Chemoenzymatic synthesis of conformationally rigid glutamic acid analogues

All stereomers of cyclohexane and cyclopentane-derived analogues of glutamic acid have been synthesized from the corresponding 3-keto-cycloalkyl carboxylic acid esters by a combination of microbial steps and standard chemical methods.     

An efficient enantioselective synthesis of (2R)-hydroxymethyl glutamic acid and an approach to the (2R)-hydroxymethyl-substituted sphingofungins

We have developed a short enantioselective synthesis of (2R)-hydroxymethyl glutamic acid (HMG) starting from Garner's aldehyde using an alkylidene carbene 1,5-CH insertion as a method to construct the quaternary stereocenter. A variety of conditions were examined for the oxidative cleavage of the key cyclopentene intermediate and we found that RuCl3/NaIO4 led directly to the desired amino bis-acid product. We were also able to show that oxidative cleavage of the cyclopentene 1,5-CH insertion product could be used to produce the amino acid-containing skeleton of the sphingofungin family of natural products.     

An efficient and general urazole synthesis

A general two-step scheme for the synthesis of N4 substituted urazoles (i.e., 1,2,4-triazolin-3,5-diones) is described. The first step involves the reaction of a primary amine with 2.5 equiv of phenyl chloroformate to produce diphenyl (N-substituted)imidodicarbonates. The second step involves the reaction of these compounds with hydrazine to produce N4 substituted urazoles. The mild reaction conditions permit synthesis of N4 oxygenated urazoles, not available via existing methodology. Bicyclic urazoles can be prepared through the subsequent reaction of these N4-protected urazoles with 2.5 equiv of NaH in DMF together with either 1,3-dibromopropane or 2-(tert-butyldimethylsilyloxy)-1,3-dibromopropane in the presence of NaI. The resultant bicyclic urazoles are observed to display varying degrees of pyrimidalization at N1 and N2, depending on substituents.     

A convenient method for efficient synthesis of isoxazole-containing thiadiazepine derivatives

Chemistry of Heterocyclic Compounds - An effective strategy has been developed for the preparation of isoxazole-containing thiadiazepine derivatives via the reaction of 1,3-diallyl sulfamide with...     

An efficient and general synthesis of pyrroles

We have discovered that a wide range of 3-alkynyl-hydroxyalkanamine derivatives undergo 5-endo-dig cyclisations when exposed to silver nitrate supported on silica gel. Subsequent in situ dehydration of the resulting and sometimes isolable hydroxy-dihydropyrroles leads to pyrroles in essentially quantitative yields using this recoverable and reusable heterogeneous catalyst.     

An efficient enantioselective synthesis of (S)-(-)-acromelobic acid

[reaction: see text] A highly efficient enantioselective synthesis of (S)-(-)-acromelobic acid (1) was achieved via asymmetric hydrogenation of dehydroamino acid derivative (3) using (R,R)-[Rh(DIPAMP)(COD)]BF(4) catalyst followed by removal of protective groups in >98% ee and good over all yield. The key intermediate (3) was prepared from the commercially available citrazinic acid (4) in six steps.     

An efficient enantioselective synthesis of florfenicol via asymmetric aziridination

An efficient enantioselective synthesis of florfenicol is accomplished in 44.7% overall yield from commercially available p-(methylsulfonyl)benzaldehyde. Key features of this synthesis are the asymmetric aziridination reaction mediated by the Wulff’s catalyst in situ derived from (R)-VANOL and diastereoselectively ring-opening of (2S,3S)-fluoroaziridine 13.     

An enantioselective total synthesis of pinnaic acid

An enantioselective and convergent total synthesis of marine natural product pinnaic acid has been achieved. Our general synthetic approach is featured with an asymmetric hydrogenation of racemic γ-keto ester 3, a diastereoselective methylation on the α-methylene of the (1R,5R)-lactone 4, and a diastereoselective Michael addition of the tertiary nitro cyclopentane. The central azaspiro[4.5]decane was constructed utilizing reductive cyclization of the δ-nitroketone followed by highly stereoselective reduction of the cyclic imine with NaBH₄. Ultimately, successive use of triethyl-2-phosphonopropionate and Heathcock's phosphorane 18 to elaborate C5 and C13 side chains completed the total synthesis of pinnaic acid.     

An enantioselective synthesis of (+)-azimic acid

Herein we report a concise enantioselective synthesis of (+)-azimic acid starting from (5S,6S)-6-methyl-5-benzyloxy-2-piperidinone 8a, which was prepared from protected (S)-3-hydroxyglutarimide 6 according to a method recently disclosed in our laboratory. The key step is a stepwise regioselective reductive alkylation of the imide 10, which established the 2,6-cis-stereochemistry in excellent diastereoselectivity.     

An enantioselective formal synthesis of berkelic acid

An enantioselective formal synthesis of berkelic acid is described. The key step involves a late-stage silyl enol ether addition to a benzannulated oxonium ion with subsequent spiroketalization leading to construction of the tetracyclic core. Thermodynamically controlled equilibration under acidic conditions affords the desired spiroketal configuration as a single diastereoisomer.     

An efficient enantioselective synthesis of the acyl side chain of polyoxypeptins

An enantioselective synthesis of the acyl side-chain 3 of polyoxypeptins 1 and 2 was achieved by the Sharpless AE, with subsequent regioselective opening of the epoxyalcohol using a Grignard reagent in the presence of CuI, and an aldol condensation using Seebach's ester. The method reported has the advantage of a concise route and excellent enantiomeric purity, as well as starting from readily available chemical substrates and the use of inexpensive reagents.     

