[3 + 2] cycloaddition on carbohydrate templates: Stereoselective synthesis of pyrrolidines

Article abstract of DOI:10.1021/ol103119u

Pyrrolidine derivatives were prepared in high diastereoselectivities and good yields via a [3 + 2] cycloaddition of a tert-butyldimethylsilyl protected carbohydrate-based allene with a diverse range of imines. The subsequent removal of the carbohydrate au

Full text of DOI:10.1021/ol103119u

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1072–1075
[3 þ 2] Cycloaddition on Carbohydrate
Templates: Stereoselective Synthesis of
Pyrrolidines
Shuting Cai, Bala Kishan Gorityala, Jimei Ma, Min Li Leow, and Xue-Wei Liu*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological University, Singapore 637371
xuewei@ntu.edu.sg
Received December 23, 2010
ABSTRACT
Pyrrolidine derivatives were prepared in high diastereoselectivities and good yields via a [3 þ 2] cycloaddition of a tert-butyldimethylsilyl
protected carbohydrate-based allene with a diverse range of imines. The subsequent removal of the carbohydrate auxiliary afforded a variety of
pyrrolidines with excellent enantioselectivities (up to 99% ee). Selective reduction of the pyrrolidines further demonstrated the potential of this
strategy.
A growing interest in the synthesis of optically pure
pyrrolidine derivatives is principally attributed to the fact
that they are components of many biologically active
molecules (Figure 1)1 that exhibit a wide variety of biolog-
ical properties2a that include antibacterial, antifungal,
and cytotoxic activities.2b,c They also serve as neuroexcita-
tory agents,2d antibiotics,2e and glycosidase inhibitors.2f
Consequently, the therapeutic effects of pyrrolidines have
led to substantial interest in their expedient synthesis.3
During the past few years, numerous synthetic strategies to
synthesize stereoselective pyrrolidines and their derivatives
have been demonstrated. Some of the existing protocols
employ aza heterocycles,4a cyclizing bis-allylic amines,4b
and utilize 1,3-dipolar cycloaddition of azomethine ylides
in the presence of chiral auxiliaries.4c Among these strategies,
cycloaddition-based reactions are attractive due to their
inherent ability to induce exclusive stereoselectivity, engender
remarkable efficiency, and improve atom economy, which
can be achieved through constructing multiple bonds in a
single step.5 The initial deployment of chiral auxiliaries in
such cycloaddition reactions predominantly utilized R-amino
acids, terpenoids, and alkaloids.6 The pioneering work of
Vasella7a and Kunz7b exploited carbohydrates as chiral
templates in a 1,3-dipolar cycloaddition reaction of chiral
(1) (a) Cheng, Y.; Huang, Z. T.; Wang, M. X. Curr. Org. Chem. 2004,
8, 325. (b) Alvarez-Ibarra, C.; Csaky, A. G.; Lopez de Silanes, I.;
Quiroga, M. L. J. Org. Chem. 1997, 62, 479. (c) Bianco, A.; Maggini,
M.; Scorrano, G.; Toniolo, C.; Marconi, G.; Villani, C.; Prato, M.
J. Am. Chem. Soc. 1996, 118, 4072.
(2) (a) Royles, B. J. L. Chem. Rev. 1995, 95, 1981. (b) Moloney,
M. G.; Trippier, P. C.; Yaqoob, M.; Wang, Z. Curr. Drug Discovery
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Kiely, J. S.; Laborde, E.; Schroeder, M. C.; Sesnie, J. A.; Shapiro, M. A.;
Suto, M. J.; Vanderroest, S. J. Med. Chem. 1993, 36, 871. (d) Johnston,
G. A. R.; Curtis, D. R.; Davies, J.; McCulloch, R. M. Nature 1974, 248,
804. (e) Hussaini, S. R.; Moloney, M. G. Org. Biomol. Chem. 2003, 1,
1838. (f) Blanco, M. J.; Sardina, F. J. Tetrahedron Lett. 1994, 35, 8493.
(3) (a) Cren, S.; Gurcha, S. S.; Blake, A. J.; Besra, G. S.; Thomas,
N. R. Org. Biomol. Chem. 2004, 2, 2418. (b) Giard, T.; Lasne, M.-C.;
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(b) Terada, Y.; Arisawa, M.; Nishida, A. Angew. Chem., Int. Ed. 2004,
€
43, 4063. (c) Karlsson, S.; Hogberg, H.-E. Tetrahedron: Asymmetry
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r
10.1021/ol103119u
Published on Web 01/26/2011
2011 American Chemical Society

