1980-1989 Natural Products

1989

Inositol-1-phosphate and inositol-1,4,5-trisphosphate  The novel 6-deoxy, 6-deoxy-6-fluoro and 6-deoxy-6-methyl myo-inositol 1,4,5-trisphosphate derivatives were derived from benzene via microbial oxidation to cis-1,2-dihydroxycyclohexa-3,5-diene and conversion through to the key epoxyacetonide. See: Microbial oxidation in synthesis: preparations of 6-deoxy cyclitol analogues of myo-inositol 1,4,5-trisphosphate from benzene S.V. Ley, M. Parra-Alvarez, A.J. Redgrave, F. Sternfeld, Tetrahedron Lett198930, 3557-3560.

Milbemycin β1  The successful sulfone anion stabilised coupling of a monocyclic C-1 to C-10 unit with the “northern hemisphere” C-11 to C-25 fragment of the milbemycins produces a compound which may be further elaborated in fourteen steps to the macrocyclic natural product (+) – milbemycin β1. See:  Total synthesis of (+)-milbemycin b1 N.J. Anthony, A. Armstrong, S.V. Ley, A. Madin, Tetrahedron Lett198930, 3209-3212 and  A highly convergent total synthesis of the spiroacetal macrolide (+)-milbemycin b1 S.V. Ley, N.J. Anthony, A. Armstrong, M.G. Brasca, T. Clarke, C. Greck, P. Grice, A.B. Jones, B. Lygo, A. Madin, R.N. Sheppard, A.M.Z. Slawin, D.J. Williams, Tetrahedron 198945, 7161-7194.

1988

Fuligorubin A  The use of t-butyl-3-oxobutanthioate and t-butyl 4-diethylphosphono-3-oxobutanthioate for the preparation of homologated derivatives suitable for amination in the presence of silver (I) trifluoroacetate to afford the corresponding beta-ketoamides is discussed. In particular Wadsworth-Emmons coupling reactions with various carbonyl compounds gave good yields of E-substituted products. Many of the beta-ketoamides were shown to be suitable precursors for 3-acyltetramic acids using a Dieckmann cyclisation with tetra-n-butyl ammonium fluoride as the cyclising base. These new reactions were applied to the total synthesis of the polyene 3-acyltetramic acid fuligorubin A.  See: Use of t-butyl 4-diethylphosphono-3-oxobutanethioate for tetramic acid synthesis: total synthesis of the plasmodial pigment fuligorubin A S.V. Ley, S.C. Smith and P.R. Woodward, Tetrahedron Lett. 198829, 5829-5832 and Further reactions of t-butyl 3-oxobutanthioate and t-butyl 4-diethylphosphono-3-oxobutanthioate: carbonyl coupling reactions, amination, use in the preparation of the 3-aceyltetramic acids and application to the total synthesis of fuligorubin A S.V. Ley, S.C. Smith, P.R. Woodward, Tetrahedron199248, 1145.1987

(+)-and (-)-Pinitol  Microbial oxidation with Pseudomonas putida of benzene affords cis-1,2-dihydroxycyclohexa-3,5-diene which may be converted in five steps and 49% overall yield to (±)-pinitol. Resolution of an intermediate alcohol with menthoxyacetyl chloride provides optically pure materials which may be independently transformed to (+)- or (-)-pinitol. Demethylation conditions for pinitol together with further reactions of related compounds were investigated. See: Microbial oxidation in synthesis: a six step preparation of (+)-pinitol from benzene S.V. Ley, S. Taylor, F. Sternfeld, Tetrahedron Lett. 198728, 225-226 and Microbial oxidation in synthesis: preparation of (+)-and (–)-pinitol from benzene S.V. Ley and F. Sternfeld, Tetrahedron 198945, 3463-3476.

