Synthesis of a trans-hydrindanone, precursor for the preparation of vitamin D analogues

Article abstract of DOI:10.1002/ejoc.201300528

We developed a very efficient and practical method for the large-scale synthesis of a trans-hydrindan derivative related to vitamin D, based on the Criegee rearrangement. This ketone is a valuable synthon for the preparation of Gemini-type vitamin D analogues or other calcitriol analogues modified at C-20, C-21 or the D-ring. Our methodology is superior to those previously reported when considering efficiency and expediency. The Criegee rearrangement was the key step for a large-scale synthesis of a trans-hydrindan derivative related to vitamin D. This work is superior to previous approaches with regards to efficiency and expediency. Copyright

Full text of DOI:10.1002/ejoc.201300528

FULL PAPER
DOI: 10.1002/ejoc.201300528
Synthesis of a trans-Hydrindanone, Precursor for the Preparation of Vitamin D
Analogues
Zoila Gándara,*[a] Marcos L. Rivadulla,[a] Manuel Pérez,[a] Generosa Gómez,[a] and
Yagamare Fall*[a]
Dedicated to Dr. Simeon Arseniyadis
Keywords: Vitamins / Criegee rearrangement / Oxidation / Dioxenium ion / Rearrangement / Hormones / Ozonolysis
We developed a very efficient and practical method for the
large-scale synthesis of a trans-hydrindan derivative related
to vitamin D, based on the Criegee rearrangement. This
ketone is a valuable synthon for the preparation of Gemini-
type vitamin D analogues or other calcitriol analogues modi-
fied at C-20, C-21 or the D-ring. Our methodology is superior
to those previously reported when considering efficiency and
expediency.
Introduction
Results and Discussion
As part of our ongoing program focusing on the synthe-
sis of vitamin D metabolites and analogues, we recently de-
signed a new and versatile synthetic methodology for the
preparation of Gemini analogue 5[3] (Scheme 1).
1α,25-Dihydroxyvitamin D3
[2,
1α,25-(OH)2-D3,
calcitriol] (Figure 1), the hormonally active form of vita-
[1]
min D3 (1, cholecalciferol), is one of the most potent in-
ducers of calcitropic effects, notably intestinal calcium ab-
sorption and bone calcium mobilization. Besides regulating
the metabolism of calcium and phosphorus, calcitriol pro-
motes cell differentiation, inhibits the proliferation of tumor
cells, and has numerous indirect effects on the immune sys-
tem.[2] However, the clinical utility of this hormone for
treatment of cancers and skin disorders is limited by its hy-
percalcemic effects. Accordingly, there is a great deal of
interest in the design and synthesis of analogues of 2 with
high cell-differentiating properties and low or negligible cal-
cemic effects.
Analogue 5 was previously synthesized by Uskokovic
and co-workers,[4] but their procedure relied on an ene reac-
tion for non-selective generation of the double side-chain
precursor and the subsequent separation of isomers. In con-
trast, our synthetic procedure uses a key sigmatropic re-
arrangement, providing a versatile method for the introduc-
tion of novel side-chains to the vitamin D scaffold giving
access to a variety of analogues with potentially interesting
biological properties. We used trans-hydrindanone 3 as a
starting material for the synthesis of key intermediate
ketone 4. Compound 3 has been used by Mouriño and co-
workers[5] as a precursor for a large number of calcitriol
analogues. To the best of our knowledge, the first and only
synthesis of ketone 3 was described by Mouriño and co-
workers[6] (Scheme 2).
DeLuca and co-workers[7] used the same synthetic se-
quence to generate 17-ketone 3a with some modification;
they prepared analogous methyl ketone 8a from aldehyde
7a, as described by Posner[8] (Scheme 3).
One major drawback of Mouriño’s methodology is the
Bayer–Villiger oxidation step requiring an unreasonable 7 d
reaction time. Moreover, aldehyde 7 was rather unstable,
and its transformation into ketone 8 through the intermedi-
acy of α-hydroperoxy aldehyde by reaction with O2 and po-
tassium tert-butoxide, in our hands, consistently provided
yields well below 50%. The alternative approach proposed
by DeLuca and co-workers may give better yields of ketone
8 but does not avoid the time-consuming Bayer–Villiger oxi-
Figure 1. Structures of cholecalciferol (1) and 1α,25-(OH)2-D3 (2).
[a] Departamento de Química Orgánica, Facultade de Química,
Universidade de Vigo,
36310 Vigo, Spain
E-mail: yagamare@uvigo.es
zoiliac@hotmail.com
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300528.
