Stereoselective Palladium-Catalyzed Approach to Vitamin D3 Derivatives in Protic Medium

Article abstract of DOI:10.1002/chem.201705656

We describe an efficient convergent synthesis of vitamin D₃ metabolites and analogues. The synthetic strategy relies on a tandem Pd-catalyzed A-ring closure and Suzuki–Miyaura coupling to the CD-side chain component to set directly the vitamin D triene system under protic conditions. This strategy enables rapid access to vitamin D₃ and 3-epi-vitamin D₃ metabolites and analogues modified at the side chain for biological evaluation and structural and metabolic studies.

Full text of DOI:10.1002/chem.201705656

A Journal of
Accepted Article
Title: Stereoselective Palladium-Catalyzed Approach to Vitamin D3
Derivatives in Protic Medium
Authors: Antonio Mourino, Diego Carballa, Rita Sigüeiro, Zaida
Rodríguez-Docampo, Flavia Zacconi, and Miguel A Maestro
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To be cited as: Chem. Eur. J. 10.1002/chem.201705656
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Stereoselective Palladium-Catalyzed Approach to Vitamin D3
Derivatives in Protic Medium
Diego Carballa,[a] Rita Sigüeiro,[a] Zaida Rodríguez-Docampo,[a] Flavia Zacconi,[a] Miguel A. Maestro,[b]
and Antonio Mouriño*[a]
In memory of Milton Hammond
Abstract: Herein, we describe an efficient convergent synthesis of
vitamin D3 metabolites and analogs. The synthetic strategy relies on
a tandem Pd-catalyzed A-ring closure and Suzuki-Miyaura coupling
to the CD-side chain component to set directly the vitamin D triene
system under protic conditions. This strategy enables a rapid access
to vitamin D3 and 3-epi-vitamin D3 metabolites and analogs modified
at the side chain for biological evaluation, and structural and
metabolic studies.
prevention of vitamin D3-linked diseases including cancer[2] and
has been used for treatment of renal osteodystrophy,
osteoporosis, and rickets.[3] A second hydroxylation at C1 of the
A-ring takes place primarily in the kidney to produce the
hormone 1,25-dihydroxyvitamin D3 [1,25(OH)2D3, calcitriol],
which is responsible for the regulation of mineral homeostasis,
cell growth, differentiation, proliferation, apoptosis, and immune
responses.[1] Other enzymatic oxidations at the side chains of
vitamin D3 and 25(OH)D3 have led to the isolation of at least 16
metabolites (Figure 1),[1,4] which have been considered
intermediates of catabolic pathways to excretion products. A few
of the above vitamin D3 metabolites exhibit biological actions.
For example, 24R,25(OH)2D3 activates signal-related kinase
phosphorylation, regulates bone fracture healing, mediates rapid
non-genomic responses, and inhibits colon carcinogenesis;[5]
and 20S(OH)D3, 20S,24R(OH)2D3 and 20S,24S(OH)2D3, show
anti-proliferative activity.[6] Epimerization of vitamin D3 at C3 has
also been identified as an alternative metabolic pathway to
produce 3-epi-vitamin D3 metabolites (Figure 2, 1A, 1B).[7]
Detailed studies on the biological profile of the majority of the
known vitamin D3 metabolites and derivatives hydroxylated at
the side chain have been limited by the lack or scarcity of
synthetic material. Intensive research efforts have been directed
towards the synthesis of 1-hydroxyvitamin D metabolites and
analogs,[8] but less attention has been put on the development of
synthetic strategies to the triene system of vitamin D3 and its
side-chain hydroxylated metabolites and analogs. The linear
classical method involves a low yielding photochemical opening
of a steroidal B-ring-diene followed by thermal sigmatropic
rearrrangement of the resulting previtamin D triene (route W,
Scheme 1).[6b,9] Convergent strategies in which a CD-side chain
fragment is coupled with an A-ring unit have been pioneered by
Lythgoe and coworkers and include the dienyne approach, that
involves the formation of a dienyne and its semihydrogenation
Introduction
Vitamin D3 (cholecalciferol) undergoes a cytochrome P450-
catalyzed hydroxylation at C25 of the side chain primarily in the
liver to generate 25-hydroxyvitamin D3 [25(OH)D3] (Figure 1).[1]
Figure 1. Structures of vitamin D3, 25-hydroxyvitamin D3 and some vitamin D3-
hydroxylated metabolites.
This major circulating metabolite has been associated with
[a]
[b]
Dr. D. Carballa, Dr. F. Zacconi, Dr. R. Sigüeiro, Prof. Dr. A. Mouriño
Departamento de Química Orgánica.
Laboratorio de Investigación Ignacio Ribas.
Universidad de Santiago de Compostela
Avda. Ciencias s/n, 15782 Santiago de Compostela (SPAIN)
E-mail: antonio.mourino@usc.es
Prof. Dr. M. A. Maestro
Departamento de Química-CICA
Universidad de A Coruña
Campus da Zapateira s/n, 15701 A Coruña (SPAIN)
Supporting information for this article is given via a link at the end of
the document.
Scheme 1. Synthetic routes to 25-hydroxyvitamin D3.
