Anti Products Research Articles

Dimethylzinc‐Mediated Additions of Alkenylzirconocenes to Aldimines. New Methodologies for Allylic Amine and C‐Cyclopropylalkylamine Syntheses.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Enantioselective total synthesis of ustiloxin D.

Ustiloxin D and phomopsin A are potent antimitotic agents that bind to tubulin and interfere with cellular microtubule function. A synthetic strategy has been developed to allow access to both of the natural products as well as a variety of variants of the ustiloxin and phomopsin family members in order to provide sufficient quantities for biological studies. Herein we report the enantioselective total synthesis of ustiloxin D using a longest linear sequence of 20 steps. Four of the five stereocenters were set using catalytic asymmetric methodologies. In particular, Evans's new Al-catalyzed asymmetric aldol reaction facilitated access to both syn and anti products corresponding to the different benzylic stereochemistries found in ustiloxins and phomopsins. In addition, due to its high functional group tolerance, Trost's Pd-mediated etherification was used to construct the chiral tertiary alkyl-aryl ether. Taken together, these synthetic strategies allow us to use densely functionalized intermediates to realize an efficient synthesis of ustiloxin D.

Dimethylzinc-mediated additions of alkenylzirconocenes to aldimines. New methodologies for allylic amine and C-cyclopropylalkylamine syntheses.

Hydrozirconation of alkynes with zirconocene hydrochloride followed by in situ transmetalation to dimethylzinc provides access to reactive alkenyl organometallic reagents from readily available precursors. Upon addition of imines, 1,2-attack leads to synthetically useful allylic amine building blocks. In the presence of CH(2)I(2) or CH(2)Cl(2), the N-metalated allylic amide intermediate is cyclopropanated and C-cyclopropylalkylamines are formed in high yield and excellent diastereoselectivities favoring the anti products. The use of enynes as starting materials for this domino reaction provides conjugated biscyclopropanes and thus allows the stereoselective formation of five new carbon-carbon bonds. A transition state that explains the need for both zirconocene complex and alkyl zinc in the cyclopropanation reaction is proposed.

Stereochemistry of the addition of dialkyl phosphites to ( S)- N, N-dibenzylphenylglycinal

The addition of various dialkyl phosphite derivatives to ( S)- N, N-dibenzylphenylglycinal 6 led to the preponderance of anti over syn diastereoisomers: from 75:25 when NEt 3 or Ti(O iPr) 4 were used to 51:49 for Li or Mg salts. In the NEt 3-catalysed reaction, partially racemised phosphonates were formed, while enantiomeric products were obtained after addition of lithium O, O-dimethylphosphonate to ( S)- 6 at −70°C. Because the syn-isomers were found to be resistant to O-benzoylation, mixtures of diastereoisomers were easily separated after esterification of the anti products. Hydrogenation of the syn-phosphonates in the presence of Boc 2O gave enantiomeric dialkyl N-Boc-2-amino-1-hydroxy-2-phenylethylphosphonates—phosphonate analogues of the docetaxel C-13 side chain.

Local production of anti-vibrio cholerae mucosal antibody in reproductive tract tissues after cholera.

To investigate whether intestinal presentation of an antigen by Vibrio cholerae, a noninvasive organism, could induce an anatomically distant mucosal immune response in reproductive tract tissues, the endocervical immune responses of women in Bangladesh were evaluated after cholera. Endocervical secretions were analyzed for secretory IgA (sIgA) antibody against the B subunit of cholera toxin (CtxB) in 9 women with cholera and 8 women with diarrhea caused by neither V. cholerae nor heat labile enterotoxin-producing Escherichia coli. Women infected with V. cholerae developed significant sIgA anti-CtxB responses in endocervical samples (P< or =.02). Antibody subtype analysis of endocervical IgA was consistent with local mucosal production (P< or =.001). Women with cholera did not develop sIgA anti-CtxB responses in serum. The ability to generate specific mucosal immune responses in reproductive tract tissues after intestinal presentation of antigen could facilitate development of vaccines effective against reproductive tract pathogens.

