Regio- and stereochemical studies on the nitroso-diels-alder reaction with 1,2-disubstituted dienes

Article abstract of DOI:10.1002/chem.201302905

The regioselectivity of the nitroso-Diels-Alder reaction between unsymmetrical acyclic dienes and Boc-nitroso (Boc=tert-butoxycarbonyl) reagent or the Wightman chiral chloronitroso reagents has been studied. With the Boc-nitroso reagent, the selectivity is a consequence of steric effects at the C1-position in the diene and electronic effects at the C2-position in the diene. The combination of an unprotected hydroxyethyl side chain at C1 and an electron-withdrawing group at C2 allows complete regioselectivity in favour of the proximal isomer. The same isomer was obtained exclusively with the chiral nitroso reagent with high enantioselectivities. A model based on steric effects is proposed. Get selective! A combination of steric and electronic effects allows the design of 1,2-disubstituted dienes for highly regioselective nitroso-Diels-Alder reactions with either Boc-nitroso reagent or a chiral chloronitroso reagent. Enantiomerically enriched functionalized cycloadducts could be obtained by asymmetric and regioselective cycloadditions (see scheme; Boc=tert-butoxycarbonyl, TBS=tert-butyldimethylsilyl, Piv=pivaloyl). Copyright

Full text of DOI:10.1002/chem.201302905

DOI: 10.1002/chem.201302905
Regio- and Stereochemical Studies on the Nitroso-Diels–Alder Reaction
with 1,2-Disubstituted Dienes
Gilles Galvani,[a] Robert Lett,[a, b] and Cyrille Kouklovsky*[a]
Abstract: The regioselectivity of the ni-
troso-Diels–Alder reaction between
unsymmetrical acyclic dienes and Boc-
nitroso (Boc=tert-butoxycarbonyl) re-
agent or the Wightman chiral chloroni-
troso reagents has been studied. With
the Boc-nitroso reagent, the selectivity
is a consequence of steric effects at the
C1-position in the diene and electronic
effects at the C2-position in the diene.
The combination of an unprotected hy-
droxyethyl side chain at C1 and an
electron-withdrawing group at C2
allows complete regioselectivity in
favour of the proximal isomer. The
same isomer was obtained exclusively
with the chiral nitroso reagent with
Keywords: asymmetric synthesis ·
cycloadditions · enol phosphate · ni-
troso-Diels–Alder reaction · regio-
selective
high enantioselectivities.
A
model
based on steric effects is proposed.
Introduction
The asymmetric version of the nitroso-Diels–Alder reac-
tion has also been the subject of intense scrutiny, leading to
the design of several chiral reagents with high levels of ste-
reoinduction,[5–7] and culminating in the achievement of the
catalytic asymmetric nitroso-Diels–Alder reaction of 2-pyri-
dylnitroso derivatives by using a chiral copper(I) complex[8]
These recent results have played an important role in the re-
newed interest for this reaction and its synthetic applica-
tions.
As for many heterocycloadditions, the regioselectivity of
the nitroso-Diels–Alder reaction is an important feature,
which may limit its scope. Indeed, reactions with unsymmet-
rical dienes often result in low regioselectivity. Cycloaddi-
tion may lead to two regioisomers, the proximal isomer, in
which the main substituent is close to the oxygen atom in
the dihydrooxazine cycloadduct, and the distal isomer, in
which the main substituent is close to the nitrogen atom in
the cycloadduct. Figure 2 shows the regiochemical outcome
for 1- and 2-substituted dienes.
Heterocycloadditions have been recognized as valuable
tools for heterocycle synthesis as well as for the selective
functionalization of acyclic compounds.[1] Amongst these re-
actions, the nitroso-Diels–Alder reaction has been the sub-
ject of intense studies and has found many applications in
the synthesis of various natural products.[2] Since the intro-
duction of the first nitroso-Diels–Alder by Wichterle in
1947,[3] several nitroso reagents have been designed for the
reaction, the most important ones being arylnitroso, chloro-
nitroso and acylnitroso reagents, which possess different sta-
bilities and reactivities. Recently, we have also introduced
acetoxynitroso derivatives as stable and easy-to-handle
chloronitroso surrogates[4] (Figure 1).
The regioselectivity of the reaction has been studied by
several groups and is believed to be a consequence of both
steric and electronic effects. Nitroso reagents are dichotomic
dienophiles reacting either with the HOMO or LUMO orbi-
tals, which makes the rationale quite difficult. Kresze and
Figure 1. Nitroso-Diels–Alder reaction.
[a] Dr. G. Galvani, Dr. R. Lett, Prof. Dr. C. Kouklovsky
Institut de Chimie Molꢀculaire et des Matꢀriaux d’Orsay
Bꢁtiment 410, Universitꢀ de Paris-Sud
91405 Orsay (France)
Fax: (33)1-69-15-46-79
E-mail: cyrille.kouklovsky@u-psud.fr
[b] Dr. R. Lett
CNRS, 91405 Orsay (France)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302905.
Figure 2. Regiochemical outcome of the nitroso-Diels–Alder reaction.
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Table 1. Rationale for regioselectivity as proposed by Houk and co-
workers.
Wichterle have studied the cycloaddition between several
arylnitroso derivatives and isoprene and have compared the
stability of dipolar transition states: although phenylnitroso
reagents give predominantly the distal isomer, reversal of re-
gioselectivity is observed when an electron-withdrawing
group is attached to the aromatic ring.[9,10] Likewise, the
proximal isomer is predominantly obtained when a chloroni-
troso derivative is used with the same diene (Scheme 1).
Steric effects are believed to be responsible for such a selec-
tivity.[11]
Alkyl and acylnitroso
Diene[a] major
selectivity level major
regioisomer regioisomer
Acylnitroso
selectivity level
proximal
medium
proximal
high
proximal
proximal
high
proximal
distal
high
weak
medium
distal
medium
weak
distal
weak
distal
–
–
–
–
proximal
high
[a] EDG=electron-donating group, EWG=electron-withdrawing group.
1, in which the substituent onto the double bond would be
a ketone precursor (silyl enol ether, enol phosphate or bro-
mide; Figure 3). The intermediate 1 would be obtained from
a nitroso-Diels–Alder reaction between a 1,2-disubstituted
À
diene 2 and a chiral nitroso reagent R* N=O (acyl- or al-
kylnitroso).[15]
Scheme 1. Literature examples of regiochemical studies for the nitroso-
Diels–Alder reaction.
Acylnitroso reagents react with dienes bearing an elec-
tron-withdrawing group, such as a nitrile, to give the proxi-
mal isomer with high selectivity. Once again, steric effects
were involved to explain this outcome.[12] The same selectivi-
ty was observed with 2-substituted dienes, the proximal
isomer being obtained with electron-poor but also with
weakly electron-rich dienes.[13] These examples illustrate the
difficulty to rationalize the regioselectivity of the reaction
on the basis of electronic and orbital effects (Scheme 1).
Houk and co-workers proposed a general rationale for
the regioselectivity of the nitroso-Diels–Alder reaction be-
tween various nitroso derivatives and monosubstituted
dienes.[14] This rationale was based on DFT calculations and
was supported by experimental results. The regioselectivity
depends on the nature of the nitroso derivative and on the
nature and position of substituents onto the diene. The con-
figuration of the diene may also play a role in the selectivity.
