Chiral Diels-Alder reaction between cyclopentadiene and nitroso derivatives: Thermal isomerisation/racemisation of the adducts

Article abstract of DOI:10.1016/j.tetasy.2012.09.005

Cyclopentadiene nitroso adducts 1a and ent-1a were synthesised in good yields and good enantiomeric excess from chiral chloro-nitroso derivatives 4 and 5 in the d-mannose and d-ribose series, respectively. The thermal racemisation of these adducts occurred below room temperature. Some other chiral Diels-Alder nitroso adducts were prepared in the d-mandelic, l-prolinol and d-O-methylprolinol series and their thermal isomerisation was specified according to the N-substitution. A simple synthesis of the chiral amido-cyclopentenol (+)-2b, an important precursor for biological interesting compounds, is presented from ent-1a.

Full text of DOI:10.1016/j.tetasy.2012.09.005

Tetrahedron: Asymmetry 23 (2012) 1467–1473
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Chiral Diels–Alder reaction between cyclopentadiene and nitroso
derivatives: thermal isomerisation/racemisation of the adducts
⇑
⇑
Jean-Marc Heuchel, Sébastien Albrecht , Christiane Strehler, Albert Defoin , Céline Tarnus
Laboratoire de Chimie Organique et Bioorganique, EA4466, Université de Haute-Alsace, ENSCMu, 3 rue Alfred Werner, F-68093 Mulhouse Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2012
Accepted 11 September 2012
Cyclopentadiene nitroso adducts 1a and ent-1a were synthesised in good yields and good enantiomeric
excess from chiral chloro-nitroso derivatives 4 and 5 in the
The thermal racemisation of these adducts occurred below room temperature. Some other chiral Diels–
Alder nitroso adducts were prepared in the -mandelic, -prolinol and -O-methylprolinol series and their
D-mannose and D-ribose series, respectively.
D
L
D
thermal isomerisation was specified according to the N-substitution. A simple synthesis of the chiral
amido-cyclopentenol (+)-2b, an important precursor for biological interesting compounds, is presented
from ent-1a.
Ó 2012 Elsevier Ltd. All rights reserved.
OH
1. Introduction
O
The bicyclic heterocycles of type 1, as well as their reduction
products of type 2, are important chiral starting materials for the
synthesis of natural compounds (Scheme 1).1–5 These chiral ad-
ducts have already been obtained by the hetero-Diels–Alder cyclo-
addition of cyclopentadiene with nitroso transients derived from
amino-acids3b,4a,d,6 or mandelic acid.7–10 Chiral monocyclic deriva-
tives of type 2 have been obtained from the enzymatic resolution
of racemic mixtures,1b,2a,5,11,12 from chemical transformations of
the aforementioned cyclopentadiene-aminoacid adducts3b,4a,d,6 or
from transformations of other chiral compounds.3a,13,14
NR
1
NHR
2
O
NO
Cl
O
O
(1
R
)
O
NHR
(4S)
O
O
(+)-3a
(+)-3b
4
Boc2O
Miller et al.15 attempted to isolate the chiral adduct 1a (R = H)
in the (1R,4S)-series after N-protection into 1b (R = Boc), but only
obtained imprecise results due to the instability of adducts 1a
and 1b. Herein we report a simple method to isolate these chiral
compounds from chiral chloro-nitroso sugars as the (1R,4S)- and
(1S,4R)-enantiomers and reduction/N-protection for the chiral
monocyclic derivative 2b (R = Boc). The enantiomeric excesses of
these reaction products were also determined. Other diastereoiso-
meric adduct mixtures were prepared from Diels–Alder reactions
CH2Cl2, EtOH
-10°C
AcO
Cl
O
NO
(4R)
NHR
O
(1 )
S
O
O
with acyl-nitroso transients in the
D
-mandelic,
L
-prolinol and
3a
5
(-)-
a
b
R = H,HCl
R = Boc
Boc2O
(-)-3b
D
-O-methylprolinol series. The thermal stabilities of these chiral
adducts were also studied.
Scheme 1.
2. Results and discussion
2.1. Synthesis of the enantiomers of 1a by chiral hetero-Diels–
Alder reaction and ee determination
⇑
Corresponding authors.
E-mail addresses: Sebastien.Albrecht@uha.fr (S. Albrecht), Albert.Defoin@uha.fr
In previous work, the chiral synthesis of the enantiomeric cyclo-
hexadiene adducts (+)-3a16 and (ꢀ)-3a17 had been described using
(A. Defoin).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.09.005

1468
J.-M. Heuchel et al. / Tetrahedron: Asymmetry 23 (2012) 1467–1473
(1
R
)
OH
O
N
D-mandeli cacid,
DCC, NEt3,
(4S)
(R)
CHCl3/EtOH
6
O
(1R )
O
4
Boc2O
O
(mannose)
N
NaHCO3
0°C
Boc
NH.HCl
(4S)
1a
1b
CH2Cl2, EtOH
-10°C
(4R)
Boc
5
NH.HCl
O
N
(ribose)
O
(1S)
1a
ent-
1b
ent-
D-mandelic acid,
DCC, NEt3,
O
CHCl3/EtOH
(4R)
N
(
)
R
O
(1S)
HO
7
Scheme 2. Formation and transformation of the primary adducts 1a/ent-1a with the nitroso dienophiles in the mannose 4 and ribose 5 series. The formulae presented
correspond to the major enantiomer or diastereoisomer.
the sugar chloronitroso derivatives 416 and 517 as dienophiles in
the -mannose and -ribose series, respectively (Scheme 1). These
dienophiles were prepared by oxidation of their corresponding oxi-
mes with tert-butyl nitrite.
In both series, the de determination by these three methods
gave comparable results. However, the HPLC determination was
more precise, and required a correction of the response factor
D
D
(Rf), which was not identical for the diastereoisomers (1R,4S,aR)
Using the same methodology, with freshly prepared cyclopenta-
diene, we were able to isolate the primary adducts 1a and ent-1a as
and (1S,4R,aR) of the mandelic adducts 6 and 7. The standard devi-
ation was approximately 0.5%. The 13C NMR spectroscopy method
gave the same values, but were less precise (approximately 1%).
