Cycloaddition precursor cycloadducts

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. 

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. 

The use of preformed enolsilane derivatives for generating oxyallyl cation species not only allows reactions to proceed at higher rates and lower temperatures, but also provides cycloaddition precursors of a controlled constitution and defined enol ether geometry, which would impact the reaction stereochemical outcome. The generation and cycloaddition of a lithium oxyallyl from dichloroketone 12 results in all four possible diastereomeric cycloadducts... 

The cycloaddition precursor 227 was prepared by alkylation and decarboxylation of enantiomericaUy pure (3-ketoester 225, which led to ketone 226. Chlorination of 226 was accomplished by quenching the corresponding lithium enolate with triflic chloride to afford a-chloroketone 227. Without purification, a-chloroketone 227 was treated with triethylamine in a solution of 2,2,2-trifluoroethanol and ethyl ether (1 1 mixture). This gave cycloadduct 230 as a 25 1 mixture of isomers in 74% yield from 227 after treatment of 229 with tosic acid. The exquisite stereoselectivity can be rationalized from diene endo attack on the face opposite of the methyl-bearing stereocenter of the cyclic oxyaUylic cation 228. Cycloadduct 230 was then subsequently converted into (+)-dactylol 224 over several steps. 

Dienamines undergo 1,4 cycloaddition with sulfenes as well as 1,2 cycloaddition. For example, l-(N,N-diethylamino)butadiene (111), when treated with sulfene (generated from methanesulfonyl chloride and triethyl-amine), produces 1,4 cycloadduct 116 in an 18 % yield and di-1,2-cycloadduct 117 in a 60 % yield (160). Cycloadduct 116 was shown not to be the precursor for 117 by treating 116 with excess sulfene and recovering the starting material unchanged (160). This reaction probably takes place by way of zwitterion 115, which can close in either a 1,4 or 3,4 manner to form cycloadducts 116 and 118, respectively. The 3,4 cycloaddition would then be followed by a 1,2 cycloaddition of a second mole of sulfene to form 117. Cycloadduct 117 must form in the 3,4 cycloaddition followed by a 1,2-cycloaddition sequence rather than the reverse sequence since sulfenes undergo cycloaddition only in the presence of an electron-rich olefinic center (159). Such a center is present as an enamine in 118, but it is not present in 119. 

The parent TMM precursor (1), now commercially available, has played a pivotal role in the execution of many synthetic plans directed at natural and unnatural targets. Reaction of (1) with 2-(methoxycarbonyl)cyclohexenone (14, R=C02Me) in the presence of palladium acetate and triethyl phosphite produced the adduct (15) in near quantitative yield. This cycloadduct is a critical intermediate in the total synthesis of a hydroxykempenone (16), a component of the defensive substances secreted by termites (Scheme 2.5) [12]. In accord with a previous observation by Trost that unactivated 2-cyclohexenone reacts poorly with TMM-Pd [13], the substrate (14, R=Me) was essentially inert in the cycloaddition. 

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. 

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. 

A pyran ring is formed in the intramolecular Diels-Alder cycloaddition of alkene-tethered enantiopure (lS,2R)-l,2-dihydroxycyclohexa-3,5-diene-l-carboxylic acid derivatives (derived from the biodihydroxylation of benzoic acid). For the three cases illustrated in Scheme 6.246, Mihovilovic and colleagues found that moderate to high yields of the desired cycloadducts could be obtained by exposing a solution of the precursor to microwave irradiation at 135-210 °C for extended periods of time... 

H)-furanones undergo efficient cycloadditions as oxa-enones 450). The cycloadducts have been successfully utilized as synthetic precursors for 8-valerolactones 473) (4.62) or for 2-cyclohexenones (4.63)474>. 

The synthesis of new 11-deoxyprostaglandin analogs with a cyclopentane fragment in the oo-chain, prostanoid 418, has been accomplished by a reaction sequence involving nitrile oxide generation from the nitromethyl derivative of 2-(oo-carbomethoxyhexyl)-2-cyclopenten-l-one, its 1,3-cycloaddition to cyclopenten-l-one and reductive transformations of these cycloadducts (459). Diastereoisomers of a new prostanoid precursor 419 with a 4,5,6,6a-tetrahydro-3aH-cyclopent[d isoxazole fragment in the oo-chain have been synthesized. Reduction of 419 gives novel 11-deoxyprostanoids with modified a- and oo-chains (460). 

