Total synthesis of the proposed structure of macrocaffrine

Article abstract of DOI:10.1016/j.tet.2007.10.005

A full account of the total synthesis of 18-demethyl-19-hydroxy-N_a-demethyl-N_b-methylsuaveoline (1), the structure assigned to macrocaffrine isolated from Rauwolfia caffra, is presented. The key steps involved are an intramolecular c

Full text of DOI:10.1016/j.tet.2007.10.005

Tetrahedron 63 (2007) 12689–12694
Total synthesis of the proposed structure of macrocaffrine
b
Masashi Ohbaa, and Itaru Natsutani
*
aAdvanced Science Research Center, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
bFaculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
Received 14 September 2007; revised 29 September 2007; accepted 1 October 2007
Available online 5 October 2007
Abstract—A full account of the total synthesis of 18-demethyl-19-hydroxy-Na-demethyl-Nb-methylsuaveoline (1), the structure assigned to
macrocaffrine isolated from Rauwolfia caffra, is presented. The key steps involved are an intramolecular cycloaddition reaction of the ox-
azole–olefin 10 and a subsequent dehydration that generated the pentacyclic pyridine derivative 14. The spectral data and specific rotation
of synthetic 1 were dissimilar to those reported for a natural sample, leaving the structure of this R. caffra alkaloid undefined.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
tion, would be derived from the oxazole–olefins 6 that are
readily available through carbonyl olefination of the alde-
hyde 7, postulated as a common intermediate (Scheme 1).
In the present paper, we wish to record the details of a study
directed toward the synthesis of macrocaffrine.
In 1983, Nasser and Court reported the isolation of the mac-
roline/sarpagine related alkaloid 18-demethyl-19-hydroxy-
Na-demethyl-Nb-methylsuaveoline (1),1 which was named
macrocaffrine,2 from the leaves of South African Rauwolfia
caffra. To date, four additional alkaloids [i.e., suaveoline
(2),2,3 norsuaveoline (3),2 macrophylline (4),1,2,3h,4 and sel-
lowiine (5)5] possessing the same skeleton as that of 1 have
been found in various species of Rauwolfia. In connection
with our continuing interest in the synthesis of pyridine-
containing natural products exploiting an intramolecular
oxazole–olefin Diels–Alder reaction,6,7 we have recently
achieved the synthesis of suaveoline (2),8 norsuaveoline
(3),8 and Na-demethyl-20-deethylsuaveoline (5),9 the struc-
ture proposed for sellowiine. An important feature of our
synthetic strategy is that all of the suaveoline-related alka-
loids, which possess a variety of substituents at the 20-posi-
N
N
H
H
O
O
NR1
1–5
NR1
N
H
N
H
H
H
CHO
R2
6
7
Scheme 1.
2. Results and discussion
For the synthesis of macrocaffrine, which has a hydroxy-
methyl group at the 20-position, we envisaged the a,b-unsat-
urated ester 10 as an oxazole–olefin substrate for an
intramolecular Diels–Alder reaction. The ester 10 was pre-
pared from the cis-1,3-disubstituted tetrahydro-b-carboline
8, readily available from L-tryptophan methyl ester accord-
ing to our previously reported procedure.8 Protection of
the amino group in 8 with benzyl bromide and Na2CO3 pro-
vided the N-benzyl derivative 9 in 75% yield (Scheme 2).
H
H
N
N
NMe
NR2
N
H
N
R1
20
20
R3
H
H
CH2OH
1
2: R1 = Me, R2 = H, R3 = Et
3: R1 = R2 = H, R3 = Et
4: R1 = H, R2 = Me, R3 = CH2CH2OH
5: R1 = R2 = R3 = H
1
The H NMR spectrum of 8 exhibited two methylene pro-
tons adjacent to the ester group at d 2.80 and 2.88, whereas
one of the corresponding protons of 9 appeared at d 1.89,
probably due to the shielding effect arising from the oxazole
ring of the conformer 9A, in analogy with the N-Boc deriv-
ative 11.8 Reduction of 9 with diisobutylaluminum hydride
(DIBALH) at ꢀ78 ꢁC, followed by the Wittig reaction
Keywords: Cycloaddition reaction; Indole alkaloids; Macrocaffrine;
Oxazoles.
* Corresponding author at present address: Yokohama College of Phar-
macy, 601 Matano-cho, Totsuka-ku, Yokohama 245-0066, Japan. Tel./
fax: +81 45 859 1369; e-mail: m.ohba@hamayaku.ac.jp
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.10.005

12690
M. Ohba, I. Natsutani / Tetrahedron 63 (2007) 12689–12694
N
O
N
O
N
O
H
H
H
1) DIBALH
+
NR
NBn
NBn
2) Ph3P=CHCO2Et
N
H
N
N
H
H
H H
H
CO2Et
CO2Et
EtO2C
(Z)-10
8: R = H
9: R = Bn
BnBr
Na2CO3
(E)-10
Scheme 2.
with ethyl (triphenylphosphoranylidene)acetate, was per-
formed as a one-pot procedure, affording the desired esters
(E)-10 and (Z)-10 in 54% and 24% yields, respectively.
treatment of (Z)-10 also afforded 15a in 17% yield, accom-
panied by the recovered starting material (entry 2). No
significant improvement was observed by elongation of
the reaction time to 24 h (entry 3). It is likely that the ox-
azole–olefin 10 comes to equilibrium with the initially
formed Diels–Alder cycloadduct 13, which provided the
diol 15a in the work-up process, instead of the desired pyr-
idine 14, since the elimination of water leading to 14 from
13 is slow. With a view to isolating the cycloaddition product
as the diol 15a, solvent containing water was next employed.
