Aziridination of 5-methyl-4H-1,3-dioxins by N-tosyliminophenyliodinane: A one-step procedure for the synthesis of α-methylserinal derivatives

Article abstract of DOI:10.1055/s-2001-14607

The methyl analogue of Garner's aldehyde, N-tosyl-4-methyl-N, O-isobutyrylideneserinal, has been prepared in a one-step reaction by CuClO₄-catalyzed aziridination of 2-isopropyl-5-methyl-4 H-1,3-dioxin with N-tosyliminophenyliodinane and transformed into α-methylserine derivatives, e.g. α-vinylalanine.

Full text of DOI:10.1055/s-2001-14607

LETTER
839
Aziridination of 5-Methyl-4H-1,3-dioxins by N-Tosyliminophenyliodinane:
A One-step Procedure for the Synthesis of -Methylserinal Derivatives
Susanne Flock, Herbert Frauenrath*
Universität Gh Kassel, Fachbereich 19 - Biologie/Chemie, Heinrich-Plett-Str. 40, 34109 Kassel, Germany
Fax +49 (0)561-8044649; E-mail: frauenra@hrz.uni-kassel.de
Received 13 March 2001
metric double-bond isomerization of 5-methylene-1,3-
dioxanes 3.15 We have also shown, that m-chloroperben-
zoic acid oxidation of 4 primarily affords acylals 5, which
readily undergo a ring-contraction in the presence of an
acid to give 4-methyl-1,3-dioxolan-4-carbaldehydes 6
(Scheme 1).16 The latter results made us assume, that a
similar nitrogen atom transfer process to 4 and rearrange-
ment should lead to -methylserinal derivatives 7
(PG = protecting group).
Abstract: The methyl analogue of Garner’s aldehyde, N-tosyl-4-
methyl-N,O-isobutyrylideneserinal, has been prepared in a one-step
reaction by CuClO4-catalyzed aziridination of 2-isopropyl-5-meth-
yl-4H-1,3-dioxin with N-tosyliminophenyliodinane and trans-
formed into -methylserine derivatives, e.g. -vinylalanine.
Key words: amino aldehydes, aziridination, rearrangements,
alkyl- -amino acids, 4H-1,3-dioxins
-
Due to their interesting biological activities, -alkyl- -
amino acids ( , -dialkylated glycines) have attracted
much attention in recent years, both as free acids and as
constituents of peptides.1 For example, incorporation of
these non-proteinogenic amino acids into short peptides
can lead to a stabilization of defined conformations, such
as -turns, 310- and -helical, or extended conformations,2
and an increased resistance towards protease enzymes.3
-Aminoisobutyric acid (AiB) and (R)-2-amino-2-meth-
ylbutyric acid (D-Iva) are important components of pep-
taibols, naturally occurring microbial peptide antibiotics,
which form trans-membrane ion channels.4 (S)- -Methyl-
DOPA, a commercial antihypertensive,5 represents a
prominent example for the use of free -alkyl- -amino ac-
ids as enzyme inhibitors.6
NiBr2Diop
LiBHEt3
O
R
O
H
4
OH
3
O
R'
[H+]/ ∆
O
O
mCPBA
O
R
O
H
O
O
R
H
5
6
O
O
aziridination
O
O
R
H
N
R
4
H
PG
7
O
O
O
O
Scheme 1
N
N
Boc
Boc
From the two most general aziridination processes, lead
tetraacetate oxidation of N-amino compounds in the pres-
ence of an olefin17 and metal-induced aziridination of ole-
fins employing [N-(p-toluenesulfonyl)imino]phenyl-
iodinane 8 as a nitrene precursor,18 we first examined the
aziridination of 4 with tosyliminophenyliodinane 8. As
presumed, treatment of rac-4a with 8 in the presence of
copper catalysts directly afforded N-tosyl-N,O-isobutyl-
ideneserinal 7a (Scheme 2). Other products analogous to
5 have not been observed. However, the Cu(II)-catalyzed
aziridinations of 4a only proceeded with moderate yields
