Convergent, enantiospecific total synthesis of the hypocholesterolemic agent (+)-compactin

Grieco, Paul A.; Lis, Randall; Zelle, Robert E.; Finn, John M.

doi:10.1021/ja00279a041

Cited by 66 publications

(23 citation statements)

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“…The aqueous layer was extracted with EtOAc and the combined organic layer was washed with a saturated aqueous NaHCO 3 solution and dried over MgSO 4 . The solvent was removed under reduced pressure and the residue was subjected to the flash silica gel chromatography to afford 0.14 g (98%) of 53 as a white solid: mp 139-141°C; IR (neat) 1798, 1736, 1340, 1150, and 702 cm −1; 1 H-NMR (CDCl 3 , 400 MHz) δ 1.42 (q, 1H, J = 12.0 Hz), 1.58, (s, 9H), 2.28 (dd, 1H, J =20.0 and 13.6 Hz), 2.45 (ddd, 1H, J = 12.0, 5.6 and 4.0 Hz), 2.61-2.68 (m, 1H), 2.68 (dd, 1H, J = 20.0 and 9.2 Hz), 4.67 (ddd, 1H, J = 12.0, 7.6 and 5.6 Hz), 5.07 (ddd, 1H, J = 7.6, 3.2 and 2.0 Hz), 6.24 (dd, 1H, J= 4.0 and 2.0 Hz), 7.37 (t, 2H, J = 7.2 Hz), 7.47 (tt, 1 H, J = 7.2 and 1.6 Hz), and 7.80 (dd, 2H, J = 7.2 and 1.6 Hz); 13 …”

Section: Tert-butyl 2-oxo-23-dihydro-indole-1-carboxylate (46)mentioning

confidence: 97%

“…The solvent was removed under reduced pressure. The residue was subjected to flash silica gel chromatography to give 0.16 g (90%) of 46 as a colorless oil: 1 H-NMR (CDCl 3 , 400 MHz) δ1.59 (s, 9H), 3.61 (s, 2H), 7.12 (t, 1H, J = 7.6 Hz), 7.23 (d, 1H, J = 7.6 Hz), 7.28 (t, 1 H, J = 7.6 Hz), and 7.77 (d, 1 H, J = 7.6 Hz); 13 5-hydroxy-2-oxo-6-phenyl-2,3,3a,4,5,6-hexahydroindole-1-carboxylate (51 5-hydroxy-3a-methyl-2-oxo-6-phenyl-2,3,3a,4 Cl] 2 ,4.0 μL (0.02 mmol) of P(OEt) 3 in 2 ml THF was added 0.07 g (0.6 mmol) of phenyl boronic acid. The reaction mixture was heated at 65°C for 2 h, cooled to rt and quenched with water.…”

Section: Tert-butyl 2-oxo-23-dihydro-indole-1-carboxylate (46)mentioning

confidence: 99%

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Rhodium(I)-Catalyzed Nucleophilic Ring-Opening Reactions of Oxabicyclo Adducts Derived from the [4 + 2]-Cycloaddition of 2-Imido-Substituted Furans

Padwa

Wang

2006

J. Org. Chem.

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A series of 2-imido substituted furans containing tethered unsaturation were prepared by the addition of the lithium carbamate of furan-2-yl carbamic acid tert-butyl ester to a solution of the mixed anhydride of an appropriately substituted 3-butenoic acid. The initially formed imido furans undergo a rapid intramolecular [4+2]-cycloaddition at room temperature to deliver the Diels-Alder cycloadducts in good to excellent yield. Isolation of the highly labile oxabicyclic adduct is believed to be a consequence of the lower reaction temperatures employed as well as the presence of the extra carbonyl group, which diminishes the basicity of the nitrogen atom thereby retarding the ring cleavage/rearrangement reaction generally encountered with related systems. By using a Rh(I)-catalyzed ring opening of the oxabicyclic adduct with various nucleophilic reagents, it was possible to prepare highly functionalized hexahydro-1 H-indol-2(3H)-one derivatives in good yield. The major stereoisomer obtained possesses a cis-relationship between the nucleophile and hydroxyl group in the ring-opened product. The stereochemistry was unequivocally established by X-ray crystallographic analysis. Coordination of Rh(I) to the alkenyl π-bond followed by a nitrogen-assisted cleavage of the carbon-oxygen bond occurs to furnish a π-allyl rhodium(III) species. Addition of the nucleophile then occurs from the least hindered terminus of the resulting π-allyl rhodium(III) complex. Proton exchange followed by rhodium(I) decomplexation ultimately leads to the cisdiastereomer.

