Oxazoline N-oxide-mediated [2+3] cycloadditions: New access to quaternary asymmetric centres

Article abstract of DOI:10.1002/1099-0690(200211)2002:21<3566::AID-EJOC3566>3.0.CO;2-F

Cycloadditions between camphor-derived oxazoline N-oxide 1 and dipolarophiles 5 or 8 afforded adducts 6 and 9, respectively, with almost complete regio- and stereoselectivity depending on the substitution patterns of the dipolarophiles. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200211)2002:21<3566::AID-EJOC3566>3.0.CO;2-F

FULL PAPER
Oxazoline N-Oxide-Mediated [2؉3] Cycloadditions: New Access to
Quaternary Asymmetric Centres
[a]
[a]
[a]
´
Stephane Collon, Cyrille Kouklovsky,* and Yves Langlois*
Dedicated to Prof. Dr. Marc Julia on the occasion of his 80th birthday
Keywords: Asymmetric synthesis / Cycloaddition / Oxazoline N-oxides
Cycloadditions between camphor-derived oxazoline N-oxide
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
1 and dipolarophiles 5 or 8 afforded adducts 6 and 9, respec- 2002)
tively, with almost complete regio- and stereoselectivity de-
pending on the substitution patterns of the dipolarophiles.
[2ϩ3] Cycloadditions are useful methods giving access to compound 11 after oxidation and subsequent BaeyerϪ
various highly functionalised five-membered rings.[1] Some Villiger rearrangement. (Scheme 2)
years ago we described a new, stereoselective [2ϩ3] cycload-
dition with the camphor-derived oxazoline N-oxide 1 as di-
pole. This powerful dipole has been used in numerous syn-
thetic applications,[2] oxazoline N-oxide-mediated [2ϩ3]
cycloadditions generally taking place with good to excellent
regio- and stereoselectivity. The approach of dipolarophiles
occurs exclusively to the si face of iminium moiety in dipole
1, as a consequence of the rigid framework and of the pres-
ence of the gem-dimethyl group. With α,β-unsaturated es-
ters the regioselectivity is intimately dependent on the al-
kene substitution: α-alkyl-substituted unsaturated esters ex-
clusively afforded 5-alkoxycarbonyl-substituted isoxazolid-
ines 3, whereas β-substituted unsaturated esters gave 4-
alkoxycarbonyl-substituted isoxazolidine derivatives 4[3]
(Scheme 1). We have previously taken advantage of the se-
lectivity for regioisomer 3 in a short synthesis of the phero-
mone frontaline.[3]
In connection with several syntheses in our laboratory,
we describe here further studies of this type of [2ϩ3] cyclo-
addition with the more highly functionalised methacrylate
derivatives 5 as dipolarophiles, as shown in Scheme 2. The
corresponding cycloadducts 6 were expected, after oxidative
hydrolysis[4] and removal of the chiral auxiliary, to give the
highly functionalised tertiary alcohols 7. As an alternative
pathway, we were also interested in the cycloaddition be-
tween dipole 1 and cycloalkenyl esters 8, since the cycload-
dition/hydrolysis sequence would result in the creation of
quaternary stereogenic centres. Oxidative hydrolysis of the
resulting adduct 9 could afford the highly functionalised
cycloalkyl derivative 10, a possible precursor of open-chain
Oxazoline N-oxide 1 was prepared according to the pre-
viously described procedure,[4] by condensation of (hydro-
xyamino)isoborneol 12[4,5] (1 equivalent, as its hydro-
chloride salt) with methyl orthoformate (4 equivalents) in
dichloromethane or in toluene in the presence of a suspen-
sion of calcium carbonate (1 equivalent) at 45 °C under
argon for 4 h. Dipole 1, which is easily hydrolysed, was
used without isolation in the subsequent cycloaddition. The
dipolarophiles 5aϪ5f and 8aϪ8c involved in these cycload-
ditions were prepared by known procedures.[6,7]
The reaction conditions and results are summarised in
Table 1. As shown, dipole 1 reacted with dipolarophiles
5aϪ5f and 8aϪ8c (entries 1Ϫ9) under mild conditions from
the less hindered α-face of the dipole (Scheme 3 and
Scheme 4).
For α-substituted dipolarophiles 5aϪ5d the regioselectiv-
ity is consistent with our previous observation with methyl
methacrylate,[3] giving rise to 5-substituted isoxazolidine ad-
ducts 6aϪ6d (entries 1Ϫ4). All these cycloadditions are
EWG-endo selective. However, cycloaddition with α-methyl-
enebutyrolactone 5c (entry 3) deserves some comment be-
cause, in contrast to the exo selectivity observed in
DielsϪAlder cycloadditions,[8] [2ϩ3] cycloadditions with
this dipolarophile remain endo selective.[9] The endo selectiv-
ity observed in [2ϩ3] cycloadditions may be due to the dif-
ference in the dipole moments in endo vs. exo transition
states, as proposed by Roush[8b] to explain the exo selectiv-
ity of [2ϩ4] cycloadditions with α-methylene dienophiles.
The exo transition state A would be higher in energy than
the endo transition state B (Figure 1), unlike in the
DielsϪAlder cycloadditions.
[a]
`
´
Laboratoire de Synthese des Substances Naturelles, Associe au
As was to be expected, methacrylonitrile 5d (entry 4) dis-
played a greater reactivity than the corresponding esters.
ˆ
´
CNRS, ICMMO, Batiment 410, Universite de Paris-Sud,
91405 Orsay, France
3566
 2002 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/02/1121Ϫ3566 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2002, 3566Ϫ3572

Oxazoline N-Oxide-Mediated [2ϩ3] Cycloadditions
FULL PAPER
Scheme 1
Scheme 2
Table 1. Cycloadditions between dipole 1 and dipolarophiles 5aϪ5f and 8aϪ8c
Entry
EWG
R
RЈ
Conditions
Yield %
endo/exo
Adduct
1
2
3
CO2Et
CO2tBu
CH2OTBDPS
CH2OBn
EWG ϩ R ϭ
C(O)O(CH2)2
CH3
H
Cl
RϩRЈ ϭ (CH2)2
RϩRЈ ϭ (CH2)3
RϩRЈ ϭ (CH2)4
PhCH3, 60 °C, 16 h
PhCH3, 60 °C, 16 h
PhCH3, 60 °C, 16 h
50
56
63
Ͼ95:5
Ͼ95:5
Ͼ95:5
6a
6b
6c
4
5
6
7
8
9
CN
CN
CN
CO2Bn
CO2Bn
CO2Bn
CH2Cl2, Rfx, 16 h
CH2Cl2, Rfx, 16 h
CH2Cl2, Rfx, 16 h
PhCH3, 80 °C, 18 h
PhCH3, 80 °C, 18 h
PhCH3, 80 °C, 18 h
60
71
56
40
50
12
95:5
90:10
66:33
Ͼ95:5
Ͼ95:5
95:5 (regio: 50:50)
6d
6e
6f
9a
9b
9c
CH3
H
Scheme 3
On the other hand, crotonitrile 5e (entry 5) reacted with
dipole 1 with reversal of regioselectivity, affording a 4-sub-
stituted isoxazolidine in adduct 6e. Surprisingly, the same
regioselectivity was observed with α-chloroacrylonitrile 5f,
giving the cycloadduct 6f as a 3:1 mixture of endo and exo
diastereomers (configuration of the major product not de-
termined Ϫ entry 6). The corresponding study in the ester
series could not be performed because of the easy poly-
merisation of α-chloroacrylate esters. Nevertheless, these re-
Figure 1. Dipole-dipole interaction in [2ϩ3]cycloadditions between
nitrone and α-methylene lactone
Eur. J. Org. Chem. 2002, 3566Ϫ3572
3567

S. Collon, C. Kouklovsky, Y. Langlois
FULL PAPER
Scheme 4
sults suggest that orbital and electronic effects, rather than experiments on the resulting adducts 6aϪ6e and, after re-
steric effects, tend to control the regioselectivity of these duction of 9aϪ9c, on compounds 13aϪ13c.
