Intramolecular 3+21 cycloaddition Diels-Alder reactions

The hetero-Diels-Alder reaction has also utilized dienophiles in which both reactive centers are heteroatoms. Kibayashi reported that the intramolecular hetero-Diels-Alder cycloaddition of chiral acylnitroso compounds, generated in situ from periodate oxidation of the precursor hydroxamic acid, showed a marked enhancement of the trans-selectivity in an aqueous medium compared with the selectivity in nonaqueous conditions (Eq. 12.55).125 The reaction was readily applied to the total synthesis of (—)-pumiliotoxin C (Figure 12.5).126... 

Ab initio Hartree-Fock and density functional theory (DFT) calculations were performed to study transition geometries in the intramolecular hetero-Diels-Alder cycloaddition reactions of azoalkenes 20 (LJ = CH2, NFI, O) (Equation 1). The order of the reactivities was predicted from frontier orbital energies. DFT calculations of the activation energies at the B3LYP level were in full agreement with the experimental results described in the literature <2001JST(535)165>. 

Inter- and intramolecular hetero-Diels-Alder cycloaddition reactions in a series of functionalized 2-(lH)-pyrazinones have been studied in detail by the groups of Van der Eycken and Kappe (Scheme 6.95) [195-197]. In the intramolecular series, cycloaddition of alkenyl-tethered 2-(lH)-pyrazinones required 1-2 days under conventional thermal conditions involving chlorobenzene as solvent under reflux conditions (132 °C). Switching to 1,2-dichloroethane doped with the ionic liquid l-butyl-3-methylimidazolium hexafluorophosphate (bmimPF6) and sealed-vessel microwave technology, the same transformations were completed within 8-18 min at a reaction temperature of 190 °C (Scheme 6.95 a) [195]. Without isolating the primary imidoyl chloride cycloadducts, rapid hydrolysis was achieved by the addition of small amounts of water and subjecting the reaction mixture to further microwave irradia-... 

In a clever piece of work, Snider et al. have used a quasi intramolecular carbonyl Diels-Alder cycloaddition to produce a key intermediate for syntheses of pseudomonic acid A (175) (Scheme 20). Thus a Lewis acid catalyzed ene reaction of alkene (170) and formaldehyde afforded (171), which com-plexed with additional formaldehyde to give (172). Intramolecular [4 + 2] cycloaddition of (172) gave adduct (173) which produced dihydropyran (174) upon hydrolysis. 

A few rare instances of intramolecular carbonyl Diels-Alder cycloaddition reactions exist (82T3087). 

Alves, C. N., Romero, O. A. S., Da Silva, A. B. F. Theoretical study on the stereochemistry of intramolecular hetero Diels-Alder cycloaddition reactions of azoalkenes. Int. J. Quantum Chem. 2003, 95, 133-136. 

Fischer-type chromium carbene complexes with 1-ethoxycyclopropylalkynyl substituents at the carbene carbon, e.g. 25, on reaction with dimethylamine and subsequent conversion of the resulting vinylcarbene with alkynes surprisingly did not give phenol derivatives, as would be expected from the known Dotz reaction, but gave cyclopenta[ )]pyrans, e.g. 26. The reaction is interpreted as a double alkyne-insertion/CO-insertion sequence with formation of a trienylketene intermediate, which undergoes intramolecular hetero-Diels-Alder cycloaddition and dimethylamine elimination. ... 

Intramolecular versions of the ene reaction using Lewis acids can be applied to nonconjugated dienes. Thus, 2.8-dienoic acid derivatives lead to cyclohexane systems27. Side products in this conversion stem from intramolecular hetero-Diels-Alder cycloaddition. Chiral Lewis acids, such as titanium alkoxidcs modified with tartaric acid derived chiral diols, lead to asymmetric induction with up to 98% ee27,88. 

