Catalytic asymmetric Tamura cycloadditions involving nitroalkenes

Article abstract of DOI:10.1039/c6ob02637k

The first examples of asymmetric Tamura cycloaddition reactions involving singly activated alkenes are reported. Homophthalic anhydride reacts with α-methyl nitrosytrenes in the presence of an alkaloid-based catalyst to generate fused bicyclic aromatic ketone products with three new stereocentres (which are susceptible to subsequent equilibration) in 12-99% ee. An unusual equilibration process which occurs in methanolic medium in the absence of a recognisable base via proton transfer at the α-carbon of an ester was investigated experimentally and computationally.

Full text of DOI:10.1039/c6ob02637k

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Catalytic asymmetric Tamura cycloadditions
involving nitroalkenes†
Cite this: DOI: 10.1039/c6ob02637k
Francesco Manoni, Umar Farid, Cristina Trujillo and Stephen J. Connon*
The first examples of asymmetric Tamura cycloaddition reactions involving singly activated alkenes are
reported. Homophthalic anhydride reacts with α-methyl nitrosytrenes in the presence of an alkaloid-
based catalyst to generate fused bicyclic aromatic ketone products with three new stereocentres (which
are susceptible to subsequent equilibration) in 12–99% ee. An unusual equilibration process which occurs
in methanolic medium in the absence of a recognisable base via proton transfer at the α-carbon of an
ester was investigated experimentally and computationally.
Received 2nd December 2016,
Accepted 6th January 2017
DOI: 10.1039/c6ob02637k
www.rsc.org/obc
Introduction
Some three decades ago, Tamura et al. reported that activated
alkynes and alkenes could undergo cycloaddition reactions
with enolisable anhydrides such as homophthalic anhydride
(1) at high temperature to form (after decarboxylation)
naphthol products.1–3 Later, it was demonstrated that the
same reaction could be mediated by strong bases.4 In an intri-
guing example, it was shown that at 0 °C, the doubly activated
olefin 2 could react with 1 on the presence of NaH to furnish
the chiral bicyclic product 3 in good yield (Fig. 1A). The dia-
stereomeric ratio was not determined. It was postulated that
the reaction proceeded through either a stepwise addition–
cyclisation mechanism involving the conjugate base of enol 1b
or a Diels–Alder reaction passing through the corresponding
anion derived from tautomer 1c.4a
While the Tamura cycloaddition has proven itself of value
in the synthesis of polycyclic aromatic natural products,5 the
general lack of examples involving the generation of chiral pro-
ducts from activated alkenes (i.e. those in which stereochemi-
cally destructive aromatisation is avoided) and the requirement
for activating groups at both alkene carbon atoms,6 has
limited the utility of the process considerably. In addition,
neither efficient catalytic nor asymmetric variants of this
process were developed until 2014. We found that the doubly
activated oxindole-based Michael acceptor 4 reacted with 1 in
the presence of the bifunctional squaramide-based catalyst 5
at 30 °C to yield (after in situ esterification) the spirocyclic
Fig. 1 Tamura cycloaddition reactions.
product
6 in excellent yield and enantiomeric excess
(Fig. 1B).7–9 To the best of our knowledge this remains the
only example of this type of catalytic asymmetric Michael-type
reaction involving enolisable anhydrides.
In order to probe the potential utility of this process
further, we wished to extend its scope to include a less
complex (but synthetically malleable) Michael acceptor – pre-
ferably one which incorporated a single activating group. This
proved to be considerably less straightforward than one might
expect. Herein we report the results of a study culminating in
the development of a protocol for the formal cycloaddition of
anhydride 1 to α-methyl nitroolefins to generate densely func-
tionalised bicyclic products of general type 8 (Fig. 1C) with the
formation of 3 contiguous stereocentres – one of which is qua-
ternary – with a high degree of control. The exploitation of a
School of Chemistry Trinity Biomedical Sciences Institute, Trinity College Dublin,
152-160 Pearse Street, Dublin 2, Ireland. E-mail: connons@tcd.ie;
Fax: (+353)16712826
†Electronic supplementary information (ESI) available: Spectra and chromato-
grams. CCDC 1519677. For ESI and crystallographic data in CIF or other elec-
tronic format see DOI: 10.1039/c6ob02637k
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highly unusual, temperature sensitive epimerisation of the time and temperature, leading to what at first appeared to be
esterified product is also documented.
irreproducible results. The minor diastereomer 13b converts to
the 13a upon completion of the reaction. This equilibration
also occurs both during and after the esterification event and
even was observed during evaporation of the solvent during
purification.12
Results and discussion
After considerable experimentation, a set of standardised
conditions were developed involving reaction at 30 °C for pre-
cisely 22 h in MTBE (0.1 M) followed by esterification at 0 °C
and a careful purification protocol which avoids concentration
of the solvent at temperatures higher than 30 °C. When this
process was strictly adhered to, the results of the cycloaddition
reactions were reproducible.
The influence on the catalyst structure on the process was
next examined (Table 1). While the urea-derivative 14 proved
effective (entry 1), it promoted less enantio- and diastereo-
selective cycloaddition than the corresponding squaramide
derivative 10 (entry 2). Augmentation of the bulk of the squar-
amide group (catalysts 15 and 16, entries 3 and 4 respectively)
led to the formation of 13a in 84% ee and 13b in almost opti-
cally pure form.
We next set about trying to exploit the amenability of 13b to
epimerisation (Table 2). Acting on the presumption that the
catalyst facilitated this process, a mixture of 13a (88% ee) and
13b (>99% ee, ca. 2 : 1 dr) was treated with excess MeOH in the
presence of catalyst 10 at 55 °C (entry 1). After 39 h the levels
of 13b in solution had reduced markedly, and the ee of 13a
had increased almost to the maximum possible based on the
assumption that 13b converts to 13a without erosion of its
enantiomeric excess. Use of the more bulky squaramide
Our investigations began with the reaction of (E)-β-nitrostyrene
(9) with homophthalic anhydride (1) in MTBE10 at ambient
temperature in the presence of the bifunctional squaramide-
based catalyst 10, which resulted in the formation of the di-
hydronaphthol product 11 in 53% yield as a mixture of diastereo-
mers (Scheme 1).
While it was gratifying to obtain proof of principle that
olefins possessing only one activating group could participate
in the process – two drawbacks immediately presented them-
selves. Firstly, the high acidity of the nitroalkane favours the
formation the enol 11 as the sole tautomer observable by
1H NMR spectroscopy, resulting in the loss of an initially
formed stereocentre. Second, 11 was not amenable to in situ
esterification by trimethylsilyldiazomethane (which allows
facile analysis of the product by CSP-HPLC and had previously
proved useful in preventing retro-cycloaddition7); instead
undergoing decomposition.
To circumvent both difficulties, the electrophile was
modified to preclude keto–enol tautomerism and the for-
mation of the reactive nitroenol unit characteristic of 11.
Repetition of the process outlined in Scheme 1 using the
β-methylnitrostyrene 12 provided a considerably more success-
ful outcome – the annulated products containing two new C–C
bonds and three contiguous stereocentres (one quaternary)
were formed as a diastereomeric pair (i.e. 13a–b) smoothly in
a relatively rapid11 and high-yielding process (Scheme 2).
With one problem solved, another immediately presented
itself: diastereocontrol was highly dependent on both reaction
Table 1 The influence of the catalyst on stereocontrol
Scheme 1 Proof of principle: a catalysed reaction of a nitroolefin with
homophthalic anhydride.
dra
13a : 13b
(acids)
dra
13a :13b
(esters)
Conv.a
(%)
ee13a
(%)
ee13b
(%)
b
b
Entry
Cat.
1
2
3
4
14
10
15
16
>98
>98
>98
>98
56 : 44
68 : 32
53 : 47
63 : 37
62 : 38
72 : 28
57 : 43
68 : 32
58
60
72
84
97
97
99
99
a Determined by 1H NMR spectroscopy. b Determined by CSP-HPLC,
see Experimental section.
Scheme 2 Prevention
cycloaddition.
of
keto–enol
tautomerism:
efficient
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Table 2 Exploitation of the epimerisation process
Table 4 Product epimerisation
Initiala
a : b
eea
(%)
eeb
Finala
a : b
eea
Yieldc
(%)
b
b
b
Loading
(mol%)
MeOH
(equiv.)
Final dra
13a : 13b
ee13a
(%)
Yieldc
(%)
b
Entry
Prod.
