Synthesis of a malimide analogue of the telomerase inhibitor UCS1025A using a dianionic aldol strategy

Article abstract of DOI:10.1055/s-2007-968000

The synthesis of a simplified analogue of UCS1025A via an aldol coupling is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-968000

LETTER
391
Synthesis of a Malimide Analogue of the Telomerase Inhibitor UCS1025A
Using a Dianionic Aldol Strategy
Synthesis of
a
Ma
e
limide
A
na
n
logue of the
a
Telomeras
t
e
Inhib
a
itor UCS1025A Marcia de Figueiredo,a Matthias Voith,a Roland Fröhlich,b Mathias Christmann*a
a
Institute of Organic Chemistry, RWTH Aachen, Landoltweg 1, 52074, Aachen, Germany
Fax +49(241)8092127; E-mail: christmann@oc.rwth-aachen.de
b
Institute of Organic Chemistry, University of Münster, Corrensstraße 40, 48149 Münster, Germany
Received 20 November 2006
with a model pyrrolizidine using an aldol approach be-
cause of steric reasons. This strategy is also hampered by
the fact that protection of the b-hydroxyl group on the
pyrrolizidine is prohibited due to facile b-elimination un-
der basic conditions. We wanted to overcome this prob-
lem (Scheme 1) by deprotonation of the free hydroxyl
group prior to the enolate formation (to form dianion 5).
From alkylation8 and aldol reactions9 of 4-hydroxypyrro-
lidin-2-ones, it was anticipated that malimide-derived
enolates (4-hydroxypyrrolidine-2,5-diones) would be at-
tacked with high facial selectivity as compared to the
oxyanion10 but with low diastereoselectivity with respect
to the newly formed hydroxyl group. The selectivity was
inconsequential to our strategy, since we oxidized this
hydroxyl group later and the keto group was in equili-
brium with its enol tautomer.
Abstract: The synthesis of a simplified analogue of UCS1025A via
an aldol coupling is described.
Key words: aldol reactions, Diels–Alder reactions, imides, natural
products, total synthesis
Telomeres1 are repetitive hexameric DNA sequences
(TTAGGG)n at the ends of the chromosomes, which
protect the chromosomal ends of DNA from being recog-
nized as double-strand DNA breaks. In most somatic
cells, telomeres also act as a cellular clock, as they shorten
each time a cell divides until a critical length is reached
and cell senescence or apoptosis occur. In over 90% of all
cancer cells the enzyme telomerase2 is activated which
makes them virtually immortal. During the course of a
screening program, Yamashita et al. isolated a new fungal
metabolite from Acremonium sp. KY4917. Apart from its
antimicrobial activity against Gram-positive bacteria,
UCS1025A (1) was identified to be a novel telomerase in-
hibitor.3 UCS1025A possesses a complex pentacyclic
framework featuring a contiguous array of eight stereo-
centers and an unprecedented furopyrrolizidine subunit
(Figure 1). Since 1 is one of the first natural product
telomerase inhibitors,4 many research groups5 have em-
barked on its synthesis and very recently, Danishefsky6
–
O
O
O
Bn
H
H
OH
R
O
R
R
Bn
O
Bn
O
O
N
N
N
O
–
HO
O
RO
3
4
5
Scheme 1 Retrosynthetic strategy
and Hoye7 reported elegant total syntheses. In this We started our synthetic studies toward UCS1025A using
communication, we present the synthesis of a malimide imide 6 and cyclohexyl carbaldehyde (7) as model sub-
analogue (2) of UCS1025A.
strates (Scheme 2).
O
O
O
O
O
H
H
OH
H
O
H
H
OH
O
a
Bn
O
Bn
O
Bn
N
N
N
Bn
N
N
+
H
H
H
O
OH
O
OH
HO
8a
HO
O
TBSO
O
H
H
6
8b
UCS1025A (1)
2
55:45
Figure 1 UCS1025A (1) and a malimide analogue (2)
O
O
H
H
O
OH
Bn
O
Bn
N
N
c
b
In our retrosynthetic plan, an aldol scission between the
keto group and the pyrrolizidine residue would provide
access to UCS1025A and analogues. In fact, Lambert and
Danishefsky were not able to couple the decalin fragment
8b
O
TBSO
TBSO
9
10
Scheme 2 Synthesis of 10. Reagents and conditions: (a) NaHMDS,
THF, 0 °C, then –78 °C, cyclohexyl carbaldehyde (7), 3.5 h, 56%; (b)
TBSCl, imidazole, DMF, r.t., 1 h, 84%; (c) Dess–Martin periodinane,
CH2Cl2, 0 °C to r.t., 2 h, 82%.
