Org. 369

Phytotoxic Compounds produced by Fusarium eguiseti. Part 1V.l Fission of Trichothecan-3a,4P-diols by Manganese Dioxide By A. W. Dawkins, Burmah Research and Development Labs., Bromborough, Cheshire

John Frederick Grove, Tropical Products Institute, London W.C.l t

The structures of the 3.4-seco-products from the oxidative fission of trichothecan-3a,4~,15-triols by activated manganese dioxide have been elucidated.

THE trans-ap-glycol system in 12,13-epoxytrichothec- 9-en-3a,4@,15-triol ( I ; R = R’ = H) (scirpentriol: for nomenclature see ref. 2) and in the 15-monoacetate (I; R = Ac, R’ = H) was shown to be stable to peri- odate314 and to lead tetra-acetate in acetic acid: but was cleaved by the latter reagent in chloroform to give, from the triol (I; R = R’ = H), in fair yield, an amor- phous hemiacetal (VIII; R = H), characterised as the acetate (VIII; R = Ac). The hemiacetal (VIII; R = H) was oxidised further by chromic oxide in dimethyl- formamide in the presence of sulphuric acid to an amorphous 8-lactone which was considered to have the structure (VII). Ring c of the trichothecan-3,4-diol skeleton was also opened by chromic oxide in acetic acid which gave,4 from the diacetate (I; R = R’ = Ac) (diacetoxyscirpenol), the aldehydo-acid (111 ; R = Ac) in addition to the ketone (11). Deacetylation of the aldehydo-acid (111; R = Ac) followed by methylation and oxidation with chromic oxide-pyridine then furnished the y-lactone (XII).

Although activated manganese dioxide in a non- hydroxylic solvent a t room temperature was originally introduced as a specific reagent for the oxidation of allylic (or benzylic) alcohols, numerous examples of the oxidation of non-allylic primary and secondary alcohols have since been r e~orded .~ In addition, the reagent oxidises hemiacetals to lactones and, a t elevated temperatures, cleavage of some aliphatic a 8-glycols has been reported.6

7 Present address: University Chemical Laboratory, Cambridge. Part 111. B. K. Tidd. J. Chem. SOC. ( C ) , 1967, 218. W. 0. Godtfredsen, J. F. Grove, and C. Tamm, Helv. Chim.

Acta, 1967, 50, 1666. a A. W. Dawkins, J. F. Grove, and B. K. Tidd, Chena. Comm.,

1965, 27; A. W. Dawkins, J . Chem. SOC. (C) , 1966, 116.

In the course of an earlier investigation of the posi- tional relationship of the ethylenic double bond and alcoholic hydroxy-groups in the C15H2,05 triol (I; R = R‘ = H), it was observed that the triol was readily oxidised by manganese dioxide at room temperature with development in the mixture of U.V. absorption at 250 nm. consistent with the formation of an ap-unsatu- rated ketone, but the structures of the products were not then apparent. Three major crystalline products were isolated, two of which, a masked aldehyde with no i.r. C=O absorption and a y-lactone, urnax. 1765 cm.-l, had the composition C15HmO5 and the third, a %lactone, vIIlel 1740 cm.-l, the composition C15H1805, respectively two and four hydrogen atoms less than the parent triol. None of these, however, showed specific U.V. absorption near 250 nm.

The reaction took a similar course with the saturated 12,13-epoxytrichothecantriol (XIII; R = H) : the tri- chothecantetraol (XV) yielded similar products though without the development of specific U.V. absorption in the mixture. The reaction did not depend, therefore, on the presence of either the 9-ene or the 12,13-epoxy-group in structure (I; R = R’ - H). N.m.r. spectroscopy (Table) has now revealed that these products arise by fission of the ring c trans-ap-glycol system, a reaction with manganese dioxide that is without close precedent. The reaction thus provides an alternative route t o tri- chothecane 3,4-seco-products which are of interest in

4 €3. P. Sigg. R. Mauli, E. Flury, and D. Hauser, Helv. Chim.

5 R. M. Evans, Quart. Rev., 1959, 13, 61; S. P. Korshunov

6 J. PadilIa and J. Herran, BoE. Inst. Quim. Univ. nut. auton.

7 P. W. Brian, A. W. Dawkins, J. F. Grove, H. G. Hemming,

A d a , 1965, 48, 962.

and L. I. Vereshchagin, Russ. Chem. Rev., 1966, 35, 942.

Mexico, 1956, 8, 3.

