Total synthesis of the Daphniphyllum alkaloid daphenylline

Article abstract of DOI:10.1038/nchem.1694

The Daphniphyllum alkaloids are a large class of natural products isolated from a genus of evergreen plants widely used in Chinese herbal medicine. They display a remarkable range of biological activities, including anticancer, antioxidant, and vasorelaxation properties as well as elevation of nerve growth factor. Daphenylline is a structurally unique member among the predominately aliphatic Daphniphyllum alkaloids, and contains a tetrasubstituted arene moiety mounted on a sterically compact hexacyclic scaffold. Herein, we describe the first total synthesis of daphenylline. A gold-catalysed 6-exo-dig cyclization reaction and a subsequent intramolecular Michael addition reaction, inspired by Dixon's seminal work, were exploited to construct the bridged 6,6,5-tricyclic motif of the natural product at an early stage, and the aromatic moiety was forged through a photoinduced olefin isomerization/6π-electrocyclization cascade followed by an oxidative aromatization process.

Full text of DOI:10.1038/nchem.1694

ARTICLES
PUBLISHED ONLINE: 30 JUNE 2013 | DOI: 10.1038/NCHEM.1694
Total synthesis of the Daphniphyllum alkaloid
daphenylline
Zhaoyong Lu†, Yong Li†, Jun Deng and Ang Li
*
The Daphniphyllum alkaloids are a large class of natural products isolated from a genus of evergreen plants widely used in
Chinese herbal medicine. They display a remarkable range of biological activities, including anticancer, antioxidant, and
vasorelaxation properties as well as elevation of nerve growth factor. Daphenylline is a structurally unique member among
the predominately aliphatic Daphniphyllum alkaloids, and contains a tetrasubstituted arene moiety mounted on a sterically
compact hexacyclic scaffold. Herein, we describe the first total synthesis of daphenylline. A gold-catalysed 6-exo-dig
cyclization reaction and a subsequent intramolecular Michael addition reaction, inspired by Dixon’s seminal work, were
exploited to construct the bridged 6,6,5-tricyclic motif of the natural product at an early stage, and the aromatic moiety
was forged through a photoinduced olefin isomerization/6p-electrocyclization cascade followed by an oxidative
aromatization process.
lant natural products have played an important role in chem- subfamily21, which represents the first breakthrough in
istry, biology and medical science for centuries1, and chemical Daphniphyllum alkaloid synthesis in nearly two decades. To date,
P
synthesis continues to serve as a powerful tool to understand however, the remaining members of this large natural product
the functions of these compounds2–5. Daphniphyllum is a genus of family, including those from the calyciphylline A (6) and daphnicy-
dioecious evergreen plants native to Asia, the leaves and roots of clidin (7) subfamilies7, which feature a 6,n,5-briged tricyclic moiety
which are used widely in Chinese herbal medicine6. About 250 (Fig. 1, total number up to about 50), have not been synthesized suc-
Daphniphyllum alkaloids have been isolated from this genus to cessfully. Notably, Dixon and co-workers developed an elegant syn-
date7. From a structural perspective, these naturally occurring mol- thesis of the tricyclic core of calyciphylline A-type Daphniphyllum
ecules usually possess a bridged and fused hexa- or pentacyclic scaf- alkaloids (Fig. 2)26, which sets an important basis for the
fold that contains continuous stereogenic centres; based on their collective synthesis of the above-mentioned subfamily members.
connectivity modes, they can be further classified into more than The highly diastereoselective intramolecular Michael addition
20 subfamilies. Shown in Fig. 1 are the molecular architectures reaction used for their construction of the 5,6-bicyclic system26,27
that represent several major subfamilies of Daphniphyllum alka- is particularly inspiring to this work (vide infra). A structurally
loids. Intrigued by these fascinating structures, a series of biosyn- unique calyciphylline A family member, isolated by Hao and
thetic hypotheses were suggested7, led by Heathcock’s elegant co-workers from the fruits of D. longeracemosum in 2009, namely
proposal for the biosynthesis of methyl homosecodaphniphyllate daphenylline (Fig. 1; 8)34, attracted our, as well as others’,
(1; Fig. 1) from a squalene derivative8,9. Although some isotopic lab- attention30,31. Daphenylline is the only Daphniphyllum alkaloid to
elling experiments were carried out7, identifying the biosynthetic incorporate an arene motif, in contrast to the other members of
network that connects all the subfamilies of Daphniphyllum alka- this aliphatic natural product family. Herein, we report the first
loids at the biochemical level remains a formidable challenge. total synthesis of daphenylline (8).
