Total Synthesis of (-)-Daphenylline

Article abstract of DOI:10.1002/anie.201601958

Total synthesis of (-)-daphenylline, a hexacyclic Daphniphyllum alkaloid, was achieved. Construction of the tricyclic DEF ring system was initiated by asymmetric Negishi coupling followed by an intramolecular Friedel-Crafts reaction. Installation of a side chain onto the tricyclic core was carried out through Sonogashira coupling, stereocontrolled Claisen rearrangement by taking advantage of the characteristic conformation of the tricyclic DEF core, and the stereoselective alkylation of a lactone. After the introduction of a glycine unit, the ABC ring system was stereoselectively constructed through intramolecular cycloaddition of the cyclic azomethine ylide.

Full text of DOI:10.1002/anie.201601958

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International Edition: DOI: 10.1002/anie.201601958
German Edition: DOI: 10.1002/ange.201601958
Natural Product Synthesis Very Important Paper
Total Synthesis of (À)-Daphenylline
Ryosuke Yamada, Yohei Adachi, Satoshi Yokoshima,* and Tohru Fukuyama*
Abstract: Total synthesis of (À)-daphenylline, a hexacyclic
Daphniphyllum alkaloid, was achieved. Construction of the
tricyclic DEF ring system was initiated by asymmetric Negishi
coupling followed by an intramolecular Friedel–Crafts reac-
tion. Installation of a side chain onto the tricyclic core was
carried out through Sonogashira coupling, stereocontrolled
Claisen rearrangement by taking advantage of the character-
istic conformation of the tricyclic DEF core, and the stereo-
selective alkylation of a lactone. After the introduction of
a glycine unit, the ABC ring system was stereoselectively
constructed through intramolecular cycloaddition of the cyclic
azomethine ylide.
advantage of the characteristic conformations of the tricyclic
intermediates.
Our retrosynthetic analysis is illustrated in Scheme 1. The
ABC ring system of daphenylline (1) would be constructed
M
ore than 250 alkaloids have been isolated from plants of
the genus Daphniphyllum.[1] These Daphniphyllum alkaloids
show structural diversity and are classified into 14 structural
types based on their characteristic ring systems. Daphenylline
(1), isolated from the fruit of D. longeracemosum by Hao and
co-workers in 2009, is the first member of the Daphniphyllum
alkaloids that contains a benzene ring in the core structure
(Figure 1).[2] Daphenylline includes a rearranged 22-nor-
Scheme 1. Retrosynthetic analysis of daphenylline.
via cycloaddition of cyclic azomethine ylide 3,[7,8] which could
be derived from aminoaldehyde 4. Extensive conformational
analysis of the tricyclic DEF core in 5 led to the conclusion
that the olefin unit and the benzene ring in 5 would be
expected to avoid coplanarity owing to steric repulsion
between the methyl group on the olefin unit and the
substituent ortho to the olefin unit (Figure 2). DFT calcu-
Figure 1. Structures of daphenylline and calyciphylline A.
calyciphylline A type skeleton,[3] the highly fused hexacyclic
system of which has attracted significant attention in the
chemical community. While several synthetic studies have
been reported to date,[4,5] Li and co-workers recently accom-
plished the first total synthesis of (À)-daphenylline.[6] Herein,
we disclose a novel total synthesis of daphenylline that takes
Figure 2. Conformation of the tricyclic core.
[*] R. Yamada, Dr. S. Yokoshima, Prof. T. Fukuyama
Graduate School of Pharmaceutical Sciences, Nagoya University
Furo-cho, Chikusa-ku, Nagoya 464-8601 (Japan)
E-mail: yokosima@ps.nagoya-u.ac.jp
lations of the possible conformers of 5 suggested that the
methyl group on the olefin unit and the hydrogen atom at C10
are situated on the same side of the tricyclic core.[9] Hence, the
a face of the olefin unit is exposed to the substituent on the
benzene ring, thereby assuring the desired stereoselectivity of
the cycloaddition of the azomethine ylide. In fact, an
attempted cycloaddition reaction of the nitrile oxide, derived
from oxime 6, proceeded stereoselectively to give 7 in 96%
fukuyama@ps.nagoya-u.ac.jp
Dr. Y. Adachi
Graduate School of Pharmaceutical Sciences, University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201601958.
