A nonclassical stereoselective semi-synthesis of drospirenone via cross-metathesis reaction

Article abstract of DOI:10.1055/s-0028-1087226

A new synthetic approach for the construction of the spirolactone moiety of the progestin drospirenone is presented. A highly efficient cross-metathesis reaction catalyzed by Grubbs-Hoveyda second-generation catalyst (6 mol%) is employed as the key step for the introduction of the ester moiety on to the vinyl group at C17. No protecting groups are required and harmful heavy-metal-based oxidants are not used and this means that this route constitutes a valuable synthetic alternative to existing approaches. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087226

PAPER
3801
A Nonclassical Stereoselective Semi-Synthesis of Drospirenone via
Cross-Metathesis Reaction
Stereoselective
S
emi-S
a
ynthesis of
r
D
rospir
e
none o Bandini,*a Michele Contento,a Andrea Garelli,a Magda Monari,a Alessandra Tolomelli,a
Achille Umani-Ronchi,*a Erika Andriolo,b Mauro Montorsib
a
Dipartimento di Chimica ‘G. Ciamician’, Università di Bologna, via Selmi 2, 40126 Bologna, Italy
Fax +39(51)2099456; E-mail: marco.bandini@unibo.it; E-mail: achille.umanironchi@unibo.it
NEWCHEM S.p.A., via Roveggia 47, 37136 Verona, Italy
b
Received 29 July 2008; revised 6 August 2008
organic hypochlorites and catalytic amounts of 2,2,6,6-
tetramethylpiperidin-1-oxyl (TEMPO)1c,d constitute a
valuable alternative.
Abstract: A new synthetic approach for the construction of the
spirolactone moiety of the progestin drospirenone is presented. A
highly efficient cross-metathesis reaction catalyzed by Grubbs–
Hoveyda second-generation catalyst (6 mol%) is employed as the
key step for the introduction of the ester moiety on to the vinyl
group at C17. No protecting groups are required and harmful heavy-
metal-based oxidants are not used and this means that this route
constitutes a valuable synthetic alternative to existing approaches.
In the present, study we wish to communicate an unprec-
edented mild and direct approach for the synthesis of
drospirenone (1) starting from 3b,5-dihydroxy-
6b,7b;15b,16b-dimethylene-5b-androst-17-one (2).
Key words: cross-metathesis, drospirenone, stereoselection, ste-
roids, synthesis
O
OH
O
17
oxidation
The ready availability of potent agents against human hy-
pertension is of high clinical and public health impor-
tance. In this field, an extensive project addressing the
discovery of new aldosterone antagonists uncovered the
remarkable activity of drospirenone (ZK 30595,
6b,7b;15b,16b-dimethylene-3-oxo-17a-pregn-4-ene-
21,17-carbolactone, 1, Figure 1).1 Drospirenone (1) is a
spirolactone analogue which exhibits both antimineralo-
corticoid and antiandrogenic activity very similar to that
of the natural hormone progesterone. It is used as an oral
contraceptive in combination with ethinylestradiol be-
cause of its positive effect in preventing or reducing the
change in blood pressure, body weight, and low-density
lipoprotein levels that are generally caused by the use of
conventional oral contraceptives. Because of its charac-
teristics, drospirenone has found good applications in
menopausal HRT (hormone replacement therapy).
OH
O
ZK 30595 (1)
Figure 1 Key oxidative step in the synthesis of drospirenone
Focusing on operational simplicity and green-ness, we de-
signed a new synthetic approach that, by avoiding the use
of protecting groups,5 will reduce the production of waste
and will shorten the synthetic sequence.
In particular, the addition of a solution of vinylmagnesium
bromide (0.7 mM in Et2O, 5.6 equiv) at 0 °C to 2 led to the
formation of 3 in a highly stereoselective manner (a-at-
tack) in 88% isolated yield (Scheme 1).
O
HO
MgBr
(5.6 equiv)
To date, numerous synthetic approaches to 1 have been re-
ported with the main focus on the construction of the key
21,17-spirolactone structure.1,2 However, most of them
require the use of harmful heavy-metal-based oxidants for
the 17-(3-hydroxypropyl) chain (Figure 1).
H
H
THF,
0 °C to r.t.
88%
H
H
HO
HO
2
3
OH
OH
Scheme 1 Stereospecific vinylation of 2 via addition of vinylmag-
nesium bromide
Among them, chromic acid,3a pyridinium dichromate,3b
and ruthenium(III) chloride/sodium bromate3c have found
widespread application even in large scale chemistry.
