Total syntheses of complanadines A and B

Article abstract of DOI:10.1002/anie.201208297

Twice as nice: Total syntheses of dimeric alkaloids, (-)-complanadines A (1) and B (2), were achieved from (-)-lycodine. The unsymmetrical motif was assembled through direct arylation of the pyridine N-oxide. The absolute configuration and specific rotations of complanadines A and B were identified. Cbz=Benzyloxycarbonyl. Copyright

Full text of DOI:10.1002/anie.201208297

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Angewandte
Communications
DOI: 10.1002/anie.201208297
Natural Products
Total Syntheses of Complanadines A and B**
Le Zhao, Chihiro Tsukano,* Eunsang Kwon, Yoshiji Takemoto, and Masahiro Hirama
ꢀ
Naturally occurring dimeric alkaloids often show distinct and/
or improved biological activities compared with those of their
monomers. To investigate the details of their biogenesis and
bioactivity, it is attractive to synthesize dimeric natural
products from their monomers, in the same way as nature
may do.[1,2] This approach is even more challenging when the
dimer is unsymmetrical, because it requires position-con-
trolled union of the two monomers.
rical as a result of a C2 C3’ bipyridyl linkage and/or different
oxidation levels of the lycodine units.[5,6] Complanadines A
(1), B (2), D, and E have been reported to induce secretion of
neurotrophic factors (NTFs) from 1321N1 human astrocy-
toma cells, thus they are lead compounds for the development
of drugs for treating Alzheimerꢀs disease.[3b–d] Because of their
challenging unsymmetrical structures and intriguing biologi-
cal activities, complanadines have attracted much attention
from organic chemists.[2] Two groups reported a total synthesis
of complanadine A in 2010.[7,8] In these pioneering studies, the
2,3’-bipyridyl framework was elegantly constructed, but there
are still no reports of efficient and versatile ways of assem-
bling unsymmetrical structures like that of complanadine B
(2).[9] Herein, we report the total syntheses of 1 and 2 by
straightforward coupling of the monomeric units, which were
prepared from a single N-protected lycodine, and the
subsequent correction of the reported specific rotation
([a]D) of natural complanadine A (1) to levorotatory.
Complanadines, isolated from the club moss Lycopodium
complanatum by Kobayashi et al., are dimeric Lycopodium
alkaloids (Scheme 1).[3,4] These compounds are unsymmet-
Retrosynthetically, pyridine mono-N-oxide 4 could be
a common intermediate for 1 and 2 (Scheme 2). Reduction of
4 would afford 1. Regioselective benzylic oxidation using the
Scheme 1. Complanadines A, B, D, and E, and lycodine.
[*] Dr. C. Tsukano, Prof. Dr. Y. Takemoto
Department of Organic Chemistry
Graduate School of Pharmaceutical Sciences, Kyoto University
Yoshida, Sakyo-ku, Kyoto 606-8501 (Japan)
E-mail: tsukano@pharm.kyoto-u.ac.jp
Scheme 2. Retrosynthesis of complanadines A and B. Cbz=benzylox-
ycarbonyl.
L. Zhao, Prof. Dr. M. Hirama
Department of Chemistry, Graduate School of Science
Tohoku University
6–3 Aramaki Aza-Aoba, Aoba-ku, Sendai 980-8578 (Japan)
N-oxide functionality would lead to ketone 2. The mono-N-
oxide 4 could be constructed by direct C2 arylation of
pyridine N-oxide 5[10,11] with 3-bromopyridine 6. Enantiopure
5 and 6 could both be prepared by chemo- and regioselective
functionalization of a single N-protected lycodine 7. So far,
there are no examples of the direct arylation of such a complex
pyridine N-oxide system.[10,11] It was therefore essential to
optimize the direct arylation reaction.