[2ϩ3] cycloadditions.
In order to use these adducts in synthesis, we performed
In contrast to our previous observations, in which tert- a series of functional group transformations as models for
butyl 2-methyl-2-pentenoate had been poorly reactive in future natural product syntheses. Accordingly, adduct 9b
this type of cycloaddition, affording a 50:50 mixture of 4- was reduced to the corresponding primary alcohol 13 (Li-
and 5-isoxazolidine adduct derivatives in 16% yield,[3] single AlH4, Et2O). Benzoylation was followed by oxidative hy-
EWG-endo adducts 9aϪ9b were obtained with cycloalkenyl drolytic cleavage of the benzoate intermediate 14 as de-
esters 8aϪ8b (Table 1, entries 7Ϫ8) (Scheme 4). This sharp scribed previously: oxidation with excess m-chloroperoxy-
difference of reactivity between acyclic and cyclic esters may benzoic acid gave the nitrone 15, which, after brief treatment
be due to ring strain relaxation in the cases of benzyl cyclo- with dilute acid (2  HCl, THF) gave the ketol 16 and the
butenecarboxylate 8a and benzyl cyclopentenecarboxylate aldehyde derivative 17 in an unoptimised 50% overall yield.
8b. The [2ϩ3] cycloaddition with benzyl cyclohexenecar-
In conclusion, we have demonstrated as an extension of
boxylate 8c (entry 9) does, however, parallel the modest re- our previous studies that oxazoline N-oxide-mediated cyclo-
activity and selectivity observed with tert-butyl 2-methyl- additions can be extended to α-substituted acrylic acid esters
2-pentenoate, a mixture of EWG-endo regioisomers being and to 1-cycloalkenyl carboxylic acid esters. The resulting
obtained in poor yield. The observed difference in the regio- adducts, obtained with very good regio- and stereoselectiv-
selectivities arising from α-substituted acyclic and cyclic es- ity, are characterised by the presence of two additional
ters in these cycloadditions is also noteworthy; theoretical highly functionalised stereogenic centres. The utility of such
calculations would probably be necessary to interpret these adducts has been demonstrated in one case by several chem-
observations. As shown in Figure 2, the regio- and stereo- ical transformations. Further uses of these adducts in nat-
selectivities of these cycloadditions were confirmed by NOE ural product synthesis are currently in development.
Figure 2. NOE experiments on compounds 6aϪc and 13aϪc
Scheme 5
3568
Eur. J. Org. Chem. 2002, 3566Ϫ3572

Oxazoline N-Oxide-Mediated [2ϩ3] Cycloadditions
FULL PAPER
the suspension was filtered through a pad of Celite, rinsed with
dichloromethane. The filtrate was concentrated in vacuo, and the
crude product was purified by flash chromatography.
Experimental Section
General Remarks: 1H and 13C NMR spectra were recorded at
250 MHz and 62.5 MHz, respectively. Optical rotations were re-
corded at 25 °C. Infrared spectra were recorded on a FT/IR appar-
atus with samples as liquid films. Chromatographic purifications
were performed on 230Ϫ400 mesh silica gel (Merck 9385) with the
indicated solvent system. Dichloromethane, pyridine and trimethyl
orthoformate were distilled from calcium hydride. Toluene, diethyl
ether and THF were distilled from sodium metal/benzophenone
ketyl. Dicyclohexylcarbodiimide was distilled under vacuum before
use. Chloroform used for optical measurements was filtered
through basic alumina before use. α-Methylene butyrolactone, cro-
tononitrile, methacrylonitrile and 2-chloroacrylonitrile were ob-
tained from commercial sources. Dipolarophiles 5a and 5b were
prepared by literature procedures. All nonaqueous reactions were
performed under an argon atmosphere in oven-dried glassware.
Ethyl (2S,3aS,4aS,5R,8S,8aR)-2-tert-Butyldimethylsilyloxymethyl-
5,10,10-trimethyl-5,8-methano-octahydroisoxazolo[3,2-b]benz-
oxazole-2-carboxylate (6a): The reaction was performed with chiral
auxiliary 12 (221 mg, 1 mmol), calcium carbonate (100 mg,
1 mmol), trimethyl orthoformate (418 µL, 4 mmol) and ethyl 2-
(tert-butyldiphenylsilyloxymethyl)acrylate (5a, 736 mg, 2 mmol) in
toluene (5 mL). After addition of the dipolarophile, the reaction
mixture was stirred at 70 °C for 16 h. The crude product was puri-
fied by chromatography (10% ethyl acetate/heptane, Rf ϭ 0.3).
