Enantioselective conjugate addition of hydroxylamines to pyrazolidinone acrylamides

Article abstract of DOI:10.1021/ol016807t

(Matrix Presented) Chiral relay templates provide amplification of selectivity in conjugate addition reactions. Reversal of stereochemistry of the product isoxazolidinones has also been demonstrated by a simple change of the Lewis acid.

Full text of DOI:10.1021/ol016807t

ORGANIC
LETTERS
2001
Vol. 3, No. 26
4181-4184
Enantioselective Conjugate Addition of
Hydroxylamines to Pyrazolidinone
Acrylamides
Mukund P. Sibi* and Mei Liu
Department of Chemistry, North Dakota State UniVersity, Fargo, North Dakota 58015
Mukund.Sibi@ndsu.nodak.edu
Received September 24, 2001
ABSTRACT
Chiral relay templates provide amplification of selectivity in conjugate addition reactions. Reversal of stereochemistry of the product
isoxazolidinones has also been demonstrated by a simple change of the Lewis acid.
Chiral Lewis acid catalysis has become one of the most
attractive and efficient methods for the synthesis of enan-
tiomerically pure compounds.1 Until now, much attention
has been focused on the design of complex ligands or chiral
auxiliaries that are often necessary for obtaining high
selectivities. We have developed a novel protocol termed
“chiral relay”2,3 in which functional groups in the achiral
templates play a crucial role in enantioselective transforma-
tions. An application of this concept was recently illustrated
in enantioselective Diels-Alder reactions.4 We present here
an extension of the chiral relay methodology to enantiose-
lective conjugate amine additions.5
We have recently shown that conjugate addition of
N-benzylhydroxylamine to enoates is a convenient enanti-
oselective method for the synthesis of â-amino acid deriva-
tives.6 To investigate whether our newly developed chiral
relay strategy is applicable in other enantioselective trans-
formations, we have examined the addition of N-benzylhy-
droxylamine to crotonates. The formation of the same
(4) Sibi, M. P.; Venkatraman, L.; Liu, M.; Jasperse, C. P. J. Am. Chem.
Soc 2001, 123, 8444.
(5) For a review see: Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56,
8033. For other reviews in the area, see: Krause, N.; Hoffmann-Ro¨der, A.
Synthesis 2001, 171. Tomioka, K. In Modern Carbonyl Chemistry, Otera,
J., Ed.; Wiley-VCH: Weinheim, 2000; pp 491. Leonard, J.; Diez-Barra,
E.; Merino, S. Eur. J. Org. Chem. 1998, 2051.
(6) For work from our laboratory, see (a) Sibi, M. P.; Shay, J. J.; Liu,
M.; Jasperse, C. P. J. Am. Chem. Soc. 1998, 120, 6615. (b) Sibi, M. P.;
Liu, M. Org. Lett. 2000, 2, 3393. For work from other laboratories see:
(c) Baldwin, S. W.; Aube´, J. Tetrahedron Lett. 1987, 28, 179. (d) Ishikawa,
T.; Nagai, K.; Kudoh, T.; Saito, S. Synlett 1998, 1291. (e) Ishikawa, T.;
Nagai, K.; Senzaki, M.; Tatsukawa, A.; Saito, S. Tetrahedron 1998, 54,
2433. (f) Baldwin, J. E.; Harwood: L. M.; Lombard, M. J. Tetrahedron
1984, 40, 4363. (g) Stamm, H.; Steudle, H. Tetrahedron Lett. 1976, 3607.
(h) Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T. Tetrahedron:
Asymmetry 1998, 9, 3945. (i) Keen, S. P.; Weinreb, S. M. Tetrahedron
Lett. 2000, 41, 4307. (j) Socha, D.; Jurczak, M.; Chmielewski, M.
Tetrahedron 1997, 53, 739. (k) Niu, D.; Zhao, K. J. Am. Chem. Soc. 1999,
121, 2456.
(1) (a) Catalytic Asymmetric Synthesis, Ojima, I. Ed.; Wiley-VCH: New
York; 2000. (b) ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: New York; 1999.
(2) For examples of chiral relay in diastereoselective transformations,
see: (a) Bull, S. D.; Davies, S. G.; Fox, D. J.; Garner, A. C.; Sellers, T. G.
R. Pure Appl. Chem. 1998, 70, 1501. (b) Bull, S. D.; Davies, S. G.; Epstein,
S. W.; Ouzman, J. V. A. J. Chem. Soc. Chem. Commun. 1998, 659. (c)
Bull, S. D.; Davies, S. G.; Epstein, S. W.; Leech, M. A.; Ouzman, J. V. A.
J. Chem. Soc., Perkin Trans. 1 1998, 2321.
(3) Examples of chiral relay in enantioselective transformations: (a)
Watanabe, Y.; Mase, N.; Furue, R.; Toru, T. Tetrahedron Lett. 2001, 42,
2981. (b) Davis, T. J.; Balsells, J.; Carroll, P. J.; Walsh, P. J. Org. Lett.
2001, 3, 2161. (c) Balsells, J.; Walsh, P. J. J. Am. Chem. Soc. 2000, 122,
1802. (d) Evans, D. A.; Campos, K. R.; Tedrow, J. S.; Michael. F. E.; Gagne´,
M. R. J. Am. Chem. Soc. 2000, 122, 7905. (e) Hiroi, K.; Ishii, M.
Tetrahedron Lett. 2000, 41, 7071. (f) Quaranta, L.; Ph. D thesis, University
of Fribourg, Switzerland, 2000. (g) Quaranta, L.; Renaud, P. Chimia 1999,
53, 364. (h) Wada, E.; Pei, W.; Kanemasa, S. Chem. Lett. 1994, 2345. (i)
Wada, E.; Yasuoka, H.; Kanemasa, S. Chem. Lett. 1994, 1637.
10.1021/ol016807t CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/04/2001

