Enantioselective Intramolecular Aldol Addition/Dehydration Reaction of a Macrocyclic Diketone: Synthesis of the Musk Odorants (R)‐Muscone and (R,Z)‐5‐Muscenone

Knopff, Oliver; Kuhne, Jérôme; Fehr, Charles

doi:10.1002/ange.200604518

Cited by 17 publications

(3 citation statements)

References 47 publications

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“…The principal odorous component of musk deer (Moschus moschiferus) musk is the chiral 15-membered ring ketone (R)-muscone [(R)-1); l-muscone; (R)-methylcyclopentadecanone; Fig. 1], whose structure was first elucidated by Ruzicka in 1926 (2), and for which numerous syntheses have been reported (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). (R)-1 has an odor detection threshold of 4.5 ng/L (6), which is lower than the threshold for (S)-muscone [(S)-1].…”

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confidence: 99%

Molecular mechanism of activation of human musk receptors OR5AN1 and OR1A1 by ( R )-muscone and diverse other musk-smelling compounds

Ahmed

Zhang

Block

et al. 2018

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

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Understanding olfaction at the molecular level is challenging due to the lack of crystallographic models of odorant receptors (ORs). To better understand the molecular mechanism of OR activation, we focused on chiral ()-muscone and other musk-smelling odorants due to their great importance and widespread use in perfumery and traditional medicine, as well as environmental concerns associated with bioaccumulation of musks with estrogenic/antiestrogenic properties. We experimentally and computationally examined the activation of human receptors OR5AN1 and OR1A1, recently identified as specifically responding to musk compounds. OR5AN1 responds at nanomolar concentrations to musk ketone and robustly to macrocyclic sulfoxides and fluorine-substituted macrocyclic ketones; OR1A1 responds only to nitromusks. Structural models of OR5AN1 and OR1A1 based on quantum mechanics/molecular mechanics (QM/MM) hybrid methods were validated through direct comparisons with activation profiles from site-directed mutagenesis experiments and analysis of binding energies for 35 musk-related odorants. The experimentally found chiral selectivity of OR5AN1 to ()- over ()-muscone was also computationally confirmed for muscone and fluorinated ()-muscone analogs. Structural models show that OR5AN1, highly responsive to nitromusks over macrocyclic musks, stabilizes odorants by hydrogen bonding to Tyr260 of transmembrane α-helix 6 and hydrophobic interactions with surrounding aromatic residues Phe105, Phe194, and Phe207. The binding of OR1A1 to nitromusks is stabilized by hydrogen bonding to Tyr258 along with hydrophobic interactions with surrounding aromatic residues Tyr251 and Phe206. Hydrophobic/nonpolar and hydrogen bonding interactions contribute, respectively, 77% and 13% to the odorant binding affinities, as shown by an atom-based quantitative structure-activity relationship model.

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confidence: 99%

Molecular mechanism of activation of human musk receptors OR5AN1 and OR1A1 by ( R )-muscone and diverse other musk-smelling compounds

Ahmed

Zhang

Block

et al. 2018

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

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“…The enantioselective aldol condensation of achiral diketone 76 , followed by an Eschenmoser fragmentation of bicyclic enone 77 , and finally hydrogenation of the macrocyclic alkyne 78 were the key steps for an efficient synthesis of ( R ,5 Z )-muscenone ( 79 ) and ( R )-muscone ( 72 ) (Scheme ) …”

Section: Ingredients Responsible For Musk Odormentioning

confidence: 99%

“…75 The enantioselective aldol condensation of achiral diketone 76, followed by an Eschenmoser fragmentation of bicyclic enone 77, and finally hydrogenation of the macrocyclic alkyne 78 were the key steps for an efficient synthesis of (R,5Z)-muscenone ( 79) and (R)-muscone (72) (Scheme 20). 76 Taking advantage of the development in rutheniumcatalyzed alkene metathesis, a very elegant synthesis of (R)-muscone ( 72) was reported and relied on several tandem ruthenium-catalyzed steps (Scheme 21). 77 Starting from optically active (R)-citronellal ((R)-11), alcohol 80 was cyclized with Grubbs second generation metathesis catalyst (81) to the corresponding macrocyclic alcohol 82.…”

Section: Ingredients Responsible For Musk Odormentioning

confidence: 99%

Hydrogenation Processes in the Synthesis of Perfumery Ingredients

Saudan

2007

Acc. Chem. Res.

227

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Homogeneous catalytic hydrogenation has played an important role in the development of modern organic synthesis. Indeed, the discovery of highly regio- and stereoselective catalysts for C=C and C=O bonds reductions has allowed the efficient synthesis of optically active compounds. As the fragrance industry has turned to synthetic ingredients to fulfill the need for novel, cost-effective, and environment-friendly products, the use of catalytic processes are more and more in demand. In this Account, we thus highlight the application of catalytic hydrogenation in the synthesis of fragrance ingredients.

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Challenges in the Synthesis of Natural and Non‐Natural Volatiles

Birkbeck¹

2010

The Chemistry and Biology of Volatiles

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Enantioselective Intramolecular Aldol Addition/Dehydration Reaction of a Macrocyclic Diketone: Synthesis of the Musk Odorants (R)‐Muscone and (R,Z)‐5‐Muscenone

Cited by 17 publications

References 47 publications

Molecular mechanism of activation of human musk receptors OR5AN1 and OR1A1 by ( R )-muscone and diverse other musk-smelling compounds

Molecular mechanism of activation of human musk receptors OR5AN1 and OR1A1 by ( R )-muscone and diverse other musk-smelling compounds

Hydrogenation Processes in the Synthesis of Perfumery Ingredients

Challenges in the Synthesis of Natural and Non‐Natural Volatiles

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