Synthesis of 2-ethyl-19-nor analogs of 1α,25-dihydroxyvitamin D 3

Article abstract of DOI:10.1002/ejoc.201201261

The synthesis of two new A-ring precursors, useful for the convergent assembly of 2α-ethyl and 2β-ethyl derivatives of 19-nor-1α,25- dihydroxyvitamin D₃, is described. These building blocks were prepared in 14 steps from quinic acid, which led to a new and practical synthesis of 2α-ethyl-14-epi-19-nor-20-epi-23-yne-1,25(OH) ₂D₃, an analog that shows a remarkably low calcemic effect in mice, while retaining the ability to promote cell differentiation and to inhibit cell proliferation in a number of human cancer cell lines. Two new phosphanone building blocks, useful for the stereocontrolled synthesis of 2-ethyl-substituted 19-nor analogs of 1α,25-dihydroxyvitamin D ₃, were prepared from quinic acid. This route offers an attractive practical solution for the introduction of these synthetically challenging but highly interesting A-ring modifications. Copyright

Full text of DOI:10.1002/ejoc.201201261

FULL PAPER
DOI: 10.1002/ejoc.201201261
Synthesis of 2-Ethyl-19-nor Analogs of 1α,25-Dihydroxyvitamin D3
Duchan R. Laplace,[a] Michel Van Overschelde,[a] Pierre J. De Clercq,[a]
Annemieke Verstuyf,[b] and Johan M. Winne*[a]
Keywords: Medicinal chemistry / Stereocontrolled synthesis / Chiral pool / Drug discovery / Vitamins
The synthesis of two new A-ring precursors, useful for the
convergent assembly of 2α-ethyl and 2β-ethyl derivatives of
19-nor-1α,25-dihydroxyvitamin D3, is described. These build-
ing blocks were prepared in 14 steps from quinic acid, which
led to a new and practical synthesis of 2α-ethyl-14-epi-19-
nor-20-epi-23-yne-1,25(OH)2D3, an analog that shows a re-
markably low calcemic effect in mice, while retaining the
ability to promote cell differentiation and to inhibit cell pro-
liferation in a number of human cancer cell lines.
decrease in calcemic potency can be achieved in the 19-nor
series by epimerisation at C-14.[8] One of these 14-epi-19-
nor analogs, inecalcitol (3),[9] is currently in phase II clinical
trials for the treatment of psoriasis and prostate cancer, and
is showing promising initial results.
Introduction
Since the discovery that 1α,25-dihydroxyvitamin D3 [1,
1α,25-(OH)2D3] has pronounced regulatory effects on the
development of malignant cells, i.e., the promotion of cell
differentiation and the inhibition of cell proliferation,[1]
there has been a huge interest in therapeutic applications of
this hormonally active metabolite of vitamin D3.[2] Other
research into the role of 1α,25-(OH)2D3 (1) has revealed
that, apart from its classical role in calcium homeostasis, it
is implicated in various interesting cellular processes such
as the production of cytokines, the secretion of insulin, and
blood-pressure regulation.[3] One of the major obstacles to
the therapeutic use of this natural secosteroid hormone is
its high toxicity, as the required supraphysiological doses
are known to cause major disruptions of calcium metabo-
lism (hypercalcemia). However, extensive structure–activity
relationship studies, facilitated by the synthesis of thou-
sands of structural analogs of 1α,25-(OH)2D3,[4] have
shown that a significant dissociation between the calcemic
and cell-differentiating activities can be achieved. Although
the precise mechanism of this dissociation is still unclear,[5]
a number of structural modifications have been associated
with a selective lowering of the hypercalcemic effects. No-
tably, the removal of the 19-exo-methylene functionality (cf.
2, Figure 1), as introduced by DeLuca,[6] is known to result
in diminished calcemic effects (2 is 10 times less calcemic
than 1), while retaining good or enhanced cell-differen-
tiating properties.[7] Our group has shown that a further
Figure 1. 1α,25-Dihydroxyvitamin D3 analogs and possible precur-
sors for the introduction of modified A-rings.
In a further exploration of 1α,25-(OH)2D3 analogs in the
14-epi-19-nor series,[10] we have examined the effect of alkyl-
ation at C-2, a modification that has been associated with
enhanced affinity for the vitamin D receptor (VDR),[11] the
biological target of 1α,25-(OH)2D3. Thus, 2α-ethyl-20-epi-
23-yne structure 4 was found to be a very promising analog.
It was shown to be 100 times less calcemic than 1, whilst
being 15 times more potent than 1 in inhibiting in vitro cell
proliferation (MCF-7 human cancer cells).[12] Although the
[a] Laboratory for Organic Synthesis, Department of Organic
Chemistry, Ghent University,
Krijgslaan 281 S4, 9000 Gent, Belgium
Fax: +32-9-264-49-98
E-mail: johan.winne@ugent.be
Homepage: http://www.orgchem.ugent.be/
[b] Clinical and Experimental Endocrinology, KULeuven
Herestraat 49, box 902, 3000 Leuven, Belgium
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201261.
728
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Eur. J. Org. Chem. 2013, 728–735

2-Ethyl-19-nor Analogs of 1α,25-Dihydroxyvitamin D3
strategy adopted for the synthesis of these 2-alkyl analogs
allowed the stereocontrolled synthesis of a large number of
epimers from common advanced intermediates, the synthe-
sis of compound 4 (and other 2-ethyl derivatives) in particu-
lar by this method proved to be quite troublesome, which
meant that very little material was produced (around 0.1%
overall yield over 21 steps in the longest linear sequence
starting from 4-ethyl benzoic acid).[10,12] To enable further
in vivo evaluation of this highly potent analog, we decided
to investigate a new synthetic route that could provide more
material. A total change in strategy was prompted by the
many problems encountered in our previous route towards
the 2-ethyl-substituted A-rings.[13] We envisaged the synthe-
sis of a 2α-ethyl-A-ring precursor 6 from readily available
d-quinic acid 5 (Figure 1). Phosphanone building block 6
could be coupled to readily available CD-ring ketone frag-
ments by the convergent Lythgoe coupling strategy,[14]
well-established stereoselective method for the convergent
construction of a range of similar 1α,25(OH)2D3 analogs.
a
Scheme 1. Olefination and alkylation strategies via known ketone
intermediate 8. Reagents and conditions: (a) NaHCO3, Dess–
Martin periodinane (1.5 equiv.), CH2Cl2; (b) Tebbe’s reagent
Cp2TiCH2ClAl(CH3)2 (3.3 equiv.), THF/toluene, –78 °C to room
temp. (TBS = tert-butyldimethylsilyl).
Results and Discussion
The highly efficient methylenation of C-4 of the quinic
In the pioneering studies of DeLuca et al. into the influ- acid derivatives (Scheme 1) now opened the possibility of
ence of alkyl substitution at C-2 of 19-nor-1α,25-(OH)2- arriving at the required 4-ethyl substituents (cf. 6, Figure 1)
D3(1),[15] a synthetic route was described based on an ole- by a homologation strategy.[17] Such a sequence, although
fination reaction of ketone 8 (and its derivatives), an inter- requiring more steps, would avoid the apparently stericaly
mediate that can be easily obtained from quinic acid 5 encumbered or otherwise demanding reactions at C-4.
