Asymmetric hetero diels-alder reaction of nitroso compounds utilizing tartaric acid ester as a chiral auxiliary

Article abstract of DOI:10.3987/COM-08-S(N)94

The regio- and enantioselective hetero Diels-Alder reaction of a nitroso compound with a cyclic dienol, cyclohexa-1,3-dienylmethanol, has been realized utilizing stoichiometric amount of tartaric acid ester as a chiral auxiliary to afford the corresponding dihydro-1,2-oxazine with complete regioselectivity and high enantioselectivity of up to 92% ee. A catalytic version of the asymmetric hetero Diels-Alder reaction of nitroso compounds with the dienol was also achieved to afford the corresponding optically active cycloadducts with up to 83% ee. The addition of MS 4A was crucial to realize reproducible high enantioselectivity.

Full text of DOI:10.3987/COM-08-S(N)94

HETEROCYCLES, Vol. 76, No. 2, 2008
1285
HETEROCYCLES, Vol. 76, No. 2, 2008, pp. 1285 - 1300. © The Japan Institute of Heterocyclic Chemistry
Received, 3rd April, 2008, Accepted, 19th May, 2008, Published online, 22nd May, 2008. COM-08-S(N)94
ASYMMETRIC HETERO DIELS-ALDER REACTION OF NITROSO
COMPOUNDS UTILIZING TARTARIC ACID ESTER AS A CHIRAL
AUXILIARY
Hiroki Sakai, Xia Ding, Tetsusuke Yoshida, Shuhei Fujinami, Yutaka
Ukaji,* and Katsuhiko Inomata*
Division of Material Sciences, Graduate School of Natural Science and
Technology, Kanazawa University, Kakuma, Kanazawa, Ishikawa 920-1192,
Japan; inomata@cacheibm.s.kanazawa-u.ac.jp
Dedicated to Professor Ryoji Noyori on the occasion of his 70th birthday.
Abstract – The regio- and enantioselective hetero Diels-Alder reaction of a
nitroso compound with a cyclic dienol, cyclohexa-1,3-dienylmethanol, has been
realized utilizing stoichiometric amount of tartaric acid ester as a chiral auxiliary
to afford the corresponding dihydro-1,2-oxazine with complete regioselectivity
and high enantioselectivity of up to 92% ee.
A catalytic version of the
asymmetric hetero Diels-Alder reaction of nitroso compounds with the dienol
was also achieved to afford the corresponding optically active cycloadducts with
up to 83% ee. The addition of MS 4A was crucial to realize reproducible high
enantioselectivity.
INTRODUCTION
The hetero Diels-Alder reaction provides a very convenient approach to the synthesis of six-membered
partially saturated heterocycles, a class of compounds that have been found extensive use as starting
materials for total syntheses of natural products.1 A wide range of nitroso compounds have been proven
to be useful dienophiles for the hetero Diels-Alder reaction to afford dihydro-1,2-oxazine derivatives,
which are key intermediates for the synthesis of biologically active nitrogen-containing chemicals.
Development of asymmetric hetero Diels-Alder reaction of nitroso compounds was for a long time
restricted to only diastereoselective reactions using chiral dienes or chiral nitroso compounds in spite of
the great potential of the synthetic methodology.2.3 Very recently catalytic hetero Diels-Alder reactions
of nitroso compounds catalyzed by chiral metal complexes were reported.4-8

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HETEROCYCLES, Vol. 76, No. 2, 2008
A novel chiral multinucleating system utilizing tartaric acid ester as a chiral auxiliary was developed in
our laboratory and it has been successfully applied to the asymmetric 1,3-dipolar cycloaddition reaction.9
The promising results obtained from the 1,3-dipolar cycloaddition tempted us to apply this strategy for
the enantioselective hetero Diels-Alder reaction of nitroso compound by the use of tartaric acid ester as a
chiral auxiliary. When a dienol is successively treated with diisopropylzinc, a stoichiometric amount of
diisopropyl (R,R)-tartrate [(R,R)-DIPT], propylzinc bromide, zinc-bridging intermediate would be
presumably formed. To the intermediate is added a nitroso compound, it can be activated and well
oriented as depicted as A in Eq. 1. The subsequent hetero Diels-Alder reaction is anticipated to proceed
to give the corresponding dihydro-1,2-oxazine derivatives in an enantioselective manner.10 Based upon
this hypothesis, the hetero Diels-Alder reaction was examined.11
OiPr
O
O
Br
Zn
R4N O
R2 R3
1) iPr2Zn
R2 R3
OH
R4N O
2) (R,R)-DIPT
O
R1
(1)
R1
R2
*
*
3) nPrZnBr
4) R4N=O
O Zn
OiPr
R3
OH
R1
O
A
RESULTS AND DISCUSSION
First, the enantioselective hetero Diels-Alder reaction of nitrosobenzene (2a) to (E)-2,4-pentadien-1-ol
(1A) was examined (Eq. 2, R = H). When 1A was treated with 1.0 equivalent of diisopropylzinc,
(R,R)-DIPT, propylzinc bromide, and 2a successively, the corresponding dihydro-1,2-oxazine derivative
was obtained as a mixture of regioisomers 3A and 4A with different N-O orientation in favor of 3A, in
which oxygen of the nitroso group oriented toward the diene carbon bearing CH2OH moiety. The
enantioselectivity of the major product 3A was 33% ee. The hetero Diels-Alder reaction to
(E,E)-2,4-hexadien-1-ol (1B) was also examined to give 3B with the enantioselectivity of 55% ee along
with the regioisomer 4B (Eq. 2, R = Me). This modest enantioselectivity encouraged us to further
investigate the reaction.
1) iPr2Zn (1.0 equiv.)
2) (R,R)-DIPT (1.0 equiv.)
PhN O
OH
(2)
regio isomers 4
R
R
3) nPrZnBr (1.0 equiv.)
4) PhN=O 2a (1.0 equiv.)
0 °C, 24 h, in CHCl3
OH
3
1
A; R = H, 37%, 33% ee
B; R = Me, 57%, 55% ee
13% yield
28% yield

