Synthesis of 2-methyl and ethyl-substituted 19-nor-1α,25- dihydroxyvitamin D3 analogues via the cyclovitamin strategy

Article abstract of DOI:10.1002/ejoc.200500289

The synthesis of several 19-nor-2-alkyl-1α,25-dihydroxyvitamin D ₃ analogues (5-14) is described following the cyclovitamin strategy. Starting from all-cis methyl 3,5-dihydroxy-4-alkyl-1-cyclohexanecarboxylate (29), the eight stereoisomeric A-r

Full text of DOI:10.1002/ejoc.200500289

FULL PAPER
Synthesis of 2-Methyl and Ethyl-Substituted 19-nor-1α,25-Dihydroxyvitamin
D3 Analogues via the Cyclovitamin Strategy
Yu-Rui Zhao,[a] Bing Guang,[a] Roger Bouillon,[b] Annemieke Verstuyf,[b]
Pierre De Clercq,*[a] and Maurits Vandewalle[a]
Keywords: Asymmetric synthesis / Drug research / Natural products / Polycycles / Vitamins
The synthesis of several 19-nor-2-alkyl-1α,25-dihydroxyvita- ethyl). In particular, from the coupling of 39 and the lithiated
min D3 analogues (5–14) is described following the cyclovita-
min strategy. Starting from all-cis methyl 3,5-dihydroxy-4-
compounds derived from the CD-ring bromides 20 and 21
possessing the natural or the 23-yne side chain, the title de-
alkyl-1-cyclohexanecarboxylate (29), the eight stereoiso- rivatives 5–14 were synthesized.
meric A-ring-precursor 2-tert-butyldiphenylsilyloxy-3α-for-
myl-1-alkylbicyclo[3.1.0]hexanes (39, 44, 46, 63, 65, 67, 69,
71) were prepared in two series: a (R = methyl) and b (R =
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
hypercalcemic effects (circa 0.1% of 1).[5–8] In continuation
of our research on the structure-activity relationship of 19-
nor compounds, we report the synthesis of 19-nor-2-methyl-
and 2-ethyl-substituted analogues with both natural and 14-
epi-CD ring systems and with the natural or 23-yne (20R
and 20S) side chain (Figure 1).
Introduction
The hormonally active form of vitamin D3, 1α,25-dihy-
droxyvitamin D3 [1, 1α,25(OH)2D3] generates biological re-
sponses by regulation of gene transcription.[1] The discovery
of the presence of specific vitamin D receptors in over 30
tissue types has stimulated investigation into the possible
functions of 1α,25(OH)2D3 (1) outside its classical role in
bone calcium homeostasis. The hormone was found to be
capable of regulating cell proliferation and differentiation of
a variety of immunological and malignant cells. The major
drawback regarding its use is the high toxicity associated
with the calcemic effect, which prevents the application of
pharmaceutical doses. Current research is therefore aimed
not only at the synthesis of analogues with superagonistic
potency but, in particular, at decoupling the effects on cell
differentiation from calcemic effects.[1,2] A large number of
analogues incorporating modifications in the A-ring, in the
CD-ring fragment, and especially in the side chain have
been synthesized and tested biologically.[1] It is now well
established that removal of the 19-exomethylene function is
beneficial; 19-nor-1α,25-dihydroxyvitamin D3 (2) displays a
smaller calcemic effect (10% of 1) while retaining good cell-
differentiating properties.[3,4] We have further observed that,
among other modifications, 14-epimers such as 3 and 4 in-
duce interesting physiological activities; they are also
among the best analogues known in that they show smaller
Considerable attention has been devoted to 2-substituted
analogues of 1α,25-dihydroxyvitamin D3.[9] In the 19-nor
series, the synthesis of 5a, 6a, the corresponding 2-hy-
droxymethyl analogues, and their 20-epimers has been de-
scribed via a Horner–Wittig reaction, known as the
Lythgoe coupling,[10] involving phosphane oxides such as
15 and 16 (Scheme 1).[11,12] Mikami et al.[12b] synthesized
the A-ring precursor 16 for 5a in a stereoselective fashion.
DeLuca et al.[11] obtained a 1:1 mixture of 5a and 6a upon
nonselective catalytic hydrogenation of 2-methylene-19-nor-
1α,25-dihydroxyvitamin D3 (from 15) and separation by re-
versed phase HPLC. Application of the Lythgoe strategy in
a stereoselective synthesis involving a 19-nor-2-substituted
phosphane oxide (steroid numbering) such as 16 is ham-
pered by the fact that this particular A-ring precursor no
longer possesses a pseudo C2 axis of symmetry as in 17;
consequently, a control element[12b] for the 5,6-double bond
geometry relative to the configuration at C-2 is required.
We decided to study a convergent synthesis of the title
compounds via the cyclovitamin approach, for which we
had some precedent for selectivity during the solvolytic
step[8] (vide infra, Scheme 1). This concept is an alternative
to the more widely used Lythgoe coupling process[10] in-
volving C-8 ketones such as 18 or 19 (vitamin D number-
ing).
[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: pierre.declercq@UGent.be
The cyclovitamin approach is based on reaction of 20 or
21 with 23 or 24, respectively, and was developed by Kamet-
ani et al.,[13] Wilson et al.,[14] and Uskokovic et al.[15] for
[b] Laboratorium for Experimentele Geneeskunde en Endocrinolo-
gie, K. U. Leuven, Onderwijs en Navorsing Gasthuisberg,
Herestraat 49, 3000 Leuven, Belgium
4414
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200500289
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Synthesis of Dihydroxyvitamin D3 Analogues
FULL PAPER
Figure 1. 1α,25-Dihydroxyvitamin D3 analogues.
the synthesis of 1, and by our group for the synthesis of
19-nor analogues such as 2, 3 and 4.[7,8] The intermediate
cyclopropyl alcohols such as 25, 26a or 27a are then sub-
jected to an acid-catalyzed stereoselective solvolysis, which
may proceed via two rotamers around the 5,6-double bond,
in equilibrium with each other. For example, starting from
Scheme 1. Synthetic intermediates en route to 1α,25-dihydroxyvita-
min D3 analogues.
20 and 23, rotamer i of 25 gives 1 with the desired 3β and is highly influential for this excellent ratio.[17b] This selectiv-
5,6-Z configurations, while rotamer ii leads to 5,6-E isomer ity gave us the incentive for exploring the cyclovitamin ap-
28. Depending on substituents and reaction conditions, the proach for the synthesis of the title compounds.
observed 1:28 ratio is at best 4:1.[16] Evidently this is of no
The “upper fragments” 20 and 21, with both the natural
consequence for the synthesis (starting from 24) of 19-nor and 23-yne side chains, have already been described.[8] The
analogues such as 2 in which the A-ring has a pseudo-C2 cis-fused C-8 ketones 19 (steroid numbering) can be ob-
axis of symmetry. After introduction of a substituent at C- tained by base-catalyzed equilibration of 18.[8,17] The trans-
2, as in 27a (from 44a), a mixture of epimers 5a and 6a fused isomers are generally produced from the Inhoffen–
could occur; however, one rotamer might be more popu- Lythgoe diol 22.[18] The synthesis of vinylic bromide 20 was
lated. We have found this to be the case during solvolysis first reported by Trost et al.[19] and by us in the case of the
directed towards 1- and/or 3-epimers of 2, where this sym- cis-fused hydrindane 21.[8,17b] The precursor for the 20S-
metry element is also absent, giving selectivities up to analogues 13 and 14 were obtained from the previously de-
18:1.[8] We observed that the bulky TBDPS protective group scribed 20-epimer of 19Ј.[7]
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tant feature of key intermediates 30 and 31 is the fact that
they permit access to all stereoisomeric bicyclic A-ring pre-
Results and Discussion
cursors. Essential transformations are (i) inversions directed
towards the required relative configuration(s) at C-1, C-2
and C-3 (steroid numbering) and (ii) cyclopropane ring for-
mation via a leaving group at an oxy-substituent. As 30 and
31 belong to different enantiomeric series, the order of the
initial steps must be inverted (e.g. 30 Ǟ 33a; a,b,c and 31
Ǟ 33b; c,b,a) for the synthesis of homologues with identical
absolute configuration. The yields and conditions given in
Schemes 2, 3 and 4 are for methyl-substituted products (a);
similar results were observed for the 2-ethyl homologues
(b).
The present report concentrates on the synthesis of the
bicyclo[3.1.0]hexane A-ring precursors such as 44a (R =
Me; a-series) and its epimers and homologues (R = Et; b-
series). The synthesis starts from methyl all-cis-3,5-dihy-
droxy-4-methyl-cyclohexanecarboxylate (29a) and the 4-
ethyl homologue 29b for which we have already described
the enzyme-catalyzed asymmetrization.[20]
Transesterification of 29a with vinyl acetate, employing
SAM II, afforded enantiopure 30 in high yield. For the
ethyl-substituted series, the corresponding dibutyrate of 29b
was the best substrate; CCL- or SAM II-mediated mono-
hydrolysis to 31 is completely enantiotoposelective (see
Scheme 2; CCL is lipase type II from Candida cyclindracea,
SAM II is lipase from Pseudomonas fluorescens). An impor-
We have previously found that in the case of 4-unsubsti-
tuted 3,5-dihydroxy-cyclohexanecarboxylates,[8] inversions
under Mitsunobu conditions[21] gave excellent results. How-
Scheme 2. (a) DIAD, Ph3P, THF, room temperature, 3 h, (b) 0.5 equiv. K2CO3, MeOH, room temperature, 6 h; (c) TBDPSCl, imidazole,
DMAP (cat.), DMF, room temperature, 10 h; (d) BH3, THF, 0 °C, 2.5 h; ii) H2O2, satd. NaHCO3, 0.5 h; (e) MsCl, Et3N, CH2Cl2, 0 °C,
3 h; (f) tBuOK, tBuOH/THF (3:2), 45–50 °C, 0.5 h; (g) i) LiAlH4, THF, 0 °C, 1.5 h; ii) TPAP, NMO, CH2Cl2, room temperature, 0.5 h;
(h) pNO2PhCO2H, DIAD, Ph3P, THF, room temperature, 24 h; (i) PPTS, PhH, 80 °C, 24 h.
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Synthesis of Dihydroxyvitamin D3 Analogues
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Scheme 3. (a) DIAD, Ph3P, THF, room temperature, 3 h; (b) 0.5 equiv. K2CO3, MeOH, room temperature, 6 h; (c) TBDPSCl, imidazole,
DMAP (cat.), DMF, room temperature, 10 h; (d) pNO2PhSO2Cl, Et3N, DMAP (cat.), CH2Cl2, room temperature, 10 h; (e) EtCO2Cs,
18-crown-6, toluene, 110 °C, 4 h; (f) i) BH3, THF, 0 °C, 2.5 h; ii) H2O2, satd. NaHCO3, 0.5 h; (g) MsCl, Et3N, cat. DMAP, CH2Cl2, 0 °C,
3 h; (h) tBuOK, tBuOH/THF (3:2), 45–50 °C, 0.5 h; (i) pNO2PhCO2H, DIAD, Ph3P, THF, room temperature, 24 h; (j) i) LiAlH4, THF,
0 °C, 1.5 h; ii) TPAP, NMO, 4-Å mol. sieves, CH2Cl2, room temperature, 0.5 h.
ever, when the hydroxy function is flanked by a cis-vicinal forded 46a,b, the precursors for analogues with a 1α,2β,3α
alkyl substituent, facile anti-elimination occurs in high configuration.
yield, as is shown by the reaction of acetate 30 to 32a (91%
We also investigated stereoselective routes via lactonic
yield of substituted cyclohexene) and of 32 to 33b. We later key intermediates. For example, hydroboration of lactone
observed that in the case of a vicinal trans-relation, the Mit- 47, available from mono-acetate 30 (3 steps), gave 48 in
sunobu inversion proceeds normally (see transformation rather low yield, which was due to concomitant lactone re-
34a,b to 40a,b, Scheme 2).
duction. After protection of the hydroxy function, 49 is an
Although we found that inversion of the p-nitrophen- intermediate, via 50 and 51, for the previously-described A-
ylsulfonate derivatives with cesium propionate[22] (see, for ring precursor 44a. Likewise, it is clear that after initial mes-
example 55 to 57a in Scheme 3) provides an acceptable ster- ylation of 48, mesylate 52 is a potential intermediate for
eoselective transformation, we decided to exploit the easy 37a and hence for precursor 39a. Despite the problem asso-
formation of cyclohexene intermediates. Hydroboration of ciated with the hydroboration step of 47, this represents an
33a,b was nonselective and afforded a separable mixture acceptable route for the synthesis of a particular vitamin
(circa 1:1) of 34a,b and 35a,b. Both diastereoisomers are D3 analogue. Because of the present purpose to synthesize
suitable for further transformation. The mesylates 37a,b led, and evaluate all stereoisomers, the route via cyclohexenes
upon base-mediated cyclopropane formation and subse- 33a,b and 56a,b (in Scheme 3) was selected.
quent conversion of the ester functions in 38a,b into formyl
The enantiomers (63a,b, 65a,b and 67a,b, respectively) of
groups, to 39a,b, the precursors for the 2α-alkyl-19-nor- the A-ring precursors 46a,b, 39a,b and 44a,b can be con-
1α,25-dihydroxyvitamin D3 analogues 5a,b, 7a,b, 9a,b and structed via 56a,b (Scheme 3) upon applying the same set
11a,b. On the other hand, Mitsunobu inversion of the hy- of reactions described in Scheme 2. Key intermediates
droxy groups in 34a,b opens, via 41a,b, a route to 44a,b, the 56a,b, the enantiomers of 33a,b, were obtained from mono-
precursors for the epimeric 2β-alkyl vitamin D3 analogues esters 30 and 31b by inverting the order of the initial 3-step
6a,b, 8a,b, 10a,b and 12a,b. Finally, mesylation of 34a,b fol- sequence shown in Scheme 2. Hydroboration of 56a,b gave
lowed by cyclopropane formation and ester reduction af- separable mixtures of 58a,b (intermediates for 67a,b) and
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Y.-R. Zhao, B. Guang, R. Bouillon, A. Verstuyf, P. De Clercq, M. Vandewalle
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Scheme 4. (a) TBDPSCl, imidazole, DMAP (cat.), DMF, room temperature, 10 h; (b) 0.5 equiv. K2CO3, MeOH, room temperature,10 h;
(c) MsCl, Et3N, DMAP (cat.), CH2Cl2, 0 °C, 3 h; (d) tBuOK, tBuOH/THF, 45–50 °C, 0.5 h; (e) i) LiAlH4, THF, 0 °C, 1.5 h; ii) TPAP,
NMO, CH2Cl2, room temperature, 0.5 h.
60a,b. The mesylates 61a,b of the latter led to A-ring pre-
cursors 65a,b, while initial Mitsunobu inversion of 60a,b
(81% yield) opened the route to 63a,b.
