Synthesis of (1α)-1,25-dihydroxyvitamin D3 with a β-positioned seven-carbon side chain at C(12)

Article abstract of DOI:10.1002/hlca.201200427

A convergent synthesis of an analogue of (1α)-1,25-dihydroxyvitamin D₃ (1b) with a C₇ side chain at C(12), i.e., of 5 (Fig.), is described. A key step of the synthesis is the assembly of the triene system by a Pd^II-catalyzed ring closure of an enol triflate ('bottom' fragment) followed by coupling of the resulting Pd^II intermediate with an alkenylboronate ('upper' fragment) (Scheme 2). The synthetic strategy allows isotopic labelling at the end of the synthesis. Copyright

Full text of DOI:10.1002/hlca.201200427

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Helvetica Chimica Acta – Vol. 95 (2012)
Synthesis of (1a)-1,25-Dihydroxyvitamin D3 with a b-Positioned
Seven-Carbon Side Chain at C(12)
by Diego M. Carballaa), Antonio Rumboa), Mercedes Torneiroa), Miguel Maestrob), and
Antonio Mourin˜o*a)
a
´
) Departamento de Quꢀmica Organica y Unidad Asociada al CSIC, Universidad de Santiago de
Compostela, ES-15782 Santiago de Compostela
(phone: þ 34600942435; fax: þ 34981595012; e-mail: antonio.mourino@usc.es)
b
˜
˜
) Departamento de Quꢀmica Fundamental, Universidad de A Coruna, ES-15701 A Coruna
Dedicated to Prof. Dr. Dieter Seebach on the occasion of his 75th birthday
A convergent synthesis of an analogue of (1a)-1,25-dihydroxyvitamin D3 (1b) with a C7 side chain at
C(12), i.e., of 5 (Fig.), is described. A key step of the synthesis is the assembly of the triene system by a
PdII-catalyzed ring closure of an enol triflate (ꢁbottomꢂ fragment) followed by coupling of the resulting
PdII intermediate with an alkenylboronate (ꢁupperꢂ fragment) (Scheme 2). The synthetic strategy allows
isotopic labelling at the end of the synthesis.
1
Introduction. – Vitamin D3 ) (1a; Fig.), before eliciting its biological function, must
be dihydroxylated to (1a)-1,25-dihydroxyvitamin D3 (1a,25(OH)2D3, 1,25D; 1b),
which is considered the hormonally active form of vitamin D3 [1]. This hormone
interacts with the vitamin D nuclear receptor (VDR) [2][3] to form a ligandꢀVDR
complex, which binds to the retinoid X receptor (RXR). The resulting heterodimer
interacts with the vitamin D response elements of the DNA to induce important
biological functions such as regulation of the mineral metabolism, cell differentiation,
cell proliferation, cell growth, apoptosis, and the immune system [1][4]. The fact that
the VDR has been found in more than 30 target tissues and cell tumors has led to the
consideration that 1a,25(OH)2D3 is involved in a wider array of biological functions
including cancer prevention [1][4][5]. However, the clinical application of
1a,25(OH)2D3 has been limited by its secondary hypercalcemic effects [6][7]. Efforts
to develop vitamin D analogues with strong cell-differentiating ability and low calcemic
action have led to the synthesis of more than 3000 vitamin D analogues, but only a few
have found clinical applications [8 – 11]. Most of the vitamin D analogues synthesized
to date are modified at the side chain [5][12], some of them with rigid units [13], and
others with longer [12][14] or shorter side chains [12][15]. Vitamin D analogues with
substituents at the C ring [16], D ring [17], C(18) [18], triene system [19], or A ring [20]
or without the C or D ring or both rings [21] have also been developed (for reviews on
the synthesis of vitamin D analogues, see [22]).
1
)
Trivial atom numbering; for systematic names, see Exper. Part.
