Wittig Homologation Research Articles

A simple and efficient approach for the preparation of dihydroxanthyletin, xanthyletin, decursinol and marmesin

A simple and efficient approach has been developed for the preparation of coumarin natural products such as dihydroxanthyletin, xanthyletin, decursinol and marmesin starting from commercially available 2,4-dihydroxybenzaldehyde with very good yields. Wittig homologation and Claisen rearrangement are the protocols used to achieve these molecules.

Stereoselective Synthesis of the C1-C16 Fragment of the Purported Structure of Formosalide B.

The first stereoselective synthesis of the C1–C16 fragment possessing stereo-enriched fully substituted tetrahydropyran (THP) along with tetrahydrofuran (THF) rings of the proposed structure of formosalide B is described in 12 longest linear steps with 22% overall yield, starting from two cheap and commercially available 1,5-pentanediol and l-glutamic acid, following a convergent approach. The key steps involve in this synthesis are Horner–Wadsworth–Emmons reaction, Sharpless asymmetric dihydroxylation, and acid-mediated ketalization to assemble the substituted THP ring, one-pot Sharpless dihydroxylation–SN2-type cyclization, and Wittig homologation to construct the THF derivative.

Hydroxylation of Eleuthoside Synthetic Intermediates by P450BM3 (CYP102A1)

A seven‐step synthesis of the first tricyclic intermediate in Danishefsky's total synthesis of eleutherobin is reported with Wittig homologation and sequential additions of metallated furan derivatives to aldehydes as key steps. Aiming to prepare hydroxylated eleutherobin analogues for cytotoxicity screening, the furan diol epimers 6 and precursors 1 and 2 were exposed to a 48‐member panel of engineered cytochrome P450BM3 variants. Both furan‐containing substrates reacted solely at the furan ring, one resulting in overall biocatalytic Achmatowicz reaction. Selective hydroxylation at four separate sp3 C–H centres was achieved in the substrates lacking the furan component. P450BM3‐catalysed hydroxylation of racemic substrates can proceed with kinetic resolution; in the case reported here, the 2°‐allylic alcohol product 10 was generated with an 82:18 enantiomeric ratio.

A facile chiral pool synthesis of 9-epi-decarestrictine-D, decarestrictine-D and O

A facile chiral pool total synthesis of 9-epi-decarestrictine-D, decarestrictine-D and O has been achieved from l-(+)-diethyl tartrate. The strategy utilized is conventional and flexible. Wittig homologation and Grubbs ring closing metathesis are the key reactions employed for the synthesis of the title molecules.

ChemInform Abstract: Chemoselective Oxidative Hydrolysis of EWG Protected α‐Arylamino Vinyl Bromides to α‐Arylamino‐α′‐bromoacetones.

ChemInformVolume 44, Issue 47 Preparative Organic Chemistry ChemInform Abstract: Chemoselective Oxidative Hydrolysis of EWG Protected α-Arylamino Vinyl Bromides to α-Arylamino-α′-bromoacetones. Vittorio Pace, Vittorio Pace Dep. Drug Nat. Prod. Synth., Univ. Wien, A-1090 Wien, AustriaSearch for more papers by this authorLaura Castoldi, Laura Castoldi Dep. Drug Nat. Prod. Synth., Univ. Wien, A-1090 Wien, AustriaSearch for more papers by this authorMaria J. Hernaiz, Maria J. Hernaiz Dep. Drug Nat. Prod. Synth., Univ. Wien, A-1090 Wien, AustriaSearch for more papers by this authorAndres R. Alcantara, Andres R. Alcantara Dep. Drug Nat. Prod. Synth., Univ. Wien, A-1090 Wien, AustriaSearch for more papers by this authorWolfgang Holzer, Wolfgang Holzer Dep. Drug Nat. Prod. Synth., Univ. Wien, A-1090 Wien, AustriaSearch for more papers by this author Vittorio Pace, Vittorio Pace Dep. Drug Nat. Prod. Synth., Univ. Wien, A-1090 Wien, AustriaSearch for more papers by this authorLaura Castoldi, Laura Castoldi Dep. Drug Nat. Prod. Synth., Univ. Wien, A-1090 Wien, AustriaSearch for more papers by this authorMaria J. Hernaiz, Maria J. Hernaiz Dep. Drug Nat. Prod. Synth., Univ. Wien, A-1090 Wien, AustriaSearch for more papers by this authorAndres R. Alcantara, Andres R. Alcantara Dep. Drug Nat. Prod. Synth., Univ. Wien, A-1090 Wien, AustriaSearch for more papers by this authorWolfgang Holzer, Wolfgang Holzer Dep. Drug Nat. Prod. Synth., Univ. Wien, A-1090 Wien, AustriaSearch for more papers by this author First published: 04 November 2013 https://doi.org/10.1002/chin.201347031Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume44, Issue47November 19, 2013 RelatedInformation

