A synthesis of freelingyne

Ingham, CF; Massy-Westropp, RA; Reynolds, GD

doi:10.1071/ch9741477

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“…The applications of furan-3,4-dicarboxylic acid and its esters have been well known in practice. 2 They are used as starting materials in the synthesis of several bioactive natural products such as zargocic acid, 3 confertin, 4 aromaticin, 5 lactral, 6 freelingyne, 7 biotin, 8 nectriafurone 9 and perrilin. 9 They are also used in the synthesis of several pharmacologically useful molecules, 10 preparation of complexes with rare earth metal ions 11 and as a potential dienes in Diels-Alder reactions for the synthesis of several novel heterocycles.…”

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confidence: 99%

A New Strategy for the Synthesis of Furan-3,4-dicarboxylic Acid

Deshpande¹,

Natu²,

Argade³

2002

Synthesis

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A New Strategy for the Synthesis of Furan-3,4-dicarboxylic Acid

Deshpande¹,

Natu²,

Argade³

2002

Synthesis

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“…Freelingyne ( 1 ), a sesquiterpene from Eremophila freelingii , features several synthetically interesting structural subunits, such as a methyl-substituted ( E )-alkene and a ( Z )-γ-alkylidenebutenolide. Although it has been synthesized twice in the past, a mixture of the Z and E isomers of 1 was obtained in either case as a consequence of nonstereoselective olefination, the reported Z / E ratio in one case 3a being 40/60. Herein, we report an efficient synthesis of freelingyne with essentially full control of the alkene geometries, employing the synthetic strategy outlined in Scheme .…”

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Efficient and Stereoselective Synthesis of Freelingyne via Pd-Catalyzed Cross Coupling and Lactonization¹

Liu

Negishi

1997

J. Org. Chem.

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Freelingyne (1), a sesquiterpene from Eremophila freelingii, 2 features several synthetically interesting structural subunits, such as a methyl-substituted (E)-alkene and a (Z)-γ-alkylidenebutenolide. Although it has been synthesized twice in the past, 3 a mixture of the Z and E isomers of 1 was obtained in either case as a consequence of nonstereoselective olefination, the reported Z/E ratio in one case 3a being 40/60. Herein, we report an efficient synthesis of freelingyne 4 with essentially full control of the alkene geometries, employing the synthetic strategy outlined in Scheme 1.The E and Z methyl-substituted alkene units were prepared by the Zr-catalyzed carboalumination with Me 3 -Al 5 and the Cu-catalyzed methylmagnesation, 6 respectively, of propargyl alcohol, followed by iodinolysis. The stereoselectivity in either case was g99%. The yield of (E)-3-iodo-2-methyl-2-propen-1-ol (2) was 53% and relatively constant. On the other hand, the yield of the Z isomer 3 obtained via methylmagnesation ranged from 30 to 75%. At this point, it is not very clear what factor is responsible for the observed yield fluctuation, but efficient and vigorous mechanical stirring of the reaction mixture appears to be essential to obtaining 3 in high yields. Conversion of 3 into (Z)-3-iodo-2-methylpropenoic acid (4) was achieved by oxidation first with PCC (2 equiv) and Celite in CH 2 Cl 2 7 and then with NaClO 2 -H 2 O 2 in the presence of NaH 2 PO 3 in MeCN 8 in 57% overall yield.After protection of 2 with 3,4-dihydro-2H-pyran in 84% yield, the Pd-catalyzed cross coupling with commercially available ethynylmagnesium chloride 9 in THF in the presence of 5 mol % of Pd(PPh 3 ) 4 afforded enyne 5 in 94% yield. The direct synthesis of terminal alkynes such as 5 using ethynylzinc or ethynylmagnesium derivatives in the Pd-catalyzed cross coupling 9 offers a distinct advantage over the Sonogashira protocol 10 which is known to require protection-deprotection of the ethynyl group. In this case, HCtCMgCl was as satisfactory as HCtCZnBr. However, cross coupling of 5 with 3-iodofuran in the presence of 5 mol % of Pd(PPh 3 ) 4 was best achieved by in situ conversion of 5 into the bromozinc derivatives via sequential treatment with n-BuLi and freshly dried ZnBr 2 . The desired cross-coupling product 6 was obtained in 82% yield along with 5 recovered in 16%. 3-Iodofuran was prepared by treatment of commercially available 3-bromofuran with n-BuLi followed by iodinolysis. After removal of the THP group in 97% yields with p-TsOH in MeOH, oxidation with Dess-Martin periodinane 11 in CH 2 Cl 2 gave the corresponding aldehyde 7 in essentially quantitative yield. Corey-Fuchs olefination 12 of 7 with CBr 4 (3 equiv) and PPh 3 (6 equiv) in the presence of K 2 CO 3 afforded the desired dibromide 8 in 95% yield. Its sequential treatment with NaN(SiMe 3 ) 2 (1.5 equiv) in THF, n-BuLi (3 equiv), and MeOH provided 9 in 86% yield.With 4 and 9 in hand, the stage was set for the crucial Pd-catalyzed cross coupling-lactonization tandem process developed recen...

