Synthesis of novel norephedrine-based chiral ligands with multiple stereogenic centers and their application in enantioselective addition of diethylzinc to aldehyde and chalcone (original) (raw)
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The Journal of Organic Chemistry, 1997
A family of enantiomerically pure (1R,2R)-1-(dialkylamino)-1-phenyl-3-(R-oxy)-2-propanols (4) has been synthesized from (2S,3S)-2,3-epoxy-3-phenylpropanol (1a), arising from the Sharpless epoxydation of cinnamyl alcohol, by two alternative sequences involving either the regioselective ring opening of the epoxide by a secondary amine (C-3 attack) and subsequent chemoselective protection of the primary hydroxy group or the reverse of these operations. A total of 19 different derivatives 4 have been prepared in an iterative process aimed at the optimization of their catalytic properties in the enantioselective addition of diethylzinc to benzaldehyde. In doing this, the steric bulk of the R-oxy group and the choice of the dialkylamino substituent as a nitrogen-containing six-membered ring have been identified as the key structural parameters for high catalytic activity and enantioselectivity in 4. Two optimized ligands fulfilling these structural requirements, 4d-Tr (R-oxy ) trityloxy, dialkylamino ) piperidino) and 4i-Tr (R-oxy ) trityloxy, dialkylamino ) 4-methylpiperazin-1-yl), depict a convenient activity and selectivity profile in the addition of Et 2 -Zn to a structurally diverse family of aldehydes. These results show how chiral ligands based on non-natural starting materials can accommodate subtle variations of the steric/electronic characteristics key to the fine tuning of catalytic properties and thus represent a convenient alternative to ligands based on natural products. For compilations of natural and non-natural enantioselective catalysts and auxiliaries, see, for example: (a) Blaser, H. U. Chem. Rev. 1992, 92, 935-952. (b) Chiral Auxiliaries and Ligands in Asymmetric Synthesis; Seyden-Penne, J., Ed.; John Wiley & Sons, Inc.: New York, 1995. (4) (a) Canas, M.; Poch, M.; Verdaguer, X.; Moyano, A.; Pericàs, M. A.; Riera, A. Tetrahedron Lett. 1991, 32, 6931-6934. (b) Poch, M.; Verdaguer, X.; Moyano, A.; Pericà s, M. A.; Riera, A. Tetrahedron Lett. 1991, 32, 6935-6938. (c) Alcón, M.; Canas, M.; Poch, M.; Moyano, A.; Pericà s, M. A.; Riera, A. Tetrahedron Lett. 1994, 35, 1589-1592. (d) Poch, M.; Alcón, M.; Moyano, A.; Pericà s, M. A.; Riera, A. Tetrahedron Lett. 1993, 34, 7781-7784. (e) Castejón, P.; Pastó, M.; Moyano, A.; Pericà s, M. A.; Riera, A. Tetrahedron Lett. 1995, 36, 3019-3022. (f) Pastó, M.; Moyano, A.; Pericà s, M. A.; Riera, A. Tetrahedron: Asymmetry 1995, 6, 2329-2342. (g) Pastó, M.; Moyano, A.; Pericàs, M. A.; Riera, A.
Applied Organometallic Chemistry, 2014
Enantiopure C 2-symmetric diol bidentate ligands have been synthesized in a straightforward manner through a three-step reaction with good yields. The synthesized C 2-symmetric diol bidentate ligands were used in the addition of diethylzinc to various aromatic aldehydes, a general catalytic benchmark reaction, in order to assess their enantioselective induction properties. The enantioselective addition of diethylzinc to 1-naphthaldehyde and 3-chlorobenzaldehyde was achieved with an enantiomeric excess (ee) of up to 98%. All synthesized ligands were also evaluated in the addition of diethyzinc to aromatic aldehydes including an extra metal such as Ti(IV) (up to 99% ee).
Polyhedron, 2012
Series of functionalized organolithium compounds were prepared and added to chiral bicyclic ketones (1R-(+)-camphor analogue 2 and 1R-(À)-fenchone 3), resulting in the preparation of a small ''library'' of chiral aminoalcohols able to serve as ligands in metal mediated asymmetric synthesis. The configuration of the chiral ligands was approved by applying advanced NMR experiments. The absolute configurations of 1,2-disubstituted planar chiral ferrocene-based aminoalcohols 15, 18 and 19 were determined by means of NMR experiments and confirmed by X-ray crystallography. The new chiral ligands were tested as pre-catalysts for the addition of diethyl zinc to benzaldehyde. The reactions proceeded with excellent conversions and a moderate degree of enantioselectivity.
