Synthesis of vitamin D3 derivatives with nitrogen-linked substituents at A-ring C-2 and evaluation of their vitamin D receptor-mediated transcriptional activity

Article abstract of DOI:10.1039/c2ob26017d

Binding of a series of novel 1α,25-dihydroxyvitamin D₃ (1,25-VD₃) derivatives, having a nitrogen-linked substituent at the 2α- or 2β-position of the A-ring (2-N-substituted compounds), with the vitamin D receptor (VDR) was investigated by means of computational docking studies. Selected compounds were synthesized by coupling A-ring synthons 6 and/or 7 with CD-ring-bearing bromomethylene 5 under Trost's conditions. The 2α- and 2β-stereoisomers of the A-ring synthons were synthesized from l-serine (8) as a single chiral source by installing vinyl and propargyl groups at opposite ends of the molecule. The activity of the obtained compounds was evaluated by means of a luciferase-based VDR transcriptional activity assay in NIH3T3 cells. Relatively small substituents incorporating a hydrogen-bonding donor, i.e., NHAc and NHMs, were effective for eliciting VDR transcriptional activity, and 2β-NHMs-1,25-VD₃ (Xa) showed the highest activity, being more potent than 1,25-VD₃. Derivatives with bulky substituents were inactive. These new insights into the structure-activity relationships of 1,25-VD₃ derivatives may be helpful in separating the various biological activities of 1,25-VD₃ and in generating novel therapeutic drug candidates. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2ob26017d

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PAPER
Synthesis of vitamin D3 derivatives with nitrogen-linked substituents at
A-ring C-2 and evaluation of their vitamin D receptor-mediated transcriptional
activity†
Junko Abe,a Yu Nagai,a Rui Higashikuni,a Keisuke Iida,a Takatsugu Hirokawa,b Hazuki Nagai,c
Kaichiro Kominato,c Toshio Tsuchida,c Michiko Hirata,a Masaki Inada,a Chisato Miyauraa and
Kazuo Nagasawa*a
Received 24th May 2012, Accepted 3rd August 2012
DOI: 10.1039/c2ob26017d
Binding of a series of novel 1α,25-dihydroxyvitamin D3 (1,25-VD3) derivatives, having a nitrogen-linked
substituent at the 2α- or 2β-position of the A-ring (2-N-substituted compounds), with the vitamin D
receptor (VDR) was investigated by means of computational docking studies. Selected compounds were
synthesized by coupling A-ring synthons 6 and/or 7 with CD-ring-bearing bromomethylene 5 under
Trost’s conditions. The 2α- and 2β-stereoisomers of the A-ring synthons were synthesized from L-serine
(8) as a single chiral source by installing vinyl and propargyl groups at opposite ends of the molecule.
The activity of the obtained compounds was evaluated by means of a luciferase-based VDR
transcriptional activity assay in NIH3T3 cells. Relatively small substituents incorporating a hydrogen-
bonding donor, i.e., NHAc and NHMs, were effective for eliciting VDR transcriptional activity, and
2β-NHMs-1,25-VD3 (Xa) showed the highest activity, being more potent than 1,25-VD3. Derivatives
with bulky substituents were inactive. These new insights into the structure–activity relationships of 1,25-
VD3 derivatives may be helpful in separating the various biological activities of 1,25-VD3 and in
generating novel therapeutic drug candidates.
enhance their biological activities,5 and some of these com-
1. Introduction
pounds are in clinical use.5a–c,e In recent structure–activity
1α,25-Dihydroxyvitamin D3 (1) (1,25-VD3) (Fig. 1), the active
metabolite of vitamin D3, plays central roles in various biologi-
cal processes, acting via its specific receptor, i.e., vitamin D
receptor (VDR), which is a member of the nuclear receptor (NR)
superfamily.1 1,25-VD3 modulates bone metabolism,2 cell pro-
liferation and cell differentiation.3 These characteristic biological
activities deeply relate with various diseases, including osteo-
porosis, cancer, secondary hyperparathyroidism and psoriasis.4
Since 1,25-VD3 and related compounds are promising candidates
for the treatment of these diseases, thousands of vitamin D
derivatives have been synthesized in attempts to separate and/or
relationship studies of vitamin D, much attention has been paid
to modification of the A-ring.5b,c,e,6 This ring contains the 1α-
and 3β-hydroxyl groups, which have important interactions with
VDR at Ser237 and Arg274 (for the 1α-hydroxyl group) and at
Ser278 and Tyr143 (for the 3β-hydroxyl group), as determined
by X-ray analysis.10 The X-ray structure also indicated the pres-
ence of an unoccupied region in the binding site of VDR near
the location of C2 of the A-ring of 1,25-VD3. Therefore, intro-
duction of substituents at C2 in the A-ring may alter the strength
or the mode of interaction of the ligand with VDR, which may
lead to conformational change of VDR, as well as changes in the
characteristic biological activities. In fact, modification at the C2
position with oxygen- or carbon-containing groups has been
intensively explored, and the resulting derivatives were reported
to show characteristic and/or new biological activities.7–9 For
example, introduction of a 2α-hydroxypropyl8 or 2α-methyl9
group increased the binding affinity for VDR by 4- and 3-fold,
respectively. These analogs also showed extremely high calcium-
mobilizing activity, having 7 and 500 times higher potency than
1,25-VD3 (1), respectively.7 Further, introduction of a 2β-hydro-
xypropoxy group afforded a compound (ED-71; 2) that appears
to increase the bone mineral density in osteoporotic patients
aDepartment of Biotechnology and Life Science, Faculty of Technology,
Tokyo University of Agriculture and Technology, 2-24-16 Naka-cho,
Koganei, Tokyo 184-8588, Japan. E-mail: knaga@cc.tuat.ac.jp;
Fax: +81-42-388-7295; Tel: +81-42-388-7295
bNational Institute of Advanced Industrial Science and Technology
Tokyo Waterfront Bio-IT Research Building, 2-4-7 Aomi, Koto-ku, Tokyo,
135-0064, Japan
cMicroBiopharm Japan Co. 3-3-6 Nihonbashihoncho, Chuo-ku, Tokyo,
103-0032, Japan
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob26017d
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calculated affinity for VDR. The docking result for the 2α-N-
benzoyl derivative (IIIc) is illustrated in Fig. 3(b). The sterically
hindered phenyl group in IIIc reduces the stability as a result of
steric interaction with Lys240 of VDR. Moderate stabilization
scores were obtained for carbamate-substituted derivatives (cate-
gory IV). The 2α-N-acyl and carbamate groups showed no sig-
nificant interaction of their carbonyl groups with amino acid
residues of VDR. In the case of 2α-N-sulfonamide substitution
(category V), no poses were obtained except for the N-methane-
sulfonamide derivative Va. This compound Va was well docked
with VDR (see Fig. 3(c)), and it showed greater stabilization
than 1,25-VD3.
The 2β-N-substituted derivatives (categories VI–X) showed
similar trends to the case of 2α-N-substitution. 2β-N-monoalkyl
groups (VIa–d), a 2β-N-acetyl group (VIIIa) and especially a
N-methanesulfonyl group (Xa) were effective for stabilization of
VDR. From the docking model (Fig. 3(d)), it appears that a
hydrogen-bonding interaction between the sulfonyl group in Xa
and Arg274 contributes to the stabilization.
Based upon these docking calculations, we selected IIb, IId–e,
IIIa–c, IVd, Va–d, VIIe, VIIIa, and Xa as synthetic targets.
2. Synthesis of 2-N-substituted vitamin D
derivatives
Fig. 1 Structures of 1α,25-dihydroxyvitamin D3 and its synthetic
analogs modified at the C2 position.
Palladium-catalyzed coupling reaction of vinyl bromide 5
(CD-ring) with an ene–yne-type A-ring synthon was developed
by Trost for the synthesis of 2-N-substituted vitamin D deriva-
tives.17 We planned to synthesize A-ring precursors of 2α- and
2β-N-substituted ene–ynes 6 and 7 from L-serine (8) as a single
chiral source by switching the positions of the vinyl and propar-
gyl groups, as depicted in Scheme 1.
without significant side effects.11 An analog of 2MD (4) having
a methylene group at C2 also caused a bone mass increment
without inducing hypercalcemia.12 These results clearly show
the potential of modifications at the C2 position in the A-ring of
the vitamin D skeleton for eliciting a broad range of biological
activities.
Here, we focused on installing nitrogen-linked functional
groups at C2 in the A-ring to obtain 2-N-substituted compounds.
Nitrogen has a different electrostatic field from oxygen or
carbon, as well as a different number of substituents and differ-
ent bond angles. Therefore, vitamin D derivatives with N-substi-
tuents at the C2 position can be expected to show different
VDR-binding modes from the corresponding oxygen and/or
carbon-substituted vitamin D derivatives, and so might have
characteristically different biological activities.13
A-ring synthons for 2α-N-substituted-1,25-VD3 derivatives
14–24 were synthesized from the key amine intermediate 13
(Scheme 2). Optically active allyl alcohol 9 was obtained from
L-serine (8) according to Katsumura’s method.18 The hydroxyl
group of 9 was protected with TBS ether to give bis-TBS ether
10 in 93% yield. The primary TBS group in 10 was selectively
deprotected with 1% HCl in ethanol to give alcohol 11. In this
reaction, the diol was co-generated in 23% yield, with 16%
recovery of the starting bis-TBS ether 10. The diol was quantita-
tively transformed back to the starting bis-TBS ether 10 with
TBSOTf and 2,6-lutidine. Oxidation of the hydroxyl group
under Swern conditions followed by reaction with propargyl
Grignard reagent gave the alcohol as a 1 : 1 mixture of diastereo-
mers,19 which were separated by column chromatography on
silica gel to give 12 in 53% yield from 11. The TBS ether and
Boc group in 12 were deprotected with TFA, and resulting diol
was protected as TBS ether with TBSOTf and 2,6-lutidine to
afford the key amine intermediate 13 in 75% yield. N,N′-Dialkyl
A-ring synthons 14–16 were synthesized in 51–60% yields by
reductive amination with the corresponding aldehydes. In the
case of NBn2-substituted 16, N-alkylation of amine 13 with
benzyl bromide in the presence of potassium carbonate was
more effective than a reductive amination protocol. N-Acyl
derivatives 17–19 were synthesized by reaction with acyl halide
or acyl anhydride in 90–96% yields. N-Sulfonamide derivatives
20–23 were synthesized by reaction of sulfonyl chloride in the
Firstly, we carried out docking studies of various 2-N-substi-
tuted vitamin D derivatives, I ∼ X (Fig. 2), with the AF2
domain of VDR using the Glide (Schrödinger, LLC).14,15 The
docking scores are summarized in Table 1.16
In the case of 2α-N-monoalkyl groups (category I, Ia–Ie),
higher stabilization was seen as the bulkiness increased from
methyl to n-butyl group, but a remarkably low stabilization score
was obtained for the N-benzyl-substituted derivative (Ie), prob-
ably because of steric hindrance. A similar trend was observed in
the case of 2α-N,N′-dialkyl substitution (category II). The 2α-N,
N′-diethyl-substituted derivative (IIb) was well docked with the
AF2 domain (see Fig. 3(a)). Among the compounds in category
II, no poses were obtained for the bulky N,N′-di-n-butyl- and
N,N′-dibenzyl-substituted compounds (IId and IIe). Substitution
of a 2α-N-amide group (category III) resulted in relatively low
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Fig. 2 Structures of 2-N-substituted vitamin D3 derivatives.
