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Chain-Extended and -Branched -Amino Acids by Alkylation of Metalated -[Bis(alkylthio)methyleneamino] Acid Esters.

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[3] Prepared by analogy with: E. Fromm and M . Block, Ber. Deut. Chem.
Ges. 32, 2212 (1899); M . DelPpine, Bull. SOC. Chim. Fr. [3] 27, 48,
57 (1902); Y. Ueno, 7: Nakai, and M . Okawara, Bull. Chem. SOC.Jap.
43, 162 (1970).
[4] Use in amino acid synthesis: D. H o p p e . Angew. Chem. 87, 450 (1975);
Angew. Chem. internat. Edit. 14, 4261 1975).
[5] Compoundsoftype(l1) and(l2)decomposeon work-up in the presence
of bases to form episulfides.
Chain-Extended and a-Branched a-Amino Acids by
AlkYlation of Metdated a-[Bis(alkylthio)methyleneamino] Acid Esters
By Dieter Hoppe"]
As esters of iminodithiocarbonic acid['] N-[bis(methylthio)methylenel- and N-( 1,3-dithiolan-2-ylidene)glycine
ethyl esters
(I a) and (I b), respectively, are conveniently obtainable from
glycine ethyl ester hydrochloride. Their reaction with potassium tert-butoxide at -70°C leads to the a-amino carbanions
( 2 ) which afford chain-extended esters (3) on treatment with
alkyl iodides or benzyl bromides between -60 and 0°C (see
Table 1). The monoalkylated products (3) are formed almost
cut course of our new synthesis is a topic for further study.
On treatment at 5-2ooc with aqueous performic acid produced in situ, the esters (3) and ( 4 ) undergo oxidative-hydrolytic dedfuration to the amino acid esters ( 5 ) and ( 6 ) , respectively.
Ethyl 2-[bis(methylthio)methylene]amino-2-(p-bromobenzyl)butyrute (4a)
Compound (I a) (4.14g, 20 mmol) in THF (10ml) is added
dropwise at - 70 "C to freshly sublimed potassium tert-butoxide[31(2.24g, 20mmol) in dry THF under N2. Stirring is
continued for IOmin, and a solution of p-bromobenzyl bromide (5.0g, 20mmol) in THF (20ml) is then added. After
warming up to room temperature, the mixture is stirred for
another 15 min and recooled to - 70°C. Potassium tert-butoxide (2.36g,21 mmol) in THF (30ml) is added from a dropping
funnel cooled with dry icelacetone, and ethyl iodide (3.4g,
22mmol) is squirted in after 15min; the reaction mixture
is then treated as above. After removal of solvent under
vacuum, the residue is taken up in ether (50ml) and water
(30ml), the organic phase washed with water and dried over
Table I . a-[Bis(alkylthio)methyleneamino] acid ethyl esters ( 3 ) and ( 4 ) prepared.
RzX (+R3X)
Product [a]
B.p. ["C/torr]
[a] The IR and 'H-NMR spectra are in accord with the structures; the products gave correct CH analyses.
[b] Distillative work-up.
[c] Purified by chromatography over silica gel (neutral) with light petroleum (40-6O0C)/diethyl ether ( 1 :2; 3: 1 for ( 4 a ) ) .
exclusively (>97 %) with one equivalent of base and the alkylating agent; renewed metalation [without isolation of (311
and alkylation permits introduction of a second alkyl group
(which may differ from R2) to form the a-branched a-amino
acid derivatives ( 4 ) .
Selective monoalkylation of relatively stable carbanions
generally runs into dificulties[21.The reason behind the clear(R~s)~c=N-cH,-co~c~H,
(la), R'
{Ib), R'
= CH3
+ R'
2-Ethyl-p-bromophenylalanineethyl ester (6 a)
= -CH,-CH2-
(R~S)~C=N-CH-CO,C~H, K@
( R'S)2C=N-&H-C02C2H,
1. (CH,),COK
2 . R'Y
( 3 ) or
HCOzH, H201
(5). R3 = H
(4). R3 = Alkyl
[*] Dr. D. Hoppe
Organisch-Chemisches Institut der Universitat
34 Gottingen, Tammannstrasse 2 (Germany)
sodium sulfate. The pale yellow oil (7.7g) left on removal
of the ether is chromatographed over silica gel (250g, neutral)
with light petroleum (40-6O0C)/diethyl ether (3 : 1) to give
( 4 a ) (6.80g, 84%) as a viscous colorless oil (Rf=0.40).-IR
(film): 1732 (C=O) and 1587cm-' (C=N). 'H-NMR (CCI,):
r=2.7 (d) and 3.1 (d), aromatic H ; 6.7 and 6.9 (AB part,
J = 13 Hz, diastereotopic benzyl H; 8.1 (9) and 9.2 (t), ethyl
H ; 5.9 (9)and 8.8 (t), ester ethyl H ; 7.6 (s) and 7.8 (s), S-methyl
H broadened by slow inversion.
