1,3-Dipolar cycloaddition reactions of azomethine ylides with a cellulose-derived chiral enone. A novel route for organocatalysts development

Article abstract of DOI:10.1021/ol3008588

Cellulose-derived chiral pyrrolidines were synthesized in excellent yields, regioselectivities, and stereoselectivities via a 1,3-dipolar cycloaddition reaction between levoglucosenone and azomethine ylides. An unprecedented isomerization event led to a new family of pyrrolidines with an unusual relative stereochemistry. Preliminary results showed that these compounds are promising organocatalysts for iminium ion-based asymmetric Diels-Alder reactions.

Full text of DOI:10.1021/ol3008588

ORGANIC
LETTERS
2012
Vol. 14, No. 10
2556–2559
1,3-Dipolar Cycloaddition Reactions
of Azomethine Ylides with a
Cellulose-Derived Chiral Enone. A Novel
Route for Organocatalysts Development
,†
Ariel M. Sarotti,* Rolando A. Spanevello, Alejandra G. Suarez,*
†
,†
ꢀ
‡
Gustavo A. Echeverrıa, and Oscar E. Piro
‡
´
´
Instituto de Quımica Rosario, Facultad de Ciencias Bioquımicas y Farmaceuticas,
Universidad Nacional de Rosario-CONICET, Suipacha 531, S2002LRK Rosario,
´
ꢀ
´
Argentina, and Departamento de Fısica and Instituto IFLP (CONICET, CCT-La Plata),
Facultad de Ciencias Exactas, Universidad Nacional de La Plata, 1900 La Plata,
Argentina
sarotti@iquir-conicet.gov.ar
Received April 4, 2012
ABSTRACT
Cellulose-derived chiral pyrrolidines were synthesized in excellent yields, regioselectivities, and stereoselectivities via a 1,3-dipolar cycloaddition
reaction between levoglucosenone and azomethine ylides. An unprecedented isomerization event led to a new family of pyrrolidines with an
unusual relative stereochemistry. Preliminary results showed that these compounds are promising organocatalysts for iminium ion-based
asymmetric DielsÀAlder reactions.
The synthesis of new chiral organic templates starting
from renewable feedstocks is of enormous value in modern
organic synthesis. As a result, intensive research activity
has been pursued worldwide to identify attractive chemical
transformations to convert biomass into highly valuable
organic chemicals.1 Levoglucosenone (1,6-anhydro-3,4-
dideoxy-β-D-glycero-hex-3-enopyranos-2-ulose) (1) is a
versatile and easily available chiral building block from
the carbohydrate family.2 Conventional pyrolysis of cellu-
lose-containing materials such as waste paper is typically
used to generate 1, but microwave irradiation of micro-
crystalline cellulose was recently found to be an effective
alternative.3 As part of our ongoing interest in the devel-
opment of new tools for asymmetric synthesis using levo-
glucosenone derivatives,4 we envisaged the use of 1 in the
preparation of novel enantiomerically pure poly substi-
tuted pyrrolidines, molecular scaffolds that are found in
ꢀ
(4) (a) Sarotti, A. M.; Spanevello, R. A.; Suarez, A. G. Tetrahedron
ꢀ
2009, 65, 3502. (b) Sarotti, A. M.; Fernandez, I.; Spanevello, R. A.;
ꢀ
Sierra, M. A.; Suarez, A. G. Org. Lett. 2008, 10, 3389. (c) Sarotti, A. M.;
ꢀ
Spanevello, R. A.; Duhayon, C.; Tuchagues, J. P.; Suarez, A. G.
ꢀ
Tetrahedron 2007, 63, 241. (d) Sarotti, A. M.; Spanevello, R. A.; Suarez,
A. G. Org. Lett. 2006, 8, 1487.
(5) (a) Enantioselective Organocatalysis; Dalko, P. I., Ed.; Wiley-VCH
€
Verlag: Weinheim, 2007. (b) Erkkila, A.; Majander, I.; Pihko, P. M. Chem.
Rev. 2007, 107, 5416. (c) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List,
B. Chem. Rev. 2007, 107, 5471. (d) Lelais, G.; MacMillan, D. W. C.
Aldrichimica Acta 2006, 39, 79. (e) Brazier, J. B.; Tomkinson, N. C. O.
Top. Curr. Chem. 2010, 291, 281.
