First total synthesis of (±)-powelline

Article abstract of DOI:10.1055/s-0028-1083526

The first total synthesis of (±)-powelline is reported in 10% overall yield over eight steps using an intramolecular oxidative phenolic coupling reaction as the key reaction.

Full text of DOI:10.1055/s-0028-1083526

LETTER
2681
First Total Synthesis of ( )-Powelline
Total
S
ynthesis of
aPowelline ny F. Anwar, Trond Vidar Hansen*
School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, P.O. Box 1068, Blindern, 0316 Oslo, Norway
Fax +47(22)855947; E-mail: t.v.hansen@farmasi.uio.no
Received 23 June 2008
drug citalapram.8 Herein we describe an efficient total
synthesis of racemic powelline.
Abstract: The first total synthesis of ( )-powelline is reported in
10% overall yield over eight steps using an intramolecular oxidative
phenolic coupling reaction as the key reaction.
Our synthesis started with the preparation of salicylalde-
hyde 6 in 96% yield from known phenol 5,9 using the
recently reported ortho-formylation method10,11 (Scheme 1).
Subjecting salicylaldehyde 6 to K2CO3 and MeI afforded
7 that was reacted under reductive amination conditions
with tyramine (8)11b to amine 9 in 76% yield over the three
steps. Subsequent monoprotection of the amine function
in 9 with TFA anhydride using a literature procedure6c af-
forded intermediate 10. Reacting this intermediate with
the hypervalent iodine reagent [bis(trifluoroacetoxy)io-
do]benzene (PIFA) in trifluoroethanol gave compound 11
in 46% yield over the two steps. Basic hydrolysis of the
Key words: Amaryllidaceae alkaloids, powelline, ortho-formyla-
tion, intramolecular Michael cyclization, phenolic oxidation
Crinine (1), powelline (2), crinamidine (3) and undulatine
(4) are representative structures of the crinine subclass of
Amaryllidaceae alkaloids (Figure 1).1 Several members
of this class of alkaloids display interesting biological
properties such as inhibitors of acetylcholinesterase,2 cy-
totoxic,3 and antimalarial4 effects. Based on their interest-
ing structures, limited supply, and the aforementioned
bioactivities, these natural products are valuable targets
for total synthesis.5
O
O
O
O
O
O
i
ii
R
N
The 2,3,4,4a-tetrahydro-1H,6H-5,10b-ethanophenanthri-
dine (cis-3a-aryloctahydroindole) skeleton characterizes
the crinine class of alkaloids. The incorporation of the
sterically congested quaternary center is the critical ele-
ment in all total syntheses of these natural products. Sev-
eral of the synthetic efforts are based on a biomimetic
approach where an amino spirodienone is believed to be
the key intermediate,1,5 which by intramolecular oxidative
phenolic coupling and Michael cyclization forms the AB/
BD rings.
CHO
Ar
OH
OR
OMe
6 R = H
7 R = Me
5
9 R = H
10 R = COCF3
Ar = 4-HOC6H4
HO
iii
NH2
8
O
O
O
OH
OR
3
1
O
O
O
O
iv
D
H
4
N
4a
O
O
O
O
N
C
A
B
H
H
CF3
N
N
OMe
OMe
6
O
11
12
R
OMe
R = H: crinine (1)
R = OMe: powelline (2)
R = H: crinamidine (3)
R = Me: undulatine (4)
v
Figure 1
OH
OH
O
O
O
O
Several total syntheses of both racemic and enantiopure
forms of crinine (1), the parent structure of this class of al-
kaloids, have been reported.6 However, to the best of our
knowledge, no total synthesis of powelline (2) has been
reported. This highly oxygenated natural product is
cytotoxic7 and a competitive inhibitor of the CNS-active
vi
H
H
N
N
OMe
OMe
2 ( )-powelline
13
Scheme 1 Reagents and conditions: (i) (a) MgCl2, Et3N, (CH2O)n,
THF, 70 °C, (96%); (b) MeI, K2CO3, DMF, 96%; (ii) (a) tyramine (8),
MeOH; (b) NaBH4, MeOH, 82% (from 7); (c) TFAA, DMAP,
CH2Cl2, 0 °C to r.t., 76%; (iii) PIFA, CF3CH2OH, 0 °C, 60%; (iv)
KOH (aq, 10%), MeOH, 77%; (v) NaBH4, CeCl3·7H2O, MeOH
(78%); (vi) (a) DEAD, Ph3P, HCO2H, THF, (53%); (b) NaOH THF,
94%.
