Synthesis of (3S)-hydroxyandrosta-5,7-diene-17-ones via intramolecular cobalt-mediated [2+2+2] cycloaddition

Article abstract of DOI:10.1055/s-2006-939064

A new method for the synthesis of lumisterin-type steroids following the D→ABCD approach is reported. A key step is the cobalt-induced cyclization of a cyclopentanoid enediyne, which was prepared via thioalkylation of the zinc enolate of a 2,3-substituted

Full text of DOI:10.1055/s-2006-939064

LETTER
905
Synthesis of (3S)-Hydroxyandrosta-5,7-diene-17-ones via Intramolecular
Cobalt-Mediated [2+2+2] Cycloaddition1
S
ynthesis of (3
S
)-H
l
ydrox
r
yandrost
i
a-5,7-d
c
iene-17-on
h
e
s
Groth,* Norbert Richter, Aris Kalogerakis
Fachbereich Chemie der Universität Konstanz, Universitäts Str. 10, Postfach M-720, 78457 Konstanz, Germany
Fax +49(7531)884155; E-mail: ulrich.groth@uni-konstanz.de
Received 7 November 2005
thioalkylation reaction5 at a very late stage of the synthe-
sis (Scheme 1). The PG2-protected hydroxy group of cy-
clopentanone 3 was then converted after deprotection,
oxidation, and a Corey–Fuchs alkynation to the desired
triple bond in 2. After cleavage of the protective group
PG1 and Swern oxidation, we introduced the propargylic
moiety enantiomerically using a chiral boron–allene com-
plex.6 Cobalt-mediated cyclization of enediyne 2 should
afford either ergosterin or lumisterin-type steroids. The si-
multaneous formation of the stereogenic center at C-9 and
C-10 of the steroid should be exclusively induced by the
trans-configured centers at C-2 and C-3 of the cyclopen-
tanone precursor since the stereogenic center in the
sidechain at C-7¢ does not have any stereochemical influ-
ence on the outcome of this cyclization.2
Abstract: A new method for the synthesis of lumisterin-type ste-
roids following the D→ABCD approach is reported. A key step is
the cobalt-induced cyclization of a cyclopentanoid enediyne, which
was prepared via thioalkylation of the zinc enolate of a 2,3-substi-
tuted cyclopentanone with a-chlorosulfides.
Key words: cobalt, cycloaddition, cyclopentanones, steroids, vita-
mins
Recently, we reported the cobalt-mediated [2+2+2] cy-
cloaddition of 4-hydroxy-substituted enediynes2 towards
2-hydroxy-substituted decahydrophenanthrenes.3 The hy-
droxy group in the propargylic position was tolerated un-
der the chosen reaction conditions. Furthermore, it has
been demonstrated that this stereogenic center does not
have any influence on the formation of the stereogenic
centers from the Z double bond, which were transformed
to trans-phenanthrenes in a diastereomeric ratio of almost
1:1. These trans-phenanthrenes represent the ABC-
framework of ergosterin or lumisterin. Consequently, a
diastereoselective synthesis of (3S)-hydroxyandrosta-5,7-
diene-17-ones 1, precursors of vitamin D, was envisioned
by following the D→ABCD approach. Recently, Mala-
cria reported the preparation of 11-aryl-substituted ste-
roids via cobalt(I)-mediated cyclization of allenediynes.4
For the synthesis of the a-chlorosulfides 7 we started from
the TBDMS-7, TBDPS-,8 and Bn9-O-protected pentynols
4 (Scheme 2). After Cp2ZrCl2-catalyzed carbo-alumina-
tion of 4 the corresponding vinyl alanes were treated with
n-BuLi and ethylene oxide to afford the E-alkenols 5.2
The alcohols 5 were mesylated and then transformed into
the phenylsulfides 6 by reaction with KSPh in dimethyl-
sulfoxide at room temperature. Finally, chlorination with
N-chlorosuccinimide in CCl4 gave the chlorides 7.
The synthesis of the cyclopentanones 9 was achieved
starting from the known racemic 3-hydroxymethyl-2-
methylcyclopentanone 8 by protection of the hydroxy
In this convergent synthesis, the racemic ring D (building
block 9) and the alkene side chain 7 were connected by a
O
O
9
2
3
7'
10
H
H
PG3O
H
PG3O
1
2
O
O
Cl
SPh
PG1O
PG1O
3
7
O
9
PG2O
Scheme 1
SYNLETT 2006, No. 6, pp 0905–0908
0
4.
