(S)- or (R)-3-(E-enoyl)-4-phenyl-1,3-oxazolidin-2-ones: ideal Michael acceptors to afford a virtually complete control of simple and face diastereoselectivity in addition reactions with glycine derivatives.

Article abstract of DOI:10.1021/ol990402f

[formula: see text] Enantiomerically pure (S)- or (R)-3-(E-enoyl)-4-phenyl-1,3-oxazolidin-2-ones were found to serve as ideal Michael acceptors in addition reactions with achiral Ni(II) complexes of glycine Schiff bases. Virtually complete control of simple and face diastereoselectivity, observed in these reactions, combined with quantitative chemical yields renders this methodology synthetically superior to the previous methods.

Full text of DOI:10.1021/ol990402f

ORGANIC
LETTERS
2
000
Vol. 2, No. 6
47-750
(
S)- or (R)-3-(E-Enoyl)-4-phenyl-1,3-
7
oxazolidin-2-ones: Ideal Michael
Acceptors To Afford a Virtually
Complete Control of Simple and Face
Diastereoselectivity in Addition
Reactions with Glycine Derivatives
,†
,‡
Vadim A. Soloshonok,* Chaozhong Cai, and Victor J. Hruby*
Department of Chemistry, UniVersity of Arizona, Tucson, Arizona 85721
hruby@mail.arizona.edu
Received December 14, 1999
ABSTRACT
Enantiomerically pure (S)- or (R)-3-(E-enoyl)-4-phenyl-1,3-oxazolidin-2-ones were found to serve as ideal Michael acceptors in addition reactions
with achiral Ni(II) complexes of glycine Schiff bases. Virtually complete control of simple and face diastereoselectivity, observed in these
reactions, combined with quantitative chemical yields renders this methodology synthetically superior to the previous methods.
The asymmetric Michael addition is among the most power-
ful reactions in synthetic organic chemistry. In particular,
reactions has been explored. In this approach additions of
various chiral glycine equivalents with R,â-unsaturated
carboxylic acid derivatives were studied and, in some cases,
1
the additions between glycine equivalents and R,â-unsatur-
ated carboxylic acid derivatives, which provide the most
straightforward and generalized approach to â-substituted
glutamic and pyroglutamic acids, glutamines, and prolines,
(3) For leading papers, see: (a) Soloshonok, V. A.; Cai, C.; Hruby, V.
J. Tetrahedron: Asymmetry 1999, 10, 4265. (b) Soloshonok, V. A.; Cai,
C.; Hruby, V. J.; Meervelt, L. V.; Mischenko, N. Tetrahedron 1999, 55,
12031. (c) Soloshonok, V. A.; Cai, C.; Hruby, V. J.; Meervelt, L. V.
Tetrahedron 1999, 55, 12045. (d) Antolini, L.; Forni, A.; Moretti, I.; Prati,
F. Tetrahedron: Asymmetry 1996, 7, 3309. (e) Gestmann, D.; Laurent, A.
J.; Laurent, E. G. J. Fluorine Chem. 1996, 80, 27. (f) Hartzoulakis, B.;
Gani, D. J. Chem. Soc., Perkin Trans. 1 1994, 2525. (g) Suzuki, K.; Seebach,
D. Liebigs Ann. Chem. 1992, 51. (h) Belokon, Yu. N.; Bulychev, A. G.;
Pavlov, V. A.; Fedorova, E. B.; Tsyryapkin, V. A.; Bakhmutov, V. I.;
Belikov, V. M. J. Chem. Soc., Perkin Trans. 1 1988, 2075. (i) El Achqar,
A.; Boumzebra, M.; Roumestant, M.-L.; Viallefont, P. Tetrahedron 1988,
44, 5319. (j) Pettig, D.; Sch o¨ llkopf, U. Synthesis 1988, 173. (k) Sch o¨ llkopf,
U.; Pettig, D.; Schulze, D.; Klinge, M.; Egert, E.; Benecke, B.; Noltemeyer,
M. Angew. Chem., Int. Ed. Engl. 1988, 27, 1194. (l) Fitzi, R.; Seebach, D.
Tetrahedron 1988, 44, 5277. (m) Hartwig, W.; Born, L. J. Org. Chem.
1987, 52, 4352. (n) Minowa, N.; Hirayama, M.; Fukatsu, S. Bull. Chem.
