Stereocontrolled intramolecular nitrile oxide cycloaddition reaction using a gauche-gauche interaction

Article abstract of DOI:10.1016/j.tetlet.2007.03.094

A gauche-gauche interaction is proposed as a powerful controlling factor for the stereochemistry in the intramolecular nitrile oxide cycloaddition reaction derived from N-protected 3-(N-allylamino)propionaldehyde and 2-(N-homoallylamino)acetaldehyde oxime

Full text of DOI:10.1016/j.tetlet.2007.03.094

Tetrahedron Letters 48 (2007) 3539–3542
Stereocontrolled intramolecular nitrile oxide cycloaddition
reaction using a gauche–gauche interaction
Michihiko Noguchi,a,* Aiko Tsukimoto,a Ayako Kadowaki,a
Jun Hikataa and Akikazu Kakehib
aDepartment of Applied Molecular Bioscience, Graduate School of Medicine, Yamaguchi University, Tokiwadai, Ube 755-8611, Japan
bDepartment of Chemistry and Material Engineering, Faculty of Engineering, Shinshu University, Wakasato, Nagano 380-8553, Japan
Received 19 January 2007; revised 15 March 2007; accepted 19 March 2007
Available online 21 March 2007
Abstract—A gauche–gauche interaction is proposed as a powerful controlling factor for the stereochemistry in the intramolecular
nitrile oxide cycloaddition reaction derived from N-protected 3-(N-allylamino)propionaldehyde and 2-(N-homoallylamino)acetalde-
hyde oximes. High levels of stereoselectivity (76% de to perfect) were obtained from the reaction involving nitrile oxides with sub-
stituents at the adjacent carbon atom to the tether nitrogen.
Ó 2007 Elsevier Ltd. All rights reserved.
Intramolecular cycloaddition reaction of nitrones and
nitrile oxides has been widely recognized as a very pow-
erful method for stereoselective construction of oxygen
and nitrogen-containing 5-membered frameworks,1
which are important motifs used as key building blocks
for total synthesis and medicinal compounds. Although
many strategies have been developed for the stereocon-
trolled intramolecular nitrone cycloaddition reaction,
limited ones are known for the intramolecular nitrile
oxides cycloaddition reaction. Especially, few examples
have been found in literatures based on the systems with
simple and acyclic tethers linking by sp3-units between
the nitrile oxide and dipolarophiles.2 In a recent paper,
we reported a regio- and diastereoselective cycloaddition
reaction of N-methyl nitrone derived from N-protected
3-(N-allylamino)propionaldehyde system.3 Therein, the
gauche–gauche interaction4 between the protective
group (P) on the amino nitrogen and the substituent
(R) at the adjacent carbon atom to the nitrogen would
effectively govern the cycloaddition transition state to
afford syn–cis fused perhydroisoxazolo[4,3-c]pyridine
derivatives selectively (Scheme 1).
Me
Me
O
N O
N
CHO
R
N
P
R
N
P
R
N
P
syn-cis fused
cycloadduct
gauche-gauche
interaction
Scheme 1. Stereocontrolled nitrone cycloaddition reaction using
gauche–gauche interaction.
reocontrol in the cycloaddition reactions having similar
transition state geometries could be attained using this
interaction. Our next concern was directed toward the
cycloaddition reaction of nitrile oxide in the same sys-
tem, expecting that more facile stereocontrol than nit-
rone one taking account for the more rigid geometry
of nitrile oxide.
Oximization of aldehyde 15 in an ordinary method
afford efficiently oximes 2 as E/Z mixtures (E/Z ratio:
3:2–2:3). We used oximes 2 without further purification
in the next reaction which is the oxidation of oximes 2.
When the treatment of oxime 2a (R = Me; P = Ts) with
sodium hyphochlorite solution (2.5 equiv) in dichloro-
methane at room temperature for 1 h, nitrile oxide cyc-
loadduct 4a6 was obtained in 86% yield as a sole product
after a short-column chromatography on silica gel. Sim-
ilar treatment of 2b–e gave also cycloadducts 4b–e in
If this gauche–gauche interaction is generally opera-
tional for intramolecular reactions, we believed that ste-
Keywords: Stereocontrol; Gauche–gauche interaction; Intramolecular
nitrile oxide cycloaddition.
