Intramolecular Diels-Alder reactions of oxazole-olefins: synthesis of the Rauwolfia alkaloids suaveoline and norsuaveoline

Article abstract of DOI:10.1016/j.tet.2007.07.070

A full account of the highly stereoselective total synthesis of two indole alkaloids, suaveoline (4) and norsuaveoline (5), is presented. Central features of the synthetic strategy include the conversion of l-tryptophan methyl ester (12) into the oxazole

Full text of DOI:10.1016/j.tet.2007.07.070

Tetrahedron 63 (2007) 10337–10344
Intramolecular Diels–Alder reactions of oxazole–olefins:
synthesis of the Rauwolfia alkaloids suaveoline
and norsuaveoline
b
b
Masashi Ohba,a, Itaru Natsutani and Takashi Sakuma
*
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 26 June 2007; revised 13 July 2007; accepted 17 July 2007
Available online 27 July 2007
Abstract—A full account of the highly stereoselective total synthesis of two indole alkaloids, suaveoline (4) and norsuaveoline (5), is pre-
sented. Central features of the synthetic strategy include the conversion of L-tryptophan methyl ester (12) into the oxazole derivative 11 and the
intramolecular Diels–Alder reaction of the oxazole–olefin 19 leading to the pentacyclic pyridine derivative 21.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The Diels–Alder reactions of oxazoles with olefins have be-
come useful tools for the preparation of highly substituted
pyridines, such as pyridoxine and its analogs, since the first
example of this cycloaddition reaction was reported by
Kondrat’eva in 1957.1,2 Although numerous studies have
described the utility of oxazoles for the construction of
pyridines, there have been few reports exploiting the intra-
molecular Diels–Alder reactions of oxazole–olefins for the
synthesis of pyridine-containing natural products.3,4 Re-
cently, we have achieved the synthesis of the indolopyrido-
naphthyridine alkaloid normalindine (1)5 and two
monoterpene alkaloids plectrodorine (2) and oxerine (3)6
through a route featuring the construction of the annulated
pyridines by intramolecular oxazole–olefin Diels–Alder re-
actions. The extension of this approach to the synthesis of
the macroline/sarpagine related indole alkaloids suaveoline
(4) and norsuaveoline (5) is described here.7
For the efficient construction of the DE rings of 4 and 5, ex-
ploiting the intramolecular oxazole–olefin Diels–Alder reac-
tion, we planned to employ 9 as a precursor (Scheme 1). The
requisite oxazole–olefin 9 would be obtained from 11
through the cis-selective Pictet–Spengler reaction11h,13 and
the subsequent introduction of an appropriate olefin moiety
to the oxazole aldehyde 10. According to our previously
reported procedure for the preparation of chiral 5-(amino-
methyl)oxazoles from a-amino esters,14 L-tryptophan methyl
ester (12) would be readily converted into the oxazole 11.
An important feature of this strategy is that other suave-
oline-related alkaloids, macrophylline (6),9e,g,15 macrocaffr-
ine (7),9e,15b and sellowiine (8),16 which possess different
substituents at the 20-position, should be derived from a va-
riety of oxazole–olefins 9 that are readily available via the
Wittig reaction of the aldehyde 10.
Me
OH
N
Me
N
Suaveoline (4) was isolated for the first time from the trunk
bark of Rauwolfia suaveolens by Potier and co-workers in
19728 and has since been found in other species of Rau-
wolfia.9 The structure and absolute stereochemistry of suave-
oline, proposed on the basis of spectroscopic data and
chemical correlation with ajmaline,8 were confirmed by ra-
cemic10 and enantiospecific11 syntheses of 4. On the other
hand, norsuaveoline (5) was reported as one of the 32 alka-
loids isolated from the stem bark of Rauwolfia caffra9e and
was synthesized by Cook and co-workers.12
N
H
HO
H
N
R
2: R = CO2Me
3: R = H
1
H
H
N
NH
D
N
NR1
E
N
R
N
H
20
Et
H
20
R2
H
4: R = Me
5: R = H
Keywords: Amino acids; Diels–Alder reaction; Indole alkaloids; 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
6: R1 = Me, R2 = CH2CH2OH
7: R1 = Me, R2 = CH2OH
8: R1 = R2 = H
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.070

10338
M. Ohba et al. / Tetrahedron 63 (2007) 10337–10344
N
O
N
O
N
H
H
H
H
CO2Me
lit. 17
O
a
12
C
4 – 8
NHBoc
NBoc
NHBoc
NBoc
CHO
N
H
N
H
N
H
N
H
H
H
14
13
9
10
R
N
O
N
H
H
O
N
O
b
d
c
H
H
NH2
O
NH
CO2Me
NH2
N
H
N
H
NH2
CO2Et
N
H
N
H
11
15
11
12
N
O
N
H
H
Scheme 1.
O
e
3
NR
C
NH
N
H
N
1
H
H
The synthesis of suaveoline (4) and norsuaveoline (5) began
with the conversion of the N-protected amino ester 13,17 de-
rived from 12, into the oxazole 14 (Scheme 2). Reaction of
13 with a-lithiated methyl isocyanide at ꢀ78 ꢁC was ef-
fected according to our previous method,14 affording 14 in
82% yield. Deprotection of 14 with trifluoroacetic acid
gave the amino oxazole 11 (98% yield), which was shown
to have 97% enantiomeric purity by Mosher’s method.
CO2Et
CO2Et
16
17: R = H
18: R = Boc
f
N
N
O
H
H
O
g
h
NBoc
CHO
NR
N
N
H
H
H
H
With the amino oxazole 11 in hand, we set out to explore the
cis-selective Pictet–Spengler reaction.11h,13 Bailey et al.
reported that the kinetically controlled Pictet–Spengler reac-
tion of 25 with the aldehyde 26, where the hydroxy-protect-
ing group is bulky and contains two remote aromatic rings
that are able to p-stack to the indole moiety, yielded only
the cis-tetrahydro-b-carboline 27,11h although the related re-
action of 12 possessing the methyl ester group instead of the
cyanomethyl group in 25 furnished a 3:1 mixture of the cis-
isomer 28 and the trans-isomer 31 (Scheme 3).18 Unfortu-
nately, application of this procedure to the amino oxazole
11 gave a mixture of 29 and 32 in 36% yield with poor
stereoselectivity (cis–trans¼3:1).
