Prostaglandin intermediate

The conversion of the bicyclo[2,2,l]heptene aldehydes (475) into PGp2a via the aldehyde (476) has previously required a number of protection and deprotection steps. An improved procedure for the conversion (475) - PGp2 in seven steps that avoids the need to prepare (476) or for protection has now been described. A new procedure for oxidative decarboxylation has been introduced that is of relevance in prostaglandin synthesis.Diels-Alder reaction between 5-cyclopentadienylmethyl methyl ether 

An alternative route to the Corey lactone intermediate (480) by way of the oxidative cleavage of (481) has been reported,and the intermediate (482), previously used in a total synthesis of sesquifenchene (see ref. 3256), has been employed for the synthesis of 12-methylprostaglandins by way of lactone (483).  

A new route to the Corey aldehyde avoiding use of thallium is reported by an ICI group. Cyclopentadiene is converted into acetoxyfulvene, which adds to chloro-acrylonitrile to give the adducts (583) in 73% overall yield. Acid hydrolysis gives first one and then, after equilibration, the other aldehyde, which can be converted, in 40 % overall yield from (583), into the keto-acetal (584) whose conversion into PG s 

Yoshikawa, E. Sasakawa, and J. Furukawa, Bull. Chem. Soc. Japan, 1974,47,2523. 

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The p-phenylbenzoate ester was prepared to protect the hydroxyl group of a prostaglandin intermediate by reaction with the benzoyl chloride (Pyr, 25°, 1 h, 97% yield). It was a more ciystalline, more readily separated derivative than 15 other esters that were investigated. It can be cleaved with K2CO3 in MeOH in the presence of a lactone. ... 

One of the first uses of the allylic sulfoxide-sulfenate interconversion was made by Jones and coworkers64, who reported exclusive suprafacial rearrangement of the allyl group in the steroidal sulfoxide 17 shown in equation 13. Two other examples are shown in equations 1465 and 1566. Evans and coworkers have demonstrated the utility of the suprafacial allylic sulfoxide-sulfenate rearrangement in a new synthesis of the tetracyclic alcohol 24 (equation 16)67, as well as in a synthesis of prostaglandin intermediates as shown in equation 1768. The stereospecific rearrangement of the unstable sulfenate intermediate obtained from the cis diol 25 indicates the suprafacial nature of this process. 

The Collins reagent in CH2CI2 oxidizes silylated primary alcohols in preference to the more hindered silylated secondary alcohols, as described for oxidation of the prostaglandin intermediate 2963 to the rather labile aldehyde 2964, which is immediately subjected to a Horner-Wittig-reaction to introduce the lower side chain [206] (Scheme 12.61). 

Scheme 14.14 Possible routes in hydrogenation of a prostaglandin intermediate.

The effect of the modifiers appears to be more evident in the case of Ru-MCM-41 catalysts. The size-controlled mesoporous channels of MCM-41 affords a better interaction of the prostaglandin intermediates with modifiers [274,275],... 

Application of Noyori s reagent to the synthesis of prostaglandin intermediates was highly successful (80). The iodovinyl ketone 57a was reduced to the (S)-carbinol 58a in a 95% synthetic yield and a 97% optical yield with (5)-56 (OR = OEt). The analogous bromovinyl ketone 57b gave the corresponding (S)-carbinol in 96% synthetic and optical yield (eq. [21]). These intermediates... 

In a synthesis of optically active allethrolone and prostaglandin intermediates, Yamada and co-workers (92) studied the reduction of certain 2-alkyl-1,3,4-cyclopentanetriones (82) with a reagent prepared by the reaction of LAH with 3 equivalents of (- )-A-methylephedrine in THF. Reduction of the cyclopen-tanetriones 82 with this reagent gave (/ )-83 in 55 to 58% e.e. (Scheme 12). Thus (/ )-83b (R2 = Ac, after acetylation) was obtained in 48% yield and 55% e.e. from 82b. The steric course and enantiomeric excess in the reduction were... 

Introduction of a methoxy group (28, R = OMe) into the aryloxy side chain in the series of prostaglandin intermediates 28 has been found [90JCS(P1)751] to affect the ring-chain equilibrium significantly in favor of the cyclic tautomer. In CDCI3, when R = H, Kj = 1, and when R = OMe, Kt = 9. 

