Concise Asymmetric Total Synthesis of ent-Ancistrocladinium A

Article abstract of DOI:10.1002/adsc.201600472

An asymmetric total synthesis of ent-ancistrocladinium A was developed via chiral phosphoric acid-catalyzed asymmetric reductive amination of 1-aryl-2-propanone and naphthylamine followed by a Bischler–Napieralski reaction. Direct use of the naphthyl moiety in the amine as a key building block in the natural product allowed us to achieve the total synthesis of ancistrocladinium A in only three steps from the known starting materials. (Figure presented.).

Full text of DOI:10.1002/adsc.201600472

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DOI: 10.1002/adsc.201600472
Concise Asymmetric Total Synthesis of ent-Ancistrocladinium A
Kyung-Hee Kima and Cheol-Hong Cheona,*
a
Department of Chemistry, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
Fax : (+82)-02-3290-3121; phone: (+82)-02-3290-3147; e-mail: cheon@korea.ac.kr
Received: May 3, 2016; Revised: June 24, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600472.
Abstract: An asymmetric total synthesis of ent-an-
cistrocladinium A was developed via chiral phos-
phoric acid-catalyzed asymmetric reductive amina-
tion of 1-aryl-2-propanone and naphthylamine fol-
lowed by a Bischler–Napieralski reaction. Direct
use of the naphthyl moiety in the amine as a key
building block in the natural product allowed us to
achieve the total synthesis of ancistrocladinium A
in only three steps from the known starting materi-
als.
Although most of the naphthylisoquinoline alka-
loids possess C,C-coupled linkages between the naph-
thalene and the isoquinoline fragments,[7] N,C-coupled
alkaloids such as ancistrocladiniums A and B have
been isolated recently (Figure 1).[8–10] Considering the
fact that N,C-coupled naphthylisoquinoline alkaloids
possess an N-aryl moiety, we envisioned that these al-
kaloids could be prepared via the chiral phosphoric
acid-catalyzed reductive amination of a ketone with
a naphthylamine carrying appropriate substituents,
provided that the stereogenic center at the C-3 posi-
tion in the dihydroisoquinoline ring could be con-
trolled in this asymmetric protocol.
Keywords: ancistrocladinium A; chiral phosphoric
acid catalysis; naphthylisoquinoline alkaloids; re-
ductive amination; total synthesis
Herein, we present a new application of chiral
phosphoric acid-catalyzed asymmetric reductive ami-
nation of 1-aryl-2-propanone 3 with naphthylamine 4
where the naphthyl moiety present in the amine was
During the past decade, we have witnessed an in-
creased interest in the chiral phosphoric acid-cata-
lyzed asymmetric reduction of ketimines, derived
from ketones and an aniline derivative A, using or-
ganic hydride sources such as Hantzsch ester and ben-
zothiazolines.[1–4] Most of the previous approaches
have focused on the preparation of chiral primary
amines II by removing the aryl group from the result-
ing chiral secondary amines I (Scheme 1a). Since elec-
tron-rich aryl moieties are necessary for the deprotec-
tion from I under oxidative conditions, the use of
amines A has been limited to electron-rich aryl-
ACHTUNGTRENNUNGamines, particularly para-methoxyphenylamine, and
other types of aniline derivatives have been rarely in-
vestigated in this asymmetric transformation.[5,6]
In contrast to the conventional approach, we envis-
aged that if an aryl group in amine A used in the
chiral phosphoric acid-catalyzed asymmetric reductive
amination of ketones could be directly utilized as
a building block in chiral compounds rather than as
a removable protecting group, the application of this
asymmetric transformation could be significantly ex-
panded to the synthesis of important chiral natural
products, in particular ones bearing N-aryl moieties
(Scheme 1b).
Scheme 1. (a) Previous work: removal of an aryl group gen-
erating primary amines II. (b) Our work: utilization of an
aryl group as a key building block.
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Scheme 2. Retrosynthetic analysis for ancistrocladinium A
(1).
Figure 1. Representative examples of naphthylisoquinoline
alkaloids with different coupling types.