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5678–5682

Synthesis of a trans-Hydrindanone, a Precursor to Vitamin D Analogues
Scheme 1.
Scheme 2. Mouriño’s method of calcitriol analog generation.
Scheme 3. DeLuca approach to 3a production.
dation step. A more efficient and reliable method for the sity during ozonolysis, and the temperatures of acetylation
large-scale synthesis of ketone 3 is therefore needed. We an- and hydrolysis. Alcohol 14 can be obtained in 80% (Table 1,
ticipated that known alkene 13[9] might suffer degradation Entry 8) or 75% yield (Table 1, Entry 10) together with
of its isopropenyl side chain through a Criegee rearrange- 16% or 2% yield, respectively, of ketone 8. Ketone 8, which
ment[10] leading to alcohol 14, a precursor of ketone 3 is also a useful starting material for the synthesis of valuable
(Scheme 4).
calcitriol analogues,[11] can be obtained in 80% yield
Accordingly, we uneventfully prepared alkene 13[9] from (Table 1, Entry 5). The quantity of Et3N and Ac2O seems to
Inhoffen–Lythgoe diol 6 and carried out the Criegee re- be important for the selectivity of the reaction. In general, a
arrangement. After much experimentation, optimal reac- large excess of both reagents is necessary. Formation of
tion conditions were established; results are summarized be- ketone 8 is favored when a larger excess of Et3N is used;
low in Table 1.
36 equiv. of Et3N and 15.4 equiv. of Ac2O (Table 1, En-
The outcome of the Criegee rearrangement of alkene 13 try 5). On the other hand when there is a slightly larger
depended on its molar concentration, on the current inten- excess of Ac2O, formation of alcohol 14 was found to be
Eur. J. Org. Chem. 2013, 5678–5682
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5679

Z. Gándara, M. L. Rivadulla, M. Pérez, G. Gomez and, Y. Fall
FULL PAPER
Scheme 4. Putative Criegee rearrangement-based method evaluated herein.
Table 1. Optimization of the Criegee rearrangement of alkene 13.
Entry
[m][a]
I[b]
Ac2O [eqiv.]
Et3N [equiv.]
T [°C][c]
Base (equiv.)
T [°C][d]
14 [%]
8 [%]
1
2
0.3
0.03
0.7
0.4
15.4ϫ2
15.4ϫ2
15.4ϫ2
15.4ϫ2
60
r.t
K2CO3 (0.5)
K2CO3 (0.5)
60
33
50
22
37
room temp.
3
4
5
6
7
0.01
0.02
0.03
0.04
0.04
0.4
0.4
0.4
0.4
0.4
15.4ϫ2
15.4ϫ2
15.4
7.5ϫ2
15.0ϫ2
18ϫ2
18ϫ2
18ϫ2
7.0ϫ2
15.0ϫ2
60
r.t
K2CO3 (1.0)
K2CO3 (1.0)
K2CO3 (1.0)
K2CO3 (1.0)
K2CO3 (1.0)
30
43
–
44
60
67
–
80
39
23
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
–30 (Ǟ 2 h)
–10 (Ǟ 1 d)
room temp. (Ǟ 2 d)
–30 (Ǟ 5 min)
–10 (Ǟ 12 h)
room temp. (Ǟ 1 d)
–30 (Ǟ 5 min)
8
9
0.04
0.04
0.4
0.4
20ϫ2
30ϫ2
18ϫ2
28ϫ2
K2CO3 (5.0)
room temp.
80
16
NaOAc (0.2)
K2CO3 (5.0)
K2CO3 (10)
room temp.
–
–
5
2
–10 (Ǟ 12 h)
room temp. (Ǟ 1 d)
–30 (Ǟ 5 min)
40
40
61
75
10
0.04
0.4
40ϫ2
38ϫ2
–10 (Ǟ 12 h)
room temp. (Ǟ 4 h)
[a] Molar concentration of alkene 13. [b] Intensity of current during ozonolysis (in A). [c] Temperature of acetylation step. [d] Temperature
of acetate hydrolysis.
favored; examples include reactions containing (i) 40 equiv. (pathway A) and alcohol 14 (pathway B) is rationalized in
of Ac2O and 36 equiv. of Et3N (Table 1, Entry 8) or Scheme 5. With alcohol 14 in hand we uneventfully pre-
(ii) 80 equiv. of Ac2O and 76 equiv. of Et3N (Table 1, En- pared target ketone 3 in 85% yield by PDC oxidation
try 10). The mechanism of formation of methyl ketone 8 (Scheme 4).
