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LiClO4 in EtherЧan Unusual Solvent.

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settes holds good for other macrolide PKS’s, and also possibly for ionophore-producing PKS’s. This ordering of
proteins in cassettes, which need not be exclusively bimodular, may hold the key to the precise control exercised by the
synthase as a whole in carrying out its synthetic operations.
It would, for example, help rationalize both the early observations of Celmer et al. on the common patterns of structure
and stereochemistry which run through families of macrolides,” * * 31 and more recent related analyses of ionophore
structures.[141Perhaps regions with common structure in diverse metabolites are produced in different organisms by
closely related cassettes derived from a common ancestral
protein. Looking ahead, it may be possible to engineer organisms to produce novel chimeric metabolites by switching
genes coding for specific cassettes from one producer to another.
If substantial amounts of active PKS proteins can be isolated by overexpression, it will be possible to investigate the
molecular mechanisms by which the cassettes carry out their
specific tasks. The protein-protein interactions which must
play a major part in the collaboration between cassettes will
make a fascinating study. Equally interesting are the molecular interactions which occur between protein components
and substrates, which presumably help define the substrate
specificity of the enzymic reactions. Progress in such studies
could be of particular significance to synthetic chemists who
have made great efforts in recent years to develop new
methodology for macrolide
Isolated PKS cassettes used in vitro may well prove to be convenient and
efficient alternative synthetic tools for carrying out limited
transformations on natural substrates and substrate analogues. In the longer term, it may be feasible to employ
different combinations of cassettes in vitro, to generate complex chimeric products with greater control than would be
possible in vivo. Chemists as well as biologists have reason to
watch developments in this field.
LiC104 in Ether-an
German version: Angew. Chem. 103 (1991) 1331
[l] S. Numa (Ed.): Fatly Acid Metabolism and its Regularion (in Cumprehensive Biochemistry, Vul. 7) Elsevier, Amsterdam 1984.
[2] E. T. Seno, C . R. Hutchinson in S. W. Queener, I. E. Day (Eds.): The
Bacteria. Vol. 9, Academic Press, New York p. 231.
[3] D. E. Cane, C. Yang, J. Am. Chem. Soc. 109 (1987) 1255.
[4] D. A. Hopwood. D. H. Sherman, Annu. Rev. Genet. 24 (1990) 37.
IS] J. Beck, S. RiDka, A. Siegner. E. Schiltz. E. Schweizer. Eur. J. Biochem. 192
(1990) 487.
J. Cortes, S. F. Haydock, G. A. Roberts, D. J. Bevitt, P. F. Leadlay, Nature
348 (1990) 176.
S. Donadio, M. J. Staver. J. B. McAlpine, J. B. Swanson, L. Katz, Science
252 (1991) 675.
H. Kleinkauf, H. von Doehren, FEES Lert. 268 (1990) 405.
P. CafFrey, B. Green. L. C . Packman, B. J. Rawlings, J. Staunton, P. F.
Leadlay, Eur. J Biochem. 195 (1991) 823.
G. A. Roberts, personal communication.
A. M. Bridges, P. F. Leadlay. W P. Revill, J. Staunton, J Chem. SOC.
Chem. Cummun. 1991.118.
W. D. Celmer, J Am. Chem. Suc. 87(1965) 1801.
D. E. Cane, W. D. Celmer, J. W. Westley, J. Am. Chem. Soc. 105 (1983)
D. O’Hagan, Nut. Prod. Rep. 1989, 205.
Editorial comment: see also the Highlight by J. Mulzer in the November
Unusual Solvent
By Herbert Waldmann *
Many reactions can be influenced in a variety of ways by
the solvent employed. This is especially the case when polarized transition states or ionic intermediates are involved in
the reaction and when the solvent is nucleophilic or electrophilic. A case to the contrary is the Diels-Alder reaction,
which remains largely unaffected by the surrounding organic
medium. In the mid-eighties, however, Breslow et aI.[l1and
Grieco et al.I2]demonstrated that Diels-Alder reactions proceed with increased reaction rate and with improved endoexo selectivity when they are carried out, not in organic
solvents but in aqueous solutions. The effect is further enhanced by salts such as LiCl (salting-in effect), whereas the
addition of guanidinium chloride has the opposite effect
(salting-out effect). The use of water as solvent for such
cycloadditions had already been described earlier by Alder et
al.’3a1and later by Koch et al.[3b1The accelerating effect of
this reaction medium is also manifested in many other react i o n ~ , [e.g.
~ ] asymmetric hetero-Diels-Alder reactionst4b]and
Prof. Dr. H. Waldmann
Institut fur Organische Chemie und Biochemie der Universitit
Gerhard-Domagk-Strasse 1
W-5300 Bonn (FRG)
V‘rlagsgesellschafi mbH, W-6940 Weinheim, 1991
asymmetric nonhetero-Diels-Alder
dl nucleophilic additions to iminium ionst4’] and carbonyl comp o u n d ~ , [ ~Claisen
rearrangement^,^^^] the benzoin condensation,’’bl and aldol reactions.[4h1It is attributed to the fact
that a suitable aggregation is generated by hydrophobic interactions between the reaction partners (hydrophobic effect), and so exercises an “internal pressure” on the reactants
encapsulated in “solvent cavities” whose effects are, in turn,
comparable with a high external pressure, at least in the case
of the Diels-Alder reaction.
