Relay catalysis by a ruthenium complex-chiral bronsted acid binary sytem for ternary reaction sequence involving enantioselective pictet-spengler-type cyclization as the key step

Article abstract of DOI:10.1055/s-0032-1318302

Relay catalysis for a ternary reaction sequence composed of double-bond isomerization, protonation of the double bond, and enantioselective Pictet-Spengler-type cyclization was accomplished using a binary catalytic system consisting of a ruthenium hydride complex and a chiral phosphoric acid as the chiral Bronsted acid catalyst. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0032-1318302

752▌
LETTER
lRetteerlay Catalysis by a Ruthenium Complex–Chiral Brønsted Acid Binary Sytem
for Ternary Reaction Sequence Involving Enantioselective Pictet–Spengler-
Type Cyclization as the Key Step
Relay Catalysis Using a Binary Catalytic System
Yasunori Toda,a Masahiro Terada*a,b
a
Department of Chemistry, Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980-8578, Japan
Fax +81(22)7956602; E-mail: mterada@m.tohoku.ac.jp
b
Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980-8578, Japan
Received: 04.01.2013; Accepted after revision: 01.02.2013
of enamide 4 by chiral phosphoric acid 2 to generate reac-
Abstract: Relay catalysis for a ternary reaction sequence composed
tive iminium ion intermediate A;7 and (iii) subsequent 6-
of double-bond isomerization, protonation of the double bond, and
endo-trig cyclization under the influence of chiral conju-
enantioselective Pictet–Spengler-type cyclization was accom-
plished using a binary catalytic system consisting of a ruthenium
gate base 2– to afford tetrahydroisoquinoline derivative 5
hydride complex and a chiral phosphoric acid as the chiral Brønsted in an optically active form.8
acid catalyst.
G
Ph
O
Key words: asymmetric catalysis, isomerization, protonation, cy-
clization, phenols
O
O
O
P
P
OH
OH
O
O
The combined use of a transition-metal catalyst and an or-
ganocatalyst has stimulated intensive interest in recent
years1 as it may potentially enable highly efficient and/or
unprecedented transformations in a one-pot operation. In-
deed, excellent approaches have been established by tak-
ing advantage of both of these catalytic approaches.
Meanwhile, two types of combinations have been devel-
oped in the binary catalytic system. One is the simultane-
ous activation of two reactants by their respective
catalysts; for instance, a metal catalyst is used to activate
a nucleophile while an organocatalyst is used to activate
an electrophile in a cooperative manner.2 The other is the
consecutive transformation using a binary catalytic sys-
tem, that is, relay catalysis for a multistep sequence in
which each catalyst promotes one type of reaction in a
one-pot sequential manner.3 Recently, we demonstrated
relay catalysis by a ruthenium complex–Brønsted acid bi-
nary system in a tandem isomerization and carbon–carbon
bond-forming sequence.3a The relay catalysis enables al-
lylamides to generate imines in situ for further transfor-
mations. However, to the best of our knowledge, the
enantioselective version of the analogous relay catalysis
has never been reported. In this communication, we report
a relay catalysis for a ternary reaction sequence composed
of double-bond isomerization, protonation of the double
bond, and enantioselective Pictet–Spengler-type cycliza-
tion using a binary catalytic system consisting of rutheni-
um hydride complex 1 and chiral phosphoric acid 2 as the
chiral Brønsted acid catalyst4,5 (Scheme 1). The ternary
reaction sequence accomplished by the proposed relay ca-
talysis involves: (i) isomerization of allylamide 3 by ru-
thenium hydride complex 1 to enamide 4;6 (ii) protonation
G
Ph
6
(R)-2
HO
R2
HO
R2
isomerization
[Ru-H] complex 1
N
N
R1
R1
R1 = EWG
R3
R3
3
4
protonation
relay catalysis
chiral phosphoric acid 2
HO
R2
HO
6-endo-trig
cyclization
N
N+
R1
R1
R2
R3
R3
2–
5
A
Scheme 1 Ternary reaction sequence mediated by ruthenium com-
plex–chiral Brønsted acid binary catalytic system
The Pictet–Spengler reaction is a powerful and efficient
methodology to synthesize tetrahydroisoquinoline or β-
carboline derivatives and has been utilized as the key step
for the synthesis of natural and unnatural alkaloids.9 In the
past decade, tremendous progress has been made in or-
ganocatalytic approaches to the Pictet–Spengler reaction.
