Levopimaric acid derived 1,2-diamines and their application in the copper-catalyzed asymmetric Henry reaction

Article abstract of DOI:10.1016/j.tet.2017.11.059

Levopimaric acid, a readily available starting material, was used in efficient syntheses of new enantiopure diamines and Schiff bases with good yields. The synthetic procedure is based on the fumaropimaric acid monomethyl ester conversion into the optical

Full text of DOI:10.1016/j.tet.2017.11.059

Tetrahedron xxx (2017) 1e8
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Levopimaric acid derived 1,2-diamines and their application in the
copper-catalyzed asymmetric Henry reaction
Tatiana B. Khlebnikova*, Vasily N. Konev, Zinaida P. Pai
Boreskov Institute of Catalysis, Akad. Lavrentiev Pr. 5, Novosibirsk, 630090, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Levopimaric acid, a readily available starting material, was used in efficient syntheses of new enantiopure
diamines and Schiff bases with good yields. The synthetic procedure is based on the fumaropimaric acid
monomethyl ester conversion into the optically pure trans-1,2-diamine via a Curtius rearrangement. New
diamines were studied as ligands in the copper-catalyzed asymmetric Henry reaction.
© 2017 Elsevier Ltd. All rights reserved.
Received 20 June 2017
Received in revised form
10 November 2017
Accepted 20 November 2017
Available online xxx
Keywords:
Chiral pool
Diterpene
Levopimaric acid
Asymmetric catalysis
Henry reaction
Enantioselectivity
1. Introduction
procedure for an optically pure diterpene derived trans-1,2-
diamine and its further use as a key compound for obtaining a
Natural products are a convenient and promising source of
renewable raw materials for organic synthesis. Chiral natural com-
pounds are widely used in drug discovery, asymmetric synthesis,
and enantiomers separation. Metal complexes with chiral ligands
based on amino acids, terpenes, carbohydrates, alkaloids have been
applied as catalysts for enantioselective reactions.1e4 Starting from
natural monoterpenes a large variety of its nitrogen derivatives
(diamines, amino alcohols, Schiff bases, imidazolines) have been
synthesized and employed as chiral inducers in asymmetric cata-
lysis.5e11 The application of diterpenes for this purpose is much less
studied. Among the few examples known, dehydroabietylamine and
isosteviol were used as chiral moieties incorporated into organo-
catalysts.12e16 Diterpene resin acids are a promising chiral source for
the construction of various optically active substances as they are
commercially available optically pure reactive compounds possess-
ing multiple stereogenic centers and modifiable functional groups.
Earlier, we developed methods for the synthesis of optically
pure nitrogen and phosphorus derivatives of diterpene resin acids
and employed the resultant mono- and bidentate N, P-ligands in
catalytic asymmetric reactions.17,18 Here we present a high yield
series of secondary amines with different substituents. These novel
diamine ligands were employed in the Cu(II)-catalyzed Henry re-
action. The asymmetric nitroaldol reaction (Henry reaction) is an
important method in organic synthesis, used for the creation of
CeC bonds via condensation of carbonyl compounds with saturated
nitroalkanes.19e22 The Henry reaction is efficiently catalyzed by
complexes of copper(I) and copper(II) with nitrogen containing li-
gands, including oxazoline (bisoxazoline),23e27 amines,28e31 amine
oxides,32 aminoalcohols,33e36 sulfonylamides,37 Schiff bases38 and
salans.39e43 Most of the chiral amine ligands used contain trans-
diamine fragments from 1,2-diaminocyclehexane29,42e47 or 1,2-
diphenylethanediamine.39,41,48,49 The essential advantage of the
Cu(II) complexes over those of Cu(I) is that they do not require inert
atmosphere for catalysis performance.32,50,51 With this regard
herein we report the employment of a new trans-1,2-diamine
scaffold type in chiral Cu(II) complex catalysts for nitroaldol
condensation.
2. Results and discussion
2.1. Synthesis of 1,2-diamine derivatives of levopimaric acid
After considering the properties of levopimaric acid 1 and the
* Corresponding author.
E-mail address: khleb@catalysis.ru (T.B. Khlebnikova).
other constituents in the starting plant feedstock52,53 we designed an
https://doi.org/10.1016/j.tet.2017.11.059
0040-4020/© 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Khlebnikova TB, et al., Levopimaric acid derived 1,2-diamines and their application in the copper-catalyzed
asymmetric Henry reaction, Tetrahedron (2017), https://doi.org/10.1016/j.tet.2017.11.059

2
T.B. Khlebnikova et al. / Tetrahedron xxx (2017) 1e8
Scheme 1. Synthesis of diamine 4 from pine oleoresin, containing levopimaric acid 1. Reagents and conditions: (a) CH3I, K2CO3, acetone, 6 h; (b) fumaric acid, 180 ꢀC, Ar, 6 h; (c)
SOCl2, DMF, 110 ꢀC, 3 h; (d) NaN3, PhCH3, þ5 ꢀC, 2 h; (e) 110 ꢀC, 2 h; (f) HCl (35%), 110 ꢀC, 2 h; (g) aqueous NaHCO3.
optimum sequence for the synthesis of the 1,2-diamine (Scheme 1).
Pine oleoresin is mainly composed (75e95%) of mixed abietic-type
resin acids,54e59 i.e. tricyclic diterpenes with a single carboxyl
group and a conjugated double bond system. The four abietic-type
acids (abietic, neoabietic, palustric and levopimaric) undergo inter-
conversion under heat or acidic conditions,60e62 and in the fresh pine
resin levopimaric acid 1 amounts to 30e50%.52,61 Owing to its cis-
diene structure, levopimaric acid easily reacts with activated dien-
ophiles at 20e30 ꢀC forming the Diels-Alder adducts.52,63 Other
abietic-type acids form the same adducts at 150 ꢀC after in situ
isomerization into levopimaric acid.63e66 Cycloaddition proceeds
with a high stereoselectivity66 and the target product is easily
separated by crystallization from both minor isomers and non-
reacted feedstock components due to a difference in the solubility
of the diastereoisomers. The obtained optically pure cycloaddition
adduct 2 contains trans-1,2-carboxyl groups, which can be used to
introduce amino groups through Curtius rearrangement.
The raw pine oleoresin with high content of abietic-type acids
was used as the starting material for the synthesis of 1,2-diamine 4
without any purification or isolation of the resin acids. In order to
avoid undesired triamine formation the oleoresin was methylated
before the diene synthesis. Cycloaddition of fumaric acid to the
methyl levopimarate was performed without a solvent at 180 ꢀC
under argon using the crude mixture of the methylated products
obtained at the previous stage. Unreacted oleoresin components
were removed from the resultant reaction mixture by extraction
with diethyl ether. The residual crude solid was crystallized from
methanol yielding individual product 2 at 50 g per 100 g of the raw
oleoresin used. The obtained monomethyl ester of fumaropimaric
acid 2 is stereochemically pure, which is confirmed by the single set
of signals in 1Н and 13С NMR spectra.
The four stage conversion of monomethyl ester of fumar-
opimaric acid 2 into trans-1,2-diamine 4 via Curtius rearrangement
was performed as a one pot procedure without any separation of
intermediates (acid dichloride, diazide and diisocyanate). The
overall yield was 78%. Intermediate diisocyanate 3 was also syn-
thesized from dicarboxylic acid 2 and isolated in a yield of 69%.
Synthesis of the target diamine 4 proceeds stereospecifically, giving
an optically pure product which is then used to obtain chiral Schiff
bases and secondary amines (Scheme 2).
New Schiff bases 5a-f were obtained in good yields (68e89%) via
trans-1,2-diamine 4 condensation with several aromatic aldehydes.
Reduction of compounds 5a-f by sodium borohydride afforded
amines 6a-f isolated in yields of 71e96% after chromatography or
crystallization. Therefore, we have synthesized new levopimaric
acid derived optically pure secondary amines 6a-f containing
various substituents at the nitrogen atoms.
2.2. New chiral diterpene derived 1,2-diamine ligands in
enantioselective Cu(II)-catalyzed Henry reaction
The enantioselectivity and catalytic activity of Cu(II) complexes
with ligands 6a-f were estimated in nitroaldol reactions using
4-nitrobenzaldehyde 7a and nitromethane 8 as model substrates.
