Catalytic asymmetric oxidative lactonizations of meso-diols using a chiral iridium complex

Article abstract of DOI:10.1016/S0040-4039(03)00228-4

A chiral amino alcohol/Ir complex catalyzes the asymmetric oxidative lactonizations of meso-diols to give the corresponding lactones in up to 81% ee.

Full text of DOI:10.1016/S0040-4039(03)00228-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2003–2006
Catalytic asymmetric oxidative lactonizations of meso-diols using
a chiral iridium complex
Takeyuki Suzuki,a Kenji Morita,a Yoshimi Matsuob and Kunio Hiroia,*
aDepartment of Synthetic Organic Chemistry, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-Ku,
Sendai 981-8558, Japan
bDepartment of Chemistry, Nagoya University, Chikusa, Nagoya 464-8602, Japan
Received 27 December 2002; revised 23 January 2003; accepted 24 January 2003
Abstract—A chiral amino alcohol/Ir complex catalyzes the asymmetric oxidative lactonizations of meso-diols to give the
corresponding lactones in up to 81% ee. © 2003 Elsevier Science Ltd. All rights reserved.
Asymmetric oxidative lactonization of meso-diols is one
of the most important methods for the preparation of
chiral lactones. Although asymmetric oxidative lac-
tonization of meso-diols has been achieved by an enzy-
matic method1 or by electrooxidation,2 there is much
room for improvement of selectivity and reactivity in
metal-catalyzed reactions. Yoshikawa et al.3 and
Takaya et al.4 have reported that a chiral Ru or Rh
phosphine complex promotes asymmetric oxidative lac-
tonization of prochiral or meso-diols in the presence of
benzalacetone as a hydrogen acceptor to afford the d-
and g-lactones in 10–29% ee in moderate to good yield.5
Recently we have developed an efficient oxidative lac-
tonization of diols using a novel Ir-ligand bifunctional
catalyst and inexpensive acetone or 2-butanone as a
hydrogen acceptor.6 We report herein the asymmetric
oxidative lactonization of meso-diols using a chiral
iridium catalyst (Scheme 1).7,8
[2.2.1]heptane-2-carboxylic acid lactone [(2R,3S)-2a]
was obtained in 99% yield with 80% ee. This product is
a synthetic intermediate of b-santalene.10 Changing the
ligand/Ir ratio affected the enantioselectivity. The cata-
lyst prepared with a lower ligand/Ir ratio (3:4:t-
C4H9OK=1:1:10) gave a lower enantiomeric excess of
66%. However the catalyst prepared with a higher ratio
(3:4:t-C4H9OK=1:6:10) did not give an improved
enantioselectivity (80% ee). KOH could also be used in
place of t-C4H9OK. The reaction using the catalyst
prepared from (R)-phenylglycinol [(R)-5] or (1R,2R)-
diphenylethanolamine [(1R,2R)-6]11 in place of
(1S,3R,4R)-4 gave (2S,3R)-2a in 97% yield with 72–
73% ee. Other chiral ligands gave less satisfactory
results: (R)-valinol, 34% yield, 61% ee, (2S,3R);
(1R,2S)-cis-1-amino-2-indanol,12 85% yield, 50% ee,
(2R,3S); (1R,2R)-N-(p-tolylsulfonyl)-1,2-diphenylethyl-
enediamine (TsDPEN),13 82% yield, 32% ee, (2S,3R);
(R)-N-methylphenylglycinol,14 95% yield, 27% ee,
(2S,3R).
Stirring a mixture of [Cp*IrCl2]2 (3) with chiral amino
alcohol [(1S,3R,4R)-4]9 and t-C4H9OK (1:2:10 mol
ratio) in CH2Cl2 at room temperature for 10 min under
argon gave a dark red suspension. The soluble portion
of this mixture could be used as a catalyst for asymmet-
ric oxidative lactonization of meso-diols. When a mix-
ture of cis-endo-2,3-bis(hydroxymethyl)bicyclo[2.2.1]-
heptane (1a)1c and the in situ prepared Ir catalyst in a
2:1 acetone–CH2Cl2 mixed solvent (1a:acetone:Ir=
1:13.6:0.005 mol ratio) was stirred at room temperature
for 45 h, (2R,3S)-cis-endo-3-(hydroxymethyl)bicyclo-
Table 1 shows some examples of the asymmetric oxida-
tive lactonization of diols 1 using the amino alcohol-
based/Ir catalyst. The general sense of asymmetric
induction with this catalytic system is schematically
illustrated in Figure 1. A gram-scale reaction of 1a was
performed without special techniques (entry 2).15 Enan-
tiomerically pure lactone 2a was obtained in 49% yield
by recrystallization from ether–hexane. In the case of
the exo-diol 1b,1c (R)-5/Ir catalyst gave the correspond-
ing lactone 2b more selectively than (1S,3R,4R)-4/Ir
catalyst (entries 5–7). The 7-oxa analogue 1c1b was also
oxidized in 73% ee to 2c (entry 9),16 which is convertible
to SQ 28,852,17 a potent cyclooxygenase inhibitor. The
* Corresponding author. Tel.: +81 22 234 4181 (ext. 2531); fax: +81
22 275 2013; e-mail: khiroi@tohoku-pharm.ac.jp
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00228-4

