Chiral Pd-catalyzed trifluoropyruvate-ene reactions with steroidal side chains for late-stage fluoromethyl-functionalization: remarkably high agonist activities of ene products even in low VDR binding affinity

Article abstract of DOI:10.1016/j.tet.2015.05.109

Abstract The highly enantioselective trifluoropyruvate-ene reactions of chiral steroid side chain olefins were achieved by dicationic palladium complexes as chiral Lewis acid catalysts to give steroidal ene-products in high diastereoselectivity. The ene p

Full text of DOI:10.1016/j.tet.2015.05.109

Tetrahedron 71 (2015) 6402e6408
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Tetrahedron
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Chiral Pd-catalyzed trifluoropyruvate-ene reactions with steroidal
side chains for late-stage fluoromethyl-functionalization:
remarkably high agonist activities of ene products even in low VDR
binding affinityq
*
Kumiko Fujita, Junpei Aida, Koichi Mikami
Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology, O-okayama, Meguro-ku, Tokyo 152-8552,
Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 April 2015
Received in revised form 25 May 2015
Accepted 28 May 2015
Available online 9 June 2015
The highly enantioselective trifluoropyruvate-ene reactions of chiral steroid side chain olefins were
achieved by dicationic palladium complexes as chiral Lewis acid catalysts to give steroidal ene-products
in high diastereoselectivity. The ene products exhibited remarkably high agonist activities for human
osteocalcin even in low vitamin D receptor binding affinity for human vitamin D hormone receptor.
Ó 2015 Elsevier Ltd. All rights reserved.
Dedicated to Professor Jiro Tsuji in the honor
of his Tetrahedron Prize
Keywords:
Ene reaction
Palladium catalyst
Trifluoropyruvate
Vitamin D3
Agonist
1. Introduction
Fujiwara-Moritani reaction2 via simultaneous oxidation with per-
benzoic acid3 (Scheme 1)4 and the Claisen rearrangement5 (Scheme
In modern organic synthesis, palladium complexes have been
widely employed as effective catalysts for carbonecarbon bond
formation1 as highlighted in the Nobel prize in Chemistry 2010 on
the ‘Palladium-Catalyzed Cross-Coupling Reactions’ primarily based
on their stable oxidation states (Pd(0) and Pd(II)) via 1) Pd(0) to/from
Pd(II) redox catalytic cycles, 2) Pd(II) to Pd(II) catalytic cycles, and 3)
Pd(II) to/from comparatively unstable Pd(IV) catalytic cycles. The
Pd(II) to Pd(II) catalytic cycles are further classified into 2e1) Pd(II)
Lewis acid catalysis particularly with coordinatively unsaturated
sixteen-electron dicationic Pd(II) complexes in preference to the
neutral Pd(II) complexes and 2e2) Pd(II) to Pd(II) catalysis involving
simultaneous oxidation process of the Pd(0) intermediary state; We
have already reported the first example of asymmetric catalytic in-
termolecular CeH bond activation/CeC bond formation, namely
2)6 catalyzed by the chiral neutral Pd(II) catalysts, Pd(II)-OxNTf and
Pd(II)-DABNTf catalysts, respectively; In contrast to the generally
observed E -> syn diastereoselectivity through the widely accepted
six-membered chair-like Claisen transition state, an intriguing E ->
anti diastereoselectivity was found via the rarely precedented boat-
like transition state (A) along with high enantioselectivity (up to 83%
ee) by the carbophilic Lewis acid Pd(II)-DABNTf catalyst (Scheme 2).
As chiral cationic Pd(II) catalysts, we have also developed dicationic
biphenylphosphine (BIPHEP)- and BINAP-Pd(II) complexes with
strongly anionic ligands such as hexafluoroantimonate (SbF-6) as
q
Taken in part from Master theses: (a) Fujita, K. Master Thesis, Tokyo Institute
Technology 2010; (b) Aida, J. Master Thesis, Tokyo Institute Technology 2010.
* Corresponding author. Tel.: þ81 3 5734 2142; fax: þ81 3 5734 2776; e-mail
address: mikami.k.ab@m.titech.ac.jp (K. Mikami).
Scheme 1. 1st example of asymmetric catalytic intermolecular C-H bond activation/C-
C bond formation.
http://dx.doi.org/10.1016/j.tet.2015.05.109
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

K. Fujita et al. / Tetrahedron 71 (2015) 6402e6408
6403
2. Results and discussion
Initially, we evaluated the transition-metal complexes, which can
be utilized efficiently as a Lewis acid catalyst, in trifluropyruvate-ene
reaction with isobutene (Table 1).19,* Encouraged by the excellent
enantioselectivities, we investigated the dicationic Pd complexes
1aed (5 mol %) prepared in situ from the corresponding dichloride
complex and 2 equiv of AgSbF6 (Table 1). As chiral ligands in the
dicationic palladium catalysts, (S)-BINAP, (S)eMeO-BIPHEP, (S)-tol-
BINAP, and (S)-SEGPHOS exhibited the excellent yields and enantio-
selectivities (entries 1e4). These reactions proceeded smoothly even
under solvent-free conditions to provide the corresponding
trifluropyruvate-ene products 3 within 10 min (entries 1e4). When
the cationic box-copper catalysts, one of the most efficient Lewis
acids,20 were employed, the solvent-free conditions were not ap-
propriate regardless of the counter anions widely screened (entries
5e6). Although the copper catalysis (0.01 mol %) was facilitated in
Et2O and led to the excellent results (99% yield, 99% ee), the catalytic
activity was extremely lower even in 0.1 mol % catalyst loading
(14e24 h) than that of the palladium catalysts (entries 8 vs. 1e4:
10 min, 0.01 mol %). Unfortunately, the iron catalyst decreased both in
the catalytic activity and enantioselctivity (entry 9). As a result, we
concluded that the Pd catalyst 1a in entry 1 was the best catalyst in
trifluoropyruvate-ene reaction, due to higher performance of cata-
lytic activity and lower-cost of the chiral ligands.19
Scheme 2. Pd(II)-DABNTf catalyzed asymmetric Claisen rearrangent via boat transi-
tion state.
effective chiral Lewis acid catalysts for the carbonyl-ene7 and Frie-
deleCrafts8 reactions with 1,2-dicarbonyl chelate substrates such as
glyoxylate and trifluoropyruvate.
