Asymmetric total syntheses of (-)-Angustureine and (-)-cuspareine via rhodium-catalyzed hydroamination

Article abstract of DOI:10.1021/acs.orglett.9b04334

Concise syntheses of the Hancock alkaloids (-)-Angustureine and (-)-cuspareine are presented, applying and refining a recently developed rhodium-catalyzed hydroamination for the stereoselective construction of the chiral secondary amine. Furthermore, the

Full text of DOI:10.1021/acs.orglett.9b04334

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Asymmetric Total Syntheses of (−)-Angustureine and
(−)-Cuspareine via Rhodium-Catalyzed Hydroamination
Dino Berthold and Bernhard Breit*
Institut fur Organische Chemie, Albert-Ludwigs-Universitat Freiburg, Albertstr. 21, 79104 Freiburg im Breisgau, Germany
̈
̈
S
* Supporting Information
ABSTRACT: Concise syntheses of the Hancock alkaloids
(−)-angustureine and (−)-cuspareine are presented, applying
and refining a recently developed rhodium-catalyzed hydro-
amination for the stereoselective construction of the chiral
secondary amine. Furthermore, the syntheses include an allene
synthesis via boron−magnesium exchange as well as the
construction of the tetrahydroquinoline motive via a hydro-
boration/Suzuki−Miyaura coupling sequence.
lkaloids bearing tetrahydroquinoline motifs are occurring
amine by allylic substitution was developed by Helmchen using
an Ir/phosphoramidite-based catalyst system.12,13
A
widely in plants, and many of them exhibit interesting
biological activities.1,2 Prominent examples include the
members of the family of Hancock alkaloids, e.g., (−)-angus-
tureine, (−)-cuspareine, (−)-galipeine, and (−)-galipinine
(Figure 1). All of these natural products were isolated by
In the recent past, our research group has developed a
rhodium-catalyzed asymmetric hydroamination of allenes with
anilines, a method which could be seen as an atom-efficient
alternative to allylic substitution.14 Herein, we report a novel
and concise total synthesis of (−)-angustureine and
(−)-cuspareine in the absence of protecting groups, enabled
by a highly enantioselective hydroamination strategy.
In the beginning, the two required allenes 1 and 2 were
synthesized in two short and efficient ways. n-Hexyl allene 1
was prepared through propargylic substitution employing
propargyl bromide and the Grignard reagent derived from n-
hexyl bromide in the presence of a copper catalyst on a 200
mmol scale reaction in 69% yield. The aryl functionalized
allene 2 was obtained in a two-step sequence starting from 2,3-
dimethoxystyrene employing an iridium-catalyzed linear
selective hydroboration and subsequent boron−magnesium
exchange.15 The obtained Grignard reagent was then trapped
in an analogous manner with propargyl bromide under copper
catalysis to give allene 2 in 60% yield over both steps (Scheme
1).
Building on our previously reported hydroamination results
provided by a Rh/Josiphos J003-2 based catalyst system, we
tested these previous standard conditions for 2-iodo aniline (7)
and n-hexyl allene (1). Surprisingly, we obtained the desired
product 8 either with EtOH as a cosolvent or with PPTS as an
additive in low optical purities (Table 1, entries 1 and 2).
Furthermore, EtOH enabled a dehalogenation by transfer
hydrogenation leading to dehalogenated allylic aniline 9. To
overcome the problem of low enantioselectivity, we tested the
sterically more demanding ligand J009-2 (entry 3). However,
in the reaction in the presence of PPTS, the desired product 8
was obtained in low yield and enantioselectivity. To exclude
Figure 1. Examples of naturally occurring tetrahydroquinoline
alkaloids.
