Short stereocontrolled synthesis of trans and cis-tetrahydro-pyrazinoisoquinolinediones

Article abstract of DOI:10.1016/S0040-4039(03)00897-9

Addition of aldehyde dimethyl acetals (here acetaldehyde) to unisolated O-trimethylsilyl derivatives of 1-acetyl-3-arylmethylpiperazine-2,5-diones (here 2,5-dimethoxyphenyl), in the presence of TMSOTf as the catalyst, gave nearly quantitatively the corres

Full text of DOI:10.1016/S0040-4039(03)00897-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4395–4398
Short stereocontrolled synthesis of trans and
cis-tetrahydro-pyrazinoisoquinolinediones
Juan Francisco Gonza´lez, Elena de la Cuesta and Carmen Avendan˜o*
Departamento de Qu´ımica Orga´nica y Farmace´utica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
Received 18 March 2003; revised 31 March 2003; accepted 4 April 2003
Abstract—Addition of aldehyde dimethyl acetals (here acetaldehyde) to unisolated O-trimethylsilyl derivatives of 1-acetyl-3-aryl-
methylpiperazine-2,5-diones (here 2,5-dimethoxyphenyl), in the presence of TMSOTf as the catalyst, gave nearly quantitatively the
corresponding N-methoxyalkyl derivatives which, under acidic treatment, gave in very good yield through a Pictet–Spengler-type
reaction involving N-acyliminium cations (6S*,11aR*)-2-acetyl-6-alkyl-3,6,11,11a-tetrahydro-2H-pyrazino[1,2-b]isoquinoline-1,4-
diones. Epimerization of the 11a-stereocentre was accomplished by radical bromination, spontaneous hydrobromide elimination
and catalytic hydrogenation, to give the (6S*,11aS*)-isomers. We propose these compounds as precursors of tetra-
hydroisoquinoline antitumour antibiotics. © 2003 Elsevier Science Ltd. All rights reserved.
Many tetrahydroisoquinoline antitumour antibiotics,
such as saframycins and ecteinascidins, are widely stud-
ied cytotoxic agents.1 Their development as antitumour
drugs, which is headed by ecteinascidin 743 (E-743)
currently undergoing advanced clinical trials, has been
limited by their natural scarcity and the complexity of
their synthesis.2–6 Although it is known that most of the
biological activity of ET-743 is maintained in simpler
synthetic analogues such as phtalascidin,7,8 structure–
activity correlations within this group of antibiotics are
relatively unexplored9–12 because most of the synthetic
work carried out so far has focused on their total
synthesis (Fig. 1).
We propose that the title compounds bearing adequate
substituents at ring A and C-6 could be precursors of
these antibiotics or their analogues since they contain
rings A-C, an N-acetyl group to facilitate the formation
of C(3) benzylidene derivatives by condensation with
aromatic aldehydes, and two carbonyl groups that can
be manipulated either to elaborate rings E-D by aro-
matic substitution (C(1)ꢀO) or to introduce substituents
Figure 1.
Keywords: acetals; N-acyliminium cations; aromatic substitution; annulations; epimerization.
* Corresponding author. Fax: 34-91-394 18 22; e-mail: avendano@farm.ucm.es
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00897-9

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J. F. Gonza´lez et al. / Tetrahedron Letters 44 (2003) 4395–4398
such as cyano at C-4 by previous reduction and forma-
tion of transient iminium species.
It is significant that, besides the good yield, these
reaction conditions are compatible with the N-acetyl
group necessary to facilitate the planned subsequent
condensation, while a previously described procedure
gave ca. 50% yield of a mixture of ( )-5 with its
N-deacetyl derivative,16 where 5 was the minor compo-
nent. We have also corroborated that our method
allows variations of ring A by using different aromatic
aldehydes, as well as variations of the C(6)-substituent
with other dimethyl acetals.
We here report an efficient route to obtain (6S*,11aR*)
and
(6S*,11aS*)-2-acetyl-7,10-dimethoxy-6-methyl-
3,6,11,11a-tetrahydro-2H-pyrazino[1,2-b]isoquinoline-
1,4-diones (5 and 7) as model compounds through a
Pictet–Spengler-type reaction involving N-acyliminium
cations.
