Synthesis of γ- and δ-lactones from 1α-hydroxy-5,6-trans-vitamin D3 by ring-closing metathesis route and their reduction with metal hydrides

Article abstract of DOI:10.1016/j.steroids.2007.03.005

New synthetic pathway towards 19-functionalized derivatives of 1α-hydroxy-5,6-trans-vitamin D₃ was described. Ring-closing metathesis (RCM) of 1α-hydroxy-5,6-trans-vitamin D₃ 1-ω-alkenoates was a key-step. Hydride reduction of result

Full text of DOI:10.1016/j.steroids.2007.03.005

steroids 7 2 ( 2 0 0 7 ) 552–558
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/steroids
Synthesis of ␥- and ␦-lactones from 1␣-hydroxy-5,6-trans-
vitamin D3 by ring-closing metathesis route and their
reduction with metal hydrides
Agnieszka Wojtkielewicz, Jacek W. Morzycki∗
Institute of Chemistry, University of Bialystok, Al. Pilsudskiego 11/4, 15-443 Bialystok, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
New synthetic pathway towards 19-functionalized derivatives of 1␣-hydroxy-5,6-trans-
vitamin D3 was described. Ring-closing metathesis (RCM) of 1␣-hydroxy-5,6-trans-vitamin
D3 1-␻-alkenoates was a key-step. Hydride reduction of resulting lactones led to the new
vitamin D3 analogues.
Received 29 November 2006
Received in revised form
15 February 2007
Accepted 8 March 2007
Published on line 18 March 2007
© 2007 Elsevier Inc. All rights reserved.
Keywords:
Ring-closing metathesis
Hydride reduction
Vitamin D3
Steroids
1.
Introduction
tions, which is especially important for these rather unstable
compounds. One of the widely applied metathetic trans-
Vitamin D3 through its active metabolite, 1␣,25-dihydroxy-
vitamnin D3, plays an important role in calcium and
phosphorus homeostasis as well as differentiation and pro-
liferation of various tumor cells [1]. Such a wide variety
of biological activity of this compound encourages organic
chemists, including our group, to synthesize new analogues
as candidate therapeutic agents for the treatment of different
diseases: cancer, psoriasis and osteoporosis [2–11].
formations is ring-closing metathesis (RCM), which allows
cyclic compounds to be obtained from acyclic diene substrates
[14,15]. Many classes of homo- and heterocyclic compounds,
including unsaturated lactones of various ring size can be suc-
cessfully synthesized via the RCM route.
2.
Experimental
Nowadays the discovery of olefin metathesis provides a
new route for synthesis of the complex molecules [12,13].
Since the development of well-defined ruthenium and molyb-
2.1.
General remarks
Melting points were determined on a Kofler apparatus of the
Boetius type. NMR spectra were recorded with a Bruker Avance
DPX 200 or Bruker Avance II 400 spectrometer using CDCl3
or C6D6 solutions with TMS as the internal standard (only
denum alkylidene catalysts, this method has become
a
powerful tool in organic synthesis. It seems to be a method
of choice for synthesis of vitamin D3 analogues as new C–C
double bonds may be formed under relatively mild condi-
∗
Corresponding author. Tel.: +48 85 7457585; fax: +48 85 7457581.
E-mail address: morzycki@uwb.edu.pl (J.W. Morzycki).
0039-128X/$ – see front matter © 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.steroids.2007.03.005

steroids 7 2 ( 2 0 0 7 ) 552–558
553
selected signals in the 1H NMR spectra are reported). Infrared
spectra were recorded on a Nicolet series II Magna-IR 550 FT-
IR spectrometer in chloroform solutions. Mass spectra were
obtained at 70 eV with AMD-604 spectrometer. The reaction
products were isolated by column chromatography performed
on 70–230 mesh silica gel (J.T. Baker).
2.2.3. (5E,7E)-(3S)-3ˇ-t-butyldimethylsilyloxy-9,10-
secocholesta-5,7,10(19)-trien-1˛-yl 4-pentenoate
(2c)
An oil; yield 69 mg (75%), eluted with hexane/AcOEt (98/2); 1
NMR ı (ppm): 6.51 (d, J = 11.5 Hz, 1H, 6-H), 5.87 (d, J = 11.5 Hz, 1H,
7-H), 5.78 (m, 1H, 4ꢀ-H), 5.62 (m, 1H, 1␤-H), 5.15 (brs 1H, 19-H),
5.05 (m, 2H, 5ꢀ-H), 4.94 (bs, 1H, 19-H), 4.14 (m, 1H, 3␣-H), 0.93
(d, J = 5.8 Hz, 3H, 21-H), 0.89 (s, 9H, TBS), 0.86 (d, J = 5.8 Hz, 6H,
26-H and 27-H), 0.56 (s, 3H, 18-H), 0.08 (s, 6H, TBS).
H
2.2.
A representative procedure for esterification
A
solution of 1␣-hydroxy-3-TBS-vitamin D3 (1) (80 mg,
15 mmol), 3-butenoic acid (0.015 ml, 0.17 mmol), N,N-
dicyclohexylcarbodiimide (35 mg, 0.17 mmol) and
2.2.4. (5E,7E)-(3S)-3ˇ-t-butyldimethylsilyloxy-9,10-
secocholesta-5,7,10(19)-trien-1˛-yl 5-hexenoate
(2d)
4-dimethylaminopyridine (2 mg) in DCM (2 ml) was stirred at
room temperature until the reaction was completed (about
2 h). The N,N-dicyclohexyl urea was filtered off and the filtrate
was washed with water, 5% acetic acid solution and again
water, dried over magnesium sulfate and the solvent was
evaporated to afford 3-butenoate 2b.
The above method was also used for preparation of esters
2c–e; acrylate 2a was obtained by routine esterification with
acryloyl chloride in DCM in presence of triethylamine.
