Stereoselectivity intramolecular cycloadditions

Intramolecular cycloadditions of substrates with a cleavable tether have also been realized. Thus esters (37a-37d) provided the structurally interesting tricyclic lactones (38-43). It is interesting to note that the cyclododecenyl system (w = 7) proceeded at room temperature whereas all others required refluxing dioxane. In each case, the stereoselectivity with respect to the tether was excellent. As expected, the cyclohexenyl (n=l) and cycloheptenyl (n = 2) gave the syn adducts (38) and (39) almost exclusively. On the other hand, the cyclooctenyl (n = 3) and cyclododecenyl (n = 7) systems favored the anti adducts (41) and (42) instead. The formation of the endocyclic isomer (39, n=l) in the cyclohexenyl case can be explained by the isomerization of the initial adduct (44), which can not cyclize due to ring-strain, to the other 7t-allyl-Pd intermediate (45) which then ring-closes to (39) (Scheme 2.13) [20]. While the yields may not be spectacular, it is still remarkable that these reactions proceeded as well as they did since the substrates do contain another allylic ester moiety which is known to undergo ionization in the presence of the same palladium catalyst. 

Intramolecular cycloadditions of furans are a useful method for creating an oxygenated cyclohexane ring in rigid cycloadducts. Thus, a MeAICI2-catalyzed intramolecular reaction [40] of compounds 34 leads stereoselectively to tricyclic cycloadducts (Equation 3.8). The reaction yield is strongly dependent on the quantity of the catalyst and the type of substituent at the olefmic double bond. Cycloadduct 35 (R = R2 = Me, Ri = R3 = R4 = H) was then converted [40b] into 1,4-epoxycadinane (36). 

The 2-azadiene system of the pyrazinone scaffold undergoes inter- and intramolecular cycloaddition reactions with a variety of (functionalized) alkenes forming bicyclic adducts, leading to the stereoselective generation of a variety of natural product analogues as well as peptidomimetics [58]. These bicyclic compounds could serve as key intermediates in the synthesis... 

Keywords Intramolecular 1,3-dipolar cycloadditions. Stereoselectivity, Nitrile oxides, SUyl nitronates. Oximes, H-Nitrones, Azides, NitrUimines... 

The intramolecular cycloaddition of the norbornadiene-tethered nitrile oxides 110 (Eq. 11 and Table 11) was reported to be highly regio- and stereoselective, providing the exo cycloadduct 111 as the exclusive product out of the four possible regio/stereoisomers [36]. The cycloadduct 111 provides a stereoselective entry into tricyclic (e.g., 112) and spirocyclic (e.g., 113) frameworks. 

Oppolzer and Robbiani have reported highly stereoselective total syntheses of alkaloids such as chelidonine by an intramolecular o-quinodimethene/nitrostyrene-cycloaddition (Scheme S.7).34 (Benzocyclobutane is used as a source of quinodimethene). The high regio- and stereoselectivity in the intramolecular cycloaddition is remarkable a strong preference for transition state, exo-N02, over transition state, emfo-N02, is responsible for the stereoselectivity. 

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. 

Highly stereoselective intramolecular cycloadditions of unsaturated N-substituted azomethine ylides have been conducted under microwave irradiation. Oritani reported that a mixture of the aldehyde 137 and N-methyl- or N-benzylglycine ethyl ester (138) on the surface of silica gel, irradiated under microwaves for 15 min, generated azomethine ylides 139 that subsequently underwent in situ intramolecular cycloadditions to afford the corresponding tricyclic compounds 140 in 79 and 81% yield, respectively (Scheme 9.42) [93],... 

In agreement with Schemes 2.211b and 2.211c, intramolecular cycloadditions of nitrones to 5-allyl- (Scheme 2.225) or 5-homoallylproline (Scheme 2.226), are fully regio- and stereoselective. These reactions are the key steps in the synthesis of functionalized azaoxobicyclo[X.3.0] alkane amino acids, mimics of a homoSer-Pro dipeptide (721). 

When choosing a concrete scheme for the synthesis of a complicated substrate in terms of the strategy proposed by Prof. Denmark, not only the characteristic features of the target product but also other factors should be taken into account. As a mle, intramolecular cycloaddition reactions proceed more easily and are characterized by higher stereoselectivity, but the starting substrates are much more difficult to synthesize. 

A trihydroxyindolizidine lactone is obtained by elaboration of an isoxazolidine synthesized by a domino stereoselective retrocycloaddition/intramolecular cycloaddition process of an enantiopure pyrroline-iV-oxide <2006TA292>. 

The intramolecular cycloaddition of phenol derivatives can lead stereoselectively to three different product types (Fig. 50) [257-259]. The competition of the three pathways depends strongly on the configuration of the double bond and the nature of the functional groups attached to it. The different products can be formed quite selectively [260] the synthetic possibilities have been summarized in Ref [261]. 

Bicyclopropylidene (1) does not undergo an intermolecular Diels-Alder reaction with furan and 2-methoxyfuran even under high pressure. Intramolecular cycloadditions of compounds 160 with a furan tethered to bicyclopropylidene, however, were easily brought about under high pressure (10 kbar) and gave cycloadducts 161 stereoselectively in yields ranging from 32 to 95% (Scheme 35) [58]. 

