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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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The Journal of Organic Chemistry

The Journal of Organic Chemistry Stereoselective Synthesis of Four Calcitriol Lactone Diastereomers at C23 and C25 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


Page 2 of 32

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Introduction 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,

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 ( 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.

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 Aring 33 in the presence of palladium (0) catalyst.

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. a JASCO P-2200 polarimeter.

1H

Optical rotations were measured on

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. in terms of chemical shift (, ppm).

Data for 13C NMR are reported

Mass spectra were recorded on JEOL JMS-T100X spectrometer

with ESI-MS mode using methanol as solvent. Crotylation

under

Zhang’s

dihydrooxazol-2-yl)-9H-carbazole (R)-L2.

condition

using 1,8-bis((R)-4-isopropyl-4,5-

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. for 4 h.

The resulting suspension was stirred at room temperature

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-1Hinden-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: []23D = +53.6 (c 0.7,

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-((tertbutyldimethylsilyl)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 2,6lutidine (0.13 mL, 1.11 mmol) and TBSOTf (0.13 mL, 0.566 mmol) at 0 °C, and the reaction mixture



was stirred at the same temperature for 2.5 h.

Page 18 of 32

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. layer was extracted with CHCl3 for three times.

The aqueous

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 monoTBS-protected homoallylic-allylic alcohol 31b (97.3 mg, 91%).

Spectral data for 31b: []23D =

+32.1 (c 0.6, CHCl3); 1H 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-1Hinden-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-TBSether 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. 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. 0 °C.

The reaction mixture was quenched with 10% Na2S2O3 solution at

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: []22D

= +57.1 (c 2.15, CHCl3); 1H NMR (400 MHz, CDCl3) δ 3.98 (s, 1H), 3.72 (d, J = 7.8 Hz, 2H), 2.862.92 (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-1Hinden-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



Page 20 of 32

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). data for 35a:

[]23

D

= +50.8 (c 1.11, CHCl3);

1H

Spectral

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. (3R,5S)-3-hydroxy-5-((R)-2-((1R,3R,4S,7R)-4-hydroxy-7-methyloctahydro-1H-inden-1yl)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 mg, 10%), respectively.

Spectral data for (23S,25R)-36a: []22D= +37.3 (c 0.9, CHCl3); 1H 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-1yl)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


Page 21 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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) Spectral data for 30a: []22D= +48.1

to give (23S,25R)-bromo olefin 30a (182.6 mg, 51%, 3 steps).

(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. (3R,5S)-5-((R)-2-((1R,3S,7R,E)-4-((Z)-2-((3S,5R)-3,5-dihydroxy-2methylenecyclohexylidene)ethylidene)-7-methyloctahydro-1H-inden-1-yl)propyl)-3-hydroxy3-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 (23.9 mg, 68%, 2 steps). Spectral data for 3a: []23D= +13.2 (c 2.4, CHCl3); 1H 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,



Page 22 of 32

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-1Hinden-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 To the reaction mixture was added H2O (8.0 L), 15% NaOH

stirred at room temperature for 3.5 h.

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. were concentrated in vacuo.

The mixture was filtered through a pad of Celite, and the filtrates

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.


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. (3S,5S)-3-hydroxy-5-((R)-2-((1R,3R,4S,7R)-4-hydroxy-7-methyloctahydro-1H-inden-1yl)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.




hexane/ethyl acetate = 1:1) to give (23S,25S)--hydroxylactone 36b (2.6 mg, 99%).

Spectral

data for 36b: []22D= +3.6 (c 0.6, CHCl3); 1H NMR (300 MHz, CDCl3) δ 4.67-4.76 (m, 1H), 4.07-


Page 23 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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. (3S,5S)-5-((R)-2-((1R,3R,7R,E)-4-(bromomethylene)-7-methyloctahydro-1H-inden-1yl)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.


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), 0.801.01 (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-2methylenecyclohexylidene)ethylidene)-7-methyloctahydro-1H-inden-1-yl)propyl)-3-hydroxy3-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



Page 24 of 32

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 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-1HTo a solution of -

inden-1-yl)-1-((S)-2-(hydroxymethyl)oxiran-2-yl)pentan-2-ol (32a).

