Schreiber’s synthesis

HF, CH3CN. In certain sensitive substrates it may be advisable to run this reaction in a polypropylene vessel, as was the case in Schreiber s synthesis of FK-506, where the yield increased from 35% to 73% after switching from the standard glass vessel. This is presumably because of the products formed when HF reacts with glass. 

Compound 6 is a pivotal intermediate in Schreiber s synthesis. It was hoped that the conspicuous and strained bridgehead cyclobutene substructure in 6 would undergo a conrotatory electrocyclic ring opening upon thermolysis to give an isomeric 1,3-diene (8, Scheme 1). In the event, when a solution of cyclobutene 6 in toluene is confined to a sealed tube and heated to 180°C for 12 h, a stereoisomeric mixture of 1,3-dienes 7 and 8 is produced in an excellent yield of 95% (7 8 ca. 5 1). Finally, irradiation of the 5 1 mixture of cis-7 and trans-8, or of each independently, establishes a photostationary state in which the desired trans isomer 8 predominates (8 7 ca. 10 1). 

An important issue in Schreiber s synthesis of Discodermolide200 was the choice of protecting group to mask the lactone until late in the synthesis. The lactone was protected in its lower oxidation state as its 0,5-acetal 101.2 prepared by treatment of the anomeric mixture of acetals 101.1 with phenylthiotrimethylsi-lane, zinc iodide, and tetrabutylammonium iodide to give a 2 1 mixture of anomeric 0,5-acetals that were separated by chromatography [Scheme 2.101]. Towards the end of the synthesis, the lactone was revived by mercury (11 )-cata -lysed hydrolysis of the 0,5-acetal in 1013 to a lactol followed by Jones oxidation to lactone 101.4 in 77% yield for the two steps. 

SCHEME 13.51 Schreiber s synthesis of (—)-hikizimycin featuring a two-directional chain-elongation strategy involving an aldehyde olefination and face-selective dihydroxylations. 

Pauson-Khand reaction was described in Schreiber s synthesis of (-l-)-epoxydic-tymene (Scheme 4) [51,52]. The Co2(CO)g-alkyne complex first participated in a Nicholas reaction to form an eight-member ring. Subsequent Pauson-Khand cychzation provided the final 5,5-ring system. 

Schreiber s Synthesis of Tri-O-Methyl Dynemicin A Methyl Ester... 

Scheme 16. Schreiber s synthesis of tri-O-methyl dynemicin A methyl ester (107).

Scheme 1.2 Schreiber s synthesis of dihydropyrans with high substitutional and stereochemical diversity. Reagents and conditions (1) 8, 20mol% 9 (or enantiomer), THF, rt (2) (i) Pd(PPh3)4, thiosalicylic acid, THF, rt (ii) R R NH, PyBOP, iPrjNEt, CH2CI2-DMF, rt (iii) HF -pyridine, THF, rt then MesSiOMe.

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