Homologues of p-Menthane Derivatives in Roman Camomile

5-Isopropyl-2-propyl-2-cyclohexen-1-one ( 1 ) and 5-isopropyl-2-(2-methylpropyl)-2-cyclohexen-1-one ( 2 ), homologues of the p-methene ketone carvotanacetone, have been identified in the oil of Anthemis nobilis. Their synthesis involved allylation of a cyclohexane-1,3-dione, and the acid-catalyzed cyclization to dihydrofurans of the 2-allylcyclohexane-1,3-diones is described. The stereochemistry of metal hydride reduction of 3-ethoxy-5-isopropyl-2-propyl-2-cyclohexen-1-one ( 18 ) is mentioned in the course of the synthesis of the natural products. Some biogenetic considerations are discussed.     

A convenient and efficient route for the allylation of aromatic amines and alpha-aryl aldehydes with alkynes in the presence of a Pd(0)/PhCOOH combined catalyst system

The allylation of aromatic amines with alkynes proceeded smoothly in the presence of catalytic amounts of Pd(PPh(3))(4) and benzoic acid. The allylation products were obtained in high yields in a regio- and stereoselective manner. The effect of various groups on the nitrogen atom of anilines was studied. Regardless of the substituent (electron withdrawing or electron donating) on the aromatic ring, the reaction proceeded well. Various functionalities, including -CH(3), -OMe, -Cl, -CN, -COOMe, -NO(2) and -COCH(3) were tolerated under the reaction conditions. Similarly, the allylation of alpha-aryl aldehydes proceeded well with the same level of regio- and stereoselectivity as the allylation of aromatic amines. This reaction provides the second example of the transition metal catalyzed direct alpha-allylation of aldehydes.     

From sigma- to pi-electrophilic Lewis acids. Application to selective organic transformations

Computed enthalpies of formation for various Lewis acid complexes with representative unsaturated compounds (aldehydes, imines, alkynes, and alkenes) provide a means to evaluate the applicability of a particular catalyst in a catalytic reaction. As expected, main group Lewis acids such as BX3 show much stronger complexes with heteroatoms than with carbon-carbon multiple bonds (sigma-electrophilic Lewis acids). Gold(I) and copper(I) salts with non-nucleophilic anions increase the relative strength of coordination to the carbon-carbon multiple bonds (pi-electrophilic Lewis acids). As representative examples for the use of sigma-electrophilic Lewis acids in organic synthesis, the Lewis acid mediated allylation reactions of aldehydes and imines with allylic organometallic reagents which give the corresponding homoallyl alcohols and amines, respectively, are mentioned. The allylation method is applied for the synthesis of polycyclic ether marine natural products, such as hemibrevetoxin B, gambierol, and brevetoxin B. As representative examples for the use of pi-electrophilic Lewis acids in organic synthesis, the Zr-, Hf-, or Al-catalyzed trans-stereoselective hydro- and carbosilylation/stannylation of alkynes is mentioned. This method is extended to sigma-pi chelation controlled reduction and allylation of certain alkynylaldehydes. Gold- and copper-catalyzed benzannulation of ortho-alkynylaldehydes (and ketones) with alkynes (and alkenes) is discovered, which proceeds through the reverse electron demand Diels-Alder type [4+2] cycloaddition catalyzed by the pi-electrophilic Lewis acids. This reaction is applied for the short synthesis of (+)-ochromycinone. Palladium and platinum catalysts act as a sigma- and/or pi-electrophilic catalyst depending on substrates and reaction conditions.     

Total synthesis of (+/-)-alpha-isosparteine, (+/-)-beta-isosparteine, and (+/-)-sparteine from a common tetraoxobispidine intermediate

