Formal desymmetrization of the diastereotopic chains in gemini calcitriol derivatives with two different side chains at C-20

Article abstract of DOI:10.1002/ejoc.200300718

Derivatives of calcitriol with two equal side chains emanating at C-20, also known as gemini, have emerged as interesting compounds, either as instruments for assessing the steric requirements of the vitamin D receptor or as drug candidates. We now describe the syntheses of gemini analogs where the two side chains differ from each other. While retaining the 2-hydroxy-2- methylpentyl moiety, common to both calcitriol and gemini, as one chain, we replaced the other with a 1,1,1-trifluoro-2-hydroxy-2-(trifluoromethyl)-3- pentynyl group. The features comprising this chain modification are commonly regarded to improve toxicity profiles and drug performance. The resulting epimeric pairs with a new stereogenic center at C-20 were resolved and the absolute configurations assigned. The side-chain desymmetrization protocols described herein serve as a basis for additional synthesis activity in this area. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200300718

FULL PAPER
Formal Desymmetrization of the Diastereotopic Chains in Gemini Calcitriol
Derivatives with Two Different Side Chains at C-20[‡]
Hubert Maehr*[a] and Milan R. Uskokovic[a]
Keywords: Alkylation / Hydroboration / Diastereoselectivity / Ene reaction
Derivatives of calcitriol with two equal side chains emana-
ting at C-20, also known as gemini, have emerged as
interesting compounds, either as instruments for assessing
the steric requirements of the vitamin D receptor or as drug
pentynyl group. The features comprising this chain modifica-
tion are commonly regarded to improve toxicity profiles and
drug performance. The resulting epimeric pairs with a new
stereogenic center at C-20 were resolved and the absolute
candidates. We now describe the syntheses of gemini ana- configurations assigned. The side-chain desymmetrization
logs where the two side chains differ from each other. While protocols described herein serve as a basis for additional syn-
retaining the 2-hydroxy-2-methylpentyl moiety, common to
both calcitriol and gemini, as one chain, we replaced the
other with a 1,1,1-trifluoro-2-hydroxy-2-(trifluoromethyl)-3-
thesis activity in this area.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
with its C-20 epimer 2, and demonstrated large differences
in their antiproliferative activities in several cell types in
favor of 2, do not dispute this hypothesis, since very similar
ligand-binding domain conformations have been demon-
strated for both agonists.[8] In view of the observation that
either of the C-20 epimers is being accommodated in the
ligand-binding domain, it becomes of interest to replace the
C-20 methyl group of calcitriol and 19-nor-calcitriol with a
second side chain. The resulting derivatives 3 and 4, now
featuring two identical side chains and commonly referred
to as gemini and 19-nor-gemini, respectively, have very re-
cently been studied by Moras.[9] In spite of the drastic in-
crease of the molecular volume caused by the second chain,
he has shown that this chain does not push for additional
space; one of the chains assumes the ‘‘natural’’ position in
the ‘‘designated’’ pocket for the calcitriol side chain, while
the other one is accommodated by an ‘‘induced fit’’.
Clearly, gemini, as a new type of agonist, would not have
been suggested as a chemical structure based on molecular
modeling but was conceived as a tool to survey the ligand-
binding domain by first producing the substance and to in-
vestigate the binding ability afterwards. Precisely the same
concept governs the present account. We are now interested
in the synthesis and subsequent evaluation of gemini anal-
ogs containing two different side chains. The stereocenter at
C-20, common to the natural hormone 1 and its epi-analog,
2, has been restored in these molecules thus providing pairs
of epimers that are uniquely qualified for the exploration of
the stereochemical requirements at the ligand-binding do-
main.
The transcription-factor activity of calcitriol is mediated
by the vitamin D receptor (VDR), heterodimerization with
the retinoid X receptor (RXR), coactivator proteins and
specific DNA binding sites.[1Ϫ3] It has been recognized that
the change in calcitriol (1) to the (S)-configuration at C-
20,[4] as in 2, can substantially and positively influence the
gene-transcription activity. This change was attributed to
the increased affinity of 2 for the VDR. Agonist-induced
conformational changes in the VDR were postulated to be
the basis of the molecular switch in nuclear calcitriol
signaling.[5Ϫ7] More recently, however, it was shown that
the interaction between the 20-epi agonist 2 and the VDR
does not significantly alter the conformation of the ligand-
binding domain from the one that accommodates the natu-
ral ligand 1. Accordingly, the ligand conformation is as-
sumed to adapt to the binding pockets of the relatively in-
variant binding domain and structural variations of the li-
gands are subject to the constraints dictated by the pock-
ets.[8]
From the vantage point of the chemist, this theory is very
appealing as it would permit the modeling, synthesis and
evaluation of compounds that must fulfil chemical criteria
in accordance with a more or less rigid ligand-binding do-
main conformation. Indeed, the studies that compared 1
[‡]
Calcitriol Derivatives with Two Different Side Chains at C-20,
Part I.
[a]
Roche Bioscience,
Palo Alto, CA 94303, USA
E-mail: hubert.maehr@roche.com
In the calcitriol series of compounds it was demonstrated
that a modification of the side chain featuring a geminal
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2004, 1703Ϫ1713
DOI: 10.1002/ejoc.200300718
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trifluoromethyl arrangement at C-25 and a triple bond be-
The therapeutic potential of the dual side chain modifi-
tween C-23 and C-24 enhances the anti-proliferative activity cation was shown to compare favorably with calcitriol (1),
of the substrate.[10,11] Thus, maintaining the constitution of whose inhibition of proliferation and induction of differen-
the calcitriol side chain for one, and providing the other tiation of various malignant cells is well established. In that
with the above-mentioned modifications, was our first study, 3 was a much more potent clonal growth inhibitor
choice for synthesis. Two scenarios could be envisioned in of a number of cancer cells.[2] That the CD-ring assembly
subsequent docking experiments with the VDR. A given constitutes an essential element for agonist activity was
stereoisomer may place the ‘‘natural’’ chain in the desig- demonstrated by the synthesis and evaluation of 5, which is
nated pocket but, due to increased size and rigidity, the devoid of this spacer and lacks biological activity even at
VDR may have difficulty in efficiently accommodating the the highest concentrations.[1] The two side chains in 5 obvi-
other. Alternatively, then, the modified and more rigid ously did not compensate for the required anchoring points
chain may occupy the pocket designated for the ‘‘natural’’ along the axis spanning the 1,3,25-trihydroxy configuration
chain so that the ‘‘natural’’ chain can be accommodated of the conventional agonists.[8]
by the ‘‘induced fit’’. Preliminary studies already suggest
In the present account we describe compounds featuring
considerable differences between the C-20 epimers in their the basic architecture of 3 and 4 described previously[13Ϫ15]
regulatory activity of cellular proliferation and differen- but limit the change to one of the side-chain constructs.
tiation, suggesting discrimination in agonist acceptance by Subsequent investigations will guide us in the determination
the VDR.[12]
of the optimum configuration required not only for accom-
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Formal Desymmetrization of the Diastereotopic Chains in Gemini Calcitriol Derivatives
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modation in the VDR but also for the maximum expression was indicated. We therefore planned to select a CD-ring
of biological activity. Preliminary studies of compounds 6 assembly containing one completed side chain and a stra-
and 7 revealed these activities to include inhibition of ren- tegically placed section with a diastereotopic face that could
nin biosynthesis[16] and cancer cell growth.[17]
be subject to hydrogen transfer from an achiral reducing
agent to produce both suitably functionalized epimers in
one step. In the course of further drug development, hydro-
gen transfer from a chiral reducing agent could later be ex-
ploited for a stereoselective production of the drug sub-
Results and Discussion
The stereo-defined construction of the two different side stance. Alkenol 12 (Scheme 1) emerged as an ideal desym-
chains at C-20, tantamount to desymmetrization of the metrization platform as it contains the preformed side chain
gemini side-chains, required a path that would not only lead of vitamin D3 and an alkene moiety disposed to function
to both epimers but also, hopefully, to the stereospecific as the diastereotopic hydrogen acceptor. More specifically,
synthesis of a particular epimer once a preferred configura- conventional hydroboration of 12 would lead to an epimeric
tion at C-20 had been established and process development pair of diols 14 and 15, suitable for further elaboration of
Scheme 1
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the second side chain. Alternatively, 12 could be subjected to the acetylene 19a as shown in Scheme 1, then treated
to an ene reaction with formaldehyde to lead to an alkene- with 1-(trimethylsilyl)imidazole to afford the disilyl ether
diol 13 wherein hydrogen transfer from the achiral reducing 19b. Addition of hexafluoroacetone furnished the side chain
agent to the newly formed diastereotopic face would pro- construct as depicted in 20a and in the target compounds
vide the epimeric pair of diols 16 and 17 that are also suit- 6a and 6b. The two silyl ether protective groups in 20a were
able for further side-chain elaboration.
cleaved simultaneously with aqueous fluorosilicic acid[22,23]
In pursuit of this plan, the key intermediate 12 was con- in acetonitrile to give the corresponding triol 20b. Sub-
structed, as shown in Scheme 1, by an ene reaction with sequent oxidation with pyridinium dichromate furnished
formaldehyde using the alkene 8 [6,13Ϫ15,18] as substrate. The ketone 21a. This compound was obtained in crystalline
resulting alcohol 9a was O-tosylated and the tosyloxy group form suitable for crystallographic analysis whose result is
in 9b displaced with dimethyl sodiomalonate leading to the illustrated in Figure 1. Although the absolute configuration
diester 10. A demethoxycarbonylation[19] led to the mono- was not determined in this study, the threo configuration of
ester 11 and subsequent treatment with methylmagnesium the bond connecting the indenone ring with the side chain
bromide gave the required alkenol 12. Hydroboration of assembly was immediately obvious and thus established the
this material provided 14 and 15 as a mixture in a ratio of (6S)-configuration [corresponding to (20S) in the steroid
2:3 that was easily separated by preparative HPLC.
nomenclature].
