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From Isocyanides via Four-Component Condensations to Antibiotic Syntheses.

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From Isocyanides via Four-Component Condensations to
Antibiotic Syntheses**
By Ivar Ugi*
In memoriam Otto Buyer
The four-component condensation of amines and carbonyl compounds with isocyanides[**‘]
and suitable acid components (water, thiosulfuric acid, hydrogen selenide, hydrogen azide,
cyanic acid, thiocyanic acid, carboxylic acids, methyl hydrogen carbonate) to form a-amino
acid derivatives was discovered in 1959. This reaction principle shares some features with
the Strecker synthesis and the Passerini reaction. The four-component condensation affords
easy and effective one-pot synthesis of complex molecules from simple building blocks.
Only in recent years, however, have the preparative advantages of the four-component condensation been exploited by numerous authors in the synthesis of diverse natural products
and related compounds, although many of the possibilities opened by this principle were
recognized more than two decades ago. In this progress report some instructive syntheses of
various antibiotics are reviewed. The design of each of these syntheses involves a four-component condensation as key step, by means of which lengthy sequences of reactions are
avoided, which otherwise would be required to achieve the synthetic goal.
1. Introduction
The essential reactions of the simple functional groups
have long been known. Almost all basic types of organic
compounds were thoroughly studied by the classical organic chemists in the last century. The isocyanides 1 and
the isocyanates 2, close chemical relatives, are among the
exceptions. For a long time, relatively little research was
carried out on either class of compounds, and it was comparatively late that they received the attention they deserve.
’
The chemistry of the isocyanates began to gather momentum in the late thirties, when Otto Buyer initiated an
intense exploration of these hitherto practically neglected
compounds. With great vision he then created the conceptional foundations of polyurethane technology: this is
based on isocyanate chemistry and the polyaddition principle, recognized by Buyer as a means of synthesizing macromolecules. Buyer thus triggered a unique development to
which the isocyanates owe their present eminent scientific,
technological, and commercial importance.
Systematic investigation of the isocyanides[’I began
about 1960. Most of the isocyanide reactions on which
synthetic methods are based were discovered only in the
last decade. Examples are the reactions of the a-metalated
isocyanides by Schollkopf et aZ.[*I,van Leusen’s “TosMIC
[*I
[**I
[***I
810
Prof. Dr. I. Ugi
lnstitut fur Organische Chemie der Technischen Universitnt Miinchen
Lichtenbergstrasse 4, D-8046Garching (Germany)
Extended version of a lecture delivered at _a scientific colloquium in
honor of Professor Otfo Buyer on November 4, 1982 in Leverkusen.
Previously, isocyanides were almost always referred to as isonitfiles.
However, according to IUPAC Rule C-833.1 only the name “isocyanides” is permissible.
0 Verlag Chemie GmbH, 6940 Weinheim, 1982
chemistry”[’], and the aldehyde-ketone syntheses of Walborski et a1,[41.
In the meantime, isocyanides have become a household
word in preparative organic chemistry, although it is not
long ago that they were seen as exotic compounds, useless
for synthetic purposes. Just a few years ago the reviewer of
an article about preparative uses of isocyanides[51called it
“intellectually rewarding”-probably
a well-meant and
courteous circumscription for “an academic topic without
practical consequences”. However, the isocyanides have
finally come into their own as preparative reagents, as demonstrated by the syntheses reviewed in this article.
Why was it more than a hundred years from the discovery of the isocyanides[’a’61to the true dawning of their
chemistry, although many interesting reactions have long
been known or predictable? The main reason was probably the lack of preparative access to pure isocyanides in
high yield until the advent of modern methods for their
preparation[Ib1. The classical isocyanide syntheses- the
“carbylamine reaction” of A . W. Hofmann[’I and the synthesis of isocyanides by alkylation of silver cyanide according to Liekd6’ and GaurierLS1-areof little use for the
preparation of pure isocyanides. The efficient modern syntheses of the isocyanides are based on the dehydration of
N-monosubstituted formamides. As early as 1867 Gautier[”
attempted to convert the latter into isocyanides by allowing them to react with P4OI0.He did not succeed, because
he had overlooked the fact that isocyanides are acid sensitive. The synthesis of isocyanides from N-monosubstituted
formamides proceeds well only when the acid-forming dehydrating agents, such as arenesulfonyl chlorides[’’], phosphorus oxychloridel’ll, sulfonyl chloride1’”, or phosgene[I3l,are used in the presence of bases.
The “phosgene procedure”, which is carried out in the
presence of triethylamine, dimethylaniline or aqueous
is generally the method of choice. The phosgene
can be substituted by “diphosgene”[Is1,which has recently
0570-0833/82/1111-0810 $02.50/0
Angew. Chem. Int. Ed. Engl. 21 (1982) 810-819
become readily available[16! Diprotonated carbonyldiimidazole is useful as a substitute for phosgene in the preparation of base-sensitive isocyanides in small quantities[”’.
The formal divalency of the isocyanide carbon atom is
responsible for the peculiarities of isocyanide chemistry.
The formation of isocyanides is generally accompanied by
conversion of tetravalent into divalent carbon, and most
reactions of the isocyanides begin with an a-addition
1-3, i. e. conversion of a divalent into a tetravalent carbon atom[’].
The pronounced ability of isocyanides to participate in
multicomponent reactions is based on the a-addition of
electrophiles and nucleophiles which may be involved in
the equilibrium 4 + 5.