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Eur. J. Org. Chem. 2013, 5678–5682

Synthesis of a trans-Hydrindanone, a Precursor to Vitamin D Analogues
Scheme 5. Mechanism of the formation of methyl ketone 8 and alcohol 14.
1253, 1163, 1078, 976, 882, 839, 776, 684 cm–1. 1H NMR (CDCl3):
δ = 4.82 (s, 1 H, 22-H), 4.70 (s, 1 H, 22-H), 4.03 (s, 1 H, 8-H), 1.99
(t, J = 9.3 Hz, 1 H, 17-H), 1.87–1.77 (m, 3 H), 1.75 (s, 3 H, 21-H),
Conclusions
We have developed a very efficient and practical method
for the safe and scalable synthesis of large quantities of 1.73–1.59 (m, 3 H), 1.49–1.34 (m, 4 H), 1.18 (m, 1 H), 0.90 (s, 9
H, CH3 tBuSi), 0.81 (s, 3 H, 18-H), 0.03 (s, 3 H, CH3 SiMe), 0.02
(s, 3 H, CH3 SiMe) ppm. 13C NMR (CDCl3): δ = 145.46 (C-20),
110.86 (CH2-22), 69.26 (CH-8), 57.99 (CH-17), 53.03 (CH-14),
42.74 (C-13), 39.67 (CH2), 34.45 (CH2), 25.81 (CH3 tBuSi), 24.74
(CH3-21), 24.48 (CH2), 22.92 (CH2), 18.02 (C tBuSi), 17.78 (CH2),
14.75 (CH3-18), –4.78 (CH3 SiMe), –5.15 (CH3 SiMe) ppm.
trans-hydrindan derivatives related to vitamin D. This
methodology includes high-yielding steps and avoids the
time-consuming Bayer–Villiger reaction (7 d) that typifies
the majority of previously reported methods.
Experimental Section
[1S-(1α,3aβ,4α,7aβ)]-Octahydro-4-(tert-butyldimethylsilyl)oxy-7a-
methyl-1H-inden-1-ol (14) and [1S-(1α,3aβ,4α,7aβ)]-Octahydro-1-
acetyl-4-[(tert-butyldimethylsilyl)oxy]-7a-methyl-1H-indene (8): An
ozonolysis reactor was charged with a solution of alkene 13 (1.2 g,
3.83 mmol) in DCM/MeOH (6:1) (93 mL). Ozone (flow 1.0 mL/
min, current intensity 0.4 A) was continuously passed through the
reaction mixture at –78 °C. The reaction turned pale blue after
15 min, indicating complete reaction. Excess ozone was then re-
moved by purging with Ar for 15 min. Et3N (21 mL, 153 mmol),
DMAP (catalytic amount), and Ac2O (14 mL, 145 mmol) were suc-
cessively added to the mixture at –78 °C, and stirring was continued
for 5 min. The solution was then warmed to –30 °C and stirred for
another 5 min, then slowly warmed to –10 °C and stirred for 12 h.
Et3N (21 mL, 153 mmol), DMAP (catalytic amount), and Ac2O
(14 mL, 145 mmol) were then added to the mixture, and stirring
was continued at room temp. for 4 h. The reaction was quenched
by slow addition of saturated aqueous NH4Cl (15 mL) at 0 °C, and
the solvent was removed. The reaction mixture was then extracted
with EtOAc (3 ϫ 70 mL). The combined organic layers were
washed with brine (3ϫ 70 mL), dried with MgSO4, filtered, and
concentrated. The resulting residue was dissolved in MeOH
(20 mL), and K2CO3 (5.2 g, 383 mmol) was added. The mixture
was heated at 40 °C for 2 h. The reaction was quenched with water
at room temp. and the solvent then removed. The reaction mixture
was extracted with EtOAc (3ϫ 30 mL). The combined organic lay-
ers were washed with brine (3ϫ 30 mL), dried with MgSO4, fil-
tered, and concentrated. The residue was purified by flash column
chromatography (100% hexane Ǟ 10% EtOAc/hexane) to afford
alcohol 14 (805 mg, 75%) and methyl ketone 8 (22 mg, 2%).
