Total synthesis of suaveoline and norsuaveoline via intramolecular oxazole-olefin Diels-Alder reaction

Article abstract of DOI:10.1016/j.tetlet.2004.06.108

Total synthesis of two Rauwolfia alkaloids, suaveoline (1) and norsuaveoline (2), has been achieved through a highly stereoselective route starting from l-tryptophan methyl ester (9) and exploiting the intramolecular Diels-Alder reaction of the oxazole-ol

Full text of DOI:10.1016/j.tetlet.2004.06.108

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6471–6474
Total synthesis of suaveoline and norsuaveoline via intramolecular
oxazole–olefin Diels–Alder reaction
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 24 May 2004; revised 16 June 2004; accepted 25 June 2004
Available online 20 July 2004
Abstract—Total synthesis of two Rauwolfia alkaloids, suaveoline (1) and norsuaveoline (2), has been achieved through a highly ster-
eoselective route starting from L-tryptophan methyl ester (9) and exploiting the intramolecular Diels–Alder reaction of the oxazole–
olefin 16.
Ó 2004 Elsevier Ltd. All rights reserved.
In 1972, Potier and co-workers reported the isolation of
a novel indole alkaloid suaveoline from the trunk bark
of Rauwolfia suaveolens and proposed the structure 1
for it on the basis of spectroscopic data and chemical
correlation with ajmaline.1,2 The structure and absolute
stereochemistry have been confirmed via racemic3 and
enantiospecific4 syntheses of 1 by two independent re-
search groups, respectively. Thereafter, four additional
alkaloids [i.e., norsuaveoline (2),2e,5 macrophylline
(3),2e,g,6 macrocaffrine (4),2e,6b and sellowiine (5)7] con-
taining a skeleton similar to that of suaveoline have been
isolated from a number of Rauwolfia species. In connec-
tion with our ongoing interest in the synthesis of annu-
lated pyridine systems8 exploiting intramolecular
oxazole–olefin Diels–Alder reactions,9 we sought possi-
ble new routes to suaveoline (1) and norsuaveoline (2)
in the present study.
From a retrosynthetic perspective, we envisaged the
oxazole derivative 6 as a precursor for an efficient con-
struction of the DE rings of the target molecules, 1
and 2, by adopting intramolecular Diels–Alder reaction.
The oxazole–olefin 6 would be obtained from 8 via the
formation of the C ring and subsequent introduction
of an appropriate olefinic dienophile to the derived
aldehyde 7. Furthermore, the requisite enantiomer 8,
in turn, would arise from L-tryptophan methyl ester
(9) through the conversion of a-amino esters into chi-
ral 5-(aminomethyl)oxazole derivatives developed ear-
lier.10 The strategy is applicable to the synthesis of
other suaveoline-related alkaloids 3–5 comprising differ-
ent substituents at the 20-position because a variety
H
of oxazole–olefins
from the aldehyde 7 postulated as a key intermediate
(Scheme 1).
6 would be readily accessible
N
NR2
D
E
N
R1
20
R3
H
1: R1 = Me, R2 = H, R3 = Et
2: R1 = R2 = H, R3 = Et
The initial step was treatment of the N-protected amino
ester 10,11 derived from 9, with a-lithiated methyl isocy-
anide, which was performed in THF at ꢀ78°C for 2.5h
3: R1 = H, R2 = Me, R3 = CH2CH2OH
4: R1 = H, R2 = Me, R3 = CH2OH
5: R1 = R2 = R3 = H
according to our previous procedure,10 giving the oxaz-
25
ole 11 [mp 163–164°C;12 ½aŠ ꢀ34:5 (c 0.50, MeOH)] in
D
82% yield. Deprotection of 11 with CF3CO2H (CH2Cl2,
0°C, 4h) provided the amino oxazole 8 in 98% yield.
The enantiomeric purity of 8 thus obtained was esti-
mated to be 97% ee by MosherÕs method. For the forma-
tion of the C ring in the aldehyde 7, the amino oxazole 8
Keywords: Alkaloids; Amino acids and derivatives; Diels–Alder reac-
tions; Indoles; Oxazoles.
*
Corresponding author. Tel./fax: +81-76-234-4428; e-mail: ohba@p.
kanazawa-u.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.108