These values were in bold in Table 1.
almost pure enantiomers (1R,4S) and (1S,4R) from the
D-mannose
and -ribose chloro-nitroso dienophiles 4 and 5, respectively. They
D
were isolated as colourless crystallised hydrochlorides by reaction
in methylene chloride/ethanol and precipitation by the addition of
dry ethyl ether. Their configuration was supposed to be the same
as for their homologue enantiomers (+)-3a and (ꢀ)-3a, respec-
tively. Due to their instability at room temperature, these adducts
were prepared at ꢀ10 °C and isolated at 0 °C. The adducts were
pure enough and so were directly N-protected at 0 °C with tert-bu-
tyl dicarbonate into both enantiomers 1b and ent-1b in order to
determine their enantiomeric excess (ee) by chiral HPLC
(Scheme 2). Their NMR data were in accordance with those of race-
mic 1a18 and 1b.15,19–21
The nitroso derivative 5 in the ribose series gave a better enantio-
meric excess (approximately 89%) than the mannose one 4 (approx-
imately 80%). We have compared these results with those obtained
by the reaction of the nitroso-derivatives 4 and 5 with cyclohexadi-
ene under the same conditions. The crystalline adducts (+)-3a22 and
(ꢀ)-3a17 obtained were then acylated into the known chiral N-Boc
derivatives (+)-3b15 and (ꢀ)-3b17, respectively (Table 1). The ee val-
ues measured in the cyclohexadiene series were in agreement with
the literature data16,17 and were appreciably better than those ob-
tained in the cyclopentadiene series (Table 1). For instance, from
the nitroso derivative 5 in the ribose series, the ee value of the ad-
duct by HPLC with cyclohexadiene (ꢀ)-3b was 96.5%, while the ee
value with the cyclopentadiene adduct ent-1b was only 88.9%.
A second approach for determining the enantiomeric excess
was accomplished by acylation of the adducts 1a and ent-1a with
D-mandelic acid in the presence of dicyclohexyl-carbodiimide
(DCC) into the stable diastereoisomers 6 and 7, respectively.
This derivatisation was carried out at three temperatures,
ꢀ10 °C, 0 °C and 25 °C. The optimal conditions for this N-acylation
were ꢀ10 °C to 0 °C, a temperature range which circumvented the
thermal racemisation of both adducts 1a and ent-1a. The values of
the diastereoisomeric excesses (de) were thus measured by three
methods: 1H and 13C NMR, and chiral HPLC. The results are pre-
sented in the Table 1, as well as the enantiomeric excesses deter-
mined from the N-Boc derivatives 1b and ent-1b (prepared from
1a/ent-1a at 0 °C) by chiral HPLC.
2.2. Diels–Alder reaction of cyclopentadiene with chiral nitroso-
dienophiles
We have already studied the Diels–Alder reaction of cyclohexa-
diene with chiral nitroso derivatives generated by the oxidation
with periodate of the hydroxamic acids 8 from the
and 9a and 9b from
-prolinol and its O-methyl derivative.22 Here-
in, the same reactions were achieved with cyclopentadiene as the
dieneophile and the hydroxamic acids 8 (in the
-series), 9a22 (in
the -series) (Scheme 3).
-series) and ent-9b23 (in the
D-mandelic acid,
L
D
L
D

J.-M. Heuchel et al. / Tetrahedron: Asymmetry 23 (2012) 1467–1473
1469
Table 1
Ee or de determinations of the adducts 1b, ent-1b, 6 and 7 with cyclopentadiene by NMR spectroscopy or by chiral HPLC according to the N-protection temperature of 1a and ent-
1a
d
Sugar series
Derivative
Temperaturea
de 1H NMRb
de 13C NMRc
Chiral HPLC
Cyclohexadienee
(+)-3b ee 92.0
D-Mannose
6
25 °C
0 °C
62
80
73
—
58
83
80
—
de 61.3
de 83.5
de 80.0
ee 80.5
ꢀ10 °C
1b
7
0 °C
(ꢀ)-3b ee 96.5
D-Ribose
25 °C
0 °C
–10 °C
0 °C
78
94
91
—
77
91
89
—
de 74.3
de 89.8
de 89.2
ee 88.7
ent-1b
For the sake of comparison, the ee data for the N-Boc (+)-3b and (ꢀ)-3b adducts in the cyclohexadiene series are also added.
a
Reaction temperature for the N-protection.
At 330 K for the signals of H-5 and H-6 at 6.34 and 6.47 ppm for the (1R,4S,
b
a
R)-isomer and at 5.74 and 6.27 ppm for the (1R,4S,
a
R)-isomer.
c
For the signals of C(7), C(
a
) and C(1) at 48.3, 72.9 and 84.9 ppm for the (1R,4S,
aR)-isomer and at 48.0, 72.4 and 84.4 ppm for the (1S,4R,
aR)-isomer, respectively.
d
Rf = 1 for the (1R,4S,
aR)-isomer, Rf = 1.379 for the (1S,4R,aR)-isomer in compounds 6 and 7. Column used was a Chiralpak AD, eluent: heptane for 1b and ent-1b or
Chiralcel OD-R, eluent: MeOH/H2O 60:40 for 6 and 7.
e
HPLC determination after N-protection with Boc2O.17 Column: Chiralpak AD, eluent: heptane/iPrOH 97:3.
OH
O
NHOH
(4R)
(R)
isomer
+
N
(R)
(1R,4S,αR)
CH2Cl2/MeOH
NEt4IO4, -60°C
O
O
7
(1S)
HO
N
90:10
OH
8
HO
(1
)
R
(S)
NHOH
O
(S)
O
isomer
+
(1S,4R,2'S)
N
N
(4S)
CH2Cl2/MeOH
NPr4IO4, 0°C
9a
10a
11a
O
MeO
O
O
OMe
(R)
NHOH
O
(1S)
(R)
isomer
(1R,4S,2'R)
N
+
N
N
CH2Cl2/MeOH
NPr4IO4, 0°C
(4
R)
10b
11b
9b
ent-
Scheme 3. Asymmetric hetero-Diels–Alder reactions of cyclopentadiene with chiral nitroso derivatives. Only the major diastereoisomer is depicted.