These structurally diverse and complex natural products display a
remarkable range of biological activities7, such as anticancer10, anti- Results and discussion
oxidation11, elevation of nerve growth factor12 and vasorelaxation13. The structural features of the bridged 6,n,5-tricyclic (n ¼ 6 or 7)
However, the systematic biological profiling of the Daphniphyllum motif (Fig. 1, bottom right) of daphenylline (8) and its congeners
alkaloids and their derivatives is hampered by the scarce supply of (for example, 6 and 7), as well as Dixon’s seminal work26 described
these compounds from natural sources.
above (Fig. 2), inspired us to envision a common intermediate such
The formidable challenge posed by their intricate structures as 9 (Fig. 3), potentially useful for the divergent synthesis of a
resulted in intensive efforts to achieve the total synthesis of number of structurally related Daphniphyllum alkaloids. In the
Daphniphyllum alkaloids7,8,14–33, which would also provide a great case of daphenylline, the most significant synthetic challenge (the
opportunity to accelerate biological and biosynthetic studies of assembly of the sterically encumbered tetrasubstituted arene set
them. Heathcock and co-workers accomplished a landmark in a sterically demanding environment) could be achieved by a
synthesis of methyl homosecodaphniphyllate (1) guided by their 6p-electrocyclization/aromatization sequence, similar to that used
biosynthetic hypothesis8,14, which formed the basis for their successful during our total synthesis of tubingensin A35. With this strategy
syntheses of methyl homodaphniphyllate16, daphnilactone A17 and in mind, we undertook a retrosynthetic analysis, as shown in
bukittinggine18 (2–4; Fig. 1), as well as secodaphniphylline19 and Fig. 3. Hexacyclic ketolactam 10 was considered to be a direct pre-
codaphniphyllin20 (side-chain analogues of 1 and 2, respectively). cursor of daphenylline (8), the seven-membered ring of which could
Recently, Carreira and co-workers disclosed the total synthesis of daph- be disassembled to afford a pentacyclic iodide 11 as the substrate for
manidin E (5; Fig. 1) from a non-methyl homodaphniphyllate-type a 7-exo-trig radical cyclization. Based on the 6p-electrocyclization/
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling
Road, Shanghai 200032, China, †These authors contributed equally to this work. e-mail: ali@sioc.ac.cn
*
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
© 2013 Macmillan Publishers Limited. All rights reserved.
1

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1694
difficult than that of the well-precedented 5-exo-dig cases36,39
ARTICLES
CO2Me
CO2Me
.
O
Attempts to form the silyl enol ether 18 in the presence of triisopro-
pylsilyl trifluoromethanesulfonate (TIPSOTf) and triethylamine
(Et3N) or diisopropylethylamine36 led to a mixture of 18 and 19
(Fig. 4) in favour of the latter. To avoid the undesired g-deproto-
nated product 19, the less basic 2,6-lutidine was employed in the
above reaction to give 18 almost exclusively. Compound 18 was
subjected to standard cationic gold cyclization conditions
(chloro(triphenylphosphine)gold(I) (Au(PPh3)Cl, 0.2 equiv.),
AgSbF6 (0.3 equiv.) and MeOH), which rapidly generated the
desired bridged bicycle 20 (28%), and a significant amount of the
direct desilylated product 15 was recovered. From a mechanistic
point of view, the formation of 20 involved protonolysis of the cor-
responding alkenyl gold species under strongly acidic conditions,
which may also lead to rapid desilylation. Thus, we examined the
effect of different silyl groups in tuning the ratio of cyclization/
desilylation products. As we expected, the tert-butyldimethylsilyl
(TBS) enol ether gave a poorer ratio (14% of 20, 74% of 15), and
the tert-butyldiphenylsilyl enol ether improved the reaction
output (60% of 20, 20% of 15). As the counterion of the gold
complex (initially from the corresponding silver salt) may have a
subtle influence on the reactivity of the active gold species40 as
well as on the Bro¨nsted acidity of the reaction environment,
various silver salts (AgBF4, AgSbF6, silver trifluoromethanesulfo-
nate (AgOTf), AgOCOCF3 and others) were also tested. To our
delight, AgOTf proved to be the most effective additive and ren-
dered 20 in 72% yield from 15 (with 11% of 15 recovered).
Replacing MeOH with other protic solvents, such as isopropyl
alcohol, did not improve the efficiency, and decreasing the catalyst
loading to 0.1 equiv. led to 70% yield of 20 with 29% of 15 recov-
ered. With 20 in hand, desulfonation with p-thiocresol in the pres-
ence of K2CO3, followed by condensation with carboxylic acid 14
under 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochlo-
Me
Me
Me
Me
Me
O
Me
Me
HN
Me
N
N
1 Methyl homoseco-
daphniphyllate
2 Methyl homo-
daphniphyllate
3 Daphnilactone A
CO2Me
CO2Me
O
N
O
Me
HO
N
Me
Me
N
OAc
HO
AcO
OAc
Yuzurimine
4 Bukittinggine
5 Daphmanidin E
O
CO2Me
H
CO2Me
H
O
Me
O
Me
OAc
Me
HO
H
H
H
N
N
N
H
Me
O
O
Me
Daphmanidin C
Calyciphylline B
6 Calyciphylline A
O
O
HO
H
Me
m
Me
O
Me
Me
H
N
H
N
N
m = 1 or 2
.