2 R'SO~H
+ co,
30 % hydrogen peroxide (7.4g, 65 mmol) and p-toluenesulfonic acid (0.05g) are added with stirring to (4a) (4.05g,
IOmmol)in98-100% formicacid (15ml)at 0°C. The temperature is maintained at 10°C for 4 h by cooling (exothermic
reaction, evolution of carbon dioxide) and then allowed to
rise and kept at 20°C for 20h. The acid is drawn off under
vacuum in a rotary evaporator (bath temperature ~ 5 0 ° C )
and 50 % formic acid (10ml) added to the residue; the mixture
is then again evaporated to dryness[4! The (cold) residue
is covered with ether (30ml), 2 N sodium hydroxide solution
(IOml, 20mmol) cooled to 0°C is added, and the mixture
is stirred until dissolution is complete. After separation of
the ethereal phase the process is repeated with 5ml of 2~
sodium hydroxide. The united solutions are washed with a
small volume of water, dried over sodium sulfate, and the
ether drawn off under vacuum. (6a) (2.7g, 90%) is obtained
as a viscous colorless oil.-IR (film): 3350 and 1590 (NH2),
Angew. Chem. internat. Edit. 1 Vol. 14 ( 1 9 7 5 )
1 No. 6
1725cm-' (C=O). 'H-NMR (CC14): s=2.6 (d) and 3.0 (d);
7.0 and 7.4 (AB part, J = 13 Hz), benzyl H; 8.3 (m) and 9.15
(t), ethyl H ; 5.9 (9) and 8.75 (t), ester ethyl H; 8.7 (br. s),
amino H.
Received: March 14, 1975 [Z 204b IE]
German version: Angew. Chem. 87. 450 (1975)
CAS Registry numbers:
f l u ) . 54985-61-4; ( l b ) , 54985-62-5; ( 3 ~ )54985-80-7;
(3h). 54985-81-8: ( 3 c ) . 54985-65-8; (3d). 54985-82-9;
( 3 ~ ) . 54985-83-0; ( 4 ~ ) .54985-84-1 ; (461. 54985-85-2:
( 6 u J . 54985-86-3
Cf. D. H o p p r . Angew. Chem. 87, 44Y (1975); Angew. Chem. internat.
Edit. 14. 424 (1975).
121 Alkylation of ethyl potassioisocyanoacetate under analogous conditions,
for instance, affords mainly dialkylation products: cf. U . Srkiillkopf,
D. H o p p ~ and
R. Jrnrsch, Angew. Chem. 83, 357 (1971); Angew. Chem.
internat. Edit. 10. 331 (1971); U . Srkollkopf, D. Hoppr. and R. Jmrsrh.
Chem. Ber. 108. in press.
[ 3 ] D. €. Prurson and C. A. Burhler. Chem. Rev. 74. 45 (1974).
[4] The crude product (containing sulfonic acid) may be used for conversion
into free amino acids by acid or alkaline hydrolysis.
The Spreading Alkaloid Stenusin from the Staphylinid
Stenus comma (Coleoptera: Staphylinidae)[**]
By Hermann Schildknecht, Dietlinde Kruuss, Jutta Connert,
Hans Essenbreis, and Nicolas Orfanides"]
Srenus comma, a staphylinid weighing 2.5 mg and measuring
only 5 mm, inhabits the sandy banks of stagnant and sluggishly
flowing bodies of water. While hunting for springtail it sometimes falls into the water and would be doomed to drowning
if it were not able to dash over the surface at about 40
to 75cm/s-as if on water skis-to reach the safety of the
bank. While doing so it makes no use of its legs but merely
dips the tip of its abdomen for a brief moment into the.wgter
and releases a tiny drop of secretion from two paired pygidial
defense glands.
C H,
'C H,
From the little reservoir of the pygidial defense glands
we have isolated, apart from 6-methyl-5-hepten-2-one and
an isopiperitenol, eucalyptole ( 1 ) (also known as 1,8cineole)['! At this stage we could have regarded the spreading
phenomenon as solved-(1) has been known as a flotation
agent for a very long time-if it had not been for the major
gas chromatographic fraction of the spreading secretion: 6 mg
of an oil, isolated from the collecting bladders (length 0.4 mni)
of a thousand beetles, which we have called stenusin.
Structural elucidation of stenusin as an N-ethyl-3-(2-methylbuty1)piperidine (2) relied heavily on mass spectrometric analysis, especially the study of metastable transitions by the
DAD1 technique''! We recognized the molecular ion at m/e
[*I Prof. Dr. H. Schildknecht [ +], Dr. D. Krauss, Dr. J. Connert, DipLChem.
