On the fate of the tryptophan stereocenter during the synthesis of hexacyclic analogues of N-acetylardeemin

Article abstract of DOI:10.1016/S0957-4166(98)00307-3

The reaction between 6-acetyl-3-alkyl-1-ethoxy-3,4,5a,6,11,11a- hexahydro-10bH-pyrazino-[2',1'-5,1]pyrrolo-[2,3-b]indole-1,4-diones and anthranilic acid was studied from a stereochemical point of view. Various degrees of epimerization of the tryptophan an

Full text of DOI:10.1016/S0957-4166(98)00307-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3025–3038
On the fate of the tryptophan stereocenter during the synthesis of
hexacyclic analogues of N-acetylardeemin
Esmeralda Caballero, Carmen Avendaño and J. Carlos Menéndez
Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
Received 23 June 1998; accepted 29 July 1998
Abstract
The reaction between 6-acetyl-3-alkyl-1-ethoxy-3,4,5a,6,11,11a-hexahydro-10bH-pyrazino-[20,10-5,1]pyrrolo-
[2,3-b]indole-1,4-diones and anthranilic acid was studied from a stereochemical point of view. Various degrees
of epimerization of the tryptophan and alanine stereocenters were observed in compounds with a cis relationship
between their H-3 and H-11a hydrogen atoms, and stereochemistry was retained in the trans compounds. These
observations are explained in terms of steric compression between the C5_O, C7–alkyl and C8_O groups in the
hexacyclic reaction products. Acylation at N-2 with o-azidobenzoyl chloride followed by an intramolecular aza
Wittig reaction afforded the target 10-acetyl-5,7,8,9a,10,14b,15,15a-octahydroindolo[300,200-40,50]pyrrolo[20,10-
3,4]pyrazino[2,1-b]quinazoline-5,8-diones with retention of all stereocenters. © 1998 Elsevier Science Ltd. All
rights reserved.
1. Introduction
The pyrazino[2,1-b]quinazoline structure is present in several families of natural products, like the
fiscalins1 and the fumiquinazolines,2 and also in N-acetylardeemin.3 The latter compound is one of the
most potent known inhibitors of multi-drug resistance to antitumor agents (MDR).4
The synthesis of the pyrazino[2,1-b]quinazoline ring system can be achieved by a number of methods.5
One of simplest consists of the reaction of iminoethers derived from 2,5-piperazinediones with anthranilic
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00307-3
tetasy 2456 Article

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E. Caballero et al. / Tetrahedron: Asymmetry 9 (1998) 3025–3038
acid.6 However, this reaction has received little attention from the stereochemical point of view in spite
of its potential in natural product synthesis. As part of our studies on the synthesis of N-acetylardeemin
analogues as potential MDR inhibitors,7 we became interested in studying the stereochemistry of the
condensation between pyrazino[20,10-5,1]pyrrolo[2,3-b]indole-1,4-dione derivatives 18 and anthranilic
acid. We report here the fate of the stereogenic centers during this transformation.
2. Results and discussion
As shown in Scheme 1, the synthesis of compounds 1a and b was initiated by preparation of Boc-
protected dipeptides 2 from L-tryptophan methyl ester and the suitable protected amino acid. Tandem
deprotection–cyclization of compounds 2 under thermal conditions afforded diketopiperazines 3. These
were cyclized in the presence of acid8–10 to compounds 4, which were finally acetylated at the indoline
nitrogen in order to increase their stability,11 yielding compounds 1a and b. In the case of glycine
derivative 4a, the acetylation reaction yielded two additional products, which were identified as the
diacetylated derivative 5 and the acetylated diketopiperazine 6.
Compounds 1c–f were prepared from L- and D-alamine and L- and D-tryptophan by a similar method,
as previously described by us.8
To our knowledge, the only literature precedent to the reaction under study is due to Rajappa
and Advani,6a who investigated the reactions between anthranilic acid and the iminoethers derived
from cyclo-(L-Pro-Gly), cyclo-(L-Pro-L-Val) and cyclo-(L-Pro-D-Val). In the first case, they observed
racemization of the proline stereogenic center, a behavior that can be attributed to acid-catalyzed
tautomerism to yield an achiral enamine I, which upon protonation reverts with equal probability to
the R or S enantiomer of the starting compound.

E. Caballero et al. / Tetrahedron: Asymmetry 9 (1998) 3025–3038
3027
Scheme 1.
We considered it of interest to examine a similar reaction of compound 1a, since it would allow the
racemization of the derived tryptophan C-15a position on a chiral substrate to be studied. The structure of
enamine II, the analogue of intermediate I depicted above, suggests that protonation from the bottom face
avoids interaction with the H-9a, H-14b and H-15 pseudoaxial protons, and should therefore be favored,
leading to retention of the S configuration at the tryptophan stereocenter. Iminoether 7 was obtained from

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E. Caballero et al. / Tetrahedron: Asymmetry 9 (1998) 3025–3038
compound 1a by treatment with triethyloxonium tetrafluoroborate in the presence of sodium carbonate.12
When this compound was melted with neat anthranilic acid at 140°C for 4 h, it afforded 8 as the only
reaction product in 76% yield (Scheme 2), confirming the stereoselective protonation of intermediate II.
Scheme 2.
On the basis of our previous observations on the behavior of 2-acyl derivatives of structures 1,8 we
predicted the possibility that the interactions between the substituents at the C-7 position and the C-5
carbonyl might exert an influence on the epimerization of the tryptophan stereocenter. Indeed, as shown in
Scheme 3, transformation of compound 1c into the corresponding iminoether 9 followed by reaction with
anthranilic acid afforded a mixture of three hexacyclic derivatives, where the major product (compound
10, 23%) retained the configuration of all stereocenters, while compounds 11 (8%) and 12 (3%) showed
epimerization at the tryptophan and alanine stereocenters, respectively. On the other hand, iminoether
13, with an R configuration at the alanine stereocenter and obtained from compound 1d, gave exclusively
the hexacyclic derivative 12 upon treatment with anthranilic acid, with retention of the stereochemistry
(Scheme 4).
In order to increase the structural variation for biological studies, we carried out the reactions of
iminoethers 14 and 16 with anthranilic acid. As expected, they behaved in the same way as their
enantiomers (13 and 9, respectively), since compound 14 led to 15 (38%) as the only product, with
retention of the stereochemistry (Scheme 5), while 16 afforded a mixture of 17 (20%), 18 (13%) and 15
(4%) (Scheme 6).
The easier epimerization of compound 10 with respect to 12 can be ascribed to the steric compression
between the C-5 and C-8 carbonyls and the C-7 methyl group, which is relieved by epimerization at C-15a
or at C-7.13 This effect is absent in compound 12, which explains its tendency to retain the configuration
of its stereocenters.

