Spirocyclic Compounds in Fragrance Chemistry: Synthesis and Olfactory Properties

Gilles, Laure; Antoniotti, Sylvain

doi:10.1002/cplu.202200227

Cited by 8 publications

(2 citation statements)

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“…2 For instance, recent comprehensive reviews emphasize the role of spirocyclic compounds in fragrance, agricultural and food chemistry. 3,4 However, majority of efforts in the field are being made by medicinal chemists, who generate the lion's share of spirocyclic topologies. This is by no means serendipitous, as foundation of the trend was laid in far 1950 th with the creation of mineralocorticoid receptor antagonist spironolactone.…”

Section: Introductionmentioning

confidence: 99%

CONCISE AND PRACTICAL AVENUES TO 5,5-Spiro-Α-Prolines

Iermolenko,

Artemenko,

Vasko

et al. 2024

Preprint

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Scaffold hopping and three-dimensionality are one of dominating notions in contemporary drug discovery process. Following these concepts is a verified and generally robust avenue to improve the biological activity of a lead against a protein target, selectivity issues as well as ADMET properties. Unfortunately, the freedom of medicinal chemists to replace molecular fragments responsible for the properties is restricted due to unrevealed areas of chemical space existing for even simple building blocks. This paper contributes to the support of drug discovery workflow and describes concise and practical synthetic approaches toward multigram preparation of value-added conformationally constrained 5-spirocyclic α-prolines from readily accessible starting materials. Direct carboxylation of 2-spiropyrrolidines was found to be a novel and promising approach to achieve the purpose and is the most fruitful for substrates with no acidic centers within a part spiro linked to pyrrolidine core. The method allows for quick and one-step preparation of the target chemicals in good yields. For substrates inapplicable to the straightforward method, an alternative synthetic avenue was designed. This 4-steps protocol deals with common for laboratory practice transformations and is comparable in its efficiency with the carboxylation method. The paper concludes a series of our works on the elaboration of efficient methods for the construction of spiro proline frameworks.

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Section: Introductionmentioning

confidence: 99%

CONCISE AND PRACTICAL AVENUES TO 5,5-Spiro-Α-Prolines

Iermolenko,

Artemenko,

Vasko

et al. 2024

Preprint

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“…Transition metals possess an incomplete d subshell, with shapes and orientations of the d orbitals that allow infeasible bonding patterns for the s and p orbitals; for example, spiroaromaticity . Purely organic spiro polycyclic aromatic compounds are those formed by two conjugated π-systems, fixed perpendicularly by a sp 3 spiro carbon that does not intervene in electronic delocalization . When this spiro carbon atom is replaced by a transition metal atom, it may itself be involved in electron delocalization, thus forming spiro aromatic compounds .…”

Section: Introductionmentioning

confidence: 99%

Preparation, Aromaticity, and Bromination of Spiro Iridafurans

Esteruelas,

Leon,

Moreno-Blázquez

et al. 2023

Inorg. Chem.

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Iridium centers of [Ir(μ-Cl)(C 8 H 14 ) 2 ] 2 (1) activate the C β (sp 2 )−H bond of benzylideneacetone to give [Ir(μ-Cl){κ 2 -C,O-[C(Ph)CHC(Me)O]} 2 ] 2 (2), which is the starting point for the preparation of the spiro iridafurans IrCl{κ 2 -C,O-[C(Ph)CHC-(Me)O]} 2 (P i Pr 3 ) (3), [Ir{κ 2 -C,O-[C(Ph)CHC(Me)-O]} 2 (MeCN) 2 ]BF 4 (4), [Ir(μ−OH){κ 2 -C,O-[C(Ph)CHC(Me)-O]} 2 ] 2 (5), Ir{κ 2 -C,O-[C(Ph)CHC(Me)O]} 2 {κ 2 -C,N-[C 6 MeH 3py]} (6), and Ir{κ 2 -C,O-[C(Ph)CHC(Me)O]} 2 {κ 2 -O,O-[acac]} (7). The five-membered rings are orthogonally arranged with the oxygen atoms in trans in an octahedral environment of the iridium atom. Spiro iridafurans are aromatic. The degree of aromaticity and the negative charge of the CH-carbon of the rings depend on ligand trans to the carbon directly attached to the metal. Aromaticity has been experimentally confirmed by bromination of iridafurans with N-bromosuccinimide (NBS). Reactions are sensitive to the degree of aromaticity of the ring and the negative charge of the attacked CH-carbon. Iridafurans can be selectively brominated, when different ligands lie trans to metalated carbons. Bromination of 3 occurs in the ring with the metalated carbon trans to chloride, whereas the bromination of 6 takes place in the ring with the metalated carbon trans to pyridyl. The first gives IrCl{κ 2 -C,O-[C(Ph)CBrC(Me)O]}{κ 2 -C,O-[C(Ph)CHC(Me)O]}(P i Pr 3 ) (8), which reacts with more NBS to form IrCl{κ 2 -C,O-[C(Ph)CBrC(Me)O]} 2 (P i Pr 3 ) (9). The second yields Ir{κ 2 -C,O-[C(Ph)CBrC(Me)O]}{κ 2 -C,O-[C(Ph)CHC(Me)O]}{κ 2 -C,N-[C 6 MeH 3 -py]} (10). The origin of the selectivity is kinetic, with the rate-determining step of the reaction being the NBS attack. The activation energy depends on the negative charge of the attacked atom; a higher negative charge allows for a lower activation energy. Accordingly, complex 7 undergoes bromination in the acetylacetonate ligand, giving Ir{κ 2 -C,O-[C(Ph)CHC(Me)O]} 2 {κ 2 -O,O-[acacBr]} (11).

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Electricity‐Driven Strain‐Release Cascade Cyclization of Bicyclo[1.1.0]butane (BCB): Stereoselective Synthesis of Functionalized Spirocyclobutyl Oxindoles

Maity,

Paul,

Sen

et al. 2024

ChemSusChem

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Spirocyclobutyl oxindoles, characterized by their unique three‐dimensional structures, are valuable building blocks for many pharmacophores and drug units. However, stereoselective synthetic strategies for these scaffolds remain underdeveloped, with most existing methods relying on transition metal catalysts and stoichiometric redox reagents. In this work, we introduce an electrochemical strain‐release driven cascade spirocyclization of bicyclo[1.1.0]butane (BCB) derivatives for the stereoselective synthesis of functionalized spirocyclobutyl oxindoles. Tetrabutylammonium bromide serves a dual purpose as both a supporting electrolyte and brominating agent. The method offers a broad substrate scope, high atom economy, and excellent diastereoselectivity. The stereoselectivity of the product is controlled by minimizing the dipolar repulsion between the amide C=O and the C–Br bonds. We also explored the methodology’s versatility by applying it to various functionalizations and demonstrated its scalability for practical use. The efficient derivatization of the products allowed for for the rapid creation a diverse library of functionalized spirocyclobutyl oxindoles.

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Spirocyclic Compounds in Fragrance Chemistry: Synthesis and Olfactory Properties

Cited by 8 publications

References 56 publications

CONCISE AND PRACTICAL AVENUES TO 5,5-Spiro-Α-Prolines

CONCISE AND PRACTICAL AVENUES TO 5,5-Spiro-Α-Prolines

Preparation, Aromaticity, and Bromination of Spiro Iridafurans

Electricity‐Driven Strain‐Release Cascade Cyclization of Bicyclo[1.1.0]butane (BCB): Stereoselective Synthesis of Functionalized Spirocyclobutyl Oxindoles

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