As demonstrated by experimental results, acylnitroso deriva-
tives often show better regioselectivity than their alkyl or
aryl counterparts (Table 1).
Figure 3. Retrosynthetic scheme for intermediate 1.
According to Houkꢃs rules, the substituent on the terminal
carbon atom of the diene should favour the proximal isomer
(which corresponds to cycloadduct 1), whereas the internal
substituent should lead to the undesired distal isomer. How-
ever, Houkꢃs rules apply only to monosubstituted dienes
and it is not sure whether the substituent effects are additive
in disubstituted dienes. Moreover, the nature of the nitroso
reagent can also influence the regioselectivity of the reac-
tion. To the best of our knowledge, no systematic study con-
cerning the regioselectivity of nitroso-Diels–Alder reactions
with 1,2-disubstituted dienes has been reported in the litera-
ture.[16] In the present article, we wish to report our studies
concerning the regioselectivity of such a reaction, as well as
stereoselectivity studies with a chiral nitroso reagent.
Results and Discussion
As a part of an ongoing synthetic project within our labo-
ratory, we faced the necessity to prepare in a regio- and ste-
reoselective fashion the 5,6-disubstituted-3,4-dihydrooxazine
Our studies began with the influence of the hydroxyl-con-
taining side chain on the regioselectivity; unprotected dienic
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C. Kouklovsky et al.
Table 2. Regioselectivity of the nitroso-Diels–Alder reactions with 3,5-
hexadien-1-ol derivatives.
alcohols have already been used in the nitroso Diels–Alder,
albeit with moderate selectivities: indeed, Bols and co-work-
ers have reported that Boc-nitroso (Boc=tert-butoxycarbon-
yl) reagent 3 reacts with 2,4-pentadien-1-ol 4 to give a 2:1
ratio of regioisomers.[17] However, reaction between the
bulkier nitrosoamidine 7 and 3,5-hexadien-1-ol 8 resulted in
a good selectivity in favour of the proximal isomer[18] 10
(Scheme 2).
Entry
Diene
R
Yield
Ratio 13/14[a]
Major compound
1
2
3
8
11
12
H
Piv
TBS
74
96
90
10:1
1:1.5
1:2
13a
14b
14c
[a] Ratio determined by 1H NMR spectroscopic analysis of the crude
product.
deleterious to the regioselectivity, regardless of the electron-
ic properties of the protecting groups: both pivaloic ester 11
and silyl ether 12 induced low regioselectivity in favour of
the distal isomer.
The observed regioselectivities may be explained by
taking account of the following features: the possibility of
intermolecular hydrogen bonding between the oxygen atom
of the nitroso function and the free hydroxyl group, as well
as steric effects, as we have observed from molecular model-
ling of the transition states: it is known that the N-Boc ni-
troso reagent adopts a s-trans conformation in the Diels–
Alder transition state; this conformation induces repulsive
interactions between the tert-butyl group of the Boc sub-
stituent and the oxygen protecting group in the cycloaddi-
tion reactions with dienes 11 and 12. This hypothesis could
account for the observed regioselectivities (Figure 4).
Scheme 2. Regioselectivity of nitroso-Diels–Alder reactions with dienic
alcohols.
Apparently, the chain length of the diene substituent has
a strong influence on the regioselectivity of the reaction. To
verify this hypothesis, the alcohol 8 was prepared and pro-
tected as its pivaloate ester 11 or the known[19] silyl ether 12.
These three dienes were submitted to a nitroso-Diels–Alder
reaction with Boc-nitroso reagent 3 according to standard
procedures: in situ periodate oxidation of N-Boc hydroxyla-
mine in the presence of the diene gave the transient nitroso
reagent 3, which reacted with the diene to give the corre-
sponding cycloadduct as a mixture of proximal and distal
isomers 13a–c/14a–c, which could be easily assigned by
using standard NMR spectroscopic techniques (Scheme 3,
Table 2).
Figure 4. Steric effects in the cycloaddition reactions between Boc-nitroso
reagent 3 and dienes 11 and 12.
These results show the remarkable influence of the chain
length on the regioselectivity: in comparison with Bolsꢃ re-
sults, one carbon homologation onto the diene resulted in
a high selectivity in favour of the proximal isomer. This
result, in agreement with Bateyꢃs observations, shows that
the nature of the diene has more influence than the nature
of the nitroso substituent. Hydroxyl group protection was
These preliminary results confirmed the importance of
both the side-chain length and the hydroxyl protecting
group, and showed the pathway for the design of 1,2-disub-
stituted dienes. Thus, the a,b-unsaturated ketone 15[20] was
selected as a precursor to the target dienes (Scheme 4). Eno-
lization of 15 was troublesome, due to several side reactions,
such as polymerization and elimination leading to the triene
17.[21] Under optimized conditions (potassium hexamethyl
disilazide (KHMDS), dimethoxyethane (DME)/toluene,
À608C), a modest yield of the silyl enol ether 16a–b could
be obtained, in a 10:1 ratio of Z/E isomers[22] that could be
separated by chromatography.
The same strategy was applied for the synthesis of the
enol phosphate 20, an electron-poor analogue to the silyl
enol ether.[23,24] Deprotonation of ketone 15 and treatment
of the corresponding enolate with diethylchlorophosphate
gave 18 as a pure Z isomer. Here also prolonged reaction
times or the use of excess reagents resulted in b-elimination
Scheme 3. Regioselectivity of nitroso-Diels–Alder reactions with 3,5-hex-
adien-1-ol derivatives.
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Regio- and Stereochemical Studies on the Nitroso-Diels–Alder Reaction
FULL PAPER
standard
conditions
(Scheme 7); results are present-
ed in Table 3.
The observed selectivities
emphasize the role of the elec-
tronic properties of the C2 sub-
stituent: with the TBS-protect-
Scheme 4. Synthesis of dienic silyl enol ether 16.
ed side chain (which disfavours
the formation of the proximal
leading to the triene 19. Desilylation of 18 gave the free al-
cohol 20 (Scheme 5).
isomer), an electron-donating group, such as OTBS, leads to
the formation of the distal isomer with good selectivity; a re-
versal of regioselectivity is ob-
served when an electron-with-
drawing group, such as an enol
phosphate or
a bromine, is
present (Table 3, entries 2–4).
The conjugation of an electron-
withrawing group and an un-
protected hydroxylated side
chain results in a dramatic en-
hancement of selectivity in
favour of the proximal isomer
Scheme 5. Synthesis of the enol phosphates 18 and 20. TBAF=tetrabutylammonium fluoride.
Finally, the vinyl bromide 24,
a
potential substrate for ni-
troso-Diels–Alder cycloaddi-
tion, was prepared from 1,3-
propanediol via the aldehyde
21, which was homologated to
the gem-dibromoalkene 22.[25] It
was crucial to perform the ho-
mologation in the presence of
triethylamine[26] as classical con-
ditions led to the corresponding
Scheme 7. Nitroso-Diels–Alder reactions between Boc-nitroso 3 and dienes 16a, 18, 20 and 24.
tribromide. The key step was
a stereoselective Negishi cou-
Table 3. Regioselectivity of nitroso-Diels–Alder reactions between Boc-
nitroso and 1,2-disubstituted dienes.
pling[27] with vinylzinc bromide, leading to the (Z)-vinyl bro-
mide, which was subsequently deprotected to give the alco-
hol 24 (Scheme 6).
