Cascade reactions asymmetric Heck reaction

SCHEME 13.5. Application an asymmetric Heck reaction/anion-capture cascade process to the total synthesis of marine sesquiterpene capnellenols 14. 

In another example, Shibasaki and co-workers applied an asymmetric Heck reaction/anion-capture cascade process to the total synthesis of marine sesquiterpenes capnellenols 14 and capnellene 17 (Schemes 13.5 and 13.6). The cascade involved the use of prochiral cyclo-pentadienyl systems for the generation of bicyclic 71-allyl-palladium species, which were then trapped by a suitable nucleophile. Initial studies in the total synthesis of capnellenols described the trapping of the 71-allylpalladium... 

Brase reported an intramolecular asymmetric Heck-intermolecular Heck cascade reaction of l,3-bis(enolnonaflates) 131 to the highly congested bicyclic compound 132 [122] (Scheme 5). Although the level of asymmetric induction is low (up to 52% ee), this result shows that the concept of two leaving groups in the desymmetrization reaction can be applied. 

Reaction Scope Cascade (or Domino) Asymmetric Intramoiecuiar Mizoroki-Heck Reactions... 

Shibasaki and coworkers [40] also demonstrated the use of soft carbanionic nucleophiles, initially sodium dimethyl malonate, in cascade asymmetric Mizoroki-Heck cyclization- j -allyl trapping sequences. This conversion succeeds with various soft carbanionic nucleophiles to provide functionalized bicyclo[3.3.0]octane derivatives 55 in excellent yields (72-92%) and up to 94% ee (Scheme 16.13). The enantioselectivity of these Mizoroki-Heck reactions is significantly diminished in the absence of NaBr a speculative rationale to account for the effect of the NaBr additive has been advanced [40]. 

Alternatively, tetrahydroanthracene 85 was also obtained directly from symmetrical ditriflate 86 by a Suzuki cross-coupling/asymmetric Mizoroki-Heck cascade reaction. In this case, reaction of ditriflate 86 with alkylborane 82, Pd(OAc)2, (S)-BINAP and K2CO3 in THF at 60 °C directly gave product 85 in high enantiopurity, albeit in 20% yield. Although the yield for this one-pot conversion was poor, this transformation represents a novel application of the asymmetric Mizoroki-Heck cyclization and remains the only reported example of cascade Suzuki cross-coupling/asymmetric Mizoroki-Heck cyclization. A series of additional synthetic transformations was required to convert 85 to pentacyclic intermediate 87, which had earlier been converted by Harada et al. [53] to halenaquinone (88) and halenaquinol (89). 

The identification of novel ways to incorporate an asymmetric intramolecular Mizoroki-Heck reaction as part of a cascade cyclization sequence has led to attractive approaches for assembling complex polycyclic molecules. Keay and coworkers [54] reported the use of a double Mizoroki-Heck cyclization as the pivotal step in the asymmetric total synthesis of xestoquinone (93), a reduced congener of halenaquinone (Scheme 16.20). In this step, naphthyl triflate 90 was cyclized with Pd2(dba)3 (dba = dibenzylideneace-tone), (5 )-BINAP and 1,2,2,6,6-pentamethylpiperidine (PMP) in toluene at 110°C to give pentacyclic product 92 with impressive efficiency and moderate enantioselectivity. This conversion proceeds by initial asymmetric 6-exo Mizoroki-Heck cyclization to form the central six-membered carbocycle and install the benzylic quaternary stereocentre. The first cyclization event is followed by a second Mizoroki-Heck reaction in which neopentyl... 

In the years since the first reports in 1989 [4,5], the scope of the asymmetric intramolecular Mizoroki-Heck reactions has been substantially increased. This transformation has now been employed as a key strategic step in total syntheses of a wide variety of polycyclic natural products. Among the features that contribute to the broad utility of asymmetric Mizoroki-Heck cyclizations are the high functional group tolerance of palladium(O)-catalysed reactions, the remarkable capacity of this transformation to forge C—C bonds in situations of considerable steric congestion and the ability to orchestrate cascade or tandem processes that form multiple rings. 

It is certain that many more applications of catalytic asymmetric intramolecular Mizoroki-Heck reactions will be described in the future. This survey makes apparent the small number of ligands that have been used thus far, with Noyori and coworkers BINAP ligand being the most widely employed [80]. Two future trends are easy to predict a larger variety of chiral ligands [56, 58, 81, 82] will be used in asymmetric Mizoroki-Heck processes and a greater variety of cascade processes involving intramolecular Mizoroki-Heck reactions will be developed. 

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. ... 

In subsequent studies, the scope of the Heck reaction/ anion-trapping cascade was further extended using soft car-banionic nucleophiles as illustrated in the asymmetric synthesis of (—)-D -capnellene 17. Treatment of prochiral vinyl triflate 15 with Pd(OAc>2, (5)-BINAP, and NaBr, as weU as the sodium enolate of diethyl (2-((rert-butyldiphe-nylsilyl)oxy)ethyl)malonate, gave the cyclic product 16 in 87% ee and 77% yield as the sole product. The use of NaBr as an additive improved the optical yields and was critical in preventing counteranion exchange between the triflate anion and the enolate anion by complexing with sodium enolate (Scheme 13.6). Compound 16 was then advanced through several steps to complete the total synthesis (—)-D -capnellene 17. 

Recent studies revealed that (2S)-tocopherols have no antioxidant effect in biological systems because they are not accepted as substrates by the a-tocopherol transfer protein (TTP), which is responsible for the transport of vitamin E into the tissue. As a result, the enantioselective synthesis of the a-tocopherol became attractive, and several groups have reported on its asymmetric synthesis. In addition, Tietze and co-workers reported on an enantioselective palladium-catalyzed total synthesis of vitamin E by employing a domino Wacker-Heck reaction (Scheme 21.15). ° In their study, reaction of 64 with methyl acrylate in CH2CI2 with catalytic amounts of Pd(TFA)2 (TEA = trifluoroacetate), the chiral ligand (5,5)-Bn-BOXAX 65, and p-benzoquinone afforded the desired chroman 66 with 96% ee in 84% yield. The enantioselective cascade reaction described therein provided the efficient construction of the chroman firamework of vitamin E 67 with concomitant introduction of part of the side chain in high yields and high enantioselectivities. 

In a narrower sense, this review covers intramolecular Mizoroki-Heck [1] reactions forming carbocycles [2] that is, the palladium-catalyzed intramolecular coupling of vinyl/aryl (pseudo-)halides with an alkene tethered by a hydrocarbon chain. Ring closures furnishing heterocycles are covered in Chapter 6 also beyond the scope of this chapter are the domino/cascade or tandem (Chapter 8) and asymmetric processes (Chapters 12 and 16) dealing with formation of a carbocycle. 

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