Last year, Grieco et aLL5]described a solvent system,
namely a 5 M solution of LiCIO, in diethyl ether, which has
a comparable, if not greater accelerating effect on Diels-Alder reactions. Already in 1986 Sauer et a1.16]investigated the
steric course of Diels-Alder reactions in such solvent systems
in order to determine the polarity of ethereal LiClO, solutions, and had already recommended them as polar solvents
for organic chemical reactions. Grieco et al. then demonstrated the astounding properties of these solutions (see
Scheme I), which according to Pocker et aI.[’] must be regarded as mixtures of the mono- and diether adduct of LiCIO,.
The reaction of cyclopentadiene 1 with ethyl acrylate 2
0570-0833l91j1010-1306 $ 3 . 5 0 + . 2 5 / 0
Angew. Chem. Int. Ed. Engl. 30 (1991) No. 10
R = Et
H20, R T, 5h
73%. endo:exo = 4 1
5h1 LiClOflt20
R T,5h
93%. endo:exo = 8:l
E M , N 4 3,
25OC. 72h,
98%. endo:exo = 6.7:1
Scheme 1 .
(R = Et) to give the bicycloheptenes 4 and 5 proceeds more
rapidly and with higher endo-selectivity in 5 M LiClO,/diethyl ether (endo:exo = 8: 1) than in water (Scheme 1). Particularly advantageous is the compatibility of the LiClO,/ether
system with substances sensitive to hydrolysis. Thus, the azadiene 6 reacts with methyl acrylate at room temperature in
the presence of the Li-salt to give the desired cycloadduct 7
in 80% yield in 5 h, whereas the same reaction in benzene
affords 7 in 75 % yield only after 72 h at 60 "C (Scheme 2).
Particularly impressive is the reaction of furan 8, which, owing to its aromaticity does not react with the thiophene derivative 9 under normal conditions (Scheme 2). In LiClO,/ether,
1) 5M LiC10flt20
R T.5h
2) CH30H
with those reported by Dauben et aI.,'*] who required 6 h and
15 kbar in order to achieve the same product ratio in their
synthesis of cantharidin by the same reaction in CH2C1,. To
explain their results Grieco et al. assume that LiClO,/ether
solutions, in analogy to water, generate an internal pressure
and press the reactants together. However, the stabilization
of a polarized transition state by the salt is not ruled out.
The latter possibility is not improbable, since, on the one
hand, the rate- and selectivity-enhancing effect of Lewis acids
on Diels-Alder reactions is well known, so that such an effect
could be attributed to the presence of Li+ ions in higher
concentration. On the other hand, it has already been possible, with ethereal solutions of LiCIO,, to accelerate a number of reactions which proceed via polarized intermediates.
Thus, Winstein et a1.['] found that the ionization of p-methoxyneophyl tosylate and a p-nitrobenzoate in a 0.1 M solution of LiCIO, in ether is respectively lo5 and lo6 times
faster than in ether itself. Pocker et a1.['1 have investigated
the properties of concentrated solutions of LiCIO, in ether,
developed concepts about their structure, showed that the
ionization of tert-butyl chloride in 5.5 M LiClO,/diethyl ether
occurs about lo6 times more rapidly than in ether, and found
that the rearrangement of I-phenylallyl chloride to 3-phenylallyl chloride takes place 85600 times more rapidly in a
3.39 M solution than without added salt ("electrostatic catalysis").
Already in the early eighties B. F6hlisch et al.rlolexploited
the advantageous effects of the medium presented here in
their detailed investigations of the [4 31 cycloadditions of
a-halogeno- or a-sulfonyloxy-substituted ketones 12 to 1,3dienes, in particular to furan (Scheme 3). The 8-oxabicy-
Scheme 2. RT
Scheme 3
5M LiCIO&t20
R T ,9.5h
70%. 10:ll = 85:15
X = Cl.OSO~CH3
R1-R4 = H, C1, Alkyl
clo[3.2.l]oct-6-en-3-ones13 formed thereby are of interest,
room temperature
however, the cycloadducts 10 and 11 are formed in 70%
yield in the ratio 85: 15 after 9.5 h at room temperature and
under atmospheric pressure. These values must be compared
Angew. Chem.Int. Ed. Engl. 30 (1991) No. 10
inter aha, as starting materials for the synthesis of tropones
and other natural products. For the cycloadditions with the
a-halogeno- or the a-mesyloxyketones 12, room temperature
suffices, and inter- and intramolecular reactions can be carried out in satisfactory to good yields. A possible use of this
method for the synthesis of natural terpenes, e.g. of the guajanolide, azulene, and hydroazulene type, seems very promising.
