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.     

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.     

Highly efficient aldol additions of DHA and DHAP to N-Cbz-amino aldehydes catalyzed by L-rhamnulose-1-phosphate and L-fuculose-1-phosphate aldolases in aqueous borate buffer

Aldol addition reactions of dihydroxyacetone (DHA) to N-Cbz-amino aldehydes catalyzed by L-rhamnulose-1-phosphate aldolase (RhuA) in the presence of borate buffer are reported. High yields of aldol adduct (e.g. 70-90%) were achieved with excellent (>98?:?2 syn/anti) stereoselectivity for most S or R configured acceptors, which compares favorably to the reactions performed with DHAP. The stereochemical outcome was different and depended on the N-Cbz-amino aldehyde enantiomer: the S acceptors gave the syn (3R,4S) aldol adduct whereas the R ones gave the anti (3R,4R) diastereomer. Moreover, the tactical use of Cbz protecting group allows simple and efficient elimination of borate and excess of DHA by reverse phase column chromatography or even by simple extraction. This, in addition to the use of unphosphorylated donor nucleophile, makes a useful and expedient methodology for the synthesis of structurally diverse iminocyclitols. The performance of aldol additions of dihydroxyacetone phosphate (DHAP) to N-Cbz-amino aldehydes using RhuA and L-fuculose-1-phosphate aldolase (FucA) catalyst in borate buffer was also evaluated. For FucA catalysts, including FucA F131A, the initial velocity of the aldol addition reactions using DHAP were between 2 and 10 times faster and the yields between 1.5 and 4 times higher than those in triethanolamine buffer. In this case, the retroaldol velocities measured for some aldol adducts were lower than those without borate buffer indicating some trapping effect that could explain the improvement of yields.     

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.     

2-ethynylaziridines as chiral carbon nucleophiles: stereoselective synthesis of 1,3-amino alcohols with three stereocenters via allenylindium reagents bearing a protected amino group

Allenylindium reagents bearing a protected amino group were effectively prepared from N-protected 3-alkyl-2-ethynylaziridines by treatment with InI in the presence of Pd(PPh(3))(4) and H(2)O. Stereoselective addition of the allenylindium to aliphatic or aromatic aldehydes affords 1,3-amino alcohols bearing three contiguous chiral centers: while 2,3-trans-2-ethynylaziridines yield syn,syn-2-ethynyl-1,3-amino alcohols predominantly, 2,3-cis-aziridines give anti,syn isomers selectively. Synthesis of highly substituted ethynylazetidines is also described.     

Diastereoselective reactions of delta-oxy-substituted allylic acetates with organocopper reagents

S(N)2' (gamma) substitutions of delta-substituted allylic acetates with Grignard reagents and copper catalysts proceed with high diastereoselectivities. With benzyloxy, methoxymethoxy, and tert-butyldimethylsiloxy groups, reactions favor the anti-isomer with selectivities up to anti:syn = >99:1. With a hydroxyl group, selectivities are reversed and the syn-isomer is favored with selectivities up to anti:syn = <1:99.     

Synthesis of Chiral alpha,delta-Dioxygenated Allylic Stannanes as Reagents for Carbohydrate Synthesis and Homologation

The delta-oxygenated allylic stannanes 4.4 and 4.5, prepared through addition of Bu(3)SnLi to gamma-OTBS crotonaldehyde 4.3c followed by etherification of the adduct with TBS-Cl or MOM-Cl, undergo transmetalation with InCl(3) and in situ addition to aldehydes leading to mainly anti adducts 5.1 or 5.2, accompanied by varying amounts of syn diastereomers. Selectivities of >95:5 can be realized with the MOM reagent 4.5 and ynals 4.3d and 4.3e or cyclohexanecarboxaldehyde 4.3a. With enals 4.3b and 4.3c, 80:20 mixtures of anti and syn adducts are formed. The S enantiomer 10.1 of stannane 4.5 has also been prepared as a reagent for carbohydrate synthesis. Accordingly, addition to alpha-ODPS acetaldehyde 10.2 in the presence of InCl(3) leads to the adduct 10.3 as an inseparable 90:10 mixture of anti and syn diastereomers. Dihydroxylation of the OTBS derivative 10.4 affords the potential altrose precursor 10.5 in 81% yield.     

