A chiral synthesis of the Strychnos and Ophiorrhiza alkaloid normalindine

Article abstract of DOI:10.1016/S0040-4020(00)00695-5

A full account of the first chiral synthesis of (-)-normalindine [(-)-4], an indolopyridonaphthyridine alkaloid isolated from Strychnos johnsonii and Ophiorrhiza filistipula, is presented. Central features of the synthetic strategy include the conversion of L-alanine methyl ester (13) into the oxazole derivative 12 and the intramolecular Diels-Alder reaction of the oxazole-olefin derivatives 27a and 30a. The correctness of the absolute configuration proposed for normalindine has been unambiguously confirmed by the present synthesis. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00695-5

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 7751±7761
A Chiral Synthesis of the Strychnos and Ophiorrhiza
Alkaloid Normalindine
*
Masashi Ohba, Hiroyuki Kubo and Hiroyuki Ishibashi
Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi, Kanazawa 920-0934, Japan
Received 13 July 2000; accepted 7 August 2000
AbstractÐA full account of the ®rst chiral synthesis of (2)-normalindine [(2)-4], an indolopyridonaphthyridine alkaloid isolated from
Strychnos johnsonii and Ophiorrhiza ®listipula, is presented. Central features of the synthetic strategy include the conversion of l-alanine
methyl ester (13) into the oxazole derivative 12 and the intramolecular Diels±Alder reaction of the oxazole±ole®n derivatives 27a and 30a.
The correctness of the absolute con®guration proposed for normalindine has been unambiguously con®rmed by the present synthesis.
q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
(2)-Normalindine (4) was reported for the ®rst time as one
of the 18 alkaloids isolated from the root bark of Strychnos
johnsonii (Loganiaceae) by Massiot et al. in 1987.2 The
structure and relative stereochemistry suggested on the
basis of its spectroscopic analysis were con®rmed via
racemic syntheses by two independent research groups.9
Thereafter, Arbain et al. also announced the isolation of
this alkaloid from the leaves of Ophiorrhiza ®listipula
(Rubiaceae) and proposed its absolute con®guration to be
(2)-4 by CD spectral evidence.3 In the present paper,
we describe the details of the ®rst chiral synthesis of
(2)-normalindine [(2)-4], which have veri®ed the correct-
ness of this proposal. A brief account of the results reported
here has been published in a preliminary form.10
The pentacyclic system 1 represents the parent framework
common to the indolo[20,30:3,4]pyrido[1,2-b][2,7]naphthy-
ridine alkaloids, which have been known to occur in the
genera, such as Strychnos, Nauclea, Camptotheca,
Mitragyna, Uncaria, Ophiorrhiza, and Anthocephalus.1±8
Although most of these alkaloids exist as lactams [e.g.
naucle®ne (2) and angustine (3)], some others including
normalindine (4),2,3 norisomalindine (5),2 cadamine (6),4
isocadamine (7),4 malindine (8),5,6 isomalindine (9),6,7 and
isomalindine-16-carboxylate (10)8 are characterized by a
stereogenic center at C(5).
Keywords: amino acids and derivatives; Diels±Alder reactions; naphthyr-
idines; oxazoles.
* Corresponding author. Tel.: 18-76-234-4475; fax: 18-76-234-1563;
e-mail: ohba@dbs.p.kanazawa-u.ac.jp
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00695-5

7752
M. Ohba et al. / Tetrahedron 56 (2000) 7751±7761
Scheme 1.
Results and Discussion
amine 19 with 2-(3-indolyl)ethyl bromide. In an attempt to
improve the ef®ciency of the conversion of 19 to 12, reduc-
tion of the amide 23, derived from 19 in 94% yield, was
tried under various conditions, but without satisfactory
results.
At the outset of the present synthesis, we planned to employ
the intramolecular oxazole±ole®n Diels±Alder reaction11,12
of 11 toward an ef®cient construction of the naphthyridine
skeleton of (2)-4 (Scheme 1). The requisite oxazole±ole®n
derivative 11 would be obtainable from 12 via the formation
of ring C and the subsequent introduction of an appropriate
ole®n moiety. In addition, our recent synthesis13 of chiral
5-(aminomethyl)oxazole derivatives from a-amino esters is
a reliable guide for the preparation of 12.
With the amino oxazole 12 in hand, we next turned our
attention to the construction of ring C in the intermediate
11. Condensation of 12 with monoethyl malonate using
diethyl phosphorocyanidate15 provided the amide 20 (98%
yield), which was then submitted to the Bischler±Napier-
alski cyclization with POCl3 in boiling CH3CN followed by
the NaBH4 reduction of the resulting iminium salt 24, giving
the amino esters 22a and 22b as a 2:1 diastereoisomeric
mixture in 31% yield from 20. In accordance with the inter-
pretation of Polniaszek,16 we postulated the hydrogen at
C(1) in the major isomer 22a as the a con®guration because
the hydride attack would prefer the sterically less hindered
iminium ion diastereoface of the conformer 24 with mini-
mized allylic 1,3-strain. On basi®cation with Na2CO3, the
iminium salt 24 was transformed to the (E)-ester 21 (46%
yield from 20), whose geometry of the exocyclic double
bond was assigned on the basis of the fact that the N(a)
proton resonated at d 13.05 (CDCl3) and the ester nCvO
The initial step was N-alkylation of l-alanine methyl ester
(13) with 2-(3-indolyl)ethyl bromide, reported by
Waldmann et al.,14 which was effected with a slight
modi®cation, giving 14 in 66% yield (Scheme 2). After
protection of 14 with di-tert-butyl dicarbonate, the resulting
N-Boc-a-amino ester 15 was converted into the oxazole 16
in 76% yield by treatment with a-lithiated methyl iso-
cyanide at 2788C according to our previous procedure.13
Deprotection of 16 with tri¯uoroacetic acid afforded the
desired amino oxazole 12 in 98% yield. Alternatively, 12
was also obtained from 1813 through deprotection (97%
yield) followed by direct N-alkylation (55%) of the primary
Scheme 2. Reagents and conditions: (a) 2-(3-indolyl)ethyl bromide, i-Pr2NEt, THF, re¯ux, 10 days for 13; 7 days for 19; (b) (Boc)2O, CHCl3, rt, 24 h;
(c) LiCH2NC, THF, 2788C, 6 h; (d) CF3CO2H, CH2Cl2, 08C, 2 h for 16; rt, 1 h for 18; (e) 1) HCuCCO2Et, CHCl3, rt, 40 h; 2) CF3CO2H, rt, 1 h;
(f) HO2CCH2CO2Et, (EtO)2P(O)CN, Et3N, DMF, rt, 2 h; (g) 1) POCl3, CH3CN, re¯ux, 4 h; 2) 10% aqueous Na2CO3; (h) 10% Pd±C, H2, AcOEt, rt, 5 h;
(i) 1) POCl3, CH3CN, re¯ux, 4 h; 2) NaBH4, MeOH, 08C, 1.5 h.

M. Ohba et al. / Tetrahedron 56 (2000) 7751±7761
7753
Scheme 3. Reagents and conditions: (a) 1) DIBALH, CH2Cl2, 2788C, 20 min; 2) Ph3PvCHCO2Et, rt, 3 h; (b) toluene, re¯ux, 24 h; (c) AcOH±xylene (1:5),
re¯ux, 8 h; (d) 1) LiOH, THF±MeOH±H2O, rt, 1.5 h; 2) (PhO)2P(O)N3, Et3N, tert-BuOH, re¯ux, 5 h; (e) 1) CF3CO2H, CH2Cl2, rt, 5 h; 2) BuONO, DMF,
708C, 30 min.
appeared at 1663 cm21 (CHCl3), suggesting the existence of
intramolecular hydrogen bonding between the NH and ester
carbonyl groups. Catalytic hydrogenation of 21 over Pd±C
in AcOEt was found to increase the diastereoselectivity of
22a and 22b to 3:1. On the other hand, the modi®ed Pictet±
Spengler cyclization17 of 12 by treatment with ethyl propio-
late followed by tri¯uoroacetic acid furnished a 1:2 mixture
of 22a and 22b in 78% yield. By analogy to an analysis
given by Waldmann et al.14 for related systems, we assumed
that this cyclization predominantly proceeded via the
preferred conformation 25 of the iminium intermediate.
aldehyde. However, when the DIBALH reduction of
22a,b followed by the Wittig reaction with ethyl (triphenyl-
phosphoranylidene)acetate was performed in a one-pot
procedure without isolating 26, a 3:1 mixture of the
(E)-esters 27a and 27b [Jˆ15.5 Hz (ole®nic protons)] and
a 3:1 mixture of the (Z)-esters 30a and 30b (Jˆ11.5 Hz)
were obtained in 59 and 26% overall yields from 22a,b,
respectively (Scheme 3).
