Expedient entry to the piperazinohydroisoquinoline ring system using a sequential Ugi/Pictet-Spengler/reductive methylation reaction protocol

Article abstract of DOI:10.1039/c1cc10759c

An expedient entry to the piperazinohydroisoquinoline ring system present in the tetrahydroisoquinoline antitumor alkaloids family is described. The synthetic sequence involves: a sequential Ugi reaction followed by an N-Boc-deprotection process and iminium formation with a spontaneous Pictet-Spengler cyclization and reductive N-methylation, with all these processes performed in a two-operation protocol in the same reaction flask.

Full text of DOI:10.1039/c1cc10759c

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COMMUNICATION
Expedient entry to the piperazinohydroisoquinoline ring system using a
sequential Ugi/Pictet–Spengler/reductive methylation reaction protocolw
Ma.-Angeles Cano-Herrera and Luis D. Miranda*
Received 9th February 2011, Accepted 17th August 2011
DOI: 10.1039/c1cc10759c
An expedient entry to the piperazinohydroisoquinoline ring
system present in the tetrahydroisoquinoline antitumor alkaloids
family is described. The synthetic sequence involves: a sequential
Ugi reaction followed by an N-Boc-deprotection process and
iminium formation with a spontaneous Pictet–Spengler cycliza-
tion and reductive N-methylation, with all these processes
performed in a two-operation protocol in the same reaction flask.
The piperazinohydroisoquinoline ring system 1 is a common
motif in a variety of natural alkaloids, including saframycins,
safracins, jorumycin, renieramycins and ecteinascidin (Fig. 1).1
This alkaloid family has attracted significant attention over the
past 30 years because these compounds display potent antitumor
and antimicrobial activities. Notably, the antiproliferative activity
of ecteinascidin 743 (Et-743) is greater than that of taxol,
camptothecin, mitomycin C, or cisplatin and it has been recently
approved for the treatment of patients with soft-tissue sarcoma.2
These compounds have remarkable biological activity, display
complex molecular architecture, and have limited availability
in nature and thus, development of practical synthetic strategies
represents an interesting challenge. A number of elegant synthetic
studies for these pentacyclic alkaloids have been described to
date,1,3,4 but most of them are long and complex reaction
sequences. Thus, the development of synthetic protocols that
access scaffolds structurally related to Et-743 using inexpensive
and practical methodologies would advance the discovery of
new and more potent anticancer agents.
Its convergent character, atom economy, operational simplicity,
and the structural diversity of the resulting adducts make the Ugi
multicomponent reaction (Ugi MCR) especially useful for the
construction of complex molecules.5 Remarkably, the meticulously
Fig. 1 The structure of piperazinohydroisoquinoline alkaloids.
sequential protocols, several bonds are created, and diminished
waste products are generated because there are fewer
purification steps.
programmed combination of a Ugi reaction with sequential
transformations amplifies the synthetic potential of this chemistry.
The combination of MCRs with sequential processes has allowed
the assembly of complex molecules in a few steps, and
generally from readily available starting materials.5 In these
We imagined that the CDE ring core 1 (Fig. 1)6 of the
tetrahydroisoquinoline alkaloids might be constructed starting
from the readily available aminoacetaldehyde dimethylacetal 9
and the N-Boc-3-(3,4-dimethoxyphenyl) alanine 10 using a
sequential combination of a four-component Ugi reaction
(Ugi 4-MCR) followed by a Pictet–Spengler cyclization
(Scheme 1).7 From the outset we planned to take advantage
of the acidic conditions generally utilized for the Eschweiler–
Clarke reductive methylation (formic acid/formaldehyde)8 for
both the deprotection of the N-Boc amine moiety followed by
´
Instituto de Quımica, Universidad Nacional Autonoma de Mexico,
Circuito Exterior, Ciudad Universitaria, Coyoaca´n Me´xico D. F.