As mentioned above, an alternative for the abortive Mit-
sunobu reaction when the hydroxy function is flanked by a
cis-vicinal 4-alkyl substituent consists of inversion of the
corresponding p-nitrophenylsulfonate with cesium propi-
onate.[22] Thus, 54 led, via 55, to 57a, the intermediate for
A-ring precursor 67a.
The synthesis of the two remaining stereoisomers 69a,b
and 71a,b (Scheme 4) does not require an inversion step.
Thus 69a was obtained starting from 30 via protection, hy-
drolysis, mesylation and cyclopropane formation; 69b was
formed from 31 upon changing the order of the reaction
sequence. Again, adapting the same set of reactions led to
enantiomers 71a,b.
With the A-ring precursors in hand, we turned our atten-
tion to the construction of the vitamin D3 skeleton by the
cyclovitamin D strategy described in Scheme 1. The vinylic
bromide 73 (Scheme 5), precursor for the (20S)-analogues
13 and 14, was obtained from ketone 72[7] as described for
21Ј.[8,17b] Reaction of the aldehydes (e.g. 44a) with the vi-
nylic lithium derivative of 20[8] led to 27a as a 1:1 epimeric
mixture at C-6[23] (Scheme 5). The subsequent acid-cata-
lyzed solvolysis involving stereoselective attack of water
proceeds by way of two rotamers, i and ii, around the 5,6-
bond (see also Scheme 1) in equilibrium with each other. It
is clear that reaction via rotamer i of 27a will lead to the
introduction of a hydroxy group at C-3 (74a and hence 6a),
while rotamer ii will introduce a C-1 hydroxy group (75a
and hence 5a). In order to be able to distinguish the stereo-
isomers 5a and 6a, the TBDPS protective group was chosen
at the origin, as it is stable under the solvolysis conditions.
As anticipated, and in parallel with previous observations,[8]
the major product 27a arises from attack at C-3; 74a and
75a were formed in a 88:12 ratio. This ratio was somewhat
more pronounced in the cis-CD ring (14-epi) series; the se-
quence starting from 44a and 21 led to the 1-TBDPS ether
Scheme 5. (a) Ph3P+CH2Br Br–, KHMDS, THF, 0 to 20 °C, 4 h;
(b) tBuLi, –70 to –10 °C, THF, 1 h; (c) PTSA, dioxane/H2O (1:1),
of 8a and the 3-TBDPS ether of 7a in a 94:6 ratio. This 55–60 °C, 4 h; (d) TBAF, THF, room temperature, 72 h.
4418 © 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
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Synthesis of Dihydroxyvitamin D3 Analogues
FULL PAPER
1
Table 1. Selected H NMR spectroscopic data of 1α,25-dihydroxyvitamin D3 analogues and their 1- and 3-TBDPS ethers (δ in ppm).
[a]
1α,25-(OH)2 Vitamin D3 analogues
1-OTBDPS
3-OTBDPS
H-6
H-7
H-1 or H-3
H-6 H-7 (H-6–
H-1 H-3
%
H-6
H-7
(H-6–
H-7)
Δδ
H-1 or H-3
H-7)
Δδ
5a
6.37
6.38
6.26
6.26
6.31
6.32
6.19
6.19
6.36
6.38
6.44
6.26
6.30
6.31
6.19
6.19
6.30
6.32
6.31
6.32
5.83
5.83
5.87
5.87
6.01
6.01
6.05
6.06
5.82
5.83
6.04
5.87
6.02
6.03
6.06
6.07
6.01
6.02
6.08
6.08
3.96, 3.61
4.14, 3.63
3.90, 3.51
4.09, 3.54
3.94, 3.59
4.15, 3.64
3.90, 3.52
4.09, 3.50
3.96, 3.61
4.14, 3.64
4.07, 3.55
4.10, 3.55
3.98, 3.60
4.15, 3.64
3.89, 3.54
4.10, 3.57
3.96, 3.60
4.15, 3.63
3.95, 3.90
3.96, 3.90
6.19 5.61 0.58
6.17 5.59 0.58
6.14 5.46 0.58
6.14 5.46 0.68
6.08 5.54 0.54
6.06 5.50 0.56
6.01 5.29 0.72
6.01 5.28 0.73
6.18 5.59 0.57
6.17 5.58 0.59
6.14 5.47 0.67
6.04 5.47 0.67
6.07 5.54 0.53
6.05 5.52 0.53
6.00 5.31 0.69
6.05 5.31 0.74
6.06 5.54 0.52
6.05 5.51 0.54
6.25 5.69 0.56
6.24 5.67 0.57
4.10 3.82 88
4.15 3.95 83
3.72 3.94 88
3.77 4.12 83
4.07 3.83 94
4.12 3.96 94
3.69 3.93 94
3.75 4.11 92
4.10 3.81 87
4.15 3.94 87
3.73 3.95 90
3.79 4.12 83
4.09 3.84 94
4.14 3.96 93
3.73 3.95 94
3.77 4.11 92
4.07 3.83 91
4.13 3.96 75
4.07 3.74 93
4.09 3.73 88
5.99
5.94
6.06
5.77
5.84
5.89
5.84
0.22
0.09
0.17
0.10
4.15, 3.75
4.10, 3.89
4.05, 3.82
4.10, 3.87
5b
6a
6b
5.94
[b]
7a
[b]
[b]
[b]
7b
8a
8b
9a
5.98
5.97
5.91
5.94
5.70
5.68
6.02
6.04
5.78
5.76
5.82
5.85
5.47
5.48
5.83
5.84
0.20
0.21
0.09
0.09
0.23
0.20
0.19
0.20
4.00, 3.72
4.15, 3.88
4.01, 3.79
4.11, 3.86
3.97, 3.72
4.15, 3.76
4.14, 3.81
4.27, 3.90
9b
10a
10b
11a
11b
12a
12b
13
14
1-epi-9a
1-epi-10a
6.13
6.12
5.99
6.00
0.14
0.12
4.00, 3.81
3.99, 3.81
[a]% of 1-OTBDPS ether found in the mixture obtained after solvolysis (step b in Scheme 5). [b] Insufficient product.
difference between trans- and cis-fused hydrindanes was H-Ar). The regioisomers (3-OTBDPS) show the signals for
consistently found (Table 1) and was independent of the 6-H and 7-H closer together (Δδ = 0.1–0.3) with now a
configuration of the bicyclic A-ring fragment.
small upfield shift for 6-H compared to the δ-values ob-
The structure of 74a was proven by NOE and COSY-2D served for the unprotected title compounds. Finally,
experiments. The vinylic protons 6-H and 7-H (AB system; TBDPS ether cleavage led to the 2-substituted analogues 5
δ = 6.14 and δ = 5.46; J = 11.3 Hz)[24] gave an NOE en- to 13.
hancement with the 4-protons and with 10α-H, respectively.
It is generally accepted that the presence of the 1α-hy-
The assignment of protons 4 and 10α followed from the droxy function is essential for receptor binding and bio-
observation of an NOE enhancement with 1-H (δ = logical activity and that these properties are influenced by
3.72 ppm) and 3-H (δ = 3.94 ppm), respectively. Localiza- the substitution pattern (see, for example 1 vs. 2) and the
tion of the latter protons follows from the trichloroacetate derived conformational behaviour of the A-ring. Therefore,
of 74a. For 3-H, a chemical shift from δ = 3.94 to δ = in order to investigate the A-ring conformation–biological
5.17 was observed, and COSY-2D experiments and NOE activity relationships we decided to prepare not only ana-
enhancements correlated with those obtained for 74a. These logues 5 to 14 but also others epimeric at C-1 and C-3. Two
results are in full agreement with those obtained for the 14- examples are 1-epi-9a and 1-epi-10a obtained by coupling
epi, 19-nor analogues unsubstituted at C-2 such as 3 and its aldehydes 69a and 71a, respectively, (Scheme 4) with vinylic
1- and/or 3-epimers.[8]
bromide 21Ј.
It is noteworthy that for the 1-OTBDPS ether series 1-
In conclusion, we have shown that the cyclovitamin route
H is downfield relative to 3-H for the isomers with a 2α- occurs in good stereoselectivity. Biological activities will be
substituent (5α, 7α, 9α, 11α, 13α, 14α), while a reversed situ- published elsewhere.
ation is observed for the 2β-substituted isomers 6β, 8β, 10β
and 12β (see Table 1). Identical observations have been
made for the stereoisomers with varying C-1, C-2 and C-3
configurations in both the 2-methyl and 2-ethyl-substituted
Experimental Section
General Remarks: All reactions were carried out under argon or
nitrogen with magnetic stirring. All solvents were purified or dried
according to standard procedures. Solutions were dried with anhy-
drous MgSO4. The solvent was removed from the filtered solutions
on a rotary evaporator. Column chromatography separations were
performed on silica gel, eluents are given between brackets. HPLC
separations were performed on a Knauer 64, a Waters 6000 A or
a Kontron 420 delivery system with refractive index detection; el-
uents are given between brackets. Optical rotations were measured
with a Perkin–Elmer 421 polarimeter and at room temperature un-
series.
In a few cases in the 14-epi series an NOE enhancement
between 7-H and an aromatic proton of the 1-OTBDPS
substituent was also observed, which by itself is a structural
proof. The simplest tool for structural identification in these
series is provided by a consistent upfield chemical shift of
7-H in 1-OTBDPS ethers for which 6-H and 7-H give a Δδ
= 0.5–0.7 (Table 1). This upfield shift is probably due to the
anisotropy of a phenyl group of the TBDPS ether, which is
in fact confirmed by the observed NOE enhancement (7-H, less otherwise stated. IR spectra were recorded on a Perkin–Elmer
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Y.-R. Zhao, B. Guang, R. Bouillon, A. Verstuyf, P. De Clercq, M. Vandewalle
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FTIR-1600 spectrometer and mass spectra on a HP-5988 spectrom-
eter. The 1H NMR spectra were recorded at 500 MHz (WH-
Bruker) and 13C NMR spectra at 200 MHz (Varian Gemini), unless
otherwise noted. The chemical shifts are expressed in ppm relative
to TMS, and coupling constants are in Hz. Elemental analyses were
carried out by ICHOR, Université Pierre et Marie Curie (Paris,
France).
51.5, 38.7, 35.3, 27.7, 27.0, 25.3, 19.4, 12.3 ppm. MS: m/z (%) =
422 [M+, 2], 401 (3), 365 (72), 333 (6), 267 (8), 255 (2), 227 (7),
213 (100), 201 (65), 163 (55), 137 (58), 105 (32), 79 (75), 41 (40).
C26H34O3Si (422.64): calcd. C 73.89, H 8.11; found C 73.72, H
8.27.
Hydroboration of 33a,b (General Procedure): To a stirred solution
of 33a (130 mg, 0.319 mmol), in THF (12 mL) was added dropwise
a BH3 solution (380 μL, 1 m in THF, 0.38 mmol) at 0 °C and stir-
ring was continued at 0 °C for 2.5 h, then H2O2 (0.5 mL) and
satd.NaHCO3 (3 mL) were added. After stirring for 0.5 h, the reac-
tion solution was poured into H2O/EtOAc and the organic layer
was separated. The aqueous layer was extracted (EtOAc), and the
combined organic extracts were washed, dried and concentrated.
The residue was purified by chromatography (isooctane/EtOAc, 9:1
to 4:1), affording 34a (48 mg, 35%) and 35a (61 mg, 45%).
Methyl (1R,5R)-5-(tert-Butyldiphenylsilyloxy)-4-methyl-3-cyclohex-
ene-1-carboxylate (33a): To a stirred solution of 30 (1.3 g, 5.65
mmol) and Ph3P (4.5 g, 17.16 mmol in THF, 15 mL), DIAD
(3.6 mL, 17.16 mmol, 95%) was added dropwise at 0 °C. After stir-
ring for 3 h at room temperature, the reaction solution was sub-
jected to flash chromatography (pentane/Et2O, 3:1) affording a
colourless oil. The oil was dissolved in a dry MeOH (20 mL), and
then treated with K2CO3 (0.36 g, 2.61 mmol). After stirring for 6 h,
the solution was poured into H2O/EtOAc and the separated aque-
ous layer was extracted with EtOAc. The organic extracts were
washed, dried and concentrated. Flash chromatography (isooctane/
EtOAc, 4:1) gave the cyclohexenol as crystals from n-hexane/ace-
tone [m.p. 70–71 °C. Rf = 0.21 (isooctane/EtOAc, 4:1). [α]D = –21.6
(c = 1.09, CHCl3). C9H14O3 (170.21): calcd. C 63.51, H 8.29; found
C 63.33, H 8.34]. TBDPSCl (1.55 mL, 98%, 5.99 mmol) was added
to a solution of the intermediate (0.83 g, 4.88 mmol), imidazole
(0.41 g, 6.02 mmol) and a catalytic amount of DMAP in dry DMF
(12 mL) at 0 °C. The resulting mixture was stirred for 10 h at room
temperature, and was then poured into H2O/EtOAc, separated, ex-
tracted (EtOAc), washed, dried, and the solvents were evaporated.
Chromatography (isooctane/EtOAc, 95:5) gave 33a (1.68 g, 73%
overall) as a colourless oil. Rf = 0.42 (isooctane/EtOAc, 9:1). [α]D
Methyl (1R,3S,4R,5R)-5-(tert-Butyldiphenylsilyloxy)-3-hydroxy-4-
methylcyclohexane-1-carboxylate (34a): Rf
= 0.21 (isooctane/
EtOAc, 4:1). [α]D = –51.8 (c = 0.55, CHCl ). IR (KBr film): ν
˜
3
=3361, 2932, 2858, 1737, 1589, 1403, 1428, 1363, 1282, 1250, 1173,
1
1111 cm–1. H NMR (CDCl3): δ = 7.70–7.36 (m, 10 H), 3.59 (s, 3
H), 3.25 (m, 1 H), 3.09 (m, 1 H), 2.12–2.05 (m, 2 H), 1.91 (dt, J =
12.7, 4.3 Hz, 1 H), 1.62 (br.s, 1 H), 1.54–1.38 (m, 3 H), 1.07 (d, J
= 6.4 Hz, 3 H), 1.05 (s, 9 H) ppm. 13C NMR (CDCl3): δ = 174.6,
135.9, 134.3, 133.6, 129.7, 127.5, 74.8, 73.0, 51.8, 47.9, 37.9, 37.1,
36.8, 27.1, 19.5, 14.5 ppm. MS: m/z (%) = 409 (M+ – H2O – H, 1),
369 (M+ – 57, 10), 337 (25), 309 (5), 199 (75), 153 (25), 121 (15),
93 (100). C25H34O4Si (426.63): calcd. C 70.38, H 8.03; found C
70.16, H 8.14.
