Total synthesis of (±)-decinine via an oxidative biaryl coupling with defined axial chirality

Article abstract of DOI:10.1021/ol3015573

The total synthesis of (±)-decinine has been achieved. The key steps in the synthesis involved the formation of lasubine II via a gold catalyzed annulation of 1-(but-3-yn-1-yl)piperidine and the formation of the 12-membered ring of decinine (1) with complementary atropselectivity via a VOF ₃-mediated oxidative biaryl coupling reaction.

Full text of DOI:10.1021/ol3015573

ORGANIC
LETTERS
2012
Vol. 14, No. 14
3712–3715
Total Synthesis of (()-Decinine via an
Oxidative Biaryl Coupling with Defined
Axial Chirality
Zhen-Hua Shan,† Ji Liu,† Ling-Min Xu,† Ye-Feng Tang,*,‡ Jia-Hua Chen,*,† and
Zhen Yang*,†
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of
Education, Beijing National Laboratory for Molecular Science (BNLMS), and Peking-
Tsinghua Center for Life Sciences at College of Chemistry of Peking University, Chengfu
Road, 202, Beijing, China, 100871, and The Comprehensive AIDS Research Center,
School of Life Science and School of Medicine, Tsinghua University, Beijing 100084, China
yefengtang@tsinghua.edu; jhchen@pku.edu.cn; zyang@pku.edu.cn
Received June 6, 2012
ABSTRACT
The total synthesis of (()-decinine has been achieved. The key steps in the synthesis involved the formation of lasubine II via a gold catalyzed
annulation of 1-(but-3-yn-1-yl)piperidine and the formation of the 12-membered ring of decinine (1) with complementary atropselectivity via a
VOF3-mediated oxidative biaryl coupling reaction.
Decinine (1) was first isolated in 1962 by Ferris from
Decodon verticillatus (L.) Ell1 and classified as a member
of the Lythraceae alkaloid family,2 whose other family
members includelythrine(2)1a,3 and lyfoline (3) (Figure1).4
† Beijing National Laboratory for Molecular Science (BNLMS) and
Peking-Tsinghua Center for Life Sciences at College of Chemistry of Peking
University.
‡ Tsinghua University.
(1) (a) Ferris, J. P. J. Org. Chem. 1962, 27, 2985. (b) Ferris, J. P.
J. Org. Chem. 1963, 28, 817. (c) Ferris, J. P.; Boyce, C. B.; Briner, R. C.
J. Am. Chem. Soc. 1971, 93, 2942. (d) Ferris, J. P.; Briner, R. C.; Boyce,
Figure 1. Naturally occurring Lythraceae alkaloids.
C. B. J. Am. Chem. Soc. 1971, 93, 2958. (e) Ferris, J. P.; Boyce, C. B.;
Briner, R. C.; Weiss, U.; Qureshi, I. H.; Sharpless, N. E. J. Am. Chem.
Soc. 1971, 93, 2963.
This family of quinolizidine alkaloids possesses a wide
profile of interesting biological activities, including anti-
inflammatory, antispasmodic, and diuretic properties.5
The structure of decinine (1) was determined by X-ray
crystallographic analysis of its derivative,6 which con-
tained a macrocyclic ring and consisted of a quinolizidine
ring and a biphenyl moiety. The strained 12-membered
(2) Wright, H.; Clardy, J.; Ferris, J. P. J. Am. Chem. Soc. 1973, 95, 6467.
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Raffauf, R. F. Lloydia 1964, 27, 25. (b) Fuji, K.; Yamada, T.; Fujita, E.;
Murata, H. Chem. Pharm. Bull. 1978, 26, 2515.
(4) Kim, H. J.; Lee, I. S.; Youn, U. J.; Chen, Q. C.; Ngoc, T. M.; Ha,
D. T.; Liu, H.; Min, B. S.; Lee, J. Y.; Seong, R. S.; Bae, K. H. J. Nat.
Prod. 2009, 72, 749.
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(b) Blomster, R. N.; Bobbitt, J. M.; Schawarting, A. E. Lloydia 1964, 27,
15. (c) Kaplan, H. R.; Malone, M. H. Lloydia 1966, 29, 348. (d) Lema,
W. J.; Blankenship, J. W.; Malone, M. H. J. Ethnopharmacol 1986, 15,
161. (e) Rother, A.; Edwards, J. M. Phytochemistry 1994, 36, 911. (f)
Malone, M. H.; Rother, A. J. Ethnopharmacol. 1994, 42, 135.
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Kirkpatrick, J. L.; Ferris, J. P.; Boyee, C. B.; Briner, R. C. Experientia
1965, 21, 247.
r
10.1021/ol3015573
Published on Web 06/29/2012
2012 American Chemical Society