(%)
(%)
Entry
Cat.
1
2
3
4
5
6
13
18
19
20
21
22
57 : 43
56 : 44
79 : 21
59 : 41
86 : 14
89 : 11
72
67
80
74
12
51
99
96
99
99
96
87
96 : 4
>99 : 1
>98 : 2
96 : 4
93 : 7
89 : 11
80
77
83
82
28
50
91
93
93
92
88
82
1
2
3
4
10
16
10
—
5
5
5
0
75
75
0
94 : 6
91 (92)d
n.d.
n.d.
90
72 : 28
65 : 35
92 : 8
n.d.
n.d.
89
75
92 (92)
a Determined by 1H NMR spectroscopy. b Determined by CSP-HPLC,
see the ESI. c Isolated yield of 13a. d Maximum calculated ee (%) in
parenthesis.
a Determined by 1H NMR spectroscopy. b Determined by CSP-HPLC,
see the ESI. c Isolated yield of the a product.
derivative 16 resulted in considerably slower rates of epimeri-
sation (entry 2). Intriguingly, repetition of the reaction involv-
ing catalyst 10 in the absence of methanol led to only trace
levels of conversion of 13b to 13a (entry 3). Finally, upon
execution of the process without an amine-based catalyst but
in the presence of methanol (entry 4), efficient epimerisation
allowed 13a to be isolated in 89% yield and 92% ee.
Attention then turned to the issue of substrate scope.
Homophthalic anhydride (1) was reacted with a range of
methylnitroalkenes 12 and 17a–g in the presence of (the con-
siderably more easily prepared) catalyst 15 and the products
esterified in situ (Table 3). Electron neutral (entries 1 and 2),
activated (entry 3) and deactivated (entry 4) nitroalkenes were
transformed into the bicyclic products 13 and 18–20 smoothly.
Diastereocontrol ranged from moderate to good (in the case of
the product 19) with a preference for the isomer with the
β-ester group. The ee of disatereomers 13a and 18–20a were
between 67 and 80%, while the minor counterparts 13b and
18–20b were formed with outstanding enantiocontrol.
Subsequent epimerisation of the products 13 and 18–22
under the previously established conditions (Table 4) pro-
ceeded as expected when the products were derived from nitro-
styrenes (entries 1–5); leading to the isolation of 13a and
18a–21a in good-excellent yield, with significant enhance-
ments in both the diastereomeric ratio and enantiomeric
excess. The ester 22a however, which incorporates an aliphatic
substituent in place of an aromatic ring – proved resistant to
epimerisation (entry 6).
The process is also compatible with a substituted homo-
phthalic anhydride (Scheme 3). Anhydride 25 was reacted with
12 catalysed by 15, which, after esterification, resulted in the
formation of 26a–b. Subjection of these to the epimerisation
conditions allowed the isolation of 26a in excellent yield,
>99 : 1 dr and 86% ee. The relative and absolute configuration
of both 26a and 26b were confirmed using X-ray crystallo-
graphic analysis.
Table 3 Substrate scope
Conv.a
(%)
dra a : b
(acids)
dra a : b
(esters)
eea
eeb
b
b
Entry
Prod.
(%)
(%)
1
2
3
4
13
18
19
20
21
22
23
24
>98
>98
95
96
>98
90
53 : 47
54 : 46
63 : 31
57 : 43
77 : 23
88 : 12
n.d.
57 : 43
56 : 44
79 : 21
59 : 41
86 : 14
89 : 11
98 : 2
72
67
80
74
12
51
49
52
99
96
99
99
96
87
—
—
5
6
7c
8d
55
51
n.d.
99 : 1
a Determined by 1H NMR spectroscopy. b Determined by CSP-HPLC,
see the ESI. c 8 days reaction time. d 7 days reaction time.
Scheme 3 Cycloaddition with 3-bromo-homophthalic anhydride.
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Table 5 Relative energies (ΔE in kcal mol−1) respect to the entrance
channel at B3LYP/6-311+G(d,p), computational level in PCM-diiso-
propylether with one and two molecules of methanol
Molecules
2MeOH molecules
1MeOH molecule
Scheme 4 Selective reduction of 13a.
13a·2MeOH
TS1
28·2MeOH
TS2
13b·2MeOH
−9.1
18.7
1.7
21.5
−10.7
−2.4
35.9
12.9
35.5
−3.2
the nitro group and the proton involved in the epimerisation
process is ca. 2.74 Å, so a mechanism involving proton transfer
mediated by the proximal nitro functional group was pro-
posed. However, calculations indicated that this mechanism is
unfavourable from the thermodynamic point of view, with a
relative energy higher than 50 kcal mol−1 with respect to the
entrance channel.
An alternative mechanism in which a proton transfer is
assisted by explicit solvent (methanol) molecules was also con-
sidered. The energy profile corresponding to the epimerisation
processes involving both one and two molecules of methanol
have been studied – the relative energies of all species with
respect to the entrance channel are summarised in Table 5. It
was found that proton transfer aided by two molecules of
MeOH was considerably more kinetically favorable than the
analogous process mediated by a single additive molecule
(Table 5).
Fig. 2 shows the potential energy surface for the mecha-
nism corresponding to epimerisation process; the entrance
channel (i.e. 13a+2MeOH) represents the sum of energies
associated with compound 13a and two explicit (unbound)
molecules of methanol. The first minimum (named
13a·2MeOH) corresponds to 13a interacting with two mole-
cules of methanol in a complex. In the first step (13a·2MeOH
to 28·2MeOH via TS1), a shuttle (concerted) deprotonation-
protonation process occurs involving both MeOH molecules
bound to both each other and the substrate, with a barrier of
Scheme 5 Deuterium incorporation experiments.
In order to demonstrate that the ketone functionality can be
manipulated in a diastereocontrolled manner, α-nitroketone 13a
(89% ee) was reduced by sodium borohydride in methanolic
solvent to produce the densely functionalised product 27 –
which contains 4 contiguous stereocentres – with excellent yield
and diastereocontrol, without any erosion of the enantiomeric
excess (Scheme 4).
We also carried out experiments with the aim of shedding
light on the mechanism of the epimerisation process
(Scheme 5). Diastereomerically pure 13a was subjected to the
epimerisation conditions in the presence of CD3OD leading to
60% incorporation of deuterium α to the ester functionality
(i.e. 13a′, Scheme 5A). This shows that even the more stable
diastereomer 13a undergoes proton transfer under these con-
ditions. An identical experiment involving the kinetic diastereo-
mer 13b yielded different data. The expected epimerisation
process occurred (70 : 30 dr); and while 13a′ was formed with
65% D incorporation, the corresponding epimer 13b′ was gen-
erated almost entirely deuterated (Scheme 5B). Therefore it
seems clear that (despite the lack of a recognisable base) the
proton transfer event is intermolecular and involves the protic
additive. These experiments also indicate that the less stable
diastereomer 13b undergoes more facile proton transfer than
its epimer 13a, which is consistent with the epimerisation of
13b to 13a being driven by a proton transfer process.
Calculations
In order to provide a better understanding of the mechanism
behind the epimerisation process a theoretical study (DFT) of
the reaction mechanism has been carried out. Both calculation
Fig. 2 Potential energy surfaces corresponding to the epimerisation
and XRD data indicated that intramolecular distance between reaction with two molecules of methanol.
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accepting group. An intriguing epimerisation process, which
proceeds in methanol in the absence of catalysts was detected
and subsequently exploited to convert the kinetic diastereomer
into its thermodynamic counterpart, with concomitant
improvement in product ee: thus the methodology allows
access to both diastereomers in enantioenriched form.
Deuterium isotope exchange experiments and DFT calcu-
lations have both shed light on the likely mechanism of
exchange, which involves shuttle proton transfer facilitated by
the protic additive.
Scheme 6 Epimerisation using ethylene glycol and ethanol.
Experimental section
Experimental details
18.7 kcal mol−1. However, the barrier associated the corres-
ponding reaction involving 13b·2MeOH to 28·2MeOH via TS2
process is slightly higher (21.5 kcal mol−1). It is noteworthy
that 13b·2MeOH is 1.6 kcal mol−1 more stable than
13a·2MeOH. While these calculations represent a simplifica-
tion of scenario associated with the actual epimerisation
event, it is consistent with the findings from the deuteration
experiments – i.e. that 13a epimerises faster than 13b, and 13b
is the more stable of the two diastereomers in the presence of
MeOH additive. We would suggest that the use of 75 equi-
valents of MeOH mitigates against the entropic penalty associ-
ated with the assembly of the two methanol molecules around
the ester functional group, without significantly altering the
bulk properties of the solvent.
