An Intramolecular Strategy

In a retrosyntbetic analysis, the choice of Level 1 or 2 intramolecular cyclization reactions can be important in choosing a disconnection. In an interactive approach, observation of such processes, which maximize simplification in the retrosyntbetic direction and allow facile bond-formation in the synthetic direction, are essential. 

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Such an intramolecular strategy was initially tested employing alkyl-substituted methylenecyclopropanes bearing a terminal acrylate ester moiety within the substituent, e.g. 4-(2-methyl-enecyclopropyl)butyl propenoate (3). This compound reacts completely within four hours to yield the bicyclic lactone 4 when (t -allyl)(t/ -cyclopentadienyl)palladium (5 mol %) is employed at 144°C. ° ... 

It will be easy to put in bond a because it is para to the MeO group, but bond b might be difficult Tire strategy is to put in bond a first and use an intramolecular reaction to force bond b to go in the right place. Succinic anhydride is a convenient four carbon electrophile ... 

This starting material A (also 224A) is an isomer of the ketone we made in fi ame 328, and is easy to make using the intramolecular strategy of that fi ame ... 

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. 

A more practical solution to this problem was reported by Larson, in which the amide substrate 20 was treated with oxalyl chloride to afford a 2-chlorooxazolidine-4,5-dione 23. Reaction of this substrate with FeCL affords a reactive A-acyl iminium ion intermediate 24, which undergoes an intramolecular electrophilic aromatic substitution reaction to provide 25. Deprotection of 25 with acidic methanol affords the desired dihydroisoquinoline products 22. This strategy avoids the problematic nitrilium ion intermediate, and provides generally good yields of 3-aryl dihydroisoquinolines. 

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. 

A new strategy for the syntheas of oxide-containing fragments of morphine has been developed. Thus, the tricyclic (ANO) morphine fragment 45 was obtained as the sole product via an intramolecular radical cyclization. The tetracyclic (ACNO) fragment 46 was synthesized in a similar fashion starting from 5,6,7,8-tetrahydroisoquinoline <96T10935>. 

Recently, a new multicomponent condensation strategy for the stereocontrolled synthesis of polysubstituted tetrahydropyran derivatives was re-published by the Marko group, employing an ene reaction combined with an intramolecular Sakurai cyclization (IMSC) (Scheme 1.14) [14]. The initial step is an Et2AlCl-promoted ene reaction between allylsilane 1-50 and an aldehyde to afford the (Z)-homoallylic alcohol 1-51, with good control of the geometry of the double bond. Subsequent Lewis acid-media ted condensation of 1-51 with another equivalent of an aldehyde provided the polysubstituted exo-methylene tetrahydropyran 1-53 stereoselectively and... 

Kraus has reported the synthesis of a tricyclic indole related to the pyrroloiminoquinone marine natural products (Scheme 10.9), in which an intramolecular SNAr and the reductive cyclization of a nitro aldehyde are involved as key steps.94 Related target compounds have been prepared by Joule and coworkers via a similar strategy.95... 

Scolastico s approach toward functionalized azabicycloalkane amino acids such as 407 using an intramolecular 1,3-dipolar cycloaddition strategy is a powerful way of synthesizing the linear system with good regio- and stereo-control (Equation 110) <2005JOC4124>. 

As described above, our synthetic strategy involves the convergent construction of the central cyclopentanone ring with a carbonylative cross-coupling reaction and a photo-Nazarov cyclization reaction (Chart 2.2). The electrophilic coupling component 51 was synthesized by an intramolecular Diels-Alder reaction [34] and the nucleophilic coupling component 52 by a vinyiogous Mukaiyama aldol reaction [35]. 

We commenced our own approach toward ( )-phomactin A with an intent to feature an oxa-[3 + 3] annulation strategy [24—28] that was developed in our lab [29-32] and, in particular, an intramolecular annulation. While oxa-[3 + 3] annulations or related reaction manifolds [33, 34] are known and can be traced back more than six decades [35], an intramolecular variants of this reaction were not known [24—28]. There were no applications of intramolecular oxa-[3 + 3] annulations in natural product synthesis [27, 28, 36] until our approach toward phomactin A was disclosed. Subsequently, an account toward ( )-likonide B was reported by Trauner [36e],... 

Although Wender s synthesis was completed prior to Hudlicky s, it was published later [65]. It utilized the technique of mefa-photocycloaddition of arenes that Wender developed into a general method of synthesis for both angular and linear triquinanes. The overall strategy was centered around an intramolecular Diels-Alder cycloaddition for construction of the internal six-membered ring of the target. 

The synthesis of the D-gulonolactam 36 was based on an intramolecular cyclisation /ring enlargement strategy involving reduction of the azido group in 35 followed by intramolecular nucleophilic attack on the lactone moiety to afford 36 in excellent yield <06T7455>. 

Another microwave-mediated intramolecular SN2 reaction forms one of the key steps in a recent catalytic asymmetric synthesis of the cinchona alkaloid quinine by Jacobsen and coworkers [209]. The strategy to construct the crucial quinudidine core of the natural product relies on an intramolecular SN2 reaction/epoxide ringopening (Scheme 6.103). After removal of the benzyl carbamate (Cbz) protecting group with diethylaluminum chloride/thioanisole, microwave heating of the acetonitrile solution at 200 °C for 2 min provided a 68% isolated yield of the natural product as the final transformation in a 16-step total synthesis. 

For the development of an appropriate strategy for cleavage from the novel syringaldehyde resin, the authors adapted a previously elaborated solution-phase model study on intramolecular Diels-Alder reactions for the solid-phase procedure (Scheme 7.60). The resulting pyridines could be easily separated from the polymer-bound by-products by employing a simple filtration step and subsequent evaporation of the solvent. The remaining resins were each washed and dried. After drying,... 

The same author used this strategy to synthesize tricydic taxoid skeletons 55, an intramolecular Diels-Alder approach that proceeds in the direction from left to right (ring A to BC) (Scheme 9.14) [56], Once again, microwave irradiation was necessary to perform the required cycloaddition in good yield. 

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