(Table, entries 1-4). Moreover, these reactions are ham-
pered by accompanying polymerization to a great extent,
and the substrate had to be used in a large excess as a ni-
trene trap. On the other hand, Evans et al. have already
pointed out, that Cu(I) are superior to Cu(II) catalysts for
such aziridinations.18 In fact, reaction of 4a with 8 cata-
lyzed by CuClO4 provided a 90:10 diastereomeric mixture
of 7a in 60% yield. Polymerization side reactions are
1
2
By far the most published syntheses of , -disubstituted
amino acids involve alkylation of chiral alanine or amino
acid enolate equivalents,7 e.g., Schöllkopf's bislactim
ether,8 Seebach's oxazolidinone and imidazolidinone,9 or
William's oxazolinone approach.10 Nevertheless, there is
still interest in developing conceptually different strate-
gies.11 In this context, the methyl analogue 1 of Garner's
aldehyde 2 appears to be an interesting precursor for the
synthesis of these compounds. Garner's aldehyde derived
from L-serine has already widely been used as chiral
building block in organic synthesis,12,13 whereas the prep-
aration of 1 was described almost recently for the first
time by a multistep reaction sequence.13,14
We have previously reported, that 5-methyl-4H-1,3-diox-
ins 4 are obtained with high enantiomeric excess by asym-
Synlett 2001 No. 6, 839–841 ISSN 0936-5214 © Thieme Stuttgart · New York

840
S. Flock, H. Frauenrath
LETTER
largely suppressed by using this catalyst, and it is particu-
larly noteworthy, that the best results were obtained with
a slight excess of tosyliminophenyliodinane 8 (Table, en-
try 8; Method A).19
(Ph3)PCH3Br
KHMDS
O
HCl (10%)
r.t., 72 h
N
HO
7a
HN
Ts
THF
H
Ts
- 78 °C → r.t., 3 h
12 (90%)
11 (83%)
OH
O
LiAlH4
N
1. HBr(32%)/HOAc
0 °C → r.t.
12 h
Et2O
H
Ts
reflux, 2 h
CrO3
H2SO4/H2O
HO2C
H2N
HO2C
HN
9 (85%)
2. ion exchange
Ts-N=I-Ph (8)
O
O
0 °C → r.t.
Ts
CuClO4 (5 mol%)
12 h
N
O
O
H
CH3CN, 20 °C
13 (85%)
14 (40%)
H
Ts
Scheme 3
7a (60%)
AgNO3
4a
CO2H
O
N
H
NaOH
dure for the synthesis of -methylserinal derivatives 7.
The synthesis of enantiomerically pure -methylserinal
derivatives by nickel complex catalyzed asymmetric
isomerization of 5-methylene-1,3-dioxanes and aziridina-
tion is under study.
THF
Ts
r.t., 12 h
10 (95%)
Scheme 2
References and Notes
Table Aziridination of 2-isopropyl-5-methyl-4H-1,3-dioxin (4a)
with tosyliminophenyliodinane (8) and copper catalysts
(1) Heimgartner, H. Angew. Chem. Int. Ed. Engl. 1991, 30, 238.
(2) (a) Oekonomopulos, R.; Jung, G. Biopolymers 1980, 19, 203.
(b) Vijayakumar, E. K. S.; Sudha, T. S.; Balaram, P.
Biopolymers 1984, 23, 877. (c) Balaram, H.; Sukumar, M.;
Balaram, P. Biopolymers 1986, 25, 2209. (d) Paul, P. K. C.;
Sukumar, M.; Bardi, R.; Piazzesi, A. M.; Valle, G.; Toniolo,
C.; Balaram, P. J. Am. Chem. Soc. 1986, 108, 6363. (e) Karle,
I. L.; Flippen-Anderson, J. L.; Sukumar, H.; Uma, K.;
Balaram, P. J. Am. Chem. Soc. 1991, 113, 3952. (f) Giannis,
A.; Kolter, T. Angew. Chem. Int. Ed. Engl. 1993, 32, 1244. (g)
Burgess, K.; Ho, K.-K.; Pal, B. J. Am. Chem. Soc. 1995, 117,
3808. (h) Paradisi, M. P.; Torrini, I.; Zecchini, G. P.; Lucente,
G.; Gavuzzo, E.; Mazza, F.; Pochetti, G. Tetrahedron 1995,
51, 2379. (i) Obrecht, D.; Altorfer, M.; Lehmann, C.;
Schönholzer, P.; Müller, K. J. Org. Chem. 1996, 61, 4080; and
references cited therein.