Indeed, excellent methods for the enantioselective version
have been realized by either chiral thiourea catalysts or
chiral phosphoric acid catalysts.10,11 In most cases, how-
ever, indole subunits have been employed as the highly
nucleophilic component.10d,11f To broaden the scope of
this fascinating transformation, we envisioned the devel-
SYNLETT 2013, 24, 0752–0756
Advanced online publication: 27.02.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1318302; Art ID: ST-2013-U0012-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Relay Catalysis Using a Binary Catalytic System
753
opment of the Pictet–Spengler-type cyclization of m-tyr- lay catalysis, we combined the established process with
amine derivative 4 having a phenol subunit as the the first step of the ternary reaction sequence, that is, the
nucleophilic component, which has been scarcely em- isomerization of 3 in a one-pot sequential manner. Table
ployed in the catalytic enantioselective version of the 2 summarizes experiments carried out to probe the scope
Pictet–Spengler reaction. It seems that the combined use of the relay catalysis.13,14 In all cases, products 5 were ob-
of chiral phosphoric acid 2 and ruthenium hydride com- tained in moderate to good yields. Investigation of the
plex 1 for the isomerization of 3 would enable us to gen- substituent effect on the aromatic ring (R2) showed that
erate iminium ion intermediate A as the highly high chemical yield and enhanced enantioselectivity were
electrophilic species via the isomerization–protonation observed by the introduction of a methoxy group (Table 2,
sequence in a one-pot operation.
entry 2).15
To ascertain the feasibility of the proposed relay catal-
ysis, we initially attempted the reaction of N-Cbz-
protected m-tyramine derivative 3a using 2 mol% of
[RuClH(CO)(PPh3)3] (1) and 5 mol% of racemic phos-
phoric acid 6 in toluene at 50 °C for 12 hours (Scheme 2).
To our delight, the binary catalytic reaction proceeded
smoothly to afford the desired tetrahydroisoquinoline de-
rivative 5a in fairly good yield, where the intermediary
iminium ion underwent the cyclization at the para posi-
tion of the phenol moiety. Indeed, the ruthenium com-
plex–Brønsted acid binary catalytic system enabled us to
establish the present ternary reaction sequence. This pre-
liminary result prompted us to further develop the enan-
tioselective version of the present relay catalysis.
Table 1 Optimization of Pictet–Spengler-Type Cyclization: Screen-
ing for N-Protecting Groupsa
HO
HO
(R)-2 (G = 9-anthryl)
(5 mol%)
N
N
R1
R1
toluene (0.2 M)
r.t.
4 (E/Z mixture)
5
a R1 = Cbz
b R1 = Boc
c R1 = P(O)(OEt)2
d R1 = P(O)(OPh)2
e R1 = P(O)(CH2)5
f R1 = P(O)Ph2
Entry
4
Time (h)
5
Yield (%)b ee (%)c
1
4a
4b
4c
4d
4e
4f
12
12
24
24
24
24
5a
5b
5c
5d
5e
5f
67
77
63
61
58
81
24
44
38
16
14
47
2
[RuClH(CO)(PPh3)3] (1)
3
(2 mol%)
phosphoric acid 6
HO
HO
4
(5 mol%)
N
N
Cbz
Cbz
5d
6d
toluene (0.2 M)
50 °C, 12 h
3a
5a 66%
a Unless otherwise noted, all reactions were carried out using 0.0075
mmol of (R)-2 (5 mol%) and 0.15 mmol of 4 in 0.75 mL of toluene.
b Isolated yield of 5.