An oil; yield 80 mg (84%), eluted with hexane/AcOEt (98/2); 1
H
NMR ı (ppm): 6.51 (d, J = 11.5 Hz, 1H, 6-H), 5.87 (d, J = 11.5 Hz, 1H,
7-H), 5.79 (m, 1H, 5ꢀ-H), 5.61 (m, 1H, 1␤-H), 5.15 (brs 1H, 19-H),
5.00 (m, 2H, 6ꢀ-H) 4.94 (bs, 1H, 19-H), 4.14 (m, 1H, 3␣-H), 0.94 (d,
J = 6.0 Hz, 3H, 21-H), 0.89 (s, 9H, TBS), 0.88 (d, J = 5.7 Hz, 6H, 26-H
and 27-H), 0.56 (s, 3H, 18-H), 0.08 (s, 6H, TBS).
2.2.5. (5E,7E)-(3S)-3ˇ-t-butyldimethylsilyloxy-9,10-
secocholesta-5,7,10(19)-trien-1˛-yl 10-undecenoate
(2e)
2.2.1. (5E,7E)-(3S)-3ˇ-t-butyldimethylsilyloxy-9,10-
secocholesta-5,7,10(19)-trien-1˛-yl 2-propenoate
(2a)
An oil; yield 86 mg (81%), eluted with hexane/AcOEt (98/2); 1
H
An oil; yield 41 mg (46%), eluted with hexane/AcOEt (98.5/1.5);
IR ꢀmax (cm−1): 1717, 1636, 1618, 1258, 1104; 1H NMR ı (ppm):
6.53 (d, J = 11.5 Hz, 1H, 6-H), 6.41 (dd, J = 17.3, 1.7 Hz, 1H, 3ꢀ-H),
6.12 (dd, J = 17.3, 10.3 Hz, 1H, 2ꢀ-H), 5.87 (d, J = 11.5 Hz, 1H, 7-
H), 5.81 (dd, J = 10.3, 1.7 Hz, 1H, 3ꢀ-H), 5.69 (m, 1H, 1␤-H), 5.16
(brs, 1H, 19H), 4.96 (brs, 1H, 19-H), 4.17 (m, 1H, 3␣-H), 2.86 (dd,
J = 10.7, 2.9 Hz, 1H), 2.66 (dd, J = 3.6, 13.8 Hz), 0.94 (d, J = 5.9 Hz,
3H, 21-H), 0.89 (s, 9H, TBS), 0.88 (d, J = 5.4 Hz, 6H, 26-H and 27-
H), 0.56 (s, 3H, 18-H), 0.1 (s, 6H, TBS); 13C NMR ı (ppm): 165.3
(C), 147.5 (C), 144.9 (C), 133.4 (C), 130.6 (CH2), 128.8 (CH), 122.7
(CH)116.0 (CH), 110.8 (CH2), 73.0 (CH), 66.6 (CH), 56.6 (CH), 56.5
(CH), 46.0 (C), 40.5 (CH2), 40.1 (CH2), 39.5 (2× CH2), 36.9 (CH2),
36.1 (CH), 29.1 (CH2), 28.0 (CH), 27.7 (CH2), 25.8 (3× CH3), 23.9
(CH2), 23.6 (CH2), 22.8 (CH3), 22.5 (CH3), 22.2 (CH2), 18.8 (CH3),
18.1 (C), 12.1 (CH3), −4.7 (2× CH3); MS EI: 568 (M+, 17), 496 (22), 75
(40); HRMS EI: calcd for C36H60O3Si: 568.4312. Found: 568.4321.
NMR ı (ppm): 6.51 (d, J = 11.5 Hz, 1H, 6-H), 5.75–5.90 (m, 2H, 7-H
and 10ꢀ-H), 5.61 (m, 1H, 1␤-H), 5.14 (brs 1H, 19-H), 5.04–4.92 (m,
3H, 19-H and 11ꢀ-H) 4.14 (m, 1H, 3␣-H), 0.94 (d, J = 5.9 Hz, 3H,
21-H), 0.89 (s, 9H, TBS), 0.88 (d, J = 5.8 Hz, 6H, 26-H and 27-H),
0.56 (s, 3H, 18-H), 0.08 (s, 6H, TBS).
2.3.
A representative procedure for metathesis
To a solution of Hoveyda second-generation catalyst (11 mg,
10 mol%) in dry toluene (20 ml) in an oven-dried Schlenk flask,
a solution of 1␣-hydroxy-3-TBS-vitamin D3 ester 2a (100 mg,
0.18 mmol) in dry toluene (300 ml) was added dropwise dur-
ing 2 h. The reaction mixture was stirred at 80 ◦C for 4 h under
argon. Then the mixture was concentrated in vacuo and lac-
tone 4a was purified by silica gel column chromatography.