Having succeeded in the syntheses of the oxazole±ole®n
derivatives 27a,b and 30a,b, we set out to explore their
intramolecular Diels±Alder reactions. The results are listed
in Table 1. The best result was obtained by heating the 3:1
mixture of the (E)-isomers 27a and 27b in boiling toluene
for 24 h: under these conditions, the adducts 28 and 29, both
embracing a con®guration for their C(13b)±H, were
produced in 53 and 5% yields, respectively. Addition of a
and Yb(OTf)3,18 failed to
12e,f
Lewis acid, such as Eu(fod)3
improve the yields of the adducts 28 and 29. Treatment of
27a,b in o-dichlorobenzene (o-DCB) at 1508C in the
presence of 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), an
application of Weinreb's procedure,12a±c resulted in a
retro-Michael reaction, providing the diene 35 in 53%
yield. In order to examine this reaction in further detail,
the adduct 28 was treated in boiling toluene for 24 h. Two
products obtained together with unaltered 28 (60%) were
the oxazole±ole®n derivative 27a (18% yield), produced via
a retro-Diels±Alder reaction, and another adduct 29 (6%),
suggesting that 27a came to equilibrium with the adducts 28
and 29 after 24 h under the conditions employed and no
epimerization between 27a and 27b occurred. In a similar
fashion, the 3:1 mixture of the (Z)-isomers 30a and 30b
afforded the adduct 31 in 40% yield. None of adducts arising
With a view to introducing an ole®nic dienophile into the
amino esters 22a,b, the above 3:1 mixture was treated with
diisobutylaluminum hydride (DIBALH) at 2788C in
CH2Cl2. Initial attempts to execute methylenation of the
aldehyde 26, assumed to be prepared, leading to the ole®n
11 (RˆH) proved fruitless because of the lability of the

7754
M. Ohba et al. / Tetrahedron 56 (2000) 7751±7761
Table 1. Intramolecular oxazole±ole®n Diels±Alder reaction of the (E)-isomers 27a,b (a 3:1 mixture of 27a and 27b was used)
Entry
Solvent
Additive (mol %)
Temp (8C)
Time (h)
Yield (%)a
28
29
1
2
3
4
5
6
7
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
o-DBC
±
±
±
±
80
17
17
24
36
17
24
24
25
40
53
53
38
48
20
±
4
5
5
5
4
6
Re¯ux
Re¯ux
Re¯ux
Re¯ux
Re¯ux
150
Eu(fod)3 (7)
Yb(OTf)3 (10)
±
a Isolated yield based on the mixture of 27a and 27b after puri®cation by ¯ash chromatography.
from the minor diastereoisomers 27b and 30b were
obtained. The stereochemistries of 28, 29, and 31 were
determined by the appearance of absorption bands assign-
able to a trans-quinolizidine ring19 in their IR spectra and
the results of detailed NOE experiments shown in Fig. 1.
trum of 36 in CDCl3 displayed two pyridine ring proton
signals at d 8.20 and 8.53 and a C(12b)±H signal at d
5.20, the latter of which is comparable to the corresponding
1
signal (d 5.03) of 38.20 On the other hand, the H NMR
spectrum of 37 showed newly the signals arising from the
C(4)-ethyl group with disappearance of the signal at d 8.20
on that of 36. The formations of 36 and 37 may be presumed
to proceed through the aziridinium ion 40 derived from the
tertiary alcohol 39 as depicted in Scheme 4.
Conversion of three adducts 28, 29, and 31 into pyridine
derivatives was next investigated. On treatment with DBN
in boiling toluene for 10 h,12a±c the adduct 28 gave 27a (10%
yield) and 35 (25%) via retro-Diels±Alder reaction and
subsequent retro-Michael reaction, respectively, together
with recovered 28 (38%), but no product possessing the
desired skeleton was obtained. However, the C(2)±O bond
cleavage of 28 was found to be ready upon exposure to
AcOH at room temperature for 1 h, affording the diol 32
in 77% yield with concomitant addition of H2O to the imino
group. The desired naphthyridine ester 33 was eventually
obtained in 18% yield along with the diol 32 (64% yield) by
heating 28 in boiling AcOH±xylene (1:5) for 8 h. Similar
treatment of 32 provided 33 in 13% yield, accompanied by
recovered 32 (62%). Under these conditions, the adduct 31
gave the results analogous to those obtained from 28,
whereas 29 exhibited unpredictable behavior. The adduct
29 disappeared within 1 h on treatment in boiling AcOH±
xylene (1:2), and two compounds 36 and 37 containing a
pyrrolo[2,3-c]pyridine skeleton were obtained in 46 and
44% yields, respectively. The structures 36 and 37 were
assigned on the basis of their spectral properties in conjunc-
tion with their elemental analyses. Thus, the 1H NMR spec-
Alkaline hydrolysis of 33 with LiOH followed by the
modi®ed Curtius rearrangement using diphenyl phosphoro-
azidate21 furnished the carbamate 34 in 64% yield. Finally,
conversion of 34 into the target compound (2)-4 was
achieved in 40% yield by treatment with CF3CO2H and
subsequent reductive deamination of the resulting arylamine
with butyl nitrite in DMF.22 The synthetic (2)-4 [mp 122±
1268C, [a]2D2ˆ22128 (c 0.29, CHCl3)] proved to be virtually
identical with a natural sample of normalindine [mp 131±
1368C, [a]Dˆ22108 (c 0.1, CHCl3)]3 by comparison of the
UV, IR, 1H NMR, and mass spectra and TLC mobility (three
solvent systems).
Figure 1. NOE data of the adducts 28, 29 and 31.

M. Ohba et al. / Tetrahedron 56 (2000) 7751±7761
7755
Scheme 4.
In conclusion, the ®rst chiral synthesis of the Strychnos and
Ophiorrhiza alkaloid normalindine has been accomplished
via the intramolecular Diels±Alder reaction of the chiral
oxazole±ole®n derivatives 27a and 30a. The present results
have not only unequivocally established the absolute con-
®guration of normalindine to be (5S,13bS)-form on the basis
of l-alanine methyl ester (13) employed as a starting
material, but also suggest that the intramolecular oxazole±
ole®n Diels±Alder reaction would be applicable to the
synthesis of various bicyclic systems comprising a pyridine
skeleton.
were combined, washed successively with H2O and satu-
rated aqueous NaCl, dried, and concentrated to leave an
orange oil. Puri®cation by ¯ash chromatography (AcOEt)
afforded 14 (6.27 g, 66%) as a slightly yellow oil,
[a]2D4ˆ223.18 (c 1.01, CHCl3); IR n
cm21: 3480
CHCl3
max
1
(NH), 1732 (ester CO). The H NMR (CDCl3) spectral
data for this sample were in agreement with those reported
in the literature.14
N-(tert-Butoxycarbonyl)-N-[2-(1H-indol-3-yl)ethyl]-l-
alanine methyl ester (15). A mixture of 14 (41.4 g,
0.168 mol) and di-tert-butyl dicarbonate (40.3 g,
0.185 mol) in CHCl3 (300 ml) was stirred at room tempera-
ture for 24 h. The reaction mixture was concentrated in
vacuo, and the residual solid was recrystallized from
MeOH, giving a ®rst crop (46.9 g) of 15. Concentration of
the mother liquor and recrystallization of the residue from
MeOH afforded a second crop (5.04 g) of 15. A further crop
(2.94 g) was obtained by concentration of the mother liquor
of the second recrystallization and subsequent puri®cation
of the residue by ¯ash chromatography [hexane±AcOEt
(2:1)]. Total yield of 15 was 54.88 g (94%). Further recrys-
tallization from MeOH provided an analytical sample as
Experimental
General method
All melting points were determined on a BuÈchi model 530
capillary melting point apparatus and are corrected. Flash
chromatography23 was carried out by using Merck silica gel
60 (No. 9385). Unless otherwise noted, the organic solutions
obtained after extraction were dried over anhydrous MgSO4
and concentrated under reduced pressure. The ratios of
solvents in mixtures are shown in v/v. Spectra reported
herein were recorded on a JEOL JMS-SX102A mass
colorless prisms, mp 136.5±1378C; [a]2D1ˆ221.78 (c 1.01,
CHCl3); MS m/z: 346 (M1); IR n
cm21: 3315 (NH),
Nujol
max
1
1746 (ester CO), 1674 (carbamate CO); H NMR (CDCl3)
d: 1.42 and 1.44 (3H, d each, Jˆ6.8 Hz, CHMe), 1.46 and
1.49 (9H, s each, tert-Bu), 2.9±3.7 (4H, m, two CH2's), 3.71
(3H, s, OMe), 4.11 and 4.60 (1H, q each, Jˆ6.8 Hz, CHMe),
7.01 and 7.04 [1H, br s each, C(2)±H], 7.12 and 7.19 [1H
each, dd, Jˆ7, 7 Hz, C(5)±H and C(6)±H], 7.36 (1H, d,
Jˆ7 Hz) and 7.62 and 7.66 (1H, d each, Jˆ7 Hz) [C(4)±
H and C(7)±H], 8.02 (1H, s, NH). Anal. Calcd for
C19H26N2O4: C, 65.88; H, 7.56; N, 8.09. Found: C, 65.87;
H, 7.57; N, 8.01.
