Stereocontrolled Synthesis of 3,6-Dimethyl-2,3,6,7,12,12a-hexahydropyrazino-β-carboline-1,4-diones

Full text of DOI:10.1021/jo971842s

2724
J . Org. Chem. 1998, 63, 2724-2727
Sch em e 1
Ster eocon tr olled Syn th esis of 3,6-Dim eth yl-
2,3,6,7,12,12a -h exa h yd r op yr a zin o[1,2-b]-â-
ca r bolin e-1,4-d ion es
Antonio Madrigal, Mercedes Grande, and
Carmen Avendan˜o*
Departamento de Quı´mica Orga´nica y Farmace´utica, F.
Farmacia, Universidad Complutense, 28040-Madrid, Spain
Received October 6, 1997
In tr od u ction
Our current interest in MDR (multi drug resistance)
reversal agents designed as analogues of the fungal
metabolite N-acetylardeemin (1)1,2 moved us to study the
dehydro-C-homo analogues 2, where rings A-C are
formed by a 1,2,3,4-tetrahydro-â-carboline structure.
The synthesis of 2 was planned through the condensa-
tion of the corresponding tetracyclic piperazinediones
with anthranilic acid (Scheme 1). The N-acylation of cis-
tetrahydro-â-carbolines with L- or D-alanine, as well as
the subsequent cyclization to the above-mentioned pip-
erazinediones, are studied here, especially the chemical
and stereochemical outcome of the cyclization step.
The diastereoselectivity of the classical Pictet-Spen-
gler reaction to give tetrahydro-â-carbolines (THBCs)
from L-tryptophan esters has been extensively studied.3
According to these precedents, cis 1,3-disubstituted TH-
BCs are the kinetically controlled products in acid
conditions, while higher temperatures (thermodynamic
control) lead to poor diastereoselectivity. In cis-THBCs,
the C-1 and C-3 substituents may adopt an equatorial
disposition, while in the trans isomers, a 1,3-diaxial
interaction exists in either of the possible conformers. The
thermodynamic stability of the trans isomers has been
related to the fact that the interactions between the Na-H
group and the C-1 substituent, which would be equato-
rial, may be more significant than those between the
axial C-1 substituent and the C-3 proton (or the C-1
proton and the C-3 substituent). This effect is obviously
more significant in derivatives of Na-substituted tryp-
tophan esters. On the other hand, the trans isomers are
exclusively formed in the reactions of Nb-benzyltryp-
tophan esters with bulky aldehydes, such as cyclohex-
anecarbaldehyde or benzaldehyde,4 probably because the
N-benzyl substituent is locked at an equatorial configu-
ration that makes an equatorial C-1 substituent in the
cis isomers very unstable. Evidence that scission of the
C(1)-N(2) bond occurs during epimerization of cis 1,3-
disubstituted Nb-benzyl-1,2,3,4-tetrahydro-â-carbolines
into their trans diastereomers under acidic conditions has
been established.5
Resu lts a n d Discu ssion
Our first objetive was the synthesis of both enanti-
omers of cis-1-methyl-1,2,3,4-tetrahydro-â-carboline-3-
carboxylic acid (3), which were prepared from L- or
D-tryptophan and acetaldehyde following Brossi’s proce-
dure,6 by using sulfuric acid as catalyst and kinetic
conditions (24 h, rt). Their corresponding methyl ester
hydrochlorides were obtained by treatment with thionyl
chloride and dry methanol.7 With these compounds at
our disposal, the N-protected N-(aminoacyl)-THBCs (Table
1) were obtained by reaction of (1S,3S)-4‚HCl (for 5 and
6) and (1R,3R)-4‚HCl (for 7 and 8) with N-Cbz (com-
pounds a ) or N-Boc (compounds b) L- or D-alanine, using
EDC [1-ethyl-3-[3′-(dimethylamino)propyl]carbodiimide]
(1) (a) Karwowski, J . P.; J ackson, M.; Rasmussen, R. R.; Humphrey,
P. E.; Poddig, J . B.; Kohl, W. L.; Scherr, M. H.; Kadam, S.; McAlpine,
J . B. J . Antibiot. 1993, 46, 374. (b) Hochlowski, J . E.; Mullaley, M.
M.; Spanton, S. G.; Whittern, D. N.; Hill, P.; McAlpine, J . B. J . Antibiot.
1993, 46, 380. (c) Marsden, S. P.; Depew, K. M.; Danishefsky, S. J . J .
