Catalytic enantioselective intramolecular Tishchenko reaction ofmeso-dialdehyde: synthesis of (S)-cedarmycins

Article abstract of DOI:10.1039/d1ra00915j

The first successful example of a catalytic enantioselective intramolecular Tishchenko reaction of ameso-dialdehyde in the presence of a chiral iridium complex is described. Chiral lactones were obtained in good yields with up to 91% ee. The obtained enantioenriched lactones were utilized for the first synthesis of (S)-cedarmycins A and B.

Full text of DOI:10.1039/d1ra00915j

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Catalytic enantioselective intramolecular
Tishchenko reaction of meso-dialdehyde: synthesis
of (S)-cedarmycins†
Cite this: RSC Adv., 2021, 11, 11606
a
b
a
a
a
a
Ismiyarto, Nobuki Kishi, Yuki Adachi, Rui Jiang, Takahiro Doi, Da-Yang Zhou,
a
b
a
a
Kaori Asano, Yasushi Obora,
and Takeyuki Suzuki
Takayoshi Suzuki, Hiroaki Sasai
a
*
Received 3rd February 2021
Accepted 11th March 2021
The first successful example of a catalytic enantioselective intramolecular Tishchenko reaction of a meso-
dialdehyde in the presence of a chiral iridium complex is described. Chiral lactones were obtained in good
yields with up to 91% ee. The obtained enantioenriched lactones were utilized for the first synthesis of (S)-
cedarmycins A and B.
DOI: 10.1039/d1ra00915j
rsc.li/rsc-advances
7
The catalytic dimerization of aldehydes giving the correspond- chiral lactones. Although asymmetric aldol-Tishchenko reac-
1
8
ing esters was rst discovered by Claisen in 1887, and is now tions for chiral 1,3-diols are known, there is no report of an
well known as the “Tishchenko reaction” (Scheme 1). asymmetric intramolecular Tishchenko reaction of meso-dia-
Claisen's method utilizing sodium alkoxides, however, could ldehydes for chiral lactones. We envisaged that the asymmetric
9
only be applied to nonenolizable aldehydes like benzaldehyde, borrowing hydrogen methodology could be applied to achieve
because enolizable aldehydes undergo aldol reactions when an enantioselective intramolecular Tishchenko reaction of
1
treated with strong bases such as sodium alkoxides. In 1906, meso-dialdehydes (Scheme 2).
a Russian chemist, Tishchenko, reported that aluminum
The initial enantioselective reduction of meso-dialdehyde 1
alkoxides were superior to sodium alkoxides in the reaction, could occur by a chiral 18 electron Ir hydride complex to afford
2
because they were more Lewis acidic and less basic. The chiral hydroxy aldehyde 2. The hydroxy aldehyde-lactol equi-
transformation of acetaldehyde into ethyl acetate is the repre- librium would generate lactol 3. Finally, irreversible oxidation
sentative application of the Tishchenko reaction in the chem- of 3 would produce the desired lactone 4.
3
ical industry. So far, a number of homogeneous catalysts
With this hypothesis in mind, we began the investigation of
exhibiting high catalytic performance for the Tishchenko reac- the intramolecular Tishchenko reaction using o-phthalaldehyde
tion have been developed to compensate for the drawback of the
4
classical aluminum alkoxide catalysts. In 2005, we reported
5
a mild Tishchenko dimerization using a Ir catalyst. The reac-
tion proceeds at room temperature and is effective with a wide
range of aldehydes. We also reported the enantioselective
6
oxidative lactonization of meso-diols for the preparation of
Scheme 1 Tishchenko reaction.
a
The Institute of Scientic and Industrial Research, Osaka University, Mihogaoka,
Ibaraki, Osaka 567-0047, Japan. E-mail: suzuki-t@sanken.osaka-u.ac.jp
b
Department of Chemistry and Materials Engineering, Faculty of Chemistry, Materials,
and Bioengineering, Kansai University, Suita, Osaka 564-8680, Japan
†
Electronic supplementary information (ESI) available: Experimental details,
compond characterization, NMR and CSI spectra. CCDC 2019330 (9) and
022569 (11). For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/d1ra00915j
Scheme 2 Strategies for enantioselective intramolecular Tishchenko
reaction.
