Concise Synthesis of Lamellarin Alkaloids by C-H/N-H Activation: Evaluation of Metal Catalysts in Oxidative Alkyne Annulation

Article abstract of DOI:10.1055/s-0036-1591209

The performance of various transition-metal catalysts was explored in the step-economical synthesis of naturally occurring lamellarin alkaloids by C-H/N-H activation. The oxidative alkyne annulation proceeded efficiently by using sustainable ruthenium(II) catalysis, which set the stage for a concise synthesis of lamellarin D, lamellarin H and derivatives thereof.

Full text of DOI:10.1055/s-0036-1591209

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
letter
A
en
R. Mei et al.
Letter
Synlett
Concise Synthesis of Lamellarin Alkaloids by C–H/N–H Activation:
Evaluation of Metal Catalysts in Oxidative Alkyne Annulation
OR
OR
RO
HO
HO
Ruhuai Mei§
Shou-Kun Zhang§
OH
Pd
Pd
X
H
Lutz Ackermann*
O
O
RO
HO
RO
HO
OR
Institut für Organische und Biomolekulare Chemie, Georg-Au-
gust-Universität, Tammanstraße 2, 37077 Göttingen, Germany
Lutz.Ackermann@chemie.uni-goettingen.de
N
H
N
O
O
Ru
OH
R = H: Lamellarin H
R = Me: Lamellarin D
http://www.ackermann.chemie.uni-goettingen.de
OR
HO
§ These authors contributed equally
Ru
H
H
Published as part of the ISHC Conference Special Section
H
H
RO
N
CO2Me
CO2Me
Ac
N
H
HO
Received: 02.07.2017
Accepted: 03.08.2017
Published online: 16.08.2017
DOI: 10.1055/s-0036-1591209; Art ID: st-2017-b0539-l
ods for versatile C–H/Het–H functionalizations that proceed
through sustainable oxidative alkyne annulations.6 Notably,
the C–H/N–H activation manifold set the stage for the step-
economical synthesis of various heterocycles,7 including
the assembly of substituted pyrroles (Scheme 1a).8 In con-
tinuation of our studies on oxidative C–H/N–H functional-
izations,6b,7,9 and given the antibiotic, anticancer and anti-
malaria activities10 of pyrrole-containing lamellarin11 alka-
loids,12 we were inspired to conduct a comparative study on
the performance of various transition-metal catalysts in the
preparation13 of naturally occurring lamellarins 4 (Scheme 1b).
A very recent independent report by Lade, Chandrasekhar
and co-workers14 prompted us to now disclose our own re-
sults on the evaluation of various rhodium,15 palladium,16
ruthenium,7,9 and cobalt17 catalysts in the key C–H/N–H
activation within the realm of a step-economical lamellarin
alkaloid synthesis.
Abstract The performance of various transition-metal catalysts was
explored in the step-economical synthesis of naturally occurring lamel-
larin alkaloids by C–H/N–H activation. The oxidative alkyne annulation
proceeded efficiently by using sustainable ruthenium(II) catalysis,
which set the stage for a concise synthesis of lamellarin D, lamellarin H
and derivatives thereof.
Key words alkaloids, C–H activation, lamellarin, natural products,
ruthenium
The past decade has witnessed the emergence of C–H
activation as an increasingly powerful tool in molecular
synthesis.1 Thereby, transformative applications to material
sciences,2 pharmaceutical industries,3 and natural product
chemistry4 have proven to be viable, with considerable re-
cent progress being achieved by the use of versatile ruthe-
nium(II) catalysts.5 In this context, we have devised meth-
Our studies were inspired by identifying pyrrole 5 as the
key intermediate for a C–H activation-based lamellarin syn-
thesis (Scheme 2). Thus, pyrrole-containing lamellarins D
