Nitrile Ylides: Diastereoselective cycloadditions using chiral oxzolidinones without Lewis acid

Article abstract of DOI:10.1021/ol9018584

"Chemical Equation Presented" Lewis acid complexation Is generally required for chiral-auxiliary-controlled stereoselectivity, and chiral Lewis acid catalysis Is frequently optimal for Introducing asymmetry. In this work, we show that nitrlle ylide cycloadditions to electron-poor acceptors attached to chiral auxiliaries proceed In high yield and stereoselectivity in the absence of Lewis acids. In contrast, chiral Lewis acids are Inferior In these cycloadditions.

Full text of DOI:10.1021/ol9018584

ORGANIC
LETTERS
2009
Vol. 11, No. 23
5366-5369
Nitrile Ylides: Diastereoselective
Cycloadditions using Chiral
Oxzolidinones Without Lewis Acid
Mukund P. Sibi,* Takahiro Soeta, and Craig P. Jasperse
Department of Chemistry and Molecular Biology, North Dakota State UniVersity,
NDSU Department 2735, PO Box 6050, Fargo, North Dakota 58108-6050
mukund.sibi@ndsu.edu
Received August 10, 2009
ABSTRACT
Lewis acid complexation is generally required for chiral-auxiliary-controlled stereoselectivity, and chiral Lewis acid catalysis is frequently
optimal for introducing asymmetry. In this work, we show that nitrile ylide cycloadditions to electron-poor acceptors attached to chiral auxiliaries
proceed in high yield and stereoselectivity in the absence of Lewis acids. In contrast, chiral Lewis acids are inferior in these cycloadditions.
Small ring heterocycles are of great interest in medicinal
chemistry.1 Over the years, a variety of stereoselective
methods have been developed for the preparation of nitrogen
heterocycles.2 A premiere method among these has been
dipolar cycloadditions (Figure 1).3 The control of relative
and absolute stereochemistry in dipolar cycloadditions has
been achieved using chiral auxiliaries, chiral Lewis acids,
and more recently by the use of organocatalysts.4 Among
the large number of known dipoles, nitrones have received
(1) (a) Sperry, J. B.; Wright, D. L. Curr. Opin. Drug DiscoVery DeV.
2005, 8, 723. (b) De Luca, L. Curr. Med. Chem. 2006, 13, 1.
(2) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell
Science: Oxford, 2000.
(3) Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry
toward Heterocycles and Natural Products; Padwa, A., Pearson, W. H.,
Eds.; John Wiley and Sons: Hoboken, NJ, 2003.
(4) For recent reviews of asymmetric 1,3-dipolar cycloadditions, see:
(a) Gothelf, K. V.; Jørgensen, K. A. Chem. ReV. 1998, 98, 863. (b) Stanley,
L. M.; Sibi, M. P. Chem. ReV. 2008, 108, 2887. (c) Kanemasa, S. Synlett
2002, 9, 1371. (d) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004,
43, 5138. (e) Pellissier, H. Tetrahedron 2007, 63, 9267.
Figure 1. Dipolar cycloadditions with unsaturated acceptors.
(5) (a) Sibi, M. P.; Ma, Z.; Jasperse, C. P. J. Am. Chem. Soc. 2004,
126, 718. (b) Sibi, M. P.; Ma, Z.; Itoh, K.; Prabagaran, N.; Jasperse, C. P.
Org. Lett. 2005, 7, 2349. (c) Evans, D. A.; Song, H.-J.; Fandrick, K. R.
Org. Lett. 2006, 8, 3351. (d) Palomo, C.; Oiarbide, M.; Arceo, E.; Garcia,
J. M.; Lopez, R.; Gonzalez, A.; Linden, A. Angew. Chem., Int. Ed. 2005,
44, 6187. (e) Suga, H.; Nakajima, T.; Itoh, K.; Kakehi, A. Org. Lett. 2005,
7, 1431.
the most attention in enantioselective dipolar cycloadditions
due to their stability and ease of synthesis.5 Other stable
dipoles have also been investigated, and we have recently
shown that diazoesters undergo chiral Lewis acid-catalyzed
cycloadditions to electron deficient acceptors to provide
10.1021/ol9018584 CCC: $40.75
Published on Web 10/30/2009
 2009 American Chemical Society

2-pyrazolines in high enantioselectivity.6 Cycloadditions with
the more reactive dipoles requiring in situ generation are much
more challenging, since the bases used to generate the dipoles
often interfere with the Lewis acids.7 We have recently
developed conditions involving in situ generated nitrile oxides8
and nitrile imines9 that undergo highly regio- and enantiose-
lective cycloadditions using chiral Lewis acid catalysis.
