Enantioselective Diels-Alder reaction with an α-chloronitroso dienophile derived from 5-O-acetyl-2,3-isopropylidenedioxy-D-ribose

Article abstract of DOI:10.1055/s-2000-8214

Crystalline 5-O-acetyl-2,3-isopropylidenedioxy-D-ribonolactone oxime (8) was synthesised from D-ribose in 40% overall yield. The chloronitroso dienophile 3b was obtained from 8 by oxidation with t-BuOCl and underwent asymmetric Diels-Alder reaction with cyclic and acyclic dienes 10-13 to give crystalline adducts 14a-17a in good yield and excellent enantiomeric excess (93-99%).

Full text of DOI:10.1055/s-2000-8214

PAPER
1719
Enantioselective Diels Alder Reaction with an -Chloronitroso Dienophile
Derived from 5-O-Acetyl-2,3-isopropylidenedioxy-D-ribose
Albert Defoin,* Muriel Joubert, Jean-Marc Heuchel, Christiane Strehler, Jacques Streith
École Nationale Supérieure de Chimie de Mulhouse, Université de Haute-Alsace, 3, rue A. Werner, F-68093 Mulhouse Cédex, France
Fax +33(0)389336875; E-mail: A.Defoin@univ-mulhouse.fr
Received 16 June 2000, revised 28 July 2000
oximes with t-butyl hypochlorite.9,20,23 In the D-mannose
Abstract: Crystalline 5-O-acetyl-2,3-isopropylidenedioxy-D-ri-
series, the crystalline lactone-oxime was easily synthe-
bonolactone oxime (8) was synthesised from D-ribose in 40% over-
sised in good overall yield in 3 steps from D-mannose.25,26
all yield. The chloronitroso dienophile 3b was obtained from 8 by
oxidation with t-BuOCl and underwent asymmetric Diels Alder re-
On the contrary, the 5-O-trityl D-ribose derivatives26,27 are
action with cyclic and acyclic dienes 10 13 to give crystalline ad- difficult to crystallise and the use of 3a is limited due to a
ducts 14a 17a in good yield and excellent enantiomeric excess
(93 99%).
mandatory chromatographic purification. In order to
avoid these difficulties, we present herein the synthesis
Key words: asymmetric Diels Alder reaction, 1,2-oxazines, D-ri-
bose derivatives, chloronitroso dienophiles, heterocycles
and the use in asymmetric Diels Alder reactions of
-chloronitroso derivative 3b in the 5-O-acetyl D-ribose
series. As a matter of fact, the crystalline oxime 8 was eas-
ily prepared on a large scale. According to the methodol-
ogy we had already used for the D-mannose nitroso
dienophile 2,14,28 primary adducts were isolated as crystal-
line hydrochlorides. Enantiomeric excess was determined
by HPLC on chiral columns by comparison with results
obtained for the corresponding racemic compounds.
Introduction
Chiralnitroso dienophiles auxiliaries have been developed
in asymmetric hetero Diels Alder reaction as N-acyl or
-chloro derivatives for methodological or synthetic
purposes1 (Scheme 1). Type 1 N-acylnitroso dienophiles
were prepared from mandelic acid,2 9 from amino acids10
or from proline7,11 and led to moderate to good diastereoi-
someric excess. Excellent asymmetric inductions were
obtained with derivatives of C2-symmetrical pyrro-
Synthesis of 5-O-Acetyl Lactone-Oxime 8
Starting from acetonide 4, which was easily available
from D-ribose,29 lactone-oxime 6 was obtained according
to the same methodology which was used in the D-man-
nose series25,26 (Scheme 2). The reaction of 4 with hydrox-
ylamine in aqueous EtOH gave the linear oxime 5 as an
(E,Z)-mixture,27 which was oxidised with sodium iodate
or sodium periodate into the crystalline cyclic oxime 6 in
ca 55% overall yield from D-ribose.
15
lidines,11 of menthol16 or camphor.11,17,18 -Chloroni-
troso dienophiles have the advantage of affording adducts
as hydrochlorides with simultaneous solvolytic release of
the auxiliary.19 Excellent chiral inductions have been de-
scribed for diacetone D-mannose derivative 2 with a wide
range of dienes9,20,21 and, more recently, for 5-O-trityl ac-
etone D-ribose derivative 3a which led to the correspond-
ing enantiomeric adducts.9,22 Excellent chiral inductions
were also observed during cycloaddition of reactive cyclic
dienes with -chloronitroso derivatives of ketones, e.g.
epiandrosterone23 and sugar ketones.24
As the monoacetylation of this hydroxylactone-oxime 6
was not specific, 5-O-acetyl derivative 8 was prepared in
two steps in 75% overall yield from 6 by peracetylation to
the bis-acetate 7, followed by a specific monodesacetyl-
ation to the oxime 8 (NaHCO3 in EtOH at 60 °C).
Oxidation of lactone-oxime 8 with t-butyl hypochlorite in
CH2Cl2 at 10 °C led to the -chloronitroso derivative 3b
as a blue resin, which was not very stable above 0 °C, no
purification was needed though, 3b had to be used at once.
The absolute configuration at C(1) is supposed to be the
same as for 3a.22
O
O
RO
5
O
N
O
N
O
Cl
N
4
1
O
O
Cl
R
2
3
O
O
O
O
O
1
2
3a R = CPh3
3b R = Ac
Diels Alder Reaction in Chiral Series
Scheme 1
As described for the D-mannose derivative 2,14,20,22,28 the
Diels Alder cycloadditions with 3b were performed un-
der the same conditions (CH2Cl2/EtOH at 10 °C) until
decolouration of the solution (Scheme 3). The reaction
These -chloronitroso dienophiles are commonly pre-
pared by oxidation of their corresponding cyclic lactone-
Synthesis 2000, No. 12, 1719–1726 ISSN 0039-7881 © Thieme Stuttgart · New York

1720
A. Defoin et al.
PAPER
HO
(1S)
(4R)
HO
HO
O
3b
O
O
N
4
1
NOH
OH
5
HO
NOH
CH2Cl2 / MeOH
Z
2
3
NH2OH
NaIO3 or
NaIO4
O
O
O
O
O
O
10
14a Z = H,HCl
14b Z = CO2Bn
14c Z = CO2t-Bu
a)
b)
6
5
4
CO2H
CO2R2
(6S)
AcO
AcO
3b
O
O
O
N
O
NOR
Ac2O / Pyr
t-BuOCl
CH2Cl2 / MeOH
Z
3b
(3S)
O
O
R1
O
O
R1
11 R1 = H
12 R1 = Me
15a R1 = R2 = H
Z = H,HCl
c)
c)
15b R1 = H R2 = Me Z = CO2Bn
16a R1 = Me R2 = H Z = H,HCl
7 R = Ac
8 R = H
9
NaHCO3 / EtOH
16b R1 = R2 = Me
Z = CO2Bn
Scheme 2
(6R)
O
3b
CH2Cl2 / MeOH
(with 20% trans-isomer)
N
Z
(3S)
rate was fast with cyclohexadiene (10) and slow (ca 1 2
d) with pentadienoic acid (11) and sorbic acid (12), lead-
ing to the corresponding chiral adducts 14a 16a as crys-
talline hydrochlorides in 75 86% yield (by direct
precipitation with anhydrous diethyl ether). Hexa-2,4-di-
ene (13) [ca 50:50 mixture of (E,E)- and (E,Z)-isomers30]
reacted rapidly with 3b and gave a mixture of the cis-ad-
duct 17a and its trans-isomer (20%). The cis adduct 17a
was isolated in 60% yield as a crystalline hydrochloride
after aqueous extraction, as described by Kresze and Va-
sella.20 Ribonolactone (9), which resulted from 3b, could
be isolated from the organic phase.