D. Lowe, and G. L. F. Norris, J . Expt. Bot., 1961, 12, 1.

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370 J. Chem. SOC. (C), 1970 connection with studies on the relationship between biological activity and chemical structure in this group of mould metabolites.8

All three products from the trio1 (I; R = R' = H) showed n.m.r. signals consistent with the presence of the

ture (VIII ; R = H) , in which the sequence of hemiacetal formation is from position 15 to 4 to 3 [(IV) + (V) (VIII)], on the basis of the n.m.r. spectrum wherein the position of a singlet at z 4-6, ascribed to the acetal hydro- gen a t position 4, was unaffected by acetylation, but a

Chemical shifts (z ; CDC1,) for hydrogens in the oxidation products of trichothecan-3orJ 4P-diols and related compounds Position

2 3 4 10 11 13 14 15 16 OAc' J 2 . 3 Ji6-gm JS-gsm (VIII; R = H)" 6.7 (d) 4.5 (d) 4.6 (s) 4.5 5.1 7-15(AB") 9-1 6-15 (AB) 8.25 1.7 58.5 (VIII; R = Ac) 6.75 (d) 3.8 (d) 4.7 (s) 4-5 5.0 7.1 (AB") 9.1 6.15 (AB) 8.2 7.8 2.0 8.5

(IX; R = H) a 5-75 (dd) 6-25 (dd) 6.55 (dd) (rx; R = A C ) 6.2 (t) 5.6 (d) 4.5 6.0 7.05 (AB") 8.6 5.95 (AB) 8-2 7.9 7.8 9.0

6.05 (s) 4-45 (s) 4.6 6.05 8-55 8-8 6.15 (s) 8.3 (XXIII; R = Ac) 6.15 (dd) 5-45 (dd)

4.4 (s) 4-5 5-95 7.1 (ABz) 6.25 (s) 6-15 (s) 4.5 5-8 7.05 (AB") 8-6 6.0(~) 8-25 6, 3 5 u 12

(VII)

4.65 5-8 8.5 8-8 6-0 (s) 8-3 7.95 9, 2.5V 12 V (XX)

(XVI; R = H) " 6.75 (s) 4.8 (s) 4.7 (s) 5.3 7.15(AB") 9.2 6.2 (AB) 9-15(d) 9-0 6-3 4-5 (s) 6-1 7.1 (AB") 9.1 6.15(AB) 9*15(d) 9.0 W X )

(XXV) 2.6 ( s ) 4.55 (s) 5-6 0.8 (s) 8.8 6.1 (AB) 9-1 (d) 9.5

(XXI) * 6-1 (s) 4.5 (s) 6.3 8.5 8.85 6.2 (AB) 9-15 (d) 9.0

5-9 (dd)

6.1 7.0(AB") 8.7 6-05 (AB) 9-15(d) 6, 3.5r 9.0 12 Y (XXII; R = H) (I 5.75 (dd) 6-35 (dd) 6.6 (dd)

(XVIII; R = H) 6.5 (s) 4-8 (s) 4.7 (s) 5.6 8.5 8-95 6.25 (AB) 9.15 (d) 8.5

(XXIV; R = Ac) 6.2 (dd) 5-5 (dd) 6-0 8.55 8.75 6.0 (AB) 9-15 (d) 7.9 9, 3.5u 9.5 1 2 ~

(XXXIII) b 5.8 (d) 7.4 (ABX) 4.65 5.75 8.6 5-8 (dd)

8.85 6-25 (AB) 8.25 0, 5-0 8.0 16 In presence of D,O. b In presence of CF3*C0,H. c Trichothecane numbering. J19-lm 4 Hz. y First-order interpretation

of an ABC pattern approximating to AMX.

i R=RIA~ I lllR=H iii or vii t

t 11 I iv R=H 1 @--co2H H H @---C02M. H

- 0 .O

R = H * I .

H2C, >CO 0 (rnt

RO-HZC 'CHO

cm, I i v , v .vi R=Ac

SCHEME 1 Ring c fission of 12,13-epoxytrichothec-9-en-3ct,4/3, 15-triol. Reagents : i, Cr03-.4cOH; ii, Pb(OAc),; iii, MnO,; iv, OH-; v, CH,N, ; vi, Cr03-C,H,N ; vii, Cr03-H2S0,

12,13-epoxideJ an intact ring A A,MX system arising doublet at T 4.5, ascribed to the hemiacetal hydrogen at from the hydrogens at positions 16, 10, and 11, and a position 3, moved downfield to 7 3-8 (J2,3 2 Hz) in the CH,=OR group attached at a tertiary position. The spectrum of the acetate (VIII; R = Ac). This result C,,H,O, masked aldehyde showed no i.r. G O absorption suggests a P-configuration for the hemiacetal hydroxy- but formed a dinitrophenylhydrazone and re-

8 3- F. Grove and P. H. Mor~mer, Biochem. Phavmacol., 1964 duced ammoniacal silver nitrate. It was assigned struc- 18, 1473.