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“…[14,[58][59][60][61] Freelingyne (27), an acetylenic furanosesquiterpene was isolated for the first time from natural sources (3) in E. freelingii with its 8,9-dihydro-(28) and 4,5,8,8,9,9-hexahydro-analogues. [62][63][64] However, later freelingyne was detected in E. rotundifolia. [65] In addition, freelingnite (29) was the first example of a 4-alkylbut-2-enolide isolated from higher plants in E. freelingii.…”

Section: Sesquiterpenes Furanosesquiterpenesmentioning

confidence: 99%

“…[74] These serrulatane diterpenes are regarded as isoprenologues of the calamenene type. [55] Linalool (19) E. longifolia [55] Menth-2-en-1-ol (20) E. longifolia [55] Abdel Nasser Singab et al [58] (-)-10,11-Dehydrongaione (22) E. rotundifolia [59] (-)-10,11-Dehydroepingaione (23) E. rotundifolia [59] (+/-)-Myoporone (24) E. maculata E. latrobei E. miniata [60] [60] [61] (+)-Myoporone (25) E. inflata [14] Abdel Nasser Singab et al Eremophila: ethnobotany, biology & chemistry [60] Freelingyne (27) E. freelingii E. rotundifolia [62,63] [65]…”

Section: Serrulatanesmentioning

confidence: 99%

“…8,9-Dihydro-freelingyne (28) E. freelingii [63] Freelingnite (29) E. freelingii [64] Eremoacetal (30) E. rotundifolia [59] Dendrolasin (31) R = H E. rotundifolia [66] 4-Hydroxydendrolasin (32) R = OH E. rotundifolia [66] Dihydrophymaspermones (E-and Z-) (33) E. rotundifolia [59] Abdel Nasser Singab et al [67] 4-Hydroxydihydromyodesmone (35) E. alternifolia E. latrobei E. scoparia [67] 1-((5S)-2-(Furan-3-yl)-2-hydroxy-5methylcyclopentyl)-3-methylbut-2en-1-one (36) E. alternifolia E. latrobei E. scoparia [67] 4-Hydroxy-4-methyl-1-(2,3,4,5tetrahydro-5-methyl[2,3′-bifuran]-5-yl) pentan-2-one (37) E. duttonii [45] (R)-5-((R,E)-4-Hydroxy-2-methyl-5-(5-oxo-2,5-dihydrofuran-3-yl)pent-2enyl)-3-methylfuran-2(5H)-one (38) R = OH E. homoplastica [68] (R,E)-4-Methyl-5-((R)-4-methyl-5-oxo-2,5-dihydrofuran-2-yl)-1-(5-oxo-2,5dihydrofuran-3-yl)pent-3-en-2-yl acetate (39) R = OAc E. homoplastica [68] (R,E)-3-Methyl-5-(2-methyl-5-(5-oxo-2,5dihydrofuran-3-yl)pent-2-enyl)furan-2(5H)-one (40) R = H E. homoplastica [68] (S,E)-2,6-Dimethyl-9-(5-oxo-2,5-dihydrofuran-3-yl)nona-2,6-dien-4-yl acetate (41) E. forrestii [68] Abdel Nasser Singab et al Eremophila: ethnobotany, biology & chemistry [17,28,69] (2R,3R,4aR,5S)-2-Hydroxy-3-isopropyl-4a,5-dimethyl-3,4,4a,5,6,7hexahydronaphthalen-1(2H)-one (43) R1 = a-OH; R2 = CH3 E. mitchellii [28,69,79] (R)-2-((2S,8S,8aR)-8,8a-Dimethyl-4oxo-1,2,3,4,6,7,8,8a-octahydronaphthalen-2-yl)propanal (44) R1 = H; R2 = CHO E. rotundifolia [80] 9-Hydroxy-7(11),9-eremophiladien-8-one (45) R = OH E. mitchellii [28,69,79] (4aR,5S)-4a,5-Dimethyl-3-(propan-2ylidene)-4,4a,5,6,7,8hexahydronaphthalen-2(3H)-one (46) R = H E. mitchellii [28,69,79] (4aR,5S)-4a,5-Dimethyl-3-(prop-1-en-2-yl)-3,4,4a,5,6,7-hexahydronaphthalen-1(2H)-one (47) R1 = H; R2 = CH3 E. mitchellii [17] 2-((8S,8aR)-8,8a-Dimethyl-4-oxo-1,2,3,4,6,7,8,8a-octahydronaphthalen-2-yl)acrylaldehyde (48) R1 = H; R2 = CHO E. mitchellii <...>…”

