New chiral 1,2-aminoalcohols derived from biomass and their application in diethyl zinc additions

Article abstract of DOI:10.1016/j.tetlet.2014.08.124

A convenient procedure for the preparation of chiral 1,2-aminoalcohols starting from levoglucosenone, a biomass derivative, is described. The 1,2-aminoalcohols, bearing primary, secondary, and tertiary amino groups, were tested as chiral catalysts in the

Full text of DOI:10.1016/j.tetlet.2014.08.124

Tetrahedron Letters 55 (2014) 5832–5835
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
New chiral 1,2-aminoalcohols derived from biomass and their
application in diethyl zinc additions
⇑
María M. Zanardi, María C. Botta, Alejandra G. Suárez
Instituto de Química Rosario—CONICET, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, S2002LRK Rosario, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient procedure for the preparation of chiral 1,2-aminoalcohols starting from levoglucosenone, a
biomass derivative, is described. The 1,2-aminoalcohols, bearing primary, secondary, and tertiary amino
groups, were tested as chiral catalysts in the asymmetric addition of diethyl zinc to benzaldehyde.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 24 July 2014
Revised 26 August 2014
Accepted 28 August 2014
Available online 6 September 2014
Keywords:
Levoglucosenone
1,2-Aminoalcohols
Chiral ligands
Asymmetric induction
Introduction
Chiral 1,2-aminoalcohols are versatile synthons for the
preparation of a wide range of biologically active compounds as
well as catalysts for asymmetric synthesis.1 One of the most
extensively studied methodologies for asymmetric carbon–carbon
bond formation is the nucleophilic addition of organometallic
reagents to carbonyl compounds.2 Despite the variety of chiral
ligands that have been synthesized and tested, mostly bearing a
1,2-aminoalcohol moiety, the development of cost-effective cata-
lysts exhibiting high reactivity and enantioselectivity remains an
active research topic. In the context of our ongoing interest in the
development of new tools for asymmetric synthesis derived from
biomass we synthesized new and efficient chiral auxiliaries and
organocatalysts starting from levoglucosenone (1) (1,6-anhydro-
O
R2
N
O
O
R1
O
R1, R2 = H or
Alkyl
OH
O
1
R
R= H
OMe
CH2OMe
CH2OPh
CH2OTBS
Scheme 1.
Results and discussion
3,4-dideoxy-b-D-glycero-hex-3-enopyranos-2-ulose) which is the
The strategy toward the preparation of the new chiral aminoal-
cohols derived from levoglucosenone was envisaged by function-
alizing the double bond of 1, using a general procedure which
involves a Diels–Alder reaction between 1 and anthracene or 9-
substituted anthracenes 2 to afford the cycloadducts 3, Scheme 2.
The chemical transformation of the ketone functionality of 3 into
an oxirane ring group would allow to produce epoxides 4, which
are key intermediates to generate the desired 1,2-aminoalcohols.
major product of the pyrolysis of acid-pretreated waste paper.3,4
This bicyclic enone has been intensively used as chiral synthon
in the synthesis of a wide variety of compounds.5 In order
to explore new applications, we envisaged the use of this easily
available member of the carbohydrate pool for the development
of new chiral 1,2-aminoalcohols (Scheme 1) and their applica-
tions in the enantioselective carbon–carbon bond forming
reactions.
Levoglucosenone was obtained through
a conventional or
microwave assisted pyrolysis of pre-treated microcrystalline cellu-
lose.4 With a convenient access to large amounts of 1 as the chiral
starting material, cycloadducts 3a–e were prepared through the
reaction of 1 with anthracene or 9-anthracene derivatives. The
introduction of a substituent at the benzylic position would allow
⇑
Corresponding author. Tel./fax: +54 341 4370477.