Methyl (1R,3R,4S,5R)-5-(tert-Butyldiphenylsilyloxy)-3-hydroxy-4-
= –82.9 (c = 0.79, CHCl ). IR (KBr film): ν = 2952, 2857, 1738,
˜
3
methylcyclohexane-1-carboxylate (35a): Rf
= 0.19 (isooctane/
1589, 1472, 1428, 1362, 1308, 1247, 1169 cm–1. 1H NMR (CDCl3):
δ = 7.73–7.37 (m, 10 H), 5.39 (m, 1 H), 4.24 (s, 1 H), 3.59 (s, 3 H),
2.39 (m, 1 H), 2.32–2.02 (m, 3 H), 1.75 (m, 1 H), 1.66 (s, 3 H), 1.07
(s, 9 H) ppm. 13C NMR (CDCl3): δ = 175.2, 137.5, 136.1, 134.4,
133.7, 129.6, 127.6, 121.9, 71.4, 51.6, 38.9, 35.2, 27.9, 27.1, 20.2,
19.5 ppm. MS: m/z (%) = 408 [M+, 1], 354 (8), 351 [M+ – 57, 73],
299 (5), 273 (6), 213 (100), 183 (75), 137 (70). C25H32O3Si (408.61):
calcd. C 73.49, H 7.89; found C 74.16, H 8.32.
EtOAc, 4:1). [α]D = –38.5 (c = 0.69, CHCl ). IR (KBr film): ν =
˜
3
3442, 2954, 2893, 2857, 1735, 1715, 1589, 1463, 1427, 1378, 1273,
1196, 1111 cm–1. 1H NMR (CDCl3): δ = 7.68–7.36 (m, 10 H), 4.17
(dt, J = 10.8, 4.7 Hz, 1 H), 3.89 (d, J = 3.1 Hz, 1 H), 3.63 (s, 3 H),
2.62 (tt, J = 11.8, 4.4 Hz, 1 H), 1.82–1.66 (m, 5 H), 1.59 (br.s, 1
H), 1.06 (s, 9 H), 0.96 (d, J = 7.2 Hz, 3 H) ppm. 13C NMR (CDCl3):
δ = 175.7, 135.8, 134.3, 129.6, 127.5, 72.0, 68.9, 51.7, 41.3, 36.6,
31.4, 29.6, 27.0, 19.3, 10.7 ppm. MS: m/z (%) = 369 (M+ – 57, 100),
339 (5), 319 (4), 273 (6), 253 (10), 199 (85), 153 (65), 135 (40).
C25H34O4Si (426.63): calcd. C 70.38, H 8.03; found C 70.21, H
8.20.
Ethyl Homologue 33b: To a stirred solution of monobutyrate 31
(1.9 g, 7.04 mmol), imidazole (1.43 g, 21.03 mmol mmol) and
DMAP (44 mg) in dry DMF (15 mL), TBDPSCl (3.6 mL, 98%,
13.57 mmol)was added dropwise. The mixture was stirred at room
temperature for 10 h. The solution was poured into H2O/EtOAc,
separated, extracted (EtOAc), washed, dried and concentrated. The
residue was dissolved in dry MeOH (80 mL), and K2CO3 (324 mg,
2.35 mmol) was added. The mixture was stirred at room tempera-
ture for 6 h, and then the solution was poured into H2O/EtOAc,
separated and extracted (EtOAc). The combined organic extracts
were washed, dried and concentrated. The residue was purified by
flash chromatography (isooctane/EtOAc, 4:1), affording the inter-
mediate alcohol (2.5 g, 81%) as a colourless oil. The oil (1.9 g, 4.32
mmol) was dissolved in dry THF (30 mL) containing Ph3P (5.77 g,
22.04 mmol). To this solution DIAD (4.1 mL, 22.04 mmol) was
added dropwise at 0 °C. After stirring overnight at room tempera-
ture the solution was concentrated. The residue was purified by
chromatography (isooctane/EtOAc, 95:5), affording 33b (1.82 g,
92%). Rf = 0.28 (isooctane/EtOAc, 95:5). [α]D = –74.8 (c = 0.81,
Ethyl Homologue 34b: Rf = 0.12 (isooctane/EtOAc, 4:1). [α]D
=
–51.1 (c = 0.52, CHCl ). IR (KBr film): ν = 3421, 2956, 2857, 1736,
˜
3
1508, 1458, 1428, 1363, 1272, 1242 cm–1. 1H NMR (CDCl3): δ =
7.69–7.36 (m, 10 H), 3.59 (s, 3 H), 3.43 (dt, J = 10.6, 4.3 Hz, 1 H),
3.33 (dt, J = 10.6, 4.3 Hz, 1 H), 2.05 (m, 2 H), 1.92 (d, J = 12.4 Hz,
1 H), 1.78 (m, 1 H), 1.70 (m, 1 H), 1.54–1.41 (m, 4 H), 1.09 (s, 9
H), 0.69 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (CDCl3): δ = 175.2,
136.5, 134.8, 133.9, 130.3, 130.1, 128.2, 127.9, 71.3, 69.8, 52.8, 52.3,
38.3, 37.5, 37.3, 27.6, 19.9, 19.1, 9.4 ppm. MS: m/z (%) = 383 (M+ –
57, 2), 351 (8), 305 (24), 273 (5), 213 (9), 199 (70), 183 (15), 153
(20), 135 (28), 107 (100), 79 (30). C26H36O4Si (440.65): calcd. C
70.87, H 8.23; found: C 70.50, H 8.33.
Ethyl Homologue 35b: Rf = 0.17 (isooctane/EtOAc, 4:1). [α]D
=
–38.9 (c = 0.81, CHCl ). IR (KBr film): ν = 3453, 2958, 2858, 1736,
˜
3
1589, 1460, 1428, 1382, 1255, 1172, 1195, 1110 cm–1. 1H NMR
(CDCl3): δ = 7.67–7.37 (m, 10 H), 4.18 (dt, J = 11.7, 4.6 Hz, 1 H),
4.02 (d, J = 2.8 Hz, 1 H), 3.63 (s, 3 H), 2.60 (m, 1 H), 1.95 (m, 1
H), 1.80 (dt, J = 12.6, 4.1 Hz, 1 H), 1.65–1.45 (m, 5 H), 1.05 (s, 9
H), 0.87 (m, 3 H) ppm. 13C NMR (CDCl3): δ = 176.2, 136.3, 134.8,
134.7, 130.1, 130.0, 128.0, 69.3, 52.1, 49.1, 36.8, 32.6, 30.0, 27.4,
CHCl ). IR (KBr film): ν = 2957, 2857, 1738, 1429, 1246, 1166,
˜
3
1108, 1064, 935, 895, 821, 740, 704 cm–1. H NMR (CDCl3): δ =
1
7.73–7.38 (m, 10 H), 5.36 (br. s, 1 H), 4.26 (br. s, 1 H), 3.58 (s, 3
H), 2.36 (m, 1 H), 2.32 (m, 1 H), 2.16 (m, 2 H), 2.02 (m, 2 H), 1.75
(m, 1 H), 1.05 (s, 9 H), 0.87 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR
(CDCl3): δ = 175.1, 136.7, 134.4, 133.5, 129.5, 127.1, 119.7, 70.2, 19.7, 17.6, 13.3 ppm. MS: m/z (%) = 383 (M+ – 57, 90), 351 (6),
4420
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 4414–4427

Synthesis of Dihydroxyvitamin D3 Analogues
FULL PAPER
333 (5), 305 (4), 273 (10), 213 (50), 199 (100), 183 (58), 153 (60),
135 (65), 107 (48). C26H36O4Si (440.65): calcd. C 70.87, H 8.23;
found C 70.75, H 8.33.
0.21 (isooctane/EtOAc, 9:1). [α]D = +130.1 (c = 0.89, CHCl3). IR
(KBr film): ν = 2915, 2855, 1778, 1449, 1436, 1219, 1147,
˜
1116 cm–1. 1H NMR (CDCl3): δ = 5.43 (br. s, 1 H), 4.53 (d, J =
5.2 Hz, 1 H), 2.85 (t, J = 3.5 Hz, 1 H), 2.48–2.33 (m, 3 H), 2.06 (d,
J = 11.1 Hz, 1 H), 1.81 (s, 3 H) ppm. 13C NMR (CDCl3): δ =
179.5, 137.5, 122.2, 78.0, 37.6, 34.4, 28.4, 21.1 ppm. MS: m/z (%)
= 165 (M+ + 1, 1), 155 (1), 139 (4), 139 (23), 119 (4), 109 (10), 94
(30), 79 (100).
Methyl (1R,3R,4R,5R)-5-(tert-Butyldiphenylsilyloxy)-3-hydroxy-4-
methylcyclohexane-1-carboxylate (41a): To a stirred solution of 34a
(0.55 g, 1.29 mmol), p-NO2PhCO2H (0.26 g, 1.56 mmol) and Ph3P
(0.41 g, 1.56 mmol) in THF (15 mL) was added DIAD (323 μL,
95%, 1.56 mmol) dropwise at room temperature. After stirring for
24 h, the solution was subjected to flash chromatography (isooc-
tane/EtOAc, 7:3). After concentration, the residue was purified by
chromatography (isooctane/EtOAc, 92:8) to give 40a (0.60 g, 81%).
Rf = 0.24 (isooctane/EtOAc, 4:1). [α]D = –61.4 (c = 0.30, CHCl3).
(1R,3R,4S,5R)-3-Hydroxy-4-methyl-6-oxabicyclo[3.2.1]octan-7-one
(48): The synthesis of 48 was carried out as described for the hydro-
boration of 33a, yielding colourless crystals from n-hexane/acetone
( 42%). M.p. 128–129 °C. Rf = 0.21 (isooctane/EtOAc, 1:1). [α]D
= –109.3 (c = 0.97, CHCl ). IR (KBr film): ν = 3448, 2933, 1766,
˜
3
IR (KBr film): ν = 2957, 2858, 1729, 1608, 1529, 1461, 1428, 1349,
˜
1359, 1273, 1227 cm–1. 1H NMR (CDCl3): δ = 4.56 (d, J = 5.9 Hz,
1 H), 3.57 (m, 1 H), 2.70 (br. s, 1 H), 2.41 (m, 1 H), 2.32 (m, 1 H),
2.16 (br. s, 1 H), 1.84 (d, J = 11.7 Hz, 1 H), 1.65 (m, 1 H), 1.58
(m, 1 H), 1.19 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR (CDCl3): δ =
178.3, 82.8, 71.5, 42.4, 37.9, 37.6, 35.5, 16.1 ppm. MS: m/z (%) =
182 (M+, 1), 161 (5), 154 (4), 128 (14), 113 (48), 97 (54), 67 (50),
55 (100). C8H12O3 (156.18): calcd. C 61.52, H 7.74; found C 59.92,
H 7.78.
1
1273, 1243 cm–1. H NMR (CDCl3): δ = 8.23 (dd, J = 8.8, 1.4 Hz,
2 H), 7.83 (dd, J = 8.8, 1.4 Hz, 2 H), 7.75 (dd, J = 8.0, 1.4 Hz, 2
H), 7.71 (dd, J = 8.0, 1.4 Hz, 2 H), 7.52–7.40 (m, 6 H), 5.33 (d, J
= 2.2 Hz, 1 H), 3.73 (dt, J = 10.6, 4.2 Hz, 1 H), 3.60 (s, 3 H), 2.46
(tt, J = 9.1, 3.5 Hz, 1 H), 2.17 (m, 2 H), 1.86 (m, 1 H), 1.73 (dt, J
= 12.5, 2.2 Hz, 1 H), 1.68 (q, J = 12.5 Hz, 1 H), 1.08 (s, 9 H), 0.94
(d, J = 6.8 Hz, 3 H) ppm. 13C NMR (CDCl3): δ = 174.6, 163.6,
150.4, 136.2, 135.4, 134.4, 133.3, 130.5, 129.7, 127.6, 127.5, 123.5,
75.9, 72.4, 51.9, 42.5, 37.3, 37.2, 30.1, 27.1, 19.4, 14.8 ppm. MS:
m/z (%) = 544 (M+ – 31, 1), 518 (M+ – 57, 31), 488 (2), 442 (1),
409 (1), 348 (19), 302 (11), 273 (10), 213 (68), 183 (48), 150 (100).
C32H37O7NSi (575.73): calcd. C 66.76, H 6.48, N 2.43; found C
66.39, H 6.50, N 2.43. A mixture of 40a (0.59 g, 1.03 mmol) and
Methyl (1S,3R,4R,5R)-3-(tert-Butyldiphenylsilyloxy)-6-hydroxy-5-
methylcyclohexane-1-carboxylate (50): The synthesis of 50 was car-
ried out from 48 as described for 32 from 31. The yield for the 2
steps was 86%. Rf = 0.21 (isooctane/EtOAc, 4:1). [α]D = –7.1 (c =
0.41, CHCl ). IR (KBr film): ν = 3445, 2953, 2858, 1734, 1684,
˜
3
K2CO3 (71 mg, 0.51 mmol) in a dry MeOH (12 mL) was stirred 1653, 1559, 1540, 1428, 1362, 1256, 1195 cm–1. 1H NMR (CDCl3):
for 6 h at room temperature, and then poured into H2O/EtOAc,
separated and extracted. The organic extracts were washed, dried
and concentrated. Flash chromatography (isooctane/EtOAc, 4:1)
gave 41a (0.42 g, 95%) as a colourless oil. Rf = 0.21 (isooctane/
δ = 7.66–7.35 (m, 10 H), 4.25 (dt, J = 10.7, 6.7 Hz, 1 H), 3.94 (m,
1 H), 3.63 (s, 3 H), 2.92 (m, 1 H), 1.98 (m, 1 H), 1.93 (dt, J = 10.1,
6.5 Hz, 1 H), 1.68–1.60 (m, 3 H), 1.05 (s, 9 H), 0.77 (d, J = 7.3 Hz,
3 H) ppm. 13C NMR (CDCl3): δ = 176.0, 135.7, 133.9, 129.7, 127.6,
73.0, 68.3, 51.8, 41.1, 36.9, 31.4, 30.5, 26.9, 19.3, 10.5 ppm. MS:
m/z (%) = 369 (M+ – 57, 14), 337 (45), 291 (8), 259 (11), 199 (92),
169 (83), 137 (100), 93 (47). C25H34O4Si (426.63): calcd. C 70.38,
H 8.03; found C 69.93, H 8.22.
EtOAc, 4:1). [α]D = –72.5 (c = 0.50, CHCl ). IR (KBr film): ν =
˜
3
3500, 3071, 2956, 2858, 1736, 1462, 1428, 1195, 1111, 1084 cm–1.