Am. Chem. Soc. 1994, 116, 11143.
(2) (a) Mart´ın-Santamar´ıa, S.; Buenadicha, F. L.; Espada, M.;
So¨llhuber, M.; Avendan˜o, C. J . Org. Chem. 1997, 62, 6424. (b) Mart´ın-
Santamar´ıa, S.; Espada, M.; Avendan˜o, C. Tetrahedron 1997, 53,
16795. (c) Bartolome´, M. T.; Buenadicha, F. L.; Avendan˜o, C.;
So¨llhuber, M. Tetrahedron: Asymmetry, in press. (d) Sa´nchez, J . D.;
Ramos, M. T.; Avendan˜o, C. Tetrahedron, in press. (e) Buenadicha,
F. L.; Bartolome´, M. T.; Aguirre, M. J .; Avendan˜o, C.; So¨llhuber, M.
Tetrahedron: Asymmetry, in press. (f) Ferna´ndez, M.; Heredia, M. L.;
De la Cuesta, E.; Avendan˜o, C. Tetrahedron, in press.
(3) (a) Bailey, P. D.; Moore, M. H.; Morgan, K. M.; Smith, D. I.;
Vermon, J . M. Tetrahedron Lett. 1994, 35, 3587. (b) Bailey, P. D.;
Hollishead, S. P.; McLay, N. R.; Morgan, K. M.; Palmer, S. J .; Prince,
S. N.; Reynolds, C. D.; Wood, S. D. J . Chem. Soc., Perkin Trans. 1 1993,
431. (c) Bailey, P. D.; McLay, N. R. J . Chem. Soc., Perkin Trans. 1
1993, 441. (d) Czerwinski, K. M.; Cook, J . M. Stereochemical Control
of the Pictet-Spengler Reaction in the Synthesis of Natural Products.
In Advances in Heteroyclic Natural Products Synthesis; Pearson, W.
H., Ed.; J AI Press: Greenwich, 1996; Vol. 3, p 217. (e) Cox, E. D.;
Cook, J . M. Chem. Rev. 1995, 95, 1797. (f) Zhang, L.-H.; Bi, Y.; Yu,
F.; Menzia, G.; Cook, J . M. Heterocycles 1992, 34, 517.
(4) Ungemach, F.; Di Pierro, M.; Wever, R.; Cook, J . M. J . Org.
Chem. 1981, 46, 164.
(5) (a) Cox, E. D.; Li, J .; Hamaker, L. K.; Yu, P.; Cook, J . M. Chem.
Commun. 1996, 2477. (b) Cox, E. D.; Hamaker, L. K.; Li, J .; Yu, P.;
Czerwinski, K. M.; Deng, L.; Bennett, D. W.; Cook, J . M.; Watson, W.
H.; Krawiec, M. J . Org. Chem. 1997, 62, 44.
(6) Brossi, A.; Focella, A.; Teitel, S. J . Med. Chem. 1973, 16, 408.
(7) Ungemach, F.; Soerens, D.; Weber, R.; Di Pierro, M.; Campos,
O.; Mokry, P.; Cook, J . M.; Silverton, J . V. J . Am. Chem. Soc. 1980,
102, 6976.
S0022-3263(97)01842-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/31/1998

Notes
Ta ble 1. Syn th esis of N-P r otected Com p ou n d s 5-8
J . Org. Chem., Vol. 63, No. 8, 1998 2725
Sch em e 2a
starting
compds
amino
acid
R
product
yield (%)
(1S,3S)-4‚HCl
(1S,3S)-4‚HCl
(1S,3S)-4‚HCl
(1S,3S)-4‚HCl
Z-L-Ala
Z-D-Ala
Boc-L-Ala
Boc-D-Ala
Cbz (1S,3S,2′S)-5a
Cbz (1S,3S,2′R)-6a
Boc (1S,3S,2′S)-5b
Boc (1S,3S,2′R)-6b
Cbz (1R,3R,2′R)-7a
Cbz (1R,3R,2′S)-8a
69
41
56
61
68
57
(1R,3R)-4‚HCl Z-D-Ala
(1R,3R)-4‚HCl Z-L-Ala
as coupling reagent.8 Reactions with N-protected L-
alanine gave compounds 5 and 8, while reactions with
N-protected D-alanine gave compounds 6 and 7.
