Reinvestigation of a transmetallation synthesis of bis(cyclopentadienyl)samarium(II) and formation of a new soluble cyclopentadienylsamarium(II) compound

The transmetallation reaction between (C₅H₅)₂Hg and activated samarium metal in tetrahydrofuran (thf)/ether did not give (C₅H₅)₂Sm(thf)₂ but (C₅H₅)₃Sm(thf), whilst reduction of the last compound with potassium in thf gave KSm(C₅H₅)₃, a soluble organosamarium(II) complex.     

Chemoenzymatic synthesis of (S)-hexafluoroleucine and (S)-tetrafluoroleucine

We have developed a short chemoenzymatic synthesis for both (S)-5,5,5,5',5',5'-hexafluoroleucine (Hfl) and (S)-5,5,5',5'-tetrafluoroleucine (Qfl) on gram scale. Qfl was incorporated into a peptide using standard solid-phase peptide synthesis protocols to measure its helix propensity. The helix propensity for Qfl is 0.68 kcal.mol-1 more favorable compared to Hfl.     

Studies toward the total synthesis of tedanolide: stereoselective synthesis of the C(8)-C(17) segment

The stereoselective synthesis of the C(8)-C(17) sub-unit (−)-5 of tedanolide (1), which involves iterative Evans aldol reactions as the key steps, is described.     

Concerning the synthesis of the tedanolide C(13)-C(23) fragment via anti-aldol reaction

Synthesis of C(13)-C(23) aldehyde 4, an important intermediate in a planned total synthesis of tedanolide, is described. The stereoselectivity of the key anti-aldol reaction of aldehyde 5 and ketone 6 (en route to 4) perfectly tracks the enantiomeric purity of 5. It is demonstrated that aldehyde 24, a precursor of 5, undergoes facile epimerization during a Swern oxidation and stabilized ylide olefination sequence.     

Total synthesis of (-)-gambierol

The first total synthesis of (-)-gambierol (1), a marine polycyclic ether toxin, has been achieved. Key features of the successful synthesis include (1) a convergent union of the ABC and EFGH ring fragments (5 and 6, respectively) via our developed B-alkyl Suzuki-Miyaura cross-coupling strategy leading to the octacyclic polyether core 4 and (2) a late-stage introduction of the sensitive triene side chain by use of Pd(PPh(3))(4)/CuCl/LiCl-promoted Stille coupling. The ABC ring fragment 5 was synthesized in a linear manner (B --> AB --> ABC), wherein the A ring was formed by intramolecular hetero-Michael reaction and the C ring was constructed via 6-endo cyclization of hydroxy epoxide 7. An improved synthetic entry to the EFGH ring fragment 6 is also described, in which SmI(2)-induced reductive cyclization methodology was applied to the stereoselective construction of the F and H rings, leading to 6 with remarkable overall efficiency. Stereoselective hydroboration of 5 and subsequent Suzuki-Miyaura coupling with 6 provided endocyclic enol ether 45 in high yield, which was then converted to octacyclic polyether core 4. Careful choice of the global deprotection stage was a key element for the successful total synthesis. Functionalization of the H ring and global desilylation gave (Z)-vinyl bromide 2. Finally, cross-coupling of 2 with (Z)-vinyl stannane 3 under Corey's Pd(PPh(3))(4)/CuCl/LiCl-promoted Stille conditions completed the total synthesis of (-)-gambierol (1).     

Trimethylstannyl (diphenylphosphino)acetate: a source of (diphenylphosphino)acetate ligand in the synthesis of coordination compounds