*
Corresponding author. Tel.: +81 836 85 9261; fax: +81 836 85
9201; e-mail: noguchi@yamaguchi-u.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.094

3540
M. Noguchi et al. / Tetrahedron Letters 48 (2007) 3539–3542
Table 1. Stereoselective cycloaddition reaction of nitrile oxides 3 leading to 4
1
2
O
O
N
N
NaOCl aq
CH=N-OH
7a
3
C
CHO
NH2OH
7
(2.5 equiv.)
rt, 1 h
3a
H
4
R
N
P
6
R
N
P
R
N5
P
R
N
P
1
2 (E/Z mixture)
4
3
Entry
Oxime
R
P
Product/yielda (%)
1
2
3
4
5
2a
2b
2c
2d
2e
Me
Me
Me
Me
Ph
Ts
Ms
CO2Et
Boc
Ts
4a/86
4b/98
4c/91
4d/91
4e/82
a Isolated yield.
1
N
2
O
1
N
2
O
O
O
7a
3
N
N
C
7a
3
NaOCl aq
CHO
C
CH=N-OH
7
7
3a
(2.5 equiv.)
3a
+
H
H
[7 (P = Ts)]
vs
N
4
N
N
N
6
4
N
6
Ts
5
Ts
rt, 1 h
P
Ts
5
R
N
P
Ts
R
R
R
R
R
5
9
8
7
6 (E/Z mixture)
3
Scheme 2. Cycloaddition reaction of nitrile oxides.
good yields nevertheless the kind of the protecting
groups (P) (Table 1).7 The structure of cycloadducts 4
were deduced to be syn-adduct on the basis of the signal
patterns of 3-H2, 3a-H and 4-H2 and 6-H and 7-H2 in
their 1H NMR spectra: two large coupling constants
were observed among 3-H (ax), 3a-H (pseudo ax) and
4-H (ax) together with the geminal coupling constants
due to 3-H2 and 4-H2 each other, while none of large
coupling were observed between 6-H (eq) and 7-H2.
Fortunately, recrystallization of 4b from benzene/hex-
ane afforded good single crystals for the X-ray structure
analysis8 and the structure of 4b was confirmed to be
(3aR*,6R*)-( )-3,3a,4,5,6,7-hexahydro-5-mesyl-6-methyl-
isoxazolo[4,3-c]pyridine (see Schemes 2, 3).
adducts 8 along with small amounts of syn-isomers 9 in
good to excellent total yields and highly stereoselectively
(Table 2).10 The structure of cycloadducts 8 and 9 was
assigned also on the basis of the signal patterns of 4-
1
H2 and 5-H in their H NMR spectra. In major 8, one
proton at a higher field (4-Hax) of the methylene protons
4-H2 was observed as ddd with two large (ax–ax and
geminal) and one small (ax–eq) coupling constants and
another (4-Heq) was observed as br dd with one large
(geminal) and two small (eq–eq) coupling constants.
The 5-Heq in 8b and 8d was observed as multiplets with
four small to medium (without ax–ax) coupling con-
stants. This means that the 5-H is occupied at the equa-
torial position. On the other hand, in minor 9e isolated,
4-Hax was observed as ddd with three large (two ax–ax
and geminal) coupling constants and another 4-Heq
was observed as ddd with one large (geminal) and two
medium (two ax–eq) coupling constants. While the irra-
diation of 5-H in 8e did not cause any apparent NOE
Stimulated by these findings, we investigated the stereo-
control of nitrile oxides
7 from 2-(N-homoallyl-
amino)acetaldehydes 5,9 in which the NP and CR in
the nitrile oxides 3 are interchanged. Therein, the pro-
tecting group was fixed to tosyl group (Ts) and the R
was varied from methyl (Me) to more bulkier phenyl
and alkyl groups. Similar treatment of oximes 6 with
sodium hyphochlorite gave also anti-nitrile oxide cyclo-
Table 2. Cycloaddition reaction of nitrile oxide 7 leading to hexa-
hydroisoxazolo[3,4-c]pyridine 8 and 9
Entry
Oxime
R
Yielda (%)
Products/ratiob
1
2
3
4
5
6
6a
6b
6c
6d
6e
6f
Me
n-Pr
i-Pr
n-Hexyl
Ph
Bn
80
90
93
98
96
73
8a/97 9a/3
8b/91 9b/9
8c/92 9c/8
8d/91 9d/9
8e/91 9e/9
8f/88 9f/12
H
H
4
N
N
N
N
Ts
Ph
Ts
H
O
O
4
3a
3a
5 H
5 H
H
H
Ph
H
3.5%
9e
8e
0%
a Isolated yield.
b Determined by 1H NMR spectra of the crude mixtures.
