Total Synthesis of Longeracinphyllin A

Article abstract of DOI:10.1021/jacs.7b09186

The first and asymmetric total synthesis of longeracinphyllin A, a hexacyclic Daphniphyllum alkaloid, has been accomplished. A tetracyclic intermediate was prepared through silver-catalyzed alkyne cyclization and Luche radical cyclization. A phosphine-promoted [3 + 2] cycloaddition reaction was exploited to construct the sterically congested E ring bearing vicinal tertiary and quaternary centers. The cyclopentenone motif was assembled by using intramolecular Horner-Wadsworth-Emmons olefination. Raney Ni reduction delivered the tertiary amine from a thioamide precursor at a late stage.

Full text of DOI:10.1021/jacs.7b09186

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Communication
Total Synthesis of Longeracinphyllin A
Jian Li, Wenhao Zhang, Fei Zhang, Yu Chen, and Ang Li
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Total Synthesis of Longeracinphyllin A
Jian Li,† Wenhao Zhang,† Fei Zhang, Yu Chen, and Ang Li*
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State Key Laboratory of Bioorganic and Natural Products Chemistry, Collaborative Innovation Center of
Chemistry for Life Sciences, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Ling-
ling Road, Shanghai 200032, China
Supporting Information Placeholder
tial substrates of the [3 + 2] cycloaddition. 13 may arise
from tetracycle 15 in a lower oxidation state. Disconnection
ABSTRACT: The first and asymmetric total synthesis of
longeracinphyllin A, a hexacyclic Daphniphyllum alkaloid,
has been accomplished. A tetracyclic intermediate was preꢀ
pared through silverꢀcatalyzed alkyne cyclization and Luche
radical cyclization. A phosphineꢀpromoted [3 + 2] cycloadꢀ
dition reaction was exploited to construct the sterically conꢀ
gested E ring bearing vicinal tertiary and quaternary cenꢀ
ters. The cyclopentenone motif was assembled by using inꢀ
tramolecular Horner−Wadsworth−Emmons olefination.
Raney Ni reduction delivered the tertiary amine from a thiꢀ
oamide precursor at a late stage.
CO2Me
CO2Me
Me
Me
Me
Me
Me
HN
N
1
2
: methyl homosecodaphniphyllate
: methyl homodaphniphyllate
Heathcock, 1988
Heathcock, 1986 & 1990
Me
O
Me
O
O
O
Me
O
O
Me
Daphniphyllum alkaloids are a large family of polycyclic
natural products (> 300 members) isolated from the everꢀ
green plants of the genus Daphniphyllum.1 They exhibit a
wide range of biological activities, including antitumor, anꢀ
tiviral, and nerve growth factorꢀregulating properties,1b and
attract considerable attention of the synthesis communiꢀ
ty.1a–c The groups of Heathcock, Carreira, Smith, Fukuyama,
and ours have accomplished the syntheses of nine Daphni-
phyllum alkaloids (1–9, Figure 1).2–13 The calyciphylline A
subfamily comprises more than 50 members, most of which
share a characteristic 6ꢀ6ꢀ5ꢀ7ꢀ5ꢀ5ꢀhexacyclic core.1c Despite
the intense efforts toward the synthesis of this subclass,1b,c,14
the only member that has been synthesized so far is
daphenylline (8, Figure 1) possessing a nonꢀrepresentative
areneꢀcontaining skeleton.10,12 Longeracinphyllin A (10,
Figure 1) is a structural representative of the subfamily,
which was isolated by Hao and coꢀworkers from the leaves
of Daphniphyllum longeracemosum.15 Its six consecutive
stereocenters including the vicinal quaternary centers pose
a challenge for chemical synthesis. Herein, we report the
first and asymmetric total synthesis of this alkaloid.