Jacquemond-Collet from the bark of Galipea officinalis
Hancock, which comprises 20 different species found in
northern South America.1b In light of their biological activity
profiles, extracts from these plants have been used in folk
medicine for the treatment of dysentery and fever.3a More
recently, extracts of the bark of Galipea officinalis also have
been shown to possess antiplasmodial and cytotoxic
activities.3b
Encouraged by these interesting biological properties, many
chemists contributed to the development of asymmetric
synthesis of these tetrahydroquinoline motifs. Bearing in
mind that the main challenge is the asymmetric generation
of the secondary amine, a variety of reactions have been
utilized as key steps,4−10 with most syntheses relying on
asymmetric catalytic hydrogenation of quinolines.11 Another
general approach for the construction of the chiral secondary
Received: December 3, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04334
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Preparation of Allenes 1 and 2
Scheme 2. Comparison of Previous and New
Hydroamination Conditions
a
a
Reaction conditions: (a) (1) 3 (1.0 equiv), Mg (1.2 equiv), THF
(0.1 M), rt−70 °C, 2 h; (2) 4 (1.2 equiv), CuBr (10 mol %), THF
(0.6 M), 0 °C−rt, 12 h, 69%; (b) HBpin (1.2 equiv), [{Ir(cod)Cl}2]
(1.0 mol %), dppp (2.0 mol %), toluene (1.0 M), rt, 18 h, 83%; (c)
(1) ClMg(CH2)4MgCl (2.0 equiv), toluene/THF (1:1, 0.3 M), 0
°C−rt, 2 h; (2) propargyl bromide (4) (1.2 equiv), CuBr (10 mol %),
THF (0.5 M), 0 °C−rt, 12 h, 72%.
Table 1. Optimization of the Hydroamination of 2-Iodo
Aniline (7) and n-Hexyl Allene (1)
a
[a] Reaction conditions: aniline (1.0 mmol), allene (1.5 mmol),
[{Rh(cod)Cl}2] (2.0 mol %), and J003-2 (5.0 mol %) in DCE/EtOH
(7:1, 2.5 mL) at 80 °C, 18 h. [b] Reaction conditions: aniline (1.0
mmol), allene (1.5 mmol), [{Rh(cod)Cl}2] (2.0 mol %), and J009-2
(5.0 mol %) in DCE (2.5 mL) at 80 °C, 18 h.
c
d
c
d
yield of 8
ee of 8
(%)
yield of 9
ee of 9
(%)
entry
ligand
additive
(%)
(%)
a
1
J003-2
J003-2
J009-2
J009-2
49
97
77
89
75
79
35
95
42
74
b
2
PPTS
PPTS
3
4
a
Scheme 3. Synthesis of (−)-Angustureine
a
Reaction conditions: 2-iodo aniline (7) (1.0 mmol) and n-hexyl
allene (1) (1.5 mmol) in DCE/EtOH (7:1, 2.5 mL) at 80 °C, 18 h.
b
Reaction conditions: 2-iodo aniline (7) (1.0 mmol), n-hexyl allene
(1) (1.0 mmol), and PPTS (10 mol %) in DCE (2.5 mL) at 80 °C, 18
c
d
h. Yield of isolated product. Determined by chiral HPLC analysis.
cod = 1,5-cyclooctadiene, PPTS = pyridinium p-toluenesulfonate.
a
Reaction conditions: (a) Formaline sol. (40 wt %, 15 equiv),
NaCNBH3 (1.5 equiv), AcOH (10 equiv), MeCN (0.1 M), rt, 18 h,
99%; (b) 9-BBN (1.05 equiv), THF (0.5 M), 0 °C−rt; then
[Pd(dppf)Cl2] (1.5 mol %), NaOHaq (3.0 M, 3.0 equiv), 80 °C, 18 h,
94%.
the possibility that the PPTS had a negative effect as an
additive, the reaction was performed in the absence of it (entry
4). To our delight, 9 was obtained in high yield and excellent
enantioselectivity, providing new optimized conditions for the
hydroamination of allenes.16
a
Scheme 4. Synthesis of (−)-Cuspareine
With these optimized conditions in hand, we sought to
examine a small scope of substrates, which did not perform
satisfactorily under the previously reported conditions.14 In all
tested substrate combinations, the desired secondary anilines
were obtained in better yields and higher enantioselectivities
by the new catalyst system (Scheme 2).