13
I
.%@
n
+ :Be
G===
4
\
I
N-C-C-B
I
I1
’ &R
10
,
,
-
I
There are many nucleophiles (:Be) whose a-aminoalkylation, 8 -+ 9 , is reversible. Reversible a-aminoalkylation
systems are generally able to react with isocyanides 1 to
form labile a-adducts 10 which undergo spontaneous rear19-291.
rangement to afford stable a-amino acid
We use the term four-component condensation[’*’ for
those reactions whose products are formed via a-addition
of an iminium ion and a nucleophile to an isocyanide, followed by a secondary reaction of the a-adduct formed (cf.
21 + 22 23 24). As a synthetic principle, four component condensation affords simple one-pot syntheses of a
large variety of compounds, whose syntheses by alternative
methods would generally require complex, multistep sequences of synthetic reactions[”]. Formulas 11-20 represent those classes of compounds available via four-component condensation of ammonia, primary and secondary
amines, or hydrazine derivatives, and carbonyl compounds
with isocyanides and suitable acidic components or their
anions, such as water, thiosulfate, hydrogen selenide, dimeth~lamine[*~I,
azide, cyanate, thiocyanate, carboxylic
acids, and monoalkyl carbonates[’d.211.
The nature of the products is primarily determined by
the acidic component HB or its anion :Be. However, in the
case of some acidic components (see 19 and 20) the essential structural features of the product also depend on
whether the amine component is primary or secondary.
+ +
Angew. Chem. Int. Ed. Engl. 21 (1982) 810-819
l
12
I
(:BO = ~ 2 0 3 ~ ~ )
I
I
1
I
-N-C-C-N-
(:Be= HSeO)
( H B = -NH-)
I
14
II
\--
I
X
XN 3
-
H - 2 3 - N -
Y
I
H
R
(:Be = NCXO)
(:BQ = R N C N O )
from prim. amine from prim. amine
(:Be = N3@)
5
stabile a - a m i n o acid derivative
l
-Pi-C-CS-NH-
-iX-C-CSe-NHI
18
16, X = 0
17, X = S
A-B
The majority of the classical multicomponent reactions,
such as the Mannich condensation and the Strecker synthesis, are a-amino-alkylations[I8].These proceed via iminium ions, highly reactive electrophiles capable of existing
as “equilibrium species” in media of low acidity. Thus,
they qualify as reaction partners for the acid-sensitive isocyanides.
1
I
I
( H B = HzO)
-“-y T-rN@I
19
-
\
-N-C-CO-NH-
15
A
R-N=C:
3
11
I 1
I
1
I
R - C 0 - N - C - C 0 - N H-
-N-C-CO-N-CO-R
( H B RCOzH)
from prim. amine
(HB = RC02H)
f r o m s e c . amine
I
I
20
The first four-component condensations, involving
rather simple components, were carried out in methanol,
and their products were isolated without recourse to chromatographic methods. Since these experiments generally
resulted in high yields of products without significant detection of by-products, the initial impression was that all
reversible side reactions were suppressed by a large thermodynamic driving force, and that hardly any irreversible
side reactions occurf211.Model experiments carried out
later in which reactants and reaction conditions were
widely varied indicated, however, that four-component
condensations do indeed compete with a variety of irreversible side reactions which impair their yield[29’. Over the
years, however, it was also found that the competing side
reactions can, as a rule, be avoided with a good understanding of the reacting system. For a given four-component condensation, it is usually possible to find-through
systematic model experiments-some conditions under
which an excellent yield can be obtained. This optimum
yield is, however, only obtained when the optimum conditions-including the precise concentrations of the reactants and a d d i t i ~ e s ~ ~ ~ l -carefully
are
observed. Most of the
four-component condensations proceed in 75-95% yield,
if the Schiff base of the enamine of the amine and carbonyl components, as well as the acid component are allowed to react in a l : l molar ratio in stirred concentrated
methanolic solution with the isocyanide at 0 oC[1d,271.
Based on the available dataLz5],mechanistic steps of
third or higher order do not take part in the reaction mechanism of four-component condensations. Under a wide variety of conditions the mechanism of the four-component
condensation is a complex system of consecutive and parallel first and second order reactions. Those steps in
which only the amine, carbonyl and acid component participate are reversible, whereas those steps in which the
isocyanide takes part are irreversible[”].
The scope and limitations of the four-component condensation and its reaction mechanism, as well as its de81 I
pendence on reaction condition^['^,^^^'^^ were, however,
first studied systematically after 1962, when I moved from
Universitat Miinchen to the Wissenschaftliches Hauptlaboratorium of Bayer AG at Leverkusen, which was then
under the directorship of Otto Bayer. His active interest in
this topic, his critical participation in discussions, his constructive ideas, and the intellectually stimulating atmosphere of the laboratory, which was strongly determined
by Buyer's personality, not only profoundly influenced,
helped, and stimulated the investigations of my research
group in Leverkusen until 1968, but also far beyond: this
period at Leverkusen is also the origin of other major research topics and areas of interest of the present author.
They all began as auxiliary projects, corollaries and "fallout" from the four-component condensation, and its most
obvious and important application, the synthesis of peptides127-291.
This in turn is the source of the preparative[301
and theoretical investigations on s t e r e o c h e m i ~ t r y [ ~and
'-~~~
~ h i r a l i t y [ ~ as
~ . ~well
~ ] , as the later work on permutation
isomers[36'and their mutual inter conversion^[^^^. These led
uia hyper~hirality[~']
to the theory of the chemical identity
group, a unified perspective of static and dynamic stereochemistry as a whole[391.
