Stereoselective Aldol Condensation Research Articles

Green chemistry approach for stereoselective aldol condensation catalyzed by amino acids under microflow conditions

Over the recent years, the pharmaceutical field has been under significant pressure to adapt to the principles of green chemistry. The industry is facing the challenge of environmental protection and securing people's health while sustaining its fundamental goals of efficiency and selectivity optimization. In this work, the reaction processes optimization has been acheived through the microfluidic approach to the widely used aldol condensation reaction. In accordance with the green chemistry principles, we have found that the best conditions include aqueous ethanol solvent and easily available amino acids used as catalysts. Asymmetric aldol condensation of para-nitrobenzaldehyde with cyclohexanone catalyzed by L-tert-Leu under microfluidic conditions provided the product with high yield and diastereoselectivity (anti/syn = 28:1) and 98% enantiomeric excess. The microfluidic reactor process, compared to the classical batch method (in a flask), provides comparable product yield, while the reaction time was reduced by an order of magnitude. It should be noted that this approach allows to carry out the reactions at low (below zero) temperatures with greater enantioselectivity.

Synthesis of Natural (-)-Antrocin and its Enantiomer via Stereoselective Aldol Reaction.

The total synthesis of (−)-antrocin and its enantiomer are presented. Antrocin (−)-1 is an important natural product which acts as an antiproliferative agent in a metastatic breast cancer cell line (IC50: 0.6 μM). The key features of this synthesis are: (a) selective anti-addition of trimethylsilyl cyanide (TMSCN) to α,β-unsaturated ketone; (b) resolution of (±)-7 using chiral auxiliary L-dimethyl tartrate through formation of cyclic ketal diastereomers followed by simple column chromatography separation and acid hydrolysis; (c) substrate-controlled stereoselective aldol condensation of (+)-12 with monomeric formaldehyde and pyridinium chlorochromate (PCC) oxidation for synthesis of essential lactone core in (−)-14; and (d) non-basic Lombardo olefination of the carbonyl at the final step to yield (−)-antrocin. In addition, (+)-9 cyclic ketal diastereomer was converted to (+)-antrocin with similar reaction sequences.

Total Synthesis of Archazolid F.

A partial bioinspired as well as the total synthesis of archazolid F, a highly potent V-ATPase inhibitory, antiproliferative polyketide macrolide, is described. Key features of the synthetic routes include a highly stereoselective aldol condensation of two elaborate fragments and macrocyclizations either by a Shiina macrolactonization or by a challenging RCM reaction of an octaene substrate. The syntheses unequivocally confirm the full architecture of this very scarce archazolid.

One-pot synthesis of carbohydrate exo-cyclic enones and hemiketals with 6,8-dioxabicyclo-[3.2.1]octane moieties. Serendipitous formation of a spironolactone when 2-pyridinecarboxaldehyde is used as the reactant. Part II

A library of exo-cyclic carbohydrate enones 2–13 were prepared via a base-catalyzed, highly stereoselective aldol condensation of dihydrolevoglucosenone 1 (cyrene) with various aromatic aldehydes. In the case of 4-chlorobenzaldehyde as a reactant, under conditions of the aldol condensation, exo-cyclic enone 9 and a secondary product 9A was isolated. When 2-pyridinecarboxaldehyde was used as a reactant, an unexpected spironolactone 19 was exclusively observed. 1H NMR, 13C NMR, MS analyses and single-crystal x-ray diffraction of the representative enone 9, the secondary product 9A, hemiketal 18, and spironolactone 19 unequivocally confirms the structural assignments. Mechanistic insights leading to the synthesized products are also proposed and discussed.

Amipurimycin: Total Synthesis of the Proposed Structures and Diastereoisomers.

The proposed diastereoisomers (1 a-d) together with their C8'-epimers (1 e-h) of amipurimycin, a unique antifungal peptidyl nucleoside antibiotic, have been synthesized for the first time. The synthetic approach is efficient and stereodivergent, and features a stereoselective aldol condensation to build the branched C9 sugar amino acid skeleton and a regio- and stereocontrolled gold(I)-catalyzed N-glycosylation to furnish the purine nucleoside. Analysis of the NMR data suggests that the previously assigned configuration of the tertiary C3' in amipurimycin should be of opposite configuration.

Amipurimycin: Total Synthesis of the Proposed Structures and Diastereoisomers

AbstractThe proposed diastereoisomers (1 a–d) together with their C8′‐epimers (1 e–h) of amipurimycin, a unique antifungal peptidyl nucleoside antibiotic, have been synthesized for the first time. The synthetic approach is efficient and stereodivergent, and features a stereoselective aldol condensation to build the branched C9 sugar amino acid skeleton and a regio‐ and stereocontrolled gold(I)‐catalyzed N‐glycosylation to furnish the purine nucleoside. Analysis of the NMR data suggests that the previously assigned configuration of the tertiary C3′ in amipurimycin should be of opposite configuration.