Why are these Pd(II) complexes so effective as Lewis acidic
catalysts? Mellor and Maley orders of stability of the first and
second transition series of divalent metals with bidentate chelate
substrates such as salicylaldehyde, glycine, 8-hydroxyquinoline,
and ethylenediamine are9 (Values in parenthese () are Allred-
Rochow electronegativity scale. Values in parenthese [] are tetra-
hedral or square planar Pauling covalent radii.): Pd (1.35) [1.32] >
Cu (1.75) [1.32] > Ni (1.75) [1.39] > Co (1.70) [1.32] > Zn (1.66) [1.31]
> Fe (1.64) > Mn (1.60) > Mg (1.23) [1.40]. Pd(II) complexes are
therefore the most stable and more Lewis acidic complexes than
Cu(II) complexes, with bidentate chelate substrates positioning
neighbouring functionalites. Although Lewis acidities of metal
complexes are dependent on ligands associated therewith.
Organofluorine compounds have attracted current attention in
the fields of pharmaceuticals, agrochemicals, and organic materials
by virtue of their unique chemical, biological, and physical proper-
ties.10 In drug design, trifluoromethyl-functionalities are logically
employed, because trifluoromethyl groups can render higher sta-
bility of CeF bond and neighboring chemical bonds againstoxidative
metabolism, and can simultaneously increase lipophilicity and po-
larity in drug candidates.11 Therefore, a variety of synthetic methods
to introduce trifluoromethyl-functionalities into organic molecules
have been reported to afford the trifluoromethyl-substituted ana-
Table 1
Trifluoropyruvate-ene reactions catalyzed by various chiral metal complexes
Entry
Cat*
X
Conditions
Conv (%)
ee (%)a
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1f
1f
1g
0.01
Neat, ꢀ20 ꢁC, 10 min
Neat, ꢀ20 ꢁC, 10 min
Neat, ꢀ20 ꢁC, 10 min
Neat, ꢀ20 ꢁC, 10 min
Neat, ꢀ20 ꢁC, 24 h
Neat, ꢀ20 ꢁC, 24 h
Et2O, ꢀ20 ꢁC, 14 h
Et2O, ꢀ20 ꢁC, 14 h
CH2Cl2, ꢀ20 ꢁC, 20 h
94
98
96
90
74
69
64
99
65
96
98
91
96
14
41
72
99
12
0.01
0.01
0.01
0.01
0.01
0.01
0.1
10
a
logs, even in optically active forms. Particularly, a-trifluoromethyl-
Enantiopurity was determined by chiral HPLC anlysis.
substituted tertiary alcohols synthesized via the catalytic asym-
metric carbonecarbon bond formation have attracted current in-
terest due to the unique biological activities of drug candidates such
as trifluoromethylated glucocorticoid receptor agonists.12
Fluorinated steroids,13 vitamin D analogs,14 in particular have
attracted much attention in their synthesis, biochemistry and bi-
ological activities. 25-Bis(trifluoromethyl) vitamin D analog is now
in market as ‘Hornel’, falecalcitriol, namely 26,26,26,27,27,27-
hexafluoro analog of the active form of 1,25-dihydroxy vitamin D3
against further oxidative metabolism at 26 and/or 27, and with in-
creased lipophilicity.15 Therefore, synthetic methods to introduce
single trifluoromethyl functionality into biologically active metab-
olites of 1,25-dihydroxy vitamin D3 in asymmetric manner have
been required in order to further examine their biological activities.
Trifluoromethyl analogs of active metabolites as tertiary 25-alcohol
derivatives, such as 26,23S-lactone and its’ intermediates16 bearing
the quaternary carbon centers17 can be synthesized via the catalytic
asymmetric carbonyl-ene reactions with trifluoropyruvate (‘tri-
fluoropyruvate-ene reactions’).7d,e
We applied the highly enantioselective trifluoropyruvate-ene
reactions catalyzed by the dicationic Pd complexes 1a to steroidal
olefins for late-stage trifluoromethyl-functionalization (Scheme 3).
The steroidal olefin 4 could be employed for the ene reactions in the
catalysis of the Pd complexes, (R)-1a and (S)-1a to afford (25S)-5
and (25R)-5 as single diastereomers in 81% and 76% yields, re-
spectively, although the relatively high catalyst loading (10 mol %)
was employed for smooth reactions; The absolute stereochemistry
for vitamin D analogs follows the general rule: (R)- and (S)-1a af-
ford (S)- and (R)-ene products.
Herein, we report the highly enantioselective trifluoropyruvate-
ene reactions as one of the most atom economical18 and catalytic
asymmetric carbonecarbon bond formations, catalyzed by dica-
tionic palladium complexes as the most effective chiral Lewis acid
catalysts to provide trifluoromethyl analogs of 26,23S-lactone and
synthetic intermediates.
