Total Synthesis of Prostaglandins F<sub>2α</sub> and E<sub>2</sub> as the Naturally Occuring Forms

Corey, E. J.; Schaaf, Thomas; Huber, Willy; Koelliker, Urs; Weinshenker, Ned M.

doi:10.1021/ja00705a609

Cited by 236 publications

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“…The other conditions, such as 12 N HCl in MeOH at 0°C, 16) conc. HCl (2 drops) in 2-PrOH at 50°C, 20) a trace of HCl in MeOH at 62°C 21) for the cleavage of MOM-ether, and an aqueous acetic acid in THF at 47°C 22) for the cleavage of tetrahydropyranyl ether, were not suitable for selective deprotection. The resulting phenol (18) was then converted into the ether (19) by means of methyl bromoacetate with sodium hydride in 93% yield.…”

Section: Resultsmentioning

confidence: 99%

“…The cleavage of the MOM-ether at the 4-position of 19 in acetic acid at 90°C smoothly provided the 4-hydroxybenzaldehyde (20) in 80% yield, and sequential treatment of 20 with trifluoromethanesulfonic anhydride (Tf 2 O) and pyridine at 0°C gave the triflate (21) in 85% yield. The palladium-catalyzed cross-coupling reaction of 21 with tributyl 1-propenyltin in the presence of PdCl 2 (PPh 3 ) 2 in DMF at 80°C afforded the appropriate o-propenyl benzaldoxime methyl ether (22) in 83% yield as a 1-aza 6p-electron system (Chart 2).…”

Section: Resultsmentioning

confidence: 99%

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Synthesis of the New Furo[3,2-h]isoquinoline Alkaloid, TMC-120B from Aspergillus ustus

Kumemura

Choshi

Hirata

et al. 2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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A total synthesis of a new furo[3,2-h]isoquinoline alkaloid TMC120-B (2), isolated from Aspergillus ustus together with two related compounds, has been completed in sixteen steps. The key step is the synthesis of the appropriate 3,7,8-trisubstituted isoquinoline framework (23) based on a thermal electrocyclic reaction of the 1-aza 6p p-electron system involving the benzene double bond. In addition, the microwave assisted electrocyclic reaction of this system was newly performed.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Synthesis of the New Furo[3,2-h]isoquinoline Alkaloid, TMC-120B from Aspergillus ustus

Kumemura

Choshi

Hirata

et al. 2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…The two prostaglandin (PG) endoperoxides, PGH2 (I, Fig. 1) and PGG2 (II), derived in vio from arachidonic acid, are very potent in inducing rapid and irreversible aggregation of human platelets through release of ADP and serotonin (1)(2)(3)(4)(5)(6)(7)(8). The endoperoxides are rapidly metabolized to a hemiacetal derivative 8-(1-hydroxy-3-oxopropyl)-9, 12L-dihydroxy-5,10-heptadecadienoic acid (PHD) in platelets, and this metabolite is released in large amounts during aggregation induced by various agents (4,5).…”

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confidence: 99%

“…The endoperoxides are also potent stimulants of vascular (rabbit aorta and umbilical artery) and air-way smooth muscle (6 Fig. 1 starting from PGA2 methyl ester acetate (IV) which is available either by total synthesis (8)(9)(10) or by extraction of the soft coral Plexaura homomalla (11). The methyl ester acetate IV was converted to a mixture of a-and ,B-10,11-epoxides (V) by reaction at -20°for 1.5 hr in methanol (18 ml/g of IV) with 0.5 eq of sodium hydroxide and 10 eq of 30% aqueous hydrogen peroxide, following a known method (12).…”

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confidence: 99%

Synthesis and biological properties of a 9,11-azo-prostanoid: highly active biochemical mimic of prostaglandin endoperoxides.

Corey¹,

Nicolaou²,

Machida³

et al. 1975

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

116

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The 9,11-azo-prostanoid III [(5Z, 9a, Ila, 13E, has been obtained by synthesis and tested for biological activity in systems which are responsive to the prostaglandin endoperoxides PGH2 (I) and PGG2 (II). The azo analog III is a powerful mimic of these endoperoxides with reference to platelet aggregation and release of serotonin when added to human platelet-rich plasma. The analog III is substantially more active (about 7 fold) than PGG2 in stimulating muscle contraction in the isolated rabbit aorta strip. The very great stability of III relative to PGH2 and PGG2 and its potency as a mimic of these important substances suggest that this azo analog will be of considerable value in future studies of the prostaglandin endoperoxides. The two prostaglandin (PG) endoperoxides, PGH2 (I, Fig. 1) and PGG2 (II), derived in vio from arachidonic acid, are very potent in inducing rapid and irreversible aggregation of human platelets through release of ADP and serotonin (1-8). The endoperoxides are rapidly metabolized to a hemiacetal derivative 8-(1-hydroxy-3-oxopropyl)-9, 12L-dihydroxy-5,10-heptadecadienoic acid (PHD) in platelets, and this metabolite is released in large amounts during aggregation induced by various agents (4, 5). A physiological role of the endoperoxide system in human platelets has been established through studies demonstrating that a hemostatic defect involving an abnormal platelet release mechanism was due to deficiency of the cyclo-oxygenase responsible for endoperoxide synthesis (3). The endoperoxides are also potent stimulants of vascular (rabbit aorta and umbilical artery) and air-way smooth muscle (6).The endoperoxides PGH2 and PGG2 are intrinsically highly unstable substances (half-life, t1/2, about 5 min in aqueous solution at 370 and pH 7.4). Further, they are transformed with great rapidity enzymically [e.g., t1/2 about 10 sec in platelet-rich plasma (PRP)]. Because of the extraordinary lability of these endoperoxides and the consequent difficulties and limitations in experimental use, the design and synthesis of a stable and active analog was deemed important. The most interesting analog for initial study appeared to be the azo compound represented by formula III in Fig. 1. It was anticipated that this substance would possess very nearly the same molecular geometry as PGH2 (I), but would be indefinitely stable at pH 7 and 370. Although there was no assurance a priori that III would behave as a close mimic of PGH2 (or PGG2) rather than as an antagonist, the experimental resolution of this question itself seemed worthwhile as a step toward a better understanding of the biochemical mode of action of PGH2.MATERIALS AND METHODS The preparation of the endoperoxides PGG2 and PGH2 has been described previously (2). Blood from healthy donors, who had not taken any drugs for at least 1 week, was collected from the antecubital vein with 0.13 volume of 0.1 M trisodium citrate. After centrifugation at 200 X g for 15 min at room temperature, PRP was removed. Calcium chloride (10 ,ul 0.25 M solutio...

