Anti-aldol Reaction Research Articles

Asymmetric total synthesis of humulane sesquiterpenoids alashanoids B, C, E, and F and 2,9-humuladien-6-ol-8-one.

Naturally occurring sesquiterpenes having humulane frameworks are structurally intriguing and possess significant biological profiles. Asymmetric synthesis of the alashanoids B, C, E, and F and 2,9-humuladien-6-ol-8-one is achieved for the first time through a linear synthetic strategy. Intramolecular late-stage Nozaki-Hiyama-Kishi (NHK) coupling is employed to access the eleven-membered macrocyclic core present in the target molecules. The NHK precursors are accessed using the Evans and non-Evans syn and anti-aldol reaction as a key transformation. X-ray and ECD analysis reconfirmed the synthesized compounds' structures and chirotopical properties.

Asymmetric Total Synthesis of (−)‐Dehydrocostus Lactone by Domino Metathesis

AbstractAn efficient total synthesis of the sesquiterpenoid (−)‐dehydrocostus lactone is reported. Our earlier approach by a domino enediyne metathesis was extended by a domino dienyne metathesis strategy to give access to suitably functionalized hydroazulene cores. Highly stereoselective asymmetric anti aldol reactions provided the enantiopure substrates for this key step of our synthesis. Multiple hydroboration/oxidation of the resulting hydroazulenes set up three out of four stereogenic centers in a single step. First, oxidation to give a diketo‐γ‐lactone enabled an enantioselective formal synthesis of the target guaianolide. Subsequently, the final steps of this approach were improved by using a double carbonyl olefination at the stage of a masked γ‐butyrolactone, which completed the synthesis in a much more efficient way.

Enantioselective Total Synthesis of the Guaianolide (-)-Dehydrocostus Lactone by Enediyne Metathesis.

The hydroazulene core of the bioactive sesquiterpenoid (-)-dehydrocostus lactone was generated by domino enediyne metathesis. A triple hydroboration/oxidation of the resultant conjugated triene installed three out of four stereogenic centers of the target in a single step. The enantiopure acyclic metathesis substrate was readily available by an asymmetric anti aldol reaction. Masking of the γ-lactone as an acetal allowed for an efficient completion of the synthesis through late-stage double carbonyl olefination.

Practical enantioselective synthesis of (3S, 4R)-3-hydroxypiperidine-4-carboxylic acid

A practical enantioselective synthesis of (3S, 4R)-3-hydroxypiperidine-4-carboxylic acid was accomplished via an unconventional Evans anti-aldol reaction followed by a one-pot azide reduction/reductive cyclization.

Total Synthesis of Cytospolide Q

A flexible and convergent strategy for the stereoselective total synthesis of bioactive marine natural product cytospolide Q has been developed. The key features of this synthesis include Evans anti-aldol reaction for the installation of C-2 and C-3 stereocenters and cycloetherification via epoxide opening followed by concomitant lactonization for the construction of tetrahydrofuran and γ-butyrolactone scaffolds. This synthetic study also revealed that protected oxygenated functionality (methyl ester or benzyl ether) at C-1 position participated readily in epoxide opening.

First Stereoselective Total Synthesis of Tumonoic Acid A and its Derivatives

An efficient protecting-group-free synthesis of tumonoic acid A and its derivatives has been accomplished. The synthesis started from commercially available n-octanal and employs the magnesium chloride catalysed anti-aldol reaction under the Evans protocol as the key step. Ethyl tumonoate A is a new tumonoic acid derivative with anti-inflammatory activity and inhibitory activity towards calcium oscillations in neocortical neurons.

Concise synthesis and revision of the proposed biogenesis of helicascolides

A concise synthesis of helicascolides A, B and C was achieved in three to five steps from commercially available materials. The key transformations of the synthesis include an Evans-Metternich anti-aldol reaction of the known β-keto imide 10 and strategic base-mediated one-pot cyclization/alkylation. Based on the new chemical evidence of ring-opening reaction of β-keto ester under biocompatible basic conditions, Krohn’s proposal for the biosynthetic relationship between helicascolide A (1) and a naturally co-existing acyclic dienone 4 was suggested in a reverse manner.