Next, we investigated as to whether the direct lactonization of
steroidal ene products proceeds or not under the dicationic

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K. Fujita et al. / Tetrahedron 71 (2015) 6402e6408
Scheme 3. (R)- and (S)-BINAP-Pd catalyzed trifluropyruvate-ene reactions with ste-
roidal olefins.
palladium catalysis (Scheme 4). In view of the sequencial ene and
lactonization reactions by the dicationic Pd catalysts, the direct
lactonization of the ene-product 3 obtained from isobutene was first
examined to provide the corresponding lactone 6 in 45% isolated
yield (Eq.1). Furthermore, examination of tandem trifluropyruvate-
ene and lactonization sequence starting from isobutene gave the
lactone product 6 in 38% isolated yield (Eq. 2). Unfortunately how-
ever, the steroid ene product (25S)-5 was not able to transform to
lactone 7 by (S)-1a under various reaction conditions (Eq. 3).
Scheme 5. Lactonization and A-ring attachment.
Pd-catalyzed trifluoropyruvate-ene reaction is efficiently applicable
for late-stage fluoromethyl-functionalization. As expected, (S)-1a
under the same reaction conditions gave the opposite single di-
astereomer (25R)-14 (Eq. 2).
Scheme 4. Sequencial ene and lactonization reactions.
Therefore, iodolactone (22S,23R,25S)-9 was synthesized via the
hydrolysis of ester (25S)-5 followed by the iodolactonization with I2
and 2,4,6-colidine.21 The trifluoromethyl analog 9 of natural-type
lactone was obtained in 86% yield as virtually single di-
astereomeric form (>99%) via the favorable six-membered transi-
tion state (B) with the sterically demanding trifluoromethyl group
in equatorial orientation, by decreasing the amount of colidine up
to 1.5 equiv in dichloromethane rather than acetonitrile at ꢀ30 ꢁ
C
(Scheme 5). The reduction of (22S,23R,25S)-9 using nBu3SnH and
AIBN led to the lactone (23S,25S)-7 in 89% yield. The desilylation
and oxidation of the silyl ether 7 gave ketone (23S,25S)-10 in 92%
yield, then bromo-olefin (23S,25S)-11 was obtained by the Wittig
olefination reaction with lithium hexamethyldisilazide. Finally, the
steroidal C,D-ring with bromo-olefin 11 underwent the Pd-
catalyzed Trost A-ring attachment22 with the chiral A-ring por-
tion of enyne to afford the trifluoromethyl analog 12 of calcitriol
lactone in 56% isolated yield.
Significantly, steroid olefin 13 even with labile B-ring triene
portion could be employed for our trifluoropyruvate-ene reaction
in the presence of (R)-1a under solvent-free conditions, providing
the desired product (25S)-14 in 43% isolated yield as a single di-
astereomer (Scheme 6, Eq. 1). The result clearly indicates that our
Scheme 6. Solvent-free late-stage trifluoropyruvate-ene reactions.

K. Fujita et al. / Tetrahedron 71 (2015) 6402e6408
6405
The steroidal trifluoropyruvate-ene products along with the
further transformed trifluoromethyl analogs of carcitriol lactone
were subjected to the biological tests generally executed for vita-
min D analogs such as agonist activities for human osteocalcin and
VDR (vitamin D receptor) binding affinity for human vitamin D
hormone receptor. VDR Binding affinity and agonist (EC50 (nM))
activity thus obtained are tabularized in Table 2.23 Interestingly, the
steroidal ene products themselves, namely the unsaturated tri-
fluoromethyl analogs of not only (25S)-methyl ester but also (25R)-
methyl ester show significantly high agonist activity (ten times and
two hundred ten times active, respectively) even with only half
level of binding affinity with VDR (1/1.8 and 1/1.6, respectively).
Particularly, the (25R)-D22(23)-methyl ester show remarkable high
agonist activity (EC50 0.003 nM) with two order of magnitude than
the parent 1,25-dihydroxy vitamin D3 (EC50 0.638 nM).
(HPLC) was conducted on JASCO PU-980, LG-980-02, DG-980-50,
MD-2010, and CO-966 instrument equipped with model UV-975
spectrometers as an ultra violet light. Dichloromethane, toluene,
and diethyl ether were purchased from Kanto Chemical Co., Inc.
Ethyl trifluoropyruvate was provided from Central Glass Co., Ltd.
Silver hexafluoroantimonate was purchased from Aldrich.
PdCl2[(S)-BINAP] was synthesized according to the reported
procedure.
4.2. General procedure for catalytic asymmetric ene reaction
with trifluoropyruvate (Table 1, entry 1)
To a solution of PdCl2[(S)-BINAP] (3.2 mg, 0.004 mmol) and ethyl
trifluoropyruvate 2a (5.3 ml, 40 mmol) was added AgSbF6 (3.0 mg,
0.0088 mmol) at room temperature under argon atmosphere. After
stirring for 30 min, isobutene (ca. 0.2 mmol) was added at ꢀ78 ꢁC.
The reaction mixture was stirred at ꢀ20 ꢁC for 10 min, and then
directly loaded onto a short silica-gel column (hexane/AcOEt¼1/1)
to remove the catalyst. Purification by silica-gel chromatography
(hexane/AcOEt¼9/1) gave alcohol product 3.24 The enantiomeric
excess was determined by chiral HPLC analysis.
