4550
J. Am. Chem. Soc. 1998, 120, 4550-4551
Scheme 1
A Catalytic Enantioselective Synthesis of the
Endothelin Receptor Antagonists SB-209670 and
SB-217242. A Base-Catalyzed Stereospecific Formal
1,3-Hydrogen Transfer of a Chiral 3-Arylindenol
William M. Clark,* Ann M. Tickner-Eldridge, G. Kris Huang,
Lendon N. Pridgen, Mark A. Olsen, Robert J. Mills,
Ivan Lantos, and Neil H. Baine
Synthetic Chemistry Department
SmithKline Beecham Pharmaceuticals
709 Swedeland Road, P.O. Box 1539
King of Prussia, PennsylVania 19406
ReceiVed NoVember 12, 1997
Scheme 2a
In the pursuit of breakthrough chemotherapeutics, endothelin-
11 and its isopeptides have garnered a significant amount of
attention within the pharmaceutical industry.2 The 21 amino acid
peptide exhibits potent constrictor activity of vascular smooth
muscle through its selective binding of the ETA/ETB receptors
and is believed to play an important role in cardiovascular and
pulmonary disease.3 Recently, SmithKline Beecham discovered
two nonpeptide ETA/ETB receptor antagonists with nanomolar
binding affinity, SB-209670 (1) and SB-217242 (2), which possess
three contiguous stereocenters upon an indan ring framework.4
During our investigations toward a viable synthesis of 1 and 2 to
support clinical development, we discovered and successfully
utilized an unusual base-catalyzed highly stereospecific 1,3-
hydrogen rearrangement of a chiral 3-arylindenol which is
described in this communication.
a Key: (a) EtOH, 25 °C, 3 h (83%); (b) PPh3 (15 mol %), K2CO3 (2
equiv), DMF, 110 °C. 0.5 h (75%); (c) THF, -15 °C, 1 h (90%, 94%
ee).
We were interested in developing a catalytic enantioselective
approach to 1 and 2, and preliminary studies indicated that 4 was
a useful substrate for an asymmetric ketone reduction (Scheme
1). Drawing from the seminal work of Itsuno5a and Corey,5b an
oxazoborolidine-catalyzed ketone reduction was determined to
deliver the indenol 5 with high enantioselectivity using the (R)-
MeCBS catalyst. With this discovery, our synthetic strategy
turned to the possibility of a stereospecific C(1) f C(3) hydrogen
transfer to prepare the indanone 6. Although suprafacial 1,3-
hydrogen transfers are forbidden due to orbital symmetry
considerations, Motherwell6a has reported that lithium alkoxides
of allylic alcohols in the presence of a Ni(II) catalyst can be
efficiently isomerized to the carbonyl product, presumably through
a nickel hydride addition-elimination pathway. The indenol 5
appeared well suited for this type of transformation since
suprafacial hydrogen delivery seemed extremely likely using a
transition metal catalyst.7
The synthesis of 5 commenced with the condensation of
piperonal with 2-bromoacetophenone 38 in preparation for a
palladium-catalyzed 5-endo-trig cyclization to furnish the inde-
none 4 (Scheme 2). Realizing the 5-endo-trig cyclization must
overcome significant distortional strain to achieve ring closure,
we reasoned the palladium d-orbitals would enable sufficient
p-orbital overlap for insertion into the olefinic bond.9 Therefore,
we were gratified to discover that treatment of the bromochalcone
with PdCl2 (5 mol %), PPh3 (15 mol %), and K2CO3 in DMF at
110 °C led to a facile cyclization and delivery of 4 in 75% yield.
The enantioselective ketone reduction was then performed via
addition of 4 to a solution of the (R)-MeCBS catalyst and BH3-
THF (1.1 equiv) in THF cooled to -15 °C to complete the
synthesis of 5 in 90% yield and 94% ee.
To our delight, 5 underwent a highly efficient and stereo-
selective hydrogen rearrangement to give the indanone 6 (Table
1). Initially we attempted the reaction with Pd(PPh3)2Cl2 and Et3N
which resulted in the formation of 6 in 95% yield with high
stereospecificity (90.6% ee) (1). Our early mechanistic assump-
tion of a palladium hydride catalyzed olefin isomerization became
uncertain, however, when we observed a slight increase in
stereospecificity (92.2% ee) with DABCO as the amine base (2).
Due to geometric constraints, DABCO should be incapable of
undergoing palladium oxidation, thus negating formation of the
palladium hydride catalytic species.10 The crucial role of the
amine base quickly became apparent when 5 was heated for 24
h at 60 °C in THF, resulting in recovered starting material in the
(1) Yanagisawa, M.; Kurihara, H.; Kimura, S.; Tomobe, Y.; Kobayashi,
M.; Mitsui, Y.; Yazaki, Y.; Goto, K.; Masaki, T. Nature 1988, 332, 411.
(2) Lago, M. A.; Luengo, J. I.; Peishoff, C. E.; Elliot, J. D. In Annual
Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Academic: San Diego,
1996; Vol. 31, p 81.
(3) Endothelin Receptors: From the Gene to the Human; Ruffolo, R. R.,
Jr., Ed.; CRC: Boca Raton, 1995.
(4) Elliot, J. D.; Lago, M. A.; Cousins, R. D.; Gao, A.; Leber, J. D.; Erhard,
K. F.; Nambi, P.; Elshourbagy, N. A.; Kumar, C.; Lee, J. A.; Bean, J. W.;
DeBrosse, C. W.; Eggleston, D. S.; Brooks, D. P.; Feuerstein, G.; Ruffolo, R.
R., Jr.; Weinstock, J.; Gleason, J. G.; Peishoff, C. E.; Ohlstein, E. H. J. Med.
Chem. 1994, 37, 1553.
(5) (a) Itsuno, S.; Ito, K.; Hirao, A.; Nakahama, S. Bull. Chem. Soc. Jpn.
1987, 60, 395. (b) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc.
1987, 109, 5551 and references therein.
(6) (a) Motherwell, W. B.; Sandham, D. A. Tetrahedron Lett. 1992, 33,
6187. For related examples, see (b) Edwards, G. L.; Motherwell, W. B.; Powell,
D. M.; Sandham, D. A. J. Chem. Soc., Chem. Commun. 1991, 1399.
(7) Anti â-hydrogen addition and/or elimination pathways are relatively
uncommon in nickel and palladium chemistrysa pathway which would lower
the stereoselectivity of 5 f 6; see: Cross, R. J. In The Chemistry of the Metal-
Carbon Bond; Hartley, S. P. F. R., Ed.; John Wiley: New York, 1985; Vol.
2, p 559.
(8) Bisarya, S. C.; Rao, R. Synth. Commun. 1993, 23, 779.
(9) To the best of our knowledge, this is the first example of a palladium-
catalyzed 5-endo-trig cyclization to form a 2H-indenone. For examples of
palladium-catalyzed and transition metal based transformations for the synthesis
of indenones, see: (a) Larock, R. C.; Doty, M. J.; Cacchi, S. J. Org. Chem.
1993, 58, 4579 and references therein.
(10) Chen, C.-Y.; Lieberman, D. R.; Larsen, R. D.; Verhoeven, T. R.;
Reider, P. J. J. Org. Chem. 1997, 62, 2676.
S0002-7863(97)03882-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/23/1998