Although initially described over 40 years ago by Huisgen
and co-workers,10 nitrile ylides, one of the more reactive dipoles,
remain as one of the least explored dipoles.11 In this work, we
describe the first examples of highly stereoselective cycload-
ditions with nitrile ylides that proceed in good to excellent
yields. Furthermore, we show that chiral auxiliaries in the
absence of Lewis acids are the best source for the introduction
of chirality in nitrile ylide cycloadditions to R,ꢀ-unsaturated
enoates and that chiral Lewis acids are ineffective.
With our recent success in the development of enantioselec-
tive dipolar cycloadditions mediated by chiral Lewis acids, we
began our work on determining an optimal protocol to carry
out cycloadditions with nitrile ylides. Toward this end, we chose
the well-known compound 2a and oxazolidinone crotonate 1a
as our starting materials. It has been established in the literature
that compound 2a generates a nitrile ylide on treatment with
an organic base.12 At the outset, we were concerned with the
high reactivity of the nitrile ylides. First, will they be compatible
with Lewis acids? Second, will they be so reactive that addition
to unactivated substrates (background reaction) competes with
addition to Lewis-acid activated substrates?
with the highly Lewis acidic hafnium, scandium, and samarium
triflates gave little or none of the desired adduct (entries
1-3).13,14 Reactions using moderately Lewis acidic copper
and zinc triflates gave no product (data not shown). Cy-
cloaddition did occur in the presence of weakly acidic
magnesium triflate, silver triflate and nickel bromide (entries
4-6). The cycloaddition product was formed as a single
compound. The observed regiochemistry in the cycloaddi-
tions is consistent with that obtained with R,ꢀ-unsaturated
esters and amides.11,15 Cycloadditions in the presence of
chiral Lewis acids were low-yielding and unselective (entries
7 and 8).16 In each of the low yielding reactions, decomposi-
tion of the ylide was observed, presumably Lewis-acid
induced.
By contrast, when the reaction was carried out in the
absence of any Lewis acid (entry 9), the reaction gave the
cycloadduct as a single isomer in 91% yield, the highest
observed in the series. These results show that the back-
ground reactivity in the absence of Lewis acid is sufficiently
high. Lewis acid activation is not only unnecessary for the
desired cycloaddition, but is instead harmful in that it
facilitates undesired decomposition of the nitrile ylide.
Relatively weak Lewis acids probably are not effective.
Lewis-acid incompatibility may be a limitation with other
highly reactive dipoles as well.
The ineffectiveness of the chiral Lewis acids for enanti-
oselective nitrile ylide cycloadditions led us to explore
reactions with acceptors appended with a chiral auxiliary
(Table 2). For initial screening, a chiral oxazolidinone derived
from phenyl glycine was used. Chelating Lewis acids are
normally used for reactions involving chiral oxazolidinone
auxiliaries, such that the carbonyl group is locked in the syn
s-cis arrangement.17 There are only a few scattered reports
of moderate to good selectivity in transformations using
chiral oxazolidinone auxiliaries in the absence of Lewis acid
To answer these questions, we carried out cycloadditions of
the nitrile ylide generated from 2a to the crotonate 1a using
Lewis acids (30 mol %) differing in strength (Table 1). Reaction
Table 1. Chiral Lewis Acid Mediated Nitrile Ylide
Cycloadditions
(6) Sibi, M. P.; Stanley, L. M.; Soeta, T. Org. Lett. 2007, 9, 1553. Also
see: Kanemasa, S.; Kanai, T. J. Am. Chem. Soc. 2000, 122, 10710.
(7) Pellissier, H. Tetrahedron 2007, 63, 3235.
(8) Sibi, M. P.; Itoh, K.; Jasperse, C. P. J. Am. Chem. Soc. 2004, 126,
5366.
