2-tert-butyl-3-methyl-2,3-dihydroimidazol-4-one-N-oxide: A new nitrone-based chiral glycine equivalent

Article abstract of DOI:10.1021/ol049505a

Cycloaddition reactions between a new homochiral imidazolone-derived nitrone afford cycloadducts in high yield and with high stereoselectivity. Subsequent cycloadduct elaboration affords the γ-lactones of γ-hydroxy-α-amino acids as well as the optically pure amino acids themselves.

Full text of DOI:10.1021/ol049505a

ORGANIC
LETTERS
2004
Vol. 6, No. 10
1653-1656
2-tert-Butyl-3-methyl-2,3-dihydroimidazol-
4-one-N-oxide: A New Nitrone-Based
Chiral Glycine Equivalent
Steven W. Baldwin* and Alan Long
Paul M. Gross Chemical Laboratory, Duke UniVersity,
Durham, North Carolina 27708-0346
steVen.baldwin@duke.edu
Received March 16, 2004
ABSTRACT
Cycloaddition reactions between a new homochiral imidazolone-derived nitrone afford cycloadducts in high yield and with high stereoselectivity.
Subsequent cycloadduct elaboration affords the γ-lactones of γ-hydroxy-r-amino acids as well as the optically pure amino acids themselves.
The known number of naturally occurring R-amino acids has
increased dramatically from the twenty (or twenty-one) that
make up most proteins to well over 700 at this time.1 The
nonproteinaceous amino acids are those amino acids that are
not found in protein main chains, either for lack of a specific
transfer RNA and codon triplet, or because they do not arise
from protein amino acids by posttranslational modification.
Many of these compounds are the end products of secondary
metabolism. Their origins are as diverse as their functions,
although for most, only little is known on both accounts.
Many others arise as intermediates of metabolic pathways
or originate from the metabolism or detoxification of foreign
compounds.
These compounds are of diverse structural type, often
bearing unusual side chains that display varying degrees of
hydroxylation and unsaturation. Many of these amino acids
have important biological roles, being found in such impor-
tant materials as cyclosporins and mushroom toxins, among
others. Others,2 such as those containing â,γ- or γ,δ-unsatu-
ration,3 profoundly perturb the biological properties of certain
natural amino acids, converting them from enzyme substrates
to irreversible inhibitors with potential therapeutic activity.
While considering possible routes to R-amino acids bearing
unusual side chains, we were attracted to the possibility of
using a glycine-derived nitrone such as 1 in 1,3-dipolar
cycloaddition reaction with alkenes. If successful, the isoxa-
zolidine products 2 would possess the necessary structural
features to permit the preparation of amino acids bearing a
hydroxyl group at the γ-position, i.e., 3. Depending on the
particular amino acid target, the hydroxyl group would either
be left intact or suitably manipulated to yield alternative func-
tionality such as side chain unsaturation. In the case of isoxa-
zolidines derived from styrene derivatives, the final result
could also be amino acids with no side chain oxygenation.
(1) (a) Ogura, K.; Inaba, T. J. Synth. Org. Chem. 1991, 49, 575-583.
(b) Hunt, S. In Chemistry and Biochemistry of the Amino Acids; Barrett,
G. C., Ed.; Chapman and Hall: New York, 1985; pp 55-139. (c) Wagner,
I.; Musso H. Angew. Chem., Int. Ed. Engl. 1983, 22, 816-828.
(2) Ottenheijm, H. C. J.; Herscheid, J. D. M Chem. ReV. 1986, 86, 697-
707.
(3) Williams, R. M.; Zhai, W. Tetrahedron 1988, 44, 5431-5440, and
refs 1-4 therein.
10.1021/ol049505a CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/16/2004