SYNLETT 2007, No. 3, pp 0391–0394
Advanced online publication: 07.02.2007
1
5.
0
2.
2
0
0
7
DOI: 10.1055/s-2007-968000; Art ID: G35506ST
© Georg Thieme Verlag Stuttgart · New York

392
R. M. de Figueiredo et al.
LETTER
After some optimization11 we found that 2.1 equivalents
of NaHMDS as base in THF gave rise to the desired prod-
ucts 8a12 and 8b in 56% yield as a 55:45 mixture of dia-
stereomers. For the major isomer 8a the crystal structure
was obtained (Figure 2), and the relative configuration of
8b was determined by comparison of the NMR spectra.
Et
O
O
H
O
Et
LiClO4
O
N
Bn
N
Bn
OTBS
O
(quant.)
O
17
15
Scheme 4 Synthesis of 17
have led to either decomposition of starting materials or a
complex mixture of products.
One of the reasons behind the decomposition could be the
facile b-elimination of TBS-OH giving rise to a highly re-
active double dienophile, which was trapped with cyclo-
pentadiene. In fact, the double Diels–Alder adduct 17 was
isolated as a 3:1 mixture of diastereomers (Scheme 4).
Figure 2 X-ray crystal structure of 8a
As precedented by the Procter group for a similar sub-
strate,13 the ring hydroxyl group could be protected selec-
tively over the side-chain hydroxyl (imidazole, TBSCl)
giving 9 in 84% yield. A screening of oxidizing agents
revealed that pyridinium chlorochromate (PCC), manga-
nese dioxide or employing Swern conditions14 led to rapid
decomposition of the starting material. Using the Dess–
Martin periodinane,15 the reaction proceeded smoothly to
give the desired b-ketoimide 10. When the less bulky
aldehydes 2-hexenal and 2,8,10-dodecatrienal were em-
ployed in the aldol coupling reaction, the yield could be
raised to 65% and 72%, respectively (Scheme 3).
O
a
O
O
BrPh3P
19
12
18
O
O
N
b
+
Bn
t-Bu
TfO–
N
H2
O
R
20
H
H
H
Me
Me
c,d
H
21 (84% ee)
22: R = CH2OH
21: R = CHO (ee >99%)
OH
Scheme 5 Synthesis of 21. Reagents and conditions: (a) t-BuOK,
19, 0 °C, then 15, 1 h, then 10% aq oxalic acid, r.t., 91% yield; (b) 20
(10 mol%), 0 °C, MeNO2–H2O (98:2), 48 h, 74%; (c) NaBH4, EtOH,
0 °C, quant., recrystallization (pentane); (d) PCC, 4 Å MS, CH2Cl2,
r.t., 0.5 h, 95%.
O
O
H
a
R
b,c
Bn
N
Bn N
OH
OH
O
O
13: R = Me
14: R =
6
We therefore decided to perform the Diels–Alder reaction
prior to the aldol coupling. Aldehyde 1817 was treated
with the commercially available Wittig reagent 19, to give
the desired trienal 12 in 91% yield (Scheme 5). This com-
pound was subjected to an organocatalytic Diels–Alder
reaction using MacMillan’s conditions.18 We could lower
the catalyst loading to 10 mol% by choosing nitromethane
as the solvent and obtained the Diels–Alder adduct in 74%
yield and 84% ee. The ee was raised to >99% by recrys-
tallization of the corresponding alcohol followed by re-
oxidation to afford the enantiopure aldehyde 21.19 This
material was coupled to the imide 6 using the previously
established conditions to give 23 as a 4:1 mixture of dia-
stereomers. The reaction was more sluggish, confirming
the tendency that increasing the size of the electrophile
lowers the reaction rate. The product was obtained as a
diastereomeric mixture in 55% yield. The major isomer
was taken forward to give, after protection and oxidation,
the desired analogue 220 of UCS1025A as a mixture of
tautomers (Scheme 6).
O
OH
O
O
H
R
R
Bn
N
Bn
N
OTBS
OTBS
O
O
15: R = Me
16: R =
Scheme 3 Synthesis of 15 and 16. Reagents and conditions: (a)
NaHMDS, THF, 0 °C, then –78 °C, 2-hexenal (11) or 2,8,10-dodeca-
trienal (12), 3.5 h, 65% and 72%, respectively; (b) TBSCl, imidazole,
DMF, r.t., 1 h, 77% and 79%; (c) PCC, 4 Å MS, CH2Cl2, r.t., 2 h, 76%
and 55%.
