Anti-aldol Reaction Research Articles

Organocatalytic Enantioselective Direct Aldol Reaction in Aqueous Media Catalyzed by a Bifunctional Diamine Catalyst

Organocatalytic direct asymmetric anti-aldol reaction was developed in aqueous medium using a BINOL-derived diamine/protic acid bifunctional catalyst. The catalytic protocol could offer the opportunity to access anti-aldol products with high level of enantioselectivities with moderate diastereoselectivities.

Anti-Aldol reactions of chiral alcohol-substituted vinylogous urethanes and the synthesis of (−)-prelactone B

This paper describes a convenient and efficient method for synthesizing chiral alcohol-substituted vinylogous urethanes, in which the double bond has E configuration was determined by single crystal X-ray analysis. In addition, we investigated the anti-aldol reactions of these chiral vinylogous urethane anions. The use of (1 S,2 R,4 R)-1-(hydroxydiphenylmethyl)-7,7-dimethylbicyclo[2,2,1]-heptan-2-ol as a chiral auxiliary, provided the best enantioselectivities, and the resulting vinylogous urethane lactone could be used for the synthesis of (−)-prelactone B. A plausible mechanism for the generation of major enantiomeric isomer was discussed.

An Aldol-Based Build/Couple/Pair Strategy for the Synthesis of Medium- and Large-Sized Rings: Discovery of Macrocyclic Histone Deacetylase Inhibitors

An aldol-based build/couple/pair (B/C/P) strategy was applied to generate a collection of stereochemically and skeletally diverse small molecules. In the build phase, a series of asymmetric syn- and anti-aldol reactions were performed to produce four stereoisomers of a Boc-protected γ-amino acid. In addition, both stereoisomers of O-PMB-protected alaninol were generated to provide a chiral amine coupling partner. In the couple step, eight stereoisomeric amides were synthesized by coupling the chiral acid and amine building blocks. The amides were subsequently reduced to generate the corresponding secondary amines. In the pair phase, three different reactions were employed to enable intramolecular ring-forming processes: nucleophilic aromatic substitution (S(N)Ar), Huisgen [3+2] cycloaddition, and ring-closing metathesis (RCM). Despite some stereochemical dependencies, the ring-forming reactions were optimized to proceed with good to excellent yields, providing a variety of skeletons ranging in size from 8- to 14-membered rings. Scaffolds resulting from the RCM pairing reaction were diversified on the solid phase to yield a 14 400-membered library of macrolactams. Screening of this library led to the discovery of a novel class of histone deacetylase inhibitors, which display mixed enzyme inhibition, and led to increased levels of acetylation in a primary mouse neuron culture. The development of stereo-structure/activity relationships was made possible by screening all 16 stereoisomers of the macrolactams produced through the aldol-based B/C/P strategy.

A Useful Modification of the Evans Magnesium Halide-Catalyzed anti-Aldol Reaction: Application to Enolizable Aldehydes.

A practical protocol for use of the magnesium halide-catalyzed anti-aldol reaction of an Evans N-acyloxazolidinone with enolizable aldehydes is reported. The yields of anti-aldol adducts for saturated or unsaturated and branched or unbranched aliphatic aldehydes are preparatively useful.

Synthetic studies on the phorboxazoles: a short synthesis of an epi-C23 tetrahydropyran core

Studies on the synthesis of the anticancer natural products, the phorboxazoles have led to the synthesis of the C21–C32 penta-substituted tetrahydropyran core which is epimeric to the natural product at C23. The synthesis was achieved in only seven linear steps. The key steps were the use of a Masamune–Abiko anti-aldol reaction, the formation of a dihydropyran precursor molecule by the use of a new ‘Maitland–Japp-like’ cyclisation, and a highly diastereoselective reductive alkylation of the dihydropyran double bond, to generate the corresponding tetrahydropyran ring in an excellent yield.

ChemInform Abstract: Studies Toward (-)-Gymnodimine: Concise Routes to the Spirocyclic and Tetrahydrofuran Moieties.

