Highly stereoselective synthesis of steroidal 2,5-diketopiperazines based on isocyanide chemistry

Article abstract of DOI:10.1016/j.tetlet.2009.03.219

In this Letter we report that the Ugi reaction/cyclization sequence on a steroidal 17-carboxaldehyde leads to novel steroidal 2,5-diketopiperazines with a noteworthy stereoselectivity. A wide variety in the substitution pattern in the heterocyclic moiety

Full text of DOI:10.1016/j.tetlet.2009.03.219

Tetrahedron Letters 50 (2009) 4022–4024
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Highly stereoselective synthesis of steroidal 2,5-diketopiperazines based
on isocyanide chemistry
*
Andrea C. Bruttomesso , Javier Eiras, Javier A. Ramírez, Lydia R. Galagovsky
Departamento de Química Orgánica and UMYMFOR (CONICET-Facultad de Ciencias Exactas y Naturales), Universidad de Buenos Aires, Pabellón 2, Piso 3,
Ciudad Universitaria, C1428EGA, Buenos Aires, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
In this Letter we report that the Ugi reaction/cyclization sequence on a steroidal 17-carboxaldehyde leads
to novel steroidal 2,5-diketopiperazines with a noteworthy stereoselectivity. A wide variety in the sub-
stitution pattern in the heterocyclic moiety was easily achieved by changing the components in the
Ugi reaction.
Received 6 March 2009
Revised 26 March 2009
Accepted 31 March 2009
Available online 5 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
2,5-Diketopiperazines
Heterocyclic steroids
Multicomponent reaction
Ugi reaction
The enzyme 17
a
-hydroxylase/17,20-lyase (17
a
-lyase or CYP17)
In this Letter we report the application of this procedure for the
synthesis of novel steroids bearing a 2,5-diketopiperazine moiety
at C-17.
is a cytochrome P-450 that catalyzes the conversion of progester-
one and pregnenolone into androgens.1 The potential therapeutic
value of 17
a
-lyase inhibitors in the treatment of androgen-depen-
The synthesis started with the steroidal aldehyde 1, which can
be obtained from dehydroepiandrosterone (DHEA) in four steps
by following a described procedure.10 The U-4CR of this aldehyde
with 2-chloroacetic acid, an amine, and an isonitrile gave the ad-
ducts 2a–9a as the only products.11 These intermediates were trea-
ted with KOH in ethanol under ultrasound irradiation12 to give the
desired steroidal diketopiperazines 2b–9b, substituted at both
nitrogen atoms (Scheme 1).
Although Marcaccini et al. have found that the cyclization step
is unsuccessful when an aliphatic aldehyde is employed, in our
case the sequence took place smoothly and in good yields (Table 1).
The stereochemistry of the new asymmetric center (C-30) was
established from NMR experiments. Firstly, all the resonances were
completely assigned using 1D and 2D NMR spectra, and the NOE’s
between diagnostic protons were determined. In every case a
correlation between the C-18 protons and the C-30 proton was
dent diseases, for example, prostate cancer, has led to much inter-
est.2 A number of steroidal inhibitors of CYP17, many of which
contain a heterocycle at C-17 (Fig. 1), have been described.3–5
2,5-Diketopiperazine is the smallest possible cyclic peptide con-
sisting of two a-amino acid residues. This highly constrained scaf-
fold is present in a large number of biologically active compounds
and serves as a privileged structure in medicinal chemistry.6,7
Many different syntheses of ketopiperazines have been de-
scribed in the past; however, multicomponent reactions (MCRs)
seem to be particularly well suited to assemble piperazines, since
more than 10 different methods have been published so far.8
Recently, Marcaccini et al. have described an interesting ap-
proach toward 2,5-diketopiperazines.9 An Ugi four-component
reaction (U-4CR) between amines, aldehydes, chloroacetic acid,
and isocyanides affords the Ugi intermediate, which is cyclized to
the title compounds upon treatment with ethanolic KOH under
ultrasonication. A limitation of this synthesis is that the U-4CR
products arising from aliphatic aldehydes give only complex reac-
tion mixtures during the cyclization.
* Corresponding author. Tel.: +54 01145763346; fax: +54 01145763385.
E-mail addresses: aachiocc@qo.fcen.uba.ar, andrea.bruttomesso@gmail.com (A.C.
Bruttomesso).
Figure 1. Chemical structures of CYP17 inhibitors.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.219