Functionalization of diazotetronic acid and application in a stereoselective modular synthesis of pulvinone, aspulvinones A-E, G, Q and their analogues.

A modular synthesis of aspulvinones A, B, C, D, E, G and the recently isolated aspulvinone Q was developed. The methodology features a highly stereoselective aldol condensation of diazotetronic acid with aldehydes to provide 5-arylidene diazotetronates. Subsequent catalytic intermolecular C-H insertion reactions of the arylidene tetronates with arenes provide a series of naturally occurring aspulvinones including aspulvinones C, D and Q which have not been synthesized before. Variation of the aldehyde and the arene components furnishes synthetic analogues of the aspulvinones.

Design, synthesis and spectroscopic characterisation of a focused library based on the polyandrocarpamine natural product scaffold

A focused library based on the marine natural products polyandrocarpamines A (1) and B (2) has been designed and synthesised using parallel solution-phase chemistry. In silico physicochemical property calculations were performed on synthetic candidates in order to optimise the library for drug discovery and chemical biology. A library of ten 2-aminoimidazolone products (3-12) was prepared by coupling glycocyamidine and a variety of aldehydes using a one-step stereoselective aldol condensation reaction under microwave conditions. All analogues were characterised by NMR, UV, IR and MS. The library was evaluated for cytotoxicity towards the prostate cancer cell lines, LNCaP, PC-3 and 22Rv1.

Total synthesis of epothilones using functionalised allylstannanes for remote stereocontrol

Two syntheses of the C(7)–C(16)-fragment 41 of epothilone D 2 were developed that were based on tin(IV) bromide mediated reactions of 5,6-difunctionalised hex-2-enylstannanes with aldehydes. In the first synthesis, (5S)-6-tert-butyldimethylsilyloxy-5-hydroxy-2-methylhex-2-enyl(tributyl)stannane 20 was reacted with (E)-but-2-enal to give (2S,7R,4Z,8E)-1-tert-butyldimethylsilyloxy-5-methyldeca-4,8-diene-2,7-diol 26 containing ca. 20% of its (7S)-epimer. Following desilylation, the crystalline (2S,7R)-triol 32 was protected as its acetonide 33 and esterified to give the (4-methoxybenzyloxy)acetate 34. An Ireland–Claisen rearrangement of this ester gave methyl (2R,3S,10S,4E,7Z)-3,7-dimethyl-10,11-(dimethylmethylene)dioxy-2-(4-methoxybenzyloxy)undeca-4,7-dienoate 35 that was converted into (2S,9S,6Z)-2,6-dimethyl-9,10-(dimethylmethylene)dioxydec-6-en-1-ol 41 by regioselective alkene manipulation, ester reduction and cleavage of the resulting terminal diol 40 with a reductive work-up. The second synthesis involved the tin(IV) bromide mediated reaction between the stannane 20 and (3S)-4-(4-methoxybenzyloxy)-3-methylbutanal 44 that gave (2S,7S,9S,4Z)-1-tert-butyldimethylsilyloxy-5,9-dimethyl-10-(4-methoxybenzyloxy)dec-4-ene-2,7-diol 45 containing ca. 20% of its (7R)-epimer. After desilylation and protection of the vicinal diol as its acetonide 46, a Barton–McCombie reductive removal of the remaining hydroxyl group gave the (2S,9S,6Z)-2,6-dimethyl-9,10-(dimethylmethylene)dioxydec-6-en-1-ol 41 after oxidative removal of the PMB-ether. The first of these syntheses uses just one chiral starting material, but the second is shorter and more convergent. It was therefore modified by the use of (5S)-6-tert-butyldimethylsilyloxy-5-(2-trimethylsilylethoxy)methoxy-2-methylhex-2-enyl(tributyl)stannane 49 that reacted with (3S)-4-(4-methoxybenzyloxy)-3-methylbutanal 44 to give a 50:50 mixture of the C(4)-epimers of (2S,9S,6Z)-10-tert-butyldimethylsilyloxy-1-(4-methoxybenzyloxy)-2,6-dimethyl-9-(2-trimethylsilylethoxy)methoxydec-6-en-4-ol 50 with high fidelity for formation of the (Z)-alkene. Following the Barton–McCombie deoxygenation, the product 52 was taken through to (2S,9S,6Z,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-(2-trimethylsilylethoxy)methoxyundeca-6,10-dienal 59 that corresponded to the fully functionalised C(7)–C(17) fragment of epothilone D 2. A precedented stereoselective aldol condensation followed by O-protection, selective deprotection, oxidation and macrocyclisation then gave the macrolide 71 that was deprotected to complete a synthesis of epothilone D 2. Finally regio- and stereo-selective epoxidation gave epothilone B 1.

