“Trimethyl lock” facilitated spirocyclizations: A structural analysis

Liu, Siming; Wang, Binghe; Nicolaou, Michalis G.; Borchardt, Ronald T.

doi:10.1007/bf01673672

Cited by 5 publications

(6 citation statements)

References 23 publications

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“…The “trimethyl lock” was found earlier to facilitate acceleration of the rate of lactonization of hydroxy-propionic acids such as Qa and amides such as Qop(a). , In this case, the great strain relief to form products such as cy5en(a), cy5ke(a), and cy6ke(a) is also of consideration. In a recent publication, the crystal structure of the aforementioned spirolactone revealed that the methyl groups of the “trimethyl lock” are no longer in close proximity as in the open structures; rather, the geminal dimethyl group at position 3 points in the opposite direction from the methyl group at position 2‘ …”

Section: Discussionmentioning

confidence: 99%

Facilitated Intramolecular Conjugate Addition of Amides of 3-(3‘,6‘-Dioxo-2‘,4‘-dimethyl-1‘,4‘-cyclohexadienyl)-3,3-dimethylpropionic Acid. 2. Kinetics of Degradation

et al. 1996

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The chemical stability studies of amides of 3-(3',6'-dioxo-2',4'-dimethyl-1',4'-cyclohexadienyl)-3,3-dimethylpropionic acid (Qa) [Qop(a-j)] were conducted in order to determine the utility of this redox-sensitive system as a potential prodrug promoiety or redox-sensitive protecting group in organic synthesis. This study showed that quinone propionic amides of aniline derivatives [Qop(a-d)] underwent rapid degradation in mildly acidic conditions (pH 4.5-6.0) to yield degradation products resulting from the intramolecular 1,2- or 1,4- conjugate addition of the amide nitrogen to the quinone ring. This conjugate addition was found to be specific base-catalyzed and independent of the para substituent on the aromatic ring of the amine. The predominant route of degradation yielded a five-membered ring spirolactam. By altering the nature of the amine component of the amide, these degradation reactions were prevented. Amides of Qa other than those of the aniline type [Qop(e-j)] were found to be substantially more stable and were thus proposed as the more suitable candidates for this potential redox-sensitive prodrug system and redox-sensitive protecting group for amines and alcohols in organic synthesis.

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Section: Discussionmentioning

confidence: 99%

Facilitated Intramolecular Conjugate Addition of Amides of 3-(3‘,6‘-Dioxo-2‘,4‘-dimethyl-1‘,4‘-cyclohexadienyl)-3,3-dimethylpropionic Acid. 2. Kinetics of Degradation

et al. 1996

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“…33 The cyclic prodrug readily released the original peptide when incubated in the presence of porcine liver esterase or in plasma, and showed a 12-fold increase in permeation through monolayers of Caco-2 cells. 33,37 One unique feature of this prodrug system is that the final product of the pro-moiety is coumarin (26), the toxicity of which has been extensively studied. Coumarin was found to be relatively nontoxic.…”

Section: (A) (B)mentioning

confidence: 99%

“…The redoxsensitive prodrug approach was evaluated with both aromatic and aliphatic amines. 18,[24][25][26] The t 1/2 values of these prodrugs after reduction to the hydroquinone 21 (X ) OH) ranged from 85 to 200 s. 18 The phosphatase-sensitive prodrugs of a series of amines, including amino acids, were evaluated as substrates for human placental alkaline phosphatase. 21 All the prodrugs in the series had similar enzyme specificities, with Michaelis constant (K m ) values ranging from 15.6 to 74.3 mM and maximum velocity (V max ) values ranging from 156.7 to 264.2 (nmol/min)/mg of protein.…”

Section: (A) (B)mentioning

confidence: 99%

Prodrug Strategies Based on Intramolecular Cyclization Reactions

Shan

Nicolaou

Borchardt

et al. 1997

Journal of Pharmaceutical Sciences

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107

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Several new prodrug systems for amines, alcohols, and peptides are reviewed. The design of these new prodrug systems takes advantage of several facile intramolecular cyclization reactions, that permit separate manipulation of the release kinetics independent of the structural features of the drug moiety. Such systems can be used for the preparation of esterase-, phosphatase-, and redox-sensitive prodrugs of amines and alcohols and esterase-sensitive cyclic prodrugs of peptides and peptide mimetics.

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“…The design takes advantage of a "trimethyl lock"facilitated cyclic ether formation (Scheme 1), [28][29][30][31] which is different from the design of the linker reported earlier from our group 27 in that the earlier linker utilized a facilitated lactone formation reaction. Consequently, the linker reported in this study allows for the preparation of peptides with free C-termini.…”

Section: Introductionmentioning

confidence: 99%

A Novel Resin Linker for Solid-Phase Peptide Synthesis Which Can Be Cleaved Using Two Sequential Mild Reactions

et al. 1999

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The interest in developing new linkers for solid-phase peptide and organic synthesis has increased tremendously as a result of the rapid development of combinatorial chemistry. Herein, we report the development of a new redox-sensitive linker for solid-phase peptide synthesis. This linker can be readily cleaved under mild conditions by using two sequential mild reactions, a reduction followed by a base (Bu4N+F-)-catalyzed cyclic ether formation. By using this new linker, two short peptides, a tetrapeptide [Boc-Trp-Ala-Gly-Gly-OH] and a pentapeptide [Boc-Asn-Ala-Ser(OBn)-Gly-Glu(OBn)-OH)], were synthesized. Because the cleavage does not use acidic conditions, this resin linker provides an alternative when acidic conditions are not desirable. Furthermore, the cleavage conditions do not affect most of the side chain protecting group. Therefore, the peptides synthesized can be used for the segment synthesis of larger peptides without the need to reprotect the side chain functional groups.

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“Trimethyl lock” facilitated spirocyclizations: A structural analysis

Cited by 5 publications

References 23 publications

Facilitated Intramolecular Conjugate Addition of Amides of 3-(3‘,6‘-Dioxo-2‘,4‘-dimethyl-1‘,4‘-cyclohexadienyl)-3,3-dimethylpropionic Acid. 2. Kinetics of Degradation

Facilitated Intramolecular Conjugate Addition of Amides of 3-(3‘,6‘-Dioxo-2‘,4‘-dimethyl-1‘,4‘-cyclohexadienyl)-3,3-dimethylpropionic Acid. 2. Kinetics of Degradation

Prodrug Strategies Based on Intramolecular Cyclization Reactions

A Novel Resin Linker for Solid-Phase Peptide Synthesis Which Can Be Cleaved Using Two Sequential Mild Reactions

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