Nitrosocarbonyl Carbohydrate Derivatives: Hetero Diels-Alder and Ene Reaction Products for Useful Organic Synthesis

Article abstract of DOI:10.1055/s-0040-1707276

The generation and trapping of two new nitrosocarbonyl intermediates bearing carbohydrate-based chiral substituents is achieved by the mild oxidation of the corresponding nitrile oxides with tertiary amine N -oxides. Their capture with suitable dienes and alkenes afforded the corresponding hetero Diels-Alder cycloadducts and ene adducts from fair to excellent yields. The entire methodology looks highly promising by the easy conversion of aldoximes into hydroxymoyl halides, widening the access to nitrosocarbonyls, versatile tools in organic synthesis.

Full text of DOI:10.1055/s-0040-1707276

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 52, A–M
paper
A
en
M. Corti et al.
Paper
Synthesis
Nitrosocarbonyl Carbohydrate Derivatives: Hetero Diels–Alder
and Ene Reaction Products for Useful Organic Synthesis
Marco Corti
(
)
n
Marco Leusciatti
Mattia Moiola
Mariella Mella
Paolo Quadrelli*
(
)
n
COR
COR
N
N
O
N
O
HDA
O
O
S
R
O
R
O
N
O
ene
reaction
HO
(
0
0
0
0
-
0
0
0
1
-
5
3
6
9
-
9
1
4
0
O
R
R
O
BnO
O
University of Pavia, Department of Chemistry,
Viale Taramelli 12, 27100 – Pavia, Italy
marco.corti03@universitadipavia.it
marco.leusciatti01@universitadipavia.it
mattia.moiola01@universitadipavia.it
mariella.mella@unipv.it
22 examples
)
n
Yields: 17–100%
(
)
n
paolo.quadrelli@unipv.it
Corresponding Author
Received: 06.07.2020
Accepted after revision: 08.08.2020
Published online: 22.09.2020
(
)
n
(
)
n
R
O
R
O
(
)
n
COR
NH2
OH
+
N
N
DOI: 10.1055/s-0040-1707276; Art ID: ss-2020-t0367-op
O
O
HDA
synthetic
elaboration
1
2
3
4
Abstract The generation and trapping of two new nitrosocarbonyl
intermediates bearing carbohydrate-based chiral substituents is
achieved by the mild oxidation of the corresponding nitrile oxides with
tertiary amine N-oxides. Their capture with suitable dienes and alkenes
afforded the corresponding hetero Diels–Alder cycloadducts and ene
adducts from fair to excellent yields. The entire methodology looks
highly promising by the easy conversion of aldoximes into hydroxymoyl
halides, widening the access to nitrosocarbonyls, versatile tools in or-
ganic synthesis.
ene
reaction
(
)
n
HO
COR
COR
N
HN
NH2
+
RCOOH
reduction
hydrolysis
(
)
(
)
n
(
)
n
n
5
6
7
8
Key words nitrosocarbonyl, hetero Diels–Alder reactions, ene reac-
tions, nitrile oxides, synthetic applications
Scheme 1 Synthetic utility of nitrosocarbonyl chemistry in HDA and
ene reactions
Nitrosocarbonyl intermediates 1 are fleeting and highly
reactive species, obtainable from a variety of sources such
as hydroxamic acids, N-hydroxycarbamates, N-hydroxy-
ureas, nitrile oxides, 1,2,4-oxadiazole-4-oxides, and nitrodi-
azoalkanes.1 Since nitrosocarbonyls (NC) do not survive for
long (their stability was determined to be up to 180 s),2
trapping with suitable dienes in hetero Diels–Alder (HDA)
reactions or with alkenes in ene reactions represents the
way to take advantage of these versatile synthetic tools. In
spite of their nature of transient species, NC 1 continue to
hold a tremendous amount of synthetic potential as inter-
mediates in the construction of a variety of biologically in-
teresting molecules.1 Their reactivity is nicely displayed in
HDA and ene reactions (Scheme 1). In the first case, the use
of a variety of acyclic or cyclic dienes allows for obtaining
the corresponding cycloadducts of type 2 that can be easily
elaborated into aminols 3 (with loss of the acyl fragment 4)
where valuable functional groups, OH and NH2, are in-
stalled in a cis stereochemical relationship on a carbocyclic
skeleton.
Moreover, the C=C bond is suitable for further derivat-
ization. Second, the ene reactions can be performed under
mild conditions with acyclic or cyclic alkenes to afford
the acylhydroxylamines 5 through the construction of a
new C–N bond; these products can be easily reduced to the
corresponding amides 6, whose hydrolysis produces new
amines of type 7 (allylic amination) along with the carboxylic
acids 8.1
However, the NC role is not, as it seems, restricted to
furnish two heteroatoms to be located in different carbon
skeletons depending upon the reaction conditions; the R–
C=O moieties, when attached to the structures, as in the
cases of compounds 2, 5, and 6, play a fundamental role, es-
pecially in the definition of the biological properties of the
entire molecules.
On pursuing our traditional investigations on the chem-
ical behavior of NCs, we wished to apply our efficient and
mild method for the generation of these fleeting intermedi-
ates to the nitrile oxides obtained from carbohydrate sourc-
es, such as the (R)-(2,2-dimethyl-1,3-dioxolan-4-one) (A)
and the (3aR,5S,6R,6aR)-6-(benzyloxy)-2,2-dimethyltetra-
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–M
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
M. Corti et al.
Paper
Synthesis
bohydrate substituted 1,3-dipoles, prompted us to investi-
gate the HDA and ene reactions of these new in situ gener-
ated NC intermediates.
We started investigating the chemical behavior of the
NC of type A (Scheme 2) containing a single stereogenic
center taking advantage of the easy synthetic elaboration of
the commercially available D-mannitol (9) (Scheme 3). All
the reported synthetic steps are well described in litera-
ture.7
O
O
( )
n
R
O
O
O
A
B
=
(
)
n
COR
N
O
O
R
HDA
O
2A,B
HO
ene
reaction
N
COR
O
N
)
O
1A,B
O
BnO
(
n
(
)
n
5A,B
Scheme 2 Synthetic pathway of substituted nitrosocarbonyl interme-
D-Mannitol (9) is protected through reaction with 2,2-
dimethoxypropane in the presence of SnCl2 as the catalyst
to afford the compound 10 in 60% yield.8 Oxidation of the
diol 10 with periodate led to the aldehyde 11 in 63% yield.8
This latter was easily transformed into the corresponding
oxime 12 through classical procedure in excellent yield
(97%); typical treatment with NCS allowed to obtain the de-
sired chloroxime 13 in 98% yield.9 The structures of all the
products reported in Scheme 3 were confirmed by spectro-
scopic analyses and found identical with the characteriza-
tions reported in cited literature.7–9
The first attempts to generate in situ the nitrosocarbon-
yl intermediate 13NC from the chloroxime 13 were con-
ducted in the presence of freshly distilled cyclopentadiene
or 1,3-cyclohexadiene in HDA cycloadditions. Following the
previous and well-established protocol,10 a DCM solution of
13 was added to a solution of 1.2 equivalents of NMO along
with 1.1 equivalents of Et3N in the presence of 1.5 equiva-
lents of the selected diene in the same anhydrous solvent
(Scheme 4).
The reaction mixtures were left at room temperature for
24 hours and subsequently washed with water. The dried
organic phases were then evaporated to dryness to leave
the crude products that were purified by column chroma-
tography to afford the desired cycloadducts 14a,b and 15a,b
in 77% and 70% yield, respectively. The structures of the
HDA cycloadducts were attributed on the basis of the corre-
sponding analytical and spectroscopic data. In 1H NMR
(CDCl3) spectra of the 2,3-oxazanorbornene moiety of cyc-
loadducts 14a,b, the olefinic protons are found at  = 6.38
and 6.60 as broad signals while the protected glyceralde-
diates in HDA and ene reactions
hydrofuro [2,3-d][1,3]dioxol-5-one (B) (see inset in Scheme
2), by the oxidation of the corresponding 1,3-dipoles with
tertiary amine N-oxides. These structural features are com-
monly found in several biological active molecules as anti-
virals and anticancer compounds.3 For example, derivatives
containing the scaffold A are typically used to prepare anti-
viral compounds3 such as in the Peramivir analogues4 or
can be found in anticancer compounds coupled with cispla-
tin.5 -Glucosidase inhibitors were prepared from the ni-
trile oxide containing the structure B derived from glucose.6
The intrinsic importance to develop novel compounds with
potential biological activities and the desire to verify the
applicability of the nitrile oxide oxidation protocol to car-
OMe
OH OH
OH
O
OMe
HO
R
R
R
O
S
R
R
OH
S
SnCl2
O
R
1,2-dimethoxyethane
(Glyme)
OH OH
O
OH
10
9
NaIO4
NaHCO3
DCM
NH2OH·HCl
Na2CO3
O
O
O
NCS
DMF
R
O
N
S
O
R
N
O
H
OH
OH
H2O
Cl
13
H
12
O
11
Scheme 3 Synthesis of the (R)-N-hydroxy-2,2-dimethyl-1,3-dioxolane-
4-carbimidoyl chloride (13) from D-mannitol (9)
O
O
O
NMO, Et3N
(
)
n
R
S
O
R
N
O
R
+
+
N
R
(
)
O
OH
R
n
DCM, r.t., 24 h
O
N
O
O
S
(
)
n
O
Cl
n = 1, 2
13
14a
15a
14b
15b
(n = 1)
(n = 2)
O
R
O
N
O
O
13NC
Scheme 4 Synthesis of HDA cycloadducts 14a,b and 15a,b by the mild oxidation of (R)-N-hydroxy-2,2-dimethyl-1,3-dioxolane-4-carbimidoyl chloride
(13) with NMO
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–M

