Annulation, , formal

In addition to the synthesis of heterocycles, the Corey-Chaykovsky reaction bestows an entry to carbocycles as well. The reaction of (trialkylsilyl)vinylketene 89 with substituted ylide 90 led exclusively to rrans-4,5-dimethyl cyclopentenone 91. The substituted ylide 90 here serves as a nucleophilic carbenoid reagent in the formal [4 +1] annulation reaction. 

Substituted and benzo-annulated oxepins readily undergo addition of bromine across the nonaromatic double bond. Bromination of 3,6-bridged oxepins can occur in two different ways, either as a 1,2-addition164 or as formal 1,4-addition to the diene system of the corresponding benzene oxide to give products i.129 138-140 164... 

After two years working as a postdoctoral fellow under Dr. H.-P. Husson (Institut de Chimie de Substance Naturelles, CNRS, Gif-sur-Yvette, France) (CNRS methods in asymmetric synthesis) (1984-85), he worked as an associate researcher under Professor Wolfgang Oppolzer (Departement de Chimie Organique, Geneve, Suisse) (aldol reaction) (1986) and was a visiting professor at the Department of Chemistry, Duke University, NC, working with Professor Fraser-Reid (free radical chemistry annulated furanoses formal total synthesis of phyllathocin). 

The formal total synthesis of racemic guanacastepene (rac-187) from Snider and co-workers (Fig. 20) was submitted six months later than the completed synthesis of Danishefsky s group [116-118]. The shortest sequence developed by the Snider group utilized the sequential cuprate addition/enolate alkylation of 2-methylcyclopent-2-enone 90 previously exploited by Piers, Williams and Danishefsky (Schemes 15 and 31). As outlined in Figs. 19 and 20, the strategies of Danishefsky and Snider are closely related. Both rely on stepwise annulations to build up the tricyclic ring system. They differ only in respect to the particular reactions that converted the monocyclic starting material (90) via bicyclic hydroazulenes (207 vs 227) into the desired tricyclic 5-7-6-system (224). 

Scheme 39 A Stork-Jung annulation completed the formal total synthesis...

The class of 3-silyl-substituted reagents provides, upon addition with aldehydes, allylic silanes that offer many options for further derivatization. Oxidative processes are described in previous sections (see the sections on Preparation of 1,2-Diols and 1,4-Diols). If the appropriate silicon substituents are chosen, formal [3+2] cycloadditions with aldehydes can be promoted under Lewis acid catalysis. For example, the mismatched addition of the Z-3-propyl-3-benzhydryldimethyl allylsilane 183 to an a-benzyloxy aldehyde proceeds with low diastereofacial selectivity in favor of product 184 however, after protection of the secondary alcohol, an efficient [3+2] annulation provides the polysubsubstituted furan 185 in good yield and acceptable stereoselectivity (Scheme 24). ° The latter is brought forward to a tricyclic unit found in the antitumor natural product angelmicin B. 

Hudlicky and Barbieri (178) developed a simple two-step strategy to generate vinyl oxiranes, and then rearrange the vinyl oxirane to form functionalized dihydrofurans in a formal [2- -3]-annulation process. Both pyrolysis and ring opening with TMSI have been used to initiate the rearrangement process (Scheme 4.90). 

In spite of its formal similarity to the above mentioned annulation processes, the reaction shown in 4.37. includes a unique migration step. Oxidative insertion of the palladium into the phenyl-iodine bond is followed by the migration of the palladium onto the more electron rich indole ring. The 2-indolylpalladium complex than carbopalladates the pendant alkync moiety and the process ends by the formal activation of a C-H bond of the phenyl substituent and subsequent reductive elimination, furnishing the pentacyclic product.48 The same strategy has been utilised in the preparation of the indoloindolone framework from /V-bcnzoyl-3-(o-iodophcnyl)-indolc in an oxidative addition - palladium migration - C-H activation sequence.49... 

Despite the obvious synthetic potential of this formal cycloaddition or annulation reaction, its application has remained little known because of the competing reaction pathways due to 1,2- versus 1,4-addition as well as C-addition versus O-addition [Scheme 4], Moreno-Manas reported a... 

The platinum-catalysed intramolecular domino annulation reaction of o-alkynylben-zaldehydes has been described as a versatile approach to naphthalenes with annulated carbocycles or heterocycles of various sizes (Scheme 32).94 A plausible mechanism for the platinum(II)-catalysed annulation reaction shows that the double annulation process most probably proceeds through the benzopyrylium cation (117), which results from the nucleophilic attack of the carbonyl oxygen at the alkyne, activated by the Lewis-acidic platinum salt. A subsequent intramolecular Huisgen-type 3 + 2-cycloaddition of the second alkyne is assumed to generate intermediate (118). Rearrangement to (119) and the formal 4 + 2-cycloaddition product (118) leads to the aromatized final (116), liberating the active catalyst. In the case of FeCl3 as the Lewis acid, we assume that intermediate (118) is oxidatively transformed to (121). 