1
Yield 50% (280 mg). H NMR (250 MHz, CDCl3): δ ϭ 7.63 (m, 2
H, Ar-H), 7.38 (broad s, 3 H, Ar-H), 5.39 (dd, J ϭ 6 and 1 Hz, 1
H, 3a-H), 4.20 (q, J ϭ 7 Hz, 2 H, OϪCH2ϪCH3), 4.00 (d, 1 H, J ϭ
8 Hz, 4a-H), 3.74 (J ϭ 18 and 10 Hz, 2 H, AB system, CH2ϪO-Si),
3.56 (d, J ϭ 8 Hz, 1 H, 8a-H), 2.71 (dd, J ϭ 12 and 5 Hz, 1 H, 3-
H endo), 2.43 (dd, J ϭ 12 and 6 Hz, 1 H, 3-H exo), 2.05 (d, J ϭ
5 Hz, 1 H, 8-H), 1.67Ϫ1.57 (m, 4 H, 2 ϫ 6-H, 2 ϫ 7-H), 1.27 (t,
J ϭ 7 Hz, 3 H, CH3ϪCH2ϪO), 1.02 (s, 9 H, tBu), 0.93, 0.92, 0.77
(3 s, 9 H, 3 ϫ CH3) ppm. 13C NMR (62.5 MHz, CDCl3): δ ϭ 172.0
(CO), 135.7, 135.6, 132.9, 132.8, 129.9, 127.9 (Ar), 98.0 (C-3a),
88.1(C-4a), 75.6 (C-8a), 67.2, 61.8 (OϪCH2ϪSi, OϪCH2ϪCH3),
49.0 (C-8), 48.1 (C-5), 46.1 (C-10), 39.7 (C-3), 31.8 (C-6), 26.8
(tBu), 25.6 (C-7), 22.4, 19.4, 14.2, 10.8 (4 ϫ CH3) ppm. IR
(CHCl3): ν˜ ϭ 3052, 2955, 1732, 1472, 1428, 1369, 1265, 1187, 1112
cmϪ1. MS (electrospray): m/z ϭ 586 [M ϩ Na], 564 [MHϩ]. [α]2D0ϭ
Ϫ34.2 (c ϭ 1.36, CHCl3). HRMS, calculated for C33H45NaNSiO5
[M ϩ Na]: 586, 29646; found 586, 29647.
General Method for the Preparation of Benzyl 1-Cycloalkene-1-carb-
oxylate: A solution of the carboxylic acid (1 equiv.) and benzyl
alcohol (1.1 equiv.) in dichloromethane (0.2 M) was cooled to 0
°C, and 4-(dimethylamino)pyridine (0.1 equiv.) and dicyclohexyl-
carbodiimide (1.2 equiv.) were successively added. The resulting
suspension was stirred at room temperature for 24 h and then con-
centrated in vacuo. The residue was purified by chromatography
(15% to 30% ethyl acetate/heptane) to give the benzyl ester.
Benzyl 1-Cyclobutene-1-carboxylate (8a): Yield 80%. Rf ϭ 0.63
(30% ethyl acetate/heptane). 1H NMR (250 MHz, CDCl3): δ ϭ
7.34 (broad s, 5 H, Ar-H), 6.79 (m, 1 H, 2-H), 5.15 (s, 2 H, Ar-
CH2), 2.72 (m, 2 H, 2 ϫ 3-H), 2.45 (m, 2 H, 2 ϫ 4-H) ppm. 13C
NMR (62.5 MHz, CDCl3): δ ϭ 162.0 (CO), 147.1 (C-2), 138.4 (C-
1), 136.0, 128.1, 127.9 (Ar), 67.8 (Ar-CH2), 29.1 (C-3), 27.1 (C-4)
ppm. MS (electrospray): m/z ϭ 211 [M ϩ Na].
tert-Butyl (2S,3aS,4aS,5R,8S,8aR)-2-Benzyloxymethyl-5,10,10-tri-
methyl-5,8-methano-octahydroisoxazolo[3,2-b]benzoxazole-2-
carboxylate (6b): The reaction was performed with chiral auxiliary
12 (221 mg, 1 mmol), calcium carbonate (100 mg, 1 mmol), trime-
thyl orthoformate (418 µL, 4 mmol) and tert-butyl 2-(benzyloxyme-
thyl)acrylate (5b, 736 mg, 2 mmol) in toluene (5 mL). After addi-
tion of the dipolarophile, the reaction mixture was stirred at 70 °C
for 16 h. The crude product was purified by chromatography (20%
ethyl acetate/heptane, Rf ϭ 0.3), affording 6b as the major adduct.
Benzyl 1-Cyclopentene-1-carboxylate (8b): Yield 98%. Rf ϭ 0.54
(20% ethyl acetate/heptane). 1H NMR (250 MHz, CDCl3): δ ϭ
7.34 (5 H, broad s, Ar-H), 6.81 (m, 1 H, 2-H), 5.17 (s, 2 H, Ar-
CH2), 2.57Ϫ2.47 (m, 4 H, 2 ϫ 3-H, 2 ϫ 5-H), 1.75 (m, 2 H, 2 ϫ
4-H) ppm. 13C NMR (62.5 MHz, CDCl3): δ ϭ 164.9 (CO), 144.1
(C-2), 136.2 (C-1), 128.2, 127.9, 127.8 (Ar), 65.6 (Ar-CH2), 33.2,
31.2 (C-3, C-5), 22.9 (C-4). MS (electrospray): m/z ϭ 225 [M ϩ
Na]. IR (CHCl3): ν˜ ϭ 3033, 2955, 1713, 1629, 1050 cmϪ1. HRMS,
calculated for C13H14O2Na [M ϩ Na]: 225.08915; found 225.08914.
1
Yield 56% (mg). H NMR (250 MHz, CDCl3): δ ϭ 7.28 (broad s,
5 H, Ar-H), 5.42 (dd, J ϭ 6 and 5 Hz, 1 H, 3a-H), 4.54 (d, J ϭ
4 Hz, 2 H, OϪCH2ϪPh), 3.97 (d, J ϭ 8 Hz, 1 H, 4a-H), 3.74 (d,
J ϭ 8 Hz, 1 H, 8a-H), 3.56 (d, J ϭ 4 Hz, 1 H, CH2ϪO), 2.63 (dd,
J ϭ 13 and 5 Hz, 1 H, 3-H endo), 2.39 (dd, J ϭ 13 and 6 Hz, 1 H,
3-H exo), 2.05 (d, J ϭ 5 Hz, 1 H, 8 H), 1.68 (m, 4 H, 2 ϫ 6-H, 2
ϫ 7-H), 1.46 (s, 9 H, tBu), 0.94, 0.92, 0.77 (3 s, 9 H, 3 ϫCH3) ppm.
13C NMR (62.5 MHz, CDCl3): δ ϭ 170.8 (CO), 137.8, 128.3, 127.8,
127.7 (Ar), 98.0 (C-3a), 88.2 (C-4a), 87.9 (C-2), 82.4 (OϪCϪMe3),
75.8 (C-8a), 73.8, 73.3 (CH2ϪOϪCH2-Ph), 49.0 (C-8), 48.1 (C-5),
46.0 (C-10), 40.6 (C-3), 31.8 (C-6), 27.9 (tBu), 25.6 (C-7), 22.4,
19.4, 10.8 (3 ϫ CH3) ppm. IR (CHCl3): ν˜ ϭ 2956, 2886, 1728, 1454,
1369, 1265, 1160, 1141, 1094 cmϪ1. MS (electrospray): m/z ϭ 466
[M ϩ Na], 424 (MH). [α]2D0ϭ Ϫ23.4 (c ϭ 1.6, CHCl3). HRMS,
Benzyl 1-Cyclohexene-1-carboxylate (8c): Yield 89%. Rf ϭ 0.56
(20% ethyl acetate/heptane). 1H NMR (250 MHz, CDCl3): δ ϭ
7.34 (broad s, 5 H, Ar-H), 7.02 (m, 1 H, 2-H), 5.15 (s, 2 H, Ar-
CH2), 2.30Ϫ2.10 (m, 4 H, 2 ϫ 3-H, 2 ϫ 6-H), 1.70Ϫ1.50 (m, 4 H,
2 ϫ 4-H, 2 ϫ 5-H) ppm. 13C NMR (62.5 MHz, CDCl3): δ ϭ 167.3
(CO), 140.1 (C-2), 136.2 (C-1), 130.1, 128.4, 127.9 (Ar), 65.8 (Ar-
CH2), 25.7 (C-3), 24.1 (C-6), 22.0, 21.3 (C-4, C-5). IR (CHCl3):
ν˜ ϭ 2955, 1713, 1264, 1243, 1087 cmϪ1. MS (electrospray): m/z ϭ
239 [M ϩ Na]. HRMS, calculated for C14H16O2Na [M ϩ Na]:
239.10480; found 239.10479.
calculated for C26H37NaNO5 (M
466.25694.