Conducting a second ene reaction with formaldehyde
Similarly, 26a, the epimer of 21a, was obtained starting
converted 12 into 13 as a mixture of (E) and (Z) isomers, with the diol 16 followed by subsequent conversions to al-
the latter isomer, however, only as a minor component. Al- dehyde 23, acetylenes 24a, 24b, 25a and triol 25b, as de-
though the mixture was readily separated by flash chroma- scribed for the synthesis of 21a and illustrated in Scheme 2.
tography, the presence of two isomers was deemed immate-
rial for the task at hand so that the ene product was used
directly in the next step. While hydrogenation of 13 with
PdϪC caused extensive hydrogenolysis of the homoallylic
alkenol, PtϪC gave a clean conversion into the desired diols
16 and 17 in nearly equal proportions. This epimeric pair
could again be separated quantitatively by chromatography
so that both epimers were now available for further ad-
vancement. The absolute configuration of the side-chain
stereocenter in each epimer, generated either by hydrobor-
ation (14/15) or hydrogenation (16/17), was not obvious for
some time, however.
The diol 17, exhibiting the shorter retention time on the
HPLC column, was oxidized to the aldehyde 18 with pyridi-
nium chlorochromate and immediately converted with
(1-diazo-2-oxopropyl)phosphonic acid dimethyl ester[20,21] Figure 1. A molecule of 21a in the crystal
Scheme 2
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Formal Desymmetrization of the Diastereotopic Chains in Gemini Calcitriol Derivatives
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To correlate the absolute configurations of the pair of epi- 15 and 16/17 was now solved; 15 and 17, the diols with the
mers derived from the hydroboration experiment with those shorter retention time on the HPLC column, are established
established for 16 and 17, it became essential to synthesize as the (R)- and (S)-epimers, respectively, as summarized in
one of the members that is part of the sequence that extends Scheme 1.
from the diol 17 to ketone 21, or from diol 16 to ketone 26,
While ketone 21a gave the disilyl ether 21b upon treat-
but starting with one of the hydroboration products 14 or ment with 1-(trimethylsilyl)imidazole, ketone 26a produced
15 and to assess its stereochemical identity by comparison. a mixture of silyl ethers 26b and 26c under similar reaction
This task was simplified as the 1H NMR spectra of the conditions (Scheme 2). The standard coupling protocol,[24]
intermediates 17 to 21 are quite different than their employing the allyldiphenylphosphane oxides 27a and 27b
counterparts in the other epimeric series extending from 16 as WittigϪHorner components,[25Ϫ27] gave the two pairs of
to 26. We selected diol 15, the component that exhibits the poly-O-silylated intermediates 28a/28b and 29a/29b, and a
shorter retention time on the HPLC column, and converted single treatment with tetrabutylammonium fluoride liber-
it into the iodo compound 22 as shown in Scheme 1. Treat- ated all protected hydroxy groups present in each species to
ment of this material with lithium acetylide DMA complex furnished the final compounds 6a, 6b, 7a and 7b as shown
in DMF gave mostly the elimination product 12, but a suf- in Scheme 3.
ficient quantity of the acetylene was produced to permit
The selection of the two pairs 6a/6b and 7a/7b for explor-
a stereochemical assignment. It could be shown that the ing stereochemical effects in the VDR gained in validity
acetylene produced in this fashion was identical with 19a, when it could be shown that the environment experienced
and rather different from the epimeric 24a. Consequently, by a particular side chain of one epimer is quite different
the stereochemical assignments for both epimeric pairs 14/ from that of the other, as suggested by their 1H NMR spec-
Scheme 3
Scheme 4
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H. Maehr, M. R. Uskokovic
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tra. Similarly, the 19F NMR spectra show the geminal tri-
fluoromethyl groups in one pair in a different chemical en-
vironment to the other. More specifically, the representa-
tives with the (20S)-configuration, as in 6a and 6b, exhibit
the geminal trifluoromethyl groups as overlapping quad-
22.66, 24.56, 25.76 (3C), 34.34, 36.20, 39.43, 42.78, 52.89, 56.64,
68.97, 69.01, 69.33, 112.72, 127.86 (2 C), 129.71 (2 C), 133.15,
143.30, 144.58 ppm. LR-FAB(ϩ): m/z ϭ 493 [M ϩ H], 491 [M Ϫ
H], 361 [M Ϫ OTBS]. HRMS-ES(ϩ) calcd. for C27H44O4SSi:
515.2628 [M ϩ Na], found 515.2622.
ruplets, while the (20R)-pair 7a/7b show the same signals Dimethyl 2-{3-[(1R,3aR,4S,7aR)-4-(tert-Butyldimethylsilanyloxy)-
7a-methyloctahydroinden-1-yl]but-3-enyl}malonate (10): A solution
of dimethyl malonate (17.17 g, 130 mmol) in toluene (50 mL) was
added dropwise to a stirred suspension of sodium hydride (4.66 g,
117 mmol) in toluene (160 mL). The suspension was heated in a
120 °C oil bath for 5 min, then a solution of tosylate 9b (9.50 g,
19.3 mmol) in toluene (100 mL) was added dropwise with vigorous
stirring. Stirring in the 120 °C bath was continued for 5 h (TLC,
ethyl acetate/hexane, 1:6). The flask was then placed into an ice
bath and pieces of ice and water (100 mL) were added to dissolve
the voluminous precipitate. The mixture was equilibrated with hex-
as singlets.
The ketone 32b, required for the synthesis of 5, was pre-
pared from diethyl 1,3-dioxolane-2,2-dibutyrate[28] 30 by a
sequence of reactions commencing with a treatment with
methylmagnesium bromide solution (Scheme 4). The re-
sulting dioxolane 31 was hydrolyzed to give the ketone 32a
that was used directly in the next step as chromatographic
purification gave variable recoveries, probably due to hemi-
acetal formation. Thus, crude 32a was converted into 32b
with 1-(trimethylsilyl)imidazole, then further condensed ane (100 mL) and the resulting aqueous phase was re-extracted
once with toluene (50 mL). The combined extracts were washed
with water (100 mL) and brine (50 mL) then dried (sodium sulfate)
and the solvents evaporated. The residual oil was concentrated to
remove most of the dimethyl malonate. The resulting oil (10.8 g)
was flash chromatographed with hexane, and ethyl acetate/hexane
(1:79 and 1:39) as mobile phases to give pure 10 (6.75 g) as an oil.
Re-chromatography of the side fractions gave an additional crop of
with 27a to afford 33, which, after deprotection, gave the
tetraol 5. To investigate the effect on product yield, we con-
ducted the condensation deliberately without the usual ex-
cess of the A-ring component and observed a value of 51%.
The pharmacological evaluation of compounds 6a, 6b, 7a
and 7b is presently ongoing.
1
10 (1.19 g), total yield 91%. H NMR: δ ϭ 0.002 and 0.012 (s, 3 H
each), 0.78 (s, 3 H), 0.88 (s, 9 H), 1.15 (m, 1 H), 1.3Ϫ1.8 (m, 11
H), 1.97Ϫ2.10 (m, 4 H), 3.38 (m, 1 H), 3.73 and 3.74 (s, 3 H each),
4.01 (m, 1 H), 4.82 and 4.89 (br. s, 1 H each) ppm. LR-FAB:
m/z ϭ 453 [M ϩ H], 451 [M Ϫ H], 431 [M Ϫ OMe], 395 [M Ϫ
C4H9], 321 [M Ϫ OTBS]. HRMS-ES(ϩ) calcd. for C25H44O5Si:
475.2850 [M ϩ Na], found 475.2863.
Experimental Section
All operations involving vitamin D analogs were conducted in am-
ber-colored glassware under nitrogen. Tetrahydrofuran was distilled
from sodium benzophenone ketyl just prior to use and solutions of
solutes were dried with sodium sulfate. Melting points were deter-
mined on a Thomas-Hoover capillary apparatus and are uncor-
rected. Optical rotations were measured at 25 °C. 1H NMR spectra
were recorded at 400 MHz with CDCl3 as solvent unless indicated
otherwise. TLC was carried out on silica gel plates (Merck G-60,
F254) with visualization under short-wavelength UV light or by
spraying the plates with 10% phosphomolybdic acid in methanol
followed by heating. Flash chromatography[29] was carried out on
40Ϫ65 µm mesh silica gel. Final products are amorphous solids
and obtained by evaporation of methyl formate solutions. Prepara-
tive HPLC was performed on a 5 ϫ 50 cm YMC column using
15Ϫ30 µm mesh silica gel at a flow rate of 100 mL/min.
Methyl
5-[(1R,3aR,4S,7aR)-4-(tert-Butyldimethylsilanyloxy)-7a-
methyloctahydroinden-1-yl]hex-5-enoate (11): A mixture of the dies-
ter 10 (8.27 g, 18.27 mmol), water /DMSO (1:100) (35 mL) and lith-
ium chloride (1.71 g) was stirred and heated under nitrogen in a
bath maintained at 160 °C for 3 h. Reaction progress was moni-
tored by TLC (ethyl acetate/hexane, 1:9 ). The light-tan solution
was cooled and was then distributed between water (100 mL) and
hexane (200 mL). The aqueous layer was extracted with hexane (2
ϫ 50 mL). The combined hexane layers were washed with water (2
ϫ 50 mL), once with brine (20 mL) then dried (sodium sulfate) and
the solvents evaporated to leave a tan oil that was flash chromato-
graphed with a stepwise gradient of dichloromethane/hexane (1:39
and 1:19), then ethyl acetate/hexane (1:79) to give 11 as a colorless
oil, 6.29 g, 87%. 1H NMR: δ ϭ 0.004 and 0.013 (s, 3 H each), 0.79
(s, 3 H), 0.89 (s, 9 H), 1.16 (m, 1 H), 1.3Ϫ1.8 (m, 12 H), 2.02 (m,
3 H), 2.30 (m, 2 H), 3.67 (s, 3 H, Me), 4.02 (m, 1 H), 4.80 and 4.88
(br. s, 1 H each) ppm. LR-APCI(ϩ): m/z ϭ 395 [M ϩ H], 393 [M
Ϫ H], 363 [M Ϫ OMe], 263 [M Ϫ OTBS]. HRMS-ES(ϩ) calcd. for
C23H42O3Si: 395.2976 [M ϩ H], found 395.2980.