2.2.2. (5E,7E)-(3S)-3ˇ-t-butyldimethylsilyloxy-9,10-
secocholesta-5,7,10(19)-trien-1˛-yl 3-butenoate
(2b)
2.3.1. (5E,7E)-(3S)-3ˇ-t-butyldimethylsilyloxy-9,10-
secocholesta-5,7,10(19)-triene-19,1˛-carbolactone
(4a)
An oil; yield 77 mg (85%), eluted with hexane/AcOEt (98/2); 1
H
NMR ı (ppm): 6.53 (d, J = 11.5 Hz, 1H, 6-H), 5.94 (m, 1H, 3ꢀ-H),
5.89 (d, J = 11.5 Hz, 1H, 7-H), 5.64 (m, 1H, 1␤-H), 5.19 (dd, J = 6.2,
1.1 Hz, 2H, 4ꢀ-H) 5.18 (brs, 1H, 19-H), 4.94 (brs, 1H, 19-H), 4.16 (m,
1H, 3␣-H), 3.09 (dm, J = 6.8 Hz, 2H, 2ꢀ-H), 0.93 (d, J = 5.9 Hz, 3H,
21-H), 0.89 (s, 9-H, TBS), 0.88 (d, J = 5.3 Hz, 6H, 26-H and 27-H),
0.56 (s, 3H, 18-H), 0.08 (s, 6H, TBS); 13C NMR ı (ppm): 170.5 (C),
147.5 (C), 144.9 (C), 133.4 (C), 130.4 (CH), 122.6 (CH), 118.5 (CH2),
116.0 (CH), 110.9 (CH2), 73.1 (CH), 66.6 (CH), 56.7 (CH), 56.5 (CH),
46.0 (C), 40.5 (CH2), 40.1 (CH2), 39.52 (CH2), 39.46 (CH2), 37.0
(CH2, CH), 36.1 (CH2), 29.1 (CH2), 28.0 (CH), 27.7 (CH2), 25.8 (3×
CH3), 23.9 (CH2), 23.6 (CH2), 22.8 (CH3), 22.6 (CH3), 22.2 (CH2),
18.8 (CH3), 18.1 (C), 12.1 (CH3), −4.7 (CH3), −4.8 (CH3); MS EI:
582 (M+, 63), 496 (25), 75 (100); HRMS EI: calcd for C37H62O3Si:
582.4468. Found: 582.4476.
An amorphous solid; yield 38 mg (40%) eluted with hex-
ane/AcOEt (94/6); IR ꢀmax (cm−1): 1739, 1615, 1257, 1062; 1H
NMR ı (ppm): 6.83 (d, J = 11.2 Hz, 1H, 6-H), 5.86 (d, J = 11.2 Hz,
1H, 7-H), 5.83 (brs, 1H, 19-H), 5.25 (dd, J = 11.7, 6.1 Hz, 1H, 1␤-
H), 4.41 (m, 1H, 3␣-H), 2.90 (m, 2H), 0.94 (d, J = 5.4 Hz, 3H, 21-H),
0.88 (d, J = 6.7 Hz, 6H, 26-H and 27-H), 0.86 (s, 9H, TBS), 0.54 (s,
3H, 18-H), 0.10 (s, 3H, TBS), 0.09 (s, 3H, TBS); 13C NMR ı (ppm):
173.8 (C), 170.9 (C), 150.2 (C), 127.0 (CH), 125.6 (C), 115.1 (CH),
109.8 (CH), 78.9 (CH), 66.6 (CH), 56.7 (CH), 56.6 (CH), 46.6 (C),
40.3 (CH2), 39.5 (CH2), 38.4 (CH2), 36.1 (CH, CH2), 35.3 (CH2),
29.4 (CH2), 28.0 (CH), 27.6 (CH2), 25.6 (3× CH3), 23.9 (2× CH2),
22.8 (CH3), 22.5 (CH3), 22.2 (CH2), 18.9 (C), 17.9 (CH3), 11.9 (CH3),
−4.9 (2× CH3); MS EI: 540 (M+, 100), 483 (10); HRMS EI: calcd for
C34H56O3Si: 540.3999. Found: 540.4006.

554
steroids 7 2 ( 2 0 0 7 ) 552–558
(m, 1H, 3␣-H), 3.77 (m, 1H, 19b-H), 3.65 (m, 1H, 19b-H), 0.93 (d,
J = 7.7 Hz, 3H, 21-H), 0.91 (s, 9H, TBS), 0.88 (d, J = 6.8 Hz, 6H, 26-H
and 27-H), 0.57 (s, 3H, 18-H), 0.10 (s, 3H, TBS), 0.09 (s, 3H, TBS);
13C NMR ı (ppm): 145.2 (C), 144.2 (C), 134.6 (C), 122.6 (CH), 122.1
(CH), 116.2 (CH), 66.5 (CH), 65.2 (CH), 61.5 (CH2), 56.6 (CH), 56.5
(CH), 48.5 (C), 42.0 (CH2), 40.5 (CH2), 39.5 (CH2), 38.2 (CH2), 36.1
(CH, CH2), 30.7 (CH2), 29.1 (CH2), 28.0 (CH), 27.7 (CH2), 25.9 (3×
CH3), 23.9 (CH2), 23.6 (CH2), 22.8 (CH3), 22.5 (CH3), 22.2 (CH2),
18.8 (CH3), 18.2 (C), 12.1 (CH3), −4.6 (CH3), −4.7 (CH3); MS EI:
558 (M+, 11), 178 (100); HRMS EI: calcd for C35H62O3Si: 558.4468.
Found: 558.4481.
2.3.2. (5E,7E)-(3S)-3ˇ-t-butyldimethylsilyloxy-19a-homo-
9,10-secocholesta-5,7,10(19)-triene-19a,1˛-carbolactone
(4b)
An amorphous solid; yield 67 mg (70%), eluted with hex-
ane/AcOEt (96/4); IR ꢀmax (cm−1): 1728, 1258, 1069; 1H NMR ı
(ppm): 6.62 (d, J = 11.4 Hz, 1H, 6-H), 5.84–5.79 (m, 2H, 7-H and
19-H), 5.31 (m, 1H, 1␤-H), 4.32 (m, 1H, 3␣-H), 3.20–3.11 (m, 2H,
19a-H), 0.93 (d, J = 5.8 Hz, 3H, 21-H), 0.86 (d, J = 6.3 Hz, 6H, 26-H
and 27-H), 0.84 (s, 9H, TBS), 0.54 (s, 3H, 18-H), 0.07 (s, 3H, TBS),
0.06 (s, 3H, TBS); 13C NMR ı (ppm): 169.6 (C), 145.8 (C), 139.4 (C),
130.5 (C), 123.2 (CH), 116.0 (CH), 112.5 (CH), 66.4 (CH), 56.6 (CH),
56.6 (CH), 46.2 (C), 40.5 (CH2), 39.8 (CH2), 39.5 (2× CH2), 36.1 (CH),
35.1 (CH2), 30.8 (CH2), 29.2 (CH2), 28.0 (CH), 27.7 (CH2), 25.8 (CH),
25.7 (3× CH3), 23.9 (CH2), 23.7 (CH2), 22.8 (CH3), 22.5 (CH3), 22.2
(CH2), 18.8 (CH3), 18.0 (C), 12.0 (CH3), −4.6 (CH3), −4.9 (CH3);
MS EI: 554 (M+, 17), 162 (100); HRMS EI: calcd for C35H58O3Si:
554.4155. Found: 554.4145.
2.4.2. (5E,7E)-(3S)-3ˇ-t-butyldimethylsilyloxy-19-
hydroxymethyl-9,10-secocholesta-5,7-dien-1˛-ol
(8)
A pale yellow amorphous solid; yield 20 mg (88%), eluted with
hexane/AcOEt (70/30); IR ꢀmax (cm−1): 3614, 1471, 1256, 1065;
1H NMR ı (ppm): 6.27 (d, J = 11.3 Hz, 1H, 6-H), 5.88 (d, J = 11.3 Hz,
1H, 7-H), 4.17 (m, 1H, 1␤-H), 4.00 (m, 1H, 3␣-H), 3.75 (m, 2H, 19b-
H), 0.95 (d, J = 6.4 Hz, 3H, 21-H), 0.90 (d, J = 6.2 Hz, 6H, 26-H and
27-H), 0.90 (s, 9H, TBS), 0.57 (s, 3H, 18-H), 0.09 (s, 3H, TBS), 0.08
(s, 3H, TBS); 13C NMR ı (ppm): 142.7 (C), 135.3 (C), 121.4 (CH),
115.7 (CH), 69.0 (CH), 68.0 (CH), 61.7 (CH2), 56.6 (CH), 56.4 (CH),
47.8 (CH), 45.7 (C), 40.7 (CH2), 40.5 (CH2), 39.5 (CH2), 36.1 (CH,
CH2), 29.7 (2× CH2), 29.0 (CH2), 28.0 (CH), 27.7 (CH2), 25.9 (3×
CH3), 23.9 (CH2), 23.5 (CH2), 22.8 (CH3), 22.6 (CH3), 22.2 (CH2),
18.8 (CH3), 18.1 (C), 12.1 (CH3), −4.8 (CH3), −4.9 (CH3); MS EI:
546 (M+, 20), 528 (31), 75 (100); HRMS EI: calcd for C34H62O3Si:
546.44682. Found: 546.44693.
2.3.3. (5E,7E)-(3S)-3ˇ-t-butyldimethylsilyloxy-19a,19b-
dihomo-9,10-secocholesta-5,7,10(19)-triene-19b,1˛-
carbolactone
(4c)
An amorphous solid; yield 5 mg (5%), eluted with hex-
ane/AcOEt (94/6); 1H NMR ı (ppm): 6.62 (d, J = 12 Hz, 1H, 6-H),
5.82 (m, 2H, 7-H and 19-H), 5.31 (m, 1H, 1␤-H), 4.32 (m, 1H, 3␣-
H), 3.21 (m, 2H), 0.93 (d, J = 6.6 Hz, 3H, 21-H), 0.88 (d, J = 6.3 Hz,
6H, 26-H and 27-H), 0.84 (s, 9H, TBS), 0.54 (s, 3H, 18-H), 0.08 (s,
3H, TBS), 0.06 (s, 3H, TBS). MS EI: 568 (M+, 3), 540 (17), 497 (5),
483 483 (4), 75 (100).
2.5.
DIBAL-H reduction of lactones
2.3.4. (5E,7E)-(3S)-3ˇ-t-butyldimethylsilyloxy-
19a,19b,19c-trihomo-9,10-secocholesta-5,7,10(19)-triene-
19c,1˛-carbolactone
To a stirred solution of lactone 4a (30 mg, 0.05 mmol) in dry
toluene (2 ml) cooled to −78 ◦C (dry ice–acetone bath) 1.7 M
solution of DIBAL-H in toluene (0.12 ml) was added. The reac-
tion mixture was maintained at −78 ◦C under argon 4 h, then
poured to water, and extracted with ether. The organic extract
was washed with water, dried over magnesium sulfate, evap-
orated and purified by silica gel column chromatography.
(4d)
An amorphous solid; yield 3 mg (3%), eluted with hex-
ane/AcOEt (94/6); 1H NMR ı (ppm): 6.62 (d, J = 11.2 Hz, 1H, 6-H),
5.82 (m, 2H, 7-H and 19-H), 5.31 (m, 1H, 1␤-H), 4.32 (m, 1H, 3␣-
H), 3.17 (m, 2H), 0.93 (d, J = 6.6 Hz, 3H, 21-H), 0.89 (s, 9H, TBS),
0.88 (d, J = 5.9 Hz, 6H, 26-H and 27-H), 0.54 (s, 3H, 18-H), 0.08 (s,
3H, TBS), 0.06 (s, 3H, TBS).
2.5.1. (5E,7E)-(3S)-3ˇ-t-butyldimethylsilyloxy-
2.4.
LAH reduction of lactones
furo[2ꢀ3ꢀ:1,10]-19-nor-9,10-secocholesta-5,7-diene
(10)
To a solution of lactone 4b (22 mg, 0.04 mmol) in dry THF (5 ml)
LiAlH4 (2.5 mg) was added at room temperature under argon.
The reaction mixture was stirred for 30 min and quenched
carefully with water. The product 5 was extracted with DCM,
the extract was washed with water, dried over magnesium
sulfate, evaporated and purified by silica gel column chro-
matography.