Reactions were carried out in tetrahydrofuran solution at room
temperature in the presence of a 5 mol% in situ catalyst prepared
from copper(II) acetate monohydrate (5 mol%) and ligands 6a-f
(5 mol%) just before the Henry reaction. The results of the reactions
are shown in Table 1. High chemical and moderate % ees were ob-
tained in nitroaldol condensation in the presence of copper com-
plexes with aminophenols (Table 1, entries 1e2) and
aminonaphthol (Table 1, entry 4). As the substituent at the o-po-
sition of ligand phenol ring increases in volume, the reaction rate
and % ee decrease (Table 1, entries 1e3). At the same time, volume
of substituents at m- or p-positions have a lesser effect on catalyst
performance (Table 1, entry 4). Obviously, the presence of phenol
donor oxygen atoms in the non-chiral substituents at ligand amino
groups is necessary for catalyst enantioselectivity. Thus, when the
phenol substituents are replaced by heterocyclic ones, the derived
metal complexes show moderate or high catalytic activity but
negligible stereodifferentiating ability (Table 1, entries 5, 6).
Therefore, in further experiments we studied catalyst performance
of copper(II) complex with only chiral ligand 6а.
The results of model reactions carried out in different solvents
are shown in Table S1 (see Supporting Information). Since the
precursors and catalyst itself well dissolve in all tested solvents, the
solvent polarity and specific interactions with metal complex
appear to be the main factors determining catalyst efficiency. Re-
actions in non-polar solvents (Table S1, entries 1e2) afforded
product in moderate yields (53e63%) with low ee (24%). Similar
results are also obtained in chlorinated hydrocarbons (Table S1,
entries 3e4). Protic solvent MeOH (Table S1, entry 5) decreases the
enantioselectivity even more (to 15% ee) most likely due to alcohol
coordination to copper providing a mixture of metal complexes. In
acetonitrile and dimethylformamide (Table S1, entries 6, 7) nitro-
aldol condensation resulted in high yield, but near racemic prod-
ucts are attained. Apparently, copper(II) forms non-chiral
complexes with these solvents, which hinder formation of
Scheme 2. Synthesis of levopimaric acid derived Schiff bases and diamines. Reagents and conditions: (a) RCHO; (b) NaBH4.
Please cite this article in press as: Khlebnikova TB, et al., Levopimaric acid derived 1,2-diamines and their application in the copper-catalyzed
asymmetric Henry reaction, Tetrahedron (2017), https://doi.org/10.1016/j.tet.2017.11.059

T.B. Khlebnikova et al. / Tetrahedron xxx (2017) 1e8
3
Table 1
Screening of Сu(II) complexes with ligands 6a-f.a
Entry
Ligand
Yield (%)b
ee (%)c
R (Scheme 2)
R1
R2
1
2
3
4
5
6
6a
6b
6c
6d
6e
6f
2-OH,3-R1,4-R2-C6H2
2-OH,3-R1,4-R2-C6H2
2-OH,3-R1,4-R2-C6H2
2-hydroxynaphthyl
2-pyridyl
H
H
98
85
33
88
98
60
40
33
10
35
0
OCH3
But
e
H
But
e
e
e
2-tiophenyl
e
e
5
a
All reactions were carried out using [7a] ¼ 0.2 M, [8] ¼ 2.0 M, [9] ¼ 0.01 M (5 mol%), [6a-f] ¼ 0.01 M (5 mol%), in THF (2 mL) at rt for 8 h.
Isolated yields after column chromatography.
Determined by HPLC on the chiral phase.
b
c
stereodiscriminating complex with the chiral ligand.67 An
improvement in enantioselectivity was achieved in tetrahydro-
furan, which appears to be the optimum solvent for the reaction
In some Henry reactions the rate is known to increase in the
presence of a combined catalytic system including an external base,
additionally activating nitromethane. The use of the base in opti-
mum concentration can also increase enantioselectivity.68 We have
investigated the effect of various amines addition on the outcome
of the reaction in the presence of the copper(II) complex with
providing the product 10а in the highest yield (99%) and with 40%
ee (Table S1, entries 8e11). Under these conditions, higher ligand/
metal ratio had no effect on the catalyst's performance (Table S1,
entries 10e11). Lowering reaction temperature to ꢁ5 ꢀC provides
an enantioselectivity increase to 48% ee beside the expected
decrease in reaction rate (Table S1, entry 9).
ligand 6а (see Table S2 in the Supporting Information, entries 4e8).
It was found out that at ꢁ5 ꢀC none of tested external bases (10 mol
%) had a significant effect on the reaction's enantioselectivity
Table 2
Scope of aldehydes.a
Entry
RCHO
R
Product
11a (mol%)
T (ꢀС)
Yield (%)b
ee (%) (S)c
1
2
3
4
5
6
7
8
7a
7a
7a
7a
7b
7b
7b
7b
7c
7d
7e
7f
7g
7g
7g
7g
7h
7i
7i
7i
7i
7j
7k
7l
7m
7n
7o
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
2-NO2C6H4
2-NO2C6H4
2-NO2C6H4
2-NO2C6H4
3-NO2C6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
2-MeC6H4
2-MeC6H4
2-MeC6H4
2-MeC6H4
3-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeOC6H4
3,4-(MeO)2C6H3
2-thienyl
Ph
10a
10a
10a
10a
10b
10b
10b
10b
10c
10d
10e
10f
10g
10g
10g
10g
10h
10i
10i
10i
10i
10j
10k
10l
10m
10n
10o
e
ꢁ5
98
98
98
95
98
98
98
83
88
75
82
82
63
35
20
11
79
80
41
18
15
72
68
84
65
6
48
65
66
78
54
72
65
82
81
56
58
56
70
75
79
81
52
46
55
57
69
51
46
40(R)d
48
25
18
100
e
ꢁ5
ꢁ25
ꢁ25
ꢁ5
100
e
100
e
ꢁ5
ꢁ25
ꢁ25
ꢁ25
ꢁ5
100
100
e
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
e
ꢁ5
e
ꢁ5
e
ꢁ5
100
e
ꢁ5
ꢁ25
ꢁ25
ꢁ5
100
e
e
ꢁ5
100
e
ꢁ5
ꢁ25
ꢁ25
ꢁ5
100
e
e
ꢁ5
e
ꢁ5
e
ꢁ5
iPr
Cy
e
ꢁ5
e
ꢁ5
7
a
All reactions were carried out using [7a-m] ¼ 0.2 M, [8] ¼ 2.0 M, [9] ¼ 0.01 M (5 mol%), [6a] ¼ 0.01 M (5 mol%) in 2 mL of THF for 240 h.
b
c
Isolated yields after column chromatography.
Determined by HPLC on the chiral phase.
Formal inversion of the stereodescriptor due to the CahneIngoldePrelog (CIP) notation.
d
Please cite this article in press as: Khlebnikova TB, et al., Levopimaric acid derived 1,2-diamines and their application in the copper-catalyzed
asymmetric Henry reaction, Tetrahedron (2017), https://doi.org/10.1016/j.tet.2017.11.059

4
T.B. Khlebnikova et al. / Tetrahedron xxx (2017) 1e8
Fig. 1. Proposed transition state models for the copper-catalyzed enantioselective Henry reaction with ligand 6a.
(Table S2, entries 4, 5, 8). At reaction temperatures of ꢁ25 ꢀC, the ee
increased (from 48 to 66%), but the reaction rate decreases
dramatically (Table S2, entry 1). Under these conditions 10 mol% of
triethylamine added to substrate increases reaction rate with no
loss in enantioselectivity (Table S2, entry 6). As the triethylamine
amount is increased to 100 mol %, the reaction rate increases even
more, but enantioselectivity decreases (Table S2, entries 2 vs 7). It
should be noted that water presence in reaction mixture has no
effect on both catalyst activity and enantioselectivity (Table S2,
entry 3).
We also studied the effect of phenols additives on the nitroaldol
reaction (Table S2, entries 8e17). Positive effect of phenols as
achiral additives on product yields and enantioselectivities for
organocatalytic Henry reaction is reported elsewhere.69 In our
Cu(II)-catalyzed case, 3-nitrophenol addition also appears to in-
crease the enantioselectivity of nitroaldol condensation (Table S2,
entries 12e16). As the phenol additive concentration increases, ее
values grow slightly (at ꢁ5 ꢀC: from 55% at 10 mol% of 3-
nitrophenol to 65% at 100 mol%). At the same time, other studied
phenols, including isomeric 2- and 4-nitrophenols, have no effect
on reaction outcome. Lowering the temperature to ꢁ25 ꢀC with
addition of equimolar amount of 3-nitrophenol to substrate im-
proves the enantioselectivity to 78%. However, reaction slows down
Investigation of the reagent concentrations and substrate/cata-
lyst ratio showed that a decrease in the value of both these pa-
rameters led to lower yields and selectivities, while their increase
had an insignificant effect on reaction outcome (Table S3, entries
6e10). Based on the above results, the optimal reaction conditions
are: ([7a] 0.2 M, [8] 2.0 M, [9] 0.01 M (5 mol%), [6a] 0.01 M (5 mol%),
[11a] 0.2 M).
