Organocatalytic Michael addition/intramolecular Julia-Kocienski olefination for the preparation of nitrocyclohexenes

Article abstract of DOI:10.1021/jo401686u

An asymmetric organocatalytic [3 + 3] annulation strategy based on a Michael addition/intramolecular Julia-Kocienski olefination sequence has been developed for the synthesis of 4-substituted-5-nitrocyclohex-1-ene compounds. The strategy is an alternative to the direct reluctant enantioselective Diels-Alder approach. The potential of the methodology has been demonstrated with a concise enantioselective formal synthesis of trandolapril.

Full text of DOI:10.1021/jo401686u

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Article
Organocatalytic Michael Addition / Intramolecular Julia –
Kocienski Olefination for the Preparation of Nitrocyclohexenes
Eduardo Rodrigo, José Luis García Ruano, and M. Belén Cid
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo401686u • Publication Date (Web): 24 Sep 2013
Downloaded from http://pubs.acs.org on September 25, 2013
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Organocatalytic Michael Addition / Intramolecular Julia – Kocienski
Olefination for the Preparation of Nitrocyclohexenes
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Eduardo Rodrigo, José Luis García Ruano, M. Belén Cid*
Department of Organic Chemistry. Universidad Autónoma de Madrid, Cantoblanco 28049, Madrid, Spain
belen.cid@uam.es
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ABSTRACT
An asymmetric organocatalytic [3 + 3] annulation strategy based on a Michael addition /
intramolecular Julia - Kocienski olefination sequence has been developed for the synthesis of 4-
substituted-5-nitrocyclohex-1-ene compounds. The strategy is an alternative to the direct reluctant
enantioselective Diels-Alder approach. The potential of the methodology has been demonstrated with a
concise enantioselective formal synthesis of trandolapril.
Introduction
Six-membered ring structures are widespread in natural and synthetic products. As a consequence, a
good deal of interest in developing novel approaches including organocatalyzed strategies for the
stereoselective synthesis of cyclohexane1 and cyclohexene2 derivatives have emerged. Particularly,
chiral cyclohexyl and cyclohexenylamine moieties are valuable building blocks present in a wide
variety of natural and non-natural compounds of interest.3 A rapid direct access to this kind of
compounds would be an asymmetric [4 + 2] cycloaddition between a diene and a nitroalkene, followed
by the reduction of the nitro group (Scheme 1).4 However, the Diels-Alder reaction of non activated
dienes with nitroalkenes requires the use of harsh conditions, specially with aliphatic nitroalkenes where
yields are low.4b
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Scheme 1. Diels-Alder as direct approach to amino cyclohexenes.
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As a consequence of the above mentioned problem, in contrast with the plethora of organocatalyzed
asymmetric Michael addition reactions,5 there are only a few examples for the stereoselective
organocatalytic Diels-Alder reactions of nitroalkenes.6 To our knowledge, there is only one example of
direct cycloaddition and it is limited exclusively to 3-hydroxy-2-pyrones and aliphatic nitroalkenes (A.1,
Scheme 2).7 Another organocatalytic enantioselective cycloaddition is based on the in situ generation of
activated dienes from enals via trienamine catalysis by chiral amines (A.2, Scheme 2).8
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Scheme 2. Organocatalytic approaches to chiral nitrocyclohexenes.
Other indirect strategies for the synthesis of these structures, such as the combination of Michael and
aldol reactions,9 as well as Michael addition-intramolecular Horner-Wadsworth-Emmons olefination,10
have been also described (B, Scheme 2). But for all these strategies the presence of an
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electronwithdrawing group at different positions is absolutely essential for the processes to occur and
remains unavoidably in the molecule at the end of the process.
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Although arylsulfones have been used in a wide range of organocatalytic processes,11 that is not the case
of heteroaryl sulfones despite the great advantage of the possibility to carry out Julia-Kocienski
olefination reactions.12,13 We reasoned that the deactivated nucleophile 1 bearing a heretoarylsulfonyl
and nitro moieties could provide enantiopure nitrocyclohexenes through a sequential protocol of
Michael addition / intramolecular Julia-Kocienski olefination (Scheme 2). The obtained compounds
would be the adducts formed from the above mentioned Diels-Alder reaction (See scheme 1).
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Regarding the viability of the strategy, it is important to note that both nitro and sulfone moieties will be
present in both steps, but only one must react in each step. Whereas the Michael addition of
nitromethane to enals via iminium activation has been widely employed,14 the reaction of substituted
nitroalkanes with a second nucleophilic unit has been scarcely used.15 Moreover, since Sylvestre Julia
introduced the modified Julia olefination in 1991,16a some adjustments have been introduced, mainly by
b
Kocienski16 and many examples of intermolecular Julia-Kocienski olefination reactions have been
described in the literature.17 Nevertheless, the intramolecular version of this reaction has been hardly
explored.18 Particularly the formation of six-membered rings has only been studied on one substrate
a
bearing gem-dimethyl groups,18 which favour the cyclation process19 because of the Thorpe-Ingold
effect.
Results and Discussion
We started our work with the synthesis of pro-bis(nucleophile) 1 bearing a phenyltetrazole moiety,
which was easily accessible in a 90% yield from sulfone 213 and nitromethane using NaOH as a base
(See table 1).20 Once the nitrocompound 1 had been synthezised, we began our studies to optimize the
Michael addition. We tested several proline-type catalysts, using CH2Cl2 as solvent and trans-2-hexenal
as model electrophile. The reaction took place only with some catalysts but exclusively through the
carbon bearing the nitro moiety affording adduct 4a as a 62:38 mixture of diastereomers. The best
conversions were obtained with prolinol-type catalysts I and III, but the enantiomeric excess were poor
in both cases (entries 1 and 3). Prolinol II and silylprolinols IV and V turned out sluggish in the absence
of additive even using a 30 mol % of catalyst (entries 2, 4 and 5). TBAB, an additive recently developed
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by us,21 led to full conversion when used with catalysts II and V, improving also the enantiomeric
excess up to 86% with catalyst V (entries 6 and 7). The more hindered catalyst VI, with a TBDMS
group, was also tested but afforded the Michael adduct with lower conversions (entry 7). A 1:1 mixture
of CH2Cl2/EtOH provided higher ee even using lower charge of catalyst (Entry 9). Finally, basic and
acidic additives were also tested (entries 10 and 11). An acidic additive led to lower conversions (entry
10), while a basic additive such as LiOAc afforded very similar results to TBAB with just a slightly
lower yield (entry 11). In order to optimize the later intramolecular Julia-Kocienski olefination, we
scaled the reaction up to 1 gram of product using conditions of entry 9. Both yield and enantiomeric
excess were maintained.
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Table 1. Optimization of the Michael addition
Catalyst
(mol%)
t
Conv. Yield ee a
Entry
Additive
Solvent
(h) (%)
(%)
(%)
1
I (30)
II (30)
III (30)
IV (30)
V (30)
II (30)
V (30)
VI (30)
V (20)
V (20)
V (20)
-----
-----
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
24
72
24
24
120
48
48
48
100
69
44
2
3
23
90
----
----
----
----
68
----
- 41
----
----
80
-----
4
-----
68
5
-----
0
6
TBAB b
TBAB b
TBAB b
TBAB c CH2Cl2/EtOH 48
BzOHd CH2Cl2/EtOH 48
AcOLid CH2Cl2/EtOH 48
100
100
66
7
69
86
8
----
95
----
90
9
100
46
10
11
----
88
----
89
100
a Determined by HPLC (see SI); b(30 mol%); c(1 equiv.), d(20 mol%);
Since the alpha-hydrogen of the nitro moiety in 4a is more acidic than the alpha-hydrogen to the
sulfonyl group, an excess of base had to be used for the Julia- Kocienski process (Table 2). When
KHMDS, the most common base for the Julia-Kocienski olefination17a, was employed, a complex
mixture was obtained (entry 1). Fortunately, we could isolate the cyclohexene 5a using Cs2CO3 as a
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base in a moderate yield, and a 71:29 mixture of diastereoisomers, being the trans isomer the major one
(entry 2). According to our experience, we expected the epimerization of the carbon bearing the nitro
moiety towards the most stable trans isomer after the cyclization process.20b Therefore we opted to try a
stronger and more soluble base to achieve a higher dr. Cyclohexene 5a could also be isolated with a
moderate yield in a dr of 69:31 using DBU (2 equiv) and CH3CN as solvent at room temperature (entry
3).22 The diastereoselectivity did not increase significantly at 0 ºC, (entry 4), but at - 40 ºC the dr
reached a satisfactory 91:9 ratio (entry 5) although lower yield was obtained. The same dr but better
yield was obtained when the reaction was carried out at r.t., but quenched at -40 ºC (entry 6). We found
optimal conditions using: a) Cs2CO3 at 70 ºC to carry out the olefination reaction followed by b) a
treatment of the crude reaction with DBU in CH3CN and quenched carefully at -40 ºC to increase the
diastereoselectivity (entry 7).
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Table 2. Intramolecular Julia-Kocienski optimization.
