Cycloaddition precursor

The total synthesis of biotin (1) described in this chapter provides an impressive example of the intramolecular nitrone-olefin [3+2] cycloaddition reaction. Aiming for a practical process, the Hoff-mann-La Roche group utilized relatively simple and inexpensive starting materials, and ingeniously controlled the crucial [3+2] cycloaddition reaction to give only one stereoisomer by confining the cycloaddition precursor to a ten-membered ring. 

Ketone rac-13 was transformed into the corresponding silylenolether and by Pd(II)-mediated Saegusa oxidation [14] into a, -unsaturated ketone rac-14. By alkylative enone transposition comprising methyl lithium addition and pyridinium chlorochromate (PCC) oxidation [15], rac-14 was finally converted into the racemic photo cycloaddition precursor rac-6. In conclusion, the bicyclic irradiation precursor rac-6 was synthesized in a straightforward manner from simple 1,5-cyclooctadiene (11) in nine steps and with an overall yield of 21%. 

Over the last 15 years, Padwa et al. (73,74) have been heavily involved with the study and application of carbonyl ylides as cycloaddition precursors in synthesis. Their work has helped make the tandem ylide formation-dipolar cycloaddition process a synthetically accessible transformation. Much of Padwa s early work focused on determining the extent and limitations of this methodology. Many of the early systems were carbocyclic in nature and helped define basic parameters such as... 

Dauben s group utilized the same retrosynthetic disconnections, but chose to add more functionality to the cycloaddition precursor. From a simple frawi-disubstituted cyclopentane, Dauben used an aldol reaction of a cyclopropylvinyl aldehyde to prepare the cycloaddition precursor. The diazo-substituted (3-ketoester was completed using a Roskamp-Padwa coupling followed by diazo-transfer. Addition of rhodium acetate to the diazo substituted p-ketoester 179 led to an excellent 86% yield of the correct diastereomer (Scheme 4.42). 

Padwa and co-workers (60,106,107) have been highly active in using carbonyl ylides for the synthesis of a number of bioactive alkaloids (Scheme 4.51). In an approach to the aspidosperma alkaloids, a push-pull carbonyl ylide was used to generate a bicyclic ylide containing a tethered indole moiety. This strategy ultimately allowed for the synthesis of the dehydrovindorosin skeleton (108). Starting from a quaternary substimted piperidone (200), elaboration of the 3-carboxylic acid provided p-ketoester amide 201. Addition of the indole tethered side chain provided a very rapid and efficient method to generate the cycloaddition precursor 203. 

Friedrichsen and co-workers (133) approached substituted benzotropolones from an aromatic substituted carbonyl ylide with a tethered alkyne as the intramolecular dipolarophUe (Scheme 4.67). Starting from an aromatic anhydride, Friedrichsen was able to make the tethered alkyne via addition of either pentyn-ol or hexyn-ol, then transform the recovered benzoic acid to the a-diazocarbonyl cycloaddition precursor. Addition of rhodium acetate resulted in the tandem formation of cyclic carbonyl ylide followed by cycloaddition of the tethered alkyne producing the tricyclic constrained ether 252. Addition of BF3 OEt2 opened the ether bridge, forming the benzotropylium ion, which subsequently rearranged to form the tricyclic benzotropolone (253). 

Finally, in a very recent disclosure, Lee et al. (165) approached the total synthesis of arteminolide using a [5 + 2] cycloaddition strategy with an oxidopyrylium ion. Despite its long history of use, Lee was the first to utilize an allene moiety both in an intra- and an intermolecular cycloaddition with oxidopyrylium ions. By utilizing a pyrone cycloaddition precursor (294) similar to those used in the Wender phorbol synthesis, Lee was able to synthesize various ring sizes and... 

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... 

D.R. Williams et al. successfully synthesized the AB ring system of norzoanthamine by the intramolecular DIels-Alder cycllzatlon of an ( )-1-nitro-1,7,9-decatriene. The key transformation for establishing the quaternary stereocenter at C12 in the cycloaddition precursor was the Eschenmoser-Clalsen rearrangement. 

The total synthesis of (+)-cyclophellitol containing a fully oxygenated cyclohexane ring was accomplished by T. Ishikawa and co-workers. The synthetic strategy was based on the intramolecular silyl nitronate [3+2] cycloaddition reaction. The cycloaddition precursor was prepared by the Henry reaction starting from a D-glucose-derived aldehyde. 

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. 

In the laboratory of A. Padwa, a novel synthetic approach to the fully functionalized core of lysergic acid was developed utilizing an intramolecular isomunchone cycloaddition pathway. The key cycloaddition precursor diazo imide was prepared using the standard Regitz diazo tranter conditions. The diazo imide then was heated with catalytic amouts of rhodium(ll)-perfluorobutyrate in dichloromethane to afford the desired cycloadduct as a single diastereomer and in excellent yield. The only reason the authors were not able to complete the total synthesis of lysergic acid was that they could not affect the isomerization of the double bond between the two six-membered rings. 

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. 

Enders described a fascinating organocatalytic one-pot asymmetric synthesis of tricyclic compounds using a triple-cascade/Diels-Alder reaction sequence. Combination of dieneal 110 with enal 111 and nitro alkene 112 in the presence of a chiral amine catalyst results in a Michael/Michael/aldol condensation sequence to yield cycloaddition precursor 113. Cooling the reaction mixture and addition of a Lewis acid promotes the desired intramolecular Diels-Alder reaction to selectively afford the highly functionalized tricyclic target 114. ... 

Nitrogen-containing heterocycles are also available via intramolecular hetero Diels-Alder reactions. Williams employed an aza diene to prepare a complex polycyclic synthetic intermediate in his synthesis of versicolamide B. Boger reported a tandem intramolecular hetero Diels-Alder/l,3-dipolar cycloaddition sequence for the synthesis of vindorosine. Cycloaddition precursor 137 undergoes an inverse electron demand Diels-Alder reaction to yield 138. This compound decomposes via a retro dipolar cycloaddition to generate nitrogen gas and a 1,3-dipole that completes the cascade by reacting with the indole alkene to afford 139. Seven more steps enable the completion of vindorosine. ... 

One application of this reaction was in the synthesis of yohimban 11.17 (Scheme 11.6). The cycloaddition precursor 11.14 could be easily built up from tryptamine 11.13 and the cyclization employed a nickel/phosphite catalyst system. Selective reduction of the less-hindered alkene, protio-desilylation and a Bischler-Napieralski reaction gave the desired pentacyclic system 11.16. Reduction of the remaining alkene gave yohimban 11.17... 

Deprotection of the silyl ether followed by a Swem oxidation of the alcohol 46 provided the aldehyde. Subsequent condensation with aminoaziridine B in MeOH afforded allenyl aziridinyUmine 40, the cycloaddition precursor (Scheme 12). 

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