Abstract:The results of studies leading to the development of enantioselective desymmetrizing, bromolactonization reactions of symmetric olefinic dicarboxylic acids, which are promoted by a C3 -symmetric trisimidazoline catalyst, are described. These processes generated carboxylic-acid-containing bromolactones in moderately high enantiomeric excesses. The results of optimization studies showed that reactions in a mixed solvent system of toluene and acetone proceeded with the highest levels of enantioselectivity. NMR st… Show more
“…Jacobsen pioneered a tertiary aminourea-catalyzed asymmetric iodolactonization using N -iodo-4-fluorophthalimide as the I + source and I 2 as an additive (Veitch and Jacobsen, 2010). In the subsequently developed metal-catalyzed and organocatalyzed asymmetric iodolactonization reactions, the combined use of an I + source (e.g., N -iodosuccinimide [NIS]) with I 2 is often effective to improve the results (Arai et al., 2015a, Arai et al., 2015b, Brindle et al., 2013, Dobish and Johnston, 2012, Fang et al., 2012, Filippova et al., 2014, Kwon et al., 2008, Lu et al., 2018, Mizar et al., 2014, Murai et al., 2014a, Murai et al., 2014b, Nakatsuji et al., 2014, Toda et al., 2014, Tripathi and Mukherjee, 2013; Tungen et al., 2012, Sakakura et al., 2007, Suresh et al., 2018, Wang et al., 2012). In 2014, we also reported a highly efficient catalytic asymmetric iodolactonization using a 3,3′-bis(aminoimino)binaphthol ligand ( L1 ) and Zn(OAc) 2 .…”
Section: Resultsmentioning
confidence: 99%
“…Such transition state models predicted facilitation of the nucleophilic attack by the carboxylate anion to one side of the alkene moiety of the meso -substrate in the five-membered lactone system to yield the (3 S , 5 R )-product preferentially. These computational results prompted us to design the catalytic asymmetric iodolactonization of prochiral diallyl acetic acids as shown in Figure 5 (Ikeuchi et al., 2012, Jiang et al., 2018, Klosowski and Martin, 2018, Knowe et al., 2018, Murai et al., 2014a, Murai et al., 2014b, Wilking et al., 2013, Wilking et al., 2016). Figure 5Catalytic Asymmetric Five-Membered Iodolactonization Using Zn 3 (OAc) 4 -3,3′-bis(aminoimino)binaphthoxide ( tri-Zn ) Catalyst…”
SummaryCooperative activation using halogen bonding and hydrogen bonding works in metal-catalyzed asymmetric halolactonization. The Zn3(OAc)4-3,3′-bis(aminoimino)binaphthoxide (tri-Zn) complex catalyzes both asymmetric iodolactonization and bromolactonization. Carboxylic acid substrates are converted to zinc carboxylates on the tri-Zn complex, and the N-halosuccinimide (N-bromosuccinimide [NBS] or N-iodosuccinimide [NIS]) is activated by hydrogen bonding with the diamine unit of chiral ligand. Halolactonization is significantly enhanced by the addition of catalytic I2. Density functional theory calculations revealed that a catalytic amount of I2 mediates the alkene portion of the substrates and NIS to realize highly enantioselective iodolactonization. The tri-Zn catalyst activates both sides of the carboxylic acid and alkene moiety, so that asymmetric five-membered iodolactonization of prochiral diallyl acetic acids proceeded to afford the chiral γ-butyrolactones. In the total description of the catalytic cycle, iodolactonization using the NIS-I2 complex proceeds with the regeneration of I2, which enables the catalytic use of I2. The actual iodination reagent is I2 and not NIS.