3-[(1R,3aR,4S,7aR)-4-(tert-Butyldimethylsilanyloxy)-7a-methyl-
octahydroinden-1-yl]but-3-enyl Tolene-4-sulfonate (9b): Tosyl chlo-
ride (5.91 g, 31 mmol) was added in one portion to a stirred solu-
tion containing the alcohol 9a (6.59 g, 19.5 mmol), dichlorometh-
ane (53 mL), triethylamine (6.0 mL, 43 mmol) and DMAP
(244 mg, 2.0 mmol). After 5 h the resulting suspension was poured
into a mixture of ice (50 g), saturated sodium hydrogen carbonate
solution (100 mL) and hexane (100 mL). The aqueous layer was re-
extracted with dichloromethane (40 mL). These combined extracts
were washed with 1:1 water-saturated sodium hydrogen carbonate
solution (122 mL), saturated sodium hydrogen carbonate solution
(100 mL), then dried (sodium sulfate) and the solvents evaporated.
The residue was purified on a short flash chromatography column
6-[(1R,3aR,4S,7aR)-4-(tert-Butyldimethylsilanyloxy)-7a-methyl-
octahydroinden-1-yl]-2-methylhept-6-en-2-ol (12): A 3  solution of
methylmagnesium bromide in diethyl ether (15 mL) was added
dropwise to an ice-cold solution of the ester 11 (5.60 g,
14.19 mmol) in diethyl ether (120 mL). After completion of the ad-
dition the mixture was stirred at room temperature for 3 h then
using ethyl acetate/hexane (1:39) as mobile phase to yield 9b as a
1
colorless oil (9.51 g, 99%). H NMR: δ ϭ Ϫ0.007 and 0.005 (s, 3 cooled again in an ice bath. A saturated solution of ammonium
H each), 0.73 (s, 3 H), 0.88 (s, 9 H), 1.05 (m, 1 H), 1.25Ϫ1.8 (m, chloride (25 mL) was added dropwise. The resulting precipitate was
10 H), 1.88 (m, 1 H), 2.28 and 2.39 (m, 1 H each), 2.45 (s, 3 H,
Me), 3.99 (m, 1 H, C4-H), 4.09 (m, 2 H), 4.81 and 4.82 (s, 1 H re-extracted with diethyl ether (100 mL) and the combined diethyl
each), 7.34 and 7.79 (d, J ϭ 8.4 Hz, 2 H each) ppm. 13C NMR
ether layers were washed with pH 7 phosphate buffer (30 mL), then
(300 MHz, CDCl3): δ ϭ Ϫ5.17, Ϫ4.79, 14.71, 17.65, 17.97, 21.61, dried (sodium sulfate) and the solvents evaporated to afford crude
dissolved by the addition of water (80 mL). The aqueous layer was
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Formal Desymmetrization of the Diastereotopic Chains in Gemini Calcitriol Derivatives
12 as a colorless oil. This material was flash-chromatographed with cooled in an ice bath and a 1  solution of boraneϪTHF in tetra-
FULL PAPER
ethyl acetate/hexane (1:39) as mobile phase until the product
started to emerge from the column (TLC, ethyl acetate/hexane, 1:4,
Rf ϭ 0.49). For subsequent elution ethyl acetate/hexane (1:19) was
used. Fractions representing pure product were pooled and the sol-
vents evaporated to give 12 as a colorless oil (3.0 g). Fractions pre-
ceding the main band contained a small amount of a less-polar
impurity (2.62 g). This material was re-chromatographed on an
hydrofuran (17 mL) was added dropwise in a reaction that was ef-
fervescent at the outset. The solution was stirred overnight at room
temperature, re-cooled in an ice bath and water (17 mL) was added
dropwise followed by solid sodium percarbonate (7.10 g, 68 mmol).
The mixture was immersed in a 50 °C bath and stirred for 70 min
to generate a solution. The two-phase system was cooled, then
equilibrated with ethyl acetate/hexane (1:1) (170 mL). The organic
HPLC column (see Exp. Sect.) using ethyl acetate/hexane (1:20) as layer was washed with water (2 ϫ 25 mL) and brine (20 mL), dried
mobile phase. After ca. 4.5 L of effluent, fractions were taken to
give additional pure 12 (1.95 g) as a colorless oil, 88%. H NMR:
and the solvents evaporated to leave the diol mixture as a colorless
oil, 2.76 g, TLC (ethyl acetate/hexane, 1:1) Rf ϭ 0.37 major, 0.30
1
δ ϭ 0.005 and 0.013 (s, 3 H each), 0.79 (s, 3 H), 0.88 (s, 9 H), 1.17 minor. This material was passed through a short flash column
(m, 1 H), 1.22 and 1.23 (s, 3 H each), 1.35Ϫ1.85 (m, 16 H), 2.01 using ethyl acetate/hexane (1:1) and silica gel G. The effluent, ob-
(m, 2 H), 4.02 (m, 1 H, C4-H), 4.78 and 4.88 (br. s, 1 H each) ppm. tained after exhaustive elution, was evaporated, taken up in ethyl
LR-FAB(ϩ): m/z ϭ 395 [M ϩ H], 377 [M Ϫ OH]. HRMS-ES(ϩ) acetate, filtered and chromatographed on an HPLC column (see
calcd. for C24H46O2Si: 395.3340 [M ϩ H], found 395.3344. Exp. Sect.) using ethyl acetate/hexane (2:1) as mobile phase. Isomer
C25H48O3Si: calcd. C 73.03, H 11.75; found C 72.82, H 11.97.
15 emerged at an effluent maximum of 2.9 L and was obtained as
a colorless oil that very slowly and incompletely solidified,
1.3114 g; m.p. 68Ϫ69 °C. [α]D ϭ ϩ45.2 (c ϭ 0.58, methanol). H
1
(Z)-3-[(1R,3aR,4S,7aR)-4-(tert-Butyldimethylsilanyloxy)-7a-
methyloctahydroinden-1-yl]but-2-en-1-ol (13a) and (E)-3-[(1R,3aR,-
4S,7aR)-4-(tert-Butyldimethylsilanyloxy)-7a-methyloctahydroinden-
1-yl]but-2-en-1-ol (13b): A 1.0  solution of dimethylaluminum
chloride in hexane (1.2 mL) was added to a stirred, cold (Ϫ20 °C)
suspension of alkene 12 (231.6 mg, 0.587 mmol) and paraformal-
dehyde (21 mg, 0.70 mmol) in dichloromethane (2 mL). The cool-
ing bath was replaced by an ice bath after 2 h and additional quan-
tities of paraformaldehyde (16 mg, 0.53 mmol) and 1  dimeth-
ylaluminum chloride solution (0.5 mL) were added. No starting
material could be detected after 10 min (TLC, EtOAc). The re-
sulting solution was stirred for an additional period of 10 min then
poured onto crushed ice and acidified with 0.1  hydrochloric acid.
The mixture was extracted with diethyl ether (2 ϫ 15 mL), the com-
bined extracts were washed with brine (10 mL), dried (sodium sul-
fate), and the solvents evaporated to a colorless oil. This material
was flash-chromatographed with ethyl acetate/hexane (1:3) as mo-
bile phase. The minor component with Rf ϭ 0.44 (4 mg) was ident-
NMR: δ ϭ Ϫ0.002 (s, 3 H), 0.011 (s, 3 H), 0.89 (s, 9 H), 0.93 (s, 3
H), 1.17 (m, 1 H), 1.22 (s, 6 H), 1.25Ϫ1.6 (m, 16 H), 1.68 (m, 1
H), 1.80 (m, 2 H), 1.89 (m, 1 H), 3.66 (dd, J ϭ 4.8 and 11 Hz, 1
H), 3.72 (dd, J ϭ 3.3 and 11 Hz, 1 H), 4.00 (m, 1 H) ppm. LR-
ES(Ϫ): m/z ϭ 412 [M], 411 [M Ϫ H]. HR-ES(ϩ): m/z calcd. for
[M ϩ Na]: 435.3265, found 435.3269.
Isomer 14 was eluted at an effluent maximum of 4.9 L, obtained
as a crystalline residue, 0.8562 g, then recrystallized from ethyl
acetate/hexane; m.p. 102Ϫ103°C. [α]D ϭ ϩ25.2 (c ϭ 0.49, meth-
anol). 1H NMR: δ ϭ Ϫ0.005 (s, 3 H), 0.009 (s, 3 H), 0.89 (s, 9 H),
0.93 (s, 3 H), 1.16 (m, 1 H), 1.22 (s, 6 H), 1.3Ϫ1.5, (m, 14 H), 1.57
(m, 2 H), 1.67 (m, 1 H), 1.80 (m, 2 H), 1.91 (m, 1 H), 3.54 (dd,
J ϭ 4.8 and 11 Hz, 1 H), 3.72 (dd, J ϭ 2.9 and 11 Hz, 1 H), 4.00
(m, 1 H) ppm. LR-ES(Ϫ): m/z ϭ 412 [M], 411 [M Ϫ H].
C24H48O3Si: calcd. C 69.84, H, 11.72; found C 69.91, H 11.76.
1
(S)-3-[(1R,3aR,4S,7aR)-4-(tert-Butyldimethylsilanyloxy)-7a-
methyloctahydroinden-1-yl]-7-methyloctane-1,7-diol (17) and (R)-3-
[(1R,3aR,4S,7aR)-4-(tert-Butyldimethylsilanyloxy)-7a-methyl-
octahydroinden-1-yl]-7-methyloctane-1,7-diol (16): A solution of the
alkenediol mixture 13a and 13b (0.61 g) in ethyl acetate was stirred
overnight in the presence of 1% PtϪC (197 mg) and under a hydro-
gen pressure of 1 atm. The catalyst was filtered off, the filtrate
concentrated and chromatographed on an HPLC column (see Exp.
