Stereoselective Synthesis of Four Calcitriol Lactone Diastereomers at C23 and C25

Article abstract of DOI:10.1021/acs.joc.9b00403

(23S,25R)-Calcitriol lactone is a major metabolite of vitamin D₃, but its synthesis has been far less well investigated than that of 1α,25(OH)₂ vitamin D₃, the active form of vitamin D₃, even though the lactone

Full text of DOI:10.1021/acs.joc.9b00403

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Article
Stereoselective Synthesis of Four Calcitriol
Lactone Diastereomers at C23 and C25
Akiko Nagata, Yusuke Akagi, Shadi Sedghi Masoud, Masahiro Yamanaka,
Atsushi Kittaka, Motonari Uesugi, Minami Odagi, and Kazuo Nagasawa
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00403 • Publication Date (Web): 15 Apr 2019
Downloaded from http://pubs.acs.org on April 15, 2019
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Stereoselective Synthesis of Four Calcitriol Lactone Diastereomers at C23 and C25
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Akiko Nagata,[a] Yusuke Akagi,[a] Shadi Sedghi Masoud,[a] Masahiro Yamanaka,[b] Atsushi Kittaka,[c]
Motonari Uesugi,[d,e,f] Minami Odagi,[a] Kazuo Nagasawa[a]*
[a]Department of Biotechnology and Life Science, Graduate Scholl of Technology, Tokyo University
of Agriculture and Technology, 2-24-16, Naka-cho, Koganei city, 184-8588, Tokyo Japan
[b]Department of Chemistry, Faculty of Science, Rikkyo University, 3-34-1 Nishi-Ikebukuro,
Toshima-ku, 171-8501, Tokyo Japan
[c]Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo 173-8605,
Japan.
[d]Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Uji, Kyoto 611-
0011, Japan
[e]Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
[f]CREST, AMED
Abstract
(23S,25R)-Calcitriol lactone is a major metabolite of vitamin D3, but its synthesis has been far less
well investigated than that of 1,25(OH)2 vitamin D3, the active form of vitamin D3, even though the
lactone is present at a significant level in serum. This paper describes stereoselective syntheses of
natural calcitriol lactone and its diastereomers at C23 and C25.
This work features (i)
diastereoselective Reformatsky-type crotylation of aldehyde 25 in the presence of chiral ligand L2 to
construct the stereochemistry at C23, and (ii) diastereoselective epoxidation of homoallylic-allylic
alcohol 31 to control the stereochemistry at C25. These key reactions allowed us to synthesize CD
ring synthon 30 with all four stereoisomers, and these were further converted into calcitriol lactones
3a-d by reaction with ene-yne-type A-rings 33 in the presence of palladium (0) catalyst.
Keywords: Calcitriol lactone, Diastereoselective Reformatosky crotylation, Sharpless epoxidation,
palladium-catalyzed coupling,
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Graphical Abstract
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Introduction
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Vitamin D3 (VD3, 1a) is a steroidal hormone that is metabolized into a variety of congeners,
including 1,25-dihydroxyvitamin D3 (1,25(OH)2D3, 1b), which is well known as the active form of
VD3 (1a, Figure 1),1 playing central roles in controlling serum calcium level, bone formation,
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induction of cellular differentiation, and regulation of immunity.2
Many synthetic studies of
1,25(OH)2D3 (1b) and its derivatives have been reported,3 and some synthetic analogs of 1b are used
to treat bone diseases, hypoparathyroidism, and psoriasis.2b,2g,4 The metabolite 1,25(OH)2D3 (1b)
is further oxidized by CYP24A1 at C24 or C23 in the side chain, leading to calcitroic acid (2) and
calcitriol lactone (3a) as end metabolites, respectively. Calcitroic acid (2) is immediately excreted
in urine, and its concentration in serum is very low (<5 pg/mL); this is consistent with the fact that no
significant biological function of 2 has ever been reported.5 On the other hand, calcitriol lactone (3a)
is present at a significant concentration in serum (ca 4 ng/mL in mice),5a though little attention has yet
been paid to its potential biological activities. In 1985, Ishizuka and co-workers determined the
absolute stereochemistry of natural 3a at C23 and C25 as (23S,25R),6 and this led them to explore the
biological functions of 3a as well as its stereoisomers at C23 and C25. In their preliminary studies,
natural (23S,25R)-3a bound weakly to VDR (chick interstinal cytosol receptor) (0.17% compared to
the natural VDR ligand 1,25(OH)2D3 (1b)), and showed weak VDR-antagonistic activity, causing
suppression of calcium concentration in serum, and bone resorption and formation. Interestingly, the
stereoisomers (23S,25S)-3b and (23R,25R)-3d have higher VDR-binding affinity than 3a (7.90% and
2.27%), and they induce an increment of calcium level in serum, in contrast to 3a. However, further
studies have been hampered by the limited availability of lactone 3a and its stereoisomers. Thus,
efficient stereoselective syntheses of the calcitriol lactone 3a and its stereoisomers 3b-d are required.
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Figure 1. Structures of vitamin D3 (1a) and its metabolites 1b, 2 and 3.
So far, calcitriol lactone (23S,25R)-3a has been synthesized by four groups.7 Hatakeyama’s and
Yamada’s groups controlled the stereochemistry at C23 by applying stereoselective iodolactonization
of (25R)-carboxylic acids 5 and 10, which were obtained by Ireland-Claisen rearrangement reaction
of (22S)-lactate 4 and Julia olefination reaction with chiral (R)-sulfone 8 derived from (R)-citramalic
acid, respectively (Scheme 1A,B).7c,d The stereoselectivities of iodolactonization were found to be
75:25 and 80:20 from 5 and 10, respectively. On the other hand, Wovkulich and Johnson constructed
the stereocenter at C23 prior to C25.7a Wovkulich constructed the stereochemistry at C23 by
diastereoselective ene-reaction of 12 and methyl-2-bromoacrylate (13) in the presence of
ethylaluminum dichloride as a Lewis acid (Scheme 1C). In this reaction, the stereochemistry at C23
was controlled in a ratio of 87:13, and the lactone 17 was synthesized by further alkylation reaction of
chiral epoxide 15 with cyanohydrin 16, although no diastereoselectivity was observed at C25.
Johnson and co-workers constructed the stereochemistry at C23 in a ratio of 98.5:1.5 by applying
Hosomi-Sakurai reaction with chiral acetal 18 and allylsilane 19 (Scheme 1D).7b
The
stereochemistry at C25 was controlled by iodocyclization of 21 to give 22 with high
diastereoselectivity, and 22 was further converted into CD-ring structure 24 for lactone 3a via chiral
triol 23. Despite these pioneering synthetic studies, however, there is still a need for facile and
practical syntheses of all four stereoisomers at C23 and C25 with high selectivities to afford sufficient
material for larger-scale studies of their biological activities.7e
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Scheme 1. Previous synthetic approaches to the CD ring of calcitriol lactone 3a
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Our group has recently reported a synthesis of C-ring synthon 30a for calcitriol lactone 3a
(Scheme 1).8 In this synthesis, Reformatsky-type crotylation was applied to the aldehyde 25, and
hydration to the lactone with exomethylene 28 was carried out under Mukaiyama’s conditions to give
29. Although the present route was efficient in terms of chemical yields, the stereoselectivity of those
two key steps, i.e., Reformatsky-type crotylation and Mukaiyama-type hydration, was poor
(diastereoselectivities for C23 and C25 were 55:45 and 50:50, respectively), and therefore we set out
to improve the synthesis of 3a, especially in terms of the stereoselectivities. In this paper, we report
a stereoselective synthesis of CD-ring 30a by applying asymmetric Reformatsky-type crotylation in
the presence of a chiral ligand, and diastereoselective epoxidation of homoallylic-allylic alcohols, for
which stereoselective epoxidation has been little explored so far. Finally, the natural form of
calcitriol lactone 3a and its three unnatural diastereoisomers 3b-d were all synthesized.
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Scheme 2. Our previous approach to the CD-ring of calcitriol lactone 30a.
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Results and Discussion
Based upon our previous results for the synthesis of 30 (Scheme 2), we planned a new synthetic
strategy as depicted in Scheme 3. In this synthesis, we aimed to achieve control of the
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stereochemistry at C23 by applying an enantioselective version of the Reformatsky-type crotylation
in the presence of a chiral ligand. Furthermore, we expected to control the stereochemistry at C25 in
30a via regioselective reductive opening of the corresponding epoxide 32, which would be generated
by utilizing the homoallylic and allylic natures of alcohol 31.
Although many examples of
stereoselective epoxidation of allylic or homoallylic alcohols have been reported,9 epoxidation with
homoallylic-allylic type alcohols has been less explored, and the stereoselectivity for particular
substrates remains unclear.
Scheme 3. Synthetic plan for the stereoselective synthesis of 3a.
1. Diastereoselective crotylation of aldehyde 25
For construction of the stereochemistry at C23, crotylation of aldehyde 25 with ethyl 2-
(bromomethyl)acrylate (26) was investigated utilizing zinc (0) or chromium (II) in the presence of
chiral ligands L110 and L211 (Table 1). We firstly examined zinc(0)-mediated enantioselective
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Reformatsky-type reaction in the presence of (R)-L1 derived from proline by Soai et al.,10 but no
reaction took place (entry 1). Next, we examined chromium (II) chloride-catalyzed asymmetric
crotylation in the presence of the carbazole-derived chiral ligands (R)-L2 and (S)-L2 developed by
Nakada.11a This afforded the corresponding homoallylic alcohols 27a and 27b in low yields with low
diastereoselectivities (entries 3 and 4). Recently, Zhang and co-workers have reported a modification
of Nakada’s protocol.11b They added CoPC (cobalt (II) phthalocyanine), LiCl, and Cp2ZrCl2 as
activating/dissociating agents for the substrates, thereby improving the yields and selectivities for the
corresponding Reformatsky reaction products. Based upon the conditions developed by Zhang and
co-workers, (23S)-homoallylic alcohol 27a was obtained in 51% yield with a 20:1 diastereomer ratio
(entry 5).12 In contrast, the diastereomer ratio of 27a and 27b was changed to 1:7 by using (S)-L2
(entry 6). These two diastereomers of 27a and 27b were easily separated by silica gel column
chromatography.
