Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2000-09-05
2001-11-13
Shah, Mukund J. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C544S244000, C548S310700, C548S335100
Reexamination Certificate
active
06316620
ABSTRACT:
BACKGROUND OF THE INVENTION
Asymmetric synthesis is becoming more and more important in the pharmaceutical industry. There is growing regulatory pressure to approve only those enantiomers of drugs that have the desired biological activity. For safety reasons and to demonstrate efficacy, regulatory agencies are taking the position that only those enantiomers with pharmaceutical action should be administered, apart from the enantiomers with little or no action or even adverse or toxic effect. The total market for enantiomerically pure pharmaceuticals is projected to be ninety billion U.S. dollars by 2000. To prepare such large quantities of drug only via resolution will often be cost prohibitive. Chiral catalysis will no doubt complement traditional methods such as resolution or chiral separation. Many asymmetric syntheses involve use of catalysts, and typically employ chiral ligands and late transition metals. Bidentate ligands play a central role in catalyst design for asymmetric synthesis. Ligands that have been used successfully in asymmetric synthesis include the BINAP family of catalysts for asymmetric reductions and isomerizations (For example, see
Asymmetric Catalysis in Organic Synthesis
, Noyori, R., Ed.; John Wiley and Sons: New York, 1994, p.16-121).
Bisoxazolines for asymmetric cyclopropanation and cycloadditions have been reported (For a review, see Ghosh, A. K.; Mathivanan, P.; and Cappiello, J.
Tetrahedron: Asymmetry
1998,9, 1-45).
Pyridyloxazolines for asymmetric hydrosilations have also been described (Brunner, H.; Obermann, U.
Chem. Ber
. 1989, 122, 499).
Even more recently, electronically “mixed” bidentate ligands with two different ligating heteroatons (N—O, P—N, P—O) have emerged. Such ligands have been shown empirically to outperform P—P bidentate ligands in a number of synthetically important transformations. Such “mixed” ligands are the phosphino-oxazolines described by Pfaltz et al. (Synthesis, 1997, 1338), Helmchen et al. (
Angew. Chem. Int. Ed. Eng
., 1997, 36 (19)2108), and Williams et al., (
Tetrahedron
, 1994, 50, 9).
The Heck reaction is one of the most versatile catalytic methods for C—C bond formation. In this reaction, an aryl or alkenyl halide or triflate is coupled with an alkene, as shown in the following scheme:
The catalytic cycle starts with an oxidative addition of organic halide or triflate to a Pd (0) complex, followed by insertion of an alkene. The resulting Pd (II) alkyl complex then undergoes &bgr;-hydride elimination. Several isomeric products can be formed, depending upon the structure of the substrate. In path (a), the C—C double bond is restored in the original position and a stereogenic center is not created. However, if &bgr;-hydride elimination takes path (b), the stereogenic C atom introduced in the insertion step is retained. For path (b), the use of chiral palladium complexes makes it possible to perform such reactions in an enantioselective manner. Pfaltz et al. showed that chiral phosphino-oxazolines are very efficient ligands for enantioselective Heck reactions (Synthesis 1997, 1338). For example, asymmetric Heck arylation, using Pd/phosphino-oxazolines, produces substituted dihydrofuran in 90% yield and 92% ee, as shown below:
The phosphino-oxazolines described and taught by Pfaltz et al., Helnchen et al. and Williams et al. are superior to BINAP catalysts in the Heck reaction in that: (a) such ligands are insensitive to the nature of the added base; (b) have more ability to suppress side products; and (c) have very high enantioselectivity. However, such phosphino-oxazolines have a major deficiency. The above Heck arylation required six (6) days, an extremely long reaction time. It appears that the R substituent of the phosphino-oxazolines is not in conjugation with the ligating atoms, and therefore functions solely in a steric role. From the long reaction time or the low turnover of these catalysts, it is clear that the donicity of the bidentate ligand is not optimized.
REFERENCES:
Jacobsen, E. N. et al, Electronic Tuning of Asymmetric Catalysts, J. Am. Chem Soc., 1991, 6703-6705, vol. 113, No. 17, American Chemical Society, Washington, DC, US.
Loiseleur, O. et al, Enantioselective Heck Reactions Catalyzed by Chiral Phosphinooxazoline-Palladium Complexes, Synthesis, 1997, 1338—1345, No. 11, Georg Thieme Verlag. Stuttgart, DE.
Allen, J.V. et al, Preparation of Novel Sulfur and Phosphorus Containing Oxazolines as Ligands for Asymmetric Catalysis, Tetrahedron, 1994, 799—808, vol. 50, No. 3, Elsevier Science Publishers, Amsterdam, NL.
Peer, M. et al, Preparation of Chiral Phosphorus, Sulfur and Selenium Containing 2-Aryloxazolines, Tetrahedron, 1996, 7547—7583, vol. 52, No. 21, Elsevier Science Publishers, Amsterdam, NL.
Loiseleur, O. et al, Enantioselective Heck reactions using chiral P, N-Ligands, Journal of Organometallic Chemistry, 1999, 16—22, vol. 576, No. 1-2, Elsevier-Sequoia S.A. Lausanne.
Boehringer Ingelheim Pharmaceuticals Inc.
Devlin M&tgr;E. M.
Liu Huang
Raymond R. P.
Shah Mukund J.
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