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An Amino-Protecting Group for Use in Peptide Synthesis Which Can Be Introduced Electrochemically.

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formed is purified by sublimation at 5OoC/0.1 torr; yield 0.9
g (43%) (S), m. p. 93-96 "C (dec.).
Received: January 9, 1980 [Z 542 b IEI
supplemented: April 8, 1980
German version: Angew. Chem. 92, 738 (1980)
CAS Registry numbers:
(4). 63950-84-5; (6). 74563-07-8: (7), 74592-15-7; 181, 74592-16-8; SO>,7446-09-5,
t-BuNSO, 38662-394; Cr(CO)6, 13007-92-6
111 E. Niecke, H.Zorn, B. Krebs, C. Henkel, Angew. Chem. 92, 737 (1980); Angew. Chem. Int. Ed. Engl. 19, 709 (1980).
[2] H. Quast, M . Heuschmann, 2nd Int. Symposium on Inorganic Ring Systems.
Gottingen 1978; Angew. Chem. 90, 921 (1978); Angew. Chem. Int. Ed. Engl.
17, 867 (1978). and references cited therein.
(31 E. Niecke, R. Kroher. G. Ringel. Chemiedozententagung, Marburg 1977; C
Ringel, Dissertation, Universitat Gottingen 1977; S. Pohl, J. Organomet.
Cbem. 142, 185, 195 (1977): E. Niecke, G. Ringel, S. Pohl, unpublished.
141 H.Zorn, Diplomarbeit. Universitat Gottingen 1975.
[5] 0. J. Scherer, N. Kuhn, H . Jungmann, 2. Naturforsch. B 33, 1321 (1978).
[6] (8) crystallizes monoclinically, space group P2,/n, a = 1126.2(3),
b= 2186.4(5), c=632.6(2) pm, p = 100.65(3)", V = 1530.8 x 10' pm', 2 = 4 (at
- 130°C). Refinement with the structure factors of 2661 observed reflections
converged to the unweighted R value of 3.5%.
[71 A comparable bond length IS observed in ions of the type [ N-P-.N
] +:
S. Pohl, Z . Naturforsch. B32, 1342(1977); A. H . Cowley, M . C. Cusher, J. S
Szobota, J. Am. Cbem. SOC.100, 7784 (1978).
[8] D. E. C. Corbridger The Structural Chemistry of Phosphorus. Elsevier, Amsterdam 1974.
By Mohamed Hassen Khalga, Giinther Jung, and Anton
Riekerl'l
In acetonitrile, sterically hindered phenols of type (1) can
be electrochemically oxidized to phenyloxylium ions which
form p-quinols or p-quinol derivatives in the presence of nucleophiles (water, alcohols and amines)[l.21.The specificity
and yield of this synthesis are usually far higher than normally attained in chemical oxidation.
We now report the application of electrochemical oxidation of 2,4,6-trisubstituted phenols to the synthesis of new Nprotected amino acids and peptide derivatives. A suitable
reagent is 3,5-di-tert-butyl-4-biphenylol
(la) which is readily
accessible by reaction of 2,6-di-tert-butyl-l,4-benzoquinone
with phenylmagnesium bromide and subsequent reduction
with z i n ~ / H C l [ ~ Introduction
.~].
of the new protecting group
3,5-di-tert-butyl-4-oxo-l
-phenyl-2,5-cyclohexadienyl(PChd)
OH
I .
R NH-CR'R2-COOR3
(3)
['I Dr. M.H. Khalifa, Prof. Dr. G. Jung, Prof. Dr. A. Rieker [ '1
Institut fur Organische Chemie der Universitat
Auf der Morgenstelle 18, D-7400 Tiibingen 1 (Germany)
[ '1 To whom correspondence should be addressed.
This work was supported by the Deutsche Forschungsgemeinschaft and the
Fonds der Chemischen Industrie.
712
0 Verlag Chemre, GmbH, 6940 Weinheim, 1980
Table 1. Yields and physical data of selected PChd-protected amino acids (3a)
and peptides derivatives.
