Cycloaddition precursor cycloadditions

Acylisocyanates or isothiocyanates undergo cycloaddition with 5-hydroxy-THISs under so mild conditions that isolation of the initial adducts becomes possible (23). In cycloaddition reactions the 5-hydroxy-THISs can be replaced by their precursors (23). 

Miscellaneous Reactions. Some hydantoin derivatives can serve as precursors of carbonium—immonium electrophiles (57). 5-Alkoxyhydantoins are useful precursors of dienophiles (17), which undergo Diels-Alder cycloadditions under thermal conditions or in the presence of acid catalysis (58). The pyridine ring of Streptonigrine has been constmcted on the basis of this reaction (59). 

Other approaches to (36) make use of (37, R = CH ) and reaction with a tributylstannyl allene (60) or 3-siloxypentadiene (61). A chemicoen2ymatic synthesis for both thienamycia (2) and 1 -methyl analogues starts from the chiral monoester (38), derived by enzymatic hydrolysis of the dimethyl ester, and proceeding by way of the P-lactam (39, R = H or CH ) (62,63). (3)-Methyl-3-hydroxy-2-methylpropanoate [80657-57-4] (40), C H qO, has also been used as starting material for (36) (64), whereas 1,3-dipolar cycloaddition of a chiral nitrone with a crotonate ester affords the oxa2ohdine (41) which again can be converted to a suitable P-lactam precursor (65). 

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). 

Cycloadditions resulting in ring-fused systems may be classified in two principal groups intramolecular and intermolecular cycloadditions. As the synthesis of the requisite precursor for an intramolecular cycloaddition is often more involved, more emphasis has been placed on those of an intermolecular nature. 

The chalcogene heterocycles have been used as stable precursors for sulfur-said selenium-cantaining hetero-l,3-dienes in cycloaddition reactions 3//-l,2,4-Thiaselenazoles are a convenient source of 4,4-bis(trifluoromethyl)-l-thia-3-aza-buta-1,3-dienes, and 3//-diselenazoles are a convenient source of 4,4-bis(trifluoromethyl)-l-selena-3-azabuta-l,3-dienes as well as bis(tnfluoro-methyl)-substrtuted nitrile ylides [137]... 

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. 

Contrary to the expectation that a sulfur-containing substituent will be a catalyst poison, a phenylthio group serves as an effective selectivity control element in TMM cycloadditions. A single regioisomer (30) was obtained from the carbonate precursor (31) in good yield. The thermodynamically more stable sulfide (32) is readily accessible from (30) via a 1,3-sulfide shift catalyzed by PhSSPh. A wide array of synthetically useful intermediates could be prepared from the sulfides (30) and (32) with simple transformations (Scheme 2.10) [20]. 

Intramolecular [3-1-2] cycloadditions, i.e., having the TMM moiety and the acceptor linked by a tether, have great synthetic utility in polycarbocycle construction. The construction of 5.5, 6.5, and 7.5 ring systems has been demonstrated with this methodology [21-25]. A number of efficient routes to acyclic precursors were developed (Scheme 2.11). The organometallic reagent (31), generated from 2-bro-mo-3-(trimethylsilyl)propene (32) [26], is a key component in the construction of... 

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. 

Substituted TMM complexes also cycloadd to aldehydes in the presence of a tin cocatalyst such as MesSnOAc and MesSnOTs [31]. Reaction of 2-heptenal with methyl precursor (6) gave a mixture of methylenetetrahydrofurans (68) and (69). This regioselectivity is reversed with 10-undecenal and methyl precursor (5), where adduct (70) now predominates over (71). As in the carbocyclic system, the phenylthio group also functions as a regiocontrol element in reaction with cyclohexyl aldehyde. The initially formed adduct (72) eliminates the element of thio-phenol on attempted allyl rearrangement, and the overall process becomes a cycloaddition approach to furans (Scheme 2.21) [20]. 

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. 

In a more recent publication the same group mentions that Ag(I) salts in combination with chiral phosphine ligands can catalyze the 1,3-dipolar cycloaddition involving the azomethine precursor 64b and methyl vinyl ketone (Scheme 6.43) [87]. The reaction, which presumably also required a stoichiometric amount of the catalyst, proceeds to give 65b in a good yield with 70% ee. 

Gratifyingly, when compound 24 is refluxed in a solution of toluene at 110°C, it undergoes quantitative [4+2] cycloaddition to polycyclic system 25. The indicated stereochemistry of 25 was anticipated on the basis of the trans,trans geometry of the phenyl-diene system in precursor 24 and the presumed preference for an exo transition state geometry. These assumptions were vindicated by the eventual conversion of 25 to endiandric acids A (1) and B (2). 

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. 

Trifluoromethyl-l,2,4-triazines and 1,2,4-triazin-5-ones are versatile precursors for azetidines and pyridines by cycloaddition reactions. Enhancement of reactivity was observed through the presence of the trifluor-omethyl group (88CPB3354). 

A novel guanidinium ylide-mediated procedure has recently been reported by Ishi-kawa [62]. Though not an imine transformation, it does employ an imine precursor in the fonn of an aldehyde. Guanidinium ylides react with aldehydes to form aziridines (Scheme 1.35). The mechanism for the formation of the aziridine is believed to involve [3+2] cycloaddition between the guanidinium ylide 112 and the aldehyde, followed by stereospecific extrusion of the urea with concomitant aziridine formation. 

Although the yields of the above reactions are high and the procedure is simple186, there are some apparent disadvantages the selection of the sulfene substituents R1 and R2 is limited, depending on the availability of the sulfonyl chloride precursors the cycloaddition leads to a mixture of cis- and trans-substituted thietane dioxides the cycloaddition reaction is reversible202 and several further transformations are necessary if a dioxide without 3-lV-substituent is required. 

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-... 

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