Having established the conditions affecting the reaction yield
and enantioselectivity, we investigated the effects of substituents
on the aromatic ring of the aldehydes on the outcome of the
nitroaldol reaction (Table 2). The reactions were studied at ꢁ5 оС
and ꢁ25 оС, both with and without 3-nitrophenol depending on
the reactivity of the aldehydes. Product yields and ee values were
examined after 10 days of the reaction, when advanced substrate
conversion was noticeable in all experiments. As can be seen from
the Table 2, nitroaldol condensation rate and enantioselectivity
depend on both electronic and steric effects of substituent on the
aldehyde aromatic ring. It was also revealed that all tested alde-
hydes formed Henry adducts with (S)-configuration of major
enantiomer.
A higher electronegativity of substituent facilitate aldehyde
activation and thus increases reaction rate. The highest yields
(83e98%) were obtained with nitro-substituted benzaldehydes
(Table 2, entries 1e9). Conversely, electron-donating substituents
deactivate aromatic aldehyde and the condensation slows (Table 2,
entries 13e23). Lowering the temperature and 3-nitrophenol
addition further reduce yields to 11e35% (Table 2, entries 13e16),
but improve the ee. According to this correlation, chlorinated
benzaldehydes should be more activated reagents than tolyl alde-
hydes and less activated than nitro substituted ones. Reaction of
chlorobenzaldehydes afforded products in 75e82% yields (Table 2,
entries 10e12). Steric factors also affect the reaction rate. The closer
that a substituent is to the formyl group in aromatic ring, the slower
the condensation is (Table 2, entries 4, 8, 9, and 10e12, and 13, 17,
18). This effect is more pronounced for the larger volume sub-
stituents. The reaction's enantioselectivity is more dependent on
the steric effect of the substituent in the aldehyde then on
its electronic properties. The highest ee are obtained for benzal-
dehydes with bulky nitro (Table 2, 54e82% ее) and methyl (Table 2,
70e81% ее) substituents at the o-position (Table 2, entries 5e8,
13e16). Variation of the distance from the formyl group to the
smaller substituent (chlorine atom) has no effect on the enantio-
selectivity (Table 2, entries 10e12). In all cases temperature
lowering and 3-nitrophenol addition decrease chemical yields but
increase ee values, i.e. the reaction decelerating factors improve
enantioselectivity. Under the same conditions, two aliphatic alde-
hydes were tested and provided the corresponding products with
low yields and enantioselectivities (Table 2, entries 26e27).
Based on our experimental observations and the previously
reported steric and electronic considerations23,28,39 we propose the
transition state models for the enantioselective Henry reaction
(Fig. 1). Two neighboring strong coordination sites at the equatorial
positions of the Cu complex are occupied by the 1,2-nitrogen atoms
considerably giving the addition product 10
а in a yield of 32%
(Table S2, entry 16). A simultaneous addition of triethylamine and
3-nitrophenol (Table S2, entry 17) in equimolar amounts (100 mol
%) at ꢁ25 ꢀC provides the same product yield (94%) as obtained at
solely triethylamine addition in concentration of 100 mol%
(Table S2, entry 7) with the lower ee (28%). Both triethylamine and
3-nitrophenol additives have effect on the reaction rate and
selectivity, but not on the product configuration. In all experiments
nitro alcohols with an (S)-configuration were produced.
To assess the contribution of components to the catalytic system
Cu(OAc)2/ligand 6a/3-nitrophenol performance, we carried out
experiments at room temperature using each of them separately as
a catalyst. According toTable S3 (see Supporting Information) in the
absence of copper(II) aminophenol 6а does not catalyze Henry re-
action with (Table S3, entry 3) or without (Table S3, entry 1) 3-
nitrophenol. Solely 3-nitrophenol also shows no catalytic perfor-
mance in this reaction (Table S3, entry 2). In all cases, the reaction
proceeds with no selectivity and nitro alcohol 10а yield never ex-
ceeds 3% over 18 h. On its own Cu(OAc)2 shows weak catalytic ac-
tivity and no enantioselectivity (Table S3, entry 4). Only Cu(II)
precursor with ligand 6а shows high catalytic activity and moder-
ate enantioselectivity (Table S3, entry 5).
Based on these results, we assume that the 3-nitrophenol does
not directly bind to the stereodiscriminating catalytic copper
complex. The reaction deceleration and improvement of enantio-
selectivity caused by 3-nitrophenol addition can be attributed to
the formation of its molecular complex with benzaldehyde (similar
to ones described elsewhere70), which hinders aldehyde coordi-
nation, but provides the better control over its orientation when
approaching to the Cu complex.
Please cite this article in press as: Khlebnikova TB, et al., Levopimaric acid derived 1,2-diamines and their application in the copper-catalyzed
asymmetric Henry reaction, Tetrahedron (2017), https://doi.org/10.1016/j.tet.2017.11.059

T.B. Khlebnikova et al. / Tetrahedron xxx (2017) 1e8
5
of the ligand. Phenol oxygen atoms of the ligand coordinate to the
30 m ꢂ 0.32 mm.
equatorial and apical positions. For maximum activation of both the
reagents in the transition state, the aldehyde carbonyl group should
bind to metal center in the equatorial position, while the oxygen
atom of nitromethane is positioned perpendicular to the ligand
plane. The aldehyde molecule coordinates to the copper ion with
the bulky R group oriented towards the less-crowded space as a
result of the steric hindrance from the upward oriented phenyl
moiety of the ligand. This implies that attack of the nitronate would
take place preliminary to Re face of the carbonyl group (TS1) to give
S isomer as the major product.
Chromatogram of methylated oleoresin and copies of spectra of
fumaropimaric acid derivatives 2e6 see in Ref. 71 (Figs. 1, S2eS6).
4.2. Synthesis of fumaropimaric acid derivatives
4.2.1. 13-Isopropyl-17,18-dinor-atis-13-ene-15b,16a-dicarboxy-4-
carboxylic acid methyl ester 2
Anhydrous potassium carbonate (55 g, 0.4 mol) and methyl io-
dide (22 mL, 0.35 mol) were added to the solution of raw pine
oleoresin (100 g, 0.27 mol of abietic-type acids) in acetone
(800 mL). The reaction mixture was refluxed for 5 h, then cooled to
room temperature and solid was filtered. The filtrate was concen-
trated under reduced pressure, the residue was dissolved in diethyl
ether (300 mL), insoluble solid was filtered, and the resulted so-
lution was evaporated under reduced pressure. The residue was
analyzed by GC-MS (see Ref. 71, Fig. 1). To the residue, fumaric acid
(55 g, 0.47 mol) was added and the reaction mixture was heated at
180e200 ꢀC under stirring and an argon atmosphere for 6 h. Then
the reaction mixture was cooled to room temperature and diethyl
ether (300 mL) was added. The resulting precipitate was filtered,
washed with hot (90 ꢀC) water (4 ꢂ 400 mL) and dried on air. The
crude product was crystallized from methanol to give the pure
diacid 2 as colourless cubic crystals; yield 50 g (43%). Character-
ization data for 2 are consistent with values previously reported.18
3. Conclusion
Therefore, we have developed a new convenient and easily
reproducible synthetic route for the diamine functionalization of
abundant resin acids applicable as building blocks with a non-
conventional scaffold. Synthesis of the new enantiomerically pure
vicinal trans-diamines and Schiff bases have been performed in few
steps with good to high yields from a commercially available plant
feedstock e oleoresin with high abietic-type acids content. Efficient
and scalable synthesis protocols using readily available starting
materials open up possibilities of broad application of the diterpene
diamines in asymmetric synthesis. These enantiopure products can
serve as useful intermediates for the construction of more complex
chiral molecules: bioactive compounds, resolving agents, auxil-
iaries and chiral catalysts. The new secondary diamines 6 were
tested as chiral ligands for the copper (II)-catalyzed asymmetric
nitroaldol reaction of nitromethane with substituted aromatic al-
dehydes, giving enantioenriched nitroalcohols with up to 98%
yields and up to 82% ee. This is the first example of diterpene based
chiral 1,2-diamine application in asymmetric catalysis and the best
result for the for the catalyst with the source of chirality composed
only by diterpene unit. Studies aimed at modifications of these li-
gands as well as applications to other asymmetric reactions are
currently ongoing in our laboratory.