Table 2
Agonist activity and VDR binding affinity of trifluoropyruvate-ene products
VDR binding affinity
Agonist EC50 (nM)26
1
0.638e0.836
4.2.1. 4-Methyl-2-hydroxy-2-trifluoromethylpentano-4-lactone
6. To a solution of PdCl2[(S)-BINAP] (32 mg, 0.04 mmol) in CH2Cl2
(4 ml) was added AgSbF6 (30.2 mg, 0.088 mmol) at room temper-
ature. After stirring for 30 min, ethyl trifluoropyruvate 2a (68 mg,
0.4 mmol) and isobutene (112 mg, 2.0 mmol) were added to the
mixture at ꢀ30 ꢁC. After the reaction mixture was stirred at ꢀ15 ꢁC
for 4 h, warmed up to 80 ꢁC, and stirred for 24 h to give 38% of 6
after silica-gel chromatography.
1/29
702
1/1.8
1/1.6
0.066
0.003
1H NMR (CDCl3, 300 MHz)
d 1.54 (s, 3H), 1.59 (s, 3H), 2.38 (d,
J¼17.7 Hz, 1H), 2.51 (d, J¼5.0 Hz, 1H), 3.75 (s, 1H); 13C NMR (CDCl3,
75 MHz)
d
28.7, 29.2, 42.4, 77.1, 83.6, 122.9 (q, 1JC-F¼285.3 Hz), 171.1;
19F NMR (CDCl3, 282 MHz)
d
ꢀ80.5 (s); HRMS (APCI) Calcd for
C7H8F3O3 [MꢀH]ꢀ 197.0426, Found: 197.0427.
4.2.2. (22E,8S,25S)-Des-A,B-8-(tert-butyldimethylsiloxy)-25-
hydroxy-27,27,27-trifluoro-26-ethoxycarbonyl-22-cholestene (25S)-
5. To a solution of (R)-BINAP-PdCl2 (8.0 mg, 0.01 mmol) in CH2Cl2
(1 ml) was added AgSbF6 (7.6 mg, 0.022 mmol) at room temper-
ature. After stirring for 30 min, ethyl trifluoropyruvate 2a (34 mg,
0.2 mmol) and 4 (33.7 mg, 0.1 mmol) were added to the mixture at
ꢀ20 ꢁC. After the reaction mixture was stirred at that temperature
3. Conclusions
In summary, we have succeeded in the highly enantioselective
trifluoropyruvate-ene reactions with steroid side chain olefins by
virtue of the most stable and Lewis acidic Pd2þ catalysts amongst
the first and second transition series of divalent metals with
bidentate chelate substrates such as trifluoropyruvate. The re-
markably high agonist activities of the ene products than the
modified trifluoromethyl analog of e.g., carcitriol lactone. De-
velopment of novel and practical reactions to provide optically
for 3 h, triethylamine (25 ml) was added at that temperature. The
solution was then quenched with satd NaHCO3 and extracted
three times with Et2O. The combined organic layer was washed
with brine, dried over MgSO4 and evaporated under reduced
pressure. The resultant residue was purified by silica-gel chro-
matography (hexane/Et2O¼20/1, after hexane only) gave 41 mg
(81%) of (25S)-5.
active a-fluoromethyl-substituted tertiary alcohol drugs and their
analogs with quaternary carbon centers is on-going in our labora-
tory in this context of late-stage fluoromethyl-functinalization.
1H NMR (CDCl3, 300 MHz)
d
ꢀ0.008 (s, 3H), ꢀ0.006 (s, 3H), 0.89
4. Experimental
4.1. General
(s, 9H), 0.91 (s, 3H), 0.95 (d, J¼6.6 Hz, 3H), 1.04e2.08 (m, 16H), 2.58
(t, J¼7.2 Hz, 2H), 3.75 (s, 1H), 3.99 (d, J¼2.1 Hz, 1H), 4.31 (t, J¼7.2 Hz,
2H), 5.20 (td, J¼7.2, 15.3 Hz, 1H), 5.43 (dd, J¼8.7, 15.3 Hz, 1H); 13C
NMR (CDCl3, 75 MHz)
d
ꢀ5.2, ꢀ4.9, 13.9, 17.6, 18.0, 20.4, 23.0, 25.8,
2
1H, 13C, and 19F NMR spectra were measured on Bruker AV300M
(300 MHz) spectrometers. Chemical shifts of 1H NMR were
expressed in parts per million relative to the singlet (
CDCl3. Chemical shifts of 13C NMR were expressed in parts per
million relative to the central line of the triplet (
¼77.0) for CDCl3.
Chemical shifts of 19F NMR were expressed in parts per million
relative to the singlet (
internal standard. Optical rotations were measured on a JASCO P-
1020. Mass spectra were measured on a JEOL JMS-T100CS (Accu-
TOF) spectrometer. IR spectra were measured on a JASCO FT/IR-
4200 spectrometer. High performance liquid chromatography
27.6, 34.4, 35.0, 39.8, 40.6, 42.1, 53.1, 56.1, 63.5, 69.4, 77.8 (q, JC-
¼28.5 Hz), 117.6, 123.4 (q, JC-F¼284.3 Hz), 143.7, 169.4; 19F NMR
1
F
d
¼7.26) for
(CDCl3, 282 MHz)
d
ꢀ78.4 (s); IR (neat, cmꢀ1) 3505, 2949, 2861,
1741, 1307, 1242, 1186, 1019, 836; HRMS (ESI-TOF) Calcd for
d
C
26H45F3O4Na1Si1 [MþNa]þ 529.2937, Found: 529.2932; [
a
]
26þ31.8
D
(c¼0.12 in CHCl3).
d
¼ꢀ63.24) for benzotrifluoride (BTF) as an
4.2.3. (22E,8S,25S)-Des-A,B-8-(tert-butyldimethylsiloxy)-25- hydroxy-
27,27,27-trifluoro-26-cholestenoic acid (25S)-8. To solution of
a
(25S)-5 (152 mg, 0.3 mmol) in a MeOH/H2O (7:3) mixture (2.5 ml),
0.5N KOH (1.81 ml, 0.91 mmol) was added. The reaction mixture

6406
K. Fujita et al. / Tetrahedron 71 (2015) 6402e6408
was stirred at 65 ꢁC for 7 h, and MeOH was removed in vacuo.