However, the concomitant pronounced formation of
byproducts as well as large volumes of heavy-metal-con-
taining waste calls for the development of milder synthet-
ic approaches.4 In this direction, the use of inorganic and
The absolute configuration of the new stereocenter at C17
was confirmed to be S also through X-ray diffraction of 3
(Figure 2). For this analysis, single crystals of 3 were ob-
tained by slow evaporation from a solution of cyclohex-
ane–ethyl acetate (20:80).
Then, in order to introduce the ester moiety, we tested the
suitability of 3 as a cross-metathesis partner in combina-
tion with some ruthenium catalysts 4a–c (Table 1).6 For
this purpose an excess of methyl acrylate (5 equiv) was
SYNTHESIS 2008, No. 23, pp 3801–3804
Advanced online publication: 06.11.2008
DOI: 10.1055/s-0028-1087226; Art ID: Z17308SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
8

3802
M. Bandini et al.
PAPER
The catalyst 4c can be also recovered from flash chroma-
tography of the reaction crude and reused (loading 6
mol%) in the model cross-metathesis reaction. Under
these conditions, 5 was isolated in moderate yield (53%,
Table 1, entry 5).
The ring-closing step to the spirolactone fragment is
known to be crucial for the overall success of the synthe-
sis. As a matter of fact, partial epimerization of the C17
carbolactone stereocenter is frequently observed during
oxidative ring-closing procedures.8 A partial solution to
this issue is described in the present synthetic approach. In
fact, the ring-closing process can be carried out also in
one-pot manner by performing the hydrogenation under
higher pressure of hydrogen (8 bar). Here, spirolactone 6
was directly isolated in fairly good yield (60%) after flash
chromatographic purification [Scheme 2 (a)]. In contrast,
lower pressures of hydrogen (i.e., 1 bar) led to exclusive
reduction of the C=C bond in quantitative manner.
Figure 2 X-ray crystal structure of 3
treated with 3 in a degassed solution (CH2Cl2) of 4 (12
mol%).
After 24 hours at reflux, the first-generation Grubbs’ cat-
alyst 4a failed to provide 5, with the recovering of unre-
acted 3 (80%). In contrast, the second-generation catalyst
4b promoted the cross metathesis in good yield (55%).
The highest yield (82%) was obtained in a shorter reaction
time (3 h) with the Grubbs–Hoveyda second-generation
catalyst 4c (12 mol%), which is known to be very efficient
in catalyzing cross-metathesis reactions involving chal-
lenging electron-deficient C=C bonds.7 Attempts to im-
prove practical aspects of the process were performed by
lowering the catalyst loading to 6 mol%. Interestingly, un-
der optimal operational conditions, 5 was isolated in 80%
yield (E/Z >20:1, Table 1, entry 4). Moreover, no preven-
tive protection of the hydroxy groups was necessary for
the cross-metathesis reaction.
Finally, with the synthesis of the C17 lactone already ac-
complished, the chemoselective oxidation–dehydration of
ring A can be performed under mild conditions; a particu-
lar concern was to avoid hazardous transition-metal-based
oxidants.
In particular, the selective oxidation of C3 by treatment of
6 with two equivalents of Dess–Martin periodinane
(CH2Cl2, r.t.) followed by acidic dehydration (PTSA 40
mol%, THF) afforded the desired drospirenone (1) in 60%
yield (two steps), without detectable concomitant epimer-
ization of the C17 position [Scheme 2 (b)].
Table 1 Screening of Ruthenium Catalysts in the Cross-Metathesis Reaction of 3 and Methyl Acrylatea
O
HO
HO
OMe
catalyst
CO2Me
CH2Cl2, reflux
H
H
H
H
HO
HO
OH
3
OH
5 (E/Z > 20:1)
N
N
Mes
Mes
PCy3
Cl
N
N
Cl
Mes
Mes
Ph
Ru
O
Cl
Ru
catalyst:
Cl
Ph
Cl
Ru
Cl
PCy3
PCy3
4a
4b
4c
Entry
Catalyst (mol%)
4a (12)
Time (h)
Yieldb (%) of 5
Recovered 3b (%)
1
24
24
3
0
55
82
80
53
80
20
8
2
4b (12)
3
4c (12)
4
4c (6)
3
9
5c
4c (6)
3
20
a All the reactions were carried out under an inert atmosphere in anhyd CH2Cl2. An excess (5 equiv) of acrylate was employed.
b After flash chromatography.
c Recycled catalyst 4c was used.
