Synthesis of highly substituted cyclohexenes via mixed Lewis acid-catalyzed Diels-Alder reactions of highly substituted dienes and dienophiles

Article abstract of DOI:10.1021/ol050361p

(Chemical Equation Presented) A high-yielding method is described for the rapid synthesis of very hindered cyclohexenes by the Diels-Alder reaction of hindered silyloxy dienes and dienophiles using the mixed Lewis acid catalyst system (AlBr₃/AlMe₃). Thus, reaction of the hindered diene 4 with various substituted enones gave good yields of the expected cycloadducts even though both partners are quite sterically hindered.

Full text of DOI:10.1021/ol050361p

ORGANIC
LETTERS
2
005
Vol. 7, No. 8
649-1651
Synthesis of Highly Substituted
Cyclohexenes via Mixed Lewis
1
Acid-Catalyzed Diels−Alder Reactions of
Highly Substituted Dienes and
Dienophiles
Michael E. Jung,* David Ho, and Hiufung V. Chu
Department of Chemistry and Biochemistry, UniVersity of California, Los Angeles,
405 Hilgard AVenue, Los Angeles, California 90095
jung@chem.ucla.edu
Received February 19, 2005
ABSTRACT
A high-yielding method is described for the rapid synthesis of very hindered cyclohexenes by the Diels
dienes and dienophiles using the mixed Lewis acid catalyst system (AlBr /AlMe ). Thus, reaction of the hindered diene 4 with various substituted
enones gave good yields of the expected cycloadducts even though both partners are quite sterically hindered.
−Alder reaction of hindered silyloxy
3
3
The Diels-Alder reaction has been a mainstay of synthetic
organic chemistry for more than 70 years due to its predict-
able reactivity and control of the regio- and stereochemistry
in the formation of the two new σ bonds in the intermolecular
of this process which demonstrates that it is quite general
for the production of highly substituted cyclohexenes.
The cycloaddition of the silyloxydiene 1 with 1-acetyl-2-
4
methylcyclopentene 2 using a 10:1 mixture of AlBr
3
/AlMe
3
1
combination of a diene and dienophile. However, despite
at 0 °C for 4 h in toluene/dichloromethane solvent afforded
an 88% yield of a 2.6:1 mixture of the stereoisomers 3x and
3n, favoring the exo product (Scheme 1). Since the cycload-
dition is most likely a stepwise process (a Mukaiyama-
Michael followed by an intramolecular Michael-like process)
its well-deserved reputation in synthesis, problems still exist
in the application of these cycloadditions to certain cases.
In particular, the use of Diels-Alder reactions to prepare
highly substituted cyclohexene systems has generally met
2
5
with failure owing to severe problems with steric hindrance.
and the two bonds are not formed simultaneously, the
Recently, we reported two examples of the preparation of a
normal Alder endo transition state rules would not be in
effect (no substantial secondary orbital overlap) and the
stereochemistry would probably be controlled by steric hin-
6,6,5-tricyclic system, using the mixed Lewis acid system,
AlBr /AlMe , via both the cycloaddition of hindered dieno-
3
3
philes with 2-silyloxydienes and the inverse-electron-demand
(
2) It is somewhat difficult to find references to the problems caused by
Diels-Alder reaction of a hindered silyl enol ether with a
severe steric hindrance in intermolecular Diels-Alder reactions, but one
can find examples where the conditions for the successful cycloaddition
are quite harsh. See, for example: (a) Engler, T. A.; Sampath, U.; Vander
Velde, D.; Takusagawa, F. Tetrahedron 1992, 48, 9399-16. (b) Nicolaou,
K. C.; Hwang, C.-K.; Sorensen, E. J.; Claiborne, C. F. J. Chem. Soc., Chem.
Commun. 1992, 1117-1118. (c) Gacem, B.; Jenner, G. J. Phys. Org. Chem.
2004, 17, 221-225.
(3) Jung, M. E.; Davidov, P. Angew Chem. 2002, 41, 4125-28.
(4) (a) Harding, K. E.; Trotter, J. W.; May, L. M. J. Org. Chem. 1977,
42, 2715-9. (b) Tabushi, I.; Fujita, K.; Oda, R. Tetrahedron Lett. 1968,
5455-8.
3
2
-acyldiene. We now report an examination of the scope
(
1) For reviews of the Diels-Alder reaction, see: (a) Nicolaou, K. C.;
Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. Angew. Chem., Int.
Ed. 2002, 41, 1668-1698. (b) Hayashi, Y. Cycloaddit.n React. Org. Synth.
2
2
(
002, 5-55. (c) Willis, M. C. Rodd’s Chem. Carbon Comput., 2nd ed.
001, 5, 275-313. (d) Whiting, A. AdV. Asymm. Synth. 1996, 126-145.
e) Oppolzer, W. Intermolecular Diels-Alder Reactions. In ComprehensiVe
Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, 1991; Vol.
, Chapter 4.1, pp 315-99.
5
1
0.1021/ol050361p CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/11/2005

