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Synthetic Strategies

THE MOURIÑO GROUP

  

 

SYNTHETIC ROUTES TO VITAMIN D METABOLITES AND ANALOGUES

 

The figure below depicts a summary of the synthetic routes that have been used in our laboratory over the last three decades to synthesize vitamin D metabolites and analogues.

 

SYNTHTETIC STRATEGIES 2

 

The Lythgoe’s Wittig-Horner Approach. This strategy is considered one of the best routes to vitamin D analogues because it provides in one step the vitamin D triene unit under mild conditions. This approach presents, however, a few disadvantages namely: (a) the preparation of small quantities of up to 50 mg of compound that requires an excess of the phosphine oxide (A-ring fragment); (b) the multistep preparation of the phosphine oxide required for coupling with the upper ketone (CD-side chain fragment), and (c) the low yield obtained in the formation of the triene unit when some
C-ring or A-ring substituted fragments are used. For details, see: B. Lythgoe, Chem. Soc. Rev. 1980, 9, 449-475. (b) E.G. Baggiolini et al. J. Org. Chem. 1986, 51, 3098- 3108. For representative examples from our laboratory, see: J. Sardina et al.  JOC 1986, 51, 1264-1269. JP. Sestelo et al. J. Org. Chem.  1993, 58, 118-123. M.A. Rey. JOC 1999, 64, 3196-3206. A. Fernández- Gacio et al. J. Org. Chem. 2000, 65, 6978-6983. R. Riveiros et al. J. Org. Chem. 2007, 72, 5777-5485

 

The Dienyne Route: This strategy, pioneered by Lythgoe and improved by the vitamin D research groups of Santiago and Riverside uses as the key step a thermal isomerization of a previtamin D to produce the vitamin D triene system through an antarafacial sigmatropic [1,7]-hydrogen shift. Advantages: (1) easy and short preparation of the A-ring enyne (botton fragment); and (2) easy preparation of the dienyne fragment by coupling an enol triflate (upper fragment) with an enyne (bottom fragment); (3) easy preparation of 19-nor previtamins D. Disadvantages: (1) the overhydrogenation during Lindlar partial hydrogenation of the triple bond to produce the previtamin D intermediate; (2) the low yield on vitamin D when thermal isomerization favors the previtamin D intermediate; and (3) the instability of the vitamin D under the thermal isomerization. For details, see: G.-D. Zhu, W.H. Okamura. Chem. Rev. 1995, 95, 1877-1952. H. Dai, G.H. Posner. Synthesis 1994, 1383-1398. For selected examples from this laboratory, see: J.L. Sarandeses et al. Tetrahedron Lett. 1986, 27, 1523-1526. J.L. Mascareñas et al. Tetrahedron 1991, 47, 3485-3498. JL. Sarandeses et al. Tetrahedron Lett 1992, 33, 5445-5448. J. Pérez-Sestelo et al. J. Org. Chem.  1993, 58, 1189-123. J. Granja et al. J. Org. Chem. 1993, 58, 124-131.

 

Pd-Catalyzed Carbocyclization-Cross-Coupling Approach: A new convergent route to the vitamin D triene system has been developed in our laboratories employing an alkenyl-metal intermediate (upper fragment) and an enol triflate (bottom fragment). Best results of this cascade process have been recently accomplished using alkenyl-boronates at room temperature. The usefulness of the process is demonstrated by the preparation of 1a,25-dihydroxy-6-methyl-vitamin D3, a vitamin D3 analogue with a methyl group at the triene system, which easily isomerizes to the previtamin D form through a thermal [1,7]-antarafacial H shift. This compound could not be prepared by other current methods such as Lythgoe’s Wittig-Horner approach. The generality of the method has been demonstrated by the efficient construction of the triene unit of other vitamin D analogues. The key features of the new strategy and advantages over existing strategies include: 1) High yield reproducibility on triene system formation, 2) The use of equimolar amounts of both upper and bottom fragments, 3) Small scale preparation of vitamin D analogues under aqueous conditions, 4) Preparation of analogues which cannot be synthesized by the current most popular methods, 5) Short access to the A-ring precursor. The new synthetic strategy is successfully being applied in our laboratory to a variety of vitamin D analogues of therapeutic potential, particularly those with modifications at the Ring-A and triene unit, and will be used for the preparation of other analogues that cannot be synthesized by the existing current routes. For details, see: P. Gogoi, R. Sigüeiro R, S. Eduardo, A. Mouriño. Chem. Eur. J. 2010, 16, 1432-1435.