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Title: Synthesis of chiral binaphthol derivatives and their applications in asymmetric alkylation, sulfoxidation and conjugate addition
Authors: Su, Liming
Degree: Ph.D.
Issue Date: 2003
Abstract: Catalytic asymmetric synthesis involving chiral ligands has been one of the most active research areas in the organic synthetic community since the manufacture of L-DOPA on a commercial scale via a catalytic process by Knowles' group at Monsanto in the early 1970's. Among the catalytic asymmetric reactions, asymmetric hydrogenation is the field that has been explored from the earliest time and to which much effort have been devoted, Numerous chiral phosphorus ligands, most popular among which have been bidentate 1igands with C2-symmetry, have been designed and successfully synthesized for the asymmetric hydrogenation purpose. The most distinguished one of them is BINAP, a fully aromatic, C2-symmetrical and axially chiral bisphosphane invented by Noyori's Group. Compared to the asymmetric hydrogenation system's complexity, asymmetric epoxidation witnessed another philosophy. Sharpless reported that a simple chiral tartrate ester combined with Ti(IV) alkoxide and t-butyl hydroperoxide was capable of epoxidizing a wide variety of allylic alcohols in good yield and with an enantiomeric excess usually greater than 90%. On account of their research's originality and excellence, Dr.Knowles,Prof.Noyori and Prof. Sharpless were awarded the Nobel Prize of Chemistry in year 2001. Generally, scientists in the areas Nobel Prize awarded will be put into a dilemma: societally, public attention may make it easy for researchers to gain material and fund supports; academically, with the laureates occur, it means that the research tends to mature and unexplored soil in this area is not easy to be found by followers. Fortunately, the Laureates of chemistry in 2001 have developed chiral catalysts successfully for only two classes of reactions, hydrogenations or oxidations, which concern with only functionalities transformation. There is no carbon chain shortening or prolonging during the asymmetric reactions. Thus there are much more opportunities for us to further investigate. One is the asymmetric conjugate addition of organometallic reagents to a,B-unsaturated compounds, which is a powerfu1 tool to form carbon-carbon bonds and simultaneously introduce new stereogenic centers in organic molecules. The prominent chiral binaphthyl backbone was selected to prepare a series of phosphites, which were used as chiral ligands for the enantioselective conjugate addition of triethylaluminum to cyclic enones in our study. The conjugate addition of triethylaluminum to cyclic enones proceeded effectively in the presence of chiral phosphites. It was found that the chirality of the terminal units rather than that of the bridging unit of the diphosphites primarily determined the configuration of the product. The preferred solvents for this reaction are toluene, ether or dichloromethane. The best enantioselectivity (94%) was obtained when the triethylaluminum addition to 2-cyclopentenone was conducted in the presence of (3,3',5,5'-tetra-tert-butyl-bi-2-phenol) bis[(S)-binaphtllyl] bisphosphite, (S,S)-83 , at a substrate-to-catalyst ratio of 100 and a catalyst concentration of 8.3x10-4M at 0 oC. Sterically encumbered 3-methyl-2-cyclopen tenone which is unreactive toward diethylzinc to form the l, 4-adduct reacted with triethylaluminum in the presence of a chiral ligand and Cu(OTf)2 with ee value up to 71.1%. Comparing results of the conjugate addition using ZnEt2 reagent, AlEt3 reagent showed the same sense of enantioselectivity and high 1,4-regioselectivity as welll. This suggests that conjugate addition of AlEt3 to enones may proceed with a similar mechanism as that of ZnEt2. Alkylation of aldehyde , another carbon-carbon forming reaction, was