1H NMR (CDCl3): δ = 7.71–7.35 (m, 10 H), 3.99 (d, J = 3.5 Hz, 1
H), 3.75 (dt, J = 10.5, 4.3 Hz, 1 H), 3.58 (s, 3 H), 2.59 (tt, J = 12.2,
3.6 Hz, 1 H), 1.97–1.91 (m, 2 H), 1.66–1.57 (m, 2 H), 1.49 (m, 1
H), 1.05 (s, 9 H), 1.02 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR (CDCl3):
δ = 175.6, 135.9, 134.7, 133.9, 129.5, 127.5, 72.3, 71.1, 51.6, 43.6,
Methyl (1S,5S)-5-(tert-Butyldiphenylsilyloxy)-4-methyl-3-cyclohex-
ene-1-carboxylate (56a): The synthesis of 56a was carried out from
30 via 53 and 54 as described for 33b from 31. The yield for the 3
steps was 81%. Rf = 0.30 (isooctane/EtOAc, 9:1). [α]D = +81.9 (c
37.2, 36.4, 35.1, 27.1, 19.5, 14.9 ppm. MS: m/z (%) = 395 (M+
–
31, 4), 370 (24), 369 (M+ – 57, 100), 337 (10), 291 (6), 259 (8), 221
(4), 215 (74), 199 (84), 183 (64), 153 (71), 105 (58), 77 (72).
= 1.91, CHCl ). IR (KBr film): ν = 3070, 2952, 2855, 1738, 1472,
˜
3
1433, 1428, 1362, 1308, 1247 cm–1. 1H NMR (CDCl3): δ = 7.73–
7.36 (m, 10 H), 5.39 (t, J = 1.8 Hz, 1 H), 4.24 (br. s, 1 H), 3.59 (s,
3 H), 2.38 (m, 1 H), 2.22–2.04 (m, 3 H), 1.75 (m, 1 H), 1.66 (s, 3
H), 1.07 (s, 9 H) ppm. 13C NMR (CDCl3): δ = 175.1, 137.4, 134.4,
133.7, 129.6, 127.6, 121.9, 71.4, 51.6, 38.8, 36.2, 27.9, 27.1, 20.2,
19.5 ppm. MS: m/z (%) = 408 [M+, 1], 387 (6), 351 (M+ – 57, 95),
319 (6), 299 (5), 273 (6), 227 (5), 213 (100), 183 (75), 137 (50), 77
(65).
Ethyl Homologue 41b: Compound 41b was synthesized from 34b
via 40b as described for 41a. Rf = 0.22 (isooctane/EtOAc, 4:1). [α]
= –63.4 (c = 0.71, CHCl ). IR (KBr film): ν = 3506, 3071, 2956,
˜
D
3
2858, 1736, 1472, 1428, 1361, 1266, 1176, 1110 cm–1. 1H NMR
(CDCl3): δ = 7.67–7.35 (m, 10 H), 4.2 (d, J = 3.2 Hz, 1 H), 3.78
(m, 1 H), 3.58 (s, 3 H), 2.57 (m, 1 H), 1.94 (dt, J = 13.1, 3.6 Hz, 2
H), 1.60–1.50 (m, 2 H), 1.43 (br. s, 1 H), 1.33 (m, 1 H), 1.13 (m, 2
H), 1.05 (s, 9 H), 0.86 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (CDCl3):
δ = 175.6, 136.0, 129.6, 129.5, 127.5, 127.4, 71.5, 66.4, 51.6, 50.2,
37.2, 36.2, 35.0, 27.1, 19.7, 19.5, 11.3 ppm. MS: m/z (%) = 383
(M+ – 57, 100), 351 (6), 305 (4), 273 (8), 199 (90), 153 (45), 135
(50), 77 (65), 57 (68). C26H36O4Si (440.65): calcd. C 70.87, H 8.23;
found C 71.02, H 8.20.
Ethyl Homologue 56b: Rf = 0.37 (isooctane/EtOAc, 9:1). [α]D
=
+74.2 (c = 1.09, CHCl ). IR (KBr film): ν = 2959, 2857, 1738,
˜
3
1652, 1589, 1456, 1428, 1388, 1246 cm–1. 1H NMR (CDCl3): δ =
7.72–7.38 (m, 10 H), 5.37 (m, 1 H), 4.26 (br. s, 1 H), 3.58 (s, 3 H),
2.35 (m, 1 H), 2.30–1.98 (m, 5 H), 1.75 (m, 1 H), 1.05 (s, 9 H), 0.87
(t, J = 7.4 Hz, 3 H) ppm. 13C NMR (CDCl3): δ = 175.1, 136.7,
134.4, 133.5, 129.5, 127.1, 119.7, 70.2, 51.5, 38.7, 35.3, 27.7, 27.0,
25.3, 19.4, 12.3 ppm. MS: m/z (%) = 422 (M+, 2), 401 (3), 365 (88),
333 (8), 287 (9), 255 (3), 227 (7), 213 (90), 183 (50), 137 (58), 107
(45), 79 (100).
(1R,5R)-4-Methyl-6-oxabicyclo[3.2.1]oct-3-en-7-one (47): A solu-
tion of 30 (0.36 g, 2.12 mmol) and PPTS (0.49 g, 1.95 mmol) in
benzene (25 mL) was stirred at 80 °C for 24 h. The reaction mixture
was cooled, diluted with Et2O and washed with satd. aqueous
NaHCO3 and brine. The organic extracts were dried, and the sol-
vents were evaporated. The residue was purified by flash
chromatography (isooctane/EtOAc, 4:1), affording 47 (0.19 g, 85%)
as colourless crystals from n-hexane/acetone. M.p. 47–48 °C. Rf =
Hydroboration of 56a,b: The syntheses of 56a,b were carried out as
described for 34a,b and 35a,b from 33a,b.
Methyl (1S,3S,4R,5S)-3-(tert-Butyldiphenylsilyloxy)-5-hydroxy-4-
methylcyclohexane-1-carboxylate (58a): Rf
=
0.18 (isooctane/
Eur. J. Org. Chem. 2005, 4414–4427
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4421

Y.-R. Zhao, B. Guang, R. Bouillon, A. Verstuyf, P. De Clercq, M. Vandewalle
FULL PAPER
EtOAc, 4:1). [α]D = +40.5 (c = 0.66, CHCl ). IR (KBr film): ν = (2) 57a: To a stirred solution of 55 (0.22 g, 0.36 mmol) and 18-
˜
3
3452, 3070, 2953, 2857, 1735, 1717, 1427, 1379, 1272, 1195 cm–1.
1H NMR (CDCl3): δ = 7.68–7.36 (m, 10 H), 4.17 (dt, J = 10.8,
4.7 Hz, 1 H), 3.89 (d, J = 2.7 Hz, 1 H), 3.63 (s, 3 H), 2.62 (m, 1
H), 1.81–1.67 (m, 5 H), 1.56 (br. s, 1 H), 1.06 (s, 9 H), 0.96 (d, J =
crown-6 (476 mg, 1.80 mmol) was added freshly prepared EtCO2Cs
(371 mg, 1.80 mmol). The mixture was stirred at 110 °C for 2.5 h,
and then cooled to room temperature. The mixture was diluted
with EtOAc, washed and concentrated. Column chromatography
7.2 Hz, 3 H) ppm. 13C NMR (CDCl3): δ = 175.7, 135.8, 134.4, (isooctane/EtOAc, 100:4) afforded 57a (95 mg, 55%), together with
129.7, 127.6, 72.0, 68.9, 56.9, 51.7, 41.3, 36.6, 31.4, 29.6, 27.0, 19.3, the elimination product. Rf = 0.26 (isooctane/EtOAc, 4:1). [α]D
=
10.6 ppm. MS: m/z (%) = 425 (M+ – 1, 1), 385 (2), 369 (M+ – 57, +30.7 (c = 0.79, CHCl ). IR (KBr film): ν = 3049, 2954, 2858,
˜
3
100), 337 (5), 291 (4), 259 (10), 221 (4), 199 (85), 153 (65).
1738, 1463, 1428, 1274, 1189, 1112 cm–1. 1H NMR (CDCl3): δ =
7.67–7.34 (m, 10 H), 4.90 (d, J = 2.9 Hz, 1 H), 3.98 (dt, J = 11.6,
4.7 Hz, 1 H), 3.65 (s, 3 H), 2.48 (m, 1 H), 2.14–1.99 (m, 2 H), 1.93
(m, 1 H), 1.87 (dt, J = 12.8, 4.2 Hz, 1 H), 1.93–1.81 (m, 3 H), 1.06
(s, 9 H), 1.04 (d, J = 7.3 Hz, 3 H), 0.97 (t, J = 7.6 Hz, 3 H) ppm.
13C NMR (CDCl3): δ = 175.1, 173.1, 135.8, 133.9, 129.7, 127.5,
74.1, 69.1, 51.8, 38.0, 37.3, 30.9, 27.7, 26.9, 26.7, 19.2, 9.9, 9.0 ppm.
MS: m/z (%) = 451 (M+ – 31, 2), 425 (M+ – 57, 21), 386 (1), 351
(15), 291 (3), 255 (27), 199 (29), 183 (19), 135 (21), 93 (26).
C28H38O5Si (482.69): calcd. C 69.67, H 7.94; found C 69.82, H
7.82.
Methyl (1S,3S,4S,5R)-3-(tert-Butyldiphenylsilyloxy)-5-hydroxy-4-
methylcyclohexane-1-carboxylate (60a): Rf
= 0.15 (isooctane/
EtOAc, 4:1). [α]D = +51.2 (c = 0.53, CHCl ). IR (KBr film): ν =
˜
3
3444, 3070, 2952, 2857, 1736, 1459, 1427, 1361, 1282, 1249,
1
1172 cm–1. H NMR (CDCl3): δ = 7.69–7.36 (m, 10 H), 3.59 (s, 3
H), 3.25 (m, 1 H), 3.08 (m, 1 H), 2.11–2.05 (m, 2 H), 1.92 (d, J =
13.0 Hz, 1 H), 1.53–1.44 (m, 4 H), 1.08 (d, J = 6.4 Hz, 3 H), 1.05
(s, 9 H) ppm. 13C NMR (CDCl3): δ = 174.5, 135.9, 134.3, 133.6,
129.7, 129.6, 127.6, 127.5, 74.8, 73.0, 51.8, 47.9, 37.9, 37.1, 36.8,
30.1, 27.0, 19.4, 14.5 ppm. MS: m/z (%) = 369 (M+ – 57, 5), 337
(8), 291 (45), 259 (4), 247 (3), 199 (72), 153 (28), 121 (25), 93 (100).
(3) 58a: Methanolysis of 57a as described for 32 gave 58a in 98%
yield.
Ethyl Homologue 58b: Rf = 0.17 (isooctane/EtOAc, 4:1). [α]D
=
+38.0 (c = 1.13, CHCl ). IR (KBr film): ν = 3453, 2958, 2858,
˜
3
Mesylate Formation (General Procedure): To a stirred solution of
the hydroxy compound and Et3N (1.5 equiv.) in CH2Cl2 (0.04–0.05
mmol/mL) was added dropwise MsCl (1.2 equiv.) at 0 °C, and the
stirring was continued for 3 h. The solution was subjected to flash
chromatography (isooctane/EtOAc, 7:3). The residue was purified
by HPLC (isooctane/EtOAc, 9:1) to give the corresponding mesyl-
ate (circa 95%).
1736, 1589, 1460, 1428, 1382, 1255 cm–1. 1H NMR (CDCl3): δ =
7.67–7.37 (m, 10 H), 4.18 (dt, J = 11.7, 4.6 Hz, 1 H), 4.02 (d, J =
2.8 Hz, 1 H), 3.63 (s, 3 H), 2.60 (m, 1 H), 1.95 (m, 1 H), 1.80 (dt,
J = 12.6, 4.1 Hz, 1 H), 1.65–1.45 (m, 6 H), 1.05 (s, 9 H), 0.87 (m,
3 H) ppm. 13C NMR (CDCl3): δ = 176.2, 136.3, 134.8, 134.7, 130.1,
130.0, 128.0, 69.3, 52.1, 49.1, 36.8, 32.6, 30.0, 27.4, 19.7, 17.6, 13.3
ppm. MS: m/z (%) = 383 (M+ – 57, 100), 351 (4), 287 (6), 273 (7),
213 (55), 199 (95), 183 (55), 153 (50), 107 (35), 55 (86).
Methyl Bicyclo[3.1.0]hexane-1-carboxylate Formation (General Pro-
cedure): To a stirred solution of the mesylate (0.03–0.05 mmol/mL)
in tBuOH/THF (3:2) was added dropwise tBuOK (1 m in tBuOH,
1.2 equiv.) at 45–50 °C, and stirring was continued for 0.5 h. The
solution was poured into H2O/EtOAc, and then the organic layer
was separated. The aqueous layer was extracted with EtOAc and
the combined organic extracts were washed, dried and concen-
trated. The residue was purified by flash chromatography (isooc-
tane/EtOAc, circa 100:3) affording the bicyclic product (circa 70%).
Ethyl Homologue 60b: Rf = 0.12 (isooctane/EtOAc, 4:1). [α]D
=
+50.7 (c = 0.52, CHCl ). IR (KBr film): ν = 3421, 2956, 2857,
˜
3
1736, 1508, 1458, 1428, 1363, 1272, 1242, 1169, 1110, 1040, 1007,
866, 822, 740, 703, 612 cm–1 1H NMR (CDCl3): δ = 7.69–7.36 (m,
.
10 H), 3.59 (s, 3 H), 3.43 (dt, J = 10.6, 4.3 Hz, 1 H), 3.33 (dt, J =
10.6, 4.3 Hz, 1 H), 2.05 (m, 2 H), 1.92 (d, J = 12.4 Hz, 1 H), 1.78
(m, 1 H), 1.70 (m, 1 H) 1.54–1.41 (m, 3 H), 1.09 (s, 9 H), 0.89 (m,
1 H), 0.69 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (CDCl3): δ = 175.2,
136.5, 134.8, 133.9, 130.3, 130.1, 128.2, 127.9, 71.3, 69.8, 52.8, 52.3,
38.3, 37.5, 37.3, 27.6, 19.9, 19.1, 9.4 ppm. MS: m/z (%) = 383 (M+ –
57, 3), 351 (9), 305 (32), 273 (6), 199 (64), 183 (15), 153 (18), 135
(35), 107 (100), 79 (35).