4.2.2. 13-Isopropyl-17,18-dinor-atis-13-ene-15b,16a-diamino-4-
carboxylic acid methyl ester 4
Neat DMF (0.2 mL, 2.6 mmol) and thionyl chloride (8.4 mL,
116 mmol) were added to the stirred suspension of 2 (20 g,
46 mmol) in toluene (80 mL). The reaction mixture was refluxed
until complete dissolution of 2. A part of the toluene (15 mL) and
the residual thionyl chloride were removed under reduced pres-
sure. The resultant toluene solution was cooled (10e15 ꢀC) and
added dropwise over 10 min to a vigorously stirred and cooled
(0e5 ꢀC) solution of sodium azide (CARE! Toxic! Explosive!) (12 g,
185 mmol) and Aliquat 336 (0.5 g, 1.2 mmol) in water (100 mL). The
reaction mixture was stirred for 2 h at 0e5 ꢀC. The organic layer was
separated and the aqueous phase was extracted with toluene
(2 ꢂ 30 mL). The combined organic layers were washed with
saturated solution of sodium chloride (1 ꢂ 30 mL) and dried over
Na2SO4. The resulting toluene solution was slowly heated with a
long reflux condenser (40 cm) (ATTENTION! The reaction is highly
exothermic!) and refluxed until the nitrogen evolution has stopped.
Then the reaction mixture was cooled to the room temperature and
concentrated hydrochloric acid (122 mL, 144 g) was added under
stirring. The vigorously stirred mixture was refluxed for 3 h and
then cooled to room temperature. The resulting precipitate was
filtered, washed with diethyl ether (200 mL), and dissolved in water
(500 mL). The saturated solution of sodium bicarbonate was added
to the resultant aqueous solution under stirring until pH value of
the reaction mixture was 8. Sodium chloride (50 g) was added and
the reaction mixture was stirred for 3 h. The resulting precipitate
was filtered, washed with water until pH 7, dried in a desiccator
over sodium hydroxide. The crude product was purified by
recrystallization from diethyl ether, to give the pure diamine 4 as a
colourless solid; yield 13.5 g (78%). Characterization data for 4 are
consistent with values previously reported.18
4. Experimental section
4.1. General information
The chemicals were of reagent purity grade, obtained from
commercial sources, and used without further purification. Pine
oleoresin OST 13-128-93 (Russian industry standard; oleoresin
contains at least 80% of abietic-type acids) was obtained from
Orgsyntez OJSC (available on request at http://orgsyntez.ru/en) and
used as received. Solvents were distilled from appropriate drying
agents prior to use, unless otherwise noted. Flash column chro-
matography was performed on silica gel (Panreac 40e63
NMR and 13C NMR spectra were recorded on Bruker DRX-500, А
400 and AV-300 spectrometers. Chemical shifts were reported in
the scale using the residual solvent peak of the CHCl3 as a refer-
m
m). 1H
М-
d
ence (7.26 ppm) for 1H NMR spectra and the middle signal in the
triplet of CDCl3 (77.00 ppm) for 13C NMR samples. Optical rotations
were measured on a polAAr 3005 instrument with a 100 mm cell
(concentration c in g/100 mL). HRMS experiments were performed
on DFS spectrometer. IR spectra were recorded using Infralum FT-
801 or Shimadzu IRAffinity-1 FT-IR spectrometers. Elemental ana-
lyses (CHN) were performed on a EURO EA 3000 Elemental
Analyzer. HPLC analyses were performed on Varian ProStar in-
strument with a ProStar 335 Photodiode Array Detector and with
chiral column Chiralcel OD-H. GC-MS analysis of methyl esters of
resin acids was carried out on SHIMADZU GCMS-QP2010 Ultra in-
strument on the basis of gas chromatograph GC-2010 plus with
mass detector and with chromatographic column GsBP1-MS
4.2.3. 13-Isopropyl-17,18-dinor-atis-13-ene-15b,16a-diisocyanato-
4-carboxylic acid methyl ester 3
Following the above procedure, the crude reaction mixture in
toluene solution (about 50 mL) was obtained from 2 (2 g, 4.6 mmol)
after Curtius rearrangement (after reflux until the nitrogen evolu-
tion has stopped). The reaction mixture was cooled to room
Please cite this article in press as: Khlebnikova TB, et al., Levopimaric acid derived 1,2-diamines and their application in the copper-catalyzed
asymmetric Henry reaction, Tetrahedron (2017), https://doi.org/10.1016/j.tet.2017.11.059

6
T.B. Khlebnikova et al. / Tetrahedron xxx (2017) 1e8
temperature. Toluene was removed under reduced pressure
yielding the crude product, which was purified by column chro-
matography (hexane/ethyl acetate ¼ 20:1) to give diisocyanate 3 as
a colourless oil; yield: 1.35 g (69%); Rf ¼ 0.9 (hexane/ethyl
crystallization; yield 78%, Rf ¼ 0.62 (hexane/ethyl acetate ¼ 7:3),
m.p. 191e192 ꢀC, ½a D
ꢃ
25: þ289 (c 0.8, CHCl3). 1H NMR (300 MHz,
CDCl3):
d
¼ 0.77 (s, 3H),1.17 (m, 7H),1.22 (m, 3H),1.32 (m, 21H),1.50
(m, 24H), 1.82 (m, 3H), 2.25 (m, 1H), 2.53 (m, 1H), 2.58 (m, 1H), 2.97
(m, 1H), 3.04 (m, 1H), 3.69 (s, 3H), 5.66 (s, 1H), 7.07 (s, 1H), 7.11 (s,
1H), 7.40 (s, 1H), 7.45 (s, 1H), 8.20 (s, 1H), 8.31 (s, 1H), 13.48 (br s,
acetate ¼ 20:1), ½a D
ꢃ
25: þ61,5 (c 0.53, CHCl3). 1H NMR (400 MHz,
CDCl3):
d
¼ 0.58 (s, 3H), 0.93 (m, 1H), 1.01e1.05 (m, 6H), 1.12e1.18
(m, 4H), 1.23e1.31 (m, 3H), 1.41e1.53 (m, 5H), 1.68 (m, 2H), 1, 89 (m,
1H), 13.68 (br s, 1H) ppm. 13C NMR (75 MHz, CDCl3):
d
¼ 179.0,
1H), 2.04 (m, 1H), 2.33 (m, 1H), 2.56 (m, 1H), 2.87 (m, 1H), 3.24 (m,
165.2, 164.1, 157.7, 157.5, 147.1, 139.8, 139.4, 136.2, 136.2, 126.6, 126.3,
125.8, 125.6, 125.0, 117.5, 117.2, 84.8, 76.9, 53.0, 51.5, 49.4, 46.9, 41.8,
40.1, 37.7, 37.2, 36.5, 34.7, 34.7, 34.3, 33.7, 33.7, 32.4, 31.1 (6 CH3),
29.1 (3CH3), 29.0 (3CH3), 21.7, 21.5, 20.4, 20.3, 16.8, 16.3, 15.9 ppm.
IR (KBr): 2954, 2869, 1721, 1624, 1595, 1467, 1441, 1387, 1361, 1272,
1248, 1173 cmꢁ1. HRMS ESI [M]þ calcd. for C53H78N2O4 806.5956,
found 806.5953.
1H), 3.63 (s, 3H), 5.38 (s, 1H). 13C NMR (100 MHz, CDCl3:
d
¼ 178.9,
148.4, 123.5, 122.9, 122.4, 69.9, 62.4, 51.8, 51.7, 49.2, 47.0, 43.4, 39.6,
37.8, 37.1, 36.5, 33.7, 32.5, 21.4, 21.1, 20.3, 20.2, 16.9, 16.6, 15.6 ppm.
IR (KBr): 2933, 2870, 2240, 1725, 1465, 1447, 1387, 1362, 1246, 1188,
1140 cmꢁ1. HRMS ESI [M]þ calcd. for C25H34N2O4 426.2513, found
426.2511.
