Designer chiral quaternary ammonium bifluorides as an efficient catalyst for asymmetric nitroaldol reaction of silyl nitronates with aromatic aldehydes

Designer chiral quaternary ammonium bifluoride 1 has been prepared, and both its catalytic and its chiral efficiency have been clearly demonstrated by achieving the first catalytic asymmetric nitroaldol reaction of silyl nitronate with aldehydes. For instance, the reaction of trimethylsilyl nitronate 2 (R(1) = Me) with benzaldehyde (R(2) = Ph) in THF in the presence of (S,S)-1 (2 mol %) proceeded smoothly at -78 degrees C, giving the corresponding nitroaldol adduct 3 (R(1) = Me, R(2) = Ph) in 92% isolated yield (anti/syn = 92:8) with 95% ee (anti isomer). The method was found to be successfully applicable to other aromatic aldehydes and silyl nitronates, and a high level of anti selectivity and enantiomeric excess was constantly observed. This finding should lead to the further development of fluoride ion-catalyzed asymmetric carbon-carbon bond-forming reactions.     

Diastereoselective additions of chiral vinylzinc reagents to alpha-chiral aldehydes

[reaction: see text] Additions of vinylic zinc bromide reagents to alpha-chiral aldehydes (R(1) = CH(2)OTBS, R(2) = Me; R(1) = Me, R(2) = OTBS) in the presence of lithiated (+)- or (-)-N-methylephedrine proceed with predominant reagent control to afford anti or syn adducts stereoselectively, except when the aldehydes possess an alkoxy substituent at the alpha- or beta-positions (R(1) = Me, R(2) = OBn; R(1) = CH(2)OBn, R(2) = Me), in which case chelation-controlled adducts predominate.     

3-Bromopropenyl esters in organic synthesis: indium- and zinc-mediated entries to alk-1-ene-3,4-diols

Metallic indium and zinc readily add to 3-bromopropenyl acetate (5) and benzoate (6) either in THF or in water, affording the corresponding 3-acyloxyallyl organometallic compounds. Nucleophilic addition to aldehydes opens a route to alk-1-ene-3,4-diols 2 in good to excellent yields. Two synthetic protocols were developed, the former involving indium in THF under Grignard conditions and the latter involving zinc in aqueous ammonium chloride under Barbier conditions. The diastereoselectivity, under all the conditions examined, mainly depends on the nature of the carbonyl compound; conjugated aldehydes afford syn adducts 2, while unconjugated aldehydes display the opposite anti stereopreference.     

Synthesis of stereopentad analogues of the C14-C22 segment of callystatin A through additions of chiral allenylzinc reagents to stereotriads.

The addition of (P)- and (M)-allenylzinc reagents, prepared in situ through Pd-catalyzed metalation of (R)- and (S)-3-butyn-2-ol mesylates, to diastereomeric stereotriad aldehydes 8, 13, 18, and 23 of syn,syn, syn,anti, anti,anti, and anti,syn stereochemistry was examined. Additions to the former two aldehydes afforded the four anti adducts with high diastereoselectivity and negligible mismatching. Significant mismatching was observed with the latter two aldehydes and the (M)-allenylzinc reagent. An evaluation of possible transition states is presented in consideration of steric and dipolar control elements.     

Methyl 2,3,4-Tri-O-benzyl-alpha-D-glucopyranosyl-Derived gamma-Silyloxy Allylic Stannanes as Reagents for S(E)2' Additions to Aldehydes

The methyl alpha-D-glucopyranoside allylic stannanes 3.1 and 3.2 were prepared from the 3-(5-pyranosyl)-2-propenal 2.1 and the cuprate Bu(3)Sn(Bu)CuCNLi(2), followed by trapping of the derived enolate with TBSCl. The major stannane, 3.1, underwent BF(3)-promoted addition to 2-nonynal to afford a single syn adduct 4.1 in 70-90% yield. The minor stannane, 3.2, gave rise to a 70:30 mixture of adduct 4.1 and the diastereomeric syn adduct 5.1 under these conditions. The stereochemistry of the adduct 4.1 was proven by degradation of the bis-TBS derivative 4.2 to aldehyde 4.3, prepared independently from the (R,Z)-gamma-OTBS crotyl stannane 4.4 and 2-nonynal along similar lines. Analogous degradation of the adducts 4.1 and 5.1 led to a ca. 65:35 mixture of aldehydes 4.3 and its enantiomer. Accordingly, it can be surmised that the addition of stannane 3.2 to 2-nonynal takes place mainly by a syn S(E)2' pathway. BF(3)-promoted additions to enal 6.1 proceeded as expected. Stannane 3.1 afforded the syn adduct 6.2 in 87-97% yield, and stannane 3.2 gave rise to a 9:1 mixture of syn and anti adducts 7.1 and 7.4 in 70-80% yield.     