13
(E,E / E,Z = 50 / 50)
17a Z = H,HCl
17b Z = CO2Bn
17c Z = CO2t-Bu
a)
b)
Reagents and conditions: a) CICO2Bn/NaHCO3, b) (t-BuCO2)2O/
NaHCO3 or Na2CO3, c) CICO2Bn/NaHCO3/H2O, then dry HCI/
MeOH
Scheme 3
cording to the procedure which had been used for the syn-
thesis of the chiral adducts, 18 reacted at a slower rate
than 3b (2 weeks at 20 °C). Hexa-2,4-diene (13) reacted
with 18 at an even slower rate (2 months at 20 °C) and
gave the racemic cis-adduct ( )-17a in poor yield (20%).
The racemic N-carbamates ( )-17b,c were synthesised
admixed with 10% trans-isomer, by Diels Alder reaction
of diene 13 with the achiral acylnitroso compounds, pre-
pared in situ by oxidation of the corresponding hydroxam-
ic acids 19 and 20 with a periodate ammonium salt. An
improved synthesis of the t-butylated hydroxamic acid
2035,36 was described according to the same method as for
the benzylated 19.37
N-Carbamate derivatives 14b,c, 15b, 16b, 17b,c were pre-
pared from 14a and 17a by N-acylation with benzyl chlo-
roformate or with t-butyl dicarbonate, or from 15a, 16a as
described for their enantiomers28 (N-acylation, then ester-
ification with HCl/MeOH). The absolute configurations
of the adducts 14a 17a, as depicted in Scheme 3, were
determined by comparison of their analytical data with
those of compounds which were described in the literature
and whose absolute configuration had been demonstrated
previously. Their spectroscopic data are identical and the
[ ]D values are opposite to those of the enantiomers of the
adducts 14a,7,14,20 15a and 16a,28 17a (as free base)20,22
which have been obtained by the reaction of dienes 10 13
with the -chloronitroso dienophile 2. The [ ]D values of
adducts 14a and 17a are in accordance with those of the
adducts which resulted from the reaction of dienes 10 and
13 with the -chloronitroso dienophile 3a.22
Determination of Enantiomeric Excess
Enantiomeric excess was determined by HPLC on three
different Daicel chiral columns (Chiralcel OD, Chiralcel
OD-R, Chiralpak AD, see Table). HPLC-measurements
could be achieved directly with the crude adducts when
these were stable entities, i.e. 14a and 17a, nevertheless
they were slightly disturbed by some minor impurities.
For this reason, HPLC measurements were performed
preferably with the N-acylated derivatives 14c, 15b, 16b,
17b. The t-butyl derivatives 17c showed too little absor-
bance and gave irreproducible results. The crystalline
Preparation of Racemic Compounds (Scheme 4)
The racemic N-carbamates ( )-14c,31 ( )-15b28 and
( )-16b28 as well as the cyclohexadiene adduct ( )-
14a32 34 are known compounds. The latter compound was
34
prepared from the achiral nitroso dienophile 1832 ac-
Synthesis 2000, No. 12, 1719–1726 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Enantioselective Diels Alder Reaction with an -Chloronitroso Dienophile
1721
Conclusion
18 / CH2Cl2, MeOH
or 19
O
N
Z
We have described the synthesis of the crystalline 5-O-
acetyl-2,3-O-isopropylidene-D-ribonolactone oxime (8)
in 40% overall yield from D-ribose. The -chloronitroso
compound 3b, which was obtained from 8 by oxidation,
proved to be a reactive dienophile and an excellent chiral
inductor indeed, leading to 93 99% ee in hetero Diels
Alder cycloaddition.
BnMe3N(+),IO4
(-)
10
(±)-14a Z = H,HCl
(±)-14b Z = CO2Bn
MeOH
18 / CH2Cl2, MeOH
or 19 or 20
O
N
Z
(-)
BnMe3N(+),IO4
MeOH
Flash chromatography (FC): silica gel (Merck 60, 230 400 mesh).
TLC: Al-roll silica gel (Merck 60, F254). Mp: Kofler hot bench or
Büchi-SMP20 apparatus, corrected. IR spectra ( in cm ): Perkin-
(±)-17a Z = H,HCl
(±)-17b Z = CO2Bn
13
(E,E / E,Z = 50 / 50)
1
(±)-17c Z = CO2t-Bu
(with 10% trans-isomer)
Elmer 157 G, [ ]D: Schmidt-Haensch Polartronic Universal pola-
rimeter. HPLC measurements: liquid chromatograph Hewlett-Pack-
O
1
ard 190. H and 13C NMR (62.9 MHz) spectra: Bruker AC-F250,
OH
NH
OH
TMS or sodium trimethylsilylpropionate-D4 (D4-TSP) in D2O (1H
NMR) and CDCl3, CD3OD, or (in D2O) CH3OH or dioxane
[ (CDCl3) = 77.0, (CD3OD) = 49.0, in D2O (CH3OH) = 50.0,
(dioxane) = 67.4 with respect to TMS] (13C NMR) as internal ref-
erences, in ppm and J in Hz. 13C attributions were ascertained by
1H-13C correlation. HRMS were measured on a MAT-311 spec-
trometer at the Université de Rennes. Microanalyses were carried
out by the Service de microanalyse de l'ICSN-CNRS, Gif s/Yvette.
N
Cl
BnO
t-BuO
NH
O
O
18
19
20
Scheme 4
Benzyl chloroformate, cyclohexa-1,3-diene, cyclohexanone-oxime,
t-butyl dicarbonate (pyrocarbonate) were purchased from Fluka,
sorbic acid from EGA-Chemie, D-ribose from Acros. Trimethyl-
benzylammonium periodate,38 t-BuOCl,36 (E,E)/(E,Z)-hexa-2,4-di-
ene,30 (2E)-penta-2,4-dienoic acid40 were prepared according to the
literature. Usual solvents and Ac2O were freshly distilled, anhyd
EtOH and MeOH distilled over Mg/MgI2, CH2Cl2 was kept over
Na2CO3.
benzylated compound 14b was not evaluated, since it was
more suitable to be obtained enantiopure by crystallisa-
tion.
The enantiomeric excess of the Diels-Alder reaction are
collected in the Table. In almost all cases, excellent results
(ee >97%) have been obtained. They are similar to those
which have been obtained with the 5-O-trityl nitroso de-
rivative 3a.22 In the case of the cyclohexadiene adduct
14a, in which two crops were obtained, the ee as indicated
for 14a and 14c is the average value. For the monosubsti-
tuted adduct of pentadienoic acid 15b, the ee value
(ee = 93%) was higher than the one we had observed with
the nitroso mannose derivative 2,28 it even rose to 98% af-
ter recrystallisation.