(9) (a) Sibi, M. P.; Stanley, L. M.; Jasperse, C. P. J. Am. Chem. Soc.
2005, 127, 8276. (b) Sibi, M. P.; Stanley, L. M.; Soeta, T. AdV. Synth.
Catal. 2006, 348, 2371.
(10) Huisgen, R.; Stangl, H.; Sturm, H. J.; Wagenhofer, H. Angew. Chem.
1962, 74, 31. (b) Bunge, K.; Huisgen, R.; Raab, R.; Stangl, H. Chem. Ber.
1972, 105, 1279.
(11) For recent reviews, see: (a) Escolano, C.; Duque, M. D.; Vazquez,
S. Curr. Org. Chem. 2007, 11, 741. (b) Kanemasa, S. Sci. Synth. 2004, 19,
67. For work on reactions of nitrile ylides or equivalents, see: (c) Bojkova,
N.; Heimgartner, H. Heterocycles 1998, 47, 781. (d) Kawashima, K.; Kakehi,
A.; Noguchi, M. Tetrahedron 2007, 63, 1630. (e) Yoo, C. L.; Olmstead,
M. M.; Tantillo, D. J.; Kurth, M. J. Tetrahedron Lett. 2006, 47, 477. (f)
Bowman, R. K.; Johnson, J. S. J. Org. Chem. 2004, 69, 8537.
(12) A variety of organic bases and solvents were evaluated. Diisopro-
pylethylamine was the base of choice and methylene chloride was the
optimal solvent.
(13) Molecular sieves (4 Å) were used to maintain the integrity of the
nitrile ylide. Nitrile ylides react with water to give the corresponding amide.
In addition, water can react with Lewis acids in the presence of amines to
make inactive metal hydroxides.
entrya
Lewis acid
ligand
yield, % entryb
ee, %c
1
2
3
4
5
6
7
8
9
Hf(OTf)4
Sc(OTf)3
Sm(OTf)3
Mg(OTf)2
AgOTf
-
-
-
-
-
-
4
nr
15
32
68
54
88
64
37
91
-
-
-
14
17
-
NiBr2
Mg(OTf)2
Mg(OTf)2
None
5
-
(14) Lewis acids have been shown to be incompatible with azomethine
ylides, see: Ma, Z.; Wang, S.; Cooper, A C. S.; Fung, K. L.; Lynch, J. K.;
Plagge, F.; Chu, D. T. W. Tetrahedron: Asymmetry 1997, 8, 883.
(15) De March, P.; El Arrad, M.; Figueredo, M.; Font, J. Tetrahedron
1998, 54, 11613.
a For detailed reaction conditions, see Supporting Information. b Isolated
yields after purification by column chromatography. c ee values were
determined by chiral HPLC.
(16) A variety of chiral Lewis acids were explored in the cycloadditions.
Results form these experiments gave low yields and or selectivity.
Org. Lett., Vol. 11, No. 23, 2009
5367

investigated in the cycloadditions (entries 6-9).19 Of these
only the ‘Superquat’ auxiliary derived from phenyl alanine
failed to give high selectivity (entry 7).20
Table 2. Chiral Auxiliaries in Nitrile Ylide Cycloadditions
Having identified optimal reaction conditions for nitrile
ylide cycloadditions, we then investigated the scope of the
dipolarophile (Table 3). For these reactions we chose the
Table 3. Scope of the Acceptor in Nitrile Ylide Cycloadditions
entrya
R1
R2 Lewis acidb prod yield,%c
drd
1
2
3
4
5
6
7
8
9
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
Bn (1c)
Bn (1d)
i-Pr (1e)
Ph2CH (1f)
H
H
H
H
H
H
Me
H
H
Cu(OTf)2
Mg(OTf)2
Sc(OTf)3
NiBr2
-
3b
3b
3b
3b
3b
3c
3d
3e
3f
trace
53
19
78
87
81
72
83
80
-
g98:2
g98:2
g98:2
g98:2
91:9
55:45
g98:2
g98:2
-
-
-
-
starting
entrya
material, R1
product
yieldb
drc
1
2
3
4
5
6
7
8
Me (1b)
H(1g)
Et (1h)
Ph (1i)
4-BrC6H4 (1j)
2-Furyl (1k)
CO2t-Bu (1l)
OPMB (1m)
3b
3g
3h
3i
3j
3k
3l
87
74
91
80
88
68
73
63
g98:2
g98:2
g98:2
g98:2
g98:2
g98:2
g98:2
g98:2
a For reaction conditions, see Supporting Information. b Lewis acid (30
mol %) was used. c Yields are for isolated materials after column
chromatography. d Diastereomeric ratios were determined by both NMR
and by hplc following reduction of the acyl oxazolidinone.
