Intramolecular isomunchnone cycloadditions

An interesting example of an intramolecular 1,3-dipolar cycloaddition of an isomunchnone with an unactivated alkene to produce a complex polycyclic compound in one step has been reported 89TL4077 89CB1081 . The isomunchnones derived from the Rh2(OAc)4 catalyzed reaction of acyclic diazoimides 92-96 were found to undergo facile cycloaddition onto the tethered it-bond to provide polycyclic adducts 97-101. A notable feature of this cycloaddition is that only one diastereomer is formed. The relative 

Lengthening the alkenyl tether by one carbon atom was observed to have no effect on the ability of the isomunchnone to cycloadd across the olefinic jc-bond. This was shown in a study of the cycloaddition behavior of diazoimide 108 which afforded cycloadduct 109 in 86% yield as a single diastereomer 92TL4731 . 

When the dipolar cycloadduct 127 derived from the unsubstituted alkenyl diazoimide 126 was exposed to BF3-OEt2, the resulting cyclized product 128 (90%) was identified as the all syn tetracyclic lactam 128 by an X-ray crystal analysis. Thus, in contrast to the other three systems, the bridgehead proton of 128 lies syn to the hydroxyl stereocenter of the original cycloadduct. 

Piperidine 141 was synthesized from the Barton-McCombie reaction 75JCSP11574 of 142 which gave the expected amido-ester (96 %) as a 3 2-mixture of diastereomers. The mixture was hydrolyzed to the corresponding carboxylic acid which, upon thermal decarboxylation, gave the desired /V-bcnzyl lactam (85% overall yield) as a single diastereomer whose structure was unequivocally established by a single-crystal X-ray analysis. Reduction of the lactam with LiAlH4 (81%) followed by debenzylation via 

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Maier and Schdffling have extended this intramolecular isomunchnone cycloaddition to a synthesis of fused furans by employing an alkyne dipolarophile. Thus the diazo acetylenes 403 are smoothly converted to furans 404 with catalytic rhodium acetate (Fig. 4.128). 

C. Intramolecular Isomunchnone Cycloaddition Pathway to Lysergic Acid... 

Rhodium(II) acetate in benzene catalyzes the decomposition of the diazoamide containing a tethered Tc-system (227) to form the 1,3-dipole of an isomunchnone which subsequently undergoes intramolecular dipolar cycloaddition to afford the cycloadduct (228) in high yield <92TU73l>. 

A formal synthesis of ( )-vallesamidine (218) has been achieved [167] based on an intramolecular dipolar cycloaddition reaction of isomunchnone. Following a study of a range of model substrates, the reaction of the cychc diazoimide 215 with Rh2(pfb)4 was carried out to obtain the desired cycloadduct 216 as a single diastereomer (Scheme 68). A series of functional group maneuvers on 216 afforded the enamide 217, which can be readily elaborated to ( )-vallesamidine (218) using a known methodology [168]. 

The 3 + 2-cycloaddition of ring-fused isomunchnones with various dipolarophiles produces predominantly die exo-dipolar adduct exo selectivity could be enhanced by the inclusion of substituents on any position of the fused five-membered ring.112 Dihydropyrimidine-fused isothiomunchnones and isomunchnones (80) undergo intramolecular 1,3-dipolar cycloadditions to form cycloadducts (81) with high regio-and stereo-selectivity (Scheme 28).113 The tandem 1,3-dipolar cycloadditions of 1,3-... 

Unique synthetic opportunities, particularly in alkaloid chemistry, are opened up on applying this protocol to diazo imides bearing a tethered heterocyclic ring. Thus, isomunchnone dipole, which is derived from these compounds, undergoes intramolecular cycloaddition across the heterocyclic CT-bond to produce bridged polyfused systems. Some examples of reactions with 2-furyl- and 1-indolyl-substituted substrates are shown in Schemes... 

In similar fashion, the conformationally restricted analogs 485 were prepared via intramolecular cycloadditions from the isomunchnones generated from a-diazo imides 484 (Fig. 4.149). The structures of these cycloadducts were established by X-ray crystallography. 

Although Maier achieved the first intramolecular 1,3-dipolar cycloaddition reaction of an isomunchnone, it was Padwa who unleashed the synthetic utility of this reaction. Thus Padwa and co-workers also found that isolated 7t-bonds can successfully and efficiently capture the in situ-generated isomunchnones, as shown by the examples 518 519 (Fig. 4.156). The alkene can also be tethered adjacent to the nitrogen atom (not shown). The indole double bond in 520 intercepts an isomunchnone 1,3-dipole to give the single diastereomer 521, the stmcture of which is supported by X-ray crystallography. 

Padwa and co-workers effected intramolecular 1,3-dipolar cycloaddition reactions of isomunchnones tethered with other examples of Ji-systems. Several substrates with tethers of varying lengths were examined in this study. For example, reaction of diazo imide 527, readily assembled from the appropriate >-alkenyl... 

Further studies by this group ° revealed that the preferred exo cycloaddition mode that is observed experimentally is supported by molecular mechanics calculations. In cases in which ring strain prevents an intramolecular cycloaddition, the isomunchnone can nevertheless be intercepted by iV-phenylmaleimide in an intermolecular reaction. 

In the full account of this rhodium-catalyzed isomunchnone generation and intramolecular 1,3-dipolar cycloaddition reaction, followed by a terminal Mannich... 

Padwa ° has concisely summarized his domino cycloaddition/iV-acyliminium ion cyclization cascade process—a tactic akin to a two-move chess combination— involving the generation of an isomunchnone 1,3-dipole, intramolecular 1,3-dipolar cycloaddition reaction, A -acyliminium ion formation, and Mannich cyclization. 

Carbonyl ylides, most often in the form of isomunchnones (formed by decomposition of diketo diazo compounds in the presence of rhodium (II) acetate, and subsequent cyclization of the intermediate rhodium carbenoid species) are by far the most studied 1,3-dipolar cycloaddition partners for indole derivatives. These cycloadditions have been employed in elegant examples of complex ring construction en route to a number of polycyclic indole-containing natural products. Preliminary work by Pirrung [54, 55] (Scheme 23) on simple intermolecular cycloadditions was followed shortly by the utilization of intramolecular examples by Padwa, Boger and others. 

Hertzog DL, Austin DJ et al (1992) Intramolecular cycloaddition of isomuenchnones derived from the rhodium(II) catalyzed cyclization of diazoimides. Tetrahedron Lett 33 4731-4734 57. Padwa A, Hertzog DL et al (1994) Intramolecular cycloaddition of isomunchnone dipoles to heteroaromatic p-systems. J Org Chem 59 7072-7084... 

As a viable approach to the synthesis of lysergic acid, intramolecular cycloaddition of alkenyl- and alkynyl-substituted diazoimides 194 across a transient isomunchnone dipole was investigated, aiming at the construction of the ring system of the quinoline ring system (C and D rings) of the ergot alkaloids (79). 

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