spectrometer,
a
Shimadzu FTIR-8100 IR spectro-
photometer, and either a JEOL JNM-GSX-500 (1H
500 MHz, 13C 125 MHz) or a JEOL JNM-EX-270 (1H
270 MHz, 13C 67.8 MHz) NMR spectrometer. Chemical
shifts are reported in d values relative to internal Me4Si.
Optical rotations were measured with a Horiba SEPA-300
polarimeter using a 1-dm sample tube. Elemental analyses
and MS measurements were performed by Dr M. Takani
and co-workers at Kanazawa University.
N-[2-(1H-Indol-3-yl)ethyl]-l-alanine methyl ester (14). A
solution of 2-(3-indolyl)ethyl bromide24 (8.66 g, 38.6
mmol), l-alanine methyl ester (13) (7.17 g, 69.5 mmol),
and N-ethyldiisopropylamine (5.00 g, 38.7 mmol) in THF
(100 ml) was heated under re¯ux in an atmosphere of N2
for 10 days. After cooling, the precipitate that resulted was
®ltered off and washed with ether. The ®ltrate and washings
(S)-[2-(1H-Indol-3-yl)ethyl][1-(5-oxazoyl)ethyl]carbamic
acid tert-butyl ester (16). A solution of methyl isocyanide
(16.4 g, 0.40 mol) in THF (400 ml) was cooled to 2788C in
an atmosphere of N2, and a 1.6 M solution (250 ml,
0.40 mol) of BuLi in hexane was added dropwise over
1.5 h. After the mixture had been stirred for 30 min, a

7756
M. Ohba et al. / Tetrahedron 56 (2000) 7751±7761
solution of 15 (27.7 g, 80.0 mmol) in THF (230 ml) was
introduced dropwise over 30 min. Stirring was then con-
tinued at 2788C for 6 h. The reaction was quenched by
adding AcOH (23 ml), and the mixture was brought to
room temperature during 30 min. After concentration of
the mixture, the residue was partitioned between H2O and
ether. The ethereal extracts were washed with saturated
aqueous NaCl, dried, and concentrated to leave a yellow
oil. Puri®cation by ¯ash chromatography [AcOEt±hexane
(1:1)] furnished 16 (21.6 g, 76%) as a colorless solid.
Recrystallization from AcOEt±hexane (1:1) gave an
concentrated in vacuo. Puri®cation of the residual oil by
¯ash chromatography [AcOEt±EtOH (5:1)] afforded 12
(3.17 g, 55%) as a pale yellow oil. This sample was identical
(by comparison of the IR and 1H NMR spectra, TLC
mobility, and speci®c rotation) with the one obtained by
method-(i).
(S)-N-[1-(5-Oxazoyl)ethyl]-1H-indole-3-acetamide (23).
A stirred mixture of 19 (252 mg, 2.25 mmol), indole-3-
acetic acid (473 mg, 2.7 mmol), and diethyl phosphoro-
cyanidate (734 mg, 4.5 mmol) in DMF (6 ml) was cooled
to 08C, and a solution of Et3N (401 mg, 4.0 mmol) in DMF
(1 ml) was added. After having been stirred at 08C for
30 min and at room temperature for 2 h, the reaction
mixture was diluted with H2O (20 ml) and extracted with
CHCl3. The CHCl3 extracts were washed successively with
saturated aqueous NaHCO3 and saturated aqueous NaCl,
dried over anhydrous Na2SO4, and concentrated. Puri®-
cation of the residual oil by ¯ash chromatography
[acetone±hexane (1:2)] gave 23 (569 mg, 94%) as a slightly
yellow solid. Recrystallization from AcOEt±hexane (1:1)
provided an analytical sample as colorless needles, mp
analytical sample as colorless prisms, mp 116±1178C;
Nujol
[a]1D7ˆ229.28 (c 1.00, CHCl3); MS m/z: 355 (M1); IR n
max
cm21: 3225 (NH), 1682 (carbamate CO); 1H NMR (CDCl3)
d: 1.50 (3H, d, Jˆ7.3 Hz, CHMe), 1.53 (9H, s, tert-Bu),
2.75±3.45 (4H, m, two CH2's), 5.22 and 5.60 (1H, br
each, CHMe), 6.90 and 6.95 [2H, br each, C(2)±H and
C(40)±H], 7.10 and 7.18 [1H each, dd, Jˆ7.5, 7.5 Hz,
C(5)±H and C(6)±H], 7.34 (1H, d, Jˆ7.5 Hz) and 7.53
(1H, br) [C(4)±H and C(7)±H], 7.81 [1H, s, C(20)±H],
8.00 (1H, s, NH).25 Anal. Calcd for C20H25N3O3: C, 67.58;
H, 7.09; N, 11.82. Found: C, 67.50; H, 7.17; N, 11.74.
118.5±119.58C; [a]2D5ˆ267.58 (c 0.99, MeOH); MS m/z:
(S)-a-Methyl-5-oxazolemethanamine (19). A solution of
1813 (850 mg, 4.0 mmol) in CH2Cl2 (12 ml) was cooled to
08C, and CF3CO2H (12 ml) was added. After stirring at
room temperature for 1 h, the reaction mixture was concen-
trated in vacuo. The residual pale yellow oil was dissolved
in a small amount of H2O, made basic with K2CO3, and
extracted with CH2Cl2. The CH2Cl2 extracts were dried
over anhydrous K2CO3 and concentrated to leave 19
269 (M1); IR n
cm21: 3435, 3300 (NH), 1624 (amide
Nujol
max
1
CO); H NMR (CDCl3) d: 1.35 (3H, d, Jˆ7 Hz, Me), 3.77
(2H, s, CH2CO), 5.33 (1H, dq, Jˆ8.5, 7 Hz, CHMe), 5.88
(1H, d, Jˆ8.5 Hz, NHCO), 6.73 [1H, s, C(40)±H], 7.14 [1H,
s, C(2)±H], 7.14 and 7.24 [1H each, dd, Jˆ7.5, 7.5 Hz,
C(5)±H and C(6)±H], 7.40 and 7.52 [1H each, d, Jˆ
7.5 Hz, C(4)±H and C(7)±H], 7.69 [1H, s, C(20)±H], 8.36
[1H, s, N(1)±H].25 Anal. Calcd for C15H15N3O2: C, 66.90;
H, 5.61; N, 15.60. Found: C, 66.93; H, 5.55; N, 15.67.
(436 mg, 97%) as a slightly yellow oil, [a]2D8ˆ213.08 (c
1.01, MeOH); CIMS m/z: 113 (MH1); IR n
cm21
:
®lm
max
3360, 3295 (NH2); 1H NMR (CDCl3) d: 1.46 (3H, d,
Jˆ6.8 Hz, Me), 1.70 (2H, s, NH2), 4.17 (1H, q, Jˆ6.8 Hz,
CHMe), 6.87 [1H, s, C(4)±H], 7.80 [1H, s, C(2)±H].
