Total synthesis of (±)-powelline and (±)-buphanidrine

Article abstract of DOI:10.1021/ol1000654

Chemical Equation Presented The total synthesis of (±)-powelline (13 linear steps in an overall yield of 6%) and (±)-buphanidrine (14 linear steps and a 6% overall yield) and has been achieved using a novel approach to the crinane skeleton. An organocatalytic oxidative coupling allowed direct construction of the key quaternary carbon-to-aryl bond in high yield allowing rapid access to the target alkaloids.

Full text of DOI:10.1021/ol1000654

ORGANIC
LETTERS
2
010
Vol. 12, No. 6
252-1254
Total Synthesis of (()-Powelline and
1
(
()-Buphanidrine
†
Katherine M. Bogle, David J. Hirst, and Darren J. Dixon*
§
,‡
School of Chemistry, The UniVersity of Manchester, Oxford Road,
Manchester M13 9PL, U.K., Department of Chemistry, Chemistry Research
Laboratory, UniVersity of Oxford, Mansfield Road, Oxford OX1 3TA, U.K., and
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, SteVenage,
Herts SG1 2NY, U.K.
darren.dixon@chem.ox.ac.uk
Received January 15, 2010
ABSTRACT
The total synthesis of (()-powelline (13 linear steps in an overall yield of 6%) and (()-buphanidrine (14 linear steps and a 6% overall yield)
and has been achieved using a novel approach to the crinane skeleton. An organocatalytic oxidative coupling allowed direct construction of
the key quaternary carbon-to-aryl bond in high yield allowing rapid access to the target alkaloids.
4
Plants of the Amaryllidaceae family have provided nearly
00 structurally diverse alkaloids that exhibit a broad
spectrum of biological activity. Several of the established
skeletal structural classes contain a catechol derivative
covalently bonded to an all-carbon-quaternary stereogenic
center.
other related alkaloids have been reported, and similar
5
chemistry has been applied recently in the synthesis of (()-
powelline. To date, no synthesis of buphanidrine has been
1
5
reported. Construction of the sterically congested arylated
quaternary stereogenic center is pivotal to the synthesis of
this class of alkaloid, and we believed that these two alkaloids
would be ideal targets to showcase our recently reported
oxidative coupling methodology for the direct formation of
Powelline (1) and buphanidrine (2) have been isolated
2
from several Amaryllidaceae species. Characterized by the
6
such motifs.
5
,10b-ethanophenanthridine crinane skeleton, both contain
three stereogenic centers, one of which is quaternary, and
differ in the substituent on the allylic alcohol. Both alkaloids
have shown affinity for the serotonin transporter in [H3]-
Key to our synthetic plan was the direct catalyzed
construction of the quaternary carbon-to-aryl bond via the
3
citalopram binding assays. Several syntheses of crinine and
(2) For the original isolation of powelline, see: (a) Boit, H. G.; Ehmke,
H. Chem. Ber. 1955, 88, 1590. For the original isolation of buphanidrine,
see: (b) Renz, J.; Stauffacher, D.; Seebeck, E. HelV. Chim. Acta 1955, 38,
1209. For structural elucidation, see: (c) Wildman, W. C. J. Am. Chem.
Soc. 1958, 80, 2567. (d) Wildman, W. C. Chem. Ind. (London) 1956, 1090.
(e) Wildman, W. C.; Fales, H. M. J. Am. Chem. Soc. 1958, 80, 6465. (f)
Fales, H. M.; Wildman, W. C. J. Am. Chem. Soc. 1960, 82, 3368. (g) Lloyd,
H. A.; Kielar, E. A.; Highet, R. J.; Uyeo, S.; Fales, H. M.; Wildman, W. C.
J. Org. Chem. 1962, 27, 373. (h) Lloyd, H. A.; Kielar, E. A.; Highet, R. J.;
Uyeo, S.; Fales, H. M.; Wildman, W. C. J. Tetrahedron Lett. 1961, 2, 105.
For other isolations, see: (i) Hauth, H.; Stauffacher, D. HelV. Chim. Acta
1961, 44, 491. (j) Goosen, A.; Warren, F. L. J. Chem. Soc. 1960, 1094. (k)
Hauth, H.; Stauffacher, D. HelV. Chim. Acta 1962, 45, 1307.