additives.18 Reaction of the crotonate derived from 4-phe-
nyloxazolidinone and the nitrile ylide derived from 2a was
thus evaluated using different Lewis acids (entries 1-4). As
was true in with the achiral oxazolidinone 1a, yields were
better with the weaker magnesium triflate and nickel
bromide Lewis acids (entries 2 and 4). We then carried
out a cycloaddition of 1b and 2a in the absence of a Lewis
acid (entry 5). As expected based on the achiral series, the
reaction gave an improved yield. Surprisingly the selectivity
was outstanding, providing the product as a single regio-
and diastereoisomer. The sense of stereoinduction was the
same as that obtained for experiments with Lewis acid
additives, again suggesting that cycloadditions that proceeded
in the presence of weak Lewis acids did not actually involve
Lewis acid-coordinated reactants. The auxiliary was cleaved
by treatment with sodium borohydride to provide a primary
alcohol. Enantiomeric excess analysis by chiral HPLC
indicated that the cycloaddition product was formed in g99%
purity. In the absence of Lewis acid acyl oxazolidinones react
with the two carbonyls anti to each other (see X-ray results
below); our results indicate that excellent face shielding is
possible from the anti arrangement. The selectivity in Table
2 reflects the highest observed diastereoselectivity for reac-
tions involving chiral oxazolidines in the absence of chelating
Lewis acids. Other chiral oxazolidinone auxiliaries were also
3m
a For detailed reaction conditions, see Supporting Information. b Yields
are for isolated materials after column chromatography. c Diastereomeric
ratios were determined by both NMR and by hplc following reduction of
the acyl oxazolidinone. The minor isomer was not detected.
4-phenyl-oxazolidin-2-one as the chiral auxiliary and 2a as
the dipole. As was discussed earlier, reaction with the
crotonate 1b was efficient and highly selective (entry 1). The
acrylate also underwent cycloaddition in good yield and high
selectivity (entry 2). Enoates with ꢀ-alkyl (entry 3), aryl
(entries 4 and 5), or heteroaryl (entry 6) substituents were
competent substrates in the dipolar cycloadditions. The yields
were good to excellent and the products were obtained as
single regio- and stereoisomers. Reactions with the fumarate
(entry 7) and the ꢀ-p-methoxybenyzloxy substituent (entry
8) also proceeded in good yields and selectivities. These
experiments demonstrate that a variety of dipolarophiles
undergo nitrile ylide cyloadditions in good yield and the
products are formed as single isomers.
After assessing the scope of the acceptor in nitrile ylide
cycloadditions we then examined the effect of the dipole on
efficiency and selectivity (Table 4), using compound 1b as
the acceptor. Nitrile ylides containing different aromatic and
heteroaromatic substituents were examined in the cycload-
dition reaction (entries 1-4). All of these reactions gave good
yields of the cycloadduct and each product was formed as a
single stereoisomer. An imidoyl chloride prepared from
pivalyl aldehyde (2e) was also competent in the cycloaddition
(17) (a) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc.
1988, 110, 1238. (b) Sibi, M. P. Aldrichimica Acta 1999, 32, 93. (c)
Castellino, S. J. Org. Chem. 1990, 55, 5197.
(18) (a) Okamura, H.; Morishige, K.; Iwagawa, T.; Nakatani
M. Tetrahedron Lett. 1998, 39, 1211. (b) Garanti, L.; Molteni, G.; Pilati,
T. Tetrahedron: Asymmetry 2002, 13, 1285. (c) Karlsson, S.; Ho¨gberg, H.-
E. Tetrahedron: Asymmetry 2001, 12, 1975. (d) Karlsson, S.; Han, F.;
Ho¨gberg, H.-E.; Caldirola, P. Tetrahedron: Asymmetry 1999, 10, 2605. (e)
Harrison-Marchand, A.; Collet, S.; Guingant, A.; Prade`rea, J.-P.; Toupet,
L. Tetrahedron 2004, 60, 1827. (f) Krysiak, J.; Kato, T.; Gornitzka, H.;
Baceiredo, A.; Mikolajczyk, M.; Bertrand, G. J. Org. Chem. 2001, 66, 8240.