SYNLETT 2008, No. 17, pp 2681–2683
x
x
.x
x
.2
0
0
8
Advanced online publication: 01.10.2008
DOI: 10.1055/s-0028-1083526; Art ID: D22208ST
© Georg Thieme Verlag Stuttgart · New York

2682
H. F. Anwar, T. V. Hansen
LETTER
(6) For syntheses of racemic crinine and epicrinine, see:
amide group in 11 also facilitated the intramolecular
Michael cyclization reaction affording racemic oxopow-
elline 12. A Luche reduction6b,12 yielded alcohol 13 in
60% yield over the two steps. A NOE effect was observed
between protons H-4a and H-3, confirming the stere-
ochemistry depicted for compound 13.13
Finally, a Mitsunobu inversion14 of the C-3 hydroxyl
group yielded racemic powelline 2 in 50% yield with
spectral data13 in accord with those previously reported.15
(a) Tam, N. T.; Cho, C.-G. Org. Lett. 2008, 10, 601.
(b) Bru, C.; Guillou, C. Tetrahedron 2006, 62, 9043.
(c) Kodama, S.; Takita, H.; Kajimoto, T.; Nishide, K.; Node,
M. Tetrahedron 2004, 60, 4901. (d) Pearson, W. H.;
Lovering, F. E. J. Org. Chem. 1998, 63, 3607. (e) Pearson,
W. H.; Lovering, F. E. Tetrahedron Lett. 1994, 35, 9173.
(f) Martin, S. F.; Campbell, C. L. J. Org. Chem. 1988, 53,
3184. (g) Martin, S. F.; Campbell, C. L. Tetrahedron Lett.
1987, 28, 503. (h) Overman, L. E.; Mendelson, L. T. J. Am.
Chem. Soc. 1981, 103, 5579. (i) Whitlock, H. W. Jr.; Smith,
G. L. J. Am. Chem. Soc. 1967, 89, 3600. (j) Muxfeldt, H.;
Schneider, R. S.; Mooberry, J. B. J. Am. Chem. Soc. 1966,
88, 3670. (k) For synthesis of (–)-crinine, see: Overman,
L. E.; Sugai, S. Helv. Chim. Acta 1985, 68, 745.
In conclusion, we have described the first total synthesis
of powelline in 10% overall yield over eight steps that
confirmed the assigned structure, and also provided us
with sufficient material for biological testing. The latter
will be reported elsewhere in due course.
(7) (a) Fennell, C. W.; Elgorashi, E. E.; van Staden, J. J. Nat.
Prod. 2003, 66, 1524. (b) Abd El Hafiz, M. A.; Ramadan,
M. A.; Jung, M. L.; Beck, J. P.; Anton, R. Planta Med. 1991,
57, 437. (c) Ramires, A.; Cabezas, F.; Bastida, J.;
Viladomat, F.; Codina, C. Rev. Latinoam. de Quim. 2001,
29, 26.
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J. Planta Med. 2006, 72, 470. (b) Risa, J.; Risa, A.;
Adsersen, A.; Gauguin, B.; Stafford, G. I.; van Staden, J.;
Jäger, A. K. J. Ethnopharmacol. 2004, 93, 177.
Acknowledgment
Financial support to H.F.A. from the University of Oslo (The Quota
Scheme) is gratefully acknowledged, as well as are the helpful dis-
cussions with Professors Lars Skattebøl and Arne J. Aasen. We also
want to thank Finn Tønnesen for some GC analyses.
(9) Baker, W.; Jukes, E. H. T.; Subrahmanyam, C. A. J. Chem.
