Double annulation route to highly substituted and functionalized trans- fused bicyclic compounds

Full text of DOI:10.1021/jo9822737

340
J . Org. Chem. 1999, 64, 340-341
decalin. The overall “double annulation” creates three new
Dou ble An n u la tion Rou te to High ly
Su bstitu ted a n d F u n ction a lized Tr a n s-F u sed
Bicyclic Com p ou n d s
C-C bonds, two new rings, two new quaternary centers, and
two or three new stereocenters in just two synthetic steps.
It proceeds stereoselectively, in good yield, and in atom-
economical fashion, and the products are highly substituted
and functionalized.
Robert B. Grossman,* Melissa A. Varner, and
Aaron J . Skaggs
Repeated efforts to condense tetraester22 1a with 3-butyn-
2-one (2) under a variety of conditions led to a complex
mixture of many products, none of which was the desired
cyclohexane 3a . Occasionally, the mono-Michael adduct was
Department of Chemistry, University of Kentucky,
Lexington, Kentucky 40506-0055
Received November 16, 1998
The development of methods for assembling complex
compounds from simple ones in as few synthetic steps as
possible is a continuing theme in organic synthesis. Methods
that allow for the formation of multiple C-C bonds ef-
ficiently and stereoselectively are especially valuable.1,2 We
now report a novel method for the synthesis of trans-fused
bicyclic compounds, especially trans-decalins, that meets
these criteria. There is a need for new and efficient methods
to prepare highly substituted and functionalized trans-
decalins, as many biologically active di- and triterpenoids
such as neotripterifordin (anti-HIV),3 longikaurin C (anti-
bacterial),4 atidine (antiarrhythmic),5 the gibberellic acids
(plant hormones),6 and azadirachtin (insect antifeedant)7,8
have highly substituted and functionalized trans-decalin or
trans-hydrindane substructures.
isolated in poor yield. We hypothesized that incipient 1,3-
diaxial interactions between two ester groups in the transi-
tion state for the second, intramolecular Michael addition
may have prevented it from taking place and that replace-
ment of two CO2Et groups with more slender CN groups
might facilitate the reaction.23
Diethyl 2,6-dicyanopimelate17,24 (1b) does in fact undergo
two sequential Michael additions to 2 in CH2Cl2 at -78 °C
under NaH catalysis to give Cs-symmetric 3b and C1-
symmetric 3b′ in 52% and 11% yield, respectively (Table 1).25
The stereochemistry of the second Michael addition deter-
mines the stereochemistry of the product, and the transition
state for this reaction is expected to resemble the product,
so it is not surprising that 3b, the major product, has both
CN groups oriented axially.
Our method begins with two Michael reactions9-11 (for-
mally an [n + 1] annulation) of two tethered carbon acids
(1) and 3-butyn-2-one (2) to give a cycloalkylacetone (3).
“Double Michael reactions” have been used in synthesis
before,12-16 but our method is especially versatile and uses
Two R-cyano ester groups are not required for the double
Michael reaction to proceed. Compounds 1c and 1d 17 also
undergo double Michael addition to 2 to give cycloalkanes
3c and 3d in 70% and 69% yields, respectively. Adduct 3c
is obtained in a 99:1 diastereomeric ratio (dr) using t-BuOK
in CH2Cl2 at -78 °C (and only 6:1 dr using NaH in THF at
0 °C); X-ray crystallographic analysis of its Dieckmann
product (vide infra) confirms that the CN and acetonyl
groups are cis in the major diastereomer, as expected.
The double Michael reaction also proceeds well when the
two carbon acids are connected by a two-carbon tether.
Diethyl 2,5-dicyanoadipate17,26 (1e) undergoes double Michael
addition to 2 to give cyclopentane 3e as an inseparable
mixture of one Cs- and one C1-symmetric diastereomer in
72% yield. When NaH is used as base in THF at -78 °C to
room temperature, the dr immediately after the starting
material is consumed is 3:2, but if the reaction mixture is
allowed to stir at room temperature, the ratio improves to
8:1. The diastereomers presumably equilibrate by a retro-
Michael reaction. The structure of the major diastereomer
is assigned as the one in which the acetonyl and CN groups
are cis because this isomer is expected to be thermodynami-
cally more stable and because its Dieckmann reaction gives
readily available starting materials.17 Also, to our knowl-
edge, our version of the double Michael reaction is the first
example involving an electrophilic alkyne, rather than two
electrophilic alkenes,9-11 and is the first to create two new
quaternary centers18,19 in a 1,3-relationship. The double
Michael reaction is followed by a Dieckmann reaction20,21
to afford a trans-fused bicyclic compound (4), usually a trans-
* To whom correspondence should be addressed. E-mail: rbgros1
@pop.uky.edu.