Sect.) using ethyl acetate/hexane (2:1) as mobile phase. The (S) iso-
mer 17 (0.32 g, colorless oil) emerged at an effluent maximum of
ified as the (Z) isomer 13a. H NMR: δ ϭ 0.005 and 0.014 (s, 3 H
each, Me2Si), 0.86 (s, 3 H), 0.88 (s, 9 H), 1.10 (m, 1 H), 1.21 and
1.22 (s, 3 H each), 1.32Ϫ1.45 (m, 3 H), 1.45Ϫ1.84 (m, 11 H), 2.05
(m, 1 H), 2.20 and 2.38 (m, 1 H each, hydroxymethyl CH2), 2.27
(m, 1 H), 2.54, (t, J ϭ 9.9 Hz, 1 H), 3.48 and 3.63 (m, 1 H each,
hydroxymethyl), 4.04 (br. s, 1 H), 5.36 (dd, J ϭ 5.5 Hz, 1 H) ppm.
Irradiation of the alkene region δ ϭ 5.35 ppm resulted in an NOE
at δ ϭ 2.20 ppm and vice versa, supporting the (Z) geometry. Com-
pound 13a preceded fractions containing mixtures of 13a and 13b
(110 mg) and the main band with Rf ϭ 0.30 representing the pure
(E) isomer 13b (80 mg). This residue was redissolved in hexane and
3400 mL: [α]2D2
ϭ ϩ91.2 (c ϭ
0.48, methanol). 1H NMR
1
(400 MHz): δ ϭ Ϫ0.005 and 0.008 (s, 3 H each, Me2Si), 0.88 (s, 9
H, Me3CϪSi), 0.92 (s, 3 H, C7a-Me), 1.15 (m, 1 H), 1.22 (s, 6 H),
1.2Ϫ1.8 (m, 21 H), 1.95 (m, 1 H), 3.62 and 3.68 (m, 1 H each,
hydroxymethyl), 4.00 (m, 1 H) ppm. LR-ES(ϩ): m/z ϭ 426 [M],
425 [M Ϫ H], 495 [M Ϫ CH2OH], 353 [M Ϫ CH2CMe2OH].
HRMS-ES(ϩ): m/z calcd. for C25H50O3Si: 449.3421 [M ϩ Na],
found 449.3423.
crystallized. H NMR: δ ϭ 0.002 and 0.012 (s, 3 H each), 0.78 (s,
3 H), 0.88 (s, 9 H), 1.12 (m, 1 H), 1.24 (s, 6 H), 1.26Ϫ1.8 (m, 14
H), 2.03 (m, 1 H), 2.19 (m, 3 H, 1 H of hydroxymethyl CH2), 2.54
(m, 1 H, 1 H of hydroxymethyl CH2), 3.60 (m, 2 H, hydroxy-
methyl), 4.01 (br. s, 1 H), 5.37 (dd, J ϭ 7, J ϭ 7.3 Hz, 1 H) ppm.
Irradiation of the angular methyl region at δ ϭ 0.78 ppm resulted
in an NOE at the alkene region δ ϭ 5.37 ppm supporting the (E)
geometry. [α]2D5 ϭ ϩ30.38 (c ϭ 0.43, methanol). LR-FAB(ϩ): m/
z ϭ 425 [M ϩ H], 423 [M Ϫ H], 407 [M Ϫ OH], 351 [M Ϫ HOC-
Me2CH2]. C25H48O3Si: calcd. C 70.70, H 11.39; found C 70.74,
H 11.38.
The (R) isomer 16, quantitatively separated from 17, was eluted at
an effluent maximum of 4100 mL (0.28 g) and obtained as a color-
less oil that crystallized from ethyl acetate; m.p. 95Ϫ96 °C. [α]D25
ϩ34.8 (c ϭ 0.89, methanol). H NMR: δ ϭ Ϫ0.006 and 0.007 (s,
ϭ
1
(R)-2-[(1R,3aR,4S,7aR)-4-(tert-Butyldimethylsilanyloxy)-7a- 3 H each), 0.88 (s, 9 H), 0.92 (s, 3 H), 1.14 (m, 1 H), 1.21 (s, 6 H),
methyloctahydroinden-1-yl]-6-methylheptane-1,6-diol (15) and (S)-2- 1.2Ϫ1.8 (m, 20 H), 1.81 (m, 1 H), 1.88 (m, 1 H), 3.63 and 3.69 (m,
[(1R,3aR,4S,7aR)-4-(tert-Butyldimethylsilanyloxy)-7a-methyl-
octahydroinden-1-yl]-6-methylheptane-1,6-diol (14): A solution of
the alkenol 12 (2.5 g, 6.33 mmol) in tetrahydrofuran (9 mL) was
1 H each), 4.00 (m, 1 H) ppm. LR-ES: m/z ϭ 426 [Mϩ], 425 [M Ϫ
H], 495 [M Ϫ CH2OH], 353 [M Ϫ CH2CMe2OH]. HRMS-ES(ϩ):
m/z calcd. for C25H50O3Si: 449.3421 [M ϩ Na], found 449.3425.
Eur. J. Org. Chem. 2004, 1703Ϫ1713
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1709

H. Maehr, M. R. Uskokovic
FULL PAPER
(S)-3-[(1R,3aR,4S,7aR)-4-(tert-Butyldimethylsilanyloxy)-7a- (S)-6-[(1R,3aR,4S,7aR)-4-(tert-Butyldimethylsilanyloxy)-7a-
methyloctahydroinden-1-yl]-7-hydroxy-7-methyloctanal (18): Pyridi- methyloctahydroinden-1-yl]-1,1,1-trifluoro-10-methyl-2-(trifluoro-
nium chlorochromate (790 mg, 3.66 mmol) was added in one por- methyl)undec-3-yne-2,10-diol (20b): The acetylene 19b was con-
tion to
a
stirred mixture containing the diol 17 (0.7369 g,
verted into 20b via 20a as described for 25b. Diol 20b, however,
was obtained in crystalline form from dichloromethane, m.p. 131
°C. 1H NMR: δ ϭ 0.94 (s, 3 H), 1.23 (m, 1 H), 1.25 (s, 6 H),
1.25Ϫ1.85 (m, 10 H), 1.88 (m, 1 H), 2.32 (dd, Jgem ϭ 16.9, J ϭ
1.727 mmol), sodium acetate (0.46 g, 1.2 mmol), Celite (500 mg)
and dichloromethane (12 mL). After 2.5 h, the mixture was diluted
with cyclohexane (5 mL) and passed through a plug of silica gel G
previously equilibrated with diethyl ether. Filtrate and diethyl ether 6.6 Hz, 1 H), 2.55 (dd, Jgem ϭ 17.2, J ϭ 4 Hz, 1 H), 4.09 (m, 1 H)
were evaporated and the residue flash-chromatographed with ethyl
ppm. [α]2D5 ϭ ϩ16.2 (c ϭ 0.44, methanol). LR-APCI(ϩ): m/z ϭ 472
[M], 471 [M Ϫ H]. HRMS-ES(Ϫ): m/z calcd. for C23H34F6O3:
471.2339 [M Ϫ H], found 471.2345. C23H34F6O3: calcd. C 58.46,
acetate/hexane (1:3) as mobile phase affording the aldehyde 18 as
1
a colorless oil, 0.61 g, 83%. H NMR: δ ϭ 0.000 and 0.012 (s, 3 H
each), 0.89 (s, 9 H), 0.95 (s, 3 H), 1.14 (m, 1 H), 1.21 (s, 6 H), H 7.25, found C 58.42, H 7.39.
1.2Ϫ2.0 (m, 19 H), 2.43 and 2.59 (m, 1 H each), 4.00 (m, 1 H),
(1R,3aR,7aR)-7a-Methyl-1-[(S)-6,6,6-trifluoro-5-hydroxy-1-(4-
hydroxy-4-methylpentyl)-5-(trifluoromethyl)hex-3-ynyl]octa-
(S)-6-[(1R,3aR,4S,7aR)-4-(tert-Butyldimethylsilanyloxy)-7a- hydroinden-4-one (21a): Pyridinium dichromate (1.16 g, 3.08 mmol)
9.77 (m, 1 H) ppm.
methyloctahydroinden-1-yl]-2-methylnon-8-yn-2-ol (19a). (a) Syn-
thesis from 18: Powdered potassium carbonate (0.34 g, 2.46 mmol)
was added to a stirred, ice-cold mixture of the aldehyde 18 (0.61 g,
was added to a stirred suspension of 20b (0.3326 g, 0.704 mmol),
Celite (0.6 g), and dichloromethane (12 mL). After 6 h the mixture
was diluted with diethyl ether (15 mL) and charged to a silica gel
1.436 mmol),
dimethyl
1-(1-diazo-2-oxopropyl)phosphonate plug (2.4 g) that was exhaustively eluted with diethyl ether. The
(0.41 g, 2.13 mmol) and methanol (9 mL). The ice bath was re-
moved after 1 h and stirring at room temperature continued for
5.5 h. The mixture was then diluted with hexane (30 mL) and water
combined diethyl ether effluent was evaporated and the residue
crystallized from ethyl acetate/hexane, 0.292 g (88%), then recrys-
tallized from the same solvent to give needles, m.p. 139Ϫ140 °C;
(20 mL), the aqueous phase was extracted once with hexane the crystal analysis is based on a crystal 0.35 ϫ 0.07 ϫ 0.05 mm,
(30 mL), and once with diethyl ether (30 mL). All three extracts
were combined, washed with water (3 ϫ 10 mL), once with brine
(10 mL), dried (sodium sulfate) and the solvents evaporated to give
a colorless oily residue, 0.6 g, which was flash-chromatographed
with ethyl acetate/hexane (1:9) as mobile phase affording 19a as a
C23H32F3O3, orthorhombic, space group P212121 with unit cell di-
˚
mensions a ϭ 8.5350(5), b ϭ 14.6309(9), c ϭ 18.7254(11) A, cell
3
volume 2338.3(2) A (Z ϭ 4), dcalcd. ϭ 1.336 g·cmϪ3. Analysis was
˚
based on 20415 reflections collected and 4782 [R(int) ϭ 0.0589]
˚
independent reflections, 123(1) K, wavelength 0.71073 A, absorp-
colorless oil, 0.5552 g, 92%. [α]2D2 ϭ ϩ43.5 (c ϭ 0.2, methanol). 1H tion coefficient 0.118 mmϪ1, F(000) ϭ 992, Theta range for data
NMR: δ ϭ Ϫ0.005 and 0.009 (s, 3 H each), 0.89 (s, 9 H), 0.90 (s,
collection 1.77 to 26.37°, data/restraints/parameters 4782/0/300.
