Inversion of the direction of stereoinduction in the coupling of chiral γ,δ-unsaturated fischer carbene complexes with o-ethynylbenzaldehyde

Article abstract of DOI:10.1021/ol025808y

(matrix presented) A variety of γ,δ-unsaturated carbene complexes that feature a stereogenic center at the β-carbon couple with 2-ethynylbenzaldehyde to afford hydrophenanthrene derivatives with a high degree of stereoinduction. The direction of stereoinduction is opposite for examples where the stereogenic center is acyclic vs examples where it is within a ring.

Full text of DOI:10.1021/ol025808y

ORGANIC
LETTERS
2002
Vol. 4, No. 13
2121-2124
Inversion of the Direction of
Stereoinduction in the Coupling of
Chiral γ,δ-Unsaturated Fischer Carbene
Complexes with o-Ethynylbenzaldehyde
Binay K. Ghorai, Suneetha Menon, Dennis Lee Johnson, and James W. Herndon*
Department of Chemistry and Biochemistry, New Mexico State UniVersity,
MSC 3C, Las Cruces, New Mexico 88003
jherndon@nmsu.edu
Received March 2, 2002
ABSTRACT
A variety of γ,δ-unsaturated carbene complexes that feature a stereogenic center at the â-carbon couple with 2-ethynylbenzaldehyde to afford
hydrophenanthrene derivatives with a high degree of stereoinduction. The direction of stereoinduction is opposite for examples where the
stereogenic center is acyclic vs examples where it is within a ring.
In a recent publication, stereoselective formation of the
steroid ring system (e.g., 5, Scheme 1) through coupling of
2-alkenylcyclopentylcarbene complexes (e.g., 2) and 2-eth-
ynylbenzaldyde (1) was reported.1 The stereochemical induc-
tion event involves an exo selective intramolecular Diels-
Alder reaction of intermediate benzofuran-alkene derivative
3;2 subsequent opening of the oxanorbornene ring in 4
followed by hydrolysis leads to the observed product 5. The
transformation in Scheme 1 represents a one-step stereo-
selective construction of the hydrophenanthrene ring system
from simple and readily available components.3 As a further
test of the synthetic utility of this transformation, the coupling
of a variety of cyclic and acyclic chiral γ,δ-unsaturated
carbene complexes were prepared and tested in their reaction
with 2-ethynylbenzaldehyde; these studies are the focus of
this Letter.
Scheme 1
(1) Ghorai, B. K.; Herndon, J. W.; Lam, Y. F. Org. Lett. 2001, 3, 3535-
3538.
(2) Intramolecular Diels-Alder reactions of isobenzofurans are generally
exo selective. (a) Meegalla, S. K.; Rodrigo, R. Synthesis 1989, 942-944.
(b) Yamaguchi, Y.; Yamada, H.; Hayakawa, K.; Kanematsu, K. J. Org.
Chem. 1987, 52, 2040-2046. (c) Tobia, D.; Rickborn, B. J. Org. Chem.
1987, 52, 2611-2615.
(3) For a discussion of the utility of this class of compounds, see:
Nicolaou, K. C.; Zhong, Y. L.; Baran, P. S.; Sugita, S. Angew. Chem., Int.
Ed. 2001, 40, 2145-2149.
10.1021/ol025808y CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/01/2002