4.3. General procedure for the synthesis of imines 5a-f
4.3.4. 13-Isopropyl-17,18-dinor-atis-13-ene-15b,16a-di(2-hydroxy-
1-naphthylmethyleneamino)-4-carboxylic acid methyl ester 5d
Imine 5d was prepared from 2-hydroxy-1-naphthaldehyde as a
yellow solid purified by crystallization; yield 74%, Rf ¼ 0.38 (hex-
The corresponding aldehyde (Scheme 2) (5.3 mmol) was added
to a stirring solution of diamine 4 (1 g, 2.7 mmol) in chloroform
(20 mL). The reaction mixture was refluxed for 8 h, then the solvent
was removed under reduced pressure yielding the crude imines
5a-f. Imines 5b, e, f were purified by column chromatography
(SiO2, hexane/ethyl acetate ¼ 8:2). Imines 5a, c, d were purified by
crystallization from ethanol.
ane/ethyl acetate ¼ 7:3), m.p. 162e164 ꢀC, ½a D
ꢃ
25: þ239.8 (c 0.5,
acetone). 1H NMR (300 MHz, CDCl3):
d
¼ 0.68 (s, 3H), 1.07 (m, 1H),
1.14 (m, 11H), 1.24 (m, 1H), 1.49 (m, 4H), 1.62 (m, 2H), 1.80 (m, 3H),
2.20 (m, 1H), 2.51 (m, 1H), 2.68 (m, 1H), 3.13 (m, 1H), 3.34 (m, 1H),
3.62 (s, 3H), 5.63 (s, 1H), 6.93e7.94 (m, 12H), 8.69 (s, 1H), 8.95 (s,
1H), 14.55 (br s, 1H), 15.28 (br s, 1H). 13C NMR (75 MHz, CDCl3):
4.3.1. 13-Isopropyl-17,18-dinor-atis-13-ene-15
b
,16
a
-di(2-
d
¼ 179.0, 173.7, 169.6, 159.1, 157.3, 149.1, 136.7, 136.0, 133.2, 132.7,
hydroxybenzylideneamino)-4-carboxylic acid methyl ester 5a
Imine 5a was prepared from salicylic aldehyde as a yellow solid
purified by crystallization; yield 89%, Rf ¼ 0.6 (hexane/ethyl
129.0 (2CH), 127.8 (2CH), 126.8, 126.3, 124.3, 123.5, 123.1, 122.8,
121.9, 118.6, 118.2, 107.7, 106.6, 80.6, 73.9, 52.8, 51.8, 49.4, 47.0, 42.4,
40.3, 37.9, 37.4, 36.7, 34.3, 32.7, 21.7, 21.5, 20.6, 20.6, 16.9, 16.5,
15.8 ppm. IR (KBr): 2928, 2867, 1722, 1624, 1545, 1473, 1336, 1245,
1183, 1140, 826, 747 cmꢁ1. HRMS ESI [M]þ calcd. for C45H50O4N2
682.3765, found 682.3760.
acetate ¼ 7:3), m.p.133e135 ꢀC, ½a D
ꢃ
25: þ330.0 (c 0.4, CHCl3). 1H NMR
(300 MHz, CDCl3):
d
¼ 0.72 (s, 3H), 1.05 (m, 2H), 1.12 (m, 7H), 1.17
(m, 4H), 1.55 (m, 6H), 1.75 (m, 3H), 2.18 (m, 1H), 2.46 (m, 1H), 2.56
(m, 1H), 2.92 (d, J ¼ 2.2 Hz, 1H), 3.06 (m, 1H), 3.66 (s, 3H), 5.59 (s,
1H), 6.83e7.01 (m, 4H), 7.19e7.37 (m, 4H), 8.15 (s, 1H), 8.27 (s, 1H),
13.43 (br s, 1H), 13.53 (br s, 1H) ppm. 13C NMR (75 MHz, CDCl3):
4.3.5. 13-Isopropyl-17,18-dinor-atis-13-ene-15
methyleneamino)-4-carboxylic acid methyl ester 5e
b,16a
-di(20-pyridyl-
d
¼ 179.5, 164.6, 163.6, 161.3, 161.2, 147.9, 132.6, 132.4, 131.6, 131.5,
Imine 5e was prepared from 2-pyridinecarbaldehyde as a off-
yellow viscous syrup purified by chromatography; yield 81%,
125.4, 118.9, 118.8, 118.6, 118.6, 117.1, 117.09, 85.5, 76.7, 53.3, 52.0,
49.9, 47.4, 42.3, 40.8, 38.3, 37.7, 37.0, 34.9, 32.9, 22.2, 21.9, 20.87,
20.85, 17.3, 16.9, 16.3. IR (KBr): 2929, 2868, 1723, 1626, 1579, 1494,
1460, 1386, 1280, 1244, 1194, 1150, 1071, 1049, 846, 757 cmꢁ1. HRMS
ESI [M]þ calcd. for C37H46N2O4 582.3457, found 582.3456.
Rf ¼ 0.22 (hexane/ethyl acetate ¼ 3:7), ½a D
ꢃ
25: þ165.0 (c 0.5, CHCl3).
1H NMR (300 MHz, CDCl3):
d
¼ 0.68 (s, 3H), 0.88 (m, 1H), 1.00 (m,
1H), 1.07 (m, 12H), 1.28 (m, 1H), 1.48 (m, 4H), 1.62 (m, 2H), 1.72 (m,
2H), 2.30 (m, 1H), 2.43 (m, J ¼ 6.8 Hz,1H), 2.48 (m,1H), 3.04 (m, 1H),
3.07 (m, 1H), 3.59 (s, 3H), 5.53 (s, 1H), 7.22 (m, 2H), 7.67 (m, 2H),
7.92 (d, J ¼ 7.7 Hz, 1H), 7.94 (d, J ¼ 7.7 Hz, 1H), 8.12 (s, 1H), 8.19 (s,
4.3.2. 13-Isopropyl-17,18-dinor-atis-13-ene-15b,16a-di(2-hydroxy-
3-methoxybenzylideneamino)-4-carboxylic acid methyl ester 5b
Imine 5b was prepared from 3-methoxy-2-hydroxy benzalde-
hyde as a yellow solid purified by chromatography; yield 79%,
1H), 8.54 (m, 2H) ppm. 13C NMR (75 MHz, CDCl3):
d
¼ 179.3, 161.0,
160.5, 154.6, 154.5, 149.1, 149.0, 146.7, 136.3, 136.2, 125.5, 124.4,
124.3, 121.3, 121.2, 85.7, 76.6, 54.0, 51.7, 49.7, 47.2, 42.2, 40.7, 37.8,
37.5, 36.7, 34.5, 32.5, 21.8, 21.8, 20.5, 20.4, 17.0, 16.6, 16.3 ppm. IR
(KBr): 2928, 2867, 1722, 1641, 1587, 1567, 1468, 1436, 1384, 1360,
1245, 1187, 1142, 1073, 992, 916, 776, 733 cmꢁ1. HRMS ESI [M]þ
calcd. for C35H44N2O4 552.3459, found 552.3460.
Rf ¼ 0.33 (hexane/ethyl acetate ¼ 7:3), m.p. 138e139 ꢀC, ½a D
ꢃ
25: þ402
(c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3):
d
¼ 0.66 (s, 3H), 1.00 (m,
2H), 1.08 (m, 7H), 1.12 (m, 4H), 1.41e1.54 (m, 6H), 1.69 (m, 3H), 2.17
(m, 1H), 2.41 (m, 1H), 2.53 (m, 1H), 2.86 (d, J ¼ 1.7 Hz, 1H), 3.02 (m,
1H), 3.62 (s, 3H), 3.87 (s, 3H), 3.90 (s, 3H), 5.53 (s,1H), 6.74e6.94 (m,
6H), 8.08 (s, 1H), 8.21 (s, 1H), 13.86 (br s, 1H), 14.16 (br s, 1H) ppm.
4.3.6. 13-Isopropyl-17,18-dinor-atis-13-ene-15b,16a-di(thioph-2-
13C NMR (100 MHz, CDCl3):
d
¼ 179.2, 164.3, 163.5, 151.8, 151.4,
ylidenamino)-4-carboxylic acid methyl ester 5f
148.3, 148.3, 147.7, 125.0,122.8, 122.7, 118.3, 118.1, 118.0, 117.8, 113.8,
113.41, 85.0, 76.0, 55.9, 55.8, 53.0, 51.8, 49.6, 47.1, 42.0, 40.2, 37.9,
37.4, 36.8, 34.5, 32.7, 21.9, 21.6, 20.6, 20.5, 17.0, 16.6, 15.3. IR (KBr):
2934, 2867, 1721, 1624, 1584, 1463, 1417, 1386, 1254, 1080, 973, 841,
781, 738 cmꢁ1. HRMS ESI [M]þ calcd. for C39H50O6N2 642.3652,
found 642.3663.