† Universidad Nacional de Rosario-CONICET.
‡ Universidad Nacional de La Plata.
(1) Lichtenthaler, F. W. Acc. Chem. Res. 2002, 35, 728.
(2) (a) Witczak, Z. J., Ed. Levoglucosenone and Levoglucosans:
Chemistry and Applications; ATL Press: Mount Prospect, 1994. (b) Sarotti,
(6) (a) Cardona, F.; Lalli, D.; Faggi, C.; Goti, A.; Brandi, A. J. Org.
€
ꢀ
Chem. 2008, 73, 1999. (b) Muller, C.; Gomez-Zurita Frau, M. A.;
Ballinari, D.; Colombo, S.; Bitto, A.; Martegani, E.; Airoldi, C.; van
Neuren, A. S.; Stein, M.; Weiser, J.; Battistini, C.; Peri, F. Chem. Med.
Chem. 2009, 4, 524. (c) Blake, A. J.; Cook, T. A.; Forsyth, A. C.; Gould,
R. O.; Paton, R. M. Tetrahedron 1992, 48, 8053. (d) Blake, A. J.; Forsyth,
A. C.; Paton, R. M. J. Chem. Soc., Chem. Commun. 1988, 440.
ꢀ
A. M.; Zanardi, M. M.; Spanevello, R. A.; Suarez, A. G. Curr. Org. Synth.
2012, DOI: 10.2174/1570212700121041794.
(3) Sarotti, A. M.; Spanevello, R. A.; Suarez, A. G. Green Chem.
ꢀ
2007, 9, 1137.
r
10.1021/ol3008588
Published on Web 04/30/2012
2012 American Chemical Society

many efficient chiral organocatalysts.5 Since1 has a unique
dipolarophilic reactivity, as was established with dipoles
such as nitrones and nitrile oxides,6 we foresaw the 1,3-
dipolar cycloaddition cycloaddition (1,3-DPC) using azo-
methine ylides(AMY) asa directroutetoachieveour goals
(Scheme 1).
Table 1. Synthesis of Chiral Pyrrolidines via 1,3-DPCa
Scheme 1. Synthetic Strategy for New Pyrrolidinic Cores De-
rived from Levoglucosenone
entry imine salt/base (equiv) solvent yieldb (%) ratio 3/4/5
1
2
2Aa AgOAc/DBU (1.2) MeCN
2Aa AgOAc/DBU (0.4) MeCN
2Aa AgOAc/DBU (0.3) MeCN
2Aa AgOAc/DBU (0.2) MeCN
2Aa AgOAc/DBU (0.3) PhMe
2Aa AgOAc/DBU (0.3) CH2Cl2
2Aa AgOAc/DBU (0.3) MeCN
2Aa AgOAc/NEt3 (0.3) MeCN
2Aa AgOAc/DBU (0.1) MeCN
2Ab AgOAc/DBU (0.3) MeCN
2Ac AgOAc/DBU (0.3) MeCN
2Ba AgOAc/DBU (0.3) MeCN
2Bb AgOAc/DBU (0.3) MeCN
2Bc AgOAc/DBU (0.3) MeCN
2Ca AgOAc/DBU (0.3) MeCN
2Cb AgOAc/DBU (0.3) MeCN
2Cc AgOAc/DBU (0.3) MeCN
24
75
94
60
59
56
56c
73
63
92
94
91
90
95
88
97
95
59:41:0
56:44:0
60:40:0
63:37:0
65:35:0
63:37:0
61:39:0
38:27:34
47:35:18
55:45:0
52:48:0
100:0:0
100:0:0
100:0:0
100:0:0
100:0:0
100:0:0
3
4
Although this methodology is perhaps one of the best
and most used methods for the convergent and stereose-
lective synthesis of pyrrolidinic cores,7 examples on the use
of carbohydrate-derived enones as the π-deficient counter-
part are scarce.8 Moreover, this strategy represents a
conceptually novel route for the synthesis of organocata-
lysts, since to the best of our knowledge there are no
precedents on the use of enantiomerically pure dipolaro-
philes in the generation of chiral pyrrolidines as potential
organocatalysts.9
5
6
7
8
9
10
11
12
13
14
15
16
17
Levoglucosenone was obtained from the microwave-
assisted pyrolysis of acid pretreated microcrystalline
cellulose.3 With the chiral enone in hand, we next set the
stage for the rapid construction of the pyrrolidine ring.