(a) previous reports: Catalyzed C-H/N-H functionalization
R2
R1
R4
R5
R2
H
R4
H
TM
+
N
R3
R5
N
R3
R1
1
2
3
(b) this report: Lamellarin scafold assembly via ruthenium(II) catalysis
OR
R'O
OR
RO
HO
OH
Ar
Ar
H
H
Ru
+
N
CO2Me
O
RO
HO
CO2Me
Ac
N
H
N
R'O
O
RO
R = H: lamellarin H (4a)
R = Me: lamellarin D (4b)
Scheme 1 Ruthenium(II)-catalyzed C–H/N–H activation for the assembly of lamellarin alkaloids
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
R. Mei et al.
Letter
Synlett
(4b) and H (4a) were traced back to diaryl-substituted pyr-
role 6, which, in turn, was suggested to derive from the
metal-catalyzed C–H/N–H activation strategy.
Table 1 Optimization of Transition-Metal-Catalyzed C–H/N–H Activa-
tion on Enamide 2a
Oi-Pr
OMe
i-PrO
OMe
OR
Pd
RO
HO
OH
OR
HO
H
H
H
Pd
cat. [TM]
cat. AgSbF6
X
H
H
+
O
N
CO2Me
CO2Me
RO
HO
N
R
O
Cu(OAc)2⋅H2O
RO
HO
Ac
i-PrO
N
OR
solvent
O
N
H
Ru
110–120 °C, 24 h
O
MeO
4
5
OH
MeO
R = H: 3a
R = Ac: 3a'
Oi-Pr
1a
2
OR
HO
Entry [TM]
Solvent
Yield 3a (%) Yield 3a' (%)
Ru
H
H
H
1
2
3
4
5
6
7
8
9
10
–
MeOH/DCE
MeOH/DCE
MeOH/DCE
MeOH/DCE
PEG-400b
–
–
H
RO
N
CO2Me
Cp*Co(CO)I2
[Cp*RhCl2]2
Pd(OAc)2
–
–
CO2Me
Ac
N
H
HO
94
15
32
trace
–
2
6
Scheme 2 Retrosynthetic analysis for lamellarin alkaloids 4
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
59
34
80
23
trace
–
PEG-400/H2Ob 44
In the initial stages of our studies, we probed the performance
of different transition-metal complexes in the envisioned
C–H/N–H functionalization of enamides 2 with alkyne 1a
(Table 1, and Table S-1 in the Supporting Information).18
The desired C–H/N–H activation was not viable in the absence
of a transition-metal catalyst (entry 1), and only trace
amounts of the products 3 were observed when using a co-
balt(III)19 catalyst (entry 2).17 In contrast, rhodium(III) and
less expensive ruthenium(II) complexes proved to be signifi-
cantly more powerful (entries 3–10), with the chemoselec-
tivity towards the NH-free pyrrole being strongly influ-
enced by a silver(I) additive (entries 5–7). As to the reaction
medium, polyethylene glycol PEG-400,20 either with or
without co-solvent, was found to be less selective as
compared to reactions conducted in the presence of protic
(co-)solvents (entries 5–10).
t-AmOHb
13
68
95
97
t-AmOH
t-AmOH/DCE
MeOH/DCE
a Reaction conditions: 1a (0.50 mmol), 2 (0.55 mmol), [TM] (10 mol%),
AgSbF6 (20 mol%), Cu(OAc)2·H2O (2.0–3.0 equiv), solvent (1.5 mL), 110–
120 °C, 24 h, yield of isolated product.
b In the absence of AgSbF6.
Oi-Pr
OMe
OMe
H
i-PrO
[RuCl2(p-cymene)]2
(5.0 mol%)
AgSbF6 (20 mol%)
H
H
H
N
+
CO2Me
Cu(OAc)2⋅H2O
MeOH/DCE
110 °C, 24 h
CO2Me
With the optimized conditions for the sustainable ru-
thenium(II) catalyst in hand, we explored the robustness
and scalability of the C–H/N–H activation with a gram-scale
reaction. Gratifyingly, under these conditions, the desired
key intermediate pyrrole 3a was delivered with comparable
levels of efficacy (Scheme 3).
N
H
Ac
i-PrO
MeO
MeO
Oi-Pr
3a: 93% (2.1 g)
1a
2
Scheme 3 Gram-scale synthesis by C–H/N–H activation
Subsequently, the synthetic utility of the ruthenium(II)-
catalyzed C–H/N–H activation was exploited by utilizing
the thus-obtained pyrrole 3a for a Suzuki–Miyaura based
synthesis of tetrasubstituted pyrrole 8a, which was con-
verted into the desired lamellarins H and D through a
Pomeranz–Fritsch13d approach (Scheme 4).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

