Highly selective Diels-Alder reactions of dienophiles with 1,3-cyclohexadiene mediated by Yb(OTf)3·2H2O and ultrahigh pressures

Article abstract of DOI:10.1021/ol0065773

(Equation Presented) Ultrahigh pressures and catalytic Yb(OTf)₃·2H₂0 were found to mediate Diels-Alder reactions of various electron-deficient dienophiles with 1,3-cyclohexadiene to produce endo-bicyclo[2.2.2]oct-2-enes in moderate t

Full text of DOI:10.1021/ol0065773

ORGANIC
LETTERS
2000
Vol. 2, No. 22
3517-3520
Highly Selective Diels−Alder Reactions
of Dienophiles with 1,3-Cyclohexadiene
Mediated by Yb(OTf)3‚2H O and
2
Ultrahigh Pressures
Aaron C. Kinsman and Michael A. Kerr*
Department of Chemistry, UniVersity of Western Ontario,
London, Ontario N6A 5B7, Canada
makerr@julian.uwo.ca
Received September 11, 2000
ABSTRACT
Ultrahigh pressures and catalytic Yb(OTf)3‚2H O were found to mediate Diels−Alder reactions of various electron-deficient dienophiles with
2
1,3-cyclohexadiene to produce endo-bicyclo[2.2.2]oct-2-enes in moderate to excellent yield and selectivity. The proposed total synthesis of
hapalindole Q based on bicyclo[2.2.2]oct-2-ene construction by Diels−Alder reaction and subsequent olefin cleavage is outlined. Preliminary
results demonstrating the viability of this strategy are presented.
The total synthesis of the hapalindoles is currently underway
in our laboratory. This group of 20 structurally related
alkaloid natural products was isolated from the terrestrial
blue-green algae Hapalosiphon fontinalis, an organism found
to exhibit antibacterial, antimycotic, and antifungal activity.1
The importance of the key cycloaddition step prompted
us to undertake a study of the reaction of 1,3-cyclohexadiene
Scheme 1. Proposed Hapalindole Q Synthesis
Our proposed synthesis of hapalindole Q 1 is presented
in Scheme 1.2 The Diels-Alder reaction (2 + 3 f 4) is the
cornerstone of our strategy because it allows expedient
generation of the carbon skeleton and secures the proper
stereochemistry. Bicyclo[2.2.2]oct-2-ene 4 is then cleaved
to cyclohexane 5, which would be subjected to double
methylenation, functional group interconversion (FGI), and
deprotection to give 1.
(1) (a) Moore, R. E.; Cheuk, C.; Yang, X.-Q.; Patterson, G. M. L.;
Bonjouklian, R.; Smitka, T. A.; Mynderse, J. S.; Foster, R. S.; Jones, N.
D.; Swartzendruber, J. K.; Deeter, J. B. J. Org. Chem. 1987, 52, 1036. (b)
Moore, R. E.; Cheuk, C.; Patterson, G. M. L. J. Am. Chem. Soc. 1984,
106, 6456.
(2) Hapalindole Q has been synthesized previously, see: Vaillancourt,
V. Albizati, K. F. J. Am. Chem. Soc. 1993, 115, 3499.
10.1021/ol0065773 CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/04/2000