The first enantioselective synthesis of chiral norbornane-type 1,4-diamine ligand
Tetrahedron-asymmetry, 2003
The asymmetric synthesis of trans-2,3-bis(aminomethyl)norbornane was performed starting with endo-2,3-norbornene dicarboxylate anhydride. Desymmetrization of meso-anhydride 1 and following selective epimerization gave the trans-monoester (+)-3 with a high enantiomeric excess (98% e.e.). LiAlH 4 reduction of the trans-monoester to the 1,4-diol, which was then treated with phthalimide under Mitsunobu conditions and, following a Gabriel type amine synthesis with hydrazine hydrate, yielded a saturated and unsaturated diamine mixture. Hydrogenation of mixture finally afforded saturated diamine (+)-8 with a yield of 37%.
Tetrahedron: Asymmetry, 2001
The effect of O, S and N atoms in aromatic ring substituents at C-1 position of tetrahydro-b-carboline ligands on the enantioselectivity of diethylzinc additions to benzaldehyde was studied when esters or tertiary alcohol functions were present at C-3. A mechanism is proposed to explain why the ester ligands 2c and 2d, in which the pyridyl N atom is at C%-2 in 2c and at C%-3 in 2d, catalyzed the addition of diethylzinc to benzaldehyde to form the (R)-and (S)-enantiomers of 1-phenyl-1-propanol, respectively. An explanation was also proposed for the moderate enantioselectivity induced by tert-alcohol 3c versus the very small enantioselectivity induced by 3d, containing a 3-pyridyl function at C-1, during diethylzinc additions. A -CH 2 -t-Bu substituent at C-1 leads to very high enantioselectivities.
Tetrahedron: Asymmetry, 1993
Starting from enantiomerically pure serine, a series of (2R,5S) and (2S,5S)-2hydroxymethyl-5-alkyl piperazines l-5 were prepared in good yields without any racemization. The use of these compounds as chiral catalysts for the enantioselective addition of diethylzinc to aldebydes is described. This paper reports the first example of the use of piperazine methanols in asymmetric synthesis. Catalytic enantioselective carbon-carbon bond forming is now recognised as one of the most important problems in organic synthesis.2 It is known that enantioselective addition of organometallic reagents to aldehydes in the presence of amino alcohols affords optically active secondary alcohols.3 Recently. in our laboratory, we found that amino pyridines also act as chiral catalysts in the enantioselective addition of diethylzinc to aldehydes. 1 T4 There are only a few examples reported, in which, optically active piperazines have been used as chiral modifiers in asymmetric reactions.5 Although C2-symmetric piperazines having an o-hydroxyphenyl substituent have been reported,sc this study represents the first example of the use of piperazine methanols in the enantioselective addition of diethylzinc to benzaldehyde. We wish to report the synthesis of (2R.5.Y) and (2.$5s)-2-hydroxyme.thyl-5-alkyl piperazines l-5 and a detailed study of the dialkylzinc-henzaldehyde addition carried out by using compounds l-5 as chirsl catalysts. The piperazines l-5 were prepared according Scheme I+ commercial amino acids were converted into the corresponding N-benzyloxycarbonyl derivatives la-5a that were Ueated with (s) or (R) H-Ser-OMeHCl to give dipeptides lb-Sb using the mixed anhydride coupling method. Deblocking the benzyloxycarbonyl group was carried by transfer hydrogenation (10% of any volatile in dry methanol to previously reported diketopiperazines
Tetrahedron, 1992
Chiral amino pyridines derived from a-aminoacids were demonstrated to be enantioselective catalysts in the addition of diethylzinc to aldehydes: optically active secondary alcohols in up to 98% ee were obtained in high yields. The temperature dependence of the stereochemical course of the reaction was found to be strictly related to the alkyl structure of the chiral catalyst. The nature of the possible catalytic complex and the origin of temperature effect was thus discussed on the basis of NMR data too. A catalytic enantioselective process is now recognised as one of the most important problems in organic synthesis.2 It is known that chiral amines and amino alcohols, mainly p-amino alcohols as ligands, may accelerate and direct the stereochemical outcome of the asymmetric alkylation of aldehydes by zinc dialkyls, sometimes achieving high stereoselectivity. Recently, in our laboratory, we found that also amino pyridines act as chiral catalysts in the enantioselective addition of diethylzinc to aldehydes. In fact, we have prepared and used 2-[(2S)-2-pyrrolidinyl]pyridine (1): ees up to 100% were observed. 4 On this basis, we have extended the investigation to other optically active amino pyridines 2-7. which have a greater conformational mobility than 1.