C-2/c-3 annulation and C-2 alkylation of indoles with 2-alkoxycyclopropanoate esters

The annulation reaction between various indoles and 2-alkoxycyclopropanoate esters is reported. Both high efficiency and complete stereochemical control were observed in some cases with this annulation process. A single stereocenter on the cyclopropane controls the diastereoselective formation of up to four new stereocenters. A different reaction course was observed with 3-substituted indole substrates, and an intervening C-3 to C-2-migration process arose that gives synthetically useful C-2 alkylation indole products.     

Synthesen 2-substituierter 3-Indol-alkansäuren

A synthetic approach to 2-alkoxycarbonyl-3-indolealkanoic acidsvia partial saponification of the corresponding diesters is presented. 2-Ethoxycarbonyl-3-indoleacetic acid as well as the homologous propionic and butyric acids may conveniently be prepared by this method. A different synthesis of 3-indoleacetic acids functionalized at position 2 can be accomplished by decomposition of ethyl diazoacetate in the presence of the indole derivative at elevated temperature. Cyclization of 2-hydroxymethyl-3-indoleacetic acid, thus prepared, yields the corresponding -valerolactone. With 1-acyl-indoles and ethyl diazoacetate addition of the carbene to the C-2=C-3 double bond prevails, resulting in the formation of cyclopropanecarboxylic esters.     

Synthesis of 2-hydroxy-3-indolinones and 3-hydroxy-2-indolinones by anionic cyclization, in situ oxidation and rearrangement

Lithiation with butyllithium of 2-(benzylamino)benzamides (N-benzyl anthranilamides) occurs at the benzylic position to give an α-amino-organolithium that cyclizes to the 3-indolinone (indoxyl) ring (similar to a Parham cyclization). Autoxidation in air gives 2-hydroxy-3-indolinones. In the absence of a proton source, rearrangement of the aryl group from C-2 to C-3 occurs to give the 3-hydroxy-2-indolinone (oxindole) ring.     

Regioselective functionalization of 2-(2′-fluorophenyl)-3-cyanopyridine and its cyclization to benzo[h]-1,6-naphthyridines

Benzo[h]-1,6-naphthyridines and 5-ones, selectively functionalized at C-2, C-3, C-5 and C-10, were obtained by alkyllithium-, lithium amide- or potassium hydroxide-induced anionic cyclization of 3-cyano-2-(2-fluorophenyl)pyridine, which was functionalized regioselectively at positions 4, 5, 6, and 6′.     

Syntheses of (R) [4-2H2] 2-Amino-3-Butenoic Acid (Vinylglycine) and (R) [4-2H2, 5-2H3] Methionine

Treatment of (R) methionine sulfoxide with NaOD led to exchange of the C-4 methylene and C-5 methyl protons; exchange of the chiral C-2 proton did not occur. Reducation with mercaptoacetic acid gave (R)-[4-²H₂, 5-²H₃] methionine. The latter was converted into its carbobenzyloxy methyl ester sulfoxide, pyrolysis of which followed by deprotection yielded (R)-[4-²H₂] vinylglcine as the hydrochloride.     

A novel fragmentation of trimethylsilyl ethers of 3β-hydroxy-Δ5-steroids

An ion formed by loss of 56 mass units from the molecular ion is often seen in mass spectra of trimethylsilyl ethers of C₁₉ and C₂₁ steroids having a 3β-hydroxy-Δ⁵ structure and an oxo group at C-17 or C-20. The nature of this fragment was investigated by the use of perdeuteriotrimethylsilyl ether derivatives and of [4-¹⁴C], [3-¹⁸O], [4,4-²H₂] and [2,2,4,4-²H] labelled derivatives of 3β-hydroxy-5-androsten-17-one and 3β-hydroxy-5-pregnen-20-one. Evidence is presented to show that the neutral fragment of mass 56 is composed of carbon atoms 1, 2 and 3, the oxygen at C-3 and four hydrogen atoms. During the fragmentation process, the trimethylsilyl group and one of the hydrogens at C-2 are transferred to the fragment that carries the charge.     

Conformational Behaviour of Substituted 2-Methoxy-2-Oxo-1,2-Oxaphospholan-3-Ols

Abstract

Conformational behaviour of about 30 2-methoxy-2-oxo-1,2- oxaphospho l an-3-0 1 s containing various substituents was examined by ¹H and ¹³C NMR. Vicinal coupling constants J(HCCH), J(HCCP), J(HCOP), J(CCOP) and J(CCCP) were employed in this study. Conformation of the 1,2-oxaphospholane ring is governed almost exclusively by substituents at C-3, C-4 and C-5, as we l l as by their orientation. The configuration of the P atom has little or no influence on conformation of the ring in diastsreomeric pairs. Strong preference of phenyl, methyl and substituted methyl groups to occupy the equatorial or pseudoequatoria l positions was observed for all but one compounds studied. In the cis-fused bicyclic syst ems conformat ionally rigid 6-membered rings forced the 1,2-oxaphospholane rings to adopt an enve l ope-l ike (E₄) conformation. No influence of the p=o……HO-C-3 hydrogen bond on conformation of the 1,2-oxaphospholane ring was found. Preferred conformations for (2R, 3R, 4R)-3-(hydroxymethyI)-2-methoxy-2-oxo-1,2-oxaphospho lane-3,4-diol and its triacetate are shown below.     