Compound 2 was obtained (98%) by condensation in
KtBuO/tBuOH of 2,5-dimethoxybenzaldehyde with 1
when CH2Cl2 was used as solvent instead of DMF,13
since the insolubility of the product drove the equi-
librium to completion. After reduction under standard
conditions, compound 3 was N-alkylated with acetalde-
hyde dimethylacetal by using trimethylsilyl triflate to
activate the unsubstituted lactam as nucleophile and the
acetal as electrophile.14,15 The success of this N-ami-
doalkylation may be explained considering that the
catalyst forms a triflate-acetal ion pair that fragments
to methyl ethylydeneoxonium triflate, which is subse-
quently trapped by the O-trimethylsilyl derivative of 3.
Compound 4, obtained as a mixture of diastereomers,
underwent an N-acyliminium ion-mediated 6-exo-trig
cyclization in refluxing formic acid to give the trans-iso-
mer ( )-5 as the only product in 85% yield (Scheme 1).
Although the trans-relationship between H-6 and H-
11a protons in compound 517 is opposite to that of ring
B in the antibiotics above mentioned, this stereochem-
istry was the expected one for a cyclization mediated by
acyliminium cations, since these ions would adopt an
E-configuration in order to minimize the steric interac-
tions between the R substituent (CH3 in the case of
compound 4) and the C(5)ꢀO group of the piperazine-
dione ring (Fig. 2).
In a very advanced pentacyclic precursor of saframycin
B, Kubo achieved the epimerization of a benzylic posi-
tion, corresponding to C-6 in 5, through N-oxidation of
an a-amine group to give an iminium cation that was
subsequently reduced.18 Since this protocol cannot be
applied to the lactam nitrogen of compound 5, we
Scheme 1.
Figure 2.

J. F. Gonza´lez et al. / Tetrahedron Letters 44 (2003) 4395–4398
4397
Scheme 2.
planned to obtain its cis-isomer by catalytic hydrogena-
tion of the unsaturated compound 6. With this aim,
compound 2 was transformed into the corresponding
N-methoxyalkyl derivative, but all cyclization attempts
to give 6 were unsuccessful. Next, we studied the
epimerization of the stereocentre C-11a through a
regioselective bromination in radical conditions
because, in spite of the presence of two benzylic posi-
tions, we expected a radical intermediate at that stere-
ocenter, taking into account its captodative character.19
In fact, the reaction of 5 with NBS and AIBN in CCl4
gave quantitatively the unsaturated compound 6 which,
after catalytic hydrogenation gave a very good yield of
the cis-isomer ( )-7 (Scheme 2).
4. Cuevas, C.; Pe´rez, M.; Mart´ın, M. J.; Chicharro, J. L.;
Ferna´ndez-Rivas, C.; Flores, M.; Francesch, A.; Gallego,
P.; Zarzuelo, M.; de la Calle, F.; Garc´ıa, J.; Polanco, C.;
Rodr´ıguez, I.; Manzanares, I. Org. Lett. 2000, 2, 2545–
2548.
5. Zhou, B.; Edmonson, S.; Padro´n, J.; Danishefsky, S. J.
Tetrahedron Lett. 2000, 41, 2039–2042.
6. Zhou, B.; Guo, J.; Danishefsky, S. J. Org. Lett. 2002, 4,
43–46.
7. Mart´ınez, E. J.; Owa, T.; Schreiber, S. L.; Corey, E. J.
Proc. Natl. Acad. Sci. 1999, 96, 3496–3501.
8. Mart´ınez, E. J.; Corey, E. J.; Owa, T. Chem. Biol. 2001,
8, 1151–1160.
9. Zewail-Foote, M.; Hurley, L. H. J. Am. Chem. Soc. 2001,
123, 6485–6495.
10. Seeman, F. C.; Hurley, L. H. J. Am. Chem. Soc. 1998,
120, 13028–13041.
In conclusion, the detailed study of the tandem N-alkyl-
ation–Pictet–Spengler-type
reactions
on
3-aryl-
11. Moore, R. M.; Seaman, F. C.; Wheelhouse, R. T.; Hurley,
L. H. J. Am. Chem. Soc. 1998, 120, 2490–2491.
12. Myers, A. G.; Plowriht, A. T. J. Am. Chem. Soc. 2001,
123, 5114–5115.