The three title alkaloids were separately prepared in stereocontrolled fashion from a common tetraoxobispidine precursor, 3,7-diallyl-2,4,6,8-tetraoxo-3,7-diazabicyclo[3.3.1]nonane (16). Bisimide 16 was generated from malonate via acid promoted cyclization of the Knoevenagel condensation adduct 1,1,3,3-propanetetracarboxamide. (+/-)-alpha-Isosparteine (dl-2) was elaborated from 16 in 28% overall yield by a two-directional synthetic sequence composed of four reactions: double addition of allylmagnesium bromide, ring-closing olefin metathesis (RCM), hydrogenation, and borane mediated reduction. (+/-)-beta-Isosparteine (dl-3) was targeted along similar lines by a strategic reversal in allylation and reduction operations on the core synthon. Thus, 16 was advanced to dl-3 in five steps and 12% overall yield by a reaction sequence commencing with sodium borohydride mediated reduction and followed by double Sakurai-type allylation of the resulting bishemiaminal. The synthesis of dl-3 was concluded by RCM and then global reduction (H2, Pd/C; LiAlH4). The final target, (+/-)-sparteine (dl-1), was secured in six steps and 11% overall yield from 16 by monoreduction and Sakurai allylation, followed by allyl Grignard addition and then RCM and global reduction as before. Reasons for the inherent C2-type regioselectivity of net double nucleophilic additions to tetraoxobispidines are discussed and enantioselective oxazaborolidine mediated reduction of the N,N'-dibenzyl congener of 16 is reported.     

Allylation of aldehydes and imines: promoted by reuseable polymer-supported sulfonamide of N-glycine

[reaction: see text] A allylation of aldehydes and imines (generated in situ from aldehydes and amines) with allyltributyltin promoted by recoverable and reusable the polymer-supported sulfonamide of N-glycine has been developed. Good to high yields were obtained in various cases. Most of the SnBu(3) residue can be recovered as Bu(3)SnCl. Highly stereoselective synthesis of N-Boc-(2S,3S)-3-hydroxy-2-phenylpiperidine 7 was achieved by using the P4a-mediated allylation of Boc-l-phenylglycinal as a key step.     

Innovative reactions mediated by zirconocene

Radical reactions mediated by Schwartz reagent and zirconocene(alkene) complex are firstly described. Schwartz reagent is a promising alternative to tributyltin hydride and the first transition metal hydrido complex used as a radical mediator in organic synthesis. A zirconocene(alkene) complex effects single electron transfer to alkyl halide to generate the corresponding alkyl radical. Secondly, serendipitous allylic C-H bond activation of the coordinating alkene of zirconocene(alkene) complex and its application to organic synthesis are summarized. By utilizing equilibrium between zirconocene(alkene) and zirconocene 2-alkenyl hydride, reaction of acid chloride with zirconocene(alkene) provides the corresponding homoallylic alcohol by sequential attacks of the hydride and 2-alkenyl moieties. A set of hydride and 2-alkenyl attacks on 1,4-diketone yields 6-heptene-1,4-diol derivative in high yield with high stereoselectivity. Selective capture of the hydride with diisopropyl ketone gives zirconocene 2-alkenyl alkoxide, which is a useful reagent for stereoselective allylation of aldehyde and imine. alpha-Halo carbonyl compounds undergo radical allylation with the zirconocene 2-alkenyl alkoxide which serves as a substitute for allyltin.     

Mechanistic studies on the B(C(6)F(5))(3) catalyzed allylstannation of aromatic aldehydes with ortho donor substituents