Synthesis 2008, No. 23, 3801–3804 © Thieme Stuttgart · New York

PAPER
Stereoselective Semi-Synthesis of Drospirenone
3803
(m, 1 H), 1.11–1.60 (m, 14 H), 0.91 (s, 3 H), 0.84 (s, 3 H), 0.77–0.88
O
O
(m, 1 H), 0.58–0.68 (m, 1 H), 0.37 (q, J = 6.3 Hz, 1 H).
HO
O
13C NMR (75 MHz, CDCl3): d = 142.6, 112.1, 83.3, 74.8, 67.1,
52.4, 44.8, 43.0, 42.4, 40.4, 37.7, 34.1, 27.7, 26.8, 25.3, 24.4, 21.7,
19.0, 18.7, 16.6, 15.3, 11.7, 8.3.
OMe
H
H2 (8 bar),
Pd/C (10%)
H
a)
H
LC-MS: m/z = 381 (M + Na),+ 739 (2 M + Na)+.
H
THF, r.t.
58%
HO
HO
OH
Anal. Calcd for C23H34O3 (358.25): C, 77.05; H, 9.56. Found: C,
77.12; H, 9.58.
5
6
OH
O
O
Methyl (E)-[3b,5,17b-Trihydroxy-6b,7b;15b,16b-dimethylene-
5b-androstan-17a-yl]propenoate (5)
O
O
Allyl alcohol derivative 3 (358 mg, 1.0 mol) was dissolved in de-
gassed CH2Cl2 (10 mL, freezing pump), and methyl acrylate (450
mL, 5.0 mol) was added. The mixture was stirred for 5 min then
Grubbs–Hoveyda II catalyst 4c (36 mg, 6 mol%) was added in one
portion. The mixture was refluxed for 3 h and the volatiles eliminat-
ed under reduced pressure. The crude product was purified by flash
chromatography to give the product as a white powder; yield: 80%;
mp 118–119 °C; Rf = 0.3 (cyclohexane–EtOAc–CH2Cl2, 70:20:10).
H
1) Dess–Martin
CH2Cl2
b)
H
2) PTSA, THF,
r.t., 60%
HO
1
6
O
OH
Scheme 2 (a) Reductive spirolactonization of 5; (b) direct oxida-
tion/dehydration in presence of Dess–Martin periodinane
[a]D25 –27.5 (c 1.0, CH2Cl2).
Considering chemical and environmental aspects, the
present semi-synthetic approach can be considered a com-
petitor to known synthetic strategies. In fact, highest over-
1H NMR (300 MHz, CDCl3): d = 7.13 (d, J = 15.6 Hz, 1 H), 6.12 (d,
J = 15.6 Hz, 1 H), 4.02 (br s, 1 H), 3.77 (s, 3 H), 3.35 (br s, 1 H),
2.71 (br s, 1 H), 2.40 (dd, J = 3.0, 15.0 Hz, 1 H), 1.71–1.87 (m, 3
all yield, in comparison with well-established protocols3b H), 1.52–1.59 (m, 2 H), 1.05–1.41 (m, 13 H), 0.95 (s, 3 H), 0.84 (s,
3 H), 0.76–0.94 (m, 1 H), 0.60–0.68 (m, 1 H), 0.38–0.46 (m, 1 H).
was obtained (25% vs. 16%) and the replacement of haz-
ardous pyridinium dichromate with Dess–Martin periodi-
nane, in the final oxidation step, was demonstrated.
13C NMR (75 MHz, CDCl3): d = 167.3, 152.4, 118.1, 83.3, 74.8,
67.1, 52.7, 51.7, 44.7, 43.2, 43.0, 40.4, 37.4, 34.2, 27.7, 26.8, 25.3,
24.7, 21.7, 19.0, 18.8, 16.9, 15.2, 11.7, 8.5.
In conclusion, in this communication a new mild and effi-
cient semi-synthesis of drospirenone is presented. No pro-
tecting groups are required and this dramatically shortens
the synthetic sequence making it suitable even for large-
scale productions.
LC-MS: m/z = 439 (M + Na)+, 855 (2 M + Na)+.
Anal. Calcd for C25H36O5 (416.26): C, 72.08; H, 8.71. Found: C,
72.08; H, 8.71.
