Ir-catalyzed oxidative desymmetrization of meso-diols

Article abstract of DOI:10.1021/ol9016436

The catalytic oxidative desymmetrlzation of meso-diols was realized using a chiral iridium catalyst. In particular, the reaction Is effective for the cyclic diols to give the corresponding hydroxy ketones In high chemical yields with high ee's. With this reaction as a key step, a shortstep synthesis of common Intermediate of ottelione and scyphostatin was achieved.

Full text of DOI:10.1021/ol9016436

ORGANIC
LETTERS
2
009
Vol. 11, No. 19
286-4288
Ir-Catalyzed Oxidative Desymmetrization
of meso-Diols
4
,
†
†
Takeyuki Suzuki,* Kazem Ghozati, Tadashi Katoh, and Hiroaki Sasai
‡
†
The Institute of Scientific and Industrial Research, Osaka UniVersity, Mihogaoka,
Ibaraki-shi, Osaka 567-0047, Japan, and Tohoku Pharmaceutical UniVersity,
4
-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
suzuki-t@sanken.osaka-u.ac.jp
Received July 18, 2009
ABSTRACT
The catalytic oxidative desymmetrization of meso-diols was realized using a chiral iridium catalyst. In particular, the reaction is effective for
the cyclic diols to give the corresponding hydroxy ketones in high chemical yields with high ee’s. With this reaction as a key step, a short-
step synthesis of common intermediate of ottelione and scyphostatin was achieved.
Desymmetrization of meso compounds is an efficient strategy
for the synthesis of chiral complex molecules. Oxidative
desymmetrization of diols has been achieved by using metal
catalysts, organocatalysts, electrooxidations, and enzymatic
catalyzed oxidative desymmetrization of primary diols has
been found to be useful for the synthesis of chiral lactones
2
c
(Scheme 1, eq 1). Herein, we describe the Ir-catalyzed
oxidative desymmetrization of secondary diols (Scheme 1,
eq 2). So far there are several reports for the oxidative
desymmetrization of secondary diols. In 1997, Noyori et al.
reported excellent ee’s with unsaturated diols using a Ru
1
methods. Recently, we have succeeded in developing several
2
kind of oxidation by an Ir catalyst. Among them, Ir-
†
1c
1h,j,k
Osaka University.
Tohoku Pharmaceutical University.
catalyst (56-70%, 87-96% ee). The Sigman
and
‡
1i
Stoltz groups have succeeded in aerobic oxidative desym-
(
1) Ru catalyst : (a) Ishii, Y.; Osakada, K.; Ikariya, T.; Saburi, M.;
Yoshikawa, S. Chem. Lett. 1982, 1179–1182. (b) Nozaki, K.; Yoshida, M.;
Takaya, H. J. Organomet. Chem. 1994, 473, 253–256. (c) Hashiguchi, S.;
Fujii, A.; Haack, K.-J.; Matsumura, K.; Ikariya, T.; Noyori, R. Angew.
Chem., Int. Ed. 1997, 36, 288–290. (d) Shimizu, H.; Nakata, K.; Katsuki,
T. Chem. Lett. 2002, 2002, 1080–1081. (e) Shimizu, H.; Onitsuka, S.; Egami,
H.; Katsuki, T. J. Am. Chem. Soc. 2005, 127, 5396–5413. (f) Nakamura,
Y.; Egami, H.; Matsumoto, K.; Uchida, T.; Katsuki, T. Tetrahedron 2007,
metrizationwithPd-sparteinecatalysts,respectively(69-79%,
7
6-95% ee). Katsuki et al. have developed the aerobic
reaction using a Ru(salen) complex (69%, 77% ee for 1,3-
1
f
indandiol). Onomura et al. reported the oxidation of 1,2-
diols such as meso-hydrobenzoin using NBS in the presence
1
l
6
3, 6383–6387. Rh catalyst: (g) Ishii, Y.; Suzuki, K.; Ikariya, T.; Saburi,
of chiral Cu complex to give 97% yield with 76% ee.