C
M. Corti et al.
Paper
Synthesis
hyde portion gave three characteristic double doublets at 
= 4.10, 4.28, and 4.71. Similarly, the cycloadducts 15a,b gave
in H NMR spectra the same distribution of signals in the
H
O
O
NMO, Et3N
R
O
R
+
O
N
1
N
OH
OH
DCM, r.t., 24 h
Cl
expected range. The obtained cycloadducts 14a,b and 15a,b
are inseparable mixtures of diastereoisomers in the ratio
1.8:1 as shown in particular by the relative heights of the
signals in the 13C NMR spectra.
O
16a–g
13
Olefins
Yield (%)
a
b
69
68
The results above reported indicate the well tolerance of
the carbohydrate residue derived from the protected D-
mannitol 10 with respect to the oxidative conditions ap-
plied to convert the in situ generated nitrile oxide from 13
into the corresponding nitrosocarbonyl intermediate 13NC.
The chemical yields are very good and no other products
were detected in the reaction mixtures with the exception
of decomposition products from the highly unstable NCs, as
known from the behavior of these fleeting intermedi-
ates.1,11 Any attempt to modify/influence the diastereoiso-
meric ratio by decreasing the reaction temperature from 0
°C to –40 °C failed, also due to the strong slowdown of the
reaction kinetics and subsequent rise of the competitive NC
dimerization/decomposition pathway that renders the de-
sired HDA cycloadducts unobtainable.
More challenging were the ene reaction experiments,
since it was known that these reaction are highly depen-
dent upon a fast trapping of the NC intermediate by the ole-
finic partner.12,13 Again, we followed the previously de-
scribed protocol for these reactions12,13 by adding a DCM
solution of 13 to DCM solutions of 1.2 equivalents NMO
along with 1.1 equivalents Et3N in the presence of 15 equiv-
alents of the selected alkenes a–g (Scheme 5). The reaction
mixtures were left at room temperature for 24 hours and
subsequently washed with water. The dried organic phases
were then evaporated to dryness to leave the crude prod-
ucts that were purified by column chromatography to af-
ford the desired ene adducts 16a–g in good overall yields
(58–71%).
c
d
66
60
Ph
e
f
58
71
64
*
g
*
Scheme 5 Synthesis of ene adducts 16a–g by the mild oxidation of
(R)-N-hydroxy-2,2-dimethyl-1,3-dioxolane-4-carbimidoyl chloride (13)
with NMO. The dot indicates the site of the nitrogen atom attachment
of the nitrosocarbonyl moiety and the asterisk in olefins f and g the site
of allylic hydrogen abstraction.
The structures of the ene adducts 16a–g were attribut-
ed on the basis of the corresponding analytical and spectro-
scopic data. The relevant physical chemical and spectro-
scopic data are shown in Table 1.
It is worth noting that compounds 16b,c,d,f,g were ob-
tained as mixtures of diastereoisomers in nearly 1:1 ratio in
all the cases. For compounds 16b,d,f,g, we were able to sep-
arate the two diastereoisomers that were singularly fully
characterized while compound 16c remained as an insepa-
rable mixture and was characterized as it is. Significantly,
Table 1 Physical and Spectroscopic Data of Ene Adducts 16a–g
b
Ene adduct 16
Mp (°C)a
IR (cm–1
)
1H NMR (DMSO-d6)
C=O, OH
HC–N
–
Olefinic Hs
OH
9.55 (s)
a
179–180
1641, 3092
4.76 (s), 4.68 (t)
b 1st diast.
2nd diast.
90–91
111–112
1640, 3092
1644, 3095
4.82 (q)
4.85 (m)
4.87 (s), 4.92 (s)
4.86 (s), 4.90 (s)
9.35 (s)
9.46 (s)
c (mix diast.)
121–123
1627, 3179
5.40 (m)
5.56, 6.02 (m)
9.39 (s)
d 1st diast.
2nd diast.
99–100
114–115
1642, 3059
1628, 3179
4.84 (m)
4.85 (m)
5.46, 5.87 (m)
5.49, 5.87 (m)
9.47 (s)
9.46 (s)
e
94–95
1650, 3200
4.56 (m)
5.23, 5.59 (s)
9.80 (s)
f 1st diast.
2nd diast.
91–92
82–83
1642, 3095
1647, 3100
4.79 (m)
4.80 (m)
5.39 (q)
5.36 (q)
9.25 (s)
9.33 (s)
g 1st diast.
2nd diast.
116–117
121–122
1646, 3098
1645, 3097
4.89 (m)
4.88 (m)
4.93 (s)
4.92 (s)
9.33 (s)
9.40 (s)
a Colorless crystals from benzene/PE.
b Nujol mull.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–M

D
M. Corti et al.
Paper
Synthesis
the use of DMSO-d6 in proton NMR spectra allowed to evi-
dence the hydroxylamine acidic proton, found in all the cas-
es in the range  = 9.25–9.80 as singlets. The dioxolane pro-
tons were found in the expected region  = 3.5–5.0 as mul-
tiplets. The results illustrated here clearly indicate the
excellent tolerance of the applied experimental conditions
(NMO, Et3N, DCM, r.t., 24 h) for the in situ generation of the
nitrosocarbonyl intermediate 13NC, also in the case of ene
reactions that require large excess of olefins to get accept-
able yields of the corresponding adducts.
was prepared from the commercially available 1,2,5,6-di-O-
isopropylidene--D-glucofuranose (17) (Scheme 6) accord-
ing to described procedures.17 Benzyl group protection of
17 afforded compound 18 in 72% yield; this latter was then
hydrolyzed to obtain the diol 19 in 87% yield.
O
O
O
O
S
R
R
R
O
O
i) NaH, Et2O, r.t.
ii) BnCl, 60 °C, 8 h
O
O
S
R
S
R
O
O
HO
17
BnO
18
Another important result is that achieved with the ste-
reoisomeric (Z)- and (E)-3-methyl-2-pentenes f and g (see
Table 1); these stereoisomeric olefins were extensively used
in the investigations of ene reactions because they allow for
fully defining the stereochemical paths and assessing the
intriguing phenomenon known as the ‘cis effect’, well-doc-
umented both in experimental and theoretical studies.14
Allylic hydrogens on the more congested side of the alkene
are exclusively abstracted, thus resembling singlet oxygen
behavior.15 Similarly to what observed before, the interme-
diate 13NC follows specifically the Markovnikov (M) path
through the addition of the electrophilic nitrogen atom to
the less substituted C=C carbon atom and nicely maintain
the ‘cis’ selectivity by abstracting the allylic hydrogen as in-
dicated in Scheme 5 by the asterisk (*) affording the expect-
ed ene adducts 16f and 16g. The spectral assignments are
fully consistent for the given structures; adduct 16f is char-
acterized by the presence of three methyl groups as singlets
and two methyls as doublets and a single olefinic proton as
a multiplet while adduct 16g has three methyl groups as
singlets, one methyl as a doublet, and one ethyl group
AcOHaq 60%
35 °C, 5 h
HO
O
O
S
R
R
R
OHC
HO
O
O
Pb(OAc)4
S
R
S
R
C6H6, Δ, 10 min
O
O
BnO
20
BnO
19
NH2OH·HCl
H2O/MeOH (10:1)
NaHCO3, Δ, 1 h
HO
HO
N
N
O
O
R
S
R
R
O
Cl2
DCM, –30 °C, 1 h
O
Cl
S
R
R
R
O
O
BnO
BnO
22
21
Scheme 6 Synthesis of the (3aR,5S,6R,6aR)-6-(benzyloxy)-N-hydroxy-
2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carbimidoyl chloride
(22) from 1,2,5,6-di-O-isopropylidene--D-glucofuranose (17)
Oxidation18 of 19 with lead tetraacetate afforded the de-
sired aldehyde 20 in excellent yield (97%), that was convert-
ed into the corresponding oxime 21 (yield: 60%, mixture of
syn and anti stereoisomers).7 Chlorination at –30 °C in DCM
solution of 21 gave the desired hydroxymoyl chloride 22 in
74% yield.19 All the structures of the above reported prod-
ucts were confirmed by spectroscopic analyses and found
to be identical with reported data.17–19
1
whose methylene shows diastereotopic protons in the H
NMR spectra. This behavior of 13NC is perfectly in keeping
with that of the nitrosocarbonyl benzene and in general of
nitrosoaromatic compounds.14–16
With the aim to further corroborate the NC generation
protocol from sugar-containing residue nitrile oxides, the
(3aR,5S,6R,6aR)-6-(benzyloxy)-N-hydroxy-2,2-dimethylte-
trahydrofuro[2,3-d][1,3]dioxole-5-carbimidoyl chloride (22)
We first investigated the in situ generation of the nitro-
socarbonyl intermediate 22NC from the chloroxime 22 in
the presence of freshly distilled cyclopentadiene and 1,3-
O
R
O
HO
N
R
R
(
)
n
O
O
R
S
OBn
O
S
(
)
R
n = 1, 2
O
S
O
O
n
Cl
N
+
R
O
NMO, Et3N
DCM, r.t., 24 h
R
S
R
R
O
O
N
BnO
22
O
R
R
(
)
n
S
O
BnO
(n = 1)
(n = 2)
23a
24a
23b
24b
O
N
O
S
R
O
O
R
R
O
BnO
22NC
Scheme 7 Synthesis of HDA cycloadducts 23a,b and 24a,b by the mild oxidation of the (3aR,5S,6R,6aR)-6-(benzyloxy)-N-hydroxy-2,2-dimethyltetra-
hydrofuro[2,3-d][1,3]dioxole-5-carbimidoyl chloride (22) with NMO.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–M

E
M. Corti et al.
Paper
Synthesis
cyclohexadiene, classical conditions to prepare HDA cy-
cloadducts. Following the well-established protocol,10
We completed our investigations on the chemical be-
havior of 22NC by performing the ene reaction experi-
ments.12,13 Again, we followed the previous described pro-
tocol for these reactions by adding a DCM solution of 22 to
DCM solutions of 1.2 equivalents of NMO along with 1.1
equivalents of Et3N in the presence of 15 equivalents of the
selected alkenes a–g (Scheme 8). The reaction mixtures
were left at room temperature for 24 hours and subse-
quently washed with water. The dried organic phases were
then evaporated to dryness to leave the crude products that
were purified by column chromatography to afford the ene
adducts 25a,b,d–g and the corresponding oxidized adducts
26a–c,f,g in fair yields.
a
DCM solution of 22 was added to a DCM solution of 1.2
equivalents of NMO along with 1.1 equivalents of Et3N in the
presence of 1.5 equivalents of the selected diene (Scheme 7).
The reaction mixtures were left at room temperature for
24 hours and subsequently washed with water. The dried
organic phases were then evaporated to dryness to leave
the crude products that were purified by column chroma-
tography to afford the desired cycloadducts 23a,b and 24a,b
in 92% and quantitative yield, respectively. The structures of
the HDA cycloadducts were attributed on the basis of the
1
corresponding analytical and spectroscopic data. In the H
NMR spectra (CDCl3) of the 2,3-oxazanorbornene moiety of
cycloadducts 23a,b, the olefinic protons are found at  =
6.42 and 6.59 as broad singlets. The glucose protected moi-
ety gave the characteristic signals in the range  = 4.29–
5.59. Similarly, the cycloadducts 24a,b gave in 1H NMR
spectra (CDCl3) the same distribution of signals in the ex-
pected range. The obtained cycloadducts 23a,b and 24a,b
are inseparable mixtures of diastereoisomers in the ratio
1:1 as shown by the relative heights of the 13C NMR signals.
These results again confirm the brilliant tolerance of the ex-
perimental conditions for the in situ generation of the ni-
trosocarbonyl intermediate 22NC that was efficiently
trapped with the selected dienes affording the HDA cy-
cloadducts in optimum yields. We did not observe any dias-
teroisomeric preference even by conducting the reaction at
lower temperatures.
Quite surprisingly, the ene reactions of the glucose de-
rivative 22 afforded mixtures of some of the desired com-
pounds of type 25 and some of the adducts 26 where the
benzylic methylene was oxidized to the corresponding C=O
group. This was confirmed from the spectroscopic analyses;
1
in the H NMR spectra of 26, the AB system corresponding
to the benzylic methylene is absent and in the IR spectra a
band in the range 1721–1731 cm–1 can now be found. Rea-
sonably, the oxidation is due to the experimental condi-
tions (vide infra). The chemical yields shown in Scheme 8
indicate a variable distribution of the two types of ene ad-
ducts; the adducts 25 are somewhat preferred with a single
exception (25c) while 26d,e are lacking. The sum of the
yields of both adducts gives comparable values as those ob-
tained from the same reactions conducted with the
chloroxime 13 (see Scheme 5).
HO
HO
HO
N
N
N
H
O
O
O
S
R
S
R
NMO, Et3N
S
R
+
O
O
O
+
O
O
Cl
DCM, r.t., 24 h
R
R
R
R
R
R
O
O
O
BnO
BzO
BnO
Ox
22
Olefins
25a–g
26a–g
Yield (%)
a
b
c
d
35
33
54
-
18
32
-
33
Ph
e
44
-
f
30
46
18
17
*
g
*
Scheme 8 Synthesis of ene adducts 25 and 26 by the mild oxidation of (3aR,5S,6R,6aR)-6-(benzyloxy)-N-hydroxy-2,2-dimethyltetrahydrofuro[2,3-
d][1,3]dioxole-5-carbimidoyl chloride (22) with NMO. The dot indicates the site of the nitrogen atom attachment of the nitrosocarbonyl moiety and the
asterisk in olefins f and g the site of allylic hydrogen abstraction.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–M