HETEROCYCLES, Vol. 76, No. 2, 2008
1287
When cyclohexa-1,3-dienylmethanol (5) was used as a diene component as shown in Eq. 3, we were
pleased to find that the reaction proceeded in complete regioselective manner to afford the corresponding
bicyclic dihydro-1,2-oxazine 6a as a sole product with enantioselectivity of 63% ee. To our surprise, the
sense of enantiofacial discrimination of 5 was opposite to that in the case of 1, that is, nitrosobenzene (2a)
attacked from re-face at the C1 position of 5, while the reaction occurred from si-face at the C2 position
of 1, as will be described later.12
1) iPr2Zn (1.0 equiv.)
O
2) (R,R)-DIPT (1.0 equiv.)
Ph
OH
N
OH
(3)
1
3) nPrZnBr (1.0 equiv.)
4) PhN=O 2a (1.0 equiv.)
0 °C, 20 h, in CHCl3
H
5
6a
91%, 63% ee
A number of conditions have been attempted to improve the chemical yield and selectivity of the present
hetero Diels-Alder reaction. An alternative procedure by successive treatment of (R,R)-DIPT with
propylzinc bromide and diisopropylzinc, followed by addition of the dienol 5 and nitrosobenzene (2a)
was tried as shown in Eq. 4. The effects of solvent and chiral auxiliary were also examined as listed in
Table 1. It was found that enantioselectivity of the cycloadduct 6a was remarkably influenced by the
solvent employed. The good chemical yields were observed in halocarbon solvents and toluene (Entries
1–3). The highest optical yield was attained in diethyl ether when (R,R)-DIPT was used as a chiral
auxiliary (Entry 8). Optimization of chemical yield and enantioselectivity was attempted with other
tartrates as the chiral auxiliary. The use of bulky di(t-butyl) (R,R)-tartrate [(R,R)-DTBT] increased
enantioselectivity of the corresponding cycloadduct 6a up to 88% ee in 76% yield in diethyl ether (Entry
14). Moreover, cycloadduct 6a was obtained with more than 91% ee when diethyl ether was replaced by
t-butyl methyl ether as a solvent, though the chemical yield decreased a little (Entry 15). It was reported
that dimerization of nitrosobenzene (2a) strongly depends on the concentration of the solution; the
monomer predominantly exists in dilute solution.13 Dilution of the reaction mixture was thus expected
to be effective to suppress the undesirable dimerization of nitrosobenzene (2a). Therefore, the reaction
was performed under the dilute conditions using t-butyl methyl ether as a solvent. Under the dilute
conditions, the reaction was conducted on a 0.5 mmol scale in 18 mL of t-butyl methyl ether as a solvent.
Gratifyingly, the chemical yield was remarkably increased from 56% to 73% with high enantioselectivity
(Entry 16). Furthermore, it was found that the slow charge of excess amount of solid nitrosobenzene
(2a) was remarkably effective: when 1.5 equivalents of solid 2a was added to the reaction mixture over a
period of 3 h, the chemical yield was improved to 94% with excellent enantioselectivity of up to 92% ee
(Entry 17).

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HETEROCYCLES, Vol. 76, No. 2, 2008
1) nPrZnBr (1.0 equiv.)
2) iPr2Zn (1.0 equiv.)
O
N
HO
HO
CO2R'
CO2R'
Ph
OH
(4)
OH
3)
H
(1.0 equiv.)
5
(1.0 equiv.)
6a
4) PhN=O 2a (1.0 equiv.)
0 °C, 20 h, solvent
Table 1. The effects of solvent and chiral auxiliarya
Entry
R’
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
Solvent
CHCl3
CH2Cl2
toluene
iPr2O
Yield/%
ee/%b
72
1
2
3
4
5
6
7
8
86
80
82
51
18
64
64
69
74
69
64
THF
57
DME
20
MeCN
Et2O
37
77
9
Et
Et2O
Et2O
43
17
60
11
10
Bn
11
12
Et2O
Et2O
83
67
46
67
13
Et2O
69
70
14
tBu
tBu
tBu
tBu
tBu
Et2O
76
56
73
94
92
88
91
89
92
91
15
tBuOMe
tBuOMe
tBuOMe
tBuOMe
16c
17c,d
18c,e
aThe reaction was carried out on a 0.5 mmol scale in 9 mL of solvent.
bEnantiomer ratios were determined by HPLC analysis (Daicel
Chiralcel OJ-H). cThe reaction was carried out on a 0.5 mmol scale in
18 mL of solvent. dThe solid 2a (1.5 equiv.) was added over a period
of 3 h. eThe solid 2a (2.0 equiv.) was added over a period of 3 h.
Next, a catalytic process of the hetero Diels-Alder reaction was investigated. That is, when 0.2
equivalent of (R,R)-DTBT was treated with 0.2 equivalent of propylzinc bromide, 1.0 equivalent of
diisopropylzinc, 1.0 equivalent of 5, and 1.5 equivalents of solid 2a successively, the corresponding
cycloadduct 6a was obtained with the enantioselectivity of 33% ee (Eq. 5).

HETEROCYCLES, Vol. 76, No. 2, 2008
1289
1) nPrZnBr (0.2 equiv.)
2) iPr2Zn (1.0 equiv.)
t
O
N
HO
HO
CO2 Bu
Ph
OH
(5)
OH
(1.0 equiv.)
t
CO2 Bu
3)
H
6a
24%, 33% ee
5
(0.2 equiv.)
4) PhN=O 2a (1.5 equiv.)
0 °C, 20 h, in tBuOMe
The conversion of all hydroxy groups in dienol 5 and DTBT into the corresponding bromozinc alkoxides
by the treatment with propylzinc bromide, was found to be more effective to improve enantioselectivity
of the corresponding cycloadduct 6a up to 66% ee (Eq. 6, Table 2, Entry 1). The cycloaddition in
CH2Cl2 or toluene as a solvent furnished 6a with higher enantioselectivity of 79 and 78% ee, respectively
(Entries 2 and 3). The reaction in ethylbenzene and cumene attained higher enantioselectivities over
80% ee (Entries 4 and 5). However, the enantioselectivities were not reproducible. Several attempts
using a 0.2 equivalent of (R,R)-DTBT, especially paying attention to anhydrous conditions, showed that
the addition of MS 4A was crucial to realize extremely anhydrous conditions to obtain reproducible
results. In the presence of MS 4A, the effect of the solvent was further examined (Entries 6–8, 10, 13
and 14). In aromatic solvents, the hetero Diels-Alder reaction proceeded smoothly to give 6a with over
70% ee. Enantioselectivities were varied depending on the kind of molecular sieves, and MS 4A was
effective for higher entioselectivity (Entries 9-12). Finally, cumene was reproducibly realized the
highest enantioselectivity of 83% ee though the difference was not so big among aromatic solvents.
1) additive
OH
2)
t
O
HO
HO
CO2 Bu
Ph
(1.0 equiv.)
5
N
OH
(6)
3) nPrZnBr (1.4 equiv.)
4) PhN=O 2a (1.5 equiv.)
slow addition (3 h)
t
CO2 Bu
H
(0.2 equiv.)
6a
0 °C, t h, solvent
Next catalytic asymmetric hetero Diels-Alder reaction of several nitroso compounds 2 with the dienol 5
was performed (Eq. 7, Table 3). In the cases of nitrosobenzenes substituted with an
electron-withdrawing group, such as nitro group, enantioselectivity was decreased, which suggested that
such nitroso compounds were reactive enough without activation by chiral zinc moiety and non-catalyzed
racemic reaction might have been accompanied (Entries 2–4). The nitrosobenzenes substituted with a
methyl or phenoxy group showed good enantioselectivities (Entries 5 and 6). The hetero Diels-Alder
reaction of the electron donating 4-(N,N-dimethylamino)-substituted nitrosobenzene 2h did not proceed at
0 °C. Coordination of dimethylamino group to zinc metal might disturb the cycloaddition reaction.

