A Facile Method for the Synthesis of Substituted<i>N</i>-Methylenecarboxamides and Alkyl<i>N</i>-Methylenecarbamates

Kupfer, Rainer; Meier, Stefan; Würthwein, Ernst‐Ulrich

doi:10.1055/s-1984-30936

Cited by 82 publications

(35 citation statements)

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“…Greater delocalization in 2 is confirmed by lesser alternation in bond lengths in 2e compared with 6e. Simple acylimines with enolizable hydrogens are normally less stable than their enamide tautomers (14), so it was important to check whether our computational methods could reproduce this preference or whether they were biased in favor of acylimines. Ground-state computations performed at the same level of theory as that of the protein fragments predicted the acylimine AcNAC(Me)OCH 2 Me to be 1.6 kcal͞mol less stable than the enamide AcNHOC(Me)ACHOMe.…”

Section: Resultsmentioning

confidence: 99%

The structure of the chromophore within DsRed, a red fluorescent protein from coral

Gross

Baird

Hoffman

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

576

594

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DsRed, a brilliantly red fluorescent protein, was recently cloned from Discosoma coral by homology to the green fluorescent protein (GFP) from the jellyfish Aequorea. A core question in the biochemistry of DsRed is the mechanism by which the GFP-like 475-nm excitation and 500-nm emission maxima of immature DsRed are red-shifted to the 558-nm excitation and 583-nm emission maxima of mature DsRed. After digestion of mature DsRed with lysyl endopeptidase, high-resolution mass spectra of the purified chromophore-bearing peptide reveal that some of the molecules have lost 2 Da relative to the peptide analogously prepared from a mutant, K83R, that stays green. Tandem mass spectrometry indicates that the bond between the alpha-carbon and nitrogen of Gln-66 has been dehydrogenated in DsRed, extending the GFP chromophore by forming OCANOCAO at the 2-position of the imidazolidinone. This acylimine substituent quantitatively accounts for the red shift according to quantum mechanical calculations. Reversible hydration of the CAN bond in the acylimine would explain why denaturation shifts mature DsRed back to a GFP-like absorbance. The CAN bond hydrolyses upon boiling, explaining why DsRed shows two fragment bands on SDS͞PAGE. This assay suggests that conversion from green to red chromophores remains incomplete even after prolonged aging. In the preceding companion paper (1), we showed that the red fluorescent protein DsRed cloned from coral by Matz et al. (2) has impressive brightness and stability against pH changes, denaturants, and photobleaching, and that it can be mutated to even longer wavelengths of excitation and emission. However, DsRed also shows slow and complex kinetics of maturation, proceeding via a green fluorescent protein (GFP)-like green intermediate to the final red species. DsRed also proves to be at least an obligate tetramer, two of which may weakly associate into an octamer (1). The present paper examines one of the most important fundamental unsolved questions about DsRed, namely the structure of the red chromophore and the mechanism by which it attains such long wavelengths. Matz et al. (2) speculated that ''an additional autocatalytic reaction, presumably inhibited in GFP, takes place during fluorophore maturation and leads to the extension of its conjugated -system.'' In an accompanying commentary, Tsien (3) raised the possibility that an amine side chain might attack the terminal carbonyl of the GFP chromophore to form an iminium cation somewhat analogous to that in rhodopsin. More recently, Terskikh et al.** suggested instead that ''the additional reaction is another cyclization within the backbone rather than attachment of a group derived from a neighboring side chain.'' All of these suggestions have been of generic reaction types rather than specific proposals of a detailed structure for the red chromophore.Our strategy relied critically on a point mutant, K83R, which remains almost entirely arrested at the green stage of maturation (1) and provides a reference standard for that intermediate...

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Section: Resultsmentioning

confidence: 99%

The structure of the chromophore within DsRed, a red fluorescent protein from coral

Gross

Baird

Hoffman

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

576

594

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“…it becomes less basic before it undergoes ring closure. For this purpose we prepared a representative imine 9 [7] bearing the electron-withdrawing ethoxycarbonyl group. Indeed deprotonation of 1b using LDA (lithium diisopropylamide) in THF at Ϫ95°C followed by addition of a THF solution of 9 afforded a mixture of the desired 4-methylenepyrrolidine 10 (35%) and the open-chain adduct 11 (20%) which were easily separated by column chromatography [Equation (1)].…”

