Pentacyclic diazo

Oxaestrone has been synthesised from 7-methoxychroman-4-one <96JCS(P1)841>. Formation of the complex chroman-3-one (16) by a Dieckmann reaction and its conversion to the 4-diazo derivative are signifcant steps in the synthesis of the pentacyclic system (17) <96TL5243>. 

In an alternative approach to annulation across the indole 2,3-tt system, Padwa and coworkers have reported approaches to the pentacyclic and hexacyclic frameworks of the aspidosperma and kopsifoline alkaloids respectively that involve as the key step a Rh(II)-promoted cyclization-cycloaddition cascade <06OL3275, 06OL5141>. As illustrated in their approach to ( )-aspidophytine 150, Rh2(OAc)4-catalyzed cyclization of a diazo ketoester 148 affords a carbonyl ylide dipole that undergoes [3+2]-cycloaddition across the indole 2,3-tt bond to generate 149 <06OL3275>. 

Mejla-Oneto and Padwa have explored intramolecular [3+2] cycloaddition reactions of push-pull dipoles across heteroaromatic jr-systems induced by microwave irradiation [465]. The push-pull dipoles were generated from the rhodium(II)-cata-lyzed reaction of a diazo imide precursor containing a tethered heteroaromatic ring. In the example shown in Scheme 6.276, microwave heating of a solution of the diazo imide precursor in dry benzene in the presence of a catalytic amount of rhodium I) pivalate and 4 A molecular sieves for 2 h at 70 °C produced a transient cyclic carbonyl ylide dipole, which spontaneously underwent cydoaddition across the tethered benzofuran Jt-system to form a pentacyclic structure related to alkaloids of the vindoline type. 

In more recent work, Chiu and co-workers [167, 168] have reported an intramolecular 1,3-dipolar cycloaddition approach toward the pseudolaric acids 85, in which the di-polarophile is an unactivated 1,1-disubstituted alkene. Hence, treatment of the diazo ketone 86 with catalytic Rh2(OAc)4 furnished a mixture of tricyclic products 87 and 88 in nearly equal proportions (Scheme 19.13). The synthesis of 2-pyridones [169] and their application to the ipalbidine core [170] has been described. The pentacyclic skeleton of the aspidosperma alkaloids was prepared via the cycloaddition of a push-pull carbonyl ylide [171]. The dehydrovindorosine alkaloids 89 have also been investigated, in which the a-diazo-/ -ketoester 90 undergoes a facile cycloaddition to furnish 91 in... 

Padwa has reported an approach to the ring system of the ribasine alkaloids 98 [174], using an intramolecular 1,3-dipolar cycloaddition of the a-diazo ketone 99 to produce the pentacyclic skeleton 100 (Scheme 19.17). Wood [175] used an intermolecular 1,3-dipolar cycloaddition of a carbonyl ylide for the total synthesis of ( )-epoxysorbicilli-nol 101 (Scheme 19.18). The key cycloaddition in this approach is the conversion of 102 to the natural product core 103, which sets the substitution pattern around the entire ring system in a single step. 

Diazo transfer to 1 followed by irradiation in the presence of bis-(trimethylsilyl)amide led to ring contraction with concomitant carbonyl extrusion, to give 7. Dehydration to the nitrile followed selenation then set the stage for a highly diastereoselective ytterbium-catalyzed Diels-Alder reaction, to give, after reduction and protection, the pentacyclic intermediate 2. 

While most of the initial studies have involved the transition metal-catalyzed decomposition of a-carbonyl diazo compounds and have been reviewed [3-51], it appears appropriate to highlight again some milestones of these transformations, since polycyclic structures could be nicely assembled from acyclic precursors in a single step. Two main reactivities of metalo carbenoids derived from a-carbonyl diazo precursors, namely addition to a C - C insaturation (olefin or alkyne) and formation of a ylid (carbonyl or onium), have been the source of fruitful cascades. Both of these are illustrated in Scheme 27 [52]. The two diazo ketone functions present in the same substrate 57 and under the action of the same catalyst react in two distinct ways. The initially formed carbenoid adds to a pending olefin to form a bi-cyclop. 1.0] intermediate 58 that subsequently cyclizes to produce a carbonyl ylide 59, that is further trapped intramolecularly in a [3 + 2] cycloaddition. The overall process gives birth to a highly complex pentacyclic structure 60. 

This reaction sequence establishes the fifth cyclobutane ring of the ladderane core and is analogous to the reaction from 3 to 5. First P-formyl ketone 26 is formed, which undergoes deformylative diazo transfer in the second step yielding a-diazo ketone 27. The desired pentacyclic carboxylic acid ester 11 is built up via a light-induced IFb rearrangement. 

Muthusamy S, Gunanathan C et al (2004) Regioselective synthesis of mono- and bis-decahy-drobenzocarbazoles via tandem reactions of a-diazo ketones. Tetrahedron 60 7885-7897 Nambu H, Hikime M et al (2009) Asymmetric approach to the pentacyclic skeleton of aspidosperma alkaloids via enantioselective intramolecular 1,3-dipolar cycloaddition of carbonyl ylides catalyzed by chiral dirhodium(II) carboxylates. Tetrahedron Lett 50 3675-3678... 

Although the CRI reaction of diazo compounds 17a and 17b yielded the pentacyclic intermediates 20 and 28, further alkylation to form a C8 quaternary carbon center was unsuccessful under various conditions. This appears to be due to steric hindrance by the bulky benzyl and cumyl groups after protection of the free amine. To improve the CRI reaction. Dr. Jun Yang modified the diazonamide substrate by replacing the amide functionality (17) with an ester... 

The total synthesis of several members of the vinca and tacaman class of indole alkaloids has also been accompHshed using push-pull dipoles in the critical cycloaddition step (2007OL3249, 2008JOC2792). The central step in the synthesis consists of an intramolecular [3-F2]-cycloaddition reaction of an a-diazo indoloamide (i.e., 19), which delivers the pentacyclic skeleton of the natural product in excellent yield (Scheme 6). The acid lability of... 

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