Asymmetric synthesis of 2H-azirine carboxylic esters by an alkaloid-mediated Neber reaction

Full text of DOI:10.1021/ja961414o

J. Am. Chem. Soc. 1996, 118, 8491-8492
8491
p-TolS(O), R ) Ph, R′ ) Me). A remarkable synthesis of
optically active azirine esters 1 is the Swern oxidation of
aziridine esters12 (e.g. trans-2, X ) H, R ) n-C3H7, R′ ) Me)
which in essence is a base-induced syn elimination reaction of
N-dimethylsulfonium intermediates 2 (X ) Me2S+). The three
aforementioned methods start with aziridine esters of high
enantiopurity, the preparation of which is rather lengthy.13 The
Neber reaction,2,14 i.e. the formation of aminoketones by
treatment of sulfonic esters of ketoximes with alkoxide, proceeds
via an azirine intermediate,2,15 and by proper modification this
reaction can be used for the synthesis of azirines2,16 but is lacking
generality mainly due to the subsequent reaction of the
azirine.2,17 Only one example of the synthesis of optically active
azirines Via this route is known in the literature. Piskunova et
al.16d reported a chiral auxiliary mediated asymmetric Neber
reaction with a de of 92%.
For the target compounds 1 ketoxime p-toluenesulfonates of
3-oxocarboxylic esters 4 are the principal starting materials. The
methylene protons in these substrates are doubly activated, thus
allowing the use of a mild base during the Neber reaction to
azirines 1.
A series of â-keto esters 3 was readily converted into the
ketoxime tosylates 4 in a simple two-step procedure in fair yields
(Scheme 1). The intermediate ketoximes must be tosylated
immediately after their preparation, as otherwise the competing
formation of isoxazolones takes place.18 The oxime tosylates
4 are obtained as a mixture of syn and anti isomers that are in
equilibrium at ambient temperature. Treatment of tosylates 4
with triethylamine in dichloromethane at room temperature for
6 h gave a smooth conversion to the desired azirines 1 in good
yields after purification by distillation19,20 (Scheme 1). Spectral
data of compounds 1b8c and 1d8c,10 are in accordance with
literature data.
Asymmetric Synthesis of 2H-Azirine Carboxylic
Esters by an Alkaloid-Mediated Neber Reaction
Marie¨lle M. H. Verstappen, Gerry J. A. Ariaans, and
Binne Zwanenburg*
Department of Organic Chemistry, NSR Center for
Molecular Structure, Design and Synthesis
UniVersity of Nijmegen, ToernooiVeld
6525 ED Nijmegen, The Netherlands
ReceiVed April 29, 1996
The highly strained and reactive 2H-azirines have been
extensively studied for various synthetic purposes, such as ring
expansion reactions,1,2 cycloaddition reactions,2,3 and preparation
of functionalized amines3 and substituted aziridines.1-3 The
applicability of these small-ring heterocycles is strongly deter-
mined by the nature of the substituents.2,3 2H-Azirine 2-car-
boxylic acids and esters are of particular interest as they form
an entre´e to e.g. nonprotein amino acids.4 Moreover, azirino-
mycin5 (1, R ) Me, R′ ) H), disydazirine6,7 (1, R ) trans-n-
C13H27CHdCH, R′ ) Me), and antazirine7 (1, R ) trans-
Br2CdCH(CH2)9CHdCH, R′ ) Me) are naturally occurring
antibiotics; the first mentioned was isolated from Streptomyces
aureus, and the latter two were isolated from the marine sponge
Dysidea fragilis.