Chemoselective oxidative hydrolysis of EWG protected α-arylamino vinyl bromides to α-arylamino-α′-bromoacetones

Vinyl bromides bearing an arylamino group in the vicinal position are chemoselectively transformed into interesting α-arylamino-α′-bromoacetones through a straightforward oxidative hydrolysis promoted by calcium hypobromite under mild acidic conditions. Significantly, this particular combination [vinyl bromides and Ca(BrO)2] avoids bromination at both the aromatic ring and activated positions in groups substituting the amine nitrogen. The usefulness of this class of brominated ketones has been shown in a Wittig homologation.

Metal-mediated alkynediol cycloisomerization: first and second generation formal total syntheses of didemniserinolipid B

A formal total synthesis of didemniserinolipid B was developed by employing a regioselective metal-mediated 6-endo-dig alkynol-cycloisomerization reaction. Two routes for the synthesis of key Burke's intermediate have been developed. Our initial approach involved the introduction of a C17-alkynol followed by Pd-mediated cycloisomerization and then coupling with the serinol unit prior to the introduction of an α,β-unsaturated ester unit through selective oxidation of 1°-OH followed by a two-carbon Wittig homologation. Alternatively, the second generation strategy featuring the serinol coupling with the C17-alkynol followed by alkyne addition to the epoxide and subsequent Au-mediated cycloisomerization of an acetonide protected alkynediol unit has been executed. This approach has avoided several late stage protection–deprotection events.

Wittig homologation of 2-(chloromethyl)-2H-chromen-2-ol derivatives: a new facile synthesis of substituted 2,3-dihydrobenzoxepine-4-carboxylates

Wittig homologation of 2-(chloromethyl)-2H-chromen-2-ol derivatives 2a–t with (ethoxycarbonylmethylene)triphenylphosphorane provided the 2-oxoethylidene-2,3-dihydrobenzoxepine-4-carboxy-lates 3a–t with Z (cis) selectivity. Various basic catalysts were studied for the reaction of 2-(chloromethyl)-2H-chromen-2-ol 2a with the combination of Wittig reagent to provide compound 3b. The reaction of 2-(chloromethyl)-2H-chromen-2-ol 2a with other Wittig reagents, such as methylene(triphenylene)phosphorane and (1-ethoxycarbonylethylidene)triphenylphosphorane provided ketone derivative 4a rather 2-oxoethylidene derivative 3b. The ketone derivative 4a was reacted with Wittig reagent (ethoxycarbonylmethylene)triphenylphosphorane to give 2,3-dihydrobenzoxepine-4-carboxylate 3b. The present approach is novel, straight forward and being reported for the first time.

The stereoselective total synthesis of (−)-achaetolide

The stereoselective total synthesis of (−)-achaetolide is described in a convergent manner. Grignard addition, Wittig homologation, acetate aldol and ring closing metathesis reactions were the key steps involved. The required olefinic alcohol fragments were synthesized from a single chiral pool material 2-deoxy-d-ribose and olefinic acid fragment was prepared from acetate aldol reaction. Both the olefinic acid and alcohols were prepared in a concise method.

