Synthesis of 1α,25-dihydroxyvitamin D analogues featuring a S 2-symmetric CD-ring core

Article abstract of DOI:10.3390/molecules14020894

Three analogues of lα,25-dihydroxyvitamin D₃ (calcitriol), featuring a transfused 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

Full text of DOI:10.3390/molecules14020894

Molecules 2009, 14, 894-903; doi:10.3390/molecules14020894
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molecules
ISSN 1420-3049
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Article
Synthesis of 1α,25-Dihydroxyvitamin D Analogues Featuring a
S2-symmetric CD-ring Core
Garrett Minne 1, Lieve Verlinden 2, Annemieke Verstuyf 2 and Pierre J. De Clercq 1,*
1
Department of Organic Chemistry, Ghent University, Krijgslaan 281, B-9000 Gent, Belgium
2
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
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.
Keywords: Suzuki coupling; Sonogashira reaction; Calcitriol analogues.
Introduction
Since the discovery that the biological action of vitamin D3 originates from the dihydroxylated
metabolite 1α,25-dihydroxyvitamin D3 (1, 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) [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 [2].

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At the molecular level calcitriol generates biological responses via signal transduction pathways in
which interaction with the nuclear receptor (n-VDR) leads to gene transcription regulation (genomic
pathway) and in which interaction with a putative membrane receptor (m-VDR) leads to rapid actions
such as transcaltachia (non-genomic pathway) [3]. A turning point in the rational development of
analogues has been the disclosure of the detailed structure of the ligand binding domain of the n-VDR,
obtained via X-ray diffraction analysis of the complex between calcitriol and a truncated mutant of the
n-VDR [4]. Interestingly, this study revealed that the position of the ligand within the binding site was
opposite to the location that was previously suggested on the basis of extensive molecular modeling
studies [5]. This could indicate that the two polar parts of the molecule are interchangeable so that
each bonding type could be associated with a different biological action. In this context we became
interested in the development of analogues featuring structural symmetry so that the two flexible parts
would become indistinguishable. Herein we wish to describe analogues 2a, 2b and 2c which are
characterized by the presence of a trans-fused decalin C,D-core with local S2-symmetry
(Scheme 1) [6].
Scheme 1. Calcitriol (1) and pseudo-symmetric analogues 2.
22
OH
20
H
25
OH
OH
H
H
7
6
C6/C7 and C20/C22
HO
OH
1
HO
OH
a : E-ene
b : yne
c : Z-ene
1
2
side chain
20
OH
17
C
D
Rside chain
8
seco-B,A
C
D
A
Rseco-B,A
HO
OH
Results and Discussion
The choice of a S2-symmetric trans-decalin core functionalized as in 2 was dictated both by
structural and synthetic considerations. Indeed symmetrical non-steroidal derivatives have been
described that were found to possess vitamin D-like activity (Figure 1). In particular 3 is able to induce
VDR-mediated transactivation, albeit much less potently than calcitriol [7]. Also in the context of

Molecules 2009, 14
896
structural modifications the following are relevant to the present work (Figure 2): (i) cyclic motifs in
the side chain (e.g. 4a) [8,9]; (ii) unsaturation at C16,C17 (e.g. 4a, 4b) [10]; (iii) unsaturation at C8,C9
(e.g. 5a, 5b) [11]; and (iv) analogues featuring an enlarged six-membered D-ring [12].
Figure 1. Non-steroidal analogue.
O
O
O
Cl
Cl
O
3
Figure 2. Structural modifications in calcitriol analogues.
R
17
OH
16
9
8
H
H
6
7
19
HO
OH
HO
OH
5a C6/C7 = yne
4a R = m-C6H4-OH
4b R = CH2CH2CMe2-OH
5b C6/C7 = Z-ene
In principle the structural features of analogues 2 should allow for very direct and convergent
syntheses in which the two identical fragments representing the side chain and the seco-B,A-ring are
introduced simultaneously on a suitable functionalized trans-decalin core in a process were
stereoisomers would not be formed. This is in contrast with the often lengthy sequences and difficult
separations that are otherwise required [13-15]. Finally, whereas most efforts in the development of
analogues have been directed towards modifications in the flexible parts, our laboratories have always
focused on the central less accessible part of the molecule, and almost as a rule, such modifications
have led to a reduction in calcemic activity [16].
The synthesis of the symmetrical analogues 2 proceeds via cross-coupling procedures involving the
central bisenol triflate derivative 8, which is readily obtained from the corresponding trans-fused
diketone 7 (Scheme 2). The synthesis of the latter has been described in detail [17,18]. It involves the
catalytic hydrogenation of 1,5-naphthalenediol over Raney Ni W-7, followed by sodium dichromate
oxidation of the resulting mixture of stereoisomeric diols (6) in an acid medium [19], which affords,
after purification by crystallization, diketone 7 in 40% overall yield. Kinetic deprotonation followed
by treatment of the enolate dianion with N-phenyltrifluoromethane sulfonamide yielded crystalline 8,
which was purified by HPLC (64%).

