Synthesis of the C1–C13 fragment of eribulin mesylate

Synthesis of the C1–C13 fragment of eribulin mesylate has been accomplished. It features a highly stereoselective construction of a trans-dihydropyran framework using three key reactions: (1) Sharpless epoxidation, (2) regioselective ring opening, and (3) olefin metathesis.     

Gram scale synthesis of the C(1)–C(9) fragment of amphidinolide C

An allylic cis-epoxide prepared by Sharpless asymmetric epoxidation was transformed in nine steps and 41% overall yield to the cyclization precursor 4 via a key one carbon homologation. Cobalt-catalyzed aerobic oxidative cyclization of 4 gave the trans-THF in 94% yield at gram scale. Subsequent manipulations, including a Still–Gennari olefination, Sharpless asymmetric dihydroxylation, Corey–Fuchs alkynylation, and Kazmaier hydrostannylation provided the fully functionalized C(1)–C(9) fragment 2 suitable for cross-coupling. The sequence is readily scalable and provides gram quantities of 2.     

Stereo-controlled synthesis of erythronolides A and B from 1,6-anhydro-β-D-glucopyranose (levoglucosan). Skeleton assembly in (C9 – C13) + (C7 – C8) + (C1 – C6) sequence

Stereospecific syntheses of erythronolides A and B have been accomplished starting from 1,6-anhydro-β-D-glucopyranose (levoglucosan) in a uniform synthetic sequence.     

Synthesis of alkyl (α-phenylthioalkenyl) ketones containing a (Z)-trisubstituted olefinic fragment

Warren"s method, which has been proposed for the synthesis of -phenylthiodialkyl ketones, appeared to be inefficient for the preparation of their alkenyl alkyl analogs. The latter were prepared in good yields by alkenylation of alkyl phenylthiomethyl ketones with alkenyl bromides.     

Synthesis of the C8–C16 fragment of amphidinolide R

An asymmetric synthesis of the C8–C16 fragment with several stereogenic centers of amphidinolide R, is described. The key reaction, Sharpless asymmetric epoxidation has provided the basis for generation of the required stereocenters. The target fragment was accomplished in a convergent manner in nine steps (longest linear synthesis of the sequence) and 32% overall yield was obtained starting from 2-butene-1,4-diol.     

Synthesis of the C10–C24 fragment of (+)-cannabisativine

The stereoselective synthesis of the C10–C24 fragment of (+)-cannabisativine has been achieved. The key steps involved in this strategy are the Sharpless asymmetric dihydroxylation, the diastereoselective allylation of an imine, and the ring closing metathesis (RCM).     

The ester enolate claisen rearrangement. Synthesis of A C(1)C(6) erythronolide fragment

An enantioselective route to the C(1)C(6) erythronolide unit 10 is described, involving the dioxanone-to-dihydropyran enolate Claisen rearrangement (7 → 8), regio- and stereoselective hydroboration to give 9a, and reductive fragmentation of the heterocyclic template (9c → 10).     

Synthesis and Biological Evaluation of C(13)/C(13′)-Bis(desmethyl)disorazole Z**

We describe the total synthesis of the macrodiolide C(13)/C(13′)-bis(desmethyl)disorazole Z through double inter-/intramolecular Stille cross-coupling of a monomeric vinyl stannane/vinyl iodide precursor to form the macrocycle. The key step in the synthesis of this precursor was a stereoselective aldol reaction of a formal Evans acetate aldol product with crotonaldehyde. As demonstrated by X-ray crystallography, the binding mode of C(13)/C(13′)-bis(desmethyl)disorazole Z to tubulin is virtually identical with that of the natural product disorazole Z. Likewise, C(13)/C(13′)-bis(desmethyl)disorazole Z inhibits tubulin assembly with at least the same potency as disorazole Z and it appears to be a more potent cell growth inhibitor.     

Synthesis of (±)-heliannuol C

A synthesis of (±)-heliannuol C is described involving Bargellini condensation, Dieckmann cyclization and ortho-ester Claisen rearrangement followed by a regioselective epoxide reduction. A new CuI-catalyzed [2+2] cycloaddition reaction is also described.     

Synthesis of a new potential antiviral agent — 9-allyloxymethylguanine

A convenient method has been developed for the synthesis of 9-allyloxymethylguanine. The direct alkylation of the trimethylsilyl derivative of guanine allyloxymethyl chloride gives a 64% yield of 9- and 7-allyloxymethylguanine (31). A mixture of 9- and 7-allyloxymethyl-N-acetylguanine (74) can be obtained in 56% yield by the condensation of diacetylguanine with allyloxymethyl acetate in dimethyl sulfoxide in the presences of p-toluenesulfonic acid.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1109–1113, August, 1993.     

Studies towards the synthesis of superstolide A. Synthesis and stereochemical assignment of the C(21)C(26) fragment of superstolide A

An asymmetric synthesis of the C(21)C(26) fragment of superstolide A is described. A fragment, corresponding to a reductive ozonolysis product of superstolide, was also prepared. Comparison of spectroscopic and optical properties of the corresponding fragment obtained by degradation of natural superstolide A allowed the confirmation of the stereochemistry of the natural product.     