Entry Solvent
Base
temp t (min) Yield
dra
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4
5
DME
THF/DMFc
CH3CN
KHMDSb -78 ºC
15
120
30
decomp
57
-
d
Cs2CO3
DBUb
DBUb
DBUb
70 ºC
r.t.
71:29
69:31
74:26
91:9
51
CH3CN
0 ºC
30
51
CH3CN
-40 ºC
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29
r.t.
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7
CH3CN
a)THF/DMFa Cs2CO3
b) CH3CN
DBUb
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57
91:9
91:9
(-40 ºC)e
70 ºC
d
120
15
DBUf (-40 ºC)e
a Determined by 1H NMR; b 2 equivalents; c;THF/DMF (3:1);
d 3 equivalents; e quenched at -40 ºC; f 1 equivalent.
Once both Michael addition and Julia-Kocienski olefination had been optimized, we checked the
substrate scope of our strategy. Interestingly, a very different behavior was observed with aliphatic and
aromatic enals in both Michael and Julia-Kocienski reactions. The Michael addition worked well using
TBAB as additive with aliphatic enals (Table 3, entries 1-7) for a variety of chains containing different
functional groups such as a double bond (3e) or an acetal (3k). The Julia-Kocienski reaction also went
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on the right track under conditions of entry 7 in table 2 (conditions A). However, Michael addition with
aromatic enals presented erratic enantioselectivity when using the same conditions utilized for the
aliphatic enals owing to reversibility.23 Nevertheless, controlling reaction times and using LiOAc as
additive, Michael adducts were obtained in good yields and enantioselectivities, both with
electrondonating and electronwithdrawing groups (Table 3, entries 8-11). In the case of the Julia-
Kocienski olefination with the aromatic substituents we observed aromatization of the cyclohexene
under conditions A.24 Therefore milder conditions B, using DBU as base at low temperature, were
employed.
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Table 3. Scope of the Michael / Julia-Kocienski process.
Michael Addition
Julia-Kocienski
Entry
R
yield
Conditions/
eeb
Additive t (h) Prod
Prod
(%) yield (%) (dr) a
(%)c
1
2
3a Pr
3b Me
3c Et
TBABd 48
95
5a
5b
5c
5d
5e
5f
90
86
90
91
90
95
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92
75
86
89
4a
A / 57 (91:9)
Bc / 45 (79:21)
A / 51 (92:8)
A / 60 (85:15)
A / 63 (75:25)
A / 61 (76:24)
A / 60 (90:10)
B / 52 (94:6)
B / 49 (91:9)
B / 50 (91:9)
B / 52 (85:15)
TBABd 48
TBABd 48
TBABd 72
TBABd 72
TBABd 72
92
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93
92
90
71
77
83
78
55
4b
4c
4d
4e
4f
3
4
3d n-Bu
5
3e
6
3f Non
7
3g CH2-CH-(OMe)2 TBABd 48
5g
5h
5i
4g
4h
4i
8
3h Ph
LiOAce
8
9
3i p-NO2-C6H4
3j p-Cl-C6H4
3k p-OMe-C6H4
LiOAce 24
LiOAce 24
4j
10
11
5j
LiOAce
4
5k
4k
a By 1H NMR, b By HPLC; c See SI; d1 equiv; e 20 mol%.
In order to illustrate the versatility of our pro-bis(nucleophile) 1, we carried out a formal synthesis of
trandolapril. Trandolapril is the ethyl ester prodrug of trandolaprilat, which is commonly prescribed as
cardiovascular drug for controlling hypertension.25 The preparation of trandolapril has been described
from cyclohexylamine 6, which was prepared using a low-yielding Diels-Alder reaction carried out
under high temperature and pressure conditions with butadiene and the corresponding nitroalkene as key
step, followed by reduction and enzymatic resolution of racemic 6.26 We envisioned that we could
develop the first enantioselective synthesis of trandolapril by preparing enantioenriched intermediate 6
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using our methodology.27 The combination of the optimized procedure for the Michael addition / Julia-
Kocienski olefination followed by simultaneous reduction of the double bond and nitro group using H2 /
Pd(C), allowed the preparation of 628 with a 94% ee, 90:10 dr and a 38% yield starting from
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vinylsulfone 2 (Scheme 3).
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Scheme 3. Formal synthesis of trandolapril.
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Conclusion
In conclusion, we have developed a sequential procedure via asymmetric catalytic Michael reaction
involving enals and pro-bis(nucleophile) 1 followed by intramolecular Julia-Kocienski olefination to
afford nitrocyclohexenes, which are versatile compounds in synthesis. The synthetic potential of this
methodology for the enantio and diastereoselective preparation of nitrocyclohexenes and
cyclohexylamines was illustrated with an enantioselective formal synthesis of trandolapril.
Experimental section
General Methods and Materials
NMR spectra were acquired using CDCl3 as the solvent, running at 300 and 75 MHz for H and 13C
1
respectively. Chemical shifts (δ) are reported in ppm relative to residual solvent signals (CHCl3, 7.26
ppm for 1H NMR, CDCl3, and 77.0 ppm for 13C NMR). In all 1H NMR spectra, multiplicity is indicated
as follows: bs (broad singlet), s (singlet), d (doublet), t (triplet), q (quartet), quin (quintuplet) or m
(multiplet). Coupling constant values (in Hertz) and number of protons for each signal are also
indicated.
Melting points were measured using Gallenkamp melting point apparatus in open capillary tubes.
Optical rotation was recorded in cells with 10 cm path length on a Perkin-Elmer 241 MC polarimeter.
For thin layer chromatography (TLC) Supelco silica gel plates with fluorescence indicator 254 nm
were used and compounds were visualized by irradiation with UV light and/or by treatment with a
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solution of KMnO4 (1.5 g), K2CO3 (10g), and 10% NaOH (1.25 mL) in H2O (200 mL) or a solution of
phosphomolybdic acid (12 g), in EtOH (250 mL) followed by heating. Flash column chromatography
(FCC) was performed using Merck pore 60 Å, 40-63 µm silica gel and compressed air.
Mass spectra were obtained in a VG AutoSpec Spectrometer in positive electrospray ionisation (ESI)
or electron impact ionisation (EI). Obtained data are expressed in mass/charge (m/z) units. Values
between parentheses indicate relative intensities with regard to the base peak.
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Enantiomeric excesses (ee) were determined by chiral-phase SFC-HPLC (HPLC in the case of 5g)
using an Agilent-1100 instrument in the indicated column and conditions in each case.
Hexane and EtOAc were supplied by Scharlau and were used without previous purification. All the
other reactants were bought in Aldrich, Fluka or Alfa Aesar and were also used without any previous
treatment.
Enals 3a–3f, and 3h, 3i and 3k are commercially available. Enals 3g and 3j and heteroaryl
vinylsulfone 213 were prepared following the literature procedure.
Preparation of aldehyde 3g29
ZnCl2 (408 mg, 3 mmol) was added to a mixture of 1-trimethylsilyloxy-1,3-butadiene (4.26 g, 30 mmol)
and trimethyl orthoformate (3.9 mL, 31 mmol) in CH2Cl2 (100 mL). The mixture was stirred vigorously
at r.t. for 16 hours whereupon it was poured into water (50 mL). The aqueous layer was extracted with
CH2Cl2 (2 × 100 mL) and the combined organic layers were washed with brine (50 mL), dried over
MgSO4, filtered and concentrated under reduced pressure. The crude was purified by flash column
chromatography (Hexane:EtOAc 8:1 to 6:1) to afford 1.81 g (Yield: 42%) of aldehyde 3g as a yellow
1
oil. H NMR (300 MHz): δ 9.51 (d, J = 7.9 Hz, 1H), 6.79 (dt, J = 15.7 and 7.0 Hz, 1H), 6.17 (dd, J =
15.7 and 7.9 Hz, 1H), 4.50 (t, J = 5.5 Hz, 1H), 3.35 (s, 6H), 2.64 (dd, J = 7.0 and 5.5 Hz, 2H) 13C-NMR
(75 MHz): 193.5 (CHO), 152.1 (CH), 134.9 (CH), 102.6 (CH), 53.2 (2 CH3), 36.2 (CH2)
Preparation of aldehyde 3j30
4-Chlorobenzaldehyde (714 mg, 5.1 mmol) was dissolved in toluene (20 mL) and
(triphenylphosphoranylidene)acetaldehyde (1.50 g, 5 mmol) was added to the solution. The mixture was
heated at 80 ºC and stirred for 24h. The solvent was removed under reduced pressure and the crude was
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purified by flash column chromatography (Hexane 4:1 EtOAc) to afford 456 mg (Yield: 55%) of
aldehyde 3j as a yellow solid. Spectroscopic and analytical data are in agreement with the literature.