General Procedures: Solvents were purified and dried by standard
procedures before use. 1H and 13C NMR spectra were recorded
with a Bruker ARX-400 spectrometer (400 MHz for 1H NMR,
100.61 MHz for 13C NMR) by using TMS as the internal standard
(chemical shifts δ in ppm, coupling constants J in Hz). Flash
chromatography (FC) was performed on silica gel (Merck 60, 230–
400 mesh); analytical TLC was performed on plates precoated with
silica gel (Merck 60 F254, 0.25 mm). Ozonolyses were carried out
with an Erwin Sander Labor ozonizer. Mass spectra (FAB, EI)
were recorded with a Fisons VG mass spectrometer and electron
spray ionization mass spectra (ESI-MS) were recorded with a
Bruker FTMS APEXIII. IR spectra were recorded with a JASCO
FT/I(R)-6100 spectrophotometer. Elemental analyses were re-
corded with a Carlo Erba 1108/combustion chromatography fun-
damental analyser.
[1R-(1α,3aβ,4α,7aα)]-(1,1-Dimethylethyl)dimethyl{[octahydro-7a-
methyl-1-(1-methylethenyl)-1H-inden-4-yl]oxy}silane (13): To a
stirred solution of iodide 12 (3.0 g, 6.88 mmol) in THF (30 mL)
was added tBuOK (1.5 g, 13.7 mmol) in DMSO (15 mL). The mix-
ture was stirred under Ar for 40 min and then poured into a mix-
ture of hexanes (40 mL) and water (40 mL). The reaction mixture
was extracted with EtOAc (3ϫ 50 mL). The combined organic lay-
ers were washed with brine (3ϫ 50 mL), dried with MgSO4, fil-
tered, and concentrated. The residue was purified by flash column
chromatography (100% hexane) to afford alkene 13 (1.78 g, 84%)
as a colorless oil. Rf = 0.9 (30% EtOAc/hexane). [α]2D1 = +35.5 (c
= 3.2, CHCl ). IR (NaCl, neat): ν = 2938, 2861, 1639, 1462, 1370,
˜
3
Eur. J. Org. Chem. 2013, 5678–5682
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5681

Z. Gándara, M. L. Rivadulla, M. Pérez, G. Gomez and, Y. Fall
FULL PAPER
Alcohol 14: White solid. M.p. 69–71 °C. Rf = 0.2 (10% EtOAc/
Acknowledgments
hexane). [α]2D1 = +37.6 (c = 2.0, CHCl ). IR (NaCl, neat): ν = 3338,
˜
3
2938, 2860, 1463, 1360, 1253, 1078, 1020, 920, 839, 772, 679 cm–1.
1H NMR (CDCl3): δ = 3.97 (d, J = 2.7 Hz, 1 H, 8-H), 3.55 (t, J =
8.5 Hz, 1 H, 17-H), 2.15–1.96 (m, 1 H, 14-H), 1.83–1.62 (m, 5 H),
1.49–1.30 (m, 4 H), 1.20 (m, 1 H), 0.95 (s, 3 H, 18-H), 0.88 (s, 9
H, CH3 tBuSi), 0.01 (s, 3 H, CH3 SiMe), –0.01 (s, 3 H, CH3 SiMe)
ppm. 13C NMR (CDCl3): δ = 82.07 (CH-17), 69.09 (CH-8), 47.95
(CH-14), 42.06 (C-13), 37.34 (CH2), 34.35 (CH2), 29.37 (CH2),
25.75 (CH3 tBuSi), 22.11 (CH2), 17.96 (C tBuSi), 17.22 (CH2),
This work was supported financially by the Xunta de Galicia (No.
EXPTE CN 2012/184). The work of the NMR, and MS divisions
of the research support services of the University of Vigo (CACTI)
is also gratefully acknowledged. Z. G. thanks the Xunta de Galicia
for an Angeles Alvariño contract.
[1] A. W. Norman, Vitamin D the Calcium Homeostatic Steroid
Hormone, Academic Press, New York, 1979.
12.53 (CH3-18), –4.65 (CH3-SiMe), –5.19 (CH3 SiMe) ppm. MS [2] For general reviews of vitamin D chemistry and biology, see:
(ESI): m/z (%) = 285.22 [M + 1]+ (30), 265.19 [M+ – H2O] (100),
177.11 (20). HRMS (ESI): calcd. for C16H33O2Si 285.22469; found
285.22443. C16H32O2Si (284.51): calcd. C 67.55, H 11.34; found C
67.47, H 11.48.
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the Steroid Hormone (Eds.: A. W. Norman, R. Bouillon, R.