3 H), 1.22 (s, 6 H), 1.2Ϫ1.6 (m, 16 H), 1.67 (m, 1 H), 1.79 (m, 2 The structure was refined by full-matrix least-squares on F2. Final
H), 1.90 (m, 1 H), 1.92 (dd, J ϭ 2.6 Hz, 1 H), 2.31 and 2.37 (m, 1 R indices [I Ͼ 2σ(I)] were R1 ϭ 0.0417 and wR2 ϭ 0.1103 and R
H each), 4.00 (m, 1 H) ppm. LR-EI(ϩ): m/z ϭ 420 [M], 405 [M Ϫ
indices (all data) R1 ϭ 0.0480 and wR2 ϭ 0.1136, absolute struc-
Me], 363 [M Ϫ C4H9]. HRMS-EI(ϩ): m/z calcd. for C26H48O2Si: ture parameter Ϫ0.3(5), largest diff. peak and hole 0.231 and
1
Ϫ0.287 e·AϪ3. [α]2D5 ϭ Ϫ5.5 (c ϭ 0.45, methanol). H NMR: δ ϭ
˚
420.3424 [M], found 420.3433.
0.64 (s, 3 H), 1.25 (s, 6 H), 1.3Ϫ2.44 (m, 21 H), 2.48 (dd, Jgem
ϭ
(b) Synthesis from 22: Lithium acetylide DMA complex (0.110 g,
1.19 mmol) was added to a solution of 22 (0.2018 g (0.386 mmol)
in dimethyl sulfoxide (1.5 mL) and tetrahydrofuran (0.15 mL). The
mixture was stirred overnight. TLC (ethyl acetate/hexane, 1:4)
showed a mixture of two spots traveling very close together (Rf ϭ
0.52 and 0.46). Flash-chromatography using ethyl acetate/hexane
(1:19) as mobile phase separated this mixture only partially. Never-
theless fractions at the beginning of the eluted band contained pure
12, which is the elimination product of 22, and was produced as
the major product. Fractions at the end of the elution band, how-
11, J ϭ 7.3 Hz, 1 H), 2.57 (dd, Jgem ϭ 17.6, J ϭ 4 Hz, 1 H) ppm.
LR-APCI(ϩ): m/z ϭ 470 [M], 469 [M Ϫ H]. HRMS-ES(Ϫ): m/z
calcd. for C23H32F6O3: 469.2183 [M Ϫ H], found 469.2189.
C23H34F6O3: calcd. C 58.71, H 6.86, found C 58.77, H 6.74.
CCDC-231751 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; Fax: (internat.) ϩ44-1223/336-033; E-mail:
ever, were also homogeneous and gave the desired acetylene upon deposit@ccdc.cam.ac.uk].
evaporation. The elution was monitored by TLC (methanol/di-
(1R,3aR,7aR)-7a-Methyl-1-[(S)-6,6,6-trifluoro-1-(4-methyl-4-
chloromethane, 1:19). The NMR spectrum of this product was
identical with 19a prepared from 18 as described above.
trimethylsilanyloxypentyl)-5-(trifluoromethyl)-5-trimethylsilanyl-
oxyhex-3-ynyl]octahydroinden-4-one (21b): A mixture of the ketone
21a (0.3184 g, 0.677 mmol), diethyl ether (3 mL), and 1-(trimethyl-
silyl)imidazole 0.30 mL, 2.04 mmol) was agitated for 1 h. The dis-
(1R,3aR,4S,7aR)-4-(tert-Butyldimethylsilanyloxy)-7a-methyl-1-[(S)-
5-methyl-1-prop-2-ynyl-5-trimethylsilanyloxyhexyl)octahydroindene
(19b): A mixture of the acetylene 19a (0.517 g, 1.23 mmol), cyclo- appearance of starting material and generation of 21b was demon-
hexane (8 mL), and 1-(trimethylsilyl)imidazole (0.29 mL, 2 mmol)
exhibited no residual 19a after 4 h (TLC, ethyl acetate/hexane, 1:9).
The mixture was applied to a silica gel G plug that was eluted with
hexane to give 19b as a colorless syrup, 0.5638 g, 93%. H NMR:
δ ϭ Ϫ0.005 and 0.008 (s, 3 H each, Me2Si), 0.10 (s, 9 H), 0.89 (s,
strated by TLC (ethyl acetate/hexane, 1:39 and methanol/dichloro-
methane, 1:19). The residue obtained after evaporation of solvent
was flash-chromatographed with a stepwise gradient of ethyl acet-
ate/hexane (1:39 to 1:19) as mobile phase to furnish 21b as a color-
less residue, 0.30 g. 1H NMR: δ ϭ 0.10 (s, 9 H), 0.28 (s, 9 H), 0.64
1
9 H), 0.91 (s, 3 H), 1.20 (s, 6 H), 1.2Ϫ1.63 (m, 14 H), 1.66 (m, 1 (s, 3 H), 1.20 (s, 6 H), 1.2Ϫ1.6 (m, 10 H), 1.66Ϫ1.82 (m, 3 H),
H), 1.74Ϫ1.84 (m, 2 H), 1.90 (m, 1 H), 1.91 (dd, J ϭ 2.6 Hz, 1 H),
2.30 and 2.37 (m, 1 H each), 4.00 (m, 1 H) ppm. LR-FAB(ϩ):
1.82Ϫ1.98 (m, 2 H), 1.98Ϫ2.08 (m, 2 H), 2.2Ϫ2.34 (m, 2 H),
2.45Ϫ2.52 (m, 2 H) ppm. LRMS-ES(ϩ): m/z ϭ 541 [M Ϫ TMS],
m/z ϭ 492 [M], 401 [M Ϫ H], 477 [M Ϫ Me], 435 [M Ϫ C4H9], 525 [M Ϫ OTMS]. HRMS-ES(ϩ): m/z ϭ calcd. for C29H48F6O3Si2:
403 [M Ϫ OTMS]. 637.2938 [M ϩ Na], found 637.2941.
1710
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 1703Ϫ1713

Formal Desymmetrization of the Diastereotopic Chains in Gemini Calcitriol Derivatives
(R)-6-[(1R,3aR,4S,7aR)-4-(tert-Butyldimethylsilanyloxy)-7a- (5 mL) and extracted with 40 and 20 mL of hexane. The combined
FULL PAPER
methyloctahydroinden-1-yl]-7-iodo-2-methylheptan-2-ol (22):
A
extracts were washed with brine (10 mL), dried (sodium sulfate)
and the solvents evaporated to give crude 25a as a colorless oil
(0.90 g). This material was dissolved in acetonitrile (10 mL), the
solution was cooled in an ice bath and fluorosilicic acid solution[23]
(2.20 mL) was added. After 4 h of stirring the desilylation was com-
plete (TLC, ethyl acetate/hexane, 1:4 and methanol/dichlorometh-
ane, 1:19). The mixture was diluted with ethyl acetate (40 mL),
water (15 mL) was added and the aqueous phase extracted with
water (2 ϫ 15 mL) and with brine (15 mL). The combined extracts
were dried (sodium sulfate) and the solvents evaporated. The re-
sulting oil was flash chromatographed to furnish 25b as a sticky
stirred mixture of triphenylphosphane (0.333 g, 1.27 mmol) and
imidazole (0.255 g, 3 mmol) in dichloromethane (3 mL) was cooled
in an ice bath and iodine (0.305 g, 1.20 mmol) was added. This
mixture was stirred for 10 min then a solution of 15 (0.4537 g,
1.10 mmol) in dichloromethane (3 mL) was added dropwise over a
10 min period. The mixture was stirred in the ice bath for 30 min
then at ambient temperature for 2 3/4 h. TLC (ethyl acetate/hexane,
1:1) confirmed the absence of starting material. A solution of so-
dium thiosulfate (0.1 g) in water (5 mL) was added, the mixture
equilibrated and the organic phase washed with 0.1  sulfuric acid
(10 mL) containing a few drops of brine then with water/brine (1:1, residue that could be converted into a white foam from dichloro-
1
2 ϫ 10 mL), once with brine (10 mL) then dried and the solvents
evaporated. The residue was purified by flash chromatography
using ethyl acetate/hexane (1:9) as mobile phase to furnish 22 as a
colorless syrup, 0.5637 g, 98%. 1H NMR: δ ϭ Ϫ0.005 (s, 3 H),
methane, 0.5280 g. [α]2D2 ϭ ϩ6.06 (c ϭ 0.33, methanol). H NMR:
δ ϭ 0.95 (s, 3 H), 1.19 (m, 1 H), 1.25 (s, 6 H), 1.25Ϫ1.91 (m, 10
H), 1.96 (m, 1 H), 2.17 (dd, Jgem ϭ 17.2, J ϭ 7 Hz, 1 H), 2.46 (dd,
Jgem ϭ 17.2, J ϭ 3.7 Hz, 1 H), 4.09 (m, 1 H) ppm. LR-APCI(ϩ):
0.010 (s, 3 H), 0.89 (s, 9 H), 0.92 (s, 3 H), 1.23 (s, 6 H), 1.1Ϫ1.6 m/z ϭ 472 [M], 471 [M Ϫ H]. HRMS-ES(Ϫ): m/z calcd. for
(m, 16 H), 1.68 (m, 1 H), 1.79 (m, 2 H), 1.84 (m, 1 H), 3.37(dd, C23H34F6O3: 471.2339 [M Ϫ H], found 471.2344.
