Highly stereoselective one-pot construction of trisubstituted tetrahydro-β-carboline-fused diketopiperazines: A synthetic route towards cialis analogues

Article abstract of DOI:10.1039/c4ra05981f

A facile and efficient synthetic method for the stereoselective preparation of trisubstituted tetrahydro-β-carboline-fused diketopiperazine derivatives is reported. The methodology represents a one-pot four-step reaction, employing the Ugi four-component

Full text of DOI:10.1039/c4ra05981f

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Highly stereoselective one-pot construction of
trisubstituted tetrahydro-b-carboline-fused
diketopiperazines: a synthetic route towards cialis
analogues†
Cite this: RSC Adv., 2014, 4, 38159
Received 19th June 2014
Accepted 18th August 2014
*
*
Mouhamad Jida,‡ Dirk Tourwe‡ and Steven Ballet‡
´
DOI: 10.1039/c4ra05981f
www.rsc.org/advances
A facile and efficient synthetic method for the stereoselective prepa- in a straightforward manner.9,10 One of the most explored MCRs
ration of trisubstituted tetrahydro-b-carboline-fused diketopiperazine is the Ugi reaction.11
derivatives is reported. The methodology represents a one-pot four-
Moreover, a variety of elegant Ugi-post-condensation modi-
step reaction, employing the Ugi four-component condensation cations have been reported in literature (e.g. Ugi/Diels Alder,12
which is followed by a Boc-deprotection, a Pictet–Spengler reaction Ugi/Buchwald–Hartwig,13 Ugi/Heck,14 Ugi/nucleophilic addi-
and a final lactamization. All THBC-DKPs were obtained in good yields tions/substitutions,15 Ugi/ring-closing metathesis,16 Ugi/Aldol
and excellent diastereomeric excess.
sequences,17 Ugi/deprotection/cyclization18 and Ugi/Pictet–
Spengler).19 N-fused polycyclic THBC-DKP alkaloid analogues of
type 1 can be derived by unication of the THBC and DKP
pharmacophores through the combination of Ugi and Pictet–
Spengler reactions, a unication that belongs to the so-called
post-Ugi Pictet–Spengler condensations procedures.19 In all
reported cases, the THBC-DKPs were isolated in low yield and
with poor diastereoselectivity. A mixture of two diastereomers
was for example obtained aer a Ugi/deprotection/amine-ester
cyclisation/Pictet–Spengler sequence,19e but other protocols
have also been developed to generate the polycyclic THBC-
DKPs.20,21 However, these methods oen require multi-step
synthesis and result in low product yields. In order to obtain
chiral THBC precursors a separation of the diastereomeric
mixtures and crystallization-induced asymmetric trans-
formation are needed.2,3,21 Recently, we have reported the
Over the past decades, the synthesis of novel tetrahydro-b-car-
bolines (THBCs) has attracted considerable interest due to the
prevalence of indoles in medicinal products.1 Indoles that are
fused with a diketopiperazine 1 moiety form an interesting
motif which is found in several natural products and which
proves to possess a wide diversity of biological activities.
Tadalal 2 (Cialis™, Icos/Lilly), for example, is a potent and
selective phosphodiesterase type 5 (PDE5) enzyme inhibitor
discovered by GlaxoSmithKline and used as a drug for the
management of erectile dysfunction.2 The analogous structure 3
exhibits antiplasmodial activity.3 While Fumitremorgin C 4
showed to be a selective inhibitor of the breast cancer resistance
protein (BCRP/ABCG2),4 THBC-DKP 5 serves as an anti-cancer
agent,5 and anti-thrombotic activity aer oral administration
can also be targeted by use of this core scaffold6 (6, Fig. 1).