Although NMR spectra of compounds 5-8 were very
complex, the relative proportion of the two Na-H signals,
which were clearly distinguished in their 1H NMR
spectra, showed mixtures of rotamers s-E and s-Z in a
2:1 ratio for compounds 5a and 7a , while in compounds
5b, 6a , 6b, and 8a , the rotamers s-Z were more important
(s-E:s-Z ) 1:1).9 In open-chain dipeptides, the s-Z
conformation is almost exclusive, but in N-(aminoacyl)-
prolines, the ratio s-E:s-Z is 7:1, which is very favorable
to their cyclization to pyrrolopiperazinedione deriva-
tives.10
a
Key: (i) Pd/C, 1:1 MeOH/AcOH, 50 psi, 16 h; (ii) F3CCO2H/
CH2Cl2, 4 h, rt; (iii) 200 °C, 30 min.
Sch em e 3a
In the case of compounds 5-8, when N-deprotection
and cyclization were carried out, the nature of the
protecting groups and the relative configuration of ste-
reocenters showed their relevance. Thus, compound 5a
(Scheme 2), after hydrogenolysis with Pd/C in 1/1 metha-
nol-acetic acid, spontaneously and quantitatively cy-
clized to the tetracyclic piperazinedione 9 (3S,6S,12aS)
while 5b, after deprotection with trifluoroacetic acid/
dichloromethane, gave 9 in 67% yield. Deprotection by
thermolysis of 5b gave low yields of a 1:1 mixture of
compounds 9 and 10 (3S,6R,12aS), which according to
NOE experiments, are epimers at C-6. Both show a cis
configuration in ring D, but ring C is cis in 9 and trans
in 10. We assume that the rearrangement of ring C from
a cis to a trans stereochemistry involves some sort of
retro-Pictet-Spengler reaction, which takes place before
the cyclization reaction.
a
Compound 11 (3R,6R,12aR), enantiomer of compound
9, was also quantitatively obtained by hydrogenolysis of
7a under the same reaction conditions as for 5a , but this
treatment gave unsatisfactory results with 8a (Scheme
3), affording the cyclic peptide anhydride 12 (3S,6R,12aR)
in very low yield. Most of the starting material, perhaps
because the s-Z conformation does not permit the cy-
clization, suffered hydrogenolysis of ring C to give L-
alanyl-D-trypthophan methyl ester (13). Hydrogenation
Key: (i) Pd/C, 1:1 MeOH/AcOH, 50 psi, 16 h; (ii) Pd/C, AcOH
(7 × 10-3 M), 50 psi; (iii) xylene, reflux; (iv) Pd/C, MeOH (7 ×
10-3 M), 20 psi, 5 h.
in concentrated acetic acid using Suzuki’s procedure11
maintained the ring C unaltered but afforded a mixture
of the N-deprotected intermediate 14 (which was not
isolated) and small amounts of the tetracyclic pipera-
zinedione 12. Although this mixture could be cyclized
by heating in refluxing xylene, the best yields of 12 (up
to 53%) were obtained by hydrogenolysis of 8a in metha-
nol at lower pressures and shorter reaction times.
(8) Sheehan, J . C.; Ledis, S. L. J . Am. Chem. Soc. 1973, 95, 875.
(9) The s-Z and s-E rotamers are sometimes referred to cis and trans
forms.
(10) Purdie, J . E.; Benoiton, N. L. J . Chem. Soc., Perkin Trans. 2
1973, 1845.
(11) Suzuki, K.; Sasaki, Y.; Endo, N.; Mihara, Y. Chem. Pharm. Bull.
1981, 29, 233.

2726 J . Org. Chem., Vol. 63, No. 8, 1998
Notes
Sch em e 4a
follows: In the simplest piperazinedione 17, only one
carbonyl band at 1667 cm-1 appears in the IR spectrum.
In tetracyclic compounds 9, 10, and 11, with a cis
stereochemistry for ring D, the absorption is shifted to
higher frequencies: 1694 and 1658 cm-1 for compounds
9 and 11 and 1690 and 1676 cm-1 for compound 10. On
the contrary, enantiomers 12 and 15, with a trans
stereochemistry for ring D, show lower frequencies: 1620
and 1579 cm-1. It is also significant in these compounds
that the H-2 and H-3 protons are clearly coupled (3J )
3.4 Hz). Finally, the diastereotopic H-12 methylene
protons show more different chemical shifts in the
tetracyclic piperazinediones 9, 10-12, and 15 than in the
more flexible piperazinedione 17.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. IR
spectra were recorded with all solid compounds compressed into
KBr pellets and liquid compounds placed (neat or dissolved in
the minimum amount of bromoform) between NaCl plates.