E. Caballero et al. / Tetrahedron: Asymmetry 9 (1998) 3025–3038
3029
Scheme 3.
Scheme 4.
Scheme 5.

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E. Caballero et al. / Tetrahedron: Asymmetry 9 (1998) 3025–3038
Scheme 6.
According to this explanation, the presence of groups bulkier than methyl at C-7 should lead to an
increased tendency to epimerization. This assumption was checked by submitting iminoether 19, derived
from the valine derivative 1b, to our usual conditions for reaction with anthranilic acid. The major product
(45%) was compound 21, epimerized at the tryptophan stereocenter, with only minor amounts (14%) of
compound 20 (Scheme 7).14
Finally, we decided to examine the possibility of preparing the target hexacyclic compounds without
epimerization. Since work by others3b and by ourselves8 shows the possibility of acylating derivatives
of the tetracyclic pyrazino[20,10-5,1]pyrrolo[2,3-b]indole-1,4-dione systems with retention of the stereo-
chemistry by use of hindered bases, we treated compound 1c with o-azidobenzoyl chloride in the presence
of KHMDS at −78°C, and obtained 22 as a single diastereoisomer in 54% yield. An intramolecular aza
Wittig reaction of 22 afforded compound 10 in 81% yield and as a single stereoisomer (Scheme 8).
Stereochemical assignments were based upon NOE experiments, which are summarized in Fig. 1.

E. Caballero et al. / Tetrahedron: Asymmetry 9 (1998) 3025–3038
3031
Scheme 7.
Scheme 8.
3. Experimental
All reagents were of commercial quality (Aldrich, Fluka, SDS, Probus) and were used as received.
Solvents (SDS, Scharlau) were dried and purified using standard techniques. The expression ‘petroleum
ether’ refers to the fraction boiling at 40–60°C. Reactions were monitored by thin layer chromatography,
on aluminum plates coated with silica gel with fluorescent indicator (Macherey–Nagel Alugram Sil
G/UV254). Catalytic hydrogenations were carried out using a Parr 3920 shaking reactor. Separations by
flash chromatography were performed on silica gel (SDS 60 ACC, 230–400 mesh). Melting points were
measured on a Reichert 723 hot stage microsope, and are uncorrected. Infrared spectra were recorded on
Buck Scientific 500 and Perkin–Elmer Paragon 1000 FT-IR spectrophotometers, with solid compounds
compressed into KBr pellets and liquid compounds placed between two NaCl disks. NMR spectra
1
were obtained on a Bruker AC-250 spectrometer (250 MHz for H, 63 MHz for 13C) spectrometer
(Servicio de Espectroscopía, Universidad Complutense), with CDCl3 or d6-DMSO as solvents. When
necessary, assignments were aided by DEPT, COSY and 13C–1H correlation experiments. Optical
rotations were determined at 25°C on a 1 ml cell, using a Perkin–Elmer 240 polarimeter operating at
the emission wavelength of a sodium lamp; concentrations are given in g/100 ml. Elemental analyses
were determined by the Servicio de Microanálisis, Universidad Complutense, on a Perkin–Elmer 2400
CHN microanalyzer.

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E. Caballero et al. / Tetrahedron: Asymmetry 9 (1998) 3025–3038
Fig. 1.
3.1. Methyl N-(tert-butyloxycarbonyl)glycyl tryptophanate (2a)
To a solution of tryptophan methyl ester (1 g, 4.6 mmol) in dry dichloromethane (50 ml) was added N-
Boc-glycine (0.88 g, 4.6 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (0.88 g, 4.6
mmol), under an argon atmosphere. The reaction was protected from light and stirred at room temperature
for 24 h. The solution was washed with 1 N aqueous HCl (7 ml) and 1 N aqueous NaHCO3 (7 ml). The
residue was chromatographed on silica gel, eluting with ethyl acetate, yielding the dipeptide 2a (1.55 g,
90%) as an off-white solid. Mp, 55°C. IR (KBr): 3334.7 (NH), 1672.9 (CO2CH3 and CO–N) cm−1. 1H-
NMR (CDCl3) δ: 8.63 (br. s, 1H, NHi); 7.49 (d, 1H, J=7.5, H-40); 7.31 (d, 1H, J=7.5, H-70); 7.12 (m, 2H,
H-50, 60); 6.94 (d, 1H, J=2.2 Hz, H-20); 6.79 (d, 1H, J=7.4, NH); 5.26 (br. s, 1H, NH); 4.90 (m, 1H, Hα-
Trp); 3.71 (d, 2H, J=4.4 Hz, Hα-Gly); 3.63 (s, 3H, CO2CH3); 3.29 (d, 2H, J=5.3, Hβ-Trp); 1.42 (s, 9H,
Boc). 13C-NMR (CDCl3) δ: 172.34 (CO2CH3); 169.47 (CO–Gly); 156.19 (CO2C(CH3)3); 136.23 (C-
70a); 127.54 (C-30a); 123.32 (C-20); 122.20 (C-40); 119.64 (C-50); 118.39 (C-60); 111.55 (C-70); 109.46
(C-30); 80.30 (CO2C(CH3)3); 52.97 (Cα-Trp); 52.56 (CO2CH3); 44.17 (Cα-Gly); 28.37 (CO2C(CH3)3);
27.62 (Cβ-Trp) ppm. [α]D25=+40.8 (c 0.50, CHCl3). Anal. calcd for C19H25N3O5: C, 60.80; H, 6.67; N,
11.20. Found: C, 60.30; H, 6.29; N, 10.92.
3.2. Methyl N-(tert-butyloxycarbonyl)-L-valyl tryptophanate (2b)
To a solution of tryptophan methyl ester (1.5 g, 6.9 mmol) in dry dichloromethane (50 ml) was added
N-Boc-L-valine (1.30 g, 6.9 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (1.32 g,

