Novel macrocyclic templates by ring enlargement of ansa-steroids

Article abstract of DOI:10.1016/j.tetlet.2004.11.017

Ring enlargement of ansa-steroids leads to a variety of novel templates which are suitable for the preparation of diverse libraries of natural product derivatives. Key steps for the synthesis of these highly functionalized templates were either an ozonolysis-derivatization-ring closing metathesis-sequence or a macrolactonization.

Full text of DOI:10.1016/j.tetlet.2004.11.017

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9569–9571
Novel macrocyclic templates by ring enlargement of ansa-steroids
Stefan Baurle, Thorsten Blume, Emmanuel Leroy, Anne Mengel,* Christian Parchmann,
¨
Kathrin Schmidt and Werner Skuballa
Schering AG, Medicinal Chemistry, Research Center Europe, 13342 Berlin, Germany
Received 15 September 2004; accepted 2 November 2004
Dedicated to Professor Dr. Johann Mulzer on the occasion of his 60th birthday
Abstract—Ring enlargement of ansa-steroids leads to a variety of novel templates which are suitable for the preparation of diverse
libraries of natural product derivatives. Key steps for the synthesis of these highly functionalized templates were either an ozonol-
ysis-derivatization-ring closing metathesis-sequence or a macrolactonization.
Ó 2004 Elsevier Ltd. All rights reserved.
Compound libraries comprising natural compound
derivatives are generally regarded as a rich source for
hits in the drug discovery process.1 We recently reported
that several compounds of a library originating from the
macrocyclic steroid-derived template 3 exhibit remark-
able inhibitory activity against phosphatase Cdc25B.2
Furthermore, we published the synthesis of a 17-mem-
bered macrocycle by opening the cyclopentane ring of
3 applying a Wagner–Meerwein rearrangement and
ozonolysis.3 Encouraged by these results we then
focused on the transformation of the ansa-steroid 3 to
more flexible structures with regard to ring size and
functionalization. Due to the enhanced flexibility within
the macrocycle, the compounds should show a higher
adaptability towards the molecular target resulting in a
possible hit enrichment in HTS.
metathesis as well as macrolactonization as key
reactions.
Ansa-steroids 3 can be easily obtained by the Winterfeldt–
Diels/Alder-retro-Diels/Alder-sequence (Scheme 1).4
Ring closing metathesis is known to be a powerful tool
for the preparation of macrocycles.5 The synthesis of 5,
with two terminal alkene functionalities suitable for
metathesis, was accomplished starting from 4. First,
the aldehyde 4 was reduced and the hydroxyl groups
were protected as silylethers. The disubstituted double
bond of 4 was cleaved by ozone at ꢀ78°C and after
reductive workup with NaBH4, treatment of the result-
ing diol with allylbromide under phase transfer condi-
tions afforded bisalkene 5 (Scheme 2).
Herein, the synthesis of these second-generation tem-
plates starting from steroids is described applying olefin
Cyclization of 5 in the presence of first generation
Grubbs catalyst6 in CH2Cl2 led to the 20-membered
R''
R'
R''
9
1
CHO
1
R'
R'
9
3
CHO
PGO
R''
BF3-Et2O
3
H
H
7
5
PGO
PGO
H
5
7
CHO
1
2
3
Scheme 1. Synthesis of ansa-steroids, R0 = H or Me.
Keywords: Steroids; Macrocycles; Ring closing metathesis; Macrolactonization; Template.
*
Corresponding author. Tel.: +49 30 46815529; fax: +49 30 46895529; e-mail: anne.mengel@schering.de
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.017