Table 1 Docking scores of 2-N-substituted vitamin D3 derivatives with the AF2 domain of VDR calculated with
Glide XP
presence of triethylamine in 80–95% yields. The N-carbamate
derivative 24 was synthesized from 12 by silylation with
TBSOTf and 2,6-lutidine in 38% yield.
Other A-ring synthons with 2β stereochemistry 32–34 were
also synthesized from L-serine (8) (Scheme 3). Optically active
Weinreb amide 25,20 derived from L-serine (8), was reacted with
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Fig. 3 Selected docking models of 2-N-substituted 1,25-VD3 with the AF2 domain of VDR calculated with Autodock.
vinyl magnesium bromide to give vinyl ketone 26 in 85% yield.
Reduction of the ketone with zinc borohydride proceeded stereo-
selectively, affording the alcohol as a single stereoisomer,21
whose hydroxyl group was protected as TBS ether to give 27 in
89% yield in 2 steps. Ozonolysis of the vinyl group of 27
followed by reduction of the resulting ozonide with sodium
borohydride gave the alcohol, which was treated with methane-
sulfonyl chloride followed by TBAF to give epoxide 28 in 76%
yield in 3 steps.22 Opening reaction of the epoxide was carried
out with trimethylsilyl acetylide in the presence of BF3·Et2O,
and the resulting hydroxyl group was protected with tert-butyl-
diphenyl chloride (TBDPSCl) to give TBDPS ether 29 in 87%
yield. The acetonide in 29 was deprotected with bismuth tribro-
mide,24 and the alcohol was oxidized with TPAP to give the
aldehyde, which was subsequently reacted with vinylmagnesium
bromide to give alcohol 30 as a mixture of two diastereomers
(dr = 1 : 1) in 59% yield in 3 steps. After separation of the
diastereomers on a silica gel column, deprotection of the
TBDPS and TMS groups and the Boc group was conducted
with TBAF and TFA, respectively, to give the diol, whose
hydroxyl groups were protected as TBS ethers to give amine
31 in 61% yield. This key intermediate was converted into
N,N′-dibenzyl 32, N-acetyl 33 and N-methanesulfonyl 34
by following the same procedures described for the synthesis of
the corresponding 2α-stereoisomers of A-ring synthons 16, 17,
and 20.
With the N-substituted A-ring synthons with 2α and 2β
stereochemistry, 14–24 and 32–34, in hand, these A-ring pre-
cursors were coupled with the CD-ring bromomethylene 5
in the presence of Pd(PPh3)4,17 and the resulting TBS-protected
coupling products were deprotected with TBAF or HF–Et3N
(Scheme 4) to afford the 2α-N-substituted vitamin D3
derivatives II–V. 2β-N-Substituted 1,25-VD3 derivatives VIIe,
VIIIa and Xa were also obtained in 33, 17 and 21% yields,
respectively.25
3. Evaluation of VDR-mediated transcription-
activating activity of 2-N-substituted 1,25-VD3
derivatives
The biological activities of these 2-N-substituted 1,25-VD3
derivatives were evaluated by means of a luciferase-based VDR
transcriptional activity assay in NIH3T3 cells.26 NIH3T3 cells
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Scheme 1 Synthetic plan for A-ring synthons 6 and 7 of 2-N-substi-
tuted vitamin D3 derivatives.
were transfected with pDR3-Luc and pGL4.74 [hLuc/TK]
normalizing vectors, then treated with 1,25-VD3 or compounds
(100 nM IIb, IId–e, IIIa–c, IVd, Va–d, VIIe, VIIIa, and Xa),
and the luciferase activity was measured. The relative intensities
of the luciferase activity of compounds versus the control or
1,25-VD3 are summarized in Fig. 4.
Among the compounds tested, 2α-NHAc-1,25-VD3 (IIIa)
showed similar activity to 1,25-VD3, while IVd and Va, bearing
NHBoc and NHMs groups at 2α, showed moderate activity.
Among the 2β stereoisomers, the 2β-N-acetyl derivative (VIIIa),
which effectively stabilized VDR in the docking studies, showed
potent activity nearly equal to that of 1,25-VD3. However,
2β-NHMs-1,25-VD3 (Xa), which appeared to exhibit a hydro-
gen-bonding interaction with Arg274 of VDR in the docking
studies, showed the highest transcriptional activity among
the derivatives synthesized, being slightly more potent than
VD3. These derivatives all have a hydrogen-bond-donating
group at the C2 position, so hydrogen bonding seems to be
important for VDR transcriptional activity. Indeed, 2α-NEt2-
1,25-VD3 (IIb), which cannot form a hydrogen bond, induced
no transcriptional activity, although it could be well docked with
VDR by calculation. Steric hindrance is also an important factor.
Compounds IIe and VIIe bearing bulky N,N′-Bn2 groups at the
2α- and 2β-position, respectively, gave no calculated docking
poses with VDR, and also failed to induce transcriptional
activity. On the other hand, NHSO2Ar can act as a hydrogen
bond donor, but it is a bulky group, and it induced only low tran-
scriptional activity. Thus, it appears that 2-N-substituted 1,25-
VD3 derivatives with a relatively small substituent group that has
hydrogen-bond donor capability are effective for eliciting VDR
transcriptional activity.
Scheme 2 Synthesis of 2α-N-substituted A-ring synthons 14–24. (a)
TBSCl, imidazole, DMAP, DMF, rt, 93%; (b) 1% HCl, EtOH, rt, 60%
(diol was generated in 23% yield, with 16% recovery of starting bis-TBS
ether 10); (c) (COCl)2, DMSO, i-Pr2NEt, CH2Cl2, −78 °C to 0 °C; (d)
propargyl magnesium bromide, THF, 0 °C; (e) Separation with silica gel
column, 53% (C3 isomer 35%); (f) 20% TFA–CH2Cl2, 0 °C to rt; (g)
TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C to rt, 75% (2 steps); (h) acetoalde-
hyde (6 eq), NaBH3CN, then AcOH, CH3CN, 0 °C to rt, 51%; (i)
n-butylaldehyde (6 eq), NaBH3CN, then AcOH, CH3CN, 0 °C to rt,
59%; ( j) BnBr, K2CO3, CH3CN, 80 °C, 60%; (k) acetic anhydride, rt,
94%; (l) pivaloyl chloride, triethylamine, CH2Cl2, 0 °C to rt, 96%; (m)
benzoic anhydride, triethylamine, THF, 0 °C to rt, 90%; (n) methane-
sulfonyl chloride, triethylamine, CH2Cl2, 0 °C to rt, 95%; (o) benzene-
sulfonyl chloride, triethylamine, CH2Cl2, rt, 83%; (p) 4-t-butyl-
benzenesulfonyl chloride, triethylamine, THF, rt, 80%; (q) 4-methoxy-
benzenesulfonyl chloride, triethylamine, THF, rt, 93%; (r) TBSOTf, 2,6-
lutidine, CH2Cl2, 0 °C, 38%.
4. Conclusion
In summary, we carried out computational docking with VDR
for a series of novel 2α- and 2β-N-substituted 1,25-VD3 deriva-
tives. Based on the results, 14 compounds were selected and syn-
thesized. A-Ring synthons for both stereoisomers were
synthesized from L-serine (8) as a single chiral source by instal-
ling vinyl and propargyl groups at opposite ends of the molecule.
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Scheme 4 Synthesis of 2α-N-substituted 1,25-VD3 derivatives; IIb
(NEt2), 20%; IId (N-nBu2), 10%; IIe (NBn2), 10%; IIIa (NHAc), 9%;
IIIb (NHCO-tBu), 57%; IIIc (NHCOPh), 25%; IVd (NHBoc), 20%; Va
(NHSO2Me), 57%; Vb (NHSO2Ph), 5%; Vc (NHSO2-4-tBuPh), 8%;
Vd (NHSO2-4-OMe-Ph), 6%. Synthesis of 2β-N-substituted 1,25-VD3
derivatives; VIIe (NBn2), 33%; VIIIa (NHAc), 17%; Xa (NHSO2Me),
21%.
Scheme 3 Synthesis of 2β-substituted A-ring synthons 32–34. (a)
vinyl magnesium bromide, THF, 0 °C, 85%; (b) Zn(BH4)2, Et2O,
−30 °C; (c) TBSCl, imidazole, DMAP, DMF, rt, 89% (2 steps); (d) O3,
CH2Cl2, MeOH, −78 °C, then NaBH4, −78 °C to rt; (e) MsCl, triethyl-
amine, CH2Cl2, 0 °C, 94% (2 steps); (f) TBAF, THF, rt, 81%; (g) tri-
methylsilyl acetylene, n-BuLi, BF3·Et2O, THF, −78 °C, 90%; (h)
TBDPSCl, imidazole, DMF, rt to 40 °C, 97%; (i) BiBr3, CH3CN–H2O,
rt, 91%; ( j) TPAP, NMO, MS-4A, CH2Cl2, rt, 92%; (k) vinyl mag-
nesium bromide, THF, 0 °C, then separation (α-isomer: 35%, β-isomer:
35%); (l) TBAF, THF, rt, 89%; (m) 20% TFA–CH2Cl2, 0 °C to rt; (n)
TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C to rt, 69% (2 steps); (o) BnBr,
K2CO3, CH3CN, NaI, 80 °C, 54%; (p) Ac2O, rt, 99%; (q) MsCl, Et3N,
CH2Cl2, 0 °C to rt, 84%.
Fig. 4 Results of dual-luciferase reporter assay for 2-N-substituted
1,25-VD3 derivatives. Data are expressed as the means SEM.
These A-rings were coupled with CD-ring bromomethylene 5
according to Trost’s protocol to afford the target compounds. In
a dual-luciferase reporter assay, IIIa, VIIIa and Xa showed
similar activity to 1,25-VD3. Our results indicate that 2-N-substi-
tuted 1,25-VD3 derivatives with a relatively small substituent
group that has the potential to form a hydrogen bond with the
receptor are effective for eliciting VDR transcriptional activity.
Further structural development studies and evaluation of various
VDR-mediated biological activities of our compounds are in
progress.
spectra were recorded on JEOL JNM-ECA 500, JNM-ECX 400
or JMTC 300. The spectra are referenced internally according to
residual solvent signals of CDCl3 (1H NMR; δ = 7.26 ppm, 13C
NMR; δ = 77.0 ppm). Data for 1H NMR are recorded as follows:
chemical shift (δ, ppm), multiplicity (s, singlet; d, doublet;
t, triplet; q, quartet; m, multiplet; br, broad), integration, coupling
constant (Hz). Data for 13C NMR are reported in terms of chemi-
cal shift (δ, ppm). Mass spectra were recorded on JEOL
JMS-T100X spectrometer with ESI-MS mode using methanol as
solvent.