The biosynthesis of ovalicin from β-trans-bergamotene

Feeding of [12, 13-13C]-β-trans-bergamotene to cultures of Pseudeurotium ovalis resulted in labeling of C-12 and C-13 of the antibiotic ovalicin, as established by ¹³C NMR.     

Direct palladium-catalyzed C-2 and C-3 arylation of indoles: a mechanistic rationale for regioselectivity

We have recently developed palladium-catalyzed methods for direct arylation of indoles (and other azoles) wherein high C-2 selectivity was observed for both free (NH)-indole and (NR)-indole. To provide a rationale for the observed selectivity ("nonelectrophilic" regioselectivity), mechanistic studies were conducted, using the phenylation of 1-methylindole as a model system. The reaction order was determined for iodobenzene (zero order), indole (first order), and the catalyst (first order). These kinetic studies, together with the Hammett plot, provided a strong support for the electrophilic palladation pathway. In addition, the kinetic isotope effect (KIE(H/D)) was determined for both C-2 and C-3 positions. A surprisingly large value of 1.6 was found for the C-3 position where the substitution does not occur (secondary KIE), while a smaller value of 1.2 was found at C-2 (apparent primary KIE). On the basis of these findings, a mechanistic interpretation is presented that features an electrophilic palladation of indole, accompanied by a 1,2-migration of an intermediate palladium species. This paradigm was used to design new catalytic conditions for the C-3 arylation of indole. In case of free (NH)-indole, regioselectivity of the arylation reaction (C-2 versus C-3) was achieved by the choice of magnesium base.     

Ring opening of nonactivated 2-(1-aminoalkyl) aziridines: unusual regio- and stereoselective C-2 and C-3 cleavage

We have studied the ring opening of nonactivated amino aziridines 1 by water under acidic conditions. Depending on the acid used, amino aziridines are cleaved at C-3 or C-2 with high regioselectivity, and total stereoselectivity, affording chiral 2,3-diaminoalkan-1-ols 3 or 1,3-diaminoalkan-2-ols 4 in high yield.     

Solid-state photodimerization of cholest-4-en-3-one

Crystalline cholest-4-en-3-one undergoes solid-state dimerization by UV radiation to give two ring A - ring A connected dimers. No dimerization occurs in solution. The first dimer, characterized by a cyclobutane ring, is formed by connection of C-2 and C-3 of a moiety with C-5' and C-6' of another moiety, respectively. The latter dimer has a six-membered ketal ring formed by connection of C-2 with C-5' and of O, linked to C-3, with C-3'. The structures have been determined by spectroscopic means. X-ray analysis of title compound evidences the proximity of the axial H-2 of a molecule to the C-4' of a molecule in the upper layer. The transfer of the hydrogen and the connection between C-2 and C-5' might be the driving force of dimerization.     

Diastereofacial Selective Addition of Ethynylcerium Reagent and Barton-McCombie Reaction as the Key Steps for the Synthesis of C-3'-Ethynylribonucleosides and of C-3'-Ethynyl-2'-deoxyribonucleosides

We describe the preparation of 3'-alkynyluridine 4a and -adenosine 4b and of 3'-alkynyl-2'-deoxyuridine 16a and -adenosine 16b starting from the corresponding nucleosides. The desired stereochemistry of the C-3' tertiary alcohol was obtained by reaction of an ethynylcerium-lithium reagent on a 3'-ketonucleoside with the hydroxyl group at C-5' unprotected. The 2'-deoxygenation was performed by a Barton-McCombie reaction under appropriate conditions where the addition of tin hydride to the triple bond was suppressed. Evaluation of the anti-HIV activity of the C-3' modified nucleosides is reported.     

Novel fragmentation reaction of 2-alkyl- and 2,4-dialkyl-3-iodo-1-oxocyclohexan-2,4-carbolactones

2-Alkyl- and 2,4-dialkyl-3-iodo-1-oxocyclohexan-2,4-carbolactones undergo lithium hydroxide- and lithium alkoxide-induced fragmentation reactions to provide butenolides, gamma-hydroxycyclohexenones, and/or gamma-butyrolactones. In general, product distribution is governed by two factors: (1) the nature of nucleophiles and (2) the steric bulkiness of the substituents at C-2 and C-4 of the cyclohexanones. Lithium hydroxide-induced fragmentation provides butenolides and gamma-hydroxycyclohexenones. In contrast, lithium alkoxide-promoted fragmentation results in predominantly 5-substituted gamma-butyrolactones along with a small amount of butenolides in limited cases. Fragmentation products induced by lithium hydroxide are largely influenced by the steric bulkiness of the substituents at C-2 and C-4 of the cyclohexanone ring. The bulky substituents render the exclusive formation of butenolides.     