Preparation of pro-bis(nucleophile) 1
1
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5
6
7
8
9
Sulfone 2 (1,41g, 6 mmol) was added to a solution of sodium hydroxide in perles (240 mg, 6 mmol) in
nitromethane (15 mL). The mixture was stirred for 3 hours, whereupon water (20 mL) was added. The
mixture was transferred into a separatory funnel and was extracted with EtOAc (2 × 25 mL). The
organic layers were combined and were washed with brine (25 mL), dried with MgSO4, filtered and
concentrated under reduced pressure to afford pro-bis(nucleophile) 1 as a white solid (1.60 g, yield:
90%), which was used for the next step without further purification. White solid Mp: 81-83 ºC 1H NMR
(300 MHz): δ 7.71-7.54 (m, 5H), 4.62 (t, J = 6.5 Hz, 2H), 3.92 (t, J = 7.1 Hz, 2H), 2.71 (quin, J = 6.8
Hz, 2H) 13C NMR (75 MHz): δ 153.1 (C), 132.8 (C), 131.6 (CH), 128.8 (2CH), 124.9 (2CH), 72.3
(CH2), 52.9 (CH2), 20.4 (CH2) MS (ESI): m/z 298 (M++1, 46), 149 (67), 119 (26), 113 (100). HRMS
(ESI): calculated for C10H12N5O4S (M++1): 298.0604; found: 298.0615.
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General procedure for the Michael Addition
Aliphatic enals (3a-g): Catalyst V (11.9 mg, 0.02 mmol) was dissolved in a 1:1 mixture of CH2Cl2 /
EtOH (0.6 mL) and the corresponding aldehyde 3a-g (4 mmol) was added to the solution. The mixture
was stirred for 5 minutes before pro-bis(nucleophile) 1 (29.7 mg, 0.1 mmol) and TBAB (32.5 mg, 0.1
mmol) were sequentially added. The reaction mixture was stirred at room temperature the indicated time
for each case (see table 3). The solvent was removed under reduced pressure and the crude was purified
by flash column chromatography to afford the corresponding Michael adducts 4a-g.
Aromatic enals (3h-k): Catalyst V (11.9 mg, 0.02 mmol) was dissolved in a 1:1 mixture of CH2Cl2 /
EtOH (0.6 mL) and the corresponding aldehyde 3h-k (4 mmol) was added to the solution. The mixture
was stirred for 5 minutes before pro-bis(nucleophile) 1 (29.7 mg, 0.1 mmol) and LiOAc (1.3 mg, 0.02
mmol) were sequentially added. The reaction mixture was stirred at room temperature the indicated time
for each case (see table 3). The solvent was removed under reduced pressure and the crude was purified
by flash column chromatography to afford the corresponding Michael adducts 4h-k.
General procedure for the synthesis of racemic compounds 4a-k.
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The racemic compounds were obtained following the same procedure above detailed for the Michael
addition, using a mixture of (R) and (S)-α-α-Diphenyl-2-pyrrolidinemethanol (15 mol% (R) and 15
mol% (S)) and TBAB (1 equiv) as additive.
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The Michael adducts had to be derivatizated into the corresponding methyl esters or into the
corresponding acetals according to methods A or B. Method A: Acetalization 0.05 mmol of the
corresponding Michael adduct were dissolved in 1 mL of benzene. p-Toluenesulfonic acid (1 mg) and
ethylenglicol (19 µL, 0.2 mmol) were added to the solution and the mixture was heated at 80 ºC
overnight. The solution was allowed to cool to room temperature, whereupon NaHCO3 (sat) (5 mL) and
EtOAc (5 mL) were subsequently added. The mixture was transferred into a separatory funnel and
extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with brine (5 mL), dried
over MgSO4, filtered and concentrated under vacuum to afford the corresponding acetal. Method B31:
Transformation into the corresponding ester. 0.05 mmol of the corresponding Michael adduct were
dissolved in a 5:1 mixture of MeOH / CH2Cl2 (1.2 mL) and the solution was stirred for 5 minutes at 0 ºC
in an ice/water bath, whereupon NBS (13 mg, 0.075 mmol, 1.5 eq) was added to the solution. The flask
was left in the bath overnight and allowed to reach r.t. The solvent was removed under reduced pressure
and the crude was purified by flash column chromatography (Hexane 4:1 EtOAc) to afford the
corresponding ester derivative.
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(3S, 4S)-4-Nitro-6-(1-phenyl-1H-tetrazol-5ylsulfonyl)-3-propylhexanal and (3S, 4R)-4-Nitro-6-(1-
phenyl-1H-tetrazol-5ylsulfonyl)-3-propylhexanal (4a)
The title compound was obtained in a 95% yield as yellowish oil after flash column chromatography
(Hexane 3:1 EtOAc) according to the general procedure, using TBAB as additive (1 equiv) as a 62:38
mixture of diastereomers. The diastereomeric ratio (dr) was determined by HPLC. The procedure to
obtain this product has been scaled up until 1 g of nitrocompound 1. Yield: 1.23 g, 93%. 1H NMR (300
MHz) (data obtain from the mixture of diastereomers): δ 9.79 (s, 1Hmajor), 9.77 (s, 1Hminor), 7.73-7.58
(m, 5Hmajor, 5Hminor), 4.91-4.77 (m, 1Hmajor, 1Hminor), 3.86-3.75 (m, 2Hmajor, 2Hminor), 2.84-2.37 (m,
5Hmajor, 5Hminor), 1.49-1.15 (m, 4Hmajor, 4Hminor), 0.93 (t, J = 6.8 Hz, 3Hmajor,), 0.92 (t, J = 6.8 Hz,
3Hminor). 13C NMR (75 MHz) (Mixture of diastereomers): δ 199.6 (CHO), 199.2 (CHO), 153.1 (2C),
132.8 (2C), 131.7 (2CH), 129.9 (4CH), 125.0 (4CH), 87.8 (CH), 87.4 (CH), 52.9 (2CH2), 44.2 (CH2),
43.9 (CH2), 35.7 (CH), 35.6 (CH), 32.9 (CH2), 31.6 (CH2), 23.9 (CH2), 23.4 (CH2), 20.2 (CH2), 19.9
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(CH2), 13.8 (2CH3). MS (ESI): m/z 396 (M++1, 56), 254 (45), 236, (54), 147 (38), 80 (35). HRMS
(ESI): calculated for C16H22N5O5S (M++1): 396.1336; found: 396.1353. The enantiomeric excess was
determined by SFC-HPLC over the corresponding methyl ester following Method B. Chiralpak IB
column [CO2/MeOH = 98:2]; flow rate 3.0 mL/min. ee = 90%, τ major = 7.5 and 8.4 min; τ minor = 7.1 and
9.9 min.
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(3S, 4S)-3-Methyl-4-nitro-6-(1-phenyl-1H-tetrazol-5ylsulfonyl)hexanal and (3S, 4R)-3-Methyl-4-
nitro-6-(1-phenyl-1H-tetrazol-5ylsulfonyl)hexanal (4b)
The title compound was obtained in a 92% yield as a yellow oil after flash column chromatography
(Hexane 2:1 EtOAc) according to the general procedure, using TBAB (1 equiv) as additive, as a 63:37
1
1
mixture of diastereomers. The diastereomeric ratio (dr) was determined by H NMR. H NMR (300
MHz) (Data obtain from the mixture of diastereomers): δ 9.77 (s, 1Hmajor), 9.74 (s, 1Hminor), 7.72-7.58 (m,
5Hmajor, 5Hminor), 4.83-4.70 (m, 1Hmajor, 1Hminor), 3.86-3.74 (m, 2Hmajor, 2Hminor), 2.88-2.38 (m, 5Hmajor
,
5Hminor), 1.09 (d, J = 6.9 Hz, 3Hminor), 1.04 (d, J = 6.9 Hz, 3Hmajor
)
13C NMR (75 MHz) (Mixture of
diastereomers): δ 199.3 (CHO), 198.8 (CHO), 153.1 (2C), 132.8 (2C), 131.6 (2CH), 129.8 (4CH), 124.9
(4CH), 89.4 (CH), 88.4 (CH), 52.7 (2CH2), 46.9 (CH2), 46.2 (CH2), 31.3 (CH), 30.9 (CH), 23.9 (CH2),
23.4 (CH2), 16.1 (CH3), 14.9 (CH3). MS (ESI): m/z 368 (M++1, 100), 338 (31), 147 (19), 119 (12).
HRMS (ESI): calculated for C14H18N5O5S (M++1): 368.1023; found: 368.1035. The enantiomeric excess
was determined by SFC-HPLC over the corresponding methyl ester following Method B. The 4
diastereomers could not be completely separated in any of the available HPLC columns. The best
conditions were the described below, which allowed to determine the ee in one of the diastereomers.
The enantiomeric excess was determined by SFC-HPLC over the corresponding methyl ester following
Method B. Chiralpak IB column [CO2/MeOH = 98:2]; flow rate 3.0 mL/min. ee = 86 %, τ
and 19.5 min; τ minor = 15.1 and 16.5 min.