Entry Diene
R
X
Yield Major
compound
Ratio 29/30[a]
With all the dienes in hand, their reactions with Boc-ni-
troso reagent were investigated. On the basis of previous ex-
periences and Houkꢃs rules, the presence of a substituent on
the C2-position should favour the distal isomer, whereas the
influence of side chain on the C1-position in the diene de-
pends on chain length and the protecting group, with a hy-
droxyethyl substituent strongly favouring the formation of
the proximal isomer. It would be interesting to see which
substituent possesses most influence. Consequently, dienes
16a, 18, 20 and 24 were reacted with the Boc-nitroso under
1
2
3
4
16a
18
20
TBS OTBS
TBS OP(O)
70
45
68
64
26a
1:7
2:1
10:1
>10:1
U
25b
25c
25d
H
H
OP(O)
Br
R
24
[a] Ratio determined by 1H NMR spectroscopic analysis of the crude
product.
(entries 3 and 4). Thus, the optimal conditions for a regiose-
lective nitroso-Diels–Alder reaction with a 1,2-disbustituted
Scheme 6. Synthesis of the vinyl bromide 24.
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C. Kouklovsky et al.
diene are: 1) A bulky substitu-
ent at C1 and an electron-do-
nating group at C2 for the distal
isomer and 2) a nonbulky sub-
stituent at C1 and an electron-
withdrawing group at C2 for the
proximal isomer.
The selectivities reported in
Table 3 can be rationalized on
the basis of steric and electronic
effects. The possibility of hydro-
gen bonding between the free
hydroxyl group (in dienes 20
and 24) and the nitroso oxygen
atom cannot be ruled out but is
not always crucial for the regio-
selectivity. Actually, the triene
Scheme 9. Cycloadditions with Wightmanꢃs reagent 28.
19, which is a byproduct in the synthesis of enol phosphate
18 reacted with the Boc-nitroso reagent 3 with complete se-
lectivity in favour of the proximal isomer 27 (Scheme 8);
this experiment tends to prove that electronic or steric ef-
fects are at least as important as noncovalent bonding in the
transition state.
Table 4. Regio- and stereoselectivity of cycloadditions with Wightmanꢃs
chloronitroso derivative 28.
Entry Diene
R
X
Yield Ratio
Major
ee
[%][a] 29/30[b] compound [%][c]
1
2
3
4
5
6
8
H
Piv
TBS
TBS OTBS
H
H
H
H
H
65
>99:1 29a
>99:1 29c
>99:1 29a[e]
–
>99:1 29d
>99/1 29e
90
72
90
–
90
81
11
12
16a
20
24
16[d]
65
[f]
–
OP(O)
Br
(OEt)2 55
40
[a] Overall yield for the cycloaddition, hydrolysis and protection. [b] De-
1
termined by H NMR spectroscopic analysis of the crude product. [c] De-
termined by HPLC analysis on chiral column. [d] Degradation of the di-
enophile was observed. [e] In situ desilylation was observed. [f] Degrada-
tion of the diene was observed.
Scheme 8. Nitroso-Diels–Alder reaction of trienic enol phosphate 19.
With all the previous reactions being performed with an
acylnitroso reagent (Boc-nitroso), it would be interesting to
check whether the rules for regioselectivity apply to other
nitroso species, especially alkylnitroso derivatives. More-
over, it would be important to evaluate the possibility for
enantioselective nitroso-Diels–Alder reactions between
chiral nitroso reagents and 1,2-disubstituted dienes, as most
of enantioselective nitroso-Diels–Alder reactions have been
developed with simple symmetrical dienes, such as cyclopen-
tadiene or cyclohexadiene. For all these reasons, we selected
the Wightman chloronitroso 28 as a model reagent for this
study. The Wightman reagent has been designed as a simple,
easily available and highly efficient dienophile for enantio-
selective nitroso-Diels–Alder reactions with simple dienes,
such as cyclopentadiene, cyclohexadiene, or cycloheptadiene
(enantiomeric excess (ee)= >96%).[5a,b]
Chloronitroso derivative 28 was prepared according to the
literature procedure and reacted with monosubstituted
dienes 8, 11, 12 and the disubstituted dienes 16a, 20 and 24
in CHCl3/iPrOH/H2O (Scheme 10). After hydrolysis of the
reaction, the crude cycloadducts 29/30 were protected as
their N-Boc derivatives for comparison with previously pre-
pared cycloadducts (Scheme 9, Table 4).
active than the Boc-nitroso derivative 3, which resulted in
longer reaction times (18–36 h). The reaction sequence in-
volving the release of hydrochloric acid prolonged reaction
times and caused the cleavage of acid-sensitive functional
groups. Thus, low yields were obtained with the poorly reac-
tive pivaloyl ester 11, due to the degradation of the carbohy-
drate backbone, probably by hydrolysis of the acetonide
(Table 4, entry 2). This was also observed for the cycloaddi-
tion with the silyl enol ether 12, for which partial desilyla-
tion occurred during cycloaddition (entry 3). Unfortunately,
the silyl enol ether 16a was unstable under the reaction con-
ditions, giving no cycloadduct (entry 4). The other dienes
(and their corresponding cycloadducts) were stable and re-
active enough to provide appreciable yields of dihydrooxa-
zines 29/30.
NMR spectroscopic analysis of the crude reaction prod-
ucts showed that all the reactions proceeded with complete
regioselectivity in favour of the proximal isomer 29, no trace
of the distal isomer being detected. Noteworthy is the selec-
tivity for the cycloaddition with pivalate 11, for which the
cycloaddition with Boc-nitroso 3 was not regioselective.
Moreover, all the cycloadditions were highly stereoselective,
giving the cycloadducts with high enantiomeric excesses.
The stereoselectivity of the cycloadditions could be ra-
tionalized after analysis of the transition states. Therefore,
The cycloaddition reactions were performed at room tem-
perature. As expected, chloronitroso reagent 28 was less re-
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Regio- and Stereochemical Studies on the Nitroso-Diels–Alder Reaction
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we examined qualitatively the steric interactions for each
transition state by molecular modelling,[28] assuming a late
transition state that would be close to the primary adduct.
For a given regioisomer, four possible transition states A–D
can be involved, leading to each of the enantiomers of the
cycloadduct. Scheme 10 represents the four possible transi-
tion states leading to the proximal isomer 29. Molecular
modelling of the transition states revealed that transition-
in Figure 6 (using diene 8 as a representative example), as-
suming that the facial approach D is favoured, the transi-
tion-state leading to the distal isomer would be disfavoured
by steric interaction between the side chain located on posi-
tion-1 of the diene and the acetonide. This proposal for re-
gioselectivity was already proposed for the cycloaddition be-
tween 1,3-disubstitued dienes and the Wightman reagent
28.[16a]
According to this proposal,
the regio- and stereoselectivity
of cycloadditions with the
Wightman reagent are gov-
erned by pure steric effects. It
should be worth pointing out
that protection of the hydroxyl
group on the side chain should
not significantly affect the re-
giochemistry of the reaction.