The γ,δ-unsaturated carbene complexes used in this study
were prepared from allylic alcohols using the four-step
transformation depicted in Scheme 2.4 The yield for conver-
Table 1. Coupling of Cyclohexenylmethylcarbene Complexes
with 2-Ethynylbenzaldehyde
Scheme 2a
a (i) CH3C(OEt)3/H+. (ii) (a) H2CdCHOEt/PhSeBr, (b) NaIO4,
then 100 °C. (iii) K2Cr(CO)5, then Me4NBr, then CH3OTf.
sion of carboxylic acids to carbene complexes was 52-70%
in all cases. The Johnson ortho ester Claisen rearrangement
was not successful in more highly substituted systems, and
a selenium-based alternative procedure was employed.5
In the first phase of these studies, Fischer carbene
complexes containing a single acyclic stereogenic center at
the â-carbon (8A,B, Scheme 3) were examined. In both cases
entrya
R2
R3
R5
R6 and R7
yield
cis:transb
C
H
Me
H
H
H
Me
H
H
H
H
Me
H
H
H
Me
64%
37%
35%
50%
58:42
d
e
Dc
Scheme 3
E
Fc
H
70:30
a Entry letters define substituents for compounds 8-10. b The ratio was
not consistent over several runs. c The selenium-based alternative was
employed for formation of 8. d The ratio could not be determined. e Only
10E-cis was obtained.
epimerization product since it is formally a Diels-Alder
adduct of a trans cyclohexene derivative. Major compound
10C-cis converts to minor compound 10C-trans upon
treatment with potassium carbonate and methanol. Since the
products only differ in configuration at an epimerizable
stereocenter, they both can ultimately result from a single
oxanorbornene derivative, 9C. Thus the Diels-Alder step
of the reactions appears to proceed with complete stereo-
examined, the reaction was completely stereoselective and
led to the compounds 10A and 10B. The direction of
stereoinduction was identical to that noted in the previous
studies involving synthesis of the steroid ring system.
Examination of the initial Diels-Alder adducts 9 reveals that
the observed stereoisomer is that where the substituent at
the stereogenic center is equatorial.6,7
The analogous compound where the alkene is contained
within a six-membered ring (8C, Table 1) afforded a mixture
of two compounds assigned as 10C-cis (37%) and 10C-trans
(27%).7 The minor product, 10C-trans, is obviously an
(6) Related intramolecular Diels-Alder reactions of simple furans afford
predominantly the equatorial isomer. (a) Woo, S. Keay, B. A. Tetra-
hedron: Asymmetry 1994, 5, 1411-1414. (b) Rogers, C.; Keay, B. A.
Tetrahedron Lett. 1991, 32, 6477-6880. (c) Ferringa, B. L.; Gelling, O.
J.; Meesters, L. Tetrahedron Lett. 1990, 31, 7201-7204. (d) Sader-Bakoumi,
L.; Charton, O.; Kunesch, N.; Tillequin, F. Tetrahedron 1998, 54, 1773-
1782. (e) Hudlicky, T.; Butora, G.; Fearnley, S. P.; Gum. A. G.; Persichini,
P. J., III; Stabile, M. R.; Merola, J. S. J. Chem. Soc., Perkin Trans. 1 1995,
2393-2398. (f) De Geyter, T.; Cauwberghs, S.; De Clercq, P. J. Bull. Soc.
Chim. Belg. 1994, 103, 433-443. (g) Metz, P.; Sto¨lting, J.; La¨ge, M.; Krebs,
B. Angew. Chem., Int. Ed. Engl. 1994, 33, 2195-2197. (h) Meiners, U.;
Cramer, E.; Froehlich, R.; Wibbeling, B.; Metz, P. Eur. J. Org. Chem. 1998,
2073-2078. (i) Woo, S.; Keay, B. A. Synlett 1996, 135-137.
(7) The stereochemistry was assigned on the basis of coupling constants
between protons at stereogenic centers (see Supporting Information). For
stereochemical assignments in similar ring systems, see: Piers, E.; Llinas-
Brunet, M.; O’Balla, R. M. Can. J. Chem. 1993, 71, 1484-1494.
(4) This carbene-complex-forming step has previously been reported.
Moser, W. H.; Hegedus, L. S. J. Am. Chem. Soc. 1996, 118, 7873-7880.
(5) Pitteloud, R.; Petrilka, M. HelV. Chim. Acta 1979, 62, 1319-1325.
2122
Org. Lett., Vol. 4, No. 13, 2002