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Org. 371

group and excludes the alternative structure (X), in which the sequence of hemiacetal formation is from posi- tion 15 to 3 to 4, where the expected multiplicities of the acetal and hemiacetal hydrogens are reversed. The acetyl derivative (VIII; R = Ac) was identical with that obtained by acetylation of the amorphous product from the oxidation of the trio1 (I; R = R' = H) with lead tetra-a~etate.~

The crystalline C,,H,,O, %lactone, also obtained by further oxidation of the hemiacetal (VIII; R = H) with

(XXIV; R = H) from the trichothecan-12-01 (XV) were deduced from their chemical and spectroscopic proper- ties, which agreed closely, where relevant, with those of the oxidation products (VIII; R = H), (VII), and (IX; R = H), respectively, of the 12,13-epoxytrichothec- 9-ene (I; R = R' = H). All the masked aldehydes [(XVI), (XVII), and (XVIII; R = H)] showed the ex- pected reducing properties ; they were oxidised by manganese dioxide to the corresponding &lactones (XIX), (XX), and (XXI) and were isomerised under

1 i v t I V I I

SCHEME 2 Interrelationships among the manganese dioxide oxidation products of some trichothecane ring c diols. i, LiAlH,-tetrahydrofuran ; ii, H2-Pd ; iii, MnO, ; iv, OH-

Reagents:

manganese dioxide in chloroform at room temperature, was assigned structure (VII), in which the hydrogen at position 2 now gave rise to a singlet (T 6.15).

Finally, the y-lactone isomeric with the hemiacetal (VIII; R = H) was shown to be the product (IX; R = H) of an intramolecular crossed Cannizzaro reaction, and was formed when the hemiacetal was treated with dilute sodium hydroxide at room temperature. In the n.m.r. spectrum of the lactone (IX; R = H) the AB part of an ABC system (approximating to AMX) arising from the hydrogens at positions 2 and 3, moved downfield about 0.8 p.p.m. on acetylation, consistent only with the presence of a hydroxymethyl substituent a t position 2. Oxidation of the lactone (IX; R = H) with chromic oxide and methylation of the product with diazomethane gave the known lactone-ester (XII) (Scheme 1).

The structures of the products (XVII; R = H), (XX), and (XXIII; R = H) from the trichothec-9-en- 12-01 (XIV) (Scheme 2); (XVI; R = H), (XIX), and (XXII; R = H) from the 12,13-epoxytrichothecane (XIII; R = H); and (XVIII; R = H), (XXI), and

mildly basic conditions to the corresponding y-lactones [(XXII), (XXIII), and (XXIV; R = H)]. Neither the 8-lactones nor the y-lactones were oxidised further by manganese dioxide. Reduction of both lactones (XX) and (XXIII; R = H) with lithium aluminium hydride gave the known tetraol (XXVI). Similar reduction of the lactones (XXI) and (XXIV; R = H) gave the dihydrotetraol (XXVII), also obtained by catalytic re- duction of the tetraol (XXVI).

Experiments with the triols (I; R = R' = H), (XIII), (XIV), and (XV) in which the reaction time was varied between 1 and 170 hr. showed that, particularly with the 12,13-epoxy-derivative (I ; R = R' = H), the total weight of crude product recovered decreased markedly as the reaction time was increased, owing possibly to the formation of acidic products, present in the reaction mixture in the form of insoluble salts. This effect was at a minimum with the 12-hydroxy-compounds (XIV) and (XV), and, based on the yield of recovered material, the proportion of y-lactone remained roughly constant whilst the proportion of S-lactone increased with time at the

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372 J. Chem. SOC. (C), 1970

expense of the hemiacetal, the proportion of which had fallen to zero after 170 hr. This result suggests that after the formation of the 15 __t 4 hemiacetal from an open-chain dialdehyde structure, e.g. (IV) , from the triol (I; R = R’ = H), the equilibrium between the two possible configurations (V) and (VI) at position 4 determines the subsequent course of the reaction. In the R-configuration (V), the OH group is correctly positioned for formation of the second hemiacetal at position 3, giving (VIII; R = H), and, after further oxidation, the 8-lactone (VII) . The S-configuration (VI) on the other hand, is correctly orientated for a hydride shift leading t o the Cannizzaro reaction product (IX; R = H) with formation of a y-lactone. This equilibrium at position 4 was influenced by the nature of the substituent at position 12, less Cannizzaro product and more 8-lactone being obtained in the presence of a 12-hydroxy-group than with a 12,13-epoxide. Oxidation of the hemiacetals to the &-lactones also took place more readily with the 12-hydroxy-compounds, the n.m.r. spectra of which were consistent with a small change in the conformation of the B/C rings.

Oxidation of the 15-monoacetate (I; R = Ac, R‘ = H) with manganese dioxide gave the hydrated dialdehyde (XI) , characterised as the bisdinitrophenylhydrazone, as sole product. The 4,15- (I; R = R’ = Ac) 3,4-, and 3’15-diacetates were unaffected by the reagent.

