Syn-aldol Reaction Research Articles

Studies toward the Synthesis of Colletotrichamide A: Construction of the C19–C30 Segment of the Molecule

AbstractA synthesis of the C19–C30 segment of the neuroprotective natural product colletotrichamide A has been achieved by performing a Sonogashira coupling of two advanced intermediate fragments: a vinyl iodide and an alkyne. A Maruoka–Keck allylation, an Evans syn-aldol reaction, and Takai olefinations served as the key steps in the synthesis of the vinyl iodide intermediate, whereas glycosidation and Ohira–Bestmann reactions were used as the pivotal steps for accessing the advanced alkyne intermediate.

Diastereo- and Enantioselective Construction of Stereochemical Arrays Exploiting Non-Classical Hydrogen Bonding in Enolborates.

We report a copper-catalyzed reductive aldol addition to aldehydes and ketones, with pinacolborane as stoichiometric reductant, that results in the generation of stereodefined syn-aldol products. Cyclic, acyclic, fused and spirocyclic aldols bearing contiguous stereocenters are obtained with excellent yields and diastereoselectivities. Moreover, enantioselective reactions could be carried out with cycloalkenones to deliver aldols bearing three contiguous stereocenters and with up to 98 % ee. Computations reveal that the enolborate intermediate undergoes the syn-aldol reaction via a twist-boat transition state that is stabilized by non-classical hydrogen bonding interactions.

One-Pot Tandem Aldol-Cycloetherification Protocol in the Enantioselective Synthesis of Davanoids.

Total synthesis of cis and trans diastereomers of prenylated davanoids like davanone, nordavanone, and davana acid ethyl ester was achieved in an enantioselective strategy. Various other davanoids could also be synthesized using standard procedures from the Weinreb amides derived from davana acids. Enantioselectivity in our synthesis was achieved employing a Crimmins' non-Evans syn aldol reaction that fixed the stereochemistry of the C3-hydroxyl group, while the C2-methyl group was epimerized in a late stage of the synthesis. A Lewis acid-mediated cycloetherification reaction was used to establish the tetrahydrofuran core of these molecules. Interestingly, a slight alteration of the Crimmins' non-Evans syn aldol protocol led to the complete conversion of the aldol adduct to the core tetrahydrofuran ring of davanoids, thus essentially dovetailing two important steps in the synthesis. The resulting one-pot tandem aldol-cycloetherification strategy enabled the enantioselective synthesis of trans davana acid ethyl esters and 2-epi-davanone/nordavanone in just three steps in excellent overall yields. The modularity of the approach will enable the synthesis of various other isomers in stereochemically pure forms for further biological profiling of this important class of molecules.

Protected syn-Aldol Compounds from Direct, Catalytic, and Enantioselective Reactions of N-Acyl-1,3-oxazinane-2-thiones with Aromatic Acetals.

A direct and asymmetric syn-aldol reaction of N-acyl-1,3-oxazinane-2-thiones with dialkyl acetals from aromatic acetals in the presence of 2-5 mol % [DTBM-SEGPHOS]NiCl2, TMSOTf, and lutidine has been developed. It has been established that the oxazinanethione heterocycle, used for the first time as a scaffold in asymmetric carbon-carbon bond-forming reactions, can be smoothly removed to give access to a variety of enantiomerically pure compounds with high synthetic value.

Asymmetric total synthesis of (+)-propolisbenzofuran B.

The first asymmetric total synthesis of (+)-propolisbenzofuran B is accomplished in 11 steps with an overall yield of 11.9%. The key steps are tandem deacetylative Sonogashira coupling-annulation reaction to synthesize the 2-substituted benzofuran core, stereoselective syn-aldol reaction and Friedel-Crafts cyclization to install the desired stereocenters & third-ring, and Stille coupling for C-acetylation.