Scheme 2
c Determined by chiral stationary phase HPLC analysis. The absolute
configuration at the C1 position of 5 was determined to be S by com-
paring the optical rotation with the reported data after derivatization.
d Isolated yields and ee were determined after derivatization of prod-
uct 5 to benzoate 7 (Scheme 3).
Before demonstrating the enantioselective version of the
relay catalysis, we attempted the transformation of en-
amides 4 into tetrahydroisoquinoline derivatives 5 via the
protonation–Pictet–Spengler-type cyclization sequence
using chiral phosphoric acid 2. The reaction was conduct-
ed using 5 mol% of chiral phosphoric acid (R)-2 (G = 9-
anthryl) in toluene at room temperature. As expected, the
reaction proceeded smoothly to afford product 5a albeit
with low enantioselectivity (Table 1, entry 1). To enhance
the enantioselectivity, a range of N-protecting groups (R1)
were investigated. As shown in Table 1, N-Boc amide im-
proved both chemical yield and enantioselectivity (entry
2).12 Further screening for the N-protecting group, such as
phosphoryl groups, resulted in a subtle change in the ste-
reochemical outcome. Among the N-protecting groups
tested, diphenylphosphinamide 4f exhibited a slightly
higher chemical yield and enantioselectivity (Table 1, en-
try 6). In terms of the removability of the N-protecting
group, N-Boc amide and diphenylphosphinamide were
employed for subsequent investigation of the enantiose-
lective relay catalysis.
BzCl, Et3N
BzO
DMAP (cat.)
5
N
R1
toluene–CH2Cl2
r.t., 12 h
7
Scheme 3
Crotylamides 3h and 3i were also applicable to the present
reaction, although the enantioselectivities were reduced
presumably due to the high reaction temperature (Table 2,
entries 3 and 4). The reaction of 3j having dimethyl sub-
stituents at the terminal position of the double bond re-
quired harsh conditions for the isomerization, affording
the product in a modest chemical yield with low enantio-
selectivity (Table 2, entry 5). The introduction of diphe-
nylphosphinamide as the N-protective group resulted in
the formation of products 5 in good yields albeit with low-
Having identified the last two steps of the ternary reaction
sequence, namely protonation and enantioselective cycli-
zation, in an effort to accomplish the enantioselective re-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 752–756

754
Y. Toda, M. Terada
LETTER
Table 2 Scope of the Relay Catalysisa
[RuClH(CO)(PPh3)3] (1)
(x mol%)
(R)-2 (G = 9-anthryl)
(y mol%)
HO
R2
HO
R2
N
N
R1
R1
R4
R4
toluene (0.2 M)
R3
R3
3
5
Entry
3
1 (mol%) (R)-2 (mol%) Temp (°C) Time (h)
5
Yield (%)b ee (%)c
1
3b R1 = Boc, R2 = R3 = R4 = H
2
2
3
3
7
3
3
5
5
5
5
8
5
5
50
50
12
12
24
24
24
24
24
5b
5g
5h
5i
62
80
78
79
50
87
72
37
53
27
33
18
28
20
2
3g R1 = Boc, R2 = MeO, R3 = R4 = H
3h R1 = Boc, R2 = H, R3 = Me, R4 = H
3
110
110
160
60
4
3i R1 = Boc, R2 = MeO, R3 = Me, R4 = H
3j R1 = Boc, R2 = H, R3 = Me, R4 = Me
3f R1 = P(O)Ph2, R2 = R3 = R4 = H
5
5j
6d
7d
5f
3k R1 = P(O)Ph2, R2 = H, R3 = Me, R4 = H
110
5k
a Unless otherwise noted, all reactions were carried out using 0.20 mmol of 3 in 1.0 mL of toluene.
b Isolated yield of 5.
c Determined by chiral stationary phase HPLC analysis.
d Isolated yields and ee were determined after derivatization of product 5 to benzoate 7 (Scheme 3).
er enantioselectivities than that observed using the N-Boc reochemical outcome and the development of other types
group (Table 2, entries 6 and 7).
of enantioselective relay catalysis are in due course.