Organic reaction in water. Part 3¹: diastereoselectivity in Michael additions of thiophenol to nitro olefins in aqueous media

Thiophenol reacts with nitro olefins in aqueous media to give the corresponding nitro-sulfides in 58-95% yield. This procedure results in selective formation of the anti products. In the case of the cyclic nitro olefin 1-nitro-cyclohexene the only product observed was the cis-1-nitro-2-(phenylthio)cyclohexane. This methodology is of interest due to the use of water as solvent, thus minimizing the cost, the operational hazards and environmental pollution.

Facial-Selective Allylation of Methyl Ketones for the Asymmetric Synthesis of -Substituted Tertiary Homoallylic Ethers

The asymmetric synthesis of enantiomerically pure α-substituted tertiary homoallylic ethers 4 a, 11 and 12 a–c by the allylation of ethyl methyl ketone (1 a) with γ-substituted allylsilanes 9 a–h is described. The allylsilanes were obtained by a nickel-catalysed Grignard cross-coupling reaction of (E)- and (Z)-(3-iodoallyl)trimethylsilane with various Grignard reagents. The reaction of the allylsilanes with 1 a in the presence of the trimethylsilyl ether of N-trifluoroacetylnorpseudoephedrine (3), and catalytic amounts of a mixture of trimethylsilyl triflate and trifluoromethanesulfonic acid led to the homoallylic ethers 4 a, 11 and 12 a–c with two new stereogenic centres, with a selectivity of 1:9 to >20:1 for the homoallylic and of 1:99 to >60:1 for the allylic centre. The facial selectivity does not depend on the configuration of the allylsilane, and in all reactions the anti product is preferentially formed. Interestingly, a pronounced switch of facial selectivity takes place with increasing length of the alkyl group of the allylsilane.

Facial-selective allylation of methyl ketones for the asymmetric synthesis of alpha-substituted tertiary homoallylic ethers.

The asymmetric synthesis of enantiomerically pure a-substituted tertiary homoallylic ethers 4a, 11 and 12a-c by the allylation of ethyl methyl ketone (la) with gamma-substituted allylsilanes 9a-h is described. The allylsilanes were obtained by a nickel-catalysed Grignard cross-coupling reaction of (E)- and (Z)-(3-iodoallyl)trimethylsilane with various Grignard reagents. The reaction of the allylsilanes with la in the presence of the trimethylsilyl ether of N-trifluoroacetylnorpseudoephedrine (3), and catalytic amounts of a mixture of trimethylsilyl triflate and trifluoromethanesulfonic acid led to the homoallylic ethers 4a, 11 and 12a-c with two new stereogenic centres, with a selectivity of 1:9 to >20:1 for the homoallylic and of 1:99 to >60:1 for the allylic centre. The facial selectivity does not depend on the configuration of the allylsilane, and in all reactions the anti product is preferentially formed. Interestingly, a pronounced switch of facial selectivity takes place with increasing length of the alkyl group of the allylsilane.

ChemInform Abstract: Highly Enantioselective Syntheses of anti Homoaldol Products by (-)-Sparteine-Mediated Lithiation/Transmetalation/Substitution of N-Boc Allylic Amines.

(−)-Sparteine-mediated lithiation/transmetalation/substitution of N-Boc allylic amines provides anti-configured homoaldol precursors in yields of 38−85% and enantiomeric ratios of 83:17−99:1. Subsequent O-protection and hydrolysis allows access to O-protected homoaldol adducts in good yields. The absolute configurations of the homoaldol products have been assigned by calculation of optical rotations and by X-ray crystallography of derivatives. A stereochemical course of reaction for the lithiation/transmetalation/substitution sequence is proposed.

Free radicals and Lewis acid. Chelation-controlled radical allylations of substituted α-halo- or α-phenylseleno-β-alkoxy esters. The endocyclic effect.

