Catalytically Asymmetric Pd/Norbornene Catalysis: Enantioselective Synthesis of (+)-Rhazinal, (+)-Rhazinilam, and (+)-Kopsiyunnanine C1-3

Article abstract of DOI:10.1021/acs.orglett.6b01790

A catalytically asymmetric palladium/norbornene-catalyzed reaction is reported, where α-aryl tetrahydroquinoline derived phosphoramidite L15 is found to be the optimum ligand. Taking advantage of this transformation, the concise and unified enantioselective syntheses of (+)-rhazinal, (+)-rhazinilam, and (+)-kopsiyunnanine C1, C2, and C3 are realized.

Full text of DOI:10.1021/acs.orglett.6b01790

Letter
pubs.acs.org/OrgLett
Catalytically Asymmetric Pd/Norbornene Catalysis: Enantioselective
Synthesis of (+)-Rhazinal, (+)-Rhazinilam, and (+)-Kopsiyunnanine
C1−3
Kun Zhao, Shibo Xu, Chongqing Pan, Xianwei Sui, and Zhenhua Gu*
Department of Chemistry, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, P. R. China
S
* Supporting Information
ABSTRACT: A catalytically asymmetric palladium/norbornene-cata-
lyzed reaction is reported, where α-aryl tetrahydroquinoline derived
phosphoramidite L15 is found to be the optimum ligand. Taking
advantage of this transformation, the concise and unified enantiose-
lective syntheses of (+)-rhazinal, (+)-rhazinilam, and (+)-kopsiyunna-
nine C1, C2, and C3 are realized.
Scheme 1. Natural Products Synthesized by Pd/NBE-
Catalysis as the Key Step and the Rhazinilam Family
Natural Products
alladium-catalyzed cross-coupling reactions have been
widely applied in organic synthesis, notably the synthesis
P
of complex natural products, due to its great capacity for the
selective construction of C−C and C−heteroatom bonds.1
Among them, Pd/norbornene (NBE)-catalyzed reaction is a
particularly powerful method for the synthesis of arenes with
1,2,3-trisubsitution via ortho C−H functionalization followed
by ipso coupling. Since discovery in 1997 by Catellani,2
Lautens was the first who realized the synthetic potential of
this reaction in 2000.3 Subsequently, a series of useful
transformations and a number of molecules with versatile
structures were synthesized by a number of groups.4,5
The utility of Pd/NBE-catalyzed domino reaction was
further demonstrated by the concise synthesis of complex
natural products. Lautens and co-workers reported an elegant
synthesis of (+)-Linoxepin by the use of a chiral alkyl iodide
(Scheme 1a).6 ( )-Goniomitine and ( )-aspidospermidine
were efficiently synthesized by the Bach group via Pd/NBE-
catalyzed α-alkylation of indoles.7 We also disclosed a concise
synthesis of ( )-rhazinal via Pd/NBE catalysis of chemo-
selective ortho-arylation of 2-iodopyrroles followed by intra-
molecular Heck cyclization.8 The high efficiency of these total
syntheses unambiguously demonstrated the powerful bond
formation ability of Pd/NBE catalysis. However, it is easy to
recognize that these molecules were synthesized either in
racemic forms or by the use of a building block with
preinstalled stereogenic atoms, and yet no catalytically
asymmetric Pd/NBE-catalyzed reaction was reported.
important to keep the stereochemical information (Scheme
2). With oxygen atom as the tether atom, high enantiospe-
cificity (es = 96%) was observed, while with NTs as the tether
the ee value dropped from 80% to 63% (es = 79%). Recently
Scheme 2. Chirality Transfer Studies
Catalytically asymmetric transformation of palladium
catalysis is a powerful method for the preparation of chiral
molecules or building blocks. However, the catalytically
asymmetric Catellani-type reaction is unexpectedly ignored
in comparison with other related Pd-catalyzed transforma-
tions. Seminal results for the asymmetric Pd/NBE catalysis
were reported by Lautens and co-workers in 2007, who
studied the intra- and intermolecular chirality transfer
reactions of aryl halide with enantio-enriched secondary
alkyl iodides.9 In intramolecular reactions, the tether is
Received: June 20, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01790
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Organic Letters
Letter
the same group developed an expedient reaction condition for
the intermolecular alkylation with secondary optically active
iodides, and the solvents played a pivotal role.10 In view of
these facts, continuing research on catalytically asymmetric
Catellani reactions is necessary and important, yet still
challenging.