Depending on the size of the forming cycle, alkenylnitrones (e.g. 168, equation 108) undergo intramolecular cycloaddition with high regio- and stereoselectivity ... 

The combination of the geometrical preference of the tether and the stereochemical preference of the dipolarophile substituent can be seen in the intramolecular cycloadditions of alkyl nitronates, (Scheme 2.6) (99). When the tether is restricted to two atoms, only the endo approach of the tether is observed in up to a 100 1 ratio, independent of the configuration of the disubstituted dipolarophile. However, in the case of a three-atom linker, there exists a matched and mismatched case with respect to the observed stereoselectivities. With a (Z)-configured dipolarophile, only the exo isomer was observed since the ester moiety also approaches on the exo to the nitronate. However, with an ( )-configured dipolarophile, the ester group is forced to approach in an endo manner to accommodate an exo approach of the tether, thus leading to lower selectivity. 

TABLE 2.31. STEREOSELECTIVITY IN THE INTRAMOLECULAR CYCLOADDITION OF SILYL NITRONATES... 

TABLE 6.13. STEREOSELECTIVITY IN INTRAMOLECULAR CYCLOADDITIONS WITH a-CHIRAL NITRILE OXIDES AND C-, 0-, OR S-CONTAINING ALKENYL CHAIN... 

Intramolecular cycloadditions of substrates possessing several stereocenters, such as those obtained from carbohydrate derivatives, have enjoyed some recent popularity. The carbohydrate skeleton provides a highly effective means for inducing stereoselectivity in intramolecular 1,3-dipolar cycloadditions. Tatsuta and co-workers (258) reported on the intramolecular cycloaddition of the B-xylo... 

The intramolecular cycloaddition of nitrile oxides to substituted furans was reported to occur with low stereoselectivity (274). Inserting a stereogenic unit within the chain connecting the dipole and dipolarophile did not increase the stereoselectivity (274). 

Intramolecular cycloaddition of the nitrile oxide intermediate generated from the unsaturated oxime 221 was used for an evenmal synthesis of la,2p,25-trihydroxy-vitamin D3 (262) (Scheme 6.90). Oxime 221, prepared from tri-O-isopropyhdene-d-mannitol (220), was processed as usual to give isoxazoline 222 in good yield and with excellent stereoselectivity. Conversion of 222 to the aldol 223 proceeded in the normal manner and further elaboration gave the desired diene intermediate 224 (262). 

Intramolecular cycloaddition of nitrile ylides to olefinic dipolarophiles linked to the dipole by a three-atom chain leads to pyrazoles fused to five-membered rings. Work on stereoselectivity in such reactions has been carried out using the reactant 266 in which the alkene moiety is linked to the C-terminus via a tether that incorporates an enantiomerically pure (R) stereogenic group (165). Both diastereo-isomers 267 and 268 were isolated and it was found that the reaction showed moderate stereoselectivity favoring 267. 

An efficient stereoselective synthesis of the (pyrrolidin-2-ylidene)glycinate intermediate 325 was reported in a total synthesis of carzinophilin (326), employing an intramolecular cycloaddition of an azide with an alkene (63) (Scheme 9.63). The arabinose derivative 319 was converted into the required azide 321 via the triflate 320. Thermolysis of the azide 321 at 50 °C in THF produced the unstable triazoline 322, which on rearrangement gave the (pyrrolidin-2-ylidene)glycinate 325 in 60-72% overall yield from the triflate 320. 

Pearson et al. (68) reported a versatile approach to pyrrolizidine and indolizidine alkaloids such as 355, 247, and 362 using intramolecular cycloadditions of azides with electron-rich dienes (Scheme 9.68). Azido dienes 353, 357, and 360 that possess a electron-donating group on the diene were prepared from the respective compounds 352, 356, and 359. On heating at 100 °C, the azido diene 353 underwent smooth intramolecular 1,3-dipolar cycloaddition in a stereoselective... 

The above dramatic dependence of regio- and stereoselectivity on the nature of the metal can be explained by the reaction mechanism shown in Scheme 11.49 (167). The nitrone cycloadditions of allylic alcohols are again magnesium-specific just like the nitrile oxide reactions described in Section 11.2.2. Magnesium ions accelerate the reaction through a metal ion-bound intramolecular cycloaddition path. On the other hand, zinc ions afford no such rate acceleration, but these ions catalyze the acetalization at the benzoyl carbonyl moiety of the nitrone to provide a hemiacetal intermediate. The subsequent intramolecular regio- and stereoselective cycloaddition reaction gives the observed products. 

Tamura et al. (170-172) discovered that, when reactions of ester-substituted nitrones with allylic alcohols are performed in the presence of an equimolar amount of titanium tetraisopropoxide under heating or at room temperature, transesterification takes place to form new nitrones bearing an inner alkene dipolarophile. The resulting nitrone substrates undergo regio- and stereoselective intramolecular cycloaddition reactions to give the ring-fused isoxazolidines (Scheme 11.52). This tandem transesterification/[3 + 2]-cycloaddition method leads to the selective... 

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