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10.1002/chem.201705656
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followed by thermal rearrangement to generate the vitamin D
triene system (route X),[10,11] and the Wittig-Horner approach that
involves the direct coupling of a phosphine-oxide-anion to the
corresponding A-ring moiety with a Grundmann’s type ketone
(CD-side chain fragment) (route Y).[12-14] The Hoffmann-La
Roche group also developed a synthetic route to vitamin D3
derivatives based on the solvolysis of cyclopropyl moieties
(route Z).[15]
Synthesis of the A-ring precursors. The synthesis of enol-
triflates 2a and 2b started with commercial (R)-(+)-limonene
oxide (4a, mixture of cis and trans isomers) and (S)-(+)-
limonene oxide (4b, mixture of cis and trans isomers),
respectively (Scheme 3). Ozonolysis of the isopropenyl side
chain of 4a in CH2Cl2/MeOH, followed by acetylation of the
resulting hydroperoxide with Ac2O in the presence of DMAP
and Et3N, and Criegee rearrangement[17] of the resulting
peroxyester in MeOH, provided, after protective silylation
(TBSCl), the desired epoxide 7a[18] in good yield (73%). Periodic
acid-oxidative cleavage of 7a in Et2O gave an aldehyde, which
was transformed directly into the vinylic dibromide 8a by
olefination with Ph3P=CBr2 in CH2Cl2 (74%, two steps).
Successive exposure of 8a to LDA and nBuLi in THF formed
the corresponding acetylenic enolate, which was trapped with
Comins' Reagent[19] to afford the desired enol-triflate 2a (65%)
(5 steps, 35% overall yield). The enol-triflate 2b was efficiently
obtained from (S)-(-)-limonene oxide 4b in similar yield under
the same reaction conditions. Deprotection of 2b with aq HF
afforded the corresponding enol trilfate 2c in 94% yield.
Results and Discussion
We describe here a rapid and efficient Pd-catalyzed strategy to
vitamin D3 metabolites and analogs in protic medium,
exemplified with the synthesis of 3-epi-vitamin D3 (1A), 3-epi-
25-hydroxyvitamin D3 (1B), 20-epi-vitamin D3 (1C), 20-epi-25-
hydroxyvitamin D3 (1D) and the natural metabolite
25-hydroxyvitamin D3 (1E) (Figure 2).
Figure 2. Target compounds: 3-epi-vitamin D3 (1A), 3-epi-25-hydroxyvitamin
D3 (1B), 20-epi-vitamin D3 (1C), 20-epi-25-hydroxyvitamin D3 (1D) and the
natural metabolite 25-hydroxyvitamin D3 (1E).
Synthetic strategy. The retrosynthetic analysis is represented
in Scheme 2. For assembling the triene systems of vitamin D3
and 3-epi-vitamin D3, we chose the mild convergent approach to
the triene unit of 1-hydroxyvitamin D3 metabolites and analogs
previously developed in our laboratories, which is based on a
Pd(0)-catalyzed ring closure and a Suzuki–Miyaura coupling
between an enol-triflate (A-ring precursor) and an alkenyl-
boronic ester (CD-side chain component).[16] The requisite key
Scheme 3. Synthesis of A-ring precursors 2a, 2b and 2c.
Synthesis of CD-side chain upper fragments. Boronate 3a,
was prepared from Grundmann’s ketone (5a) through vinyl
bromide 9, and boronates 3b and 3c were prepared from
Inhoffen-Lythgoe diol (10) (Scheme 4).[16a] The synthesis of
boronate 3d started with alcohol 11,[20] which was converted to
alcohol 14 by known procedures (79%, 3 steps).[21] Removal of
the C25-hydroxyl group of 14 was accomplished by dehydration
with phosphorus oxychloride in pyridine followed by
Pd-catalyzed hydrogenation of the resulting olefins to provide 15,
which upon deprotection with hydrofluoric acid and subsequent
oxidation with pyridinium dichromate generated the known[22]
ketone 5d. Olefination of 5d by Trost method[23] using the ylide
Ph3P=CHBr, prepared by reaction of Ph3PCH2Br2 with KOtBu in
toluene, provided the alkenyl bromide 17. Miyaura Pd-catalyzed
Br-B interchange employing bis(pinacolato)diboron and
PdCl2(dppf)ꞏCH2Cl2 as the catalyst[24] in the presence of
enol-triflates
2 (precursors of the A-ring moieties) were
envisaged to arise from commercially available (R)-(+)- and
(S)-(-)-limonene oxides 4. The required boronic esters 3 would
be synthesized from the corresponding ketones 5 by Wittig-
chemistry and Pd-catalyzed Br-B interchange.
R
R
H
H
TfO
Pd0-Cat
Ring Closure
H
H
XO
Cross Coupling
pinB
2
3
X = TBS or H
HO
R = Alkyl, hydroxyalkyl
or ester side-chain
R
O
1
tricyclohexylphosphine[16a]
and
potasium
acetate
in
H
O
dimethylsulfoxide afforded the desired boronate 3d (9 steps,
30% overall yield). The boronate 3e was prepared from alcohol
14, through the alkenyl bromide 19,[25] as previously described
(4 steps, 44% overall yield).[21]
pin =
B
O
H
4
O
5
Scheme 2. Retrosynthetic analysis of vitamin D3, 3-epi-vitamin D3 and side-
chain derivatives.
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(entries 6 and 7). Pleasingly, the Pd-catalyzed process was
successfully applied to the unprotected enol-triflate 2c and
boronate 3b to deliver directly the desired metabolite
25-hydroxyvitamin D3 (1E, 60% isolated yield) together with the
corresponding direct coupled product 1E’ (20% yield determined
a
H
H
H
9, X = Br
20, X = SnnBu3
21, X = ZnBr
H
H
H
O
5a
3a
X
pinB
CO2Me
1
OH
by H NMR of the crude reaction mixture). To the best of our
OH
a
H
H
H
knowledge this is the first example in which the vitamin D triene
system is generated by a convergent process without A-ring
hydroxyl-protection.
H
H
H
HO
10
3b
3c
pinB
pinB
b
X
CO2Me
OH
Table 1. Synthesis of vitamins 1A-1D by Pd(0)-catalyzed carbocyclization-
H
H
d
H
e
cross coupling.