Minor products from oxidation of the triols (I; R = R’ = H) and (XIII; R = H) were the CI4 ccp-unsatu- rated aldehydes (XXXI) and (XXV), respectively, A,, 251-253 nm. (c 15,000), vms. ca. 1660 and 1620 cm.-l. In the n.m.r. spectrum of the aldehyde (XXV) the value of Jsem (9.5 Hz) for the hydrogens at position 15 (tri- chothecane numbering) showed them to be present in a five-membered cyclic ether, consistent with hemiacetal formation (z 465) at position 4. Structure (XXV) was then preferred to the alternative, in which the free formyl group occupies position 2, as being more consistent with the chemical shift (T 2.6) of the olefinic hydrogen, indicative of a =CH-0- group.9 The @-unsaturated aldehydes (XXXI) and (XXV) are responsible for the specific U.V. absorption of the reaction mixtures from the oxidation of the triols (I; R = R’ = H) and (XIII; R = H) : their formation appears to require the presence of a 12,13-epoxy-group. Reasonable hypothetical mech- anisms (Scheme 3) could involve oxidation of the 4p- secondary alcohol group to a 4-one coupled with either (a) base-catalysed isomerisation of the epoxide to the keto-aldehyde (XXIX) followed by retro-Michael fission of ring c between positions 2 and 3 and oxidation of the a-ketol (XXX; R = CH,OH), or (b) fragmentation of the p-hydroxy-epoxide system to the glyoxal (XXVIII ; R = OH, R’ = CHO) followed by oxidation of the allylic alcohol to give the common intermediate (XXX; R = CHO). Oxidative fission of the glyoxal residue in

J. F. Grove, J . Chem. SOC., 1964, 3234. lo J. Gutzwiller, R. Mauli, H. P. Sigg, and C. Tamm, Helv.

Chim. Acta, 1964, 47, 2234.

(XXX; R = CHO) with loss of one carbon atom leads to the aldehyde (XXXI). In support of these hypo- theses it was observed that the 4p-hydroxy-substituent in the triol (XXXII) (‘ dihydroverrucarol B ’) lo was

CqlCHO ’-.

H2C, ,cCH*OH

Hypothetical schemes for the formation of the a@- 0

SCHEME 3 unsaturated aldehydes (XXV) and (XXXI)

rapidly and quantitatively oxidised by manganese di- oxide, giving the 4-one (XXXIII), isolated in the hemi- ketal form 8 Hz) as judged by the i.r. spectrum, which showed no C=O absorption. Surprisingly, the

I

4p-01 in the 3,E-diacetate of the triol (I; R = R‘ = H) resisted oxidation as did the 3or-01 in the acetates (I; R = R’ = Ac) and (XIII; R = Ac). Only in the case of the aldehyde (XXXI) was there spectroscopic evidence of its formation (c) from a 3,4-seco-product, presumably by p-hydroxy-epoxide fragmentation of the hemiacetal (VIII; R = H) to the intermediate (XXVIII; R = H, R‘ = OCHO) followed by hydrolysis and oxidation of the allylic alcohol group.

EXPERIMENTAL

M.p.s are corrected. Unless otherwise stated, i.r. spectra were determined for Nujol mulls and U.V. spectra for solu- tions in ethanol. N.m.r. spectra were obtained for solutions in deuteriochloroform, with tetramethylsilane as internal standard (Varian HA 100 spectrometer). Light petroleum had b.p. 40-60°. Silica gel (B.D.H.) was,used for chroma- tography. Acetylations were carried out with pyridine- acetic anhydride at room temperature for 18-24 hr.

Oxidations with Manganese Dioxide .-The compound, in a convenient volume of chloroform, was shaken at room temperature for a given length of time with 10 times its

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Org. 373 weight of activated manganese dioxide.11 After filtration, the residue was extracted 3 times with an equal volume of boiling chloroform. The crude product, recovered from the combined filtrate and extracts, was chromatographed on a column of silica gel by the method of fractional elution. Yields are expressed as proportions (yo) of the weight of crude product.

(a) 12, l3-Epoxytrichothec-9-en-3aJ4~, 15-tviol (I ; R = R' = H). After a reaction time of 4 hr. the triol (1 g.) afforded a glass (622 mg.). Elution of the column (100 ml. fractions) with ether-light petroleum (2 : 3; 300 ml.) gave a gum (39 mg., 6%) which crystallised from ether-light petroleum in prisms (13 mg.), n1.p. 132', of 3,4-seco- 4,15 : 12,13-die~oxy-4-hydroxyt~ichothec-9-en-3-oic acid 3 -+ 4-Zactone (VII) (Found: C, 64.5; H, 6-55. Cl5HI8O6 re- quires C, 64.7; H, 6.5%), vmX. 1750, 1683, and 830 cm.-l; vmax. (CH,Cl,) 1740 cm.-l; end absorption only in the U.V.

Continued elution with the same eluant gave a solid (32 ing., 5%) which crystallised from ether-light petroleum in prisms, m.p. 155-158" of the aldehyde (XXXI) [Found:

(mass spectrum) 250.122793. Cl~H1804 requires M 250.120500 (C = 12~000000)], vmx. 3300, 2750, 1652, and 1620 cm.-1, A,n,,. 253 nm. (c 15,900). It reduced ammoniacal silver nitrate on warming.