Molecules 2009, 14
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Scheme 2. Synthesis of bis-enol triflate 8.
OTf
OH
O
H
H
1. (i-Pr)2NH, n-BuLi, −78 °C
2. PhNTf2, −40 °C, THF
Na2Cr2O7
HOAc, H2SO4
H
H
60%
64%
TfO
OH
O
8
6
7
The synthesis of analogues 2a, 2b and 2c involves the known enyne 9 as central intermediate
[11,20]. Depending on the nature of the C−C linkage at C17 and C8 either a Suzuki coupling (cf. 2a)
or Sonogashira coupling (cf. 2c) is applied (Scheme 3) [21,22].
Scheme 3. Synthesis of analogues 2a, 2b and 2c.
R
H
H
8
, Na2CO3, Ph3As
PdCl2(dppf), THF
TBAF
70%
2a
O
R
O
57%
B
R
11a
10
catecholborane
9-BBN (cat.), THF
R
H
H
8, Et2NH/DMF, 25 °C
TBAF
51%
(Ph3P)2Pd(OAc)2, CuI
2b
100%
TBSO
OTBS
9
11b
R
H2, Lindlar, EtOAc
quinoline
78%
R =
TBSO
TBS = tert-BuMe2Si
R
OTBS
H
TBAF
81%
2c
H
R
11c
After extensive experimentation the Suzuki cross-coupling involving reaction of bisenol triflate 8
and intermediate 10, which is obtained via addition of catecholborane to enyne 9 in the presence of 9-
borabicyclononane (9-BBN) [23], afforded 11a using
a
combination of 1,1’-
bis(diphenylphosphino)ferrocene palladium(II)chloride (PdCl2(dppf)) with sodium carbonate as the

Molecules 2009, 14
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base and the ligand triphenylarsine as reducing agent (57% yield) [24,25]. Deprotection with
tetrabutylammonium fluoride (TBAF, THF) led to crystalline 2a (70% yield).
The procedure developed by Castedo and Mouriño for coupling of a C-ring vinyl triflate with an A-
ring terminal alkyne led to the desired 11b in quantitative yield [26]. Semi-hydrogenation of the yne-
moieties with Lindlar catalyst in the presence of quinoline gave 11c in 78% yield. Eventual
deprotection with TBAF yielded the crystalline analogues 2b (51%) and 2c (81%).
The biological evaluation of the analogues includes the determination of the binding affinity for the
porcine intestinal VDR, and the in vitro antiproliferative activity on breast cancer MCF-7 cells [27].
The analogues 2a, 2b and 2c did not show any relevant biological activity. This result shows that the
side-chain fragment of the analogues in this series is probably too large.
Conclusions
In the present work advantage is taken of the S2-symmetry of the readily available bisenol triflate 8
to introduce simultaneously fragments that may be considered as structural variations of the classical
side-chain and of the seco-B,A-ring of calcitriol. The attachment of these fragments proceed in an
efficient way via palladium catalyzed cross-couling processes involving either a Sonogashira reaction
or a Suzuki coupling. Unfortunately the prepared calcitriol analogues 2a, 2b and 2c were devoid of
biological activity.
Experimental
General
TLC were run on glass plates precoated with silica gel (Merck, 60F-254). Column chromatography
was performed on silica gel (Merck, 230-400 mesh) or Florisil (100-200 mesh). IR spectra were
1
13
recorded on a Perkin-Elmer series 1600 FT-IR spectrometer. H-NMR and C-NMR spectra were
recorded on a Bruker AM-500 spectrometer. Mass spectra (EI) were recorded on a Hewlett-Packard
5898A spectrometer at 70 eV.
(4aR,8aS)-octahydronaphthalene-1,5-dione (7). To a solution of decalin-1,5-diol 6 (8.86 g, 52 mmol)
in benzene (70 mL) is slowly added dropwise the Cr(VI) oxidant over a period of 3 hours, during
which period the temperature is kept at 6 °C. The oxidant is prepared separately by the successive
addition to water (68 mL) of glacial acetic acid (11.5 mL), concentrated sulfuric acid (21 mL) and
sodium dichromate dihydrate (15.51 g, 52 mmol). After stirring overnight the aqueous phase is
separated and further extracted with toluene (3 x 25 mL). The combined organic phases are washed
with water (25 mL), with a saturated solution of sodium bicarbonate (25 mL) and water again (25 mL).
After concentration in vacuo the obtained residue is crystallized from benzene-petroleum ether (4:3) to
yield 5.15 g of white crystalline diketone 7 (60% yield). Rf = 0.62 (dichloromethane/ethyl acetate,
9:1); m.p. 167-168 °C; IR (KBr): 2943 (s), 2908 (m), 2857 (m), 1702 (s), 1349 (m), 1261 (m), 564 (m),
1
488 cm-1; H-NMR (500 MHz, C6D6): δ = 2.10 (dddd, J = 13.6, 4.2, 2.1, 2.1 Hz, 2 H), 1.83 (dm, J =
13.8 Hz, 2 H), 1.65 (td, J = 13.7, 6.2 Hz, 2 H), 1.59-1.57 (m, 2 H), 1.55-1.49 (m, 2 H), 1.41-1.32 (m, 2