(S)-3-[[2-(1H-Indol-3-yl)ethyl][1-(5-oxazoyl)ethyl]amino]-
3-oxopropanoic acid ethyl ester (20). Diethyl phosphoro-
cyanidate (4.05 g, 24.8 mmol) and Et3N (2.51 g,
24.8 mmol) were successively added to a chilled, stirred
solution of 12 (3.17 g, 12.4 mmol) and monoethyl malonate
(2.46 g, 18.6 mmol) in DMF (100 ml). The mixture was
stirred at room temperature for 2 h and concentrated in
vacuo. The residue was partitioned between H2O and
CHCl3, and the CHCl3 extracts were washed successively
with saturated aqueous NaHCO3 and saturated aqueous
NaCl, dried, and concentrated. Puri®cation of the residual
oil by ¯ash chromatography (AcOEt) furnished 20 (4.50 g,
(S)-N-[1-(5-Oxazoyl)ethyl]-1H-indole-3-ethanamine (12).
(i) From 16: A mixture of 16 (1.21 g, 3.4 mmol),
CF3CO2H (5 ml), and CH2Cl2 (5 ml) was stirred at 08C for
2 h. The reaction mixture was then concentrated in vacuo,
and the residue was dissolved in H2O (20 ml). The aqueous
solution was made basic with K2CO3 and extracted with
CHCl3. The CHCl3 extracts were dried over anhydrous
K2CO3 and concentrated to leave a yellow oil, which was
puri®ed by ¯ash chromatography [AcOEt±EtOH (5:1)] to
98%) as a slightly yellowish oil, [a]2D8ˆ238.88 (c 1.00,
give 12 (855 mg, 98%) as a pale yellow oil, [a]2D2ˆ239.58
CHCl3); MS m/z: 369 (M1); IR n
cm21: 3480 (NH),
CHCl3
max
CHCl3
max
1
(c 1.00, CHCl3); MS m/z: 255 (M1); IR n
cm21: 3480
1736 (ester CO), 1646 (amide CO); H NMR (CDCl3) d:
1.27 (2H) and 1.33 (1H) (t each, Jˆ7 Hz, CH2Me), 1.60
(3H, d, Jˆ6.8 Hz, CHMe), 2.64 (2/3H), 2.75 (1/3H), 2.84
(2/3H), and 2.98 (1/3H) (ddd each, Jˆ13.5, 11, 5.5 Hz,
CH2CH2N), 3.40 and 3.42 (2/3H each, AB type d's,
Jˆ15.5 Hz) and 3.63 and 3.72 (1/3H each, AB type d's,
Jˆ15.5 Hz) (CH2CO), 3.3±3.5 (2H, m, CH2CH2N), 4.20
(4/3H) and 4.27 (2/3H) (q each, Jˆ7 Hz, CH2Me), 5.10
(1/3H) and 5.99 (2/3H) (br q each, Jˆ6.8 Hz, CHMe),
6.91 (2/3H) and 6.95 (1/3H) [d each, Jˆ2 Hz, C(2)±H],
7.00 (1/3H) and 7.09 (2/3H) [d each, Jˆ1 Hz, C(40)±H],
7.10 (1/3H), 7.13 (2/3H), 7.17 (1/3H), and 7.20 (2/3H)
[dd each, Jˆ8, 8 Hz, C(5)±H and C(6)±H], 7.33 (1/3H),
7.37 (2/3H), 7.44 (2/3H), and 7.59 (1/3H) [d each,
Jˆ8 Hz, C(4)±H and C(7)±H], 7.82 (1/3H) and 7.87
(2/3H) [s each, C(20)±H], 8.04 (1/3H) and 8.16 (2/3H)
1
(NH); H NMR (CDCl3) d: 1.40 (3H, d, Jˆ6.8 Hz, Me),
1.59 (1H, br, CH2NH), 2.85±3.0 (4H, m, two CH2's), 3.95
(1H, q, Jˆ6.8 Hz, CHMe), 6.85 [1H, s, C(40)±H], 7.01 [1H,
d, Jˆ2.5 Hz, C(2)±H], 7.10 and 7.19 [1H each, dd, Jˆ7.5,
7.5 Hz, C(5)±H and C(6)±H], 7.36 and 7.56 [1H each, d,
Jˆ7.5 Hz, C(4)±H and C(7)±H], 7.73 [1H, s, C(20)±H],
8.06 [1H, s, N(1)±H];25 HRMS m/z calcd for C15H17N3O:
255.1371, found: 255.1390.
(ii) From 19: A mixture of 19 (2.54 g, 22.7 mmol), 2-(3-
indolyl)ethyl bromide24 (5.09, 22.7 mmol), N-ethyldiiso-
propylamine (2.93 g, 22.7 mmol), and THF (50 ml) was
heated under re¯ux in an atmosphere of N2 for 7 days.
The reaction mixture was diluted with ether, washed with
saturated aqueous NaCl, dried over anhydrous K2CO3, and

M. Ohba et al. / Tetrahedron 56 (2000) 7751±7761
7757
(s each, NH);25 HRMS m/z calcd for C20H23N3O4: 369.1689,
found: 369.1693.
(1 ml), the reaction mixture was concentrated in vacuo,
and the residue was partitioned between CHCl3 and H2O.
The CHCl3 extracts were washed with saturated aqueous
NaCl, dried, and concentrated. Puri®cation of the residual
oil by ¯ash chromatography [AcOEt±hexane (4:1)] yielded
a 2:1 mixture26 (30 mg, 31% from 20) of 22a and 22b.
[S-(E)]-[2,3,4,9-Tetrahydro-2-[1-(5-oxazoyl)ethyl]-1H-
pyrido[3,4-b]indol-1-ylidene]acetic acid ethyl ester (21).
A mixture of 20 (443 mg, 1.2 mmol), POCl3 (1.84 g,
12 mmol), and CH3CN (10 ml) was heated under re¯ux
for 4 h. After cooling, the solvent and excess POCl3 were
distilled off in vacuo. The residual oil, after washing with
hexane, was dissolved in CHCl3, and the CHCl3 solution
was poured into 10% aqueous Na2CO3 (10 ml). The aqueous
layer was separated from the organic layer and extracted
with CH2Cl2. The CH2Cl2 extracts and the above organic
layer were combined, washed successively with 10%
aqueous Na2CO3 and saturated aqueous NaCl, dried over
anhydrous K2CO3, and concentrated. Puri®cation of the
residual oil by ¯ash chromatography [AcOEt±hexane
(1:1)] provided 21 (192 mg, 46%) as a pale yellow oil,
(iii) Via the modi®ed Pictet±Spengler reaction of 12: A
solution of 12 (682 mg, 2.67 mmol) and ethyl propiolate
(288 mg, 2.9 mmol) in CHCl3 (10 ml) was stirred at room
temperature for 40 h. After addition of tri¯uoroacetic acid
(0.52 ml, 6.7 mmol), stirring was continued for a further 1 h.
The reaction mixture was concentrated in vacuo, and the
residue was partitioned between CHCl3 and 10% aqueous
Na2CO3. The CHCl3 extracts were washed with saturated
aqueous NaCl, dried, and concentrated to leave a yellow oil.
Puri®cation by ¯ash chromatography (AcOEt) gave a 1:2
mixture26 (736 mg, 78%) of 22a and 22b.
[a]2D8ˆ224.08 (c 0.50, CHCl3); MS m/z: 351 (M1); IR
CHCl3
max
n
cm21: 3200 (NH), 1663 (ester CO); 1H NMR
[S-[Rp,Rp-(E)]]- and [R-[Rp,Sp-(E)]]-4-[2,3,4,9-Tetrahydro-
2-[1-(5-oxazoyl)ethyl]-1H-pyrido[3,4-b]indol-1-yl]-2-
butenoic acid ethyl ester (27a and 27b) and [S-[Rp,Rp-
(Z)]]- and [R-[Rp,Sp-(Z)]]-4-[2,3,4,9-tetrahydro-2-[1-(5-
oxazoyl)ethyl]-1H-pyrido[3,4-b]indol-1-yl]-2-butenoic
acid ethyl ester (30a and 30b). A stirred solution of a 3:1
mixture (1.55 g, 4.39 mmol) of 22a and 22b in CH2Cl2
(40 ml) was cooled to 2788C in an atmosphere of N2, and
a 0.98 M solution (8.9 ml, 8.7 mmol) of DIBALH in hexane
was added dropwise over 5 min. After the mixture had been
stirred at 2788C for 20 min, the reaction was quenched by
adding MeOH (4 ml). Stirring was continued for a further
20 min, and a solution of ethyl (triphenylphosphoranyl-
idene)acetate (1.68 g, 4.8 mmol) in CH2Cl2 (30 ml) was
added. After having been brought to room temperature
during 1.5 h and stirred for 3 h, the reaction mixture was
washed successively with saturated aqueous NaHCO3 and
saturated aqueous NaCl, dried over anhydrous K2CO3, and
concentrated to leave a brown oil, which was then subjected
to ¯ash chromatography [AcOEt±hexane (2:1)]. Earlier
(CDCl3) d: 1.33 (3H, t, Jˆ7 Hz, CH2Me), 1.65 (3H, d,
Jˆ6.8 Hz, CHMe), 2.86 [2H, dd, Jˆ6.5, 6.5 Hz, C(4)±
H's], 3.24 and 3.44 [1H each, ddd, Jˆ12, 6.5, 6.5 Hz,
C(3)±H's], 4.21 (2H, q, Jˆ7 Hz, CH2Me), 5.17 (1H, s,
CHCO2Et), 5.33 (1H, q, Jˆ6.8 Hz, CHMe), 7.07 [1H, s,
C(40)±H], 7.09 and 7.26 [1H each, dd, Jˆ8, 8 Hz, C(6)±H
and C(7)±H], 7.47 and 7.52 [1H each, d, Jˆ8 Hz, C(5)±H
and C(8)±H], 7.87 [1H, s, C(20)±H], 13.05 (1H, s, NH);25
HRMS m/z calcd for C20H21N3O3: 351.1583, found:
351.1592.