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HETEROCYCLES, Vol. 76, No. 2, 2008
Table 2. The effect of solvent and additive (molecular sieves)a
Entry
1
Solvent
tBuOMe
CH2Cl2
Additive
--
t/h
20
20
20
20
20
41
44
40
20
20
20
20
20
20
Yield/% ee/%b
83
83
99
80
81
69
69
71
70
77
72
78
81
86
66
79
78
81
81
60
47
70
67
74
66
44
77
83
2
--
3
toluene
--
4
ethylbenzene
cumene
tBuOMe
Et2O
--
5
--
6
MS 4A
MS 4A
MS 4A
MS 3A
MS 4A
MS 5A
MS 13X
MS 4A
MS 4A
7
8
CH2Cl2
9
toluene
10
11
12
13
14
ethylbenzene
cumene
aThe reaction was carried out on a 0.5 mmol scale in 18 mL of solvent.
bEnantiomer ratios were determined by HPLC analysis (Daicel
Chiralcel OJ-H).
1) MS 4A
OH
2)
t
O
N
HO
HO
CO2 Bu
Ar
(1.0 equiv.)
5
OH
(7)
3) nPrZnBr (1.4 equiv.)
4) ArN=O 2 (1.5 equiv.)
slow addition (3 h)
t
CO2 Bu
H
(0.2 equiv.)
6
0 °C, 20 h, cumene
Table 3. Catalytic hetero Diels-Alder reaction of nitroso
compounds 2a
Entry
Ar
Yield/%
86
ee/%b
1
2
3
4
5
6
7
8
Ph
a
b
c
83
p(O2N)C6H4
p(MeO2C)C6H4
pBrC6H4
89
33
76
69
d
e
90
70
pMeC6H4
80
70c
83
p(PhO)C6H4
p(BuO)C6H4
p(Me2N)C6H4
f
76
g
h
41
49
--
--
aThe reaction was carried out on a 0.5 mmol scale in 18 mL of
solvent. bEnantiomer ratios were determined by HPLC analysis
(Daicel Chiralcel OJ-H). cThe regioisomer was obtained in 7%
yield.

HETEROCYCLES, Vol. 76, No. 2, 2008
1291
Furthermore, catalytic asymmetric hetero Diels-Alder reaction to acyclic dienols 1A and 1B was carried
out. However, the enantioselectivities were poor (Eq. 8).
1) MS4A
OH
2)
R
t
(1.0 equiv.)
HO
HO
CO2 Bu
PhN O
1
regio isomers 4
(8)
R
3) nPrZnBr (1.4 equiv.)
4) PhN=O 2a (1.5 equiv.)
slow addition (3 h)
t
OH
CO2 Bu
3
(0.2 equiv.)
A; R = H, 28%, 10% ee
B; R = Me, 22%, 7% ee
5% yield
11% yield
0 °C, 20 h, cumeme
The absolute stereochemistry at the C6 position of 3B was confirmed to be S by chemical correlation:
25
cycloadduct 3B (55% ee) was transformed to compound 8 ([α]D +5 (c 0.12, CHCl3)) according to
Scheme 1. The absolute configuration of 8 was determined to be R by the comparison with specific
optical rotation of the known (R)-8 (56% ee; [α]D +4.0 (c 1.0, CHCl3)).14 The stereochemistry of 3A was
tentatively assigned to be S.
PhN O
PhNH
O
1) O3, then NaBH4
O
1) Zn, aq HCl
R
O
O
PhCOO
6S
2) PhCOCl, Et3N
45% (2 steps)
2) Me2C(OMe)2
cat. TsOH
57% (2 steps)
OH
H
H
7
3B
8
(55% ee)
Scheme 1
Furthermore, the absolute configuration of 6a was determined to be 1R,4S as follows: the
enantiomerically rich 6a was treated with (S)-N-(4-nitrophenylsulfonyl)phenylalanyl chloride and
triethylamine in the presence of a catalytic amount of DMAP in CH2Cl2 to give the corresponding ester 9
(71%). The absolute stereochemistry of 9 was determined to be 1R,4S by X-ray crystallographic
analysis of its single crystal, obtained by recrystallization from EtOAc, as shown in Figure 1. The
stereochemistry of 6b-6g was tentatively assigned to be 1R,4S.

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HETEROCYCLES, Vol. 76, No. 2, 2008
Although the precise reaction mechanism is not yet clear, the plausible transition state in the
stoichiometric reaction of nitrosobenzene (2a) and dienol 1 is shown in Figure 2 to rationalize the
absolute configuration of 3B determined above. Four kinds of transition state, endo-1, exo-1, endo-2,
and exo-2, are possible. Among them, endo-1 and exo-1 might be disfavored due to steric hindrance
between benzene ring of nitrosobenzene and the ester moiety of the tartrate. The cycloaddition might
proceed via exo-2 leading to (6S)-product in order to avoid steric congestion between benzene ring of
nitrosobenzene and diene moiety in dienol 1 in preference to a secondary orbital interaction found in
endo-2. When the cyclic dienol 5 was reacted with nitrosobenzene, both endo-3 and exo-3 are possible,
in which steric repulsion between the benzene ring of nitrosobenzene and cyclohexadiene moiety of
dienol 5 is not so much different each other as shown in Figure 3. In this case, the secondary orbital
interaction might prefer endo-3, leading to 1R,4S, to exo-3. In the catalytic reaction to 5, it is not yet
clear whether the similar intermediate to that in the stoichiometric reaction was produced along with the
generation of ZnBr2 or a different intermediate was formed. As a comparable level of chiral induction
was realized in the reaction of 2a and 5, the essential part of the structure in the transition state might be
common.
OR'
O
R'O
OR'
O
R'O
O
O
O
O
Zn
Zn
O
Zn
O
Br
Br
Zn
O
O
O
O
O
O
N
N
N
N
H
H
H
H
R
R
endo-1
exo-1
OR'
O
R'O
O
OR'
O
R'O
O
O
Zn
O
Zn
O
Zn
O
Br
Br
Zn
O
O
O
O
O
N
N
LUMO
H
H
HOMO
H
H
R
R
secondary
orbital
interaction
endo-2
exo-2
Figure 2