Among thedifferentstrategiesdevelopedfor the formation
of azomethine ylides (AMYs), one of the most simple,
mild, and reliable procedures consists of the in situ gen-
eration of stabilized N-metalated AMYs from iminoesters
using silver and lithium counterions.7
In order to optimize the reaction conditions, we
started our study using the iminoester 2Aa and silver
acetate as metalated-1,3-dipole precursors. As shown
in Table 1, up to three stereoisomers were isolated,
namely endo-3Aa, exo-4Aa, and 5Aa (C7 epimer of
3Aa). From the collected data (entries 1À9), we found
that the overall yield was highly affected upon changes
in solvent, temperature and catalyst load while the
influence on the endo/exo selectivity was not signifi-
cantly affected. This study allowed us to identified the
optimal experimental conditions to carry out this che-
mical transformation (0.3 equiv of AgOAc, 0.3 equiv of
DBU, MeCN, rt, 94%, entry 3).
a Unless otherwise shown, all reactions were carried out at room
temperature using 1.5 equiv of 2. b Yield corresponds to isolated
compounds after column chromatography. c The reaction was carried
out at 0 °C.
According to entries 1À7 in Table 1, only the endo and
exo isomers were obtained in modest selectivity. The 2,5-
syn relationship between the phenyl and ester groups on
the main products 3 and 4 can be interpreted on the basis of
the net preference of the metallo-dipole to adopt a
W-shaped geometry.7 However, with the use of 0.1 equiv
of metal salt (entry 9) or NEt3 as base (entry 8) variable
amounts of isomer 5 were detected. There are precedents
in the literature in which stereomutated isomers are
found,8À10 a result that is generally explained on the basis
of the isomerization of the ylide.7 However, while in those
cases the aromatic moiety and the EWG of the dipolar-
ophile are in a syn relationship, in our case both groups
are anti.
To evaluate the scope of this cycloaddition protocol, a
representative set of aryl imines of glycine, alanine and
phenylalanine methyl esters were reacted with 1 under the
optimized experimental conditions (Table 1, entries 10À17).
(7) (a) Stanley, L. M.; Sibi, M. P. Chem. Rev. 2008, 108, 2887. (b)
Pellissier, H. Tetrahedron 2007, 63, 3235. (c) Pandey, G.; Banerjee, P.;
Gadre, S. R. Chem. Rev. 2006, 106, 4484. (d) Coldham, I.; Hufton, R.
Chem. Rev. 2005, 105, 2765.
ꢀ
(8) Bashiardes, G.; Cano, C.; Mauze, B. Synlett 2005, 4, 587.
(9) During the preparation of this manuscript, Cossıo and co-workers
reported the synthesis of enantiomerically enriched pyrrolidines vı
asymmetric 1,3-DPC and their use in organocatalyzed aldol reactions:
´
´
a
(10) (a) Garcıa Ruano, J. L.; Tito, A.; Peromingo, M. T. J. Org.
´
ꢀ
Chem. 2002, 67, 981. (b) Casas, J.; Grigg, R.; Najera, C.; Sansano, J. M.
Eur. J. Org. Chem. 2001, 1971. (c) Tsuge, O.; Kanemasa, S.; Yoshioka,
M. J. Org. Chem. 1988, 53, 1384.
ꢀ
ꢀ
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Conde, E.; Bello, D.; de Cozar, A.; Sanchez, M.; Vazquez, M. A.;
Cossıo, F. P. Chem. Sci. 2012, DOI: 10.1039/c2sc20199b.
´
Org. Lett., Vol. 14, No. 10, 2012
2557

To our delight, very good yields were obtained in all cases.
Interestingly, while the stereoselectivity remained modest
when using glycine derivatives (entries 10 and 11), the endo
adducts were exclusively formed after the insertion of a
substituent at the R-position of the dipole precursor
(entries 12À17). These results suggest that the replacement
of an hydrogen atom by bulkier groups (Me or Bn) has
a greater impact on the destabilization of the competing
exo transition state, probably due to unfavorable steric
interactions.
The stereochemical assignments of all compounds were
unequivocally established via NOE experiments (Figure 1).