The aldol products were converted into the corresponding
b-ketoimides 15 and 16 as substrates for inter- and in-
tramolecular Diels–Alder reactions. This time PCC was
the superior oxidant. Interestingly, both compounds exist
as a 1:1 tautomeric mixture as indicated in Scheme 2.
Unfortunately, so far all attempts to generate Diels–Alder
products (heat, Lewis acids, hexafluoroisopropanol16)
Synlett 2007, No. 3, 391–394 © Thieme Stuttgart · New York

LETTER
Synthesis of a Malimide Analogue of the Telomerase Inhibitor UCS1025A
393
San Diego CA, March 13–17, 2005; American Chemical
Society: Washington D.C., 2005, ORGN 665.
(c) Christmann, M. Abstracts of Papers, 229th National
Meeting of the American Chemical Society, San Diego CA,
March 13–17, 2005; American Chemical Society:
Washington D.C., 2005, ORGN 378.
O
H
O
O
H
H
OH
H
Bn
O
N
Bn
N
a
+
HO
H
21
O
OH
H
6
23
(6) Lambert, T. H.; Danishefsky, S. J. J. Am. Chem. Soc. 2006,
128, 426.
b
(7) Hoye, T. R.; Dvornikovs, V. J. Am. Chem. Soc. 2006, 128,
2550.
(8) (a) Beyersbergen van Henegouwen, W. G.; Hiemstra, H. J.
Org. Chem. 1997, 62, 8862. (b) Washburn, D. G.;
Heidebrecht, R. W. Jr.; Martin, S. F. Org. Lett. 2003, 5,
3523.
O
O
H
H
H
H
OH
H
O
Bn
O
Bn
O
N
N
H
c
TBSO
TBSO
H
H
2
24
(9) Huang, P. Q.; Zheng, X.; Wang, S. L.; Ye, J. L.; Jin, L. R.;
Chen, Z. Tetrahedron: Asymmetry 1999, 10, 3309.
(10) Shieh, H.-M.; Prestwich, D. G. J. Org. Chem. 1981, 46,
4319.
Scheme 6 Synthesis of 2. Reagents and conditions: (a) NaHMDS,
THF, 0 °C, then –78 °C, 21, 3.5 h, 55%; (b) TBSCl, imidazole, DMF,
r.t., 4 h, 77%; (c) PCC, 4 Å MS, CH2Cl2, r.t., 2 h, 67%.
(11) Typical Procedure: THF (4.5 mL) was cooled to 0 °C and
NaHMDS (1.02 mL, 2.0 M in THF, 2.05 mmol) was added.
To this solution the benzyl-protected (S)-3-hydroxy-
pyrrolidine-2,5-dione (0.20 g, 0.97 mmol) in THF (3.2 mL)
was added dropwise and after complete addition the solution
was stirred at 0 °C for an additional 5 min to give a yellowish
suspension. The reaction mixture was cooled to –78 °C,
cyclohexyl carbaldehyde (0.12 mL, 0.97 mmol) in THF
(2.2 mL) was added dropwise and the resulting mixture was
stirred at –78 °C for 1 h. The reaction was quenched with sat.
NH4Cl (5 mL) and diluted with Et2O (30 mL) and CH2Cl2
(10 mL). The organic layer was washed with sat. NH4Cl
(2 × 5 mL), dried (Na2SO4) and concentrated. Purification by
column chromatography (SiO2; n-pentane–Et2O, 1:1 → 1:3)
gave 8a and 8b as a mixture of diastereomers in 31% and
25% yields, respectively.
In summary, the synthesis of an advanced analogue of
UCS1025A has been achieved employing a dianionic
aldol approach. Efforts toward UCS1025A as well as
structure–activity relationship studies are ongoing and the
results will be reported in due course.
Acknowledgment
We thank the Fonds der Chemischen Industrie for a Liebig fel-
lowship (M.C.), the Deutsche Forschungsgemeinschaft (SPP1179
Organokatalyse) and Prof. Dieter Enders for his encouragement and
support.
(12) Compound 8a: mp 135–137 °C; [a]25D –49.8 (c = 1.01,
acetone); Rf 0.19 (n-pentane–Et2O, 1:1). 1H NMR (400
MHz, CDCl3): d = 7.18–7.27 (m, 5 H), 4.66 (d, J = 5.2 Hz, 1
H), 4.61 (d, J = 14.6 Hz, 1 H), 4.57 (d, J = 14.3 Hz, 1 H), 3.96
(dd, J = 2.2, 9.1 Hz, 1 H), 2.93 (dd, J = 2.3, 5.1 Hz, 1 H), 2.20
(br s), 1.95 (d, J = 12.4 Hz, 1 H), 1.58–1.76 (m, 4 H), 1.44–
References and Notes
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1.55 (m, 1 H), 1.02–1.26 (m, 3 H), 0.84–0.96 (m, 2 H). 13
C
(3) (a) Nakai, R.; Ogawa, H.; Asai, A.; Ando, K.; Agatsuma, T.;
Matsumiya, S.; Akinaga, S.; Yamashita, Y.; Mizukami, T. J.