Furthermore, product 19 allowed us to determine the
absolute configuration, which was found to be the same as that
obtained for the previous, J003-2 based method.
As we were now capable of synthesizing catalysis products 8
and 17 in high yield and enantioselectivity, the synthesis of
(−)-angustureine and (−)-cuspareine was envisioned next. In
contrast to the synthesis of Helmchen,12a the methylation of
the secondary aniline was performed first for both natural
products, as we assumed that the free amine could complicate
the intramolecular Suzuki coupling by promoting unwanted
side reactions.17 In both cases, the amine methylation
proceeded smoothly through reductive amination in good
yields (Schemes 3 and 4). However, for the hydroboration of
a
Reaction conditions: (a) (CH2O)n (15 equiv), NaCNBH3 (10
equiv), AcOH (10 equiv), MeCN (0.1 M), rt, 18 h, 94%; (b) 9-BBN
(2.5 equiv), THF (0.8 M), 70 °C, 20 min; then [Pd(dppf)Cl2] (5.0
mol %), Cs2CO3 (2.0 equiv), DMF/H2O (15:1, 0.4 M), 80 °C, 24 h,
63%.
the allylic double bond and the subsequent intramolecular
Suzuki coupling, slightly different conditions had to be applied.
Transformation of allylic aniline toward (−)-angustureine
occurred under mild conditions, employing only 1 equiv of 9-
BBN at rt, furnishing quantitively the desired hydroboration
product. Its subsequent treatment with [Pd(dppf)Cl2] and an
B
DOI: 10.1021/acs.orglett.9b04334
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
of Angostura Bark. Planta Med. 1999, 65, 250−254. Jacquemond-
Collet, I.; Bessiere, J.-M.; Hannedouche, S.; Bertrand, C.; Fouraste, I.;
Moulis, C. Identification of the alkaloids of Galipea officinalis by gas
chromatography−mass spectrometry. Phytochem. Anal. 2001, 12,
312−319.
aqueous NaOH solution at 80 °C furnished (−)-angustureine
in 94 and 83% yield over three steps starting from allene 1.
The synthesis of (−)-cuspareine starting from allylic amine
17, however, did not succeed satisfactorily employing the same
reaction conditions. Conversely, more forceful reaction
conditions had to be chosen in order to guarantee complete
hydroboration. Furthermore, the previously used conditions
for the Suzuki coupling resulted in low yields. Finally, after
being freed from the solvent (THF), the hydroboration
intermediate was reacted in the presence of [Pd(dppf)Cl2] and
Cs2CO3 in a solvent mixture of DMF/H2O. These reaction
conditions provided (−)-cuspareine in 63% yield and 25%
overall yield in four steps starting with commercially available
4-vinyl veratrole (5).
In conclusion, we have developed concise, enantioselective,
and protecting-group-free syntheses of (−)-angustureine and
(−)-cuspareine. In this context, we improved the catalyst
system of our previously developed hydroamination of allenes
with anilines now reaching higher yields and enantioselectiv-
ities. This allylic addition can be seen as an atom efficient
alternative to the conventionally applied allylic substitution.
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α-(trifluoromethyl)-1(2H)-quinolineethanol as Potent and Orally
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ASSOCIATED CONTENT
* Supporting Information
■
(3) (a) Mester, I. Alkaloids from root bark of Zanthoxylum simulans.
Fitoterapia 1973, 44, 123−152. (b) Jacquemond-Collet, I.; Benoit-
Vical, F.; Valentin, A.; Stanislas, E.; Mallie, M.; Fouraste, I.
Antiplasmodial and Cytotoxic Activity of Galipinine and other
Tetrahydroquinolines for Galipea officinalis. Planta Med. 2002, 68,
68−69.
