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This paper describes the development of a new variant of stereoselective strain-release driven reactions (formal homo [3 + 2] dipolar cycloadditions) which utilize housane (1) to construct functionalized amino alcohols and pyridine-substituted cyclopentanes in two to three steps from simple and easily available building blocks (nitrones and pyridine N-oxides respectively).

The rich stereochemistry of the self-assembled monolayers (SAMs) of four butanethiols on Au(111) is described, the SAMs containing up to 12 individual C, S, or Au chiral centers per surface unit cell. This is facilitated by synthesis of enantiomerically pure 2-butanethiol (the smallest unsubstituted chiral alkanethiol), followed by in situ scanning tunneling microscopy (STM) imaging combined with density functional theory molecular dynamics STM image simulations. Even though butanethiol SAMs manifest strong headgroup interactions, steric interactions are shown to dominate SAM structure and chirality. Indeed, steric interactions are shown to dictate the nature of the headgroup itself, whether it takes on the adatom-bound motif RS(•)Au(0)S(•)R or involves direct binding of RS(•) to face-centered-cubic or hexagonal-close-packed sites. Binding as RS(•) produces large, organizationally chiral domains even when R is achiral, while adatom binding leads to rectangular plane groups that suppress long-range expression of chirality. Binding as RS(•) also inhibits the pitting intrinsically associated with adatom binding, desirably producing more regularly structured SAMs.

The interactions between the substrate and the ligand in the Sharpless AD reaction have been examined in detail, using a combination of substrate competition experiments and molecular modeling of transition states. There is a good agreement between computational and experimental results, in particular for the stereoselectivity of the reaction. The influence of each moiety in the second-generation ligand (DHQD)2PHAL on the rate and selectivity of the reaction has been elucidated in detail. 2005 Elsevier B.V. All rights reserved.

This paper describes a study of reactivity and enantioselectivity for a series of methyl-substituted styrenes in the Jacobsen-Katsuki (Mn(salen)-catalyzed) epoxidation reaction. Competition experiments provided kinetic data for the reactivity of the seven possible methyl-substituted styrenes (mono-, di- and trisubstituted) relative to styrene itself, ee values were measured by chiral GC, and absolute configurations were secured by chemical correlation. Of particular interest was the switch in absolute configuration at the benzylic position of the epoxides derived from (Z)- and (E)-alpha,beta-dimethylstyrene, respectively. The results could be rationalized in terms of an approach vector with the phenyl substituent proximal to the salen. As opposed to alkyl groups, a proximal phenyl group has very little effect on the rate of the reaction. Consideration of distal vs proximal approach allows prediction of absolute stereochemistry as a function of alkene substitution pattern. Trisubstituted alkenes with one phenyl group cis to the alkene hydrogen can be identified as a favored substrate class in the title reaction, with both rate and selectivity close to the classic (Z)-beta-substituted styrene substrates.

A study on the Stille reaction of alkenyl iodides and stannanes with structural resemblance to retrosynthetic fragments of a projected total synthesis of the marine alkaloid zoanthamine was carried out. A range of reaction conditions was examined, and a protocol developed by Corey utilizing excess copper(I) chloride and lithium chloride was found to be most efficient. The methodology was successfully applied to join two major fragments of the zoanthamine skeleton.

Copper mediated allylic substitutions and conjugate additions to geranyl, cinnamyl and allylic indole compounds have been investigated with the aim of finding a method for the creation of the all-carbon quaternary centre present in the natural product lyngbyatoxin A. Reaction conditions have been found giving a 68% SN2' selectivity in the copper mediated addition of PhMgBr to geranyl chloride, as well as 99% and 95% SN2' selectivity in the copper catalysed addition of EtMgBr to cinnamyl chloride and acetate, respectively. When the optimised reaction conditions were applied to the corresponding allylic compounds containing a 7-substituted indole moiety, the regioselectivity was reversed giving only the SN2 product. The allylic indole-containing substrates were also found to be unproductive in Pd- or Mo-catalysed SN2'-type substitution reactions. In related studies, copper catalysed conjugate addition of EtMgBr to the tricyclic lactam 6-methyl-pyrrolo[3,2,1-ij]quinolin-4-one gave a maximum of 20% of the 1,4-addition product.

