Stepwise acid-promoted double-Michael process: An alternative to Diels-Alder cycloadditions for hindered silyloxydiene-dienophile pairs

Article abstract of DOI:10.1021/ol062980j

(Chemical Equation Presented) The hindered diene 1 reacts with 3-methylcyclohexenone 6 catalyzed by triflimide to produce the Mukaiyama Michael product 7 (low-temperature quenching) or the [4+2] cycloadduct 8 (quenching at 0°C). Reaction of the hindered d

Full text of DOI:10.1021/ol062980j

ORGANIC
LETTERS
2007
Vol. 9, No. 2
375-378
Stepwise Acid-Promoted Double-Michael
Process: An Alternative to Diels
−Alder
Cycloadditions for Hindered
Silyloxydiene−Dienophile Pairs
Michael E. Jung* and David G. Ho
Department of Chemistry and Biochemistry, UniVersity of California,
Los Angeles, 405 Hilgard AVenue, Los Angeles, California 90095
jung@chem.ucla.edu
Received December 9, 2006
ABSTRACT
The hindered diene 1 reacts with 3-methylcyclohexenone 6 catalyzed by triflimide to produce the Mukaiyama Michael product 7 (low-temperature
quenching) or the [4 2] cycloadduct 8 (quenching at 0 C). Reaction of the hindered diene 23 with 2-methylcyclohexenone 12 with 5:1
+
°
AlBr3:AlMe3 afforded a 71% yield of a 1.9:1 mixture of two cycloadducts. Hydrolysis of the major isomer gave the dione 27
′, a model for the
BCD ring system of pentacyclic triterpenes.
The major drawback of the traditional Diels-Alder reaction
is its severe limitation on substituents on the diene and
dienophile partners due to the considerable amount of steric
hindrance encountered with highly substituted substrates in
the transition state for concerted (and nonsynchronous)1
cycloadditions.2,3 Recently, we have shown that very hindered
cyclohexene systems can be prepared via a direct [4+2]
cycloaddition between quite hindered 2-silyloxydienes and
cyclic dienophiles catalyzed by a mixed Lewis acid, e.g., 1
and 2 giving 3 in excellent yield with a 5:1 mixture of AlBr3:
AlMe3 (Scheme 1).4 This ketone, which has three contiguous
Scheme 1
(1) Diels-Alder reactions often proceed via a concerted but nonsyn-
chronous transition state. (a) Houk, K. N. J. Am. Chem. Soc. 1973, 95,
4092-4. (b) Dewar, M. J. S.; Olivella, S.; Rzepa, H. S. J. Am. Chem. Soc.
1978, 100, 5650-9. (c) Boeckmann, R. K., Jr.; Ko, S. S. J. Am. Chem.
Soc. 1980, 102, 7146-9.
(2) For reviews of Diels-Alder reactions, see: (a) Nicolaou, K. C.;
Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. Angew. Chem., Int.
Ed. 2002, 41, 1668-98. (b) Hayashi, Y. Cycloaddit. React. Org. Synth.
2002, 5-55. (c) Whiting, A. AdV. Asymmetric Synth. 1996, 126-145. (d)
Oppolzer, W. Intermolecular Diels-Alder Reactions. In ComprehensiVe
Organic Synthesis; Trost, B. M., Ed.; Pergamon Press, Oxford, UK, 1991;
Vol. 5, Chapter 4.1, pp 315-99.
(3) It is somewhat difficult to find references to the problems caused by
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.
quaternary centers, can be hydrolyzed to the corresponding
dione 4 in excellent yield. On treatment with acidic methanol,
(4) Jung, M. E.; Ho, D.; Chu, H. V. Org. Lett. 2005, 7, 1649-51.
10.1021/ol062980j CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/19/2006