0
4.
2
0
0
6
Advanced online publication: 14.03.2006
DOI: 10.1055/s-2006-939064; Art ID: G34205ST
© Georg Thieme Verlag Stuttgart · New York

906
U. Groth et al.
LETTER
O
O
a
OH
b, c
R2
R1O
R1O
a
9a
9b
9c
TBDMS
Bz
4
5
Cl
R1
Bn
R2O
HO
8
9
SPh
d
SPh
7a
7b
7c
TBDMS
Scheme 3 Reagents and conditions: (a) rac-9a: R2 = TBDMS,
TBDMS-Cl (1.2 equiv), imidazole (2.5 equiv), DMF, 0 °C to r.t., 3 h
(70%); rac-9b: R2 = Bz, BzCl (1.25 equiv), pyridine (1.25 equiv),
CH2Cl2, r.t., 18 h (74%); rac-9c: R2 = Bn, BnOC=NHCCl3 (2 equiv),
CH2Cl2–THF (5:1), 0 °C, 2 h (60%).
R1O
TBDPS
Bn
R1O
6
7
Scheme 2 Reagents and conditions: (a) (i) AlMe3 (3 equiv),
Cp2ZrCl2 (40 mol%), toluene, 0 °C, 30 min, then 4, 50 °C, 76 h; (ii)
n-BuLi (3 equiv), –65 °C to –40 °C, then ethylene oxide (3.5 equiv);
(b) Et3N (1.5 equiv), MsCl (1.1 equiv), CH2Cl2, –10 °C, 15 min; (c) t-
BuOK (1.2 equiv), PhSH (1.2 equiv), DMSO, r.t., 1 h; (d) NCS (1.3
equiv), CCl4, r.t., 12 h. 7a: R1 = TBDMS (60% overall yield), 7b:
R1 = TBDPS (55% overall yield), and 7c: R1 = Bn (44% overall
yield).
silyl protected rac-10b decomposed under the same con-
ditions. Protection of 11 with TBDPSCl and imidazole,
resulted in cleavage of the TBDMS group under mild con-
ditions and Swern oxidation of the alcohol obtained pro-
vided the aldehyde rac-12. Corey–Fuchs alkynation,11
desilylation with TBAF·3H2O, and oxidation under the
same conditions as above gave aldehyde rac-13, which
was converted to the enediyne 14 using Yamamoto’s
chiral allenylboronic ester6 and protection of the propar-
gylic alcohol obtained as its MEM ether.
group as its silyl ether rac-9a (TBDMSCl and imidazole),
as its benzoate ether rac-9b (BzCl and pyridine), or as
its benzyl ether rac-9c (benzyltrichloroacetimidate)
(Scheme 3).10
The a-thioalkylation of cyclopentanones 9 was achieved
by deprotonation of these cyclopentanones with potassi-
um hydride, transmetalation of the generated enolates
with ZnCl2 into the zinc enolates and reaction with the
a-chlorophenyl sulfides 7. However, only alkylation of
the TBDMS-O-protected cyclopentanone 9a with the
TBDPS- and Bn-O-protected alkenes 7b and 7c was suc-
cessful. While reductive desulfurization of rac-10c with
lithium in diethyl amide gave the desired alkene 11 with
concomitant cleavage of the benzyl protecting group, the
Subsequent CpCo(CO)2-mediated [2+2+2] cycloaddition
of the diastereomeric pair 14/14¢ (1:1) in refluxing toluene
with exposure to visible light followed by oxidative de-
metallation with FeCl3 afforded the (3S)-hydroxyandros-
ta-5,7-diene-17-ones 15 (Scheme 5).12 Both the ratio and
the absolute configuration of the obtained steroids were
determined by comparison of their 13C NMR spectra with
the 13C NMR spectrum of an authentic sample of (3b)-3-
methoxyethoxymethoxyandrosta-5,7-dien-17-one 17.14
O
O
SPh
a
b
9a + 7b,c
HO
R1O
TBDMSO
O
rac-11
rac-10b R1 = TBDPS
rac-10c R1 = Bn
OTBDMS
f, g, h
O
c, d, e
TBDPSO
O
O
rac-12
rac-13
O
O
i, j
MEMO
MEMO
14'
14
Scheme 4 Reagents and conditions: (a) KH (1 equiv), THF, r.t., then ZnCl2 (2.5 equiv), –15 °C to –80 °C, then 7, –80 °C to r.t., 15 h; 7b:
