Chiral Synthons Research Articles

A Flexible Approach to (S)‐5‐Alkyl Tetramic Acid Derivatives: Application to the Asymmetric Synthesis of (+)‐Preussin and Protected (3S,4S)‐AHPPA.

AbstractFor Abstract see ChemInform Abstract in Full Text.

General Three‐Carbon Chiral Synthons from Carbohydrates: Chiral Pool and Chiral Auxiliary Approaches

AbstractFor Abstract see ChemInform Abstract in Full Text.

2‐C‐Formyl Glycals: Emerging Chiral Synthons in Organic Synthesis

AbstractFor Abstract see ChemInform Abstract in Full Text.

Asymmetric synthesis of dialkyloxy-3-alkylammonium cationic lipids.

The cationic diether-linked cytofectin DOTMA (available commercially as a mixture, Lipofectin comprised of DOTMA:DOPE, 1:1) and analogues including DIMRIE and DORIE are frequently used for in vitro and in vivo transfections. Despite this wide usage direct synthetic routes to the optical isomers have received little attention to date. Here we describe strategies to synthesize enantiomers of DOTMA and analogues, including an extremely concise procedure to the trimethylammonium salts. One strategy utilized N-protection, as the imine, with concomitant ether formation and deprotection during the workup. Methylation of the 1-amino-2,3-dialkyloxypropane then generated the trimethylammonium cationic lipids directly. This methodology was extended to synthesize a novel headgroup functionalized lipid. A second route was also developed using an alternative chiral synthon.

Discovery and Synthesis of a Potent, Selective and Orally Bioavailable EP4 Receptor Agonist

An optimized analog of prostaglandin E 2 which incorporates a γ-lactam in place of the cyclopentanone ring and which incorporates metabolically stabilized side chains, has been identified and shown to exhibit potent and selective EP4 receptor agonism. The compound (2) (L-000902688) is also well absorbed on oral dosing and exhibits a long half-life making it an excellent tool for the study of the role of EP4 receptor in physiology and disease. An efficient synthesis of 2 from a chiral synthon is described.

A Flexible Approach for the Asymmetric Synthesis of N-Protected (R)-5-Alkyl Tetramates and (R)-5-Alkyl Tetramic Acid Derivatives

A flexible two-step asymmetric approach to N-protected (R)-5-alkyl tetramates and (R)-5-alkyl tetramic acid derivatives is described. The method is based on the diastereoselective alkylation of (R)-phenylglycinol derived tetramates 7 and 8, which are the first synthetic equivalents to chiral nonracemic tetramate 5-carbanionic synthons A.

Synthesis of L‐6‐Chloropyrroloindoline of Chloptosin Cyclohexapeptide

Chloptosin is an apoptosis‐inducing dimeric cyclohexapeptide. Enantioselective synthesis of L‐6‐chloropyrroloindoline, as the key chiral synthon of the cyclohexapeptide of chloptosin, was successfully achieved starting from 3‐chloroaniline by utilizing Fischer indole/Schöllkopf protocol and oxidative cyclization of resulting L‐6‐chlorotryptophan.

Regio- and diastereocontrolled preparative oxidation of methyloctalones by a biomimetic porphyrin catalyst.

Both enantiomers of methyloctalone were oxidized by a biomimetic manganese/porphyrin/imidazole catalytic system in order to obtain sufficient amounts of various model metabolites. The double bond proved to be less sensitive than the ring methylenes. Hydroxylation occurred mainly in the allylic position (position 8) and also at positions 7 and 6. In position 8, two diastereomers were obtained while in positions 7 and 6 the reaction was diastereospecific. In the case of position 8 only the oxidation yielded a keto compound. The efficiency of this method for the preparation of functionalized chiral synthons was better than it was for biological pathways.

The Direct and Enantioselective Organocatalytic α‐Oxidation of Aldehydes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Fragmentation of carbohydrate anomeric alkoxy radicals: a new synthesis of chiral 1-halo-1-iodo alditols.

