The Enantioselective Synthesis of Eburnamonine, Eucophylline, and 16′-epi-Leucophyllidine

Article abstract of DOI:10.1002/anie.202106184

A synthetic approach to the heterodimeric bisindole alkaloid leucophyllidine is disclosed herein. An enantioenriched lactam building block, synthesized through palladium-catalyzed asymmetric allylic alkylation, served as the precursor to both hemispheres. The eburnamonine-derived fragment was synthesized through a Bischler–Napieralski/hydrogenation approach, while the eucophylline-derived fragment was synthesized by Friedl?nder quinoline synthesis and two sequential C?H functionalization steps. A convergent Stille coupling and phenol-directed hydrogenation united the two monomeric fragments to afford 16′-epi-leucophyllidine in 21 steps from commercial material.

Full text of DOI:10.1002/anie.202106184

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: The Enantioselective Synthesis of Eburnamonine, Eucophylline,
and 16’-epi-Leucophyllidine
Authors: Christopher Reimann, Fa Ngamnithiporn, Kohei Hayashida,
Daisuke Saito, Katerina Korch, and Brian Stoltz
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202106184
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10.1002/anie.202106184
Angewandte Chemie International Edition
COMMUNICATION
The Enantioselective Synthesis of Eburnamonine, Eucophylline,
and 16’-epi-Leucophyllidine
Christopher E. Reimann†,[a] Aurapat Ngamnithiporn†,[a],[c] Kohei Hayashida, [a],[b] Daisuke Saito, [a],[b]
Katerina M. Korch,[a] Brian M. Stoltz*[a]
[a]
Dr. C.E. Reimann, Dr. A. Ngamnithiporn, Dr. K. Hayashida, Dr D. Saito, Katerina M. Korch, Prof. Dr. B. M. Stoltz
Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering
1200 E. California Blvd. MC 101-20, Pasadena, CA 91125 (USA)
*Email: stoltz@caltech.edu
†These authors contributed equally
[b]
[c]
Dr. K. Hayashida, Dr D. Saito
Discovery Research Laboratories, Nippon Chemiphar Co., Ltd. 1-22 Hikokawado, Misato, Saitama 341-005, Japan
Dr. A. Ngamnithiporn
Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54 Kamphaeng Phet 6 Road, Bangkok, 10210, Thailand
Supporting information for this article is given via a link at the end of the document.
Abstract: A synthetic approach to the heterodimeric bisindole alkaloid
leucophyllidine is disclosed herein. An enantioenriched lactam
building block, synthesized through Pd-catalyzed asymmetric allylic
alkylation, serves as the precursor to both hemispheres. The
eburnamonine-derived fragment is synthesized through a Bischler–
Napieralski/hydrogenation approach while the eucophylline-derived
fragment is synthesized by a Friedländer quinoline synthesis and two
sequential C-H functionalization steps. A convergent Stille coupling
and phenol-directed hydrogenation unite the two monomeric
fragments affording 16’-epi leucophyllidine in 21 steps from
commercial material.
examples to date rely on biomimetic reactions to accomplish
these convergent couplings, but as these reactions are substrate-
controlled, the inherent reactivity can be difficult to overturn4 and
prohibitive to analog synthesis.5
Leucophyllidine (1) is a heterodimeric bisindole alkaloid that
was first isolated from the bark of the Malaysian woody climber
Leuconotis griffithi in 2009.6 It is composed of two polycyclic
fragments: a southern tetracyclic vinylquinoline fragment derived
from eucophylline (5) and
containing fragment derived
a
northern pentacyclic indole-
from eburnamine (6).
Biosynthetically, an enzyme-mediated electrophilic aromatic
substitution of an eburnamine-derived iminium ion is proposed to
unite the two hemispheres (Scheme 1b, left). Structurally, the
molecule contains nine rings, four stereogenic carbons (including
two all-carbon quaternary centers) and a sterically hindered
C(sp)3–C(sp)2 bond that joins the two natural products.