2
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as a model substrate (Table 1). When a mixture of o-phtha-
10
i
laldehyde (6a) in CH Cl containing the Ir complex 5a, PrOH,
2
i
2
and K CO (6a : 5a : PrOH : K CO ¼ 100 : 1 : 20 : 20 mol ratio)
2
3
2
3
ꢀ
was stirred at 30 C for 7 h, lactone (7a) was obtained in 97%
yield (entry 1). The reaction did not proceed at all in the absence
of Ir catalyst (entry 2). Interestingly, the reaction without the
Scheme 3 Synthesis of meso-dialdehyde 10.
i
additional hydrogen donor, PrOH, also gave the lactone, but
the yield was low (entry 3). To enhance the reactivity, the
addition of a base was necessary. Without base or with a lower
amount of base, the reaction proceeded in less than 28% yield
8
3% yield with 78% ee (Table 2, entry 1). The reaction in
5a
acetonitrile proceeded quantitatively, but the enantioselectivity
was diminished (entry 2). The reaction in the presence of K PO4
slightly increased the chemical yield and ee (entry 3). Finally,
2 2
the addition of a phosphoric acid, (PhO) PO H, increased the
enantioselectivity (91% ee, entry 4). Similar positive effects of
the phosphoric acid on the enantioselectivity were also
observed with 10 mol% of chiral phosphoric acids such as TRIP
3
(entries 4, 5). The reaction of 2,3-naphthalene dicarboxaldehyde
6b also proceeded similarly under optimized conditions (entry
15
6).
Encouraged by these results, we next examined the enan-
tioselective intramolecular Tishchenko reaction of a meso-dia-
ldehyde. With the utility of the product in mind, we selected the
meso-aldehyde 10 as a model substrate (Scheme 3). The requi-
site aldehyde was prepared in 3 steps from cis-3-cyclobutene-
0
0
0
(
TRIP ¼ 3,3 -bis(2,4,6-triisopropylphenyl)-1,1 -binaphthyl-2,2 -
diylhydrogen phosphate). However (R)-TRIP and (S)-TRIP gave
the same enantioselectivity.
11
1
,2-dimethanol 8. Protection of the diol with diphenyldiazo-
The absolute conguration of 11 was unambiguously deter-
mined by single crystal X-ray crystallographic analysis using the
optically pure lactone obtained by recrystallization (Fig. 1).
To compare the enantioselective intramolecular Tishchenko
reaction with the enantioselective oxidative lactonization, the
corresponding diol 12 was treated with the same catalyst in the
presence of acetone as an oxidant, to afford the desired lactone
methane followed by dihydroxylation gave the anti-diol 9 in 58%
yield as the major isomer. The relative conguration of 9 was
unambiguously determined by the crystalline sponge (CS)
12
13
method. Oxidative cleavage of 9 by silica gel-supported NaIO
gave the desired meso-dialdehyde 10.
4
6
With the meso-dialdehyde 10 in hand, we investigated the
enantioselective intramolecular Tishchenko reaction using
a chiral Ir complex. Aer screening the catalysts and reaction
conditions, we were pleased to nd that the enantioselective
intramolecular Tishchenko reaction was realized for the rst
11 in 92% yield and 79% ee with (5aS,8aR) conguration
(Scheme 4). The addition of (PhO) PO H did not improve the
2
2
enantioselectivity in this reaction system (87%, 78% ee).