[S-(Rp,Rp)]- and [R-(Rp,Sp)]-2,3,4,9-Tetrahydro-2-[1-(5-
oxazoyl)ethyl]-1H-pyrido[3,4-b]indole-1-acetic acid ethyl
ester (22a and 22b). (i) Via catalytic hydrogenation of
21: A solution of 21 (2.96 g, 8.42 mmol) in AcOEt
(150 ml) was hydrogenated over 10% Pd±C (3.0 g) at
room temperature and atmospheric pressure for 5 h. The
catalyst was removed by ®ltration, and the ®ltrate was
concentrated in vacuo to leave a pale yellow oil. Puri®cation
by ¯ash chromatography (AcOEt) afforded a 3:1 mixture26
fractions furnished a 3:1 mixture26 (426 mg, 26%) of 30a
CHCl3
max
(2.76 g, 93%) of 22a and 22b as a pale yellow oil, MS m/z:
and 30b as a pale yellow glass, MS m/z: 379 (M1); IR n
353 (M1); IR n
cm21: 3450 (NH), 1717 (ester CO); 1H
cm21: 3470 (NH), 1705 (ester CO); H NMR (CDCl3) d:
CHCl3
max
1
NMR (CDCl3) d: 1.25 (9/4H) and 1.28 (3/4H) (t each,
Jˆ7 Hz, CH2Me), 1.45 (3/4H) and 1.48 (9/4H) (d each,
Jˆ6.8 Hz, CHMe), 2.5±3.35 [6H, m, C(3)±H's, C(4)±H's,
and CH2CO2Et], 4.1±4.25 (3H, m, CHMe and CH2Me),
4.28 (3/4H, dd, Jˆ8.8, 5 Hz) and 4.46 (1/4H, dd, Jˆ8.8,
3.5 Hz) [C(1)±H], 6.89 (3/4H) and 6.93 (1/4H) [s each,
C(40)±H], 7.08 and 7.15 [1H each, dd, Jˆ7.5, 7.5 Hz,
C(6)±H and C(7)±H], 7.30 (3/4H) and 7.31 (1/4H) (d
each, Jˆ7.5 Hz) and 7.466 (1/4H) and 7.474 (3/4H) (d
each, Jˆ7.5 Hz) [C(5)±H and C(8)±H], 7.77 (3/4H) and
7.81 (1/4H) [s each, C(20)±H], 8.47 (3/4H) and 8.50
(1/4H) (s, NH);25 HRMS m/z calcd for C20H23N3O3:
353.1739, found: 353.1746.
1.27 (9/4H) and 1.29 (3/4H) (t each, Jˆ7 Hz, CH2Me), 1.46
(9/4H) and 1.47 (3/4H) (d each, Jˆ6.8 Hz, CHMe), 2.5±2.8
and 3.0±3.4 [6H, m each, C(1)-CH2, C(3)±H's, and C(4)±
H's], 4.06 (3/4H, dd, Jˆ7, 3.5 Hz) and 4.1±4.2 (1/4H, m)
[C(1)±H], 4.16 (3/2H) and 4.20 (1/2H) (q each, Jˆ7 Hz,
CH2Me), 4.24 (3/4H) and 4.32 (1/4H) (q each, Jˆ6.8 Hz,
CHMe), 5.77 (1/4H) and 5.78 (3/4H) (d each, Jˆ11.5 Hz,
CHˆCHCO2Et), 6.34 (1/4H) and 6.44 (3/4H) (dt each,
Jˆ11.5, 8 Hz, CHvCHCO2Et), 6.88 (3/4H) and 6.93
(1/4H) [s each, C(40)±H], 7.07 (1/4H), 7.08 (3/4H), 7.12
(1/4H), and 7.14 (3/4H) [dd each, Jˆ7.5, 7.5 Hz, C(6)±H
and C(7)±H], 7.30 (1/4H), 7.31 (3/4H), 7.45 (1/4H), and
7.46 (3/4H) [d each, Jˆ7.5 Hz, C(5)±H and C(8)±H],
7.79 (3/4H) and 7.82 (1/4H) [s each, C(20)±H], 8.30 (1H,
s, NH);25 HRMS m/z calcd for C22H25N3O3: 379.1896,
found: 379.1895.
(ii) Via reduction of the iminium salt 24: The iminium salt
24, prepared from 20 (100 mg, 0.27 mmol) in a manner
similar to that described above for 21 without treatment
with 10% aqueous Na2CO3, was dissolved in MeOH
(4 ml). NaBH4 (40 mg, 1.1 mmol) was added to the
MeOH solution under ice-cooling, and the mixture was
then stirred at 08C for 1.5 h. After addition of acetone
Later fractions in the above chromatography gave a 3:1
mixture26 (990 mg, 59%) of 27a and 27b as a pale yellow
glass, MS m/z: 379 (M1); IR n
(ester CO); H NMR (CDCl3) d: 1.26 (3/4H) and 1.29
cm21: 3470 (NH), 1709
CHCl3
max
1

7758
M. Ohba et al. / Tetrahedron 56 (2000) 7751±7761
(9/4H) (t each, Jˆ7 Hz, CH2Me), 1.41 (3/4H) and 1.48
(9/4H) (d each, Jˆ6.8 Hz, CHMe), 2.55±2.9 and 3.15±3.3
[6H, m each, C(1)±CH2, C(3)±H's, and C(4)±H's], 3.87
(3/4H) and 4.05 (1/4H) [t each, Jˆ6.5 Hz, C(1)±H], 4.08±
4.22 (3H, m, CHMe and CH2Me), 5.80 (3/4H) and 5.85
(1/4H) (d each, Jˆ15.5 Hz, CHvCHCO2Et), 6.84 (3/4H)
and 6.91 (1/4H) [s each, C(40)±H], 6.90 (1/4H) and 6.95
(3/4H) (dt each, Jˆ15.5, 7.5 Hz, CHvCHCO2Et), 7.08
(1/4H), 7.09 (3/4H), 7.14 (1/4H), and 7.15 (3/4H) [dd
each, Jˆ7.5, 7.5 Hz, C(6)±H and C(7)±H], 7.28 (1H),
7.46 (1/4H), and 7.48 (3/4H) [d each, Jˆ7.5 Hz, C(5)±H
and C(8)±H], 7.77 (3/4H) and 7.81 (1/4H) [s each, C(20)±
H], 8.14 (1/4H) and 8.23 (3/4H) (s each, NH);25 HRMS m/z
calcd for C22H25N3O3: 379.1896, found: 379.1909.
