Synthesis of 1
,25-Dihydroxyvitamin D Analogues Featuring a
-symmetric CD-ring Core
, Lieve Verlinden
, Annemieke Verstuyf
and Pierre J. De Clercq
Department of Organic Chemistry, Ghent University, Krijgslaan 281, B-9000 Gent, Belgium
Laboratory of Experimental Medicine and Endocrinology, Catholic University of Leuven,
Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium
Author to whom correspondence should be addressed; E-mail: Pierre.DeClercq@UGent.be.
Received: 29 January 2009; in revised form: 17 February 2009 / Accepted: 23 February 2009 /
Published: 24 February 2009
Three analogues of 1
(calcitriol), featuring a
fused decalin C,D-core with local
-symmetry, and possessing identical side-chain and
seco-B,A-ring structures, have been synthesized starting from readily available (4a
). 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.
Suzuki coupling; Sonogashira reaction; Calcitriol analogues.
Since the discovery that the biological action of vitamin D
originates from the dihydroxylated
, calcitriol) and that, next to its classical role in the regulation
of calcium homeostasis, these actions also involve immunomodulation, cell differentiation and
antiproliferation, there has been an intense search for structural analogues of calcitriol that might show
a separation in calcemic and antiproliferative-prodifferentiating activities (Scheme 1) . In this
context various successful structural modifications have been introduced in each one of the three parts
that one may distinguish in its structure: the rigid central C,D-ring system and the flexible parts of the
molecule, comprising the side chain and the seco-B,A-ring .