(Scheme 1). We decided to adopt this relatively straightfor- Thus, the α-hydroxy ester in 11 was converted into the vici-
ward strategy to develop a route towards the envisaged A- nal diol by sodium borohydride reduction, and the diol was
ring precursor (i.e., 6). In our hands, oxidation of alcohol protected as its benzylidene acetal (12, Scheme 2). Initially,
7[16] with Dess–Martin periodinane proved to be the most the corresponding acetonide was prepared, but this protect-
efficient method for preparing this ketone. Consistent with ing group proved difficult to remove later on in the se-
the results reported by DeLuca,[15b] we found that the steri- quence. Treatment of exo-methylenecyclohexane 12 with an
cally congested C-4 ketone functionality of 8 was quite re- excess of borane–THF complex, and oxidation of the re-
sistant towards most olefination reactions. The use of stan- sulting alkylborane with hydrogen peroxide in the presence
dard Wittig or Horner–Wadsworth–Emmons olefination of sodium hydroxide, gave the expected primary alcohol
procedures led mostly to decomposition of the starting ma- (i.e., 13) as a mixture of four diastereoisomers. Oxidation
terial, yielding only traces of the desired olefins (i.e., 9a or of the primary hydroxy group to the corresponding alde-
9b, respectively). When a Wittig olefination was performed hyde with Dess–Martin periodinane, followed by a smooth
with the sterically less demanding methylidenetri- Wittig olefination with methylenetriphenylphosphorane,
phenylphosphorane, the expected methylenated product next gave vinylcyclohexane intermediate 14. Catalytic hy-
(i.e., 11) was obtained in a reproducible 25% yield, as was drogenation in the presence of palladium on activated car-
previously reported by DeLuca.[15a] Alternatively, the intro- bon readily saturated the vinyl group to give the desired
duction of the required two-carbon fragment proceeded rel- ethyl substituent and conveniently removed the benzylidene
atively smoothly by reaction of ketone 8 with either ethyl- acetal protecting group as well. Oxidative cleavage of the
magnesium bromide or vinylmagnesium bromide. However, resulting vicinal diol (i.e., 15) then gave cyclohexanone 16
all attempts at deoxygenation of the resulting tertiary C-4 as a single diastereoisomer. A Peterson-type olefination
hydroxy groups in 10a or 10b (or their derivatives) failed, with the anion derived from methyl (trimethylsilyl)acetate,
as this hydroxy group proved quite inert to further derivati- finally gave α,β-unsaturated ester 17 in a very good overall
sation. Finally, after screening a large number of different yield of 30% (starting from quinic acid). As can be expected
conditions for the olefination of ketone 8, we found that in this type of pseudo-C2-symmetric substrate, the stereo-
Tebbe’s reagent, at –78 °C, gave methylenated derivative 11 chemical induction of the silyloxy ether substituents was
in excellent yield. The remarkable superiority of Tebbe’s very low, and compound 17 was obtained as a 3:2 mixture
reagent in this case can be readily rationalised by the small of (Ra) and (Sa) axial epimers. These diastereoisomers could
steric demand and low basicity of this reagent.
not be separated at this stage.
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J. M. Winne et al.
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Scheme 3. Diastereomer separation and synthesis of the phos-
phanone A-ring precursors. Reagents and conditions: (a) iBu2AlH,
CH2Cl2, –78 °C to room temp., 3 h; (b) nBuLi, THF, 0 °C, 30 min;
TsCl, 0 °C, 10 min; LiPPh2, 0 °C, 1 h; H2O2, CH2Cl2, 0 °C to room
temp., 30 min.
Scheme 2. Homologation by a hydroboration/oxidation/olefination
sequence. Reagents and conditions: (a) NaBH4, MeOH; (b) benzal-
dehyde dimethyl acetal, PPTS (pyridinium para-toluenesulfonate),
CH2Cl2, 40 °C, 22 h; (c) BH3·THF, THF, 0 °C to room temp., 1 h;
NaOH, H2O2, 0 °C to room temp., 1 h; (d) Dess–Martin
periodinane (1.5 equiv.), NaHCO3, CH2Cl2, room temp., 1 h;
(e) Ph3P=CH2, –30 °C to room temp., 2 h; (f) Pd(OH)2/C, H2
(1 atm), EtOH, CH2Cl2; (g) NaIO4, H2O, MeOH, 0 °C to room
temp., 2 h, (h) Me3SiCH2CO2Me, LDA, THF, –78 °C, 2 h.
Reduction of enoate methyl esters 17 with diisobutylalu-
minium hydride gave the corresponding allylic alcohols (i.e.,
18 and 19), which were readily separated by chromatog-
raphy on silica gel (Scheme 3). Finally, the lithium anion
derived from 18 was tosylated and treated with lithium di-
phenylphosphide, and the resulting phosphane was oxidised
in situ with hydrogen peroxide to give the desired A-ring
precursor (i.e., 6). Likewise, epimer 19 was converted into
the corresponding A-ring phosphanone (i.e., 20).
Figure 2. Stereochemical assignments based on the analysis of
NMR spectra, showing the observed diagnostic nuclear Overhauser
effects (NOE).
desired 1α,25(OH)2D3 analog (i.e., 4; Scheme 4). Deproton-
The stereochemistry of the axial asymmetry around the ation of phosphanone 6, followed by Horner–Wittig reac-
exocyclic double bond in allylic alcohols 18 and 19, was tion (Lythgoe coupling) with known ketone 21[18] readily
unambiguously established through a detailed examination gave conjugated diene 22 as a single olefinic isomer.
1
of their 1D and 2D H and 13C NMR spectra, including Lythgoe couplings are usually run with a two- to three-fold
NOESY experiments (Figure 2). The protons attached to excess of the phosphanone, a procedure that reliably gives
the stereogenic carbon centers, which adopt axial and equa- high conversions of the ketone reaction partner. For our
torial orientations in the preferred chair conformation, were purposes, we chose to run this reaction using an excess of
easily identified for both epimers by examination of their ketone 21, as this can be prepared in only five steps from
vicinal coupling constants. Then COSY correlations al- readily available vitamin D2.[18] This approach gave better
lowed the identification of the neighbouring cyclohexane conversions of phosphanone fragment 6, mainly because it
methylene protons, and these in turn showed very clear nu- allowed a much better (and more reliable) recovery of the
clear Overhauser effects (NOE) across the exocyclic alkene, unreacted phosphanone starting material. Finally, treat-
which allowed the assignment of 18 as the (Sa) isomer and ment of a methanolic solution of coupled product 22 with
19 as the (Ra) isomer [corresponding to α and β orienta- dilute hydrochloric acid removed both the silyl ether and
tions, respectively, of the ethyl substituent in the final 1α,25- the ethoxyethyl ether protecting groups. The resulting triol
1
(OH)2D3 structure].
gave H and 13C NMR spectra that matched those of ana-
With the 2α-ethyl A-ring precursor phosphanone (i.e., 6) log 4 obtained in our previous synthesis. Furthermore, ini-
in hand, we turned our attention to the synthesis of the tial biological experiments have confirmed the previously
730
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Eur. J. Org. Chem. 2013, 728–735

2-Ethyl-19-nor Analogs of 1α,25-Dihydroxyvitamin D3
60 °C), referred to as petroleum ether herein. TLC plates were visu-
alized by using anisaldehyde (5% anisaldehyde in ethanol with 1%
sulfuric acid) or PMA (5% phosphomolybdic acid in ethanol) solu-
tions. Flash column chromatography was performed by using
BIOSOLVE silica gel (0.063–0.200 mm particle size, 20–30 g silica/
1 g compound). HPLC separations were performed with a Kontron
420 delivery system with refractive-index detection. 1H NMR spec-
tra were recorded at 300 or 500 MHz, 13C NMR spectra were re-
corded at 75 or 125 MHz. Chemical shifts (δ) are reported in units
of parts per million (ppm), with the residual 1H or 13C peaks of
the solvent used as internal standards (CDCl3: δH = 7.26 ppm and
δC = 77.16 ppm). Where given, proton shifts of overlapping signals
were determined from an HSQC spectrum. The following abbrevi-
ations are used to explain the observed multiplicities: s, singlet; d,
doublet; t, triplet; q, quadruplet; m, multiplet; br., broad; band,
several overlapping signals; AB, AB system with strongly skewed
signals; app, apparent (only the observed average coupling constant
can be quoted, in the absence of information on the real J values).