13. Gallina, C.; Liberatori, A. Tetrahedron 1974, 30, 667–673.
14. Herna´ndez, F.; Lumetzberger, A.; Avendan˜o, C.; So¨llhu-
ber, M. Synlett 2001, 1387–1390.
methylpiperazine-2,5-diones has progressed from the
discovery of a very much improved N-alkylation proce-
dure to the optimization of the subsequent cyclization20
and, although this cyclization is not possible in aryl-
methylydene derivatives, the imposed trans-relationship
between H-6 and H-11a protons may be reverted by
radical
bromination
followed
by
catalytic
hydrogenation.21
15. Murata, S.; Suzuki, M.; Noyori, R. Tetrahedron 1988, 44,
4259–4275.
16. Ong, Ch. W.; Lee, H. Ch. Aust. J. Chem. 1990, 43,
773–775.
17. The trans-relationship between protons H-6 and H-11a in
5 was confirmed by conclusive NOE experiments (H-11a
and C(6)-methyl).
Acknowledgements
Financial support from CICYT (SAF2000-0130/99)
and a FPI fellowship (J. F. Gonza´lez) are gratefully
acknowledged.
18. Kubo, A.; Saito, N.; Yamauchi, R.; Sakai, Sh.-i. Chem.
Pharm. Bull. 1987, 35, 2158–2161.
19. Caballero, E.; Avendan˜o, E.; Mene´ndez, J. C. Tetra-
hedron 1999, 55, 14185–14198.
References
20. N-Amidoalkylation of 3 and cyclization of 4. Synthesis of
( )-5: To a solution of 2 (500 mg, 1.63 mmol) in dry
CH2Cl2 (25 mL), under an Ar atmosphere and at −78°C
1. Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102,
1669–1730 and references cited therein.
i
was added with stirring Pr2NEt (0.31 mL, 1.79 mmol)
2. Corey, E. J.; Gin, D. Y.; Kania, R. S. J. Am. Chem. Soc.
1996, 118, 9202–9203.
3. Endo, A.; Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, T.;
and TMSOTf (0.35 mL, 1.96 mmol). After 4 h at the
same temperature, acetaldehyde dimethyl acetal (0.21
mL, 1.96 mmol) and TMSOTf (0.01 mL) were added,
and the reaction was kept for additional 4 h. This mix-
Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 6552–6554.

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J. F. Gonza´lez et al. / Tetrahedron Letters 44 (2003) 4395–4398
ture was poured onto a saturated NaHCO3 aqueous
Isomerizarion of 5. Synthesis of ( )-6: A solution of 5 (13
mg, 0.039 mmol), AIBN (0.6 mg, 0.004 mmol) and NBS
(7 mg, 0.04 mmol) in CCl4 (2 mL) was refluxed under an
Ar atmosphere for 1 h. The unreacted NBS was filtered
from the cooled reaction, the solvent was evaporated
under reduced pressure and the residue was chro-
matographed (ethyl acetate/hexane, 8:2) to give ( )-6 (13
mg, ꢀ100%): mp 170–171°C, IR (KBr) 1697 and 1621
cm−1, lH (250 MHz, CDCl3) 7.60 (s, 1H, H-11), 6.86 (d,
1H, J=9.0 Hz, H-9), 6.74 (d, 1H, J=9.0 Hz, H-8), 6.17
(q, 1H, J=6.6 Hz, H-6), 4.96 (d, 1H, J=17.6 Hz, H-3),
3.94 (d, 1H, J=17.6 Hz, H-3), 3.84 (s, 3H, OCH3), 3.82
(s, 3H, OCH3), 2,66 (s, 3H, Ac), 1.26 (d, 1H, J=6.6 Hz,
6-Me); lC (62.5 MHz, CDCl3) 172.1 (Ac), 161.8 (C-1),
160.7 (C-4), 150.2 (C-10), 148.7 (C-7), 125.0 and 125.1
(C-6a and C10a), 118.2 (C-11a), 109.8 (C-11), 56.0 and
55.8 (OMe), 44.9 (C-6), 45.5 (C-3), 27.1 (6-Me), 19.1
(Ac). Anal. calcd for C17H18N2O5: C, 61.81; H, 5.49; N,
8,48. Found: C, 61.57; H, 5.32; N, 8.16.
