W. Basil Whalley

The chemistry of fungi. Part LXVIII. The absolute configuration of (+)-sclerotiorin and of the azaphilones

X-Ray crystallographic examination of N-methylsclerotioramine, derived from (+)-sclerotiorin, has defined the absolute stereochemistry of the derivative and hence that of (+)-sclerotiorin and of the other members of the azaphilone group of fungal metabolites.

Unsaturated steroids. Part 6. A route to cholesta-5,7-diene-1α,3β-diol; preparation of steroidal 4,6,8(14)-trienes

Bromination of 5α-cholest-7-en-3-one to give the corresponding 2ζ,4ζ-dibromo-derivative followed by dehydro-bromination gives cholesta-1,4,7-trien-3-one (3). The corresponding cholesta-1,3,5,7-tetraen-3-yl acetate (4) was converted by the method of Kaneko et al. into the adduct of cholesta-1,5,7-trien-3β-ol with 4-phenyl-1,2,4-triazoline-3,5-dione. The corresponding dimethyl-t-butylsilyl ether was transformed into the 1α,2α-epoxide, which was readily converted into cholesta-5,7-diene-1α,3β-diol (8). Treatment of the adduct from a steroidal 5,7-dien-3-one and 4-phenyl-1,2,4-triazoline-3,5-dione with boron trifluoride–ether yields the corresponding 4,6,8(14)-trien-3-one (10).

Unsaturated steroids. Part 12. Synthesis of 1α,3β-dihydroxy-24-nor-9,10-secochola-5,7,10(19)trien-23-oic (calcitroic) acid and of the cholic-and 25-homocholic acid analogues

The three title compounds have been synthesized by the same general method. Thus, methyl 3β-hydroxy-24-nor-5α-chol-7-en-23-oate (3; R = CO2Me), derived from 3β-acetoxypregn-7-ene-22-carbaldehyde (2), gave methyl 3-oxo-24-nor-5α-chol-7-en-23-oate (4; R = H,R′= CH3). Bromination of this to the 2ξ,4ξ-dibromo derivative (4; R = Br, R′= Me) followed by dehydrobromination formed the corresponding 1,4,7-triene-3-one (5). The corresponding enol acetate (6) was reduced to the 1,5,7-triene (7) which was converted into the adduct (8; R = H) with 4-phenyl-1,2,4-triazoline-3,5-dione; the 3β-dimethyl-t-butylsilyl ether of (8;R = H)gave the 1α,2α-epoxide(9; R = Me2ButSi). Removal of the silyl ether group with acid, and then of the triazoline residue with pyridine–1,5-diazabicyclo[4.3.0] non-5-ene gave methyl 3β-hydroxy-1α,2α-epoxy-24-norchola-5,7-dien-23-oate (10; R = Me). Reduction of the corresponding acid (10; R = H) gave 1α,3β-dihydroxy-24-norchola-5,7-dien-23-oic acid (11; R = H). Photolysis/thermolysis of the corresponding methyl ester (11; R = Me) followed by saponification gave 1α,3β-dihydroxy-24-nor-9,10-secochola-5,7,10(19)trien-23-oic acid (calcitroic acid)(1; R = H, n= 1). The analogous cholic (1; R = H, n= 2) and 25-homocholic acid (1; R = H, n= 3) derivatives were similarly synthesized.

The chemistry of fungi. Part 80. The X-ray crystallographic structure of 8aβ-bromo-5aα,5,6,7,8,8a-hexahydro-1,7α-dihydroxy-8α-methoxycarbonylxanthone monohydrate, a rearrangement product of methyl 2α-bromo-2β-(2,6-dimethoxybenzoyl)-7-oxabicyclo[2.2.1]heptane-3β-carboxylate: A novel route to xanthones: The synthesis of pinselin.

