“…Formation of the C(8)−C(9) bond in 1 was envisioned to result from the addition of an organometallic reagent 3 to Weinreb amide 2 . A novel Mitsunobu chain extension with sulfonimide 4 and deprotection of the o -nitrophenylsulfonyl group should complete the highly convergent segment assembly . Hydroxamate 2 can be obtained from the Evans-oxazolidinone-derived imide 5 , which also serves to install the α-carbonyl stereocenter at C(7).…”
Section: Total Syntheses Of (7s10r)- and (7r10r)-pitiamide Amentioning
confidence: 99%
“…Conversion of the methyl ester into the primary amide 22 with trimethylaluminum and ammonium chloride according to the useful protocol of Weinreb et al followed by N-nosylation provided imide 4 in 73% overall yield from 7 . The amide nitrogen was activated with the nosyl 51 group to facilitate the planned Mitsunobu displacement. , 5 …”
Section: Total Syntheses Of (7s10r)- and (7r10r)-pitiamide Amentioning
confidence: 99%
“…Desilylation now proceeded uneventfully, and Mitsunobu displacement of the primary hydroxyl group led to imide 25 in 76% yield from 23 . To the best of our knowledge, this is the first application of a nosyl-protected amide in a segment coupling . The desired (7 S ,10 R )-diastereomer of pitiamide A was readily obtained after deprotection of the nosyl group with thiophenol and potassium carbonate in dimethylformamide (DMF), removal the ethoxy ethyl ether with pyridinium p -toluenesulfonate (PPTs) in MeOH, and oxidation with Dess−Martin periodinane .…”
Section: Total Syntheses Of (7s10r)- and (7r10r)-pitiamide Amentioning
We report the joint application of ab initio computations and total synthesis to assign the absolute configuration of a new natural product. The expected specific rotations of the (7S,10R)-and (7R,10R)-isomers of pitiamide A in a CHCl 3 solvent continuum model were determined as +8 and -39, respectively, by CADPAC calculations of the electric-dipole-magnetic-dipole polarizability tensor. Total syntheses of these two stereoisomers of the marine metabolite were achieved by a convergent strategy that utilized Evans' oxazolidinone alkylation, a novel water-accelerated modification of Negishi's zirconocene-catalyzed asymmetric carbometalation as well as an unusual segment condensation via Mitsunobu alkylation of a nosyl-activated amide. The experimental optical rotation measurements confirmed the results of the computational optical rotation predictions. On the basis of NMR comparisons, the configuration of pitiamide A was assigned as (7R,10R). These studies highlight the considerable structural significance of [R] D data, but, because the optical rotation of the natural product was different from either synthetic diastereomer, our work serves also as an illustration of potential problems with obtaining accurate experimental [R] D data for natural samples.The chlorinated lipid pitiamide A (1) was isolated in 1997 from an extract of a mixed assemblage of Lyngbya majuscula and Microcoleus sp. growing on intact colonies of the hard coral Porites cylindrica on Guam. 1 Pitiamide may act as a feeding deterrent to both vertebrate and invertebrate herbivore species, but the determination of its biological profile has been limited by the lack of availability of sufficient quantities of the natural product.The structure of this unusual vinyl chloride-containing marine metabolite (Figure 1) was determined by 2D NMR spectral analysis and mass spectroscopy, and its [R] D was found to be -10.3 (c 3.0, CHCl 3 , 27°C). 2 The absolute and relative configurations at C(7) and C(10) were not assigned. Pitiamide A is a temperature-and light-sensitive oil, and due to the flexibility of most of its backbone chain, a stereochemical assignment based entirely on NMR spectroscopic methods has not been realized. Elucidation of its relative and absolute stereochemistry by circular dichroism (CD) is also not promising, in particular since the stereocenter at C(10) is not part of a strongly asymmetrically perturbed chromophore absorbing at λ >180 nm (vide infra). Accordingly, calculation of the expected molar rotation of pitiamide A diastereomers and enantiomers represents the most attractive solution to this structural problem, but is most challenging due to the unusually high level of flexibility in the lipid backbone. 3 Recently, we devised a Monte Carlo/ab initio approach to assign the configuration of the complex natural product hennoxazole A from computation of the electric-dipole magneticdipole polarizability tensor of suitable fragment molecules. 3 The computed rotations are Boltzmann-weighted averages of values obtained for individual f...