A yellow foam; yield 11 mg (40%), eluted with hexane/AcOEt
(99/1); IR ꢀmax (cm−1): 1624, 1259, 1089, 838; 1H NMR (C6D6) ı
(ppm,): 7.27 (d, J = 1.9 Hz, 1H, 19a-H), 7.04 (d, J = 11.4 Hz, 1H, 6-
H), 6.66 (d, J = 1.9 Hz, 1H, 19-H), 6.50 (d, J = 11.4 Hz, 1H, 7-H), 4.30
(m, 1H, 3␣-H), 3.16–3.28 (m, 2H), 3.09 (d, J = 5.2 Hz, 1H), 2.95 (d,
J = 7.8 Hz, 1H), 2.84 (m, 1H), 1.19 (d, J = 7.1 Hz, 3H, 21-H), 1.15 (d,
J = 7.7 Hz, 6H, 26-H and 27-H), 1.13 (s, 9H, TBS), 0.86 (s, 3H, 18-H),
0.23 (s, 3H, TBS), 0.19 (s, 3H, TBS); 13C NMR ı (ppm): 150.1 (C),
142.5 (CH), 142.0 (C), 125.7 (C), 120.0 (C), 117.0 (CH), 116.0 (CH),
105.8 (CH), 68.7 (CH), 56.7 (CH), 56.5 (CH), 45.9 (C), 40.6 (CH2),
39.5 (CH2), 36.2 (CH, CH2), 35.4 (CH2), 33.9 (CH2), 29.0 (CH2), 28.0
(CH), 27.7 (CH2), 25.7 (3× CH3), 23.9 (CH2), 23.6 (CH2), 22.8 (CH3),
22.6 (CH3), 22.2 (CH2), 18.9 (CH3), 18.1 (C), 12.0 (CH3), −4.6 (2×
CH3); MS EI: 524 (M+, 100), 509 (4), 481 (1), 167 (16); HRMS EI:
calcd for C34H56O2Si: 524.4050. Found: 524.4061.
Analogous LAH reduction of lactone 4a was carried out at
0 ◦C.
2.4.1. (5E,7E)-(3S)-3ˇ-t-butyldimethylsilyloxy-19-
hydroxyethyl-9,10-secocholesta-5,7-10(19)-trien-1˛-ol
(5)
An amorphous solid; yield 22 mg (98%), eluted with hex-
ane/AcOEt (70/30); IR ꢀmax (cm−1): 3380, 1469, 1259, 1091; 1H
NMR ı (ppm): 6.46 (d, J = 11.4 Hz, 1H, 6-H), 5.89 (d, J = 11.4 Hz,
1H, 7-H), 5.66 (m, 1H, 19-H), 4.79 (t, J = 3.1 Hz, 1H, 1␤-H), 4.11
Analogous DIBAL-H reduction of lactone 4b afforded a
diastereomeric mixture of lactols 7, which could not be sepa-

steroids 7 2 ( 2 0 0 7 ) 552–558
555
2.6.3. (5E,7E)-(3S)-furo[2ꢀ3ꢀ:1,10]-19-nor-9,10-
rated into individual pure compounds, in the ratio 6:4 as arose
from integration of the 19b-H signals at ı: 5.05 (m) and 5.42 (t,
J = 4.6 Hz) in the 1H NMR spectrum.
secocholesta-5,7-dien-3ˇ-ol
(11)
A yellow amorphous solid; yield 13 mg (93%), eluted with hex-
ane/AcOEt (90/10); IR ꢀmax (cm−1): 3611, 1624, 1034; 1H NMR ı
(ppm,): 7.30 (d, J = 2.0 Hz, 1H, 19a-H), 6.59 (d, J = 11.5 Hz, 1H, 6-
H), 6.54 (d, J = 2.0 Hz, 1H, 19-H), 5.95 (d, J = 11.5 Hz, 1H, 7-H), 4.31
(m, 1H, 3␣-H), 3.06 (dd, J = 16.4, 4.7 Hz, 1H), 2.89 (dm, J = 12.7 Hz,
1H), 2.74 (m, 3H), 0.94 (d, J = 6.4 Hz, 3H, 21-H), 0.89 (d, J = 6.6 Hz,
3H, 26-H/27-H), 0.88 (d, J = 6.6 Hz, 3H, 26-H/27-H), 0.58 (s, 3H, 18-
H); 13C NMR ı (ppm): 149.0 (C), 143.3 (C), 142.3 (CH), 124.1 (C),
120.4 (C), 118.7 (CH), 115.8 (CH), 105.8 (CH), 67.2 (CH), 56.6 (CH),
56.5 (CH), 46.0 (C), 40.5 (CH2), 39.5 (CH2), 36.1 (CH, CH2), 34.0
(CH2), 33.0 (CH2), 29.0 (CH2), 28.0 (CH), 27.7 (CH2), 23.9 (CH2),
23.6 (CH2), 22.8 (CH3), 22.6 (CH3), 22.3 (CH2), 18.8 (CH3), 12.1
(CH3); MS EI: 410 (M+, 88), 367 (3), 57 (100); HRMS EI: calcd for
2.6.
Deprotection of compounds 5, 8 and 10
To a stirred solution of TBS-ether 10 (18 mg, 0.03 mmol) in dry
THF (1 ml), cooled to 0 ◦C, 1 M solution of TBAF in THF (0.11 ml)
was added. The reaction mixture was removed from the cool-
ing bath and stirred for about 30 min at room temperature to
complete the reaction (TLC control). The reaction mixture was
then poured into water and extracted with ether. The organic
extract was washed with water, dried over magnesium sulfate,
evaporated and purified by silica gel column chromatography.
Analogous deprotection reactions of compounds 5 and 8
were also performed.
C28H42O2: 410.3185. Found: 410.3197.
2.6.1. (5E,7E)-(3S)-19-hydroxyethyl-9,10-secocholesta-
5,7-10(19)-triene-1˛,3ˇ-diol
(6)
3.