Where given, assignments of resonances were confirmed by stan-
dard COSY, HSQC, and HMBC 2D NMR experiments. Infrared
spectra (IR) were recorded with a Perkin–Elmer 1600 series FTIR
spectrometer and are reported in wavenumbers (cm–1). Samples
were prepared as thin films (neat) on KBr plates. Mass spectra
(MS) were recorded with an Agilent ESI single quadrupole detector
type VL. High resolution mass spectra (HRMS) were recorded
with an Agilent Accurate-Mass Quadrupole Time-of-Flight mass
spectrometer. Melting point ranges were determined with an Elec-
trothermal 9100 melting point apparatus.
observed high degree of dissociation of the calcemic and
cell-differentiating activities of this analog.
Scheme 4. Synthesis of 2α-ethyl analog 4. Reagents and conditions:
(a) nBuLi (1.0 equiv.), THF, –78 °C to 0 °C, 10 min; then 21
(2.4 equiv.), –78 °C to 0 °C, 2 h (brsm = based on recovered starting
material); (b) MeOH, HCl (1% aq.), room temp., 18 h.
Conclusions
A second-generation synthesis has been investigated for
a 1α,25-(OH)2D3 analog 4 that has shown one of the most
promising biological activities with respect to the develop-
ment of therapeutic applications. The synthesis was com-
pleted in 16 steps from readily available d-quinic acid,
which shortens the longest linear sequence by five steps
compared to the previous synthesis, and the overall yield
was improved over the previous synthesis by more than an
Methyl (3R,5R)-3,5-Bis[(tert-butyldimethylsilyl)oxy]-1-hydroxy-4-
oxocyclohexanecarboxylate (8): Anhydrous sodium hydrogen carb-
onate (5.52 g, 76.6 mmol) was added to a solution of alcohol 7[15a]
(4.16 g, 9.58 mmol) in dichloromethane (80 mL). The resulting
heterogeneous mixture was stirred at room temperature, and Dess–
Martin periodinane (6.09 g, 14.4 mmol) was added portionwise
order of magnitude [1.3% (3.0% brsm) vs. 0.1%]. This will over a 10 min period. After stirring for a further 3 h, sodium hydro-
gen carbonate (satd. aq.; 75 mL) and sodium thiosulfate (satd. aq.;
75 mL) were added, and the resulting biphasic mixture was stirred
vigorously for 30 min or until two clear liquid phases were ob-
tained. The separated aqueous phase was extracted with dichloro-
methane (2ϫ 200 mL), and the combined organic extracts were
dried with magnesium sulfate and concentrated under reduced
pressure. The crude residue was dissolved in petroleum ether and
filtered through a small plug of silica gel (20 g), which was washed
with a 9:1 mixture of petroleum ether/ethyl acetate. The filtrate was
concentrated in vacuo to give ketone 8 (4.14 g, Ͼ99%) as a color-
allow an extensive evaluation of this analog in a number of
animal disease models, and this research is now underway.
For this new synthesis, a highly practical route was devel-
oped to A-ring precursor fragments 6 and 20, which can be
used to incorporate a 19-nor-2-ethyl A-ring into a range of
new analogs of 1α,25-(OH)2D3 with complete control of the
stereochemistry. These structural modifications have been
associated with consistently improved biological activities,
but the synthesis of such modified analogs has been prob-
lematic until now. Our 14-step route to these two building less oil that solidified upon refrigerated storage. It gave a 1H NMR
spectrum identical to that described in the literature.[15a] M.p. 46–
blocks lends itself well to laboratory scale up, as more than
half of these steps gave crude products that could be used
without further purification (only 6 chromatographic purifi-
cations were required).
In conclusion, this work offers a complementary ap-
proach to C-2-functionalised analogs of 1α,25-(OH)2D3.
46.5 °C (recryst. from CH2Cl2). [α]2D1 = –13.1 (c = 1.00, CHCl3).
IR: ν
= 3464, 1730 (s), 1464 (m), 1449 (m) cm–1. 1H NMR
˜
max
(500 MHz, CDCl3, 21 °C): δ = 5.03 (dd, J = 11.6 and 6.5 Hz, 1 H,
Si-O-CH), 4.61 (s, 1 H, -OH), 4.40 (t, J = 3.5 Hz, 1 H, Si-O-CH),
3.78 (s, 3 H), 2.54 (ddd, J = 13.3, 6.5, and 3.6 Hz, 1 H), 2.36 (dd,
J = 14.9 and 3.5 Hz, 1 H), 2.27 (dt, J = 14.9 and 3.5 Hz, 1 H), 2.21
(dd, J = 13.3 and 11.6 Hz, 1 H), 0.91 (s, 9 H), 0.90 (s, 9 H), 0.13
(s, 3 H), 0.12 (s, 3 H), 0.09 (s, 3 H), 0.05 (s, 3 H) ppm. 13C NMR
(125 MHz, CDCl3, 21 °C): δ = 206.6 (C), 173.2 (C), 76.1 (CH), 75.4
(C), 69.9 (CH), 53.0 (CH3), 46.8 (CH2), 41.3 (CH2), 25.9 (CH3),
25.7 (CH3), 18.5 (C), 18.0 (C), –4.7 (CH3), –5.0 (CH3), –5.2 (CH3),
–5.2 (CH3) ppm. HRMS (ESI): calcd. for C20H41O6Si2 [M + H]+
433.2436; found 433.2434.
Experimental Section
General Information: All chemicals and solvents were purchased
and used without any further purification, except dichloromethane,
which was distilled from CaH2 prior to use. All reactions were per-
formed under argon or nitrogen with magnetic stirring and were
monitored by thin layer chromatography (TLC) using SIL G-25
UV254 pre-coated silica gel plates (0.25 mm thickness). The stan-
dard non-polar eluant used was petroleum ether (boiling range 40–
Methyl (3R,5R)-3,5-Bis[(tert-butyldimethylsilyl)oxy]-1-hydroxy-4-
methylenecyclohexanecarboxylate (11): The preparation of Tebbe’s
reagent was adapted from Grubbs’ procedure: A reaction vessel
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J. M. Winne et al.
FULL PAPER
was charged with titanocene dichloride (7.99 g, 31.1 mmol) and
kept under a constant flow of dried argon. By using a cannula, a
solution of trimethylaluminium (2 m solution in toluene; 34.2 mL,
68.4 mmol) was slowly added to the solid titanocene dichloride at
room temperature, and the resulting mixture was stirred under a
small but constant flow of dried argon for 72 h. Then, additional
trimethylaluminium (2 m solution in toluene; 12.5 mL, 24.9 mmol)
was added, and the dark red-brown solution was stirred for a fur-
ther 20 h. In a separate reaction flask, a solution of 8 (4.00 g,
9.24 mmol) in tetrahydrofuran (20 mL) was cooled to –78 °C, and
then the solution of freshly prepared Tebbe’s reagent obtained
above (ca. 50 mL, max. 31.1 mmol) was slowly added to this solu-
tion by cannula over a 40 min period. The resulting mixture was
stirred at –78 °C for a further 20 min, and then allowed to warm
gradually to room temperature over 1 h. After stirring at room tem-
perature for 30 min, the mixture was cooled to –78 °C, and then
sodium hydroxide (1.0 m aq.; 8 mL) was carefully added. The re-
sulting heterogeneous mixture was stirred vigorously and allowed
to warm slowly to 0 °C, and then further sodium hydroxide (1.0 m
aq.; 80 mL) was added. The mixture was then poured into tert-
butyl methyl ether (200 mL), and the separated aqueous phase was
further extracted with dichloromethane (3ϫ 100 mL). The com-
bined organic extracts were dried with magnesium sulfate and con-
centrated under reduced pressure. Flash chromatography (petro-
leum ether/ethyl acetate, 98:2) gave hydroxy ester 11 (3.78 g, 95%)
as a colorless oil that solidified upon refrigerated storage, and gave
(s, 3 H, Si-Me), 0.06 (s, 3 H, Si-Me) ppm. 13C NMR (125 MHz,
CDCl3, 21 °C): δ = 151.1 (C), 107.7 (CH2), 75.3 (CH), 74.2 (CH2),
70.3 (CH2), 66.1 (CH), 45.6 (CH2), 40.0 (CH2), 25.6 (CH3), 25.3
(CH3), –5.04 (CH3), –5.1 (CH3), –5.2 (CH3), –5.7 (CH3) ppm.
