Ru(II)-and Ir(I) Catalyzed Hydrogen Peroxide Oxidation of Hydroxamic Acids and their Subsequent Hetero Diels-Alder Cycloadditions with Chiral N-Dienyl Lactams

Article abstract of DOI:10.2174/157017810791824955

Asymmetric hetero Diels-Alder (HDA) reaction of highly reactive acyl nitroso intermediates are reported. Transient acyl nitroso compounds 2a'-c' are formed by Ru(II)-or Ir(I)-catalyzed hydrogen peroxide oxidation of hydroxamic acids 2a-c and are trapped i

Full text of DOI:10.2174/157017810791824955

Letters in Organic Chemistry, 2010, 7, 475-478
475
Ru(II)- and Ir(I) Catalyzed Hydrogen Peroxide Oxidation of Hydroxamic
Acids and their Subsequent Hetero Diels-Alder Cycloadditions with Chiral
N-Dienyl Lactams
Ahmad Fakhruddin, Kesiny Phomkeona, Abdel-Moneim Abu-Elfotoh, Kazutaka Shibatomi and
Seiji Iwasa*
School of Materials Science, Toyohashi University of Technology, Tempaku-cho, Toyohashi, Aichi 441-8580, Japan
Received October 19, 2009: Revised April 26, 2010: Accepted April 26, 2010
Abstract: Asymmetric hetero Diels-Alder (HDA) reaction of highly reactive acyl nitroso intermediates are reported.
Transient acyl nitroso compounds 2a’-c’ are formed by Ru(II)- or Ir(I)-catalyzed hydrogen peroxide oxidation of
hydroxamic acids 2a-c and are trapped in situ by the optically pure N-dienyl-L-pyroglutamates 1a-b to afford the
corresponding diastereomeric adducts 3a-f and 4a-f up to 98% yield (70% de) and 72% de (70% yield) with complete
regioselectivity at 0 ˚C to room temperature.
Keywords: Nitroso intermediate, hydrogen peroxide, ruthenium catalyst, iridium catalyst, hetero Diels-Alder reaction, 1, 2-
oxazine.
INTRODUCTION
In recent years, the synthesis of heteroatom-substituted
dienes and their use in the DA reaction has become an area
of major interest. There are several examples of N-dienyl
amides and carbamates, which are excellent enophiles in the
DA reactions [4]. Recently, some chiral aminodienes have
been described in the literature [5]. Among the optically
active 1-aminodienes, the N-dienyl pyroglutamate
The asymmetric hetero Diels-Alder (HDA) reaction is an
effective transformation, permitting rapid and stereoselective
access to the multifunctionalized organic molecules and
often represents a pivotal reaction step in the total synthesis
of natural products. Thus, pyrrolidine derivatives, amino
alcohols and aza sugars are easily available from HDA
(S)
(S)
(S)
O
O
O
R1O2C
R1O2C
R1O2C
N
N
N
(R)
[RCON=O]
(S)
O
N
O
N
2a'; R=OBn, 2b'; R=Ph, 2c'; R=OtBu
COR
COR
3a-f
major
4a-f
minor
Ru(II)- / Ir(I) -
cat.(5mol%)
H2O2(4equiv.)
1a; R1=CH3
1b; R1=C2H5
THF/MeOH
0oC-r.t.
[RCONHOH]
2a; R=OBn, 2b; R=Ph, 2c; R=OtBu
Scheme 1.
reactions [1]. In principle, asymmetric HDA reaction can be
achieved, either with a chiral diene, with a chiral dienophile
or with a chiral Lewis acid catalyst. In the case of acyl
nitroso dienophiles, the HDA cycloaddition was resistant to
asymmetric catalysis [2] and this happened because of high
reactivity of the nitroso moiety, as recently demonstrated by
time-resolved IR spectroscopy [3].
derivatives are reported to be very efficient dienes in
asymmetric HDA reactions [6].
During the course of our continuous research, we wished
to apply our novel Ru(II)-or Ir(I)-catalyzed hydrogen
peroxide oxidation system [7] to synthesize some optically
active compounds through the versatile HDA transformation.
In this aspect, chiral N-dienyl-L-pyroglutamates have been
chosen as 4ꢀ electon source and in situ generation of
acylnitroso species as 2ꢀ electron source to furnish optically
active [4+2]ꢀ cycloadducts.
*Address correspondence to this author at the School of Materials Science,
Toyohashi University of Technology, Tempaku-cho, Toyohashi, Aichi 441-
8580, Japan; Tel: +81-532-44-6817; Fax: +81-523-44-6817;
E-mail: iwasa@ens.tut.ac.jp
Here, we report the asymmetric HDA reactions of chiral
alkyl-N-dienyl-L-pyroglutamates
with
acyl
nitroso
1570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