Experimental
Bis-TBS ether 10. To a solution of 9 (16.7 mmol) in DMF
(50 mL) was added imidazole (2.7 g, 40.1 mmol), DMAP
(204 mg, 1.67 mmol) and TBSCl (3 g, 20.0 mmol), and the
mixture was stirred for 24 h at room temperature. To the reaction
mixture was added H2O and then it was extracted with ethyl
General
Flash chromatography was performed on Silica gel 60 (spherical,
particle size 40–100 μm; Kanto). Optical rotations were
measured on a JASCO P-2200 polarimeter. H and 13C NMR
1
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acetate. The organic layer was washed with H2O and brine, and
the extracts were dried over MgSO4, filtered, and concentrated
in vacuo. The residue was purified by silica gel chromatography
(hexane–ethyl acetate = 100 : 1) to give 10 (6.9 g, 15.5 mmol,
93%). [α]2D2 = +3.4 (c 1.3, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 5.76–5.90 (m, 1H), 5.10–5.28 (m, 2H), 4.62 (d, J = 7.3 Hz,
1H), 4.27 (brs, 1H), 3.76 (m, 1H), 3.69–3.55 (m, 2H), 1.42 (s,
9H), 0.89 (s, 9H), 0.88 (s, 9H), 0.07–0.01 (m, 12H); 13C NMR
(75 MHz, CDCl3) δ 155.6, 138.3, 116.2, 79.0, 73.1, 61.3, 56.4,
28.4, 25.8, 18.2, 18.1, −5.3, −5.5; HRMS: calcd for
C22H47NO4Si2Na, 468.2941; found, 468.2940.
in vacuo to give diol. To a solution of the resulting diol in
dichloromethane (8 mL) was added 2,6-lutidine (0.6 mL,
4.84 mmol) and TBSOTf (0.6 mL, 2.42 mmol), and the mixture
was stirred at 0 °C for 40 min. To the reaction mixture was
added saturated NaHCO3, then it was extracted with ethyl
acetate. The organic layer was washed with H2O and brine, and
dried over MgSO4, filtered, and concentrated in vacuo. The
residue was purified by silica gel chromatography (hexane–ethyl
acetate = 40 : 1) to give 13 (250 mg, 0.65 mmol, 75% from 12).
1
[α]2D4 = −3.6 (c 0.2, CHCl3); H NMR (400 MHz, CDCl3) δ
5.83–5.74 (m, 1H), 5.26–5.17 (m, 2H), 4.10–4.04 (m, 1H),
3.95 (t, J = 7.4 Hz), 2.86 (dd, J = 6.9, 2.8 Hz, 1H), 2.65–2.32
(m, 2H), 1.99 (t, J = 2.7 Hz, 1H), 0.91–0.88 (m, 18H),
0.12–0.03 (m, 12H); 13C NMR (100 MHz, CDCl3) δ 139.2,
117.8, 81.2, 76.4, 70.4, 70.2, 58.3, 25.9, 24.9, 18.1, −3.3, −4.0;
HRMS: calcd for C20H42NO2Si2, 384.2754; found, 384.2725.
Alcohol 11. A solution of 10 (3.2 g, 7.18 mmol) in HCl and
ethanol (1 : 99, 240 mL) was stirred for 15 min at room tempera-
ture. To the reaction mixture was added saturated NaHCO3, then
it was concentrated in vacuo. The residue was extracted with
ethyl acetate and the organic layer was washed with H2O and
brine, and dried over MgSO4, filtered, and concentrated
in vacuo. The residue was purified by silica gel chromatography
(hexane–ethyl acetate = 4 : 1) to give 11 (1.43 g, 4.31 mmol,
60%). [α]2D2 = −20.8 (c 5.2, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 5.88–5.79 (m, 1H), 5.40–5.18 (m, 3H), 4.52 (s, 1H),
3.97 (d, J = 11.4 Hz, 1H), 3.60–3.45 (m, 2H), 1.43 (s, 9H),
0.91–0.86 (m, 9H), 0.08–0.02 (m, 6H); 13C NMR (125 MHz,
CDCl3) δ 155.7, 137.5, 116.3, 79.5, 76.0, 61.9, 54.6, 28.3, 25.7,
25.6, 18.0, −3.6; HRMS: calcd for C16H33NO4SiNa, 354.2077;
found, 354.2060.
2α-N-Ethylamine 14. To
a solution of 13 (100 mg,
0.26 mmol) in acetonitrile (2.6 mL) was added acetoaldehyde
(88 μL, 1.56 mmol) and NaBH3CN (41 mg, 0.65 mmol) at room
temperature, and the mixture was stirred for 50 min. To the
reaction mixture was added acetic acid until the pH of the mixture
reached 3. The resulting mixture was stirred for 1.5 h and
quenched by saturated NaHCO3. The reaction mixture was
extracted with ethyl acetate. The organic layer was washed with
brine, and the extracts were dried over MgSO4, filtered, and con-
centrated in vacuo. The residue was purified by silica gel chrom-
atography (hexane–ethyl acetate = 100 : 1) to give 14 (58 mg,
0.13 mmol, 51%). [α]2D0 = +4.8 (c 0.9, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 5.98–5.87 (m, 1H), 5.28–5.12 (m, 2H),
4.38 (t, J = 8.9 Hz, 1H), 4.28–422 (m, 1H), 2.88–2.74 (m, 4H),
2.65–2.57 (m, 2H), 2.28–2.20 (m, 1H), 1.95 (t, J = 2.8 Hz, 1H),
0.97 (t, J = 7.1 Hz, 6H), 0.9–0.86 (m, 18H), 0.13–0.02 (m,
12H); 13C NMR (100 MHz, CDCl3) δ 141.9, 117.2, 82.4, 74.3,
72.3, 69.8, 67.0, 47.9, 26.0, 24.4, 18.1, 16.4, −2.4, −4.1, −4.6;
HRMS: calcd for C24H50NO2Si2, 440.3380; found, 440.3353.
Alcohol 12. To a solution of (COCl)2 (0.6 mL, 7.29 mmol) in
dichloromethane (30 mL) was added DMSO (1 mL, 14.3 mmol)
dropwise at −78 °C. The reaction mixture was stirred for 10 min
at −78 °C, and to the mixture was added dropwise a solution of
11 (1.05 g, 3.17 mmol) in dichloromethane (20 mL). The
reaction mixture was stirred for 1.5 h at −78 °C, and diisopropyl-
ethylamine (5 mL, 28.5 mmol) was added. The resulting mixture
was warmed to room temperature for 30 min. To the reaction
mixture was added 1 N HCl, and the mixture was extracted with
dichloromethane. The extracts were washed with H2O, dried
over MgSO4, filtered, and concentrated in vacuo to give alde-
hyde. To a prepared solution of propargyl magnesium bromide
(1 M in THF, 17 mL, 17.1 mmol) was added aldehyde in THF
(15 mL) at 0 °C, and the mixture was stirred for 40 min. The
resulting mixture was quenched by 1 N HCl at 0 °C and
extracted with ethyl acetate. The organic layer was washed with
H2O and brine, and the extracts were dried over MgSO4, filtered,
and concentrated in vacuo. The residue was purified by silica gel
chromatography (hexane–ethyl acetate = 13 : 1) to give 12
(148 mg, 0.296 mmol, 53% from 11). [α]2D2 = −25.6 (c 2.2,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 5.90–5.82 (m, 1H),
5.39–5.20 (m, 3H), 4.61–4.57 (m, 1H), 4.27 (t, J = 6.9 Hz, 1H),
3.61 (s, 1H), 3.58 (dd, J = 8.9, 2.0 Hz, 1H), 2.35 (ddd, J = 58.3,
16.5, 2.9 Hz, 2H), 2.01 (t, J = 2.9 Hz, 1H), 1.44 (s, 9H), 0.91 (s,
9H), 0.08 (s, 3H), 0.04 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 155.6, 137.2, 116.7, 80.5, 79.6, 76.6, 70.1, 68.3, 55.0, 28.4,
25.8, 23.6, 18.0, −4.8, −5.3; HRMS: calcd for C19H35NO4SiNa,
392.2233; found, 392.2267.
2α-N-n-Butylamine 15. To a solution of 13 (100 mg,
0.26 mmol) in acetonitrile (2.6 mL) was added n-butylaldehyde
(140 μL, 1.56 mmol) and NaBH3CN (41 mg, 0.65 mmol) at
room temperature, and the mixture was stirred for 1 h. To the
reaction mixture was added acetic acid until the pH of the
mixture reached 3. The resulting mixture was stirred for 1 h and
quenched by saturated NaHCO3. The reaction mixture was
extracted with ethyl acetate. The organic layer was washed with
brine, and the extracts were dried over MgSO4, filtered, and
concentrated in vacuo. The residue was purified by silica gel
chromatography (hexane–ethyl acetate = 100 : 1) to give 15
(76 mg, 0.15 mmol, 59%). [α]2D1 = +1.6 (c 0.6, CHCl3);
1H NMR (400 MHz, CDCl3) δ 6.03–5.88 (m, 1H), 5.30–5.12
(m, 2H), 4.40 (t, J = 8.6 Hz, 1H), 4.28–4.20 (m, 1H), 2.89–2.62
(m, 5H), 2.60–2.49 (m, 2H), 2.31–2.21 (m, 1H), 1.95 (t, J =
2.5 Hz, 1H), 1.42–1.30 (m, 4H), 1.29–1.14 (m, 4H), 0.84–0.92
(m, 24H), 0.15–0.02 (m, 12H); 13C NMR (75 MHz, CDCl3) δ
141.9, 117.1, 82.5, 74.6, 72.5, 69.9, 67.6, 54.6, 33.3, 26.0, 24.6,
20.5, 18.1, −2.4, −4.1; HRMS: calcd for C28H58NO2Si2,
496.4006; found, 496.4010.