6472
M. Ohba et al. / Tetrahedron Letters 45 (2004) 6471–6474
N
N
O
N
O
H
H
H
H
O
CO2Me
1– 5
C
NBoc
NBoc
CHO
NH2
NH2
N
N
N
N
H
H
H
H
H
H
6
7
8
9
R
Scheme 1.
was first converted into the amide 12 in 88% yield by
condensation with monoethyl malonate employing the
coupling reagent diethyl phosphorocyanidate13 (Et3N,
DMF, 0°C, 30min then room temperature, 30min).
The Bischler–Napieralski cyclization of 12 was effected
in POCl3 (room temperature, 6days) without a co-sol-
vent by following the method of Hino and co-workers,14
amino ester 14. The secondary amino group of 14 was
first protected with di-tert-butyl dicarbonate (boiling
CHCl3, 24h) to afford 15 [mp 188.5–190°C;12
26
½aŠ þ227 (c 0.25, CHCl3)] in 87% yield. The 1H
D
NMR spectrum of 14 exhibited two methylene protons
adjacent to the 1-position at d 2.80 and 2.88 in CDCl3,
whereas the corresponding protons of the N-Boc deriv-
ative 15 appeared at d 1.85 (4/9H), 1.99 (5/9H) and d
2.60 (5/9H), 2.71 (4/9H) in CDCl3.16 The large upfield
shift, which one of the two methylene protons of 15 in
question showed, may be interpreted in terms of the
shielding effect arising from the oxazole ring on the basis
of the contribution of the conformer 15A. Such confor-
mation that both C(1)- and C(3)-substituents occupy
pseudo-axial positions17 is favorable for the intramolec-
ular Diels–Alder reaction tried after the introduction of
an olefinic moiety. The N-protected ester 15 was then
treated with diisobutylaluminum hydride (DIBALH)
in CH2Cl2 at ꢀ78°C for 80min to provide the aldehyde
7, a key intermediate for our strategy, in 95% yield. The
Wittig reaction of 7 with the phosphorane, derived from
n-propyltriphenylphosphonium bromide and t-BuOK,
affording the enamino ester 13 [mp 213–214°C;12
29
½aŠ ꢀ156 (c 0.20, CHCl3)]15 in 50% yield after basifica-
D
tion of the resulting iminium salt. On catalytic hydro-
genation of 13 with PearlmanÕs catalyst and hydrogen
(EtOH, 1atm, room temperature, 22h), the cis-1,3-di-
substituted tetrahydro-b-carboline 14 was preferentially
obtained in 84% yield without accompanying the trans-
isomer. The stereochemical assignment of 14 was con-
firmed by a 10% NOE enhancement observed for the
C(1)-proton signal on the irradiation of the C(3)-proton
signal (Scheme 2).
We next turned our attention to the introduction of an
olefinic dienophile, required for the subsequent intramo-
lecular oxazole–olefin Diels–Alder reaction, into the
N
O
N
O
(for 8)
H
H
H
CO2Me
HO2CCH2CO2Et
(Boc)2O
CH3NC/n-BuLi
9
NHR
O
NH
NHBoc
(EtO)2P(O)CN
Et3N/DMF
N
N
N
H
H
H
CO2Et
10
11: R = Boc
8: R = H
12
CF3CO2H
N
N
O
N
(for 15)
DIBALH
H
H
H
1) POCl3
2) Na2CO3
O
O
Pd(OH)2–C
3
C
NH
NR
NBoc
CHO
H2
N
H
N
N
1
H
H
H
H
CO2Et
CO2Et
7
13
14: R = H
15: R = Boc
(Boc)2O
N
H
(for 16)
DBN/xylene
(for 18)
MeI/NaH
N
H
H
+
O
–
Ph3P(CH2)2CH3Br
NR
N
NR
NR
N
t-BuOK
N
H
N
H
H
H
Me
H
Et
Et
Et
18: R = Boc
2: R = H
19: R = CH2Ph
20: R = Boc
1: R = H
CF3CO2H
PhCH2Br/Et3N
CF3CO2H
16: R = Boc
17: R = H
CF3CO2H
Scheme 2.

