Intramolecular tsujitrost-type allylation of carboxylic acids: Asymmetric synthesis of highly π-allyl donative lactones

Article abstract of DOI:10.1021/jacs.5b05786

TsujiTrost-type asymmetric allylation of carboxylic acids has been realized by using a cationic CpRu complex with an axially chiral picolinic acid-type ligand (Cl-Naph-PyCOOH: naph = naphthyl, py = pyridine). The carboxylic acid and allylic alcohol intramolecularly condense by the liberation of water without stoichiometric activation of either nucleophile or electrophile part, thereby attaining high atom- and step-economy, and low E factor. This success can be ascribed to the higher reactivity of allylic alcohols as compared with the allyl ester products in soft Ru/hard Br?nstead acid combined catalysis, which can function under slightly acidic conditions unlike the traditional Pd-catalyzed system. Detailed analysis of the stereochemical outcome of the reaction using an enantiomerically enriched D-labeled substrate provides an intriguing view of enantioselection.

Full text of DOI:10.1021/jacs.5b05786

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Intramolecular Tsuji-Trost-type Allylation of Carboxylic Ac-
ids: Asymmetric Synthesis of Highly π-Allyl Donative Lac-
tones
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Yusuke Suzuki, Tomoaki Seki, Shinji Tanaka, and Masato Kitamura*
Graduate School of Pharmaceutical Sciences, Graduate School of Science, and Research Center for Materials Science,
Nagoya University, Chikusa, Nagoya 464-8601
Supporting Information Placeholder
Scheme 1. Synthetic processes to alkenyl lactones by
catalytic asymmetric intramolecular Tsuji-Trost-type
allylation.
ABSTRACT: Tsuji-Trost-type asymmetric allylation of car-
boxylic acids has been realized by using a cationic CpRu com-
plex with an axially chiral picolinic acid-type ligand (Cl-Naph-
PyCOOH: naph = naphthyl, py = pyridine). The carboxylic acid
and allylic alcohol intramolecularly condense by the liberation
of water without stoichiometric activation of either nucleo-
phile or electrophile part, thereby attaining high atom- and
step-economy, and low E factor. This success can be ascribed
to the higher reactivity of allylic alcohols as compared with
the allyl ester products in soft Ru/hard Brønstead acid com-
bined catalysis, which can function under slightly acidic condi-
tions unlike the traditional Pd-catalyzed system. Detailed
analysis of the stereochemical outcome of the reaction using
an enantiomerically enriched D-labeled substrate provides an
intriguing view of enantioselection.
X
OM
–MX
*
O
excellent
π-allyl
M: metal ion
O
X: halide, acetoxy etc.
donor
II
O
I
–H2O
OH
high functional
convertibility
OH
O
III
PF6
O H+
PF6
O
O
O
–
Optically active lactones represent a ubiquitous motif
found in natural products and pharmaceuticals,1 and are also
valuable chiral starting materials for asymmetric syntheses.2
In particular, as shown in Scheme 1, simple lactones I with an
allyloxycarbonyl moiety attract much attention from organic
synthetic chemists because of their high functional converti-
bility. Among many excellent catalytic enantioselective ap-
proaches to asymmetric lactone synthesis including intramo-
lecular hydrocarboxylation of allenes,3 Wacker-type oxidative
cyclization of alkenylalkanoic acids,4 dearomative oxidative
spirolactonization,5 ring closure of o-iodobenzoates with al-
dehydes,6 and [2+2] cycloaddition of ketenes and aldehydes,7
intramolecular Tsuji-Trost-type allylation of carboxylate II
seems to be the most tangible, but it is limited to only a
specific case.8 This may be ascribed mainly to the fact that the
alkenyl lactone I is an excellent π-allyl donor, as Trost demon-
strated the utility of I in the Pd-catalyzed synthesis of the α-
tocopherol side chain in 1979 at a very early stage of Tsuji-
Trost chemistry.9
R
N
R
N
Ru II
RuIV
Cl
Cl
(R)-1
(R)-2
(R)-Cl-Naph-PyCOOH/CpRu complexes
Naph: naphthalene, Py: pyridine
tive C-,10 N-,11 O-,12 and S-allylation13 under slightly acidic
conditions,"14 the CpRu(II)/Cl-Naph-PyCOOH15 combined
catalyst 1 and its π-allyl complex 2,16 which were designed on
the basis of the intramolecular redox-mediated donor-
acceptor bifunctional catalyst (Intramol-RDACat),14a,17 were
applied to the process III to I.