it gives the methoxytwistanone 5 via an intramolecular aldol
process as shown in A, which is presumably accelerated due
to a vicinal gem-dimethyl effect.5 We report here the novel
stepwise acid-promoted double Michael reaction6 of very
hindered 2-silyloxydienes with hindered ketone dienophiles
in the presence of the very strong Brønsted acid triflimide
(Tf2NH) to ultimately afford the products of a difficult [4+2]
cycloaddition.
In our previous work, we used a 5:1 mixture of AlBr3:
AlMe3 as a strong Lewis acid system in which we could
guarantee the lack of even traces of HBr since it was thought
that the presence of adventitious amounts of HBr would be
detrimental to the desired Diels-Alder cycloaddition, in
particular by causing decomposition of the electron-rich
diene.7 However, in an attempt to accelerate some hindered
cycloadditions, we decided to carry out the reaction in the
presence of triflimide, a very strong Brønsted acid.8 Thus
treatment of the 2-silyloxydiene 1 with 3-methylcyclohex-
enone 6 in the presence of 1-5% triflimide in dichlo-
romethane at -78 °C for 2 h afforded, after quenching at
-78 °C, the Mukaiyama Michael9 product 7 in 92% yield
(Scheme 2). Treatment of this new silyloxyenone 7 with
Diels-Alder [4+2] cycloaddition, which can be carried out
by using our mixed Lewis acid catalyst. If one lets the
reaction of 1 and 6 in the presence of triflimide warm to 0
°C before quenching, then the ketone 8 is produced in 89%
isolated yield. Hydrolysis of the silyl enol ether of 8 gives
the cis dione 9, which can be equilibrated to a 15:85 mixture
of 9 and 10, favoring the more stable trans dione. Thus we
have shown that the apparent cycloaddition of 1 and 6 in
the presence of triflimide proceeds via the Mukaiyama
Michael adduct 7.
We believe that the true catalyst in this process is tert-
butyldimethylsilyl triflimide, TBSNTf2 11. The silyl triflim-
ide 11 was prepared by the method of Ghosez, namely by
addition of triflimide to the corresponding allylsilane.11
Addition of this silyl triflimide 11 to a solution of 1 and 6
in dichloromethane does afford both the simple Michael
adduct 7 and the double Michael product 8, depending on
time and conditions.
When the enone dienophile is unhindered (no â-alkyl
group), the initial Michael reaction also works very well.
Thus addition of 1 to 2-methylcyclohexenone 12 with either
Tf2NH or the mixed Lewis acid with quenching at -78 °C
gave the Mukaiyama Michael product 13 in 95% yield
(Scheme 3). However, hindrance at the R-carbon of the enone
Scheme 2
Scheme 3
now slows the intramolecular Michael so that triflimide no
longer is reactive enough to promote the second Michael
process. However, the use of AlMe3 converted 13, in 89%
yield, into the [4+2] cycloadduct 14, which on hydrolysis
affords the dione 15. The mixed Lewis acid system afforded
in 60% yield the double bond isomer 16, which is calculated
to be somewhat more stable than 14.
triflimide or silyl triflate (TBSOTf) gives the second,
intramolecular Michael product, namely the ketone 8, in
51-63% yield.10 This would be the product of the direct
We have found that the triflimide-catalyzed processes can
be much cleaner than the cycloadditions using the mixed
aluminum Lewis acid that we reported earlier. Thus reaction
of the diene 1 with 1-acetyl-2-methylcyclopentene 17 in the
presence of Tf2NH was much cleaner giving the desired
adduct 18 with much less of the diene-dimerization product
19 (Scheme 4). Again if one quenches the initial Tf2NH
(5) Jung, M. E.; Piizzi, G. Chem. ReV. 2005, 105, 1735-1766.
(6) For a review of base-catalyzed double Michael additions leading to
bicyclic products, see: Jung, M. E. Stabilized Nucleophiles with Electron
Deficient Alkenes and Alkynes. In ComprehensiVe Organic Synthesis; Trost,
B. M., Ed.; Pergamon Press: Oxford, UK, 1991; Vol. 4, Chapter 1.1, pp
1-67.
(7) a) Jung, M. E.; Davidov, P. Angew. Chem. 2002, 41, 4125-28.
(8) The pKa of triflimide is estimated to be -16 while that of triflic acid
has been calculated to be -14. Bordwell, F. G. Acc. Chem. Res. 1988, 21,
456-463.
(9) (a) Narasaka, N.; Soai, K.; Aikawa, Y.; Mukaiyama, T. Bull. Chem.
Soc. Jpn. 1976, 49, 779-83. (b) For a review, see: Lee, V. Conjugate
Additions of Carbon Ligands to Activated Alkenes and Alkynes. In
ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
Oxford, UK, 1991; Vol. 4, Chapter 1.3, pp 139-168.
(10) For an example of a triflimide-promoted Michael addition (and
closure to the [2+2] product), see: Takasu, K.; Ishii, T.; Inanaga, K.; Ihara,
M. Org. Synth. 2006, 83, 193.
(11) Mathieu, B.; Ghosez, L. Tetrahedron Lett. 1997, 38, 5497-
5500.
376
Org. Lett., Vol. 9, No. 2, 2007