Highly stereoselective asymmetric aldol routes to tert-butyl-2-(3,5-difluorophenyl)-1-oxiran-2-yl)ethyl)carbamates: Building blocks for novel protease inhibitors

Enantioselective syntheses of tert-butyl ((S)-2-(3,5-difluorophenyl)-1-((S)-oxiran-2-yl)ethyl)carbamate and ((S)-2-(3,5-difluorophenyl)-1-((R)-oxiran-2-yl)ethyl)carbamate are described. We utilized asymmetric syn- and anti-aldol reactions to set both stereogenic centers. We investigated ester-derived Ti-enolate aldol reactions as well as Evans’ diastereoselective syn-aldol reaction for these syntheses. We have converted optically active ((S)-2-(3,5-difluorophenyl)-1-((S)-oxiran-2-yl)ethyl)carbamate to a potent β-secretase inhibitor.

Synthesis of fully functionalized aglycone of lycoperdinoside A and B.

This article reported the synthesis of fully functionalized aglycone of lycoperdinoside A and B. Pd-catalyzed Stille-Migita cross coupling between E-vinyl iodide 6 and E-vinyl stannane 23 established the highly substituted E,E-diene unit present in lycoperdinoside A and B. The other two Z-olefins present in the molecule were introduced by means of cis-selective Horner-Wadsworth-Emmons reaction with Still-Gennari phosphonate. Evans syn- and anti-aldol reactions were utilized to fix six of the seven stereo centres present in the aglycone.

A concise approach for the synthesis of bitungolides: total syntheses of (-)-bitungolide B & E.

The first total synthesis of (-)-bitungolide B and a second-generation total synthesis of (-)-bitungolide E are described. The cornerstone of the approach comprises a convergent and flexible route involving Brown crotylation, highly diastereoselective substrate controlled Paterson anti-aldol reaction, hydroxyl-directed 1,3-syn/anti reduction, Barton-McCombie deoxygenation and RCM reactions. Via this route, a common intermediate 13 is readily accessible for the synthesis of the family of bitungolides A-E and franklinolides A-C.

Highly stereoselective anti-aldol reactions catalyzed by simple chiral diamines and their unique application in configuration switch of aldol products

Chiral derivatives of trans-1,2-diaminocyclohexane with different N,N-dialkyl groups in well-defined orientations have been synthesized, and applied as catalysts for the asymmetric aldol reaction between a variety of aldehydes and ketones. Enantiomeric catalyst 1j catalyzed the reaction in ethanol and provided excellent diastereoselectivity and enantioselectivity. Significantly, simple replacement of organic solvents with water switched the products of the aldol reactions from anti to syn configuration. Such catalytic reactions led to the products with anti to syn diastereoselectivity up to 99:1 in ethanol, while in water gave the products with syn to anti diastereoselectivity up to 99:1.

Total synthesis of emericellamides A and B

A concise total synthesis of emericellamides A and B, two cyclic depsipeptides exhibiting antibacterial and cytotoxic activities, is reported. A Paterson anti-aldol reaction and a hydroxy directed 1,3-anti reduction were applied for construction of the polypropionate unit with the required stereochemistry in emericellamides A and B. An FDPP mediated macrolactamization was used to construct the macrocycle of emericellamides A and B.

2-(10′,10′-Dimethyl-3′-sulfanylidene-4′-azatricyclo[5.2.1.01,5]decan-2′-yl)-10,10-dimethyl-4-azatricyclo[5.2.1.01,5]decane-3-thione

The title compound, C28H40N2O2S2, was obtained as a minor product from an anti-aldol reaction between the corresponding N-propionyl­thiol­actam and benzaldehyde. The asymmetric unit contains one half-molecule, which is completed by inversion symmetry. The molecule displays a nearly eclipsed conformation along the central C—C bond with a C—C—C—C— torsion angle of 20.4 (3)°.

Total Synthesis of ent‐Hyperione A and ent‐Hyperione B

Hyp-notic: The total syntheses of (−)-hyperione A and (−)-hyperione B, enantiomers of norlignans found in Hypericum chinense, are described. By using a single chiral precursor, derived from an Evans anti-aldol reaction, both compounds were synthesized in ten steps. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Stereoselective synthesis of the C15–C30 subunit of dolabelides A–D

A highly stereoselective synthesis of the C15–C30 subunit of the cytotoxic macrolides dolabelides A–D has been accomplished by utilizing anti selective aldol reaction, Wittig olefination for the introduction of a trisubstituted (E)-double bond, selective hydroboration, Brown asymmetric allylation, Wilkinson hydrogenation and stereoselective keto reduction for the installation of C19 hydroxy group as key steps.