Biologically, leucophyllidine (1) is cytotoxic toward drug-
sensitive and drug-resistant human KB cells and a dose-
dependent inhibitor of nitrous oxide (NO) synthase. 7 Dimeric
alkaloids generally exhibit stronger biological activities than their
component monomers,8 and though the mechanisms of action
are poorly understood, they are hypothesized to promote higher
target affinity or greater stabilization of protein-protein
interactions.9 Despite successful synthesis of both eucophylline
(5) 10,11 and eburnamine (6) 12,13 no successful synthesis of
Heterodimeric bisindole alkaloids comprise a diverse class of over
200 natural products, which arise from the union of two
monoterpenoid indole alkaloids with at least one C–C bond
(Scheme 1a).1 While monomeric indole alkaloids are frequently
pursued synthetic targets, reports toward their dimeric
counterparts are far less prevalent due to a number of additional
synthetic challenges.2 Each monomer is often a natural product
or close derivative thereof, meaning one must essentially
complete two total syntheses en route to one higher-order
structure. Furthermore, the successful execution of convergent
disconnection strategies demand reactions that forge sterically
congested C–C bonds between densely functionalized
frameworks with complete regio- and stereocontrol.3 A majority of
a. Representative heterodimeric bisindole alkaloids
O
OH
OH
Me
N
N
N
Me
MeO
H
O
N
O
N
Me
N
O
Me
N
HO
N
H
MeO
N
H
H
COOMe
H
MeOOC
NH
HN
N
H
Me
Me
MeO
N
Me
N
N
OH
MeO
O
N
Me
OAc
COOMe
MeOOC
OMe
O
HO
Me
Me
OH
Conophylline (4)
Leucophyllidine (1)
Vinblastine (2)
Haplophytine (3)
b. Biosynthetic hypothesis and unsuccessful biomimetic coupling attempt by Pandey (2017)
N
Me
H
H
H
N
N
Enzyme-
mediated
Me
N
N
N
N
N
2% HCl (aq)
reflux, 7 d
9% yield
+
Friedel–Crafts
Alkylation
HO
H
H
H
N
N
OH
Me
Me
Me
N
N
OH
OH
iso-leucophyllidine, 7
Leucophyllidine (1)
Eucophylline (5)
Eburnamine (6)
Scheme 1. Heterodimeric bisindole alkaloids and efforts toward leucophyllidine
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10.1002/anie.202106184
Angewandte Chemie International Edition
COMMUNICATION
leucophyllidine (1) has been completed to date. A report from
Pandey and coworkers details an assumed “biomimetic” Friedel–
Crafts alkylation that generated isoleucophyllidine 7 as the
exclusive product (Scheme 1b, right).
completing the synthesis of eburnamonine (8) in five steps from
lactam 10 and ten steps from commercially available material. To
our knowledge, this is the shortest asymmetric synthesis of
eburnamonine to date and the first to employ asymmetric
catalysis. 21 Eburnamonine (8) is finally advanced to enamine
triflate 23, thus completing the first coupling partner.
H
N
N
O
O
O
O
LDA, THF
n-BuLi
–78 → –30 °C
THF, –78 °C
O
NH
NBz
O
NBz
then 13
–78 → 23 °C
then BzCl
78 → 23 °C
Me
Eburnamonine (8)
(11), δ-
valerolactam
94% yield
10g scale
12
70% yield
15g scale
14
H
Me
O
N
Me
N
O
O
NH
Me
O
Convergence and Divergence
Pd(OAc)2 (1 mol %)
16 (5 mol %)
Cs2CO3, EtI
H
O
NBz
NBz
Me
CH2Cl2, 23 °C
MTBE, 60 °C
N
N
OH
10
Me
Leucophyllidine (1)
Me
89% yield
15g scale
15
91% yield, 92% ee
14g scale
17
Br
Me
O
Me
O
NaH, DMF
0 → 23 °C
N
N
OMe
LiOH•H2O
O
NH
N
9
MeOH/H2O
(10:1), 23 °C
then 18
O
Scheme 2. Retrosynthetic analysis of leucophyllidine. Red circle = α-amino
stereogenic center. Blue circle = all-carbon quaternary stereogenic center.