NMR spectra were obtained at 250 or 300 MHz for 1H and 75.4
or 62.9 MHz for 13C with CDCl3 and DMSO-d6 as solvents in
the Servicio de Resonancia, Universidad Complutense. Combus-
tion elemental analyses were determined by the Servicio de
Microana´lisis, Universidad Complutense Madrid. Reactions
were monitored by thin-layer chromatography, on aluminum
plates coated with silica gel with fluorescent indicator. Solutions
were dried with anhydrous Na2SO4 and evaporated under
reduced pressure (water aspirator) in a rotary evaporator.
Separations by flash chromatography were performed on silica
gel (230-400 mesh). All reagents were of commercial quality
and were used as received.
N-Acyla t ion of Tet r a h yd r o-â-ca r b olin es. Gen er a l
Meth od . Syn th esis of Com p ou n d s 5-8. N-Carbobenzoxy-
or N-Boc-L- or D-alanine (16.14 mmol) and EDC (12.28 mmol)
were added to the corresponding tetrahydro-â-carboline hydro-
chloride (4‚HCl). The reaction was kept in the dark under an
anhydrous calcium chloride tube and was magnetically stirred
for 24 h. After concentration to dryness at low pressure, the
residue was extracted with a mixture of chloroform (15 mL) and
1 N hydrochloric acid (16 mL). The separated organic phase
was washed with 1 N sodium bicarbonate (15 mL), dried, and
concentrated. Purification of the residue by column chroma-
tography with ethyl acetate for compounds a and 1:1 ethyl
acetate/chloroform for compounds b as solvents gave compounds
5-8. (NMR data for minor rotamers, when distinguishable, are
given in parentheses.)
a
Key: (i) Pd/C, MeOH (7 × 10-3 M), 20 psi, 5 h; (ii) 200 °C, 30
min; (iii) F3CCO2H, CH2Cl2, 4 h, rt.
Hydrogenolysis of 6a in these reaction conditions
(Scheme 4) produced, besides the desired piperazinedione
15 (3R,6S,12aS), the decomposition product D-alanyl-L-
tryptophan methyl ester (16). To improve the yields of
compound 15, the cyclization of the Boc derivative 6b was
studied, but its pyrolysis was unsuccessful, giving only
traces of compound 15 together with L-tryptophan-D-
alanine anhydride (17), which is probably formed by
cyclization of 16. Finally, the treatment of 6b with
trifluoroacetic acid in dichloromethane gave a very good
yield of 15 (82%).
It is clear that when the deprotection and cyclization
sequence in N-(aminoacyl)-THBCs is prevented by geo-
metric reasons, the retro-Pictet-Spengler reactions com-
pete. The yields of this sequence go down from com-
pounds 5 and 7, which may be quantitatively cyclized,
to compounds 6 and 8. The synthesis of 12 and 15 may
become difficult because of the greater proportion of the
s-Z conformers in the starting N-(aminoacyl) compounds
(6 and 8) in comparison to compounds 5 and 7 (see above).
This assumption is supported by molecular mechanics
calculations (MM2), which showed that interatomic
distances between the amino and the carboxylate groups
in the deprotected aminoacyl compounds derived from 6
and 8 are greater than 3 Å. Our experiments confirm
previous reports about the effects produced by changes
in the solvent on the population of rotamers and, conse-
quently, on the success of the cyclization of dipeptides to
piperazinediones.12 According to results showed in Scheme
2 (i.e., the 9:10 ratio ) 1:1), it can be concluded that
diastereomers 9 and 10, in which ring C adopts a cis and
trans stereochemistry, respectively, have similar ener-
gies.
Met h yl (1S,3S,2′S)-1,2,3,4-t et r a h yd r o-1-m et h yl-N′-ca r -
boben zoxy-L-a la n yl-â-ca r bolin e-3-ca r boxyla te (5a ). Start-
ing from (1S,3S)-4 (2 g, 8.19 mmol) dissolved in 1,4-dioxane (3.6
mL), Cbz-L-alanine (4.2 g, 18.8 mL) and EDC (5.39 g, 14.0 mL),
a yield of 2.2 g (69%) of 5a was obtained. Mp: 241-242 °C. IR
(KBr): 3361, 1743, 1694, 1628 cm-1 1H NMR (CDCl3, 250 MHz)
.