Treatment of 1,2-fluorohydrins, 1,2-chlorohydrins, 1,2-bromohydrins, and 1,2-iodohydrins of the D-gluco, D-galacto, D-lacto, L-rhamno, D-allo, L-arabino, 3-deoxy-D-gluco, and 3,4-dideoxy-D-gluco families of carbohydrates with the (diacetoxyiodo)benzene/iodine system afforded 1-fluoro-1-iodo, 1-chloro-1-iodo, 1-bromo-1-iodo, and 1,1-diiodo alditols, respectively, in excellent yields. The reaction was achieved by radical fragmentation of the C1bond;C2 bond, triggered by the initially formed anomeric alkoxy radical, and subsequent trapping of the C2-radical by iodine atoms. This methodology is compatible with the stability of the protective groups most frequently used in carbohydrate chemistry. The potential utility of these 1-halo-1-iodo alditols as chiral synthons was evaluated by their transformation into alk-1-enyl iodides and in the Takai E-olefination reaction.

Chemical transformation of abietic acid to new chiral derivatives

Chemical transformations of the C-ring abietic acid (1a) for the preparation of some new chiral synthons are described. From the intermediate keto-aldehyde 9, readily available from 1b through the ozonide 2, the new tetracyclic diterpene 4 was synthesized. Additionally, from 13 and 17, previously prepared from 2, the bicyclic compounds 14, 15 and 16 and the derivatives containing the abeo-abietane[6,6,5] framework 19 and 20 were also synthesized.

2‐C‐Formyl Glycals: Emerging Chiral Synthons in Organic Synthesis

AbstractNaturally occurring carbohydrates and their derivatives have been useful during the last few decades as “chiral pool” constituents in the enantioselective synthesis of biologically active natural and non‐natural products. The ready availability of a wide range of carbohydrates in nature and their multichiral architecture, coupled with their well defined stereochemistry, make them attractive starting materials in organic synthesis. The synthesis of key intermediates by incorporation of suitable functional groups onto carbohydrates, which can then be further exploited, has always been a challenging task. In this context, 2‐C‐formyl glycals, a new class of carbohydrates incorporating an α,β‐unsaturated carbonyl system, have recently emerged as potential synthons for numerous organic transformations. Four different syntheses of 2‐C‐formyl glycals have been reported so far. However, the importance of 2‐C‐formyl glycals has become well established after our development of a more general, one‐step synthesis, employing the well known Vilsmeier−Haack reaction. Synthetic transformations of these 2‐C‐formyl glycals have resulted in a variety of new compounds of significant synthetic and biological interest. 2‐C‐Formyl glycals have been shown to be ideal substrates for chemo‐, regio‐ and stereoselective glycosidation, nucleophilic addition/substitution and cycloaddition reactions. The reported syntheses and applications of these important “chiral intermediates” are presented. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

Tartrate dehydrogenase reductive decarboxylation: stereochemical generation of diastereotopically deuterated hydroxymethylenes

Tartrate dehydrogenase catalyzes the reductive decarboxylation of meso-tartrate to glycerate. Concomitant with the ketonization of the intermediate enolate the C3 hydroxymethylene of glycerate necessarily acquires a proton from solvent. In D 2O, the proton is shown to be added stereospecifically to form (2 R,3 R)-[3- 2H]glycerate. The 1H-NMR assignments of the diastereotopic C3 protons of glycerate were confirmed by the enzymatic conversion of [1 R- 2H]fructose-6-phosphate to (2 R,3 R)-[3- 2H]glycerate. The decarboxylation-protonation occurs with retention of configuration, implying that the general acid is positioned on the same face of the intermediate as the departing carboxylate. The stereochemically pure (2 R,3 R)-[3- 2H]glycerate is readily synthesized and serves as a chiral hydroxymethylene synthon as demonstrated by the synthesis of (2 S,3 R)-[3- 2H]serine.

A flexible approach to (S)-5-alkyl tetramic acid derivatives: application to the asymmetric synthesis of (+)-preussin and protected (3S,4S)-AHPPA.

[reaction: see text] A flexible asymmetric approach to 5-alkyl tetramic acid derivatives is described, which is based on the use of 9 as the first synthetic equivalent to chiral nonracemic tetramic acid 5-carbanionic synthon 9b. The existence of the carbanion intermediate 9b was proven by trapping with trimethylchlorosilane. Application of the present method to the synthesis of antifungal alkaloid (+)-preussin, as well as protected (3S,4S)-AHPPA 6, is also described.