isoxazolidinone irrespective of different achiral templates
would simplify product analysis. At the onset, we had two
goals in mind: (1) the use of a simple, readily available chiral
ligand which only minimally controls the chiral environment
such that the relay group affects on selectivity and (2)
optimization of the conjugate additions at practical temper-
atures (-25 °C and higher). Results from these studies are
presented here.
Two different types of pyrazolidinones were selected as
relay templates for evaluation in conjugate addition reactions.
One series of templates contained gem-dimethyl substitution7
at C-5 with variation of the relay Z group (R1 ) Me, see
structure 1, Figure 1). The second template contained a large
Table 1. Effect of Ligand and Lewis Acid on
Enantioselectivitya,b
yield (%), ee (%)
Mg(ClO4)2 Zn(OTf)2
10 (S) 70 (S)
entry
ligand
1
2
3
4
5a
5b
5c
5d
71
73
71
69
80
84
80
73
4 (S)
14 (S)
1 (-)
50 (S)
41 (S)
17 (S)
a For reaction details see Supporting Information. Ee’s were determined
using chiral HPLC. bThe configuration of 6 was established by converting
it to known 3-aminobutyric acid comparing the sign of rotation of the
product acid with that reported in the literature.
acid irrespective of the nature of the ligand (entries 1-4).
This may suggest that the chiral ligand and the N(1)-benzyl
group are shielding opposite faces of the double bond. In
contrast, higher levels of enantioselectivities were achieved
when zinc triflate was used in conjunction with the same
box-ligands. The chemical efficiency was good in all cases.
Another trend is noteworthy. The C-4 isopropyl substituent
of bisoxazoline 5a is relatively small and often provides poor
face shielding.8 We were delighted to see that much higher
selectivity was obtained using the same ligand with the relay
substrate, indicating that there is chiral amplification (entry
1). The absolute stereochemistry for the conjugate addition
product 6 was determined by converting it to a known
compound.9 The large difference in selectivity in reactions
with the two different Lewis acids may indicate that geometry
around the metal affects whether there is consonance or
dissonance between the relay group and the substituent in
the chiral ligand.
In our previous work, the bisoxazoline derived from amino
indanol 7 in combination with Mg Lewis acids provided high
selectivity in conjugate amine additions.6a,b In light of this
result, we undertook a more detailed study on the effect of
different relay substituents and chiral Lewis acids on
selectivity in the conjugate additions (Scheme 2). Two
catalysts: magnesium perchlorate with ligand 7 (catalyst A)
and zinc triflate with ligand 5a (catalyst B) were tested, and
these results are tabulated in Table 2. For the series of
substrates with C(5) gem-dimethyls, as size of the relay group
Figure 1.
diphenylmethyl relay group but lacks C-5 substitution (R1
) H; Z ) CHPh2, structure 1, Figure 1). The templates had
the following characteristics: (1) ready availability, (2) easy
attachment and detachment, (3) easy variation of the relay
group Z, (4) carbonyl group as a donor site for Lewis acid
coordination.
The conjugate amine addition to the N-benzyl-substituted
relay template 4c was assessed first (Scheme 1 and Table
Scheme 1
Table 2. Effect of Relay Substituents on Enantioselectivitya
catalyst A
yieldb eec yieldb ee
(%) (%)
(%) (%)c
75 76 (R)11 74 28 (S)
catalyst B
1). Chiral Lewis acids derived from simple and readily
available bisoxazolines in combination with Mg(ClO4)2 and
Zn(OTf)2 were evaluated by conducting the reactions at 0
°C and using a catalyst loading of 30 mol %. These results
are tabulated in Table 1. Conjugate additions were not
selective when magnesium perchlorate was used as the Lewis
entry
substrate
1
2
3
4
5
6
4a R1 ) Me, R ) H
4b R1 ) Me, R ) ethyl
4c R1 ) Me, R ) benzyl
70 52 (R)
67 78 (R)
74 49 (S)
71 68 (S)
73 70 (S)
75 75 (S)
72 57 (S)
4d R1 ) Me, R ) 2-CH2naphthyl 75 78 (R)
4e R1 ) Me, R ) 1-CH2naphthyl 77 81 (R)
(7) gem-Dialkyl substitution has been effectively used to control rotamers
in the design of chiral auxiliaries. For relevant contributions, see: Onimura,
K.; Kanemasa, S. Tetrahedron 1992, 48, 8631. (a) Bull, S. D.; Davies, S.
G.; Hones, S.; Sanganee, H. J. J. Chem. Soc., Perkin Trans. 1 1999, 387.
(b) Bull, S. D.; Davies, S. G.; Key, M.-S.; Nicholson, R. L.; Savory, E. D.
Chem. Commun. 2000, 1721.
4f R1 ) H, R ) CH(Ph)2
71 84 (R)
a All reactions were carried out at 0 °C and using 30 mol % of the chiral
Lewis acid. Isolated yields. Ee’s were determined using chiral HPLC.
b
c
4182
Org. Lett., Vol. 3, No. 26, 2001