Further elution of the column with ether-light petroleum (9 : 11; 1 1.) gave a glass (206 mg., 33%) which, on re- peated recrystallisation from ether, formed prisms, m.p. 131-140", of 3,4-seco-12,13-epoxy-15-hydroxyt~ichothec-9- en-3,4-dione 15 3 4 3 3-hemiacetal (VIII; R = H) (Found: C, 64.0; H, 7.3. C15H2005 requires C, 64-3; H, 7-2%), vmaz 3425, 3370, 1685, and 830 cm.-l; end absorption only in the U.V. It reduced Fehling's solution, restored the colour to Schiff's reagents and reduced ammoniacal silver nitrate at room temperature. The 2,4-dinitrophenyZ- hydrazone, after chromatography on bentonite-kieselguhr (4 : l), crystallised from methanol in plates, m.p. 177- 180" (Found: C, 64.4; €3, 5.5. C2,H2,N,08 requires C, 54.8; H, 5.25y0).

The acetate (VIII; R = Ac) crystallised from ether- light petroleum in prisms, m.p. 145-153", identical (mixed m.p. and i.r. spectra) with material m.p. 149- 152' prepared by oxidation of the triol (I; R = R' = H) with lead tetra-acetate and acetylation of the p r o d ~ c t . ~

Continued elution of the column with ether-light petrol- eum (1 : 1; 1 1.) gave a glass (199 mg., 32%) which was subjected to short-path distillation a t 90°/10-6 mm. The product, 3,4-seco-12,13-e~oxy-3,15-dihydroxytrichothec-9- en-4-oic acid 4-+ 15-Zactone (IX; R = H) (Found: C, 64.35; H, 7.25. C,6H2006 requires C, 64-3; H, 7.2y0), v,,,. 3410, 1765, and 1680 cmrl, end absorption only in the u.v., did not reduce ammoniacal silver nitrate or form derivatives with reagents for the carbonyl group. The glassy acetate (IX; R = Ac) was purified by short-path distillation at 80°/10-6 mm. (Found: C, 62.8; H, 6.9. Cl7H22Oe requires C, 63-35; H, 6~9%)~ vmax. 1773, 1747, 1680, and 835 crn.-l.

Further elution of the column with ether followed by ether-methanol (99 : 1) gave a series of intractable gums (65 mg.).

After a reaction time of only 1 hr., the weight of crude product amounted t o 90% of the weight of starting material and was made up of the s-lactone (VII) (2%), the hemiacetal (VIII; R = H) (39%), and the y-lactone (IX; R = H) (24%). When the reaction time was extended to 24 and 170 hr., the weights of crude product were 60 and 46%

respectively of the weight of starting material and consisted of the s-lactone (VII) (8 and 16%), the hemiacetal (VIII; R = H) (14 and O%), and the y-lactone (IX; R = H) (42 and 48% , respectively).

(b) 12,13-E~oxyt~ichothecan-3a,4~,15-~rioZ (XIII; R = H) (with Mr. J. J. W. COPPEN). The triol (650 mg.) afforded a glass (550 mg., 84%) after 4 hr. shaking. Elution of the column (100 nil. fractions) with ether-light petroleum (3 : 7; 200 ml.) gave a glass (52 mg., 10%) which formed prisms (14 mg.), m.p. 172-173' (from ether-light petroleum) , of 3,4-seco-4,15 : 12,13-die~oxy-4-Jzydroxytricho~heca~z-3-oi~ acid 34-4-Zactone (XIX) [Found: C, 64-3; H, 7.35%; equiv. (lactone titration) 270. C16H2006 requires C, 64.3 ; H, 7.2%; M 2801, vmx* 1745 cm.-l.

Continued elution of the column with the same eluant (200 ml.) gave a solid (6 mg.) which crystallised from ethyl acetate-light petroleum in prisms, m.p. 149-151', of the aldehyde (XXV) [Found: C, 66-4; 13, 8.6%; A4 (mass spectrum) 252. C14H2004 requires C, 66.6; H, 8.0%; M , 2521, v,, 3320, 1645, and 1610 c.m.-l, vmaX (CH,Cl,) 3595, 1670, and 1625 cm.-l, A,, 251 nm. (E 14,000). It reduced ammoniacal silver nitrate on warming.

Further elution of the column with ether-light petroleum (2 : 3; 500 ml.) gave a gum (206 mg., 38%) which crystallised from ether-light petroleum in prisms, m.p. 1 15-144O, of 3,4-seco-12,13-e~oxy-15-hydroxytr~chothecan-3,4-dione 15 3 4 3 3-hemiacetal (XVI; R = H) (Found: C, 63.6, 64.0; H, 8.0, 8.0. C15H2205 requires C, 63.8; H, 7-85%), v,, 3405 cm.-l. It reduced Fehling's solution and gave a silver mirror with ammoniacal silver nitrate.