10
Et
19: R = Boc
20: R = H
H
H
j
i
N
N
NR
NR
N
H
N
Me
H
H
Et
Et
21: R = Boc
5: R = H
23: R = Boc
4: R = H
24: R = Me
k
l
k
m
22: R = CH2Ph
In 1984, Massiot’s group published a modification of the
Pictet–Spengler cyclization of tryptamines using activated
alkynes as partners.19 Treatment of 11 with ethyl propio-
late followed by trifluoroacetic acid, however, afforded an
inseparable 2:1 mixture of 17 and 35 in 57% yield
(Scheme 4). The modified Pictet–Spengler cyclization of
the Nb-benzyl derivative 33, prepared by reductive alkyl-
ation of 11, was also tried, but provided 34 and 36 as
an inseparable mixture in 74% yield with high trans-selec-
tivity (cis–trans¼1:19).20
Scheme 2. Reagents and conditions: (a) LiCH2NC, THF, ꢀ78 ꢁC, 2.5 h; (b)
CF3CO2H, CH2Cl2, 0 ꢁC, 4 h; (c) HO2CCH2CO2Et, (EtO)2P(O)CN, Et3N,
DMF, 0 ꢁC, 30 min then rt, 30 min; (d) (1) POCl3, rt, 6 days; (2) 10% aque-
ous Na2CO3; (e) 20% Pd(OH)2–C, H2, EtOH, 1 atm, rt, 22 h; (f) (Boc)2O,
CHCl3, reflux, 24 h; (g) DIBALH, CH2Cl2, ꢀ78 ꢁC, 80 min; (h)
Ph3P]CHCH2CH3, benzene, rt, 30 min; (i) DBN, xylene, reflux, 9 h;
(j) NaH, MeI, DMF, rt, 20 min; (k) CF3CO2H, CH2Cl2, 0 ꢁC, 3 h; (l)
PhCH2Br, Et3N, CH3CN, rt, 40 min; (m) 35% aqueous HCHO, NaBH4,
AcOH, rt, 1 h.
enamino ester structure and geometry of the exocyclic dou-
ble bond in 16 were assigned on the basis of the facts that
one olefinic proton appeared at d 5.03 and the indole
Na-proton (d 8.21 or 8.59) resonated at higher field than the
corresponding proton (d 13.05) of the previously reported
enamino ester 375b that possesses the E configuration due
to intramolecular hydrogen bonding between the Na-proton
and the ester carbonyl group. Hydrogenation of 16 employ-
ing Pearlman’s catalyst proceeded stereoselectively, fur-
nishing the cis-tetrahydro-b-carboline 17 in 84% yield
with no accompanying trans-isomer. The cis relationship
for the C(1)- and C(3)-protons in 17 was confirmed by
NOE experiments.
Since the Pictet–Spengler reaction of the amino oxazole 11
failed to give the desired cis-1,3-disubstituted tetrahydro-
b-carboline in satisfactory yield and with the desired selec-
tivity, we next investigated the construction of the C ring by
taking advantage of the Bischler–Napieralski cyclization/
reduction technology. Condensation of 11 with monoethyl
malonate using diethyl phosphorocyanidate21 as a coupling
reagent provided the amide 15 (88% yield), which was then
subjected to the Bischler–Napieralski cyclization with
POCl3 according to the method of Hino and co-workers.22
Basification of the resulting iminium salt with Na2CO3
afforded the (Z)-ester 16 in 50% yield from 15. The

M. Ohba et al. / Tetrahedron 63 (2007) 10337–10344
10339
H
H
R
R
1) OHC(CH2)2OTBDPS
H
R
+
NH
NH
26
N
H
N
H
H
H
NH2
2) CF3CO2H
N
H
OTBDPS
OTBDPS
25, 12, 11
27–29
30–32
N
O
25, 27, 30 : R = CH2CN
12, 28, 31 : R = CO2Me
11, 29, 32 : R =
Scheme 3.
Table 1. Intramolecular Diels–Alder reactions of the oxazole–olefin 19
Entry Solvent Additive (equiv) Temp (ꢁC) Time (h) 21, yield (%)
Having succeeded in the stereoselective construction of the
C ring, our attention turned next to the introduction of an ole-
finic dienophile into the amino ester 17. For this purpose, the
amino group of 17 was first protected with di-tert-butyl
dicarbonate to give 18 in 87% yield. The 1H NMR spectrum
of 17 indicated two methylene protons adjacent to the ester
group at d 2.80 and 2.88, whereas one of the corresponding
protons of the N-Boc derivative 18 appeared at d 1.85 and
1.99.23 The large upfield shift in 18 is probably due to the
shielding effect arising from the oxazole ring of the con-
former 18A, where both C(1)- and C(3)-substituents occupy
pseudo-axial positions.13b Such a conformation, after the
introduction of an olefinic dienophile at the 1-position, is
favorable for the intramolecular Diels–Alder reaction. The
N-protected ester 18 was then reduced with diisobutylalumi-
num hydride (DIBALH) at ꢀ78 ꢁC to afford the aldehyde
10, a key intermediate of our strategy, in 95% yield. To
achieve the synthesis of suaveoline (4) and norsuaveoline
(5), which have an ethyl group at the 20-position, the Wittig
reaction of 10 was carried out using the phosphorane
prepared from n-propyltriphenylphosphonium bromide and
t-BuOK, furnishing the (Z)-olefin 19 in 73% yield. The
assignment of geometry in 19 was based on the coupling
constant (J¼10.5 Hz) between the two olefinic protons of
the amine 20 derived from 19.
