Synthesis and Biological Activity of 25-Hydroxy-2-methylene-vitamin D₃ Analogues Monohydroxylated in the A-ring

Abstract

The 20R- and 20S-isomers of 25-hydroxy-2-methylene-vitamin D3 and 3-desoxy-1α,25-dihydroxy-2-methylene-vitamin D3 have been synthesized. Two alternative synthetic routes were devised for preparation of the required A-ring synthons, starting from the chiral compound derived from the (-)-quinic acid and, alternatively, from the commercially available achiral precursor, monoprotected 1,4-cyclohexanedione. The A-ring dienynes were coupled by the Sonogashira process with the respective C,D-ring fragments, the enol triflates derived from the protected (20R)- or (20S)-25-hydroxy Grundmann ketones. All four compounds possessed significant in vivo activity on bone calcium mobilization and intestinal calcium transport. The presence of a 2-methylene group increased intestinal calcium transport activity of all four analogues above that of the native hormone, 1α,25-dihydroxyvitamin D3. In contrast, bone calcium mobilization was equal to that produced by 1α,25-dihydroxyvitamin D3 in compounds having a (20S)-configuration or diminished to one-tenth that of 1α,25-dihydroxyvitamin D3 in compounds with a (20R)-configuration.

Synthesis and Biological Activity of 2-Methylene Analogues of Calcitriol and Related Compounds

“…The A-ring building block 14 was than coupled with the C,D-ring vinyl triflates 15 – 18 , obtained from the corresponding Grundmann ketones. , Three former hydrindane compounds were described in literature, ,, and 18 was prepared in an analogous fashion (Supporting Information). Thus, Sonogashira reaction of dienyne 14 with the vinyl triflate 15 carried out using reactions described by Mourino furnished the expected trienyne 39 (Scheme ) in which the triple bond was selectively hydrogenated by a Lindlar catalyst poisoned with quinoline.…”

“…The known vinyl triflates 15 , 16 , and 17 were obtained according to the procedure of De Clercq et al; an analogous method was used for the preparation of the (20 S )-trilate 18 (Supporting Information) from the corresponding Grundmann ketone. The starting hydroxy ester 20 and lactone 32 were synthesized from (−)-quinic acid ( 19 ).…”

“…To explore the surprising high biological activity of 2MD, 1-desoxy and 3-desoxy analogues of 2MD were synthesized . We also prepared the (20 R )- and (20 S )-25-hydroxy-2-methylene­vitamin D 3 compounds 4 and 5 and the (20 R ) and (20 S ) isomers of 3-desoxy-1α,25-dihydroxy-2-methylene­vitamin D 3 ( 6 and 7 ) . Biological activities of these analogues were compared with previously obtained 2-methylene-substituted vitamin D compounds.…”

A Practical Solution to Stereodefined Tetrasubstituted Olefins

“…These tetrasubstituted alkenals are very useful building blocks for the synthesis of compounds with a stereodefined tetrasubstituted CC bond (Scheme ). For example, treatment with trimethylsilyldiazomethane has been shown to give enyne ( Z )- 8 in 70% yield; 1,2-addition with organic magnesium or lithium reagents afforded propargylic alcohol ( Z )- 9 or secondary allylic alcohol ( Z )- 10 in 81% yield or 85% yield, respectively; , the conjugated dienes ( Z )- 11 could be prepared by a Wittig reaction in 76% yield; reduction with NaBH 4 or oxidation with NaClO 2 /H 2 O 2 afforded primary allylic alcohol ( Z )- 12 or α,β-unsaturated carboxylic acid ( Z )- 13 in 94% yield or 74% yield, respectively. , …”

“…13 These tetrasubstituted alkenals are very useful building blocks for the synthesis of compounds with a stereodefined tetrasubstituted CC bond (Scheme 4). For example, treatment with trimethylsilyldiazomethane has been shown to give enyne (Z)-8 in 70% yield; 20 1,2-addition with organic magnesium or lithium reagents afforded propargylic alcohol (Z)-9 or secondary allylic alcohol (Z)-10 in 81% yield or 85% yield, respectively; 21,22 the conjugated dienes (Z)-11 could be prepared by a Wittig reaction in 76% yield; 23 reduction with NaBH 4 or oxidation with NaClO 2 /H 2 O 2 afforded primary allylic alcohol (Z)-12 or α,β-unsaturated carboxylic acid (Z)-13 in 94% yield or 74% yield, respectively. 24,25 In summary, we have observed a regiospecific conjugate addition of 2,3-allenals with organozinc reagents, which, upon protonation, introduces the R group of R 2 Zn to the center carbon atom of the 2,3-allenals, providing stereodefined tetrasubstituted 2-alkenals with the R group trans to the formyl group in high yields with a very broad scope.…”