E. Caballero et al. / Tetrahedron: Asymmetry 9 (1998) 3025–3038
3033
6.9 mmol), under an argon atmosphere. The reaction and purification were carried out as in the synthesis
of 1a, yielding the dipeptide 2b (2.03 g, 71%) as an off-white solid. Mp, 136–138°C. IR (KBr): 3324.2
1
(NH), 1659.3 (CO2CH3 and CO–N) cm−1. H-NMR (CDCl3) δ: 8.14 (br. s, 1H, NHi); 7.51 (d, 1H,
J=7.6, H-40); 7.33 (d, 1H, J=7.7, H-70); 7.14 (m, 2H, H-50, 60); 7.02 (d, 1H, J=2.1 Hz, H-20); 6.74 (d,
1H, J=7.6, NH); 5.03 (d, 1H, J=8.4 Hz, NH); 4.90 (m, 1H, Hα-Trp); 3.90 (m, 1H, Hα-Val); 3.64 (s, 3H,
CO2CH3); 3.29 (m, 2H, Hβ-Trp); 2.06 (m, 1H, CH(CH3)2); 1.41 (s, 9H, Boc); 0.89 and 0.82 (2d, J=6.8
Hz, CH(CH3)2). 13C-NMR (CDCl3) δ: 172.10 (CO2CH3); 171.44 (CO–Val); 155.84 (CO2C(CH3)3);
136.14 (C-70a); 127.43 (C-30a); 123.13 (C-20); 122.16 (C-40); 119.61 (C-50); 118.42 (C-60); 111.35
(C-70); 109.51 (C-30); 79.82 (CO2C(CH3)3); 59.69 (Cα-Val); 52.79 (Cα-Trp); 52.34 (CO2CH3); 31.14
(CH(CH3)2); 28.28 (CO2C(CH3)3); 27.61 (Cβ-Trp); 19.10 and 17.54 (CH(CH3)2) ppm. [α]D25=+51.6
(c 0.50, CHCl3). Anal. calcd for C22H31N3O5: C, 63.31; H, 7.43; N, 10.07. Found: C, 63.73; H, 7.33; N,
9.88.
3.3. (3S)-3-(3-Indolylmethyl)-2,5-piperazinedione (3a)
Compoud 2a (1.92 g, 5.12 mmol) was heated at 200°C under a stream of argon for 4 h. The off-white
residue was identified as compound 3a. Yield, 0.9 g (73%). Mp, 300–301°C. IR (KBr): 3337.6, 3215.5
(NH); 1668.0 (CO–NH). 1H-NMR (d6-DMSO) δ: 10.94 (br. s, 1H, NHi); 8.13 (d, 1H, J=2.3 Hz, NH);
7.79 (s, 1H, NH); 7.55 (d, 1H, J=7.8, H-40); 7.33 (d, 1H, J=8.0, H-70); 7.00 (m, 3H, H-20, 50, 60); 4.02
(m, 1H, H-3); 3.30 (dd, 1H, J=17.2 and 2.8 Hz, H-6); 3.24 (m, 1H, Hβ-Trp); 3.01 (dd, 1H, J=14.4 and
4.6 Hz, Hβ-Trp); 2.77 (d, 1H, J=17.2, H-6) ppm. 13C-NMR (d6-DMSO) δ: 167.92 and 165.95 (2CO);
135.87 (C-70a); 127.43 (C-30a); 124.55 (C-20); 120.85 (C-40); 118.64 (C-50); 118.39 (C-60); 111.13 (C-
70); 108.28 (C-30); 55.39 (C-3); 43.78 (C-6); 29.13 (CH2) ppm. [α]D25=+43.2 (c 0.25, DMSO). Anal.
calcd for C13H13N3O2: C, 64.20; H, 5.35; N, 17.28. Found: C, 63.82; H, 5.32; N, 16.92.
3.4. (3S,6S)-3-(3-Indolylmethyl)-6-isopropyl-2,5-piperazinedione (3b)
Compoud 2b (2.03 g, 4.9 mmol) was heated at 200°C under a stream of argon for 7 h. The off-white
residue was identified as compound 3b. Yield, 1.52 g (75%). Mp, 215–217°C. IR (KBr): 3333.6, 3198.7
(NH); 1668.1 (CO–NH). 1H-NMR (d6-DMSO) δ: 10.87 (br. s, 1H, NHi); 8.02 (s, 1H, NH); 7.90 (s, 1H,
NH); 7.59 (d, 1H, J=7.7, H-40); 7.28 (d, 1H, J=7.9, H-70); 7.07 (s, 1H, H-20); 6.98 (m, 2H, H-50, 60);
4.14 (br. s, 1H, H-3); 3.48 (br. s, 1H, H-6); 3.22 (dd, 1H, J=14.3 and 4.7 Hz, Hβ-Trp); 3.06 (dd, 1H
J=14.4 and 4.4 Hz, Hβ-Trp); 1.63 (m, 1H, CH(CH3)2); 0.59 and 0.15 (2 d, 6H, J=6.9 Hz, CH(CH3)2)
ppm. 13C-NMR (d6-DMSO) δ: 167.33 and 166.24 (2CO); 135.96 (C-70a); 127.88 (C-30a); 124.44 (C-
20); 120.61 (C-40); 118.85 (C-50); 118.12 (C-60); 110.95 (C-70); 108.74 (C-30); 59.22 (C-6); 55.12 (C-3);
31.04 (CH(CH3)2); 18.27 and 16.01 (CH(CH3)2) ppm. [α]D25=−63.6 (c 0.55, DMSO). Anal. calcd for
C16H19N3O2: C, 67.37; H, 6.67; N, 14.74. Found: C, 67.01; H, 6.37; N, 14.37.
3.5. (5aR,10bS,11aS)-6-Acetyl-1,3,4,5a,6,10b,11,11a-octahydro-2H-pyrazino[20 ,10-5,1]-pyrrolo[2,
3-b]indole-1,4-dione (1a)
Compound 3a (800 mg, 2.1 mmol) was added in one portion to trifluoroacetic acid (10 ml). The
suspension was stirred until complete disolution (ca. 2 min), and was poured onto a vigorously stirred
biphasic system of dichloromethane (40 ml) and 20% aqueous potassium carbonate (40 ml), externally
cooled with an ice bath. The pH of the aqueous layer was adjusted to 8 and it was extracted with
dichloromethane (20×10 ml). The combined organic layers were dried over anhydrous sodium sulfate