Compound ( )-7: mp 153–154°C, IR (KBr) 1713 and
1674 cm−1, lH (250 MHz, CDCl3) 6.75 (s, 2H, H-8 and
H-9), 5.83 (q, 1H, J=6.7 Hz, H-6), 5.13 (d, 1H, J=16.9
Hz, H-3), 4.06 (dd, 1H, J=12.2 and 4.4 Hz, H-11a), 3.82
(m, 2H, H-11 and H-3), 3.81 (s, 3H, OCH3), 3.80 (s, 3H,
OCH3), 2.76 (dd, 1H, J=16.0 and 12.2 Hz, H-11), 2.64
(s, 3H, Ac), 1.33 (d, 1H, J=6.7 Hz, 6-Me); lC (62.5
MHz, CDCl3) 171.1 (Ac), 168.3 (C-1), 165.1 (C-4), 150.0
and 149.1 (C-10 and C-7), 127.5 and 121.8 (C-6a and
C10a), 109.8 and 109.4 (C-8 and C-9), 56.5 (C-6), 55.9
and 55.6 (OMe), 45.8 and 45.7 (C-11a and C-3), 27.2
(6-Me), 21.9 (C-11), 19.1 (Ac). Anal. calcd for
C17H20N2O5: C, 61.44; H, 6.07; N, 8.43. Found: C, 61.50;
H, 6.02; N, 8.17.
solution and extracted with CH2Cl2 (30 mL×3). The
combined extracts were washed with H2O and brine,
dried over anhydrous Na2SO4, filtered and concentrated.
Flash chromatography of the crude product (hexane/
ethyl acetate, 3:2) gave pure 4 (560 mg, 95%) as a 1:1
mixture of diastereomers. IR (KBr) 1699 and 1651 cm−1
;
lH (250 MHz, CDCl3) 6.74 (s, 2H), 6.73 (s, 2H), 6.72 (d,
1H, J=2.0 Hz), 6.59 (d, 1H, J=2.0 Hz), 5.74 (q, 1H,
J=6.1 Hz), 5.65 (q, 1H, J=6.2 Hz), 4.79 (d, 1H, J=17.8
Hz), 4.76 (d, 1H, J=17.9 Hz), 4.40 (dd, 1H, J=8.8 and
5.5 Hz), 4.34 (dd, 1H, J=9.5 and 5.8 Hz), 3.91 (d, 1H,
J=17.8 Hz), 3.71 (s, 3H), 3.70 (s, 3H), 3.69 (s, 3H), 3.66
(s, 3H), 3.64 (d, 1H, J=17.9 Hz), 3.41 (s, 3H), 3.34–3.18
(m, 3H), 3.12 (s, 3H), 3.04 (dd, 1H, J=13.4 and 9.0 Hz),
2.45 (s, 3H), 2.40 (s, 3H), 1.39 (d, 1H, J=6.2 Hz), 1.37
(d, 1H, J=6.1 Hz); dC (62.5 MHz, CDCl3) 171.2, 167.6,
167.1, 165.6, 165.5, 153.3, 153.2, 151.6, 151.4, 123.8,
123.7, 117.1, 113.0, 112.9, 110.9, 110.7, 81.2, 81.1, 57.8,
56.7, 55.8, 55.5, 55.4, 55.4, 55.3, 55.2, 53.3, 46.0, 45.7,
34.0, 33.9, 26.7, 26.6, 19.7, 18.5. Anal. calcd for
C18H24N2O6: C, 59.33; H, 6.64; N, 7.69. Found: C, 58.98;
H, 6.50; N, 7.60.
21. A solution of 4 (150 mg, 0.41 mmol) in formic acid (8
mL) was refluxed for 3 h. The solution was cooled to rt
and poured onto a saturated NaHCO3 aqueous solution
and extracted with CH2Cl2 (10 mL×3). The combined
extracts were washed with H2O and brine, dried over
anhydrous Na2SO4, filtered and evaporated. The residue
was chromatographed using ethyl acetate/hexane (8:2) as
eluent to give pure ( )-5 (116 mg, 85%): mp 208°C (lit.16
206–207°C). lC (62.5 MHz, CDCl3) 171.9, 168.2, 161.5,
150.7, 149.7, 126.8, 121.0, 108.4, 108.2, 55.6, 55.5, 52.8,
45.8, 44.6, 27.6, 27.3, 18.4.