Tethered dipolarophile

Pyranopyrroloimidazoles have been prepared stereospecifically by an intramolecular 1,3-dipolar cycloaddition reaction. Either enantiomer of the imidazoline derivative 176 (the -enantiomer is shown) may react with the bromoacetyl-containing acrylate dipolarophile 177, in the presence of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), to give the diastereomerically pure tricyclic product 178 in moderate yield (Equation 15). This reaction involves quaternization of the imidazole N, reaction of the quaternary salt with base to give the 1,3-dipole, which can then react, intramolecularly and stereospecifically, with the tethered dipolarophile <1997TL1647>. 

The photolysis of epoxides containing a tethered dipolarophile can result in the intramolecular capture of the transient ylide and lead to the synthesis of more highly complex ring systems. Eberbach and co-workers (28-30) conducted several studies regarding this type of process to probe the viability of the method (Scheme 4.22). 

The tandem double intramolecular 4 + 3/3 + 2-cycloaddition of the nitroalkene (10) produced the nitroso acetal (11) in 77% yield. Further functional group manipulations allowed for the conversion to the partial core (12) of the complex polycyclic alkaloid daphnilactone B in high yield (Scheme 3).6 The tandem intramolecular 4 + 2/3 + 2-cycloaddition cascade of 1,3,4-oxadiazoles (13) to polycyclic adducts (14) was investigated by considering the tethered initiating dienophile, the tethered dipolarophile, the 1,3,4-oxadiazole C(2) and C(5) substituents, the tether lengths and sites, and the central heterocycle (Scheme 4).7... 

SCHEME 16.31 Spiro mode of intramolecular cycloaddition with C(3) tethered dipolarophiles. 

C(6) Tethered Dipolarophile Tandem, double-intramolecular cycloadditions of nitroalkenes in which the dipolarophile is attached to the C(5) or C(6)-carbon of dienophile has been more extensively studied. For example, a series of nitroalkenes has been prepared wherein the dipolarophile is attached to the C(6)-carbon 411a-c (Scheme 16.79)... 

SCHEME 16.79 Tandem, double intramolecular cycloadditions of nitroaUcenes with C(6)-tethered dipolarophile and hydrogenolysis of the resulting nitroso acetals. 

C(5) Tethered Dipolarophile The last of the known variants of the tandem, double-intramolecular cycloaddition differs by the point of attachment of the dipolarophile in... 

When a-tethered nitro ilkenes bearing three or four methylene chains and ester-activated dipolarophiles react with vinyl ethers, splro mode tandem cycloaddidon takes place to give tricyclic splro nitroso acetals In good yield and high diastereoselecdvity CScheme 8.46. ... 

Inter [4 +2]/intra [3+2] This type of tandem reaction using nitroalkenes has been explored most extensively. Four subfamilies of tandem cycloaddition exist, which arise from the four different points of attachment of the dipolarophilic tether. They are defined as fused, spiro, and bridged modes, as depicted in Scheme 8.37.149... 

Di- and trisubstituted nitroalkenes tethered to dipolarophiles (unsaturated esters, nitriles) undergo tandem [4+2]/[3+2] cycloadditions with 2,3-dimethyl-2-butene or butyl vinyl ether in the presence of Lewis acids (Eq. 8.112). For the dimethylene tether, the E-configuration of the dipolarophile is preferred, and the products arise selectively from a syn-endo pathway.177... 

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. 

Since the dipolarophile is not predisposed toward one face of the dipole at the point of attachment, the facial selectivity is governed by the configuration of the acetal center on the starting nitronate. As with the intermolecular case (Section 2.4.3.2), the preferred approach of the dipolarophile is distal to the acetal substituent. Lower facial selectivity is observed in the case of a four-atom tether, presumably due to the additional heating involved in driving the reaction to completion. 

