Stereoselective synthesis of orthogonally protected 2,3-disubstituted morpholines using a base-catalysed cascade reaction

The stereoselective synthesis of differentially protected [3-(hydroxymethyl)morpholin-2-yl]methanols is described, starting from chiral epoxides. The key step involves a one-pot oxazolidinone formation via intramolecular epoxide opening and concomitant cyclisation to form the morpholine ring. Selective deprotection reveals the free hydroxymethyl group at either the 2- or 3-position of the morpholine.     

Stereoselective synthesis of partially protected azasugar derivatives

Five-membered azasugar derivatives with partially protected hydroxyl groups, and their fluorinated derivatives were synthesized via the key intermediates of norbornyl-like bicyclic acetals using d-xylose and d-glucose as starting materials. The glycosylation of the azasugar intermediate and 1-methylenesugar was also explored. Translated from Chemical Journal of Chinese Universities, 2006, 27 (4) (in Chinese)     

Solid-phase synthesis of bis-heterocyclic compounds from resin-bound orthogonally protected lysine

An efficient method for the solid-phase synthesis of bis-heterocyclic compounds from resin-bound orthogonally protected lysine is presented. The initial reaction step involves the exhaustive reduction of resin-bound tetra-amides using borane-THF, followed by cyclization of the resulting tetra-amine with either carbonyldiimidazole, thiocarbonyldiimidazole, or oxalyldiimidazole to generate resin-bound bis-cyclic ureas, bis-cyclic thioureas, and bis-cyclic diketopiperazines, respectively. Cleavage from the solid support using hydrogen fluoride, followed by extraction and lyophilization, yields the desired bis-heterocyclic compounds in excellent yield and high purity.     

A concise stereoselective synthesis of orthogonally protected lanthionine and beta-methyllanthionine

Lantibiotics such as nisin are active against most Gram-positive bacteria and constitute an important class of antibacterial agents. These ribosomally synthesized peptides contain either one or both of the unusual amino acids meso-lanthionine (m-Lan) or beta-methyllanthionine (beta-MeLan). Nucleophilic ring opening of sulfamidates allows facile preparation of stereochemically pure derivatives of m-Lan and beta-MeLan with orthogonal protection for solid phase synthesis of lantibiotic analogues.     

An efficient synthesis of N-arylated, orthogonally protected racemic aspartates

A brief and efficient synthesis of variously N-arylated racemic aspartates has been achieved by two consecutive reactions in one-pot, in which imine or equivalent, formed in situ from various anilines and ethyl glyoxylate, reacted with the Reformatsky reagent, tert-butyl 2-bromozinc acetate. Notably the two esters are orthogonally protected for the convenience of further derivatization.     

A short diastereoselective synthesis of orthogonally protected diaminosuccinic acid derivatives

Homogeneous, Rh-catalyzed hydrogenation of heteromeric olefinic glycine dimers presents an efficient route to diastereomerically pure, orthogonally protected diaminosuccinic acid derivatives depending on the double bond geometry of the starting material. The products were obtained as racemates.     

Stereoselective synthesis of protected 3-amino-3,6-dideoxyaminosugars

New syntheses of densely functionalized protected derivatives of 3-amino-3,6-dideoxyaminosugars have been accomplished in an efficient and straightforward manner. The key step of such approaches involves a highly stereoselective titanium-mediated aldol addition of a chiral α-bromo ketone, easily available from lactate esters, to crotonaldehyde. Further functional group transformations, including a new regioselective Staudinger-aza-Wittig reaction of an azidodiacetate, afford in a few steps and high yield the desired carbohydrates as advanced intermediates capable of participating in subsequent glycosylation reactions.     

An efficient RCM-based synthesis of orthogonally protected meso-DAP and FK565

A condensation--ring-close--ring-open sequence was employed for the synthesis of orthogonally protected meso-2,6-diaminopimelic acid, starting from easily accessible chiral synthons. Condensation of suitably protected L-allylglycine and D-vinylglycinol derivatives was followed by Grubbs' ring-closing metathesis to generate the key lactam intermediate. This strategy has been applied to a concise total synthesis of the potent immunostimulatory peptide FK565.     

Synthesis of orthogonally protected lanthionines

Synthetic approaches to the lantibiotics, a family of thioether-bridged antimicrobial peptides, require flexible synthetic routes to a variety of orthogonally protected derivatives of lanthionine 1. The most direct approaches to lanthionine involve the reaction of cysteine with an alanyl beta-cation equivalent. Several possibilities exist for the alanyl beta-cation equivalent, including direct activation of serine under Mitsunobu conditions: however, the low reactivity of sulfur nucleophiles in the Mitsunobu reaction has previously precluded its use in the synthesis of the lantibiotics. We report here a new approach to the synthesis of protected lanthionine, using a novel variant of the Mitsunobu reaction in which catalytic zinc tartrate is used to enhance the nucleophilicity of the thiol. In the course of these studies, we have also demonstrated that the synthesis of lanthionine from trityl-protected beta-iodoalanines is prone to rearrangement, via an aziridine, to give predominantly trityl-protected alpha-iodo-beta-alanines, and hence norlanthionines, as the major products.     