Catalysis of 3-pyrrolidinecarboxylic acid and related pyrrolidine derivatives in enantioselective anti-Mannich-type reactions: importance of the 3-acid group on pyrrolidine for stereocontrol

The development of enantioselective anti-selective Mannich-type reactions of aldehydes and ketones with imines catalyzed by 3-pyrrolidinecarboxylic acid and related pyrrolidine derivatives is reported in detail. Both (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid and (R)-3-pyrrolidinecarboxylic acid efficiently catalyzed the reactions of aldehydes with alpha-imino esters under mild conditions and afforded anti-Mannich products with high diastereo- and enantioselectivities (anti/syn up to 99:1, up to >99% ee). For the reactions of ketones with alpha-imino esters, (R)-3-pyrrolidinecarboxylic acid was an efficient catalyst (anti/syn up to >99:1, up to 99% ee). Evaluation of a series of pyrrolidine-based catalysts indicated that the acid group at the beta-position of the pyrrolidine ring of the catalyst played an important role in forwarding the carbon-carbon bond formation and in directing anti-selectivity and enantioselectivity.     

Diastereoselective aldol additions of chiral beta-hydroxy ethyl ketone enolates catalyzed by Lewis bases

The trichlorosilyl enolates derived from chiral ethyl ketones bearing a beta-hydroxyl group and an alpha-stereogenic center were employed in the phosphoramide-catalyzed aldol reaction. The addition of Z-enolates to achiral aldehydes produced aldol products in good yields and high syn relative diastereoselectivities. The internal diastereoselectivity is controlled by the catalyst configuration, allowing for selective formation of either syn diastereomer. [reaction: see text]     

Scandium-catalyzed allylboration of aldehydes as a practical method for highly diastereo- and enantioselective construction of homoallylic alcohols

A general approach for the allylation of aldehydes using stable, air-tolerant camphor-based chiral allylboronates under Sc(OTf)3 catalysis is described. This practical methodology provides both syn and anti propionate units and other homoallylic alcohols with very high levels of diastereo- and enantioselectivity for several substrates, including functionalized aliphatic aldehydes useful toward the elaboration of complex natural products.     

Synthesis of screening substrates for the directed evolution of sialic acid aldolase: towards tailored enzymes for the preparation of influenza A sialidase inhibitor analogues

The stereoselective synthesis of two epimeric screening substrates, (4R, 5R, 6R)- and (4S, 5R, 6R)-6-dipropylcarbamoyl-2-oxo-4,5,6-trihydroxy-hexanoic acid, for the directed evolution of sialic acid aldolase is described. The complementary methods relied on stereoselective indium-mediated additions of ethyl alpha-bromomethyl acrylate to functionalised aldehydes. With an alpha-hydroxy aldehyde, (2R, 3R)-2,3-dihydroxy-4-oxo butanoic acid dipropylamide, the addition was chelation controlled, and the syn product, (6R, 5R, 4S)-6-dipropylcarbamoyl-2-methylidene-4,5,6-trihydroxy-hexanoic acid ethyl ester, was obtained. In contrast, the stereochemical outcome of the addition to (2R, 3R)-N,N-dipropyl-2,3-O-isopropylidene-4-oxobutyramide was consistent with Felkin-Anh control, and the anti adduct, (4R, 5R, 6R)-6-dipropylcarbamoyl-2-methylidene-4-hydroxy-5,6-O-isopropylidene-hexanoic acid ethyl ester, was the major product. Ozonolysis and deprotection gave the screening substrates as mixtures of furanose and pyranose forms, in good yields.     