Carolic, carlosic and carlic acids  Dianions generated from S-t-butyl acetothioacetate were alkylated with a variety of electrophiles at the gamma-carbon centre. Treatment of the alkylated products with 2-hydroxy esters in the presence of silver(I) salts gave transesterified acetoacetate derivatives in good yields. These acetoacetates were cyclised efficiently to acyltetronic acid derivatives using tetrabutyl ammonium fluoride in THF solution at room temperature. By an appropriate choice of substituents the total syntheses of the fungal metabolite natural products carlosic, carolic, and carlic acids have been achieved. See: Preparation of acyltetronic acids using t-butyl acetothioacetate: total synthesis of the fungal metabolites carolic, carlosic and carlic acids P.M. Booth, C.M.J. Fox, S.V. Ley, J. Chem. Soc., Perkin Trans. 1 1987, 121-129.

1986

Indolactam V  A synthesis of the macrolactam tumour promoter indolactam V is described in 11 steps from 4-aminoindole. See: Synthetic approaches to the teleocidin-related tumour promoters: a total synthesis of indolactam V S.E. de Laszlo, S.V. Ley and R.A. Porter, J. Chem. Soc., Chem. Commun1986, 344-346.

Pheromones from Dacus oleae and Paravespula vulgaris  Reaction of 3,4-dihydro-2H-pyran or 2-methoxytetrahydropyran with benzenesulphinic acid gave 2-benzenesulphonyl tetrahydropyran. Deprotonation followed by alkylation with carbonyl compounds or halides gave cyclic enol ether addition products by spontaneous elimination of benzenesulfinic acid. Interception of the initial addition products with aldehydes by reductive desulfonylation to give alkylated tetrahydropyran derivatives proeeeded in moderate yield using sodium naphthalenide. Several of the cystic enol ether addition products were further converted to spiroketals including syntheses of natural product pheromones from Dacus oleae and Paravespula vulgarise. See: Alkylation reactions of anions derived from 2-benzenesulphonyl tetrahydropyran and their application to spiroketal synthesis S.V. Ley, B. Lygo, F. Sternfeld, A. Wonnacott, Tetrahedron 198642, 4333-4342.

1985

Parasorbic acid, carpenter bee pheromone malyngolide  Preparation of three delta-lactonic natural products, parasorbic acid, the carpenter bee pheromone and malyngolide has been achieved from π-allyltricarbonyliron lactone complexes as the key synthetic intermediates. See: Natural product synthesis using π-allyltricarbonyliron lactone complexes: synthesis of parasorbic acid, the carpenter bee pheromone and malyngolide A.M. Horton and S.V. Ley, J. Organometallic Chem. 1985285, C17-C20.

Norcardicin A  A short five-step synthesis, in 79% overall yield, of (–)-3-Oxo-1 -[(p-benzyloxyphenyl) benzyloxy-carbonylmethyl]azetidin-2-one, a precursor for nocardicin synthesis has been developed from isoprene monoepoxide. The key steps of the procedure rely on the efficient transformation of 2–4-n3-(1-formyloxy-2-methylbut-3-en-2-ylato)tricarbonyliron into the corresponding diastereoisomeric lactam complexes using D-(–)-benzyl-(p-benzyloxyphenyl)glycinate and ZnCl2·TMEDA and their oxidation with CAN to 3-isopropenylazetidinone derivatives. See: Use of π-allyltricarbonyliron lactam complexes in the preparation of nocardicin derivatives: synthesis of (–)-3-oxo-1-[(p-benzyloxyphenyl)-benzyloxycarbonylmethyl]azetidin-2-one S.T. Hodgson, D.M. Hollinshead, S.V. Ley, C.M.R. Low, D.J. Williams. J. Chem. Soc., Perkin Trans. 1 1985, 2375-2381.

Nonacetic acid   See: Synthetic applications of ynes, enes and ones; organoselenium-mediated cyclisation reactions in organic synthesis S.V. Ley, Chem. and Ind1985, 101-106.