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Table 1. Stereoselective crotylation of 25 in the presence of chiral ligands L1 and L2.
Entry
Conditions
Yield (%)[a]
dr. (27a:27b)[b]
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6
Zn, (R)-L1, NH4Cl, THF/H2O, 90 °C
N.R.
N.R.
14
---
CrCl2, Mn, TMSCl, DIPEA, THF, rt
---
CrCl2, (R)-L2, Mn, TMSCl, DIPEA, THF, rt
CrCl2, (S)-L2, Mn, TMSCl, DIPEA, THF, rt
CrCl2, (R)-L2, Mn, CoPC, LiCl, Cp2ZrCl2, PS, THF, rt
CrCl2, (S)-L2, Mn, CoPC, LiCl, Cp2ZrCl2, PS, THF, rt
1:1
1:2.5
20:1
1:7
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67
1
[a]Yield of mixture of 27a and 27b. [b]Determined by H NMR analysis. CoPC = Cobalt (II)
phthalocyanine, DIPEA = diisopropylethylamine, PS = Proton Sponge, THF = tetrahydrofuran.
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2. Diastereoselective epoxidation of homoallylic-allylic alcohol 31
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With homoallylic alcohol 27a in hand, diastereoselective epoxidation was examined under the
Sharpless conditions,13 i.e., tert-butylhydroperoxide with 10 mol% of vanadium oxide acetylacetonate
in toluene at 0 °C. Under these conditions, the corresponding epoxide 34 was obtained in 99% yield,
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but without diastereselectivity (Scheme 4).
Thus, we decided to explore the epoxidation of
homoallylic-allylic type alcohols 31a-c and bis-TBS ether 31d. Homoallylic-allylic alcohol 31a was
obtained by reduction of the ester in 27a with DIBAL-H in 81% yield. Mono-TBS ether 31b was
synthesized from 27a by reaction with TBSOTf in the presence of 2,6-lutidine followed by reduction
of the ester with DIBAL-H in 93% yield from 27a. Mono- and bis-TBS ethers 31c and 31d were
synthesized by reaction with 10 equivalents of TBSCl, imidazole and DMAP at 0 °C in 59% and 40%
yield, respectively (Scheme 4).
Scheme 4. Epoxidation of homoallylic alcohol 27a, and preparation of homoallylic-allylic alcohols
31a-d.
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With homoallylic-allylic type alcohols 31a-c and bis-TBS ether 31d in hand, epoxidation reaction
was examined with (i) TBHP-VO(acac)2 and (ii) m-CPBA for every substrate; the results are
summarized in Table 2. (23S,25R)-32a was obtained from 31a in 99% yield with 10:1 dr with TBHP
in the presence of 10 mol% of VO(acac)2. On the other hand, (23S,25S)-32b was obtained in 82%
yield from 31b by reaction with m-CPBA, with a diastereomer ratio of 10:1.
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Table 2. Epoxidation of homoallylic-allylic alcohols 31a-d.
[a]
TBHP, VO(acac)2
m-CPBA[b]
Yield (%)[c] dr. (25R:25S)[d]
Entry
Substrate
Product (R1, R2)
Yield (%)[c] dr. (25R:25S)[d]
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31b
31c
31d
32a (H, H)
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1:10
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1:1
32b (TBS, H)
32c (H, TBS)
32d (TBS, TBS)
[a]Condition A: VO(acac)2 (10 mol%), TBHP (6.0 equiv.), CH2Cl2 (0.1 M), 0 °C. [b]Condition B: m-
CPBA (3.0 equiv.), CH2Cl2 (0.05 M), 0 °C. [c]Yield of mixture of two diastereomer. [d]Determined
by 1H NMR analysis.
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To understand the outcomes of these highly stereoselective epoxidations of 31a and 31b, DFT
calculations were carried out using the allylic diol models from which the CD-ring structure had been
removed to reduce computation time (Figure 2,3).14 In the case of 31a, based on previous studies on
the TBHP-VO(acac)2-mediated epoxidation,15 transition state (TS) modeling and exploration were
conducted, and we identified two stable TSs, TSOH_R and TSOH_S, leading to the 25R- and 25S-
isomers of 32a, respectively. Both TSOH_R and TSOH_S were obtained through ligand exchange of
the oxovanadium species with the hydroxyl group at C26. TSOH_R is 1.1 kcal/mol more stable than
TSOH_S, in qualitatively good agreement with the experimental results. The hydroxyl group at C23
forms hydrogen bonds with the oxovanadium species in TSOH_R (2.05, 2.00, and 2.48 Å) and TSOH_S
(1.92 Å), and the former plays a key role in stabilizing TSOH_R. Epoxidation of 31a would proceed
via more stable TSOH_R to afford the 25R isomer of 32a predominantly (Figure 2).16
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Figure 2. DFT calculation of homoallylic-allylic diol 31a for epoxidation with TBHP-VO(acac)2.
The relative electronic energies are shown in parentheses.
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In the case of 31b, the hydroxyl group at C26 acts as a directing group for the incoming m-CPBA
in both TSOSi_R and TSOSi_S, leading to the (25R)- and (25S)-isomers of 32b, respectively. In contrast
to TSOH, TSOSi_R is 1.7 kcal/mol less stable than TSOSi_S, in qualitatively good agreement with the
experimental results. Whereas m-CPBA approaches from the Re-face of the olefin to avoid steric
repulsion with the sterically demanding siloxy group in TSOSi_R, m-CPBA forms hydrogen bonds with
the hydroxyl group at C26 as well as the acidic hydrogen atom at C23 in TSOSi_S. In addition, the
acidic hydrogen atom at C26 interacts with the siloxy group. These multiple hydrogen bonds
stabilize TSOSi_S (2.22, 2.38, and 2.55 Å) more than TSOSi_R (2.19 and 2.66 Å), thus affording the
(25S)-isomer of 32b predominantly (Figure 3).
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Figure 3. DFT calculation for epoxidation of allylic alcohol 31b with m-CPBA. The relative
electronic energies are shown in parentheses.
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3. Synthesis of (23S,25R)-calcitriol lactone 3a and its stereoisomers 3b-d
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Synthesis of (23S,25R)-calcitriol lactone 3a was conducted from (23S,25R)-epoxy diol 32a
(Scheme 5). Reduction of the epoxide in (23S,25R)-32a with LiAlH4 followed by oxidation of the
resulting triol 35a with TPAP gave the lactone.17 Then, deprotection of the TBS ether was carried
out with TsOH to give lactone 36a, and the diastereomers at C25 were separated at this stage by silica
gel column chromatography. The secondary alcohol in 36a was oxidized to ketone with TPAP, and
the tertiary alcohol at C25 was protected as the TES ether by reaction with triethylsilyl chloride in the
presence of imidazole. Wittig reaction of the resulting ketone with bromomethyltriphenylphospnium
bromide was conducted to give CD-ring synthon 30a bearing bromomethylene in 14% yield from
(23S,25R)-32a in 7 steps.18a Then, coupling reaction of the CD-ring 30a with ene-yne type A-ring
synthon 3318b was carried out in the presence of Pd(PPh3)4 and triethylamine, followed by deprotection
of TES ether to give (23S,25R)-calcitriol lactone 3a in 68% yield. Synthesis of (23S,25S)-calcitriol
lactone 3b was carried out as follows. Reduction of (23S,25S)-32b with LiAlH4 followed by
selective deprotection of TBS ether at C23 with TBAF gave 35b, which was subjected to lactone
formation and bromoolefination as described for the synthesis of 30a to generate CD-ring synthon 30b
from (23S,25S)-32b. Then, the CD-ring 30b was coupled with A-ring 33to give (23S,25S)-calcitriol
lactone 3b in 56% yield.
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Scheme 5. Synthesis of (23S,25R)-calcitriol lactone 3a and (23S,25S)-3b.
For the synthesis of (23R,25S)-calcitriol lactone 3c and (23R,25R)-calcitriol lactone 3d, (23R,25R)-
epoxy 32a and (23R,25S)-epoxy 32b were synthesized from (23R)-homoallylic alcohol 27b (Scheme
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6). After reduction of the ester group in 27b, the resulting homoallylic-allylic alcohol was subjected
to epoxidation under condition A described in Table 2, and the corresponding epoxy alcohol
(23R,25S)-32a was obtained in 58% yield with 10:1 diastereoselectivity. On the other hand, epoxy
alcohol (23R,25R)-32b was obtained with high diastereoselectivity (dr > 20:1) by reaction with (i)
TBSOTf and 2,6-lutidine, (ii) DIBAL-H, and (iii) m-CPBA. These epoxy alcohols 32a and 32b were
converted into CD-ring lactones 36c and 36d, and syntheses of (23R,25S)-calcitriol lactone 3c and
(23R,25R)-calcitriol lactone 3d, respectively, were completed by reaction with A-ring 33 followed by
deprotection of silyl ethers with HF-triethyl amine complex.
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Scheme 6. Synthesis of (23R,23S)- and (23R,25R)-calcitriol lactones 3c and 3d.
Conclusion
We have achieved stereoselective syntheses of calcitriol lactone (23S,25R)-3a and its
diastereomers at C23 and C25. This synthesis features (i) diastereoselective Reformatsky-type
crotylation of aldehyde 25 in the presence of chiral ligand L2 to construct the stereochemistry at C23,
and (ii) diastereoselective epoxidation of homoallylic-allylic alcohol 31a,b to control the
streochemistry at C25, affording CD ring synthon 30a-d stereoselectively.
Stereoselective
epoxidation of alcohol 31 bearing both homoallylic- and allylic-moieties have been little studied
so far, but DFT calculations afforded insights into the stereochemistry outcome. The CD-ring
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synthons were converted into calcitriol lactone diastereomers 3a-d by reaction with ene-yne-type A-
ring 33 in the presence of palladium (0) catalyst.