An efficient asymmetric synthesis of (–)-wodeshiol

An efficient synthesis of (–)-wodeshiol 1 is described. The key reactions include highly stereoselective aldol condensation of piperonal with the dianion of chiral oxazolidinone, subsequent intramolecular ring cyclization of the aldol product 8 and a diastereocontrolled oxygenation of dilactone 7 in good yield.

ChemInform Abstract: Facile Synthesis of Racemic 2-Hexyl-3-hydroxy-4-pentanolide(NFX-2) and Its Optical Resolution.

Abstract A facile stereoselective synthesis of a constituent of antimycin A1 and also the new virginiamycin inducing factor, NFX-2((−)-1) has been achieved. (2RS,3RS,4SR)-2-Hexyl-3-hydroxy-4-pentanolide((±)-1) was obtained by stereoselective intramolecular aldol condensation of 2-(2-bromooctanoyloxy)-1-propanal(7) as the key reaction. (±)-1 was kinetically resolved by asymmetric esterification with a lipase, affording optically pure (−)-1 and its enantiomer (+)-1.

ChemInform Abstract: Facile Syntheses and Rearrangements of Peptide Derived β-Lactams.

Abstract Stereoselective aldol condensation of a 4, 5-diphenyl-oxazolin-2-one (Ox) glycine provided α-amino- β-hydroxy acid 4 , which, after coupling with phenylglycine derivatives, was directly cyclized to β lactams. Ozonolysis cleaved both the Ox and isopropylidene groups and initiated a Chapman rearrangement to the corresponding α-benzamido-β-acyl-2 azetidinone 8 . Subsequent reduction induced a diastereoselective rearrangement to the corresponding γ-lactone 13 .

ChemInform Abstract: Synthesis of 18-Demethyltaxoid via Stereoselective Allylation and Intramolecular Aldol Condensation Reactions.

Optically active novel 18-demethyltaxiods were successfully synthesized from 2α,10β-dibenzyloxy-11β-(t-butyldimethylsiloxy)-7β-hydroxy-1α-(p-methoxybenzyloxy)-8β,15,15-trimethyl-4-methylene-trans-bicyclo[6.4.0]dodecan-9-one (2) which corresponds to the BC ring system of Taxol by stereoselective allylation and intramolecular aldol condensation reactions.

Total Synthesis of Grandisine D

Total synthesis of grandisine D (5) was achieved by a Brønsted acid mediated Morita-Baylis-Hillman (MBH) ring-closure reaction and stereoselective aldol condensation with (S)-5-methylcyclohexenone (9) as key steps. The MBH approach was also applicable for the construction of the aza-fused bicyclic systems of pyrrolizidine and stemona alkaloids.

Methods for the synthesis of carbon‐13 labelled acids and esters

AbstractSyntheses of isotopically labelled putative biosynthetic intermediates to the natural products monocerin 1, hectochlorin 2 and strobilurin A 3 are described. For the preparation of [9,10‐13C2]dihydroisocoumarin 10, a stereoselective aldol condensation of 13C2‐acetylated chiral auxiliary 5 was used to assemble the labelled C9‐C14 fragment. The preferred approaches to the syntheses of [1,2‐13C2]5,5‐dichlorohexanoic acid 15 and the N‐acetylcysteamine derivative of [1,2‐13C2]cinnamic acid 19 involved a Horner‐Wadsworth‐Emmons chain extension and Knoevenagel reaction, respectively. Copyright © 2007 John Wiley & Sons, Ltd.

An Efficient Asymmetric Synthesis of Furofuran Lignans: (+)‐Sesamin and (‐)‐Sesamin.

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An efficient asymmetric synthesis of furofuran lignans: (+)-sesamin and (−)-sesamin

An efficient synthesis of (+)-sesamin 1a and (−)-sesamin 1b is described. The key reactions include highly stereoselective aldol condensation of piperonal 7 with the dianion of chiral oxazolidinone 8, followed by intramolecular ring cyclization of aldol product 11 in high yield.

Stereoselective synthesis of radiolabelled avermectins

AbstractThe natural products avemectin B1a 1a and B1b 1b were each site‐specifically 14C labelled at carbon 23 in a convergent synthesis for metabolism, residue, and environmental studies. The 12‐step radiosynthesis involved a stereoselective aldol condensation and later a coupling to a protected avermectin degradate 2 in a one‐pot Wittig condensation/spiroketalization to reconstitute the dioxaspirane configuration found in the natural products. Copyright © 2004 John Wiley & Sons, Ltd.

Stereoselective Aldol Condensation of Boron Enolates to trans α,β‐Epoxy Aldehydes.

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Synthesis of the diketopiperazine dipodazine

The diketopiperazine derivative dipodazine (1), isolated from Penicillium dipodomyis, has been synthesized via a stereoselective aldol condensation from N-protected indole-3-carboxaldehyde and 1,4-diacetyl-2,5-piperazinedione (3) in the presence of cesium carbonate.