1990-1999 Natural Products

1999

(±)-Epibatidine  A ten-step synthesis of (±)-epibatidine is described, using an organised array of polymer supported reagents and sequestering agents in a successive manner. No chromatographic purification steps are required to afford the product in >90% purity. See: Synthesis of the potent analgesic compound (±)-epibatidine using an orchestrated multi-step sequence of polymer supported reagents J. Habermann, S.V. Ley, J.S. Scott, J. Chem. Soc., Perkin Trans. 11999, 1253-1256.

(±)-Oxomaritidine and (±)-epimaritidine  The concise synthesis of the alkaloids (±)-oxomaritidine and (±)-epimaritidine in high yield are described, which employs a sequence of five- and six-step reactions respectively, using solely polymer supported reagents in an orchestrated successive manner. See: Synthesis of the alkaloids (±)-oxomaritidine and (±)-epimaritidine using an orchestrated multi-step sequence of polymer supported reagents S.V. Ley, O. Schucht, A.W. Thomas, P.J. Murray, J. Chem. Soc., Perkin Trans. 11999, 1251-1252 and A Flow Process for the Multi-Step Synthesis of the Alkaloid Natural Product Oxomaritidine: A New Paradigm for Molecular Assembly I.R. Baxendale, J. Deeley, C.M. Griffiths-Jones, S.V. Ley, S. Saaby and G. Tranmer, J. Chem. Soc., Chem. Commun2006, 2566-2568.


Erythroskyrine  
The first total synthesis of erythroskyrine, a polyenoyltetramic acid mycotoxin and principal pigment of Penicillium Islandicum Sopp., is described using a palladium(II) catalysed oxycarbonylation to create the furan-derived bicyclic portion and the phosphonate ester to furnish both the polyenoyl chain and the N-methyl(S)-valine derived tetramic acid terminus. See: Total synthesis of the polyenoyl tetramic acid mycotoxin erythroskyrine D.J. Dixon, S.V. Ley, T. Gracza, P. Szolcsanyi, J. Chem. Soc., Perkin Trans. 1 1999, 839-842.

Physarorubinic acid  The total synthesis of physarorubinic acid, a polyenoyltetramic acid plasmoidal pigment from Physarum polycephalum, is described in a series of steps from (E)-3-iodoacrylic acid 6 and employs aminolysis of the pentaene thioester 11 as a key synthetic step. Lacey–Dieckmann cyclisation and subsequent deprotection then affords physarorubinic acid 1 in high yield and purity. See: Total synthesis of the plasmoidal pigment physarorubinic acid, a polyenoyl tetramic acid D.J. Dixon, S.V. Ley, D.A. Longbottom, J. Chem. Soc., Perkin Trans. 1 1999, 2231-2232.

Glycodelin glycans  The concise synthesis of nine diantennary oligosaccharides by chemical and chemoenzymatic protocols is presented. The compounds display Lewis X, Lewis Y, sialyl Lewis X and T-antigen epitopes supported on a 3,6-branched trimannose core. They derive from the glycans of the human glycoproteins Glycodelin-A and Glycodelin-S believed to be involved in regiospecific suppression of the female immune system. See: Synthesis of glycans from the glycodelins: two undeca-, two deca-, three nona-, and octa- and a heptasaccharide, D Depré, A. Düffels, L.G. Green, R. Lenz, S.V.Ley, C-H. Wong, Chem. Eur. J19995, 3326-3340.

1233A  The total synthesis of the beta-lactone cholesterol synthase inhibitor 1233A (1) is described employing the oxidative decomplexation of a (π-allyl)tricarbonyliron lactone (2) as the key synthetic step. See: Total synthesis of the cholesterol biosynthesis synthase inhibitor 1233A via a π-Allyltricarbonyliron Lactone Complex S.V. Ley, R.W. Bates, E. Fernández-Megía, S.V. Ley, K. Rück-Braun, D.M.G. Tilbrook, J. Chem. Soc., Perkin Trans. 1 1999, 1917-1926.