a) 5 Mol% based on the limiting component. b) All reactions were
carried out in dry CH3CN. Method A: 1 equiv. 4a, 1.5 equiv. 8; Me-
thod B: 1 equiv. 8, 2 equiv. 4a. c) Reaction time after complete con-
version of 4a (Method A) or 8 (Method B). d) Calculated for
(3) (a) Khosla, A.; Stachowiak, K.; Sunby, R. R.; Bumpus, F. G.;
Pirion, F.; Lintner, K.; Fermandjian, S. Proc. Natl. Acad. Sci.
USA 1981, 78, 757. (b) Toniolo, C.; Crisma, M.; Pegoraro, S.;
Becker, E. L.; Polinelli, S.; Boesten, W. H. J.; Schoemaker, H.
E.; Meijer, E. M.; Kamphuis, J.; Freer, R. Peptide Res. 1991,
4, 66.
CF3SO3Cu
C6H6. e) Calculated for Cu(CH3CN)4ClO4.20
(4) (a) Jung, G.; Brückner, H.; Schmitt, H. In Structure and
Activity of Natural Peptides; Voelter, W.; Weitzel, G., Eds.;
de Gruyter, Berlin, 1981; p 75. (b) Toniolo, C.; Bonora, G. M.;
Bavoso, A.; Benedetti, E.; di Blasio, B.; Pavone, V.; Pedone,
C. Biopolymers 1983, 22, 205. (c) Boheim, G. In Molecular
Biology of Neuroreceptors and Ion Channels; Maelicke, A.,
Ed.; Springer, New York, 1989; p 401. (d) Rebuffat, S.;
Goulard, C.; Bodo, B. J. Chem. Soc., Perkin Trans. 1 1995,
1845. (e) Chikanishi, T.; Hasumi, K.; Harada, T.; Kawasaki,
N.; Endo, A. J. Antibiot. 1997, 50, 105.
The applicability of -methylserinal derivative 7a as a
building block for organic synthesis was demonstrated by
transformation into amino alcohol 9 and -methylserine
derivative 10, respectively (Scheme 2). Furthermore, Wit-
tig reaction of 7a followed by acetal cleavage afforded
amino alcohol 12 as a single diastereomer after recrystal-
lization of the crude reaction mixture from pentane
(Scheme 3). Subsequent Jones oxidation of 12, acidic
deprotection of the resulting N-tosyl- -vinylalanine 13
and ion exchange gave -vinylalanine 14 in an acceptable
overall yield.21
(5) Stinson, S. Chem. Eng. News 1992, 252, 46.
(6) (a) Walsh, J. J.; Metzler, D. E.; Powell, D.; Jacobson, R. A. J.
Am. Chem. Soc. 1980, 102, 7136. (b) Arnone, A.; Briley, P.
D.; Rogers, P. H.; Hyde, C. C.; Metzler, C. M. In Molecular
Structure and Biological Activity; Griffin, J. F.; Duax, W. L.,
Eds.; Elsevier, New York, 1981; p 57. (c) Saari, W. S.;
Halczenko, W.; Cochran, D. W.; Dobrinska, M. R.; Vicek, W.
