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Biomimetic Synthesis of Skyrin.

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OH 0
OH
€I 0
(3h). 57459-07-1 ; 14). 57459-08-2: (Sa). 57459-09-3; (.chi. 57459-10-6:
(JC), 57459-11-7: ( S d ) , 57459-12-8; (SF], 57459-13-9; 1/51, 57459-14-0
Constituents of Fungi, Part 26.-Part 25: H . Fujimofo, H . F h c h , and
B. Frunck, Chem. Ber. 108, 1224 (1975).
R . H . Thonisont Naturally Occurring Quinones. Academic Press, London
1971, pp. 1 and 367; W B. Turner: Fungal Metabolites. Academic Press,
London 1971, p. 74.
B. Franck, F . Hiiper, D. Criiger, and D. Erge, Chem. Ber. 101, 1954
(1968): B. Fruiwk and H . Flusch, Fortschr. Chem. Org. Naturst. 30,
151 (1973).
S. Cutenheck and L. Malrnsfrorn, Acta Chem. Scand. 23, 3493 (1969).
All compounds prepared for the first time were characterized by elemental
analysis and spectroscopic data.
[I]
(lj
CH3
[2]
OK 0
CH3
COzCH3
KO
HO
(2a), K
(2b), R
C H3
H3C02C H O
(3b1,R
CH3
-
[5]
= CH3
[4 + 21-Cycloaddition of the pale yellow leucopenta(methy1
ether) (4)[51(obtainable from emodin ( I ) ) , which also serves
as a sensitizer (m.p. 126"C), with singlet oxygen (02,
h > 350nm, + 10°C in ether, 25min) led to a 73 % yield of
the endoperoxide ( S a ) [ 5 Jcolorless
;
prisms, m. p. 174°C (dec.);
mass spectrum: m/e 374 (1.3%, Ma), 342 (loo%, M'-02);
UV (ether): h,,, 297, 281, 231 nm. Partial ketal hydrolysis
(0.2N aq. HCl/dioxane 1 :4, 2 h, 20°C) of ( S a ) afforded the
hydroperoxide ( 6 ) c 5 ]as starting material for the ring-opening
acid-catalyzed rearrangement; 88 % yield, pale yellow prisms
of m. p. 182°C (dec.); mass spectrum: m/e 360 (5 %, Ma),
327 (18, Me-OOH); UV (ethanol): h,,, 343, 293nm; 'HNMR (CDC13): 6 8.70 (s, 1H, OOH).
(1)
[4]
(3aj; R = H
= H
=
[3]
OR
OC H,
H&3
H3C0
-
C H3
Biomimetic Synthesis of Skyrin[l] [**I
By Burchard Franck, Rabi Chahin, Hans-Georg Eckert, Rainer
Langenberg, and Volker Radtke[*]
Skyrin ( 4 ) , the main pigment of the toxic rice fungus Penicillium islandicum, is a potential['] and in some cases proven[31
biosynthetic precursor for almost 40 structurally related mycotoxins[4*51 from molds and lichens. As demonstrated by labeling experiment^'^^ 61, it can arise from emodin ( I ) in the
fungal cell, probably via a condensation proceeding by the
mechanism of phenol oxidation. We now report the first biomimetic synthesis of skyrin ( 4 ) from emodin ( I ) and emodinanthrone (2) by chemical oxidation.
OH
0
OH 0
OH
OH
OC H3
0
H H
(4)
H O r \'011 C0
OH
H
3
H
o OH g 0 C OHH
(41
(3)
OH
HO
H O A,
\
0
H,CO
(5a)
-
OCH3
@
'J
$
H ~ C O HO-0
OCH3 C H3
-
0
(2bj
+
(3b)
Rearrangement of the hydroperoxide (6) (conc. H,SO$acetone, 3 h, 20°C) proceeded in 50 % yield (rearrangement of
the endoperoxide ( S a ) via the intermediate ( 6 ) in 70 % yield)
to give a crystalline 3 :4 mixture of the isomeric secoanthraquinones (2 b ) and (3 b). After ester hydrolysis the components
were separated by chromatography (PLC: silica gel,
CHC13/CH30H= 19: 1) and again esterified (CH2N2). ( 2 b ) ,
m.p. 162°C and ( 3 b ) , m.p. 157"C, were identified by their
'H-NMR spectra[51.
Like ( S a ) , the endoperoxides ( S b ) and (Sc) could be
obtained in yields of up to 80 % from natural hydroxyanthraquinones, and ( 5 d ) and ( 5 e ) from synthetic ones, and transformed into secoanthraquin~nes'~~.
Hence promising pathways open up for facile syntheses of natural products.
