Synthesis of a Ribose‐Incorporating Medium Ring Scaffold via a Challenging Ring‐Closing Metathesis Reaction

Rankin, Stuart S.; Caldwell, John; Cronin, Nora; Montfort, R.L.M. van; Collins, Ian

doi:10.1002/ejoc.201600756

Cited by 7 publications

(3 citation statements)

References 29 publications

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“…When acetic acid was used as a buffer to reduce the basicity of TBAF, it resulted in the desired product in 30–50% yields, along with partial Fmoc deprotection. When we followed another protocol by Collins and co-workers using a 9:1 mixture of TFA:H 2 O, we achieved the desired products in 40–55% yields with unidentified impurities, which were more prominent in the case of nucleobase A. Moreover, purification of the products was difficult because of unsatisfactory chromatographic separation.…”

Section: Resultsmentioning

confidence: 97%

“…We measured the thermal stability of PMO (manually synthesized and machine-synthesized) and com-pared with Gene Tools PMO and DNA by a UV melting experiment (Table 7). The T m values of the control DNA: DNA (no tail) (60.8 °C) (entry 1) and DNA: DNA (nanog) (58.5 °C) (entry 3) were less stable than no tail PMO (21): DNA (67.5 °C) (entry 2) and Nanog PMO (33):DNA (66 °C) (entry 4) by 6−7 °C. The stability of the duplex PMO:DNA was in close agreement with the Gene Tools PMO: DNA duplex (62 °C) (entry 6).…”

Section: Evaluation Of Antisense Efficacy Of 25-mer No Tail Pmo In Ze...mentioning

confidence: 99%

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Synthesis of Phosphorodiamidate Morpholino Oligonucleotides Using Trityl and Fmoc Chemistry in an Automated Oligo Synthesizer

Kundu

Ghosh

et al. 2022

J. Org. Chem.

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Phosphorodiamidate morpholino oligonucleotides (PMOs) constitute 3 out of the 11 FDA-approved oligonucleotide-based drugs in the last 6 years. PMOs can effectively silence disease-causing genes and modify splicing. However, PMO synthesis has remained challenging for a variety of reasons: inefficient deprotection and coupling methods and instability of monomers. Here, we report the development of a suitable combination of resin supports, deblocking and coupling reagents for synthesizing PMOs using either trityl or Fmoc-protected chlorophosphoramidate monomers. The synthesized PMOs using both the methods on a solid support have been validated for gene silencing in a zebrafish model. The protocol was successfully transferred into an automated DNA synthesizer to make several sequences of PMOs, demonstrating for the first time the adaptation of regular PMOs in a commercial DNA synthesizer. Moreover, PMOs with longer than 20-mer sequences, including FDA-approved Eteplirsen (30-mer), were achieved in >20% overall yield that is superior to previous reports. Hybridization study shows that PMOs exhibit a higher binding affinity toward complementary DNA relative to the DNA/DNA duplex (>6 °C). Additionally, the introduction of Fmoc chemistry into PMOs opens up the possibility for PMO synthesis in commercial peptide synthesizers for future development.

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Section: Resultsmentioning

confidence: 97%

Section: Evaluation Of Antisense Efficacy Of 25-mer No Tail Pmo In Ze...mentioning

confidence: 99%

Synthesis of Phosphorodiamidate Morpholino Oligonucleotides Using Trityl and Fmoc Chemistry in an Automated Oligo Synthesizer

Kundu

Ghosh

et al. 2022

J. Org. Chem.

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“…al. 24 to use 9:1 mixture of TFA:H 2 O and obtained the products in 40 to 55 % yields with the impurities. In the case of nucleobase A, this impurity was more.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Phosphorodiamidate Morpholino Oligonucleotides Using Trityl and Fmoc Chemistry-A New Method Amenable to Automated Synthesizer

Ghosh¹,

Kundu²,

Ghosh³

et al. 2020

Preprint

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Phosphorodiamidatemorpholino oligonucleotides (PMO) are routinely used for gene silencing and the recently developed PMO-based drug “Exondys51” has highlighted the importance of PMO as excellent antisense reagents. However, the synthesis of PMO has remained challenging. Here a method for the synthesis of PMO using either trityl or Fmoc-protected active morpholino monomers using chlorophosphoramidate chemistry in the presence of a suitable coupling agent on a solid support has been reported. After screening several coupling agents (tetrazole, 1,2,4-triazole, ETT, iodine, LiBr and dicyanoimidazole), ETT and iodine were found to be suitable for efficient coupling. Fmoc chemistry was not known for PMO synthesis because the preparation of Fmoc-protected chlorophosphoramidate monomers was not trivial. Synthesis of Fmoc-protected activated monomers and their use in PMO synthesis is reported for the first time. 25-mer PMO has been synthesized using both the methods and validated in vivo in the zebrafish model by targeting the no tail gene. Methods have been transferred in DNA synthesizer which has become user friendly for PMO synthesis and opened a new avenue to explore PMO for various applications. Fmoc chemistry could be suitable for scalable approach of PMO synthesis using peptide synthesizer as it is a neutral oligomer like peptide.

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Regio‐ and Diastereoselective Functionalization of 3‐Amino‐hexahydrooxazoninones

et al. 2018

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The regio‐ and diastereoselectivity of transformations of nine‐membered lactams with a Z double bond in the cyclic tether towards building blocks for medicinal chemistry was evaluated. To this end, 3‐aminohexahydrooxazoninones were synthesized using a standard ring‐closing metathesis (RCM) approach of easily available O,N‐bisallylated serine derivatives. The obtained Z double bond in the medium sized lactam was used as a handle to evaluate the stereoselectivity of electrophile induced transformations. It was shown that dibromination and electrophilic activation by NBS followed by attack of O‐nucleophiles proceeded in a diastereoselective manner. Cyclization of obtained bromohydrins and face‐selective epoxidation gave access to both diastereomers of the epoxidized lactams. Finally, a Heck‐reaction of a bromobenzyl moiety at the lactam N‐atom with the Z‐double bond resulted in the diastereoselective formation of bicyclic bridged nine‐membered lactams.

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Synthesis of a Ribose‐Incorporating Medium Ring Scaffold via a Challenging Ring‐Closing Metathesis Reaction

Cited by 7 publications

References 29 publications

Synthesis of Phosphorodiamidate Morpholino Oligonucleotides Using Trityl and Fmoc Chemistry in an Automated Oligo Synthesizer

Synthesis of Phosphorodiamidate Morpholino Oligonucleotides Using Trityl and Fmoc Chemistry in an Automated Oligo Synthesizer

Synthesis of Phosphorodiamidate Morpholino Oligonucleotides Using Trityl and Fmoc Chemistry-A New Method Amenable to Automated Synthesizer

Regio‐ and Diastereoselective Functionalization of 3‐Amino‐hexahydrooxazoninones

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