ꢃ 2012 Verlag Helvetica Chimica Acta AG, Zꢄrich

Helvetica Chimica Acta – Vol. 95 (2012)
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Figure. Vitamin D3 (1a), (1a)-1,25-dihydroxyvitamin D3 (1b), and analogues 2 – 5
Recently, Dino Moras and co-workers published the crystal structure of an
engineered ligand-binding domain of the vitamin D receptor (VDR-LBD) that lacks a
flexible insertion domain between helices H1 and H3; the mutant VDR bound to
1a,25(OH)2D3 (VDRꢀ1,25D complex) exhibited similar conformation, transactivation
ability, and biophysical properties than the wild-type counterpart [23]. The crystal
structure of the VDRꢀ1,25D complex shows the H-bonding nature of the interactions
between each of the three OH groups of the ligand with the mutant vitamin D receptor
(1a-OH with both Ser-237 and Arg-274, 3b-OH with both Tyr-143 and Ser-278, and 25-
OH with both His-305 and His-397). We have recently utilized the structural features of
Morasꢂ crystallographic structure of the VDRꢀ1,25D complex to design active vitamin
D analogues [17b][24]. For example, we synthesized the 12b-methyl analogue 2, which
binds strongly to the VDR [16b], and the analogue 3, which lacks the natural side chain
at C(17) and binds significantly to the VDR [16c]. Inspired by the interesting biological
profile of compounds 2 and 3 and the potent biological activity of ꢁgeminiꢂ analogue 4, a
vitamin D analogue with two side chains [25], and related compounds [25], we
designed and synthesized the new analogue 5, which possesses the normal side chain of
1a,25(OH)2D3 and a hydroxylated C7 side chain at C(12).

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Helvetica Chimica Acta – Vol. 95 (2012)
Results. – The synthetic plan for the synthesis of the target vitamin D3 analogue 5 is
depicted in Scheme 1 and involves the construction of the triene system by stereo-
selective Pd-catalyzed cyclization of the enol triflate 7 followed by SuzukiꢀMiyaura
coupling of the resulting PdII intermediate with the cyclic alkenylboronate 6 according
to a methodology recently developed in this laboratory [26]. The boronate 6 was
constructed in a linear fashion from the InhoffenꢀLythgoe diol 8, which is usually
prepared by degradation of vitamin D2.
Scheme 1. Synthetic Plan for the Target (1a)-1,25-Dihydroxyvitamin D3 Analogue 5. TBS ¼ tBuMe2Si.
The synthesis of the target compound 5 is outlined in Scheme 2. The required triol 9
[27] was prepared in 27% overall yield (16 steps) from InhoffenꢀLythgoe diol 8
following known methods [28][16b,c]. Transformation of triol 9 into iodo derivative 10
was selectively accomplished with iodine and triphenylphosphine (83% yield). Ni0-
Catalyzed oxidative addition [29] of iodo derivative 10 to methyl acrylate provided
methyl ester 11 (62% yield), which was oxidized with DessꢀMartin periodinane to keto
derivative 12 (92%). Conversion of 12 to bromomethylene derivative 13 was
accomplished in 72% yield by a Wittig reaction with the ylide Ph3P¼CHBr, generated
from (Ph3PCH2Br)Br and tBuOK following a modification of the Trost procedure [26].
The upper-fragment cyclic boronate 6 was prepared in 72% yield by Miyaura boryla-
tion [30] of 13 with bis(pinacolato)diborane (¼4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi-
1,3,2-dioxaborolane) in the presence of [1,1’-bis(diphenylphosphino-kp)ferrocene]di-
chloropalladium(II)ꢀdichloromethane complex as the catalyst and tricyclohexylphos-
phine as ligand. The triene system was installed in 92% yield by treatment of alkenyl-
boronate 6 with an equimolar amount of enol triflate 7 in the presence of a catalytic
amount of [PdCl2(Ph3P)2] and K3PO4 in H2O/THF. Finally, treatment of the resulting
methyl ester 14 with methylmagnesium bromide followed by removal of the protecting
groups gave the desired analogue 5 in 86% yield (20% overall yield from triol 9, 8 steps).
