.3–0.7 (m, 4H). 13C NMR (CDCl3, 90 MHz, l relative to CDCl3): 203.8, 173.0, 135.6,
135.5, 133.4, 133.3, 131.8, 129.8, 129.7, 127.8, 76.4, 66.6, 63.4, 52.2, 47.5, 46.0, 39.9, 39.2, 39.0,
35.8, 34.3, 33.2, 32.3, 31.3, 29.7, 26.9, 25.1, 23.0, 22.2, 22.0, 20.8, 19.3, 15.5.
Acknowledgements
This work was generously supported by the Deutsche Forschungsgemeinschaft. J.J. appreci-
ates Habilitation stipends from the Deutsche Forschungsgemeinschaft and Fazit-Stiftung. We

U. Reiser et al. / Tetrahedron: Asymmetry 11 (2000) 3345–3349
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thank BASF AG, Ludwigshafen, Germany, Bayer AG, Leverkusen, Germany, Pfizer GmbH,
Karlsruhe, Germany and Haarmann & Reimer GmbH, Holzminden, Germany, for the donation
of chemicals and laboratory equipment.
References
1. Roush, W. R. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol.
5, p. 513, and references cited therein.
2. Taber, D. F.; Saleh, S. A. J. Am. Chem. Soc. 1980, 102, 5085–5088. Brasca, M. G.; Broughton, H. B.; Craig, S.;
Ley, S. V.; Somovilla, A. A.; Toogood, P. L. Tetrahedron Lett. 1988, 29, 1853–1856. Boeckman, R. K.; Demko,
D. M. J. Org. Chem. 1982, 47, 1789–1792.
3. De Jong, J. C.; van Bolhuis, F.; Feringa, B. L. Tetrahedron: Asymmetry 1991, 2, 1247–1262. De Jong, J. C.;
Jansen, J. F. G. A.; Feringa, B. L. Tetrahedron Lett. 1990, 31, 3047–3050. De Jong, J. C.; Feringa, B. L. J. Org.
Chem. 1988, 53, 1125–1127.
4. Rispens, M. T.; Keller, E.; de Lange, B.; Zijlstra, R. W. J.; Feringa, B. L. Tetrahedron: Asymmetry 1994, 5,
607–624. Keller, E.; de Lange, B.; Rispens, M. T.; Feringa, B. L. Tetrahedron 1993, 49, 8899–8910.
5. Jauch, J. Synlett 1999, 1325–1327.
6. X-Ray crystallography: crystal data and details of the structure determination are presented in Table 1. Suitable
single crystals for the X-ray diffraction study were grown by slow evaporation of a n-pentane solution of 2. A clear
colorless needle (0.65×0.10×0.05 mm) was stored under perfluorinated ether, transferred in a Lindemann capillary,
fixed and sealed. Preliminary examination and data collection were carried out on a Kappa CCD area detector
diffraction system (Nonius; Mach3) equipped with a rotating anode and graphite monochromated MoKa
radiation (Nonius; Fr951). The unit cell parameters were obtained by full-matrix least-squares refinements of
99137 reflections. Data collection was performed at 123 K (exposure time: 60 s per frame; 8 sets, 8 and V-scans,
D8/DV: 1°; dx: 40.0 mm). A total number of 138016 reflections were collected. Raw data were corrected for
Lorentz, polarization, and decay effects and were scaled with the program Denzo-SMN. After merging (Rint
=
0.0612) a sum of 13626 independent reflections remained and were used for all calculations. All ‘heavy atoms’ of
the asymmetric unit were refined anisotropically. All hydrogen atoms were located in the difference Fourier map
and refined with individual isotropic temperature parameters. Full-matrix least-squares refinements were carried
out by minimizing Sw(F2o–Fc2)2 with SHELXL-97 weighting scheme and stopped at shift/err <0.001. The correct
enantiomer is fixed by the synthetic route and confirmed by Flack’s parameter x=0.10 (9). Neutral atom scattering
.
factors for all atoms and anomalous dispersion corrections for the non-hydrogen atoms were taken from
International Tables for Crystallography. All calculations were performed on a DEC 3000 AXP workstation and
an Intel Pentium II PC, with the Strux-V system, including the programs Platon, Sir92, and SHELXL-97.
7. Harkin, S. A.; Jones, R. H.; Tapolczay, D. J.; Thomas, E. J. J. Chem. Soc., Perkin Trans. 1 1989, 489–497.
Thomas, E. J.; Whitehead, J. W. F. J. Chem. Soc., Perkin Trans. 1 1989, 499–505. Thomas, E. J.; Whitehead, J.
W. F. J. Chem. Soc., Perkin Trans. 1 1989, 507–518. Sauter, R.; Thomas, E. J.; Watts, J. P. J. Chem. Soc., Perkin
Trans. 1 1989, 519–523. Merifield, E.; Thomas, E. J. J. Chem. Soc., Chem. Commun. 1990, 464–466. Thomas, E.
J.; Watts, J. P. J. Chem. Soc., Chem. Commun. 1990, 467–469.
8. For IMDA reactions with trienes, which cyclize spontaneously at room temperature upon oxidation of an allylic
alcohol to the vinyl ketone, see: Taber, D. F.; Gunn, B. P. J. Am. Chem. Soc. 1979, 101, 3992–3993. Gras, J. L.;
Bertrand, M. Tetrahedron Lett. 1979, 20, 7301–7304. Vig, O. P.; Trehan, I. R.; Kumar, R. J. Chem. Ind. 1977, 15B,
319–322. Vig, O. P.; Trehan, I. R.; Malik, N.; Kumar, R. J. Chem. Ind. 1978, 16B, 449–451. For a related reaction,
see: Oppolzer, W.; Snowdon, R. L. Tetrahedron Lett. 1976, 17, 4187–4190.
9. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156. Boeckman, R. J. In Encyclopedia of Reagents for
Organic Synthesis; Paquette, L. A., Ed.; John Wiley & Sons: New York, 1995; Vol. 7, pp. 4982–4987, and
references cited therein. Speicher, A.; Bomm, V.; Eicher, T. J. Prakt. Chemie 1996, 338, 588–590.