Double diastereoselection in anti aldol reactions mediated by dicyclohexylchloroborane between an l-erythrulose derivative and chiral aldehydes

Anti aldol reactions of an l-erythrulose derivative with several α-chiral aldehydes mediated by dicyclohexylboron chloride are examined. Good yields and stereoselectivities are observed. The results are best explained when the reactions are assumed to occur via boat-like transition states with minimization of 1,3-allylic strain and avoidance of syn pentane interactions.

Direct anti and regio-specific aldol reactions of cyclododecanone catalyzed by alkali metal hydroxides: implications for supramolecular helical design

The direct aldol condensation of benzaldehyde to cyclododecanone (CDD), catalyzed by NaOH is expected to yield bis-benzylidene cyclododecanone, but we interestingly ended up with novel β-hydroxy carbonyl compounds and monobenzylidene cyclododecanone derivatives in the cases of 2-halo substituted benzaldehydes. This exceptional behaviour is due to the capability of the CDD ring to exist in the zwitter ionic form. The formation of monobenzylidine derivatives can be due to less stable hydrogen bonds between –OH and –CO groups, electrostatic interaction between aldehyde substituents and metal enolates and the bulkiness of the benzaldehyde ring substituents. We extensively optimized the reaction conditions using different solvents and alkali metal hydroxide catalysts and we are getting high yield, regio-specificity and high diastereoselectivity (anti-aldol) in β-hydroxy carbonyl compounds. The representative crystal structures were examined and they suggest the tendency of anti-aldol compounds to form supramolecular helical motifs. The β-hydroxyl carbonyl derivatives form supramolecular helices via O–H⋯O hydrogen bonds with two anti-aldol units per turn and a pitch of ∼6 A. The cyclododecanone ring adopts the minimum energy [3333] square conformation. The nucleophile will attack only from the less hindered side of the carbonyl group in the CDD ring.

Total Synthesis of the Spirocyclic Imine Marine Toxin (−)-Gymnodimine and an Unnatural C4-Epimer

The first total synthesis of the marine toxin (-)-gymnodimine (1) has been accomplished in a convergent manner. A highly diastereo- and enantioselective exo-Diels-Alder reaction catalyzed by a bis-oxazoline Cu(II) catalyst enabled rapid assembly of the spirocyclic core of gymnodimine. The preparation of the tetrahydrofuran fragment utilized a chiral auxiliary based anti-aldol reaction. Two major fragments, spirolactam 56 and tetrahydrofuran 55, were then coupled through an efficient Nozaki-Hiyama-Kishi reaction. An unconventional, ambient temperature t-BuLi-initiated intramolecular Barbier reaction of alkyl iodide 64 was employed to form the macrocycle. A late stage vinylogous Mukaiyama aldol addition of a silyloxyfuran to a complex cyclohexanone 83 appended the butenolide, and a few additional steps provided (-)-gymnodimine (1). A diastereomer of the natural product was also synthesized, C4-epi-gymnodimine (90), derived from the vinylogous Mukaiyama aldol addition.

Total synthesis of the proposed structure of iriomoteolide-1a

Full details of the total synthesis of the proposed structure of iriomoteolide-1a ( 1) are described. The key steps include (i) a Sakurai reaction between allylsilane 11 and aldehyde 10 that bears both a tertiary chiral center and vinyl iodide moiety (ii) an anti-aldol reaction to construct the C18/C19 chiral centers (iii) a B-alkyl Suzuki–Miyaura coupling reaction to assemble the C7–C23 fragment, and (iv) a macrocyclic ring-closing metathesis to complete the construction of the target molecule. Two different approaches to access penultimate precursor 2 are delineated. The NMR spectra of the synthetic iriomoteolide-1a ( 1) were found not to match those reported for the natural product bringing into question its true structural identity.

ChemInform Abstract: 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.