This communication focuses on the asymmetric synthesis of
azirine esters 1. Previous synthesis of azirine esters are based
on the photolysis or thermolysis of azido alkenoates8 or on a
transformation of an isoxazole ring.9 These routes to azirines
are not suited for the preparation of single enantiomers of the
target compounds. Recently, elimination reactions of ap-
propriately N-substituted aziridine 2-carboxylic esters 2 were
successfully used for the preparation of azirine esters 1 of high
enantiopurity, Viz. dehydrochlorination from N-chloroaziridines10
(e.g. trans-2, X ) Cl, R ) Ph, R′ ) Me) and the elimination
of sulfenic acid from N-sulfinylaziridines11 (e.g. cis-2, X )
We then investigated a series of chiral tertiary bases for the
reaction of 4b to achieve an asymmetric synthesis. In all cases
studied the azirine was obtained (Table 1); however, asymmetric
conversion was only observed for the three pairs of cinchona
alkaloids.21 With sparteine, brucine, and strychnine virtually
no optically active heterocycle was formed. The best results
were obtained with dihydroquinidine, and therefore the reaction
conditions were optimized using this base. The solvent of
choice turned out to be toluene (Table 1), the optimum
concentration 2 mg/mL, and the best reaction temperature 0 °C.
Quinidine gave essentially the same results under these condi-
tions and was used in subsequent reactions. It should be noted
that in a hydroxylic solvent such as ethanol no asymmetric
conversion was observed. The results for the substrates 4a-e
(1) (a) Leonard, N. J.; Zwanenburg B. J. Am. Chem. Soc. 1967, 89,
4456-4465. (b) Crist, D. R.; Leonard, N. J. Angew. Chem., Int. Ed. Engl.
1969, 8, 962-974.
(2) For reviews on azirine chemistry, see: (a) Padwa, A.; Woolhouse,
A. D. In ComprehensiVe Heterocyclic Chemistry; Lowowski, W., Ed.;
Pergamon Press: New York, 1984; Vol. 7, Chapter 5, p 47. (b) Nair, V. In
Heterocyclic Compounds; Hassner A., Ed.; John Wiley and Sons: New
York, 1983; Vol. 42.1, Chapter 2, pp 215-332.
(3) For reviews on cycloadditions to azirines, see: (a) Anderson, D. J.;
Hassner, A. Synthesis 1975, 483-495. (b) Hassner, A. Heterocycles 1980,
14, 1517-1528.
(4) Haddach, M.; Pastor, R.; Riess, J. G. Tetrahedron, 1993, 49, 4627-
4638.
(5) (a) Stapley, E. O.; Hendlin, D.; Jackson, M.; Miller, A. K. J. Antibiot.
1971, 24, 42-47. (b) Miller, T. W.; Tristram, E. W.; Wolf, F. J. J. Antibiot.
1971, 24, 48-50.
(6) Molinski, T. F.; Ireland, C. M. J. Org. Chem. 1988, 53, 2103-2105.
(7) Salomon, C. E.; Williams, D. H.; Faulkner, D. J. J. Nat. Prod. 1995,
58, 1463-1466.
(8) (a) Harvey, G. R.; Ratts, K. W. J. Org. Chem. 1966, 31, 3907-
3910. (b) Hassner, A.; Fowler, F. W. J. Am. Chem. Soc. 1968, 90, 2869-
2875. (c) Shin, C.; Yonezawa, Y.; Yoshimura, J. Chem. Lett. 1976, 1063-
1066. (d) Wade, T. N.; Guedj, R. Tetrahedron Lett. 1979, 3953-3954.
(9) (a) Nishiwaki, T.; Kitamura, T.; Nakano, A. Tetrahedron 1970, 26,
453-465. (b) Auricchio, S.; Vajna de Pava, O. J. Chem. Res. Synop. 1983,
132. (c) Ueda, S.; Naruto, S.; Yoshida, T. Sawayama, T.; Uno, H. J. Chem
Soc., Perkin Trans. 1 1988, 1013-1021.
(10) Legters, J.; Thijs, L.; Zwanenburg, B. Recl. TraV. Chim. Pays-Bas
1992, 111, 75-78.
(11) Davis, F. A.; Reddy, G. V.; Liu, H. J. Am. Chem. Soc. 1995, 117,
3651-3652.
(12) Gentilucci, L.; Grijzen, Y.; Thijs, L.; Zwanenburg, B. Tetrahedron
Lett. 1995, 36, 4665-4668.