1998

Okadaic acid  The total synthesis of the protein phosphatase inhibitor okadaic acid 1 is reported using a convergent coupling strategy of three components, all of which may be prepared using chemistry developed in our laboratories. See: Total synthesis of the protein phosphatase inhibitor okadaic acid S.V Ley, A C. Humphries, H. Eick, R. Downham, A.R. Ross, R.J. Boyce, J.B.J. Pavey, J. Pietruszka, J. Chem. Soc., Perkin Trans. 1 1998, 3907-3912.

(+)-Goniodiol  A high-yielding enantioselective total synthesis of the bioactive styryllactone (+)-goniodiol has been realised, starting from readily available (S)-glycidol. A key step is an oxygen-to-carbon rearrangement of a silyl enol ether linked via an anomeric centre, facilitating the rapid and diastereoselective construction of this functionalised system. See: A total synthesis of (+)-Goniodiol using an anomeric oxygen-to-carbon rearrangement D.J. Dixon, S.V. Ley and E.W. Tate, J. Chem. Soc., Perkin Trans. 1 1998, 3125-3126 and A Highly Enantioselective Total Synthesis of (+)-Goniodiol E.W. Tate, D.J. Dixon and S.V. Ley, Org. Biomol. Chem20064, 1698-1706.

Glycosylphosphatidylinositol anchor  Six building blocks, six reaction steps: The recently developed innovative methodology facilitated the convergent synthesis of the complex oligosaccharide core 1 (shown here with protecting groups) for the total synthesis of a glycosylphosphatidylinositol (GPI) anchor. The key factors are the tuning of the reactivity of the building blocks by using 1,2-diacetal protecting groups and the desymmetrization of glycerol and myo-inositol with a chiral bis(dihydropyran). See: Rapid assembly of oligosaccharides: total synthesis of a glycosylphosphatidylinositol anchor of Trypanosoma brucei D.K. Baeschlin, A. Chaperon, V. Charbonneau, L.G. Green, S.V. Ley, U. Lücking, E. Walther, Angew. Chem., Int. Ed. Engl., 1998, 3423-3428 and 1,2-Diacetals in Synthesis: Total Synthesis of a Glycosylphosphatidylinositol Anchor of Trypanosoma brucei D.K. Baeschlin, A.R. Chaperon, L.G. Green, M.G. Hahn, S.J. Ince, S.V. Ley, Chem. Eur.J., 20006, 172.

1997

(+)-D-Conduritol B  Using (2S,2’S)-2,2′-diphenyl-6,6′-bi(3,4-dihydro-2 H-pyran) to effect a simultaneous protection–resolution of a myo-inositol derivative, a new synthesis of (+)-D-conduritol B has been achieved. See: Dispiroketals in synthesis. Part 23. A new route to (+)-D-conduritol B from myo-inositol J.E. Innes, P.J. Edwards, S.V. Ley, J. Chem. Soc., Perkin Trans. 1 1997, 795-796.

High Mannose Type Nonasaccharide  The high-mannose nonasaccharide is part of the glycoprotein gp 120 of the viral coat of HIV-1. The mannan portion of this triantennary glycan was prepared by a number of consecutive glycosidation steps without the need for any protecting-group manipulation. This was achieved by carefully tuning the reactivity of the glycosyl donors by employing our cyclohexane-1,2-diacetal (CDA) methodology. The method was further extended with one-pot procedures for oligosaccharide synthesis, thus reducing the number of steps to form the protected nonasaccharide from the monosaccharide building blocks to five. See: A new strategy for oligosaccharide assembly exploiting cyclohexane-1,2-diacetal methodology: an efficient synthesis of a high mannose type nonasaccharide P. Grice, S.V. Ley, J. Pietruszka, H.M.I. Osborn, H.W.M. Priepke, S.L. Warriner, Chem. Eur. J. 19973, 431-440 and Synthesis of High-Mannose Type Neoglycolipids Active Targeting of Liposomes to Macrophages for Gene Therapy A. Düffels, L. G. Green, S.V. Ley and A.D. Miller, Chem. Eur. J., 20006, 1416.