Several methods have been developed for the synthesis of
tetrahydro-b-carboline (THBC) scaffolds.1 One of the most
straightforward ways involves
a Pictet–Spengler reaction
between a tryptamine derivative and an aldehyde.7 Similarly,
diketopiperazines (DKPs) represent an important class of
interesting bioactive molecules.8 Multicomponent reactions
(MCRs) are especially amenable to produce diketopiperazines
Research Group of Organic Chemistry, Departments of Chemistry and Bio-engineering
Sciences, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium. E-mail:
mouhamad.jida@vub.ac.be; sballet@vub.ac.be
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra05981f
‡ MJ was in charge of the design and synthesis of all compounds. MJ, DT and SB
contributed equally to the manuscript preparation.
Fig. 1 Structurally related bioactive and naturally occurring THBC-
based DKPs compounds.
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Table 1 Optimization of the lactamization stepa
preparation of N-benzyl-2-substituted piperazines in racemic
form and derived from DKPs by a Ugi-4CR/deprotection/
lactamization/reduction reaction.22 In pursuit of this work, a
retrosynthetic approach to synthesize THBC-based DKP deriv-
atives of type 1 by a one-pot four step Ugi/deprotection/Pictet–
Spengler/lactamization is shown in Fig. 2.
Herein, we report a new synthetic method to stereoselectively
obtain functionalized THBC-based DKPs. It allows the synthesis
of novel, optically pure Tadalal (compound 2 in Fig. 1)
analogues by a one-pot four-step procedure. In order to study the
feasibility of the proposed protocol and to nd the best reaction
conditions for the synthesis of the prototype THBC-based DKP
derivatives, N-Boc-L-tryptophan, benzylamine, formaldehyde and
tert-butyl isocyanide were chosen as model substrates. The Ugi-
4CR reaction was rst carried out at room temperature in
MeOH for 18 h, affording the classical Ugi products in excellent
purity as judged by HPLC at UV 215 nm and LCMS analysis.
Then, a TFA-promoted Boc removal (30% TFA in DCM at room
temperature for 3 h), followed by a Pictet–Spengler reaction
between the deprotected peptoid products and benzaldehyde
(3 equiv. of TFA in DCM at room temperature for 18 h) was
carried out, yielding the desired THBC 7 in excellent overall yield
as a mixture of 2 diastereomers (93% yield, 75/25 dr) with 4
rotamers being present in total (Scheme 1).
Entrya
Temp (ꢀC)
Time (h minꢁ1
)
Convb (%)
1c
100
130
100
120
150
150
150
150
150
180
180
180
180
180
180
18 h
18 h
Traces
7
6
10
20
2c
3d
10 min
10 min
10 min
30 min
60 min
120 min
90 min
90 min
80 min
60 min
70 min
80 min
18 h
4d
5d
6d
39
70
7d
8d
100
91
100
100
92
98
100
91
9d
10d
11d,e
12d
13d
14f
15g
a
b
Reaction conditions: 7a (0.5 mmol), AcOH (3 mL). Determined by
c
HPLC of the crude reaction mixture. The reaction was performed
under classical heating conditions. The reaction was performed in
AcOH (0.17 M) under microwave irradiation. Isolated in 95% yield as
a single trans diastereomer. The reaction was performed in TFA
under microwave irradiation. The reaction was performed in a
sealed vial placed in an oil bath.
Because we recently investigated microwave-assisted
conversions,23 the development of such conditions was of
particular interest to optimize the subsequent lactamization
step towards the desired THBC-DKPs. The results are summa-
rized in Table 1.