Scheme 4
Scheme 6
reaction at low temperature, one isolates an 8:1 mixture of
the stereoisomeric Mukaiyama Michael adducts 20ab. We
assume the less hindered E isomer is the major isomer
formed.
We also wanted to examine the possible use of these
cycloadditions for the synthesis of the trimethyldecalin
portion of several naturally occurring terpenes, both of the
bicyclic diterpene and pentacyclic triterpene classes. For this
reason we examined the addition of 1 with the enone ester
2112 with triflimide, first at -78 °C, then warming to -40
°C, to give the desired cycloadduct 22 with very little of the
diene dimer 19 (Scheme 5). We are currently looking at the
istry of the major compound 24 although NOE experiments
did not show a correlation between the two methyl groups.
The silyl enol ether was hydrolyzed to give a dione that
we expected to have the trans-decalin structure, e.g.,
compound 26. Therefore we were surprised to see an NOE
correlation between the two methyl groups since in neither
26 nor 27 would one expect such a correlation. We postu-
lated that because of the two severe 1,3-diaxial interac-
tions of the methyl groups with the rings of the perhydro-
phenanthrene system, compound 27 might exist prefer-
entially in the conformation 27′, which would show the
observed NOE. A single-crystal X-ray structure confirmed
that assignment. Thus the cycloaddition-hydrolysis of 23
and 12 gives the desired contiguous quaternary centers in
the desired trans orientation as the major component of a
1.9:1 mixture.
Scheme 5
Also the [4+2] cycloaddition of the hindered diene 23 with
another hindered dienophile 28 promoted by the mixed Lewis
acid catalyst gave a 6.4:1 mixture of the two cycloadducts
29 and 30 favoring the all-cis stereoisomer in 88% yield
(Scheme 7). The stereochemical determination was again
done by a single-crystal X-ray structure.
conversion of compounds such as 22 into biologically active
diterpenes, e.g., haterumaimide E.13
Scheme 7
We also examined the use of cyclic hindered dienes in
these cyclizations as a route to the synthetically challenging
BCD ring system of pentacyclic triterpenes which have two
contiguous quaternary centers. We wanted to know whether
cycloadditions of these hindered systems could be applied
to the trans-C8,C14-dimethyl unit of pentacyclic triterpenes.
Thus we reacted the hindered diene 2314 with 2-methyl-
cyclohexenone 12 with the 5:1 mixture of Lewis acids at
-5 °C for 2 d and isolated a 71% yield of a 1.9:1 mixture
of two cycloadducts, 24 and a still unidentified isomer 25
(Scheme 6). It was impossible to determine the stereochem-
Finally the most hindered diene we have examined thus
far, the trimethylcyclohexenyl silyl enol ether 31,15 underwent
a [4+2] cycloaddition with the hindered dienophile 2-meth-
ylcyclohexenone 12 promoted by the mixed Lewis acid
catalyst to give the cycloadduct 32 in an unoptimized 61%
(12) The enone ester is prepared from 3-ethoxycyclohexenone by
alkylation of the anion (LDA) with ethyl bromoacetate, followed by addition
of methyl Grignard reagent and hydrolysis in an overall yield of 79%. See:
Horiguchi, Y.; Nakamura, E.; Kuwajima, I. J. Am. Chem. Soc. 1989, 111,
6257-65.
(13) Uddin, M. J.; Kokubo, S.; Suenaga, K.; Ueda, K.; Uemura, D.
Heterocycles 2001, 54, 1039-1047.
(14) This diene is unknown but the TMS analogue is known. (a)
Rubottom, G. M.; Gruber, J. M. J. Org. Chem. 1978, 43, 1599-602. (b)
Stanetty, P.; Mihovilovic, M. D.; Mereiter, K.; Vollenkle, H.; Renz, F.
Tetrahedron 1998, 54, 875-894.
(15) This diene is prepared from 2-acetyl-1,3,3-trimethylcyclohexene
in good yield. See: Jung, M. E.; Murakami, M. Org, Lett. 2006, 8,
5857-59.
Org. Lett., Vol. 9, No. 2, 2007
377

yield after 8 days at -5 °C. Acidic methanolysis afforded
an 8:2 mixture of the tetramethyldiones 33 and 34 in which
the stereochemical determination was done by extensive
NOESY experiments on all three compounds, 32-34. Thus
the trans-diaxial arrangement of the two quaternary methyls
is favored in both the less substituted system 24 and the more
highly substituted one 32. This is a good model for the BCD
ring system of pentacyclic triterpenes.
In summary, we have described the stepwise double
Michael process in which a very hindered 2-silyloxydiene
reacts with an enone in the presence of triflimide to give
either the initial Michael product (quenching at low tem-
perature) or the [4+2] cycloadduct. In addition we have
reported the synthesis of very hindered perhydrophenanthrene
systems related to the central core of pentacyclic triterpenes.
Further studies on the use of these concepts and intermediates
for the synthesis of natural products are in progress and will
be reported in due course.
Scheme 8
Acknowledgment. We thank the National Science Foun-
dation (CHE 0314591 and CHE 0614591) for generous
support of this work and Dr. Masayuki Murakami for the
preparation of diene 31.
Supporting Information Available: Experimental pro-
cedures and proton and carbon NMR data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL062980J
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Org. Lett., Vol. 9, No. 2, 2007