Thus, treatment of (E)-10 in boiling THF–H2O (10:1, v/v)
for 48 h afforded the diol 15a in 61% yield along with an-
other diol 15b in 33% yield (entry 4). Similar results were
also obtained from (Z)-10 (entry 5).
N
N
H
NBoc
CO2Et
O
H
O
EtO2C
H
N
H
NBn
H
N
H
9A
11
With the oxazole–olefins (E)-10 and (Z)-10 in hand, we set
out to explore their intramolecular Diels–Alder reaction. Al-
though treatment of (E)-10 with 1,5-diazabicyclo[4.3.0]non-
5-ene (DBN) in boiling xylene was first tried according to
our precedent in the synthesis of suaveoline (2) and norsua-
veoline (3),8 the diene 12 was obtained through a retro-Mi-
chael reaction (Scheme 3). Therefore, the Diels–Alder
reaction of 10 was conducted in the absence of DBN, and
the results are given in Table 1. When (E)-10 was treated
in boiling toluene for 2 h, the diol 15a was obtained in
19% yield together with unaltered (E)-10 (entry 1). Similar
Having successfully developed an effective intramolecular
cycloaddition reaction of 10, we next examined this step in
further detail. On treatment in boiling THF–H2O (10:1) for
48 h, the diol 15a gave a 75:25 equilibrium mixture of 15a
and 15b, probably through the imine 16 (Scheme 4). Simi-
larly, the minor diol 15b came to the same equilibrium after
48 h. The time-course of the intramolecular cycloaddition
1
reaction of (E)-10 at 60 ꢁC was followed by means of H
NMR spectroscopic analysis. It may be seen from Table 2
that the diol 15a is first produced and then the isomeric
diol 15b is slowly formed by epimerization of 15a at the
17-position. This view is consistent with the result described
in Table 1 where treatment of (E)-10 in boiling toluene
yielded 15a as a sole product.
N
O
N
O
H
H
DBN
NHBn
NBn
N
H
N
H
xylene
H
On the other hand, when (E)-10 was heated in anhydrous
THF at 60 ꢁC for 12 h, we observed the cycloadduct 13a
as a 1:1 mixture with (E)-10 by 1H NMR spectroscopy. Ma-
tsuo and Miki reported that the stereochemistries of the
cycloadducts 17 and 18 can be determined based on the
value of the coupling constant between the protons HA and
HB.10 The proton HA in 17, where HB occupies the exo-po-
sition, appears as a doublet (JAB¼4 Hz), whereas the singlet
HA (JAB¼0 Hz) indicates that HB occupies the endo-position
CO2Et
CO2Et
(E)-10
12
N
O
H
H
N
O
NBn
NBn
N
H
N
H
Δ
H
H
H
CO2Et
10
13
CO2Et
Table 1. Intramolecular cycloaddition reactions of the oxazole–olefins
(E)-10 and (Z)-10a
Entry Substrate Solvent
Time (h) Yield (%) Recovery (%)
H
H
OH
HO
15a
15b 10
17
N
NH
NBn
NBn
1
2
3
4
5
(E)-10
(Z)-10
(E)-10
(E)-10
(Z)-10
Toluene
Toluene
Toluene
2
2
24
19
17
26
61
62
0
0
0
33
34
42
23
27
0
N
H
N
H
H
H
H
CO2Et
CO2Et
THF–H2Ob 48
THF–H2Ob 48
15a: 17α-OH
15b: 17β-OH
14
0
a
All reactions were carried out in boiling solvent.
10:1, v/v.
b
Scheme 3.

M. Ohba, I. Natsutani / Tetrahedron 63 (2007) 12689–12694
12691
H
H
H
OH
OH
HO
HO
NBn
HO
NBn
17
NH
N
NH
NBn
N
H
N
H
N
H
H
H
H
H
H
H
CO2Et
CO2Et
CO2Et
16
15b
15a
Scheme 4.
Table 2. Time-course of the intramolecular cycloaddition reaction of the
oxazole–olefin (E)-10 in THF–H2O (10:1, v/v) at 60 ꢁC
acid in MeOH for 1.5 h, affording the Nb-methyl derivative
20 in 96% yield. On application of the reductive methylation
conditions to the Nb-benzyl derivative 14, except for elonga-
tion of the reaction time to 5 h, debenzylation and methylation
proceeded at the same time to give the Nb-methyl analog 20 in
quantitative yield. Finally, reduction of 20 with LiAlH4 fur-
nished the desired compound 1 in 94% yield. Unfortunately,
the 1H NMR and mass spectral data and specific rotation for
synthetic 1 were in disagreement with those reported for mac-
rocaffrine,1 and thus its chemistry is not yet fully understood.