Scheme 2
increases (from H to 1-naphthylmethyl), so does the enan-
performed with the 1-naphthylmethyl template 4e. We were
able to obtain both enantiomers of the product with high
selectivities, 96% and 83%, respectively, when using mag-
nesium or zinc Lewis acid and at moderate temperature (-25
°C). In addition, substrate 4e is less reactive than 4f but often
more selective.
tioselectivity in reactions with either of the two catalyst
systems (entries 1-5). This is consistent with our proposed
chiral relay model operating to amplify the stereochemical
information from the chiral ligand to the reaction center. The
use of bulky 1-naphthylmethyl as the relay group gave the
highest selectivity of 81% ee (R) using catalyst A (entry 5).
In contrast, reactions with 4e using catalyst B gave the
enantiomeric (S) product in 75% ee. It is important to note
that ligand 5a and 7 have the same configuration at C-4.
Thus a simple change in the Lewis acid reVerses the
enantioselectiVity, allowing either (R) or (S) enantiomers to
be formed with similarly high selectiVities.10
Figure 2 summarizes the results of p-methoxybenzylhy-
The effectiveness of template 4f with a bulky diphenyl-
methyl substituent at the N(1) position but without C(5) gem-
dimethyl groups was also explored. This template was found
to be the most selective (84% R, entry 6, Table 2) when
catalyst A was used and only moderately selective in the
catalyst B mediated reaction (57%, S).
Figure 2.
The effect of temperature on conjugate addition using the
two best relay templates was examined next. When magne-
sium perchlorate in conjunction with ligand 7 was used as
the chiral Lewis acid (CLA), the complex formed between
the CLA and substrate 4f was relatively stable even at
elevated temperatures. Good selectivity was obtained when
reaction was carried out at room temperature (entry 1, Table
3). Decreasing the reaction temperature, further increased
the ee to as high as 96% at -60 °C (entry 4, Table 3). On
the other hand, enantioselectivities of zinc and i-Pr-box (5a)
catalyzed reactions were not temperature dependent; moder-
ate ee’s were observed at all temperatures but with reversal
of product configuration. Similar temperature study was also
droxylamine conjugate additions to different templates:
pyrrolidinone 8 (nonrelay template) and two pyrazolidinone
relay templates 4e,f. Significant enantioselectivity enhance-
ment was observed with the relay templates over pyrrolidi-
none (nonrelay template) at different reaction temperatures
and using different catalyst. In addition, a reversal of
stereochemistry was obtained when magnesium or zinc Lewis
acid was employed. Control experiments with nonrelay
template 8 clearly indicate the advantages of using the readily
prepared relay templates in enantioselective transformations.
These results exemplify the use of achiral templates to relay
Table 3. Effect of Temperature on Enantioselectivitya
a 30 mol % of the chiral Lewis acid was used in all reactions. Ee’s were determined using chiral HPLC. b Reaction at -40 °C for 22 h.
Org. Lett., Vol. 3, No. 26, 2001
4183

