Synthesis of Nature‐Inspired Medium‐Sized Fused Heterocycles from Amino Acids

Ventosa-Andrés, Pilar; La–Venia, Agustina; Ripoll, Carlos Alfonso Barea; Hradilová, Ludmila; Krchňák, Viktor

doi:10.1002/chem.201501746

Cited by 17 publications

(21 citation statements)

References 41 publications

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“…However, there are success stories using approaches that address frontloading of both extracts and subsequent fractions with desired physico-chemical properties prior to screening for drug discovery [24,35]. If NPs are often referred to as 'sources of inspiration', it simply implies that 'lead-like' libraries could be designed, starting from NP scaffolds, with many examples available in the literature [24,35,[43][44][45][46]. However, when an NP is used as the guiding structure for the creation of 'NP-like' libraries, controlling certain molecular descriptors (e.g.…”

Section: Strategy For Designing a Library With Focused Propertiesmentioning

confidence: 99%

“…NPs are known for containing fused medium-sized rings ( Figure 6). In an attempt to mimic such NPs, Ventosa-Andrés et al synthesized several molecular scaffolds containing medium-sized fused heterocycles using amino acids [46]. This is because amino acids are known to be useful building blocks used in natural reservoirs as well as chemistry laboratories to create structural diversity.…”

Section: Case Studymentioning

confidence: 99%

“…N, O, and S. The details of the synthetic strategy are beyond this discussion. The reader is invited to consulted the original paper for further details [46].…”

Section: Case Studymentioning

confidence: 99%

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“Drug-Likeness” <em>versus</em> “Natural Product-Likeness”

Ntie‐Kang¹,

Nyongbela²,

Ayimele³

et al. 2018

Preprint

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We discuss further details on the concepts of “drug-likeness”, “lead-likeness”, and “natural product-likeness”. The discussion will first focus on natural products as drugs, then a discussion of previous studies in which the complexities of the scaffolds and chemical space of naturally occurring compounds have been compared with synthetic, semi-synthetic compounds and FDA-approved drugs. This is followed by guiding principles for designing “drug-like” natural product libraries for lead compound discovery purposes. We end up by presenting a tool for measuring “natural product-likeness” of compounds and a brief presentation of machine learning approaches and a binary quantitative structure-activity relationship (QSAR) for classifying drugs from non-drugs and natural compounds from non-natural ones, respectively.

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Section: Strategy For Designing a Library With Focused Propertiesmentioning

confidence: 99%

Section: Case Studymentioning

confidence: 99%

See 1 more Smart Citation

“Drug-Likeness” <em>versus</em> “Natural Product-Likeness”

Ntie‐Kang¹,

Nyongbela²,

Ayimele³

et al. 2018

Preprint

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show abstract

“…Typically, a cyclic iminium is formed from an amide nitrogen and an aldehyde attached to acyclic intermediate. Then, a cyclic N -acyliminium ion is transformed into fused or bridged structures by intramolecular nucleophilic addition [ 12 , 13 ]. Specifically, oxygen has previously served as an internal nucleophile in the preparation of five- [ 14 , 15 ], six- [ 16 , 17 , 18 , 19 ], seven- [ 13 , 20 ] and eight-membered lactam rings [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Traceless Solid-Phase Synthesis of [6,7,8 + 5,6,7]-Fused Molecular Frameworks

Giménez-Navarro

Krchňák

2018

Molecules

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We report two synthetic strategies for traceless solid-phase synthesis of molecular scaffolds comprising 6- to 8-membered rings fused with 5- to 7-membered rings. Traceless synthesis facilitated preparation of target molecules without any trace of polymer-supported linkers. The cyclization proceeded via acid-mediated tandem N-acylium ion formation followed by the nucleophilic addition of O- and C-nucleophiles. The presented synthetic strategy enabled, through the use of simple building blocks without any conformational preferences, the evaluation of the predisposition of different combinations of ring sizes to form fused ring molecular scaffolds. Compounds with any combination of [6,7 + 5,6,7] ring sizes were accessible with excellent crude purity. The 8-membered cyclic iminium was successfully fused only with the 5-membered cycle and larger fused ring systems were not formed, probably due to their instability.

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“…[36] and references cited therein), synthesis of larger rings using simple building blocks failed. [36] and references cited therein), synthesis of larger rings using simple building blocks failed.…”

Section: Introductionmentioning

confidence: 99%

Traceless Solid‐Phase Synthesis of Fused Chiral Macrocycles via Conformational Constraint‐Assisted Cyclic Iminium Formation

Schütznerová

Oliver

Slough

et al. 2017

Chemistry A European J

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Natural products comprising chiral molecular scaffolds containing fused medium-sized cycles and macrocycles represent an important and relevant pharmacological target for the discovery and development of new drugs. Here, we describe traceless solid-phase synthesis of acyclic intermediates amenable to cyclization to medium (11) and large (12) fused rings. The key aspect of the synthetic strategy is incorporation of a specific conformation constraint that facilitates cyclization in favor of 11- and 12-membered rings rather than possible 7-membered ones. The role of constraints in preorganization required for cyclization is supported by computational analysis. The synthesis involves cyclic N-sulfonyliminium-nucleophilic addition chemistry as the key ring-forming reaction and proceeds with complete stereocontrol of the newly formed stereogenic center. We document the scope and limitations of this strategy in the synthesis of 11+5, 11+6, 11+7, and 12+6 fused rings representing molecular scaffolds with 3D architecture that mimic complex natural products.

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Synthesis of Nature‐Inspired Medium‐Sized Fused Heterocycles from Amino Acids

Cited by 17 publications

References 41 publications

“Drug-Likeness” <em>versus</em> “Natural Product-Likeness”

“Drug-Likeness” <em>versus</em> “Natural Product-Likeness”

Traceless Solid-Phase Synthesis of [6,7,8 + 5,6,7]-Fused Molecular Frameworks

Traceless Solid‐Phase Synthesis of Fused Chiral Macrocycles via Conformational Constraint‐Assisted Cyclic Iminium Formation

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