9570
S. Ba¨urle et al. / Tetrahedron Letters 45 (2004) 9569–9571
Table 1. Metathesis reactions via Figure 1
Entry
Olefin
R1
R2
Cata
Condition
Yield (%)
1
2
3
4
5
6
7
8
9
5
CH2Oallyl
CH2Oallyl
A
A
B
B
B
B
B
B
B
DCM, rt, 6.5h
DCM, rt, 2d
DCM, rt, 2d
DCM, rt, 2d
DCM, D, 4h
DCM, D, 4h
DCM, D, 4h
DCM, D, 1h
MePh, D, 4h
36
—
69
34
73
70
34
—
20
8a
8a
8b
8b
8c
8d
8e
8e
CH2Oacryl
CH2Oacryl
CHMeOallyl
CHMeOallyl
CHMeOallyl
CHMeOallyl
CMe@CH2
CMe@CH2
CH2Oacryl
CH2Oacryl
CO2allyl
CO2allyl
CO2CH2allyl
CO2(CH2)2allyl
CO2CH2allyl
CO2CH2allyl
a A = RuCl2(PCy3)2@CHCHCMe2, B = (IMES)(PCy3)Cl2Ru@CHPh; IMES = 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene.
R1
R2
O
catalyst
O
metathesis
OPG3
PG1O
products
conditions
a-d
OAc
OAc
CHO
H
TBSO
HO
H
OPG2
6, 9a-e
5, 8a-e
H
OTBS
4
5
5, 8a: PG1+2 = TBS; PG3 = Ac
8b-e: PG1 = Ac; PG2 = Piv; PG3 = Bz
Scheme 2. (a) NaBH4, MeOH, CH2Cl2, 0°C, 40min; (b) TBSCl,
imidazole, DMAP, 4A molecular sieves, CH2Cl2, 90%; (c) O3, CH2Cl2,
˚
Figure 1. Metathesis reactions (Table 1).
MeOH, ꢀ78°C, 3min, NaBH4, EtOH, 0°C, 1h, 82%; (d) allylbromide,
NBu4+HSO4ꢀ, NaOH, toluene, H2O, rt, 6h, 80%.
with bisacrylester 8a (Table 1, entries 2 and 3). The yield
of the cyclization product of 8b was improved by
increasing the temperature (Table 1, entries 4 and 5).
Cyclization of 8c and 8d having an allylether and an
homoallylester or 4-pentenester moiety could only be
accomplished at reflux temperature in dichloromethane
(Table 1, entries 6 and 7). Even higher temperature
(refluxing toluene) had to be applied for the combina-
tions of the methylallyl and homoallyl structures in 8e
(Table 1, entries 8 and 9). All metathesis products were
obtained as mixtures of E/Z-isomers.
O
O
O
O
a
b, c, d
5
OAc
OH
TBSO
HO
H
H
6
7
OTBS
OH
Scheme 3. (a) (PCy3)2Cl2Ru@CHPh = Grubbs catalyst, first genera-
tion,6 CH2Cl2, rt, 6.5h, 36%; (b) H2/Pd–C/Na2CO3, EtOAc; (c)
NaOMe, 5% in MeOH; (d) CSA, CH2Cl2/MeOH 1:1, 50% (three
steps).
Our second approach towards more flexible novel tem-
plates is based on the incorporation of amino acids. This
allows the introduction of a broad variety of functional
groups as well as the modification of the lipophilicity of
the molecule. Compound 13 with an incorporated ala-
nine linker was synthesized as a prototype, starting from
10.8 First an amidation with alanine benzyl ester
afforded 11 in 47% yield. Reduction of the keto group
in 11 followed by deprotection of the carboxylic acid
moiety gave 12 as a mixture of epimers. Macrocycliza-
tion using Yamaguchi conditions and cleavage of
the three silyl ethers in the presence of camphorsulfonic
acid led finally to the fully deprotected 18-mem-
bered macrocycle 13 (Scheme 4).à
macrocycle 6 within 4h (36% yield, mixture of E/Z-iso-
mers) (Scheme 3). Hydrogenation of the double bond
and subsequent cleavage of the protecting groups gave
the saturated macrocycle 7.
To show that this ring enlargement is generally applic-
able, different types of olefins were subjected to the
metathesis reaction (Fig. 1 and Table 1). The dienes
8a–e were synthesized in a similar fashion to 5. The
more reactive Grubbs catalyst of the second generation7
was necessary to obtain the desired product starting
In summary, we have presented a novel approach to new
conformationally flexible and highly functionalized
macrocycles derived from steroids. These macrocycles
can now be exploited for the generation of diverse com-
pound libraries.
Selected analytical data for compound 7: 1H NMR (CDCl3): d = 0.88
(s, 3H), 1.28–1.75 (m, 12H), 1.78–1.99 (m, 2H), 2.10–2.25 (m, 2H),
2.70 (dd, J = 7/14Hz, 1H), 2.93 (dd, J = 5/14Hz, 1H), 3.15–3.44 (m,
8H), 3.45–3.52 (m, 1H), 3.90–4.02 (m, 2H), 4.62 (d, J = 13Hz, 1H),
4.75 (d, J = 13Hz, 1H), 7.06 (dd, J = 2/8Hz, 1H), 7.27 (d, J = 8Hz,
1H), 7.30 (d, J = 2Hz, 1H); 13C NMR (CDCl3): d = 14.1, 24.8, 26.2,
26.7, 27.0, 28.2, 30.7, 33.2, 35.3, 43.3, 44.5, 47.7, 63.2, 70.1, 70.8, 70.8,
71.1, 71.3, 79.9, 128.8, 128.9, 130.2, 136.1, 137.5, 140.4; MS (ESI):
m/z = 421 [M+1], 438 [M+18].
à Selected analytical data for compound 13: MS (Cl–NH3): m/z = 448
[M+H+], 465 [M+NH4+].

