Functionalized Azamacrocycles and Large-Ring α-Amino Esters by One-Pot Syntheses from Methyl 2-Siloxy-2-vinylcyclopropanecarboxylates

Abstract

Siloxycyclopropane 1 served as starting material for intermediate alkylation products 2, 7, 11, 14, and 17, which were elongated to provide a variety of precursor compounds bearing terminal N-benzyl groups. These substrates were subjected to a cesium fluoride-promoted ring-opening/ring-closure sequence to afford azamacrocycles 19, 21, 22, 23, 25, 26, 27, and 28 in moderate to good yields. The cyclic products have different ring sizes and numbers of nitrogen atoms, and may incorporate meta-substituted benzene or pyridine units. A second approach employed glycine derivative 29 as the

Donor−Acceptor-Substituted Cyclopropane Derivatives and Their Application in Organic Synthesis

“…These reaction sequences have obvious potential for preparation of large heterocycles that are difficult to obtain by alternative methods. 137 Fluoride-promoted ring opening of siloxycyclopropane 310 under aprotic conditions in the presence of vinylphosphonium salts 311 furnished cyclopentene derivatives 312 in good yields (Scheme 86). Here, the intermediate ester enolate generated by desilylation and ring cleavage underwent a Michael addition followed by an intramolecular Wittig reaction.…”

“…A similar synthesis employs dimethyl malonate 280 (Scheme 79) as starting material, and chain elongation under introduction of the amino acid moiety with 457 provided a precursor for the related extended macroheterocyclic compound 460. 137 The methods described in Schemes 84 and 85 were also applied to syntheses of macrocycles containing peptide substructures. Thus, the glycine/proline derivative 461 was cyclized to compound 462 in moderate yield (Scheme 127).…”

“…Compound 301 was used for the ring-cleavage/ring-closure cascade, furnishing azecine derivative 302 in low yield together with the dimer. Alternatively, 301 may be chain-elongated and then leads to compounds better suitable for ring closure. , Reaction of bromide 279 with 1,4-(dibenzylamino)-2-butene dihydrochloride ( 303 ) furnished cyclopropane derivative 304 in reasonable yield, which was converted into the 15-membered ring 305 incorporating two nitrogen atoms, with moderate efficiency. Following this general modular approach for construction of the precursors, other macroheterocycles, e.g.…”

“…By treatment with hydrazine hydrate, pyridinophane 307 was transformed into macrocyclic pyridazinone 309 in moderate yield. These reaction sequences have obvious potential for preparation of large heterocycles that are difficult to obtain by alternative methods 84

85

…”

“…The precursor obtained, 458 , was treated with fluoride to induce the anticipated ring-opening/ring-closure cascade, which actually provided cyclic functionalized amino acid derivative 459 . A similar synthesis employs dimethyl malonate 280 (Scheme ) as starting material, and chain elongation under introduction of the amino acid moiety with 457 provided a precursor for the related extended macroheterocyclic compound 460 126 …”

Donor−Acceptor-Substituted Cyclopropane Derivatives and Their Application in Organic Synthesis

“…These reaction sequences have obvious potential for preparation of large heterocycles that are difficult to obtain by alternative methods. 137 Fluoride-promoted ring opening of siloxycyclopropane 310 under aprotic conditions in the presence of vinylphosphonium salts 311 furnished cyclopentene derivatives 312 in good yields (Scheme 86). Here, the intermediate ester enolate generated by desilylation and ring cleavage underwent a Michael addition followed by an intramolecular Wittig reaction.…”

“…A similar synthesis employs dimethyl malonate 280 (Scheme 79) as starting material, and chain elongation under introduction of the amino acid moiety with 457 provided a precursor for the related extended macroheterocyclic compound 460. 137 The methods described in Schemes 84 and 85 were also applied to syntheses of macrocycles containing peptide substructures. Thus, the glycine/proline derivative 461 was cyclized to compound 462 in moderate yield (Scheme 127).…”

“…Compound 301 was used for the ring-cleavage/ring-closure cascade, furnishing azecine derivative 302 in low yield together with the dimer. Alternatively, 301 may be chain-elongated and then leads to compounds better suitable for ring closure. , Reaction of bromide 279 with 1,4-(dibenzylamino)-2-butene dihydrochloride ( 303 ) furnished cyclopropane derivative 304 in reasonable yield, which was converted into the 15-membered ring 305 incorporating two nitrogen atoms, with moderate efficiency. Following this general modular approach for construction of the precursors, other macroheterocycles, e.g.…”

“…By treatment with hydrazine hydrate, pyridinophane 307 was transformed into macrocyclic pyridazinone 309 in moderate yield. These reaction sequences have obvious potential for preparation of large heterocycles that are difficult to obtain by alternative methods 84

85

…”

