Highly stereocontrolled and regiocontrolled syntheses of 2,3,4-trisubstituted alkanoates and lactones

New chlorodiols (±)-3 and (±)-5 are densely functionalized and versatile synthons. They are converted in one step on a gram scale into 2-chlorolactones (±)-6 and (±)-7 and into 4-hydroxy glycidate esters (±)-9 and (±)-10. The 4-hydroxy glycidate esters (±)-9 and (±)-10 are converted stereospecifically and regiospecifically into oxazolines (±)-13 and (±)-14 and into cyclic carbamates (±)-18-(±)-20. The 4-hydroxy glycidate ester (±)-10 undergoes stereocontrolled and regiocontrolled epoxide opening by sodium azide to form the 2-azido-3,4-dihydroxy alkanoate (±)-21. Finally, chlorodiol (±)-5 reacts stereospecifically with silver triflate to form the 2,3-dihydroxyfuranone (±)-26.     

Highly stereocontrolled and regiocontrolled syntheses of polyoxygenated [2.2.2]oxabicyclic synthons

Highly oxygenated cyclohexanes (known as cyclitols or carba-sugars) were synthesized regiospecifically and stereoselectively via a key inverse electron demand Diels–Alder cycloaddition of electron poor 2-pyrones with electron rich tert-butyldimethylsilyl vinyl ether. The resulting [2.2.2]oxabicyclic lactones proved to be versatile synthons; syn-dihydroxylations were achieved with very high stereocontrol, with up to five stereocenters being produced from commercially available or easily prepared planar starting materials.     

Synthesis of benzothiophene derivatives by Pd-catalyzed or radical-promoted heterocyclodehydration of 1-(2-mercaptophenyl)-2-yn-1-ols

Novel and convenient approaches to benzothiophene derivatives 3 and 5 have been developed, based on heterocyclization reactions of 1-(2-mercaptophenyl)-2-yn-1-ols 2 or 4, respectively, readily available from alkynylation of 2-mercaptobenzaldehydes or 1-(2-mercaptophenyl) ketones 1. In particular, 1-(2-mercaptophenyl)-2-yn-1-ols 2, bearing a CH(2)R substituent on the triple bond (R = alkyl, aryl), were conveniently converted in fair to good yields (55-82%) into (E)-2-(1-alkenyl)benzothiophenes 3 when allowed to react in the presence of catalytic amounts (2 mol %) of PdI(2) in conjunction with KI (KI:PdI(2) molar ratio =10) at 80-100 °C in MeCN as the solvent, through a heterocyclodehydration process. On the other hand, 2-alkoxymethylbenzothiophenes 5 were selectively obtained in fair to excellent yields (49-98%) via a radical-promoted substitutive heterocyclodehydration process, by reacting 1-(2-mercaptophenyl)-2-yn-1-ols 4 (bearing an alkyl or aryl substituent on the triple bond) in alcoholic media at 80-100 °C in the presence of a radical initiator, such as AIBN.     

Efficient and selective syntheses of (all-E)- and (6E,10Z)-2'-O-methylmyxalamides D via Pd-catalyzed alkenylation--carbonyl olefination synergy

Highly efficient and selective syntheses of both (all- E) and (6 E,10 Z)-isomers of 2'- O-methylmyxalamide D ( 2 and 3), in which the crucial conjugated pentaene moieties were assembled in > or =98% stereoselectivity through the use of two Pd-catalyzed alkenylation reactions, the Horner-Wadsworth-Emmons (HWE) olefination, and either the Corey-Schlessinger-Mills modified (CSM-modified) Peterson olefination for 2 or the Still-Gennari olefination for 3, are reported. Either 2 or 3 was prepared in 16% yield in seven steps from propargyl alcohol.     

Highly stereocontrolled synthesis of (2e,4z)-dienic esters by alumina catalyst

Thermal treatment of β-allenic esters ($\text{2}$) with alumina catalyst in aprotic solvents yielded (2E,4Z)-dienoic esters ($\text{3}$) in 57-58% yield with 91-100% stereoselectivity.     