E-mail address: suarez@iquir-conicet.gov.ar (A.G. Suárez).
http://dx.doi.org/10.1016/j.tetlet.2014.08.124
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

M. M. Zanardi et al. / Tetrahedron Letters 55 (2014) 5832–5835
5833
R
O
O
O
O
7
3
O
O
O
O
(CH3)3SI
O
R
[4+2]
NaH
THF / DMSO
RT
1
R
R= 2a H
R= 4a H (70%)
R= 3a H (78%)
2b OMe (97%)
4b
OMe (76%)
3b
OMe (73%)
2c
2d
CH2OMe (96%)
CH2OPh (95%)
4c CH2OMe (77%)
4d CH2OPh (74%)
4e CH2OTBS (76%)
3c CH2OMe (87%)
3d CH2OPh (90%)
3e CH2OTBS (78%)
2e CH2OTBS (94%)
NaN3
DMSO
140 ºC
O
NHR1R2
Reflux
NR1R2
4a-e
O
O
N3
R1 and R2=
H or Alkyl
O
OH
R
OH
5a R= H, NHR1R2= piperidine (98%)
6a R= H, R1= H, R2= iPr (85%)
R
7a
8a
R= H, R1= H, R2= cyclohexyl (71%)
R= H, R1= H, R2= benzyl (87%)
R= 9a H (76%)
5b R= OMe, NHR1R2= piperidine (97%)
9c
CH2OMe (82%)
5c R= CH2OMe, NHR1R2= piperidine (94%)
i
6c
R= CH2OMe, R1= H, R2= Pr (79%)
7c R= CH2OMe, R1= H, R2= cyclohexyl (99%)
5d R= CH2OPh, NHR1R2= piperidine (90%)
LiAlH4
THF, RT
5e
R= CH2OTBS, NHR1R2= piperidine (52%)
O NH2
1,2-aminoalcohols with
secondary and tertiary amines
O
OH
R
R= 10a H (95%)
10c
CH2OMe (98%)
1,2-aminoalcohols
with primary amine
Scheme 2.
to place different groups as another element of steric control. Pre-
viously results demonstrated that structurally related chiral auxil-
iaries which contain this kind of substitution showed to be more
efficient in the asymmetric reaction tested.3 We considered the
1,6-andrydro bridge above the plane of the pyranose ring and the
aromatic rings below it. The epoxides were isolated as a single iso-
mer in good yields and identified as the product derived from the
attack of the ylide to the carbonyl group from the same face of the
1,6-anhydro bridge. This is in contrast to the reported results
preparation of 9-derived anthracenes 2b–e with
a methoxy,
methoxymethyl, phenoxymethyl, and tert-butyldimethylsilyl-
oxymethyl (OTBS) substituent groups. The 9-derived anthracenes
2c–d were synthesized in a simple and efficient way from commer-
cially available 9-anthracenemethanol.6 9-Methoxyanthracene
(2b) was obtained in 97% yield from anthrone by refluxing with
trimethylorthoformate and sulfuric acid for seven days.7 The
Diels–Alder reaction between 1 and 2a–b with catalytic amounts
of FeCl3 produced the desired cycloadducts 3a–b in good yields.
Cycloadducts 3c–e were prepared through a Diels–Alder reaction
using thermal conditions, as described in previous reports.6
There are precedents in the literature about the functionaliza-
tion of the keto group of levoglucosenone derivatives.8,9 It was
reported that the generation of the oxirane ring was carried out
employing the Corey–Chaykovsky reaction,9,10 for this reason, we
chose this methodology in order to obtain the spiro-epoxide 4.
The reaction proceeds through the addition of a sulfur ylide to
the keto group of the cycloadduct 3a–e to produce the correspond-
ing epoxide derivatives 4a–e. The diastereoselective conversion of
3 relies mainly on the competitive steric hindrance exerted by the
where the ylide attack occurred exclusively from the a face of
the keto group of 1, only due to the steric encumbrance exerted
by the 1,6-anhydro bridge.9 There are precedents which demon-
strated that the aromatic rings below the pyranose ring favor the
approach of the reagent from the opposite face.3,6 The stereochem-
ical assignments were made possible by the use of 1H NMR spin
decoupling and NOE data. The NOE observed between H-3 and
H-7 indicated the proximity of these nuclei through the space sug-
gesting the configuration at C-2 in compounds 4a–e.