1
2
3
4
5
6
o-DCB
—
160
o-DCB Cu(OTf)2 (0.05) 160
8
3
12
24
24
9
12
0
21
50
65
69
o-DCB DBN (1.5)
Xylene DBN (1.6)
Xylene DBN (5.0)
Xylene DBN (20)
160
Reflux
Reflux
Reflux
Addition of Cu(OTf)2 failed to give 21 due to rapid decom-
position of 19 (entry 2), although we reported that this Lewis
acid prompted the cycloaddition leading to cyclopenta[c]-
pyridines.24 However, treatment of 19 in o-DCB at 160 ꢁC
in the presence of 1.5 equiv of 1,5-diazabicyclo[4.3.0]-
non-5-ene (DBN), an application of Weinreb’s procedure,3,4c
improved slightly the yield of 21 (entry 3). Furthermore, al-
teration of the solvent from o-DCB to xylene raised the yield
of 21 to 50% (entry 4). By use of 5.0 equiv of DBN, the pyr-
idine 21 was obtained in 65% yield (entry 5). Ultimately,
treatment of 19 with 20 equiv of DBN in boiling xylene for
9 h gave 21 in 69% yield as the best result (entry 6). It is likely
that DBN might serve as a scavenger of H2O and promote the
conversion of the initially formed Diels–Alder cycloadduct
into the pyridine 21.3b
Methylation of 21 with MeI was performed in the presence
of NaH in DMF, affording the indole Na-Me derivative 23
in 98% yield. Finally, removal of the Boc group in 23 with
trifluoroacetic acid provided the first target compound 4
N
O
H
EtO2C
N
Me
N
H
N
H
EtO2C
NBoc
1
[[a]2D8 ꢀ1.4 (c 0.50, CHCl3)] in 82% yield. The H and
O
N
H
13C NMR (CDCl3), UV (EtOH), CD (cyclohexane), and
mass spectral data for this sample were in agreement with
those reported for natural suaveoline [[a]D 0ꢂ2 (c 1,
CHCl3)]8,9f and/or Cook’s synthetic sample [[a]2D5 ꢀ9.33
(c 0.30, CHCl3)].11a,b In addition, the spectral properties
and specific rotation of 24 [[a]2D9 ꢀ91.1 (c 0.92, CHCl3)],
prepared from 4 according to Potier’s procedure,8 were
18A
37
The results of the intramolecular Diels–Alder reaction of the
oxazole–olefin 19 are summarized in Table 1 and several
comments are in order. When a solution of 19 in o-dichloro-
benzene (o-DCB) was heated at 160 ꢁC for 8 h, the desired
pyridine 21 was obtained, but only in 12% yield (entry 1).
N
O
N
O
N
H
H
H
1)
HC CCO2Et
O
+
NR
NR
2) CF3CO2H
NHR
N
H
N
H
N
H
H
H
CO2Et
CO2Et
11, 33
17, 34
35, 36
11, 17, 35 : R = H 33, 34, 36 : R = CH2Ph
Scheme 4.

10340
M. Ohba et al. / Tetrahedron 63 (2007) 10337–10344
found to match those reported for Nb-methylsuaveoline
[[a]D ꢀ93 (c 0.89, CHCl3),8 [a]D25 ꢀ89.25 (c 0.37,
CHCl3)11a,b]. On the other hand, deprotection of 21 with tri-
fluoroacetic acid furnished the second target compound 5
[[a]3D0 +19.6 (c 0.50, CHCl3)] in 88% yield. Although the
1H and 13C NMR (CDCl3), CD (EtOH) spectra, and TLC
mobility (three solvent systems) of this sample were shown
to be virtually identical with those of Cook’s synthetic nor-
suaveoline [[a]2D7 ꢀ3.2 (c 1.00, CHCl3)],12 the specific rota-
tions of the two synthetic samples were in disagreement.25
However, we found again that the specific rotation of 22
[[a]2D7 ꢀ132.2 (c 0.50, CHCl3)], derived from 5, matched
that recorded for Nb-benzylnorsuaveoline [[a]2D7 ꢀ143.2 (c
1.00, CHCl3)].12
brown solid. Purification by flash chromatography
[AcOEt–hexane (1:1)] gave 14 (13.3 g, 82%) as a slightly
yellow solid. Recrystallization from AcOEt–hexane (1:1)
provided an analytical sample as colorless minute needles,
mp 163–164 ꢁC. [a]2D5 ꢀ34.5 (c 0.50, MeOH); IR (Nujol)
n, cmꢀ1: 3370 (NH), 1678 (carbamate CO); 1H NMR
(CDCl3) d: 1.41 (9H, s), 3.31 (2H, br), 4.90 (1H, br), 5.25
(1H, br), 6.80 (1H, s), 6.88 (1H, s), 7.11 (1H, dd, J¼8,
7.5 Hz), 7.19 (1H, dd, J¼8, 7.5 Hz), 7.35 (1H, d, J¼8 Hz),
7.50 (1H, d, J¼8 Hz), 7.81 (1H, s), 8.06 (1H, s). Anal. Calcd
for C18H21N3O3: C, 66.04; H, 6.47; N, 12.84. Found: C,
65.81; H, 6.51; N, 12.74.
4.1.2. (S)-a-(5-Oxazolyl)-1H-indole-3-ethanamine (11). A
mixture of 14 (8.29 g, 25.3 mmol), trifluoroacetic acid
(60 mL), and CH2Cl2 (60 mL) was stirred at 0 ꢁC for 4 h.
The reaction mixture was concentrated invacuo, and the resi-
due was dissolved in H2O. The aqueous solution was made
basic with K2CO3 and extracted with CHCl3. The CHCl3 ex-
tracts were washed with brine, dried, and concentrated to
leave a yellow oil. Purification by flash chromatography
[AcOEt–EtOH (5:2)] furnished 11 (5.64 g, 98%) as a pale
yellow oil. [a]2D6 +23.4 (c 0.50, MeOH); MS m/z: 227
3. Conclusion
The total synthesis of the Rauwolfia alkaloids, suaveoline (4)
and norsuaveoline (5), was achieved with 10% and 11%
overall yields, respectively, from L-tryptophan methyl ester
(12) through a route featuring the efficient construction of
the annulated pyridine by the intramolecular Diels–Alder
reaction of the oxazole–olefin 19. The utility of the aldehyde
10, a key intermediate of our synthetic strategy, has been ex-
emplified by our recent synthesis of Na-demethyl-20-de-
ethylsuaveoline, the structure proposed for sellowiine (8).26
1
(M+); IR (CHCl3) n, cmꢀ1: 3480 (NH), 3370 (NH2); H
NMR (CDCl3) d: 1.62 (2H, br), 3.08 (1H, dd, J¼14, 9 Hz),
3.34 (1H, dd, J¼14, 5 Hz), 4.41 (1H, dd, J¼9, 5 Hz), 6.91
(1H, s), 7.01 (1H, d, J¼2.5 Hz), 7.13 (1H, dd, J¼8, 7 Hz),
7.21 (1H, dd, J¼8.5, 7 Hz), 7.38 (1H, d, J¼8.5 Hz), 7.58
(1H, d, J¼8 Hz), 7.84 (1H, s), 8.11 (1H, s); HRMS calcd
for C13H13N3O: 227.1059, found: 227.1054. For determina-
tion of the enantiomeric purity of this sample, a mixture of
the Mosher amides was prepared from (R)-a-methoxy-a-
4. Experimental
4.1. General methods
1
(trifluoromethyl)phenylacetyl chloride. Based on H NMR
All melting points were determined on a Yamato MP-1 cap-
illary melting point apparatus. Flash chromatography27 was
carried out using Merck silica gel 60 (No. 9385). Unless oth-
erwise noted, the organic solutions obtained after extraction
were dried over anhydrous K2CO3 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 spectrophotometer, 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. 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.
