Recovery of Chiral -Ferrocenylalkylamines on Stereoselective Peptide Synthesis by Four-Component Condensation.

plexeslq. According to X-ray crystallographic and spectroscopic findings the crystalline hydrates of the mineral acids may
also be formulated as oxonium salts; but their low melting
points make it difficult to prepare single crystals large enough
for neutron diffraction experiments.
We have now succeeded in preparing a single crystal of
hydrogen bromide dihydrate H B r . 2 H z 0 weighing cu. 130mg
in a lead-glass capillary by controlled passage of a hot-wire
loop along the capillary in a stream ofcold
The positions
of the 0 and Br atoms were already known from an earlier
X-ray structure
from which the probable presence
o f H 5 0 f and Br- ions was concluded. Our neutron diffraction
analysis has not only made it possible to confirm the location
of the 0 and Br atoms but also of the H atoms, and to
measure the H50: ion exactly.
H5O2Brcrystallizes monoclinically in the space group P21/c
with the lattice constants (-40°C) a=4.23, b= 12.57,
c = 6.94 A;
p= 101.4"; Z = 4 ; dexp ( - 15"C)= 2.1 1 L5],
d,,, =2.15 gcm-3. Three-dimensional neutron diffraction data
were collected with the help of the CP5 reactor at the Argonne
National Laboratory. Structure determination based on the
positions of the Br and 0 atoms found by X-ray studies,
as well as isotrobic and anisotropic refinement for all atoms
with 522 independent data corrected for absorption
(p= 1.62C ~ T -I ) with maximum diffraction angle 2 8 = 80"
(hn=1.142A) gave an agreement factor of R=0.149 (0.094
for 373 reflections > 1 0).
The resulting positions of the atoms
are listed in Table 1.
Table I . Atomic coordinates of H 5 0 2 B r (in brackets: estimated standard
deviation to the last decimal place).
x
0.0244(9)
0.5622(16)
0.3037( 18)
0.4271(22)
0.7041(24)
0.4026(28)
0.2223(25)
0.232 l(25)
($
I'
0.33 14(3)
0. I253(4)
0.0599(6)
0.0966(6)
0.1872(8)
0.1433(7)
-0.01 15(8)
0. I023(7)
0.1553(5)
0.0421(10)
0.2964( 10)
0. I657( 14)
0.0791(15)
- 0.0774( 16)
0.301 6( 13)
0.3972( 15)
Br
a
3.26
0
0
3.24
Fig. I . The cation Hs02in hydrogen bromide dihydrate. Atomic distances
in A, underlined values for distances between 0 and Br atoms: standard
deviation 0.01 A (for the quoted angle 0.8").
Figure 1 shows thediaquahydrogen cation with four symmetry equivalent bromide ions as hydrogen bridging partners.
The central 0-H-0
bridge is remarkably short (mean value
of previously determined 0-0 distances in cations of this
type amounts to 2.44A). The hydrogen atom is not exactly
central, even in this short bridge, a finding that can be corre492
lated with the slight asymmetrical environment of the two
oxygen atoms in view of the bond lengths and 0-Br contacts.
A deviation of about 5" from the straight 0-H-0
arrangement was previously observed in all H50: ions, which are
not fixed at 180" by a center of symmetry.
In contrast to the terminal hydrogen atoms, the central
atom shows its largest vibration amplitude almost in the
bond direction-a finding which in similar cases was explained
in terms of a broad, flat potential
There is no
evidence of disorder of the hydrogen atom between two
half-occupied sites.
Received: April 23, 1976 [Z 467 IE]
German version: Angew. Chem. 88. 507 (1976)
CAS Registry number:
H502Br, 51222-77-6
[I] J . M. Williams and S. W Peferson, Acta Crystallogr. A25, S113 (1969);
[2]
[3]
[4]
[5]
[6]
J . - 0 . Lundgren and J . M . Williams, J . Chem. Phys. 58, 788 (1973); J . - 0 .
Luitdgren and R . TeUqren. Acta Crystallogr. B30, 1937 (I 974).
J . M . Williams and S. W Peferson. J. Am. Chem. SOC.91, 776 (1969);
G . D. Brunfon and C. K . J o h n s o n , J . Chem. Phys. 62, 3797 (1975).
Samples with a molar ratio of exactly I : 2 were prepared by Prof. J .
E . Finholr, Carlton College, Northfield, Minn. (USA).
Lundgren, Acta Crystallogr. 8 2 6 , 1893 (1970).