ϩ Na): 466.25693; found
General Experimental Procedure for Asymmetric [2؉3] Cycloaddi-
tions with Oxazoline N-Oxide (1): Hydroxyamino alcohol hydro- (2S,3aS,4aS,5R,8S,8aR)-5,10,10-Trimethyl-11-oxo-12-oxa-5,8-
chloride 12 (1 equiv.) and powdered calcium carbonate (1 equiv.)
were suspended in anhydrous dichloromethane or toluene. Trime-
thyl orthoformate (4 equiv.) was added and the resulting suspension
was stirred at 45 °C for 4 h. The dipolarophile (2Ϫ4 equiv.) was
then added (pure or as a solution in the corresponding solvent),
and the mixture was stirred at the appropriate temperature for the
methano-2,2-pentano-octahydroisoxazolo[3,2-b]benzoxazole
(6c):
The reaction was performed with chiral auxiliary 12 (443 mg,
2 mmol), calcium carbonate (200 mg, 2 mmol), trimethyl orthofor-
mate (836 µL, 8 mmol) and α-methylene-γ-butyrolactone (5c,
490 mg, 5 mmol) in toluene (10 mL). After addition of the di-
polarophile, the reaction mixture was stirred at 60 °C for 16 h. The
appropriate time (see Table 1). After cooling to room temperature, crude product was purified by chromatography (35% ethyl acetate/
Eur. J. Org. Chem. 2002, 3566Ϫ3572 3569

S. Collon, C. Kouklovsky, Y. Langlois
FULL PAPER
heptane, Rf ϭ 0.25), affording 6c as the major adduct. Yield 63% romethane (5 mL). After addition of the dipolarophile, the reaction
1
(370 mg). H NMR (250 MHz, CDCl3): δ ϭ 5.48 (dd, J ϭ 6 and mixture was stirred at 45 °C for 16 h. The crude product was puri-
5 Hz, 1 H, C3aϪH), 4.34 (ddd, J ϭ 12, 8 and 4 Hz, 1 H, one of 3Ј-
fied by chromatography (10% ethyl acetate/heptane, Rf ϭ 0.3).
H), 4.24 (partially masked ddd, 1 H, one of 3Ј-H), 4.23 (d, J ϭ Yield 56% (154 mg). The cycloadduct was obtained as an insepar-
8 Hz, 1 H, 4a-H), 3.62 (d, J ϭ 8 Hz, 1 H, 8a-H), 2.65 (dd, J ϭ 13 able mixture of diastereoisomers, the 3:1 ratio of compounds being
and 6 Hz, 1 H, 3-H endo), 2.44 (ddd, 1 H, J ϭ 13, 8, 4 Hz, one of
determined by integration of the 3-H signals for both products (δ ϭ
4Ј-H), 2.34 (dd, J ϭ 13 and 7 Hz, 1 H, 3-H exo), 2.23 (ddd, 1 H, 5.39 ppm for the minor isomer; δ ϭ 5.33 ppm for the major isomer)
1
1
J ϭ 12, 8 and 4 Hz, one of 4Ј-H), 1.97 (d, J ϭ 5 Hz, 1 H, 8-H), in the H NMR spectrum. H NMR (250 MHz, CDCl3): δ ϭ 5.39
1.67, 1.44 (2 m, 4 H, 2 ϫ 6-H, 2 ϫ 7-H), 0.94, 0.92, 0.77 (3 s, 9 H,
(s, 1 H, 3a-H, minor isomer), 5.33 (s, 1 H, 3a-H, major isomer),
3 ϫ CH3) ppm. 13C NMR (62.5 MHz, CDCl3): δ ϭ 176.6 (CO), 4.18 (AB system, 2 H, 2 ϫ 2-H ), 4.09 (d, J ϭ 8 Hz, 1 H, 4a-H),
97.8 (C-3a), 87.8 (C-4a), 83.6 (C-2), 74.5 (C-8a), 65.6 (C-3Ј), 48.5 3.28 (d, J ϭ 8 Hz, 1 H, 8a-H), 2.08 (d, J ϭ 5 Hz, 1 H, 8-H),
(C-8), 47.9 (C-5), 46.5 (C-10), 40.3 (C-3), 35.8 (C-4Ј), 31.6 (C-6), 1.67Ϫ1.40 (m, 4 H, 2 ϫ 6-H, 2 ϫ 7-H), 0.92, 0.87, 0.77 (3 s, 9 H,
25.0 (C-7), 22.1, 19.5, 10.7 (3 ϫ CH3) ppm. IR (CHCl3): ν˜ ϭ 2990,
3 ϫ CH3) ppm. 13C NMR (62.5 MHz, CDCl3, major isomer): δ ϭ
2956, 1776, 1372, 1267, 1189, 1166, 1021 cmϪ1. MS (electrospray): 113.6 (CN), 106.7 (C-3a), 90.9 (C-4a), 76.1 (C-2), 74.3 (C-8a), 62.9
m/z ϭ 316 [M ϩ Na], 294 (MH). [α]2D0 ϭ Ϫ36.1 (c ϭ 2.7, CHCl3).
HRMS, calculated for C16H23NNaO4 [M ϩ Na]: 316.15248;
found 316.15248.
(C-3), 49.0 (C-8), 48.9 (C-5), 45.9 (C-10), 31.2 (C-6), 25.4 (C-7),
22.1, 18.8, 10.7 (3 ϫ CH3). 13C NMR (62.5 MHz, CDCl3, minor
isomer): δ ϭ 116.0 (CN), 101.1 (C-3a), 91.9 (C-4a), 75.7 (C-2), 74.3
(C-8a), 60.5 (C-3), 49.0 (C-8), 48.9 (C-5), 45.9 (C-10), 31.2 (C-6),
25.4 (C-7), 22.1, 18.8, 10.7 (3 ϫ CH3) ppm.