Our syntheses commenced with the preparation of 7 in
enantiopure form. After a number of experiments, racemic
ketone 8[6c] was found to be readily resolved on an amylose
chiral column (Daicel Chiral-Pak AS) when a mixture of
Dr. E. Kwon
Research and Analytical Center for Giant Molecules
Graduate School of Science, Tohoku University
6–3 Aramaki Aza-Aoba, Aoba-ku, Sendai, 980-8578 (Japan)
[**] We gratefully thank Profs. J. Kobayashi, H. Morita, and T. Kubota for
providing the natural products and 1H and 13C NMR spectra. This
work was financially supported by a Grant-in-Aid for Scientific
Research on Innovation Area “Molecular Activation Directed toward
Straightforward Synthesis” from The Ministry of Education, Culture,
Sports, Science and Technology (Japan) (C.T.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201208297.
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Scheme 3. Total syntheses of (ꢀ)-lycodine and (ꢀ)-complanadines A and B. Reaction conditions: a) HSCH2CH2SH, BF3·OEt2, CH2Cl2, 88%;
b) Ph3SnH, AIBN, toluene, 110 8C, 86%; c) HSCH2CH2SH, BF3·OEt2, CH2Cl2; d) Raney Ni (W-2), EtOH, reflux, 70% (2 steps); e) mCPBA, CH2Cl2,
0 8C to RT, 92 %; f) [{Ir(cod)(OMe)}2], tBudpy, [B(pin)]2, THF, reflux; g) CuBr2, MeOH/H2O (1:1), reflux, 60% (2 steps); h) Pd(OAc)2,
tBuDavePhos, Cs2CO3, pivalic acid, mesitylene, 1308C, 62% (see text for details and optimization of the reaction conditions); i) Pd(OH)2/C,
HCO2NH4, MeOH, 67%; j) Ac2O, 1258C, d.r. = 3:1; k) K2CO3, MeOH; l) DMP, CH2Cl2, 76%, (3 steps) ; m) 6m aq. HCl, 70 8C, 78%. AIBN=2,2’-
azobisisobutylnitrile, tBudpy=4,4’-di-tert-butyl-2,2’-bipyridyl, [B(pin)]2 =bis(pinacolato)diboron, Cbz=benzyloxycarbonyl, cod=cyclooctadiene,
mCPBA=meta-chloroperbenzoic acid, DMP=Dess–Martin periodinane, pin=pinacolato, THF=tetrahydrofuran.
ethanol/n-hexane/diethylamine (5.8%/94%/0.2%) was used
as the eluent (Scheme 3), thus providing (+)- and (ꢀ)-8 in
48% and 47% yields, respectively. Thioketalization of (+)-8,
and subsequent treatment with Raney nickel, afforded (ꢀ)-
lycodine (3). The 1H and 13C NMR data and specific rotation
of the synthetic sample are fully consistent with those of the
natural product.[5a,c]
Furthermore, the absolute configuration of (ꢀ)-3 was
unambiguously determined by X-ray crystallography of
synthetic HBr salt of (ꢀ)-3 (Figure 1). To our knowledge,
the absolute configuration of natural (ꢀ)-lycodine (3) was
directly and rigorously established for the first time.[12a,b]
With the enantiodefined and enantiopure (ꢀ)-3 and
(+)-7[13] in hand, we could synthesize (+)-N-Cbz-lycodine
N’-oxide (5) and (+)-N-Cbz-bromolycodine (6) and inves-
tigate the assembly of the unsymmetrical dimer by a Pd-
catalyzed coupling reaction (Scheme 3).[13,14] Before conduct-
ing the direct arylation of these complex molecules, we
examined the reaction between model compounds 9 and 10
(Table 1). When 9 and 10 were treated with a catalytic amount
Table 1: Direct arylation of pyridine N-oxide 9 and bromopyridine 10.