N-PChd derivative
PChd-Gly-OH
PChd-t-Ala-OH
PChd-Aib-OEt
PChd-Aib-OH
PChd-L-Leu-OBzI
PChd-L-Leu-OH
PChd-L-Pro-OBzl
PChd-L-Pro-OH
PChd-L-Leu-Gly-NH2
PChd-L-Pro-L-Leu-Gly-NH2
Yield
[%I
M.p.
I"C1
90 tai
94 la1
97 Ibl
94 14
89 Ibl
60 Icl
59 1'4
57 Icl
85 Id1
75 [d]
167-168
181-1 83
88-89
169-171
86-87
131-133
144-145
81-82
148
116-1 18
la]::
RF
[gI
(el
-
0.30 (11)
0.45 (11)
0.26 (I)
0.48 (11)
0.41 (I)
0.69 (11)
0.29 (I)
0.56 (11)
0.58 (11)
0.54 (11)
- 125.9
~
- 169.5
- 185.3
+
55.3
+
+
51.3 [Q
70.5
+ 183.8
[a] Based on (la) after hydrolysis of (3). [b] Based on ( l a ) (on reaction of H-AibOEt with (lo)in a molar ratio of 1 : I the yield is 82%). [c] Based on hydrolysis of
(3). [d] Based on coupling of PChd-Leu-OH and PChd-Pro-OH, respectively. [el
c= 1 , ethanol. [Q c=O.4. [g] (I) Dichloromethane/light petroleum (3:2), (11)
chloroform/methanol (8: 1).
The alkali-stable PChd group can be quantitatively removed by 50% trifluoroacetic acid (TFA) in dichloromethane within 15 min at 25 "C. The protecting group regenerates a phenol (4)['] which can easily be separated from the
amino acid ester (5) by extraction with diethyl ether.
An Amino-Protecting Group for Use in Peptide
Synthesis Which Can Be Introduced
Electrochemically[**J
[**I
is accomplished by anodic oxidation of (la) in dichloromethane in the presence of the free amino acid esters (2) at an
anode potential of + 1300 mV us Ag/O.Ol M Ag@at a platinum electrode in an undivided cell.
The N-(PChd)-amino acid esters (3a) (Table 1) are usually
formed cleanly, with high selectivity, and without racemization. Polyfunctional amino acids have to be completely
blocked except for the amino group to be protected.
TFA/CH2C12
(301
H,C, NH-CR'R2-COOEt
(4i
$"
C6H5
+
F3
H2N-CR'R"COOEt
*
TFA
(5)
These mild acidolysis conditions permit selective use of
this protecting group alongside benzyloxycarbonyl, benzyloxy, and benzyl ester protecting groups, even in syntheses involving repeated coupling and deblocking steps.
Particularly useful is the quantitative hydrogenolytic removal with Pd/C (10%)in methanol which regenerates the
protecting group in its original form (la). This method of removal permits its use alongside all hydrogenolysis-stable
protecting groups, e. g. the Boc group.
The applicability of the PChd protecting group in peptide
synthesis has been tested in the case of the MSH inhibitor HL-Pro-L-Leu-Gly-NH,["I (see Table I). Coupling of PChd-LLeu-OH with H-Gly-NH2 by the DCC/HOBt method afforded Pchd-~-Leu-Gly-NH~.
The H-L-L~U-GIY-NH~
generated both by acidolysis as well as hydrogenolysis was then
reacted with PChd-L-Pro-OH by the same method to give
well-crystalline, unequivocally characterized PChd-L-Pro-LLeu-Gly-NH, which, on hydrogenolysis, gave chromatographically pure, racemate-free H-L-Pro-L-Leu-Gly-NH2.Thus
the new protecting group fulfils the requirements of unequivocal peptide syntheses[']. The PChd group also facilitates
ready fast monitoring of the course of reaction by means of
UV detection. Easy recovery of the phenol (la) after hydro-
0570-0833/80/0909-0712
d 02.50/0
Angew. &hem Int. Ed. Engl. 19 (1980) No. 9
genolytic removal of the protecting group should prove valuable, above all when working on a large scale.