Imine 5f was prepared from 2-thiophenecarbaldehyde as a off-
yellow solid purified by chromatography; yield 68%; Rf ¼ 0.53
(hexane/ethyl acetate ¼ 7:3), m.p. 108e109 ꢀC; ½a D
ꢃ
25: þ258,9 (c 1,
CHCl3). 1H NMR (300 MHz, CDCl3):
d
¼ 0.68 (s, 3H), 1.00 (m, 2H),
1.08 (m, 8H), 1.15 (s, 3H), 1.50 (m, 6H), 1.73 (m, 3H), 2.28 (m, 1H),
2.42 (m, 2H), 2.86 (m, 1H), 2.93 (m, 1H), 3.62 (s, 3H), 5.51 (s, 1H),
6.98e7.03 (m, 2H), 7.20 (m, 2H), 7.29 (m, 1H), 7.34 (m, 1H), 8.12 (s,
4.3.3. 13-Isopropyl-17,18-dinor-atis-13-ene-15
3,5-di-tert-butylbenzylideneamino)-4-carboxylic acid methyl
ester 5c
b
,16a
-di(2-hydroxy-
1H), 8.20 (s, 1H) ppm. 13C NMR (75 MHz, CDCl3):
d
¼ 179.3, 152.8,
152.3, 146.4, 143.0, 142.7, 129.8, 129.5, 128.2, 128.0, 127.1, 127.0,
125.5, 85.7, 76.7, 54.0, 51.6, 49.8, 47.2, 42.3, 40.8, 37.8, 37.5, 36.8,
34.6, 32.5, 21.9, 21.7, 20.6, 20.4, 17.0, 16.5, 16.3 ppm. IR (KBr): 3089,
2947, 2865, 1719, 1673, 1626, 1518, 1419, 1234, 1214, 1046, 757, 728,
Imine
5c
was
prepared
from
3,5-di-tert-butyl-2-
hydroxybenzaldehyde as
a
light yellow solid purified by
Please cite this article in press as: Khlebnikova TB, et al., Levopimaric acid derived 1,2-diamines and their application in the copper-catalyzed
asymmetric Henry reaction, Tetrahedron (2017), https://doi.org/10.1016/j.tet.2017.11.059

T.B. Khlebnikova et al. / Tetrahedron xxx (2017) 1e8
7
662 cmꢁ1. HRMS ESI [M]þ calcd. for C33H42N2O2S2 562.2682, found
562.2675.
J ¼ 13.6 Hz, 1H), 4.11 (d, J ¼ 13.6 Hz, 1H), 5.38 (s, 1H), 6.93 (d,
J ¼ 2.2 Hz, 1H), 6.96 (d, J ¼ 2.2 Hz, 1H), 7.24 (d, J ¼ 2.2 Hz, 1H), 7.26
(d, J ¼ 2.2 Hz, 1H), 10.70 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3):
4.4. General procedure for the synthesis of Aminophenols 6a-f
d
¼ 179.1, 154.6, 154.1, 149.0, 140.7, 140.5, 135.9, 135.8, 124.2, 123.4,
123.2, 123.1, 122.9, 121.9, 121.8, 71.8, 63.1, 53.2, 51.8, 51.0, 49.5, 49.0,
47.1, 42.2, 38.1, 37.2, 36.5, 35.1, 34.8, 34.7, 34.3, 34.0, 34.0, 32.6, 31.6
(3CH3), 31.5 (3CH3), 30.0 (3CH3), 29.4 (3CH3), 21.8, 21.0, 20.4, 20.2,
17.0, 16.7, 15.6 ppm. IR (KBr): 2953, 2868, 1727, 1480, 1461, 1444,
1389, 1361, 1237, 1164, 876 cmꢁ1. HRMS ESI [M]þ calcd. for
Sodium borohydride (150 mg, 4 mmol) was added portion wise
to a stirred solution of the corresponding imine 5 a-f (1 mmol) in
ethanol (10 mL) at room temperature. The mixture was stirred at
room temperature for 8 h and concentrated under reduced pres-
sure. Then 10 mL of water was added to the residue and the mixture
was extracted with ethyl acetate (2 ꢂ 20 mL). The combined
organic layers were dried over Na2SO4, the solvent was removed
under reduced pressure, and the residue was purified by column
chromatography (SiO2, hexane/ethyl acetate ¼ 7:3).
C53H82O4N2 810.6269, found 810.6265.
4.4.4. 13-Isopropyl-17,18-dinor-atis-13-ene-15b,16a-di[(2-
hydroxynaphthalen-1-yl)methylamino]-4-carboxylic acid methyl
ester 6d
Aminophenol 6d was prepared from imine 5d as a colourless
solid; yield 79%, Rf ¼ 0.37 (hexane/ethyl acetate ¼ 7:3), m.p.
4.4.1. 13-Isopropyl-17,18-dinor-atis-13-ene-15b,16a-di[(2-
hydroxybenzyl)amino]-4-carboxylic acid methyl ester 6a
99e101 ꢀC, ½a D
ꢃ
25: þ39.3 (c 0.3, CHCl3). 1H NMR (400 MHz, CDCl3):
Aminophenol 6a was prepared from imine 5a as a colourless
solid; yield 96%, %, Rf ¼ 0.32 (hexane/ethyl acetate ¼ 7:3), m.p.
d
¼ 0.66 (s, 3H), 0.92 (m, 6H), 1.04 (m, 2H), 1.17 (m, 3H), 1.22 (m, 1H),
1.37 (m, 1H), 1.47 (m, 4H), 1.56 (m, 2H), 1.74 (2H), 1.90 (m, 1H), 2.12
(m,1H), 2.24 (m, 2H), 2.56 (m,1H), 2.87 (m,1H), 3.69 (s, 3H), 4.12 (d,
J ¼ 14.3 Hz, 1H), 4.44 (d, J ¼ 14.3 Hz, 1H), 4.54 (d, J ¼ 14.3 Hz, 1H),
178e179 ꢀC, ½a D
ꢃ
25: þ16.4 (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3):
d
¼ 0.65 (s, 3H), 0.96 (m, 1H), 1.02 (m, 6H), 1.06 (m, 1H), 1.16 (s, 3H),
1.20 (m, 1H), 1.30 (m, 1H), 1.42 (m, 4H), 1.53 (m, 2H), 1.71 (m, 2H),
1.82 (m, 1H), 2.02 (m, 1H), 2.15 (m, 1H), 2.30 (m, 1H), 2.41 (m, 1H),
2.75 (m, 1H), 3.66 (s, 3H), 3.83 (d, J ¼ 13.6 Hz, 1H), 3.89 (d,
J ¼ 13.6 Hz, 1H), 3.95 (d, J ¼ 13.6 Hz, 1H), 4.06 (d, J ¼ 13.6 Hz, 1H),
5.40 (s, 1H), 6.74 (m, 1H), 6.81 (m, 2H), 6.88 (m, 1H), 6.97 (m, 1H),
7.03 (m, 1H), 7.14 (m, 1H), 7.20 (m, 1H) ppm. 13C NMR (100 MHz,
4.59 (d, J ¼ 14.3 Hz, 1H), 5.43 (s, 1H), 7.04e7.96 (m, 12H) ppm. 13
C
NMR (100 MHz, CDCl3):
d
¼ 179.1, 156.7, 156.4, 149.0, 132.2, 132.0,
129.4, 129.2, 128.9, 128.6, 128.5, 128.2, 126.5, 126.4, 124.2, 122.5,
122.4, 120.8 (2CH), 119.2, 119.1, 112.3, 112.2, 73.3, 62.6, 53.1, 52.0,
49.2, 47.1, 44.3, 44.2, 42.4, 38.1, 37.3, 36.6, 35.3, 34.3, 32.5, 21.7, 21.1,
20.3, 20.2, 17.0, 16.7, 15.7 ppm. IR (KBr): 2929, 2867, 1721, 1622,
1598, 1519, 1467, 1268, 1240, 1163, 1102, 814, 745 cmꢁ1. Elemental
analysis (%): сalcd. for C37H50N2O4 C 78.68, H 7.92, N 4.08; found C
78.71, H 7.90, N 4.10.
CDCl3):
d
¼ 179.4,158.7,158.3,149.5,129.5,129.3,128.8,128.7,124.8,
123.1, 123.07, 119.8, 119.5, 116.9, 116.8, 73.7, 63.6, 53.8, 52.3, 50.8,
50.3, 49.8, 47.6, 43.0, 38.8, 37.9, 37.2, 35.9, 34.9, 33.1, 22.2, 21.6, 21.0,
20.8, 17.5, 17.2, 16.2. IR (KBr): 3282, 2926, 2865, 1708, 1612, 1590,
1476, 1446, 1387, 1248, 1193, 1139, 1104, 845, 797, 752 cmꢁ1. HRMS
ESI [M]þ calcd. for C37H50N2O4 586.3765, found 586.3768.
4.4.5. 13-Isopropyl-17,18-dinor-atis-13-ene-15b,16a-di[(2-
pyridylmethyl)amino]-4-carboxylic acid methyl ester 6e
Aminophenol 6e was prepared from imine 5e as a off-yellow
viscous syrup; yield 77%, Rf ¼ 0.2 (hexane/ethyl acetate ¼ 3:7),
4.4.2. 13-Isopropyl-17,18-dinor-atis-13-ene-15b,16a-di[(2-
hydroxy-3-methoxybenzyl)amino]-4-carboxylic acid methyl ester
6b
½
a D
ꢃ
25: þ3.1 (c 0.98, CHCl3). 1H NMR (400 MHz CDCl3):
d
¼ 0.56 (s,
3H), 0.82 (m, 2H), 0.93 (m, 6H), 1.07 (m, 4H), 1.25 (m, 2H), 1.35 (m,
3H), 1.43 (m, 2H), 1.60 (m, 2H), 1.90 (m, 2H), 2.13 (m, 1H), 2.26 (m,
2H), 2.55 (m, 1H), 3.58 (s, 3H), 3.75 (d, J ¼ 14.3 Hz, 1H), 3.79 (d,
J ¼ 14.0 Hz, 1H), 3.83 (d, J ¼ 14.3 Hz, 1H), 3.93 (d, J ¼ 14.0 Hz, 1H),
5.34 (s, 1H), 7.06 (m, 2H), 7.30 (m, 2H), 7.54 (m, 2H), 8.42 (m, 1H),
Aminophenol 6b was prepared from imine 5b as a off-yellow
solid; yield 71%, Rf ¼ 0.1 (hexane/ethyl acetate ¼ 7:3), m.p.