(CDCl3) analysis employing the methoxy groups (major
isomer: d 3.19, minor isomer: d 3.16) of the mixture, an
enantiomeric purity of 97% was assigned to the oxazole
amine 11.
4.1.3. Pictet–Spengler reaction of the amino oxazole 11
and the aldehyde 26: preparation of the tetrahydro-
b-carbolines 29 and 32. A mixture of 11 (50 mg,
˚
0.22 mmol), 26 (90 mg, 0.29 mmol), and 3 A molecular
sieves in CH2Cl2 (5 mL) was stirred at room temperature
for 24 h. After addition of trifluoroacetic acid (four drops)
at ꢀ78 ꢁC, the mixture was stirred at ꢀ78 ꢁC for 1 h and
at room temperature for 1 h, made basic with 10% aqueous
Na2CO3, and extracted with CHCl3. The CHCl3 extracts
were washed with brine, dried, and concentrated. The resid-
ual oil was then subjected to flash chromatography [AcOEt–
hexane (1:1)]. Earlier fractions afforded the 1,3-trans-iso-
mer 32 (11 mg, 10%) as a pale yellow oil. MS m/z: 521
4.1.1. (S)-[2-(1H-Indol-3-yl)-1-(5-oxazolyl)ethyl]carba-
mic acid 1,1-dimethylethyl ester (14). A solution of methyl
isocyanide (9.21 g, 0.224 mol) in THF (250 mL) was cooled
to ꢀ78 ꢁC in an atmosphere of N2, and a 1.6 M solution
(140 mL, 0.224 mol) of BuLi in hexane was added dropwise
over 30 min. After the mixture had been stirred for 40 min,
a solution of 1317 (15.8 g, 49.6 mmol) in THF (120 mL)
was introduced dropwise over 40 min. Stirring was contin-
ued at ꢀ78 ꢁC for 2.5 h, and the reaction was quenched by
adding AcOH (14 mL). The reaction mixture was warmed
to room temperature and concentrated under reduced pres-
sure. The residue was partitioned between H2O and ether,
and the ethereal extracts were washed with brine, dried
over anhydrous MgSO4, and concentrated to leave a pale
1
(M+); H NMR (CDCl3) d: 1.13 (9H, s), 2.05 (2H, m),
2.97 (1H, ddd, J¼15.5, 7, 1.5 Hz), 3.18 (1H, dd, J¼15.5,
5 Hz), 3.93 (1H, m), 3.98 (1H, m), 4.30 (1H, t, J¼6.5 Hz),
4.44 (1H, dd, J¼7, 5 Hz), 6.89 (1H, s), 7.1–7.7 (14H, m),
7.81 (1H, s), 8.43 (1H, s). Later fractions of the above chro-
matography furnished the 1,3-cis-isomer 29 (30 mg, 26%) as
1
a pale yellow oil. MS m/z: 521 (M+); H NMR (CDCl3) d:
1.12 (9H, s), 1.94 (1H, ddd, J¼14.5, 7.5, 4 Hz), 2.24 (1H,
m), 2.97 (1H, ddd, J¼15, 10.5, 2.5 Hz), 3.13 (1H, ddd,
J¼15, 4, 2.5 Hz), 3.96 (2H, m), 4.28 (1H, dd, J¼10.5,
4 Hz), 4.46 (1H, m), 7.06 (1H, s), 7.1–7.7 (14H, m), 7.86
(1H, s), 8.91 (1H, s).

M. Ohba et al. / Tetrahedron 63 (2007) 10337–10344
10341
4.1.4. Modified Pictet–Spengler reaction of the amino
oxazole 11 and ethyl propiolate: preparation of the tetra-
hydro-b-carbolines 17 and 35. A solution of 11 (43 mg,
0.19 mmol) and ethyl propiolate (91 mg, 0.93 mmol) in
CH2Cl2 (2 mL) was heated under reflux for 4 days. After
cooling to ꢀ78 ꢁC, trifluoroacetic acid (0.15 mL) was
added. The mixture was then stirred at ꢀ78 ꢁC for
30 min and at room temperature for 1 h and worked up
as described above for 29 and 32. Purification of the crude
oil by flash chromatography [AcOEt–hexane (4:1)] pro-
vided a 2:1 mixture (35 mg, 57%) of 17 and 35 as a yellow
oil. 1H NMR (CDCl3) trans-isomer 35 d: 1.29 (3H, t,
J¼7 Hz), 2.92 (2H, m), 2.95 (1H, m), 3.18 (1H, dd, J¼
16.5, 5 Hz), 4.25 (2H, q, J¼7 Hz), 4.39 (1H, dd, J¼8,
5 Hz), 4.50 (1H, t, J¼7.5 Hz), 6.93 (1H, s), 7.12 (1H,
dd, J¼8, 7 Hz), 7.18 (1H, dd, J¼8.5, 7 Hz), 7.35 (1H,
d, J¼8.5 Hz), 7.51 (1H, d, J¼8 Hz), 7.84 (1H, s), 8.64
4.1.7. (S)-3-[[2-(1H-Indol-3-yl)-1-(5-oxazolyl)ethyl]-
amino]-3-oxopropanoic acid ethyl ester (15). To a cooled
solution of 11 (2.80 g, 12.3 mmol) in DMF (70 mL) were
successively added monoethyl malonate (2.12 g,
16 mmol), diethyl phosphorocyanidate (4.08 g, 25 mmol),
and Et3N (2.51 g, 25 mmol). After stirring at 0 ꢁC for
30 min and at room temperature for 30 min, the reaction
mixture was concentrated in vacuo, and the residue was par-
titioned between H2O and AcOEt. The AcOEt extracts were
washed with brine, dried over anhydrous MgSO4, and con-
centrated to leave a brown oil, which was purified by flash
chromatography [AcOEt–hexane (10:1)] to give 15
(3.71 g, 88%) as a yellow solid. Recrystallization from
AcOEt–hexane (1:2) afforded an analytical sample as color-
less needles, mp 109–110 ꢁC. [a]D28 ꢀ51.6 (c 0.50, CHCl3);
IR (Nujol) n, cmꢀ1: 3320 (NH), 1740 (ester CO), 1647
1
(amide CO); H NMR (CDCl3) d: 1.26 (3H, t, J¼7.5 Hz),
1
(1H, s). The H NMR spectral data arising from the cis-
3.26 and 3.28 (2H, d each, J¼18 Hz), 3.34 (2H, d,
J¼7 Hz), 4.14 (2H, q, J¼7.5 Hz), 5.60 (1H, dt, J¼8,
7 Hz), 6.83 (1H, s), 6.92 (1H, d, J¼2 Hz), 7.10 (1H, dd,
J¼8.5, 8 Hz), 7.19 (1H, dd, J¼8.5, 8 Hz), 7.34 (1H, d,
J¼8.5 Hz), 7.52 (1H, d, J¼8.5 Hz), 7.60 (1H, d, J¼8 Hz),
7.81 (1H, s), 8.10 (1H, s). Anal. Calcd for C18H19N3O4: C,
63.33; H, 5.61; N, 12.31. Found: C, 63.29; H, 5.56; N, 12.22.