Furthermore, the nature and
electronic properties of the 2-
substituent in the diene should
also not affect the selectivity of
the reaction.
To verify this hypothesis, cy-
cloadditions between Wight-
manꢃs reagent 28 and 1,4-disub-
Scheme 10. Putative transition states for the cycloaddition leading to the proximal isomer 29.
states A and B are disfavoured
due to severe steric interactions
between the CH2OTBDPS ap-
pendage and the terminal meth-
ylene of the diene. Moreover,
steric interactions between the
chlorine atom and the hydrogen
atom located on the sp2 carbon
atom (distance of 2.27 and
2.84 ꢄ, respectively) disfavour
the same transition-states
A
and B, whereas transition-state
C is disfavoured by the equiva-
lent interaction (distance of
2.33 ꢄ) and another between
the hydrogen and the acetonide
oxygen atom (distance: 1.87 ꢄ).
Figure 5 shows the molecular
modelling of transition states
with diene 24. Transition-state
D should be the most favoured
one; this transition state would
lead to the R enantiomer (R)-
29, which is consistent with pre-
viously reported results:[29]
The determination of the pre-
ferred facial approach in the cy-
cloaddition may account for the
regiochemical control: as shown Figure 5. Molecular modelling of the putative transition states with diene 24 (X=Br, R=H).
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C. Kouklovsky et al.
Figure 6. Transition states for both possible regioisomers in the cycloaddition reaction between Wightmann derivative 28 and diene 8.
stituted dienes, such as ethyl sorbate 31, and its reduction
product 32 were undertaken (Scheme 11, Table 5):
(Scheme 11) is destabilized by steric interactions between
the methyl substituent and the acetonide group. Therefore,
other transition-states may be involved, resulting in the for-
mation of the other enantiomer. Moreover, the low regiose-
lectivities could be explained by the weak difference of
steric hindrance between the methyl substituent or the R
group with the acetonide (see Figure 5). This experience val-
idates our hypothesis for the stereochemical induction in the
Wightman reagent and shows the necessity for appropriate
substitution patterns for a selective nitroso-Diels–Alder re-
action.
Cycloadditions with ethyl sorbate 31 and its reduction
product 2,4-hexadien-1-ol 32[30] were slow and increased
Cycloaddition reactions between Wightman reagent 28
and both 1,2- and 1,4-disubstituted dienes reveals some in-
sights about the role of each substituent in the chiral nitroso
reagent: although the TBDPS substituent of the primary hy-
droxyl group of the xylose backbone, as well as the chlorine
atom contributes to facial control, the acetonide group plays
an important role in the regiochemical control with unsym-
metrical dienes. The combination of all these features allows
highly selective reactions (Figure 7).
Scheme 11. Cycloadditions of 28 with 1,4-disubstituted dienes.
Table 5. Regio- and stereoselectivity of the cycloadditions of 28 with 1,4-
disubstituted dienes.
Entry Diene
R
Yield [%] Ratio ee major[b] ee minor [%][b]
33/34[a]
1
2
31
32
CO2Et
CH2OH
60
70
1.5:1
4:1
0
42
n.d.[c]
72
[a] Determined by 1H NMR spectroscopic analysis of the crude product.
[b] Determined by HPLC analysis on a chiral column. [c] Not deter-
mined.
amounts of diene were required for appreciable conversion.
Furthermore, regio- and enantioselectivity were significantly
reduced relative to those obtained with 1,2-disubstituted
dienes. Especially, the proximal isomer 33a was found to be
nearly racemic.[31] It is probable that the transition-state D
Figure 7. Elements for selectivity in the cycloaddition reactions with
Wightman reagent 28.
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Regio- and Stereochemical Studies on the Nitroso-Diels–Alder Reaction
FULL PAPER
then the pure distal cycloadduct 14b (9 mg, 6%) as colourless oils (96%
global yield of cycloadducts, 13b/14b 1:1.5).
Conclusion
Data for distal isomer 14b: Rf =0.12 (AcOEt/heptane 10:90); 1H NMR
(360 MHz, C6D6; TMS): d=5.45 (ddt, 1H, J=10.4, 4.5, 2.3 Hz), 5.27 (dt,
1H, J=10.4, 1.8 Hz), 4.58 (m, 1H), 4.41 (brd, 1H, J=15.9 Hz), 4.22 (m,
1H), 4.15 (m, 1H), 3.68 (ddd, 1H, J=15.9, 3.9, 1.6 Hz), 1.99 (m, 1H),
1.81 (m, 1H), 1.41 (s, 9H; tBu), 1.20 ppm (s, 9H; tBu); 13C NMR
(360 MHz, C6D6): 177.9 (COO), 155.1 (NCOO), 126.9 (=CH), 124.9 (=
CH), 81.2 (OCMe3), 67.6 (CH2O), 61.8 (CH2OPiv), 52.1 (CHN), 39.2
We have demonstrated the possibility of performing highly
regioselective nitroso-Diels–Alder cycloadditions with 1,2-
disubstituted dienes leading to the selective formation of the
proximal isomer. However, the factors ruling the regioselec-
tivity strongly depend on the nature of the nitroso reagent.
With the Boc-nitroso dienophile, the selectivity of the reac-
tion is a consequence of steric effects at the C1-position of
the diene, and electronic effects at the C2-position. For the
latter, we have highlighted the utility of enol phosphates as
stable and electron-withdrawing analogues to silyl enol
ethers in cycloaddition reactions. This work has also led to
an analysis of the factors governing the regio- and stereose-
lectivity of asymmetric nitroso-Diels–Alder reactions with
the chiral Wightman nitroso reagent, for which complete
regio- and stereoselectivities were observed with 1,2-disub-
stituted dienes. For this cycloaddition, we have proposed
a model based only on steric factors. These results should
lead to a rational design of the diene substitution pattern for
selective cycloadditions, and increase the synthetic scope of
the nitroso-Diels–Alder reaction.
(Me3C), 32.8 (CH2CH2OPiv), 28.7 (CACHTNURGTNENUG(CH3)3), 27.7 ppm (CCAHTUNGTREN(NUGN CH3)3); MS
(ESI): m/z: 336 [M+Na+], 280 [M+Na+ÀMe2C=], 236 [M+Na+ÀMe2C=
ÀCO2]; HRMS (ESI-QTOF): m/z: calcd for C16H27NO5Na: 336.1787
[M+Na]+; found: 336.1792.
The proximal racemic cycloadduct 13b could not be isolated as a pure
compound and was partially characterized in mixtures with 14b by
1H NMR spectroscopy. 1H NMR (360 MHz, C6D6; TMS): d=5.35–5.27
(m, 2H), 4.50–4.41 (m, 1H), 4.34–4.27 (m, 2H), 3.97 (brd, 1H, J=
17.6 Hz), 3.81 (brd, 1H, J=17.6 Hz), 1.89–1.74 (m, 1H), 1.70–1.57 (m,
1H) 1.44 (s, 9H), 1.15 ppm (s, 9H).