The computer assisted efforts towards understanding the
mechanism of the four-component condensation[251,in order to make best use of it synthetically, led Giinter Kau$
hold and myself to design and implement the Leverkusen
peptide synthesis planning program[403411,
an intellectual
ancestor of the theory of the BE- and R-matrice~[~~I,
and to
develop the concepts, algorithms, and computer programs
for the deductive solution of a great variety of chemical
problems[431,which are based on this unified theory of constitutional chemistry.
Last, but not least, some of our experimental work deserves mention, whose origin and motivation also stems
from the four-component condensation: the chemistry of
the a-ferrocenylalkylamines and related
which serve as chiral auxiliary materials in the synthesis of
peptide segments by the four-component condensation['91,
the studies on functionalized polymers[45J,and the development of new protective groups for the four-component
synthesis of peptide segments. Later, this work led to the
development of protective groups that can be selectively
cleaved by Co' phthalocyanine in neutral solution: these
are used in peptide and oligonucleotide synthesis[471.Even
our work on phosphorus chemistry[481is a consequence of
the four-component condensations, via the related stereochemical
2. Four-Component Condensation of
Carboxylic Acids and Primary Amines with
Aldehydes and Isocyanides
The reaction of primary amines 22 and aldehydes 23or better still, the Schiff bases of 22 and 23 -with carboxylic acids 21 and isocyanides 24 leads via the a-adducts 25
to the a-acylamino carboxylic acid amides 26['d,21*25-291
From a mechanistic standpoint (cf. [361), and according to
the essential structural features of the products 26, this
type of four-component condensation may be viewed as a
812
"cross-breed of the a-aminoalkyIati~n['~~
with the Passerini
reaction[lc1.
Rl-COzH
+
R2-NH2
+ K3-CH0 +
22
23
21
R'-C0-0,
,c
- HIO
24
K3
=N-R4 + R'-C0-N-&<0-xH-R4
I
R ~ - ~ X H I- C H
R3
-
CN-R4
RZ
25
26
This variant of four-component condensation opens up
new ways of synthesizing many natural products and their
analogs, including numerous antibiotics and their precursors.
Various syntheses of antibiatics have recently been reported in which a four-component condensation of the last
mentioned type plays a key role. These syntheses, with the
exception of syntheses of peptide antibiotics, are reviewed
in this article.
3. Bicyclomycin
Bicyclomycin, 27, an antibiotic which is active against
gram negative bacteria, has been isolated in crystalline
form from culture filtrates of Streptomyces sapporonenIts unusual structure, as elucidated by X-ray crystall ~ g r a p h y [ ~and
~ I ,its promising antibiotic
make its
synthesis a ~ h a l l e n g e [ ~ ' ~ ~ ~ ] .
0<bH
-0
)
::+:
27
CHzOH
Fukuyama, Robins, and Sa~hleben[~''
have recently performed an impressive synthesis of 39 and 40, which can be
seen as a model and a precursor of a total synthesis of 27.
The formation of 32 by four-component condensation of
28 to 31 to give the polyfunctional compound 32 is a key
step (DBU = diazabicycl0[5.4.0]undecene~~~~,
m-CPBA =rnchlorobenzoic acid).
According to Fukuyama et al.[521
this approach provides
an access not only to bicyclomycin, but also to a variety of
analogous compounds. Their structure is predetermined by
the educts of the initial four-component condensation.
4. Asymmetrically-Induced Four-Component
Condensation and the Synthesis of Furanomycin
As a model reaction for the asymmetrically-induced synt h e s i ~ [ ~ 'of
. ~ chiral
~]
amino acid and peptide derivatives,
the formation of 45-p and 45-n by four-component condensation of 41 to 44 has been thoroughly studied[ld,25.271
The ratio Qpn[561
of the products 45-p and 4 5 4 depends
strongly on the reaction condition^^^^^"^. Computer-assisted analysis of Qpnas a function of the concentrations of
Angew. Chem. Int. Ed. Engl. 21 (1982) 810-819
d/\,OAC
+
J-COzH
Pr-NH;
+ EtOCOzCHzCHO
29
28
+
CN-Pr
30
31
.4 cO/\/\/OAC
\
OCOzEt
32
A c 0,-Y-J
0A
-
NaOH
A../k-Pr
I/
34
O
J'OC02Et
33
-
Pr-N
-
Pr-N
tions, i. e. pairs of reactions whose products and transition
states are stereoisomeric, are involved. These four pairs of
reactions differ with respect to their formal reaction order[251,and correspond to four competing reaction mechanisms. The observable overall stereoselectivity results from
the concentration-dependent relative contribution of the
individual pairs of corresponding reaction^[^'.^^^, each of
which has its characteristic concentration-independent
"intrinsic" stereoseIecti~ity[~'~.
The relative yield of a given
stereoisomer is maximized if conditions prevail under
which that pair of corresponding reactions dominates
whose "intrinsic stereoselectivity" most favors this stereoisomer. Moreover, the contributions of the unfavorable
pairs of corresponding reactions must be minimized.
The results of the above model experiments were used
by Joullii et al.[s7b)
in their synthesis of (+)-furanomycin
47 and related compounds. Katagiri et al.'581isolated the
p0
*r - x G >
PhSeCl
-
48
antibiotic furanomycin 47 from culture filtrates of Streptornyces threornyceticus and assigned to it the structure 48
based on spectroscopic data. Later, on the basis of NMR
data[57-s91and preparative result^^^'^^^^, which were obtained partly via four-component condensations, the corrected structure, 47, or (+)-furanomycin was obtained.