Fragmentation of carbohydrate anomeric alkoxyl radicals. A new synthesis of chiral beta-iodo azides, vinyl azides, and 2H-azirines.

[reaction: see text] The reaction of 3-azido-2,3-dideoxy-hexopyranose compounds from the d-gluco, d-galacto, d-lacto, and l-arabino carbohydrate series, with (diacetoxyiodo)benzene and iodine, generated 2-azido-1,2-dideoxy-1-iodo-alditols with one carbon less than the starting carbohydrate. These beta-iodo azides could be transformed by dehydroiodination into vinyl azides, which in turn afforded 3-monosubstituted 2H-azirines under thermal conditions. These beta-iodo azides and 2H-azirines may be interesting chiral synthons for the preparation of more complex heterocyclic systems.

The direct and enantioselective organocatalytic alpha-oxidation of aldehydes.

The first direct enantioselective catalytic alpha-oxidation of carbonyls has been accomplished. The use of enamine catalysis has provided a new organocatalytic strategy for the enantioselective oxyamination of aldehydes, to generate alpha-oxyaldehydes, important chiral synthons for natural product and medicinal agent synthesis. The use of l-proline as the asymmetric catalyst has been found to mediate the oxidation of a large variety of aldehyde substrates with nitrosobenzene serving as the electrophilic oxidant. A diverse spectrum of aldehyde substrates can also be accommodated in this new organocatalytic transformation. While catalyst quantities of 2 mol % were generally employed in this study, successful oxidations conducted using catalyst loadings as low as 0.5 mol % are described.

Unusual peptides containing the 2,6-diaminopimelic acid framework: Stereocontrolled synthesis, X-ray analysis, and computational modelling. Part 2

The stereocontrolled synthesis of peptides 6, 9 and 14, structural variants of 2,6-diaminopimelic acid, was carried out starting from the chiral synthon 1, easily obtained from l-valine. The configuration of the introduced stereogenic centres has been assigned on the basis of 1H NMR spectroscopic data. X-Ray crystal structure and conformation analysis of 5 are also reported.

Degradation of triterpenic compounds from olive-pressing residues. Synthesis of trans-decalin type chiral synthons

Three seco-C-ring triterpenic compounds were obtained from oleanolic or maslinic acids from olive-mill solid wastes by photochemical and chemical reactions. From these oleantriene compounds, different remarkable sesquiterpene and nor-sesquiterpene fragments such as 3β-hydroxydrimenol ( 13 ) and epoxydecalone ( 16 ) were achieved through oxidative cleavages of the double bonds in the opened C-ring.

Cyclopentane Ring Fusion to -Iodo and -Bromo Levoglucosenone Derivatives with 2,2-Dimethyl-1,3-dinitropropane

Levoglucosenone and some its a-halo derivatives are convenient chiral synthons for cyclopropanes, cyclohexanes, norbornanes, and heterocyclic systems [133]. However, there are no published data on direct preparation of cyclopentane derivatives from these accessible compounds. We now report on the stereospecific synthesis of fused cyclopentene derivative IV via the Michael reaction, nucleophilic substitution in a-bromo and a-iodo levoglucosenone derivatives I and II with 2,2-dimethyl-1,3-dinitropropane (III). The reaction involves generation of 1,3-dianion from III, and the product yields are 82 and 67%, respectively. The reaction mechanism is most likely to include (as in the cyclopropanation [4]), 1,3-shift of the negative charge in the carbanion formed by conjugate 1,4-addition. Further transformation of intermediate A can follow two pathways (Scheme 1), but only one of these is operative. It leads to formation of less strained five-membered ring (anion B). Stabilization of dinitrocyclopentyl anion is achieved via intramolecular neutralization, followed by elimination of nitrite ion. The configuration of new asymmetric centers (2R) and (3S) was established on the basis of the H NMR spectra. The large coupling constant J2, 3 (10.1 Hz) and the lack of coupling with 1-H indicate b-orienta-

A General Protocol for the Regio High‐Yielding Opening of Different Glycidol Derivatives.

AbstractFor Abstract see ChemInform Abstract in Full Text.