In conclusion, aziridination of 5-methyl-4H-1,3-dioxins 4
with tosyliminophenyliodinane 8 in the presence of
CuClO4 as a catalyst proves to be a straightforward proce-
Synlett 2001, No. 6, 839–841 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Aziridination of 5-Methyl-4H-1,3-dioxins by N-Tosyliminophenyliodinane
841
C.; Titus, D. G.; Gaul, S. L.; Sweet, C. S. J. Med. Chem. 1984,
(1 C, CH(CH3)2), 16.9 (1 C, CH3), 18.7 (1 C, CH(CH3)2), 21.6
(1 C, Ph-CH3), 32.0 (1 C, CH(CH3)2), 71.2 (1 C, N-C-CH3),
73.2 (1 C, O-CH2), 96.3 (1 C, O-CHR-N), 127.5 (2 C,
aromatic C), 129.8 (2 C, aromatic C), 137.6 (1 C, aromatic C),
144.2 (1 C, aromatic C), 198.5 (1 C, CHO); IR(ATR):
= 665; 709; 821; 864; 933; 1066; 1084; 1157; 1188; 1305;
1341; 1401; 1467; 1598; 1736; 2829; 2879; 2975; Anal. Calcd
for C15H21NO4S, C 57.86; H 6.80; N 4.50. Found C 57.37; H
6.60; N 4.51.
27, 713. (d) Ramalingam, K.; Woodard, R. W. Tetrahedron
Lett. 1985, 26, 1135. (e) Jung, M. J. In Chemistry and
Biochemistry of the Amino Acids; Barett, G. C., Ed.; Chapman
and Hall, London, 1985; p 227. (f) Tendler, S. J. B.;
Threadgill, M. D.; Tisdale, M. J. J. Chem. Soc., Perkin Trans.
1 1987, 2617.
(7) For pertinent reviews, see: (a) Williams, R. M. Synthesis of
Optically Active -Amino Acids; Pergamon Press, Oxford,
1989; Organic Chemistry Series, Vol. 7. (b) Duthaler, R. O.
Tetrahedron 1994, 50, 1539. (c) Seebach, D.; Sting, A. R.;
Hoffmann, M. Angew. Chem. Int. Ed. Engl. 1996, 35, 2708.
(d) Wirth, T. Angew. Chem. Int. Ed. Engl. 1997, 36, 225.
(e) Cativiela, C.; Díaz-de-Villegas, M. D. Tetrahedron:
Asymmetry 1998, 9, 3517.
(8) (a) Schöllkopf, U. Pure Appl. Chem. 1983, 55, 1799.
(b) Schöllkopf, U. Top. Curr. Chem. 1983, 109, 65.
(c) Schöllkopf, U.; Busse, U.; Kilger, R.; Lehr, P. Synthesis
1984, 271. (d) Schöllkopf, U.; Westphalen, K.-O.; Schröder,
J.; Horn, K. Liebigs Ann. Chem. 1988, 781.
(20) Kubas, G. J.; Inorg. Synth. 1979, 19, 90.
(21) 11: 1H NMR (500 MHz, CDCl3, 22 °C, TMS): = 0.80 (d, 3
H, J = 6.9, C(CH3)2), 1.00 (d, 3 H, J = 6.9 Hz, C(CH3)2), 1.56
(s, 3 H, CH3), 2.23 (dq, 1 H, J = 6.9, 2.8 Hz, CH(CH3)2), 2.42
(s, 3 H, Ph-CH3), 3.57 (d, 1 H, J = 8.4 Hz, O-CH2), 3.86 (d, 1
H, J = 8.4 Hz, O-CH2), 5.08 (d, 1 H, J = 2.8 Hz, O-CH-N),
5.21 (d, 1 H, Jcis = 10.8 Hz, CH = CH2), 5.29 (d, 1 H,
J
J
trans = 17.4 Hz, CH = CH2), 6.02 (dd, 1 H, Jcis = 10.8 Hz,
trans = 17.4 Hz, CH = CH2), 7.28 (m, 2 H, aromatic CH); 7.72
(m, 2 H, aromatic CH); 13C NMR (125 MHz, CDCl3, 22 °C,
TMS): = 15.0 (1 C, CH(CH3)2), 18.7 (1 C, CH(CH3)2), 21.4
(1 C, CH3), 21.5 (1 C, Ph-CH3), 32.0 (1 C, CH(CH3)2), 66.6 (1
C, N-C-CH3), 78.4 (1 C, O-CH2), 96.2 (1 C, O-CHR-N), 115.1
(1 C, CH = CH2), 127.5 (2 C, aromatic C), 129.4 (2 C,
aromatic C), 138.9 (1 C, aromatic C), 140.4 (1 C, CH = CH2),
143.2 (1 C, aromatic C); IR (ATR): = 662, 709, 750, 822,
914, 942, 1009, 1052, 1084, 1156, 1200, 1266, 1301, 1338,
1466, 1598, 1738, 2879, 2933, 2977. Anal. Calcd for
C16H23NO3S, C 62.11; H 7.49; N 4.53. Found C 62.25; H 7.27;
N 4.43.