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yield as the sole isomer. In addition, use of the steric bias in
the tricyclic core should permit the stereoselective construc-
tion of the side chain in 4. We thus began our synthesis by
constructing the tricyclic DEF core.
We employed the asymmetric Negishi coupling reaction
reported by Arp and Fu (Scheme 2).[10] Reduction of the
Scheme 3. Stereoselective installation of the side chain. a) Tf2O, pyri-
dine, CH2Cl2, 08C, 73%; b) propargyl alcohol, PdCl2(dppf)·CH2Cl2,
pyrrolidine, TBAI, DMF, 608C, 86%; c) H2, Lindlar catalyst, quinoline,
EtOAc, RT, 98%; d) n-butyl vinyl ether, Hg(OAc)2, 608C, 74%;
e) iBu3Al, hexane, 108C, 90%, d.r. 5.9:1; f) TBSCl, imidazole, DMF, RT,
96%; g) 9-BBN, THF, 08C; aq. H2O2, aq. NaOH, 08C to RT, quant.;
h) AZADOL, PhI(OAc)2, phosphate buffer (pH 6.8), MeCN, RT; i) TFA,
CH2Cl2, RT, 63% (2 steps); j) LDA, THF, À788C; MeI, HMPA, 08C,
67%. AZADOL=2-hydroxy-2-azaadamantane, 9-BBN=9-borabicyclo-
[3.3.1]nonane, dppf=1,1’-bis(diphenylphosphino)ferrocene,
DMF=N,N-dimethylformamide, HMPA=hexamethylphosphoric tri-
amide, LDA=lithium diisopropylamide, TBAI=tetra-n-butylammo-
nium iodide, TBS=tert-butyldimethylsilyl.
Scheme 2. Preparation of the tricyclic core. a) NaBH4, CH2Cl2, MeOH,
RT, 99%; b) PCl3, pyridine, CH2Cl2, À108C; c) 10, NiBr2·diglyme, (S)-
iPr-Pybox, DMA, 08C; d) aq. NaOH, EtOH, RT, 45% (3 steps);
e) TFAA, TFA, CH2Cl2, RT; aq. Na2CO3, MeOH, RT, 81%; f) BBr3,
CH2Cl2, 08C, quant.; g) MeMgBr, THF, 08C; MgBr2, TsOH·H2O, THF,
508C, 68%. DMA=N,N-dimethylacetamide, TFA=trifluoroacetic acid,
TFAA=trifluoroacetic anhydride.
commercially available 6-methoxyindan-1-one (8) with
NaBH4 followed by treatment with PCl3 afforded chloroin-
dane 9. Reaction of 9 with zinc reagent 10 in the presence of
NiBr2/Pybox as a catalyst gave carboxylic acid 11 with e.r. 97:3
after hydrolysis of the resulting ester. The optical purity could
be improved by recrystallization of the corresponding salt
with (R)-1-phenylethylamine from cyclohexane (e.r. > 99:1).
An intramolecular Friedel–Crafts reaction of 11 was effected
by treatment with TFAA and TFA to furnish cyclic ketone 12.
After cleavage of the methyl ether with BBr3,[11] addition of
methylmagnesium bromide followed by dehydration afforded
the tricyclic DEF core 13.
We next focused on installing the side chain with good
control of the stereogenic centers (Scheme 3). After triflation
of the hydroxy group in 13, Sonogashira coupling with
propargyl alcohol was carried out, giving 14 in good yield.
Partial reduction of the alkyne moiety in 14 afforded cis-allyl
alcohol 15, onto which a vinyl group was introduced. Upon
treatment of 16 with iBu3Al in hexane at 108C, Al-mediated
Claisen rearrangement[12] proceeded stereoselectively (d.r.
5.9:1) to give olefinic alcohol 17 as the major isomer.[13] The
stereochemistry of the Claisen rearrangement was remotely
controlled by the stereogenic center at C10. This could be
rationalized as follows. Owing to the cis geometry of the allyl
vinyl ether moiety, it is expected to be inclined to the plane of
the benzene ring. Moreover, the allyl vinyl ether moiety
should be positioned to avoid steric repulsion with the methyl
group, which is oriented obliquely with respect to the plane of
the tricyclic core (Figure 3).[14,15] In this conformation, the
methyl group covers one face of the double bond. As a result,
the vinyl group reacted on the other face, leading to 17 as the
major isomer. After separation of the diastereomers, 17 was
converted into lactone 18 through a four-step sequence
Figure 3. Conformation of allyl vinyl ether 16.
involving protection of the alcohol, hydroboration,
AZADO oxidation,[16] and lactonization under acidic con-
ditions. Methylation at the a-position of the lactone occurred
stereoselectively upon successive treatment with LDA and
iodomethane to furnish 19 in 67% yield.