As the calculations indicated that two methanol molecules
seem to assist in the epimerisation of 13a in cyclical fashion,
we predicted that ethylene glycol could serve as a useful substi-
tute in which the system would incur less of an entropic
penalty as catalysis proceeded. Under the standard reaction
conditions the epimerisation proceeded faster with ethylene
glycol than methanol giving 13b product almost exclusively in
24 h, with partial decomposition (presumably via ketalisation),
whereas use of EtOH as an additive provided no discernible
epimerisation whatsoever (Scheme 6). We cannot rule out the
possibility that more than 2 alcohol molecules are involved in
the transition state, however the efficacy of ethylene glycol and
our calculations indicate that a two-molecule pathway is ener-
getically feasible.
Proton Nuclear Magnetic Resonance (NMR) spectra were
recorded on Bruker DPX 400 MHz and Bruker Avance II
600 MHz spectrometers, using as solvent CDCl3 or DMSO-d6
and referenced relative to residual CHCl3 (δ = 7.26 ppm) DMSO
(δ = 2.50 ppm). Chemical shifts are reported in ppm and coup-
ling constants (J) in Hertz. Carbon NMR spectra were recorded
on the same instruments (100.6 MHz and 150.9 MHz respect-
ively) with total proton decoupling. All melting points are
uncorrected. Infrared spectra were obtained on a Perkin Elmer
Spectrum 100 FT-IR spectrometer equipped with a universal
ATR sampling accessory. ESI mass spectra were acquired using
a Waters Micromass LCT-time of flight mass spectrometer
(TOF), interfaced to a Waters 2690 HPLC. The instrument was
operated in positive or negative mode as required. EI mass
spectra were acquired using a GCT Premier Micromass time of
flight mass spectrometer (TOF). The instrument was operated
in positive mode. APCI experiments were carried out on a
Bruker microTOF-Q III spectrometer interfaced to a Dionex
UltiMate 3000 LC or direct insertion probe. The instrument
was operated in positive or negative mode as required. Agilent
tuning mix APCI-TOF was used to calibrate the system. Flash
chromatography was carried out using silica gel, particle size
0.04–0.063 mm. TLC analysis was performed on precoated
60F254 slides, and visualized by UV irradiation and KMnO4
staining. Optical rotation measurements are quoted in units of
10−1 deg cm2 g−1. Methanol (MeOH), ethylene glycol, and iso-
propyl alcohol (i-PrOH) were dried over activated 3 Å molecular
sieves. Commercially available anhydrous t-butyl methyl ether
(MTBE) was used. Analytical CSP-HPLC was performed on
Daicel Chiralpak, AD, AD-H, IA, or Chiralcel OD, OD-H, OJ-H
(4.6 mm × 25 cm) columns. The X-ray crystallography data for
crystal sample cis-26b was collected on a Rigaku Saturn 724
CCD diffractometer. Compound 12 was bought from Aldrich
and was used without further purification.
Conclusions
The recently developed C–C bond forming asymmetric Tamura
cycloaddition reaction has been extended to include nitro-
alkene substrates. In the presence of a bulky squaramide-based
bifunctional catalyst, homophthalic anhydrides react with
these electrophiles to give a pair of fused bicyclic ketone dia-
stereomeric products (with the generation of three new stereo-
Procedure for synthesis of homophthalic anhydride 1
centres) with poor-moderate diastereocontrol and moderate- A 100 mL round-bottomed flask containing a magnetic stirring
excellent enantiocontrol. The minor diastereomer is invariably bar was charged with homophthalic acid (2.0 g, 11.1 mmol).
formed in higher enantiomeric excess. This is the first Acetic anhydride (25 mL) was added, the flask was fitted with
example of an asymmetric Tamura cycloaddition reaction a condenser and the reaction mixture was heated at 80 °C for
involving an alkene which is substituted with a single electron 2 h. The excess acetic anhydride was removed in vacuo and the
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solid obtained was triturated with diethyl ether (10 mL), fil- graphically isolated together. Temperature was maintained
tered and dried to obtain homophthalic anhydride (1) as an below 30 °C during the removal of the solvent under reduced
off white solid (1.53 g, 85%). M.p. 141–142 °C (lit.12 pressure.
m.p. 143–144 °C); δH (400 MHz, DMSO-d6) 8.05 (1 H, d, J =
General procedure C: enantioselective preparation of products
13 and 18–24 (Tables 1 and 3)
7.9), 7.75 (1 H, app. t), 7.52 (1 H, app. t), 7.44 (1 H, d, J = 7.8),
4.28 (2 H, s); HRMS (m/z – ESI) Found: 161.0232 (M − H)−
C9H5O3 requires: 161.0239. Spectral data for this compound An oven-dried 10 mL reaction vessel containing a magnetic
were consistent with those in the literature.13
stirring bar under argon atmosphere was charged with the
relevant β-methyl-(E)-nitroalkene (0.246 mmol) and with a
corresponding catalyst (0.0123 mmol – 5 mol%). Anhydrous
General procedure A: preparation of nitroalkenes (12, 17a–g)
An oven-dried 25 mL round-bottomed flask containing a mag- MTBE (2.5 mL, 0.1 M) was then added via syringe and the reac-
netic stirring bar under argon atmosphere was charged with tion mixture was warmed to room temperature (Table 1) or the
dry THF (2.5 mL), t-butanol (2.5 mL) and nitroethane (1.1 mL, equilibrated temperature of 30 °C while stirring (Table 3). The
15.0 mmol). The mixture was then cooled at 0 °C and the rele- relevant anhydride (0.246 mmol) was then added to the
vant aldehyde (10.0 mmol), followed by potassium t-butoxide mixture and the reaction was allowed to stir for the time indi-
(t-BuOK, 112.2 mg, 1.00 mmol – 10 mol%), were added. The cated in Tables 1 and 3. The diastereomeric ratio of the acid
reaction was allowed to warm to room temperature and was product formed was then determined by 1H NMR spectro-
allowed to stir for 12 h. The mixture was then poured into scopic analysis. The reaction was cooled to 0 °C and anhydrous
water (10 mL) and extracted with EtOAc (3 × 10 mL), the com- MeOH (0.75 mL, 18.5 mmol), followed by trimethyl-
bined organic phases were dried over anhydrous MgSO4, fil- silyldiazomethane (2.0 M solution in diethyl ether, 0.15 mL,
tered and concentrated under reduced pressure to give the 0.300 mmol), were added via syringe to the reaction that was
relative crude β-nitroalcohol that was used in the next step allowed to stir for 20 min. The crude reaction mixture contain-
without any further purification.
ing the diastereomeric esters was directly loaded onto the
The relative β-nitroalcohol obtained was dissolved in di- silica column and the two diastereomers were chromato-
chloromethane (10 mL) and added via syringe to a 50 mL graphically isolated together. Temperature was maintained
oven-dried reaction vessel containing a magnetic stirring bar below 30 °C during the removal of the solvent under reduced
under argon atmosphere and cooled to −10 °C. To this solu- pressure. The diastereomeric ratio and the enantiomeric
tion was then added via syringe trifluoroacetic anhydride excess of the product formed, upon esterification, were then
(TFAA, 1.5 mL, 10.5 mmol) and the reaction was allowed to stir determined by CSP-HPLC using the conditions indicated in
for 30 min at −10 °C. Triethylamine (2.8 mL, 20.0 mmol) was each case.
then added dropwise and the reaction was allowed to stir for
additional 30 min at −10 °C. The resulting mixture was
quenched with the addition of saturated aqueous NH4Cl solu-
General procedure D: optimised epimerisation reaction
(Tables 2 and 4)
tion (15 mL) and extracted with EtOAc (3 × 10 mL). The com- The two isolated diastereomers of the product formed with the
bined organic phases were then dried over anhydrous MgSO4, general procedure C were then dissolved in a mixture of MTBE
filtered and concentrated in vacuo to give a residue that was (2.5 mL) and MeOH (0.75 mL) and transferred via syringe to
purified by flash column chromatography, eluting from 100% an oven-dried 10 mL round-bottomed flask containing a mag-
hexanes to 5% EtOAc in hexanes to furnish the relative netic stirring bar. The flask was fitted with a condenser and
nitroalkene (12 and 17a–g).