Results and discussion
A foam; yield 4 mg (95%), eluted with hexane/AcOEt (10/90);
1H NMR ı (ppm): 6.52 (d, J = 11.4 Hz, 1H, 6-H), 5.92 (d, J = 11.4 Hz,
1H, 7-H), 5.73 (t, J = 8.1 Hz, 1H, 19-H), 4.85 (t, J = 3.2 Hz, 1H, 1␤-H),
4.18 (m, 1H, 3␣-H), 3.82 (m, 1H, 19b-H), 3.67 (m, 1H, 19b-H), 3.18
(dm, J = 12.0 Hz, 1H), 2.73 (dm, J = 12.5 Hz, 1H), 0.95 (d, J = 6.3 Hz,
3H, 21-H), 0.90 (d, J = 6.6 Hz, 3H, 26-H/27-H), 0.89 (d, J = 6.6 Hz,
3H, 26-H/27-H), 0.58 (s, 3H, 18-H); 13C NMR ı (ppm): 144.8 (C),
144.7 (C), 133.6 (C), 123.1 (CH), 122.5 (CH), 116.2 (CH), 65.8 (CH),
64.9 (CH), 61.5 (CH2), 56.6 (CH), 56.5 (CH), 45.9 (C), 41.4 (CH2),
40.5 (CH2), 39.5 (CH2), 37.5 (CH2), 36.1 (CH2, CH), 30.7 (CH2), 29.7
(CH2), 29.2 (CH), 28.0 (CH2), 27.7 (CH2), 23.9 (CH2), 22.8 (CH3),
22.6 (CH3), 22.3 (CH2), 18.8 (CH3), 12.1 (CH3).
The aim of this work was to elaborate a simple synthetic
approach to the 19-functionalized vitamin D3 derivatives.
Cross metathesis (CM) of suitably protected vitamin D3 (in
5,6-cis and 5,6-trans series) with various olefins failed. There-
fore the synthesis of vitamin D3 lactones via RCM approach
was attempted. In our early studies vitamin D3 long-chain
esters with a terminal double bond were prepared and sub-
jected to metathesis. However, instead of RCM, self metathesis
(SM) of unsaturated esters was only observed, probably due to
insufficient conformational flexibility of ring A [16]. Further
attempts of RCM were carried out with 1␣-hydroxy-vitamin
D3 esters containing unsaturated acyl unit at the position 1.
This approach also completely failed – even RCM of 1␣-OH-
D3 3-butenoate, which was expected to afford product of a
six-membered ring closure, did not work. The most likely rea-
son of this failure is the steric hindrance caused by the CD
ring fragment of a steroid molecule. Inspection of the Dreid-
ing stereomodels indicated that the C10–C19 double bond in
1␣-hydroxy-5,6-trans-vitamin D3 derivatives is more accessi-
ble than in the 5,6-cis isomers. To check, if the steric hindrance
is the main reason of the failure, the RCM reaction of 1␣-
hydroxy-5,6-trans-vitamin D3 3-butenoate was performed and
the desired six-membered lactone was obtained as the main
product. The synthesis of the lactone and its further trans-
formations to the 19-functionalized 1␣-OH-D3 derivatives was
2.6.2. (5E,7E)-(3S)-19-hydroxymethyl-9,10-secocholesta-
5,7-diene-1˛,3ˇ-diol
(9)
An oil; yield 3 mg (89%), eluted with hexane/AcOEt (5/95); 1H
NMR ı (ppm): 6.34 (d, J = 11.3 Hz, 1H, 6-H), 5.88 (d, J = 11.3 Hz, 1H,
7-H), 4.14 (m, 1H, 1␤-H), 4.06 (m, 1H, 3␣-H), 3.75 (m, 2H, 19a-H),
0.93 (d, J = 6.3 Hz, 3H, 21-H), 0.88 (d, J = 6.6 Hz, 3H, 26-H/27-H),
0.87 (d, J = 6.6 Hz, 3H, 26-H/27-H), 0.56 (s, 3H, 18-H); 13C NMR
ı (ppm): 142.5 (C), 135.2 (C), 122.7 (CH), 115.1 (CH), 68.9 (CH),
67.5 (CH), 61.5 (CH2), 56.6 (CH), 56.4 (CH), 53.4 (CH2), 47.5 (CH),
45.7 (C), 40.5 (CH2), 39.5 (CH2), 36.1 (CH, CH2), 29.7 (CH2), 29.6
(CH2), 29.1 (CH2), 28.0 (CH), 27.6 (CH2), 23.9 (CH2), 23.5 (CH2),
22.8 (CH3), 22.6 (CH3), 22.3 (CH2), 18.8 (CH3), 12.1 (CH3).
Scheme 1

556
steroids 7 2 ( 2 0 0 7 ) 552–558
metathesis. In the next experiments, the reaction tempera-
ture was raised to 40 ◦C without significant change of reaction
course. Only the use of catalysts of the second generation
(either Grubbs or Hoveyda) at 80 ◦C in dry and degassed toluene
proved effective in the RCM products (4a or 4b) formation
(Scheme 3).
Such effect of temperature, mentioned above, was not
reported earlier for similar compounds [20]. The influence of
other reaction conditions on the reaction course, e.g. type of
catalyst, dilution (tested concentration: 0.5–1.5 mM), mode of
reagent addition, appeared to be much less important. For sub-
strates 2a and 2b, a slightly better yield of RCM product was
achieved with the second-generation Hoveyda (HII) promoter.
It was found that 10 mol% of catalyst was the optimal load;
higher amount of catalyst or its portionwise addition did not
improve the yield. 5,6-trans-vitamin D3 19,1-carbolactone (4a)
was obtained in 40% yield in presence of HII catalyst. The lac-
tone was accompanied by dimer 3a (23%)—the SM reaction
product. The remaining material was mainly the unreacted
starting ester 2 (about 30%).