Soc. 1934, 1681.
(10) (a) Hofsløkken, N. U.; Skattebøl, L. Acta Chem. Scand.
1999, 53, 258. (b) Hansen, T. V.; Skattebøl, L. Org. Synth.
2005, 82, 64.
(11) (a) Anwar, H. F.; Hansen, T. V. Tetrahedron Lett. 2008, 49,
4443. (b) Anwar, H. F.; Skattebøl, L.; Hansen, T. V.
Tetrahedron 2007, 63, 9997. (c) Hansen, T. V.; Skattebøl,
L. Tetrahedron Lett. 2005, 46, 3829. (d) Hansen, T. V.;
Skattebøl, L. Tetrahedron Lett. 2005, 46, 3357. (e) Anwar,
H. F.; Skattebøl, L.; Skramstad, J.; Hansen, T. V.
Tetrahedron Lett. 2005, 46, 5285.
References and Notes
(1) (a) Martin, S. F. The Amaryllidaceae Alkaloids, In Alkaloids,
Vol. 30; Brossi, A., Ed.; Academic: New York NY, 1987,
251. (b) Hoshin, O. The Amaryllidaceae Alkaloids, In
Alkaloids, Vol. 51; Cordell, G. A., Ed.; Academic: New
York NY, 1998, 323. (c) Jin, Z. Nat. Prod. Rep. 2007, 24,
886. (d) Jin, Z. Nat. Prod. Rep. 2005, 22, 111. (e) Jin, Z.
Nat. Prod. Rep. 2003, 20, 606. (f) Jin, Z.; Li, Z.; Huang, R.
Nat. Prod. Rep. 2002, 19, 454. (g) Nguyen, T. N. T.;
Titorenkova, T. V.; Bankova, V. S.; Handjieva, N. V.;
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Phytochem. Rev. 2007, 6, 125. (i) Lewis, J. R. Nat. Prod.
Rep. 1990, 7, 549.
(12) Luche, J. L.; Rodriguez-Hahn, L.; Crabbe, P. J. Chem. Soc.,
Chem. Commun. 1978, 601.
(13) Analytical and Spectroscopic Data of Selected Compounds:
Compound 9: white solid; mp 147–149 °C. 1H NMR (300
MHz, DMSO-d6): d = 9.20 (br s, 1 H), 6.94 (d, J = 8.4 Hz, 2
H), 6.71 (d, J = 7.9 Hz, 1 H), 6.63 (d, J = 8.4 Hz, 2 H), 6.52
(d, J = 7.9 Hz, 1 H), 5.94 (s, 2 H), 3.82 (s, 3 H), 3.56 (s, 2 H),
3.41 (br s, 1 H), 2.54–2.63 (m, 4 H). 13C NMR (75 MHz,
DMSO-d6): d = 155.44, 147.90, 141.40, 136.26, 130.49,
129.45, 125.94, 122.06, 115.07, 102.30, 100.89, 59.47,
50.51, 47.68, 35.00. HRMS: m/z [M+] calcd for C17H19NO4:
301.1314; found: 301.1302.
(2) Elgorashi, E. E.; Stafford, G. I.; Van Staden, J. Planta Med.
2004, 70, 260.
(3) (a) Likhitwitayawuid, K.; Angerhofer, C. K.; Chai, H.;
Pezzuto, J. M.; Cordell, G. A.; Ruangrungsi, N. J. Nat. Prod.
1993, 56, 1331. (b) Lin, L. Z.; Hu, S. F.; Chai, H. B.;
Pengsuparp, T.; Pezzuto, J. M.; Cordell, G. A.; Ruangrungsi,
N. Phytochemistry 1995, 40, 1295. (c) McNulty, J.; Nair,
J. J.; Codina, C.; Bastida, J.; Pandey, S.; Gerasimoff, J.;
Griffin, C. Phytochemistry 2007, 68, 1068.
(4) (a) Hoet, S.; Opperdoes, F.; Brun, R.; Quetin-Leclercq, J.
