Cycloaddition precursor products

Another attractive method for E ring formation featured an intramolecular [2+3]cycloaddition of an azide moiety, emanating from the indole 3-position via a two-carbon linker, to, now, an electron-rich version of the C15-C16 double bond.19 The cycloaddition precursor 10 was made via 9, in turn assembled by regioselective cocylization of protected methoxyacetylene (Scheme 5). In a puzzling turn of events, thermolysis of the azide product in toluene at moderate temperature (to minimize nitrene formation) and in low concentration (to suppress intermolecular reactions) produced the two oxidized pentacyclic products 11 and 12 in a 2 1 ratio. Performing the reaction in a more polar solvent (DMF, 80 °C, 7 d) altered the ratio to 5 1.20... 

In the laboratory of S.F. Martin, a biomimetic approach toward the total synthesis of ( )-strychnine was developed by using tandem vinylogous Mannich addition and HDA reaction to construct the pentacyclic heteroyohimboid core of the natural product.The commercially available 4,9-dihydro-3/-/-P-carboline was first converted to the corresponding A/-acylium ion and then reacted with 1-trimethylsilyloxybutadiene in a vinyiogous Mannich reaction. The resulting cycloaddition precursor readily underwent the expected HDA reaction in 85% yield. 

The first natural product synthesized using the bis-heteroannulation strategy was evodone, a structurally simple member of the naturally occurring furanoterpenes. The synthesis began with commercially available 4-methyl-8-valerolactone 170, which was converted to the cycloaddition precursor 171 in fom steps (Fig. 3.52). 

Given the previously discussed examples of the [S-(-2] cycloaddition, one can imagine a variety of approaches to the synthesis of molecules like dictamnol. One which has found success is given in Scheme 8. The cycloaddition precursor is prepared in three steps fi om commercially available cyclopropanecarboxaldehyde. Cycloaddition of alcohol 68 proceeds in 69% yield to provide cycloadduct 70. The yield of the cycloaddition is improved to 80% by protecting the alcohol as a TBS ether (69), although the combined yield for cycloaddition and deprotection is 70%. With two additional steps from 70, dictanuiol (71a) was prepared in 10% overall yield, marking the first application of the metal-catalyzed [5+2] cycloaddition in natural product synthesis. 

Reaction of U-acetoxy-2-azetidinone (413) with siloxydienes (414), in the presence of zinc chloride, gives the displacement product (416) as the major component but low yields of cycloaddit ion products (415) are also obtained, making this a novel one-step synthesis of the carbacephalosporin framework from a monocyclic azetidinone precursor. Two other routes to the carbacepham system involving cyclization of monocyclic azetidinone intermediates have also appeared. Beckwith et al. have described a radical-induced ring closure of 4-phenylthioazetidinones (417) to afford cyclized... 

The anhydride of thiophene-2,3-dlcarboxylic acid is of interest as a precursor of 2,3-didehydrothiophene. Evidence for the generation of this elusive intermediate is obtained by the isolation of [4-1-2] and [2-1-2] cycloaddition products with dienes (81T4151). 

On the other hand, the corresponding tin precursor (63) undergoes smooth cycloaddition with a wide variety of aldehydes to produce the desired methylene-tetrahydrofnran in good yields [32, 33]. Thus prenylaldehyde reacts with (63) to give cleanly the cycloadduct (64), whereas the reaction with the silyl precursor (1) yields only decomposition products (Scheme 2.20) [31]. This smooth cycloaddition is attributed to the improved reactivity of the stannyl ether (65) towards the 7t-allyl ligand. Although the reactions of (63) with aldehydes are quite robust, the use of a tin reagent as precursor for TMM presents drawbacks such as cost, stability, toxicity, and difficult purification of products. 

A simple approach for the formation of 2-substituted 3,4-dihydro-2H-pyrans, which are useful precursors for natural products such as optically active carbohydrates, is the catalytic enantioselective cycloaddition reaction of a,/ -unsaturated carbonyl compounds with electron-rich alkenes. This is an inverse electron-demand cycloaddition reaction which is controlled by a dominant interaction between the LUMO of the 1-oxa-1,3-butadiene and the HOMO of the alkene (Scheme 4.2, right). This is usually a concerted non-synchronous reaction with retention of the configuration of the die-nophile and results in normally high regioselectivity, which in the presence of Lewis acids is improved and, furthermore, also increases the reaction rate. 

Due to the two electron-donating groups in the bicyclic product 150 and the unhydrolyzed precursor of 148, they should be quite reactive dienes in Diels-Alder reactions. However, such [4+2] cycloadditions were observed only for the cyclohexane-annelated cyclopentadienes 151b, which equilibrate with the more reactive isomers 154 by 1,5-hydrogen shifts (Scheme 33). The [4+2] cycload-... 

The Diels-Alder reaction of 2-vinylfurans 73 with suitable dienophiles has been used to prepare tetrahydrobenzofurans [73, 74] by an extra-annular addition these are useful precursors of substituted benzofurans (Scheme 2.29). In practice, the cycloadditions with acetylenic dienophiles give fully aromatic benzofurans directly, because the intermediate cycloadducts autoxidize during the reaction or in the isolation procedure. In the case of a reaction with nitro-substituted vinylbenzofuran, the formation of the aromatic products involves the loss of HNO2. 

If the attacking radical contains an adequately placed radical acceptor functionality, the possibility of a radical cycloaddition is provided, offering a procedure to construct cyclic products from acyclic precursors. For this type of ring-forming process, in which two molecular fragments are united with the formation of two new bonds, the term annulation has been adopted (Scheme 3.3). 

Malacria and coworkers [274] used an intermolecular trimerization of alkynes to gain efficient access to the skeleton of the phyllocladane family. Thus, the Co-cata-lyzed reaction of the polyunsaturated precursor 6/4-4 gave 6/4-5 in 42% yield. Here, six new carbon-carbon bonds and four stereogenic centers are formed. The first step is formation of the cyclopentane derivative 6/4-6 by a Co-catalyzed Conia-ene-type reaction [275] which, on addition o f his( Iri me ill y I si ly 1) e thy ne (btmse), led to the benzocyclobutenes 6/4-7 (Scheme 6/4.2). The reaction is terminated by the addition of dppe and heating to reflux in decane to give the desired products 6/4-5 by an electrocyclic ring opening, followed by [4+2] cycloaddition. 

Asymmetric 1,3-dipolar cycloaddition of cyclic nitrones to crotonic acid derivatives bearing chiral auxiliaries in the presence of zinc iodide gives bicyclic isoxazolidines with high stereoselectivity (Eq. 8.51). The products are good precursors of (3-amino acids such as (+)sedridine.73 Many papers concerning 1,3-dipolar cycloaddition of nitrones to chiral alkenes have been reported, and they are well documented (see Ref. 63). 

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