3b,5-Dihydroxy-6b,7b;15b,16b-dimethylene-5b,17a-pregnane-
21,17-carbolactone (6)
1H NMR spectra were recorded by means of Varian Gemini-200
(200 MHz) or Varian INOVA-300 (300 MHz) spectrometers with
TMS as reference. 13C NMR spectra were recorded on a Varian
Gemini-200 (50 MHz) or Varian INOVA-300 (75 MHz) spectrom-
eters with complete proton decoupling with the solvent as the inter-
nal standard (CDCl3: d = 77.0). LC-ESI MS were obtained with
Agilent Technologies MSD1100 single-quadrupole mass spectrom-
eter. IR analysis were performed with a FT-IR NICOLET 380 spec-
trophotometer.
a,b-Unsaturated ester 5 (298 mg, 0.72 mmol) was dissolved in re-
agent grade THF (10 mL) followed by the addition of Pd/C (10%)
(75 mg). The mixture was stirred overnight under an atmosphere of
H2 (8 bar). Then, after filtration over Celite, the solvent was evapo-
rated and the crude product was purified by flash chromatography
to give a white solid; yield: 58% (two steps); mp 168–170 °C;
Rf = 0.3 (cyclohexane–EtOAc, 50:50).
[a]D25 –14.0 (c 0.16, CH2Cl2).
1H NMR (300 MHz, CDCl3): d = 4.10 (q, J = 7.5 Hz, 1 H), 4.04 (br
s, 1 H), 2.90 (br, 1 H), 2.43–2.65 (m, 4 H), 1.72–2.23 (m, 4 H),
1.20–1.55 (m, 14 H), 0.94 (s, 3 H), 0.84 (s, 3 H), 0.80–0.82 (m, 1
H), 0.61–0.70 (m, 1 H), 0.51 (q, J = 8.4 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 176.7, 96.4, 74.6, 67.0, 52.1, 44.7,
43.0, 41.9, 40.4, 37.3, 33.7, 30.7, 29.3, 27.7, 26.8, 25.2, 24.2, 21.5,
19.7, 19.0, 16.7, 15.0, 11.7, 10.0.
6b,7b;15b,16b-Dimethylene-5b,17a-pregn-20-ene-3b,5,17-triol
(3)
3b,5-Dihydroxy-6b,7b;15b,16b-dimethylene-5b-androst-17-one
(2, 1.5 g, 4.6 mmol) was dissolved in anhyd THF (40 mL) under N2.
The soln was cooled to 0 °C then 0.7 M vinylmagnesium chloride
in THF (35 mL, 25 mmol, 5.6 equiv) was added dropwise. The re-
action was allowed to warm to r.t. over 2 h, then quenched with sat.
NH4Cl (15 mL). The organic solvent was evaporated under reduced
pressure and the aqueous layer was extracted with CH2Cl2 (3 × 25
mL). The combined organic phases were dried (Na2SO4) and the
volatiles removed under reduced pressure. Pure 3 was obtained
through flash chromatographic purification as a white powder;
yield: 88%; mp 158–160 °C; Rf = 0.3 (cyclohexane–EtOAc, 50:50).
LC-MS: m/z = 409 (M + Na)+, 795 (2 M + Na)+.
Anal. Calcd for C24H34O4 (386.25): C, 74.58; H, 8.87. Found: C,
74.51; H, 8.90.
Drospirenone (6b,7b;15b,16b-Dimethylene-3-oxo-17a-pregn-4-
ene-21,17-carbolactone, 1)
In a flamed two–necked round–bottom flask were added in se-
quence: anhyd CH2Cl2 (10 mL), 6 (160 mg, 0.42 mol), and Dess–
Martin reagent (363 mg, 0.83 mmol). The mixture was stirred at r.t.
overnight when the reaction was judged complete by TLC. H2O (10
mL) was added and after stirring for 15 min, the insoluble white res-
idue was removed by filtration over Celite. The two phases were
separated and the aqueous layer extracted with CH2Cl2 (3 × 10 mL).
[a]D –40.0 (c 0.1, CH2Cl2).
1H NMR (300 MHz, CDCl3): d = 6.02 (dd, J = 10.8, 16.8 Hz, 1 H),
5.28 (dd, J = 1.5, 16.8 Hz, 1 H), 5.15 (dd, J = 1.2, 10.8 Hz, 1 H),
4.03 (br s, 1 H), 3.49 (m, 1 H), 2.72 (br s, 1 H), 2.20 (dd, J = 3.3,
12.4 Hz, 1 H), 1.93–1.99 (m, 2 H), 1.80–1.87 (m, 1 H), 1.64–1.76
Synthesis 2008, No. 23, 3801–3804 © Thieme Stuttgart · New York

3804
M. Bandini et al.
PAPER
The combined organic phases were combined, dried (Na2SO4), and
concentrated under vacuum. The crude was then dissolved in re-
agent grade THF (5 mL) and PTSA (10 mg, 40 mol%) was added.