Scheme 3
Table 4. Conjugate Additions to Cinnamates
a Isolated yields. 30 mol % of the Lewis acid was used. bEe’s determined
by HPLC analysis.
and amplify the chiral information from chiral Lewis acid
to the reaction center.
Taking advantage of the practical aspects (high selectivity
and moderate temperature) of the relay strategy, we then
explored the conjugate addition reactions to cinnamates
(Scheme 3). Once again, ee’s with all relay substrates are
considerably higher than the low selectivity obtained with
the nonrelay substrate pyrrolidinone cinnamate 11 (Table 4).
Substrate 4f gave the highest selectivity: 88% ee at 0 °C,
this is comparable with the selectivity obtained with the
nonrelay substrate 11 at much lower temperature.6b
At the present time we do not have definitive stereochem-
ical models for the sense of stereoinduction observed in the
conjugate addition experiments. The formation of enantio-
meric products using catalyst A and B suggests different
geometries around the metal.12,13
In conclusion, we have demonstrated the use of a novel
class of achiral templates, pyrazolidinones, to perform chiral
relay in enantioselective conjugate amine additions. Both
enantiomers of the product may be obtained in high enan-
tiomeric purity at moderate reaction temperatures. Experi-
ments to determine the crystal structure of these templates
and a better understanding of the architecture of the ligand-
metal-substrate complex are underway.
Acknowledgment. This work was supported in part by
a grant from the National Science Foundation (CHE-
9983680). Mei Liu thanks ND-EPSCoR for a doctoral
dissertation fellowship.
Supporting Information Available: Characterization
data for compounds 1-10 and experimental procedures. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(8) Only 29% ee was obtained with pyrrolidinone crotonate (nonrelay
substrate) in i-Pr-box ligand catalyzed conjugate addition of p-methoxy-
benzyl hydroxylamine.
(9) Amoroso, R.; Cardillo, G.; Sabatino, P.; Tomasini, C.; Trere, A. J.
Org. Chem. 1993, 58, 5615.
(10) For a review on reversal of stereochemistry, see: Sibi, M. P.; Liu,
M. Curr. Org. Chem. 2001, 5, 719. (a) Evans, D. A.; Johnson, J. S.; Burgey,
C. S.; Campos, K. R. Tetrahedron Lett. 1999, 40, 2879. (b) Sibi, P.; Ji, J.;
Wu, J. H.; Gu¨rtler, S.; Porter, N. A. J. Am. Chem. Soc. 1996, 118, 9200.
(11) Reasons for the high selectivity in this case are not clear at the
present time. It may reflect a different chelation with N(1) nitrogen and the
Lewis acid.
(12) Penta- and hexacoordinated zinc complexes are well-known and
used for understanding reaction mechanisms of zinc enzymes: (a) Bock,
C. W.; Katz, A. K.; Glusker, J. P. J. Am. Chem. Soc. 1995, 117, 3754. (b)
Bhattacharya, S.; Kumar, S. B.; Dutta, S. K.; Tiekink, E. T. T.; Chaudhury.
M. Inorg. Chem. 1996, 35, 1967.
OL016807T
(13) For issues related to metal geometry in chiral Lewis acid catalysis,
see: (a) ref 10. (b) Sibi, M. P.; Shay, J. J.; Ji, J. Tetrahedron Lett. 1997,
38, 5955. (c) Porter, N. A.; Feng, H.; Kavrakova, I. K. Tetrahedron Lett.
1999, 40, 6713. (d) Murakata, M.; Tsutsui, H.; Hoshino, O. Org. Lett. 2001,
3, 299. (e) Evans, D. A.; Kozlowski, M. C.; Tedrow, J. S. Tetrahedron
Lett. 1996, 37, 7481. (f) Yao, S.; Johannsen, M.; Jorgensen, K. A. J. Chem.
Soc., Perkin Trans. 1 1997, 2345.
4184
Org. Lett., Vol. 3, No. 26, 2001