(+)-Thienamycin  The pi-allyltricarbonyliron lactone complex, formed by reaction of E-1,2-epoxy-2-methyl-6,6-dimethoxyhex-3-ene with co-ordinatively unsaturated iron carbonyl species, was reacted with benzylamine to give a lactam complex by an Sn’-like mechanism. This complex upon oxidation with Ce(IV) afforded cis-3-isopropenyl-4-[(2′,2′-dimethoxy)ethyl]-N-benzylazetidin-2-one which was chemically modified into trans-3-(1′-hydroxyethyl)-4-[(2′,2-dimethoxy)ethyl] azetidin-2-one, a key intermediate previously used in the synthesis of the antibiotic thienamycin. Similar reaction with (S)-(-)-alpha-methylbenzylamine afforded a separable mixture of diastereoisomeric iron lactam complexes. These complexes could be individually converted to the corresponding optically active ?-lactam derivatives and, hence, are precursors for the synthesis of either natural (+)-thienamycin or unnatural (-)-thienamycin. See:  Synthesis of the β-lactam antibiotic (+)-thienamycin via an intermediate π-allyltricarbonyliron lactone complex S.T. Hodgson, D.M. Hollinshead, S.V. Ley, Tetrahedron 198541, 5871-5878.

1984

Indanomycin  The total synthesis of the ionophore antibiotic X-14547A (indanomycin) is described by using a convergent strategy. 2-Ethylvalerolactone was converted into ethyl (E,E,E)-11-[[(beta-3-methoxy)ethoxy]methoxy]-6-ethyl- 2,7,9-undecatrienoate in eight steps. Intramolecular Diels-Alder reaction of 8 at 110 oC followed by deprotection to give the racemic tricyclic lactone proceeded with very high stereoselectivity (>90%)and in 38% overall yield from 2-ethylvalerolactone. The tricyclic lactone was resolved via the diastereomeric amides to provide the optically pure lactones. Reaction with 1-pyrrolyl magnesium bromide gave the pyrrolyl carbonyl derivative whose structure was determined by X-ray crystallography. Alternatively, the optically pure lactone was reacted with 2-lithio-14[(trimethylsilyl)ethoxy]methyl]pyrrole to give the corresponding N-SEM protected pyrrolyl carbonyl. Elaboration afforded the phenylsulfone which constituted an appropriate right-hand fragment suitable for later coupling. Synthesis of the left-hand tetrahydropyranyl-unsaturatedaldehyde was achieved by using levoglucosan(1,6-anhydroglucopyranose) as the starting material. Coupling with the lithio anion followed by trapping with benzoyl chloride gave the benzoyloxy phenyl sulfones. Reduction of these with sodium amalgam stereoselectively afforded the E,E-diene. The synthesis was completed by deprotection and hydrolysis to afford the antibiotic X-14547A (indanomycin). See: Total synthesis of the ionophore antibiotic X-14547A (indanomycin) M.P. Edwards, S.V. Ley, S.G. Lister, B.D. Palmer, D.J. Williams, J. Org. Chem198449, 3503-3516 and Novel rearrangement of the ionophore antibiotic X-14547 (indanomycin) and related derivatives induced by lithium tetrafluoroborate M.P. Edwards and S.V. Ley, J. Chem. Soc., Perkin Trans. 1 1984, 1761-1763.

(2S,8R)-8-methyl-2-phenyl-1,7-dioxaspiro[5.5]undecan-4(R)-ol  Alkenyl hydroxyketones undergo cyclisation via their hemiacetal form, in the presence of N-phenylselenophthalimide (NPSP) and a Lewis acid, to give the corresponding phenylseleno-substituted spiroacetals. Using this methodology the synthesis of trans- and cis-2-methyl-1,6-dioxaspiro-[4.4]nonane, trans- and cis-2-ethyl-1,6-dioxaspiro[4,4]nonane (chalcogran), trans- and cis-2-methyl-1,6-dioxaspiro[4,5]decane, trans-7-methyl-1,6-dioxaspiro[4.5]decane, trans-2-methyl-1,7-dioxaspiro[5.5]undecane, and (2S,8R)-8-methyl-2-phenyl-1,7-dioxaspiro[5.5]undecane-4-one has been achieved, after reductive removal of selenium using Raney-nickel in diethyl ether. Compound is the principal aggregation pheromone from Pityogenes chalcographus(L), whilst compounds (3) and (4) constitute the pheromone components of the common wasp, Paravespula vulgaris. The structure of the spiroacetal (6) was determined as a result of X-ray crystallography of a later derivative, obtained by sodium borohydride reduction of the spiroacetal. See: Synthesis of spiroacetals using organoselenium mediated cyclisation reactions, x-ray molecular structure of (2S, 8R)-8-methyl-2-phenyl-1,7-dioxaspiro-[5.5]undecan-4(R)-ol A.M. Doherty, S.V. Ley, B. Lygo, D.J. Williams, J. Chem. Soc., Perkin Trans. 1 1984, 1371-1377.