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“…To a suspension of 32.4 g of methoxymethyltriphenylphosphonium chloride in 150 ml of tetrahydrofuran stirred in an ice-methanol bath was added 69.4 ml of BuLi (1.6 M in hexane) in 45 ml of tetrahydrofuran. After 30 min a solution of 10 g of lactol (compound 4) [22] in 90ml of tetrahydrofuran was added. The mixture was stirred for 1.5 h. The solvent was evaporated and the residue partitioned between methylene dichloride and water.…”

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confidence: 99%

Decreased Rate of Metabolism Induced by a Shift of the Double Bond in Prostaglandin F_2α from the ⁵ to the ⁴ Position

Gréen¹,

Samuelsson²,

Magerlein³

1976

European Journal of Biochemistry

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The synthesis of an isomer of prostaglandin F,,, 9a, 1 1 a, 1 5(S)-trihydroxyprosta-4-cis,l3-trunsdienoic acid is described. The metabolism of this compound in the rat has been investigated. The rate of degradation by B-oxidation was slowed down considerably. Thus 10-200/, of the injected isomer was excreted in the urine unchanged indicating a longer half-life in the circulation than for prostaglandin Fz,. More over 2 % was excreted as Cz0 metabolites, 11 -18 % as CI8 metabolites and 8 -15 % as CI6 metabolites. This relative resistance to degradation by b-oxidation is of considerable biochemical and pharmacological interest.The metabolism of prostaglandins in vivo has been investigated in a number of species, including man, during the past decade [l-141. There are mainly five types of reactions which occur: oxidation of the alcohol group at C-15; reduction of the d13-double bond; reduction of the keto group formed at C-15 leading to a 15-(S)-hydroxy group; two steps of P-oxidation ; and w-hydroxylation with formation of w-1 or (0-2 hydroxy compounds. The 0-1 hydroxy metabolites can be further oxidized to dicarboxylic acids. The keto group in the five-membered ring of prostaglandin E compounds can in some species be reduced to an alcohol group with a-or P-configuration [6,10, 131.Oxidation at C-15, which usually initiates the metabolic degradation of the prostaglandins is followed by reduction of the d13-double bond [15,16]. The first step is catalyzed by a prostaglandin specific dehydrogenase which, as well as the Al3-reductase is widely distributed in animal tissues [17]. The efficient action of these enzymes results in a very short half-life of primary prostaglandins in the circulating blood [7,18]. Thus, 1.5 min after intravenous injection of tritium-labeled prostaglandin Fza to man only 3 -4 -.~ Ahhresiufion. Me,Si, trimethylsilyl.Trivial Names. Prostaglandin E,, 1 la,l5(S)-dihydroxy-9-ketoprosta-5-&,I 3-rrcms-dienoic acid; prostaglandin F,,, 9u.l la,15(S)-trihydroxyprosta-5-cis, 13-trans-dienoic acid.

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Total Synthesis of Prostaglandins F_2α and E₂ as the Naturally Occuring Forms

Cited by 236 publications

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Synthesis of the New Furo[3,2-h]isoquinoline Alkaloid, TMC-120B from Aspergillus ustus

Synthesis of the New Furo[3,2-h]isoquinoline Alkaloid, TMC-120B from Aspergillus ustus

Synthesis and biological properties of a 9,11-azo-prostanoid: highly active biochemical mimic of prostaglandin endoperoxides.

Decreased Rate of Metabolism Induced by a Shift of the Double Bond in Prostaglandin F_2α from the ⁵ to the ⁴ Position

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Total Synthesis of Prostaglandins F2α and E2 as the Naturally Occuring Forms

Cited by 236 publications

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Synthesis of the New Furo[3,2-h]isoquinoline Alkaloid, TMC-120B from Aspergillus ustus

Synthesis of the New Furo[3,2-h]isoquinoline Alkaloid, TMC-120B from Aspergillus ustus

Synthesis and biological properties of a 9,11-azo-prostanoid: highly active biochemical mimic of prostaglandin endoperoxides.

Decreased Rate of Metabolism Induced by a Shift of the Double Bond in Prostaglandin F2α from the 5 to the 4 Position

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Total Synthesis of Prostaglandins F_2α and E₂ as the Naturally Occuring Forms

Decreased Rate of Metabolism Induced by a Shift of the Double Bond in Prostaglandin F_2α from the ⁵ to the ⁴ Position