Mechanistic studies on the B(C(6)F(5))(3) catalyzed allylstannation of isomeric substituted benzaldehydes are reported. Confirming a report by Maruoka et al., good (5:1) to excellent (>20:1) selectivities for ortho over para isomers are observed when 1:1 mixtures (X = OMe, Cl, F, OTBS) are allylstannated with C(3)H(5)SnBu(3) in the presence of B(C(6)F(5))(3) (2.5% per CHO). The best selectivities are observed for the anisaldehydes. Multinuclear NMR studies on solutions of B(C(6)F(5))(3) and C(3)H(5)SnBu(3) (1:1 to 1:5) show that the borane abstracts the allyl group from the organotin reagent, forming an adduct (C(6)F(5))(3)B...CH(2)CHCH(2)SnBu(3), 1, or ion pair [(C(6)F(5))(3)BCH(2)CH=CH(2)](-)[Bu(3)SnCH(2)CHCH(2)SnBu(3)](+), 2, depending on the reagent ratio. These compounds are important in the mechanism of Lewis acid catalyzed 1,3-isomerization of substituted allyl stannanes. When allyltin reagent is added to solutions of B(C(6)F(5))(3) and ortho-anisaldehyde (1:5) at -60 degrees C, conversion to the stannylium ion pair [Bu(3)Sn(ortho-anisaldehyde)(2)](+)[o-ArCH(allyl)OB(C(6)F(5))(3)](-), o,o-4, is observed. The structure of this species was confirmed by (1)H, (11)B, (19)F, and (119)Sn NMR spectroscopy and by forming related ion pairs (o-5 and o,o-5) utilizing the [B(C(6)F(5))(4)](-) counteranion via reaction of [Bu(3)Sn](+)[B(C(6)F(5))(4)](-) with aldehyde. The anion in o,o-4 is formed via direct allylation of the ortho-anisaldehyde/B(C(6)F(5))(3) adduct o-3, while the cation arises upon aldehyde ligation of the resulting tributylstannylium ion. The crystal structure of the related derivative ortho-C(6)H(4)(OMe)CHO x SnMe(3)BF(4), 6, showed that the aldehyde binds the tin nucleus only through the carbonyl oxygen. Similar reactions using para-anisaldehyde show that formation of p,p-4 occurs at a much slower rate, again demonstrating the preference for the ortho substituted substrates. For similar experiments using benzophenone, however, formation of the ion pair [Bu(3)Sn(Ph(2)CO)(2)](+)[(C(3)H(5))B(C(6)F(5))(3)](-), 8, was observed, illustrating the differences subtle changes in substrate can bring. Ion pair 8 is formed via the trapping of 1 by the benzophenone substrate. In the presence of excess aldehyde and allyltin reagent, ion pair o,o-4 catalyzes the allylstannation of aldehyde to give the product stannyl ether. Several lines of experimental evidence suggest this is the true catalyst in the system. The chemoselectivity observed thus does not rely on classical chelation control in any way. Rather, we propose that the ortho donor group stabilizes the developing positive charge at the beta carbon of the allyl group and the tin atom during the allylation event. This stabilization renders the ortho substituted substrates kinetically favored toward allylation irrespective of the Lewis acid employed.     

Structurally Defined Allyl Compounds of Main Group Metals: Coordination and Reactivity

Organometallic allyl compounds are important as allylation reagents in organic synthesis, as polymerization catalysts, and as volatile metal precursors in material science. Whereas the allyl chemistry of synthetically relevant transition metals such as palladium and of the lanthanoids is well‐established, that of main group metals has been lagging behind. Recent progress on allyl complexes of Groups 1, 2, and 12–16 now provides a more complete picture. This is based on a fundamental understanding of metal–allyl bonding interactions in solution and in the solid state. Furthermore, reactivity trends have been rationalized and new types of allyl‐specific reactivity patterns have been uncovered. Key features include 1) the exploitation of the different types of metal–allyl bonding (highly ionic to predominantly covalent), 2) the use of synergistic effects in heterobimetallic compounds, and 3) the adjustment of Lewis acidity by variation of the charge of allyl compounds.     

Synthesis of substituted benzenes and phenols by ring-closing olefin metathesis

New synthetic approaches to substituted aromatic compounds are reported. Ring-closing olefin metathesis (RCM)/dehydration and RCM/tautomerization are the key processes in the synthesis of substituted benzenes 3 and phenols 6, respectively. Readily accessible 1,5,7-trien-4-ols 7, which are the precursors of benzenes, were prepared from beta-halo-alpha,beta-unsaturated aldehydes 11 or beta-halo-alpha,beta-unsaturated esters 19 by utilizing reliable transformations in which cross-coupling with vinylic metal reagents 12 and allylation with allylic metal reagents 13 were employed as carbon-carbon bond forming reactions. RCM of 7, followed by dehydration, afforded a wide variety of substituted benzenes 3. In addition, RCM of 1,5,7-trien-4-ones 9, which were prepared by oxidation of 7, furnished various substituted phenols 6 by automatic tautomerization.     

结构新颖的金属双核烯丙基试剂的合成及其芳香醛烯丙基化反应

报道了一个简捷的芳香醛的烯丙基化反应的新体系. 通过使用新型的金属双核烯丙基锡试剂(含有Sn—M键, M=Mn或Fe)与醛在二氯甲烷中反应, 无需使用任何辅助试剂, 直接得到较高产率(42％~98％)的高烯丙基醇. 实验结果证明过渡金属基团及M—Sn键具有相当高的活化锡原子上的烯丙基基团的作用.     