The distinct advantage of the present relay catalysis is
highlighted by comparison with a control experiment us-
ing amide 8 (Table 2, entry 6 vs. Scheme 4).16 The reac-
tion of propionaldehyde (9) with 8 in the presence of acid
2 resulted in a considerable amount of 8 that remained un-
changed. It can be considered that the condensation reac-
tion of aldehyde 9 with amide 8 does not favor the
generation of an iminium intermediate, because the nu-
cleophilicity of the nitrogen atom of 8 is considerably re-
duced by the introduction of the electron-withdrawing and
sterically demanding phosphinyl group.
Acknowledgment
This work was partially supported by a Grant-in-Aid for Scientific
Research on Innovative Areas ‘Advanced Molecular Transforma-
tions by Organocatalysts’ from MEXT, Japan and a Grant-in-Aid
for Scientific Research (Grant No. 20245021) from the JSPS. We
also thank the JSPS for a research fellowship for Young Scientists
(Y.T.).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
EtCHO (9) (1.5 equiv)
(R)-2 (G = 9-anthryl)
HO
HO
References and Notes
(5 mol%)
HN
N
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R1
R1
toluene (0.2 M)
60 °C, 24 h
8 R1 = P(O)Ph2
<5% conversion
5f
Scheme 4
In conclusion, we have demonstrated a relay catalysis for
a ternary reaction sequence composed of double-bond
isomerization, protonation of the double bond, and enan-
tioselective Pictet–Spengler-type cyclization using a bina-
ry catalytic system consisting of a ruthenium hydride
complex and a chiral phosphoric acid as the chiral Brøn-
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© Georg Thieme Verlag Stuttgart · New York

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To a dried test tube were added (R)-2 (G = 9-anthryl; 5
mol%, 7.01 mg) and 3b (55.5 mg, 0.20 mmol). The mixture
was dissolved in toluene (1.0 mL), and then the atmosphere
was replaced with argon. [RuClH(CO)(PPh3)3] (1) (2 mol%,
3.81 mg) was added in portion at r.t., and the tube was
flushed again with argon. After stirring at 50 °C for 12 h, the
reaction mixture was diluted with sat. aq NaHCO3 and
extracted with CH2Cl2 (3×). The combined organic layers
were dried over Na2SO4, filtered, and concentrated. After
purification by flash column chromatography on silica gel
(hexane–EtOAc = 10:1 to 2:1 as eluent), 5b was obtained in
62% yield as a white solid. The ee of 5b was determined by
chiral stationary phase HPLC analysis.
Compound 5b: white solid; Rf = 0.50 (hexane–EtOAc = 2:1).
HPLC analysis Chiralpak IA (hexane–2-PrOH = 90:10, 0.8
mL/min, 254 nm, 30 °C): tR (major) = 10.1 min; tR (minor) =
12.5 min (37% ee); [α]D26 +24.5 (c 1.1, CHCl3); rotamer
(major/minor = 60:40) was observed. 1H NMR (500 MHz,
CDCl3): δ = 0.95–0.97 (3 H, m), 1.48 (9 H, s), 1.68–1.80 (2
H, m), 2.64–2.67 (1 H, m), 2.81–2.89 (1 H, m), 3.12–3.14
(0.60 H, m), 3.26–3.30 (0.40 H, m), 3.89–3.91 (0.40 H, m),
4.14–4.16 (0.60 H, m), 4.86–4.99 (2 H, m), 6.59 (1 H, s),
(d) Krompiec, S.; Pigulla, M.; Kuźnik, N.; Krompiec, M.;
Baj, S.; Mrowiec-Bialoń, J.; Kasperzyk, J. Tetrahedron Lett.