This paper deals with an approach to the enantioselective total synthesis of Lyngbyatoxin A, with focus on the stereocontrolled introduction of the quaternary stereogenic centre. The key step in the synthesis involves an enantiospecific Lewis-acid mediated rearrangement of chiral vinyl epoxides carrying a 7-substituted indole moiety.

A vinylsilane-ketiminium ion cyclization involving iminium species derived from amines 6 and 7 was investigated experimentally as a possible approach to some biologically interesting 1-azaspirocycles. However, even under conditions of microwave irradiation at high temperatures no such cyclization was observed whereas (in line with previous results) the corresponding vinylsilane-aldiminium ion cyclizations were more successful. Aldiminium species substituted α to nitrogen displayed no diastereoselectivity in the cyclization of precursors derived from 6 while high trans diastereoselectivity could be obtained for iminium species derived from 7. Quantum-mechanical investigations of the general reaction mechanism underlined the lack of reactivity of ketiminium species and also convincingly explained the observed diastereoselectivities of aldiminium species. The calculations further revealed that (Z)-vinylsilanes cyclize via a silicon-stabilized β-carbocation, and that any formal aza-Cope rearrangement of the starting material to an allylsilane-iminium species does not take place in a concerted fashion. However, the calculations show that the aza-Cope rearrangement precedes cyclization for the corresponding (E)-vinylsilanes, the overall reaction being energetically slightly less favoured than cyclization of the (Z)-isomers.

A series of derivatives of 3-methyl-2-buten-1-ol has been used to test the scope and limitations of the copper-catalysed asymmetric cyclopropanation of trisubstituted alkenes by ethyl diazoacetate in the presence of C2-symmetric bis(oxazoline) ligands. In the best case, a trans/cis ratio of 91:9, with 92% ee for the major isomer, was obtained from the reaction of the p-methoxybenzoate derivative. The highest ee was 95%, for the trans isomer of a 80:20 diastereomer mixture (acetate derivative).

[reaction: see text] A racemic aldehyde can undergo parallel kinetic resolution (PKR) by simultaneous reaction with two different chiral phosphonates, differing either in the structure of the chiral auxiliary or in the structure of the phosphoryl group (i.e., one (E)- and one (Z)-selective reagent). This strategy allows conversion of a racemic aldehyde to two different, synthetically useful chiral products with essentially doubled material throughput and similar or improved selectivities as compared to conventional kinetic resolution.

This paper describes the use of selenium-based [2,3] sigmatropic rearrangement in combination with ruthenium-catalyzed ring-closing metathesis (RCM) for the synthesis of azaspiro ring systems, as exemplified by the reactions of model substrates 5 and 6 . The methodology has been applied to a short and efficient formal total synthesis of the alkaloid (±)-perhydrohistrionicotoxin ( 2 ). Thus, (±)-depentylperhydrohistrionicotoxin, 1 , a known key intermediate for the synthesis of 2 , was synthesised from 2,3-epoxycyclohexan-1-one in 10 laboratory operations and ca. 20% overall yield. The synthetic route is potentially enantioselective, and key steps were the [2,3] sigmatropic rearrangement of 11 to 12 via the corresponding allylic selenide (86% yield) and ruthenium-catalyzed RCM of 13 to 14 (80%).

A comparative study has been made of the performance of differently substituted Ca-symmetric bis(aziridine) ligands in a variety of metal-mediated asymmetric reactions. The metals studied were osmi ...

The chiral aziridino alcohols 1 -3 have been prepared either from amino acids (1a from serine; 1b - 1i and 3 from threonine; 2a - 2e from allo-threonine) or via asymmetric synthesis (1j, 1k, 1l and ...

Enantioselective Addition of Organolithium Reagents to Imines Mediated by C2-Symmetric Bis(aziridine) Ligands

A convergent enantioselective total synthesis of the neurotoxic spirocyclic alkaloid (−)-perhydrohistrionicotoxin (2) is described. A Lewis acid-mediated intramolecular imine ene-type reaction was used for the key spirocyclisation step (14 to 3, with 3 being obtained as a single diastereoisomer). Spirocyclisation precursor 14 was prepared from enantiomerically pure ketone 13, itself available via an efficient one-pot, three-component, coupling reaction involving chiral electrophiles 9 and 10. The stereogenic centres of 9 and 10 derive in turn from Sharpless kinetic resolution, which allowed access to both chiral electrophiles from a common racemic precursor, 8.