We next studied the synthesis of chiral 1,2-aminoalcohols with
primary, secondary, and tertiary amino groups. Our purpose was to
determine if the amino substitution could exert any influence on
the enantioselective capacity of these chiral ligands, as it was
reported for other catalysts.11 To achieve this goal, a toluene
solution of epoxides 4a–e was refluxed with piperidine, isopropyl-
amine, cyclohexylamine, or benzylamine to produce the corre-
sponding 1,2-aminoalcohols with secondary and tertiary amino
group 5-8, in moderate to excellent yields. The ring opening
reaction of 4a and 4c with isopropylamine to give aminoalcohols

5834
M. M. Zanardi et al. / Tetrahedron Letters 55 (2014) 5832–5835
Table 1
Evaluation of the inductive capability of 1,2-aminoalcohols in the ZnEt2 addition reaction to benzaldehyde at room temperaturea
O
NR1R2
O
O
OH
OH
OH
H
+
(S)
(R)
R
ZnEt2
Entry
Ligand
Yield (%)
eeb (%)
Config.c
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
6a
7a
8a
10a
6c
95
98
84
70
92
76
94
83
81
97
84
70
34
24
50
0
30
4
14
6
44
20
26
4
S
R
R
—
R
R
R
S
S
10
11
12
R
R
S
7c
10c
a
b
c
1.1 M in hexane, 2 equiv regarding to benzaldehyde.
Determined by HPLC with Chiralcel OD-H column.
Main enantiomer of 1-phenyl-1-propanol assigned by the literature data13 and confirmed by polarimetry through [
a] measurements.
D
6a and 6c were too slow under conventional thermal reaction con-
dition. In order to reduce the reaction time, we assayed the use of
microwave assisted methodology and we obtained the desired
compounds 6a and 6c in higher yields with the concomitant reduc-
tion in reaction times.12 In order to synthesize 1,2-aminoalcohols
with the primary amino group, the oxirane ring of 4a and 4c was
converted to azidoalcohols 9a and 9c by the reaction with
sodium azide followed by the reduction with LiAlH4 to afford the
1,2-aminoalcohols 10a and 10c.
Once the syntheses of 1,2-aminoalcohols were achieved in
enantiomeric pure form, they were evaluated as chiral ligands in
the enantioselective addition of diethylzinc to benzaldehyde. The
reactions were performed using standard conditions2 with 2 equiv
of Et2Zn in the presence of 20% of the chiral ligand, Table 1.
The 1,2-aminoalcohols 5a–e containing the tertiary amino
group were the first ligands to be tested (entries 1–5). The outcome
of the nucleophilic addition demonstrated that the 1-phenyl-1-
propanol was obtained in good to excellent yields. The best enanti-
oselectivities were observed with ligands 5a and 5c, having a
hydrogen or a methoxymethyl substituent at the benzylic position.
These experimental results suggested that there was no correlation
between the substitution at the benzylic position with the effi-
ciency of the enantiomeric induction. We then turned our atten-
tion to evaluate the effect of the substitution at the amino group.
For this reason, we evaluated aminoalcohols 6–8a,c and 10a,c with
secondary and primary amino groups, structurally related to the
most efficient catalysts 5a and 5c containing a tertiary amino
group. The reactions catalyzed by these 1,2-aminoalcohols (entries
6–12) afforded the addition product in good to excellent yields. The
induction capacities observed were from moderate to low. The
comparison of the inductive capacity between all chiral ligands
evaluated demonstrates that the most efficient one was 5c, having
Table 2
Study of the ZnEt2 addition to benzaldehyde catalyzed by 5c under different reaction conditionsa
O
N
O
O
OH
OH
OH
H
+
(S)
(R)
MeO
ZnEt2
5c
Entry
5c (mol %)
Additive (equiv)
Yield (%)
eeb (%)
1
2
3
4
5
6
7
8
9
5
10
20
30
40
20
10
10
20
—
—
—
—
86
82
84
77
78
51
85
78
60
26
32
50
66
48
24
40
16
6
—
LiCl (0.6)
N1,N2-ditosyl-1,2-ethanediamine (0.1)
Ni(acac) (0.05)
Ti(OiPr)4 (1.2)
a
1.1 M in hexane, 2 equiv regarding to benzaldehyde.
Determined by HPLC with Chiralcel OD-H column.
