Enantioselective Heck-type reactions

Asymmetric synthesis has become the most relevant route to enantiomerically pure compounds, and transition-metal-induced reactions aie increasingly important in the array of methods for the enantioselective construction of new asymmetric centers. Catalytic processes, in which chiral information is transferred from a small fraction of a chiral 

Quite interestingly, the minor product 2-phenyl-2,5-dihydrofuran (200) has the opposite configuration, i.e., (5)-200, compared to that of (/ )-199. However, this compound is produced with a significantly lower enantiomeric excess. It is possible that this is caused by a kinetic resolution effect in the alkene complex 205 the jr-bound hydridopalladium moiety in complex 205 could add again to the double bond. Base influence is also noteworthy, and the highest enantiomeric excess was achieved with l,8-bis(bisdimethylamino)naphthalene ( proton sponge ). 

A different case arises with the use of the /m-butyldihydrooxazole 208 as a ligand on palladium [207]. In this case, a rapid dissociation of the complex 205 gives only 200, with an especially high enantiomeric excess. 

The enormous potential of intramolecular Heck reactions has been demonstrated impressively in elegant syntheses of even the most complicated natural-product skeletons. The intramolecular Heck reaction on the non-chiral iodoalkenes 209 and the corresponding 

Recently, other oxazole-type ligands have been used in such enantioselective couplings with very good success [413]. 

Other asymmetric intramolecular Heck reactions using two enantiotopic double bonds gave similarly good results [173, 415]. The desymmetrization of the 2-substituted benzyloxyhexahydronaphthalene derivative 361-X gave the tetracycle 

This methodology has been utilized by Overman et al. in their elegant total syntheses of various natural products (Section 8.6), such as quadrigemine C [416], psycholeine [416], and other molecules of this type [417]. 

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In the same year, a series of Ci-symmetric chiral triazolium Pd(II) complexes were prepared by Enders et al. As typically reported with the use of Ci-symmet-ric ligands, their NHC-metal complexes were obtained as diastereomeric mixtures due to the restricted rotation around the carbene-metal bond [6]. Without further elaboration, the authors stated that these complexes were used in an enantioselective Heck-type reaction achieving low asymmetric inductions. Soon thereafter, the authors investigated the coordination behavior of chiral triazolium salts 35 with [Rh(COD)Cl]2 and obtained a mixture of axially chiral complexes 36 with a diastereomeric excess of up to 94% (Scheme 3.20). These complexes were used as catalysts in asymmetric hydrosilylation reactions, achieving up to 44% ee for aromatic and ahphatic ketones [38,39]. 

Optically active cis-decalins can be obtained from substrates such as 4 by a Heck-type reaction with PdCl2/(R)-l (1 1) as the catalyst.8 Addition of various silver salts improves the yield and enantioselectivity. For cyclization of 4 to 5, the highest enantioselectivity was observed by use of Ag3P04 and CaC03 (2 equiv. of each) with 1 -methyl-2-pyrrolidinone (NMP) as solvent (60°). 

A rhodium(l)-catalyzed system in THF is also effective in the Mizoroki-Heck-type reaction of arylsilanediols with acrylates (Scheme 4).53 Interestingly, the use of aqueous THF switches the reaction to 1,4-addition forming /3-arylated esters. The proposed catalytic cycles for these reactions involve 1,4-addition of an arylrhodium species to an acrylate. The change of the reaction pathway is probably because, in aqueous THF, the resultant Rh enolate 6 undergoes protonolysis rather than /3-elimination. Similar Rh-catalyzed 1,4-additions to a,/3-unsaturated carbonyl compounds have been achieved with arylsilicones,54 arylchlorosilanes,55 and aryltrialkoxysilanes.56,57 The use of a cationic Rh-binap complex leads to highly enantioselective 1,4-additions of alkenyl- and arylsilanes.58 583... 

Finally, it should be mentioned that two years later, an enantioselective oxidative (boron) Heck-type reaction was reported by Jung and coworkers [32] for a dinuclear NHC-derived CNO-based pincer complex for which for the first time a Pd /Pd" mechanism was suggested to be operative with palladium pincer-type crosscoupling catalysts. Reaction mechanisms without a change of the palladium s oxidation state have never been proposed to be operative for Heck cross-couphng reactions, but have been shown to be operative for xylene-derived selenium-based pincer complexes and related systems in the cross-couphng of vinyl epoxides (and aziridines) with organoboronic acids [24d, 33]. 

Oxidative Heck-Type Reactions (Fujiwara Moritani Reactions) 357 9.2.3 Enantioselective Fujiwara—Moritani Reactions... 