Ribose Derivatives, 2,3-O-Isopropylidene-D-ribose Oxime (5)25
A solution of 429 (26.8 g, from 20.0 g of D-ribose, 0.13 mol),
NH2OH•HCl (14.7 g, 0.21 mol, 1.5 equiv) and NaHCO3 (18.9 g,
0.23 mol, 1.6 equiv) in EtOH (160 mL) and H2O (160 mL) was
stirred at 60 °C for 4 5 h. EtOH was then evaporated, the aqueous
solution extracted with EtOAc (6 7 × 150 mL) and the pH was ad-
justed to 7. The organic phases were washed with 20% NaCl solu-
tion, dried (MgSO4) and evaporated to give crude 5 (24.6 g, 90%)
as a colourless resin, which was used for the next step. The 1H NMR
data were identical with those reported in Lit.27
2,3-O-Isopropylidene-D-ribono- -lactone-Oxime (6)26
To a solution of 5 (24.6 g, 0.12 mol) and NaOAc•3 H2O (8.2 g,
60 mmol) in EtOH (500 mL), was added a solution of NaIO3 (11.9
g, 60 mmol, 0.5 equiv) or NaIO4 (9.6 g, 45 mmol, 0.4 equiv) in H2O
(210 mL) and the mixture stirred at 75 °C for 16 24 h. The solids
were discarded, EtOH was evaporated, iodide reduced with
Na2SO3, the aqueous solution adjusted to 7 with NaHCO3 and ex-
tracted with EtOAc (8 × 150 mL). The organic phases were washed
with 20% brine, dried (MgSO4) and evaporated to give crude 6
(18 g). Crystallisation from Et2O or i-PrOH/i-Pr2O gave pure 6
(14.4 g, 55% from D-ribose); colourless crystals; mp 109 110 °C
Table Asymmetric Cycloaddition of Chiral Dienophile 3b with
Dienes 10 13
Dienes Adducts or Yield (%) Chiral Column
Derivatives
ee (%)
10
10
11
12
13
13
14a
14c
15b
16b
17ac
17bc
86
–
76
75
60
63
Chiralpak AD
Chiralpak AD
Chiralcel OD-R
Chiralcel OD-R
Chiralcel OD
Chiralpak AD
96a
95
21
(i-PrOH/i-Pr2O); [ ]D 84 (c = 1, CHCl3).
93 95b
>99
97d
IR (KBr): = 3510, 3410, 1695, 1380, 1230, 1210, 1085, 1070
1
cm .
1H NMR (CDCl3): = 7.74 (br s, 1 H, NOH), 5.17 (d, 1 H, H-2),
4.82 (d, 1 H, H-3), 4.69 (s, 1 H, H-4), 3.96 (br d, 1 H, Ha-5), 3.72
(br d, 1 H, Hb-5), 3.46 (br s, 1 H, OH-5), 1.49 (s, 3 H, CH3), 1.38 (s,
3 H, CH3). J2,3 = 6.0, J3,4 = 1.0, J4,5a = 2.5, J4,5b = 2.2, J5a,5b = 12.4
Hz.
98d
a ee = 99% for the first crop of crystallisation.
b ee = 98% after recrystallisation of 15a.
c With 20% of trans-isomer.
d For the major cis-isomer only.
Synthesis 2000, No. 12, 1719–1726 ISSN 0039-7881 © Thieme Stuttgart · New York

1722
A. Defoin et al.
PAPER
13C NMR (CDCl3): = 159.7 (C-1), 113.4(CMe2), 88.0, 79.8, 77.5
(C-2,C-3,C-4), 62.4 (C-5), 26.8, 25.5 (2 CH3).
13C NMR (CDCl3): = 170.3 (MeCO), 126.8 (C-1), 115.4 (CMe2),
89.3 (C-2), 86.8 (C-3), 81.6 (C-4), 62.9 (C-5), 25.7, 25.1 (2 CH3),
20.7 (CH3CO).
Anal. calcd for C8H13NO5 (203.2): C 47.29, H 6.45, N 6.89, found:
C 47.2, H 6.5, N 7.1.
Diels Alder Reactions; General Procedure
To a solution of 3b (0.53 g, 1.64 mol) in CH2Cl2 (1.6 mL) was added
at 10 °C the corresponding diene 10 13 (1.5 2 equiv) in EtOH
(0.4 mL) and the solution stirred at 10 °C until discoloration (1
24 h). Anhyd Et2O (5 mL) was then added. Adducts 14a 16a crys-
tallised out and were isolated by filtration after 2 3 h at 0 °C and
washed with anhyd Et2O. Adduct 17a was extracted with H2O (see
below).
1,5-O-Diacetyl-2,3-O-isopropylidene-D-ribonolactone-Oxime
(7)
To a solution of 6 (22.0 g, 0.108 mol) in pyridine (80 mL) at r.t. in
a water bath was added Ac2O (41 mL, 0.43 mol, 4 equiv) dropwise
and the mixture stirred for 3.3 h. MeOH (30 mL) was then added
and the solvents were evaporated. Crystallisation from i-Pr2O (30
mL) at 0 °C overnight gave pure 7 (25.9 g, 83%) in two crops after
filtration and washing with i-Pr2O; colourless crystals; mp 116
5-Acetyl-2,3-O-isopropyliden-D-ribonolactone (9)
19
8 °C (i-PrOH); [ ]D 122 (c = 1, CHCl3).
The above organic phase was evaporated and the crude 9 (0.42 g,
quant.) was crystallised from i-Pr2O and washed with i-Pr2O at 0 °C
to give the pure 9 (0.25 g, 67%; colourless crystals; mp 47 49 °C
IR (KBr): = 2980, 2935, 1750, 1738, 1660, 1375, 1255, 1235,
1
1215, 1187, 1075 cm .
(i-Pr2O); [ ]D 59 (c = 1, CHCl3) (Lit.41 mp 50 51 °C (EtOAc);
19
1H NMR (CDCl3): = 5.25 (d, 1 H, H-2), 4.89 (t, 1 H, H-4), 4.76
(dd, 1 H, H-3), 4.41 (dd, 1 H, Ha-5), 4.20 (dd, 1 H, Hb-5), 2.17 (s,
3 H, CH3CO), 2.08 (s, 3 H, CH3CO), 1.51 (s, 3 H, CH3), 1.39 (s, 3
H, CH3). J2,3 = 6.0, J3,4 = 1.0, J4,5a = 2.8, J4,5b = 2.5, J5a,5b = 12.6 Hz.
13C NMR (CDCl3): = 169.8, 167.6 (2 MeCO), 162.6 (C-1), 114.2
(CMe2), 85.6 (C-2), 79.1 (C-4), 77.7 (C-3), 63.5 (C-5), 26.7, 25.5 (2
CH3), 20.5, 19.2 (2 CH3CO).
[ ]D 59, Lit.42 mp 47.5 °C).
IR (KBr): = 2970, 2930, 1780, 1750, 1375, 1228, 1218, 1170,
1
1080 cm .
1H NMR (CDCl3): = 4.79 (d, 1 H, H-2), 4.78 (t, 1 H, H-4), 4.71 (d,
1 H, H-3), 4.38 (dd, 1 H, Ha-5), 4.24 (dd, 1 H, Hb-5), 2.09 (s, 3 H,
CH3CO), 1.50 (s, 3 H, CH3), 1.41 (s, 3 H, CH3), J2,3 = 5.7, J3,4 = 0,
J4,5a = 2.9, J4,5b = 2.5, J5a,5b = 12.5 Hz.
13C NMR (CDCl3): = 20.5 (CH3CO), 25.5, 26.7 (2 CH3), 63.4 (C-
5), 75.1(C-2), 77.7 (C-3), 79.5 (C-4), 113.7(CMe2), 169.7(MeCO),
173.4 (C-1).
Anal. calcd for C12H17NO7 (287.3): C 50.17, H 5.97, N 4.88, found:
C 50.2, H 5.8, N 4.7.