98% yield
11g scale
10
92% yield
19
Me
O
RuCl3•xH2O
(3 mol %), NaIO4
PhNHNH2•HCl
TsOH•H2O
O
HOOC
N
MeOH, reflux
53% yield
MeCN/H2O
(3:1), 0 °C
O
Given the structural challenges and promising bioactivity of
leucophyllidine (1), we began synthetic studies toward this
important target.14 Our retrosynthetic analysis was guided by a
“convergent-divergent” strategy, where a convergent late-stage
cross-coupling and hydrogenation would forge the α-amine
stereocenter—a motif found in multiple natural products within
this class—from oxidized congener eburnamonine (8) and
eucophylline derivative 9 (Scheme 2). Both fragments would then
be accessed in divergent fashion15 from enantioenriched lactam
10, bearing an all-carbon quaternary stereocenter accessible
through our laboratory’s Pd-catalyzed asymmetric allylic
alkylation technology.16 We believe that a route to leucophyllidine
(1) leveraging catalyst-control to synthesize these strategic C–C
bonds would ultimately provide a foundation for a general strategy
toward natural and unnatural dimeric alkaloids.
75% yield
20
H
N
ClO4
POCl3
Me
MeOOC
O
N
MeCN, reflux
N
H
N
then 1M LiClO4
Me
COOMe
21
95% yield
22
LHMDS
THF, –78*C
H
H
N
H2, Pd/C
DMF, 23 °C
N
N
N
then DBU
then HMPA, PhNTf2
78 → 23 °C
O
TfO
Me
Eburnamonine
Me
78% yield
3.4:1 d.r.
(8)
71% yield
23
O
CF3
O
CN
Shortest asymmetric synthesis of
eburnamonine (10 steps) and first
to use asymmetric catalysis
O
N
13
O
Our synthesis of eburnamonine commences with a revised
approach to our previously-disclosed lactam 10 (Scheme 3).16
Benzoyl protection of δ-valerolactam (11 à 12) is followed by C-
acylation to yield β-amidoester 14 and alkylation to generate
(p-CF3C6H4)P
Br
t-Bu
(R)-CF3-t-BuPHOX, 16
O
18
Scheme 3. Enantioselective total synthesis of eburnamonine.
racemic
quaternary
lactam
15.
An
enantioselective
decarboxylative allylic alkylation using low loadings17 of a Pd-(II)
precatalyst and (R)-CF3-t-BuPHOX ligand 16 forges the all-
carbon quaternary center of lactam 17 in 91% yield and 92% ee.
Finally, Bz-cleavage affords divergent intermediate 10,
completing the five-step sequence on decagram scale and
providing enough material to synthesize both monomers.
While direct N-alkylation of lactam 10 with β-indolyl
electrophiles proved challenging due to their instability under
basic conditions, we successfully employ alkyl bromide18 18 to
synthesize acetal 19. Oxidative cleavage of the allyl group
furnishes carboxylic acid 20, which undergoes Fischer indole
synthesis with concomitant esterification to afford indole 21.
Though Bischler–Napieralski cyclization to iminium perchlorate
22 proceeds smoothly, we were disappointed to observe the
diastereoselective hydrogenation conditions described by
Schlessinger10f fail to deliver any reduced products.19 After further
Our approach to eucophylline (5) begins with amide
reduction and Boc-protection of the divergent intermediate
(Scheme 4, 10 à 24). Anti-Markovnikov Wacker oxidation22 then
generates aldehyde 25 with no detectable amount of the ketone
isomer. Using modified Friedländer conditions,23 aldehyde 25
24
and amino alcohol
26 are advanced to quinoline 27,
incorporating a bromide to facilitate the late-stage convergent
coupling. Finally, Re-catalyzed oxidation25 affords N-oxide 28 on
gram-scale.
Our strategy toward eucophylline (5) hinges on a sequence
involving two C–H functionalization events to complete the core:
intramolecular quinoline amination at C2, followed by alkylation at
C4. Optimization of both transformations led to the discovery of
unexpected reactivity. N-oxide 28 is first subjected to Sn(OTf)2 to
cleave the Boc-protecting group. 26 Following the addition of
triethylamine at elevated temperatures, we were surprised to find
the desired C–N bond of tetracycle 29 had formed in 79% yield.