isomer were in agreement with those of 17 obtained by
reduction of 16.
4.1.5. (S)-N-Benzyl-a-(5-oxazolyl)-1H-indole-3-ethan-
amine (33). A solution of 11 (225 mg, 0.99 mmol) and benz-
aldehyde (138 mg, 1.30 mmol) in MeOH (4 mL) was heated
under reflux for 2 h. After cooling to 0 ꢁC, NaBH4 (61 mg,
1.6 mmol) was added, and the mixture was stirred at room
temperature for 3 h and concentrated in vacuo. The residue
was partitioned between CHCl3 and H2O. The CHCl3 ex-
tracts were washed with brine, dried over anhydrous
MgSO4, and concentrated to leave a yellow oil. Purification
by flash chromatography [AcOEt–hexane (2:1)] gave 33
(259 mg, 82%) as a slightly yellow oil. [a]2D6 ꢀ36.7 (c
4.1.8. [S-(Z)]-[2,3,4,9-Tetrahydro-3-(5-oxazolyl)-1H-pyr-
ido[3,4-b]indol-1-ylidene]acetic acid ethyl ester (16). A
mixture of 15 (219 mg, 0.64 mmol) and POCl3 (3 mL) was
stirred at room temperature for 6 days. After excess POCl3
was removed by vacuum distillation, the residue was dis-
solved in CHCl3. The CHCl3 solution was poured into
10% aqueous Na2CO3 (18 mL), and the aqueous layer was
separated and extracted with CHCl3. The combined CHCl3
extracts were washed successively with saturated aqueous
NaHCO3 and brine, dried, and concentrated. Purification
of the residual oil by flash chromatography [AcOEt–hexane
(1:2)] provided 16 (104 mg, 50%) as a slightly yellow solid,
which was recrystallized from AcOEt–hexane (1:3) to give
an analytical sample as colorless fine needles, mp 213–
0.51, MeOH); MS m/z: 317 (M+); IR (CHCl3) n, cmꢀ1
:
1
3480, 3300 (NH); H NMR (CDCl3) d: 1.62 (1H, br), 3.23
(1H, dd, J¼14.5, 8 Hz), 3.25 (1H, dd, J¼14.5, 6.5 Hz),
3.59 and 3.77 (2H, d each, J¼13.5 Hz), 4.18 (1H, dd, J¼8,
6.5 Hz), 6.90 (1H, s), 6.92 (1H, br s), 7.05–7.25 (7H, m),
7.35 (1H, d, J¼8 Hz), 7.50 (1H, d, J¼8 Hz), 7.85 (1H, s),
8.01 (1H, s); HRMS calcd for C20H19N3O: 317.1528, found:
317.1528.
214 ꢁC. [a]D29 ꢀ156 (c 0.20, CHCl3); IR (CHCl3) n, cmꢀ1
:
1
3470, 3310 (NH), 1651 (CO); H NMR (CDCl3) d: 1.31
(3H, t, J¼7 Hz), 3.31 (1H, dd, J¼15.5, 8 Hz), 3.37 (1H,
dd, J¼15.5, 5.5 Hz), 4.19 (2H, q, J¼7 Hz), 4.96 (1H, dd,
J¼8, 5.5 Hz), 5.03 (1H, s), 6.98 (1H, s), 7.16 (1H, dd, J¼
8, 7 Hz), 7.29 (1H, dd, J¼7.5, 7 Hz), 7.38 (1H, d,
J¼8 Hz), 7.57 (1H, d, J¼7.5 Hz), 7.82 (1H, s), 8.21 (1H,
s), 8.59 (1H, s). Anal. Calcd for C18H17N3O3: C, 66.86; H,
5.30; N, 13.00. Found: C, 66.63; H, 5.27; N, 12.79.
4.1.6. Modified Pictet–Spengler reaction of the N-benz-
ylamino oxazole 33 and ethyl propiolate: preparation of
the tetrahydro-b-carbolines 34 and 36. The reaction of
33 (59 mg, 0.19 mmol) and work-up of the reaction mixture
were effected in a manner similar to those described above
for 17 and 35. Purification of the crude oil by flash chroma-
tography [AcOEt–hexane (1:2)] furnished a 1:19 mixture
1
(57 mg, 74%) of 34 and 36 as a pale brown oil. H NMR
(CDCl3) cis-isomer 34 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, d, J¼10.5 Hz), 4.40 (1H, d, J¼6.5 Hz), 6.64 (1H, s),
7.13 (1H, dd, J¼8, 7 Hz), 7.19 (1H, dd, J¼8, 7 Hz), 7.25–
7.5 (6H, m), 7.57 (1H, d, J¼8 Hz), 7.84 (1H, s), 8.78 (1H,
s); trans-isomer 36 d: 1.21 (3H, t, J¼7 Hz), 2.95 (1H, dd,
J¼17, 9.5 Hz), 3.00 (1H, dd, J¼17, 5 Hz), 3.07 (1H, dd,
J¼15.5, 4 Hz), 3.18 (1H, dd, J¼15.5, 10.5 Hz), 3.44 and
3.72 (2H, d each, J¼14 Hz), 4.10 (2H, m), 4.23 (1H, dd,
J¼9.5, 5 Hz), 4.54 (1H, dd, J¼10.5, 4 Hz), 7.13 (1H, s),
7.1–7.35 (7H, m), 7.33 (1H, d, J¼8 Hz), 7.57 (1H, d,
J¼8 Hz), 7.90 (1H, s), 8.66 (1H, s).