Time (h)
Ratioa
(E)-10
15a
15b
3
6
12
24
48
60
91
66
38
21
5
9
34
56
70
74
75
0
0
6
9
21
25
0
Estimated by 1H NMR spectroscopy.
a
3. Conclusion
as shown in 18. Since the C(21)-proton of the cycloadduct
13a was observed as a doublet (J¼4 Hz) at d 6.18 in
CDCl3, the C(20)-proton was assigned the exo-position. In
addition, the structure of the major diol 15a was confirmed
by a 10% NOE enhancement observed for the C(15)-proton
signal on irradiation of the C(17)-proton signal. Accord-
ingly, the minor diol, the C(17)-epimer of 15a, was deter-
mined to have the structure 15b.
The total synthesis of 18-demethyl-19-hydroxy-Na-de-
methyl-Nb-methylsuaveoline (1), the structure proposed for
macrocaffrine isolated from R. caffra, has been accom-
plished through a route featuring the construction of the
annulated pyridine by the intramolecular cycloaddition
reaction of the oxazole–olefin 10 and subsequent dehydra-
tion of the diol 15. Owing to the dissimilarity of the spectral
properties and specific rotations of the two samples, the
structure of macrocaffrine needs to be corrected, although
we are unable to propose a new structure for this alkaloid.
It is hoped that the knowledge obtained on synthetic 1 will
be of great help toward further isolation of this alkaloid, if
it is present, from natural sources.
H
H
OH
HO
H
17
N
NH
NBn
NBn 15
O
21
N
H
N
H
NOE
H
20
H
H
H
H
CO2Et
CO2Et
13a
15a
4. Experimental
O
O
OEt
H
OEt
H
CO2Me
CO2Me
Me
Me
4.1. General methods
CO2Me
HB
N
N
Melting point was determined on a Yamato MP-1 capillary
melting point apparatus. Flash chromatography12 was carried
out 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 spectrometer, a Hitachi U-3010 UV spectro-
photometer, a Shimadzu FTIR-8400 IR spectrophotometer,
a JASCO J-820 spectropolarimeter, or a JEOL JNM-GSX-
500 (1H 500 MHz, 13C 125 MHz) NMR spectrometer. Chem-
ical 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.
HA
HA
CO2Me
HB
17
JAB = 4 Hz
18
JAB = 0 Hz
Conversion of the diols 15a,b into the pyridine derivative 14
was next investigated. After considerable experimentation,
we observed the formation of 14 in 21% yield through dehy-
dration of 15a employing the Burgess reagent.11 Similarly,
the diol 15b was dehydrated to provide 14 in 44% yield.
The best result was obtained on treatment with DBN in boil-
ing o-dichlorobenzene (o-DCB) for 3 h: under these condi-
tions, the pyridine 14 was produced in 78% and 67% yields,
respectively, from 15a and 15b (Scheme 5).
4.2. (1S,3S)-2,3,4,9-Tetrahydro-3-(5-oxazolyl)-2-(phenyl-
methyl)-1H-pyrido[3,4-b]indole-1-acetic acid ethyl ester
(9)
The final transformations from 14 to 1 proceeded without in-
cident. Debenzylation of 14 by means of catalytic hydrogen-
olysis afforded 19 (91% yield), which was then subjected to
reductive methylation3a with aqueous HCHO, Pearlman’s
catalyst, and hydrogen in the presence of a trace of acetic
A mixture of 88 (4.07 g, 12.5 mmol), Na2CO3 (13.3 g,
125 mmol), and benzyl bromide (7.4 mL, 62 mmol) in

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M. Ohba, I. Natsutani / Tetrahedron 63 (2007) 12689–12694
H
H
DBN
Pd(OH)2–C
H2
N
N
NBn
NH
15a,b
N
H
N
H
H
H
CO2Et
CO2Et
19
14
HCHO, AcOH
Pd(OH)2–C, H2
H
H
HCHO, AcOH
Pd(OH)2–C, H2
LiAlH4
N
N
NMe
NMe
N
H
N
H
H
H
CO2Et
CH2OH
20
1
Scheme 5.