Influence of carrier ligand NH hydrogen bonding to the O6 and phosphate group of guanine nucleotides in platinum complexes with a single guanine ligand

Coordinated N,N',N"-trimethyldiethylenetriamine (Me3dien) has several possible configurations: two have mirror symmetry (R,S configurations at the terminal nitrogens) and the terminal N-Me's anti or syn with respect to the central N-Me (anti-(R,S) and syn-(R,S) isomers, respectively), and two are nonsymmetrical (R,R and S,S configurations at terminal nitrogens, rac denotes a 1:1 mixture of the two isomers). For each configuration, two Me3dienPtG atropisomers can be formed (anti or syn orientation of central N-Me and G 06, G = guanine derivative), and these can be observed since the terminal N-Me's decrease the rate of G rotation about the Pt-N7 bond. In symmetrical syn-(R,S)-Me3dienPtG derivatives with G = 9-EtG and 3'-GMP, the anti rotamer, which can form O6-NH H-bonds, was slightly favored over the syn rotamer but never more than 2:1. This anti rotamer is also favored by lower steric repulsion between the terminal N-Me's and G O6; thus, the contribution of O6-NH H-bonding to the stability of the anti rotamer could be rather small. With G = 5'-GMP, an O6-NH H-bond in the anti rotamer and a phosphate-NH H-bond in the syn rotamer can form. Only the syn rotamer was detected in solution, indicating that NH H-bonds to 5'-phosphate are far more important than to O6, particularly since steric factors favor the anti rotamer. Interconversion between rotamers was faster for syn-(R,S)- than for rac-Me3dien derivatives. This appears to be determined by a smaller steric impediment to G rotation of two "quasi equatorial" N-Me's, both on one side of the platinum coordination plane (syn-(R,S) isomer), than one "quasi equatorial" and one "quasi axial" N-Me on either side of the coordination plane (rac isomer).     

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.     

Synthesis and Characterization of Oxotechnetium(V) Mixed-Ligand Complexes Containing a Tridentate N-Substituted Bis(2-mercaptoethyl)amine and a Monodentate Thiol

A series of 22 mixed-ligand complexes of the general formula TcOL(1)L(2), where L(1)H(2) are N-substituted bis(2-mercaptoethyl)amine ligands, [SN(R)S], and L(2)H are monodentate thiols as coligand, is reported. The complexes were prepared by the ligand exchange method using Tc-gluconate as precursor and equimolar quantities of the two ligands. In all cases the syn stereoisomer was formed in high yield and isolated as a crystalline product. In four cases HPLC analysis demonstrated the presence of the anti stereoisomer in the reaction mixture. Although the yield was less than 1%, one anti isomer, 4a, was successfully isolated as brown crystals. The isolated complexes were characterized by spectroscopic methods and elemental analysis. The formation of the two diastereomers, syn and anti, was expected due to the configuration of the nitrogen substituent (R) with respect to the central TcO core. The X-ray crystallography showed that the coordination geometry of the syn isomers 9, 11, and 18 is trigonal bipyramidal while for the anti isomer 4a it is distorted square pyramidal. This is the first documentation of syn/anti isomerism in N-substituted TcO[SN(R)S][S] mixed-ligand complexes.     

Highly enantioselective michael addition of silyl nitronates to alpha,beta-unsaturated aldehydes catalyzed by designer chiral ammonium bifluorides: efficient access to optically active gamma-nitro aldehydes and their enol silyl ethers

Highly enantioselective Michael addition of silyl nitronates to alpha,beta-unsaturated aldehydes has been accomplished by the utilization of designer N-spiro C2-symmetric chiral quaternary ammonium bifluoride 1 as an efficient catalyst, providing direct access to both optically active gamma-nitro aldehydes, a very useful precursor to various complex organic molecules including aminocarbonyls, and their enol silyl ethers, a Mukaiyama donor of potential synthetic utility for further selective transformations. For instance, the reaction of trimethylsilyl nitronate 2 (R1 = Me) with trans-cinnamaldehyde (R2 = Ph, R3 = H) in toluene in the presence of (R,R)-1 (2 mol %) proceeded smoothly at -78 degrees C to give the desired enol silyl ether 3 (R1 = Me, R2 = Ph, R3 = H) in 90% isolated yield (anti/syn = 83:17) with 97% ee (anti isomer), and simple treatment of 3 thus obtained with 1 N HCl in THF at 0 degrees C afforded the corresponding gamma-nitro aldehyde 4 quantitatively without loss of diastereo- and enantioselectivity.     