Conclusions. – An efficient convergent synthesis of 5, an analogue of (1a)-1,25-
dihydroxyvitamin D3 bearing a C7 side chain at C(12), was developed. A key step of the
synthesis was the Pd-catalyzed assembly of the triene system in the presence of OH and
ester functionalities in aqueous medium. The synthetic strategy allows isotopic

Helvetica Chimica Acta – Vol. 95 (2012)
1845
Scheme 2. Synthesis of the Target Analogue 5. TBS ¼ tBuMe2Si.
a) I2, Ph3P, 1H-imidazole, THF, ꢀ 208 ! r.t. b) Zn, NiCl2 · 6 H2O, py, CH2¼CHCOOMe, r.t. c)
DessꢀMartin periodinane, CH2Cl2. d) (Ph3PCH2Br)Br, tBuOK, toluene, ultrasounds, ꢀ 17 ! 08; then 12.
e) [PdCl2(dppf)] · CH2Cl2, Cy3P, Pin2B2, AcOK, DMSO, 808. f) 7, [PdCl2(Ph3P)2], K3PO4, THF, H2O. g)
MeMgBr, Et2O, 08. h) Bu4NF, THF.
labelling at the end of the synthesis. Biological testing of the new vitamin D analogue is
in progress in our laboratory.
We thank the Spanish Ministry of Education and Innovation (projects SAF 2007-67205 and
SAF 2010-15291) for financial support and the Center of Supercomputing of Galicia (CESGA) for
allocating computer time. We thank Dishman-Netherlands BV for a generous gift of vitamin D2 used for
´
´
´
the preparation of the InhoffenꢀLythgoe diol, and Dr. X. C. GonzalezꢀAvion and Dr. X. Perez for
preliminary experiments.

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Helvetica Chimica Acta – Vol. 95 (2012)
Experimental Part
General. Pyridinium dichromate (PDC) was prepared following Coreyꢂs procedure [31].
(Ph3PCH2Br)Br was prepared as reported [32]. Zinc was activated according to Amaregoꢂs indications
[33]. All reactions involving oxygen- or moisture-sensitive compounds were carried out under Ar.
Reaction temp. referred to external bath temp. All solvents were distilled under Ar immediately prior to
use: THF and Et2O from Na/benzophenone, toluene from Na, CH2Cl2 from P2O5, pyridine from CaH2,
and DMSO from CaH2 and stored over activated 4 ꢅ molecular sieves. Acetone/dry ice baths were used
for reactions at low temperature. Alternatively, acetone baths were cooled with a CC-100 Cryocool-
immersion cooler, provided with a temp. regulator. Sonications were carried out in a 120 – 240 W, 35 kHz
ultrasonic cleaning bath. Org. extracts were dried over anh. Na2SO4 and concentrated with a rotary
evaporator at aspirator pressure (20 – 30 Torr). TLC: aluminium-backed Merck-60 silica gel plates
(0.2 mm thickness); visualization under UV light at 254 nm and by immersion of the plate in a soln.
containing either p-anisaldehyde (2.5%), acetic acid (1%), and sulfuric acid (3.4%) in 95% ethanol or a
soln. of ceric ammonium nitrate (0.5 g) and ammonium molybdate (4.8 g) in H2O (100 ml) and H2SO4
(5.6 ml) followed by heating with a hot gun. Flash column chromatography (FC): Merck silica gel (230 –
400 mesh). IR Spectra: Bruker spectrometer, model IFS-66V FT-IR; ˜n in cmꢀ1. NMR Spectra: Bruker-
DPX 250-MHz spectrometer, unless otherwise stated; CDCl3 solns.; chemical shifts d in ppm downfield
from Me4Si (¼0.0 ppm) with the residual solvent signal at d(H) 7.26 (s in CDCl3) and d(C) 77.0 (t in
CDCl3) as internal standard, coupling constants J in Hz; distortionless enhancement by polarization
transfer (DEPT) for the assignment of C types. Low- and high-resolution (HR) MS: Micromass
Instruments Autospec (EI) and Bruker-Microtof spectrometer (ESI-TOF); in m/z (rel. %).
