Acids asymmetric Heck reactions

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. 

A short five-step synthesis of a bifuran, namely ( )-2,2 -bis(diphenylphosphino)-3,3 -binaphtho[2,l-I>]furan (BINAPFu) from naphthofuranone via a low-valent titanium-mediated dimerization was reported. The newly developed resolution procedure for phosphines was utilized to provide the optically active bidentate phosphine ligands (BINAPFu), which consistently outperforms BINAP in the asymmetric Heck reaction between 2,3-dihydrofuran and phenyl triflate . Another way in which a benzofuranone can be converted into benzo[7 ]furan is by treatment of the former with 1-BU2AIH at -78°C followed by an acidic work up <00TL5803>. 

Significant developments in this area have been reported by Overman as well As illustrated in Scheme 5, a Pd-catalyzed asymmetric Heck reaction leads to the formation of cyclic amide 24 subsequent treatment with aqueous acid delivers 29 in 84 % yield and 93 % ee151 Optically pure 25 is obtined after recrystallization (80% recovery). Follow-up functionalization, shown in Scheme 5, affords either physostigmine 26 or physovenine 27 It is difficult to imagine an alternative, and nearly efficient or selective, approach to the construction of these target molcules. 

Gilbertson SR, Fu Z. Chiral P. N-ligands based on ketopinic acid in the asymmetric Heck reaction. Org. Lett. 2001 3(2) 161-164. 

For the performance of an enantioselective synthesis, it is of advantage when an asymmetric catalyst can be employed instead of a chiral reagent or auxiliary in stoichiometric amounts. The valuable enantiomerically pure substance is then required in small amounts only. For the Fleck reaction, catalytically active asymmetric substances have been developed. An illustrative example is the synthesis of the tricyclic compound 17, which represents a versatile synthetic intermediate for the synthesis of diterpenes. Instead of an aryl halide, a trifluoromethanesul-fonic acid arylester (ArOTf) 16 is used as the starting material. With the use of the / -enantiomer of 2,2 -Z7w-(diphenylphosphino)-l,F-binaphthyl ((R)-BINAP) as catalyst, the Heck reaction becomes regio- and face-selective. The reaction occurs preferentially at the trisubstituted double bond b, leading to the tricyclic product 17 with 95% ee. °... 

Novel C2-symmetric thiophene-containing ligands have recently been prepared and utilized in asymmetric synthesis. Dithiophene 158 was utilized as a ligand in the asymmetric reduction of p-ketoesters (prostereogenic carbonyl) and acrylic acids (carbon-carbon double bond) <00JOC2043>. Dibenzo[b]thiophene 159 was utilized as a ligand in enantioselective Heck reactions of 2-pyrrolines <00SL1470>. 

The remarkable affinity of the silver ion for hahdes can be conveniently applied to accelerate the chiral palladium-catalyzed Heck reaction and other reactions. Enantioselectivity of these reactions is generally increased by addition of silver salts, and hence silver(I) compounds in combination with chiral ligands hold much promise as chiral Lewis acid catalysts for asymmetric synthesis. Employing the BINAP-silver(I) complex (8) as a chiral catalyst, the enantioselective aldol addition of tributyltin enolates (9) to aldehydes (10) has been developed." This catalyst is also effective in the promotion of enantioselective allylation, Mannich, ene, and hetero Diels-Alder reactions. 

Hu et al. [104] disclosed that the spiro phosphine oxide ligand (/ )-30a is highly efficient for the Pd-catalyzed Heck reaction of cyclic and heterocyclic olefins with aryl triflates. An asymmetric domino Heck cyclization was established using catalyst Pd/(/ )-30a to form fused carbo- and heterocycles with excellent stereoselectivity (Scheme 42) [105]. This method was used in a short synthesis of (-)-martinellic acid, a primary ingredient in traditional eye medicine in South America. 

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. 

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