1N HCl was added until pH 1e2 was reached, and the reaction
mixture was extract with EtOAc (3ꢂ20 ml), dried over Na2SO4,
and evaporated under reduced pressure to give 136 mg (95%) of
(25R)-8.
purified by silica-gel chromatography to give 76.5 mg (92%) of
(23S,25S)-100.
1H NMR (CDCl3, 300 MHz)
d
0.94 (s, 3H), 0.98 (d, J¼6.6 Hz,
3H), 1.05e1.90 (m, 15H), 2.00 (d, J¼12.9 Hz, 1H), 2.11 (dd, J¼9.3,
14.1 Hz, 1H), 2.85 (dd, J¼6.3, 14.1 Hz, 1H), 4.08 (s, 1H), 4.47 (br s,
1H NMR (CDCl3, 300M Hz)
d
ꢀ0.003 (s, 3H), ꢀ0.012 (s, 3H), 0.89
1H), 4.63 (d, J¼8.1 Hz, 1H); 13C NMR (CDCl3, 75 MHz)
d 13.5, 17.3,
(s, 9H), 0.92 (s, 3H), 0.95 (d, J¼6.6 Hz, 3H) 1.06e2.10 (m, 15H), 2.64
(m, 2H), 4.00 (s, 1H), 5.24 (td, J¼7.2, 15.3 Hz, 1H), 5.51 (dd, J¼8.7,
18.4, 22.4, 27.2, 32.5, 33.4, 37.7, 40.4, 42.0, 42.8, 52.5, 56.8, 69.3,
75.8, 76.0 (q, JC-F¼31.5 Hz), 123.3 (q, JC-F¼283.4 Hz), 171.6; 19F
2
1
15.3 Hz, 1H); 13C NMR (CDCl3, 75 MHz)
d
ꢀ5.2, ꢀ4.9, 13.9, 17.6, 18.0,
NMR (CDCl3, 282 MHz)
d
ꢀ80.1 (s).
20.3, 23.0, 25.8, 27.7, 34.4, 35.2, 39.9, 40.6, 42.1, 53.1, 56.0, 69.4, 77.9
IR (neat, cmꢀ1) 3450, 2932, 1782, 1457, 1193; HRMS (APCI) Calcd
2
25
(q, JC-F¼28.5 Hz), 116.9, 123.1 (q, 1JC-F¼284.5 Hz), 144.9, 173.4; 19F
for C18H26F3O4 [MꢀH]ꢀ 363.1783, Found: 367.1776; [
(c¼0.11 in CHCl3).
a]
þ35.5
D
NMR (CDCl3, 282 MHz)
1727, 1248, 1181.
d
ꢀ78.1 (s); IR (neat, cmꢀ1) 3412, 2938, 2855,
HRMS (APCI) Calcd for C24H41F3O4 Na 1Si1 [MþNa]þ 501.2624,
4.2.7. (23S,25S)-Des-A,B-25-hydroxy-25-trifluoromethyl-cholestane-
8-one-26,23-lactone (23S,25S)-10. To a solution of (23S,25S)-100
(76.5 mg, 0.21 mmol) in CH2Cl2 (4.2 ml) was added tetra-n-pro-
pylammonium perruthenate (7.4 mg, 0.021 mmol), 4-
methylmorpholine N-oxide (98.4 mg, 0.84 mmol) and powdered
molecular sieves 4A at 0 ꢁC. The mixture was stirred for 2 h at the
temperature and loaded on silica-gel chromatography to give
65.4 mg (86%) of (23S,25S)-10.
Found: 501.2615; [
a
]
27þ28.6 (c¼0.21 in CHCl3).
D
4.2.4. (8S,22S,23S,25S)-Des-A,B-8-(tert-butyldimethylsiloxy)-22-
iodo-25-hydroxy-25-trifluoromethylcholestane-26,23-lactone
(22S,23R,25S)-9. A solution of (25S)-8 (23.9 mg, 0.05 mmol) and
2,4,6-collidine (9.9 ml, 0.075 mmol) in Et2O (3.6 ml) was stirred at
room temperature for 30 min, the mixture was cooled to ꢀ30 ꢁC,
and then I2 (38.1 mg, 0.15 mmol) was added. After 24 h, the mixture
was diluted with CHCl3, washed with aq Na2S2O3 and brine, dried
over Na2SO4, and evaporated under reduced pressure. The resultant
residue was purified by silica-gel chromatography to give 26.0 mg
(86%) of (22S,23S,25S)-9.