94%
99%
H
H
H
TBSO
c
TBSO
TBSO
13
14
67%
11 (X = OH)
(85%) 12 (X = I)
f
H
H
H
i
g,h
k
64%
71%
85%
TBSO
H
H
H
O
17
5d
15
Br
j
70%
Entry
1[a]
Triflate
Boronate
Conditions
Products
OH
OH
H
H
H
k
1) PdCl2(PPh3)2, K2CO3,
THF/H2O; 2) TBAF, THF
1A (57)
1A' (15)
2a
3a
69%
H
H
H
3d
3e
19
pinB
Br
pinB
1) PdCl2(PPh3)2, Cs2CO3,
THF/H2O; 2) TBAF, THF
1A (53)
1A' (20)
2[a]
2a
2a
3a
3c
Scheme 4. Synthesis of upper fragments. Boronates 3a-3c: a) Ref. [16a]. 3a:
2 steps, 53%; 3b: 5 steps, 30%; 3c: 3 steps, 34%. Boronate 3d: b) Ref. [20],
35% ;c) I2, PPh3, imidazole, THF, -20 ºC to RT; d) CH2=CHCO2Me, Zn,
NiCl2ꞏ6H2O, py; e) MeMgBr, THF, 0 ºC to RT; f) POCl3, py, 0 ºC; H2, 10% Pd/C,
EtOAc; g) HF, CH2Cl2/CH3CN (91%); h) PDC, CH2Cl2 (94%); i) Ph3P=CHBr,
PhMe/tBuOH, -17 ºC to 0 ºC; j) B2pin2, PdCl2(dppf)ꞏCH2Cl2, PCy3, KOAc,
DMSO, 80 ºC. Boronate 3e: k) Ref. [21]. PDC: pyridinium dichromate, dppf:
1,1’-bis(diphenylphosphino)ferrocene.
1) PdCl2(PPh3)2, K3PO4,
dppf, THF/H2O; 2) TBAF,
THF; 3) MeMgBr, THF
1B (30)
1B' (30)
3[b]
PdCl2(PPh3)2, K3PO4,
PTS/H2O (2%)
complex
mixture
4[b]
5[b]
6[c]
7[b]
8
2a
2a
2b
2b
2c
3c
3b
3d
3e
3b
1) PdCl2(PPh3)2, K3PO4,
THF/H2O; 2) HF, S
1B (56)
1B' (12)
Synthesis of vitamins 1A-1E. With enol-triflates
2 and
boronates 3 in hand, we proceeded to study the Pd-catalyzed
tandem carbocyclization–Suzuki-Miyaura coupling process to
assemble the triene system of our target vitamin D3 derivatives 1
(Table 1). Slow addition of a solution of boronate 3a (1 equiv) in
THF to a mixture of 2a (1.5 equiv), PdCl2(PPh3)2 (5 mol%), and
aq K2CO3 in THF, followed by vigorous stirring for 30 min
delivered, after standard desilylation, 3-epi-vitamin D3 (1A) in
57% yield together with diene 1A’ (15%) (entry 1). The latter is
formed by direct coupling between the enol-triflate 2a and
boronate 3a. Replacement of K2CO3 by Cs2CO3 did not improve
the yield on the vitamin D triene product (entry 2). The use of
1) PdCl2(PPh3)2, Cs2CO3,
PhH/H2O; 2) HF, S
1C (55)
+ mixture
1) PdCl2(PPh3)2, K3PO4,
THF/H2O; 2) HF, S
1D (55)
1D' (20)
PdCl2(PPh3)2, K3PO4,
THF/H2O
1E (60)
1E' (20)
[a] Slow addition of 3a over 2a for 30 min, RT. [b] RT, 30 min. [c] RT, 5 h.
S: CH3CN/CH2Cl2 (3:1). dppf: 1,1’-bis(diphenylphosphino)ferrocene. TBAF:
nBu4NF. 2a (R), (X = TBS). 2b (S), (X = TBS). 2c (S), (X = H). TBS: SitBuMe2.
1,1’-bis(diphenylphosphino)ferrocene (dppf) as
a bidentate
ligand provided, after deprotection and methylation, a 1:1
mixture of compounds 1B and 1B' in moderate yield (entry 3).
Attempts to improve the carbocyclization process using a
micellar medium such as aqueous polyoxyethany--tocopheryl
sebacate (PTS)[26] as a surfactant resulted in the formation of a
complex mixture of products (entry 4). The carbocyclization-
coupling process employing boronate 3b and aq K3PO4
generated the vitamin D system in similar yield (entry 5). The 20-
epi-derivatives 1C and 1D were also obtained in similar yield
from enol-triflate 2b and boronates 3d and 3e, respectively.
Attempts to improve the efficiency of the carbocyclization-cross
coupling versus the direct cross coupling under Stille conditions
[Pd(PPh3)4, LiCl, THF, 80 ºC][27] using the alkenyl stannane 20
(Scheme 4) and enol-triflate 2a produced a complex mixture of
products. Interestingly, the Negishi method[28] (21, 2a, Pd(PPh3)4,
Et3,N, THF) favors the formation of the direct cross-coupled
product 1A’ (58% yield after deprotection) versus the
carbocyclization-cross-coupling product 1A (17%), presumably
as the result of a faster direct transmetalation step.
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(R)-8,8-Dibromo-5-(tert-butyldimethylsilyloxy)oct-7-en-2-one
(8a).
Periodic acid (2.54 g, 11.1 mmol) was added to a solution of 7a (0.9 g,
3.7 mmol) in dry Et2O (50 mL). The mixture was stirred at RT for 30 min.