DMF (50 mL) was stirred at room temperature for 25 h. The
reaction mixture was concentrated in vacuo, and the residue
was partitioned between H2O and CHCl3. The CHCl3
extracts were washed with brine, dried, and concentrated
to leave a brown oil. Purification by flash chromatography
[AcOEt–hexane (1:2)] provided 9 (3.88 g, 75%) as a pale
yellow glass. [a]2D8 +132 (c 0.25, CHCl3); MS m/z: 415
J¼8, 7.5 Hz), 7.2–7.4 (6H, m), 7.54 (1H, d, J¼7.5 Hz),
7.73 (1H, s), 8.43 (1H, s); HRMS calcd for C27H27N3O3:
441.2052, found: 441.2047. Later fractions in the above
chromatography gave (E)-10 (2.21 g, 54%) as a pale yellow
glass. [a]2D8 +94.5 (c 0.25, CHCl3); MS m/z: 441 (M+); IR
(CHCl3) n, cmꢀ1: 3470 (NH), 1709 (CO); 1H NMR
(CDCl3) d: 1.31 (3H, t, J¼7 Hz), 1.95–2.15 (2H, m), 3.15
(1H, dd, J¼16, 3 Hz), 3.31 (1H, ddd, J¼16, 6, 1.5 Hz),
3.95 and 4.02 (2H, d each, J¼14 Hz), 4.04 (1H, dd, J¼7,
6.5 Hz), 4.20 (2H, q, J¼7 Hz), 4.45 (1H, dd, J¼6, 3 Hz),
5.67 (1H, d, J¼15.5 Hz), 6.69 (1H, s), 6.94 (1H, ddd,
J¼15.5, 8.5, 6.5 Hz), 7.16 (1H, dd, J¼8, 7.5 Hz), 7.20
(1H, dd, J¼8, 7.5 Hz), 7.25–7.45 (6H, m), 7.58 (1H, d,
J¼7.5 Hz), 7.79 (1H, br s), 7.81 (1H, s); HRMS calcd for
C27H27N3O3: 441.2052, found: 441.2051.
1
(M+); IR (CHCl3) n, cmꢀ1: 3440 (NH), 1715 (CO); H
NMR (CDCl3) d: 1.22 (3H, t, J¼7.5 Hz), 1.89 (1H, dd,
J¼17, 10.5 Hz), 2.60 (1H, dd, J¼17, 2.5 Hz), 3.11 (1H,
dd, J¼16, 1.5 Hz), 3.31 (1H, ddd, J¼16, 6.5, 1.5 Hz), 4.03
and 4.06 (2H, d each, J¼13.5 Hz), 4.11 (2H, m), 4.36 (1H,
br d, J¼10.5 Hz), 4.40 (1H, br d, J¼6.5 Hz), 6.64 (1H, s),
7.13 (1H, dd, J¼8, 7 Hz), 7.19 (1H, dd, J¼8, 7.5 Hz),
7.25–7.5 (6H, m), 7.57 (1H, d, J¼7.5 Hz), 7.84 (1H, s),
8.78 (1H, s); HRMS calcd for C25H25N3O3: 415.1896,
found: 415.1887.
4.4. Retro-Michael reaction of (E)-10: preparation
of the diene 12
4.3. [1S(E),3S]-4-[2,3,4,9-Tetrahydro-3-(5-oxazolyl)-2-
(phenylmethyl)-1H-pyrido[3,4-b]indol-1-yl]-2-butenoic
acid ethyl ester [(E)-10] and [1S(Z),3S]-4-[2,3,4,9-tetra-
hydro-3-(5-oxazolyl)-2-(phenylmethyl)-1H-pyrido[3,4-
b]indol-1-yl]-2-butenoic acid ethyl ester [(Z)-10]
A solution of (E)-10 (30 mg, 0.068 mmol) and DBN (42 mg,
0.34 mmol) in xylene (2 mL) was heated under reflux for 6 h
in an atmosphere of N2. The reaction mixture was concen-
trated in vacuo, and the residue was partitioned between
H2O and CHCl3. The CHCl3 extracts were washed with
brine, dried, and concentrated. Purification of the residual
oil by flash chromatography [AcOEt–hexane (1:1)] afforded
12 (12 mg, 40%) as a yellow oil. MS m/z: 441 (M+); 1H NMR
(CDCl3) d: 1.34 (3H, t, J¼7 Hz), 3.27 (1H, dd, J¼14,
6.5 Hz), 3.30 (1H, dd, J¼14, 7 Hz), 3.59 and 3.76 (2H,
d each, J¼13.5 Hz), 4.12 (1H, dd, J¼7, 6.5 Hz), 4.25 (2H,
q, J¼7 Hz), 5.93 (1H, d, J¼15 Hz), 6.54 (1H, dd, J¼15,
11 Hz), 6.78 (1H, s), 6.84 (1H, d, J¼15 Hz), 7.0–7.4 (9H,
m), 7.41 (1H, dd, J¼15, 11 Hz), 7.82 (1H, s), 8.35 (1H, s).