4.1.9. (1S,3S)-2,3,4,9-Tetrahydro-3-(5-oxazolyl)-1H-pyr-
ido[3,4-b]indole-1-acetic acid ethyl ester (17). A solution
of 16 (3.18 g, 9.8 mmol) in EtOH (100 mL) was hydroge-
nated over 20% Pd(OH)2–C (3.2 g) at room temperature
and atmospheric pressure for 22 h. The catalyst was re-
moved by filtration, and the filtrate was concentrated in va-
cuo to leave a yellow oil, which was purified by flash
chromatography [AcOEt–hexane (5:1)] to afford 17
(2.70 g, 84%) as a pale yellow glass. [a]2D5 +27.9 (c 0.25,
CHCl3); MS m/z: 325 (M+); IR (CHCl3) n, cmꢀ1: 3465,
1
3425 (NH), 1720 (CO); H NMR (CDCl3) d: 1.31 (3H, t,
J¼7 Hz), 1.75 (1H, br), 2.80 (1H, dd, J¼16.5, 8.5 Hz),
2.88 (1H, dd, J¼16.5, 4.5 Hz), 2.99 (1H, ddd, J¼15, 10.5,
2.5 Hz), 3.13 (1H, ddd, J¼15, 4, 2 Hz), 4.24 and 4.27 (2H,

10342
M. Ohba et al. / Tetrahedron 63 (2007) 10337–10344
dq each, J¼14.5, 7 Hz), 4.30 (1H, dd, J¼10.5, 4 Hz), 4.67
(1H, dddd, J¼8.5, 4.5, 2.5, 2 Hz), 7.08 (1H, s), 7.12 (1H,
dd, J¼8, 7 Hz), 7.18 (1H, dd, J¼8.5, 7 Hz), 7.35 (1H, d,
J¼8.5 Hz), 7.51 (1H, d, J¼8 Hz), 7.89 (1H, s), 8.79 (1H,
s); HRMS calcd for C18H19N3O3: 325.1427, found:
325.1429.
by flash chromatography [AcOEt–hexane (1:3)] afforded
19 (342 mg, 73%) as a slightly yellow glass. [a]2D5 +119 (c
0.56, CHCl3); MS m/z: 407 (M+); IR (CHCl3) n, cmꢀ1
:
1
3460 (NH), 1686 (CO); H NMR (CDCl3) d: 0.84 (3H, t,
J¼7.5 Hz), 1.57 (9H, s), 1.64 (1H, br), 1.79 (2H, br), 2.25
(1H, br), 3.27 (2H, m), 5.10 (1H, br), 5.45–5.65 (2H, m),
5.93 and 6.10 (1H, br each), 6.59 and 6.61 (1H, s each),
7.14 (1H, dd, J¼7.5, 7 Hz), 7.18 (1H, dd, J¼7.5, 7 Hz),
7.28 (1H, d, J¼7.5 Hz), 7.55 (1H, d, J¼7.5 Hz), 7.75 and
7.76 (1H, s each), 7.94 and 8.03 (1H, br each); HRMS calcd
for C24H29N3O3: 407.2209, found: 407.2209. A portion of
this sample was deprotected with trifluoroacetic acid in
CH2Cl2 to furnish 20 as a pale yellow solid. 1H NMR
(CDCl3) d: 0.99 (3H, t, J¼7.5 Hz), 1.71 (1H, br), 2.11
(2H, dt, J¼7.5, 7.5 Hz), 2.53 (1H, m), 2.73 (1H, ddd,
J¼15, 9, 8 Hz), 2.96 (1H, dd, J¼15, 11 Hz), 3.13 (1H, dd,
J¼15, 4 Hz), 4.29 (1H, dd, J¼11, 4 Hz), 4.37 (1H, m),
5.52 (1H, ddd, J¼10.5, 9, 5.5 Hz), 5.69 (1H, dt, J¼10.5,
7.5 Hz), 7.08 (1H, s), 7.12 (1H, dd, J¼8, 7.5 Hz), 7.18
(1H, dd, J¼8, 7.5 Hz), 7.32 (1H, d, J¼8 Hz), 7.50 (1H, d,
J¼8 Hz), 7.88 (1H, s), 8.09 (1H, s).
4.1.10. (1S,3S)-2-[(1,1-Dimethylethoxy)carbonyl]-
2,3,4,9-tetrahydro-3-(5-oxazolyl)-1H-pyrido[3,4-b]in-
dole-1-acetic acid ethyl ester (18). A mixture of 17 (2.34 g,
7.2 mmol) and di-tert-butyl dicarbonate (2.41 g, 11 mmol)
in CHCl3 (30 mL) was heated under reflux for 24 h. The re-
action mixture was concentrated in vacuo, and the residue
was purified by flash chromatography [AcOEt–hexane
(1:2)] to give 18 (2.67 g, 87%) as a yellow solid. Recrystal-
lization from AcOEt–hexane (1:1) provided an analytical
sample as colorless needles, mp 188.5–190 ꢁC. [a]D26 +227
(c 0.25, CHCl3); IR (Nujol) n, cmꢀ1: 3420 (NH), 1709 (ester
CO), 1690 (carbamate CO); 1H NMR (CDCl3) d: 1.27 (3H,
br), 1.56 (9H, s), 1.85 and 1.99 (1H, br each), 2.60 and 2.71
(1H, br each), 3.28 (2H, d, J¼3.5 Hz), 4.18 (2H, br), 5.44
and 5.55 (1H, br each), 5.91 and 6.09 (1H, br each), 6.61
(1H, s), 7.13 (1H, dd, J¼8, 7.5 Hz), 7.19 (1H, dd, J¼8.5,
7.5 Hz), 7.34 (1H, d, J¼8.5 Hz), 7.55 (1H, d, J¼8 Hz),
7.79 (1H, s), 8.96 and 9.08 (1H, br each). Anal. Calcd for
C23H27N3O5: C, 64.93; H, 6.40; N, 9.88. Found: C, 64.83;
H, 6.43; N, 9.76.