The reaction was quenched by slowly addition of H2O (50 mL). The
mixture was extracted with Et2O (3×15 mL). The combined organic
phases were washed with sat Na2S2O3 (3×30 mL) and brine (30 mL),
dried, filtered and concentrated in vacuo. The resulting aldehyde was
used in the next experiment without further purification. A solution of ylide
Ph3P=CBr2 in dry CH2Cl2 was prepared as follows: dry CH2Cl2 (40 mL)
was added to a mixture of Zn powder (0.73 g, 11.1 mmol) and
triphenylphosphine (2.91 g, 11.1 mmol). The mixture was stirred at 0 ºC
for 10 min. CBr4 (3.68 g, 11.1 mmol) was added in three portions. The
mixture was stirred at RT for 1.5 h. To this suspension of the ylide was
added via cannula the above aldehyde dissolved in dry CH2Cl2 (15 mL).
The mixture was stirred at RT for 30 min, diluted with hexanes and
filtered through a short pad of celite and silica gel washing with hexanes
(100 mL) and CH2Cl2/hexanes (1:1, 100 mL). After concentration in
vacuo, the residue was purified by flash chromatography (SiO2,
Ø 3×6 cm, 2% Et2O/hexanes) to give 8a [1.13 g, 2.73 mmol, 74%,
Conclusions
In conclusion, we have developed an efficient convergent route
to 3-epi-vitamin D3 (1A), 20-epi-vitamin D3 (1C), and 25-hydroxy-
vitamin D3 derivatives 1B, 1D and 1E, starting from
Grundmann’s ketone (5a) or Inhoffen-Lythgoe diol (10) as
precursors of the CD-side chain units and commercial (R)-(+)-or
(S)-(-)-limonene oxides as precursors of the A-ring moieties.
Yields of 1A-1E from limonene oxide  18% (7 steps). Yields of
1A-1E through CD-ring: 1A (30%, 4 steps), 1B (17%, 7 steps),
1C (4.5%, 16 steps), 1D (7%, 14 steps);1E (18%, 6 steps). The
synthetic approach features a highly stereoselective tandem Pd-
catalyzed carbocyclization and Suzuki–Miyaura-cross coupling
to generate rapidly and directly small amounts of vitamin D3
metabolites and derivatives under protic conditions for biological
testing, structural elucidation, and metabolic studies.
25
Rf = 0.50 (5% EtOAc/hexanes), yellowish oil, []D = +18.3 (c = 1.0,
CHCl3)]. 1H NMR (250 MHz, CDCl3)  6.41 (1H, t, J = 7.3 Hz; H-7), 3.88-
3.69 (1H, m; H-5), 2.46 (2H, t, J = 7.4 Hz; H-3), 2.32-2.15 (2H, m), 2.11
(3H, s; H-1), 1.80-1.51 (2H, m), 0.85 (9H, s; tBuSi), 0.02 (3H, s; MeSi),
0.01 ppm (3H, s; MeSi); 13C NMR (63 MHz, CDCl3)  208.2 (C; C-2),
135.0 (CH; C-7), 90.0 (C; C-8), 69.3 (CH; C-5), 40.4 (CH2), 38.9 (CH2),
30.4 (CH2), 29.9 (CH3; C-1), 25.7 (CH3; tBuSi), 17.9 (C; C-Si), -4.6 (CH3;
MeSi), -4.8 ppm (CH3; MeSi); IR (film) 1718, 1623 cm-1; HRMS (ESI-
TOF) m/z calcd for C14H26Br2O2SiNa (M+Na)+ 434.9961, found 434.9941.
Experimental Section
For details on general materials and methods, see Supplementary
Information (SI).
cis- and trans-(3R)-6-Methyl-7-oxabicyclo[4.1.0]heptan-3-ol tert-
butyldimethyl ether (7a). Modified procedure: A mixture ozone/oxygen
(0.7 bar, 0.1 NL/h, 50 W) was bubbled through a -78 ºC cooled solution
of (R)-(+)-limonene (4a, 5 g, 32.8 mmol) in dry MeOH (5.5 mL) and dry
CH2Cl2 (100 mL) for 1 h. The excess of ozone was removed with a
stream of argon for 30 min. The mixture was stirred at RT for 40 min and
then cooled to -33 ºC. Dry Et3N (32 mL, 229.9 mmol) was slowly added
over 30 min. DMAP (0.56 g, 4.6 mmol) and Ac2O (21.7 mL, 229.9 mmol)
were slowly and successively added keeping the temperature between
-33 and -25 ºC. The mixture was allowed to reach -5 ºC and stirred for
1.5 h. The reaction was quenched by the slow addition of dry MeOH
(12.5 mL). The mixture was diluted with hexanes (75 mL), and
successively washed with sat citric acid (10%, 2x60 mL) and sat NaHCO3
(2x60 mL). The organic phase was dried, filtered and concentrated in
vacuo. The residue was dissolved in dry MeOH (68 mL) and dry NaOAc
(0.54 g, 6.6 mmol) was added in one portion. The mixture was stirred at
37 ºC for 20 h and then concentrated in vacuo. The residue was purified
by flash chromatography (SiO2, Ø 4×10 cm, 30% EtOAc/hexanes) to give
a mixture of diastereoisomers 6a[29] [3.75 g, 29.3 mmol, 89%, Rf = 0.30
(60% EtOAc/hexanes), colorless oil]. Imidazole (1.05 g, 15.44 mmol)
and tert-butydimethylsilyl chloride (1.16 g, 7.72 mmol) were successively
added to a solution of 6a (0.9 g, 7.02 mmol) in dry DMF (15 mL). The
mixture was stirred at RT for 18 h. The reaction was quenched with sat
NH4Cl (40 mL). The mixture was extracted with diethyl ether (3×15 mL).