δ: 7.81 (s, 1H) (8.04); 7.52 (d, 1H, J ) 7.5 Hz); 7.30 (m, 6H);
7.16 (m, 2H); 5.98 (d, 1H, J ) 6.7 Hz); 5.54 (q, 1H, J ) 6.4 Hz);
5.13 (s, 2H); 5.02 (m, 2H); 3.64 (m, 4H); 3.04 (dd, 1H, J ) 14.3,
5 Hz) (2.92); 1.52 (d, 3H, J ) 6.6 Hz) (1.65); 1.42 (d, 3H, J ) 6.4
Hz). 13C NMR (DMSO-d6, 63 MHz) δ: 173.5 (172.5); 172.0
(171.6); 155.5 (155.2); 136.4; 134.2; 128.0 (128.5); 126.3; 121.3;
118.8; 118.1; 111.2; 103.8; 65.6 (65.8); 53.0; 52.2; 49.2; 47.8; 22.0;
19.4 (19.2); 18.8 (18.3). Anal. Calcd for C25H27N3O5: C, 66.80;
H, 6.05; N, 9.35. Found: C, 66.46; H, 6.10; N, 9.13.
Meth yl (1R,3R,2′R)-1,2,3,4-tetr a h yd r o-1-m eth yl-N′-ca r -
boben zoxy-D-a la n yl-â-ca r bolin e-3-ca r boxyla te (7a ). Start-
ing from (1R,3R)-4‚HCl (0.64 g, 2.3 mmol) dissolved in 1,4-
dioxane (1.2 mL), Cbz-D-alanine (0.70 g, 3.1 mmol), and EDC
(0.75 g, 1.9 mmol), a yield of 0.7 g (68%) of 7a was obtained.
Mp, IR, 1H NMR, and 13C NMR were identical to the above-
described enantiomer.
Selected NOE experiments have proved the stereo-
chemistry described. The more significant spectroscopic
data (see Experimental Section) can be summarized as
Meth yl (1R,3R,2′S)-1,2,3,4-tetr a h yd r o-1-m eth yl-N′-ca r -
boben zoxy-L-a la n yl-â-ca r bolin e-3-ca r boxyla te (8a ). Start-
ing from (1R,3R)-4 (1 g, 3.56 mmol) dissolved in 1,4-dioxane (1.8
mL), Cbz-L-alanine (1.09 g, 4.8 mmol), and EDC (1.17 g, 3.07
(12) Paradisi, M. P.; Zecchini, G. P.; Torrini, I.; Lucente, G. J .
Heterocycl. Chem. 1990, 27, 1661.

Notes
J . Org. Chem., Vol. 63, No. 8, 1998 2727
mmol), a yield of 0.9 g (57%) of 8a was obtained. Mp 250-252
1.57 (d, 3H, J ) 6.7 Hz); 1.50 (d, 3H, J ) 6.5 Hz). 13C NMR
(CDCl3, 63 MHz) δ: 169.8; 165.7; 136.0; 135.1; 126.1; 121.9;
119.8; 118.1; 111.3; 105.4; 56.6; 56.0; 48.7; 23.3; 22.1; 16.8. Anal.
Calcd for C16H17N3O2‚H2O: C, 63.77; H, 6.10; N, 13.94. Found:
C, 63.66; H, 6.31; N, 13.75.
°C. IR (KBr): 3350, 1744, 1682, 1610 cm-1 1H NMR (CDCl3,
.
250 MHz) δ: 8.16 (s, 1H) (8.30); 7.52 (d, 1H, J ) 6.8 Hz); 7.35
(m, 6H); 7.15 (m, 2H); 5.92 (d, 1H, J ) 6.7 Hz); 5.62 (q, 1H, J )
6.5 Hz); 5.15 (m, 3H); 4.86 (m, 1H); 3.62 (m, 4H) (3.64); 2.96 (m,
1H) (2.40); 1.54 (d, 3H, J ) 6.6 Hz) (1.67); 1.45 (d, 3H, J ) 6.5
Hz) (1.34). 13C NMR (DMSO-d6, 63 MHz) δ; 176.2; 172.5 (172.7);
156.2 (156.0); 136.3; 136.2; 128.7 (128.4); 127.5; 123.3; 122.2;
119.6; 111.5; 109.4; 67.1; 52.8; 52.6; 50.7; 49.6; 27.5; 18.6; 18.5.