It is also important to highlight that all reactions displayed
complete π-facial selectivity, since the 1,6-anhydro bridge
of 1 acts as an efficient element of stereocontrol, directing
the attack of the dipole for the less hindered R face of
the molecule. Another salient feature of this system is the
remarkable levels of regioselectivity achieved. The only
isolated regioisomers arise from the bonding of the most
electrophilic center of the dipolarophile with the most
nucleophilic carbon of the dipole.
Figure 2. Drawing of the 5Ba molecule showing the displace-
ment ellipsoids of the non-H atoms at the 30% probability level.
Table 2. Microwave-Assisted Isomerization of Adducts endo-3
temp
yieldb
(%)
ratio
entry
3
solvent additivea (°C)
time
5/4
1
2
Ba CDCl3
Ba CHCl3
Ba PhMe
Ba CHCl3
Ba CHCl3
Bb CHCl3
Bc CHCl3
Ca CHCl3
Cb CHCl3
Cc CHCl3
Aa CHCl3
Aa CHCl3
Ab CHCl3
Ac CHCl3
25c
30 days
14
63
44
23
92
91
87
88
90
90
91
82
80
84
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
150 60 min
150 210 min
150 300 min
150 20 min
150 20 min
150 20 min
150 20 min
150 20 min
150 20 min
150 20 min
3
4
NEt3
5
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
6
7
Figure 1. Key NOE correlations for stereochemical assigne-
ments of isomers 3 (endo), 4 (exo), and 5.
8
9
10
11
12
13
14
0:100
During the course of this study, we realized that 3Ba
suffered slow decomposition after being accidentally left in
a CDCl3 solution at room temperature for a period of one
month. After column chromatography, we were able to
isolate a new compound in low yield, which on the basis of
extensive NMR experiments was assigned as 5Ba, a C7
epimer of 3Ba. The structure of 5Ba was further unambi-
guosly established in the solid by X-ray diffraction analysis
as shown in the ORTEP11 plot of Figure 2.
This result was totally unexpected in view of the fact that
no precedents in the literature regarding isomerization at
the benzylic position of structurally related 1,3-dipolar
adducts could be found. Hence, we next explored this
serendipitous outcome more thoroughly. Taking into ac-
count the evident slow isomerization rate at room tem-
perature, the use of microwave irradiation to accelerate the
process seemed appropriate. Heating a solution of 3Ba in
CHCl3 at 150 °C for 60 min resulted in the total consump-
tion of the starting material, to give the desired product
5Ba in 63% yield (Table 2, entry 2). Interestingly, the use
of toluene as solvent (entry 3) required much longer
60
60
60
240 min
240 min
240 min
49:51
38:62
52:48
a We used 10% v/v of additive in all cases. b Yield corresponds to
isolated compounds after column chromatography. c This reaction was
carried out without microwave irradiation.
irradiation time and resulted in lower yield of the product.
Considering that small amounts of HCl can be generated
by decomposition of chloroform, it can be postulated that
the difference in the performance between those two
solvents may be due, at least in part, to the tiny acidity of
the former one. In fact, the addition of NEt3 dramatically
decreased both the epimerization rate and yield (entry 4).
On the other hand, acetic acid was an effective additive,
leading to the rapid formation of 5Ba in high yield
(entry 5). The scope of this procedure was further explored
by submitting other endo adducts to the optimal experi-
mental conditions found. As depicted in entries 6À10, the
isomerized compounds 5 bearing a quaternaty carbon at
C8 were obtained in very good yields in all cases. Interest-
ingly, the use of 3Aa resulted in the complete inversion of
both stereocenters at C7 and C8, allowing to obtain 4Aa in
good yield (entry 11). The synthesis of epimerized products
(11) Johnson, C. K. ORTEP-II. A Fortran Thermal-Ellipsoid Plot
Program. Report ORNL 5318, Oak Ridge National Laboratory, Oak
Ridge, TN, 1976.
2558
Org. Lett., Vol. 14, No. 10, 2012

Scheme 2. Proposed Mechanisms for the Isomerization
Scheme 3. DielsÀAlder Reaction between (E)-Cinnamaldehyde
and Cyclopentadiene Catalyzed by 5Ba
equilibrium should be clearly displaced toward 5Ba, in
perfect agreement with the experimental findings.
