Boron from lab to launch: Christopher D. Hewitt and Karl Matos from BASF Corporation, USA, review recent developments in the use of borane reagents for commercial-scale API synthesis, which were highlighted when more than 150 scientists met at the 5th BASF Boron Conference in March 2009 in Hyderabad, India.

The 5th BASF Boron Conference featured presentations from leading academic and pharmaceutical researchers from the global chemical community under the banner, "From Lab to Launch--Discover New Horizons." As such, the focus was on new innovations in organometallic cross-coupling reactions and the practical application of boron and organo-zinc reagents for the commercial-scale synthesis of complex molecules. Some highlights from this conference are summarized below. Professor Akira Suzuki opened the conference with a compelling presentation highlighting the versatility and general application of the organo-boron cross-coupling reaction that bears his name. Recent improvements in this methodology allow the coupling of base-sensitive compounds through the careful selection of solvent and base systems.

The elegant lithium triethylborohydride-mediated hydrodesulfonlylation reaction of basic C5 building blocks was shown by Professor Sangho Koo from Myong Ji University to facilitate the efficient synthesis of natural carotenoid products. (1) The quality of the boron reagent is critical to the success of this, and the related palladium-catalysed LiBHEt3-mediated elimination of protected allylic alcohols, to make lavandulol. Azateraryl compounds have widespread application as functional materials. Professor Mayumi Nishida of Koei Chemical showed that efficient Suzuki-Miyaura 2-chloropyridine coupling can be achieved using Pd/C and the low-cost PPh3 ligand as key intermediates in the synthesis of these important compounds. (2) A clear advantage of this, compared with some alternative technologies, is the ease of recovery of the heterogeneous catalyst.

Dr Stuart Mickel from Novartis presented on the total synthesis of (+)-discodermolide. Novartis scientists needed to prepare this complex natural product in multigram quantities for clinical studies. Their 27-step synthesis gave an overall yield of 0.08%--a remarkable average of 91% per step, Figure 1. Key steps included a diisopinocampheylchloroborane (DPC)-catalysed aldol reaction that was shown to be highly sensitive to traces of moisture. This finding is consistent with those of our own scientists who have also detected significant reductions in product yields and enantiomeric excess resulting from the trace moisture contamination of DPC. Protection group chemistry is important for many functional groups but, until recently, was limited for boronic acids. Professor Suginome from Kyoto University, Japan, presented an elegant iterative Suzuki-coupling strategy through the 1,8-diaminonaphthalene protection of boronic acids. (3a-d)

Enantioselective Reagents

A boron conference would be incomplete without a lecture on new enantioselective reagents. Professor John Soderquist demonstrated that his new air- and thermally stable 9-borabicyclo(3.3.2)decane reagents are an effective addition to the toolbox for these important reactions. Professor Negishi from Purdue University, USA, gave a comprehensive overview of the tremendous utility of coupling chemistry in the synthesis of complex organic molecules. His lecture focused on carbocoupling through organo-zinc, -aluminum and --zirconium reagents (Negishi coupling) with a particular focus on recent advances in the Pd-catalysed synthesis of alkenes, dienes, enynes, diynes and their oligomers. The utility of organo-zinc Negishi coupling reagents was further elaborated by Dr Andreas Leitner from BASF, who demonstrated the step efficiency and yield improvements that can result from adopting this strategy in the commercial-scale synthesis of heterobiaryl and other important intermediates. Dr Leitner additionally highlighted that the commercial-scale synthesis of these building blocks by BASF means that the advantages described are available for API synthesis at all stages of development--from lab to launch.

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Further work by BASF scientists was presented by Dr Karl Matos; he showed that the reductive amination of aldehydes and ketones with boranes is an important direct transformation of carbonyl compounds into amines, which are, themselves, ubiquitous functionalities in current drugs and active pharmaceutical intermediates. Amine boranes are effective reagents for direct reductive aminations owing to their acid stability and functional group compatibility. Matos highlighted the recently developed new amine borane, 5-ethyl-2-methylpyridine borane (PEMB), as an excellent reducing agent for reductive amination. PEMB is a liquid with high thermal stability at ambient temperatures and low reactivity with protic solvents. These characteristics of PEMB make it an attractive amine borane for selective reductions. The utility of PEMB in reductive aminations was demonstrated in this presentation. Additional presentations by industrial scientists were made by Dr Murugan from AstraZeneca, Dr Rao from Aptuit Laurus and Dr Singh from Ranbaxy.

In closing the conference, Dr Stephan Koser from BASF commented on the breadth and utility of the chemistry and the "blue ocean" of new opportunities that the innovations presented. He further highlighted the support for these innovations through the commercial availability of the necessary reagents from "lab to launch" through BASF. The next BASF Boron conference was announced by Dr Ulrich Bueschges, Group Vice President of BASF's Global Business Unit, Inorganic Specialties, and will take place in Germany in 2010.

References

(1.) J. Kuk, et al., J. Org. Chem. 73(5), 1991-1994 (2008).

(2.) T. Tagata and M. Nishida, J. Org. Chem. 68, 9412-9415 (2003).

(3.) M. Suginome, H. Noguchi and K. Hojo, J. Am. Chem. Soc. 129, 758-759 (2007).

(3a.) H. Noguchi, et al., Org. Lett. 10, 377-380 (2008).

(3b.) M. Suginome, et al., Manuscript in Preparation.

(3c.) N. Iwadate and M. Suginome, J. Organomet. Chem. (2009): In Press (a special issue on organoboron chemistry).

(3d.) N. Iwadate and M. Suginome, Manuscript Submitted for Publication.

Further Information

Christopher D. Hewitt and Karl Matos

BASF Corporation

1424 Mars Evans City Road

Evans City, Pennsylvania 16033, USA.

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