6,n,5-bridged tricycle
7 Daphnicyclidin A
8 Daphenylline
ride (EDC HCl)/1-hydroxybenzotriazole (HOBt) conditions
afforded amide 21 in 72% overall yield. Compound 21 underwent
intramolecular Michael addition26,27 promoted by K2CO3 in
CH3CN at 100 8C to give 9 in 86% yield, together with 9% of the
chromatographically separable C6 diastereomer. Interestingly,
treatment of 21 with potassium hexamethyldisilazide (KHMDS)
Figure 1 | Selected natural products that represent major subfamilies of
Daphniphyllum alkaloids. The 6,n,5-bridged tricycle (bottom right) indicates
a common structural motif shared by 6, 7 and 8, as well as the related
Daphniphyllum subfamily members (up to about 50). A versatile intermediate
for the divergent synthesis of these Daphniphyllum alkaloids could be devised
based on this structural motif.
O
O
KHMDS,
O
i. LiHMDS; I2
ii. BnNH2
18-crown-6,
allylOTs
aromatization strategy, deconstruction of the benzene ring of 11
would give a cis-triene 12, which could be further disconnected at
the C1–C13 bond to give the devised bridged tricyclic intermediate
9 and a suitable side-chain coupling partner. Compound 9 was
traced back to bridged-bicyclic amine 13 and carboxylic acid 14.
The recombination of these two fragments could be achieved
through an amide-bond formation followed by an intramolecular
1,4-addition; both reactions are well-precedented in Dixon’s syn-
thesis of the calyciphylline A-type skeleton (Fig. 2)26,27. A gold-
catalysed alkyne-cyclization process (Toste–Conia-ene reaction)36
could be exploited to construct 13 from the silyl enol ether gener-
ated from ketone 15. This precursor should be readily accessible
from the known hydroxy enone 16 and sulfonamide 17 through a
Mitsunobu reaction. Notably, the C18 stereochemistry of 8 could
be established by facial selective hydrogenation of the corresponding
methylene substrate at a suitable stage.
Me
Me
78%
iii. Et3N
6
Me
BnN
OMe
BnN
CO2Me
O
O
O
O
O
Cl
OMe
A single
diastereomer
43−51% (overall)
O
O
O
LiCl, 170 o
C
Me
Me
H
Me
73%
6
BnN
BnN
BnN
CO2Me
H
O
O
O
Tricyclic core of
calyciphylline
A-type alkaloids
A 3.2:1 mixture of
diastereomers at C6
Based on the above analysis, we started our adventure with the
initial aim to reach the bridged tricycle 9, as shown in Fig. 4.
Coupling of the enantioenriched hydroxy enone 16 (six steps
from m-methylanisole, 98% enantiomeric excess (e.e.))37 and sulfo- Figure 2 | An inspiring synthesis of the tricyclic core of calyciphylline
namide 17 under Mitsunobu conditions provided compound 15 in A-type alkaloids by Dixon and co-workers26. A highly diastereoselective
86% yield, which retained high enantiopurity (97% e.e.). Not sur- intramolecular Michael addition reaction was developed for the construction
prisingly, the following gold-catalysed 6-exo-dig cyclization36,38 to of the 5,6-bicyclic system. LiHMDS, lithium hexamethyldisilazide;
construct the bridged [3.3.1]bicyclic system turned out to be more Ts, p-toluenesulfonyl.
2
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
© 2013 Macmillan Publishers Limited. All rights reserved.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1694
ARTICLES
H
H
Me
Me
reagents were also fruitless. To our delight, however, photo-
isomerization of the trans-triene afforded the desired cis-isomer.
Indeed, treatment of ketone 9 with KHMDS and N-phenylbis(tri-
fluoromethanesulfonimide) (PhNTf2) furnished the corresponding
triflate, which further underwent Suzuki coupling with trans-boro-
nate 22 to render triene 23 with good overall efficiency. Irradiation
of 23 with a 125 W Hg lamp for five minutes provided 12 readily42.
Surprisingly, this cis-triene was found to be reluctant to enter
the 6p-electrocyclization pathway under thermal conditions43;
elevating the reaction temperature merely led to skeletal
decomposition. Inspired by Trauner’s seminal work44,45, we
examined 6p-electrocyclization promoted by a Lewis acid to take
advantage of the carbonyl functionality conjugated to the triene
system of 12. Unfortunately, a variety of Lewis acids, such as
diethylaluminium chloride, boron trifluoride diethyl etherate,
SnCl4 and copper(I) trifluoromethanesulfonate35, failed to effect
the desired cyclization, and desilylation followed by decomposition
gradually occurred under these conditions. The failure of these
efforts may be attributable to the formidable steric hindrance gener-
ated in the disrotatory cyclization process. The conrotatory pathway
is expected to develop less steric congestion and, encouragingly, we
occasionally detected a trace amount of cyclization product under
photoirradiation conditions in the process of triene isomerization.