Soc. Jpn. 1987, 60, 1761. (o) Belokon, Yu. N.; Bulychev, A. G.; Ryzhov,
M. G.; Vitt, S. V.; Batsanov, A. S.; Struchkov, Yu. T.; Bakhmutov, V. I.;
Belikov, V. M. J. Chem. Soc., Perkin Trans. 1 1986, 1865. (p) Sch o¨ llkopf,
U.; Pettig, D.; Busse, U. Synthesis 1986, 737.
2
,3
have been extensively studied over the past 15 years.
Analysis of the relevant literature2-4 reveals that thus far only
one strategy to control the stereochemical outcome in these
†
Vadim A. Soloshonok: Department of Chemistry, The University of
Arizona, 1306 East University, Tucson, AZ 85721. Fax: (520) 621-4964.
e-mail: vadym@u.arizona.edu.
‡
Regents Professor Victor J. Hruby: Department of Chemistry, The
University of Arizona, 1306 East University, Tucson, AZ 85721. Fax: (520)
6
21-8407. e-mail: hruby@mail.arizona.edu.
1) (a) Oare, D. A.; Heathcock, C. H. Topics in Stereochemistry; Eliel,
E. L., Wilen, S. H., Eds.; Wiley: New York, 1990; Vol. 19, pp 227-407.
b) Oare, D. A.; Henderson, M. A.; Sanner, M. A.; Heathcock, C. H. J.
Org. Chem. 1990, 55, 132.
2) For reviews, see: (a) Duthaler, R. O. Tetrahedron 1994, 50, 1539.
b) Ohfune, Y. Acc. Chem. Res. 1992, 25, 360. (c) Williams, R. M. Synthesis
of Optically ActiVe R-Amino Acids; Pergamon Press: Oxford, 1989.
(
(
(
(
1
0.1021/ol990402f CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/24/2000

reasonably high levels of asymmetric induction at both the
in our reactions, cannot be considered as a chelating agent,
such a powerful stereocontrolling effect of the 4-phenyl-1,3-
oxazolidin-2-one moiety on the Michael acceptors 2 was
R- and â-positions of the resultant glutamic acid derivatives
2
-4
were obtained.
Surprisingly, the alternative strategy, an
7
application of chiral derivatives of R,â-unsaturated carboxylic
rather surprising. In addition to our interest in the origin of
1
0
acids in the reactions with achiral glycine equivalents,
stereoselectivity in these reactions, the results obtained
offered a pleasant bonus of further improving of synthetic
efficacy of our method by employing achiral Ni(II) com-
plexes in place of chiral (S)-1.
5
remains virtually unexplored so far. We wish to report that
the enantiomerically pure 3-(E-enoyl)-4-phenyl-1,3-oxa-
zolidin-2-ones serve as ideal chiral Michael acceptors to
afford virtually complete control of simple and face diaste-
reoselectivity in the corresponding addition reactions with
Ni(II) complexes of glycine Schiff bases. Extraordinarily high
chemical and optical yields, combined with the extreme
simplicity of the experimental procedure, render this new
strategy synthetically superior over the previously reported
approaches.
Recently we discovered that the Ni(II) complex of the
chiral Schiff base of glycine with (S)-o-[N-(N-benzylprolyl)-
amino]benzophenone 1 and chiral 3-(E-enoyl)-4-phenyl-1,3-
oxazolidin-2-ones 2 (Scheme 1) represent a unique combi-
First we studied the reaction between the Ni(II) complex
of the Schiff base of glycine with o-[N-R-pycolylamino]-
benzophenone 4a, the achiral analogue of (S)-1, and (R)-3-
(E-crotonyl)-4-phenyl-1,3-oxazolidin-2-one (2a) (Scheme 2).