An elegant stereoselective four-component synthesis of
(+)-furanomycin by Joullie et al.[57b1,
that was carried out
in several variations, starts from D-glucose, which is converted into the aldehyde 53 via 49. The four-component
C H2-S e P h
35
47
mCPBA
Ac2O
36
d'" 4"'H2lNi
v
H O 5 . f
TsO
COzEt
39
PhSe
OH
49
50
40
OMe
the starting materials 41 to 43 in methanol at 0°C revealed that four competing pairs of corresponding reac-
Ph-COzH
OH
Ph
I
+ R.le-C-NH2
I
H
41
42-S
Ph
iPr
I
I
Me< -N--C
-C 0-h H-tB u
I 1
I
+
+ iPr-CHO
CN-tBu
Ph
CO-NH-tBu
I
I
Me-C -N--C - i P I'
I
1
H CO H
Ph
Ph
I
51
Me
Me
52
53 + 41
+
42-R + 44
X
Ph-CO-N
CO-NH-tBu
MH "-
45-11
.1
4
1 PI
C OzH
I
H2N-C-r Pr
e
53
- H2O
X
P h - C 0-N
=
Ph-Me
HCOjH
55-n, X
= H
I+' ,"
54-p,
x = p;",,
4
HCOlH
55-p, X = H
H
1
1
46-S
46-R
47
48
I
-C OzH
Angew. Chem. Int. Ed. Engl. 21 (1982) 810-839
C 0-NH-rBu
H
H
H&<
8'"
CshN
Me
@OMe
OH
54-11,X
45 - p
I
T,0H/H20,
I
n co H
I
- H20
44
43
+
-
-
flEzz
I
HCI
HCI
813
condensation of 53 with 41, (R)-a-phenylamine 42-R, and
tert-butyl isocyanide 44 yields 54-n and 54-p. Acidolysis
of 54-n with formic acid leads to 5 5 4 , whose hydrolysis
affords 47.
Nocardicin A, 75, has already been synthesized by conventional methods‘67J.The advantages offered by fourcomponent condensation for the synthesis of p-lactams
were used impressively by Isenring and Hojheinzf681at the
Hoffmann-La Roche laboratories in their synthesis of 21
5. Nocardicin and Analogs
The recent literature indicates that interest in the p-lactams is still
because of their outstanding antibiotic properties and few undesirable side effects. Even
monocyclic p-lactams with noteworthy antibiotic activity
have been found. In 1976 some Japanese a ~ t h o r s [ ~ ’iso, ~ ~ ] 66-S
lated nocardicin A, 75, the first monocyclic p-lactam with
potentially useful antibacterial properties. Together with
six analogs, the nocardicins B-G[641, it occurs in the culture broths of Nocardia uniformis.
The formation of four-membered rings by cyclization of
acyclic precursors is generally impeded by Baeyer strain
and conformationnal effects ; hence, formation of b-lactams from p-amino acids is not easyf651.However, conversion of p-amino acids into b-lactams by four-component
condensation proceeds smoothly, as a rule, in very good
yields[’d.26.661.
For example, the difunctional 56 reacts
smoothly with 43 and 44 in methanol to form 59[’d.261.
HOzC-CH2-CHz-NH2
-t
QC H z P h
OCHzPh
69 - S
70
QCHzPh
OCHzPh
-
iPr-CHO
56
61
43
e
@O2C-C H z-C H2-N H=C H-i P r
3
57
H
iPr
-
(+$N-tBu
0
-N-CH-iPr
0 CO-NH-tBu
58
59
OH
In the synthesis of 0-lactams by four-component condensation a seven-membered ring (cf. 58) is formed, which
closes relatively easily. The b-lactam system (cf. 59) is obtained from the a-adduct by a secondary transannular
0,N-acyl transfer.
BH3
THF
PhzCHOzC
Boc-NH
H
)tc
62
(Et02C-N=)2. Ph3P
H~OH
*
63
SeO2
Boc-NH
64
PhzC HOzC
Boc-NH
nocardicin
As examples, we select the syntheses of nocardicin D, 74, and A, 75. The acid 65, required for the last step, is first prepared from D-asparagine
60-R. An important step following the four-component
condensation to 69-S is the conversion of 71 into 72 by
diazabicycl~undecane~~~~.
69-R, obtained analogously to
6 9 4 , reacts via 76 to afford 71 and 72.
In this context the four component synthesis of 3-aminonocardinic acid by Hatanaka et ~ 1also. deserves
~ ~to be~
mentioned.
LoiQeo,
O2H
65
814
74,x=o
7 5 , X = NOH
61
60 - R
Ph2CHOzC H
)\/COzH
Boc-NH
Nocardicin D
Nocardicin A
Angew. Chem. In:. Ed. Engl. 21 (1982) 810-819
~
ACozMe
6. Penam Derivatives
__j
PhtN-CHz-COzMe
The first preliminary studies towards the synthesis of
penicillin derivatives by four-component condensation
were carried out more than 20 years ago by Ugi and Wischhiiferl'lo1.3-Thiazoline derivatives 78, prepared by Asinger
c~ndensation'~']
of B-oxoesters, ammonia and a-mercaptoisobutyraldehyde, and subsequent ester hydrolysis, were
allowed to react with isocyanides in the two-phase system
water/petroleum ether to afford the penam derivatives, 81.
Despite the general lability of penam derivatives, the products 81 could be purified by sublimation in vucuo. This
four-component condensation proceeds via the bicyclic aadduct 79, in which, due to strain, the seven-membered
ring can only be cis-annelated. Thus, in 81 the fLlactam
moiety and the carbamoyl group must be cis-related.
NaHS
1) HC02Me + Na
2) TsCl
TsO
82
g
NH H
M C 0 2 M e
S
NPht
NPht
83
-
LiI
86
87
88
89
N-R"
H
Q
77
78
,L?