Continued elution of the column with the same solvent (300 ml.) gave a glass (151 mg., 27%) which was subjected to short-path distillation at 80°/10-4 mm. and then crystal- lised, from ether-light petroleum, in needles, m.p. 104', of 3,4-seco-12,13-e~oxy-3,15-dih~yd~oxyt~ichothecan-4-oi~ acid 4+ 15-Zactone (XXII; R = H) (Found: C, 64-15; H, 8.05. C1,H,,O, requires C, 63.8; H, 7.85%) vmx. 3450 and 1770 cm.-l, vmx. (CH,Cl,) 1765 cinrl. The amorphous acetate (XXII; R = Ac) (Found: C, 63-2; H, 7-7; Ac, 14.9. Cl7H2,,O, requires C, 62.95; H, 7.45; 1Ac 13.3%), vmax. 1770 and 1746 cm.-l, was eluted from silica gel by ether- light petroleum (2 : 3).

After a reaction time of 24 hr., 840/, of the weight of triol (XIII; R = H) was again recovered, consisting of the s-lactone (XIX) (19%) and y-lactone (XXII; R = H)

(c) Trichothec-9-en-3~,4J3,12,15-tetraoZ (XIV). After 4 hr. shaking, the tetraol (1 g.) gave a glass (843 mg.). After a series of gummy fractions (69 mg.) had been eluted from the column with ether-light petroleum (3 : 7; 1-5 l.), ether- light petroleum (2 : 3; 700 ml.) gave a glass (166 mg., 20%) which crystallised from ether in prisms or plates and from ethyl acetate-light petroleum in prisms (87 mg.), m.p. 216-217", of 3,4-sec0-4,15-e~oxy-4,12-dihydroxytri- chothec-9-en-3-oic acid 3 +- 4-Zactone (XX) (Found : C, 64-3 ; H, 7.3%; equiv. (lactone titration) 280. C1,H,,O, re- quires C, 64.3; H, 7.2% ; M 2801, v , , ~ ~ , 3425 and 1723 cm.-l; end absorption only in the U.V.

Continued elution of the column with ether-light petro- leum (2 : 3; 1.4 l.) gave a series of gummy fractions (396 mg., 35%) which formed needles from ether. Recrystall- isation from ethyl acetate-light petroleum gave prisms (1 76

l1 J. Attenburrow, A. F. B. Cameron, J. H. Chapman, R. M. Evans, B. A. Hems, A. B. A. Jansen, and T. Walker, J . Chem. SOG., 1952, 1094.

(50%)-

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374 J. Chem. SOC. (C), 1970 mg.), m.p. 147-160", of 3,4-seco-12,15-diJzydroxytricJzothec- 9-en-3,4-dione 15 3 4 3 3-henaiacetal (XVII; R = H) (Found: C, 63.55; H, 8.0. C15H2205 requires C, 63.8; 7.85%), vmX. 3250 and 1680 cni.-l; end absorption only in the U.V. It reduced Schiff's reagent, Fehling's solution and ammoniacal silver nitrate. The amorphous acetate (XVII; R = Ac) (Found: C, 63.1; H, 7.2. Cl,H2,0, requires C, 62-95; H, 7.45%) was eluted from silica gel by ether-light petroleum (1 : 4).

Further elution of the column with ether (1 1.) gave gummy fractions (214 mg., 25%) from which 3,4-seco- 3,12,15-trihydroxytrichothec-9-en-4-oic acid 4 -+ 15-Eactone (XXIII; R = H) [Found: C, 63.75; H, 7.9%; equiv. (lactone titration) 290. C15H2205 requires C, 63.8; H, 7.85%; M 2821, vmx. (CHC1,) 3415, 1756, and 1685 cm.-l end absorption only in the u.v., was obtained by short-path distillation at 160-170"/10-4 mm. The acetate (XXIII ; R = Ac) formed prisms, m.p. 187-188", from ethvl acetate- light petroleum (Found: C, 62.4; H, 7.3. C17H2406 re- quires C, 62.95; H, 7.45%), vmx. 3430, 1760, 1752, and 1680 cm.-l, v,,,. (CH,Cl,) 1754 and 1743 cm:l. Hydrolysis of the acetate (XXIII; R = Ac) with O.1N-sodium hvdrox- ide at room temperature for 16 hr. and recovery by acidifica- tion and continuous extraction with chloroform regenerated the lactone (XXIII; R = H).

When the reaction time was increased to 24 and 170 hr., the weight recovered fell to 78 and 71% respectively of the weight of starting material, made up of the 8-lactone (XX) (32 and 47y0), the hemiacetal (XVII; R = H) (28 and O%), and the y-lactone (XXIII; R = H) (28 and 28% respec- tively).

(d) Trichothecan-3a,4PJ 12,15-tetvaol (XV). The tetraol (1.0 8.) gave a glass (772 mg.) after 4 hr. Elution of the column with ether-light petroleum (2 : 3) (50 ml. fractions) gave (i) 700 ml., 87 mg. gum; (ii) 500 ml., 133 mg. (17%) solid; (iii) 1 l., 262 nig., solid; (iv) 1.1 l., 67 mg. semisolid: and (v) 1 1. 177 mg. glass.