Section: Resultsmentioning

confidence: 99%

Stereoselective Addition of Sulfone Carbanions to C=N: A Critical Dependence on the Stability and Reactivity of the Amide Anions in MIRC Reactions

et al. 2004

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“…2,3 N-Carboalkoxy amines having a chiral tertiary carbon center are stereoselectively constructed by these reactions. Given this, N-carboalkoxy ketimines should be attractive electrophilic targets for creating chiral quaternary carbon centers; however, only a few N-carboalkoxy ketimines have been prepared [4][5][6][7][8][9][10][11] and most did not have acidic a-protons. Preparation of N-carboalkoxy ketimines is more difficult than preparation of N-carboalkoxy aldimines 4 because of the lower reactivity of ketones and the tendency of N-carboalkoxy ketimines to tautomerize into the corresponding ene carbamates.…”

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confidence: 99%

A mild and convenient synthesis of N-carbobenzyloxy ketimines

et al. 2006

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N-Carbobenzyloxy (Cbz) ketimines were prepared conveniently from N-Cbz amines by oxidation with N-tert-butylbenzenesulfinimidoyl chloride.N-Carboalkoxy aldimines are often used as nitrogen-containing electrophiles for carbon-carbon bond forming reactions, especially for highly enantioselective reactions such as the Mannich type reaction 1 and the aza-Henry reaction. 2,3 N-Carboalkoxy amines having a chiral tertiary carbon center are stereoselectively constructed by these reactions. Given this, N-carboalkoxy ketimines should be attractive electrophilic targets for creating chiral quaternary carbon centers; however, only a few N-carboalkoxy ketimines have been prepared 4-11 and most did not have acidic a-protons. Preparation of N-carboalkoxy ketimines is more difficult than preparation of N-carboalkoxy aldimines 4 because of the lower reactivity of ketones and the tendency of N-carboalkoxy ketimines to tautomerize into the corresponding ene carbamates. Hoch reported that N-carboethoxy ketimines were prepared from diethyl ketals and NH 2 CO 2 Et in the presence of a trace amount of PhNH 3 Cl at 90-100 uC, 5 but it was later found that N-carboethoxy ketimines obtained by Hoch's method included ene carbamate. 6,7 N-Carboalkoxy ketimines are also prepared from NH ketimines 8,9 or N-silyl ketimines, 10 though available NH ketimines and N-silyl ketimines have been limited to non-enolizable ones; i.e., diaryl and aryl tert-butyl ketimines. 11 We have found that N-tert-butylbenzenesulfinimidoyl chloride (1){ oxidized various organic compounds under very mild reaction conditions. 12 We expected that the above-mentioned labile Ncarboalkoxy ketimines would be synthesized under mild conditions by 1-mediated oxidation of the corresponding N-carboalkoxy amines. We describe here the oxidation of a variety of N-carbobenzyloxy (Cbz) amines to N-Cbz ketimines using 1.First, oxidation of N-Cbz-1-phenylethylamine (2a) to the corresponding N-Cbz ketimine 3a was tried using the following procedure: 2a was treated with n-BuLi in THF at 278 uC and then 1 was added at the same temperature. As expected, the 1-mediated oxidation of 2a proceeded rapidly at 278 uC and the desired product 3a was obtained in 97% yield after chromatography on silica gel. It was noted that ene carbamate 3a9 13 was not obtained by this procedure. The crystalline product 3a was stable in a refrigerator for several months, while a part of 3a tautomerized to 3a9 after keeping the solution of 3a in chloroform at room temperature for 10 days. The scope and limitations of the present 1-mediated oxidation were investigated for the reaction of various N-Cbz protected amines 2 giving N-Cbz aryl alkyl ketimines 3 (Table 1). N-Cbz phenyl ethyl ketimine 3b, N-Cbz phenyl propyl ketimine 3c, and N-Cbz phenyl isopropyl ketimine 3d were isolated in high yields regardless of the steric hindrance. It was found that yields of N-Cbz aryl ketimines 3 depended strongly on the substituents on the phenyl ring. In the presence of an electronattracting group, such as chloride, ketimine 3g ...

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A Facile Method for the Synthesis of SubstitutedN-Methylenecarboxamides and AlkylN-Methylenecarbamates

Cited by 82 publications

References 0 publications

The structure of the chromophore within DsRed, a red fluorescent protein from coral

The structure of the chromophore within DsRed, a red fluorescent protein from coral

Stereoselective Addition of Sulfone Carbanions to C=N: A Critical Dependence on the Stability and Reactivity of the Amide Anions in MIRC Reactions

A mild and convenient synthesis of N-carbobenzyloxy ketimines

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