Organocatalytic Asymmetric Synthesis of Bridged Acetals with Spirooxindole Skeleton (original) (raw)
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Angewandte Chemie International Edition, 2009
The structural complexity and well-defined three-dimensional architecture of natural molecules are generally correlated with specificity of action and potentially useful biological properties. This complexity has inspired generations of synthetic chemists to design novel enantioselective strategies for assembling challenging target structures and reproducing the rich structural diversity inherent in natural molecules. This symbiotic correlation between natural compounds synthesis and the discovery of effective asymmetric-generally catalytic -technologies lies at the heart of the synthetic chemistry innovation. Despite the substantial advances made thus far, the construction of highly strained polycyclic structures (particularly those that contain spiro-stereocenters) and the generation of all-carbon quaternary stereocenters still remain daunting targets for synthesis. The spirocyclic oxindole core is featured in a number of natural products [6] as well as medicinally relevant compounds [7] ), but its stereocontrolled synthesis, particularly installing the challenging spiro-quaternary stereocenter, poses a great synthetic problem. Only a few venerable asymmetric transformations, such as cycloaddition processes [8] or the intramolecular Heck reaction, [9] have proven suitable for achieving this challenging goal.
Organic Letters, 2009
The enantioselective synthesis of stereochemically and structurally diverse spirocyclic oxindoles by [5+2]-annulation of chiral crotylsilanes bearing a primary alcohol is described. The annulation products were further elaborated to polycyclic oxindoles by Pd (0) catalysis. Spirooxindoles are commonly occurring heterocyclic ring systems found in many natural products and pharmaceuticals. 1 A range of biologically active compounds possessing the spiropyrrolidine framework is well documented. 1a-c For instance, coerulescine (1), the simplest spirooxindole found in nature, displays a local anaesthetic effect. 2a,b Polycyclic
Chemistry - A European Journal, 2012
Biologically active spirocyclopropane derivatives of indoles emerged recently as potent drug candidates. Thus, spirooxindole 1 exhibited nanomolar activity as an HIV-1 nonnucleoside reverse transcriptase inhibitor on both wild-type and drug-resistant mutant viruses, whereas compounds of type 2 showed promising antitumor activity and were also effective for treatment of obesity and diabetes (Scheme 1). The stereochemistry of these compounds plays a crucial role in their biological activity.
Journal of Organic Chemistry, 2023
The present study reports an asymmetric organocascade reaction of oxindole-derived alkenes with 3-bromo-1nitropropane efficiently catalyzed by the bifunctional catalyst. Spirooxindole-fused cyclopentanes were produced in moderate-togood isolated yields (15-69%) with excellent stereochemical outcomes. The synthetic utility of the protocol was exemplified on a set of additional transformations of the corresponding spirooxidondole compounds. 1 C1 K2CO3 24 17/1 58 99 2 C2 K2CO3 24 3/1 39 92 3 C3 K2CO3 24 3/1 58 91 4 C1 Na2CO3 48 20/1 55 99 5 C1 NaHCO3 168 20/1 32 99 6 C1 DIPEA 24 2/1 49 98 7 e C1 K2CO3 2 3/1 38 91 8 f C1 K2CO3 3 8/1 23 99 9 g C1 K2CO3 24 >20/1 59 99 10 h C1 K2CO3 18 >20/1 57 99 11 i C1 K2CO3 45 >20/1 64 99 a Reactions were conducted with 1a (0.1 mmol), 2a (0.2 mmol), corresponding base (0.2 mmol), and catalyst (20 mol%) in DCM (1.0 ml) at room temperature. b Determined by 1 H-NMR of the crude reaction mixture (3a/4a). c Isolated yield of 3a after column chromatography. d Determined by chiral HPLC analysis. e EtOAc was used. f MTBE was used. g CHCl3 was used. h Reaction was conducted with 1a (0.10 mmol), 3a (0.15 mmol), C1 (20 mol%) in CHCl3 (1.0 ml) at room temperature. i Reaction was conducted with 1a (0.10 mmol), 3a (0.15 mmol), C1 (1 mol%) in CHCl3 (1.0 ml) at room temperature.