Anodic oxidation of the phenol (lb) in the presence of amino acid esters (2) afforded N-(I ,3,5-tri-tert-butyl-4-oxo-2,5cyclohexadieny1)amino acid esters; however, the yield obtained is lower (<50%). Removal of this protecting group
can only be accomplished by catalytic hydrogenation. Finally, the PChd group can also be introduced electrochemically
to protect the carboxy group of N-protected amino acids.
General procedure
(la) (2.82 g, 10 mmol), (2) (20mmol), and 2,6-dimethylpyridine (2.14 g, 20 mmol) are dissolved in dichloromethane
(150 ml) which is 0.1 M in Et,NBF,. After saturation with Nz
the mixture is electrolyzed at Pt gauze electrodes in an undivided cell[*'. The initial anode potential is chosen (ca.
+ 1000 mV us Ag/O.Ol M Ag@)such that the current lies below 130 mA. In the course of electrolysis the current falls o f t
the electrode potential is then increased stepwise to + 1300
mV and the reaction continued until (Za) has been completely consumed. The solvent is removed in uucuo and the residue washed repeatedly with diethyl ether. The oily residue of
PChd-amino acid ester (3u) and 2,6-dimethylpyridine, obtained after removal of the ether, can be separated by a single filtration over silica gel (light petroleum 60-90 "C/dichloromethane 2 :1 as eluent) and crystallization from alcohol. Oily PChd-amino acid esters (Gly, Ala) can also be hydrolyzed with 0 . 2 N NaOH in CH,OH/H,O (4: 1) immediately upon extraction.
Received March 3, 1980 [Z 543 IE]
German version: Angew. Chem. 92, 739 (1980)
CAS Registry numbers:
(la), 2668-47-5; H-Gly-OH, 56-40-6; L-H-Ala-OH, 56-41 -7; H-Aib-OEt, 111349I ; H-Aib-OH. 62-57-7, L-H-Leu-OBzl. 1738-69-8; L-H-Leu-OH. 61-90-5; L-HPro-OBzl, 41 324-66-7; L-H-Pro-OH, 147-85-3; L-H-Leu-Gly-NH2, 39705-58-3; LH-Pro-L-Leu-Gly-NH2, 2002-44-& PChd-Gly-OH, 74763-73-8; PChd-L-AlaOH. 74763-74-9; PChd-Aib-OEt, 74763-75-0; PChd-Aib-OH. 74763-76.1: PChdL-Leu-0921, 74763-77-2; PChd-L-Leu-OH, 74763-78-3; PChd-L-Pro-OBzI,
74763.794. PChd-L-Pro-OH, 74763-80-7; PChd-L-Leu-Gly-NH,, 74763-81-8;
PChd-L-Pro-L-Leu-Gly-NH2, 74763-82-9; 2,6-di-tert-butyl-1,4-benzoquinone.
719-22-2 phenyl bromide, 108-86-1
[l] A. Ronlan. V D. Parker, J. Chem. SOC.C 1971, 3214.
121 A. Rieker, E:L. Dreher, H . Geisel, M.H . Khalifo. Synthesis t978, 851.
[3] A . Rieker, P. Ziemek, Z . Naturforsch. B 20, 640 (1965).
[4] A . Rieker, K. Scheffler, Justus Liebigs Ann. Chem. 689, 78 (1965).
[5] Cf. A. Nishmaga. K. Nakamura. T. Matsuura, A. Rieker, D. Koch, R. Griesshammer, Tetrahedron 35, 2943 (1979).
161 R. A. Boissonnas, Sl. Guttmann, P A. Jaquenoud, J.-P. Waller, Helv. Chim.
Acta 38, 1491 (1955).
[7] E. Wimsch in Houben-Weyl-Muller: Methoden der organischen Chemie. 4th
Edit., Vol. XV/l. Thieme, Stuttgart 1974.
