One-Pot Organocopper Chemistry and Stereospecific Nucleoside Formation

A researcher at the University of California has made several inventions related to organic syntheses involving higher-order cuprates. Higher-order organocuprates are reagents containing copper atoms to which are bound multiple negatively-charged ligands in ethereal solvents, and have been successfully exploited as highly selective and efficient means of making carbon-carbon bonds. The use of cuprates in 1,4-conjugate addition reactions for introduction of unsaturated carbanions is particularly attractive due to the control over double-bond geometry offered by such a reaction. In many organic compounds of biological significance, this control is particularly valuable. Prostaglandins, for example, require the controlled addition of an alkenyl moiety to an unsaturated ketone.

Prior to this research, only a few multistep pathways of limited scope were available for the synthesis of organocuprates. The key discovery by the UC researcher was the development of a general synthetic method for generating cuprates via transmetalation of zirconocene intermediates (UC Case 89-360). This discovery has made possible high-yield one-pot carbon-carbon bond formation proceeding from the addition of ligand precursors to the final conjugate addition products via zirconocene/cuprate intermediates. Several patents have issued on this technology, covering several variations of key cuprate coupling reactions.

Subsequent work has further extended the application of these cuprates to 1,4-conjugate additions specifically to unsaturated ketones, followed by electrophilic trapping of the resulting enolate by a second substituent (UC Case 93-002). Thus, a three-component coupling can be effected between an unsaturated ketone, a cuprate, and an electrophilic coupling partner in the presence of a trivial zincate. Such a coupling thus effects a crucial step that previously has been a serious obstacle to practical prostaglandin synthesis.

Finally, in another line of research this UC researcher has considered one of the key stereochemical features of nucleoside and nucleoside-analog chemistry. A novel method for synthesizing nucleosides was devised that allows for precise control of the stereochemistry of the bond between a deoxyribose sugar and a pyrimidine base (UC Case 91-116). Ultimately, this invention will eliminate the stereoisomer separation step characteristic of most current synthetic methods.

Altogether, this invention portfolio offers an integrated package for the synthesis of biologically-important organic compounds. Prostaglandins are a powerful group of hormones controlling blood pressure and other important physiological functions, indicating the possibility of significant commercial value for the organocuprate technologies. The nucleoside technology likewise could have important applications in the field of pharmaceutical syntheses, especiallyin manufacturing novel AZT-like nucleoside analogs for preventing the spread of retroviral infections.

With regards to the patent rights Available for licensing, three cases in this portfolio are currently active, with two having issued patents. Rights to all of these inventions have been assigned exclusively to the Regents of the University of California and are available for commercial licensing.

U.C. case 89-360 has issued as U.S. Patents 5,072,010 (issued December 10th, 1991), 5,166,382 (issued November 24th, 1992), and 5,286,889 (issued February 15th, 1994); with additional claims for a process for introducing a 1-alkenyl ligand into a target molecule pending.

5,072,010 has one independent claim for the preparation of higher order cuprate complexes by means of transmetalation from a corresponding zirconocene intermediate. This method makes it possible to make vinylic side chains directly from acetylenic precursors via reactive cuprates in a one-pot operation.

5,166,382 also has one independent claim for a transmetalation method, differing from 5,072,010 with respect to the non-zirconocene reactant employed.

5,286,889 likewise has one independent transmetalation claim, differing from 5,072,010 in that the cuprate complex formed has a 1-alkenyl ligand bonded to copper in place of an anionic ligand.

U.C. case 93-002 has issued as U.S. Pat. 5,405,981 (issued April 11th, 1995) with two independent claims covering the addition of substituents to ketones/enolates. Once claim is for the sequential 1,4 conjugate addition of substituents to an unsaturated ketone using a cuprate formed according to 89-360 followed by electrophilic trapping of the resulting enolate with an electrophilic precursor. The other is for the 1,4 addition of a substituent to an enone using a 89-360 cuprate.

U.C. case 91-116 involves a short synthetic scheme which allows for 100% stereoselectivity in coupling reactions between (di)deoxyriboses and pyrimidine bases without recourse to modification of the ribose or expensive materials.

REFERENCE: 1993-002

Patents:
US 5,405,981   [MORE INFO]

Type of Offer: Licensing



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