Jˆ15.5, 10.5, 5.5, 2 Hz) [C(8)±H's], 2.83 [1H, dd, Jˆ4,
3.5 Hz, C(1)±H], 3.30 [1H, q, Jˆ6.5 Hz, C(5)±H], 3.60
[1H, ddd, Jˆ12, 2, 1 Hz, C(13b)±H], 4.13 and 4.17 (1H
each, dq, Jˆ11, 7 Hz, CH2Me), 6.12 [1H, d, Jˆ4 Hz,
C(2)±H], 7.09 and 7.14 [1H each, dd, Jˆ7.5, 7.5 Hz,
C(10)±H and C(11)±H], 7.30 and 7.48 [1H each, d,
Jˆ7.5 Hz, C(9)±H and C(12)±H], 7.67 (1H, s, NH), 7.91
[1H, s, C(4)±H]; 13C NMR (CDCl3) d: 14.2 (q), 16.8 (q),
21.9 (t), 34.1 (t), 34.8 (d), 46.5 (t), 52.7 (d), 56.1 (d), 58.4
(d), 61.3 (t), 91.5 (s), 95.4 (d), 109.2 (s), 110.8 (d), 118.3 (d),
119.5 (d), 121.6 (d), 127.2 (s), 133.6 (s), 136.2 (s), 169.9 (s),
171.4 (d). Anal. Calcd for C22H25N3O3: C, 69.64; H, 6.64; N,
11.07. Found: C, 69.62; H, 6.63; N, 10.93.
[1S-(1a,2a,4aa,5a,13bb,14ab)]-1,2,7,8,13,13b,14,14a-
Octahydro-5-methyl-5H-2,4a-epoxyindolo[20,30:3,4]-
pyrido[1,2-b][2,7]naphthyridine-1-carboxylic acid ethyl
ester (31). A solution of a 3:1 mixture (100 mg,
0.26 mmol) of 30a and 30b in toluene (10 ml) was heated
under re¯ux in an atmosphere of N2 for 24 h. The reaction
mixture was concentrated in vacuo to leave a brown glass,
which was subjected to ¯ash chromatography (AcOEt).
From earlier fractions, a mixture of 30a and 30b was
recovered (42 mg, 42%). Later fractions furnished 31
(40 mg, 40%) as a pale brown solid. Recrystallization
from AcOEt gave an analytical sample as colorless minute
[1R-(1a,2b,4ab,5b,13ba,14aa)]- and [1R-(1a,2a,4aa,
5b,13ba,14aa)]-1,2,7,8,13,13b,14,14a-Octahydro-5-methyl-
5H-2,4a-epoxyindolo[20,30:3,4]pyrido[1,2-b][2,7]naphthyri-
dine-1-carboxylic acid ethyl ester (28 and 29). (Entry 3 in
Table 1.) A solution of a 3:1 mixture (650 mg, 1.71 mmol)
of 27a and 27b in toluene (65 ml) was heated under re¯ux in
an atmosphere of N2 for 24 h. The reaction mixture was
concentrated in vacuo to leave a brown glass, which was
puri®ed by ¯ash chromatography [AcOEt±hexane (1:1) and
then AcOEt]. The ®rst fractions to elute afforded 29 (31 mg,
5%) as a pale brown solid. Recrystallization from EtOH
gave an analytical sample as colorless needles, mp 181±
needles, mp 208±2108C (dec); [a]2D5ˆ24.38 (c 0.50,
CHCl3
max
1828C (dec); [a]2D0ˆ252.38 (c 0.51, CHCl3); MS m/z: 379
CHCl3); MS m/z: 379 (M1); IR n
cm21: 3470 (NH),
(M1); IR n
cm21: 3475 (NH), 2835, 2810, 2735 (trans-
2850, 2805 (trans-quinolizidine ring19), 1724 (ester CO); 1H
NMR (CDCl3) d: 1.25 (3H, t, Jˆ7 Hz, CH2Me), 1.40 [3H, d,
Jˆ6.5 Hz, C(5)-Me], 1.51 (1H, ddd, Jˆ12, 12, 12 Hz) and
2.21 (1H, ddd, Jˆ12, 6, 1 Hz) [C(14)±H's], 2.08 [1H, ddd,
Jˆ12, 8, 6 Hz, C(14a)±H], 2.44 (1H, ddd, Jˆ11, 10.5, 4 Hz)
and 3.46 (1H, ddd, Jˆ11, 5.5, 2.5 Hz) [C(7)±H's], 2.62 [1H,
d, Jˆ8 Hz, C(1)±H], 2.75 (1H, ddd, Jˆ15.5, 4, 2.5 Hz) and
2.94 (1H, dddd, Jˆ15.5, 10.5, 5.5, 2 Hz) [C(8)±H's], 3.29
[1H, q, Jˆ6.5 Hz, C(5)±H], 3.57 [1H, ddd, Jˆ12, 2, 1 Hz,
C(13b)±H], 4.11 and 4.21 (1H each, dq, Jˆ10.7, 7 Hz,
CH2Me), 6.20 [1H, s, C(2)±H], 7.09 and 7.14 [1H each,
dd, Jˆ7.5, 7.5 Hz, C(10)±H and C(11)±H], 7.30 and 7.48
[1H each, d, Jˆ7.5 Hz, C(9)±H and C(12)±H], 7.69 (1H, s,
NH), 7.80 [1H, s, C(4)±H]; 13C NMR (CDCl3) d: 14.3 (q),
16.6 (q), 21.9 (t), 30.4 (t), 34.5 (d), 46.3 (t), 48.3 (d), 56.0
(d), 58.3 (d), 61.2 (t), 89.3 (s), 96.0 (d), 109.3 (s), 110.8 (d),
118.3 (d), 119.5 (d), 121.6 (d), 127.2 (s), 133.6 (s), 136.2 (s),
170.6 (s), 170.6 (d). Anal. Calcd for C22H25N3O3: C, 69.64;
H, 6.64; N, 11.07. Found: C, 69.39; H, 6.60; N, 10.92.
CHCl3
max
quinolizidine ring19), 1730 (ester CO); 1H NMR (CDCl3) d:
1.14 (1H, ddd, Jˆ13, 13, 11 Hz) and 2.46 (1H, ddd, Jˆ13,
4, 2.5 Hz) [C(14)±H's], 1.33 (3H, t, Jˆ7 Hz, CH2Me), 1.39
[3H, d, Jˆ6.5 Hz, C(5)-Me], 2.16 [1H, ddd, Jˆ13, 6, 4 Hz,
C(14a)±H], 2.21 [1H, d, Jˆ6 Hz, C(1)±H], 2.52 (1H, ddd,
Jˆ11, 11, 4 Hz) and 3.63 (1H, ddd, Jˆ11, 5.5, 2 Hz) [C(7)±
H's], 2.79 (1H, dddd, Jˆ15, 4, 2, 2 Hz) and 2.92 (1H, dddd,
Jˆ15, 11, 5.5, 2.5 Hz) [C(8)±H's], 3.11 [1H, q, Jˆ6.5 Hz,
C(5)±H], 3.70 [1H, dddd, Jˆ11, 2.5, 2.5, 2 Hz, C(13b)±H],
4.24 and 4.26 (1H each, dq, Jˆ10.5, 7 Hz, CH2Me), 6.12
[1H, s, C(2)±H], 7.11 and 7.15 [1H each, dd, Jˆ7.5, 7.5 Hz,
C(10)±H and C(11)±H], 7.29 and 7.50 [1H each, d,
Jˆ7.5 Hz, C(9)±H and C(12)±H], 7.69 (1H, s, NH), 8.16
[1H, s, C(4)±H]; 13C NMR (CDCl3) d: 14.3 (q), 15.1 (q),
22.4 (t), 34.7 (t), 42.7 (d), 46.9 (t), 49.5 (d), 58.2 (d), 60.5
(d), 61.4 (t), 90.2 (s), 97.6 (d), 109.0 (s), 110.8 (d), 118.3 (d),
119.7 (d), 121.8 (d), 127.0 (s), 133.9 (s), 136.1 (s), 171.8 (s),
171.9 (d). Anal. Calcd for C22H25N3O3: C, 69.64; H, 6.64; N,
11.07. Found: C, 69.29; H, 6.62; N, 10.97.
Retro-Michael reaction of 27a,b. A solution of a 3:1
mixture (40 mg, 0.11 mmol) of 27a and 27b in o-DCB
(10 ml) was heated with DBN (12 mg, 0.10 mmol) at
1508C in an atmosphere of Ar for 2.5 h. After cooling, the
reaction mixture was concentrated in vacuo to leave a brown
oil. Puri®cation of the oil by preparative TLC (silica gel,
AcOEt) afforded 35 (21 mg, 53%) as a yellow foam, MS m/
A mixture of 27a and 27b was recovered (129 mg, 20%)
from the second fractions to elute in the above chroma-
tography. The third fraction provided 28 (342 mg, 53%)
as a pale brown solid. Recrystallization of the solid from
MeOH yielded an analytical sample as colorless needles,
mp 208±2118C (dec); [a]2D0ˆ11368 (c 0.49, CHCl3); MS
m/z: 379 (M1); IR n
cm21: 3475 (NH), 2850, 2805,
z: 379 (M1); H NMR (CDCl3) d: 1.32 (3H, t, Jˆ7 Hz,
CHCl3
max
1
2760 (trans-quinolizidine ring19), 1732 (ester CO); 1H
NMR (CDCl3) d: 1.29 (3H, t, Jˆ7 Hz, CH2Me), 1.38 [3H,
d, Jˆ6.5 Hz, C(5)-Me], 1.65 (1H, ddd, Jˆ12, 12, 12 Hz)
and 2.42 (1H, ddd, Jˆ12, 6, 1 Hz) [C(14)±H's], 2.20 [1H,
ddd, Jˆ12, 6, 3.5 Hz, C(14a)±H], 2.43 (1H, ddd, Jˆ11,
10.5, 4 Hz) and 3.48 (1H, ddd, Jˆ11, 5.5, 2.5 Hz) [C(7)±
H's], 2.76 (1H, ddd, Jˆ15.5, 4, 2.5 Hz) and 2.95 (1H, dddd,
CH2Me), 1.39 (3H, d, Jˆ6.8 Hz, CHMe), 2.8±3.05 (4H,
m, two CH2's), 3.94 (1H, q, Jˆ6.8 Hz, CHMe), 4.23 (2H,
q, Jˆ7 Hz, CH2Me), 5.94 (1H, d, Jˆ15.1 Hz,
CHvCHCO2Et), 6.61 (1H, dd, Jˆ15.6, 11.2 Hz,
ArCHvCH), 6.82 [1H, s, C(40)±H], 7.00 (1H, d, Jˆ
15.6 Hz, ArCHvCH), 7.07 and 7.21 [1H each, dd, Jˆ7.5,
7.5 Hz, C(5)±H and C(6)±H], 7.29 and 7.52 [1H each, d,

M. Ohba et al. / Tetrahedron 56 (2000) 7751±7761
7759
Jˆ7.5 Hz, C(4)±H and C(7)±H], 7.46 (1H, dd, Jˆ15.1,
11.2 Hz, CHvCHCO2Et), 7.73 [1H, s, C(20)±H], 8.54
[1H, s, N(1)±H];25 HRMS m/z calcd for C22H25N3O3:
method-(i) provided 33 (30 mg, 13%) as a pale yellow solid
together with unaltered 32 (155 mg, 62%).
1
379.1896, found: 379.1895. On the basis of the H NMR
(iii) From 31: A solution of 31 (50 mg, 0.13 mmol) in
AcOH (1 ml) and xylene (5 ml) was heated under re¯ux
in an atmosphere of Ar for 8 h. The reaction mixture was
worked up as described above under method-(i), giving 33
(6.0 mg, 13%) as a pale yellow solid and 32 (27 mg, 52%) as
a yellow glass.
spectrum, this sample is presumed to be a mixture of the
four possible isomers based on two ole®nic double bond.
The signals arising from the (E,E)-isomer comprising 70%
of the isomers are described above.
(5S-trans)-5,7,8,13,13b,14±Hexahydro-5-methylindolo-
[20,30:3,4]pyrido[1,2-b][2,7]naphthyridine-1-carboxylic
acid ethyl ester (33). (i) From 28: A solution of 28
(374 mg, 1.0 mmol) in AcOH (3 ml) and xylene (15 ml)
was heated under re¯ux in an atmosphere of Ar for 8 h.
After concentration of the reaction mixture, the residual
brown glass was dissolved in CHCl3. The CHCl3 solution
was washed successively with saturated aqueous NaHCO3
and saturated aqueous NaCl, dried, and concentrated to
leave a brown glass, which was then subjected to ¯ash chro-
matography [hexane±acetone (2:1)]. Earlier fractions
furnished 33 (65 mg, 18%) as a yellow solid. Recrystalliza-
tion from EtOH afforded an analytical sample as colorless
Degradation of the adduct 29. A solution of 29 (50 mg,
0.13 mmol) in AcOH (1 ml) and xylene (2 ml) was heated
under re¯ux in an atmosphere of N2 for 1 h. After cooling,
the reaction mixture was concentrated in vacuo and the
residue was dissolved in CHCl3. The CHCl3 solution was
washed successively with 10% aqueous Na2CO3 and satu-
rated aqueous NaCl, dried, and concentrated in vacuo to
leave a brown oil, which was submitted to ¯ash chroma-
tography [AcOEt±hexane (1:1)]. Earlier fractions provided
37 (21 mg, 44%) as a pale yellow solid. Recrystallization
from EtOH furnished an analytical sample as colorless
prisms, mp 180±181.58C; [a]2D2ˆ21848 (c 0.25, CHCl3);
needles, mp 198±2008C; [a]2D4ˆ22688 (c 0.35, CHCl3); MS
MS m/z: 361 (M1); IR n
cm21: 3140 (NH), 1709
Nujol
max
m/z: 361 (M1); IR n
cm21: 3470 (NH), 2810, 2760
(ester CO); H NMR (CDCl3) d: 1.35 (3H, t, Jˆ7 Hz,
OCH2Me), 1.36 (3H, t, Jˆ7.5 Hz, ArCH2Me), 2.73 (1H,
ddd, Jˆ15.5, 4, 2 Hz) and 2.80 (1H, ddd, Jˆ15.5, 11,
4.5 Hz) [C(7)±H's], 3.03 and 3.06 (1H each, dq, Jˆ15,
7.5 Hz, ArCH2Me), 3.50 (1H, ddd, Jˆ14.5, 11, 4 Hz) and
4.25 (1H, ddd, Jˆ14.5, 4.5, 2 Hz) [C(6)±H's], 3.53 (1H, dd,
Jˆ17.5, 9.5 Hz) and 3.78 (1H, dd, Jˆ17.5, 2.5 Hz) [C(13)±
H's], 4.32 (2H, q, Jˆ7 Hz, OCH2Me), 5.16 [1H, dd, Jˆ9.5,
2.5 Hz, C(12b)±H], 7.07 and 7.15 [1H each, dd, Jˆ7.5,
7.5 Hz, C(9)±H and C(10)±H], 7.31 and 7.42 [1H each, d,
Jˆ7.5 Hz, C(8)±H and C(11)±H], 7.98 (1H, s, NH), 8.51
[1H, s, C(2)±H]; 13C NMR (CDCl3) d: 12.1 (q), 14.3 (q),
20.0 (t), 29.1 (t), 35.4 (t), 44.6 (t), 60.0 (d), 60.8 (t), 109.8
(s), 110.9 (d), 118.1 (d), 119.8 (d), 121.4 (s), 122.1 (d),
126.9 (s), 134.2 (s), 136.2 (s), 141.5 (d), 142.2 (s),
144.6 (s), 148.4 (s), 166.0 (s). Anal. Calcd for
C22H23N3O2: C, 73.11; H, 6.41; N, 11.63. Found: C,
73.18; H, 6.42; N, 11.55.
CHCl3
max
1
(trans-quinolizidine ring19), 1717 (ester CO); 1H NMR
(CDCl3) d: 1.42 (3H, t, Jˆ7 Hz, CH2Me), 1.62 [3H, d,
Jˆ6.5 Hz, C(5)±Me], 2.55 (1H, ddd, Jˆ11, 11, 4 Hz) and
3.58 (1H, dd, Jˆ11, 5 Hz) [C(7)±H's], 2.84 (1H, dd, Jˆ15,
4 Hz) and 3.00 (1H, dddd, Jˆ15, 11, 5, 2 Hz) [C(8)±H's],
3.14 (1H, dd, Jˆ17, 11 Hz) and 3.84 (1H, dd, Jˆ17, 2.5 Hz)
[C(14)±H's], 3.70 [1H, br d, Jˆ11 Hz, C(13b)±H], 3.87
[1H, q, Jˆ6.5 Hz, C(5)±H], 4.40 (2H, q, Jˆ7 Hz,
CH2Me), 7.11 and 7.17 [1H each, dd, Jˆ7.5, 7.5 Hz,
C(10)±H and C(11)±H], 7.33 and 7.52 [1H each, d,
Jˆ7.5 Hz, C(9)±H and C(12)±H], 8.03 (1H, s, NH), 8.63
[1H, s, C(4)±H], 8.99 [1H, s, C(2)±H]; 13C NMR (CDCl3)
d: 14.3 (q), 21.9 (t), 22.8 (q), 33.2 (t), 48.9 (t), 54.8(d), 57.4
(d), 61.3 (t), 109.0 (s), 110.9 (d), 118.3 (d), 119.5 (d), 121.7
(d), 124.2 (s), 127.0 (s), 134.1 (s), 136.4 (s), 136.6 (s), 144.8
(s), 148.9 (d), 151.9 (d), 166.0 (s). Anal. Calcd for
C22H23N3O2: C, 73.11; H, 6.41; N, 11.63. Found: C,
72.83; H, 6.40; N, 11.60.