Molecules 2009, 14
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H), 1.07 (qt, J = 13.5, 4.1 Hz, 2 H) ppm; 13C-NMR (125 MHz, CDCl3): δ = 209.77 , 55.43 (CH), 41.13
(CH2), 24.92 (CH2), 24.36 (CH2) ppm; MS: m/z (%) = 166 (M+, 49), 138 (14), 123 (24), 110 (38), 98
(25), 97 (52), 95 (39), 84 (100), 83 (97), 68 (43), 67 (70), 55 (80).
Bis-trifluoromethanesulfonate derived from (4aS,8aR)-3,4,4a,7,8,8a-hexahydronaphthalene-1,5-
diol (8). To a cooled (0 °C) solution of diisopropylamine (0.97 mL, 6.92 mmol) in THF is added
dropwise a solution of n-butyllithium in hexane (4.43 mL of a 1.51 M solution, 6.92 mmol). After
stirring for 1 hour a solution of diketone 7 (0.5 g, 3.01 mmol) in THF (20 mL) is added dropwise at
−78 °C. After stirring for 5 hours at −78 °C N-phenyltrifluoromethane sulfonamide (2.364 g, 6.62
mmol) is added. After further stirring for 16 hours at −40 °C, the reaction mixture is brought to room
temperature. After concentration in vacuo the residue is purified by column chromatography on silica
gel with isooctane/ethyl acetate (9:1) as the eluent, followed by HPLC (95:5) to yield 822 mg of white
crystalline bisenol triflate 8 (64%). Rf = 0.57 (isooctane/ethyl acetate, 9:1); m.p. 78-80 °C; IR (KBr):
2978 (m), 2956 (m), 2933 (m), 2877 (m), 1681 (m), 1415 (s), 1324 (m), 1252 (s), 1206 (s), 1143 (s),
1094 (s), 1051 (m), 935 (s), 870 (s), 626 (s), 604 (s) cm-1; 1H-NMR (500 MHz, CDCl3): δ = 5.79 (t, J =
2.4 Hz, 2 H), 2.59−2.52 (m, 2 H), 2.40 (ABm, J = 18.2 Hz, 2 H), 2.35−2.26 (m, 2 H), 2.22−2.18 (m, 2
H), 1.54−1.42 (m, 2 H) ppm; 13C-NMR (125 MHz, CDCl3): δ = 148.7 (C), 118.7 (CH), 118.6 (CF3, q,
JCF = 319 Hz), 41.8 (CH), 23.7 (CH2), 23.0 (CH2) ppm; MS: m/z (%) = 430 (M+, 3), 147 (28), 119
(20), 91 (55), 79 (20), 77 (29), 69 (100), 55 (81).
(4aR,8aS)-1,2,4a,5,6,8a-hexahydro-4,8-di((E)-2-((3S,5R)-3,5-dihydroxycyclohex-1-
enyl)vinyl)naphtha-ene (2a). To a solution of alkyne 9 (180 mg, 0.43 mmol) in THF (0.5 mL) is added
dropwise a 1 M solution of catecholborane in THF (0.74 mL, 0.74 mmol). After stirring at room
temperature for 15 min a 0.5 M solution of 9-borabicylo[3.3.1]nonane (9-BBN) in THF (125 μL, 0.063
μmol) is added. After stirring for 5 hours at 60 °C the reaction is brought to room temperature. To the
red-orange solution is added via double-tipped needle a degassed solution of bisenol triflate 8 (50 mg,
0.116 mmol), 1,1’-bis(diphenylphosphino)ferrocene palladium(II) chloride (PdCl2(dppf), 9.8 mg,
0.012 mmol) and triphenylarsine (6 mg, 0.020 mmol) in THF, followed by a degassed 2 M sodium
carbonate solution (0.4 mL, 0.81 mmol). After further stirring for 60 hours in the dark at room
temperature the mixture is poured into water and extracted with methyl tert-butyl ether. After drying
(magnesium sulfate) and concentration in vacuo the brown residue is purified by column
chromatography (pentane/ethyl acetate, 98:2) to yield 57.1 mg of 11a (57%) as an oil which is further
subjected to deprotection.
To a solution of 11a (210 mg, 0.242 mmol) in THF (2 mL) is added a 1 M solution of
tetrabutylammonium fluoride in THF (2.0 mL, 2 mmol). After stirring overnight at room temperature
the mixture is concentrated in vacuo. The brown residual oil is purified by repeated (2 times) column
chromatography on silica gel (ethyl acetate/methanol, 92:8) to yield 70 mg of analogue 2a as a white
crystalline solid (70%). Rf = 0.34 (ethyl acetate/methanol, 9:1); m.p. 195 °C (decomposition); optical
rotation: [α]D = −86° (c = 0.07, methanol); IR (KBr): 3386 (s), 3330 (s), 2932 (s), 1620 (m), 1040 (s),
972 (s), 964 (s) cm-1; 1H-NMR (500 MHz, CD3OD): δ = 6.24 (s, 4 H), 5.83 (br s, 2 H), 5.73−5.72 (m, 2
H), 4.43−4.38 (m, 2 H), 4.16−4.11 (m, 2 H), 2.56 (dm, J = 16.7 Hz, 2 H), 2.31−2.17 (m, 8 H), 2.03
(ddm, J = 16.8, 7.1 Hz, 2 H), 1.88 (ABm, J = 13.1 Hz, 2 H), 1.82−1.76 (m, 2 H), 1.22−1.12 (m, 2 H)