Received: September 29, 1975 [Z 321a IE]
German version: Angew. Chem. 87, 845 (1975)
CAS Registry numbers:
i l l . 518-82-1 : i 2 a ) . 57459-04-8: 12h), 57459-05-9: f 3 u ) . 57459-06-0:
Aiigiw.
Chem. intcrnur. Edit. J Voi. 14 ( 1 9 7 5 ) 1 No. I 2
3
\
/
\
I
OH
OH 0
\
CH3
/
OH
CH3
Oxidation of emodin ( I ) with K3[Fe(CN),] in the molar
ratio 1 : 4 ( 0 . 0 6 ~NaOH, 2h, 20°C) initially gave a 30%
yield['] of amorphous 5,7'-bisemodinyl(3) as the sole isolable
oxidation product; the compound does not melt below 360°C;
mass spectrum: m/e 538 (15%, M'); UV (CH3OH): h,,,
445, 288, 254, 220nm; IR (KBr): 1680, 1630 (C=O) cm-'.
It was identified as the crystalline hexamethyl (m.p. 285287 "C)and hexaacetyl derivative (m. p. 153"C) and by analysis
of 'H-NMR spectra and pK, measurements (80 % aq. dimethylformamide)[8*9!
In order to establish by isotopic dilution analysis whether
the desired skyrin ( 4 ) might nevertheless have been formed,
the oxidation was repeated with biosynthetically prepared"
[U-14C]emodin ( 1 ) . Admixture of inactive skyrin ( 4 ) to the
['I
Prof. Dr. B. Franck, Dr. R. Chahin, Dr. H . G . Eckert. Dip].-Chem.
R. Langenherg, and Dr. V. Radtke
Organisch-Chemisches lnstitut der Universitat
44 Miinster, OrlCans-Ring 23 (Germany)
[**I This work was supported by the Landesamt fur Forschung des Landes
Nordrhein-Wcstfalen.
819
oxidation mixture, re-isolation and repeated thorough chromatographic purification to constant radioactivity (a) silica gel
G impregnated with tartaric acid, CHC13 + 2 % C H 3 0 H ;
b) acetylated polyamide 6-Ac (ex Macherey, Nagel & Co.),
SO::, aq. CH,OH) afforded radioactive skyrin 14). Its I4C
content showed that [U-I4C]emodin ( I ) was transformed
in 0.28% yield into skyrin ( 4 ) on oxidation, thus proving
formation of skyrin by in uitro phenol oxidation.
Formation of 5,7'-bisemodinyl (3) as the major product
of emodin oxidation reveals some steric hindrance of position
5 of emodin by the n orbitals of the carbonyl oxygen at
C-10 which are coplanar with the ring skeleton; this hindrance
should be lower in emodinanthrone (2). Accordingly, when
compound (2), which is readily accessible from emodin (I),
was subjected to oxidation by K3[Fe(CN),] a 1.2% yield
of skyrin ( 4 ) (m.p. 360"C, dec., also characterized as the
hexa(methy1 ether) could be isolated, together with (3) (1.0 %)
and higher condensed products after chromatographic workup
(PLC, see above)18'.
These results show that skyrin ( 4 ) is formed from emodin
(1) by phenol oxidation, and in 4.3-fold higher yield from
emodinanthrone (2). A condensation mechanism of this kind
can therefore also be considered for the biosynthesis of skyrin.
Selective Photochemical Fries Rearrangement of
Phenyl Acetate in the Presence of P-Cyclodextrin
By Masaaki Ohara and Kuguko Watunabe"]
The Fries rearrangement of phenyl esters, e.g. (I), affords
a mixture of 0- and p-hydroxy ketones, e.g. (2) and (3).
In addition, solvolysis gives phenol ( 4 ) . This rearrangement
can also be carried out photochemically['].
We attempted to obtain one of the positionally isomeric
rearrangement products preferentially by joint irradiation of
phenyl acetate ( I ) and 0-cyclodextrin. P-Cyclodextrin, a cyclic
oligosaccharide made up of seven D-glucose units, can form
inclusion complexes; this technique has been used on several
occasions to induce a stereoselective course of an organic
reaction''].
Table 1. Influence of p-cyclodextrin on the course of the photochemical Fries rearrangement of phenyl acetate ( I )
(reaction conditions as given in procedure).
Reaction iniixture
( m o la r rat i 0)
Con\er\ion
"'<,I
12
41
25.2
(1)
p-Cyclodextrin: ( 1 ) (0.45: I )
Methyl ?-n-glucopyranoside: / / ) (3.1 : 1)
Former unsuccessful attempts to prepare skyrin by oxidation
of emodin["] were construed as a reason for assuming an
alternative non-oxidative mechanism for the biosynthesis of
skyrin ( 4 ) from emodin (l)14].