In a preliminary study toward the total synthesis of the kopsane alkaloid 140, which may exhibit cholinergic activity, the formal [3 + 2] annulation reaction of 3-alkylindoles with 1,1-cyclopropane diesters was studied in the presence of Yb(OTf)3 either at elevated temperature or at high pressure. For example, N-methyltetrahydrocarbazole (141) with styryl-substituted cyclopropane 142 produced a mixture of diastereomeric adducts 143a and 143b (3 1) in 49% yield at 1.3 GPa for 7 days (Scheme 39) [89]. 

Selection of the responses is one of the most important problems of a preliminary study of the research subject, since a correct definition of research objective means correct selection of the responses. An incorrect selection of the responses annuls all further research activities. Depending on the subject and research objective, optimization parameters or responses may be quite different. To formalize the procedure of selection of the responses, with no intention of being detailed and complete, Fig. 2.3 gives the block diagram of the most frequently used optimization parameters. 

Nakamura disclosed recently a formal [4+2] cycloaddition of pentaarylbromo-fullerene 245 with a large variety of arylalkynes 246 catalyzed by 20 mol% of Cul in the presence of pyridine and sodium acetate as a base (Fig. 65) [338]. The reaction provided fullerene-annulated dihydronaphthalenes 247 in 78-94% yield. 

The synthesis of polysubstituted tetrahydrofurans was also achieved in a stereoselective manner by a formal [3+2] cycloaddition of an allylsilane with a-triethylsiloxy aldehydes. An example showing the mechanism is illustrated <02JA3608>. In another approach, allylsilane was also allowed to react with a-keto esters in a [3+2] annulation reaction, providing highly substituted tetrahydrofurans in good yields as single diastereomers <02OL2945>. 

A clear two step formation of a pyrone by an enantioselective Mukaiyama-aldol and acid catalysed aldol dihydropyrone annulation using aliphatic and aromatic aldehydes and l-methoxy-3-trimethylsilyloxy-l,3-butadiene in the presence of a tryptophan-derived oxazaborolidine was described by Corey et al. [115]. The resulting pyrone which could be assigned as a formal Diels-Alder adduct was obtained with a 67-82% ee and 57 -100% yield. 

The preparation of 10 represents a formal total synthesis of a-cuparenone. An annulation related to that depicted in eq. 2, which was a key step in an... 

Novel carbon frameworks have been developed from polycyclic hydrocarbons. Thus, Kuck and coworkers143 have recently reported an unexpected tandem reaction, which formally consists of a condensation/cyclodehydrogenation sequence starting from triptidan-9-one 233 leading to the fn/wso-tetracyclic propellane 234 (Scheme 72). The reaction of the tribenzo[3.3.3]propellane ketone 233 with benzylhthium/TMEDA afforded an efficient one-pot peri annulation of a dihydronaphthalene (Scheme 72). The key step of this unexpected tandem reaction was determined to be a nucleophilic cychzation followed by hydride elimination. 

Two sequential electrochemical annulations of an electron-rich 3,4-disubstituted furan ring were employed to generate the fused tricyclic ring system of arteannuins. The second reaction, as depicted below, represented the formation of a quaternary carbon center by a formal 6-endo cyclization under these anodic oxidation conditions <07OL4599>. 

Annulations of allylic cation species with diene moieties are formally classified according to a mechanistic descriptor (Class A and B), where Class A is a concerted mechanism and Class B is the stepwise one as shown in Scheme 12. 

Alkoxy iron complexes of the type (316) will also react with alkynes to give six-membered ring products that, like the two-alkyne annulation, are formally the result of a [2 -i- 2 -i- 1 + 1] cycloaddition. The formation of these pyrone complexes (317) have only been reported from the reactions of alkynes with iron-carbene complexes. These pyrones are also the only product from the reaction of an alkyne with any carbene complex which incorporates one alkyne, two carbon monoxides and the carbene ligand. 

Boger and others (82JOC3761 82JOC3763 83JOC623 85JA5754) used this pyridine annulation for the formal total synthesis of antitumor, antibiotic streptonigrin (63) by an intermolecular Diels-Alder reaction between 1,2,4-... 

W.H. Moser and co-workers developed a new and efficient method for the stereocontrolled construction of spirocyclic compounds, including the spirocyclic core of the antitumor agent fredericamycin The strategy involved a one-pot aldol additioniBrook rearrangement cyclization sequence beginning from arene chromium tricarbonyl complexes and can formally be described as a [3+2] annulation. 

H.J. Schafer et al. achieved the formal total synthesis of the trinorguaiane sesquiterpenes ( )-clavukerin and ( )-isoclavukerin by using the Danheiser cyciopentene annulation as the key step. Racemic 4-methylcyclohept-2-en-1-one was reacted with (trimethylsilyl)allene in the presence of 1.7 equivalents of TiCU in dichloromethane at -78 °C to afford a 1 1 mixture of the c/s-fused diastereomers, which were easily separated by HPLC. The diastereomers were then converted to key fragments of earlier total syntheses of the above mentioned natural products. 

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