Me
Me
Me
Me
Me
HN
Me
N
3
4
: secodaphniphylline
Heathcock, 1990
: codaphniphylline
Heathcock, 1995
O
O
O
Me
Me
Me
O
Me
N
N
5
6
: daphnilactone A
Heathcock, 1989
: bukittinggine
Heathcock, 1992
CO2Me
CO2Me
H
N
N
Me
Me
HO
HO
We first undertook a retrosynthetic analysis of 10 (Figure
2). A key issue for the synthesis of calyciphylline Aꢀtype
alkaloids was considered to be the construction of the steriꢀ
cally congested E ring bearing quaternary C8. Among 5ꢀ
membered ring forming reactions, the phosphineꢀmediated
[3 + 2] cycloaddition between an allenoate and an electronꢀ
deficient alkene, which was pioneered by Lu and coꢀ
workers,16 may allow an expedient access to the E ring, and
meanwhile provide a flexible carboxylate handle to build the
cyclopentenone motif. Based on this strategy, an initial disꢀ
connection at the C10=C17 bond of 10 was envisioned, leadꢀ
ing to compound 11 as a precursor for intramolecular Hornꢀ
er−Wadsworth−Emmons (HWE) olefination. Further simꢀ
plification of 11 gave pentacyclic ester 12, which could be
disassembled into enedione 1317 and allenoate 14 as potenꢀ
OAc
7
9
: daphmanidin E
Carreira, 2011
: calyciphylline N
Smith, 2014
H
Me
Me
O
H
O
Me
Me
H
N
N
H
H
8
10
: daphenylline
: longeracinphyllin A
(this work)
Li, 2013
Yokoshima & Fukuyama, 2016
Figure 1. Selected Daphniphyllum alkaloids.
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chael addition.10,25 Treatment with DBU at 95 °C afforded
1
the cyclization product, which underwent aldol condensaꢀ
tion with paraformaldehyde in one pot, to provide tricyclic
enone 23 (69% overall yield from 21) as a single detectable
diastereomer. Sequential desilylation and iodination furꢀ
nished compound 16 with good efficiency. In our synthesis
of epoxyeujindole A,26 the Luche conditions (CuI, Zn, pyriꢀ
dine/water, sonication) were superior to conventional radiꢀ
cal ones for an intramolecular conjugate addition. We used
such conditions to effect the ring closure of 16. The resultꢀ
ant tetracycle was subjected to hydrogenation to establish
the C18 stereochemistry. Inspired by our previous experiꢀ
ence with asymmetric hydrogenation of unfunctionalized
olefins,27 we exploited a rhodiumꢀbased catalytic system
{[Rh(cod)Cl]2/PPh3/AgBF4 (1:2:3)} to achieve an excellent
level of facial selectivity. Thus, the key intermediate 15 was
obtained in 98% yield as a single detectable diastereomer.
In this case, the hydrogenation with Crabtree catalyst was of
unsatisfactory reproducibility, and that with Pd/C gave the
undesired configuration of C18. The structures of 15 and its
precursor were verified by Xꢀray crystallographic analysis
(Scheme 1). The preparation of 15 was carried out on
decagram scale.
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Scheme 1. Preparation of a Tetracyclic Interme-
diate on Decagram Scale
Figure 2. Retrosynthetic analysis of longeracinphyllin A.
of the C9−C10 bond of 15 provided iodide 16 as a precursor
for 7ꢀendoꢀtrig radical cyclization. 16 was traced back to
readily available materials 17–19 and formaldehyde. Altꢀ
hough tetracyclic compounds similar to 15 had been syntheꢀ
sized by us18 and Bonjoch et al.,19 respectively, a rapid and
scalable approach to 15 was still desired for the synthesis of
10 as well as other congeners from the calyciphylline A subꢀ
family.
The synthesis commenced with a largeꢀscale preparation
of tetracycle 15 (Scheme 1). Enantioenriched alcohol 17
(99% ee) was obtained through enzymatic resolution of its
racemic form (see SI),20 which then underwent a known
twoꢀstep sequence10 to arrive at alkynyl silyl enol ether 20
as a substrate of Tosteꢀtype cyclization.21 Under modified
Toste
conditions
[Au(PPh3)NTf2
(6
mol%),
MeOH/toluene],18 the 6ꢀexoꢀdig cyclization product 21 was
obtained in 66% yield. Further decrease of the catalyst loadꢀ
ing resulted in unsatisfactory efficiency, and the byproduct
from direct desilylation of 20 interfered the chromatoꢀ
graphic purification of 21. Inspired by the silverꢀcatalyzed
spirocyclization of alkynyl silyl enol ethers reported by
Miesch et al.,22 we developed a scalable and costꢀeffective
protocol to prepare 21. In the presence of AgNTf2 and
CyJohnPhos, 20 underwent cyclization to give 21 in 84%
yield on 100 g scale, along with the 7ꢀendoꢀdig cyclization
product 22 in 5% yield; 2,4,6ꢀtriꢀtertꢀbutylpyrimidine23
(TTBP) and 4 Å molecular sieves were crucial to suppress
acidꢀpromoted desilylation of the substrate. The use of
CyJohnPhos led to excellent regioselectivity of the cyclizaꢀ
tion. The optimization of the reaction conditions was deꢀ
tailed in the SI.
