Catalytic Enantioselective Nitroso Diels-Alder Reaction

Article abstract of DOI:10.1021/jacs.5b11273

The nitroso Diels-Alder (NDA) reaction is an attractive strategy for the synthesis of 3,6-dihydro-1,2-oxazines and 1-amino-4-hydroxy-2-ene derivatives. Herein we report the Cu(I)-DTBM-Segphos catalyzed asymmetric intermolecular NDA reaction of variously substituted cyclic 1,3-dienes using highly reactive nitroso compounds derived from pyrimidine and pyridazine derivatives. In most of the cases studied, the cycloadducts were obtained in high yields (up to 99%) with very high regio-, diastereo-, and enantioselectivities (up to regioselectivity > 99:1, d.r. > 99:1, and >99% ee). As an application of this methodology, formal syntheses of conduramine A-1 and narciclasine were accomplished.

Full text of DOI:10.1021/jacs.5b11273

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Article
Catalytic Enantioselective Nitroso Diels-Alder Reaction
Biplab Maji, and Hisashi Yamamoto
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b11273 • Publication Date (Web): 26 Nov 2015
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Catalytic Enantioselective Nitroso Diels-Alder Reaction
Biplab Maji* and Hisashi Yamamoto*
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Molecular Catalyst Research Center, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi 487-8501, Japan
ABSTRACT: The nitroso Diels-Alder (NDA) reaction is an attractive strategy for the synthesis of 3,6-dihydro-1,2-oxazines
and 1-amino-4-hydroxy-2-ene derivatives. Herein, we report Cu(I)-DTBM-Segphos catalyzed asymmetric intermolecular
NDA reaction of variously substituted cyclic 1,3-dienes using highly reactive nitroso compounds derived from pyrimidine
and pyridazine derivatives. In most cases studied, the cycloadducts were obtained in high yields (up to 99%) with very high
regio-, diastereo-, and enantioselectivities (up to regioselectivity >99:1, d.r. >99:1, >99% ee). As an application of this meth-
odology, formal syntheses of conduramine A-1 and narciclasine were accomplished.
Introduction
and regioselectivities were obtained, the enantioselectivi-
ties were only moderately high and the scope of the dienes
was limited. Later, Studer et al. broadened the scope of the
NDA reaction of 2-nitrosopyridine 1b using copper-Wal-
phos-CF3 as a catalyst.4d-f This chiral Cu-nitrosopyridine-
complexes also undergo other types of cycloaddition reac-
tions.5 We had also published organocatalytic diastereo-
and enantioselective synthesis of nitroso Diels-Alder-type
bicycloketones using nitrosobenzenes.4h,i While this work
was in progress, Masson et al. reported chiral phosphoric
acid catalyzed regio-, diastereo-, and enantioselective NDA
reactions of 1,3-diene-1-carbamates with nitrosobenzenes.4j
However, in spite of these advancements, a general and
uniformly high enantioselective route for NDA reaction
with a very broad substrate scope is highly demanding, es-
pecially in view of the high synthetic potential of the NDA-
adducts.
Nitroso compounds 1 are highly fascinating hetero-electro-
philes. They are able to selectively transfer either one or
both of the hetero-atoms in a variety of asymmetric oxida-
tion reactions.1 In this context, the nitroso Diels-Alder
(NDA)1a,2 reaction is of high interest to the synthetic com-
munities for its unique ability to transform a simple 1,3-
diene 2 into complex 3,6-dihydro-1,2-oxazines 3 in a single
step (Scheme 1). The NDA adducts 3 can easily be con-
verted into corresponding 1-amino-4-hydroxy-2-ene deriv-
atives 4 which are important building blocks for the syn-
theses of several natural products and biologically active
molecules; some of them are shown in Scheme 1.3
Scheme 1. Nitroso Diels-Alder reaction and its syn-
thetic utility
The prominent success of nitroso chemistry largely relies
on the identification of the proper source of reactive ni-
troso compounds. Hetero-atom stabilized nitroso com-
pounds are unreactive towards dienes.3a,6 The acylnitroso
compounds1b,7 are, on the other hand, too reactive for the
development of asymmetric intermolecular NDA reac-
tion.4a,8 We envisage that the reactivities of the 2-nitro-
sopyridines could be enhanced by inclusion of another het-
ero-atom and those highly reactive nitroso compounds
might undergo NDA reaction with high enantioselectivi-
ties with differently substituted 1,3-dienes. Herein, as an
extension of our continuous effort to utilize nitroso com-
pounds in asymmetric oxidation reactions,4b,c,h,i,9 we report
an improved Cu-catalyst for highly regio-, diastereo- and
enantioselective NDA reaction using highly reactive and
readily available nitroso compounds derived from pyrimi-
dine and pyridazine derivatives 1. As an application of this
method, formal syntheses of conduramine-A-1 and narci-
clasine are described.