An approach to aliphatic 1,8-stereocontrol: diastereoselective syntheses of (±)-patulolide C and (±)-epipatulolide C

The tin(iv) bromide promoted reaction of 7-hydroxy-7-phenylhept-2-enyl(tributyl)stannane 11 with benzaldehyde gave a mixture of the epimeric 1,8-diphenyloct-3-ene-1,8-diols 12 and so indirect methods were developed for aliphatic 1,8-stereocontrol to complete diastereoselective syntheses of (±)-patulolide C 1 and (±)-epipatulolide C 40. (5Z)-3,7-syn-7-(2-Trimethylsilylethoxy)methoxyocta-1,5-dien-3-ol 17 was prepared from the tin(iv) chloride promoted reaction of 4-(2-trimethylsilylethoxy)methoxypent-2-enyl(tributyl)stannane 16 with acrolein (1,5-syn : 1,5-anti = 96 : 4). An Ireland-Claisen rearrangement of the corresponding benzoyloxyacetate 21 with in situ esterification of the resulting acid using trimethylsilyldiazomethane gave methyl (4E,7Z)-2,9-anti-2-benzyloxy-9-(2-trimethylsilylethoxy)methoxydeca-4,7-dienoate 22 together with 10-15% of its 2,9-syn-epimer 26, the 2,9-syn- : 2,9-anti-ratio depending on the conditions used. An 88 : 12 mixture of esters was taken through to the tert-butyldiphenylsilyl ether 38 of (±)-patulolide C 1 together with 6% of its epimer 39, by reduction, a Wittig homologation and deprotection/macrocyclisation. Following separation of the epimeric silyl ethers, deprotection of the major epimer 38 gave (±)-patulolide C 1. The success of 2,3-Wittig rearrangements of allyl ethers prepared from (5Z)-3,7-syn-7-(2-trimethylsilylethoxy)methoxyocta-1,5-dien-3-ol 17 was dependent on the substituents on the allyl ether. Best results were obtained using the pentadienyl ether 56 and the cinnamyl ether 49 that rearranged with >90 : 10 stereoselectivity in favour of (1E,5E,8Z)-3,10-syn-1-phenyl-10-(2-trimethylsilylethoxy)methoxyundeca-1,5,8-trien-3-ol 50. This product was taken through to the separable silyl ethers 38 and 39, ratio 7 : 93 by regioselective epoxidation and alkene reduction using diimide, followed by deoxygenation, ozonolysis, a Wittig homologation and selective deprotection/macrocyclisation. Deprotection of the major epimer 39 gave (±)-epipatulolide C 40.

An Efficient Stereoselective Approach for the Synthesis of (+)‐(4S,5S)‐Muricatacin

AbstractAn efficient stereoselective total synthesis of (+)‐(4S,5S)‐muricatacin was accomplished in good yields from inexpensive, commercially available chemicals ((+)‐diethyl tartrate (DET) and undecan‐1‐ol) by utilizing Mitsunobu and JuliaKocienski reactions, Wittig homologation, Swern oxidation, and lactonization.

Computationally guided organometallic chemistry: preparation of the heptacyclic pyrazine core of ritterazine N.

Diels-Alder cycloaddition of 10 followed by Wittig homologation and intramolecular diene cyclozirconation of the resulting triene under equilibrating conditions led to the tricyclic 6-6-5 ketone 5 with high diastereocontrol. The derived alpha-azido ketone 16 cyclized efficiently to the heptacyclic pyrazine core of ritterazine N.

Synthetic study of tautomycin. Part 2: Synthesis of Ichihara's fragment based on regioselective enzymatic acetylation of complex molecule

Formal synthesis of tautomycin, which inhibits type 1 and type 2A protein phosphatases, was achieved. Spiroketal diol 21 was synthesized from alcohol 2 or 11 . The regioselective enzymatic acetylation of 21 with the lipase ‘Amano PS’ gave monoacetate 23 in 90% yield, which was converted into Ichihara's intermediate 31 based on Julia coupling and Wittig homologation.

Asymmetric syntheses of pectenotoxins-4 and -8, part II: synthesis of the C20-C30 and C31-C40 subunits and fragment assembly.