(8b,12b)-12-(7-Hydroxy-7-methyloctyl)-22-iodo-de-A,B-23,24-dinorcholan-8-ol (¼(3R,3aR,4R,
7S,7aR)-Octahydro-3-[(1S)-2-iodo-2-methylethyl]-a,a-3a-trimethyl-1H-indene-4-heptanol; 10). Triphe-
nylphosphine (272 mg, 1.04 mmol) and 1H-imidazole (127 mg, 1.86 mmol) were successively added to a
soln. of 9 (147 mg, 0.41 mmol) in THF (10 ml). The mixture was cooled to ꢀ 208, and I2 (208 mg,
0.82 mmol) was added in five portions each 15 min. After 15 min, the mixture was removed from the
cooling bath and stirred for 30 min at r.t. The reaction was quenched by slow addition of sat. NaHCO3
soln. (15 ml) and sat. Na2S2O3 soln. (15 ml). The aq. layer was extracted with AcOEt (3 ꢁ 25 ml), the
combined org. layer dried and concentrated, and the residue purified by FC (SiO2 (1 ꢁ 8 cm), 10 – 20%
AcOEt/hexanes): 10 (159 mg, 83%). Colorless oil. Rf 0.55 (50% AcOEt/hexanes). IR (film): 3413 (br.,
1
OH), 2930s (CH), 2860s (CH). H-NMR (250 MHz): 4.01 (br. d, J ¼ 1.9, HꢀC(8)); 3.48 (dd, J ¼ 2, 9.5,
1 HꢀC(22)); 2.89 (dd, J ¼ 9.5, 9.5, 1 HꢀC(22)); 1.19 (s, Me2COH); 1.11 (d, J ¼ 6.7, Me(21)); 0.86 (s,
Me(18)). 13C-NMR (62.9 MHz): 71 (COH); 68.7 (CH(8)); 56.6 (CH); 53 (CH); 49.4 (CH); 45.4 (C(13));
43.9 (CH2); 36.9 (CH); 34 (CH2); 31.4 (CH2); 30.1 (CH2); 29.9 (CH2); 29.2 (Me2COH); 28.2 (CH2); 24.3
(CH2); 23.6 (CH2); 23.5 (Me); 22.2 (CH2); 20.2 (CH2); 14.8 (CH2(22)); 11.3 (Me). EI-MS: 446 (19, [M ꢀ
H2O]þ), 428 (27, [M ꢀ 2 H2O]þ), 319 (20, [M ꢀ H2O ꢀ I]þ). HR-EI-MS: 446.2066 (C22H39IOþ; calc.
446.2046).
Methyl (8b,12b)-8-Hydroxy-12-(7-hydroxy-7-methyloctyl)-de-A,B-cholan-24-oate (¼ Methyl
(dR,1R,3aR,4S,7R,7aR)-Octahydro-4-hydroxy-7-(7-hydroxy-7-methyloctyl)-d,7a-dimethyl-1H-indene-
1-pentanoate; 11). Freshly distilled methyl acrylate (330 ml, 3.66 mmol) and NiCl2 · 6 H2O (196 mg,
0.82 mmol) were successively added to a suspension of activated Zn (239 mg, 3.66 mmol) in pyridine
(6 ml). The mixture was heated at 608 for 2 h. The red mixture was allowed to warm to r.t., and a soln. of
10 (85 mg, 0.18 mmol) in pyridine (2 ml) was added dropwise via cannula. After 20 min, AcOEt (10 ml)
was added, and the mixture was filtered through a layer of silica gel. The solids were washed with AcOEt
(3 ꢁ 15 ml). The resulting filtrate was successively washed with 10% aq. HCl soln. (3 ꢁ 30 ml) and sat.