Nat. Prod. Rep. 2004, 21, 353. (b) Sener, B.; Orhan, I.;
Satayavivad, J. Phytother. Res. 2003, 17, 1220.
Compound 10: colorless oil. 1H NMR (300 MHz, CDCl3):
d= 6.98–7.02 (m, 2 H), 6.74–6.80 (m, 2 H), 6.51–6.53 (m, 2 H),
5.94 (d, J = 3.0 Hz, 2 H), 5.20 (br s, 1 H), 4.63 (s, 1 H), 4.42
(s, 1 H), 4.01 (d, J = 7.8 Hz, 3 H), 3.41–3.50 (m, 2 H),
2.70–2.84 (m, 2 H). 13C NMR (75 MHz, CDCl3): d = 155.04,
154.84, 150.02, 149.85, 142.43, 142.12, 136.59, 136.53,
130.63, 130.35, 130.24, 129.91, 123.83, 122.10, 120.70,
119.93, 116.01, 115.83, 103.24, 102.95, 101.62, 101.52,
60.04, 59.90, 48.63, 44.59, 34.75, 32.38. HRMS: m/z [M+]
calcd for C19H18F3NO5: 397.1137; found: 397.1125.
Compound 11: yellow crystals; mp 142–144 °C. 1H NMR
(300 MHz, CDCl3): d = 6.94 (m, 1 H), 6.81 (m, 1 H),
6.21–6.27 (m, 3 H), 5.90 (s, 2 H), 4.91 (d, J = 5.7 Hz, 2 H),
4.03 (d, J = 8.0 Hz, 3 H), 3.88 (m, 2 H), 2.36 (t, J = 6.3 Hz,
2 H). 13C NMR (75 MHz, CDCl3): d = 185.65, 185.43,
157.95 (m), 153.18, 152.95, 149.36, 149.32, 141.94, 141.05,
137.25, 136.06, 130.97, 130.46, 127.49, 127.48, 122.57,
122.16, 118.74, 118.55, 114.92, 114.74, 104.94, 104.39,
(c) Schwikkard, S.; Van Heerden, F. R. Nat. Prod. Rep.
2002, 19, 675. (d) Citoglu, G.; Tanker, M.; Gumusel, B.
Phytother. Res. 1998, 12, 205. (e) Weniger, B.; Italiano, L.;
Beck, J. P.; Bastida, J.; Bergonon, S.; Codina, C.; Lobstein,
A.; Anton, R. Planta Med. 1995, 61, 77.
(5) (a) Hudlicky, T. J. Heterocycl. Chem. 2000, 37, 535.
(b) Rinner, U.; Hudlicky, T. Synlett 2005, 365. (c)Agarwal,
S.; Caemmerer, S.; Filali, S.; Froehner, W.; Knoell, J.; Krahl,
M. P.; Reddy, K. R.; Knolker, H.-J. Curr. Org. Chem. 2005,
9, 1601. (d) Chapleur, Y.; Chretien, F.; Ahmed, S. I.; Khaldi,
M. Curr. Org. Synth. 2006, 3, 341. (e) Hudlicky, T. Arkivoc
2006, (vii), 276. (f) Ghosal, S.; Saini, K. S.; Razdan, S.
Phytochemistry 1985, 24, 2141.
Synlett 2008, No. 17, 2681–2683 © Thieme Stuttgart · New York

LETTER
102.08, 101.73, 60.21, 49.16, 48.71, 45.65 (d, J = 3.4 Hz),
Total Synthesis of Powelline
2683
experiment was recorded on a Bruker Avance DPX-600
MHz spectrometer at 300.3 K with F2 acquisition
parameters D1 = 2.00 s and D8 = 0.89 s using DMSO-d6 as
solvent.
44.64, 40.47 (d, J = 3.4 Hz), 40.00, 35.47, 33.90. HRMS:
m/z [M+] calcd for C19H16F3NO5: 395.0981; found:
395.0968.