4.1.13. (6S,13S)-4-Ethyl-6,7,12,13-tetrahydro-6,13-
imino-5H-pyrido[30,40:5,6]cyclooct[1,2-b]indole-14-carb-
oxylic acid 1,1-dimethylethyl ester (21). A mixture of 19
(297 mg, 0.73 mmol), DBN (1.80 g, 14.5 mmol), and xylene
(10 mL) was heated under reflux for 9 h in an atmosphere of
Ar. The reaction mixture was concentrated in vacuo to leave
a dark brown oil, which was purified by flash chromato-
graphy [AcOEt–hexane (1:1) and then AcOEt] to give 21
(196 mg, 69%) as a yellow solid. Recrystallization from
AcOEt–hexane (2:1) yielded an analytical sample as color-
less needles, mp 230–232 ꢁC. [a]D25 ꢀ6.0 (c 0.25, CHCl3);
IR (Nujol) n, cmꢀ1: 3300 (NH), 1661 (CO); 1H NMR
(CDCl3) d: 1.15 (3H, t, J¼7.5 Hz), 1.48 and 1.50 (9H, s
each), 2.50 (2H, q, J¼7.5 Hz), 2.86 (1H, d, J¼15.5 Hz),
2.91 and 2.94 (1H, d each, J¼17 Hz), 3.22 and 3.27 (1H,
dd each, J¼17, 5.5 Hz), 3.43 and 3.47 (1H, dd each,
J¼15.5, 5.5 Hz), 5.58 and 5.60 (1H, d each, J¼5.5 Hz),
5.76 and 5.78 (1H, d each, J¼5.5 Hz), 7.04 and 7.06 (1H,
dd each, J¼8, 7.5 Hz), 7.11 and 7.13 (1H, dd each, J¼8,
7.5 Hz), 7.27 (1H, d, J¼8 Hz), 7.36 and 7.39 (1H, d each,
J¼8 Hz), 7.91 and 8.05 (1H, br each), 8.16 (1H, s), 8.37
(1H, s). Anal. Calcd for C24H27N3O2: C, 74.01; H, 6.99;
N, 10.79. Found: C, 73.89; H, 7.02; N, 10.72.
4.1.11. (1S,3S)-1,3,4,9-Tetrahydro-3-(5-oxazolyl)-1-(2-
oxoethyl)-2H-pyrido[3,4-b]indole-2-carboxylic acid 1,1-
dimethylethyl ester (10). A stirred solution of 18
(518 mg, 1.22 mmol) in CH2Cl2 (5 mL) was cooled to
ꢀ78 ꢁC in an atmosphere of N2, and a 1.0 M solution
(2.4 mL, 2.4 mmol) of DIBALH in hexane was added drop-
wise over 5 min. The reaction mixture was stirred at ꢀ78 ꢁC
for 80 min and quenched by adding MeOH (0.2 mL). After
stirring for a further 30 min at room temperature, the mixture
was concentrated in vacuo. The residue was purified by flash
chromatography (AcOEt) to furnish 10 (440 mg, 95%) as
a colorless glass. [a]D26 +181 (c 0.25, CHCl3); MS m/z: 381
(M+); IR (CHCl3) n, cmꢀ1: 3440 (NH), 1717 (aldehyde
CO), 1690 (carbamate CO); 1H NMR (CDCl3) d: 1.56
(9H, s), 2.10 (1H, br), 2.92 (1H, br), 3.28 (2H, d,
J¼3.5 Hz), 5.59 and 5.63 (1H, br each), 5.93 and 6.10
(1H, br each), 6.63 (1H, s), 7.14 (1H, dd, J¼7.5, 7 Hz),
7.20 (1H, dd, J¼7.5, 7 Hz), 7.33 (1H, d, J¼7.5 Hz), 7.55
(1H, d, J¼7.5 Hz), 7.83 (1H, s), 8.44 and 8.62 (1H, br
each), 9.76 (1H, s); HRMS calcd for C21H23N3O4:
381.1689, found: 381.1673.
4.1.14. (6S,13S)-4-Ethyl-6,7,12,13-tetrahydro-7-methyl-
6,13-imino-5H-pyrido[30,40:5,6]cyclooct[1,2-b]indole-14-
carboxylic acid 1,1-dimethylethyl ester (23). A mixture of
21 (100 mg, 0.26 mmol) and 60% NaH (23 mg, 0.58 mmol)
in DMF (3 mL) was stirred at 0 ꢁC, and a solution of MeI
(40 mg, 0.28 mmol) in DMF (2 mL) was added. After stir-
ring for 20 min at room temperature, the reaction mixture
was concentrated in vacuo. The residue was partitioned be-
tween H2O and AcOEt. The AcOEt extracts were washed
with brine, dried, and concentrated to furnish 23 (102 mg,
98%) as a slightly yellow glass. [a]3D0 ꢀ14.9 (c 0.50,
CHCl3); MS m/z: 403 (M+); IR (CHCl3) n, cmꢀ1: 1686
4.1.12. (1S,3S)-1,3,4,9-Tetrahydro-3-(5-oxazolyl)-1-(2Z)-
2-pentenyl-2H-pyrido[3,4-b]indole-2-carboxylic acid
1,1-dimethylethyl ester (19). A mixture of n-propyltriphe-
nylphosphonium bromide (978 mg, 2.5 mmol) and t-BuOK
(259 mg, 2.3 mmol) in benzene (10 mL) was heated under
reflux for 2 h in an atmosphere of N2. After cooling, a solu-
tion of 10 (440 mg, 1.15 mmol) in benzene (5 mL) was
added, and the resulting mixture was stirred at room temper-
ature for 30 min. The mixture was then poured into H2O
(20 mL), and the aqueous layer was separated from the or-
ganic layer and extracted with ether. The ethereal extracts
and the above organic layer were combined, dried over anhy-
drous MgSO4, and concentrated. Purification of the residue
1
(CO); H NMR (CDCl3) d: 1.15 (3H, t, J¼7.5 Hz), 1.49
(9H, s), 2.50 (2H, q, J¼7.5 Hz), 2.86 (1H, d, J¼17 Hz),
2.88 (1H, d, J¼15 Hz), 3.25 and 3.29 (1H, dd each, J¼17,
5.5 Hz), 3.43 and 3.48 (1H, dd each, J¼15, 5.5 Hz), 3.74
(3H, s), 5.59 and 5.64 (1H, d each, J¼5.5 Hz), 5.76 and

M. Ohba et al. / Tetrahedron 63 (2007) 10337–10344
10343
5.85 (1H, d each, J¼5.5 Hz), 7.04 (1H, dd, J¼8, 7.5 Hz),
7.16 (1H, dd, J¼8, 7.5 Hz), 7.25 (1H, d, J¼8 Hz), 7.38
and 7.40 (1H, d each, J¼8 Hz), 8.16 (1H, s), 8.37 (1H, s);
HRMS calcd for C25H29N3O2: 403.2260, found: 403.2257.
