Organic Synthesis–2. Plenary Lectures Presented at the Second International Symposium on Organic Synthesis

135 Pages·1979·5.321 MB·English

by  S. Sarel (Eds.)

INTERNATIONAL UNION OF PURE AND APPLIED CHEMISTRY
lUPAC Secretariat: Bank Court Chambers, 2-3 Pound Way,
Cowley Centre. Oxford, OX4 3YF, UK
Organizing Committee
S. Sard
Chairman:
R. Ben-Shoshan
Secretary:
I. Agranat
Members:
M. Albeck
D. Becker
P. Bracha
R. Haber
Μ. Lahav
Η. J. Ε. Loewenthal
S. Schatzmiller
Y. Yovell
International Union of Pure and Applied Chemistry
(Organic Chemistry Division)
in conjunction with
The Israel Academy of Sciences and Humanities
and
The Israel Chemical Society
Organic Syntliesis - 2
Plenary lectures presented at the
Second International Symposium on
Organic Synthesis,
Jerusalem-Haifa, Israel, 10 - 15 September 1978
Symposium Editor:
S. Sarel
Hebrew University of Jerusalem, Israel
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The contents of this book appear in Pure and Applied Chemistry,
Vol, 51, No. 6(1979)
Printed in Great Britain by A. Wheaton & Co., Ltd., Exeter
ISBN 0 08 022363 X
Pure & Appl, Chem,, Vol. 51, pp. 1219-1233. 0033-4545/79/0601-1219 $02.00/0
Pergamon Press Ltd. 1979. Printed in Great Britain.
© lUPAC
NEW METHODS IN PEPTIDE SYNTHESIS, BASED ON SUPERNUCLEOPHILES
H. Eckert, W. Breuer, J. Geller, I. Lagerlund, M. Listl,
D. Marquarding, S. Stüber, I. Ugi (Sneaker), S. Zahr and
H. V. Zychlinski
Organisch-Chemisches Institut, Technische Universität München,
Lichtenbergstr. 4, D-8046 Garching, W.-Germany
Summary;
The fragmentation of S-halogenated alkyl groups and δ-halogenated butenyl
groups from the N- and C-termini of α-amino acids and peptide derivatives
by the supernucleophilic Co"^-phthalocyanine anion as well as related
reactions are presented as the basis of some new protecting group techniques
and synthetic methods for peptides.
1. Introduction
In the past decades a prolific development of new protecting group tech­
niques for peptide synthesis has taken place, and yet there is not enough
variety in conditions and reagents for the removal of protecting groups'* .
In fact, only a few basic types of reagents and conditions are used for
the deprotection of blocked functional groups in peptide derivatives; and
one type of deblocking techniques seems to be preferred, namely acidolysis.
An increase in the number of options in deprotection conditions and more
selectivity in the removal of the blocking groups are still desirable. New
protecting groups are particularly needed for the synthesis of branched
peptides, multi-chain peptides with interchain linkaaes, and many peptides
containing trifunctional amino acids, as well as for the synthesis of
peptides by a segment strategy. In order to be a real supplement to the
collection of known protecting groups, any new group ought to survive some,
or all, of the conditions which are used in the removal of the customary
protecting groups, and the new groups ought to be cleaved from a blocked
functional group under conditions which do not affect other types of
protecting groups.
We wish to report on the development of a new class of protecting groups
which have only little in common with the standard set of protecting
groups with respect to deprotecting conditions. The new groups are
generally stable towards quite strongly acidic, or basic conditions, as
well as many reagents that are used during peptide syntheses. Their removal
is accomplished in essentially neutral solution at 0 - 20°, often within
a few seconds, by treatment with supernucleophiles.
