Stanislaw Marczak

A synthesis of (+)-pederin. The metallated dihydropyran approach.

Abstract The addition of a 6-lithio-3,4-dihydro-2 H -pyran to a methyl oxamate ester in the preseuce of TMEDA is a key step in the synthesis of a masked 1,2,3-tricarbonyl moiety used to construct the N-(1-alkoxy-1-alkyl)-amide bridge of the potent cytotoxic agent pederin. A Pd(0)-catalysed stannylation of an O-trifluoromethylsulfonyl ketene acetal provides an efficieat synthesis of the 6-(trimethylstannyl)-3,4-dihydro-2 H -pyran which transmetallates to the lithium daivative on treatment with n -BuLi.

Synthesis and anti-inflammatory properties of 1alpha,25-dihydroxy-16-ene-20-cyclopropyl-24-oxo-vitamin D3, a hypocalcemic, stable metabolite of 1alpha,25-dihydroxy-16-ene-20-cyclopropyl-vitamin D3.

1alpha,25(OH)(2)-16-ene-20-cyclopropyl-vitamin D(3) (13) is several fold more potent than the natural hormone 1alpha,25-dihydroxyvitamin D(3) (1) as an anti-inflammatory agent. Here, we have further analyzed the anti-inflammatory properties of 13, confirming it as the most potent analogue tested within this family. We then determined the structures of all the natural metabolites of 13, including the 24-oxo metabolite 14, and carried out its synthesis. A comparison of 13 with 14 showed a similar induction of the primary VDR target genes CYP24A1 and CAMP and comparable anti-inflammatory properties as revealed by a similar inhibition of TNF-alpha, IL-12/23p40, IL-6, and IFN-gamma production. Interestingly, 14 displays a 3-fold lower calcemic activity in vivo compared to 13. Collectively, these findings indicate that the strong potency of 13 can be explained by the accumulation of its stable 24-oxo metabolite, which shows immunoregulatory and anti-inflammatory properties superimposable to those exerted by 13 itself.

Pederin: The Metallated Dihydropyran Approach. Stereoselective Reduction ofN-AcylimidatesviaRhodium-Catalysed Hydroboration

A synthesis of the insect toxin pederin (1) based upon the union of metallated dihydropyran 8 with the oxamate ester derivative 9 is described. Noteworthy features include (a) a new method for the construction of metallated dihydropyrans which tolerates heteroatom functionality and (b) a rhodium-catalyzed hydroboration reaction which enables stereocontrolled formation of the stereogenic centre at C10

Synthesis of (+)-disparlure using the reaction of 6-methylheptyl phenyl sulphone with trimethylsilyl ethylene oxide and asymmetric epoxidation

Abstract Lithiated sulphone 2 was reacted with trimethyl(oxiranyl)silane 3 to yield allylic alcohol 4 ; the latter was epoxidized by the Sharpless procedure and the corresponding hydroxy-epoxide 5b was transformed into (+)-disparlure 6 via tosylate 5c .

A total synthesis of the C/D rings - side chain fragment of vitamin D and sterols, using Mukaiyama - Michael conjugate addition

Abstract Vitamin D and the sterol C/D - side chain fragments 16 and 17 were synthesized from ketene acetal 4 derived from 6-methylheptanoic acid, 2-methylcyclopent-2-en-1-one ( 5 ) and allyl methyl carbonate, using Mukaiyama-Michael conjugate addition and Tsuji alkylation as the key steps.

The first synthesis and biological testing of the enantiomer of 1α,25-dihydroxyvitamin D 3

Abstract The 1α,25-dihydroxyvitamin D 3 enantiomer was synthesized and examined in biological tests. The ring A precursor was prepared from vitamin D 2 employing the Mitsunobu reaction for inversion of the configuration at C-3 and SeO 2 hydroxylation at C-1. The CD rings-side chain portion was synthesized from an optically active hexanoic acid derivative using diastereoselective tandem Mukaiyama–Michael addition and vinylsulfone reduction as the key steps. The ring A and CD rings building blocks were combined using the Julia alkenylation reaction. 1α,25-Dihydroxyvitamin D 3 enantiomer shows no significant affinity to the vitamin D receptor.

The reaction of trimethylsilyl ethylene oxide with α-sulfonyl anions and α,α-sulfonyl dianions. A method for stereocontrolled synthesis of (E)- and (Z)-allylic alcohols

Abstract Trimethylsilyl ethylene oxide has been shown to react with α-sulfonyl carbanions generated from representative primary alkyl phenyl sulfones to give the corresponding O-trimethylsilyl allylic alcohols, with higher selectivity of ( Z )-isomers. The reaction proceeds by attachment of the nucleophile to the α-position of the α,β-epoxyalkylsilane followed by a carbon-to-oxygen shift to the trimethylsilyl group and expulsion of the benzenosulfonyl anion. The reaction of trimethylsilyl ethylene oxide with α,α-sulfonyl dianions followed by partial protonation of the immediate adducts affords O-trimethylsilyl allylic alcohols, mainly ( E )-isomers. The reaction of trimethylsilyl ethylene oxide with α-sulfonyl carbanions generated from secondary alkyl phenyl sulfones affords α-trimethylsilyl carbinols as the only or predominant product. In this case the attachment of the nuclephile takes place at the β-position of the α,β-epoxyalkysiane. The origin of the regio- and stereo-selectivity in reactions of sulfonyl carbanions with α,β-epoxyalkylsilanes is discussed.

Short total synthesis of the CD rings — side chain fragment of 25-hydroxyvitamin D3 and De-AB-Cholestane derivatives, involving two tandem Mukaiyama-Michael conjugate additions

A concise synthesis of the key building block (2) for 25-hydroxyvitamin D is described. Compound 2 has been prepared in 7 steps starting from ketene acetal 5b, unsaturated ketone 7 and ethylene ketal 11.

Synthesis and biological activity of the 1α,25-dihydroxyvitamin D3 diastereomer with unnatural configuration at the rings C/D side-chain moiety

1Alpha,25-dihydroxyvitamin D3 diastereomer, differing from the parent compound in configuration at four asymmetric carbon atoms in the rings C/D and side chain (C13, C14, C17 and C20), was synthesized and shown to have a significant affinity for the vitamin D receptor.

Directive and shielding effects of the trimethylsilyl group. Unprecedented β-selectivity in the reaction of α,β-epoxyalkylsilanes with hindered α-sulphonyl anions

Anions generated from hindered primary and secondary alkyl phenyl sulphones react with trimethylsilyloxirane to yield a mixture of products of addition in α- and β-positions or exclusively the product of addition in the β-position.