Synthesis of chiral 5-substituted cyclohex-2-enones from 5-trimethylsilylcyclohex-2-enone

Asaoka, Morio; Shima, Kunihisa; Takei, Hisashi

doi:10.1039/c39880000430

Cited by 33 publications

(10 citation statements)

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“…The choice of these particular enones was predicated on a combination of their accessibility in optically pure form (where appropriate), their commercial availability or ease of synthesis, and because the products formed after oxidative coupling and ring-closure mapped onto substructures of interest to us. ( R )- and ( S )-carvone [( R )- 7 and ( S )- 7 ] and methylvinylketone ( 12 ) are commercially available, while compounds 1 – 6 were prepared in 99% ee from (5 R )-trimethylsilylcyclohexenone as a readily available chiral synthon. − Compounds 8 , and 9 could be easily made from ( R )- or ( S )-carvone, respectively. Enone 10 could be produced from commercially available (−)-quinnic acid, and a simple allylation of cyclohexenone delivered enone 11 .…”

Section: Resultsmentioning

confidence: 99%

“…These highly versatile chiral starting materials could be prepared in 2-steps from ( E )-3-(trimethylsilyl)prop-2-en-1-ol on a 10-g scale using the organocatalytic Robinson annulation protocol devised by Jørgensen and co-workers . Conjugate addition of isopropenylmagnesium bromide to ( S ) -43 proceeded with complete facial selectivity to deliver the requisite enone fragment 42 following oxidative elimination of the TMS substituent with CuCl 2 (47% over two steps). , Synthesis of enone fragment 3 involved a similar sequence of events beginning with the diastereocontrolled conjugate addition of vinylmagnesium bromide to ( R )- 43 and subsequent exposure of the thus formed ketone to CuCl 2 . 1,2-Addition of methyllithium and oxidative transposition using PCC installed the necessary 3-methylsubstituent, thereby producing the desired product 3 in 39% over the four steps.…”

Section: Resultsmentioning

confidence: 99%

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A Strategy for the Convergent and Stereoselective Assembly of Polycyclic Molecules

Robinson

Thomson

2018

J. Am. Chem. Soc.

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The stereoselective oxidative coupling of cyclic ketones via silyl bis-enol ethers followed by ring-closing metathesis is shown to be a general and powerful reaction sequence for the preparation of diverse polycyclic scaffolds from simple precursors. The modular strategy successfully constructs substructures prevalent in numerous bioactive natural product families, varying in substitution and carbocyclic composition. Several of the prepared compounds were shown to possess potent cytotoxic activity against a panel of tumor cell lines. The utility of this strategy was further demonstrated by a concise and highly convergent 17-step formal synthesis of the complex antimalarial marine diterpene, (+)-7,20-diisocyanoadociane.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

A Strategy for the Convergent and Stereoselective Assembly of Polycyclic Molecules

Robinson

Thomson

2018

J. Am. Chem. Soc.

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“…A modification of the procedure for oxidative elimination of β-trimethylsilyl ketones described by Fleming and co-workers enabled the conversion of 7 to the 4,4-disubstituted-2-cyclohexen-1-one 10 in 93% yield. This efficient preparation of chiral 2-cyclohexen-1-ones is expected to have substantial value in asymmetric synthesis.…”

Section: Resultsmentioning

confidence: 99%

Desymmetrization of Benzoic Acid in the Context of the Asymmetric Birch Reduction−Alkylation Protocol. Asymmetric Total Syntheses of (−)-Eburnamonine and (−)-Aspidospermidine

1997

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The highly diastereoselective potassium in ammonia reduction−ethylation (EtI) of the chiral 2-(trimethylsilyl)benzamide 1b to give 1,4-cyclohexadiene 3 is the key step in asymmetric syntheses of (−)-eburnamonine (4) and (−)-aspidospermidine (5). Cyclohexadiene 3 was converted to cyclohexanone 7, which provided the trimethylsilyl-substituted butyrolactone 9 utilized for the synthesis of 4 and butyrolactone 13 required for the synthesis of 5. The preparation of 9 depended upon the completely regioselective silicon-directed Baeyer−Villiger oxidation 7 → 8; Baeyer−Villiger oxidation of the cyclohexenone 10 also was regioselective to give the desired enol lactone 11 in 92% yield. Remarkable diastereoselectivity was observed for the kinetically controlled cyclization of the acyl imminium ion derived from the vinyl-substituted carboxaldehyde 16b; treatment of 16b with 5 equiv of CF3CO2H in CH2Cl2 at −55 °C gave an 18:1 mixture of 17 and its C(3) β-epimer in 93% yield. The oxidation of alcohol 18 containing sensitive indole and piperidine rings was best carried out with tetrapropylammonium perruthenate/N-methylmorpholine N-oxide to give (−)-eburnamonine (4) in 97% yield. The asymmetric synthesis of (−)-aspidospermidine 5 involved the conversion of butyrolactone 13 to the hydroxylactam 22, the Harley-Mason cyclization of 22 to 23, and reduction of 23 with LiAlH4.