Two-carbon homologation of aldehydes via silyl ketene acetals. 2. Study of the stereochemical control in the formation of (E)-alkenoic acids.

The condensation of C,O,O-tris(trimethylsilyl)ketene acetal 1 with aldehydes 2 in the presence of catalytic amounts of mercuric iodide at room temperature affords syn and anti beta-trimethylsiloxy alpha-trimethylsilyl alkanoic acid silyl esters 3 in good yields. These new compounds gave, under acidic or basic conditions, E and (or) Z enoic acids 4. The paths for the formation of these alkenoic acids are discussed.     

Intramolecular syn and anti hydrosilylation and silicon-assisted cross-coupling: highly regio- and stereoselective synthesis of trisubstituted allylic alcohols

[reaction: see text] The geometrical isomers of 6-ethylidenedioxadisilacyclohexane were prepared by intramolecular hydrosilylation of an unsymmetrical disiloxane by the use of Pt (syn) and Ru (anti) catalysts. This new class organosilicon reagents underwent cross-coupling reactions with a range of aryl iodides to afford (E)- and (Z)-trisubstituted allylic alcohols in a highly stereospecific fashion.     

Highly enantio- and diastereoselective Brassard type hetero-Diels-Alder approach to 5-methyl-containing alpha,beta-unsaturated delta-lactones

Two efficient new chiral copper (II) Schiff base complexes were developed for the highly enantio- and diastereoselective HDA reaction of Brassard type diene 1b with aldehydes, to afford the corresponding 5-methyl-containing alpha,beta-unsaturated delta-lactone derivatives in moderate yields, high enantioselectivities (up to 99% ee) and excellent diastereoselectivities (up to 99:1 anti/syn). On the basis of the absolute configuration of 4a-4j disclosed by X-ray diffraction and CD analysis, a possible transition-state model for the enantio- and diastereoselective catalytic reaction has been proposed.     

Asymmetric Petasis Borono‐Mannich Allylation Reactions Catalyzed by Chiral Biphenols

Chiral biphenols catalyze the asymmetric Petasis borono‐Mannich allylation of aldehydes and amines through the use of a bench‐stable allyldioxaborolane. The reaction proceeds via a two‐step, one‐pot process and requires 2–8 mole % of 3,3′‐Ph₂‐BINOL as the optimal catalyst. Under microwave heating the reaction affords chiral homoallylic amines in excellent yields (up to 99 %) and high enantioselectivies (er up to 99:1). The catalytic reaction is a true multicomponent condensation reaction whereas both the aldehyde and the amine can possess a wide range of structural and electronic properties. Use of crotyldioxaborolane in the reaction results in stereodivergent products with anti‐ and syn‐diastereomers both in good diastereoselectivities and enantioselectivities from the corresponding E‐ and Z‐borolane stereoisomers.     

2-Piperidino-1,1,2-triphenylethanol: a highly effective catalyst for the enantioselective arylation of aldehydes