The azomethine ylide was generated by treatment of A -benzyl-Af-(methoxy-methyl)-trimethylsilylmethylamine (155) with TFA and underwent the required cycloaddition step with chiral dipolarophile 156, stereocontrol being induced by Evan s auxiliary. The ot, p-unsaturated acid dipolarophile was tethered to a chiral oxazoladine in two easy, high-yielding steps. The auxiliary served three purposes to give asymmetric control to the reaction, to allow for separation of the reaction products by generating column separable diastereoisomers, and hnally to activate the olefin in the cycloaddition step (Scheme 3.45). 

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... 

In a similar approach, Garner et al. (78) made use of silicon-based tethers between ylide and dipolarophile during their program of research into the application of azomethine ylides in the total asymmetric synthesis of complex natural products. In order to form advanced synthetic intermediates of type 248 during the asymmetric synthesis of bioxalomycins (249), an intramolecular azomethine ylide reaction from aziridine ylide precursors was deemed the best strategy (Scheme 3.84). Under photochemically induced ylide formation and subsequent cycloaddition, the desired endo-re products 250 were formed exclusively. However, due to unacceptably low synthetic yields, this approach was abandoned in favor of a longer tether (Scheme 3.85). 

Harwood and Lilley (87) reported the tandem generation and intramolecular trapping of a stabilized azomethine ylide, derived from the enantiopure template examined in detail in Section 3.2.3. Condensation of 5-hexenal with template 205 under standard conditions led to in situ ylide generation and subsequent cycloaddition of the tethered alkene to furnish 296 as a single enantiomer in 95% yield after purification and this despite the fact that the dipolarophile is unactivated. Hydro-genolytic destruction of the template revealed the bicyclic amino acid 297 in 75% yield (Scheme 3.97). 

However, by considering models of the anti configured ylide (Fig. 3.18), it was concluded that the inclusion of a three-carbon tether forces the reactive centers to be too sterically constrained to suffer intramolecular cycloaddition with an alkyne dipolarophile. Conversely, the syn ylide is able to achieve the correct approach for such a process, despite the steric interaction with the phenyl ring. Extension of the interim chain by one methylene unit using 6-heptynal, introduced a greater degree of flexibility into the system, allowing for the formation of the expected diaster-eoisomers (Scheme 3.101). 

The same research group has demonstrated a similar intramolecular process in the construction of bicychc adducts 326 (92). The CsF desilyation of precursors 327, after subsequent reaction of the internal dipolarophile, dehvered the expected cycloadducts with complete stereocontrol when either thioether and ether tethers or activated and unactivated dipolarophiles were used. In contrast with intermolecular protocols, the reaction was successful with both activated and unactivated alkenes. In addition, unlike the previous example, formation of both six (n = 2)- and five (n= l)-membered rings occurs (Scheme 3.109). 

Epoxide 96 was prepared such that photolytic conversion to the carbonyl ylide could be followed by an intramolecular cycloaddition with the tethered pendant olefin. However, photolysis of epoxide 96 led only to the formation of the regio-isomer 97 and the aldehyde 98 with no evidence of the corresponding cycloadduct. It was presumed that 97 arose from the ylide by thermal recyclization to the epoxide while 98 could form through the loss of a carbene from the ylide. The failure of the tethered alkene to undergo cycloaddition may have resulted from a poor trajectory for the cycloaddition. An extended analogue (99) allowed greater flexibility for the dipolarophile to adopt any number of conformations. Photolysis of epoxide 99 did lead to formation of the macrocyclic adduct 100, albeit in modest yields. 

A number of intramolecular cycloadditions of alkene-tethered nitrile oxides, where the double bond forms part of a ring, have been used for the synthesis of fused carbocyclic structures (18,74,266-271). The cycloadditions afford the cis-fused bicyclic products, and this stereochemical outcome does not depend on the substituents on the alkene or on the carbon chain. When cyclic olefins were used, the configuration of the products found could be rationalized in terms of the transition states described in Scheme 6.49 (18,74,266-271). In the transition state leading to the cis-fused heterocycle, the dipole is more easily aligned with the dipolarophile if the nitrile oxide adds to the face of the cycloolefin in which the tethering chain resides. In the trans transition state, considerable nonbonded interactions and strain would have to be overcome in order to achieve good parallel alignment of the dipole and dipolarophile (74,266). 

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. 

---