The radical allylation of a series of α-halo or α-phenylseleno-β-alkoxy esters in the presence of MgBr2·OEt2 is reported and compared with analogous reactions under non-chelating conditions. The addition of MgBr2·OEt2 gives excellent selectivity favoring anti products; in some cases ratios &gt;100:1 are obtained. Varying the substrate substituents reveals that these reactions are quite tolerant of alkyl functionalities at the β-position. Changes to the alkoxy function indicate that a chelate is involved in the reaction. The reactions are successful with secondary iodides, bromides, and phenylselenides, as well as tertiary iodides, which all give very high ratios under chelation control. Performing less well under the same conditions are substrates with a radical exocyclic to a tetrahydrofuran ring. EDTA titration is used to determine the amount of Mg2+ dissolved in the allylation reaction mixture, and 13C NMR is employed to better define the nature of the complex formed (chelate or monodentate) prior to the reaction. Competition experiments suggest that the chelate and monodentate pathways are in competition for the radical allylation with allyltributyltin.Key words: allylation, radicals, Lewis acid, stereoselectivity, 1,2-induction.

Diastereoselective addition reactions of racemic chiral vinyl sulfimides

S-Aryl S-vinyl sulfimides are prepared by a new method via Horner–Wadsworth–Emmons reagents generated in situ. Lewis acid-catalysed Diels–Alder reaction of S-ethenyl-S-phenyl-N-tosylsulfimide with cyclopentadiene leads to the endo anti product with good diastereofacial and endo–exo selectivities. A range of alcohols and amines, with the limitation that they be practically usable in large excess, add to β-aryl vinyl sulfimides with modest diastereoselectivity. The major products of both the cycloaddition and the nucleophilic additions are rationalised by a model invoking addition to the least-hindered face of the s-cisconformation of the vinyl sulfimide.

Stereoselective production of β-amino alcohols and β-thioacyl alcohols via an application of the non-aldol aldol process

The mesylates used as protecting groups to permit the formation of bis(polypropionates) via the non-aldol aldol process can be easily displaced with good nucleophiles, e.g., azide, thioacetate, acetate, to generate β-azido (and β-amino) alcohols, β-thioacyl alcohols, and aldols of the opposite chirality, e.g., syn isomers afford anti products. Thus the anti mesylate 15 affords the all-anti mzido aldol system 16 in good yield.

Competing intermolecular and intramolecular hydride transfers in the ionic hydrogenation of (2-alkoxyphenyl)di(1-adamantyl)methanols †

ortho-Lithiation of anisole followed by reaction with di(1-adamantyl) ketone gives syn-(2-anisyl)di(1-adamantyl)methanol with the C–OH proton intramolecularly hydrogen-bonded to the methoxy group. Reaction of the alcohol with trifluoroacetic acid (TFA) in dichloromethane leads to a trifluoroacetate and a substituted phenol. These are formed via a carboxonium ion, resulting from an intramolecular 1,5-hydride shift of the initially formed carbocation. Ionic hydrogenation of the alcohol with TFA and a hydrosilane in dichloromethane results in the expected anti and syn deoxygenation products as well as the trifluoroacetate and the phenol. anti-(2-Anisyl)diadamantylmethane (benzylic hydrogen remote from methoxy, confirmed by a single crystal X-ray diffraction study) is formed directly from the carbocation while the syn isomer results from reduction of the carboxonium ion. Reduction of the carbonium ion is more hydrosilane-selective than that of the carboxonium ion. Kinetic isotope effects (kH/kD) on the reaction of the carbocation at room temperature average 1.50 for triethylsilane and dimethylphenylsilane. Analogous reaction of the (2-ethoxyphenyl) derivative gives only syn-(2-ethoxyphenyl)diadamantylmethane and the substituted phenol. Kinetic isotope effects on the reduction of the corresponding carboxonium ion average 1.34 for the same hydrosilanes.