(9) Studer, A.; Seebach, D. Liebigs Ann. Chem. 1995, 217; and
references cited therein.
(10) (a) Williams, R. M.; Im, M.-N. J. Am. Chem. Soc. 1991, 113,
9276. (b) Williams, R. M. Aldrichim. Acta 1992, 25, 11.
(11) For example, see: (a) O`Donnell, M. J.; Wu, S. Tetrahedron
Lett. 1992, 3, 591. (b) Lygo, B.; Crosby, J.; Peterson, J. A.
Tetrahedron Lett. 1999, 40, 8671. (c) Ooi, T.; Takeuchi, M.;
Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2000, 122, 5228.
(12) (a) Garner, P.; Park, J. M. J. Org. Chem. 1987, 52, 2361.
(b) Garner, P.; Park, J. M. Org. Synth. 1992, 70, 18. (c)
McKillop, A.; Taylor, R. J. K.; Watson, R. J.; Lewis, N.
Synthesis 1994, 31.
12: 1H NMR (500 MHz, CDCl3, 22 °C, TMS): = 1.23 (s, 3
H, CH3), 2.43 (s, 3 H, Ph-CH3), 3.48 (d, 1 H, J = 11.3 Hz, O-
CH2), 3.55 (d, 1 H, J = 11.3 Hz, O-CH2), 5.13 (d, 1 H,
(13) For an extensive bibliography on the use of Garner’s aldehyde
in organic synthesis, see: Avenoza, A.; Cativiela, C.; Corzana,
F.; Peregrina, J. M.; Zurbano, M. M. J. Org. Chem. 1999, 64,
8220.
(14) (a) Alías, M.; Cativiela, C.; Díaz-de-Villegas, M. D.; Gálvez,
J. A.; Lapeña, Y. Tetrahedron: Asymmetry 1993, 4, 1145. (b)
Alías, M.; Cativiela, C.; Díaz-de-Villegas, M. D.; Gálvez, J.
A.; Lapeña, Y. Tetrahedron 1998, 54, 14963.
(15) Frauenrath, H.; Reim, S.; Wiesner, A. Tetrahedron:
Asymmetry 1998, 9, 1103.
(16) Wattenbach, C.; Maurer, M.; Frauenrath, H. Synlett 1999,
303.
(17) (a) Atkinson, R. S.; Grimshire, M. J.; Kelly, B. J. Tetrahedron
1989, 45, 2875. (b) Atkinson, R. S.; Kelly, B. J. J. Chem. Soc.,
Perkin Trans. 1 1989, 1515. (c) Atkinson, R. S.; Coogan, M.
P.; Cornell, C. L. J. Chem. Soc., Chem. Commun. 1993, 1215.
(18) Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J. Am. Chem. Soc.
1994, 116, 2742; and references cited therein.
Jcis = 10.8 Hz, CH = CH2), 5.20 (d, 1 H, Jtrans = 17.3 Hz,
CH = CH2), 5.74 (dd, 1 H, Jcis = 10.8 Hz, Jtrans = 17.3 Hz,
CH = CH2), 7.29 (m, 2 H, aromatic CH); 7.77 (m, 2 H,
aromatic CH); 13C NMR (125 MHz, CDCl3, 22 °C, TMS):
= 21.4 (1 C, CH3), 21.5 (1 C, Ph-CH3), 61.0 (1 C, N-C-CH3),
68.9 (1 C, HOCH2C), 115.8 (1 C, CH = CH2), 127.2 (2 C,
aromatic C), 129.5 (2 C, aromatic C), 139.6 (1 C, CH = CH2),
139.7 (1 C, aromatic C), 143.2 (1 C, aromatic C); IR (ATR):
= 705, 809, 925, 974, 1057, 1092, 1152, 1317, 1414, 1601,
2917, 2990, 3126, 3435; Anal. Calcd for: C12H17NO3S, C
56.45; H 6.71; N 5.49. Found C 56.48; H 6.62; N 5.49.