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E. Caballero et al. / Tetrahedron: Asymmetry 9 (1998) 3025–3038
1
and evaporated. The residue was examined by H-NMR and identified as compound 4a, and was used
for the next step without further purification.
A solution of the crude compound 4a (539 mg, 1.44 mmol) in pyridine (8 ml) and acetic anhydride
(2.34 ml) was stirred at room temperature for 3 h. The solution was diluted with dichloromethane (10
ml) and filtered to remove compound 3a (191 mg, 42%), from ring opening of the starting material. The
filtrate was evaporated, and the residue was diluted with dichloromethane (10 ml) and washed with water
(10 ml). The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was
chromatographed on silica gel, eluting with ethyl acetate, yielding 150 mg (24%) of compound 1a, 30
mg (4%) of 2,6-diacetylpyrazino[20 ,10-5,1]pyrrolo[2,3-b]indole-1,4-dione (5) and 23 mg (4%) of (3S)-
1-acetyl-3-(3-indolylmethyl)-2,5-piperazinedione (6).
1
Data for 4a: H-NMR (CDCl3) δ: 7.11 (m, 2H, H-8, 10); 6.78 (t, J=7.4, H-9); 6.61 (d, J=7.7, H-7);
6.16 (br. s, 1H, NHi); 5.78 (d, 1H, J=6.8, H-5a); 5.06 (br. s, 1H, N2-H); 4.06 (m, 3H, H-3, H-10b, H-11a);
3.88 (dd, 1H, J=16.8 and 4.1, H-3); 2.72 (dd, 1H, J=13.1 and 6.1, H-11); 2.44 (m, 1H, H-11) ppm.
Data for 1a: Mp, 100–102°C. IR (KBr): 3265.2 (NH), 1678.3 (C_O) cm−1. 1H-NMR (CDCl3) δ: 8.02
(d, 1H, J=7.7, H-7); 7.28 (m, 2H, H-9, 10); 7.13 (t, 1H, J=7.1, H-8); 6.77 (br. s, 1H, NH); 6.42 (d, 1H,
J=6.5, H-5a); 4.15 (t, 1H, J=6.7, H-10b); 4.08 (d, 1H, J=16.8, H-3); 3.88 (m, 2H, H-3, 11a); 2.73 (dd,
1H, J=12.7 and 5.5, H-11); 2.64 (s, 3H, Ac), 2.33 (m, 1H, H-11) ppm. [α]D25=−168.3 (c 0.52, CHCl3).
Anal. calcd for C15H15N3O3: C, 63.16; H, 5.26; N, 14.74. Found: C, 62.76; H, 5.19; N, 14.32.
1
Data for 5: Mp, 78–80°C. IR (KBr): 3341.4 (NH), 1711.0 (C_O) cm−1. H-NMR (CDCl3) δ: 8.02
(d, 1H, J=7.7); 7.30 (m, 2H); 7.15 (t, 1H, J=7.2); 6.30 (d, 1H, J=5.9); 4.83 (d, 1H, J=17.1); 4.13 (m,
2H); 3.94 (d, 1H, J=17.1); 2.80 (dd, 1H, J=13.0 and 6.1); 2.64 (s, 3H); 2.55 (s, 3H); 2.45 (m, 1H) ppm.
[α]D25=−116.0 (c 0.28, CHCl3). Anal. calcd for C17H17N3O4: C, 62.38; H, 5.20; N, 12.84. Found: C,
62.04; H, 5.45; N, 12.48.
1
Data for 6: Mp, 88–90°C. IR (KBr): 3321.3 (NH); 1699.0 (CO–NH). H-NMR (d6-DMSO) δ: 8.25
(br. s, 1H, NHi); 7.56 (d, 1H, J=7.8, H-40); 7.38 (d, 1H, J=8.0, H-70); 7.16 (m, 2H, H-50, 60); 7.07 (d, 1H,
J=2.1 Hz, H-20); 6.24 (s, 1H, NH); 4.41 (m, 1H, H-3); 4.15 (d, 1H, J=18.1, H-6); 3.53 (d, 1H, J=18.1,
H-6); 3.37 (m, 2H, Hβ-Trp); 2.55 (s, 3H, COCH3) ppm. 13C-NMR (d6-DMSO) δ: 171.82 (COCH3);
168.79 and 166.27 (2CO); 136.37 (C-70a); 126.61 (C-30a); 124.21 (C-20); 123.03 (C-40); 120.31 (C-50);
118.38 (C-60); 111.70 (C-70); 108.51 (C-30); 57.10 (C-3); 45.81 (C-6); 30.31 (Cβ-Trp); 27.36 (COCH3)
ppm. [α]D25=+15.7 (c 0.14, DMSO). Anal. calcd for C15H15N3O3: C, 63.16; H, 5.26; N, 14.74. Found:
C, 62.78; H, 5.67; N, 14.12.
3.6. (3S,5aR,10bS,11aS)-6-Acetyl-3-isopropyl-1,3,4,5a,6,10b,11,11a-octahydro-2H-pyrazino[20 ,10-5,
1]pyrrolo[2,3-b]indole-1,4-dione (1b)
The method described for the synthesis of 1a was used, starting from 560 mg (1.96 mmol) of
compound 3b. The yields obtained were: 291.2 (52%) of diketopiperazine 3b and 177 mg (30%) of
compound 1b.
Data for 4b: 7.10 (m, 2H); 6.76 (t, 1H, J=7.4); 6.59 (d, 1H, J=7.7); 5.75 (d, 1H, J=6.9); 3.92 (m, 3H);
2.60 (m, 2H); 2.36 (m, 1H); 0.90 (d, 6H) ppm.
1
Data for 1b: Mp, 96–98°C. IR (KBr): 3285.7 (NH), 1741.5 and 1671.8 (2C_O) cm−1. H-NMR
(CDCl3) δ: 8.04 (d, 1H, J=7.9); 7.35 (m, 2H); 7.12 (td, 1H, J=7.4 and 1.0); 6.48 (d, 1H, J=6.7); 6.25
(br. s, 1H); 4.15 (t, 1H, 6.8); 3.97 (br. s, 1H); 3.90 (dd, 1H, J=11.8 and 5.3); 2.69 (dd, 1H, J=12.6
and 5.3); 2.63 (s, 3H); 2.59 (m, 1H); 2.25 (m, 1H); 1.05 (d, 3H, J=7.2); 0.91 (d, 3H, J=6.8) ppm. 13C-
NMR (CDCl3) δ: 170.90, 168.54, 165.12, 143.23, 130.49, 128.87, 124.99, 123.96, 118.46, 76.64, 60.52,
57.23, 43.74, 36.33, 29.32, 24.13, 19.07, 16.14 ppm. [α]D25=−108.2 (c 0.50, CHCl3). Anal. calcd for
C18H21N3O3: C, 66.06; H, 6.42; N, 12.84. Found: C, 66.48; H, 6.78; N, 12.45.

