Thiopyridyl esters

With both building blocks 103 and 109 in hand, the total synthesis of lb was completed as shown in Scheme 17. Coupling of acid 103 and alcohol 109 under Yamaguchi conditions to give ester 110 and subsequent desilylation followed by chemoselective oxidation provided hydroxy acid 111. Lactonization of the 2-thiopyridyl ester derived from 111 in the presence of cupric bromide produced the macrodiolide 112 in 62% yield, which was finally converted to pamamycin-607 (lb) via one-pot azide reduction/double reductive AT-methylation. In summary, 36 steps were necessary to accomplish the synthesis of lb from alcohols 88 and 104, sulfone 91, ketone 93, and iodide rac-97. 

This thiopyridyl ester uniquely activates the carbonyl as well as the hydroxyl group by proton exchange. 

In 2003, a new Sml2-mediated carbon carbon bond-forming reaction was reported by Skrydstrup for the direct synthesis of peptide mimics for evaluation as protease inhibitors.90 For example, the low-temperature coupling of 4-thiopyridyl ester 100, derived from Cbz-protected phenylalanine, with the dipeptide acrylamide 101 gave the peptide analogue 102 in a 61% yield (Scheme 7.43). Ketone 102 represents a ketomethylene isostere of the tetra-peptide Phe Gly Leu Phe. Ketomethylene isosteres and the corresponding reduced analogues, hydroxyethylene isosteres, represent important and pharmaceutically relevant classes of protease inhibitors.91,92... 

The same year, Gerlach described a synthesis of optically active 1 from (/ )- ,3-butanediol (7) (Scheme 1.2). The diastereomeric esters produced from (-) camphorsulfonyl chloride and racemic 1,3-butanediol were fractionally recrystallized and then hydrolized to afford enantiomerically pure 7. Tosylation of the primary alcohol, displacement with sodium iodide, and conversion to the phosphonium salt 8 proceeded in 58% yield. Methyl-8-oxo-octanoate (10), the ozonolysis product of the enol ether of cyclooctanone (9), was subjected to Wittig condensation with the dilithio anion of 8 to give 11 as a mixture of olefin isomers in 32% yield. The ratio, initially 68 32 (E-.Z), was easily enriched further to 83 17 (E Z) by photolysis in the presence of diphenyl disulfide. The synthesis was then completed by hydrolysis of the ester to the seco acid, conversion to the 2-thiopyridyl ester, and silver-mediated ring closure to afford 1 (70%). Gerlach s synthesis, while producing the optically active natural product, still did not address the problem posed by the olefin geometry. 

Aldol condensation between ketone 307 and aldehyde 298 afforded the E,E)-dienone 308 in 41% yield. Nonselective reduction of the C-9 ketone and base hydrolysis then produced a 77% yield of the seco acids 309. Lactonization utilizing the Corey thiopyridyl ester method and selective oxidation of the C-9 allylic hydroxyl group afforded the protected aglycone 310 in 59% yield. 

The first synthesis of vermiculine by Corey, outlined in Scheme 4.14, employed an isopropenyl group as a protected version of the acetone sidechain. Aldehyde 57, the Dibal reduction product of readily available dimethyl 2,2-dimethoxyglutarate, was condensed with dimethallyl cadmium and the resulting alcohol silylated to produce 58 (70%). Reduction of ester 58 to the aldehyde followed by two-carbon homologation afforded a 94% yield of a,P unsaturated ester 59. Hydrolysis of 59 to the to the acid and conversion to the 2-thiopyridyl ester (77%) set the stage for double lactonization. This transformation was accomplished by thermolysis of a diluted solution of the thioester, affording a 30% yield of the diasteromeric diolides 60a and 60b (1 1). The former was then converted by oxidation into the synthetic 56 and the latter into the meso isomer 61, both in 70% yield. 

The radical 28 reacts with alkenes, PTOC esters, and allylstannane with good selectivity. The oxazolidine with Ri = t-Bu is particularly effective as an auxiliary group. Thus, the radical 28 having R = (C6Hn)CH2 and Rj = -Bu reacts with allytributylstannane with a selectivity greater the 20 1 at 80 °C, and its reaction with PTOC esters gives a 60 1 mixture of thiopyridyl ester products at room temperature. 

There are several alternative methods for the formation of acylsilanes these include the reaction of silyl cuprates with acid halides, palladium-assisted coupling of acyl halides with hexamethyldisilane, the reaction of thiopyridyl esters with tris(trimethylsilyl)aluminum in the presence of Cu salts, and the hydroboration of trimethylsilyl-substituted alkynes. While all of these procedures are complementary, the method involving the title corqtound provides an easy, inexpensive route to acylsilanes. 

Erythromycin I ------------------- " 17 Substrates (all thiopyridyl esters) of which only 3 could be lactonized. Two gave low yields but. 

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