H. W B. Roozeboom, Recl. Trav. Chim. Pays-Bas 4, 344 (1885).
A. Sequeira, C. A. Berkebile, and W C . Hamilton, J. Mol. Struct. 1 ,
283 (1967-1968); A. L . Macdonald, J . C. Speakman, and D . Hadzi,
J. Chem. SOC.Perkin 11 1972, 825.
Recovery of Chiral a-Ferrocenylalkylamineson Stereoselective Peptide Synthesis by Four-Component Condensation[**]
By Gerhard Eberle and Iuar Ugifl
a-Ferrocenylalkylamines ( 4 ) have proved well suited as
chiral amine components for stereoselective peptide syntheses
by four-component condensation[']. In combination with the
recently discovered multiplication of stereoselectivity121and
the enhancement of stereoselectivity by addition of quaternary
ammonium salts of the acid component (3)[31 products (5)
[and (7)] of almost uniform stereochemistry can be obtained
by use of the amines ( 4 ) , and especially wferrocenylisobutylamine (4b)[1'21 (Scheme 1).
Conventional methods of removing the chiral ferrocenylalkyl group from the condensation product ( 5 ) [ ' 3 2 1 have not
hitherto permitted recovery of the chiral amine ( 4 ) . This
is a considerable drawback since the amines ( 4 ) are usually
only preparable with great difficulty['].
Ratajczak and Misterkiewics recently reportedl41 that a-ferrocenylethanol (9 a ) reacts with thioglycolic acid (6) in the
presence of trifluoroacetic acid to form ( 8 a ) , and that (9a)
is accessible from ( 8 a ) by hydrolysis in the presence of HgC12,
the reaction (8a) -+ ( 9 a ) belonging to the retentive SN1 typec5].
We have now found that N-(a-ferrocenylalky1)-peptide deri-vatives ( 5 ) are smoothly cleaved by (6) in the presence of
trifluoroacetic acid into (7) and ( 8 ) , with complete retention
of configuration at the chiral center bearing the ferrocenyl
ligand.
For instance, treatment of the tripeptide derivative ( 5 c)I6l
at room temperature in 0.05 M acetone solution with an excess
[*I Dipl.-Chem. G. Eberle and Prof. Dr. I. Ugi
Organisch-Chemisches Institut der Technischen Universitat
Arcisstrasse 21, 8000 Miinchen 2 (Germany)
[**I This work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie.
Aiigew. Chem. I n t . Ed. Engi.
1 &I/.I5 (1976) No. X
(I)
,,,.
+ OHC-R'
P'-NC
yH2
(3) P2-C02H +
1
P' -NH-CO-c
I
P2-CO-N
CAS Registry numbers:
( 4 a ) . 59685-04-0; ( 4 6 ) , 54053-41-7; ( 5 ~ ) .59643-30-0; ( 5 d ) , 59643-31-1 ;
(6). 68-11-1; (7c), 59620-86-9; (7d). 3442-63-5; ( 8 a ) . 56498-34-1; ( a h ) ,
59643-32-2
(2)
(4)
[I]
H-R'
15)
F c-& H-Rz
HgCIz
NH3
[2]
NH&l
[3]
(6)
+ HS-CH-CO2H
[CFI-COIH]
[4]
[S]
[6]
( I ')
RO~C-CHR'-NH-CO-CHR'!-NC
a , R 2 = CH3;
b , R2 = C H ( C H 3 ) 2
Scheme 1. Stereoselective synthesis of the peptide derivatives ( 5 ) by four-component condensation ofcompounds ( I ) to (4). cleavage of ( 5 ) with thioglycolic acid in the presence of trifluoroacetic acid to give the peptides (7) and
(a-ferrocenylalky1thio)acetic acids ( 8 ) and recovery of the chiral starting
component (4). ( I ) is an isocyanide derived from an a-amino acid or peptide
acid ester ( 1 ' ) . (2) is an
ester, preferably an N-(a-isocyanoacy1)-a-amino
a-amino aldehyde OHC-CHR-NH2
and (3) is an a-amino acid or a
peptide with an N-terminal protective group. Fc=ferrocenyl.
of thioglycolic acid (6) and a catalytic amount of trifluoroacetic acid over 24 h affords a 94 % yield of the cleavage products
( 8 a ) and (7c).-Reaction
of (5d)c6l in trifluoroacetic acid
with thioglycolic acid (6) for 48h furnishes ( 8 b ) and (7d)
in 87 % yield.
OH
I
+ HS-CHZ-CO~H
I
(CF3-COzHI
F C-C -C H3
H
1. Ugi et ai. in I: Wolman: Peptides 1974. Wiley, New York and Israel
University Press, Jerusalem, 1975, p. 71, and references cited therein.
R . Urban and 1. Ugi,Angew. Chem. 87, 67 (1975); Angew. Chem. Int.
Ed. Engl. 14, 61 (1975).
D.Rehn, D.Marquarding, and 1. Ugr, to be published; I. Ugi, K . Oflermann,
H . Herlinger, and D. Marquarding, Justus Liebigs Ann. Chem. 709, 1
(1967); I . U g i and G . Kaufhofd, ibid. 709, I 1 (1967).