= 15.1
major
(3S, 4S)-3-Ethyl-4-nitro-6-(1-phenyl-1H-tetrazol-5ylsulfonyl)hexanal and (3S, 4R)-3-Ethyl-4-nitro-
6-(1-phenyl-1H-tetrazol-5ylsulfonyl)hexanal (4c)
The title compound was obtained in a 94% yield as yellowish oil after flash column chromatography
(Hexane 3:1 EtOAc) according to the general procedure, using TBAB as additive as a 64:36 mixture of
diastereomers. The diastereomeric ratio (dr) was determined by HPLC. 1H NMR (300 MHz) (data
obtain from the mixture of diastereomers): δ 9.80 (s,1Hmajor) 9.78 (s, 1Hminor), 7.73-7.59 (m, 5Hmajor
,
5Hminor), 4.93-4.79 (m, 1Hmajor, 1Hminor), 3.86-3.77 (m, 2Hmajor, 2Hminor), 2.83-2.39 (m, 5Hmajor, 5Hminor),
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1.57-1.37 (m, 2Hmajor, 2Hminor), 0.97 (t, J = 7.4 Hz, 3Hmajor, 3Hminor). 13C NMR (75 MHz) (Mixture of
diastereomers): δ 199.6 (CHO), 199.2 (CHO), 153.1 (2C), 132.8 (2C), 131.7 (2CH), 129.8 (4CH), 124.9
(4CH), 87.5 (CH), 87.3 (CH), 52.8 (2CH2), 43.7 (CH2), 43.5 (CH2), 37.4 (CH), 37.2 (CH), 23.9 (CH2),
23.7 (CH2), 23.4 (CH2), 22.6 (CH2), 11.4 (CH3), 11.0 (CH3). MS (ESI): m/z 382 (M++1, 20), 254 (30),
147 (28), 80 (100). HRMS (ESI): calculated for C15H20N5O5S (M++1): 382.1179; found: 382.1194. The
enantiomeric excess was determined by SFC-HPLC over the corresponding methyl ester following
Method B. Chiralpak IB column [CO2/MeOH = 98:2]; flow rate 3.0 mL/min. ee = 90 %, τ major = 8.5 and
8.9 min; τ minor = 8.1 and 9.5 min.
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(3S, 4S)-3-Butyl-4-nitro-6-(1-phenyl-1H-tetrazol-5ylsulfonyl)hexanal and (3S, 4R)-3-Butyl-4-nitro-
6-(1-phenyl-1H-tetrazol-5ylsulfonyl)hexanal (4d)
The title compound was obtained as yellowish oil in a 93% yield after flash column chromatography
(Hexane 3:1 EtOAc) according to the general procedure, using TBAB as additive (1 equiv) as a 64:36
mixture of diastereomers. The diastereomeric ratio (dr) was determined by HPLC. 1H NMR (300 MHz)
(data obtain from the mixture of diastereomers): δ 9.78 (s, 1Hmajor), 9.76 (s, 1Hminor), 7.73-7.56 (m,
5Hmajor, 5Hminor), 4.92-4.74 (m, 1Hmajor, 1Hminor), 3.87-3.71 (m, 2Hmajor, 2Hminor), 2.84-2.36 (m, 5Hmajor
,
5Hminor), 1.50-1.12 (m, 6Hmajor, 6Hminor), 0.97-0.78 (m, 3Hmajor, 3Hminor). 13C NMR (75 MHz) (Mixture of
diastereomers): δ 199.7 (CHO), 199.2 (CHO), 153.1 (2C), 132.8 (2C), 131.7 (2CH), 129.8 (4CH), 125.0
(4CH), 87.8 (CH), 87.5 (CH), 52.8 (2CH2), 44.1 (CH2), 43.9 (CH2), 35.9 (CH), 35.7 (CH), 30.4 (CH2),
29.2 (CH2), 29.0 (CH2), 28.7 (CH2), 23.8 (CH2), 23.3 (CH2), 22.5 (2CH2), 13.8 (2CH3). MS (ESI): m/z
410 (M++1, 55), 149 (100), 147 (39), 119 (30), 80 (20). HRMS (ESI): calculated for C17H24N5O5S
(M++1): 410.1492; found: 410.1513. The enantiomeric excess was determined by SFC-HPLC over the
corresponding methyl ester following Method B. Chiralpak IB column [CO2/MeOH = 98:2]; flow rate
3.0 mL/min. ee = 91%, τ major = 7.8 and 8.7 min; τ minor = 7.5 and 10.1 min.
(3S, 6Z)-3-((1S)-1-Nitro-3-(1-phenyl-1H-tetrazol-5ylsulfonyl)propylnon-6-enal and (3S, 6Z)-3-
((1R)-1-Nitro-3-(1-phenyl-1H-tetrazol-5ylsulfonyl)propylnon-6-enal (4e)
The title compound was obtained in a 92% yield as yellowish oil after flash column chromatography
(Hexane 3:1 EtOAc), using TBAB as additive (1 equiv) according to the general procedure. The
1
diastereomeric ratio (dr) could not be properly determined. H NMR (300 MHz) (data obtain from the
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mixture of diastereomers): δ 9.79 (s, 1Hmajor), 9.77 (s, 1Hminor), 7.73-7.57 (m, 5Hmajor, 5Hminor), 5.52-5.38
1
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(m, 1Hmajor, 1Hminor), 5.32-5.18 (m, 1Hmajor, 1Hminor), 4.94-4.80 (m, 1Hmajor, 1Hminor), 3.87-3.75 (m,
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2Hmajor, 2Hminor), 2.86-2.38 (m, 4Hmajor, 4Hminor), 2.17-1.92 (m, 5Hmajor, 5Hminor), 1.60-1.36 (m, 2Hmajor
,
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2Hminor), 1.00-0.90 (m, 3Hmajor, 3Hminor). 13C NMR (75 MHz) (Mixture of diastereomers): δ 199.6
(CHO), 199.1 (CHO), 153.0 (2C), 133.7 (CH), 133.5 (CH), 132.8 (2C), 131.6 (2CH), 129.9 (4CH),
126.6 (2CH), 125.0 (4CH), 87.5 (CH), 87.2 (CH), 52.8 (2CH2), 44.0 (CH2), 43.7 (CH2), 35.3 (2CH),
30.7 (CH2), 29.2 (CH2), 24.3 (CH2), 24.1 (CH2), 23.9 (CH2), 23.4 (CH2), 20.6 (2CH2), 14.2 (2CH3)
MS (ESI): m/z 436 (M++1, 23), 254 (100), 236 (64), 149 (18). HRMS (ESI): calculated for C19H26N5O5S
(M++1): 436.1649; found: 436.1681. The enantiomeric excess was determined by SFC-HPLC over the
corresponding acetal following Method A. The 4 diastereomers could not be completely separated in
any of the available HPLC columns. The best conditions were the described below, which allowed to
determine the ee in one of the diastereomers. The enantiomeric excess was determined by SFC-HPLC
over the corresponding acetal following Method A. Chiralpak IB column [CO2/MeOH = 98:2]; flow rate
3.0 mL/min. ee = 90%, τ major = 15.1 and 16.2 min; τ minor = 16.2 and 17.3 min.
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(3S)-3-((1S)-1-Nitro-3-(1-phenyl-1H-tetrazol-5ylsulfonyl)propyl)dodecanal and (3S)-3-((1R)-1-
Nitro-3-(1-phenyl-1H-tetrazol-5ylsulfonyl)propyl)dodecanal (4f)
The title compound was obtained in a 90% yield as yellowish oil after flash column chromatography
(Hexane 4:1 EtOAc) according to the general procedure, using TBAB as additive (1 equiv) as a 61:39
mixture of diastereomers. The diastereomeric ratio (dr) was determined by HPLC. 1H NMR (300 MHz)
(data obtain from the mixture of diastereomers): δ 9.77 (s, 1Hmajor), 9.75 (s, 1Hminor), 7.72-7.56 (m,
5Hmajor, 5Hminor), 4.90-4.77 (m, 1Hmajor, 1Hminor), 3.86-3.74 (m, 2Hmajor, 2Hminor), 2.83-2.35 (m, 5Hmajor
,
5Hminor), 1.48-1.17 (m, 16Hmajor, 16Hminor), 0.88 (t, J = 6.9 Hz, 3Hmajor, 3Hminor). 13C NMR (75 MHz)
(Mixture of diastereomers): δ 199.8 (CHO), 199.3 (CHO), 153.1 (2C), 132.8 (2C), 131.6 (2CH), 129.8
(4CH), 125.0 (4CH), 87.8 (CH), 87.5 (CH), 52.9 (2CH2), 44.1 (CH2), 43.9 (CH2), 36.0 (CH), 35.8 (CH),
31.8 (CH2), 30.7 (CH2), 29.5-29.1 (10CH2), 27.0 (CH2), 26.6 (CH2), 23.8 (CH2), 23.4 (CH2), 22.6
(2CH2), 14.1 (2CH3). MS (ESI): m/z 480 (M++1, 22), 254 (100), 236 (69), 80 (12). HRMS (ESI):
calculated for C22H34N5O5S (M++1): 480.2275; found: 480.2298. The enantiomeric excess was
determined by SFC-HPLC over the corresponding acetal following Method A. Chiralpak IB column
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[CO2/MeOH = 98:2]; flow rate 3.0 mL/min. ee = 95%, τ major = 16.9 and 19.2 min; τ minor = 18.1 and 21.2
min.