Conformational study on indoline compounds. Structures of 2-phenyl-3-arylimino-3H-indole 1-Oxide, 1,2-dihydro-2-phenyl-2-benzyl- and 2-tert-Butyl-3-phenylimino-3H-indole 1-oxyls

Reacting 1-hydroxy-2-phenylindole with nitrosobenzene, 2-phenyl-3-phenylimino-3H-indole 1-oxide (1) is produced in only one of the two possible diastereomers. The latter reacts with tert-butylmagnesium chloride and benzylmagnesium chloride giving, after oxidation, the corresponding aminoxyls which show the same configuration of the phenylimino group at C-3 as in 1 . This has been demonstrated by means of nmr spectros-copy and X-ray crystal structure and represents an unexpected stereospecific reaction.     

Structural assignments of 2-aryl and 3-arylbenzofurans by carbon-13 nmr

The ^1–3C chemical shifts of 2-aryl and 3-arylbenzofurans are discussed. Pairs of isomers can be differentiated based on the chemical shifts of C-2 in 3-arylbenzofurans and C-3 in 2-arylbenzofurans. A signal near 100 ppm (101 ± 1.7) indicates a 2-arylbenzofuran and a signal near (141 ± 1.3) indicates a 3-arylbenzofuran.     

异戊二烯稀土催化聚合过程中配合物结构及其转化的~(13)C-NMR研究

本文用~(13)C-NMR研究了异戊二烯(IP)在均相催化剂(CF_3CO_2)_2LnCl·EtOH—(i-Bu)AlH—o-C_6D_4Cl_2作用下的聚合过程。单体首先被活化同稀土配位生成η~4-IP稀土配合物(反式和顺式),然后η~4-IP的C-3和C-4插入Ln-H键生成η~3-烯丙基稀土配合物——η~3-(2-甲基)丁烯基稀土配合物(同式和对式)。二维~(13)C-NMR交换谱表明η~4-IP和0η~3-烯丙基的每对异构体在常温下分别进行慢交换反应(互变异构),这一过程使插入反应在常温下得以进行。     

Synthesis of stable isoxazolines by [3+2] cycloaddition of oxaziridines with alkynes

N-Alkyl substituted oxaziridines undergo a [3+2] cycloaddition reaction with a variety of terminal alkynes to give the product isoxazolines, whose stability appears to depend on the electronic properties of the groups on the C-3 and C-5 positions. The presence of an electron withdrawing group on C-5 and/or an electron donating group on C-3 causes isomerization of the isoxazolines to β-amino enones.     

Facile Synthesis of (2R,3S)-2-Benzyloxy-3-hydroxybutyrolactone

The heterocyclic diols derived from L-dimethyl tartrate are important chiral synthons in organic synthesis. In particular, L-threosolactone and L-threosolactam structures are versatile precursors for the synthesis of biologically active molecules. Structurally, these functionalized five-membered rings contain two hydroxyl groups with R and S stereochemistry on C-2 and C-3 respectively. The preparation of (2R,3S)-2-benzyloxy-3-hydroxybutyrolactone (3) and of its derivatives, drawing upon L-dimethyl tartrate as an inexpensive chiral starting material, is described. The presented synthetic procedures are easy and effective for preparing L-threoso analogs. This protocol is also a better alternative in a large scale setup. All structures 3–6 and 8 are characterized using ¹H and ¹³C NMR spectroscopy.     

2-Ketophenyl Assisted Biomimetic Synthesis of 3-Thio Substituted Glycals at Room Temperature

Herein we designed a strategy for the synthesis of regioselective and stereoselective displacement of C-3 acetate group in the presence of other C-4 and C-6 acetate of 2-ketophenyl-glycal by different aromatic and cyclic aliphatic thiol nucleophiles taking inspiration from cytosolic esterase mediated thiolation of glucosamine sugars into cellular glycan. Under a mild base condition at room temperature, the protocol generated a library of 3-arylthiosugars with excellent yields and high axial selectivity. This stereoselective approach tolerated well with different ester-protected glycals and thiophenols, aliphatic cyclic thiols, and mercaptans. A variety of control experiments were conducted to establish the mechanism and reason behind the stereoselectivity.     

An unusual reaction at C-3 of 4-methoxy-6-methyl-2-pyrone

Triacetic acid lactone methyl ether, 4, can be lithiated at C-3 under kinetically controlled conditions. Further reaction with (E)-2-methyl-3-(4-nitrophenyl)propenal results in an unusual condensation at C-3.