(a) Methyl (1S,3R,4S,5S)-3-(tert-Butyldiphenylsilyloxy)-4-methylbi-
cyclo[3.1.0]hexane-1-carboxylate (38a): Rf
= 0.24 (isooctane/
EtOAc, 97:3). [α]D = –53.8 (c = 0.65, CHCl ). IR (KBr film): ν =
˜
3
2957, 2858, 1724, 1472, 1428, 1367, 1292, 1222, 1149 cm–1. 1H
NMR (CDCl3): δ = 7.65–7.36 (m, 10 H), 3.84 (m, 1 H), 3.64 (s, 3
H), 2.24 (dd, J = 12.5, 8.5 Hz, 1 H), 2.03 (dd, J = 13.5, 6.6 Hz, 1
H), 1.93 (dd, J = 12.7, 7.2 Hz, 1 H), 1.59 (m, 1 H), 1.18 (dd, J =
8.4, 4.8 Hz, 1 H), 1.05 (d, J = 6.9 Hz, 3 H), 1.05 (s, 9 H), 0.56 (t,
J = 5.2 Hz, 1 H) ppm. 13C NMR (CDCl3): δ = 174.9, 135.7, 133.9,
129.6, 127.6, 72.9, 51.8, 37.2, 34.1, 33.3, 27.2, 27.0, 19.4, 19.5, 15.1
ppm. MS: m/z (%) = 408 (M+, 1), 353 (M+ – 57, 21), 351 (87), 296
(13), 237 (8), 213 (100), 183 (58), 135 (61), 77 (67). C25H32O3Si
(408.61): calcd. C 73.49, H 7.89; found C 73.57, H 8.04. Enanti-
omer (66a): [α]D = +52.2 (c = 0.76, CHCl3).
Methyl (1S,3S,4R,5S)-3-(tert-Butyldiphenylsilyloxy)-4-methylcyclo-
hexane-1-carboxylate (58a)
(1) 55: To a stirred solution of 54 (0.21 g, 0.49 mmol), Et3N
(172 μL, 1.23 mmol) and DMAP (6 mg, 0.05 mmol) in CH2Cl2
(8 mL) was added p-nitrobenzenesulfonyl chloride (136 mg, 0.61
mmol) at 0 °C and stirring was continued for 10 h. The solution
was submitted to flash chromatography (isooctane/EtOAc, 9:1) to
give 55 (0.27 g, 90%). Rf = 0.27 (isooctane/EtOAc, 4:1). [α]D = –
3.2 (c = 0.40, CHCl ). IR (KBr film): ν = 3072, 2955, 2858, 1737,
˜
3
1608, 1535, 1428, 1351, 1288, 1251, 1187 cm–1. 1H NMR (CDCl3):
δ = 8.35 (dd, J = 7.1, 1.7 Hz, 2 H), 7.99 (dd, J = 7.1, 1.7 Hz, 2 H), Ethyl Homologue 38b: Rf = 0.28 (isooctane/EtOAc, 95:5). [α]D
=
7.60–7.35 (m, 10 H), 4.39 (dt, J = 12.1, 4.7 Hz, 1 H), 3.63 (s, 3 H), –36.2 (c = 1.04, CHCl ). IR (KBr film): ν = 2958, 1724, 1428, 1366,
˜
3
3.62 (m, 1 H), 2.17 (m, 1 H), 2.05 (dt, J = 12.9, 1.7 Hz, 1 H), 1.88 1233, 1158 cm–1. 1H NMR (CDCl3): δ = 7.67–7.38 (m, 10 H), 3.87
(m, 1 H), 1.79 (m, 1 H), 1.73 (m, 1 H), 1.66 (m, 1 H), 1.03 (s, 9
(q, J = 7.2 Hz, 1 H), 3.64 (s, 3 H), 2.18 (m, 1 H), 1.92 (m, 1 H),
H), 1.00 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR (CDCl3): δ = 173.4, 1.75 (m, 1 H), 1.56 (s, 2 H), 1.22 (m, 2 H), 1.05 (s, 9 H), 0.96 (t, J
150.5, 142.9, 135.6, 133.4, 129.9, 128.8, 127.7, 124.4, 81.9, 70.6,
52.1, 39.5, 37.4, 30.1, 27.8, 26.8, 19.1, 5.4 ppm. MS: m/z (%) = 554
(M+ – 57, 21), 494 (2), 416 (3), 384 (57), 351 (32), 304 (9), 258 (7),
= 7.4 Hz, 3 H), 0.55 (t, J = 5.1 Hz, 1 H) ppm. 13C NMR (CDCl3)
δ = 175.1, 135.8, 135.7, 134.0, 129.8, 127.7, 73.1, 51.8, 44.1, 34.3,
:
31.4, 27.5, 27.0, 21.3, 19.3, 18.5, 12.0 ppm. MS: m/z (%) = 422
213 (67), 153 (49), 93 (100). C31H37O8SiNS (611.79): calcd. C 60.86, (M+, 27), 365 (M+ – 57, 26), 337 (3), 287 (5), 213 (40), 199 (52),
H 6.09, N 2.29; found C 61.09, H 6.30, N 2.29.
153 (22), 135 (100), 79 (35), 57 (25). C26H34O3Si (422.63): calcd. C
4422
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 4414–4427

Synthesis of Dihydroxyvitamin D3 Analogues
FULL PAPER
73.89, H 8.11; found C 73.72, H 8.31. Enantiomer (66b): [α]D
+36.5 (c = 1.07, CHCl3).
=
2931, 1724, 1428, 1288, 1224, 1147 cm–1. 1H NMR (CDCl3): δ =
7.63–7.36 (m, 10 H), 4.19 (t, J = 6.0 Hz, 1 H), 3.62 (s, 3 H), 2.30
(m, 2 H), 1.97 (d, J = 14.2 Hz, 1 H), 1.85 (m, 1 H), 1.64 (t, J =
4.6 Hz, 1 H), 1.35 (dd, J = 8.7, 3.9 Hz, 1 H), 1.09 (s, 9 H), 0.99 (d,
J = 6.9 Hz, 3 H) ppm. 13C NMR (CDCl3): δ = 175.1, 136.0, 134.1,
133.6, 129.5, 127.5, 75.0, 51.4, 40.4, 38.1, 35.4, 29.5, 27.0, 19.2,
18.4, 12.9 ppm. MS: m/z (%) = 408 (M+), 377, 351, 319, 273, 245,
199, 158, 153, 121 (100), 77, 57. Enantiomer (70a): [α]D = +13.9 (c
= 0.65, CHCl3). C25H32O3Si (408.61): calcd. C 73.49, H 7.89; found
C 73.41, H 8.13.
(b) Methyl (1S,3R,4S,5S)-3-(tert-Butyldiphenylsilyloxy)-4-methylbi-
cyclo[3.1.0]hexane-1-carboxylate (43a): Rf 0.21 (isooctane/
=
EtOAc, 100:3). [α]D = –100.4 (c = 1.15, CHCl ). IR (KBr film): ν
˜
3
= 3048, 2956, 2858, 1727, 1589, 1472, 1428, 1369, 1346, 1259,
1
1199 cm–1. H NMR (CDCl3): δ = 7.65–7.35 (m, 10 H), 3.63 (s, 3
H), 3.30 (dd, J = 12.3, 7.4 Hz, 1 H), 2.27–2.19 (m, 2 H), 1.99 (dd,
J = 12.8, 7.1 Hz, 1 H), 1.78 (dt, J = 8.6, 5.2 Hz, 1 H), 1.07 (m, 1
H), 1.04 (s, 9 H), 0.87 (d, J = 6.6 Hz, 3 H), 0.45 (t, J = 5.1 Hz, 1
H) ppm. 13C NMR (CDCl): δ = 174.8, 135.9, 134.0, 129.6, 127.5,
77.4, 51.6, 41.7, 36.4, 32.3, 26.9, 26.7, 19.2, 15.9, 15.5 ppm. MS:
m/z (%) = 408 (M+, 5), 377 (6), 351 (M+ – 57, 65), 317 (6), 273 (5),
225 (4), 213 (100), 183 (43), 135 (40), 84 (72). C25H32O3Si (408.61):
calcd. C 73.49, H 7.89; found C 73.32, H 8.01. Enantiomer (62a):
[α]D = +99.5 (c = 0.72, CHCl3). C25H32O3Si (408.61): calcd. C
73.49, H 7.89; found C 73.47, H 8.06.
Ethyl Homologue 68b: Rf = 0.28 (cyclohexane/EtOAc, 94:6).
[α]D = –29.4 (c = 0.61, CHCl ). IR (KBr film): ν = 2958, 1723,
˜
3
1427, 1366, 1298, 1224, 1148 cm–1. 1H NMR (CDCl3): δ = 7.63–
7.35 (m, 10 H), 4.18 (t, J = 5.9 Hz, 1 H), 3.61 (s, 3 H), 2.26 (m, 1
H), 2.06 (m, 1 H), 1.98 (d, J = 14.3 Hz, 1 H), 1.92 (m, 1 H), 1.67
(t, J = 4.3 Hz, 1 H), 1.48 (m, 2 H), 1.36 (dd, J = 12.1, 3.9 Hz, 1
H), 1.05 (s, 9 H), 0.89 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR (CDCl3):
δ = 175.3, 136.1, 134.3, 133.5, 129.6, 127.5, 74.6, 51.6, 48.3, 37.8,
33.3, 29.9, 27.1, 20.9, 19.3, 18.5, 13.3 ppm. MS: m/z (%) = 422
(M+, 2), 391 (4), 365 (M+- 57, 40), 337 (8), 287 (12), 259 (10), 225
(8), 199 (65), 135 (100), 105 (38). Enantiomer (70b): [α]D = +28.4
(c = 0.75, CHCl3).
Ethyl Homologue 43b: Rf = 0.28 (isooctane/EtOAc, 95:5). [α]D
=
–102.9 (c = 0.65, CHCl ). IR (KBr film): ν = 2957, 2857, 1725,
˜
3
1589, 1461, 1428, 1371, 1327, 1262, 1197, 1154 cm–1. 1H NMR
(CDCl3): δ = 7.68–7.35 (m, 10 H), 3.63 (s, 3 H), 3.37 (q, J = 8.1 Hz,
1 H), 2.21 (m, 2 H), 2.09 (m, 1 H), 1.98 (dd, J = 12.8, 7.1 Hz, 1
H), 1.86 (dt, J = 8.6, 5.1 Hz, 1 H), 1.08 (q, J = 5.0 Hz, 2 H), 1.05
(s, 9 H), 0.90 (t, J = 7.1 Hz, 3 H), 0.45 (t, J = 5.1 Hz, 1 H) ppm.
13C NMR (CDCl3): δ = 175.2, 136.2, 134.3, 129.9, 127.8, 127.7,
76.4, 51.9, 49.3, 36.6, 30.4, 27.3, 26.9, 24.2, 19.5, 16.5, 13.0 ppm.
MS: m/z (%) = 422 (M+, 1), 407 (2), 365 (M+ – 57, 75), 309 (4),
213 (90), 199 (20), 183 (35), 135 (30), 77 (45), 41 (48). C26H34O3Si
(422.63): calcd.C 73.89; H 8.11; found C 73.70, H 8.25. Enantiomer
(62b): [α]D = +103.5 (c = 0.72, CHCl3).
(1S,3S,4S,5S)-3-(tert-Butyldiphenylsilyloxy)-4-methylbicyclo[3.1.0]-
hexane-1-carbaldehyde (39a) (General Procedure): To a solution of
38a (132 mg, 0.324 mmol) in THF (10 mL) at 0 °C was added drop-
wise LiAlH4 (485 μL, 0.485 mmol, 1 m in THF). The mixture was
stirred at 0 °C for 1.5 h, and then EtOAc (3 mL) was added. After
stirring for 0.5 h, the reaction was quenched with a minimum of
H2O. The mixture was filtered through Celite and the filtrate was
dried and concentrated. The residue was purified by flash
chromatography (isooctane/EtOAc, 4:1) to afford the primary
alcohol (120 mg, 97%) as a colourless oil. Rf = 0.21 (isooctane/
(c) Methyl (1R,3R,4R,5R)-2-(tert-Butyldiphenylsilyloxy)-4-methyl-
bicyclo[3.1.0]hexane-1-carboxylate (45a): Rf = 0.21 (isooctane/
EtOAc, 100:3). [α]D = +7.1 (c = 0.58, CHCl ). IR (KBr film): ν =
˜
EtOAc, 4:1). [α]D = –4.6 (c = 0.35, CHCl ). IR (KBr film): ν =
3
˜
3
3332, 3070, 2930, 2858, 1472, 1428, 1390, 1219, 1112, 1008 cm–1.
1H NMR (CDCl3): δ = 7.66–7.35 (m, 10 H), 3.91 (m, 1 H), 3.52
(d, J = 2.0 Hz, 2 H), 2.03 (m, 1 H), 1.91–1.82 (m, 2 H), 1.45 (br.
s, 1 H), 1.05 (s, 9 H), 1.04 (d, J = 7.7 Hz, 3 H), 0.92 (m, 1 H), 0.27
(m, 2 H) ppm. 13C NMR (CDCl3): δ = 137.6, 134.2, 129.6, 127.5,
73.4, 68.6, 37.5, 35.0, 29.9, 27.9, 26.9, 19.2, 15.3, 13.5 ppm. MS:
m/z (%) = 380 (M+, 1), 363 (1), 323 (M+ – 57, 11), 305 (4), 267 (2),
245 (21), 227 (9), 199 (100), 152 (4), 135 (12), 107 (85). C24H32O2Si
(380.60): calcd. C 75.74, H 8.47; found C 75.34, H 8.62. The inter-
mediate alcohol (100 mg, 0.263 mmol) was dissolved in CH2Cl2
(10 mL) containing NMO (48 mg, 97%, 0.397 mmol) and 4-Å mol-
ecular sieves (130 mg), and then TPAP (9.5 mg, 97%, 0.03 mmol)
was added. The mixture was stirred at room temperature for 0.5 h,
and then was subjected to flash chromatography (isooctane/EtOAc,
4:1). Evaporation of the solvents and column chromatography (iso-
octane/EtOAc, 9:1) afforded 39a (93 mg, 95%) as a colourless oil.
Rf = 0.22 (isooctane/EtOAc, 95:5). [α]D = –49.4 (c = 0.99, CHCl3).
3071, 2956, 2858, 1724, 1589, 1472, 1428, 1390, 1366, 1292, 1222,
1190, 1151, 1112 cm–1. 1H NMR (CDCl3): δ = 7.62–7.36 (m, 10
H), 3.89 (d, J = 6.3 Hz, 1 H), 3.64 (s, 3 H), 2.45 (dd, J = 14.3,
6.2 Hz, 1 H), 2.03 (m, 1 H), 1.94 (d, J = 14.3 Hz, 1 H), 1.69 (d, J
= 1.3 Hz, 1 H), 1.66 (t, J = 7.7 Hz, 1 H), 1.47 (m, 1 H), 1.05 (s, 9
H), 0.66 (d, J = 7.4 Hz, 3 H) ppm. 13C NMR (CDCl3): δ = 175.4,
135.9, 134.2, 129.8, 127.8, 80.7, 51.8, 44.7, 36.7, 35.9, 30.9, 27.1,
20.9, 19.4, 19.0 ppm. MS: m/z (%) = 408 (M+, 4), 377 (7), 351
(M+ – 57, 43), 319 (7), 273 (8), 245 (16), 199 (47), 153 (41), 121
(100), 77 (58). C25H32O3Si (408.61): calcd. C 73.49, H 7.89; found
C 73.36, H 8.01. Enantiomer (64a): [α]D = –7.4 (c = 0.70, CHCl3).
