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A variety of tetrahydropyranoindoles and related scaffolds are synthesized from allylic ethers via an isomerization/oxocarbenium cyclization sequence.

This new approach represents an attractive alternative to the classical Pictet—Spengler reaction.

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.

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 .

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.

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.

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.

The chiral bis(aziridines) 4, 6 and 7 have been synthesized and evaluated as chelating ligands for a variety of asymmetric transformations mediated by metals. The processes studied were the asymmetric addition of osmium tetroxide to olefins, copper-catal

Simple Aziridino Alcohols as Chiral Ligands. Enantioselective Additions of Diethylzinc to N-Diphenylphosphinoylimines

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.

This paper describes the construction of three key intermediates 11, 15 and 23 for a projected total synthesis of the marine alkaloid zoanthamine. These building blocks, corresponding to the C-1-C-5, C-6-C-10, and C-11-C-24 fragments of the target molecu

Preparation and Use of Aziridino Alcohols as Promoters for the Enantioselective Addition of Dialkylzinc Reagents to N-(Diphenylphosphinoyl) Imines

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.

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

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 ...

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 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.

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 α-oxygen-substituted, racemic aldehydes were initially transformed by asymmetric HWE reactions into mixtures of two major α,β-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 γ-substituted ester was obtained as the overall product, in high isomeric pu...

A novel method for the synthesis of bicyclic amines has been developed. Cyclisation of 1,6-dienes by intramolecular hydrovinylation in the presence of catalytic amounts of allylpalladium chloride dimer afforded bicyclic amines in one step. Added phosphines, silver salts, as well as the nature of the N-protecting group influenced the yield and selectivity of the reactions. Most strikingly, intramolecular hydrovinylation allowed the preparation of diastereomerically pure bicyclic amines as e.g. hexahydroindoles 2a–2d.

This tutorial review presents some recent examples of intramolecular Diels–Alder (IMDA) reactions as key complexity-generating steps in the total synthesis of structurally intricate natural products. The opportunities afforded by transannular (TADA) versions of the IMDA reaction in complex molecule assembly are also highlighted. The review is aimed at a wide audience, ranging from advanced undergraduates to seasoned practitioners of total synthesis; since this is an educational overview, only selected highlights from the period 2000–2009 are presented, along with chosen references to other, more comprehensive, reviews.

The tricyclic compound 13, representing the framework of the cylindricine 4 and lepadiformine 5alkaloids, was prepared in a single operation via the first example of a transannular Mannich reaction involving a macrocyclic diketoamine 12.

The complex marine alkaloid norzoanthamine (2) was envisioned to be assembled from three key building blocks: the C1-C5 fragment A, the C6-C10 fragment B, and the C11-C24 fragment C. The synthesis of fragment A was achieved in 14 steps and 33% overall yield from (R)-gamma-hydroxymethyl-gamma-butyrolactone. Fragment B was made in two steps from PMB-protected 4-pentynol in 76% yield. The C11-C24 fragment C was made from (S)-carvone via (R)-isocarvone in 18 steps (6% overall yield). The convergent stereoselective synthesis of the entire carbon framework (C1-C24) of the target molecule was achieved via the following assemblage. Alkenyl iodide 20 derived from the C11-C24 fragment C was coupled to fragment B (C6-C10) through a high-yielding Stille coupling reaction of these two sterically very demanding coupling partners, affording the key Diels-Alder precursor 24. The intramolecular Diels-Alder reaction proceeded smoothly in excellent yield and diastereoselectivity, generating the tricyclic trans-anti-trans perhydrophenanthrene motif of norzoanthamine (C6-C24). The final fragment coupling between lithiated fragment A (C1-C5) and aldehyde 40 (C6-C24) has also been successfully accomplished affording the entire carbon framework of the natural product.

Substituted aryl aminobenzophenone p38 MAP kinase inhibitors were synthesized in good to excellent yields using palladium-catalyzed aryl amination under conditions of microwave irradiation. Various ligands have been screened, and the reaction conditions were optimized. These coupling reactions are suitable for various anilines and aryl bromides that bear a variety of functional groups. Some leaving groups (iodides, chlorides, triflates, and tosylates) other than bromides have also been investigated. By this method, a large number of aryl aminobenzophenone p38 MAP kinase inhibitors were prepared in short order.

A series of terminal propargylic alcohols and their derivatives were subjected to Pd-catalyzed silastannation. In all reactions, complete regio- and stereoselectivities were observed with the tributyltin moiety exclusively adding to the internal carbon of the triple bond in a cis fashion, including the first example of a diyne bis-silastannation. Silastannation reaction products could sequentially be protiodesilylated or iododestannylated, thus providing synthetic routes to 1,1-gem-disubstituted alkenylstannanes and iodides, respectively.

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 title ketone has been synthesised in 96% e.e. from the corresponding methyl ester and MeLi. The [α]D value for the product was considerably higher than values previously reported for the enantiomer.

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 '.

Enantiomerically pure 2,3- epoxy alcohols are transformed readily and stereospecifically to the corresponding aziridines, regioselective ring-opening of which allows subsequent conversion to chiral β-lactams suitable for elaboration to the title antibiotic.

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.

Two stereocontrolled routes to the alkaloid depentylperhydrohistrionicotoxin 3 , are described. The key steps are alkylation, with retention of configuration, of the iodide 8 and the mesylate 12 , respectively. A tricyclic aziridinium species is proposed as the reactive intermediate in the latter reaction. The synthesis of 3 represents a formal total synthesis of the title alkaloid.