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Letter
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1) NBS, 98%
2) cat. [Pd], 91%
1) NBS, 98%
2) cat. [Pd], 87%
Bpin
B(OH)2
OMe
OMe
i-PrO
OMe
i-PrO
OMe
i-PrO
Oi-Pr
OMe
MeO
i-PrO
3) cat. TsOH⋅H2O, 86%
OMOM
OH
i-PrO
7a
7b
O
O
O
CO2Me
N
H
N
H
N
H
i-PrO
i-PrO
O
i-PrO
CO2Me
N
H
3a
8b
i-PrO
8a
MeO
MeO
MeO
3a
3)
MeO
4)
OMe
OMe
OMe
OMe
Br
Br
9
9
82%
4) TfOH, 91%
81%
5) TfOH, 94%
OR1
OR1
OR2
OMe
R2O
i-PrO
O
R1O
R2O
O
O
MeO
N
N
O
i-PrO
4d
1 = Me, R2 = i-Pr: (4c)
Scheme 5 Synthesis of lamellarin analogue 4d
R
6) BCl3, 96%
R1 = Me, R2 = H: lamellarin D (4b)
R1 = R2 = H: lamellarin H (4a)
7) BBr3, 93%
[RuCl2(p-cymene)]2
Ph
H
H
Ph
H
(2.5 mol%)
AgSbF6 (10 mol%)
H
+
Scheme 4 Synthesis of lamellarins H (4a) and D (4b). Reagents and con-
ditions: (1) NBS, DMF, 0 °C, 1 h, 98%; (2) Pd2(dba)3 (7.5 mol%), dppf (15
mol%), Na2CO3, DME/H2O, 110 °C, 36 h, 87%; (3) TsOH·H2O (25 mol%),
MeOH, 16 h, 110 °C, 86%; (4) Cs2CO3, DMF, 110 °C, 24 h, 81%; (5) TfOH,
CH2Cl2, 0 to 23 °C, 1.5 h, 94%; (6) BCl3, CH2Cl2, –78 to 23 °C, 3.5 h, 96%;
(7) BBr3, CH2Cl2, –78 to 23 °C, 17 h, 93%.
N
CO2Me
Ph
CO2Me
Cu(OAc)2⋅H2O
MeOH/DCE
110 °C, 24 h
N
H
Ph
Ac
1b
2
3b: 89%
1) NBS, 99%
2) cat. [Pd], 78%
B(OH)2
Ph
OH
Ph
With the key pyrrole 3a in hand, we subsequently pre-
pared the novel lamellarin derivative 4d, being devoid of
oxygenation elements at one β-aryl motif, in only four steps
(Scheme 5). Notably, the installation of the annulated lac-
tone was achieved in a palladium-catalyzed one-pot syn-
thesis with excellent isolated yield of pyrrole 8b.
7b
O
Ph
CO2Me
N
Ph
H
N
H
O
8c
3b
3)
OMe
OMe
Br
9
The strategy of combining the ruthenium(II)-catalyzed
C–H/N–H activation with the palladium-catalyzed one-pot
annulation further set the stage for the preparation of trun-
cated lamellarin analogue 4e (Scheme 6), highlighting the
modular nature of our approach.
62%
4) TFAA/TFA
64%
O
O
N
4e
Scheme 6 Synthesis of truncated lamellarin analogue 4e
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

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In summary, we have disclosed the first comparative
evaluation of transition-metal catalysts in the C–H/N–H ac-
tivation of enamides for the step-economical synthesis of
lamellarin alkaloids. A sustainable ruthenium(II) biscarbox-
ylate catalyst proved to be particularly effective for the key
oxidative alkyne annulation, which provided modular ac-
cess to the naturally occurring alkaloids lamellarin D and H
as well as truncated derivatives thereof.
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Funding Information
Generous support by the European Research Council under the Euro-
pean Community’s Seventh Framework Program (FP7 2007–
2013)/ERC Grant agreement no. 307535, and the China Scholarship
Council (fellowships to R.M. and S.-K.Z.) is gratefully acknowledged.
E
u
or
p
e
a
n
Research
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591209.
S
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p
p
ortioInfgrmoaitn
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D