1976
`
`1165
`
`View Article Online I Journal Homepage I Table of Contents for this issue
`
`Crystal and Molecular Structure of Compactin. a New Antifungal Meta-
`bolite from Penicillium brevicompactum
`Beecham Pharmaceuticals Research Division. Brockham Park.
`
`By Allan G. Brown ‘ and Terry C. Smele.
`Betchworth. Surrey RH3 7AJ
`Trevor J. King. Department of Chemistry, The University, Nottingham NG7 2RD
`Rainer I-lasenkamp and Ronald H. Thompson. Department of Chemistry. University of Aberdeen, Old
`Aberdeen A89 2UE, Scotland
`
`{7-[1.2.6,7,6.8a~hexahydro-2-rnethyl-8-(2-methylbutyryloxy)naphthyl]-3-
`structure of compactin (I)
`The
`hydroxvheptan-5-olide}. a metabolite isolated from cultures of Penici/I/"um brevicompactum, has been determined
`by a combination of spectroscopic. chemical, and X~ray crystallographic methods.
`
`METABOLITES isolated previously from strains of Penicil-
`Iium brevicomjmctum‘ include mycophenolic acid and
`related compounds, the pebrolide sesquiterpenes, and the
`brevianamides. We describe here a new compound,
`compactin (I), which was isolated from a culture believed
`to be Penicillium brevicomjzactum and was detected by
`its antifungal activity.’
`Compactin, C231-{a405, is optically active and shows u.v.
`absorption typical of a trausoid conjugated diene. The
`i.r. spectrum shows hydroxy and lactone absorption,
`consistent with the formation of a benzoate, and the
`solubility of compactin, which is neutral, in aqueous
`
`for the 8-lactone (III), from Cephalosparirrm recafe1',3 and
`cryptocaryalactone (IV), from the roots of Cryptocarya
`bourdilloni,‘ respectively.
`The 1H n.m.r. spectrum of compactin (I) at high field
`shows two methyl doublets at 8 1.13 and 0.90 (each with
`_] '7 Hz) and a methyl triplet at 8 0.88 (] 7.5 Hz) ascribed
`to the ethyl group. Both doublets collapse to singlets on
`irradiation at 8 2.37, indicating the presence of either an
`isopropylidene
`(Me2CH) group with non-equivalent
`methyls or
`two ethylidene (CH,-CH<) groups,
`the
`methine carbon atom(s) being adjacent to a carbonyl
`group or a carbon—ca:bon double bond. A study of the
`6.0brlml
`H
`
`6.87lmlH / o
`o
`
`O
`/\/KO
`
`H L.L0lrnl
`
`Me
`
`5.5Llml H
`
`H S.95lddl
`
`ll)
`
`MI]
`
`sodium hydroxide and its recovery on acidification.
`The carbonyl band at 1 710 cm'1 (in KBr) is shifted to
`1 724 cm“ in chloroform solution, and later work (see
`below) showed that this must arise from an ester group.
`The five oxygen atoms in compactin are thus identified.
`The 8—lactone system in (I) was identified from the ‘H
`n.m.r. assignments shown and appropriate decoupling
`and exchange experiments, and by dehydration to the
`a;3~unsaturated lactone (II) in the i.r. spectrum of which
`the carbonyl absorption had moved to l 730 cm'1. The
`anhydro-compound (II) was first obtained in an attempt
`to prepare a 12-bromophenylsulphonyl derivative, and
`was also made by heating compactin with potassium
`hydrogen sulphate in dimethylformarnide. The relevant
`spectroscopic data for (I) and (II) agree well with those
`1 Vt’. B. Turner,
`‘ Fungal Metabolites,’ Academic Press,
`London. 1971.
`1 M. Richards, A. R. Clare, C. Reading, and M. S. Verrall, in
`preparation.
`
`60 and 100 MHz n.m.r. spectra revealed that the methyl-
`ene protons of the ethyl group are strongly coupled to
`2.61.
`H5.99
`
`6.83
`
`3.06 HO +12
`
`0
`
`L.3£H
`
`0
`[c“2][C“3
`
`“
`I..7
`
`H / 0
`O
`
`4.55:1
`
`cH,- c|H-c.-+:cHPh
`C0;Me
`
`um
`
`III!
`
`another adjacent group; thus the unit CH3-CH,-Cllf or
`CH,'CH,-CH< must be present. Combining the latter
`with an ethylidenc group next to a carbonyl gives the
`fragment CH3-CH,°CHMe°CO-. That
`this is derived
`3 R. F. Veeonder, F. H. Stodola, and VV. K. Rohwedder,
`Cauad.
`Biochem., 1972. 50, 363.
`‘ R. T. Govindachari and P. C. Parthasarathy, Tetrahedron
`Letters, 1971, 3401.
`
`Sawai Ex 1024
`
`Page 1 of 6
`
`
`
`2_3,“m’o
`
`"/
`
`.
`HL 62lml
`
`o.aam 1"
`H3”,
`
`7
`
`-2 H
`
`Me 0.90:4:
`”/H 2.3'Ilml
`H
`5.71 lddl
`
`
`
`
`
`
`
`Publishedon0lJanuaryI976DownloadedbyReprintsDeskon22/07/2015l4:25:37
`
`
`
`
`
`
`
`
`
`1165
`
`View Article Online I Journal Homepage I Table of Contents for this issue
`
`Crystal and Molecular Structure of Compactin. a New Antifungal Meta-
`bolite from Penicillium brevicompactum
`Beecham Pharmaceuticals Research Division. Brockham Park.
`
`By Allan G. Brown ‘ and Terry C. Smele.