Bischler–Napieralski reaction. Chiral amine 2 could
be synthesized via the chiral phosphoric acid-cata-
lyzed asymmetric reductive amination of ketone 3
directly utilized as a key building block of ent-ancis- and naphthylamine 4.[12,13]
trocladinium A (ent-1) via chiral phosphoric acid-cat-
However, a few concerns were raised at the initial
alyzed asymmetric reductive amination followed by stages of our synthesis. Although a PMP amine has
Bischler–Napieralski reaction. Direct use of the naph- been widely utilized in the chiral phosphoric acid-cat-
thalene moiety in the amine as a key building block alyzed asymmetric reductive amination of ketones
in the natural product enabled us to complete the leading to the corresponding chiral amines in high
total synthesis of ent-1 in only three steps from the enantioselectivity, there have been no reports on the
known starting materials.
chiral phosphoric acid-catalyzed asymmetric reductive
The first total synthesis of ancistrocladinium A (1) amination of ketones with a naphthylamine. Thus,
was reported by the Bringmann group in 2010.[9b] The both the reactivity and the enantioselectivity in the
À
N C bond formation via the Buchwald–Hartwig ami- chiral phosphoric acid-catalyzed reductive amination
nation of naphthyl bromide with (S)-1-aryl-2-propyla- of ketone 3 with naphthylamine 4 were potential
mine, which was prepared from naturally occurring major concerns. In addition, since naphthylamine 4
chiral l-alanine in five steps,[11] provided (S)-N-naph- was reported to be unstable and undergo decomposi-
thyl-1-aryl-2-propylACHTNUTGRNEUNG
amine. Subsequent formation of tion under ambient conditions,[8a] the stability of 4
the dihydroisoquinoline ring via Bischler–Napieralski presented another concern. Furthermore, since the
reaction completed the synthesis of 1. However, the atropo-epimer of ancistrocladinium A, (P)-1, was not
previous synthesis started with a chiral pool (e.g., a- prepared as the major product in the previous synthe-
amino acid) to control the stereogenic center at the sis, althouth (P)-1 was obtained as the minor atro-
C-3 position in the dihydroisoquinoline moiety, and poisomer along with (M)-1 as an inseparable mixture,
there have been no reports on the total synthesis of our third concern was whether we could prepared
1 via catalytic asymmetric transformations. Further- both (M)-1 and (P)-1, respectively.
more, although in the previous synthesis of 1, the nat-
Keeping these anticipated challenges in mind, we
urally predominant (M)-isomer of ancistrocladinium began the total synthesis of ancistrocladinium A (1)
A, (M)-1, was obtained as the major atropo-isomer by optimizing the chiral phosphoric acid-catalyzed
along with its atropo-epimer, (P)-1, as an inseparable asymmetric reductive amination of ketone 3 with
mixture in a ratio of 2.5:1, no attempts to prepare naphthylamine 4 (Table 1). Since naphthylamine 4
(P)-1 have been made and no general guidelines for was reported to be unstable, and N-Boc-protected
the synthesis of (P)-1 have been provided.
naphthylamine 5 was reported to be stable,[9a] we first
Our retrosynthetic analysis for ancistrocladinium A attempted to utilize 5 as a precursor for 4. Particular-
(1) is depicted in Scheme 2. Ancistrocladinium A (1) ly, if the Boc group in 5 could be removed by a rela-
could be prepared from chiral amine 2 through the tively strong chiral phosphoric acid, naphthylamine 4
formation of the dihydroisoquinoline ring via a could be generated in situ from 5, and be directly
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Table 1. Investigation of the reaction parameters.
removal of the Boc group from 5 with trifluoroacetic
acid (TFA). When 5 was treated with TFA, the cleav-
1
age of the Boc group in 5 was evident in the H NMR
analysis of a crude mixture, but 4 underwent decom-
position during the purification process, preventing us
from isolating free amine 4 in a pure form. Thus, we
decided to directly subject the resulting free amine 4
to the asymmetric reductive amination without fur-
ther purification.[13] When the crude sample of 4 was
directly subjected to the asymmetric reductive amina-
tion of ketone 3 using Hantzsch ester as an organic
hydride source with phosphoric acid 6a, to our de-
light, the formation of amine 2 was observed at 908C
after 40 h, albeit in a moderate yield and with low
enantioselectivity (entry 2). With this result in hand,
we then investigated several chiral phosphoric acids 6
derived from chiral BINOL derivatives bearing differ-
ent aryl substituents at the 3,3’-positions on the
BINOL framework (entries 2–8). Among the phos-
phoric acids 6 tested, 6g bearing 4-mesityl-2,6-dime-
thylphenyl substituents at the 3,3’-positions was
chosen for further investigation since 6g provided the
desired amine 2 with the highest enantioselectivity
(57% ee, entry 8).