The reaction with
D
-mandelohydroxamic acid 8 was carried out
and chemical correlation. This suggested a (1S,4R)-configuration
for the unsubstituted adduct ent-1a obtained from the ribose
chloro-nitroso dienophile 5 as assumed in Section 2.1. We therefore
observed the same configuration for these cyclopentadiene adducts
as in the cyclohexadiene series. As a result, we supposed the same
correlation in the prolinol series whose adduct configuration in the
cyclohexadiene series22 had already been proven unambiguously.
The configurations of the major cyclopentadiene-prolinol adducts
were consequently (1R,4S,20S) for 10a and (1S,4R,20R) for 11b.
under the same conditions as in the literature7,8 (CH2Cl2/MeOH,
ꢀ78 °C) to give a similar 90:10 diastereoisomer mixture, which
was identical to the coupling adduct 7. The physical data of the
pure diastereoisomers (1R,4S,aR) and (1S,4R,aR) from 6 and 7,
respectively, were not given in the literature, and so we have fully
characterised these compounds.
The reaction with the nitroso compounds derived from the pro-
line-hydroxamic acids 9a and ent-9b gave diastereoisomeric mix-
tures 10a/11a and 11b/10b, which appeared to be thermally
unstable at room temperature and whose evolution is studied be-
low. The crude reaction mixture at 0 °C was pure enough to be
used directly after treatment, but without chromatographic purifi-
cation to avoid any isomerisation. The isomeric ratios were deter-
mined by 1H NMR spectroscopy.
In Table 2 the diastereoisomeric ratios of the adducts with the
nitroso compound derived from the studied hydroxamic acids are
reported. For the sake of comparison, the results in the cyclohexa-
diene series are also reported: The ratios are nearly the same for all
three series.
2.3. Thermal isomerisation of the Diels–Alder adducts
In contrast to the chiral cyclohexadiene adducts (+)-3a or
(ꢀ)-3a, which are stable at room temperature, the cyclopentadiene
adducts 1a and ent-1a underwent a retro-Diels–Alder which led to
slow racemisation even at room temperature.
This thermal isomerisation was studied for the chiral adducts
1a and ent-1a, the N-Boc adduct ent-1b and the aforementioned
diastereoisomeric mixtures 6, 7, 10a/11a and 11b/10b.
The thermal stability of chiral adducts 1a and ent-1a was
studied qualitatively at three temperatures (ꢀ10 °C, 0 °C and
The absolute configuration of the major mandelic adduct isomer
7 has already been determined as (1S,4R,
a
R)8 by X-ray structure
25 °C) by coupling with D-mandelic acid to give the diastereoiso-

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J.-M. Heuchel et al. / Tetrahedron: Asymmetry 23 (2012) 1467–1473
Table 2
Diastereoisomeric ratios of the hetero-Diels–Alder cycloaddition with the cyclopentadiene and chiral dienophiles by NMR spectroscopy in comparison with the results obtained
with the cyclohexadiene
Hydroxamic acid
Adducts
Conditions
NMR ratio
Cyclohexadiene series
8
9a
ent-9b
7
CH2Cl2/MeOH, ꢀ60 °C
CH2Cl2/MeOH, 0 °C
CH2Cl2/MeOH, 0 °C
10:90a
81:19c
85:15e
14:86a,b
76:24c,d
85:15c,d
10a/11a
11b/10b
a
b
c
Diastereoisomeric ratio (1R,4S,aR)/(1S,4R,aR).
Lit.7.
Diastereoisomeric ratio (1R,4S,20S)/(1S,4R,20S).
At rt, lit.22 with (20S) prolinol moiety.
Diastereoisomeric ratio (1S,4R,20R)/(1R,4S,20R).
d
e
meric mixtures 6 and 7, respectively, as presented in Section 2.1. It
is noteworthy that it was not possible to study their de directly by
HPLC, because of possible racemisation during the measurements,
which were carried out at room temperature. The results of the
diastereoisomeric excesses (de) determination are presented in Ta-
ble 1. The de value at ꢀ10 °C and the values at 0 °C were nearly
similar. In contrast, at 25 °C, these values were clearly lower and
emphasised racemisation during the N-protection. In conclusion,
these N-unsubstituted adducts are stable below 0 °C and racemise
above this temperature.
The crude chiral N-Boc adduct ent-1b was obtained with good
enantiomeric excess (ee ca 88%, Table 1). Its racemisation was
investigated by heating a solution in toluene at different tempera-
tures for 2 h. The ratio of both enantiomers (1S,4R) and (1R,4S) was
measured by chiral HPLC in order to approximately determine the
kinetic data by calculation. The half-life values of this racemisation,
according to the temperature, are reported in Table 3. This adduct
racemised at 50 °C and quickly at 70 °C and above. Classic chro-
matographic purification would consequently lead to partial rac-
emisation and for this reason no isolation was attempted.
In both the prolinol series, the evolution of the adduct mixtures
10a/11a and 10b/11b was studied by NMR spectroscopy at two
temperatures (5 °C and at 30 °C) in deuterated chloroform. The
diastereoisomeric ratio was obtained by comparison of the H-1
and H-4 signals at 5.0–5.2 ppm which were well-separated. These
prolinol adducts, which possessed a urea function, isomerised
slowly at 5 °C, and quickly at 30 °C. In both series, the kinetic major
diastereoisomers were thermodynamically the less stable ones and
became the minor ones at equilibrium.
scribed above. In this solvent, numerous NMR-signals were well-
separated and allowed good determination. The results are pre-
sented in Table 3. These mandelic adducts, possessing an amide
function, were stable until 70 °C and isomerised above this tem-
perature with a subequimolar mixture at the equilibrium.
In conclusion, the thermal stability of the cyclopentadiene ad-
ducts studied is strongly dependent on the N-acyl substituent. No
N-acyl substituent or a urea functionality leads to an unstable ad-
duct above 0–5 °C; a carbamate group raises this instability above
room temperature. In contrast, an amide function, as for mandelic
adducts 6 and 7, leads to a stable adduct until the normal retro-
Diels–Alder temperature (above 70 °C).