Under optimized conditions (500 W Hg lamp, 15 minutes), trans-
triene 23 converted cleanly into pentacyclic compound 24 (as a
single diastereomer in 71% yield) through a photoinduced isomer-
ization/electrocyclization cascade with the intermediacy of cis-
O
Me
Me
18
H
H
N
N
O
Radical
cyclization
8 Daphenylline
10
6π-electrocyclization/
aromatization
Pd-catalysed coupling
13
Me
Me
O
O
1
CO2Me
N
CO2Me
I
N
O
O
OTBS
12
11
Au-catalysed
alkyne cyclization
Michael addition
O
Me
O
OTBS
O
+
CO2Me
N
Me
NH
HO2C
CO2Me
OTBS
9
14
13
Amide formation
O
O
i. TBDPSOTf,
O2N
O
2,6-lutidine, −78 oC
O
O
O
ii. Au(PPh3)Cl,
AgOTf, MeOH
+
17, PPh3,
HN
S
Me
o-Ns
Me
OH
DIAD, 0 o
C
O
N
Me
86%
70% (two steps, 29%
of 15 recovered)
Me
N
Me
17
16
15
o-Ns
N
OH
o-Ns
16
15
20
Figure 3 | Retrosynthetic analysis of daphenylline. The key strategies
include (1) a radical cyclization for the assembly of the seven-membered
ring, (2) a sequence of 6p-electrocyclization/aromatization for the
construction of the tetrasubstituted arene, (3) an intramolecular Michael
i. K2CO3,
p-thiocresol
ii. 14, HOBt,
72%
(two
steps)
EDC·HCl, Et3N
addition to form the pyrrolidine ring with the desired stereochemistry and
(4) a gold(I)-catalysed 6-exo-dig cyclization to prepare the bridged 6,6-
bicyclic building block (13). Inspired by Dixon’s work26, intermediate 9 is
O
devised on the basis of the common structural motif of daphenylline-related
Daphniphyllum alkaloids. The 6p-electrocyclization/aromatization strategy,
which was applied to our previous synthesis of tubingensin A, plays a
determining role in the entire daphenylline plan. o-Ns, 2-nitrobenzenesulfonyl.
O
Me
Me
N
K2CO3, 100 o
C
CO2Me
CO2Me
6
O
N
86%
O
OTBS
OTBS
in tetrahydrofuran (THF) at 278 8C afforded the undesired C6
epimer as the major product (ꢀ3:1 diastereomeric ratio (d.r.)).
In contrast, Dixon and co-workers observed the desired stereo-
chemistry at C6 when synthesizing the 5,6-bicyclic system
through an intramolecular Michael addition under KHMDS
conditions (Fig. 2)26. The structure of 9 was confirmed by X-ray
crystallographic analysis of its desilylated derivative (Fig. 4; Tm
144–147 8C, ethyl acetate (EtOAc)/n-hexane 1:1). All the above
transformations were performed readily on a multigram scale with
consistent efficiency.
ORTEP of 9a (desilylated 9)
9
21
O
OSiR2R'
OSiR2R'
R2R'SiOTf, base
Me
o-Ns
Me
o-Ns
N
N
N
o-Ns
15
18
19
With the tricyclic intermediate 9 in hand, we focused our atten-
tion on the construction of the challenging tetrasubstituted arene Figure 4 | Construction of the bridged tricycle 9. A gold(I)-catalysed alkyne
motif, as shown in Fig. 5a. cis-Triene 12 was considered a suitable cyclization was exploited to construct the bridged 6,6-bicycle 20. Silyl enol
precursor to explore the feasibility of the 6p-electrocyclization/ ether 18, the substrate for this reaction, was prepared from enone 15 (inset);
aromatization strategy. However, well-recognized approaches, such 2,6-lutidine as a base was found to suppress the formation of the undesired
as partial hydrogenation41 of the corresponding ynediene, proved regioisomeric silyl enol ether 19. An intramolecular Michael addition
to be unsatisfactory because of the poor positional selectivity; assembled 9 in a diastereoselective manner. DIAD, diisopropyl
attempts to prepare seemingly simple cis-boronate/stannane azodicarboxylate; TBDPSOTf, tert-butyldiphenylsilyl trifluoromethanesulfonate.
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
© 2013 Macmillan Publishers Limited. All rights reserved.
