Chemoselectivity cyclization

In the reactions of 4-amino-l-azadienes 295 with esters of glyoxylic acid, chemoselective cyclization occurred with displacement of the amino group NHR, and 2/7-1,3-oxazine-2-carboxylic acid derivatives 296 were formed in high yields instead of the corresponding 1,2-dihydropyrimidines usually obtained in the reactions of 295 with aliphatic or aromatic aldehydes (Equation 28) <1996T3095>. 

This section concludes with a description of tandem synthetic strategies (Section 14.1.6) in which sequential reactions involve combinations of steps such as dendrimer formations combined with cyclic peptides (Section 14.1.6.1), chemoselective cyclization combined with divergent syntheses (Section 14.1.6.3), and many thiol-based reactions and cyclizations (Sections 14.1.6.4—14.1.6.7) J18 ... 

A more versatile reducing agent is samarium diiodide, which promotes chemoselective cyclizations of functionalized keto aldehydes in a stereodefined manner to form 2,3-dihydrocyclopentane carboxylate derivatives in good yields and with diastereoselectivities of up to 200 1 (equation 38)7 The reaction proceeds via selective one-electron reduction of the aldehyde component and subsequent nucleophilic attack on the ketone moiety. Stereochemical control is established by chelation of the developing diol (19) with Sm " " which thereby selectively furnishes cis diols (equation 39). The stereoselective M/-cyclization of 1,5-diketones to cis cyclopentane-1,2-diols using TiCU/Zn has been used to prepare stereodefined sterically hindered acyclic 1,2-diols when a removable heteroatom, such as sulfur or selenium, is included in the linking chain (equation 40). 

A variety of natural products have been synthesized via application of reductive pinacolic couplings. An early example is the cyclization of the keto aldehyde (51) to the alkene (52 equation 89) a precursor to the terpene, cuparene (18).A modified McMurry procedure provides a novel route to steroids such as estrone methyl ether, via chemoselective cyclization of the keto aldehyde (53 equation 90). The... 

Scheme 40 Beccalli s chemoselective cyclization of indole carboxamide derivatives...

In 2003, Beccalli et al. reported an intramolecular variant, allowing chemoselective cyclization of indole carboxamide derivatives into (3-carbolinones (path A) or pyrazino[l,2-a]indoles (path B) (Scheme 40) [68]. The chemoselectivity of the cyclization could be controlled by the reaction conditions. PdCl2(MeCN)2 and benzoquinone in DMF/THF made possible C-H functionalization at the C3 position of indole, whilst Pd(OAc)2 in Na2CC>3 and -Bu4XC1 in DMF resulted in intramolecular amination of the double bond (N-H functionalization). 

Scheme 17. Chemoselective cyclizations directed by the captodative effect...

Fukuzumi T, Ju L, Bode JW (2012) Chemoselective cyclization of unprotected linear peptides by a-ketoacid-hydroxylamine amide-ligation. Org Biomol Chem 10 5837-5844... 

Magomedov NA, Ruggiero PL, Tang Y. Chemoselective cyclizations of divinyl ketones to cyclohexenones mediated by Lewis acid and base. Org. Lett. 2004 6 3373-3375. 

Palladium catalyzed cycloisomerizations of 6-cn-l-ynes lead most readily to five-membered rings. Palladium binds exclusively to terminal C = C triple bonds in the presence of internal ones and induces cyclizations with high chemoselectivity. Synthetically useful bis-exocyclic 1,3-dienes have been obtained in high yields, which can, for example, be applied in Diels-Alder reactions (B.M. Trost, 1989). 

The field of alkaloid synthesis via tandem cyclizations favors the application of (TMSlsSiH over other radical-based reagents, due to its very low toxicity and high chemoselectivity. For example, cyclization of the iodoarylazide 102, mediated by (TMSlsSiH under standard experimental conditions, produced the N-Si(TMS)3 protected alkaloid 103 that after washing with dilute acid afforded the amine 104 in an overall 83% yield from 102 (Reaction 81). ° The formation of the labile N-Si(TMS)3 bond was thought to arise from the reaction of the product amine 104 with the by-product (TMSlsSil. The skeletons of ( )-horsfiline, ( )-aspidospermidine and (+ )-vindoline have been achieved by this route. - ... 

In another route employing alkynes, it was found that heating propargyl azadienes 7 in toluene at 25-60 °C produces pyrrolic imines 8 which hydrolyze upon work-up to afford 3-acylpyrroles 9 <96JOC2185>. This exo-dig cyclization occurs with complete chemoselectivity wherein the more substituted nitrogen is involved in the cyclization. 