Given its importance, a huge effort was devoted to the
development of catalytic, enantioselective NDA reaction.4
However, the development of such a process has long been
regarded as challenging, due to the high reactivity of the
nitroso compounds 1 which undergo a [4+2]-cycloaddition
reaction without any activation. The first enantioselective
intermolecular NDA reaction was reported by Ukaji and
Inomata using a stoichiometric amount of zinc-tartaric
acid complex as a chiral promoter.4k In 2004, we reported
the first example of copper-Segphos-catalyzed enantiose-
lective intermolecular NDA reaction of 6-methyl-2-nitro-
sopyridine 1a with cyclic 1,3-dienes.4b Although high yields
Results and Discussion
Syntheses of nitroso compounds. Highly reactive ni-
troso pyrimidines (1c–i), pyridazines (1j,k), and triazine
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observed using a -acidic Diflourphos ligand (89% ee).17
Astonishingly, we found that the enantioselectivity was
significantly improved to 97% ee using the more electron-
rich and sterically bulky DTBM-Segphos as the ligand.
However, similarly bulky bisphosphine ligands having a
wider dihedral angle DTBM-OMe-BIPHEP15 and DTBM-
Garphos18 were slightly less effective. Thus, we chose this
Cu(I)-DTBM-Segphos catalyst system for development of
further reactions.
(1m) were conveniently prepared in >90% yields in one
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step by MnO2 oxidation of the corresponding hydroxyl
amines following the modified procedure reported by Mos-
kalenko et al. (see Chart 2 for the structures).10 All other
nitroso compounds 1n–q were prepared according to the
literature procedure.3e,11
Reaction optimization. Effect of temperature and Lewis
acid catalysts. To optimize the reaction conditions, we in-
itially performed the NDA reaction of 4,6-dimethyl-2-ni-
trosopyrimidine 1c with 1,3-cyclohexadiene 2a using
Cu(CH3CN)4BF4-(S)-Segphos as catalyst at various temper-
atures (Table 1). While the reaction was very sluggish at –
78oC, the product 3ac was obtained with lower enantiose-
lectivities at –40 and –20oC (entries 1–3). However, after
addition of a diene at –78oC, if the reaction mixture is
placed in a –40oC bath, the enantioselectivity could be im-
proved to 75% ee (entry 4). Finally, if the diene was added
at –85oC and then the temperature was gradually increased
to –40oC over a period of 2 h, the ee was increased to 78%
(entry 5). Variation of metal salts resulted in lower enanti-
oselectivities (entries 6–9).
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Chart 1. Effect of ligands on NDA reactiona
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Table 1. Effect of temperature and metal salts on NDA
reactiona
entry
M-salt
temp (oC)
yield (%)b ee (%)c
1
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
AgOTf d
<20%
97
nd
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75
78
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–78
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9
–40
97
–20
99
–78 to –40
–85 to –40
–78 to –40
–78 to –40
–78 to –40
–78 to –40
aReaction conditions: 0.1 mmol of 1c, 0.12 mmol of 2a in 1.5
mL of THF. Yield of the isolated products are given. ee was
determined by HPLC using a chiral stationary phase. A nega-
tive ee value indicates the opposite enantiomer of the NDA
adduct.