Molecules 2009, 14
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13
ppm; C-NMR (125 MHz, CD3OD): δ = 141.03 (C), 137.15 (C), 131.06 (CH), 129.87 (CH), 129.81
(CH), 129.45 (CH), 126.75 (CH), 126.66 (CH), 123.41 (CH), 66.03 (CH), 64.96 (CH), 42.95 (CH),
42.89 (CH), 40.70 (CH2), 34.59 (CH2), 28.10 (CH2), 27.82 (CH2) ppm; MS: m/z (%) = 374 (4), 356
(23), 338 (75), 179 (28), 167 (57), 154 (31), 141 (82), 128 (68), 115 (61), 91 (100), 86 (31), 49 (48),
45 (46).
(4aR,8aS)-1,2,4a,5,6,8a-hexahydro-4,8-di((E)-2-((3S,5R)-3,5-dihydroxycyclohex-1-
enyl)ethynyl)napht-halene (2b). To a solution of bisenol triflate 8 (500 mg, 1.16 mmol) and enyne 9
(1.023 g, 2.79 mmol) in diethylamine/dimethyl formamide (1:1, 26 mL) are added copper(I) iodide (66
mg, 0.35 mmol) and bistriphenylphosphine palladium(II) acetate (87 mg, 0.12 mmol). The reaction
mixture is further stirred at room temperature in the dark for 3 hours. The reaction mixture is poured
into water and further extracted with diethyl ether. The combined organic phases are washed with
brine and dried (sodium sulfate). After concentration in vacuo the residue is purified by column
chromatography on silica gel with pentane/dichloromethane (7:3) as the eluent, followed by HPLC
(isooctane/ethyl acetate, 95:5), to yield 1.0 g of white crystalline 11b which is further subjected to
deprotection.
To a solution of 11b (100 mg, 0.12 mmol) in THF (3 mL) is added a 1 M solution of TBAF in THF
(0.76 mL, 0.76 mmol). After stirring for 17 hours at room temperature the reaction mixture is directly
eluted (ethyl acetate/methanol, 9:1) on a short column of silica gel. The residue obtained after
concentration in vacuo is purified by crystallization (2 times) from methanol to yield 24 mg of white
crystalline 2b (51% yield). Rf = 0.59 (ethyl acetate/methanol, 8:2); m.p. 225 °C (decomposition);
optical rotation: [α]D = −52° (c = 0.05, methanol); IR (KBr): 3360 (s), 2929 (s), 1261 (s), 1086 (s),
1048 (s), 809 (s) cm -1; 1H-NMR (500 MHz, DMSO-d6): δ = 6.07 (br s, 2 H), 5.94 (t, J = 1.8 Hz, 2 H),
4.74 (d, J = 5.8 Hz, 2 H), 4.64 (d, J = 4.0 Hz, 2 H), 4.24−4.18 (m, 2 H), 3.95−3.90 (m, 2 H), 2.30−2.22
13
(m, 8 H), 1.97−1.90 (m, 4 H), 1.67−1.59 (m, 4 H), 1.28−1.23 (m, 2 H) ppm; C-NMR (125 MHz,
DMSO-d6): δ = 136.09 (CH), 135.45 (CH), 123.75 (C), 119.20 (C), 90.51 (C), 87.24 (C), 63.06 (CH),
62.05 (CH), 39.47 (CH), 38.90 (CH2), 38.21 (CH2), 26.29 (CH2), 25.96 (CH2); MS (APCI): m/z = 389
(2; M+-OH).
(4aR,8aS)-1,2,4a,5,6,8a-hexahydro-4,8-di((Z)-2-((3S,5R)-3,5-dihydroxycyclohex-1-
enyl)vinyl)naphtha-lene (2c). To a solution of enyne 11b (200 mg, 0.232 mmol) in ethyl acetate is
added quinoline (3 mL of a 0.17 M solution in hexane, 0.232 mmol) and Lindlar catalyst (120 mg,
purchased from Aldrich and dried for 3 hours in vacuo). The mixture is stirred under an atmosphere of
hydrogen at room temperature and the reaction followed by TLC. After disappearance of starting
material diethyl ether is added and the mixture filtered over Celite®. After concentration in vacuo the
residue is purified by column chromatography on silica gel with isooctane/ethyl acetate (98:2) as the
eluent and by HPLC with 0.2% methyl tert-butyl ether in isooctane as the eluent to yield 157 mg of
11c as a colorless oil (78%) which is further subjected to deprotection.
To a solution of 11c (143 mg, 0.17 mmol) in THF (7 mL) is added TBAF (1 mL of a 1 M solution in
THF, 1 mmol) dropwise. After stirring for 24 hours at room temperature the reaction mixture is
directly eluted (ethyl acetate/methanol, 9:1) on a column of silica gel to yield 55 mg of white
crystalline 2c (81%). Rf = 0.27 (ethyl acetate/methanol, 9:1); m.p. 135 °C (decomposition); optical