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Experimental Sections
General Experimental Methods. Unless otherwise stated, reactions were performed under an
argon atmosphere using freshly dried solvents.
All reactions were monitored by thin-layer
chromatography using Merck silica gel 60 F254 pre-coated plates (0.25 mm) and were visualized by
UV, p-anisaldehyde staining. Flash column chromatography was performed under pressurization
using silica gel (particle size 40-100 m) purchased from Cica. Optical rotations were measured on
a JASCO P-2200 polarimeter. 1H and 13C NMR spectra were recorded on JEOL JNM-AL300 (300
MHz) and JEOL JNM-ECX 400 (400 MHz). The spectra are referenced internally according to
residual solvent signals of CDCl3 (1H NMR;  = 7.26 ppm, 13C NMR;  = 77.0 ppm). Data for 1H
NMR are recorded as follows: chemical shift (, ppm), multiplicity (s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; br, broad), coupling constant (Hz), integration. Data for 13C NMR are reported
in terms of chemical shift (, ppm). Mass spectra were recorded on JEOL JMS-T100X spectrometer
with ESI-MS mode using methanol as solvent.
Crotylation under Zhang’s condition using 1,8-bis((R)-4-isopropyl-4,5-
dihydrooxazol-2-yl)-9H-carbazole (R)-L2. To a mixture of anhydrous chromium (II) chloride
(3.9 mg, 0.0317 mmol), 1,8-bis((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)-9H-carbazole ((R)-L2, 15.6
mg, 0.04 mmol,) and Proton sponge (10.1 mg, 0.047 mmol) was added THF (1.0 mL) under argon
atmosphere. The resulting mixture was stirred vigorously at room temperature for 2.5 h before it was
transferred into a vessel charged with Phthalocyanine cobalt (II) (1.4 mg, 0.0025 mmol), ZrCp2Cl2
(38.0 mg, 0.130 mmol), LiCl (7.1 mg, 0.168 mmol) and Manganese powder (25.0 mg). Then ethyl
2-(bromomethyl)acrylate (26) (30 L, 0.218 mmol) and aldehyde 25 (34.6 mg, 0.102 mmol) in
THF solution were added in succession. The resulting suspension was stirred at room temperature
for 4 h. The reaction mixture was diluted with ethyl acetate and the resulting suspension was filtered
over a pad of silica gel using ethyl acetate as eluent. Volatiles were evaporated in vacuo, and the
residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate = 30:1) to give
27a (23.5 mg, 51%, dr. = 20:1), 28 (16.3 mg, 39%). Spectral data for 27a: []25D= +43.6 (c 1.2,
CHCl3); 1H NMR (300 MHz, CDCl3)  6.26 (d, J = 1.7 Hz, 1H), 5.66 (s, 1H), 4.21 (qd, J = 7.2, 2.4
Hz, 2H), 3.98 (d, J = 2.4 Hz, 1H), 3.83 (brs, 1H), 2.69 (dd, J = 14.1, 1.7 Hz, 1H), 2.15 (dd, J = 14.1,
9.3 Hz, 1H), 1.30 (t, J = 7.2 Hz, 3H), 0.97 (d, J = 6.5 Hz, 3H), 0.92 (s, 3H), 0.88 (s, 9H), 0.00 (s, 3H),
-0.01 (s, 3H) ppm; 13C{1H} NMR (75 MHz, CDCl3)  167.3, 137.6, 127.3, 69.2, 68.7, 60.6, 57.3, 52.8,
43.6, 42.0, 40.5, 39.7, 34.2, 33.1, 27.3, 25.6, 22.8, 18.9, 17.7, 17.4, 13.9, 13.5, -5.0, -5.4 ppm; HRMS
(ESI) m/z calcd for C26H48O4SiNa: 475.3220 [M+Na]+; found: 475.3212.
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Crotylation under Zhang’s condition using 1,8-bis((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)-
9H-carbazole (S)-L2. To a mixture of anhydrous chromium (II) chloride (4.2 mg, 0.034 mmol),
1,8-bis((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)-9H-carbazole ((S)-L2, 11.7 mg, 0.030 mmol,) and
Proton sponge (6.4 mg ,0.030mmol) was added THF (0.8 mL) under an argon atmosphere. The
mixture was stirred vigorously at room temperature for 4 h before it was transferred into a vessel
charged with Phthalocyanine cobalt (II) (2.9 mg, 0.005 mmol), ZrCp2Cl2 (43.8 mg, 0.15 mmol), LiCl
(6.4 mg, 0.15 mmol) and Manganese powder (22.0 mg). Then 2-ethyl (bromomethyl)acrylate (26)
(27.6 L, 0.20 mmol) and aldehyde 25 (33.9 mg, 0.1 mmol) in THF solution were added in succession.
The resulting suspension was stirred at room temperature for 4 h. The reaction mixture was diluted
with ethyl acetate and the resulting suspension was filtered over a pad of silica gel using ethyl acetate
as eluent. Volatiles were evaporated in vacuo. The residue was purified by column chromatography
on silica gel (n-hexane/ethyl acetate = 30:1) to give 27b (30.4 mg, 67%, dr. = 1:7), 28 (3.4 mg 9%).
Spectral data for 27b: []21D = +44.6 (c 1.5, CHCl3); 1H NMR (300 MHz, CDCl3)  6.22 (s, 1H), 5.63
(s, 1H), 4.20 (qd, J = 7.2, 1.4 Hz, 2H), 3.97 (s, 1H), 3.88-3.78 (m, 1H), 2.48 (dd, J = 13.7, 3.8 Hz, 1H),
2.34 (dd, J = 13.7, 8.2 Hz, 1H), 1.29 (t, J = 7.2 Hz, 3H), 0.92 (s, 3H), 0.91 (d, J = 5.1 Hz, 3H), 0.87
(s, 9H), -0.01 (s, 3H), -0.02 (s, 3H) ppm; 13C{1H} NMR (75 MHz, CDCl3)  167.4, 137.7, 127.1, 69.3,
67.3, 60.6, 57.3, 52.9, 43.4, 42.1, 41.4, 40.6, 34.3, 31.9, 27.3, 25.6, 22.9, 18.4, 17.8, 17.5, 14.0, 13.6,
-5.0, -5.3 ppm; HRMS (ESI) m/z calcd for C26H48O4SiNa: 475.3220 [M+Na]+; found: 475.3243.
(4S,6R)-6-((1R,3R,4S,7R)-4-((tert-butyldimethylsilyl)oxy)-7-methyloctahydro-1H-
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inden-1-yl)-2-methyleneheptane-1,4-diol (31a). To a solution of -hydroxyester 27a (505.8 mg,
1.117 mol) in CH2Cl2 (5.6 mL) were added DIBAL-H (1 M solution in toluene, 4.5 mL, 4.47 mmol)
in sequence at -78 °C, and the reaction mixture was stirred at the same temperature for 30 min. To
the reaction mixture was added 2-propanol (3.2 mL) at -78 °C, and the resultant mixture was
warmed to room temperature. Then, H2O and silica gel were added, and allowed to stir for 1 h. The
slurry was filtered through a pad of Celite, and the filtrates were concentrated in vacuo. The residue
was purified by column chromatography on silica gel (n-hexane/ethyl acetate; 5:1) to give
homoallylic-allylic alcohol 31a (367.2 mg, 80%). Spectral data for 31a: []23 = +53.6 (c 0.7,
D
CHCl3); 1H NMR (300 MHz, CDCl3) δ 5.10 (s, 1H), 4.93 (s, 1H), 4.03 (s, 2H), 3.96 (s, 1H), 3.77-3.79
(m, 1H), 2.38 (d, J = 13.8 Hz, 1H), 0.98-2.03 (m, 15H), 0.86-0.94 (m, 12H), -0.02 (d, J = 4.5 Hz, 6H);
13C{1H} NMR (75 MHz, CDCl3) δ 146.0, 114.4, 69.4, 69.3, 66.1, 57.4, 52.9, 43.6, 42.1, 41.4, 40.7,
34.3, 33.3, 27.5, 25.7, 22.9, 19.0, 17.9, 17.6, 13.7, -4.9, -5.2 ppm; HRMS (ESI) m/z calcd for
C24H46O3Si1Na: 433.3114 [M+Na]+; found: 433.3124.
(4S,6R)-4-((tert-butyldimethylsilyl)oxy)-6-((1R,3R,4S,7R)-4-((tert-
butyldimethylsilyl)oxy)-7-methyloctahydro-1H-inden-1-yl)-2-methyleneheptan-1-ol
(31b).
To a solution of -hydroxyester 27a(101.5 mg, 0.224 mmol) in CH2Cl2 (0.44 mL) was added 2,6-
lutidine (0.13 mL, 1.11 mmol) and TBSOTf (0.13 mL, 0.566 mmol) at 0 °C, and the reaction mixture
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was stirred at the same temperature for 2.5 h. To the reaction mixture was added saturated NaHCO3
aq., and the aqueous layer was extracted with CH2Cl2 three times. The combined organic layer was
washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (n-hexane/ethyl acetate = 100:1) to give TBS-protected -
hydroxyester (115.7 mg, 91%). To a solution of TBS-protected -hydroxyester (115.7 mg, 0.204
mmol) in CH2Cl2 (1.0 mL) were added DIBAL-H (1 M solution in toluene, 0.44 mL, 0.44 mmol) in
sequence at -78 °C, and the reaction mixture was stirred at the same temperature for 2h. To the reaction
mixture was added MeOH (0.31 mL) at -78 °C, the resultant mixture was warmed to room temperature.