(19) Other auxiliaries were also investigated. For example, reaction of
crotonate derived from camphor sultam and 2a gave the cycloadduct in
77% yield and 56% de.
(20) Bull, S. D.; Davies, S. G.; Nicholson, R. L.; Sanganee, H. J.; Smith,
A. D. Org. Biomol. Chem. 2003, 1, 2886.
5368
Org. Lett., Vol. 11, No. 23, 2009

enabling us to assign absolute stereochemistry for the
cycloadduct (Figure 2). The dihydropyrrole product had
Table 4. Scope of the Nitrile Ylide in Cycloadditions
entry
nitrile ylide, Ra
product
yield, %b
drc
1
2
3
4
Ph (2a)
3b
3n
3o
3p
3q
3r
87
83
84
84
73
64
g98:2
g98:2
g98:2
g98:2
g98:2
g98:2
4-BrC6H4 (2b)
2-Furyl (2c)
2-Thiophenyl(2d)
t-Bu (2e)
Figure 2. Model for explaining stereochemical outcome in nitrile
ylide cycloaddition to chiral acyl oxazolidinones.
5
6d
Ph (2f)
a For reaction conditions, see Supporting Information. b Yields are for
isolated materials after column chromatography. c Diastereomeric ratios were
determined by both NMR and by hplc following reduction of the acyl
oxazolidinone. The minor isomer was not detected. d Two equivalents of a
phosphazene base (P1-t-Bu) was used for the preparation of the ylide.
the (2R,3S,4S) configuration. The stereochemical outcome
for the reaction is consistent with exo cycloaddition to
an s-cis conformer of the oxazolidinone with the two
carbonyls in an anti orientation (dipole-dipole repulsion).
The high selectivity in the present work can be accounted
for by selective approach of the dipole to the CR-re face
of the dipolarophile, while approach to the CR-si face is
disfavored by steric interactions between the dipole and
the chiral substituent of the auxiliary. It is likely that the
steric size at both ends of the dipole facilitates the high
diastereoselectivity, particularly on the end approaching
the r-carbon of the enoyl group which is nearer the
blocking group of the auxiliary.
(entry 5). The p-nitrobenzyl group is not a requirement for
the preparation of the ylide; upon treatment with a stronger
phosphazene base N-benzyl imidoyl chloride 2f gave the
nitrile ylide, which underwent cycloaddition with good
efficiency and high selectivity (entry 6). These experiments
demonstrate that there is reasonable scope for the nitrile ylide
in diastereoselective cycloadditions.
In the present work the nitrile ylide adds to the
unsaturated acceptor in a highly regioselective manner.
This is consistent with a dominant interaction between
the HOMO of the dipole and the LUMO of the acceptor.21
Furthermore, the cycloaddition to the chiral oxazolidinone
leads to a single stereoisomer. As is evident from Tables
1 and 2, the reaction rates are good even without Lewis
acids, and reactions with the highly reactive nitrile ylides
do not require activation. The formation of the same
stereoisomer in the presence and absence of a Lewis acid
additive (Table 2) suggests that Lewis acids play no role
in the stereochemical outcome of the reaction. We have
obtained an X-ray crystal structure of the product 3r, thus
In conclusion, we have demonstrated for the first time that
nitrile ylide cycloaddition to electron poor acceptors proceeds
in high yield and selectivity. Our work demonstrates that
outstanding stereocontrol is possible with acyl oxazolidinones
in the absence of Lewis acids, a process not commonly
appreciated.
Acknowledgment. We thank the National Science Foun-
dation (NSF-CHE-0709061) for financial support of this
work.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(21) (a) Caramella, P.; Houk, K. N. J. Am. Chem. Soc. 1976, 98, 6397.
(b) Ess, D. H.; Jones, G. O.; Houk, K. N. AdV. Synth. Catal. 2006, 348,
2337.
OL9018584
Org. Lett., Vol. 11, No. 23, 2009
5369