The results are summarized in Table 1. In the presence of
1 mol% of (R)-1 or its π-allyl complex (R)-2,16 the reaction of
(E)-3 successfully proceeded in N,N-dimethylacetamide
(DMA) at 100 °C to give, after 20 min, the γ-ethenyl-
substituted γ-lactone 4 in a quantitative yield with an S/R
enantiomer ratio (er) of 99:1 (entries 1 and 2). With a sub-
strate/catalyst (S/C) ratio of 500, the enantioselectivity de-
creased to 97:3 and the reaction required 5 h to realize 98%
yield (entry 3). At 50 °C, the reaction also gave an er of 99:1,
but it took 15 h to reach completion (entry 4). The solvents
DMA, DMF, t-BuOH, and THF attained er ratios of 94:6–99:1
(entries 5, 6, and 9), whereas acetone, CH2Cl2, toluene, and i-
The aim of the present study was to realize the more direct
process of "III to I," in which the carboxylic acid and allylic
alcohol dehydratively condense without stoichiometric activa-
tion of either nucleophile or electrophile, thereby satisfying
the criteria of high atom-economy and step-economy, and low
E factor. As part of an ongoing project of "catalytic dehydra-
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Table 1. Asymmetric Dehydrative Lactonization of (E)-3
Catalyzed by (R)-1 or (R)-2a
Table 2. Scope and Limitation of (R)-2-Catalyzed
Asymmetric Lactone Synthesisa
1
Substrate
Product
er (S:R)
time
(h)
Yield
(%)
2
3
4
5
6
7
8
9
S
R
OH
(R)-1 or -2
+
O
O
OH
O
OH
(E)-3
O
O
1d
2
10
97
93
97:3
O
(S)-4
(R)-4
O
OH
O
(S)-4
(E)-3
solvent
time (h)
yield (%)b
er (S:R)c
99:1
OH
1
DMA
DMA
0.3
0.3
5
>99
>99
98
O
1.5
12:88
2
3d
4e
5
99:1
O
O
OH
(R)-4
10
11
12
13
14
15
16
17
18
19
20
21
22
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24
25
26
27
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
DMA
97:3
(Z)-3
DMA
15
1
>99
>99
>99
70
99:1
3
2
1
OH
DMF
98:2
3
4
1
90
91
99:1
96:4
O
6
t-BuOH
acetone
CH2Cl2
THF
1
97:3
O
OH
O
7
15
3
85:15
54:46
94:6
3
1
OH
2
8
>99
>99
75
24
O
O
OH
O
9
2
10
toluene
15
75:25
OH
5
4
92
14:86
aCatalyts (R)-1 and (R)-2 were prepared in situ by mixing
[RuCp(CH3CN)3]PF6 with (R)-Cl-Naph-PyCOOH and (R)-Cl-Naph-
PyCOOCH2CH=CH2, respectively. Reactions were carried out in a 1-
mmol scale under the conditions of [(E)-3] = 100 mM and [(R)-1] or [(R)-
2] = 1 mM (1 mol%) in a 100-°C oil bath unless otherwise specified.
Except for entry 1, (R)-2 catalyst was used. b1H-NMR yield. Determined
by GC analysis.18 d[(E)-3] = 500 mM and [(R)-2] = 1 mM (0.2 mol%).
O
O
OH
O
OH
6e
7e
10
10
32f
90
98:2g
99:1g
O
OH
c
O
O
OH
e50 °C.