[formula: see text] (-)-Gymnodimine is a member of a unique class of potent marine toxins possessing imines within a spirocylic array. Herein we report the synthesis of the tetrahydrofuran fragment and a strategy toward the spirocyclic imine fragment of this family of toxins. Key reactions include an asymmetric anti-aldol reaction to set the stereochemistry of the tetrahydrofuran and a formal, intermolecular Diels-Alder reaction involving an alpha-methylene-delta-lactam and a dienyne.

Potent and selective inhibition of human cytochrome P450 3A4 by seco-pancratistatin structural analogs

seco-Derivatives of the anticancer agent pancratistatin bearing the 2 S,3 S,4 S,5 S configuration were accessed via a novel, highly diastereoselective anti-aldol reaction. Structure–activity relationships reveal important insights into the seco-pancratistatin pharmacophore as a potent and selective inhibitor of human cytochrome P450 3A4 (CYP3A4), and highlight features of concern in advancing a potent, selective anticancer agent in the pancratistatin series.

A biomimetic approach to the synthesis of a mycolic acid motif

A new method for the stereoselective synthesis of the ( R,R)-β-hydroxy-α-alkyl fatty acid fragment of mycolic acids, via an asymmetric anti-aldol reaction is reported. The ‘mycolic acid motif’ fragment was prepared in three steps and >98% ee.

Formal Total Synthesis of (−)-Saliniketals

A highly stereoselective formal total synthesis of the ornithine decarboxylase inhibitors (-)-saliniketals A and B is described. The salient features of the synthesis are the utilization of a desymmetrization technique to create six contiguous chiral centers from a single bicyclic precursor as well as substrate-controlled Grignard reaction, intramolecular Wacker-type oxidation, and antialdol reaction following Pirrung-Heathcock conditions.

Synthesis of Bioactive Natural Products by Asymmetric syn- and anti-Aldol Reactions.

The use of several variants of the asymmetric aldol reaction as key steps in the syntheses of bioactive target molecules is described.

Total synthesis of (−)-talaumidin and (−)-galbelgin

( − )-Talaumidin (1) and ( − )-galbelgin (2) have been synthesized via 4-pentenoic acid as a starting material with the overall yield of about 17.8 and 16.9%, respectively. The key steps include Evans asymmetry anti-aldol reaction, TBS protection, hydroboration, oxidation, Friedel–Crafts arylation, etc.

Concerning the Synthesis of the Tedanolide C(13)−C(23) Fragment via Anti-Aldol Reaction

Synthesis of C(13)-C(23) aldehyde 4, an important intermediate in a planned total synthesis of tedanolide, is described. The stereoselectivity of the key anti-aldol reaction of aldehyde 5 and ketone 6 (en route to 4) perfectly tracks the enantiomeric purity of 5. It is demonstrated that aldehyde 24, a precursor of 5, undergoes facile epimerization during a Swern oxidation and stabilized ylide olefination sequence.

Concise syntheses of (+)- and (−)-methylenolactocins and phaseolinic acids

(+)- and (−)-Methylenolactocins and phaseolinic acids are synthesized in four steps via asymmetric syn- and anti-aldol reactions of chiral N-succinyl-2-oxazolidinones using the same set of reagents.

Two-directional total synthesis of efomycine M and formal total synthesis of elaiolide

The anti-inflammatory agent efomycine M ( 1) has been synthesized from macrodilactone 38 and vinyliodide 42 by a two-directional total synthesis in 17 steps over the longest linear sequence with an overall yield of 7%. The C 2-symmetric macrodiolide 38 has been prepared by Yamaguchi macrolactonization of seco-acid 26. The central stereopentad of 1 was obtained by a highly efficient anti-aldol reaction followed by a diastereoselective ketone reduction. Additionally, we have completed a formal total synthesis of elaiolide ( 3) by converting macrodiolide 37 into Paterson's methylketone 13.

