2022
DOI: 10.1021/acs.joc.2c00862
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Kinetic Resolution of 2-Aryl-4-methylenepiperidines toward Enantioenriched Functionalizable Piperidine Fragments

Abstract: The base n -BuLi with sparteine allows a kinetic resolution of N -Boc-2-aryl-4-methylenepiperidines. The 2,2-disubstituted products and recovered starting materials were isolated with high enantiomeric ratios. From VT-NMR spectroscopy and DFT studies, the rate of rotation of the N -Boc group is fast. Lithiation and trapping of the enantioenriched starting materials gave 2,2-disubstituted piperidines with retention of stereochemistry. Function… Show more

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Cited by 5 publications
(19 citation statements)
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“…For example, with 2,4-disubstitued N -Boc piperidine cis - 5b , the lowest energy conformation will likely be a twist-boat conformation with both substituents in pseudo-equatorial positions. 18 In contrast, the epimeric 2,4-disubstituted N -Boc piperidine trans - 5b will adopt a lower energy conformation, with an equatorial 4-substituent and the 2-substituent adopting an axial orientation to avoid unfavourable A 1,3 -type strain between the Boc group and the 2-substituent. 18 a Thus, base-mediated epimerisation under thermodynamic conditions should convert cis - 5b into trans - 5b (Scheme 1).…”
Section: Resultsmentioning
confidence: 99%
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“…For example, with 2,4-disubstitued N -Boc piperidine cis - 5b , the lowest energy conformation will likely be a twist-boat conformation with both substituents in pseudo-equatorial positions. 18 In contrast, the epimeric 2,4-disubstituted N -Boc piperidine trans - 5b will adopt a lower energy conformation, with an equatorial 4-substituent and the 2-substituent adopting an axial orientation to avoid unfavourable A 1,3 -type strain between the Boc group and the 2-substituent. 18 a Thus, base-mediated epimerisation under thermodynamic conditions should convert cis - 5b into trans - 5b (Scheme 1).…”
Section: Resultsmentioning
confidence: 99%
“…Finally, an alternative route to selected trans -isomers would be the use of Beak's α-lithiation-trapping methodology, 18 a ,19 with which we have much experience. 11 a ,20 For this, it was envisaged starting with N -Boc methyl piperidines 7 and carrying out α-lithiation (using s -BuLi/TMEDA) and subsequent trapping with carbon dioxide (followed by methylation) to give methyl pipecolinates trans - 5 (Scheme 1).…”
Section: Resultsmentioning
confidence: 99%
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“…With the 2-arylpiperazines 2 in hand, we were interested in exploring a kinetic resolution protocol developed in our laboratories . This chemistry relies on coordination of the chiral base to the carbonyl oxygen atom of the Boc group, so it is important to determine the ratio of rotamers and the rate of rotation of the carbonyl group.…”
mentioning
confidence: 99%
“…A model to illustrate the preference is shown (Figure ), in which the (+)-enantiomer of sparteine when coordinated to BuLi favors lithiation of the ( S ) enantiomer of the piperazines 2 . To favor the other enantiomer, (−)-sparteine could be used …”
mentioning
confidence: 99%