Fraction (ii) was crystallised from ether-light petroleum followed by ethyl acetate-light petroleum, giving prisms (107 mg.), m.p. 203-204", of 3,4-seco-4,15-epoxy-4,12-di- hydroxytricJzothecan-3-oic acid 3 3 4-Zactone (XXI) [Found : C, 63.7; H, 7.95% ; equiv. (lactone titration) 282. C15HZz- 0, requires C, 63.8; H, 7.85% ; M 2821, v,,,, 3425 and 1720 cm.-l; end absorption only in the U.V.

Fraction (iii), together with the solid part of fraction (iv), was crystallised from ether giving prisms (295 mg., 38y0), m.p. 128-145". Further recrystallisation from ethyl acetate-light petroleum afforded prisms, m.p. 143-165", of 3,4-seco-12,15-dihyd~oxytrichothecun-3,4-dione 15 -+ 4 -+ 3- hemiacetal (XVIII; R = H) (Found: C, 63-7; H, 8.5. Cl5H2,O5 requires C, 63.35; H, 8.5%), vmx. 3440, 3320, and 3280 cm.-l; end absorption only in the U.V. It reduced Fehling's solution and ammoniacal silver nitrate. The oily part of fraction (iv) combined with fraction (v) (204 mg., 26y0) gave the amorphous 3,4-sec0-3,12,15-trihydroxytvi- chothecan-4-oic acid 4 -+ 15-lactone (XXIV; R = H) [Found: C, 63.7; H, 8.65%; equiv. (lactone titration) 321. C15H,&, requires C, 63-35; H, 8.5% ; M 2841, v,,,. 3450 and 1764 cm.-l; end absorption only in the U.V. The acetate (XXIV; R = Ac) was eluted from silica gel by ether-light petroleum (3 : 7) and crystallised from ether-light petroleum in prisms, m.p. 88" (Found: C, 62-7; H, 8.15; Ac, 12-8. C17H2606 requires C, 62.55; H, 8.0; lAc, 13.20/,), vmax. 3435, 1753, and 1743 cm.-l, vmas. (CH2CIz) 1752 and 1745

cm.-l. Hydrolysis of the acetate, as described in (c) re- generated the lactone (XXIV; R = H).

After 170 hr. shaking 79% of the weight of starting material was recovered of which 63% was the 8-lactone

(e) 15-A cetoxy-l2,13-epon-ytrichothec-9-en-3u,4P-diol (I ; R r= Ac, R' = H). The diol (100 mg.) furnished a glass (95 mg.) after 4 hr. Elution of the column with ether- light petroleum (1 : 1) (150 ml. in 25 ml. fractions) gave a gum (82 mg.), a portion of which was subjected to short path distillation at 1 20-140°/10-5 mm. The glassy product, 3,4-seco-l5-acetoxy- 12,13-epoxytrichothec-9-elz-3,4-dio~ae hydvate (XI) (Found: C, 60.85; H, 7.15. C1,H,,O, re- quires C, 60.0; H, 7-1%), vmax. 3400, 1745, and 1670 cm.-l, reduced Fehling's solution and ammoniacal silver nitrate. The bisdinitropl~enylhyda~one crystallised from methanol in orange-yellow prisms, m.p. 155-157" (Found: C, 50.9; H, 4.5. C2sH,oNsOl, requires C, 51.0; H, 4.4%).

Only intractable products were obtained when the di- aldehyde (XI) was treated with dilute sodium hydroxide at room temperature.

(f) Trichothec-9-en-4P, 12,15-trioZ (XXXII). After 3 hr. the trio1 (70 mg.) afforded a solid which crystallised from ethyl acetate in prisms (62 mg.), m.p. 232", of 12,15-di- hydvoxytvichotJzec-9-en-4-one hemiacetal (XXXIII) (Found : C, 67.75; H, 8.25. C15H2201 requires C, 67.65; H, 8.3%), v,,,. 3415 and 3360 cm.-l. Increasing the reaction time to 72 hr. gave an identical result.

(g) The hemiacetals (VIII; R = H), (XVI; R = H), (XVII; R = H), and (XVIII; R = H). After 18 hr. the hemiacetal (VIII ; R = H) (1 1 mg.) afforded a gum (1 1 mg.) which showed specific U.V. absorption at 250 nm. Chroma- tography (10 ml. fractions) and elution with ether-light petroleum (1 : 1) (10 ml.) gave the 8-lactone (VII) (4 mg.), identified by i.r. spectrum. Subsequent fractions (8 mg.) proved intractable. Oxidation of the hemiacetals (XVI; R = H), (XVII; R = H), and (XVIII; R = H) for only 4 hr. gave the corresponding 8-lactones (XIX), (XX), and (XXI) in almost quantitative yield.

(h) Miscellaneous. 4P, 15-Diacetoxy-12,13-epoxytricho- thec-9-en-3a-01 (I; R = R' = Ac), (250 mg.), 4@,15-di- acetoxy-12,13-epoxytrichothecan-3a-o1 (XI11 ; R = Ac) (100 mg.), 3a,4~-diacetoxy-12,13-epoxytrichothec-9-en- 15-01 (50 mg.), and 3u, 15-diacetoxy- 12,13-epoxytrichothec-9-en- 4p-01 (10 mg.) were recovered after being shaken with manganese dioxide under the usual conditions for 170, 24, 24, and 120 hr., respectively.