1996

Tetronasin  Studies towards the synthesis and biosynthesis of tetronasin, an acyltetronic acid ionophore are described, together with an account of some novel methodology which is more widely applicable for the synthesis of other acyltetronic acids. See: Synthesis and chemistry of the ionophore antibiotic tetronasin S.V. Ley, J.A. Clase, D.J. Mansfield, H.M.I. Osborn, J. Heterocyclic Chem199633, 1533-1544 and Synthesis of the acyltetronic and acid ionophore tetronasin (ICI M139603) S.V. Ley, D.S. Brown, J.A. Clase, H.M.I. Osborn, D. Wadsworth, E.S. Stokes, A.J. Fairbanks, J. Chem. Soc., Perkin Trans. 1,1998, 2259-2276.

1995

β-dimorphecolic acid  A highly enantioselective synthesis of beta-dimorphecolic acid 1 is reported. The synthesis features a diastereoselective reduction of the ketone 4, in which the tricarbonyliron lactone tether induces a 1,5 transfer of chirality, followed by a stereoselective decarboxylation to create all the stereochemical elements of 1. Selective oxidation of the primary alcohol in the diol 17 serves to introduce the acid functionality. See: Synthesis of β-dimorphecolic acid exploiting highly stereoselective reduction of side-chain carbonyl group of a π-allyltricarbonyliron lactone complex S.V. Ley and G. Meek, J. Chem. Soc., Chem. Commun1995, 1751-1752 and Synthesis of β-dimorphecolic acid exploiting highly  stereoselective reduction of a side-chain carbonyl group in a π-allyltricarbonyliron lactone complex S.V. Ley, G. Meek, J. Chem. Soc. Perkin Trans. 1 1997, 1125-1134.

1994

Immunodominant epitope of group specific polysaccharide of group B Streptococci  The reactivity of sugars in glycosylation reactions can be tuned by the cyclohexane-1,2-diacetal (CDA) protecting group. In the efficient synthesis of trisaccharide 1 from three monosaccharide units, no functional group conversions are necessary between glycosylation steps. See: A Facile One-pot Synthesis of a Trisaccharide Unit from the Common Polysaccharide Antigen of the Group B Streptococci using Cyclohexane-1,2-diacetal Protected Rhamnosides S.V. Ley and H.W.M. Priepke, Angew. Chem., Int. Ed. Engl199433, 2292.

1993

(+)-Milbemycin a1  The total synthesis of the antiparasitic spiroketal macrolide (+)-milbemycin a1 is reported, following Julia sulfone anion coupling of the sulfone 3 with a northern hemisphere aldehyde 2 and subsequent functional group elaboration. See: Total synthesis of the spiroketal macrolide (+)-milbemycin a1 S. V. Ley, A. Madin and N. Monck, Tetrahedron Lett199334, 7479.

1992

CP-61,405 (routiennocin)  The total synthesis of the spiroketal ionophore antibiotic routiennocin (CP-61,405) employing π-allyltricarbonyl iron lactone complexes is described. These complexes were used as precursors for the preparation of substituted 2-phenylsulphonyl pyrans which, in turn, were coupled with iodoacetonides to afford spiroketals. Elaboration of the spiroketals by tetra-n-propylammonium perruthenate (TPAP) oxidation and coupling with 2-lithio-1-[beta-(trimethylsilyl)ethoxymethyl] pyrrole followed by further oxidation, deprotection, oxidation and benzoxazole formation afforded the natural product. The preparation of the amino phenol fragment necessary for benzoxazole formation involved a novel amination procedure using benzeneselenenic anhydride and hexamethyldisilazane followed by samarium diiodide reduction. See: Total synthesis of ionophore antibiotic CP-61,405 (routiennocin) D. Díez-Martin, N.R. Kotecha, S.V. Ley, S. Mantegani, J.C. Menéndez, H.M. Organ, A.D. White, B.J. Banks, Tetrahedron199248, 7899; Total synthesis of the carboxylic acid ionophore antibiotic CP-61,405 (routiennocin): preparation of the inherent spiroketal unit via a reverse coupling process D. Diez-Martin, N.R. Kotecha, S.V. Ley, J.C. Menendez, Synlett1992, 399 and Total synthesis of the carboxylic acid ionophore antibiotic CP-61,405 (routiennocin) N.R. Kotecha, S.V. Ley, S. Mantegani, Synlett1992, 395.