the mixture was heated at reflux temperature for the time indi-
cated in Tables 2 and 4. Solvent was removed in vacuo and the
residue obtained was analysed by 1H NMR spectroscopy to
General procedure B: racemic preparation of products 13, 18–24
An oven-dried 10 mL reaction vessel containing a magnetic determine the diastereomeric ratio of product formed upon
stirring bar under argon atmosphere was charged with the epimerisation reaction. The major diastereomer (trans) was
relevant β-methyl-(E)-nitroalkene (0.246 mmol) and with the then isolated by flash column chromatography, eluting from
relevant homophthalic anhydride (0.246 mmol). Anhydrous 100% hexanes to 20% EtOAc in hexanes and the enantiomeric
MTBE (2.5 mL, 0.1 M), followed by N,N-diisopropylethylamine excess was determined by CSP-HPLC analysis using the con-
(0.086 mL, 0.0492 mmol – 20 mol%), were then added via ditions indicated in each case.
syringe and the reaction mixture was allowed to stir at room
temperature for 22 h. The reaction mixture containing the
General procedure E: epimerisation reaction (Schemes 5 and 6)
corresponding carboxylic acid was then cooled to 0 °C and The two isolated diastereomers of the product formed with the
anhydrous MeOH (0.75 mL, 18.5 mmol), followed by trimethyl- general procedure C were then dissolved in a mixture of MTBE
silyldiazomethane (2.0 M solution in diethyl ether, 0.15 mL, (2.5 mL) and CD3OD (0.75 mL) or EtOH or ethylene glycol and
0.300 mmol) were added via syringe and the reaction was transferred via syringe to an oven-dried pressure tube contain-
allowed to stir for 20 min. The crude reaction mixture contain- ing a magnetic stirring bar. The tube was sealed and then the
ing the diastereomeric esters was directly loaded onto the mixture was heated at reflux temperature for the time indi-
silica column and the two major diastereomers were chromato- cated in Schemes 5 and 6. Solvent was removed in vacuo and
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1
the residue obtained was analysed by H NMR spectroscopy to (lit.16 m.p. 46–47 °C); TLC (hexanes : EtOAc, 9 : 1 v/v): Rf = 0.35.
determine the diastereomeric ratio of product formed upon Spectral data for this compound were consistent with those in
epimerisation reaction. Then the P-iodoanisole was added as the literature.16 δH (400 MHz, CDCl3): 7.86 (1 H, s), 7.64 (1 H,
an internal standard to check the deuterium insertion.
d, J = 1.7), 6.82 (1 H, d, J = 3.5), 6.58 (1 H, dd, J = 1.7, 3.5), 2.60
3-(tert-Butylamino)-4-(((S)-(6-methoxyquinolin-4-yl)((1S,2S,4S,5R)- (3 H, s); HRMS (m/z – APCI-DIP): Found: 154.0499 (M + H)+
5-vinylquinuclidin-2-yl)methyl)amino)cyclobut-3-ene-1,2-dione (15). C7H8NO3 requires: 154.0494.
Synthesised according to the literature procedure and the spec-
(E)-(4-Nitropent-3-en-1-yl)benzene (17e). Prepared according
tral data for this compound were consistent with those in the to general procedure A, using freshly distilled hydrocinnam-
literature.7 M.p. 250 °C decomposition; TLC (EtOAc : MeOH, aldehyde (1.3 mL, 10.0 mmol). After purification, product 17e
9 : 1 v/v): Rf = 0.10; δH (400 MHz, CDCl3): 8.70 (1 H, d, J = 4.0), was obtained as yellow oil (1.31 g, 69%). TLC (hexanes : EtOAc,
8.02 (1 H, d, J = 9.2), 7.78 (1 H br), 7.56 (1 H, d, J = 4.0), 7.40 9 : 1 v/v): Rf = 0.36. Spectral data for this compound were con-
(1 H, d, J = 9.2), 6.29–5.84 (1 H, m), 5.82–5.65 (1 H, m), sistent with those in the literature.17 δH (400 MHz, CDCl3):
5.05–4.88 (2 H, m), 3.96 (3 H, s), 3.67–3.27 (2 H, m), 3.15 (1 H, 7.31 (2 H, app. t), 7.23–7.18 (1 H, t, J = 7.4 H-3), 7.18–7.09 (3 H,
app. t), 2.82–2.62 (2 H, m), 2.36–2.19 (1 H, m), 1.75–1.52 (3 H, m), 2.80 (2 H, t, J = 7.5), 2.53 (2 H, app. q), 2.03 (3 H, s);
m), 1.51–1.38 (1 H, m), 1.17 (9 H, s), 0.91–0.72 (1 H, m); HRMS δC (100 MHz, CDCl3): 148.3, 140.1, 135.0, 128.7, 128.5, 126.6,
(m/z – ESI): Found: 475.2712 (M + H)+ C28H35N4O3 requires: 34.4, 30.1, 12.5; HRMS (m/z – APCI-DIP): Found: 190.0868
475.2709.
(M − H)− C11H12NO2 requires: 190.0863.
(E)-(2-Nitroprop-1-en-1-yl)cyclohexane
(17f).
Prepared
Characterisation data for synthesised of nitroalkenes (17a–g)
according to general procedure A, using freshly distilled cyclo-
(E)-2-(2-Nitroprop-1-en-1-yl)naphthalene (17a). Prepared hexanecarboxaldehyde (1.21 mL, 10.0 mmol). After purifi-
according to general procedure A, using recrystallised cation, product 17f was obtained as yellow oil (1.08 g, 65%).
2-naphthaldehyde (1.56 g, 10.0 mmol). After purification, TLC (hexanes : EtOAc, 9 : 1 v/v): Rf = 0.61. Spectral data for this
product 17a was obtained as a yellow solid (1.60 g, 75%). compound were consistent with those in the literature.15 δH
M.p. 86–87 °C (lit.13 m.p. 81–83.5 °C); TLC (hexanes: EtOAc, (400 MHz, CDCl3): 6.97 (1 H, d, J = 10.0), 2.34–2.20 (1 H, m),
9 : 1 v/v): Rf = 0.43. Spectral data for this compound were con- 2.17 (3 H, s), 1.84–1.63 (5 H, m), 1.40–1.16 (5 H, m); δC
sistent with those in the literature.14 δH (400 MHz, CDCl3): (100 MHz, CDCl3): 146.4, 141.0, 37.7, 31.8, 25.7, 25.4, 12.7;
8.26 (1 H, s), 7.95–7.84 (4 H, m), 7.61–7.50 (3 H), 2.55 (3 H); δC HRMS (m/z – APCI): Found: 170.1176 (M + H)+ C9H16NO2
(100 MHz, CDCl3): 147.9, 133.9, 133.7, 133.1, 130.7, 129.9, requires: 170.1168.
128.8, 128.6, 127.9, 127.8, 127.1, 126.5, 14.3; νmax (neat)/cm−1
:
(E)-4-Methyl-2-nitropent-2-ene (17g). Prepared according to
3066, 2979, 2928, 1623, 1510, 1440, 1386, 1313, 1159, 1028, general procedure A, using freshly distilled isobutyraldehyde
991, 954, 930, 826, 759, 725; HRMS (m/z – APCI): Found: (0.913 mL, 10.0 mmol). After purification, product 17g was
214.0863 (M + H)+ C13H12NO2 requires: 214.0865.
obtained as yellow oil (813.2 mg, 63%). TLC (hexanes : EtOAc,
(E)-1-Chloro-4-(2-nitroprop-1-en-1-yl)benzene (17b). Prepared 9 : 1 v/v): Rf = 0.54. Spectral data for this compound were con-
according to general procedure A, using recrystallised 4-chloro- sistent with those in the literature.15 δH (400 MHz, CDCl3):
benzaldehyde (1.41 g, 10 mmol). After purification, product 6.95 (1 H, d, J = 10.3, H-3), 2.66–2.50 (1 H, m, H-2), 2.17 (3 H,
17b was obtained as
a yellow solid (1.44 g, 73%). s, H-4), 1.11 (6 H, d, J = 6.7, H-1); HRMS: Analysis of product
M.p. 81–82 °C (lit.15 m.p. 84–85 °C); TLC (hexanes : EtOAc, 17g by high resolution mass spectrometry was not successful
9 : 1 v/v): Rf = 0.46. Spectral data for this compound were con- despite intensive efforts. ESI, EI, APCI and APCI-DIP tech-
sistent with those in the literature.15 δH (400 MHz, CDCl3): niques were all performed. Due to technical issues on the
8.03 (1 H, s), 7.44 (2 H, d, J = 8.8), 7.37 (2 H, d, J = 8.8), 2.44 instrument, the CI technique could not be performed. As
(3 H, s); δC (100 MHz, CDCl3): 148.2, 136.2, 132.4, 131.3, 130.9, proof for the formation of 17g, the 1H NMR spectrum is
129.4, 14.1.
attached in the ESI.†
(1R,2S,3S)-Methyl
(E)-1-Methoxy-4-(2-nitroprop-1-en-1-yl)benzene (17c). Prepared
3-methyl-3-nitro-4-oxo-2-phenyl-1,2,3,4-
according to general procedure IX, using freshly distilled tetrahydronaphthalene-1-carboxylate (trans-13a, Table 4, entry 1).