under these conditions, the electron-rich silyl enol ether can
react with the Lewis acid to produce the zwitterion I, which
is a very activated dienophile and can add to the diene 4 to
give 6. The structure of 6 was proven by its preparation from
Scheme 1
4
and mesityl oxide and its conversion to the dione 8, which
was identified by its high symmetry.
Since 1-acylcyclohexenes are generally less reactive than
1-acylcyclopentenes in cycloadditions, we wanted to test the
reactivity of the higher homologue. Reaction of the substi-
6
tuted diene 4 with 1-acetyl-2-methylcyclohexene 9 in the
presence of 5:1 AlBr /AlMe at -5 °C for 48 h gave a 5:1
3 3
mixture of the desired cycloadduct 10 and the byproduct 6
in 75% yield (Scheme 3). Reduction and methanolysis
drance. In this case, the trimethylene bridge is less sterically
demanding than the methyl and acetyl groups on the dieno-
phile and thus the exo isomer 3x is the major product as
shown in Figure 1.
Scheme 3
Figure 1.
More highly substituted dienes can also be used in this
process. For example, the silyl enol ether 4 prepared from
mesityl oxide was reacted with 2 using a 5:1 mixture of
afforded the dione 11 in 99% yield (based on 10), which is
also a very sterically encumbered molecule with three
contiguous quaternary centers.
Substituted cyclic ketones can also be used as dienophiles
in this process. For example, the relatively unhindered
3 3
AlBr /AlMe at -5 °C for 48 h to produce a 5:1 mixture of
the desired cycloadduct 5 and the byproduct 6 in 78% yield
(Scheme 2). Although these two compounds could not be
3
-methylcyclohex-2-en-1-one 12 reacted with the substituted
diene 4 in the presence of 5:1 AlBr /AlMe at -5 °C for 48
h to give the desired cycloadduct 13 in 82% yield (Scheme
Scheme 2
3
3
4
). As in most reactions with relatively unhindered dieno-
Scheme 4
separated, treatment of the mixture with DIBAL at -78 °C
reduced the byproduct 6 and allowed the isolation, after silyl
enol ether methanolysis, of the dione 7 in 95% yield (based
on 5). This ketone is an extremely congested molecule
possessing three contiguous quaternary centers in a compact
system. We propose that the byproduct arises via the follow-
ing pathway: since the desired cycloaddition is quite slow
philes, no more than a trace of the byproduct 6 was observed
(5) Even though this is likely a stepwise process, it should still be
considered a Diels-Alder reaction since Diels and Alder only described
the reaction of a diene and dienophile to give a cyclohexene without
implying any mechanistic detail; thus, this reaction should be considered a
Diels-Alder reaction by their definition.
(
6) (a) Groves, J. K.; Jones, N. J. Chem. Soc. C 1968, 2898-900. (b)
Hudlicky, T.; Srnak, T. Tetrahedron Lett. 1981, 22, 3351-4.
1650
Org. Lett., Vol. 7, No. 8, 2005

