Pd-catalyzed chemoselective catellani orth -arylation of iodopyrroles: Rapid total synthesis of rhazinal

Article abstract of DOI:10.1021/ja404494u

A Pd-catalyzed chemoselective Catellani reaction of iodopyrroles was developed. The rare chemoselectivity between two different aryl halides was realized by optimizing the kinetics of the different steps of this multicomponent process. The new developed method led to the rapid synthesis of rhazinal in a highly efficient manner.

Full text of DOI:10.1021/ja404494u

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Palladium-Catalyzed Chemoselective Catellani ortho-
Arylation of Iodopyrroles: Rapid Total Synthesis of Rhazinal
Xianwei Sui, Rui Zhu, Gencheng Li, Xinna Ma, and Zhenhua Gu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja404494u • Publication Date (Web): 11 Jun 2013
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Palladium-Catalyzed Chemoselective Catellani ortho-Arylation
of Iodopyrroles: Rapid Total Synthesis of Rhazinal
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Xianwei Sui,† Rui Zhu,† Gencheng Li, Xinna Ma and Zhenhua Gu*
Department of Chemistry, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026,
China
Supporting Information Placeholder
Scheme 1. Catellani Reaction
ABSTRACT: A palladium-catalyzed chemoselective Catella-
ni reaction of iodopyrroles was developed. The rare
(a) The Classic Catellani Reaction
chemoselectivity between two different aryl halides was real-
ized by optimizing kinetics of the different steps of this mul-
R1
R1
R3
R2
cat. [Pd0]
I
ticomponent process. The new developed method led to a
rapid synthesis of rhazinal in a high efficient manner.
R2
I
R3
+
+
(b) Four Possible Products in the Non-selective Biaryl Catellani Reaction
Transition metal-catalyzed cross-coupling reactions have
been proven to be highly beneficial transformations for or-
ganic synthesis and revolutionized synthesis planning in
natural products total synthesis. Transition-metal-catalyzed
domino or multi-component reactions enable the assembly
of complex molecules in a single step with a rapid build-up
of complexity.1 Among them, the Catellani reaction stands
out as a powerful tool to construct poly-functionalized aro-
matic rings.2 Contributions from the Catellani,3 Lautens4 and
other groups5 expanded the utility of this transformation to
various structurally divergent poly-functionalized aromatic
compounds. Typically, a combination of an aryl halide and
an alkyl halide is necessary to circumvent chemoselectivity
problems (Scheme 1a). The reaction with two different aryl
halides has been rarely reported potentially due to poor
chemoselectivity.3a-c,4f This point is illustrated in Scheme 1b,
showing the formation of four theoretically possible biaryl
products when two distinct aryl halides are used as sub-
strates. Herein we report an application of an efficient
chemoselective norbornene-mediated Catellani reaction in a
concise total synthesis of rhazinal with two different aryl
halides as the reaction components.
Rhazinilam family of natural products represent a class of
compounds with interesting biological activity. (-)-
Rhazinilam (1) was first isolated in 1965 from Mesodinus aus-
trilia,6 and later from Rhazya stricta Decaisne7 and Kopsia
singapurensis.8 (-)-Rhazinal (2)9, (-)-rhazinicine (3)10 and
kopsiyunnanines (4-6)11 were isolated in 1999, 2001, and 2009,
respectively. It was found that (-)-rhazinilam (1), which
mimics the effects of both vinblastine and TaxolTM, could
induce an irreversible assembly of tubulin and inhibit cold-
induced disassembly of microtubules.12 It showed strong
cytotoxicity towards various cancer cell lines in vitro, while
having no activity in vivo, which led to several studies di-
rected at its analogue synthesis and their biological evalua-
tion.13
R
R
Ar2
Ar1
Ar1
Ar2
Y
X
Ar1
Ar2
R
+
+
R
R
Ar1
Ar2
Ar1
Ar2
X, Y = Br, I, OTf ect.
Scheme 2. Rhazinilam Family Natural Products
HN
HN
O
HN
O
O
N
N
N
RO
R
O
R = H, (–)-rhazinilam (1)
R = CHO, (–)-rhazinal (2)
rhazinicine (3)
R = Me, kopsiyunnanine C1 (4)
R = Et, kopsiyunnanine C2 (5)
R = H, kopsiyunnanine C3 (6)
Structurally, compounds in the rhazinilam family share a
tetracyclic framework which contains an axial chiral pyrrole
aniline biaryl fragment and a strained nine-membered lac-
tam bearing a quaternary carbon center. The unusual struc-
ture provided a popular platform for the development of new
strategies and methods, and more than ten syntheses in this
area have been reported to date.14 Carbon-hydrogen bond
functionalization strategy was adopted by the groups of
Sames, Trauner and Gaunt;15 while Nelson and co-workers
constructed the quaternary carbon center via a gold-
catalyzed allene cyclization.16 During the synthesis of (-)-
rhazinal, Banwell and co-workers constructed the tetrahy-
droindolizine fragment via asymmetric imminium-ion catal-
ysis.17 Zakarian’s synthesis features a Heck-type transannular
cyclization of a 13-membered lactam, where the six- and
nine-membered rings as well as a quaternary carbon center
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were constructed in one step through axial-to-point chirality
alkyl fragment 19 could be obtained via a routine three-step
transfer.18
manipulation: Johnson-Claisen rearrangement,25 reduction
and iodination reactions. Alkylation of the known io-
dopyrrole 2026 with iodide 19 delivered the model compound
in excellent yield.