4-methoxybenzaldehyde (1.2 mL, 10.0 mmol). After purifi- Prepared according to the consecutive use of general pro-
cation, product 17c was obtained as a yellow solid (1.26 g, cedures C and D using catalyst 15 (5.8 mg, 0.0123 mmol –
65%). M.p. 41–42 °C (lit.15 m.p. 46–47 °C); TLC 5 mol%). Upon epimerisation, the reaction gave a diastereo-
(hexanes : EtOAc, 9 : 1 v/v): Rf = 0.26. Spectral data for this com- meric mixture of esters in a 96 : 4 (trans : cis) ratio. The major
pound were consistent with those in the literature.14 diastereomer (trans-13a) was purified by flash column chrom-
δH (400 MHz, CDCl3): 8.07 (1 H, s), 7.43 (2 H, d, J = 8.7), 6.98 atography, eluting in gradient from 100% hexanes to 20%
(2 H, d, J = 8.7), 3.86 (3 H, s), 2.47 (3 H, s); HRMS (m/z – APCI): EtOAc in hexanes, to give a white solid (75.8 mg, 91%). M.
Found: 194.0812 (M + H)+ C10H12NO3 requires: 194.0817.
p. 180–181 °C; TLC (hexanes : EtOAc, 8 : 2 v/v): Rf = 0.24; [α]D20
=
(E)-2-(2-Nitroprop-1-en-1-yl)furan (17d). Prepared according +90.8 (c = 0.20, CHCl3). CSP-HPLC analysis: Chiralpak AD-H
to general procedure A, using freshly distilled furan-2-carb- (4.6 mm × 25 cm), hexane/IPA: 95/5, 1.0 mL min−1, RT,
aldehyde (0.828 mL, 10.0 mmol). After purification, product 17d UV detection at 254 nm, retention times: trans-13a 14.0 min
was obtained as a yellow solid (918.8 mg, 60%). M.p. 46–48 °C (minor enantiomer) and 25.0 min (major enantiomer); cis-13b
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7.9 min (major enantiomer) and 8.9 min (minor enantiomer);
(1R,2S,3S)-Methyl 2-(4-chlorophenyl)-3-methyl-3-nitro-4-oxo-
δH (400 MHz, CDCl3): 8.22 (1 H, d, J = 8.0), 7.67 (1 H, app t), 1,2,3,4-tetrahydronaphthalene-1-carboxylate (trans-19a, Table 4,
7.53 (1 H, app t), 7.38–7.31 (4 H, m), 7.29–7.22 (2 H, m), entry 3). Prepared according to the consecutive use of general
4.82 (1 H, d, J = 12.3), 4.58 (1 H, d, J = 12.3), 3.57 (3 H, s), procedures
1.72 (3 H, s); δC (100 MHz, CDCl3): 189.9, 171.0, 138.9, 135.4, (48.6 mg, 0.246 mmol) and anhydride
C
and D, using β-methyl-(E)-nitroalkene 17b
(39.9 mg,
1
133.3, 129.6, 129.2, 129.1, 129.07, 129.0, 128.8, 127.3, 97.0, 0.246 mmol). Upon epimerisation, the reaction gave a diaster-
52.8, 50.3, 48.9, 16.2; νmax (neat)/cm−1: 3008, 2955, 1732, 1692, eomeric mixture of esters in a >98 : 2 (trans : cis) ratio. The
1598, 1550, 1453, 1345, 1211, 1166, 970, 794, 733, 700; HRMS major diastereomer (trans-19a) was purified by flash column
(m/z – ESI): Found: 338.1027 (M − H)− C19H16NO5 requires: chromatography, eluting in gradient from 100% hexanes to
338.1028.
20% EtOAc in hexanes, to give a white solid (85.6 mg, 93%).
(1S,2S,3S)-Methyl
3-methyl-3-nitro-4-oxo-2-phenyl-1,2,3,4- M.p. 200–202 °C; TLC (hexanes : EtOAc, 8 : 2 v/v): Rf = 0.24;
tetrahydronaphthalene-1-carboxylate (cis-13b, Table 3, entry 1). [α]2D0 = +88.5 (c = 0.20, CHCl3); CSP-HPLC analysis. Chiralpak
Prepared according to general procedure C using catalyst 15 AD-H (4.6 mm × 25 cm), hexane/IPA: 95/5, 1.0 mL min−1, RT,
(5.8 mg, 0.0123 mmol – 5 mol%). The cis-diastereomer (cis- UV detection at 254 nm, retention times: trans-19a 19.9 min
13b) was purified by flash column chromatography, eluting in (minor enantiomer) and 38.8 min (major enantiomer); cis-19b
gradient from 100% hexanes to 20% EtOAc in hexanes, to give 8.7 min (major enantiomer) and 9.7 min (minor enantiomer);
a white solid. M.p. 76–78 °C; TLC (hexanes : EtOAc, 8 : 2 v/v): δH (400 MHz, CDCl3): 8.22 (1 H, d, J = 7.2), 7.68 (1 H, app. t),
Rf = 0.39; [α]2D0 = −76.4 (c = 0.10, CHCl3); CSP-HPLC analysis: 7.54 (1 H, app. t), 7.38–7.29 (3 H, m), 7.21 (2 H, d, J = 6.8), 4.81
Chiralpak AD-H (4.6 mm × 25 cm), hexane/IPA: 95/5, 1.0 mL (1 H, d, J = 12.3), 4.52 (1 H, d, J = 12.3), 3.60 (3 H, s), 1.70 (3 H,
min−1, RT, UV detection at 254 nm, retention times: cis-13b s); δC (100 MHz, CDCl3): 189.5, 170.8, 138.5, 135.8, 135.2,
7.6 min (major enantiomer) and 8.6 min (minor enantiomer); 131.8, 130.5, 129.7, 129.4, 129.2, 128.7, 127.3, 96.8, 52.9, 49.7,
δH (400 MHz, CDCl3): 8.18 (1 H, d, J = 7.8), 7.65 (1 H, app. t), 48.8, 16.1; νmax (neat)/cm−1: 3001, 2956, 2924, 2851, 1741,
7.52 (1 H, app. t), 7.42 (1 H, d, J = 7.9), 7.22–7.26 (1 H, m), 7.18 1698, 1596, 1550, 1491, 1438, 1290, 1255, 1166, 1091, 1004,
(2 H, app. t), 6.97 (2 H, d, J = 7.4), 4.66 (1 H, d, J = 6.2), 4.58 844, 795, 740; HRMS (m/z – ESI): Found: 372.0639 (M − H)−
(1 H, d, J = 6.2), 3.45 (3 H, s), 1.64 (3 H, s); δC (100 MHz, C19H15NO5Cl requires: 372.0639.
CDCl3): 187.5, 170.8, 136.9, 134.6, 133.7, 132.2, 130.8, 129.6,
(1R,2S,3S)-Methyl
2-(4-methoxyphenyl)-3-methyl-3-nitro-
129.1, 128.9, 128.5, 128.2, 93.3, 53.1, 52.3, 46.1, 21.7; νmax 4-oxo-1,2,3,4-tetrahydronaphthalene-1-carboxylate (trans-20a,
(neat)/cm−1: 3004, 2952, 1743, 1701, 1599, 1542, 1457, 1298, Table 4, entry 4). Prepared according to the consecutive use of
1200, 1179, 1003, 941, 816, 765, 705; HRMS (m/z – ESI): Found: general procedures C and D, using β-methyl-(E)-nitroalkene
338.1026 (M − H)− C19H16NO5 requires: 338.1028.