´
´
´
04510, Mexico. E-mail: lmiranda@unam.mx
w Electronic supplementary information (ESI) available: Experimental
details, synthesis of 10b, characterization data and copies of the
1H NMR, and 13C NMR spectra for the products. CCDC 831117.
For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c1cc10759c
c
10770 Chem. Commun., 2011, 47, 10770–10772
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Table 1 Synthesis of the piperazinohydroisoquinoline ring system
Ugi adduct yield Product 12 yield
(%)
Entry Aldehyde R2
(%)
d.r.c
1
2
8a
8b
H 15a (51)
CH2CH3 15b (93)
12a (66),a (52)b
12b (70),a (47)b
—
1 : 1
3
4
5
8c
8d
8e
15c (82)
12c (88),a (60)b
12d (81),a (58)b
12e (91),a (61)b
1 : 1
1 : 1
1 : 1
Scheme 1 Synthesis of the piperazinohydroisoquinoline ring system
using a sequential Ugi/Pictet–Spengler/reductive methylation reaction
protocol.
15d (94)
15e (82)
the Pictet–Spengler cyclization and also for the reductive
methylation of the resulting secondary amine, and to conduct
the reactions in a single flask. Our intended outcome from
these four consecutive reactions was the desired heterocyclic
scaffolds containing the N-Me functionality found in the
natural products. Herein, we describe preliminary results of
our efforts in this field.
6
7
8f
15f (82)
15g (65)
12f (69),a (55)b
12g (95),a (54)b
1 : 1
1 : 1
To test the feasibility of the proposed protocol reactions, we
started with the aminoacetaldehyde dimethylacetal 9, (ꢀ)-(S)-
N-Boc-3-(3,4-dimethoxyphenyl) alanine 10, and tert-butyl
isocyanide 11 as the amine, carboxylic acid and isocyanide
components in the Ugi reaction, respectively, in combination
with several aldehydes.z Initially, we observed that when the Ugi
reaction was performed at room temperature in methanol, using
approximately equimolar amounts of the four components and
indium trichloride as the Lewis acid, the reactions were lengthy
(48 h). The reaction was completed in a straightforward manner
within a few hours (1–2 h) when the reaction was carried out at
50 1C using microwave irradiation.9 Under these conditions,
aliphatic (Table 1, entries 1 and 2) and aromatic (entries 3–7)
aldehydes 8a–g afforded good yields of the desired Ugi
adducts 15a–g.
8g
Conditions: (i) MeOH, InCl3 (20 mol%), 50 1C, mw, 1–2 h;
(ii) HCOOH net, HCOH (37% in water, 17 eq.), 60 1C, 1 h.a Yield from
15a–g, the Ugi adduct was purified and then submitted to the H2CO/
b
HCOOH conditions. Overall yields from 8a–g, the Ugi adducts were
c
not purified. Determined from the NMR spectra.