1983

Ajugarin I  The first total synthesis of the polyoxygenated diterpene insect antifeedant ajugarin I has been achieved by a route which involves a new method for the construction of 3-substituted-delta-2-butenolides. See: The total synthesis of the clerodane diterpene insect antifeedant, ajugarin I S.V. Ley, N.S. Simpkins, A.J. Whittle, J. Chem. Soc., Chem. Commun1983, 503-505 and Total synthesis of the insect antifeedant ajugarin I and degradation studies of related clerodane diterpenes P.S. Jones, S.V. Ley, N.S. Simpkins, A.J. Whittle, Tetrahedron 198642, 6519-6534.

Isodrimeninol, drimenin and danilol  The stereospecific preparation of various 1-vinyl-2,6,6-trimethylcyclohex-1-enes (6) as potential diene precursors in the Diels-Alder reaction with dimethyl acetylenedicarboxylate have been investigated. The reaction of the parent diene (6a) with dimethyl acetylenedicarboxylate affords an adduct (18) in 94% yield. This species was reductively isomerised using 10%Pd/C/H2 and a mineral acid to give a trans- fused decalin diester (19). Reduction of (19) with lithium aluminium hydride afforded Il4,4a,5,6,8,8a- octahydro-5,8,8a-trimethyl-l P14aa,8a-naphthalene-l,2-dimethanol(24) a key starting material for the highly efficient syntheses of five drimane sesquiterpene natural products, cinnamolide (1), polygodial (2), isodrimeninol (3), drimenin (4), and warburganal (5). Microbial oxidation reactions using C. elegans or A. niger of (2), (24), and (1) gave good yields of the corresponding 3p-hydroxy derivatives, (30), (31), and (32). Several other unusually substituted drimane derivatives are reported. See: The Diels-Alder route to drimane related sesquiterpenes; synthesis of cinnamolide, polygodial, isodrimeninol, drimenin, and warburganal D.M. Hollinshead, S.C. Howell, S.V. Ley, M. Mahon, N.M. Ratcliffe, P.A. Worthington, J. Chem. Soc., Perkin Trans. 1 1983, 1579-1589.

1982

Hirsutene A short synthesis of the sesquiterpene hirsuteness has developed in which the key step involved intramolecular cyclization of a β-oxoester to an alkene using N-phenylselenophthalimide and tin terrachloride. See: A short synthesis of (+/-)-hirsutene involving the use of an organoselenium mediated cyclization reaction S.V. Ley and P. J. Murray, J. Chem. Soc., Chem. Commun1982, 1252-1253 and Total synthesis of the sesquiterpene hirsutene using an organoselenium-mediated cyclisation reaction S.V. Ley, P.J. Murray, B.D. Palmer, Tetrahedron 198541, 4765-4769.

Massoialactone  A variety of tricarbonyliron lactone complexes undergo thermal decomposition upon warming in deoxygenated solvents to give products arising from decarbonylation, decarboxylation, and rearrangement pathways. The products of the reactions were characterised by spectroscopic or X-ray crystallographic methods, or in some cases, by independent synthesis. Mechanisms to account for the various transformations are also proposed (massoialactone). See: Thermal rearrangement reactions of tricarbonyliron lactone complexes G.D. Annis, S.V. Ley, C.R. Self, R. Sivaramakrishnan, D.J. Williams, J. Chem. Soc., Perkin Trans. 1 1982, 1355-1361.