here. Acidic hydrolysis of the silyl enol ether afforded the
expected dione, which can exist in two conformations, 14ab.
On treatment with acidic methanol, the ring juncture stere-
ochemistry was epimerized to give an 85:15 mixture of the
trans and cis diones 15 and 14. This mixture could also be
prepared by treatment of 13 directly with excess tosic acid
in methanol. Molecular mechanics calculations (MM2)
indicate a 1.3 kcal/mol difference in energy favoring 15 over
Reaction of the more hindered 4-methyl-1,3-pentadiene-2-
1
0a
carboxylate 20 with the two substituted dienophiles 21ab
with 10:1 AlBr /AlMe at 0 °C gave modest yields (44%
3
3
and 23%, respectively) of the cyclohexenecarboxylates 22ab,
which was not surprising since esters are known to be
relatively poor electron-withdrawing groups and the dienes
are less activated than our earlier one (Scheme 6). However,
14b. The fact that one can isomerize the cis ring juncture to
the trans opens up the possibility of using this process for
the synthesis of the AB ring system of various terpenoid
natural products.
Scheme 6
The value of a new synthetic method is determined by its
ability to work even in difficult cases, and we believe that
this new mixed Lewis acid catalyzed process meets this
criterion. The very sterically hindered dienophile, 2,3-
dimethylcyclohex-2-en-1-one 16, reacted with the dimethyl-
substituted diene 4 in the presence of 5:1 AlBr
3 3
/AlMe at
-
5 °C for 48 h to give the desired tetramethyl cycloadduct
17 in 79% yield (Scheme 5). Acidic hydrolysis as before
Scheme 5
the corresponding 2-acetyldiene 2310b gave higher yields
(
2
69% and 37%, respectively) of the desired cycloadducts
4ab under much milder conditions. Therefore, the quite
highly substituted cyclohexene esters and ketones 22 and
4 can be prepared very rapidly in fair to good yield directly
2
from the activated dienes and the hindered dienophiles. We
have not yet studied other electron-withdrawing groups as
activating groups for this process on either the diene or
dienophile but plan to do so soon.
In summary, we have demonstrated that highly substituted
cyclohexene systems can be prepared directly by a Diels-
Alder reaction in either the direct or inverse-electron-demand
mode catalyzed by the novel mixed Lewis acid system AlBr
AlMe . The preparation of such systems and their use in
synthesis is currently under study in our laboratory.
3
/
3
gave the dione 18 in 93% yield. However, acidic metha-
nolysis of the silyl enol ether did not afford the expected
dione 18 but rather gave a different product which exhibited
Acknowledgment. We thank the National Science Foun-
dation (CHE0314591) for their financial support. H.V.C.
thanks the National Institutes of Health for support via Grant
No. GM08496.
1
3
only a single ketone resonance at δ 219.0 in the C NMR
1
and one methoxy singlet at δ 3.2 in the H NMR. We have
assigned the methoxy twistanone structure 19 to this product.
The formation of hydroxy twistanones from diones similar
to 18 has been reported previously. Here, the twistanone
Supporting Information Available: Spectroscopic data
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
7
19 is the major product of a 3:1:1 mixture along with the
dione 18 and another, as yet, unidentified product. Presum-
ably the reaction proceeds via the attack of the enol of the
ketone on the R-methoxy carbocation (oxocarbenium ion)
in an aldol-type process as shown in II. The mutual steric
repulsion of the four methyl groups may well favor the
OL050361P
(8) Simple molecular mechanics calculations (MM2) indicate that the
driving force for forming the twistanone 19 from the diketone is far greater
than that for the formation of the unsubstituted twistanone presumably due
to the buttressing steric effect of the four methyl groups. For a review of
gem-dialkyl effects, see: Jung, M. E. Synlett 1999, 843-46. Jung, M. E.
Synlett 1990, 186-90. Jung, M. E.; Piizzi, G. Chem. ReV. 2005, in press.
(9) As with the previous case, this reaction is presumably stepwise,
namely a Mukaiyama-Michael addition followed by an intramolecular aldol
condensation onto the very hindered ketone.
8
cyclization in a kind of geminal and vicinal polyalkyl effect.
We also decided to explore briefly the generality of the
9
inverse-electron-demand Diels-Alder reaction of a hindered
3
silyl enol ether with a 2-acetyldiene that we reported earlier.
(
10) (a) Prepared by Stille coupling of ethyl 2-tributylstannylacrylate with
(
7) (a) Yordy, J. D.; Reusch, W. J. Am. Chem. Soc. 1977, 99, 1965-8.
1-bromo-2-methylpropene. (b) Prepared by Stille coupling of 2-tributyl-
stannyl-1-butenol with 1-bromo-2-methylpropene followed by Swern oxida-
tion.
(
b) Yordy, J. D.; Reusch, W. J. Org. Chem. 1975, 40, 2086-8. (c) B e´ langer,
A.; Poupart, J.; Deslongchamps, P. Tetrahedron Lett. 1968, 2127-8.
Org. Lett., Vol. 7, No. 8, 2005
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