Prostaglandins side chain synthesis

The starting material for the synthesis of 37 was 38, prepared in turn from malic acid, both enantiomers of which are commercially available. The choice of this starting material facilitated determination of C28 stereochemistry as both enantiomers could be used in this coupling reaction. Note that this Wittig reaction provided largely the Z olefin geometry as expected (recall introduction of the upper prostaglandin side chain via a similar reaction). 

The tin-to-lithium exchange in alkenyltins is characterized by the preservation of the alkene stereochemistry and is compatible with several functionalities on the alkene moiety such as amino, hydroxyl and ester groups. The transmetallation of functionalized vinyltins has found an application in the synthesis of complex molecules such as unsaturated fatty acids [362], prostaglandin side-chain [363], various antibiotics ]364] and a biotoxin [365]. 

Because compound 156 is a rigid framework that can be readily generated from a dimer of cyclopentadiene, this compound offers an ideal structure on which many reactions can be carried out stereoselectively. Scheme 5-47 shows the synthesis of prostaglandin Ai or A2 (158). After the two side chains have... 

Compound 78, or prostanoic acid, the simplest prostaglandin compound, contains an a-side chain and also an co-side chain. Asymmetric synthesis of prostaglandins must involve the assembly of these subunits, as well as the introduction of other functionalities. 

This chapter has introduced the asymmetric synthesis of several types of natural products erythronolide A, 6-deoxyerythronolide, rifamycin S, prostaglandins and baccatin III, the polycyclic part of taxol, as well as the taxol side chain. The... 

The analogue in which carbon replaces oxygen in the enol ring should of course avoid the stability problem. The synthesis of this compound initially follows a scheme similar to that pioneered by the Corey group. Thus, acylation of the ester (7-2) with the anion from trimethyl phosphonate yields the activated phosphonate (7-3). Reaction of the yhde from that intermediate with the lactone (7-4) leads to a compound (7-5) that incorporates the lower side chain of natural prostaglandins. This is then taken on to lactone (7-6) by sequential reduction by means of zinc borohydride, removal of the biphenyl ester by saponification, and protection of the hydroxyl groups as tetrahydropyranyl ethers. 

This enantioselective preparation of allylic alcohols has been applied to the synthesis of the side chain of prostaglandins . The addition to functionalized aldehydes, such as 483, allows the synthesis of C2-symmetrical 1,4-diols, such as 484, with excellent diastereoselectivity and enantioselectivity . An extension of this method allows the synthesis of C3-symmetrical dioF . Aldol-type products result from the catalytic enantioselective addition of functionalized dialkylzincs to 3-TIPSO-substituted aldehydes, such as 485, followed by a protection-deprotection and oxidation sequence affording 486 in 70% yield and 91% ee (Scheme 118) . The addition to a-alkoxyaldehydes provides a... 

A variation of this route was applied to the preparation of a-methylenecyclo-pentane 179, an intermediate that was employed for the synthesis of prostaglandin PGF2o, (180) (Scheme 6.82). The acetonide-protected oxime-diol 175 [derived from propanal (174)] was treated with sodium hypochlorite without the addition of base. This led to the tricyclic adduct 176 with high stereoselectivity. One of the side chains was subsequently elaborated and the fully protected cyclopentano-isoxazo-line (177), when exposed to Raney Ni/boron trichloride, gave the 2-hydroxymethyl-cyclopentanone (178). This compound was dehydrated using mesyl chloride/ pyridine to furnish enone (179) (324). In another related synthesis of PGF2q, the p-side-chain (3-hydroxyoctenyl) was introduced prior to the cycloaddition (325). 

Cyclopentanones. Hewson et ah have used the related reagent, 1-methylthiovi-nyl(triphenyl)phosphonium chloride (1) for a synthesis of prostaglandin D, methyl ester (8). Thus reaction of the diketodithiane 2 with 1 in the presence of NaH gives 3, which is readily converted into the enone 4. Addition of the cuprate reagent 5 to 4 shows unexpected selectivity in favor of the natural (rani-arrangement of the side chains, perhaps because of the spiro dithiane unit. 

Ono, N. Yoshida, Y. Tani, K. Okamoto, S. Sato, F. A highly efficient approach to prostaglandins via radical addition of a side chains to methylenecyclopentanones. Total synthesis of natural PGEj, limaprost and new prostaglandin derivatives. Tetrahedron Lett. 1993, 34, 6427-6430. 

In many cases, the second side chain of the cyclopentane ring of prostaglandins possesses a double bond with ( )-geometry at C-13. The introduction of this side chain is usually achieved by olefination with phosphonate anions according to the Homer technique. However, because of the vicinal oxygen function at C-15 it is also recommended to introduce the side chain via ( )-stereoselective Wittig synthesis... 

A stereospecific total synthesis of prostaglandins E3 and F3, containing an additional double bond in this side chain, starts from the optically active phosphonium salt 161. In this synthesis the ( )-13-double bond and the 15-hydroxy function are generated simultaneously by condensation of the chiral bicyclic aldehyde 163 with the P-oxido ylide 162 obtained by treatment of 161 with methyllithium. The corresponding phosphonium salt S) +)-161, already possessing the (Z)-configurated A17-double bond of prostaglandins, was prepared from (S)(—)-tartaric acid 1351 (Scheme 29). 

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