Conjugate Reduction of <FONT FACE=Symbol>a,b</FONT>-Unsaturated Carbonyl Compounds. Selective Inhibition of Benzyl Ether Hydrogenolysis by NH4OH/MeOH

Towards the total synthesis of Stawamycin. Synthesis of C11-C21 fragment

“…This unpurified aldehyde was directly subjected to a Wittig homologation with the requisite stabilized ylide reagent 9 to afford a,b-unsaturated ester (-)-10 in 86% yield over two steps (E:Z/>95:5 diastereoselectivity). Selective hydrogenation of the double bond in the a,b-unsaturated ester (-)-10 under very mild conditions (H 2 /Pd/C, 25 o C, 1 atm, 40 min, 91%) afforded ester (-)-11 leaving the PMB group intact 4 . Careful reduction of (-)-11 with diisobutylaluminum hydride in toluene at -90 o C afforded the desired aldehyde that was directly submitted to a Wittig reaction with phosphorane 12 to afford the corresponding a,b-unsaturated Weinreb amide (-)-13 (E:Z/ > 95:5) in 78% overall yield for the two-step sequence 5 .…”

Short Synthesis of the 6,6-Spiroketal Cores of Spirofungins A and B

“…The unpurified aldehyde was directly subjected to a Horner−Wadsworth−Emmons homologation with the required phosphonate reagent to give the α,β-unsaturated ketone 12 in 90% isolated yield ( E : Z > 95:05) over the two-step sequence . Selective hydrogenation of the double bond proceeded smoothly, leaving the PMB group intact to give the corresponding methyl ketone, which, after treatment with N,N -dimethyl hydrazine in the presence of TMSCl as a dehydrating agent, gave the corresponding hydrazone 13 (18 S ,19 R ) in 87% yield for the two-step sequence . Starting from oxazolidinone ( S )- 8 , we were able to prepare hydrazone 14 (18 R ,19 S ), with the intention of preparing the initially proposed spiroketal of spirofungin B (see Scheme ).…”

“…To check the best conditions for carrying out the required hydrazone coupling as well as the spiroketalization reactions leading to analogues of spirofungins lacking the stereocenter at C11, we first prepared the two enantiomeric primary alkyl iodides ( R )- 15 and ( S )- 15 from commercially available methyl ( R )- and ( S )-3-hydroxy-2-methylpropionate esters and ) . After extensive experimental work, we found that the best conditions for this coupling involved treatment of hydrazone 13 with n -BuLi (1.1 equiv) in THF at −78 °C, to give a lithiated hydrazone that participated in a smooth alkylation reaction with primary iodide ( R )- 15 .…”

“…We next investigated the coupling of hydrazone 13 with alkyl iodide ( S )- 15 (Scheme ). Treatment of hydrazone 13 with n -BuLi (1.1 equiv) in THF at −78 °C, followed by addition of the primary iodide ( S )- 15 and hydrazone hydrolysis provided ketone 18 in 87% overall yield (Scheme ) . Removal of the silicon protecting groups with HF-pyridine followed by spiroketalization gave the desired spiroketal 19 as the only isolated product, in 82% yield.…”

“…With fragments C11−C13 ( 7 ) and C14−C20 ( 13 and 14 ) in hand, their coupling was undertaken (Schemes and ). To prepare the initially proposed structure of spirofungin B, treatment of hydrazone 14 with n -BuLi (1.1 equiv) in THF at −78 °C, followed by addition of primary alkyl iodide 7 and hydrolysis gave ketone 23 in 87% overall yield (Scheme ) . Compound 23 was subjected to acid deprotection and spiroketal formation by treatment with HF-pyr in THF to give 24 as the only spiroisomer in 78% yield.…”