Anal. Calcd for C25H27N3O5: C, 66.80; H, 6.05; N, 9.35.
Found: C, 66.49; H, 6.06; N, 9.36.
Met h yl (1S,3S,2′R)-1,2,3,4-t et r a h yd r o-1-m et h yl-N′-ca r -
boben zoxy-D-a la n yl-â-ca r bolin e-3-ca r boxyla te (6a ). Start-
ing from (1S,3S)-4 (1 g, 3.56 mmol) dissolved in 1,4-dioxane (1.8
mL), Cbz-L-alanine (1.09 g, 4.8 mmol), and EDC (1.17 g, 3.07
mmol), a yield of 0.64 g (41%) of 6a was obtained. Mp, IR, 1H
NMR, and 13C NMR were identical to the above-described
enantiomer.
Data for Compound 10. Mp: 291-292 °C. IR (KBr): 3320,
3090, 1690, 1676 cm-1 1H NMR (DMSO-d6, 250 MHz) δ: 11.03
.
(s, 1H); 8.41 (s, 1H); 7.33 (d, 1H; J ) 7.5 Hz); 7.32 (d, 1H; J )
7.5 Hz); 7.03 (m, 2H); 5.26 (q, 1H, J ) 6.2 Hz); 4.20 (dd, 1H, J
) 11.7, 4.7 Hz); 4.10 (q, 1H, 11.7 Hz); 3.50 (dd, 1H, J ) 15.4, 4.7
Hz); 2.78 (dd, 1H, J ) 11.7, 15.4 Hz); 1.37 (d, 3H, J ) 6.2 Hz);
1.34 (d, 3H, J ) 6.6 Hz). 13C NMR (DMSO-d6, 63 MHz) δ: 170.3;
170.1; 135.8; 135.7; 125.8; 120.8; 118.7; 117.8; 111.2; 104.4; 55.3;
49.1; 47.6; 23.2; 21.8; 19.2. Anal. Calcd for C16H17N3O2‚H2O:
C, 63.77; H, 6.10; N, 13.94. Found: C, 64.39; H, 6.19; N, 13.78.
Data for compound 11. They were identical to those of
compound 9.
Meth yl (1S,3S,2′S)-1,2,3,4-tetr a h yd r o-1-m eth yl-N′-(ter t-
bu th oxyca r bon yl)-L-a la n yl-â-ca r bolin e-3-ca r boxyla te (5b).
Starting from (1S,3S)-4 (0.416 g, 1.48 mmol) dissolved in 1,4-
dioxane (0.7 mL), Boc-L-alanine (0.259 g, 1.36 mmol), and EDC
(0.45 g, 2.35 mmol), a yield of 0.230 g (56%) of 5b was obtained.
(3S,6R,12a R)-3,6-Dim eth yl-2,3,6,7,12,12a -h exa h yd r op y-
r a zin o[1,2-b]-â-ca r bolin e-1,4-d ion e (12). To a solution of 0.34
g (0.7 mmol) of 8a in methanol (100 mL) was added 0.7 g of
10% C-Pd. After reduction with hydrogen (20 psi, 5h), filtra-
tion, and concentration, the residue was purified by column
chromatography on silica gel (1/2 ethyl acetate/chloroform) to
give 0.053 g (53% yield) of 12. Mp: 243-244 °C. IR (KBr):
Mp: 185-186 °C. IR (KBr): 3290, 1727, 1687, 1636 cm-1 1H
.
NMR (CDCl3, 250 MHz) δ: 7.94 (s, 1H) (7.90); 7.52 (d, 1H, J )
7.5 Hz); 7.32 (d, 1H, J ) 6.8 Hz); 7.12 (m, 2H); 5.90 (s, 1H); 5.54
(q, 1H, J ) 5.4 Hz); 4.80 (m, 2H); 3.67 (m, 4H); 3.06 (dd, 1H, J
) 15.6 and 5.0 Hz); 1.46 (m, 12H); 1.38 (d, 3H, J ) 5.4 Hz) (1.36).
13C NMR (CDCl3, 63 MHz) δ: 174.4 (172.2); 170.7 (169.8); 155.6;
136.3; 133.4; 127.4; 123.1; 121.9; 119.4; 111.2; 109.4; 53.5; 52.5;
49.9; 48.4; 28.3; 27.5; 22.7; 19.7 (19.6). Anal. Calcd for
C22H29N3O5: C, 63.60; H, 7.04; N, 10.11. Found: C, 63.74; H,
7.12; N, 10.22.