Amine 13. A solution of 12 (298 mg, 0.81 mmol) in TFA and
dichloromethane (1 : 4, 8 mL) was stirred at 0 °C for 5 min and
room temperature for 1 h. The reaction mixture was concentrated
2α-N,N′-Dibenzylamine 16. To a solution of 13 (100 mg,
0.26 mmol) in acetonitrile (3 mL) was added K2CO3 (360 mg,
7832 | Org. Biomol. Chem., 2012, 10, 7826–7839
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2.61 mmol) and BnBr (0.13 mL, 2.61 mmol) at room tempera-
ture, and the mixture was stirred at 80 °C for 10 h. To the result-
ing mixture was added saturated NH4Cl, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
brine, and the extracts were dried over MgSO4, filtered, and con-
centrated in vacuo. The residue was purified by silica gel chrom-
atography (hexane–ethyl acetate = 100 : 1) to give 16 (89 mg,
0.16 mmol, 60%). [α]2D4 = −14.4 (c 3.9, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.40–7.16 (m, 10H), 6.08–5.97 (m, 1H),
5.44–5.27 (m, 2H), 4.54 (t, J = 8.7 Hz, 1H), 4.s35–4.29 (m,
1H), 3.96 (dd, J = 134.7, 13.8 Hz, 4H), 2.91 (dd, J = 8.5,
2.6 Hz, 1H), 2.67–2.58 (m, 1H), 2.39–2.31 (m, 1H), 1.68 (t, J =
2.5 Hz, 1H), 0.89 (s, 9H), 0.82 (s, 9H), 0.13–0.03 (m, 12H);
13C NMR (100 MHz, CDCl3) δ 142.0, 140.9, 129.4, 127.9,
126.5, 117.6, 81.6, 75.1, 72.8, 69.8, 63.8, 56.5, 25.9, 18.1, −2.5,
−4.0, −4.5; HRMS: calcd for C34H54NO2Si2, 564.3693; found,
564.3682.
1H NMR (400 MHz, CDCl3) δ 7.74–7.68 (m, 2H), 7.50–7.38
(m, 3H), 6.54 (d, J = 9.7 Hz, 1H), 6.01–5.91 (m, 1H), 5.14–5.06
(m, 2H), 4.42–4.38 (m, 1H), 4.34 (t, J = 9.2 Hz, 1H), 4.09 (t,
J = 8.7 Hz, 1H), 2.47–2.30 (m, 2H), 2.00 (t, J = 2.7 Hz, 1H),
0.95 (s, 9H), 0.90 (s, 9H), 0.17 (d, J = 5.5 Hz, 6H), 0.68 (d, J =
1.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 166.9, 139.3,
135.0, 131.3, 128.6, 126.7, 117.7, 80.2, 76.1, 71.0, 69.1, 56.1,
25.9, 25.6, 18.1, −2.9, −4.0, −4.6; HRMS: calcd for C27H45-
NO3Si2Na, 510.2836; found, 510.2806.
2α-N-Methanesulfonylamine 20. To a solution of 13 (60 mg,
0.16 mmol) in dichloromethane (2 mL) was added triethylamine
(53 μL, 0.37 mmol) and methanesulfonyl chloride (15 μL,
0.19 mmol) at 0 °C, and the mixture was stirred for 40 min at
room temperature. To the resulting mixture was added saturated
NaHCO3, and the mixture was extracted with ethyl acetate. The
organic layer was washed with brine, and the extracts were dried
over MgSO4, filtered, and concentrated in vacuo. The residue
was purified by silica gel chromatography (hexane–ethyl
2α-N-Acetylamine 17. A solution of 13 (66 mg, 0.17 mmol)
in acetic anhydride (0.5 mL) was stirred for 15 min at room
temperature. The resulting mixture was concentrated in vacuo to
give 17 (69 mg, 0.16 mmol, 94%). [α]2D5 = −12.8 (c 0.4,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 5.91–5.82 (m, 1H), 5.69
(d, J = 9.7 Hz, 1H), 5.15–5.03 (m, 2H), 4.32–4.27 (m, 1H), 4.11
(t, J = 9.2 Hz, 1H), 3.96 (t, J = 8.6 Hz, 1H), 2.40–2.26 (m, 2H),
2.02 (t, J = 2.6 Hz, 1H), 1.94 (s, 3H), 0.92 (s, 9H), 0.88 (s, 9H),
0.14 (d, J = 4.0 Hz, 6H), 0.05 (s, 6H); 13C NMR (125 MHz,
CDCl3) δ 169.8, 139.4, 117.4, 75.9, 70.9, 68.7, 55.8, 25.9,
25.4, 23.6, 18.1, −2.9, −4.0, −4.6; HRMS: calcd for
C22H43NO3Si2Na, 448.2679; found 448.2674.
acetate = 20 : 1) to give 20 (69 mg, 0.19 mmol, 95%). [α]D26
=
1
−5.0 (c 0.9, CHCl3); H NMR (400 MHz, CDCl3) δ 5.94–5.84
(m, 1H), 5.32–5.23 (m, 2H), 4.65 (d, J = 9.2 Hz, 1H), 4.23–4.17
(m, 1H), 4.11 (t, J = 6.9 Hz, 1H), 3.77–3.70 (m, 1H), 3.03 (s,
3H), 2.58–2.48 (m, 1H), 2.41–2.33 (m, 1H), 2.07 (t, J = 2.8 Hz,
1H), 0.89 (d, J = 1.8 Hz, 18H), 0.13 (d, J = 5.5 Hz, 6H), 0.08
(d, J = 5.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 138.5,
118.2, 79.9, 75.6, 71.5, 69.9, 60.5, 42.7, 25.8, 25.1, 18.2, 18.0,
−3.5, −4.0, −4.6; HRMS: calcd for C21H43NO4SSi2Na,
484.2349; found, 484.2358.
2α-N-Benzenesulfonylamine 21. To a solution of 13 (110 mg,
0.29 mmol) in dichloromethane (3 mL) was added triethylamine
(0.1 mL, 0.69 mmol) and benzenesulfonyl chloride (45 μL,
0.34 mmol) at room temperature, and the mixture was stirred for
6 h. The reaction mixture was diluted with H2O and extracted
with ethyl acetate. The organic layer was washed with brine, and
the extracts were dried over MgSO4, filtered, and concentrated
in vacuo. The residue was purified by silica gel chromatography
(hexane–ethyl acetate = 40 : 1) to give 21 (124 mg, 0.24 mmol,
83%). [α]1D8 = −26.5 (c 0.9, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.91–7.85 (m, 2H), 7.59–7.44 (m, 3H), 5.74–5.62 (m,
1H), 5.13–4.85 (m, 2H), 4.15 (q, J = 4.6 Hz, 1H), 4.00 (t, J =
7.8 Hz, 1H), 3.58 (t, J = 8.3 Hz, 1H), 2.14–206 (m, 1H), 1.98
(t, J = 2.5 Hz, 1H), 1.93–1.83 (m, 1H), 0.86 (s, 18H), 0.07 (d, J =
5.5 Hz, 6H), 0.02 (d, J = 3.7 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 141.8, 138.7, 132.4, 128.9, 127.0, 118.1, 80.2, 75.7,
71.1, 69.4, 59.9, 24.8, 18.1, 18.0, −3.3, −4.3, −4.5, −4.7;
HRMS: calcd for C26H45NO4SSi2Na, 546.2506; found,
546.2500.
2α-N-Pivaloylamine 18. To
a solution of 13 (60 mg,
0.16 mmol) in dichloromethane (1.6 mL) was added Et3N
(33 μL, 0.23 mmol) and pivaloyl chloride (23 μL, 0.19 mmol) at
room temperature, and the mixture was stirred for 4 h. To the
reaction mixture was added saturated NH4Cl, and the mixture
was extracted with ethyl acetate. The organic layer was washed
with brine, and the extracts were dried over MgSO4, filtered, and
concentrated in vacuo. The residue was purified by silica gel
chromatography (hexane–ethyl acetate = 20 : 1) to give 18
(71 mg, 0.15 mmol, 96%). [α]2D7 = −1.6 (c 1.1, CHCl3);
1H NMR (400 MHz, CDCl3) δ 6.03 (d, J = 9.1 Hz, 1H),
5.91–5.80 (m, 1H), 5.11–5.01 (m, 2H), 4.34–4.29 (m, 1H), 4.06
(t, J = 9.2 Hz, 1H), 3.93 (t, J = 8.7 Hz, 1H), 2.31–2.24 (m, 2H),
2.00 (t, J = 2.8 Hz, 1H), 1.14 (s, 9H), 0.92 (s, 9H), 0.88 (s, 9H),
0.14 (s, 6H), 0.05 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
177.7, 139.5, 117.2, 80.4, 76.2, 70.9, 69.1, 55.1, 38.7, 27.6,
25.9, 25.4, 18.0, −2.9, −4.0, −4.5, −4.6; HRMS: calcd for
C25H49NO3Si2Na, 490.3149; found, 490.3123.
2α-N-Benzoylamine 19. To a solution of 13 (120 mg,
0.31 mmol) in THF (3 mL) was added triethylamine (90 μL,
0.63 mmol) and benzoic anhydride (106 mg, 0.47 mmol) at
room temperature, and the mixture was stirred for 15 min. To the
resulting mixture was added saturated NH4Cl, and the mixture
was extracted with ethyl acetate. The organic layer was washed
with brine, and the extracts were dried over MgSO4, filtered, and
concentrated in vacuo. The residue was purified by silica gel
chromatography (hexane–ethyl acetate = 20 : 1) to give 19
(136 mg, 0.28 mmol, 90%). [α]2D5 = −17.2 (c 1.2, CHCl3);
2α-N-(4-tert-Butyl)-benzenesulfonylamine 22. To a solution of
13 (65 mg, 0.17 mmol) in THF (2 mL) was added triethylamine
(57 μL, 0.41 mmol), 4-tert-butyl-benzenesulfonyl chloride
(47 mg, 0.20 mmol) at room temperature, and the mixture was
stirred for 8 h. The reaction mixture was warmed to 60 °C and
stirred additional 8 h. The resulting mixture was diluted with
H2O at room temperature and the mixture was extracted with
ethyl acetate. The organic layer was washed with brine, and
the extracts were dried over MgSO4, filtered, and concentrated
in vacuo. The residue was purified by silica gel chromatography
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1
(hexane–ethyl acetate = 30 : 1) to give 22 (78.9 mg, 0.14 mmol,
80%). [α]1D9 = −18.7 (c 2.7, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.82–7.76 (m, 2H), 7.51–7.45 (m, 2H), 5.74–5.59 (m,
1H), 5.12–4.85 (m, 2H), 4.16–4.09 (m, 1H), 4.01 (t, J = 7.6 Hz,
1H), 3.58–3.48 (m, 1H), 2.16–1.92 (m, 3H), 1.33 (s, 9H), 0.86
(d, J = 1.4 Hz, 18H), 0.60 (s, 6H), 0.01 (d, J = 3.4 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ 156.2, 138.7, 126.9, 125.8,
117.8, 80.4, 75.6, 70.9, 69.6, 59.9, 35.1, 31.1, 25.8, 24.8, 18.1,
18.0, −3.3, −4.3, −4.5, −4.7; HRMS: calcd for C30H53NO4-
SSi2Na, 602.3132; found, 602.3137.
26 (4.37 g, 17.1 mmol, 85%). [α]2D0 = −33.0 (c 0.7, CHCl3); H
NMR (300 MHz, CDCl3) δ 6.56 (ddd, J = 10.3, 17.2, 17.2 Hz,
1H), 6.34 (dd, J = 4.4, 17.2 Hz, 1H), 5.85 (dd, J = 1.3, 10.3 Hz,
1H), 4.78–4.53 (m, 1H), 4.23–4.13 (m, 1H), 4.00–3.98 (m, 1H),
1.72–1.34 (m, 15H); 13C NMR (100 MHz, CDCl3) δ 196.7
151.3 131.8 129.9 95.2 80.7 65.6 63.9 28.3 28.2; HRMS:
(ESI, M + Na+) calcd for C13H21NO4Na, 278.1368; found,
278.1360.