79
N-R"
CO-XH-R"
R R'
j R'
80
a, R
= H,
Hatanaka et a1.[76J
recently reported a synthesis of 96. In
its relative brevity, this synthesis sets new standards for the
carbapenem field. The key step is a four-component con-
81
R' = Me,
b, R
= Me, R' = H
Using a similar route Sjiiberg[721
obtained the amide of a
stereoisomer of penicillin G, but in very low overall yield,
because formation of the required 3-thiazoline derivative
by Asinger condensation did not proceed satisfactorily.
Schutz and Ugi[731
found the route 82-86 to 3-thiazoline derivatives, which can be converted into 6-aminopenam derivatives or their stereoisomers. Here, as also in
the synthesis of cepham derivatives (see Section 8), the
thienolate 84 is the key intermediate (Pht = phthaloyl).
Demethylation of 86 by LiI in dimethylformamide and
pyridine gives 87, whose four-component condensation
with 44 in waterldioxane produces 88. According to
NMR results the asymmetric C-atoms in the b-lactam
moiety of 88 have the same configurational relationship as
in the natural penicillins.
The conversion of 88 into penicillin G would require
substitution of the phthalimido by a phenylacetamido
group, as well as that of the trans-carbamoyl by a cis-carboxy group. All these operations are possible, but their execution on the penam system requires further model experiments. Analogous considerations apply to the synthesis of the cephalosporins (Section 8).
7. Carbapenem Derivatives
Thienamycin 90 and related carbapenem derivatives are
distinguished by outstanding antibiotic
accordingly, their syntheses deserve particular attention[751.
Angew. Chem. lnt. Ed. Engl. 21 (1982) 810-819
91
92
CONHCH,
kOOBz
93
94
95
96
-.
densation of 92 with formaldehyde and methyl isocyanide
yielding 93. A modified Dieckmann condensation 94 95
and subsequent condensation of 95 with protected cysteamine leads to 96 (Pnb =p-nitrobenzyl, Bz= benzyl).
The authors indicate that an analogous total synthesis of
the thienamycin 90 is well underway.
815
8. Cepham Derivatives and Related Compounds
Just et al.[77,781
attempted the synthesis of the oxacepham
derivatives 97 as outlined below. This synthesis was planned as a model for analogous syntheses of cepham derivatives, and its conceptual design is ingenious and convincing.
so
o+wo
CO-NHR
91, R = E t , c H e x
NH-C 0 - P h
The synthesis starts from mannitol diacetonide, from
which the glyceraldehyde acetonide 98 is obtained by oxidative glycol cleavage. The latter is converted into 99 by
condensation with formaldehyde, subsequent protection of
the aldehyde function with N-methyl cystearnine and, finally, reaction with methanesulfonyl chloride. The 4-hydroxymethylene-5-oxazolone 100 and trichloroethanol
react to give 101, whose sodium enolate reacts with 99,
yielding 102. The labile aldehyde 103 is obtained by reductive cleavage of the trichloroethyl group and deblocking the aldehyde group by mercury(I1) chloride. Aldehyde
103 was allowed to react in situ with ammonia and iso-
cyanides in the hope that it would form a dihydroxazine
derivative 104, whose four-component condensation with
an isocyanide ought to yield 97. Instead, a Passerini reaction[”] takes place between 103 and the isocyanide to form
105[781.
Presumably discouraged by this result of their model
study, Just et ~ l . [ ~seem
* ] to have abandond their planned
synthesis of cepham derivatives. Their synthetic concept is
by no means unrealistic, and after minor modification
could well be realized (see 106-111). After the successful
synthesis of some penam derivatives we[791
took note of the
concept of Just et
profiting considerably from their
ideas and results. The thioenolate 84, which had already
proved its value in the penam synthesis[731,
was allowed to
react with the mesylate 106, a reaction already described
by Just et al.17’]in 1973. Treatment of the resulting product,
-
I
0
t
o2
N-)0
+
NaS
NPht
\OMS
84
106
I
0
k
‘0
=CHO
0
’
h 7
HO
98
100
Ph
1
ClsCCHzOH
111
101
Y
112
NaOEt
99
107, with aqueous acetic acid yields the aldehyde 108, and
when a slow stream of ammonia is passed over a stirred solution of this in tetrahydrofuran at 0 “C, the tetrahydrothiazine derivative 109 is formed: from this, 110 is obtained by demethylation. Its reaction with tert-butyl isocyanide leads to the cepham derivative 111, whose essential configurational relations correspond to those of the
natural cephalosporins, according to NMR data. It is intended to convert 111 or some analog obtained by fourcomponent condensation into a cephalosporin 112.
102
0
NH-CO-Ph
1
1) HgCI,
2 ) Zn/HG
0x0
%- Y J J Y O Z H
0-Ph
C H-NH-C 0 - P h
I
104
ICN-R
CN-R
X CO-NHR
0 OL,
97
816
9. Perspectives
Although the four-component condensation, its versatility and most of its preparative advantages have been
known for more than two decades“’], practitioners of organic synthesis have not made much use of it until recently. In many areas the required “supporting chemistry” has
only been developed in recent years. For example, twenty
years ago it was known that stereoselective four-component condensations are, in principle, useful for the synthesis of peptide segments[291;however, syntheses of this type
Angew. Chem. I n t . Ed. Engl. 21 (1982) 810-819
did not become practicable until chiral a-ferrocenylalkylamines became accessible via the “Mannich condensation
with exchanged roles”[44c1,and subsequent resolution of
the enantiomers with the aid of (-)-diisopropylidene-20x0-L-gulonic acid[*’] became feasible. The facile recovery
of the chiral amine components of such peptide syntheses[”’ also had to be solved. Furthermore, were it not
for the non-linear stereoselectivity effect of destructively
selective reaction^[^^.^^.^^',discovered in 1975, stereochemically pure peptide segments could hardly have been synthesized by four-component condensation. The development of novel protective and auxiliary groups which can
be removed by Co’ supernu~leophiles[~~~
may also prove to
be essential.