5-O-Acetyl-2,3-O-isopropylidene-D-ribonolactone-Oxime (8)
To a stirred solution of 7 (10.0 g, 0.035 mol) in EtOH (40 mL) was
added finely pulverised NaHCO3 (10 g, 0.12 mol, 3.5 equiv) and the
solution stirred for 2.5 h at 60 °C. EtOAc (50 mL) was then added,
the solids filtred off and washed with EtOAc. Evaporation of the
solvents and crystallisation from Et2O gave 8 (5.4 g, 64%). The
mother liquors were evaporated, acetylated with Ac2O (8 mL) in py-
ridine (16 mL) for 3.5 h as above to give 7 (ca 3.5 g after washing
with i-Pr2O), which was monodeacylated as above and gave a sec-
ond crop of 8 (2.0 g, 22%); colourless crystals; mp 137 139 °C
( )-(1S,4R)-2-Oxa-3-azabicyclo[2,2,2]oct-5-ene Hydrochloride
[( )-14a]
Following the general procedure, 3b [from 8 (0.5 g, 2.04 mmol)]
was reacted with 10 (0.3 mL, 3.1 mmol, 1.5 equiv, the solution was
centrifuged to eliminate polymers). The reaction mixture became
colourless in 15 min and ( )-14a (0.227 g, 76%) was isolated. A
second crop (26 mg, 12%) was obtained after 1 d at 10 °C; colour-
21
less crystals; mp 210 215 °C (dec., EtOH/Et2O); [ ]D 25 (c = 1,
20
MeOH) [Lit.22 mp 135 °C (dec.); [ ]D 25.2 (c = 1.2, CHCl3).
19
IR (KBr), 1H NMR (D2O) and 13C NMR (D2O): same values as in
(i-PrOH); [ ]D 122° (c = 1, CHCl3).
Lit.20b for the (1R,4S)-enantiomer.
1
IR (KBr): = 3420, 2985, 1740, 1688, 1225, 1155, 1088, 928 cm .
1H NMR (D2O): = 6.90 (dd, 1 H, J = 5.8, 8.4 Hz, H-6), 6.63 (dd,
1 H, J = 6.2, 8.4 Hz, H-5), 5.00 (br s, 1 H, H-1), 4.59 (br s, 1 H, H-
4), 2.26 (m, 1 H), 2.16 (m, 1 H), 1.60 (m, 2 H).
1H NMR (CDCl3, 10% CD3OD): d = 6.86 (ddd, 1 H, H-6), 6.67
(ddd, 1 H, H-5), 4.90 (dt, 1 H, H-1), 4.63 (m, 1 H, H-4), 2.49 (m, 1
H, Hexo-8), 2.39 (m, 1 H, Hexo-7), 1.54 (m, 2 H, Hendo-7, Hendo-8).
1H NMR (CDCl3): = 7.10 (br s, 1 H, NOH), 5.11 (d, 1 H, H-2),
4.83 (t, 1 H, H-3), 4.74 (dd, 1 H, H-4), 4.38 (dd, 1 H, Ha-5), 4.22
(dd, 1 H, Hb-5), 2.09 (s, 3 H, CH3CO), 1.51 (s, 3 H, CH3), 1.40 (s,
3 H, CH3). J2,3 = 6.0, J3,4 = 1.0, J4,5a = 3.2, J4,5b = 3.0, J5a,5b = 12.5
Hz.
13C NMR (CDCl3): = 170.2 (MeCO), 157.4 (C-1), 114.0 (CMe2),
84.2 (C-2), 79.3 (C-4), 77.1 (C-3), 64.0 (C-5), 26.8, 25.6 (2 CH3),
20.6 (CH3CO).
J1,5 = 1.5, J1,6 = 5.8, J1,7exo = 3.9, J1,7endo = 1.5, J4,5 = 6.2, J4,6 = 1.6,
J4,8endo = J4,8exo = ca 3.0, J5,6 = 8.4 Hz.
(1R,4S)-Enantiomer: Lit.14 mp 205 210 °C (dec.); [ ]D20 +27.5
(c = 1, MeOH), Lit.20b mp 135 °C (dec.); [ ]D20 +24.4 (c = 5,
CHCl3); Lit.20a [ ]D20 +24.0 (c = 5, MeOH)].
Anal. calcd for C10H15NO6 (245.2): C 48.97, H 6.17, N 5.71, found:
C 49.0, H 6.1, N 5.6.
5-O-Acetyl-2,3-O-isopropylidene-1-C-nitroso-D-ribofuranosyl
Chloride (3b)
( )-(6S)-3,6-Dihydro-2H-1,2-oxazine-6-carboxylic Acid Hydro-
chloride [(–)-15a]
To a stirred solution of 8 (0.40 g, 1.64 mol) in CH2Cl2 (2.0 mL) at
10 °C, was added dropwise t-BuOCl (0.22 mL, 2.0 mol,
1.2 equiv). The mixture became dark blue and was evaporated at r.t.
after 0.5 h to give 3b (0.53 g, quant.). The compound is too unstable
for elemental analysis; unstable dark blue resin (to be stored at
20 °C); [ ]D20 +1770 (c = 1, CHCl3).
Following the general procedure, 3b [from 8 (0.3 g, 1.22 mmol)]
was reacted with 11 (0.19 g, 1.94 mmol, 1.6 equiv). The reaction
mixture became yellowish in 16 24 h and ( )-15a (0.153 g, 76%)
was isolated; colourless crystals; mp 160-165 °C (dec, EtOH/Et2O);
19
[ ]D 189 (c = 1, H2O) [(6R)-enantiomer: Lit.28 mp 157 158 °C
(dec); [ ]D22 +128 (c = 1, H2O)].
1
IR (CHCl3): = 2985, 1743, 1580, 1385, 1378, 1228, 1080 cm .
IR (KBr): = 3400, 3040 2600, 1740, 1590, 1398, 1205, 1070,
805, 745 cm .
1
1H NMR (CDCl3): = 5.63 (d, 1 H, H-2), 4.95 (dd, 1 H, H-3), 4.78
(dt, 1 H, H-4), 4.43 (dd, 1 H, Ha-5), 4.27 (dd, 1 H, Hb-5), 2.14 (s, 3
H, CH3CO), 1.30 (s, 3 H, CH3), 1.28 (s, 3 H, CH3). J2,3 = 5.8,
1H NMR (D2O): = 3.90 (dm, 1 H, Hb-3), 4.04 (dm, 1 H, Ha-3),
5.30 (s, 1 H, H-6), 6.16 (dm, 1 H, H-4), 6.28 (dm, 1 H, H-5),
J3a,3b = 17.3, J3a,4 = 2.5, J3a,5 = 2.3, J3a,6 = 2.7, J3b,4 = 4.3, J3b,5 = 1.7,
J3,4 = 1.5, J4,5a = J4,5b = 5.4, J5a,5b = 12.2 Hz.
J3b,6 = 1.7, J4,5 = 10.8, J4,6 = 2.7, J5,6 = 3.2.
Synthesis 2000, No. 12, 1719–1726 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Enantioselective Diels Alder Reaction with an -Chloronitroso Dienophile
1723
(6R)-Enantiomer: 1H NMR (D2O) and 13C NMR (D2O), same data
solvents evaporated to give a resin which crystallised from i-Pr2O/
as in Lit.28
cyclohexane and was washed with i-Pr2O/cyclohexane to give pure
( )-14b (0.12 g, 65%). A second crop (25 mg, 13%) was obtained
by FC (EtOAc/cyclohexane, 1:1); total yield: 78%; colourless crys-
Anal. calcd for C5H8ClNO3 (165.6): C 36.27, H 4.87, N 8.46, Cl
21.41, found: C 36.0, H 4.8, N 8.1, Cl 21.8.