The combined organic phases were dried, filtered and concentrated in
vacuo. The residue was purified by flash chromatography (SiO2, Ø
3×6 cm, 2% Et2O/hexanes) to give diastereoisomers 7a[18] [1.4 g,
5.77 mmol, 82%, Rf = 0.75 (20% EtOAc/hexanes), colorless oil)]. 1H NMR
(250 MHz, CDCl3)  3.86-3.73 (0.3H, m; H-3), 3.62-3.40 (0.7H, m; H-3),
2.93 (0.3H, d, J = 4.1 Hz; H-1), 2.85 (0.7H, d, J = 5.3 Hz; H-1), 2.23-1.88
(2H, m), 1.87-1.57 (2H, m), 1.56-1.32 (2H, m), 1.29 and 1.26 (3H,
overlapped s; Me-6), 0.85 (9H, overlapped s; tBuSi), 0.01 ppm (6H, s;
Me2Si); 13C NMR (63 MHz, CDCl3)  67.6 (CH), 64.0 (CH), 58.5 (CH),
58.4 (CH), 57.5 (C; C-6), 57.1 (C; C-6), 34.4 (CH2), 34.2 (CH2), 29.0
(CH2), 28.7 (CH2), 27.7 (CH2), 25.8 (CH3; tBuSi), 25.1 (CH2), 23.5 (CH3;
Me-6), 22.7 (CH3; Me-6), 18.1 (C; C-Si), -4.7 (CH3; MeSi), -4.9 ppm (CH3;
Me-6); IR (film) 2954, 2929, 2856, 1472, 1463 cm-1; HRMS (EI)+ m/z
calcd for C13H26O2Si (M)+ 242.1697, found 242.1695.
(R)-5-(tert-Butyldimethylsilyloxy)oct-1-en-7-yn-2-yl trifluoromethane-
sulfonate (2a). A solution of 8a (0.476 g, 1.15 mmol) in dry THF (5 mL)
was added to a -78 ºC cooled solution of lithium diisopropylamide in dry
THF (6.4 mL, 3.44 mmol, 0.53 M). The mixture was stirred at -78 ºC for
1 h. Then N-(5-chloro-2-pyridyl)triflimide (0.78 g, 1.98 mmol) was added
and the reaction mixture was allowed to warm slowly to -20 ºC for 4 h.
The reaction was quenched by addition of H2O (30 mL) and aq HCl (5%,
5 mL). The mixture was extracted with MTBE (3×15 mL). The combined
organic phases were dried, filtered and concentrated. The residue was
purified by flash chromatography (SiO2, Ø 2×10 cm, 3% MTBE/hexanes)
to give 2a [0.29 g, 0.75 mmol, 65%, Rf = 0.80 (5% Et2O/hexanes),
colorless oil, [α]D25 = +23.7 (c = 0.9, CHCl3)]. 1H NMR (250 MHz, CDCl3)
δ 5.11 and 4.96 (1H and 1H, each d, J = 3.3 Hz; H-1), 3.92-3.78 (1H, m;
H-5), 2.51-2.24 (4H, m), 2.01 (1H, t, J = 2.4 Hz; H-8), 0.88 (9H, s; tBuSi),
0.08 (3H, s; MeSi), 0.06 ppm (3H, s; MeSi); 13C NMR (63 MHz, CDCl3) δ
156.8 (C; C-2), 118.5 (C, q, J = 320 Hz; CF3), 104.1 (CH2; C-1), 80.5 (C;
C-7), 70.6 (CH; C-8), 69.5 (CH; C-5), 32.7 (CH2), 29.6 (CH2), 27.2 (CH2),
25.7 (CH3; tBuSi), 17.9 (C; C-Si), -4.5 (CH3; MeSi), -4.9 ppm (CH3;
MeSi); IR (film) 3315, 1670 cm-1; HRMS (ESI-TOF): m/z calcd for
C
15H25F3O4SSiNa (M+Na)+ 409.1085, found 409.1087.
(20S)-8β-(tert-Butylsilyloxy)-des-A,B-cholestane (15). Phosphoryl
chloride (420 μL, 4.50 mmol) was added to a 0 ºC cooled solution of 14
(0.198 g, 0.50 mmol) in dry pyridine (6 mL). After 3.5 h, the reaction was
quenched by slowly addition of MeOH (1 mL) to destroy the excess of
POCl3. MeOH was removed in vacuo. Aq HCl (5%, 20 mL) was added.
The mixture was extracted with Et2O (3×15 mL). The combined organic
phases were dried, filtered and concentrated. The residue was dissolved
in EtOAc (10 mL) and a catalytic amount of Pd/C (10 mg, 10%) was
added. The suspension was stirred under hydrogen atmosphere (balloon
pressure) at RT for 10 h. The reaction mixture was filtered through a
short pad of silica gel, washing with EtOAc (30 mL). After concentration
in vacuo, the residue was purified by flash chromatography (SiO2, Ø
2×12 cm, hexanes) to give 15 [128 mg, 0.34 mmol, 67%, Rf = 0.95
(hexanes), colorless oil, [α]D = +22.1 (c = 0.3, CHCl3)]. 1H NMR
25
This article is protected by copyright. All rights reserved.