NaHCO3 soln. (2 ꢁ 30 ml), dried, and concentrated and the residue purified by FC (SiO2 (1 ꢁ 8 cm), 15%
AcOEt/hexanes): 11 (48 mg, 62%). Colorless oil. Rf (60% AcOEt/hexanes) 0.50. IR (film): 3429 (br.,
OH), 2930s (CH), 2862s (CH), 1740s (C¼O). 1H-NMR (250 MHz): 3.98 (br. s, HꢀC(8)); 3.66 (s,
CO2Me); 1.20 (s, Me2COH); 0.92 (d, J ¼ 6.8, Me(21)); 0.82 (s, Me(18)). 13C-NMR (62.9 MHz): 174.3
(C(25)); 71 (COH); 69.2 (CH(8)); 57.4 (CH); 53.7 (CH); 51.5 (Me); 49.9 (CH); 45.4 (C(13)); 44 (CH2);
34.5 (CH2); 34 (CH2); 33.3 (CH2); 32.9 (CH); 31.3 (CH2); 30.2 (CH2); 30 (CH2); 29.2 (2 Me); 28.2 (CH2);

Helvetica Chimica Acta – Vol. 95 (2012)
1847
24.3 (CH2); 24 (CH2); 23.5 (CH2); 22.6 (CH2); 22.2 (Me); 20.9 (CH2); 11.3 (Me). EI-MS: 406 (13,
[M ꢀ H2O]þ), 388 (47, [M ꢀ 2 H2O]þ). HR-EI-MS: 406.3432 (C26H46Oþ3 ; calc. 406.3447).
Methyl (12b)-12-(7-Hydroxy-7-methyloctyl)-8-oxo-de-A,B-cholan-24-oate (¼ Methyl (dR,1R,3aR,
7R,7aR)-Octahydro-7-(7-hydroxy-7-methyloctyl)-d,7a-dimethyl-4-oxo-1H-indene-1-pentanoate; 12).
DessꢀMartin periodinane (120 mg, 0.283 mmol) was added to a soln. of 11 (93 mg, 0.218 mmol) in
CH2Cl2 (6 ml). The mixture was stirred for 1 h in the absence of light. The mixture was filtered through a
layer of silica gel. The solids were washed with AcOEt (3 ꢁ 15 ml), and the resulting filtrate was
concentrated. The residue was purified by FC (SiO2 (1.5 ꢁ 5 cm), 20% AcOEt/hexanes): 12 (86 mg,
93%). Colorless oil. Rf (45% AcOEt/hexanes) 0.25. IR (film): 3508 (br., OH), 2956s (CH), 2931s (CH),
2860s (CH), 1739s (C¼O), 1717s (C¼O). 1H-NMR (250 MHz): 3.65 (s, CO2Me); 1.20 (s, Me2COH); 0.94
(d, J ¼ 6.8, Me(21)); 0.57 (s, Me(18)). 13C-NMR (62.9 MHz): 212.5 (C(8)); 174.1 (C(25)); 71 (COH); 62.2
(CH); 56.9 (CH); 52.4 (C(13)); 51.5 (MeO); 49 (CH); 43.9 (CH2); 40.4 (CH2); 34.3 (CH2); 33 (CH); 32.6
(CH2); 30.8 (CH2); 30.1 (CH2); 29.9 (CH2); 29.6 (CH2); 29.2 (Me2COH); 28.2 (CH2); 24.3 (CH2); 23.9
(CH2); 21.8 (Me); 21.2 (CH2); 19.3 (CH2); 10.1 (Me). EI-MS: 404 (71, [M ꢀ H2O]þ), 386 (7, [M ꢀ
2 H2O]þ). HR-EI-MS: 404.3284 (C26H44Oþ3 ; calc. (404.3290).
Methyl
(8E,12b)-8-(Bromomethylene)-12-(7-hydroxy-7-methyloctyl)-de-A,B-cholan-24-oate
(¼ Methyl (dR,1R,3aR,4E,7R,7aR)-4-(Bromomethylene)octahydro-7-(7-hydroxy-7-methyloctyl)-d,7a-
dimethyl-1H-indene-1-pentanoate; 13). A suspension of (Ph3PCH2Br)Br (544 mg, 1.25 mmol) in toluene
t
(9 ml) was prepared by sonication for 30 min. After cooling to ꢀ 178, 1m BuOK in THF (1.23 ml,
1.23 mmol) was added, and the resulting mixture was stirred for 3 h. A soln. of 12 (66 mg, 0.156 mmol) in
toluene (6 ml) previously cooled to 08 was added via cannula. The mixture was stirred for 2 h at ꢀ 178
and 3 h at r.t. The reaction was quenched by addition of sat. NH4Cl soln. (1 ml), and the mixture was
filtered through a layer of silica gel. The solids were washed with AcOEt (3 ꢁ 15 ml), and the filtrate was
concentrated. The residue was purified by FC (SiO2 (2 ꢁ 6 cm), 15% AcOEt/hexanes): 13 (56 mg, 72%).