Then, saturated Rochelle salt aq. (0.53 mL) was added, and allowed to stir for 2.5 h. The aqueous
layer was extracted with CHCl3 for three times. The combined organic layer was washed with
saturated Rochelle salt and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (n-hexane/ethyl acetate = 10:1) to give mono-
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TBS-protected homoallylic-allylic alcohol 31b(97.3 mg, 91%). Spectral data for 31b:[]23
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+32.1 (c 0.6, CHCl3); H NMR (300 MHz, CDCl3) δ 5.11 (s, 1H), 4.91 (s, 1H), 3.91-4.04 (m, 4H),
3.26 (s, 1H), 2.20-2.39 (m, 2H), 1.00-1.97 (m, 15H), 0.88-0.92 (m, 24H), -0.01-0.08 (m, 12H); 13C
{1H} NMR (100 MHz, CDCl3) δ 145.85, 114.5, 70.7, 69.4, 66.7, 57.8, 53.0, 43.0, 42.2, 40.8, 40.5,
34.4, 32.8, 27.3, 25.9, 25.8, 23.0, 18.8, 18.1, 18.0, 17.7, 13.7, -4.5, -4.6, -4.8, -5.2 ppm; HRMS (ESI)
m/z calcd for C30H60O3Si2Na: 547.3979 [M+Na]+; found: 547.3995.
(4S,6R)-6-((1R,3R,4S,7R)-4-((tert-butyldimethylsilyl)oxy)-7-methyloctahydro-1H-
inden-1-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)hept-1-en-4-ol (31c) and (S)-5-((R)-2-
((1R,3R,4S,7R)-4-((tert-butyldimethylsilyl)oxy)-7-methyloctahydro-1H-inden-1-yl)propyl)-
2,2,3,3,10,10,11,11-octamethyl-7-methylene-4,9-dioxa-3,10-disiladodecane (31d). To a solution
of homoallylic-allylic alcohol 31a (50.6 mg, 0.123 mmol) in DMF (1.2 mL) was added imidazole
(163.0 mg, 2.39 mmol), TBSCl (186.0 mg, 1.23 mmol) and DMAP (58.6 mg, 0.48 mmol) at 0 °C, and
the resulting mixture was stirred at the same temperature for 1.5 h. To the reaction mixture was
quenched with H2O, and the resulting mixture was extracted with Et2O three times. The combined
organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (n-hexane/ethyl acetate = 100:1 to 20:1) to give
(23S)-mono-TBS-protected homoallylic-allylic alcohol 31c(30.9 mg, 59%) and (23S)-bis-TBS-
ether 31d(30.2 mg, 39%). Spectral data for 31c: []22D = +44.7 (c 0.9, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 5.14 (s, 1H), 4.95 (s, 1H), 4.10 (s, 2H), 3.99 (s, 1H), 3.78 (s, 1H), 2.66 (s, 1H), 2.43 (d, J =
13.8 Hz, 1H), 1.05-2.00 (m, 28H), 0.90 (d, J = 9.6 Hz, 24H), 0.09 (d, J = 2.1 Hz, 9H), -0.00 (d, J =
4.1 Hz, 6H); 13C{1H} NMR (75 MHz, CDCl3) δ 145.8, 111.2, 70.2, 69.4, 66.2, 57.7, 53.1, 44.1, 42.2,
40.8, 40.4, 34.4, 33.14, 27.4, 25.9, 25.8, 23.0, 19.3, 18.4, 18.1, 18.0, 17.7, 13.7, -4.3, -4.5, -4.8, -5.2, -
5.4 ppm; HRMS (ESI) m/z calcd for C30H60O3Si2Na: 547.3979 [M+Na]+; found: 547.3974.; Spectral
data for 31d: []21D = +34.6 (c 1.9, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 5.12 (d, J = 1.7 Hz, 1H),
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4.86 (s, 1H), 3.99 (s, 1H), 3.84 (d, J = 8.9 Hz, 1H), 2.26 (dd, J = 13.9, 3.6 Hz, 1H), 0.99-2.05 (m,
16H), 0.87-0.93 (m, 33H), -0.01-0.06 (m, 21H); 13C{1H} NMR (75 MHz, CDCl3) δ 145.7, 113.8, 69.6,
68.6, 66.5, 57.5, 52.9, 43.5, 42.3, 41.7, 40.7, 34.5, 27.6, 25.9, 25.8, 25.6, 23.0, 19.2, 18.5, 18.3, 18.0,
17.7, 13.7, -1.2, -3.6, -4.8, -5.2, -5.4 ppm; HRMS (ESI): m/z calcd for C36H74O3Si3Na: 661.4843
[M+Na]+; found: 661.4805.
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Epoxidation of 31a using TBHP and VO(acac)2. To a solution of homoallylic-allylic alcohol
31a(367.2 mg, 0.894 mmol) in CH2Cl2 (8.9 mL) was added VO(acac)2 (23.6 mg, 0.090mmol) and
TBHP (6.94 M solution in CH2Cl2, 0.77 mL, 5.34 mmol) at 0 °C, and the reaction mixture was stirred
at the same temperature for 1 h. The reaction mixture was quenched with 10% Na2S2O3 solution at
0 °C. Afetr separated the organic layer, the aqueous layer was extracted with CH2Cl2 three times.
The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo.
The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate = 4:1) to
give epoxide (23S,25R)-32a(376.7 mg, 99%, dr. = 10:1). Spectral data for (23S,25R)-32a: []22
D
= +57.1 (c 2.15, CHCl3); 1H NMR (400 MHz, CDCl3) δ 3.98 (s, 1H), 3.72 (d, J = 7.8 Hz, 2H), 2.86-
2.92 (m, 1H), 2.71 (d, J = 4.6 Hz, 1H), 1.94 (d, J = 12.4 Hz, 1H), 1.01-1.86 (m, 17H), 0.88-0.94 (m,
15H), -0.01 (d, J = 6.0 Hz, 6H); 13C{1H} NMR (75 MHz, CDCl3) δ 69.3, 68.4, 64.7, 59.1, 57.3, 53.0,
50.8, 44.5, 42.2, 40.7, 39.5, 34.4, 33.3, 27.6, 25.8, 23.0, 19.2, 18.0, 17.6, 13.7, -4.8, -5.2 ppm; HRMS
(ESI) m/z calcd for C24H46O4SiNa: 449.3063 [M+Na]+; found: 449.3103.
Epoxidation of 31b using m-CPBA. To a solution of mono-TBS-protected homoallylic-allylic
alcohol 31b (25.0 mg 0.0476 mmol) in CH2Cl2 (0.95 mL) was added m-CPBA (24.8 mg, 0.144 mmol)
at 0 °C, and the resulting mixture was stirred at the same temperature for 1.5 h. To the reaction
mixture was added Ca(OH)2, and the resulting mixture was filtered through a pad of Celite, and the
filtrates were concentrated in vacuo. The residue was purified by column chromatography on silica
gel (n-hexane/ethyl acetate = 10:1) to give epoxide (23S,25S)-32b (21.3 mg, 83%, dr 1:10). Spectral
data for (23S,25S)-32b: []23D = +53.3 (c 0.42, CHCl3); 1H NMR (300 MHz, CDCl3)  3.96 (d, J =
10.7 Hz, 2H), 3.68 (s, 2H), 2.88 (d, J = 4.8 Hz, 1H), 2.81 (d, J = 4.8 Hz, 0.1H), 2.76 (d, J = 4.8 Hz,
1H), 2.65 (d, J = 4.8 Hz, 0.1H) 2.20 (d, J = 14.4 Hz, 1H), 0.99-1.85 (m, 17H), 0.88-0.89 (m, 24H),
0.14-0.18 (m, 0.6H), 0.08 (d, J = 2.8 Hz, 6H), -0.00 (d, J = 3.4 Hz, 6H); 13C{1H} NMR (75 MHz,
CDCl3) δ 69.3, 68.5, 64.4, 58.0, 57.6, 53.0, 52.2, 44.0, 42.2, 40.8, 39.5, 34.4, 33.1, 27.5, 25.8, 22.9,
18.8, 18.0, 17.9, 17.6, 13.8, -4.2, -4.6, -4.8, -5.2 ppm; HRMS (ESI) m/z calcd for C30H60O4Si2Na:
563.3928 [M+Na]+; found: 563.3890.
(2R,4S,6R)-6-((1R,3R,4S,7R)-4-((tert-butyldimethylsilyl)oxy)-7-methyloctahydro-1H-
inden-1-yl)-2-methylheptane-1,2,4-triol (35a). To a solution of epoxide (23S,25R)-32a (12.9 mg,
0.0302 mmol) in THF (0.6 mL) was added LiAlH4 (4.0 mg, 0.11 mmol) at 0 °C, and the resulting
mixture was stirred at room temperature for 2.5 h. To the reaction mixture was added H2O (4.0 L),
15% NaOH aq (4.0 L) and H2O (12.0 L) at 0 °C, and the resulting mixture was stirred at same
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temperature for 30 min, and dried over MgSO4. The mixture was filtered through a pad of Celite, and
the filtrates were concentrated in vacuo. The residue was purified by column chromatography on silica
gel (n-hexane/ethyl acetate = 1:1) to give (23S,25R)-triol 35a (10.3 mg, 80%, dr. = 10:1). Spectral
data for 35a: []23D = +50.8 (c 1.11, CHCl3); 1H NMR (300 MHz, CDCl3) δ 3.98-4.06 (m, 2H), 3.67
(d, J = 10.7 Hz, 1H), 3.43-3.47 (m, 1H), 1.02-1.97 (m, 23H), 0.88-0.93 (m, 15H), -0.00 (d, J = 4.1 Hz,
6H); 13C{1H} NMR (75 MHz, CDCl3) δ 69.4, 66.2, 57.4, 53.0, 45.2, 42.2, 40.7, 34.4, 33.2, 29.7, 27.6,
26.1, 25.8, 23.0, 19.1, 18.0, 17.6, 14.1, 13.8, -4.8, -5.2 ppm; HRMS (ESI) m/z calcd for C24H48O4SiNa:
451.3211 [M+Na]+; found: 451.3238.