optimization, we discovered that heterogeneous hydrogenation in
20
DMF
with subsequent addition of DBU promotes
diastereoselective hydrogenation and lactamization in one pot,
2
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10.1002/anie.202106184
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COMMUNICATION
Though N-oxide activation typically requires a more strongly
electrophilic activating group (e.g. PyBrOP27 ), we believe the
Sn(II) cation promotes the intramolecular cyclization.28
could be obtained using Pd(PPh3)4 and copper (I) thiophene-2-
carboxylate (CuTC) to afford dimer 35 as
a mixture of
atropisomers in 54% yield after only 10 minutes.34 Initially, we
hypothesized that the trisubstituted Δ16’,17’-olefin would be more
electron-rich than the monosubstituted Δ5,6-vinyl group, enabling
chemoselective reduction with mild hydride sources under acidic
conditions. Unfortunately, a complex mixture of products was
observed, likely due to 1,6-reduction of the vinylquinoline motif.
Me
O
Me
1. LiAlH4,
Et2O, reflux
Pd(PhCN)2Cl2 (15 mol %)
CuCl2•2H2O (15 mol %)
NH
NBoc
AgNO2 (7.5 mol %)
t-BuOH/MeNO2 (15:1)
O2 , 23°C
2. Boc2O, DMAP
MeCN, 0 → 23 °C
69% yield, 2 steps
74% yield
10
Me
24
Me
26 (1.3 equiv)
1,4-dioxane, 80 °C
Br
a. Stille coupling and hydrogenation of vinylquinoline substrate
NBoc
NBoc
then KOt-Bu
Ph2CO, 80 °C
Me
O
MeO
N
Pd(PPh3)4 (10 mol %)
CuTC (1.1 equiv)
H
N
X
72% yield
Br
N
25
27
+
NMP, 25 °C, 10 min
Me
TfO
OMe
N
N
Sn(OTf)2
CH2Cl2, 23 °C
MeReO3
(20 mol %)
Me
NBoc
9, R = Br
23
54% yield
Pd(PPh3)4 (10 mol %)
Sn2Me6 PhMe, 90 °C
then Et3N
23 → 40 °C
H2O2 (aq.)
CH2Cl2, 23 °C
MeO
N
O
34, R = SnMe3
70% yield
80% yield
28
79% yield
HO
H
H
5
Me
Me
N
N
NaBH4
AcOH
6
Me
Me
N
N
Bz2O2, TFA
Br
Br
16’
MeCN
23 → 50 °C
Blue LED
MeOH, 23 °C
17’
MeO
N
N
Me
Me
N
N
OMe
OMe
OMe
N
N
N
N
29
77% yield
30
35
putitive
O
Me
Me
Reduction in presence of reactive vinylquinoline warhead deemed challenging
DMP, NaHCO3
32, NaHMDS
Br
Br
b. Stille coupling and hydrogenation of formylquinoline substrate
CH2Cl2
0 → 23 °C
THF, –78 °C
O
Me
N
N
OMe
N
N
OMe
Pd(PPh3)4 (10 mol %)
CuTC (1.1 equiv)
H
N
X
N
+
31
89% yield
85% yield
9
NMP, 25 °C, 10 min
Me
Me
TfO
n-BuLi,
THF, –78 °C
OMe
N
N
Me
Ref. 10
31, R = Br
23
69% yield
then
NH4Cl, 0 °C
Pd(PPh3)4 (10 mol %)
Sn2Me6 PhMe, 90 °C
N
N
OMe
N
N
OH
36, R = SnMe3
75% yield
41% yield
(5)
Eucophylline
33
H
N
H
N
O
HO
Me
Me
N
N
N
t-Bu
Br
Conditions
N
N
OH
NH2
Shortest asymmetric synthesis of
eucophylline (16 steps) and first
to use asymmetric catalysis
N
MeO
MeO2S
Me
Me
OMe
OMe
N
N
N
N
26
32
37
Homo- and heterogeneous hydrogenation, HAT, PCET,
and hydrofunctionalization all failed to reduce C=C bond
Scheme 4. Enantioselective formal synthesis of eucophylline.
Scheme 5. Stille coupling and attempted reductions.
Tetracycle 29 is subsequently exposed to photoredox-
29
mediated Minisci conditions
to generate hydroxymethyl
quinoline 30. After performing control experiments, we were
delighted to observe an Ir-photocatalyst was not required for this
transformation, and the bromoquinoline motif is believed to act as
its own photocatalyst. Similar reactivity has been observed in
related electron-deficient heteroarenes 29,30 and aryl bromides31
have been shown to exhibit prolonged excited state lifetimes.
