Stereocontrolled asymmetric synthesis of syn-E-1,4-diol-2-enes using allyl boronates and its application in the total synthesis of solandelactone F

The solandelactones A-H comprise a novel class of oxygenated fatty acids bearing an eight-membered lactone, trans cyclopropane, and a 2-ene-1,4-diol subunit. The relative stereochemistry of the 1,4-diol subunit is anti in solandelactones A, C, E & G, and syn in solandelactones B, D, F & H. Having prepared one member of the solandelactones bearing anti stereochemistry (solandelactone E), we have targeted the syn series and developed methodology for the synthesis of enantioenriched syn-2-ene-1,4-diols. The methodology comprises asymmetric deprotonation of an alkyl 2,4,6-triisopropylbenzoate using sBuLi/sparteine, followed by addition of the α-lithiobenzoate to β-silyl vinyl boronic acid ethylene glycol ester. The boron-ate complex generated undergoes a 1,2-metallate rearrangement furnishing an intermediate allyl boronic ester which is trapped by an aldehyde in the presence of MgBr(2) to furnish anti-β-hydroxy E-allylsilanes in good yields, high diastereoselectivity and high enantioselectivity. These sensitive products were oxidized using mCPBA to the corresponding epoxides and subsequently treated with acid to furnish syn-E-2-ene-1,4-diols (~4:1 d.r.). Application of the methodology to appropriately functionalized aldehyde and ω-alkenyl 2,4,6-triisopropylbenzoate coupling partners, led to a short, highly selective route to solandelactone F (bearing a syn-E-2-ene-1,4-diol).     

The Synthesis of β,γ- and α,β-Unsaturated Aldehydes via Polyene Epoxides

A substitute for the Darzens glycidic ester synthesis for converting unsaturated ketones or aldehydes into the homologated β,γ- or α,β-unsaturated aldehydes employing sulfur ylides is described. The carbonyl group is converted into the unsaturated oxirane which is then rearranged to the new aldehyde. High yields of isomerically pure aldehydes are available by this method and the process is of practical importance in the conversion of β-ionone into the β-C₁₄-aldehyde, a key intermediate in the Isler synthesis of vitamin A. The efficient preparation of α- and β-cyclocitral by the novel process is also described.     

2,3‐Diaryl‐3‐hydroxy­propionic acid inter­mediates in the synthesis of threo forms of 1,2‐diaryl‐1,3‐propane­diols

Racemic threo‐3‐hydroxy‐2,3‐diphenyl­propionic acid, C₁₅H₁₄O₃, (I), crystallizes from ethyl acetate as a conglomerate of separate (+)‐ and (−)‐crystals. The geometries of (I) and its methyl ester are compared. Reduction of (I) gives threo‐1,2‐diphenyl‐1,3‐propane­diol. The synthesis of threo forms of 1,2‐diaryl‐1,3‐propane­diols via 2,3‐diaryl‐3‐hydroxy­propionic acids is discussed.     

Development of Chiral Spiro Phosphoramidites for Rhodium-Catalyzed Enantioselective Reactions

A series of 1,1′-spirobiindane-7,7′-diol ( SPINOL ) analogues bearing a 2,2′-dimethyl-, cyclopentyl-, or cyclohexyl-fused ring were synthesized, and their distinct structural features were elucidated by X-ray crystallography. On the basis of these scaffolds, chiral monophosphoramidite ligands 6 a – m were synthesized, which demonstrated excellent enantioselectivity in Rh^I-catalyzed asymmetric hydrogenation of a dehydro amino acid methyl ester. Ligands 6 a – m were also successfully applied in the Rh^I-catalyzed enantioselective [4+2] cycloaddition of α,β-unsaturated imines with isocyanates, which afforded the corresponding pyrimidinones in good yields (60–92 %) with high enantioselectivities (75–92 % ee).     