J ϭ 4 and 10 Hz, 1 H), 3.47 (dd, J ϭ 3 and 10 Hz, 1 H), 4.00 (m,
(1R,3aR,7aR)-7a-Methyl-1-[(R)-6,6,6-trifluoro-5-hydroxy-1-(4-
hydroxy-4-methylpentyl)-5-(trifluoromethyl)hex-3-ynyl]octahydro-
inden-4-one (26a): The triol 25b was oxidized to 26a and crys-
1 H) ppm. LR-EI(ϩ): m/z ϭ 522 [M], 465 [M Ϫ C4H9], 477 [M Ϫ
C4H9 Ϫ H2O]. HR-EI(ϩ): m/z calcd. for C24H47IO2Si: 522.2390,
found 522.2394.
tallized as described for the preparation of 21a; m.p. 159 °C. [α]D22
ϭ
1
Ϫ17.4 (c ϭ 0.34, methanol). H NMR: δ ϭ 0.66 (s, 3 H), 1.26 (s,
6 H), 1.25Ϫ2.4 (m, 18 H), 2.16Ϫ2.31 (m, 3 H) 2.44Ϫ2.53 (m, 2 H)
ppm. LR-APCI(ϩ): m/z ϭ 470 [M], 469 [M Ϫ H]. HRMS-ES (Ϫ):
m/z calcd. for C23H32F6O3: 469.2183 [M Ϫ H], found 469.2186.
C23H34F6O3: calcd. C 58.71, H 6.86; found C 58.75, H 6.91.
(S)-3-[(1R,3aR,4S,7aR)-4-(tert-Butyldimethylsilanyloxy)-7a-
methyloctahydroinden-1-yl]-7-hydroxy-7-methyloctanal (23): The
diol 16 was converted into 23 as described for the synthesis of 18
1
and obtained as a colorless oil. H NMR: δ ϭ 0.000 and 0.016 (s,
3 H each), 0.89 (s, 9 H), 0.96 (s, 3 H), 1.16 (m, 1 H), 1.21 (s, 6 H),
1.2Ϫ2.1 (m, 19 H), 2.33 and 2.42 (m, 1 H each), 4.00 (m, 1 H),
9.78 (m, 1 H) ppm.
(1R,3aR,7aR)-7a-Methyl-1-[(R)-6,6,6-trifluoro-1-(4-methyl-4-
trimethylsilanyloxypentyl)-5-(trifluoromethyl)-5-trimethylsilanyl-
oxyhex-3-ynyl]octahydroinden-4-one (26b) and (1R,3aR,7aR)-7a-
Methyl-1-[(R)-6,6,6-trifluoro-5-hydroxy-1-(4-methyl-4-trimethyl-
silanyloxypentyl)-5-(trifluoromethyl)hex-3-ynyl]octahydro-
(R)-6-[(1R,3aR,4S,7aR)-4-(tert-Butyldimethylsilanyloxy)-7a-
methyloctahydroinden-1-yl]-2-methylnon-8-yn-2-ol (24a): The alde-
hyde 23 was converted into 24a as described for the preparation of
19a and obtained as a colorless oil: [α]2D2 ϭ ϩ29.0 (c ϭ 0.51, meth-
anol). 1H NMR: δ ϭ Ϫ0.006 and 0.007 (s, 3 H each), 0.89 (s, 9 H),
0.92 (s, 3 H), 1.17 (m, 1 H), 1.22 (s, 6 H), 1.2Ϫ1.7 (m, 17 H),
inden-4-one (26c):
A mixture of the ketone 26a (0.4116 g,
0.8748 mmol), diethyl ether (4 mL), and 1-(trimethylsilyl)imidaz-
ole) (0.40 mL, 2.73 mmol) was agitated for 15 h. The solution was
evaporated and the residue flash-chromatographed with ethyl acet-
ate/hexane (1:39 and 1:4) as mobile phase. The first solvent eluted
26b, the second 26c. Although the mixture of these two compounds
was used in the next step, the two components were separated for
analysis. Thus, the disilyl ether 26b was obtained as a colorless oil,
0.3751 g. 1H NMR (400 MHz): δ ϭ 0.00 (s, 9 H), 0.18 (s, 9 H),
0.56 (s, 3 H), 1.11 (s, 6 H), 1.1Ϫ1.9 (m, 17 H), 1.96 (m, 1 H), 2.16
(m, 2 H), 2.36 (m, 1 H) ppm. LR-ES(ϩ): m/z ϭ 655 [M Ϫ TMS
ϩ TFA Ϫ H], 541 [M Ϫ TMS]. Compound 26c was also obtained
1.74Ϫ1.88 (m, 2 H), 1.90 (dd, J ϭ 2.6 Hz, 1 H), 2.14 (ddd, Jgem
ϭ
16.8, J ϭ 6, J ϭ 2.4 Hz, 1 H), 2.33 (ddd, Jgem ϭ 17.2, J ϭ 3.6, J ϭ
3.2 Hz, 1 H), 4.00 (m, 1 H) ppm. LR-EI(ϩ): m/z ϭ 420 [M], 405
[M Ϫ Me], 363 [M Ϫ C4H9].
(1R,3aR,4S,7aR)-4-(tert-Butyldimethylsilanyloxy)-7a-methyl-1-
[(R)-5-methyl-1-prop-2-ynyl-5-trimethylsilanyloxyhexyl)octa-
hydroindene (24b): The acetylene 24a was converted into 24b as
described for the preparation of 19b and obtained as a colorless
oil. [α]2D2 ϭ ϩ29.0 (c ϭ 0.51, methanol). 1H NMR: δ ϭ Ϫ0.006 and
0.007 (s, 3 H each), 0.10 (s, 9 H), 0.89 (s, 9 H), 0.92 (s, 3 H), 1.18
(m, 1 H), 1.20 (s, 6 H), 1.2Ϫ1.63 (m, 14 H), 1.66 (m, 1 H),
1.74Ϫ1.87 (m, 2 H), 1.89 (dd, J ϭ 2.6 Hz, 1 H), 1.93 (m, 1 H), 2.13
(ddd, Jgem ϭ 16.9, J ϭ 6, J ϭ 2.4 Hz, 1 H), 2.33 (ddd, Jgem ϭ 17.2,
J ϭ 3.3, J ϭ 3.1 Hz, 1 H), 3.99 (m, 1 H) ppm. LR-EI(ϩ): m/z ϭ
420 [M], 405 [M Ϫ Me], 363 [M Ϫ C4H9].
1
as an oil, 0.1234 g. H NMR: δ ϭ 0.00 (s, 9 H), 0.54 (s, H), 1.11
(s, 6 H), 1.1Ϫ2.0 (m, 7 H), 2.1Ϫ2.2 (m, 2 H), 2.3Ϫ2.4 (m, 1 H)
ppm. LR-ES(ϩ): m/z ϭ 655 [M ϩ TFA Ϫ H], 541 [M Ϫ H].
(1R,3S)-5-{2-[(1R,3aS,7aR)-7a-Methyl-1-[(S)-6,6,6-trifluoro-5-
hydroxy-1-(4-hydroxy-4-methylpentyl)-5-(trifluoromethyl)hex-3-
ynyl]octahydroinden-(4E)-ylidene]ethylidene}-4-methylenecyclo-
hexane-1,3-diol (6a):
A stirred solution of 27a (0.2528 g,
(R)-6-[(1R,3aR,4S,7aR)-4-(tert-Butyldimethylsilanyloxy)-7a- 0.434 mmol) in tetrahydrofuran (2 mL) was cooled to Ϫ75 °C and
methyloctahydroinden-1-yl]-1,1,1-trifluoro-10-methyl-2-(trifluoro-
methyl)undec-3-yne-2,10-diol (25b): A solution of the acetylene 24b
(0.5746 g, 1.166 mmol) in tetrahydrofuran (5 mL) was cooled in a
dry-ice bath, then a 1.6  solution of butyllithium in hexane
a 1.6  solution of butyllithium in hexane (0.28 mL, 44 mmol) was
added dropwise to generate a deep-red ylide solution. After 10 min,
a solution of 21b in tetrahydrofuran (2 mL) was added during a
period of 20 min. The reaction was quenched after 4.5 h by the
(1.0 mL) was added dropwise over an 8 min period. To this solution addition of pH 7 phosphate buffer (4 mL). The mixture was
was added hexafluoroacetone (ca. 0.5 mL), previously condensed
in a dry-ice-filled trap. Already after 5 min starting material was
no longer detectable (TLC, 1:9 ethyl acetate hexane, 25a had Rf ϭ
0.7). To the mixture was added dropwise pH 7 phosphate buffer
warmed to room temperature then extracted with hexane (35 mL).
The hexane layer was washed with brine (5 mL), dried (sodium
sulfate) and the solvents evaporated to give a colorless oil that was
flash-chromatographed with ethyl acetate/hexane (1:79 and 1:39) as
Eur. J. Org. Chem. 2004, 1703Ϫ1713
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1711

H. Maehr, M. R. Uskokovic
FULL PAPER
mobile phase. The mixture of the tetra- and trisilyl ethers 28a was
eluted using the latter solvent, obtained as a colorless, honey-like
syrup (0.197 g) wherein the trisilyl ether predominated, then dis-
give a residue that was dissolved in methyl formate (5 mL), filtered
and the solvents evaporated to yield 7a as a foam, 0.1035 g, 79%
total yield for both condensation and deprotection. [α]D ϭ ϩ15.0
solved in a 1  solution of tetrabutylammonium fluoride (3 mL). (c ϭ 0.39, methanol). UV: λmax. (ε) ϭ 215 (14953), 265 nm (17848).
The deprotection was monitored by TLC using ethyl acetate as
solvent. After 24 h the mixture was diluted with brine (5 mL),
stirred for 5 min then distributed between ethyl acetate (35 mL and
1H NMR ([D6]DMSO): δ ϭ 0.52 (s, 3 H, C7a-Me), 1.05 (s, 6 H),
1.1Ϫ1.5 (m, 16 H), 1.79 (m, 2 H), 1.94 (m, 2 H), 2.2Ϫ2.5 (m, 5 H),
2.80 (m, 1 H), 3.98 (br. s, 1 H), 4.07 (br. s, 1 H), 4.19 (br. s, 1 H),
water (8 mL). The organic layer was washed with water (5 ϫ 4.55 (br. s, 1 H), 4.75 and 5.22 (br. s, 1 H each) 5.99 (d, J ϭ 10.7 Hz,
10 mL), brine (5 mL), and dried (sodium sulfate). The resulting
residue was flash-chromatographed with ethyl acetate/hexane (2:3
and 2:1) as mobile phase. The latter solvent eluted the product. The
residue was taken up in methyl formate, filtered and the solvents
evaporated to provide 6a as a foam, 0.1134 g, 78% total yield for
condensation and deprotection: [α]D ϭ ϩ11.1 (c ϭ 0.31, methanol).