HRMS (ESI): calcd. for C20H43O4Si2 [M + H]+ 403.2694; found
403.2689.
This crude diol (1.88 g, 4.86 mmol) was dissolved in dichlorometh-
ane (60 mL), and benzaldehyde dimethyl acetal (5.60 mL,
37.45 mmol) and pyridinium p-toluenesulfonate (58.7 mg,
0.234 mmol) were added. The resulting mixture was warmed to
40 °C and stirred at this temperature for 22 h. The reaction mixture
was poured into sodium hydrogen carbonate solution (satd. aq.;
50 mL). The organic phase was separated, and the aqueous phase
was extracted with dichloromethane (3ϫ 100 mL). The combined
organic extracts were washed with brine (30 mL), dried with mag-
nesium sulfate and concentrated under reduced pressure. The resi-
due was co-evaporated with toluene (3ϫ 50 mL) and dried in
vacuo. This gave dioxolane 12 (2.36 g, Ͼ99%) as a colorless viscous
oil, as the expected 1:1 mixture of acetal epimers (as judged by
integration of the 1H NMR spectrum). 1H NMR (300 MHz,
CDCl3, 21 °C): δ = 7.48 (m, 2 H, ArH), 7.35 (m, 3 H, ArH), 5.81
[s, 0.5 H, (RO)2CHPh], 5.80 [s, 0.5 H, (RO)2CHPh], 5.07 (br. d, J
= 5.0 Hz, 1 H, =CH2), 4.90 (br. d, J = 5.0 Hz, 1 H, =CH2), 4.54
(d, J = 3.0 Hz, 0.5 H), 4.51 (d, J = 3.1 Hz, 0.5 H), 4.44 (d, J =
4.6 Hz, 0.5 H), (d, J = 4.6 Hz, 0.5 H), 4.16 (d, J = 9.1 Hz, 0.5 H),
4.14 (d, J = 8.2 Hz, 0.5 H), 3.97 (d, J = 9.1 Hz, 0.5 H), 3.95 (d, J
= 8.2 Hz, 0.5 H), 2.34 (dd, J = 11.2 and 4.6 Hz, 0.5 H), 2.31 (dd,
J = 12.1 and 4.6 Hz, 0.5 H), 2.02 (dd, J = 11.2 and 3.0 Hz, 0.5 H),
1.98 (dd, J = 12.1 and 3.1 Hz, 0.5 H), 1.97 (m, 1 H), 1.67 (m, 1
H), 0.93 (s, 4.5 H), 0.91 (s, 4.5 H), 0.89 (s, 4.5 H), 0.87 (s, 4.5 H),
0.10 (s, 1.5 H), 0.08 (s, 1.5 H), 0.07 (s, 1.5 H), 0.06 (s, 1.5 H), 0.05
(s, 1.5 H), 0.03 (s, 1.5 H), 0.02 (s, 1.5 H), 0.01 (s, 1.5 H) ppm.
a
1H NMR spectrum that corresponded to that reported in the
literature.[15a] M.p. 29 °C (recryst. from CH2Cl2). [α]2D1 = –34.7 (c =
1.03, CHCl ). IR: ν
= 3467 (br), 1739 (s), 1250 (s) cm–1. 1H
˜
3
max
NMR (500 MHz, CDCl3, 21 °C): δ = 5.16 (t, J = 1.7 Hz, 1 H,
C=CHH), 4.96 (2 overlapping s, 2 H, OH and C=CHH), 4.77 [br.
dd, J = 11.3 and 4.8 Hz, 1 H, Si-O-CH], 4.69 (t, J = 3.0 Hz, 1 H,
Si-O-CH), 3.75 (s, 3 H, -O-CH3), 2.30 (dd, J = 12.3 and 4.8 Hz, 1
H, CHH-COSi), 2.09 (d, J = 3.0 Hz, 2 H, 2 CHH-COSi), 1.80 (dd,
J = 12.3 and 11.3 Hz, 1 H, CHH-COSi), 0.91 (s, 9 H, Si-CMe3),
0.88 (s, 9 H, Si-CMe3), 0.11 (s, 3 H, Si-Me2), 0.08 (s, 3 H, Si-
Me2), 0.08 (s, 3 H, Si-Me2), 0.07 (s, 3 H, Si-Me2) ppm. 13C NMR
(125 MHz, CDCl3, 21 °C): δ = 174.0 (C), 150.4 (C), 108.6 (CH2),
76.8 (C), 75.4 (CH), 66.1 (CH), 52.7 (CH3), 46.7 (CH2), 41.0 (CH2),
26.0 (3 CH3), 25.8 (3 CH3), 18.4 (C), 18.0 (C), –4.7 (CH3), –4.7
(CH3), –4.8 (CH3), –5.2 (CH3) ppm. HRMS (ESI): calcd. for
C21H43O5Si2 [M + H]+ 431.2644; found 431.2646.
{(7R,9R)-7,9-Bis[(tert-butyldimethylsilyl)oxy]-2-phenyl-1,3-dioxa-
spiro[4.5]decan-8-yl}methanol (13): A solution of dioxolane 12
(1.15 g, 2.57 mmol) in tetrahydrofuran (80 mL) was cooled to 0 °C,
and a solution of borane–tetrahydrofuran complex (1 m in tetra-
hydrofuran; 7.71 mL, 7.71 mmol) was added. The resulting mixture
was stirred at room temperature for 1 h. The reaction mixture was
cooled to 0 °C, and then sodium hydroxide (15% aq.; 32.8 mL)
was added, followed by hydrogen peroxide (35% aq.; 47.9 mL). The
resulting mixture was warmed to room temperature and stirred vig-
orously for 1 h. Ammonium chloride solution (satd. aq.; 20 mL)
was added, and the heterogeneous mixture was concentrated under
reduced pressure. The aqueous residue (ca. 80 mL) was extracted
with dichloromethane (4ϫ 100 mL), and the combined organic ex-
tracts were washed with sodium thiosulfate (satd. aq.; 40 mL) and
brine (40 mL), then dried with magnesium sulfate and concentrated
under reduced pressure. This gave crude alcohol 13 (0.98 g, 75%)
as a colorless oil. This mixture of four diastereoisomers was imme-
diately used in the next step without further purification. HRMS
(ESI): calcd. for C27H49O5Si2 [M + H]+ 509.3113; found 509.3114.
{[(7R,9R)-8-Methylene-2-phenyl-1,3-dioxaspiro[4.5]decane-7,9-diyl]-
bis(oxy)}bis(tert-butyldimethylsilane) (12): A solution of α-hydroxy
ester 11 (2.13 g, 4.96 mmol) in methanol (12 mL) was cooled to
0 °C, and sodium borohydride (600 mg, 15.9 mmol) was added.
