Catalytic asymmetric Heck reaction

The Heck reaction has proven to be an extremely useful method for the formation of C-C bond at a vinyl carbon centre. There are numerous reported examples of enantioselctive Pd catalyzed C-C bond forming reactions.10"13 Surprisingly, reports of Heck transformations using amino acid based phosphine, phosphinite ligands are rare. Recently Gilbertson reported a proline derived phosphine-oxozoline ligand in a catalytic asymmetric Heck reaction.5 In this paper we present some novel amino acids derived ligands as part of a catalytic system for use in asymmetric Heck reactions. 

Pd-catalyzed Heck reactions are among the most effective methods for the formation of quaternary carbon centers. Considering the significance and the strategic difficulties associated with the synthesis of quaternaiy carbons, particularly in the optically enriched or pure form, it is not a surprise that the development of catalytic asymmetric Heck reactions has held center stage for the past few years. One of the leading labs in this area is that of Shibasaki, who in 1993 reported a concise total synthesis of eptazodne 23 (Scheme 4).141 Thus, treatment of silyl ether 18 with 10 mol% Pd(OAc>2 and 25 mol% (S)-19 leads to the formation of 20 in 90 % yield and 90% ee As illustrated in Scheme 4, once the quaternary carbon center is synthesized efficiently and selectively, the target molecule is accessed in a few steps. 

Lapierre, J.B., Geib, S.J. and Curran, D.P. (2007) Low-temperature Heckreactions of axiaUy chiral o-iodoacrylanilines occur with chirality transfer implications for catalytic asymmetric Heck reactions. J. Am. Chem. Soc., 129, 494—5. 

One additional example of forming a quarternary stereocenter in alkaloid total synthesis by using a catalytic asymmetric Heck reaction was reported in 2005 by Overman et al. The complex indole alkaloid minfiensine 33 exhibits impressive biological activities (Scheme 13.9). It was... 

Pd complexes 9-12 were tested for their catalytic behavior in the asymmetric Heck reaction involving the phenylation of 2,3-dihydrofuran (Scheme 3). The results are summarized in Table 2. The two isomeric products of 2-phenyl-2,5-dihydrofuran are formed with varying yields from 80% to 0%. The obtained ee s are high. Complex 12 is shown to be catalytically inactive. The lack of catalysis in complex 12 is rationalized by differences in the steric requirements between the diphenylphosphinites 1-3 (cone angle >140°) and the more sterically hindered cyclohexyl-phosphinite 4 (cone angle >170°) and the resulting stereochemistry on the Pd center. The ligands in complex 12 adopt a... 

One active field of research involving the Heck reaction is asymmetric Heck reactions (AHR). The objective is to achieve enantiomerically-enriched Heck products from racemic substrates using a catalytic amount of chiral ligands, making the process more practical and economical Although intermolecular Heck reactions that occurred onto carbocyclic arenes are rare, they readily take place onto many heterocycles including thiophenes, furans, thiazoles, oxazoles,... 

There has also been considerable interest and progress in the development of asymmetric Heck reactions (AHR) [68], This methodology allows for the preparation of enantiomerically enriched products from achiral substrates using a catalytic amount of a chiral palladium complex, making the process practical and economical. For example, treatment of triflate 71 with catalytic Pd(OAc)2/(R)-BlNAP provided oxindole 72 in 96% yield and 88% ee [69]. 

The intermolecular asymmetric Heck reaction, a palladium-catalysed carbon-carbon bond forming process, is an efficient method for the preparation of optically active cyclic compounds.[1] Very recently, a new catalytic system has been developed based on palladium complexes having l-[4-(5)-tert-butyl-2-oxazolin-2-yl]-2-(5)-(diphenylphosphino)ferrocene (1) as the chiral ligand121 (Figure 5.2), which we have shown to be efficient catalysts for the enantioselective intermolecular Heck reaction of 2,3-dihydrofuran (2).[3] In contrast to complexes derived... 