21
tals; mp 58 60 °C (i-Pr2O); [ ]D 10 (c = 1, CHCl3).
( )-(3S,6S)-3-Methyl-3,6-dihydro-2H-1,2-oxazine-6-carboxylic
Acid Hydrochloride [(-)-16a]
IR (KBr): = 2940, 1687, 1405, 1345, 1262, 1108, 1073, 1048, 960,
1
908, 742, 695 cm .
Following the general procedure, 3b [from 8 (0.19 g, 0.78 mmol)]
was reacted with 12 (0.14 g, 1.25 mmol, 1.6 equiv). The reaction
mixture became green in 24 h and ( )-16a (0.10 g, 71%) was isolat-
ed. An impure second crop (ca 7 mg, 4%) was obtained after 1 3 d
at 10 °C; colourless crystals; mp 165 170 °C (dec., MeOH/
1H NMR (CHCl3): = 7.34 (m, 5 H, C6H5), 6.55 (m, 2 H, H-5, H-
6), 5.14, 5.20 (2 d, 2 H, J = 12.4, CH2Ph), 4.82, 4.76 (2 m, 2 H, H-
1, H-4), 2.18 (m, 2 H, Hexo-7, Hexo-8), 1.50, 1.38 (2 m, 2 H, Hendo-7,
Hendo-8)
21
Et2O); [ ]D 131 (c = 1, H2O) [(6R)-enantiomer: Lit.28 mp 170-
Anal. calcd for C14H15NO3 (245.3): C 68.55, H 6.16, N 5.71, found:
C 68.4, H 5.9, N 5.7.
172 °C (dec); [ ]D20 +125 (c = 1, H2O)].
1H NMR (D2O): = 1.42 (d, 3 H, CH3-3), 4.24 (q, 1 H, H-3), 5.20
(m, 1 H, H-6), 6.05 (dt, 1 H, H-5), 6.22 (d, 1 H, H-4). J3,4 = ca 2.3,
J3,5 = 2.7, J3,6 = ca 2.7, J3,Me-3 = 7.0, J4,5 = 10.8, J4,6 = ca 2.7,
( )-t-Butyl (1S,4R)-2-Oxa-3-azabicyclo[2,2,2]oct-5-ene-3-car-
boxylate [(-)-14c]
Same procedure as for ( )-14b was used. Compound ( )-14a
(60 mg, 0.4 mmol) and NaHCO3 (0.12 g, 1.4 mmol, 4 equiv) in
MeOH (0.5 mL) reacted with t-butyl dicarbonate (0.13 g, 0.6 mmol,
1.5 equiv). The crude resin was purified by FC (EtOAc/cyclohex-
ane, 3:7) to give pure ( )-14c (60 mg, 70%). For the ee determina-
tions, the first and the second crops of 14c were separately acylated.
For analytical purposes, ( )-14c was recrystallised before use;
J5,6 = 2.7 Hz.
Anal. calcd for C6H10 ClNO3 (179.6): C 40.11, H 5.61, N 7.80, Cl
19.74, found: C 40.1, H 5.6, N 7.7, Cl 19.8.
1
(3R,6R)-Enantiomer: IR (KBr), H NMR (D2O) and 13C NMR
(D2O), same values as in Lit.28
22
(+)-(3S,6R)-3,6-Dimethyl-3,6-dihydro-2H-1,2-oxazine [(+)-17a]
Following the general procedure, 3b [from 8 (0.40 g, 1.64 mmol) re-
acted with 13 (0.80 mL, 7.0 mmol, ca 3.5 mmol (E,E)-diene,
2.0 equiv). The reaction mixture became green in 2 3 h. Et2O (10
mL) was added and (+)-17a was extracted with H2O (4 × 2 mL), the
aqueous phases were extracted with Et2O and lyophilised. Purifica-
tion by dissolution in anhyd THF, centrifugation and evaporation
gave crude product (0.20 g, 85%) as colourless resin, which crystal-
lised from THF/Et2O (2:1) to give pure (+)-17a (0.144 g, 60%) (as
a mixture with 20% of trans-isomer). For analytical purposes, re-
crystallised (+)-17a contained 6% trans-isomer; colourless crystals;
mp 127-128 °C (THF or EtOAc); [ ]D20 +85 (c = 1, CHCl3)
cream resin; [ ]D 20 (c = 1, CHCl3).
1
IR (CHCl3): = 2975, 2935, 1710, 1690, 1370, 1160, 1075 cm .
1H NMR (CHCl3): 1.30, 1.44 (2 m, 2 H, Hendo-7, Hendo-8), 1.46 (s, 9
H, t-Bu), 2.15 (m, 2 H, Hexo-7, Hexo-8), 4.74 (m, 2 H, H-1, H-4), 6.55
(m, 2 H, H-5, H-6).
HR-MS calc. for C11H17NO3:211.1208, found: 211.1203.
(1R,4S)-enantiomer and racemic 14c: 1H NMR (CHCl3) and 13C
NMR (CHCl3), same data as in Lit.21 and Lit.,31 respectively.
( )-6-Benzyl, 2-Methyl (6S)-3,6-Dihydro-2H-1,2-oxazine-2,6-
dicarboxylate [(-)-15b]
Same procedure as for the (6R)-enantiomer28 was used: To a stirred
suspension of ( )-15a (91 mg, 0.55 mmol) and NaHCO3 (0.185 g,
2.2 mmol, 4 equiv) in anhyd MeOH (1 mL) was added dropwise
ClCO2Bn (93 µL, 0.66 mmol, 1.2 equiv) at r.t. under Ar. After
4.5 h, the solids were separated by centrifugation and washed with
anhyd MeOH, the solvents evaporated and the resulting resin was
stirred in 5% anhyd HCl in MeOH (1.5 mL) for 30 mn. After evap-
oration, the residue was dissolved in CH2Cl2 or Et2O, the insolubles
were separated by centrifugation, and the solvents evaporated to
give ( )-15b (0.144 g, 95%). For analytical purposes, adduct
( )-15a was recrystallised before use and ( )-15b purified by FC
IR (KBr): = 3400, 2870, 2620, 2500, 1563, 1444, 1380, 1115,
1022, 960, 728 cm .
1
1H NMR (CDCl3): = 5.86 (m, 2 H, H-4, H-5), 5.21 (q, 1 H, J = 6.7,
H-6), 4.06 (m, 1 H, H-3), 1.61 (d, 3 H, J = 6.7, CH3), 1.36 (d, 3 H,
J = 6.7, CH3).
13C NMR (CDCl3): = 128.4,123.4 (C-4, C-5), 74.6 (C-6), 49.8 (C-
3), 18.3, 16.3 (2 CH3).
1H NMR (CDCl3), trans-isomer: = 5.86, 5.73 (2 m, 2 H, H-4, H-
5), 5.21 (m, 1 H, H-6), 4.18 (m, 1 H, H-3), 1.59 (d, 3 H, J = 7.0,
CH3), 1.35 (d, 3 H, J = 6.7, CH3).
24
(CH2Cl2/Et2O 9:1); colorless resin; [ ]D 116 (c = 1, CHCl3)
[(6R)-enantiomer: Lit.28 [ ]D17 +115 (c = 1, CHCl3)].