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(c) Nakai, R.; Ishida, H.; Asai, A.; Ogawa, H.; Yamamoto,
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(4) Telomestatin: (a) Shinya, K.; Wierzba, K.; Matsuo, K.-I.;
Ohtani, T.; Yamada, Y.; Furihata, K.; Hayakawa, Y.; Seto,
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(c) Doi, T.; Yoshida, M.; Shinya, K.; Takahashi, T. Org.
Lett. 2006, 8, 4165. Dictyodendrins: (d) Warabi, K.;
Matsunaga, S.; van Soest, R. W. M.; Fusetani, N. J. Org.
Chem. 2003, 68, 2765. (e) Fürstner, A.; Domostoj, M. M.;
Scheiper, B. J. Am. Chem. Soc. 2006, 128, 8087.
NMR (100 MHz, CDCl3): d = 177.8, 176.2, 135.2, 128.7
(2 × C), 128.3 (2 × C), 127.9, 73.2, 67.3, 51.8, 42.7, 41.3,
29.3, 28.8,, 26.3, 25.9, 25.8. IR (KBr): 3462, 2924, 2851,
1696, 1438, 1407, 1356, 1168, 697 cm–1. MS (EI): m/z
(%) = 318 (26), 317 (83) [M+], 299 (23), 234 (77), 205 (74),
204 (36), 127 (17), 106 (26), 96 (25), 95 (31), 92 (23), 91
(100), 73 (26), 71 (18), 56 (30). Anal Calcd for C18H23NO4:
C, 68.12; H, 7.30; N, 4.41. Found: C, 67.84; H, 7.76; N, 4.26.
(13) Edmonds, D. J.; Muir, K. W.; Procter, D. J. J. Org. Chem.
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(20) Compound 2: colorless oil; Rf 0.38 (pentane–EtOAc, 10:1).
1H NMR (300 MHz, CDCl3): d = 11.51 (s), 7.18 (m), 5.38
(m), 5.22 (d, J = 9.9 Hz), 4.76 (s), 4.68 (d, J = 4.2 Hz), 4.54
(d, J = 14.3 Hz), 4.53 (d, J = 14.3 Hz), 4.44 (d, J = 14.1 Hz),
4.42 (d, J = 14.1 Hz), 3.65 (d, J = 4.2 Hz), 2.95 (dd, J = 5.4,
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229th National Meeting of the American Chemical Society,
Synlett 2007, No. 3, 391–394 © Thieme Stuttgart · New York

394
R. M. de Figueiredo et al.
LETTER
11.1 Hz), 2.62 (m), 2.18 (d, J = 8.2 Hz), 1.33–1.68 (m),
1.08–1.22 (m), 0.90 (d, J = 6.7 Hz, Me), 0.72 (s), 0.71 (s),
0.08 (s), 0.03 (s), 0.01 (s), 0.00 (s). 13C NMR (75 MHz,
CDCl3): d = 204.8, 176.8, 174.7, 174.2, 173.5, 170.1, 135.6,
134.9, 131.4, 130.8, 130.4 (2 × C), 128.7 (2 × C), 128.6 (2 ×
C), 128.5 (4 × C), 127.9, 127.8, 101.7, 70.1, 68.1, 64.5, 57.4,
46.9, 42.9, 42.5, 42.3, 41.5, 37.3, 36.2, 34.6, 32.8 (2 × C),
30.5, 30.2, 29.8, 26.5, 26.4, 26.3, 26.2, 25.6 (3 × C), 25.4 (3
× C), 18.1, 17.9, 17.5, –3.9, –4.4, –4.9, –5.4. IR (CHCl3):
3674, 3745, 2929, 2856, 2361, 2335, 1709, 1675, 1215, 839,
757 cm–1. MS (EI): m/z (%) = 438 (100)[M – 57], 363 (11),
214 (7), 91 (46), 75 (42). HRMS: m/z [M – 57] calcd for
C25H32NO4Si: 438.21006; found: 438.21006.
Synlett 2007, No. 3, 391–394 © Thieme Stuttgart · New York