Finally, to demonstrate proof-of-principle of the useful-
ness of levoglucosenone-derived chiral pyrrolidines in
asymmetric synthesis, some of the compounds synthesized
in this work were evaluated as novel organocatalysts in
iminium-ion based DielsÀAlder reactions between (E)-
cinnamaldehyde (6) and cyclopentadiene (7).15 As a repre-
sentative example, in Scheme 3 are shown the results
obtained with 5Ba, one of the most promising catalysts.16
It is important to point out that few organocatalytic systems
have been reported to have a marked preference toward the
exo adducts.17 Preliminary results showed that the other
evaluated compounds are also active catalysts, making this
system an excellent candidate for further optimization.16
In summary, we have reported the synthesis of chiral
pyrrolidines derived from renewable feedstocks using 1,3-
dipolar cycloadditions between N-metalated azomethine
ylides and levoglucosenone. We have shown that these
reactions proceed with excellent yields and selectivities. An
unprecedented isomerization event led to the formation of
a new family of pyrrolidines with a relative stereochemistry
5 derived from glycine was achieved at lower temperature
(entries 12À14), in good overall yield and modest 5/4
selectivity. This novel epimerization proved to be of great
synthetic value, allowing access to a new isomer class of
polyfunctionalyzed pyrrolidines in a straightforward man-
ner with a relative stereochemistry not accessible vıa direct
´
1,3-DPC. Moreover, this experimental finding might sup-
port an alternative path to explain the formation of vari-
able amounts of stereomutated 2,5-anti isomers in AMY
dipolar reactions.
The proposed mechanism for the observed epimeriza-
tion consists in a tandem retro-MannichÀMannich equili-
bration (Scheme 2), which have been suggested to explain
isomerization in spiro oxindole alkaloids.12 Another plau-
sible path consists in a retro-aza-Michael transformation
followed by an aza-Michael ring closure of the resulting
enone.13 Moreover, we found that after reduction of the
ketone group of 3Ba, the corresponding alcohol remained
unchanged after 60 min of irradiation at 150 °C in a
CHCl3ÀAcOH solution. This experimental result indi-
cates that the carbonyl function is necessary for the success
of the reaction, supporting both mechanistic proposals.
We also computed the Gibbs free energies of compounds
3Ba and 5Ba at the B3LYP/6-31G(d) level of theory using
Gaussian 09.14 Our results indicated that the former
is 6.75 kcal/mol less stable than its epimer suggesting
that, under a thermodynamically controlled process, the
not accessible vıa direct 1,3-DPC. The promising results
´
obtained in the organocatalyzed DielsÀAlder reactions
provided evidence for the potential application of these
molecular scaffolds in iminium ion-based organocatalysis,
which to the best of our knowledge has no precedents.
Further work aimed at the optimization, mechanism elu-
cidation, and broadening the scope of the asymmetric
DielsÀAlder cycloadditions are currently being underta-
ken and will be published in due course.
Acknowledgment. This research was supported by AN-
PCyT, CONICET, and UNR from Argentina. We also
(12) (a) Wenkert, E.; Udelhofen, J. H.; Bhattacharyya, N. K. J. Am.
Chem. Soc. 1959, 81, 3763. (b) Cravotto, G.; Battista Giovenzana, G.;
Pilati, T.; Sisti, M.; Palmisano, G. J. Org. Chem. 2001, 66, 8447. (c) Laus,
´
thank to Mr. Salvador Drusın from UNR for helpful
collaboration.
€
G.; Brossner, D.; Senn, G.; Wurst, K. J. Chem. Soc., Perkin Trans. 2
1996, 1931. (d) Laus, G. J. Chem. Soc., Perkin Trans. 2 1998, 315.
(13) This alternative mechanism was proposed by one of the
reviewers.
(14) Frisch, M. J. et al. Gaussian 09, Revision B.01, Gaussian, Inc.:
Wallingford, CT, 2009.
(15) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2000, 122, 4243.
(16) To see other experimental results, see the Supporting
Information.
Supporting Information Available. Experimental pro-
cedures for the synthesis of all compounds, characteriza-
tion data, copies of 1H and 13C NMR spectra of new pro-
ducts, X-ray data of compound 5Ba, and computational
data associated with this paper. This material is available
free of charge via the Internet at http://pubs.acs.org.
(17) (a) Kano, T.; Tanaka, Y.; Maruoka, K. Org. Lett. 2006, 8, 2687.
(b) Gotoh, H.; Hayashi, Y. Org. Lett. 2007, 9, 2859.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 10, 2012
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