In an analogous reaction, 3-butenoate 2b yielded 70% of
the RCM product 4b and the SM by-product 3b (24%). Interest-
ingly, no terminal olefin isomerization was observed during
this reaction. This is quite surprising since in many reports,
comparable systems were found to be prone to isomeriza-
tion under metathetic conditions, especially, if the GII catalyst
was used [21–24]. In some cases the isomerized substrate was
obtained even as the main reaction product under conditions
analogous to ours [25].
Other 1␣-hydroxy-5,6-trans-vitamin D3 esters (2c–e) were
also subjected to metathesis under the same conditions
(10 mol% of HII catalyst; dilution = 0.5 mM; 80 ◦C; toluene,
4–16 h). Although many successful applications of RCM to the
synthesis of medium sized rings are known, in the case of 2c–e,
the major products were dimers 3c–e, formed as a result of SM.
The desired lactones 4 were obtained in very low yields (below
5%) or as in the case of attempted closure of a 12-membered
ring, lactone 4e was not observed at all. Also in the case of
these substrates, no double bond isomerization was observed.
Further synthesis of 19-functionalized vitamins consisted
of reduction of the obtained lactones (4a, 4b) with metal
hydrides. Reduction of ␦-lactone 4b with LAH afforded the
desired unsaturated diol 5. A similar reaction of ␥-lactone 4a
proceeded with simultaneous reduction of the C10–C19 dou-
ble bond but the diene core remained intact and diol 8 was
obtained. Reduction of ␥-lactone 4a with the more selective
DIBAL-H yielded the furan derivative 10. Furan ring formation
during reduction of ␣,␤-unsaturated ␥-lactones is known in
Scheme 2
described in our preliminary communication [16]. Now, we
present results of our further study on metathesis of 1␣-
hydroxy-5,6-trans-D3 ␻-unsaturated esters with various sized
acid chain (C3, C4, C5, C6, and C11). Further reductive trans-
formations of the ␥- and ␦-lactones obtained by the RCM
methodology are also described in this paper.
Five 1␣-hydroxy-3-TBS-5,6-trans-vitamin D3 ␻-alkenoates
(compounds 2b–e) were prepared in high yields by reaction of
1 with ␻-alkenoic acids in presence of DCC and DMAP. Only
in the case of 1␣-hydroxy-3-TBS-5,6-trans-vitamin D3 acry-
late (2a), esterification was carried out using the acid chloride
method (Scheme 1). All esters obtained were found to be rather
unstable and were subjected to RCM reactions immediately
without thorough purification.
In the first RCM experiments, acrylate 2a and 3-butenoate
2b reactions were studied that theoretically allow for a closure
of a five or six-membered lactone ring, respectively. Accord-
ing to literature, synthesis of unsatured lactones through RCM
has been accomplished using either Grubbs (first- or second-
generation) or Hoveyda catalysts [14–19]. The synthesis of
phosphonate or silicon analogues of 1␣-hydroxy-5,6-trans-
vitamin D3 by a similar approach was achieved in presence
of the second-generation Grubbs catalyst [20]. We decided to
test all three commercially available metathesis promoters:
Grubbs first-generation (GI), Grubbs second-generation (GII)
and Hoveyda second-generation (HII) (Scheme 2).
Bearing in mind the low stability of 1␣-hydroxy-5,6-trans-
vitamin D3 esters (2), we carried out the first experiments
under relatively mild conditions: 20 mol% of catalyst in dry
and degassed dichloromethane at room temperature. It was
assumed that such quantities of catalyst might be necessary
because of possible chelation of the ruthenium complex by
the triene moiety. However, no RCM reaction was observed
for all three catalysts under these conditions. The only iso-
lated products were dimers 3a or 3b, formed as a result of self
Scheme 3

steroids 7 2 ( 2 0 0 7 ) 552–558
557
Scheme 4
r e f e r e n c e s
literature [26,27] (Scheme 4). The presence of a rigid furan sys-
tem in the molecule causes a change of A ring conformation,
as is evident from the 1H NMR spectrum showing a broadened
3␣-H signal. This proves that the 3␤-substituent assumes an
equatorial position, favorable for biological activity of vitamin
D analogues [28,29].
A similar reduction of ı-lactone 4b with DIBAL-H afforded
the mixture of diastereomeric lactols 7 in the ratio 6:4 (by inte-
gration of the 19b-H signals in the 1H-NMR spectrum) that
were rather difficult to separate. The mixture can be used
for further transformations towards different 1␣-hydroxy-
vitamin D3 analogues.
[1] Holick MF, editor. Vitamin D: physiology, molecular biology
and clinical applications. Totowa, NJ: Humana Press; 1999.
[2] Bouillon RM, Okamura WH, Norman AW. Structure-function
relationships in the vitamin D endocrine system. Endocr Rev
1995;16:200–7.
[3] Muralidharan KR, De Lera AR, Isaeff SD, Norman AW,
Okamura WH. Studies of vitamin D (calciferol) and its
analogs. 45. Studies on the A-ring diastereomers of
1␣,25-dihydroxyvitamin D3. J Org Chem 1993;58:1895–9.
[4] Perlman KL, Sicinski RR, Schnoes HK, DeLuca HF.
1␣,25-Dihydroxy-19-nor-vitamin D3, a novel vitamin
D-related compound with potential therapeutic activity.
Tetrahedron Lett 1990;31:1823–4.
[5] Kanzler S, Halkes S, van de Velde JP, Reischl W. A novel class
of vitamin D analogs. Synthesis and preliminary biological
evaluation. Bioorg Med Chem Lett 1996;6:1865–8.
[6] Kroszczyn´ ski W, Morzycka B, Morzycki JW. A never ending
story of vitamin D. Wiadomos´ci Chemiczne 2002;56:793–809.