d
e
f
g
Under classical heating conditions in glacial acetic acid, the
reaction did not proceed when the mixture was heated at 100 ꢀC
in an oil bath for 18 hours (entry 1, Table 1). Performing the
reaction at 130 ꢀC slightly increased the conversion (7%
conversion as detected by RP-HPLC, entry 2, Table 1). We thus
turned our attention to explore the microwave irradiation
parameters to optimize the reaction. When the reaction was
carried out under microwave conditions, only a limited
conversion (6%) was observed aer 10 minutes (entry 3,
Table 1). To our satisfaction, more of the desired product was
observed upon further increase of the temperature (entries 4
and 5, Table 1). Ensuing optimization showed that increased
reaction time and temperature was appropriate for a cyclization
in good to excellent yield (Table 1, entries 6–13). Successive
temperature increase from 100 ꢀC to 180 ꢀC and applying a
reaction time of 10 to 80 min afforded total conversion to 8a
(100% conversion, 95% isolated yield, entry 11, Table 1). Grat-
ifyingly, only a single diastereomer, characterized as the trans
isomer by NOESY studies (see ESI†) was observed by RP-HPLC.
When using TFA instead of AcOH, the full conversion obtained
at 180 ꢀC for 80 minutes was accompanied by the formation of
by-products in the reaction mixture (entry 14, Table 1). Although
much longer reaction times were needed, a good conversion
(91%) was also obtained in sealed vials, which were placed in an
oil bath at 180 ꢀC for 18 h. (entry 15, Table 1). Next, the optimal
conditions (entry 11, Table 1) were chosen to explore the
substituent scope of this methodology. At this temperature and
reaction time, full conversion and high diastereomeric excesses
were obtained for a wide array of enantiopure THBC-based DKP
scaffolds, as summarized in Table 2. This amine–amide cycli-
sation mode provides an alternative for the amine–ester DKP
formation, as reported by Tyagi,19e and has the advantage to give
a single diastereomer in high yield. In contrast to reported
methodologies, this method allows to prepare cialis derivatives
with high diversity.
Fig. 2 Retrosynthetic strategy.
Scheme 1 Sequential Ugi/deprotection/Pictet–Spengler reaction for
the synthesis of THBC 7a.
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Table 2 Substrate scope
Entry
1
THBC-DKP product
Yielda (%) d.e.b (%)
Entry
9c,d
THBC-DKP product
Yielda (%) d.e.b (%)
81(>98)
73(>98)
2
77(>98)
10
74(>98)
3
75(>98)
70(>98)
76(>98)
11
73(>92)
75(>98)
79(>98)
4c
12d
5c
13
6c
71(>98)
73(>98)
14
15
72(>98)
7
80
8
68(>98)
16
75
a
Isolated yields aer silica gel column chromatography. b Diastereomeric excess determined by 1H and 13C NMR spectra or HPLC. c One equiv. of
d
Et3N was added to neutralize the methylamine hydrochloride. Isolated yields from Boc-D-Trp-OH.
With enantiopure Boc-(L/D)-Trp-OH as chiral amino acids in (entries 1–3, Table 2) and the desired products 8a were isolated
hand, we initiated a study to explore the scope of the one- with high yields and excellent diastereomeric excess. We here-
pot four-step Ugi/deprotection/Pictet–Spengler/lactamization with demonstrated for the rst time that in the microwave-
sequence. The reaction of three different isocyanides with assisted intramolecular-cyclization process, the readily avail-
Boc-L-Trp-OH, benzylamine and benzaldehyde was examined able cyclohexyl- and benzyl isocyanide (entries 2 and 3, Table 2)
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ꢀ
can also be used as convertible isocyanides (with total conver- irradiation, 180 C, 80 min), the desired compound 8i, THBC-
sion) when an intramolecular nucleophile is present, thus based DKP derivative, was obtained in high diastereomeric
offering a cost effective alternative to Armstrong's isocyanide.24 excess (91% yield, 96/4 dr), in favour of the trans (6R, 12aS)
The electron-donating or electron-withdrawing properties of diastereomer. However, performing the reaction at 160 ꢀC for 40
substituents in the aldehyde component, involved in the Pictet– min, a moderate conversion was obtained and the desired
Spengler reaction, were well tolerated and have no inuence on product 8i/8i0 was isolated as a mixture of trans and cis diaste-
the yield and diastereomeric excess of the reaction, as reomers (52% yield, 70/30 dr). Prolonged heating of the isolated
ꢀ
compounds (8b–h) were isolated in an enantiopure form in mixture 8i/8i0 for 6 hours at 180 C afforded a mixture of trans
good yields (entries 4–10, Table 2). Interestingly, 12a-epi-tada- diastereomer 8i (6R, 12aS) and its stereoisomer 8j (6S, 12aR)
lal 8f and its enantiomer 6-epi-tadalal 8g could be accessed (88% yield, 42/58 dr). To understand the epimerization of 8i at
starting from either L- or D-Trp-OH (entries 8 and 9, Table 2). the C-12a and C-6 positions, heating compound 8i under the
Next, chiral a-branched amines were used in the Ugi reaction same conditions (180 ꢀC, 6 hours) led to a separable mixture of
and gave the expected compounds (8i–k) in excellent yields and trans diastereomer 8j (6S, 12aR) in 49% yield and 8i (39%)
d.e. (%) (entries 11–13, Table 2). The reaction with (S)-1-methyl (Scheme 2).