R1 = TBDPS (32%, 10b); 7c: R1 = Bn (35%, 10c); (b) R1 = Bn, Li (3 equiv), EtNH2, –20 °C to reflux (68%); (c) TBDPSCl (1.2 equiv), imidazole
(2.5 equiv), DMF, r.t. (94%); (d) 1% HCl in EtOH, r.t., 2 h (80%); (e) (COCl)2, Et3N, DMSO, CH2Cl2, –65 °C (94%); (f) (i) PPh3 (4 equiv),
CBr4 (2 equiv), CH2Cl2, 0 °C, 30 min, then 12, 30 min (76%); (ii) t-BuLi (3 equiv), THF, –80 °C, 30 min (78%); (g) TBAF·3H2O (1.2 equiv),
THF, r.t., 4 h (90%); (h) (COCl)2, Et3N, DMSO, CH2Cl2, –65 °C (78%); (i) CH2=C=CHB(OH)2 (1 equiv), D-(–)-diisopropyl tartrate (2 equiv),
toluene, –80 °C, then 13, 24 h (78%); (j) i-Pr2NEt (1.5 equiv), CH3OCH2CH2OCH2Cl (1.5 equiv), CH2Cl2, 0 °C to r.t., 18 h (88%).
Synlett 2006, No. 6, 905–908 © Thieme Stuttgart · New York

LETTER
Synthesis of (3S)-Hydroxyandrosta-5,7-diene-17-ones
907
This was synthesized starting from commercially Table 1 Selected 13C NMR data
available13 (3b)-3-androsta-5-en-17-one 16 by employing
Steroida 15a
15¢a
75.81
15¢b
71.00
15b
75.31
17b
75.32
the phenylsulfoxide method of Confalone and co-workers
(Scheme 6).14
C-3
C-5
C-6
C-18
70.74
Starting from a 1:1 mixture of 14 and 14¢ the formation of
the stereogenic centers C-9 and C-10 should be controlled
only by the cyclopentanoid moiety. Consequently, the
diastereomeric pairs 15a/15¢a and 15b/15¢b must be ob-
tained each in a 1:1 ratio. The lumisterin and ergosterin
140.82
120.00
13.66
7
142.15
119.66
13.81
7
139.16
119.54
13.95
1
141.16
119.21
13.51
1
141.14
119.22
13.50
–
precursors ratio of 15a/15b was found to be 7:1 after the Ratio
13C NMR data of 15b were determined, which coincided
a Chemical shift in ppm.
with those of 17, prepared from 16 (Scheme 6). Table 1
shows selected data and the ratio of the prepared steroids.
b Prepared from 16 in enantiomerically and diastereomerically pure
form.
O
substituted cyclopentanones and cyclopentanes are well-
known,1a the synthesis of the steroid skeleton described
herein offers a new convergent approach to vitamin D
compounds (deltanoids) following the construction prin-
ciple D→ABCD. Extension of this strategy to the synthe-
sis of substituted steroids (provitamin analogues), which
can been transformed directly, after photolysis and ther-
mal isomerization, to related vitamin D is under investiga-
tion.
2
7'
3
MEMO
1. CpCo(CO)2, hν,
toluene, 120 °C
14
O
2. FeCl3
33%
MEMO
14'
Acknowledgment
O
O
The authors are grateful to the Fonds der Chemischen Industrie for
financial support and the Wacker Chemie GmbH for valuable star-
ting materials. N.R. thanks the Cusanus Werk – Bischöfliche Hoch-
begabtenförderung for a doctoral fellowship.
H
H
H
H
MEMO
MEMO
15'a
15'b
References and Notes
O
O
18
(1) (a) Stereoselective Synthesis of Steroids and Related
Compounds, VIII. For part VII, see: Groth, U.; Halfbrodt,
W.; Kalogerakis, A.; Köhler, T.; Kreye, P. Synlett 2004,
291. (b) Transition Metal Catalyzed Reactions in Organic
Synthesis, XI. For part X, see: Groth, U.; Huhn, T.;
Kesenheimer, C.; Kalogerakis, A. Synlett 2005, 1758.