The reaction mixture was stirred at room temperature overnight,
and then water (10 mL) and brine (10 mL) were added. The re-
sulting heterogeneous mixture was stirred for 30 min and then con-
centrated under reduced pressure. The aqueous residue (ca. 20 mL)
was extracted with dichloromethane (5ϫ 100 mL). The combined
organic extracts were dried with magnesium sulfate and concen-
trated under reduced pressure to give the expected diol (1.99 g,
Ͼ99%) as a colorless solid, which was immediately used in the
next step. Data for this intermediate: 1H NMR (500 MHz, CDCl3,
{[(7R,9R)-2-Phenyl-8-vinyl-1,3-dioxaspiro[4.5]decane-7,9-diyl]bis-
(oxy)}bis(tert-butyldimethylsilane) (14): Anhydrous sodium hydro-
gen carbonate (860 mg, 11.9 mmol) was added to a solution of
21 °C): δ = 5.11 (br. s, 1 H, =CHH), 4.90 (br. s, 1 H, =CHH), 4.78 alcohol 13 (700 mg, 1.51 mmol) in dichloromethane (30 mL). The
(br. s, 1 H, Si-O-CH), 4.76 (br. s, 1 H, HOCH2COH), 4.64 (br. s, resulting heterogeneous mixture was stirred at room temperature,
1 H, Si-O-CH), 3.37 (dd, J = 11.0 and 3.0 Hz, 1 H, CHHOH), 3.28 and Dess–Martin periodinane (960 mg, 2.26 mmol) was added por-
(dd, J = 11.0 and 7.6 Hz, 1 H, CHHOH), 2.26 (dd, J = 7.6 and tionwise over a 10 min period. After stirring for 1 h, sodium hydro-
3.0 Hz, 1 H, CH2OH), 2.07 (2 overlapping br. d, J = 13.0 Hz, 2 H, gen carbonate (satd. aq.; 10 mL) and sodium thiosulfate (satd. aq.;
2 CHH-COSi), 1.50 [br. d, J = 13.0 Hz, 1 H, CHH-COSi], 1.32 [br. 10 mL) were added. The resulting biphasic mixture was stirred vig-
d, J = 13.0 Hz, 1 H, CHH-COSi], 0.91 [s, 9 H, Si-C(CH3)3], 0.88 orously for 30 min or until two clear liquid phases were obtained.
[s, 9 H, Si-C(CH3)3], 0.10 (s, 3 H, Si-Me), 0.08 (s, 3 H, Si-Me), 0.07
The separated aqueous phase was extracted with dichloromethane
732
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 728–735

2-Ethyl-19-nor Analogs of 1α,25-Dihydroxyvitamin D3
(4ϫ 50 mL), and the combined organic extracts were washed with
brine (20 mL), dried with magnesium sulfate, and concentrated un-
der reduced pressure. The crude residue (696 mg) was immediately
used in the next step. For this, a solution of n-butyllithium (2.5 m
methyl (trimethylsilyl)acetate (406 μL, 2.47 mmol) was added drop-
wise, and the reaction mixture was stirred at –78 °C for an ad-
ditional 10 min. A solution of ketone 16 (272 mg, 0.68 mmol) in
tetrahydrofuran (1.4 mL) was then added to the reaction mixture
in hexanes; 1.62 mL, 4.05 mmol) was added dropwise to a stirred by cannula. The resulting mixture was stirred at –78 °C for 2 h,
suspension of methyltriphenylphosphonium bromide (1.47 g,
4.12 mmol) in tetrahydrofuran (120 mL) at –50 °C. The resulting
bright yellow mixture was stirred vigorously and warmed to –10 °C
over 1 h. The reaction mixture was then cooled to –30 °C, at which
point a solution of the aldehyde obtained above (696 mg) in tetra-
hydrofuran (10 mL) was added dropwise over 5 min. The resulting
mixture was stirred at –30 °C for 30 min and was then warmed
slowly to room temperature over 90 min. The reaction mixture was
diluted with petroleum ether (100 mL), and the precipitate was re-
moved by filtratrion through a plug of Celite, which was washed
thoroughly with petroleum ether (5ϫ 50 mL). The combined fil-
trates were concentrated under reduced pressure to give dioxolane
14 (518 mg, 75% over two steps, mixture of four diastereoisomers)
as a colorless oil, which was used in the next step without further
purification. HRMS (ESI): calcd. for C28H49O4Si2 [M + H]+
505.3164; found 505.3152.
and then ammonium chloride (satd. aq.; 2 mL) was added. After
warming to room temperature, the mixture was poured into dichlo-
romethane (50 mL) and water (20 mL), and extracted with dichlo-
romethane (2ϫ 50 mL). The organic extract was dried with magne-
sium sulfate and concentrated under reduced pressure. Flash
chromatography (petroleum ether/ethyl acetate, 9:1 to 1:9 gradient)
gave methyl enoate 17 (238 mg, 77%) as a colorless oil [obtained
as a 2:3 mixture of (Ra) and (Sa) isomers, determined by integration
of the H NMR spectrum]. H NMR (300 MHz, CDCl3, 21 °C): δ
= 5.72 (br. s, 0.4 H, CH=), 5.63 (br. s, 0.6 H, CH=), 4.17 (m, 1 H,
Si-O-CHeq), 3.81 (m, 1 H, Si-O-CHax), 3.69 (br. s, 1.8 H, OCH3),
3.67 (br. s, 1.2 H, OCH3), 3.54 (m, 1 H, -CHH-C=), 2.48–2.05
(band, 3 H, -CHH-C = and CH2-C=), 1.65–1.55 (m, 1 H, EtCH),
1.45–1.35 (m, 2 H, CH3CH2), 0.92 (t, J = 7.2 Hz, 3 H, CH2CH3),
0.90 [s, 9 H, SiC(CH3)3], 0.86 [s, 5.4 H, SiC(CH3)3], 0.83 (s, 3.6 H,
SiC(CH3)3), 0.07–0.03 [band of overlapping s, 12 H, 2 Si(CH3)2]
ppm. HRMS (ESI): calcd. for C23H47O4Si2 [M + H]+ 443.3007;
found 443.3000.
1
1
(3R,5R)-3,5-Bis[(tert-butyldimethylsilyl)oxy]-4-ethyl-1-(hydroxy-
methyl)cyclohexanol (15): A solution of crude dioxolane 14
(325 mg, 0.64 mmol) in dichloromethane (12 mL) was added to a
suspension of palladium hydroxide [20 wt.-% loading (dry basis) on
carbon; 300 mg, ca. 0.3 mmol] in ethanol (12 mL). The reaction
vessel was purged and placed under hydrogen. The mixture was
stirred vigorously for 2 h, then purged with nitrogen and filtered
through a plug of Celite, which was washed extensively with tert-
butyl methyl ether. The combined filtrates were concentrated under
reduced pressure to give diol 15 (268 mg, Ͼ99%) as a colorless
solid (mixture of cis and trans diastereoisomers). HRMS (ESI):
calcd. for C21H47O4Si2 [M + H]+ 419.3007; found 419.3022.
(Sa)-2-{(3R,5R)-3,5-Bis[(tert-butyldimethylsilyl)oxy]-4-ethyl-
cyclohexylidene}ethanol (18) and (Ra)-2-{(3R,5R)-3,5-Bis[(tert-
butyldimethylsilyl)oxy]-4-ethylcyclohexylidene}ethanol (19): A solu-
tion of diisobutylaluminium hydride (1.2 m in toluene; 4.56 mL,
5.48 mmol) was added dropwise to a stirred solution of methyl eno-
ate 19 (336 mg, 0.75 mmol, 3:2 epimer ratio) in dichloromethane
(4.0 mL), cooled to –78 °C. The resulting mixture was stirred at
–78 °C for 1 h and was then allowed to slowly warm to room tem-
perature over 2 h. Then, potassium sodium tartrate (2.0 m aq.;
5 mL) was added, and the resulting heterogeneous mixture was
stirred vigorously for 30 min. After the addition of water (15 mL)
and dichloromethane (50 mL), the phases were separated, and the
aqueous phase was further extracted with dichloromethane (3ϫ
25 mL). The combined organic extratcs were dried with magnesium
sulfate and concentrated under reduced pressure. The crude residue
was subjected to flash chromatography (petroleum ether to petro-
leum ether/ethyl acetate, 9:1, gradient), which gave three fractions:
(Ra) epimer 19 eluted first as a pure diastereomer (112 mg), fol-
lowed by a mixture of the two epimers (130 mg), and then (Sa)
epimer 18 (37 mg) eluted in pure form. The fraction of unseparated
epimers (which was enriched in 18) was further purified by prepara-
tive HPLC (5% ethyl acetate in hexanes). Combination of all pure
fractions gave pure 18 (104 mg total, 33%) as a colorless solid, and
pure 19 (150 mg total, 48%) as a colorless oil.