3

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1694
ARTICLES
triene 1246–48. In a stepwise experiment, purified 12 was subjected to
the same conditions to give 24 (ꢀ50% overall yield from 23). The
yield of 24 significantly decreased when O2 was not strictly excluded
(vide infra). This cyclohexadiene displayed unexpected reactivity in
the subsequent aromatization process; treatment with various oxi-
dants or dehydrogenation reagents, such as 2,3-dichloro-5,6-
a
O
i. KHMDS, PhNTf2,
−78 o
ii. 22, Pd(PPh3)4,
K2CO3, 60 o
C
O
Me
Me
O
C
CO2Me
CO2Me
N
73% (two steps)
N
Me
Me
O
dicyano-p-benzoquinone,
2-iodoxybenzoic
acid,
MnO2,
O
OTBS
O
B
OTBS
I2/MeOH, Pd/C and Pd(OCOCF3)2, failed to aromatize it, but
resulted in skeletal decomposition on prolonged reaction times.
Finally, in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU)/air at elevated temperature49, 24 was converted into arene
25 in 67% yield, taking advantage of the C8 proton acidity
induced by the carbonyl group conjugated to the cyclohexadiene
system. Compound 25 retained high enantiopurity (96% e.e.,
measured by high-performance liquid chromatography using syn-
thetic (+)-25 as a reference).
Interestingly, a clean, but unexpected, transformation occurred
to furnish hexacyclic lactone 26 when 23 was photoirradiated in
the presence of air, as shown in Fig. 5b. Desilylation of 26 gave
alcohol 27, the structure of which was determined by X-ray crystal-
lographic analysis of single crystals of (+)-27 (Tm 136–138 8C,
EtOAc/n-hexane 1:1). We postulate that cyclohexadiene 24
reacted with singlet O2 to provide the Diels–Alder adduct 28,
which may further undergo Norrish type I fragmentation to
generate the diradical species 29. The O–O bond could
cleave homolytically and recombine with the diradical to
render 26. Thus, the stereochemical outcome of the conrotatory
6p-electrocyclization was verified indirectly by the structural
elucidation of 27.
9
23
Me
Me
O
22
hυ (Hg lamp,
Me
O
500 W), 0 oC
CO2Me
N
O
OTBS
71%
Me
12
Me
O
O
O
8
DBU, air, 60 o
C
H
H
CO2Me
N
N
67%
CO2Me
OTBS
O
OTBS
24
25
b
O
Me
Having forged the pentacyclic scaffold of the natural product, we
entered the final stage of the total synthesis, as shown in Fig. 6.
According to our retrosynthetic analysis, a suitable precursor for
the 7-exo-trig cyclization needed to be prepared. Thus, ketone 25
was converted into enone 30, in 81% overall yield, through a
sequence of silyl enol ether formation and Saegusa–Ito oxidation50.
Desilylation followed by iodination furnished compound 11, which
set the stage for the intramolecular 1,4-addition. The radical
cyclization reaction was initiated by 2,2′-azobisisobutyronitrile
(AIBN) at 75 8C; tris(trimethylsilyl)silane ((TMS)3SiH) was found
to be superior to tributyltin hydride as a hydride source. It was
crucial to add CH2Cl2 as cosolvent to obtain an excellent
and consistent yield, presumably because of the poor solubility of
11 in toluene. Under the above conditions, the primary radical
attacked the enone moiety to afford compound 31 (98%) as a
single diastereomer. The excellent facial selectivity is
attributable to the strong stereochemical bias of the substrate.
With the hexacyclic core of daphenylline in hand, a series of
reductions was performed. Hydrogenation of the exocyclic C¼C
bond with Crabtree’s catalyst provided the desired C18 diastereomer
predominantly (.30:1 d.r.), but reduction with Pd/C led to the
opposite stereochemical output. This product was subjected to
O
Me
O
hυ, 0 o
C
H
H
CO2Me
N
CO2Me
N
O
OTBS
OTBS
23
24
1O2
O
H
O
O
O
Me
O
Me
O
O
Norrish type I
fragmentation
H
H
H
N
N
CO2Me
CO2Me
O
OTBS
OTBS
28
29
O–O bond cleavage/
recombination
71%
Me
O
O
O
.
Krapcho demethoxycarbonylation conditions (LiCl H2O, dimethyl
H
H
N
sulfoxide, 160 8C) employed by Dixon and co-workers in their
synthesis of the tricyclic core of calyciphylline A-type
alkaloids (Fig. 2)26, in this case to give compound 10 as a single
detectable diastereomer. The structure of 10 was unambiguously
verified by X-ray crystallographic analysis (Fig. 6, Tm 165–167 8C,
EtOAc/n-hexane 1:1), which ensured the connectivity of
the hexacyclic scaffold and stereochemical output of the radical
cyclization, hydrogenation and decarboxylation reactions.
Finally, deoxygenation promoted by Pd/C under a H2 atmosphere,
followed by LiAlH4 reduction of the lactam moiety, rendered
synthetic daphenylline (8) in 66% yield over two steps. The
daphenylline purified with silica gel displayed identical spectral
and physical properties to those of an authentic sample provided
by Hao and co-workers34.