†
The University of Manchester.
University of Oxford.
GlaxoSmithKline.
‡
§
(
1) For reviews on Amaryllidaceae alkaloids, see: (a) Jin, Z. Nat. Prod.
Rep. 2009, 26, 363. (b) Jin, Z. Nat. Prod. Rep. 2007, 24, 886. (c) Jin, Z.
Nat. Prod. Rep. 2005, 22, 111. (d) Jin, Z. Nat. Prod. Rep. 2003, 20, 606.
(
e) Nguyen, T. N. T.; Titorenkova, Tz. V.; St. Bankova, V.; Handjieva,
N. V.; Popov, S. S. Fitoterapia 2002, 73, 183. (f) Lewis, J. R. Nat. Prod.
Rep. 2002, 19, 223. (g) Jin, Z.; Li, Z.; Huang, R. Nat. Prod. Rep. 2002, 19,
4
54.
10.1021/ol1000654  2010 American Chemical Society
Published on Web 02/22/2010

oxidative coupling of readily prepared pro-nucleophile of
reacted with 3-methoxycatechol 6 in the presence of 10 mol
type 5 and commercially available 3-methoxycatechol 6
% of PS-BEMP and superstoichiometric polymer-supported
periodate (PS-IO ). The crude catechol intermediate was
4
-
7
(
Scheme 1). We envisaged that transformation of 4 to the
key cyclohexandione late-stage intermediate 3 common to
both targets would be possible via formal reductive homolo-
gation followed by Dieckmann-type cyclization. From cy-
clohexandione 3 reductive manipulation, deprotection and
Pictet-Spengler cyclization should provide rapid access to
the target alkaloids.
not purified but reacted directly with bromochloromethane
under standard conditions to give the desired methylenedioxy
product 9 in 52% yield over the two steps (Scheme 2).
8
Scheme 2. Total Synthesis of (()-Powelline
Scheme 1
.
Synthetic Plan for the Total Synthesis of Powelline
and Buphanidrine
In order to heighten the acidity of the pro-nucleophile 5,
an electron-withdrawing protecting group (P ) EWG) for
the pyrrolidinone was desirable. N-Boc was chosen for ease
of selective removal at a later stage in the synthesis. Initially,
the methyl ester pro-nucleophile 8 was synthesized and
(3) (a) Sandager, M.; Nielsen, N. D.; Stafford, G, I.; van Staden, J.; J a¨ ger,
A. K. J. Enthopharmacol. 2005, 98, 367. (b) Neergaard, J. S.; Andersen, J.;
Pedersen, M. E.; Stafford, G. I.; van Staden, J.; J a¨ ger, A. K. S. Afr. J. Bot.
2
009, 75, 371. (c) Elgorashi, E. E.; Stafford, G. I.; J a¨ ger, A. K.; van Staden,
J. Planta Med. 2006, 72, 470. (d) Weniger, B.; Italiano, L.; Beck, J.-P.;
Bastida, J.; Bergonon, S.; Codina, C.; Lobstein, A.; Anton, R. Planta Med.
1
995, 61, 77.
With the protected oxidative coupling product in hand,
we continued the planned synthesis of the key cyclohexan-
dione intermediate of type 3. A three-carbon homologation
of the lactam was required to give the keto-ester 11 substrate
ready for the Dieckmann-type cyclization. A chemoselective
reduction of the ketonic γ-lactam carbonyl with Superhydride
gave aminol 10. A subsequent acetylation then allowed us
to conduct an N-acyliminium ion homologation using (iso-
propenyloxy)trimethylsilane as a nucleophilic trap and
(
4) See refs 1, 6(l), 11, and 12. For selected recent synthetic efforts to
crinane-type alkaloids, see: (a) Nguyen, T. T.; Chang, J.; Jung, E.-J.; Cho,
C.-G. J. Org. Chem. 2008, 73, 6258, and ref 2 cited therein. (b) Zhang,
F.-M.; Tu, Y.-Q.; Liu, J.-D.; Fan, X.-H.; Shi, L.; Hu, X.-D.; Wang, S.-H.;
Zhang, Y.-Q. Tetrahedron 2006, 62, 9446, and refs 3-5 cited therein. For
a biomimetic approach, see: (c) Kodama, S.; Takita, H.; Kajimoto, T.;
Nishide, K.; Node, M. Tetrahedron 2004, 60, 4901.
