Evans Syn Research Articles

Azide‐free Enantioselective Synthesis of Clinical Antibiotic (1R,2R)‐Chloramphenicol (Chloromycetin)

AbstractThe enantioselective synthesis of the broad‐spectrum antibiotic (1R,2R)‐chloramphenicol and its congener is described here. Our approach is based on the Evans asymmetric aldol reaction, which involves the use of a chiral ‘glycine enolate equivalent’ derived from N‐(N‐Boc‐glycinyl) oxazolidinone and p‐nitrobenzaldehyde. The reaction is catalyzed by TiCl4 and Hunig's base DIPEA, resulting in the production of both Evans syn‐ and non‐Evans anti‐adducts in a 3 : 1 diastereomeric ratio with 85 % combined yield. We achieved diastereoselectivity control in the reaction using Lewis acid TiCl4 along with DIPEA. Subsequently, the syn‐ and anti‐aldol products were transformed into (1R,2R)‐ and (1R,2S)‐chloramphenicol, respectively, using a three‐step method. The stereochemistry of the clinically used chloramphenicol was confirmed by measuring the optical rotation of the final compounds.

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.

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.

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 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.

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.

Noninnocent Role of N-Methyl Pyrrolidinone in Thiazolidinethione-Promoted Asymmetric Aldol Reactions

The origin of stereoselectivity in the reaction between α-azido titanium enolate derived from chiral auxiliary N-acyl thiazolidinethione and benzaldehyde is established using the DFT(B3LYP) method. A nonchelated transition state with N-methyl-2-pyrrolidinone (NMP) bound to a TiCl(3) enolate is found to be energetically the most preferred model responsible for the formation of an Evans syn aldol product. The TS model devoid of NMP, although of higher energy, is found to be successful in predicting the right stereochemical outcome.

Asymmetric Synthesis of (-)-9-epi-Metazocine

(–)-9-epi-Metazocine was synthesized through an Evans syn aldol reaction, ring-closing metathesis reaction and intramolecular radical cyclization.

Synthesis of (4R,6S,7R)-7-hydroxy-4,6-dimethyl-3-nonanone and (3R,5S,6R)-6-hydroxy-3,5-dimethyl-2-octanone

The synthesis of (4R,6S,7R)-7-hydroxy-4,6-dimethyl-3-nonanone and (3R,5S,6R)-6-hydroxy-3,5-dimethyl-2-octanone is described as their acetates using a desymmetrization strategy as well as an Evans syn aldol strategy.

Transition State Models for Probing Stereoinduction in Evans Chiral Auxiliary-Based Asymmetric Aldol Reactions

The use of chiral auxiliaries is one of the most fundamental protocols employed in asymmetric synthesis. In the present study, stereoselectivity-determining factors in a chiral auxiliary-based asymmetric aldol reaction promoted by TiCl(4) are investigated by using density functional theory methods. The aldol reaction between chiral titanium enolate [derived from Evans propionyl oxazolidinone (1a) and its variants oxazolidinethione (1b) and thiazolidinethione (1c)] and benzaldehyde is examined by using transition-state modeling. Different stereochemical possibilities for the addition of titanium enolates to aldehyde are compared. On the basis of the coordination of the carbonyl/thiocarbonyl group of the chiral auxiliary with titanium, both pathways involving nonchelated and chelated transition states (TSs) are considered. The computed relative energies of the stereoselectivity-determining C-C bond formation TSs in the nonchelated pathway, for both 1a and 1c, indicate a preference toward Evans syn aldol product. The presence of a ring carbonyl or thiocarbonyl group in the chiral auxiliary renders the formation of neutral TiCl(3)-enolate, which otherwise is energetically less favored as compared to the anionic TiCl(4)-enolate. Hence, under suitable conditions, the reaction between titanium enolate and aldehyde is expected to be viable through chelated TSs leading to the selective formation of non-Evans syn aldol product. Experimentally known high stereoselectivity toward Evans syn aldol product is effectively rationalized by using the larger energy differences between the corresponding diastereomeric TSs. In both chelated and nonchelated pathways, the attack by the less hindered face of the enolate on aldehyde through a chair-like TS with an equatorial disposition of the aldehydic substituent is identified as the preferred mode. The steric hindrance offered by the isopropyl group and the possible chelation are identified as the key reasons behind the interesting stereodivergence between Evans and non-Evans products normally reported for the title reaction. The application of an activation strain model on the critical TSs has been effective toward rationalizing the origin of stereoselectivity. Improved interaction energy between the reactants is found to be the key stabilizing factor for the lowest energy TS in both chelated and nonchelated pathways. The present study provides newer insights on the role of titanium(IV) toward modulating stereoselectivity in aldol reactions.

