Switch in asymmetric induction sense in cycloadditions using camphor-based nitroso dienophiles

Article abstract of DOI:10.1016/S0957-4166(02)00192-1

We have observed a unique reversal in the absolute stereochemistry of the principal adducts from the cycloadditions of camphor-based acylnitroso dienophiles as compared to the adducts obtained through reactions of the corresponding camphor-based chloronitroso compounds.

Full text of DOI:10.1016/S0957-4166(02)00192-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 691–695
Switch in asymmetric induction sense in cycloadditions using
camphor-based nitroso dienophiles
Ying-Chuan Wang, Tzung-Min Lu, Shanmugham Elango, Chao-Kuo Lin, Chia-Tzung Tsai and
Tu-Hsin Yan*
Department of Chemistry, National Chung-Hsing University, Taichung, Taiwan, ROC
Received 13 February 2002; accepted 1 April 2002
Abstract—We have observed a unique reversal in the absolute stereochemistry of the principal adducts from the cycloadditions
of camphor-based acylnitroso dienophiles as compared to the adducts obtained through reactions of the corresponding
camphor-based chloronitroso compounds. © 2002 Elsevier Science Ltd. All rights reserved.
1
. Introduction
chiral nitroso synthons, we were stimulated to evaluate
the stereochemical sense of the cycloadditions with
acylnitroso and chloronitroso derived from the same
chiral ketopinic acid 1 (Scheme 1). We wish to report
herein that a unique reversal in the absolute stereo-
chemistry of the principal adducts is observed in the
cycloadditions with camphor-based acylnitroso 3 as
compared to the adducts obtained through the corre-
sponding reactions of the camphor-based chloronitroso
6 (Scheme 2).
Asymmetric hetero Diels–Alder reactions with C-
nitroso compounds have gained enormous importance
in recent years as they allow ready access to chiral
bicyclic dihydrooxazines. Subsequent elaboration of the
cycloadducts would deliver unsaturated 1,4-amino alco-
hols of variable ring size (depending on the diene
employed in the reaction) which upon further manipu-
lation would lead to many valuable compounds includ-
1
ing
carbocyclic
nucleosides
(five-membered),
2
amaryllidaceae alkaloids (six-membered) and alkaloids
such as physoperuvine, epibatidine, calystegine B and
tropane (seven-membered). Though there is a plethora
2
3
2. Results and discussion
of reports on hetero Diels–Alder reactions using chiral
nitroso starting materials, including acylnitroso and
chloronitroso compounds, these methods suffer from
one or more shortcomings such as modest diastereo-
selectivity, lack of generality, and inaccessibility to both
antipodes from the same chiral auxiliary. To date,
The acylnitroso 3 was generated by in situ oxidation of
the chiral hydroxamic acid 2 with periodate salts. The
starting hydroxamic acid 2 was readily prepared as
follows: one-pot treatment of acid 1 first with SOCl at
2
2
5°C for 12 h, followed by concentration and immedi-
ate treatment with a solution of HONH ·HCl (1.2
2
chloronitroso dienophiles derived from steroids,
mannofuranose, -xylofuranose, -xylose and -xylose
affording high diastereoselectivity have been devel-
D-
equiv.), NEt3 (5 equiv.) and Me SiCl (3 equiv.) in
3
D
L
D
CH CN, initially at 0°C and then at 25°C for 8 h
3
3
,4
afforded 2 in 96% isolated yield. The requisite chloroni-
oped. The synthetic flexibility of this methodology
would be greatly enhanced if a single readily available
chiral auxiliary can be channeled into both enantiomers
of a specific molecule simply by changing the reaction
profile. Earlier work in our laboratories established the
feasibility of employing the same chiral dihydrooxazine
as a precursor to prepare both enantiomeric cyclopen-
1
c
tenoids. As a natural extension of the development of
*
0
Corresponding author. E-mail: thyan@mail.nchu.edu.tw
Scheme 1.