1219
1220 Η. ECKERT et al,
2. Supernucleophiles
The term "supernucleophile" was introduced by Schrauzer and Deutsch^ for
nucleophiles with a relative nucleophilicity nj^j^j = log (ky/k^^Q^) ^ 10. The
phenomenon of supernucleophilicity was discovered, when the above-mentioned
authors observed, that alkylating agents react extremely fast with certain
anionoid Co"'" complexes (see Table 1), e.g. reduced derivatives of vitamin
and its model compound cobaloxime (CoOx),^ as well as Co phthalocyanine
(CoPc)
Table 1. The relative nucleophilicity n^„ ^ of some nucleophiles
Nucleophile Y Reference
^Mel
MeOH 0.00 3
CI" 4.37 3
Br" 5.79 3
CN" 6.70 3
l" 7.42 3
8.95 3
^2^3""
Ph-S" 9.92 3
[Co-^Pc]" 10.8 4, 14
[Co-'-0x(-^PBu3) ]" 13.3 2
[Co-^Ox(-^Py) ]" 13.8 2
14.4 2
The supernucleophilic properties of the aforementioned Co"'" complexes are
due to the spin paired weakly antibonding 3d^2 orbital of the central
atom, combined with the planarity of the tetradentate chelating ligand
system.^'^
The alkylation of Co"'' supernucleophiles produces the corresponding alkyl-
Co"^-complexes.2'4'6'7,8
When treated with acids, the ß-hydroxyethyl-o-Co"'""'"^ derivatives of
and CoOx undergo fragmentation (see Scheme 1)^
Scheme 1
HO-CH^-CH^-Hal + [Co"'"]" HO-CH^-CH^-Co"'--'""'" ^ >
H2O + CH2=CH2 + [Co"'""'""'"]
Eckert, Schrauzer and Ugi^^ performed a series of model experiments in
order to find out whether or not a protecting group technique can be
based on the fragmentation of 3-halogenated alkoxy compounds by (2)
according to Scheme 2.
New methods in peptide synthesis 1221
Scheme 2
Y-CO-OCH2-CH2-X + [Co-'-Ox ( ^ py) ] "-ijp-^ Y-CO-0-CH2-CH2-Co-'"-'--'"Ox py)
(1) (2) (3)
— Y-CO2H (or YH + CO^) + CH2=CH2 + [Co^^^Ox(^py)]"^ (4)
X = CI, Br; Y = Ph, NHPh, N(CH3)Ph, Val-Ot-Bu
The isolatable ß-acyloxyethyl-o-Co"'"''"''" compounds (3) were formed in 8 - 21%
yield, and reacted to form the indicated products in 81 - 98% yield on
treatment with acids or nucleophiles (0H~, CN~, BH^") under suitable
conditions.
The model experiments with (1) and (2) demonstrated not only the general
feasibility of a protecting group technique which is based on the frag­
mentation of ß-halogenated alkyl compounds and their analogs by super­
10,11
nucleophiles, but also disadvantages of (2) as a preparative reagent.
Its preparation requires much skill and care, due to its sensitivity
towards protons and oxidizing reagents (e.g. (2) reacts with compounds of
the type (1) not only according to Scheme 2, but it showed also a marked
tendency to participate in side reactions, some with disintegration of the
complex.^ ^)
3. Co'^'-Phthalocyanine anion and its Chemistry
In 1963 Taube et al.^^ reported the formation of (6) by reduction of (5),
a dark blue commercial pigment (Scheme 3)
Scheme 3
or
(6)
A dark green 0,1 Μ solution of [Co"''Pc]Na is obtained by shaking a sus­
pension of (5) in dry acetonitrile with Na/Hg under N2. This solution can
be stored under N2 at 0 - 25° indefinitely.^^ The crystalline lithium salt
of (6) is conveniently obtained by reducing (5) in THF by di-lithium benzo-
phenone in 91% yield. The crystalline material forms stable solutions in
water, alcohols, acetonitrile, DMSO, acetone, pyridine and monoglyme. The
acidity of such solutions may be changed by adding phenol, or 2.6-di-t-
1 4
butyl phenol.
In its chemistry [Co'^'Pc]" differs significantly from [Co'^'Ox (^py) ] ~, and
the reduced B^2 derivatives.
1222 Η. ECKERT et al.
The redox potential of [Co-'-Pc]" is with -0.37 ^ rather far on the
positive side, relative to the -0.77 to -1.12 V of rather similar metal"^-
phthalocyanines,''^'''^ as well as the -1.0 to -1.2 V of [Co-^B. and
I — 5 17 —
[Co 0x]~ derivatives. ' The weak reducing properties of po^Pc]" are
advantageous in its use as a deblocking reagent for peptide derivatives.