ChemInform Abstract: Titanium Enolates of Thiazolidinethione Chiral Auxiliaries: Versatile Tools for Asymmetric Aldol Additions.

[formula: see text] Asymmetric aldol additions using chlorotitanium enolates of thiazolidinethione propionates proceed with high diastereoselectivity for the or syn product depending on the nature and amount of the base used. With (-)-sparteine as the base, selectivities of 97:3 to > 99:1 were obtained for the Evans syn products with 2 equivalents of base and for the non-Evans syn when 1 equiv of base was employed. The thiazolidinethione auxiliaries are easily removed, and the aldol adducts can be readily transformed to various functional groups. Even direct reduction to the aldehyde with diisobutylaluminum hydride is possible.

The Pivotal Role of Chelation as a Stereochemical Control Element in Non-Evans Anti Aldol Product Formation

The origin of stereoselective formation of Evans syn and non-Evans anti aldol products in the reaction between titanium enolate derived from N-succinyloxazolidinone and benzaldehyde is established by using transition-state modeling. The chelated transition-state model is found to hold the key to otherwise less likely non-Evans anti aldol product, whereas the nonchelated model offers a convincing rationalization toward Evans syn aldol product. The computed results are in agreement with the reported experimental observations.

Stereospecific Total Synthesis of (+)-Davana Acid, (+)-Nordavanone and (+)-Davanone

A short, total synthesis of (+)-davana acid, (+)-nordavanone and (+)-davanone, which are principle components of davana oil, is described. The notable features are the use of the Evans syn aldol reaction and cyclic ether formation by an intramolecular S N 2 displacement reaction as key steps.

Characterization of the types of the Neotropical Pseudisobrachium (Hymenoptera: Bethylidae), with a key to species

The identity of many Neotropical species of Pseudisobrachium Kieffer, 1904 is currently unreachable, mostly because the available descriptions and illustrations are not sufficiently accurate to allow precise identifications. To help solve the problem, 115 valid species and their junior synonyms were examined. Twelve nomenclatural acts are made, and 110 valid species are recognized for the Neotropical region. Two lectotypes are designated: Pristocera crassicornis Westwood and Pristocera haemorrhoidalis Westwood. Seven new species-group synonyms are proposed: Pseudisobrachium retusum Evans syn. nov. for P. pauxillum Evans; P. cunco Perez syn. nov. for P. erythrocephalum Evans; P. navajo Evans, P. rectangulatum Evans, P. emarginatum Evans and P. foutsi Evans syn. nov. for P. flavinervis Fouts; P. acuminatum Waichert & Azevedo syn. nov. for P. latum Waichert & Azevedo. The following new genus-group synonym is established: Parisobrachium Kieffer syn. nov. for Dissomphalus Ashmead. The following new combination and reinstated name are proposed: Dissomphalus albipes (Kieffer) comb. nov. and nom. rev. from Pseudisobrachium paraguayense Kieffer.