Some chemical transformations of the mandelic adduct of
cyclopentadiene 79,24,25 or of substituted ones10 have been de-
scribed in the literature to give chiral monocyclic derivatives when
the reduction of the N–O bond was carried out at 0 °C without rac-
emisation.9,10 This is in agreement with our study. It is noteworthy
that a few other chiral nitroso-adducts with cyclopentadiene have
been described in the O-methyl mandelic series,8 with amino-acid
derivatives,6a with C2-symmetrical disubstituted pyrrolidines26 or
with camphor derivatives27 with racemisation not being noticed.
Although some catalysed transformations of the Boc-derivative
1b have been described above 30 °C,28 the possibility of a thermal
ring opening in the first step was not suspected.
2.4. Synthesis of the chiral amidocyclopentenol (+)-2b
According to our results, the synthesis of this monocyclic chiral
compound (+)-2b by reductive heterocyclic ring opening of the
adduct 1b could only occur below 0 °C. Therefore, the classic
reduction method with molybdenum carbonyl at 80 °C2a,11a should
only give a racemised compound. It is noteworthy that only a few
transformations of chiral adducts have been described in the liter-
We next studied the thermal stability of the diastereoisomeric
mandelic adduct mixtures, either adduct 7, produced by the
Diels–Alder reaction with the
preponderant (1S,4R, R)-isomer, or the adduct 6, prepared previ-
ously with a preponderant (1R,4S, R)-isomer from the N-protec-
D-mandelic derivative 8 with the
a
a
ature and were proven to give chiral compounds with [
given.
a] values
tion of the chiral adduct 1a. A solution of 6 or 7 was heated in
toluene-d8 at different temperatures between 30 °C and 100 °C
for 2 h. The determination of the diastereoisomeric ratio was car-
ried out by 1H NMR spectroscopy in this solvent and the kinetic
data of the isomerisation were obtained by calculations as de-
Direct reduction of the N–O bond of racemic Boc-derivative rac-
1b in cyclopentene 2b at low temperature was achieved with a
low-valente Ti derivative29 at ꢀ25 °C or with an aluminium or so-
dium amalgam at 0 °C.10 Herein we report a very simple one-pot
Table 3
Calculated half-lives (t1/2) for the isomerisation/racemisation of the different adducts studied according to the temperature
Adducts
Initial ratio
5 °C
30 °C
50 °C
70 °C
90 °C
100 °C
Final ratioa
ent-1bb,c
6b,e
94:7
92:8
10:90
80:20
15:85
19 h
No evolution
No evolution
2.5 h
0.5 hd
3.7 h
3.2 h
50:50
47:53
47:53
29:71
62:38
1.0 h
0.9 h
7b,e
10a/11af
10b/11bf
5 d
3 d
4.0 h
4.0 h
a
b
c
d
e
f
Calculated at the end of the isomerisation.
In toluene-d8.
Enantiomer ratio (1S,4R)/(1R,4S).
At 80 °C.
Diastereoisomer ratio (1R,4S,aR)/(1S,4R,aR).
In CDCl3.

J.-M. Heuchel et al. / Tetrahedron: Asymmetry 23 (2012) 1467–1473
1471
Boc2O
Na2CO3
Zn/AcOH
Et2O, 0°C
Et2O, 0°C
(4R)
(4R)
Boc
NH
OH
2b
NH.HCl
O
NH2
OH
72%
(1S)
(1S)
2a
ent-1a
(+)-
Scheme 4.
procedure from the primary chiral adduct ent-1a, possessing a bet-
ter enantiomeric purity (ee 89%) with the major configuration
being (1S,4R) (Scheme 4).
tBuOCl (0.35 mL, 2.94 mmol, 1.5 equiv), which caused the solution
to become deep blue. After 30 min, the solution was evaporated
at rt to give crude chloro-nitroso derivative 4. To the blue solution
of crude 4 in CH2Cl2 (3 mL) and EtOH (0.3 mL) at ꢀ10 °C was added
cyclopentadiene (0.3–0.35 mL, 3.6–4 mmol, 1.8–2 equiv) with stir-
ring. The solution turned colourless after a few seconds and, after
30 min at this temperature, dry Et2O (6 mL) was added with stir-
ring. A white precipitate formed and, after 1 h at ꢀ10 °C, it was
quickly isolated by centrifugation, washed with dry Et2O
(2 ꢁ 0.5–1 mL) and dried in vacuo at 0 °C to give 1a (164–190 mg,
62–70%). 1a: colourless crystals, too unstable to be purified. Mp
125–130 °C (dec). IR (KBr): 786, 835, 881, 1344, 1376, 1451, 1535,
The N–O bond was reduced with zinc in a solvent mixture of
acetic acid/ether at 0 °C, and after basification with excess sodium
carbonate, the resulting amino-alcohol 2a was N-protected with
tert-butyl dicarbonate at this temperature in a one pot procedure.
After purification by crystallisation, we obtained amido-alcohol
(+)-2b in good overall yield with the major (1S,4R)-configuration,
whose physical data were in agreement with those of the
literature.12,13
2537, 2563, 2881, 3053 cmꢀ1 1H NMR (D2O, 295 K): d 2.09 (dt,
.
3. Conclusion
Hb-7); 2.19 (d, Ha-7); 5.22 (s, H-4); 5.63 (m, H-1); 6.67 (ddd, H-
5); 6.87 (ddd,H-6); J(1,5) = 1.8, J(1,6) = 2.5, J(1,7a) = 2.0,
J(4,5) = 2.5, J(4,6) = 1.3, J(4,7a) = 2.0, J(5,6) = 5.5, J(7a,7b) = 10.3 Hz.
Data in agreement with those in the literature18 for the racemate.
13C NMR: d (D2O, 295 K): d 49.2 (C(7)) ; 67.2 (C(4)) ; 87.6 C(1);
134.5 (C(5)) ; 141.3 (C(6)).