E. Caballero et al. / Tetrahedron: Asymmetry 9 (1998) 3025–3038
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3.7. Iminoethers derived from compounds 1. General procedure
To a solution of the starting diketopiperazine (0.32 to 1.00 mmol) and triethyloxonium tetrafluoro-
borate (3 equiv.) in dry dichloromethane (50 ml) was added solid sodium carbonate (5 equiv.). The
suspension was stirred at room temperature for 24–43 h, under an argon atmosphere, and was then poured
onto ice water (3 ml). The organic layer was decanted from the aqueous phase, which was extracted
with dichloromethane (5×10 ml). The combined organic layers were dried over sodium sulfate and
evaporated. The residue was chromatographed on silica gel, eluting with petroleum ether:ethyl acetate
(2:1). The yields obtained were: compound 7, 40%; compound 9, 60%; compound 13, 61%; compound
14, 71%; compound 16, 68%; compound 19, 17%.
Data for 7: Mp, 236–238°C. IR (KBr): 1703.5 and 1659.0 (2C_O, C_N) cm−1. 1H-NMR (CDCl3) δ:
8.11 (d, 1H, J=7.9, H-7); 7.25 (m, 2H, H-9, 10); 7.12 (t, 1H, J=7.4, H-8); 6.60 (d, 1H, J=7.1, H-5a); 4.12
(m, 5H, H-3, H-10b, OCH2CH3); 3.86 (m, 1H, H-11a); 2.60 (s, 3H, Ac); 2.55 (dd, 1H, J=12.3 and 5.2,
H-11); 2.14 (m, 1H, H-11); 1.25 (t, 3H, J=7.2, OCH2CH3) ppm. 13C-NMR (CDCl3) δ: 171.06, 166.28,
159.33, 143.43, 130.48, 128.81, 124.75, 124.04, 119.07, 75.75, 61.87, 55.33, 51.83, 43.47, 37.95, 24.23,
14.25 ppm. [α]D25=−294.4 (c 0.16, CHCl3). Anal. calcd for C17H19N3O3: C, 65.18; H, 6.07; N, 13.42.
Found: C, 64.82; H, 6.11; N, 13.11.
Data for 9: Mp, 188–189°C. IR (KBr): 3388.1 (NH); 1666.8 (2C_O, C_N) cm−1. 1H-NMR (CDCl3)
δ: 8.10 (d, 1H, J=8.1); 7.24 (m, 2H); 7.12 (t, 1H, J=7.4); 6.54 (d, 1H, J=6.8); 4.11 (m, 4H); 3.89 (m,
1H); 2.63 (s, 3H); 2.56 (dd, 1H, J=12.4 and 4.9); 2.13 (m, 1H); 1.49 (d, 3H, J=7.1); 1.24 (t, 3H, J=7.1)
ppm. [α]D25=−256.0 (c 0.50, CHCl3). Anal. calcd for C18H21N3O3: C, 66.04; H, 6.47; N, 12.84. Found:
C, 65.89; H, 6.37; N, 12.60.
Data for 13: Mp, 225–226°C. IR (KBr): 1699.7 and 1661.1 (2C_O, C_N) cm−1. 1H-NMR (CDCl3)
δ: 8.09 (d, 1H, J=7.9); 7.26 (m, 2H); 7.08 (m, 1H); 6.59 (d, 1H, J=7.2); 4.09 (m, 4H); 3.82 (dd, 1H,
J=11.4 and 4.8); 2.55 (s, 3H); 2.53 (m, 1H); 2.08 (m, 1H); 1.34 (d, 3H, J=7.2); 1.21 (t, 3H, J=7.1) ppm.
[α]D25=−200.6 (c 0.50, CHCl3). Anal. calcd for C18H21N3O3: C, 66.04; H, 6.47; N, 12.84. Found: C,
65.85; H, 6.52; N, 12.64.
1
Data for 14: Mp, 224°C. IR (KBr): 1700.0 and 1661.7 (2C_O, C_N) cm−1. H-NMR (CDCl3) δ:
8.12 (d, 1H, J=8.0); 7.26 (m, 2H); 7.11 (t, 1H, J=7.4); 6.63 (d, 1H, J=7.2); 4.11 (m, 4H); 3.85 (dd, 1H,
J=11.8 and 5.1); 2.58 (s, 3H); 2.54 (m, 1H); 2.11 (m, 1H); 1.37 (d, 3H, J=7.2); 1.24 (t, 3H, J=7.1) ppm.
[α]D25=+193.8 (c 0.50, CHCl3). Anal. calcd for C18H21N3O3: C, 66.04; H, 6.47; N, 12.84. Found: C,
65.82; H, 6.67; N, 12.62.
Data for 16: Mp, 187–188°C. IR (KBr): 1699.1 and 1662.2 (2C_O, C_N) cm−1. 1H-NMR (CDCl3)
δ: 8.07 (d, 1H, J=7.9); 7.28 (m, 2H); 7.09 (t, 1H, J=7.4); 6.51 (d, 1H, J=6.9); 4.07 (m, 4H); 3.85 (m,
1H); 2.60 (s, 3H); 2.55 (dd, 1H, J=12.4 and 5.2); 2.13 (m, 1H); 1.47 (d, 3H, J=7.2); 1.22 (t, 3H, J=7.1)
ppm. [α]D25=+251.8 (c 0.50, CHCl3). Anal. calcd for C18H21N3O3: C, 66.04; H, 6.47; N, 12.84. Found:
C, 65.86; H, 6.71; N, 12.58.
1
Data for 19: Mp, 98–100°C. IR (KBr): 1671.6 (2C_O, C_N) cm−1. H-NMR (CDCl3) δ: 8.12 (d,
1H, J=8.0); 7.24 (m, 2H); 7.10 (td, 1H, J=7.4 and 1.1); 6.63 (d, 1H, J=7.2); 4.12 (m, 3H); 3.94 (t, 1H
J=3.1); 3.82 (m, 1H); 2.64 (m, 1H); 2.60 (s, 3H); 2.50 (dd, 1H, J=12.1 and 5.0); 2.04 (m, 1H); 1.25 (t,
3H, J=7.1); 1.11 (d, 3H, J=6.9); 0.72 (d, 1H, J=6.8) ppm. [α]D25=−178.9 (c 0.28, CHCl3). Anal. calcd
for C20H25N3O3: C, 67.61; H, 7.04; N, 11.83. Found: C, 67.97; H, 7.30; N, 11.44.

