Stereoselective Synthesis of (–)-Heliannuol E by α-Selective ­Propargyl Substitution

Ogawa, Narihito; Uematsu, Chihiro; Kobayashi, Yuichi

doi:10.1055/s-0040-1719844

Cited by 5 publications

(2 citation statements)

References 7 publications

(12 reference statements)

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“…We found the α selective substitution of phosphate 1 with ArMgBr by using CuCN and CuBr•Me 2 S to give acetylenes 2 (Scheme 1) and the γ regioselective reaction with Cu(acac) 2 [29]. The substitution was successfully applied for the synthesis of biologically active compounds [29][30][31][32]. With these results in mind, we focused our attention on aryl lithium compounds (ArLi), with the expectation that several preparations of ArLi would expand the scope of the reagents.…”

Section: Introductionmentioning

confidence: 99%

Substitution of Secondary Propargylic Phosphates Using Aryl-Lithium-Based Copper Reagents

et al. 2023

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The substitution of secondary propargylic phosphates ROP(O)(OEt)2 where R = [Ph(CH2)2]C(H)(C≡CTMS)] Ph(CH2)2CH(OP(O)(OEt)2)(C≡CTMS) with copper reagents derived from PhLi and copper salts such as CuCl, CuCN, and Cu(acac)2 was studied to establish an ArLi-based reagent system. Among the reagents prepared, PhLi/CuCl (2:1) showed 98% α regioselectivity (rs), while PhLi/Cu(acac)2 was γ selective (>99% rs). PhLi prepared in situ from PhI and PhBr by Li-halogen exchange with t-BuLi was also used for the α selective substitution. A study using the (S)-phosphate disclosed 99% enantiospecificity (es) and the inversion of the stereochemistry. The substitution of five phosphates with substituted aryl reagents produced the corresponding propargylic products with high rs and es values. Similar reactivity and selectivity were observed with 2-furyl and 2-thienyl reagents, which were prepared via direct lithiation with n-BuLi.

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Section: Introductionmentioning

confidence: 99%

Substitution of Secondary Propargylic Phosphates Using Aryl-Lithium-Based Copper Reagents

et al. 2023

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“…Syntheses of flurbiprofen, heliannuol, and a TNF inhibitor are demonstrations of the potency of this method. 3,4 As a new target, we chose the (S)-isomer of nyasol (1, Figure 1), 5,6 which is structurally different from the previous targets. (S)-1 has been isolated from Asparagus africanus 7 and A. cochinchinensis, 8 whereas the (R)-isomer is found in Anemarrhena asphodeloides 9 and Hypoxis nyasica.…”

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Synthesis of (S)-Nyasol through a Copper-Catalyzed Propargylic Substitution

Kobayashi

Hirotsu

2022

Synlett

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(S)-Nyasol was selected as the target to demonstrate the efficiency of the copper-catalyzed substitution of secondary propargylic phosphates. The key phosphate (R)-TBDPSO(CH2)2CH(C≡CC6H4OTBS)-(OP(O)(OEt)2) was synthesized from TBDPSO(CH2)2CO2H in four steps. The substitution of the phosphate with TBSOC6H4MgBr in the presence of CuBr·Me2S as a catalyst in THF/DME proceeded with both stereo- and regioselectivity at the propargylic position. All the silyl groups in the propargylic product, TBDPSO(CH2)2CH(C≡CC6H4OTBS)(C6H4OTBS), were removed, and the acetylene bond was reduced using active Zn to produce the cis olefin. Finally, the HO(CH2)2 moiety was converted to CH2=CH-, thus producing (S)-nyasol with 97% cis selectivity, 94.5% ee, and >99% es. Similarly, dihydro-nyasol was synthesized via hydrogenation of the substitution product followed by construction of the terminal olefin.

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Six-membered ring systems: with O and/or S atoms

Santos¹,

Silva²

2023

Progress in Heterocyclic Chemistry

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Stereoselective Synthesis of (–)-Heliannuol E by α-Selective Propargyl Substitution

Abstract: This paper describes a stereoselective synthesis of (–)-heliannuol E through intramolecular cyclization of a phenol mesylate. The introduction of the aromatic group was achieved by α-selective propargyl substitution of a propargylic phosphate.

Cited by 5 publications

References 7 publications

Substitution of Secondary Propargylic Phosphates Using Aryl-Lithium-Based Copper Reagents

Substitution of Secondary Propargylic Phosphates Using Aryl-Lithium-Based Copper Reagents

Synthesis of (S)-Nyasol through a Copper-Catalyzed Propargylic Substitution

Six-membered ring systems: with O and/or S atoms

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Stereoselective Synthesis of (–)-Heliannuol E by α-Selective ­Propargyl Substitution

Abstract: This paper describes a stereoselective synthesis of (–)-heliannuol E through intramolecular cyclization of a phenol mesylate. The introduction of the aromatic group was achieved by α-selective propargyl substitution of a propargylic phosphate.

Cited by 5 publications

References 7 publications

Substitution of Secondary Propargylic Phosphates Using Aryl-Lithium-Based Copper Reagents

Substitution of Secondary Propargylic Phosphates Using Aryl-Lithium-Based Copper Reagents

Synthesis of (S)-Nyasol through a Copper-Catalyzed Propargylic Substitution

Six-membered ring systems: with O and/or S atoms

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Stereoselective Synthesis of (–)-Heliannuol E by α-Selective Propargyl Substitution