1H NMR (CDCl3, 300 MHz)
d
0.64 (s, 3H), 1.03 (d, J¼6.3 Hz, 3H),
1.24e2.32 (m, 15H), 2.44 (dd, J¼7.5, 11.4 Hz, 1H), 2.86 (dd, J¼6.3,
14.4 Hz, 1H), 4.29 (s, 1H), 4.59e4.67 (m, 1H); 13C NMR (CDCl3,
75 MHz) d 12.5, 18.5, 19.1, 23.9, 27.4, 32.6, 37.7, 38.9, 40.8, 42.7, 49.9,
2
1
56.7, 61.8, 75.5, 75.9 (q, JC-F¼31.6 Hz), 123.1 (q, JC-F¼288.8 Hz),
1H NMR (CDCl3, 300 MHz)
d
0.00 (s, 3H), 0.01 (s, 3H), 0.89 (s, 9H),
171.2, 212.3; 19F NMR (CDCl3, 282 MHz)
d
ꢀ80.1 (s); IR (neat, cmꢀ1
)
0.94 (d, J¼6.0 Hz, 3H), 1.01 (s, 3H), 1.12e1.95 (m, 14H), 2.28 (dd,
J¼9.0, 14.4 Hz, 1H), 3.18 (dd, J¼6.0, 14.4 Hz, 1H), 4.01 (d, J¼2.4 Hz,
1H), 4.10 (dd, J¼1.5, 10.5 Hz, 1H), 4.75 (ddd, J¼6.0, 9.0 10.5 Hz, 1H);
3439, 2945, 2850, 1778, 1694, 1406, 1150; HRMS (APCI) Calcd for
C
18H24F3O4 [MꢀH]ꢀ 361.1627, Found: 361.1313; [
a
]
D
26 þ11.9 (c¼0.17
in CHCl3).
13C NMR (CDCl3, 75 MHz)
d
ꢀ5.2, ꢀ4.9, 1.0, 15.0, 16.1, 17.6, 18.0, 22.8,
25,8, 26.3, 34.3, 36.6, 39.3, 40.7, 42.2, 48.9, 52.9, 56.3, 69.3, 76.2 (q,
4.2.8. (23S,25S)-Des-A,B-8-bromomethylidene-25-hydroxy-25-
trifluoromethylcholestane-26,23-lactone (23S,25S)-11. To a solution
of bromomethyltriphenylphosphonium bromide (393 mg,
0.9 mmol) in toluene (2.4 ml) was added lithium hexamethyldisi-
lazane (151 mg, 0.9 mmol) at ꢀ78 ꢁC, and the mixture was warmed
up to 0 ꢁC and stirred for 10 min. After cooling to ꢀ78 ꢁC, to the
resulting solution was added (23S,25S)-10 (65.4 mg, 0.18 mmol) in
toluene (1.2 ml) dropwise, and the mixture was stirred at ꢀ30 ꢁC for
2 h. To the reaction mixture was added satd NH4Cl. The resulting
mixture was warmed up to room temperature and extracted with
AcOEt. The organic layer was washed with brine, dried over MgSO4,
filtered and concentrated under reduced pressure. The resultant
residue was purified by silica-gel chromatography to give 6.8 mg
(0.016 mmol, 18%) of (23S,25S)-11.
2JC-F¼31.8 Hz), 123.0 (q, JC-F¼283.4 Hz), 170.9; 19F NMR (CDCl3,
1
282 MHz)
1212.
d
ꢀ80.2 (s); IR (neat, cmꢀ1) 3416, 2949, 2855, 1770, 1460,
HRMS (APCI) Calcd for
C
24H41F3I1O4Si1 [MþH]þ 605.1771,
27
Found: 605.1756; [
a]
ꢀ0.89 (c¼0.11 in CHCl3).
D
4.2.5. (8S,23S,25S)-Des-A,B-8-(tert-butyldimethylsiloxy)-25-
hydroxy-25-trifluoromethylcholestane-26,23-lactone (22S,25S)-7. To
a solution of (22S,23S,25S)-9 (125 mg, 0.21 mmol) in benzene
(7.9 ml) was added n-BuSnH (110 ml, 0.42 mmol) and AIBN (6.9 mg,
0.042 mmol). The reaction mixture was stirred for 3 min at 65 ꢁC,
and diluted with Et2O. The reaction mixture was washed with
brine, and dried over MgSO4 and evaporated under reduced pres-
sure. The resultant residue was purified by silica-gel chromatog-
raphy to give 100 mg (89%) of (23S,25S)-7.
1H NMR (CDCl3, 300 MHz)
d
0.60 (s, 3H), 1.03 (d, J¼6.6 Hz, 3H),
1.19e2.05 (m, 15H), 2.13 (ddd, J¼1.2, 9.3, 14.4 Hz, 1H), 2.88 (dd,
1H NMR (CDCl3, 300 MHz)
d
ꢀ0.002 (s, 3H), 0.01 (s, 3H), 0.89 (s,
J¼6.3, 14.4 Hz, 1H), 4.60e4.69 (m, 1H), 5.66 (s, 1H), 5.95 (s, 1H);
9H), 0.94 (s, 3H), 0.98 (d, J¼6.6 Hz, 3H), 1.13e1.89 (m, 14H), 1.97 (td,
19F NMR (CDCl3, 282 MHz)
d
ꢀ80.2 (s); IR (neat, cmꢀ1) 3433,
J¼2.7, 12.3 Hz, 1H), 2.12 (dd, J¼9.3, 14.4 Hz, 1H), 2.86 (dd, J¼6.0,
3087, 2938, 2860, 1782, 1718, 1172; HRMS (APCI) Calcd for
25
14.4 Hz,1H), 3.43 (s,1H), 4.00 (d, J¼2.4 Hz,1H), 4.60e4.69 (m,1H); 13
C
C
19H25Br1F3O3 [MꢀH]ꢀ 439.0919, Found: 439.0939; [
a
]
þ74.3
D
NMR (CDCl3, 75 MHz)
d
ꢀ5.2, ꢀ4.9,13.7,17.6,18.0,18.5, 23.0, 25.8 (2C),
(c¼0.11 in CHCl3).
