Synthesis of (<i>R</i>)-(+)-4-Methylcyclohex-2-ene-1-one

Tun, Maung Kyaw Moe; Herzon, Seth B.

doi:10.1021/jo3017956

Cited by 6 publications

(4 citation statements)

References 22 publications

(37 reference statements)

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“…Many examples are reported in the literature for the preparation of enantiomerically enriched cyclohexenones . In particular, we were keen to explore a sequence consisting of a selective monohydrogenation of a cyclohexadiene followed by Saegusa oxidation (Scheme ), which has proven useful for the synthesis of natural products and complex organic structures.…”

Section: Resultsmentioning

confidence: 99%

Fit-for-Purpose Synthesis of a KRAS^G12C Covalent Inhibitor, via a Diastereoselective Hayashi Arylation

Molinaro,

Wong,

White

et al. 2024

Org. Process Res. Dev.

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An enabling, fit-for-purpose synthesis of stereochemically pure KRAS G12C covalent inhibitor 1, a potential new treatment for cancer, is described. The synthetic route provided 1 in 13 steps from commercially available 2-fluoro-5-methylaniline (2), tert-butyl (S)-3-methylpiperazine-1-carboxylate ( 8) and (S)-(1-methylpyrrolidin-2-yl)methanol (10). A key transformation in this sequence was the diastereoselective 1,4-addition of an aryl boronate derived from 2 with rac-4-methylcyclohex-2-en-1-one (rac-4) in a Hayashi arylation that sets two relative stereocenters of the target molecule. This in turn inspired the development of an improved synthesis of (R)-4-methylcyclohex-2-en-1-one ((R)-4) via optimized methodology for the asymmetric monohydrogenation of 1,4-dienes, thus setting the stage for a fully asymmetric synthesis of inhibitor 1.

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Section: Resultsmentioning

confidence: 99%

Fit-for-Purpose Synthesis of a KRAS^G12C Covalent Inhibitor, via a Diastereoselective Hayashi Arylation

Molinaro,

Wong,

White

et al. 2024

Org. Process Res. Dev.

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“…A more straightforward route was developed later (Scheme 17b). 46 The deprotonation of ( R )-(+)-pulegone and trapping of the resulting enolate with N -phenyl bis(trifluoromethanesulfonimide) (PhNTf 2 ) provided a vinyl triflate. Selective ozonolysis of the electron-rich olefin formed ketone 79 .…”

Section: Huperzine Amentioning

confidence: 99%

Huperzine alkaloids: forty years of total syntheses

Cheng,

Song,

Chen

2024

Nat. Prod. Rep.

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“…( R )-Pulegone ( 40 ) was converted to ( R )-4-methyl-cyclohex-2-ene-1-one ( 38 ) by a three-step sequence comprising enol triflate formation, reduction, and oxidative cleavage of the alkene (44% overall, Scheme ). Dibromopyridine 39 is a known compound and was prepared in one step from commercial reagents . The two fragments were united by a Noyori three-component coupling involving a diastereoselective 1,4-addition of dimethlyphenylsilyl cuprate to ( R )-4-methyl-cyclohex-2-ene-1-one ( 38 ), followed by trapping of the enolate with the dibromopyridine 39 to yield 41 (84–91%).…”

Section: Introductionmentioning

confidence: 99%

Metric-Based Analysis of Convergence in Complex Molecule Synthesis

2021

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Conspectus Convergent syntheses are characterized by the coupling of two or more synthetic intermediates of similar complexity, often late in a pathway. At its limit, a fully convergent synthesis is achieved when commercial or otherwise readily available intermediates are coupled to form the final target in a single step. Of course, in all but exceptional circumstances this level of convergence is purely hypothetical; in practice, additional steps are typically required to progress from fragment coupling to the target. Additionally, the length of the sequence required to access each target is a primary consideration in synthetic design. In this Account, we provide an overview of alkaloid, polyketide, and diterpene metabolites synthesized in our laboratory and present parameters that may be used to put the degree of convergence of each synthesis on quantitative footing. We begin with our syntheses of the antiproliferative, antimicrobial bacterial metabolite (−)-kinamycin F (1) and related dimeric structure (−)-lomaiviticin aglycon (2). These synthetic routes featured a three-step sequence to construct a complex diazocyclopentadiene found in both targets and an oxidative dimerization to unite the two halves of (−)-lomaiviticin aglycon (2). We then follow with our synthesis of the antineurodegenerative alkaloid (−)-huperzine A (3). Our route to (−)-huperzine A (3) employed a diastereoselective three-component coupling reaction, followed by the intramolecular α-arylation of a β-ketonitrile intermediate, to form the carbon skeleton of the target. We then present our syntheses of the hasubanan alkaloids (−)-hasubanonine (4), (−)-delavayine (5), (−)-runanine (6), (+)-periglaucine B (7), and (−)-acutumine (8). These alkaloids bear a 7-azatricyclo[4.3.3.01,6]dodecane (propellane) core and a highly oxidized cyclohexenone ring. The propellane structure was assembled by the addition of an aryl acetylide to a complex iminium ion, followed by intramolecular 1,4-addition. We then present our synthesis of the guanidinium alkaloid (+)-batzelladine B (9), which contains two complex polycyclic guanidine residues united by an ester linkage. This target was logically disconnected by an esterification to allow for the independent synthesis of each guanidine residue. A carefully orchestrated cascade reaction provided (+)-batzelladine B (9) in a single step following fragment coupling by esterification. We then discuss our synthesis of the diterpene fungal metabolite (+)-pleuromutilin (10). The synthesis of (+)-pleuromutilin (10) proceeded via a fragment coupling involving two neopentylic reagents and employed a nickel-catalyzed reductive cyclization reaction to close the eight-membered ring, ultimately providing access to (+)-pleuromutilin (10), (+)-12-epi-pleuromutilin (11), and (+)-12-epi-mutilin (12). Finally, we discuss our synthesis of (−)-myrocin G (13), a tricyclic pimarane diterpene that was assembled by a convergent annulation. In the final section of this Account, we present several paramaters to analyze and quantitativ...

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Synthesis of (R)-(+)-4-Methylcyclohex-2-ene-1-one

Cited by 6 publications

References 22 publications

Fit-for-Purpose Synthesis of a KRAS^G12C Covalent Inhibitor, via a Diastereoselective Hayashi Arylation

Fit-for-Purpose Synthesis of a KRAS^G12C Covalent Inhibitor, via a Diastereoselective Hayashi Arylation

Huperzine alkaloids: forty years of total syntheses

Metric-Based Analysis of Convergence in Complex Molecule Synthesis

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Synthesis of (R)-(+)-4-Methylcyclohex-2-ene-1-one

Cited by 6 publications

References 22 publications

Fit-for-Purpose Synthesis of a KRASG12C Covalent Inhibitor, via a Diastereoselective Hayashi Arylation

Fit-for-Purpose Synthesis of a KRASG12C Covalent Inhibitor, via a Diastereoselective Hayashi Arylation

Huperzine alkaloids: forty years of total syntheses

Metric-Based Analysis of Convergence in Complex Molecule Synthesis

Contact Info

Product

Resources

About

Fit-for-Purpose Synthesis of a KRAS^G12C Covalent Inhibitor, via a Diastereoselective Hayashi Arylation

Fit-for-Purpose Synthesis of a KRAS^G12C Covalent Inhibitor, via a Diastereoselective Hayashi Arylation