formed in the Pictet–Spengler cyclization (14 - 12) would be
spontaneously fixed by the chiral center already present in the
starting material. One of the diastereoisomers of the adduct
12f was separated and its structure was confirmed by an X-ray
analysis (Fig. 2). Interestingly, when a benzaldeyde (15c–g) is
used in the Ugi reaction, the final products 12c–g contained the
natural product-like A-ring along with the properly functionalized
C-a derivative (Scheme 1). Furthermore, when the suitably
substituted racemic amino acid 10b10 was prepared and submitted
to the same reaction sequence under the optimized one-pot
conditions, the piperazinohydroisoquinoline ring system 12h
containing a penta-functionalized benzene moiety was obtained
We then assessed the viability of the one-pot transformation
of the Ugi adducts 15a–g into the desired piperazinohydro-
isoquinolines 12a–g. We were pleased to observe that the
treatment of 13a–g using neat formic acid and formaldehyde
furnished the desired target molecules 12a–g in good yields as
a 1 : 1 diastereomeric mixture (Scheme 1, Table 1). Thus, under
these conditions all processes depicted in Scheme 1, the N-Boc
and acetal deprotections (13), the formation of the cyclic
iminium 14, and the intramolecular Pictet–Spengler process
followed by the reductive methylation, generally took place
with high efficiency. We then established that the entire
sequence of consecutive reactions could be carried out in the
same reaction flask simply by evaporating the solvent after the
Ugi reaction was completed, and then adding the reactive mixture
of H2CO/HCOOH. Under these conditions, comparable yields
of the desired heterocyclic scaffolds 12a–g were obtained,
initiated from the readily available starting materials
(Table 1). Furthermore, as an optically pure amino acid 10
was originally used in the Ugi reaction, the new chiral center
Fig. 2 X-Ray analysis of one of the diastereoisomers of 12f.11
Chem. Commun., 2011, 47, 10770–10772 10771
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1 For
a
R. M. Williams, Chem. Rev., 2002, 102, 1669.
review of these compounds see: J. D. Scott and
2 G. J. Aune, T. Furuta and Y. Pommier, Anti-Cancer Drugs, 2002,
13, 545.
3 (a) B. J. Wright, C. Chan and S. J. Danishefsky, J. Nat. Prod.,
2008, 71, 409; (b) P. Magnus and K. S. Matthews, J. Am. Chem.
Soc., 2005, 127, 12476; (c) S. Obika, Y. Yasui, R. Yanada and
Y. Takemoto, J. Org. Chem., 2008, 73, 5206; (d) M. H. Todd,
C. Ndukabu and P. A. Barlett, J. Org. Chem., 2002, 67, 3985.
4 (a) Y. Tang and Z. Liu, Tetrahedron Lett., 2003, 44, 7091;
(b) W. Jin, S. Metobo and R. M. Williams, Org. Lett., 2003,
5, 2095; (c) D. Fishlock and R. M. Williams, J. Org. Chem., 2008,
73, 9594; (d) J. W. Lane, Y. Chen and R. M. Williams, J. Am.
Chem. Soc., 2005, 127, 12684; (e) S. Lee and S. Park, J. Comb.
Chem., 2006, 8, 50; (f) J. F. Gonzalez, L. Salazar, E. Cuesta and
C. Avendano, Tetrahedron, 2005, 61, 7447; (g) Y. Chang, T. Sun,
M. Chiang, P. Lu, Y. Huang, L. Liang and C. Ong, Tetrahedron,
2007, 63, 8781; (h) S. Aubry, S. Pellet-Rostaing, B. Fenet and
M. Lemaire, Tetrahedron Lett., 2006, 47, 1319; (i) G. Vincent,
W. Jonatha and R. M. Williams, Tetrahedron Lett., 2007, 48, 3719.
5 For a review of Ugi reaction see: (a) A. Domling and I. Ugi,
Angew. Chem., Int. Ed., 2000, 39, 3168; (b) A. Domling, Chem.
Rev., 2006, 106, 17; (c) I. Ugi, Pure Appl. Chem., 2001, 73, 187;
(d) I. Ugi, A. Domling and B. Werner, J. Heterocycl. Chem., 2000,
37, 647; (e) I. Ugi and A. Domling, in Combinatorial Chemistry: a
practical approach, ed. H. Fenniri, Oxford University Press,
Oxford, 2000, 287–302; (f) I. Akritopoulou-Zanze and
S. W. Djuric, Heterocycles, 2007, 73, 125; (g) S. Marcaccini and
Scheme 2 Conditions: (i) 11, 9, 8a, MeOH, mw. 50 1C, 50 watts, 2 h.
(ii) HCOOH, CH2O/H2O 37%, 60 1C, 1 h. (iii) Acetone/water (9/1),
DDQ, r.t., 2 h.
in good yields (Scheme 2). As expected the oxidation of this
latter product afforded the quinone 16 which represents the
complete east-side of several natural products shown in Fig. 1.