M. Ohba et al. / Tetrahedron Letters 45 (2004) 6471–6474
6473
was performed in benzene (room temperature, 30min)
Acknowledgements
to give the oxazole–olefin 16 in 73% yield with high Z
selectivity. The geometry in 16 was determined on the
basis of the coupling constant (J=10.5Hz) between
two olefinic protons of the amine 17 obtained by depro-
tection of 16.
We are grateful to Prof. J. M. Cook (University of Wis-
consin–Milwaukee) for providing us with a sample and
spectral copies of synthetic norsuaveoline.
N
O
EtO2C
References and notes
3
NBoc
1
1. (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.
N
H
15A
2. Suaveoline (1) has been found in other species of Rauwol-
fia, see: (a) Iwu, M. M.; Court, W. E. Planta Med. 1977,
32, 88–99; (b) Akinloye, B. A.; Court, W. E. J. Ethno-
pharmacol. 1981, 4, 99–109; (c) Amer, M. M. A.; Court,
W. E. Planta Med. 1981, 43, 94–95; (d) Amer, M. A.;
Court, W. E. Phytochemistry 1981, 20, 2569–2573; (e)
Nasser, A. M. A. G.; Court, W. E. J. Ethnopharmacol.
1984, 11, 99–117; (f) Endreß, S.; Takayama, H.; Suda, S.;
Kitajima, M.; Aimi, N.; Sakai, S.; Sto¨ckigt, J. Phytochem-
istry 1993, 32, 725–730; (g) Sheludko, Y.; Gerasimenko, I.;
Unger, M.; Kostenyuk, I.; Stoeckigt, J. Plant Cell Rep.
1999, 18, 911–918.
3. (a) Trudell, M. L.; Cook, J. M. J. Am. Chem. Soc. 1989,
111, 7504–7507; (b) Trudell, M. L.; Soerens, D.; Weber, R.
W.; Hutchins, L.; Grubisha, D.; Bennett, D.; Cook, J. M.
Tetrahedron 1992, 48, 1805–1822; (c) Gennet, D.; Michel,
P.; Rassat, A. Synthesis 2000, 447–451.
4. (a) Fu, X.; Cook, J. M. J. Am. Chem. Soc. 1992, 114,
6910–6912; (b) Fu, X.; Cook, J. M. J. Org. Chem. 1993,
58, 661–672; (c) Bailey, P. D.; McLay, N. R. J. Chem.
Soc., Perkin Trans. 1 1993, 441–449; (d) Bailey, P. D.;
Collier, I. D.; Hollinshead, S. P.; Moore, M. H.; Morgan,
K. M.; Smith, D. I.; Vernon, J. M. J. Chem. Soc.,
Perkin Trans. 1 1997, 1209–1214; (e) Bailey, P. D.;
Morgan, K. M.; Smith, D. I.; Vernon, J. M. J. Chem.
Soc., Perkin Trans. 1 2000, 3566–3577; (f) Bailey, P. D.;
Morgan, K. M. J. Chem. Soc., Perkin Trans. 1 2000,
3578–3583.
5. For the enantiospecific synthesis of norsuaveoline (2), see:
(a) Wang, T.; Yu, P.; Li, J.; Cook, J. M. Tetrahedron Lett.
1998, 39, 8009–8012; (b) Li, J.; Wang, T.; Yu, P.; Peterson,
A.; Weber, R.; Soerens, D.; Grubisha, D.; Bennett, D.;
Cook, J. M. J. Am. Chem. Soc. 1999, 121, 6998–7010.
6. (a) Amer, M. M. A.; Court, W. E. Planta Med.
1980(Suppl.), 8–12; (b) Nasser, A. M. A. G.; Court, W.
E. Phytochemistry 1983, 22, 2297–2300.
Having succeeded in the synthesis of the oxazole–olefin
16, we set out to explore its intramolecular Diels–Alder
reaction. After considerable experimentation, we found
that the best result was obtained by treatment of 16 in
boiling xylene in the presence of 1,5-diazabicy-
clo[4.3.0]non-5-ene (DBN) for 9h; under these condi-
tions, the desired pyridine 18 [mp 230–232°C;12
25
½aŠ ꢀ 6:0 (c 0.25, CHCl3)] was produced in 69% yield.
D
It seems likely that DBN might serve as a scavenger of
H2O at the high temperature employed and promote
the conversion of the initially formed Diels–Alder cyclo-
adduct into the pyridine 18.18 Finally, methylation of 18
with MeI in DMF (NaH, room temperature, 20min)
and subsequent deprotection of the resulting Na-methyl
derivative 20 with CF3CO2H (CH2Cl2, 0°C, 3h)
28
provided the first target compound 1 [½aŠ ꢀ 1:4 (c
D
1
0.50, CHCl3)] in 80% yield from 18. The H and 13C
NMR (CDCl3), UV (EtOH), CD (cyclohexane), and
mass spectral data for the synthetic 1 proved to be virtu-
ally identical with those reported for natural suaveoline
[½aŠD0 ꢁ 2 (c 1, CHCl3)]1,2f and/or CookÕs synthetic sam-
25
ple [½aŠ ꢀ 9:33 (c 0.30, CHCl3)].4a,b On the other hand,
D
removal of the Boc group in 18 with CF3CO2H
(CH2Cl2, 0°C, 3h) furnished the second target com-
30
pound 2 [mp 258–262°C; ½aŠ þ 19:6 (c 0.50, CHCl3)]
D
in 88% yield. Although the specific rotation of 2 thus ob-
tained was in disagreement with that of norsuaveoline
27
[½aŠ ꢀ 3:2 (c 1.00, CHCl3)] synthesized previously by
D
Cook and co-workers,5,19 they were virtually identical
with each other by comparison of the 1H and 13C
NMR (CDCl3) and CD (EtOH) spectra and TLC mobil-
ity (three solvent systems). In addition, we found that
7. (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.
8. (a) Ohba, M.; Kubo, H.; Fujii, T.; Ishibashi, H.; Sargent,
M. V.; Arbain, D. Tetrahedron Lett. 1997, 38, 6697–6700;
(b) Ohba, M.; Kubo, H.; Ishibashi, H. Tetrahedron 2000,
56, 7751–7761; (c) Ohba, M.; Izuta, R.; Shimizu, E.
Tetrahedron Lett. 2000, 41, 10251–10255; (d) Ohba, M.;
Izuta, R. Heterocycles 2001, 55, 823–826.
the spectral data and specific rotation for 19
27
D
tion of 2, matched those of Nb-benzylnorsuaveoline
[½aŠ ꢀ 132:2 (c 0.50, CHCl3)], derived from benzyla-
27
[½aŠ ꢀ 143:2 (c 1.00, CHCl3)] reported in the litera-
D
ture.5
In conclusion, a highly stereoselective total synthesis of
two Rauwolfia alkaloids, suaveoline (1), and norsuaveo-
line (2), has been accomplished via a route featuring an
efficient construction of the DE rings by the intramolec-
ular Diels–Alder reaction of the oxazole–olefin 16.
Further studies directed toward the synthesis of suaveo-
line-related alkaloids 3–5 using the aldehyde 7, a key
intermediate of our synthetic strategy, are in progress
in our laboratory.
9. For the intramolecular oxazole–olefin Diels–Alder reac-
tion, see: (a) Levin, J. I.; Weinreb, S. M. J. Am. Chem. Soc.
1983, 105, 1397–1398; (b) Sun, X.; Janvier, P.; Zhao, G.;
´
Bienayme, H.; Zhu, J. Org. Lett. 2001, 3, 877–880, and
references cited therein.
10. Ohba, M.; Kubo, H.; Seto, S.; Fujii, T.; Ishibashi, H.
Chem. Pharm. Bull. 1998, 46, 860–862.