17c (47.5 mg, 0.246 mmol) and anhydride 1 (39.9 mg,
(1R,2S,3S)-Methyl 3-methyl-3-nitro-4-oxo-1,2,3,4-tetrahydro- 0.246 mmol). Upon epimerisation, the reaction gave a diastereo-
[2,2′-binaphthalene]-1-carboxylate (trans-18a, Table 4, entry 2). meric mixture of esters in a 96 : 4 (trans : cis) ratio. The
Prepared according to the consecutive use of general pro- major diastereomer (trans-20a) was purified by flash column
cedure C and D, using β-methyl-(E)-nitroalkene 17a (52.5 mg, chromatography, eluting in gradient from 100% hexanes to
0.246 mmol) and anhydride 1 (39.9 mg, 0.246 mmol). Upon 20% EtOAc in hexanes, to give a white solid (83.2 mg, 92%).
epimerisation, the reaction gave a diastereomeric mixture of M.p. 193–195 °C; TLC (hexanes : EtOAc, 8 : 2 v/v): Rf = 0.17;
esters in a >99 : 1 (trans : cis) ratio. The major diastereomer [α]2D0 = +81.0 (c = 0.10, CHCl3); CSP-HPLC analysis: Chiralpak
(trans-18a) was purified by flash column chromatography, AD-H (4.6 mm × 25 cm), hexane/IPA: 95/5, 1.0 mL min−1, RT,
eluting in gradient from 100% hexanes to 20% EtOAc in UV detection at 254 nm, retention times: trans-20a 22.7 min
hexanes, to give
a
white solid (88.7 mg, 93%). M.p. (minor enantiomer) and 41.0 min (major enantiomer); cis-20b
10.9 min (major enantiomer) and 12.2 min (minor enantio-
205–207 °C; TLC (hexanes : EtOAc, 8 : 2 v/v): Rf = 0.21; [α]D20
=
+116.3 (c = 0.10, CHCl3); CSP-HPLC analysis: Chiralcel OD-H mer); δH (400 MHz, CDCl3): 8.21 (1 H, d, J = 7.9), 7.66 (1 H,
(4.6 mm × 25 cm), hexane/IPA: 95/5, 1.0 mL min−1, RT, UV app. t), 7.52 (1 H, app. t), 7.32 (1 H, d, J = 7.8), 7.18 (2 H, d, J =
detection at 254 nm, retention times: trans-18a 19.8 min 8.2), 6.86 (2 H, d, J = 8.2), 4.76 (1 H, d, J = 12.4), 4.52 (1 H, d,
(minor enantiomer) and 22.6 min (major enantiomer); cis-18b J = 12.4), 3.79 (3 H, s), 3.58 (3 H, s), 1.70 (3 H, s); δC (100 MHz,
10.5 min (major enantiomer) and 11.5 min (minor enantio- CDCl3): 190.1, 171.1, 159.9, 139.0, 135.6, 130.3, 129.6, 129.0,
mer); δH (400 MHz, CDCl3): 8.25 (1 H, d, J = 7.9), 7.87–7.79 128.9, 127.3, 125.1, 114.4, 97.2, 55.3, 52.8, 49.7, 49.1, 16.1;
(3 H, m), 7.74 (1 H, s), 7.69 (1 H, app. t), 7.59–7.47 (3 H, m), νmax (neat)/cm−1: 3000, 2960, 2927, 2849, 1739, 1693, 1595,
7.37 (2 H, app. d), 5.0 (1 H, d, J = 12.2), 4.72 (1 H, d, J = 12.2), 1550, 1513, 1438, 1385, 1344, 1294, 1250, 1182, 1107, 1027,
3.52 (3 H, s), 1.78 (3 H, s); δC (100 MHz, CDCl3): 189.9, 171.0, 837, 796, 737; HRMS (m/z – ESI): Found: 368.1147 (M − H)−
138.9, 135.7, 133.4, 133.3, 130.8, 129.7, 129.1, 128.9 (2C), C20H18NO6 requires: 368.1134.
128.8, 128.4, 127.8, 127.3, 126.9, 126.7, 126.3, 97.1, 52.9, 50.4,
(1R,2R,3S)-Methyl 2-(furan-2-yl)-3-methyl-3-nitro-4-oxo-1,2,3,4-
49.0, 16.4; νmax (neat)/cm−1: 3063, 3029, 3009, 2955, 2924, tetrahydronaphthalene-1-carboxylate (trans-21a, Table 4, entry 5).
2850, 1729, 1691, 1599, 1548, 1392, 1346, 1289, 1201, 1159, Prepared according to the consecutive use of general pro-
968, 820, 733; HRMS (m/z – ESI): Found: 388.1194 (M − H)− cedures C and D, using β-methyl-(E)-nitroalkene 17d (37.7 mg,
C23H18NO5 requires: 388.1185.
0.246 mmol) and anhydride 1 (39.9 mg, 0.246 mmol). Upon
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epimerisation, the reaction gave a diastereomeric mixture of tained 17% of dimethyl homophthalate as impurity that was
esters in a 93 : 7 (trans : cis) ratio. The major diastereomer not possible to separate. The given yield is calculated based on
(trans-21a) was purified by flash column chromatography, the mass return of the impure sample considering the spectro-
eluting in gradient from 100% hexanes to 20% EtOAc in scopically determined amount of the known impurity
hexanes, to give
a
white solid (71.1 mg, 88%). M.p. (42.2 mg, 50%). TLC (hexanes : EtOAc, 8 : 2 v/v): Rf = 0.38;
CSP-HPLC analysis: Chiralpak AD (4.6 mm × 25 cm), hexane/
136–138 °C; TLC (hexanes : EtOAc, 8 : 2 v/v): Rf = 0.22; [α]D20
=
+20.3 (c = 0.20, CHCl3); CSP-HPLC analysis: Chiralpak AD-H IPA: 90/10, 1.0 mL min−1, RT, UV detection at 254 nm, reten-
(4.6 mm × 25 cm), hexane/IPA: 95/5, 1.0 mL min−1, RT, UV tion times: trans-23a 6.6 min (major enantiomer) and 7.4 min
detection at 254 nm, retention times: trans-21a 11.7 min (minor enantiomer); δH (400 MHz, CDCl3): 8.07 (1 H, d, J =
(minor enantiomer) and 15.7 min (major enantiomer); cis-21b 7.7), 7.60 (1 H, app. t), 7.44 (1 H, app. t), 7.31 (1 H, d, J = 7.8),
8.7 min (major enantiomer) and 9.7 min (minor enantiomer); 4.11 (1 H, d, J = 8.8), 3.77 (3 H, s), 3.62–3.55 (1 H, m),
δH (400 MHz, CDCl3): 8.18 (1 H, d, J = 7.9), 7.67 (1 H, app. t), 1.79–1.49 (8 H, m), 1.48–1.36 (1 H, m), 1.35–0.95 (5 H, m); δC
7.51 (1 H, app.), 7.40 (1 H, app. s), 7.36 (1 H, d, J = 7.8), (100 MHz, CDCl3): 189.8, 172.9, 138.9, 135.2, 129.7, 128.7,
6.37–6.30 (1 H, m), 6.29–6.23 (1 H, m), 4.99 (1 H, d, J = 12.0), 128.6, 128.3, 96.7, 52.9, 48.2, 45.5, 39.3, 33.9, 30.0, 27.2, 26.8,
4.57 (1 H, d, J = 12.0), 3.70 (3 H, s), 1.72 (3 H, s); δC (100 MHz, 26.1, 18.2; νmax (neat)/cm−1: 2929, 2854, 1735, 1704, 1596,
CDCl3): 189.2, 171.0, 148.1, 143.6, 138.1, 135.7, 129.6, 129.1, 1549, 1449, 1432, 1289, 1199, 1161, 1081, 967, 740; HRMS
128.8, 127.4, 110.8, 110.5, 96.2, 53.1, 47.5, 44.6, 16.8; νmax (m/z – ESI): Found: 344.1488 (M − H)− C19H22NO5 requires:
(neat)/cm−1: 2954, 2923, 2852, 1732, 1694, 1598, 1549, 1436, 344.1498.
1347, 1293, 1206, 1160, 974, 920, 731; HRMS (m/z – ESI):
(1R,2R,3S)-Methyl 2-isopropyl-3-methyl-3-nitro-4-oxo-1,2,3,4-
tetrahydronaphthalene-1-carboxylate (trans-24a, Table 3, entry
Found: 328.0838 (M − H)− C17H14NO6 requires: 328.0821.