Further studies are underway to elucidate the reaction
mechanism of this transformation.
To complete the synthesis, alcohol 30 is oxidized to
aldehyde 31, then a Julia–Kocienski olefination with tetrazole 32
generates vinylquinoline 9 in 87% yield.32 Proto-debromination
with n-BuLi then affords O-methyl eucophylline 33, which could
be advanced to eucophylline (5) under conditions described by
Landais,10 thus completing the formal synthesis in 11 steps from
divergent intermediate 10.
We then elected to use the formylquinoline substrate 31 as
any over-reduction would still produce synthetically tractable
material (Scheme 5b). Gratifyingly, we discovered that both
stannane 36 and dimer 37 were obtained in higher yields than the
respective vinyl intermediates. Despite employing a number of
different reaction manifolds to saturate this Δ16’,17’-olefin, we
were unable to obtain any desired olefin-reduced products.
Given the steric encumbrance of this alkene, we
hypothesized that the phenolic oxygen of the natural product
might be employed as a directing group to facilitate this otherwise
intractable hydrogenation.35 To this end, dimeric aldehyde 37 is
first protected as the acetal and demethylated to furnish phenol
38 (Scheme 6). We were delighted to observe that hydrogenation
with [Rh(COD)(dppb)]BF4 afforded smooth and quantitative
reduction of the trisubstituted alkene as a single diastereomer
39. 36 Acetal cleavage then unmasks the aldehyde, which is
homologated with a Peterson olefination. 37 At this point, we
obtained X-ray quality crystals of 40 and we were dismayed to
find that the reduction had occurred with the undesired
stereochemistry to provide 16’-epi-leucophyllidine.
To avoid regioselectivity concerns associated with
biomimetic couplings, we elected to forge the central C–C bond
through a Stille coupling.33 Vinylquinoline 9 is first advanced to the
trimethylstannane 34 in good yield (Scheme 5a). After brief
optimization, we found that efficient cross-coupling with triflate 23
3
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10.1002/anie.202106184
Angewandte Chemie International Edition
COMMUNICATION
allylic alkylation, is advanced to eburnamonine and eucophylline
in ten and sixteen steps respectively, marking the shortest
asymmetric synthesis of either natural product to date. A highly
efficient Stille coupling unites the two polycyclic hemispheres and
a directed hydrogenation is used to advance to the epimeric
natural product. We believe that further investigations of C(sp)3-
C(sp)2 coupling strategies could ultimately provide access to this
natural product and other related heterodimeric bisindole
alkaloids.
1. HOCH2CH2OH
BF3 • OEt2
CH2Cl2, 0 °C
H
H
O
N
N
O
O
Me
Me
N
N
2. NaH, EtSH
DMF, 140 °C
Me
Me
OMe
OH
N
N
N
N
60% yield,
2 steps
37
38
H
O
N
O
[Rh(COD)(dppb)]BF4
(10 mol %)
1. HCl (aq)
THF/H2O (1:1), 70 °C
Me
N
16’
H2 (20 bar), LiOt-Bu
MeOH, 23 °C
2. TMSCH2MgCl
THF, 23 °C
3. KH, THF, 23 °C
Me
OH
N
N
99% yield
> 20:1 d.r. at C16'
39% yield, 3 steps
39
Acknowledgements
H
N
Me
N
H
We thank the NIH-NIGMS (R01GM080269) for financial support.
Portions of this research were also funded by the NSF under the
CCI Center for Selective C-H functionalization (CCHF) CHE-
1700982. A.N. thanks the Royal Thai Government Scholarship
Program. D.S. and K.H. thank Nippon Chemiphar for funding. We
thank Dr. David VanderVelde (Caltech) for NMR expertise, Dr.
Scott Virgil (Caltech) for instrumentation and analytical support,
Dr. Michael Takase and Larry Henling (Caltech) for assistance
with X-ray analysis, and Dr. Mona Shahgholi and Naseem Torian
(Caltech) for mass spectroscopy. Professor Toh-Seok Kam (U.