After stirring at r.t. for 1 h, H2O (10 mL) was added and the THF
evaporated under reduced pressure. After usual workup of the re-
maining aqueous layer (CH2Cl2, brine, Na2SO4), analytically pure
drospirenone was obtained by flash chromatography as a white sol-
id; yield: 60% (two steps); mp 200 °C; Rf = 0.3 (cyclohexane–
EtOAc, 45:55).
[a]D25 –181 (c 0.5, CHCl3).
1H NMR (200 MHz, CDCl3): d = 6.05 (s, 1 H), 2.39–2.61 (m, 4 H),
1.09 (s, 3 H), 1.00 (s, 3 H), 0.42–0.62 (m, 1 H), 0.82–2.19 (m, 18 H).
References
(1) (a) Elger, W.; Beier, S.; Pollow, K.; Garfield, R.; Shi, S. Q.;
Hillisch, A. Steroids 2003, 68, 891. (b) Wiechert, R. In
Analogue-based Drug Discovery; Fischer, J.; Ganellin, C.
R., Eds.; Wiley-VCH: Berlin, 2006, Chap. 20, 395.
(c) Costantino, F.; Lenna, R.; Piuri, S. WO 2006,061,309,
2006. (d) Seilz, C.; Seba, H. WO 2007,009,821, 2007.
(2) Gálik, G.; Horváth, J.; Sörös, B.; Mahó, S.; Tuba, Z.;
Balogh, G. WO 2006,059,168, 2006.
(3) (a) Sam, K. M.; Auger, S.; Luu-The, V.; Poirier, D. J. Med.
Chem. 1995, 38, 4518. (b) Bittler, D.; Hofmeister, H.;
Laurent, H.; Nickisch, K.; Nickolson, R.; Petzoldt, K.;
Wiechert, R. Angew. Chem., Int. Ed. Engl. 1982, 21, 696;
Angew. Chem. 1982, 94, 718. (c) Mohr, J.-Y.; Nickisch, K.
US 6,933,395, 2005.
13C NMR (75 MHz, CDCl3): d = 197.6, 176.4, 171.1, 125.6, 103.8,
95.9, 51.6, 51.5, 41.5, 37.2, 36.9, 34.0, 33.8, 30.5, 29.1, 24.2, 20.7,
19.6, 19.5, 18.8, 18.7, 17.4, 16.5, 9.7.
(4) Waldemar, A.; Chantu, R. S.-M.; Pralhad, A. G. Chem. Rev.
2001, 101, 3499.
LC-MS: m/z = 367 (M + H)+, 755 (2 M + Na)+.
(5) Crabtree, R. H. Science 2007, 318, 756.
Anal. Calcd for C24H30O3 (366.22): C, 78.65; H, 8.25. Found: C,
78.55; H, 8.16.
(6) (a) Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-
VCH: Weinheim, 2003. (b) Schrock, R. R.; Hoveyda, A. H.
Angew. Chem. Int. Ed. 2003, 42, 4592. (c) Connon, S. J.;
Blechert, S. Angew. Chem. Int. Ed. 2003, 42, 1900.
(d) Astruc, D. New J. Chem. 2005, 29, 42. (e) Clavier, H.;
Grela, K.; Kirschning, A.; Mauduit, M.; Nolan, S. P. Angew.
Chem. Int. Ed. 2007, 46, 6786. (f) Nicolaou, K. C.; Bulger,
P. G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4490.
(g) Schrodi, Y.; Pedersen, R. L. Aldrichimica Acta 2007, 2,
45; and references therein.
Acknowledgment
This work was supported by M.I.U.R. (Rome) and from University
of Bologna. We thank Newchem S.p.A. for financial support.
(7) Hoveyda, A. H.; Gillingham, D. G.; Van Veldhuizen, J. J.;
Kataoka, O.; Garber, S. B.; Kingsbury, J. S.; Harrity, J. P. A.
Org. Biomol. Chem. 2004, 2, 8.
(8) Nickisch, K.; Bittler, D.; Laurent, H.; Wiechert, R.
Tetrahedron Lett. 1986, 27, 5463.
Synthesis 2008, No. 23, 3801–3804 © Thieme Stuttgart · New York