27.3, 32.5, 34.4, 37.7, 40.7, 42.3, 42.8, 53.1, 69.3, 76.1 (q, 2JC-F¼31.5 Hz),
123.3 (q, 1JC-F¼283.4 Hz), 171.5; 19F NMR (CDCl3, 282 MHz)
d
ꢀ80.2
4.2.9. 25-Trifluoromethyl-1a,25-dihydroxy-26,23-carcitriol lactone
(23S,25S)-12. To a solution of A-ring precursor enyne (4.0 mg,
0.01 mmol) and (23S,25S)-11 (3.2 mg, 0.0073 mmol) in toluene/
(s); IR (neat, cmꢀ1) 3438, 2943, 2861, 1787, 1466, 1202, 1162, 834;
HRMS (APCI) Calcd for C24H40F3O4Si1 [MꢀH]ꢀ 477.2645, Found:
477.2656; [
a
]
26 þ24.6 (c¼0.18 in CHCl3).
NEt3 (730
m
l, toluene/NEt3¼1: 3) were added Pd(PPh3)4 (2.5 mg,
D
0.002 mmol), and the mixture was stirred at 110 ꢁC for 4 h,
according to the reported procedure.20 The mixture was filtered
through a silica-gel pad, and concentrated. The residue was sub-
jected to silica-gel preparative TLC to give crude mixture of the
protected derivative (3.0 mg, 56%). To the crude mixture dissolved
4.2.6. (8S,23S,25S)-Des-A,B-8,25-dihydroxy-25-trifluoro-methyl-
cholestane-26,23-lactone (23S,25S)-100. To a solution of (23S,25S)-7
(100 mg, 0.21 mmol) in MeOH (4.2 ml) was added p-TsOH (47.0 mg,
0.27 mmol) and the resulting mixture was stirred for 12 h at 65 ꢁC.
The reaction mixture was diluted with AcOEt and satd NaHCO3 was
added. The resulting mixture was extracted with AcOEt. The or-
ganic layer was washed with brine, dried over MgSO4, filtered and
concentrated under reduced pressure. The resultant residue was
in THF (273 ml), was added HF/Py (70%,116 m
l) at 0 ꢁC, and stirred for
2 h. To the mixture was added satd NH4Cl. The resulting mixture
was warmed up to room temperature and extracted with AcOEt,
dried over MgSO4, filtered and concentrated under reduced

K. Fujita et al. / Tetrahedron 71 (2015) 6402e6408
6407
pressure. The resultant residue was purified by silica-gel chroma-
tography to give 0.7 mg (34%) of (23S,25S)-12.
purified by silica-gel chromatography to give (25S)-140 (1.4 mg,
62%).
1H NMR (CDCl3, 300 MHz)
d
0.58 (s, 3H), 1.02 (d, J¼6.6 Hz, 3H),
1H NMR (CDCl3, 300 MHz)
d 0.58 (s, 3H), 0.83e0.90 (m, 4H), 0.99
1.23e1.75þ1.83e2.10 (m, 22H), 2.28e2.35 (m, 1H), 2.60 (dd, J¼0.9,
11.1 Hz, 1H), 2.83e2.86 (m, 1H), 4.22e4.24 (m, 1H), 4.43e4.44 (m,
1H), 5.00 (s, 1H), 5.34 (s, 1H), 6.00 (d, J¼11.4 Hz, 1H), 6.37 (d,
(d, J¼6.3Hz, 3H), 1.25e2.07 (m, 13H), 2.27e2.34 (m, 3H), 3.05 (d,
J¼7.5 Hz, 1H), 3.76 (s, 1H), 3.86 (s, 3H), 4.20e4.23 (m, 1H),
4.40e4.42 (m, 1H), 5.00 (s, 1H), 5.21e5.28 (m, 1H), 5.32 (s, 1H), 5.45
(dd, J¼8.7, 15.6 Hz, 1H), 6.01 (d, J¼10.8 Hz, 1H), 6.37 (d, J¼11.4 Hz,
J¼11.7 Hz, 1H); 19F NMR (CDCl3, 282 MHz)
ꢀ80.2 (s); HRMS (APCI)
25
d
Calcd for C27H36F3O5 [MꢀH]ꢀ 497.2515, Found: 497.2535; [
a
]
1H); 19F NMR (CDCl3, 282 MHz)
d
ꢀ78.3 (s).
D
þ26.5 (c¼0.04 in CHCl3).
4.2.14. (25R)-Trifluoromethyl–22-dehydrocarcitriol (25R)-140. (25R)-
140 was synthesized in 56% yield according to a similar manner to
that of (25S)-140.
4.2.10. Steroid olefin 13. To
a
solution of methyltriphenyl-
phosphonium bromide (61 mg, 0.17 mmol) in THF (0.9 ml) was
added n-BuLi (0.11 ml of a 1.35 M solution in hexane, 0.15 mmol) at
1H NMR (CDCl3, 300 MHz)
d 0.54 (s, 3H), 0.83e0.88 (m, 4H), 1.00
0
ꢁC. After the mixture was stirred for 1 h, a solution of calcitroic
(d, J¼6.0 Hz, 3H), 1.23e2.06 (m, 13H), 2.27e2.34 (m, 1H), 2.58e2.63
(m, 2H), 2.83 (d, J¼15.3Hz, 1H), 3.74 (s, 1H), 3.88 (s, 3H), 4.20e4.22
(m, 1H), 4.40e4.43 (m, 1H), 4.99 (s, 1H), 5.23 (dd, J¼7.8, 15.9 Hz,1H),
5.32 (s, 1H), 5.46 (dd, J¼8.7, 15.6 Hz,1H), 6.01 (d, J¼11.4 Hz,1H), 6.37
aldehyde (29.4 mg, 0.05 mmol) in THF (0.2 ml) was added slowly.