TBS ether 27. To a solution of 26 (334.5 mg, 1.31 mmol) in
diethyl ether (13 mL) was added a 0.18 M diethyl ether solution
of Zn(BH4)2 (5 mL) at −20 °C, and the mixture was stirred for
1 h. To the resulting mixture was added 1 N HCl at 0 °C and the
mixture was extracted with ethyl acetate. The extracts were
washed with brine, and the organics were dried over MgSO4,
filtered, and concentrated in vacuo to give alcohol (328.7 mg).
To a solution of the resulting alcohol (328.7 mg) in DMF (2 mL)
was added imidazole (215 mg, 3.16 mmol), TBSCl (238 mg,
1.58 mmol) and DMAP (16 mg, 0.132 mmol) at room tempera-
ture, and the mixture was stirred for 5 h. To the reaction mixture
was added saturated NaHCO3, and the mixture was extracted
with ethyl acetate. The organic layer was washed with brine, and
the extracts were dried over MgSO4, filtered, and concentrated
in vacuo. The residue was purified by silica gel chromatography
(hexane–ethyl acetate = 50 : 1) to give 27 (434.7 mg, 1.17 mmol,
89% from 26). [α]D21 = −34.9 (c 1.2, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 5.84–5.67 (m, 1H), 5.28–5.04 (m, 2H),
4.59–4.21 (m, 1H), 4.03 (d, J = 5.1 Hz, 1H), 3.90–3.83 (m, 1H),
3.83–3.71 (m, 1H), 1.46 (s, 9H), 0.88 (s, 9H), 0.00 (s, 6H);
13C NMR (125 MHz, CDCl3) δ 152.7, 152.1, 139.2, 138.9,
116.2, 115.5, 94.2, 94.0, 79.9, 79.7, 74.3, 71.9, 64.3, 63.1, 61.6,
61.4, 28.4, 26.7, 25.9, 25.8, 25.2, 23.2, 18.0, −4.4, −4.6;
HRMS: (ESI, M + Na+) calcd for C19H37NO4SiNa, 394.2389;
found, 394.2387.
2α-N-(4-Methoxy)-benzenesulfonylamine 23. To a solution of
13 (90 mg, 0.24 mmol) in THF (2 mL) was added triethylamine
(79 μL, 0.56 mmol) and 4-methoxybenzenesulfonyl chloride
(58 mg, 0.28 mmol) at room temperature, and the mixture was
stirred for 3 h. To the reaction mixture was added saturated
NH4Cl, and the mixture was extracted with ethyl acetate. The
organic layer was washed with brine, and the extracts were dried
over MgSO4, filtered, and concentrated in vacuo. The residue
was purified by silica gel chromatography (hexane–ethyl acetate
= 15 : 1) to give 23 (122 mg, 0.22 mmol, 93%). [α]1D8 = −27.2
(c 2.3, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J =
9.0 Hz, 2H), 6.94 (d, J = 8.9 Hz, 2H), 5.77–5.62 (m, 1H),
5.14–5.03 (m, 2H), 4.84 (d, J = 8.9 Hz, 1H), 4.19–4.11 (m, 1H),
4.01 (t, J = 7.7 Hz, 1H), 3.86 (s, 3H), 3.58–3.49 (m, 1H),
2.18–1.89 (m, 3H), 0.86 (s, 18H), 0.07 (d, J = 2.4 Hz, 6H), 0.02
(d, J = 3.5 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 162.6,
138.8, 133.6, 129.2, 118.0, 114.0, 80.4, 75.7, 71.0, 69.4, 59.8,
55.6, 25.9, 24.9, 18.1, 18.0, −3.3, −4.3, −4.5, −4.7; HRMS:
calcd for C27H47NO5SSi2Na, 576.2611; found, 576.2606.
2α-N-tert-Butoxycarbonylamine 24. To a solution of 12
(124 mg, 0.34 mmol) in dichloromethane (3 mL) was added 2,6-
lutidine (78 μL, 0.67 mmol) and TBSOTf (85 μL, 0.37 mmol) at
0 °C, and the mixture was stirred for 50 min at room tempera-
ture. To the resulting mixture was added 2,6-lutidine (40 μL) and
TBSOTf (50 μL) additionally at room temperature. The reaction
mixture was diluted with H2O, and extracted with ethyl acetate.
The organic layer was washed with brine, and the extracts were
dried over MgSO4, filtered, and concentrated in vacuo. The
residue was purified by silica gel chromatography (hexane–ethyl
Epoxide 28. A solution of 27 (3.12 g, 8.4 mmol) in dichloro-
methane (40 mL) and methanol (40 mL) was treated with ozone
at −78 °C with stirring for 40 min. Then NaBH4 (1.9 g,
50.4 mmol) was added to the resulting mixture, which was
warmed up slowly to room temperature over 12 h. To the reac-
tion mixture was added 3 N HCl, and the organic layer was
extracted with dichloromethane. The extracts were dried over
MgSO4, filtered, and concentrated in vacuo to give alcohol
(3.2 g). To a solution of the alcohol (3.2 g) in dichloromethane
(30 mL) was added triethylamine (1.8 mL, 12.6 mmol) and
methanesulfonyl chloride (1.3 mL, 16.8 mmol) at room tempera-
ture, and the mixture was stirred for 1.5 h. The resulting mixture
was diluted with H2O and extracted with dichloromethane, and
the extracts were dried over MgSO4, filtered, and concentrated
in vacuo. The residue was purified by silica gel chromatography
(hexane–ethyl acetate = 10 : 1) to give mesylate (3.59 g,
7.91 mmol, 94% from 27). To a solution of mesylate (175.3 mg,
0.386 mmol) in THF (5 mL) was added TBAF (505 mg,
1.93 mmol) at room temperature, and the mixture was stirred for
10 min. To the reaction mixture was added saturated NH4Cl, and
the organic layer was extracted with ethyl acetate. The extracts
were washed with brine, dried over MgSO4, filtered, and concen-
trated in vacuo. The residue was purified by silica gel chromato-
graphy (hexane–ethyl acetate = 20 : 1) to give 28 (75.8 mg,
acetate = 50 : 1) to give 24 (62.4 mg, 0.13 mmol, 38%). [α]D24
=
1
−20.7 (c 0.8, CHCl3); H NMR (400 MHz, CDCl3) δ 5.95–5.83
(m, 1H), 5.15–5.08 (m, 2H), 4.69 (d, J = 10.1 Hz, 1H),
4.29–4.22 (m, 1H), 3.97 (t, J = 8.7 Hz, 1H), 3.78 (t, J = 9.2 Hz,
1H), 2.47–2.25 (m, 2H), 2.01 (t, J = 2.7 Hz, 1H), 1.41 (s, 9H),
0.91 (s, 9H), 0.88 (s, 9H), 0.12 (d, J = 4.6 Hz, 6H), 0.05 (s, 6H);
13C NMR (100 MHz, CDCl3) δ 155.8, 139.4, 117.4, 80.6, 78.9,
76.0, 70.7, 69.2, 57.2, 28.4, 25.9, 25.2, 18.1, −2.9, −4.1, −4.5,
−4.6; HRMS: calcd for C25H49NO4Si2Na, 506.3098; found,
506.3075.
Vinyl ketone 26. To a solution of 25 (5.80 g, 20.1 mmol) in
THF (40 mL) was added vinylmagnesium bromide (1 M in THF,
25 mL, 25 mmol) at 0 °C, and the mixture was stirred for 2 h at
room temperature. The resulting mixture was quenched by 1 N
HCl at 0 °C and extracted with ethyl acetate. The organic layer
was washed with brine, and the extracts were dried over MgSO4,
filtered, and concentrated in vacuo. The residue was purified by
silica gel chromatography (hexane–ethyl acetate = 10 : 1) to give
7834 | Org. Biomol. Chem., 2012, 10, 7826–7839
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0.311 mmol, 81%). [α]2D2 = +12.5 (c 1.1, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 4.10–3.95 (m, 2H), 3.61–3.38 (m, 1H),
3.00 (s, 1H), 2.89 (s, 1H), 2.86–2.70 (m, 1H), 1.69–1.42 (m,
15H); 13C NMR (100 MHz, CDCl3) δ 152.3, 151.7, 94.3, 93.7,
80.4, 80.0, 66.0, 65.4, 59.2, 58.9, 52.3, 51.9, 48.3, 48.2, 28.3,
28.2, 27.4, 26.6, 24.2, 23.0; HRMS: (ESI, M + Na+) calcd for
C12H21NO4Na, 266.1368; found, 266.1361.
ethyl acetate. The extracts were washed with brine, dried over
MgSO4, filtered, and concentrated in vacuo. The residue was
purified by silica gel chromatography (hexane–ethyl acetate =
20 : 1) to give 30 (79.3 mg, 0.179 mmol, 35%). [α]2D5 = −12.8
1
(c 1.2, CHCl3); H NMR (300 MHz, CDCl3) δ 7.70–768 (m,
4H), 7.49–7.38 (m, 6H), 5.78 (ddd, J = 16.6, 10.9, 5.4 Hz, 1H),
5.39–5.29 (m, 2H), 5.16 (d, J = 10.3 Hz, 1H), 4.81–4.78 (m,
1H), 4.12–4.09 (m, 1H), 3.76–3.74 (m, 1H), 2.41 (dd, J =
17.7 6.3 Hz, 1H), 2.34 (dd, J = 17.7, 4.6 Hz, 1H), 1.40 (s, 9H),
1.10 (s, 9H), 0.13 (s, 9H); 13C NMR (125 MHz, CDCl3) δ
155.9, 137.2, 135.8, 132.8, 132.1, 130.1, 127.8, 115.8, 102.3,
88.2, 79.2, 73.0, 70.9, 56.9, 28.3, 26.9, 25.5, 19.3, −0.12;
HRMS: (ESI, M + Na+) calcd for C32H47NO4Si2Na, 588.2941;
found, 588.2934.