Synthesis and Biological Evaluation of Fully Functionalized seco-Pancratistatin Analogues

The total synthesis of fully functionalized polyhydroxyamide B,C- seco-analogues of the anticancer compound pancratistatin (PST) ( 1) is reported. Key steps include an Evans' MgCl 2-promoted anti-aldol reaction between a functionalized l-threose derivative and ( R)-(+)-oxazolidinone to stereoselectively form the C-1/C-10b bond and a regiospecific radical-mediated oxidative fragmentation of a 1,3-benzylidene. The B,C- seco compounds 25 and 26 exhibited low activity (ED 50 > 30 microg/mL) for inducing apoptosis in human cancer cells.

Highly Enantioselective Direct syn- and anti-Aldol Reactions of Dihydroxyacetones Catalyzed by Chiral Primary Amine Catalysts

We present herein simple primary-tertiary diamine-Brønsted acid conjugates that catalyze both syn- and anti-aldol reactions of dihydroxyacetones (DHAs) with high diastereoselectivities and enantioselectivities. This type of organocatalysts functionally mimics all four DHA aldolases, namely L-fuculose-1-phosphate aldolase, D-tagatose-1,6-diphosphate aldolase, D-fructose-1,6-diphosphate aldolase, and L-rhamnulose-1-phosphate aldolase.

Total synthesis of malyngamide X and its 7′ S- epi isomer

Stereoselective syntheses of malyngamide X ( 1) and its 7′( S)-epimer are described. A Lewis acid (Et 2AlCl) mediated anti-aldol reaction was employed to generate the stereocenters C-7 and C-8. The route is convergent and provides a convenient access to the synthesis of structural variants of malyngamide X. Stereochemistry at C-7′ in the molecules of natural and synthetic 1, and 7′( S)- epi 1 was confirmed by NMR chiral solvation experiments.

Synthetic Studies toward the Generation of Uridine-Amino Alcohol-Based Small Optimized Libraries

An efficient synthesis of a versatile scaffold 3, anti-2-chloro-3- hydroxy ester can be achieved via a boron mediated diastereofacial anti-aldol reaction of 2-(N-methylbenzyl-N-2,4,6-trimethylbenzyl)-amino-1-phenylpropanol chloroester 1 and the uridyl aldehyde derivative 2. Generation of uridine-amino alcohol-based library is demonstrated by using the scaffold 3.

Total Synthesis of the Cyclodepsipeptide Apratoxin A and Its Analogues and Assessment of Their Biological Activities

A novel total synthesis of apratoxin A is described, with key steps including the assembly of its ketide segment through a D-proline-catalyzed direct aldol reaction and Oppolzer's anti aldol reaction and the preparation of its thiazoline unit in a biomimetic synthesis. An oxazoline analogue of apratoxin A has also been elaborated by a similar approach. This compound has a potency against HeLa cell proliferation only slightly lower than that of apratoxin A, whilst a C(40)-demethylated oxazoline analogue of apratoxin A displays a much lower cytotoxicity and the C(37)-epimer and C(37) demethylation product of this new analogue are inactive. These results suggest that the two methyl groups at C(37) and C(40) and the stereochemistry at C(37) are essential for the potent cellular activity of the oxazoline analogue of apratoxin A. Further biological analysis revealed that both synthetic apratoxin A and its oxazoline analogue inhibited cell proliferation by causing cell cycle arrest in the G1 phase.

Achieving High Selectivity and Facile Displacement with a New Thiol Auxiliary for Boron-Mediated Aldol Reactions

Synthesis of a new thiol auxiliary (1) is readily achieved (in five or six steps, >74% overall yield from norephedrine) and is shown to give high diastereoselectivity in boron-mediated anti-aldol reactions with a range of aldehydes. This new thiol auxiliary may be directly displaced by a range of nucleophiles under very mild conditions, to give the corresponding phosphonate esters, alcohols, acids, SNAC thiolesters, and methyl esters.