We have reported the synthesis of some chiral nitroso adducts
of cyclopentadiene. In contrast with the nitroso-cyclohexadiene
adducts, which are thermally stable, these adducts racemise/
isomerise easily. Moreover, we have specified the conditions of this
racemisation/isomerisation which occurred at temperatures be-
tween 0 °C to 70 °C according to the N-acyl substituent. We have
also reported a simple synthesis of the important chiral monocyclic
amido-alcohol (+)-2b, which is used as a starting material for
numerous syntheses of natural compounds.
4.2.2. (1S,4R)-2-Oxa-3aza-bicyclo[2,2,1]hept-5-ene, hydrochlor-
ide ent-1a
Same procedure as for 1a with 5-O-acetyl-3,4-isopropylidene-
ribonolactone-oxime17 (0.40 g, 1.6 mmol) in CH2Cl2 (3 mL) and
tBuOCl (0.3 mL, 2.5 mmol, 1.5 equiv), to give crude 5 (0.5 g, quant.).
To a solution of 5 in CH2Cl2 (3 mL) and EtOH (0.3 mL) at ꢀ10 °C was
added cyclopentadiene (0.25 mL, 3 mmol, 2 equiv). The solution
turned colourless after a few seconds and after 30 min, the same
treatment as for 1a gave ent-1a (153 mg, 72%) as colourless crys-
tals. Mp 125–130 °C (dec). Same IR and NMR data as for 1a.
4. Experimental
4.1. General
Flash chromatography (FC): silica gel (Merck 60, 230–
400 mesh). TLC: Al-roll silica gel (Merck 60, F254). Mp: Kofler hot
4.2.3. (1R,4S)-2-Oxa-3aza-bicyclo[2,2,2]oct-5-ene, hydrochloride
(+)-3a
bench or Büchi-SMP20 apparatus, corrected. IR spectra (
m in
cmꢀ1): Nicolet 405 FT-IR, [
a]
D Perkin–Elmer 341 LC. HPLC measure-
Same procedure as for 1a with 4 [1.0 g, 3.26 mmol, prepared
from mannonolactone-oxime diacetonide16 (0.89 g, 3.26 mmol)]
in CH2Cl2 (10 mL), and a centrifuged solution of cyclohexadiene
(0.5 mL, 5.2 mmol, 1.6 equiv) in EtOH (3.0 mL) at ꢀ10 °C. The solu-
tion quickly became colourless and, after stirring for 4 h, dry Et2O
(20 mL) was added. The white precipitate was isolated after 1 h at
ꢀ10 °C by filtration and washed with dry Et2O (2 ꢁ 2 mL). A second
crop appeared in the filtrate and was isolated after 2 d at ꢀ10 °C to
give (+)-3a30 (global yield 0.42 g, 87%), with the same IR and NMR
data as in the literature16,18 and also in the literature17 for the
(1S,4R)-enantiomer (ꢀ)-3b.
ments: liquid chromatography Hewlett–Packard 1090. 1H (100 or
400 MHz) and 13C NMR (62.9 or 100 MHz) spectra: Bruker AC-
F25 or Bruker Avance 400; tetramethylsilane (TMS) in CDCl3,
CD3OD (d(CD3OD) = 3.30) or natrium (d4)-trimethylsilylpropionate
(d4-TSP) in D2O (1H NMR) and CDCl3, CD3OD, or (in D2O) CH3OH or
dioxane [d(CDCl3) = 77.0, d(CD3OD) = 49.0, in D2O d(CH3OH) = 50.0,
d(dioxane) = 67.4 with respect to TMS] (13C NMR) as internal stan-
dard; d in ppm and J in Hz. 13C attributions were ascertained by
1H–13C correlation. High resolution (HR)-MS were measured on
an Agilent Technologies 6510 (QTof) spectrometer in ENSCMu,
Université de Haute Alsace, Mulhouse, France.
The usual solvents were freshly distilled, dry EtOH and MeOH
were distilled over Mg/MgI2, dry Et2O was distilled and stored
over Na, dry iPrOH distilled over CaO, and CH2Cl2 was kept over
Na2CO3.
4.3. Derivatisation of adducts
4.3.1. tert-Butyl (1R,4S)-2-oxa-3-aza-bicyclo[2,2,1]hept-5-ene-3-
carboxylate 1b
A solution of 1a (30 mg, 0.22 mmol) in MeOH (1 mL) was stirred
for 4 h at 0 °C with NaHCO3 (45 mg, 0.53 mmol, 3.6 equiv). To this
stirred solution of the free base was added Boc2O (66 mg,
0.30 mmol, 2 equiv) after which the mixture was stirred at 0 °C
for another 2 h with TLC monitoring (free base 1a Rf 0.2, 1b Rf 0.6
in AcOEt). The solids were filtered off and the solution evaporated
4.2. Adducts from chloro-nitroso derivatives 4 and 5
4.2.1. (1R,4S)-2-Oxa-3aza-bicyclo[2,2,1]hept-5-ene, hydrochlor-
ide 1a
To a stirred solution of mannonolactone-oxime diacetonide16
(0.55 g, 2.01 mmol) in CH2Cl2 (4 mL) at ꢀ10 °C was added dropwise

1472
J.-M. Heuchel et al. / Tetrahedron: Asymmetry 23 (2012) 1467–1473
at 0 °C to give crude 1b as a resin (0.16 g, quant.), which was not
purified further and used for determining the ee values by chiral
HPLC. 1H NMR: same data as in the literature15,19 for the racemate.
CHar); 132.2 (C(5)) ; 135.3 (C(6); 136.7 (Cs-ar); 176.0 (NCO). HR-
MS (ESI+IsoTof) calcd for C13H14NO3 [M+H]+: 232.0968; found:
232.0961; calcd for C13H13NNaO3 [M+Na]+: 254.0788; found:
254.0783. HPLC conditions: Chiralcel OD-R chiral column; solvent:
4.3.2. tert-Butyl (1S,4R)-2-oxa-3-aza-bicyclo[2,2,1]hept-5-ene-3-
carboxylate ent-1b
MeOH/water 60:40; injected volume: 5
pressure: 80 bars; flow: 0.5 mL/Min; analysis time: 20 min; reten-
lL; k detection: 254 nm;
Same procedure with ent-1a (20 mg, 0.15 mmol) to give crude
tion times: for (1R,4S,
mer 7 Rt = 13.3 min.
aR)-isomer 6 Rt = 15.1 min, for (1S,4R,aR)-iso-
ent-1b (quant.). Same 1H NMR data as for 1b. HPLC conditions: Chi-
ralpack AD chiral column; solvent: heptane; injected volume: 5 lL;
k detection: 254 nm; pressure: 28 bars; flow: 0.5 mL/min; analysis
time: 10 min; retention times: for 1b Rt = 8.2 min, for ent-1b
Rt = 7.8 min.
