Synthesis of 1α,25-Dihydroxyvitamin D Analogues Featuring a S2-symmetric CD-ring Core

Abstract

Three analogues of 1α,25-dihydroxyvitamin D3 (calcitriol), featuring a trans-fused decalin C,D-core with local S2-symmetry, and possessing identical side-chain and seco-B,A-ring structures, have been synthesized starting from readily available (4aR,8aS)-octahydronaphthalene-1,5-dione (7). The very short sequences involve the simultaneous introduction of the side-chain and seco-B,A-ring fragments via Suzuki and Sonogashira coupling reactions. The analogues are devoid of relevant biological activity.

The Synthesis and Biological Evaluation of D-Ring-Modified Vitamin D Analogues

“…The 1β-analogues (31,33) showed significant antiproliferative activity in murine keratinocytes and malignant melanoma cells, and this was equally potent to or even more potent than 1α,25(OH) 2 D 3 (2). On the other hand, 1α-analogues (30,32) were much less potent than their 1β-counterparts (31,33). In addition, 31 and 33 showed no calcemic activity in vivo.…”

“…The same authors subsequently reported the 1-hydroxymethyl-24,24-difluoro-16-ene analogues (30)(31)(32)(33) in 1998 [19]. The 16-ene-homoallylic alcohol (35) provided by an ene reaction of olefin (34) was first converted to tosylate via tosylation of the primary hydroxy group and triethylsilylation of the secondary hydroxy group.…”

“…The trans-decalin pair represented one of the rare examples that the 20-epimer exhibited reduced biological activities when compared with the analogues with the natural 20R-configuration [32]. De Clercq's group developed the trans-decalin core structure for pseudo-S 2 -symmetrical vitamin D analogues (188,190) [33]. For the synthesis, bis-triflate 185 was prepared from crystalline diketone 184 [34], and enyne 186 was connected in two-ways using Suzuki-Miyaura coupling and Sonogashira coupling reactions followed by appropriate chemical treatments to afford 188 and 190 in crystalline form, respectively (Scheme 18).…”

“…De Clercq’s group developed the trans -decalin core structure for pseudo - S 2 -symmetrical vitamin D analogues ( 188 , 190 ) [ 33 ]. For the synthesis, bis-triflate 185 was prepared from crystalline diketone 184 [ 34 ], and enyne 186 was connected in two-ways using Suzuki–Miyaura coupling and Sonogashira coupling reactions followed by appropriate chemical treatments to afford 188 and 190 in crystalline form, respectively ( Scheme 18 ).…”

Analogs of Calcitriol

“…This type of analog featuring structural symmetry could bind in two different and opposite directions within the LBD. Figure 76.5 presents pseudo-symmetrical analogs with a trans-fused decalin CD-core with local S 2 -symmetry possessing identical seco-B,A-ring structures (GM 7, GM 8, GM 15, and GM 14) [27]. The side chain section contains structural modifications similar to the so-called arocalciferols [28] and 16-ene analogs [29].…”