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(3R,5S)-3-hydroxy-5-((R)-2-((1R,3R,4S,7R)-4-hydroxy-7-methyloctahydro-1H-inden-1-
yl)propyl)-3-methyldihydrofuran-2(3H)-one (36a). To a mixture of dried MS 4A (13 mg) in
acetonitrile (0.5 mL) was added NMO (60.9 mg, 0.520 mmol) at room temperature, and the reaction
mixture was stirred at the same temperature for 1.5 h. TPAP (1.8 mg, 0.0051 mmol) and a solution
of (23S,25R)-triol 35a (10.3 mg, 0.0240 mmol) in CH2Cl2 (0.3 mL) was added to the reaction mixture
at room temperature, and the resultant was stirred at the same temperature for 2.5 h. The reaction
mixture was directly subjected to silica gel column chromatography (n-hexane/ethyl acetate = 4:1) to
give -hydroxylactone (6.2 mg, 56%). To a solution of -hydroxylactone (326.9 mg, 0.770 mmol)
in MeOH (18 mL) was added p-TsOH·H2O (616.8 mg, 3.24 mmol) at room temperature, and the
reaction mixture was stirred at the same temperature for 23 h. To the reaction mixture was quenched
with saturated NaHCO3 aq., then the resulting mixture was extracted with ethyl acetate three times.
The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo.
The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate = 1:1) to
give (23S,25R)- -hydroxylactone 36a (128.8 mg, 54%) and (23S,25S)--hydroxylactone 36b (23.3
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mg, 10%), respectively. Spectral data for (23S,25R)-36a: []22D= +37.3 (c 0.9, CHCl3); H NMR
(300 MHz, CDCl3) δ 4.38-4.48 (m, 1H), 4.08 (d, J = 2.8 Hz, 1H), 2.72 (s, 1H), 2.38 (dd, J = 12.7, 5.5
Hz, 1H), 1.05-2.05 (m, 20H), 0.99 (d, J = 6.5 Hz, 3H), 0.94 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3)
δ 179.8, 76.4, 73.3, 69.1, 56.5, 52.4, 43.3, 41.8, 41.4, 40.2, 33.4, 32.9, 27.4, 24.2, 22.4, 18.9, 17.3,
13.4 ppm; HRMS (ESI) m/z calcd for C18H30O4Na: 333.2042 [M+Na]+; found: 333.2022.
(3R,5S)-5-((R)-2-((1R,3R,7R,E)-4-(bromomethylene)-7-methyloctahydro-1H-inden-1-
yl)propyl)-3-methyl-3-((triethylsilyl)oxy)dihydrofuran-2(3H)-one (30a). To a solution of (23S,
25R)-36a (220.0 mg, 0.344 mmol) in CH2Cl2 (14.0 mL) was added NMO (340.2 mg, 2.90 mmol) and
MS 4A (367.9 mg) at 0 °C, and the reaction mixture was stirred at the same temperature for 30 min.
To the reaction mixture was added TPAP (30.9 mg, 0.088 mmol) at 0 °C, and the resulting mixture
was stirred at room temperature for 30 min. The reaction mixture was directly subjected to silica gel
column chromatography (n-hexane/ethyl acetate = 1:1) to give ketone (233.9 mg, 99%). To a
solution of the ketone (233.9 mg) in DMF (7.0 mL) was added imidazole (248.0 mg, 3.64 mmol),
DMAP (21.0 mg, 0.17 mmol) and TESCl (0.50 mL, 2.99 mmol) at room temperature, and the resulting
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mixture was stirred at the same temperature for 2.5 h. The reaction mixture was quenched with H2O,
and the aqueous layer was extracted with Et2O three times. The combined organic layer was washed
with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (n-hexane/ethyl acetate = 5:1) to give TES-protected ketone.
To a suspension of BrCH2PPh3Br (1.80 g, 4.13 mmol) in THF (5.2 mL) was added NaHMDS (1.9 M
in THF solution, 1.9 mL, 3.61 mmol) at 0 °C. After stirring for 30 min, a solution of TES-protected
ketone (302.1 mg, 0.715 mmol) in THF (2.0 mL) was added at the same temperature, and the resulting
mixture was stirred at the same temperature for 2.5 h. The reaction mixture was quenched with
saturated NH4Cl aq., and the aqueous layer was extracted with Et2O three times. The combined
organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate = 50:1 to 10:1)
to give (23S,25R)-bromo olefin 30a (182.6 mg, 51%, 3 steps). Spectral data for 30a: []22D= +48.1
(c 1.2, CHCl3); 1H NMR (300 MHz, CDCl3)  5.63 (s, 1H), 4.33 (dt, J = 15.1, 6.2 Hz, 1H), 2.83-2.94
(m, 1H), 2.33 (dd, J = 12.4, 5.5 Hz, 1H), 1.91-1.99 (m, 4H), 1.15-1.67 (m, 13H), 0.91-1.01 (m, 13H),
0.56-0.71 (m, 9H) ppm; 13C{1H} NMR (75 MHz, CDCl3) δ 177.8, 144.7, 97.5, 75.4, 75.1, 55.7, 45.5,
45.4, 41.8, 39.7, 33.7, 30.9, 27.8, 25.0, 22.4, 21.9, 19.2, 11.7, 6.8, 6.0 ppm; HRMS (ESI) m/z calcd for
C25H43BrO3SiNa: 521.2063 [M+Na]+; found: 521.2073.
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(3R,5S)-5-((R)-2-((1R,3S,7R,E)-4-((Z)-2-((3S,5R)-3,5-dihydroxy-2-
methylenecyclohexylidene)ethylidene)-7-methyloctahydro-1H-inden-1-yl)propyl)-3-hydroxy-
3-methyldihydrofuran-2(3H)-one: (23S,25R)-Calcitriol lactone (3a). To a solution of (23S,25R)-
bromo olefin 30a (39.7 mg, 0.079 mmol) and ene-yne 33 (43.7 mg, 0.119 mmol) and Et3N (0.8 mL)
in toluene (0.8 mL) was added Pd(PPh3)4 (25.9 mg, 0.022 mmol) at room temperature, then the
resulting mixture was heated at 90 °C. After stirring for 1 h, the reaction mixture was filtered through
a pad of Celite, and the filtrates were concentrated in vacuo. The residue was chromatographed on
silica gel (n-hexane/ethyl acetate = 50:1) to give coupling product (50.1 mg). To a solution of the
coupling product (50.1 mg, 0.064 mmol) in THF (2.1 mL) was added 3HF·Et3N (0.2 mL, 1.23 mmol)
at 0 °C. After stirring for 48 h, the reaction was quenched with saturated NaHCO3 aq., and the
resulting mixture was extracted with ethyl acetate three times. The combined organic layer was
washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was
chromatographed on silica gel (n-hexane/ethyl acetate = 1:4) to give (23S,25R)-calcitriol lactone 3a
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(23.9 mg, 68%, 2 steps). Spectral data for 3a: []23D= +13.2 (c 2.4, CHCl3); H NMR (300 MHz,
CDCl3)  6.34 (d, J = 11.0 Hz, 1H), 6.00 (d, J = 11.0 Hz, 1H), 5.30 (s, 1H), 4.98 (d, J = 12.7 Hz, 1H),
4.36-4.46 (m, 3H), 4.20 (t, J = 3.3 Hz, 1H), 3.64 (br, 1H), 2.78-2.86 (m, 1H), 2.55 (d, J = 10.7 Hz,
1H), 2.16-2.38 (m, 5H), 1.85-2.03 (m, 3H), 1.57-1.68 (m, 4H), 1.38-1.51 (m, 8H), 1.11-1.35 (m, 3H),
1.00 (d, J = 6.2 Hz, 3H), 0.50 (d, J = 16.9 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 179.7, 147.4,
142.4, 133.3, 124.6, 117.3, 111.8, 73.3, 70.6, 66.7, 56.4, 56.1, 45.8, 45.0, 43.3, 42.6, 41.6, 40.3, 33.7,
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28.9, 27.9, 24.2, 23.4, 22.2, 19.2, 14.1, 11.9 ppm; HRMS (ESI) m/z calcd for C27H40O5Na: 467.2773
[M+Na]+; found: 467.2757.
(2S,4S,6R)-6-((1R,3R,4S,7R)-4-((tert-butyldimethylsilyl)oxy)-7-methyloctahydro-1H-
inden-1-yl)-2-methylheptane-1,2,4-triol (35b). To a solution of (23S,25S)-epoxide 32b (21.3mg,
0.0394 mmol) in THF (0.8 mL) was added LiAlH4 (8.0 mg, 0.21 mmol) at 0 °C, and the mixture was
stirred at room temperature for 3.5 h. To the reaction mixture was added H2O (8.0 L), 15% NaOH
aq (8.0 L) and H2O (24.0 L) at 0 °C, and the resulting mixture was stirred at the same temperature
for 30 min, and then added MgSO4. The mixture was filtered through a pad of Celite, and the filtrates
were concentrated in vacuo. The residue was purified by column chromatography on silica gel (n-
hexane/ethyl acetate = 5:1) to give TBS-protected triol (15.1 mg, 71%). To a solution TBS-protected
triol (15.1 mg, 0.0278 mmol) in THF (0.6 mL) was added TBAF (1 M solution in THF, 42 L, 0.042
mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 20 h. The reaction
mixture was quenched with brine, and the resulting mixture was extracted with ethyl acetate for three
times. The combined organic layer was washed with brine, dried over MgSO4, filtered, and
concentrated in vacuo. The residue was purified by column chromatography on silica gel (n-
hexane/ethyl acetate = 3:1 to 1:1) to give (23S,25S)-triol 35b (15.2 mg, 71%, dr. = 1:10, 2 steps).
Spectral data for 35b: []22D = -10.0 (c 0.04, CHCl3); 1H NMR (300 MHz, CDCl3) δ 4.16 (d, J = 7.9
Hz, 1H), 3.98 (s, 1H), 3.43 (s, 2H), 1.03-1.97 (m, 15H), 0.88-0.95 (m, 15H), -0.00 (d, J = 4.1 Hz, 6H);
13C{1H} NMR (75 MHz, CDCl3) δ 73.1, 70.9, 69.4, 67.7, 57.4, 53.0, 45.1, 43.1, 42.2, 40.8, 34.4, 33.2,
29.7, 27.6, 25.8, 23.9, 23.1, 19.1, 18.0, 13.8, -4.8, -5.2 ppm; HRMS (ESI) m/z calcd for C24H48O4SiNa:
451.3211 [M+Na]+; found: 451.3220.