Table 1. Optimization Studiesa
Figure 1. Biologically active natural products.
entry
catalyst
solvent
time (h)
yieldb (%)
dec (%)
N-(alkoxyalkyl)nitrones and in a Diels-Alder reaction
with acrylates respectively, which prompted a widespread
exercise of carbohydrate matrices to construct diversified
highly stereoselective molecular skeletons.7c
1
2
3
4
5
6
7
8
9
AgBF4
AgClO4
AgNO3
AgOTf
AuCl
acetone
acetone
acetone
acetone
acetone
acetone
CH2Cl2
toluene
THF
3
20
11
71
54
62
64
48
75
71
79
77
86
81
83
84
87
92
90
3
1
2
Indubitably, carbohydrates are enantiomerically pure
candidates which exert their chirality on prochiral faces of
the substrate to synthesize many chiral drugs as well as
natural products.8 In addition to their low cost,9a the most
pre-eminent feature of carbohydrate auxiliaries lies in their
differing configurations of the carbohydrate scaffold,
which aid in installing diverse template geometries, thus
enabling the introduction of a wide variety of coordinative
sites.9b The efficient use of carbohydrate derivatives as
stereodifferentiating auxiliaries in chiral synthesis, parti-
cularly in cycloaddition reactions, has been corrobo-
rated.10 Notably, an allene ether version of the Nazarov
cyclization was recently reported by Tius et al. which
employed carbohydrate chiral auxiliaries appended to
lithiated allenes.11a Over the past few decades, numerous
examples of lithiated allenes as building blocks in the
synthesis of pyrrolidines and pyrrole derivatives have been
demonstrated.11b For example, Ressig reported a [3 þ 2]
cycloaddition, where a variety of pyrrolidines and pyrroles
were synthesized from lithiated allenes.12
1
AuCl3
1
AgNO3
AgNO3
AgNO3
1
0.5
0.5
a See ref 15. b Isolated yield of major diastereomer. c Determined by
crude 1H NMR spectroscopy.
Ashighlightedinthe recentreportbyTius, theTBSether
protected carbohydrate auxiliary not only produces good
selectivity but also prevents aggregation during the addi-
tion of butyllithium, therefore bestowing a better nucleo-
phile for the reaction with various imines.14 This discovery
underpinned our selection of a TBS ether protected carbo-
hydrate as the auxiliary in this cycloaddition reaction.
Therefore, the optimization studies were based on the
cycloaddition reaction between a TBS ether protected
carbohydrate allene 1 and an imine substrate with a simple
phenyl substituent 2a (Table 1).15
At the outset of the optimization studies, a variety of
silver and gold catalysts were chosen for screening because
of their high efficacy in many organic transformations;16a,b
especially their role in many cycloaddition reactions is
worthy of note.16c,d Intriguingly, our initial preliminary
survey had shown that the choice of the catalyst is largely
contingent on the yields of the products. The first set of
experiments, utilizing AgBF4 and AgClO4 in acetone
(Table 1, entries 1 and 2) did not provide satisfactory
results, producing the pyrrolidine derivatives in low
yields (20% and 11% respectively). However, in the above
set of reactions, diastereoselectivities were found to be
In line with our strong interests in carbohydrate synthe-
sis and our efforts in developing new methodologies for the
synthesis of biologically potent heterocycles,13 herein we
report a proficient synthesis of pyrrolidines via a [3 þ 2]
cycloaddition between a tert-butyldimethylsilyl (TBS) pro-
tected carbohydrate-based lithiated allene and a range of
imines.
(7) (a) Vasella, A. Helv. Chim. Acta 1977, 60, 1273. (b) Kunz, H.;
€
Muller, B.; Schanzenbach, D. Angew. Chem., Int. Ed. 1987, 26, 267.
(c) Boysen, M. Chem.;Eur. J. 2007, 13, 8648.
(8) Wang, Y.; Yu, J.; Miao, Z.; Chen, R. Chem.;Eur. J. 2009, 15,
9290.
(9) (a) King, S. B.; Ganem, B. J. Am. Chem. Soc. 1991, 113, 5089.
(b) Howland, J. L. Biochem. Educ. 1996, 24, 69.
(10) Totani, K.; Takao, K.; Tadano, K. Synlett 2004, 12, 2066.
(11) (a) Banaag, A. R.; Tius, M. A. J. Org. Chem. 2008, 73, 8133.
(b) Moreno-Clavijo, E.; Carmona, A. T.; Reissig, H.-U.; Moreno-
Vargas, A. J.; Alvarez, E.; Robina, I. Org. Lett. 2009, 11, 4778.
(12) Kaden, S.; Brockmann, M.; Reissig, H. U. Helv. Chim. Acta
2005, 88, 1826.
(13) (a) Lorpitthaya, R.; Xie, Z. Z.; Sophy, K. B.; Luo, J. L.; Liu,
X.-W. Chem.;Eur. J. 2010, 16, 588. (b) Gorityala, B. K.; Cai, S.;
Lorpitthaya, R.; Ma, J.; Pasunooti, K. K.; Liu, X.-W. Tetrahedron Lett.
2009, 50, 676. (c) Lorpitthaya, R.; Sophy, K. B.; Kuo, J. L.; Liu, X.-W.
Org. Biomol. Chem. 2009, 7, 1284. (d) Vedachalam, S.; Zeng, J.;
Gorityala, B. K.; Antonio, M.; Liu, X.-W. Org. Lett. 2009, 12, 352.
(e) Liu, X.-W.; Le, T. N.; Lu, Y. P.; Xiao, Y. J.; Ma, J. M.; Li, X. Org.
Biomol. Chem. 2008, 6, 3997. (f) Cheng, X.-M.; Liu, X.-W. J. Comb.
Chem. 2007, 9, 906.
(14) Banaag, A. R.; Tius, M. A. J. Am. Chem. Soc. 2007, 129, 5328.
(15) To LiCl (3.0 equiv) was added a solution of 1 (1.0 equiv) in THF
(5 mL) at -78 °C. The mixture was stirred for 5 min, and then n-BuLi
(2.0 equiv) was added dropwise and stirred for 45 min. 2a (2.0 equiv) in
THF (10 mL) was then added over 15 min and stirred for 3 h at -78 °C. A
brown oil was yielded after standard workup. To a solution of the brown
oil in toluene (10 mL) was added AgNO3 (0.2 equiv), and the mixture
was stirred for 30 min at 60 °C. The mixture was filtered, evaporated, and
purified by column chromatography to afford compound 3a (see
Supporting Information).
(16) (a) Naodovic, M.; Yamamoto, H. Chem. Rev. 2008, 108, 3132.
(b) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180. (c) Gung, B.; Craft, D.;
Bailey, L.; Kirschbaum, K. Chem.;Eur. J. 2010, 16, 639. (d) Yamashita,
Y.; Guo, X.-X.; Takashita, R.; Kobayashi, S. J. Am. Chem. Soc. 2010,
132, 3262.
Org. Lett., Vol. 13, No. 5, 2011
1073

