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Industry: academic mix contributes to forum's success.

The Ninth International Conference on Organic Synthesis, sponsored by IUPAC, and held at the downtown Montreal campus of the Universite du Quebec a Montreal, attracted more than 1,000 delegates representing 35 countries. Sessions were divided into three sections: Strategies and Reagents for Stereocontrol in Synthesis; Advances in Asymmetric Synthesis; Biomolecules in Organic Synthesis.

In the last 10 years, great advances have been made in achieving stereocontrol in organic synthesis. New and important strategies and reagents have allowed chemists to achieve an unprecedented degree of control. The conference was a forum for scientists to discuss these achievements. The objective was to bring together scientists working in the areas of organic synthesis, bio-organic and organometallic chemistry, and synthetic methodology.

Twenty-three speakers took part in the conference. This included 15 invited speakers. A poster display attracted 250 exhibits and there were more than 50 oral presentations on the best of the posters. The posters featured work from around the world.

Conference co-chairman Jean-Claude Richer, FCIC, said the only problem organizers had was "too many people!" He was pleased with the academic:industry mix of delegates (about 2 to 1, industry:academic). The pharmaceutical industry was especially well represented. They are the ones to use the body of knowledge presented, Richer explained. There was a large contingent of students, even from Europe.

The program was organized with no concurrent sessions so delegates did not miss a thing. The poster presentations were held in the afternoon after the sessions had ended.

Speakers were predominantly academic but Richer noted that this was due to the fact that companies will generally not speak about their most recent developments because of patents and proprietary knowledge concerns.

Richer added, however, that the main themes had much appeal to industry. "These are areas where they are working."

The invited speakers were all "tops in their fields", said Richer, so no one paper could be labeled as the "star" of the show. To develop new methods to realize synthesis and to contribute to the development of the technology necessary to make it happen were the main principles behind the conference.

In the area of strategies for stereocontrol in organic synthesis, Gilbert Stork led off the conference speaking about his synthesis of the D-vitamin, calcitriol. His strategy involved using radical cyclization to build the core bicyclic unit with high stereocontrol. Gerald Pattenden also described the ingenious use of radical cyclization to build complex polycyclic molecules in cascade radical macrocyclization-transannular processes and Janine Cossy described construction of polycyclic natural products by addition of radical anions derived by photoreductions of unsaturated ketones. Stereospecific construction of complex polycyclic structures such as steroids and triterpenes via macrocyclic Diels-Alder reactions were discussed by Pierre Deslongchamps, FCIC.

Another major theme of lectures on synthetic strategies was the development and optimization of organometallic reagents for synthesis. Ed Piers, FCIC, addressed the use of bifunctional organometallic reagents to construct polycyclic compounds. Among others, he demonstrated the use of vinyl-germanium cuprates for Michael additions to |alpha~, |beta~-unsaturated ketones followed by transmetallation with n-butyllithium. The rapid exchange of lithium for germanium allows formation of the vinyl anion and cyclization to proceed in competition with addition to the ketone.

Mark Lautens, MCIC, described organolithium and organocuprate mediated opening of bicyclic ethers as a strategy for stereoselective synthesis. Jean F. Normant discussed his highly diastereoselectivity use of bisorganometallic reagents such as allyl vinyl zinc species to provide coupled products of predictable stereochemistry. The versatile and elegant use of palladium to mediate construction of polycyclic structures from acyclic polyenes was described by Larry Overman. Multiple cyclizations can be effected in a cascade and can proceed with high diastereoselectivity.

Ian Paterson described the synthesis of complex acyclic and macrocyclic polypropionate derived-natural products based on optimized strategies for stereoselective formation of syn-syn and anti-syn aldol adducts using tin and boron enolates. High enantioselectivity can also be achieved through the use of chiral borane catalysts to effect aldols starting with acyclic ketones.

An impressive combination of modern synthetic technologies were used by David Evans, in his total synthesis of the complex organophosphate tumor promoter calyculin A. The construction utilized enantioselective aldol reactions as well as Stille and Wittig couplings to prepare the sensitive cyanotetraene part of the molecule.

