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Exhaustive tert-Butoxycarbonylation of Peptide Nitrogens.

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however, does not permit resolution of such sharp features
near the atoms.
Quantum-chemical calculations on a double-zeta basis
(omitting the p functions on hydrogen and all d functions)
give poor agreement with the experimental results.
Received: January 31, 1985;
revised: March 14, 1985 [ Z I150 IE]
German version: Angew. Chem. 97 (1985) 511
CAS Registry numbers:
NaZSzO,,7712-98-1; H,NSO,, 5329- 14-6.
[I] a) K. Angermund, K. H. Claus, R. Goddard, C. Kriiger, Angew. Chem. Y7
(1985) 241: Angew. Chem. i n f . Ed. Engl. 2 4 (1985) 237; b) International
Union o f Crystallography, Actn Cry.Ftu/logr.A 4 0 (1984) 184: M. Breitenstein, H. Dannohl, H. Meyer, A. Schweig, R. Seeger. U. Seeger, W. Zittlau, In!. Rev. Phys. Chem. 3 (1983) 335.
(21 a) J. W. Bats, H. Fuess, Actn Crmrullugr. B , in press; b) Y. Elerman, J. W.
Bats, H. Fuess, ihid. C3Y (1983) 5 15.
(31 J. W. Bats, Y . Elerrnan, H. Fuess, Actu Cry?tu// press.
[4] N. K . Hansen, P. Coppens, A r t u Crysrullogr. A 3 4 (1978) 909.
[5] D. W. J. Cruickshank, M. Eisenstein, J. M d . Strurr.. in press.
I ip. I. L c l l . c\pcrinicnldl \L.IIIL dcluImdiion dcn\ii) 111 \.i:SLJ,. I C W I L I I I ~ ~
1.0 A - '. Right: theoretical static deformation density in HINSOI. Contour
interval 0.1 e l k ' . The zero contour (dashed) is omitted in the experimental
map but included in the theoretical map. Top: electron deformation density
in the 0 - S - 0 plane. Below: electron deformation density in the X-S-0
plane ( X = S , N). Solid lines and dotted (or dashed) lines represent positive
and negative densities, respectively.
tive maxima in the S - 0 bond and the minima near sulfur
are similar in all maps. Also, the deformation density in
the vicinity of the S - 0 bonds shows approximate axial
symmetry in both experimental and theoretical maps.
In the molecular XSO mirror planes (Fig. 1, bottom), the
maxima and minima in NazS2O3and H3NS03 are similar.
The S-0 bond maxima even have similar slight skewnesses, and the asymmetry of the lone pairs of electrons on
oxygen in Na2S203, with the higher density on the S-S
side, is also apparent in the theoretical maps.
The biggest difference between theory and experiment is
that in the theoretical maps for sulfamic acid the theoretical maxima for the nonbonding electrons on oxygen are
appreciably higher in the OSO plane than in the XSO
plane, whereas in the experimental maps for thiosulfate
this is not the case. The difference between sulfamic acid,
which may be regarded as the zwitterion (H,N)+(SO,)-,
and S,O:- is not unexpected. First, it is consistent with
differences we have found theoretically between SO 5 and
SO:- (the maps for H 3 N S 0 3 and SOY being very similar). Secondly, it is consistent with the differing bond character in the two molecules. I n sulfamic acid the S - N bond
length corresponds to that of a single bond, while the S-0
length of 1.441 A shows considerable double-bond character. This explains the non-uniform distribution of nonbonding electrons on the oxygen atom. I n the thiosulfate
anion the S-S bond length of 2.007 A indicates some double-bond character, and the S-0 length of 1.479 A is typical for that in a sulfate group. Thus, a more uniform distribution of non-bonding electrons is to be expected near
the oxygen atom in the thiosulfate.
