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Facile Synthesis of -Dehydro Amino Acid Esters.

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to the bracketed compound ( 7 0 ) (j-,,, = 255.5 nm) the longest
wavelength absorption exhibits a 3.5 nm bathochromic shift.
Received: February 2, 1977 [Z 665 IE]
German version: Angew. Chem. 89, 338 (1977)
CAS Registry numbers:
( 4 ) . 61846-70-6: ( 5 ) . 61846-71-7: (6). 61846-72-8: ( ? a ) , 61846-73-9;
61846-74-0: ( 7 c ) . 61846-75-1; ( 7 d J . 61846-76-2: (7e), 61846-77-3;
61846-78-4: ( 7 g ) %61846-79-5: ( 7 h ) , 61846-80-8; ( 7 i ) , 61900-04-7:
61846-81-9: (711, 61846-82-0; ( 7 m ) , 61846-83-1: ( 7 n ) , 61846-84-2:
61846-85-3: ( 7 p ) . 61846-86-4; (74), 61846-87-5
(7b),
(7.{J+
(7k),
(7o),
R'
(1), X = H
12), x = c1
1. HCI
2. NH3
( a ) , R = R' = CH,
( b ) , R = H, R'= (CH,),CH
Ic),
(3)
AH
R = CH,, R' = CZH,
3.
K\
C=C-COOCH,
R1'
I
(4)
N H2
Procedure
~
Reviews: R. H . Martin, Angew. Chem. 8 6 , 721 (1974): Angew. Chem.
Int. Ed. Engl. 13, 649 (1974): H . Wynbery, Acc. Chem. Res. 4. 65 (1971).
Review: K . Mislow, D. Cusr, P . Fiiiocchiaro, R . J . Boettcher. Top.
Curr. Chem. 47, 1 (1974); f. Viigtle, G . Hohner, Angew. Chem. 87,
522 (1975): Angew. Chem. Int. Ed. Engl. 14, 497 (1975): cf. also H .
4 . Stauh, E. Wehinger. Angew. Chern. 8 0 , 240 (1968): Angew. Chem.
Int. Ed. Engl. 7 , 225 (1968).
In contrast. "head-to-tail" bridged helicenes are still unknown.
For use of the helix model, cf. R. S . Cahn, C . Ingold, V: Preloy, Angew.
Chem. 7 8 , 413 (1966); Angew. Chem. Int. Ed. Engl. 5, 385 (1966).
Reviews: F. Vbgtle, P . Neiimanii, Angew. Chem. 84, 75 (1972); Angew.
Chem. Int. Ed. Engl. I / , 73 (1972): Chimia 26, 64 (1972): Top. Curr.
Chem. 48, 67 (1974).
( 7 u ) can be detected together with the dimer by mass spectrometry.
F. C'iiqtlc. J Criitze. Angew. Chem. 8 7 , 543 (1975): Angew. Chem.
Int. Ed. Engl. 14, 559 (1975): J . Griitze, f. Viigtle, Chem. Ber. 110
( I 977). in press.
Attempts t o resolve the racernate ofthe carboxylic acid (7i) synthesized
for this express purpose with (-)-a-phenylethylamine and with brucine
have not yet led to the desired result.
The second AB system of the p-phenylene protons lies in the usual
aromatic region.
R . L Cloirgh. J . D . Roberts, J. Am. Chem. Soc. 99 (1977), in press.
We are indebted t o Prol. Roberts for communicating these results prior
t o their publication.
Facile Synthesis of a$-Dehydro Amino Acid E s t e r s [ * * ]
By UIrich Schmidt and EIisabeth Ohleu[*]
Dedicated to Projkssor Hans Nowotny
a,B-Dehydro amino acid esters ( 4 ) serve as components
of antibiotic peptides and as biosynthetic intermediates''].
One method for the preparation of the esters ( 4 ) starts from
tert-butoxycarbonyl amino acid ester^[^.^'. The cc-imino acid
esters (3) tautomeric with ( 4 ) are accessible by N-chlorination/dehydrochlorinationof a-amino acid esters ( 1
'I. Rearrangement of the %-imino compounds into the esters ( 4 )
has not hitherto been observed. However, dehydrochlorination
of N-(chloro)phenylalanineester gives exclusively the thermodynamically more stable ester (a-aminocinnamic ester)[41.
We have now found that the a-imino acid esters (3) can
be rearranged into the hydrochlorides of the a$-dehydro
amino acid esters by treatment with hydrogen chloride at
low temperature. The esters ( 4 ) can be liberated from the
hydrochlorides by ammonia. In the above reaction sequence
it is unnecessary to isolate the cc-imino acid esters (3). After
dehydrochlorination of the N-chloro compounds ( 2 ) they
are rearranged directly in the reaction solution. a,P-Dehydrovaline methyl ester ( 4 a ) , -leucine methyl ester ( 4 b ) , and
-isoleucine methyl ester ( 4 c) are readily accessible by this
method.