The Ambiphilicity of l,l-Diethoxy-4,4,4-trifluoro-3(triflu0romethyl)-1,2-butadiene[**~
By Rolf W. Saalfrank, Winjiiied Paul, and Heide Liebenow"'
Electron-rich or electron-deficient allenes, e. g. tetrakis(dimethy1amino)allene or allenetetracarboxylic acid tetraethyl
ester, respectively react at the central atom C 2 with electrophiles or nucleophiles to give dipolar productsci1.Ambiphilic
carbenes, e. g. chloro(methoxy)carbene, exhibit electrophilic
and nucleophilic selectivity, respectively, towards electronrich and electron-deficient olefins"]. If the donor substituent
(Do) in an ambiphilic carbene (2) is replaced by a stabilized
['I Univ.-Doz Dr. R. W. Saalfrank, Dipl.-Chem. W. Paul, H. Liebenou
lnstitut fur Organische Chemie der Universitat Erlangen-Niimberg
Henkestrasse 42, D-8520 Erlangen (Germany)
I"]
Donor/Acceptor-SubstitutedAllenes, Part 5. This work was supported by
the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Indusirie.-Part 4: R. W. Saalfmnk, E. Ackermann, H. WinkIer, R. Bohme, Chem.
Ber., in press
Angew. Chem. Int. Ed. Engi. 19 (1980) No. 9
A.
.Do
)Do
A'
'Do
(3)
anion, and the acceptor substituent (A) is replaced by a stabilized cation, then one obtains a dipolar carbene (2) which
can also be regarded as allene (3). We have now found that
such donor/acceptor-substituted allenes are likewise ambiphilic, i. e. can react at the central atom C2 both electrophilically as well as nucleophilically.
Reaction of hexafluoroacetone (4) with (2,2-diethoxyviny1idene)triphenylphosphorane (5) affords the thermally
surprisingly stable 3-(diethoxymethylene)-2,2,2-triphenyl4,4-bis(trifluoromethy1)-1,2X5-oxaphosphetane (6)13] (yield
92%; m.p. 109"C, dec.), which only decomposes above
100 "C into triphenylphosphane oxide and 1,l-diethoxy4,4,4-trifluoro-3-(trifluoromethyl)-1,2-butadiene (7). The
characterization of (6) as a derivative of pentavalent phosphorus was achieved ,'P [ 'H) -NMR spectroscopically (Table
1). The 13C{'H) -NMR spectrum contains only four signals
(Table 1) for the three phenyl groups. The equilibration of
the apical and equatorial positions of the trigonal-bipyramidal structure (6) already takes place rapidly ( I3C-NMR time
scale) at room temperature by a ligand-rearrangement process.
Table 1 Some characteristic spectroscopic data of the compounds (6)-(12)
[a]
(6), 'H-NMR: 0.63 (t. 3H, CHI), 1.29 (I,3H, CH3). 3.33 (4, 2H, CHI). 3.92 (4.
2H. CHI), 7.15 to 7.80 (m, 15H, phenyl-H); "CC:'H)-NMR: 164.38 (d,
=C(OEt),, 2Jpc=12.2), 140.45 (d, 3 phenyl-C, 'Jpc=100.7), 133.08 (d, 6 phenyl-C, IJPc= 10.6), [b]. 128.94 (d, 3 phenyl-C, 4Jpc=2.3), 127.45 (d, 6 phenyl-C,
IJpc=f3.0), 106.66 (d, =C-P,
'Jpc=144.9), 66.62 (s, CH2), 66.37 (s, CH2).
14.14 (S, CHI), 13.95 (s, CHI); I9F-NMR: 5.86 (s, 6F, CF,); "P['H;-NMR:
- 49.09
(7). 'H-NMR: 1.39 (1, 6H, CH,), 3.64 (q. 4H, CHd; "C('H;-NMR: 199.57 (m,
=k),
160.26 (s, =C(OW2), 118.82 (q, CF3, ' J ~ ~ = 2 7 5 . 6 )109.36
,
(sept,
=C(CF3)2. 2J~c=37.3),68.89 (S, CH,), 14.23 (S. CH,): '9F-NMR: - 14.52 (s, 6F.
CF3); IR (Film): v(C=C=C) = 1965 cm - '
(8a), 'H-NMR 1.18 (1, 3H, CH,), 1.30 it. 3H, CH,), 3.88 (q, 2H, CHI), 3.99 (q.