Scheme 3. NOE measurements of anti-8e and syn-adduct 9e.

M. Noguchi et al. / Tetrahedron Letters 48 (2007) 3539–3542
3541
R
O
N
O
H
N
C
H
P
H
N
4 (syn-adduct)
TS-1
O
R
N
P
N
H
C
O
R
N
P
N
H
O
H
N
C
R
H
3
(
anti-adduct)
P
N
R
N
P
TS-2
H
O
N
O
N
N
C
Ts
H
H
H
N
N
8 (anti-adduct)
9 (syn-adduct)
Ts
Ts
H
TS-3
O
R
H
N
R
C
N
O
N
Ts
O
N
N
C
R
Ts
R
7
H
TS-4
H
H
R
Scheme 4. Transition state geometries for the cycloaddition reaction of nitrile oxides 3 and 7.
enhancement of 3a-H, that in 9e caused an NOE
enhancement of 3a-H (3.5%) (Scheme 4). This suggests
a 1,3-diaxial relationship between 3a-H and 5-H in 9e
and we deduced that 5-H occupies the axial position.
Finally, the structure of major 8d was confirmed
unambiguously to be (3aR*,5R*)-( )-5-hexyl-6-tosyl-
3,3a,4,5,6,7-hexahydroisoxazolo[3,4-c]pyridine by X-
ray single crystal structure analysis.8
In conclusion, we have demonstrated the usefulness of
the gauche–gauche interaction as a stereocontrolling
factor in the intramolecular cycloaddition reaction of
nitrile oxides. We believe that this methodology could
be applied to an efficient stereoselective preparation of
simple bicyclic heterocyclic systems through the depro-
tection. Extension of the present strategy to other intra-
molecular reactions is currently under progress.
The outcome of the stereoselectivities in the intramole-
cular cycloaddtion reaction of nitrile oxides 3 and 7
could be explained by transition state geometry: in the
transition states the acyclic tethers linking the nitrile
oxide and alkenyl moiety in 3 and 7 should be held in
a chair-like piperidine ring conformation. When protect-
ing group P occupies the equatorial position in the tran-
sition state of the cycloaddition of nitrile oxide 3, the
substituent R is expected to occupy the axial position
in order to avoid the gauche–gauche interaction between
the P and R moiety. Consequently, the exclusive forma-
tion of syn-cycloadduct 4 results via TS-1 (Scheme 4).
On the other hand, a somewhat different situation was
found in the transition state TS-3 of the cycloaddition
of nitrile oxide 7; additional 1,3-diaxial interactions with
the R substituent, similarly in an axial position avoids
any gauche–gauche interaction with one of the methy-
lene protons adjacent to the amino nitrogen and the in-
ner vinylic proton of the dipolarophile moiety, should be
taken into account (Scheme 4). As shown in Table 2, the
intramolecular cycloaddition reaction of nitrile oxide 7
afforded mixtures of anti-8 and syn-cycloadducts 9 and
the highest stereoselection (8:9 = 97:3) was accom-
plished in the reaction of 7a, which bears methyl group
as a substituent (R = Me), the least sterically bulky
group.
References and notes
1. For recent reviews on nitrone cycloadditions: (a) Freder-
ickson, M. Tetrahedron 1997, 53, 403–425; (b) Gothelf, K.
V.; Jørgensen, K. A. Chem. Commun. 2000, 1449–1457; (c)
Bates, R. W.; Sa-Ei, K. Tetrahedron 2002, 58, 5878–5978;
(d) Adams, J. P. J. Chem. Soc., Perkin Trans. 1 2002,
2586–2597; For recent reviews on nitrone and nitrile oxide
cycloadditions: (e) Chiacchio, U.; Rescifina, A.; Romeo,
G. Targets in Heterocyclic Systems 1997, 1, 225–276; (f)
Loubinoux, B.; Gerardin, P.; Schneider, R.; Ahrach, M.;
Boelle, J. Trends Heterocycl. Chem. 1995, 4, 135–158; (g)
Namboothin, I. N. N.; Hassner, A. Top. Curr. Chem.
2001, 216, 1–49.
2. Chiacchio, U.; Corsaro, A.; Librando, V.; Rescifina, A.;
Roberto, G. Tetrahedron 1996, 52, 14323–14334; Enders,
D.; Haertwig, A.; Runsink, J. Eur. J. Org. Chem. 1998,
1793–1802; Marrugo, H.; Dogbeavou, R.; Breau, L.