(RS)-tert-Butyl-6-(2-tert-butyldimethylsilyloxyethyl)-3,6-dihydro-2H-1,2-
oxazine-2-carboxylate (13c) and (RS)-tert-butyl-3-(2-tertbutyldimethylsi-
lyloxyethyl)-3,6-dihydro-2H-1,2-oxazine-2-carboxylate (14c): Prepared
according to the general procedure with diene 12. Chromatography over
silica gel (AcOEt/heptane 5:95) gave a 1:2 mixture of the proximal 13c
and distal 14c cycloadducts as a colourless oil (376 mg, 90%).
Data for the proximal isomer 13c: Rf =0.51 (AcOEt/heptane 10:90);
1H NMR (360 MHz, CDCl3; TMS): d=5.82–5.75 (m, 2H), 4.59 (m, 1H),
4.06 (brd, 1H, J= ~17 Hz), 3.96 (brd, 1H, J= ~17 Hz), 3.82 (m, 1H),
3.74 (m, 1H), 1.86 (ddt, 1H, J=14.3, J=8.5, J=5.1 Hz), 1.70 (m, 1H),
1.47 (s, 9H), 0.87 (s, 9H), 0.042 (s, 3H; SiMe2), 0.037 ppm (s, 3H; SiMe2);
13C NMR (100 MHz, CDCl3): d=155.2 (NCOO), 128.8 (=CH), 122.6 (=
Experimental Section
À
CH), 81.4 (OCMe3), 75.5 (CH O), 59.6 (CH2OTBS), 45.0 (CH2N), 36.5
General procedure for the nitroso-Diels–Alder reactions with the N-Boc
(CH2CH2OTBS), 28.6 (C
A
G
(SiCH3); MS (ESI): m/z: 366 [M+Na+], 310 [M+Na+ÀMe2C=], 266
[M+Na+ÀMe2C=ÀCO2]; HRMS (ESI-QTOF) m/z: calcd: 366.2077
[M+Na+], found: 366.2081.
nitroso reagent (3):
2.16 mmol) and the diene (1.43 mmol) in CH2Cl2 (2 mL) was cooled to
08C with stirring and solution of tetrabutylammonium periodate
A solution of N-Boc hydroxylamine (287 mg,
a
(455 mg, 1.05 mmol) in CH2Cl2 (3 mL) was added over 25 min. The reac-
tion mixture was stirred for 3 h at 08C, and then allowed to warm to RT
within 1 h. The reaction mixture was diluted with ether (20 mL) and
washed with saturated sodium thiosulfate solution (10 mL). The aqueous
layer was extracted with ether (3ꢅ20 mL). The combined organic layer
was dried (Na2SO4), filtered and concentrated in vacuo. The crude prod-
uct was purified by chromatography to give the pure cycloadduct.
Data for distal isomer 14c: Rf =0.45 (AcOEt/heptane 10:90); 1H NMR
(360 MHz, CDCl3; TMS): d=5.87 (ddt, 1H, J=10.4, 4.2, 2.0 Hz), 5.79
(ddt, 1H, J=10.4, 3.7, 1.5 Hz), 4.59 (dq, 1H, J=15.7, 2.0 Hz), 4.48 (m,
1H), 4.11 (ddd, 1H, J=15.7, 3.7, 1.5 Hz), 3.74–3.62 (m, 2H), 1.94 (m,
1H), 1.81 (m, 1H), 1.47 (s, 9H), 0.87 (s, 9H), 0.03 ppm (s, 6H); 13C NMR
(90 MHz, CDCl3): 154.9 (NCOO), 127.3 (HC=), 123.8 (HC=), 81.5
(OCMe3), 67.7 (CH2O), 60.2 (CH2OTBS), 52.1 (CHN), 36.3
(CH2CH2OTBS), 28.6 ((CH3)3C), 26.2 ((CH3)3C), 18.5 (CMe3), À5.1
(SiCH3), À5.2 ppm (SiCH3); MS (ESI): m/z: 366 [M+Na+], 310 [M+Na+
ÀMe2C=], 266 [M+Na+ÀMe2C=ÀCO2]; HRMS (ESI-QTOF): m/z: calcd
for C17H33 NO4SiNa: 366.2077 [M+Na]+; found: 366.2076.
(RS) tert-Butyl-6-(2-hydroxyethyl)-3,6-dihydro-2H-1,2-oxazine-2-carbox-
ylate (13a): Prepared according to the general procedure with diene 8.
Flash chromatography over silica gel (AcOEt/heptane, 40:60) gave a 10:1
mixture of the proximal 13a and distal 14a cycloadducts as a light-yellow
oil (243 mg, 74%).
(RS)-tert-Butyl-4-tert-butyldimethylsilyloxy-3-(2-tertbutyldimethylsilyloxy-
Data for proximal isomer 13a: Rf =0.20 (AcOEt/heptane 40:60);
1H NMR (360 MHz, CDCl3; TMS): d=5.81–5.71 (m, 2H), 4.61 (brd, 1H,
J=9.3 Hz), 4.05 (brd, 1H, J= ~18 Hz), 3.93 (brd, 1H, J=18 Hz), 3.85–
3.72 (m, 2H), 2.7 (brs; OH), 1.81 (m, 1H), 1.74 (m, 1H), 1.45 ppm (s,
9H); 13C NMR (90 MHz, CDCl3): d=155.2 (NCOO), 128.4 (HC=), 122.7
(HC=), 82.1 (OCMe3), 77.1 (CHON), 60.0 (CH2OH), 45.1 (CH2NO), 35.7
(CH2CH2OH), 28.4 ppm ((CH3)3C); MS (ESI): m/z: 252 [M+Na+], 196
[M+Na+ÀMe2C=CH2], 152 (M+Na+ÀMe2C=ÀCO2); HRMS (ESI-
QTOF): m/z: calcd for C11H19NO4Na: 252.1212 [M+Na+]; found:
252.1213.
ethyl)-3,6-dihydro-2H-1,2-oxazine-2-carboxylate (26a):
A solution of
Bu4NIO4 (112 mg, 0.26 mmol) in dichloromethane (3 mL) was added to
a solution of BocNHOH (70 mg, 0.52 mmol) and diene 16a (110 mg,
2 mmol) in dichloromethane (2 mL) over 25 min at 08C. The reaction
mixture was stirred for 2 h at the same temperature. The mixture was
then diluted with ether (20 mL) and treated with an aqueous saturated
Na2S2O3 solution (10 mL). After extraction with ether (3ꢅ20 mL), the or-
ganic phase was dried over Na2SO4 and concentrated under vacuum to
afford
a brown oil that was purified by silica gel chromatography
(AcOEt/heptane 5:95) to afford a mixture of the proximal 25a and distal
26a cycloadducts as a colourless oil (67 mg, 70%, 25/26 1:7).
The minor distal cycloadduct 14a could not be isolated as a pure com-
pound and was partially characterized in mixtures with 13a for a distinct
Data for the distal isomer 26a: Colourless oil. Rf =0.44 (AcOEt/heptane,
10:90): 1H NMR (250 MHz, CDCl3; TMS): d=4.78 (dd, 1H, J=4.1,
1.0 ppm), 4.64 (d, 1H, J=14.5 ppm), 4.27 (brt, 1H, J=6.4 Hz), 4.12 (dd,
1H, J=14.3, 4.1 Hz), 3.67 (t, 2H, J=6.5 Hz), 1.97–1.86 (m, 2H), 1.47 (s,
1
resonance in H NMR (360 MHz, CDCl3; TMS): d=4.55 (brd, 1H, CHN
or CH2ON; J=15.3 Hz).