99
99
AuCl e
99
3
e
Ni(OTf)2
78
0
Effect of structure of nitroso compounds. To study the ef-
fect of the steric and electronic properties of iminonitroso
compounds on enantioselectivities, we have performed
their NDA reactions with 1,3-cyclohexadine 2a using a
Cu(I)-DTBM-Segphos catalyst and the results are summa-
rized in Chart 2. Replacement of the methyl groups of 1c
with bulkier isopropyl ( 1d) or phenyl groups ( 1e) re-
sulted in lower enantioselectivities. A similar results were
obtained for the replacement of the methyl groups with hy-
drogen as the parent 2-nitrosopyrimidine 1f and 5-methyl-
2-nitrosopyrimidines 1g yielded the NDA-adducts 3af and
3ag in 84% and 94% ee, respectively. In contrast to 2-nitro-
sopyrimidines (1c–g), two representative 4-nitrosopyrim-
idines (1h,i) underwent NDA reactions with poor enanti-
oselectivities. Interestingly, 3-nitrosopyridazines (1j,k)
were found to be very reactive nitroso-dienophiles and we
e
Pd(OAc)2
87
0
aReaction conditions: 0.1 mmol of 1c, 0.12 mmol of 2a in 1.5
mL of THF. bYields of the isolated products are given. cee was
d
determined by HPLC using a chiral stationary phase. EtCN
solvent. eCH2Cl2 solvent.
Effect of ligands. To further improve the enantioselectiv-
ity, various diphosphine ligands with different steric and
electronic properties were surveyed, and the results are
summarized in Chart 1. The venerable BINAP12 gave similar
enantioselectivity to that of Segphos.13 The spiro phosphine
ligand SDP14 and ferrocene-based bisphosphine ligands
were less efficient. Likewise, a less satisfactory result was
obtained using Me-Duphos15 and Walphos ligands16: 35 and
33% ee, respectively. The first significant improvement was
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were pleased to find 3-methyl-6-nitrosopyridazine 1j as the
best, delivering the NDA-adduct 3aj in a 99% yield with
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99% ee. In this case, the catalyst loading could be lowered
to 5 mol% without significant alteration of yield and enan-
tioselectivity (99% and 98%, respectively). However, when
the catalyst loading was further decreased to 2 mol%, the
enantioselectivity went down to 95%.
Scope of the NDA reaction and its applications. We
then performed cycloaddition reactions of a variety of 1,3-
dienes with highly reactive iminonitroso compounds 1c
and 1j (hereafter abbreviated as pyM-NO and pyD-NO, re-
spectively) using the improved catalytic system
Cu(CH3CN)4BF4-DTBM-Segphos in THF to determine the
scope and the limitation of the method. Gratifyingly, all of
the reactions went to completion, the cycloadducts were
obtained in very high yields, and the enantioselectivities
exceed those previously reported.
In the triazine series, 2,4-dimethoxy-6-nitroso-1,3,5-tria-
zine 1l is unstable and the stable 2-nitroso-4,6-di(pyrroli-
din-1-yl)-1,3,5-triazine 1m yielded the NDA adduct 3am in
an 85% yield with 31% ee.19 At this point, we are also inter-
ested in studying other types of heteroaromatic iminoni-
troso compounds for NDA reaction. 5-Methyl-3-nitrosoi-
soxazole 1n introduced by Miller gave 94% of the NDA ad-
duct 3an with 24% ee under the same conditions.3e Disap-
pointingly, 2-nitrosobenzo[d]oxazole 1o,11a 2-nitro-
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NDA reactions with symmetrical 1,3-dienes. First sym-
metrical 1,3-dienes 2a–h were tested and the results are
summarized in Chart 3. Under optimal conditions, cyclo-
pentadiene 2b, 1,3-cycloheptadiene 2c, and cis,cis-1,3-cy-
clooctadiene 2d took part NDA reaction with the nitroso
compounds 1c,j in very high yields and with very high en-
antioselectivities. In 2009, Miller et al. introduced N-Cbz
and N-Boc protected aza-spirodienes (2e,f) for the prepa-
ration of racemic spirocyclic carbocyclic nucleoside ana-
logues and spironoraristeromycin using NDA reaction.3i,j
Surprisingly, when we subjected the aza-spirodienes 2e,f
to optimal conditions, the cycloadducts 3ej and 3fj were
obtained in 94% yield, 99% ee and 92% yield, 98% ee, re-
spectively. A similar result was obtained for the carbocyclic
spiro[4.4]nona-1,3-diene 3g: 95% yield and 97% ee. Using a
sobenzo[d]thiazole 1p,11b
and 1-methyl-2-nitroso-1H-
benzo[d]imidazole 1q11a delivered racemic products. It is
worth mentioning that, under identical conditions, 2-ni-
trosopyridine 1b gave 99% of the NDA adduct with 94% ee.
