Hiyama coupling reaction development

Pitavastatin (3) was launched in 2003 and is currently marketed in Japan under the trade name Livalo . Like rosuvastatin and fluvastatin, pitavastatin is a completely synthetic HMG-CoA reductase inhibitor that was developed by Kowa, Nissan Chemical, and Sankyo (Sorbera et al., 1998). Multiple syntheses of pitavastatin have been reported and an exhaustive review of these efforts is beyond the scope of this text (Hiyama et al., 1995a, b Minami and Hiyama, 1992 Miyachi et al., 1993 Takahashi et al., 1993, 1995 Takano et al., 1993). Instead, we will focus our discussion on two related and innovative synthetic approaches that differ strategically from the routes we have previously examined for rosuvastatin and fluvastatin. These routes to pitavastatin employed palladium-mediated coupling reactions to install the 3,5-dihydroxyheptanoic acid side-chain. This key retrosynthetic disconnection is highlighted in Scheme 12.6, in which a suitable functionalized side-chain (52 or 53) is attached to the heterocyclic core of pitavastatin (51) through palladium-mediated coupling. 

The use of alkenylsilyl ethers in palladium-catalyzed cross-coupHng reactions has long been known. In fact, only a year after Hiyama s landmark report on the TBAF-promoted coupling reactions of vinyltrimethylsilane, Tamao and Ito capitahzed on the use of alkoxy-substituted silanes as viable components for such reactions (cf Scheme 7.4). The generahty of the silyl ether coupHng added a useful class of organosilicon substrates that are complementary to the fluorosilanes developed by Hiyama et al. These studies showed that other heteroatom-based... 

Welker developed a useful synthetic strategy involving silyl substituted dienes. He can easily prepare large quantities of 2-silicon-substituted 1,3-dienes that readily participate in Diels-Alder reactions followed by cross-coupling reactions to yield aryl substituted cyclohexenes. Diene 94 smoothly combines with A-phenylmaleimide (95) to fiimish a silyl cyclohexene that undergoes Hiyama cross-coupling with iodobenzene to provide 96. ... 

The palladium-catalyzed reaction of alkenyl-, aryl-, alkynyl- and alkylsiloxanes with aryl, alkyl, and alkenyl halides and triflates in the presence of activators is known as the Hiyama cross-coupling reaction and several reviews have been published. This chapter will present major developments and examples of recent carbon-carbon bond formation methodology and improvements as well as their use in natural products synthesis in the last few years. 

To date, nearly all studies of the Hiyama reaction have focused on couplings of Csp -X electrophiles. Fu developed the first method for achieving the room-temperature Hiyama couplings of unactivated alkyl bromides and iodides. Palladium-catalyzed reactions of alkyl bromides and iodides 18 with aryltrimethoxysilanes 19 in the presence of phosphorus ligand and TBAF afforded coupled products 20 in moderate to good yields. 

Many reviews have been published in the last few years on the applications of the Hiyama cross-coupling reaction in organic synthesis. In general, preparation of biaryls or heterobiaryls is the most common application of this reaction since new methodology development is based on examples of these. The most prevalent applications of the aryl and heteroaryl halides with organosilane precursors involve reactions such as vinylations, alkenylations, and alkynylations. The reader is encouraged to consult these key reviews. This section will describe some of the more recent applications published in the last few years. 

The Nozaki-Hiyama-Kishi (NHK) reaction involves the mild addition of chro-mium(II) organometallics to aldehydes to give homoallylic alcohols in a regio- and stereo-controlled fashion.111 A very significant achievement in the chromium organometallic chemistry was accomplished by Fiirstner who developed a catalytic version of the NHK reaction based on the coupled use of the redox Mn(0)/Cr(III) couple and trimethylsilyl chloride (TMSC1).[21 Moreover, the integration of the Fiirstner protocol with the addition of the Jacobsen s Salen /V,/V -bis(3,5-di-f-butylsalicylidene)-l,2-cyclohexanediamine] and triethylamine allowed Cozzi, Umani-Ronchi, et al. to develop a catalytic enantioselective route to homoallylic alcohols.[3]... 

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