C6H5
C6H5
O
C6H5
OH
C6H5
O
O
PrOH led to decreased reactivity and/or selectivity (entries 7,
8, and 10). No reaction occurred in CH3CN.18
OH
8
0.5
1
88h
95
98:2
O
OH
The scope and limitations of the reaction are shown in
Table 2. First, the validity of the present reaction was con-
firmed in a 10-g scale reaction with S/C = 500 (entry 1).18
When the C=C double bond stereochemistry of 3 was switched
from E to Z, the stereochemical outcome was altered and the
enantioselectivity was decreased to 12:88 (entry 2) (vide in-
fra). Introduction of a methyl substituent either at either C(2)
or C(3) of the allylic alcohol moiety in (E)-3 was acceptable,
giving nearly optically pure hop lactone19 and lavender lac-
tone20 (entries 3 and 4). The high enantiocontrol of the oxy-
gen-containing tetra-substituted carbon center is noteworthy.
An isobenzofuranone derivative was also prepared from cin-
namyl alcohol-type substrate, although the enantioselectivity
was lower at 86:14 (entry 5). The er at the 16% conversion
stage was 92:8, indicating this particular product racemizes,
probably via a carbocation intermediate, under acidic condi-
tions. Elongation of the tether of (E)-3 by one methylene led
to oligomerization of the initially formed δ-ethenyl-δ-
valerolactone and diene formation,21 giving the desired δ-
lactone with a 98:2 er in 32% yield (entry 6). Introduction of
two phenyl groups at the α position resulted in quantitative
formation of the desired δ-lactone (entry 7). The benzene-
condensed substrate (E)-5 gave the dihydroisocoumarin de-
rivative (S)-6 with a 98:2 er together with the diene product 7
in 5% yield (entry 8). Formation of the diene could be sup-
pressed in t-BuOH, although the enantioselectivity decreased
to 90:10 (entry 9). For (Z)-5, the stereochemical outcome was
inverted with less deterioration in er than observed for (Z)-3
(entry 10). A further increase in the methylene chain ((CH2)4)
did not produce ε-lactone, but resulted mainly in the for-
mation of diene compounds (entry 11).18 Intermolecular re-
action of (E)-hept-2-en-1-ol with benzoic acid gave the linear
allyl ester product under the standard conditions.
O
O
9i
90:10
(S)-6
(E)-5
OH
O
10
6
77j
6:94
OH
O
(R)-6
O
(Z)-5
OH
k
11
—
1
—
—
O
OH
aConditions: 0.7–1-mmol scale; [substrate] = 100 mM; [(R)-2] = 1 mM
(1 mol%); DMA; 100 °C unless otherwise specified. In all cases, the con-
vesions were >99%. bIsolated yield. cDetermined by GC or HPLC analy-
sis except for entries 6 and 7.18 d10-g scale; [substrate] = 500 mM; [(R)-2]
= 1 mM (0.2 mol%). e70 °C. fUndetermined compounds formed.18 gThe
er was determined, after converting to the hydroxy ester, by the 1H-NMR
analysis of the MTPA ester.18 h2-(Buta-1,3-dien-1-yl)benzoic acid was
obtained in ca. 5% yield.18 iIn t-BuOH. j2-(Buta-1,3-dien-1-yl)benzoic
acid was obtained in ca. 15% yield.18 kA 2:1 E/Z mixture of octa-5,7-
dienoic acid was mainly obtained.18
E substrates are converted by (R)-1 or (R)-2 to the corre-
sponding product with the alkenyl group up when the struc-
tures are drawn as in Table 2. In order to gain information on
the reaction pathway that would explain the stereochemical
outcome, the products of the reaction using C(1)D-labeled (E)-
522 were analyzed. As shown in Figure 1, a 81.0:19.0 mixture