A. C. Bruttomesso et al. / Tetrahedron Letters 50 (2009) 4022–4024
4023
Scheme 1. General synthetic procedure: Reagents and conditions: (a) ClCH2COOH, R1NH2, R2NC, EtOH or MeOH, rt; (b) KOH, EtOH, ultrasound irradiation, rt.
Table 1
Amine R1-NH2
Isonitrile R2-NC
Yielda
71%, 2b
NH2
NC
NC
NC
68%, 3b
57%, 4b
63%, 5b
83%, 6b
NH2
Figure 2. NOE correlations for compound 2b.
Three possible competing mechanisms have been proposed.13
In our case two of these could be working. On one side, the direct
attack of the isocyanide from the less hindered face of the proton-
ated E-imine. On the other side the iminium ion is attacked first by
the carboxylate to give a thermodynamic intermediate stabilized
by intramolecular hydrogen-bond and then the substitution by
the isocyanide proceeds with inversion of configuration. In both
case the rate-limiting step is the isocyanide attack pathway, lead-
ing to an adduct with S stereochemistry at C-30.13,14
NH2
NH2
NC
NC
NH2
NH2
O
NC
65%, 7b
In order to rationalize our results, we performed a conforma-
tional search for the protonated E-imine from 1 and methylamine,
putative intermediate in the formation of 3b, looking for the lower
energy conformations.15 Figure 3 shows that both the CH3-18 and
the steroidal skeleton block the Si-face of the imine, inducing the
observed attack.
In conclusion, in the present work we show that this synthetic
sequence is suitable for the synthesis of the 2,5-diketopiperazine
scaffold attached to the C-17 of the steroidal nucleus. Furthermore,
a wide variety in the substitution pattern in the heterocycle can be
easily achieved by changing the components in the U-4CR. Notably,
the synthesis resulted to have a high stereoselectivity.
OEt
72%, 8bb
55%, 9b
S
NC
NH2
NH2
O
O
O
P
NC
EtO
OEt
a
Isolated total yields from 1.
b
Treatment of adduct 8a with KOH/EtOH gave the cyclization product with
substitution of p-toluenesulfinyl by ethoxy group.
The use of steroids in multicomponent reactions leading to het-
erocyclic compounds has not been fully exploited yet.16,17 Thus,
further studies are under way to expand this methodology to other
steroids and heterocycles.
observed. Moreover, the NOESY spectra showed correlations be-
tween the protons belonging to the substituents at N-10 or/and
the C-60 with the trimethylsilyl moiety, whereas protons at C-18
correlated with those of the substituents at N-40, confirming the
S stereochemistry at C-30. As an example, Figure 2 depicts these
correlations for compound 2b.
Any of the four components can in principle, if chiral, control
the generation of the new stereogenic center. Taking into consider-
ation that the U-4CR reaction usually suffers from a low stereose-
lectivity, even with aldehydes that are known to give excellent
asymmetric induction in the reaction with other kinds of C-nucle-
ophiles, our results are noteworthy.13
The stereochemical outcome was the same in each case, irre-
spective of the amine or isonitrile employed. This suggests that
the asymmetry is induced by the rigid steroidal frame.
Figure 3. Optimized conformation of the E-imine intermediate in the formation of
3b. Observed attack.