The resulting mixture was stirred at 0 ꢁC for 30 min and quenched by
satd NH4Cl. The mixture was extracted with Et2O, washed with
brine, dried over Na2SO4, and evaporated under reduced pressure.
The resultant residue was purified by silica-gel chromatography to
give 25.2 mg (86%) of 13.
(d, J¼11.1 Hz, 1H); 19F NMR (CDCl3, 282 MHz)
d
ꢀ78.4 (s).
Acknowledgements
1H NMR (CDCl3, 300 MHz)
d 0.060e0.064 (m, 12H), 0.54 (s, 3H),
0.85e0.88 (m, 18H), 0.93 (d, J¼6.6 Hz, 3H), 1.26e2.27 (m, 17H), 2.46
(dd, J¼3.9, 13.2Hz, 1H), 2.82 (d, J¼10.5 Hz, 1H), 4.15e4.23 (m, 1H),
4.36e4.39 (m, 1H), 4.86 (d, J¼2.4Hz, 1H), 4.97 (s, 1H), 5.01 (d,
J¼3.3 Hz, 1H), 5.18 (d, J¼1.5 Hz, 1H), 5.71e5.85 (m, 1H), 6.02 (d,
J¼11.4 Hz, 1H), 6.24 (d, J¼11.1 Hz, 1H); HRMS (APCI) Calcd for
This research was supported by Japan Science and Technology
Agency (JST) (ACT-C: Creation of Advanced Catalytic Trans-
formation for the Sustainable Manufacturing at Low Energy, Low
Environmental Load). We are grateful to Prof. K. Nagasawa of Tokyo
University of Agriculture and Technology and Prof. S. Hatakeyama
of Nagasaki University for useful discussion and generous gift of
steroidal starting materials. We are grateful toTeijin Pharma Ltd. for
the biological tests executed for the trifluoromethyl analogues of
vitamin D metabolites. We thank Central Glass Co., Ltd. for the gift
of ethyl trifluoropyruvate. We also thank Takasago International Co.
for providing (S)- and (R)-BINAP, (S)-tol-BINAP, and (S)-SEGPHOS.
C
36H65O2Si2 [MþH]þ 585.4523, Found: 585.4544.
4.2.11. (25S)-Trifluoromethyl-1a,3b-bis(tert-butyldimethyl-silyloxy)-
22-dehydrocarcitriol methyl ester (25S)-14. To a solution of (R)-
BINAP-PdCl2 (9.6 mg, 0.012 mmol) in CH2Cl2 (1 ml) was added
AgSbF6 (8.2 mg, 0.024 mmol) at room temperature. After stirring
for 30 min, the solution was added to a mixture of methyl tri-
fluoropyruvate 2b (337 ml, 3 mmol) and 13 (17.6 mg, 0.03 mmol) at
References and notes
ꢀ40 ꢁC for 2.5 h. The solution was quenched by satd NaHCO3 and
extracted three times with Et2O. The combined organic layer was
washed with brine, dried over MgSO4 and evaporated under re-
duced pressure. The resultant residue was purified by silica-gel
chromatography to give 5.1 mg (43%) of (25S)-14.
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1H NMR (CDCl3, 300 MHz)
d 0.04e0.06 (m, 12H), 0.53 (s, 3H),
0.87e0.88 (m,18H), 0.98 (d, J¼6.6 Hz, 3H),1.23e1.33þ1.41e2.05 (m,
13H), 2.17e2.27 (m, 2H), 2.45 (dd, J¼3.6, 9.9 Hz, 1H), 2.57e2.62 (m,
2H), 2.83 (d, J¼10.8Hz, 1H), 3.73 (s, 1H), 3.88 (s, 3H), 4.17e4.22 (m,
1H), 4.36e4.39 (m, 1H), 4.86 (d, J¼2.1 Hz, 1H), 5.18 (d, J¼1.5Hz, 1H),
5.21e5.28 (m, 1H), 5.46 (dd, J¼8.7, 15.3 Hz, 1H), 6.01 (d, J¼11.1 Hz,
1H), 6.22 (d, J¼11.4 Hz, 1H); 19F NMR (CDCl3, 282 MHz)
ꢀ78.3 (s);
d
6. (a) Akiyama, K.; Mikami, K. Tetrahedron Lett. 2004, 45, 7217; (b) Mikami, K.;
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741.4558.
4.2.12. (25R)-Trifluoromethyl-1
a
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b
-bis(tert-butyldimethyl-silyloxy)-
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1H NMR (CDCl3, 300 MHz)
d 0.02e0.04 (m, 12H), 0.60 (s, 3H),
0.80e0.89 (m, 18H), 1.02 (d, J¼6.6 Hz, 3H), 1.15e1.34 and
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ꢀ78.4 (s).
4.2.13. (25S)-Trifluoromethyl-22-dehydrocarcitriol
(25S)-140. To
a solution of (25S)-14 (3.2 mg, 0.0043 mmol) in THF (0.3 ml)
was added HF/Py (0.13 ml) at 0 ꢁC, and stirred for 4 h. To the
mixture was added satd NaHCO3, washed with brine, extracted by
AcOEt, dried over MgSO4 and concentrated. The residue was
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