957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00192-1

6
92
Y.-C. Wang et al. / Tetrahedron: Asymmetry 13 (2002) 691–695
Scheme 2.
troso dienophile 6 was readily prepared from the acid 1
via a three-step protocol: (a) esterification (SOCl2/
MeOH, 25°C, 10 h), (b) formation of oxime
diastereomeric adducts was obtained and X-ray crystal-
lographic analysis indicated that the major adduct from
the cycloaddition corresponded to the absolute configu-
ration depicted as 8 (78% isolated yield). Reductive
cleavage of the N-acyl bond of 8 followed by acid
25
(
HONH ·HCl/MeOH/NaOAc, 65°C, 20 h) and (c) oxi-
2
dation (t-BuOCl/CH Cl , 0°C, 6 h). The overall iso-
2
2
lated yield of chloronitroso 6 from acid 1 is 88%. The
assignment of the position of the nitroso group i.e. cis
25
3c
treatment gave 10a, [h]D –23.8 (c 0.6, H O) [lit. [h]D
2
4e
25
–
24 (c 1.1, H O), lit. [h]D –11.0 (c 1.0, EtOH)].
2
to the CMe bridge was firmly established for 6 by
2
Analysis of both oxazines 9a and 10a from the NMR of
X-ray crystallographic analysis. Exposure of a mixture
corresponding -camphor-10-sulfonamides indicated
D
of 2 and cyclohexadiene (1.5 equiv.) in CH Cl to
2
2
that they had ee of >98%. Whether the cycloadditions
of acylnitroso 3 proceed via the s-cis or s-trans con-
former remains to be established. Semiempirical (AM1)
calculations on 3 indicate the s-trans conformation of
acylnitroso to be 1.24 kcal/mol lower in energy than the
s-cis conformation. The major adduct from the
cycloaddition corresponds to the reaction of the
acylnitroso from the s-trans conformation assuming an
endo approach from the less hindered side (Scheme 3).
These results are in marked contrast to those of Streith
who postulated an s-cis acylnitroso conformation to
elucidate the sense of asymmetric induction in the
+
−
Et N IO (1.1 equiv.) at –78°C for 6 h afforded the
4
4
corresponding cycloadduct in 96% yield as a 91:9
diastereomeric mixture, wherein diastereomerically
homogeneous adduct 7 was easily obtained either by
recrystallization or by silica gel chromatography in 81%
yield (Scheme 3). A closer analysis of the X-ray crystal
structure of adduct 7 revealed its absolute stereochem-
istry. Partial reduction of the N-acyloxazine 7 with
LiAlH4 in THF at 0°C for 3 h followed by acid
treatment led to the corresponding dihydrooxazine
2
5
hydrochloride 9a (91% yield), [h] –24.9 (c 1.1, MeOH)
D
4
d
25
4e
25
[
lit. [h]D –25.2 (c 5.0, CHCl ), lit. [h]D –24.8 (c 1.0,
3
5
MeOH)], along with recovered aldehyde 11, which
could be easily converted to the ketopinic acid. Using
cycloheptadiene also gave satisfactory results with
acylnitroso 3 where a 94% yield of a 92:8 mixture of
cycloadditions of carbamoylnitroso dienophile. In view
of the previously reported experimental evidence for the
importance of dipole–dipole force in determining the
relative energies of transition structures in the aldol
6
reaction, we surmise that a dipole–dipole interactions
between ring carbonyl and acylnitroso groups, although
difficult to assess, might be an important contributor in
influencing the conformer preference. On the other
hand, these observations parallel those noted by Proc-
ter who has convincingly established through the use of
molecular mechanics calculations that a hydrogen
bonded to the NꢀO group in the s-trans conformation
of acylnitroso derived from mandelic acid might be an
important factor governing cycloaddition diastereo-
7
selectivity. Interestingly, switching the dienophile from
acylnitroso 3 to chloronitroso 6 redirected the sense of
asymmetric induction while providing excellent
diastereoselectivity and yield. Thus, one-pot treatment
of 6 with cyclohexadiene in CH Cl at 0°C for 15 h,
2
2
followed by i-PrOH/H O treatment at room tempera-
2
Scheme 3.
ture to effect hydrolysis of the resulting cycloadduct

Y.-C. Wang et al. / Tetrahedron: Asymmetry 13 (2002) 691–695
693
provided oxazine hydrochloride 9b (88%), +24.5 (c 1.1,
chiral nitroso synthons for construction of both
antipodes of bicyclic oxazines in high enantioselectivity
through cycloaddition. The fact that chloronitroso 6
provides exceptionally high levels of asymmetric induc-
tion enhances its importance as a chiral nitroso syn-
thon. Significantly, the remarkable ease of preparation
of 2 and 6, together with non-destructive chiral auxil-
iary removal make camphor-based nitroso compounds
attractive choices for asymmetric cycloadditions.