With 6g as the optimal catalyst, we further investi-
gated the effect of a dehydration agent in this asym-
metric amination reaction. Changing a dehydration
agent from 4ꢁ molecular sieves into 5ꢁ molecular
sieves slightly improved the enantioselectivity (en-
tries 8 and 9). The reaction medium turned out to
strongly affect the outcome of this transformation;
the reaction performed in tert-butyl methyl ether
(TBME) provided the desired product 2 in a much
better enantioselectivity than that carried out in tolu-
ene (entry 10). Lowering the reaction temperatures
had a slightly beneficial influence on the enantioselec-
tivity to provide 2 in 80% ee at 408C (entry 11). Final-
ly, reaction in a dilute concentration (0.050M) slightly
improved the enantioselectivity, affording 2 in 82% ee
(entry 12). Under these optimized conditions,[14] this
transformation could be carried out on a 1.0 mmol
scale to provide 2 in 76% yield in 85% ee (entry 13).
The absolute stereochemistry of the resulting amine 2
was assigned as the (R)-configuration by comparing
the optical rotation of amine 2 with the reported
value.[15]
[a]
4 was prepared by the treatment of 5 with TFA, followed
by basification with NaOH, extraction with dichlorome-
thane, and concentration. The crude mixture of 4 was
used directly in the reductive amination.
[b]
Isolated yield.
[c]
Enantiomeric excess (ee) was determined by HPLC anal-
ysis using a chiral AS-H column.
Boc-protected naphthylamine 5 was used.
No reaction.
Not determined.
The other enantiomer was obtained as the major prod-
uct.
At 508C.
[d]
[e]
[f]
[g]
[h]
[i]
At 408C.
Concentration of 0.050M.
1.0 mmol scale.
[j]
[k]
With ent-2 in hand, we attempted to complete the
total synthesis of ent-ancistrocladinium A (ent-1).
used in the reductive amination reaction. With this Since the atropo-epimer of ancistrocladinium A (P)-
expectation in mind, we first directly applied com- 1 has not been prepared in the previous synthesis, we
pound 5 to asymmetric reductive amination with were particularly interested in the preparation of both
ketone 3. However, no reaction was observed under of the atropo-diastereomers of ent-ancistrocladinium
these conditions, and 5 remained intact even after A if possible (Scheme 3). When ent-2 was subjected
a long reaction time (entry 1).
to acylation with acetyl chloride in the presence of
Since this result implied that a chiral phosphoric DMAP, to our delight, tertiary amide 7 and its rota-
acid is not acidic enough to deprotect the Boc-group mer 8 were obtained in 56% and 35% yields, respec-
in 5, we attempted to isolate naphthylamine 4 after tively, after column chromatography on silica.[16]
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ent-9 and (M)-ent-9 with a ratio of 1:3 was treated
with a solution of TFA in MeOH, the ratio of the two
atropo-diastereomers remained unchanged even after
24 h. However, when the same mixture was subjected
to the similar conditions in the presence of Sephadex,
the axial epimerization gradually took place to pro-
vide a mixture of (P)-ent-9 and (M)-ent-9 with a 2:1
ratio, respectively. Although the chiral axis in ancis-
trocladinium A is known to be configurationally sta-
ble,[9b] this result strongly suggested that the atropo-
epimerization could take place during the purification
with Sephadex and thus, a new purification protocol
must be designed for the better preparation of both
atropo-diastereomers of ancistrocladinium A.[14]
In conclusion, we have developed a new protocol
of chiral phosphoric acid-catalyzed reductive amina-
tion of ketone with arylamine where the aryl moiety
was utilized as a key building block in natural prod-
ucts bearing an N-aryl moiety. The utility of this ap-
proach was successfully demonstrated in the asym-
metric total synthesis of ent-ancistrocladinium A (ent-
Scheme 3. Total synthesis of ent-ancistrocladinium A (ent-1).
When compound 7 was treated with POCl3, ent-an- 1) via the chiral phosphoric acid-catalyzed asymmetric
cistrocladinium A [(P)-ent-9], carrying chloride as reductive amination of ketone 3 and naphthylamine 4
a counter anion, was obtained as the major product and subsequent Bischler–Napieralski reaction. Direct
along with its atropo-epimer [(M)-ent-9] in a 4:1 ratio use of the naththyl moiety in arylamine 4 as a key
in the crude mixture.[17–19] Rather unexpectedly, ero- building block in the synthesis of ent-1 allowed us to
sion of atropo-purity was observed during the purifi- complete this total synthesis in only three steps from
cation process with Sephadex to afford a mixture of the reported starting materials. Furthermore, we de-
(P)-ent-1 and (M)-ent-1 with a ratio of 2:1 in 81% scribed an unexpected atropo-epimerization along the
yield, which is similar to the ratio reported by the N,C-axis in ent-1 during the purification process with
Bringmann group.[9b] An even more unexpected, but Sephadex, which led to a mixture of the naturally oc-
disappointing, result was observed in the Bischler–Na- curring atropo-isomer and its atropo-epimer in the
pieralski cyclization of compound 8. Bischler–Napier- ratio of 2:1 regardless of the atropo-purity of the
alski reaction of 8 provided the atropo-epimer of ent- starting materials. Further applications of this proto-
ancistrocladinium A, (M)-ent-9, as the major product col to the asymmetric syntheses of other natural prod-
along with (P)-ent-9 in a ratio of around 3:1 in the ucts bearing N-aryl groups are currently underway in
crude mixture. Unfortunately, however, significant our laboratory and will be reported in due course.