Anal. calcd for C6H12ClNO3 (149.6): C 48.16, H 8.10, N 9.37, Cl
23.65, found: C 47.7, H 8.1, N 9.5, Cl 23.8.
IR (CHCl3): = 3020, 2950, 1735, 1710, 1435, 1405, 1350, 1320,
1
The free base was prepared by stirring (+)-17a with the same weight
of Na2CO3 and water in the appropriate solvent for 2 h; [ ]D20 +44
(c = 1, CH2Cl2); [Lit.22 [ ]D20 +52.2 (c = 1, CH2Cl2)].
1H NMR (CDCl3): = 5.84 (ddd, 1 H, H-4), 5.73 (dt, 1 H, H-5),
4.34 (m, 1 H, H-6), 3.50 (m, 1 H, H-3), 1.25 (d, 3 H, CH3-6), 1.24
(d, 3 H, CH3-3). J3,4 = 3.5, J3,5 = 1.6, J3,6 = 2.4, J3,Me-3 = 6.9,
1225, 1090, 1080 cm .
1H NMR (CDCl3): = 3.74 (s, 3 H, OCH3), 4.15 (s, 2 H, 2 H-3), 5.07
(s, 1 H, H-6), 5.23, 5.26 (2 d, 2 H, J = 12.3, CH2Ph), 6.01 (s, 2 H, H-
4, H-5), 7.36 (m, 5 H, C6H5).
HRMS: m/z calcd for C14H15NO5: 277.0950, found: 277.0949.
(6R)-Enantiomer: Same data as in Lit.28
J4,5 = 10.4, J4,6 = 2.0, J5,6 = 2.0, J6,Me-6 = 6.7 Hz.
1
(3R,6S)-Enantiomer: H NMR and 13C NMR (CDCl3) data as in
(+)-(6)-Benzyl, (2)-Methyl (3S,6S)-3-methyl-3,6-dihydro-2H-
1,2-oxazine-2,6-dicarboxylate [(+)16b]
Lit.20b
The same procedure as for the preparation of (3R,6R)-enantiomer28
and ( )-15b was used. Reaction of ( )-16a (100 mg, 0.55 mmol)
with NaHCO3 (0.186 g, 2.2 mmol, 4 equiv) and ClCO2Bn (94 µL,
0.66 mmol, 1.2 equiv) gave (+)-16b (0.143 g, 88%). For analytical
purposes, adduct ( )-16a was recrystallised before use and (+)-16b
purified by FC (CH2Cl2/Et2O, 9:1); colorless resin; [ ]D24 +51
Adducts; ( )-Benzyl (1S,4R)-2-Oxa-3-azabicyclo[2,2,2]oct-5-
ene-3-carboxylate [( )-14b]; Typical Procedure
A suspension of ( )-14a (0.113 g, 0.88 mmol) and Na2CO3 (0.187
g, 1.76 mmol, 2 equiv) in Et2O (2 mL) and H2O (30 µL) was stirred
at r.t. for 1 h under Ar. Benzyl chloroformate (0.14 mL, 0.99 mmol,
1.1 equiv) was then added and the mixture stirred for 3 h. The or-
ganic phase was decanted, solids were washed with Et2O and the
(c = 1, CHCl3) [(6R)-Enantiomer: Lit.28 [ ]D 55 (c = 1, CHCl3)].
17
Synthesis 2000, No. 12, 1719–1726 ISSN 0039-7881 © Thieme Stuttgart · New York

1724
A. Defoin et al.
PAPER
1H NMR (CDCl3): = 1.38 (d, 3 H, CH3-3), 3.81 (s, 3 H, OCH3),
4.54 (m, 1 H, H-3), 5.18 (m, 1 H, H-6), 5.18, 5.26 (2 d, 2 H, J = 12.3,
CH2Ph), 5.97 (dt, 1 H, H-4), 5.91 (ddd, 1 H, H-5), 7.36 (m, 5 H,
C6H5). J3,4 = 4.2, J3,5 = 1.2, J3,6 = 2.9, J3,Me-3 = 6.7, J4,5 = 10.3,
colorless crystals; mp 204-206 °C (dec., EtOH) [Lit.32 mp 160 °C
(dec., EtOH), Lit.40 mp 164-168 °C (dec.), Lit.41 mp 162-163 °C
(dec.)].
IR (KBr): = 2950 2500, 1458, 1420, 1390, 1367, 1287, 1172,
J4,6 = 2.3, J5,6 = 1.4 Hz.
1
1068, 949, 930, 866, 782, 710, 658 cm .
HRMS: m/z calcd for C15H17NO5: 291.1106, found: 291.1106.
Same NMR data as for (–)-14a.
(3R,6R)-Enantiomer: IR (CHCl3), 1H NMR (CDCl3) and 13C NMR
( )-3,6-Dimethyl-3,6-dihydro-2H-1,2-oxazine [( )-17a]
Same procedure as for ( )-14a. Reaction of 18 (7 mmol) with 13
(2.4 mL, 21 mmol, 1.5 equiv of (E,E)-diene] for 2 months at
20 °C. Same workup as for (+)-17a gave crystalline ( )-17a as
pure cis-isomer (0.20 g, 20%); colorless flakes; mp 190-195 °C
(EtOAc/EtOH, subl.).
(CDCl3), same data as in Lit.28
Benzyl (3S,6R)-3,6-Dimethyl-3,6-dihydro-2H-1,2-oxazine-2-
carboxylate (17b)
To an aqueous solution of 17a (8 mL) [from aqueous extraction of
the reaction mixture of 3b (0.82 mmol) and 13 (0.4 mL, 3.5 mmol,
2 equiv of (E,E)-diene)] was added dioxane (1 mL), NaHCO3 (0.28
g, 3.4 mmol, 4 equiv) and ClCO2Bn (0.132 mL, 0.94 mmol,
1.2 equiv). The reaction mixture was stirred for 2 h at r.t., then ex-
tracted with Et2O (2 × 10 mL), the organic phase dried (MgSO4)
and evaporated. Purification by FC (CH2Cl2) gave 17b (0.13 g,
63%) (as a mixture with 20% of trans-isomer); colorless resin.
1
IR (KBr): = 2610, 1578, 1370, 1290, 1160, 1090, 1030, 735 cm .
Same 1H NMR data as for 17a.
Anal. calcd for C6H12ClNO3 (149.6): C 48.16, H 8.10, N 9.37, Cl
23.65, found: C 48.4, H 8.1, N 9.4, Cl 23.2.
( )-Benzyl cis-3,6-Dimethyl-3,6-dihydro-2H-1,2-oxazine-2-car-
boxylate [( )-17b]
IR (CHCl3): = 2980, 1690, 1655, 1448, 1410, 1358, 1303, 1115,
1
1083, 1063 cm .
To a solution of 13 [0.41 mL, 3.6 mmol, 1.5 equiv of (E,E)-diene]
and Me3BnN·IO4 (0.14 g, 0.4 mmol, 0.33 equiv) in MeOH (2 mL)
at 0 °C, was added portionwise 19 (0.2 g, 1.2 mmol) in 30 min and
the brownish solution stirred for 1 h. Et2O (20 mL) was added and
the organic solution washed with aq Na2CO3 solution (containing
some Na2SO3 for decolorization) and H2O, dried (MgSO4) and
evaporated. Purification by FC (CH2Cl2) gave ( )-17b (0.25 g,
83%) mixed with 10% of trans isomer; colorless resin. Same IR
(CHCl3) and 1H NMR (CDCl3) data as for 17b.