2004
T. Suzuki et al. / Tetrahedron Letters 44 (2003) 2003–2006
Scheme 1. Asymmetric oxidative lactonization of meso-diols.
In summary, the chiral Ir complexes catalyze asymmet-
ric oxidative lactonization. The properties of the Ir
catalysts should be readily modifiable to afford more
efficient catalysts, because various chiral amino alcohol
derivatives are available. Although the enantioselectiv-
ity does not yet rival that of the enzymatic method, this
method is attractive due to the good reactivity and
simple operation. Our results should provide a basis for
designing more efficient catalyst systems.
reaction of cis-2,3-bis(hydroxymethyl)bicyclo[2.2.2]-
octane 1d1c gave 2d in 68% ee and 94% yield (entry 11).
Although the olefinic analogue 1e1c disturbed the cata-
lytic activity of (1S,3R,4R)-4/Ir catalyst (55% yield
after 72 h, entry 14), (R)-5/Ir catalyst afforded 2e
quantitatively in 76% ee without difficulty (entry 15).
Monocyclic diol 1f gave 2f in good yield with only
moderate enantioselectivity (entry 18).18 The product is
the synthetic intermediate of NPC 12626,19 a potent
NMDA antagonist, and RU44570,20 an ACE inhibitor.
Since transfer hydrogenation of ketone is reversible, the
prolonged exposure of the chiral product to the reac-
tion conditions decreased the product enantiomeric
excess.13,21 However the enantioselectivity of the reac-
tion of 1a under standard conditions using (1S,3R,4R)-
4/Ir catalyst remained constant (80% ee) throughout the
reaction (17%, after 1 h; >99%, after 24 h, >99% after
72 h). This result indicates the absence of the reverse
process from the product lactone.6 Moreover the corre-
sponding lactol with the same enantiomeric excess
(80%) was also obtained in 14% yield at the early stage
of the reaction of 1a (after 1 h), indicating that kinetic
resolution of the lactol intermediate is not particularly
significant for the enantioselectivity.
Figure 1. General sense of asymmetric oxidative lactonization
catalyzed by the Ir complex.

T. Suzuki et al. / Tetrahedron Letters 44 (2003) 2003–2006
2005
Table 1. Asymmetric oxidative lactonization of meso-diols 1 catalyzed by a chiral Ir(III) complexa
Entry
Diol
Amino alcohol
Time (h)
Lactone
eec (%)
No.
Yieldb (%)
Config.d
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1b
1b
1c
1c
1c
1d
1d
1d
1e
1e
1e
1f
(1S,3R,4R)-4
(1S,3R,4R)-4
(R)-5
(1R,2R)-6
(1S,3R,4R)-4
(R)-5
(1R,2R)-6
(1S,3R,4R)-4
(R)-5
(1R,2R)-6
(1S,3R,4R)-4
(R)-5
(1R,2R)-6
(1S,3R,4R)-4
(R)-5
(1R,2R)-6
(1S,3R,4R)-4
(R)-5
45
48
24
48
40
24
36
45
24
45
50
40
36
72
40
36
40
24
30
2a
2a
2a
2a
2b
2b
2b
2c
2c
2c
2d
2d
2d
2e
2e
2e
2f
99
97e
97
97
97
95
94
92
96
98
94
94
96
55
99
98
97
96
95
80
(2R,3S)
(2R,3S)g
(2S,3R)
(2S,3R)
(2R,3S)
(2S,3R)i
(2S,3R)
(2S,3S)
(2R,3R)j
(2R,3R)
(2R,3S)k
(2S,3R)
(2S,3R)
(2R,3S)m
(2S,3R)
(2S,3R)
(1R,2S)
(1S,2R)o
(1S,2R)
81 (\99)f
73
72
32h
60h
22h
62
9
73
46
10
11
12
13
14
15
16
17
18
19
68h
59h
48h
79h,l
76h,l
55h,l
9n
1f
1f
2f
2f
42n
18n
(1R,2R)-6
a Unless otherwise stated, the reaction was conducted at 30°C using 0.500 mmol of a diol in 2:1 acetone–CH2Cl2 mixed solvent (0.67 M)
containing 0.5 mol% of the catalyst. Diol:acetone molar ratio=1:13.6.
b Isolated yield.
c HPLC analysis using a Daicel Chiralcel OD column unless otherwise specified.
d Determined by the sign of rotation of the isolated product.
e Result of a 1 g scale reaction.
f After recrystallization from ether–hexane.
g [h]2D5 −156.4° (c 1.01, CHCl3);10 >99% ee.
h Chiralpak AS column.
i [h]2D1 +57.3° (c 0.60, CHCl3);1c 60% ee.
j [h]2D2 +85.8° (c 1.00, CHCl3);9 73% ee.
k [h]2D5 +82.0° (c 0.50, CHCl3);1c 68% ee.
l Determined after conversion to 2d.
m [h]2D5 −71.0° (c 1.00, CHCl3);1c 79% ee.
n GC analysis using a chiral Chrompack CP-Chirasil-DEX CB column or HPLC analysis using a Daicel Chiralcel OD column.
o [h]2D1 +21.7° (c 0.50, CHCl3);1a 42% ee.
Acknowledgements
1043–1044; (b) Tanaka, H.; Kawakami, Y.; Goto, K.;
Kuroboshi, M. Tetrahedron Lett. 2001, 42, 445–448 and
references cited therein.
This work was financially supported by the Uehara
Memorial Foundation. We thank Professor Yoshio
Okawa of Tohoku Pharmaceutical University for the
use of the GC. We also thank Dr. Hiroto Nakano for
providing their chiral amino alcohol ligands.
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Org. Chem. 1986, 51, 2822–2824.
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mg, 0.016 mmol), (1S,3R,4R)-4 (4.1 mg, 0.032 mmol) and
t-C4H9OK (18.0 mg, 0.160 mmol) in CH2Cl2 (3.2 mL)
was stirred for 10 min at room temperature. During this