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).     

Chemistry of N-Boc-N-tert-butylthiomethyl-protected alpha-aminoorganostannanes: diastereoselective synthesis of primary beta-amino alcohols from alpha-aminoorganostannanes

Reaction of N-Boc-N-tert-butylthiomethyl-protected alpha-aminoorganostannanes with n-BuLi generates the corresponding alpha-aminoorganolithiums. Reactions of these organolithiums with aromatic aldehydes provides N-protected beta-amino alcohols with diastereoselectivities up to >99:1 anti/syn; with aliphatic aldehydes, diastereoselectivities were typically 1:1. Diastereoselectivities varied depending on the amount of aldehyde used. The N-protected beta-amino alcohols could be deprotected to primary amines by treatment with NaH to generate oxazolidinones followed by basic hydrolysis. Alternatively, treatment of the protected amino alcohols with acid furnished cyclic acetals that could be deprotected to primary amines with BF(3).OEt(2) and HS(CH(2))(3)SH. Transmetalation of enantiomerically enriched organostannanes with n-BuLi at -95 degrees C provided organolithiums that, although less configurationally stable than N-Boc-N-methyl-protected alpha-aminoorganolithiums, could be trapped with aldehydes with near-complete retention of configuration.     

Diastereoselective syntheses of new analogues of the farnesyltransferase inhibitor RPR 130401

The access to several benzo[f]perhydroisoindolic analogues of farnesyltransferase inhibitors from a single dienic precursor is reported. An initial [4 + 2] cycloaddition between diphenylisobenzofuran6 and pyrrolines 11, 14, and 15 led to either the syn or the anti isomers, depending on the mode of activation of the cycloaddition. The syn diastereomers were isolated in 90% de under 12 kbar at room temperature, while their anti counterparts were obtained with the same selectivity by warming the reaction mixture to 110 degrees C in toluene at atmospheric pressure. Both syn and anti adducts were separately N-deprotected, and the resulting amines reacted with an activated ester derived from the acid (20) to afford the final targets (5). Two new analogues (5a and 5b) of the FT inhibitor RPR 130401 were thus synthesized in a mere three-step synthetic scheme with overall yields from 30 to 60%.     

anti-selective direct asymmetric Mannich reactions catalyzed by axially chiral amino sulfonamide as an organocatalyst

A direct asymmetric Mannich reaction using a novel axially chiral amino trifluoromethanesulfonamide (S)-3 has been developed in highly anti-selective and enantioselective manners. Thus, in the presence of a catalytic amount of (S)-3, the reactions between aldehydes and the alpha-imino ester 4 proceed smoothly to give the functional beta-amino aldehydes with significantly higher anti/syn ratio and enantioselectivity than previously possible.     

Additions of enantioenriched allenylzinc and indium reagents to lactic aldehyde ethers

Allenylzinc and indium reagents were generated in situ through Pd(0)-catalyzed metalation of (R)- and (S)-3-butyn-2-ol methanesulfonate with Et(2)Zn and InI. These reagents add to the benzyl and TBS ethers of (S)-lactic aldehyde to afford diastereomeric stereotriads in moderate to high yield. The (S)/(S) combination afforded the anti,anti adducts with 94:6-100:0 diastereoselectivity. The (R)/(S) combination was mismatched, affording a mixture of anti,syn and syn,anti adducts in diastereomeric ratios of ca. 80:20-85:15. Addition of the racemic allenylmetal reagents to the (S)-lactic aldehyde ethers afforded the products of matched and mismatched pairings in equal amount.