In the experimental maps the densities of the oxygen
non-bonding electrons are nearly as spread out as those of
the bonding electrons, whereas in the theoretical maps the
densities of the oxygen non-bonding electrons exhibit
small sharp peaks. The method of experimental analysis,
5 10
0 VCH Verlugsgesell.schnji mhH. 0-6940 Weinheim. I985
Exhaustive tert-Butoxycarbonylation of Peptide
By Leif Grehn and Urf Ragnarsson*
We have recently described an efficient and convenient
method for the preparation of Boc-pyrroles and Boc-indoles (Boc = tert-butoxycarbonyl) using Boc,O in dry acetonitrile or dichloromethane"] with 4-dimethylaminopyridine (DMAP) as ~ a t a l y s t . ' ~By
, ~ this
procedure we have also
synthesized tryptophan derivatives protected on the indole
nitrogen and shown that such compounds may be useful
for peptide synthesis in s ~ l u t i o n . ' However,
when excess
BoczO was used in these preparations, several byproducts
were frequently obtained. Spectral evidence indicated that
these crude mixtures contained substances with Boc
groups on amide nitrogens. To elucidate the scope of this
reaction, we have now investigated the action of Boc,O/
DMAP on some simple model substrates.
It was found that the urethane moiety in Boc-Gly-OBzl
was completely acylated using only a slight excess of
Boc,O/DMAP in acetonitrile, affording the N.N-diacyl
compound 1 in high yield. 1 is surprisingly stable and
could be handled without special precautions. Since diacylation of amino nitrogens is relatively difficult to accomplish in most cases, this novel approach may prove useful
for the preparation of diacylamino derivatives in general.
In particular, mixed diacyl analogues might be available
by stepwise synthesis.
When Boc-Pro-Gly-OMe was treated with 1.1 equivalent
of the reagent mixture, acylation occurred smoothly at the
only available nitrogen atom, giving 2 in excellent yield.
('1 Dr. L. Grehn, Dr. U. Ragnarsson
Institute of Biochemistry. BMC, University of Uppsala
Box 576, S-75123 Uppsala (Sweden)
This work was supported by the National Swedish Board for Technical
Development and the Swedish Natural Science Research Council.
OS70-0833/85/0ciO6-0lO$ 02.50/0
Angew. Chem. i n t . Ed. Engl. 2 4 (1985) No. 6
The outcome of this reaction thus appears to open u p new
possibilities for the facile protection of peptide bonds with
Boc groups. In the same way, both amide hydrogens in ZPro-NH, (Z = benzyloxycarbonyl) could easily be replaced
by Boc employing 2.2 equivalents of Boc20. The product
3, like I and 2, was sufficiently stable to withstand normal
workup including aqueous extractions (Table 1). Both Boc
groups were smoothly removed from 3 with 33% trifluoroacetic acid in dichloromethane within 45 min (TLC) at
room temperature.
Table I . Yield and physical data of the Boc derivatives 1-3. All new compounds gave satisfactory elemental analyses (C, H, N). The yields are based
on the crude product. which was pure by TLC (toluene :acetonitrile, 2 : I).
"C-NMR (CDCI,, G(CDCI,)= 77.0).
I : 95"/0 yield, m.p. =30.5-31.0°C (petroleum ether, 10 mL/g, active charcoal, -70°C): "C-NMR: 169.0 (ester CO), 151.8, 83.1, 27.9 (Boc), 135.4,
128.5, 12X.3, 66.8 (benzyl), 47.4 (Gly CH2)
2 : 100% yield, m.p.=93.0-93.5"C (as for 1 but 50 mL/g); [a]g -41.2
( c = 1, DMF); I3C-NMR: 17561175.2 (peptide CO), 169.5/169.2 (ester CO),
154.4/153.8, 84.2/84.0, 28.4/28.2 (peptide Boc), 151.8/151.7, 79.4, 27.8 (aBoc), 61.W60.8 (Pro, &), 30.9130.2 (Pro, PC), 23.5/22.8 (Pro, yC), 46.9146.5
(Pro, 6C), 52.1 (ester Me), 45.3 (Gly CHZ)[a1
3: 87Oh yield; oil (as for 1 , but 25 mL/g). The white precipitate melts below
0°C but later solidifies at room temperature; [a]C -31.2 ( c = I , DMF); "CNMR: 173.5/173.2 (amide CO), 149.1, 85.0, 27.5 (Boc), 154.6/154.1, 136.8,
128.3, 127.8. 127.3, 66.9 (2). 60.6/59.8 (Pro, aC), 30W29.9 (Pro, PC), 23.61
22.9 (Pro, yC), 47.1/46.6 (Pro, 6C) [a]
Azahexamethineneutrocyanines from a
By Gerhard Maas* and Bernhard Feith
Nucleophilic ring-opening reactions of quaternary pyridinium salts which initially involve a-addition of the nucleophile are always likely to succeed if the heterocycle
bears a strong electron-attracting substituent on the nitrogen atom.['' It would appear that pyridinium salts bearing a cationic substituent, have-with the exception of one
(2-pyridinio)pyridinium salt'*I-so far never been used for
such rearrangements.