(2S,3aS,4aS,5R,8S,8aR)-2,5,10,10-Tetramethyloctahydro-5,8-
methanoisoxazolo[3,2-b]benzoxazole-2-carbonitrile (6d): The reac-
tion was performed with chiral auxiliary 12 (443 mg, 2 mmol), cal-
cium carbonate (200 mg, 2 mmol), trimethyl orthoformate (836 µL,
8 mmol) and methacrylonitrile (670 mg, 10 mmol) in dichlorome-
thane (10 mL). After addition of the dipolarophile, the reaction
mixture was stirred at 45 °C for 16 h. The crude product was puri-
fied by chromatography (20% ethyl acetate/heptane, Rf ϭ 0.3), af-
fording 6d as the major adduct. Yield 60% (314 mg). Mixture of
endo/exo adducts: 1H NMR (250 MHz, CDCl3): δ ϭ 5.49 (dd, J ϭ
6 and 1 Hz, 1 H, 3a-H), 4.24 (d, J ϭ 8 Hz, 1 H, 4a-H), 3.89 (d,
J ϭ 8 Hz, 1 H, 8a-H), 2.69 (dd, J ϭ 10 and 1 Hz, 1 H, 3-H endo),
2.37 (dd, J ϭ 10 and 6 Hz, 1 H, 3-H exo), 2.07 (d, J ϭ 5 Hz, 1 H,
8-H), 1.73Ϫ1.40 (m, 4 H, 2 ϫ 6-H, 2 ϫ 7-H), 1.61 (s, 3 H, 2-Me),
0.92, 0.88, 0.78 (3 s, 9 H, 3 ϫCH3) ppm. 13C NMR (62.5 MHz,
CDCl3): δ ϭ 155.2 (CN), 98.7 (C-3a), 89.8 (C-4a), 77.3 (C-2), 76.6
(C-8a), 49.7, 49.6, 45.8, 45.5, 31.6 (C-6), 25.6 (C-7), 25.1 (2-Me),
22.5, 18.9, 10.9 (3 ϫ CH3) ppm. IR (CHCl3): ν˜ ϭ 2965, 2950, 2250,
Benzyl (2S,3S,3aS,4aS,5R,8S,8aR)-5,10,10-Trimethyl-2,3-ethano-
5,8-methano-octahydroisoxazolo[3,2-b]benzoxazole-3-carboxylate
(9a): The reaction was performed with chiral auxiliary 12 (30 mg,
0.13 mmol), calcium carbonate (13 mg, 0.13 mmol), trimethyl or-
thoformate (58 µL, 0.53 mmol) and benzyl 1-cyclobutene-1-carb-
oxylate (8a, 100 mg, 0.26 mmol) in toluene (1.5 mL). After addition
of the dipolarophile, the reaction mixture was stirred at 60 °C for
16 h. The crude product was purified by chromatography (20%
ethyl acetate/heptane, Rf ϭ 0.37), affording 9a as the major adduct.
1
Yield 40% (20 mg). H NMR (250 MHz, CDCl3): δ ϭ 7.40Ϫ7.25
(broad s, 5 H, Ar-H), 5.21 (AB system, 2 H, CH2ϪAr), 5.13 (s, 1
H, 3a-H), 4.99 (dd, 1 H, 2-H), 3.74 (d, J ϭ 8 Hz, 1 H, 4a-H), 3.24
(d, J ϭ 8 Hz, 1 H, 8a-H), 2.38 (m, 2 H, 2Ј ϫ 2-H), 2.09 (m, 2 H,
2 ϫ 3Ј-H), 2.01 (d, J ϭ 5 Hz, 1 H, 8-H), 1.73Ϫ1.54 (m, 4 H, 2 ϫ
6-H, 2 ϫ 7-H), 0.88, 0.78, 0.72 (3 s, 9 H, 3 ϫ CH3) ppm. 13C NMR
(62.5 MHz, CDCl3): δ ϭ 170.4 (CO), 135.6, 128.4, 127.9 (Ar), 104.2
(C-3a), 89.6 (C-4a), 81.3 (C-2), 73.8 (C-8a), 66.6 (CH2-Ar), 61.7
(C-3), 48.5 (C-8), 47.9 (C-5), 45.9 (C-10), 31.2 (C-6), 28.1, 22.5 (C-
2Ј, C-3Ј), 25.0 (C-7), 22.0, 19.0, 10.4 (3 ϫ CH3) ppm. MS
(electrospray): m/z ϭ 406 [M ϩ Na], 384 [M ϩ 1]. [α]2D0 ϭ Ϫ124
(c ϭ 2.3, CHCl3).
1380, 1050 cmϪ1
.
(2S,3S,3aS,4aS,5R,8S,8aR)-2,5,10,10-Tetramethyl-5,8-methano-
octahydroisoxazolo[3,2,b]benzoxazole-3-carbonitrile (6e): The reac-
tion was performed with chiral auxiliary 12 (443 mg, 2 mmol), cal-
cium carbonate (200 mg, 2 mmol), trimethyl orthoformate (836 µL,
8 mmol) and (E)-crotonitrile (670 mg, 10 mmol) in dichlorome-
thane (10 mL). After addition of the dipolarophile, the reaction
mixture was stirred at 45 °C for 16 h. The crude product was puri-
fied by chromatography (15% ethyl acetate/heptane, Rf ϭ 0.3), af-
fording 6e as the major adduct. Yield 71% (372 mg). 1H NMR
(250 MHz, CDCl3): δ ϭ 5.43 (d, J ϭ 7 Hz, 1 H, 3a-H), 4.28 (dq,
J ϭ 10 and 6 Hz, 1 H, 2-H), 4.12 (d, J ϭ 8 Hz, 1 H, 4a-H), 3.31
(d, J ϭ 8 Hz, 1 H, 8a-H), 2.92 (dd, J ϭ 10 and 6.7 Hz, 1 H, 3-H),
2.12 (d, J ϭ 5 Hz, 1 H, 8-H), 1.70, 1.40 (m, 4 H, 2 ϫ 6-H, 2 ϫ 7-
H), 1.42 (d, J ϭ 6 Hz, 3 H, 2-Me), 0.96, 0.88, 0.78 (3 s, 9 H, 3 ϫ
CH3) ppm. 13C NMR (62.5 MHz, CDCl3): δ ϭ 115.2 (CN), 97.0
(C-3a), 90.2 (C-4a), 75.6 (C-2), 75.1 (C-8a), 48.9 (C-3), 48.6 (C-5),
45.8 (C-8), 45.5 (C-10), 31.3 (C-6), 25.5 (C-7), 16.5 (2-Me), 22.1,
18.7, 10.6 (3 ϫ CH3) ppm. IR (CHCl3): ν˜ ϭ 2950, 2260 cmϪ1. MS
(CI NH3): m/z ϭ 263 [MHϩ], 180. [α]2D0ϭ Ϫ167 (c ϭ 1, CHCl3).