4
d
25
MeOH) [lit. [h]D +22.4 (c 5.0, CHCl )], along with
3
recovered keto ester 5 (92%) (Scheme 4). Sulfonation of
9
b with camphor-10-sulfonyl chloride afforded sulfon-
25
amide 12 (mp 131–132°C, [h] +59.2 (c 0.6, CH Cl )).
D
2
2
X-Ray crystallographic analysis fully confirms the
assigned absolute chemistry. Interestingly, a unique
reversal in the absolute stereochemistry of the principal
adduct obtained from 6 was observed as compared to
the adduct obtained from acylnitroso 3. More signifi-
1
cantly, not only did the 600 MHz H NMR spectrum of
1
2 show only a single set of absorptions for the two
4. Experimental
diastereotopic protons at C(10) (l 2.81, d, J=14.4 Hz
13
and 3.51, d, J=14.4 Hz) , the 150 MHz C spectrum
showed 16 different absorptions (16 inequivalent C
environments). The enantiomeric purity of 9b was
assessed to be >98%. Cycloheptadiene gave an
analogous result albeit in somewhat longer reaction
time. After stirring at 0°C for 40 h to effect cycloaddi-
tion and further treatment with MeOH/1N HCl (25°C,
4.1. General procedure
1
13
Melting points are uncorrected. H and C NMR
spectra were recorded with a Varian VXR 300 (300 75
MHz) or 400 (400 100 MHz). IR spectra were recorded
on a Perkin–Elmer FT-IR 1750. Optical rotations were
measured with a Perkin–Elmer P 241 polarimeter in a
10 cm cell with the solvent indicated.
2
days) to effect hydrolysis, the desired oxazine hydro-
25 3c 25
chloride 10b, [h]D +24.2 (c 0.8, H O) [lit. [h]D +24 (c
2
1.0, H O)], was isolated in 71% yield. Assignment of the
4.2. (+)-Ketopinohydroxamic acid 2
2
absolute configuration of the bicyclic oxazine was pro-
vided, as before, by conversion of 10b to sulfonamide
A magnetically stirred solution of ketopinic acid 1 (3.67
25
1
3, (mp 108–109°C, [h] +88.9 (c 1.4, CH Cl )), and
g, 20 mmol) and SOCl (35 mL) was stirred at room
D
2
2
2
examination of its X-ray crystal structure. Again, the
sense of asymmetric induction is opposite to that
obtained from acylnitroso 3 and was in accord with our
expectation that the diene approaches preferentially
from the less hindered face of the nitroso i.e. syn to the
chlorine atom. In addition, it was not surprising to
observe that the sulfonamide 13 showed only a single
set of the two doublet absorptions for the C(10) methyl-
temperature for 12 h, concentrated, and treated with a
solution of HONH ·HCl (1.68 g, 24 mmol), NEt (13.9
2
3
mL, 100 mmol) and Me SiCl (7.7 mL, 60 mmol) in
3
CH CN (100 mL) at 0°C. After 8 h at 25°C, the solvent
3
was evaporated, and the residue was taken up in
CH Cl , washed with water, dried, concentrated and
2
2
chromatographed on silica gel (elution with 33%
EtOAc/hexane) to afford 2 as a white solid (3.8 g,
1
−1
ene protons in the 600 MHz H NMR spectrum, sug-
96%): mp 106–107°C; IR (neat) 3276, 1732, 1634 cm ;
1
gestive of complete asymmetric induction (l 2.91 and
H NMR (300 MHz, CDCl ) l 10.06 (bs, 1H), 7.89 (bs,
3
3.57, J=15 Hz).
1H), 2.62–2.48 (m, 2H), 2.22–2.01 (m, 3H), 1.68–1.43
1
3
(
m, 2H), 1.26 (s, 3H), 0.98 (s, 3H); C NMR (75 MHz,
CDCl ) l 215.97, 166.80, 64.08, 50.45, 45.76, 43.42,
3
25
2
7.97, 27.55, 20.60, 20.24; [h]D +91.0 (c 0.5, CH Cl );
2 2
high-resolution MS m/e calcd for C H NO :
3. Conclusion
1
0
15
3
1
97.1055, found: 197.1058.