Compound 12: white crystals; mp 175–177 °C (lit.16 mp
177–178 °C). 1H NMR (300 MHz, DMSO-d6): d = 7.86 (d,
J = 10.3 Hz, 1 H), 6.93 (s, 1 H), 5.90–5.94 (m, 3 H), 4.03 (d,
J = 17.3 Hz, 1 H), 3.88 (s, 3 H), 3.64 (d, J = 17.3 Hz, 1 H),
3.46 (m, 1 H), 3.36 (m, 1 H), 2.81 (m, 1 H), 2.48 (m, 1 H),
2.30 (m, 1 H), 2.13 (m, 2 H). 13C NMR (75 MHz, DMSO-
d6): d = 197.93, 150.97, 147.91, 140.49, 137.45, 133.57,
127.89, 117.62, 100.71, 97.34, 67.96, 59.00, 57.41, 53.69,
44.48, 44.48, 39.78. HRMS: m/z [M+] calcd for C17H17NO4:
299.1158; found: 299.1151.
Compound 2: white crystals; mp 165–167 °C (dec.). 1H
NMR (300 MHz, CDCl3): d = 6.56 (s, 1 H), 6.52 (d, J = 10.0
Hz, 1 H), 5.95 (dd, J = 10.0, 5.1 Hz, 1 H), 5.85 (ABq, 2 H),
4.35 (m, 1 H), 4.28 (d, J = 17.3 Hz, 1 H), 3.97 (s, 3 H), 3.85
(d, J = 17.3 Hz, 1 H), 3.43 (m, 2 H), 2.90 (m, 1 H), 2.15 (m,
2 H), 1.94 (m, 1 H), 1.76 (m, 1 H). 13C NMR (75 MHz,
CDCl3): d = 148.23, 140.93, 138.83, 133.45, 131.68, 127.64,
116.42, 100.62, 96.79, 63.72, 62.62, 59.14, 58.40, 53.56,
44.22, 43.68, 32.39. HRMS: m/z [M+] calcd for C17H19NO4:
301.1314; found: 301.1307.
Compound 13: white crystals; mp 102–104 °C. 1H NMR
(600 MHz, DMSO-d6): d = 6.67 (s, 1 H), 6.38 (dd, J = 10.2,
2.1 Hz, 1 H), 5.88 (ABq, 2 H), 5.61 (d, J = 10.2 Hz, 1 H),
4.90 (br s, 1 H), 4.16 (m, 1 H), 4.06 (d, J = 17.3 Hz, 1 H),
3.86 (s, 3 H), 3.62 (d, J = 17.3 Hz, 1 H), 3.22 (m, 1 H), 3.02
(dd, J = 13.2, 3.4 Hz, 1 H), 2.77 (m, 1 H), 1.98 (m, 1 H), 1.92
(m, 1 H), 1.82 (m, 1 H), 1.42 (m, 1 H). 13C NMR (75 MHz,
DMSO-d6): d = 147.53, 140.30, 139.77, 133.12, 132.69,
127.65, 117.03, 100.42, 97.14, 65.88, 65.82, 58.86, 57.74,
52.70, 44.73, 43.91, 34.37. HRMS: m/z [M+] calcd for
C17H19NO4: 301.1314; found: 301.1316. The NOESY
(14) (a) Mitsunobu, O.; Yamada, M.; Mukaiyama, T. Bull. Chem.
Soc. Jpn. 1967, 40, 935. (b) Mitsunobu, O.; Yamada, M.
Bull. Chem. Soc. Jpn. 1967, 40, 2380. (c) Mitsunobu, O.
Synthesis 1981, 1. (d) Lawrence, S. PharmaChem. 2002, 1,
12.
(15) (a) Frahm, A. W.; Ali Ahmed, A.; Ramadan, M. A. Magn.
Reson. Chem. 1985, 23, 804. (b) Kobayashi, S.; Tokumoto,
T.; Kihara, M.; Imakura, Y.; Shingu, T.; Taira, Z. Chem.
Pharm. Bull. 1984, 32, 3015.
(16) Wildman, W. C. Chem. Ind. (London) 1956, 1090.
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