also carried out in the presence of binaphthol derivatives with good yields and enantioselectivies. In order to investigate the electronic and steric effect on this reaction, a series of binaphthol derivatives with electronic-donating groups or electronic-withdrawing groups at 6,6'-positions were synthesized. (S)-7,7'-dimethoxyl-1, 1'-bi-2-naphthol, (S)-93 , with two methoxyl groups at 7, 7'-position was also synthesized for this purpose. Compared to (S)-BINOL (S)-89, (S)-6,6'-Dibromo-2,2'-dihydroxy-l,l'-binaphthyl (S)-90 and (S)-6,6'-dimethyl-1,1'-bi-2-naphthol (S)91 bearing electron-donating groups at 6,6'-position gave slightly enhanced activities and selectivities; (S)-6, 6'-dicyano-1, 1'-bi-2-naphthol (S)-92 with electron-withdrawing groups at 6,6'-position showed nearly the same result with that of (S)-89; (S)-93 with methoxyl group at 7,7'-position gave a slightly decreased selectivity. Considering that (S)-93 was not enantio-pure (ee only 97.3%), such a decrease is negligible. Thus, we conclude that substituents on 6, 6'-or 7,7'-positions of the binaphthol ring gave no significant influence on both enantioselectivities and conversions for the asymmetric addition of triethylaluminum to benzaldehyde. Chiral binaphthols with two chirogenic aminoalkyl groups at the 3, 3'-position of the (R)-BINOL can be used as chiral ligands in the enantioselective addition of diethylzinc to aldehydes with good to high selectivities and yields. The S-aminoalkyl groups combined with (R)-BINOL gave better results than that of the R-aminoalky1 with (R)-BINOL. Chiral ligands with tertiary aminoalky1 groups are superior to those with secondary aminoalky1 groups. Among these chiral aminoalkylbinaphthols, (R)-3, 3'-Bis-({methyl-[(S)-1-phenyl -ethyl]-amino}-methyl) -[l, l']binaphthalenyl-2,2'-diol (114) showed the best enantioselectivity for the addition of diethylzinc to aldehydes. The chirality of the binaphthol rather than that of the aminoalkyl groups determined the configuration of the products. The best ee (89%) was achieved for the addition of diethylzinc to 4-nitrobenzaldehyde. It was suggested that the aminoalkylbinaphthol ligands act as diols rather than amino acids in the asymmetric addition of diethylzinc to aldehydes. The main demerit of the general diol system for the diethylzinc addition to aldehydes is that a large amount of titanium tetrapropyloxide (usually 7 equiv excess than the ligand) is required for the reaction to proceed effectively;whereas no titanium involves in the asymmetric addition using aminoalkylbinaphthol ligands. Chiral Sulfoxides with a stereogenic sulfur atom resulting from stereo-electronic differences existing between the four substituents: a lone electronic pair, oxygen, and two different carbonous groups, is an important class of compounds arousing a large interest as chiral auxiliaries in asymmetric synthesis and as intermediates in the pharmaceutical industry. (S)-2,2'-dihydroxy-5, 5', 6, 6', 7, 7', 8, 8',octahydro-1, 1'-binaphthyl (S)-88, (S)-6,6'-dibromo -1, l'-bi-2-naphthol (S)-90 and (S)-3,3'-Dibromo-2,2'-dihydroxy-l,l'-binaphthyl (S)-136 have never been reported as catalysts for the asymmetric oxidation of sulfoxides. We investigated the titanium-catalytic asymmetric oxidation of sulfides to sulfoxides with these chiral binaphthol derivatives. The effect of catalyst concentration and the water amount added to the system was also tested. Among them,(S)-6,6'-dibromo-l, l'-bi-2-naphthol (S)-90 gave the best enantioselectivity for the reaction. Both aliphatic sulfides and aryl alkyl-sulfides can be oxidized with good selectivities and yield. The best ee (85%) was obtained for phenyl methyl sulfide with (S)-90 as chiral ligand.
Subjects: Hong Kong Polytechnic University -- Dissertations
Enantioselective catalysis
Pages: xi, 202 leaves : ill. ; 30 cm
Appears in Collections:Thesis

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