13: 1H NMR (500 MHz, CDCl3, 22 °C, TMS): = 1.59 (s, 3
H, CH3), 2.42 (s, 3 H, Ph-CH3), 5.24 (dd, 1 H, Jcis = 10.6, 1.2
Hz, CH = CH2), 5.38 (dd, 1 H, Jtrans = 17.3, 1.2 Hz,
CH = CH2), 5.86 (dd, 1 H, Jcis = 10.6, Jtrans = 17.3 Hz,
CH = CH2), 7.28 (m, 2 H, aromatic CH), 7.76 (m, 2 H,
aromatic CH); 13C NMR (125 MHz, CDCl3, 22 °C, TMS):
= 21.5 (1 C, Ph-CH3), 22.1 (1 C, CH3), 62.8 (1 C,
(19) 7a: N-Tosyliminophenyliodinane 8 (15 mmol, 5.598 g) was
added in small portions under nitrogen over a period of 3 h to
a solution of 4a (10 mmol, 1.422 g) and CuClO4 (164 mg, 5
mol%) in dry acetonitrile (25 mL). After complete conversion
of the 4a (monitored by GC) the solvent was evaporated under
reduced pressure, and the residue was filtered through a plug
of silica gel with EtOAc as eluent. Then the solvent was
removed in vacuo, and the crude mixture was recrystallized
from cyclohexane to afford carbaldehyde 7a as a colorless
solid; mp 121 °C; yield 1.868 g (6.0 mmol, 60%). 1H NMR
(500 MHz, CDCl3, 22 °C, TMS): = 0.92 (d, 3 H, J = 6.9 Hz,
C(CH3)2), 1.02 (d, 3 H, J = 6.9 Hz, C(CH3)2), 1.43 (s, 3 H,
CH3), 2.34 (dq, 1 H, J = 6.9, 2.8 Hz, CH(CH3)2), 2.45 (s, 3 H,
Ph-CH3), 3.48 (d, 1 H, J = 8.8 Hz, O-CH2), 4.18 (d, 1 H,
J = 8.8 Hz, O-CH2), 5.00 (d, 1 H, J = 2.8 Hz, O-CH-N), 7.34
(m, 2 H, aromatic CH), 7.74 (m, 2 H, aromatic CH), 9.74 (s, 1
H, CHO); 13C NMR (125 MHz, CDCl3, 22 °C, TMS): = 14.4
NCCOOH), 117.3 (1 C, CH = CH2), 127.1 (2 C, aromatic C),
129.5 (2 C, aromatic C), 137.0 (1 C, CH = CH2), 139.2 (1 C,
aromatic C), 143.4 (1 C, aromatic C), 176.8 (1 C, COOH); IR
(ATR): = 555, 666, 704, 814, 886, 925, 970, 1092, 1154,
1302, 1323, 1431, 1527, 1597, 1708, 3256, 3356; Anal. Calcd.
for: C12H15NO4S, C 53.52; H 5.61; N 5.20. Found C 53.42; H
5.56; N 5.18.
14: 1H NMR and 13C NMR are in good agreement with the
literature22,23; Anal. Calcd. for: C5H9NO2, C 52.16; H 7.88; N
12.17. Found C 52.09; H 7.83; N 11.96.
(22) Weber, T.; Aeschimann, R.; Maetzke, T.; Seebach, D. Helv.
Chim. Acta 1986, 69, 1345.
(23) Colson, P.-J.; Hegedus, L. S. J. Org. Chem. 1993, 58, 5918.
Article Identifier:
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Synlett 2001, No. 6, 839–841 ISSN 0936-5214 © Thieme Stuttgart · New York