The methodology based on nitroso DieIs-alder reaction that proved useful in the synthesis of tropane alkaloids also seemed to open an attractive route to some other alkaloids. Compared to the intramolecular imino Diels-Alder reaction (ref. Ic) the intramolecular variant of the nitroso Diels-Alder reaction has received far less attention (refs. 6b 12), despite the enormous potential it holds for alkaloid synthesis. With this in mind we proceeded to examine the application of the intramolecular nitroso Diels-Alder cycloaddition in the synthesis of alkaloids possessing saturated nitrogen heterocyclic ring systems. 

The hetero-Diels-Alder reaction of steroidal dienes (156) with nitroso-aromatics are regioselective with two stereoisomers (157) and (158) produced in a 2 1 ratio (Scheme 60) The regio-, stereo-, and enantio-selectivity of 4 -I- 2-cycloadditions of nitrosoalkenes to alkenes have been extensively reviewed.The intramolecular acylnitroso Diels-Alder cycloaddition of (159) produced the bicyclic adducts (160) in high yields (Scheme 61). ... 

The intramolecular aza Diels-Alder cycloaddition is also a valuable tool for the synthesis of alkaloids as demonstrated by the stereocontrolled synthesis of ( )-lepadifor-mine 137 (Scheme 41.29). This tricyclic alkaloid has been isolated from several species of Clavenia and Polycitoridae sea squirts and is moderately cytotoxic toward various tumor cell lines and effective to block potassium ion channels. Initial attempts to perform the aza Diels-Alder reaction with the racemic imino-diene t-butyl ester 134 in toluene at temperatures up to 165°C did not lead to the observation of any cycloadducts but to double bonds isomerization products. The corresponding free carboxylic acid only suffered decarboxylation. The addition of trifluoroacetic acid to generate an imminium species was also unsuccessful. 

Robinson, J.M., Sakai, T., Okano, K., Kitawaki, T. and Danheiser, R.L. (2010) Formal [24-24-2] cycloaddition strategy based on an intramolecular propargylic ene reaction/Diels-Alder cycloaddition cascade. Journal of the American Chemical Society, 132(32), 11039-11041. 

UV irradiation. Indeed, thermal reaction of 1-phenyl-3,4-dimethylphosphole with (C5HloNH)Mo(CO)4 leads to 155 (M = Mo) and not to 154 (M = Mo, R = Ph). Complex 155 (M = Mo) converts into 154 (M = Mo, R = Ph) under UV irradiation. This route was confirmed by a photochemical reaction between 3,4-dimethyl-l-phenylphosphole and Mo(CO)6 when both 146 (M = Mo, R = Ph, R = R = H, R = R" = Me) and 155 (M = Mo) resulted (89IC4536). In excess phosphole, the product was 156. A similar chromium complex is known [82JCS(CC)667]. Complex 146 (M = Mo, R = Ph, r2 = R = H, R = R = Me) enters [4 -H 2] Diels-Alder cycloaddition with diphenylvinylphosphine to give 157. However, from the viewpoint of Woodward-Hoffmann rules and on the basis of the study of UV irradiation of 1,2,5-trimethylphosphole, it is highly probable that [2 - - 2] dimers are the initial products of dimerization, and [4 - - 2] dimers are the final results of thermally allowed intramolecular rearrangement of [2 - - 2] dimers. This hypothesis was confirmed by the data obtained from the reaction of 1-phenylphosphole with molybdenum hexacarbonyl under UV irradiation the head-to-tail structure of the complex 158. 

The Diels-Alder cycloaddition is the best-known organic reaction that is widely used to construct, in a regio- and stereo-controlled way, a six-membered ring with up to four stereogenic centers. With the potential of forming carbon-carbon, carbon-heteroatom and heteroatom-heteroatom bonds, the reaction is a versatile synthetic tool for constructing simple and complex molecules [1], Scheme 1.1 illustrates two examples the synthesis of a small molecule such as the tricyclic compound 1 by intermolecular Diels-Alder reaction [2] and the construction of a complex compound, like 2, which is the key intermediate in the synthesis of (-)chlorothricolide 3, by a combination of an intermolecular and an intramolecular Diels-Alder cycloaddition [3]. 

