Asymmetric synthesis Heck reaction

The Shibasaki group [27] developed an enantioselective total synthesis of (+)-xes-toquinone (6/1-38) using an asymmetric double Heck reaction with BINAP as chi-... 

B. Dounay, L. E. Overman, The Asymmetric Intramolecular Heck Reaction in Natural Product Total Synthesis, Chem. Rev. 2003, 103, 2945-2963. 

One of the emerging applications of 4,5-dihydroimidazole-based compounds is as chiral auxiliaries in metal complexes used for asymmetric synthesis for example, 457 in ruthenium-catalyzed DielsAlder reactions <2001 J(P 1)1500, 2006JOM(691)3445> 458 in diethylzinc addition to aldehydes <2003SL102> 459 in asymmetric intramolecular Heck reactions <20030L595> and 460 in ruthenium-catalyzed epoxidation <2005OL3393> and iridium-catalyzed hydrogenation of imines <2004TA3365>. 

Seminal contributions to the development of asymmetric cyclic Heck reaction were made in 1989 by Overman [72] and Shibasaki [73]. These and other groups have since developed the reaction as a useful tool for asymmetric synthesis of complex natural products as indicated by representative examples shown in Schemes 20 [74-76] and 21 [77-79]. For further details, the readers are referred to recent reviews [43,57]. 

Dounay AB, Overman LE. The asymmetric intramolecular Heck reaction in natural product total synthesis. Chem. Rev. 2003 103 2945-2963. 

The Asymmetric Intramolecular Heck Reaction in Natural Product Total Synthesis ... 

Metal-Catalyzed Cross-Coupling Reactions, Vol. 1,2nd edn (eds A. de Meijere and F. Diederich), Wiley-VCH Verlag GmbH, Weinheim, Germany, pp. 217-315 (c) Dounay, A.B. and Overman, L.E. (2003) The asymmetric intramolecular Heck reaction in natural product total synthesis. Chem. Rev., 103, 2945-63 (d) Link, J.T. (2002) The intramolecular Heck reaction. Org. React., 60, 157-534 (e) Shibasaki, M. and Miyazaki, F. (2002) Asymmetric Heck reactions, in... 

Kilroy, T.G., Cozzi, P.G., End, N. and Guiry, P.J. (2004) The application of HETPHOX ligands to the asymmetric intermolecuiar Heck reaction of 2,3-dihydrofuran and 2,2-disubstituted-2,3-dihydrofurans. Synthesis, 1879-88. 

A variety of other reaction variables, such as the solvent, base and various additives, can have profound effects on asymmetric Mizoroki-Heck cyclizations. These factors have been discussed in recent reviews [3]. The reaction temperature can also play an important role. At temperatures above 100 °C, catalyst decompositiou can contribute to deterioration of enantioselectivity [23, 24], Nonetheless, there are numerous examples of successful asymmetric Mizoroki-Heck cyclizations at higher temperature. Carrying out palladium-catalysed reactions in microwave reactors is now common [25], with several examples of microwave-accelerated asymmetric Mizoroki-Heck reactions being reported [26, 27]. Under microwave heating conditions, reaction times can be reduced and rigorous exclusion of oxygen is often not required. This technology was used to promote an asymmetric Mizoroki-Heck cyclization in the recent total synthesis of minliensine (see Section 16.4.4). 

Overman and coworkers have extensively developed the utility of asymmetric Mizoroki-Heck reactions for constructing quaternary carbon stereocentres through various alkaloid total synthesis endeavours. A particular focus of these studies has been the catalytic asymmetric synthesis of enantioenriched 3,3-disubstituted oxindoles, because oxindoles of this type are versatile precursors of many natural alkaloids, hi an early, unanticipated discovery, it was found that either enantiomer of spirocychc oxindole 103 could be formed with moderate selectivity using a single enantiomer of a chiral diphosphine ligand (Scheme 16.24) [13]. Specifically, the use of Ag3P04 as an HI scavenger in the cyclization of 102 produced (S)-103 in 71% ee, whereas use of the amine base PMP under otherwise identical reaction conditions yielded (7 )-103 in 66% ee. 

Dounay, A.B., Hatanaka, K., Kodanko, J. et al. (2003) Catatytic asymmetric synthesis of quaternary carbons bearing two aryl substituents. Enantioselective s3mthesis of 3-alkyl-3-aryl oxindoles by catalytic asymmetric intramolecular Heck reactions. J. Am. Chem. Soc., 125, 6261-71. 

Shibasaki has also reported impressive applications of the asymmetric intramolecular Heck reaction. For example, the Shibasaki group have applied their chemistry to the synthesis of compound 64, a key intermediate in the total synthesis of two complex triquinane sesquiterpenes 65 and 66, by making use of a Heck reaction/anion capture cascade sequence. ... 

Asymmetric cyclization using chiral ligands has been studied. After early attempts[142-144], satisfactory optical yields have been obtained. The hexahy-dropyrrolo[2,3-6]indole 176 has been constructed by the intramolecular Heck reaction and hydroaryiation[145]. The asymmetric cyclization of the enamide 174 using (S j-BINAP affords predominantly (98 2) the ( )-enoxysilane stereoisomer of the oxindole product, hydrolysis of which provides the ( l-oxindole aldehyde 175 in 84% yield and 95% ec. and total synthesis of (-)-physostig-mine (176) has been achieved[146]. 

Asymmetric Heck reaction in synthesis of heterocycles 97T7371. 

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>. 

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>. 

The asymmetric synthesis of a galanthamine alkaloid relies also on the intramolecular Heck reaction for the preparation of the benzo[h]furan-based key intermediate with a crucial chiral quaternary center, which eventually leads to the synthesis of (-)-galanthamine <00JA11262>. A similar approach towards the construction of galanthamine ring system via an intramolecular Heck reaction has also been investigated <00SL1163>. 

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. 

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