Molecules 2009, 14
901
1
rotation: [a]D = −41° (c = 0.11, methanol); IR (KBr): 3362 (s), 2916 (s), 1654 (w), 1637 (w) cm -1. H-
NMR (500 MHz, DMSO-d6): δ = 5.91−5.80 (m, 4 H), 5.65 (m, 1 H), 5.63 (m, 1 H), 5.45 (m, 1 H), 5.41
(m, 1 H), 4.60 (d, J = 5.5 Hz, 1 H), 4.56 (d, J = 5.6 Hz, 1 H), 4.53 (d, J = 4.3 Hz, 1 H), 4.51 (d, J = 4.2
Hz, 1 H), 4.22−4.19 (m, 2 H), 3.87−3.79 (m, 2 H), 2.38 (ABd, J = 17.3, 4.5 Hz, 1 H), 2.25 (ABd, J =
17.1, 4.7 Hz, 1 H), 2.18−2.10 (m, 6 H), 1.99−1.91 (m, 3 H), 1.86 (ABd, J = 17.2, 7.5 Hz, 1 H),
1.70−1.64 (m; 2 H), 1.58−1.51 (m, 2 H), 1.23−1.15 (m, 2 H) ppm; 13C-NMR (125 MHz, DMSO-d6): δ
= 138.55 (C), 138.49 (C), 134.73 (C), 134.55 (C), 131.63 (CH), 131.47 (CH), 131.05 (CH), 129.81
(CH), 129.72 (CH), 126.65 (CH), 126.28 (CH), 63.70 (CH), 62.68 (CH), 40.80 (CH), 40.72 (CH),
38.04 (CH2), 37.56 (CH2), 26.47 (CH2), 26.10 (CH2) ppm; MS: m/z (%) = 392 (7; M+ - 18), 141 (28),
129 (34), 128 (31), 117 (37), 114 (37), 105 (36), 91 (100), 78 (41), 43 (75), 40 (45).
Acknowledgements
This work was supported by grants G.0553.06 and G.0587.09 from Fonds voor Wetenschappelijk
Onderzoek (FWO) and the KULeuven Research Council (EF/05/007 Symbiosys). The authors thank
B.K. Tan and S. Marcelis for excellent technical assistance.
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