`Betchworth. Surrey RH3 7AJ
`Trevor J. King. Department of Chemistry, The University, Nottingham NG7 2RD
`Rainer I-lasenkamp and Ronald H. Thompson. Department of Chemistry. University of Aberdeen, Old
`Aberdeen A89 2UE, Scotland
`
`{7-[1.2.6,7,6.8a~hexahydro-2-rnethyl-8-(2-methylbutyryloxy)naphthyl]-3-
`structure of compactin (I)
`The
`hydroxvheptan-5-olide}. a metabolite isolated from cultures of Penici/I/"um brevicompactum, has been determined
`by a combination of spectroscopic. chemical, and X~ray crystallographic methods.
`
`METABOLITES isolated previously from strains of Penicil-
`Iium brevicomjmctum‘ include mycophenolic acid and
`related compounds, the pebrolide sesquiterpenes, and the
`brevianamides. We describe here a new compound,
`compactin (I), which was isolated from a culture believed
`to be Penicillium brevicomjzactum and was detected by
`its antifungal activity.’
`Compactin, C231-{a405, is optically active and shows u.v.
`absorption typical of a trausoid conjugated diene. The
`i.r. spectrum shows hydroxy and lactone absorption,
`consistent with the formation of a benzoate, and the
`solubility of compactin, which is neutral, in aqueous
`
`for the 8-lactone (III), from Cephalosparirrm recafe1',3 and
`cryptocaryalactone (IV), from the roots of Cryptocarya
`bourdilloni,‘ respectively.
`The 1H n.m.r. spectrum of compactin (I) at high field
`shows two methyl doublets at 8 1.13 and 0.90 (each with
`_] '7 Hz) and a methyl triplet at 8 0.88 (] 7.5 Hz) ascribed
`to the ethyl group. Both doublets collapse to singlets on
`irradiation at 8 2.37, indicating the presence of either an
`isopropylidene
`(Me2CH) group with non-equivalent
`methyls or
`two ethylidene (CH,-CH<) groups,
`the
`methine carbon atom(s) being adjacent to a carbonyl
`group or a carbon—ca:bon double bond. A study of the
`6.0brlml
`H
`
`6.87lmlH / o
`o
`
`O
`/\/KO
`
`H L.L0lrnl
`
`Me
`
`5.5Llml H
`
`H S.95lddl
`
`ll)
`
`MI]
`
`sodium hydroxide and its recovery on acidification.
`The carbonyl band at 1 710 cm'1 (in KBr) is shifted to
`1 724 cm“ in chloroform solution, and later work (see
`below) showed that this must arise from an ester group.
`The five oxygen atoms in compactin are thus identified.
`The 8—lactone system in (I) was identified from the ‘H
`n.m.r. assignments shown and appropriate decoupling
`and exchange experiments, and by dehydration to the
`a;3~unsaturated lactone (II) in the i.r. spectrum of which
`the carbonyl absorption had moved to l 730 cm'1. The
`anhydro-compound (II) was first obtained in an attempt
`to prepare a 12-bromophenylsulphonyl derivative, and
`was also made by heating compactin with potassium
`hydrogen sulphate in dimethylformarnide. The relevant
`spectroscopic data for (I) and (II) agree well with those
`1 Vt’. B. Turner,
`‘ Fungal Metabolites,’ Academic Press,
`London. 1971.
`1 M. Richards, A. R. Clare, C. Reading, and M. S. Verrall, in
`preparation.
`
`60 and 100 MHz n.m.r. spectra revealed that the methyl-
`ene protons of the ethyl group are strongly coupled to
`2.61.
`H5.99
`
`6.83
`
`3.06 HO +12
`
`0
`
`L.3£H
`
`0
`[c“2][C“3
`
`“
`I..7
`
`H / 0
`O
`
`4.55:1
`
`cH,- c|H-c.-+:cHPh
`C0;Me
`
`um
`
`III!
`
`another adjacent group; thus the unit CH3-CH,-Cllf or
`CH,'CH,-CH< must be present. Combining the latter
`with an ethylidenc group next to a carbonyl gives the
`fragment CH3-CH,°CHMe°CO-. That
`this is derived
`3 R. F. Veeonder, F. H. Stodola, and VV. K. Rohwedder,
`Cauad.
`Biochem., 1972. 50, 363.
`‘ R. T. Govindachari and P. C. Parthasarathy, Tetrahedron
`Letters, 1971, 3401.
`
`Sawai Ex 1024
`
`Page 1 of 6
`
`
`
`2_3,“m’o
`
`"/
`
`.
`HL 62lml
`
`o.aam 1"
`H3”,
`
`7
`
`-2 H
`
`Me 0.90:4:
`”/H 2.3'Ilml
`H
`5.71 lddl
`
`
`
`
`
`
`
`Publishedon0lJanuaryI976DownloadedbyReprintsDeskon22/07/2015l4:25:37
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`
`Published on 01 January 1976 Downloaded by Reprints Desk on 22/07/2015 14:25:37
`
`View Article Online
`
`Sawai Ex 1024
`Page 2 of 6
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`Published on 01 January 1976 Downloaded by Reprints Desk on 22/07/2015 14:25:37
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`View Article Online
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`Sawai Ex 1024
`Page 3 of 6
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`Published on 01 January 1976 Downloaded by Reprints Desk on 22/07/2015 14:25:37
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`View Article Online
`
`Sawai Ex 1024
`Page 4 of 6
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`Published on 01 January 1976 Downloaded by Reprints Desk on 22/07/2015 14:25:37
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`View Article Online
`
`Sawai Ex 1024
`Page 5 of 6
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`Published on 01 January 1976 Downloaded by Reprints Desk on 22/07/2015 14:25:37
`
`View Article Online
`
`Sawai Ex 1024
`Page 6 of 6
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