Cycloaddition strategies

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]. 

Scheme 6. Vollhardt s tandem alkyne cyclotrimerization/o-quinodimethane cycloaddition strategy for polycycle synthesis.

Finally, many [4+2] cycloaddition strategies utilizing various substituted thiophenes as dienes have been reported. The reaction between 2-(prop-l-enyl)-l-benzo[fo]thiophene and 3-chlorocyclobut-3-ene-l,2-dione followed by bromination and loss of HBr gives a... 

FIGURE 4.36 A diastereoselective cycloaddition strategy for (+ )-berkelic acid 69. 

Huang, Y. Pettus, T. R. R. A cycloaddition strategy for use toward berkelic acid, a MMP inhibitor and potent anticancer agent displaying a unique chroman spiroketal motif. Synlett 2008, 1353-1356. 

Hassner and coworkers have developed a one-pot tandem consecutive 1,4-addition intramolecular cycloaddition strategy for the construction of five- and six-membered heterocycles and carbocycles. Because nitroalkenes are good Michael acceptors for carbon, sulfur, oxygen, and nitrogen nucleophiles (see Section 4.1 on the Michael reaction), subsequent intramolecular silyl nitronate cycloaddition (ISOC) or intramolecular nitrile oxide cycloaddition (INOC) provides one-pot synthesis of fused isoxazolines (Scheme 8.26). The ISOC route is generally better than INOC route regarding stereoselectivity and generality. 

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>. 

Two possible intramolecular disconnections are available for the [2.2.2] bicyclo-octane ring system (path A and path B, Scheme 1.4). The choice between the initial [4+2] disconnections A and B at first appears inconsequential leading to idealized intermediates of comparable complexity (54 and 57). However, when the [4+2] and [3+2] disconnections are considered in sequence, the difference becomes clear. For path A, retrosynthetic [3+2] disconnection of intermediate 54 leads to the conceptual precursor 56, which embodies a considerable simplification. In contrast, path B reveals a retrosynthetic [3+2] disconnection of intermediate 57 to provide the precursor 59, a considerably less simplified medium-ring bridged macrocycle. Thus, unification of the [3+2]/[4+2] dual cycloaddition strategy, using the staging... 

The power of this tropylium ion cycloaddition strategy for the synthesis of complex molecules can be seen in synthesis of dactylol 231 by Feldman and coworkers (Scheme 52)111. Irradiation of 229 (prepared from 4-methyltropone in two steps) afforded... 

In a related area, a novel 1,3-dipolar cycloaddition strategy involving 1,2-isopropylidene furanoside-fused oxepane derivatives and 4-0-allyl nitrone or nitrile oxide species to give chiral oxepinopyran and oxepinooxepane systems has been described <00TL10135>. 

Intermolecular Reactions Intermolecular 1,3-dipolar cycloaddition reactions of nitrones to olefins seem to be the most studied. They are widely used for the synthesis of different enantiomerically pure compounds, including biologically active ones. For example, two new glycosidase inhibitors have been obtained by the nitrone cycloaddition strategy (Fig. 2.32) (733). 

Interestingly, the alkyne-oxazole Diels-Alder cycloaddition strategy provides a unique entry to some furyl stannanes [52]. Thus, thermolysis of bis(tributylstannyl)acetylene (50) and 4-phenyloxazole (51) led to a separable mixture of 3,4-bis(tributylstannyl)furan (52, 19% yield) and 3-tributylstannylfuran (53, 23% yield). 

Probably the best alternative to the present procedure, in terms of generality, is the use of a cycloaddition strategy that can give access to a wide range of different sized spirocyclic molecules.14... 

The [3+2] cycloaddition strategy provides an effective method to access valuable intermediates for the construction of biologically important alkaloids, amino acids, amino carbohydrates and P-lactams [58-62]. The reaction involves the concerted pericyclic addition of a dipole and a dipolarophile and considerable efforts have been made to render these reactions asymmetric nsing Lewis acid catalysis and chiral anxiliaries [63]. 

A diverse range of heterocycles and other chiral building blocks that can be generated by this cycloaddition strategy ... 

Pirrung [153] has described the synthesis of ( )-pongomol 66 via the rhodium(II)-mediated reaction of the diazacyclohexane dione 67, to afford the fused bicyclic ketone 68 (Scheme 19.8). Moreover, this group [154] also detailed a similar approach in their synthesis of ( )-isoeuparin 69 (Scheme 19.9). Pirrung and Lee [155] expanded their rhodium(II)-mediated dihydrofuran cycloaddition strategy, for the conversion of the... 

Scheme 17 Synthesis of cyclic peptidomimetics by sequential Zhu-3CR/azide-alkyne dipolar cycloaddition strategy...