(3R,5R)-3,5-Bis[(tert-butyldimethylsilyl)oxy]-4-ethylcyclohexanone
(16): A solution of diol 15 (328 mg, 0.76 mmol) in methanol
(35 mL) was cooled to 0 °C, and a solution of sodium periodate
(716 mg, 3.35 mmol) in water (5 mL) was added in portions over
10 min. After stirring at room temperature for 2 h, water (35 mL)
was added, and the mixture was concentrated under reduced pres-
sure. The aqueous residue (ca. 40 mL) was extracted with dichloro-
methane (4ϫ 50 mL). The combined organic phases were dried
with magnesium sulfate and concentrated under reduced pressure,
which gave cyclohexanone 16 (273 mg, 90 %) as a colorless oil.
[α]2D1 = –45.7 (c = 1.26, CHCl ). IR: νmax = 1723 (s), 1472 (m) cm–1.
˜
3
1H NMR (300 MHz, CDCl3, 21 °C): δ = 4.34 (ddd, J = 6.7, 4.6,
and 2.5 Hz, 1 H, Si-O-CHeq), 4.04 (br. ddd, J = 12.7, 8.2, and
4.8 Hz, 1 H, Si-O-CHax), 2.63 (ddd, J = 14.5, 4.8, and 1.1 Hz, 1 H,
CHeqHCO), 2.45 (m, 2 H, CH2), 2.33 (dd, J = 14.5 and 8.2 Hz, 1
H, CHHaxCO), 1.65 (m, 2 H, CH3CH2), 1.48 (m, 1 H, EtCH), 0.99
(t, J = 7.3 Hz, 3 H, CH3CH2), 0.89 [s, 9 H, SiC(CH3)3], 0.86 [s, 9
H, Si-C(CH3)3], 0.07 (s, 3 H, Si-CH3), 0.06 (2 overlapping s, 6 H,
2 Si-CH3), 0.05 (s, 3 H, SiCH3) ppm. 13C NMR (75 MHz, CDCl3,
21 °C): δ = 207.8 (C), 69.7 (CH), 67.4 (CH), 50.2 (CH), 49.0 (CH2),
48.4 (CH2), 25.4 (3 CH3), 25.3 (3 CH3), 18.7 (CH2), 17.6 (2 C),
11.6 (CH3), –4.8 (CH3), –4.9 (CH3), –5.3 (CH3), –5.5 (CH3) ppm.
HRMS (ESI): calcd. for C20H43O3Si2 [M + H]+ 387.2745; found
387.2749.
Data for (Ra) epimer 18: [α]2D1 = –19.6 (c = 0.58, CHCl ). IR: ν
˜
3
max
= 3316 (br), 1472 (m) cm–1. H NMR (300 MHz, CDCl3, 21 °C):
δ = 5.48 (t, J = 7.1 Hz, 1 H, C=CH-), 4.17–4.06 (band, 3 H, Si-O-
CHeq and -CH2-OH), 3.74 (ddd, J = 9.2, 8.2, and 4.3 Hz, 1 H, Si-
O-CHax), 2.48 (dd, J = 14.0 and 5.3 Hz, 1 H, CHHeqC=), 2.41 (dd,
J = 13.2 and 4.3 Hz, 1 H, CHHeqC=), 2.05 (dd, J = 13.2 and
9.2 Hz, 1 H, CHHaxC=), 2.02 (br. d, J = 14.0 Hz, 1 H, CHHaxC=),
1.68–1.50 (m, 1 H, CHHCH3), 1.40–1.28 (band, 3 H, CHHCH3,
CH-CH2CH3 and OH), 0.90 (t, J = 7.4 Hz, 3 H, CH2CH3), 0.89
[s, 9 H, SiC(CH3)3], 0.86 [s, 9 H, Si-C(CH3)3], 0.05 (2 overlapping
1
Methyl 2-{(3R,5R)-3,5-Bis[(tert-butyldimethylsilyl)oxy]-4-ethyl- s, 6 H, 2 SiCH3), 0.04 (2 overlapping s, 6 H SiCH3) ppm. 13C NMR
cyclohexylidene}acetate (17): A solution of n-butyllithium (2.5 m in
hexane; 0.99 mL, 2.47 mmol) was added dropwise to diisopropyl-
amine (347 μL, 2.47 mmol) in tetrahydrofuran (2.0 mL) at –78 °C.
(75 MHz, CDCl3, 21 °C): δ = 138.1 (C), 124.6 (CH), 70.9 (CH),
68.1 (CH), 58.9 (CH2), 52.1 (CH), 44.8 (CH2), 35.5 (CH2), 25.9 (3
CH3), 25.8 (3 CH3), 18.9 (CH2), 18.10 (C), 18.06 (C), 12.2 (CH3),
The resulting mixture was stirred at –78 °C for 10 min. Then, –4.2 (CH3), –4.3 (CH3), –4.8 (CH3), –5.0 (CH3) ppm. HRMS (ESI):
Eur. J. Org. Chem. 2013, 728–735
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
733

J. M. Winne et al.
FULL PAPER
calcd. for C16H29OSi [M + H – H2O – HOTBS]+ 265.1982; found
265.1983.
70.7 (d, J = 1.8 Hz, CH), 68.0 (d, J = 1.6 Hz, CH), 51.7 (CH), 44.2
(CH2), 35.3 (d, J = 1.8 Hz, CH2), 30.4 (d, J = 70.1 Hz, CH2), 29.7
(CH2), 27.0 (CH), 25.9 (3 CH3), 25.7 (3 CH3), 18.8 (C), 18.0 (C),
12.2 (CH3), –4.2 (CH3), –4.4 (CH3), –4.8 (CH3), –5.0 (CH3) ppm.
HRMS (ESI): calcd. for C34H56O3PSi2 [M + H]+ 599.3500; found
599.3496.