Here we report the use of 2-piperidino-1,2,2-triphenylethanol (5) as an outstanding catalyst for the ligand-catalyzed arylation of aldehydes. The use of 5 and a 2/1 mixture of Et(2)Zn/Ph(2)Zn provided the corresponding chiral diarylcarbinols with enantiomeric excess of up to 99% ee. The effect of temperature on the reaction enantioselectivity was studied and the inversion temperature (T(inv)) was determined to be 10 degrees C for reaction with p-tolylaldehyde. Most remarkably, lowering the amount of catalyst (5) to 0.5 mol % still afforded excellent levels of enantiocontrol (93.7% ee). Kinetics of the catalyzed and uncatalyzed arylation of aldehydes was studied by means of in situ FT-IR. The background uncatalyzed addition rates to p-tolylaldehyde when using pure Ph(2)Zn and Et(2)Zn/Ph(2)Zn (2/1) suggest that in the latter case a mixed zinc species forms (EtPhZn) minimizing the undesired nonselective addition. Formation of EtPhZn was modeled at the DFT calculation level. A four-center TS (TS-V) corresponding to the Et/Ph scrambling was localized along with two dimers (D-IV and D-VI). The model supports the hypothesis that Et/Ph exchange is a kinetically facile process. Gas evolution experiments during the formation of the active catalyst showed that the formation of an active site with a ONZn-Et (10) moiety is kinetically favored over ONZn-Ph (11). Finally, the phenyl transfer to benzaldehyde was modeled at the PM3(tm) level through anti and syn 5/4/4 tricyclic TS structures for both 10 and 11. The model could correctly predict the sense and selectivity of the overall process and predicted that 11 should be more selective than 10.     

Stereoretentive elimination and trans-olefination of the dicationic dipalladium moiety [Pd2Ln]2+ bound on 1,3,5-trienes

The reaction of [Pd(2)(CH(3)CN)(6)][BF(4)](2) (1) with 1,3,5-hexatriene, 1,6-diphenyl-1,3,5-hexatriene (DPHT), or 2,2,9,9-tetramethyl-3,5,7-decatriene (DBHT) afforded bi-eta(3)-allyldipalladium complexes 3, 4, or 5. The reaction of 1 and DBHT proceeded in a stereospecific (syn) manner when the reaction was carried out in CD(2)Cl(2) under aerobic conditions, while a mixture of two diastereomers was formed under N(2) atmosphere. The two diastereomers (5-E,Z,E-antifacial and 5-E,E,E-antifacial) formed from DBHT were isolated, and the structure of 5-E,Z,E-antifacial, which was kinetically formed from the reaction of 1 and (E,E,E)-DBHT, was determined by X-ray diffraction analysis. Addition of phosphine ligands (PPh(3) or dppm) to the dinuclear adduct 5-E,Z,E-antifacial or 5-E,E,E-antifacial in acetonitrile resulted in the stereospecific (syn) elimination of [Pd(2)(PPh(3))(2)(CH(3)CN)(4)][BF(4)](2) (2) or [Pd(2)(dppm)(2)(CH(3)CN)(2)][BF(4)](2) (6). During the PPh(3)-induced dinuclear elimination, the phosphine adducts 7 that retain bi-eta(3)-allyldipalladium structure were observed initially. The phosphine adduct generated from 5-E,E,E-antifacial was isolated and structurally characterized by X-ray diffraction analysis. The reaction of 1 and DPHT in CH(2)Cl(2) afforded unique dipalladium sandwich compounds [Pd(2)(mu-eta(3):eta(3)-DPHT)(2)][BF(4)](2) (8). Interconversion between the sandwich complexes and half-sandwich complexes occurred in a stereoretentive manner. The structure of the sandwich complex 8-E,Z,E formed from 4-E,E,E-antifacial and (E,Z,E)-DPHT was determined by X-ray diffraction analysis. Transfer of the dipalladium moiety [Pd(2)(CH(3)CN)(4)](2+) from DPHT ligand of 4-E,E,E-antifacial onto DBHT ligand proceeded in a stereoretentive manner. The observed stereoretentive dinuclear process is featured by the pairwise behavior of two palladium atoms sitting on the triene pi-plane. In the dinuclear elimination, the two Pd atoms that are initially in the divalent state and bound on the opposite faces (antifacial) come to the synfacial positions to form a Pd-Pd bond prior to dissociation. These results represent the unique property of conjugated olefin as the multidentate ligands for metal-metal moieties.     