For some synthetic goals, four-component condensation
has given rise to a shift in emphasis. In the synthesis of blactam antibiotics by conventional methods, construction
of the b-lactam moiety is the central issue. However, in
syntheses using the four-component condensation, the blactam part of an antibiotic only receives attention because
of its lability towards acids and bases.
Progress in understanding the mechanism of the fourcomponent condensation and its side reactions[291will extend its applications. Studies of this type may lead to the
selection of reaction conditions under which the formation
of by-products is practically avoided, and the desired product-and if need be one of several stereoisomers-is obtained in maximum yield and purity.
It is foreseeable that the scope and efficiency of fourcomponent condensations will grow with the development
of new reagents and techniques. The following comments
on the syntheses of antibiotics reviewed in this progress report may illustrate and support this statement.
Alkylamines and alkyl isocyanides, whose alkyl group
can be selectively cleaved under mild conditions may, for
example, be useful for the synthesis of bicyclomycin 27
and related compounds.
Straightforward syntheses of the nocardicins (e.g. 74,
75) would be possible if a derivative of L-a,b-diaminopropionic acid with a suitably protected a-amino group, such
as 113, where available.
C H 2-C H-N P h t
I
I
NH2 C 0 2 H
I13
Since azidoacetaldehyde has recently become available[821,the synthesis of 113 should be feasible from a condensation product of the following four-components: tert-
axy
NC
114a, X Y
114b, XY
= OBZ
= N3
butyl monophthalate, azidoacetaldehyde, (R)-a-ferrocenyl-isobutylamine[Mbl,and an isocyanide with a selectively
cleavable carbamoyl group.
The synthesis of furanomycin 47 and related compounds can probably be improved by using a chiral a-ferrocenylalkylamine as the asymmetrically inducing amine
component, and by combining a productively stereoselective four-component condensation with a destructively stereoselective cleavage of the chiral auxiliary group[831.
The synthesis of b-lactam antibiotics by four-component
condensation requires the conversion of the carboxylic
acid amide group originating from the isocyanide component into a free carboxy group. Neither the cleavage of amides by nitrosation, used by Isenring and Hofheinz[681in
their synthesis of nocardicin nor the imidochloride method
used by Hatanaka et UI.[’~I is universally applicable. Accordingly, the cleavability of the o-hydroxy- and o-aminoanilides 116a and 116b, respectively, by acylating derivatives of carbonic acid, such as carbonyldiimidazole
(CDI)1841,
is leading to novel b-lactam antibiotic syntheses
via four-component condensation. Kametani et
have
recently demonstrated that the racemate of an (abranched) b-amino-b’-hydroxycarboxylicacid can be synthesized via diastereoselective 1,3-dipolar cycloaddition of
a nitrone to some alkyl crotonates, and subsequent hydrogenolysis of the resulting isoxazoline derivative. This could
serve as the starting material for a synthesis of racemic
thienamycin 90 by a four-component condensation. If a
chiral nitrone with powerful asymmetric inducing power
were used in an analogous synthesis, a chiral P-amino-B‘hydroxycarboxylic acid would be formed, which in combination with the results of Hatanaka et ~ l . [ ’and
~ l amide
cleavage according to 114 -,119 could be the basis of the
conceivably most effective synthesis of thienamycin 90.
Since on the one hand it can be anticipated that thiemycin
will not be produced microbiologically, and on the other
that, because of the particularly favorable profile of this
class of substances, one of its derivatives will find a place
in the clinic, the thienamycin synthesis outlined could become the most important application of the four-component concensation in the near future.
Progress in isocyanide chemistry is dependent, to some
extent, on the development of an “imbedding chemistry”
as illustrated by the examples of advances in the area of
antibiotics discussed here. Isocyanide chemistry still has
ample virgin territory at its frontiers. Further advances
will, however, only lead to optimum success if isocyanide
chemistry and the rest of organic chemistry are well interfaced.
- axH-
4CCb1
ati-CO-R
115a, XY
=
115b, XY =
NH-C 0-R
OBz
I
Angew. Chem. Int. Ed. Engl. 21 (1982) 810-819
HzO
= 0
= XH
+
HOzC-R
I
C 0-R
= 0
= NH
116a, X
116b, X
E3
a>.-CO-R
117a, X
117b, X
CDI
H2iat
H
118a, X
118b, X
= 0
= NH
119a, X = 0
119b, X = NH
817
Thefinancial support of the work of our group in thisfield
by the Deutsche Forschungsgemeinschaft and the Fonds der
Chemischen Industrie is gratefully acknowledged.
Received: April 1, 1982 [A 431 IE]
German version: Angew. Chem. 94 (1982) 826
[I] 1. Ugi: Isonitrile Chemistry, Academic Press, New York 1971; a) Chapter
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16 (1977) 339.
[31 A. M. van Leusen, J. Wildeman, 0. H. Oldenziel, J. Org. Chem. 42
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191 A. Gautier, Ann. Chim. (Paris) 141 17 (1869) 103, 203.
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[I21 H. M. Walborsky, G. E. Niznik, J. Org. Chem. 37 (1972) 187.
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[IS] G. Skorna, I. Ugi, Angew. Chem. 89 (1977) 267; Angew. Chem. lnt. Ed.
