Exo-methylene functionality

When preformed iminium salts are utilized in Mannich reactions, the reaction medium no longer needs to be a protic solvent, so the use of aprotic solvents allows the transformation of sensitive intermediates such as metal enolates. L.A. Paquette et al. carried out the highly regioselective introduction of an exo-methylene functionality during the total synthesis of (-)-O-methylshikoccin by reacting a potassium enolate with the Eschenmoser salt. The resulting p-A/,A/-dimethylamino ketone was converted to the corresponding quaternary ammonium salt and elimination afforded the desired a,p-unsaturated ketone (Eschenmoser methenylation). 

In a sodium ethoxide catalyzed condensation of 3,5-bis(arylmethylene)-4-piperidones 22 with ureas or thioureas, one of the exo-methylene functions is used to build up the pyrimidine part of a 8-methylene-l,4,5,6,7,8-hexahydropyrido[4,3-ethanolic solution of 1-methyl-3,5-bis(ferrocenylmethylene)-4-piperidone with an excess of thiourea in the presence of sodium ethoxide, the corresponding pyrido[4,3-r/]pyrimidine-2-thiol is obtained.512 The use of guanidine in this reaction affords the corresponding 2-amino compounds.513... 

Normally this is reacted with an alkene bearing electron withdrawing substituents, which make the substrate prone to Michael-type 1,4-addition. The resulting cyclisation product, exemplified by 41, has an exo methylene functionality. The mechanism is thought to be stepwise, consisting of nucleophilic attack at carbon followed by attack of the resulting enolate on the ir-allyl palladium unit. 

Intermediate 40 would be produced through a coupling reaction between the appropriately functionalized decalin aldehyde 41 (available from alcohol 42) and 3-lithio-y-pyrone 23. Intermediate 42 would be formed through the strategic [2,3]-Wittig rearrangement of stannylmethyl ether 43. On the basis of the results accumulated from the nalanthalide synthesis (cf. Section Total Synthesis of (—)-Nalanthalide and Scheme 6), we expected that the C9 stereogenic center and the C8 exo-methylene function in the product 42 would be simultaneously formed. Intermediate 43, in turn, would be derived from 14 [17]. 

More recently, Yang et al. [123] have examined a new approach in which a reactive functional group was introduced into polyolefins using methylenecyclopropane (Scheme 27). Thus, ethylene (1.0 atm) was copolymerized with methylenecyclopropane (0.25-2.5 ml) using [LnH(C5Me5)2]2 (Ln = Sm, Lu) in toluene at 25 °C. It was shown that 10-65 units of exo-methylenes were incorporated per 1000-CH2- units and the resulting polymer had an Mw of 66-92 x 103, yet its Mw/Mn was > 4. 

Tributyl tin radical mediated cyclization of the glucose derived exo-methylene furanose derivatives led to highly functionalized cA-fused bicyclic ethers. The product could subsequently be transformed into optically active tricyclic nucleoside analogue or oxepine derivative (Fig. 51).67... 

A Claisen-Ireland rearrangement has been applied to 1-exo-methylene pyranoses bearing enolizable ester functionalities at C-2 (Scheme 12a).65... 

When, furthermore, phenols (368) are coupled with 1 in the presence of a Pd° catalyst, the phenoxy-methyl-1,3-dienes 369 are produced [158]. As aryl allyl ethers, these can be made to undergo a Claisen rearrangement (205 °C, DMF) and the ensuing 2-(l,3-dienylmethyl)phenols 370 finally cydize in the presence of a trace of acid to a mixture of exo-methylene chromans 371 (major product) and dihydrobenzofur-ans 372 - a remarkable generation of functional and structural complexity from simple starting materials with 100% atom economy and underlining impressively the synthetic versatility of modern allene chemistry ... 

Research Focus Preparation of polymethylmethacrylate derivatives containing pendant sulfonyl or exo-methylene lactone functions. 

Tetrahydropyrans 182, formed by this process, proved to be highly valuable intermediates for the synthesis of 2,3,4,6-tetrasubstituted tetrahydropyrans. Indeed, the exo-methylene double bond can be easily transformed, with high stereocontrol, into a variety of useful functionalities. For example, Marko et al. used this approach during the total synthesis of pseudomonic acid analogue (Scheme 13.65) [49]. 