4.4. Diels–Alder adducts
4.4.1. (1S,4R,
bicyclo[2,2,1]hept-5-ene 7
Same procedure as in literature.7 To a stirred solution of cyclo-
pentadiene (50 L, 0.6 mmol, 1.5 equiv) in CH2Cl2 and MeOH
aR)-3-(a-Hydroxyphenylacetyl)-2-oxa-3-aza-
4.3.3. tert-Butyl (1R,4S)-2-oxa-3-aza-bicyclo[2,2,2]oct-5-ene-3-
carboxylate (+)-3b and tert-butyl (1S,4R)-2-oxa-3-aza-bicyclo-
[2,2,2]oct-5-ene-3-carboxylate (ꢀ)-3b
l
(1 + 1 mL), were added 10 beads of molecular sieves 4 Å and
NEt4IO4 (165 mg, 0.51 mmol, 1.2 equiv). The solution was cooled
at ꢀ60 °C in a dry ice/acetone bath and 8 (70 mg, 0.42 mmol)
was added portionwise. After 4 h the reaction mixture was left at
rt, and then Et2O (20 mL) was added and the organic phase washed
with NaHCO3 (1M, 10 mL) containing some Na2SO3, then with 20%
brine (3 ꢁ 10 mL), dried (MgSO4) and evaporated to give 7 (88 mg,
Same procedure as for 1b with 3a and (ꢀ)-3a to give crude (+)-
3b15 and (ꢀ)-3b17 respectively which were not purified and ana-
lysed directly. HPLC conditions: Chiralpack AD chiral column; sol-
vent: iPrOH/heptane 3:97; injected volume: 5 lL; k detection:
254 nm; pressure: 35 bars; flow: 0.8 mL/min; analysis time:
13 min; retention times: for (+)-3b Rt = 10.8 min, for (ꢀ)-3b Rt =
9.7 min.
91%) as 90:10 (1S,4R,aR)/(1R,4S,aR) isomeric mixture as yellowish
crystals (same physical data as above).
4.3.4. (1R,4S,
lo[2,2,1]hept-5-ene 6
To a stirred solution of 1a (70 mg, 0.52 mmol) and
aR)-3-(a-Hydroxyphenylacetyl)-2-oxa-3-aza-bicyc-
4.4.2. (1R,4S,20S)-N-[ -20-Hydroxymethylpyrrolidine-10-carbonyl]-
L
D-mandelic
2-oxa-3-aza-bicyclo[2,2,1]hept-5-ene 10a and its (1S,4R,20S)-
acid (105 mg, 0.70 mmol, 1.4 equiv) in dry EtOH (2 mL) at 0 °C or
ꢀ10 °C was added NEt3 (0.1 mL, 0.72 mmol, 1.4 equiv). The solution
turned a clear yellow in 10 min after which was added dropwise a
solution of DCC (175 mg, 0.85 mmol, 1.6 equiv) in dry CH2Cl2
(0.5 mL). A white precipitate appeared and the solution was stirred
at 0 °C or ꢀ10 °C for 16 h. The solvent was then evaporated at rt and
the residue dissolved in Et2O. The insolubles were filtered or centri-
fuged off, the solution evaporated at rt and the crude product puri-
fied by flash chromatography (cyclohexane/AcOEt 4:6, Rf 0.4) to give
6 (71 mg, 59%). For analytical purposes, it was purified by dissolu-
tion in AcOEt, the insolubles centrifuged off, the solution evaporated
at rt and the crystals obtained washed at 0 °C with iPrOH (0.5 mL). 6
isomer 11a
To a stirred solution of cyclopentadiene (60 lL, 0.72 mmol,
1.5 equiv) in CH2Cl2 (1.5 mL) and MeOH (1 mL), 10 beads of molec-
ular sieves 4 Å and NPr4IO4 (62 mg, 0.17 mmol, 0.33 equiv) at 0 °C,
9a (80 mg, 0.50 mmol) were added portionwise and the solution
stirred at 0 °C until completion of the reaction (1–2 h, tlc monitor-
ing). The same work-up as reported above gave the adduct mixture
10a/11a as a yellowish resin (103 mg, 84%). The diastereoisomeric
ratio was 81:19 for the crude reaction mixture and 75:25 to 69:31
after work-up. 10a/11a: yellowish resin. IR (KBr): 802, 849, 1049,
1291, 1329, 1420, 1628, 2965, 3434 cmꢀ1 1H NMR (CDCl3,
.
400 MHz, 295 K, M for 10a, m for 11a): d 1.48 (m, 1H m, Hb-30);
1.58 (m, 1H M, Hb-30); 1.65–1.90 (m, 4H m,M); 1.92 (dt, 1H M,
J = 9.8, 2.2 Hz, Ha-7); 1.99 (dt, 1H m, J = 9.4, 2.0 Hz, Ha-7); 1.96–
(containing 5% of the (1S,4R,
a
R)-isomer): colourless crystals. Mp
131–132 °C. ½a 2D5
ꢂ
¼ ꢀ78 (c 0.25, CHCl3). IR (KBr): 706, 737, 758,
800, 825, 843, 912, 838, 1022, 1326, 1345, 1435, 1631, 3034,
2.05 (m, 1H m,M, Ha-30); 3.40–3.55 (m, 2H m, 1H M, Hb-
a
M,);
m,
3384 cmꢀ1
.