macrolactone structure incorporates three stereogenic cen-
ters, two of which are part of the macrocycle, and an
induced chiral biaryl axis, representing a significant syn-
thetic challenge.
We became fascinated with the idea of testing this
biomimetic synthesis to explore the possibility of emulat-
ing this oxidative pathway in the laboratory. Herein, we
report the synthesis of decinine (1) using a VOF3-mediated
nonphenolic oxidative biaryl coupling reaction11 for the
formation of the 12-membered ring. The reaction pro-
ceeded in the presence of an excess of TFA12 and enabled
the unprecedented coupling of a biaryl substrate contain-
ing a quinolizidine subunit.
Lasubine II (8) is an essential fragment in many bioac-
tive alkaloids, and studies aimed at developing concise and
convergent synthetic approaches to the compound are an
ongoing, with many unique methods having already been
developed in this area.14
The construction of biaryl compounds, particularly
unsymmetrical and axially chiral biaryls, continues to
represent a challenging goal in organic synthesis.7
Although Lythraceae alkaloids can be synthesized using
both acid-catalyzed lactonization and ring closing meta-
thesis (RCM) reactions as the key steps in the formation of
their macrocyclic rings,8 earlier efforts to affect the same
transformation using the oxidative biaryl coupling for the
formation of alkaloids failed to afford any annulated
product.9
Retrosynthetically, it was anticipated that the macro-
cyclic ring of decinine (1) could be constructed via the
oxidative biaryl coupling of ester 6, which could itself be
obtained via the condensation reaction of acrylic acid 7
and lasubine II (8) (Scheme 2). It was also envisaged that
the chirality already present in lasubine II (8) would
determine the steric course of the coupling reaction, pro-
viding the desired axial chirality in decinine (1) through a
chirality transfer13 process.
Scheme 1. Biosynthetic Analysis of Quinolizidine Alkaloids
Scheme 2. Retrosynthetic Analysis
Biosynthetically, compounds 1ꢀ3 can be traced back to
phenol 4 (Scheme 1), which presumably undergoes an
oxidative biaryl coupling reaction, followed by a series of
functionalizations to afford quinolizidine alkaloids, such
as 1ꢀ3.10 It is therefore conceivable, for example, that
decinine (1) could be derived from ester 4 via an initial
intramolecular oxidative biaryl coupling to afford the
annulated product 5, followed by a 1,4-reduction and
regioselective dimethylation.10d
The transition-metal-catalyzed cyclization of alkynes is
one of the most powerful methods for the construction of
(7) For reviews on biaryl synthesis, see: (a) Shimizu, H.; Nagasaki, I.;
Saito, T. Tetrahedron 2005, 61, 5405. (b) Bringmann, G.; Mortimer,
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Chem., Int. Ed. 2005, 44, 5384. (c) Hassan, J.; Sevignon, M.; Gozzi, C.;
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protect tertiary amines during the oxidation. Schwartz, M.; Rose, B.;
Vishnurajjala, B. J. Am. Chem. Soc. 1973, 95, 612.
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Synthesis 1992, 503. (c) Kagan, H. B.; Riant, O. Chem. Rev. 1992, 92,
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Org. Lett., Vol. 14, No. 14, 2012
3713

