The Stereochemistry of the Addition of Chlorotitanium Enolates of N-Acyl Oxazolidin-2-ones to 5- and 6- Membered N-Acyliminium Ions

Pilli, Ronaldo Aloise; Böckelmann, Maria Alice; Alves, Conceição de Fátima

doi:10.1590/s0103-50532002000100021

Cited by 2 publications

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“…Recently, competitive reactions with a silyl enol ether using equimolar amounts of the two 2-ethoxycarbamate precursors were found to yield the product arising from reaction with the five-membered exocyclic N -CO 2 C 2 H 5 ion (see below) in an amount six times greater than that from its six-membered ring analogue . Accordingly, the reaction of titanium(IV) enolates of N -acyloxazolidin-2-ones with N -Boc five- and six-membered ring N -acyliminium ions revelead the same pattern …”

Section: Discussionmentioning

confidence: 95%

Intrinsic Gas-Phase Electrophilic Reactivity of Cyclic N-Alkyl- and N-Acyliminium Ions

et al. 2001

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The intrinsic gas-phase reactivity of cyclic N-alkyl- and N-acyliminium ions toward addition of allyltrimethylsilane (ATMS) has been compared using MS(2) and MS(3) pentaquadrupole mass spectrometric experiments. An order of electrophilic reactivity has been derived and found to agree with orders of overall reactivity in solution. The prototype five-membered ring N-alkyliminium ion 1a and its N-CH(3) analogue 1b, as well as their six-membered ring analogues 1c and 1d, lack N-acyl activation and they are, accordingly, inert toward ATMS addition. The five- and six-membered ring N-acyliminium ions with N-COCH(3) exocycclic groups, 3a and 3b, respectively, are also not very reactive. The N-acyliminium ions 2a and 2c, with s-trans locked endocyclic N-carbonyl groups, are the most reactive followed closely by 3c and 3d with exocyclic (and unlocked) N-CO(2)CH(3) groups. The five-membered ring N-acyliminium ions are more reactive than their six-membered ring analogues, that is: 2a > 2c and 3c > 3d. In contrast with the high reactivity of 2a, its N-CH(3) analogue 2b is inert toward ATMS addition. For the first time, the transient intermediates of a Mannich-type condensation reaction were isolated-the beta-silyl cations formed by ATMS addition to N-acyliminium ions-and their intrinsic gas-phase behavior toward dissociation and reaction with a nucleophile investigated. When collisionally activated, the beta-silyl cations dissociate preferentially by Grob fragmentation, that is, by retro-addition. With pyridine, they react competitively and to variable extents by proton transfer and by trimethylsilylium ion abstraction-the final and key step postulated for alpha-amidoalkylation. Becke3LYP/6-311G(d,p) reaction energetics, charge densities on the electrophilic C-2 site, and AM1 LUMO energies have been used to rationalize the order of intrinsic gas-phase electrophilic reactivity of cyclic iminium and N-acyliminium ions.

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Section: Discussionmentioning

confidence: 95%

Intrinsic Gas-Phase Electrophilic Reactivity of Cyclic N-Alkyl- and N-Acyliminium Ions

et al. 2001

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“…N -Unsubstituted amino acid 20h was synthesized by sequential cleavage of the p -methoxybenzyl ether (PMB) group and the chiral auxiliary in 19f . In a similar manner, preparation of amino acids 23i – k with cyclic amines was accomplished by stereoselective coupling of the Evans imide 17 with α-methoxy heterocycles 21i – k followed by basic hydrolysis of the oxazolidinone auxiliary …”

Section: Chemistrymentioning

confidence: 99%

Discovery and Preclinical Pharmacology of a Selective ATP-Competitive Akt Inhibitor (GDC-0068) for the Treatment of Human Tumors

et al. 2012

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The discovery and optimization of a series of 6,7-dihydro-5H-cyclopenta[d]pyrimidine compounds that are ATP-competitive, selective inhibitors of protein kinase B/Akt is reported. The initial design and optimization was guided by the use of X-ray structures of inhibitors in complex with Akt1 and the closely related protein kinase A. The resulting compounds demonstrate potent inhibition of all three Akt isoforms in biochemical assays and poor inhibition of other members of the cAMP-dependent protein kinase/protein kinase G/protein kinase C extended family and block the phosphorylation of multiple downstream targets of Akt in human cancer cell lines. Biological studies with one such compound, 28 (GDC-0068), demonstrate good oral exposure resulting in dose-dependent pharmacodynamic effects on downstream biomarkers and a robust antitumor response in xenograft models in which the phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin pathway is activated. 28 is currently being evaluated in human clinical trials for the treatment of cancer.

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The Stereochemistry of the Addition of Chlorotitanium Enolates of N-Acyl Oxazolidin-2-ones to 5- and 6- Membered N-Acyliminium Ions

Cited by 2 publications

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Intrinsic Gas-Phase Electrophilic Reactivity of Cyclic N-Alkyl- and N-Acyliminium Ions

Intrinsic Gas-Phase Electrophilic Reactivity of Cyclic N-Alkyl- and N-Acyliminium Ions

Discovery and Preclinical Pharmacology of a Selective ATP-Competitive Akt Inhibitor (GDC-0068) for the Treatment of Human Tumors

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