A . Ratajczak and B. Misterkiewicz, J. Organomet. Chem. 91. 73 (1975).
G . Gokef and I . Ugi, Angew. Chem. 83, 178 (1971); Angew. Chem.
Int. Ed. Engl. 10, 191 (1971); G . Gokef, D. Marquarding, and I . Ugi,
J. Org. Chem. 37, 3052 ( I 972).
For preparation of these compounds by four-component condensation:
D.Marquarding, D. Rehn, I . Ugi,and R . Urban, to be published.
S-CH2-C OzH
I
Hi0
* Fc-C-CH,
[HSCI2 1
I
H
I
F C-C-C H3
I
H
(5cj
-
I
I
H
19a)
(7c)
Pht-Gly-Val-Gly-OBu'
I
Fc-C-CH(CH~)~
I
H
OHC-Val-Val-Val-OlIe
+ 180)
Pht-Gly-Val-Gly-QBu'
(7d)
+
+ 186)
l5d)
The readily accessible racemic S-(a-ferroceny1alkyI)thioglycolic acids (8a),(8b) can be enantiomerized with the aid
of ( - )-ephedriner41and ( - )-pseudoephedrine, thus transforming the reaction (8) - ( 4 ) into a new productive approach
to chiral a-ferrocenylalkylamines ( 4 ) .
Received: April 28, 1976 [Z 468 IE]
German version: Angew. Chem. 88, 509 (1976)
Anyew. Chem. lnt. Ed. Engl.
1 Vof. 15
11976) No. 8
By Manfred Christl and Gertrud Freitag"]
Carbocations having the molecular formula C7H? have
been studied in great detailC'l, not least because of the theoretical interest attracted by the bonding in the tropylium ion
and the 7-norbornadienyl cation. Although a member of
this family, the tricyclo[4.1 .0.O2.']heptenyl cation ( I ) has
so far remained
We now wish to report a facile
entry to this system and its rearrangement.
OH
The S-(a-ferrocenyla1kyI)thioglycolic acids (8a),(8b) thus
obtained are optically pure, as demonstrated by comparison
with literature data and by further reaction to the amines
( 4 ) . Dissolution of (R)-(8a) or (R)-(8b) in concentrated
ammonia and addition of NH4CI and HgCI2 (molar ratio
1 :2:2) affords, after reaction for 7 to 9 h at 25"C, ( 4 a ) in
78 % yield and ( 4 b ) in 73 % yield, respectively. Both amines
( 4 ) are 98 to 99 % optically pure.
OHC-Val-Val-Val-OMe
New Isomer of
Fc-C-CH~
(8 ul
(90)
Tricyclo[4.1.0.02~7]heptenyl Cation-A
the Tropylium Ion[**]
O n standing for 15h at 80°C in an inert solvent such
as tetrachloromethane, 7,7-dibromotetracyclo[4.1 .0.02*4.0335]heptane ( 2 ) is smoothly transformed into 4,5-dibromotricyclo[4.1 .0.02*7]hept-3-ene(3)C2I, thus providing some indication
of the considerable stability of the 4-bromotricycloheptenyl
cation ( 4 ) . Departure of the endo bromine as an anion and
disrotatory ring opening of the 1,6-bond in (2) lead directly
to ( 4 ) , which is trapped by the bromide ion to form (3).
In 50 % aqueous acetone containing triethylamine compound
( 2 ) is no longer stable at room temperature. The polar solvent
facilitates ionization to give ( 4 ) which, on reaction with water
as nucleophile, furnishes the alcohol (5)C3J, b.p. 40-60°C
(bath)/O.Ol torr, m. p. 62-65 "C. Compound ( 5 ) is also accessible from (3) in 60-70 % yield by solvolysis in tetrahydrofuran/water or acetone/water mixtures containing triethylamineat room temperature. O n treatment with sodium in liquid
ammonia at -70°C ( 5 ) is converted in ca. 6 0 % yield into
the bromine-free species tricycl0[4.1.0.0~~~]hept-4-en-3-ol
(6)[31, b.p. 75-78"C/15 torr, m.p. 16--19"C, which has
recently been synthesized via another
The 3,5-dinitrobenzoates are accessible from ( 5 ) and (6)
in the usual way by treatment with 3,s-dinitrobenzoyl chloride.
Entirely as would be expected from the solvolysis behavior
of (3),6 hours' refluxing of (S)-dinitroben~oate[~l,
m. p. 122124"C, in 65 % aqueous acetone in the presence of diisopropylethylamine merely afforded a 65% yield of ( 5 ) . In contrast,
[*] Dr. M. Christl and G. Freitag
Institut fur Organische Chemie der Universitat
Am Hubland, 8700 Wiirzburg (Germany)
[**] This work was supported by the Deutsche Forschungsgemeinschaft.
493