HETEROCYCLES, Vol. 76, No. 2, 2008
1293
OR'
R'O
OR'
O
R'O
O
O
O
O
O
Zn
O
Zn
O
Br
Br
Zn
O
Zn
O
O
O
O
O
N
LUMO
N
HOMO
secondary
orbital
interaction
endo-3
exo-3
Figure 3
In conclusion, we could establish an enantioselective hetero Diels-Alder reaction with nitroso compounds
by utilizing tartaric acid ester as a chiral auxiliary. This approach will offer an appealing entry to the
synthesis of six-membered heterocycles that are versatile synthetic intermediates for total syntheses of
various natural products.
EXPERIMENTAL
1H NMR spectra were recorded on a JEOL Lambda 400 NMR spectrometer. Chemical shifts were
determined in the δ−scale relative to TMS (δ = 0 ppm) as an internal standard. IR spectra were
measured on a JASCO FT/IR-230 spectrometer. MS spectra were recorded with a JEOL SX-102A mass
spectrometers. THF and Et2O were freshly distilled from sodium diphenylketyl. CHCl3 was passed
through aluminium oxide (Merck 1076) twice and further dried over MS 3A before use. All other
solvents were distilled and dried over drying agents. Thin-layer chromatography (TLC) and flash
column chromatography were performed by using Merck silica gel 60 PF254 (Art. 7749) and Cica-Merck
silica gel 60 (No. 9385-5B), respectively.
Stoichiometric asymmetric hetero Diels-Alder reaction of nitrosobenzene (2a) to
(E,E)-2,4-hexadien-1-ol (1B) (Eq. 2): To a solution of (E,E)-2,4-hexadien-1-ol (1B) (49 mg, 0.5
mmol) in CHCl3 (3 mL) was added diisopropylzinc (1.0 M solution in hexane, 0.5 mL, 0.5 mmol) at 0 °C
under an argon atmosphere and stirred for 10 min. A solution of (R,R)-DIPT (117 mg, 0.5 mmol) in
CHCl3 (3 mL) was further added dropwise and the resulting solution was kept for 10 min at the same
temperature. Propylzinc bromide (0.5 M solution in THF, 1 mL, 0.5 mmol) was added to the resulting
solution. Stirring was continued for 1 h, followed by addition of nitrosobenzene (2a) (54 mg, 0.5 mmol)
in CHCl3 (3 mL). The resulting mixture was kept for 24 h at 0 °C and then treated with a saturated aq

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HETEROCYCLES, Vol. 76, No. 2, 2008
NH4Cl solution. After warming to rt, the solvent was removed in vacuo and the residue was partitioned
between EtOAc and water. The organic extracts were washed successively with water, brine and dried
over Na2SO4. Evaporation of the solvent and separation of the residue by preparative TLC
(hexane/EtOAc = 2/1, v/v) afforded the products 3B (59 mg, 57%) and 4B (29 mg, 28%) as colorless oils.
Enantiomer ratio of 3B was determined by HPLC analysis (Daicel Chiralcel OD-H, hexane/EtOH = 30/1,
v/v).
In a similar manner, asymmetric hetero Diels-Alder reaction of nitrosobenzene (2a) to
(E)-2,4-pentadien-1-ol (1A) was carried out.
(S)-(2-Phenyl-3,6-dihydro-2H-1,2-oxazin-6-yl)methanol (3A): An oil. [α]D25 +5 (c 0.46, EtOH; 33%
ee). IR (neat) 3390, 3041, 2926, 2865, 2819, 1598, 1491, 1454, 1431, 1389, 1350, 1292, 1213, 1183,
1156, 1100, 1080, 1043, 1009, 876, 757, 691 cm–1. 1H NMR (CDCl3) δ = 2.57 (1H, brs), 3.77–3.92 (4H,
m), 4.62–4.64 (1H, m), 5.89 (1H, dd, J = 10.25, 1.71 Hz), 6.09 (1H, m), 7.03 (1H, t, J = 7.32 Hz), 7.16
(2H, d, J = 8.29 Hz), 7.32 (2H, dd, J = 8.29, 7.32 Hz). HRMS (EI+) M+, Found: m/z 191.09541. Calcd
for C11H13NO2:191.09463.
(2-Phenyl-3,6-dihydro-2H-1,2-oxazin-3-yl)methanol (4A): An oil. IR (neat) 3396, 3040, 2933,
2883, 2842, 1596, 1492, 1454, 1435, 1387, 1259, 1228, 1183, 1072, 1044, 1018, 975, 840, 758, 693 cm–1.
1H NMR (CDCl3) δ = 2.26 (1H, dd, J = 7.56, 4.88 Hz), 3.76 (1H, ddd, J = 11.47, 7.56, 3.90 Hz), 3.84 (1H,
ddd, J = 11.47, 6.83, 4.88 Hz), 4.14–4.19 (1H, m), 4.16 (1H, dd, J = 15.86, 1.95 Hz), 4.41 (1H, dd, J =
15.86, 2.44 Hz), 5.97–5.98 (2H, m), 6.70 (1H, t, J = 7.32 Hz), 7.11 (2H, d, J = 8.78 Hz), 7.31 (2H, dd, J =
8.78, 7.32 Hz). HRMS (EI+) M+, Found: m/z 191.09389. Calcd for C11H13NO2:191.09463.
((3S,6S)-3-Methyl-2-phenyl-3,6-dihydro-2H-1,2-oxazin-6-yl)methanol (3B): An oil. [α]D25 +122 (c
0.63, EtOH; 55% ee). IR (neat) 3371, 3038, 2974, 2929, 2869, 1598, 1492, 1453, 1390, 1362, 1340,
1258, 1185, 1133, 1085, 1047, 953, 896, 853, 757, 736, 694 cm–1. 1H NMR (CDCl3) δ = 1.10 (3H, d, J =
6.59 Hz), 2.79 (1H, br), 3.79 (1H, dd, J = 11.95, 5.86 Hz), 3.89 (1H, dd, J = 11.95, 3.17 Hz), 4.08 (1H,
qdd, J = 6.59, 2.20, 1.95 Hz), 4.60–4.62 (1H, m), 5.80 (1H, ddd, J = 10.25, 1.95, 1.70 Hz), 6.05 (1H, ddd,
J = 10.25, 3.90, 2.20 Hz), 7.04 (1H, t, J = 7.32 Hz), 7.14 (2H, d, J = 7.81 Hz), 7.31 (2H, dd, J = 7.81, 7.32
Hz). HRMS (EI+) M+, Found: m/z 205.10972. Calcd for C12H15NO2: 205.11028.
6-Methyl-2-phenyl-3,6-dihydro-2H-1,2-oxazin-3-yl)methanol (4B): An oil. IR (neat) 3397, 3038,
2975, 2930, 2871, 1597, 1492, 1453, 1388, 1372, 1329, 1258, 1184, 1146, 1126, 1086, 1034, 958, 929,
882, 842, 756, 693 cm–1. 1H NMR (CDCl3) δ = 1.27 (3H, d, J = 6.83 Hz), 2.34 (1H, dd, J = 7.08, 6.59
Hz), 3.76 (1H, ddd, J = 11.22, 7.08, 3.90 Hz), 3.82 (1H, ddd, J = 11.22, 6.59, 4.39 Hz), 4.13–4.18 (1H,
m), 4.48 (1H, qdd, J = 6.83, 4.39, 1.22 Hz), 5.86 (1H, dt, J = 10.25, 1.22 Hz), 5.93 (1H, ddd, J = 10.25,
4.39, 1.22 Hz), 6.98 (1H, t, J = 7.32 Hz), 7.07 (2H, d, J = 8.78 Hz), 7.30 (2H, dd, J = 8.78, 7.32 Hz).
HRMS (EI+) M+, Found: m/z 205.11113. Calcd for C12H15NO2: 205.11028.

