Peptide Synthesis —BIO-PROTOCOL
Synthetic access to the chemical diversity of DNA and RNA 5′‐aldehyde lesions.
Terminal alkyne synthesis by C-C coupling - Organic …
Alkylation of the N-3 position on thymidine can occur from the reaction of acrylonitrile (which is produced in situ when the cyanoethyl protecting group is eliminated) with thymidine during ammonia deprotection. It is especially noticeable when synthesizing very long oligonucleotides. The result is in an impurity that runs on reverse phase HPLC like an n+1 peak. It is easily recognized by mass spectrometry as a +53 Da species. This side reaction can be minimized by using a larger volume of ammonia when cleaving the oligo or using AMA, since methylamine is better at scavenging acrylonitrile. However, this side reaction can be eliminated completely by treating the column after the synthesis is completed with a solution of 10% diethylamine (DEA) in acetonitrile prior to cleavage in ammonia. Typically, the column if fitted with a syringe and a few milliliters of the DEA solution are pushed through slowly over a 5 minute period. Alternatively, the synthesizer can be set up with the DEA solution on one of the additional ports. In this way, the DEA rinse can be automated by writing a custom end procedure.
The activators used in DNA synthesis are mild organic acids. They protonate the nitrogen of the phosphoramidite, leading to the highly reactive tetrazolide intermediate. However, because these activators are acidic, they can remove a small percentage of the 5’-DMT from the dG phosphoramidite during the coupling step, which, in turn, can react with activated dG phosphoramidite. This leads to the formation of a GG dimer and its subsequent incorporation in the sequence. Over the large number of couplings in the synthesis of long oligonucleotides, this can lead to a significant n+1 peak. As with the n-1 impurity, this too is DMT-ON and difficult to separate from the full-length oligo. The reason that GG dimer addition is seen rather than AA or TT is that guanosine detritylates faster than the other bases and hence leads to more dimer formation. To minimize this side reaction, strongly acidic activators such as BTT which has a pKa of 4.1, and ETT (pKa 4.3) should be avoided. Probably the best activator is DCI. While a strong activator, its pKa is 5.2 – even less acidic than tetrazole. DCI is a much better nucleophile than the tetrazole derivatives and this compensates for its lower acidity.
Pyridine synthesis - Organic chemistry
Compare also , and preformed Vilsmeier reagent . Monograph: Synthesis Using Vilsmeier Reagents, C. M. Marson, P. R. Giles, CRC Press, Boca Raton, FL (1994). Formylation can be extended to less active substrates, e.g. acenaphthene or mesitylene, with the DMF-triflic anhydride reagent: J. Chem. Soc., Chem. Commun., 1571 (1990). Under Vilsmeier conditions, electron-rich alkenes can be converted to ɑß-unsaturated aldehydes; see, e.g.: Synthesis, 752 (1976); and ketones to ß-chloroenals: Synthesis, 496 (1985); Org. Synth. Coll., 5, 215 (1973).
Owing to their unusual structural motifs and promising pharmacological properties, colchicine (1) and NCME (2) have attracted considerable attention from synthetic chemists, which has resulted in several elegant total syntheses of 1 and 2. Recently, we developed an enantioselective synthesis of colchicine (1) from commercially available and inexpensive 2,3,4-trimethoxybenzaldehyde (5). The challenging tricyclic 6–7–7 core of colchicinoids was efficiently introduced using an intramolecular oxidopyrylium-mediated [5 + 2] cycloaddition reaction. In our continuing efforts toward the synthesis of biologically active natural products, we herein describe a modified concise and highly enantioselective synthesis of colchicine using the Wacker oxidation for the regioselective construction of the highly oxidized tropolone C-ring. Moreover, asymmetric total syntheses of β-lumicolchicine and NCME were also achieved.