Table 1. Diels-Alder Reactions of Benzylidene Acetone with 1,3-Cyclohexadiene
7 with electron-deficient dienephiles. The antidepressant and
CNS stimulation activity3 displayed by bicyclo[2.2.2]oct-2-
ene derivatives provided further impetus for the investigation
presented herein.
reaction, enhanced diastereoselectivity and higher yields are
achieved by using Lewis acid catalysis,8 high pressure (HP),
or these conditions in concert.9 Indeed, employing hyperbaric
conditions and the mild Lewis acid Yb(OTf)3‚2H2O we
observed remarkably superior selectivity (>95% de) and
yield (96%, entry 3).10 In addition, reaction times were
reduced compared with the thermal conditions (2 vs 4 d). It
was found that the ytterbium catalyst is essential for the
reaction at high pressure; in its absence <5% conversion
was observed (entry 4). Conversely, reaction at ambient
pressure and temperature with 10 mol % catalyst produced
no reaction, illustrating the necessity of the hyperbaric
condition (entry 5). Heating 8 and 7 in toluene with 10 mol
% Yb(OTf)3‚2H2O led to significant reduction in yield and
extensive polymerization (entry 6).
In the course of surveying the literature, it became clear
that optimizing the Diels-Alder reaction of 7 with dieno-
philes of type 2 would not be a trivial task; what appears to
be a textbook cycloaddition is, in practice, very difficult.
For example, thermal reaction of 7 with â-nitrostyrene,4
trans-cinnimaldehyde,3,5 or cis-ethyl cinnamate6 reportedly
gives only low to moderate yields of the corresponding
cycloadducts (20-25%, 22-54%, and 38%, respectively).
Reaction of benzylidene acetone 8 with cyclopentadiene
occurs in marginally better yield (35-64%),7 and so the
reaction of 7 with 8 was chosen as an initial model for our
system.
(8) Carruthers, W. Cycloaddition Reactions in Organic Synthesis; Per-
gamon: New York, 1990. Oppolzer, W. In ComprehesiVe Organic
Synthesis; Trost, M. B., Fleming, I., Paquette, L. A., Eds.; Pergamon: 1991,
New York; Vol 5, p 315.
(9) Kla¨rner, F.-G.; Diedrich, M. K.; Wigger, A. E. In Chemistry Under
Extreme or Non-Classical Conditions; van Eldik, R., Hubbard, C. D., Eds.;
Wiley: New York, 1997; Chapter 3. Jurczak, J.; Gryko, D. T. In Chemistry
Under Extreme or Non-Classical Conditions; van Eldik, R., Hubbard, C.
D., Eds.; Wiley: New York, 1997; Chapter 4. Isaacs, N. S. In High-Pressure
Techniques in Chemistry and Physics; Harwood, L. M., Moody, C. J., Eds.;
Oxford: New York, 1997; Chapter 7. Ibata, T. In Organic Synthesis at
High Pressures; Matsumoto, K., Acheson, R. M., Eds.; Wiley: Toronto,
1991; Chapter 9.
The results of the optimization study are summarized in
Table 1. Thermal conditions were found to give acceptable
yields of cycloadducts 9 (75%) but poor selectivity (entries
1 and 2, ∼25% de). It is known that in the Diels-Alder
(3) Cashin, C. H.; Fairhurst, J.; Horwell, D, C.; Pullar, I. A.; Sutton, S.;
Timms, G. H.; Wildsmith, E.; Wright, F. Eur. J. Med. Chem. 1978, 13,
495.
(4) Allen, C. F. H.; Bell, A.; Gates, J. W., Jr. J. Org. Chem. 1943, 8,
373. Allen, C. F. H.; Bell, A. J. Am. Chem. Soc. 1939, 61, 521.
(5) Sopov, N. P.; Kovner, M. L. J. Gen. Chem. USSR 1958, 28, 2184.
(6) Akbulut, N.; Hartsough, D.; Kim, J.-I.; Schuster, G. B. J. Org. Chem.
1989, 54, 2549.
(10) The stereochemistry of the major product was assigned as endo on
the basis of 1H NMR, 13C NMR, gCOSY, gHSQC, gHMBC, and NOESY
experiments.
(7) Dinwiddie, J. G., Jr.; McManus, S. P. J. Org. Chem. 1963, 28, 2416.
3518
Org. Lett., Vol. 2, No. 22, 2000

Table 2. Diels-Alder Reactions of Various Dienophiles with 1,3-Cyclohexadiene
Under the hyperbaric conditions, the catalyst loading could
be reduced to 5 mol % without significant effect on the yield
or selectivity (entry 7). However, when it was reduced further
to 1 mol %, the conversion was low (35% after 5 days) and
the selectivity was reduced (76% de, entry 8). If a stoichio-
metric proportion of cyclohexadiene was used instead of a
3-fold excess, the reaction rate was somewhat retarded (86%
conversion after 3 days, entry 9).
greater reactivity of Sc(OTf)3 compared to Yb(OTf)3‚2H2O
in the Diels-Alder reaction has been observed previously.11
Conventional Lewis acid conditions were then employed
for comparison. At -78 °C, both BF3‚Et2O (entry 14) and
SnCl4 (entry 15) resulted in poor yields (<20%) and
extensive polymerization. Several groups have achieved high
yields (>90%) in the Lewis acid catalyzed reaction of
cyclohexadiene with R,â-unsaturated esters, ketones, and
aldehydes.12 This suggests that the origin of the polymeri-
zation in the current case may be the benzylidene acetone
8. Furthermore, in the presence of Lewis acids, reaction of
Use of Sc(OTf)3 or Cu(OTf)2, either at high or ambient
pressure, led to polymerization and lower yields (<60%),
but selectivity remained high (>90% de, entries 10-13). The
Org. Lett., Vol. 2, No. 22, 2000
3519