2004, 45, 5257. (e) Formentín, P.; Gimeno, N.; Steinke, J. H.
G.; Vilar, R. J. Org. Chem. 2005, 70, 8235. (f) Krompiec, S.;
Pigulla, M.; Kuźnik, N.; Krompiec, M.; Marciniec, B.;
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 752–756

756
Y. Toda, M. Terada
LETTER
6.64–6.68 (1 H, m), 6.96–6.97 (1 H, m). 13C NMR (125.65
MHz, CDCl3): δ = 10.88, 11.18, 28.44, 28.66, 29.73, 30.09,
37.01, 38.48, 55.24, 56.08, 79.86, 80.19, 113.49, 114.98,
115.10, 128.00, 128.30, 129.29, 129.51, 135.21, 135.46,
154.73, 154.83, 155.38, 155.46. IR (ATR): 3330, 2971,
2932, 2875, 1687, 1656, 1613, 1427, 1232, 1160, 918, 863
cm–1. ESI-HRMS: m/z calcd for C16H23NO3Na [M + Na]+:
300.1570; found: 300.1569.
+49.7 (c 1.2, CHCl3); rotamer (major/minor = 55:45) was
observed. 1H NMR (500 MHz, CDCl3): δ = 0.98–0.99 (3 H,
m), 1.48 (9 H, s), 1.71–1.80 (2 H, m), 2.57–2.61 (1 H, m),
2.74–2.86 (1 H, m), 3.09–3.13 (0.55 H, m), 3.23–3.27 (0.45
H, m), 3.85–3.92 (3.45 H, m), 4.16–4.18 (0.55 H, m), 4.84–
4.86 (0.55 H, m), 4.96–4.98 (0.45 H, m), 5.53 (1 H, brs), 6.57
(1 H, s), 6.65–6.66 (1 H, m). 13C NMR (125.65 MHz,
CDCl3): δ = 10.85, 11.09, 27.64, 27.78, 28.31, 29.57, 29.96,
36.62, 38.33, 55.06, 55.84, 79.22, 79.51, 109.29, 109.63,
114.21, 114.46, 126.52, 126.81, 129.15, 129.51, 144.06,
144.16, 144.95, 145.03, 154.92, 155.04; IR (ATR): 3369,
2969, 2932, 2842, 1683, 1515, 1420, 1364, 1271, 1241,
1111, 932, 863 cm–1. ESI-HRMS: m/z calcd for
(14) The reaction of the product 5b with ruthenium complex 1
and chiral phosphoric acid 2 under the same reaction
conditions (50 °C, 12 h). 5b was recovered quantitatively,
and no racemization of 5b was observed.
(15) (a) The absolute configuration was determined to be S by
optical rotation after derivatization to (S)-1-ethyl-6,7-
dimethoxy-1,2,3,4-tetrahydroisoquinoline: [α]D24 –24.2 (c
2.2, CH2Cl2); literature value of S-isomer [α]D20 –51.9 (c 2.1,
CH2Cl2). See: Polniaszek, R. P.; Kaufman, C. R. J. Am.
Chem. Soc. 1989, 111, 4859. (b) Compound 5g: white solid;
Rf = 0.45 (hexane–EtOAc = 2:1). HPLC analysis Chiralpak
IA (hexane–EtOH = 96:4, 1.0 mL/min, 254 nm, 30 °C): tR
C17H25NO4Na [M + Na]+: 330.1676; found: 330.1675.
(16) Kobayashi and co-workers showed that the Pictet–Spengler
reaction of benzaldehyde with m-tyramine using Brønsted
acids, such as sulfonic acid and carboxylic acid, gave the
corresponding product in low yield, see: Manabe, K.;
Nobutou, D.; Kobayashi, S. Bioorg. Med. Chem. 2005, 13,
5154.
25
(minor) = 11.3 min; tR (major) = 21.9 min (53% ee); [α]D
Synlett 2013, 24, 752–756
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