1
2
3
4
5
6
7
8
The key features of our own synthetic plan are listed in
Scheme 3. One phenyl-pyrrole bond and one six-membered
ring are projected to be formed in one step via the nor-
bornene-mediated Catellani reaction. The pivotal issue is to
match the reactivity of 2-halopyrrole and 2-haloaniline com-
ponents. By tuning the nature of substituents and halogen
atoms, as well as reaction conditions, we expect that 1) dur-
ing the initial oxidative addition step, palladium(0) will react
preferentially with aryl halides 7 rather than 8; 2) pyrrolylpal-
ladium species 9 would undergo the insertion reaction with
norbornene faster than the intramolecular Heck reaction
giving undesired product 13;19 and 3) once the carbopal-
ladacycle formed, the palladium(II) species 1020 will selec-
tively react with 8 rather than 7, which will give the unde-
sired bipyrrole compound 15. Reductive elimination of 11,
followed by norbornene release, should deliver 12, which is
expected to undergo the intramolecular Heck reaction af-
fording the fully assembled core structure.21,22 Thus, a major
goal of the study was to identify reaction components that
would have optimal relative kinetics in the various steps of
the multistep process, driving the reaction toward desired
cross-coupling/Heck product.
Scheme 4. Synthesis of Model Compound 16
9
10
11
12
13
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19
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With 16 in hands, we conducted the non-symmetric
biaryl coupling/Heck reaction with various 2-haloaniline
derivatives and their analogues (Figure 1). All the reactions of
16 with 8b-i gave either the direct Heck-type product 22 or
an uncharacterized dimer of 16. Fortunately, heating the
mixture 16 with 1-bromo-2-nitrobenzene 8a in the presence
of palladium dichloride, triphenylphosphine, norbornene in
acetonitrile gave the biaryl product 21 in 11% yield as along
with 10% of the direct Heck cyclization product 22 (Table 1,
entry 1).4o The screening of the solvents found that the reac-
tion in dioxane could give the desired product in 77% yield,
with no significant amount of 22 being detected (entries 2-4).
Scheme 3. Proposed Key Transformation in the Syn-
thesis of Rhazinilam Family Natural Products
A
similar yield (72%) was obtained when tri(2-
furyl)phosphine was used as a ligand (entry 5), while the
reaction became sluggish when bidentate phosphine ligands
such as BINAP or dppe were used (entries 6 and 7). Different
bases were also screened and it was found that K2CO3 is also
an effective base (entry 8). The reaction with KOt-Bu as the
base led to decomposition of iodopyrrole substrate 16 (entry
9) while with 2,6-lutidine resulted in very poor conversion
(entry 10).
Figure 1. 2-Haloaniline Derivatives and Their Analogues
Initially we tried to introduce the carboxyl group via the
ruthenium-catalyzed alkene cross-metathesis with acrylates.
However, presumably due to steric hindrance of neopentylic
vinyl group under various conditions with Grubbs 2nd or
Hoveyda-Grubbs 2nd catalysts, alkene 21 is either unstable or
inert. After unsuccessful functionalization of the terminal
C=C double bond by various methods including hydrobora-
tion,27 hydrozirconation28 and hydrocarbonylation,29 we re-
designed our approach to include the desired carboxy group
in the precursor to the key cascade metal-catalyzed process.
Thus, a group of substrates 26a-e were synthesized (Scheme
5), which could be accessed from the known acid 23 via three
to five-step manipulation.
Preliminary screening experiments with different substi-
tuted 2-halopyrroles revealed that 2-iodopyrrole with an
electron-withdrawing substituent on the aromatic ring is
necessary for successful cross-coupling (For details see Sup-
porting Information).23 As a result, the easily available com-
pound 16 was chosen as our model substrate, whose synthe-
sis was listed in Scheme 4. Starting from the known alcohol
17, which was synthesized from acetylacetone following Am-
ri’s procedure24 (For details see Supporting Information), the
Table 1. Non-symmetric Biaryl Coupling of 16 with 1-
Bromo-2-nitrobenzene (8a)a
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the desired product 27e in 85% yield (entry 5). Currently, the
1
origin of this unusual substituent effect is unclear.
2
3
4
5
6
7
8
9
With the fully functionalized core structure 27e in hands,
the synthesis of rhazinal (2) could be completed in three
steps (Scheme 6). In the presence of Pd/C at three atmos-
phere pressure of hydrogen, both the nitro group and the
double bond could be reduced to deliver 28 in high yield.