Scheme 2
Scheme 1
The reaction conducted at room temperature in DMF in the
presence of 15 mol % of DBU was completed in 50 min,
giving rise to only one detectable diastereomer, 5, by NMR
(500 MHz) in quantitative chemical yield (Table 1, entry
1
). Despite the excellent diastereoselectivity obtained, the
1
1
reaction rate was unsatisfactory slow, as compared with
the 5 min reaction of chiral (S)-1 with 2a. Therefore, we
6
examined, under the same reaction conditions, the addition
Table 1. Addition Reactions of Ni(II) Complexes 4a,b with
a
(S)- or (R)-3-(E-Enoyl)-4-phenyl-3-oxazolidin-2-ones 2a-h
nation of nucleophilic glycine equivalent and Michael
acceptor, respectively, to afford virtually complete control
of simple and face diastereoselectivity in the corresponding
products 5, 6a -h
b
c
confignd
entry 4a ,b 2a -h
time
yield, % de, %
6
addition reactions. A distinguishing feature of these reac-
1
2
3
4
5
6
7
8
9
a
b
b
b
b
b
b
b
b
b
(R)-a
(R)-a
(S)-a
(R)-b
(R)-c
(R)-d
(R)-e
(R)-f
(S)-g
(S)-h
50 min
20 min
20 min
20 min
20 min
4 he
10 min
10 min
5 min
99
99
99
99
99
15f
98
96
98
99
>98
>94
>94
>94
>94
(2R,3R)-5
(2R,3R)-6a
(2S,3S)-6a
(2R,3R)-6b
(2R,3R)-6c
tions, as compared with the previously reported methods, is
that they proceeded at room temperature in the presence of
catalytic amounts of DBU, giving rise to the sole diastere-
omeric products in quantitative chemical yield. However, a
most unexpected observation was the fact that the stereo-
chemical outcome in these reactions was overwhelmingly
controlled by the chirality of Michael acceptor 2. Thus, the
additions of (S)-1 with (S)-2 gave rise to (S)-(2S,3S)-3 (R )
Alk) while application of (R)-2 furnished (S)-(2R,3R)-3 (R
>99g (2R,3R)-6d
>94
>94
>94
>94
(2R,3S)-6e
(2R,3S)-6f
(2S,3R)-6g
(2S,3R)-6h
10
30 min
a
All reactions were run in DMF in the presence of 15 mol % of DBU
)
Alk) derivatives. The slower reaction rates in the former
b
at ambient temperature. Ratio 4a,b/(S)-or (R)-2 1/1.05-1.1. Isolated yield
c
of crude product. Determined by NMR (500 MHz) analysis of the crude
case were the only noticeable effect of complex (S)-1
chirality on the addition process. Since DBU, used as a base
reaction mixtures. d The absolute configuration of the products was
determined on the basis of chiroptical properties of the Ni complexes 5
and 6a-h, as well as by comparison of the optical rotation of the
corresponding pyroglutamic acids 9 isolated from the corresponding
(
4) Seebach, D.; Hoffman, M. Eur. J. Org. Chem. 1998, 1337.
e
(5) (a) Shibuya, A.; Kurishita, M.; Ago, C.; Taguchi, T. Tetrahedron
complexes with literature data; see also the text. Less then 30% conversion
f
1
996, 52, 271. A correction for the absolute configuration of products
of the starting materials. Isolated yield (column chromatography) of the
diastereomerically pure compound. g Diastereo- and enantiomerically pure
compound isolated by chromatography of the reaction mixture. Since the
reaction was incomplete and accompanied by formation of some byproducts,
the original stereochemical outcome could not be determined using NMR
analysis of the crude reaction mixture. See also text.
reported in the paper was subsequently made: (b) Shibuya, A.; Sato, A.;
Taguchi, T. Bioorg. Med. Chem. Lett. 1998, 8, 1979. (c) Ezquerra, J.;
Pedregal, C.; Merino, I.; Fl o´ rez, J.; Barluenga, J.; Garc ´ı a-Granda, S.; Llorca,
M.-A. J. Org. Chem. 1999, 64, 6554.
(6) Soloshonok, V. A.; Cai, C.; Hruby, V. J. Angew. Chem., Int. Ed., in
press.
748
Org. Lett., Vol. 2, No. 6, 2000

between oxazolidinone (R)-2a and a Ni(II) complex of the
Schiff base of glycine with o-[N-R-pycolylamino]acetophe-
none 4b (Scheme 3). To our satisfaction, the reaction
yield (entry 3). The crude compound (2S,3S)-6a was
decomposed without any purification to afford the corre-
sponding enantiomerically pure pyroglutamic acid (2S,3S)-
9
. Synthesis of (2S,3S)-9 was performed on a 10 g scale,
1
2
demonstrating the preparative efficiency of the method.
Finally, to find out the origin of the observed stereochemical
outcome, we subjected the diastereomerically pure product
Scheme 3
(
5
(
4
2R,3R)-6a to the original reaction conditions, except that
0 mol % of DBU was used. Analysis of the reaction mixture
4 days) revealed some trace amounts of starting complexes
b as well as up to 2% of decomposition products, and
compound (2R,3R)-6a was isolated in 95% chemical yield
and was stereochemically intact. The data obtained allow
us to conclude that the addition reaction under study is
virtually irreversible and the observed stereochemical out-
come is likely kinetically controlled.
