Macrocyclic Substrates Research Articles

Transamidation-Driven Molecular Pumps.

We report a new class of synthetic molecular pumps that use a stepwise information ratchet mechanism to achieve the kinetic gating required to sequester their macrocyclic substrates from bulk solution. Threading occurs as a result of active template reactions between the pump terminus amine and an acyl electrophile, whereby the bond-forming reaction is accelerated through the cavity of a crown ether. Carboxylation of the resulting amide results in displacement of the ring to the collection region of the thread. Conversion of the carbamate to a phenolic ester provides an intermediate rotaxane suitable for further pumping cycles. In this way rings can be ratcheted onto a thread from one or both ends of appropriately designed molecular pumps. Each pumping cycle results in one additional ring being added to the thread per terminus acyl group. The absence of pseudorotaxane states ensures that no dethreading of intermediates occurs during the pump operation. This facilitates the loading of different macrocycles in any chosen sequence, illustrated by the pump-mediated synthesis of a [4]rotaxane containing three different macrocycles as a single sequence isomer. A [5]rotaxane synthesized using a dual-opening transamidation pump was structurally characterized by single-crystal X-ray diffraction, revealing a series of stabilizing CH···O interactions between the crown ethers and the polyethylene glycol catchment region of the thread.

Stereodivergent Synthesis of Lankacyclinol and Its C2/C18-Congeners Enabled by a Bioinspired Mannich Reaction.

Lankacidin-group antibiotics are complex polyketides typically with a synthetically challenging 17-membered carbocyclic ring. Herein we evolved an alternative palladium-catalyzed coupling-based strategy for constructing this structural moiety. After assembling the two advanced fragments under basic conditions in a biphasic system, of the four possible Mannich adducts, two separable adducts bearing identical C2-stereochemistries were formed in high combined yields, and the ratio of them can be altered by changing the reaction conditions from dichloromethane and 23 °C (18R/18S, 1.5:1) to toluene and 100 °C (18R/18S, 1:3.5). Subsequent base-promoted decarboxylation at lower temperatures unexpectedly favored the formation of the 2,18-anti product, which is less accessible via the reaction carried out on known macrocyclic substrates. All four biosynthetically related C2/C18-isomeric lankacyclinols can be smoothly yielded after Stille macrocyclization, followed by global desilylation. The antimycobacterial activity of the synthetic lankacyclinols and several macrolatonic congeners were preliminarily evaluated.

Catalyst-Controlled Transannular Polyketide Cyclization Cascades: Selective Folding of Macrocyclic Polyketides.

The biomimetic synthesis of aromatic polyketides from macrocyclic substrates by means of catalyst-controlled transannular cyclization cascades is described. The macrocyclic substrates, which feature increased stability and fewer conformational states, were thereby transformed into several distinct polyketide scaffolds. The catalyst-controlled transannular cyclizations selectively led to aromatic polyketides with a defined folding and oxygenation pattern, thus emulating β-keto-processing steps of polyketide biosynthesis.

Catalyst‐Controlled Transannular Polyketide Cyclization Cascades: Selective Folding of Macrocyclic Polyketides

AbstractThe biomimetic synthesis of aromatic polyketides from macrocyclic substrates by means of catalyst‐controlled transannular cyclization cascades is described. The macrocyclic substrates, which feature increased stability and fewer conformational states, were thereby transformed into several distinct polyketide scaffolds. The catalyst‐controlled transannular cyclizations selectively led to aromatic polyketides with a defined folding and oxygenation pattern, thus emulating β‐keto‐processing steps of polyketide biosynthesis.

2+2+2] Cycloaddition Reactions of Macrocyclic Systems Catalyzed by Transition Metals. A Review

Polyalkyne and enediyne azamacrocycles are prepared from arenesulfonamides and various alkyne and alkene derivatives either under basic or neutral conditions. The new family of macrocyclic substrates is tested in the [2+2+2] cycloaddition reaction. Several catalysts are used for the cycloisomerization reaction, and their enantioinduction is evaluated as appropriate. The effect of the structural features of the macrocycles, namely the ring size, substituents in precise positions and the number and type of unsaturations, on the [2+2+2] cycloaddition reaction has also been studied.

TEMPO/NaIO4−SiO2: A Catalytic Oxidative Rearrangement of Tertiary Allylic Alcohols to β-Substituted α,β-Unsaturated Ketones

The novel catalytic method for the oxidative rearrangement of tertiary allylic alcohols to beta-substituted alpha,beta-unsaturated ketones is described. TEMPO/NaIO4-SiO2 causes facile and efficient oxidative rearrangement of various acyclic substrates as well as medium-sized and macrocyclic substrates.

Oxidative Rearrangement of Tertiary Allylic Alcohols Employing Oxoammonium Salts

Practical and highly efficient methods for oxidative rearrangement of tertiary allylic alcohols to beta-substituted alpha,beta-unsaturated carbonyl compounds employing oxoammonium salts are described. The methods developed are applicable to acyclic substrates as well as medium membered ring substrates and macrocyclic substrates. The counteranion of the oxoammonium salt plays crucial roles on this oxidative rearrangement.

Comparative study of conformational effects on stereoselective lipase catalysed acetylation of sec hydroxy groups in diastereomeric 14-membered lactones and their acyclic analogs

Stereoselective acetylation of sec hydroxy groups in a diastereomeric (1:1) mixture of macrocyclic lactones 14, 15, catalysed by seven microbial lipases in n-heptane afforded the C(7)- O-acetyl derivative 17 with up to 99% diastereomeric excess (d.e.), whereas acetylation of their acyclic analogs 10, 11 afforded C(5)- O-acetyl derivative 13 with up to 93% d.e. Six lipases, from Pseudomonas cepacia (PCL), Pseudomonas fluorescens (PFL), Geotrichum candidum (GCL), Candida cylindracea (CCL) and Pseudomonas cepacia immobilised on ceramics (PS-C) predominantly acetylate cyclic diastereomer (3 S,7 S)- 15 to (3 S,7 S)- 17; only Candida antarctica-B (CAL-B) lipase predominantly acetylates (3 S,7 R)- 14 to (3 S,7 R)- 16. With acyclic analogs 10, 11 the same set of lipases exhibited different diastereoselective bias; CAL-B, GCL and CCL predominantly acylate (1 S,5 S)- 11 to (1 S,5 S)- 13, whereas PCL, PS-C, PFL and PSL acylate predominantly (1 S,5 R)- 10 to (1 S,5 R)- 12. Only GCL exhibited higher stereoselectivity for an acyclic pair of stereoisomers with higher conformational flexibility, over cyclic diastereomeric substrates with a conformationally restricted macrocyclic ring. The preference of PCL for macrocyclic substrates is particularly interesting, in view of the recently suggested binding mode of a series of acyclic sec alcohols in the extended conformation.

Chemical consequences of conformation in macrocyclic compounds : An effective approach to remote asymmetric induction

In this paper we show that the conformational properties of medium- and large-ring organic molecules have profound consequences on the stereochemical course of their chemical reactions. Kinetic enolate alkylations, dimethylcuprate additions and catalytic hydrogenations were examined on a variety of monosubstituted 8- to 12-membered macrocyclic ketones and lactones, and the diastereomeric composition of the products was determined. In many systems a single Me substituent provided enough conformational bias to allow highly stereoselective formation of new asymmetric centers. The diastereoselection exhibited by the reactions investigated appears to be intimately associated with the conformational properties of the macrocyclic substrates employed since simple molecular mechanics calculations allowed semiquantitative prediction of the product distributions in every case.