highly functionalized carbocyclic molecules,15 and gold-
(I/III) catalysts have been widely used in this regard
because of their unique π-acidity and alkynophilicity.16
Zhang and co-workers recently reported the application of
a Au-catalyzed tandem cyclization to the synthesis of
piperidine-4-ones from substituted 3-butynyl amines via
a two-step formal [4 þ 2] approach.17 We were intrigued by
the efficiency and mild reaction conditions of Zhang’s
protocol and decided to synthesize Lasubine II (8) accord-
ing to the same methodology.
Thus, aldehyde 9 was reacted with piperidine perchlo-
rate 10 in the presence of a catalytic amount of piperidine
in refluxing benzene under DeanꢀStark conditions to give
the iminium salt 11 in 89% yield.18 Compound 11 was then
reacted with the Grignard reagent 1219 to afford butynyl
piperidine 13 in 73% yield.
With lasubine II 8 in hand, we proceeded to explore the
oxidative biaryl annulation for the synthesis of the target
molecule decinine (1). Phenol 17 was the preferred choice
of substrate because its oxidativeannulation through17a21
was able to afford decinine (1) directly.
Thus, phenylacrylic acid15wascoupledwith lasubine II
(8) in the presence of EDCI and DMAP to give ester 16 in
85% yield, which was then catalytically hydrogenated with
palladium on carbon to afford 17 in 91% yield (Scheme 4).
Unfortunately, although several oxidative agents were
investigated under various conditions to promote the
oxidative biaryl coupling, none of the desired product
was formed, with substrate 17 simply decomposing in the
majority of cases.
Lasubine II (8) was constructed from substrate 13 using
a formal [4 þ 2] approach involving the sequential treat-
ment of 13 with m-CPBA and Ph3PAuNTf217 to give the
desired product quinolizinone 14 in 60% yield. Compound
14 was then reduced with L-selectride to afford lasubine II
(8) in 66% yield,20 together with its diastereoisomer 8a in
14% yield (Scheme 3).
Scheme 4. First Generation of Oxidative Biaryl Coupling
Scheme 3. Synthesis of Lasubine II (8)
The oxidative coupling was then investigated using
phenol 4, which was regarded to be a potential substrate
in the biomimetic syntheses of Lythraceae alkaloids.10
Phenol 4 was prepared from ketone 14 via a five-step
linear sequence (Scheme 5). Ketone 14 was demethylated
with BBr3 in CH2Cl2 at ꢀ40 °C, and the resulting diphenol
intermediate was protected as the corresponding benzyl
etherby treatment with BnBrinthe presenceof K2CO3 and
a catalytic amount of KI (50 Mol%) in an acetone solvent
to give 18 in 44% yield over the two steps. Compound 18
was then reduced stereoselectively with L-selectride20 in
THF to afford alcohol 19 in 64% yield.
Following the condensation of alcohol 19 with phenyl
acrylic acid 15, the resulting ester 20 was subjected to
catalytic hydrogenation toaffordphenol 4. Unfortunately,
although several oxidative agents were again investigated
under various conditions to promote the oxidative biaryl
coupling, none of the desired product was formed, with
substrate 4 suffering a similar fate as substrate 17 and
simply decomposing in the majority of cases.
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Angew. Chem., Int. Ed. 2006, 45, 200. (d) Zhang, L.; Sun, J.; Kozmin, S.
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(b) Gupton, J. T.; Coury, J.; Moebus, M.; Fitzwater, S. Synth. Commun.
1986, 16, 1575.
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D. L.; LaMunyon, D. H. J. Org. Chem. 1992, 57, 5807. (c) Mancheno, O. G.;
Arrayas, R. G.; Adrio, J.; Carretero, J. C. J. Org. Chem. 2007, 72, 10294.
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Dominguez, E. Curr. Org. Chem. 2002, 6, 1433. (b) Dohi, T.; Ito, M.;
Yamaoka, N.; Morimoto, K.; ujioka, H.; Kita, Y. Tetrahedron 2009, 65,
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Org. Lett., Vol. 14, No. 14, 2012

During the course of performing experiments on the
oxidative biaryl coupling of esters 21ꢀ25 using VOF3 as an
oxidant at the optimized reaction conditions (see the
Supporting Information for details of the optimization
process), the anticipated annulated products 26 and 27
were isolated from their corresponding starting materials
24 and 25 in yields of 7% and 32%, respectively. In
contrast, substrates 21ꢀ23 did not afford the desired
products under the different reaction conditions tested.
It is worthy of note that a large excess of TFA played a
decisive role in reducing the oxidative tendency of the
tertiary amine in the substrate via the formation of
its corresponding amine salt. This effectively mitigated
any oxidation of the amine in the presence of a required
excess of the VOF3 oxidative agent. On the other hand,
the electron-deficient PNB group may also contribute
to the annulation of substrate 25 due to its stability
toward TFA during the nonphenolic oxidative biaryl
coupling.11c
Scheme 5. Second Generation Biaryl Coupling Approach
We then proceeded to explore the total synthesis of
decinine (1). Thus, lactone 27 was subjected to Pd-cata-
lyzed hydrogenation22 in ethyl acetate to give (()-decinine
1 in 80% yield (Scheme 7). The NMR data for the
synthesized decinine (1) were identical to the data reported
for material isolated from natural sources.23
Scheme 6. Syntheses of Biaryl Esters 21ꢀ25 and Their Oxidative
Biaryl Couplings
Scheme 7. Synthesis of Decinine
In summary, we have achieved for the first time the total
synthesis of racemic decinine (1) over a nine-step linear
sequence in an overall yield of 4.7%. The key steps in the
sequence were the VOF3-mediated oxidative biaryl cou-
pling and the gold-catalyzed annulation. It is envisaged
that the developed chemistry may be applied to the total
syntheses of other biologically important and naturally
occurring macrocyclic quinolizidine alkaloids, as well as
their analogs.
In light of the challenges encountered with the phenolic
oxidative biaryl coupling, we proceeded to test the VOF3-
mediated nonphenolic oxidative biaryl coupling11 for the
formation of the macrocyclic ring. Thus, five additional
biaryl esters 21ꢀ25 were prepared according to the chem-
istry depicted in Scheme 6 (details of their syntheses are
provided in the Supporting Information).
Acknowledgment. This work was supported by the
National Science Foundation of China (Grant Nos.
20832003, 21072006, and 21072111).
Supporting Information Available. Experimental pro-
cedure, 1H and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.
acs.org.
(22) Tanaka, M.; Wakamatsu, T.; Ikeya, Y.; Mitsuhashi, H.; Maruno,
M. Tetrahedron 1995, 51, 11703.
(23) Hughes, D. W.; Spenser, I. D.; Wrobel, J. T. Magn. Reson.
Chem. 2000, 38, 707.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 14, 2012
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