We have demonstrated a novel example to illustrate a
stereocontrolled chiral oxazine synthesis. These results
represent, to our knowledge, the first example of
employing the same chiral auxiliary to obtain different
4
.3. Methyl (1R,2S)-2-chloro-2-nitroso-1-bornanecar-
boxylate 6
A magnetically stirred solution of ketopinic acid 1 (9.15
g, 50 mmol) and SOCl (75 mL) was stirred at room
2
temperature for 12 h, concentrated, and treated with
MeOH (250 mL). After 10 h at 25°C, NaOAc (16.4 g,
2
00 mmol) and HONH ·HCl (4.2 g, 60 mmol) were
2
added, and the mixture was heated at 70°C for 45 h.
The solution was concentrated, and the residue was
taken up in CH Cl , washed with water, dried and
2
2
concentrated. The crude oxime 5 taken up in CH Cl ,
2
2
cooled to 0°C, and treated dropwise with t-BuOCl (5.6
g, 52 mmol). After 10 h, the reaction mixture was
concentrated and chromatographed on silica gel (elu-
tion with hexane) to afford 6 as a blue solid (10.8 g,
−
1
1
8
8%): mp 27–28°C; IR (neat) 2958, 1733 cm ; H
NMR (400 MHz, CDCl ) l 3.59 (s, 3H), 2,85 (dt,
3
J=14.8, 3.6 Hz, 1H), 2.59–2.52 (m, 1H), 2.36–2.29 (m,
1H), 2.09–2.06 (m, 1H), 2.05–2.01 (m, 1H), 1.62 (d,
Scheme 4.

6
94
Y.-C. Wang et al. / Tetrahedron: Asymmetry 13 (2002) 691–695
J=14.8 Hz, 1H), 1.57–1.49 (m, 1H), 1.32 (s, 3H),
dropwise with Jones’ reagent until a reddish-yellow
color persisted. The reaction mixture was poured into
water (10 mL) and extracted with CH Cl (3×20 mL).
The combined organic layers were dried and concen-
trated to give the recovered ketopinic acid 1 (310
mg). Evaporation of the combined aqueous layers
1
3
1
1
2
.27 (s, 3H); C NMR (100 MHz, CDCl ) l 170.91,
19.65, 65.88, 52.79, 51.65, 46.20, 41.97, 31.24, 26.82,
2.87, 22.11; high-resolution MS (FAB+) m/e calcd
3
2
2
for C H ClNO : 246.0819, found: 246.0811.
1
1
16
3
afforded 9a as a white solid (0.27 g, 91%): mp 135–
4
.4. (1R,2S)-2-[(1%S,2%R)-2-oxo-1-Bornylcarbonyl]-2-
1
1
36°C; H NMR (400 MHz, D O) l 6.69 (dd, J=7.6,
aza-3-oxabicyclo[2.2.2]-5-octene 7
2
6
.8 Hz, 1H), 6.42 (dd, J=7.6, 6.8 Hz, 1H), 4.81–4.79
(
1
m, 1H), 4.43–4.39 (m, 1H), 2.07–1.92 (m, 2H), 1.45–
To a solution of 2 (395 mg, 2.0 mmol) and 1,3-cyclo-
13
.33 (m, 2H); C NMR (100 MHz, CDCl ) l 136.28,
3
25
hexadiene (0.23 mL, 2.4 mmol) in CH Cl (5 mL) at
2
2
+
−
6
78°C was added Et N IO − (0.7 g, 2.2 mmol). After
h the reaction mixture was concentrated and chro-
128.08, 71.49, 49.04, 21.39, 16.70; [h] −24.5 (c 1.1,
MeOH); high-resolution MS m/e calcd for C H NO:
6 9
111.0684, found: 111.0686.
D
4
4
matographed on silica gel (elution with 30% EtOAc/
hexane). There was isolated 0.45 g (81%) of 7 as a
white solid: mp 108–109°C; IR (neat) 1736, 1639
4.7. (1R,5S)-7-Aza-6-oxabicyclo[3.2.2]-8-nonene-hydro-
chloride 10a and intermediate 11
−
1
1
cm ; H NMR (400 MHz, CDCl ) l 6.56 (dd, J=
3
6
5
2
3
.0, 3.0 Hz, 1H), 6.47 (dd, J=6.0, 3.0 Hz, 1H), 5.23–
.16 (m, 1H), 4.63–4.57 (m, 1H), 2.41–2.31 (m, 2H),
.18–2.08 (m, 3H), 1.97–1.78 (m, 3H), 1.41–1.22 (m,
To a solution of 8 (578 mg, 2.0 mmol) in THF (5
mL) at 0°C was added LiAlH (1 M in THF, 2 mL,
4
13
H), 1.14 (s, 3H), 1.02 (s, 3H); C NMR (100 MHz,
2 mmol). After 2 h at room temperature, the reaction
mixture was cooled to 0°C, treated dropwise with
water and extracted with ether (2×20 mL). The com-
bined organic extracts were extracted with HCl (0.5N,
4 mL×2). The ether layer was concentrated to give
the epimeric hydroxy aldehydes 11 as evidenced by
CDCl ) l 215.97, 166.80, 134.22, 133.45, 78.44, 64.08,
3
5
2
0.45, 45.76, 43.45, 43.42, 27.97, 27.92, 27.55, 20.60.