We then constructed the 5ꢀ and 7ꢀmembered rings fused
to the bridged bicyclic system (Scheme 1). Deprotection of
the nosyl group of 21 followed by condensation with carꢀ
boxylic acid 19 afforded a substrate for intramolecular Miꢀ
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Scheme 2. Completion of the Synthesis of Longeracinphyllin A
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With a large quantity of 15 in hand, we completed the synꢀ
Table 2. Studies of Phosphine Promoters for the
[3 + 2] Cycloaddition of 14 and 25 a
thesis of 10 (Scheme 2). αꢀSelenation of this ketone folꢀ
lowed by oxidative elimination afforded α,βꢀunsaturated
enone 24 with good overall efficiency, the γꢀproton of which
was remarkably acidic. Exposure of the enone to DABCO
and air furnished enedione 25 in 91% yield, presumably
through enolate peroxidation and hydroxyl elimination.
Et3N was ineffective because of weaker basicity, and
DBU/air caused skeletal decomposition. Doyle allylic C–H
oxidation28 [Rh2(cap)4, tꢀBuOOH] gave a moderate yield of
25. We examined a variety of phosphine promoters for the
[3 + 2] cycloaddition of 25 and 14 (Table 2). In the presence
of 30 mol% Ph3P (entry 1), the [3 + 2] and [4 + 2]29 cycloadꢀ
ducts 26 and 27 were obtained in 31% and 40% yields, reꢀ
spectively. Their structures were confirmed by Xꢀray crysꢀ
tallographic analysis (Table 2). The reaction profile was
slightly cleaner using (4ꢀFC6H4)3P; however, overall effiꢀ
ciency was similar (entry 2). Bu3P preferentially accelerated
the [4 + 2] reaction, leading to 27 in 67% yield (entry 3).
Inspired by Wallace's work,30 we directed our attention to
diphosphines. BINAP showed low reactivity (entry 4), and
the use of 1,4ꢀbis(diphenylphosphino)butane (DPPB) gave
27
as
the
major
product
(entry
5).
1,1'ꢀ
Bis(diphenylphosphino)ferrocene (DPPF) turned out to be
an optimal promoter for the [3 + 2] pathway, providing 26
in 45% yield on a gram scale (entry 6). Notably, the elecꢀ
tronꢀdeficiency of the olefin was crucial for the cycloaddiꢀ
tion; enone 24 was essentially unreactive under similar
conditions. Treatment of 26 with an excess of
LiCH2PO(OMe)2 afforded βꢀketophosphonate 28.31 The
chemoselectivity of the addition may be attributable to the
rapid formation of a ketone enolate that prevented the nuꢀ
cleophilic attack. Sequential hydrogenation and intramolecꢀ
ular HWE olefination furnished hexacycle 29 in 91% overall
yield. The order of these two reactions was important: the
HWE reaction of 28 was inefficient, and the C=C bond of
the E ring was found to migrate to the nonꢀconjugated posiꢀ
tion, presumably due to the strain of the unsaturated
[3.3.0]ꢀbicyclic system. The preparation of 29 was perꢀ
formed on a gram scale. For the following Krapcho demethꢀ
oxycarbonylation, commonly used DMSO10,18 was not a
suitable solvent. MeCN turned out to be optimal in this case,
entry
promoters
Ph3P
26 (%)
31
27 (%)
40
1
2
3
4
5
6
(4ꢀFC6H4)3P
Bu3P
35
38
5
67
(±)ꢀBINAP
DPPB
15
23
21
57
DPPF
45
22
a 30 mol% phosphine or diphosphine, 14 (1.2 equiv), CHCl3,
22 °C, 24 h.
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(6) Heathcock, C. H.; Stafford, J. A.; Clark, D. L. J. Org. Chem.
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biogenetic ancestor of Daphniphyllum alkaloids, see: Piettre, S.;
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(13) For an elegant synthesis of isodaphlongamine H, a presumed
Daphniphyllum alkaloid yet to be isolated from nature, see: Chatꢀ
topadhyay, A. K.; Ly, V. L.; Jakkepally, S.; Berger, G.; Hanessian, S.
Angew. Chem., Int. Ed. 2016, 55, 2577.
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Aꢀtype alkaloids published after ref. 1b, see: Shao, H.; Bao, W.;
Jing, Z.ꢀR.; Wang, Y.ꢀP.; Zhang, F.ꢀM.; Wang, S.ꢀH.; Tu, Y.ꢀQ. Org.
Lett. 2017, 19, 4648.
(15) Di, Y.ꢀT.; He, H.ꢀP.; Lu, Y.; Yi, P.; Li, L.; Wu, L.; Hao, X.ꢀJ. J.