Received: September 29, 1975 [ Z 321 b IE]
German version: Angew. Chem. 87.846 (1975)
CAS Registry numbers:
( I ) , 51R-82-1; (2). 491-60-1 ; (31, 57458-95-4;
/.?)-hexamethyl deriv., 57458-96-5; /3/-hexaacetyl deriv.. 57458-97-6:
(41. 602-06-2
Constituents of Fungi, Part 27.-Part 26: B. Franck and B. Brryer-Lohr,
Angew. Chem. 87, 845 (1975); Angew. Chem. internal. Edit. 14, 818
(1975).
W B. i k n e r ' Fungal Metabolites. Academic Press. London 1971, p.
74.
H . Backhaus, Dissertation, Universitlt Miinster 1974: M . Roy, Dissertation, Universitit Mtinster 1974.
N . Takeda, S. Seo, Y Ogiliuru, U . Sankuwu, I. Iiiaka, I. Kiragawa,
and S. Shibara, Tetrahedron 29, 3703 (1973).
B. Fraiick and H . Flasrh, Fortschr. Chem. Org. Naturst. 30, 151 (19731.
L'. Sunkawa, Y E b i m k a , and S. Shibura, Tetrahedron Lett. 1973, 2125.
Systematic investigations showed K,[Fe(CN),] to be superior to the
following oxidizing agents with regard to formation of bisemodinyls:
VOCI,. DDQ (2,3-d1chloro-5,6-dicyano-l.4-ben~oquinone).
Ce(SO,),.
MnO,, FeCl,, CrO,.
The compounds described were characterized by elemental analysis
and spectroscopic data.
According to I R and UV spectra, compound (3) IS identical with
a product obtained by Ikekuwu [lo] in 5 % yield by autoxidation
of emodin ( I ) . The structure of a 5,4'-bisemodinyl assumed by that
author can now be ruled out in favor of ( 3 ) on the basis of the
presently available spectroscopic data.
7: Ikekaxa, Chem. Pharm. Bull. 11, 749 (1963).
D. Grbyrr, D. Erge, B. Franck. I/. Ohnsorye, H . Flasck, and F . Huper,
Chem. Ber. 1 0 1 , 1970 (1968).
Relative yields ["<I
o-Hydroxyp-Hydroxyacetophenone
acetophenone
(2)
(31
(4)
25.7
11.2
32.4
48.6
19.8
35.0
25.7
69.0
32.6
Phenol
POI 11
01//lo
1:1
6.2 : 1
1:l
We have now found that the photochemical Fries rearrangement of phenyl acetate (1) in the presence of P-cyclodextrin
in an aqueous medium does indeed follow a stereoselective
course. The experimental results are summarized in Table
1 . Only the three reaction products listed were detected. The
content of tarry products was negligible. The isomers (2)
and (3) are stable under the reaction conditions.
As seen from Table 1, p-hydroxyacetophenone (3) is preferentially formed in the presence of p-cyclodextrin, the formation
of phenol falling from ca. 50 to ca. 20%. Moreover, the
conversion increased about 3.5-fold. A control experiment
showed that methyl rx-D-glucopyranoside, which corresponds
to a structural unit of p-cyclodextrin, has hardly any influence
on the ratio of positional isomers.
Procedure :
A mixture of ( I ) (3m1, 23.6mmol) and P-cyclodextrin (12g,
10.6mmol) in H 2 0 (300ml) was irradiated with UV light
(100 W Hg high pressure lamp) for 38 h at 30°C with continuous passage of N2.The reaction mixture was then extracted
several times with ether. The dried ether extract was evaporated
in a vacuum and analyzed by gas chromatography.
Received: September 22, 1975 [Z 330 IE]
German version: Angew. Chem. 87.880 (1975)
[*] Prof. Dr. M. Ohara [ - ] and M. Pharm. Sci. K . Watanabe
[ '1
Faculty of Pharmaceutical Sciences. Josai University
Sakado, Saitama (Japan)
T o whom correspondence should be addressed.
H . Kobsu, J. Org. Chem. 27, 2293 (1962); J . C. Aiirlersoii and C. B.
Reese, J. Chem. Sac. 1963, 17x1.
[2] F . Crainer and H . Hertier, Naturwissenschaften 54,625 (1967); R. Breslow
and P. Campbell, Bioorg. Chem. 1, 140 (1971).
[I]
Aiiyeu. Chrm. iiireriiut. Edir.
Vol. 14 (1975)
No. I Z
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