The derivatives of [CoPc]~ have a pronounced tendency to form Co''"''"Pc, while
Co"''"^"^ is rather strongly favored by the derivatives of B^ ^ CoOx.^^'^^
This has immediate consequences for the reactions of [Co'^'Pc]'" with 3-halo-
genated alkoxy compounds. These reactions do not lead to (9), in analogy
to the chemistry of [CoB^^]~ and [Co'^Ox]", but to the formal oxidation of
I - 18
two mole equivalents of [Co Pc] according to Scheme 4.
scheme 4 ^ ^«2=^Η2 * ",^^''
Z-CH2CH2-X + [Co-^Pc]"^:^Z-CH2CH2-Co-'--'--^Pc
(7) (6) (8) Z" + CH^=CH^ + 2 Co-'-'^Pc
^ ^ (5)
X = Halogen, Ζ = leaving group with 0, N, S, a: X=Br, Ζ =0H
b: X = Br, Ζ = Ph-C02
Table 2. The reaction of 3-halogenalkyl compounds (7) with cobalt(I)
phthalocyanine anion (6) according to Scheme 4.
Ζ X Reaction time Yield (%) of
isolated Z-H
Br 40 min 66
^6«5-^^2
C,H3-C02 CI 50 h 77
CgH5-NH-C02 Br 45 min 86^)
CgH5-NH-C02 CI 60 h 83^)
C.H^-O Br 80 min 62
C,H3-S Br 95 min 60
CgH5-N-CH3 Br 53
a) CgH3-NH2 was isolated.
b) No evolution of ethylene was observed.
New methods in peptide synthesis 1223
Table 3. The second order overall rate constants of some reactions
according to Scheme 4 in methanol at 25°
Ζ X Conductometrically Gas-volumetrically
determined rate determined rate
const. (l/mol*sec) const. (1/mol'sec)
CgHg-CO^ Br 2.5 · 10"^ 1.7 · 10"^
-
BOC-Phe-Ala-0 Br 1.6 · 10"^
-
CgH3-C02 CI 5 · 10-5
-
MeO-Val-COj Br 6.4 · 10"·^
-
tBuO-Ala-Val-Ala-COj Br 9.7 · 10"^
C,H5-0 Br 1.5 · 10"^ 8.7 · 10""^
-
CgH5-S Br 7.3 · 10""^
Br Br 2.7 · lO"'' 2 · 10-^ ^)
a) Corrected for a statistical factor 2.
Table 4. Gas-•volumetrically determined time for 50, 90 and 100%
completion of the reactions according to Scheme 4 of the
listed benzoic acid esters with (6)
Reactant
r^o^imin) "^00%
0COOCH2CH2CI 270 2000 3000
0COOCH2CH2Br 2 10 40
0COOCH2CH2CO(III)PC 1 10 40
Side reactions which could affect the coordinative sphere are suppressed
by the extreme stability of the metal ligand system in (5)^^. The high
lattice energy of it is responsible for its insolubility in all customary
solvents.
Primary alkylating agents R-X react with [Co Pc]' fast and well to form
,20^
R-Co"'""''"^Pc^^. With secondary alkylhalides the formation of olefins is
14
observed.
The second order reactions between [Co'^'Pc]" and a variety of organic
halides in methanol at 25° were followed by conductivity measurements^^.
The dependence of the reaction rate on the structure of the organic halide
(see Table 5) is a useful guideline in the design of protective groups
which are removable by treatment with [Co"^Pc]".
1224 Η. ECKERT et al.