Me
OH
16’-epi-leucophyllidine, 40
epi-Leucophyllidine obtained as the exclusive product
N
N
Scheme 6. Completion of 16’-epi-leucophyllidine
Despite this unexpected result, we remained optimistic that
the desired stereochemistry could be installed. We first attempted
to perform the hydrogenation with
of Malaya) is acknowledged for providing
leucophyllidine for direct analytical comparison.
a sample of
a chiral Rh-complex,
hypothesizing that we could overturn substrate bias once again
through catalyst control. Employing asymmetric phenol-directed
hydrogenation conditions, we observed exclusive formation of the
undesired C16’ stereocenter (38 à 39, Scheme 7a), when either
enantiomer of BPE-phos ligand (L1 and L2) was used. Given the
difficulty in overriding the inherent diastereoselectivity of this
reduction, we then attempted a late-stage epimerization using
various conditions including acidic, basic, oxidative and
photochemical manifolds. Unfortunately, in all cases, we
observed either no reaction or decomposition of the substrate
(Scheme 7b; see SI for more details).
Keywords: alkaloids • convergence • cross-coupling •
divergence • total synthesis
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H. Ueda, Chem. Pharm. Bull. 2020, 68, 117–128.
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[Rh(cod)L1]BF4 or
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H
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O
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O
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OH
N
N
N
N
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39
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K. Awang, A.H.A. Hadi, H. Morita, J. Nat. Prod. 2010, 73, 1727–1729.
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H
H
N
N
Me
Me
N
Conditions
N
acidic,
basic,
oxidative,
photochemical
H
H
Me
Me
OH
OH
N
N
N
N
16’-epi-leucophyllidine, 40
leucophyllidine (1)
Ph
Attempts to overturn
diastereoselectivity
pre- and post-reduction
were unsuccessful
Ph
Ph
Ph
[9]
a) T. Volshchuk, N.S. Farina, O.R. Wauchope, M. Kiprowska, P.
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Curr. Med. Chem. 2006, 13, 131–154.
P
P
P
P
L1
L2
Ph
Ph
Ph
Ph
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4518–4521.
Scheme 7. Attempted asymmetric hydrogenation and epimerization.
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[12] For racemic total syntheses of eburnamonine or eburnamine, see: (a)
M.F. Bartlett, W.I. Taylor, J. Am. Chem. Soc. 1960, 82, 5941–5946; (b)
J.E.D. Barton, J. Harley-Mason, J. Chem. Soc. Chem. Comm. 1965,
298–299; (c) E. Wenkert, B. Wickberg, J. Am. Chem. Soc. 1965, 87,
1580–1589. (d) D. Cartier, J. Lévy, J. LeMen, Bull. Soc. Chim. Fr. 1976,
In summary, we report the enantioselective synthesis of
eburnamonine, eucophylline, and 16’-epi-leucophyllidine through
a convergent-divergent strategy. An enantioenriched lactam
building block, accessible through Pd-catalyzed enantioselective
4
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1961; (e) G. Costerousse, J. Buendia, E. Toromanoff, J. Martell, J. Bull.
Soc. Chim. Fr. 1978, 355; (f) J.L. Hermann, R.J. Cregge, J.E. Richman,
G.R. Kieczykowski, S.N. Normandin, M.L. Quesada, C.L Semmelhack,
A.J. Poss, R.H. Schlessinger, J. Am. Chem. Soc. 1979, 101, 1540–1544;
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876; (n) A.I. Meyers, J. Romine, A.J. Robichaud, Heterocycles 1990, 30,
339–340; (o) P. Gmeiner, P.L. Feldman, M.Y. Chu-Moyer, H. Rapoport
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Prasad, J.E. Nidhiry, Synlett 2012, 23, 1477–1480.
[28] The reaction was revealed to be highly sensitive to water. For more
details, see SI.
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Krska, J. Org. Chem. 2016, 81, 6980–6987.
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[14] Our group has successfully completed divergent syntheses of
monoterpenoid indole alkaloids through building blocks enabled by allylic
alkylation. See: a) B.P. Pritchett, J. Kikuchi, Y. Numajiri, B.M. Stoltz,
Angew Chem Int. Ed. 2016, 55, 13529–13532; Angew. Chem. 2016, 128,
13727–13730; b) B.P. Pritchett, E.J. Donckele, B.M. Stoltz Angew. Chem.