Highly enantioselective nitroaldol reactions catalyzed by copper(II) complexes derived from substituted 2-(pyridin-2-yl)imidazolidin-4-one ligands

Ten optically pure substituted 2-(pyridin-2-yl)imidazolidin-4-ones, 1a-d, 2a-4a, and 2b-4b, were prepared and characterized. The absolute configurations of individual ligands were determined by X-ray analysis or NOESY experiments. The Cu(II) complexes of the respective ligands were studied as enantioselective catalysts of the nitroaldol (Henry) reaction of aldehydes with nitromethane, giving the corresponding substituted 2-nitroalkanols. In the case of an anti arrangement of the imidazolidin-4-one ring, the obtained result was 91-96% ee, whereas in the case of syn arrangement, a significant drop to 25-27% ee was observed.     

A Convenient Preparation of 2-(2-Arylidene)- and 2-(2-Polyhydroxyalkylidene)hydrazono-4-imidazolidinones with Various Heterocyclic Side Chain Substituents at Position 5 as Potential Antiviral and Antitumor Agents

A variety of novel 5-[( Z )-arylidene]-2-[(2-( E )-arylidene)hydrazono]-4-imidazolidinones 1a-c to 4a , b and 5-[( Z )-arylidene]-2-[(2-( E )-polyhydroxyalkylidene)hydrazono]-4-imidazolidinones 5a-c to 7a-c were prepared from the reaction of 5-[( Z )-arylidene]-2-methylmercaptohydantoins 8a-c with 2-( E )-arylidene hydrazones 13a-d and/or 2-( E )-monosaccharides hydrazones 16a-c . The linear structure, and not that of the angular isomer, has been selected for the products. This structure has been confirmed from a model study of the condensation of 5-[( Z )-2-thienylidene]-2-hydrazono-4-imidazolidinone 9a with benzaldehyde and D -galactose, respectively. The acetylation and benzoylation reactions of compounds 1-7 have been studied. All the new compounds were tested for their potential antiviral and antitumor activities.     

A tandem non-aldol aldol Mukaiyama aldol reaction

[reaction: see text] A new one-pot tandem aldol process is described in which a secondary epoxy silyl ether is converted into the 1,5-bis-silyloxy-3-alkanone in good yield. Thus, treatment of the epoxy silyl ether 8 with TBSOTf and base affords the silyl enol ether 9 via non-aldol aldol rearrangement and addition of benzaldehyde and TBSOTf gives the ketone 10 with 4:1 syn selectivity. The diastereoselectivity changes to an anti preference for most aldehydes. This anti selectivity overwhelms the normal Felkin-Ahn preference; namely, the 1,5-anti isomer predominates even when it is anti-Felkin-Ahn.     

Analysis of the optical and geometrical isomer distributions in selected propylene glycol acetals

For the first time, relative distributions of optical and geometrical isomers in selected propylene glycol acetals are determined. Resolution of the four acetal isomers possible through the reaction of racemic propylene glycol (PG) with selected aldehydes is demonstrated. The four isomers are ascribed to the presence of syn and anti geometrical isomers for each optically active PG acetal enantiomer. Thus, the (+) and well as (-) enantiomer are found to have a pair of syn and anti geometrical isomers. The ratio of the (+) and (-) isomers in the product remains at an approximate 50:50 ratio, as expected. However, somewhat unexpectedly, the syn/anti geometrical isomer ratio systematically varies with the nature of the substituent comprising the side chain of the aldehyde. Mechanisms involving electronic and minimal steric effects are advanced as possible reasons for the change in the syn/anti PG acetal ratios.     

Unusual palladium-catalyzed silaboration of allenes using organic iodides as initiators: mechanism and application