Table 5. The conductometrically determined second order rate constants of
the reaction between cobalt(I)phthalocyanine anion and various
organic halides in methanol at 25°
Substrate Rate const. (1/mol'sec)
CH2CH2CH2CH2CI 5 · 10"5
Q,^^C^^Z\ 2.6
CH3CH200CCH2C1 3.1
CH3CHC12
7.0 •
CH3CC13 1.4
C^HcCOOCH^CCl-. > 4.5
DD ¿6
CgH5COOC(CH3)2CCl3 > 6
CH3CH2Br 1.1 • 10-2
CH3CH2CH2Br 1.2 • 10-2
a)
CH3CH2CH2CH2Br 1.6 • 10-2
(CH3)2CHCH2Br 1 .0 • 10-3
HOCH2CH2Br 1.7 • 10-3
b)
BrCH2CH2Br 2.7 • 10-1
b)
BrCH2CH2CH2Br 1.7 • 10-2
b)
BrCH2CH2CH2CH2Br 2.0 • 10-2
c)
CH3I 7.4
CH3CH2CH2CH2I 3.1 10-^
CH3OTS 1.5 10-2
CH3CH2CH2CH2OTS 1.3 • 10-3
a) Erroneously given as 2.9 · lo"*^ 1/mol.sec in Ref. 4.
b) Corrected for a statistical factor 2.
c) from Ref. 4.
The influence of the leaving group Ζ is particularly well illustrated by
1 8
the following model experiments:
The alkylation of [Co-'-Pc]" by ß-bromo ethanol (7a) with X = Br, Ζ = OH
yields isolatable (8a) which can be 0-benzoylated to form (8b) with
Ζ = O^C-Ph. The latter cannot be directly prepared from (7b) with
I -
X = Br and Ζ = O^C-Ph, because (8b) reacts too fast with [Co Pc] according
to Scheme 4 (see also Table 4). When isolated (8b) is treated with [Co PI c] -
the formation of 93% Co'^'^Pc, 100% of ethylene and 60% of benzoic acid is
observed. Here [CoPc]" acts as a reducing agent towards (8b). The reductive
change of (8b) can also be achieved with NaBH^.
New methods in peptide synthesis 1225
4. Protection of Amino Groups
We know from preliminary studies (see also Table 5), that the 3-chloroethyl
group is cleaved by (6) too slowly to be useful as a protective
1 21 22 27
group. The 3-bromoethyl group " " ' would react fast enough with (6),
but it tends to give side reactions, since it is quite reactive as an
alkylating agent. The derivatives of trichloroethanol '''23,27 2,2-dibromo-
14 27
propanol ' are reactive enough towards (6), and they a1r e2 7n ot reactive
as alkylating agents, but they are labile towards bases '
Nevertheless, the trichloroethyl (TE) group h2a3s already been successfully
used in Woodward's Cephalosporine synthesis , where no particular
stability of the protecting group was needed. It was then removed by
treatment with Zn/AcOH by which the protected compound was not damaged.
24
To our knowledge, the trichloro-t-butyl group (TCB) is the only one among
the simple 3-halogenated alkyl groups which is highly reactive towards (6),
and is otherwise chemically inert (see Table 7), because it is neither
CH-acidic nor an alkylating agent.
Model experiments have shown that the TCB group cannot be used to protect
the carboxyl group of amino acids. The formation of the esters (12) from
carboxylic acids (10) and chloretone (11) turned out to be difficult, in
some cases impossible.
Scheme 5
^e Me
R-CO-X + HO-(j:-CCl^ ^ R-CO-O-Cj-CCl^
(10) (11) (12)
X = OH, CI, O2C-CF3
The direct esterification could not be achieved under any condition. The
chloroacetate (12a) with R = CH2CI of (11) was obtained in 17% yield by
refluxing (11) for four days in CICH2COCI, and the o-nitrocinnamate (12b),
R = o-N02-CgH4-Ch=CH (mp 90°C) resulted in 60% yield by treating o-nitro-
cinnamyl chloride with (11) for 48h at 160°C. Analogously, TCB bromo acetate
is formed in 68% yield in 3h. To our surprise (12b) was also formed in
75% yield by treating o-nitrocinnamic acid and (11) with trifluoro acetic
anhydride for 30 min at 40°C 25,26^ ^^^^ diketene is refluxed in ether for
seven days 71% of the acetoacetate of chloretone (12c), R = Me-C0-CH2
are produced. We have not yet succeeded in producing TCB esters of amino
acid derivatives in a similar manner.
In contrast to the carboxylic group, chloretone (11) has proven its value
in the protection of amino groups and other acylatable groups (see Scheme 6)^^.