M.; Yoshikawa, S. J. Org. Chem. 1986, 51, 2822–2824. Pd catalyst: (h)
Jensen, D. R.; Pugsley, J. S.; Sigman, M. S. J. Am. Chem. Soc. 2001, 123,
Despite these efforts, there is no report which achieved both
high yields and high ee’s.
7
7
475–7476. (i) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2001, 123,
725–7726. (j) Mandal, S. K.; Jensen, D. R.; Pugsley, J. S.; Sigman, M. S.
J. Org. Chem. 2003, 68, 4600–4603. (k) Mandal, S. K.; Sigman, M. S. J.
Org. Chem. 2003, 68, 7535–7537. Cu catalyst: (l) Onomura, O.; Arimoto,
H.; Matsumura, Y.; Demizu, Y. Tetrahedron Lett. 2007, 48, 8668–8672.
Organocatalyst: (m) Jakka, K.; Zhao, C. G. Org. Lett. 2006, 8, 3013–3015.
Electrooxidation: (n) Yanagisawa, Y.; Kashiwagi, Y.; Kurashima, F.; Anzai,
J.-i.; Osa, T.; Bobbitt, J. M. Chem. Lett. 1996, 1043–1044. (o) Tanaka, H.;
Kawakami, Y.; Goto, K.; Kuroboshi, M. Tetrahedron Lett. 2001, 42, 445–
(2) (a) Suzuki, T.; Morita, K.; Tsuchida, M.; Hiroi, K. Org. Lett. 2002,
4, 2361–2363. (b) Suzuki, T.; Morita, K.; Tsuchida, M.; Hiroi, K. J. Org.
Chem. 2003, 68, 1601–1602. (c) Suzuki, T.; Morita, K.; Matsuo, Y.; Hiroi,
K. Tetrahedron Lett. 2003, 44, 2003–2006. (d) Suzuki, T.; Yamada, T.;
Matsuo, T.; Watanabe, K.; Katoh, T. Synlett 2005, 1450–1452. (e) Suzuki,
T.; Matsuo, T.; Watanabe, K.; Katoh, T. Synlett 2005, 1453–1455. (f)
Suzuki, T.; Yamada, T.; Watanabe, K.; Katoh, T. Bioorg. Med. Chem. Lett.
2005, 15, 2583–2585. (g) Suzuki, T.; Morita, K.; Ikemiyagi, H.; Watanabe,
K.; Hiroi, K.; Katoh, T. Heterocycles 2006, 69, 457–461.
4
48. For reviews, see: (p) Jones, J. B. Tetrahedron 1986, 42, 3351–3403.
q) Schoffers, E.; Golebiowski, A.; Johnson, C. R. Tetrahedron 1996, 52,
769–3826.
(
3
10.1021/ol9016436 CCC: $40.75
Published on Web 09/08/2009
 2009 American Chemical Society

N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine) was found
to be the optimum ligand in selectivity (>99% ee, entry 6).
Scheme 1. Two Types of Oxidative Desymmetrization
Table 2. Oxidative Desymmetrization of meso-Diols
entry diol solvent concn of 1 (M) time (h) yield (%) ee (%)
a
e
f
1
2
3
4
5
6
7
1a
1a
1b
1b
1c
1c
1c
A
C
A
C
C
C
C
2
2
2
2
2
0.5
0.1
14
14
5
97
95
92
92
32
70
91
91
>99
93
>99
95
a
b
b
Table 1. Ligand Screening for the Oxidative Desymmetrization
4
a
c
of meso-Indan-1,3-diol
24
24
10
c
90
-71
c,d
g
a
c
b
With 1 mol % of catalyst at 30 °C. With 1 mol % of catalyst at 40
d
°
C. With 10 mol % of catalyst at 60 °C. The catalyst prepared from 3
e
f
g
was used instead of 5. A ) acetone. C ) cyclohexanone. Cyclohexanone/
CH Cl ) 1:20.