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E. Caballero et al. / Tetrahedron: Asymmetry 9 (1998) 3025–3038
3.8. 10-Acetyl-5,7,8,9a,10,14b,15,15a-octahydroindolo[300 ,200-40,50]pyrrolo[20,10-3,4]-pyrazino[2,
1-b]quinazoline-5,8-diones. General procedure
A mixture of the suitable iminoether (0.140 to 0.398 mmol) and anthranilic acid (2 equiv.) was melted
at 140°C under a stream of argon and kept at this temperature for 4–6 h. The melt was cooled and
triturated with 20% aqueous ammonium hydroxide, and the mixture was extracted with dichloromethane
(5×5 ml). The combined organic layers were dried over sodium sulfate and evaporated. The residue was
chromatographed on silica gel, eluting with petroleum ether:ethyl acetate (2:1). The yields obtained were:
starting from iminoether 7, 76% of compound 8; starting from iminoether 9, 23% of compound 10, 8%
of compound 1115 and 3% of compound 12; starting from iminoether 13, 44% of compound 12; starting
from iminoether 14, 38% of compound 15; starting from iminoether 16, 20% of compound 17, 13% of
compound 18 and 4% of compound 15; starting from iminoether 19, 14% of compound 20 and 45% of
compound 21.
Data for 8: Mp, 285–287°C. IR (KBr): 1678.9 (2C_O, C_N) cm−1. 1H-NMR (CDCl3) δ: 8.26 (dd,
1H, J=8.0 and 1.2, H-4); 8.04 (d, 1H, J=7.7, H-11); 7.78 (td, 1H, J=8.3 and 1.5, H-2); 7.66 (d, 1H,
J=7.6, H-1); 7.50 (t, J=8.0, H-3); 7.34 (m, 2H, H-12, 14); 7.27 (t, 1H, J=7.0, H-13); 6.37 (d, 1H, J=6.1,
H-9a); 5.24 (d, 1H, J=17.6, H-7); 4.54 (dd, 1H, J=10.8 and 5.7, H-15a); 4.26 (t, 1H, J=6.3, H-14b); 4.20
(d, 1H, J=17.6, H-7); 3.12 (dd, 1H, J=13.1 and 5.8, H-15); 2.71 (m, 1H, H-15); 2.68 (s, 3H, Ac) ppm.
[α]D25=+10.2 (c 0.22, CHCl3). Anal. calcd for C22H18N4O3: C, 68.39; H, 4.66; N, 14.51. Found: C,
68.08; H, 4.35; N, 14.47.
Data for 10: Mp, 187–188°C. IR (KBr): 1676.1 (2C_O, C_N) cm−1. 1H-NMR (CDCl3) δ: 8.25 (dd,
1H, J=8.0 and 1.0); 8.21 (d, 1H, J=8.1); 7.75 (t, 1H, J=7.6); 7.51 (m, 2H); 7.29 (m, 2H); 7.16 (t, 1H,
J=7.2); 6.86 (d, 1H, J=7.8); 5.42 (q, 1H, J=7.0); 4.54 (dd, 1H, J=12.5 and 4.8); 4.29 (t, 1H, J=7.9); 2.76
(dd, 1H, J=10.0 and 4.9); 2.50 (s, 3H); 2.32 (m, 1H); 1.70 (d, 3H, J=7.0) ppm. 13C-NMR (CDCl3) δ:
170.82, 167.96, 160.20, 147.79, 146.99, 143.91, 135.16, 129.47, 129.23, 127.45, 127.00, 126.79, 124.87,
(double signal), 120.51, 117.15, 76.79, 58.23, 52.23, 44.53, 41.83, 24.43, 21.11 ppm. [α]D25=−34.0 (c
0.50, CHCl3). Anal. calcd for C23H20N4O3: C, 68.99; H, 5.03; N, 13.99. Found: C, 69.02; H, 5.20; N,
13.77.
Data for 11: Mp, 135°C. IR (KBr): 1680.1 (2C_O, C_N) cm−1. 1H-NMR (CDCl3) δ: 8.15 (dd, 1H,
J=8.0 and 1.2); 7.77 (d, 1H, J=8.0); 7.71 (dd, 1H, J=6.9 and 1.4); 7.60 (d, 1H, J=7.6); 7.42 (t, 1H, J=7.5);
7.26 (t, 1H, J=7.7); 7.06 (t, 1H, J=7.7); 6.91 (t, 1H, J=7.5); 6.23 (d, 1H, J=6.0); 5.37 (q, 1H, J=7.3); 4.90
(dd, 1H, J=10.0 and 3.4); 4.11 (m, 1H); 3.72 (dd, 1H, J=11.5 and 5.9); 2.89 (m, 1H); 2.60 (s, 3H); 1.60
(d, 3H, J=7.4) ppm. [α]D25=+101.0 (c 0.80, CHCl3). Anal. calcd for C23H20N4O3: C, 68.99; H, 5.03; N,
13.99. Found: C, 68.77; H, 5.27; N, 13.98.
Data for 12: Mp, 262–263°C. IR (KBr): 1681.9 (2C_O, C_N) cm−1. 1H-NMR (CDCl3) δ: 8.27 (d,
1H, J=7.3); 8.06 (d, 1H, J=7.7); 7.77 (td, 1H, J=8.4 and 1.5); 7.65 (d, 1H, J=8.2); 7.50 (t, 1H, J=7.0);
7.36 (m, 2H); 7.18 (t, 1H, J=7.4); 6.37 (d, 1H, J=6.1); 5.44 (q, 1H, J=7.1); 4.55 (dd, 1H, J=10.8 and
5.7); 4.25 (t, 1H, J=6.3); 3.17 (dd, 1H, J=13.1 and 5.7); 2.71 (s, 3H); 2.67 (m, 1H); 1.50 (d, 3H, J=7.1)
ppm. [α]D25=−49.8 (c 0.41, CHCl3). Anal. calcd for C23H20N4O3: C, 68.99; H, 5.03; N, 13.99. Found:
C, 68.80; H, 5.28; N, 13.69.
Data for 15: Mp, 263–264°C. IR (KBr): 1680.4 (2C_O, C_N) cm−1. 1H-NMR (CDCl3) δ: 8.25 (d,
1H, J=7.3); 8.05 (d, 1H, J=7.6); 7.77 (td, 1H, J=8.3 and 1.4); 7.65 (d, 1H, J=8.1); 7.50 (t, 1H, J=6.9);
7.36 (m, 2H); 7.17 (t, 1H, J=7.4); 6.37 (d, 1H, J=6.1); 5.44 (q, 1H, J=7.0); 4.54 (dd, 1H, J=10.7 and
5.6); 4.25 (t, 1H, J=6.3); 3.17 (dd, 1H, J=13.0 and 5.7); 2.71 (s, 3H); 2.67 (m, 1H); 1.50 (d, 3H, J=7.1)
ppm. [α]D25=+49.2 (c 0.25, CHCl3). Anal. calcd for C23H20N4O3: C, 68.99; H, 5.03; N, 13.99. Found:
C, 68.74; H, 5.00; N, 13.69.
Data for 17: Mp, 185–186°C. IR (KBr): 1679.7 (2C_O, C_N) cm−1. 1H-NMR (CDCl3) δ: 8.28 (d,