“…The precursor obtained, 458 , was treated with fluoride to induce the anticipated ring-opening/ring-closure cascade, which actually provided cyclic functionalized amino acid derivative 459 . A similar synthesis employs dimethyl malonate 280 (Scheme ) as starting material, and chain elongation under introduction of the amino acid moiety with 457 provided a precursor for the related extended macroheterocyclic compound 460 126 …”

Donor−Acceptor-Substituted Cyclopropane Derivatives and Their Application in Organic Synthesis

“…These reaction sequences have obvious potential for preparation of large heterocycles that are difficult to obtain by alternative methods. 137 Fluoride-promoted ring opening of siloxycyclopropane 310 under aprotic conditions in the presence of vinylphosphonium salts 311 furnished cyclopentene derivatives 312 in good yields (Scheme 86). Here, the intermediate ester enolate generated by desilylation and ring cleavage underwent a Michael addition followed by an intramolecular Wittig reaction.…”

“…A similar synthesis employs dimethyl malonate 280 (Scheme 79) as starting material, and chain elongation under introduction of the amino acid moiety with 457 provided a precursor for the related extended macroheterocyclic compound 460. 137 The methods described in Schemes 84 and 85 were also applied to syntheses of macrocycles containing peptide substructures. Thus, the glycine/proline derivative 461 was cyclized to compound 462 in moderate yield (Scheme 127).…”

“…Compound 301 was used for the ring-cleavage/ring-closure cascade, furnishing azecine derivative 302 in low yield together with the dimer. Alternatively, 301 may be chain-elongated and then leads to compounds better suitable for ring closure. , Reaction of bromide 279 with 1,4-(dibenzylamino)-2-butene dihydrochloride ( 303 ) furnished cyclopropane derivative 304 in reasonable yield, which was converted into the 15-membered ring 305 incorporating two nitrogen atoms, with moderate efficiency. Following this general modular approach for construction of the precursors, other macroheterocycles, e.g.…”

“…By treatment with hydrazine hydrate, pyridinophane 307 was transformed into macrocyclic pyridazinone 309 in moderate yield. These reaction sequences have obvious potential for preparation of large heterocycles that are difficult to obtain by alternative methods 84

85

…”

“…The precursor obtained, 458 , was treated with fluoride to induce the anticipated ring-opening/ring-closure cascade, which actually provided cyclic functionalized amino acid derivative 459 . A similar synthesis employs dimethyl malonate 280 (Scheme ) as starting material, and chain elongation under introduction of the amino acid moiety with 457 provided a precursor for the related extended macroheterocyclic compound 460 126 …”

Donor−Acceptor-Substituted Cyclopropane Derivatives and Their Application in Organic Synthesis

“…These reaction sequences have obvious potential for preparation of large heterocycles that are difficult to obtain by alternative methods. 137 Fluoride-promoted ring opening of siloxycyclopropane 310 under aprotic conditions in the presence of vinylphosphonium salts 311 furnished cyclopentene derivatives 312 in good yields (Scheme 86). Here, the intermediate ester enolate generated by desilylation and ring cleavage underwent a Michael addition followed by an intramolecular Wittig reaction.…”

“…A similar synthesis employs dimethyl malonate 280 (Scheme 79) as starting material, and chain elongation under introduction of the amino acid moiety with 457 provided a precursor for the related extended macroheterocyclic compound 460. 137 The methods described in Schemes 84 and 85 were also applied to syntheses of macrocycles containing peptide substructures. Thus, the glycine/proline derivative 461 was cyclized to compound 462 in moderate yield (Scheme 127).…”

“…Compound 301 was used for the ring-cleavage/ring-closure cascade, furnishing azecine derivative 302 in low yield together with the dimer. Alternatively, 301 may be chain-elongated and then leads to compounds better suitable for ring closure. , Reaction of bromide 279 with 1,4-(dibenzylamino)-2-butene dihydrochloride ( 303 ) furnished cyclopropane derivative 304 in reasonable yield, which was converted into the 15-membered ring 305 incorporating two nitrogen atoms, with moderate efficiency. Following this general modular approach for construction of the precursors, other macroheterocycles, e.g.…”

“…By treatment with hydrazine hydrate, pyridinophane 307 was transformed into macrocyclic pyridazinone 309 in moderate yield. These reaction sequences have obvious potential for preparation of large heterocycles that are difficult to obtain by alternative methods 84

85

…”

“…The precursor obtained, 458 , was treated with fluoride to induce the anticipated ring-opening/ring-closure cascade, which actually provided cyclic functionalized amino acid derivative 459 . A similar synthesis employs dimethyl malonate 280 (Scheme ) as starting material, and chain elongation under introduction of the amino acid moiety with 457 provided a precursor for the related extended macroheterocyclic compound 460 126 …”