(1) Parsons, P. J .; Penkett, C. S.; Shell, A. J . Chem. Rev. 1996, 96, 195.
(2) Tietze, L. F. Chem. Rev. 1996, 96, 115.
(3) Corey, E. J .; Liu, K. J . Am. Chem. Soc. 1997, 119, 9929.
(4) Fujita, T.; Takeda, Y.; Shingu, T. Heterocycles 1981, 16, 227.
(5) Pelletier, S. W.; Mody, N. V. In The Alkaloids; Rodrigo, R. G. A., Ed.;
Academic Press: New York, 1981; Vol. 18, Chapter 2, p 99-216.
(6) Mander, L. N. Chem. Rev. 1992, 92, 573.
(7) Ley, S. V.; Denholm, A. A.; Wood, A. Nat. Prod. Rep. 1993, 109.
(8) Mordue (Luntz), A. J .; Blackwell, A. J . Insect Physiol. 1993, 39, 903.
(9) Bergmann, E. D.; Ginsburg, D.; Pappo, R. Org. React. 1959, 10, 179.
(10) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Pergamon Press: Oxford, 1992.
(11) Little, R. D.; Masjedizadeh, M. R.; Wallquist, O.; McLoughlin, J . I.
Org. React. 1995, 47, 315.
(12) Bhardwaj, C. L.; Ireson, J . C.; Lee, J . B.; Tyler, M. J . Tetrahedron
1977, 33, 3279.
(13) Britten-Kelly, M.; Willis, B. J .; Barton, D. H. R. Synthesis 1980, 27
and references therein.
(14) Padwa, A.; Watterson, S. H.; Ni, Z. J . Org. Chem. 1994, 59, 3256
and references therein.
(15) Ihara, M.; Makita, K.; Fujiwara, Y.; Tokunaga, Y.; Fukumoto, K. J .
Org. Chem. 1996, 61, 6416 and references therein.
(16) Holton, R. A.; Williams, A. D.; Kennedy, R. M. J . Org. Chem. 1986,
51, 5480.
(20) Hauser, C. R.; Swamer, F. W.; Adams, J . T. Org. React. (N.Y.) 1954,
8, 59.
(21) Schaefer, J . P.; Bloomfield, J . J . Org. React. (N.Y.) 1967, 15, 1.
(22) Bailey, W. J .; Sorenson, W. R. J . Am. Chem. Soc. 1954, 76, 5421.
(23) ∆∆G° ) 1.30 kcal/mol for the two chair conformers of methyl
cyclohexanecarboxylate, while ∆∆G° ) 0.24 kcal/mol for the two chair
conformers of cyclohexanecarbonitrile. Lowry, T. H.; Richardson, K. S.
Mechanism and Theory in Organic Chemistry, 3rd ed.; Harper & Row: New
York, 1987.
(24) Carpenter, H. C. H.; Perkin, W. H., J r. J . Chem. Soc. 1899, 75, 921.
(25) A third, Cs-symmetric diastereomer (not shown) could be isolated
when the double Michael reaction was carried out at room temperature.
(26) Best, S. R.; Thorpe, J . F. J . Chem. Soc. 1909, 685.
(17) Grossman, R. B.; Varner, M. A. J . Org. Chem. 1997, 62, 5235-5237.
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(19) Fuji, K. Chem. Rev. 1993, 93, 2037.
10.1021/jo9822737 CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/29/1998

Communications
J . Org. Chem., Vol. 64, No. 2, 1999 341
Ta ble 1.a
functionalized polycyclic compounds. For example, although
3d suffers from addition of EtOH to the CN groups under
the standard Dieckmann conditions,31 hydrogenation of 3d
over Pd/C in AcOH affords trans-perhydroisoquinoline 5 as
a single stereoisomer in 69% yield.32 The selectivity of the
reductive amination for the equatorial CN group is note-
worthy.
The number of new C-C bonds, rings, and quaternary
centers created with our method, its high stereoselectivity,
and the ready availability of the requisite starting materials
allow our method to be compared favorably to such estab-
lished routes to trans-fused bicyclic compounds as the
Robinson annulation,33 the intramolecular Diels-Alder
reaction,34 and polyolefin cascade cyclizations.35 Moreover,
our method immediately provides quaternary centers at C4
and C10 (diterpenoid numbering) of the decalin ring system,
with all three substituents at these centers functionalized.
The preparation of trans-decalins with two or three func-
tionalized substituents at quaternary C4 and C10 has been
accomplished only occasionally and usually with poor ste-
reoselectivity,36,37 Corey’s recent synthesis of neotripterifor-
din by a cation-π cyclization being a notable exception.3 The
lack of synthetic methods in this area is a serious problem,
as numerous di- and triterpenoids that feature highly
functionalized trans-decalin substructures have interesting
biological activity in combination with low toxicity.3-8
Experiments to expand the scope of the double annulation
reaction further and to apply it to the synthesis of various
polyterpenoids are in progress.38-40
Ack n ow led gm en t. The authors thank the National
Science Foundation (CAREER award to R.B.G., Grant No.