A highly regio- and stereoselective method for the synthesis of various 2-silylallylboronates 7 from allenes 1 and 2-(dimethylphenylsilanyl)-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (5) catalyzed by palladium complexes and initiated by organic iodides is described. Treatment of monosubstituted aryl and alkylallenes RCH=C=CH(2) (1a-m) and 1,1-dimethylallene (1n) with borylsilane 5 in the presence of Pd(dba)(2) (5 mol %) and organic iodide 3a (10 mol %) afforded the corresponding silaboration products 7a-n in moderate to excellent yields. This catalytic silaboration is totally regioselective with the silyl group of 5adding to the central carbon and the boryl group to the unsubstituted terminal carbon of allene. Furthermore, the reactions show very high E stereoselectivity with the Z/E ratios lying in the range from 1/99 to 7/93. In the absence of an organic iodide, silaboration of 1 with 5 still proceeds, but gives products having completely different regiochemistry as that of 7. The silaboration chemistry can be applied to the synthesis of homoallylic alcohols. Treatment of allenes (1) with borylsilane 5 and aldehydes 14 in the presence of Pd(dba)(2) (5 mol %) and 3a (10 mol %) at 80 degrees C in ethyl acetate for 5 h afforded homoallylic alcohols 15a-p in one pot in good to excellent yields, with exceedingly high syn selectivity (>93%). Mechanistic pathways involving an unusual palladium-catalyzed three-component assembling reaction of dimethylphenylsilyl iodide, allene 1, and borylsilane 5 were proposed to account for these catalytic reactions.     

A conformational study of phospha(III)- and phospha(V)-guanidine compounds

Spectroscopic, crystallographic, and computational studies of the substituent distribution about the "NCN" unit in a series of phospha(III)- and phospha(V)-guanidines, R(2)PC{NR'}{NHR'} and R(2)P(E)C{NR'}{NHR'} (R = Ph, Cy; R' = (i)Pr, Cy; E = S, Se), are reported. In the phosphorus(III) systems, the P-diphenyl substituted compounds are observed as only one isomer, shown by NMR spectroscopy to be the E(syn)-(alpha) configuration. In contrast, the corresponding P-dicyclohexyl derivatives exist as a mixture of E(syn)-(alpha) and Z(anti) in solution. Spectroscopic techniques are unable to determine whether the latter isomer exists as the alpha- or beta-conformer relative to rotation about the P-C(amidine)() bond; however, DFT calculations indicate a low-energy structure for the N,N'-dimethyl model complex in the beta-conformation. In their oxidized sulfo and seleno forms, the P-diphenyl compounds are present as an interconverting equilibrium mixture of the E(syn)-(beta) and Z(syn)-(beta) isomers in solution ( approximately 3:2 ratio), whereas for the P-dicyclohexyl analogues, the latter configuration (in which the nitrogen substituents are in a more sterically unfavorably cisoid arrangement about the imine double bond) is the dominant form. Intramolecular E...HN (E = S, Se) interactions are observed in solution for the Z(syn)-(beta) configuration of both P-substituted species, characterized by J(SeH) coupling in the NMR spectrum for the P(V)-seleno compounds and a bathochromic shift of the NH absorption in the infrared spectrum. An X-ray crystallographic analysis of representative Ph(2)P(E)- and Cy(2)P(E)-substituted species shows exclusively the E(syn)-(beta) configuration for the P-diphenyl substituted compounds and the Z(syn)-(beta) form for the P-dicyclohexyl derivatives, independent of the chalcogen and the nitrogen substituents. Results from a DFT analysis of model compounds fail to identify a compelling electronic argument for the observed preferences in substituent orientation, suggesting that steric factors play an important role in determining the subtle energetic differences at work in these systems.     

Highly selective addition of chiral,sulfonimidoyl substituted bis(allyl)titanium complexes to N-sulfonyl alpha-imino esters: asymmetric synthesis of gamma,delta-unsaturated alpha-amino acids bearing a chiral,electron-withdrawing nucleofuge at the delta-position

