Abstract:. Can. J. Chem. 63, 2844 (1985). The key chiral synthons, (R)-3-isopropenyl-6-heptenoic acid and (R)-3-isopropenyl-6-heptenal, needed for the synthesis of (3Z,6R)-3-methyl-6-isopropenyl-3,9-decadien-I-yl acetate, a component of the sex pheromone of the California red scale, Aonidiella aurantii, have been prepared by asymmetric synthesis. The chiral acid was synthesized in 86% ee by an asymmetric 1,4-addition of isopropenylmagnesium bromide to the I-ephedrine amide derived from (E)-2,6-heptadienoic acid, follow… Show more
“…After 2 h (when the reaction was complete as evidenced by TLC) CH2Cl2 (150 mL) was added, and the mixture was filtered through a short pad of Celite. The solvent was evaporated, and the remaining liquid was chromatographed on a column of silica gel using CHCl 3-MeOH (98:2) as eluent to give 8a 14 as an oil (4.4 g, 76%). 1 H NMR: δ 9.91 (t, J ) 1 Hz, 1 H, H-1), 5.80 (m, 1 H, H-4), 5.21 (m, 2 H, H-5), 2.12 (m, 2 H, H-2), 1.95 (m, 2 H, H-3).…”
N-(5,5-Diacetoxypent-1-yl)doxorubicin (1b) is an intensely cytotoxic doxorubicin analogue that retains full potency against tumor cells that express elevated levels of P-glycoprotein and are resistant to doxorubicin. 1b was designed to be hydrolyzed in the presence of carboxylate esterases to N-(5-oxypent-1-yl)doxorubicin, an aldehyde capable of existing in equilibrium with a cyclic carbinolamine. To investigate the structural determinants of potency for 1b, we have prepared a series of chemically related compounds in which various omega-[bis(acetoxy)]alkyl or omega-[bis(acetoxy)]alkoxyalkyl groups are substituted at the 3'-amino position of the daunosamine sugar. These groups were selected to assess the effect of chain length, oxygen substitution, and carbinolamine ring size on analogue potency. The compounds were evaluated for their ability to inhibit the in vitro growth of the following cell lines: (a) Chinese hamster ovary (CHO) cells, (b) a CHO cell mutant 100-fold resistant to doxorubicin that expresses elevated levels of P-glycoprotein, (c) a murine ductal cell pancreatic adenocarcinoma (Panc 02), and (d) a murine mammary carcinoma (CA 755). The most potent members of the series were those that could form a straight chain aldehyde intermediate after esterase-mediated hydrolysis of the omega-bis(acetoxy) groups and give rise to 5- or 6-membered ring carbinolamines. Analogues capable of forming 7-, 8-, or 9-membered carbinolamines were markedly less active. The N-methyl derivative of 1b, which cannot give rise to a cyclic carbinolamine, was 2 orders of magnitude less potent than 1b. A branched chain analogue, 1f, which contained a tertiary carbon atom adjacent to the omega-bis(acetoxy) groups, was also substantially less active than its nonbranched counterpart, 1a. These findings suggest that the chain length of the 3'-amino substituents and the ability of the derived aldehydes to form 5- or 6-membered carbinolamines are critical determinants of biologic potency.
“…After 2 h (when the reaction was complete as evidenced by TLC) CH2Cl2 (150 mL) was added, and the mixture was filtered through a short pad of Celite. The solvent was evaporated, and the remaining liquid was chromatographed on a column of silica gel using CHCl 3-MeOH (98:2) as eluent to give 8a 14 as an oil (4.4 g, 76%). 1 H NMR: δ 9.91 (t, J ) 1 Hz, 1 H, H-1), 5.80 (m, 1 H, H-4), 5.21 (m, 2 H, H-5), 2.12 (m, 2 H, H-2), 1.95 (m, 2 H, H-3).…”
N-(5,5-Diacetoxypent-1-yl)doxorubicin (1b) is an intensely cytotoxic doxorubicin analogue that retains full potency against tumor cells that express elevated levels of P-glycoprotein and are resistant to doxorubicin. 1b was designed to be hydrolyzed in the presence of carboxylate esterases to N-(5-oxypent-1-yl)doxorubicin, an aldehyde capable of existing in equilibrium with a cyclic carbinolamine. To investigate the structural determinants of potency for 1b, we have prepared a series of chemically related compounds in which various omega-[bis(acetoxy)]alkyl or omega-[bis(acetoxy)]alkoxyalkyl groups are substituted at the 3'-amino position of the daunosamine sugar. These groups were selected to assess the effect of chain length, oxygen substitution, and carbinolamine ring size on analogue potency. The compounds were evaluated for their ability to inhibit the in vitro growth of the following cell lines: (a) Chinese hamster ovary (CHO) cells, (b) a CHO cell mutant 100-fold resistant to doxorubicin that expresses elevated levels of P-glycoprotein, (c) a murine ductal cell pancreatic adenocarcinoma (Panc 02), and (d) a murine mammary carcinoma (CA 755). The most potent members of the series were those that could form a straight chain aldehyde intermediate after esterase-mediated hydrolysis of the omega-bis(acetoxy) groups and give rise to 5- or 6-membered ring carbinolamines. Analogues capable of forming 7-, 8-, or 9-membered carbinolamines were markedly less active. The N-methyl derivative of 1b, which cannot give rise to a cyclic carbinolamine, was 2 orders of magnitude less potent than 1b. A branched chain analogue, 1f, which contained a tertiary carbon atom adjacent to the omega-bis(acetoxy) groups, was also substantially less active than its nonbranched counterpart, 1a. These findings suggest that the chain length of the 3'-amino substituents and the ability of the derived aldehydes to form 5- or 6-membered carbinolamines are critical determinants of biologic potency.
“…69 In an interesting comparative study, Whittaker and coworkers used three different methods of asymmetric induction to generate key dienal 177 enantioselectively. 70 The rst (Scheme 27A) began with two-carbon chain extension of 4-pentenal 183 with malonic acid and pyridine/pyrrolidine. Although the acid 184 was obtained as an E/Z mixture, the conditions used for conversion to the acid chloride 185 resulted in isomerization of the (Z)-isomer, producing pure (E)- Enantioselective addition of isopropenylmagnesium bromide created the chiral center, followed by hydrolysis of the imine to aldehyde (R)-177.…”
Section: Overview Of Scale and Mealybug Pheromonesmentioning
This article comprehensively reviews the syntheses of all known sex pheromones of scales and mealybugs, describes how they were identified, and how the synthetic pheromones are used in insect management.
“…Oxazolines provide a useful vehicle for the introduction of groups by a conjugate addition (Scheme 172). 561,682,705,706,[711][712][713][714][715] The Michael addition of a stabilized carbanion to these conjugated oxazolines does not provide high degrees of asymmetric induction. 617,687 Oxazoline 151, a nonchelating auxiliary, has shown to provide excellent stereoselection in aliphatic systems; the tert-butyl substituent provides the best selectivity.…”
Section: Conjugate Additionsmentioning
confidence: 99%
“…Oxazolines provide a useful vehicle for the introduction of groups by a conjugate addition (Scheme ). ,,,,− 172 …”
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