Table 2. Exploration of the Substrate Scope of the Formation of
Pyrrolidine Derivativesa
Figure 2. X-ray structure of pyrrolidine derivative 3c.
of the catalyst established, we proceeded to examine
solvent effects. Surprisingly, all of the screened solvents
provided high diastereoselectivities, with minor variation
in the reaction times (Table 1, entries 3, 7-9). Following a
detailed analysis of the optimized results, toluene was
identified as the most suitable solvent, furnishing 3a in
good yield (75%) and de (92%) within a short reaction
time of 30 min (Table 1, entry 8). From the optimization
results, we concluded that 0.2 equiv of AgNO3 in toluene
was the most suitable set of conditions for this cycloaddi-
tion reaction.
Finally, as this cycloaddition protocol was being delin-
eated, we began to scrutinize the flexibility and scope of
the reaction on a variety of imines. To our delight, this
strategy was compatible with a wide array of aromatic as
well as nonaromatic imines. Hence, diastereomers 3a-3m
were obtained in relatively good yields (62-80%) with
high diastereoselectivities (90-95%) (Table 2). A careful
examination of the results revealed several characteristics
of this cycloaddition reaction that are noteworthy. The
presence of electron-donating (3b-3c) (Figure 2) and
electron-withdrawing substituents (3d-3h) on aromatic
imines provided consistent yields, indicating that the
choice of substituents on the aromatic imines have little
ornoeffectonthe yields of the reactions. However, itcould
be observed that imines bearing an electron-withdrawing
NO2 group (3g) and a furan moiety (3j) provided slightly
lower yields of the cyclizedproduct in contrast tothe restof
the substituents. Interestingly, the substituents on the
aromatic imines were relatively important determinants
of the diastereoselectivities. As illustrated, most of the
aromatic imines with electron-withdrawing substituents
furnished the cyclized 3e-3h with high de (∼95%), while
aromatic imines with electron-donating groups, aliphatic
imines, and heterocyclic and naphthyl imines produced the
desired product in slightly lower de (90-92%). Results
pertaining to the aliphatic imines (3k-3m) also unveiled
good yields (72-80%) and de (90-93%). This further
supported and strengthened the foundation of our strategy
by showcasing the good flexibility and tolerance of this
cycloaddition reaction to a range of imine compounds.
a See ref 15. b Isolated yield of the major diastereomer. c Determined
by crude 1H NMR spectroscopy.
promising. Among the silver catalysts tested, the reaction
yield (71%) and diastereoselectivity (86% de) were signifi-
cantly enhanced when AgNO3 was employed. Subse-
quently, gold catalysts were examined as we envisioned
that the usage of gold catalysts would produce good yields
and diastereoselectivities. Gratifyingly, the results attained
were in harmony with our predictions, as both AuCl and
AuCl3 (Table 1, entries 5 and 6) showed relatively good
yields (62-64%) and diastereoselectivities (83-84%).
However, in contrast to AuCl and AuCl3, the choice of
AgNO3 allows the acquirement of good yields and diaste-
reoselectivities at a much lower cost. The advantages dis-
played by AgNO3 rendered its selection as the optimal
catalyst for this cycloaddition reaction. With the influence
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Org. Lett., Vol. 13, No. 5, 2011