Consideration of several features of nitrones and their
cycloaddition reactions leads to the conclusion that the above
reaction would be best conducted using a nitrone that was
constrained within a ring.4 To this end we have previously
reported the preparation and reactions of two chiral oxazi-
none-derived nitrones, 4a and 4b.5 Tamura and co-workers
have independently reported some related chemistry of
nitrone 4a.6 In addition, a homochiral lactone-derived five-
membered ring acyl nitrone based on menthone has been
reported by Katagiri, 5a,7 while a lactam-centered homochiral
acyl nitrone derived from menthone has also been reported,
5b.8
We describe here the preparation and evaluation of a new
chiral five-membered ring nitrone as a chiral glycine
equivalent. As indicated in the following discussion, nitrone
7 is a versatile cycloaddition partner with a wide range of
alkenes. Furthermore, the isoxazolidine cycloadducts derived
from 7 can be converted to useful products by several
hydrogenolytic techniques.
Nitrone 7 is conveniently prepared from Seebach’s tert-
butyl-substituted imidazolidinone 69 by direct oxidation with
one of several different reagents. In our hands the most
successful oxidation method employs catalytic methyltrioxo-
rhenium (MTO) in the presence of a urea/hydrogen peroxide
(UHP) complex.10 In a typical experiment, nitrone 7 (S
configuration) was obtained from (R)-6 in 80% purified yield
as a white crystalline solid, mp 89-90 °C, [R]D ) +224° (c
1.04, CHCl3). Diagnostic 1H and 13C NMR resonances for 7
include a singlet for the imine proton at δ ) 7.06 and a
signal for the imine carbon at δ ) 94.9, respectively. Nitrone
7 prepared in this manner can be refrigerated and used as
needed. Because both enantiomers of 6 are available from
the same resolution procedure, both enantiomers of nitrone
7 are also readily available.11
Scheme 1
CHCl3, it was found that passing 7 through a silica gel
column, eluting with ethyl acetate/petroleum ether, led to
its complete racemization. One possible explanation for this
observation involves the intermediacy of an acyl iminium
species such as 8 followed by recyclization.
Nitrone 7 undergoes ready cycloaddition reactions with a
wide range of alkenes. The reactions, which are somewhat
slower than the corresponding reactions with nitrone 4, occur
with the normal regiochemical outcome expected for cy-
cloadditions of this kind. In all cases studied, the stereo-
chemical outcome of the cycloaddition reaction is the result
of reaction from the less hindered R-face of nitrone 7 and
places the isoxazolidine 5-alkyl/aryl substituent of the major
stereoisomer in the exo position as indicated for the reaction
of 7 with styrene (9a) (Scheme 2).12 Stereochemical ratios
Scheme 2
Although optically pure nitrone 7 could be recovered
essentially unchanged after heating for 12 h at reflux in
(exo/endo) ranged from 5:1 to >20:1. Table 1 shows the
results of the cycloaddition of nitrone 7 with five different
alkenes, 9a-e. In all cases, the yields of the crude products
were excellent. For cycloadducts 10b-e the major isomer
was isolated in pure form after simple crystallization or flash
chromatography.13
The conversion of cycloadducts 10a-e to the correspond-
ing γ-hydroxy-R-amino acids, isolated either as their γ-lac-
tones or the free amino acids, involves initial N-O bond
hydrogenolysis followed by imidazolidinone hydrolysis. For
the two styrene-derived cycloadducts 10a and 10b, N-O
bond cleavage was accomplished using Zn/HOAc/Ac2O
(Scheme 3). This reductive method avoids unwanted hydro-
genolysis of the benzylic oxygen. The derived diacetates 11a
and 11b were then converted to the free amino alcohols 12a
and 12b by reaction with MeOH/K2CO3 (Method A).
The other three non-aryl-derived cycloadducts 10c-e were
converted to the free amino alcohols 12c-e directly under
(4) For a recent review of nitrones and their cycloaddition reactions,
see: Jones, R. C. F.; Martin, J. N. In Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry toward Heterocycles and Natural Products; Padwa,
A., Pearson, W. H., Eds.; John Wiley: New York, 2002; 59, 1, pp 1-81.
(5) (a) Long, A.; Baldwin, S. W. Tetrahedron Lett. 2001, 42, 5343-
5346. (b) Baldwin, S. W.; Young, B. G.; McPhail, A. T. Tetrahedron Lett.
1998, 39, 6819-6822.
(6) (a) Tamura, O.; Gotanda, K.; Terashima, R.; Kikuchi, M.; Miyawaki,
T.; Sakamoto, M. Chem. Commun. 1996, 1861-1862. (b) Tamura, O.;
Kuroki, T.; Sakai, Y.; Takizawa, J.; Yoshino, J.; Morita, Y.; Mita, N.;
Gotanda, K.; Sakamoto, M. Tetrahedron Lett. 1999, 40, 895-898. (c)
Tamura, O.; Gotanda, K.; Yoshino, J.; Morita, Y.; Terashima, R.; Mayumi,
K.; Miyawaki, T.; Mita, N.; Yamashita, M.; Ishibashi, H.; Sakamoto, M. J.
Org. Chem. 2000, 65, 8544-8551,
(7) (a) Katagiri, N.; Sato, H.; Kurimoto, A.; Okada, M.; Yamada, A.;
Kaneko, C. J. Org. Chem. 1994, 59, 8101-8106. (b) Katagiri, N.; Okada,
M.; Kaneko, C.; Furuya, T. Tetrahedron Lett. 1996, 37, 1801-1804. (c)
Katagiri, N.; Sato, H.; Okada, M.; Morishita, Y.; Kaneko, C. Chem.
Commun. 1996, 2137-2138. (d) Katagiri, N.; Sato, H.; Okada, M.;
Morishita, Y.; Kaneko, C. Tetrahedron 1997, 53, 5727-5746.
(8) (a) Westermann, B.; Walter, A.; Flo¨rke, U.; Altenbach, H.-J. Org.
Lett. 2001, 3, 1375-1378. (b) Vogt, A.; Altenbach, H.-J.; Hahn, M.-G.;
Matthaus, M. S. P.; Hermann, A. R. U.S. Patent No. 6,121,487 (issued
Sept 19, 2000).
(9) (a) Naef, R.; Seebach, D. HelV. Chim. Acta 1985, 68, 135-143. (b)
Polt, R.; Seebach, D. J. Am. Chem. Soc. 1989, 111, 2622-2632. (c) Fitzi,
R.; Seebach, D. Tetrahedron 1988, 44, 5277-5292.
(10) (a) Goti, A.; Nanelli, L. Tetrahedron Lett. 1996, 37, 6025-6028.
(b) Murray, R.; Iyanar, K. J. Org. Chem. 1996, 61, 8099-8102.
(11) Specific rotation of (R)-7 similarly prepared from (S)-6 was [R]D
) -221° (c 0.520, CHCl3).
(12) In one experiment, careful chromatography of the crude product
from the reaction of 7 with styrene afforded a minor amount (1.4%) of a
third isomer that apparently had arisen from reaction syn to the tert-butyl
group. This conclusion was reached on the basis of an 8.4% NOE
enhancement between the aminal and R-protons in the NMR spectrum.
(13) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923-
2925.
1654
Org. Lett., Vol. 6, No. 10, 2004