A stirred solution of 9 (3.88 g, 9.34 mmol) in CH2Cl2
(40 mL) was cooled to ꢀ78 ꢁC in an atmosphere of N2,
and a 0.95 M solution (24.5 mL, 23.3 mmol) of DIBALH
in hexane was added dropwise over 10 min. After the mix-
ture had been stirred at ꢀ78 ꢁC for 1 h, the reaction was
quenched by adding MeOH (6 mL). Stirring was continued
for a further 20 min, and a solution of ethyl (triphenylphos-
phoranylidene)acetate (3.77 g, 10.8 mmol) in CH2Cl2
(15 mL) was added. The reaction mixture was then stirred
at ꢀ78 ꢁC for 30 min and at room temperature for 1.5 h,
washed successively with saturated aqueous NaHCO3 and
brine, dried, and concentrated to leave a brown oil, which
was subjected to flash chromatography [AcOEt–hexane
(1:2)]. Earlier fractions afforded (Z)-10 (1.00 g, 24%) as
a pale yellow glass. [a]2D7 +79.7 (c 0.25, CHCl3); MS m/z:
441 (M+); IR (CHCl3) n, cmꢀ1: 3465 (NH), 1705 (CO); 1H
NMR (CDCl3) d: 1.25 (3H, t, J¼7 Hz), 2.15 (1H, ddd,
J¼15, 8, 7.5 Hz), 3.00 (1H, dddd, J¼15, 7.5, 4, 1.5 Hz),
3.15 (1H, dd, J¼16, 4 Hz), 3.22 (1H, ddd, J¼16, 5.5,
1.5 Hz), 3.92 and 3.97 (2H, d each, J¼14 Hz), 4.13 (2H, q,
J¼7 Hz), 4.16 (1H, m), 4.40 (1H, dd, J¼5.5, 4 Hz), 5.70
(1H, d, J¼11.5 Hz), 6.38 (1H, ddd, J¼11.5, 8, 7.5 Hz),
6.70 (1H, s), 7.13 (1H, dd, J¼7.5, 7 Hz), 7.18 (1H, dd,
4.5. Diels–Alder reaction of (E)-10 and (Z)-10:
preparation of the diols 15a and 15b
(i) From (E)-10 (Table 1, entry 4): A solution of (E)-10
(112 mg, 0.25 mmol) in THF–H2O (10:1, 13 mL) was
heated under reflux for 48 h in an atmosphere of Ar. The re-
action mixture was concentrated in vacuo, and the residue
was subjected to flash chromatography [AcOEt–hexane
(2:1)]. Earlier fractions furnished 15a (71 mg, 61%) as
a slightly yellow foam. [a]2D4 ꢀ264 (c 0.25, CHCl3); MS
m/z: 459 (M+); IR (CHCl3) n, cmꢀ1: 3470, 3445, 3335
(NH, OH), 1668 (CO), 1622 (a,b-unsaturated ester C]C);
1H NMR (CDCl3) d: 1.14 (3H, t, J¼7 Hz), 1.94 (1H, ddd,

M. Ohba, I. Natsutani / Tetrahedron 63 (2007) 12689–12694
12693
J¼13.5, 12.5, 4.5 Hz), 2.62 (1H, ddd, J¼12.5, 4.5, 2 Hz),
2.64 (1H, d, J¼17.5 Hz), 2.85 (1H, ddd, J¼13.5, 4.5,
3 Hz), 3.13 (1H, dd, J¼17.5, 7.5 Hz), 3.38 (1H, d,
J¼7.5 Hz), 3.37 (1H, d, J¼12 Hz), 3.67 and 3.69 (2H,
d each, J¼13.5 Hz), 3.9–4.05 (3H, m), 4.60 (1H, d,
J¼6.5 Hz), 4.85 (1H, br), 4.89 (1H, d, J¼12 Hz), 7.12
(1H, dd, J¼7.5, 7 Hz), 7.16 (1H, dd, J¼8, 7.5 Hz), 7.25–
7.35 (6H, m), 7.38 (1H, dd, J¼6.5, 2 Hz), 7.49 (1H, d,
J¼8 Hz), 8.16 (1H, s); HRMS calcd for C27H29N3O4:
459.2158, found: 459.2161. Later fractions in the above
chromatography provided 15b (38 mg, 33%) as a slightly
yellow foam. [a]2D4 ꢀ142 (c 0.25, CHCl3); MS m/z: 459
(M+); IR (CHCl3) n, cmꢀ1: 3465, 3340 (NH, OH), 1668
(CO), 1624 (a,b-unsaturated ester C]C); 1H NMR
(CDCl3) d: 1.13 (3H, t, J¼7.5 Hz), 1.96 (1H, ddd, J¼13,
12.5, 4 Hz), 2.33 (1H, br), 2.50 (1H, dd, J¼12.5, 4.5 Hz),
2.85 (1H, ddd, J¼13, 4.5, 3 Hz), 3.0–3.1 (2H, m), 3.64 and
3.67 (2H, d each, J¼13 Hz), 3.65 (1H, m), 3.9–4.0 (3H,
m), 4.40 (1H, br), 5.05 (1H, br), 5.42 (1H, dd, J¼5.5,
5 Hz), 7.09 (1H, dd, J¼7.5, 7 Hz), 7.12 (1H, dd, J¼7.5,
7 Hz), 7.25–7.35 (7H, m), 7.51 (1H, d, J¼7.5 Hz), 8.17
(1H, s); HRMS calcd for C27H29N3O4: 459.2158, found:
459.2159.
J¼17 Hz), 3.45 (1H, dd, J¼17, 6.5 Hz), 3.8–4.1 (6H, m),
6.18 (1H, d, J¼4 Hz), 7.1–7.45 (8H, m), 7.56 (1H, d,
J¼7.5 Hz), 7.73 (1H, s), 8.04 (1H, s).