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(3R, 4S)-3-(2,2-Dimetoxyethyl)-4-nitro-6-(1-phenyl-1H-tetrazol-5-ylsulfonyl)hexanal and (3R, 4R)-
3-(2,2-Dimetoxyethyl)-4-nitro-6-(1-phenyl-1H-tetrazol-5-ylsulfonyl)hexanal (4g)
The title compound was obtained in a 71% yield as yellow oil after flash column chromatography
(Hexane 2:1 EtOAc) according to the general procedure, using TBAB (1 equiv) as additive as a 64:36
mixture of diastereomers. The diastereomeric ratio (dr) was determined by 1H NMR. The enantiomeric
excess was determined by HPLC over the cyclohexene derivative. The procedure to obtain this product
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has been scaled up until 0.9 g of nitrocompound 1. Yield: 969 mg, 71% H NMR (300 MHz) (data
obtain from the mixture of diastereomers): δ 9.72 (s, 1Hmajor, 1Hminor), 7.73-7.56 (m, 5Hmajor, 5Hminor),
5.00-4.68 (m, 1Hmajor, 1Hminor), 4.45-4.33 (m, 1Hmajor, 1Hminor), 3.90-3.74 (m, 2Hmajor, 2Hminor), 3.35-3.27
(m, 6Hmajor, 6Hminor), 2.91-2.39 (m, 5Hmajor, 5Hminor), 1.88-1.49 (m, 2Hmajor, 2Hminor). 13C NMR (75 MHz)
(Mixture of diastereomers): 199.5 (CHO), 199.0 (CHO), 153.1 (2C), 132.8 (2C), 131.7 (2CH), 129.8
(4CH), 125.0 (4CH), 103.3 (CH), 102.9 (CH), 87.8 (CH), 87.3 (CH), 54.0 (2CH3) 53.7 (2CH3), 52.8
(2CH2), 44.6 (CH2), 44.0 (CH2), 33.5 (CH2), 32.5 (CH2), 32.0 (CH), 31.8 (CH), 23.9 (CH2), 23.1
(CH2).MS (ESI): m/z 464 (M++23, 91), 410 (20), 338 (15), 186 (25), 149 (36), 135 (17). HRMS (ESI):
calculated for C17H23N5O7SNa (M++23): 464.1210; found: 464.1205.
(3R, 4S)-4-Nitro-3-phenyl-6-(1-phenyl-1H-tetrazol-5-ylsulfonyl)hexanal and (3R, 4R)-4-Nitro-3-
phenyl-6-(1-phenyl-1H-tetrazol-5-ylsulfonyl)hexanal (4h)
The title compound was obtained in a 77% yield as a pale yellow solid (mp = 57-59 ºC) after flash
column chromatography (Hexane 3:1 EtOAc) according to the general procedure, using LiOAc as
additive (20 mol %) as a 54:46 mixture of diastereomers (33 mg, 77% yield). The diastereomeric ratio
1
(dr) was determined by HPLC. H NMR (300 MHz) (data obtain from the mixture of diastereomers): δ
9.70 (s, 1Hminor), 9.56 (s, 1Hmajor), 7.71-7.57 (m, 5Hmajor, 5Hminor), 7.41-7.10 (m, 5Hmajor, 5Hminor), 5.11-
4.94 (m, 1Hmajor, 1Hminor), 3.90-3.73 (m, 2Hmajor, 2Hminor), 3.70-3.59 (m, 1Hmajor, 1Hminor) 3.25-3.11 (m,
1Hminor), 3.08-2.94 (m, 1Hmajor, 1Hminor) 2.85-2.74 (m, 1Hmajor), 2.69-2.40 (m, 1Hmajor, 2Hminor) 2.31-2.16
(m, 1Hmajor). 13C NMR (75 MHz) (Mixture of diastereomers): δ 198.7 (CHO), 197.9 (CHO), 153.1 (C),
152.8 (C), 136.5 (C), 136.1 (C), 132.7 (2C), 131.6 (2CH), 129.8 (4CH), 129.5 (2CH), 129.1 (2CH),
128.6 (2CH), 128.0 (4CH), 125.0 (2CH), 124.9 (2CH), 89.6 (CH), 89.3 (CH), 52.6 (CH2), 52.3 (CH2),
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46.3 (CH2), 45.3 (CH2), 43.3 (CH), 42.4 (CH), 24.7 (CH2), 24.2 (CH2). MS (ESI): m/z 430 (M++1, 31),
368 (19), 254 (100), 236 (64). HRMS (ESI): calculated for C19H20N5O5S (M++1): 430.1179; found:
430.1176. The enantiomeric excess was determined by SFC-HPLC over the corresponding acetal
following Method A. Chiralpak IA column [CO2/MeOH = 90:10]; flow rate 3.0 mL/min. ee = 92%, τ
major = 6.9 and 13.8 min; τ minor = 10.2 and 11.7 min.
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(3R, 4S)-4-Nitro-3-(4-nitrophenyl)-6-(1-phenyl-1H-tetrazol-5-ylsulfonyl)hexanal and (3R, 4R)-4-
Nitro-3-(4-nitrophenyl)-6-(1-phenyl-1H-tetrazol-5-ylsulfonyl)hexanal (4i)
The title compound was obtained in a 83% yield as a yellow solid (mp = 56-61 ºC) after flash column
chromatography (Hexane 2:1 EtOAc) according to the general procedure, using LiOAc as additive (20
mol %) as a 55:45 mixture of diastereomers. The diastereomeric ratio (dr) was determined by HPLC. 1H
NMR (300 MHz) (data obtain from the mixture of diastereomers): δ 9.74 (s, 1Hminor), 9.53 (s, 1Hmajor),
8.25-8.17 (m, 2Hmajor, 2Hminor) 7.72-7.58 (m, 5Hmajor, 5Hminor), 7.46-7.34 (m, 2Hmajor, 2Hminor), 5.16-5.06
(m, 1Hmajor, 1Hminor), 4.06-3.92 (m, 1Hmajor, 1Hminor), 3.90-3.73 (m, 2Hmajor, 2Hminor), 3.84-3.62 (m,
1Hmajor, 1Hminor) 3.32-3.21 (m, 1Hminor), 3.15-3.01 (m, 1Hmajor, 1Hminor) 2.99-2.81 (m, 1Hmajor), 2.72-2.47
(m, 1Hmajor, 2Hminor) 2.37-2.19 (m, 1Hmajor). 13C NMR (75 MHz) (Mixture of diastereomers): δ 197.5
(CHO), 196.8 (CHO), 153.0 (C), 152.8 (C), 147.9 (2C), 144.0 (C), 143.7 (C), 132.6 (2C), 131.7 (2CH),
129.9 (4CH), 129.5 (2CH), 129.2 (2CH), 125.0 (2CH), 124.8 (2CH), 124.6 (2CH), 124.3 (2CH), 88.8
(CH), 88.0 (CH), 52.5 (CH2), 52.3 (CH2), 46.0 (CH2), 45.3 (CH2), 42.6 (CH), 41.9 (CH), 24.8 (2CH2).
MS (ESI): m/z 475 (M++1, 11), 242 (100), 149 (20), 147 (23). HRMS (ESI): calculated for C19H19N6O7S
(M++1): 475.1030; found: 475.1053. The enantiomeric excess was determined by SFC-HPLC over the
corresponding acetal following Method A. Chiralpak IB column [CO2/MeOH = 85:15]; flow rate 3.0
mL/min. ee = 75%, τ major = 6.8 and 12.1 min; τ minor = 9.7 and 10.7 min.
(3R, 4S)-4-Nitro-3-(4-chlorophenyl)-6-(1-phenyl-1H-tetrazol-5-ylsulfonyl)hexanal and (3R, 4R)-4-
Nitro-3-(4-chlorophenyl)-6-(1-phenyl-1H-tetrazol-5-ylsulfonyl)hexanal (4j)
The title compound was obtained in a 78% yield as yellowish oil after Flash column chromatography
(Hexane 3:1 EtOAc) according to the general procedure, using LiOAc as additive (20 mol%) as a 55:45
mixture of diastereomers. The diastereomeric ratio (dr) was determined by HPLC. 1H NMR (300 MHz)
(data obtain from the mixture of diastereomers): δ 9.69 (s, 1Hmajor), 9.57 (s, 1Hminor), 7.69-7.55 (m,
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5Hmajor, 5Hminor), 7.34-7.25 (m, 2Hmajor, 2Hminor), 7.17-7.06 (m, 2Hmajor, 2Hminor) 5.08-4.95 (m, 1Hmajor
,
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1Hminor), 3.90-3.59 (m, 3Hmajor, 3Hminor), 3.24-3.11 (m, 1Hminor), 3.05-2.91 (m, 1Hmajor, 1Hminor) 2.87-2.76
(m, 1Hmajor), 2.68-2.42 (m, 1Hmajor, 2Hminor) 2.30-2.15 (m, 1Hmajor). 13C NMR (75 MHz) (Mixture of
diastereomers): δ 198.3 (CHO), 197.5 (CHO), 153.0 (C), 152.8 (C), 135.1 (C), 134.7 (C), 134.5 (2C),
132.7 (2C), 131.7 (2CH), 129.8 (4CH), 129.7 (2CH), 129.4 (4CH), 129.3 (2CH), 125.0 (2CH), 124.9
(2CH), 89.3 (CH), 88.2 (CH), 52.6 (CH2), 52.3 (CH2), 46.2 (CH2), 45.3 (CH2), 42.5 (CH), 41.7 (CH),
24.6 (CH2), 24.4 (CH2). MS (ESI): m/z 464 (M++1, 48), 149 (23), 147 (100), 119 (89). HRMS (ESI):
calculated for C19H19N5O5SCl (M++1): 464.0789; found: 464.0791. The enantiomeric excess was
determined by SFC-HPLC over the corresponding acetal following Method A. Chiralpak IB column
[CO2/MeOH = 90:10]; flow rate 3.0 mL/min. ee = 86%, τ major = 6.3 and 12.1 min; τ minor = 9.0 and 11.0
min.