Pseudo-alpha-d-glucopyranose  Cis-3,5-Cyclohexadiene-1,2-diol, derived from benzene by microbial transformation using Pseudomonas putida, was converted to the enzyme inhibitor pseudo-alpha-D-glucopyranose. See: Microbial oxidation in synthesis: preparation of pseudo-alpha-D-glycopyranose from benzene L. L. Yeung and S.V. Ley, Synlett1992, 291.

1991

Norruspoline and ruspolinone  Several 2-phenylsulphonyl-piperidines and -pyrrolidines were prepared from the corresponding N-acyl aminals by treatment with benzenesulphinic acid. On reaction with various carbon nucleophiles these sulphones gave good yields of substitution products. Typical nucleophiles used in these studies were organometallic reagents derived from Grignard reagents and zinc halide together with silyl enol ethers, silyl ketene acetals, allylsilanes and trimethylsilyl cyanide in the presence of a Lewis acid. These methods were employed in the synthesis of two natural product alkaloids; norruspoline and ruspolinone. See: Substitution reactions of 2-phenylsulphonyl-piperidines and -pyrrolidines with carbon nucleophiles: Synthesis of the pyrrolidine alkaloids norruspoline and ruspolinone D.S. Brown, P. Charreau, T. Hansson, S.V. Ley, Tetrahedron199147, 1311.

Avermectin B1a  A highly convergent total synthesis of the anthelmintic macrolide avermectin B1a is described. The key features of this synthesis include the introduction of the C(11)–C(15) portion by selective ring opening of a symmetrical 1,4-bis-epoxide followed by reaction with the anion derived from the 3-methyl-2-(1-methylpropyl)-6-phenylsulphonylpyran to afford the ‘northern’ C(11)–C(25) fragment. Coupling of the derived C(11)–C(25) aldehyde unit with a C(1)–C(10)‘southern’ fragment was achieved via a novel deconjugative vinyl sulphone anion sequence. Macrolactonisation and subsequent introduction of the 3,4-double bond gave the aglycone portion. The oleandrosyloleandrose disaccharide was introduced by a novel silver-mediated coupling between the 5-acetylated aglycone and the thiocarbonylimidazolide. Final deacetylation was accomplished using Super-Hydride to give the natural product. See: Total synthesis of the anthelmintic macrolide avermectin B1a S.V. Ley, A. Armstrong, D. Díez-Martín, M.J. Ford, P. Grice, J. Knight, H.C. Kolb, A. Madin, C.A. Marby, S. Mukherjee, A.N. Shaw, A.M.Z. Slawin, S. Vile, A.D. White, D.J. Williams, M.Woods, J. Chem. Soc., Perkin Trans. 1 1991, 667-692 and See: The Champagne Route to Avermectins and Milbemycins in Strategy and Tactics in Organic Synthesis Vol. 3, S.V. Ley and A. Armstrong, T. Lindberg, Ed. Acad. Press, 1991, 273-291.

(–)-Heliotridane and (–)-isoretronecanol  A novel synthesis of the pyrrolizidine alkaloids (-)-heliotridane and (-)-isoretronecanol is described. The key steps involve the conversion of a proline-derived carbamate into the pi-allyltricarbonyliron lactam complex and the exhaustive carbonylation of this to give the pivotal intermediate gamma-lactam. See: Synthesis of the alkaloids (−)-heliotridane and (−)-isoretronecanol via π-allyltricarbonyliron lactam complexes G. Knight and S.V. Ley, Tetrahedron Lett199132, 7119.