The regioselectivity of nucleophilic ring opening of some 3,4-epoxy and 3,4-aziridino alcohols has been studied. The nucleophiles chosen were complex hydrides (LiAlH4, Red-Al and DIBAL) and Lipshutz- or Gilman-type organocuprate reagents. The C-4 substituent in the substrates was varied in order to study steric and electronic effects on the ring opening reactions. For alkyl substituents at C-4, most of the results can be explained on the basis of intramolecular delivery of the nucleophile to C-3 via a six-membered transition state, leading to 1,4-diols or 1,4-amino alcohol derivatives. In general, the epoxy alcohols gave poorer regioselectivity than the N-tosyl aziridino alcohols, for which selectivities of >95:5 were routinely obtained. The activating effect of a phenyl group at C-4 led to a switch in regiochemistry, with the 1,3-diol or 1,3-amino alcohol derivative as the major product.

A convergent enantioselective total synthesis of the natural product (-)-balanol (1) is described. In addition to benzophenone fragment 8, key intermediates are chiral bicyclic aziridine 3 and the corresponding epoxide 4, both of which undergo highly regio- and stereoselective nucleophilic ring-opening reactions, allowing control of the two stereogenic centres of the target molecule. The structure and reactivity of 3 and 4 have been investigated in some detail.

A study has been made of the regio-and Stereoselectivity of the ring opening reactions of the 3-aryl substituted aziridines 1 and 2. The regiochemical outcome is apparently decided by a balance of electronic activation at C-3 by the phenyl group and the chelating effects of C-1 oxygen functionality which can direct nucleophiles intramoleculary to C-2 or C-3. Good levels of regiocontrol for either C-3 or C-2 attack are obtained particularly for the reactions of aziridino alcohols 1a and 2a with hydride reagents, while methyl-transfer reagents such as LiMe 2 Cu and AlMe 3 tend to give exclusive C-3 attack with inversion (cuprate) or inversion plus retention (trialkylaluminum). Possible reaction mechanisms (inter-vs. intramolecular) are discussed.

Three different routes to the hexahydroazepine unit of the natural products balanol ( 1 ) and ophiocordin ( 2 ) are described. The common starting material is the chiral epoxy alcohol 3 which is converted to the balanol degradation product 10 (Scheme 1) or to suitably protected derivatives thereof: 15 (Scheme 2) and 19 (Scheme 3). A key step in the first route is the acid-catalysed ring-opening of bicyclic aziridine 8 which proceeds in good chemical yield (71% isolated) and with remarkable regioselectivity (98:2 in favour of the desired regioisomer).

The readily available C2-symmetric bis(aziridines) 1 can act as ligands in a variety of asymmetric transformations mediated by transition metals. In the best cases, >95% ee can be obtained.

A systematic study has been made of the utility of readily available C 2 -symmetric aziridines as auxiliaries for asymmetric alkylation and aldol rea

A synthetic approach to the marine alkaloid Zoanthamine is outlined. Starting with (-)- perilly alkohol, the C-11 to C-20 fragment 9b has been synthesized in 12 operations and > 30% overall yield. Model studies for a proposed intramolecular Diels-Alder strategy are also described.

Herein is described the synthesis of a novel class of peptidyl FVIIa inhibitors having a C-terminal benzyl ketone group. This class is designed to be potentially suitable as stabilization agents of liquid formulations of rFVIIa, which is a serine protease used for the treatment of hemophilia A and B inhibitor patients. A library of compounds was synthesized with different tripeptide sequences, N-terminals and d -amino acids in the P3 position. Cbz- d -Phe–Phe–Arg–bk (33) was found to be the best candidate with a potency of Ki = 8 μM and no substantial inhibition of related blood coagulation factors (thrombin and FXa). Computational studies revealed that 33 has a very stable binding conformation due to intramolecular hydrogen bonds, which cannot be formed with l -Phe in the P3 position. Nonpolar amino acids were found to be superior, probably due to a minimization of the cost of desolvation upon binding to FVIIa.

