Carbonyl ylides cyclizations

An alkenyl group can be attached at either carbon atom of the carbonyl ylide. Cyclization normally affords fused bicyclic tetrahydrofurans, although with large rings bridged products have been observed. 

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]. 

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>. 

Reactions.—Nucleophilic Attack at Carbon. (/) Carbonyls. Methyl arylglyoxylates react with trisdimethylaminophosphine (TDAP) to form m-a/S-dimethoxycarbonyl-stilbene oxides.63 The initially formed zwitterion (61) reacts with a second molecule of the ester to form a fra/ -diphenyl-1,4,2-dioxaphospholan intermediate, which undergoes a concerted symmetry-allowed retrograde n2s + 4 cycloaddition to give a carbonyl ylide, conrotatory cyclization of which leads to the cw-oxirans (62) (Scheme 3). 

The proposed reaction pathway invokes initial formation of carbonyl ylide 100 by intramolecular cyclization of the intermediate keto carbenoid onto the oxygen atom of the amide. Subsequent isomerization to the azomethine ylide is followed by 1,3-dipolar cycloaddition to DMAD to furnish the intermediate cycloadduct 101, which undergoes in situ alkoxy 1,3-shift to the final drhydropyrrolizine 102 (Scheme 3.28). 

The carbonyl ylide 1 can undergo an internal cyclization reaction to generate the corresponding epoxide 2, which is in fact an equilibrium process, and epoxides themselves have frequently served as precursors to carbonyl ylides. Other pathways such as concerted rearrangements and internal proton transfers have also been observed to neutralize the charged ylide intermediate and give substituted ethers as represented by 3. Perhaps the best known studies and most synthetically useful... 

Laser flash photolysis of 18 (Ar = -N02C6H4) led to the formation of the aryl chlorocarbene detected at 320 nm. In the presence of acetone, a new species was observed at X = 590 nm that was assigned the structure of carbonyl ylide 19. The ylide, formed by attack of acetone on the carbene, was shown to be irreversible, where the lifetime of the ylide (1.35 ps, fecyciization = 7.40 x 10 s ) was controlled by cyclization to the aryl epoxide 22. The rate constant for the cycloaddition of substituted benzaldehydes to produce dehydrodioxolane (21) was determined experimentally (e.g., p-ClPhCHO=6.16 x 10 M s ). 

It was shown that carbonyl ylides can collapse to the corresponding epoxides through an intramolecular cyclization process. This reaction should be reversible and therefore epoxides could also serve as precursors to carbonyl ylides. Calculations have shown that the ylide is >60 kcal/mol less stable than the corresponding... 

A further study on six-membered ylide formation examined the use of an aliphatic ester in place of a ketone as the Lewis base donor for carbonyl ylide formation. Although the same keto-substituted system underwent an intramolecular cyclization readily, the ester derivative gave no cycloaddition products. Padwa and co-workers (37,76) points to the major electronic differences between the two carbonyl groups to rationalize the disparity in carbonyl ylide formation. 

Isomunchnones play a large part in the synthetic efforts Padwa and co-workers (91-94,96,98,110,111). The Lycopodium alkaloids are a large family of natural products and have inspired numerous synthetic routes to approach these compounds. Interest in this class of alkaloids stems from the myriad of biological properties they exhibit. Padwa utilized the carbonyl ylide methodology in tandem with a cationic 71-cyclization to complete a formal synthesis of ( ) lycopodine (Scheme 4.55) (96,112). 

Dittami et al. (170,171) was able to generate a carbonyl ylide via photocycliza-tion of an aryl vinyl ether (Scheme 4.85). The photocyclization proceeded through a six-electron rearrangement providing initially the carbonyl ylide, then subsequent to the cyclization, a dipolar cycloaddition takes place with a pendant olefinic tether. 

There are very few examples of photolysis being used for preparation of a carbonyl ylide. The Dittami protocol follows work completed from his lab with aryl vinyl sulfides. Photolysis, followed by cycloaddition, led to the cycloadduct 305 in excellent yield and stereoselectivity. If the aryl vinyl ether 304 was subjected to irradiation in a mixed solution of toluene-methanol at 366 nm rather than a single solvent of toluene, cyclized product was obtained, but no cycloadduct was formed. If a simple phenyl aryl ether was subjected to the same tandem conditions, the cyclized product was generated, but no cycloadduct was detected. 

Padwa and Prein (105,106) applied chiral, but racemic, isomiinchnone dipoles in diastereoselective 1,3-dipolar cycloadditions. The carbonyl ylide related isomiinch-none derivative rac-70 was obtained from the rhodium-catalyzed cyclization of diazo-derivative rac-69 (Scheme 12.24) (105). The reactions of the in situ formed dipole with a series of alkenes was described and in particular the reaction with maleic acid derivatives 71a-c gave rise to reaction with high selectivities. The tetracyclic products 72a-c were all obtained in good yield with high endo/ exo and diastereofacial selectivities. In another paper by the same authors, the reactions of racemic isomilnchnones having an exo-cyclic chirality was described (106). 

As part of a mechanistic and synthetic study of nucleophihc carbenes the spirocyclic 4(5/l)-oxazolone 18 has been obtained from benzoyl isocyanate (Scheme 6.1) Thermal extrusion of nitrogen from the 1,3,4-oxadiazoline 14 produced the carbonyl ylide 15 that fragmented via loss of acetone to the aminooxycarbene 16. Spectroscopic data [gas chromatography-mass spectrometry (GC-MS), infrared (IR), proton and C-13 nuclear magnetic resonance ( H and NMR)] of the crude thermolysate was consistent with 18. The formation of 18 was rationalized to result from nucleophihc addition of 16 to benzoyl isocyanate followed by cyclization of the dipolar intermediate 17. Thermolysis of 19 and 21 under similar reaction conditions afforded 20 and 22 respectively, also identified spectroscopically as the major products in the thermolysate. 

Z)-Styryloxiranes 154 undergo a thermal ring expansion reaction to give carbonyl ylides 155, which cyclize to 2,7-dihydro-3,4-benzoxepines 156 (Scheme 47) (79TL4049 85CB4035). 

Diene systems of the type 158 have been studied by O Shea and Sharp [96JCS(Pl)515].The oxiranes 157 were subjected to flash vacuum pyrolysis at 625°C, to yield some new hetero-fused dihydrobenzoxepines 159. This 1,7-electrocyclization of carbonyl ylides 158, irrespective of whether the heterocyclic ring under attack is electron rich or electron poor, parallels the cyclization of the analogous nitrile ylides (Scheme 48). 

Cyclization-cycloaddition of an a-diazoacetophenone. Reaction of 1 with Rh2(OAc)4 in C6H6 at 25° results in 2 in 87% yield. This reaction is considered to involve a carbonyl ylide (a), which is trapped internally by the neighboring double bond.2... 

Open-chain Carbonyl Ylide-Alkene Cyclizations 1161... 

A wider range of cyclizations occurred to conjugated ester dipolarophiles. Thus, (221) underwent thermolysis to the corresponding carbonyl ylide, which cyclized to give mainly bridged cycloadduct.122 The homologous oxirane with a five-carbon chain was also studied and gave only the transfused product (222) in 73% yield at 55% conversion. 

Dihydrofurans are valuable synthetic compounds. Nevertheless, little is known about intramolecular cycloaddition of carbonyl ylides to alkynes. In one example, alkynyl pyran-4-one (233) was cyclized to dihydrofuran (234 Scheme 69).128 Possibly this reaction proceeds via an oxidopyrylium ylide intermediate as shown. 

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