(13) (a) Legters, J.; Thijs, L.; Zwanenburg, B. Tetrahedron Lett. 1989,
30, 4881-4884. (b) Legters, J.; Thijs, L.; Zwanenburg, B. Recl. TraV. Chim.
Pays-Bas 1992, 111, 1-15. (c) Davis, F. A.; Zhou, P.; Reddy, G. V. J.
Org. Chem. 1994, 59, 3243-3245.
(14) Neber, P. W.; Burghard, A. Justus Liebigs Ann. Chem. 1932, 493,
281-294.
(15) Cram, D. J.; Hatch, M. J. J. Am. Chem. Soc. 1953, 75, 33-38.
(16) (a) Parcell, R. F. Chem. Ind. 1963, 1396-1397. (b) Padwa, A.;
Carlsen, P. H. J. J. Am. Chem. Soc. 1977, 99, 1514-1523. (c) Mu¨ller, F.;
Karwe, A.; Mattay, J. J. Org. Chem. 1992, 57, 6080-6082. (d) Piskunova,
I. P.; Eremeev, A. V.; Mishnev, A. F.; Vosekalna, I. A. Tetrahedron 1993,
49, 4671-4676.
(17) O’Brien, C. Chem. ReV. 1964, 64, 81-89.
(18) (a) Jacquier, R.; Petrus, C.; Petrus, F.; Verducci, J. Bull. Soc. Chim.
Fr. 1970, 7, 2685-2690. (b) Schulz, H.; Wakil, S. J. Anal. Biochem. 1970,
37, 457-461. (c) Katritzky, A. R.; Barczynski, P.; Ostercamp, D. L.; Yousaf,
T. I. J. Org. Chem. 1986, 51, 4037-4042.
(19) The purity of the compounds is >95% (1H-NMR and GLC analyses).
(20) The ketoxime tosylate from ethyl 2-methyl-3-oxobutanoate did not
react with Et3N, but needed the stronger base tBuOK for its conversion in
the corresponding azirine.
(21) The enantiopurity of the azirine esters 1 was determined by 1H-
NMR measurements in CHCl3 using Yb(tfc)3 as chiral shift reagent by the
shift difference of the C2-protons and (except for 1d) the C4-protons.
S0002-7863(96)01414-X CCC: $12.00 © 1996 American Chemical Society

8492 J. Am. Chem. Soc., Vol. 118, No. 35, 1996
Communications to the Editor
Scheme 1
Scheme 2
Table 1. Influence of Base and Solvent in the Enantioselective
Synthesis of 1b Via the Neber Reaction (at Ambient Temperature)
base
solvent
CH2Cl2
yielda (%)
ee21 (%)
Scheme 3
sparteine
brucine
strychnine
cinchonine
cinchonidine
quinine
53
38
37
52
43
34
37
41
47
75
47
48
59
77
74
0
5 (+)
4 (+)
32 (-)
24 (+)
24 (+)
45 (-)
22 (+)
47 (-)
0
8 (-)
45 (-)
47 (-)
63 (-)
70 (-)
quinidine
In the above enantioselective azirine synthesis a stoichiometric
amount of alkaloid base was used. This drawback could be
overcome by regenerating the alkaloid base in situ (Scheme 2).
This regeneration process should not interfere with the abstrac-
tion of the methylene protons, as this would lead to a decrease
or even a complete loss of enantioselectivity. Excellent results
were obtained when 10-20 equiv of potassium carbonate were
added to the reaction mixture at room temperature using only
10 mol % of quinidine.23 It was necessary to perform this
reaction at ambient temperature as this reaction hardly proceeded
at 0 °C. However, as in the case of the stoichiometric process,
this resulted in a somewhat lower ee (∼70%).
dihydroquinine
dihydroquinidine
dihydroquinidine
ethanol
acetonitrile
ether
hexane
CS2
toluene
a Not optimized.