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[I61 A. Efrati, 1. Feinstein, L. Wackerle, A. Goldmann, J. Org. Chem. 45
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[I91 1. Ugi, R. Meyr, U. Fetzer, C. Steinbriickner, Angew. Chem. 71 (1959)
386.
I201 C. Steinbriickner, Dissertation, Universitat Miinchen 1961.
1211 1. Ugi, Angew. Chem. 74 (1962) 9; Angew. Chem. lnt. Ed. Engl. 1 (1962)
8.
[22] The abbreviation “4CC” is frequently used for “four-component condensation”, as well as the term “Ugi reaction”, which was introduced by
McFarland [23] and Sjoberg [24].
1231 J. W. McFarland, J. Org. Chem. 28 (1963) 2179. (This paper is a report
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1241 K. Sjaberg, Suen. Kem. Tidskr. 75 (1963) 493.
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(261 I. Ugi, C. Steinbriickner, Chem. Ber. 94 (1961) 2802.
[27] a) 1. Ugi, K. Offermann, H. Herlinger, D. Marquarding, Justus Liebigs
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[28] 1. Ugi in J. Meienhofer, E. Gross: The Peprides, Vol. 2, Academic Press,
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[31] I. Ugi in: Jahrbuch der Akademie der Wissenschaften in Gottingenfur das
Jahr 1964, Vandenhoeck u. Rupprecht, Gottingen 1965, p. 21; Z. Naturforsch. B 20 (1965) 405.
[32] E. Ruch, I. Ugi, Theor. Chim. Acra 4 (1966) 287; Top. Stereochem. 4
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[34] E. Ruch, A. Schonhofer, 1. Ugi, Theor. Chim. Acra 7 (1967) 420; see also
E. Ruch, Acc. Chem. Res. 5 (1972) 49.
I351 J. Dugundji, R. Kopp, D. Marquarding, 1. Ugi, Top. Curr. Chem. 75
(1978) 165.
1361 1. Ugi, D. Marquarding, H. Klusacek, G. Gokel, P. Gillespie, Angew.
Chem. 82 (1970) 741; Angew. Chem. lnt. Ed. Engl. 9 (1970) 703.
818
I371 P. Gillespie, P. Hoffmann, H. Klusacek, D. Marquarding, S. Pfohl, F.
Ramirez, E. A. Tsolis, 1. Ugi, Angew. Chem. 83 (1971) 691; Angew.
Chem. lnd. Ed. Engl. 10 (1971) 687; 1. Ugi, D. Marquarding, H. Klusacek, P. Gillespie, F. Ramirez, Acc. Chem. Res. 4 (1971) 288; F. Ramirez,
1. Ugi, F. Lin, S. Pfohl, P. Hoffmann, D. Marquarding, Tetrahedron 30
(1974) 371.
(381 J. Dugundji, D. Marquarding, 1. Ugi, Chem. Scr. 9 (1976) 74; 11 (1977)
17.
I391 J. Dugundji, R. Kopp, D. Marquarding, 1. Ugi: Stereochemistry in Perspective - Interpretation of Stereochemistry by the Theory of Chemical
Idenfity Groups - Permutational Isomerism, Reaction Schemata and the
Tracing of interconversion Pathways, Lecture Note Series, Springer, Berlin, in preparation; see also J. Dugundji, J. Showell, R. Kopp, D. Marquarding, l. Ugi, Isr. J. Chem. 20 (1980) 20.
[40] 1. Ugi, Ref. Chem. Prog. 30 (1969) 289.
1411 1. Ugi, Intra-Sci. Chem. Rep. 5 (1971) 229.
(421 J. Dugundji, I. Ugi, Top. Curr. Chem. 39 (1973) 19.
I431 W. Schubert, I. Ugi, J. Am. Chem. Soc. 100 (1978) 37; 1. Ugi, J. Bauer, J.
Brandt, J. Friedrich, J. Gasteiger, C. Jochum, W. Schubert, Angew.
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Bauer, J. Brandt, J. Friedrich, J. Gasteiger, C. Jochum, W. Schuben, J.
Dugundji in J. Bargon: Computational Methods in Chemistry, Plenum
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1980, 70; (MI 1980, 1301, 1401, 1501; J. Brandt, J. Bauer, R. M. Frank,
A. V. Scholley, Chem. Scr. 18 (1981) 53: J. Bauer, I. Ugi, J. Chem. Res.,
in press; J. Dugundji, C. Jochum, J. Gasteiger, I. Ugi, 2. Naturforsch., in
press.
(441 a) D. Marquarding, P. Hoffmann, H.Heitzer, 1. Ugi, J. Am. Chem. SOC.
92 (1970) 1969; G. Gokel, P. Hoffmann, H. Klusacek, D. Marquarding,
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Ugi, ibid. 82 (1970) 360 and 9 (1970) 371; J. Am. Chem. SOC.92 (1970)
5389; L. F. Batelle, R. Bau, G. W. Gokel, R. T.Oyakawa, I. Ugi, Angew.
Chem. 84 (1972) 164; Angew. Chem. lnt. Ed. Engl. I 1 (1972) 138; J. Am.
Chem. SOC.95 (1973) 482: G. W. Gokel, D. Marquarding, I. Ugi, J. Org.
Chem. 37 (1972) 3052; G. Eberle, 1. Ugi, Angew. Chem. 88 (1976) 509:
Angew. Chem. Int. Ed. Engl. 5 (1976) 492; D. Marquarding, H. Burghard, I. Ugi, R. Urban, H. Klusacek, J. Chem. Res. (S) 1977. 82; (M)
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(1978) 977; c ) R. Herrmann, I. Ugi, Angew. Chem. 90 (1978) 734; Angew.