(cis-6-Methyltetrahydropyran-2-yl) acetic acid  A short stereospecific synthesis of (cis-6-methyltetrahydropyran-2-yl)acetic acid has been achieved from readily available starting materials using a novel organoselenium-mediated cyclization of alkenyl-substituted β-oxoesters. See: Synthesis of (cis-6-methyltetrahydropyran-2-yl) acetic acid involving the use of an organoselenium mediated cyclization reaction S.V. Ley, B. Lygo, H. Molines, J.A. Morton, J. Chem. Soc., Chem. Commun1982, 1251-1252; Synthesis of (+/-)cis-6-methyltetrahydropyran-2-yl acetic acid a natural product from Viverra civetta using organoselenium-mediated cyclisation reactions S.V. Ley, B. Lygo, H. Molines, J. Chem. Soc., Perkin Trans. 11984, 2403-2405 and Diastereoselective Oxygen to Carbon Rearragements of Anomerically Linked Enol Ethers and the Total Synthesis of (+)-S,S-(cis-6-Methyltetrahydropyran-2-yl)acetic Acid a Component of Civet D.J. Dixon, S.V. Ley and E.W. Tate, J. Chem. Soc., Perkin Trans. 12000, 2385.

Methyl-1,6-dioxaspiro[4,5]decane  Three naturally occurring methyl-1,6-dioxaspiro[4.5]decanes have been prepared in good yield using organoselenium mediated reactions during the crucial cyclization process. See: Synthesis of methyl-1,6-dioxaspiro[4,5]decanes using organoselenium mediated cyclisation reactions S.V. Ley and B. Lygo, Tetrahedron Lett 198223, 4625-4628 and Alkylation reactions of anions derived from 2-benzenesulphonyl tetrahydropyran and their application to spiroketal synthesis S.V. Ley, B. Lygo, F. Sternfeld, A. Wonnacott, Tetrahedron 198642, 4333-4342.

1981

Cinnamolide and polygodial  Starting from 2,6,6-trimethyl-1-vinylcyclohex-1-ene a short synthesis of the sesquiterpenes cinnamolide and polygodial has been achieved with 60% and 57% overall yields, respectively. Synthesis of cinnamolide and polygodial S.C. Howell, S.V. Ley, M. Mahon, P.A. Worthington, J. Chem. Soc., Chem. Commun1981, 507-508 and The Diels-Alder route to drimane related sesquiterpenes; synthesis of cinnamolide, polygodial, isodrimeninol, drimenin, and warburganal D.M. Hollinshead, S.C. Howell, S.V. Ley, M. Mahon, N.M. Ratcliffe, P.A. Worthington, J. Chem. Soc., Perkin Trans. 1 1983, 1579-1589.

Euryfuran, confertifolin and valdiviolide  Trans-3,4,4a,5,6,7,8,8a-Octahydro-5,5,8a-trimethylnaphthalene-1 (2H)-one was converted into the drimane sesquiterpene euryfuran in 59% yield. Euryfuran was then used as a starting material for the synthesis of two other drimane natural products, confertifolin and valdiviolide. The preparation of valdiviolide constitutes the first total synthesis of this molecule. See: Synthesis of euryfuran, valdiviolide and confertifolin S.V. Ley and M. Mahon, Tetrahedron Lett. 198122, 4747-4750 and Synthesis of the drimane-related sesquiterpenes euryfuran, confertifolin and valdiviolide S.V. Ley and M. Mahon, J. Chem. Soc. Perkin Trans. 1 1983, 1379-1381.

Warburganal  From readily available starting materials a short stereospecific synthesis of the biologically active molecule warburganal has been achieved in 20% overall yield. See: Synthesis of (+/-)-warburganal S.V. Ley and M. Mahon, Tetrahedron Lett198122, 3909-3912 and The Diels-Alder route to drimane related sesquiterpenes; synthesis of cinnamolide, polygodial, isodrimeninol, drimenin, and warburganal D.M. Hollinshead, S.C. Howell, S.V. Ley, M. Mahon, N.M. Ratcliffe, P.A. Worthington, J. Chem. Soc., Perkin Trans. 1 1983, 1579-1589.