With these results in hand we studied next the generality
of the method. Since the acetophenone-derived complex 4b,
designed and introduced for the first time by our group,13
was found to be superior over the benzophenone derivative
occurred at a substantially higher rate (20 min) with the same
perfect stereochemical outcome: the only diastereomeric
product 6a was obtained (entry 2). These results suggest that
the substituent at the ketimine carbon in complexes 4a,b (Ph
or Me, respectively) influences only the reaction rate, while
both simple and face selectivity in the addition reaction are
controlled by the Michael acceptor used. To assign the
absolute stereochemistry of products 5 and 6a, we decom-
posed these complexes to afford pyroglutamic acid 9, along
with a 95-97% recovery of ligand 8, and the chiral auxiliary
4
a, we used the former glycine complex in the rest of the
study. First we investigated the addition reactions between
the Ni(II) complex 4b and (R)-3-(E-enoyl)-4-phenyl-3-
oxazolidin-2-ones 2b-d bearing an alkyl substituent R on
the C,C double bond using the standard reaction conditions:
DMF solution, 15 mol % of DBU, ambient temperature
(Scheme 2). Under these conditions, ethyl- and n-propyl-
containing oxazolidin-2-ones (R)-2b and (R)-2c readily
reacted with complex 4b to afford the corresponding dia-
stereomers (2R,3R)-6b and (2R,3R)-6c, respectively, as major
reaction products in excellent isolated yield (Table 1, entries
10 (Scheme 4). Comparison of the spectroscopic and
4
and 5). NMR (500 MHz) analysis of the crude reaction
mixture revealed that two more diastereoisomers, or byprod-
Scheme 4
(7) Despite the fact that chiral 4-substituted 1,3-oxazolidin-2-ones
represent a group of one of the most studied and useful auxiliaries in organic
8
chemistry, their use in controling the face selectivity of Michael acceptors
in the DBU-catalyzed reactions under study was not straightforward. To
the best of our knowledge, a successful application of chiral oxazolidines
in asymmetric synthesis requires the use of a chelating agent to ensure a
stereocontrolling effect of the substituent at the C-4 stereogenic carbon of
the oxazolidine ring. In particular, N-(E-enoyl)-4-phenyl-1,3-oxazolidin-2-
9
ones (2) exist exclusively in the s-cis conformation with the phenyl on the
oxazolidine ring being pointed away from the C,C double bond to exercise
effective control of the face selectivity of the latter.
(
8) Evans, D. A. Aldrichimica Acta 1982, 15, 23.
(9) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1988,
1
10, 1238.
(10) The corresponding mechanistic studies are currently in progress.
11) The reactions of complex 4a with more sterically demanding Michael
(
acceptors 2, such as N-cinnamyl derivative 2e, containing a phenyl group,
require even longer reaction times and thus were accompanied by formation
of some byproducts.
(12) A solution of diastereomerically pure complex (2S,3S)(S)-6a (15
mmol) in MeOH (50 mL) was slowly added with stirring to a mixture of
aqueous 3 N HCl and MeOH (90 mL, ratio 1/1) at 70 °C. Upon
disappearance of the red color of the starting complex, the reaction mixture
was evaporated in vacuo to dryness. Water (80 mL) was added, and the
resultant mixture was treated with excess concentrated NH4OH and extracted
with CHCl3 (3 × 100 mL). The CHCl3 extracts were dried over MgSO4
and evaporated in vacuo to afford a 1:1 mixture (99%) of ligand 8 and
chiral auxiliary (S)-10. The aqueous solution was evaporated in vacuo,
dissolved in a minimum amount of water, and loaded on cation-exchange
resin Dowex 50 × 2 100. The column was washed with water, and the
acidic fraction was collected to give, after evaporation in vacuo, pyro-
glutamic acid (2S,3S)-9a (96%). An analytically pure sample of the product
was obtained by crystallization of the compound from THF/n-hexane.
chiroptical properties of acid 9 with the literature data
revealed its (2R,3R) absolute configuration. Application of
the (S)-configured 3-(E-crotonyl)-4-phenyl-3-oxazolidin-2-
one (2a) in the addition with complex 4b mirrored the results
obtained in the reaction of (R)-2a, giving rise to only the
diastereomeric product (2S,3S)-6a, in quantitative chemical
(13) Soloshonok, V. A.; Cai, C.; Hruby, V. J. Tetrahedron Lett. 2000,
41(2), 135.