0.24, 8.57; [h]D +37.6 (c 2.0, CH Cl ); high-resolu-
25
2
2
tion MS m/e calcd for C H NO : 275.1514, found:
16
21
3
2
7
75.1513. Anal. calcd for C H NO : C, 69.79; H,
.68; N, 5.09. Found: C, 69.39; H, 7.64; N, 5.21%.
16 21 3
1
the aldehydic H NMR signals at l 9.84 and 9.75. As
described above the ether layer was concentrated and
the residue was immediately oxidized to give the
recovered ketopinic acid 1 (305 mg). Evaporation of
the combined aqueous layers afforded 10a as a white
solid (0.29 g, 90%): mp 150–151°C; IR (neat) 1741,
4
.5. (1R,2S)-2-[(1%S,2%R)-2-oxo-1-Bornylcarbonyl]-2-
aza-3-oxabicyclo[3.2.2]-8-nonene 8
To a solution of 2 (395 mg, 2.0 mmol) and 1,3-cyclo-
heptadiene (0.26 mL, 2.4 mmol) in CH Cl (5 mL) at
−
−
1
1
1609 cm ; H NMR (400 MHz, CDCl ) l 6.46 (dd,
2
2
3
+
78°C was added Et N IO − (0.7 g, 2.2 mmol). After
h, the reaction mixture was concentrated and chro-
J=5.6, 4.0 Hz, 1H), 6.39 (dd, J=5.6, 4.0 Hz, 1H),
4.89–4.86 (m, 1H), 4.58–4.55 (m, 1H), 2.37–2.31 (m,
1H), 2.07–1.97 (m, 2H), 1.91–1.85 (m, 1H), 1.65–1.60
4
4
6
matographed on silica gel (elution with 16% EtOAc/
hexane) to give 0.46 g (78%) of 8 as a white solid:
13
(m, 1H), 1.41–1.32 (m, 1H); C NMR (100 MHz,
−
1
1
mp 135–136°C; IR (neat) 1741, 1609 cm ; H NMR
400 MHz, CDCl ) l 6.28 (dd, J=6.3, 3.0 Hz, 1H),
CDCl ) l 130.77, 125.10, 77.43, 54.12, 30.61, 26.11,
3
25
(
17.79; [h]D −22.5 (c 0.8, H O); high-resolution MS
3
2
6
4
3
.20 (dd, J=6.3, 3.0 Hz, 1H), 5.22–5.16 (m, 1H),
.60–4.56 (m, 1H), 2.48–2.39 (m, 1H), 2.36–2.11 (m,
H), 1.98–1.27 (m, 9 H), 1.19 (s, 3H), 1.10 (s, 3H);
m/e calcd for C H NO: 126.0910, found: 126.0909.
7
12
1
3
C NMR (100 MHz, CDCl ) l 211.20, 164.70,
References
3
29.88, 127.19, 76.53, 66.98, 51.08, 49.66, 43.91,
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7
23
3
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2
3
chloride 9a and intermediate 11
9
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mL) at 0°C was added LiAlH (1 M in THF, 2 mL,
4
2
mmol). After 2 h at room temperature, the reaction
mixture was cooled to 0°C, treated dropwise with
water and extracted with ether (2×20 mL). The com-
bined organic extracts were extracted with HCl (0.5N,
2
×4 mL). The ether layer was concentrated to give
the epimeric hydroxy aldehydes 11, as evidenced by
the aldehydic H NMR signals at l 9.84 and 9.75.
1
The unstable intermediate 11 was immediately taken
up in acetone (5 mL), cooled to 0°C and treated

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