Pd-catalyzed synthesis of 3-(diarylmethylene)-2-oxindoles and 3-(arylmethylene)-2-oxindoles

An efficient method for the stereoselective synthesis of 3-(diarylmethylene)-2-oxindoles and 3-(arylmethylene)-2-oxindoles via carbopalladation is described. In this approach, an Ugi-4-component reaction (4-CR) adduct was used as the starting material. A one-pot sequence involving intermolecular carbopalladation C-H activation/C-C bond formation efficiently afforded the oxindole derivatives.     

Highly stereoselective synthesis of (Z)-1,2-dihaloalkenes by a Pd-catalyzed hydrohalogenation of alkynyl halides

An unprecedented Pd-catalyzed hydrohalogenation of alkynyl halides for the regio- and stereoselective synthesis of (Z)-1,2-dihaloalkenes has been realized using [(allyl)PdCl](2) as the catalyst and cis,cis-1,5-cyclooctadiene as the ligand. The advantages of this protocol are well illustrated by the assembly of trisubstituted (Z)-enynes and multifunctional benzenes via iterative cross-coupling reactions or tandem Diels-Alder-aromatization reactions, respectively.     

A useful preparation of 5-nitro-2-furan derivatives

Alkyl-(5-bromo-2-furyl) carbinols 1 are converted with good yields into the corresponding 5-nitro derivatives 2 by reaction with silver nitrite. Furthermore, the singular reactivity of pyridinium chlorochromate towards products 2 results in high yields of (5-nitro-2-furyl) alkyl ketones 3 with a long side chain.     

Naturally-occurring acetylenic compounds and derivatives : Regio- and stereocontrolled chloroformylation of 2-(1-propynyl)thiophene and 2-phenyl-5-(1-propynyl)thiophene

2-Phenyl-5-(1-propynyl)thiophene (1), isolated from Coreopsis grandiflora, and 2-(1-propynyl)thiophene (5), an immediate precursor in the synthesis of junipal (2), were synthesized in high yield by a Pd-catalyzed reaction between propyne and 2-iodo-5-phenylthiophene (4) or 2-iodothiophene (6), respectively. Reaction of 5 with the Vilsmeier reagent derived from POCl₃ and N-methylformanilide (MFA) afforded a mixture from which it was possible to isolate (E)-3-chloro-2-methyl-3-(2-thienyl)acrolein (10) in 37.7% yield. The structure and stereochemistry of 10 was unequivocally established by X-ray diffraction of a single crystal of the 2,4-dinitrophenylhydrazone of 10. GLC analysis showed that 10 was contaminated by ca 7% with an isomer to which, on the basis of ¹H-NMR and mass spectra, the structure of (Z)-3-chloro-2-methyl-3-(2-thienyl)acrolein (11) was attributed.Contrary to what was expected from the literature, junipal (2) represented only a minor component in the reaction mixture obtained by the Vilsmeier reaction on 5.Reaction of 1 with POCl₃ and MFA afforded (44.6% yield) a (E)-3-chloro-2-methylacrolein to which the structure 15 was attributed. Compound 15 was also contaminated by ca 10% of an isomer 16, which very probably corresponded to the (Z)-stereoisomer of 15.     

The indenobenzazepine-spirobenzylisoquinoline rearrangement; stereocontrolled syntheses of (±)-raddeanine and (±)-yenhusomine

Stereoselective rearrangement of indenobenzazepine cis ketols $\text{2}$ and $\text{5}$ with TPAA in pyridine produces spirobenzylisoquinolines $\text{3}$ and $\text{6}$, respectively. The latter product is also obtained by rearrangement of trans ketol $\text{7}$. The transformation of ketols $\text{5}$ and $\text{7}$ must, therefore, proceed through the intermediacy of aziridinium cation $\text{9}$. A similar process obtains in the transformation of $\text{2}$ to $\text{3}$. NaBH₄ reduction of $\text{3}$ gives (±)-raddeanine ($\text{4}$). Rearrangement of diol $\text{10}$ supplies $\text{4}$ directly. (±)-Yenhusomine ($\text{13}$) is obtained from the reamangement of either diol, $\text{11}$ or $\text{12}$. In like fashion, diols $\text{14}$ and $\text{15}$ supply spirobenzylisoquinoline $\text{17}$.     