1H NMR (CDCl3): = 7.34 (m, 5 Harom), 5.77(ddd, 1 H, H-4), 5.67
(dt, 1 H, H-5), 5.25, 5.18 (2 d, 2 H, J = 12.3 Hz, CH2), 4.65 (m, 1 H,
H-6), 4.48 (m, 1 H, H-3), 1.32 (d, 3 H, CH3), 1.27 (d, 3 H, CH3).
J3,4 = 4.3, J3,5 = 1.6, J3,6 = ca 2.6, J3,Me = 6.6, J4,5 = 10.3, J4,6 = 2.0,
J5,6 = 1.2. J6,Me = 6.6 Hz.
1H NMR (CDCl3), trans isomer: = 5.76 (m, 2 H, H-4, H-5), 5.14,
5.28 (2 d, 2 H, J = 12.3, CH2), 4.49 (m, 2 H, H-3, H-6),1.34 (d, 3 H,
J = 6.6 Hz, CH3), 1.29 (d, 3 H, J = 6.6 Hz, CH3).
Anal. calcd for C14H17NO3 (247.3): C 68.00, H 6.93, N 5.66, found:
C 67.5, H 6.8, N 5.6.
Anal. calcd for C14H17NO3 (247.3): C 68.00, H 6.93, N 5.66, found:
C 67.8, H 6.8, N 5.4.
( )-t-Butyl cis-3,6-dimethyl-3,6-dihydro-2H-1,2-oxazine-2-car-
boxylate [( )-17c]
(+)-t-Butyl (3S,6R)-cis-3,6-Dimethyl-3,6-dihydro-2H-1,2-ox-
azine-2 carboxylate [(+)-17c]
The same procedure as for ( )-17b was used. Reaction of 13
[0.51 mL, 4.5 mmol, 1.5 equiv of (E,E)-diene], Me3BnN·IO4 (0.17
g, 0.5 mmol, 0.33 equiv) in MeOH (2 mL) at 0 °C and 20 (0.2 g,
1.50 mmol). Purification by FC (CH2Cl2) gave pure cis-isomer ( )-
17c (0.18 g, 55%) and a 75:25 mixture of cis/trans isomers (0.15 g,
45%); colorless resin. Same IR (CHCl3), 1H NMR (CDCl3) data as
for (+)-17c.
To an aqueous solution of (+)-17a (8 mL) [from 3b (0.82 mmol) as
for 17b] were added MeOH (1 mL), aq Na2CO3 solution (1.6 mL,
1.6 mmol, 2 equiv) and t-butyl dicarbonate (0.37 g, 1.6 mmol,
2 equiv), the solution stirred for 1 d at r.t., then extracted and puri-
fied as for 17b to give pure cis-isomer (+)-17c (80 mg, 46%) and a
40:60 mixture of cis/trans-isomers (27 mg, 16%); colorless resin;
[ ]D17 +165 (c = 1, CHCl3).
HRMS: m/z calcd for C11H19NO3: 213.1365, found: 213.1371.
IR (CHCl3): = 2975, 1700, 1690, 1647, 1392, 1367, 1322, 1310,
1160, 1118 cm .
1
t-Butyl N-Hydroxycarbamate (20)
A suspension of NH2OH·HCl (9.6 g, 0.14 mol, 1.5 equiv) and
Na2CO3 (9.5 g, 90 mmol, 0.97 equiv) in Et2O (60 mL) and H2O
(2 mL) at r.t. was stirred for 0.5 1 h, then cooled to 0 °C and a so-
lution of t-butyl dicarbonate (20.0 g, 92 mmol) in Et2O (20 mL) was
added dropwise. The mixture was then stirred at r.t. for 4 h. The so-
lution was decanted, the solids were washed twice with Et2O and the
solvents evaporated to give 20 as a yellowish resin which crystal-
lised in cyclohexane or toluene/cyclohexane in several crops (10.3
g, 85%); colorless crystals; mp 60 62 °C (toluene/cyclohexane,
2:1) (Lit.36 mp 58 59 °C).
1H NMR (CDCl3): = 5.77(ddd, 1 H, H-4), 5.67 (dt, 1 H, H-5), 4.62
(m, 1 H, H-6), 4.41 (m, 1 H, H-3), 1.50 (s, 9 H, 3 CH3), 1.30 (d, 3
H, CH3-3), 1.26 (d, 3 H, CH3-6). J3,4 = 4.3, J3,5 = 1.6, J3,6 = 2.4,
J3,Me = 6.6, J4,5 = 10.3, J4,6 = 2.1, J5,6 = 1.2, J6,Me = 6.8 Hz.
1H NMR (CDCl3), trans-isomer: = 5.74 (m, 2 H, H-4, H-5), 4.43
(m, 2 H, H-3, H-6), 1.50 (s, 9 H, 3 CH3), 1.35 (d, 3 H, J = 6.6 Hz,
CH3), 1.27 (d, J = 6.6 Hz, CH3).
HRMS: m/z calcd for C11H19NO3: 213.1365, found: 213.1371.
1
IR (KBr): = 3400, 2980, 1725, 1370, 1250, 1160, 1115 cm .
Racemic Series; ( )-2-Oxa-3-azabicyclo[2,2,2]oct-5-ene Hydro-
chloride [( )-14a]; Typical Procedure
A modified literature procedure14,32 was used. To a stirred solution
of cyclohexanone oxime (0.79 g, 7 mmol) in CH2Cl2 (8 mL) at 0 °C
was added t-BuOCl (1.0 mL, 85 mmol, 1.2 equiv). After 15 min, the
blue solution was evaporated at r.t. until the distillate started to
aquire blue color. To this concentrated solution of 18 in CH2Cl2
(3 mL) at 20 °C was added 10 (1.0 mL, 10.5 mmol, 1.5 equiv) in
EtOH (1 mL). The solution was left at 20 °C and became yellow
after 15 d. Anhyd Et2O (8 mL) was then added and the precipitate
of ( )-14a (0.91 g, 88%) was isolated as for ( )-14a in two crops;
HPLC Determination of Enantiomeric Excess
For 14a: Chiralpak AD Daicel column, solvent: heptane/i-PrOH
(97:3) (k’ = 4.81, k'2 = 5.19, k'2/k'1 = 1.08, resolution = 2.47, flow
1
rate = 0.8 mL/min, detection at = 230 nm, temp. 22 °C), retention
time (intensity) for ( )-14a: ( )-14a, tR(1) 23.5 min (296), (+)-14a,
tR(2) 25.1 min (299), for chiral 14a (first crop): tR(1) 23.5 min
(1774), tR(2) 25.3 min (7.4): ee 99%, for the second crop: tR(1) 23.8
min (361), tR(2) 25.5 min (37): ee 81%, total ee 96%.
Synthesis 2000, No. 12, 1719–1726 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Enantioselective Diels Alder Reaction with an -Chloronitroso Dienophile
1725
For 14c: Chiralpak AD Daicel column, solvent: heptane/i-PrOH
(97:3) (k’ = 1.40, k’ = 1.68, k’ /k’ = 1.19, resolution = 2.00, flow
(9) Faitg, Th., Soulié, J., Lallemand, J.-Y., Ricard, L.
Tetrahedron: Asymmetry 1999, 10, 2165.
1
2
2
1
rate = 0.8 mL/min, detection at = 254.4 nm, temp. 22 °C), reten-
tion time (intensity) for ( )-14c: ( )-14c at tR(1) 9.7 min, (+)-14c at
tR(2) 10.8 min, for chiral 14c (from the first crop of 14a): tR(1) 9.7
min (1166), tR(2) 10.9 min (21): ee 96.5%, from the second crop of
14c: tR(1) 9.4 min (2091), tR(2) 10.6 min (256): ee 80%, total ee
95%.