476 Letters in Organic Chemistry, 2010, Vol. 7, No. 6
Fakhruddin et al.
RESULTS AND DISCUSSION
Since Ru(II) complexes Ru(pybox)(pydic) A-D have
been reported from our research group as an efficient catalyst
system for the oxidation of hydroxamic acids and phenol
derivatives [7], we applied them for the synthesis of transient
acyl nitroso intermediates (Fig. 1). Acyl nitroso dienophiles
2a’-c’ derived from the corresponding hydroxamic acids 2a-
c were reacted to chiral N-dienyl pyroglutamates 1a-b with
complete regioselectivity and lead to pairs of diasteriomers
3a-f and 4a-f. The results are summarized in Table 1. The
major diastereomers 3a-f have (6S) configuration as already
observed by Defoin et al. [6b]. Quantitative measurements of
O
O
N
N
O
N
O
Ru
R
R
N
O
O
Catalysts: A-D
A; R=H
1
the diastereomeric mixtures were monitored by H-NMR
B; R=Me
C; R=Ph
D; R=iPr
(integration ratios of analogous signals). Table 1 shows the
relative amounts of major 3a-f, and minor 4a-f cycloadducts
1
as monitored by H-NMR for HDA reactions of dienophiles
Fig. (1).
2a’-c’ with dienes 1a-b in THF or MeOH at 0 ˚C to room
temperature.
intermediates generated from Ru(II)- or Ir(I)-catalyzed
In case of Ru(II) catalysts, MeOH was the solvent of
choice compare to THF (entries 1-2 and 5-6). Whereas, Ir(I)-
catalyzed HDA reactions were carried out in THF medium
hydrogen peroxide oxidation of hydroxamic acids (Scheme
1).
Table 1. Cycloadducts 3a-f and 4a-f Obtained by Diels-Alder Reactions of Chiral Dienes 1a-b with Ru(II)- or Ir(I)-Catalyzed
Hydrogen Peroxide Oxidation of Hydroxamic Acids 2a-c
Entry
Diene
Hydroxamic Acid
Catalysta
Solvent
Time(h)
%Yieldb
Adduct
3/4c
d.ed.
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2b
2c
2c
2c
2c
2c
2a
2b
2c
A
A
THF
MeOH
MeOH
MeOH
THF
22
14
27
4
59
49
74
45
49
63
62
51
80
51
87
48
64
66
52
70
73
88
81
68
67
91
70
98
73/27
79/21
78/22
79/21
71/29
79/21
70/30
69/31
70/30
83/17
83/17
84/16
84/16
80/20
82/18
73/27
79/21
85/15
82/18
79/21
79/21
85/15
86/14
85/15
46
58
56
58
42
58
40
38
46
65
65
68
66
60
64
44
58
70
64
58
58
70
72
70
3
B
4
C
5
D
22
8
3a/4a
6
D
MeOH
THF
7
E
24
24
3
8
F
THF
9e
10
11
12
13
14
15
16e
17
18
19
20
21
22
23
24
none
A
CH2Cl2
MeOH
MeOH
MeOH
MeOH
THF
12
4
B
C
9
3b/4b
D
8
E
22
22
3
F
THF
none
A
CH2Cl2
MeOH
MeOH
MeOH
THF
3
3c/4c
C
4
D
3
E
22
22
4
3d/4d
3e/4e
3f/4f
F
THF
D
MeOH
MeOH
MeOH
D
22
D
4
aCat E: [IrCl(coe)2]2 and cat. F: [IrCl(cod)]2. bYield of two diastereomers. cThe ratio of two diastereoisomers as determined by 1H-NMR from their crude mixture. dDiastereomeric
excess eSee Ref. [6b].