Synthesis and evaluation of calystegine B2 analogues as glycosidase inhibitors.

A practical synthesis of polyhydroxylated 6-oxa-nor-tropanes incorporating the essential structural features of calystegine B(2) from 5-deoxy-5-thioureido and 5-ureido-L-idofuranose precursors is presented. The methodology relies on the ability of pseudoamide-type nitrogen atoms (thiourea, urea, and carbamate) to undergo nucleophilic addition to the masked aldehyde group of the monosaccharide. The generated hemiaminal functionality may further undergo in situ intramolecular glycosidation to give the bicyclic aminoacetal compounds, the whole process being favored by the anomeric effect. A series of derivatives bearing different substituents at nitrogen has been prepared and screened against several glycosidases in comparison with xylonojirimycin-type piperidine analogues. Interestingly, strong and highly specific inhibition of bovine liver beta-glucosidase was observed for 6-oxacalystegine B(2) analogues incorporating aromatic pseudoaglyconic groups. On the basis of these data, a 1-azasugar inhibition mode is proposed for this family of glycomimetics.     

Synthesis of syn-vicinal diamines via the stereoselective allylation of acyclic chiral α-amino aldimines

The stereoselective allylation of acyclic chiral α-amino aldimines affording vicinal diamines, mediated by various Lewis acids (TiCl₄, SnCl₄, MgBr₂·OEt₂, BF₃·OEt₂, ZnCl₂), is described. The TiCl₄-mediated allylation of an α-N-Boc aldimine afforded the allylation product with syn-selectivity, which in turn was used for the synthesis of an intermediate of an oseltamivir derivative.     

Investigation into the allylation reactions of aldehydes promoted by the CeCl3.7H2O-NaI system as a Lewis acid

The Lewis acid promoted allylation of aldehydes has become an important carbon-carbon bond forming reaction in organic chemistry. In this context, we have developed an alternative over existing catalytic processes, wherein aldehydes are subject in acetonitrile to reaction of allylation with allyltributylstannane in the presence of 1.0 equiv of cerium(III) chloride heptahydrate (CeCl(3).7H(2)O), an inexpensive and mild Lewis acid. The allylation has been accelerated by using an inorganic iodide as a cocatalyst, and various iodide salts were examined. The procedure must use allylstannane reagent instead of allylsilane reagent, desirable for environmental reasons, but high chemoselectivity was observed, and this is opposite the results obtained with other classical Lewis acids such as TiCl(4) and Et(2)O.BF(3).     

Diastereoselective allylation of N-glyoxyloyl-(2R)-bornane-10,2-sultam and (1R)-8-phenylmenthyl glyoxylate: synthesis of (2S,4S)-2-hydroxy-4-hydroxymethyl-4-butanolide

The diastereoselective addition of allylsilanes and allylstannanes to N-glyoxyloyl-(2R)-bornane-10,2-sultam 1 and (1R)-8-phenylmenthyl glyoxylate 7 in the presence of Lewis acids has been studied. We obtained diastereoselectivities up to 84% and 94% for the allylation of 2 and 7, respectively. The application of the allylation products of 1 or 2 in the synthesis of 4-butanolides, for example (2S,4S)-2-hydroxy-4-hydroxymethyl-4-butanolide 13 is presented.     

Catching the first oligomerization event in the catalytic formation of polyaminoboranes: H3B·NMeHBH2·NMeH2 bound to iridium

We report the first insertion step at a metal center for the catalytic dehydropolymerization of H(3)B·NMeH(2) to form the simplest oligomeric species, H(3)B·NMeHBH(2)·NMeH(2), by the addition of 1 equiv of H(3)B·NMeH(2) to [Ir(PCy(3))(2)(H)(2)(η(2)-H(3)B·NMeH(2))][BAr(F)(4)] to give [Ir(PCy(3))(2)(H)(2)(η(2)-H(3)B·NMeHBH(2)·NMeH(2))][BAr(F)(4)]. This reaction is also catalytic for the formation of the free linear diborazane, but this is best obtained by an alternative stoichiometric synthesis.     