HETEROCYCLES, Vol. 76, No. 2, 2008
1295
Stoichiometric asymmetric hetero Diels-Alder reaction of nitrosobenzene (2a) to
cyclohexa-1,3-dienylmethanol (5) (Table 1, Entry 17): To a solution of (R,R)-DTBT (131 mg, 0.5
mmol) in t-butyl methyl ether (9 mL) was added propylzinc bromide (0.5 M solution in THF, 1 mL, 0.5
mmol) at 0 °C under an argon atmosphere and the resulting solution was kept for 15 min with stirring.
Diisopropylzinc (1.0 M solution in hexane, 0.5 mL, 0.5 mmol) was further added at the same temperature.
After stirring for another 15 min, a solution of cyclohexa-1,3-dienylmethanol (5) (55 mg, 0.5 mmol) in
t-butyl methyl ether (9 mL) was added. Stirring was continued for 1 h, followed by addition of solid
nitrosobenzene (2a) (81 mg, 0.75 mmol) over a period of 3 h. The resulting mixture was kept for 20 h at
0 °C and then treated with a saturated aq NH4Cl solution. After warming to rt, the solvent was removed
in vacuo and the residue was partitioned between EtOAc and water. The organic extracts were washed
successively with water, brine and dried over Na2SO4. Evaporation of the solvent and separation of the
residue by preparative TLC (hexane/EtOAc = 2/1, v/v) afforded the desired cycloadduct 6a as a colorless
oil (101 mg, 94%). Enantiomer ratio was determined to be 92% ee by HPLC analysis (Daicel Chiralcel
OJ-H, hexane/EtOH = 2/1, v/v).
(1R,4S)-(3-Phenyl-2-oxa-3-azabicyclo[2.2.2]oct-5-en-1-yl)methanol (6a): An oil. [α]D25 –60 (c 1.69,
EtOH; 92% ee). IR (neat) 3389, 3057, 2934, 2860, 1596, 1488, 1451, 1377, 1224, 1190, 1101, 1058,
972, 907, 872, 849, 806, 763, 698 cm–1. 1H NMR (CDCl3) δ = 1.28 (1H, ddd, J = 12.20, 11.95, 4.15 Hz),
1.62 (1H, ddt, J = 12,69, 11.95, 3.17 Hz), 1.89 (1H, brs), 2.06 (1H, ddd, J = 12.20, 9.51, 3.17 Hz), 2.34
(1H, dddd, J = 12.69, 9.51, 4.15, 2.92 Hz), 3.86 (1H, d, J = 12.20 Hz), 3.90 (1H, d, J = 12.20 Hz), 4.42
(1H, dddd, J = 5.60, 3.17, 2.92, 1.44 Hz), 6.17 (1H, dd, J = 8.27, 5.60 Hz), 6.53 (1H, dd, J = 8.27 1.44
Hz), 6.93 (1H, t, J = 7.32 Hz), 6.99 (2H, d, J = 7.81 Hz), 7.21 (2H, dd, J = 7.81, 7.32 Hz). HRMS
(FAB+) (M + H)+, Found: m/z 218.11831. Calcd for C13H16NO2: 218.11810.
Representative Procedure for catalytic asymmetric hetero Diels-Alder reaction of nitrosobenzene
(2a) to cyclohexa-1,3-dienylmethanol (5) (Table 3, Entry 1): MS 4A (300 mg) was activated by
heating prior to use under reduced pressure. To a mixed solution of (R,R)-DTBT (26 mg, 0.1 mmol) and
cyclohexa-1,3-dienylmethanol (5) (55 mg, 0.5 mmol) in cumene (18 mL) in the presence of MS 4A was
added propylzinc bromide (0.5 M solution in THF, 1.4 mL, 0.7 mmol) at 0 °C under an argon atmosphere.
After stirring for 10 min, solid nitrosobenzene (2a) (81 mg, 0.75 mmol) was added over a period of 3 h.
The resulting mixture was kept for 20 h at 0 °C and then treated with a saturated aq NH4Cl solution, and
the solvent was evaporated. The organic substances were extracted with EtOAc, followed by washing
with H2O, brine, and dried over Na2SO4. After evaporating the solvent, the residue was purified by a
column chromatography (SiO2, hexane/EtOAc = 2/1, v/v) to give the corresponding hetero Diels-Alder
adduct 6a as a colorless oil (93 mg, 86%). Enantiomer ratio was determined to be 83% ee by HPLC
analysis (Daicel Chiralcel OJ-H, hexane/EtOH = 2/1, v/v).