Having succeeded in the stereocontrolled installation of
the side chain, we turned our attention to cycloaddition of the
cyclic azomethine ylide to construct the ABC ring system
(Scheme 4). Reduction of the lactone moiety in 19 with
LiAlH4 afforded a diol. After protection of the less hindered
hydroxy group with a TIPS group, a glycine unit was
introduced through a Mitsunobu reaction with N-Ns glycinate
21.[17,18] Removal of the Ns and TIPS groups in 22 was
followed by protection of the secondary amine with a Boc
group. The resulting primary alcohol was oxidized with Dess–
Martin periodinane to furnish aldehyde 23. Cleavage of the
Boc group by heating in toluene at 2008C with microwave
irradiation triggered the formation of a cyclic azomethine
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[8] Construction of the AC ring system by means of cycloaddition of
a 2-azaallyl anion based on the Pearsonꢀs protocol has been
reported. Subsequent N-alkylation formed the B ring (see
Ref. [4a]).
Scheme 4. Intramolecular cycloaddition of the cyclic azomethine ylide
and completion of the synthesis. a) LiAlH4, THF, 08C, 99%; b) TIPSCl,
imidazole, DMF, RT, 64%; c) 21, DEAD, Ph3P, toluene, 708C, 85%;
d) PhSH, K2CO3, DMF, 508C, 92%; e) TBAF, THF, RT; Boc2O, aq.
NaHCO3, CH2Cl2, RT, 83%; f) Dess–Martin periodinane, CH2Cl2, RT,
93%; g) NaOAc, BHT, MS4A, toluene, microwave, 2008C, 53%;
h) NH3, MeOH, 708C, 79%; i) Burgess reagent, CH2Cl2, RT, 94%;
j) NaBH4, MeOH, reflux, 36%. BHT=3,5-di-tert-butyl-4-hydroxytoluene,
Boc=tert-butyloxycarbonyl, DEAD=diethyl azodicarboxylate, Ns=2-
nitrobenzenesulfonyl, TBAF=tetra-n-butylammonium fluoride, TIPS=
triisopropylsilyl.
ylide, which underwent intramolecular cycloaddition to give
hexacyclic compound 24 in 53% yield as the sole isomer.
Finally, the methyl ester 24 was converted into an amino-
nitrile, which was reduced with NaBH4 to furnish (À)-
daphenylline (1).
In conclusion, we have achieved the total synthesis of (À)-
daphenylline (1). The characteristic conformation of the
tricyclic DEF core was fully utilized to construct the
stereogenic centers by means of a remote stereocontrolled
Claisen rearrangement and intramolecular cycloaddition of
a cyclic azomethine ylide.
Acknowledgements
This work was financially supported by JSPS KAKENHI
(Grant Numbers 25221301, 26713001), and the Platform
Project for Supporting in Drug Discovery and Life Science
Research (Platform for Drug Discovery, Informatics, and
Structural Life Science) from the Ministry of Education,
Culture, Sports, Science and Technology of Japan (MEXT)
and the Japan Agency for Medical Research and Develop-
ment (AMED).
[9] An exhaustive conformational search of 5a (X = Me) using the
Conflex program and DFT calculations of each conformer
strongly suggested that the aforementioned conformation was
energetically favorable. For details, see the Supporting Informa-
tion.
[10] F. O. Arp, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 10482 – 10483.
[11] HPLC analysis confirmed that no racemization of the resulting
ketone took place.
Keywords: alkaloids · cycloaddition · natural products ·
rearrangement · stereoselective synthesis
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experiments after conversion into the
isoxazolines 25 or 26. For details, see
the Supporting Information.
[14] Claisen rearrangement of the trans-
allyl vinyl ether proceeded with
a lower stereoselectivity (d.r. = 2:1).
[18] Introduction of the glycine unit through reductive amination of
the corresponding aldehyde did not provide the desired product.
[15] A conformational search of 5b (X =
(Z)-1-propenyl) and DFT calcula-
tions also suggested that the afore-
mentioned conformation was favorable. For details, see the
Supporting Information.
Received: February 25, 2016
Published online: April 8, 2016
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