A highly enantioselective catalyst for asymmetric hydroformylation of [2.2.1]-bicyclic olefins Jinkun Huang, * Emilio Bunel, * Alan Allgeier, Jason Tedrow, Thomas Storz, J. Preston, TiffanyCorrell,DeanaManley,TroySoukup,RandyJensen,RashidSyed,GeorgeMoniz, Robert Larsen, Michael Martinelli and Paul J. Reider Chemical Process Research & Development, Amgen Inc., One Amgen Center Dr., Thousand Oaks, CA 91320, USA Received 31 August 2005; accepted 2 September 2005 Available online 26 September 2005 Abstract—Rh(CO) 2 (acac)/TangPhos was found to be a highly enantioselective catalyst for asymmetric hydroformylation of nor- bornyleneundermildconditions.Applicationoftheprotocoltothedesymmetrizationofother[2.2.1]-bicyclicolefinsgavemoderate to excellent enantioselectivity (55–92% ee). Ó 2005 Elsevier Ltd. All rights reserved. Hydroformylation of olefins represents one of the most important reactions in industry catalyzed by homo- geneous catalysts. Regio- and stereoselective hydrofor- mylation has emerged as an attractive tool in organic synthesisbecauseopticallyactivealdehydesareversatile intermediates for various pharmaceuticals, agrochemi- cals, and other fine chemicals. A large number of chiral ligands including phosphines, phosphites, P–O, P–N, and P–S ligands have been developed as rhodium and platinum catalysts for asymmetric hydroformylation. 1 The first highly enantioselective hydroformylation was reported in 1991 by Consiglio using a bisphosphine PtCl 2 /SnCl 2 system. 2 A breakthrough in asymmetric hydroformylation was achieved in 1993 for the hydro- formylation of styrene by a phosphinophosphite/Rh complex(upto95%ee). 3 AlthoughRhandPtcatalyzed asymmetrichydroformylationhasbeenextensivelystud- ied in the past three decades, practical applications of this important transformation are far less documented than asymmetric hydrogenations. Most of the studies havebeenfocusedonthedevelopmentofchiralligands. 4 As with many other asymmetric catalytic systems, a benchmark substrate, styrene, is often chosen to evalu- ate the effectiveness of those ligands. Ironically, it has been well recognized that no universal catalyst exists for all substrates. This situation makes catalyst screen- ing become more and more important as more chiral ligands are commercially available. In this letter, we report our discovery of a highly enantioselective hydro- formylation catalytic system (using a specific ligand family) that works for a specific family of substrates. We chose the highly strained norbornylene (1) as our initial target-oriented substrate for asymmetric hydro- formylationtoobtainthechiral exo-norbornylaldehyde (2). Enantioselective hydroformylation of this [2.2.1]- bicyclicolefinisinterestingduetothefollowingfeatures: (1) desymmetrization of the olefin will generate three chiral carbon centers upon one C–C bond formation; (2) there are no regio-selectivity issues due to the sym- metry of such olefins, although high enantioselectivity, endo- and exo-selectivities are important; and (3) func- tional groups located opposite to the C@C bond could be versatile, which may lead to interesting building blocks. In spite of these features, few studies of hydro- formylation of this type of substrates have been docu- mented and only low selectivities (20–60% ee) were reported in the case of norbornylene. 5 On the outset, a ligand pool of more than 130 chiral phosphines, phosphites, phosphinophosphites, and phosphoramidites was screened for asymmetric hydro- formylation of norbornylene. We were gratified to find that all ligands gave exclusively exo-product (exo/endo >99%)and,furthermore,the C 2 -symmetricDuPhos-like bisphosphines (3–8, Fig. 1, Table 1) were outstanding 0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2005.09.012 Keywords: Asymmetric hydroformylation; TangPhos; [2.2.1]-Bicyclic olefin. * Corresponding authors. Tel.: +1 805 313 6538; fax: +1 805 480 1346;e-mail: jhuang@amgen.com Tetrahedron Letters 46 (2005) 7831–7834 Tetrahedron Letters