(2) Applications to natural products synthesis: (a) Johnson, E.
P.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1991, 113, 381.
(b) Germanas, J.; Aubert, C.; Vollhardt, K. P. C. J. Am.
Chem. Soc. 1991, 113, 4006. (c) Pérez, D.; Siesel, B. A.;
Malaska, M. J.; David, E.; Vollhardt, K. P. C. Synlett 2000,
306. (d) Eichberg, M. J.; Dorta, R. L.; Lamottke, K.;
Vollhardt, K. P. C. Org. Lett. 2000, 2, 2479. (e) Eichberg,
M. J.; Dorta, R. L.; Grotjahn, D. B.; Lamottke, K.; Schmidt,
M.; Vollhardt, K. P. C. J. Am. Chem. Soc. 2001, 123, 9324.
For the synthesis of the taxoid core, see also:
9
10
H
H
H
H
3
5
MEMO
MEMO
6
15a
15b
lumisterin precursor
ergosterin precursor
:
7
1
Scheme 5
O
O
H
H
H
H
(f) Phansavath, P.; Aubert, C.; Malacria, M. Tetrahedron
Lett. 1998, 39, 1561. (g) Petit, M.; Chouraqui, G.;
Phansavath, P.; Aubert, C.; Malacria, M. Org. Lett. 2002, 4,
1027.
HO
MEMO
16
17
Scheme 6
(3) Groth, U.; Richter, N.; Kalogerakis, A. Eur. J. Org. Chem.
2003, 4634.
(4) (a) Wiechert, R. Angew. Chem., Int. Ed. Engl. 1970, 9, 321;
Angew. Chem. 1970, 82, 331. (b) Wiechert, R. Angew.
Chem., Int. Ed. Engl. 1970, 16, 506; Angew. Chem. 1977, 89,
513. (c) Quinkert, G.; Stark, H. Angew. Chem., Int. Ed. Engl.
1983, 22, 637; Angew. Chem. 1983, 95, 651. (d) Steglich,
W.; Fugmann, B.; Lang-Fugmann, S. RÖMPP Natural
In summary, the formation of the tetracyclic core 1 is re-
ported via an intramolecular cobalt-mediated [2+2+2] cy-
cloaddition of an enediyne, which has been synthesized
starting from a substituted thiochloride and a 2,3-disubsti-
tuted cyclopentanone. Since several chiral syntheses of
Synlett 2006, No. 6, 905–908 © Thieme Stuttgart · New York

908
U. Groth et al.
LETTER
Products; Thieme: Stuttgart, 2000, 608. (e) Krause, S.;
Schmalz, H.-G. In Organic Synthesis Highlights, IV; Wiley-
VCH: Weinheim, 2000, 212. (f) Posner, G. H.; Kahraman,
M. Eur. J. Org. Chem. 2003, 3889. (g) Habermehl, G.;
Hammann, P. E.; Krebs, H. C. Naturstoffchemie; Springer:
Berlin, 2002, 49. (h) Recently, a new method for the
construction of steroids was reported: Sünnemann, H. W.; de
Meijere, A. Angew. Chem. 2004, 116, 913; Angew. Chem.
Int. Ed. 2004, 43, 895. (i) For the use of the D→ABCD
approach in the synthesis of steroids see also: Vollhardt, K.
P. C. Pure Appl. Chem. 1985, 57, 1819. (j) Petit, M.;
Aubert, C.; Malacria, M. Org. Lett. 2004, 6, 3937.
Torr). The residue was dissolved in degassed Et2O–pentane
(1:4, 10 mL) and filtered through celite under an argon
atmosphere. FeCl3·H2O (0.49 g, 1.8 mmol) was dissolved in
MeCN (20 mL), pentane (20 mL) was added and the mixture
cooled to –20 °C. At this temperature the filtrate was added
under stirring, and stirring was continued for 30 min. The
reaction mixture was cooled to –60 °C and the pentane layer
was removed from the frozen MeCN layer. The MeCN layer
was allowed to warm to –20 °C, pentane (15 mL) was added,
and the above procedure was repeated four times. The
pentane layers were combined, the solvent was removed in
vacuo (30 °C/18 Torr), and the residue purified by
(5) Groth, U.; Huhn, T.; Richter, N. Liebigs Ann. Chem. 1993,
49.
chromatography on silica gel (Et2O–pentane, 1:1) to afford
steroids 15 (66.65 mg, 0.18 mmol, 33%).