These results show that both enantiomers of the lactone can
be prepared using the same catalyst by selecting the appropriate
reaction system (Scheme 5). The enantioselective intra-
molecular Tishchenko reaction and the enantioselective
14
time. Thus, treatment of 10 with Cp*Ir [(R,R)-Tsdpen] (5b;
TsDPEN ¼ N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine)
i
(
(
10 mol%) and PrOH (20 mol%) in the presence of K
2
CO
3
ꢀ
40 mol%) in CH
2
Cl
2
at 30 C for 24 h provided the desired 11 in
a
Table
meso-dialdehyde 10
2 Enantioselective intramolecular Tishchenko reaction of
Table 1 Intramolecular Tishchenko reaction of aromatic dialdehydes
a
i
Entry
Aldehyde
Ir (5a)
PrOH
K
2
CO
3
(x mol%)
Yield (%)
b
c
Entry
Solvent
Base
Additive
Yield (%)
Ee (%)
1
2
3
4
5
6
6a
6a
6a
6a
6a
6b
+
—
+
+
+
+
+
+
—
+
+
+
20
20
20
—
10
20
97
0
24
6
28
97
1
2
3
4
CH Cl2
CH CN
CH Cl2
CH Cl2
2
3
2
2
K2CO3
K2CO3
K3PO4
K2CO3
None
None
None
(PhO) PO H
83
>99
87
78
68
80
91
2
2
78
a
b
All the reactions were carried out on a 0.15 mmol scale of 10. Isolated
a
c
All the reactions were carried out on a 0.15 mmol scale of 6.
yield. Determined by chiral HPLC.
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information on the catalyst, cold spray ionization mass spec-
16
trometry (CSI-MS) was conducted. The sample prepared from
b and iPrOH gave a prominent peak at m/z 695 corresponding
to the 18 electron Ir hydride complex, Cp*IrH
5
+
[
1
TsNCHPhCHPhNH
equiv. of (PhO) PO
to Cp*IrH[TsNCHPhCHPhNH
2
] + H . The Ir complex formed from 5b and
i
2
2
H in PrOH exhibited a peak at m/z 965 due
+
2
2
][OPO(OPh) ] + Na . These
results indicate that Cp*Ir, TsDPEN, and phosphoric acid
contribute to the formation of an efficient asymmetric
15
environment.
Having succeeded in the rst intramolecular enantiose-
lective Tishchenko reaction of meso-dialdehyde, we then
applied our method to the synthesis of several natural products.
Fig. 1 POV-ray depiction of (5aS,8aR)-11. Thermal ellipsoid is drawn at
the 50% probability level. H atoms on benzene rings are omitted for Cedarmycins were isolated in 2001 by the Frumai and Igarashi
1
7
clarify.
groups from a plant called Cryptomeria japonica. Cedarmycins
exhibit antibiotic activity with cedarmycin A showing potent
activity against candida glabrata IFO 0622, comparable to
amphotericin B. To date, two groups have reported different
18
methods for the racemic synthesis of the cedarmycins.
However, no reports on the catalytic asymmetric synthesis or
the absolute congurations of these compounds have been
published. As shown in Scheme 6, the deprotection of 11 under
hydrogenolysis conditions afforded the desired cis-diol 14.
Sequential double acylation/elimination of 14 proceeded in the
presence of DBU to give cedarmycins A (15a) and B (15b) in 76%
and 85% yields, respectively. By comparison of their optical
rotations, the absolute congurations of cedarmycins A and B
were determined to be (S). It should be noted that cleavage of
the acetal moiety of 11 by acid hydrolysis caused partial race-
mization of 15. The racemization likely occurred by the recyc-
lization of cis-14 by the nucleophilic attack of the g-hydroxy
group under acidic conditions.
Scheme 4 Enantioselective oxidative lactonization of meso-diol 12.
In conclusion, we have achieved the rst enantioselective
intramolecular Tishchenko reaction of meso-dialdehydes and
applied this methodology to the synthesis of natural products.
Chiral lactones are useful chiral building block for the organic
synthesis. The direct conversion of 1,4-dialdehydes to g-
lactones is attractive from the view point of environmentally
19
benign redox neutral process. Additional studies on the
substrate scope and reaction mechanism are currently in
progress in our laboratory.