)[43
p] Prof. Dr.
U . Schmidt, Dr E. Ohler
Organisch-Chemisches lnstitut der Universitit
Wiihringer Strasse 38, A-I090 Wien (Austria)
[**I Dehydro Amino Acids, Part 9. This work was supported by the Fonds
ziir Forderung der wissenschaftlichen Forschung in 0sterreich.- Part 8:
ref. [I]. Also: Amino Acids and Peptides, Part 22.-Part 21 : ref. [l].
Aiiqen.
R\
,CH-C-COOCH,
R\
,CH-CH-COOCH,
R'
ihX
Chem. Inr. Ed. Eiiyl. 16 ( 1 9 7 7 ) N o . 5
a,B-Dehydro amino acid methyl esters ( 4 ) : tert-ButyI hypochloriter6](1 equiv.) is added dropwise to an ice-cooled, stirred
solution of amino acid methyl ester ( I ) (10 mmol) in anhydrous
ether (20mlj with exclusion of light. After 30min the ether
is removed in uacuo. A solution of the residue in chloroform
(50ml) is quickly treated with 0.5 N hydrochloric acid (IOmlj,
washed with water (lOml), and briefly dried over Na2S04
at 0°C. After complete removal of solvent in uacuo the almost
pure N-chloroamino acid methyl ester (2) is obtained.
A solution of diazabicyclo[5.4.0]undecene (DBU) (1.52 g,
10mmol)in anhydrous ether (20ml) is quickly added dropwise
to a vigorously stirred solution of (2) (10mmol) in anhydrous
ether (80ml) at room temperature. After 30min the mixture
is cooled to 0°C and DBU.HCI filtered off under suction.
The ethereal solution of the crude imino acid ester (3) is
treated at -7O"C, with vigorous stirring, with a 1 N solution
of hydrogen chloride in anhydrous ether ( 1 1 ml). After 15 min
the solution is stirred for another 6 h at O"C, then allowed
to stand for 15h at -2O"C, and subsequently evaporated
to dryness in cacim. Residual ( 4 ) .HCI is repeatedly digested
with anhydrous ether and rapidly filtered off under suction.
In order to liberate ( 4 ) the crystalline (4)'HCI is dissolved
in anhydrous chloroform and dry NH3 is passed through
the ice-cooled solution for 10min; ammonium chloride is
filtered off and the filtrate concentrated in ~'acuo.The oily
residue is distilled in a bulb tube at 11 torr and an air-bath
temperatureofca. 1 10"C.-(4a)[31: yield 80 % based on ( 1 a ) :
( 4 k ~ ) [ ~yield
' : 63 "/, based on ( 1 b ) . 'H-NMR (CDC13): no
evidence for the presence of cis-trans isomers; 6 = 1.06 (d,
3.76 (s, 3H): 5.41
6H); 2.43 (m, 1 H); 3.22 (br. s, 2Hj;
(d, 1 H) (accompanied by signals of ca. 10% of (3b)).-(4c):
yield 75% based on ( l c ) . 'H-NMR (CDCI3): (shows the
signals of Z- and E isomer in the ratio of about 1 : 1): 6 = 1.02
and 1.04 (t, 3H); 1.74 and 2.02 (s, 3H); 2.12 and 2.46 (q,
2H); 3.40 (br. s, 2H); 3.76 (s, 3H).
Received: January 19. 1977 [Z 662a IE]
German version: Angew. Chem. 89, 344 (1977)
CAS Registry numbers:
( 1 ~ )4070-48-8;
.
( 1 b ) , 2666-93-5: ( 1 ~ 2577-46-0:
) ~
( 2 ~ ) 62125-88-6:
.
(2h),
55739-09-8: ( 2 ~ )62125-89-7:
.
1 4 0 ) , 10409-27-5; ( 4 a ) . H C I , 53267-36-0; cis( 4 b ) . 62125-90-0: cis-(4b).HCI, 62125-91-1 : t r u n a - ( l h J , 62125-92-2: t r o w
( 4 b ) . HCI, 621 25-93-3: c i s - ( 4 c ) ,621 25-94-4: c i s - ( 4 c ) .HCI. 62 125-95-5: truiis( 4 ~ )62125-96-6:
.
/ r u i i s - ( 4 c ) .HCI, 62125-97-7
H . Poise/, Chem. Ber. 110, 948 (1977).