Treatment of methyl 2α-bromo-2β-(2,6-dimethoxybenzoyl)-7-oxabicyclo[2.2.1] heptane-3β-carboxylate (1; R1= H, R2= Br) with boron trichloride gives 8aβ-bromo-5aα-5,6,7,8,8a-hexahydro-1,7α-dihydroxy-8α-methoxycarbonylxanthone (4; R = H), as a monohydrate, the crystals of which are triclinic, space group F with 8 molecules in a cell of dimensions a= 8.648(1), b= 17.597(3), c= 20.309(3)A, α= 94.36(1), β= 91.39(1), γ= 93.41 (1)°. The structure was solved by the heavy atom method and refined by full-matrix least-squares calculations with anisotropic thermal parameters; R= 0.050 for 2 939 reflexions with I > 3σ(I). Dehydrobromination of (4; R = H) gave 5,6,7,8-tetrahydro-1,7α-dihydroxy-8α-methoxycarbonylxanthone (5) which was oxidised to 5,6,7,8-tetrahydro-1-hydroxy-8α-methoxycarbonyl-7-oxoxanthone (6). Bromination/dehydrobromination of (6) gave a monobromo-1,7-dihydroxy-8-methoxycarbonylxanthone. Application of this process to methyl 2α-bromo-2β-(2,6-dimethoxy-4-methylbenzoyl)-7-oxabicyclo[2.2.1] heptane-3β-carboxylate (1; R1= Me, R2= H) gave 1,7-dihydroxy-8-methoxycarbonyl-3-methylxanthone (pinselin)(3; R1= R2= Me) in high yield. This process provides a novel route to xanthones of type (3).

Unsaturated steroids. Part 3. Synthesis of steroidal 22,24(28)-dienes, ergosta-5,7,22,24(28)-tetraen-3β-ol, and cholesta-5,7,22-trien-3β-ol

Dehydrobromination of 22,23-dibromo-5β-ergostane with 1,5-diazabicyclo[3.4.0]non-5-ene (DBN) gives 5β-ergosta-22,24(28)-diene (3). This structure has been confirmed by partial synthesis.Ergosteryl acetate is readily regenerated from its adduct (8) with 4-phenyl-1,2,4-triazoline-3,5-dione by the action of warm DBN. The adduct reacts with bromine to yield the 22,23-dibromo-derivative, which forms ergosta-5,7,22,24(28)-tetraen-3β-ol (7) directly, in high yield, when heated with DBN.The structure (9)(cholesta-5,7,22-trien-3β-ol) assigned to a metabolite of the protozoan, Tetrahymena pyriformis, has been confirmed by partial synthesis from stigmasterol.

The chemistry of fungi. Part LXX. Synthesis of some xanthones

Oxidation with hexacyanoferrate(III) of 2,3′,4,6-tetrahydroxybenzophenone (2; R1= OH, R2= R3= H) gave 1,3,7-trihydroxyxanthone (3; R1= OH, R2= R3= H) by a para-intramolecular coupling; other 2,3′-hydroxylated benzophenones reacted similarly. The same reagent and 2,4,5′-trihydroxy-2′-methoxy-3-methylbenzophenone (7; R1= R2= Me, R3= H) formed 6-hydroxy-4a-methoxy-5-methylxanthen-2(4aH),9-dione (12) which was aromatised (i) by hydrochloric acid to 4-chloro-2,6-dihydroxy-5-methylxanthone (11) and (ii) by zinc and acetic acid to 2,6-dihydroxy-5-methylxanthone (3; R1= R2= H, R3= Me). Other 2,5′-hydroxylated benzophenones behaved similarly. Whereas hexacyanoferrate(III) produced 1,4,6-trihydroxy-5-methylxanthone (14; R2= H, R1= Me) from 2,2′,4,5′-tetrahydroxy-3-methylbenzophenone (7; R1= R3= H, R2= Me), the same ketone with 2,3-dichloro-5,6-dicyano-p-benzoquinone gave 2-(2,4-dihydroxy-3-methylbenzoyl)-p-benzoquinone (8), which rapidly formed 1,4,6-trihydroxy-5-methylxanthone (14; R1= Me, R2= H) by an internal Michael addition. Similar results were obtained with cognate benzophenones.