Later fractions in the above chromatography afforded 36
(20 mg, 46%) as a pale yellow solid, which was recrystal-
lized from EtOH to give an analytical sample as colorless
Later fractions in the above chromatography provided 32
(251 mg, 64%) as a yellow glass, MS m/z: 397 (M1); IR
CHCl3
max
n
cm21: 3460 (NH), 1669 (ester CO); 1H NMR (CDCl3)
minute needles, mp 224±2278C; [a]2D5ˆ241.78 (c 0.20,
cm21: 3155 (NH),
max
Nujol
d: 1.24 (3H, t, Jˆ7 Hz, CH2Me), 1.27 [3H, d, Jˆ7 Hz, C(5)-
Me], 1.62 [1H, ddd, Jˆ13.5, 12, 12 Hz, C(14)±Hb], 2.50
(1H, br) and 3.45 (1H, dd, Jˆ11, 4 Hz) [C(7)±H's], 2.75±
2.85 [3H, m, C(5)±H, C(14)±Ha, and C(14a)±H], 2.87 (1H,
m) and 3.37 (1H, ddd, Jˆ13.5, 4, 3.5 Hz) [C(8)±H's], 3.65
[1H, br, C(13b)±H], 4.11 (2H, q, Jˆ7 Hz, CH2Me), 4.71
[1H, d, Jˆ4.5 Hz, C(4)±H], 5.53 [1H, br, N(3)±H], 7.08
and 7.13 [1H each, dd, Jˆ7.5, 7.5 Hz, C(10)±H and
C(11)±H], 7.30 and 7.46 [1H each, d, Jˆ7.5 Hz, C(9)±H
and C(12)±H], 7.43 [1H, br d, Jˆ5.5 Hz, C(2)±H], 8.19
[1H, br, N(13)±H]; HRMS m/z calcd for C22H27N3O4:
397.2002, found: 397.2003.
CHCl3); MS m/z: 333 (M1); IR n
1715 (ester CO); 1H NMR (CDCl3) d: 1.37 (3H, t,
Jˆ7 Hz, OCH2Me), 2.69 (1H, dd, Jˆ15.5, 4.5 Hz) and
2.97 (1H, ddd, Jˆ15.5, 12, 5 Hz) [C(7)±H's], 3.47 (1H,
ddd, Jˆ14.5, 12, 4.5 Hz) and 4.09 (1H, dd, Jˆ14.5, 5 Hz)
[C(6)±H's], 3.61 (1H, dd, Jˆ17.5, 9.5 Hz) and 3.77 (1H, dd,
Jˆ17.5, 2 Hz) [C(13)±H's], 4.34 (2H, q, Jˆ7 Hz,
OCH2Me), 5.20 [1H, dd, Jˆ9.5, 2 Hz, C(12b)±H], 7.07
and 7.15 [1H each, dd, Jˆ7.5, 7.5 Hz, C(9)±H and
C(10)±H], 7.31 and 7.42 [1H each, d, Jˆ7.5 Hz, C(8)±H
and C(11)±H], 8.12 (1H, s, NH), 8.20 [1H, s, C(4)±H], 8.53
[1H, s, C(2)±H]; 13C NMR (CDCl3) d: 14.3 (q), 17.4 (t),
35.7 (t), 42.3 (t), 59.4 (d), 61.0 (t), 109.1 (s), 110.9 (d), 118.2
(d), 119.8 (d), 122.3 (d), 123.4 (s), 126.9 (s), 132.5 (d),
133.9 (s), 136.2 (s), 141.5 (d), 141.7 (s), 147.6 (s), 165.7
(s). Anal. Calcd for C20H19N3O2: C, 72.05; H, 5.74; N,
12.60. Found: C, 71.80; H, 5.74; N, 12.49.
(ii) From 32: A stirred solution of 32 (251 mg, 0.63 mmol)
in AcOH (2 ml) and xylene (10 ml) was heated under re¯ux
in an atmosphere of Ar for 8 h. Work-up of the reaction
mixture in a manner similar to that described above under

7760
M. Ohba et al. / Tetrahedron 56 (2000) 7751±7761
(5S-trans)-(5,7,8,13,13b,14±Hexahydro-5-methylindolo-
[20,30:3,4]pyrido[1,2-b][2,7]naphthyridin-1-yl)carbamic
acid tert-butyl ester (34). To a stirred solution of 33
(79.5 mg, 0.22 mmol) in THF (3 ml) and MeOH (1.5 ml)
in an atmosphere of Ar was added a solution of LiOH
(32 mg, 1.3 mmol) in H2O (1 ml). The resulting mixture
was stirred at room temperature for 1.5 h and then concen-
trated in vacuo. After addition of 1N aqueous HCl (1.3 ml),
the precipitate was ®ltered off, washed with H2O, and dried.
The slightly yellow solid (73.6 mg) thus obtained was
dissolved in tert-BuOH (2.5 ml), and the solution was
then heated under re¯ux with diphenyl phosphoroazidate
(90 mg, 0.33 mmol) and Et3N (35 mg, 0.35 mmol) in an
atmosphere of Ar for 5 h. The reaction mixture was then
concentrated in vacuo to leave a yellow oil, which was
dissolved in CHCl3. The CHCl3 solution was washed
successively with saturated aqueous NaHCO3 and saturated
aqueous NaCl, dried, and concentrated. Puri®cation of the
residual oil by ¯ash chromatography (AcOEt) afforded 34
(56.8 mg, 64% from 33) as a colorless solid. Recrystalliza-
tion from AcOEt±hexane (1:1) and drying over P2O5 at
2 mmHg and 508C for 5 h produced an analytical sample
as colorless minute prisms, mp 183±1858C (dec);
(21), 170 (21), 169 (58), 144 (18), 143 (14), 137 (17), 115
MeOH
max
(12); UV l
(7870), 290 (6390); IR n
nm (e): 224 (38600), 269 (8230), 282
cm21: 3410, 3180, 2980,
KBr
max
2855, 2814, 1601, 1572, 1499, 1460, 1412, 1391, 1371,
1324, 1315, 1300, 1269, 1061, 741; HRMS m/z calcd for
C19H19N3: 289.1579, found: 289.1578. The 1H NMR
(CDCl3) and 13C NMR (CDCl3) spectral data for this sample
were in agreement with those reported for natural sample3
and for (^)-4,9b respectively.
Acknowledgements
We are grateful to Professors M. V. Sargent (University of
Western Australia) and D. Arbain (University of Andalas)
for providing us with a sample and spectral copies of natural
normalindine and to Emeritus Professor T. Fujii (Kanazawa
University) for his interest and encouragement.
References
[a]2D1ˆ22058 (c 0.11, CHCl3); MS m/z: 404 (M1); IR n
Nujol
1. (a) Jahangir; Brook, M. A.; MacLean, D. B.; Holland, H. L.
Tetrahedron 1987, 43, 5761±5768 and references cited therein.
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max
1
cm21: 3330, 3170 (NH), 1696 (carbamate CO); H NMR
(CDCl3) d: 1.57 (9H, s, tert-Bu), 1.58 [3H, d, Jˆ6.5 Hz,
C(5)±Me], 2.49 (1H, ddd, Jˆ11.5, 11, 4 Hz) and 3.52
(1H, ddd, Jˆ11.5, 5, 2 Hz) [C(7)±H's], 2.57 (1H, dd,
Jˆ16, 11 Hz) and 2.96 (1H, d, Jˆ16 Hz) [C(14)±H's],
2.80 (1H, ddd, Jˆ15, 2, 2 Hz) and 2.93 (1H, m) [C(8)±
H's], 3.56 [1H, br d, Jˆ11 Hz, C(13b)±H], 3.77 [1H, q,
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Â
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[20,30:3,4]pyrido[1,2-b][2,7]naphthyridine [(2)-normal-
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room temperature for 5 h. The reaction mixture was then
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with CHCl3 containing a small amount of EtOH. The CHCl3
extracts were washed with saturated aqueous NaCl, dried
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Â
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1
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