CO2Me
O
OR
26 R = TBS
27 R = H
HF·py, 0 o
C
ORTEP of ( )-27
92%
Figure 5 | Assembly of the pentacyclic intermediate 25. a, Trans-triene 23
underwent a photoinduced C¼C bond isomerization/6p-electrocyclization
cascade reaction to afford the compact pentacyclic product 24, which
further aromatized to 25 under oxidative conditions. b, An unexpected
photoinduced cascade reaction occurred when 23 was photoirradiated in the
presence of air. A postulated mechanism involved a Norrish type I
fragmentation followed by O–O bond homolysis and radical recombination.
.
HFpy, hydrogen fluoride pyridine.
4
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
© 2013 Macmillan Publishers Limited. All rights reserved.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1694
ARTICLES
i. TMSOTf, Et3N,
7. Kobayashi, J. & Kubota, T. The Daphniphyllum alkaloids. Nat. Prod. Rep.
26, 936–962 (2009).
8. Piettre, S. & Heathcock, C. H. Biomimetic total synthesis of proto-
daphniphylline. Science 248, 1532–1534 (1990).
9. Heathcock, C. H. The enchanting alkaloids of yuzuriha. Angew. Chem. Int. Ed.
31, 665–681 (1992).
10. Kobayashi, J., Inaba, Y., Shiro, M., Yoshida, N. & Morita, H. Daphnicyclidins
A–H, novel hexa- or pentacyclic alkaloids from two species of Daphniphyllum.
J. Am. Chem. Soc. 123, 11402–11408 (2001).
11. Mu, S-Z. et al. Secophnane-type alkaloids from Daphniphyllum oldhami.
Chem. Biodivers. 4, 129–138 (2007).
12. Morita, H. et al. Daphmanidins C and D, novel pentacyclic alkaloids from
Daphniphyllum teijsmanii. Org. Lett. 7, 459–462 (2005).
13. Matsuno, Y. et al. Pordamacrines A and B, alkaloids from Daphniphyllum
macropodum. J. Nat. Prod. 70, 1516–1518 (2007).
14. Ruggeri, R. B., Hansen, M. M. & Heathcock, C. H. Total synthesis of (+)-methyl
homosecodaphniphyllate: a remarkable new tetracyclization reaction. J. Am.
Chem. Soc. 110, 8734–8736 (1988).
Me
Me
−78 o
C
O
O
ii. Pd(OAc)2
CO2Me
OTBS
CO2Me
OTBS
N
N
81% (two steps)
O
O
25
30
i. HF·py, 0 o
ii. I2, PPh3,
imidazole
C
93%
(two steps)
O
(TMS)3SiH, AIBN,
75 oC
H
Me
O
Me
O
O
CO2Me
I
98%
N
N
CO2Me
15. Heathcock, C. H., Davidsen, S. K., Mills, S. & Sanner, M. A. Total synthesis of
(þ)-methyl homodaphniphyllate. J. Am. Chem. Soc. 108, 5650–5651 (1986).
16. Ruggeri, R. B. & Heathcock, C. H. Biomimetic total synthesis of (+)-methyl
homodaphniphyllate. J. Org. Chem. 55, 3714–3715 (1990).
17. Heathcock, C. H., Ruggeri, R. B. & McClure, K. F. Daphniphyllum alkaloids.
15. Total syntheses of (+)-methyl homodaphniphyllate and (+)-daphnilactone
A. J. Org. Chem. 57, 2585–2594 (1992).
11
31
i. H2, Crabtree's
catalyst
ORTEP of 10
86% (two steps)
ii. LiCl·H2O, 160 o
C
18. Heathcock, C. H., Stafford, J. A. & Clark, D. L. Daphniphyllum alkaloids. 14.
Total synthesis of (+)-bukittinggine. J. Org. Chem. 57, 2575–2585 (1992).
19. Stafford, J. A. & Heathcock, C. H. Asymmetric total synthesis of
(–)-secodaphniphylline. J. Org. Chem. 55, 5433–5434 (1990).
20. Heathcock, C. H., Kath, J. C. & Ruggeri, R. B. Daphniphyllum alkaloids. 16. Total
synthesis of (þ)-codaphniphylline. J. Org. Chem. 60, 1120–1130 (1995).
21. Weiss, M. E. & Carreira, E. M. Total synthesis of (þ)-daphmanidin E. Angew.
Chem. Int. Ed. 50, 11501–11505 (2011).
H
Me
O
H
Me
i. Pd/C, MeOH
ii. LiAlH4, 40 o
C
Me
Me
H
H
N
N
66% (2 steps)
O
8 Daphenylline
10
22. Ikeda, S., Shibuya, M., Kanoh, N. & Iwabuchi, Y. Synthetic studies on
daphnicyclidin A: enantiocontrolled construction of the BCD ring system.
Org. Lett. 11, 1833–1836 (2009).
23. Dunn, T. B., Ellis, J. M., Kofink, C. C., Manning, J. R. & Overman, L. E.
Asymmetric construction of rings A–D of daphnicyclidin-type alkaloids.