We have now found that the N-tetrammethyl formamidinio)pyridinium salt 2, which is readily accessible from the
"dication ether" salt lf3]
and pyridine, is also attacked at
the a-C atom by the anions of active methylene compounds 3 ; as usual the primary product 4 undergoes ringopening to give 6. N-protonation of the isolated compound 6b was verified by a weak vicinal coupling with H6. On reaction with bases the deep-colored azaneutrocyanines 7a-d are formed. Their all-trans configuration is
proven by the X-ray structure analysis of 7a (see Fig. 1)
[a] Doubling of signals due to the presence of two conformers [S].
Acyclic diacylamines have been reported previously but
such compounds are often unstable and may revert to
m o n o a ~ y l a m i n e s . 'Peptide
~ ~ ~ ~ bonds carrying trifluoroacetyl groups are known but they are also sensitive to hydrolysis."' With respect to stability, therefore, the new Boc compounds are superior to earlier diacylamines. Moreover,
their lipophilic properties enhance their solubilities in solvents frequently used in peptide synthesis.
Experimental Procedure
DMAP (12 mg, 0.1 mmol) was added t o a stirred solution of the peptide derivative (1.0 mmol) in dry acetonitrile (2-3 mL) followed by Boc10 (240 mg,
1.1 mmol). After stirring for 5 h at room temperature, all peptide starting material was consumed (TLC, toluene :acetonitrile, 2 : I). The brownish reaction
mixture was evaporated at room temperature and the oily residue partitioned
between ether (50 mL) and I M aqueous K H S O l (25 mL). The organic extract
was thoroughly washed in turn with 1 M aqueous solutions of KHSO, and
N a H C 0 3 and finally brine and dried over MgS04. Evaporation to complete
dryness (high vacuum, room temperature) left a light yellow oil, which was
chromatographically pure. Recrystallization from petroleum ether (decolorizing carbon) gave an analytically pure product (see Table I).
Received: February I , 1985;
supplemented: March 29, 1985 [Z 1151 IE]
German version: Angew. Chem. 97(1985) 519
3-7 a
Angew. Chem Inr Ed. Engl. 24 11985) No. 6
[I] L. Grehn, U. Ragnarsson, Angew. Chem. 96 (1984) 291; Angew. Chem. Int.
Ed. Engt. 23 (1984) 296.
(21 G. Hofle, W. Steglich, H. Vorbruggen, Angew. Chem. 90 (1978) 602; An9ew. Chem. Inl. Ed. Engl. 17 (1978) 569.
[ 3 ] E. F. V. Scriven, Chem. SOC.Reu. 12 (1983) 129.
I41 L. Grehn. U . Ragnarsson, J . Chem. SOC. Chem. Commun. 1984, 1699.
[S] J. C. Sheehan, E. J. Corey, J . Am. Chem. SOC.74 (1952) 4555.
161 J . W. Barton in J. F. W. McOmie (Ed.): Protectiue Groups in Organic
Chemistr!. Plenum, London 1973, p. 46.
171 F. Weygand, R. Geiger, U. Glockler, Chem. Ber. 89 (1956) 1543.
[81 W. Voelter, S. Fuchs, R. H . Seuffer, K. Zech, Monatsh. Chem. IOS (1974)
I 110.
1'1 Priv.-Doz. Dr. G. Maas, Dipl.-Chem. B. Feith
Fachbereich Chemie der Universitat
Erwin-Schrodinger-Strasse,D-6750 Kaiserslautern (FRG)
I**] Dication Ethers, Part 9. This work was supported by the Deutsche Forschungsgemeinschaft.-Part 8: G. Maas, J . Chem. SOC.Perkin Trans. 2,
in press.
0 VCH Verlagsgesellschafr mbH. 0-6940 Weinheim. 1985
0570-0833/85/0606-05I1 $ 02.50/0
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nitrogen, exhaustive, tert, butoxycarbonylation, peptide
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