(10) Ritter, A. R., Miller, M. J. J. Org. Chem. 1994, 59, 4602.
Ghosh, A., Miller, M. J. Tetrahedron Lett. 1995, 36, 6399.
(11) Gouverneur, V., McCarthy, S.J., Mineur, C., Belotti, D., Dive,
G., Ghosez, L. Tetrahedron 1998, 54, 10537.
(12) Gouverneur, V., Ghosez, L. Tetrahedron: Asymmetry 1990, 1,
363.
(13) Defoin, A., Pires, J., Tissot, I., Tschamber, Th., Bur, D.,
Zehnder, M., Streith, J. Tetrahedron: Asymmetry 1991, 2,
1209.
(14) Defoin, A., Brouillard-Poichet, A., Streith, J. Helv. Chim.
Acta 1991, 74, 103.
(15) Shustov, G.V., Rauk, A. Tetrahedron Lett. 1995, 36, 5449.
(16) Aoyagi, S., Tanaka, R., Naruse, M., Kiyabashi, Ch. J. Org.
Chem. 1998, 63, 8397.
(17) Martin, St.F., Hartmann, M., Josey, J.A. Tetrahedron Lett.
1992, 33, 3583.
(18) Gouverneur, V., Dives, G., Ghosez, L. Tetrahedron:
Asymmetry 1991, 2, 1173.
(19) Reviews: Kirby, G.W. Chem. Soc. Rev. 1977, 6, 1.
Kresze, G., Firl, J. Fortschr. Chem. Forsch. 1969, 11, 245.
(20) (a) Felber, H., Kresze, G., Braun, H., Vasella, A. Tetrahedron
Lett. 1984, 25, 5381.
For 15b: Chiralcel OD-R Daicel column, solvent: MeOH/H2O 75/
25 (k’ = 1.86, k'2 = 2.50, k'2/k'1 = 1.34, resolution = 7.11, flow
1
rate = 0.5 mL/min, detection at: = 254.4 nm, temp. 22 °C), reten-
tion time (intensity) for ( )-15b: ( )-15b at tR(1) 17.2 min (170),
(+)-15b at tR(2) 21.0 min (172), for chiral 15b: tR(1) 17.4 min
(1587), tR(2) 21.8 min (32 56): ee 93 95%. After recrystallisation
of 15a in MeOH/Et2O, ee 98%.
For 16b: Chiralcel OD-R Daicel column, solvent: MeOH/H2O
(80:20) (k’ = 1.52, k'2 = 1.85, k'2/k'1 = 1.21, resolution = 2.98, flow
1
rate = 0.5 mL/min, detection at = 254.4 nm, temp. 22 °C), reten-
tion time (intensity) for ( )-16b: (+)-16b at tR(1) 13.8 min (663),
( )-16b at tR(2) 15.4 min (696), for chiral 16b: tR(1) 13.9 min
(3421), tR(2) 15.7 min (7): ee >99%.
For 17a: Chiralcel OD Daicel column, solvent: heptane/i-PrOH
(99:1) (k’ = 2.93, k'2 = 3.33, k'2/k'1 = 1.14, resolution = 2.16, flow
1
(b) Felber, H., Kresze, G., Prewo, R., Vasella, A. Helv. Chim.
Acta 1986, 69, 1137, corrigendum: Braun, H., Charles, R.,
Kresze, G., Sabuni, M., Winkler, J. Liebigs Ann. Chem. 1987,
1129.
rate = 0.8 mL/min, detection at = 230.4 nm, temp. 22 °C), reten-
tion time (intensity) for ( )-17a: unknown at tR 13.2 min (37), (+)-
17a at tR(1) 14.6 min (278), ( )-17a at tR(2) 16.0 min (329),
2 unknowns at tR 17.6 min (36) and 19.3 min (18), for chiral 17a:
tR(1) 14.3 min (919), tR(2) 16.3 min (13): ee 97%.
(21) Zhang, D.-Y., Süling, C., Miller, M.J. J. Org. Chem. 1998, 63,
885.
(22) Braun, H., Felber, H., Kresze, G., Schmidtchen, Fr.P., Prewo,
R., Vasella, A. Liebigs Ann. Chem. 1993, 261.
(23) Sabuni, M., Kresze, G., Braun, H. Tetrahedron Lett. 1984, 25,
5377.
(24) Hall, A., Bailey, P.D., Rees, D.C., Wightman, R.H. J. Chem.
Soc., Chem. Comm. 1998, 2251.
(25) Vasella, A. Helv. Chim. Acta 1977, 60, 1273.
(26) Aebischer, B.M., Hanssen, H.W., Vasella, A.T., Schweiger,
W.B. J. Chem. Soc., Perkin 1 1982, 2139.
(27) Vasella, A. Helv. Chim. Acta 1977, 60, 426.
(28) Defoin, A., Sarazin, H., Sifferlen, Th., Strehler, Ch., Streith, J.
Helv. Chim. Acta 1998, 81, 1417.
(29) Kaskar, B., Heise, Gl.L., Michalak, R.S., Vishnuvajjala, B.R.
Synthesis 1990, 1131.
For 17b: Chiralpak AD Daicel column, solvent: heptane/i-PrOH
(95:5) (k’ = 1.66, k'2 = 2.37, k'2/k'1 = 1.43, resolution = 5.17, flow
1
rate = 0.8 mL/min, detection at: = 254.4 nm, temp. 23.8 °C), re-
tention time (intensity) for ( )-17b: (3S,6R)-17b at tR(1) 11.0 min
(323), unknown at tR 12.2 min (37), (3R,6S)-17b at tR(2) 14.0 min
(284), for chiral 17b: tR(1) 11.0 min (812), tR(2) 14.1 min (4): ee
98%.
Acknowledgement
The support of the Centre National de la Recherche Scientifique
(UPRES-A 7015) is gratefully acknowledged. We also wish to
thank the Région Alsace for a Ph. D. grant to Miss Joubert.
(30) Adams, R., Geissman, T.A. J. Am. Chem. Soc. 1939, 61, 2083.
Houben-Weyl, Methoden der Organischen Chemie, 4th ed.;
Muller, E., Ed.; Thieme Verlag: Stuttgart, 1970; Vol V-1c, p
17.
(31) Nelsen, St.F., Thompson-Colon, J.A., Kirste, B., Rosenhouse,
A., Kaftory, M. J. Am. Chem. Soc. 1987, 109, 7128.
(32) Kresze, G., Kysela, E. Liebig’s Ann. Chem. 1981, 202
(33) Kesler, E. J. Heterocycl. Chem. 1980, 17, 1113.
(34) Riddell, F.G., Turner, E.S., Boyd, A. Tetrahedron 1979, 35,
259.
(35) Bach, P., Bols, M. Tetrahedron Lett. 1999, 40, 3461.
Zhang, D.-Y., Ghosh, A., Süling, C., Miller, M.J. Tetrahedron
Lett. 1996, 37, 3799.
(36) Carpino, L.A., Giza, Ch.A., Carpino, B.A. J. Org. Chem.
1959, 81, 955.
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Synthesis 2000, No. 12, 1719–1726 ISSN 0039-7881 © Thieme Stuttgart · New York

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Synthesis 2000, No. 12, 1719–1726 ISSN 0039-7881 © Thieme Stuttgart · New York