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Coupling of Sterically Hindered Peptide BondsЧA Renaissance of the Acid Chloride Method.

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121 A. Bino, F. A. Cotton, 2. Dori, B. W. S. Kolthammer, J. A m . Chem. SOC.
103 (1981) 5779, and references cited therein.
131 B. E. Bursten, F. A. Cotton, M. B. Hall, R. C. Najjar, Inorg. Chem. 21
(1982) 302.
141 Reaction of the reactants in the molar ratio 1:I, tetrahydrofuran (THF),
12 h, room temperature, chromatography on silica gel (toluene/THF).
[5] Similar reactions have been investigated by F.G.A. Stone et al. (F. G. A.
Stone, private communication).
After removal[31of the Peoc group from 4, 5 is coupled
with the free amino function on the O-Peoc-hydroxyisovaleroyl chloride 7 obtained from 6[41to give the completely
protected sporidesmolic acid B derivative 8. The structure
of 8 was confirmed by the 200-MHz 'H-NMR spectrum.HNMe2ICH30H
ooc
*
H-Val-MeLeu-OtBu
5 , 84%
Peoc-Hyiv-OH
Coupling of Sterically Hindered Peptide BondsA Renaissance of the Acid Chloride Method**
Peoc-Val-OH
2
(COCIh
CH2CIz
Peoc-Valql
J.
-
Peoc-Hyiv-Val-MeLeu-OrBu
2) HNMez/CHsOH
81%
8 , 89%
Successive cleavage of the tert-butyl group and the Peoc
group at 0 "C affords the free sporidesmolic acid B 1. Its
melting point and IR spectrum were identical with those of
an authentic sample obtained from natural sporidesmolide
I[']. The rotation ([a];= - 106.7 (c=0.47, glacial acetic
acid)) also almost reached that of the natural product
([a]:= - 108, glacial acetic acid), thus indicating that no
racemization has taken place on using this acid chloride
method despite the twofold activation and condensation
involved.
Received: June 3, 1981 [Z 162 IE]
revised: June 7, 1982
German version: Angew. Chem. 94 (1982) 637
CAS Registry numbers:
1, 3200-76-8; 2,61083-76-9; 3, 82414-77-5: 4, 82414-76-4: 5, 82414-78-6; 6 ,
82414-79-7: 7, 82414-80-0; 8, 82414-81-1; H-MeLeu-Of-Bu, 42807-86-3.
[I] M. Bodanszky, Y. S. Klausner, M. A. Ondetti: Peptide Synthesis. 2nd
edit., Wiley, New York 1976, p. 89ff.
121 J. A. Ovchinnikov, W. T. Ivanov, A. A. Kiryushkin, K. Kh. Khalilulina,
lsv. Akad. Nauk S S S R . Otd. Khim. Nauk 1963, 578.
[3] a) H. Kunz, Chem. Ber. 109 (1976) 2670; b) Angew. Chem. 90 (1978) 63;
Angew. Chem. lnt. Ed. Engl. 19 (1978) 67.
141 H. Kunz, H.-H. Bechtolsheimer, Synthesis 1982, 303.
151 W. D. Russel, M. E. Brown, Biochim. Biophys. Acta 38 (1960) 382.
H-MeLeu-Or Bu
Fyridinr
3, quant .
New Method for the Synthesis of N-Vinylamides**
4 , 81%
on warming to room temperature. Since only volatile byproducts are formed there is no fear of contamination of
the resulting peptides. Solvent and excess oxalyl chloride
are removed in uacuo. Because of its high reactivity we
could couple 3 with N-methylleucine tert-butyl ester to
give the Peoc-dipeptide ester 4, for the synthesis of 1. This
process, which requires 1 h at -20 " C ,followed by 12 h at
room temperature, is of general utility for the synthesis of
sterically hindered peptide bonds.
[*) Prof. Dr. H. Kunz, H.-H. Bechtolsheimer
lnstitut fur Organische Chemie der Universitat
Johann-Joachim-Becher-Weg 18-20, D-6500 Maim (Germany)
This work was supported by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie.
630
Pyridine
-
Peoc-Val-MeLeu-OtBu
[**I
1
4
1) HCI/CH,CIz
1
1
kov et al.''] resorted to the acid chlorides of N-and O-benzyloxycarbonyl-protected synthons, despite the danger of
benzyl chloride cleavage and the side reactions of the
Leuchs-anhydrides.
The extremely acid-stable 2-(tripheny1phosphonio)ethoxycarbonyl (Peoc) protecting group developed by ud3]
now enables synthesis of the stable acid chlorides of the
amino and hydroxy acids, even at room temperature. In
contrast to amino acids with other N-protecting groups
even oxalyl chloride can be used as reagent. For example,
after addition of reagent at 0°C in dichloromethane, the
acid chloride 3 is smoothly generated from Peoc-valine 2
Pe oc -H yiv-Cl
7, 95%
6
By Hans-Heinrich Bechtolsheimer and Horst Kunz*
Dedicated to Professor Klaus Weissermel on the occasion
of his 60th birthday
Because of the high incidence of side reactions, high
susceptibility to racemization, and contamination by phosphorus compounds, activation of the carboxy group via the
acid chloride has largely lost significance in peptide synthesis"]. The advantages of the high reactivity of the acid
chloride are thus no longer exploited.
However, in the coupling of sterically demanding amide
bonds, as they frequently occur e . g . in natural depsipeptides, a strong activation of the carboxylic acid cannot be
circumvented. Hence, for the formation of the strongly
hindred amide bonds of sporidesmolic acid B 1 OvchinnoH-Hyiv-Val-MeLeu-OH
(COCI)*
_?*
0 Verlag Chemie GmbH, 6940 Weinheim. 1982
By Giinter SchrnitP and Wolfgang Ebertz
Dedicated to Professor Friedrich Asinger on the occasion
of his 75th birthday
Attempted basic hydrolysis of 2-ferrocenyl-2-oxazolines,
interesting intermediates for the preparation of 1,2-disubstituted ferrocenes''], led to the discovery of novel, general
reaction patterns for 2-oxazolines. It was found that 2-oxazolines 1 having at least one H-atom in the 4-position always isomerize to N-vinylamides 2 on reaction with potassium tert-butoxide (KOrBu) in solvents such as hexamethylphosphoric triamide (HMPT), dimethyl sulfoxide or
dimethoxyethane if C-5 is substituted by at least one alkyl
[*I Priv.-Doz. Dr. G. Schmitt, Dr. W. Ebertz
lnstitut fur Technische Chemie und Petrolchemie
der Technischen Hochschule
Worringer Weg I , D-5100 Aachen (Germany)
[**I This work was supported by the Fonds der Chemischen Industrie.
0570-0833/82/0808-0630 $ 02.50/0
Angew. Chem. In!. Ed. Engl. 21 (1982) No. 8
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