Cf. H . Poisrl, U . Schmidr, Chem. Ber. 108. 2547 (1975); B. W B K W J ~ ~ ,
Nature 224, 595 (1969). and references cited therein.
H . Porsrl, U . Schmidt, Angew. Chem. 88, 295 (1976): Angew. Chem.
Int. Ed. Engl. 15. 294 (1976).
H . Poisu/,Chem. Ber. 110,942 (1977).-Earlier synthesis of dehydrovaline
ester from the corresponding x-nitro r.P-dehydro carboxylic methyl
ester: C . Shill, M . Masuki, M . Ohto, J. Org. Chem. 32, 1860 (1967).
In the analogous synthesis of the dehydroleucine ester [ C . Shin. M .
Masnki,M.Ohtu, Bnll.Chem.Soc. Jpn.43,3219(1970)] thenitro precursor
was difficult to prepare and the product characterized inadequately.
327
[5] H . Poise/, U . Schmidt, Chem. Ber. 108, 2547 (1975).--~-Iminoisovaleric
ester from woxoisovalericester and phosphane imide: C. Shin, M . Mnsnki,
M . Ohtu, Bull. Chem. Soc. Jpn. 44, 1657 (1971).
[6] An excess of fert-butyl hypochloriteis t o be avoided, because the N-chloro
compound ( 2 ) very easily reacts to give the N,N-dichloro compound
which seriously interferes with the reaction.
Activation of Double Bonds in Dehydro Amino Acids:
A Model for Pyridoxal-ContainingEnzymes in Elimination-Addition Reactions[**]
By Ulrich Schmidt and Erhard Prantzr]
N-Pyridoxylideneaminoacrylic acid is frequently assumed
as an intermediate of elimination and exchange reactions on
pyridoxal-containing enzymes''. 'I. Short-lived intermediates
in pyridoxal-containing enzymes with an absorption region
at 455-470 nm were interpreted as N-pyridoxylideneaminoacrylic acid13].It was hitherto impossible to prepare derivatives of this acid for use in biomimetic studies. Nor could
simpler models such as N-salicylideneaminoacrylic acid derivatives be obtained by p-elimination from substituted serines
and cy~teines[~l.
I1
NOl
( 1 ) - ( 4 ) CHR
(2), R =
(CH3)2C=C-COOCH3
AHR
(41, R =
HWHz
(5), R = H
( 6 ) . R = CH,CO
(51, ( 6 )
In connection with our syntheses of dehydro amino acid
derivatives with free amino groups". 51 we have now succeeded
in the direct condensation of dehydrovaline ester with benzaldehyde, salicylaldehyde, 4-nitrosalicylaldehyde, and pyridoxal to give the Schiff bases ( I ) to ( 4 ) . These compounds are
instructive models for the pronounced reactivity of N-pyridoxylideneaminoacrylic acid. The extreme ease of addition to
the o-hydroxyl compounds (2) to ( 4 ) could be demonstrated
with phenylmethanethiol :
Addition of phenylmethanethiol proceeds very reluctantly
in the presence of 1 mol of diazabicyclo[5.4.0]undecene (DBU)
as catalyst when attempted with 0.2 M ethanolic solutions
of dehydrovaline methyl ester (5 )[51, N-acetyldehydrovaline
methyl ester (6)16], and N-benzylidenedehydrovaline methyl
ester (1 ). Only 10-1 5 % conversion takes place within 1 h.
In contrast, addition to the o-hydroxyl Schiff bases (2) and
(3) is 50% complete within tornin, and 85-90% within
1 h.
The pyridoxylidene compound ( 4 ) cannot be included in
this series owing to its sparing solubility. However, in 0.02 M
solution the salicylidene compounds (2) and (3) have reacted
to the extent of 30% within 20min and the pyridoxylidene
compound ( 4 ) to the extent of 50 %.
These facts demonstrate that the introduction of electron
acceptors (nitro group) and transition to the electron-poorer
pyridine system (pyridoxylidene compound) fail to accelerate
[*] Prof. Dr. U. Schmidt. Mag. E. Prantz
Organisch-Chemisches lnstitut der Universitit
Wahringer Strasse 38, A-1090 Wien (Austria)
[**I Dehydro Amino Acids, Part 10. This work was supported by the Fonds
zur Forderung der wissenschaftlichen Forschung in 0sterreich.-Part 9 :
ref. [I].--Also: Amino Acids and Peptides, Part 23. -Part 22: ref. [l].
328
the reaction markedly. The significant enhancement of the
ease of addition in the aminoacryloyl system is attributable
to the o-hydroxyl group.