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(3S,5S)-3-hydroxy-5-((R)-2-((1R,3R,4S,7R)-4-hydroxy-7-methyloctahydro-1H-inden-1-
yl)propyl)-3-methyldihydrofuran-2(3H)-one (36b). To a mixture of dried MS 4A (17.5 mg) in
acetonitrile (0.7 mL) were added NMO (41.0 mg, 0.350 mmol) at room temperature, and the mixture
was stirred at the same temperature for 1.5 h. To the resultant was added TPAP (2.5 mg, 0.0071
mmol) and a solution of triol 35b(15.2 mg, 0.0355 mmol) in CH2Cl2 (0.3 mL) at room temperature,
and the mixture was stirred at the same temperature for 1 h. The reaction mixture was purified by
column chromatography on silica gel (n-hexane/ethyl acetate = 4:1) to give (23S,25S)-TBS-protected
-hydroxylactone (3.4 mg, 21%). To a solution of (23S,25S)-TBS-protected -hydroxylactone (3.4
mg, 0.008 mmol) in MeOH (0.5 mL) was added p-TsOH·H2O (5.8 mg, 0.030 mmol) at room
temperature, and the mixture was stirred at the same temperature for 87 h. The reaction mixture was
quenched with saturated NaHCO3 aq., and the resulting mixture was extracted with ethyl acetate three
times. The combined organic layer was washed with brine, dried over MgSO4, filtered, and
concentrated in vacuo. The residue was purified by column chromatography on silica gel (n-
hexane/ethyl acetate = 1:1) to give (23S,25S)--hydroxylactone 36b(2.6 mg, 99%). Spectral
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data for 36b: []22D= +3.6 (c 0.6, CHCl3); H NMR (300 MHz, CDCl3) δ 4.67-4.76 (m, 1H), 4.07-
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4.15 (m, 1H), 2.37-2.52 (m, 2H), 1.05-2.08 (m, 27H), 0.99 (d, J = 6.2 Hz, 3H), 0.94 (s, 3H); 13C{1H}
NMR (75 MHz, CDCl3) δ 178.2, 73.4, 69.1, 56.5, 52.4, 43.4, 41.8, 41.1, 40.2, 33.3, 32.9, 27.4, 23.8,
22.4, 18.8, 17.3, 13.3 ppm; HRMS (ESI) m/z calcd for C18H30O4Na: 333.2042 [M+Na]+; found:
333.2049.
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(3S,5S)-5-((R)-2-((1R,3R,7R,E)-4-(bromomethylene)-7-methyloctahydro-1H-inden-1-
yl)propyl)-3-methyl-3-((triethylsilyl)oxy)dihydrofuran-2(3H)-one (30b). To a solution of
(23S,25S)--hydroxylactone 36b (196.2 mg, 0.632 mmol) in CH2Cl2 (14.0 mL) was added NMO
(299.6 mg, 2.56 mmol), and MS 4A (341.1 mg) at 0 °C, and the reaction mixture was stirred at the
same temperature for 10 min. To the mixture was added TPAP (30.9 mg, 0.088 mmol) at 0 °C, and
the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was directly
subjected to silica gel column chromatography (n-hexane/ethyl acetate = 1:1) to give ketone (173.6
mg, 89%). To a solution of ketone (173.6 mg) in DMF (7.0 mL) was added imidazole (197.6 mg,
2.90 mmol), DMAP (19.0 mg, 0.16 mmol) and TESCl (0.38 mL, 2.27 mmol) at room temperature,
and the mixture was stirred at the same temperature for 2 h. The reaction mixture was quenched with
H2O, and the resulting mixture was extracted with Et2O three times. The combined organic layer
was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (n-hexane/ethyl acetate = 5:1) to give TES-protected
ketone. To a suspension of BrCH2PPh3Br (1.24 g, 2.85 mmol) in THF (4.0 mL) was added NaHMDS
(1.9 M in THF solution, 1.2 mL, 2.28 mmol) at 0 °C. After stirring for 30 min, a solution of TES-
protected ketone (181.9 mg, 0.43 mmol) in THF (1.0 mL) was added at the same temperature, and the
mixture was stirred for 1.5 h. To the reaction mixture was added saturated NH4Cl aq, and the mixture
was extracted with Et2O three times. The combined organic layer was washed with brine, dried over
MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on
silica gel (n-hexane/ethyl acetate; 50:1 to 10:1) to give (23S,25S)-bromo olefin 30b (108.8 mg, 3 steps
39%). Spectral data for 30b: []25D= +45.7 (c 0.9, CHCl3); 1H NMR (300 MHz, CDCl3) δ 5.62 (s,
1H), 4.58-4.67 (m, 1H), 2.82-2.89 (m, 1H), 2.34 (dd, J = 13.2, 5.0 Hz, 1H), 1.16-1.68 (m, 13H), 0.80-
1.01 (m, 13H), 0.55-0.68 ppm (m, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 176.6, 144.7, 97.5, 75.4,
55.7, 55.7, 46.4, 45.4, 41.0, 39.7, 33.8, 30.9, 27.8, 23.6, 22.4, 21.9, 19.1, 11.7, 6.7, 5.8 ppm; HRMS
(ESI) m/z calcd for C25H43BrO3SiNa: 521.2063 [M+Na]+; found: 521.2100.
(3S,5R)-5-((R)-2-((1R,3S,7R,E)-4-((Z)-2-((3S,5R)-3,5-dihydroxy-2-
methylenecyclohexylidene)ethylidene)-7-methyloctahydro-1H-inden-1-yl)propyl)-3-hydroxy-
3-methyldihydrofuran-2(3H)-one: (23S,25S)-Calcitriol lactone (3b). To a solution of (23S,25S)-
bromo olefin 30b (51.4 mg, 0.10 mmol) and ene-yne 33 (53.8 mg, 0.146 mmol) in toluene (1.0 mL)
and Et3N (1.0 mL) was added Pd(PPh3)4 (23.9 mg, 0.021 mmol) at room temperature, then the reaction
mixture was heated at 90 °C. After stirring for 1 h, the reaction mixture was filtered through a pad
of Celite and the filtrates were concentrated in vacuo. The residue was chromatographed on silica
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gel (n-hexane/ethyl acetate = 100:1) to give coupling product (62.6 mg). To a solution of the
coupling product (62.6 mg, 0.080 mmol) in THF (2.1 mL) was added 3HF·Et3N (0.26 mL, 1.60 mmol)
at 0 °C. After stirring for 36 h, the reaction was quenched with saturated NaHCO3 aq., and the
aqueous layer was extracted with ethyl acetate three times. The combined organic layer was washed
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with brine, dried over MgSO4, filtered, and concentrated in vacuo.
The residue was
chromatographed on silica gel (n-hexane/ethyl acetate = 1:4) to give (23S,25S)-calcitriol lactone 3b
(25.6 mg, 2 steps 56%). Spectral data for 3b: []23D= +4.5 (c 2.6, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 6.35 (d, J = 11.0 Hz, 1H), 6.00 (d, J = 11.4 Hz, 1H), 5.31 (s, 1H), 4.98 (s, 1H), 4.66-4.75 (m, 1H),
4.40-4.44 (m, 1H), 4.21 (d, J = 3.1 Hz, 1H), 3.10 (s, 1H), 2.78-2.83 (m, 1H), 2.57 (d, J = 10.7 Hz, 1H),
2.44 (dd, J = 13.4, 5.5 Hz, 1H), 2.25-2.33 (m, 1H), 1.82-2.13 (m, 10H), 1.14-1.73 (m, 12H), 1.01 (d,
J = 6.2 Hz, 3H), 0.54 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 178.1, 147.5, 142.6, 133.1, 124.8,
117.2, 112.9, 111.8, 73.5, 70.7, 66.8, 60.4, 56.4, 56.2, 45.8, 45.1, 43.3, 42.7, 41.3, 40.3, 33.9, 29.0,
27.9, 24.1, 23.5, 22.2, 21.0, 19.2, 14.2, 11.9 ppm; HRMS (ESI) m/z calcd for C27H40O5Na: 467.2773
[M+Na]+; found: 467.2763.
(2R,4R)-4-((1R,3R,4S,7R)-4-((tert-butyldimethylsilyl)oxy)-7-methyloctahydro-1H-
inden-1-yl)-1-((S)-2-(hydroxymethyl)oxiran-2-yl)pentan-2-ol (32a).
To a solution of -
hydroxyester 27b (109.0 mg, 0.241 mmol) in CH2Cl2 (1.2 mL) was added DIBAL-H (1 M solution in
toluene, 1.0 mL, 1.0 mmol) at -78 °C, and the mixture was stirred at the same temperature for 4 h.
To the reaction mixture was quenched with MeOH (0.31 mL) at -78 °C. The resultant mixture was
warmed to room temperature, and then, saturated Rochelle salt solution (0.53 mL) was added. After
stirring for 2.5 h, the resulting mixture was extracted with CHCl3 three times. The combined organic
layer was washed with saturated Rochelle salt solution and brine, dried over MgSO4, filtered, and
concentrated in vacuo. The residue was purified by column chromatography on silica gel (n-
hexane/ethyl acetate = 5:1) to give homoallylic-allylic alcohol (78.7 mg, 80%). To a solution of
homoallylic-allylic alcohol (76.8 mg, 0.187 mmol) in CH2Cl2 (1.9 mL) was added VO(acac)2 (5.0 mg,
0.019mmol) and TBHP (6.94 M solution in CH2Cl2, 0.16 mL, 1.12 mmol) at 0 °C, and the mixture
was stirred at the room temperature for 17 h. To the reaction mixture was quenched with 10%
Na2S2O3 solution at 0 °C, and the resulting mixture was extracted with CH2Cl2 three times. The
combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo.