4.9. (6S,13S)-6,7,12,13-Tetrahydro-14-(phenylmethyl)-
6,13-imino-5H-pyrido[30,40:5,6]cyclooct[1,2-b]indole-
4-carboxylic acid ethyl ester (14)
(i) From 15a: A solution of 15a (20.0 mg, 0.044 mmol) and
DBN (56 mg, 0.45 mmol) in o-DCB (1 mL) was heated un-
der reflux for 3 h in an atmosphere of N2. The reaction mix-
ture was concentrated in vacuo, and the residue was
partitioned between CHCl3 and H2O. The CHCl3 extracts
were washed with brine, dried, and concentrated to leave
a yellow oil, which was purified by flash chromatography
[AcOEt–hexane (1:1)] to furnish 14 (14.4 mg, 78%) as
a pale yellow solid. Recrystallization from AcOEt–hexane
(1:2) afforded an analytical sample as colorless needles,
mp 215–216 ꢁC. [a]D25 ꢀ30.7 (c 0.30, CHCl3); IR (Nujol)
n, cmꢀ1: 3285 (NH), 1720 (CO); 1H NMR (CDCl3) d: 1.35
(3H, t, J¼7 Hz), 2.72 (1H, d, J¼16 Hz), 3.42 (1H, dd,
J¼18, 1.5 Hz), 3.50 (1H, dd, J¼16, 5 Hz), 3.57 (1H, dd,
J¼18, 6 Hz), 3.81 and 3.93 (2H, d each, J¼13.5 Hz), 4.22
(1H, d, J¼6 Hz), 4.31 (2H, q, J¼7 Hz), 4.45 (1H, d,
J¼5 Hz), 7.06 (1H, dd, J¼7.5, 7.5 Hz), 7.12 (1H, dd, J¼8,
7.5 Hz), 7.25–7.4 (6H, m), 7.42 (1H, d, J¼8 Hz), 7.84
(1H, s), 8.55 (1H, s), 8.89 (1H, s); 13C NMR (CDCl3) d:
14.2 (q), 25.8 (t), 34.1 (t), 49.4 (d), 53.5 (d), 56.4 (t), 61.0
(t), 104.7 (s), 110.9 (d), 118.2 (d), 119.6 (d), 121.9 (d),
125.2 (s), 127.1 (s), 127.4 (d), 128.5 (d), 128.7 (d), 133.6
(s), 136.1 (s), 136.4 (s), 138.3 (s), 145.0 (s), 149.9 (d),
151.5 (d), 166.0 (s). Anal. Calcd for C27H25N3O2: C,
76.57; H, 5.95; N, 9.92. Found: C, 76.41; H, 6.11; N, 9.74.
(ii) From (Z)-10 (Table 1, entry 5): A solution of (Z)-10
(90 mg, 0.20 mmol) in THF–H2O (10:1, 10 mL) was heated
under reflux for 48 h in an atmosphere of Ar. The reaction
mixture was worked up as described above under method
(i), giving 15a (58 mg, 62%) and 15b (32 mg, 34%). The
products 15a and 15b thus obtained were identical (by
comparison of the IR and 1H NMR spectra and TLC
behavior) with authentic samples prepared by method (i),
respectively.
4.6. Equilibration of the diols 15a and 15b
(ii) From 15b: Dehydration of 15b (20.0 mg, 0.044 mmol)
with DBN and work-up of the reaction mixture were carried
out in a manner similar to that described above under method
(i), providing 14 (12.3 mg, 67%) as a pale yellow solid. This
sample was identical (by comparison of the 1H NMR
spectrum and TLC mobility) with the one obtained by
method (i).
A solution of 15a (20 mg, 0.044 mmol) in THF–H2O (10:1,
2.2 mL) was heated under reflux for 48 h in an atmosphere of
N2. The reaction mixture was concentrated in vacuo to leave
a yellow oil, which was estimated to be a 75:25 mixture of
1
15a and 15b by H NMR analysis. Similar treatment of
15b provided the same equilibrium mixture.
4.10. (6S,13S)-6,7,12,13-Tetrahydro-6,13-imino-5H-
pyrido[30,40:5,6]cyclooct[1,2-b]indole-4-carboxylic
acid ethyl ester (19)
4.7. Time-course of the intramolecular cycloaddition
reaction of (E)-10
A solution of (E)-10 (70 mg, 0.16 mmol) in THF–H2O
(10:1, 14 mL) was stirred at 60 ꢁC under N2. At intervals,
aliquots (0.8 mL) were withdrawn and concentrated in
vacuo. The ratio of the components in the residual oil was
determined by H NMR analysis. The results are summa-
rized in Table 2.
A solution of 14 (56 mg, 0.13 mmol) in MeOH (3 mL) was
hydrogenated over 20% Pd(OH)2–C (56 mg) at room tem-
perature and atmospheric pressure for 28 h. The catalyst
was removed by filtration, and the filtrate was concentrated
in vacuo to leave a yellow oil. Purification by flash chroma-
tography [CHCl3–MeOH (20:1)] gave 19 (40 mg, 91%) as
a pale yellow oil. [a]D24 +171 (c 0.50, CHCl3); MS m/z:
333 (M+); IR (CHCl3) n, cmꢀ1: 3465, 3375 (NH), 1713
(CO); 1H NMR (CDCl3) d: 1.36 (3H, t, J¼7 Hz), 1.78
(1H, br), 2.88 (1H, dd, J¼15.5, 1 Hz), 3.37 (1H, dd,
J¼15.5, 5 Hz), 3.49 (1H, dd, J¼18.5, 1 Hz), 3.56 (1H, dd,
J¼18.5, 5.5 Hz), 4.32 (2H, q, J¼7 Hz), 4.57 (1H, d, J¼
5.5 Hz), 4.74 (1H, d, J¼5 Hz), 7.05 (1H, dd, J¼8, 7.5 Hz),
7.12 (1H, dd, J¼8, 7.5 Hz), 7.27 (1H, d, J¼8 Hz),
7.38 (1H, d, J¼8 Hz), 7.92 (1H, s), 8.60 (1H, s), 8.90 (1H,
s); HRMS calcd for C20H19N3O2: 333.1477, found:
333.1478.