F
M. Corti et al.
Paper
Synthesis
Table 2 Physical and Spectroscopic Data of Ene Adducts 25a,b,d–g and 26a–c,f,g
b
Ene adduct 25
Mp (°C)a
IR (cm–1
)
1H NMR (DMSO-d6)

C=O, OH
HC–N
Olefinic Hs
OH
9.55 (s)
a
184–185
1631, 3140
–
4.73, 4.74 (s)
b 1st diast.
2nd diast.
175–177
178–180
1619, 3110
1634, 3158
4.86 (q)
4.85 (m)
4.91, 4.94 (s)
4.85 (m)
9.33 (s)
9.42 (s)
d (mix diast.)
e
192–194
195–196
180–182
1639, 3158
1624, 3152
1626, 3149
4.87 (m)
4.65 (AB)
4.94
5.49, 5.91 (m)
5.29, 5.61 (s)
4.87, 4.94 (s)
9.51 (s)
9.86 (s)
9.34 (s)
f (mix diast.)
g 1st diast.
2nd diast.
178–179
185–186
1640, 3134
1628, 3176
4.92 (q)
4.95 (q)
4.95 (s)
4.89, 4.92 (s)
9.27 (s)
9.36 (s)
b
Ene Adduct 26
Mp (°C)a
IR (cm–1
)
1H NMR (DMSO-d6)
HC–N
C=O, OH
Olefinic Hs
4.71 (s)
OH
a
208–209
200 (dec.)
225 (dec.)
209–210
196–197
1638, 1721, 3176
1635, 1731, 3170
1635, 1725, 3164
1632, 1724, 3086
1637, 1725, 3116
–
9.71 (s)
9.49 (s)
9.57 (s)
9.36 (s)
9.43 (s)
b (mix diast.)
c (mix diast.)
f (mix diast.)
g (mix diast.)
4.83 (q)
5.39 (m)
4.80 (q)
4.94 (q)
4.85, 4.93 (s)
5.83, 5.99 (s)
5.35 (q)
4.89, 4.92 (s)
a Colorless crystals from benzene/PE.
b Nujol mull.
The structures of the ene adducts 25a,b,d–g and the
corresponding oxidized adducts 26a–c,f,g were attributed
on the basis of the corresponding analytical and spectro-
scopic data and the relevant information are gathered in Ta-
ble 2 along with their physical data.
lowed for defining the stereochemical paths and again as-
sessing the ‘cis effect’.14 Allylic hydrogens of (Z)- and (E)-3-
methyl-2-pentenes f and g were abstracted on the more
congested side of the alkene.15 Intermediate 22NC follows
specifically the M path through the addition of the electro-
philic nitrogen atom to the less substituted C=C carbon
atom and nicely maintain the ‘cis’ selectivity as indicated in
Scheme 8 by the asterisk (*) affording the expected ene ad-
ducts. The structures of adducts 25f,g and 26f,g are fully
consistent with their spectral data analogously with the
previous observations. This behavior of 22NC is perfectly in
keeping with that of the nitrosocarbonyl benzene and in
general of nitrosoaromatic compounds.14–16
We have investigated the NC generation protocol ap-
plied to nitrile oxides bearing chiral substituents prepared
from carbohydrate sources. For these ‘proof of concept’
studies we decided to install on the nitrile oxide moiety
(i.e., on the corresponding hydroxymoyl chlorides 13 and
22) two substituents of different complexity easily pre-
pared from commercially available D-mannitol (9) and
1,2,5,6-di-O-isopropylidene--D-glucofuranose (17), fol-
lowing the well-described literature procedures.7–9,17–19 The
aim was to verify the compatibility of the oxidative condi-
tions of the in situ generated nitrile oxides with the mainte-
nance of the nitrosocarbonyl structure in view of their trap-
ping with dienes or alkenes to get a variety of HDA and ene
adducts. In fact, by inserting carbohydrate substituents on
the CO–NO moiety, it was not obvious or predictable a
chemical behavior in full agreement with that of aliphatic
or aromatic nitrosocarbonyl intermediates.10 The fast di-
Adducts 25b,d,f,g as well as 26b,c,f,g were obtained as
mixtures of diastereoisomers in nearly 1:1 ratio with the
exception of 25d (dr, 1.4:1), 26b (dr, 5:1), 26c (dr, 4.3:1),
and 26g (dr, 9.5:1). These data are, however, too random to
describe a specific diastereoselection. For compounds 25b,g
we were able to separate the two diastereoisomers that
were singularly fully characterized. The diagnostic hydrox-
ylamine acidic proton signals were found in all the cases in
the range  = 9.27–9.86 as singlets. The protected glucose
portion of the molecules gave the expected signals, found in
the region  = 4.2–6.0. The experimental conditions some-
what affect the chemical outcome of the ene reactions as
previously accounted with partial oxidation of the benzylic
methylene of some of the ene adducts. Reasonably, due to
the extremely short life-time of the NC intermediates in
general (22NC does not escape this behavior) it is difficult
to believe that the oxidation can occur at the NC generation
step; more probably it occurs on the final ene adducts and
not in all the cases in the same manner. Nevertheless the
chemical yields are good if we consider the sum of both
types of adducts and somewhat comparable with those of
compounds 16.
Similarly to what was described above for compounds
16, the ene reactions in the presence of the stereoisomeric
(Z)- and (E)-3-methyl-2-pentenes f and g (see Table 2) al-
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–M

G
M. Corti et al.
Paper
Synthesis
merization route that nitrosocarbonyl could be a detrimen-
tal and strongly competitive pathway determining a failure
of the investigations at hand.11,20 A second task was to verify
the resistance of the carbohydrate protections under the
experimental conditions. In this field, the results were sub-
stantially positive: totally in the case of the reactions with
hydroxymoyl chloride 13 and in part with compound 22. A
brief comment to the chemical yields can be done regarding
the results obtained for the adducts 26c and 25d; the low
yields are not surprising since we have demonstrated that
cyclopentene and cyclohexene are at the end of the reactiv-
ity scale, four time less reactive than trisubstituted ole-
fins.13 In this latter case, the presence of the benzylic moi-
ety as protecting group containing a highly reactive methy-
lene21 led to the isolation of the oxidized ene adducts 26
bearing a benzoyl group, reasonably from the oxidation of
the corresponding benzyl protected adducts 25. The oxida-
tion of the benzylic methylene seems to occur by means of
the excess NMO or, maybe, by other oxidants generated in
solution. Control experiments conducted on some adducts
of type 25 in the presence of excess NMO both at room tem-
perature and upon heating did not lead to the correspond-
ing oxidized compounds 26. Hence, the reason for the oxi-
dation of the benzylic methylene has to be ascribed to other
species formed during the NC generation. It remains sur-
prisingly and difficult to explain the occurrence of this be-
havior in the ene reaction only. Lastly, we aimed to verify
the possibility to have a chirality induction effect on the dia-
stereoisomeric ratio of both HDA and ene adducts, wherev-
er applicable. This final task failed even by changing the ex-
perimental conditions by decreasing the reaction tempera-
ture to favor a more rigid approach between the addends in
HDA cycloaddition reactions and in the ene additions. Un-
fortunately, nitrosocarbonyl fleeting intermediates, surviv-
ing for 180 s only,2 are hardly manageable from this point
of view.
The key point for discussing the asymmetric induction
can be easily illustrated by the reaction shown in Scheme 9.
The chiral hydroxamic acid 27 is oxidized under classical
conditions by means of tetrapropylammonium periodate to
afford the corresponding nitrosocarbonyl intermediate that
is trapped by a chiral diene 28 to give the expected HDA cy-
cloadducts 29a,b in 32% overall yield.22 In spite of the low
chemical yields, the possibility for the hydroxamic acid 27
to form an intramolecular hydrogen bond surviving after
the oxidation to NC as well as the stereochemical con-
straints imposed by the chiral diene build the correct tran-
sition structures (TS) 30a or 30b, which are responsible for
the asymmetric induction. These features are lacking in our
tested intermediates 13NC and 22NC. Many examples can
be found in literature and the hydroxamic acids are used
exclusively for the generation of chiral NCs and in a good
number of cases chiral dienes are also contributing in the
final result.1 No examples are found in the case of nitrile ox-
ides; these results are indeed the first examples reported in
literature although not leading to any stereopreference.
MeOOC
O
(S)
N
MeOOC
O
O
MeOOC
+
O
O
(S)
(S)
28
N
N
OH
Ph (R)
H
N
(S)
O
N
OH
(R)
O
N
OH
OH
nPr4NIO4
DCM, r.t., MS
O
(R) Ph
(R) Ph
27
29a
29b
=
/
ΣY = 32%
MeOOC
O
MeOOC
O
(S)
(S)
H
N
N
TS =
O
N
O
O
or
(R)
O
N
Ph
(R)
H
O
O
Ph
30a
30b
O
N
O
(S) O
(R) O
(R)
O
N
O
O
(R) (R)
O
BnO
O
22NC
13NC
Scheme 9 Double asymmetric induction with chiral nitrosocarbonyl 27 and chiral diene 28
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–M