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In a similar manner, catalytic asymmetric hetero Diels-Alder reaction of nitroso compounds 2b-2h was
performed.
((1R,4S)-3-(4-Nitrophenyl)-2-oxa-3-azabicyclo[2.2.2]oct-5-en-1-yl)methanol (6b): A solid. Mp
126–127 °C (from EtOH). [α]D25 –3 (c 1.17, EtOH; 33% ee). IR (KBr) 3569, 3385, 3105, 2928, 1589,
1504, 1491, 1335, 1263, 1182, 1116, 1051, 979, 968, 845, 751, 718 cm–1. 1H NMR (CDCl3) δ = 1.32
(1H, ddd, J = 12.69, 11.95, 4.15 Hz), 1.70 (1H, ddt, J = 13.17, 11.95, 3.17 Hz), 1.86 (1H, t, J = 6.83 Hz),
2.11 (1H, ddd, J = 12.68, 9.51, 3.17 Hz), 2.34 (1H, dddd, J = 13.17, 9.51, 4.15, 3.17 Hz), 3.92 (1H, dd, J
= 12.20, 6.83 Hz), 3.96 (1H, dd, J = 12.20, 6.83 Hz), 4.67 (1H, dtd, J = 5.61, 3.17, 1.46 Hz), 6.31 (1H, dd,
J = 8.29, 5.61 Hz), 6.54 (1H, dd, J = 8.29, 1.46 Hz), 7.03 (2H, d, J = 9.27 Hz), 8.11 (2H, d, J = 9.27 Hz).
Found: C, 59.60; H, 5.49; N, 10.67%. Calcd for C13H14N2O4: C, 59.53; H, 5.38; N, 10.68%.
Methyl 4-((1R,4S)-1-(Hydroxymethyl)-2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)benzoate (6c):
A
25
solid. Mp 129–130 °C (from EtOAc/hexane). [α]D –38 (c 0.84, EtOH; 69% ee). IR (KBr) 3476,
2966, 2936, 2909, 2858, 1685, 1600, 1504, 1433, 1315, 1283, 1255, 1238, 1227, 1184, 1172, 1114, 1097,
1059, 1007, 981, 855, 776, 715 cm–1. 1H NMR (CDCl3) δ = 1.32 (1H, ddd, J = 12.44, 11.95, 4.15 Hz),
1.67 (1H, dddd, J = 12.93, 11.95, 3.17, 2.93 Hz), 1.90 (1H, t, J = 7.07 Hz), 2.09 (1H, ddd, J = 12.44, 9.51,
3.17 Hz), 2.34 (1H, dddd, J = 12.93, 9.51, 4.15, 2.93 Hz), 3.89 (3H, s), 3.89 (1H, dd, J = 12.20, 7.07 Hz),
3.94 (1H, dd, J = 12.20, 7.07 Hz), 4.58–4.61 (1H, m), 6.25 (1H, dd, J = 8.29 5.61 Hz), 6.51 (1H, dd, J =
8.29, 1.22 Hz), 7.00 (2H, d, J = 8.54 Hz), 7.90 (2H, d, J = 8.54 Hz). Found: C, 65.28; H, 6.30; N, 5.02%.
Calcd for C15H17NO4: C, 65.44; H, 6.22; N, 5.09%.
25
((1R,4S)-3-(4-Bromophenyl)-2-oxa-3-azabicyclo[2.2.2]oct-5-en-1-yl)methanol (6d): An oil. [α]D
+70 (c 0.63, EtOH; 70% ee). IR (neat) 3390, 3056, 2935, 2861, 1584, 1483, 1455, 1398, 1376, 1225,
1191, 1058, 1003, 972, 827, 714 cm–1. 1H NMR (CDCl3) δ = 1.29 (1H, ddd, J = 12.44, 11.95, 4.15 Hz),
1.64 (1H, ddt, J = 12.93, 11.71, 3.17 Hz), 1.93 (1H, brs), 2.06 (1H, ddd J = 12.44, 9.51, 3.17 Hz), 2.33
(1H, dddd, J = 12.93, 9.51, 4.15, 2.92 Hz), 3.87 (1H, d, J = 12.20 Hz), 3.92 (1H, d, J = 12.20 Hz), 4.39
(1H, dddd, J = 5.61, 3.17, 2.92, 1.46 Hz), 6.18 (1H, dd, J = 8.29, 5.61 Hz), 6.53 (1H, dd, J = 8.29, 1.46
Hz), 6.87 (2H, d, J = 8.78 Hz), 7.31 (2H, d, J = 8.78 Hz). HRMS (FAB+) (M + H)+, Found: m/z
269.02847. Calcd for C13H15NO2Br: 296.02861.
25
((1R,4S)-3-(4-Tolyl)-2-oxa-3-azabicyclo[2.2.2]oct-5-en-1-yl)methanol (6e): An oil. [α]D –56 (c
0.93, EtOH; 83% ee). IR (neat) 3390, 3024, 2933, 2861, 1610, 1505, 1453, 1377, 1223, 1190, 1100,
1059, 1014, 973, 849, 822, 750, 704 cm–1. 1H NMR (CDCl3) δ = 1.27 (1H, td, J = 12.20, 4.16 Hz), 1.61
(1H, dddd, J = 12.68, 12.20, 3.42, 2.93 Hz), 1.85 (1H, brs), 2.05 (1H, ddd J = 12.20, 9.86, 3.42 Hz), 2.26
(3H, s), 2.30–2.37 (1H, m), 3.85 (1H, d, J = 12.20 Hz), 3.90 (1H, d, J = 12.20 Hz), 4.36 (1H, ddd, J =
5.85, 2.93, 2.68 Hz), 6.18 (1H, dd, J = 8.29, 5.85 Hz), 6.53 (1H, d, J = 8.29 Hz), 6.88 (2H, d, J = 8.05 Hz),
7.01 (2H, d, J = 8.05 Hz). HRMS (FAB+) (M + H)+, Found: m/z 232.13350. Calcd for C14H18NO2:

HETEROCYCLES, Vol. 76, No. 2, 2008
1297
232.13375.
25
((1R,4S)-3-(4-Phenoxyphenyl)-2-oxa-3-azabicyclo[2.2.2]oct-5-en-1-yl)methanol (6f): An oil. [α]D
–69 (c 1.04, EtOH; 76% ee). IR (neat) 3390, 3058, 2934, 2861, 1589, 1489, 1455, 1376, 1239, 1102,
1058, 974, 871, 847, 759, 693 cm–1. 1H NMR (CDCl3) δ = 1.28 (1H, ddd, J = 12.46, 11.95, 4.15 Hz),
1.62 (1H, dddd, J = 12.93, 11.95, 3.42, 2.92 Hz), 2.05 (1H, ddd J = 12.46, 9.51, 3.42 Hz), 2.23 (1H, brs),
2.34 (1H, dddd, J = 12.93, 9.51, 4.15, 2.92 Hz), 3.85 (1H, d, J = 12.20 Hz), 3.90 (1H, d, J = 12.20 Hz),
4.33 (1H, dtd, J = 5.86, 2.92, 1.46 Hz), 6.19 (1H, dd, J = 8.54, 5.86 Hz), 6.56 (2H, dd, J = 8.54, 1.46 Hz),
6.88 (2H, d, J = 9.03 Hz), 6.94 (2H, d, J = 8.78 Hz), 6.97 (2H, d, J = 9.03 Hz), 7.04 (1H, t, J = 7.32 Hz),
7.29 (2H, dd, J = 8.78, 7.32 Hz). HRMS (FAB+) (M + H)+, Found: m/z 310.14438. Calcd for
C19H20NO3: 310.14432.
(3-(4-Phenoxyphenyl)-2-oxa-3-azabicyclo[2.2.2]oct-5-en-4-yl)methanol (Regioisomer of 6f): An oil.
IR (neat) 3358, 3027, 2925, 2852, 1610, 1588, 1507, 1488, 1313, 1229, 1163, 1100, 1049, 900, 872, 830,
751, 691 cm–1. 1H NMR (CDCl3) δ = 1.26 (1H, t, J = 7.56 Hz), 1.66–1.76 (1H, m), 1.85 (1H, dd J =
10.73, 7.56 Hz), 2.02–2.07 (1H, m), 2.17 (1H, brs), 3.51 (1H, d, J = 10.73 Hz), 3.55 (1H, d, J = 10.73 Hz),
3.89–3.94 (1H, m), 5.81 (1H, d, J = 10.00 Hz), 5.98 (1H, dd, J = 10.00, 2.20 Hz), 6.62 (2H, d, J = 8.78
Hz), 6.90 (2H, d, J = 8.78 Hz), 6.93 (2H, d, J = 8.54 Hz), 7.01 (1H, t, J = 7.32 Hz), 7.27 (2H, dd, J = 8.54,
7.32 Hz). HRMS (FAB+) (M + H)+, Found: m/z 310.14387. Calcd for C19H20NO3: 310.14432.
25
((1R,4S)-3-(4-Butoxyphenyl)-2-oxa-3-azabicyclo[2.2.2]oct-5-en-1-yl)methanol (6g): An oil. [α]D
–831 (c 0.232, EtOH; 54% ee). IR (neat) 3348, 2932, 2867, 1615, 1514, 1473, 1393, 1295, 1231, 1032,
972, 901, 819 cm–1. 1H NMR (CDCl3) δ = 0.96 (3H, t, J = 7.32 Hz), 1.47 (2H, sext, J = 7.32 Hz),
1.65–2.05 (5H, m), 1.79–1.86 (1H, m), 1.99–2.04 (1H, m), 3.50 (1H, d, J = 10.98 Hz), 3.54 (1H, d, J =
10.98 Hz), 3.83–3.90 (1H, m), 3.89 (2H, t, J = 6.58 Hz), 5.78 (1H, d, J = 10.25 Hz), 5.97 (1H, dd, J =
10.25, 1.71 Hz), 6.59 (2H, d, J = 8.78 Hz), 6.58 (2H, d, J = 8.78 Hz). HRMS (FAB+) (M + H)+, Found:
m/z 290.17539. Calcd for C17H24NO3: 290.17562.
Transformation of 3B to 8. N-[(S,Z)-4-[(S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-3-buten-2-yl]aniline
(7): To a MeOH (3 mL) solution of 3B (58 mg, 0.28 mmol, 55% ee) was added zinc powder (97 mg, 1.48
mmol) and 3 M aq HCl (1.0 mL, 3.0 mmol) and the suspension was stirred vigorously at rt overnight.8a
The reaction mixture was quenched by adding a saturated aq NaHCO3 solution (2 mL). After filtration
of the insoluble substance, the filtrate was extracted with CHCl3. The combined organic extracts were
dried over Na2SO4 and concentrated under reduced pressure. To a mixed solution of the condensed
residue and a catalytic amount of TsOH·H2O in DMF (4 mL) were added acetone (1.3 mL) and
Me2C(OMe)2 (0.26 mL, 1.9 mmol) under a nitrogen atmosphere, and the mixture was stirred at 0 °C
overnight. The reaction was quenched by the addition of a saturated aq NaHCO3 solution (1 mL), and
the solution was extracted by Et2O. The combined organic extracts were washed successively with