Trimethylstannyl (diphenylphosphino)acetate (1), which is readily accessible from potassium (diphenylphosphino)acetate and trimethylstannyl chloride, may serve as the source of (diphenylphosphino)acetate anion in the preparation of coordination compounds. Thus, the reactions between [M(cod)Cl₂] (M = Pd and Pt; cod = η²:η²-cycloocta-1,5-diene) and two equivalents of 1 give [M(Ph₂PCH₂CO₂-κ²O,P)₂] (2 and 3), while the reaction of [{Pd(μ-Cl)Cl(PFur₃)}₂] (4; Fur = 2-furyl) with one equivalent of 1 yields [SP-4-3]-[PdCl(Ph₂PCH₂CO₂-κ²O,P)(PFur₃)] (5). The reactions of 1 with the dimers [{Rh(η⁵-C₅Me₅)Cl(μ-Cl)}₂] and [{Ru(η⁶-1,4-MeC₆H₄(CHMe₂))Cl(μ-Cl)}₂] (at 1-to-metal ratio 1:1) produce O,P-chelated complexes as well, albeit as stable adducts with the liberated Me₃SnCl: [RhCl(η⁵-C₅Me₅)(Ph₂PCH₂CO₂-κ²O,P)] · Me₃SnCl (6) and[RuCl(η⁶-1,4-MeC₆H₄(CHMe₂))(Ph₂PCH₂CO₂-κ²O,P)] · Me₃SnCl (8). The related complexes with P-monodentate (diphenylphosphino)acetic acid, [RhCl₂(η⁵-C₅Me₅)(Ph₂PCH₂CO₂H-κ,P)] (7) and [RuCl₂(η⁶-1,4-MeC₆H₄(CHMe₂))(Ph₂PCH₂CO₂H-κP)] (9), were obtained by bridge splitting in the dimers with the phosphinocarboxylic ligand. All new compounds were characterized by spectral methods and combustion analyses, and the structures of 2 · 3CH₂Cl₂, 3, 4, 5, 6 and 8 were determined by X-ray crystallography.     

Short synthesis of (-)-cephalotaxine using a radical cascade

The short total synthesis of (-)-cephalotaxine is described. The concise construction of the pentacyclic core of this alkaloid was achieved by a radical cascade involving 7-endo and 5-endo cyclizations.     

Enantioselective synthesis of the key intermediate of the acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor (R-106578) using 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP)-Ru(OAc)2 as a catalyst

Acidic segment of an acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor, R-106578 was synthesized by enantioselective hydrogenation of the Z-olefine (9-(Z)) using (R)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP)-Ru(OAc)2 as a catalyst in methanol at 100 degrees C, 5 kgf/cm2 of H2 pressure. The requisite Z-olefine was prepared regioselectively via coumarin derivative (5).     

The synthesis of poly(hydroxamic acid) from poly(acrylamide)

Poly(hydroxamic acid) in gel or water soluble from was prepared from the reaction of poly(acrylamide) and hydroxylamine in basic aqueous solution (pH > 12) at room temperature. The polymers were composed of 70% hydroxamic acid groups, less than 5% carboxylic acid groups, and 25% unreacted amide groups. The polymers exhibited high affinity to iron(III) and copper(II) in the pH range of 1 to 5 with a high binding rate. A binding of 3 mmol/g for both metals was achieved. Preliminary tests demonstrated the urease inhibitory activity of both linear and crosslinked poly(hydroxamic acids).     

Studies on the total synthesis of sanglifehrin A: stereoselective synthesis of the C(29)-C(39) fragment

A highly stereoselective synthesis of the C(29)-C(39) fragment of the potent immunosuppressant sanglifehrin A has been accomplished by a sequence involving 16 steps (18% overall yield) from N-propionyloxazolidinone 9. Key steps are a diastereoselective hydroboration, and a diastereoselective epoxidation of an allylic alcohol followed by a 1,5-anti boron-mediated aldol reaction of methyl ketone 4 with chiral aldehyde 5.     

Total synthesis of (-)-cocaine and (-)-ferruginine

Total synthesis of tropane alkaloids (-)-cocaine and (-)-ferruginine were accomplished in nine steps each and in 55% and 46% overall yields, respectively, starting from the known Betti base derivative (+)-(7aR,10R,12S)-10-(1H-benzotriazol-1-yl)-7a,8,9,10-tetrahydro-12-phenyl-12H-naphtho[1,2-e]pyrrolo[2,1-b][1,3]oxazine. In this novel route, RCM reaction and 1,3-dipolar cycloaddition were employed as key steps for the enantioselective construction of tropane skeleton and the regioselective introduction of 3-bromo-2-isoxazoline ring as masked cis-2,3-disubstituents. To obtain the desired precursor (2S,5R)-2-allyl-5-vinylpyrrolidine for RCM reaction, we developed a general and practical method for the preparation of enantiopure cis-2,5-disubstituted pyrrolidines bearing alkene- and/or alkyne-containing substituents. We also offered two highly efficient pathways for the conversion of the 3-bromo-2-isoxazoline ring into the desired cis-2,3-disubstituted groups in (-)-cocaine and (-)-ferruginine.     