1H NMR (CDCl3, 400 MHz, 295 K): d 1.80 (s, CH2(7));
); 5.06 (d, J = 6.5 Hz, H- ); 5.28, 5.33 (2
Hb-50 m,M); 3.55–3.70 (m, 1H m, 2H M, Ha-
a m,M, Hb-a
4.08 (d, J = 6.5 Hz, OH-
a
a
3.75 (ddd, 1H m, J = 3.4, 9.1, 13.2 Hz, Ha-50); 3.80 (ddd, 1H M,
J = 6.4, 8.6, 12.9 Hz, Ha-50); 4.15 (m, 1H m,M, H-20); 4.15, 4.34 (2
broad s, 1H m,M, OH); 4.99 (quint, 1H m, J =2.0 Hz, H-4); 5.07
(m, 1H m,M, H-4 M, H-1 m); 5.15 (dq, 1H M, J = 0.8, 2.0 Hz, H-1);
6.37 (ddd, 1H m, J = 1.7, 2.7, 6.4 Hz, H-5 or H-6); 6.44 (ddd, 1H
M, J = 1.8, 2.7, 6.2 Hz, H-5 or H-6); 6.50 (dt, 1H M, J = 6.2, 2.3 Hz,
H-6 or H-5); 6.62 (dt, 1H m, J = 6.4, 2.3 Hz, H-6 or H-5). 13C NMR
(CDCl3, 62.5 MHz, 295 K): Major adduct 10a, d 24.8 C(40); 28.3
broad s, H-1, H-4); 6.40, 6.65 (2 broad s, H-5, H-6);7.30–7.45 (m,
4Har). 13C NMR (CDCl3, 62.5 MHz, 295 K): d 48.3 (C(7)) ; 63.0
(C(4)) ; 72.9 (Ca); 84.9 C(1); 127.2, 128.1, 128.5 (3 CHar); 133.0,
136.8 (C(5), C(6)) ; 139.3 (Cs-ar); 176.0 (NCO). HR-MS (ESI+IsoTof)
calcd for C13H14NO3 [M+H]+: 232.0968; found: 232.0971.
4.3.5. (1S,4R,
lo[2,2,1]hept-5-ene 7
Same procedure as for 6 with ent-1a (50 mg, 0.37 mmol),
aR-)-3-(a-Hydroxyphenylacetyl)-2-oxa-3-aza-bicyc-
C(30); 48.1 (C(7)); 8.9 (C(50)); 61.6 (C(20)); 64.4 (C(4)); 67.4 (C
a);
D
-man-
83.3 (C(1)); 134.4, 135.9 (C(5),C(6)); 164.4 (NCO). Minor adduct
delic acid (68 mg, 0.45 mmol, 1.2 eq) in dry EtOH (1.1 mL) at 0 °C or
ꢀ10 °C and NEt3 (0.06 mL, 0.43 mmol, 1.2equiv.), then DCC
(120 mg, 0.58 mmol, 1,6 equiv) in dry CH2Cl2 (0.4 mL) to give 7
(53 mg 61%). For analytical purposes, 7 was purified as for 6. 7 (con-
11a d 24.4 C(40); 28.1 C(30); 48.0 (C(7)); 49.8 (C(50)); 61.7 (C(20));
64.5 (C(4)); 67.3 (Ca); 83.4 (C(1)); 132.9, 138.0 (C(5),C(6)) ; 164.7
(NCO). HR-MS (ESI+IsoTof) calcd for C11H17N2O3 [M+H]+:
225.1234; found: 225.1228.
taining 2% of the (1R,4S,
a
R)-isomer): colourless crystals. Mp 127–
128 °C. ½a 2D5
ꢂ
¼ þ69 (c 0.25, CHCl3). IR (KBr): 700, 721, 736, 763,
4.4.3. (1S,4R,20R)-N-[ -(20-Methoxymethyl)pyrrolidine-10-carb-
D
796, 828, 846, 942, 1013, 1060, 1291, 1336, 1456, 1655, 3026,
onyl]-2-oxa-3-aza-bicyclo[2,2,1]hept-5-ene (11b) and its
3073, 3364 cmꢀ1
J = 8.6 Hz, Hb-7); 1,95 (d, J = 8.6 Hz, Ha-7); 4.10 (d, J = 7.0 Hz,
OH- ); 5.15 (broad s, H-4); 5.22 (d, J = 7.0 Hz, H- ); 5.36 (broad s,
.
1H NMR (CDCl3, 400 MHz, 295 K): d 1.77 (d,
(1R,4S,20S)-isomer 10b
Same procedure as for 10a/11a with cyclopentadiene (37 lL,
a
a
0.50 mmol, 1.5 equiv) and NPr4IO4 (60 mg, 0.16 mmol, 0.4 equiv),
and ent-9b (67 mg, 0.40 mmol) to give 10b/11b (81 mg, 88%) as a
15:85 mixture before work-up; 17:83 mixture after work-up.
10b/11b: yellowish resin. IR (KBr): 850, 1113, 1329, 1411, 1644,
H-1); 5.62, 6.26 (2 broad s, H-5, H-6); 7.26 (s, 5Har). Data in agree-
ment with those of the literature.7 13C NMR (CDCl3, 62.5 MHz,
295 K): 48.0 (C(7)) ; 62.7 (C(4)) ; 72.4 (Ca); 84.4 C(1); 128.0 (3

J.-M. Heuchel et al. / Tetrahedron: Asymmetry 23 (2012) 1467–1473
1473
2996, 2890, 3490 cmꢀ1 1H NMR (CDCl3, 400 MHz, 295 K): Major
.
References
isomer. 11b d 1.74 (d, 1H, J = 8.5 Hz, Hb-7); 1.75 (m, 1H); 1.91
(dt, 1H, J = 8.5, 2.0 Hz, Ha-7); 1.86–2.0 (m, 3H); 3.33 (dd, 1H, Hb-
a
a
1. (a) Li, F.-Z. h.; Miller, M. J. J. Org. Chem. 2006, 71, 5221–5227; (b) Li, F.-Zh.;
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method as in the literature2a for the resolution of 2.