Chart 2. Effect of steric and electronic properties of ni-
troso compounds on NDA reactiona
Chart 3. Enantioselective NDA reaction with symmet-
rical dienes 2a–ha
aReaction conditions: 0.1 mmol of nitroso compound, 0.12
mmol of 2a in 1.5 mL of THF. Yields of the isolated products
are given. ee was determined by HPLC using a chiral station-
b
ary phase. 99%, 98% ee with 5 mol% catalyst loading and
99%, 95% ee with 2 mol% catalyst loading.
In order to realize the reactivity order between the ni-
troso compounds 1b,c,j, we performed the following com-
petition experiment (Eq. 1). Accordingly, when 1 equivalent
1,3-hexadiene 2a was reacted with equimolar mixture of
1b,c,j (1 equivalent each) in the presence of 10 mol% (with
respect to 2a) of Cu(CH3CN)4BF4-DTBM-Segphos in THF,
the ratio of the NDA adducts was 3ab:3ac:3aj = 17:17:66.
This result indicates that, under this condition, 1j is far
more reactive than 1b and 1c. A computational study is cur-
rently ongoing in order to understand the high reactivities
and selectivities obtained for the NDA reactions of the pyr-
idazine derivative 1j.
aReaction conditions: 0.1 mmol of nitroso compound 1c,j,
0.12 mmol of 1,3-diene 2a–h in 1.5 mL of THF. Yields of the
isolated product are given. ee was determined by HPLC using
b
a chiral stationary phase. Reaction performed with 5 mol%
catalyst loading in 0.2 mmol scale.
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5 mol% catalyst, the acetal protected meso-cyclohexa-3,5- ee). Likewise, a high regioselectivity (>99:1) was observed
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diene-1,2-diol 2h reacted with 1j to yield the NDA product
3hj in a quantitative yield with perfect diastereo- and en-
antioselectivities (d.r. >99:1 and >99% ee) for four consec-
utive stereocenters.20
for the NDA reaction of 2-phenyl cyclohexa-1,3-diene 2k
using 5 mol% of the catalyst. 2-tert-butyldimethylsiloxy-
1,3-cyclohexadiene 2l and 2-tert-butyldimethylsiloxy-1,3-
cycloheptadiene 2m similarly underwent NDA reactions
with very high regio- and enantioselectivities. We then
studied the regioselectivity of the NDA reactions of 2,3-
and 2,4-disubstituted 1,3-cyclohexadienes (2n,o). In these
cases also, only one regioisomer could be observed, and the
NDA adducts 3nj and 3oj were obtained with very high en-
antioselectivities (>99% and 97% ee, respectively). In all
cases, the regiochemical assignments were made based on
NMR spectroscopy and comparison with a similar struc-
ture in the literature. The high proximal selectivities of
these reactions were in accordance with the computational
studies for the related Cu(I)-catalyzed NDA reaction of the
2-nitrosopyridines.23d Finally, the NDA reaction of N-
CO2Me azacyclohexadiene 2p with 1c,j resulted in the for-
mation of a mixture of regioisomers (10:1 and 2:1, respec-
tively). In both cases, the major isomers 3pc and 3pj were
formed with very high enantioselectivities (99% and 96%
ee, respectively).
To explain the utility of the highly enantioenriched NDA
adducts, we consider their conversion to corresponding 4-
aminocyclohex-2-en-1-ol derivatives 4, which proceeded
smoothly, as depicted in Scheme 2. Accordingly, the O,N-
protected intermediate 9 was obtained via Mo(CO)6-
mediated reductive N–O bond cleavage,21 and O- and N-
protection. The pyrimidyl group was then cleaved by
quaternization with MeOTf, followed by hydrolysis with
NaOH. Similar treatment of the cycloadduct 3hj delivered
the intermediate 10 from which the pyridazyl group can be
removed by first quaternization with 3-iodopropyl triflate,
NaBH4 reduction and then second quaternization and hy-
drolysis with NaOH in one pot. The absolute configuration
of the adduct 11 was determined by comparing the optical
rotation with previously reported data and, hence, the ab-
solute configuration of the NDA 3hj can be determined.