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(3R, 4S)-4-Nitro-3-(4-metoxyphenyl)-6-(1-phenyl-1H-tetrazol-5-ylsulfonyl)hexanal and (3R, 4R)-4-
Nitro-3-(4-metoxyphenyl)-6-(1-phenyl-1H-tetrazol-5-ylsulfonyl)hexanal (4k)
The title compound was obtained as yellow oil after flash column chromatography (Hexane 2:1 EtOAc)
according to the general procedure, using LiOAc as additive (20 mol%) as a 54:46 mixture of
1
diastereomers (25 mg, 55% yield). The diastereomeric ratio (dr) was determined by HPLC. H NMR
(300 MHz) (data obtain from the mixture of diastereomers): δ 9.70 (s, 1Hminor), 9.56 (s, 1Hmajor), 7.71-
7.57 (m, 5Hmajor, 5Hminor), 7.13-7.01 (m, 2Hmajor, 2Hminor), 6.89-6.81 (m, 2Hmajor, 2Hminor) 5.05-4.89 (m,
1Hmajor, 1Hminor), 3.82-3.57 (m, 6Hmajor, 6Hminor) 3.40-3.29 (m, 1Hminor), 3.03-2.89 (m, 1Hmajor, 1Hminor
)
2.81-2.70 (m, 1Hmajor), 2.67-2.40 (m, 1Hmajor, 2Hminor) 2.36-2.17 (m, 1Hmajor). 13C NMR (75 MHz)
(Mixture of diastereomers): δ 199.0 (CHO), 198.2 (CHO), 159.6 (C), 159.5 (C), 153.0 (C), 152.8 (C),
132.8 (C), 132.7 (C), 131.7 (2CH), 129.8 (4CH), 129.1 (4CH), 128.1 (C), 127.9 (C), 125.0 (2CH), 124.9
(2CH), 114.9 (2CH), 114.5 (2CH), 89.7 (CH), 88.4 (CH), 55.3 (2CH3), 52.6 (CH2), 52.4 (CH2), 46.4
(CH2), 45.4 (CH2), 42.6 (CH), 41.8 (CH), 24.6 (CH2), 24.2 (CH2). MS (ESI): m/z 460 (M++1, 100), 282
(12), 163 (41), 149 (30), 119 (22). HRMS (ESI): calculated for C20H22N5O6S (M++1): 460.1285; found:
460.1263. The enantiomeric excess was determined by SFC-HPLC over the corresponding acetal
following Method A. Chiralpak IB column [CO2/MeOH = 90:10]; flow rate 3.0 mL/min. ee = 80%, τ
major = 5.9 and 10.2 min; τ minor = 7.7 and 12.0 min.
General procedure for the intramolecular Julia-Kocienski olefination
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The Journal of Organic Chemistry
Note: Nitrocyclohexenes with short aliphatic chains (5b and 5c) presented low stability working with
them and the isolation was difficult.32
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Method A: The corresponding adduct 4a-g (0.09 mmol) was dissolved in a 3:1 mixture of THF and
DMF (2 mL) and Cs2CO3 (3 equiv), was added to the solution in one portion under stirring at 70 ºC. The
reaction was stirred for 2 hours at that temperature, whereupon it was allowed to cool to r.t. The reaction
was quenched with a sat. aq. NH4Cl solution (5 mL) and water (5 mL) and EtOAc (10 mL) were
subsequently added. The mixture was transferred into a separatory funnel and extracted with EtOAc (2
× 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over
MgSO4, filtered and concentrated under vacuum. The crude was dissolved in CH3CN (2 mL) and the
flask was put in a CH3CN / CO2 bath at -40 ºC and DBU (16 µL, 0.1 mmol) was added dropwise. The
reaction was stirred for 15 minutes at -40 ºC whereupon it was carefully quenched dropwise with a sat.
aq. NH4Cl solution (5 mL). Water (5 mL) and EtOAc (10 mL) were subsequently added and the mixture
was transferred into a separatory funnel and extracted with EtOAc (2 × 10 mL). The combined organic
layers were washed with brine (10 mL), dried over MgSO4, filtered and concentrated under vacuum.
The crude was purified by flash column chromatography to afford the corresponding cyclohexenes 5a-g
indicated in each case.
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When method A was used with Michael adduct 4i, the biaryl by-product derived from loss of the nitro
group and subsequent aromatization of the cyclohexene was observed by 1H NMR spectra. Therefore,
method B was used for adducts with an aromatic substituent.
Method B: The corresponding adduct 4h-k (0.09 mmol) was dissolved in CH3CN (2 mL), and the
mixture was stirred at 0 ºC for 1 minute and DBU (2 equiv) was added. The reaction was stirred for 30
minutes at 0 ºC whereupon it was put in a CH3CN / CO2 bath at -40 ºC, stirred for 15 minutes and
carefully quenched dropwise with a sat. aq. NH4Cl solution (5 mL). Water (5 mL) and EtOAc (10 mL)
were subsequently added and the mixture was transferred into a separatory funnel and extracted with
EtOAc (2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4,
filtered and concentrated under vacuum. The crude was purified by flash column chromatography to
afford the corresponding cyclohexenes 5h-k indicated in each case.
(4S, 5S)-5-Nitro-4-propylcyclohex-1-ene (5a)
The title compound was obtained in a 57% yield as pale yellow oil after flash column chromatography
(Hexane 20:1 EtOAc) as a 91:9 mixture of diastereomers following method A. The diastereomeric ratio
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(dr) was determined by 1H NMR. 1H NMR (300 MHz) (91:9 Mixture of diastereomers): δ 5.75-5-58 (m,
2Hmajor, 2Hminor), 4.72 (td, J = 6.1 and 3.5 Hz, 1Hminor), 4.48 (td, J = 10.0 and 5.7 Hz 1Hmajor), 2.77-2.09
(m, 4Hmajor, 4Hminor), 1.90-1.74 (m,1Hmajor, 1Hminor), 1.43-1.20 (4Hmajor, 4Hminor), 0.89 (t, J = 7.2 Hz,
3Hmajor, 3Hminor). 13C NMR (75 MHz) (Mixture of diastereomers): Major diastereomer: δ 126.1 (CH),
122.4 (CH), 87.8 (CH), 36.6 (CH), 34.2 (CH2), 30.3 (CH2), 29.4 (CH2), 19.1 (CH2), 14.0 (CH3). Minor
diastereomer: δ 125.9 (CH), 122.1 (CH), 83.8 (CH), 36.0 (CH), 31.5 (CH2), 28.2 (CH2), 27.1 (CH2),
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20.2 (CH2), 14.0 (CH3). MS (EI): m/z 122 (M-NO2 , 3), 79 (100), 67 (11). HRMS (EI): calculated for
+
C9H14 (M-NO2 ): 122.1097; found: 122.1096
(4S, 5S)-4-Methyl-5-nitrocyclohex-1-ene (5b)
The title compound was obtained in a 45% yield as pale yellow oil after flash column chromatography
(Hexane 20:1 EtOAc) as a 79:21 mixture of diastereomers. The compound could be isolated to obtain
NMR data. However, the reaction and the purification had to be performed carefully because the
compound presented low stability5. Method B was used, but quenching the reaction at 0 ºC after 15
1
1
minutes. The diastereomeric ratio (dr) was determined by H NMR. H NMR (300 MHz) (79:21
Mixture of diastereomers): δ 5.73-5.58 (m, 2Hmajor, 2Hminor), 4.66 (ddd, J = 8.1, 5.8 and 3.6 Hz, 1Hminor),
4.41 (td, J = 10.1 and 5.7 Hz, 1Hmajor), 2.79-2.25 (m, 4Hmajor, 4Hminor), 1.95-1.79 (m, 1Hmajor, 1Hminor),
1.03 (d, J = 6.5 Hz, 1Hmajor), 1.00 (d, J = 6.5 Hz, 1Hminor). 13C NMR (75 MHz) (Mixture of
diastereomers): Major diastereomer: δ 126.3 (CH), 122.6 (CH), 88.9 (CH), 32.5 (CH2), 32.4 (CH), 30.4
(CH2), 17.8 (CH3). Minor diastereomer: δ 125.3 (CH), 121.9 (CH), 84.4 (CH), 31.4 (CH2), 30.8 (CH),
25.8 (CH2), 14.5 (CH3). MS and HRMS could not be obtained due to the instability of the compound.