Table 1. Isoxazolidine Derivatives 10a-e Obtained from the
1,3-Dipolar Cycloaddition of 7 to Alkenes 9a-e
Table 2. γ-Hydroxy-R-amino Acids and Lactones Derived
from Cycloadducts 10a-e
a Reactions were performed with 2-10 equiv alkene in ClCH2CH2Cl at
reflux for 5-52 h. The structure of the major isomer is shown. b Total yield
of exo and endo isomers (purified major isomer). c Exo refers to 5-alkyl or
aryl substituent; determined by integration of 1H NMR spectra of unpurified
reaction mixture. d Major isomer not isolated in pure form.
a Method A: (1) Zn/HOAc/Ac2O; (2) K2CO3/MeOH; (3) 6 N HCl, reflux.
Method B: (1) Pd/C, ammonium formate/MeOH; (2) 6 N HCl, reflux.
b Amino alcohol, lactone. c After basic hydrolysis, neutralization, ion
exchange chromatography, and lyophilization. d Reference 15. e Reference
20. f Extensive decomposition during hydrolysis step.
no significant problem. If pure lactone (free of MeNH3Cl)
was required, it could be obtained after recrystallization. For
instance, recrystallization of lactone 13e from methanol af-
forded the pure lactone hydrochloride, mp 240-242 °C. Op-
tically active lactone 13a has been previously prepared by
Hegedus.15 Melting point, NMR spectra (1H and 13C), and
specific rotation are in accord with those previously reported.
It is worth noting that lactone 13e, obtained in optically
pure form in three steps from methyl crotonate in 78.5%
overall yield, contains all of the connectivity and stereo-
chemical information found in important â-lactam antibiotics
such as thienomycin (Scheme 4). In fact, lactone 13e, as its
methyl ester acetamide 15, has been previously used as an
intermediate for the synthesis of â-lactam 16. In our hands,
when 15 was prepared from 13e (MeOH/H+, then AcCl/
Et3N), the physical properties of the material obtained were
in complete accord with those reported previously.16
Scheme 3
transfer hydrogenolysis conditions using ammonium formate
in the presence of palladium (Method B).14 As shown in
Table 2, the yields of purified products for the N-O cleavage
process ranged from 68 to 97%. Treatment of the amino
alcohols 12a-e with aqueous 6 N HCl then afforded the
amino γ-lactone hydrochloride salts 13a-e in excellent yield.
Scheme 3 illustrates the conversion of 10a to lactone 13a.
The lactones prepared by these processes were admixed
with 1 equiv of MeNH3Cl, which for most purposes posed
Lactones 13a-d, were either admixed with MeNH3Cl or,
after purification, conveniently converted to the ring-opened
(15) Hegedus, L.; Schmeck, C. J. Am. Chem. Soc. 1994, 116, 9927-
9934.
(14) Johnstone, R. A. W.; Wilby, A. H. Chem. ReV. 1985, 85, 129-
170.
(16) Ohtake, H.; Imada, Y.; Murahashi, S. I. J. Org. Chem. 1999, 64,
3790-3791, and references therein.
Org. Lett., Vol. 6, No. 10, 2004
1655