40% yield of 3 with decent enantioselectivity. Ligands L5 and
L6 with an acyclic amino group had very low chiral induction.
Phosphoramidites bearing cyclic amine moieties, such as L7−
L9, were screened, and inferior to moderate ee values were
observed. It was found that the substituent at the α-position
of tetrahydroquinoline greatly affected the stereoselectivity of
this reaction. The α-methyl tetrahydroquinoline derived L10,
which was synthesized by You and co-workers in 2009, gave
an improved enantioselectivity (72% ee).19 Further inves-
tigation on the solvent effect by the use of L10 as the ligand
did not find a better solvent than fluorobenzene, which was
used in the later screenings. Changing the configuration of the
amino moiety or replacing the α-methyl group to the ethyl
group in the tetrahydroquinoline structure (L11, L12) only
led to a drop in both the yield and enantioselectivity.
Rhazinilam,11 rhazinal,12 and rhazinicine13 have drawn
significant attention from many synthetic chemists because
of their unique bioactivities toward various cancer cell lines
and the interesting diversely substituted pyrrole skeleton
(Scheme 1b).14,15 Kopsiyunnanine C1−3 were isolated in
2009,16 and there is no report regarding their total synthesis
to date. Kopsiyunnanine C1−2 contain methoxymethyl or
ethoxymethyl functionality, which was rarely found in natural
products. Herein we report a catalytically asymmetric version
of Pd/norbornene catalysis and its application in the unified
synthesis five members of rhazinilam family natural prod-
ucts.17
Further optimization focused on the α-aryl tetrahydroquino-
line derived phosphoramidites, whose syntheses were detailed
in Scheme 4. The semireduction of 2-arylquinolines20 gave the
Studies began with the asymmetric version of the key
domino reaction of our previous racemic synthesis of
rhazinal.8 Poor conversion was observed when bidentated
ligands, such as (R)-BINAP and (R)-DIOP, were used. The
reactions with a TADDOL-based monodentated ligand, such
as L1 and L2, gave very poor enantioselectivity (Scheme 3).
The screening of a [2′-methoxy-(1,1′-binaphthalen)-2-yl]-
diphenylphosphine[MOP]-type ligand indicated that L3 was
superior over its analogues; however the reaction did not give
satisfactory yields and ee’s in various conditions.18 The
reaction with SIPNOL-based phosphoramidite L4 afforded a
Scheme 4. Synthesis of Phosphoramidites
a
Scheme 3. Reaction Conditions Optimization
desired tetrahydroquinoline by following Rueping’s procedure
via 9-phenanthrenyl chiral phosphoric acid (CPA) catalysis in
the presence of Hantzsch ester.21 The tetrahydroquinoline
with PCl3 in toluene followed by the addition of (S)-BINOL
gave the enantiopure phosphoramidites in moderate yields.
Pleasingly, the reaction with α-(p-tolyl) tetrahydroquinoline
based ligand L13 delivered the product in 82% ee, and the
ligand L14 gave marginally lower enantioselectivity. 2,4-
Dimethylphenyl tetrahydroquinoline derived ligand L15
showed good stereoselectivity and afforded 3 in 88% ee.
However, the bulkier ligand L16 and 2-(3′,5′-dimethylphenyl)
1,2,3,4-tetrahydroquinoline based ligand L17 did not show
better asymmetric induction.
