Base catalyzed degradations of rapamycin

Steffan, Robert J.; Kearney, Robert M.; Hu, D. C. K.; Failli, Amedeo; Skotnicki, Jerauld S.; Schiksnis, Robert A.; Mattes, James F.; Chan, Keith; Caufield, Craig E.

doi:10.1016/s0040-4039(00)79204-5

Cited by 29 publications

(20 citation statements)

References 8 publications

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“…36,37 A similar reaction was reported for rapamycin, albeit under harsher conditions. [13][14][15] The mass spectral and chromatographic data are consistent with addition of a single water molecule to the "southern" part, as expected for this rearrangement, and introduction of a new stereocenter in 6. Acid 2 is expected to undergo a series of reactions analogous to those shown for 3 in Scheme 2.…”

Section: Proposed Mechanism Of Base-catalyzed Degradation Processessupporting

confidence: 71%

“…Acid-catalyzed cyclization that affords stereoisomers of hydroxydiketomorpholine in the course of LC separation can be excluded because only one peak was observed when degradation mixtures containing one isomer of 3 produced from 1 were analyzed. 15,16 Moreover, no effect of acid concentration on the HPLC profiles was observed for secorapamycin. NMR spectra of rapamycin and secorapamycin salt acquired under conditions mimicking the HPLC analysis (1:1 THF-d 8 /D 2 O) were consistent with a single structure shown above.…”

Section: Proposed Mechanism Of Base-catalyzed Degradation Processesmentioning

confidence: 98%

“…Epimerization at C31 was reported to occur when diethylamine or 4-N,Ndimethtylaminopyridine were used to produce secorapamycin from rapamycin. 15 The isomerization center is apparently removed when 1 and 2 undergo a retro-aldol reaction affording the "southern" and "northern" fragments. The intermediate with RT 20.0 and 11.4 min (THF-and MeCN-based mobile phase, respectively) was assigned to the "southern" fragment (4) that was present largely as a single isomeric form.…”

Section: Proposed Mechanism Of Base-catalyzed Degradation Processesmentioning

confidence: 99%

“…12 It is also known that 1 can afford secorapamycin in non-aqueous media, including pure aprotic solvents, in the presence of a base. [13][14][15][16] Relative to 3, the kinetics and mechanism of formation and degradation in aqueous media are not well understood. It is often assumed that compound 3 is formed through the dehydration of 2.…”

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confidence: 99%

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Degradation of rapamycin and its ring-opened isomer: Role of base catalysis

Il’ichev¹,

Alquier²,

Maryanoff³

2007

Arkivoc

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Rapamycin is a natural macrolide immunosuppressant with a distinct mechanism of action. Quantitative analysis of rapamycin poses many challenges associated with facile degradation and the multitude of isomeric forms. The primary goal of this study was to compare degradation of rapamycin and its ring-opened isomer, secorapamycin, in aqueous solution under identical conditions. Reaction kinetics and mechanisms were studied in 30/70 vol/vol acetonitrile-water mixtures containing either MeCOONH 4 (apparent pH 7.3) or NaOH (apparent pH 12.2). Degradation kinetics was well described by the first-order rate law. For rapamycin in 237 and 23.7 mM solutions of MeCOONH 4 , apparent half-lives of 200 h and 890 h were obtained. When compared to the latter value, the rapamycin half-life was reduced by 3 orders of magnitude in the pH 12.2 solution. Under all conditions studied, secorapamycin degradation was significantly slower than that of the parent compound. Both specific and general base catalysis was observed for reactions of rapamycin and secorapamycin. Two primary products of rapamycin degradation were identified as individual isomers of secorapamycin and a hydroxy acid formed via lactone hydrolysis. No evidence for the interconversion between the products was obtained. In highly basic solutions, both products undergo fragmentation and water addition reactions.

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Section: Proposed Mechanism Of Base-catalyzed Degradation Processessupporting

confidence: 71%

Section: Proposed Mechanism Of Base-catalyzed Degradation Processesmentioning

confidence: 98%

Section: Proposed Mechanism Of Base-catalyzed Degradation Processesmentioning

confidence: 99%

mentioning

confidence: 99%

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Degradation of rapamycin and its ring-opened isomer: Role of base catalysis

Il’ichev¹,

Alquier²,

Maryanoff³

2007

Arkivoc

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“…Additionally, the use of a sulfone acyl anion equivalent should avoid any undesired b-elimination, which has been documented to occur in the presence of the C32 ketone. [24] Lithiation of a trisubstituted olefin at C29 followed by its addition to a suitable electrophile at C28 was anticipated for the union of 4 and 5. Although control of the resulting secondary carbinol stereochemistry was uncertain, we felt confident that the adjacent stereodefined C27-methyl ether might provide some advantage.…”

Section: Introductionmentioning

confidence: 99%

Total Synthesis of Rapamycin

Ley

Tackett

Maddess

et al. 2009

Chemistry A European J

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For over 30 years, rapamycin has generated a sustained and intense interest from the scientific community as a result of its exceptional pharmacological properties and challenging structural features. In addition to its well known therapeutic value as a potent immunosuppressive agent, rapamycin and its derivatives have recently gained prominence for the treatment of a wide variety of other human malignancies. Herein we disclose full details of our extensive investigation into the synthesis of rapamycin that culminated in a new and convergent preparation featuring a macro-etherification/catechol-templating strategy for construction of the macrocyclic core of this natural product.

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An intramolecular ionic hydrogen bond stabilizes a cis amide bond rotamer of a ring‐opened rapamycin‐degradation product

Zhou

Stewart

Dhaon

2004

Magnetic Reson in Chemistry

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Rapamycin (1), a macrolide immunosuppressant, undergoes degradation into ring-opened acid products 2 and 3 under physiologically relevant conditions. The unsaturated product (3) was isolated and studied in this work. Unlike 1, which has its amide primarily in a trans conformation in solution, 3 has both cis and trans conformations in approximately a 1:1 ratio in dimethyl sulfoxide (DMSO). The amount of cis rotamer was increased dramatically in the presence of an organic base such as triethylamine. The detailed NMR results indicate that the cis rotamer is stabilized through an intramolecular ionic hydrogen bond of the carboxylate anion with the tertiary alcohol as part of a nine-membered ring system. This hydrogen bond was characterized further in organic media and the trans-cis rotamer equilibria were used to estimate the relative bond strengths in several solvents. The additional stabilization arising from this ionic hydrogen bond in the cis rotamer was determined to be 1.4 kcal mol(-1) in DMSO-d6, 2.0 kcal mol(-1) in CD3CN and 1.1 kcal mol(-1) in CD3OD.

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Base catalyzed degradations of rapamycin

Cited by 29 publications

References 8 publications

Degradation of rapamycin and its ring-opened isomer: Role of base catalysis

Degradation of rapamycin and its ring-opened isomer: Role of base catalysis

Total Synthesis of Rapamycin

An intramolecular ionic hydrogen bond stabilizes a cis amide bond rotamer of a ring‐opened rapamycin‐degradation product

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