E. Caballero et al. / Tetrahedron: Asymmetry 9 (1998) 3025–3038
3037
1H, J=7.9); 8.22 (d, 1H, J=8.2); 7.77 (td, 1H, J=7.7 and 1.5); 7.52 (m, 2H); 7.30 (m, 2H); 7.16 (t, 1H,
J=7.3); 6.87 (d, 1H, J=7.8); 5.43 (q, 1H, J=7.0); 4.55 (dd, 1H, J=12.5 and 4.8); 4.30 (t, 1H, J=7.9); 2.77
(dd, 1H, J=12.0 and 4.9); 2.50 (s, 3H); 2.34 (m, 1H); 1.71 (d, 3H, J=7.0) ppm. [α]D25=+50.3 (c 0.17,
CHCl3). Anal. calcd for C23H20N4O3: C, 68.99; H, 5.03; N, 13.99. Found: C, 68.86; H, 5.20; N, 13.69.
Data for 18: Mp, 135–136°C. IR (KBr): 1679.8 (2C_O, C_N) cm−1. 1H-NMR (CDCl3) δ: 8.15 (dd,
1H, J=7.9 and 1.1); 7.77 (d, 1H, J=8.0); 7.71 (dd, 1H, J=6.9 and 1.3); 7.61 (d, 1H, J=7.6); 7.43 (t, 1H,
J=7.4); 7.26 (t, 1H, J=7.7); 7.06 (t, 1H, J=7.6); 6.90 (t, 1H, J=7.5); 6.23 (d, 1H, J=5.9); 5.37 (q, 1H,
J=7.2); 4.91 (dd, 1H, J=10.0 and 3.3); 4.11 (m, 1H); 3.72 (dd, 1H, J=11.4 and 5.9); 2.88 (m, 1H); 2.60
(s, 3H); 1.59 (d, 3H, J=7.4) ppm. [α]D25=−110.7 (c 1.14, CHCl3).
1
Data for 20: Mp, 77–80°C. IR (KBr): 1677.8 (2C_O, C_N) cm−1. H-NMR (CDCl3) δ: 8.25 (d,
1H, J=6.5); 8.17 (d, 1H, J=8.0); 7.90 (d, 1H, J=8.4); 7.76 (m, 2H); 7.53 (m, 2H); 7.18 (m, 1H); 6.11
(d, 1H, 7.7); 5.36 (d, 1H, J=3.1); 4.60 (dd, 1H, J=12.0 and 5.2); 4.28 (t, 1H, J=6.5); 2.83 (dd, 1H,
J=14.1 and 5.6); 2.60 (s, 3H); 2.50 (m, 1H); 2.05 (m, 1H); 1.32 (d, 3H, J=6.9); 0.92 (d, 3H, J=6.9) ppm.
[α]D25=+23.1 (c 0.07, CHCl3). Anal. calcd for C25H23N4O3: C, 70.26; H, 5.39; N, 13.11. Found: C,
69.85; H, 5.19; N, 12.90.
1
Data for 21: Mp, 92–94°C. IR (KBr): 1678.6 (2C_O, C_N) cm−1. H-NMR (CDCl3) δ: 8.14 (dd,
1H, J=8.0 and 1.2); 7.71 (m, 2H); 7.59 (d, 1H, J=7.4); 7.42 (td, 1H, J=8.1 and 1.2); 7.25 (d, 1H, J=6.9);
7.00 (t, 1H, J=7.7); 6.80 (t, 1H, J=6.6); 6.22 (d, 1H, J=5.8); 5.15 (d, 1H, J=9.8); 4.95 (dd, 1H, J=9.8
and 2.6); 4.08 (t, 1H, J=6.7); 3.77 (br. d, 1H, J=15.4); 2.83 (m, 1H); 2.59 (s, 3H); 2.26 (m, 1H); 1.23 (d,
3H, J=6.7); 0.93 (d, 3H, J=6.7) ppm. [α]D25=+121.6 (c 0.44, CHCl3). Anal. calcd for C25H23N4O3: C,
70.26; H, 5.39; N, 13.11. Found: C, 70.56; H, 5.28; N, 12.89.
3.9. (3S,5aR,10bS,11aS)-6-Acetyl-2-(o-azidobenzoyl)-3-methyl-1,3,4,5a,6,10b,11,11a-octahydro-2H-
pyrazino[20,10-5,1]pyrrolo[2,3-b]indole-1,4-dione (22)
o-Azidobenzoyl chloride was prepared by heating at 80°C for 3 h, under an argon atmosphere a
solution of o-azidobenzoic acid (326 mg, 6.0 mmol) in thionyl chloride (2.18 ml, 90 mmol). The excess
thionyl chloride was evaporated under reduced pressure. Dry benzene (2×5 ml) was added to the residue
and evaporated. The crude o-azidobenzoyl chloride was inmediately used for the acylation step, which
was performed as follows. To a cooled (−78°C) solution of compound 1c8 (100 mg, 0.33 mmol) in
dry THF (20 ml) was dropwise added a 0.5 M solution of potassium hexamethyldisilazide in toluene
(0.8 ml, 1.2 equiv.). The solution was stirred at −78°C for 15 min, becoming intensely yellow, and was
then treated with a solution of the crude o-azidobenzoyl chloride in THF (10 ml). The solution was
stirred at −78°C for 3 h, was left to warm to room temperature over 20 h and was then poured over
saturated aqueous ammonium chloride (10 ml), which was extracted with dichloromethane (6×10 ml).
The combined dichloromethane layers were dried over sodium sulfate and evaporated, and the residue
was chromatographed on silica gel, eluting with petroleum ether:ethyl acetate (4:1). Yield, 79.1 mg (54%)
of compound 22. Mp, 74–75°C. IR (KBr): 2129.6 (N3); 1680.2 (2C_O, C_N) cm−1. 1H-NMR (CDCl3)
δ: 8.18 (d, 1H, J=8.3, H-7); 7.46 (td, 1H, J=7.8 and 1.6, H-50); 7.37 (dd, 1H, J=7.7 and 1.5, H-60); 7.28
(m, 2H, H-9, 10); 7.20 (m, 1H, H-30); 7.12 (m, 2H, H-40, 8); 6.73 (d, 1H, J=7.5, H-5a); 5.06 (q, 1H,
J=7.0, H-3); 4.22 (t, 1H, J=7.5, H-10b); 4.13 (dd, 1H J=12.4 and 5.0, H-11a); 2.57 (s, 3H, Ac); 2.53 (dd,
J=12.2 and 5.0, H-11); 2.23 (m, 1H, H-11); 1.68 (d, 3H, J=7.8, C3–CH3) ppm. [α]D25=−63.3 (c 0.62,
CHCl3). Anal. calcd for C23H20N6O4: C, 62.16; H, 4.50; N, 18.92. Found: C, 61.97; H, 4.69; N, 18.63.