Compound 28 showed a pair of atropisomers (~1:1) due to the
slow rotation of pyrrole-phenyl bond at room temperate in
CDCl3, however, this did not affect the final cyclization reac-
tion. Removal of the tert-butyl group under standard acidic
conditions afforded amino acid 29, which could be smoothly
cyclized to afford macrolactam rhazinal (2) with 2-chloro-1-
methylpyridinium iodide (Mukaiyama reagent)30 in a diluted
Entry
Ligand
Base
solvent
Yield
of
21
(2.5 equiv)
/%b
1
PPh3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
CH3CN
DMF
11c,d
2
PPh3
<2
10
11
3
PPh3
toluene
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
67
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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4
PPh3
77
1
solution. The H and 13C NMR data of synthetic 2 is identical
5
P(2-furyl)3
rac-BINAP
dppe
72
6
<2e
35d
51
to those of the natural or previous synthesized rhazinal.
7
8
PPh3
Table 2. Remote Substituent Effect of Non-symmetric
Biaryl Coupling of 26 with 1-Bromo-2-nitrobenzenea
9
PPh3
KOt-Bu
2,6-lutidine
<2
<2e
10
PPh3
Entry
Yield of 27 /% b
<5 (27a) c
40 (27b)
R (26)
a
The reaction was conducted with 16 (0.1 mmol), 8a (6
1
2
3
4
5
Me (26a)
Et (26b)
equiv), PdCl2 (10 mol%), ligand (20 mol%) (for rac-BINAP
and dppe, 10 mol%), base (2.5 equiv) and norbornene (6
equiv) at 85 oC. b Isolated yields. c The reaction was conduct-
ed at 81 oC, 22 was isolated in 10% yield. d an unknown dimer
of 16 was also isolated. e Crude 1H NMR indicated most of SM
i-Pr (26c)
Bn (26d)
t-Bu (26e)
66 (27c)
33 (27d)
85 (27e)
unchanged. BINAP
binaphthyl, dppe = 1, 2-bis(diphenylphosphino)ethane.
=
2,2'-bis(diphenylphosphino)-1,1'-
a
The reaction was conducted at 0.28-0.33 mmol scale, for
b
c
details see Supporting Information. Isolated yields. The
reaction is about 50% conversion on the analysis of crude
mixture.
Scheme 5. Synthesis of Compound 27
Scheme 6. Complete the Synthesis of Rhazinal (2)
O2N
H2N
Pd/C, H2
MeOH
H2N
CO2tBu
OHC
OHC
OHC
N
N
N
94%
CO2tBu
CO2tBu
27e
28
H2N
N
2-Chloro-1-methyl-
pyridinium iodide
Et3N, PhMe/THF
HN
O
F3CCO2H, CH2Cl2
N
OHC
OH
80% two steps
H
O
O
Selective reduction of the known acid 2318 to alcohol, fol-
lowed by tosylation gave 24 in 64% yield. Deprotection of
tert-butyl ester with trifluoroacetic acid, subsequent esterifi-
cation and alkylation would give the desired key precursors
26 (Scheme 5). To our disappointment, under identical con-
ditions for the cascade metal-catalyzed process, the methyl
ester substrate 26a gave only a trace amount of the desired
product with poor conversion (~50%) (Table 2, entry 1).
However, 40% yield of the cross-coupling/Heck product 27b
was obtained when ethyl ester 26b was used (entry 2). In
order to obtain more information about this remote substit-
uent effect, three additional substrates 26c-e were prepared
in the same manner. Interestingly the reaction of isopropyl
(26c) or benzyl ester (26d) afforded the cyclization products
in 66% and 33% yields, respectively (entries 3 and 4). The
best results were obtained when tert-butyl ester 26e was
used. Under our standard conditions, the reaction delivered
rhazinal (2)
29
In summary, a concise and efficient synthesis of rhazinal
was developed. The synthesis features the tandem Catellani-
type ortho-arylation/intramolecular Heck reaction which
enables access to the core structure in a rapid and modular
fashion. In this case, a rare chemoselectivity between two
different aryl halides was realized by optimizing kinetics of
the different steps of this multicomponent process. This ob-
servation provides additional insight for extending the utility
of Catellani reaction in complex molecule synthesis.
ASSOCIATED CONTENT
Supporting Information Experimental procedures, charac-
1
terization data, H and 13C NMR spectra for all new com-
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AUTHOR INFORMATION
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Nagaoka, M.; Zhang, R.; Takayama, H. J. Nat. Prod. 2009, 72, 204.
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(21) A transmetallation mechanism from two palladium(II) species
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Corresponding Author
zhgu@ustc.edu.cn
Author Contributions
†These authors contributed equally.
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Notes
The authors declared no competing financial interest.
ACKNOWLEDGMENT
This work was financially supported by National Natural
Science Foundation of China (21272221) and the Recruitment
Program of Global Experts.
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O2N
H
CO Bu
2t
one-step
transformation
Br
8a
HN
I
NO2
+
O
CO2tBu
N
H
OHC
85%
N
N
H
O
O
6
rhazinal (2)
27e
26e
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