Colorless oil. Rf (40% AcOEt/hexanes) 0.51. IR (film): 3457 (br., OH), 3084w (¼CH), 2954s (CH),
1
2931s (CH), 2861s (CH), 1741s (C¼O), 1632w (C¼C). H-NMR (250 MHz): 5.61 (s, HꢀC(7)); 3.65 (s,
CO2Me); 1.20 (s, Me2COH); 0.92 (d, J ¼ 6.8, Me(21)); 0.46 (s, Me(18)). 13C-NMR (62.9 MHz): 174.2
(C(25)); 144.8 (C(8)); 97 (CH(7)); 71 (COH); 56.7 (CH); 56.1 (CH); 51.5 (MeO); 49.5 (CH); 48.8
(C(13)); 44 (CH2); 34.4 (CH2); 33.6 (CH); 32.6 (CH2); 31.2 (CH2); 31 (CH2); 30.2 (CH2); 30 (CH2); 29.2
(Me2COH); 28.3 (CH2); 28.1 (CH2); 24.3 (CH2); 23.9 (CH2); 22.3 (CH2); 21.9 (Me); 21.3 (CH2); 9.6
(Me). EI-MS: 480 (4, [M ꢀ H2O]þ), 401 (100, [M ꢀ H2O ꢀ Br]þ). HR-EI-MS: 480.2596 (C27H45BrOþ2 ;
calc. 480.2306).
Methyl (8E,12b)-12-(7-Hydroxy-7-methyloctyl)-8-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
methylene]-de-A,B-cholan-24-oate (¼ Methyl (dR,1R,3aS,4E,7R,7aR)-Octahydro-7-(7-hydroxy-7-meth-
yloctyl)-d,7a-dimethyl-4-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-1H-indene-1-penta-
noate; 6). Cy3P (2 mg, 0.007 mmol) and [PdCl2(dppf)] · CH2Cl2 (3 mg, 0.003 mmol) were dissolved in
DMSO (2 ml), and the mixture was stirred for 25 min. A soln. of 13 (56 mg, 0.112 mmol) in DMSO
(2 ml), KOAc (33 mg, 0.336 mmol), and Pin2B2 (57 mg, 0.224 mmol) were successively added. The
mixture was heated to 808 for 3 h and then cooled to r.t. The reaction was quenched by addition of H2O
(15 ml). The aq. layer was extracted with AcOEt (4 ꢁ 25 ml), the combined org. layer dried and
concentrated, and the residue purified by FC (SiO2 (2 ꢁ 5 cm), 10 – 15% AcOEt/hexanes): 6 (44 mg,
72%). Colorless oil. Rf (40% AcOEt/hexanes) 0.48. IR (film): 3515 (br., OH), 2931s (CH), 2861s (CH),
1742s (C¼O), 1640s (C¼C). 1H-NMR (250 MHz): 4.88 (s, HꢀC(7)); 3.65 (s, CO2Me); 1.25 (s,
2 Me2COB); 1.20 (s, Me2COH); 0.92 (d, J ¼ 6.8, Me(21)); 0.45 (s, Me(18)). 13C-NMR (62.9 MHz): 174.3
(C(25)); 166 (C(8)); 82.5 (COB); 71 (COH); 58.8 (CH); 57.1 (CH); 51.4 (MeO); 50 (CH); 49.4 (C(13));
44 (CH2); 34.5 (CH2); 33.6 (CH); 33.2 (CH2); 32.6 (CH2); 31.3 (CH2); 30.2 (CH2); 30.1 (CH2); 30 (CH2);
29.2 (Me2COH); 28.2 (CH2); 24.9 (1 Me2COB); 24.8 (1 Me2COB); 24.3 (CH2); 24 (CH2); 22.6 (CH2);
21.9 (CH3); 21.1 (CH2); 9.8 (CH3). EI-MS: 546 (3, M), 528 (13, [M ꢀ H2O]þ), 399 (100, [M ꢀ
C6H16BO3]þ). HR-EI-MS: 546.4464 (C33H59BOþ5 ; calc. 546.4456).