of (S)-(E)-5-d and (R)-(E)-5-d was converted in DMA, under
the influence of the R catalyst, to a 74.9:17.6:0.8:1.7:3.8:1.2
mixture of, respectively, (S)-(Z)-6-d (SZ), (S)-(E)-6-d (SE), (R)-
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S
Z
1
E
E
R
OH
OH
S
2
3
4
5
6
7
8
O
D
D
H
H D
OH
OH
O
O
O
O
O
H
O
OH
D
S
Z
–
(S)-(E)-5-d
(R)-(E)-5-d
N
O
H+
R
19.0
O
H
81.0
D
O
II
Ru
inside
leaving
Cl
1 mol% (R)-2
DMA or t-BuOH
100 °C, 30 min
–H2O
(S)-(Z)-6-d (SZ)
>99% convn
(S)-(E)-5-d/(R,RRu)-1
9
–H2O
O
fast
10
11
12
13
14
15
16
17
18
19
20
21
22
Z
R
Z
Z
H
S
H
H
O
1
O
2
OH
O
D
O
D
1
3
OH
D
3
D
N
O
RuIV
N
O
R
R
D
O
RuIV
O
O
π-σ-π via
σ-C(1)–Ru
HO
(R)-(Z)-6-d (RZ)
2.7a
(Z)-7-d
(S)-(Z)-6-d (SZ)
70.2a
O
Cl
Cl
0.8a
inside attack
74.9a
3.8a 0a
INTendo-syn,anti-Re
π-σ-π via
σ-C(3)–Ru
INTendo-syn,syn-Si
C(3)
C(3)
E
E
R
D
S
D
E
D
O
O
2
O
OH
3
D
inside attack
1
O
H
O
H
N
O
IVD
N
O
IV
R
OH
H
HO
O
R
Ru
Ru
π-σ-π via
σ-C(1)–Ru
O
O
(S)-(E)-6-d (SE)
18.4a
O
(E)-7-d
Cl
INTendo-anti,anti-Si
Cl
(R)-(E)-6-d (RE)
8.6a
1.7a
INTendo-anti,syn-Re
17.6a
1.2a 0a
C(3)
C(3)
fast
–H2O
O
–
Figure 1. Reaction using D-labeled 5 and (R)-2 in DMA
O
OH
N
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
D
E
R
1
or t-BuOH.
aThe molar ratio was determined by H-
O
H+
R
O
RuII
O
O
H
NMR and/or HPLC analysis of the crude reaction mix-
inside
leaving
ture, (S)-6, (R)-6, and 7.18
Cl
(Z)-5/(R,RRu)-1
(R)-(E)-6-d (RE)
(Z)-6-d (RZ), (R)-(E)-6-d (RE), (Z)-7-d, and (E)-7-d (S:R =
97.4:2.6, 6:7 = 95:5). The most tangible pathway would be
one in which the 81.0 part and 19.0 part are transformed
mainly to the SZ and RE lactones with a 98:2 er and the SE and
RZ lactones with a 96:4 er, respectively. The SZ/RE and
SE/RZ combination is also supported by the result obtained in
t-BuOH (Figure 1, red values): the ratio of SZ/RE and SE/RZ
lactone was 89.1:10.9 and 87.2:12.8, respectively. Although
there is some deviation from the ideal, these values are close
to the observed value. Another combination, SZ/RZ and
SE/RE, gave an er ratio that was inconsistent with the ob-
served value in either DMA or t-BuOH.
Figure 2. Supposed reaction pathways of (R)-1-catalyzed
intramolecular dehydrative allylation. PF6 was omitted
for clarify. Blue D indicates H in (Z)-5.
In summary, we have realized, for the first time, the direct
Tsuji-Trost-type synthesis of various γ- and δ-alkenyl substi-
tuted lactones by using ω-carboxyl-substituted allylic alcohols
as the substrate. Furthermore, the deuterium labeling exper-
iment has provided insight into our understanding of the
mechanism. The electrophilicity of allyl carboxylates is higher
than that of allylic alcohols, but the use of Intramol-
RDACat,14a,17 which works in a slightly acidic condition, can
alter this situation. The hydroxy oxygen atom in allylic alco-
hol substrate I is more efficiently activated by a hard Brøn-
stead acid as compared with the less basic acyloxy group in
alkenyl lactone product III, thereby lowering the degree of
product inhibition to move the reaction to the entropically
favored product side by liberation of "H2O." This new method
should further enhance the utility of Tsuji-Trost-type asym-
metric allylation,24 widening the scope of retrosynthetic anal-
yses of natural and unnatural important chiral compounds.