Ellison RA, Lukenbach ER, Chiu C-W (1975) Cyclopentenone synthesis by aldol condensation. Synthesis of a key prostaglandin intermediate. Tetrahedron Lett 16 499-502... 

An approach to the synthesis of a prostaglandin intermediate began with 2-furanacetonitrile (71JOC3191). Friedel-Crafts acylation with pimelic half-ester acid chloride and Wolff-Kishner reduction of the product with concomitant hydrolysis of the nitrile group to acid yielded the diester (78) on diazomethane treatment. Ring opening of the furan by a standard procedure yielded a diketo diester (79) which on refluxing in aqueous methanolic potassium carbonate underwent hydrolysis and cyclization to the diacid (80 Scheme 19). 

This stereochemical control in hex-5-enyl radical cyclizations can be used for the synthesis of highly functionalized cyclopentanes with vicinal trans- or cis-dialkyl-substituents. The synthesis of a versatile prostaglandin intermediate, Corey lactone 12, from the intermediate 6a (Y = OMe) has been described [14]. 

In early studies of these reactions, the turnover efficiency was not always high, and stoichiometric amounts of the promoters were often necessary to obtain reasonable chemical yields (Scheme 105) (256). This problem was first solved by using chiral alkoxy Ti(IV) complexes and molecular sieves 4A for reaction between the structurally elaborated a,/3-unsaturated acid derivatives and 1,3-dienes (257). Use of alkylated benzenes as solvents might be helpiul. The A1 complex formed from tri-methylaluminum and a C2 chiral 1,2-bis-sulfonamide has proven to be an extremely efficient catalyst for this type of reaction (258). This cycloaddition is useful for preparing optically active prostaglandin intermediates. Cationic bis(oxazoline)-Fe(III) catalysts that form octahedral chelate complexes with dienophiles promote enantioselective reaction with cyclopentadiene (259). The Mg complexes are equally effective. 

Electroreduction [5b] (with chiral quat as the supporting electrolyte) has been compared with chemical reduction (NaBH4) in the presence of chiral quats for ketone (up to 28% op) and imine (up to 22% op) reductions [57,58], The reduction (NaBH4) of a chiral a,p-enone prostaglandin intermediate in the presence of ephedra-derived catalysts led to the formation of the enol with 70% de [59]. Other reductions with lower asymmetric inductions are noted for ketone [lli,24h,24i,47e,60], imine [5b,57], and hydrodehalogenation of a cyclic a,a-dichlo-roamide [61],... 

Transmetallation of silyl enol ethers of ketones and aldehydes with Pd(II) generates Pd(II) enolates, which are usefull intermediates. Pd(II) enolates undergo alkene insertion and -elimination. The silyl enol ether of 5-hexen-2-one (241) was converted to the Pd enolate 242 by transmetallation with Pd(OAc)2, and 3-methyl-2-cyclopentenone (243) was obtained by intramolecular insertion of the double bond and -elimination [148], Formally this reaction can be regarded as carbopalladation of alkene with carbanion. Preparation of the stemodin intermediate 246 by the reaction of the silyl enol ether 245, obtained from 244, is one of the many applications [149]. Transmetallation and alkene insertion of the silyl enol ether 249, obtained from cyclopentadiene monoxide (247) via 248, afforded 250, which was converted to the prostaglandin intermediate 251 by further alkene insertion. In this case syn elimination from 250 is not possible [150]. However, there is a report that the reaction proceeds by oxypalladation of alkene, rather than transmetallation of silyl enol ether with Pd(OAc)2 [151]. 

These are excellent chiral hydroborating agents and have been utilized in the synthesis of many natural products. (+)-IPC2BH has been satisfactorily employed to obtain intermediates required in prostaglandin F2a synthesis 214) (Scheme 7) and the Fried prostaglandin intermediate 215). Similar treatment of 35 with (-)-IPC2BH affords 37, an antipode of 36. 

An approach to a prostaglandin intermediate employed a cyclopropanol oxidation with a mixed chro-mate/cerate reagent shown in equation (26), but the yield was unacceptably low. Although no information on the selectivity is available, the trans stereochemistry of oxidative cleavage in the reported product is of note. In these more complex substrates, side reactions and low yields plague the reaction, which will see only limited use in synthesis unless a better reagent system is developed. 

Based on this method, simple and efficient syntheses of prostaglandin intermediates, Queen bee substance, zearalenone, dihydrojasmone, jasmone, diplodialide B, lasiodiplodin methyl ether, ... 

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