Ru(II)- and Ir(I) Catalyzed Hydrogen Peroxide Oxidation of Hydroxamic Acids
Letters in Organic Chemistry, 2010, Vol. 7, No. 6 477
(entries 7-8, 14-15, and 20-21), since Ir(I) catalysts were
dissolved well in THF rather than MeOH. Diene 1a reacted
with the acyl nitroso dienophile 2a’ generated from the
oxidation of hydroxamic acid 2a and produced
diastereomeric pair (3a and 4a) with a maximum 74% yield
(entry 3) and 58% de (entries 2,4 and 6). When the same
diene reacted with the other two acyl nitroso intermediates
(2b’ and 2c’), maximum 87% yield (entry 11) with 68% de
(entry 12) of diastereomeric pair (3b and 4b) was observed
for the former and 88% yield with 70% de (entry 18) was
found for the latter hydroxamic acid. Ru(II)-catalyzed
asymmetric HDA reactions were rapidly proceeded as
compared to that of Ir(I). It appeared that the asymmetric
induction slightly increased with the size of R1 (entries 22-
24) and this increasing could be attributed to the bulkiness of
the ester R1 group as previously reported [6b]. The best
induction was observed for the 3e/4e pair (entry 23, de = 72)
in methanol at 0 ˚C to room temperature and highest yield
was found for 3f/4f pair (entry 24, yield = 98%). Although,
moderate yields and diastereoselectivities were achieved by
using acyl nitroso intermediate 2a’ (entries 1-8), high yield
and diastereoselectivity (entry 11) were obtained in case of
acyl nitroso intermediate 2b’ compared with the previously
reported (entry 16) [6b]. This exciting result proves that the
generation of the acyl nitroso intermediates via metal
catalysis improved the HDA cycloaddition in terms of yield
and diastereoselectivity. A series of Ru(II)(pybox)(pydic)
catalysts were surveyed, and almost similar extant of
moderate to good yields as well as de were observed.
However, the use of Ru(II)-complex with chiral ligands does
not produce any significant amount of asymmetric induction
via the trapping of acyl nitroso intermediates. In all
cycloadditions, a classical HDA reaction is assumed to
occur, the dienophile approaching from the less hindered
side, i.e., anti with respect to the ester moiety of the chiral
pyroglutamate auxiliary. Furthermore, the s-trans
conformation between the amide and the butadiene moiety is
postulated in the transition state, therefore p-orbital
interactions are optimal, as already suggested by Oppolzer
et al. [4a] and Dofoin et al. [6b] in a similar case.
chiral N-dienyl lactams with acyl nitroso intermediates
generated in situ by using Ru(II)(pybox)(pydic) or Ir(I)-
catalyzed hydrogen peroxide oxidation of hydroxamic acids.
REFERENCES
[1]
For reviews of nitroso Diels-Alder reactions, see: (a) Iwasa, S.;
Fakhruddin, A.; Nishiyama H. Synthesis of acylnitroso
intermediates and their synthetic applications. Mini-Rev. Org.
Chem., 2005, 2, 157. (b) Vogt, P. F.; Miller, M. J. Development
and applications of amino acid-derived chiral acylnitroso hetero
Diels-Alder reactions. Tetrahedron, 1998, 54, 1317.
[2]
(a) Yamamoto, Y.; Yamamoto, H. Catalytic, highly enantio, and
diastereoselective nitroso Diels-Alder reaction. J. Am. Chem. Soc.,
2004, 126, 4128. (b) Ding, X.; Ukaji, Y.; Fujinami, S.; Inomata, K.
The first enantioselective hetero Diels-Alder reaction of nitroso
compound utilizing tartaric acid ester as a chiral auxiliary. Chem.
Lett., 2003, 32, 582.
[3]
[4]
Cohen, A. D.; Zeng, B.; Kings, S. B.; Toscano, J. P. Direct
observation of an acyl nitroso species in solution by time-resolved
IR. J. Am. Chem. Soc., 2003, 125, 1444.
(a) Oppolzer, W.; Fröstl, W. The perparation of trans-N-Acyl, N-
alkyl-1-amino-1,3-butadienes, preliminary communication. Helv.
Chim. Acta, 1975, 58, 587. (b) Overman, L. E.; Clizbe, L. A.
Synthesis of trichloroacetamido-1,3-dienes: useful aminobutadiene
equivalents for the Diels-Alder reaction. J. Am. Chem. Soc., 1976,
98, 2352.
[5]
(a) Janey, J. M.; Iwama, T.; Kozmin, S. A.; Rawal, V. H. Racemic