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956; Tetrahedron 37 (1981) 1001.
I451 G. Skorna, R. Stemmer, I. Ugi, Chem. Ber. 111 (1978) 806; G. Skorna, 1.
Ugi, ibid. 111 (1978) 3965; R. Arshady, 1. Ugi, 2. Naturforsch. B 36
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21 (1982) 374; Angew. Chem. Suppl. 1982, 761.
1461 E. Schnabel, H. Herzog, P. Hoffmann, E. Klauke, 1. Ugi, Angew. Cfiem.
80 (1968) 396; Angew. Chem. l n t . Ed. Engl. 7 (1968) 380; Justus Liebigs
Ann. Chem. 716 (1968) 175; E. Bricas: Peptides 1968, North-Holland,
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31 (1975) 1399.
147) H. Eckert, 1. Ugi, Angew. Chem. 87 (1975) 847; Angew. Chem. Int. Ed.
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Ugi, Z. Narurforsch. B 34 (1979) 1159; H. Eckert, I. Lagerlund, I. Ugi,
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Ugi, S. Zahr, H. von Zychlinski, Pure Appl. Chem. 51 (1979) 1219; R. G.
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(481 F. Ramirez, S. Glaser, P. Stern, P. D. Gillespie, 1. Ugi, Angew. Chem. 85
(1973) 39; Angew. Chem. lnt. Ed. Engl. 12 (1973) 66; D. Marquarding,
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Ramirez, P. Stern, S. L. Glaser, I. Ugi, P. Lemmen, Phosphorus 3 (1973)
165; F. Ramirez, S. L. Glaser, P. Stern, 1. Ugi, P. Lemmen, Tetrahedron
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1491 T. Miyoshi, N. Miyairi, H. Aoki, M. Kohsaka, H. Sakai, H. Imanaka, J.
Antibiot. 25 (1972) 659: Bicyclomycin has also been also isolated from
Angew. Chem. lnt. Ed. Engl. 21 (1982) 810-819
cultures of Sfreptomycesaizunensis: S . Miyamura, N. Ogasawara, H. Otsuka, S . Niwayama, H. Tanaka, T. Take, T. Uchiyama, H. Ochiai, K.
Abe, K. Koizumi, K. Asao, K. Mutsuki, H. Hoshino, ibid. 25 (1972) 610;
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1511 M. Nishida, Y. Mine, T. Matsubara, S. Goto, S. Kuwahara, J. Antibiof.
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[52] T. Fukuyama, D. Robins, A. Sachleben, Tefrahedron Left. 22 (1981)
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[531 a) L. V. Dunkerton, R. M. Ahmed, Tefrahedron Left. 21 (1980) 1803; R.
M. Williams, ibid. 22 (1981) 2341; b) C.-G. Shin, Y. Sato, J. Yoshimura,
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1541 H. Oediger, F. Moller, Angew. Chem. 79 (1967) 5 3 ; Angew. Chem. Int.
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1551 J. D. Morrison, H. S. Mosher, Asymmetric Organic Reactions, PrenticeHall, Englewood Cliffs 1971 ; Y. Izumi, A. Tai: Sfereodifferenfiafing
Reactions. Academic Press, New York 1977.
1561 By
way of analogy to the multiplication of algebraic signs
and (+ I)( - I)=(- I)( I ) = ( - I)) we
call the (R), (R)- and the ( S ) , (S)-isomers the “p”-isomers (“positive”)
and the ( R ) , ( S ) , and (S)(R)-isomers the “n”-isomers (“negative”)
[3I, 321; see also D. Seebach, V. Prelog, Angew. Chem. 94 (1982) 696; Angew. Chem. Int. Ed. Engl. 21 (1982) 654.
[ 5 i a) M. M. Joullie, P. C. Wang, J. E. Semple, J. Am. Chem. SOC.102 (1980)
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1581 K. Katagiri, K. Tori, Y. Kimura, T. Yoshida, T. Nagasaki, H. Minato, J.
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1591 Cf. D. Marquarding, P. Hoffmann, H. Heitzer, 1. Ugi, J. Am. Chem. SOC.
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[60] T. Masamune, M. Ono, Chem. Lett. 1975, 625; T. Masamune, M. Ono,
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1621 H. Aoki et at., J. Antibiof.29 (1976) 492.
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[64] J. Hosoda et al., Agric. Biot. Chem. 41 (1977) 2013.
I651 J. C. Sheehan, E. J. Corey, Org. React. 9 (1957) 388.
I661 R. Neidlein, Arch. Pharm. 298 (1965) 491.
((
+ I)( + I)=( - I)( - I ) = ( + 1)
Angew. Chem. Int. Ed. Engl. 21 (1982) 810-819
+
1671 D. Reuschling, H. Pietsch, A. Linkies, Tetrahedron Lett. 1978, 615; T.
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1681 a) H. P. Isenring, W. Hofheinz, Synthesis 1981, 385; b) ESOC II, Stresa,
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[69] M. Hatanaka, N. Noguchi, T. Ishimaru, Butt. Chem. SOC.Jpn. 55 (1982)
1234.
I701 a) I. Ugi, E. Wischhafer, Chem. Ber. 95 (1961) 136; cf. also E. Wischh6fer, Dissertation, Universitat Miinchen 1962; b) M. Hatanaka, Y. Yamamoto, H. Nitta, T. Ishimaru, Tetrahedron Left. 22 (1981) 3883.
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1721 K. Sjaberg, Habilitationsschrift, Technische Universitat Stockholm
1970.
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819
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