(4S, 5S)-4-Ethyl-5-nitrocyclohex-1-ene (5c)
The title compound was obtained in a 51% yield as pale yellow oil after flash column chromatography
(Hexane 20:1 EtOAc) as a 92:8 mixture of diastereomers following method A. The diastereomeric ratio
(dr) was determined by 1H NMR. 1H NMR (300 MHz) (92:8 Mixture of diastereomers): δ 5.75-5-57 (m,
2Hmajor, 2Hminor), 4.75 (td, J = 6.2 and 3.2 Hz, 1Hminor) 4.50 (td, J = 9.9 and 5.5 Hz 1Hmajor), 2.79-2.11 (m,
4Hmajor, 4Hminor), 1.91-1.76 (m, 1Hmajor, 1Hminor), 1.57-1.32 (2Hmajor, 2Hminor), 0.93 (t, J = 7.5 Hz, 3Hmajor
,
3Hminor). 13C NMR (75 MHz) (Mixture of diastereomers): Major diastereomer: δ 126.1 (CH), 122.4
(CH), 87.5 (CH), 38.3 (CH), 30.4 (CH2), 29.0 (CH2), 24.8 (CH2), 10.3 (CH3). Minor diastereomer: δ
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125.9 (CH), 122.1 (CH), 83.2 (CH), 38.1 (CH), 27.8 (CH2), 27.2 (CH2), 22.4 (CH2), 11.6 (CH3) MS and
HRMS could not be obtained due to the instability of the compound.
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(4S, 5S)-4-Butyl-5-nitrocyclohex-1-ene (5d)
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The title compound was obtained in a 60% yield as pale yellow oil after flash column chromatography
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(Hexane 20:1 EtOAc) as a 85:15 mixture of diastereomers following method A. The diastereomeric
ratio (dr) was determined by 1H NMR. 1H NMR (300 MHz) (85:15 Mixture of diastereomers): δ 5.74-5-
55 (m, 2Hmajor, 2Hminor), 4.73 (td, J = 6.0 and 3.3 Hz, 1Hminor) 4.49 (td, J = 9.9 and 5.6 Hz 1Hmajor), 2.78-
2.09 (m, 4Hmajor, 4Hminor), 1.92-1.73 (m, 1Hmajor, 1Hminor), 1.43-1.20 (6Hmajor, 6Hminor), 0.88 (t, J = 7.4 Hz,
3Hmajor, 3Hminor). 13C NMR (75 MHz) (Mixture of diastereomers): Major diastereomer: δ 126.1 (CH),
122.4 (CH), 87.8 (CH), 36.8 (CH), 31.7 (CH2), 30.3 (CH2), 29.5 (CH2), 28.1 (CH2), 22.6 (CH2) 13.9
(CH3). Minor diastereomer: δ 125.9 (CH), 122.1 (CH), 83.9 (CH), 36.3 (CH), 32.0 (CH2), 30.4 (CH2),
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29.3 (CH2), 27.1 (CH2), 22.7 (CH2) 13.9 (CH3). MS (EI): m/z 136 (M-NO2 , 2), 79 (100), 67 (14).
+
HRMS (EI): calculated for C10H16 (M-NO2 ): 136.1252; found: 136.1248
(4S, 5S)-4-((3Z)-Hex-3-enyl)-5-nitrocyclohex-1-ene (5e)
The title compound was obtained in a 63% yield as pale yellow oil after Flash column chromatography
(Hexane 20:1 EtOAc) as a 75:25 mixture of diastereomers. Method A. The diastereomeric ratio (dr) was
1
1
determined by H NMR. H NMR (300 MHz) (75:25 Mixture of diastereomers): δ 5.76-5-58 (m,
2Hmajor, 2Hminor), 5.45-5.32 (m, 1Hmajor, 1Hminor), 5.30-5.19 (m, 1Hmajor, 1Hminor), 4.73 (td, J = 5.9 and 3.2
Hz, 1Hminor) 4.49 (td, J = 9.8 and 5.6 Hz, 1Hmajor), 2.79-1.95 (m, 8Hmajor, 8Hminor), 1.93-1.77 (m, 1Hmajor
,
1Hminor), 1.48-1.27 (2Hmajor, 2Hminor), 0.95 (t, J = 7.5 Hz, 3Hmajor, 3Hminor). 13C NMR (75 MHz) (Mixture
of diastereomers): Major diastereomer: δ 132.6 (CH), 127.6 (CH), 126.0 (CH), 122.4 (CH), 87.6 (CH),
36.4 (CH), 32.0 (CH2), 30.2 (CH2), 29.4 (CH2), 23.5 (CH2), 20.5 (CH2) 14.3 (CH3). Minor diastereomer:
δ 132.7 (CH), 127.8 (CH), 125.8 (CH), 122.2 (CH), 83.7 (CH), 35.6 (CH), 31.6 (CH2), 28.1 (CH2), 27.2
(CH2), 24.5 (CH2), 22.7 (CH2) 14.3 (CH3). MS (EI): m/z 232 (M+ +23, 36), 179 (47), 163 (100), 149
(42). HRMS (EI): calculated for C12H19NO2Na (M+ +1): 232.1308; found: 232.1314
(4S, 5S)-5-Nitro-4-nonylcyclohex-1-ene (5f)
The title compound was obtained in a 61% yield as pale yellow oil after flash column chromatography
(Hexane 30:1 EtOAc) as a mixture 76:24 of diastereomers following method A. The diastereomeric
ratio (dr) was determined by 1H NMR. 1H NMR (300 MHz) (76:24 Mixture of diastereomers): δ 5.74-5-
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56 (m, 2Hmajor, 2Hminor), 4.73 (td, J = 3.6 and 6.1 Hz, 1Hminor) 4.49 (td, J = 9.9 and 5.5 Hz 1Hmajor), 2.78-
2.11 (m, 4Hmajor, 4Hminor), 1.90-1.76 (m, 1Hmajor, 1Hminor), 1.35-1.19 (m, 16Hmajor, 16Hminor), 0.89 (t, J =
7.2 Hz, 3Hmajor, 3Hminor). 13C NMR (75 MHz) (Mixture of diastereomers): Major diastereomer: δ 126.1
(CH), 122.3 (CH), 87.8 (CH), 36.8 (CH), 32.0 (CH2), 31.8 (CH2), 30.3 (CH2), 29.8-29.1 (5CH2), 25.9
(CH2), 22.6 (CH2) 14.1 (CH3). Minor diastereomer: δ 125.9 (CH), 122.1 (CH), 83.8 (CH), 36.2 (CH),
32.0 (CH2), 31.8 (CH2), 30.3 (CH2), 29.8-29.1 (5CH2), 25.9 (CH2), 22.6 (CH2) 14.1 (CH3). MS (EI): m/z
276 (M+ +23, 40), 207 (24), 163 (55), 149 (43). HRMS (EI): calculated for C15H27NO2Na (M+ +23):
276.1934; found: 276.1947
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(4R, 5S)-4-(2, 2-Dimethoxyethyl)-5-nitrocyclohex-1-ene (5g)
The title compound was obtained in a 60% yield as pale yellow oil after flash column chromatography
(Hexane 8:1 EtOAc) as a mixture 90:10 of diastereomers following method A. The diastereomeric ratio
(dr) was determined by 1H NMR. The procedure to obtain this product has been scaled up until 300 mg
of 4g, maintaining yield and dr. 1H NMR (300 MHz) (90:10 Mixture of diastereomers): δ 5.73-5.55 (m,
2Hmajor, 2Hminor), 4.75-4.66 (td, J = 3.4 and 6.0 Hz, 1Hminor), 4.55-4.38 (m, 2Hmajor, 1Hminor), 3.30-3.22 (m,
6Hmajor, 6Hminor), 2.78-2.07 (m, 4Hmajor, 4Hminor), 1.99-1.81 (m, 1Hmajor, 1Hminor), 1.77-1.57 (m, 1Hmajor
,
1Hminor), 1.53-1.41 (m, 1Hmajor, 1Hminor). 13C NMR (75 MHz) (Mixture of diastereomers): Major
diastereomer: δ 125.8 (CH), 122.4 (CH), 101.9 (CH), 87.0 (CH), 53.4 (CH3), 51.8 (CH3), 34.8 (CH2),
33.3 (CH), 30.0 (CH2), 29.7 (CH2). Minor diastereomer: δ 125.8 (CH), 122.2 (CH), 102.8 (CH), 83.4
(CH), 53.1 (CH3), 52.7 (CH3), 32.5 (CH2), 32.2 (CH), 28.6 (CH2), 27.4 (CH2). MS (ESI): m/z 238
(M++23, 81), 153 (29), 137 (61), 105 (100). HRMS (ESI): calculated for C10H17NO4Na (M++23):
238.1049; found: 238.1055. The enantiomeric excess was determined by HPLC using a Chiralpak IB
column [Hexane/iPrOH = 99:1]; flow rate 0.5 mL/min. ee = 94%, τ
= 40.1 and 47.4 min; τ
=
minor
major
38.3 and 43.7 min. The ee was determined over a 74:26 diastereomers mixture.