Agglomerin A and (±)-carolinic acid  A variety of O-methyl-3-acyl tetronates were prepared in good yield from the corresponding acid chlorides via a palladium catalyzed acylation of O-methyl 3-(tri-n-butylstannyl) tetronates. This new synthetic method was then exploited for the total synthesis of the novel antibiotic agglomerin A, as well as the fungal metabolite (±) carolinic acid. See: The total synthesis of agglomerin a and (¬±)-carolinic acid: a general method for the preparation of 3-acyl tetronic acids via direct acylation of o-methyl 3- stannyl tetronates S.V. Ley, M.L. Trudell, D.J. Wadsworth, Tetrahedron1991, 47, 8285.

Valilactone  Synthesis of the esterase inhibitor valilactone is reported employing the oxidation of π-allyltricarbonyliron lactone complexes with ceric ammonium nitrate to afford the inherent β-lactone ring. See: Synthesis of the β-lactone esterase inhibitor valilactone using π-allyltricarbonyliron lactone complexes R.W. Bates, R. Fernández-Moro, S.V. Ley, Tetrahedron Lett.199132, 2651 and The use of p-allyltricarbonyliron lactone complexes in the synthesis of b-lactone esterase inhibitor (–)-valilactone R.W. Bates, R. Fernández-Moro and S.V. Ley, Tetrahedron199147, 9929.

Osmundalactone  A highly convergent total synthesis of the anthelmintic macrolide avermectin B1a is described. The key features of this synthesis include the introduction of the C(11)–C(15) portion by selective ring opening of a symmetrical 1,4-bis-epoxide followed by reaction with the anion derived from the 3-methyl-2-(1-methylpropyl)-6-phenylsulphonylpyran to afford the ‘northern’ C(11)–C(25) fragment. Coupling of the derived C(11)–C(25) aldehyde unit with a C(1)–C(10)‘southern’ fragment 2 was achieved via a novel deconjugative vinyl sulphone anion sequence. Macrolactonisation and subsequent introduction of the 3,4-double bond gave the aglycone portion. The oleandrosyloleandrose disaccharide was introduced by a novel silver-mediated coupling between the 5-acetylated aglycone and the thiocarbonylimidazolide. Final deacetylation was accomplished using Super-Hydride to give the natural product. See: Total synthesis of the anthelmintic macrolide avermectin B1a S.V. Ley, A. Armstrong, D. Díez-Martín, M.J. Ford, P. Grice, J. Knight, H.C. Kolb, A. Madin, C.A. Marby, S. Mukherjee, A.N. Shaw, A.M.Z. Slawin, S. Vile, A.D. White, D.J. Williams, M.Woods, J. Chem. Soc., Perkin Trans. 1 1991, 667-692.

1990

L-(–)-Oleandrose  L-(-)-Oleandrose (2,6-dideoxy-3-O-methyl-arabino-hexose) was prepared in only three steps from (S)-(-)-methyl lactate and (3-butenylsulphonyl)benzene, without the use of protecting groups. A stereocontrolled reduction and a thermodynamically controlled exchange reaction afforded the required arabino configuration. See: An efficient three step synthesis of L(-)-oleandrose from S(-)-methyl lactate M.J. Ford and S.V. Ley, Synlett1990, 771.
(+)-Conduritol F A synthesis of the naturally occurring cyclohexenetetrol (+)-conduritol F and its unnatural antipode has been developed in five steps from benzene using Pseudomonas putida oxidation to introduce the necessary cis-1,2-diol functionality. See: Microbial oxidation in synthesis: concise preparation of (+)-conduritol F from benzene S.V. Ley and A.J. Redgrave, Synlett1990, 393.