(1a,12b)-3-O-[(tert-Butyl)dimethylsilyl]-1-{[(tert-Butyl)dimethylsilyl]oxy}-12-(7-hydroxy-7-meth-
yloctyl)-24-(methoxycarbonyl)-25,26,27-trinorvitamin D3 (¼ Methyl (dR,1R,3aS,4E,7R,7aR)-4-{(2Z)-2-
{(3S,5R)-3,5-bis{[(1,1-dimethylethyl)dimethylsilyl]oxy}-2-methylenecyclohexylidene}ethylidene}octahy-
dro-7-(7-hydroxy-7-methyloctyl)-d,7a-dimethyl-1H-indene-1-pentanoate; 14). A 2m aq. K3PO4 soln.

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Helvetica Chimica Acta – Vol. 95 (2012)
(0.9 ml, 1.8 mmol) and [PdCl2(PPh3)2] (2 mg, 0.003 mmol) were successively added to a soln. of 6 (36 mg,
0.066 mmol) and 7 (40 mg, 0.077 mmol) in THF (2 ml). The mixture protected from light was vigorously
stirred for 1 h. Then H2O (1 ml) was added, and the aq. layer was extracted with AcOEt (3 ꢁ 10 ml). The
combined org. layer was dried and concentrated and the residue purified by FC (SiO2 (2 ꢁ 6 cm), 8%
AcOEt/hexanes): 14 (48 mg, 92%). Colorless oil. Rf (30% AcOEt/hexanes) 0.54. 1H-NMR (250 MHz):
6.21 (d, J ¼ 11.2, HꢀC(6)); 6.00 (d, J ¼ 11.2, HꢀC(7)); 5.18 (s, 1 HꢀC(19)); 4.85 (s, 1 HꢀC(19)); 4.37 (m,
HꢀC(1)); 4.19 (m, HꢀC(3)); 3.65 (s, CO2Me); 1.21 (s, Me2COH); 0.98 – 0.77 (m, Me(21), 2 Me3CSi); 0.44
(s, Me(18)); 0.05 (overlapped s, 2 Me2Si). 13C-NMR (62.9 MHz): 174.3 (C(25)); 148.4 (C); 140.7 (C);
134.9 (C); 123.2 (CH); 117.7 (CH); 111 (CH2); 71.8 (CH); 71.1 (COH); 67.5 (CH); 57.2 (CH); 56.9 (CH);
51.4 (MeO); 50.1 (CH); 49.1 (C(13)); 45.9 (CH2); 44.8 (CH2); 44 (CH2); 34.5 (CH2); 33.7 (CH); 32.6
(CH2); 31.4 (CH2); 30.2 (CH2); 30 (CH2); 29.7 (CH2); 29.2 (Me2COH); 28.8 (CH2); 28.2 (CH2); 25.8
(2 Me3CSi); 24.4 (CH2); 24 (CH2); 22.4 (CH2); 21.9 (Me); 21.4 (CH2); 18.2 (CSi); 18.1 (CSi); 9.7 (Me);
ꢀ 4.7 (1 Me2Si); ꢀ 4.8 (1 MeSi); ꢀ 5.1 (1 MeSi).