A sequence of two thermal intramolecular cycloadditions has been used to develop a short synthetic approach to tetrahydrothiopyrans [122], The multiple process includes an m m-hetero- and an intramolecular-carbon Diels-Alder reaction. An intramolecular /zctcro-Diels-Alder reaction of divinyl-thioketone 134 afforded a 9 1 mixture of cycloadducts 135 and 136 which then underwent a second intramolecular cycloaddition which syn o H-2)-exo-diastereoselectively led to hexacyclic tetrahydrothiopyrans 137 and 138, respectively (Scheme 2.51). 

Lewis-acid catalysis is effective in intermolecular as well as intramolecular /zomo-Diels-Alder reactions. Thus, complex polycyclic compounds 93 have been obtained in good yield by the cycloaddition of norbornadiene-derived dienynes 92 by using cobalt catalyst, whereas no reaction occurred under thermal conditions [91] (Scheme 3.18). 

In contrast LP-DE gives disappointing results for intramolecular imino Diels-Alder reactions, even in the presence of CSA. This is due to the fact that weak acids become strong acids in highly polar media such as 5.0m LP-DE and the protonation of diene, with concomitant diene isomerization, competes with cycloaddition [42]. This observation was supported by using trifluoroacetic acid (TEA). The imine 33 (Scheme 6.21) in LP-DE at room temperature in the presence of TEA gave a 1 1 mixture of cycloadduct 34 and the isomerized diene 35 within the unreacted imine 33. No Diels-Alder cycloadduct 36 was detected. 

Diels-Alder Reaction in Unconventional Reaction Media Intramolecular Diels-Alder cycloadditions of bis-diene substrates [94]... 

One of the very rare examples of a combination of a radical with a pericydic reaction - in this case a [4+2] Diels-Alder cycloaddition - is depicted in Scheme 3.83 [133]. The sequence, elaborated by Malacria and coworkers, is based on the premise that the vinyl radical 3-341 formed from the substrate 3-340 using tributyltin hydride exists mainly in the Z -form. This is reduced by a hydrogen atom to form a 1,3-diene, which can undergo an intramolecular Diels-Alder reaction via an exotransition state reaction (the chain lies away from diene). 

Deslongchamps and coworkers [26] used a combination of a transannular Diels-Alder cycloaddition and an intramolecular aldol reaction in the synthesis of the unnatural enantiomer of a derivative of the (+)-aphidicolin (4-74), which is a diterpe-noic tetraol isolated from the fungus Cephalosporium aphidicolia. This compound is an inhibitor of DNA polymerase, and is also known to act against the herpes simplex type I virus. In addition, it slows down eukaryotic cell proliferation, which makes it an interesting target as an anticancer agent... 

Cycloaddition reactions of furans are still widely used as key steps in the construction of complex molecules including natural products. As an example, the intramolecular Diels-Alder cycloaddition of 2-amido substituted furans provides a useful tool for the synthesis of fused, nitrogen-containing poly-heterocycles. Thus, thermolysis of 3-substituted amidofuran produces tricyclic indolinone 39 as a 2 1 mixture of diastereomers via amidofuran cycloaddition-rearrangement methodology, which serves as a key intermediate in the total synthesis of ( )-dendrobine, a major component of the Chinese ornamental orchid Dendrobium nobile . 

Reaction of a-allenyl alcohol 147 with methanesulfonyl chloride and triethylamine in toluene at 190 °C, in a sealed tube, led to the tricyclic dihydropyrrolizin-4-one 149 in 35% yield. This transformation involves a domino mesylation/ intramolecular Diels-Alder cycloaddition via diene 148 (Scheme 29) <2002CC1472>. 

The use of vinylallenes as the diene component in Diels-Alder reactions is very common, thus resulting in their ubiquitous use in natural product synthesis. A vinylal-lene has even been proposed by Schreiber and Kiessling [10] as a biogenetic intermediate in the synthesis of the skeleton of esperamicin A (32 —> 33). Their synthetic approach to esperamicin A (34) was modeled after this biogenetic proposal in which a Type II intramolecular Diels-Alder cycloaddition was used to gain access to the highly unsaturated bicyclic core of 34 (Scheme 19.8) [10]. 

---