Intramolecular coupling synthesis

The cyclized products 393 can be prepared by the intramolecular coupling of diphenyl ether or diphenylamine(333,334]. The reaction has been applied to the synthesis of an alkaloid 394[335]. The intramolecular coupling of benzoyl-A-methylindole affords 5-methyl-5,10-dihydroindenol[l,2-b]indol-10-one (395) in 60% yield in AcOH[336]. Staurosporine aglycone (396) was prepared by the intramolecular coupling of an indole ring[337]. 

Synthesis of camptothecin (163) is another example[133]. The iboga alkaloid analog 164 has been synthesized smoothly by the intramolecular coupling of iodoindole and unsaturated ester to form an eight-membered ring. Af-Methyl protection of the indole is important for a smooth reaction[134]. An efficient construction of the multifunctionalized skeleton 165 of congeners of FR900482 has been achieved[135]. 

The intramolecular coupling of organostannanes is applied to macrolide synthesis. In the zearalenone synthesis, no cyclization was observed between arylstannane and alkenyl iodide. However, intramolecular coupling take.s place between the alkenylstannane and aryl iodide in 706. A similar cyclization is possible by the reaction of the alkenylstannane 707 with enol triflate[579]. The coupling was applied to the preparation of the bicyclic 1,3-diene system 708[580]. 

Diazotization and intramolecular coupling of suitable aromatic amines can also be used for the synthesis of 1,2,5-triazocines.12... 

Suitably positioned vinyl halide can undergo Heck-type intramolecular coupling to generate dienes (equations 124 and 125)216,217. When one of the reacting partners in the Heck reaction is a diene, trienes are obtained (equation 126)218. Heck coupling of ally lie alcohols and alkenyl iodides has been employed for the synthesis of vitamin A and related compounds (equation 127)219,220. A similar double Heck reaction on a Cio-diiodide with a Cis-allylic alcohol leads to -carotene as a mixture of isomers (equation 128)209e. 

Several examples of transition metal catalysis for the synthesis of piperidines appeared this year. Palladium catalyzed intramolecular urethane cyclization onto an unactivated allylic alcohol was described as the key step in the stereoselective synthesis of the azasugar 1-deoxymannojirimycin . A new synthetic entry into the 2-azabicyclo[3.3.1]nonane framework was accomplished through a palladium mediated intramolecular coupling of amine tethered vinyl halides and ketone enolates in moderate yields . A palladium catalyzed decarboxylative carbonylation of 5-vinyl... 

This route was also employed for the synthesis of macrocydic allenes 169 via intramolecular coupling of aromatic dialdehydes 168 [88]. Depending on the ring size, chemical yields of up to 90% of the desired products were achieved (Scheme 2.53). Furthermore, the introduction of additional oxygen atoms into the tether did not diminish the efficiency of the protocol and therefore allowed an access to allenic crown ethers of type 171. 

The stereoselective intramolecular coupling of a ketene dithioacetal to an oxygen nucleophile to afford (10), was used as a key step in the total synthesis of (+)-nemorensic acid [229]. 

Intramolecular coupling reactions could also be performed, as demonstrated by the synthesis of the tetracyclic derivative 558 <2006JOC1969>. 

Distinctly more hindered than the dioncophyllinc A-lactone 1, but still axially prostereogenic, is 6 which is obtained by intramolecular coupling in 87 % yield (see Section 2.2.2.2) which is the corresponding precursor for the synthesis of the related naphthalenylisoquinoline alkaloid (+)-ancistrocladisine10. 

A recent development in the synthesis of 3//-3-benzazepin-2-ones has been the photocyc-lization of A-(chloroacetyl)phenethylamines (Scheme 25). Ring closure is by homolysis of the alkyl halide followed by intramolecular coupling of the alkyl radical with an aromatic radical cation. Yields are good, especially with a stabilizing electron-donating group (MeO, NMe2) at the position meta to the ethylamino function (i.e. ortho or para to the site of cyclization). Isomeric benzazepinones are normally obtained (Scheme 25) with meta-substituted phenethylamines (80H(14)ll). 

A number of related couplings have been reported during the synthesis of the alkaloid ( )-cryptopleurine149 and also intramolecular coupling of diaryl amides to dibenzazepine and dibenzazodne structures.150 A versatile method for the preparation of tetrahydroquinolines and jololidines has been developed.151 The method involves the anodic oxidation of AT,AT-dimethyl-aniline in methanol to afford a-methoxylated or a, a -dimethoxylated compounds and subsequent treatment of products with Lewis acids in the presence of olefins. 

A. Chenede, E. Perrin, E. D. Rekai, and P. Sinay, Synthesis of C-disaccharides by a samarium diiodide induced intramolecular coupling reaction of tethered sugars, Synlett p. 420 (1994). 

This method is particularly effective with cyclic substrates, and the combined effects of intramolecular and intermolecular asymmetric induction give up to 76 1 (kf/ks) differentiation between enantiomers of a cyclic allylic alcohol. This kinetic resolution provides a practical method to resolve 4-hydroxy-2-cyclopentenone, a readily available but sensitive compound. Hydrogenation of the racemic compound at 4 atm H2 proceeds with kf/ks =11, and, at 68% conversion, gives the slow-reacting R enantiomer in 98% ee. The alcoholic product is readily convertible to its crystalline, enantiomerically pure fert-butyldimethylsilyl ether, an important building block in the three-component coupling synthesis of prostaglandins (67). 

Lewis acid catalyzed intramolecular coupling of allylsilanes with aziridines serves as a useful route for the synthesis of carbocycles having the y-amino olefin unit 104 (equation 80)149. However, this reaction does not occur in an intermolecular manner. 

Oxidative homocoupling of aromatic and heteroaromatic rings proceeds with Pd(OAc)2 in AcOH. Biphenyl (165) is prepared by the oxidative coupling of benzene [104,105], The reaction is accelerated by the addition of perchloric acid. Biphenyl-tetracarboxylic acid (169), used for polyimide synthesis, is produced from dimethyl phthalate (168) commercially [106], Intramolecular coupling of the indole rings 170 is useful for the synthesis of staurosporine aglycone 171 [107]. 

Hennings, D. D. Iwama, T. Rawal, V. H. Palladium-catalyzed (Ullmann-type) homocoupling of aryl halides a convenient and general synthesis of symmetrical biaryls via inter- and intramolecular coupling reactions. Org. Lett. 1999, 1, 1205-1208. 

Interestingly, CDI can also be utilised for the introduction of substituents by inter- or intramolecular coupling of OH moieties of the polysaccharide via a carbonate function. This synthesis was used to obtain dextran with 2-hydroxyethyl methacrylate moieties (dex-HEMA) and dex-HEMA with lactate spacer functions (Fig. 32). A new class of dextran derivatives (DS < 0.2) that can be polymerised containing hydrolysable groups is accessible [177]. 

As for the biaryl ether containing macrocycles, an array of bioactive macrocycles with an endo aryl-aryl bond exist in nature. A new palladium catalyzed reaction has been recently developed in which bis(pinacolato)diborane(4) mediated the process to reach such a structural motif. The reaction consists of a domino process involving a Miyaura s arylboronic ester synthesis and an intramolecular Suzuki-coupling. Synthesis of a bicyclic A-B-O-C ring system of RP-66453 273, a neurotensine receptor antagonist, with an endo aryl-aryl and an endo aryl-aryl ether bond was described (Scheme 53).141... 

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