H
M. Corti et al.
Paper
Synthesis
On the basis of the above reported comments, the main
positive outcome of the illustrated results is the possibility
to elaborate synthetically carbohydrate compounds to ac-
cess different aldehyde derivatives that can easily converted
into the corresponding oximes as precursors of the nitrile
oxides needed for the NC intermediate generation by taking
advantage of the mild and efficient protocol described in
the present work. The efficiency is quite remarkable since it
is worth noting that the HDA and ene adducts were the
only products observed with no dimerization of the corre-
sponding nitrile oxide to the furoxans or with a limited de-
composition by dimerization of the nitrosocarbonyl inter-
mediates under the applied experimental conditions.
This opportunity has an intrinsic value from the syn-
thetic point of view since several structures of biological ac-
tive molecules contain the prepared scaffolds, in an identi-
cal form or slight modified, as shown in two examples I
(2-{4-[(4R,5R)-5-benzo[d]thiazole-2-carbonyl-2,2-dimethyl-
1,3-dioxolane-4-carbonyl]piperazin-1-yl}benzonitrile)23
All melting points are uncorrected. Elemental analyses were carried
out in-house. 1H and 13C NMR spectra were recorded on a 300 MHz
spectrometer (solvents specified). Chemical shifts are expressed in
ppm from internal TMS () and coupling constants (J) are in hertz
(Hz). Standard abbreviations were used for defining signal multiplici-
ties. Minor diastereoisomer signals are shown in square brackets
when applicable. IR spectra were collected on samples prepared as
Nujol mulls and absorptions () are in cm–1. Column chromatography
and TLC: silica gel H60 and GF254, respectively; eluents: cyclohex-
ane/EtOAc (9:1) to pure EtOAc.
When diastereosomeric mixtures are obtained, yields near the single
stereisomers indicate the sum of both compounds.
D-Mannitol (9) and 1,2,5,6-di-O-isopropylidene--D-glucofuranose
(17) were purchased from chemical suppliers.7–9,17–19 Cyclopentadi-
ene was used freshly distilled and 1,3-cyclohexadiene was purchased
and used as it is. Alkenes a–g were purchased from chemical suppli-
ers and used as they are. Other reagents and solvents were purchased
from chemical suppliers and used without any further purification.
Compounds 10–13 were prepared according the established proce-
dures,7–9 and their structures were confirmed by comparison with the
reported spectroscopic data. Analogously, compounds 18–22 were
prepared according the established procedures,17–19 and their struc-
tures were confirmed by comparison with the reported spectroscopic
data.
and
II
{ethyl
5-(3-ethoxy-3-oxoprop-1-yn-1yl)-1-
[(3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahy-
drofuro[3,4-d][1,3]dioxol-4-yl]-1H-1,2,3-triazole-4-carbox-
ylate}24 in Figure 1. Two different heterocyclic compounds
can behave as inhibitor of HRV 3C protease or cell death in-
ductor by caspase and in both structures the nitrosocarbon-
yl substituents can be easily recognized.
HDA Cycloaddition Reactions of (R)-N-Hydroxy-2,2-dimethyl-1,3-
dioxolane-4-carbimidoyl Chloride (13) with Cyclopentadiene and
1,3-Cyclohexadiene; General Procedure
A DCM solution (50 mL) of 13 (1.80 g, 10 mmol, 1 equiv) was added to
a DCM solution (100 mL) of NMO (1.41 g, 12 mmol, 1.2 equiv) along
with Et3N (1.11 g, 11 mmol, 1.1 equiv) in the presence of the selected
diene (15 mmol, 1.5 equiv). The reaction mixtures were left at r.t. for
24 h and subsequently washed with H2O (2 × 30 mL). The dried or-
ganic phases were then evaporated to dryness to leave the crude
products that were purified by column chromatography to afford the
desired cycloadducts 14a,b and 15a,b.
NC
N
N
O
R
R
N
COOEt
HO
N
O
R
R
R
O
N
O
O
R
N
O
COOEt
O
II
S
I
inductor of cell death by
caspase and autophagy24
HRV 3C protease inhibitor23
2-Oxa-3-azabicyclo[2.2.1]hept-5-en-3-yl-[(R)-2,2-dimethyl-1,3-di-
oxolan-4-yl]methanone (14a,b)
O
N
O
O
Yield: 1.73 g (77%); white crystals (benzene/PE); mp 74–75 °C.
S
R
O
R
O
N
O
IR (Nujol): 1681 (C=O) cm–1
.
O
R
R
O
1H NMR (CDCl3, 300 MHz):  = 6.60 (br s, 1 H, =CH), 6.38 (br s, 1 H,
=CH), 5.40 (br s, 1 H, CHO), 5.32 (br s, 1 H, CHN), 4.71 (t, J = 7 Hz, 1 H,
CHO), 4.28 (t, J = 7 Hz, 1 H, CHO), 4.10 (m, 1 H, CHO), 2.01 and 1.80 (m,
1 H + 1 H, CH2), 1.49 (s, 3 H, CH3), 1.40 (s, 3 H, CH3).
13C NMR (CDCl3, 300 MHz):  = 170.4 (C=O), 132.7, 132.4, 131.6, 131.2
(CH=CH), 72.1, [71.9], 70.4, [69.7], 65.9, [64.0], 62.7 (OCO, CHO, CHN),
30.8, 25.6 (CH2), 23.5, [23.0], 20.6, [20.5] (CH3).
BnO
O
22NC
13NC
Figure 1 Structures of two biological active compounds having com-
mon structural features with chiral nitrosocarbonyls 13NC and 22NC
In conclusion, we have reported the generation and
trapping of two new nitrosocarbonyl intermediates bearing
carbohydrate-based chiral substituents by the mild oxida-
tion of nitrile oxides with tertiary amine N-oxides. Their
capture with suitable dienes and alkenes afforded the cor-
responding HDA cycloadducts and ene adducts from fair to
excellent yields. The entire methodology looks highly
promising by the easy conversion of aldoximes to hydroxy-
moyl halides, widening the access to a wider and wider ar-
ray of nitrosocarbonyls, versatile tools in organic synthesis.
Anal. Calcd for C11H15NO4 (225.24): C, 58.66; H, 6.71; N, 6.22. Found:
C, 58.65; H, 6.70; N, 6.24.
2-Oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl-[(R)-2,2-dimethyl-1,3-di-
oxolan-4-yl]methanone (15a,b)
Yield: 1.67 g (70%); white crystals (benzene/PE); mp 84–85 °C.
IR (Nujol): 1688 (C=O) cm–1
.
1H NMR (CDCl3, 300 MHz):  = 6.66 (m, 1 H, =CH), 5.50 (m, 1 H, =CH),
5.22 (s, 1 H, CHO), 4.80 (s, 1 H, CHN), 4.61 (t, J = 7 Hz, 1 H, CHO), 4.27
(t, J = 7 Hz, 1 H, CHO), 4.00 (dd, J = 7 Hz, 1 H, CHO), 2.12 (m, 4 H,
CH2CH2), 1.50 (s, 3 H, CH3), 1.41 (s, 3 H, CH3).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–M

I
M. Corti et al.
Paper
Synthesis
13C NMR (CDCl3, 300 MHz):  = 170.4, [168.8] (C=O), 132.7, [132.4],
[131.6], 131.2 (CH=CH), 72.2, [72.1], 70.4, [69.7] (CHO, CHN), 64.0,
[62.7] (CH2O), 47.4, [47.2], 30.8, [25.6] (CH2), 23.3, [23.0], 21.1, [20.6]
(CH3).
13C NMR (DMSO-d6, 300 MHz):  = 169.7 (C=O), 144.0 (C=), 112.1
(=CH2), 109.6 (OCO), 72.9 (CHO), 66.8 (CH2O), 54.3 (CHN), 25.7, 25.6,
20.4, 14.8 (CH3).
Anal. Calcd for C11H19NO4 (229.28): C, 57.63; H, 8.35; N, 6.11. Found:
C, 57.65; H, 8.31; N, 6.11.
Anal. Calcd for C12H17NO4 (239.27): C, 60.24; H, 7.16; N, 5.85. Found:
C, 60.25; H, 7.19; N, 5.84.
(4R)-N-(Cyclopent-2-en-1-yl)-N-hydroxy-2,2-dimethyl-1,3-dioxol-
Ene Reactions of (R)-N-Hydroxy-2,2-dimethyl-1,3-dioxolane-4-
ane-4-carboxamide (16c), Mixture of Diastereoisomers
carbimidoyl Chloride (13) with Olefins a–g; General Procedure
Yield: 1.50 g (66%); white crystals (benzene/PE); mp 121–123 °C.
To a DCM solution (100 mL) of the corresponding olefin a–g (15
mmol, 15 equiv) were added NMO (1.41 g, 12 mmol, 1.2 equiv) and
distilled Et3N (1.11 g, 11 mmol, 1.1 equiv). (R)-N-Hydroxy-2,2-di-
methyl-1,3-dioxolane-4-carbimidoyl chloride (13; 1.80 g, 10 mmol, 1
equiv) was then dissolved in DCM (50 mL) and the solution was added
dropwise to the olefin solutions under stirring at r.t. The reaction
mixtures were left to react for 24 h. After this period of time, the mix-
tures were washed with H2O (2 × 30 mL) and the organic phases were
dried (anhyd Na2SO4). The residues obtained after the solvent evapo-
ration were submitted to chromatographic separation for isolation
and purification of the products.
IR (Nujol): 3179 (O–H), 1627 (C=O) cm–1
.
1H NMR (DMSO-d6, 300 MHz):  = 9.39 (s, 1 H, OH), 6.02 and 5.56 (m,
1 H + 1 H, CH=CH), 5.40 (m, 1 H, CHN), 4.85 (m, 1 H, CHO), 4.20 and
3.85 (m, 2 H, CH2O), 2.5–1.7 (m, 4 H, CH2), 1.37 (s, 3 H, CH3), 1.31 (s, 3
H, CH3).
13C NMR (DMSO-d6, 300 MHz):  = 170.1 (C=O), 135.4, [135.2], 129.1,
[128.8] (CH=CH), 109.6, [109.5] (OCO), 73.0, [72.9], 66.8, [66.7],
(CH2O), 61.6 (CHN), 31.3, 25.9, 25.8, 25.6 (CH2, CH3).
Anal. Calcd for C11H17NO4 (227.26): C, 58.14; H, 7.54; N, 6.16. Found:
C, 58.15; H, 7.51; N, 6.16.
(R)-N-(2,3-Dimethylbut-3-en-2-yl)-N-hydroxy-2,2-dimethyl-1,3-
dioxolane-4-carboxamide (16a)
(4R)-N-(Cyclohex-2-en-1-yl)-N-hydroxy-2,2-dimethyl-1,3-dioxol-
ane-4-carboxamide (16d), 1st Diastereoisomer
Yield: 1.68 g (69%); white crystals (benzene/PE); mp 179–180 °C.
Yield: 1.45 g (60%); white crystals (benzene/PE); mp 99–100 °C.
IR (Nujol): 3092, 1641 (C=O) cm–1
.
IR (Nujol): 3059 (O–H), 1642 (C=O) cm–1
.
1H NMR (DMSO-d6, 300 MHz):  = 9.55 (s, 1 H, OH), 4.83 (dd, J = 7, 6
Hz, 1 H, CHO), 4.76 and 4.68 (s + t, J = 1 Hz, 1 H + 1 H, =CH2), 4.21 and
3.82 (dd, J = 9, 7 Hz, 1 H + 1 H, CH2O), 1.66 (s, 3 H, CH3), 1.38 (s, 3 H,
CH3), 1.36 (s, 3 H, CH3), 1.33 (s, 3 H, CH3), 1.30 (s, 3 H, CH3).
1H NMR (DMSO-d6, 300 MHz):  = 9.47 (s, 1 H, OH), 5.87 and 5.46 (m,
1 H + 1 H, CH=CH), 4.88 (dd, J = 8, 6 Hz, 1 H, CHO), 4.84 (m, 1 H, CHN),
4.21 and 3.88 (m, 2 H, CH2O), 2.1–1.5 (m, 6 H, CH2), 1.37 (s, 3 H, CH3),
1.31 (s, 3 H, CH3).
13C NMR (DMSO-d6, 300 MHz):  = 170.5 (C=O), 149.3 (C=), 109.4
(CH2=), 108.3 (OCO), 73.8, 64.8 (CHO, CHN), 66.7 (CH2O), 25.7, 25.6,
25.1, 24.7, 19.0 (CH3).
13C NMR (DMSO-d6, 300 MHz):  = 170.4 (C=O), 130.8, 127.3 (CH=CH),
109.6 (OCO), 72.9 (CHO), 66.9 (CH2O), 51.9 (CHN), 25.8, 25.6, 25.1,
23.9, 20.6 (CH2 and CH3).
Anal. Calcd for C12H21NO4 (243.30): C, 59.24; H, 8.70; N, 5.76. Found:
C, 59.25; H, 8.70; N, 5.74.
Anal. Calcd for C12H19NO4 (241.29): C, 59.73; H, 7.94; N, 5.81. Found:
C, 59.75; H, 7.93; N, 5.82.
(4R)-N-Hydroxy-2,2-dimethyl-N-(3-methylbut-3-en-2-yl)-1,3-di-
oxolane-4-carboxamide (16b), 1st Diastereoisomer
(4R)-N-(Cyclohex-2-en-1-yl)-N-hydroxy-2,2-dimethyl-1,3-dioxol-
ane-4-carboxamide (16d), 2nd Diastereoisomer
Yield: 1.56 g (68%); white crystals (benzene/PE); mp 90–91 °C.
Yield: 1.45 g (60%); white crystals (benzene/PE); mp 114–115 °C.
IR (Nujol): 3092 (O–H), 1640 (C=O) cm–1
.
IR (Nujol): 3179 (O–H), 1628 (C=O) cm–1
.
1H NMR (DMSO-d6, 300 MHz):  = 9.35 (s, 1 H, OH), 4.87 and 4.92 (s,
1 H + 1 H, =CH2), 4.91 (m, 1 H, CHO), 4.82 (q, J = 7 Hz, 1 H, CHN), 4.21
and 3.86 (dd, J = 8, 6 Hz, 2 H, CH2O), 1.67 (s, 3 H, CH3), 1.37 (s, 3 H,
CH3), 1.32 (s, 3 H, CH3), 1.21 (d, J = 7 Hz, 3 H, CH3).
1H NMR (DMSO-d6, 300 MHz):  = 9.46 (s, 1 H, OH), 5.87 and 5.49 (m,
1 H + 1 H, CH=CH), 4.88 (dd, J = 8, 6 Hz, 1 H, CHO), 4.85 (m, 1 H, CHN),
4.21 and 3.84 (m, 2 H, CH2O), 2.0–1.5 (m, 6 H, CH2), 1.37 (s, 3 H, CH3),
1.32 (s, 3 H, CH3).
13C NMR (DMSO-d6, 300 MHz):  = 170.4 (C=O), 143.7 (C=), 112.2
(=CH2), 109.6 (OCO), 72.8 (CHO), 66.7 (CH2O), 54.5 (CHN), 25.8, 25.6,
20.5, 14.8 (CH3).
13C NMR (DMSO-d6, 300 MHz):  = 170.5 (C=O), 131.0, 126.9 (CH=CH),
109.6 (OCO), 72.9 (CHO), 66.8 (CH2O), 52.0 (CHN), 25.8, 25.6, 25.2,
23.9, 20.6 (CH2 and CH3).
Anal. Calcd for C11H19NO4 (229.28): C, 57.63; H, 8.35; N, 6.11. Found:
C, 57.64; H, 8.34; N, 6.10.
Anal. Calcd for C12H19NO4 (241.29): C, 59.73; H, 7.94; N, 5.81. Found:
C, 59.72; H, 7.94; N, 5.80.
(4R)-N-Hydroxy-2,2-dimethyl-N-(3-methylbut-3-en-2-yl)-1,3-di-
oxolane-4-carboxamide (16b), 2nd Diastereoisomer
(R)-N-Hydroxy-2,2-dimethyl-N-(2-phenylallyl)-1,3-dioxolane-4-
carboxamide (16e)
Yield: 1.56 g (68%); white crystals (benzene/PE); mp 111–112 °C.
Yield: 1.61 g (58%); white crystals (benzene/PE); mp 94–95 °C.
IR (Nujol): 3095 (O–H), 1644 (C=O) cm–1
.
IR (Nujol): 3200 (O–H), 1650 (C=O) cm–1
.
1H NMR (DMSO-d6, 300 MHz):  = 9.46 (s, 1 H, OH), 4.90 and 4.86 (s, 1
H + 1 H, =CH2), 4.85 (m, 1 H + 1 H, CHN, CHO), 4.24 (t, J = 7 Hz, 1 H,
CHO), 3.85 (dd, J =7 Hz, 1 H, CH2O), 1.64 (s, 3 H, CH3), 1.36 (s, 3 H,
CH3), 1.32 (s, 3 H, CH3), 1.22 (d, J = 7 Hz, 3 H, CH3).
1H NMR (DMSO-d6, 300 MHz):  = 9.80 (s, 1 H, OH), 7.48 (m, 2 Harom),
7.30 (m, 3 Harom), 5.59 and 5.23 (s, 1 H + 1 H, =CH2), 4.88 (dd, J = 8, 6
Hz, 1 H, CHO), 4.56 (AB syst, 2 H, CH2N), 4.15 and 3.69 (m, 2 H, CH2O),
1.35 (s, 3 H, CH3), 1.31 (s, 3 H, CH3).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–M