6474
M. Ohba et al. / Tetrahedron Letters 45 (2004) 6471–6474
11. Sato, K.; Kozikowski, A. P. Tetrahedron Lett. 1989, 30,
4073–4076.
12. Recrystallized from AcOEt–hexane.
13. Shioiri, T.; Yokoyama, Y.; Kasai, Y.; Yamada, S.
Tetrahedron 1976, 32, 2211–2217.
14. Torisawa, Y.; Hashimoto, A.; Nakagawa, M.; Seki, H.;
Hara, R.; Hino, T. Tetrahedron 1991, 47, 8067–
8078.
16. Two methylene protons adjacent to the 1-position in 15
showed two sets of signals, respectively, owing to the
restricted rotation of the carbamate group.
17. Bailey, P. D.; Hollinshead, S. P.; McLay, N. R.; Morgan,
K.; Palmer, S. J.; Prince, S. N.; Reynolds, C. D.; Wood, S.
D. J. Chem. Soc., Perkin Trans. 1 1993, 431–439.
18. Levin, J. I.; Weinreb, S. M. J. Org. Chem. 1984, 49,
4325–4332.
15. The enantiomeric purity of 13 was determined to be more
than 96% by means of 1H NMR spectroscopy using a
chiral shift reagent.
19. Such disagreement may be due to traces of impurities: a
private communication from Prof. J. M. Cook (University
of Wisconsin–Milwaukee).