); 3.34 (s, 3H, OMe); 3.40–3.49 (m, 1H, Hb-50); 3.53 (dd, 1H, Ha-
); 3.66 (m, 1H, Ha-50); 4.17 (ddt, 1H, H-20); 5.07 (quint, 1H,
2. (a) Li, F.-Zh.; Brogan, J. B.; Gage, J. L.; Zhang, D.; Miller, M. J. J. Org. Chem. 2004,
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J = 2.0 Hz, H-4); 5.13 (quad, 1H, J = 2.0 Hz, H-1); 6.42, 6.47 (2dt,
2H, H-5, H-6); J(20,aa) = 3.4, J(20,ab) = 7.2, J(
aa,ab) = 9.2,
J(20,30) = 5.5, J(1,5) = J(1,6) = J(1,7a) = J(4,5) = J(4,6) = J(4,7a) = 2.0,
J(5,6) = 5.6 Hz. Minor isomer 10b: d 1.70–2.00 (m, 6H); 3.27 (dd,
1H, J = 7.2, 9.4 Hz, Hb-
a
); 3.32 (s, 3H, OMe); 3.40–3.49 (m, 1H,
Hb-50); 3.51 (dd, 1H, J = 3.6, 9.4 Hz, Ha-
a
); 3.60 (m, 1H, Ha-50);
4.20 (m, 1H, H-20); 5.00 (quint, 1H, J = 2.0 Hz, H-4); 5.06 (broad s,
1H, H-1); 6.33, 6.60 (2dt, 2H, J = 5.6, 2.0 Hz, H-5, H-6). 13C NMR
(CDCl3, 62.5 MHz, 295 K): Major isomer 11b d 23.7 (C(40)); 27.5
(C(30)); 48.0 C(7)); 48.3 (C(50)); 57.5, 58.9 (OMe, C(2)); 64.3
(C(4)); 73.1 (C
a); 83.1 (C(1)); 134.0, 135.8 (C(5),C(6));
161.9(NCO). Minor isomer d 24.4 (C(40)); 27.8 (C(30)); 47.9 C(7));
48.9(C(50)); 57.4, 59.0 (OMe, C(2)); 64.4 (C(4)); 73.0 (C
a); 83.0
(C(1)); 132.7, 137.9 (C(5),C(6)); 161.9 (NCO). HR-MS (ESI+) calcd
for C12H19N2O3 [M+H]+: 239.1390; found: 239.1387.
11. (a) Mulvihill, M. J.; Gage, J. I.; Miller, M. J. J. Org. Chem. 1998, 63, 3353–3357; see
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4.4.4. (1S,4R)-4-tert-Butylcarbonylamino-cyclopent-2-en-1-ol
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629–635.
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Tetrahedron: Asymmetry 1991, 2, 1209–1221.
At 0 °C a solution of ent-1a (89% ee, 50 mg, 0.37 mmol) in MeOH
(1 mL) and AcOH (0.25 mL, 4.3 mmol, 11 equiv.) was reduced with
stirring with Zn dust (100 mg, 1.53 mmol, 4 equiv.) for 1 h. This
solution of 2a was N-protected at 0 °C by adding pulverised Na2CO3
(0.25 g, 2.5 mmol) and Boc2O (110 mg, 0.50 mmol, 1.4 equiv.). Next
Et2O (3 mL) was added with stirring, the mixture centrifuged and
the organic phase separated; this step was then repeated. The com-
bined organic phases were dried (MgSO4) and evaporated at rt to
give a resin, which was crystallised and washed in cyclohexane/
iPr2O (3:1) at 0 °C to give (+)-2b (54 mg. 72%). (+)-2b (ee 89%): Col-
ourless crystals. Mp 66–67 °C (iPr2O) [lit.12 oil; lit.13 58–59 °C; lit.15
64–65.5 °C for the racemate; lit.2a 103–104 °C for the (1R,4S)-enan-
tiomer]. ½a 2D5
ꢂ
¼ þ67 (c 1, CHCl3) [lit.13 +65.3 (c 0.6, CHCl3); lit.12 +64
(c 1, CHCl3) ee 92%; lit.2a ꢀ69 (c 1, CHCl3) ee 98%, for the (1R,4S)-
enantiomer]. IR (KBr): 3356, 2977, 2935, 2867, 1678, 1515, 1365,
1290, 1249, 1173, 1089, 1066, 997, 755, 596 cmꢀ1. 1H NMR (CDCl3,
400 MHz, 295 K): d 1.44 (s, CMe3); 1.54 (broad dt, Hb-5; ca 2.5
(broad s, OH-1); 2.73 (ddd, Ha-5); 4.43 (ddtt, H-4); 4.69 (tddd, H-
1); 4.91 (broad d, NH-4); 5.84 (ddd, H-3); 5.98 (ddd, H-2);
24. Muxworthy, J. P.; Wilkinson, J. A.; Procter, G. Tetrahedron Lett. 1995, 36, 7535–
7538.
25. Mulvihill, M. J.; Surman, M. D.; Miller, M. J. J. Org. Chem. 1998, 63, 4874–4875.
No rotatory [a] values of the transformation products were given herein.
26. Gouverneur, V.; Ghosez, L. Tetrahedron: Asymmetry 1990, 1, 353–366.
27. Martin, S. F.; Hartmann, M.; Josey, J. A. Tetrahedron Lett. 1992, 33, 3583–3586.
28. (a) Machin, B. P.; Howell, J.; Mandel, J.; Blanchard, N.; Tamm, W. Org. Lett. 2009,
10, 2077–2080; (b) Machin, B. P.; Ballantine, M.; Mandel, J.; Blanchard, N.;
Tamm, W. J. Org. Chem. 2009, 74, 7261–7266.
J(1,2) = 2.4,
J(1,3) = J(1,4) = 1.0,
J(1,5a) = 7.1,
J(1,5b) = 3.6,
29. Cesario, C.; Tardibono, L. P., Jr.; Miller, M. J. J. Org. Chem. 2009, 74, 448–451.
30. Defoin, A.; Brouillard-Poichet, A.; Streith, J. Helv. Chim. Acta 1991, 73, 103–109.
J(2,3) = 5.4, J(2,4) = 1.6, J(3,4) = 2.3, J(4,NH) = J(4,5a) = 8,3, J(4,5b) =
= 4.1, J(5a,5b) = 14.3 Hz. Same d values as in the literature.12,15,21
For the 13C NMR (CDCl3, 62.5 MHz, 295 K): same values as in the
literature.12,15,21