Efficient synthesis of orthogonally protected anti-2,3-diamino acids

An asymmetric synthesis of anti-2,3-diamino acids is reported. The enolates of N,N-dibenzylated β³-amino esters were treated with di-tert-butyl azodicarboxylate (DBAD) to afford their N′,N″-di-Boc-2-hydrazino derivatives with excellent anti diastereoisomeric ratio. Final Boc removal and reductive cleavage of the hydrazino bond led to the expected 2,3-diamino esters having only one free amino group. In comparison with other asymmetric C-2 amination procedures, this method does not need the use of expensive chiral reagents and/or chiral auxiliaries, while leads to products which can be orthogonally protected.     

The stereocontrolled synthesis of orthogonally protected (R)-α-methyltryptophan

An expedient and highly stereocontrolled route to (R)-α-methyltryptophan and its orthogonally protected analogs has been developed via a four-step conversion from L-alanine in good overall yields. The stereochemistry of the products is confirmed by X-ray diffraction analysis, NMR spectroscopy and optical rotations.     

Asymmetric synthesis of orthogonally protected trans-cyclopropane gamma-amino acids via intramolecular ring closure

The synthesis of enantiomerically-enriched trans-cyclopropane amino- and hydroxy-acids can be achieved by intramolecular ring closure in moderate to good yields. The optically active cyclopropane precursors are easily prepared in a short sequence from inexpensive, commercially available olefins and tert-butyl acetate. Several leaving groups and bases were compared for the cyclopropanation step, showing that the diphenylphosphinate and tosyl leaving groups give the best results when used in combination with either LDA or NaHMDS.     

Stereoselective total synthesis of protected sulfamisterin and its analogues

The stereoselective synthesis of sulfamisterin I and its unnatural analogues II and V in their protected form was achieved through a common strategy. The Wittig reaction of aldehydes VIII and IX with the C₁₄ hydrophobic side-chain X served as the key C-C connecting transformation. Subsequent functional group inter-conversions in the coupling products XI and XX completed the total synthesis.     

An expedient synthesis of orthogonally protected lysinoalanine from Aloc-protected Garner’s aldehyde

An expedient synthesis of orthogonally protected lysinoalanine has been developed. We have prepared a novel Garner’s aldehyde derivative bearing an Aloc group; reductive amination of this aldehyde with Fmoc-Lys-OPMB gave the lysinoalanine skeleton. This was then transformed into an orthogonally protected lysinoalanine derivative suitable for the synthesis of side-chain bridged cyclic peptides by solid phase peptide synthesis methods.     

An improved synthesis of a trifurcated newkome-type monomer and orthogonally protected two-generation dendrons

The one-step synthesis of amino-polyether tri-tert-butyl ester monomer 2, by condensation of TRIS with tert-butyl acrylate, is reported. The nitrogen of the monomer can be protected with a Cbz group; subsequent removal of the tert-butyl esters with formic acid affords a triacid that is coupled to three monomers to afford an orthogonally protected two-generation, trifurcated polyether-polyamide dendron. The Cbz protecting group may be removed from the second-generation dendron without disturbing the tert-butyl esters of the periphery.     

Straightforward synthesis of orthogonally protected piperidin-3-ylmethanamine and piperidin-4-ylmethanamine derivatives

The 1,3- and 1,4-disubstituted piperidines are important building blocks in medicinal chemistry and drug discovery. We present the synthesis of orthogonally protected piperidin-3-ylmethanamine and piperidin-4-ylmethanamine derivatives from commercially available nipecotamide, isonipecotamide, nipecotic acid and isonipecotic acid. This is a straightforward two-step procedure that gives high overall yields. Purification of the intermediates using this procedure is not necessary, and the final compounds are purified by simple flash column chromatography.     

Synthesis of orthogonally protected 2-deoxystreptamine stereoisomers

Enantiomerically pure 4,6-diaminocyclohexenols are obtained from carbohydrate derived 1,7-dienes by ring-closing metathesis and palladium catalyzed allylic amination using o-nitrobenzenesulfonylamides as nucleophiles. In the latter reaction the use of a cyclic carbonate as a leaving group proved to be essential to facilitate a smooth substitution. The obtained compounds were converted into orthogonally protected diaminocyclitols, which are stereoisomers of the naturally occurring 2-deoxystreptamine, a constituent of aminoglycoside antibiotics.