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. stirring for 2.5 h, the resulting mixture was extracted with CHCl3 three times.

After

The combined organic

layer was washed with saturated Rochelle salt solution and brine, dried over MgSO4, filtered, and concentrated in vacuo.


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: []22D

= +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.


Page 25 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(2S,4R,6R)-6-((1R,3R,4S,7R)-4-((tert-butyldimethylsilyl)oxy)-7-methyloctahydro-1Hinden-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 filtrates were concentrated in vacuo.

The mixture was filtered through a pad of Celite and

The residue was purified by column chromatography on

silica gel (n-hexane/ethyl acetate = 4:1 to 2:1) to give (23R,25S)-triol 35c (41.8 mg, 70%, dr. = 10:1). Spectral data for 35c: []24D = +11.1 (c 0.37, CHCl3); 1H NMR (300 MHz, CDCl3) δ 3.99 (m, 2H), 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-1yl)propyl)-3-methyldihydrofuran-2(3H)-one (36c).


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.




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-1yl)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)--



hydroxylactone 36c (90.7 mg, 0.292 mmol). 1H

Page 26 of 32

Spectral data for 30c: []22D= +112.5 (c 0.4, CHCl3);

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-2methylenecyclohexylidene)ethylidene)-7-methyloctahydro-1H-inden-1-yl)propyl)-3-hydroxy3-methyldihydrofuran-2(3H)-one: (23R,23S)-Calcitriol lactone (3c).

(23R,23S)-

Calcitriol lactone 3c was synthesized by same 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-((tertbutyldimethylsilyl)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.


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. allowed to stirred for 2.5 h.

Then, saturated Rochelle salt solution (0.55 mL) was added, and 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,


Page 27 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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 give epoxide (23R,25R)-32b (27.8 mg, 92%, dr. = 1:10).

Spectral data for (23R,25R,)-32b: []25D =

+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, 30H), 0.09 (d, J = 2.4 Hz, 6H), -0.01 (d, J = 3.1 Hz, 6H), 13C{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-1Hinden-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-1yl)propyl)-3-methyldihydrofuran-2(3H)-one (36d).


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



give (23R,25R)-TBS-protected--hydroxylactone (6.2 mg, 56%).

Page 28 of 32

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. (3R,5R)-5-((R)-2-((1R,3R,7R,E)-4-(bromomethylene)-7-methyloctahydro-1H-inden-1yl)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). 1H-NMR

Spectral data for 36d: []22D= +90.2 (c 0.9, CHCl3);

(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-2methylenecyclohexylidene)ethylidene)-7-methyloctahydro-1H-inden-1-yl)propyl)-3-hydroxy3-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


Page 29 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


The Supporting Information is available free of charge on the ACS Publication website. Copies of 1H and 13C NMR spectra for the compounds, and computational experimental data are available. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] 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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Computational details are shown in Supporting Information.

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Changing the OH group in 31a to OTBS ether, i.e., compound 31b, affects the structural stability by loosing the hydrogen bonds with oxovanadium species, and particularly in TSOH_R, decreased the relative energy difference between TS_R and TS_S (Table 2, entry 2). See supporting information (Figure S3).

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Freund, R. R. A.; Arndt, H. D. Synthesis of (±)-4,5-dia-Parthenolide, an Unnatural Parthenolide Stereoisomer. J. Org. Chem. 2016, 81, 11009-11016.

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(a) Trost B. M.; Dumas J.; Villa M. New strategies for the synthesis of vitamin D metabolites via palladium-catalyzed reactions. J. Am. Chem. Soc. 1992, 114, 9836-9845.

(b) Kato, Y.;

Nakano, Y.; Sano, H.; Tanatani, A.; Kobayashi, H.; Shimazawa, R.; Koshino, H.; Hashimoto, Y.; Nagasawa, K. Synthesis of 1,25-dihydroxyvitamin D3-26,23-lactams (DLAMs), a novel series of 1,25-dihydroxyvitamin D3 antagonist. Bioorg. Med. Chem. Lett. 2004, 14, 2579-2583.


Stereoselective Synthesis of Four Calcitriol ... - ACS Publications

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