Table 3. Evaluation of the Enantioselectivity of Pyrrolidine
Derivatives
Scheme 1. Selective Reduction of Pyrrolidine 4b
further investigated the flexibility of the reaction by em-
ploying a heterocyclic substituted compound. Corre-
sponding to the above results, a good enantioselectivity
of 89% with 92% yield was achieved for a furan substi-
tuted compound (4f).
To exemplify the experimental success of this protocol
and its potentialutilityinsynthesis, weproceededtoreduce
the pyrrolidine 4b which is substituted with a methoxy
group on the aromatic ring. The reduction of 4b was
performed by employing NaBH4 in methanol with
CeCl3 7H2O as the catalyst, providing 6 as the major
3
isomer (Scheme 1). Subsequent evaluation of the crude
1H NMR revealed a diastereomeric ratio of 96%. This
strategy is useful in preserving the stereoselectivity of
natural products such as (þ)-preussin18a as these natural
products are extremely important in peptidomimetics.18b
In conclusion, a [3 þ 2] cycloaddition on a TBS ether
protected carbohydrate template has been established.
This methodology utilized lithiated allene and imines, in
the presence of AgNO3, to synthesize pyrrolidine deriva-
tives in good yields and diastereoselectivities. In addition,
excellent enantioselectivities were obtained for a range of
pyrrolidines after removal of the carbohydrate auxiliary.
Subsequently, selective reduction of the pyrrolidines re-
inforced the potential application of the strategy in organic
synthesis, further justifying that our strategy is of impor-
tance to synthetic chemistry. This novel protocol constitu-
tes one of the best examples in exploiting chiral carbo-
hydrate auxiliaries in synthesizing optically pure bioactive
pyrrolidines, thereby paving the way for further investiga-
tion in utilizing carbohydrate templates for enantioselec-
tive synthesis.
a Isolated yield. b Determined by chiral HPLC. c Stereochemistry
determined by optical rotation and X-ray crystallography (see Support-
ing Information).
The enantioselectivity was subsequently probed by re-
moval of the carbohydrate auxiliary using Danishefsky’s
method.17 In the presence of phenylthiol (5 equiv) and
BF3 OEt2 (0.5 equiv), the major diastereomer was cleaved
3
to recover the auxiliary (Table 3). This improves the atom
economy, thus offering a unique advantage to the reaction.
In addition, the resulting pyrrolidines were obtained in
excellent yields (90-96%) with good to excellent enantio-
meric selectivity (89-99%). Evaluation of the results
showed that, for aromatic compounds substituted with
bromine (4d) and trifluoromethyl (4e), an enantioselectiv-
ity of 99% was attained. This impressive selectivity was
further substantiated for the methoxy (4b) substituted
aromatic compound, in which a more than 99% enantio-
meric ratio was obtained. Encouraged by these results, we
Acknowledgment. Financial support from Nanyang
Technological University (RG50/08) and the Ministry of
Health, Singapore (NMRC/H1N1R/001/2009) are grate-
fully acknowledged.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) Halcomb, R. L.; Boyer, S. H.; Wittman, M. D.; Olson, S. H.;
Denhart, D. J.; Liu, K. K. C.; Danishefsky, S. J. J. Am. Chem. Soc. 1995,
117, 5720.
(18) (a) Huang, P.-Q.; Wu, T.-J.; Ruan, Y.-P. Org. Lett. 2003, 5,
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