Like alkenes, methoxyallene undergo [5 + 2]-cycloaddition with the oxidopyrylium ion formed from the precursor 254 and triethylamine. The allenic terminal C=C bond adds from its sterically less encumbered face to afford the [5 + 2]-cycloadduct [186],... 

Two other applications of catalyst 364, i.e. in cycloaddition reactions of a-substituted acroleins with dienes 374 and 376, have been depicted in equations 110 and 111237. Cycloadducts 375 and 377 have been used as precursors in the syntheses of cassiol and gibberellic acid, respectively. The use of catalysts 364 and 369b in cycloadditions with acrolein resulted in low enantioselectivities with opposite face selectivities. 

A diastereoselectivity of 85% was obtained in the reaction of 494 with chiral diene 508 (equation 148)307. This reaction showed once again the high reactivity of two unactivated reactants toward cycloaddition in the presence of chromium(O). Cycloadduct 509 was considered to be a model precursor for the convergent synthesis of the unusual sesterpene cerorubenol (510). 

The enantioselective catalytic 1,3-dipolar cycloaddition of linear or cyclic nitrones to enals was accomplished using the half-sandwich rhodium(III) complex S, Rc)-[(ri -C5Me5)Rh (/ )-Prophos (H20)](SbF6)2 as catalyst precursor [33, 34]. At —25°C, quantitative conversions to the cycloadducts, with up to 95% ee, were achieved (Scheme 10). The intermediate with the dipolarophile coordinated to the rhodium has been isolated and completely characterized, including the X-ray determination of its molecular structure [33, 34]. 

The same group expanded the scope of the aza-Diels-Alder reaction of electron-rich dienes to Brassard s diene 97 (Scheme 37) [60]. In contrast to Danishefsky s diene, it is more reactive, but less stable. Akiyama et al. found chiral BINOL phosphate (R)-3m (3 mol%, R = 9-anthryl) with 9-anthryl substituents to promote the [4 + 2] cycloaddition of A-arylated aldimines 94 and Brassard s diene 97. Subsequent treatment with benzoic acid led to the formation of piperidinones 98. Interestingly, the use of its pyridinium salt (3 mol%) resulted in a higher yield (87% instead of 72%) along with a comparable enantioselectivity (94% ee instead of 92% ee). This method furnished cycloadducts 98 derived from aromatic, heteroaromatic, a,P-unsaturated, and aliphatic precursors 94 in satisfactory yields (63-91%) and excellent enantioselectivities (92-99% ee). NMR studies revealed that Brassard s diene 97 is labile in the presence of phosphoric acid 3m (88% decomposition after 1 h), but comparatively stable in the presence of its pyridinium salt (25% decomposition after 1 h). This observation can be explained by the fact that the pyridinium salt is a weak Brpnsted acid compared to BINOL phosphate 3m. 

The stmctural complexity and biological activity of the cyathane family of diterpenes has stimulated considerable interest from synthetic chemists, as reflected in the number and diversity of approaches reported thus far [42]. Our own strategy for cyathane synthesis is based on a rhodium-catalyzed [5+2] cycloaddition. The precursor for this reaction was fashioned ultimately from commercially available and inexpensive (S)-(-)-limonene. Treatment of the ketone 139 with 5 mol% [RhCl(CO)2]2 in 1,2-dichloro-ethane gave cycloadduct 140 (Scheme 13.14) in 90% yield and in analytically pure form after simple filtration through a plug of neutral alumina [43]. 

Methylene-6-phenyl-2-trichloromethyl-5,6-dihydro-4i/-l,3-oxazine 137 proved applicable as a precursor for a 2-acylamino-l,3-diene as a Diels-Alder cycloaddition partner. Treatment of 137 with DMAD in the presence of Zn(OTf)2 (0.2 equiv) in toluene at 100 °C provided cycloadduct 138 in 57% yield after 2 days (Equation 13) <2006OL3537>. 