Facile approach towards the synthesis of homochiral functionalised alcohols from 4- O-[( tert)-butyldimethylsilyl]-2,3- O-cyclohexylidene- l-threose of ( l)-(+)-tartaric acid origin

( l)-(+)-Diethyl tartarate 2 has been transformed into the aldehyde 6. Grignard additions to 6 take place with moderate diastereoselectivity giving predominant formation of the anti products 8a– e. However, in each case the diastereoalcohols are easily separable by column chromatography giving rise to the formation of a series of functionalised homochiral alcohols 7 and 8. On the other hand Zn mediated allylation and propargylation of 6 in the presence of water proceeded efficiently with almost absolute (>99%) stereoselective formation of versatile functionalised homoallylic 8d and homopropargylic 8e alcohols respectively.

Enantioselective and Diastereoselective Additions of Allylic Stannanes to Aldehydes Promoted by a Chiral (Acyloxy)borane Catalyst

A modified Yamamoto Lewis acid (CAB), prepared from the 2,6-dimethoxybenzoic ester of (R,R)-tartaric acid, and 1.5 equiv of BH3·THF was employed in additions of crotyltributyltin (6) and allyltributyltin (9) to representative achiral aldehydes in the presence of 2 equiv of (CF3CO)2O. The crotyltin additions proceeded with good to excellent diastereoselectivity and enantioselectivity affording the syn adducts 7a−e of 70−90% ee as major products (78:22−92:8). Addition of allylstannane 9 to cyclohexanecarboxaldehyde (1a) afforded the (R)-adduct of only 55% ee. In contrast, the use of Keck's BINOL catalyst gave 10, the allyl adduct of 1a, of 87% ee. However, addition of the crotylstannane to 1a with this catalyst led to a 65:35 mixture of syn and anti adducts 7a and 8a of 95% and 49% ee. Additions of crotylstannane 6 to (R)- and (S)-2-methyl-3-ODPS-propanal [(R)-11 and (S)-11] promoted by the modified CAB Lewis acid afforded the syn,syn and syn,anti products 12 and 14 in large predominance (98:2 and 90:10), indicative of effective complex control in the transition state. The results are consistent with the Corey H-bonded aldehyde transition-state proposal.

Solvent-Dependent Stereoselectivity in the Addition ofp-CH3OC6H4OH to (E)-1,2-Di-tert-butyl-1,2-dimesityldisilene. Evidence for Rotation around the Si−Si Bond in the Zwitterionic Intermediate

The diastereoselectivity of the addition of p-CH3OC6H4OH to (E)-1,2-di-tert-butyl-1,2-dimesityldisilene (2) in benzene and in THF is reported, and the mechanistic implications of the results are discussed. In both benzene and in THF the stereochemistry of the products is independent of the phenol concentration (in the range of phenol excess of 2−300 equiv). The syn:anti product ratio is 90:10 in benzene and of 20:80 in THF, i.e., with stereochemical preference opposite to that in benzene. The finding that the stereochemistry of the products is independent of the phenol concentration indicates that in the second step of the addition reaction intermolecular proton transfer (from a second molecule of phenol) does not occur. Thus, the anti-addition product results from rotation around the Si−Si bond in the zwitterionic intermediate followed by intramolecular proton transfer. The very different product ratios in benzene and in THF support the formation of zwitterionic intermediates and suggest a longer lifetim...

N,Se‐Acetals: Preparation and use in diastereoselective radical reactions

AbstractA new facile synthesis of N,S‐ and N,Se‐acetals starting from aldehydes and primary amines is presented (Schemes 3–5). These acetals are used as precursors for stereoselective radical deuteration and allylation reactions (Schemes 6 and 7, Tables 1 and 2). The stereochemical outcome of the reactions depends on the radical trap and the substituents at the N‐atom. Deuterations give always anti products with moderate to high selectivities. The allylation reactions give either syn or anti products with low to moderate selectivities. The observed stereoselectivities can be explained with a model based on minimization of A1,3 strain and are controlled by steric and stereoelectronic effects.