C15H22N2O2: calcd. C 68.67%, H 8.45%, N 10.68; found C 68.22%,
H 7.99%, N 10.25%.
Benzyl (2S,3S,3aS,4aS,5R,8S,8aR)5,10,10-Trimethyl-5,8-methano-
2,3-propano-octahydroisoxazolo[3,2-b]benzoxazole-3-carboxylate
(9b): The reaction was performed with chiral auxiliary 12 (221 mg,
1 mmol), calcium carbonate (100 mg, 1 mmol), trimethyl orthofor-
mate (436 µL, 4 mmol) and benzyl 1-cyclopentene-1-carboxylate
(8b, 767 mg, 3.8 mmol) in toluene (15 mL). After addition of the
dipolarophile, the reaction mixture was stirred at 60 °C for 16 h.
The crude product was purified by chromatography (20% ethyl
acetate/heptane, Rf ϭ 0.38), affording 9b as the major adduct. Yield
50% (396 mg). 1H NMR (250 MHz, CDCl3): δ ϭ 7.40Ϫ7.26 (broad
s, 5 H, Ar-H), 5.20 (m, 4 H, CH2ϪAr, 2-H and 3a-H), 3.79 (d, J ϭ
8 Hz, 1 H, 4a-H), 3.32 (d, J ϭ 8 Hz, 1 H, 8a-H), 2.08 (d, J ϭ 5 Hz,
1 H, 8-H), 2.0Ϫ1.2 (m, 10 H, 2 ϫ 6-H, 2 ϫ 7-H, 2 ϫ 2Ј-H, 2 ϫ
3Ј-H, 2 ϫ 4Ј-H), 0.92, 0.88, 0.78 (9 H, 3 s, 3 ϫ CH3) ppm. 13C
NMR (62.5 MHz, CDCl3): δ ϭ 171.6 (CO), 135.6, 128.9, 128.0,
127.9 (Ar), 105.9 (C-3a), 89.4 (C-4), 86.1 (C-2), 74.6 (C-8a), 69.5
(C-3), 66.6 (CH2-Ar), 48.8 (C-8), 48.1 (C-5), 45.9 (C-10), 34.7, 30.2,
23.9 (C-2Ј, C-3Ј, C-4Ј), 31.3 (C-6), 25.1 (C-7), 22.1, 19.0, 10.6 (3 ϫ
CH3) ppm. IR (CHCl3): ν˜ (cmϪ1): 3054, 2959, 1727, 1265, 1056.
(3RS,3aS,4aS,5R,8S,8aR)-3-Chloro-5,10,10-trimethyl-5,8-methano-
octahydroisoxazolo[3,2-b]benzoxazole-3-carbonitrile (6f): The reac-
tion was performed with chiral auxiliary 12 (221 mg, 1 mmol), cal- MS (electrospray): m/z ϭ 420 [M ϩ Na], 398 [M ϩ 1]. [α]2D0ϭ
cium carbonate (100 mg, 1 mmol), trimethyl orthoformate (418 µL,
4 mmol) and 2-chloroacrylonitrile (5f, 500 mg, 10 mmol) in dichlo-
Ϫ146.7 (c ϭ 1.97, CHCl3). HRMS, calculated for C24H31NO4Na
[M ϩ Na]: 420.21508; found 420.21507.
3570
Eur. J. Org. Chem. 2002, 3566Ϫ3572

Oxazoline N-Oxide-Mediated [2ϩ3] Cycloadditions
FULL PAPER
Benzyl (2S,3S,3aS,4aS,5R,8S,8aR)-5,10,10-Trimethylperhydro-5,8-
10), 34.2, 30.1, 23.3 (C-2Ј, C-3Ј, C-4Ј), 31.7 (C-6), 25.3 (C-7), 22.1,
methano-benzo[d]isoxazolo[3,2-b]benzoxazole-3-carboxylate
and Benzyl (2R,3R,3aS,4aS,5R,8S,8aR)-5,10,10-Trimethylperhydro-
5,8-methanobenzo[d]isoxazolo[3,2-b]benzoxazole-2-carboxylate: The 2D0ϭ Ϫ158.5 (c
(9c) 18.9, 10.8 (3 ϫ CH3) ppm. IR (CHCl3): ν˜ ϭ 3348, 2955, 2880, 1050
cmϪ1. MS (electrospray): m/z ϭ 316 [M ϩ Na], 294 [M ϩ 1]. [α]
0.7, CHCl3). HRMS, calculated for
ϭ
reaction was performed with the chiral auxiliary 12 (221 mg,
1 mmol), calcium carbonate (100 mg, 1 mmol), trimethyl orthofor-
mate (418 µL, 4 mmol) and benzyl 1-cyclohexene-1-carboxylate (8c,
880 mg, 4 mmol) in toluene (5 mL). After addition of the di-
polarophile, the reaction mixture was stirred at 60 °C for 16 h. Ana-
lysis of the crude product showed a 1:1 ratio of regioisomers. The
crude product was purified by chromatography (20% ethyl acetate/
heptane); first to elute was the 4-regioisomer 9c (Rf ϭ 0.45), fol-
lowed by the 5-regioisomer (Rf ϭ 0.4). The combined yield for both
compounds was 12% (50 mg).
C17H27NaNO3 [M ϩ Na]: 316.18886; found 316.18886.