Silyl ether 29. To
a solution of trimethylsilylacetylene
(1.6 mL, 11.3 mmol) in THF (45 mL) was added n-butyllithium
(1.6 M in hexane, 6.8 mL, 11.3 mmol) at 0 °C, and the mixture
was stirred for 10 min. To the reaction mixture was added a solu-
tion of 28 (1.83 g, 7.53 mmol) in THF (15 mL) and BF3–Et2O
(1.9 mL, 15.0 mmol) at −78 °C. After being stirred for 1 h, tri-
ethylamine (10 mL, 75.2 mmol) was added to the resulting
mixture. The reaction mixture was warmed to room temperature,
and concentrated in vacuo. The residue was filtered through a
pad of silica gel using ethyl acetate to give alcohol (2.32 g,
6.78 mmol, 90%). To a solution of alcohol (2.21 g, 6.47 mmol)
in DMF (1 mL) was added imidazole (1.7 g, 25.9 mmol) and
TBDPSCl (2.5 mL, 9.71 mmol) at room temperature, and the
mixture was stirred at 40 °C for 8 h. To the reaction mixture was
added saturated NaHCO3, and the organic layer was extracted
with ethyl acetate. The extracts were washed with brine, dried
over MgSO4, filtered, and concentrated in vacuo. The residue
was purified by silica gel chromatography (hexane–ethyl acetate
= 100 : 1) to give 29 (3.63 g, 6.26 mmol, 97%). [α]1D7 = −61.0
Amine 31. To a solution of 30 (665.4 mg, 1.18 mmol) in THF
(10 mL) was added TBAF (771 mg, 2.95 mmol) at room tem-
perature, and the mixture was stirred for 40 min. To the reaction
mixture was added saturated NH4Cl, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
brine, and the extracts were dried over MgSO4, filtered, and con-
centrated in vacuo. The residue was purified by silica gel chrom-
atography (hexane–ethyl acetate = 2 : 1) to give diol (268.6 mg,
1.05 mmol, 89%). To the diol (268.6 mg, 1.05 mmol) was added
a mixed solution of TFA and dichloromethane (1 : 4, 5 mL) at
0 °C, and the mixture was stirred for 2 h at room temperature.
The reaction mixture was concentrated in vacuo to give diol
(309.3 mg). To a solution of the diol (309.3 mg) in dichloro-
methane (3 mL) was added 2,6-lutidine (1.4 mL, 12.6 mmol)
and TBSOTf (1.2 mL, 5.25 mmol) at 0 °C, and the mixture was
stirred for 8 h at room temperature. To the reaction mixture was
added saturated NaHCO3, and extracted with ethyl acetate. The
organic layer was washed with H2O and brine, dried over
MgSO4, filtered, and concentrated in vacuo. The residue was
purified by silica gel chromatography (hexane–ethyl acetate =
50 : 1) to give 31 (278.1 mg, 0.726 mmol, 69% from the diol).
1
(c 1.7, CHCl3); H NMR (300 MHz, CDCl3) δ 7.75–7.67 (m,
4H), 7.45–7.34 (m, 6H), 4.46 (dd, J = 8.3, 2.1 Hz, 1H),
4.33–4.20 (m, 1H), 4.04–3.91 (m, 2H), 2.23–2.12 (m, 2H),
1.59–1.35 (m, 15H), 1.08 (s, 9H), 0.12 (s, 9H); 13C NMR
(125 MHz, CDCl3) δ 153.2, 152.4, 135.8, 135.7, 134.7, 134.2,
129.7, 129.6, 127.6, 127.5, 103.6, 103.1, 94.3, 93.6, 87.2, 79.9,
71.2, 70.7, 63.5, 62.3, 61.1, 28.4, 27.0, 26.4, 19.4, −0.06;
HRMS: (ESI, M + Na+) calcd for C33H49NO4Si2Na, 602.3097;
found, 602.3079.
1
[α]1D9 = −1.9 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3) δ
Allyl alcohol 30. To a solution of 29 (3.63 g, 6.26 mmol) in
acetonitrile (40 mL) was bismuth tribromide (281 mg,
0.626 mmol) at room temperature, and the mixture was stirred
for 1 h. To the reaction mixture was added H2O (0.1 mL) at
room temperature and the mixture was stirred for 30 min. To the
resulting mixture was added saturated NaHCO3, and the organic
layer was extracted with ethyl acetate. The extracts were washed
with brine, dried over MgSO4, filtered, and concentrated
in vacuo. The residue was purified by silica gel chromatography
(hexane–ethyl acetate = 10 : 1) to give alcohol (3.09 g,
5.72 mmol, 91%). To a solution of the alcohol (322 mg,
0.596 mmol) in dichloromethane (6 mL) was added NMO
(83 mg, 0.709 mmol) and MS 4Å (330 mg) at room temperature,
then TPAP (23 mg, 0.0656 mmol) was added and the resulting
mixture was stirred for 20 min. The reaction mixture was filtered
through a pad of silica gel using ethyl acetate, and eluted frac-
tions were concentrated in vacuo to give aldehyde (297.1 mg,
0.550 mmol, 92%). To a solution of the aldehyde (212.4 mg,
0.513 mmol) in THF (5 mL) was added vinylmagnesium
bromide (1 M in THF, 1.5 mL, 1.5 mmol) at 0 °C, and the
mixture was stirred for 30 min. To the reaction mixture was
added 1 N HCl at 0 °C, and organic layer was extracted with
5.87 (ddd, J = 17.4, 10.5, 7.3 Hz, 1H), 5.21 (d, J = 17.4 Hz,
1H), 5.16 (d, J = 10.5 Hz, 1H), 4.12 (dd, J = 5.9, 7.3 Hz, 1H),
3.82 (ddd, J = 4.4, 4.4, 6.7 Hz, 1H), 2.83 (dd, J = 4.58, 5.50 Hz,
1H), 2.53 (dd, J = 17.4, 6.87, 2.75 Hz, 1H), 2.44 (dd, J = 17.4,
4.58, 2.75 Hz, 1H), 1.93 (t, J = 2.75 Hz, 1H), 0.89 (s, 9H), 0.88
(s, 9H), 0.11 (s, 3H), 0.075 (s, 3H), 0.068 (s, 3H), 0.030 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 139.3, 116.5, 82.4, 75.0, 71.8,
69.8, 61.0, 25.9, 25.8, 22.5, 18.1, 18.0, −3.5, −3.7, −4.6, −4.7;
HRMS: (ESI, M + H+) calcd for C20H42NO2Si2, 384.2754;
found, 384.2745.
2β-N,N′-Dibenzylamine 32. To a solution of 31 (30.4 mg,
0.0792 mmol) in acetonitrile (1 mL) was added K2CO3 (66 mg,
0.475 mmol) and BnBr (38 μL, 0.317 mmol) at room tempera-
ture, and the mixture was stirred for 1 h at 80 °C. To the reaction
mixture was added NaI (14 mg, 0.095 mmol) at room tempera-
ture, and the mixture was stirred at 80 °C for 21 h. To the reac-
tion mixture was added saturated NH4Cl at room temperature,
and organic layer was extracted with ethyl acetate. The extracts
were washed with brine, dried over MgSO4, filtered, and concen-
trated in vacuo. The residue was purified by silica gel chromato-
graphy (hexane–ethyl acetate = 100 : 1) to give 32 (24 mg,
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 7826–7839 | 7835

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0.0426 mmol, 54%). [α]2D6 = +6.8 (c 0.2, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 7.38–7.14 (m, 10H), 6.08 (ddd, J = 7.91,
10.3, 17.5 Hz, 1H), 5.16 (d, J = 17.2 Hz, 1H), 4.99 (d, J =
9.9 Hz, 1H), 4.65 (dd, J = 5.1, 7.9 Hz, 1H), 4.28 (ddd, J = 4.8,
5.1, 7.4 Hz, 1H), 4.09 (d, J = 14.1 Hz, 2H), 3.84 (d, J = 13.8,
2H), 2.96 (dd, J = 4.8, 5.1 Hz, 1H), 2.76 (dd, J = 2.7, 7.2,
16.8 Hz, 1H), 2.34 (ddd, J = 2.7, 5.1, 16.8 Hz, 1H), 1.77 (t, J =
2.7 Hz, 1H), 0.90 (s, 9H), 0.87 (s, 9H), 0.085 (s, 3H), 0.060 (s,
3H), 0.044 (s, 3H), 0.040 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 141.9, 140.9, 129.1, 128.1, 126.6, 115.2, 76.4, 73.1, 70.8,
69.8, 64.7, 56.0, 53.5, 29.8, 26.3, 26.1, 18.3, −3.3, −3.4, −4.2,
−4.4; HRMS: (ESI, M + H+) calcd for C34H54NO2Si2,
564.3693; found, 564.3648.
in vacuo. The residue was purified by silica gel chromatography
(hexane–ethyl acetate = 50 : 1) to give bis silylether. To a sol-
ution of in THF (3 mL) was added TBAF (71 mg, 0.27 mmol)
at room temperature, and the mixture was stirred at 60 °C for
3 h. To the reaction mixture was added saturated NH4Cl at room
temperature, and the mixture was extracted with ethyl acetate.
The organic layer was washed with brine, dried over MgSO4,
filtered, and concentrated in vacuo. The residue was purified by
silica gel chromatography (CHCl3–methanol = 5 : 1) to give IIb
1
(8 mg, 0.02 mmol, 22%). [α]2D2 = +9.6 (c 0.6, CHCl3); H NMR
(400 MHz, CDCl3) δ 6.42 (d, J = 11.5 Hz, 1H), 5.94 (d, J =
11.0 Hz, 1H), 5.32 (s, 1H), 5.00 (s, 1H), 4.45–4.35 (m, 1H),
4.20–4.31 (m, 1H), 3.79–3.36 (m, 5H), 2.84–2.75 (m, 1H), 2.44
(t, J = 11.9 Hz, 1H), 2.25–0.70 (m, 37H), 0.50 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 143.8, 143.6, 130.6, 125.5,
117.3, 117.1, 71.5, 70.0, 69.0, 65.3, 56.5, 56.3, 47.8, 45.9, 44.6,
44.4, 40.5, 36.3, 36.1, 29.5, 29.2, 29.1, 27.6, 23.4, 22.1, 20.8,
18.8, 12.1; HRMS: calcd for C31H54NO3 488.4104; found,
488.4078.
2β-N-Acetylamine 33. A solution of 31 (127.6 mg,
0.333 mmol) in acetic anhydride (0.3 mL) was stirred for 20 min
at room temperature. The reaction mixture was concentrated
in vacuo to give 33 (140.1 mg, 0.329 mmol, 99%). [α]D17
=
1
+8.90 (c 0.6, CHCl3); H NMR (300 MHz, CDCl3) δ 5.87 (d,
J = 9.6 Hz, 1H), 5.80 (ddd, J = 17.4, 10.1, 7.3 Hz, 1H), 5.19 (d,
J = 17.4 Hz, 1H), 5.11 (d, J = 10.1 Hz, 1H), 4.48 (d, J = 7.3 Hz,
1H), 3.97 (ddd, J = 9.6, 7.8, 1.8 Hz, 1H), 3.93–3.87 (m, 1H),
2.56 (ddd, J = 16.9, 6.4, 2.8 Hz, 1H), 2.36 (ddd, J = 16.9, 5.0,
2.8 Hz, 1H), 2.02 (t, J = 2.7 Hz, 1H), 2.00 (s, 3H), 0.91 (s, 9H),
0.90 (s, 9H), 0.14 (s, 3H), 0.12 (s, 3H), 0.098 (s, 3H), 0.056
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 169.9, 138.6, 116.2,
81.8, 72.4, 71.5, 70.3, 58.2, 24.8, 23.4, 18.1, 18.0, −4.4, −4.6;
HRMS: (ESI, M + Na+) calcd for C22H43NO3Si2Na, 448.2679;
found, 448.2667.