Selective addition of the chiral, sulfonimidoyl substituted bis(allyl)titanium complexes 5a-d, which are configurationally labile in regard to the Calpha-atoms, to N-toluenesulfonyl (Ts)-, N-2-trimethylsilylethanesulfonyl (SES)-, and N-tert-butylsulfonyl (Bus) alpha-imino ester (9a-c) in the presence of Ti(OiPr)(4) and ClTi(OiPr)(3) afforded with high regio- and diastereoselectivities in good yields the (syn, E)-configured beta-alkyl-gamma,delta-unsaturated alpha-amino acid derivatives 2a-g, which carry a chiral, electron-withdrawing nucleofuge at the delta-position and a cyclohexyl, an isopropyl, a phenyl, and a methyl group at the beta-position. Addition of the cyclic bis(allyl)titanium complex 14 to N-Bus alpha-imino ester 9c afforded with similar high regio- and diastereoselectivities the (E)- and (Z)-configured amino acid derivatives (E)-8 and (Z)-8. Reaction of complexes 5a-d with alpha-imino esters 9a-c in the presence of Ti(OiPr)(4) occurs stepwise to give first the mono(allyl)titanium complexes containing 2a-g as ligands, which react in the presence of ClTi(OiPr)(3) with a second molecule of 9a-c with formation of two molecules of 2a-g. Formation of (S,R,E)-configured homoallylic amines 2a-g entails Si,Re,E processes of alpha-imino esters 9a-c with the (R,R)-configured bis(allyl)titanium complexes (R,R)-5a-d and (R)-configured mono(allyl)titanium complexes (R)-17a-d, both of which are most likely in rapid equilibrium with their (S,S)-diastereomers and (S)-diastereomers, respectively. Interestingly, in the reaction of 5a-d with aldehydes, the (S,S)-configured complexes (S,S)-5a-d are the ones which react faster. Reaction of the N-titanated amino acid derivatives Ti-2a and Ti-2b with N-Ts alpha-imino ester 9a led to the highly diastereoselective formation of imidazolidinones 15a and 15b, respectively. Cleavage of the sulfonamide group of the N-Bus amino acid derivative 2d with CF(3)SO(3)H gave quantitatively the sulfonimidoyl functionalized amino acid H-2d. A Ni-catalyzed cross-coupling reaction of the amino acid derivative 2e with ZnPh(2) led to a substitution of the sulfonimidoyl group by a phenyl group and furnished the enantiomerically pure protected alpha-amino acid Bus-1. Two new N-sulfonyl alpha-imino esters, the SES and the Bus alpha-imino esters 9b and 9c, respectively, have been synthesized from the corresponding sulfonamides by the Kresze method in medium to good yields. The N-SES alpha-imino ester 9b and the N-Bus alpha-imino ester 9c should find many synthetic applications, in particular, in cases where the N-Ts alpha-imino ester 9a had been used before.     

Conjugate additions of 1-propenylphosphonates to metalated Schöllkopf's bis-lactim ether: stereocontrolled access to 2-amino-3-methyl-4-phosphonobutanoic acids

Diastereoselectivity in the conjugate addition of metalated Sch?llkopf's bis-lactim ethers 5a-e to (E)- and (Z)-1-propenylphosphonates 4a,b was studied experimentally and theoretically and utilized to achieve a direct and stereocontrolled synthesis of all four diastereoisomers of 2-amino-3-methyl-4-phosphonobutanoic acid, 6a,b and their enantiomers. The relative stereochemistry was assigned from an NMR study of cyclic derivatives 13a,b. According to semiempirical calculations, both in vacuo (PM3) or a dielectric continuum (PM3/COSMO), initial lithium-phosphoryl coordination, without an energy barrier, to form a solvated chelate complex is followed by the rate-determining reorganization to the 1,4-addition product through an eight-membered transition state. The translation of the Z,E geometry into a syn, anti configuration at the adducts originates from an orientational preference in the transition state for a compact disposition of the reaction partners.     

Aldol addition of lithium and boron enolates of 1,3-dioxan-5-ones to aldehydes. A new entry into monosaccharide derivatives

Methods allowing control of stereoselectivity in aldol reactions of enolates derived from 1,3-dioxan-5-ones (4) are described. Boron enolates, generated in situ, react with benzaldehyde to give the corresponding anti aldol selectively (the anti:syn ratio of up to 96:4) and in high yield. Lithium enolates give high anti selectivity only with aldehydes branched at the alpha-position. Enantioselective deprotonation of C(S) symmetrical dioxanones (e.g., 4b) can be accomplished efficiently, with enantiomeric excess of up to 90%, with chiral lithium amide bases of general structure PhCH(Me)N(Li)R (9, 10) if the R group is sufficiently bulky (e.g, R = adamantyl) or is fluorinated (e.g., R = CH2CF3). Dioxanone boron and lithium enolates react readily with glyceraldehyde derivatives (19), yielding protected ketohexoses (20 and 21).