S. Ba¨urle et al. / Tetrahedron Letters 45 (2004) 9569–9571
9571
Drug Discovery 2000, 32, 217–252; (e) Schreiber, S. L.
Science 2000, 287, 1964–1969.
2. Ba¨urle, S.; Blume, T.; Gunther, J.; Henschel, D.; Hillig, R.
¨
BnO
O
OH
O
NH
O
O
C.; Husemann, M.; Mengel, A.; Parchmann, C.; Schmid,
E.; Skuballa, W. Bioorg. Med. Chem. Lett. 2004, 14, 1673–
1677.
a
O
OTBS
TBSO
OTBS
TBSO
3. Ba¨urle, S.; Blume, T.; Mengel, A.; Parchmann, C.;
Skuballa, W.; Ba¨sler, S.; Scha¨fer, M.; Sulzle, D.; Wrona-
¨
H
OTBS
H
10
11
Metzinger, H.-P. Angew. Chem., Int. Ed. 2003, 42, 3961–
3964.
OTBS
HO
O
4. (a) Winterfeldt, E. Chimia 1993, 47, 39–45; (b) Prelle, A.;
Winterfeldt, E. Heterocycles 1989, 28, 333–346; (c) Chowd-
hury, P.-K.; Prelle, A.; Schomburg, D.; Thielmann, M.;
Winterfeldt, E. Liebigs Ann. Chem. 1987, 1095–1099; (d)
Schomburg, D.; Thielmann, M.; Winterfeldt, E. Tetrahe-
dron Lett. 1985, 26, 1705–1706.
O
O
O
NH
N
O
OH
H
b-c
TBSO
d-e
OTBS
OH
HO
5. (a) Smith, A. B., III; Adams, C. M.; Kozmin, S. A.; Paone,
D. V. J. Am. Chem. Soc. 2001, 123, 5925–5937; (b) Hu, X.;
Nguyen, K. T.; Verlinde, C. L. M. J.; Hol, W. G. J.; Pei, D.
J. Med. Chem. 2003, 46, 3771–3774; (c) Vassilikogiannakis,
G.; Margaros, I.; Tofi, M. Org. Lett. 2004, 6, 205–208; (d)
Shi, Z.-D.; Lee, K.; Wei, C.-Q.; Roberts, L. R.; Worthy, K.
M.; Fisher, R. J.; Burke, T. R. J. Med. Chem. 2004, 47,
788–791; (e) Boger, D. L.; Long, J. J. Am. Chem. Soc. 2001,
123, 8515–8519.
H
H
OTBS
OH
12
13
Scheme 4. (a) EDC, hydroxybenzotriazole, L-alanine benzylester,
Et3N, 47%; (b) NaBH4, CH2Cl2, MeOH; (c) H2/Pd–C, CF3CH2OH,
Na2CO3, quant.; (d) 2,4,6-trichlorobenzoylchloride, Et3N, THF,
DMAP, toluene, rt, 2h; (e) CSA.
References and notes
6. (a) Fu, G. C.; Nguyen, S. B. T.; Grubbs, R. H. J. Am.
Chem. Soc. 1993, 115, 9856–9857; (b) Schwab, P.; France,
M. B.; Ziller, J. W.; Grubbs, R. H. Angew. Chem., Int. Ed.
1. (a) Breinbauer, R.; Vetter, I. R.; Waldmann, H. Angew.
Chem., Int. Ed. 2002, 41, 2878–2890; (b) Hall, D. G.;
Manku, S.; Wang, F. J. Comb. Chem. 2001, 3, 125–150; (c)
Wessjohann, L. A. Curr. Opin. Chem. Biol. 2000, 4, 303–
309; (d) Grabley, S.; Thiericke, R.; Sattler, I. Ernst Schering
Research Foundation Workshop: Role of Natural Products in
1995, 34, 2039–2041; (c) Furnster, A. Angew. Chem., Int.
Ed. 2000, 39, 3012–3043.
¨
7. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953–956.
8. 10 was synthesized in a similar way to 5.