(6) (a) Haruta, R.; Ishiguro, M.; Ikeda, N.; Yamamoto, H. J. Am.
Chem. Soc. 1982, 104, 7667. (b) Ikeda, N.; Isao, A.;
Yamamoto, H. J. Am. Chem. Soc. 1986, 108, 483.
(7) Pereira, R.; Iglesias, B.; Lera, A. R. Tetrahedron 2001, 57,
7871.
(8) Baldwin, J. E.; Romeril, S. P.; Lee, V.; Claridge, T. D. W.
Org. Lett. 2001, 3, 1145.
(9) Franck, X.; Araujo, M. E. V.; Julian, J.-C.; Hocquemiller,
R.; Figadère, B. Tetrahedron Lett. 2001, 42, 2801.
(10) Eckenberg, P.; Groth, U.; Huhn, T.; Richter, N.; Schmeck,
C. Tetrahedron 1993, 49, 1619.
(11) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769.
(12) Cobalt-mediated [2+2+2] cycloaddition: A solution of
enediyne 14 (200 mg, 0.54 mmol) in toluene (80 mL) was
cooled to –70 °C and the apparatus was evacuated for 3 min
(0.5 Torr). The flask was allowed to warm to r.t. and the
apparatus was filled with argon. The solution of enediyne in
toluene was cooled to –70 °C and the above procedure was
repeated twice. CpCo(CO)2 (117 mg, 0.65 mmol) was added
and the reaction mixture was refluxed under radiation with
visible light until no starting material could be detected by
TLC analysis. The reaction mixture was cooled to r.t. and
volatile components were removed in vacuo (20 °C/0.1
Compound 15a/15¢a (signals of the major diastereomeric
pair): Rf = 0.27 (Et2O–PE, 1:1). 1H NMR (250 MHz,
CDCl3): d = 0.76 and 0.84 (2 s, 6 H, 2 × CH3), 1.20–2.80 (m,
16 H, CH2, CH), 3.40 (s, 3 H, OCH3), 3.50–3.64 and 3.66–
3.79 (2 × m, 5 H, OCH2CH2O, OCH), 4.78 (dd, J = 6 Hz,
6 Hz, 2 H, OCH2O), 5.47–5.68 (m, 2 H, C=CHC=CH).
13C NMR (50.3 MHz, CDCl3): d = 13.66 and 13.81 (C-18),
18.05, 18.38, 20.20, 20.23, 26.17, 28.80, 29.06, 33.96,
35.78, 35.85, 35.93, 36.12, 37.08, 38.03, and 38.28 (C-1, C-
2, C-4, C-10, C-11, C-12, C-15, C-16), 20.30 (C-19), 46.27
and 46.58 (C-9), 46.77 (C-13), 59.04 (C-23), 66.78 and
71.79 (C-21, C-22), 70.74 and 75.81 (C-3), 93.35 and 93.73
(C-20), 116.50, 116.57, 119.66 and 119.99 (C-6, C-7),
137.46, 137.94, 140.82 and 142.15 (C-5, C-8), 220.97 and
221.15 (C-17). MS (70 eV): m/z (%) = 374 (2) [M+], 268
+
(100) [M – C4H10O3]+, 89 (35) [C4H10O3 ], 59 (60)
[C3H7O+]. HRMS: m/z calcd C23H34O4 for 374.2457; found:
374. 2459.
(13) Purchased from Aldrich.
(14) (a) Confalone, P. N.; Kulesha, I. D.; Uskoković, M. R. J.
Org. Chem. 1981, 46, 1030. (b) Okabe, M.; Sun, R.-C.;
Scalone, M.; Jibilian, C. H.; Hutchings, S. D. J. Org. Chem.
1995, 60, 767.
Synlett 2006, No. 6, 905–908 © Thieme Stuttgart · New York