10.1002/chem.201705656
Chemistry - A European Journal
FULL PAPER
(250 MHz, CDCl3)  4.01 (1H, d, J = 2.0 Hz; H-8), 2.05-0.99 (20H, m),
0.94-0.84 (18H, m; H-18, H-26, H-27 and tBuSi), 0.82 (3H, d, J = 6.5 Hz;
H-21), 0.02 (3H, s; MeSi), 0.01 ppm (3H, s; MeSi); 13C NMR (63 MHz,
CDCl3)  69.5 (CH; C-8), 56.5 (CH), 53.2 (CH), 42.2 (C; C-13), 40.7
(CH2), 39.5 (CH2), 35.6 (CH2), 34.9 (CH), 34.6 (CH2), 28.1 (CH), 27.3
(CH2), 25.8 (CH3; tBuSi), 24.0 (CH2), 23.0 (CH2), 22.8 and 22.7 (CH3;
C-26 and C-27), 18.6 (CH3), 18.0 (C; C-Si), 17.8 (CH2), 14.0 (CH3), -4.8
(CH3; MeSi), -5.1 ppm (CH3; MeSi); IR (film) 2954, 2930, 2858 cm-1;
HRMS (EI) m/z calcd for C24H48OSi (M)+ 380.3474, found 380.3457.
mixture was extracted with EtOAc (3×25 mL) and the combined organic
phases were dried, filtered and concentrated. The residue was purified
by flash chromatography (SiO2, Ø 1×6cm, 10-30% EtOAc/hexanes) to
give 1D [56 mg, 0.14 mmol, 55%, Rf = 0.38 (40% EtOAc/hexanes), white
25
foam, [α]D = +9.1 (c = 1.3, 96% EtOH)] and 1D’ [20 mg, 0.05 mmol,
25
20%, Rf = 0.45 (40% EtOAc/hexanes), colorless oil, [α]D = +36.4
(c = 1.5, 96% EtOH)]. 1D: 1H NMR (400 MHz, CDCl3)  6.21 and 6.01
(1H and 1H, each d, J = 11.2 Hz; H-6 and H-7), 5.02 (1H, s; H-19), 4.80
(1H, d, J = 1.5 Hz; H-19), 3.94-3.87 (1H, m; H-3), 2.80 (1H, dd, J = 3.6,
11.9 Hz), 2.55 (1H, dd, J = 3.6, 13.1 Hz), 2.43-2.31 (1H, m), 2.30-2.21
(1H, m), 2.20-2.09 (1H, m), 2.04-1.22 (19H, m), 1.19 (6H, s; H-26 and
H-27), 0.83 (3H, d, J = 6.5 Hz; H-21), 0.52 ppm (3H, s; H-18); 13C NMR
(101 MHz, CDCl3)  145.0 (C), 142.0 (C), 135.2 (C), 122.3 (CH; C-6), 117.5
(CH; C-7), 112.3 (CH2; C-19), 71.1 (C; C-25), 69.2 (CH), 56.3 (CH), 56.1
(CH), 45.9 (CH2), 45.8 (C; C-13), 44.2 (CH2), 40.4 (CH2), 36.0 (CH2), 35.4
(CH), 35.1 (CH2), 32.0 (CH2), 29.2 (CH3; C-26 and C-27), 29.0 (CH2), 27.3
(CH2), 23.5 (CH2), 22.1 (CH2), 20.8 (CH2), 18.5 (CH3), 12.2 ppm (CH3;
C-18); IR (CHCl3) 3410, 2937, 2874, 1712 cm-1; HRMS (ESI-TOF) m/z,
calcd for C27H44O2Na (M+Na)+ 423.3234, found 423.3230. 1D’: H NMR
(400 MHz, CDCl3)  5.36 (1H, s; H-7), 4.97 and 4.75 (1H and 1H, each s;
H-6), 3.80-3.71 (1H, m; H-3), 2.93-2.85 (1H, m), 2.46-2.13 (4H, m), 2.05
(1H, t, J = 2.5 Hz; H-19), 2.03-1.78 (4H, m), 1.71-1.24 (15H, m), 1.21
(6H, s; H-26 and H-27), 0.85 (3H, d, J = 6.5 Hz; H-21), 0.56 ppm (3H, s;
H-18); 13C NMR (101 MHz, CDCl3) δ 145.4 (C), 142.6 (C), 121.5 (CH;
C-7), 112.6 (CH2), 80.8 (C), 71.1 (C, C-25), 70.8 (CH; C-19), 69.3 (CH;
C-3), 56.2 (CH), 56.0 (CH), 45.6 (C; C-13), 44.3 (CH2), 40.4 (CH2), 36.0
(CH2), 35.4 (CH), 34.7 (CH2), 33.7 (CH2), 29.8 (CH2), 29.3 and 29.2
(CH3; C-26 and C-27), 27.4 (CH2), 27.3 (CH2), 23.7 (CH2), 22.2 (CH2),
20.9 (CH2), 18.6 (CH3; C-21), 12.2 ppm (CH3; C-18); IR (film) 3388,
2927, 2871, 1627 cm-1; HRMS (ESI-TOF) m/z calcd for C27H44O2Na
(M+Na)+ 423.3234, found 423.3251.