C25H32O3Si (408.61): calcd. C 73.49, H 7.89; found C 73.67, H
8.02.
Ethyl Homologue 45b: Rf = 0.26 (isooctane/EtOAc, 95:5). [α]D
=
+16.1 (c = 1.05, CHCl ). IR (KBr film): ν = 2959, 2858, 1723,
˜
3
1560, 1428, 1365, 1297, 1274, 1220, 1150 cm–1. 1H NMR (CDCl3):
δ = 7.67–7.37 (m, 10 H), 3.96 (d, J = 6.6 Hz, 1 H), 3.64 (s, 3 H),
2.37 (m, 1 H), 1.94 (d, J = 14.2 Hz, 1 H), 1.83 (t, J = 7.3 Hz, 1 H),
1.73 (m, 1 H), 1.68 (t, J = 5.2 Hz, 1 H), 1.48 (m, 1 H), 1.03 (s, 9 H),
0.94 (m, 2 H), 0.63 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (CDCl3): δ
= 174.8, 135.5, 135.4, 129.2, 127.2, 127.1, 78.5, 51.2, 35.9, 34.2,
30.2, 29.6, 26.5, 26.1, 20.3, 18.5, 11.3 ppm. MS: m/z (%) = 422
(M+, 2), 365 (M+ – 57, 82), 213 (100), 199 (20), 183 (40), 153 (10),
135 (60), 77 (42), 49 (70). C26H34O3Si (422.63): calcd. C 73.89, H
8.11; found C 73.77, H 8.19. Enantiomer (64b): [α]D = –15.9 (c =
0.70, CHCl3).
IR (KBr film): ν = 2931, 2858, 1702, 1459, 1427, 1389, 1219 cm–1.
˜
1H NMR (CDCl3): δ = 8.80 (s, 1 H), 7.65–7.37 (m, 10 H), 3.93 (m,
1 H), 2.24 (dd, J = 12.9, 9.3 Hz, 1 H), 2.13 (m, 1 H), 1.81 (dd, J =
12.9, 7.2 Hz, 1 H), 1.68 (dd, J = 8.9, 5.6 Hz, 1 H), 1.20 (dd, J =
8.8, 6.0 Hz, 1 H), 1.05 (s, 9 H), 1.03 (d, J = 8.1 Hz, 3 H), 0.86 (t,
J = 5.6 Hz, 1 H) ppm. 13C NMR (CDCl3): δ = 200.1, 135.7, 133.8,
129.7, 127.6, 72.7, 37.9, 36.7, 32.7, 30.6, 26.8, 19.2, 17.6, 14.7 ppm.
MS: m/z (%) = 321 (M+ – 57, 86), 305 (7), 279 (14), 243 (20), 199
(100), 181 (35), 139 (68), 105 (58), 77 (64).
(d) Methyl (1S,3S,4R,5S)-2-(tert-Butyldiphenylsilyloxy)-4-methylbi- Ethyl Homologue 39b: Rf = 0.28 (isooctane/EtOAc, 9:1). [α]D
cyclo[3.1.0]hexane-1-carboxylate (68a): Rf 0.33 (isooctane/ –33.3 (c = 0.57, CHCl ). IR (KBr film): ν = 3070, 2960, 2857, 2711,
EtOAc, 9:1). [α]D = –13.2 (c = 1.61, CHCl ). IR (KBr film): ν = 1700, 1472, 1428, 1389, 1270, 1217, 1175, 1111, 1027 cm–1. 1H
=
=
˜
3
˜
3
Eur. J. Org. Chem. 2005, 4414–4427
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4423

Y.-R. Zhao, B. Guang, R. Bouillon, A. Verstuyf, P. De Clercq, M. Vandewalle
NMR (CDCl3): δ = 8.81 (s, 1 H), 7.64–7.35 (m, 10 H), 3.95 (q, J
1616, 1471, 1428, 1377, 1110 cm–1. 1H NMR (CDCl3): δ = 7.71–
FULL PAPER
= 7.8 Hz, 1 H), 2.19 (m, 1 H), 1.91–1.78 (m, 4 H), 1.25 (m, 1 H), 7.35 (m, 10 H), 6.14 (d, J = 11.3 Hz, 1 H), 5.46 (d, J = 11.3 Hz, 1
1.17 (m, 1 H), 1.05 (s, 9 H), 0.95 (t, J = 7.2 Hz, 3 H), 0.84 (t, J = H), 3.94 (m, 1 H), 3.72 (td, J = 8.9, 4.2 Hz, 1 H), 2.72 (m, 1 H),
5.6 Hz, 1 H) ppm. 13C NMR (CDCl3): δ = 200.0, 135.7, 135.5, 2.66 (dd, J = 13.3, 4.0 Hz, 1 H), 2.37–2.44 (m, 2 H), 2.25 (dd, J =
133.7, 129.7, 129.6, 127.6, 73.1, 43.6, 38.2, 31.7, 30.1, 26.8, 20.9,
19.1, 17.6, 11.7 ppm. MS: m/z (%) = 335 (M+ – 57, 55), 280 (10),
257 (18), 227 (15), 199 (100), 181 (30), 139 (50), 105 (45), 77 (65).
C25H32O2Si (392.60): calcd. C 76.48, H 8.21; found C 76.32, H
8.40.
13.6, 5.2 Hz, 1 H), 2.05–1.85 (m, 4 H), 1.80 (m, 1 H), 1.70–1.60
(m, 3 H), 1.50–1.24 (m, 13 H), 1.23 (s, 6 H), 1.07 (s, 9 H), 1.03 (d,
J = 6.9 Hz, 3 H), 0.93 (d, J = 6.5 Hz, 3 H), 0.45 (s, 3 H) ppm. 13C
NMR (CDCl3): δ = 142.2, 135.9, 134.8, 134.2, 132.1, 129.6, 127.5,
122.9, 115.4, 73.9, 71.4, 71.1, 56.5, 56.2, 45.6, 44.4, 43.3, 40.4, 36.5,
36.4, 36.1, 30.1, 29.2, 28.8, 27.7, 27.1, 25.5, 22.5, 22.3, 20.8, 19.4,
18.8, 14.0, 11.9 ppm. MS: m/z (%) = 656 (M+, 1), 638 (M+ – 18,
1), 600 (M+ – tBu + H, 1), 581 (3), 563 (2), 503 (3), 472 (1), 400
(4), 365 (6), 321 (9), 239 (11), 199 (100), 149 (19), 135 (52), 59
(88). 75a: Rf = 0.19 (isooctane/EtOAc, 4:1). [α]D = +18.3 (c = 0.31,
(1S,3R,4R,5S)-3-(tert-Butyldiphenylsilyloxy)-4-methylbicyclo[3.1.0]-
hexane-1-carbaldehyde (44a): Compound 44a was synthesized from
43a as described for 39a in 93% yield as a colourless oil. Rf = 0.38
(isooctane/EtOAc, 4:1). [α]D = –109.3 (c = 0.16, CHCl3). IR (KBr
film): ν = 3048, 2958, 2858, 1702, 1589, 1472, 1428, 1389, 1362,
˜
CHCl ). IR (KBr film): ν = 3405, 3071, 2958, 2879, 1459, 1429,
˜
3
1
1252, 1182, 1112, 1086 cm–1. H NMR (CDCl3): δ = 8.78 (s, 1 H),
1376, 1217, 1147, 1076, 1053 cm–1. 1H NMR (CDCl3): δ = 7.71–
7.36 (m, 10 H), 5.99 (d, J = 11.2 Hz, 1 H), 5.77 (d, J = 11.2 Hz, 1
H), 4.00 (m, 1 H), 3.71 (td, J = 8.1, 4.2 Hz, 1 H), 2.68 (dd, J =
13.8, 5.1 Hz, 1 H), 2.58 (dd, J = 13.7, 5.9 Hz, 1 H), 2.29 (dd, J =
13.7, 3.7 Hz, 1 H), 2.23 (dd, J = 13.1, 3.9 Hz, 1 H), 2.07–1.82 (m,
5 H), 1.68–1.23 (m, 17 H), 1.22 (s, 6 H), 1.05 (s, 9 H), 1.03 (d, J =
6.7 Hz, 3 H), 0.93 (d, J = 6.5 Hz, 3 H), 0.51 (s, 3 H) ppm. 13C
NMR (CDCl3): δ = 142.3, 135.9, 134.9, 133.0, 129.5, 127.5, 123.4,
115.4, 74.4, 71.3, 71.1, 56.5, 56.2, 45.7, 44.4, 44.0, 40.5, 36.4, 36.1,
34.8, 30.1, 29.4, 28.8, 27.6, 27.0, 25.4, 23.4, 22.2, 20.8, 19.4, 18.8,
13.6, 12.0 ppm. MS: m/z (%) = 656 (M+, 1), 599 (M+ – tBu, 1),
581 (3), 521 (1), 468 (1), 400 (1), 365 (6), 325 (5), 245 (8), 199 (61),
183 (18), 135 (42), 59 (100). A solution of 74a (27 mg, 0.041 mmol)
in THF (0.5 mL) was treated with TBAF (3.5 mL, 1 m in THF).
After stirring at room temperature in the dark for 72 h, the solution
was subjected to flash chromatography (isooctane/EtOAc, 1:1). The
residue was purified by HPLC (isooctane/EtOAc, 3:2) affording 6a
7.65–7.35 (m, 10 H), 3.39 (dd, J = 15.5, 7.8 Hz, 1 H), 2.26–2.22
(m, 2 H), 1.88 (m, 2 H), 1.08 (m, 1 H), 1.05 (s, 9 H), 0.93 (d, J =
7.7 Hz, 3 H), 0.75 (t, J = 5.5 Hz, 1 H) ppm. 13C NMR (CDCl3): δ
= 199.9, 135.9, 133.8, 129.7, 127.6, 77.3, 41.5, 37.4, 33.7, 30.8, 26.9,
19.1, 15.7, 15.2 ppm. MS: m/z (%) = 321 (M+ – 57, 48), 319 (8),
309 (11), 259 (24), 199 (100), 181 (40), 153 (20).
Ethyl Homologue 44b: Rf = 0.34 (isooctane/EtOAc, 9:1). [α]D
=
–110.9 (c = 0.53, CHCl ). IR (KBr film): ν = 3070, 2959, 2857,
˜
3
2710, 1704, 1462, 1428, 1257 cm–1. H NMR (CDCl3): δ = 8.80 (s,
1
1 H), 7.64–7.35 (m, 10 H), 3.46 (q, J = 7.3 Hz, 1 H), 2.21 (t, J =
11.3 Hz, 1 H), 2.09 (br. s, 1 H), 1.96 (d, J = 5.1 Hz, 1 H), 1.87 (m,
1 H), 1.62 (m, 2 H), 1.12 (s, 1 H), 1.04 (s, 9 H), 0.90 (t, J = 7.2 Hz,
3 H), 0.74 (t, J = 5.6 Hz, 1 H) ppm. 13C NMR (CDCl3): δ = 199.6,
135.8, 133.8, 129.6, 127.4, 75.9, 48.7, 37.2, 33.6, 28.6, 26.8, 23.9,
19.1, 15.3, 12.6 ppm. MS: m/z (%) = 335 (M+ – 57, 50), 279 (4),
227 (10), 199 (100), 181 (20), 139 (45), 105 (32), 77 (60).
(11 mg, 82%). R = 0.21 (isooctane/EtOAc, 1:1). IR (KBr): ν =
˜
f
(E)-(1R,3aR,7aR)-4-Bromomethylidene-1-[(1S)-5-(1-ethoxyethoxy)-
1,5-dimethylhex-3-ynyl]-7a-methyloctahydroindene (73): Compound
3422, 2946, 1618, 1452, 1376, 1350, 1150, 1056 cm–1. 1H NMR
(CDCl3): δ = 6.26 (d, J = 11.2 Hz, 1 H), 5.87 (d, J = 11.2 Hz, 1
H), 3.51 (td, J = 10.1, 4.7 Hz, 1 H), 3.08 (dd, J = 12.9, 4.0 Hz, 1
H), 2.79 (dd, J = 12.9, 4.0 Hz, 1 H), 2.44 (d, J = 13.1 Hz, 1 H),
2.37 (m, 1 H), 2.04–1.98 (m, 3 H), 1.90 (t, J = 10.7 Hz, 2 H), 1.80–
1.23 (m, 18 H), 1.22 (s, 6 H), 1.14 (d, J = 6.8 Hz, 3 H), 0.94 (d, J
= 6.5 Hz, 3 H), 0.55 (s, 3 H) ppm. MS: m/z (%) = 418 (M+, 9), 400
(6), 385 (4), 357 (5), 317 (2), 289 (6), 245 (8), 203 (4), 189 (6), 149
(27), 135 (41), 84 (58), 59 (100).
73 was obtained from 72 as described for the 20(R) epimer in ref.[8]
.
Rf = 0.65 (isooctane/ethyl acetate, 4:1). [α]2D5 = +20.7 (c = 0.75,
acetone). IR (KBr film): ν = 2978, 2234, 1455, 1381, 1252, 1195,
˜
1122, 1081, 1052, 976 cm–1. 1H NMR (300 MHz, [D6]benzene): δ
= 5.54 (br. s, 1 H), 5.25 (br. q, J = 4.9 Hz, 1 H), 3.50 (dq, J = 7.2,
9.1 Hz, 1 H), 3.38 (dq, J = 7.2, 9.1 Hz, 1 H), 2.40 (m, 1 H), 1.80
(m, 3 H), 0.7–1.5 (m, series of H), 1.47 (s, 3 H), 1.36 (s, 3 H), 1.29
(d, J = 5.4 Hz, 3 H), 1.03 (t, J = 7.0 Hz, 3 H), 0.68 (d, J = 6.4 Hz,
3 H), 0.56 (s, 3 H) ppm.
2α-Methyl-19-nor-1α,25-dihydroxyvitamin D3 (5a): Rf = 0.18 (isooc-
tane/EtOAc, 1:1). [α]D = +26.6 (c = 0.14, CHCl3). IR (KBr film):
2β-Methyl-19-nor-1α,25-dihydroxyvitamin D3 (6a) (General Pro-
cedure): To a stirred solution of 20 (65 mg, 0.151 mmol) in THF
(2.0 mL) was added dropwise tBuLi (197 μL, 1.7 m in pentane,
0.334 mmol) at –78 °C. After stirring at –78 °C for 1 h, the reaction
was warmed to –10 °C and was stirred for 0.5 h. The solution was
cooled down to –78 °C again, and then a solution of 44a (80 mg,
0.212 mmol) in THF (1.5 mL) was added dropwise. The reaction
was stirred at –78 °C for 1 h, and then the reaction was quenched
by addition of satd. NH4Cl. The solution was diluted with Et2O,
washed with saturated NaHCO3 and brine, dried and concentrated.