Int. Ed. 2017, 56, 12624–12627; Angew. Chem. Int. Ed. 2017, 41,
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[15] For a recent review of divergent strategy in total synthesis, see: L. Li, Z.
Chen, X. Zhang, Y. Jia, Chem. Rev. 2018, 118, 3752–3832.
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Stoltz, Nature Chem. 2012, 4, 130–133.
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[18] G.N. Varseev, M.E. Maier, Org. Lett. 2005, 7, 3881–3884.
[19] Reproducibility issues with this transformation were previously reported.
See: C.S. Lancefield, L. Zhou, T. Lébl, A.M.Z. Slawin, N.J. Westwood
Org. Lett. 2012, 14, 6166–6169.
[20] L. Szabo, G. Kalaus, C. Szantay, Archiv der Pharmazie, 1983, 316, 629–
638.
[21] Following the initiation of these studies,
a route to related C19-
oxoeburane alkaloids through Pd-catalyzed asymmetric allylic alkylation
was published. See: B.M. Trost, Y. Bai, W-J. Bai, J.E. Schultz, J. Am.
Chem. Soc. 2019, 141, 4811–4814.
[22] (a) Z.K. Wickens, B. Morandi, R.H. Grubbs, Angew. Chem. Int. Ed. 2013,
52, 11257–11260; Angew. Chem. 2013, 125, 11467–11470; (b) Z.K.
Wickens, K. Skakuj, B. Morandi, R.H. Grubbs, J. Am. Chem. Soc. 2014,
136, 890–893; (c) K.E. Kim, J. Li, B.M. Stoltz, R.H. Grubbs J. Am. Chem.
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[23] H. Vander Mierde, P. Van Der Poort, F. Verpoort, Tetrahedron Lett. 2009,
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[24] Amino alcohol 26 is synthesized in three steps from 2-amino-4-
methoxybenzoic acid. See SI for details
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5
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10.1002/anie.202106184
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
Insert graphic for Table of Contents here.
H
Me
N
Me
Me
O
H
N
N
N
+
NH
H
O
Me
N
N
OMe
N
N
OH
Me
Eburnamonine
O-methyl eucophylline
16’-epi-leucophyllidine
Insert text for Table of Contents here.
A strategy to synthesize the dimeric natural product leucophyllidine is described using a “convergent-divergent” approach. An
enantioenriched lactam building block is advanced in divergent fashion to complete syntheses of both eburnamonine and eucophylline
in 10 and 16 steps respectively. A convergent cross-coupling and hydrogenation sequence is then employed to afford 16’-epi-
leucophyllidine.
Institute and/or researcher Twitter usernames: @thestoltzgroup
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Our group has successfully completed divergent syntheses of monoterpenoid indole alkaloids through building blocks enabled by allylic alkylation. See: a) B.P. Pritchett, J. Kikuchi,
Y. Numajiri, B.M. Stoltz, Angew Chem Int. Ed. 2016, 55, 13529; Angew. Chem. 2016, 128, 13727; b) B.P. Pritchett, E.J. Donckele, B.M. Stoltz Angew. Chem. Int. Ed. 2017, 56,
12624; Angew. Chem. Int. Ed. 2017, 41, 12798.
For a recent review of divergent strategy in total synthesis, see: L. Li, Z. Chen, X. Zhang, Y. Jia, Chem. Rev. 2018, 118, 3752–3832.
D.C. Behenna, Y. Liu, T. Yurino, J. Kim, D.E. White, S.C. Virgil, B.M. Stoltz, Nature Chem. 2012, 4, 130.
A.N. Marziale, D.C. Duquette, R.A. Craig II, K.E. Kim, M. Liniger, Y. Numajira, B.M. Stoltz, Adv. Synth Catal. 2015, 357, 2238.
G.N. Varseev, M.E. Maier, Org. Lett. 2005, 7, 3881.
Reproducibility issues with this transformation were previously reported. See: C.S. Lancefield, L. Zhou, T. Lébl, A.M.Z. Slawin, N.J. Westwood Org. Lett. 2012, 14, 6166.
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This article is protected by copyright. All rights reserved.