Rh-catalyzed cycloisomerization and a kinetic resolution process to conduct a formal synthesis (Scheme 11). Starting from the easy accessed enyne ester 28, a kinetic resolution process gives a highly functionalized y-lactone 29 with excellent enantioselectivity. Considering the ideal yield can only be as high as 50%, this transformation is very efficient. Further reduction of the exo-methylene proved highly selective and the three adjacent chiral center unit 30 could be obtained in high yield [71]. 

In addition to the compounds described by Suffness and Cordell in their 1985 review, the principal structures of which will be mentioned here, many new taxane-type substances have been discovered in extracts of yew since 1968. Each of these compounds may be classed as a particular type of taxane derivative characterized either by substitutions on certain carbon atoms (C-1, C-7, C-13) or by a particular functionality at C-20 (exo methylene, epoxide, oxetane, or direct linkage to C-2). 

Weyershausen, B, Nieger, M, Doetz, K H, Stereospecific exo-selective Diels-Alder reactions with carbohydrate-functionalized a-exo-methylene-2-oxacyclopentylidene chromium complexes, J. Org. Chem., 64, 4206-4210, 1999. 

In the laboratory of J.L. Wood, an expeditious approach to the densely functionalized isotwistane core of CP-263,114 was developed. For the proposed radical cyclization, an exo-methylene group was installed on a five-membered lactone ring. It was discovered that both the formation of the lactone ring and the Eschenmoser methenylation could be conducted in a one-pot operation by simply treating the a-acetoxy ketone with excess amounts of LiTMP and then with Eschenmoser s salt. 

Cyclic exo-methylene compounds bearing a chiral acetal function prove to be excellent dieno-philes in the noncatalyzed Diels-Alder reaction. Dioxolanones 8 react with cyclopentadiene (9) and acyclic dienes 12 and 15 to afford adducts with diastereoselectivities as high as 100% 28,29. The major adduct 16 from the addition of 8b to diene 15 has been applied to the synthesis of the top half of kijanolide30. 

Ergosterol also arises from lanosterol by a one-carbon addition to C-24 followed by a shift of the A24 double bond to the exo position, forming a A24 methylene function. There follows oxidative removal of the three methyls at C-14 and C-4 with concomitant shift of the A24 double bond to A22 position isomerization of A8 position to A7 and formation of an additional A5 double bond yielding ergosterol. 

The volatile monoterpene karahana ether 48 shows an xo-methylene function which can be retrosynthetically correlated with a triple bond, that is, it can be generated via a radical-mediated 6-exo-dig intramolecular cyclization of a suitable alkyl radical onto an alkyne function (equation 42) . ... 

The Ferrier carbocyclization reaction of an enol-acetate substrate gives an a,p-dihydroxy-cyclohexanol derivative (see Schemes 12.7 and 12.81. This transformation would be effective for the chiral synthesis of inositol derivatives. A retrosynthetic plan for the marine natural product tetrodotoxin 88 based on the enol-acetate version of Ferrier carbocyclization is shown in Scheme 12.22. Tetrodotoxin 88 was planned to be synthesized from lactone 89, the precursor of which would be highly functionalized cyclohexane 90. Cyclohexane 90 was envisioned to arise from cyclohexanone 91. For the preparation of 91, Ferrier carbocyclization of enol acetate 92 would be a suitable transformation. d-Glucose derivative 93 possessing an exo-methylene at C-3 would serve as a promising precursor of 92. 

In contrast to C(2)-linked terminal alkynes 145, gold-catalyzed alkylation of C(3)-linked tetrahydrofurans bearing terminal alkyne functions 148 mainly led to the formation of major product exo-methylene cyclopentanes 149 and minor products 150 (Scheme 55). This reversed selectivity might be explained by the relative stability of intermediates III and V. Steric constrains should be weaker for the fused bicyclic intermediate V (in Scheme 55) than intermediate HI (in Scheme 54), thus allowing a rapid [l,2]-hydride shift, which leads to VI rather than a [1,2]-alkyl shift, which leads to III. 

The work of Garranti and Zecchi provides additional examples in which cyclization was shown to occur with alkynes and alkenes. They have, however, identified further limitations regarding chain length and hence ring size of final products. Pocar and co-workers have illustrated the intermolecular version of this reaction by use of nitrile oxides and tran5-1,3-diaminopropenes. A base is necessary for reaction to occur, and of several tried, triethylamine proved superior. The exo-methylene isoxazolines (363) were obtained after elimination of one of the amino-functions. When sodium methoxide in methanol was used, however, the reverse elimination occurred to give the isoxazole (362) (Scheme 52). 

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