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E. Caballero et al. / Tetrahedron: Asymmetry 9 (1998) 3025–3038
3.10. Alternative synthesis of compound 10 by intramolecular aza Wittig reaction of compound 22
To a solution of compound 22 (36.8 mg, 0.083 mmol) in dry toluene (5 ml) was added tributylphos-
phine (30 µl, 0.13 mmol). The solution was stirred at room temperature for 2 h. The solvent was evapo-
rated and the residue was chromatographed on silica gel, eluting with petroleum ether:dichloromethane
(2:1) and then with ethyl acetate. Yield, 27 mg (81%) of compound 10, as a white solid.
Acknowledgements
We thank CICYT for financial support (grants SAF-94-0517 and SAF-97-0143).
References
1. Wong, S.-M.; Musza, L. L.; Kydd, G. C.; Kullnig, R.; Gillum, A. M.; Cooper, R., J. Antibiotics, 1993, 46, 545.
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H.; Shingu, T., Tetrahedron Lett., 1992, 33, 1621. (b) Takahashi, C.; Matsushita, T.; Doi, M.; Minoura, K.; Shingu, T.;
Kumeda, Y.; Numata, A., J. Chem. Soc., Perkin Trans. 1, 1995, 2345.
3. (a) Isolation and structural characterization: Karwowski, J. P.; Jackson, M.; Rasmussen, R. D.; Humphrey, P. E.; Poddig,
J. B.; Kohl, W. L.; Scherr, M. H.; Kadam, S.; McAlpine, J. B., J. Antibiotics, 1993, 46, 374. (b) Total synthesis: Marsden,
S. P.; Depew, K. M.; Danishefsky, S. J., J. Am. Chem. Soc., 1994, 116, 11143.
4. Hochlowski, J. E.; Mullally, M. M.; Spanton, S. G.; Whittern, D. N.; Hill, P.; McAlpine, J. B., J. Antibiotics, 1993, 46,
380. For a review on multi-drug resistance, see: Kane, S. E., Advances in Drug Research, 1996, 28, 181.
5. (a) Kametani, T.; Higa, T.; Van Loc, C.; Ihara, M.; Koizum, M.; Fukumoto, K., J. Am. Chem. Soc., 1976, 98, 6186. (b)
Kametani, T.; Higa, T.; Van Loc, C.; Ihara, M.; Fukumoto, K., J. Am. Chem. Soc., 1977, 99, 2306. Related procedures: (c)
Bock, M. G.; DiPardo, M.; Pitzenbetrger, S. M.; Homnick, C. F.; Sproger, J. P.; Freidinger, R. M., J. Org. Chem., 1987,
52, 1646. Takeuchi, H.; Hagiwara, S.; Eguchi, S., Tetrahedron, 1989, 45, 6373.
6. (a) Rajappa, S.; Advani, B. G., Tetrahedron, 1973, 29, 1299. (b) Rajappa, S.; Advani, B. G., J. Chem. Soc., Perkin Trans.
1, 1974, 2122.
7. (a) Martín-Santamaría, S.; Buenadicha, F. L.; Espada, M.; Söllhuber, M.; Avendaño, C., J. Org. Chem., 1997, 62, 6424.
(b) Martín-Santamaría, S.; Espada, M.; Avendaño, C., Tetrahedron, 1997, 53, 16795. (c) Sánchez, J. D.; Ramos, M.
T.; Avendaño, C., Tetrahedron, 1998, 54, 969. (d) Bartolomé, M. T.; Buenadicha, F. L.; Avendaño, C.; Söllhuber, M.,
Tetrahedron: Asymmetry, 1998, 9, 249. (e) Bartolomé, M. T.; Buenadicha, F. L.; Aguirre, M. J.; Avendaño, C.; Söllhuber,
M., Tetrahedron: Asymmetry, 1998, 9, 483. (f) Madrigal, A.; Grande, M.; Avendaño, C., J. Org. Chem., 1998, 63, 2724.
8. Caballero, E.; Avendaño, C.; Menéndez, J. C., Tetrahedron: Asymmetry, 1998, 9, 967.
9. Hino, T.; Nakagawa, M. In The Alkaloids, Vol. 34; Brossi, A., Ed.; Pergamon Press: Oxford, 1988; p. 1.
10. Crich, D.; Lim, B. L., Heterocycles, 1993, 36, 1199 and references therein.
11. Otherwise, they revert easily to the starting diketopiperazines.
12. Fukuyama, T.; Frank, R. K.; Laird, A. A., Tetrahedron Lett., 1985, 26, 2955.
13. Piperazine rings of compounds 10, 11, 15, 21 and 22 have been depicted as deformed boats with the C-7 alkyl group in a
pseudoaxial position in order to explain the NOEs between the C-7 alkyl groups and the H-15a proton. This conformation
partially relieves the strain due to compression between the C5_O, C7–alkyl and C8_O groups, although not as efficiently
as epimerization at the tryptophan stereocenter.
14. This behavior is similar to the one found by Rajappa and Advani for a similar reaction of cyclo-(L-Pro–L-Val), although
they do not give the actual yields of both stereoisomers. See Ref 6a.
15. Compounds 11 and 15 were initially recovered as a mixture with compounds 1c and 1f, respectively, arising from the
hydrolysis of the starting iminoethers. Their chromatographic separation was not possible, and therefore the mixture
was treated with triethyloxonium tetrafluoroborate to transform 1c and 1f into 9 and 14, respectively, which allowed
the purification of the hexacyclic compounds 11 and 15.