In principle, the introduction of a methylene group between
the A-ring and the B-ring by using different starting materials
would give access to the suitably functionalized pentacyclic
system of the target natural products (Fig. 1). Efforts to
address this issue are currently underway in our laboratory.
In conclusion, a practical protocol for rapid construction of the
piperazinohydroisoquinoline motif, containing the requisite
functionality present in the tetrahydroisoquinoline natural products
family, is described. The synthetic strategy involves a sequential Ugi
reaction followed by a Boc-deprotection process and iminium
formation with a spontaneous Pictet–Spengler cyclization and
finally a reductive N-methylation, with all the processes in the
two-operation protocol being performed in the same reaction flask.
T. Torroba, Multicomponent Reactions, ed. J. Zhu and H. Bienayme,
Wiley-VCH, Weinheim, Germany, 2005, ch. 2, pp. 33–75.
6 For a review of construction of related piperazine scaffolds using a
multicomponent reaction see: A. Domling and Y. Huang,
Synthesis, 2010, 2859.
´
7 For related Ugi/Pictet–Spengler combinations see: L. El Kaim,
M. Gageat, L. Gaultier and L. Grimaud, Synlett, 2007, 500; R. V.
A. Orru, A. Znabet, J. Zonneveld, E. Janssen, F. J. J. De Kanter,
M. Helliwell, N. J. Turner and E. Ruijter, Chem. Commun., 2010,
46, 7706; A. Domling, W. Wang and E. Herdtweck, Chem.
Commun., 2010, 46, 770; A. Domling, H. Chao and H. Liu,
Chem.–Eur. J., 2010, 16, 12296; A. Domling and H. Liu, J. Org.
Chem., 2009, 74, 6895; A. Domling, W. Wang, S. Ollio and
E. Herdtweck, J. Org. Chem., 2011, 76, 637.
8 W. Eschweiler, Ber. Dtsch. Chem. Ges., 1905, 38, 880; H. T. Clarke,
H. B. Gillespie and S. Z. Weisshaus, J. Am. Chem. Soc., 1933,
55, 4571.
9 Microwave reactions were conducted using a CEM Discover
Synthesist Unit(CEM Corp., Matthews, NC). http://www.cem.
com/page176.html.
Notes and references
z General procedure for the one-pot reaction. To a mixture of
aminoacetaldehydedimethylacetal 9 (41.73 mg, 0.3969 mmol, 1.2 equiv.),
(ꢀ)-(S)-N-Boc-3-(3,4-dimethoxyphenyl) alanine 10 (129.15 mg, 0.3969
mmol, 1.2 equiv.), and tert-butylisocyanide 11 (0.037 mL,
0.3308 mmol, 1 equiv.) and InCl3 (20 mol%) in MeOH anhydrous
(1.1 mL) the corresponding aldehyde 8a–g was added at room
temperature (1 equiv.). The resulting solution was heated at 50 1C
for 1–2 h, using microwave irradiation. The reaction mixture was
concentrated under reduced pressure. Then to a solution of this later Ugi
adduct crude in formic acid (0.5 mL), 37% solution of formaldehyde in
water was added at room temperature (2.4018 mmol, 17 equiv.), and
extracted with AcOEt (3 ꢁ 5 mL). The mixture was stirred for 1 h at
60 1C. The reaction mixture was washed with water (2 ꢁ 5 mL), and
saturated aqueous NaHCO3, and the organic layer was dried over
anhydrous Na2SO4, and concentrated under reduced pressure. The
resulting residue was purified by flash column chromatography.
10 For the synthesis of this compound see the ESIw.
11 The absolute stereochemistry of this compound was suggested as
[1(R)-4(R)-6(S)] on the basis of the use of optically pure (ꢀ)-(S)-N-
Boc-3-(3,4-dimethoxyphenyl) alanine 10 as starting material in the
Ugi reaction.
c
10772 Chem. Commun., 2011, 47, 10770–10772
This journal is The Royal Society of Chemistry 2011