2
2
b
entry
ligand
yield (%) ee (%)
3
c
1
2
3
4
5
6
a
(1S,3R,4R)-2-azanorbornyl methanol
(1R,2R,6S,7R,9R)-3
(1S,2R)-cis-1-amino-2-indanol
(R)-phenylglycinol
(1R,2R)-diphenylethanolamine
(R,R)-4
13
95
25
22
34
54
73
95
71
55
51
4
c
>99
Since ligand 4 showed the best selectivity, next we
The reaction was conducted using 0.133 mmol of 1a in 1:2
Cl mixed solvent (0.67 M) containing 1 mol % of the catalyst.
For ligand structures, see the Supporting Information. (R)-2a was
examined the substrate generality of the oxidative desym-
acetone-CH
2
2
5
b
c
mtrization with preformed Ir complex 5. The reaction in
obtained.
higher concentration increased the yield (Table 2, entry 1).
Cyclohexanone, which has higher oxidation potential than
acetone, afforded >99% ee with 95% yield (entry 2). It is
noteworthy that we did not observe the overoxidation product
(1,3-indandione) in this system. Moreover, the treatment of
2
2
a under the same conditions for 14 h gave no diketone but
a without losing the optical purity. Similarly, the reaction
of 1b proceeded smoothly in cyclohexanone (entry 4).
However, the reaction of acyclic 1,3-diol 1c needed higher
catalyst loading, and the 1,3-diphenyl-1-propanone was
obtained as byproduct in 21% yield with higher concentration
Initial screening of several chiral ligands was carried out
using meso-indan-1,3-diol (1a) as a substrate. Stirring a
mixture of [Cp*IrCl
2
]
2
4 9
with chiral ligand and t-C H OK (1:
6
conditions (entry 5). Decreasing the concentration sup-
2
:10 molar ratio) in CH
2
Cl at room temperature for 10 min
2
pressed the byproduct formation to give moderate yield and
ee (entry 6). The catalyst prepared from ligand 3 gave 91%
yield and moderate ee (entry 7). However, application of
the same conditions of entry 6 to the reaction of 1,2-diols
such as meso-hydrobenzoin gave unsatisfactory results (23%
ee).
under argon gave a dark red suspension. The soluble portion
of this mixture was used as a catalyst for oxidative desym-
metrization of meso-diols (Table 1). When the Ir catalyst
4
with ligand 3 in 2:1 acetone-CH
Cl
2 2
was stirred at 40 °C
for 15 h (1a/acetone/Ir ) 1:7:0.01 molar ratio), ꢀ-hydroxy
ketone 2a was obtained in 95% yield with 95% ee (entry 2).
The ligands which are effective in the asymmetric oxidative
lactonization gave lower selectivities (entries 1 and 4). The
other amino alcohol ligands also afforded 2a in moderate
ee’s (entries 3 and 5). Finally, TsDPEN ligand (TsDPEN )
Oxidation of meso-diols could include the kinetic resolu-
tion pathway as shown in Scheme 2. To gain mechanistic
(
5) (a) Mashima, K.; Abe, T.; Tani, K. Chem. Lett. 1998, 1199–1200.
(b) Mashima, K.; Abe, T.; Tani, K. Chem. Lett. 1998, 1201–1202. (c)
Murata, K.; Ikariya, T.; Noyori, R. J. Org. Chem. 1999, 64, 2186–2187.
(
6) Although the mechanism for the formation of 1,3-diphenyl-1-
(
3) Alonso, D. A.; Guijarro, D.; Pinho, P.; Temme, O.; Andersson, P. G.