In the preceding communication,[1] the proposed synthesis plan identified the two principal pectenotoxin-4 subunits II and III (Figure 1). It was our intention to couple these fragments through the alkylation of the metalloenamine derived from hydrazone III, readily available from the coupling of advanced intermediates IV and V (transform T2), by epoxide II. However, this investigation revealed that the above bond construction was not feasible due to the decomposition of metalloeneamine III under the reaction conditions.[2] Accordingly, the objective in the present communication is the synthesis of the subunits IV and V, and the completion of the syntheses of pectenotoxin-4 (1) and pectenotoxin-8 by a revised fragment coupling strategy, where epoxide alkylation (transform T1) precedes diene formation (transform T2). The plan for the construction of the F-ring tetrahydrofuran IV was to involve a C37 hydroxy-directed epoxidation of olefin VI with a subsequent ring closure by the C32 hydroxy moiety (transform T3). Finally, the stereoselective formation of the E-ring tetrahydrofuran V from its acyclic precursor VII was based on an iodoetherification precedent provided by Bartlett and Rychnovsky (transform T4). The synthesis of the ring-E synthon V began with the known aldol adduct adduct 2 (Scheme 1).[4] Reduction of 2 (LiBH4, THF, 0 8C), and selective protection of the primary alcohol (TBSCl, Im, CH2Cl2, 100% over two steps) afforded allylic alcohol 3.[5] Acylation of 3 with the PMB-protected lactic acid 4[6] (DCC, DMAP, CH2Cl2, 52%), followed by carbonyl olefination of 5a with Tebbe reagent[7] afforded the 1,5-diene 5b. Claisen rearrangement of 5b in refluxing toluene gave the desired rearrangement product 6 in 82% yield for the two steps. Chelate-controlled reduction of the resulting ketone (Zn(BH4)2, Et2O, 78 8C, 86%, d.r. 86:14) provided the precursor for the key iodoetherification reaction. In spite of the modest selectivity that was observed for the formation of the desired tetrahydrofuran 7 (NIS, CH3CN, 40 8C, 89%, d.r. 72:28), this outcome proved sufficient to pursue the planned route. Successive radical dehalogenation of 7 (Bu3SnH, AIBN, toluene, 100%) and deprotection of the primary TBS ether (TBAF, THF, 95%) afforded alcohol 8. Oxidation with Dess± Martin reagent[8] (py, CH2Cl2, 99%), Wittig homologation (EtOC(O)CC(CH3)PPh3, THF, 65 8C; 100% E :Z> 95:5), and ester reduction (LiAlH4, Et2O, 0 8C, 92%) completed the carbon assembly of the E-ring fragment. Benzyl protection (NaH, BnBr, TBAI, THF/DMF, 94%) followed by PMB deprotection (DDQ, CH2Cl2/pH 7 buffer, 95%) gave alcohol 10. Oxidation to the methyl ketone[8] (Dess±Martin periodinane, py, CH2Cl2, 93%), and hydrazone formation (TMSCl, CH2Cl2/Me2NNH2, 100%) completed the synthesis of hydrazone 11. As summarized in Figure 1, the first stage of the synthesis of the ring-F fragment IV will be simplified to the construction of the C31±C35 phosphonium salt, the C36±C40 aldehyde, and their union through a Wittig coupling to afford the Zolefin VI. The synthesis of the C31±C35 phosphonium salt began with the known triol derivative 12 (Scheme 2).[9] Protection of the hydroxy group at C33 of 12 as a PMB ether (PMBBr, NaH, THF/DMF, 95%) followed by reductive ozonolysis (O3, EtOH, then DMS, then NaBH4, 95%) afforded alcohol 13. Transformation of 13 to the corresponding iodide (I2, Im, Ph3P, CH2Cl2, 0 8C, 89%) proceeded smoothly, but careful control of the temperature was required to access phosphonium salt 14 (Ph3P, CH3CN, 55 8C, 89%).[10] The synthesis of the aldehyde partner 17 began with protection of the hydroxy group at C37 of aldol adduct 15[11] as a base-sensitive triphenylsilyl ether (TPSCl, Im, DMAP, DMF, 0 8C, 98%; Scheme 2). Half reduction of the S-phenyl thioester[12] (Pd/C, Et3SiH, acetone, 95%), and olefination under modified Lombardo conditions[13] ([Cp2ZrCl2], Zn dust, CH2I2, THF, 0 8C, 84%) afforded olefin 16. RhodiumCOMMUNICATIONS

Enantioselective synthesis of the excitatory amino acid (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid.

