Synthesis intramolecular strategy

A few type lb intramolecular strategies for construction of the indole core have appeared. In their synthesis of (+)-vinblastine, the Fukuyama group employed radical cyclization of thioanilide 93 to generate the indole skeleton of 94 in 77% yield <07OL4737>. 

The efficient synthesis of racemic triphyophilline (60) paved the way for the first asymmetric total synthesis of the 5,1-linked napthylisoquinoline alkaloid (-)-ancistrocladine (1) (ref. 47). The approach once again relied on the successful intramolecular strategy used previously and required the development of asymmetric synthesis of the tetrahydroisoquinoline portion of 1. The route to isoquinoline segment 79 began with the synthesis of homochiral amphetamine derivative 83 via a reductive methylation protocol (Scheme 10) (ref. 54, 55) Thus, condensation of ketone 80 with (S)-... 

As intramolecular strategies minimize the problems of the poor regioselectivity obtained in intermolecular reactions, they are therefore more useful in synthesis. When the precursor radical is part of the chain connecting the arene, for example, substrate 7, the radical intermediate 8 is formed... 

The strategy of using intramolecular reactions to set up the correct relationslup between two groups is of more general importance. We obviously want to disconnect bonds a and b in TM 328 so that we add a four carbon fragment to PhOMe in the synthesis. 

A similar intramolecular Diels-Alder strategy was employed in an efficient synthesis to an appropriately functionalized hydrindanone nucleus (212). After functionalization, Diels-Alder cyclization, and appropriate functional group manipulation, this hydrindanone was converted into ( )-cortisone. The overall process afforded ( )-cortisone in a total of 18 chemical steps in approximately 3% yield. 

An intriguing application of Zincke processes occurred in Marazano s synthesis of dimeric, tetrameric, and even octameric pyridinium macrocycles, including cyclostellettamine B, a sponge-derived natural product. The same strategy produced a synthesis of haliclamine A (121, Scheme 8.4.41), a cytotoxic sponge metabolite. Intermediate 119, itself produced via a Zincke route, underwent an intramolecular Zincke reaction, providing macrocycle 120, which was reduced to the natural product. 

Intramolecular nucleophilic displacement reactions of aromatic nitro group by various nucleophiles include cydization reactions, which provide practical methods for the synthesis of a variety of heterocycles. 1 hope that the text of this review suggests a wide range of potential of this reaction in organic synthesis of various heterocycles. However, it is necessary to stress that some structural types described in this review could be prepared with similar, or even better yields by other methods. In spite of this, there are many heterocyclic systems for the synthesis of which the denitrocyclization strategy is a method of choice. 

The "acyl effect" proves crucial in the formation of the perhydroazulene systems cyclization can only take place with the presence of an acyl group on the TMM portion whereas the parent hydrocarbon fails. For example, treatment of substrate (51) with the palladium catalyst gave a mixture of the bicyclic compounds (52) and (53) in 51% yield. The formation of endocyclic olefin (52) is presumed to occur when the first formed (53) was exposed to silica gel during purification [22]. This intramolecular cycloaddition strategy was utilized in a highly diastereoselec-tive preparation of a key intermediate (54) in the total synthesis of (-)-isoclavuker-in A (55) (Scheme 2.16) [21]. 

Double intramolecular S Ai reaction leads to a model bicyclic C-O-D-O-E ring, as shown in Eq 9 9 " Synthesis of a model 22-membered AEl-C-0-D ring of vancomycin using similar strategy has been reported Totiil synthesis of vancomycin has been accomplished by Nicolaon and coworkers ... 

Several elegant synthetic strategies have been devised for biotin (1) this chapter describes one of the total syntheses developed at Hoffmann-La Roche. This insightful synthesis employs a derivative of L-cysteine, a readily available member of the chiral pool,2 as the starting material, and showcases the powerful intramolecular nitrone-olefin [3+2] cycloaddition reaction. 

The elegant, enantiospecific synthesis of biotin (1) by Hoffmann-La Roche1 is based on a strategy that takes advantage of the powerful intramolecular nitrone-olefin cycloaddition reaction. Our analysis begins with model studies in which the straightforward conversion of L-cysteine (2) into aldehyde 3 (see Scheme 1) constitutes... 

Scheme 3. Overman s intramolecular Heck strategies for the synthesis of (-)-morphine (9).

The intramolecular Heck reaction presented in Scheme 8 is also interesting and worthy of comment. Rawal s potentially general strategy for the stereocontrolled synthesis of the Strychnos alkaloids is predicated on the palladium-mediated intramolecular Heck reaction. In a concise synthesis of ( )-dehydrotubifoline [( )-40],22 Rawal et al. accomplished the conversion of compound 36 to the natural product under the conditions of Jeffery.23 In this ring-forming reaction, the a-alkenylpalladium(n) complex formed in the initial oxidative addition step engages the proximate cyclohexene double bond in a Heck cyclization, affording enamine 39 after syn /2-hydride elimination. The latter substance is a participant in a tautomeric equilibrium with imine ( )-40, which happens to be shifted substantially in favor of ( )-40. 

Our strategy is based on the premise that the 31-membered ring and the conjugated triene array of the natural product could be fashioned simultaneously by a tandem inter-/intramolecular Stille coupling. Moreover, the mild conditions under which Stille couplings can be performed fueled hopes that the crucial stitching cycliza-tion could be conducted on a fully deprotected seco bis(vinyl iodide) (see 145, Schemes 40 and 54) the stitching cyclization would thus be the final operation in the synthesis. 

The intramolecular Michael addition11 of a nucleophilic oxygen to an a,/ -unsaturated ester constitutes an attractive alternative strategy for the synthesis of the pyran nucleus, a strategy that could conceivably be applied to the brevetoxin problem (see Scheme 2). For example, treatment of hydroxy a,/ -unsaturated ester 9 with sodium hydride furnishes an alkoxide ion that induces ring formation by attacking the electrophilic //-carbon of the unsaturated ester moiety. This base-induced intramolecular Michael addition reaction is a reversible process, and it ultimately affords the thermodynamically most stable product 10 (92% yield). 

For that reason an intramolecular benzannulation was developed, which incorporates all components for the intramolecular alkoxycarbonylation into the naphthoquinone 105 [65]. Based on that strategy a short and convergent pathway for the synthesis of racemic deoxyfrenolicin 108 was accomplished. Xu et al. replaced the allylacetylene 100 in the reaction sequence for nanaomycin A by alkynoate 106. The benzannulation product 107 was an appropriate precursor for a subsequent tandem oxa-Pictet-Spengler cyclisation/DDQ-induced coupling reaction [66]. Following this strategy the total synthesis of enan-tiomerically pure deoxyfrenolicin could be accomplished (Scheme 48). 

The selectivity for two-alkyne annulation can be increased by involving an intramolecular tethering of the carbene complex to both alkynes. This was accomplished by the synthesis of aryl-diynecarbene complexes 115 and 116 from the triynylcarbene complexes 113 and 114, respectively, and Danishefsky s diene in a Diels-Alder reaction [70a]. The diene adds chemoselectively to the triple bond next to the electrophilic carbene carbon. The thermally induced two-alkyne annulation of the complexes 115 and 116 was performed in benzene and yielded the steroid ring systems 117 and 118 (Scheme 51). This tandem Diels-Alder/two-alkyne annulation, which could also be applied in a one-pot procedure, offers new strategies for steroid synthesis in the class O—>ABCD. 

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