The pigments of ‘dragon's blood’ resin. Part VIII. Synthesis of (±)-dracorubin and of (±)-nordracorubin

(±)-Dracorubin (3,4-dihydro-5-methoxy-8-methyl-2,12-diphenyl-2H-dipyrano[2,3-a:2′,3′,4′-kl]xanthen-9-one) has been synthesised. Condensation of 7-benzyloxy-5-methoxy-6-methylflavan-4-ol with 7-hydroxy-5-methoxyflavan gave 7-benzyloxy-4-(7-hydroxy-5-methoxyflavan-8-yl)-5-methoxy-6-methylflavan, which was successively acetylated, debenzylated, and oxidised to 4-(7-acetoxy-5-methoxyflavan-8-yl)-5-methoxy-6-methyl-2-phenyl-1-benzopyran-7-one. Cyclisation of this anhydro-base with sodium methylsulphinylmethanide gave (±)-dracorubin. (±)-Nordracorubin has been synthesised similarly.

The chemistry of fungi. Part 74. Synthesis of (±)-5-butyl-6,8-dihydroxy-3-pentyl-3,4-dihydroisocoumarin

The title compound (1; R1= Bun, R2= H), which corresponds to the (+)-dihydro-derivative of fusamarin (2), a metabolite of an unidentified species of Fusarium, has been synthesised. (2-Butyl-3,5-dimethoxyphenyl)acetic acid (3; R1= OH, R2= Bun) was obtained from ethyl 3,5-dimethoxyphenylacetate by way of the corresponding 2-formyl derivative (3; R1= OEt, R2= CHO). Reaction of the acid chloride (3; R1= Cl, R2= Bun) with pentylmagnesium bromide furnished 1-(2-butyl-3,5-dimethoxyphenyl)heptan-2-one (4; Ru = Bun), which was reduced to the alcohol (5; R1= H, R2= Bun). Formylation of the acetate (5; R1= Ac, R2= Bun), followed by oxidation and hydrolysis of the ester residue, gave (±)-5-butyl-3-pentyl-6,8-dimethoxy-3,4-dihydroisocoumarin (1; R1= Bun, R2= Me), which was demethylated to (1; R1= Bun, R2= H). In model experiments (±)-6,8-dihydroxy-3-pentyl-3,4-dihydroisocoumarin (1; R1= R2= H) and related derivatives, together with associated isochromans of type (7), have been synthesised.

Conformational studies. Part 8. Crystal and molecular structure of 17β-iodoacetoxy-4,4-dimethylandrostan-5-en-3-one

Crystals of the title complex (2) are monoclinic, space group P21, a= 6.394(2), b= 11.303(4), c= 15.566(4)A, β= 92.92(2)°, Z= 2. The structure has been refined by full-matrix least-squares calculations to a final R of 0.046 for 1 065 observed reflections. The conformations of the rings are: A, skewed boat; B, half-chair; C, chari; and D, half-chair distroted towards a C(13) envelope.

The chemistry of fungi. Part LXIX. A new synthesis of the grisane system: X-ray crystallographic examination of (±)-methyl 5,7-di-bromo-2′α,5′α-epoxy-4-methoxy-3-oxogrisane-6′β-carboxylate

Addition of furan to methyl 4-(2,6-dimethoxyphenyl)-4-oxobut-2-ynoate (4; R = CO2Me) followed by hydrogenation of the adduct gave methyl 3-(2,6-dimethoxybenzoyl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate (6; R = Me). This was demethylated to the corresponding 3-(2-hydroxy-6-methoxybenzoyl) derivative (6; R = H), which was cyclised by bases to give (a)(±)-methyl 2′α,5′α-epoxy-4-methoxy-3-oxogrisane-6′β-carboxylate (9; R = H), the structure of which was deduced chemically and spectroscopically, and unequivocally defined by X-ray crystallography, together with (b) the isomeric 6′α-carboxylate. Both grisanes were converted into (±)-methyl 2′α-hydroxy-3-oxogris-5′-ene-6′-carboxylate (11).