The residue was purified by flash chromatography (isooctane/
1
ν = 3354, 2958, 1454, 1054 cm–1. H NMR (CDCl ): δ = 6.37 (d,
˜
3
J = 11.3 Hz, 1 H), 5.83 (d, J = 11.3 Hz, 1 H), 3.96 (m, 1 H), 3.61
(td, J = 9.4, 4.6 Hz, 1 H), 3.20 (m, 2 H), 3.02 (dt, J = 12.0, 4.8 Hz,
2 H), 2.80 (dd, J = 13.6, 4.3 Hz, 2 H), 2.60 (dd, J = 12.9, 4.4 Hz,
1 H), 2.23 (d, J = 12.6 Hz, 1 H), 2.14 (t, J = 10.3 Hz, 1 H), 2.06–
1.20 (m, 18 H), 1.22 (s, 6 H), 1.14 (d, J = 6.9 Hz, 3 H), 0.98 (d, J
= 7.4 Hz, 3 H), 0.54 (s, 3 H) ppm. MS: m/z (%) = 418 (M+, 1), 400
(M+ – H2O, 18), 382 (6), 340 (22), 295 (12), 271 (9), 233 (32), 191
(22), 149 (85), 135 (25), 92 (100).
Ethyl Homologue 5b: Rf = 0.18 (isooctane/EtOAc, 3:2). [α]D
=
EtOAc, 94:1) to afford intermediate 27a (53 mg, 48%) as a colour- +28.0 (c = 0.21, CHCl ). IR (KBr film): ν = 3389, 2958, 1454,
˜
3
less oil. The intermediate oil (53 mg, 0.073 mmol) was dissolved in
dioxane/H2O (3:1, 4 mL) containing PTSA (4 mg, 0.023 mmol).
The mixture was stirred in the dark at 55–60 °C for 4 h and then
the solution was diluted with Et2O, washed with saturated
NaHCO3 and brine), dried and concentrated. The residue was puri-
fied by HPLC (isooctane/EtOAc, 4:1), affording 74a (38 mg) and
75a (5 mg) in 88% yield. 74a: Rf = 0.22 (isooctane/EtOAc, 4:1).
1188, 1045 cm–1. 1H NMR (CDCl3): δ = 6.38 (d, J = 11.3 Hz, 1
H), 5.83 (d, J = 11.3 Hz, 1 H), 4.14 (m, 1 H), 3.63 (m, 1 H), 2.87
(dd, J = 13.9, 4.0 Hz, 1 H), 2.80 (dd, J = 12.7, 4.5 Hz, 1 H), 2.61
(dd, J = 12.5, 4.1 Hz, 1 H), 2.20–1.22 (m, 24 H), 1.21 (s, 6 H), 1.00
(t, J = 7.4 Hz, 3 H), 0.91 (d, J = 6.7 Hz, 3 H), 0.53 (s, 3 H) ppm.
13C NMR (CDCl3): δ = 143.3, 131.5, 124.1, 115.4, 71.7, 71.3, 68.0,
56.7, 56.5, 50.9, 45.9, 45.5, 44.6, 40.6, 36.5, 36.2, 35.7, 30.2, 29.5,
29.1, 27.8, 25.6, 23.6, 22.4, 20.9, 18.9, 12.2, 11.8 ppm. MS: m/z (%)
[α]D = –15.7 (c = 0.76, CHCl ). IR (KBr film): ν = 3394, 2942,
˜
3
4424
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 4414–4427

Synthesis of Dihydroxyvitamin D3 Analogues
= 432 (M+, 1), 414 (6), 371 (2), 303 (5), 267 (6), 245 (8), 208 (6), (M+, 2), 414 (28), 381 (4), 301 (4), 267 (8), 245 (10), 199 (30), 149
FULL PAPER
173 (10), 149 (30), 133 (40), 81 (65), 55 (100).
(30), 105 (50), 81 (70), 59 (100).
Ethyl Homologue 6b: Rf = 0.22 (isooctane/EtOAc, 3:2). [α]D
=
2α-Methyl-19-nor-23-yne-1α,25-dihydroxyvitamin D3 (9a): Rf = 0.18
+42.1 (c = 0.32, CHCl ). IR (KBr film): ν = 3378, 2959, 1454, (isooctane/EtOAc, 1:1). [α]D = +42.7 (c = 0.11, CHCl3). IR (KBr
˜
3
1378 cm–1. 1H NMR (CDCl3): δ = 6.26 (d, J = 11.3 Hz, 1 H), 5.87
(d, J = 11.3 Hz, 1 H), 4.09 (m, 1 H), 3.54 (m, 1 H), 3.10 (dd, J =
12.7, 4.3 Hz, 1 H), 2.80 (dd, J = 12.8, 4.5 Hz, 1 H), 2.38 (m, 2 H),
2.05–1.25 (m, 25 H), 1.22 (s, 6 H), 1.00 (t, J = 7.4 Hz, 3 H), 0.94
(d, J = 6.5 Hz, 3 H), 0.54 (s, 3 H) ppm. 13C NMR (CDCl3): δ =
143.1, 131.4, 123.5, 115.4, 71.2, 67.7, 56.6, 56.4, 51.5, 45.9, 44.5,
44.2, 40.6, 37.9, 36.5, 36.2, 31.0, 29.5, 29.3, 29.1, 27.8, 23.6, 22.4,
20.9, 20.3, 18.9, 12.2, 11.7 ppm. MS: m/z (%) = 432 (M+, 1), 414
(5), 303 (8), 267 (8), 245 (15), 208 (5), 173 (5), 135 (30), 105 (35),
81 (70), 59 (100).
film): ν = 3368, 2929, 1614, 1454, 1377, 1261, 1166, 1024 cm–1. H
1
˜
NMR (CDCl3): δ = 6.36 (d, J = 11.1 Hz, 1 H), 5.82 (d, J = 11.1 Hz,
1 H), 3.96 (br. s, 1 H), 3.61 (m, 1 H), 2.80 (d, J = 14.1 Hz, 2 H),
2.60 (d, J = 12.8 Hz, 1 H), 2.28–1.52 (m, 17 H), 1.51 (s, 6 H), 1.38–
1.25 (m, 3 H), 1.13 (d, J = 6.7 Hz, 3 H), 1.06 (d, J = 6.3 Hz, 3 H),
0.54 (s, 3 H) ppm. MS: m/z (%) = 414 (M+, 14), 396 (M+ – H2O,
8), 381 (7), 353 (4), 317 (12), 267 (3), 241 (9), 199 (13), 185 (16),
161 (21), 105 (37), 84 (52), 43 (100).
Ethyl Homologue 9b: Rf = 0.18 (isooctane/EtOAc, 3:2). [α]D
=
+23.1 (c = 0.26, CHCl ). IR (KBr film): ν = 3367, 2958, 2238,
˜
3
14-epi-2α-Methyl-19-nor-1α,25-dihydroxyvitamin D3 (7a): Rf = 0.20 1455, 1378, 1167 cm–1. 1H NMR (CDCl3): δ = 6.38 (d, J = 11.2 Hz,
(isooctane/EtOAc, 1:1). [α]D = +61.1 (c = 0.34, CHCl3). IR (KBr 1 H), 5.83 (d, J = 11.1 Hz, 1 H), 4.14 (m, 1 H), 3.64 (td, J = 9.8,
film): ν = 3384, 2960, 1455, 1379, 1147, 1043 cm–1. 1H NMR 4.8 Hz, 1 H), 2.97 (m, 1 H), 2.87 (dd, J = 13.9, 4.3 Hz, 1 H), 2.80
˜
(CDCl3): δ = 6.31 (d, J = 11.2 Hz, 1 H), 6.01 (d, J = 11.2 Hz, 1
H), 3.97 (dd, J = 5.6, 2.4 Hz, 1 H), 3.59 (td, J = 9.5, 4.6 Hz, 1 H),
2.84 (dd, J = 13.9, 4.6 Hz, 1 H), 2.59 (dd, J = 12.8, 4.4 Hz, 1 H),
2.47(dt, J = 14.6, 5.1 Hz, 1 H), 2.21 (d, J = 13.7 Hz, 1 H), 2.15–
(dd, J = 12.8, 4.5 Hz, 1 H), 2.30–1.51 (m, 17 H), 1.50 (s, 6 H),
1.46–1.25 (m, 5 H), 1.06 (d, J = 6.6 Hz, 3 H), 0.98 (t, J = 7.4 Hz,
3 H), 0.54 (s, 3 H) ppm. MS: m/z (%) = 428 (M+, 2), 410 (10), 370
(8), 331 (5), 313 (8), 295 (4), 241 (3), 199 (8), 161 (20), 149 (40), 91
2.08 (m, 2 H), 1.88–1.21 (m, 22 H), 1.22 (s, 6 H), 1.14 (d, J = (40), 43 (100).
6.9 Hz, 3 H), 0.92 (s, 3 H), 0.88 (d, J = 6.7 Hz, 3 H) ppm. 13C
2β-Methyl-19-nor-23-yne-1α,25-dihydroxyvitamin D3 (10a): Rf
=
NMR (CDCl3): δ = 143.4, 131.6, 124.2, 118.5, 72.4, 71.6, 71.1,
57.8, 54.6, 45.3, 44.9, 44.4, 43.9, 37.9, 35.5, 34.5, 34.0, 29.9, 29.4,
29.2, 26.8, 24.8, 22.3, 21.9, 21.7, 19.8, 13.6 ppm. MS: m/z (%) =
418 (M+, 1), 400 (M+ – H2O, 22), 387 (7), 357 (4), 340 (5), 289
(14), 271 (21), 245 (19), 191 (17), 147 (29), 133 (38), 81 (59), 59
(100).
0.18 (isooctane/EtOAc, 1:1). [α]D = +28.2 (c = 0.37, CHCl3). IR
(KBr film): ν = 3380, 2930, 1455, 1377, 1346, 1166, 1041 cm–1. H
1
˜
NMR (CDCl3): δ = 6.44 (d, J = 11.3 Hz, 1 H), 6.04 (d, J = 11.3 Hz,
1 H), 4.07 (dd, J = 4.1, 3.0 Hz, 1 H), 3.68 (td, J = 10.1, 4.8 Hz, 1
H), 3.24 (dd, J = 12.9, 3.8 Hz, 1 H), 2.97 (dd, J = 12.9, 4.4 Hz, 1
H), 2.60 (d, J = 3.6 Hz, 1 H), 2.51 (dd, J = 13.8, 3.4 Hz, 1 H), 2.44
(dd, J = 16.6, 3.4 Hz, 1 H), 2.26–2.16 (m, 5 H), 2.07 (m, 2 H), 1.68
Ethyl Homologue 7b: Rf = 0.20 (isooctane/EtOAc, 3:2). [α]D
=
+34.4 (c = 0.48, CHCl ). IR (KBr film): ν = 3372, 2958, 1464, (s, 6 H), 1.88–1.66 (m, 8 H), 1.52–1.41 (m, 3 H), 1.31 (d, J = 6.8 Hz,
˜
3
1378, 1190, 1044 cm–1. 1H NMR (CDCl3): δ = 6.32 (d, J = 11.3 Hz,
3 H), 1.24 (d, J = 6.5 Hz, 3 H), 0.72 (s, 3 H) ppm. MS: m/z (%) =
1 H), 6.01 (d, J = 11.3 Hz, 1 H), 4.15 (br. s, 1 H), 3.64 (m, 1 H),
414 (M+, 18), 396 (M+ – H2O, 8), 376 (7), 356 (4), 353 (1), 317
2.92 (m, 1 H), 2.59 (m, 1 H), 2.47 (m, 1 H), 2.18–2.05 (m, 3 H), (15), 267 (4), 241 (9), 199 (21), 173 (23), 161 (25), 105 (42), 91 (53),
1.86–1.24 (m, 23 H), 1.22 (s, 6 H), 1.00 (t, J = 7.4 Hz, 3 H), 0.89
(d, J = 6.8 Hz, 3 H), 0.86 (s, 3 H) ppm. 13C NMR (CDCl3): δ =
143.5, 131.6, 124.2, 118.7, 71.6, 71.2, 68.0, 58.0, 54.7, 51.0, 45.6,
45.4, 44.5, 38.0, 35.7, 34.7, 34.1, 30.0, 29.5, 29.3, 27.0, 24.9, 22.3,
22.0, 21.8, 20.0, 19.8, 11.8 ppm. MS: m/z (%) = 432 (M+, 2), 414
(15), 386 (4), 265 (5), 245 (10), 199 (20), 161 (15), 135 (30), 81 (50),
55 (100).
43 (100).
Ethyl Homologue 10b: Rf = 0.19 (isooctane/EtOAc, 3:2). [α]D
+24.9 (c = 0.54, CHCl ). IR (KBr film): ν = 3378, 2930, 1454,
=
˜
3
1166, 1039 cm–1. 1H NMR (CDCl3): δ = 6.26 (d, J = 11.2 Hz, 1
H), 5.87 (d, J = 11.2 Hz, 1 H), 4.10 (m, 1 H), 3.55 (m, 1 H), 3.10
(dd, J = 12.9, 4.1 Hz, 1 H), 2.80 (dd, J = 12.5, 4.2 Hz, 1 H), 2.40–
1.53 (m, 18 H), 1.52 (s, 6 H), 1.50–1.24 (m, 5 H), 1.07 (d, J =
6.5 Hz, 3 H), 1.00 (t, J = 7.4 Hz, 3 H), 0.56 (s, 3 H) ppm. 13C
NMR (CDCl3): δ = 142.6, 131.6, 123.4, 115.5, 86.1, 81.3, 71.2,
14-epi-2β-Methyl-19-nor-1α,25-dihydroxyvitamin D3 (8a): Rf = 0.18
(isooctane/EtOAc, 1:1). [α]D = +38.7 (c = 0.40, CHCl3). IR (KBr
film): ν = 3382, 2958, 1455, 1377, 1212, 1045 cm–1. 1H NMR 67.6, 65.4, 56.3, 55.7, 51.0, 45.7, 44.1, 40.4, 37.9, 36.0, 31.9, 30.1,
˜
(CDCl3): δ = 6.19 (d, J = 11.2 Hz, 1 H), 6.05 (d, J = 11.2 Hz, 1
29.0, 27.7, 25.7, 23.5, 22.3, 20.2, 19.2, 12.2, 11.6 ppm. MS: m/z (%)
H), 3.90 (dd, J = 6.2, 3.0 Hz, 1 H), 3.52 (td, J = 10.1, 4.6 Hz, 1 = 428 (M+, 1), 410 (2), 370 (4), 331 (3), 267 (3), 241 (4), 199 (8),
H), 3.08 (dd, J = 12.9, 4.4 Hz, 1 H), 2.41–2.48 (m, 2 H), 2.33 (dd,
J = 13.2, 4.2 Hz, 1 H), 2.15–2.03 (m, 2 H), 1.94–1.80 (m, 2 H),
1.72–1.23 (m, 19 H), 1.22 (s, 6 H), 1.13 (d, J = 6.9 Hz, 3 H), 0.92
(s, 3 H), 0.88 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR (CDCl3): δ =
143.2, 131.6, 123.7, 118.6, 71.9, 71.7, 71.1, 57.9, 54.6, 45.4, 44.4,
44.1, 43.9, 37.9, 37.4, 34.5, 34.0, 29.8, 29.4, 29.2, 26.8, 24.8, 22.4,
173 (8), 149 (20), 105 (30), 91 (45), 43 (100).