Scheme
5 Comparison of enantioselective intramolecular Tish-
chenko reaction with enantioselective oxidative lactonization.
oxidative lactonization are complementary, indicating both
reactions pass through the same transition state.
i
In this reaction, we used 16 electron Ir complex 5b and PrOH
to generate the 18 electron Ir hydride complex. To obtain Scheme 6 Catalytic enantioselective synthesis of cedarmycins A and
B.
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T. Shirai, T. Iwasaki, K. Kanemoto and Y. Yamamoto,
Chem.–Asian J., 2020, 15, 1858–1862.
Conflicts of interest
There are no conicts to declare.
8 (a) C. M. Mascarenhas, S. P. Miller, P. S. White and
J. P. Morken, Angew. Chem., Int. Ed., 2001, 40, 601–603; (b)
C. Schneider and M. Hansch, Synlett, 2003, 2003, 837–840;
Acknowledgements
(
c) V. Gnanadesikan, Y. Horiuchi, T. Ohshima and
M. Shibasaki, J. Am. Chem. Soc., 2004, 126, 7782–7783; (d)
J. Mlynarski and M. Mitura, Tetrahedron Lett., 2004, 45,
This work was supported by JSPS KAKENHI (Grant No.
26410047, 17K05784, 20K05494) and Uehara Memorial Foun-
7549–7552; (e) Y. Horiuchi, V. Gnanadesikan, T. Ohshima,
dation. This work was also supported in part by “Dynamic
Alliance for Open Innovation Bridging Human, Environment
and Materials” in “Network Joint Research Center for Materials
and Devices” (No. 20194015) from the Ministry of Education,
Culture, Sports, Science and Technology of Japan (MEXT). We
are also grateful to Tsuyoshi Matsuzaki, Hitoshi Haneoka, and
Tsunayoshi Takehara of the Comprehensive Analysis Center of
ISIR for their assistance.
H. Masu, K. Katagiri, Y. Sei, K. Yamaguchi and
M. Shibasaki, Chem. –Eur. J., 2005, 11, 5195–5204; (f)
J. Mlynarski, J. Jankowska and B. Rakiel, Chem. Commun.,
2005, 4854–4856; (g) J. Mlynarski, J. Jankowska and
B. Rakiel, Tetrahedron: Asymmetry, 2005, 16, 1521–1526; (h)
K. Rohr, R. Herre and R. Mahrwald, Org. Lett., 2005, 7,
4499–4501; (i) M. Stodulski, J. Jazwinski and J. Mlynarski,
Eur. J. Org. Chem., 2008, 2008, 5553–5562; (j) T. Asano,
S. Kotani and M. Nakajima, Org. Lett., 2019, 21, 4192–4196.
(a) M. H. S. A. Hamid, P. A. Slatford and J. M. J. Williams, Adv.
Synth. Catal., 2007, 349, 1555–1575; (b) T. Suzuki, Chem. Rev.,
2011, 111, 1825–1845; (c) J. M. Ketcham, I. Shin,
T. P. Montgomery and M. J. Krische, Angew. Chem., Int. Ed
9
Notes and references
1
2
3
L. Claisen, Ber. Dtsch. Chem. Ges., 1887, 20, 646–650.
W. Tischtschenko, J. Russ. Phys. Chem., 1906, 38, 355–418.
B. N. Pattanaik and H. C. Mandalia, Int. J. Curr. Res. Rev.,
.
,
2014, 53, 9142–9150; (d) T. Kwok, O. Hoff,
R. J. Armstrong and T. J. Donohoe, Chem. –Eur. J., 2020, 26,
2912–12926.
Org. Chem., 2001, 5, 225–255; (b) T. Seki, T. Nakajo and 10 T. Suzuki, K. Morita, M. Tsuchida and K. Hiroi, Org. Lett.,
M. Onaka, Chem. Lett., 2006, 35, 824–829; (c)
2002, 4, 2361–2363.