The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate = 6:1 to 2:1)
to give epoxide (23R,25S)-32a (58.0 mg, 73%, dr. = 10:1). Spectral data for (23R,25S)-32a: []22
D
= +22.6 (c 0.50, CHCl3); 1H NMR (300 MHz, CDCl3) δ 3.98 (m, 2H), 3.82-3.58 (m, 2H), 2.85 (d, J =
4.5 Hz, 1H), 2.73 (d, J = 4.5 Hz, 1H), 2.00-0.96 (m, 13H), 0.96-0.83 (m, 15H), 0.01-0.04 (m, 6H);
13C{1H} NMR (75 MHz, CDCl3) δ 69.4, 66.5, 64.7, 58.9, 57.3, 53.0, 50.7, 44.3, 42.2, 41.3, 40.7, 34.4,
31.8, 27.5, 25.8, 23.0, 18.5, 18.0, 17.6, 13.8, -4.8, -5.2 ppm; HRMS (ESI) m/z calcd for C24H46O4SiNa:
449.3063 [M+Na]+; found 449.3040.
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(2S,4R,6R)-6-((1R,3R,4S,7R)-4-((tert-butyldimethylsilyl)oxy)-7-methyloctahydro-1H-
inden-1-yl)-2-methylheptane-1,2,4-triol (35c). To a solution of epoxide (23R,25S)-32a (58.0 mg,
0.136 mmol) in THF (2.8 mL) was added LiAlH4 (23.9 mg, 0.63 mmol) at 0 °C, and the mixture was
stirred at the room temperature for 4 h. To the reaction mixture was added H2O (24.0 L), 15%
NaOH aq (24.0 L) and H2O (72.0 L) at 0 °C, and the resulting mixture was stirred at same
temperature for 30 min, and dried over MgSO4. The mixture was filtered through a pad of Celite and
the filtrates were concentrated in vacuo. The residue was purified by column chromatography on
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silica gel (n-hexane/ethyl acetate = 4:1 to 2:1) to give (23R,25S)-triol 35c (41.8 mg, 70%, dr. = 10:1).
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Spectral data for 35c: []24 = +11.1 (c 0.37, CHCl3); H NMR (300 MHz, CDCl3) δ 3.99 (m, 2H),
D
3.68 (d, J = 11.0 Hz, 1H), 3.43 (d, J = 6.5 Hz, 1H), 2.03-1.20 (m, 13H), 0.97-0.85 (m, 15H), 0.05-0.03
(m, 6H); 13C{1H} NMR (75 MHz, CDCl3) δ 86.1, 75.9, 69.4, 57.3, 53.1, 49.0, 48.6, 42.0, 37.6, 31.5,
25.8, 23.6, 18.0, 11.1, 9.1, -4.8, -5.2 ppm; HRMS (ESI) m/z calcd for C24H48O4SiNa: 451.3211
[M+Na]+; found: 451.3258.
(3S,5R)-3-hydroxy-5-((R)-2-((1R,3R,4S,7R)-4-hydroxy-7-methyloctahydro-1H-inden-1-
yl)propyl)-3-methyldihydrofuran-2(3H)-one (36c). To a mixture of dried MS 4A (20 mg) in
acetonitrile (0.4 mL) was added NMO (46.9 mg, 0.520 mmol) at room temperature, and the mixture
was stirred at the same temperature for 1.5 h. To the mixture was added TPAP (1.8 mg, 0.0051
mmol) and a solution of (23R,25S)-triol (17.2 mg, 0.0240 mmol) in CH2Cl2 (0.2 mL), and the mixture
was stirred at the same temperature for 2.5 h. The reaction mixture was directly subjected to silica
gel column chromatography (n-hexane/ethyl acetate = 1:1) to give (23R,25S)-TBS-protected -
hydroxylacton (10.3 mg, 61%). To a solution of (23R,25S)-TBS-protected -hydroxylactone (24.2
mg, 0.0570 mmol) in MeOH (1.2 mL) was added p-TsOH·H2O (38.0 mg, 0.20 mmol) at room
temperature, and the mixture was stirred at the same temperature for 18 h. The reaction mixture was
quenched with saturated NaHCO3 aq., and the resulting mixture was extracted with ethyl acetate three
times. The combined organic layer was washed with brine, dried over MgSO4, filtered, and
concentrated in vacuo. The residue was purified by column chromatography on silica gel (n-
hexane/ethyl acetate = 1:1) to give (23R,25S)--hydroxylactone 36c (10.3 mg, 58%, 2 steps) and
(23R,25R)- -hydroxylactone 36d (1.5 mg, 8%, 2 steps), respectively. Spectral data for (23R,25S)-
36c: []23D = +48.4 (c 0.9, CHCl3); 1H NMR (300 MHz, CDCl3) δ 4.42-4.50 (m, 1H), 4.09 (d, J = 7.2
Hz, 1H), 2.69 (s, 1H), 2.35 (dd, J = 12.7, 5.5 Hz, 1H), 1.04-2.08 (m, 24H), 0.97 (t, J = 6.5 Hz, 6H);
13C{1H} NMR (75 MHz, CDCl3) δ 179.8, 74.9, 73.4, 69.1, 56.7, 52.5, 43.6, 42.2, 41.9, 40.3, 33.3,
32.3, 27.1, 24.2, 22.4, 18.3, 17.3, 13.4 ppm; HRMS (ESI) m/z calcd for C18H30O4Na: 333.2042
[M+Na]+; found: 333.2060.
(3S,5R)-5-((R)-2-((1R,3R,7R,E)-4-(bromomethylene)-7-methyloctahydro-1H-inden-1-
yl)propyl)-3-methyl-3-((triethylsilyl)oxy)dihydrofuran-2(3H)-one (30c).
(23R,23S)-Bromo
olefin 30c was synthesized by same procedures discribed scheme 5 in 39% yield from (23R,25S)--
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hydroxylactone 36c (90.7 mg, 0.292 mmol). Spectral data for 30c: []22D= +112.5 (c 0.4, CHCl3);
1H NMR (300 MHz, CDCl3) δ 5.64 (s, 1H), 4.36-4.41 (m, 1H), 2.84-2.91 (m, 1H), 2.24-2.35 (m, 1H),
1.13-2.02 (m, 20H), 0.96 (q, J = 8.0 Hz, 12H), 0.57-0.72 (m, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ
178.0, 144.8, 97.6, 75.2, 74.0, 56.0, 55.8, 45.8, 45.5, 42.6, 39.8, 32.9, 30.9, 27.5, 25.1, 22.5, 22.0, 18.6,
11.8, 6.9, 6.1 ppm; HRMS (ESI) m/z calcd for C25H43BrO3SiNa: 521.2063 [M+Na]+; found: 521.2059.
(3S,5R)-5-((R)-2-((1R,3S,7R,E)-4-((Z)-2-((3S,5R)-3,5-dihydroxy-2-
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methylenecyclohexylidene)ethylidene)-7-methyloctahydro-1H-inden-1-yl)propyl)-3-hydroxy-
3-methyldihydrofuran-2(3H)-one: (23R,23S)-Calcitriol lactone (3c). (23R,23S)-
Calcitriol lactone 3c was synthesized bysame procedures discribed scheme 5 in
70% yield from (23R,25R)-bromo olefin 30c (50.7mg, 0.102mmol). Spectral data for
(23R,23S)-calcitriol lactone 3c: []22D = +36.1 (c 1.6, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 6.35 (d, J = 11.0 Hz, 1H), 6.01 (d, J = 11.0 Hz,
1H), 5.31 (s, 1H), 4.97 (s, 1H), 4.41 (q, J = 3.7 Hz, 2H), 4.21 (d,
J = 3.1 Hz, 1H), 2.79-2.83 (m, 1H), 1.48-2.58 (m, 20H), 1.22-1.34
(m, 6H), 0.99 (d, J = 6.2 Hz, 3H), 0.55 (s, 3H); 13C{1H} NMR (75 MHz,
CDCl3) δ 179.8, 147.5, 142.5, 133.3, 124.6, 117.3, 111.8, 75.0, 73.5,
70.6, 66.7, 56.7, 56.3, 45.9, 45.1, 43.6, 42.6, 42.4, 40.4, 33.1,
28.9, 27.6, 24.3, 23.5, 22.2, 18.7, 12.0 ppm; HRMS (ESI) m/z calcd
for C27H40O5Na 467.2773 [M+Na]+; found 467.2764.
((R)-2-((2R,4R)-2-((tert-butyldimethylsilyl)oxy)-4-((1R,3R,4S,7R)-4-((tert-
butyldimethylsilyl)oxy)-7-methyloctahydro-1H-inden-1-yl)pentyl)oxiran-2-yl)methanol
(23R,25R)-32b. To a solution of -hydroxyester 27b(100.0 mg, 0.221 mmol) in CH2Cl2 (0.44 mL)
was added 2,6-lutidine (0.13 mL, 1.11 mmol) and TBSOTf (0.13 mL, 0.566 mmol) at 0 °C, and the
mixture was stirred at the same temperature for 3.5 h. The reaction mixture was quenched with
saturated NaHCO3 aq., and the mixture was extracted with CH2Cl2 three times. The combined
organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate = 100:1) to give
TBS-protected -hydroxyester (120.5 mg, 95%). To a solution of TBS-protected -hydroxyester
(120.5 mg, 0.213 mmol) in CH2Cl2 (1.1 mL) was added DIBAL-H (1 M solution in toluene, 0.46 mL,
0.46 mmol) at -78 °C, and the reaction mixture was stirred at the same temperature for 2 h. The
reaction mixture was quenched with MeOH (0.32 mL) at -78 °C, and the resulting mixture was
warmed to room temperature. Then, saturated Rochelle salt solution (0.55 mL) was added, and
allowed to stirred for 2.5 h. The aqueous layer was extracted with CHCl3 three times. The
combined organic layer was washed with saturated Rochelle salt solution and brine, dried over MgSO4,
filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel
(n-hexane/ethyl acetate = 10:1) to give mono-TBS-protected homoallylic-allylic alcohol (114.0 mg,
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99%, 2 steps). To a solution of the mono-TBS-protected homoallylic-allylic alcohol (29.3 mg,
0.0558 mmol) in CH2Cl2 (1.1 mL) was added m-CPBA (28.9 mg, 0.167 mmol) at 0 °C, and the mixture
was stirred at the same temperature for 30 min. To the reaction mixture was added Ca(OH)2, and the
resulting mixture was filtered through a pad of Celite, and the filtrates were concentrated in vacuo.