83e85 ꢀC, ½a D
ꢃ
25: þ37.5 (c 0.4, CHCl3). 1H NMR (300 MHz, CDCl3):
d
¼ 0.64 (s, 3H), 0.95 (m, 1H), 1.02 (m, 6H), 1.08 (m, 1H), 1.15 (m, 4H),
1.34 (m, 1H), 1.44 (m, 4H), 1.55 (m, 1H), 1.70 (m, 2H),1.88 (m, 1H),
2.04 (m, 1H), 2.20 (m, 1H), 2.33 (m, 1H), 2.42 (m, 1H), 2.76 (m, 1H),
3.68 (s, 3H), 3.87 (s, 3H), 3.90 (m, 6H), 4.09 (d, J ¼ 13.3 Hz, 1H), 5.39
8.47 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3):
d
¼ 15.9, 16.5, 16.9,
20.2, 20.4, 20.7, 21.8, 32.5, 34.2, 35.6, 36.6, 37.2, 37.8, 42.7, 47.0,
49.5, 51.6, 52.3, 53.1, 53.6, 64.7, 72.8, 121.5, 121.6, 122.2, 122.3,
124.4, 136.1, 136.2, 147.6, 148.7, 148.9, 159.8, 160.3, 179.3 ppm. IR
(KBr): 619, 664, 755, 847, 994, 1048, 1104, 1140, 1189, 1246, 1294,
1341, 1361, 1387, 1433, 1473, 1570, 1592, 1642, 1724, 2846, 2867,
2947, 3313 cmꢁ1. HRMS ESI [M]þ calcd. for C35H48O2N4 556.3772,
found 556.3762.
(s, 1H), 6.55e6.88 (m, 6H), 10.38 (br s, 1H), 11.01 (br s, 1H) ppm. 13
C
NMR (75 MHz, CDCl3):
d
¼ 178.7, 148.6, 147.8, 147.7, 147.0, 146.3,
123.8, 123.9, 122.4, 120.2, 119.8, 118.6, 118.2, 110.7, 110.5, 72.9, 62.9,
55.5, 55.3, 52.9, 51.6, 49.4, 48.9, 46.7, 42.0, 37.8, 36.9, 36.2, 35.1, 34.0,
32.2, 21.3, 20.7, 20.1, 20.0, 16.7, 16.3, 15.3 ppm. IR (KBr): 2932, 2865,
1721, 1645, 1588, 1477, 1245, 1187, 1076, 975, 833, 771, 733 cmꢁ1
.
Elemental analysis (%): calcd. for C37H50N2O4 C 72.41, H 8.41, N 4.33;
found C 72.44, H 8.39, N 4.35.
4.4.6. 13-Isopropyl-17,18-dinor-atis-13-ene-15b,16a-di(((thiophen-
2-yl)-methyl)amino)-4-carboxylic acid methyl ester 6f
Aminophenol 6f was prepared from imine 5f as a colourless
solid; yield 81%, Rf ¼ 0.5 (hexane/ethyl acetate ¼ 7:3), m.p.
4.4.3. 13-Isopropyl-17,18-dinor-atis-13-ene-15b,16a-di[(2-
hydroxy-3,5-di-tert-butylbenzyl)amino]-4-carboxylic acid methyl
ester 6c
75e77 ꢀC, ½a D
ꢃ
25: þ61 (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3):
d
¼ 0.61 (s, 3H), 0.89 (m, 2H), 0.99 (m, 6H),1.13 (m, 4H),1.28 (m,1H),
Aminophenol 6c was prepared from imine 5c as a colourless
solid; yield 77%, Rf ¼ 0.63 (hexane/ethyl acetate ¼ 7:3), m.p.
1.41 (m, 4H), 1.50 (m, 2H), 1.67 (m, 2H), 1.88 (m, 2H), 2.17 (m, 1H),
2.29 (m, 2H), 2.57 (m, 1H), 3.66 (s, 3H), 3.82 (d, J ¼ 14.3 Hz, 1H), 3.90
(d, J ¼ 14.3 Hz, 2H), 4.04 (d, J ¼ 14.3 Hz, 1H), 5.36 (s, 1H), 6.83e6.94
(m, 4H), 7.13e7.19 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3):
130e132 ꢀC, ½a D
ꢃ
25: ꢁ31.4 (c 0.051, CH3COCH3). 1H NMR (400 MHz,
CDCl3):
d
¼ 0.64 (s, 3H), 0.93 (m,1H), 0.98 (d, J ¼ 6.6 Hz, 3H), 0.99 (d,
J ¼ 6.6 Hz, 3H), 1.07 (m, 1H), 1.16 (s, 3H), 1.19 (m, 1H), 1.25 (m, 9H),
1,28 (m, 2H), 1.30 (m, 1H), 1.31 (s, 9H), 1.39 (m, 2H), 1.44 (m, 18H),
1.48 (m, 2H), 1.53 (m, 2H), 1.70 (m, 2H), 1.82 (m, 1H), 1.96 (m, 1H),
2.18 (m, 1H), 2.30 (m, J ¼ 6.6 Hz, 1H), 2.39 (m, 1H), 2.74 (m, 1H), 3.66
(s, 3H), 3.81 (d, J ¼ 13.6 Hz, 1H), 3.94 (d, J ¼ 13.6 Hz, 1H), 4.01 (d,
d
¼ 179.2, 147.9, 145.5, 144.3, 126.3, 126.2, 124.5, 124.5, 124.04,
124.01, 123.9, 72.1, 64.0, 53.6, 51.6, 49.4, 47.0, 45.7, 45.3, 42.7, 37.9,
37.2, 36.6, 35.6, 34.3, 32.5, 21.8, 20.8, 20.5, 20.3, 16.9, 16.6, 15.8 ppm.
IR (KBr): 3105, 3070, 2983, 2947, 2868, 2829, 1721, 1458, 1443, 1387,
1368, 1331, 1246, 1215, 1190, 1165, 1140, 1104, 1079, 851, 827, 758,
Please cite this article in press as: Khlebnikova TB, et al., Levopimaric acid derived 1,2-diamines and their application in the copper-catalyzed
asymmetric Henry reaction, Tetrahedron (2017), https://doi.org/10.1016/j.tet.2017.11.059

8
T.B. Khlebnikova et al. / Tetrahedron xxx (2017) 1e8
698 cmꢁ1. HRMS ESI [M]þ calcd. for C33H46O2N2S2 566.2995, found
566.2988.
Wiley-VCH; 2001:159e181.
20. Shibasaki M, Groger H, Kanai M. In: Jacobsen EN, Pfaltz A, Yamamoto H, eds.
€
Comprehensive Asymmetric Catalysis. Heidelberg: Springer; 2004:131e133.
suppl. 1.
21. Murugavel G, Sadhu P, Punniyamurthy T. Chem Rec. 2016;16:1906.
22. Chen X, Lu Z. Org Biomol Chem. 2017;15:2280.
4.5. General procedure for the enantioselective Henry reaction
23. Evans DA, Seidel D, Rueping M, Lam HW, Shaw JT, Downey CW. J Am Chem Soc.
2003;125:12692.
Chiral ligand 6a-f (20
mmol) was added to the solution of
24. Li ZH, Zhou ZM, Hao XY, et al. Appl Catal A General. 2012;425e426:28.
25. Aydin AE, Yuksekdanaci S. Tetrahedron Asymmetry. 2013;24:14.
Cu(OAc)2$H2O (4.0 mg, 20
mmol) in THF (2 mL). Reaction mixture
was stirred for 1 h to give an olive green or dark blue solution, then
aldehyde 7a-o (0.4 mmol) was added followed by the amine or
phenol addition in a given quantity (if additives were used, see
Tables S1eS3). The reaction mixture was cooled to the selected
ꢀ
26. Wolinska E. Tetrahedron Asymmetry. 2014;25:1122.
ꢀ
27. Cruz H, Aguirre G, Madrigal D, Chavez D, Somanathan R. Tetrahedron Asym-
metry. 2016;27:1217.