J. Org. Chem. 1998, 63, 2749–2751.
4) Nordin, S. J. M.; Roth, P.; Tarnai, T.; Alonso, D. A.; Brandt, P.;
propanone is not clear, initial oxidation and following dehydration could
give R,ꢀ-unsaturated ketone. The reduction of the double bond could afford
the saturated ketone. See: Fujita, K.; Asai, C.; Yamaguchi, T.; Hanasaka,
F.; Yamaguchi, R. Org. Lett. 2005, 7, 4017–4019.
(
Andersson, P. G. Chem.sEur. J. 2001, 7, 1431–1436.
Org. Lett., Vol. 11, No. 19, 2009
4287

insight into the present reaction, oxidative kinetic resolution
7
of 1-indanol was carried out. The reaction of racemic
Scheme 3. Catalytic Asymmetric Synthesis of the Synthetic
1
-indanol with (R,R)-5 in cyclohexanone proceeded at 30
C for 7 h, and (S)-indanol was recovered with 50% yield
and >99% ee.
Intermediate of Ottelione A and Scyphostatin
°
Scheme 2. Oxidative Kinetic Resolution
With the efficient catalytic oxidative desymmetrization of
meso-diols in hand, we attempted the catalytic asymmetric
preparation of the common synthetic intermediate 10 for
scyphostatin and ottelione (Scheme 3). Scyphostatin is the
most potent and specific sphingomyelinase inhibitor, and
otteliones are expected as new leads for cancer chemothera-
peutic agents. In the previous synthetic route, the corre-
cleavage of cyclic bromo ether gave the meso-diol 9. The
oxidative desymmterization of 9 successfully proceeded in
the presence of KO-t-Bu (60%, >99% ee).
In conclusion, we have demonstrated the efficient Ir-
catalyzed oxidative desymmetrization of meso-diols. This
method might be useful for the synthesis of other complex
molecules.
8
9
1
1
sponding TBDMS-protected compound was synthesized from
8
(
-)-quinic acid in 10 steps. The requisite meso-diol was
prepared from p-benzoquionone in six steps. The allyl alcohol
Acknowledgment. This work was supported by Encour-
agement of Young Scientists from JSPS, Uehara Memorial
Foundation. We are also thankful to the technical staff of
the Comprehensive Analysis Center of ISIR for their
assistance.
1
0
6
4
was treated with 3 mol % of OsO and NMO (N-
methylmorpholine N-oxide), affording the triol 7 in 73%
yield. After protection of the cis-diol moiety of 7, reductive
(
7) For an example of Ir-catalyzed oxidative kinetic resolution, see: Arita,
S.; Koike, T.; Kayaki, Y.; Ikariya, T. Angew. Chem., Int. Ed. 2008, 47,
447–2449.
8) (a) Izuhara, T.; Katoh, T. Tetrahedron Lett. 2000, 41, 7651–7655.
Supporting Information Available: Experimental details
and characterization of products. This material is available
free of charge via the Internet at http://pubs.acs.org.
2
(
(
b) Izuhara, T.; Katoh, T. Org. Lett. 2001, 3, 1653–1656. (c) Katoh, T.;
Izuhara, T.; Yokota, W.; Inoue, M.; Watanabe, K.; Nobeyama, A.; Suzuki,
T. Tetrahedron 2006, 62, 1590–1608.
OL9016436
(
9) (a) Araki, H.; Inoue, M.; Katoh, T. Org. Lett. 2003, 5, 3903–3906.
(
b) Araki, H.; Inoue, M.; Suzuki, T.; Yamori, T.; Kohno, M.; Watanabe,
K.; Abe, H.; Katoh, T. Chem.sEur. J. 2007, 13, 9866–9881.
10) Hiroya, K.; Kurihara, Y.; Ogasawara, K. Angew. Chem., Int. Ed.
995, 34, 2287–2289.
(11) The trans-diol was obtained as a byproduct (13% NMR yield, >99%
ee). See the Supporting Information.The details will be discussed in an
upcoming paper.
(
1
4288
Org. Lett., Vol. 11, No. 19, 2009