as a colorless solid, mp 216–220 ꢁC. [a]D27 ꢀ132.2 (c 0.50,
CHCl3); MS m/z: 379 (M+); 1H NMR (CDCl3) d: 1.15
(3H, t, J¼7.5 Hz), 2.48 (2H, q, J¼7.5 Hz), 2.72 (1H, d,
J¼15.5 Hz), 2.80 (1H, d, J¼17 Hz), 3.21 (1H, dd, J¼17,
6 Hz), 3.47 (1H, dd, J¼15.5, 5 Hz), 3.79 and 3.93 (2H,
d each, J¼13.5 Hz), 4.22 (1H, d, J¼6 Hz), 4.40 (1H, d,
J¼5 Hz), 7.06 (1H, dd, J¼8, 7.5 Hz), 7.12 (1H, dd, J¼8,
7.5 Hz), 7.25–7.4 (6H, m), 7.42 (1H, d, J¼8 Hz), 7.94
(1H, s), 8.13 (1H, s), 8.29 (1H, s); 13C NMR (CDCl3) d:
13.9 (q), 22.9 (t), 25.9 (t), 31.9 (t), 49.5 (d), 53.5 (d), 56.5
(t), 105.4 (s), 110.9 (d), 118.2 (d), 119.6 (d), 121.8 (d),
127.3 (s), 127.3 (d), 128.5 (d), 128.8 (d), 133.5 (s), 135.2
(s), 136.1 (s), 137.0 (s), 138.6 (s), 140.3 (s), 146.2 (d),
146.7 (d); HRMS calcd for C26H25N3: 379.2049, found:
379.2054.
4.1.15. (6S,13S)-4-Ethyl-6,7,12,13-tetrahydro-7-methyl-
6,13-imino-5H-pyrido[30,40:5,6]cyclooct[1,2-b]indole
(suaveoline) (4). A mixture of 23 (117 mg, 0.29 mmol) and
trifluoroacetic acid (0.5 mL) in CH2Cl2 (2 mL) was stirred at
0 ꢁC for 3 h. The reaction mixture was then poured into cold
10% aqueous Na2CO3 (5 mL) and extracted with CHCl3.
The organic extracts were washed with brine, dried, and con-
centrated. Purification of the residue by flash chromato-
graphy [CHCl3–MeOH (10:1)] provided 4 (72 mg, 82%)
as a colorless foam. [a]2D8 ꢀ1.4 (c 0.50, CHCl3); MS m/z:
303 (M+); UV (EtOH) lmax, nm (log 3): 226 (4.47), 272
(3.89), 284 (3.85); CD (cyclohexane) lext, nm (D3): 301
(+2.22), 295 (+0.85), 291 (+2.49), 275 (ꢀ0.70), 264
(+1.22), 254 (+0.07), 238 (+8.19), 217 (ꢀ14.4); HRMS
Acknowledgements
1
calcd for C20H21N3: 303.1736, found: 303.1739. The H
We are grateful to Prof. J. M. Cook (University of Wiscon-
sin–Milwaukee) for providing us with a sample and spectral
copies of synthetic norsuaveoline.
and 13C NMR (CDCl3) spectral data for this sample were
in agreement with those reported for natural suaveoline.9f
4.1.16. (6S,13S)-4-Ethyl-6,7,12,13-tetrahydro-7,14-
dimethyl-6,13-imino-5H-pyrido[30,40:5,6]cyclooct[1,2-
b]indole (Nb-methylsuaveoline) (24). Methylation of 4
(25 mg, 0.082 mmol) was effected by the same procedure
as described in the literature,8 affording 24 (23 mg, 84%)
as a colorless oil. [a]D29 ꢀ91.1 (c 0.92, CHCl3); MS m/z:
317 (M+); UV (EtOH) lmax, nm (log 3): 225 (4.44), 272
(3.86), 283 (3.81); HRMS calcd for C21H23N3: 317.1892,
References and notes
1. 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, pp 417–472, Part A.
2. (a) Kondrat’eva, G. Y. Khim. Nauka i Prom. 1957, 2, 666–667;
Chem. Abstr. 1958, 52, 6345a; (b) Kondrat’eva, G. Y. Izv. Akad.
Nauk SSSR., Otdel. Khim. Nauk 1959, 484–490; Chem. Abstr.
1959, 53, 21940d.
1
found: 317.1898. The H and 13C NMR (CDCl3) spectral
data for this sample were in agreement with those reported
for (ꢀ)-Nb-methylsuaveoline by Fu and Cook.11b
3. (a) Levin, J. I.; Weinreb, S. M. J. Am. Chem. Soc. 1983, 105,
1397–1398; (b) Levin, J. I.; Weinreb, S. M. J. Org. Chem.
1984, 49, 4325–4332.
4.1.17. (6S,13S)-4-Ethyl-6,7,12,13-tetrahydro-6,13-imi-
no-5H-pyrido[30,40:5,6]cyclooct[1,2-b]indole (norsuaveo-
line) (5). Deprotection of 21 (92 mg, 0.24 mmol) and
work-up of the reaction mixture were performed as de-
scribed above for 4, giving 5 (60 mg, 88%) as a colorless
solid. Recrystallization from AcOEt–hexane (2:1) furnished
colorless needles, mp 258–262 ꢁC. [a]D30 +19.6 (c 0.50,
CHCl3); MS m/z: 289 (M+); UV (EtOH) lmax, nm (log 3):
225 (4.47), 272 (3.94), 283 (3.88), 291 (3.78); CD (EtOH)
lext, nm (D3): 295 (4.65), 291 (3.91), 288 (5.34), 274
(ꢀ0.20), 263 (3.56), 250 (1.92), 241 (2.74), 227 (ꢀ28.1);
HRMS calcd for C19H19N3: 289.1579, found: 289.1581.
The 1H and 13C NMR (CDCl3) and CD spectra and TLC mo-
bility (three solvent systems) of this sample were virtually
identical with those of synthetic norsuaveoline.12
4. For other intramolecular oxazole–olefin Diels–Alder reactions,
see: (a) Shimada, S.; Tojo, T. Chem. Pharm. Bull. 1983, 31,
4247–4258; (b) Levin, J. I. Tetrahedron Lett. 1989, 30, 2355–
2358; (c) Subramanyam, C.; Noguchi, M.; Weinreb, S. M.
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b]indole (Nb-benzylsuaveoline) (22). Benzyl bromide
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