(RS) tert-Butyl-6-(2-tert-butylcarbonyloxyethyl)-3,6-dihydro-2H-1,2-oxa-
zine-2-carboxylate (13b) and (RS) tert-butyl-3-(2-tert-butylcarbonyloxy-
ethyl)-3,6-dihydro-2H-1,2-oxazine-2-carboxylate (14b): Prepared accord-
ing to the general procedure with diene 11. Chromatography over silica
gel (AcOEt/heptane 10:90) gave a first fraction that was a 1:1.2 mixture
of the proximal 13b and distal 14b cycloadducts (146 mg, 90%), and
9H), 0.91 (s, 9H), 0.86 (s, 9H), 0.16 (s, 3H), 0.15 (s, 3H), 0.02 ppm (s,
13
À
6H); C NMR (90 MHz, CDCl3): 155.2 (=C O), 150.0 (NCOO), 98.6
(HC=), 81.7 (quat, OCMe3), 66.6 (CH2ON), 60.0 (CH2OTBS), 54.9
(CHN), 34.4 (CH2CH2OTBS), 28.5 ((CH3)3C), 26.2 ((CH3)3C), 25.8
((CH3)3C), 18.5 (quat, tBu), 18.2 (quat, tBu), À4.2 (SiCH3), À4.4 (SiCH3),
Chem. Eur. J. 2013, 19, 15604 – 15614
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
15611

C. Kouklovsky et al.
À5.1 ppm (SiCH3); MS (ESI): m/z: 496 [M+Na+], 440 [M+Na+ÀMe2C=
], 396 [M+Na+ÀMe2C=ÀCO2]; HRMS (ESI-QTOF): m/z: calcd for
C23H47NO5Si2Na: 496.2891 [M+Na]+; found: 496.2882.
Data for proximal isomer 25c: Rf =0.28 (AcOEt/heptane 70:30);
1H NMR (400 MHz, CDCl3; TMS): d=5.67 (m, 1H), 4.54 (brd, 1H, J=
9.8), 4.14 (quint., 4H, J=7.3 Hz), 4.08 (m, 2H), 3.90–3.77 (m, 2H), 2.06–
1.90 (m, 2H), 1.47 (s, 9H), 1.33 ppm (t, 6H, J=7.2 Hz); 13C NMR
The minor proximal cycloadduct 25a could not be isolated as a pure
compound and was partially characterized in a mixture with 26a for dis-
tinct resonances in 1H NMR (250 MHz, CDCl3; TMS): d=4.84 (td, 1H;
CHN or CH2ON, J=3.3, J=1.0 Hz).
À
(100 MHz, CDCl3): 155.0 (=C O), 146.4 (NCOO), 105.3 (HC=), 82.8
(quat., OCMe3), 77.7 (CHON), 65.0 (OCH2CH3), 60.3 (CH2OH), 44.2
(CH2N), 32.7 (CH2CH2OH), 28.4 ((CH3)3C), 16.3 ppm (CH2CH3); MS
(ES): m/z: 404 [M+Na+], 348 [M+Na+ÀMe2C=], 304 [M+Na+ÀMe2C=
ÀCO2], 273; HRMS (ESI-QTOF): m/z: calcd for C15H28NO8PNa
[M+Na]+; 404.1450; found: 404.1460.
(RS)-tert-Butyl-5-diethylphosphoryloxy-6-(2-tert-butyldimethylsilyloxy-
ethyl)-3,6-dihydro-2H-1,2-oxazine-2-carboxylate (25b) and (RS)-tert-
butyl-4-diethylphosphoryloxy-3-(2-tert-butyldimethylsilyloxyethyl)-3,6-di-
The minor distal cycloadduct 26c could not be isolated as a pure com-
pound and was partially characterized in mixtures with 25c for distinct
resonances in 1H NMR (400 MHz, CDCl3; TMS): d=4.59 (brd, 1H;
CHN or CH2ON, J=15.4 Hz).
hydro-2H-1,2-oxazine-2-carboxylate (26b):
A solution of Bu4NIO4
(43 mg, 0.1 mmol) in dichloromethane (1 mL) was added to a solution of
Boc-NHOH (25 mg, 0.2 mmol) and diene 18 (69 mg, 0.2 mmol) in di-
chloromethane (1 mL) over 25 min at 08C, and the reaction mixture was
then stirred for 2 h at this temperature. The cooling bath was then re-
moved to allow the mixture to warm up to RT. After further stirring for
30 mn, TLC analysis showed still some unreacted diene 18. Hence, Boc-
NHOH (21 mg, 0.16 mmol) and Bu4NIO4 (87 mg, 0.2 mmol) were added
without any solvent to the reaction mixture at RT. After further stirring
at RT for 2 h 30 min, the mixture was then diluted with ether (20 mL)
and treated with an aqueous saturated sodium thiosulfate solution
(10 mL). After extraction with ether (3ꢅ20 mL), the organic phase was
dried over Na2SO4 and concentrated under vacuum to afford a brown oil
that was purified by silica gel chromatography over Merck 60 TLC plates
(AcOEt/heptane 40:60, double elution) to afford the proximal cycload-
duct 25b (colourless oil, 29 mg, 30%) and the distal cycloadduct 26b
(colourless oil, 15 mg, 15%).
(RS)-tert-Butyl-5-bromo-6-(2-hydroxyethyl)-3,6-dihydro-2H-1,2-oxazine-
2-carboxylate (25d): A solution of Bu4NIO4 (202 mg, 0.47 mmol) in di-
chloromethane (2 mL) was added to a solution of Boc-NHOH (124 mg,
0.93 mmol) and diene 24 (112 mg, 0.62 mmol) in dichloromethane (1 mL)
over 25 min at 08C. The reaction mixture was then stirred for 2 h at that
temperature. The cooling bath was then removed to allow the mixture to
warm up to RT. After further stirring for 2 h, TLC analysis still showed
some unreacted diene 24. Hence, after cooling at 08C, Boc-NHOH
(130 mg, 0.97 mmol) and a solution of Bu4NIO4 (207 mg, 0.47 mmol) in
dichloromethane (1 mL) were added over 20 min to the reaction mixture.
After further stirring at 08C for 1 h 30 min, the cooling bath was re-
moved and after 20 min at RT, the reaction mixture was then diluted
with ether (20 mL) and treated with an aqueous saturated sodium thio-
sulfate solution (10 mL). After extraction with ether (3ꢅ20 mL), the or-
ganic phase was dried over Na2SO4 and concentrated under vacuum to
afford a brown oil that was purified by flash chromatography over silica
gel (AcOEt/heptane 30:70) to give as the only product the proximal cy-
cloadduct 25d (colourless oil, 125 mg, 64% yield).