The regio- and stereoselective carbonylation of optically pure trans vinylaziridine 5 to trans 3-vinylazetidinone 6 is catalyzed by Pd(0). Compound 6 is then transformed to a known key intermediate for the total synthesis of the carbapenem antibiotic (+)-PS-5.

This paper describes two enantioselective aziridine-based routes toward 1β-methylthienamycin, 2, and related carbapenems, the key steps being completely regioselective ring-opening reactions of the chiral aziridines 7 and 10 with AlMe3.

Nucleophilic ring-opening of trans and cis aziridino alcohols 1 ( 1′ ) and 2 ( 2′ ) by hydride- and by methyl-transfer reagents has been studied. In general, good to excellent C-2 selectivity was observed (the regioselectivity being better for the trans isomers) and the results can be interpreted in terms of directive effects exerted by the C-1 hydroxyl group. However, complete C-3 selectivity was observed in the reactions of 1 and 2 with AlMe 3 , indicating a complexation effect of the C-4 benzyloxy group in those cases.

The C2-symmetric aziridines 1 and 1′ (available from (+)- and (−)-tartaric acid, respectively) are excellent chiral auxiliaries for asymmetric alkylation and aldol reactions.

A novel and diastereoselective entry to the β-lactam nucleus of the carbapenems starting from L-glutamic acid is exemplified by the synthesis of the potential (+)-PS-5 intermediate 13 .

The non-racemic C2-symmetric azirdines7 and8, easily available from (+)- and (-)-tartaric acid, respectively, undergo rapid nucleophilic attack to yield products formally derived from the β-cation ofL- orD-aspartic acid.

Pyrrolidine-2,4-diones have been identified as a novel starting point for the synthesis of peptide analogues. This paper describes a method for the efficient and diastereoselective incorporation of this moiety into peptide chains to furnish di- and tripeptide analogs. The stability of these pyrrolidinone modified di- and tripeptides was found to be markedly improved when compared to that of a natural peptide. In addition, solid phase peptide synthesis employing a pyrrolidinone containing tripeptide is demonstrated.

The pyrrolidine-2,4-diones have been identified as a convenient starting point for the synthesis of peptide analogues. Herein we describe an optimized two-step reductive amination procedure, which provides a small library of pyrrolidinone-containing dipeptide analogues in high yield and excellent diastereoselectivity.

The development and application of three new solid-supported reagents for use in the synthesis or olefination of carbonyl compounds are described. The reagents include the Weinreb amide, Mukaiyama's S-2-pyridyl thioate and a Peterson methylenation reagent. As solid-supports p-benzyl alcohol resin, Wang resin and Merrifield resin (1–2% crosslinked polystyrene) have been used.

This paper describes the development of a straightforward experimental protocol for copper-mediated cross-coupling of amino acid derived beta-amido-alkylzinc iodides 1 and 3 with a range of acid chlorides. The present method uses CuCN.2LiCl as the copper source and for organozinc reagent 1 the methodology appears to be limited to reaction with more stable acid chlorides, providing the desired products in moderate yields. When applied to organozinc reagent 3, however, the protocol is more general and provides the products in good yields in all but one of the cases tested.

A new method for enantioconvergent synthesis has been developed. The strategy relies on the combination of an asymmetric Horner-Wadsworth-Emmons (HWE) reaction and a palladium-catalyzed allylic substitution. Different alpha-oxygen-substituted, racemic aldehydes were initially transformed by asymmetric HWE reactions into mixtures of two major alpha,beta-unsaturated esters, possessing opposite configurations at their allylic stereocenters as well as opposite alkene geometry. Subsequently, these isomeric mixtures of alkenes could be subjected to palladium-catalyzed allylic substitution reactions with carbon, nitrogen, and oxygen nucleophiles. In this latter step, the respective (E) and (Z) alkene substrate isomers were observed to react with opposite stereospecificity: the (E) alkene reacted with retention and the (Z) alkene with inversion of stereochemistry with respect to both the allylic stereocenter and the alkene geometry. Thus, a single gamma-substituted ester was obtained as the overall product, in high isomeric purity. The method was applied to a synthesis of a subunit of the iejimalides, a group of cytotoxic macrolides.