Another major theme of the conference was advances in asymmetric synthesis. It was clear from many presentations that chiral asymmetric synthetic methods have reached a high level in the past several years and many approaches have now been optimized to make the construction of essentially homochiral synthons from achiral starting materials a practical reality for the modern synthetic chemist.

The power of chiral auxiliaries in synthesis was exemplified by lectures given by Leon Ghosez, Ben Feringa and Andre Charette, MCIC. Ghosez employed keteneiminium and nitrosocarbamyl reagents prepared from chiral amides to effect 2 + 2 and 2 + 4 cycloadditions with high enantioselectivity. Such reagents provide versatile methods to prepare chiral cyclobutanones, amino acids and amino alcohols with enantiomeric excesses in some cases of |is greater than~ 98%.

Feringa has made efficient use of 5-menthyl-oxy-2(5H)-furanones to provide enantiomerically pure synthons through "crystallization induced epimerization". These synthons undergo a number of transformations such as Diels-Alder cyclizations and Michael additions with high diastereoselectivity providing useful entries to |beta~-aminoacids, |beta~-lactams and natural products such as lignans.

Charette described his use of sugars and related cyclic acetals as chiral templates for synthesis of polyols and cyclopropane derivatives, again with excellent diastereoselectivity.

The development of chiral organometallic complexes as reagents for asymmetric synthesis has exploded in the last few years. Exquisite enantioselectivity has now been achieved, in some cases with catalytic methods using complexes of titanium, nickel, osmium, copper, palladium and related transition metals. Lectures by Yuri Belokon; Rudolf Duthaler, Tamio Hayashi, Koichi Narasaka, Dieter Seebach, and Barry Sharpless all demonstrated impressive uses of such complexes.

Narasaka described the catalytic use of tartrate-derived chiral 1,4-diols to form in situ titanium complexes which catalyze 2 + 2 and 2 + 4 cycloadditions of 3-alkenyl-1,3-oxazolidin-2-one with very high enantiomeric excesses (usually |is greater than~ 90%).

Seebach discussed the catalytic use of similar complexes derived from tetraaryl dioxolane dimethanols (TADDOLs) and tetraisopropoxy titanium to mediate asymmetric addition of organozinc compounds to compounds such as saturated and unsaturates aldehydes. These complexes also mediate enantioselective alanate reductions of ketones.

Duthaler spoke about the use of cyclopentadienyltitanium-TADDOLS to mediate enantioselective additions of organolithium species to carbonyls and to effect aldol reactions as well as additions of allyl titanium species to carbonyls. Again, in many cases ee's of |is greater than~ 90% are achieved.

Sharpless explained the discovery and evolution of his chiral ligands for catalytic asymmetric osmylation and diol formation derived from dihydroquinidine and dihydroquinine. These reagents are now commercially available. Excellent ee's (|is greater than~ 90%) are obtained for diols formed from most olefins. This method is a significant advance on the Sharpless epoxidation procedure and is much more versatile because it is not limited to allylalcohols.

The final theme of the conference was the use of biomolecules in organic synthesis. The use of enzymes for enantioselective hydrolysis, reduction of ketones, oxidation of alcohols, and peroxidation of olipins was described by Stanley Roberts. Claudio Fuganti described the use of Baker's yeast for similar transformations and M. Bhupathy described the use of a specific esterase for efficient synthesis of leukotriene |D.sub.4~ antagonist, MK-0679. This industrial scale use of enzymes in synthesis involves the esterase hydrolysis of a prochiral diester to provide a single enantiomer acid ester in high chemical (|is greater than~ 90%) and enantiomer (|is greater than~ 99%) yield. Notably the synthesis of MK-0679 (the R-enantiomer) was significantly more efficient than the synthesis of the racemate (MK-571)! Clearly, use of enzymes in industrial synthesis has come of age.
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Title Annotation:9th International Conference on Organic Synthesis
Author:Young, R.N.
Publication:Canadian Chemical News
Date:Jan 1, 1993
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