Stereoselective Reactions of Phthalimido‐Substituted Radicals Derived from (±)‐Threonine: A comparison with reactions of N‐phthaloyliminium ions

AbstractStereoselective reactions of phthalimido‐substituted radicals derived from (±)‐threonine with different radical traps are reported (Scheme 3, Table 1). A strong influence of the nature of the radical trap on the stereoselectivity was noticed. Small nucleophilic radical traps gave preferentially the syn products. The observed selectivities are explained with the A1,3 strain model and depend on steric and electronic effects (Fig. 2). Reactions with electrophilic radical traps such as diphenyl diselenide gave the anti diastereoisomers with moderate stereocontrol, presumably due to stereoelectronic effects. The same stereochemical outcome, i.e., preferential formation of the anti products, was observed for the reactions of the related N‐phthaloyliminium ion (Scheme 5, Table 2). The stereochemistry of the ionic reaction is rationalized by a Felkin‐Anh model (Fig. 3).

Allylation of Phosphorus, Arsenic, and Antimony Trihalides by Allylic Stannanes. Synthesis, Spectroscopic Characterization, and Quantum Chemical Investigations of Allylic Phosphines, Arsines, and Stibines.

The reaction between an allylic tributylstannane and a phosphorus, arsenic, or antimony trihalide led to the corresponding allylic phosphine, arsine, or stibine dihalides. With phosphorus derivatives, only the gamma-regioselection was observed, as shown by the formation of (1-methyl-2-propenyl)- (2e,f)or (1,1-dimethyl-2-propenyl)dihalophosphines (2g,h) starting from crotylstannanes 1c,c' or prenylstannane 1d, respectively, and PCl(3) or PBr(3). On heating at 80 degrees C, some of these phosphines led to the corresponding thermodynamic products. Allylic dichloroarsines 3a-d were also prepared and kinetic compounds 3c,d completely rearranged at room temperature into the corresponding crotyl- (3e,e') and prenyldichloroarsines (3f). For antimony derivatives, even at low temperature (-90 degrees C), crude mixtures containing only the thermodynamic products were observed. While allylic dihalophosphines and -arsines are not efficient allylation reagents of electrophiles, allylic dichlorostibines 4a,c reacted with benzaldehyde to lead to the corresponding homoallyl alcohols. Syn and anti products were mainly produced starting from crotyldichlorostibines (4e,e'). The primary allylic phosphines 7a-f, arsines 8a-f, and stibines 9a,bhave been prepared by the chemoselective reduction of the corresponding allylic dihalophosphines, -arsines, or -stibines with LAH in tetraglyme or with Bu(3)SnH as reducing agent and characterized by (1)H and (13)C NMR spectroscopy and mass spectrometry. The primary allylic arsines and stibines are the first elements of new classes of compounds. Several allylic phosphines and arsines were investigated by ab initio quantum chemical methods and photoelectron spectroscopy. The most stable structure of these compounds is when the C-E (E = P, As) bond is out of the plane of the allyl system. This conformation is stabilized by the hyperconjugation between the pi-orbital and the C-E sigma-bond. Due to this geometrical arrangement, the phosphorus (arsenic) lone pair interacts strongly and unprecedently with the pi-system. The strength of this interaction is due to the close proximity of the pi and the n(P) (n(As)) levels.

Stereocontrolled Synthesis of Multi-Functional Bioactive Compounds

Synthetic strategy and concept of multi-step synthesis of biologically important compounds are discussed with special reference under stereochemical control. A-strain in cyclic exo-olefin was expanded to acyclic cases to allow high stereoselectivity in conjugate addition, epoxidation, etc. A special synthetic methodology named heteroconjugate addition has been improved in various aspects (i) preparation of heteroolefin, (ii) diastereo-switching of syn or anti product, (iii) enantio-switching of D or L from D-sugar analog and (iv) coupling with other fragments in the total syntheses of maytansinoids, okadaic acid, tautomycin, etc. Recent advances on sugar acetylene chemistry are also introduced to use the corresponding biscobalthexacarbonyl complexes and Nicholas type reaction for medium-size ether ring formation. These syntheses request multiple organic reactions such as carbanions, carbenium cations, organometallic reagents, heteroatom chemistry for bond formation in good harmony with functional group preparation of the target natural products.