(1R,2R,3S)-Methyl 3-methyl-3-nitro-4-oxo-2-phenethyl-1,2,3,4- 8). Prepared according to general procedure C, using β-methyl-
tetrahydronaphthalene-1-carboxylate (trans-22a, Table 4, entry (E)-nitroalkene 17g (39.8 mg, 0.246 mmol) and anhydride 1
6). Prepared according to the consecutive use of general pro- (39.9 mg, 0.246 mmol). Upon esterification, the reaction gave a
cedures C and D, using β-methyl-(E)-nitroalkene 17e (47.0 mg, diastereomeric mixture of esters in a >99 : 1 (trans : cis) ratio.
0.246 mmol) and anhydride 1 (39.9 mg, 0.246 mmol). Upon The major diastereomer (trans-24a) was isolated by flash
epimerisation, the reaction gave a diastereomeric mixture of column chromatography, eluting in gradient from 100%
esters in a 89 : 11 (trans : cis) ratio. The major diastereomer hexanes to 20% EtOAc in hexanes, to give a pale yellow oil
(trans-22a) was purified by flash column chromatography, which contained 3% of dimethyl homophthalate as impurity
eluting in gradient from 100% hexanes to 20% EtOAc in that was not possible to separate. The given yield is calculated
hexanes, to give
a
white solid (74.0 mg, 82%). M.p. based on the mass return of the impure sample considering
the spectroscopically determined amount of the known
138–140 °C; TLC (hexanes : EtOAc, 8 : 2 v/v): Rf = 0.29; [α]D20
=
−38.8 (c = 0.20, CHCl3); CSP-HPLC analysis: Chiralpak IA impurity (35.2 mg, 47%). TLC (hexanes : EtOAc, 8 : 2 v/v): Rf =
(4.6 mm × 25 cm), hexane/IPA: 95/5, 1.0 mL min−1, RT, UV 0.37 [α]D20 = −53.4 (c = 0.20, CHCl3)*; CSP-HPLC analysis:
detection at 254 nm, retention times: trans-22a 11.8 min Chiralpak AD (4.6 mm × 25 cm), hexane/IPA: 90/10, 0.5 mL
(major enantiomer) and 13.5 min (minor enantiomer); cis-22b min−1, RT, UV detection at 254 nm, retention times: trans-24a
9.8 min (minor enantiomer) and 13.9 min (major enantiomer); 16.8 min (major enantiomer) and 17.7 min (minor enantio-
δH (400 MHz, CDCl3): 8.12 (1 H, d, J = 7.9), 7.64 (1 H, app. t), mer); δH (400 MHz, CDCl3): 8.08 (1 H, d, J = 7.9), 7.61 (1 H,
7.48 (1 H, app. t), 7.32–7.24 (3 H, m), 7.20 (1 H, t, J = 7.3), 7.11 app. t), 7.45 (1 H, app. t), 7.30 (1 H, d, J = 7.8), 4.08 (1 H, d, J =
(1 H, d, J = 7.4), 3.94 (1 H, d, J = 10.5), 3.82 (3 H, s), 3.75–3.66 8.8), 3.77 (3 H, s), 3.71–3.63 (1 H, m), 1.87 (1 H, m), 1.74 (3 H,
(1 H, m), 2.57 (2 H, app. t), 1.82–1.64 (5 H, m); δC (100 MHz, s), 1.05 (3 H, d, J = 7.0), 0.94 (3 H, d, J = 7.0); δC (100 MHz,
CDCl3): 189.8, 172.4, 140.8, 138.4, 135.5, 129.2, 129.0, 128.9, CDCl3): 189.8, 172.8, 138.9, 135.2, 129.6, 128.7, 128.6, 128.3,
128.7, 128.4, 127.8, 126.5, 96.4, 53.0, 50.8, 43.4, 34.2, 96.7, 52.9, 47.9, 45.2, 28.5, 23.6, 18.8, 17.9; νmax (neat)/cm−1
:
32.8, 16.1; νmax (neat)/cm−1: 3063, 3004, 2958, 2924, 2878, 2970, 2894, 1737, 1697, 1599, 1550, 1453, 1386, 1288, 1158,
1732, 1689, 1597, 1549, 1451, 1342, 1293, 1210, 1165, 999, 969, 969, 792, 733, 659; HRMS (m/z – ESI): Found 304.1190 (M − H)−
752, 729; HRMS (m/z – ESI): Found: 390.1335 (M + Na)+ C16H18NO5 requires: 304.1185. * [α]2D0 refers to trans-24a contain-
C21H21NO5Na requires: 390.1317.
ing 3% impurity.
(1R,2R,3S)-Methyl 2-cyclohexyl-3-methyl-3-nitro-4-oxo-1,2,3,4-
tetrahydronaphthalene-1-carboxylate (trans-23a, Table 3, entry
Synthesis of compound 25 7-bromoisochromane-1,3-dione
7). Prepared according to general procedure C, using β-methyl- The anhydride 25 was synthesised from 5-bromo-2-(carboxy-
(E)-nitroalkene 17f (41.6 mg, 0.246 mmol), catalyst 15 methyl) benzoic acid 25a which was synthesised from homo-
(23.3 mg, 0.0492 mmol – 20 mol%) and anhydride 1 (39.9 mg, phthalic acid. In a three-necked 250 mL round-bottomed flask
0.246 mmol). Upon esterification, the reaction gave a diaster- containing a magnetic stirring bar, homophthalic acid (5.00 g,
eomeric mixture of esters in a 98 : 2 (trans : cis) ratio. The 27.8 mmol) and potassium bromate (6.58 g, 39.4 mmol)
major diastereomer (trans-23a) was isolated by flash column were mixed in water (30 mL). The flask was then fitted with a
chromatography, eluting in gradient from 100% hexanes to condenser and the reaction mixture was heated at 90 °C. A
20% EtOAc in hexanes, to give a pale yellow oil which con- mixture of sulfuric acid (24 mL, 95%) and water (40 mL) was
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added dropwise to the resulting mixture at 90 °C over a period The minor diastereomer (cis-26b) was purified by flash column
of 30 min. After completion of addition, the mixture was chromatography, eluting in gradient from 100% hexanes to
allowed to stir for 2 h and was cooled to the room temperature. 20% EtOAc in hexanes, to give a white solid (36.1 mg, 35%).
The solid formed was isolated by suction filtration, washed M.p. 185–186 °C; TLC (hexanes : EtOAc, 8 : 2 v/v): Rf = 0.24;
with water and recrystallised from EtOAc/hexanes (4 : 1) to [α]2D0 = −69.7 (c = 0.20, CHCl3); CSP-HPLC analysis: Chiralpak
furnish the acid 25a as
a
white solid (4.23 g, 58%). IA (4.6 mm × 25 cm), hexane/IPA: 95/5, 1.0 mL min−1, RT, UV
M.p. 214–216 °C (lit.18 m.p. 216–217 °C). Spectral data for this detection at 254 nm, retention times: cis-26b 8.0 min (minor
compound were consistent with those in the literature.18 δH enantiomer) and 8.6 min (major enantiomer); δH (400 MHz,
(400 MHz, DMSO-d6):*7.98 (1 H, d, J = 2.0), 7.71 (1 H, dd, J = CDCl3): 8.30 (1 H, d, J = 1.5), 7.75 (1 H, dd, J = 1.5, 8.5), 7.34
2.0, 8.1), 7.31 (1 H, d, J = 8.1), 3.91 (2 H, s). *The protic signals (1 H, d, J = 8.5), 7.30–7.23 (1H, m), 7.20 (2 H, app. t), 6.93 (2 H,
(H-5 and H-6) are not visible in DMSO-d6.
d, J = 7.6), 4.64 (1 H, d, J = 6.1), 4.47 (1 H, d, J = 6.1), 3.45 (3 H,
An oven-dried 10 mL round-bottomed flask containing a s), 1.62 (3 H, s); δC (151 MHz, CDCl3): 186.3, 170.3, 137.4,
magnetic stirring bar was charged with 5-bromo-2-(carboxy- 135.6, 133.7, 133.3, 132.8, 130.8, 129.5, 129.2, 129.1, 122.9,
methyl)benzoic acid (25a, 500.0 mg, 1.93 mmol). Freshly dis- 93.1, 53.1, 52.4, 45.7, 21.6; νmax (neat)/cm−1: 3088, 3000, 2948,
tilled acetyl chloride (5.0 mL) was added, the flask was fitted 1745, 1705, 1593, 1543, 1433, 1196, 1176, 1003, 903, 836, 702;
with a condenser and the reaction mixture was heated at reflux HRMS (m/z – ESI): Found: 416.0123 (M − H)− C19H15NO5Br
temperature under an argon atmosphere for 16 h. The reaction requires: 416.0134.