2022
The present study reports an asymmetric organocascade reaction of oxindole-derived alkenes with 3-bromo-1nitropropane efficiently catalyzed by the bifunctional catalyst. Spirooxindole-fused cyclopentanes were produced in moderate-togood isolated yields (15-69%) with excellent stereochemical outcomes. The synthetic utility of the protocol was exemplified on a set of additional transformations of the corresponding spirooxidondole compounds. 1 C1 K2CO3 24 17/1 58 99 2 C2 K2CO3 24 3/1 39 92 3 C3 K2CO3 24 3/1 58 91 4 C1 Na2CO3 48 20/1 55 99 5 C1 NaHCO3 168 20/1 32 99 6 C1 DIPEA 24 2/1 49 98 7 e C1 K2CO3 2 3/1 38 91 8 f C1 K2CO3 3 8/1 23 99 9 g C1 K2CO3 24 >20/1 59 99 10 h C1 K2CO3 18 >20/1 57 99 11 i C1 K2CO3 45 >20/1 64 99 a Reactions were conducted with 1a (0.1 mmol), 2a (0.2 mmol), corresponding base (0.2 mmol), and catalyst (20 mol%) in DCM (1.0 ml) at room temperature. b Determined by 1 H-NMR of the crude reaction mixture (3a/4a). c Isolated yield of 3a after column chromatography. d Determined by chiral HPLC analysis. e EtOAc was used. f MTBE was used. g CHCl3 was used. h Reaction was conducted with 1a (0.10 mmol), 3a (0.15 mmol), C1 (20 mol%) in CHCl3 (1.0 ml) at room temperature. i Reaction was conducted with 1a (0.10 mmol), 3a (0.15 mmol), C1 (1 mol%) in CHCl3 (1.0 ml) at room temperature.
Angewandte Chemie International Edition, 2006
MHz (13 C). 1 H NMR spectra were reported relative to Me 4 Si (δ 0.0). 13 C NMR spectra were reported relative to Me 4 Si (δ 0.0) or CDCl 3 (δ 77.0). IR spectra were recorded on a JASCO FT/IR-410 spectrometer using NaCl (neat) or KBr pellets (solid). Mass spectra were recorded on Hitachi M-80 or JEOL JMS-SX102A. Melting points were recorded on a Yanaco MP-3S. HPLC was carried out using a SHIMADZU SPD-10A, LC-9A, CTO-10ASvp and C-R6A. Thin-layer chromatography (TLC) was performed on Silica gel 60 F 254 plates (Merck). Preparative thin-layer chromatography was performed on Wakogel B-5F. Flash column chromatography was performed on PSQ 100B silica gel (Fuji Silysia Co., Ltd., Japan) or Alumina A-Super I (ICN Biomedicals). Copper (I) chloride and 2-aminopyridine were purchased from Kanto Chemical Co., Inc., Tokyo, Japan. Sodium methoxide (25 w/w% solution in methanol) was purchased from Aldrich. DME was purchased from Wako Pure Chemical Industries Ltd. and distilled from CaH 2 before use. THF and Et 2 O were purchased from Wako Pure Chemical Industries Ltd. in anhydrous grade. CH 2 Cl 2 , benzene, CH 3 CN and DMF were distilled from CaH 2 before use. All other reagents were commercially available and used without further purification. All moisture sensitive reactions were performed under an argon atmosphere in flame-dried glassware and all reactions were monitored by TLC and/or HPLC analysis. Synthesis of Indole Substrates. N I 7d N Me Me 1) nBuLi 2) I 2 Et 2 O N 8d Me acrolein, TFA N-methylaniline CH 2 Cl 2 , iPrOH CHO I 2-Iodo-1-methyl-1H-indole (7d). The iodoindole 7d was synthesized according to a modified procedure of Shirley et al. [1] To a solution of N-methylindole (7.00 g, 53.40 mmol) in Et 2 O (160 mL) at 0 °C was added nBuLi (30 mL, 2.67 M in hexane, 80.10 mmol). The solution was stirred for 0.5 h at 0 °C and heated to reflux for 3h. After cooling to 15 °C, iodine (14.90 g, 58.70 mmol) was added and stirred for 1h at 15 °C. The reaction was quenched with 20% aq. Na 2 S 2 O 3 (50 mL) and AcOEt (50 mL) was added, the organic Supporting Information 3/26 layer was separated, and the aqueous layer was extracted with AcOEt (50 mL). The organic layers were combined, washed with sat. aq. NaHCO 3 (50 mL) and H 2 O (50 mL), dried over MgSO 4 , filtered, and concentrated in vacuo. The residue was purified by recrystallization from petroleum ether (20 mL) to afford 7d (5.78g, 42%) as a light brown crystal. The filtrate was concentrated in vacuo, the residue was purified by flash chromatography (silica gel, hexane/AcOEt = 70/1), and then by recrystallization from hexane (15 mL) to afford 7d (2.74g, 20%) as a white crystal. R f 0.50
Molecules (Basel, Switzerland), 2018
Taking into account the postulated reaction mechanism for the organocatalytic epoxidation of electron-poor olefins developed by our laboratory, we have investigated the key factors able to positively influence the H-bond network installed inside the substrate/catalyst/oxidizing agent. With this aim, we have: (i) tested a few catalysts displaying various effects that noticeably differ in terms of steric hindrance and electron demand; (ii) employed α-alkylidene oxindoles decorated with different substituents on the aromatic ring (-), the exocylic double bond (-), and the amide moiety (-). The observed results suggest that the modification of the electron-withdrawing group (EWG) weakly conditions the overall outcomes, and conversely a strong influence is unambiguously ascribable to either the -protected or -unprotected lactam framework. Specifically, when the NH free substrates (-) are employed, an inversion of the stereochemical control is observed, while the introduction of a Boc pro...