Org. Lett. 11, 5658–5661 (2009).
Figure 6 | Completion of the total synthesis of daphenylline. The last ring
of the natural product was forged by a 7-exo-trig radical cyclization. Facial
selective hydrogenation followed by Krapcho demethoxycarbonylation gave
an advanced intermediate 10, which converted readily into daphenylline
through two reductions. TMSOTf, trimethylsilyl trifluoromethanesulfonate.
´
´
24. Belanger, G., Boudreault, J. & Levesque, F. Synthesis of the tetracyclic core
of daphnilactone B-type and yuzurimine-type alkaloids. Org. Lett. 13,
6204–6207 (2011).
Conclusion
We accomplished the total synthesis of the Daphniphyllum alkaloid
daphenylline. The synthesis features a gold-catalysed 6-exo-dig
cyclization reaction for the construction of a bridged bicyclic
motif, and a photoinduced olefin isomerization/6p-electrocycliza-
tion/aromatization sequence to forge the sterically compact arene.
The chemistry developed may find use in the synthesis of other
polycyclic natural products and pharmaceutically interesting mol-
ecules. The above endeavour represents the first example of a chemi-
cal synthesis of a member of the Daphniphyllum alkaloid
subfamilies that share a bridged 6,n,5-tricyclic motif. Taking advan-
tage of the versatility of the tricyclic intermediate 9, studies towards
the total synthesis of related Daphniphyllum alkaloids are currently
underway, which, together with this work, should accelerate further
biological and biosynthetic investigations of these fascinating
natural products.
25. Coldham, I., Watson, L., Adams, H. & Martin, N. G. Synthesis of the core
ring system of the yuzurimine-type Daphniphyllum alkaloids by cascade
condensation, cyclization, cycloaddition chemistry. J. Org. Chem. 76,
2360–2366 (2011).
26. Sladojevich, F., Michaelides, I. N., Darses, B., Ward, J. W. & Dixon, D. J.
Expedient route to the functionalized calyciphylline A-type skeleton via a
Michael addition–RCM strategy. Org. Lett. 13, 5132–5135 (2011).
27. Kourra, C., Klotter, F., Sladojevich, F. & Dixon, D. J. Alkali base-initiated
Michael addition/alkyne carbocyclization cascades. Org. Lett. 14,
1016–1019 (2012).
28. Darses, B. et al. Expedient construction of the [7–5–5] all-carbon tricyclic core
of the Daphniphyllum alkaloids daphnilongeranin B and daphniyunnine D.
Org. Lett. 14, 1684–1687 (2012).
29. Xu, C., Wang, L., Hao, X. & Wang, D. Z. Tackling reactivity and selectivity
within a strained architecture: construction of the [6262527] tetracyclic
core of calyciphylline alkaloids. J. Org. Chem. 77, 6307–6313 (2012).
30. Li, H. et al. Rapid construction of the [6262625] tetracyclic skeleton of the
Daphniphyllum alkaloid daphenylline. Chem. Asian J. 7, 2519–2522 (2012).
31. Fang, B. et al. Synthesis of the tetracyclic core (ABCE rings) of daphenylline.
J. Org. Chem. 77, 8367–8373 (2012).
32. Yang, M. et al. Tandem semipinacol-type 1,2-carbon migration/aldol reaction
toward the construction of [5–6–7] all-carbon tricyclic core of calyciphylline
A-type alkaloids. Org. Lett. 14, 5114–5117 (2012).
33. Yao, Y. & Liang, G. Rapid construction of the ABC ring system in the
Daphniphyllum alkaloid daphniyunnine C. Org. Lett. 14, 5499–5501 (2012).
34. Zhang, Q. et al. Daphenylline, a new alkaloid with an unusual skeleton, from
Daphniphyllum longeracemosum. Org. Lett. 11, 2357–2359 (2009).
35. Bian, M. et al. Total syntheses of anominine and tubingensin A. J. Am. Chem.
Soc. 134, 8078–8081 (2012).
Received 31 December 2012; accepted 3 May 2013;
published online 30 June 2013
References
1. Balunas, M. J. & Kinghorn, A. D. Drug discovery from medicinal plants.
Life Sci. 78, 431–441 (2005).
2. Keasling, J. D., Mendoza, A. & Baran, P. S. Synthesis: a constructive debate.
Nature 492, 188–189 (2012).
3. Tarselli, M. A. et al. Synthesis of conolidine, a potent non-opioid analgesic
for tonic and persistent pain. Nature Chem. 3, 449–453 (2011).
4. Wender, P. A. et al. Gateway synthesis of daphnane congeners and their protein
kinase C affinities and cell-growth activities. Nature Chem. 3, 615–619 (2011).
5. Mendoza, A., Ishihara, Y. & Baran, P. S. Scalable enantioselective total
synthesis of taxanes. Nature Chem. 4, 21–25 (2012).