Figure 2 shows one possible reaction pathways explaining
the stereo relationship in Figure 1. The (R)-Cl-Naph-
PyCOOH/CpRu(II) catalyst (R,RRu)-116 captures (S)-(E)-5-d via
a
soft/soft and hard/hard interaction. In the sub-
strate/catalyst complex (S)-(E)-5-d/(R,RRu)-1, Intramol-
RDACat mechanism14a,17 facilitates formation of the π-allyl
intermediate INTendo-syn,anti-ReC(3), in which the π-allyl ligand
takes a stable endo conformation toward CpRu,23 such that
the C(3) substituent is syn to C(2)H and anti to the COO group
of the R ligand. The sterically unfavored intermediate moves
to the sterically favored INTendo-syn,syn-SiC(3) via π-σ-π isomeri-
zation through C(1)–Ru bond rotation. Here, the nucleophilic-
ity of COOH in the substrate is enhanced by formation of a
hydrogen bond with the basic carboxylate oxygen atom of the
R ligand, and thus COOH attacks the π-allyl C(3) from the in-
side to give the SZ lactone and (R)-1. A small contribution of
INTendo-anti,syn-ReC(3) generated via a C(3)–Ru bond rotation
followed by the hydrogen-bond-assisted inside attack gives
RE lactone. The stereochemical outcome of the reaction of
diastereomeric (Z)-5 as well as the lower enantioselectivity
can be also understood by assuming the reaction pathways in
Figure 2.
ASSOCIATED CONTENT
Supporting information provides details of the general proce-
dure for asymmetric lactonization, and the NMR spectral data
of the substrates and products. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
kitamura@os.rcms.nagoya-u.ac.jp
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(11) Seki, T.; Tanaka, S.; Kitamura, M. Org. Lett. 2012, 14, 608–
611.
(12) (a) Saburi, H.; Tanaka, S.; Kitamura, M. Angew. Chem. 2005,
117, 1758–1760; Angew. Chem. Int. Ed. 2005, 44, 1730–1732. (b)
Tanaka, S.; Seki, T.; Kitamura, M. Angew. Chem. 2009, 121, 9110–
9113; Angew. Chem. Int. Ed. 2009, 48, 8948–8951. (c) Tanaka, S.;
Suzuki, Y.; Saburi, H.; Kitamura, M. Tetrahedron 2015,
http://dx.doi.org/10.1016/j.tet.2015.04.088.
1
2
3
4
5
6
Author Contributions
‡These authors contributed equally.
Funding Sources
No competing financial interests have been declared.
(13) (a) Tanaka, S.; Pradhan, P. K.; Maegawa, Y.; Kitamura, M.
Chem. Commun. 2010, 46, 3996–3998. (b) Jaisankar, P.; Tanaka, S.;
Kitamura, M. J. Org. Chem. 2011, 76, 1894–1897.
(14) Reviews: (a) Kitamura, M.; Miyata, K.; Seki, T.; Vatmurge,
N.; Tanaka, S. Pure Appl. Chem. 2013, 85, 1121–1132. (b) Bandini, M.;
Cera, G.; Chiarucci, M. Synthesis 2012, 504–512. (c) Sundararaju, B.;
Achard, M.; Bruneau, C. Chem. Soc. Rev. 2012, 41, 4467–4483.
7
8
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ACKNOWLEDGMENT
This work was aided by a Grant-in-Aid for Scientific Research
(No. 25E07B212) and (22750088; 24510112; 24106713)
from the Ministry of Education, Culture, Sports, Science and
Technology (Japan), and an Advanced Catalytic Transfor-
mation Program for Carbon Utilization (ACT-C) from Japan
Science and Technology Agency (JST).
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(15)
Cl-Naph-PyCOOH:
6-(2-chloronaphthalen-1-yl)-5-
methylpyridine-2-carboxylic acid.
(16) The catalyst (R)-1 and -2 were prepared in situ by mixing
[RuCp(CH3CN)3]PF6 with (R)-Cl-Naph-PyCOOH and (R)-Cl-Naph-
PyCOOCH2CH=CH2, respectively. Due to the easier manipulation
1
of the allyl ester, (R)-2 was used in most cases. The H-NMR spec-
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10320–10321. (b) Kanbayashi, N.; Onitsuka, K. J. Am. Chem. Soc.
