Ylides cycloaddition cascade

Rh(l)-catalyzed [2-I-2-I-2] cyclotrimerization of 1,6-diynes (e.g., 1391 and 1394) with monoynes (e.g., 1392) in combination with stereospecific Ag(i)-catalyzed aldimine (metallo)azomethine ylide — cycloaddition cascades affords rapid access to complex heterocyclic benzene derivatives 1393 and 1395 in one-pot processes with the generation of five new bonds, four stereocenters and three rings (Schemes 266 and 267) <2000T8967>. 

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>. 

Tandem carbonyl ylide generation from the reaction of metallo carbenoids with carbonyl continues to be of great interest both mechanistically and synthetically. Effective carbonyl ylide formation in transition metal catalyzed reactions of diazo compounds depends on the catalyst, the diazo species, the nature of the interacting carbonyl group and competition with other processes. The many structurally diverse and highly successful examples of tetrahydrofuran formation cited in this mini-review clearly indicate that the tandem cyclization/cycloaddition cascade of metallo carbenoids has evolved as an important strategy in both carbo- and heterocyclic synthesis. 

Mejia-Oneto JM, Padwa A (2006) Application of the Rh(II) cyclization/cycloadditi(Hi cascade for the total synthesis of (H—)-aspidophytine. Org Lett 8 3275-3278 Mejia-Oneto JM, Padwa A (2008) Total synthesis of the alkaloid (+—)-aspidophytine based on carbonyl ylide cycloaddition chemistry. Helv Chim Acta 91 285-302 Hong X, France S et al (2006) Cycloaddition protocol for the assembly of the hexacyclic framework associated with the kopsifoline alkaloids. Org Lett 8 5141-5144 Hong X, France S et al (2007) A dipolar cycloaddition approach toward the kopsifoline alkaloid framework. Tetrahedron 63 5962-5976... 

In another important application of this methodology, ( )-illudin M (79), a toxic sesquiterpene [91,92] isolated from the jack-o -lantern mushroom, has been synthesized [93] by Kinder and co-workers via the spirocyclic carbonyl ylide 48. Rh2 (OAc)4-mediated decomposition of or-diazo ketone 47 in the presence of cyclopentenone 77 afforded the key cycloadduct 78 as a single diastereomer, bearing the complete skeleton of the natural product. Functional group manipulations of the adduct 78 led to a total synthesis of ( )-illudin M (79) (Scheme 23). Padwa and co-workers also executed the syntheses of illudin, ptaquilosin and the closely related isodehydroilludin [78,94] using carbonyl yUdes. This carbonyl ylide cyclization-cycloaddition cascade approach (Scheme 23) has been further extended towards a short synthesis of the acylfulvenes [95], pterosin [79] and pterosin family of sesquiterpenes [96-99]. 

Stabilized azomethine ylides can easily be formed using amino acids and their esters to generate an imine that is subsequently alkylated to generate an iminium ion. Decarboxylation or deprotonation then affords the reactive azomethine yhde. Coldham and coworkers examined the scope of this type of condensation—alkylation—cycloaddition cascade wherein the... 

Coldham and coworkers reported a tandem condensation/cyclization/intramolec-ular cycloaddition cascade process to form fused tricychc amines, using azomethine ylides (derived from a-amino-acids or esters). This chemistry was apphed for the constmction of the pyrrolo[l,2-a]azepine ring system of the Stemona alkaloids (Scheme 4.20) [39]. Condensation of the aldehyde 96 bearing a dipolarophile (an... 

Subsequently, a formal [4+l]/[3+2] cycloaddition cascade reaction with sulfur ylides and nitroolefin derivatives 263 was carried out in a similar manner by the same group. The isoxazoline A-oxide 259 intermediates underwent a series of intramolecular reactions, affording fused heterocyclic structures 264 with excellent diastereoselectivities (Scheme 2.68) [97]. 

SCHEME 2.68 Formal [4+1]/[3 +2] cycloaddition cascade reaction with sulfur ylides and... 

SCHEME 21.16. Ylide formation/[3 -I- 2] cycloaddition cascade for the synthesis of (—)-colchicine. 

Diels-Alder reaction of the 1,3,4-oxadiazole with the pendant olefin and loss of N2, the C2-C3 7t bond participates in a subsequent 1,3-dipolar cycloaddition with the carbonyl ylide to generate complex polycycles such as 45 as single diastereomers with up to six new stereocenters. That the cascade reaction is initiated by a Diels-Alder reaction with the alkene rather than with the indole is supported by the lack of reaction even under forcing conditions with substrate 46, in which a Diels-Alder reaction with the indole C2-C3 n bond would be required [26a]. 

A 1,3-dipolar cycloaddition of the nonstabilized azomethine ylide 6 is the key step in a three-component reaction. The azomethine ylides were generated from (2-azaallyl)stannanes or (2-azaallyl)silanes 5 through an intramolecular iV-alkylation/demetallation cascade. The ylides underwent cycloaddition reactions with dipolarophiles yielding indolizidine derivatives 7-9 <2004JOC1919> (Scheme 1). 

Hodgson and co-workers have studied the intramolecular cascade carbonyl ylide formation-cycloaddition with chiral Rh(ii) catalysts.After screening a series of chiral Rh(ii) catalysts, high enantioselectivity was achieved in the reaction of 98 by using the Rh(ii) catalyst with binaphthyl phosphate-derived chiral ligands dirhodium(ii) tetrakis[(i )-6,6 -didodecylbinaphtholphosphate] [Rh2(i -DDBNP)4] (Equation (13)). 

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. 

The 1,3-dipolar cycloadditions of azomethine ylides with aldehydes readily produced high yields of oxazolidines, which hydrolysed to anti a-amino-y -hydroxy esters." Non-stabilized azomethine ylides with isotonic anhydrides produced oxa-zolidine intermediates, which were converted into l,3-benzodiazepin-5-ones via ringopening-decarboxylation-ring-closing reaction cascades." ... 

Most recently, Waldmann and co-workers disclosed a cascade transformation to allow the highly diastereo- and enantioselective synthesis of structurally complex 5,5,5-tricyclic products with eight stereocenters, which initiated by copper-catalyzed aerobic oxidation of cyclopentadiene to cyclopentadienone followed by catalytic asynunetric double 1,3-dipolar cycloaddition with azomethine ylides (Scheme 18) [33]. 

CuOTf-catalyzed synthesis of polysubstituted pyrroles from a-diazoketones, nitroalkenes, and amines was reported by Lu, Wang, and coworkers. The corresponding polysubstituted pyrroles could be obtained in moderate yields using air as the oxidant. This cascade process of the polysubstituted pyrrole formation involves an NH insertion of carbene, a copper-catalyzed oxidative dehydrogenation of amine, and a [3+2] cycloaddition of azomethine ylide [21] (Scheme 8.9). 

Recently, Cheng et al. achieved the synthesis of the diastereoisomers of spiro-tryprostatin A 53a and 53b in nine steps based on the bisphosphoric acid-catalyzed 1,3-dipolar cycloaddition reaction of azomethine ylides with methyl 2-(2-nitrophe-nyl) acrylates 50a, which showed the great potential of this cascade reaction in the total synthesis of natural products (Scheme 2.14) [25],... 

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