(8E,20S)-8-Bromomethylene-des-A,B-cholestane (17). A suspension
of (bromomethylene) triphenylphosphonium bromide (1.48 g, 4.40 mmol)
in dry toluene (12 mL) was sonicated at RT for 30 min and then cooled to
-17 ºC. After 15 min, a solution of KOtBu in THF (1.97 mL, 3.36 mmol,
1.7 M) was added dropwise and the yellow mixture was stirred at RT for
1.5 h and at 0 ºC for 30 min. The mixture was cooled to -17 ºC. A 0 ºC
cooled solution of ketone 5d (150 mg, 0.57 mmol) in dry toluene (5 mL)
was added dropwise via cannula. The reaction mixture was stirred at
-17 ºC for 1.5 h and at RT for 2 h. The reaction was quenched with sat
NH4Cl (1 mL). The mixture was filtered through a short pad of silica gel,
washing with EtOAc (20 mL). After concentration in vacuo, the residue
was purified by flash chromatography (SiO2, Ø 2×8 cm, hexanes) to give
17 [137 mg, 0.401 mmol, 71%, Rf = 0.95 (5% EtOAc/hexanes), colorless
oil, [α]D25 = +68.1 (c = 1.1, CHCl3)]. 1H NMR (250 MHz, CDCl3)  5.64 (1H,
s; H-7), 2.96-2.80 (1H, m), 2.08-0.99 (19H, m), 0.97-0.78 (9H, m; H-21,
H-26 and H-27), 0.56 ppm (3H, s; H-18); 13C NMR (63 MHz, CDCl3) 
145.1 (C; C-8), 97.3 (CH; C-7), 55.9 (CH), 55.4 (CH), 45.5 (C; C-13),
39.7 (CH2), 39.4 (CH2), 35.7 (CH2), 35.4 (CH), 31.0 (CH2), 28.0 (CH),
27.3 (CH2), 23.9 (CH2), 22.7 and 22.6 (CH3; C-26 and C-27), 22.6 (CH2),
21.9 (CH2), 18.6 (CH3), 12.0 ppm (CH3); IR (film) 3084, 2933, 1631 cm-1;
HRMS (EI) m/z calcd for C19H33Br (M)+ 340.1766, found 340.1768.
Pd-catalyzed direct formation of 25-hydroxyvitamin D3 (1E). Aq
K3PO4 (0.5 mL, 2 M) and PdCl2(PPh3)2 (1.1 mg, 0.0015 mmol) were
(8E,20S)-8-[(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-il)methylene]-
des-A,B-cholestane (3d). PCy3 (6 mg, 0.02 mmol) and
PdCl2(dppf)ꞏCH2Cl2 (9 mg, 0.01 mmol) were dissolved in dry DMSO
(2 mL). The mixture was stirred at RT for 30 min. A solution of 17
(100 mg, 0.293 mmol) in dry DMSO (3 mL), B2pin2 (189 mg, 0.74 mmol)
and KOAc (73 mg, 0.74 mmol) were successively added. The reaction
mixture was stirred at 80 ºC for 2 h, cooled to RT and then diluted with
H2O (20 mL). The mixture was extracted with EtOAc (3×20 mL). The
combined organic phases were dried, filtered and concentrated. The
residue was purified by flash chromatography (SiO2, Ø 1.5×10 cm, 5%
EtOAc/hexanes) to give 3d [80 mg, 0.206 mmol, 70%, Rf = 0.51 (5%
successively added to
a solution of vinyl boronate 3b (10 mg,
0.0245 mmol) and enol-triflate 2c (8 mg, 0.029 mmol) in THF (0.5 mL).
The mixture was vigorously stirred at RT for 50 min and filtered through a
short pad of silica gel washing with EtOAc (20 mL). After concentration in
vacuo, the residue was purified by HPLC (Luna 5m, SiO2, Ø 1.1x25 cm,
5% iPrOH/hexanes) to give 25-hydroxyvitamin D3 (1E, 5.9 mg,
0.0029 mmol, 60%, white foam)[14d] and 1E' (1.2 mg).
Synthesis of 1A via tandem carbocyclation/Negishi-coupling. A
solution of tBuLi in pentane (410 μL, 0.598 mmol, 1.46 M) was added
dropwise to a -78 ºC cooled solution of vinyl bromide 9 (93 mg,
0.272 mmol) in dry THF (5 mL). The mixture was stirred at -78 ºC for 45
min. A solution of ZnBr2 in dry THF (350 μL, 0.354 mmol, 1 M) was
added. The reaction mixture was stirred at 0 ºC for 1.5 h and cooled to
-40 ºC. After 15 min, a mixture of enol-triflate 2a (70 mg, 0.181 mmol),
Pd(PPh3)4 (16 mg, 0.014 mmol) and Et3N (370 μL, 2.72 mmol) in dry THF
(4 mL) was added dropwise via cannula. The reaction mixture was stirred
at RT for 2.5 h. The reaction was quenched by slow addition of sat NH4Cl
(30 mL). The mixture was extracted with MTBE (3×10 mL). The
combined organic phases were dried, filtered and concentrated. The
residue was dissolved in dry THF (4 mL). A solution of TBAF in THF
(320 μL, 0.32 mmol, 1 M) was added. The mixture was stirred at RT for
12 h. The reaction was quenched by addition of sat NH4Cl (25 mL). The
mixture was extracted with EtOAc (3×10 mL) and the combined organic
phases were dried, filtered and concentrated. The residue was purified
by flash chromatography (SiO2, Ø 2×8 cm, 3% EtOAc/hexanes) to give
and 1A [8 mg, 0.021 mmol, 17%], and 1A’ [40 mg, 0.104 mmol, 58%].