Synthesis of (1Z)-deacylcnicin

Cnicin is a germacranolide sesquiterpene lactone with a 10-membered ring, two internal olefins, two exo olefins, and an ester side chain. The natural product is a potent inhibitor of Trypanosoma brucei, which causes human African trypanosomiasis. This study examined the synthesis of cnicin via the Evans syn aldol reaction, the indium-promoted diastereoselective Barbier reaction, and ring-closing metathesis (RCM). While RCM did not afford natural (1E)-form as the major product, the synthesis of (1Z)-deacylcnicin was achieved.

Highly diastereoselective asymmetric syn-aldol reactions of (R)-(N-tosyl)phenylalaninol propionate-derived titanium enolate and bidentate aromatic and aliphatic aldehydes

Asymmetric aldol reactions of ester-derived titanium enolates of (R)-(N-tosyl)phenylalaninol propionate and bidentate aromatic aldehydes has been investigated. Substrate scope of this aldol reaction was examined with a variety of bidentate aromatic aldehydes to provide syn-aldol products with high diastereoselectivity and isolated yields. Both enantiomers of N-(tosyl)phenylalaninol are readily prepared from commercially available and optically active phenylalaninol. Mild saponification removed the chiral auxiliary and furnished optically active β-hydroxy carboxylic acids.

Development of Methods for Convergent Synthesis of Chloroalkene Dipeptide Isosteres and Its Application.

Improved methods of convergent synthesis for peptidomimetic utilizing a chloroalkene dipeptide isostere (CADI) are reported. In this synthesis, Fmoc- or Boc-protected carboxylic acids can be produced from N- and C-terminal analogues corresponding to each amino acid starting material via an Evans syn aldol reaction, followed by a [3.3] sigmatropic rearrangement utilizing the Ichikawa allylcyanate rearrangement reaction. With this strategy, an Fmoc-protected CADI can be directly applied for solid-phase peptide synthesis. Using this approach, we have also identified the CADI-containing cyclo[-Lys-Leu-Val-Phe-Phe-] peptidomimetic, which is a superior inhibitor of amyloid-β aggregation than the parent peptide.

Synthesis of the tetrahydropyran fragment of (+)-Ratjadone A

The synthesis of 2,3,4,6-tetrasubstituted tetrahydropyran unit of ratjadone A was achieved. Pivotal reaction sequence in the synthesis include non-Evans syn aldol reaction of a chiral aldehyde obtained from l -malic acid and Uenishi’s palladium catalyzed stereoselective intramolecular S N 2′ reaction to form the tetrahydropyran ring. • Formal synthesis of ratjadone A is accomplished. • Lipase mediated resolution is used for the synthesis of a pivotal allyl alcohol intermediate. • Uenishi’s palladium catalyzed intramolecular S N 2′ reaction is used to construct the tetrahydropyran ring.

An RCM‐Based Total Synthesis of the Antibiotic Disciformycin B

The total synthesis of the potent new antibiotic disciformycin B (2) is described, which shows significant activity against methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA/VRSA) strains. The synthetic route is based on macrocyclization of a tetraene substrate to the 12-membered macrolactone core by ring-closing olefin metathesis (RCM). Although macrocyclization was accompanied by concomitant cyclopentene formation by an alternative RCM pathway, conditions were established to give the macrocycle as the major product. Key steps in the construction of the RCM substrate include a highly efficient Evans syn-aldol reaction, the asymmetric Brown allylation of angelic aldehyde, and the stereoselective Zn(BH4 )2 -mediated 1,2-reduction of an enone. The synthesis was completed by late-stage dehydrative glycosylation to introduce the d-arabinofuranosyl moiety and final chemoselective allylic alcohol oxidation.