Org. Lett., Vol. 2, No. 6, 2000
749

1
4
ucts, were present in the mixture but in amounts not greater
than 2-3%. In contrast, the addition of complex 4b with
oxazolidin-2-one (R)-2d, containing the bulky isopropyl
group, proceeded at a very slow rate (entry 6). After 4 h of
reaction, conversion of the starting materials was not higher
than 30% and substantial amounts of byproducts were
detected by TLC. Though we isolated the target product 6d
in 15% yield (flash chromatography), these results suggest
that the present method could not be extended to substrates
containing tertiary alkyl R groups.
that for the reaction of the phenyl-containing (R)-2e (entry
7 vs 8), despite the fact that the 2-naphthyl group might be
considered to be more sterically demanding than the phenyl
group. On the other hand, substrate (S)-2g, with enhanced
electrophilicity of the C,C double bond due to the electron-
withdrawing effect of the trifluoromethyl group, reacted
almost instantly with complex 4b, affording the product
diastereomer (2S,3R)-6g in excellent chemical yield and
optical purity (entry 9). In this case the reaction went to
completion even when a 1/1 ratio of the starting compounds
was used. As expected, the addition of the methoxy-
containing derivative (S)-2h with complex 4b occurred at a
substantially lower reaction rate but with the same syntheti-
cally excellent stereochemical outcome (entry 10). These data
clearly suggest that the pattern of the substitution (steric or
electronic) on the phenyl ring in Michael acceptors 2e-h
influences only the rate of the addition and does not affect
the stereochemical outcome of the reaction. As one can see
from Table 1, in all cases studied, the major diastereomers
(2R,3S)-6e,f or (2S,3R)-6g,h were obtained in excellent
chemical yields and in, at least, 94% diastereomeric excess
(entries 7-10).
In summary, we have demonstrated that the new strategy
for controlling the stereochemical outcome of the asymmetric
Michael addition reactions developed in this work is
methodologically superior to the previous methods, most
notably in terms of generality and synthetic efficiency.
Excellent chemical yields and diastereoselectivity, combined
with the simplicity of the experimental procedures, render
the present method of immediate use for preparing various
3-substituted pyroglutamic acids and related amino acids
available via conventional transformations of the former. The
full scope of the method and mechanism of these Michael
addition reactions are currently under study.
To examine the applicability of the method to aromatic
series, which would lead to the synthesis of the corresponding
-aryl-substituted amino acids, we chose substrates contain-
ing classical phenyl and naphthyl groups 2e and 2f, as well
as derivatives bearing a phenyl ring with electron-withdraw-
ing and electron-donating 2g and 2h substituents. The
addition of Ni(II) complex 4b with N-cinnamyl derivative
3
(
R)-2e (entry 7) occurred at a high reaction rate, similar to
the rates observed in the aliphatic series (entries 2-5), giving
rise to the corresponding product 6e in excellent chemical
yield and diastereomeric purity. Analysis of the crude
reaction mixture (NMR) showed that the content of the major
diastereomer 6e was at least 97%, while three other theoreti-
1
4
cally possible diastereomeric products and/or byproducts
were formed in an amount not greater than 3%. To determine
the absolute configuration of product 6e, it was decomposed
using our standard procedure to afford the corresponding
pyroglutamic acid 9e which gave spectral and chiroptical
properties consistent with its (2R,3S) absolute stereochem-
1
5
istry. These data allowed us to conclude that in both the
aliphatic and aromatic series the sense of stereochemical
preferences is the same, giving rise almost exclusively to
the products (with combination of the trigonal centers) with
relative topicity like.17
The addition of complex 4b with 2-naphthyl derivative
R)-2f (entry 8) occurred unexpectedly at the same rate as
Acknowledgment. The work was supported by the grants
from U.S. Public Health Service and the National Institute
of Drug Abuse (DA 06284, DA 04248, and DK 17420). The
views expressed are those of the authors and not necessarily
those of the USPHS.
(
(14) Due to the minute integral intensity of some peaks found in the
NMR spectra of the crude reaction mixtures, it was impossible to conclude
whether they belong to another diastereoisomers or to byproducts.
(15) The (2R,3S) absolute stereochemistry for the aromatic derivatives
is a consequence of the Cahn-Ingold-Prelog priorities (see ref 16) and is
stereochemically equivalent to the (2R,3R) absolute configuration in the
aliphatic series of compounds.
Supporting Information Available: Experimental pro-
cedures and characterization of the compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(
16) Cahn, R. S.; Ingold, C.; Prelog, V. Angew. Chem., Int. Ed. Engl.
966, 5, 385.
17) Seebach, D.; Prelog, V. Angew. Chem., Int. Ed. Engl. 1982, 21,
54.
1
(
6
OL990402F
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Org. Lett., Vol. 2, No. 6, 2000