2α-N-Substituted vitamin D3 derivatives IId–e, IIIa–c, IVd,
Va–d. As described for IIb, IId–e, IIIa–c, IVd and Va–d were
obtained from the corresponding A-ring synthons (15–24).
2α-N,N′-Dibutyl-1α-25(OH)2 vitamin D3 (IId). [α]2D3 = +20.7
(c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.49 (d, J =
10.8 Hz, 1H), 5.94 (d, J = 10.9 Hz, 1H), 5.30 (s, 1H), 5.02 (s,
1H), 4.63 (s, 1H), 4.15–4.29 (m, 1H), 3.35–2.72 (m, 9H),
2.40–2.25 (m, 1H), 2.20–0.70 (m, 42H), 0.51 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 144.1, 132.1, 130.9, 128.5, 126.1, 116.7,
72.5, 71.1, 68.4, 64.5, 56.5, 56.3, 51.0, 45.9, 44.4, 43.7, 40.5,
36.4, 36.1, 31.9, 29.7, 29.6, 29.4, 29.1, 27.6, 23.5, 22.7, 22.2,
20.9, 20.8, 18.8, 14.1, 14.0, 12.1; HRMS: calcd for C35H62NO3,
544.4730; found, 544.4711.
2β-N-Methanesulfonylamine 34. To
a
solution of 31
(92.8 mg, 0.242 mmol) in dichloromethane (2 mL) was added
triethylamine (81 μL, 0.581 mmol) and methanesulfonyl chlor-
ide (22 μL, 0.290 mmol) at room temperature, and the mixture
was stirred for 15 min. The resulting mixture was quenched with
saturated NH4Cl and extracted with ethyl acetate. The organic
layer was washed with brine, and the extracts were dried over
MgSO4, filtered, and concentrated in vacuo. The residue was
purified by silica gel chromatography (hexane–ethyl acetate =
2α-N,N′-Dibenzyl-1α-25(OH)2 vitamin D3 (IIe). [α]3D1 = +18.3
1
(c 0.5, CHCl3); H NMR (400 MHz, CDCl3) δ 7.38–7.18 (m,
10H), 6.47 (d, J = 11.4 Hz, 1H), 5.94 (d, J = 11.4 Hz, 1H), 5.21
(d, J = 1.9 Hz, 1H), 4.89 (d, J = 1.8 Hz, 1H), 4.66 (d, J =
1.8 Hz, 1H), 4.26–4.08 (m, 2H), 3.93 (dd, J = 178.4, 13.7 Hz,
4H), 2.82 (d, J = 12.4 Hz, 1H), 2.76 (dd, J = 13.1, 5.3 Hz, 1H),
2.60 (dd, J = 10.1, 2.3 Hz, 1H), 2.18–0.68 (m, 30 H), 0.52 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 144.0, 139.5, 131.5, 129.1,
127.1, 126.1, 116.7, 114.3, 72.3, 71.1, 66.1, 64.1, 56.5, 56.3,
54.5, 45.9, 44.4, 43.3, 40.4, 36.4, 36.1, 29.4, 29.3, 29.2, 27.6,
23.4, 22.2, 20.8, 18.8, 12.1; HRMS: calcd. for C41H57NO3Na,
634.4236; found, 634.4231.
30 : 1) to give 34 (94.2 mg, 0.204 mmol, 84%). [α]D18
=
+15.2 (c 0.9, CHCl3); 1H NMR (300 MHz, CDCl3) δ 5.94 (ddd,
J = 7.2, 10.3, 17.2 Hz, 1H), 5.25 (d, J = 17.2 Hz, 1H), 5.22 (d,
J = 10.3 Hz, 1H), 4.85 (d, J = 8.9 Hz, 1H), 4.42 (dd, J = 2.4,
7.2 Hz, 1H), 3.91 (dd, J = 5.16, 10.6 Hz, 1H), 3.53 (ddd, J =
2.7, 5.5, 8.6, Hz, 1H), 3.08 (s, 3H), 2.59 (ddd, J = 2.4, 5.1,
17.2 Hz, 1H), 2.47 (ddd, J = 2.7, 5.1, 17.2 Hz, 1H), 208–2.02
(m, 1H), 0.91 (s, 9H), 0.89 (s, 9H), 0.15 (s, 3H), 0.12 (s,
3H), 0.088 (s, 3H), 0.059 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 138.3, 116.9, 81.1, 73.3, 71.3, 62.5, 42.3, 25.8,
25.7, 24.1, 18.0, −3.8, −4.1, −4.5, −4.7; HRMS: (ESI,
M + Na+) calcd for C21H43NO4SSi2Na, 484.2349; found,
484.2368.
2α-N-Acetyl-1α-25(OH)2 vitamin D3 (IIIa). [α]2D6 = +62.8
(c 0.6, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.46 (d, J =
11.4 Hz, 1H), 6.28 (d, J = 8.3 Hz, 1H), 5.93 (d, J = 11.5 Hz,
1H), 5.35 (d, J = 1.8 Hz, 1H), 5.09 (d, J = 1.9 Hz, 1H), 4.31 (d,
J = 3.3 Hz, 1H), 4.03–3.96 (m, 1H), 3.89 (ddd, J = 9.7, 9.7, 4.6
Hz, 1H), 2.83 (d, J = 12.8 Hz, 1H), 2.70 (dd, J = 13.7, 4.6 Hz,
1H), 2.34–2.25 (m, 1H), 2.08 (s, 3H), 2.08–0.80 (m, 30H), 0.53
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.2, 144.5, 144.0,
130.7, 126.1, 117.0, 116.6, 74.7, 71.1, 70.6, 58.1, 56.4, 56.3,
45.9, 44.3, 43.4, 40.4, 36.4, 36.1, 29.5, 29.4, 29.2, 27.6, 23.5,
23.4, 22.2, 20.8, 18.8, 12.1; HRMS: calcd for C29H47NO4Na,
496.3403; found, 496.3399.
2α-N,N′-Diethyl-1α-25(OH)2 vitamin D3 (IIb). To a solution
of 5 (37 mg, 0.09 mmol) and 14 (45 mg, 0.10 mmol) in toluene
and triethylamine (1 : 1, 2 mL) was added Pd(PPh3)4 (about
50 mg) at room temperature. The resulting mixture was stirred at
room temperature for 15 min and 90 °C for 2 h. The reaction
mixture was cooled to room temperature, and diluted with ethyl
acetate, filtered through a pad of Celite, and concentrated
7836 | Org. Biomol. Chem., 2012, 10, 7826–7839
This journal is © The Royal Society of Chemistry 2012

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2α-N-Pivaloyl-1α-25(OH)2 vitamin D3 (IIIb). [α]2D3 = +37.5
(c 1.8, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.48–6.37
(m, 2H), 5.94 (d, J = 11.4 Hz, 1H), 5.35 (s, 1H), 5.08 (s, 1H),
4.33 (d, J = 3.2 Hz, 1H), 4.05–3.93 (m, 1H), 3.93–3.84 (m, 1H),
2.82 (d, J = 12.3 Hz, 1H), 2.65 (dd, J = 13.5, 4.4 Hz, 1H),
56.4, 56.3, 45.9, 44.3, 41.6, 40.4, 36.3, 36.0, 29.3, 29.2, 29.1,
27.6, 23.4, 22.1, 20.8, 18.8, 12.1; HRMS: calcd for
C33H49NO5SNa, 594.3229; found, 594.3271.
2α-N-(4-tert-Butyl)-benzenesulfonyl-1α-25(OH)2 vitamin D3
(Vc). [α]1D8 = +12.0 (c 0.4, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 7.85 (d, J = 8.6 Hz, 2H), 7.55 (t, J = 8.6 Hz, 2H), 6.42
(d, J = 11.5 Hz, 1H), 5.87 (d, J = 10.9 Hz, 1H), 5.24 (d, J =
8.6 Hz, 1H), 5.11 (d, J = 1.7 Hz, 1H), 5.01 (d, J = 1.7 Hz, 1H),
3.90 (d, J = 3.5 Hz, 1H), 3.86 (ddd, J = 13.7, 9.1, 4.6 Hz, 1H),
3.22 (dt, J = 8.6, 3.4 Hz, 1H), 2.79 (d, J = 12.6 Hz, 1H), 2.68
(dd, J = 13.8, 4.6 Hz, 1H), 2.21 (t, J = 11.8 Hz, 1H), 2.10–0.60
(m, 39H), 0.50 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 156.9,
144.6, 143.8, 137.1, 130.2, 127.0, 126.3, 126.2, 116.8, 116.5,
73.4, 71.1, 68.7, 61.9, 56.4, 56.3, 45.9, 44.4, 41.6, 40.4, 36.3,
36.1, 31.6, 31.1, 29.4, 29.2, 29.1, 27.6, 23.5, 22.1, 20.8, 18.8,
12.0; HRMS: calcd for C37H57NO5SNa, 650.3855; found,
650.3858.
2.30 (t, J = 11.4 Hz, 1H), 2.05–0.80 (m, 39H), 0.52 (s, 3H); 13
C
NMR (100 MHz, CDCl3) δ 180.8, 144.2, 132.1, 128.5, 125.8,
116.7, 116.4, 74.2, 71.1, 70.8, 57.8, 56.4, 56.3, 45.9, 44.3, 43.2,
40.4, 38.9, 36.3, 36.1, 29.5, 29.3, 29.2, 27.7, 27.6, 23.5, 22.2,
20.8, 18.8, 12.0; HRMS: calcd for C32H53NO4Na, 538.3872;
found, 538.3834.
2α-N-Benzoyl-1α-25(OH)2 vitamin D3 (IIIc). [α]2D3 = +26.2 (c
1
1.3, CHCl3); H NMR (400 MHz, CDCl3) δ 7.89–7.31 (m, 5H),
6.98 (d, J = 8.0 Hz, 1H), 6.46 (d, J = 11.4 Hz, 1H), 5.97 (d, J =
11.4 Hz, 1H), 5.38 (s, 1H), 5.12 (s, 1H), 4.45 (d, J = 3.4 Hz,
1H), 4.25–4.17 (m, 1H), 4.09–4.00 (m, 1H), 2.83 (t, J =
13.1 Hz, 1H), 2.71 (dd, J = 13.8, 4.6 Hz, 1H), 2.36 (t, J =
11.8 Hz, 1H), 2.23–0.80 (m, 30H), 0.53 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 169.1, 144.1, 132.5, 132.0, 131.8, 131.0,
128.5, 127.2, 125.8, 116.8, 74.3, 71.1, 70.4, 58.5, 56.4, 56.3,
45.9, 44.3, 43.2, 40.4, 36.3, 36.1, 29.4, 29.3, 29.1, 27.6, 23.5,
22.2, 20.8, 18.8, 12.1; HRMS: calcd for C34H49NO4Na,
558.3559; found, 558.3540.
2α-N-(4-Methoxy)-benzenesulfonyl-1α-25(OH)2 vitamin D3 (Vd).