The reductive coupling/silylation reaction was extended to more complicated polyenes, such as the triene-substituted cyclopentanol 73, which cyclizes to provide 74 with a 72% yield and 6 1 dr after oxidation (Eq. 10) [44], The reaction is chemoselective the initial insertion occurs into the allyl substituent, which then inserts into the less hindered of the two remaining olefins, leaving the most hindered alkene unreacted. 

Alternatively, Ballini devised a new strategy to synthesize tri-alkylated pyrroles from 2,5-dialkylfurans and nitroalkanes <00SL391>. This method involves initial oxidation of 2,5-dimethylfuran with magnesium monoperoxyphthalate to cA-3-hexen-2,5-dione (6). Conjugate addition of the nitronate anion derived from the nitro compound 7 to 6 followed by chemoselective hydrogenation of the C-C double bond of the resulting enones 8 (obtained by elimination of nitrous acid from the Michael adduct) completes the conversion to the alkylated y-diketones 9. Final cyclization to pyrroles 10 featured improved Paal-Knorr reaction conditions involving reaction of the diketones with primary amines in a bed of basic alumina in the absence of solvent. 

Palladium-catalyzed cyclization of alkenes and alkynes were reported by Balme and co-workers.143 144 Intramolecular carbopalladation occurs to give polycyclic compounds. It has been shown that the nucleophile type has a large influence on the cyclization process. Both 5-exo- and 6-endo-cyclization are observed for substrates with nitrile (116 and 118) and ester (120, 122, and 124) substituents, respectively (Scheme 36). When a mixed nucleophile (CN and C02Me) is used, a mixture of 5-exo and 6-endo products is obtained. The chemoselectivity is controlled by the size of the nucleophile used. The stereochemistry of the initial double bond plays an important role on the stereoselectivity of the cyclization. (Z)-olefins (118 and 120) and (/. )-olefins (116 and 124) afford as- (119 and 121) and trans-cyclization products (117 and 123), respectively. 

The initially formed titanium enolate 80 adds, in a diastereoselective fashion, to the electrophilic center of the activated oxime. The generated adduct 81 cyclizes chemoselectively to afford the desired /f-azetine, which is converted, with retention of configuration, to the corresponding /3-amino carbonyl compounds 82 via 3V-acetylation followed by hydrolysis. 

Garbay reported the chemoselective reduction of a a-dehydrophenylala-nine substrate bearing a p-acrylate moiety [105]. Robinson et al. have also used a tandem, one-pot asymmetric hydrogenation-hydroformylation-cyclization approach to generate six- to eight-membered cyclic a-amino acids [136]. 

The same starting material can also be employed to synthesize the antipode (i )-methanophenazine [(i )-lOj, as R)-3l may easily be transformed into lactone (S)-30 by chemoselective reduction of the ester functionality [43] and subsequent cyclization. 

The total synthesis of the carbazomycins emphasizes the utility of the iron-mediated synthesis for the construction of highly substituted carbazole derivatives. The reaction of the complex salts 6a and 6b with the arylamine 20 leads to the iron complexes 21, which prior to oxidative cyclization have to be protected by chemoselective 0-acetylation to 22 (Scheme 13). Oxidation with very active manganese dioxide followed by ester cleavage provides carbazomycin B 23a [93] and carbazomycin C 23b [94]. The regioselectivity of the cyclization of complex 22b to a 6-methoxycarbazole is rationalized by previous results from deuterium labeling studies [87] and the regiodirecting effect of the 2-methoxy substituent of the intermediate tricarbonyliron-coordinated cyclo-hexadienylium ion [79c, 79d]. Starting from the appropriate arylamine, the same sequence of reactions has been applied to the total synthesis of carbazomycin E (carbazomycinal) [95]. 

For the quinone imine cyclization of iron complexes to carbazoles the arylamine is chemoselectively oxidized to a quinone imine before the cyclodehydrogenation [99]. The basic strategy of this approach is demonstrated for the total synthesis of the 3-oxygenated tricyclic carbazole alkaloids 4-deoxycarbazomycin B, hyellazole, carazostatin, and 0-methylcarazostatin (Scheme 17). 

The chemoselective addition of silyl radical to the double bond of the (3-alkenyloxyenone derivative 24 was instead planned in Reaction (7.29) and accompanied by a 5-exo-trig radical cyclization leading to the diastereomeric cyclic ether products [40]. 

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