A short enantioselective synthesis of the spirocyclic alkaloid (+)-Nitramine ( 1 ) is reported, the azaspiro ring system being formed via intramolecular ring-opening of the chiral epoxy sulfone 7 .

The conformations and dynamic processes in two bicyclophanes have been analysed on the basis of temperature-dependent 1H NMR spectra. Both bicyclophanes are suggested to have a lowest-energy conformation of D3 symmetry in which the substituents at all ethylene bridges are gauche+ (or gauche−) oriented. The interconversion of the mirror image conformers of each bicyclophane equilibrates the two hydrogens in each methylene group, the barriers being ca 36 and 37 kJ mol−1, respectively, as determined by line-shape analysis.

An efficient enantioselective total synthesis of the antibiotic (+)-negamycin is described, the absolute stereochemistry deriving from ( R )-(+)-malic acid and subsequent use of the Sharpless asymmetric epoxidation reaction.

N-tosyl amides and lactams can be prepared easily and under mild conditions by the inter- or intramolecular condensation of carboxylic acids and secondary sulfonamides. The coupling reagent used is dicyclohexyl-carbodiimide (DCC) in the presence of 4-pyrrolidinopyridine (4-PPY) and the reactions proceed readily, usually in high yield, at room temperature.

The title compound has been synthesised by a reductive coupling of bibenzyl-4,4′- dicarbaldehyde and its dynamic properties and photoinduced isomerisations are briefly described.

The molecular structure and dynamic behaviour of the bridged [4n] annulene 1,6:9,14-bismethano-[16]annulene is unravelled by NMR and X-ray investigations, combined with force field calculations.

An enantioselective synthesis of the carbapenem antibiotic (+)-PS-5 is described. The starting point is the chiral Sharpless epoxy-alcohol 3 which is transformed stereospecifically to the aziridine 6 . Regioselective ring-opening of 6 by LiEt2Cu followed by RuO4 oxidation yields the β-sulfonamido carboxylic acid 8 which is cyclised under mild conditions and in excellent yield to the N-tosyl azetidinone 9 . Deprotection at nitrogen, unmasking of the side-chain hydroxyl and oxidation then furnishes 11 , a known advanced intermediate for (+)-PS-5.

The title compounds, 1 and 1 ', are readily available in four steps from 2-benzyloxymethyl-2-propen-1-ol, the key step being Sharpless asymmetric epoxidation to give the chiral epoxides 5 or 5 '. The total chemical yield of 1 or 1 ' is 50%, the final products being obtained essentially optically pure. By suitable protecting group manipulation, both title enantiomers can be produced from either of the antipodal epoxides 5 or 5 '.

Reductive coupling of cychoheptatriene-1,6-dialdehyde using a low-valent titanium reagent provides a one-step route to a paratropic bismethano [16] annulene.

Two simple, efficient and stereocontrolled routes to the cis -azaspiro-[5-5]-undecan-8-ol skeleton of the histrionicotoxin alkaloids are described.

Three cyclophanes, each displaying a different type of dynamic process, have been studied by NMR methods. The barriers to these processes are attributed mainly to the decrease in π-electron overlap between the benzene rings and adjacent double bonds which occurs in the transition state for each process. In [5 2 ] paracyclophanetetraene, two successive flippings of the benzene rings interconvert the two hydrogens in the methylene groups (Scheme 1). In tetramethyl [2 4 ] paracyclophanetetraene, the passage of one methyl group through the central cavity of the molecule interconverts two conformations of similar, but not equal, free energy (Scheme 2). In [2 6 ] orthoparacyclophanehexaene, the orthosubstituted rings change sides by passing through the centre of the cyclophane (Scheme 3).

The structure and dynamic stereochemistry of a novel paracyclophane formed by electrocyclic ring closure of a hexatriene-bridged precursor are described.

An enantioselective total synthesis of the 14-membered macrolide antibiotic ingramycin, 1 , is described. In a convergent approach three chiral fragments A , B and C are assembled, the allylic bromide A deriving its chirality from L -serine while the asymmetric centres in sulfones B and C are introduced via the Sharpless enantioselective epoxidation technique. After coupling of these fragments and a highly efficient macrolactonisation (82% yield) a final deprotection step furnishes the target compound.