atropo-epimerization occurred during the purification
with Sephadex to provide a mixture of (P)-ent-1 and
(M)-ent-1 in a ratio of 2:1 after the purification with
Sephadex, which was a similar ratio as that from the
Experimental Section
reaction with compound 7.
Procedure
With these unexpected results in hand, we explored
several reaction parameters to influence the atropo-
epimerization in ancistrocladinium A during the pu-
rification process with Sephadex. First, the effect of
a mixture of MeOH and TFA, used as an eluent
during the purification on Sephadex, on the axial epi-
To a solution of 5 (0.63 g, 2.0 mmol, 2.0 equiv.) in dichloro-
methane (5.0 mL) was added TFA (0.40 mL) and the reac-
tion mixture was stirred at room temperature and monitored
by TLC. After the complete consumption of 5, 1.0N NaOH
solution was slowly added to the reaction mixture until the
pH value of the crude mixture reached 11. The crude mix-
merization was investigated. When a mixture of (P)- ture was extracted with dichloromethane. The organic layers
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were combined, dried over MgSO4 and concentrated to
afford the crude product – naphthylamine 4 as dark brown
oil; yield: 0.27 g (1.2 mmol, 64%). The crude product of 4
was used for the chiral phosphoric acid-catalyzed asymmet-
ric reductive amination without further purification.
Int. Ed. 2006, 45, 3683; b) Z.-Y. Han, H. Xiao, X.-H.
Chen, L.-Z. Gong, J. Am. Chem. Soc. 2009, 131, 9182.
[5] A PMP group can be generally removed under oxida-
tive conditions: a) A. Cordova, Synlett 2003, 1651;
b) J. M. M. Verkade, L. J. C. Hemert, P. J. L. M. Quaed-
flieg, P. L. Alsters, F. L. Delft, F. P. J. T. Rutjes, Tetrahe-
dron Lett. 2006, 47, 8109; c) for an example of the re-
moval of a PMP moiety in the chiral amines, obtained
from chiral phosphoric acid catalysis, under oxidative
conditions, see: A. Henseler, M. Kato, K. Mori, T.
Akiyama, Angew. Chem. 2011, 123, 8330; Angew.
Chem. Int. Ed. 2011, 50, 8180.
[6] For the development of the asymmetric reductive ami-
nation of ketones with amines bearing a more easily re-
movable protecting group, see: V. N. Wakchaure, M.
Nicoletti, L. Ratjen, B. List, Synlett 2010, 2708.
[7] For reviews on naphthylisoquinoline alkaloids, see:
a) G. Bringmann, F. Pokorny, in: The Alkaloids, (Ed.:
G. A. Cordell), Academic Press, New York, 1995, Vol.
46, pp 127–271; b) S. R. M. Ibrahim, G. A. Mohamed,
Fitoterapia 2013, 91, 305; c) C. Jiang, Z. Li, P. Gong, S.
Kang, M. Liu, Y. Pei, Y. Jing, H. Hua, Fitoterapia 2015,
106, 194.
To a 50-mL round-bottom flask equipped with a stirring
bar were added ketone 3 (0.19 g, 1.0 mmol), Hantzsch ester
(0.37 g, 1.5 mmol), catalyst 6g (0.080 g, 0.10 mmol) and 5ꢁ
molecular sieves (1.0 g). Then, a solution of naphthylamine
4 in tert-butyl methyl ether (TBME) was added to the above
test tube. The reaction mixture was allowed to stir at 408C
and monitored by TLC. After all the ketone 3 was com-
pletely consumed, the reaction mixture was cooled to room
temperature, and filtered to remove molecular sieves. The
filtrate was concentrated and purified by column chromatog-
raphy on silica gel using hexanes/ethyl acetate (6:1) as an
eluent to provide the desired product 2 as light yellow oil;
yield: 0.31 g (0.78 mmol, 78%); 85% ee.