Tetrahedron Lett. 1999, 40, 8979–8983; Uddin, Md. J.;
Kikuchi, M.; Takedatsu, K.; Arai, K.-I.; Kakehi, A.; Irie,
R.; Shirai, H.; Yamamoto, I. Synthesis 2000, 365–375;
Ishikawa, T.; Urano, J.; Ikeda, S.; Kobayashi, Y.; Saito, S.
Angew. Chem., Int. Ed. 2002, 41, 1586–1588; Scott, J. P.;
Oliver, S. F.; Brands, K. M. J.; Brewer, S. E.; Davies, A.
J.; Gibb, A. D.; Hands, D.; Keen, S. P.; Sheen, F. J.;
Reamer, R. A.; Wilson, R. D.; Dolling, U.-H. J. Org.
Chem. 2006, 71, 3086–3092.

3542
M. Noguchi et al. / Tetrahedron Letters 48 (2007) 3539–3542
3. Tanaka, M.; Hikata, J.; Yamamoto, H.; Noguchi, M.
9. Aldehydes 5 were prepared according to the following
scheme:11
Heterocycles 2001, 55, 223–226.
4. We used the term of A1,3-strain for this interaction.
However, in order to obtain a better understanding for
this chemistry, we prefer the term of gauche–gauche
interaction correctly.
SiMe3
(1.2 equiv.)
Ref. 11
Br
CH(OEt)2
R-CHO
H
N
(1.0 equiv.)
+
(2.0 equiv.)
Ts
5. Aldehydes 1 were prepared according to the following
scheme:
R
TsNH2
(0.7 equiv.)
BF3 OEt2 (1.0 equiv.)
dry CH3CN, rt. 2 h
K2CO3 (2.5 equiv.)
18-Crown-6-ehet (0.1 equiv.)
dry DMF, 120 ºC, 24 h
(60-82%)
NH2
CO2R2
P-Cl or Boc2O
(1.5 equiv.)
CH(OEt)2
(2.0 equiv,\.)
CHO
CO2R2
(1.0 equiv.)
R
5 M HCl
N
N
H
R
N
Ts
EtOH, 50 ºC, 24 h
Et3N (2.2 equiv.),
THF, rt, 2-60 h
Ts
R
acetone,
60 ºC, 2h
R
R
2 = Et,
t
-Bu
(48%-quant.)
DIBAL-H (1.5 equiv.)
toluene, -50 ºC , 2 h
(25-42%)
5 (63-85%)
CO2R2
CHO
N
P
R
N
P
R
10. To a solution of oxime 6b (0.93 g, 0.40 mmol) in CH2Cl2
(4 mL) cooled at 0 °C was added dropwise a 5% aqueous
sodium hyphochlorite (1.5 mL, 2.5 equiv) for 12 min.
After completing the addition, the reaction mixture was
allowed to warm to room temperature and to stir for
additional 1 h. The reaction mixture was extracted with
CH2Cl2 and the organic layer was dried over anhydrous
magnesium sulfate and evaporated to dryness. The residue
was subjected to a flash column chromatography on silica
gel to afford 9b (8%) as an eluent of hexane/ethyl acetate
(5/1) and 8b (82%) as an eluent of hexane/ethyl acetate (3/
1). Compound 8b: Colorless plates from hexane/benzene;
mp 70 °C; 1H NMR (CDCl3; 270 MHz) 0.97 (3H, t,
J = 6.9 Hz, 5-CH2CH2CH3), 1.12 (1H, ddd, J = 5.0, 11.5,
13.2 Hz, 4-H), 1.36–1.49 (3H, m, 5-CHHCH2CH3), 1.74
(1H, m, 5-CHHCH2CH3), 1.84 (1H, ddd, J = 1.3, 5.9,
13.2 Hz, 4-H), 2.42 (3H, s, Ts-CH3), 3.27 (1H, dd, J = 6.9,
11.6 Hz, 3-H), 3.37 (1H, m, 3a-H), 3.86 (1H, dd, J = 1.0,
16.2 Hz, 7-H), 4.10 (1H, m, 5-H), 4.45 (1H, dd, J = 6.9,
9.2 Hz, 3-H), 4.85 (1H, d, J = 16.2 Hz, 7-H), 7.30 (2H, br
d, J = 8.3 Hz, Ar-H), 7.70 (2H, br d, J = 8.3 Hz, Ar-H);
13C NMR (CDCl3; 67.8 MHz) 13.6 (5-CH2CH2CH3), 19.3
(5-CH2CH2CH3), 21.5 (Ts-CH3), 32.1 (5-CH2CH2CH3),