J
M. Corti et al.
Paper
Synthesis
13C NMR (DMSO-d6, 300 MHz):  = 170.0 (C=O), 141.7 (C=), 137.8,
128.3, 127.8, 125.8 (arom), 115.1 (=CH2), 109.7 (OCO), 72.7 (CHO),
66.6 (CH2O), 51.2 (CH2N), 25.7, 25.6 (CH3).
1H NMR (DMSO-d6, 300 MHz):  = 9.40 (br s, 1 H, OH), 4.92 (s, 2 H,
=CH2), 4.88 (m, 1 H + 1 H, CHO, CHN), 4.23 (t, J = 8 Hz, 1 H, CHO), 3.83
(m, 1 H, CHO), 1.95 (m, 2 H, CH2), 1.36 (s, 3 H, CH3), 1.32 (s, 3 H, CH3),
1.23 (d, J = 6 Hz, 3 H, CH3), 0.97 (t, J = 7 Hz, 3 H, CH3).
13C NMR (DMSO-d6, 300 MHz):  = 169.7 (C=O), 149.4 (C=), 109.9
(=CH2), 109.6 (OCO), 72.9 (CHO), 66.8 (CH2O), 53.0 (CHN), 26.1, 25.7,
25.6, 15.0, 12.0 (CH2 and CH3).
Anal. Calcd for C15H19NO4 (277.32): C, 64.97; H, 6.91; N, 5.05. Found:
C, 64.99; H, 6.90; N, 5.01.
(4R)-N-Hydroxy-2,2-dimethyl-N-[(E)-3-methylpent-3-en-2-yl]-
1,3-dioxolane-4-carboxamide (16f), 1st Diastereoisomer
Anal. Calcd for C12H21NO4 (243.30): C, 59.24; H, 8.70; N, 5.76. Found:
C, 59.24; H, 8.72; N, 5.74.
Yield: 1.73 g (71%); white crystals (benzene/PE); mp 91–92 °C.
IR (Nujol): 3095 (O–H), 1642 (C=O) cm–1
.
HDA Cycloaddition Reactions of (3aR,5S,6R,6aR)-6-(Benzyloxy)-N-
hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carbi-
midoyl Chloride (22) with Cyclopentadiene and 1,3-Cyclohexadi-
ene; General Procedure
1H NMR (DMSO-d6, 300 MHz):  = 9.25 (s, 1 H, OH), 5.39 (q, J = 3 Hz,
1 H, C=CH), 4.89 (t, J = 3 Hz, 1 H, CHO), 4.79 (m, H, CHN), 4.20 (t, J = 7
Hz, 1 H, CHO), 3.85 (m, 1 H, CHO), 1.58 (d, J = 7 Hz, 3 H, CH3), 1.55 (s, 3
H, CH3), 1.37 (s, 3 H, CH3), 1.31 (s, 3 H, CH3), 1.18 (d, J = 7 Hz, 3 H, CH3).
A DCM solution (80 mL) of 22 (3.28 g, 10 mmol, 1 equiv) was added to
a DCM solution (150 mL) of NMO (1.41 g, 12 mmol, 1.2 equiv) along
with Et3N (1.11 g, 11 mmol, 1.1 equiv) in the presence of the selected
diene (15 mmol, 1.5 equiv). The reaction mixtures were left at r.t. for
24 h and subsequently washed with H2O (2 × 50 mL). The dried or-
ganic phases were then evaporated to dryness to leave the crude
products that were purified by column chromatography to afford the
desired cycloadducts 23a,b and 24a,b.
13C NMR (DMSO-d6, 300 MHz):  = 170.1 (C=O), 134.1 (C=), 120.0
(=CH), 109.6 (OCO), 72.8 (CHO), 66.7 (CH2O), 55.7 (CHN), 25.8, 25.6,
14.7, 14.1, 13.2 (CH3).
Anal. Calcd for C12H21NO4 (243.30): C, 59.24; H, 8.70; N, 5.76. Found:
C, 59.26; H, 8.70; N, 5.73.
(4R)-N-Hydroxy-2,2-dimethyl-N-[(E)-3-methylpent-3-en-2-yl]-
1,3-dioxolane-4-carboxamide (16f), 2nd Diastereoisomer
(3aR,5S,6R,6aR)-6-(Benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-
d][1,3]dioxol-5-yl-2-oxa-3-azabicyclo[2.2.1]hept-5-en-3-ylmetha-
none (23a,b)
Yield: 1.73 g (71%); white crystals (benzene/PE); mp 82–83 °C.
IR (Nujol): 3100 (O–H), 1647 (C=O) cm–1
.
1H NMR (DMSO-d6, 300 MHz):  = 9.33 (s, 1 H, OH), 5.36 (q, J = 3 Hz,
1 H, C=CH), 4.88 (dd, J = 8, 6 Hz, 1 H, CHO), 4.80 (m, 1 H, CHN), 4.23
(dd, J = 9, 7 Hz, 1 H, CHO), 3.83 (dd, J = 8, 7 Hz, 1 H, CHO), 1.58 (d, J = 7
Hz, 3 H, CH3), 1.51 (s, 3 H , CH3), 1.36 (s, 3 H, CH3), 1.32 (s, 3 H, CH3),
1.19 (d, J = 7 Hz, 3 H, CH3).
13C NMR (DMSO-d6, 300 MHz):  = 169.6 (C=O), 134.4 (C=), 119.9
(=CH), 109.6 (OCO), 72.9 (CHO), 66.8 (CH2O), 55.4 (CHN), 25.7, 25.6,
14.8, 14.0, 13.2 (CH3).
Yield: 3.44 g (92%); white crystals (benzene/PE); mp 143–144 °C.
IR (Nujol): 1692 (C=O) cm–1
.
1H NMR (DMSO-d6, 300 MHz):  = 7.30 (m, 5 Harom), 6.59 and 6.42 (br
s, 1 H + 1 H, CH=CH), 5.59 (br s, 1 H, OCHO), 5.49 (br s, 1 H, CHO), 5.32
(br s, 1 H, CHN), 4.78 (d, J = 2 Hz, 1 H, CHO), 4.70 and 4.50 (AB syst, 1 H
+ 1 H, CH2Ph), 4.50 (1 H, CHO), 4.29 (d, J = 2 Hz, 1 H, CHO), 1.75 (br, 2
H, CH2), 1.40 (s, 3 H, CH3), 1.25 (s, 3 H, CH3).
13C NMR (CDCl3, 300 MHz):  = 169.7 [164.9] (C=O), 137.1, 135.9,
132.4, 128.4, 128.3, 128.2, 128.0, 127.8, 127.7, 127.5, 127.4 (arom),
112.4, 112.2, 105.7, 105.5 (CH=CH), 105.3 (OCO), 82.7, 82.5, 82.0, 80.3,
75.1, 72.1 (CHO, CHN), 48.3, (CH2), 26.8, 26.2 (CH3).
Anal. Calcd for C12H21NO4 (243.30): C, 59.24; H, 8.70; N, 5.76. Found:
C, 59.23; H, 8.71; N, 5.77.
(4R)-N-Hydroxy-2,2-dimethyl-N-(3-methylenepentan-2-yl)-1,3-
Anal. Calcd for C20H23NO6 (373.41): C, 64.33; H, 6.21; N, 3.75. Found:
C, 64.35; H, 6.20; N, 3.74.
dioxolane-4-carboxamide (16g), 1st Diastereoisomer
Yield: 1.56 g (64%); white crystals (benzene/PE); mp 116–117 °C.
IR (Nujol): 3098 (O–H), 1646 (C=O) cm–1
.
(3aR,5S,6R,6aR)-6-(Benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-
d][1,3]dioxol-5-yl-2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-ylmetha-
none (24a,b)
1H NMR (DMSO-d6, 300 MHz):  = 9.33 (s, 1 H, OH), 4.93 (s, 2 H, =CH2),
4.89 (m, 1 H + 1 H, CHO, CHN), 4.21 (t, J = 8 Hz, 1 H, CHO), 3.86 (m, 1
H, CHO), 1.99 (m, 2 H, CH2), 1.37 (s, 3 H, CH3), 1.31 (s, 3 H, CH3), 1.21
(d, J = 6 Hz, 3 H, CH3), 0.98 (t, J = 7 Hz, 3 H, CH3).
13C NMR (DMSO-d6, 300 MHz):  = 170.3 (C=O), 149.0 (C=), 110.2
(=CH2), 109.6 (OCO), 72.8 (CHO), 66.7 (CH2O), 53.1 (CHN), 26.2, 25.8,
25.6, 14.9, 12.0 (CH2 and CH3).
Yield: 3.84 g (quant.); yellowish oil.
IR (Nujol): 1670 (C=O) cm–1
.
1H NMR (CDCl3, 300 MHz):  = 7.30 (m, 5 Harom), 6.62 and 6.50 (m, 1 H
+ 1 H, CH=CH), 6.09 (d, J = 2 Hz, 1 H, OCHO), 5.34 (br s, 1 H, CHO), 4.80
(d, J = 2 Hz, 1 H, CHO), 4.74 (br s, 1 H, CHN), 4.62 (d, J = 2 Hz, 1 H,
CHO), 4.72 and 4.55 (AB syst, 1 H + 1 H, CH2Ph), 4.36 (d, J = 2 Hz, 1 H,
CHO), 2.19 and 2.00 (m, 2 H + 2 H, CH2CH2), 1.46 (s, 3 H, CH3), 1.32 (s,
3 H, CH3).
13C NMR (CDCl3, 300 MHz):  = 171.0 (C=O), 137.1, 135.9, 132.4,
128.4, 128.3, 128.2, 128.0, 127.8, 127.7, 127.5, 127.4 (arom), 112.4,
112.2, 105.7, 105.5 (CH=CH), 105.3 (OCO), 82.7, 82.5, 82.0, 80.3, 75.1,
72.1 (CHO, CHN), 48.3, 28.8 (CH2), 26.3, 26.2 (CH3).
Anal. Calcd for C12H21NO4 (243.30): C, 59.24; H, 8.70; N, 5.76. Found:
C, 59.25; H, 8.71; N, 5.73.
(4R)-N-Hydroxy-2,2-dimethyl-N-(3-methylenepentan-2-yl)-1,3-
dioxolane-4-carboxamide (16g), 2nd Diastereoisomer
Yield: 1.56 g (64%); white crystals (benzene/PE); mp 121–122 °C.
IR (Nujol): 3097 (O–H), 1645 (C=O) cm–1
.
Anal. Calcd for C21H25NO6 (387.43): C, 65.10; H, 6.50; N, 3.62. Found:
C, 65.11; H, 6.49; N, 3.64.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–M