Aerobic Copper-Catalyzed Organic Reactions - …
Organofluorine compounds are becoming increasingly important in different fields, such as material science, agro chemistry, and the pharmaceutical industry. Nucleophilic trifluoromethylation is one of the widely used methods to incorporate a trifluoromethyl moiety into organic molecules. We have carried out extensive studies to develop varieties of easily accessible nucleophilic catalysts to promote such reactions. TMS-protected trifluoromethylated alcohols were prepared from both aldehydes and ketones in excellent yields using catalytic amount of amine -oxide. Carbonate and phosphate salts also showed efficient catalytic activity toward this reaction. These reactions were highly solvent dependent, and DMF was found to be the most suitable one among the various solvents studied. All these reactions proceeded under very mild conditions, giving clean products and avoiding the use of any fluoride initiators or expensive catalysts, and extremely water-free conditions. The mechanism for the reaction is discussed in detail. DFT calculations were performed on the possible reaction intermediates using the Gaussian 03 program at B3LYP/6-311+G* level to support the proposed mechanism.
Our synthesis began with the preparation of 6 (>99% ) from 5 in 5 steps in 21.8% overall yield, as reported previously (). The diastereoselective reduction of the ketone group in 6, followed by the chemoselective methylation of the resulting alcohol, afforded 8 in 75% yield (1.0 g scale). The structure of 8 was unambiguously confirmed using X-ray crystallography. After extensive experimentation, we found that the regioselective Wacker oxidation of the substituted olefin using air as a co-oxidant gave ketone 9 in good yield. We reasoned that the methoxy group at C10 in 8 was critical for this regioselective outcome. Finally, the double elimination of the oxa-bridge in 9 proceeded smoothly using a slightly modified version of Cha’s procedure in the presence of TMSOTf and Me2EtN in DCM to complete our total synthesis of (−)-1 in 81% yield in >99% . The 1H and 13C NMR spectra of synthetic 1, as well as its optical rotation, were identical to those of the natural product.
Allen was born in 1984 in Kutztown, Pennsylvania
PDF Downloads : Oriental Journal of Chemistry
Simple and efficient solid-phase synthesis of unprotected peptide aldehyde for peptide segment ligation
Asymmetric Total Syntheses of Colchicine, β …
The Multiple Faces of Eugenol
Alkylamines (C1-C6) - Chemical Economics Handbook …
Bouveault aldehyde synthesis | SpringerLink
A concise and highly enantioselective synthesis of colchicine (>99% ) in eight steps and 9.3% overall yield, without the need for protecting groups, was developed. A unique Wacker oxidation was used for enabling regioselective construction of the highly oxidized and synthetic challenging tropolone C-ring. Furthermore, asymmetric syntheses of β-lumicolchicine and -acetylcolchinol--methyl ether (NCME) were achieved. Notably, NCME was synthesized from β-lumicolchicine by an unusual decarbonylation and electrocyclic ring-opening cascade reaction.
Synthesis of amides - Organic chemistry
N, N-Dimethylformamide is commonly used as a solvent. It is used as a reagent in Bouveault aldehyde synthesis and also in Vilsmeier-Haack reaction. It acts as a catalyst in the synthesis of acyl chlorides. It is used for separating and refining crude from olefin gas. DMF along with methylene chloride acts as a remover of varnish or lacquers. It is also used in the manufacture of adhesives, fibers and films.
NaIO4/DMF, A reagent for conversion of organic halides …
Even if the coupling efficiency is high and maintained throughout the length of the sequence, there are a number of side reactions that can lead to poor quality oligos. The most prominent of these is depurination. Trichloroacetic acid (TCA), which is the standard acid used in deblock solutions, is quite strong, with a pKa of approximately 0.7. Detritylation using TCA is quite fast and, for this reason, it is the standard deblocking reagent on most DNA synthesizers. However, TCA is strong enough to protonate the N7 nitrogen of adenosine and guanosine, which can lead to depurination and the formation of abasic sites. Upon deprotection, the abasic sites cleave, leading to the production of DMT-ON species truncated at the 3'-terminus, greatly complicating down-stream purification.
a well known transformation in organic synthesis
In summary, we developed a concise and highly enantioselective synthesis of colchicine (>99% ) in eight steps in 9.3% overall yield without the need for protecting groups. An unusual Wacker oxidation was used for enabling the regioselective construction of the highly oxidized tropolone C-ring. β-Lumicolchicine was prepared through a 4π-electrocyclization reaction with a much-improved yield compared with existing procedures, and the allocolchicinoid NCME was synthesized from β-lumicolchicine through a novel decarbonylation/electrocyclic ring-opening cascade reaction.
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