Procedure
N-Salicylidenerlehytiro~~aline
methyl ester ( 2 ) : The water
formed on reaction of a solution of dehydrovaline methyl
ester (1.29g, 0.01 mol) (5) and salicylaldehyde (1.22g) in
anhydrous benzene (50 ml) is removed by azeotropic distillation (progress of reaction checked by TLC; silica gel/chloroform; Rf of (2) = 0.7). When no starting material can be
detected by TLC the residue left on distilling off the benzene
is itself subjected to high-vacuum bulb-tube distillation at
a bath temperature of 140°C. Yield 1.75 g (75 %) of a yellow
oil which crystallizes in a refrigerator (m.p. 20-25°C). 'HNMR (CDCl'): 6=2.00 (s with doublet character, 6H); 3.80
(s, 3H); 6.78-7.44 (m, 4H); 8.06 (s, 1 H); 10.26 (br. s, 1 H).
( 1 1: pale yellow oil, yield 72 %. 'H-NMR (CDCI'): 6 = 1.98
(s, 3H); 2.08 (s, 3H); 3.80 Is, 3H); 7.20 --7.90(m, 5H): 8.12
(s, 1 H).
( 3 ) : m.p. 156°C from benzene/light petroleum, yield 82 %.
'H-NMR (CDC13): 6 ~ 2 . 0 8(s,6H); 3.88 (s, 3H); 7.20-7.76
(m, 3H); 8.36 (s, 1 H); 11.06 (s, 1 H).
N-Pj,ridoxylidenedehydroi:alinemethyl ester ( 4 ) :A solution
of dehydrovaline methyl ester (5) (1.29g) and pyridoxal hydrochloride (2.04g) in methanol (150ml) is stirred at 50°C
for 2 h. After approx. ',$h the hydrochloride of ( 4 ) starts
to precipitate. The reaction mixture is evaporated down to
50ml, filtered, washed with anhydrous ether. and dried in
a vacuum (yield 1.0 g, 32');)).The suspension of the hydrochloride in dichloromethane is treated twice with saturated
NaHC0' solution and twice with water, dried, and evaporated.
The residue is recrystallized from benzene to give 0.87g of
yellow crystals of m.p. 148°C (dec.). 'H-NMR (CDCl'):
6=2.06 (s, 3H); 2.10 (s, 3H); 2.52 (s, 4H); 3.84 (s, 3H); 7.76
(s, 2H); 7.87 (s, 1 H); 8.8 (s, 1 H); 13.26 (br. s, 1 H). UV
(C2H50H): h,,,=218,
295nm; on addition of aluminum
nitrate a weak maximum appears at 485 nm whose extinction
increases with time.
Received: January 19, 1977 [Z 662b IE]
German version: Angew. Chem. 89. 345 (1977)
CAS Registry numbers:
(1),62125-73-9: (2),62125-74-0: ( 3 ) , 62125-75-1: ( 4 ) , 62125-76-2: ( 4 ) . H C I ,
62125-77-3; ( 5 ) . 10409-27-5; ( 6 ) , 39239-88-8; benzaldehyde. 100-52-7; salicylaldehyde, 90-02-8; 4-nitrosalicylaldehyde, 2460-58-4; pyridoxal. 66-72-8;
phenylmethanethiol. 100-53-8
[I]
[2]
[3]
[4]
[S]
[6]
L'. Schmidt, E. h l r r , Angew. Chem. 89, 344 (1977): Angew. Chem.
Int. Ed. Engl. 16. 327(1977).
For example, aspai-tatearninotransferase, cystathionine y-synthetase, and
tryptophanase.
Y Krrruhe. E Mor,sushima, J. Am. Chem. Soc. 98, 3725 11976). references
cited therein: cf. A . E . Brurrnsteiii el al., Em. J. Blochem. 53, 429 11975).
K. Kiirte. U . Schmidt, Monatsh. Chem. 102, 207 (1971).
H . Poise!, U . Schmidr, Angew. Chem. 88, 295 (1976): Angew. Chern.
Int. Ed. Engl. 15, 294 (1976).
H. Poise/, U . Schmidt, Chem. Ber. 108, 2547 (1975).
Synthesis and Some Reactions of l,l-Dimethyl-2,2-bis(trimethylsily1)-1-silaethenec 1
'
By Nils Wiberg and Gerhard Preiner[*l
The preparation of unsaturated compounds of type >Si=E
(e. g . E =C(, N--, 0)with silicon having coordination number
[*] Prof. Dr. N. Wiberg, DipLChem. G. Preiner
Institut fur Anorganische Chemie der Universitit
Meiserstrasse 1. D-8000 Munchen 2 (Germany)
Anyew. Chem. I n r . Ed. Engl. 16 (1977) N o . 5
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