Acknowledgements
This work was supported by National Research Foundation
of Korea (NRF) grants funded by the Korean Government
(NRF-2013R1A1A1008434, NRF-20100020209 and NRF-
2015R1D1A1A01057200). C.-H.C. is also thankful for finan-
cial support from an NRF grant funded by the Korean Gov-
ernment (NRF-2014-011165, Center for New Directions in
Organic Synthesis).
[8] For the isolation of N,C-coupled naphthylisoquinoline
alkaloids, see: a) ancisheynine: L.-K. Yang, R. P.
Glover, K. Yonganathan, J. P. Sarnaik, A. J. Godbole,
D. D. Soejarto, A. D. Buss, M. S. Butler, Tetrahedron
Lett. 2003, 44, 5827; b) ancistrocladiniums A and B: G.
Bringmann, I. Kajahn, M. Reichert, S. E. H. Pedersen,
J. H. Faber, T. Gulder, R. Brun, S. B. Christensen, A.
Ponte-Sucre, H. Moll, G. Heubl, V. Mudogo, J. Org.
Chem. 2006, 71, 9348; c) G. Bringmann, B. Hertlein-
Amslinger, I. Kajahn, M. Dreyer, R. Brun, H. Moll, A.
Stich, K. N. Ioset, W. Schmitz, L. H. Ngoc, Phytochem-
istry 2011, 72, 89.
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mann, Angew. Chem. 2006, 118, 3765; Angew. Chem.
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[10] For the synthesis of N,C-coupled naphthylisoquinoline
alkaloid derivatives, see: A. Ponte-Sucre, T. Gulder, A.
´
Wegehaupt, C. Albert, C. Rikanovic, L. Schꢂflein, A.
Frank, M. Schultheis, M. Unger, U. Holzgrabe, G.
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[11] For the previous synthesis of this compound via the
ring-opening reaction of aziridine prior to the report in
ref.[8b], see: T. R. Hoye, M. Chen, Tetrahedron Lett.
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[12] For examples of the chiral phosphoric acid-catalyzed
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[13] An asymmetric reductive amination strategy has been
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AHCTUNGTREGiNNNU soquinoline alkaloids. However, all previous reports
relied on the preparation of chiral amines via the dia-
stereoselective reductive amination of ketone 3 with
chiral phenethylamine followed by the removal of the
chiral auxiliary from the reductive amination products;
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a) G. Bringmann, R. Weirich, H. Reuscher, J. R.
Jansen, L. Kinzinger, T. Ortmann, Liebigs Ann. Chem.
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might take place under the reaction conditions, a mix-
ture of the isolated atropisomers with a ratio of 4:1 was
re-subjected to the reaction conditions. However,
under such conditions, no interconversion of the two
atropisomers was observed and the ratio of the two iso-
mers mixture remained constant even after 12 h. For
details, please see the Supporting Information.
[14] For details, see the Supporting Information.
[15] The optical rotation ([a]2D0) value of 2 was found to be
À74 (c=0.13, CH3OH). Since this value has the oppo-
site sign to the reference value of (S)-2 {+51 (c=0.13,
CH3OH)}, we assigned the absolute stereochemistry of
2 as the (R)-configuration, despite the difference in
measured [a]2D0 value in comparison to the literature
value. For the reported [a]2D0 value of 2, see: ref.[8b]).
[16] The N,C-axes in tertiary amides 7 and 8 are configura-
tionally stable at temperatures below 508C. However,
they undergo isomerization at temperatures above
508C. For example, treatment of each amide (either 7
or 8) in toluene at 1008C for 6 h led to a mixture of 7
and 8 with a ratio of 1.4:1, regardless of the starting
amide. For details, please see the Supporting Informa-
tion.
[18] We also investigated the possibility of interconversion
of two atropisomers during the Bischler–Napieralski re-
action. However, there was no interconversion of the
two atropisomers during the reaction and the ratio of
two atropisomers did not change throughout the Bis-
chler–Napieralski reaction. For details, please see the
Supporting Information.
[19] The N,C-axes in the resulting atropisomers, (P)-ent-9
and (M)-ent-9, were configurationally stable at temper-
atures below 1008C. When a mixture of the isolated
two atropisomers with a ratio of 4:1 was treated at
1008C for 12 h, no change in the ratio of the two iso-
mers was observed. For details, please see the Support-
ing Information.
[17] In order to check whether interconversion between ini-
tially formed atropisomers, (P)-ent-9 and (M)-ent-9,
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Concise Asymmetric Total Synthesis of ent-
7
Ancistrocladinium A
Adv. Synth. Catal. 2016, 358, 1 – 7
Kyung-Hee Kim, Cheol-Hong Cheon*
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