3432, 3286, 1620, 1579 cm-1 1H NMR (DMSO-d6, 250 MHz) δ:
.
11.05 (s, 1H); 8.46 (d, 1H, J ) 3.4 Hz); 7.52 (d, 1H; J ) 7.3 Hz);
7.32 (d, 1H; J ) 7.2 Hz); 7.02 (m, 2H); 5.20 (q, 1H, J ) 6.2 Hz);
4.24 (dd, 1H, J ) 11.4, 4.1 Hz); 3.94 (dq, 1H, J ) 7.1, 3.4 Hz);
3.44 (dd, 1H, J ) 15.4, 1 Hz); 2.72 (dd, 1H, J ) 15.4, 11.4 Hz);
1,42 (d, 3H, J ) 6.2 Hz); 1.32 (d, 3H, J ) 7.1 Hz). 13C NMR
(DMSO-d6, 63 MHz) δ: 169.5; 167.5; 136.0; 135.7; 125.9; 120.8;
118.7; 117.7; 111.2; 104.7; 54.5; 50.9; 48.0; 23.2; 22.5; 19.5. Anal.
Calcd for C16H17N3O2‚H2O: C, 63.77; H, 6.10; N, 13.94. Found:
C, 64.04; H, 6.32; N, 13.69.
Meth yl (1S,3S,2′R)-1,2,3,4-tetr a h yd r o-1-m eth yl-N′-(ter t-
bu th oxyca r bon yl)-D-a la n yl-â-ca r bolin e-3-ca r boxyla te (6b).
Starting from (1S,3S)-4 (0.57 g, 2.04 mmol) dissolved in 1,4-
dioxane (1 mL), Boc-D-alanine (0.311 g, 1.63 mmol), and EDC
(0.75 g, 3.92 mmol), a yield of 0.694 g (61%) of 6b was obtained.
(3R,6S,12a S)-3,6-Dim et h yl-2,3,6,7,12,12a -h exa h yd r op y-
r a zin o[1,2-b]-â-ca r bolin e-1,4-d ion e (15). A solution of 0.138
g (0.41 mmol) of 6b in a 1/2 mixture of trifluoroacetic acid/
dichloromethane (2 mL) was magnetically stirred for 4 h at room
temperature. After neutralization with 10% ammonium hy-
droxide, the dichloromethane extracts were dried under anhy-
drous sodium sulfate, filtered, and evaporated to give a residue
that after purification afforded 0.094 g (82% yield) of 15. Mp,
IR, 1H NMR, and 13C NMR were identical to the above-described
enantiomer 12.
Mp: 204-206 °C. IR (KBr): 3320, 1750, 1690, 1647 cm-1 1H
.
NMR (CDCl3, 250 MHz) δ: 9.10 (s, 1H) (9.24); 7.55 (m, 1H); 7.32
(m, 1H); 7.16 (m, 2H); 5.82 (d, 1H, J ) 6 Hz) (5.88) 5.66 (q, 1H,
J ) 6.6 Hz); 5.37 (dd, 2H, J ) 7, 5.6 Hz); 4.85 (m, 1H); 3.64 (s,
3H); 3.57 (dd, 1H, J ) 15.6, 5.6 Hz); 2.97 (dd, 1H, J ) 15.6, 7.0
Hz); 1.50 (m, 15H) 13C NMR (CDCl3, 63 MHz) δ 173.3 (173.6);
171.8 (171.4); 153.3; 136.3; 133.2; 126.3; 121.8; 119.3; 118.2;
110.9; 105.5; 54.1; 52.3; 49.9; 48.1; 28.3; 28.2 (28.0); 22.3; 19.3
(19.4). Anal. Calcd for C22H29N3O5: C, 63.60; H, 7.04; N, 10.11.
Found: C, 63.81; H, 6.99; N, 10.29.
(3S,6S,12a S)-3,6-Dim et h yl-2,3,6,7,12,12a -h exa h yd r op y-
r a zin o[1,2-b]-â-ca r bolin e-1,4-d ion e (9), (3S,6R,12a S)-3,6-
Dim et h yl-2,3,6,7,12,12a -h exa h yd r op yr a zin o[1,2-b]-â-ca r -
bolin e-1,4-d ion e (10), a n d (3SR,6R,12a R)-3,6-Dim et h yl-
2,3,6,7,12,12a -h exa h yd r op yr a zin o[1,2-b]-â-ca r b olin e-1,4-
d ion e (11). Meth od A. To a solution of 0.45 g (1.59 mmol) of
5a or 7a in a 1/1 mixture of acetic acid/methanol (100 mL) was
added 0.22 g of 10% C-Pd. After reduction with hydrogen (50
psi, 16 h), filtration, and concentration, the residue was purified
by column chromatography on silica gel (1/2 ethyl acetate/
chloroform) to give 0.277 g (98% yield) of 9 or 11.