8 with other dienes affords only low to moderate yields (30-
57%) of cycloadducts.13
The optimized conditions14 were applied to a number of
other substrates to determine the scope of the reaction (Table
2). Results of thermal reaction conditions are provided for
comparison in some cases.
The yields range from good to excellent, and generally
the selectivity is high. In the highest yielding case, chalcone
10a underwent Diels-Alder reaction to give cycloadduct 11a
in 94% yield and 90% de (entry 1).10
cycloadduct 11h, but the selectivity was deemed unaccept-
ably low for use in the synthesis of hapalindole Q (60% de,
entry 12). It was demonstrated that the catalyst was essential
for the success of this reaction (entry 13). An encouraging
result for the synthesis project was achieved when reaction
of indolylidene acetone 10i afforded cycloadduct 11i in 78%
yield and >95% de (entry 15).17
Attempted cycloadditions between 7 and cinnamaldehyde
10j at HP with and without Yb catalysis did not produce
useful yields of desired cycloadducts (entries 16 and 17).
The method was found to be effective for enones 10b-d
(entries 2, 4, and 5), but was unsuccessful on hindered enone
10e (entry 7) and trans-ethyl cinnamate 10f (entry 8). In the
case of cyclohexenone 10d, thermal conditions15 are reported
to afford only 6% yield of 11d, while the current method
provides a yield (66%, entry 5) comparable to that of
conventional Lewis acid catalysis (65-80% with AlCl3).16
With pentenone 10b, thermal conditions allow good yield
of cycloadducts 11b (58%, entry 3), but the selectivity is
poor (18% de) relative to those achieved using HP and
ytterbium catalysis.
The improved electron-withdrawing capacity of the nitro
group permitted cycloaddition of â-nitrostyrene 10g in the
absence of catalyst (compare entries 9 and 10) and thus a
cleaner reaction and improved yield of 11g. The hindered
indolylidene diethylmalonate 10h gave a 79% yield of
Unfortunately, 1,3-dimethyl-1,3-cyclohexadiene 3 was
found to polymerize in the presence of the Yb catalyst at
HP; however, it was stable in the absence of the Lewis acid.
Since it has been demonstrated that nitrodienophiles undergo
HP-mediated cycloaddition without activation, the reaction
of 3 with such dienophiles should be feasible. In point of
fact, 3 reacted (13 kbar, 7 d, CH2Cl2) with 2 (Scheme 1; PG
) Ts, EWG ) NO2) to give adduct 4 in 25% unoptimized
yield (86% de).18
In summary, a high yielding method for the selective
construction of endo-bicyclo[2.2.2]oct-2-ene systems via
Diels-Alder reaction has been developed. The reaction is
facilitated by the combined effects of high pressure and
Yb(OTf)3‚2H2O catalysis and is particularly useful for
electron-deficient ketodienophiles that may be prone to
polymerization.
(11) Kobayashi, S.; Hachiya, I.; Araki, M.; Ishitani, H. Tetrahedron Lett.
1993, 34, 3755.
Acknowledgment. We thank NSERC and Medmira
Laboratories Inc. for funding. A.C.K. is the recipient of an
Ontario Graduate Scholarship in Science and Technology.
X-ray services were provided by Dr. Michael Jennings. MS
analyses were performed by Doug Hairsine. We are grateful
to Chris Kirby for consultation regarding NMR experiments.
(12) (a) Fumaric esters, TiCl4: Hartmann, H.; Hady, A. F. A.; Sartor,
K.; Weetman, J.; Helmchen, G. Angew. Chem., Int. Ed. Engl. 1987, 26,
1143. (b) Maleic esters, Et2AlCl: Maruoka, K.; Akakura, M.; Saito, S.;
Ooi, T.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 6153. (c) Fumaric
ester, AlCl3: Ito, Y. N.; Ariza, X.; Beck, A. K.; Boha´cˇ, A.; Ganter, C.;
Gawley, R. E.; Ku¨hnle, F. N. M.; Tuleja, J.; Wang, Y. M.; Seebach, D.
HelV. Chim. Acta 1994, 77, 2071. (d) MVK and acrolein, CH3ReO3: Zhu,
Z.; Espenson, J. H. J. Am. Chem. Soc. 1997, 119, 3507. (e) Acrylic ester,
BCl3: Sarakinos, G.; Corey, E. J. Org. Lett. 1999, 1, 1741.
(13) Minami, T.; Chikugo, T.; Hanamoto, T. J. Org. Chem. 1986, 51,
2210. Shibata, J.; Shiina, I.; Mukaiyama, T. Chem. Lett. 1999, 313.
(14) General Experimental Procedure. In an argon-purged Teflon tube,
1,3-cyclohexadiene (∼3 equiv) was added to a ∼1 M solution of dieneophile
(1∼2 mmol) in CH2Cl2. Following addition of Yb(OTf)3‚2H2O (∼10 mol
%), the tube was sealed and placed in a high-pressure reactor at ∼13 kbar
for the time indicated in Table 2. After depressurization, the reaction mixture
was concentrated in vacuo and purified by flash chromatography.
(15) Nakazaki, M.; Naemura, K.; Kondo, Y.; Nakahara, S. Hashimoto,
M. J. Org. Chem. 1980, 45, 4440. Hirao, K.; Unno, S.; Yonemitsu, O. Chem.
Commun. 1977, 577.
Supporting Information Available: Full experimental
procedures and spectroscopic data for compounds endo-9,
exo-9, 10h, 10i, endo-11a-c, exo-11a-b, and 11g, 11h,
endo-11i. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0065773
(16) Fringuelli, F.; Guo, M.; Minuti, L.; Pizzo, F.; Taticchi, A.; Wenkert,
E. J. Org. Chem. 1989, 54, 710. Morlender-Vais, N.; Mandelbaum, A. J.
Mass Spectrom. 1997, 32, 1124.
(17) See Supporting Information for X-ray structure and crystallographic
data.
(18) Details of these results will be reported in due course.
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Org. Lett., Vol. 2, No. 22, 2000