K
M. Corti et al.
Paper
Synthesis
Ene Reactions of (3aR,5S,6R,6aR)-6-(Benzyloxy)-N-hydroxy-2,2-di-
methyltetrahydrofuro[2,3-d][1,3]dioxole-5-carbimidoyl Chloride
(22) with Olefins a–g; General Procedure
2 H, PhCH2), 4.41 (d, J = 4 Hz, 1 H, CHO), 1.59 (s, 3 H, CH3), 1.42 (s, 3 H,
CH3), 1.28 (s, 3 H, CH3), 1.21 (d, J = 7 Hz, 3 H, CH3).
13C NMR (DMSO-d6, 300 MHz):  = 166.0 (C=O), 143.9 (=C), 137.7,
128.1, 127.6, 127.4 (arom), 112.2 (=CH2), 110.8 (OCO), 104.1 (CHO),
82.5, 81.4, 78.3, 70.8 (CHO, CH2Ph), 54.2 (CHN), 26.8, 26.2, 20.6, 14.7
(CH3).
To a DCM solution (150 mL) of the corresponding olefin a–g (15
mmol, 15 equiv) were added NMO (1.41 g, 12 mmol, 1.2 equiv) and
distilled Et3N (1.11 g, 11 mmol, 1.1 equiv). (3aR,5S,6R,6aR)-6-(Benzyl-
oxy)-N-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-
carbimidoyl chloride (22; 3.28 g, 10 mmol, 1 equiv) was then dis-
solved in DCM (80 mL) and the solution was added dropwise to the
olefin solution under stirring at r.t. The reaction mixtures were left to
react for 24 h. After this period of time, the mixtures were washed
with H2O (2 × 50 mL) and the organic phases were dried (anhyd Na2-
SO4). The residues obtained after the solvent evaporation were sub-
mitted to chromatographic separation for isolation and purification of
the products.
Anal. Calcd for C20H27NO6 (377.44): C, 63.65; H, 7.21; N, 3.71. Found:
C, 63.67; H, 7.20; N, 3.70.
(3aR,5S,6R,6aR)-6-(Benzyloxy)-N-(cyclohex-2-en-1-yl)-N-hydroxy-
2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxamide
(25d), Mixture of Diastereoisomers
Yield: 1.29 g (33%); white crystals (benzene/PE); mp 192–194 °C.
IR (Nujol): 3158 (O–H), 1639 (C=O) cm–1
.
1H NMR (DMSO-d6, 300 MHz):  = 9.51 [9.46] (s, 1 H, OH), 7.32 (m, 5
Harom), 5.98 (d, J = 4 Hz, 1 H, OCHCO), 5.91 and 5.49 (m, 1 H + 1 H,
CH=CH), 5.02 (d, J = 4 Hz, 1 H, CHO), 4.87 (m, 1 H, CHN), 4.71 (d, J =
4 Hz, 1 H, CHO), 4.54 (AB syst, 2 H, PhCH2), 4.38 (d, J = 4 Hz, 1 H, CHO),
2.00–1.50 (m, 6 H, CH2), 1.41 (s, 3 H, CH3), 1.28 (s, 3 H, CH3).
(3aR,5S,6R,6aR)-6-(Benzyloxy)-N-(2,3-dimethylbut-3-en-2-yl)-N-
hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-car-
boxamide (25a)
Yield: 1.37 g (35%); white crystals (benzene/PE); mp 184–185 °C.
IR (Nujol): 3140 (O–H), 1631 (C=O) cm–1
.
13C NMR (DMSO-d6, 300 MHz):  = 166.8, [166.7] (C=O), 137.8,
[137.7], 131.2, [130.6], 128.1, 127.6, 127.5, 127.4, 126.9, 126.8 (arom),
110.9 (CH=CH), 104.3 (OCO), 82.6, [82.5] (CHN), 81.9, [81.7], 78.7,
[78.6], 71.2 (CHO), 51.7 (CH2), 26.8, 26.2, 25.3, [25.1], 23.9, 20.7, [20.5]
(CH3).
1H NMR (DMSO-d6, 300 MHz):  = 9.55 (s, 1 H, OH), 7.31 (m, 5 Harom),
5.93 (d, J = 4 Hz, 1 H, OCHO), 4.96 (d, J = 4 Hz, 1 H, CHO), 4.74 and 4.73
(s, 1 H + 1 H, =CH2), 4.63 (t, J = 4 Hz, 1 H, CHO), 4.61 and 4.49 (AB syst,
2 H, CH2Ph), 4.38 (t, J = 4 Hz, 1 H, CHO), 1.64 (s, 3 H, CH3), 1.41 (s, 3 H,
CH3), 1.38 (s, 3 H, CH3), 1.36 (s, 3 H, CH3), 1.27 (s, 6 H, CH3).
13C NMR (DMSO-d6, 300 MHz):  = 166.8 (C=O), 149.4 (C=), 137.7,
128.0, 127.8, 127.5 (arom), 110.7 (CH2=), 108.2 (OCO), 104.1, 82.7,
81.5, 79.1, 71.0 (CHO), 64.9 (CH2O), 26.7, 26.2, 25.1, 24.6, 19.2 (CH3).
Anal. Calcd for C22H27NO6 (389.45): C, 64.77; H, 6.99; N, 3.60. Found:
C, 64.75; H, 7.01; N, 3.60.
(3aR,5S,6R,6aR)-6-(Benzyloxy)-N-hydroxy-2,2-dimethyl-N-(2-phe-
nylallyl)tetrahydrofuro[2,3-d][1,3]dioxole-5-carboxamide (25e)
Anal. Calcd for C21H29NO6 (391.46): C, 64.43; H, 7.47; N, 3.58. Found:
C, 64.45; H, 7.46; N, 3.54.
Yield: 1.71 g (44%); white crystals (benzene/PE); mp 195–196 °C.
IR (Nujol): 3152 (O–H), 1624 (C=O) cm–1
.
1H NMR (DMSO-d6, 300 MHz):  = 9.86 (s, 1 H, OH), 7.53 (d, J = 7 Hz,
2 Harom) 7.30 (m, 8 Harom), 5.98 (d, J = 4 Hz, 1 H, OCHCO), 5.61 and 5.29
(s, 1 H + 1 H, =CH2), 5.06 (d, J = 4 Hz, 1 H, CHOBn), 4.73 (d, J = 4 Hz, 1 H,
CHO), 4.65 (AB syst, 2 H, CH2N), 4.50 (AB syst, 2 H, PhCH2), 4.38 (d, J =
4 Hz, 1 H, CHO), 1.40 (s, 3 H, CH3), 1.27 (s, 3 H, CH3).
(3aR,5S,6R,6aR)-6-(Benzyloxy)-N-hydroxy-2,2-dimethyl-N-(3-
methylbut-3-en-2-yl)tetrahydrofuro[2,3-d][1,3]dioxole-5-carbox-
amide (25b), 1st Diastereoisomer
Yield: 2.04 g (54%); white crystals (benzene/PE); mp 175–177 °C.
IR (Nujol): 3110 (O–H), 1619 (C=O) cm–1
.
13C NMR (DMSO-d6, 300 MHz):  = 167.0 (C=O), 141.0 (=C), 137.9,
137.7, 128.4, 128.1, 127.8, 127.6, 127.5, 125.7 (arom), 115.3 (=CH2),
110.9 (OCO), 104.3 (CHO), 82.4, 81.8, 78.4, 71.0 (CHO, CH2Ph), 51.5
(CHN), 26.7, 26.2 (CH3).
1H NMR (DMSO-d6, 300 MHz):  = 9.33 (s, 1 H, OH), 7.31 (m, 5 Harom),
5.98 (d, J = 4 Hz, 1 H, OCHCO), 5.07 (d, J = 4 Hz, 1 H, CHO), 4.94 and
4.91 (s, 1 H + 1 H, =CH2), 4.86 (q, J = 7 Hz, 1 H, CHN), 4.74 (d, J = 4 Hz, 1
H, CHO), 4.54 (AB syst, 2 H, PhCH2), 4.41 (d, J = 4 Hz, 1 H, CHO), 1.70 (s,
3 H, CH3), 1.42 (s, 3 H, CH3), 1.28 (s, 3 H, CH3), 1.17 (d, J = 7 Hz, 3 H,
CH3).
Anal. Calcd for C22H27NO6 (389.45): C, 64.77; H, 6.99; N, 3.60. Found:
C, 64.75; H, 7.01; N, 3.60.
13C NMR (DMSO-d6, 300 MHz):  = 166.9 (C=O), 143.7 (=C), 137.8,
128.1, 127.5 (arom), 112.4 (=CH2), 110.9 (OCO), 104.3 (CHO), 82.6,
81.7, 78.6, 71.1 (CHO, CH2Ph), 54.3 (CHN), 26.8, 26.2, 20.7, 14.5 (CH3).
(3aR,5S,6R,6aR)-6-(Benzyloxy)-N-hydroxy-2,2-dimethyl-N-[(E)-3-
methylpent-3-en-2-yl]tetrahydrofuro[2,3-d][1,3]dioxole-5-car-
boxamide (25f), Mixture of Diastereoisomers
Anal. Calcd for C20H27NO6 (377.44): C, 63.65; H, 7.21; N, 3.71. Found:
C, 63.65; H, 7.23; N, 3.69.
Yield: 1.17 g (30%); white crystals (benzene/PE); mp 180–182 °C.
IR (Nujol): 3149 (O–H), 1626 (C=O) cm–1
.
1H NMR (DMSO-d6, 300 MHz):  = 9.34 [9.36] (s, 1 H, OH), 7.30 (m, 5
Harom), 5.96 [5.95] (d, J = 4 Hz, 1 H, OCHO), 5.01 (d, J = 4 Hz, 1 H, CHO),
4.94 and 4.87 (s, 1 H + 1 H, =CH2), 4.94 (1 H, CHN), 4.77 (d, J = 4 Hz,
1 H, CHO), 4.52 (AB syst, 2 H, PhCH2), 4.38 (d, J = 4 Hz, 1 H, CHO), 1.90
(m, 2 H, CH2), 1.48 [1.41] (s, 3 H, CH3), 1.28 [1.25] (s, 3 H, CH3), 1.22
[1.20] (d, J = 7 Hz, 3 H, CH3), 0.76 [0.75] (t, J = 7 Hz, 3 H, CH3).
13C NMR (DMSO-d6, 300 MHz):  = 165.7 [164.6] (C=O), 148.5 (=C),
133.8, 129.2, 128.9, 128.8, 128.1, 127.6 (arom), 111.3 [110.5] (=CH),
104.3 (OC), 82.7, 77.2, 77.0 (CHO, CH2Ph), 53.0 (CHN), 26.6, 26.3, 26.2,
14.4, 11.9 (CH3).
(3aR,5S,6R,6aR)-6-(Benzyloxy)-N-hydroxy-2,2-dimethyl-N-(3-
methylbut-3-en-2-yl)tetrahydrofuro[2,3-d][1,3]dioxole-5-carbox-
amide (25b), 2nd Diastereoisomer
Yield: 2.04 g (54%); white crystals (benzene/PE); mp 178–180 °C.
IR (Nujol): 3158 (O–H), 1634 (C=O) cm–1
.
1H NMR (DMSO-d6, 300 MHz):  = 9.42 (s, 1 H, OH), 7.30 (m, 5 Harom),
5.96 (d, J = 4 Hz, 1 H, OCHO), 5.07 (d, J = 4 Hz, 1 H, CHO), 4.85 (m, 1 H
+ 1 H + 1 H, =CH2 and CHN), 4.74 (d, J = 4 Hz, 1 H, CHO), 4.54 (AB syst,
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–M