b

M. M. Zanardi et al. / Tetrahedron Letters 55 (2014) 5832–5835
5835
a tertiary amino group which is in agreement with the tendency
Acknowledgments
observed in other systems.11
In as much as 5c proved to be the most selective 1,2-aminoalco-
hol in the chemical reaction tested, we considered this aminoalco-
hol to study the different reaction conditions that may have
influence on the induction capacity. Ethylation of benzaldehyde
does not occur without the addition of an aminoalcohol; however
the presence of 100 mol % of catalyst does not cause the reaction to
proceed either. Only the addition of a small amount of ligand accel-
erates the organometallic reaction efficiently.14 On the other hand,
the addition of different types of substances, such as bis-sulfona-
mides or inorganic salts which can act as Lewis acid like Ti(OiPr)4,
Ni(acac), or LiCl, have proved to affect the enantioselectivities of
other aminoalochols reported in the literature.15–20 For this reason,
we tested the effect of the catalyst amount and the presence of
additives. The results are summarized in Table 2.
This research was supported by the UNR, ANPCyT, CONICET,
Fundación J. Prats, Argentina, MMZ and MCB thank the CONICET
for the award of a fellowship.
Supplementary data
Supplementary data (experimental procedures for the synthesis
of all compounds, characterization data, and copies of 1H and 13C
NMR spectra of new products) associated with this article can
be found, in the online version, at http://dx.doi.org/10.1016/j.
tetlet.2014.08.124.
References and notes
1. (a) Juaristi, E.; Anaya de Parrodi, C. Synlett 2006, 2699; (b) Ager, D. J.; Prakash,
I.; Schaad, D. R. Chem. Rev. 1998, 96, 837.
2. (a) Steiner, D.; Sethofer, S. G.; Gorlaski, C. T.; Singaram, B. Tetrahedron:
Asymmetry 2002, 13, 1477; (b) Goldfuss, B.; Houk, K. N. J. Org. Chem. 1998, 63,
8998; (c) Oguni, N.; Omi, T. Tetrahedron Lett. 1984, 25, 2823; (d) Oguni, N.; Omi,
T.; Yamamoto, Y.; Nakamura, A. Chem. Lett. 1983, 841.
3. (a) Llompart, D.; Sarotti, A. M.; Corne, V.; Suárez, A. G.; Spanevello, R. A.;
Echeverría, G. A.; Piro, O. E.; Castellano, E. E. Tetrahedron Lett. 2014, 55, 2394;
(b) Sarotti, A. M.; Spanevello, R. A.; Suárez, A. G.; Echeverría, G. A.; Piro, O. E.
Org. Lett. 2012, 14, 2556; (c) Sarotti, A. M.; Fernández, I.; Spanevello, R. A.;
Sierra, M. A.; Suárez, A. G. Org. Lett. 2008, 10, 3389; (d) Sarotti, A. M.;
Spanevello, R. A.; Duhayon, C.; Tuchagues, J. P.; Suárez, A. G. Tetrahedron 2007,
63, 241; (e) Sarotti, A. M.; Spanevello, R. A.; Suárez, A. G. Org. Lett. 2006, 8, 1487.
4. (a) Levoglucosenone and Levoglucosans: Chemistry and Applications; Witczak, Z. J.,
Ed.; ATL Press: Mount Prospect, USA, 1994; (b) Sarotti, A. M.; Spanevello, R. A.;
Suárez, A. G. Green Chem. 2007, 9, 1137.
5. Sarotti, A. M.; Zanardi, M. M.; Spanevello, R. A.; Suárez, A. G. Curr. Org. Synth.
2012, 9, 439.