(1a,12b)-1,25-Dihydroxy-12-(7-hydroxy-7-methyloctyl)vitamin D3 (¼(1R,3S,5Z)-4-Methylene-5-
{(2E)-2-{(1R,3aS,7R,7aR)-octahydro-1-{(1R)-5-hydroxy-1,5-dimethylhexyl]-7-(7-hydroxy-7-methyloc-
tyl)-7a-methyl-4H-inden-4-ylidene}ethylidene}cyclohexane-1,3-diol; 5). A 3m MeMgBr soln. in Et2O
(102 ml, 0.306 mmol) was added dropwise to a cooled (ꢀ 788) soln. of 14 (40 mg, 0.051 mmol) in Et2O
(4 ml). After 15 min, the cooling bath was removed, and the mixture was stirred at r.t. for 1 h in the
absence of light. The reaction was quenched at 08 by slow addition of sat. NH4Cl soln. (10 ml). The aq.
t
layer was extracted with BuOMe (3 ꢁ 10 ml). The combined org. layer was dried and concentrated to
1
give a colorless oil (39 mg, 0.049 mmol; Rf (30% AcOEt/hexanes) 0.25. H-NMR (250 MHz, CD2Cl2):
6.25 (d, J ¼ 11.2, HꢀC(6)); 6.02 (d, J ¼ 11.2, HꢀC(7)); 5.19 (s, 1 HꢀC(19)); 4.85 (s, 1 HꢀC(19)); 4.41 (m,
HꢀC(1)); 4.16 (m, HꢀC(3)); 1.17 (s, 2 Me2COH); 0.96 – 0.83 (m, Me(21), 2 Me3CSi); 0.47 (s, Me(18));
0.05 (m, 2 Me2Si). This colorless oil was dissolved in THF (4 ml) and treated with 1m Bu4N in THF
(600 ml, 0.6 mmol). After stirring for 20 h in the dark, the reaction was quenched by addition of sat.
NH4Cl soln. (15 ml). The aq. layer was extracted with AcOEt (3 ꢁ 15 ml), the combined org. layer dried
and concentrated, and the residue purified by FC (SiO2 (2 ꢁ 6 cm), 60 – 90% AcOEt/hexanes): 5 (25 mg,
86%). White foam. Rf (90% AcOEt/hexanes) 0.18. IR (CHCl3): 3366 (br., OH), 2928s (CH), 2856s
(CH), 1648w (C¼C). 1H-NMR (400 MHz, CD2Cl2): 6.34 (d, J ¼ 11.3, HꢀC(6)); 6.00 (d, J ¼ 11.3,
HꢀC(7)); 5.29 (s, 1 HꢀC(19)); 4.95 (s, 1 HꢀC(19)); 4.37 (dd, J ¼ 4.4, 7.5, HꢀC(1)); 4.15 (ddd, J ¼ 3.6, 3.6,
10.3, HꢀC(3)); 2.81 (dd, J ¼ 3.8, 13.4, HꢀC(9)); 2.55 (dd, J ¼ 3.3, 13.4, 1 HꢀC(4)); 2.26 (dd, J ¼ 6.6, 13.4,
1 HꢀC(4)); 1.16 (overlapped s, Me2COH, Me(26)/Me(27)); 0.93 (d, J ¼ 6.8, Me(21)); 0.48 (s, Me(18)).
13C-NMR (100 MHz, CD2Cl2): 148.6 (C(10)); 143.4 (C(8)); 133.9 (C(5)); 125.2 (CH(6)); 117.4 (CH(7));
111.9 (CH2(19)); 71.3 (COH, C(25)); 71.3 (CH(1)); 67.3 (CH(3)); 57.9 (CH); 57.7 (CH); 50.7 (CH); 49.9
(C(13)); 45.9 (CH2(4)); 45 (CH2); 44.6 (CH2); 43.5 (CH2); 34.4 (CH); 34.1 (CH2); 32 (CH2); 30.8 (CH2);
30.6 (CH2); 30.3 (CH2); 30 (CH2); 29.6 (Me2COH); 29.6 (Me(26), Me(27)); 28.8 (CH2); 24.9 (CH2); 23.8
(CH2); 23.1 (CH2); 22.3 (Me(21)); 21.9 (CH2); 10.2 (Me(18)). ESI-TOF-MS: 581 (100, [M þ Na]þ), 541
(0.3, [M ꢀ OH]þ), 523 (24, [M ꢀ OH ꢀ H2O]þ). HR-ESI-TOF-MS: 581.4538 (C36H62NaOþ4 ; calc.
581.4540).
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Received August 8, 2012