Practical and stereocontrolled syntheses of both (1R,3S)- and (1R,3R)-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylates

The title compounds of (1R*,3S*) configuration were prepared from 3-formyl-2,2-dimethyl-cyclopropanecarboxylate by addition of CF₃CCl₂ZnCl, acetylation, and reductive β-elimination with zinc, whereas the (1R*,3R*) isomer was derived from Me₂C=CHCH(OH)CCl₂CF₃ by diazoacetylatlon. Cu(II) catalyzed intramolecular cyclization, and the zinc reduction.     

Highly selective cascade couplings for the syntheses of functionalized piperidinones and bispidines

Efficient cascade couplings to synthesize functionalized piperidinones 1 and bispidines 2 and 3 have been developed. Simple modifications to the reaction conditions allow for the highly controlled and selective formation of each compound. In addition, the cis isomer of 1 can be selectively obtained under acidic conditions, while the preparation of the corresponding trans isomer can also be readily realized through a base-catalyzed, dynamic crystallization-driven process.     

Highly functionalized benzene syntheses by directed mono or multiple magnesiations with TMPMgCl.LiCl

The direct magnesiation of highly functionalized aromatics bearing an ester, a nitrile, or a ketone can be readily performed by using an OBoc as a directing group and TMPMgCl.LiCl as a base. It allows, for example, the preparation of a meta-magnesiated benzophenone in >95%. After quenching, highly functionalized and substituted benzenes are obtained. [reaction: see text].     

Diversity-oriented synthesis of functionalized quinolin-2(1H)-ones via Pd-catalyzed site-selective cross-coupling reactions

Biologically active 3-amino-4-arylquinolin-2(1H)-ones and 3-alkenyl-4-arylquinolin-2(1H)-ones were synthesized in an efficient and concise manner, utilizing readily available 4-hydroxyquinolin-2(1H)-one as starting material. The key steps, which introduced selectivity and diversity in the synthesis, were the palladium-catalyzed site-selective Suzuki-Miyaura/Buchwald-Hartwig amination and Suzuki-Miyaura/Heck coupling reactions of 3-bromo-4-trifloxy-quinolin-2(1H)-one.     

Highly functionalized dihydrofuran derivatives: Synthesis by diastereoselective intramolecular Wittig reaction

3a,8a‐Dihydroxy‐1,3,3a,8a‐tetrahydro‐ indeno[1,2‐d]imidazole‐2,8‐dione 3 reacts with dialkyl acetylenedicarboxylates in the presence of triphenylphosphine to produce some novel interesting dihydrofuran derivatives diastereoselectively. © 2006 Wiley Periodicals, Inc. Heteroatom Chem 17:277–279, 2006; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20202     

Highly regioselective Pd-catalyzed allylic alkylation of fluorobis(phenylsulfonyl)methane

A highly regioselective palladium-catalyzed allylic alkylation of fluorobis(phenylsulfonyl)methane has been studied. Using different allylic carbonates, a variety of terminal mono-fluoromethylated compounds were achieved in 85-99% yields with high regioselectivities.     

Application of the intramolecular magnesium-ene reaction to the stereocontrolled total syntheses of (±)-12-acetoxysinularene and (±)-5-epi-12-acetoxysinularene

The sesquiterpene (±)-12-acetoxysinularene (1) and its C(5)-epimer (13) were each synthesized stereoselectively from the norbornyl-iodoacetal 7 in 5% and 7% overall yields. The critical step (10) → (11) involves the regio- and stereoselective “magnesium-ene” reaction (6) → (5).     

The syntheses of pteridin-2-one derivatives from diaminomaleonitrile (DAMN)

1,3-Dimethyl-4-iminopteridin-2-one, 1,3-dimethylpteridine-2,4-dione, 1-methylpteridine-2,4-dione, 4-alkoxy-1-methylpteridin-2-one, and 4-alkylamino-1-methylpteridin-2-one were synthesized from diaminomaleonitrile (DAMN) through pyrazine-2,3-dicarbonitrile. The synthetic procedures consist of the condensation of DAMN with glyoxal, the nucleophilic substitution of pyrazine-2,3-dicarbonitrile with methylamine, the reaction of 3-methylaminopyrazine-2-carbonitrile with electrophiles such as methyl isocyanate and methyl chloroformate in the presence of sodium hydride, and the transformation of 3-(methoxycarbonylmethyl)aminopyrazine-2-carbonitrile into the pteridine derivatives.