1A: 1H NMR (400 MHz, CDCl3)  6.23 and 6.04 (1H and 1H, each d,
J = 11.2 Hz; H-6 and H-7), 5.05 (1H, s; H-19), 4.83 (1H, d, J = 1.9 Hz;
H-19), 3.92-3.82 (1H, m; H-3), 2.81 (1H, dd, J = 3.7, 11.7 Hz), 2.57 (1H,
EtOAc/hexanes), colorless oil, [α]D = +26.2 (c = 0.2, CHCl3)]. 1H NMR
25
(250 MHz, CDCl3)  4.90 (1H, s; H-7), 3.17 (1H, d, J = 11.7 Hz), 2.1-1.3
(15H, m), 1.26 (12H, s; pinB), 1.19-1.00 (4H, m), 0.86 (6H, d, J = 6.6 Hz;
H-26 and H-27), 0.82 (3H, d, J = 6.2; H-21), 0.53 ppm (3H, s; H-18);
13C NMR (63 MHz, CDCl3)  166.3 (C; C-8), 108.3 (CH; C-7), 82.5 (C;
pinB), 58.0 (CH), 56.4 (CH), 46.2 (C; C-13), 40.3 (CH2), 39.4 (CH2), 35.7
(CH2), 35.4 (CH), 33.2 (CH2), 28.1 (CH), 27.1 (CH2), 24.9 and 24.8 (CH3;
pinB), 24.3 (CH2), 23.9 (CH2), 22.7 and 22.6 (CH3; C-26 and C-27), 22.2
(CH2), 18.6 (CH3), 12.3 ppm (CH3); IR (film) 3421, 2954, 2930, 2871,
1639 cm-1; HRMS (ESI-TOF) m/z calcd for C25H46BO2 (M+H)+ 389.3590,
found 389.3576.
20-Epi-25-hydroxyvitamin D3 (1D). Aq K3PO4 (3.5 mL, 2 M) and
PdCl2(PPh3)2 (9 mg, 0.015 mmol) were successively added to a solution
of vinyl boronate 3e (103 mg, 0.254 mmol) and enol-triflate 2b (117 mg,
0.305 mmol) in THF (5 mL). The mixture was vigorously stirred at RT for
30 min. Then H2O (20 mL) was added and the mixture was extracted with
EtOAc (3×15 mL). The combined organic phases were dried, filtered and
concentrated. The residue was dissolved in dry CH2Cl2 (2 mL) and dry
CH3CN (5 mL). Aq HF (48%, 12 drops) was added. The mixture was
stirred at RT for 5 h and then poured into sat NaHCO3 (40 mL). The
This article is protected by copyright. All rights reserved.

10.1002/chem.201705656
Chemistry - A European Journal
FULL PAPER
dd, J = 3.7, 12.9 Hz), 2.45-2.33 (1H, m), 2.31-2.21 (1H, m), 2.20-2.07 (1H,
m), 2.06-0.96 (21H, m), 0.92 (3H, d, J = 6.4 Hz; H-21), 0.86 (6H,
overlapped d, J = 6.6 Hz; H-26 and H-27), 0.54 ppm (3H, s; H-18);
13C NMR (101 MHz, CDCl3)  144.9 (C), 142.3 (C), 135.2 (C), 122.2 (CH;
C-6), 117.4 (CH; C-7), 112.6 (CH2; C-19), 69.7 (CH; C-3), 56.0 (CH),
56.3 (CH), 46.1 (CH2), 45.9 (C; C-13), 40.5 (CH2), 39.5 (CH2), 36.1 (CH2),
36.1 (CH), 35.4 (CH2), 32.3 (CH2), 29.0 (CH2), 28.0 (CH), 27.6 (CH2),
23.8 (CH2), 23.6 (CH2), 22.8 and 22.5 (CH3; C-26 and C-27), 22.3 (CH2),
18.8 (CH3; C-21), 11.9 ppm (CH3; C-18); IR (KBr) 3407, 2951, 2871,
1716 cm-1; HRMS (ESI-TOF) m/z calcd for C27H45O (M+H)+ 385.3465,
found 385.3467. 1A’: 1H NMR (400 MHz, CDCl3) δ 5.36 (1H, s; H-7),
5.02-4.92 (1H, m; H-6), 4.76 (1H, s; H-6), 3.83-3.68 (1H, m; H-3), 2.93-
2.84 (1H, m), 2.48-2.29 (2H, m), 2.28-2.12 (2H, m), 2.05 (1H, t, J = 2.6
Hz; H-19), 2.03-1.80 (4H, m), 1.72-0.97 (17H, m), 0.93 (3H, d, J = 6.4 Hz;
H-21), 0.88 and 0.86 (3H and 3H, each d, J = 1.9 Hz; H-26 and H-27),
0.56 ppm (3H, s; H-18); 13C NMR (101 MHz, CDCl3) δ 145.4 (C), 142.8
(C), 121.4 (CH; C-7), 112.6 (CH2; C-6), 80.8 (C), 70.8 (CH; C-19), 69.3
(CH; C-3), 56.6 (CH), 56.0 (CH), 45.6 (C; C-13), 40.5 (CH2), 39.5 (CH2),
36.1 (CH2 and CH), 34.7 (CH2), 33.8 (CH2), 29.8 (CH2), 28.0 (CH), 27.6
(CH2), 27.4 (CH2), 23.9 (CH2), 23.7 (CH2), 22.8 and 22.5 (CH3; C-26 and
C-27), 22.3 (CH2), 18.7 (CH3; C-21), 12.0 ppm (CH3; C-18); IR (film)
3312, 2950, 2868, 1628 cm-1; HRMS (EI) m/z calcd for C27H45O (M)+
384.3387, found 384.3381.
[8]
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Procedures and analytical data for 6b, 7b, 8b, 2b, 2c, 12, 13, 14, 16, 5d,
18, 5e, 19, 3e, 1A, 1A’, 1B, 1B’, 1C, are given in the Supporting
Information.
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Acknowledgements
We thank the Spanish Ministry of Science and Innovation (MSI)
and the European Regional Development Fund (project:
SAF2010-15291) and Xunta de Galicia (project GPC2014/001)
R.S. thanks to the Xunta de Galicia for a post-doctoral fellowship
(Axudas posdoutorais, plan I2C, mod B).
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Keywords: vitamin D • design • synthesis • palladium
homogeneus catalysis
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