benzylamine and (R)-1-methyl benzylamine allowed to identify a
The mechanism by which the conversion of the cis diaste-
double stereochemical change at C-6 and C-12a. When using reomers into the more thermodynamically stable trans diaste-
(S)-1-methyl benzylamine, product 8i was obtained with a minor reomers takes place is tentatively rationalized (Scheme 3).
amount of epimer 8i0 (3–4%) (entry 11, Table 2). In contrast,
Under microwave irradiation in acidic conditions, the Pictet–
only single THBC-DKP diastereoisomers 8j and 8k were Spengler reaction is reversible through a retro process in which
observed by 1H NMR and HPLC (entries 12 and 13, Table 2). a C–N bond is broken,25 allowing the cis-isomer (6S, 12aS) to
Using benzaldehyde in the Ugi reaction, an excellent d.e. (%) isomerize to the thermodynamically more stable trans isomer 8i
was obtained for the compound 8l, and the product was isolated (6R, 12aS). This is realized by an intramolecular addition of the
as a single diastereomer (3R, 6R, 12aS) (entry 14, Table 2). An adjacent double bond of the lactim onto the Re-face (top side) of
epimerization at C-3, probably occurring through enolization of the olen iminium intermediate 9 in which the fused THBC-
the initially formed diastereomeric mixture in glacial acetic DKP have a trans chair–chair junction (less strained and more
acid, yields the single, more stable, trans diastereomer 8l. The stable conformation).20c,d Furthermore, under microwave
conguration of 8l was conrmed by NOESY studies (see ESI†). conditions, in the presence of an acid and upon prolonged
Application of the Pictet–Spengler reaction with cyclohexanone heating, this trans isomer 8i could be converted into enol form
produced the spirocyclic-tetrahydro-b-carbolines and nally led A, through enolization in which the hydrogen-transfer of the
to THBC-DKP 8m in good yield (entry 15, Table 2). In addition, hydroxyl group to the Si-face of sp2-hybridized C-12a is able to
the Pictet–Spengler reaction with formaldehyde afforded the regenerate compound 8i (more stable). The hydrogen-transfer
desired compound 8n in good yield (entry 16, Table 2).
to the Re-face of C-12a in enol A produces intermediate cis
In order to gain a better insight into the observed acid- (6R, 12aR), which ultimately leads to the more stable trans
catalyzed epimerization in the tetracyclic compound 8i, we isomer 8j (6S, 12aR) via a tandem ring-opening and stereo-
decided to study the origin of the observed stereoselectivity aer selective intramolecular addition process.
the lactamization step (Scheme 2). Using the reaction condi-
In summary, we have developed an efficient and novel ster-
tions of the above described Ugi/deprotection/Pictet–Spengler eoselective strategy for the preparation of various optically pure
sequence intermediate 7i (Scheme 2) was isolated in excellent and trisubstituted tetrahydro-b-carboline-fused diketopiper-
yield as a mixture of two diastereomers (95% yield, 53/47 dr). azines (THBC-DKPs), containing three potential points of
When the lactamization was carried out in glacial acetic diversity, by a one-pot tandem Ugi/Boc-deprotection/Pictet–
acid, applying the optimal reaction conditions (microwave Spengler/lactamization sequence. We demonstrated for the rst
Scheme 3 Proposed mechanism for the acid-catalyzed epimerization
Scheme 2 Epimerization study.
at the C-6 and C-12a positions.