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Section: Tert-butyl 2-oxo-23-dihydro-indole-1-carboxylate (46)mentioning

confidence: 97%

Section: Tert-butyl 2-oxo-23-dihydro-indole-1-carboxylate (46)mentioning

confidence: 99%

Rhodium(I)-Catalyzed Nucleophilic Ring-Opening Reactions of Oxabicyclo Adducts Derived from the [4 + 2]-Cycloaddition of 2-Imido-Substituted Furans

Padwa

Wang

2006

J. Org. Chem.

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“…The final conversion into the E or Z methylidyne derivatives of OS 23a, 23b and 25a, 25b was accomplished with tetrabutylammonium fluoride in anhydrous THF, in 77% and 78% yield respectively. [35][36][37] The OS analogues having the methylidyne function at the C-29 position of the squalene skeleton (29a and 29b) and the nor analogues (27a and 27b) (Scheme 6) were synthesized, although a survey of the literature showed no previously reported method. prop-2-ynyl]triphenylphosphonium bromide in anhydrous THF was reacted with an excess of butyllithium (see the Experimental section) and subsequently with 1-bromo-3-methylbut-2-ene, followed by the C 22 squalene aldehyde monobromohydrin 20 (Scheme 6).…”

Section: Synthesis Of 13-enynesmentioning

confidence: 99%

Synthesis of (E)- and (Z)-29-methylidyne-2,3-oxidosqualene derivatives as inhibitors of liver and yeast oxidosqualene cyclase

Ceruti

Viola

Balliano

et al. 2002

J. Chem. Soc., Perkin Trans. 1

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The synthesis of (E )-and (Z )-29-methylidyne-2,3-oxidosqualene derivatives is described starting from the C 22 and C 17 squalene aldehyde monobromohydrins. The conversion was achieved by means of a Wittig reaction, followed by desilylation of the terminal acetylene. For trisubstituted 1,3-enynes, preliminary alkylation with a suitable allyl bromide was performed. A new procedure for the synthesis of squalene aldehyde C 27 , C 22 and C 17 monobromohydrins is also described. Some of the new compounds behaved as inhibitors of pig liver and yeast oxidosqualene cyclase and were time-dependent inhibitors of the animal enzyme.

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“…This is primarily because these compounds, some of which occur naturally, are in many cases attractive molecular scaffolds for the preparation of products with relevant biological activity [1]. In particular, racemic 7-oxanitronorbornenes have been used for example to prepare the hypocholesterolemic agent (þ)-compactin [2] and b-aminoacids [3].…”

Section: Introductionmentioning

confidence: 99%

Discriminating between two chiral diastereoisomeric 7-oxanitronorbornenes by conventional X-ray powder diffractometry

Cumbrera

Ortiz

Araújo

et al. 2010

Zeitschrift Für Kristallographie

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X-ray powder diffractometry in a conventional laboratory powder diffractometer was used to discriminate between two chiral diastereoisomeric 7-oxanitronorbornenes that could not be distinguished unambiguously by nuclear magnetic resonance spectroscopy. It was found that the traditional approach consisting of successive steps of molecular modeling, direct-space methods, and crystallographic Rietveld refinement is not efficient for that purpose. This was attributed to the minimization trajectories in the phase spaces becoming trapped in local minima. On the contrary, the use of a final Rietveld refinement incorporating additional energy constraints limited the number of physically-reasonable atomic arrangements, thus allowing in this case unequivocal differentiation between the two nearly identical chiral diasteroisomeric 7-oxanitronorbornenes. This was possible thanks to the use of a multiobjective global optimization procedure ("Pareto optimization") that searches for the minimum of a cost function defined as the weighted average of the crystallographic and energy residuals.

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Convergent, enantiospecific total synthesis of the hypocholesterolemic agent (+)-compactin

Cited by 66 publications

References 0 publications

Rhodium(I)-Catalyzed Nucleophilic Ring-Opening Reactions of Oxabicyclo Adducts Derived from the [4 + 2]-Cycloaddition of 2-Imido-Substituted Furans

Rhodium(I)-Catalyzed Nucleophilic Ring-Opening Reactions of Oxabicyclo Adducts Derived from the [4 + 2]-Cycloaddition of 2-Imido-Substituted Furans

Synthesis of (E)- and (Z)-29-methylidyne-2,3-oxidosqualene derivatives as inhibitors of liver and yeast oxidosqualene cyclase

Discriminating between two chiral diastereoisomeric 7-oxanitronorbornenes by conventional X-ray powder diffractometry

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