The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate = 10:1) to
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give epoxide (23R,25R)-32b (27.8 mg, 92%, dr. = 1:10). Spectral data for (23R,25R,)-32b: []25
=
D
+18.8 (c 0.43, CHCl3); 1H NMR (300 MHz, CDCl3) δ 3.98 (s, 2H), 3.80 (d, J = 12.0 Hz, 1H), 3.53 (d,
J = 12.0 Hz, 1H), 2.90 (d, J = 4.8 Hz, 1H), 2.67 (d, J = 4.8 Hz, 2H), 2.18-0.94 (m, 18H), 0.94-0.71 (m,
13
30H), 0.09 (d, J = 2.4 Hz, 6H), -0.01 (d, J = 3.1 Hz, 6H), C{1H} NMR (75 MHz, CDCl3) δ 69.4,
67.6, 64.8, 57.3, 53.1, 52.9, 52.5, 51.8, 43.3, 40.7, 34.4, 31.7, 25.8, 23.0, 20.8, 19.0, 17.9, 13.6, -4.8, -
5.1 ppm; HRMS (ESI) m/z calcd for C30H60O4Si1Na 563.3927 [M+Na]+; found 563.3937.
(2R,4R,6R)-6-((1R,3R,4S,7R)-4-((tert-butyldimethylsilyl)oxy)-7-methyloctahydro-1H-
inden-1-yl)-2-methylheptane-1,2,4-triol (35d). To a solution of triol (23R,25R)-32b (24.6 mg,
0.0455 mmol) in THF (0.8 mL) was added LiAlH4 (9.5 mg, 0.11 mmol) at 0 °C, and the mixture was
stirred at room temperature for 2.5 h. To the reaction mixture was added H2O (8.0 L), 15% NaOH
aq (8.0 L) and H2O (24.0 L) at 0 °C, and the resulting mixture was stirred at the same temperature
for 30 min, and dried over MgSO4. The resulting mixture was filtered through a pad of Celite, and
the filtrates were concentrated in vacuo. The residue was purified by column chromatography on
silica gel (n-hexane/ethyl acetate = 6:1 to 1:1) to give (23R,25R)-TBS-protected triol (16.0 mg, 65%).
To a solution of (23R,25R)-TBS-protected triol (16.0 mg) in THF (0.6 mL) was added TBAF (1 M
solution in THF, 44 L, 0.044 mmol) at 0 °C, and the mixture was stirred at room temperature for 22
h. To the reaction mixture was added saturated NaCl aq., and the aqueous layer was extracted with
ethyl acetate three times. The combined organic layer was washed with brine, dried over MgSO4,
filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica
gel (n-hexane/ethyl acetate = 5:1) to give (23R,25R)-triol 35d (10.9 mg, 85%). Spectral data for 35d:
[]25D = +21.0 (c 0.70, CHCl3); 1H NMR (300 MHz, CDCl3) δ 4.21-4.11 (m, 1H), 3.99 (s, 1H), 3.42
(s, 2H), 2.03-1.03 (m, 23H), 0.99-0.82 (m, 15H), 0.02-0.06 (m, 6H); 13C{1H} NMR (75 MHz, CDCl3)
δ 76.6, 72.7, 70.9, 69.4, 66.1, 57.3, 53.1, 44.8, 42.3, 40.7, 31.8, 27.6, 25.8, 24.2, 23.0, 18.6, 17.6, 13.8,
-4.8, -5.2 ppm; HRMS (ESI) m/z calcd for C24H48O4SiNa: 451.3211 [M+Na]+; found: 451.3253.
(3R,5R)-3-hydroxy-5-((R)-2-((1R,3R,4S,7R)-4-hydroxy-7a-methyloctahydro-1H-inden-1-
yl)propyl)-3-methyldihydrofuran-2(3H)-one (36d). To a mixture of dried MS 4A (13 mg) in
acetonitrile (0.5 mL) was added NMO (60.9 mg, 0.520 mmol) at room temperature, and the mixture
was stirred at the same temperature for 1.5 h. To the resulting mixture was added TPAP (1.8 mg,
0.0051 mmol) and a solution of (23R,25R)-triol 35d (10.3 mg, 0.0240 mmol) in CH2Cl2 (0.3 mL) at
room temperature, and the mixture was stirred at the same temperature for 2.5 h. The reaction
mixture was directly subjected to silica gel column chromatography (n-hexane/ethyl acetate = 4:1) to
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give (23R,25R)-TBS-protected--hydroxylactone (6.2 mg, 56%). To a solution of (23R,25R)-TBS-
protected--hydroxylactone (6.2 mg, 0.0146 mmol) in MeOH (2.4 mL) was added p-TsOH·H2O (72.9
mg, 0.383 mmol) at room temperature, and the mixture was stirred at the same temperature for 87 h.
The reaction mixture was quenched with saturated NaHCO3 aq., and the mixture was extracted with
ethyl acetate three times. The combined organic layer was washed with brine, dried over MgSO4,
filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica
gel (n-hexane/ethyl acetate = 1:1) to give (23R,25R)--hydroxylactone 36d (3.4 mg, 60%) and
(23R,25S)--hydroxylactone 36c (0.34 mg, 6%), respectively. Spectral data for 36d: []24D= +91.8 (c
1.1, CHCl3); 1H NMR (300 MHz, CDCl3) δ 4.72-4.79 (m, 1H), 4.10 (d, J = 15.1 Hz, 1H), 2.70 (s, 1H),
2.42 (dd, J = 13.4, 5.8 Hz, 1H), 1.98-2.04 (m, 1H), 1.69-1.88 (m, 7H), 1.04-1.60 (m, 12H), 0.90-0.99
(m, 6H); 13C{1H} NMR (75 MHz, CDCl3) δ 178.4, 75.9, 73.6, 69.2, 56.8, 52.5, 43.7, 42.0, 41.9, 40.3,
33.3, 32.5, 27.1, 23.9, 22.4, 18.3, 17.3, 13.4 ppm; HRMS (ESI) m/z calcd for C18H30O4Na: 333.2042
[M+Na]+; found: 333.2032.
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(3R,5R)-5-((R)-2-((1R,3R,7R,E)-4-(bromomethylene)-7-methyloctahydro-1H-inden-1-
yl)propyl)-3-methyl-3-((triethylsilyl)oxy)dihydrofuran-2(3H)-one (30d).
(23R,23R)-Bromo
olefin 30d was synthesized by same procedures discribed scheme 5 in 39% yield from (23R,25R)--
hydroxylactone 36d (77.2 mg, 0.249 mmol). Spectral data for 36d: []22D= +90.2 (c 0.9, CHCl3);
1H-NMR (300 MHz, CDCl3) δ 5.64 (s, 1H), 4.64-4.73 (m, 1H), 2.80-2.91 (m, 1H), 2.32 (dd, J = 13.1,
4.8 Hz, 1H), 1.18-2.03 (m, 20H), 0.90-1.01 (m, 12H), 0.57-0.67 (m, 9H); 13C{1H} NMR (75 MHz,
CDCl3) δ 176.8, 144.8, 97.6, 75.8, 75.5, 56.1, 55.8, 46.8, 45.6, 41.9, 39.8, 33.2, 31.0, 27.5, 23.7, 22.5,
22.0, 18.6, 11.9, 6.8, 5.8 ppm; HRMS (ESI): m/z calcd for C25H43BrO3SiNa 521.2063 [M+Na]+; found
521.2061.
(3R,5R)-5-((R)-2-((1R,3S,7R,E)-4-((Z)-2-((3S,5R)-3,5-dihydroxy-2-
methylenecyclohexylidene)ethylidene)-7-methyloctahydro-1H-inden-1-yl)propyl)-3-hydroxy-
3-methyldihydrofuran-2(3H)-one: (23R,25R)-Calcitriol lactone (3d).
(23R,23S)-Calcitriol
lactone 3d was synthesized by same procedures discribed scheme 5 in 78% yield from (23R,25R)-
bromo olefin 30d (45.0 mg, 0.090 mmol). Spectral data for 3d: []23D = +32.4 (c 2.7, CHCl3); 1H NMR
(300 MHz, CD3OD)  6.32 (d, J = 11.0 Hz, 1H), 6.09 (d, J = 11.4 Hz, 1H), 5.29 (s, 1H), 4.73-4.78 (m,
1H), 4.35 (t, J = 5.8 Hz, 1H), 4.11-4.12 (m, 1H), 2.84-2.89 (m, 1H), 2.52 (dd, J = 13.2, 2.9 Hz, 1H),
2.22-2.35 (m, 2H), 1.24-2.15 (m, 23H), 1.04 (d, J = 6.5 Hz, 3H), 0.59 (s, 3H); 13C{1H} NMR (75
MHz, CD3OD)  179.9, 149.8, 142.3, 135.8, 124.9, 119.1, 112.1, 77.2, 74.5, 71.5, 67.4, 58.1, 57.5,
47.0, 46.1, 45.3, 43.7, 43.3, 41.9, 34.8, 30.0, 28.7, 24.6, 23.7, 23.3, 19.3, 12.4 ppm; HRMS (ESI) m/z
calcd for C27H40O5Na 467.2773 [M+Na]+; found 467.2752.
ASSOCIATED CONTENT
Supporting Information
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available.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: knaga@cc.tuat.ac.jp
Notes
The authors declare no competing financial interest.
Acknowledgements
This work was supported in part by AMED-CREST, Japan Agency for Medical Research and
Development, a Grant-in-Aid for Scientific Research on Innovative Areas “Middle Molecular Strategy”
(no. JP16H01134) from The Ministry of Education, Culture, Sports, Science and Technology, Japan,
and the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant number JP26282214,
JP16K17897. This work was inspired by the international and interdisciplinary environments of
JSPS Asian CORE Program of ACBI (Asian Chemical Biology Initiative).
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(a) Feldman, D.; Pike, J. W.; Adams, J.S. (Eds.) Vitamin D (3rd ed.), 2011, Elsevier Academic
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