UV (methanol): λmax. (ε) ϭ 212 (16247), 264 (18315) nm. 1H NMR:
δ ϭ 0.55 (s, 3 H, C7a-Me), 1.25 (s, 6 H), 1.2Ϫ1.8 (m, 18 H), 1.90
(m, 3 H), 2.02 (m, 2 H), 2.16 (m, 1 H), 2.33 (m, 2 H), 2.58 (m, 2
H), 2.83 (m, 1 H), 4.24 (m, 1 H), 4.43 (m, 1 H), 5.00 and 5.33 (s,
2 H each), 6.02 (d, J ϭ 11.4 Hz, 1 H), 6.37 (d, J ϭ 11.4 Hz, 1
H) ppm. 19F NMR (376 MHz): δ ϭ Ϫ76.63 and Ϫ76.67 (2q, 6 F,
overlapping) ppm. LR-ES(ϩ): m/z ϭ 719 [M ϩ TFA Ϫ H], 607
[M ϩ H], 606 [M], 605 [M Ϫ H]. HRMS-ES(ϩ): m/z calcd. for
C32H44F6O3: 629.3036 [M ϩ Na], found 629.3039.
1 H), 6.20 (d, J ϭ 10.7 Hz, 1 H), 8.94 (s, 1 H) ppm. 19F NMR
(376 MHz): δ ϭ Ϫ76.74 (s, 6 F) ppm. LR-ES(ϩ): m/z ϭ 719 [M ϩ
TFA
Ϫ H], 605 [M Ϫ H]. HRMS-ES(ϩ): m/z calcd. for
C32H44F6O4: 629.3036 [M ϩ Na], found 629.3035.
(1R,3R)-5-{2-[(1R,3aS,7aR)-7a-Methyl-1-[(R)-6,6,6-trifluoro-5-
hydroxy-1-(4-hydroxy-4-methylpentyl)-5-(trifluoromethyl)hex-3-
ynyl]octahydroinden-(4E)-ylidene]ethylidene}-cyclohexane-1,3-diol
(7b): According to the procedure given above for the preparation
of 6a, reagent 27b (0.2730 g, 0.478 mmol) in tetrahydrofuran
(2 mL) was deprotonated with a 1.6  solution of butyllithium in
hexane (030 mL) at Ϫ75 °C then allowed to react with a 3:1 mix-
ture of the ketones 26b and 26c (0.1227 g, 0.2056 mmol) in tetra-
hydrofuran (2 mL) to furnish the mixture of the tetra- and trisilyl
ethers 29b which were purified by flash chromatography using 1:39
ethyl acetate/hexane to elute 29b (R3 ϭ TMS) and 29b (R3 ϭ H)
as a mixture. This mixture was deprotected in a 1  solution of
tetrabutylammonium fluoride in tetrahydrofuran (3 mL) within
48 h and purified by flash chromatography (ethyl acetate/hexane,
2:3 and 2:1 ) to give a residue that was dissolved in methyl formate
(5 mL), filtered and the solvents evaporated to yield 7b as a foam,
0.0934 g, 76% total yield for both condensation and deprotection.
[α]D ϭ ϩ43.8 (c ϭ 0.38, methanol). UV: λmax. (ε) ϭ 242 (34229),
(1R,3R)-5-{2-[(1R,3aS,7aR)-7a-Methyl-1-[(S)-6,6,6-trifluoro-5-
hydroxy-1-(4-hydroxy-4-methylpentyl)-5-(trifluoromethyl)hex-3-
ynyl]octahydroinden-(4E)-ylidene]ethylidene}-cyclohexane-1,3-diol
(6b): According to the procedure given above for the preparation
of 6a, reagent 27b (2685 mg, 0.470 mmol) in tetrahydrofuran
(2 mL) was deprotonated with a 1.6  solution of butyllithium in
hexane (0.30 mL) at Ϫ75 °C then allowed to reacted with the ke-
tone 21b (0.1428 g, 0.232 mmol) in tetrahydrofuran (2 mL) to fur-
nish the mixture of the tetra- and tri-silyl ethers 28b and purified
by flash chromatography (0.2141 g). This material was deprotected
in a 1  solution of tetrabutylammonium fluoride in tetrahydrofu-
ran (2 mL) within 48 h and purified by flash chromatography (2:3
and 2:1 ethyl acetat/hexane) to give a residue that was dissolved in
methyl formate (5 mL), filtered and the solvents evaporated to fur-
nish 6b as a foam, 0.1204 g, 87%. [α]D ϭ ϩ42.9 (c ϭ 0.35, meth-
anol). UV: λmax. (ε) ϭ 242 (34077), 251 (40515), 260 (27531), 234
1
251 (40595), 260 (27657), 226 (sh, 13529), 234 nm (sh, 22676). H
NMR ([D6]DMSO): δ ϭ 0.52 (s, 3 H), 1.05 (s, 6 H), 1.1Ϫ1.7 (m,
19 H), 1.7Ϫ2.1 (m, 5 H), 2.28 (m, 2 H), 2.42 (s, 1 H), 2.45 (m, 2
H), 2.75 (m, 1 H), 3.80 (br. s, 1 H), 3.87 (br.s, 1 H), 5.81 (d J ϭ
11.7 Hz, 1 H), 6.08 (d, J ϭ 11.7 Hz, 1 H), 8.42 (s, 1 H) ppm. 19F
NMR (376 MHz): δ ϭ Ϫ76.75 (s, 6 F) ppm. LR-APCI(ϩ): m/z ϭ
577 [M Ϫ OH], 559 [M Ϫ H2O]. HRMS-ES(ϩ): m/z calcd. for
C31H44F6O4: 617.6588 [M ϩ Na], found 617.6586.
5-[2-(4-Hydroxy-4-methylpentyl)-4,4-dimethyl-1,3-dioxolan-2-yl]-2-
methylpentan-2-ol (31): A solution of the diester 30 (3.02 g,
10 mmol) in tetrahydrofuran (90 g) was cooled in an ice bath and
a 3  solution of methylmagnesium bromide in diethyl ether was
added at an internal temperature below 10 °C. The mixture was
stirred at room temperature for 1.5 h, then re-immersed in the ice
bath and saturated ammonium chloride (25 mL) was added drop-
wise below 25 °C. The resulting mixture was equilibrated with
water (25 mL), ethyl acetate (100 mL) and a small amount of 2 
hydrochloric acid to generate a clear aqueous layer. The aqueous
layer was re-extracted with ethyl acetate (3 ϫ 50 mL) and the or-
ganic layers combined and washed with 1:1 brine/water (25 mL)
and brine (10 mL) then dried and the solvents evaporated to leave
an oily residue that was purified by flash chromatography using
ethyl acetate/hexane (1:1) and ethyl acetate as mobile phase to af-
1
(sh, 22354), 223 (sh, 13098) nm. H NMR: δ ϭ 0.55 (s, 3 H), 1.25
(s, 6 H), 1.2Ϫ2.1 (m, 22 H), 2.23 (m, 2 H), 2.35 (m, 2 H), 2.48 (m,
1 H), 2.56 (m, 2 H), 2.77 (m, 2 H), 4.05 (m, 1 H), 4.09 (m, 1 H),
5.86 (d, J ϭ 11 Hz, 1 H), 6.31 (d, J ϭ 11 Hz, 1 H) ppm. 19F NMR
(376 MHz): δ ϭ Ϫ76.63 and Ϫ76.64 (2q, 6 F, overlapping) ppm.
LR-APCI(ϩ): m/z ϭ 577 [M Ϫ OH], 559 [M Ϫ OH Ϫ H2O].
HRMS-ES(ϩ): m/z calcd. for C31H44F6O4: 617.6588 [M ϩ Na],
found 617.6590.
(1R,3S)-5-{2-[(1R,3aS,7aR)-7a-Methyl-1-[(R)-6,6,6-trifluoro-5-
hydroxy-1-(4-hydroxy-4-methylpentyl)-5-(trifluoromethyl)hex-3-
ynyl]octahydroinden-(4E)-ylidene]ethylidene}-4-methylenecyclo-
hexane-1,3-diol (7a): According to the procedure given above for
the preparation of 6a, reagent 27a (0.2333 g, 0.400 mmol) in tetra-
hydrofuran (2 mL) was deprotonated with a 1.6  solution of butyl-
lithium in hexane (0.25 mL) at Ϫ75 °C then allowed to react with
a 3:1 mixture of the ketones 26b and 26c (0.1295 g, 0.2166 mmol)
in tetrahydrofuran (2 mL) to furnish the mixture of the tetra- and
tri-silyl ethers 29a, which were purified by flash chromatography
using ethyl acetate/hexane (1:79) to elute 29a (R3 ϭ TMS) and
ethyl acetate/hexane (1:39) as mobile phase to elute 29a (R3 ϭ H).
Both products were deprotected in a 1  solution of tetrabutylam-
1
ford 31 as a colorless oil, 2.60 g, 95%. H NMR (300 MHz): δ ϭ
1.21 (s, 12 H), 1.47 (m, 8 H), 1.64 (m, 4 H), 3.97 (s, 4 H) ppm. LR-
MS (ϩ)LSIM m/z ϭ 292 [M ϩ NH4], 274 [M], 257 [M Ϫ OH], 239
[M Ϫ OH Ϫ H2O], 213 [M Ϫ OH Ϫ H2O Ϫ C2H4O]. C15H30O4:
calcd. C 65.66, H 11.02; found C 65.27, H 10.96.
