Enrico G. Baggiolini

Stereoselective total synthesis of 1α,25S,26-trihydroxycholecalciferol

A total synthesis of 1α,25S,26-trihydroxycholecalciferol (2) has been accomplished via an efficient convergent approach. The remote chiral center at C-25 was introduced by a regiospecific and diastereoselective 1,3-dipolar cycloaddition of the C-23 nitrone 27 with methyl methacrylate. Subsequent transformation of the resulting isoxazolidine led to the key synthon 3, which on coupling to the anion 4 and deprotection produced the metabolite 2.

Stimulatory effect of 1α,25-dihydroxyvitamin D3 on the formation of skin tumors in mice treated chronically with 7, 12-dimethylbenz[a]anthracene

The effect of 1 alpha, 25-dihydroxyvitamin D3 (1 alpha, 25-(OH)2D3) and its 24,24-difluoro analog on the formation of skin tumors in mice was evaluated in a complete carcinogenesis model using 7,12-dimethylbenz[a]anthracene (DMBA) as the carcinogen. Twice weekly topical application of 0.25-0.50 nmol of 1 alpha, 25-(OH)2D3 or 0.05-0.10 nmol of the difluoro analog of 1 alpha, 25-(OH)2D3 1 hour prior to treatment with 50 nmol DMBA stimulated tumor formation several fold compared to animals receiving DMBA alone. Topical application of 0.50 nmol of 1 alpha, 25-(OH)2D3 24 hours after treatment with DMBA, or half of this dose of the vitamin D3 metabolite, applied 1 hour before and 24 hours after treatment with DMBA, also stimulated tumor formation several fold. These results are in marked contrast to the potent inhibitory effect of 1 alpha, 25-(OH)2D3 and its difluoro analog on the formation of skin tumors in mice promoted by 12-O-tetradecanoylphorbol-13-acetate.

Stereospecific synthesis of the lythgoe's ring a aldehyde for the preparation of 1α-hdroxylated tachysterols and calciferols

Abstract The dihydroxyaldehyde 1 , an important intermediate for the synthesis of 1α-hydroxylated vitamin D derivatives via the corresponding tachysterol precursors, was prepared from (S)-(+)-carvone ( 6 ). The sequence involves as central step, the decarboxylation and rearrangement of the epoxyglycidic acid 15 , prepared from carvone oxide 7 .

Use of Fourier transform 1H NMR in the identification of vitamin D2 metabolites

The use of Fourier transform 1H NMR to characterize vitamin D2 metabolites is described. A 300-MHz spectrometer capable of generating a 6-microseconds pulse and a sweep width of 4000 Hz was used. High-resolution spectra were obtained on 5 micrograms of material using standard 5-mm NMR tubes fitted with glass inserts and isotopically enriched chloroform-d solvent. The data acquisition time under these conditions was 4 h. Application of this technique to a variety of both synthetic and naturally occurring vitamin D2 metabolites, in addition to synthetic delta 22-1,25-dihydroxyvitamin D3, resulted in the reassignment of the chemical shifts for the C-21 and C-28 methyl groups of vitamin D2. The C-21 methyl group resonance is now assigned to the doublet appearing at delta 1.01, whereas the C-28 signal corresponds to the doublet at delta 0.90. An examination of the spectrum of 24 (R),25-dihydroxyvitamin D2 also led to the reassignment of the side-chain methyl group resonances. This technique is an additional means of identifying microgram quantities of vitamin D metabolites.

Synthesis of d-biotin from cysteine

Abstract A novel approach to d-biotin from cysteine, which a utilizes the nitrate oxide To enolthioether double bond cyclization for the formation of C2-C3 of the thiophane ring and the incorporation of the 3-N in the biotin molecule, Is described. the cis relation of the n-butyl side chain and the sulfur in respect to isoxazolidine ring in the bicycle diastereomers 9 And 12 is characterized by an NMR signal For The α- methylene protons of the side chain as a multiplelet at δ1.82 AND 1.80, respectively, ownfield from the multiplet at 1.33 AND 1.32, respectively, for the other two methylenes of the side chain.

Stereocontrolled synthesis of 19-epiajmalicine from loganin aglucone

Abstract The rare naturally occurring heteroyohimbine alkaloid 19-epiajmalicine (1) was prepared from loganin aglucone 6 via a sequence which involves as the central step the conversion of the δ-lactone 7, easily derived from 6, to the 6-epielenolic acid acetal 8. After transformation of the latter to the aldehyde ester 12, reductive condensation with tryptamine to give the lactam 13 and Bischler-Napieralski reaction resulted in the formation of the desired alkaloid 1.

A simple method for generation of antibodies with specificity for 1,25-dihydroxyergocalciferol and 1,25-dihydroxycholecalciferol

A simple method for production of antisera with high affinity and selectivity for 1 alpha, 25-dihydroxyergocalciferol and 1 alpha, 25-dihydroxychole-calciferol is described. 1 alpha-Hydroxy-25,26,27-trisnorcholecalciferol-24-oic acid was coupled directly to bovine serum albumin. Rabbits immunized with this conjugate rapidly produced antibodies that bound 3H-1 alpha,-25-dihydroxycholecalciferol with high affinity and demonstrated nearly equal reactivity with 1 alpha, 25-dihydroxyergocalciferol and poor reactivity with 25-hydroxycholecalciferol; 24,25-dihydroxycholecalciferol; 25,26-dihydroxycholecalciferol; and 1 beta,25-dihydroxycholecalciferol. The use of one of these antisera has led to the development of a specific assay for 1 alpha,25-dihydroxyergocalciferol and 1 alpha,25-dihydroxycholecalciferol in human serum.

Dipolar Cycloaddition Route to the Synthesis of 1a,25-Dihydroxy-26-norvitamin D2 Derivatives

The intramolecular dipolar cycloadditions of nitrones derived from aldehydes (8) and (14) were found to proceed with a high degree of diastereoselectivity. By taking advantage of the functionality and stereochemical features residing in the cycloadducts (10) and (11), respectively, the two novel vitamin D 2 derivatives (1c) and (1d) were synthesized

Total synthesis of 1α,25,28-trihydroxyergocalciferol

Abstract A convergent total synthesis of 1α,25,28-trihydroxyergocalciferol (1), using an available A ring synthon and a CD synthon which was prepared via a thermodynamically controlled dipolar cycloaddition of methyl 3,3-dimethylacrylate and a C-23 nitrone followed by subsequent removal of the nitrogen function, is described.