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time that the readily available cyclohexyl- and benzyl isocyanide
applied in the Ugi-4CR can used as convertible isocyanides in
Z. Urbanczyk-Lipkowska, D. Tourwe and S. Ballet, Org.
Lett., 2013, 15, 5866.
post-condensation Ugi modications when an intramolecular 12 (a) A. Basso, L. Ban and R. Riva, Eur. J. Org. Chem., 2010,
nucleophile is present. This original procedure is suitable for
the synthesis of 12a-epi-cialis 8f and its enantiomer 6-epi-cialis
1831; (b) A. Ilyin, V. Kysil, M. Krasavin, I. Kurashvili and
A. V. Ivachtchenko, J. Org. Chem., 2006, 71, 9544.
8g in an enantiopure form, and should prove useful for the 13 F. Bonnaterre, M. Bois-Choussy and J. Zhu, Org. Lett., 2006,
synthesis of new compound libraries with a wide structural
diversity.
8, 4351.
14 A. Salcedo, L. Neuville, C. Rondot, P. Retailleau and J. Zhu,
Org. Lett., 2008, 10, 857.
15 (a) L. Ban, R. Riva and A. Basso, Synlett, 2010, 23.
16 T. P. Ribelin, A. S. Judd, I. Akritopoulou-Zanze, R. F. Henry,
J. L. Cross, D. N. Whittern and S. W. Djuric, Org. Lett., 2007,
9, 5119.
Acknowledgements
This work was supported by a collaboration convention between
`
´
the Ministere du Developpement Economique, de l’Innovation
´
et de l’Exportation du Quebec and the Research Foundation –
17 Z. Xu, F. De Moliner, A. P. Cappelli and C. Hulme, Angew.
Chem., Int. Ed., 2012, 51, 8037.
Flanders (FWO Vlaanderen) (PSR-SIIRI-417 & FWOAL570).
18 T. Niexy, P. Tempest and C. Hulme, Tetrahedron Lett., 2002,
43, 1637.
Notes and references
¨
19 (a) W. Wang, S. Ollio, E. Herdtweck and A. Domling, J. Org.
1 (a) J. Stçckigt, A. P. Antonchick, F. Wu and H. Waldmann,
Angew. Chem., Int. Ed., 2011, 50, 8538; (b) M. Shiri, Chem.
Rev., 2012, 112, 3508.
Chem., 2011, 76, 637; (b) W. Wang, E. Herdtweck and
¨
¨
A. Domling, Chem. Commun., 2010, 46, 770; (c) L. El Kaım,
M. Gageat, L. Gaultier and L. Grimud, Synlett, 2007, 500;
(d) M.-A. Cano-Herrera and L. D. Miranda, Chem.
Commun., 2011, 47, 10770; (e) V. Tyagi, S. Khan and
P. M. S. Chauhan, Synlett, 2013, 24, 1291.
2 A. C.-M. Daugan, US Pat., US5859006, 1999.
3 T. B. Beghyn, J. Charton, F. Leroux, G. Laconde, A. Bourin,
P. Cos, L. Maes and B. Deprez, J. Med. Chem., 2011, 54, 3222.
4 S. K. Rabindran, D. D. Ross, L. A. Doyle, W. Yang and
L. M. Greenberger, Cancer Res., 2000, 60, 47.
5 H. A. Mohamed, N. M. R. Girgis, R. Wilcken, M. R. Bauer,
H. N. Tinsley, B. D. Gary, G. A. Piazza, F. M. Boeckler and
A. H. Abadi, J. Med. Chem., 2011, 54, 495.
6 J. Liu, G. Wu, G. Cui, W. X. Wang, M. Zhao, C. Wang,
Z. Zhang and S. Peng, Bioorg. Med. Chem., 2007, 15, 5672.
7 G. Whaley, In Organic Reactions, Wiley, New York, 1951, vol.
6, p. 151.