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“…To our surprise a more bulky isopropyl group ( 1 b ) led to a slight decrease in the selectivity ( s =39; Table 1, entry 10), and substrate 1 c containing a phenyl group at the 5‐position also gave a lower selectivity ( s =19; Table 1, entry 11) than 1 a . Resolution of the synthetically important 5‐trimethylsilyl‐2‐cyclohexenone ( 1 d ) was also successful, providing 86 % ee at 56 % conversion ( s =14, Table 1, entry 12) 3a, 16b, 17…”

Section: Methodsmentioning

confidence: 99%

Highly Enantioselective Copper-Phosphoramidite Catalyzed Kinetic Resolution of Chiral 2-Cyclohexenones

et al. 2001

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Chiral 2-cyclohexenones are attractive building blocks for the synthesis of a variety of natural products. A limited number of naturally occurring optically active cyclohexenones such as pulegone, piperitone, and carvone are cheap, readily available, and widely used for this purpose. [1] The development of routes to other optically active 2-cyclohexenones includes the preparation of nonnatural cyclohexenones from naturally occurring ones; for example, 4-methyland 5-methylcyclohexenone can be derived from pulegone and carvone. [2] Recently the groups of Corey and Sato introduced elegant methods for the synthesis of enantiomerically pure 2-cyclohexenones which can easily be converted into a variety of other chiral 2-cyclohexenones. [3] Although both methods are widely applicable they consist of multistep syntheses to obtain the desired 2-cyclohexenone synthons. On the other hand a variety of racemic 2-cyclohexenones is readily accessible. This encouraged us to develop a general method towards optically active 2-cyclohexenones by kinetic resolution of racemic 2-cyclohexenones based on the copper ± phosphoramidite catalyzed 1,4-addition to enones [Eq. (1)]. [4] It was anticipated that the high enantioselectivity obtained with these catalysts in the 1,4-addition of diethylzinc to 2-cyclohexenone (b 98 % ee, [Eq. (1)]), [4] combined with the high trans-diastereoselectivity generally found in the addition of organometallic reagents to, for example, 5-alkyl-substituted 2-cyclohexenones, [5] should provide high selectivity in the kinetic resolution of such compounds [Eq. (2)]. [6,7] To check the viability of this new approach we tested the ligands L1 ± L5 in the kinetic resolution of racemic 5-substituted 2-cyclohexenones 1 a ± d under the conditions typical for the asymmetric 1,4-addition as shown in Scheme 1. By using [Cu(OTf) 2 ] (1 mol %), (S,R,R)-L1 (2 mol %), and Et 2 Zn (0.8 equiv) in toluene at À 40 8C for the resolution of (AE)-5methyl-2-cyclohexenone (1 a) on a 1 mmol scale, an ee of 88 % Scheme 1. Kinetic resolution of racemic 5-substituted 2-cyclohexenones 1 a ± d under the conditions typical for asymmetric 1,4-addition.was reached at 48 % conversion indicating a selectivity (s) of 120 (Table 1, entry 1). [8±10] Accordingly after 20 min 53 % conversion had taken place and unreacted 1 a with 99 % ee was found. This high selectivity makes the resolution synthetically applicable. [11] Based on the expected trans-diastereoselectivity and the fact that the 1,4-addition of Et 2 Zn to 2-cyclohexenone in the presence of L1 produces (S)-3-ethylcyclohexanone we predicted the unreacted enantiomer to be (R)-1 a which turned out to be correct. [4d, 5, 12] A good correlation was observed between the results with the ligands L1 ± L5 in the 1,4-addition of diethylzinc to 2-cyclohexenone and the results in the kinetic resolution (Table 1, entries 1 ± 9). The most successful ligands in the 1,4addition, namely (S,R,R)-L1, (S,R)-and (S,S)-L2 (Table 1, entries 3 and 4), and (S,R,R)-L3 (Table 1, entry 5), also give the highest ...

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Synthesis of chiral 5-substituted cyclohex-2-enones from 5-trimethylsilylcyclohex-2-enone

Abstract: Optically active and racemic 5-substituted cyclohex-2-enones were synthesized from 5-trimethylsilylcyclohex-2-enone.In connection with our continuing study' on the utilization of 5-trimethylsilylcyclohex-2-enone (1) in natural product

Cited by 33 publications

References 1 publication

A Strategy for the Convergent and Stereoselective Assembly of Polycyclic Molecules

A Strategy for the Convergent and Stereoselective Assembly of Polycyclic Molecules

Desymmetrization of Benzoic Acid in the Context of the Asymmetric Birch Reduction−Alkylation Protocol. Asymmetric Total Syntheses of (−)-Eburnamonine and (−)-Aspidospermidine

Highly Enantioselective Copper-Phosphoramidite Catalyzed Kinetic Resolution of Chiral 2-Cyclohexenones

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