Entry
Ligand
Additive
Base
Yield [%][a]
1
2
3
4
5
tBu3P·HBF4
Cy3P·HBF4
tBuDavePhos
tBuDavePhos
tBuDavePhos
None
None
None
PivOH
PivOH
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
33%
37%
41%
46%
56%
[a] Yield of the isolated product.
of Pd(OAc)2, tBu3P·HBF4, and potassium carbonate in
mesitylene at 1208C, according to the method reported by
Fagnou and co-workers,[10a,c,e] bipyridine mono-N-oxide 11
was formed in 33% yield (entry 1). With the sterically more-
demanding phosphine ligand Cy3P·HBF4 a slightly higher
yield was achieved (entry 2). The use of the more electron-
rich and bulkier ligand, 2-di-tert-butyl-phosphino-2’-(N,N-
Figure 1. X-ray structure of HBr salt of (ꢀ)-3. Counter-anions are
omitted for clarity. Thermal ellipsoids are shown at the 50% probability
level.[12c]
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dimethylamino)biphenyl (tBuDavePhos),[15] increased the
yield to 41% (entry 3). Addition of pivalic acid (PivOH)
resulted in an increased yield (46%; entry 4).[10e,f] We found
that using cesium carbonate as the base improved the yield to
56% (entry 5).
biological activities of the enantiomers of natural complana-
dines A and B will be reported in due course.
Received: October 16, 2012
Published online: December 20, 2012
(+)-N-Cbz-lycodine N’-oxide (5) was synthesized by
mCPBA oxidation of (+)-7. Miyaura–Hartwig borylation[16]
of (+)-7, which was carried out by using the procedure of
Sarpong and Fischer,[7] and subsequent bromination with
CuBr2,[17] provided (+)-N-Cbz-bromolycodine (6) regioselec-
tively. The optimized reaction conditions (Pd(OAc)2
(20 mol%), tBuDavePhos (24 mol%),[15] Cs2CO3 (3 mol
equiv) and pivalic acid (0.3 molequiv) in mesitylene at
1308C) were applicable the coupling of (+)-5 and (+)-6 to
give the desired key intermediate (+)-4 in 62% yield.
The mono-N-oxide (+)-4 was first converted into com-
planadine A (1). Reduction of the N-oxide and Cbz groups
with ammonium formate in the presence of Pd(OH)2
Keywords: alkaloids · biomimetic synthesis · complanadine ·
direct arylation · total synthesis
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[1] For reviews on the synthesis of dimeric natural products, see: M.
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Chem. 1960, 38, 1823; c) T. T. Nakashima, P. P. Singer, L. M.
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2010, 132, 5924.
[9] Sarpong and co-workers recently completed a total synthesis of
complanadine B (2), see J. N. Newton, D. F. Fischer, R. Sarpong,
Angew. Chem. 2013, DOI: 10.1002/ange.201208571; Angew.
Chem. Int. Ed. 2013, DOI: 10.1002/anie.201208571.
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Chem. Soc. 2008, 130, 3266; d) H.-Q. Do, R. M. K. Khan, O.
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1
furnished (ꢀ)-complanadine A (1; Scheme 3).[13] The H and
13C NMR, and high resolution mass spectra of synthetic
complanadine A were identical to those of the natural
product. However, the specific rotation of the synthetic
complanadine A purified by HPLC turned out to be levo-
25
rotatory (½aꢁD ¼ꢀ168 (c = 0.16, MeOH)), which was the
24
opposite of that reported for the natural product (½aꢁD ¼ +
148 (c = 0.3, MeOH))[3a,b] and those of synthetic samples
24
reported by Siegel co-workers (½aꢁD ¼ + 14.58 (c = 0.3,
MeOH))[8] and by Sarpong and Fischer ([a]D =+ 22.28 (c =
0.85, CHCl3)).[7] We therefore re-examined the [a]D of natural
complanadine A, which was gifted by Kobayashi and co-
workers,[18] and found that the natural product purified by
25
HPLC has ½aꢁD ¼ꢀ168 (c = 0.04, MeOH), which is consistent
with that of our synthetic sample.[19] The reported [a]D values
for complanadine A therefore need to be corrected.
The regioselective benzylic oxidation of (+)-4 by proto-
tropy and subsequent Claisen-type rearrangement of O-
acetylated pyridine N-oxide, achieved by heating in acetic
anhydride,[20] gave acetate 12 as a 3:1 epimeric mixture.