CHE-9733201) and the University of Kentucky for their
generous support of this work. We also thank Dr. Brian
Patrick, Michael Lloyd, and Alberto Carrillo for analyzing
4c and 4e by X-ray diffraction.
Su p p or tin g In for m a tion Ava ila ble: Experimental details for
the preparation and full characterization of compounds 3-5 and
diethyl 2,7-dicyanosuberate and X-ray structural information for
4c and 4e.
a
b
E ) CO2Et. Determined by GC-MS of the crude reaction
mixture. c Isolated yield of >95% pure products. Not applicable.
d
e After equilibration.
a trans-hydrindane with cis CN groups (vide infra). We have
thus far been unable to induce diethyl 2,7-dicyanosuberate
(which has a four-carbon tether) to undergo the double
Michael reaction.
When 3b, 3b′, 3c, or 3e is heated in absolute EtOH with
an excess of NaOEt, a Dieckmann reaction occurs to form a
new, six-membered ring. Treatment of the immediate prod-
uct with TsOH and EtOH in benzene then affords the
corresponding enol ether. In every case, only a single regio-
and diastereoisomer is obtained. The large coupling con-
stants between the methine H’s in 4b, 4b′, 4c, and 4e and
their trans vicinal neighbors (11.7, 12.4, 12.5, and 11.2 Hz,
respectively) are consistent only with a trans ring fusion in
each of these compounds.27 Thus, only the isomers derived
from attack of the nascent enolate of 3 on an equatorial
CO2Et group are obtained. Two inequivalent equatorial CO2-
Et groups are present in 3c, so two trans-decalins could be
obtained in principle, but the Dieckmann reaction gives only
a single product, 4c, whose regiochemistry has been unam-
biguously established by X-ray analysis of a single crystal.
Compound 3e of 5:1 dr gives only a single stereoisomer of
4e in modest yield after chromatography, but small amounts
of three other species (16:1:1:1 ratio) with similar retention
times and mass spectra are observed in the GC trace of the
crude reaction mixture. The CN groups of isolated 4e are
shown to be cis by X-ray crystallography. The crude GC-
MS spectrum suggests that side reactions involving the loss
of CO2Et may account for the low yield. The regiochemistries
of enol ether formation in 4 are assigned by analogy to
known compounds28-30 and are confirmed by the X-ray
analyses of 4c and 4e.
J O9822737
(28) Grossman, R. B.; Ley, S. V. Tetrahedron 1994, 50, 11553-11568.
(29) de la Puente, M. L.; Grossman, R. B.; Ley, S. V.; Simmonds, M. S.
J .; Blaney, W. M. J . Chem. Soc., Perkin Trans. 1 1996, 1517-1521.
(30) de la Puente, M. L.; Ley, S. V.; Simmonds, M. S. J .; Blaney, W. M.
J . Chem. Soc., Perkin Trans. 1 1996, 1523-1529.
(31) A wide variety of other conditions have also been explored, but the
Dieckmann product of 3d has never been obtained in good, reproducible
yield.
(32) The stereochemistry was confirmed by coupling constant analysis
and a NOESY experiment.
(33) J ankowski, P. Tetrahedron 1998, 54, 12071.
(34) Ciganek, E. Org. React. (N.Y.) 1984, 32, 1.
(35) Hoffmann, H. M. R. Angew. Chem., Int. Ed. Engl. 1992, 31, 1332.
(36) Meyer, W. L.; Goodwin, T. E.; Hoff, R. J .; Sigel, C. W. J . Org. Chem.
1977, 42, 2761.
(37) Kametani, T.; Kato, Y.; Honda, T.; Fukumoto, K. J . Am. Chem. Soc.
1976, 98, 8185.
(38) Preliminary results suggest that the double Michael reaction
proceeds with ketoester, cyano ketone, and nitroalkane nucleophiles and
with alkynoate and internal alkynone electrophiles.
(39) Grossman, R. B.; Skaggs, A. J .; Kray, A. E.; Patrick, B. O. Manuscript
in preparation.
(40) Grossman, R. B.; Pendharkar, D. S.; Patrick, B. O. Manuscript in
preparation.
The double Michael adducts are potentially useful starting
materials for the synthesis of a variety of other highly
(27) Compound 4b can only have a trans ring fusion. If 4b′, 4c, or 4e
had a cis ring fusion, the methine H would be equatorial with respect to
the B ring in the lower-energy conformer, and a smaller coupling constant
to the vicinal trans H would be expected.