A. M. P. Koskinen and A. O. Kataja, in Organic Reactions, 11 N. Gauvry, C. Comoy, C. Lescop and F. Huet, Synthesis, 1999,
2011, 3, 23–40.
4
(a) O. P. Tormakangas and A. M. P. Koskinen, Recent Res. Dev.
1
ed. S. E. Denmark, John Wiley & Sons, Inc., Hoboken,
1999, 574–576.
2015, vol. 86, pp. 105–410; (d) R. Dhanya, T. Shilpa, 12 Y. Inokuma, S. Yoshioka, J. Ariyoshi, T. Arai, Y. Hitora,
S. Saranya and G. Anilkumar, ChemistrySelect, 2020, 5, 754–
K. Takada, S. Matsunaga, K. Rissanen and M. Fujita,
Nature, 2013, 495, 461–466.
763.
5
(a) T. Suzuki, T. Yamada, T. Matsuo, K. Watanabe and
T. Katoh, Synlett, 2005, 2005, 1450–1452; (b) T. Suzuki,
1
3 Y. L. Zhong and T. K. Shing, J. Org. Chem., 1997, 62, 2622–
2624.
T. Yamada, K. Watanabe and T. Katoh, Bioorg. Med. Chem. 14 K. Mashima, T. Abe and K. Tani, Chem. Lett., 1998, 1201–
Lett., 2005, 15, 2583–2585.
1202.
T. Suzuki, K. Morita, Y. Matsuo and K. Hiroi, Tetrahedron 15 (a) C. Li, B. Villa-Marcos and J. Xiao, J. Am. Chem. Soc., 2009,
6
7
Lett., 2003, 44, 2003–2006.
131, 6967–6969; (b) W. J. Tang and J. L. Xiao, Synthesis, 2014,
6, 1297–1302; (c) S. Tribedi, C. M. Hadad and R. B. Sunoj,
(a) Z. Shen, H. A. Khan and V. M. Dong, J. Am. Chem. Soc.,
4
2008, 130, 2916–2917; (b) D. Hojo, K. Noguchi and
Chem. Sci., 2018, 9, 6126–6133.
K. Tanaka, Angew. Chem., Int. Ed., 2009, 48, 8129–8132; (c)
D. H. Phan, B. Kim and V. M. Dong, J. Am. Chem. Soc.,
1
6 S. Sakamoto, M. Fujita, K. Kim and K. Yamaguchi,
Tetrahedron, 2000, 56, 955–964.
2
009, 131, 15608–15609; (d) Z. Shen, P. K. Dornan, 17 T. Sasaki, Y. Igarashi, N. Saito and T. Furumai, J. Antibiot.,
H. A. Khan, T. K. Woo and V. M. Dong, J. Am. Chem. Soc.,
2001, 54, 567–572.
009, 131, 1077–1091; (e) M. C. Willis, Angew. Chem., Int. 18 (a) H. S. Yang, X. X. Qiao, Q. Cui and X. H. Xu, Chin. Chem.
2
Ed., 2010, 49, 6026–6027; (f) H. A. Khan, K. G. M. Kou and
V. M. Dong, Chem. Sci., 2011, 2, 407–410; (g) S. K. Murphy
and V. M. Dong, J. Am. Chem. Soc., 2013, 135, 5553–5556;
Lett., 2009, 20, 1023–1024; (b) M. G. Lloyd, M. D'Acunto,
R. J. K. Taylor and W. P. Unsworth, Tetrahedron, 2015, 71,
7107–7123.
(
5
h) L. Souillart and N. Cramer, Angew. Chem., Int. Ed., 2014,
3, 9640–9644; (i) X. Wu, Z. Chen, Y. B. Bai and
1
9 S. H. Bergens, D. P. Fairlie and B. Bosnich, Organometallics,
1990, 9, 566–571.
V. M. Dong, J. Am. Chem. Soc., 2016, 138, 12013–12016; (j)
©
2021 The Author(s). Published by the Royal Society of Chemistry
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