L
M. Corti et al.
Paper
Synthesis
Anal. Calcd for C21H29NO6 (391.46): C, 64.43; H, 7.47; N, 3.58. Found:
C, 64.45; H, 7.50; N, 3.58.
(3aR,5S,6R,6aR)-5-[Hydroxy(3-methylbut-3-en-2-yl)carbamoyl]-
2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl Benzoate
(26b), Mixture of Diastereoisomers
(3aR,5S,6R,6aR)-6-(Benzyloxy)-N-hydroxy-2,2-dimethyl-N-(3-
methylenepentan-2-yl)tetrahydrofuro[2,3-d][1,3]dioxole-5-car-
boxamide (25g), 1st Diastereoisomer
Yield: 0.70 g (18%); white crystals (benzene/PE); mp 200 °C (dec.).
IR (Nujol): 3170 (O–H), 1731 (C=O, ester), 1635 (C=O) cm–1
1H NMR (DMSO-d6, 300 MHz):  = 9.49 [9.33] (s, 1 H, OH), 7.90 (m, 2
arom), 7.68 (m, 1 Harom), 7.54 (m, 2 Harom), 6.08 (d, J = 4 Hz, 1 H, OCHO),
.
Yield: 1.80 g (46%); white crystals (benzene/PE); mp 178–179 °C.
H
IR (Nujol): 3134 (O–H), 1640 (C=O) cm–1
.
5.58 (d, J = 4 Hz, 1 H, CHO), 5.24 (d, J = 4 Hz, 1 H, CHO), 4.93 and 4.85
(s, 1 H + 1 H, =CH2), 4.83 (q, J = 3 Hz, 1 H, CHN), 4.77 (d, J = 4 Hz, 1 H,
CHO), 1.69 (s, 3 H, CH3), 1.48 (s, 3 H, CH3), 1.40 (s, 3 H, CH3), 0.93 (s, 3
H, CH3).
13C NMR (DMSO-d6, 300 MHz):  = 165.8, [164.6] (C=O), [143.6] 143.2
(C=), 137.7, 133.8, 129.2, 128.9, 128.8, 128.1, 127.5 (arom), 112.6,
[111.4] (CH=CH), 104.3 (OCO), 82.7, [81.6], [78.5], 77.2, 77.0, [71.1]
(CHO), 54.4, [54.3] (CHN), [26.8], 26.6, 26.1, 20.7, [14.5], 14.3 (CH3).
1H NMR (DMSO-d6, 300 MHz):  = 9.27 (s, 1 H, OH), 7.32 (m, 5 Harom),
5.98 (d, J = 4 Hz, 1 H, OCHCO), 5.05 (d, J = 4 Hz, 1 H, CHOBn), 4.95 (s, 2
H, =CH2), 4.92 (q, J = 7 Hz, 1 H, CHN), 4.74 (d, J = 4 Hz, 1 H, CHO), 4.55
(AB syst, 2 H, PhCH2), 4.39 (d, J = 4 Hz, 1 H, CHO), 1.99 (m, 2 H, CH2),
1.41 (s, 3 H, CH3), 1.28 (s, 3 H, CH3), 1.17 (d, J = 7 Hz, 3 H, CH3), 0.99 (t,
J = 7 Hz, 3 H, CH3).
13C NMR (DMSO-d6, 300 MHz):  = 166.8 (C=O), 149.0 (=C), 137.7,
128.1, 127.5 (arom), 110.8 (=CH2), 110.3 (OCO), 104.3 (CHO), 82.6,
81.7, 78.5, 71.1 (CHO, CH2Ph), 52.8 (CHN), 26.8, 26.3, 26.2, 14.6, 12.0
(CH2 and CH3).
Anal. Calcd for C20H25NO7 (391.42): C, 61.37; H, 6.44; N, 3.58. Found:
C, 61.35; H, 6.41; N, 3.58.
Anal. Calcd for C21H29NO6 (391.46): C, 64.43; H, 7.47; N, 3.58. Found:
C, 64.42; H, 7.49; N, 3.59.
(3aR,5S,6R,6aR)-5-[Cyclopent-2-en-1-yl(hydroxy)carbamoyl]-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl Benzoate (26c),
Mixture of Diastereoisomers
(3aR,5S,6R,6aR)-6-(Benzyloxy)-N-hydroxy-2,2-dimethyl-N-(3-
methylenepentan-2-yl)tetrahydrofuro[2,3-d][1,3]dioxole-5-car-
boxamide (25g), 2nd Diastereoisomer
Yield: 1.25 g (32%); white crystals (benzene/PE); mp 225 °C (dec.).
IR (Nujol: 3164 (O–H), 1725 (C=O, ester), 1635 (C=O) cm–1
.
1H NMR (DMSO-d6, 300 MHz):  = 9.57 [9.53] (s, 1 H, OH), 7.90 (m, 2
Harom), 7.69 (m, 1 Harom), 7.54 (m, 2 Harom), 6.09 (m, 1 H, OCHO), 5.99
and 5.83 (m, 1 H + 1 H, CH=CH), 5.53 (d, J = 4 Hz, 1 H, CHO), 5.19 (t, J =
4 Hz, 1 H, CHO), 5.39 (m, 1 H, CHN), 4.77 (t, J = 4 Hz, 1 H, CHO), 2.40–
1.60 (m, 4 H, CH2), 1.47 (s, 3 H, CH3), 1.28 (s, 3 H, CH3).
13C NMR (DMSO-d6, 300 MHz):  = 165.0, [164.2] (C=O), 133.9, 133.4,
128.9, 128.6, 128.4, 128.1, 127.6, 127.1 (arom), 111.0 (CH=CH), 104.0
(OCO), 82.2, 76.9, 76.8 (CHO), 61.0 (CH2O), 30.8, 26.2, 25.8, 24.9 (CH2
and CH3).
Yield: 1.80 g (46%); white crystals (benzene/PE); mp 185–186 °C.
IR (Nujol): 3176 (O–H), 1628 (C=O) cm–1
.
1H NMR (DMSO-d6, 300 MHz):  = 9.36 (s, 1 H, OH), 7.30 (m, 5 Harom),
5.95 (d, J = 4 Hz, 1 H, OCHO), 5.05 (d, J = 4 Hz, 1 H, CHO), 4.92 and 4.89
(s, 1 H + 1 H, =CH2), 4.95 (m, 1 H, CHN), 4.75 (d, J = 4 Hz, 1 H, CHO),
4.53 (AB syst, 2 H, PhCH2), 4.36 (d, J = 4 Hz, 1 H, CHO), 1.90 (m, 2 H,
CH2), 1.42 (s, 3 H, CH3), 1.28 (s, 3 H, CH3), 1.23 (d, J = 7 Hz, 3 H, CH3),
0.78 (t, J = 7 Hz, 3 H, CH3).
13C NMR (DMSO-d6, 300 MHz):  = 166.0 (C=O), 149.4 (=C), 137.7,
128.1, 128.0, 127.5, 127.4, 127.3 (arom), 110.8 (=CH2), 110.0 (OCO),
104.1 (CHO), 82.4, 81.4, 78.4, 70.7 (CHO, CH2Ph), 52.7 (CHN), 26.7,
26.1, 14.8, 11.8 (CH2 and CH3).
Anal. Calcd for C20H23NO7 (389.40): C, 61.69; H, 5.95; N, 3.60. Found:
C, 61.68; H, 5.93; N, 3.58.
(3aR,5S,6R,6aR)-5-{Hydroxy[(E)-3-methylpent-3-en-2-yl]carbam-
oyl}-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl Benzoate
(26f), Mixture of Diastereoisomers
Anal. Calcd for C21H29NO6 (391.46): C, 64.43; H, 7.47; N, 3.58. Found:
C, 64.42; H, 7.49; N, 3.59.
Yield: 0.73 g (18%); white crystals (benzene/PE); mp 209–210 °C.
(3aR,5S,6R,6aR)-5-[(2,3-Dimethylbut-3-en-2-yl)(hydroxy)carbam-
oyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl Benzoate
(26a)
IR (Nujol): 3086 (O–H), 1724 (C=O, ester), 1632 (C=O) cm–1
.
1H NMR (DMSO-d6, 300 MHz):  = 9.36 (s, 1 H, OH), 7.89 (m, 2 Harom),
7.68 (m, 1 Harom), 7.54 (m, 2 Harom), 6.07 (d, J = 4 Hz, 1 H, OCHO), 5.57
(d, J = 3 Hz, 1 H, CHO), 5.35 (q, J = 3 Hz, 1 H, =CH), 5.21 (d, J = 4 Hz, 1 H,
CHO), 4.80 (q, J = 6 Hz, 1 H, CHN), 4.75 (d, J = 4 Hz, 1 H, CHO), 1.58 (s, 3
H, CH3), 1.55 (s, 3 H, CH3), 1.48 (s, 3 H, CH3), 1.29 (s, 3 H, CH3), 0.90 (d,
J = 7 Hz, 3 H, CH3).
13C NMR (DMSO-d6, 300 MHz):  = 165.5, [164.6] (C=O), 133.8,
[133.7], 129.2, 128.9, 128.7, 128.1, 127.5 (arom), 120.4 (=CH), 111.3
(OCO), 104.3, 82.7, 77.2, 77.0 (CHO), 55.6 (CHN), 26.6, [26.2], 14.3,
[14.2], 13.2 (CH3).
Yield: 1.34 g (33%); white crystals (benzene/PE); mp 208–209 °C.
IR (Nujol): 3176 (O–H), 1721 (C=O, ester), 1638 (C=O) cm–1
.
1H NMR (DMSO-d6, 300 MHz):  = 9.71 (s, 1 H, OH), 7.89 (m, 2 Harom),
7.67 (m, 1 Harom), 7.53 (m, 2 Harom) 6.02 (d, J = 4 Hz, 1 H, OCHO), 5.58
(d, J = 3 Hz, 1 H, CHO), 5.15 (d, J = 4 Hz, 1 H, CHO), 4.71 (s, 2 H, =CH2),
4.58 (s, 1 H, CHO), 1.53 (s, 3 H, CH3), 1.47 (s, 3 H, CH3), 1.32 (s, 3 H,
CH3), 1.28 (s, 3 H, CH3), 1.24 (s, 3 H, CH3).
13C NMR (DMSO-d6, 300 MHz):  = 165.6, 164.6 (C=O), 148.9 (C=),
133.8, 129.4, 128.9, 128.6 (arom), 111.2 (CH2=), 108.5 (OCO), 104.1,
82.6, 77.5, 77.4, 65.0 (CHO, CN), 26.5, 26.1, 25.0, 24.4, 18.9 (CH3).
Anal. Calcd for C21H27NO7 (405.45): C, 62.21; H, 6.71; N, 3.45. Found:
C, 62.22; H, 6.73; N, 3.43.
Anal. Calcd for C21H27NO7 (405.45): C, 62.21; H, 6.71; N, 3.45. Found:
C, 62.22; H, 6.70; N, 3.44.
(3aR,5S,6R,6aR)-5-[Hydroxy(3-methylenepentan-2-yl)carbamoyl]-
2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl Benzoate (26g),
Mixture of Diastereoisomers
Yield: 0.69 g (17%); white crystals (benzene/PE); mp 196–197 °C.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–M