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Lu, X. Tetrahedron Lett. 1999, 40, 549. (c) Lu, X.; Zhang, C.; Xu, Z.
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(17) In a paper describing a concise synthesis of a tricyclic motif of
calyciphylline Aꢀtype alkaloids, Stockdill et al. proposed an interꢀ
mediate similar to 13 in the retrosynthetic analysis section. See:
Stockdill, J. L.; Lopez, A. M.; Ibrahim, A. A. Tetrahedron Lett.
2015, 56, 3503.
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and compound 30 was obtained in 95% yield. Both enone
1
2
3
4
5
6
7
8
and lactam carbonyls of 30 were thiolated with Lawesson
reagent, and more labile thioenone was oxygenated with air,
leading to thioamide 31 with good efficiency. Reduction
with Raney Ni rendered longeracinphyllin A (10). The specꢀ
tra and physical properties of the synthetic sample were
identical to those reported for the natural product.15 The
structures of 10, 29, 30, and 31 were verified by Xꢀray crysꢀ
tallographic analysis (Scheme 2).
We subsequently exploited the efficiency and flexibility of
the current route in the synthetic approaches to structurally
relevant Daphniphyllum alkaloids daphnipaxianine A32 and
himalenine D,33 as described in the SI. Two analogues corꢀ
responding to these two alkaloids, respectively, were preꢀ
pared from the advanced intermediate 30. Further studies
are underway in our laboratories.
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In summary, we have accomplished the first total syntheꢀ
sis of longeracinphyllin A (10). The decagram preparation
of tetracycle 15, featuring silverꢀcatalyzed alkyne cyclization
and Luche radical cyclization, formed a basis of the syntheꢀ
sis. The sterically congested E ring containing vicinal terꢀ
tiary and quaternary carbons was constructed through a Lu
[3 + 2] cycloaddition reaction promoted by DPPF. The late
intermediate 29 was prepared on a gram scale. These enꢀ
deavors may facilitate the biological studies of this alkaloid
and analogues thereof.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on
the ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
*ali@sioc.ac.cn
(22) Schäfer, C.; Miesch, M.; Miesch, L. Chem. Eur. J. 2012, 18,
8028.
Author Contributions
†J.L. and W.Z. contributed equally.
(23) Li, Y.; Zhu, S., Li, J.; Li, A. J. Am. Chem. Soc. 2016, 138, 3982.
(24) For silver and amine coꢀcatalyzed enantioselective desymmeꢀ
trizing alkyne cyclization reported recently, see: Manzano, R.; Datta,
S.; Paton, R. S.; Dixon, D. J. Angew. Chem., Int. Ed. 2017, 56, 5834.
(25) Sladojevich, F.; Michaelides, I. N.; Darses, B.; Ward, J. W.;
Dixon, D. J. Org. Lett. 2011, 13, 5132.
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13764.
(27) Zhang, Z.; Wang, J.; Li, J.; Yang, F.; Liu, G.; Tang, W.; He, W.;
Fu, J. J.; Shen, Y. H.; Li, A.; Zhang, W. D. J. Am. Chem. Soc. 2017,
139, 5558.
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2004, 126, 13622.
(29) Yao, W.; Dou, X.; Lu, Y. J. Am. Chem. Soc. 2015, 137, 54.
(30) Wallace, D. J.; Sidda, R. L.; Reamer, R. A. J. Org. Chem. 2007,
72, 1051.
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883.
(32) Mu, S.ꢀZ.; Li, C.ꢀS.; He, H.ꢀP.; Di, Y.ꢀT.; Wang, Y.; Wang, Y.ꢀH.;
Zhang, Z.; Lü, Y.; Zhang, L.; Hao, X.ꢀJ. J. Nat. Prod. 2007, 70,
1628.
ACKNOWLEDGMENT
We thank Dr. David Edmonds for discussion, and Xiaoli Bao
and Lingling Li from the Instrumental Analysis Center of
Shanghai Jiao Tong University for Xꢀray crystallographic
analysis. Financial support was provided by Ministry of Sciꢀ
ence & Technology (2013CB836900), National Natural Sciꢀ
ence Foundation of China (21525209, 21290180, and
21621002), Chinese Academy of Sciences (Strategic Priority
Research Program XDB20000000 and Key Research Proꢀ
gram of Frontier Sciences QYZDBꢀSSWꢀSLH040), Shanghai
Science and Technology Commission (15JC1400400 and
17XD1404600), and K. C. Wong Education Foundation.
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