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HETEROCYCLES, Vol. 76, No. 2, 2008
water and brine, and then dried over Na2SO4. Evaporation of the solvent and separation of the residue
by preparative TLC (hexane/EtOAc = 6/1, v/v) afforded 7 (40 mg) in 57% yield in 2 steps. An oil.
[α]D25 +61 (c 0.40, EtOH). IR (neat) 3384, 3052, 2984, 2930, 2871, 1603, 1505, 1371, 1317, 1254, 1214,
1155, 1060, 860, 749, 693 cm–1. 1H NMR (CDCl3) δ = 1.28 (3H, d, J = 6.83 Hz), 1.42 (3H, s), 1.45 (3H,
s), 3.55 (1H, dd, J = 8.05, 7.81 Hz), 3.65 (1H, brs), 4.06 (1H, dd, J = 8.05, 6.10 Hz), 4.27 (1H, dq, J =
7.56, 6.83 Hz), 4.98 (1H, td, J = 7.81, 6.10 Hz), 5.50 (1H, dd, J = 11.22, 7.56 Hz), 5.55 (1H, dd, J = 11.22,
7.81 Hz), 6.62 (2H, d, J = 8.54 Hz), 6.70 (1H, t, J = 7.32 Hz), 7.16 (2H, dd, J = 8.54, 7.32 Hz). HRMS
(EI+) M+, Found: m/z 247.15700. Calcd for C15H21NO2: 247.15723.
(R)-(2,2-Dimethyl-1,3-dioxolan-4-yl)methyl Benzoate (8): Under an oxygen atmosphere, ozone
containing oxygen was bubbled into a CH2Cl2 (10 mL) solution of 7 (28 mg, 0.11 mmol) for 1 h at –78 °C.
After the color of the solution changed to blue, ozone free oxygen was further bubbled until the color of
the solution became colorless again, and NaBH4 (66 mg, 1.74 mmol) and EtOH (10 mL) was added.
After warming to rt, the resulting solution was allowed to be stirred at 50 °C for 1 h and at rt overnight.15
The reaction was quenched by the addition of water (10 mL), and extracted by CHCl3. The organic
extracts were dried over Na2SO4 and concentrated under reduced pressure to give a residue containing
(2,2-dimethyl-1,3-dioxolan-4-yl)methanol. A mixture of the residue, triethylamine (29 mg, 0.29 mmol),
benzoyl chloride (33 mg, 0.24 mmol), and a catalytic amount of DMAP in CH2Cl2 (1 mL) was stirred for
3 h under a nitrogen atmosphere at rt. To the solution was added water, and the resulting solution was
extracted with EtOAc. The combined extracts were dried over Na2SO4 and concentrated under reduced
pressure.
Purification by TLC on silica gel (hexane/EtOAc
=
7/1, v/v) gave
(R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl benzoate (8) (12 mg) in 45% yield in 2 steps. Enantiomer
ratio of the obtained 8 was confirmed to be 55% ee by HPLC analysis (Daicel Chiralcel OD-H,
hexane/iPrOH = 100/1, v/v). An oil. [α]D +5 (c 0.12, CHCl3), (lit.,14 ((R)-isomer, 56% ee; [α]D +4.0
25
(c 1.0, CHCl3)). IR (neat) 2986, 2928, 1724, 1603, 1584, 1452, 1372, 1315, 1275, 1218, 1176, 1158,
1070, 1027, 976, 847, 712 cm–1. 1H NMR (CDCl3) δ = 1.40 (3H, s), 1.47 (3H, s), 3.89 (1H, dd, J = 8.29,
5.86 Hz), 4.15 (1H, dd, J = 8.29, 6.34 Hz), 4.38 (1H, dd, J = 11.47, 5.61 Hz), 4.41 (1H, dd, J = 11.47,
4.64 Hz), 4.42–4.50 (1H, m), 7.43-7.48 (2H, m), 7.55–7.59 (1H, m), 8.05–8.07 (2H, m).
((1R,4S)-3-Phenyl-2-oxa-3-azabicyclo[2.2.2]oct-7-en-1-yl)methyl
(S)-N-(4-Nitrophenylsulfonyl)phenylalanate: To a mixed solution of 6a (104 mg, 0.48 mmol, 70%
ee), triethylamine (0.067 mL, 0.48 mmol) and a catalytic amount of DMAP in CH2Cl2 (5 mL) was added
(S)-N-(4-nitrophenylsulfonyl)phenylalanyl chloride (178 mg, 0.48 mmol) at rt under a nitrogen
atmosphere. The resulting solution was kept at the same temperature for 3 d with stirring. The solvent
was removed in vacuo and the residue was partitioned between EtOAc and water. The organic extracts
were washed successively with water, brine and dried over Na2SO4. Evaporation of the solvent and

HETEROCYCLES, Vol. 76, No. 2, 2008
1299
separation of the residue by preparative TLC (CH3Cl/MeOH = 30/1, v/v) afforded the desired product
(186 mg, 71%). A solid. IR (KBr) = 3105, 3057, 2927, 2849, 1739, 1596, 1529, 1487, 1455, 1435,
1349, 1312, 1239, 1166, 1092, 1029, 974, 916, 853, 764, 737, 703, 685 cm–1. 1H NMR (CDCl3) δ = 1.24
(1H, m), 1.63 (1H, ddd, J = 12.93, 6.34, 3.17 Hz), 1.96 (1H, dddd, J = 12.69, 9.27, 6.59, 3.17 Hz), 2.35
(1H, dddd, J = 12.69, 6.34, 3.66, 2.20 Hz), 3.05 (1H, dd, J = 13.91, 7.32 Hz), 3.19 (1H, dd, J = 13.91,
5.12 Hz), 4.19 (1H, d, J = 11.95 Hz), 4.35 (1H, ddd, J = 9.27, 7.32, 5.12 Hz), 4.44 (1H, d, J = 11.95 Hz),
4.48 (1H, m), 5.55 (1H, d, J = 9.27 Hz), 6.14 (1H, dd, J = 8.29, 5.61 Hz), 6.20 (1H, d, J = 8.29 Hz),
6.92–6.99 (3H, m), 7.06–7.08 (2H, m), 7.19–7.25 (5H, m), 7.79 (2H, d, J = 8.78 Hz), 8.12 (2H, d, J =
8.78 Hz). Single crystal of 9·EtOAc was obtained by recrystallization from EtOAc. Mp 89–92 °C
(from EtOAc). Found: C, 60.29; H, 5.54; N, 6.53%. Calcd for C32H35N3O9S: C, 60.27; H, 5.53; N,
6.59%. Crystal data: C32H35N3O9S, FW 637.70, orthorhombic, P212121, a = 8.568(2) Å, b = 11.395(3) Å,
c = 31.586(9) Å, V = 3083(1) Å3, Z = 4. Dcalc = 1.373 g/cm3. R = 0.048 (Rw = 0.059) for 3338
reflections with I > 3.00σ(I) and 406 variable parameters.
ACKNOWLEDGEMENTS
The present work was financially supported in part by a Grant-in-Aid for Scientific Research on Priority
Areas “Advanced Molecular Transformations of Carbon Resources” from The Ministry of Education,
Culture, Sports, Science and Technology (MEXT), a Grant-in-Aid for Scientific Research from Japan
Society for the Promotion of Science (JSPS), and the Asahi Glass Foundation.
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6. Although an enantioselective hetero Diels-Alder reaction of a nitroso compound promoted by an
antibody was reported, the enantioselectivity was not sufficient; A. A. P. Meekel, M. Resmini, and U.
K. Pandit, Bioorg. Med. Chem., 1996, 4, 1051.
7. Related nitroso Diels-Alder-type ring formation: N. Momiyama, Y. Yamamoto, and H. Yamamoto, J.
Am. Chem. Soc., 2007, 129, 1190.
8. A sequential method to access chiral 1,2-oxazines by an asymmetric α-oxyamination of carbonyl
compounds and conjugate addition to vinylphosphonium salts, followed by an intramolecular Wittig
reaction was reported: a) S. Kumarn, A. J. Oelke, D. M. Shaw, D. A. Longbottom, and S. V. Ley,
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11. Preliminary results have been reported: D. Xia, Y. Ukaji, S. Fujinami, and K. Inomata, Chem. Lett.,
2003, 32, 582.
12. The previous assignment of absolute stereochemistry of 311 was incorrect and should be corrected as
described in this manuscript.
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