Table 2. Synthesis of Azirine Carboxylic Esters 1 with a
Stoichiometric Amount of Base Under Optimal Conditions
yield 4 (%) yield 1 (%) ee21 (%)
4
R
R′
base
Reduction of the azirine esters 1 with NaBH4 leads exclu-
sively to the formation of cis-aziridine carboxylic esters 224
(Scheme 3), which are difficult to obtain by other methods.
When the reduction is performed with optically active azirine
1b, no trace of the trans-aziridine24b could be observed by NMR;
therefore, the cis/trans ratio must be over 95:5. Furthermore
no loss of chirality is observed.25 Thus, the Neber reaction
provides an alternative route to optically active aziridine
carboxylic esters 2 (X ) H), which are important for the
synthesis of various anomalous amino acids.
In conclusion, we accomplished a convenient novel catalytic
asymmetric synthesis of azirine carboxylic esters by the Neber
reaction of ketoxime tosylates derived from 3-oxocarboxylic
esters.
a
b
Me Me quinidine
79
72
40
43
38
29
72
85
58
81 (R)
82 (R)
55 (S)
44 (R)
80 (R)
80 (R)
57 (S)
Me Et
quinidine
quinine
c
d
e
Me tBu quinidine
92
60
54
nPr Et
Bz Et
quinidine
quinidine
quinine
are collected in Table 2. It is of importance to note that the
pseudoenantiomers of the alkaloid bases gave opposite antipodes
of the products 1. The absolute configuration of the azirines
was established by correlation with the optical rotation of
compound 1a12 (R20 ) -77.2°, CHCl3, c ) 0.5), indicating
D
that the use of quinidine as the base leads predominantly to the
Acknowledgment. This communication is dedicated to Professor
Nelson J. Leonard on the occasion of his 80th birthday.
(R)-enantiomer.
To explain this asymmetric Neber reaction, it is suggested
that the alkaloid bases form a tightly bound complex with the
ketoxime tosylate. Since the presence of an alcohol function
in the alkaloid base seems to be a prerequisite, it is suggested
that hydrogen bonding of the base and the substrate through
this hydroxyl group is a governing factor in the enantiodiffer-
entiation during the abstraction of the methylene protons. This
proposal is supported by the observation that in a hydroxylic
solvent no asymmetric induction takes place and that additives
such as LiCl and especially H2O lower the optical yield
considerably. Furthermore, calculations at the semiempirical
level22 have shown that a hydrogen bond between the dihyd-
roquinidine OH and one of the SdO moieties of the ketoxime
tosylate leads to a stable complex in which the aromatic parts
of the two molecules are placed in a favorable edge-on position.
Supporting Information Available: Experimental procedures and
analytical data for compounds 1, 2b, and 4 (7 pages). See any current
masthead page for ordering and Internet access instructions.
JA961414O
(23) General procedure for the catalytic asymmetric synthesis of azirine
esters 1: A solution of ketoxime tosylate 4 (200 mg) in dry toluene (10
mL) was added gradually to a vigorously stirred solution of quinidine (0.1-
0.25 equiv) and a large excess of K2CO3(s) (10 equiv) in dry toluene (90
mL) at room temperature. After 24 h the mixture was filtered, and dilute
aqueous HCl (50 mL, 0.05 M) was added. The resulting mixture was
extracted three times with diethyl ether (50 mL). The combined organic
layers were washed with brine, dried over MgSO4, and concentrated in Vacuo
to give the azirine ester 1. The crude product was purified by bulb-to-bulb
distillation.
(24) (a) Sziemies, G.; Mannhardt, K.; Junius, M. Chem. Ber. 1977, 110,
1792-1803. (b) Gelas-Mialhe, Y.; Touraud, E.; Vessiere, R. Can. J. Chem.
1982, 60, 2830-2851.
(25) The enantiopurity of the aziridine ester 2b was determined by GLC
analysis of the camphanoyl derivative.
(22) Mopac 93 @ Fujitsu. Calculations performed with the AM1
Hamiltonian.