The acyclic precursor is an oc, 3-unsaturated amido aldehyde that was condensed with iV-methylhydroxylamine to generate the nitrone ( )-48, which then underwent a spontaneous cycloaddition with the alkene to afford the 5,5-ring system of the isoxazolidinyl lactam 47. The observed product arises via the ( )-nitrone transition state A [or the (Z)-nitrone equivalent] in which the position of the benzyl group ot to the nitrone effectively controls the two adjacent stereocenters while a third stereocenter is predicted from the alkene geometry. Both transition states maintain the benzyl auxiliary in an equatorial position and thus avoid the unfavorable 1,3-diaxial interaction with the nitrone methyl or oxygen found in transition state B. Semiempirical PM3 calculations confirm the extra stability, predicting exclusive formation of the observed product 47. Related cycloadducts from the intramolecular reaction of nitrones containing ester- rather than amide-tethered alkene functionality are also known (83-85). 

Grigg et al. (34) also conducted extensive studies of the thermal 1,2-prototropic generation of azomethine ylides and this can be exemplihed by the diastereofacially selective cycloaddition of 7-aminocephalosprin ylide precursors. Condensation of aryl aldehydes with 120, in refluxing toluene, furnished imines 121, which, in the presence of A -phenylmaleimide, furnished a mixture of cycloadducts 122 and 123 in essentially quantitative yield in a 2 1 ratio. The only observed products... 

In synthetic efforts toward the DNA reactive alkaloid naphthyridinomycin (164), Gamer and Ho (41) reported a series of studies into the constmction of the diazobicyclo[3.2.1]octane section. Constmction of the five-membered ring, by the photolytic conversion of an aziridine to an azomethine ylide and subsequent alkene 1,3-dipolar cycloaddition, was deemed the best synthetic tactic. Initial studies with menthol- and isonorborneol- tethered chiral dipolarophiles gave no facial selectivity in the adducts formed (42). However, utilizing Oppolzer s sultam as the chiral controlling unit led to a dramatic improvement. Treatment of ylide precursor 165 with the chiral dipolarophile 166 under photochemical conditions led to formation of the desired cycloadducts (Scheme 3.47). The reaction proceeded with an exo/endo ratio of only 2.4 1 however, the facial selectivity was good at >25 1 in favor of the desired re products. The products derived from si attack of the ylide... 

At about the same time, Wenkert and c-workers (75) reported a similar smdy into the intramolecular 1,3-dipolar cycloaddition of 2-alkenoyl-aziridine derived azomethine ylides. Thermolysis of 231 at moderate temperature (85 °C) produced 232 as a single isomer in 58% yield. Similarly, 233 furnished 234 in 67% yield. In each case, the same stereoisomers were produced regardless of the initial stereochemistry of the initial aziridine precursors. However, the reaction proved to be sensitive to both the substituents of the aziridine and tether length, as aziridines 235 and 236 furnished no cycloadducts, even at 200 °C (Scheme 3.79). 

Lil in EtOAc, which underwent subsequent ylide formation and cycloaddition in AC2O, furnished the desired cycloadduct 318 in reasonable yield with concomitant loss of the silyl group. The reaction proved to be general, with a range of products (319-322) being synthesized from the corresponding acid precursors. The presence of the silyl group appears to be essential to the reaction, since its replacement with other functionalities led to a distinct reduction in reaction efficiency (Scheme 3.106). 

Harwood and co-workers (105) utihzed a phenyloxazine-3-one as a chiral derived template for cycloaddition (Scheme 4.50). An oxazinone template can be formed from phenylglycinol as the template precursor. The diazoamide needed for cycloaddition was generated by addition of diazomalonyl chloride, trimethyl-dioxane-4-one, or succinimidyl diazoacetate, providing the ester, acetyl, or hydrogen R group of the diazoamide 198. After addition of rhodium acetate, A-methylmaleimide was used as the dipolarophile to provide a product that predominantly adds from the less hindered a-face of the template in an endo fashion. The cycloaddition also provided some of the adduct that approaches from the p-face as well. p-Face addition also occurred with complete exo-selectivity. Mono- and disubstituted acetylenic compounds were added as well, providing similar cycloadducts. 

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