and a Diels-Alder reactions of 1-(2-Oxazolidinon-3-yl)-3-siloxy-
1,3-butadienes. J. Org. Chem., 2000, 65, 9059. (b) Kozmin, S. A.;
Rawal, V. H. Chiral amino siloxy dienes in the Diels-Alder
reaction: applications to the asymmetric synthesis of 4-substituted
and 4,5-disubstituted cyclohexenones and the total synthesis of (-)-
ꢀꢁElemene. J. Am. Chem. Soc., 1999, 121, 9562. (c) Murphy, J. P.;
Nieuwenhuyzen, M.; Reynolds, K.; Sarma, P.; Stevenson, P. J.
Chiral dienamides-substrates for asymmetric synthesis of amido
cyclohexenes. Tetrahedron Lett., 1995, 36, 9533.
[6]
[7]
(a) Menezes, R. F.; Zezza, C. A.; Sheu, J.; Smith, M. B. Ethyl N-
dienyl pyroglutamates: novel asymmetric dienes. Tetrahedron
Lett., 1989, 30, 3295. (b) Behr, J. -B.; Defoin, A.; Pires, J.; Streith,
J.; Macko, L.; Zehnder, M. Chiral N-dienyl-L-pyroglutamic esters
in asymmetric hetero-Diels-Alder reactions with acylnitroso
dienophiles. Tetrahedron, 1996, 52, 3283.
(a) Iwasa, S.; Fakhruddin, A.; Widagdo, H. S.; Nishiyama, H. A
rapid and efficient synthesis of quinone derivatives: Ru(II)- or Ir(I)-
catalyzed hydrogen peroxide oxidation of phenols and
methoxyarenes. Adv. Synth. Catal., 2005, 347, 517. (b) Iwasa, S.;
Fakhruddin, A.; Tsukamoto, Y.; Kameyama, M; Nishiyama, H.
Iridium(I)-catalyzed hydrogen peroxide oxidation of hydroxamic
acids and hetero Diels-Alder reaction of the acyl nitroso
intermediates with cyclopentadiene. Tetrahedron Lett., 2002, 43,
6159. (c) Iwasa, S.; Tajima, K.; Tsushima, S.; Nishiyama, H. A
mild oxidation method of hydroxamic acids: efficient trapping of
acyl nitroso intermediates. Tetrahedron Lett., 2001, 42, 5897.
EXPERIMENTAL SECTION
General procedure is shown in (Table 1, entry 22): To a
solution of hydroxamic acid 2c (49.0 mg, 0.36 mmol) and N-
dienyl-L-pyroglutamate ester 1b (71.2 mg, 0.3 mmol) in
MeOH (3 mL) was added a solid of Ru(pybox-I-pr)(pydic)
(9.0 mg, 0.015 mmol) and was stirred for 2 minutes. Then, it
was placed in an ice-bath to lower the temperature to 0 ˚C
and followed by addition of hydrogen peroxide (31%, 132
mL, 1.2 mmol). The resulting reddish mixture was stirred for
4 h at room temperature. The organic phase was extracted
with CH2Cl2, and dried with Na2SO4. The solvent was
removed under reduced pressure and the residue was then
purified by column chromatography on silica gel
25.7
[8]
3f: yellowish resin; Rf (Et2O) = 0.64; [ꢀ]D = -96.27 (c = 0.25,
CHCl3); IR (film) : 2979, 2919, 1732, 1714, 1659, 1476, 1409,
1
1367, 1239, 1169, 1093, 1018 cm-1; H-NMR (300 MHz, CDCl3):
ꢂ= 6.20 (br qn, J = 2.2 Hz, 1H), 6.06 (dddd, J = 1.65, 1.92, 3.29,
10.17 Hz, 1H), 5.73 (ddt, J = 2.2, 2.75, 10.17 Hz, 1H), 4.31 (dd, J =
1.65, 9.07 Hz, 1H), 4.12 (dddd, J = 1.65, 2.2, 3.29, 17.86 Hz, 1H),
4.03 (dddd, J = 1.92, 2.2, 2.47, 17.86 Hz, 1H), 2.64-2.47 (m, 1H),
2.44-2.23 (m, 2H), 2.05-1.91 (m, 1H), 1.50 (s, 9H), 1.45 ppm (s,
9H);13C-NMR (100 MHz, CDCl3): ꢂ= 175.9, 172.2, 155.2, 128.1,
(Hexane:EtOAc
=
4:1) to give asymmetric HDA
cycloadducts 3f and 4f (109 mg) in 98% isolated yield [8].
123.6, 82.3, 82.2, 77.6, 58.6, 44.5, 29.6, 28.5, 28.1, 24.4 ppm. 4f:
25.3
CONCLUSION
colorless crystal; Rf (Et2O) = 0.48; mp : 127-128 ˚C; [ꢀ]D
=
+18.92 (c = 0.1, CHCl3); IR (KBr): 2972, 2931, 1731, 1714, 1652,
In conclusion, moderate to high yields with good
diastereoselectivities were achieved in HDA cycloaddition of
1479, 1455, 1416, 1216, 1136, 1091, 1022 cm-1; 1H-NMR (300

478 Letters in Organic Chemistry, 2010, Vol. 7, No. 6
Fakhruddin et al.
MHz, CDCl3): ꢀ= 6.09 (dddd, J = 1.65, 2.75, 3.85, 10.17 Hz, 1H ),
5.8 (br qn, J = 2.2 Hz, 1H), 5.86 (ddt, J = 1.93, 2.2, 10.17 Hz, 1H),
4.28 (dd, J = 2.20, 8.79 Hz, 1H), 4.14 (dddd, J = 1.92, 2.75, 3.85,
17.58 Hz, 1H), 3.96 (ddd, J = 2.2, 4.95, 17.58 Hz, 1H), 2.69-2.54
(m, 1H), 2.41-2.18 (m, 2H), 2.12-2.00 (m, 1H), 1.49 (s, 9H), 1.46
ppm (s, 9H);13C-NMR (100 MHz, CDCl3): ꢀ= 176.2, 171.6, 155.5,
124.3, 123.9, 82.5, 82.2, 79.6, 59.2, 45.1, 30.6, 28.5, 28.1, 24.0
ppm.