H. Essenbreis, and N. Orfanides
Organisch-Chemisches lnstitut der Universitat
69 Heidelberg. Im Neuenheimer Feld 270 (Germany)
[ +] T o whom correspondence should be addressed.
[**I Part 60 of Arthropod Defense Substances. This work was supported
by the Fonds der Chemischen Industrie and the Deutsche Forschungsgenieinschaft. We are grateful to V Purhz (Schlitz/Hesse) for identification of the
beetle and to Prof. Dr. H . Kuhri and Dr. D. Mijbius (Gottingen) for determination of thrust-time diagrams.-Part
59: H . Srhildknrckr, H . Holrkorrr, D.
K I Y I I I Aand
~ . H . Tuckrci, Liebigs Ann. Chem., in press.
183 (CllH25N) and the key fragments m / e 30, 44, 58, 72,
and 113.The 220 MHz 'H-NMR spectrum showed absorption
corresponding to an N-ethyl group at 6 = 2.3 ppm (q, J = 7 Hz,
CH2)and at 1.05 ppm (t, J = 7 Hz, CH3) as well as an absorption at 2.76ppm due to two protons situated x to nitrogen.
Of decisive importance for our structural proposal (2) was
the exclusive appearance of the ion at m/e 113 with significant
intensity in the mass spectrum of the natural product, in
contrast to the spectra of synthetic piperidines and perhydroazepines of molecular formula C ,2H,,N. This ion of odd mass
number can arise directly from the molecular ion of (2)
by loss of a pentenyl group from position 3 and a hydrogen
migration. The pentyl side chain should also be branched
such that a propyl fragment cannot be eliminated.
We have prepared (2) by total synthesis; the IR, 'H-NMR,
and MS spectra were practically identical with those of stenusin; the specific rotation [a]:& of the synthetic product[31
was 5.4k0.3" (c=3mg/ml ethanol) and that of the natural
product 5.8 0.3' ( c = 1.I 5 mg/ml ethanol). The absolute configuration of the insect alkaloid is currently being determined.
The ratio of the main components of the secretion of the
pygidial defense glands- 1 &cineole ( I ) and stenusin (2)amounts to 1 : 14. We may therefore assume that St. comma
survives primarily owing to the properties of stenusin. However, the most striking property of stenusin is its extremely
high spreading effect. If a spreading pressure-time diagram
is plotted for constant spreading area with the aid of a film
balance developed by Hans Kuhn (Gottingen) then a spreading
pressure of p=28.5 dyn/cm is found for (2), and only 2.2
dyn/cm for ( I ) ! The large difference arises from the tenfold
lower water solubility of stenusin (2) compared to 1,8-cineole
(1) (0.03 and 0.3
respectively). From these values it may
be assumed that (2) is the actual spreading substance. Velocity-displacement curves that we have determined by means
of a cine camera show a propagation rate of 32.5cm/s for
(2) and only 18 cm/s for (1 ). Hence (2) spreads much faster
than (1 ) and is therefore more valuable for the nonswimmer
St. comma. Both substances are terpenoid in character; in
the course of evolution the oxygen heterocycle (1) was transformed into the faster spreading nitrogen heterocycle (2)-a
terpenoid alkaloid. Compound ( I ) is active against various
microbes14'. The presence of the original ( 1 ) and the derived
defense substance ( 2 ) in the same organism constitutes the
highly interesting finding of a comprehensive analysis of the
defense substances of a staphylinid.
Received: January 24, 1975;
in shortened form: March 17, 1975 [I 205 IE]
German version: Angew. Chem. 87. 421 11975)
CAS Registry numbers:
( 2 ) . 54985-88-5
D. Brrger, Dissertation, Universitat Heidelberg 1968.
[2] J . Connerr. Dissertation, Universitat Heidelberg 1973.
[3] N. Orfunidrs. Diplomarbeit, Universitat Heidelberg 1975.
[4] Ullmanns Encyklopadie der Technischen Chemie. 3rd. Edit., Vol. 14,
p. 773. Urban und Schwarzenberg, Munchen 1963.
1,343,N-Silyl Shift in Silylated Thioamides[**]
By Wolfgang Walter and Hans- Wolfgang Luke[*]
Trimethylsilylamides exist in the amide form (N-silylation),
the iniidate form (0-silylation), or as an equilibrium mixture
of the two forms['].
[ + I and Dipl.-Chem. H.-W. Luke
Institut fur Organische Chemie und Biochemie der Universitat
2 Hamburg 13. Papendamm 6 (Germany)
[*] Prof. Dr. W. Walter
[ + ] T o whom correspondence should be addressed.
[**I This work was supported by the Verband der Chemischen Industrie.
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acid, branches, chains, alkylation, esters, amin, methyleneamino, bis, extended, alkylthio, metalated
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