[7] Yamada S, Nakayama K, Takayama H, Itai A, Iitaka Y. Studies
of vitamin D oxidation. 3. Dye-sensitized photooxidation of
vitamin D and chemical behavior of vitamin D
In the final step, the 3␤-hydroxyl group in compounds 5, 8
and 10 was deprotected with TBAF in a standard manner to
afford the corresponding alcohols 6, 9 and 11.
4.
Conclusion
It was proved that the RCM strategy can be successfully
applied to the synthesis of ␥- and ␦-lactones from 1␣-hydroxy-
5,6-trans-vitamin D3 unsaturated esters. The synthesis of
larger rings was of a low yield or failed. The subsequent reduc-
tion of the obtained RCM products afforded 19-functionalized
derivatives of 1␣-hydroxy-5,6-trans-vitamin D3, which can be
photochemically transformed into the 5,6-cis isomers (the 5,6-
cis configuration occurs in natural vitamin D3), as was proved
previously by us [16].
6,19-epidioxides. J Org Chem 1983;48:3477–83.
[8] Yamada S, Suzuki T, Takayama H, Miyamoto K, Matsunaga I,
Nawata Y. Stereoselective synthesis of (5E)- and (5Z)-vitamin
D3 19-alkanoic acids via vitamin D3-sulfur dioxide adducts. J
Org Chem 1983;48:3483–8.
[9] Addo JK, Ray R. Synthesis and binding-analysis of
5E-[19-(2-bromoacetoxy)methyl]25-hydroxyvitamin D3 and
5E-25-hydroxyvitamin
D3-19-methyl[(4-azido-2-nitro)phenyl]glycinate: novel
C
19-modified affinity and photoaffinity analogs of
Acknowledgment
25-hydroxyvitamin D3. Steroids 1998;63:218–23.
[10] Swamy N, Addo JK, Ray R. Development of an affinity-driven
cross-linker: isolation of a vitamin D receptor associated
factor. Bioorg Med Chem Lett 2000;10:361–4.
This work was supported by the Polish State Committee for
Scientific Research (Grant No. 3 T09A 013 27).

558
steroids 7 2 ( 2 0 0 7 ) 552–558
[11] Addo JK, Swamy N, Ray R. The C19 position of
analogues via ring-closing metathesis. Org Lett
2003;5:669–72.
25-hydroxyvitamin D3 faces outward in the vitamin D
sterol-binding pocket of vitamin D-binding protein. Bioorg
Med Chem Lett 2002;12:279–81.
[21] Formentin P, Gimeno N, Steinke JHG, Vilar R. Reactivity of
Grubbs’ catalysts with urea- and amide-substituted olefins.
Metathesis and isomerization. J Org Chem 2005;70:8235–8.
[22] Schmidt B. In situ conversion of a Ru metathesis catalyst to
an isomerization catalyst. J Chem Soc; Chem Commun
2004:742–3.
[23] Schmidt B. Catalysis at the interface of ruthenium-carbene
and ruthenium-hydride chemistry: organometallic aspects
and applications to organic synthesis. Eur J Org Chem
2004:1865–81.
[12] Grubbs RH. Olefin metathesis. Tetrahedron 2004;60:7117–40.
[13] Connon SJ, Blechert S. Recent developments in olefin
cross-metathesis. Angew Chem Int Ed Engl 2003;42:1900–23.
[14] Deiters A, Martin SF. Synthesis of oxygen- and
nitrogen-containing heterocycles by ring-closing
metathesis. Chem Rev 2004;104:2199–238.
[15] Armstrong SK. Ring closing diene metathesis in organic
synthesis. J Chem Soc; Perkin Trans 1998;1:371–88.
[16] Wojtkielewicz A, Morzycki JW. Application of ring-closing
metathesis to the synthesis of 19-functionalized derivatives
of 1␣-hydroxyvitamin D3. Org Lett 2006;8:839–42.
[17] Chatterjee AK, Morgan JP, Scholl M, Grubbs RH. Synthesis of
functionalized olefins by cross and ring-closing metatheses.
J Am Chem Soc 2000;122:3783–4.
[24] Alcaide B, Almendros P. Non metathetic behavior patterns of
Grubb’s carbine. Chem Eur J 2003;9:1258–62.
[25] de la Torre MC, Deometrio AM, Alvaro E, Gracia I, Sierra MA.
Synthesis of ␣-onoceradiene-like terpene dimers by
intermolecular metathesis processes. Org Lett 2006;8:593–6.
[26] Minuto H, Nagasaki T. Studies on sesquiterpenoids. Part
XVII. Total synthesis of ( )-lindestrene. J Chem Soc (C)
1968:621–4.
[27] Minuto H, Nagasaki T. A new method for the synthesis of
furan compounds. J Chem Soc (C) 1966:377–9.
[28] Peleg S, Posner GH. Vitamin D analogs as modulators of
vitamin D receptor action. Curr Top Med Chem
2003;3:1555–72.
[18] Furstner A, Thiel OR, Ackermann L, Schanz H-J, Nolan SP.
Ruthenium carbene complexes with
N,Nꢀ-bis(mesityl)imidazol-2-ylidene ligands: RCM catalysts
of extended scope. J Org Chem 2000;65:2204–7.
[19] Bassetti M, DꢀAnnibale A, Fanfoni A, Minissi F. Synthesis of
␣,␤-unsaturated 4,5-disubstituted ␥-lactones via ring-closing
metathesis catalyzed by the first-generation Grubbs’
catalyst. Org Lett 2005;7:1805–8.
[29] Rochel N, Wurtz JM, Mitschler A, Klaholz B, Moras D. The
crystal structure of the nuclear receptor for vitamin D bound
to its natural ligand. Mol Cell 2000;5:173–9.
[20] Ahmed M, Atkinson CE, Barrett AGM, Malagu K, Procopiou
PA. Synthesis of C-19-functionalized 1␣-hydroxyvitamin D2