An efficient and enantioselective total synthesis of naturally occurring L-783277

Naturally occurring L-783277 which belongs to 14-membered resorcylic acid lactones (RALs) turned out to be a potent kinase inhibitor against MEK (MAP kinase kinase). We successfully accomplished efficient and enantioselective total synthesis of L-783277 based on convergent assembly of one aromatic unit and two chiral building blocks with efficient orthogonal protection-deprotection strategy. Three key steps composed of olefin cross metathesis, addition of acetylene derivative to aldehyde, and Yamaguchi macrolactonization were subsequently employed to construct the framework of L-783277. The optical rotation value of L-783277 is for the first time presented in this Letter.     

An efficient synthesis of chiral homophenylalanine derivatives via enantioselective hydrogenation

Chiral homophenylalanine derivatives were synthesized via enantioselective hydrogenation of 5a and 5b catalyzed by rhodium complexes bearing chiral phosphine and phosphinite legands. Enantiomeric excesses up to 96.2% were achieved when S-spiroOP(S-1) was used as a chiral ligand under 500 psi of H₂ pressure in acetone.     

An efficient and general route to gem-difluoromethylenated alpha,beta-unsaturated delta-lactones: high enantioselective synthesis of gem-difluoromethylenated goniothalamins

An efficient and general strategy to gem-difluoromethylenated alpha,beta-unsaturated delta-lactones in high yields from various aldehydes (including aliphatic, aromatic, alpha,beta-unsaturated, and sterically hindered aldehydes) has been developed. This methodology was successfully applied for the preparation of two enantiomers of gem-difluoromethylenated goniothalamins (S)-1 and (R)-1. gem-Difluoropropargylation of cinnamaldehyde followed by the resolution of resulting homopropargylic alcohols mediated by lipase from Pseudomonas (AK) gave alcohols (R)-6 and (S)-6. Selective hydrogenation of the triple bond of (S)-6 and (R)-6 to double bond with Lindlar catalyst in the presence of quinoline afforded the expected product (S)-8 and (R)-8, respectively. Deprotection of (S)-8 and (R)-8 followed by oxidation of the resulting 1,5-diols with catalytic 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and excess bis-acetoxyiodobenzene (BAIB) provided the target molecules gem-difluoromethylenated goniothalamins (S)-1 and (R)-1 in high yields, respectively.     

An efficient and enantioselective approach to the azaspirocyclic core of alkaloids: formal synthesis of halichlorine and pinnaic acid

A novel, highly stereoselective synthesis of an azaspirocyclic core, which contains four stereogenic carbons consistent with structures of natural halichlorine and pinnaic acid, is presented. Lipase PS-catalyzed selective acylation, asymmetric methylation on the alpha-methylene of the bicyclic lactone, and an asymmetric Michael addition of the tertiary nitro cyclopentane were concisely used to conquer the challenging problem of successfully constructing the C9 quarternary carbon center with complete stereocontrol. The spiropiperidine ring was formed by reduction of the delta-nitroketone, intramolecular condensation, and then highly stereoselective reduction of the cyclic nitrone with NaBH(4). This spirocyclic core is a key intermediate in Danishefsky's synthesis of pinnaic acid and halichlorine.     

The enantioselective synthesis of tetracyclic methyllycaconitine analogues

A new enantioselective synthesis of ABEF ring analogues of methyllycaconitine has been developed using a chiral cobalt(III) salen-catalyzed Diels-Alder reaction to form the B ring. Subsequent elaboration to form the A, E and F rings was achieved by sequential Dieckmann, Mannich and Wacker-type cyclizations to afford tetracyclic analogues in 97.5% ee.     

An efficient enantioselective total synthesis of a trifluoromethyl analog of blastmycinolactol

A novel synthetic strategy for the total synthesis of fluorinated analog of blastmycinolactol has been developed using α-pinene based alkoxyallylboration, chelation controlled diastereoselective reduction, and a single step lactonization of the 1,4-diol to the γ-lactone as key steps.     

Approaches to the enantioselective synthesis of ferrugine and its analogues

A four-step synthetic route, to ferrugine (2α-benzoyltropane), its methyl analogue (2-acetyltropane) and their N-benzyl analogues is reported. The reaction sequence uses tropinone or N-benzylnortropinone aldols as key intermediates. Reduction of aldol derived N-tosylhydrazones and oxidation of the side chain hydroxyl group followed by spontaneous diastereomer equilibration provides the final products. Relative configuration of the exo,anti N-methyl and N-benzyl aldols was retained during N-tosylhydrazone formation. The relative stereochemistry of N-tosylhydrazones was assigned by single crystal diffraction. The final products, ferrugine and its methyl analogue, were synthesized in enantiomerically pure form via asymmetric deprotonation of tropinone using chiral lithium amide/lithium chloride aggregate prepared in situ from (S,S)-N,N-bis(1-phenylethyl)amine hydrochloride.     

An enantioselective synthesis of β2-amino acid derivatives

Enantioselective hydrogenation of a series of (E)-α-substituted β-amidoacrylates using Rh(I)-catalysts with chiral phosphine ligands (BPE, DuPHOS) gives β²-amino acid derivatives with enantioselectivities of up to 67%. A β^2,3-amino acid derivative was also synthesised with similar enantioselectivity (⩽65%) from the corresponding prochiral enamide.