(
(
5) Anwar, H. F.; Hansen, T. V. Synlett 2008, 2681.
6) (a) Bogle, K. M.; Hirst, D. J.; Dixon, D. J. Org. Lett. 2007, 9, 4901.
For selected publications on the synthesis of arylated quaternary stereo-
centres, see for organocatalytic methods: (b) Bella, M.; Kobbelgaard, S.;
Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 3670. (c) Kobblegaard, S.;
Bella, M.; Jørgensen, K. A. J. Org. Chem. 2006, 71, 4980. (d) Aleman, J.;
Richter, B.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2007, 46, 5515. For
Pd-catalyzed coupling: (e) Ahman, J.; Wolfe, J. P.; Troutman, M. V.;
Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 1918. (f) Lee,
S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402. (g) Moradi, W. A.;
Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7996. (h) Hamada, T.;
Chieffe, A.; Ahman, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
3 2
BF ·OEt as the mediator. The diastereoselectivity in the
formation of 11 was dependent upon the reaction solvent
and ranged from 3:1 in dichloromethane to 7:1 in acetone.
The Dieckmann-type cyclization, mediated by 2.1 equiv of
potassium tert-butoxide, proceeded smoothly to give the
diketone as a single diastereoisomer. Interestingly, none of
the other bases screened gave conversion to the desired 5,6-
1
261. For Ni-catalyzed coupling: (i) Spielvogel, D. J.; Buchwald, S. L.
J. Am. Chem. Soc. 2002, 124, 3500. For Cu-catalyzed coupling: (j) Xie,
X.; Chen, Y.; Ma, D. J. Am. Chem. Soc. 2006, 128, 16050. For
Mizoroki-Heck couplings: (k) Dounay, A. B.; Hatanaka, K.; Kodanko,
J. J.; Oestreich, M.; Overman, L. E.; Pfeifer, L. A.; Weiss, M. M. J. Am.
Chem. Soc. 2003, 125, 6261. For the application of Mizoroki-Heck coupling
in crinane alkaloids synthesis, see: (l) Bru, C.; Thal, C.; Guillou, C. Org.
Lett. 2003, 5, 1845.
(7) Harrison, C. R.; Hodge, P. J. Chem. Soc., Perkin. Trans. 1 1982,
509.
(8) Clark, J. H.; Holland, H. L.; Miller, J. M. Tetrahedron Lett. 1976,
17, 3361.
Org. Lett., Vol. 12, No. 6, 2010
1253

bicycle. Furthermore, the yield and diastereoselectivity of
the cyclization step were found to be independent of the
diastereomeric ratio of the keto-ester starting material 11.
This is consistent with a rapid and reversible base-catalyzed
epimerization process, presumably via retro-Michael/Michael
addition, occurring faster than the Dieckmann-type cycliza-
tion step to give the cis-fused 5,6-bicyclic diketone. The
diketone product (of type 3) was difficult to handle and so
Scheme 3. Total Synthesis of (()-Buphanidrine
was transformed without purification into methyl enol ether
9
1
2. The DIBAL reduction/acid hydrolysis of alkyl enol ether
1
0
systems to their enone products is well precedented.
However, in THF and toluene the predominant product was
that resulting from a competing reaction sequence of 1,4-
reduction, elimination of methanol, and a further 1,4-
reduction to give a saturated ketone (see the Supporting
Information for details). Switching the reaction solvent to
dichloromethane significantly reduced the amount of 1,4-
reduction product obtained and gave the desired cyclohex-
enone 13 in 58% yield over two steps. The cis stereochem-
istry of 13 was unambiguously proven by single-crystal X-ray
diffraction (Scheme 2, inset).
deprotection Pictet-Spengler sequence was followed (Scheme
). Again, the Pictet-Spengler step was found to be
3
regioselective, forming the desired isomer in a ∼10:1 ratio.