Reduction ofthe Lactones (XX), (XXIII; R = H), (XXI), and (XXIV; R = H) with Lithium Aluminium Hy&ide.- The lactone (XX) (48 mg.) in tetrahydrofuran (25 ml.) was heated under reflux for 18 hr. with lithium aluminium hydride (200 "8.). Recovery of the product in the usual way by continuous extraction in chloroform gave a gum (41 mg.) which crystallised from ethyl acetate-ether in prisms (21 mg.), m.p. 153-154", of 3,4-secotrichothec-9-en- 3,4,12,15-tetraol (XXVI) (lit.,* 159-160') (Found: C, 63-2; H, 9.4. Calc. for C,,H,,O, C, 62.9; H, 9.2%), vmas. 3510, 3320br, and 1680 cm.-l. Under similar conditions the lactone (XXIII; R = H) (115 mg.) yielded the tetraol (XXVI) (88 mg.) m.p. 155", identified by comparison of i.r. spectra.

The lactone (XXI) (45 mg.) when reduced gave a glass (49 mg.) which was chromatographed on silica gel. Elution with ether-light petroleum (2 : 3) gave a glass (15 mg.)

(XXI).

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Org. 375 which crystallised from ether in prisms (1 mg.), n1.p. 125O, of the tetraol (XXVII) (see later).

In a similar experiment the lactone (XXIV; R = H) (50 mg.) gave the tetraol (XXVII) (2 mg.) after chromatography on silica gel followed by crystallisation from ether.

The lactones (XX) and (XXI) were recovered after being heated under reflux with lithium aluminium hydride in ether for 2-8 hr.

Catalytic Reduction of the Tetraol (XXVI) .-The tetraol (36 mg.) in acetic acid (10 ml.) was shaken at room tempera- ture for 4 hr. in hydrogen over reduced platinum oxide (10 mg.). Filtration and recovery afforded a glass (34 mg.) which crystallised from methanol in needles, m.p. 133" (28 mg.), of 3,4-secotrichothecan-3,4,12,15-tetraoZ (XXVII) [Found: C, 59-0; H, 9.8; M (mass spectrum) 288. C,,H,,- O,,H,O requires C, 5 8 - 8 ; H, 9.90/,; M (anhydrous) 2881, ymax. 3435, 3300, and 3100 cm.-l.

Oxidation of the Lactone (IX; R = H).-The lactone (32 mg.) in acetone (3 ml.) a t 0" was treated with chromic oxide- sulphuric acid 1 2 (0.1 ml.) for 15 min. The mixture was diluted with water and extracted with ether. The neutral portion (14 mg.) of the product was intractable. The gummy acidic portion (12 mg.), obtained by estraction with sodium hydrogen carbonate and recovery, was methylated in ether at 0' with ethereal diazomethane. The product crystallised from ethyl acetate-light petroleum in prisms (6 rng.), m.p. 128-130" (lit.,4 127-130"), of the lactone-

l2 K. Bowden, I. M. Heilbron, E. R. H. Jones, and B. C. L. Weedon, J . Chena. SOC., 1946, 39.

ester (XII) [Found: M (mass spectrum) 308. Calc. for C1,H,,O,: M 308j, vmx. 1752 cmr1, identified by the n.m.r. spectrum.

Cnnnizzaro Reactions with 3,4-Secotrichothecan-3,4-diones. -(a) The hemiacetal (VIII; R = H) (100 mg.) in methanol (1 ml.) and 2~-sodium hydroxide (2 ml.) was set aside for 6 hr. a t room temperature. The solution was acidified to pH 4 with B~-hydrochloric acid and rapidly extracted with ethyl acetate. Recovery afforded a glass (75 mg.), the i.r. spectrum of which was identical with that of the y-lactone

(b) The hemiacetal (XVIII; R = H) (20 mg.) in methanol (1 ml.) was treated with 2~-sodium hydroxide (0.5 ml.) a t room temperature for 1 hr. Water was added to dissolve the precipitate of the sodium salt of the product and the solution was acidified with concentrated hydrochloric acid. Extraction with ethyl acetate furnished the amorphous y-lactone (XXIV; R = H) (17 mg.) identified by i.r. spec- trum.

(IX; R = H).

We thank Messrs. P. Hodges and J. J. W. Coppen for technical assistance, Rlr. P. Boshoff , Imperial College, London, for some of the mass spectra, and NIr. P. Jenkins, S.R.C. Service a t Imperial College for the n.m.r. spectra. Part of this work was supported by a grant from the Agricul- tural Research Council to J. F. G. during the tenure of a Comyns Berkeley Bye-Fellowship a t Gonville and Caius College, Cambridge.

[9/1320 Received, August 4th, 19691

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