1
4.8. Intramolecular cycloaddition reaction of (E)-10 in
anhydrous THF
A solution of (E)-10 (70 mg, 0.16 mmol) in anhydrous THF
(14 mL) was stirred at 60 ꢁC for 12 h under N2. The reaction
mixture was concentrated in vacuo to give a yellow oil,
which was found to be a 1:1 mixture of (E)-10 and the cyclo-
adduct 13a by 1H NMR analysis. Compound 13a: 1H NMR
(CDCl3) d: 1.20 (3H, t, J¼7.5 Hz), 1.71 (1H, m), 1.8–2.2
(2H, m), 2.87 (1H, dd, J¼4, 3.5 Hz), 3.01 (1H, d,

12694
M. Ohba, I. Natsutani / Tetrahedron 63 (2007) 12689–12694
4.11. (6S,13S)-6,7,12,13-Tetrahydro-14-methyl-6,13-
imino-5H-pyrido[30,40:5,6]cyclooct[1,2-b]indole-
4-carboxylic acid ethyl ester (20)
4.32 and 4.34 (2H, d each, J¼13 Hz), 4.52 (1H, br), 7.05
(1H, dd, J¼8, 7.5 Hz), 7.10 (1H, dd, J¼8, 7.5 Hz), 7.25
(1H, d, J¼7.5 Hz), 7.38 (1H, d, J¼7.5 Hz), 8.07 (1H, s),
1
8.29 (1H, s), 8.59 (1H, br); H NMR (acetone-d6) d: 2.53
(i) From 19: A mixture of 19 (10 mg, 0.030 mmol), 35%
aqueous HCHO (0.01 mL), acetic acid (0.01 mL), and
MeOH (1 mL) was shaken under H2 in the presence of
20% Pd(OH)2–C (10 mg) at room temperature and atmos-
pheric pressure for 1.5 h. The catalyst was filtered off,
and the filtrate was concentrated in vacuo to leave an oil,
to which were added 10% aqueous Na2CO3 (2 mL) and
H2O (5 mL). The mixture was then extracted with CHCl3,
and the CHCl3 extracts were washed with brine, dried over
anhydrous K2CO3, and concentrated. Purification of the res-
idue by flash chromatography [CHCl3–MeOH (20:1)] fur-
nished 20 (10 mg, 96%) as a colorless oil. [a]2D6 +85.6 (c
(3H, s), 2.66 (1H, dd, J¼15.5, 1 Hz), 2.83 (1H, br), 3.03
(1H, dd, J¼17, 2.5 Hz), 3.31 (1H, dd, J¼17, 6 Hz), 3.41
(1H, dd, J¼15.5, 5.5 Hz), 4.24 (1H, d, 6 Hz), 4.30 (1H, d,
J¼5.5 Hz), 4.53 (2H, s), 6.91 (1H, dd, J¼8.5, 8 Hz), 6.99
(1H, dd, J¼8, 8 Hz), 7.26 (1H, d, J¼8.5 Hz), 7.33 (1H, d,
J¼8 Hz), 8.22 (1H, s), 8.39 (1H, s), 9.95 (1H, s); 13C
NMR (CDCl3) d: 25.3 (t), 31.0 (t), 40.2 (q), 51.8 (d), 54.3
(d), 60.5 (t), 104.0 (s), 111.1 (d), 118.2 (d), 119.4 (d),
121.8 (d), 127.0 (s), 132.9 (s), 133.9 (s), 135.2 (s), 136.2
(s), 141.2 (s), 146.6 (d), 148.0 (d); HRMS calcd for
C19H19N3O: 305.1528, found: 305.1523.
0.50, CHCl3); MS m/z: 347 (M+); IR (CHCl3) n, cmꢀ1
:
1
References and notes
3465 (NH), 1715 (CO); H NMR (CDCl3) d: 1.35 (3H, t,
J¼7 Hz), 2.59 (3H, s), 2.71 (1H, d, J¼16 Hz), 3.46 (1H, d,
J¼18.5 Hz), 3.47 (1H, dd, J¼16, 5 Hz), 3.63 (1H, dd, J¼
18.5, 5.5 Hz), 4.18 (1H, d, J¼5.5 Hz), 4.32 (2H, q, J¼
7 Hz), 4.35 (1H, d, J¼5 Hz), 7.05 (1H, dd, J¼7.5, 7 Hz),
7.12 (1H, dd, J¼8, 7 Hz), 7.28 (1H, d, J¼8 Hz), 7.39 (1H,
d, J¼7.5 Hz), 7.93 (1H, br), 8.58 (1H, s), 8.90 (1H, s);
HRMS calcd for C21H21N3O2: 347.1634, found: 347.1631.