2,10-Dihydroxy-2,10-dimethylundecan-6-one (32a): A solution of 31
(2.60 g, 9.48 mmol) in tetrahydrofuran was cooled in an ice bath
monium fluoride in tetrahydrofuran (3 mL) within 27 h and puri- and 2  hydrochloric acid was added. The solution was allowed to
fied by flash chromatography (ethyl acetate/hexane, 2:3 and 2:1) to remain at room temperature for 21 h then sodium hydrogen car-
1712
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 1703Ϫ1713

Formal Desymmetrization of the Diastereotopic Chains in Gemini Calcitriol Derivatives
FULL PAPER
bonate (4 g) was added in portions whilst stirring. Ethyl acetate
[1]
(50 mL) was added and the aqueous layer extracted with ethyl acet-
ate (3 ϫ 25 mL). The combined extracts were washed with brine
(20 mL) then dried (sodium sulfate) and the solvents evaporated to
give crude 32a as a colorless oil (2.13 g). A small portion was puri-
fied by flash chromatography (ethyl acetate/hexane, 1:1 ). 1H NMR
(300 MHz): δ ϭ 1.20 (m, 12 H), 1.43 (m, 4 H), 1.65 (m, 4 H), 2.43
(t, J ϭ 7 Hz, 4 H) ppm.
Y. Bury, M. Herdick, M. R. Uskokovic, C. Carlber, J. Cell.
Biochem. 2001, S36, 179Ϫ190.
J.-I. Hisatake, J. OЈKelly, M. R. Uskokovic, S. Tomoyasu, H.
P. Koeffler, Blood 2001, 97Ϫ8), 2427Ϫ2433.
[2]
[3]
[4]
M. Herdick, C. Carlberg, J. Mol. Biol. 2000, 304(5), 793Ϫ801.
Stereobonds in chemical structures are drawn according to a
proposed convention: H. Maehr, J. Chem. Inf. Comput. Sci.
2002, 42, 894Ϫ902.
M. R.Uskokovic, P. S.Manchand, S. Peleg, A. W. Norman, in
Vitamin D; Chemistry, Biology and Clinical Applications of the
Steroid Hormone (Eds.: A. W. Norman, R. Bouillon, M. Thom-
asset), Proceedings of the 10th workshop on vitamin D; Stras-
bourg, France, May 24Ϫ29, 1997, p. 19Ϫ21.
[5]
[6]
2,10-Dimethyl-2,10-bis(trimethylsilanyloxy)undecan-6-one (32b): 1-
(Trimethylsilyl)imidazole (2 mL, 13.6 mmol) was added to a solu-
tion of 32a (1.10 g) in dichloromethane (20 mL). The colorless mix-
ture was allowed to remain at room temperature overnight then
diluted with water (10 mL), stirred for 10 min and further admixed
with dichloromethane (40 mL). The aqueous layer was re-extracted
with dichloromethane (10 mL) and the combined extracts were
washed with water (50 mL) then dried (sodium sulfate) and the
solvents evaporated to leave a 32b as a colorless oil (1.74 g) that
was flash chromatographed (ethyl acetate/hexane, 1:19). LR(ϩ)
LSIMS: m/z ϭ 375 [M ϩ H], 285 [M Ϫ OTMS].
A. W. Norman, P. S. Manchand, M. R. Uskokovic, W. H. Oka-
mura, J. A. Takeuchi, J. E. Bishop, J.-I. Hisatake, H. P. Koeffler,
S. Peleg, J. Med. Chem. 2000, 43(14), 2719Ϫ2730.
M. Herdick, Y. Bury, M. Quack, M. R. Uskokovic, P. Polly, C.
Carlberg, Mol. Pharmacology 2000, 57(6), 1206Ϫ1217.
G. Tocchini-Valentini, N. Rochel, J. W. Wurtz, A. Mitschler, D.
Moras, PNAS 2001, 98, 5491Ϫ5496.
[7]
[8]
[9]
D. Moras, 12th Workshop on Vitamin D, July 6Ϫ10, 2003,
Maastricht, The Netherlands, Abstracts, p. 3.
(1S,5R)-1,5-Bis(tert-butyldimethylsilanyloxy)-2-methylene-3-{7-
methyl-3-[4-methyl-4-(trimethylsilanyloxy)pentyl]-7-(trimethyl-
silanyloxy)oct-2-en-(Z)-ylidene}cyclohexane (33): According to the
procedure given for the preparation of 6a, reagent 27a (0.609 g,
1.04 mmol) in tetrahydrofuran (20 mL) was deprotonated with a
1.6  solution of butyllithium in hexane (0.6 mL) then allowed to
react with 32b (0.375 g, 1 mmol) in tetrahydrofuran (3.5 mL) to
furnish 33 which was purified by flash chromatography using ethyl
acetate/hexane (1:19) as mobile phase to yield pure 33 as a colorless
oil, 0.38 g, 51.4%. 1H NMR (300 MHz): δ ϭ 0.06Ϫ0.10 (m, 30 H),
0.87 and 0.88 (s, 9 H each), 1.20 (s, 12 H), 1.44 (m, 14 H), 1.82 (m,
2 H), 2.13 (m, 2 H), 2.20 (m, 1 H), 2.42 (m, 1 H), 4.18 (m, 1 H),
4.39 (m, 1 H), 4.88 and 5.21 (s, 1 H each), 6.14 (s, 2 H) ppm.
[10]
M. R. Uskokovic, G. P. Studzinski, S. G. Reddy, in The 16-ene
Vitamin D analogs, in Vitamin D (Eds.: D. Feldmann, F. H.
Glorieux, J. W. Pike), p. 1045Ϫ1070, Academic Press, 1997.
M. R. Uskokovic, A. W. Norman, P. S. Manchand, G. P. Stud-
zinski, M. J. Campbell, H. P. Koeffler, A. Takeuchi, M.-L. Siu-
Caldera, D. S. Rao, S. G. Reddy, Steroids 2001, 66, 463Ϫ471.
S. Christakos, et al., work in progress.
[11]
[12]
[13]
P. S. Manchand, M. R. Uskokovic, U.S. Patent (1999), US
6008209, 13 pp.
[14]
[15]
[16]
P. S. Manchand, M. R. Uskokovic, WO 9849138 (1998) 35 pp.
P. S. Manchand, M. R. Uskokovic, WO 9912894 (1999) 60 pp.
Y. C. Li, Lecture, Eleventh Annual Providence Symposium on
Vitamin D, Abstract #9, September 24Ϫ26, 2003, Seekonk,
Massachussetts.
M. F. Holick, unpublished results.
M. J. Calverley, Steroids 2001, 66, 249Ϫ255.
A. P. Krapcho, J. F. Weimaster, J. M. Eldridge, E. G. E. Jahngen
Jr., A. J. Lovey, W. P. Stephens, J. Org. Chem. 1978, 43,
138Ϫ147.
P. Callant, L. DЈHaenens, M. Vandewalle, Synthetic Communi-
cations 1984, 14, 155Ϫ161.
S. Ohira, Synthetic Communications 1989, 19, 561Ϫ564.
A. S. Pilcher, P. DeShong, J. Org. Chem. 1993, 58, 5130Ϫ5134.
We prepared fluorosilicic acid by adding, in very small por-
tions, silica gel G to an ice-cooled, commercially available 48%
hydrofluoric acid contained in a polyethylene bottle. The solu-
tion was ready for use as soon as permanent sediment of silica
gel was present. Subsequent deprotection experiments were
conducted in regular glassware.
B. Lythgoe, Chem. Soc. Rev. 1981, 10, 449Ϫ475.
G. D. Zhu, W. H. Okamura, Chem. Rev. 1995, 95 1877Ϫ1952.
H. Dai, G. H. Posner, Synthesis 1994, 1383Ϫ1398.
E. G. Baggiolini, J. A. Iacobelli, B. M. Hennessy, A. D. Batcho,
J. F. Sereno, M. R. Uskokovic, J. Org. Chem. 1986, 51,
3098Ϫ3108.
(1R,3S)-5-[7-Hydroxy-3-(4-hydroxy-4-methylpentyl)-7-methyloct-2-
en-(Z)-ylidene]-4-methylenecyclohexane-1,3-diol (5): Compound 33
obtained above was dissolved in tetrahydrofuran (2 mL), a 1 
solution of tetrabutylammonium fluoride in tetrahydrofuran
(5 mL) was added and kept at room temperature for 24 h, then
water (10 mL) and ethyl acetate (75 mL) were added. The aqueous
phase was re-extracted with ethyl acetate (3 ϫ 25 mL). The com-
bined extracts were washed with water (20 mL) and brine (25 mL),
dried (sodium sulfate) and the solvents evaporated. The residue
was flash-chromatographed (ethyl acetate/hexane, 1:1 ) to give 5 as
colorless foam, 154 mg. [α]D ϭ ϩ24.5 (c ϭ 0.6, ethanol). 1H NMR
(300 MHz): δ ϭ 1.21 (s, 12 H), 1.4Ϫ1.6 (m, 14 H), 1.98 (m, 2 H),
2.08 (m, 2 H), 2.31 (m, 1 H), 2.61 (m, 1 H), 4.22 (m, 1 H), 4.43
(m, 1 H), 4.99 and 5.33 (s, 1 H each), 6.16 (d, J ϭ 11.5 Hz, 1 H),
6.27 (d, J ϭ 11.5 Hz, 1 H). LR(ϩ) LSIMS: m/z ϭ 473 [M ϩ
TGLY], 366 [M], 349 [M Ϫ OH], 331 [M Ϫ OH Ϫ H2O], 313 [M
Ϫ OH Ϫ 2H2O]. HR-FAB m/z calcd. for C22H38O4: 389.2660 [M
ϩ Na], found 389.2668. C22H38O4: calcd. C 72.09, H 10.45; found
C 71.67, H 10.54.
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
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2923Ϫ2925.
Acknowledgments
We are grateful to Mr. Vance Bell for mass spectra, Mr. Gino Sasso
for NMR spectra and Prof. Christopher Frampton for a crystal
structure analysis.
Received November 11, 2003
Eur. J. Org. Chem. 2004, 1703Ϫ1713
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1713