2H, CHI), 7.12 to 7.70 (m. 5H, phenyl-H); "C;'H;-NMR: 158.53 (5,
=C(OEt)d, 157.15 (qt. =CF2, 'J~c=300.5, 'JFC-4.0). [b], 89.49 (s. -CPh),
87.42 (m. =CCFI); I9F-NMR: -0.75 (quin, dq), 1 F, =CF. 2JFF=11.0,
(dq, 1F, =CF, 2Jm=11.0, " J ~ ~ = 1 7 . 1 )-19.44
,
(dd, 3F.
4 J ~ ~ = 1 1 . 0 )-2.18
,
0,
CFi, 4 J ~ ~ = 1 1 .4J~F=17.1)
(8b), 'H-NMR: 1.23 (t, 3H, CHa), 1.28 (1, 3H, CHI), 1.73 (s. 3H, CHI), 3.80 (9,
2H, CHI), 3.88 (4,2H, CHI); "Cj'H:-NMR: 156.38 (s, =C(OEt)?), 156.16 (qt,
=CF2, ' J ~ ~ = 2 9 7 . 5'J~cZ4.0).
,
123.25 (ddq, CF,, 'J~c=271.6, ' J ~ c 1 5 . 0 ) .
87.00 (m, =CCF3), 8488 (s, =CCH,); I9F-NMR: 18.67 (dd, 3F. CF,.
4 J ~ ~ = 1 1 . "JFF=~O.O),
5,
0.60 to -1.45 (m. 2F, =CF,)
(96). 'H-NMR: 1.24 (1, 9H. CHI), 3.55 (q,6H, CH2), 6.66 (s, broad, 1 H, =CH);
"C:'Hj-NMR 143.46 (m, =CH), [b]. 12089 (q. CFI, 'JFc=276.1), 119.55 (q,
CF,, 'J~c=276.1). 110.74 (s, C(0Et)t); "F-NMR: -14.32 (dq, 3F, F,C' (?),
4 J ~ ~ = 8 . 2"Jnf=1.5),
.
-20.57 (9,3F, FIG", " J F F = ~ . ~ )
(lo), 'H-NMR: 1.36 (1. 3H, CH3). 3.38 (q, 2H, CHI), 6.95 (s, broad, 1 H, -CH);
"C:'H:-NMR: 162.02 (s, COOEt), 132.82 (m, =CH), [h], 120.34 (9, CF3,
'JFC=274.1), 119.63 (q.CF,, 'JFc=275.5); "F-NMR: - 13.27 (dq, 3F, FIC" (?),
'JFF= 6.8, 4 J n =
~ 1.4). - 17.50 (9, 3 F, F3Ch,4 J= 6.8)
~ ~
( I t ) , 'H-NMR: 1.36 (t. 6H, CH,), 3.65 (4, 4H, CH,), 7.20 to 7.93 (m, 5H, phenyl-H); "C i 'Hi -NMR: 156.53 (s, C=O), 153.07 (s, =CC(OEt),), [b], 119.93 (q.
CF,, 'J~c=275.4), 119.41 (4.CF,, 'J~c=276.9),109.84 (s, C(OEt),); "F-NMR:
),
(9.3F, CF3, 4JFF=7.8)
-17.13 (9,3F, CF3, 4 J ~ ~ = 7 . 8-20.32
(12). 'H-NMR: 1.36 (t, 3H, CH,), 4.43 (q, 2H, CHI), 7.16 to 7.90 (m. 6H, phenyl-H and NH); "Ci'H:-NMR 161.90 and 157.05 (twos, CONH and COOEt),
142.42 (S, =CCOOEt), [b], 119.99 (4.2 CF,, 'J~c=277.0);I9F-NMR: 17.88 (q,
(q, 3F, CF3, 4 J ~ ~ = 7 . 7 )
3F, CF3, 4 J ~ ~ = 7 . 7 )-18.75
,
la] C D C L 6 values, J [Hz]: 'H-NMR (60.00 MHz) and "C:'H:-NMR (25.15
MHz) TMS int.; IYF-NMR (94.09 MHz) F3CCOOH ext. and "P:'H:-NMR
(40.48 MHz) &PO4 ext. [bl The positions of CF, and/or C(CFI)2 are not
clear.
0 Verlag Chemie, GmbH, 6940 Weinheim, 1980
0S70-0833/80/0909-0713
$02.50/0
713
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