Data for the proximal isomer 25b: Rf =0.63 (double elution, AcOEt/hep-
tane 40:60); 1H NMR (400 MHz, CDCl3; TMS): d=5.66 (brt, 1H, J=
3.4 Hz), 4.50 (brd, 1H, J=9.7 Hz), 4.14 (quint., 4H, J=7.3 Hz), 4.11–
4.00 (m, 2H), 3.90–3.84 (m, 1H), 3.78–3.73 (m, 1H), 1.99–1.82 (m, 2H),
1.47 (s, 9H), 1.33 (brt, 6H, J=7.1 Hz), 0.86 (s, 9H), 0.039 (s, 3H),
0.033 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): 154.9 (quat., =C<C->
O), 146.9 (quat., NCOO), 105.2 (HC=), 81.9 (quat., OCMe3), 75.3
(CHON), 64.9 (OCH2CH3), 59.0 (CH2OTBS), 43.9 (CH2N), 33.6
(CH2CH2OTBS), 28.5 ((CH3)3C), 26.1 ((CH3)3C), 18.4 (quat., tBu), 16.3
(CH2CH3), À5.1 ppm (SiCH3).
1
Rf =0.36 (AcOEt/heptane 50:50); H NMR (250 MHz, CDCl3; TMS): d=
6.13 (m, 1H), 4.57 (d, 1H, J=10.5 Hz), 4.06 (m, 2H), 3.85 (m, 2H), 2.40
(brs; OH), 2.20 (m, 1H), 1.95 (m, 1H), 1.48 ppm (s, 9H); 13C NMR
(90 MHz, CDCl3): 155.1 (quat., NCOO), 124.4 (HC=), 121.4 (BrC=), 82.9
(quat., OCMe3), 81.5 (CHON), 60.2 (CH2OH), 47.6 (CH2NO), 33.6
(CH2CH2OH), 28.4 ppm ((CH3)3C); MS (ESI): m/z: 332, 330 [M+Na+],
276, 274 [M+Na+ÀMe2C=], 232, 230 [M+Na+ÀMe2C=ÀCO2]; HRMS
(ESI-QTOF): m/z: calcd for C11H1879BrNO4Na: 330.0317 [M+Na]+;
found: 330.0313; calcd for C11H1881Br NO4Na: 332.0296; found: 332.0296.
Data for the distal isomer 26b: Rf =0.57 (double elution, AcOEt/heptane
1
40:60); H NMR (400 MHz, CDCl3; TMS): d=5.64 (brd, 1H, J=3.5 Hz),
4.66 (brd, 1H, J=14.8 Hz), 4.49 (brt, 1H, J=5.9 Hz), 4.21 (brdd, 1H,
J=15.0, 4.0 Hz), 4.16 (dquint., 4H, J=7.4, 2.7 Hz), 3.69 (t, 2H, J=
6.4 Hz), 1.96 (q, 2H, J=6.4 Hz), 1.47 (s, 9H), 1.34 (t, 6H, J=7.2 Hz),
0.86 (s, 9H), 0.02 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): 154.8 (quat.,
General procedure for asymmetric nitroso-Diels–Alder reactions with
Wightman chloronitroso reagent 28: A solution of the diene (0.5 mmol)
in chloroform (1 mL) was added dropwise to a solution of the chloroni-
troso reagent 28 (0.75 mmol) and water (0.2 mL) in iso-propanol (1 mL).
The blue reaction mixture was stirred at room temperature for 20 h, and
then diluted with CH2Cl2 (20 mL) and extracted with water (5ꢅ10 mL).
The organic layer was discarded, and the combined aqueous layer con-
centrated in vacuo to give a brown solid that was triturated with cyclo-
hexane. The crude dihydrooxazinium chloride was suspended in CH2Cl2,
whereas triethylamine (0.7 mL, 5 mmol) and di-tert-butyldicarbonate
(144 mg, 0.75 mmol) were successively added. After stirring overnight at
room temperature, the mixture was diluted with ether (10 mL), washed
with saturated ammonium chloride solution (5 mL), dried (Na2SO4), fil-
tered and concentrated in vacuo. The crude product was purified by chro-
matography to give the pure N-Boc protected dihydrooxazine.
À
=C O), 146.2 (quat., NCOO), 105.4 (HC=), 82.2 (quat., OCMe3), 66.3
(CH2ON), 64.9 (OCH2CH3), 59.6 (CH2OTBS), 53.2 (CHN), 34.1
(CH2CH2OTBS), 28.5 ((CH3)3C), 26.1 ((CH3)3C), 18.5 (quat, tBu), 16.3
(CH2CH3), À5.2 ppm (SiCH3); MS (ESI): m/z: 518 [M+Na+], 462
[M+Na+ÀMe2C=], 418 [M+Na+ÀMe2C=ÀCO2]; HRMS (ESI-QTOF):
m/z: calcd for C21H42NO8PSiNa: 518.2315 [M+Na]+; found: 518.2316.
(RS)-tert-Butyl-5-diethylphosphoryloxy-6-(2-hydroxyethyl)-3,6-dihydro-
2H-1,2-oxazine-2-carboxylate (25c) and (RS)-tert-butyl-4-diethylphos-
phoryloxy-3-(2-hydroxyethyl)-3,6-dihydro-2H-1,2-oxazine-2-carboxylate
(26c): A solution of Bu4NIO4 (24 mg, 0.55 mmol) in dichloromethane
(1 mL) was added to a solution of Boc-NHOH (15 mg, 0.11 mmol) and
diene 20 (28 mg, 0.11 mmol) in dichloromethane (0.5 mL) over 25 min at
08C. The reaction mixture was then stirred for 2 h at that temperature.
The cooling bath was then removed to allow the mixture to warm up to
RT. After further stirring for 1 h, TLC analysis still showed some un-
reacted diene 20. Hence, Boc-NHOH (7 mg, 0.05 mmol) and Bu4NIO4
(6 mg, 0.014 mmol) were added without any solvent to the reaction mix-
ture at RT. After further stirring at RT for 1 h, the mixture was then di-
luted with ether (10 mL) and treated with aqueous saturated sodium thi-
osulfate solution (5 mL). After extraction with ether (3ꢅ10 mL), the or-
ganic phase was dried over Na2SO4 and concentrated under vacuum to
(6R)-2-tert-Butyloxycarbonyl-6-(2-hydroxyethyl)-3,6-dihydro-2H-1,2-oxa-
zine (29a): Cycloaddition was accomplished with diene 8. Yield: 65%
(74 mg); yellow oil; Rf =0.20 (AcOEt/heptane 40:60); 1H NMR
(360 MHz, CDCl3; TMS): d=5.81 (m, 1H), 5.76 (m, 1H), 4.63 (brd, 1H,
J=9.4 Hz), 4.08 (m, 1H), 3.97 (m, 1H), 3.89–3.77 (m, 2H), 2.3 (brs;
OH), 1.88 (m, 1H), 1.77 (m, 1H), 1.48 ppm (s, 9H); 13C NMR (90 MHz,
CDCl3): 155.2 (NCOO), 128.4 (HC=), 122.7 (HC=), 82.1 (OCMe3), 77.1
(CHON), 60.0 (CH2OH), 45.1 (CH2NO), 35.7 (CH2CH2OH), 28.4 ppm
((CH3)3C); MS (ESI): 252 [M+Na+], 196 [M+Na+ÀMe2C=], 174
[M+H+ÀMe2C=], 130 [M+H+ÀMe2C=ÀCO2]; HRMS (ESI-QTOF):
m/z: calcd for C11H19NO4Na: 252.1212 [M+Na]+; found: 252.1204;
afford
a yellow oil that was purified by silica gel chromatography
(AcOEt/heptane, 60:40) to afford a 10:1 mixture of the proximal cyco-
loadduct 25c and the distal cycoadduct 26c as a light yellow oil (26 mg,
68%).