4024
A. C. Bruttomesso et al. / Tetrahedron Letters 50 (2009) 4022–4024
CONHCH–, 1H, d, J = 6.1 Hz), 7.04 (Ar, 2H, d, J = 7.5 Hz), 7.23 (Ar, 3H, m) ppm;
Acknowledgments
13C NMR (CDCl3, 500 MHz) d ꢀ4.6 ((CH3)2SiO), 2.9 ((CH3)3SiO), 15.1 (C18), 18.3
((CH3)3CSiO), 19.4 (C19), 20.8, 23.4, 24.8, 24.7, 25.5, 25.9 ((CH3)3CSiO), 30.9,
32.0, 32.2, 32.9, 33.3, 34.5, 36.6 (C10), 37.3, 42.3 (–COCH2Cl), 42.8, 47.8
(–CONHCH–), 48.9 (C13), 49.6 (–NCH2Ph), 49.8, 50.1, 58.1 (–NHCOCHN–), 72.6
(C3), 90.5 (C17), 120.8 (C6), 125.3, 127.0, 128.8, 138.4, 141.8 (C5), 166.7
(–NHCOCH–), 169.3 (–COCH2Cl) ppm. Anal. Calcd for C45H73ClN2O4: C, 67.76;
H, 9.22; N, 3.51. Found: C, 67.71; H, 9.24; N, 3.56.
This work was supported by Grants from the Universidad de
Buenos Aires (UBACyT X-84) and the Agencia Nacional de Promo-
ción Científica y Técnica (ANPCyT PICT 2007-00914). We are grate-
ful to UMYMFOR (UBA-CONICET) for the analytical and
spectroscopic determinations.
12. General synthetic procedure: Compounds 2a–9a (100 mg) were treated with a
solution of KOH (100 mg) in EtOH (10 ml). The resulting suspension was
transferred to the vessel and ultrasonicated at room temperature for 30 min.
The solvent was evaporated under reduced pressure and the residue was taken
in dichloromethane and purified by silica gel column chromatography
(hexane/EtOAc gradient).Data for compound 2b, (3b-(tert-butyl)dim-
References and notes
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11. General synthetic procedure: The carboxaldehyde 1 (90 mg, 0.18 mmol) was
dissolved in methanol or ethanol (5 mL) and 1 equiv of the amine and 2-
chloroacetic acid was added. The mixture was stirred for 15 min at room
temperature and 1 equiv of the isonitrile was added. The reaction mixture was
maintained at room temperature for 6 h. The solvent was evaporated under
reduced pressure and the residue was taken in dichloromethane and purified
by silica gel column chromatography (hexane/EtOAc gradient). Data for
compound 2a, 87% yield; colorless solid; mp 172–174 °C; 1H NMR (CDCl3,
500 MHz) d 0.06 ((CH3)2SiO, 6H, s), 0.17 ((CH3)3SiO, 9H, s), 0.8 (18-H, 3H, s),
0.89 ((CH3)3CSiO, 9H, s), 1.01 (19-H, 3H, s), 3.50 (3-H, 1H, m), 3.66 (–CONHCH–,
1H, m), 3.69 (–COCHaHbCl, 1H, d, J = 12.7 Hz), 3.91 (–COCHaHbCl, 1H, d,
J = 12.7 Hz), 4.47 (–NCHaHbPh, 1H, d, J = 18.0 Hz), 5.13 (–NHCOCHN–, 1H, s),
5.33 (6-H, 1H, d, J = 5.2 Hz), 5.98 (–NCHaHbPh, 1H, d, J = 18.0 Hz), 6.11 (–
ethylsilyloxy-17b-{30[(10-cyclohexyl-40-benzyl)-20,50-diketopiperazinyl]}-17
a-
trimethylsililoxy androstane) 82% yield; colorless solid; mp 111–112 °C; 1H
NMR (CDCl3, 500 MHz) d 0.06 ((CH3)2SiO, 6H, s), 0.21 ((CH3)3SiO, 9H, s), 0.8
(18-H, 3H, s), 0.89 ((CH3)3CSiO, 9H, s), 1.01 (19-H, 3H, s), 3.50 (3-H, 1H, m), 3.68
(–NCHaHbPh, 1H, d, J = 15.5 Hz), 3.88 (–COCHaHbN, 1H, d, J = 16.5 Hz), 3.93
(–COCHaHbN, 1H, d, J = 16.5 Hz), 4.01 (–NCOCHN–, 1H, s), 4.31 (–COCH2NCH–,
1H, m), 5.33 (6-H, 1H, d, J = 5.2 Hz), 5.54 (–NCHaHbPh, 1H, d, J = 15.5 Hz), 7.11
(Ar, 2H, d, J = 7.5 Hz), 7.27 (Ar, 3H, m) ppm; 13C NMR (CDCl3, 500 MHz) d ꢀ4.6
((CH3)2SiO), 3.0 ((CH3)3SiO), 15.2 (C18), 18.3 ((CH3)3CSiO), 19.4 (C19), 20.5,
23.9, 25.3, 25.5, 25.9 ((CH3)3CSiO), 29.5, 29.9, 30.1, 31.8, 32.1, 32.3, 34.0, 36.7
(C10), 37.4, 42.8, 45.6 (–COCH2N), 49.0 (–NCH2Ph), 49.1 (C13), 49.3, 50.1, 52.5
(–COCH2NCH–), 62.6 (–NCOCHN–), 72.5 (C3), 89.8 (C17), 120.7 (C6), 127.3,
127.6, 128.9, 136.0, 141.8 (C5), 166.4 (–NCOCHN–), 166.8 (-COCH2N) ppm.
Anal. Calcd for C45H72N2O4Si2: C, 71.00; H, 9.53; N, 3.68. Found: C, 70.97; H,
9.56; N, 3.65.
13. Banfi, L.; Basso, A.; Guanti, G.; Riva, R. In Multicomponent Reactions; Zhu, J.,
Bienyamé, H., Eds.; Wiley-VCH: Weinheim, 2005; pp 1–32.
14. Marcaccini, S.; Torroba, T. Nat. Protocol. 2007, 2, 632–639.
15. Molecular modeling: A random conformational search of the lowest energy
structures was performed for the model using the Tripos Molecular Field as
implemented in the SYBYL 7.2 software. The selected conformation was
optimized in vacuo at the B3LYP/6-31G (d,p) level by using GAUSSIAN98 and
proved to be a local minimum via normal mode analysis.
16. Dömling, A.; Kehagia, K.; Ugi, I. Tetrahedron 1995, 51, 9519–9522.
17. Alonso, F.; Acebedo, S. L.; Bruttomesso, A. C.; Ramírez, J. A. Steroids 2008, 73,
1270–1276.