by Bolte have clarified some earlier confusion associated
with various spectral data.20 Spectral information and the
specific rotation for 14d prepared by the method described
herein (four steps, 72.1% yield) are in complete accord with
that for the authentic material. Data for amino acid 13a have
also been previously reported15 and are in complete accord
with that determined in the context of this study.
Scheme 4
In conclusion, nitrone 7 has been shown to be a versatile
1,3-dipole. The cycloaddition reactions are regiochemically
regular and proceed with high stereoselectivity. The isoxa-
zolidine cycloadducts can be readily transformed into
R-amino-γ-lactones, which are then easily transformed into
γ-hydroxy-R-amino acids. Further applications of this ef-
ficient methodology to other products of biological interest
are currently in progress.
γ-hydroxy-R-amino acids by careful base hydrolysis followed
by ion exchange chromatography on DOWEX 50W-X8 and
lyophilization (Table 2). A similar hydrolysis of lactone 13e,
in an attempt to prepare the open chain amino acid, afforded
considerable decomposition of starting material. Given the
particular arrangement of functional groups in 13e, this result
is not altogether surprising.
Acknowledgment. We acknowledge NSF (CHE 95
22580) for assistance in the purchase of the 400 MHz NMR
instrument used in this work. A.L. thanks the Burroughs
Wellcome Foundation for a graduate fellowship. Partial
financial support by the Research Corporation (RA0305) is
also acknowledged.
Two of these amino acids have been previously reported.
Of particular interest is the glutamic acid derivative 14d.
Both (2S,4S)-amino acid 14d and its (2S,4R)-isomer are
natural products, the former occurring in Pandanus Veitchii17
and the latter in Ledenbergia roseo-aena.18 Both diastereo-
isomers occur in Phyllitis scolopendrium.19 Recent studies
Supporting Information Available: Typical experimen-
tal procedures and structural characterization data for com-
pounds 10a-h, 12a-e, 13a-e, and 14a-d. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL049505A
(17) Alderweireldt, F.; Jadot, J.; Casimir, J.; Loffet, A. Biochim. Biophys.
(19) Meier, L. K.; Sorensen, J. Phytochemistry 1979, 18, 1173-1175.
(20) (a) He´laine, V.; Rossi, J.; Gefflaut, T.; Alaux, S.; Bolte, J. AdV.
Synth. Catal. 2001, 343, 692-697. (b) He´laine, V.; Bolte, J. Tetrahedron:
Asymmetry 1998, 9, 3855-3861.
Acta 1967, 136, 89-94.
(18) Jadot, J.; Casimir, J.; Loffet, A. Biochim. Biophys. Acta 1967, 136,
79-88.
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