2010, 132, 1206–1207. For other asymmetric catalyses producing
chiral allyl esters, see: (c) Kirsch, S. F.; Overman, L. E. J. Am. Chem.
Soc. 2005, 127, 2866–2867. (d) Covell, D. J.; White, M. C. Angew.
Chem. Int. Ed. 2008, 47, 6448–6451.
(9) (a) Trost, B. M.; Klum, T. P. J. Am. Chem. Soc. 1979, 101, 6756–
6758. (b) Trost, B. M.; Zhang, T. Angew. Chem. Int. Ed. 2008, 47,
3759–3761.
(18) For the details, see Supporting Information.
(19) Pai, Y.; Fang, J.; Wu, S. J. Org. Chem. 1994, 59, 6018–6025.
(20) Ômura, H.; Yakumaru, K.; Honda, K.; Itoh, T. Naturwissen-
schaften 2013, 100, 373–377.
(21) Saotome, K.; Kodaira, Y. Macromol. Chem. Phys. 1965, 82, 41–
52.
(22) The D-labeled substrate was prepared on the basis of asym-
metric (n-C4H9)3SnD reduction using Ti(Oi-C3H7)4/(S)-BINOL com-
plex.18 For the first report on analysis of the D-contained alkene ste-
reochemistry in mechanistic study on a Mo-catalysis, see: (a) Lloyd-
Jones, G. C.; Krska, S. W.; Hughes, D. L.; Gouriou, L.; Bonnet, V.
D.; Jack, K.; Sun, Y.; Reamer, R. A. J. Am. Chem. Soc. 2004, 126,
702–703. See also: (b) Madrahimov, S. T.; Hartwig, J. F. J. Am. Chem.
Soc. 2012, 134, 8136–8147.
(23) (a) Bi, S.; Ariafard, A.; Jia, G.; Lin, Z. Organometallics 2005, 24,
680–686. (b) Kondo, T.; Ono, H.; Satake, N.; Mitsudo, T.; Watanabe,
Y. Organometallics 1995, 14, 1945–1953. For the molecular structures
of a series of CpRu(IV) π-allyl complexes of picolinate derivatives in
crystals, see: ref 12c.
(24) Reviews: (a) Trost, B. M.; Zhang, T.; Sieber, J. D. Chem. Sci.
2010, 1, 427–440. (b) Lu, Z.; Ma, S. Angew. Chem. Int. Ed. 2008, 47,
258–297. (c) Mohr, J. T.; Stoltz, B. M. Chem. Asian J. 2007, 2, 1476–
1491. (d) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921–
2944.
(10) (a) Miyata, K.; Kutsuna, H.; Kawakami, S.; Kitamura, M. An-
gew. Chem. Int. Ed. 2011, 50, 4649–4653. (b) Miyata, K.; Kitamura, M.
Synthesis 2012, 44, 2138–2146.
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high π-allyl donor for
traditional Tsuji-Trost reaction
0.2–1 mol%
OH
catalyst
n
n
n
+
+ H2O
O
O
DMA
70–100 °C
OH
O
O
O
n = 0 or 1
up to >99% yield
up to 99:1 er
catalyst:
PF6
PF6
O
O
–
O H+
donor
9
acceptor
or
R
N
IV O
Ru
R
N
10
11
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II
Ru
reaction pathway:
H2O leaving to Ru side
π-σ-π isomerization
COOH attack from Ru side
Cl
Cl
intramolecular redox-mediated
donor-acceptor bufunctional
catalyst
(Intramol-RDACat)
5
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Scheme 1. Synthetic processes to alkenyl lactones by catalytic asymmetric intramolecular Tsuji-Trost-type
allylation.
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Figure 1. Reaction using D-labeled 5 and (R)-2 in DMA or t-BuOH. aThe molar ratio was determined by
1H-NMR and/or HPLC analysis of the crude reaction mixture, (S)-6, (R)-6, and 7.18
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Figure 2. Supposed reaction pathways of (R)-1-catalyzed intramolecular dehydrative allylation. PF6 was
omitted for clarify. Blue D indicates H in (Z)-5.
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