6. Sarotti, A. M.; Spanevello, R. A.; Suárez, A. G. Tetrahedron 2009, 65, 3502.
7. Pirkle, W. H.; Finn, J. M. J. Org. Chem. 1983, 48, 2779.
8. (a) Witczak, Z. J.; Kaplon, P.; Kolodziej, M. J. Carbohydr. Chem. 2002, 21, 1; (b)
Witczak, Z. J.; Mielguj, R. Synlett 1996, 108; (c) Taniguchi, T.; Nakamura, K.;
Ogasawara, K. Synlett 1996, 971.
All the reactions tested gave the R-1-phenyl-1-propanol as
major enantiomer. We could observe that the increment of the
amount of 5c (from 5 to 30 mol %, entries 1–4) increased the
enantioselectivity (from 26 to 66%). However, the ee decreased
with the use of more than 30 mol % of chiral ligand (entry 5). This
is in good agreement with the literature reports14,19 where it was
found that the stoichiometry of the aldehyde, dialkylzinc, and cat-
alyst strongly affects the reactivity and selectivity.14 All the reac-
tions performed in the presence of additives (entries 6–9) did not
increase the enantioselectivity; moreover it had a deleterious
effect. The reactions performed at lower temperature, as 0 °C with
30 mol % of 5c were less selective (ee 52%) than the reaction car-
ried out in the same experimental condition at room temperature
(entry 4). From all the reactions assayed the only condition that
allows to improve the enantioselectivity obtained with 5c was to
increase the catalytic amount of ligand up to 30 mol %, in this con-
dition we obtained the benzylalcohol with an ee of 66%.
In summary, this is the first report of the preparation of 1,2-
aminoalcohols with primary, secondary, and tertiary amino groups
derived from levoglucosenone and their application in the enantio-
selective diethylzinc addition to benzaldehyde. It is important to
point out that all 1,2-aminoalcohols tested in this study were
recovered and could be reused. The syntheses of the aminoalcohols
were simple and effective, allowing to obtain the desired com-
pounds in three or four steps (depending on the substitution of
the amino group) from levoglucosenone. The wide variety of amino
groups present in this new family of aminoalcohols, show the ade-
quate functionalization for further transformation into other chiral
derivatives. The level of induction obtained, in addition to the fact
that the starting material is easily obtained from biomass, makes
this system an excellent model to be exploited in other asymmetric
reactions and a starting point for the development of new chiral
catalysts.
9. (a) Gelas-Mielhe, Y.; Gelas, J. Carbohydr. Res. 1990, 199, 243; (b) Gelas-Mialhe,
Y.; Gelas, J.; Avenel, D.; Brahmi, R.; Gillier-Panadraud, H. Heterocycles 1986, 24,
931.
10. (a) Peng, Y.; Yang, J.; Li, W. Tetrahedron 2006, 62, 1209; (b) Corey, E.;
Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353.
11. (a) Cimarelli, C.; Palmieri, G.; Volpini, E. Tetrahedron: Asymmetry 2002, 13,
2417; (b) Lu, J.; Xu, X.; Wang, S.; Wang, C.; Hu, Y.; Hu, H. J. Chem. Soc., Perkin
Trans. 1 2002, 2900.
12. See Supporting information.
13. Roudeau, R.; Gomez Pardo, D.; Cossy, J. Tetrahedron 2006, 62, 2388.
14. Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley & Sons: New
York, 1994. pp 264.
15. Costa, A. M.; García, C.; Carroll, P. J.; Walsh, P. J. Tetrahedron 2005, 61, 6442.
16. Muñoz-Muñiz, O.; Juaristi, E. J. Org. Chem. 2003, 68, 2369.
17. Sosa-Rivadeneyra, M.; Muñoz-Muñiz, O.; Anaya de Parrodi, C.; Quintero, L.;
Juaristi, E. J. Org. Chem. 2003, 68, 3781.
18. Balsells, J.; Walsh, P. J. J. Am. Chem. Soc. 2000, 122, 1802.
19. Unaleroglu, C.; Aydin, A. E.; Demir, A. S. Tetrahedron: Asymmetry 2006, 17, 742.
20. Almansa, R.; Guijarro, D.; Yus, M. Arkivoc 2006, 6, 18.