The absolute configurations of the adducts 3 in Chart 3
were assigned by analogy. Importantly, 11 could easily be
transformed to tetracetylated conduramine A-1 5 in one
step.4f,22
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Chart 4. Enantioselective NDA reaction with unsym-
metrical dienes 2i–pa
Scheme 2. Synthesis of protected 4-aminocyclohex-2-
en-1-ol 4a and tetracetylated conduramine A-1 5
aReaction conditions: 0.1 mmol of nitroso compound 1c,j,
0.12 mmol of 1,3-diene 2i–p in 1.5 mL of THF. Yields of the iso-
lated product are given. ee was determined by HPLC using a
chiral stationary phase. Reaction performed with a 5 mol%
catalyst loading in 0.2 mmol scale.
Reagents and conditions: a) Mo(CO)6, NaBH4, CH3CN-H2O;
b) TBDPS-Cl, imidazole, DMF; c) LiHMDS, CbzCl, THF; d)
MeOTf, CH2Cl2, then 2 N NaOH, MeOH; e) TBS-Cl, imidazole,
DMF; LiHMDS, ClCO2Me, THF; f) I(CH2)3OTf, CH2Cl2, then
NaBH4, MeOH, then 2 N NaOH, MeOH.
b
Studer et al. reported a Cu(I)-Walphos-CF3 catalyzed di-
vergent reaction of the racemic 5-substituted 1,3-cyclohex-
adienes in which only two products were formed with very
high enantioselectivities out of eight possible stereoiso-
mers.4d The high regioselectivities obtained for the reac-
tion of 2-substituted 1,3-cyclohexadienes 2i–o prompted us
to study the reaction of racemic 2,6-disubstituted 1,3-cyclo-
hexadienes 2q–u. We hope, in this case, that the regiose-
lectivity will be governed by the 2-substituents and, hence,
NDA reactions with unsymmetrical 1,3-dienes. Then un-
symmetrical 1,3-dienes 2i–p were examined (Chart 4). Con-
trol of the regioselectivity has long been regarded as a key
issue while developing NDA reactions with unsymmetrical
1,3-dienes.23
Under optimal conditions, the NDA reactions of 2-butyl
and 2-benzyl cyclohexa-1,3-dienes (2i,j) delivered the cy-
cloadducts 3ij and 3jj in very high yields with perfect regio-
and enantioselectivities (>99:1 regioselectivity and >99%
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one of the enantiomers of the racemic dienes will react
with nitroso compounds faster than the other.
1
2
3
4
As shown in page S34 of the supporting information, five
representative 2,6-disubstituted 1,3-cyclohexadienes 2q–u
were synthesized in good yields over three steps.
5
The NDA reaction of racemic 2,6-disubstituted 1,3-cyclo-
hexadienes 2q–u were conducted in THF using 10 mol% of
Cu(I)-DTBM-Segphos catalyst and 2.3 equivalent of the
dienes (Chart 5). Pleasingly, the NDA reaction proceeded
smoothly, and only one regioisomer of the products (3qj–
3tj) was formed in high yields (91–98% yields) with excel-
lent diastereo- (d.r. >99:1) and enantioselectivities (99%
ee). However, for the 6-methyl substituted diene 2u, the
major isomer 3uj was formed in a 69% yield and >99% ee
with a 4:1 mixture with another isomer whose structure has
not been determined.