selectivity, followed by partial epimerization at the allylic
position. The direction of stereoinduction is opposite to that
observed in the acyclic case in Scheme 3 and the steroid
case in Scheme 1.
stable products in both cases. Compound 9B, the equatorial
isomer, is considerably more stable than 9B′ and, it is likely
that steric interactions between the methyl group and the
oxanorbornene bridge are also felt in the transition state. This
result is consistent with previous studies of six-membered
ring-forming intramolecular Diels-Alder reactions of furans
that feature a single stereogenic center in a totally saturated
tether;6 however, highest selectivities were observed in
thermodynamic control.6a,g,i Since Diels-Alder reactions of
isobenzofurans are unlikely to be reversible, the high
stereoselectivity is due to kinetic control. Calculations show
that 9C is more stable than 9C′ by 3.0 kcal/mol in the most
stable conformation. The relative stereochemistry between
the original stereogenic center and the adjacent stereogenic
center is opposite for 9B and 9C.
The reaction was examined for a variety of cyclohexenyl-
methylcarbene complexes of varying substitution pattern, and
the results are depicted in Table 1. In all cases, the original
stereocenter was completely effective in controlling the
stereochemistry of the initial Diels-Alder adduct, and only
compounds 10-cis and/or 10-trans and no other isomers were
observed. As predicted, the overall efficiency of the reaction
was considerably less as the cyclohexene ring became more
hindered, and lower yields were obtained using 10D and 10E.
In most cases, a mixture of stereoisomers was obtained that
could be converted to a single stereoisomer, 10-trans, upon
base treatment. Successful isolation of the pure kinetic
product was successful only in entry E, where there is no
acidic proton at the three-ring junction.
Simulation of the entire Diels-Alder step was undertaken
in order to understand the factors favoring 9C over 9C′
(Figure 2). The simulation was performed using Hartree-
As noted in Table 1 and Schemes 1 and 3, the original
stereogenic center at the â-position of the carbene complex
is completely effective in controlling the stereochemistry
during the Diels-Alder step. In all cases, two different exo
stereoisomers are possible; however, all of the products are
derived from a single diastereomer of intermediate oxa-
norbornene derivative 9. However, the direction of induction
is opposite for the cases of Scheme 3 and the cases in Table
1. In Scheme 3, both the stereogenic center and the alkene
are acyclic, while the stereogenic center and the dienophile
are both within the same ring for the systems in Table 1.
The stereogenic center is part of a ring in the steroidal
examples of Scheme 1. However, the dienophile is acyclic;
the direction of stereoinduction is the same in these cases as
that observed for the examples in Scheme 3. Similar reactions
involving cyclohexene dienophiles proceed in the same
direction of stereoinduction.8
The Diels-Alder step was examined computationally for
the reactions of 2-ethynylbenzaldehyde (1) with carbene
complexes 8B and 8C.9 Comparison of the energies for the
most stable conformations of exo Diels-Alder adducts
(Figure 1) reveals that the observed products are the more
Figure 2. Calculated reaction profile for the Diels-Alder reactions
leading to 9C and 9C′.
Frock calculations using the 6-31G* basis set. The reaction
profile was established by taking the energy-minimized
conformations of 9C (solid line) and 9C′ (dashed line) and
lengthening the C-C bonds formed in the Diels-Alder step
to 3 Å in 10 steps. Although the calculated reaction profile
is based on the retro-Diels-Alder reaction, the graph in
Figure 2 is presented as the forward reaction (the final points
on the right represent 9C and 9C′). The transition state for
9C′ is 5.6 kcal/mol less stable than the transition state for
9C. The cyclohexene ring in the transition state precursor
to 9C′ deviates substantially from the ideal half-chair
(8) (a) Grieco, P. A.; Kaufman, M. D.; Daeuble, J. F.; Saito, N. J. Am.
Chem. Soc. 1996, 118, 2095-2096. (b) Blond, A.; Paltzer, N.; Guy, A.;
D’Hotel, H.; Serva, L. Bull. Soc. Chim. Fr. 1996, 133, 283-293.
(9) The program MacSaprtan Pro v. 1.04 was utilized in this study.
Figure 1. Heats of formation for compounds 9B, 9B′, 9C, 9C′.
Org. Lett., Vol. 4, No. 13, 2002
2123

In summary, stereoselective construction of the hydro-
phenanthrene ring system has been realized through coupling
of â-substituted γ,δ-unsaturated carbene complexes and
2-ethynylbenzaldehyde. A high degree of asymmetric induc-
tion was observed in the critical step, intramolecular Diels-
Alder reaction of an isobenzofuran intermediate. The direc-
tion of asymmetric induction was opposite for complexes
where the stereogenic center is acyclic and those where the
â,γ, and δ-carbons of the carbene complex are in a ring
system.
Acknowledgment. We thank the National Institutes of
Health for Financial Support. We thank Mr. Alejandro
Camacho for valuable experimental assistance. B.K.G. is
thankful to the Bengal Engineering College (Deemed Uni-
versity), Howrath, India for sabbatical leave.
Figure 3. Calculated transition states for formation of 9C (left)
and 9C′ (right).
conformation. The cyclohexene ring of the transition state
precursor to 9C is in the desired half-chair conformation.
The energy differences are even greater in earlier points along
the reaction pathway. For the first point on the graph, the
conformation of the isobenzofuran leading to 9C′ is 9.0 kcal/
mol higher in energy for the reaction producing 9C′ than
that leading to 9C.
Supporting Information Available: Experimental pro-
cedures and compound characterization data for reactions
producing compounds 8 and 10 and discussion of stereo-
chemical assignments. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL025808Y
2124
Org. Lett., Vol. 4, No. 13, 2002