Palladium-catalyzed allylation and deacylative allylation of 3-acetyl-2-oxindoles with allylic alcohols

The Pd-catalyzed allylation of 3-acetyl-2-oxindoles with allyl alcohol is performed using 3 mol% of Pd(dba)₂, rac-BINAP and BINOL phosphoric acid as catalytic mixture. This procedure allows the in situ synthesis of 3-allyl-2-oxindole by adding Triton B to the reaction mixture. The deacylative allylation of 3-acetyl-3-methyl-2-oxindoles with allylic alcohols is carried out with 3 mol% of Pd(OAc)₂, dppp and 1.5 equiv. of LiOtBu as base affording the corresponding 3,3-disubstituted 2-oxindoles in good yields. Both methodologies can be combined for the preparation of unsymmetrical 3,3-diallylated 2-oxindoles such as compound 7. The DaA must be carried out in the absence of oxygen in order to avoid the competitive formation of 3-alkyl-3-hydroxy-2-indoles. The later compounds can be easily obtained by deacylative oxidation of 3-alkylated 3-acetyl-2-oxindoles with LiOEt at rt under air.     

An atom efficient route to N-aryl and N-alkyl pyrrolines by transition metal catalysis

The synthesis of N-aryl, N-tosyl, and N-alkyl pyrrolines from allyl alcohols and amines has been developed. The reaction sequence includes a palladium-catalyzed allylation step in which non-manipulated allyl alcohol is used to generate the diallylated amine in good to excellent yield. An excess of allyl alcohol was necessary for efficient diallylation of the amine, where the excess alcohol could be recycled three times. For aryl and tosyl amines, Pd[P(OPh)(3)](4) was used and for benzyl and alkyl amines a catalytic system comprising Pd(OAc)(2), P(n)Bu(3), and BEt(3) was used. Both the electronic properties and the steric influence of the amine affected the efficiency of the allylation. The isolated diallylated amines were transformed into their corresponding pyrrolines by ring-closing metathesis catalyzed by (H(2)IMes)(PCy(3))Cl(2)RuCHPh in good to excellent yield. A one-pot reaction was developed in which aniline was transformed into the corresponding pyrroline without isolating the diallylated intermediate. This one-pot reaction was successfully scaled-up to 1 mL of aniline in which the N-phenyl pyrroline was isolated in 95% yield. The versatility of the reaction in which 3-methyl-1-phenyl pyrroline was prepared in two-steps was demonstrated.     

Counterintuitive kinetics in Tsuji-Trost allylation: ion-pair partitioning and implications for asymmetric catalysis

The kinetics of Pd-catalyzed Tsuji-Trost allylation employing simple phosphine ligands (L = Ar3P, etc.) are consistent with turnover-limiting nucleophilic attack of an electrophilic [L2Pd(allyl)]+ catalytic intermediate. Counter-intuitively, when L is made more electron donating, which renders [L2Pd(allyl)]+ less electrophilic (by up to an order of magnitude), higher rates of turnover are observed. In the presence of catalytic NaBAr'F, large rate differentials arise by attenuation of ion-pair return (via generation of [L2Pd(allyl)]+ [BAr'F]-) a process that also increases the asymmetric induction from 28 to 78% ee in an archetypal asymmetric allylation employing BINAP (L*) as ligand. There is substantial potential for analogous application of [M]n+([BAr'F]-)n cocatalysis in other transition metal catalyzed processes involving an ionic reactant or reagent and an ionogenic catalytic cycle.     

Enantiospecific total synthesis of the putative structure of cryptopyranmoscatone B2

Total synthesis of THP tethered pyrone containing natural product cryptopyranmoscatone B2 was accomplished from commercially available 2-deoxyribose. The key THP unit was assembled by FeCl₃ catalyzed cyclization of an allyl alcohol. Brown allylation and RCM reactions were employed to construct the lactone unit. The synthesis represents the first total synthesis of the putative structure of the natural product.     

Total Synthesis of Aculeatins A and B from L‐Malic Acid

An efficient total synthesis of the cytotoxic spiroketal natural products aculeatin A and B is described. The synthesis of the 1,3,5‐triol moiety with appropriate configuration was accomplished from the commercially available L ‐malic acid. The key steps in this synthesis are the Barbier allylation, LiAlH₄/LiI‐mediated syn‐stereoselective 1,3‐asymmetric reduction, and phenyliodine bis(trifluoroacetate) (=[bis(trifluoroacetoxy)iodo]benzene; PIFA) mediated oxidative spirocyclization.