Data for (Sa) epimer 19: [α]2D1 = –28.2 (c = 0.70, CHCl3). 1H NMR
(500 MHz, CDCl3, 21 °C): δ = 5.47 (t, J = 7.2 Hz, 1 H, C=CH-),
4.15 [dd, J = 11.9 (AB) and 7.2 Hz, 1 H, CHHOH], 4.081 (ddd, J
= 5.9, 3.5, and 2.5 Hz, 1 H, Si-O-CHeq), 4.078 [dd, J = 11.9 (AB),
7.2 Hz, 1 H, CHHOH], 3.75 (ddd, J = 8.3, 7.6, and 3.8 Hz, 1 H,
(Ra)-2-{(3R,5R)-3,5-Bis[(tert-butyldimethylsilyl)oxy]-4-ethyl-
Si-O-CHax), 2.55 (dd, J = 13.3 and 3.8 Hz, 1 H, CHHeqC=), 2.21 cyclohexylidene}ethyldiphenylphosphane Oxide (20): This product
[dd, J = 13.4 (AB) and 5.9 Hz, 1 H, CHHC=], 2.14 [dd, J = 13.4
(AB) and 2.5 Hz, 1 H, CHHC=], 2.01 (dd, J = 13.3 and 8.3 Hz, 1
was prepared from allylic alcohol 19 (104 mg, 0.251 mmol) as de-
scribed above for the preparation of α-ethylphosphanone 6 from
H, CHHaxC=), 1.55–1.35 (band, 3 H, CHCH2CH3), 1.18 [br. s, 1 allylic alcohol 18. Flash chromatography (ethyl acetate/petroleum
H, OH], 0.90 (t, J = 7.3 Hz, 3 H, CH2CH3), 0.89 [s, 9 H, SiC- ether, 1:9) gave β-ethylphosphanone 20 (124 mg, 82%) as a waxy
(CH3)3], 0.86 [s, 9 H, SiC(CH3)3], 0.06 (s, 3 H, SiCH3), 0.050 (s, 3
solid. [α]2D1 = –55.9 (c = 1.02, CHCl ). IR: νmax = 1475, 1438, 1252,
˜
3
H, SiCH3), 0.046 (s, 3 H, SiCH3), 0.02 (s, 3 H, SiCH3) ppm. 13C
1192 cm–1. H NMR (300 MHz, CDCl3, 21 °C): δ = 7.76–7.67 (m,
1
NMR (125 MHz, CDCl3, 21 °C): δ = 138.3 (C), 124.8 (CH), 71.0 4 H, ArH), 7.56–7.41 (m, 6 H, ArH), 5.23 (td, J = 7.7 and 6.8 Hz,
(CH), 68.5 (CH), 58.6 (CH2), 51.6 (CH), 43.1 (CH2), 36.0 (CH2), 1 H, C=CH-), 4.01 (ddd, J = 5.0 and 2ϫ ca. 2.5 Hz, 1 H, SiOCH),
25.9 (3 CH3), 25.8 (3 CH3), 19.0 (CH2), 18.13 (C), 18.08 (C), 12.2 3.60 (ddd, J = 2ϫ ca. 8.8 and 3.9 Hz, 1 H, SiOCH), 3.10 [dd, J =
(CH3), –4.1 (CH3), –4.4 (CH3), –4.8 (CH3), –5.0 (CH3) ppm.
15.0 (2JHP) and 7.7 Hz, 1 H, CH2P=O], 2.31 (dd, J = 13.8 and
4.1 Hz, 1 H, CHeqHC=), 2.14 [dd, J = 13.5 (AB) and 4.9 Hz, 1 H,
CHeqHC=], 2.04 [br. d, J = 13.5 (AB) Hz, 1 H, CHHaxC=], 1.98–
1.82 (br. m, 1 H, CHHaxC=), 1.60–1.49 (m, 1 H, CHEt), 1.35–1.15
(m, 2 H, -CH2CH3), 0.87 [s, 9 H, SiC(CH3)3], 0.85 (br. t, J = 7.5 Hz,
3 H, -CH2CH3), 0.81 [s, 9 H, Si-C(CH3)3], 0.01 (s, 3 H, SiCH3),
0.00 (s, 3 H, SiCH3), –0.01 (s, 3 H, SiCH3), –0.05 (s, 3 H, SiCH3)
ppm. 13C NMR (75 MHz, CDCl3, 21 °C): δ = 139.1 (d, J =
11.9 Hz, C), 132.9 (d, J = 97.2 Hz, C), 132.6 (d, J = 98.8 Hz, C),
131.8 (d, J = 2.5 Hz, CH), 131.7 (d, J = 2.5 Hz, CH), 131.2 (d, J
= 9.5 Hz, 2CH), 131.0 (d, J = 9.5 Hz, 2CH), 128.6 (d, J = 11.4 Hz,
2CH), 128.5 (d, J = 11.4 Hz, 2CH), 113.2 (d, J = 8.9 Hz, CH), 70.7
(d, J = 1.8 Hz, CH), 68.1 (d, J = 1.9 Hz, CH), 51.7 (CH), 43.3 (d,
J = 2.0 Hz, CH2), 36.9 (CH2), 30.3 (d, J = 69.8 Hz, CH2), 25.9 (3
CH3), 25.8 (3 CH3), 19.2 (CH2), 18.1 (2 C), 11.9 (CH3), –4.1 (CH3),
–4.4 (CH3), –4.7 (CH3), –5.1 (CH3) ppm. HRMS (ESI): calcd. for
C34H56O3PSi2 [M + H]+ 599.3500; found 599.3480.
(Sa)-2-{(3R,5R)-3,5-Bis[(tert-butyldimethylsilyl)oxy]-4-ethyl-
cyclohexylidene}ethyldiphenylphosphane Oxide (6): A solution of n-
butyllithium (2.5 m in hexanes; 0.156 mL, 0.390 mmol) was added
dropwise to a solution of allylic alcohol 18 (81 mg, 0.195 mmol) in
tetrahydrofuran (2.5 mL) at 0 °C. After stirring at 0 °C for 30 min,
a solution of para-toluenesulfonyl chloride (51.7 mg, 0.271 mmol)
in tetrahydrofuran (450 μL) was added by cannula, and the re-
sulting mixture was stirred for 10 min. In a separate reaction flask,
a solution of n-butyllithium (2.5 m in hexanes; 0.81 mL, 2.03 mmol)
was added dropwise to a solution of diphenylphosphane (390 mg,
2.09 mmol) in tetrahydrofuran (3.2 mL) at 0 °C. The resulting mix-
ture was stirred at 0 °C for 5 min, and then part of this freshly
prepared diphenylphosphide solution (840 μL, 0.19 mmol) was
added to the first reaction flask at 0 °C. The resulting mixture was
stirred at 0 °C for 1 h. Then, a few drops of anhydrous methanol
(ca. 0.1 mL) were added, and the reaction mixture was concen-
trated under reduced pressure. The oily residue was redissolved in
dichloromethane (2.0 mL) and cooled to 0 °C, and then a hydrogen
peroxide solution (2.0 mL, 10% in water) was added. The resulting
heterogeneous mixture was stirred vigorously at room temperature
for 30 min. Then, sodium sulfite (satd. aq.; 1 mL) was added care-
fully. After stirring for 5 min, the separated aqueous phase was ex-
tracted with dichloromethane (5ϫ 10 mL), and the combined or-
ganic extracts were dried with magnesium sulfate and concentrated
under reduced pressure. The residue was purified by flash
chromatography (ethyl acetate/petroleum ether, 1:9), to give phos-
phanone 6 (83 mg, 71%) as a colorless solid. [α]2D1 = –4.4 (c = 0.26,
(1R,3R,Sa)-2-Ethyl-5-{(E)-2-[(1R,3aR,7aR)-1-(6-hydroxy-6-meth-
ylhept-4-yn-2-yl)-7a-methylhexahydro-1H-inden-4(2H)-ylidene]-
ethylidene}cyclohexane-1,3-diol (4): A solution of n-butyllithium
(2.5 m in hexanes; 54.4 μL, 0.136 mmol) was added dropwise to
solution of phosphanone 6 (81.0 mg, 0.135 mmol) in tetra-
hydrofuran (1.1 mL) at –78 °C. The resulting bright red solution
was stirred at –78 °C for 5 min, and then at 0 °C for 5 min. The
reaction mixture was then re-cooled to –78 °C, and a solution of
ketone 21[18] (113 mg, 0.325 mmol) in tetrahydrofuran (0.5 mL) was
added dropwise over 5 min. The reaction mixture was warmed
gradually to 0 °C and stirred at this temperature for 2 h. Then am-
CHCl ). IR: ν
= 1498, 1462, 1250, 1169 cm–1
.