36. Staben, S. T. et al. Gold(I)-catalyzed cyclizations of silyl enol ethers:
application to the synthesis of (þ)-lycopladine A. Angew. Chem. Int. Ed. 45,
5991–5994 (2006).
37. Piers, E. & Oballa, R. M. Concise total syntheses of the sesquiterpenoids
(2)-homalomenol A and (2)-homalomenol B. J. Org. Chem. 61,
8439–8447 (1996).
6. Editorial Committee of the Administration Bureau of Traditional Chinese
Medicine in Chinese Materia Medica (Zhonghua Bencao), Vol. 4, 865–867
(Shanghai Science & Technology Press, 1999).
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
5
© 2013 Macmillan Publishers Limited. All rights reserved.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1694
ARTICLES
38. Huwyler, N. & Carreira, E. M. Total synthesis and stereochemical revision of
the chlorinated sesquiterpene (+)-gomerone C. Angew. Chem. Int. Ed. 51,
13066–13069 (2012).
49. Ikeda, S., Mori, N. & Sato, Y. Regioselective cyclic cotrimerization of
a,b-enones and alkynes by a nickel-aluminum catalyst system. J. Am. Chem. Soc.
119, 4779–4780 (1997).
39. Nicolaou, K. C., Tria, G. S., Edmonds, D. J. & Kar, M. Total syntheses of
(+)-platencin and (2)-platencin. J. Am. Chem. Soc. 131, 15909–15917 (2009).
40. Phipps, R. J., Hamilton, G. L. & Toste, F. D. The progression of chiral
anions from concepts to applications in asymmetric catalysis. Nature Chem.
4, 603–614 (2012).
41. Nicolaou, K. C., Petasis, N. A., Zipkin, R. E. & Uenishi, J. The endiandric
acid cascade. Electrocyclizations in organic synthesis. 1. Stepwise,
stereocontrolled total synthesis of endiandric acids A and B. J. Am. Chem. Soc.
104, 5555–5557 (1982).
42. Jung, M. E. & Duclos, B. A. Synthetic approach to analogues of betulinic acid.
Tetrahedron 62, 9321–9334 (2006).
43. Trost, B. M., Pfrengle, W., Urabe, H. & Dumas, J. Palladium-catalyzed
alkylative cyclization of 1,6- and 1,7-enynes. J. Am. Chem. Soc. 114,
1923–1924 (1992).
50. Ito, Y., Hirao, T. & Saegusa, T. Synthesis of a,b-unsaturated carbonyl
compounds by palladium(II)-catalyzed dehydrosilylation of silyl enol ethers.
J. Org. Chem. 43, 1011–1013 (1978).
Acknowledgements
This paper is dedicated to Dawei Ma for his contributions to China’s natural product
synthesis on the occasion of his 50th birthday. We thank X-J. Hao for providing an
authentic sample of daphenylline, Z-J. Yao for assistance with the cryoprobe NMR facility
and D. J. Edmonds and R. Denton for helpful discussions. Financial support was provided
by the Ministry of Science & Technology (2013CB836900) and the National Natural
Science Foundation of China (21290180, 21172235 and 21222202).
Author contributions
Z.L. and Y.L. contributed equally to this work. A.L., Z.L. and Y.L. conceived the synthetic
route and analysed the results. Z.L., Y.L. and J.D. conducted the experimental work.
A.L. directed the project and wrote the manuscript.
44. Bishop, L. M., Barbarow, J. E., Bergman, R. G. & Trauner, D. Catalysis of
6p electrocyclizations. Angew. Chem. Int. Ed. 47, 8100–8103 (2008).
45. Beaudry, C. M., Malerich, J. P. & Trauner, D. Biosynthetic and biomimetic
electrocyclizations. Chem. Rev. 105, 4757–4778 (2005).
46. Bru¨ckner, S., Baldwin, J. E., Moses, J., Adlington, R. M. & Cowley, A. R.
Mechanistic evidence supporting the biosynthesis of photodeoxytridachione.
Tetrahedron Lett. 44, 7471–7473 (2003).
47. Jacobsen, M. F., Moses, J. E., Adlington, R. M. & Baldwin, J. E. The total
synthesis of spectinabilin and its biomimetic conversion to SNF4435C and
SNF4435D. Org. Lett. 7, 2473–2476 (2005).
Additional information
Supplementary information and chemical compound information are available in the
online version of the paper. Reprints and permissions information is available online at
www.nature.com/reprints. Correspondence and requests for materials should be
addressed to A.L.
48. Miller, A. K. & Trauner, D. Mining the tetraene manifold: total synthesis of
complex pyrones from Placobranchus ocellatus. Angew. Chem. Int. Ed. 44,
4602–4606 (2005).
Competing financial interests
The authors declare no competing financial interests.
6
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
© 2013 Macmillan Publishers Limited. All rights reserved.