An enantioselective synthesis of the alpha,alpha-dialkyl-alpha-amino acid (1S,3R)-ACPD has been achieved using an alkylidene carbene 1,5-CH insertion reaction as a key step. The ketone cyclization precursor was synthesized from Garner's aldehyde in high yield via a Wittig homologation and subsequent catalytic hydrogenation. Treatment of the ketone with 1.2 equiv of lithio(trimethylsilyl)diazomethane in THF resulted in the formation of the corresponding cyclopentene-containing CH-insertion product in 62-69% yield in high enantiomeric excess. Subsequent functional group manipulation allowed the synthesis of the amino acid (1S,3R)-ACPD to be completed.

A New Asymmetric Formylation of Aldehydes

Efficient asymmetric formylation of aldehydes is possible by Horner–Wittig homologation of aldehydes and subsequent Sharpless asymmetric dihydroxylation of the intermediate prochiral ketene acetals 2. As is demonstrated for compounds 1, this novel sequence allows synthesis of α-hydroxy carboxylates 3 in high enantiomeric purity.

A new stereocontrolled, pyrylium-based route to conjugated dienynes: The first synthesis of carduusyne A

A new stereocontrolled route to conjugated dienynes is described, utilising organometallic addition to pyrylium salts followed by Wittig homologation and dehydrohalogenation. The utility of this methodology is illustrated in the first total synthesis of the marine metabolite Carduusyne A.

Expedient synthesis of unsaturated amide alkaloids from Piper spp: Exploring the scope of recent methodology

The Sakai aryl aldehyde – cyclic ketone aldol – Grob fragmentation sequence was extended to cinnamaldehyde and cyclohexanone, and the product was elaborated to analogues of the alkaloid piperstachine. The effects of substituents on the reaction involving cinnamaldehyde were studied. The aldol-fragmentation sequence failed with benzaldehyde when cyclooctanone or cyclobutanone was substituted for cyclohexanone or cyclopentanone, and the reasons for this failure were examined. Four-carbon Wittig homologation of the piperonal–cyclobutanone aldol-fragmentation product, a hypothetical route to alkaloids such as retrofractamide A, was thus not viable. Instead, three-carbon homologation of the readily available piperonal–cyclopentanone product, using alkyne chemistry recently disclosed by Lu and Trost, afforded these alkaloids in excellent overall yield. The alkyne isomerization was also used to effect efficient syntheses of pellitorine and several other non-aromatic 2E,4E-dienoic Piper amide alkaloids. Key words: Piper, amides, alkaloids, insecticides, aldol, fragmentation, cinnamaldehydes, alkyne, redox, isomerization.

Synthesis of (2E,6E)‐[10‐3H]farnesol and (2E6E)‐[10‐3H]farnesal for insect dehydrogenase studies

Abstract[10‐3H]Farnesol ((2E,6E)‐3,7,11‐trimethyl‐2,6,10‐dodecatrien‐1‐ol) and [10‐3H]farnesal ((2E,6E)‐3,7,11‐trimethyl‐2,6,10‐dodecatrien‐1‐al) were synthesized by sequential reduction and oxidation of the corresponding tert‐butyldiphenylsilyl protected 11,12,13‐trisnoraldehyde, followed by Wittig homologation using isopropyltriphenylphosphorane. Direct reduction of the C‐12 allylic bromide or allylic chloride proved to be an nonviable method, resulting in either multiple decomposition products or significant double bond transposition. Oxidation of the [10‐3H]labelled trisnoralcohol with pyridinium chlorochromate resulted in essentially complete retention of the radiolabel as was established for the corresponding deuterated material. [3H]labelled farnesol and farnesal were obtained in 78% and 74% yields, respectively, from the trisnoraldehyde. These materials were used as radiotracers for examining the enzymatic activity of insect farnesol and farnesal dehydrogenase, key enzymes in the biosynthesis of juvenile hormone.

Angiogenic factors: syntheses of 12(R)- and 12(S)-hydroxyeicosa-5(Z),8(Z),14(Z)-trienoic acid and their 14,15-dehydro analogs

The title autacoids and acetylenic analogs were conveniently prepared from 2-deoxy- D-ribose via Barton deoxygenation, cuprate coupling, and Wittig homologation. 12(R)-HETrE, but not the 12(S)-isomer, significantly stimulated microvessel endothelial cell proliferation and proto-oncogene mRNA levels at sub-nano to picomolar concentrations. A high affinity binding site for 12(R)-HETrE was detected on microvessle endothelial cells.