Section: Serrulatanesmentioning

confidence: 99%

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The genus Eremophila (Scrophulariaceae): an ethnobotanical, biological and phytochemical review

Singab

Youssef

Ashour

2013

Journal of Pharmacy and Pharmacology

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Objectives Eremophila (Scrophulariaceae) is an endemic Australian genus with 214 species, which is commonly known as Fuchsia bush, Emu bush or Poverty bush. Plants of this genus played an important role for the Australian Aborigines who used them widely for medicinal and ceremonial purposes. Many studies have been carried out on many species of this genus and have generated immense data about the chemical composition and corresponding biological activity of extracts and isolated secondary metabolites. Key findings Thorough phytochemical investigations of different Eremophila species have resulted in the isolation of more than 200 secondary metabolites of different classes with diterpenes as major constituents. Biological studies and traditional clinical practice demonstrated that Eremophila and its bioactive compounds possess various pharmacological properties. Plants were employed especially as a cardiotonic drug and also as potent anti-inflammatory, antimicrobial and antiviral agents. Summary Further investigations are required to explore other Eremophila species, to evaluate the different biological activities of either their extracts or the isolated compounds and the possible underlying modes of action.

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A synthesis of freelingyne

Cited by 30 publications

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A New Strategy for the Synthesis of Furan-3,4-dicarboxylic Acid

A New Strategy for the Synthesis of Furan-3,4-dicarboxylic Acid

Efficient and Stereoselective Synthesis of Freelingyne via Pd-Catalyzed Cross Coupling and Lactonization¹

The genus Eremophila (Scrophulariaceae): an ethnobotanical, biological and phytochemical review

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A synthesis of freelingyne

Cited by 30 publications

References 0 publications

A New Strategy for the Synthesis of Furan-3,4-dicarboxylic Acid

A New Strategy for the Synthesis of Furan-3,4-dicarboxylic Acid

Efficient and Stereoselective Synthesis of Freelingyne via Pd-Catalyzed Cross Coupling and Lactonization1

The genus Eremophila (Scrophulariaceae): an ethnobotanical, biological and phytochemical review

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Efficient and Stereoselective Synthesis of Freelingyne via Pd-Catalyzed Cross Coupling and Lactonization¹