The rare reports of quinolizidine formation by a nitrone cycloaddition strategy include the racemic total synthesis of lasubine II (58), one of a series of related alkaloid isolated from the leaves of Lagerstoemia subcostata Koehne (Scheme 1.14) (104). While these alkaloids were previously accessed by infennolecular nitrone cycloaddition reactions, this more recent report uses an intramolecular approach to form the desired piperidine ring. Thus, cycloaddition of nitrone 59 affords predominantly the desired bridged adduct 60 along with two related... 

A number of other simple cyclic amine targets with oxygen substitution have been prepared using a nitrone cycloaddition strategy to provide both the N- and 0-functionalities. These include the pyrrolidines darlinine 193 and analogues (248), (+)-preussin (194) (249) and the piperidines (—)-allosedamine (195) (250), and the related structure 196 (251) as well as analogous (3-aminoketones (Fig. 1.4) (252). 

Further examples of the endocychc nitrone route to spirocychc adducts are the total syntheses of (—)-histrionicotoxin (230) by Holmes and of cyhndricines by Weinreb. Histrionicotoxin is one of many spiropiperidine alkaloids isolated from the poison-arrow frog Dendrobates histrionicus and has been the subject of many attempted total syntheses by a nitrone cycloaddition strategy that failed to provide the desired regioisomer, possibly through unfavorable steric interactions (265-268). Unlike these reports, Holmes and co-workers (101) found that the intermolecular reaction of nitrone (231), prepared by the 1,3-APT of the corresponding alkynyl-hydroxylamine carrying Oppolzer s chiral sultam auxiliary, afforded the styrene... 

Padwa and co-workers (120-122) also utilized this carbonyl ylide cycloaddition strategy to advance to the aromatic pterosin family of compounds. The same intermediates used to approach the nonaromatic illudins and ptaqualosides are also useful for aromatic formation through cleavage and dehydration (Scheme 4.62). 

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... 

Ogawa et al. (12) used an intramolecular azide-alkene cycloaddition strategy to synthesize the oxygen-bridged aza[15]annulene 52 and the aza[15]annulene dicar-boxylate 55 (Scheme 9.12). 1,3-Dipolar cycloaddition of vinyl azide to the acrylate moiety followed by extrusion of nitrogen gave the aziridine 51. Rearrangement of 51 afforded the aza[15]annulene 52. The same approach was used to synthesize the aza[15]annulene 55. 

Vogel and Delavier (26) reported a synthesis of the 6-azabicyclo[3.2.2]nonane skeleton 130 using an intramolecular azide-alkene cycloaddition strategy (Scheme 9.26). When refluxed in xylene, the azide 126 underwent an intramolecular 1,3-dipolar cycloaddition with the internal alkene. Nitrogen extrusion and subsequent rearrangement led to a mixmre of compounds 128, 129, and 130. Reactions of azides with the double bond of dienes were also used in various total syntheses of alkaloids, and will be discussed later in Section 9.2.2. 

Robba and co-workers (71) synthesized the 2-azapyrrolo[l,2-a]indole ring system via a mtinchnone cycloaddition strategy (Scheme 10.22). Thus, trapping the mtinchnone derived from proline derivative 116 gave pyrrole 117 in 75% yield. Further elaboration yielded the desired 118 and subsequent target compounds. 

Padwa and co-workers (232,233) adapted their thioisomiinchnone generation-cycloaddition strategy to the synthesis of several tetrahydroisoquinoline alkaloids and the indolo[2,3-a]quinolizidine alkaloid alloyohimbane 333 (Scheme 10.44). 

Solid-phase library synthesis of triazolopyridazines via a [4+2] cycloaddition strategy has been accomplished <99TL619>. Intramolecular bis-Mannich reaction of 3-aryl-5-mercapto-13,4-triazole, formaldehyde and a-phenylethylamine yields chiral 5-aryltriazolo[3,4-ft]-[133]thiadiazine derivatives. These compounds have been screened for antibacterial activities and some of them show potent biological activity <99SC2027>. 

Since their introduction by Huisgen (see <1995H(40)1> and references therein), the 1,3-dipolar cycloaddition remains the single most powerful method for the construction of five-membered heterocycles. Literature examples of this approach in an inter- and intramolecular fashion for the assembly of nonconjugated examples of bicyclic 5-5 heterocycles with l 2-heteroatom orientation are common. Heterocycles with either [1,2,4], [1,2,5], or [1,2,6] heteroatom locants (204, 205, and 206, respectively) can be assembled utilizing this approach. The stereoelectronic aspects of the various cycloaddition strategies are not discussed here. 

Kociehski s group assembled the 3-lactone segment utilizing a Lewis acid-catalyzed [2 + 2] cycloaddition strategy. In the presence of a catalytic amount of boron trifluoride etherate, the [2 + 2] cycloaddition between aldehyde 28 and trimethylsilylketene 29 took place rapidly and cleanly to give a mixture of diastereomers of P-lactone 30. After a delicate desilylation and a flash chromatography, the desired diastereomer 31 was obtained in 55% yield. 

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