Synthesis of the northern fragment of an epothilone D analogue from (−)-carvone

A simple and effective synthesis of the chiral thiazole-containing fragment of an epothilone D analogue from (?)-carvone is described.     

Synthesis of C1–C11 eribulin fragment and its diastereomeric analogues

A practical stereoselective synthesis of the central C1–C10 fragment of eribulin and its two diastereomeric analogues is developed. Our approach relied on the use of l-ascorbic acid as the starting material which allowed accessing a key intermediate with a syn diol moiety (C9 and C10 of eribulin) and a carboxylic ester group. A functionalized six membered lactone having several required hydroxyl groups was then obtained. In a number of steps, the lactone was converted to an intermediate for our key oxa-Michael reaction. A regio- and stereocontrolled intramolecular oxa-Michael reaction completed the synthesis of the C1–11 fragment having a trans-fused tetrahydropyrans with the exact stereochemistry of various hydroxyl groups, as in eribulin.     

Synthesis of (+)-drim-9(11)-en-8α-ol from sclareol

A drimane-type sesquiterpenoid, (+)-drim-9(11)-en-8-ol, was synthesized from sclareol in four steps. The ozonolysis product of sclareol diacetate reacts with Cu(OAc)₂·H₂O to give 8-acetoxy-14,15-bisnorlabdan-13-one. Photolysis of this compound followed by alkaline hydrolysis results in the target compound belonging to the normal steric series. (+)-Drim-9(11)-en-8-ol acetate is highly unstable and decomposes during chromatography on SiO₂.     

Synthesis and structure of the first representative of pentacoordinate C,O-chelates with a dipeptide fragment,the fluorosilane Ts—Gly—(S)-Pro—N(Me)CH2SiMe2F

A reaction of bicyclic 2-sila-5-piperazinone, 2,2,4-trimethyl-1,4-diaza-2-silabicyclo-[4.3.0]nonan-5-one containing a proline moiety, and N-tosylglycine acyl chloride with subsequent hydrolysis of the primary unstable product to the intermediate disiloxane and its treatment with BF₃?OEt₂ furnished a first representative of pentacoordinate C,O-chelate halosilanes with a dipeptide fragment, namely, Ts—Gly—(S)-Pro—N(Me)CH₂SiMe₂F.

     

Synthesis of a secretoglobin 3A2 type C (98–139) fragment by Dawson’s native chemical ligation

A secretoglobin 3A2 type C (98–139) peptide was synthesized by native chemical ligation between ¹¹⁵Ile and ¹¹⁶Cys residues using Dawson’s linker. The peptide-N-acyl-benzimidazolinone-glycine amide, a C-terminal thioesters precursor, was provided from 3-amino-4-(methylamino)benzoic acid. In addition, an N-terminal cysteine fragment, the (116–139) peptide, was prepared by ordinary Fmoc-solid phase peptide synthesis. Native chemical ligation of the (98–115) fragment with the Dawson’s linker and the (116–139) peptide smoothly proceeded to give SCGB3A2 type C (98–139) peptide.     

Synthesis and crystal structure of HOs3(CO)9(CCSiMe3)

The functionalised cluster Os₃(CO)₁₀(CH₃CN)₂ reacts at room temperature with trimethylsilylacetylene to afford the orange derivative Os₃(CO)₁₀(Me₃SiC₂H) which undergoes decarbonylation and hydrogen migration to give the cluster HOs₃(CO)₉(CCSiMe₃), which has been fully characterised by an X-ray diffraction study.     

Synthesis of a new Class of Chiral β—Mercaptoalcohols from Amino Acids

The syntheses of three new optically active β-mercaptoalcohols,(R)-1,1-diphenyl-2-mercapto-3-methyl-1-butanol,(R)-1,1-diphenyl-2-mercapto-4-methyl-1-pentanol,and (R)-1,1-diphenyl-2-mercapto-1-benzenepropanol from the corresponding amino acids are described.The enantiomeric excesses of these β-mercaptoalcohols were determined by ^1H NMR as their (S)-mandeloyl derivatives.     

Stereo selective synthesis of C3–C12 fragment of iriomoteolide-1a

A convergent and flexible synthetic route for the synthesis of C3–C12 fragment of iriomoteolide-1a is described. The key steps are: Mannich reaction, Keck asymmetric allylation, Sharpless asymmetric epoxidation and cross-metathesis protocol.     

Karlotoxin synthetic studies: concise synthesis of a C(42–63) B-ring tetrahydropyran fragment

Starting from natural d-mannose, a C(42–63) B-ring tetrahydropyran fragment in karlotoxin 2 has been prepared via a common THP intermediate in a concise manner. E-Selective Julia–Kocienski olefination efficiently assembled a C(51–63) chlorodiene subunit and a C(42–50) tetrahydropyran segment.