(2S,3R,3aS,4aS,5R,8S,8aR)-3-(Benzoyloxymethyl)-5,10,10-tri-
methyl-5,8-methano-2,3-propano-octahydroisoxazolo[3,2-b]benz-
oxazole (14): A solution of the alcohol 13 (53 mg, 0.18 mmol), ben-
zoic acid (44 mg, 0.36 mmol, 2 equiv.), dicyclohexylcarbodiimide
(46 mg, 0.22 mmol, 1.25 equiv.) and 4-dimethylaminopyridine
(2 mg, 0.02 mmol, 0.1 equiv.) in dichloromethane (5 mL) was
stirred at room temperature for 5 h and then filtered through a
short pad of silica gel, eluting with dichloromethane. The filtrate
was concentrated in vacuo and the crude product was purified by
1
Compound 9c (4-Regioisomer): H NMR (250 MHz, CDCl3): δ ϭ chromatography (15% ethyl acetate/toluene) to give the benzoic es-
1
7.34 (5 H, broad s, Ar-H), 5.20 (s, 2 H, CH2ϪAr), 4.95 (s, 1 H, 3a-
H), 4.45 (m, 1 H, 2-H), 3.80 (d, J ϭ 8 Hz, 1 H, 4a-H), 3.40 (d, J ϭ
ter 14 as a colourless oil (57 mg; yield 80%). H NMR (250 MHz,
CDCl3): δ ϭ 8.0Ϫ7.45 (m, 5 H, Ar-H), 5.10 (s, 1 H, 3a-H), 4.50
8 Hz, 1 H, 8a-H), 2.10 (d, J ϭ 5 Hz, 1 H, 8-H), 1.85Ϫ1.55 (m, 8 (d, J ϭ 3 Hz, 1 H, 2-H), 4.35 (AB system, 2 H, CH2ϪOCOAr),
H, 4 ϫ CH2), 1.50Ϫ1.20 (m, 4 H, 2 ϫ C-6, 2 ϫ C-7), 0.90, 0.85, 3.95 (d, J ϭ 8 Hz, 1 H, 4a-H), 3.31 (d, J ϭ 8 Hz, 1 H, 8a-H), 2.05
0.75 (9 H, 3 s, 3 ϫ CH3) ppm. 13C NMR (62.5 MHz, CDCl3): δ ϭ (d, J ϭ 5 Hz, 1 H, 8-H), 1.91Ϫ1.52 (m, 6 H, 3 ϫ CH2), 0.95, 0.90,
170.8 (CO), 136.0, 128.5, 128.0, 127.9 (Ar), 105.5 (C-3a), 90.2 (C-
4a), 77.7 (C-2), 74.5 (C-8a), 66.6 (CH2-Ar), 59.7 (C-3), 49.5 (C-8), 166.5 (CO), 130.0, 129.5, 128.4 (Ar), 106.2 (C-3a), 90.0 (C-4a), 87.4
48.1 (C-5), 45.4 (C-10), 31.4 (C-6), 25.7 (C-7), 28.8, 24.2, 22.7, 19.9 (C-2), 75.1 (C-8a), 65.9 (CH2ϪOCOAr), 60.7 (C-3), 49.1 (C-8), 48.5
(4 ϫ CH2), 22.2, 18.8, 10.8 (3 ϫ CH3) ppm. IR (CHCl3): ν˜ (cmϪ1): (C-5), 45.9 (C-10), 34.5, 31.0, 23.7 (3 ϫ CH2), 31.6 (C6), 25.3 (C7),
0.77 (3 s, 9 H, 3 ϫ CH3) ppm. 13C NMR (62.5 MHz, CDCl3): δ ϭ
2934, 1732, 1455, 1239, 1163, 1140, 1015. MS (electrospray): m/z ϭ
434 [M ϩ Na]. [α]2D0 ϭ Ϫ104.5 (c ϭ 0.5, CHCl3). HRMS, calculated
for C25H33NNaO4 [M ϩ Na]: 434.23073; found 434.23072.
22.2, 19.1, 10.7 (3 ϫ CH3) ppm. IR (CHCl3): ν˜ ϭ 2954, 2884, 1722,
1451, 1272, 1111, 1070 cmϪ1. MS (electrospray): m/z ϭ 420 [M ϩ
Na], 388 [M ϩ 1]. [α]2D0 ϭ Ϫ96.1 (c ϭ 1.4, CHCl3). HRMS, calcu-
lated for C24H31NNaO4 [M ϩ Na]: 420.21508; found 420.21507.
5-Regioisomer: 1H NMR (250 MHz, CDCl3): δ ϭ 7.34 (5 H, broad
s, Ar-H), 5.20 (m, 3 H, CH2ϪAr, 3a-H), 3.80 (d, J ϭ 8 Hz, 1 H, (1S,2S)-1-Benzoyloxymethyl-2-hydroxycyclopentane-1-carbox-
4a-H), 3.60 (d, J ϭ 8 Hz, 1 H, 8a-H), 2.9 (m, 1 H, 3-H), 2.08 (d, aldehyde (17): solution of the benzoic ester 14 (46 mg,
J ϭ 5 Hz, 1 H, 8-H), 1.85Ϫ1.5 (m, 8 H, 4 ϫ CH2), 1.45Ϫ1.20 (m, 0.12 mmol) in diethyl ether (4 mL) was cooled to 0 °C, and meta-
4 H, 2 ϫ 6-H, 2 ϫ 7-H), 0.90, 0.85, 0.7 (9 H, 3 s, 3 ϫ CH3) ppm. chloroperoxybenzoic acid (77 mg, 0.42 mmol, 3.5 equiv.) was added
13C NMR (62.5 MHz, CDCl3): δ ϭ 173.3 (CO), 135.5, 128.6, 128.3, in one portion. The solution was stirred at room temperature for
127.9 (Ar), 102.7 (C-3a), 89.1 (C-4a), 84.3 (C-2), 77.9 (C-8a), 66.7 3 h and then extracted with ethyl acetate (20 mL). The solution was
A
(CH2-Ar), 49.4 (C-8), 48.4 (C-5), 47.6 (C-3), 45.2 (C-10), 31.8 (C- washed twice with saturated aqueous sodium carbonate (20 mL)
6), 25.8 (C-7), 29.7, 24.5, 21.7, 20.7 (4 ϫ CH2), 22.6, 19.2, 10.9 (3 and then with water and brine (10 mL each), dried (Na2SO4), fil-
ϫ CH3) ppm. IR (CHCl3): ν˜ (cmϪ1): 2933, 1737, 1455, 1220, 1116, tered and concentrated in vacuo. The crude product was immedi-
1094. MS (electrospray): m/z ϭ (434 v[M ϩ Na]. [α]2D0ϭ Ϫ43.5 (c ϭ
ately used in the next reaction. The crude product from the above
0.5, CHCl3). HRMS, calculated for C25H33NNaO4 [M ϩ Na]: reaction was dissolved in tetrahydrofuran (2 mL), and 2  hydro-
434.23073; found 434.23072.
chloric acid (0.5 mL) was added. The solution was stirred at room
temperature for 15 min, and then partitioned between saturated so-
dium bicarbonate and ethyl acetate (20 mL each). The organic
phase was washed with water and brine (20 mL), dried (Na2SO4),
filtered and concentrated in vacuo. The residue was purified by
preparative TLC (30% diethyl ether/pentane, Rf ϭ 0.2) to give the
aldehyde 17 as a colourless oil (18 mg; overall yield 50%). 1H NMR
(250 MHz, CDCl3): δ ϭ 9.85 (s, 1 H, CHO), 8.0Ϫ7.31 (m, 5 H,
Ar-H), 4.45 (AB system, 2 H, 2 ϫ 1Ј-H), 3.45 (m, 1 H, 2-H), 2.05
(broad s, 1 H, exchangeable with D2O, OH), 1.85Ϫ1.52 (m, 6 H, 3
ϫ CH2) ppm. 13C NMR (62.5 MHz, CDCl3): δ ϭ 203.7 (CHO),
167.0 (CO), 133.2, 129.6, 128.5 (Ar), 77.9 (C-1Ј), 66.6 (C-2), 65.7
(C-1), 34.5, 28.1, 21.1 (3 ϫ CH2) ppm. IR (CHCl3): ν˜ ϭ 3440,
2960, 2876, 1722, 1602, 1280, 1070 cmϪ1. MS (electrospray): m/z ϭ
519 [2M ϩ Na], 271 [M ϩ Na]. [α]2D0 ϭ 8.4 (c ϭ 0.57, CHCl3).