1H NMR monium chloride (sat. aq.; 2 mL) was added, and the tetra-
(300 MHz, CDCl3, 21 °C): δ = 7.76–7.64 (m, 4 H, ArH), 7.54–7.40 hydrofuran was removed under reduced pressure. The aqueous resi-
(m, 6 H, ArH), 5.27 [ddd, J = 9.6, 5.8, and 5.8 (3JHP) Hz, 1 H, due was extracted with dichloromethane (3ϫ 20 mL). The com-
˜
3
max
C=CH-], 3.99 (ddd, J = 5.9 and 2ϫ ca. 2.5 Hz, 1 H, SiOCH), 3.68
(ddd, J = 2ϫ ca. 8.1 and 4.1 Hz, 1 H, SiOCH), 3.15 [ddd, J = 14.8
(AB), 13.8 (2JHP), and 9.6 Hz, 1 H, CHHP=O], 3.03 [br. ddd, J =
16.5 (2JHP), 14.8 (AB), and 5.8 Hz, 1 H, CHHP=O], 2.34 (br. d, J
= 13.5 Hz, 1 H, CHHC=), 2.14 (dd, J = 14.2 and 5.6 Hz, CHHC=),
bined organic extracts were dried with magnesium sulfate and con-
centrated in vacuo. Flash chromatography (ethyl acetate/petroleum
ether, 1:9) gave protected analog 22 (17.5 mg, 24%) as a waxy solid
and phosphanone 6 (51 mg, 63%), which was recovered unchanged
and reused for the preparation of more 22. Data for the coupling
product, obtained as a 1:1 mixture of acetal epimers: 1H NMR
(300 MHz, CDCl3, 21 °C): δ = 6.09 [br. d, J = 11.4 (AB) Hz, 1 H,
CH=], 5.96 [br. d, J = 11.4 (AB) Hz, 1 H, CH=], 5.113 [q, J = 5.2
and 0.8 Hz, 0.5 H, CH(OR)2], 5.111 (q, J = 5.2 Hz, 0.5 H), 4.14–
4.10 (m, 1 H, Si-O-CH), 3.76–3.66 (m, 1 H, SiOCH), 3.69 [dq, J =
9.4 (AB) and 7.0 Hz, 1 H, OCHHCH3], 3.49 [dq, J = 9.4 (AB) and
7.0 Hz, 1 H, OCHHCH3], 2.74 (dd, J = 14.0 and 4.0 Hz, 1 H,
CHHC=), 2.55–2.41 (m, 2 H), 2.36–1.50 (band, 20 H), 1.55 [s, 6
H, -C(CH3)2], 1.50 (s, 3 H), 1.43 (s, 1 H), 1.32 [t, J = 5.2 Hz, 1 H,
5
1.94 [ddd, J = 13.5, ca. 7.5, and ca. 6.5 (homoallylic JHP) Hz, 1
H, CHHC=], 1.62 (br. d, J = 14.2 Hz, 1 H, CHHC=), 1.52–1.43
(m, 1 H, CHEt), 1.38–1.20 (m, 2 H, -CH2CH3), 0.85 (br. t, J =
7.4 Hz, 3 H, -CH2CH3), 0.84 [s, 9 H, SiC(CH3)3], 0.83 [s, 9 H, Si-
C(CH3)3], 0.00 (s, 3 H, SiCH3), –0.01 (3 overlapping s, 9 H, 3
SiCH3) ppm. 13C NMR (75 MHz, CDCl3, 21 °C): δ = 139.6 (d, J
= 11.9 Hz, C), 132.7 (d, J = 98.3 Hz, C), 132.6 (d, J = 97.8 Hz, C),
131.8 (d, J = 2.6 Hz, CH), 131.7 (d, J = 2.6 Hz, CH), 131.1 (d, J
= 9.1 Hz, 2CH), 131.0 (J = 9.1 Hz, 2CH), 128.51 (d, J = 11.5 Hz,
2CH), 128.50 (d, J = 11.5 Hz, 2CH), 113.1 (d, J = 8.7 Hz, CH), (RO)2CHCH3], 1.19 (t, J = 7.0 Hz, 3 H, OCH2CH3), 0.93 (t, J =
734
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Eur. J. Org. Chem. 2013, 728–735

2-Ethyl-19-nor Analogs of 1α,25-Dihydroxyvitamin D3
[4] a) R. Bouillon, W. H. Okamura, A. Norman, Endocr. Rev.
1995, 16, 200–257; b) G. Eelen, C. Gysemans, L. Verlinden,
E. Vanoirbeek, P. De Clercq, D. Van Haver, C. Mathieu, R.
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452.
7.5 Hz, 3 H, CHCH2CH3), 0.90 [s, 9 H, SiC(CH3)2], 0.84 [s, 9 H,
SiC(CH3)2], 0.073 (s, 3 H, SiCH3), 0.067 (s, 3 H, SiCH3), 0.05 (s, 3
H, SiCH3), 0.03 (s, 3 H, SiCH3) ppm.
Dilute HCl (1% aq.; 2 mL) was added to a solution of compound
22 (37.9 mg, 0.059 mmol) in methanol (5 mL) at room temperature.
The resulting mixture was stirred in the dark at room temperature
for 18 h. Sodium hydrogen carbonate solution (satd. aq.; 2 mL) was
added, and the methanol was removed by concentration in vacuo.
The aqueous residue was extracted with dichloromethane (5ϫ
15 mL), and the combined organic extracts were dried with magne-
sium sulfate and concentrated under reduced pressure. Flash
chromatography (ethyl acetate/hexane, 4:6) and HPLC purification
(ethyl acetate/hexane, 4:6) gave 1α,25-(OH)2D3 analog 4 (19.5 mg,
77%) as a colorless solid that gave a 1H NMR spectrum consistent
with that reported earlier.[12] 1H NMR (500 MHz, CDCl3, 21 °C):
δ = 6.31 (d, J = 11.3 Hz, 1 H, CH=), 6.01 (d, J = 11.3 Hz, 1 H,
CH=), 4.15 (br. s, 1 H, CHeqOH), 3.63 (ddd, J = 2ϫ ca. 9.6 Hz
and 4.6 Hz, 1 H, CHaxOH), 2.89 (dd, J = 14.0, and 4.6 Hz, 1 H,
CHHC=), 2.59 (dd, J = 12.8 and 4.6 Hz, 1 H, CHHC=), 2.48 (ddd,
J = 14.5, 4.5, and 4.3 Hz, 1 H, CHH), 2.18–2.00 (band, 6 H, CH,
3 CHH, CH2), 1.88–1.58 (band, 7 H, 2 CH, 3 CHH, CH2), 1.53–
1.46 (band, 3 H, 2 CHH, CHH), 1.50 [s, 6 H, HOC(CH3)2], 1.42–
1.20 (band, 3 H, 2 CHH, CH), 1.00 (t, J = 7.4 Hz, 3 H, CH2Me),
0.94 (d, J = 6.6 Hz, 3 H, CHMe), 0.93 (s, 3 H, CqMe) ppm. 13C
NMR (125 MHz, CDCl3, 21 °C): δ = 143.1 (C), 131.8 (C), 124.1
(CH), 118.8 (CH), 86.2 (C), 81.9 (C), 71.5 (CH), 67.9 (CH), 65.4
(C), 57.3 (CH), 51.9 (CH), 50.8 (CH), 45.5 (CH2), 45.4 (C), 37.0
(CH2), 35.6 (CH2), 33.5 (CH), 31.8 (2 CH3), 29.9 (CH2), 26.4
(CH2), 25.4 (CH2), 24.5 (CH2), 22.2 (CH2), 21.7 (CH3), 19.9 (CH2),
17.2 (CH3), 11.7 (CH3) ppm. HRMS (ESI): calcd. for C28H43O2
[M + H – H2O]+ 411.3257; found 411.3261.
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[7]
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Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C NMR spectra of final product and key
intermediates.
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an allyl group from allyltributyltin to a thiocarbamate derived
from 7, in a radical chain reaction. This approach seemed less
suited for our purposes.
Acknowledgments
We thank the UGent for financial support.
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Received: September 21, 2012
Published Online: December 10, 2012
Eur. J. Org. Chem. 2013, 728–735
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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