was then cooled to room temperature and the excess acetyl
(1R,2S,3S,4S)-Methyl 4-hydroxy-3-methyl-3-nitro-2-phenyl-1,2,3,4-
chloride was removed in vacuo. The solid obtained was tritu- tetrahydronaphthalene-1-carboxylate (trans-27, Scheme 4). An
rated with diethyl ether (5 mL), filtered and dried to give 25 as oven-dried 10 mL round-bottomed flask containing a magnetic
an off white solid (404.7 mg, 87%). M.p. 176–177 °C (lit. stirring bar was charged with trans-13a (83.5 mg, 0.246 mmol)
M.p. 171–173 °C). Spectral data for this compound were con- and anhydrous MeOH (2.5 mL, 0.1 M) under argon atmo-
sistent with those in the literature.19 δH (400 MHz, DMSO-d6): sphere. To the mixture was added NaBH4 (37.2 mg,
8.13 (1 H, d, J = 2.0), 7.94 (1 H, dd, J = 2.0, 8.3), 7.41 (1 H, d, J = 0.984 mmol) and the reaction was allowed to stir at room
8.3), 4.23 (2 H, s); HRMS (m/z – ESI): Found: 238.9335 temperature for 16 h. The excess NaBH4 was then quenched by
(M − H)− C9H4BrO3 requires: 238.9344.
(1R,2S,3S)-Methyl 6-bromo-3-methyl-3-nitro-4-oxo-2-phenyl- lowed by removal of MeOH under reduced pressure. The
addition of a saturated aqueous NH4Cl solution (5 mL) fol-
1,2,3,4-tetrahydronaphthalene-1-carboxylate (trans-26a, Scheme 3). resulting aqueous mixture was then extracted with EtOAc
Prepared according to the consecutive use of general pro- (3 × 10 mL). The combined organic extracts were dried over
cedures C and D, using β-methyl-(E)-nitrostyrene (12, 40.1 mg, anhydrous MgSO4, filtered and the solvent was removed
0.246 mmol) and anhydride 25 (59.3 mg, 0.246 mmol). Upon under reduced pressure to afford a crude diastereomeric
epimerisation, the reaction gave a diastereomeric mixture of mixture of product 27 in a >98 : 2 (trans : cis) ratio. The major
esters in a >99 : 1 (trans : cis) ratio. The major diastereomer diastereomer (trans-27) was purified by flash column
(trans-26a) was purified by flash column chromatography, chromatography, eluting in gradient from 100% hexanes to
eluting in gradient from 100% hexanes to 20% EtOAc in 20% EtOAc in hexanes, to give a white solid (76.6 mg, 91%).
hexanes, to give a white solid (94.9 mg, 92%). M.p. 68–70 °C; M.p. 197–195 °C; TLC (hexanes : EtOAc, 8 : 2 v/v): Rf = 0.27;
TLC (hexanes : EtOAc, 8 : 2 v/v): Rf = 0.36; [α]2D0 = +72.2 (c = 0.20, [α]D20 = +122.1 (c = 0.20, CHCl3); CSP-HPLC analysis: Chiralcel
CHCl3); CSP-HPLC analysis: Chiralpak IA (4.6 mm × 25 cm), ODH (4.6 mm × 25 cm), hexane/IPA: 90/10, 1.0 mL min−1, RT,
hexane/IPA: 95/5, 1.0 mL min−1, RT, UV detection at 254 nm, UV detection at 254 nm, retention times: 9.2 min (major enan-
retention times: trans-26a 14.7 min (minor enantiomer) and tiomer) and 11.7 min (minor enantiomer); δH (400 MHz,
18.8 min (major enantiomer); cis-26b 8.0 min (minor enantio- CDCl3):* 7.68 (1 H, d, J = 7.5), 7.44–7.37 (1 H, m), 7.36–7.29
mer) and 8.6 min (major enantiomer); δH (400 MHz, CDCl3): (5 H, m), 7.29–7.22 (2 H, m), 5.91 (1 H, s), 4.42 (1 H, d, J =
8.33 (1 H, d, J = 2.1), 7.77 (1 H, dd, J = 2.1, 8.3), 7.37–7.31 (3 H, 11.8), 4.28 (1 H, d, J = 11.8), 3.57 (3 H, s), 1.49 (3 H, s); δC
m), 7.26–7.20 (3 H, m), 4.78 (1 H, d, J = 12.0), 4.49 (1 H, d, J = (100 MHz, CDCl3): 172.3, 136.4, 134.4, 130.9, 129.1, 128.9,
12.0), 3.57 (3 H, s), 1.71 (3 H, s); δC (100 MHz, CDCl3): 188.8, 128.8, 128.6, 128.5, 127.0, 126.5, 95.9, 74.9, 52.7, 50.6, 50.0,
170.6, 138.4, 137.4, 133.0, 132.2, 130.4, 129.3, 129.2 (2C), 10.8; νmax (neat)/cm−1: 3472, 3214, 1722, 1544, 1445, 1352,
129.1, 123.4, 96.6, 53.0, 50.2, 48.6, 16.3; νmax (neat)/cm−1
:
1301, 1193, 1054, 989, 750, 702; HRMS (m/z – APCI): Found:
3080, 3038, 2958, 1741, 1698, 1589, 1547, 1433, 1341, 1293, 342.1336 (M + H)+ C19H20NO5 requires: 342.1338. *The protic
1251, 1169, 990, 907, 756, 705; HRMS (m/z – ESI): Found: signal (H-13) is not visible in CDCl3.
416.0125 (M − H)− C19H15NO5Br requires: 416.0134.
Methyl
(1R,2S,3S)-3-methyl-3-nitro-4-oxo-2-phenyl-1,2,3,4-
(1S,2S,3S)-Methyl
6-bromo-3-methyl-3-nitro-4-oxo-2-phenyl- tetrahydronaphthalene-1-carboxylate-1-d, 13a′. Prepared from
1,2,3,4-tetrahydronaphthalene-1-carboxylate (cis-26b, Scheme 3). the general procedure E. δH (400 MHz, CDCl3): 8.22 (1 H, d,
Prepared according to general procedure C, using β-methyl-(E)- J = 8.0), 7.67 (1 H, app. t), 7.53 (1 H, app. t), 7.38–7.31 (4 H,
nitrostyrene (12, 40.1 mg, 0.246 mmol) and anhydride 25 m), 7.29–7.22 (2 H, m), 4.82 (1 H, m), 4.58 (0.6 H, 0.4D, d, J =
(59.3 mg, 0.246 mmol). Upon esterification, the reaction gave a 12.3), 3.57 (3 H, s), 1.72 (3 H, s); δD (400 MHz, CDCl3): 4.57
diastereomeric mixture of esters in a 58 : 42 (trans : cis) ratio. (1D, s).
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Computational details
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The geometry of the isolated molecules as well as those of the
different stationary structures of the Potential Energy Surface
(PES) were optimised by using the B3LYP20 density functional
theory (DFT) approach, which combines the Becke’s three-
parameter nonlocal hybrid exchange potential with the nonlo-
cal correlation functional of Lee, Yang and Parr with standard
6-311+G(d,p) basis sets.21 Vibrational analyses were performed
to confirm that the different optimized structures corre-
sponded to true minima of the PES or to transition states. All
calculations were carried out with the Gaussian09 program.22
The self-consistent reaction field (SCRF) calculations using the
PCM solvation model were carried out re-optimising the gas-
phase optimised structures. The dielectric constant in the
PCM calculations was set to ε = 3.38 to simulate diisopropyl-
ether similar to the solvent medium used in the experimental
studies. All the calculations have been carried out at 342 K of
temperature.
Acknowledgements
We thank Science Foundation Ireland and the European
Research Council for financial support, and are grateful to
Dr Brendan Twamney for X-Ray crystallographic analysis.
Thanks are given to the Irish Centre for High-End Computing
(ICHEC) for the provision of computational facilities.
6 This does not apply to α,β-unsaturated imines, which are
an isolated exception see ref. 9 and: (a) A. Georgieva,
E. Stanoeva, S. Spassov, M. Haimova, N. De Kimpe,
M. Boeleus, M. Keppens, A. Kemme and A. Mishnev,
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E. Stanoeva, I. Topalova and C. Tchanev, J. Chem. Res.,
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