Ring systems intramolecular Heck reaction

In the synthesis of morphine, bis-cyclization of the octahydroisoqtiinolinc precursor 171 by the intramolecular Heck reaction proceeds using palladium trifluoroacetate and 1,2,2,6,6-pentamethylpiperidine (PMP). The insertion of the diene system forms the rr-allylpalladium intermediate 172, which attacks the phenol intramolecularly to form the benzofuran ring (see Section 1.1.1.3). Based on this method, elegant total syntheses of (-)- and (+ )-dihydrocodei-none and (-)- and ( + )-morphine (173) have been achieved[141]. 

This reaction also represents an example of the intramolecular Heck reaction, a variant that has gained some importance in recent years. Another instructive example of the potential of this reaction for the construction of ring systems has been reported by de Meijere and coworkers, taking advantage of a sequence of four consecutive intramolecular Heck reactions. The bromodiene-yne 18 reacts in a sequence of domino reactions within 3 d at 80 °C under Heck conditions to give the tetracyclic product 19 in 74% yield ... 

A novel approach towards the construction of the morphine skeleton is demonstrated by the total synthesis of ( )-desoxycodeine-D. One of the key steps for this synthesis is the palladium-catalyzed intramolecular Heck reaction. Therefore, this synthetic strategy for the construction of the polycyclic ring systems has provided an efficient access to the complete pentacyclic skeleton of morphine <00TL915>. 

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>. 

Grigg s group synthesized a unique bicyclic P-lactam 108 via an intramolecular Heck reaction from 107 [87, 88]. The 7-membered ring was formed via an unusual insertion at C(3) of furan, an aromatic rc-system. 

TV-substituted methylenephthalimide derivatives served as the starting material for the preparation of a series of tetracyclic systems. The intramolecular Heck reaction of these compounds (4.10.) led in each case to the formation of a carbon-carbon bond between the exocyclic carbon atom of the olefin bond and the aryl moiety. The formation of five, six and seven membered rings was achieved with near equal efficiency, enabling the preparation of some isoindolobenzazepine alkaloids.11... 

Intramolecular versions of the Heck reaction are very useful for the construction of ring systems. The entropic advantage of having both coupling partners present in the same molecule increases the efficiency of the insertion reaction and leads to efficient reactions. Moreover the intramolecular version can be carried out on hindered substituted alkenes, whereas the intermolecular Heck reaction is largely restricted to monosubstituted alkenes. These reactions illustrate the syn stereochemistry of both the insertion reaction and the elimination. A number of multicyclic natural products have been synthesized using intramolecular Heck reactions to assemble the skeletons, and this has become a powerful synthetic tool for such compounds. 

Another method for activating the versatile alkenyl halide moiety was the oxidative addition of a late transition metal species, which would then facilitate insertion of the C13-C14 double bond. The Rawal,7h Bonjosch,7e and Mori7b syntheses of 1 all employed a Pd-mediated intramolecular Heck reaction to build the F ring of the molecule.71 Our system, in as much as it contained additional unsaturation, was somewhat different from those in the literature and thus had the potential for displaying new chemistry. For example, in Rawal s approach (Scheme... 

The intramolecular Heck reaction has been well established as a powerful tool for the construction of complex polycyclic ring systems in the context of natural product synthesis. 

Synthesis of the eco-analogues 173 of ergot alkaloids was achieved employing an intramolecular Heck-reaction on the precursor 174, followed by full deprotection of the intermediate 17S. The same ring system was also created by a ring-closing metathesis approach <03OL3519>. 

Cascade reactions provide valuable strategies, especially for the construction of various carbo- and heterocyclic systems with three, four, or more annelated rings [166]. The Heck reaction has successfully been employed in various inter-inter- and intra-inter- as well as all-intramolecular reaction cascades. 

Intramolecular Heck reactions provide a powerful tool for the construction of car-bocyclic and heterocyclic ring systems. Note in the example below that unlike the other Heck reactions shown, the double bond does not end up in its original position due to the requirement of a 5 yn-P-hydride elimination after the 5yn-alkene insertion. 