32.6 (4-C), 38.6 (7-C), 41.7 (3a-C), 52.2 (5-C), 73.7 (3-C),
127.2, 129.7, 137.2, 143.7 (Ts-C), 153.0 (7a-C). Compound
9b: Colorless paste; 1H NMR (CDCl3; 270 MHz) 0.90
(3H, t, J = 7.2 Hz, 5-CH2CH2CH3), 1.18–1.34 (4H, m, 5-
CH2CH2CH3), 1.45 (1H, ddd, J = 8.9, 10.6 Hz, 4-H), 2.33
(1H, td, J = 7.6, 13.2 Hz, 4-H), 2.44 (3H, s, Ts-CH3), 2.69
(1H, m, 3a-H), 3.63 (1H, dd, J = 8.3, 11.5 Hz, 3-H), 3.97
(1H, m, 5-H), 4.08 (1H, dd, J = 2.0, 18.2 Hz, 7-H), 4.40
(1H, dd, J = 8.3, 9.9 Hz, 3-H), 4.67 (1H, d, J = 18.2 Hz, 7-
H), 7.31 (2H, br d, J = 8.3 Hz, Ar-H), 7.69 (2H, br d,
J = 8.3 Hz, Ar-H); 13C NMR (CDCl3; 67.8 MHz) 13.8 (5-
CH2CH2CH3), 19.3 (5-CH2CH2CH3), 21.4 (Ts-CH3), 21.6
(5-CH2CH2CH3), 32.3 (4-C), 40.1 (7-C), 44.0 (3a-C), 53.1
(5-C), 73.9(3-C), 127.3, 129.9, 137.2, 143.9 (Ts-C), 157.8
(7a-C).
1 (46-67%)
(68-92%)
6. To a solution of oxime 2a (0.148 g, 0.50 mmol) in CH2Cl2
(5 mL) cooled at 0 °C was added dropwise a 5% aqueous
sodium hyphochlorite (1.5 mL, 2.5 equiv) for 30 min.
After completing the addition the reaction mixture was
allowed to warm to room temperature and to stir for
additional 1 h. The reaction mixture was extracted with
CH2Cl2 and the organic layer was dried over anhydrous
magnesium sulfate and evaporated to dryness. The residue
was subjected to a flash column chromatography on silica
gel to afford 4a (86%) as an eluent of hexane/ethyl acetate
(3/1). Compound 4a: Colorless prisms from 2-propanol;
mp 125 °C; IR (KBr) 1340, 1280 (SO2); 1H NMR (CDCl3;
270 MHz) 0.98 (3H, d, J = 6.9 Hz, 6-CH3), 2.43 (3H, s,
Ts-CH3), 2.46–2.59 (2H, m, 7-H2), 2.90 (1H, dd, J = 11.2,
13.2 Hz, 4-H), 3.32 (1H, m, 3-H), 3.77 (1H, dd, J = 8.6,
9.9 Hz, 3-H), 4.23 (1H, dd, J = 6.9, 13.2 Hz, 4-H), 4.48
(1H, dd, J = 8.6, 10.6 Hz, 3-H), 4.59 (1H, m, 6-H), 7.32,
7.70 (each 2H, each br d, J = 8.3 Hz, Ar-H); 13C NMR
(CDCl3; 67.8 MHz) 16.2 (6-CH3), 21.5 (Ts-CH3), 31.0 (7-
C), 44.2 (4-C), 46.9 (3a-C), 48.9 (6-C), 70.6 (3-C), 126.9,
130.0, 137.4, 143.8 (Ar-C), 155.1 (7a-C).
7. During the preparation of this manuscript, a communica-
tion on the intramolecular nitrile oxide cycloaddition
stereocontrolled based on the same as our strategy was
found; Kadowaki, A.; Nagata, Y.; Uno, H.; Kamimura,
A. Teterahedron Lett. 2007, 48, 1823–1825.
8. Structures of hexahydroisoxazolo[4,3-c]pyridine 4a and
hexahydroisoxazolo[3,4-c]pyridine 8d were confirmed by
single crystal X-ray structure analysis and their crystallo-
graphic data have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publica-
tion numbers CCDC 621689 for 4a and CCDC 621692 for
8d. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK (fax: +44-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk).
11. Veenstra, S. J.; Schmid, P. Tetrahedron Lett. 1997, 38,
997–1000.