1. Nasser, A. M. A. G.; Court, W. E. Phytochemistry 1983, 22,
2297–2300.
2. Nasser, A. M. A. G.; Court, W. E. J. Ethnopharmacol. 1984, 11,
99–117.
3. (a) Majumdar, S. P.; Potier, P.; Poisson, J. Tetrahedron Lett.
1972, 1563–1566; (b) Majumdar, S. P.; Poisson, J.; Potier, P.
Phytochemistry 1973, 12, 1167–1169; (c) Iwu, M. M.; Court,
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Court, W. E. J. Ethnopharmacol. 1981, 4, 99–109; (e) Amer,
M. M. A.; Court, W. E. Planta Med. 1981, 43, 94–95; (f)
Amer, M. A.; Court, W. E. Phytochemistry 1981, 20, 2569–
2573; (g) Endreß, S.; Takayama, H.; Suda, S.; Kitajima, M.;
(ii) From 14: A mixture of 14 (11 mg, 0.026 mmol), 35%
aqueous HCHO (0.01 mL), acetic acid (0.01 mL), and
MeOH (1 mL) was shaken under H2 in the presence of
20% Pd(OH)2–C (11 mg) at room temperature and atmos-
pheric pressure for 5 h. Work-up of the reaction mixture in
a manner similar to that described above under method (i)
provided 20 (9.0 mg, 100%). This sample was identical
(by comparison of the 1H NMR spectrum and TLC behavior)
with the one obtained by method (i).
€
Aimi, N.; Sakai, S.; Stockigt, J. Phytochemistry 1993, 32, 725–
730; (h) Sheludko, Y.; Gerasimenko, I.; Unger, M.; Kostenyuk,
I.; Stoeckigt, J. Plant Cell Rep. 1999, 18, 911–918.
4. Amer, M. M. A.; Court, W. E. Planta Med. 1980, 8–12.
5. (a) Batista, C. V. F.; Schripsema, J.; Verpoorte, R.; Rech, S. B.;
Henriques, A. T. Phytochemistry 1996, 41, 969–973; (b) Rech,
S. B.; Batista, C. V. F.; Schripsema, J.; Verpoorte, R.; Henriques,
A. T. Plant Cell, Tissue Organ Cult. 1998, 54, 61–63.
6. (a) Ohba, M.; Kubo, H.; Fujii, T.; Ishibashi, H.; Sargent, M. V.;
Arbain, D. Tetrahedron Lett. 1997, 38, 6697–6700; (b) Ohba,
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2000, 41, 10251–10255; (d) Ohba, M.; Izuta, R.; Shimizu, E.
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7. For a recent review on the oxazole Diels–Alder reactions, see:
Levin, J. I.; Laakso, L. M. The Chemistry of Heterocyclic
Compounds; Palmer, D. C., Ed.; John Wiley and Sons:
Hoboken, NJ, 2003; Vol. 60, Part A, pp 417–472.
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4.12. (6S,13S)-6,7,12,13-Tetrahydro-14-methyl-6,13-
imino-5H-pyrido[30,40:5,6]cyclooct[1,2-b]indole-
4-methanol (1)
A stirred suspension of LiAlH4 (25 mg, 0.66 mmol) in THF
(3 mL) was cooled to 0 ꢁC, and a solution of 20 (57 mg,
0.16 mmol) in THF (2 mL) was added. After the mixture
had been stirred for 30 min, the reaction was quenched by
adding 4% aqueous NaOH. The insoluble material was fil-
tered off and washed with ether. The filtrate and washings
were combined, dried over anhydrous MgSO4, and concen-
trated in vacuo. Purification of the residue by flash chroma-
tography [CHCl3–MeOH (10:1)] afforded 1 (47 mg, 94%) as
a colorless foam. [a]2D3 ꢀ46.0 (c 0.30, MeOH); MS m/z: 305
(M+); IR (CHCl3) n, cmꢀ1: 3465, 3395 (NH, OH); UV
(MeOH) lmax (log 3): 222 (4.46), 270 (3.88), 282 (sh)
(3.83), 290 (3.71); CD (MeOH) lext, nm (D3): 295 (2.98),
291 (1.79), 287 (2.93), 273 (ꢀ2.80), 259 (2.37), 251
9. Ohba, M.; Natsutani, I. Heterocycles 2004, 63, 2845–2850.
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2925.
1
(2.01), 240 (2.74), 224 (ꢀ24.5); H NMR (CDCl3) d: 2.41
(3H, s), 2.62 (1H, d, J¼16 Hz), 2.80 (1H, d, J¼17.5 Hz),
3.22 (1H, dd, J¼17.5, 5.5 Hz), 3.36 (1H, dd, J¼16,
5.5 Hz), 3.86 (1H, d, J¼5.5 Hz), 4.15 (1H, d, J¼5.5 Hz),