Thomasset), Vitamin D Workshop, Riverside, CA, 1997; b) D.
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Methyl Ketone 8: Colorless oil. Rf = 0.4 (10 % EtOAc/hexane).
[α]2D1 = +71.1 (c = 0.6, CHCl ). IR (NaCl, neat): ν = 2933, 2858,
˜
3
1705, 1463, 1356, 1253, 1160, 1078, 1024, 922, 838, 774, 682 cm–1.
1H NMR (CDCl3): δ = 4.04 (s, 1 H, 8-H), 2.48 (t, J = 9.0 Hz, 1 H,
17-H), 2.21 (m, 1 H), 2.10 (s, 3 H, CH3 Ac), 2.01 (dt, J = 12.3,
3.6 Hz, 1 H), 1.90–1.77 (m, 1 H), 1.74–1.56 (m, 3 H), 1.53–1.36 (m,
5 H), 0.88 (s, 9 H, CH3 tBuSi), 0.86 (s, 3 H, 18-H), 0.02 (s, 3 H,
CH3 SiMe), 0.00 (s, 3 H, CH3 SiMe) ppm. 13C NMR (CDCl3): δ
= 209.51 (C=O), 68.86 (CH-8), 64.45 (CH-17), 53.18 (CH-14),
43.67 (C-13), 43.67 (CH2), 39.74 (CH2), 31.51 (CH3-21), 25.70
(CH3 tBuSi), 17.57 (CH2), 15.48 (CH2), –4.89 (CH3 SiMe), –5.25
(CH3 SiMe) ppm. MS (ESI): m/z (%) = 311.46 [M + 1]+ (43),
253.32 [M+ – tBu] (89), 225 (21), 179 (9). HRMS (ESI): calcd. for
C18H35O2Si 311.35677; found 311.37368. C18H34O2Si (310.55): C
69.62, H 11.03; found C 69.76, H 11.26.
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8β-[(tert-Butyldimethylsilyl)oxy]des-A,B-androstan-17-one (3): To a
stirred solution of alcohol 14 (935 mg, 3.29 mmol) in DCM
(30 mL) was added PDC (3.71 g, 9.87 mmol) and a catalytic
amount of PPTS at room temp. After 16 h, the reaction mixture
was filtered through a bed of Celite, and the solvent was removed.
The reaction mixture was extracted with EtOAc (3ϫ 40 mL). The
organics layers were washed with aqueous NaCl (3ϫ 40 mL), dried
with MgSO4, filtered, and concentrated. The residue was purified
by flash column chromatography (100% hexane Ǟ 10% EtOAc/
hexane) to afford ketone 3 (790 mg, 85%) as a colorless oil. Rf =
0.4 (10% EtOAc/hexane). [α]2D1 = +36.2 (c = 0.6, CHCl3). IR (NaCl,
neat): ν = 2935, 2889, 2858, 1741, 1465, 1375, 1165, 1078, 1029,
˜
1
974, 901, 839, 777, 688 cm–1. H NMR (CDCl3): δ = 4.08 (s, 1 H,
8-H), 2.36 (m, 1 H), 1.93 (m, 2 H), 1.68 (m, 4 H), 1.45 (m, 2 H),
1.33 (m, 1 H), 1.15 (m, 1 H), 1.03 (s, 3 H, 18-H), 0.83 (s, 9 H, CH3
tBuSi), –0.02 (s, 6 H, CH3 SiMe) ppm. 13C NMR (CDCl3): δ =
220.51 (C=O), 69.69 (CH-8), 48.49 (CH-14), 47.24 (C-13), 35.04
(CH2), 34.06 (CH2), 32.02 (CH2), 25.71 (CH3 tBuSi), 21.31 (CH2),
17.76 (C tBuSi), 16.94 (CH2), 16.38 (CH3-18), –4.86 (CH3 SiMe),
–5.17 (CH3 SiMe) ppm. MS (ESI-TOF): m/z (%) = 283.20
[M + 1]+ (19), 267.19 [M+ – Me] (63), 226.19 [M+ – tBuSi] (63).
HRMS (ESI): calcd. for C16H31O2Si 283.20839; found 283.2078.
C16H30O2Si (282.50): C 68.03, H 10.70; found C 67.64, H 10.75.
Supporting Information (see footnote on the first page of this arti-
Received: April 11, 2013
Published Online: July 23, 2013
1
cle): Copies of H and 13C NMR spectra for 13, 14, 8 and 3.
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Eur. J. Org. Chem. 2013, 5678–5682