Chiral complexes 27 were tested in oxidative Heck-type reactions of boronic acids with acyclic alkenes (Equation (9.2)). Product yields were modest however, enantioselectivities were excellent (9(C98% ee). Other examples of functionalised benzimidazol-2-ylidene Pd complexes include 28 and 29 (Figure 9.6), which required high temperatures and long reaction times to afford reasonable conversions. ... 

Shibasaki and coworkers [87] described the first enantioselective combination of this type in their synthesis of halenaquinone (6/1-162) (Scheme 6/1.43). The key step is an intermolecular Suzuki reaction of 6/1-159 and 6/1-160, followed by an enantioselective Heck reaction in the presence of (S)-BINAP to give 6/1-161. The ee-value was good, but the yield was low. 

Phosphino-imidazoline ligands of this type were originally synthesized by Bu-sacca and coworkers and used in an enantioselective Heck reaction [28]. 

The Heck reaction in its original form is not a chirogenic reaction. However, the situation changes if cyclic alkenes are employed as a coupling component, as was initially shown by Larock et al. [6]. In such cases, non-conjugated, chiral products of type 6 are formed because only one syn-Y atom is available for f-W elimination in the intermediates of type 7 (Scheme 3). While racemic mixtures are obtained with achiral catalysts, such transformations of course afford the possibility of achieving enantioselective Heck reactions. 

In most of the palladium-catalysed domino processes known so far, the Mizoroki-Heck reaction - the palladium(0)-catalysed reaction of aryl halides or triflates as well as of alkenyl halides or triflates with alkenes or alkynes - has been apphed as the starting transformation accordingly to our classification (Table 8.1). It has been combined with another Mizoroki-Heck reaction [6] or a cross-coupling reaction [7], such as Suzuki, Stille or Sonogashira reactions. In other examples, a Tsuji-Trost reaction [8], a carbonylation, a pericyclic or an aldol reaction has been employed as the second step. On the other hand, cross-couphng reactions have also been used as the first step followed by, for example, a Mizoroki-Heck reaction or Tsuji-Trost reactions, palladation of alkynes or allenes [9], carbonylations [10], aminations [11] or palladium(II)-catalysedWacker-type reactions [12] were employed as the first step. A novel illustrative example of the latter procedure is the efficient enantioselective synthesis of vitamin E [13]. 

Recently, they report the enantioselective carboetherification reaction to corresponding tetrahydrobenzofuran (up to >95% ee) with the commercially available (S,S)-tBu-box ligand. The intermolecular C-C bond could be formed by alkyl Heck-type couplings with vinyl arenes. DFT (Density functional theory) transition state calculations are consistent with a c/s-oxycupration stereo-determining transition state, and there is good agreement between experimental and calculated levels of enantiomeric excess [147] (Scheme 8.77). 

In 1999, Mikami s group reported the first example of an intermolecular asymmetric Fujiwara-Moritani reaction of benzene with cyclic alkenes using a Pd catalyst co-ordinating to a chiral sulfonylamide-oxazoline ligand (Scheme 7.24). With PhCOs Bu as the oxidant, the coupling reaction occurred with moderate enantioselectivity (up to 49% ee), although the chemical yield was low. The reaction is considered to involve the formation of a phenyl-Pd species via electrophilic C-H substitution by Pd(ii), and Heck-type cyclization followed by re-oxidation of the resultant Pd(0) species. 

To account for the differences in reactivity and enantioselectivity observed in Heck reactions of unsaturated triflates and halides, two distinct mechanistic pathways have been proposed (as shown in the margin). The "cationic" pathway is generally invoked to describe asymmetric Heck reactions of unsaturated triflates or halides in the presence of Ag(I) or T1(I) additives. In the absence of such additives the Heck reaction is expected to proceed through a "neutral" reaction pathway. The modest enantioselectivity often observed in Heck reactions of this type has been attributed to the formation of a neutral palladium-alkene complex by partial ligand dissociation. ... 

The first examples of asymmetric Heck cyclizations that form quatemaiy carbon centers with high enantioselectivity came from our development of an asymmetric synthesis of the pharmacologically important alkaloid (—)-physostigmine (184) and congeners (Scheme 6-31) [68]. In the pivotal reaction, (Z)-2-butenanilide iodide 182 was cyclized with Pd-(5)-BINAP to provide oxindole 183 in 84% yield and 95% ee after hydrolysis of the intermediate silyl enol ether. With substrates of this type, cyclizations in the presence of halide scavengers took place with much lower enantioselectivity [68]. 

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