14-epi-2α-Methyl-19-nor-23-yne-1α,25-dihydroxyvitamin D3 (11a):
Rf = 0.19 (isooctane/EtOAc, 1:1). [α]D = +55.1 (c = 0.11, CHCl3).
IR (KBr film): ν = 3362, 2959, 2929, 1450, 1376, 1329, 1243, 1175,
˜
1127 cm–1. 1H NMR (CDCl3): δ = 6.30 (d, J = 11.3 Hz, 1 H), 6.02
(d, J = 11.3 Hz, 1 H), 3.98 (m, 1 H), 3.60 (td, J = 9.4, 4.6 Hz, 1
H), 2.83 (dd, J = 13.9, 4.6 Hz, 1 H), 2.59 (dd, J = 12.8, 4.3 Hz, 1
H), 2.41 (dt, J = 12.5, 3.8 Hz, 1 H), 2.27–1.99 (m, 5 H), 1.87 (m,
1 H), 1.76–1.52 (m, 11 H), 1.49 (s, 6 H), 1.33–1.25 (m, 3 H), 1.13
(d, J = 6.7 Hz, 3 H), 1.02 (d, J = 6.5 Hz, 3 H), 0.95 (s, 3 H) ppm.
21.8, 21.6, 19.8, 14.0 ppm. MS: m/z (%) = 418 (M+, 1), 401 (M+
–
H2O + H, 1), 387 (2), 357 (4), 370 (1), 293 (1), 292 (5), 260 (2), 199
(35), 183 (11), 153 (25), 111(28), 93 (100).
Ethyl Homologue 8b: Rf = 0.21 (isooctane/EtOAc, 3:2). [α]D
=
+17.0 (c = 0.15, CHCl ). IR (KBr film): ν = 3369, 2958, 1455, 13C NMR (CDCl3): δ = 142.9, 131.9, 124.1, 118.5, 86.1, 81.7, 72.5,
˜
3
1378, 1190, 1044 cm–1. 1H NMR (CDCl3): δ = 6.19 (d, J = 11.2 Hz,
71.6, 65.4, 57.7, 52.6, 44.9, 44.9, 43.9, 37.7, 35.5, 33.9, 31.7, 31.7,
1 H), 6.06 (d, J = 11.3 Hz, 1 H), 4.09 (m, 1 H), 3.50 (m, 1 H), 3.11
29.4, 27.9, 25.2, 24.5, 22.5, 21.8, 20.0, 13.6 ppm. MS: m/z (%) =
(dd, J = 12.7, 4.2 Hz, 1 H), 2.97 (m, 1 H), 2.47 (m, 1 H), 2.38 (m, 653 (M+ + H, 1), 634 (M+ – H2O, 5), 597 (M+ – 57 + H, 2), 459
1 H), 2.18–1.25 (m, 25 H), 1.22 (s, 6 H), 0.99 (t, J = 7.4 Hz, 3 H), (1), 385 (4), 361 (3), 335 (3), 267 (4), 199 (90), 183 (38), 135 (75),
0.90 (d, J = 6.7 Hz, 3 H), 0.88 (s, 3 H) ppm. MS: m/z (%) = 432
43 (100).
Eur. J. Org. Chem. 2005, 4414–4427
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4425

Y.-R. Zhao, B. Guang, R. Bouillon, A. Verstuyf, P. De Clercq, M. Vandewalle
FULL PAPER
Ethyl Homologue 11b: Rf = 0.24 (isooctane/EtOAc, 3:2). [α]D
=
(m, 3 H), 1.19 (d, J = 7.2 Hz, 3 H), 1.01 (d, J = 6.7 Hz, 3 H), 0.96
+22.3 (c = 0.38, CHCl ). IR (KBr film): ν = 3370, 2958, 2874, (s, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 142.2, 129.8, 125.0,
˜
3
2233, 1731, 1614, 1462, 1378, 1337, 1240, 1167 cm–1. 1H NMR 118.7, 86.0, 81.8, 73.3, 73.1, 65.4, 57.4, 52.6, 44.9, 44.9, 38.9, 37.6,
(CDCl3): δ = 6.31 (d, J = 11.3 Hz, 1 H), 6.03 (d, J = 11.3 Hz, 1
H), 4.15 (m, 1 H), 3.64 (m, 1 H), 2.89 (m, 1 H), 2.60 (dd, J = 12.8,
36.5, 33.9, 31.7, 31.7, 29.3, 27.8, 25.1, 24.4, 22.4, 21.8, 20.1, 14.5
ppm. MS: m/z (%) = 414 (M+, 1), 396, (M+ – H2O, 9), 381 (5), 363
4.3 Hz, 1 H), 2.45–1.51 (m, 18 H), 1.50 (s, 6 H), 1.40–1.25 (m, 5 (7), 356 (4), 299 (7), 267 (8), 241 (9), 213 (12), 185 (14), 147 (21),
H), 1.02 (t, J = 7.4 Hz, 3 H), 0.91 (d, J = 6.9 Hz, 3 H), 0.88 (s, 3 107 (21), 107 (26), 91 (45), 43 (100).
H) ppm. 13C NMR (CDCl3): δ = 143.1, 132.1, 124.2, 118.7, 86.2,
1,14-bisepi-2β-Methyl-19-nor-23-yne-1α,25-dihydroxyvitamin-D3 (1-
epi-10a): Rf = 0.21 (isooctane/EtOAc, 4:1). [α]D +20.42 (c = 0.31,
81.8, 71.7, 68.0, 57.9, 53.3, 52.8, 51.0, 45.6, 45.1, 37.9, 35.8, 34.2,
31.9, 30.2, 29.5, 28.2, 25.6, 25.3, 24.7, 22.7, 21.9, 20.2, 11.9 ppm.
CHCl ). IR (KBr film): ν = 3353, 2930, 1611, 1455, 1376, 1169,
˜
MS: m/z (%) = 428 (M+, 2), 410 (M+ – 18, 8), 370 (5), 313 (5), 277
3
1070, 1028, 988, 948, 882, 729 cm–1. 1H NMR (CDCl3): δ = 6.32
(d, J = 11.3 Hz, 1 H), 6.08 (d, J = 11.3 Hz, 1 H), 3.96 (br. s, 1 H),
3.90 (br. s, 1 H), 3.06 (dd, J = 14.1, 3.2 Hz, 1 H), 2.49–2.38 (m, 3
H), 2.25–1.50(m, 16 H), 1.49 (s, 6 H), 1.32–1.24 (m, 3 H), 1.18 (d,
J = 7.2 Hz, 3 H), 1.02 (d, J = 6.6 Hz, 3 H), 0.95 (s, 3 H) ppm. MS:
m/z (%) = 396 (M+ – H2O, 24), 378 (8), 335 (2), 299 (13), 267 (12),
241 (13), 199 (18), 185 (20), 145 (21), 105 (51), 91 (74), 43 (100).
(6), 199 (30), 149 (35), 142 (30), 91 (50), 43 (100).
14-epi-2β-Methyl-19-nor-23-yne-1α,25-dihydroxyvitamin D3 (12a):
Rf = 0.18 (isooctane/EtOAc, 1:1). [α]D = +43.8 (c = 0.21, CHCl3).
IR (KBr film): ν = 3358, 2929, 1455, 1377, 1338, 1239, 1166 cm–1.
˜
1H NMR (CDCl3): δ = 6.19 (d, J = 11.4 Hz, 1 H), 6.06 (d, J =
11.4 Hz, 1 H), 3.89 (dd, J = 6.3, 3.2 Hz, 1 H), 3.54 (td, J = 10.1,
4.6 Hz, 1 H), 3.07 (dd, J = 12.9, 4.2 Hz, 1 H), 3.01 (m, 1 H), 2.46–
2.31 (m, 3 H), 2.23 (dd, J = 16.7, 3.5 Hz, 2 H), 2.15–2.01 (m, 3 H),
1.94–1.86 (m, 2 H), 1.78–1.50 (m, 8 H), 1.49 (s, 6 H), 1.35–1.25 (m,
3 H), 1.14 (d, J = 6.7 Hz, 3 H), 1.03 (d, J = 6.6 Hz, 3 H), 0.88 (s,
3 H) ppm. MS: m/z (%) = 652 (M+, 1), 634 (M+ – H2O + 1, 6),
594 (M+ – 57 + H, 2), 537 (3), 459 (2), 396 (1), 378 (4), 321 (5),
261 (6), 199 (100), 183 (27), 135 (72).
Acknowledgments
P. De C. and M. V. thank the F.W.O. and the “Ministerie voor Wet-
enschapsbeleid” for financial support to the laboratory. Y.-R. Z.
and B. G. thank the Ghent University for postdoctoral fellowships.
Ethyl Homologue 12b: Rf = 0.22 (isooctane/EtOAc, 3:2). [α]D
=
+8.9 (c = 0.69, CHCl ). IR (KBr film): ν = 3381, 2958, 2233, 1454,
˜
3
1383, 1166 cm–1. 1H NMR (CDCl3): δ = 6.19 (d, J = 11.3 Hz, 1
H), 6.07 (d, J = 11.3 Hz, 1 H), 4.10 (m, 1 H), 3.57 (m, 1 H), 3.10
(dd, J = 12.8, 4.3 Hz, 1 H), 2.97 (m, 1 H), 2.38 (m, 2 H), 2.22 (m,
2 H), 2.15–2.00 (m, 3 H), 1.94–1.86 (m, 2 H), 1.84–1.51 (m, 9 H),
1.50 (s, 6 H), 1.45–1.24 (m, 5 H), 0.98 (t, J = 7.5 Hz, 3 H), 0.90 (d,
J = 6.7 Hz, 3 H), 0.88 (s, 3 H) ppm. 13C NMR (CDCl3): δ = 142.8,
132.1, 123.5, 118.3, 86.3, 81.6, 71.0, 67.7, 57.8, 52.0, 51.0, 45.1,
44.1, 37.9, 37.8, 34.0, 31.9, 31.7, 30.1, 28.8, 28.2, 25.5, 24.8, 22.6,
22.0, 20.2, 19.9, 11.6 ppm. MS: m/z (%) = 428 (M+, 2), 410 (6),
313 (4), 277 (4), 241 (4), 199 (15), 173 (10), 149 (30), 105 (25), 91
(40), 43 (100).
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14,20-Bis-epi-2α-methyl-19-nor-23-yne-1α,25-dihydroxyvitamin D3
(13): Rf = 0.17 (isooctane/EtOAc, 1:1). [α]D = –3 (c = 0.1, CHCl3).
IR (KBr film): ν = 3365, 2929, 2228, 1441, 1244, 1020 cm–1. 1H
˜
NMR (300 MHz, CDCl3): δ = 6.30 (d, J = 11 Hz, 1 H), 6.01 (d, J
= 11 Hz, 1 H), 3.96 (m, 1 H), 3.60 (td, J = 9.4, 4.6 Hz, 1 H), 2.83
(dd, J = 14, 4.8 Hz, 1 H), 2.59 (dd, J = 12.8, 4.1 Hz, 1 H), 2.41
(dt, J = 14.8, 4.8 Hz, 1 H), 2.23–1.99 (m, 5 H), 1.87 (m, 1 H), 1.76–
1.52 (m, 11 H), 1.49 (s, 6 H), 1.38–1.24 (m, 3 H), 1.14 (d, J =
6.8 Hz, 1 H), 0.91 (d, J = 6.6 Hz, 3 H), 0.88 (s, 3 H) ppm.
14,20-Bis-epi-2α-ethyl-19-nor-23-yne-1α,25-dihydroxyvitamin
D3
(14): Rf = 0.30 (isooctane/EtOAc, 1:1). [α]D = –4 (c = 0.05, CHCl3).
IR (KBr film): ν = 3335, 2948, 2286, 1452, 1152, 1026 cm–1. 1H
˜
NMR (300 MHz, CDCl3): δ = 6.32 (d, J = 11.6 Hz, 1 H), 6.02 (d,
J = 11.6 Hz, 1 H), 4.15 (m, 1 H), 3.63 (td, J = 9.5, 4.2 Hz, 1 H),
2.89 (dd, J = 14.8, 5.2 Hz, 1 H), 2.59 (m, 1 H), 2.48 (dd, J = 14.3,
4.9 Hz, 1 H), 2.18–1.30 (series of H), 1.49 (s, 6 H), 1.38–1.2 (m, 5
H), 1.01 (t, J = 7.4 Hz, 3 H), 0.94 (d, J = 6.7 Hz, 3 H), 0.88 (s, 3
H) ppm.
3,14-bisepi-2α-Methyl-19-nor-23-yne-1α,25-dihydroxyvitamin-D3 (1-
epi-9a): Rf = 0.21 (isooctane/EtOAc, 3:2). [α]D +53.11 (c = 0.31,
CHCl ). IR (KBr film): ν = 3345, 2928, 1455, 1362, 1232, 1167,
˜
3
1103, 1067, 1038, 944, 874, 750 cm–1. H NMR (CDCl3): δ = 6.31
1
[10] B. Lythgoe, T. A. Moran, M. E. N. Nambudiry, J. Tideswell,
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(d, J = 11.3 Hz, 1 H), 6.08 (d, J = 11.3 Hz, 1 H), 3.95 (d, J =
2.1 Hz, 1 H), 3.90 (d, J = 2.9 Hz, 1 H), 3.05 (d, J = 14.1 Hz, 1 H),
2.49–2.40 (m, 4 H), 2.26–1.50 (m, 15 H), 1.49 (s, 6 H), 1.31–1.23
4426
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 4414–4427

Synthesis of Dihydroxyvitamin D3 Analogues
FULL PAPER
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[23] The low yields (circa 50%) observed here are due to the small
scale; similar couplings carried out on gram scale (see ref. 8)
give circa 70% yields.
[24] For assignment of the chemical shift values for H-6 and H-7
in 19-nor analogues, see ref.[8]
.
Received: April 25, 2005
Published Online: August 26, 2005
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kin Trans. 1 1997, 2608–2612; b) G. A. Leyes, W. H. Okamura,
Eur. J. Org. Chem. 2005, 4414–4427
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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