15612
www.chemeurj.org
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 15604 – 15614

Regio- and Stereochemical Studies on the Nitroso-Diels–Alder Reaction
FULL PAPER
[a]2D5 =À4.3 (c=1.1 in CH2Cl2); enantiomeric ratio (e.r.): (HPLC)=
G. Kettschau, Top. Curr. Chem. 1997, 189, 1–120; e) J. Streith, A.
Defoin, Synlett 1996, 189–200; f) J. Streith, A. Defoin, Synthesis
1994, 1107–1117; g) S. M. Weinreb, R. R. Staib, Tetrahedron 1982,
38, 3087–3128; h) S. M. Weinreb, in Comprehensive Organic Synthe-
sis (Eds. B. M. Trost, I. Fleming, L. A. Paquette), Pergamon Press,
New York, 1991, pp. 401–512; i) G. W. Kirby, Chem. Soc. Rev. 1977,
6, 1–24; j) G. Kresze, J. Firl, Fortschr. Chem. Forsch. 1969, 11, 245–
284.
19.9:1.
(6R)-2-tert-Butyloxycarbonyl-6-(2-tert-butylcarbonyloxyethyl)-3,6-dihy-
dro-2H-1,2-oxazine (29c): Cycloaddition was accomplished with diene 11.
Yield: 16% (25 mg); yellow oil; Rf =0.14 (AcOEt/heptane 10:90);
1H NMR (360 MHz, CDCl3; TMS): d=5.83 (brdq, 1H, J=10.2, 1.8 Hz),
5.77 (brdq, 1H, J=10.2, 1.8 Hz), 4.55 (m, 1H), 4.24 (dd, 2H, J=7.3,
5.7 Hz), 4.07 (brdq, 1H, J=17.4, 2 Hz), 3.98 (brdq, 1H, J=17.4, 2 Hz),
2.01–1.82 (m, 2H), 1.48 (s, 9H), 1.18 ppm (s, 9H); 13C NMR (75 MHz,
CDCl3): 178.6 (quat., OOCtBu), 155.1 (quat., NCOO), 127.9 (HC=),
123.4 (HC=), 81.7 (quat., OCMe3), 75.1 (CHON), 60.9 (CH2OPiv), 44.9
(CH2NO), 38.9 (OOCCMe3), 32.5 (CH2CH2OPiv), 28.5 ((CH3)3C),
27.4 ppm ((CH3)3C); MS (ESI): m/z: 336 [M+Na+], 280 [M+Na+
ÀMe2C=], 258 [M+H+ÀMe2C=]; HRMS (ESI-QTOF): m/z: calcd for
C16H27NO5Na: 336.1787 [M+Na]+; found: 336.1772; [a]2D5 = +6.4 (c=0.2
in CH2Cl2); e.r. (HPLC): 6.2:1.
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(6R)-2-tert-Butyloxycarbonyl-5-diethylphosphoryl-6-(2-hydroxyethyl)-3,6-
dihydro-2H-1,2-oxazine (29d): Compound 29d was obtained from diene
20 by a slight modification of the cycloaddition protocol: A solution of
the diene 20 (76 mg, 0.3 mmol) in chloroform (0.5 mL) was added drop-
wise at RT to
a solution of the chloronitroso reagent 28 (207 mg,
0.43 mmol) and water (0.005 mL, 0.3 mol) in iso-propanol (0.5 mL),. The
blue reaction mixture was stirred at room temperature for 24 h, and then
diluted with CH2Cl2 (20 mL) and treated with an aqueous solution of
phosphate buffer (10 mL). The aqueous phase was extracted with di-
chloromethane (3ꢅ20 mL). The whole organic solution was dried over
Na2SO4 and concentrated under vacuum to afford a crude green/kaki oil
that gave after chromatography (dichloromethane/MeOH 95:5) a colour-
less oil. Nitrogen protection was performed according to the general pro-
tocol. Yield: 55% (105 mg). Yellow oil; Rf =0.28 (AcOEt/heptane
70:30); 1H NMR (400 MHz, CDCl3; TMS): d=5.68 (m, 1H), 4.55 (brd,
1H, J=9.0 Hz), 4.15 (quint., 4H, J=7.4 Hz), 4.10 (m, 2H), 3.91–3.78 (m,
2H), 2.05–1.96 (m, 2H, OH), 1.48 (s, 9H), 1.34 Hz (dt, 6H, J=7.1,
13
À
1.0 Hz); C NMR (100 MHz, CDCl3): 155.0 (=C O), 146.4 (NCOO),
105.3 (HC=), 82.8 (q, OCMe3), 77.6 (CHON), 65.0 (OCH2CH3), 60.3
(CH2OH), 44.2 (CH2N), 32.7 (CH2CH2OH), 28.4 ((CH3)3C), 16.3 ppm
(CH2CH3); MS (ES): m/z: 404 [M+Na+], 348 [M+Na+ÀMe2C=], 304
[M+Na+ÀMe2C=ÀCO2], 273; HRMS (ESI-QTOF): m/z: calcd for
C15H28NO8PNa: 404.1450 [M+Na]+; found: 404.1460; [a]2D5 = +11.7 (c=
0.6 in CH2Cl2); e.r. (HPLC): 17.8:1.
(6R)-5-Bromo-2-tert-butyloxycarbonyl-6-(2-hydroxyethyl)-3,6-dihydro-
2H-1,2-oxazine (29e): Cycloaddition was accomplished with diene 24.
Yield: 40% (62 mg); colourless oil; Rf =0.36 (AcOEt/heptane 50:50);
1H NMR (360 MHz, CDCl3; TMS): d=6.11 (m, 1H), 4.56 (brd, 1H, J=
10.1 Hz), 4.04 (m, 2H), 3.83 (m, 2H), 2.70 (brs, 1H; OH), 2.17 (m, 1H),
1.93 (m, 1H), 1.46 ppm (s, 9H); 13C NMR (90 MHz, CDCl3): 155.1
(quat., NCOO), 124.4 (HC=), 121.4 (BrC=), 82.9 (quat, OCMe3), 81.5
(CHON), 60.2 (CH2OH), 47.6 (CH2NO), 33.6 (CH2CH2OH), 28.4 ppm
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(ACHTUNGTRENNUNG
(CH3)3C); MS (ESI): m/z: 332, 330 [M+Na+], 276, 274 [M+Na+
ÀMe2C=], 232, 230 [M+Na+ÀMe2C=ÀCO2]; HRMS (ESI-QTOF): m/z:
calcd for C11H1879BrNO4Na: 330.0317 [M+Na]+; found: 330.0313; calcd
for C11H1881BrNO4Na 332.0296; found 332.0296; [a]2D7 =À16.2 (c=0.36 in
CH2Cl2); e.r. (HPLC): 9.5:1.
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This research was supported by Universitꢀ de Paris-Sud and CNRS. We
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Received: July 24, 2013
Published online: October 7, 2013
15614
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