Photochemical synthesis of the cyanodiacetylene HC(5)N: a cryogenic matrix experiment

The reactivity of intermolecular complexes cyanoacetylene:acetylene and dicyanoacetylene:acetylene, trapped in solid argon matrixes at 10 K and irradiated with vacuum UV, has been studied. FTIR measurements, together with (2)H, (15)N, (13)C labeling experiments and with density functional theory (DFT) calculations (B3LYP/aug-cc-pVTZ), pointed to the formation of cyanodiacetylene HC(5)N (cyanobutadiyne). This synthetic route is potentially important for chemical models of the Titan's atmosphere.     

Ionic-liquid-supported peptide synthesis demonstrated by the synthesis of Leu(5)-enkephalin

A new strategy for the synthesis of oligopeptides was developed using an ionic liquid as a soluble support. The efficiency of this ionic liquid-phase approach was demonstrated by the synthesis of a bioactive pentapeptide, Leu(5)-enkephalin, in good yield and reasonable purity. The structures and purities of the reaction intermediates in each step were verified easily by routine spectroscopic analysis, and no chromatographic procedures were needed during the synthesis.     

Expeditious asymmetric synthesis of a stereoheptad corresponding to the C(19)-C(27)-ansa chain of rifamycins: formal total synthesis of Rifamycin S

In the presence of sulfur dioxide and an acid promoter, (-)-(1E,3Z)-2-methyl-1-((1S)-1-phenylethoxy)penta-1,3-dien-3-yl isobutyrate reacts with (Z)-3-(trimethylsilyloxy)pent-2-ene giving a silyl sulfinate intermediate that undergoes, in the presence of palladium catalyst, a desilylation and retro-ene elimination of SO(2) with formation of (-)-(1Z,2S,3R,4S)-1-ethylidene-2,4-dimethyl-5-oxo-3-((1S)-1-phenylethoxy)-heptyl isobutyrate as major product. This ethyl ketone undergoes cross-aldol reaction with (2S)-2-methyl-3-[(tert-butyldimethylsilyl)oxy]propanal giving an aldol that is reduced into a stereoheptad corresponding to the C(19)-C(27)-segment of Rifamycins with high diastereoselectivity and enantiomeric excess.     

On the synthesis of ammonium xenon(VI) hexafluoromanganate(IV)

The reaction between NH₄MnF₃ and xenon hexafluoride yields ammonium xenon(VI) hexafluoromanganate(IV). The persistance of the NH⁺₄ in the environment of the XeF₆, during the synthesis of the salt, can be attributed to the positive charge because XeF₆ is electrophylic and will oxidize neutral or negatively charged species but not cations. Ammonium xenon(VI) hexafluoromanganate(IV) was characterized by chemical analysis, magnetic susceptibility measurements, thermogravimetric studies and vibrational spectroscopy. The spectroscopic evidence supports the formulation NH⁺₄XeF⁺₅MnF²₆^?.     

Formal synthesis of (±)-perhydrohistrionicotoxin

The syntheses of 1-benzyl-7-butyl-1-azaspirocyclo[5.5]undec-7-ene (14) [a formal precursor of perhydrohistrionicotoxin (2)] and the thermodynamically preferred, exocyclic isomer (13) in six steps from the readily available $\text{N}$-benzyloxycarbonyl-10-amino-Δ^1,9-octalin (5) are reported.     

Total synthesis of (-)-stemoamide

A stereocontrolled total synthesis of (-)-stemoamide (1) is presented. The synthesis starts from commercially available (S)-pyroglutaminol (4). A chemoselective iodoboration of 5 was used to access key intermediate 3. The beta,gamma-unsaturated azepine derivative 2 was obtained via a Pd(0)-catalyzed sp(2)-sp(3) Negishi cross-coupling using a Reformatsky nucleophile followed by a ring-closing metathesis reaction. The required C8-C9 trans-stereochemistry of 1 was accessed through a stereoselective bromolactonization/1,4-reduction sequence.     

Asymmetric synthesis of the putative structure of (-)-oryzoxymycin

[reaction: see text] A short asymmetric synthesis of (2'S,5R,6R)-2'-[6-amino-5-hydroxy-1,3-cyclohexadiene-1-carbonyloxy]propionic acid, the enantiomer of the reported structure of (+)-oryzoxymycin is described. The reported spectral data does not match that obtained for synthetic "oryzoxymycin".     

Regioselective synthesis of (±)-gabaculine hydrochloride

3- Cyclohexenecarboxylic acid (2) has been functionalized to the protected amino acid 5 in a novel reaction sequence, the crucial step being the acid catalysed cyclization of the γ, δ-unsaturated isocyanate 3 to the bicyclic lactam 4. 5 was converted into gabaculine hydrochloride (1 · HCl).