N-Boc-Protected α-Amino Acids by 1,3-Migratory Nitrene C(sp3)−H Insertion

N-Boc-protected α-amino acids are synthesized in two steps from linear or branched carboxylic acid feedstocks. In the first step, the carboxylic acid is coupled with tert-butyl aminocarbonate (BocNHOH) to generate azanyl ester (acyloxycarbamate) RCO₂NHBoc. In the second step, this azanyl ester undergoes a stereocontrolled iron-catalyzed 1,3-nitrogen migration to generate the N-Boc-protected non-racemic α-amino acid. This straightforward protocol is applicable to the catalytic asymmetric synthesis of α-monosubstituted α-amino acids with aryl, alkenyl, and alkyl side chains. Furthermore, α,α-disubstituted α-amino acids are accessible in an enantioconvergent fashion from racemic carboxylic acids. The new method is also advantageous for the synthesis of α-deuterated α-amino acids. N-Boc-protected α-amino acids synthesized using this two-step protocol are ready-to-use building blocks.     

Synthese von endo- und exo-1,3-Dimethyl-2,9-dioxa-bicyclo[3.3.1]nonan

Synthesis of endo- and exo-1,3-dimethyl-2,9-dioxabicyclo[3.3.1]nonane The synthesis of a host-specific substance in norway spruce infested by Trypodendron lineatum OLIV . is described (cf. scheme 1 and 2). Alkylation of the acetyl-acetone di-anion (II) with 3-methyl-3-buten-1-yl-bromide (I) followed by sodium boro-hydride reduction yields erythro- and threo-8-methyl-8-nonen-2,4-diol (IV and V) which are separated by chromatography. Their configurations were established by converting them under equilibrium conditions into one (VI) or two (VII and VIII) benzal derivatives. Oxidative cleavage with ozone of the terminal double bond in the erythro diol IV produces a dihydroxy ketone IX which spontaneously cyclizes to endo-1,3-dimethyl-2,9-dioxa-bicyclo[3.3.1]nonane (X). The threo diol V is converted by the same reaction sequence exclusively into exo-1,3-dimethyl-2,9-dioxa-bicyclo-[3.3.1]nonane (XII). Comparison of the NMR. data of the two acetals X and XII with that of the natural product establishes the endo configuration of the latter. A second, more convenient, synthesis of a mixture of the acetals X and XII starting from the bromo-acetal XIII is also reported.     

An Easy Entry to (1S, 2S) and (1R, 2R)-Threo-Ifenprodil

A facile and practical synthesis of enantiomerically pure (L) or (D)-threo-Ifenprodil was accomplished from (1S, 2S)- and (1R, 2R)-threo-1-(p-nitrophenyl)-2-amino-propan-1, 3-diol via 3-phenylthio derivatives followed by Raney nickel reduction and conversion of the aromatic amine into phenol.     

Stereoselective total synthesis of (+)-sapinofuranone B

Two approaches for the total synthesis of (+)-sapinofuranone B have been described. The first strategy utilizes the methodology developed earlier in our group to get the chiral propargyl alcohol and the second strategy involves generation of threo-1,2-diol derivative by diastereoselective and enantioselective addition of [(Z)-γ-methoxymethoxyallyl]diisopinocampheylborane onto aldehyde and cross metathesis as the key steps.     

Neue Antipodenpaare zur optischen Spaltung recemischer Basen

As new reagents for optical resolution of racemic bases the enantiomorphs of N-(1-phenyl-ethyl)-succinamic acid (I) and N-(1-phenyl-ethyl)-phthalamic acid (II) have been prepared. Optical resolution with I of (1-phenyl-ethyl)-amine, 2-amino-butane-1-ol, threo-1-(4-nitrophenyl)-2-amino-propane-1, 3-diol and with II of 1-phenyl-2-amino-propane is described.     

A Concise Enantioselective Pathway to Carbocyclic Nucleoside: Asymmetric Synthesis of Carbocyclic Moiety of Carbovir

(-)-Trans-4-t-butyldimethylsilyloxymethyl-2-cyclopentenol (13), a key intermediate for the synthesis of (-)-carbovir (15), was synthesized by using enantioselective bicyclic ring construction of chiral α-diazo-β-keto ester 3 catalyzed by rhodium (II) acetate.     