With optically active key intermediate 3 in hand, we
continued our efforts for the synthesis of rhazinilam and the
related natural products (Scheme 5). One step transformation
of 3 could reduce both the nitro group and C−C double
bond under Pd/C and H2 to deliver 4 in high yield (Scheme
5a). Removal of the tert-butyl group in 4 with TFA, followed
by intramolecular amide bond formation, gave (+)-rhazinal
(5) in 80% yield. The reduction of the aldehyde group by
NaBH4/EtOH and quenching with aqueous NaOH gave
(+)-kopsiyunnanine C3 (6) in excellent yield.22 The removal
of the aldehyde functionality of 3 via decarbonylation with
stoichiometric Wilkinson catalyst afforded 7, which was readily
converted to (+)-rhazinilam in good overall yield via
hydrogenation, basic hydrolysis, and macrolactam formation
(Scheme 5b).
a
Unless stated otherwise, the reaction was conducted with 1 (0.10
mmol, 1.0 equiv), 2a (0.60 mmol), Pd(OAc)2 (10 mol %), ligand (20
mol %), and Cs2CO3 (0.25 mmol) in dioxane (0.10 M). PhF was
used as the solvent.
b
The attempt to synthesize (+)-kopsiyunnanine C1 and C2
by the etherification of (+)-kopsiyunnanine C3 was
B
DOI: 10.1021/acs.orglett.6b01790
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Organic Letters
Letter
Scheme 5. Synthesis of (+)-Rhazinal, (+)-Kopsiyunnanine
C3, and (+)-Rhazinilam
Scheme 6. Synthesis of (+)-Kopsiyunnanine C1 and C2
unsuccessful in our hands. The N-alkylation of the amide
functionality was superior over etherification. Thus, by
treatment of 6 with 1.0 equiv of NaH and 1.0 equiv of
TsOMe, N-Me-6 was obtained in quantitative yield, while
N,O-diMe-6 was formed as the sole product when excess NaH
and 2.0 equiv of TsOMe were used (Scheme 6a). It is
interesting to observe that the reduction of our model
compound A by NaBH4 in MeOH, followed by acidic workup
(1 N HCl), gave the ether derivative in high yields (Scheme
6b). The ethers were possibly formed by acid-catalyzed
iminium ion formation and nucleophilic addition of the
alcohols. Unfortunately, the ether decomposed after the
reduction of the nitro group to an amine or other related
further transformation. The reduction of (+)-rhazinal (5) in
MeOH,23 followed by the treatment of 1 N HCl, resulted in
the decomposition of the material (Scheme 6c). Alternatively,
hydrolysis of the tert-butyl ester of 4 by trifluoroacetic acid,
followed by the treatment of NaBH4 to give the alcohol 10,
which was carefully acidified to pH 1−2 with aqueous HCl to
form the ethers 10a or 10b. The sensitive crude amino acids
should be kept in the solution all the time, and they were
used directly for the macrolactam formation without
purification to deliver (+)-kopsiyunnanine C1 (11) and C2
(12) in satisfactory overall yields (Scheme 6d). The analytic
data of these synthetic samples well matched those reported
for natural products.
In conclusion, we present here a catalytically asymmetric
palladium/norbornene-catalyzed domino ortho-arylation and
Heck cyclization reaction. It demonstrates the first example of
catalytically asymmetric Catellani-type reaction. The α-aryl
tetrahydroquinoline derived phosphoramidite was superior
over other ligands, and excellent enantioselectivity was
achieved. Taking advantage of this method, five members of
the rhazinilam family natural products were enantioselectively
synthesized in a concise and unified manner. The newly
discovered acid-catalyzed ether formation of (pyrrol-2-yl)
methanol provided a convenient approach for the synthesis of
kopsiyunnanine C1−2.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01790.
■
S
Analytical data, experimental procedures, and NMR
spectra for all compounds reported (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: zhgu@ustc.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the ‘973’ project from the
MOST of China (2015CB856600), NSFC (21272221,
21472179), and Strategic Priority Research Program of the
Chinese Academy of Sciences (XDB20000000). X.S. thanks
the Grant from China Postdoctoral Science Foundation
(2015M581995). We thank Professor L. Gong and Professor
C
DOI: 10.1021/acs.orglett.6b01790
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Letter
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DOI: 10.1021/acs.orglett.6b01790
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