“…Jacobsen pioneered a tertiary aminourea-catalyzed asymmetric iodolactonization using N -iodo-4-fluorophthalimide as the I + source and I 2 as an additive (Veitch and Jacobsen, 2010). In the subsequently developed metal-catalyzed and organocatalyzed asymmetric iodolactonization reactions, the combined use of an I + source (e.g., N -iodosuccinimide [NIS]) with I 2 is often effective to improve the results (Arai et al., 2015a, Arai et al., 2015b, Brindle et al., 2013, Dobish and Johnston, 2012, Fang et al., 2012, Filippova et al., 2014, Kwon et al., 2008, Lu et al., 2018, Mizar et al., 2014, Murai et al., 2014a, Murai et al., 2014b, Nakatsuji et al., 2014, Toda et al., 2014, Tripathi and Mukherjee, 2013; Tungen et al., 2012, Sakakura et al., 2007, Suresh et al., 2018, Wang et al., 2012). In 2014, we also reported a highly efficient catalytic asymmetric iodolactonization using a 3,3′-bis(aminoimino)binaphthol ligand ( L1 ) and Zn(OAc) 2 .…”
Section: Resultsmentioning
confidence: 99%
“…Such transition state models predicted facilitation of the nucleophilic attack by the carboxylate anion to one side of the alkene moiety of the meso -substrate in the five-membered lactone system to yield the (3 S , 5 R )-product preferentially. These computational results prompted us to design the catalytic asymmetric iodolactonization of prochiral diallyl acetic acids as shown in Figure 5 (Ikeuchi et al., 2012, Jiang et al., 2018, Klosowski and Martin, 2018, Knowe et al., 2018, Murai et al., 2014a, Murai et al., 2014b, Wilking et al., 2013, Wilking et al., 2016). Figure 5Catalytic Asymmetric Five-Membered Iodolactonization Using Zn 3 (OAc) 4 -3,3′-bis(aminoimino)binaphthoxide ( tri-Zn ) Catalyst…”
SummaryCooperative activation using halogen bonding and hydrogen bonding works in metal-catalyzed asymmetric halolactonization. The Zn3(OAc)4-3,3′-bis(aminoimino)binaphthoxide (tri-Zn) complex catalyzes both asymmetric iodolactonization and bromolactonization. Carboxylic acid substrates are converted to zinc carboxylates on the tri-Zn complex, and the N-halosuccinimide (N-bromosuccinimide [NBS] or N-iodosuccinimide [NIS]) is activated by hydrogen bonding with the diamine unit of chiral ligand. Halolactonization is significantly enhanced by the addition of catalytic I2. Density functional theory calculations revealed that a catalytic amount of I2 mediates the alkene portion of the substrates and NIS to realize highly enantioselective iodolactonization. The tri-Zn catalyst activates both sides of the carboxylic acid and alkene moiety, so that asymmetric five-membered iodolactonization of prochiral diallyl acetic acids proceeded to afford the chiral γ-butyrolactones. In the total description of the catalytic cycle, iodolactonization using the NIS-I2 complex proceeds with the regeneration of I2, which enables the catalytic use of I2. The actual iodination reagent is I2 and not NIS.
“…This compound is the representative example of piperidinyl acetic acid γ-secretase modulators, which has been extensively used as a lead compound and a tool molecule in AD studies. Ketone 4a could be easily prepared in 2 steps by conjugate addition followed by decarboxylation from commercially available starting materials 10 and 11 . As described in Scheme , the reaction sequence involving N-tert -butanesulfinyl imine formation, diastereoselective reduction, and desymmetrizing lactam formation could afford 6a .…”
Section: Resultsmentioning
confidence: 99%
“…Ketone 4a could be easily prepared in 2 steps by conjugate addition followed by decarboxylation from commercially available starting materials 10 and 11. 8 As described in Scheme 4, the reaction sequence involving N-tert-butanesulfinyl imine formation, diastereoselective reduction, and desymmetrizing lactam formation could afford 6a. Selective amide reduction then produced piperidinyl acetic ester 2a.…”
A desymmetrization-based approach
for the synthesis of piperidinyl
acetic acid γ-secretase modulators has been developed. The synthetic
sequence features the use of N-tert-butanesulfinyl
imine reduction and a diastereoselective lactam formation to set up
the chiral centers. The synthetic utility is demonstrated by the concise
asymmetric synthesis of γ-secretase modulator GSM-1.
“…Dicarboxylic acids containing an alkene functionality in a central position can be desymmetrised through intramolecular halolactonisation. A bromolactonisation of this type was reported by Fujioka and co-workers 244 using the previously developed C 3 -symmetric trisimidazoline catalyst C-159 [245][246][247] capable of chelating carboxylic acids through hydrogen bonding in a chiral environment (Scheme 132). A solvent system of 4 : 1 toluene/ acetone was found to be optimal for using this interaction to achieve stereocontrol.…”
Organocatalytic enantioselective desymmetrisation of achiral or meso compounds is a powerful strategy for the construction of enantiomerically enriched complex molecules, often with multiple stereocentres and in high selectivities. Recent years have seen increasing use of organocatalysts in desymmetrisation methodology, in contrast to traditional metal- or enzyme-catalysed reactions, with many impressive advances made in the current decade. This review will provide an overview of the field since 2010, with the aim of highlighting both the practical applications and elegance of enantioselective desymmetrisation to the wider synthetic community.
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