Proline derivatives incorporating hydrophobic long-chain derived from natural and synthetic fatty acids

The α-hydrophobic long chain-α-amino esters are prepared by α-hydroxylation of a series of fatty acid esters [derived from oleic acid (OA), linoleic acid (LA), arachidonic acid (ARA) and docosahexaenoic acid (DHA)] followed by Mitsunobu reaction and hydrazinolysis of the phthalimide. These amino esters are mixed with aldehydes and electrophilic alkenes to give very good chemical yields and diastereoselectivities of prolinate derivatives incorporating a hydrophobic long chain at the α-position. This multicomponent 1,3-dipolar cycloaddition (1,3-DC) takes place at room temperature. The synthesis of the homologue hydrophobic chain of OA is performed by its oxidation to aldehyde/racemic N-tert-butylsulfinyl imine/Neff reaction. Final 1,3-DC with benzaldehyde and N-methylmaleimide affords homologue prolinate derivative in good yield.     

Syntheses of 4, 5-Di-O-bexzyl-2-deoxy-2-C-methyl L-lyxose and Methyl 4, 5-Di-O-bexzyl-2-deoxy-2-C-methyl-3-O-metkyl-L-lyxonate

The title compounds, which possess C-methyl groups at the α-position of carbonyl groups and vicinal hydroxyl groups with syn (three) relationship, were synthesized efficiently from known 3-decxy-1, 2-O-isopropylidene-3-C-methyl-α-D-allofuranose. The synthetic routes involve: 1) inversion of C-5 configuration of the starting sugar, 2) suitable protection of the 5, 6-diol, and 3) glycol cleavage of the 1, 2-diol to an aldehyde or direct oxidation of the diol to carboxylic acid.     

A synthesis of optically active α-quaternary α-amino acids and esters by assembling three components, ketones, (R)-chloromethyl p-tolyl sulfoxide, and sodium azide, via sulfinyloxiranes

Treatment of lithium α-sulfinyl carbanion of chloromethyl p-tolyl sulfoxides with ketones at low temperature afforded adducts in almost quantitative yields, which were exposed to t-BuOK to give sulfinyloxiranes in high yields. The sulfinyloxirane was reacted with benzylamine to give α-amino aldehyde, which was oxidized with iodine in methanol to afford α-amino carboxylic ester in moderate yield. The sulfinyloxiranes were treated with sodium azide to afford α-azido aldehydes in good yields. Oxidation with NaClO₂ followed by catalytic hydrogenation of the azido group of the α-azido aldehydes gave α-quaternary α-amino acids in good overall yields. The oxidation of the azido aldehydes with iodine in methanol in the presence of KOH followed by the catalytic hydrogenation resulted in α-quaternary α-amino acid methyl esters in good yields. When these reactions were carried out starting from unsymmetrical ketones and optically pure (R)-chloromethyl p-tolyl sulfoxide, a new method for a synthesis of optically active α-quaternary α-amino acids and esters in good overall yields was realized.     

Synthesis of nonactin (author's transl)]

Synthesis of Nonactin. The macrotetrolide antibiotic nonactin (I), containing four units of a C₁₀ hydroxy acid, has been synthesized starting from two adequately protected derivatives (III and IV) of nonactic acid (II). The 32-membered ring of the macrotetrolide is built up by a sequence of condensation and deprotection steps leading first to a product with two, and subsequently to one with four nonactic acid residues (VIII) which is then cyclized in the presence of Ag⁺-ions. Two reactions forming ester bonds have been developed to condense the hydroxy acids and to effect the final cyclization. In one the activation of the carboxyl group is achieved by conversion into the mixed anhydride with 2,4,6-trimethylbenzene sulfonyl chloride in pyridine. In the other the Ag⁺-ion induced reaction of a S-(2-pyridyl) hydroxy carbothioate is used to form the corresponding macrocyclic lactone. In the case of nonactin the ring closure is promoted by the coordinating effect of Ag⁺-ions present in the reaction mixture.     