Methanolysis of the acetate of 12, subsequent oxidation using
Dess–Martin periodinane,[21] and removal of the N-Cbz group
under acidic conditions completed the first total synthesis of
1
(ꢀ)-complanadine B (2). Its H and 13C NMR spectra, high
25
resolution mass spectra, and ½aꢁD of ꢀ288 (c = 0.11, MeOH)
23
are identical to those of the natural product (½aꢁD ¼ꢀ138 (c =
0.5, MeOH).
In summary, we have accomplished the total syntheses of
dimeric alkaloids complanadines A and B, the unsymmetrical
motif of which was concisely constructed by Pd-catalyzed
direct arylation of pyridine N-oxide with a bromopyridine
derivative. We confirmed their absolute configurations, and,
furthermore, the [a]D of complanadine A was corrected. The
present synthetic strategy could be applied not only to the
syntheses of other complanadine congeners that possess
monomeric units with different oxidation levels, but also to
the syntheses of other dimeric alkaloids. This synthesis
strongly suggests an intermediacy of an mono-N-oxide, such
as 4, in the biosynthesis of dimeric alkaloids; this interesting
finding requires further clarification. Investigation of the
[11] For selected examples of direct arylations of pyridine N-oxides
ꢀ
through C H activation of arenes and heteroarenes, see: a) S. H.
Cho, S. J. Hwang, S. Chang, J. Am. Chem. Soc. 2008, 130, 9254;
b) P. Xi, F. Yang, S. Qin, D. Zhao, J. Lan, G. Gao, C. Hu, J. You, J.
Am. Chem. Soc. 2010, 132, 1822; c) A. D. Yamaguchi, D.
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Mandal, J. Yamaguchi, K. Itami, Chem. Lett. 2011, 40, 555; d) X.
Gong, G. Song, H. Zhang, X. Li, Org. Lett. 2011, 13, 1766.
[12] a) Structurally defined natural lycopodine was chemically trans-
formed to lycodine in 1960. However, it was identified only by
m.p., mixed m.p., UV, and IR spectra at that time, see: F. A. L.
Anet, M. V. Rao, Tetrahedron Lett. 1960, 1, 9; The absolute
configuration of lycopodine was determined afterward, see:
b) M. U. Haque, D. Rogers, J. Chem. Soc. Perkin Trans. 2 1975,
93, c) CCDC 905380 ((ꢀ)-3) contains the supplementary crys-
tallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif. See the Supporting Infor-
mation for the details of the X-ray crystallographic analysis of
HBr salt of (ꢀ)-3.
[14] As both enantiomers of lycodine are readily available, we
performed the total syntheses of both enantiomers of compla-
nadines A and B. Only the synthesis of (ꢀ)-complanadines from
(ꢀ)-lycodine is described herein. Yields of each step of the
synthesis of (+)-ent-enantiomer series are described in the
Supporting Information.
[15] A. Aranyos, D. W. Old, A. Kiyomori, J. P. Wolfe, J. P. Sadighi,
S. L. Buchwald, J. Am. Chem. Soc. 1999, 121, 4369.
[16] a) T. Ishiyama, J. Takagi, K. Ishida, N. Miyaura, N. R. Anastasi,
J. F. Hartwig, J. Am. Chem. Soc. 2002, 124, 390; b) J. M. Murphy,
X. Liao, J. F. Hartwig, J. Am. Chem. Soc. 2007, 129, 15434.
[17] A. L. S. Thompson, G. W. Kabalka, M. R. Akula, J. W. Huffman,
Synthesis 2005, 547.
[18] We are highly grateful to Prof. Kobayashi and co-workers for
their generous gift of natural complanadine A.
[19] Synthetic complanadine A derived from (+)-ent-lycodine is
dextrotatory [(+)].
[13] We found that all N-Cbz protected lycodine derivatives synthe-
sized from (ꢀ)-lycodine (3) become dextrotatory [(+)], and
similarly that N-N’-bisprotection of (ꢀ)-complanadine A is
likely to change the sign of specific rotation ([a]D) to dextro-
tatory (see below).
[20] G. Kobayashi, S. Furukawa, Pharm. Bull. Jpn. 1953, 1, 347.
[21] D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155.
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