Synopsis of Prosierola (Hymenoptera: Bethylidae)

The identity of many species of Prosierola is currently unknown, mostly because the available taxonomic information is not sufficiently accurate to allow for precise identifications. To solve this problem, nine valid species were investigated. Neotropical species of Bethylinae were also examined in order to find possible misclassified species of Prosierola. In this paper six nomenclatural changes are made, and six valid species recognized. The lectotype of Parasierola flavicoxis Kieffer is designated. The following new species-group synonyms are established: Prosierola lata (Cameron) syn. nov. for Prosierola nasalis (Westwood); Prosierola insularis Evans syn. nov. for Prosierola cubana Evans, and Prosierola bicarinata (Brues) syn. nov. for Prosierola flavicoxis (Kieffer), and Prosierola variegata Evans syn. nov. for Prosierola obliqua Evans. The following new combination is established: Prosierola flavicoxis (Kieffer) from Goniozus.

Total Synthesis of Cruentaren B

A convergent total synthesis of the cytotoxic natural product cruentaren B is completed in 26 steps (longest linear sequence) with an overall yield of 7.1%. For the construction of the C1-C11 benzolactone fragment of the molecule, the key steps used were O-methylation, using a Mitsunobu reaction, a Stille coupling method to construct the C7-C8 bond, and a Brown's asymmetric crotylboration reaction for the direct enantioselective installation of the two chiral centers present in this fragment. For diastereoselective installation of the chiral centers in the C12-C20 polyketide fragment, an Evans syn aldol reaction on a chiral aldehyde, derived from methyl (R)-3-hydroxyl-2-methylpropionate, and subsequently a Mukaiyama aldol reaction were employed. For the construction of the C21-C28 tail, a "non-Evans" syn aldol reaction was used. The three fragments were coupled by an SN2 reaction and a Wittig olefination reaction followed by standard functional group manipulations to furnish the target molecule.

Synthesis of Nonactin and the Proposed Structure of Trilactone

[reaction: see text] An efficient enantioselective route to nonactin using a novel beta-inversion of an Evans syn aldol to construct the THF ring is presented. Through total synthesis, the structure for trilactone proposed in the literature is shown likely to be incorrect.

An Improved Procedure for Asymmetric Aldol Additions with N‐Acyl Oxazolidinones, Oxazolidinethiones and Thiazolidinethiones.

AbstractFor Abstract see ChemInform Abstract in Full Text.

An Improved Procedure for Asymmetric Aldol Additions withN-Acyl Oxazolidinones, Oxazolidinethiones and Thiazolidinethiones

Asymmetric aldol additions using chlorotitanium enolates of N-acyl oxazolidinones, oxazolidinethiones and thiazoli­dinethiones proceed with high diastereoselectivity for the ‘Evans syn’ product using one equivalent of titanium tetrachloride, one equivalent of diisopropylethylamine and one equivalent of N-methyl-2-pyrrolidinone. Typical selectivities of 94:6 to >98:2 were obtained using N-propionyl oxazolidinones, oxazolidinethiones and thiazolidinethiones at 0 °C with stoichiometric amounts of aldehyde. Glycolate imides also gave high selectivities and high yields using this procedure.

Flexible Routes to the 5‐Hydroxy Acid Fragment of the Cryptophycins

AbstractTwo solutions to establishing the anti stereochemistry of the vicinal stereocenters in the 5‐hydroxy acid subunit of cryptophycin, based on initial Evans syn aldol reactions between an N‐(propionyl)oxazolidinone 4 and a C3 aldehyde, were developed. In the first route, the secondary hydroxy group was inverted by use of Mitsunobu reaction conditions, whereas the second route features an inversion of the methyl‐bearing stereocenter, achieved by reductive removal of the chiral auxiliary, elimination to afford the terminal alkene, and anti‐selective hydroboration. The aryl part can be attached either by Wittig−Horner olefination or by a modified Julia coupling. Both routes provide the hydroxy acid 16 in a very efficient manner. The substrate for the hydroboration, alkene 22, could also be obtained from (S)‐malic acid. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)