Synthesis of 1,2-Dihydropyridines, 2,3-Dihydro-4(1H)-pyridinone,and 1,2,3,4-Tetrahydropyridines via N-Acyl N,O-Hemiacetal Formation

New procedures are described for the synthesis of α,β-ethylenic and acetylenic aldehydes from 2-butene- and 2-butyne-1,4-diol, respectively (see Scheme 1). These are applied to the preparation of a particular δ-acetylamino-α,β-ethylenic aldehyde ((E)- 5 ) as well as of its acetylenic analogue 15 . On heating in the presence of a silyl enol ether, the former undergoes a complete dehydrative cyclization affording the N-acetyl-1,2-dihydropyridine 19 . The addition of HCl to aldehyde (E)- 5 results in the production of the 4-chloro-1,2,3,4-tetrahydropyridine 22 which is hydrolyzed to the corresponding alcohol 23 on silica gel. Similarly, the addition of HCl or HBr to the δ-acetyl-amino-α,β-acetylenic aldehyde 15 leads to the previously unknown 4-halo-1,2-dihydropyridines 26 ; these are easily hydrolyzed to the 2,3-dihydro-4(1H)-pyridinone 27 . The ring-forming process involves a N-acyl N,O-hemiacetal as intermediate which is eventually dehydrated.     

Toward carboxylate group functionalized A4, A2B2, A3B oxaporphyrins and zinc complex of oxaporphyrins

Series of new oxaporphyrins were isolated from the reaction of furan-1,4-diol, pyrrole, and an aldehyde under Lindsey’s conditions, which gives easy access to ester group functionalized oxaporphyrins. The ester substituents can be readily hydrolyzed to terminal carboxylic acid in the presence of KOH. The Zn(II) oxaporphyrins have been synthesized from the reaction of free base with ZnCl₂ and fully characterized by variable temperature NMR, 2D NMR, and single crystal X-ray diffraction studies.     

Total synthesis of 3,4-dihydroxyprolines, -threo- -norvaline and (2S,3R,4R)-2-amino-3,4-dihydroxytetrahydrofuran-2-carboxylic acid methyl ester

The Henry reaction between -glyceraldehyde and ethyl nitroacetate allowed the practical development of a diastereoselective synthesis of 3,4,5-trihydroxy-2-nitropentanoic acid esters, which were reduced to polyoxamic acids, which were used in a new diastereoselective synthesis of 3,4-dihydroxyprolines and new enantioselective syntheses of -threo- -norvaline and (2S,3R,4R)-2-amino-3,4-dihydroxytetrahydrofuran-2-carboxylic acid methyl ester.     

A “one-pot” synthesis of α-(p-toluenesulfonyl)-aminobenzylphosphinodipeptide derivatives containing a P?N bond

With acetyl chloride as the solvent, the condensation reaction of p-toluenesulfonamide, an aromatic aldehyde and phenyldichlorophosphine given a reactive intermediate, α-(p-toluenesulfonyl)-aminobenzylphosphinic chloride, which reacts with glycine ethyl ester to give the corresponding phosphinopeptide (6) containing a P? N bond directly.     

Notiz über die Bestimmung der absoluten Konfiguration von (+)-2-Hydroxy-2, 3-dimethylbuttersäure

Note on the Determination of the Absolute Configuration of (+)-2-Hydroxy-2, 3-dimethylbutyric Acid Chemical correlation of the title compound 1 with (S)-3-isopropyl-3-methyl-5-trimethylsilyl-4-penten-2-one ( 2 ) showed (+)- 1 to have (S)-configuration. Key step was the Baeyer-Villiger oxidation of a very hindered, optically active methyl keton to the corresponding acetoxy compound with trifluoroperacetic acid using slightly modified buffer conditions. It is found, that the erythro/threo assignment of an α, α-disubstituted β-hydroxyester intermediate can be based on the observation, that the ¹H-NMR. signal of H? C(β) of the erythro isomer appears at lower field than that of the threo isomer.     

Studies Directed Towards the Biosynthesis of the C7N Unit of Rifamycin B: A New Synthesis of Quinic Acid from Shikimic Acid

The synthesis of quinic acid ( 4 ) via epoxide 13 , starting from shikimic acid ( 5 ), is described (Scheme 1). Treatment of 13 with thiophenol yielded not only 17 , but also the γ-lactones 18 and 19 as result of migration of silyl groups within a cis- and trans-diol system. The conversion provides a direct stereoselective epoxidation of a shikimic-acid derivative as well as an alternative pathway for the preparation of 4 . A shorter approach via the disilylated epoxide 22 was unsuccessful because the γ-lactone 25 was obtained in place of the desired α-hydroxy ester 24 (Scheme 2).