HRMS, calculated for C28H32NaO8 [2 M ϩ Na]: 519.19949;
found 519.19948.
(2S,3R,3aS,4aS,5R,8S,8aR)-3-(Hydroxymethyl)-5,10,10-trimethyl-
5,8-methano-2,3-propano-octahydroisoxazolo[3,2-b]benzoxazole
(13b):
A suspension of lithium aluminium hydride (36 mg,
0.95 mmol, 4 equiv.) in dry diethyl ether (6 mL) was cooled to 0
°C, and a solution of cycloadduct 9b (188 mg, 0.47 mmol, 1 equiv.)
in diethyl ether (2 mL) was added dropwise. The grey suspension
was stirred at 0 °C for one hour, and then quenched by careful
addition of saturated aqueous ammonium chloride (3 mL). Anhyd-
rous sodium sulfate was added, and the mixture was filtered
through Celite, rinsing with diethyl ether. The solution was washed
with saturated brine solution (20 mL), dried (Na2SO4), filtered and
concentrated in vacuo. The crude product was purified by chroma-
tography (20 to 50% ether/pentane) to give the alcohol 13b as a
colourless oil (129 mg; yield 93%). 1H NMR (250 MHz, CDCl3):
δ ϭ 5.08 (s, 1 H, 3a-H), 4.30 (d, J ϭ 3 Hz, 1 H, 2-H), 3.90 (d, J ϭ
8 Hz, 1 H, 4a-H), 3.7 (d, 1 H, J ϭ 11 Hz, one of CH2ϪOH), 3.4
(d, 1 H, J ϭ 11 Hz, one of CH2ϪOH), 3.3 (d, J ϭ 8 Hz, 1 H, 8a-
H), 2.5 (broad s, 1 H, OH), 2.05 (d, J ϭ 5 Hz, 1 H, 8-H), 2.0Ϫ1.5
(m, 6 H, 2 ϫ 2Ј-H, 2 ϫ 3Ј-H, 2 ϫ 4Ј-H), 1.47Ϫ1.17 (m, 4 H, 2 ϫ
6-H, 2 ϫ 7-H), 0.95, 0.88, 0.78 (3 s, 9 H, 3 ϫ CH3) ppm. 13C NMR
(62.5 MHz, CDCl3): δ ϭ 106.5 (C-3a), 90.2 (C-4a), 85.5 (C-2), 75.7
(C-8a), 64.6 (CH2-OH), 63.4 (C-3), 49.1 (C-8), 48.6 (C-5), 45.8 (C-
[1]
[1a]
For reviews on [2ϩ3] cycloadditions, see:
P. Deshong, S.
W. Lander, Jr., J. M. Leginus, C. M. Dicken, in Advances in
Cycloaddition (Ed.: D. P. Curran); JAI Press: Greenwich, 1988;
[1b]
vol. 1, pp. 87Ϫ128.
W. Carruthers, Cycloaddition Reactions
Eur. J. Org. Chem. 2002, 3566Ϫ3572
3571

S. Collon, C. Kouklovsky, Y. Langlois
FULL PAPER
[1c]
in Organic Synthesis; Pergamon Press: Oxford, 1990.
Little, in Comprehensive Organic Synthesis (Eds.: B. M. Trost,
R. D.
known alcohol: H.-S. Byun, K. C. Reddy, R. Bittman, Tetra-
hedron Letters 1994, 35, 1371Ϫ1374. Ester 5b was prepared by
nucleophilic substitution of the known tert-butyl 2-(bromome-
thyl)acrylate with sodium benzyloxide: B. Giese, T. Linker, Syn-
thesis 1992, 46Ϫ48.
I. Fleming); Pergamon Press: Oxford, 1991; vol. 5, pp.
[1d]
239Ϫ270.
A. Padwa, Intermolecular 1,3-dipolar cycloaddi-
tions. In Comprehensive Organic Synthesis (Eds.: B. M. Trost,
I. Fleming, M. F. Semmelhack), Pergamon Press; Oxford, 1991;
vol. 4, Chapter 9, pp. 1069Ϫ1109. [1e]K. V. Gothelf, K. A. Jor-
ensen, Chem. Rev. 1998, 98, 863Ϫ909.
O. Dirat, C. Kouklovsky, M. Mauduit, Y. Langlois, Pure Ap-
plied Chem. 2000, 72, 1721Ϫ1737.
[8] [8a]
K. Takeda, I. Imaoka, E. Yoshii, Tetrahedron 1994, 50,
[8b]
10839Ϫ10848.
1992, 57, 3380Ϫ3387.
W. R. Roush, B. B. Brown, J. Org. Chem.
[8c]
W. Adam, R. Albert, L. Hasemann,
V. O. N. Salgado, B. Nestler, E.-M. Peters, F. Prechtl, H. G.
von Schnering, J. Org. Chem. 1991, 56, 5782Ϫ5785. [8d] F. Foti-
adu, F. Michel, G. Buono, Tetrahedron Lett. 1990, 31,
4863Ϫ4867. [8e] For a recent example in the α-methylene lactam
series, see: J. Ishihara, M. Horie, Y. Shimada, S. Tojo, A. Mu-
rai, Synlett 2002, 403Ϫ406.
[2]
[3]
C. Kouklovsky, O. Dirat, T. Berranger, Y. Langlois, M.-E. Tran
Huu Dau, C. Riche, J. Org. Chem. 1998, 63, 5123Ϫ5128.
T. Berranger, Y. Langlois, J. Org. Chem. 1995, 60, 1720Ϫ1726.
[4]
[5]
´
S. W. Baldwin, R. B. McFayden, J. Aube, J. D. Wilson, Tetra-
[9] [9a]
hedron Lett. 1991, 32, 4431Ϫ4433.
D. Alonso-Perarnau, P. de March, M. el Arrad, M. Fig-
[6]
[7]
Esters 8a؊8c were prepared by Steglich esterification of the
corresponding acid, see Exp. Sect. Cyclobutenecarboxylic acid
was obtained in two steps from commercially available cyclobu-
tanecarboxylic acid, according to: W. G. Dauben, J. R. Wise-
man, J. Am. Chem. Soc. 1967, 89, 3545Ϫ3549.
ueredo, J. Font, T. Parella, Tetrahedron 1997, 53, 14763Ϫ14772.
[9b]
P. Dalla Croce, R. Ferraccioli, C. La Rosa, Heterocycles
[9c]
1995, 40, 349Ϫ355.
A. Sk. Ali, M. I. Wazeer, Tetrahedron
Lett. 1992, 33, 3219Ϫ3222.
Received June 12, 2002
[O02319]
Ester 5a was obtained by protection of the corresponding
3572
Eur. J. Org. Chem. 2002, 3566Ϫ3572