The intramolecular asymmetric Heck reaction has featured in the synthesis of complex heterocyclic compounds. Bidentate ligands, such as diphosphines (especially BINAP) and phosphine—oxazolines, have been used as a chiral ligand of the asymmetric Heck reaction. Imbos et al. demonstrated that the mono-dentate phosphoramidite 513 was an effective ligand for the asymmetric Heck reaction of the prochiral cyclohexadienone 511 (Scheme 153).227 The reaction of 511 in the presence of catalytic amounts of Pd-(OAc)2 and the chiral phosphoramidite 513 gave the 4a-methoxy-4a//-benzo[c]chromen-2(6E/)-one 512 in 71% yield with 96% ee. By contrast, the reaction of... 

Kiely, D. and Guiry, PJ. (2003) Palladium complexes of phosphinamine ligands in the intramolecular asymmetric Heck reaction. Journal of Organometallic Chemistry, 687, 546-561. Dounary, A.B., Hatanaka, K., Kodanko, J.J. et al. (2003) Catalytic asymmetric synthesis of quaternary carbons bearing two aryl substituents. Enantioselective synthesis of 3-alkyl-3-aryl... 

Treatment with excess trifluoroacetic acid furnished the (dihydroiminoethano) carbazole 107 in 71% overall yield. Epoxidation of the alkene followed by a two-step protecting group modification gave epoxide 108, which underwent an oxidative epoxide opening followed by silyl protection to give silyl ether 109. Alloc deprotection, alkylation with (Z)-2-iodo-2-butenyl tosylate, followed by an intramolecular Heck reaction delivered pentacyclic diamine 110. A three-step formation of the p-ketoester 111 followed by a three-step reduction process afforded ester 112, which underwent a reduction and deprotection sequence to provide minfien-sine (99). A sequential catalytic asymmetric Heck-(V-acyliminium ion cyclization for the delivery of the enantiopure 3,4-dihydro-9a,4a-(iminoethano)-9//-carbazole is the highlight of the synthesis. 

Ashimori, A., Bachand, B., Caller, M.A. et al. (1998) Catalytic asymmetric synthesis of quaternary carbon centers. Exploratory studies of intramolecular Heckreactions of (Z)-a,/S-unsaturated anilides and mechanistic investigations of asymmetric Heck reactions proceeding via neutral intermediates. J. Am. Chem. Soc., 120, 6488-99. 

For recent reviews of the asymmetric Heck reaction, see (a) Shibasaki, M., Boden, C.D.J. and Kojima, A. (1997) The asymmetric Heck reaction. Tetrahedron, 53, 7371-95 (b) Shibasaki, M. and Vogl, E.M. (1999) Heck reaction, in Comprehensive Asymmetric Catalysis, Vol. 2 (eds E.N. Jacobsen, A. Pfaltz and H. Yamamoto), Springer, Berlin, pp. 457-87 (c) Donde, Y. and Overman, L.E. (2000) Asymmetric intramolecular Heck reactions, in Catalytic Asymmetric Synthesis (ed. I. Ojima), WUey-VCH Verlag GmbH, New York, pp. 675-97 (d) Dounay, A.B. and Overman, L.E. (2003) The as5mmetric intramolecular Heck reaction in natural product total synthesis. Chem. Rev., 103, 2945-64 (e) Shibasaki, M., Vogl, E.M. and Ohshima, T. (2004) Asymmetric Heck reaction. Adv. Synth. Catal., 346,1533-52. 

Kagechika, K. and Shibasaki, M. (1991) Asymmetric Heck reaction a catalytic asymmetric synthesis of the key intermediate for A -capneUene-3i3,8j8,10o -triol and A -capnellene-3/S,8/3,10a,14-tetrol. J. Org. Chem., 56,4093 (b) Kagechika, K., Ohshima, T. and Shibasaki, M. (1993) Asymmetric Heck reaction-anion capture process. A catalytic asymmetric synthesis of the key intermediates for the capneUenols. Tetrahedron, 49, 1773-82 (c) Ohshima, T., Kagechika, K., Adachi, M., et al. (1996) Asymmetric Heck reaction-carbanion capture process. Catalytic as5mmetric total synthesis of (—)-A LcapneUene. J. Am. Chem. Soc., 118, 7108-16 (d) Itano, W., Ohshima, T. and Shibasaki, M. (2006) Synthesis of the tricyclic core of 5a-capneUenols using asymmetric Heck reaction-carbanion capture process. Synlett, 3053-6. 

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