Progress towards the Synthesis of (‐)‐Ushikulide A: Synthesis of C1‐C15 Aliphatic and C17‐C31 Spiroketal Fragments by an Aldol Approach

AbstractA convergent approach towards the total synthesis of an immunosuppressant (‐)‐ushikulide A, has been described. Herein, we disclose the synthesis of the C1‐C15 linear fragment and the C17‐C31 spiroketal fragment of (‐)‐ushikulide A by the aldol approach. The C1‐C15 aliphatic fragment was synthesized by applying Evans syn aldol, acetate aldol reaction and the C17‐C31 spiroketal fragment of (‐)‐ushikulide A was achieved via non‐Evans syn aldol as well as spiroketalization reaction. The precursors for the spiroketalization reaction were synthesized from a common intermediate, derived from the non‐Evans syn aldol reaction.

Studies towards the Synthesis of Aldgamycin – M

AbstractA convergent and highly stereoselctive synthesis of macrolide framework of aldgamycin – M is described. The salient features of the synthesis are the utilization of enzymatic desymmetrization, Crimmin's non‐Evans syn aldol reaction, Wittig olefination, Yamaguchi esterification and Ring closing metathesis reaction (RCM).

Studies towards the Synthesis of Portentol

AbstractA highly stereoselective and competent approach for studies towards the synthesis of Portentol has been described. The salient features of the synthesis are the utilization of desymmetrization protocol, Crimmin's non‐Evans syn aldol reaction, C−C bond formation through an intermolecular Aldol reaction and Barton‐McCombie deoxygenation.

Formal synthesis of Pellasoren – A

A convergent and highly stereoselective formal synthesis of Pellasoren – A is described. The salient features of the synthesis are the utilization of enzymatic desymmetrization, Crimmin’s non-Evans syn aldol, Lindlar’s and Wittig reaction.

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.

Novel L-threonine-based ionic liquid supported organocatalyst for asymmetric syn-aldol reaction: activity and recyclability design

Novel L-threonine-based ionic liquid supported organocatalyst for asymmetric syn-aldol reaction: activity and recyclability design

Studies Towards the Synthesis of Stereoisomer of Acremolide B

A convergent synthetic approach towards all carbon chain frame work of cyclicdepsipeptides acremolides A–D is described. The two key fragments, acyclic chain with four chiral centers and a dipeptide with two chiral centers were coupled together through an amide bond formation. Sharpless asymmetric epoxidation and Evans syn aldol reaction are the other key reactions involved in generating chiral centers.in the aliphatic side chain fragment.

Unified total synthesis of (+)-chinensiolide B and (+)-8-epigrosheimin.

An expedient synthetic approach has been developed for the unified total synthesis of (+)-chinensiolide B and (+)-8-epigrosheimin. The point of divergence was provided by the lactone aldehyde 6, in which four contiguous stereocenters were achieved by a stereocontrolled Evans syn-aldol reaction of a R-carvone derived enantiopure aldehyde and chiral N-succinyl-oxazolidinone. The lactone aldehyde 6 was synthesized in multigram quantity in three steps. Highly optimized chemo- and stereoselective reactions and functional group interconversion enabled us to assemble (+)-chinensiolide B and (+)-8-epigrosheimin from 6.

Formal Total Synthesis of Brevisamide by Using a Tandem Isomerization/C–O and C–C Bond Formation Reaction

AbstractA highly stereoselective formal total synthesis of brevisamide is described that proceeds through a convergent pathway and utilizes our own tandem isomerization/C–O and C–C bond formation reaction as the key step to construct the trans‐2,6‐disubstituted dihydropyran ring system. Other significant reactions in this synthesis include an iodolactonization, a Crimmins‐modified “non‐Evans” syn aldol reaction, and a Horner–Wadsworth–Emmons olefination.

Enantioselective Reductive Syn-Aldol Reactions of 4-Acryloylmorpholine: Preparation of (2R, 3S)-3-Hydroxy-2-methyl-1-morpholino-5-phenylpentan-1-one

Enantioselective Reductive Syn-Aldol Reactions of 4-Acryloylmorpholine: Preparation of (2R, 3S)-3-Hydroxy-2-methyl-1-morpholino-5-phenylpentan-1-one