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04334.
All synthetic procedures for new compounds as well as
1
their analytical data, involving H NMR and 13C NMR
(4) For a recent review on synthesis of Hancock alkaloids, see:
spectra and scanned HPLC chromatograms for chiral
compounds (PDF)
Munoz, G. D.; Dudley, G. B. Synthesis of 1,2,3,4-Tetrahydroquino-
̃
lines including Angustureine and Congeneric Alkaloids. A Review.
Org. Prep. Proced. Int. 2015, 47, 179−206.
Accession Codes
(5) Asymmetric syntheses based on aza-Michael additions:
(a) Davies, S. G.; Ichihara, O. Asymmetric synthesis of R-β-amino
butanoic acid and S-β-tyrosine: Homochiral lithium amide equivalents
for Michael additions to α,β-unsaturated esters. Tetrahedron:
Asymmetry 1991, 2, 183−186. (b) Bentley, S. A.; Davies, S. G.;
Lee, J. A.; Roberts, P. M.; Thomson, J. E. Conjugate Addition of
Lithium N-Phenyl-N-(α-methylbenzyl)amide: Application to the
Asymmetric Synthesis of (R)-(−)-Angustureine. Org. Lett. 2011, 13,
2544−2547. (c) Davies, S. G.; Fletcher, A. M.; Houlsby, I. T. T.;
Roberts, P. M.; Thompson, J. E. Structural Revision of the Hancock
Alkaloid (−)-Galipeine. J. Org. Chem. 2017, 82, 10673−10679.
CCDC 1885897 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: bernhard.breit@chemie.uni-freiburg.de.
ORCID
́
́
́
́
(d) Fustero, S.; Moscardo, J.; Jimenez, D.; Perez-Carrion, M. D.;
́
́
Sanchez-Rosello, M.; del Pozo, C. Organocatalytic Approach to
Benzofused Nitrogen-Containing Heterocycles: Enantioselective
Total Synthesis of (+)-Angustureine. Chem. - Eur. J. 2008, 14,
9868−9872. (e) Taylor, L. L.; Goldberg, F. W.; Hii, K. K. Asymmetric
synthesis of 2-alkyl-substituted tetrahydroquinolines by an enantiose-
lective aza-Michael reaction. Org. Biomol. Chem. 2012, 10, 4424−
4432.
Bernhard Breit: 0000-0002-2514-3898
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(6) Asymmetric syntheses based on Mitsunobu inversions:
(a) Theeraladanon, C.; Arisawa, M.; Nagakawa, M.; Nishida, A.
Total synthesis of (+)-(S)-angustureine and the determination of the
absolute configuration of the natural product angustureine Tetrahe-
dron. Tetrahedron: Asymmetry 2005, 16, 827−831. (b) Ryu, J. S.
Hydroarylation for the Facile Synthesis of 2-substituted Tetrahy-
droquinoline: A Concise Synthesis of (+)-(S)-Angustureine. Bull.
Korean Chem. Soc. 2006, 27, 631−632. (c) Madhubabu, M. V.;
Shankar, R.; Krishna, T.; Satish Kumar, Y.; Chiraneevi, Y.;
Muralikrishna, C.; Rama Mohan, H.; More, S. S.; Vasaveswara, M.
V.; Akula, R. A convergent approach towards the synthesis of the 2-
alkyl-substituted tetrahydroquinolines alkaloid (−)-cuspareine. Tetra-
hedron: Asymmetry 2017, 28, 1803−1807.
This work was supported by the DFG. Laura Stachowiak is
thanked for her skillful technical assistance. We thank Dr.
Daniel Kratzert for X-ray crystal structure analysis.
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(16) Concerning the higher yield and enantiomeric purities of the
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D
DOI: 10.1021/acs.orglett.9b04334
Org. Lett. XXXX, XXX, XXX−XXX