M
M. Corti et al.
Paper
Synthesis
IR (Nujol): 3116 (O–H), 1725 (C=O, ester), 1637 (C=O) cm–1
.
(6) Zhang, P.; Wei, C.; Wang, E.; Wanga, W.; Liu, M.; Yin, Q.; Chen,
H.; Wang, K.; Li, X.; Zhang, J. Carbohydr. Res. 2012, 351, 7.
(7) Tronchet, J. M. J.; Barbalat-Rey, F.; Le-Hong, N. M.; Burger, U.
Carbohydr. Res. 1973, 29, 297.
(8) Schmid, C. R.; Bryant, J. D.; Dowlatzedah, M.; Phillips, J. L.;
Prather, D. E.; Schantz, R. D.; Sear, N. L.; Vianco, C. S. J. Org.
Chem. 1991, 56, 4056.
(9) Liu, K. C.; Shelton, B. R.; Howe, R. K. J. Org. Chem. 1980, 45, 3916.
(10) Quadrelli, P.; Mella, M.; Gamba Invernizzi, A.; Caramella, P. Tet-
rahedron 1999, 55, 10497.
(11) Quadrelli, P.; Campari, G.; Mella, M.; Caramella, P. Tetrahedron
Lett. 2000, 41, 2019.
1H NMR (DMSO-d6, 300 MHz):  = 9.43 (s, 1 H, OH), 7.89 (m, 2 Harom),
7.67 (m, 1 Harom), 7.53 (m, 2 Harom), 6.06 (d, J = 4 Hz, 1 H, OCHO), 5.58
(d, J = 4 Hz, 1 H, CHO), 5.22 (d, J = 4 Hz, 1 H, CHO), 4.92 and 4.89 (s, 1 H
+ 1 H, =CH2), 4.94 (q, J = 8 Hz, 1 H, CHN), 4.75 (d, J = 4 Hz, 1 H, CHO),
1.99 (m, 2 H, CH2), 1.47 (s, 3 H, CH3), 1.29 (s, 3 H, CH3), 0.96 (m, 6 H,
CH3).
13C NMR (DMSO-d6, 300 MHz):  = 165.7, [164.6] (C=O), 148.5 (C=),
133.8, 129.2, 128.9, 128.1, 127.6 (arom), 111.4 (=CH2), 110.5 (OCO),
104.3, 82.7, 77.2, 77.0 (CHO), 53.0 (CHN), 26.6, 26.3, 26.2, 14.4, 11.9
(CH3).
Anal. Calcd for C21H27NO7 (405.45): C, 62.21; H, 6.71; N, 3.45. Found:
C, 62.20; H, 6.72; N, 3.45.
(12) Quadrelli, P.; Mella, M.; Caramella, P. Tetrahedron Lett. 1998, 39,
3233.
(13) Hameed, K. K.; Amin, A. A.; Hussain, F. H. S.; Memeo, M. G.;
Moiola, M.; Quadrelli, P. Synthesis 2019, 51, 1383.
(14) (a) Quadrelli, P.; Mella, M.; Piccanello, A.; Romano, S.;
Caramella, P. J. Org. Chem. 2007, 72, 1807. (b) Quadrelli, P.;
Romano, S.; Piccanello, A.; Caramella, P. J. Org. Chem. 2009, 74,
2301. For ‘cis effect’, see also: (c) Leach, A. G.; Houk, K. N. Chem.
Commun. 2002, 1243. (d) Clennan, E. L. Tetrahedron 2000, 56,
9151.
Funding Information
We thank ‘VIPCAT – Value Added Innovative Protocols for Catalytic
Transformations’ project (CUP: E46D17000110009) for valuable fi-
nancial support. We also thank for the financial support the project
‘Scent of Lombardy’ (CUP: E31B19000700007).()
(15) (a) Adam, W.; Krebs, O. Chem. Rev. 2003, 103, 4131. (b) Leach, A.
G.; Houk, K. N. Org. Biomol. Chem. 2003, 1, 1389. (c) Leach, A. G.;
Houk, K. N. J. Am. Chem. Soc. 2002, 124, 14821. (d) Orfanopoulos,
M.; Bellarmine Grdina, M. Sr.; Stephenson, L. M. J. Am. Chem.
Soc. 1979, 101, 275. (e) Lu, X. Org. Lett. 2004, 6, 2813.
(16) (a) Adam, W.; Krebs, O.; Orfanopoulos, M.; Stratakis, M.;
Vougioukalakis, G. C. J. Org. Chem. 2003, 68, 2420. (b) See also:
Adam, W.; Bottke, N.; Engels, B.; Krebs, O. J. Am. Chem. Soc.
2001, 123, 5542. (c) Singleton, D. A.; Hang, C. J. Am. Chem. Soc.
1999, 121, 11885. (d) Vougioukalakis, G. C.; Orfanopoulos, M.
Synlett 2005, 713.
Acknowledgment
University of Pavia is gratefully acknowledged for supporting the re-
search activities that allowed us to obtain the reported results.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707276. Su
p
p
ortingInformationS
u
p
p
ortingI
n
formatio
n
(17) Gramera, R. E.; Bruce, R. M.; Hirase, S.; Whistler, R. L. J. Org.
Chem. 1963, 28, 1401.
(18) Wolfrom, M. L.; Hanessian, S. J. Org. Chem. 1962, 27, 1800.
(19) Tronchet, J. M. J.; Martin, O.; Zumwald, J.-B.; Le-Hong, N.; Perret,
F. Helv. Chim. Acta 1975, 58, 1735.
(20) Quadrelli, P.; Mella, M.; Caramella, P. Tetrahedron Lett. 1999, 40,
797.
(21) Ma, D.; Xia, C.; Tian, H. Tetrahedron Lett. 1999, 40, 8915.
(22) Defoin, A.; Pires, J.; Tissot, I.; Tschamber, T.; Bur, D.; Zehnder,
M.; Streith, J. Tetrahedron: Asymmetry 1991, 2, 1209.
(23) Zhang, Q.; Cao, R.; Liu, A.; Lei, S.; Li, Y.; Yang, J.; Li, S.; Xiao, J.
Bioorg. Med. Chem. Lett. 2017, 27, 4061.
(24) Amdouni, H.; Robert, G.; Driowya, M.; Furstoss, N.; Métier, C.;
Dubois, A.; Dufies, M.; Zerhouni, M.; Orange, F.; Lacas-Gervais,
S.; Bougrin, K.; Martin, A. R.; Auberger, P.; Benhida, R. J. Med.
Chem. 2017, 60, 1523.
References
(1) (a) Memeo, M. G.; Quadrelli, P. Chem. Rev. 2017, 117, 2108.
(b) For a latest report on nitrosocarbonyl generation, see:
Uraoka, S.; Shinohara, I.; Shimizu, H.; Noguchi, K.; Yoshimura,
A.; Zhdankin, V. V.; Saito, A. Eur. J. Org. Chem. 2018, 6199.
(2) Cohen, A. D.; Zeng, B.-B.; King, S. B.; Toscano, J. P. J. Am. Chem.
Soc. 2003, 125, 1444.
(3) Quadrelli, P.; Moiola, M. In Modern Applications of Cycloaddition
Chemistry; Quadrelli, P., Ed.; Elsevier: Amsterdam, 2019, 1–83.
(4) Chiu, D.-C.; Lin, T.-C.; Huang, W.-I.; Cheng, T.-J.; Tsaic, K.-C.;
Fang, J.-M. Org. Biomol. Chem. 2017, 15, 9910.
(5) Haines, A. H.; Morley, C.; Murrer, B. A. J. Med. Chem. 1989, 32,
742.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–M