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7
8
9
Motivated by the high regio-, diastereo-, and enantiose-
lectivities of the NDA reaction of racemic 2,6-disubstituted
1,3-cyclohexadienes rac-2q–u, we want to extend it further
to more challenging 2-aryl-5,6-dihydroxy-1,3-cyclohexadi-
enes rac-2v,w. Retrosynthetically, the NDA adducts 3v,w
could easily be connected to hydroxylated phenanthrido-
nes, e.g., narciclasine 6a and lycoricidine 6b25, via N–O
bond cleavage and Bischler-Napieralski cyclization26
(Scheme 4). Narciclasine and its derivatives are an inter-
esting class of biologically active molecules belonging to
the Amaryllidaceae family of alkaloids. These compounds
exhibit unusually high levels of antitumor and antiviral ac-
tivity25 and are the subject of great interest in the synthetic
community.27
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Chart 5. Enantioselective NDA reaction of racemic 2,6-
disubstituted 1,3-cyclohexadienes 2q–u a
Scheme 4. Retrosynthetic analysis of the synthesis of
narciclasine and lycoricidine
aReaction conditions: 0.1 mmol of nitroso compound 1j, 0.23
mmol of 1,3-diene 2q–u in 1.5 mL of THF. Yield of the isolated
product is given. ee was determined by HPLC using a chiral
stationary phase.
When exactly two equivalents of the diene 2r were used
for the NDA reaction, efficient kinetic resolution of the
racemates took place (Scheme 3). The NDA adduct 3rj was
obtained in a 46% yield with 99% ee. Whereas the unre-
acted diene was recovered in a 47% yield and its enantiose-
lectivity was determined by converting it to the corre-
sponding NDA adduct (ent-3rj, 90%, 85% ee). This result
corresponds to a selectivity factor s >500 for the kinetic res-
olution of the diene 2r, which is remarkably high24 and to
best of our knowledge it represents the first example of ki-
netic resolution in asymmetric nitroso Diels-Alder chem-
istry.
Syntheses of the dienes 2v,w are shown in Scheme 5. The
racemic cyclohexenone derivative 12 was prepared in large
scale from 1,4-cyclohexadiene 13 using the procedure re-
ported by Krow.28 The required dienes rac-2v,w can then
be prepared from 13 over two steps with moderate yields.29
Scheme 5. Synthesis of the dienes 2v,w
Reagents and conditions: a) LiHMDS, 5-Cl-PyNTf2, THF; b)
(7-methoxybenzo[d][1,3]dioxol-5-yl)magnesium bromide, CuI
(10 mol%), THF; c) benzo[d][1,3]dioxol-5-ylmagnesium bro-
mide, CuI (10 mol%), THF.
Scheme 3. Kinetic resolution of racemic diene 2r via
enantioselective NDA reaction
The NDA reaction of the dienes rac-2v,w was similarly
performed in THF using 10 mol% of the Cu(I)-DTBM-
Segphos complex as catalyst (Scheme 6). The cycloaddition
proceeded smoothly and the NDA adducts 3vj and 3wj
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Supporting Information. Complete experimental proce-
were formed in 92% and 96% yields, respectively with ex-
cellent regio-, diastereo- and enantioselectivities (>99:1 re-
gioselectivity, d.r. > 99:1, 99 and 98% ee, respectively).
1
2
3
4
5
6
7
8
dures and full compound characterization, including HPLC
traces and NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
Scheme 6. Enantioselective NDA reaction of rac-2v,w
AUTHOR INFORMATION
Corresponding Author
E-mail: biplabmaji@isc.chubu.ac.jp;
hyamamoto@isc.chubu.ac.jp
Notes
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The authors have no competing financial interests to declare.
ACKNOWLEDGMENTS
The N–O bond of the adduct 3vj was cleaved easily using
Mo(CO)6/NaBH4 in CH3CN/H2O to give the intermediate
15 in a 96% yield (Scheme 7).21 The O-protection using
TBSOTf, the O-silylation took place smoothly within 1 h in
CH2Cl2. N-carbamoylation was performed by the treatment
of the corresponding Li-amide with ClCO2Me in THF to
give the intermediate 16 in a 71% yield after 2 steps. Then,
the cleavage of the pyridazinyl group under similar condi-
tions described in Scheme 2 and benzoyl protection deliver
17 in a 61% yield (2 steps). The intermediate 17 could be
transformed to narciclasine 6a following the method in the
literature.27e,l
This work was supported by the ACT-C, the JST, and a Grant-
in-Aid for Scientific Research (No. 23225002). The author
thank Dr. Y. Shimoda for helpful discussion.
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In conclusion, we have demonstrated an improved catalyst
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