Ecteinascidin 743 is a potent antitumor agent that was isolated from a marine tunicate. T. Fukuyama et al. applied the intramolecular Heck reaction as the key step in the assembly of the central bicyclo[3.3.1] ring system.Toward this end, the cyclic enamide precursor was exposed to 5 mol% of palladium catalyst and 20 mol% of a phosphine ligand in refluxing acetonitrile to afford the desired tricyclic intermediate in 83% isolated yield. 

In 2006 Fukuyama published a total synthesis of racemic morphine starting from isovanillin and a cyclohexene-epoxide [16, 17]. The key features in their synthesis are (1) a construction of the ether linkage between A and C rings by Tsuji-Trost coupling, (2) an intramolecular Heck reaction to construct A-C-E tricyclic system, and (3) an intramolecular Mannich-type reaction of a ketone with an aminal to provide the pentacyclic structure of morphine in a one-step reaction by double cyclization. 

The intramolecular Heck reaction to construct the polycyclic benzofuran skeleton in morphine was reported by Overman [21] in their synthesis of (+)- and (-)-dihydroisocodeine in 1993, and after that, the Heck cyclization has been extensively studied by Cheng [22], Hsin [23, 24], Hudlicky [25] (see Sect. 2.2.3), Trost (see Sect. 2.2.1), and Guillou (see Sect. 2.1.2). In Fukuyama s synthesis, the Heck reaction of 11 works well and successfully provided the A-C-E tricyclic ring system 13 in 87% yield after deprotection of the TBS group in the intermediary enol ether 12. 

The naphth[3,2,l-cr/]indole ring system, e.g. 290, was constructed by Miki in very good yield via an intramolecular Heck reaction of triflate 289 [284]. The corresponding bromide furnished 290 in 74% yield. Interestingly, attempted radical cyclization of the bromide with BujSnH failed. 

There are also excellent total syntheses of spirotryprostatins which do not apply intermolecular functionalisation of the indole 3-position with a C5 prenyl-type precursor and are, therefore, not discussed in detail. Carreira and co-workers started from 3-diazo-2-oxindole, which was used in a Rh(I)-catalysed cyclopropanation of 1,3-pentadiene. The resulting cyclopropane was subjected to Mgl2-catalysed ring expansion and added to an imine affording the spiro[5.5] partial structure [130, 131]. Overman and Rosen built up the indole system by intramolecular Heck reaction of a functionalised iodoaniline [132,133]. In a model study building up the indole system, Cacchi and co-workers synthesised 3-prenylindoles via Pd-catalysed cyclisation of orf/io-alkynyltrifluoroacetanilides with prenyl esters [134]. 

Palladium-catalyzed reactions have been used to substitute the isoquinoline ring. With the differential reactivity of the 1- and 3-positions of 1,3-dichloroi.soquinoline regioselective arylation at the 3-position is possible <97JGS(P1)927>. The intramolecular Heck reaction of A-2-bromobenzoyl-1-methylene-1,2,3,4-tetrahydroisoquinoline via a 6-ent/o process provides an entry into the protoberberine ring system <97TL1057>. 

The ABC-ring system of (—)-galanthamine has also been constructed using intramolecular Heck reactions with a particularly notable and early example being described by Trost et al. Specifically, they showed (Scheme 2) that on exposure to 15 mol% Pd(OAc)2, 15 mol% of the ligand diphenylphosphinopropane (dppp), and 3 mol equivalents of AgaCOs, the allylic ether 5, itself the product of an asymmetric allylic alkylation reaction, was converted into compound 6. This was then carried forward over a further four steps into (—)-galanthamine. 

The intramolecular Heck reaction provides a general access to carbocyclic (Sect. IV.2.2.1) and heterocyclic (Sect. IV.2.2.2) systems. All ring sizes from three- to nine-membered and even larger rings are achievable. However, certain restrictions apply in those cases in which rings smaller than six-membered are formed that is, these rings are accessible only by n-exo processes (Scheme 4). 

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