The favored acceleration of ionic conversions and reactions with polarized transition states by the system LiCIO,/
diethyl ether also follows from the surprising observation
made by Grieco et al.'"] that allyl vinyl ethers, contrary to
expectation, do not undergo [3,3]-sigmatropic rearrange-
0 VCH VeriagsgesellschaftmbH. W-6940Weinheim,1991
0570-0833/91l1010-1307 $3.50+ ,2510
3M LiClO@t,O
R T, Ih
H2O-CH3OH (2.5~1)
90%. 15a:Mb = 5:l
80°C, 24h, 85%
15a: -CH2CH0
3M LiC104/Etq0
RT, l h
H20-NC.jHs (3:l)
W"C,36h, 21 %
Scheme 4.
ments in 3 M LiClO,/diethyl ether solutions, but give aldehydes in [1,3]-sigmatropic rearrangements (Scheme 4). Thus,
e.g., 14 reacts under these conditions to give 15 in 90% yield
within 1 h at room temperature (in 5 M salt solution the
reaction is already complete after 10 min), and also the fenestrane 17 is transformed into the aldehyde 18 in high yield.
These observations, particularly the steric course of the rearrangements, are in sharp contrast to the findings that 14
undergoes the expected Claisen rearrangement to 16 in water-methanol (2.5: 1) at 80°C and that also the fenestrane 17
rearranges to 19 in water-pyridine (3:l) at 90°C.
In all cases the [1,3]-sigmatropic rearrangements take place
at room temperature and make the products available in high
yields under the mildest conditions. The authors demonstrate on the basis of crossover experiments that ionic intermediates must indeed be involved, and they verify the importance of Li' ions being present: the use of a 1.8 M tetrabutylammonium perchlorate solution as solvent has no advantageous effect on the rearrangement.
The solvent system LiClO,/diethyl ether has already proven to be an excellent medium for diverse reactions. It is to be
expected that further uses will be found. The fantasy of the
experimentalist must not be confined to the concentrated
solutions of LiClO, in ether, which also can be regarded as
a salt with little ether additive.['' Thus, Jueger et al.['21have
recently reported that the low-melting (m. p. z 12°C) ethylammonium nitrate 3 (Scheme 1) likewise offers advantages
as solvent; Diels-Alder reactions are considerably accelerat-
0 VCH Verlagsgeseifschafi mbH.
W-6940 Weinhein?, 1991
ed and proceed more selectively in this salt than in organic
solvents. The effect is, however, less pronounced than on
changing over to water or LiClO,/ether.
German version: Angew. Chem. 103 (1991) 1336
[l] a) R. Breslow, U. Maitra, Tetrahedron Let/. 25(1984) 1239-1240, and references cited therein; h) review: R. Breslow, Acc. Chem. Res. 24 (1991)
150 - 164.
[2] P. A. Grieco, P. Galatsis, R. F. Spohn, Tetrahedron 42 (1986) 2847-2853,
and references cited therein.
[3] a) 0. Diels, K. Alder, Justus Liebigs Ann. Chem. 490 (1931) 243-257;
b) H . Koch, J. Kotlan, H. Markert, Monatsh. Chem. 96 (1965) 1646-1657.
[4] a) Review: H. U. Reissig, Nachr. Chem. Tech. Lab. 34 (1986) 1169-1 171;
b) H. Waldmann, Liebigs Ann. Chem. 1989,231-238, and references cited
therein; c) H. Waldmann, M. Drager, ibid. 1990, 681-685; d) A. Lubineau, Y. Queneau, Tetrahedron 45 (1989) 6697-6712; e)S. D. Larsen,
P. A. Grieco, W. E Fobare, J. Am. Chem. SOC. 108 (1986) 3512-3513;
f ) H. Waldmann, Synlert 1990, 627-628, and references cited therein;
g) P. A. Grieco, E. B. Brandes, S. McCann, J. D. Clark, J. Org. Chem. 54
(1989) 5849-5851; h) A. Luhineau, ibid. 51 (1986) 2142-2144.
[5] P. A. Grieco, J. J. Nunes, M. D. Gaul, J. Am. Chem. SOC.112 (1990) 45954596.
[6] R. Braun, J. Sauer, Chem. Ber. 119 (1986) 1269-1274.
[7] Y. Pocker, D. L. Ellsworth, J. Am. Chem. SOC.99(1977) 2276-2284,22842293, and references cited therein.
[8] W. G. Dauben, C. R. Kessal, K. H. Takemura, J. Am. Chem. SOC. 102
(1980) 6893-6894.
[9] S. Winstein, S . Smith. D. Darnisch, .
Am. Chem. Soc. 81 (1959) 55115512.
[lo] a) R. Herter, B. Fohlisch, Synthesis 1982, 976-979; b) B. Fohlisch,
D. Krimmer, E. Gerlach, D. Kashammer, Chem. Ber. 121 (1988) 15851593, and references cited therein.
[ l l ] P. A. Grieco, J. D. Clark, C. T. Jagoe, J. Am. Chem. SOC.113 (1991) 54885489.
[12] D. A. Jaeger, C. E. Tucker, Tefrahedron Lett. 30 (1989) 1785-1788.
0S70-0X33~9ljf010-130XS 3.50+ ,2510
Angew. Chem. fnt. Ed. Engl. 30 (1991) No. 10
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