1
[α]2D0 = +12.2 (c 0.5, CHCl3); H NMR (500 MHz, CDCl3) δ
7.86 (d, J = 9.1 Hz, 2H), 7.00 (d, J = 8.6 Hz, 2H), 6.42 (d, J =
11.5 Hz, 1H), 5.87 (d, J = 11.5 Hz, 1H), 5.22 (d, J = 8.6 Hz,
1H), 5.18 (s, 1H), 5.03 (d, J = 1.1 Hz, 1H), 3.99 (d, J = 3.5 Hz,
1H), 3.88 (s, 3H), 3.88–3.81 (m, 1H), 3.19 (dt, J = 8.6, 3.5 Hz,
1H), 2.79 (d, J = 13.2 Hz, 1H), 2.67 (dd, J = 13.2, 4.6 Hz,
1H), 2.20 (t, J = 11.8 Hz, 1H), 2.10–0.60 (m, 39H),
0.50 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 163.1, 144.6,
143.8, 131.7, 130.3, 129.3, 126.1, 116.9, 116.5, 114.4,
73.4, 71.1, 68.7, 61.9, 56.4, 56.3, 55.6, 45.9, 44.3, 41.6, 40.4,
36.3, 36.0, 29.3, 29.2, 29.1, 27.6, 23.5, 22.1, 20.8, 18.8,
12.0; HRMS: calcd for C34H51NO6SNa, 624.3335; found,
624.3337.
2α-N-tert-Butoxycarbonyl-1α-25(OH)2 vitamin D3 (IVd).
1
[α]3D1 = +44.7 (c 0.8, CHCl3); H NMR (400 MHz, CDCl3) δ
6.44 (d, J = 11.0 Hz, 1H), 5.94 (d, J = 11.0 Hz, 1H), 5.35 (s,
1H), 5.07 (s, 1H), 4.35 (d, J = 2.7 Hz, 1H), 3.92–3.84 (m, 1H),
3.73–3.64 (m, 1H), 2.82 (d, J = 12.8 Hz, 1H), 2.67 (dd, J =
13.5, 4.8 Hz, 1H), 2.27 (t, J = 11.5 Hz, 1H), 2.06–0.72 (m,
30H), 1.46 (s, 9H), 0.52 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
157.2, 144.3, 144.1, 131.1, 128.0, 125.8, 116.7, 80.4, 74.7, 71.1,
70.5, 59.1, 56.4, 56.3, 45.9, 44.3, 43.2, 40.4, 36.3, 36.1, 29.7,
29.3, 29.2, 28.3, 27.6, 23.4, 22.2, 20.8, 18.8, 12.1; HRMS: calcd
for C32H53NO5Na, 554.3821; found, 554.3814.
2β-N,N′-Dibenzyl-1α-25(OH)2 vitamin D3 (VIIe). To a solu-
tion of 5 (40 mg, 0.0346 mmol) and 32 (42 mg, 0.0737 mmol)
in toluene and triethylamine (1 : 1, 2 mL) was added Pd(PPh3)4
(about 50 mg) at room temperature. The resulting mixture was
stirred at room temperature for 15 min, then 100 °C for 3 h. The
resulting mixture was cooled to room temperature, and diluted
with ethyl acetate, filtered through a pad of Celite, and concen-
trated in vacuo. The residue was purified by silica gel chromato-
graphy (hexane–ethyl acetate = 20 : 1) to give bis silylether. To a
solution of bis silylether in THF (1.0 mL) was added HF–Et3N
(1.0 mL), and the mixture was stirred for 15 h. To the reaction
mixture was added saturated NaHCO3, and the mixture was
stirred for 30 min. The resulting mixture was extracted with
ethyl acetate, and the organic layer was washed with brine. The
extracts were dried over MgSO4, filtered, and concentrated in
vacuo. The residue was purified by silica gel chromatography
(CHCl3–MeOH = 9 : 1) to give VIIe (8.7 mg, 0.0142 mmol,
21%). [α]1D8 = −35.3 (c 0.1, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 7.33–7.24 (m, 10H), 6.34 (d, J = 10.8 Hz, 1H), 6.08
(d, J = 10.8 Hz, 1H), 5.46 (s, 1H), 4.94 (s, 1H), 4.52 (s, 1H),
4.44 (d, J = 10.8 Hz, 1H), 4.16 (d, J = 13.7 Hz, 2H), 3.66 (d,
J = 13.7 Hz, 2H), 2.80 (dd, J = 3.4, 12.6 Hz, 1H), 2.56 (d, J =
10.8 Hz, 1H), 2.38–0.83 (m, 26H), 0.93 (d, J = 5.7 Hz, 3H),
0.53 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 143.7, 139.4,
131.7, 131.0, 128.8, 128.5, 127.1, 126.2, 116.9, 110.4, 71.0,
66.6, 66.0, 65.8, 56.4, 56.3, 54.2, 50.9, 45.9, 44.3, 40.3, 36.3,
2α-N-Methanesulfonyl-1α-25(OH)2 vitamin D3 (Va). [α]D14
=
+29.4 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.45
(d, J = 11.5 Hz, 1H), 5.93 (d, J = 11.4 Hz, 1H), 5.39 (s, 1H),
5.12 (s, 1H), 5.01 (d, J = 8.3 Hz, 1H), 4.47 (s, 1H), 4.00–3.87
(m, 1H), 3.51–3.38 (m, 1H), 3.01 (s, 3H), 2.82 (d, J = 11.9 Hz,
1H), 2.70 (dd, J = 13.5, 4.3 Hz, 1H), 2.35–2.20 (m, 1H),
2.10–0.75 (m, 30H), 0.53 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 144.6, 143.9, 130.3, 126.0, 116.9, 116.5, 74.2,
71.1, 69.3, 61.9, 56.5, 56.3, 46.0, 44.4, 42.1, 41.4, 40.4,
36.3, 36.1, 29.7, 29.4, 29.3, 27.6, 23.5, 22.2, 20.8, 18.8,
12.1; HRMS: calcd for C28H47NO5SNa, 532.3073; found,
532.3076.
2α-N-Benzenesulfonyl-1α-25(OH)2 vitamin D3 (Vb). [α]D17
=
1
+29.2 (c 0.8, CHCl3); H NMR (400 MHz, CDCl3) δ 7.94 (d,
J = 7.8 Hz, 1H), 7.62 (t, J = 7.4 Hz, 1H), 7.55 (t, J = 7.6 Hz,
2H), 6.42 (d, J = 11.4 Hz, 1H), 5.87 (d, J = 11.5 Hz, 1H), 5.31
(d, J = 8.3 Hz, 1H), 5.15 (s, 1H), 5.02 (d, J = 1.3 Hz, 1H), 3.94
(s, 1H), 3.91–3.81 (m, 1H), 3.23 (ddd, J = 8.7, 8.7, 3.2 Hz, 1H),
2.79 (d, J = 12.8 Hz, 1H), 2.67 (dd, J = 13.6, 4.9 Hz, 1H), 2.32
(s, 1H), 2.20 (t, J = 11.7 Hz, 1H), 2.05–0.82 (m, 30H), 0.50 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 144.6, 143.7, 140.3, 133.0,
130.2, 129.3, 127.1, 126.1, 116.9, 116.5, 73.4, 71.1, 68.7, 62.0,
This journal is © The Royal Society of Chemistry 2012
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2β-N-Substituted vitamin D derivatives VIIIa and Xa. As
described for VIIe, VIIIa and Xa were obtained from the corres-
ponding A-ring synthons (33 and 34), respectively.
2β-N-Acetyl-1α-25(OH)2 vitamin D3 (VIIIa). [α]2D0 = −15.6
1
(c 0.3, CHCl3); H NMR (500 MHz, CDCl3) δ 6.39–6.33 (m,
2H), 6.03 (d, J = 11.4 Hz, 1H), 5.59 (s, 1H), 5.09 (s, 1H),
4.13–4.04 (m, 2H), 3.96–3.89 (m, 1H), 2.80 (d, J = 10.8 Hz,
1H), 2.61 (d, J = 13.1 Hz, 1H), 2.15 (d, J = 14.3 Hz, 1H), 2.08
(s, 3H), 2.20–0.84 (m, 24H), 0.93 (d, J = 5.1 Hz, 3H), 0.54 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 172.4, 145.1, 144.1, 131.0,
125.9, 116.7, 112.2, 73.7, 71.0, 69.4, 58.4, 56.5, 56.3, 46.0,
44.3, 42.4, 40.3, 36.3, 36.0, 29.6, 29.3, 29.2, 27.5, 23.7, 23.3,
22.1, 20.7, 18.8, 11.8; HRMS: (ESI, M + Na+) calcd for
C29H47NO4Na, 496.3402; found, 496.3405.
2β-N-Methanesulfonyl-1α-25(OH)2 vitamin D3 (Xa). [α]D21
=
1
−41.4 (c 0.3, CHCl3); H NMR (400 MHz, CDCl3) δ 6.35 (d,
J = 10.9 Hz, 1H), 6.00 (d, J = 11.4 Hz, 1H), 5.52 (s, 1H), 5.24
(d, J = 8.24 Hz, 1H), 5.12 (s, 1H), 4.23–4.14 (m, 2H), 3.39–3.32
(m, 1H), 3.09 (s, 3H), 2.80 (d, J = 10.9 Hz, 1H), 2.57 (d, J =
14.6 Hz, 1H), 2.44 (d, J = 14.2 Hz, 1H), 2.09–0.84 (m, 24H),
0.93 (d, J = 5.9 Hz, 3H), 0.54 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 144.5, 144.1, 130.9, 125.7, 116.6, 112.3, 71.6, 71.1,
69.8, 62.6, 56.5, 56.3, 46.0, 44.3, 42.0, 41.4, 40.3, 36.3, 36.0,
29.6, 29.3, 29.2, 27.5, 23.7, 22.3, 20.7, 18.8, 11.8; HRMS: (ESI,
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M
+
Na+) calcd for C28H47NO5SNa, 532.3072; found,
532.3089.
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Acknowledgements
This study was supported in part by the Advanced research for
medical products Mining Programme of the National Institute of
Biomedical Innovation (NIBIO) and Grant-in Aid for Scientific
Research on Innovative Areas.
14 R. A. Friesner, J. L. Banks, R. B. Murphy, T. A. Halgren, J. J. Klicic,
D. T. Mainz, M. P. Repasky, E. H. Knoll, M. Shelley, J. K. Perry,
D. E. Shaw, P. Francis and P. S. Shenkin, J. Med. Chem., 2004, 47,
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15 Vitamin D3 derivatives were docked into the X-ray structure of VDR
(PDB code: 1DB1) using Glide 5.0 (Schrödinger, LLC). Hydrogen-
bonding interaction between compounds and VDR and their visualization
were generated by PyMOL (Schrödinger, LLC).
Notes and references
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7838 | Org. Biomol. Chem., 2012, 10, 7826–7839
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(Scheme 3) afforded 28 as a sole product. [α]2D2 = +12.5 (c 1.1, CHCl3).
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This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 7826–7839 | 7839