Meth od B. A solution of 0.100 g (0.3 mmol) of 5b in a 1/2
mixture of trifluoroacetic acid/dichloromethane (2 mL) was
magnetically stirred for 4 h at room temperature. After neu-
tralization with 10% ammonium hydroxide, the dichloromethane
extracts were dried under anhydrous sodium sulfate, filtered,
and evaporated to give a residue that, by column chromatogra-
phy on silica gel (1/2 ethyl acetate/chloroform), gave 0.06 g (67%
yield) of 9.
Data for 13 and 16. Mp: 247-248 °C. IR (KBr): 3410, 1733,
1652 cm-1 1H NMR (CDCl3, 250 MHz) δ: 8.57 (s, 1H); 7.55 (d,
.
1H, J ) 7.5 Hz); 7.34 (d, 1H; J ) 7.5 Hz); 7.10 (m, 2H); 6.91 (s,
1H); 4.15 (q, 1H, J ) 6.7 Hz); 3.77 (m, 6H); 2.02 (s, 2H); 1.40
(m, 4H). 13C NMR (CDCl3, 63 MHz) δ: 176.1; 170.5; 135.9;
127.7; 123.2; 122.0; 119.3; 118.5; 112.2; 111.3; 56.9; 53.3; 26.2;
25.3; 16.5. Anal. Calcd for C15H20N3O3: C, 62.05; H, 6.94; N,
14.47. Found: C, 62.24; H, 6.92; N, 14.40.
(3S,6R)-3-(3′-In d olylm eth yl)-6-m eth ylp ip er a zin e-2,5-d i-
on e (17). Heating of 6b (0.46 g, 1.4 mmol) at 200 °C for 30 min
under a stream of argon, followed by purification by column
chromatography (ethyl acetate), gave 0.100 g (29%) of 17. Mp:
280-282 °C. IR (KBr): 3325, 3197, 1667 cm-1
.
1H NMR
(DMSO-d6, 250 MHz) δ: 10.91 (s, 1H); 8.04 (s, 1H); 7.91 (s, 1H);
7.53 (d, 1H; J ) 7.7 Hz); 7.32 (d, 1H; J ) 7.7 Hz); 7.05 (s, 1H);
6.97 (m, 2H); 4.02 (q, 1H, J ) 7 Hz); 3.24 (dd, 1H, J ) 14.5, 4.5
Hz); 2.96 (m, 2H); 1.32 (d, 3H, J ) 7 Hz). 13C NMR (DMSO-d6,
63 MHz) δ: 170.3; 169.9; 137.7; 129.3; 126.3; 122.7; 120.5; 120.2;
113.0; 110.2; 57.7; 50.5; 30.9; 20.1. Anal. Calcd for
Meth od C. Heating of 5b (0.300 g, 0.9 mmol) at 200 °C for
30 min under a stream of argon, followed by purification by
column chromatography on silica gel (1/2 ethyl acetate/chloro-
form), afforded 0.030 g (12% yield) of 9 and 0.030 g (12% yield)
of 10.
C
14H15N3O2: C, 65.62; H, 5.46; N, 16.44. Found: C, 65.68; H,
5.52; N, 16.22.
Data for Compound 9. Mp: 238-240 °C. IR (KBr): 3293,
3121, 1694, and 1658 cm-1 1H NMR (CDCl3, 250 MHz) δ: 7.93
.
Ack n ow led gm en t. We thank CICYT for financial
support (Projects SAF94-0517 and SAF97-0143).
(s, 1H); 7.57 (d, 1H, J ) 7.0 Hz); 7.38 (d, 1H, J ) 7.0 Hz); 7.20
(m, 2H); 5.90 (s, 1H); 5.44 (q, 1H, J ) 6.5 Hz); 4.20 (m, 2H);
3.62 (dd, 1H, J ) 15.7, 4.6 Hz); 3.10 (dd, 1H, J ) 15.7, 15.1 Hz);
J O971842S