8 (a) B. Nicholson, G. K. lloyd, B. R. Miller, M. A. Palladino,
Y. kiso, Y. Hayashi and S. T. C. Neuteboom, Anti-Cancer
20 (a) K. Pulka, Curr. Opin. Drug Discovery Dev., 2010, 13, 669; (b)
S. Xiao, X.-X. Shi, F. Ni, J. Xing, J.-J. Yan and S.-L. Liu, Eur. J.
Org. Chem., 2010, 1711; (c) R. Vedantham, S. Shanmugam,
P. VNKV-Vetukuri, M. Khagga and R. Bandichhor, Arkivoc,
2013, 22; (d) F. Airaghi, A. Fiorati, G. Lesma, M. Musolino,
A. Sacchetti and A. Silvani, Beilstein J. Org. Chem., 2013, 9,
147.
21 (a) P. J. Dunn, Org. Process Res. Dev., 2005, 9, 88; (b)
J. D. Revell, N. Srinivasan and A. Ganesan, Synlett, 2004,
1428; (c) Y. Ma, H. Wu, J. Zhang and Y. Li, Chirality, 2013,
25, 656; (d) S. Xiao, X. Lu, X. X. Shi, Y. Sun, L. L. Liang,
X. H. Yu and J. Dong, Tetrahedron: Asymmetry, 2009, 20, 430.
22 M. Jida, M. Soueidan, N. Willand, L. Pelinski, G. Laconde,
R. Deprez-Poulain and B. Deprez, Tetrahedron Lett., 2011,
52, 1705.
¨
Drugs, 2006, 17, 25; (b) A. Domling and W. R. Abraham,
Drug Des. Rev., 2005, 2, 13.
9 (a) A. D. Borthwick, Chem. Rev., 2012, 112, 3641; (b)
¨
A. Domling and Y. Huang, Synthesis, 2010, 17, 2859.
10 (a) C. Hulme and V. Gore, Curr. Med. Chem., 2003, 10, 51; (b)
L. A. Wessjohann, D. G. Rivera and O. E. Vercillo, Chem. Rev.,
2009, 109, 796.
23 For selected examples, see: (a) M. Jida, R. Deprez-Poulain,
S. Malaquin, P. Roussel, F. Agboussou-Niedercorn,
B. Deprez and G. Laconde, Green Chem., 2010, 12, 961; (b)
M. Jida, O. M. Soueidan, B. Deprez, G. Laconde and
R. Deprez-Poulain, Green Chem., 2012, 14, 909.
¨
11 (a) A. Domling and I. Ugi, Angew. Chem., Int. Ed., 2000, 39,
¨
3168; (b) A. Domling, Chem. Rev., 2006, 106, 17; (c)
S. Marcaccini and T. Torroba, Nat. Protoc., 2007, 2, 632; (d)
G. Koopmanschap, E. Ruijter and R. V. A. Orru, Beilstein J.
24 C. Hulme, J. Peng, S.-Y. Tang, C. J. Burns, I. Morize and
R. Labaudiniere, J. Org. Chem., 1998, 63, 8021.
25 M. L. Van Linn and J. M. Cook, J. Org. Chem., 2010, 75, 3587.
¨
Org. Chem., 2014, 10, 544; (e) A. Domling, K. Wang and
W. Wang, Chem. Rev., 2012, 112, 3083; (f) M. Jida, C. Betti,
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