(4R, 5S)-5-Nitro-4-phenyl-cyclohex-1-ene (5h)
The title compound was obtained in a 52% yield as colorless oil after flash column chromatography
(Hexane 10:1 EtOAc) as a mixture 94:6 of diastereomers following method B. The diastereomeric ratio
(dr) was determined by 1H NMR. 1H NMR (300 MHz) (94:6 Mixture of diastereomers): δ 7.36-7.18 (m,
5Hmajor, 5Hminor), 6.02-5.90 (m, 1Hminor) 5.88-5.69 (m, 2Hmajor, 1Hminor), 4.99-4.82 (m, 1Hmajor, 1Hminor
)
3.77-3.68 (m, 1Hminor) 3.43 (td, J = 11.0 and 5.9 Hz, 1Hmajor), 2.91-2.26 (m, 4Hmajor, 4Hminor). 13C NMR
(75 MHz) Major diastereomer: δ 139.9 (C), 128.9 (2 CH), 127.6 (CH), 127.4 (2 CH), 126.6 (CH), 122.7
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(CH), 87.4 (CH), 44.2 (CH), 33.2 (CH2), 31.3 (CH2). Minor diastereomer could not be assigned due to
the small proportion of this diastereomer compared with the major one. MS (EI): m/z 226 (M+ +23, 28),
157 (100), 149 (19), 129 (13). HRMS (EI): calculated for C12H13NO2Na (M+ +23): 226.0838; found:
226.0834
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(4R, 5S)-5-Nitro-4-(4-nitro)-phenyl-cyclohex-1-ene (5i)
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The title compound was obtained in a 49% yield as colorless oil after flash column chromatography
(Hexane 8:1 EtOAc) as a mixture 91:9 of diastereomers following method B. The diastereomeric ratio
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(dr) was determined by H NMR. H NMR (300 MHz) (91:9 Mixture of diastereomers): δ 8.19 (d, J =
8.7 Hz, 2Hmajor), 8.15 (d, J = 8.8 Hz, 2Hminor), 7.42 (d, J = 8.7 Hz, 2Hmajor) 7.38 (d, J = 8.8 Hz, 2Hminor),
7.21-7.11 (m, 2Hmajor, 2Hminor), 6.01-5.94 (m, 1Hminor) 5.88-5-73 (m, 2Hmajor, 1Hminor), 5.07-4.88 (m,
1Hmajor, 1Hminor) 3.91-3.81 (m, 1Hminor) 3.56 (td, J = 11.2 and 6.0 Hz, 1Hmajor), 2.92-2.26 (m, 4Hmajor
,
4Hminor), 13C NMR (75 MHz) (Mixture of diastereomers): Major diastereomer: δ 147.5 (C), 131.0 (C),
128.4 (2CH), 125.9 (CH), 124.2 (2CH), 123.0 (CH), 86.7 (CH), 44.1 (CH), 32.9 (CH2), 31.1 (CH2).
Minor diastereomer could not be assigned due to the small proportion of this diastereomer compared
with the major one. MS (EI): m/z 271 (M+ +23, 13), 202 (16), 169 (18), 149 (61), 113 (16). HRMS (EI):
calculated for C12H12N2O4Na (M+ +23): 271.0689; found: 271.0696
(4R, 5S)-5-Nitro-4-(4-chloro)-phenyl-cyclohex-1-ene (5j)
The title compound was obtained in a 50% yield as colorless oil after flash column chromatography
(Hexane 10:1 EtOAc) as a mixture 91:9 of diastereomers following method B. The diastereomeric ratio
(dr) was determined by 1H NMR. 1H NMR (300 MHz) (91:9 Mixture of diastereomers): δ 7.34-7.24 (m,
2Hmajor, 2Hminor), 7.21-7.11 (m, 2Hmajor, 2Hminor), 5.99-5.91 (m, 1Hminor) 5.86-5-70 (m, 2Hmajor, 1Hminor),
4.99-4.82 (m, 1Hmajor, 1Hminor) 3.74 (td, J = 6.4 and 4.2 Hz 1Hminor) 3.41 (td, J = 11.1 and 5.8 Hz,
1Hmajor), 2.90-2.23 (m, 4Hmajor, 4Hminor). 13C NMR (75 MHz) (Mixture of diastereomers): Major
diastereomer: δ 138.5 (C), 132.4 (C), 129.1 (2CH), 128.7 (2CH), 126.3 (CH), 122.8 (CH), 87.3 (CH),
43.8 (CH), 33.1 (CH2), 31.2 (CH2). Minor diastereomer could not be assigned due to the small
+
proportion of this diastereomer compared with the major one. MS (EI): m/z 191 (M-NO2 , 46), 153
+
(100), 149 (21), 125 (18). HRMS (EI): calculated for C12H12Cl (M-NO2 ): 191.0622; found: 191.06427
(4R, 5S)-5-Nitro-4-(4-methoxy)-phenyl-cyclohex-1-ene (5k)
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The title compound was obtained in a 52% yield as colorless oil after Flash column chromatography
(Hexane 10:1 EtOAc) as a mixture 85:15 of diastereomers following method B. The diastereomeric
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1
ratio (dr) was determined by H NMR. H NMR (300 MHz) (85:15 Mixture of diastereomers): δ 7.19-
6
7
7.09 (m, 2Hmajor, 2Hminor), 6.91-6.80 (m, 2Hmajor, 2Hminor), 6.03-5.89 (m, 1Hminor) 5.86-5.64 (m, 2Hmajor
,
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1Hminor), 4.97-4.80 (m, 1Hmajor, 1Hminor) 3.84-3.70 (m, 4Hmajor, 4Hminor) 3.36 (td, J = 11.0 and 5.9 Hz,
1Hmajor), 2.96-2.25 (m, 4Hmajor, 4Hminor). 13C NMR (75 MHz) (Mixture of diastereomers): Major
diastereomer: δ 158.9 (C), 132.0 (C), 129.3 (2CH), 126.7 (CH), 122.6 (CH), 114.2 (2CH), 87.7 (CH),
55.2 (CH3), 43.5 (CH), 33.2 (CH2), 31.2 (CH2). Minor diastereomer: δ 158.7 (C), 130.0 (C), 129.2
(2CH), 128.8 (CH), 124.5 (CH), 114.0 (2CH), 84.6 (CH), 53.7 (CH3), 40.1 (CH), 31.9 (CH2), 31.5
(CH2). MS (EI): m/z 256 (M+ +23, 9), 187 (100), 149 (15), 121 (66). HRMS (EI): calculated for
C13H15NO3Na (M+ +23): 256.0944; found: 256.0942
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General procedure for the reduction of compound 5g
Nitrocyclohexene 5g (42 mg, 0.2 mmol) was dissolved in MeOH (2 mL), and the flask was charged in
open air with Pd/C catalyst (10% w/t, 30 mg). The mixture was stirred for 5 minutes, whereupon the
solution was purged with a hydrogen balloon for 10 minutes and was heated at 50 ºC under hydrogen
atmosphere for 24 h. After this time, the solution was filtered through a short pad of celite washing with
MeOH (2 x 10 mL). The solvent was removed under reduced pressure to afford compound 6 (34 mg,
1
yield: 98%) as a colorless oil as a 90:10 mixture of diastereomers. H NMR (300 MHz) (Mixture of
diastereomers): δ 4.55-4.41 (m, 1Hmajor, 1Hminor), 3.31 (d, J = 4.1 Hz, 6Hmajor, 6Hminor), 2.40-2.12 (m,
3Hmajor, 3Hminor), 2.07 – 1.94 (m, 1Hmajor, 1Hminor), 1.92-1.58 (m, 4Hmajor, 4Hminor), 1.45-1.07 (m, 6Hmajor
,
6Hminor). 13C NMR (75 MHz) (Mixture of diastereomers): Major diastereomer: δ 103.1 (CH), 54.8 (CH),
53.0 (CH3), 52.1 (CH3), 41.8 (CH), 36.5 (CH2), 36.0 (CH2), 31.6 (CH2), 25.9 (CH2), 25.3 (CH2). Minor
diastereomer: δ 103.4 (CH), 52.9 (CH3), 52.4 (CH3), 49.8 (CH), 41.7 (CH), 37.0 (CH2), 36.0 (CH2), 31.9
(CH2), 27.1 (CH2), 24.7 (CH2). MS (ESI): m/z 188 (M++1, 74), 121 (26), 105 (100). HRMS (ESI):
calculated for C10H22NO2 (M++1): 187.1572; found: 187.1581
Acknowledgment
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We thank the Spanish Government (CTQ-2012-35957) and Comunidad Autónoma de Madrid
(S2009/PPQ-1634). ER thanks the Spanish Ministry of Science for a predoctoral fellowship.
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Supporting Information Available.
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Chemical correlation, spectra of compounds 1, 3g, 4a-k and 5a-k and 6, as well as chiral SFC-HPLC
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conditions. This material is available free of charge via the Internet at http:/pubs.acs.org.
References and Footnotes
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(23) We have observed this phenomena in other nucleophiles such as arylacetic acid surrogate: see ref 21 and
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(24) See Experimental section for more details
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(25) Henning, R.; Urbach, H. EP 84.164, 1983.
(26) Ebel, K.; Ohlback, F. US 6.559.318, 2003
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compounds was assigned by analogy from 5g (see SI).
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