In order to convert intermediate 13 into the target alkaloids,
a diastereoselective reduction of the cyclohexenone carbonyl
was required. Under standard Luche reduction conditions,
the desired diastereomer 14 was produced as the minor
component of a separable 5.5:1 mixture. Mesylation and
inversion of the allylic alcohol has been shown to be an
effective but lengthy strategy for synthesis of the desired
(
6
()-Buphanidrine was synthesized in 14 linear steps and a
1
13
% overall yield. The spectroscopic data ( H NMR,
C
NMR) and high-resolution mass spectrometric data of
synthetic buphanidrine were in excellent agreement with the
14
published data.
In summary, the total synthesis of (()-powelline (13 linear
steps in an overall yield of 6%) and (()-buphanidrine (14
linear steps and a 6% overall yield) has been achieved. In a
novel approach to the crinane skeleton, an organocatalytic
oxidative coupling allowed direct construction of the key
quaternary carbon-to-aryl bond in high yield, allowing rapid
access to the target alkaloids. Efforts toward an enantiose-
lective total synthesis are ongoing and will be reported in
due course.
1
1
allylic alcohol in related alkaloids. However, when this
approach was adopted on our system, loss of the stereo-
chemical integrity of the allylic alcohol was observed.
Pleasingly, a screen of reducing agents for 13 showed that
L-Selectride efficiently generated the desired diastereomer
14 as the major isomer (3.5:1 dr). NOE studies on both allylic
alcohol diastereomers allowed assignment of relative stere-
ochemical configurations. Facile deprotection of the Boc
group was accomplished in neat TFA, and the free base of
amine 15 was used directly in the final Pictet-Spengler
cyclization without purification. Formation of the final ring
was readily achieved through reaction with formaldehyde
in 6 M HCl at room temperature in 10 min, completing the
Acknowledgment. We gratefully thank The University
of Manchester and GlaxoSmithKline (for a studentship to
K.M.B.), the EPSRC for a Leadership Fellowship to D.J.D.,
and the Oxford Chemical Crystallography Service for the
use of the instrumentation.
1
3-step total synthesis of (()-powelline. Gratifyingly, the
Supporting Information Available: Experimental pro-
cedures, spectral data for compounds 8-17, 1, and 2, and
crystallographic data (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
two possible regioisomers in the Pictet-Spengler reaction
were formed with an ∼7:1 ratio in favor of the desired
1
2
1
13
product. The spectroscopic data ( H NMR, C NMR) and
high-resolution mass spectrometric data of synthetic pow-
1
3
elline were consistent with the published data.
OL1000654
For the total synthesis of buphanidrine, allylic alcohol 14
was O-methylated under standard conditions and the same
(13) (a) See ref 5. (b) Frahm, A. W.; Ali, A. A.; Ramadan, M, A. Magn.
Reson. Chem. 1985, 23, 804. (c) Zetta, L.; Gatti, G.; Fuganti, C. J. C. S.
J. Chem. Soc., Perkin Trans. 2 1973, 1180. (d) Kobayashi, S.; Tokumoto,
T.; Kihara, M.; Imakura, Y.; Shingu, T.; Taira, Z. Chem. Pharm. Bull. 1984,
32, 3015.
(
(
(
9) Clerici, A.; Pastori, N.; Porta, O. Tetrahedron 2001, 57, 217.
10) William, A. D.; Kobayashi, Y. J. Org. Chem. 2002, 67, 8771.
11) (a) Bru, C.; Guillou, C. Tetrahedron 2006, 62, 9043. (b) Martin,
S. F.; Campbell, C. L. J. Org. Chem. 1988, 53, 3184.
(14) (a) Viladomat, F.; Codina, C.; Bastida, J.; Mathee, S.; Campbell,
W. E. Phytochemistry 1995, 40, 961. (b) Neergaard, J. S.; Andersen, J.;
Pedersen, M. E.; Stafford, G. I.; van Staden, J.; J a¨ ger, A. K. S. Afr. J. Bot.
2009, 75, 371.
(
12) (a) Tam, N. T.; Cho, C.-G. Org. Lett. 2008, 10, 601. (b) Magnus,
P.; Sebhat, I, K. J. Am. Chem. Soc. 1998, 120, 5341. (c) Kim, S.; Ko, H.;
Kim, E.; Kim, D. Org. Lett. 2002, 4, 1343.
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