“…Formation of the C(8)−C(9) bond in 1 was envisioned to result from the addition of an organometallic reagent 3 to Weinreb amide 2 . A novel Mitsunobu chain extension with sulfonimide 4 and deprotection of the o -nitrophenylsulfonyl group should complete the highly convergent segment assembly . Hydroxamate 2 can be obtained from the Evans-oxazolidinone-derived imide 5 , which also serves to install the α-carbonyl stereocenter at C(7).…”
Section: Total Syntheses Of (7s10r)- and (7r10r)-pitiamide Amentioning
confidence: 99%
“…Conversion of the methyl ester into the primary amide 22 with trimethylaluminum and ammonium chloride according to the useful protocol of Weinreb et al followed by N-nosylation provided imide 4 in 73% overall yield from 7 . The amide nitrogen was activated with the nosyl 51 group to facilitate the planned Mitsunobu displacement. , 5 …”
Section: Total Syntheses Of (7s10r)- and (7r10r)-pitiamide Amentioning
confidence: 99%
“…Desilylation now proceeded uneventfully, and Mitsunobu displacement of the primary hydroxyl group led to imide 25 in 76% yield from 23 . To the best of our knowledge, this is the first application of a nosyl-protected amide in a segment coupling . The desired (7 S ,10 R )-diastereomer of pitiamide A was readily obtained after deprotection of the nosyl group with thiophenol and potassium carbonate in dimethylformamide (DMF), removal the ethoxy ethyl ether with pyridinium p -toluenesulfonate (PPTs) in MeOH, and oxidation with Dess−Martin periodinane .…”
Section: Total Syntheses Of (7s10r)- and (7r10r)-pitiamide Amentioning
We report the joint application of ab initio computations and total synthesis to assign the absolute configuration of a new natural product. The expected specific rotations of the (7S,10R)-and (7R,10R)-isomers of pitiamide A in a CHCl 3 solvent continuum model were determined as +8 and -39, respectively, by CADPAC calculations of the electric-dipole-magnetic-dipole polarizability tensor. Total syntheses of these two stereoisomers of the marine metabolite were achieved by a convergent strategy that utilized Evans' oxazolidinone alkylation, a novel water-accelerated modification of Negishi's zirconocene-catalyzed asymmetric carbometalation as well as an unusual segment condensation via Mitsunobu alkylation of a nosyl-activated amide. The experimental optical rotation measurements confirmed the results of the computational optical rotation predictions. On the basis of NMR comparisons, the configuration of pitiamide A was assigned as (7R,10R). These studies highlight the considerable structural significance of [R] D data, but, because the optical rotation of the natural product was different from either synthetic diastereomer, our work serves also as an illustration of potential problems with obtaining accurate experimental [R] D data for natural samples.The chlorinated lipid pitiamide A (1) was isolated in 1997 from an extract of a mixed assemblage of Lyngbya majuscula and Microcoleus sp. growing on intact colonies of the hard coral Porites cylindrica on Guam. 1 Pitiamide may act as a feeding deterrent to both vertebrate and invertebrate herbivore species, but the determination of its biological profile has been limited by the lack of availability of sufficient quantities of the natural product.The structure of this unusual vinyl chloride-containing marine metabolite (Figure 1) was determined by 2D NMR spectral analysis and mass spectroscopy, and its [R] D was found to be -10.3 (c 3.0, CHCl 3 , 27°C). 2 The absolute and relative configurations at C(7) and C(10) were not assigned. Pitiamide A is a temperature-and light-sensitive oil, and due to the flexibility of most of its backbone chain, a stereochemical assignment based entirely on NMR spectroscopic methods has not been realized. Elucidation of its relative and absolute stereochemistry by circular dichroism (CD) is also not promising, in particular since the stereocenter at C(10) is not part of a strongly asymmetrically perturbed chromophore absorbing at λ >180 nm (vide infra). Accordingly, calculation of the expected molar rotation of pitiamide A diastereomers and enantiomers represents the most attractive solution to this structural problem, but is most challenging due to the unusually high level of flexibility in the lipid backbone. 3 Recently, we devised a Monte Carlo/ab initio approach to assign the configuration of the complex natural product hennoxazole A from computation of the electric-dipole magneticdipole polarizability tensor of suitable fragment molecules. 3 The computed rotations are Boltzmann-weighted averages of values obtained for individual f...
“…Based on the chemistry developed by Trost, we thought it likely that the reaction of the nucleobase with a π-allylpalladium intermediate would be both regioselective and stereoselective (see Scheme 3). The formation of the π-allylpalladium complex would be facilitated by the relief of the four membered ring strain 25 and the formation of the requisite cis-1,4-substituted cyclopentenoid moiety would proceed with a net retention of configuration as a consequence of the well established double inversion that is operative in these reactions. Finally, further manipulation of intermediate 15 might then result in the formation of the carbocyclic nucleoside Abacavir 2b.…”
An enantiopure β-lactam with a suitably disposed electron withdrawing group on nitrogen, participated in a π-allylpalladium mediated reaction with 2,6-dichloropurine tetrabutylammonium salt to afford an advanced cis-1,4-substituted cyclopentenoid with both high regio- and stereoselectivity. This advanced intermediate was successfully manipulated to the total synthesis of (-)-Abacavir.
“…For example, compound 7 was subjected to auxiliary removal and N−N bond cleavage as depicted in Scheme . Thus, treatment of 7 with sodium borohydride delivered alcohol 8 (84%) . Reduction of 8 with PtO 2 in 1.2 M methanolic HCl at 80 psi H 2 , followed by isolation of the bisammonium hydrochloride salt and subsequent treatment with excess benzoyl chloride provided 9 in 79% overall yield from 7 (two steps).…”
We report the diastereoselective addition of a wide range of nucleophiles to chiral pyrazolines to provide facile access to a range of useful densely functionalized building blocks for asymmetric synthesis. Coupled with the asymmetric cycloaddition reaction of Me(3)SiCHN(2) to chiral acrylates, access to these chiral heterocycles is considerably expanded.
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