28. Kodama K, Sugawara K, Hirose T. Chem Eur J. 2011;17:13584.
29. Liu F, Gou S, Li L, Yan P, Zhao C. J Mol Catal A Chem. 2013;379:163.
30. Ao C, Men J, Wang Y, et al. Tetrahedron Asymmetry. 2016;27:589.
31. Shaw S, White JD. Acc Chem Res. 2016;49:1825.
32. Mei H, Xiao X, Zhao X, et al. J Org Chem. 2015;80:2272.
33. Guo J, Mao J. Chirality. 2009;21:619.
34. Xu F, Lei C, Yan LEI, Tu J, Li G. Chirality. 2015;27:761.
35. Lu G, Zheng F, Wang L, et al. Tetrahedron Asymmetry. 2016;27:732.
36. Chen W, Zhou ZH, Chen HB. Org Biomol Chem. 2017;15:1530.
37. Arai T, Taneda Y, Endo Y. Chem Comm. 2010;46:7936.
38. Song Q, An X, Xia T, Zhou X, Shen T. C R Chim. 2015;18:215.
39. Xiong Y, Wang F, Huang X, Wen Y, Feng X. Chem Eur J. 2007;13:829.
40. White JD, Shaw S. Org Lett. 2012;14:6270.
temperature (see Tables 2, S1eS3) and nitromethane (214
mL,
4 mmol) was added. The mixture was stirred for the selected period
from 8 h to 240 h (see Tables 1 and 2, S1eS3), then solvent was
removed under reduced pressure, residue was purified by column
chromatography (SiO2, hexane/ethyl acetate ¼ 8:2) to give the pure
product. The product was analyzed by HPLC and 1H NMR. The
characterization data for all enantiomers of the nitro alcohols were
in accordance with data published previously.23,72e74
41. Das A, Kureshy RI, Prathap KJ, et al. Appl Catal A General. 2013;459:97.
42. Wei YL, Yang KF, Li F, Zheng ZJ, Xu Z, Xu LW. RSC Adv. 2014;4:37859.
43. Kannan M, Punniyamurthy T. Tetrahedron Asymmetry. 2014;25:1331.
44. Kowalczyk R, Sidorowicz Ł, Skarzewski J. Tetrahedron Asymmetry. 2008;19:
2310.
45. Kowalczyk R, Skarzewski J. Tetrahedron Asymmetry. 2009;20:2467.
46. Chunhong Z, Liu F, Gou S. Tetrahedron Asymmetry. 2014;25:278.
47. Song SE, Nguyen QT, Yu JJ, Lee HI, Jeong JH. Polyhedron. 2014;67:264.
48. Shi Y, Mao Z, Xue Q, Zhu C, Hu H, Cheng Y. Inorg Chem Commun. 2012;20:259.
49. Arai T, Watanabe M, Yanagisawa A. Org Lett. 2007;9:3595.
50. Steurer M, Bolm C. J Org Chem. 2010;75:3301.
Acknowledgements
This work was carried out within the framework of the budget
project N 0303-2016-0008 for Boreskov Institute of Catalysis. We
are grateful to Chemical Service Center of SB RAS for NMR and HR-
MS measurements. We are grateful to Orgsyntez OJSC for supplying
the pine oleoresin. We are grateful to Dr. L.V. Malysheva for IR and
HPLC measurements and Dr. S.A. Prikhod'ko for GC-MS
measurements.
51. Spangler KY, Wolf C. Org Lett. 2009;11:4724.
52. Sandermann W. reprint of the original 1st ed. 1960. In: Naturharze,
€
€
Terpentinol, Tallol. Chemie und Technologie. WILEY-VCH, Verlag; 1961. pp.
39e54, 150e163.
Appendix A. Supplementary data
53. Fiebach K, Grimm D. In: . Ullmann's Encyclopedia of Industrial Chemistry. vol. 31.
Weinheim: Wiley-VCH; 2012:477e494.
54. Fleck EE, Palkin S. Ind Eng Chem Anal Ed. 1942;14:146.
55. Harris GC. J Am Chem Soc. 1948;70:3671.
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.2017.11.059.
56. Baldwin D, Loeblich V, Lawrence R. Ind Eng Chem Chem Eng Data Ser. 1958;3:
342.
57. Arbuzov BA, Khismatullina AG. Bull Acad Sci USSR Div Chem Sci (Engl Transl).
1958;7:155.
References
1. Blaser HU. Chem Rev. 1992;92:935.
2. Blaser HU, Pugin B, Spindler F. J Mol Catal A Chem. 2005;231:1.
58. Joye Jr NM, Lawrence RV. J Chem Eng Data. 1967;12:279.
59. Bardyshev II , Bulgakov AN, Pertsovskii AL. Chem Nat Compd. 1970;6:556.
60. Takeda H, Schuller WH, Lawrence RV. J Org Chem. 1968;33:1683.
61. Enoki A. Wood research. 59/60. Bulletin of the Wood Research Institute, Kyoto
University; 1976:49.
62. Portugal I, Vital J, Lobo LS. Chem Eng Sci. 1996;51:2577.
63. Halbrook NJ, Lawrence RV. J Am Chem Soc. 1958;80:368.
64. Hovey AG, Hodgins TS. Ind Eng Chem. 1940;32:272.
65. Zalkow LH, Brannon DR. J Org Chem. 1964;29:1296.
66. Halbrook NJ, Lawrence RV, Dressler RL, Blackstone RC, Herz W. J Org Chem.
1964;29:1017.
67. Ishiguro SI, Jeliazkova BG, Ohtaki H. J Solut Chem. 1987;16:1.
68. Christensen C, Juhl K, Hazell RG, Jørgensen KA. J Org Chem. 2002;67:4875.
69. Chen X, Wang J, Zhu Y, et al. Chem Eur J. 2008;14:10896.
70. Naeem A, Khan IM, Ahmad A. Russ J Phys Chem A. 2011;85:1840.
71. Khlebnikova TB, Konev VN, Pai ZP. Data Brief. 2017 (In press).
72. Li JL, Liu L, Pei YN, Zhu HJ. Tetrahedron. 2014;70:9077.
73. Reddy BVS, Reddy SM, Manisha S, Madan C. Tetrahedron Asymmetry. 2011;22:
530.
ꢀ
ꢁ
3. Woodward S, Dieguez M, Pamies O. Coord Chem Rev. 2010;254:2007.
4. Benessere V, Litto RD, Roma AD, Ruffo F. Coord Chem Rev. 2010;254:390.
5. Alami MSIE, Amrani MAE, Agbossou-Niedercorn F, Suisse I, Mortreux A. Chem
Eur J. 2014;21:1398.
6. Boobalan R, Chang YM, Chen C, Lee GH. ChemistrySelect. 2016;1:2028.
7. Jiao T, Tu J, Li G, Xu F. J Mol Catal A Chem. 2016;416:56.
8. Xu F, Yan L, Lei C, Zhao H, Li G. Tetrahedron Asymmetry. 2015;26:338.
9. Filippova L, Stenstrøm Y, Hansen TV. Molecules. 2015;20:6224.
€
10. Csillag K, Szakonyi Z, Fülop F. Tetrahedron Asymmetry. 2013;24:553.
ꢀ
ꢂ
ꢀ
ꢃꢂ ꢂ
11. Tydlitat J, Bures F, Kulhanek J, Mloston G, Ruzicka A. Tetrahedron Asymmetry.
2012;23:1010.
12. Zhang G, Zhang Y, Jiang X, Yan W, Wang R. Org Lett. 2011;13:3806.
13. Zhang G, Zhang Y, Yan J, et al. J Org Chem. 2012;77:878.
14. An Y, Qin Q, Wang C, Tao J. Chin J Chem. 2011;29:1511.
15. Ma Z, Liu Y, Huo L, Gao X, Tao J. Tetrahedron Asymmetry. 2012;23:443.
16. Liu ZM, Li NK, Huang XF, et al. Tetrahedron. 2014;70:2406.
17. Khlebnikova TB, Karpyshev NN, Tolstikova OV, Tolstikov AG. Chirality. 2004;16:
40.
74. Jin W, Li X, Huang Y, Wu F, Wan B. Chem Eur J. 2010;16:8259.
18. Konev VN, Khlebnikova TB, Pai ZP. Chem Sustain Dev. 2011;19:159.
19. Ono N. In: Feuer H, ed. The Nitro Group in Organic Synthesis. first ed. New York:
Please cite this article in press as: Khlebnikova TB, et al., Levopimaric acid derived 1,2-diamines and their application in the copper-catalyzed
asymmetric Henry reaction, Tetrahedron (2017), https://doi.org/10.1016/j.tet.2017.11.059