Diastereoselective synthesis of (+)-nephrosterinic acid and (+)-protolichesterinic acid

A diastereoselective synthesis of (+)-nephrosterinic acid and (+)-protolichesterinic acid, common members of the paraconic acids is described. The synthesis is based on a diastereoselective orthoester Johnson–Claisen rearrangement of a (Z)-allyl alcohol with a vicinal dioxolane moiety as key steps. The synthesis is completed in 10 steps and with overall yields of 15.9% for (+)-nephrosterinic acid and 16.4% for (+)-protolichesterinic acid.     

Asymmetric synthesis of (+)-1-epiaustraline and attempted synthesis of australine

A diastereoselective synthesis of the pyrrolizidine alkaloid, (+)-1-epiaustraline has been achieved via a diastereoselective syn-dihydroxylation of a pyrrolo[1,2-c]oxazol-3-one precursor that was readily prepared by a RCM reaction. Attempts to extend this methodology to the synthesis of australine were not successful since the final pyrrolidine ring closure to produce the desired pyrrolizidine of the target molecule was not productive.     

Syntheses of spiro[cyclopropane-1,3′-oxindole]-2-carboxylic acid and cyclopropa[c]quinoline-7b-carboxylic acid and their derivatives

The synthesis of spiro[cyclopropane-1,3′-oxindole]-2-carboxylic acid, including novel 3-(2- and 3-pyridyl)-substituted analogues and the novel cyclopropa[c]quinoline-7b-carboxylic acid and their ester and amide derivatives is described. These syntheses involve diastereoselective cyclopropanation reactions of methyl 2-(2-nitrophenyl)acrylate and (3E)-(pyridin-2-ylmethylene)- and (3E)-(pyridin-3-ylmethylene)-1,3-dihydro-2H-indol-2-one with ethyl (dimethyl sulfuranylidene) acetate (EDSA). The synthesis of methyl cyclopropa[c]quinoline-7b-carboxylate involves a regioselective reductive cyclization of a nitro-diester precursor. The relative stereochemistry of key compounds has been determined by single-crystal X-ray structural analysis.     

Diastereoselective synthesis of new polyhydroxylated indolizidines from (l)-glutamic acid

A diastereoselective synthesis of two new swainsonine's analogues 1a and 1b with the piperidine ring fused to a phenyl nucleus at C6-C7, namely (1R, 2S, 10R, 10aR)-(+)-1,2,10-trihydroxy-1,2,3,5,10,10a-hexahydrobenzo[f] indolizine (1a) and (1S, 2R, 10R, 10aR)-(+)-1,2,10-trihydroxy-1, 2, 3, 5, 10, 10a-hexahydrobenzo[f] indolizine (1b), is described. Throughout this work, the effectiveness of the tricyclic indolizidine dione 5, readily available in three steps from the cheap l-glutamic acid, as an attractive platform for chemo- and stereodivergent transformations is illustrated. The key steps involved totally diastereoselective ketone reduction of compound 5 and catalytic cis-dihydroxylation of the unsaturated amide 10. The synthetic strategy also allowed for the diastereoselective synthesis of benzoanalogues of the 1,8a-di-epi-lentiginosine 3a ((1R, 2S, 10aR)-(+)-1,2-dihydroxy-1, 2, 3, 5, 10, 10a-hexahydrobenzo[f]indolizine) and 2,8a-di-epi-lentiginosine 3b ((1S, 2R, 10aR)-(+)-1,2-dihydroxy-1,2,3,5,10,10a-hexahydrobenzo[f]indolizine).     

A concise enantioselective synthesis of (+)-goniodiol and (+)-8-methoxygoniodiol via Co-catalyzed HKR of anti-(2SR, 3RS)-3-methoxy-3-phenyl-1, 2-epoxypropane

A short, enantioselective synthesis of (+)-goniodiol and (+)-8-methoxygoniodiol, cytotoxic styryllactones, has been achieved in high optical purities (99% ee). The strategy employs Co-catalyzed HKR of racemic anti-(2SR, 3RS)-3-methoxy-3-phenyl-1, 2-epoxypropane and Lewis acid-mediated diastereoselective allylation of aldehyde as chiral inducing key reactions.     

A facile method for synthesis of (R)-(−)- and (S)-(+)-homocitric acid lactones and related α-hydroxy dicarboxylic acids from d- or l-malic acid

We report here a simple and convenient route for the stereoselective synthesis of (R)-(−)- and (S)-(+)-homocitric acid lactones, which play very important roles in biochemistry. The method involves only three steps, starting from the readily available methyl 3-iodopropionate and d-malic acid or l-malic acid, respectively. The stereoconfiguration of the target molecules has been achieved via a self-regeneration approach with over 98% diastereoselectivity and significantly improved yield over the previous methods.     

A novel synthesis, including asymmetric synthesis, of α-quaternary α-amino acid methyl esters from ketones via sulfinyloxiranes

Sulfinyloxiranes were synthesized from ketones and chloromethyl p-tolyl sulfoxide in two steps in almost quantitative yields. The sulfinyloxiranes were treated with NaN₃ in the presence of NH₄Cl to afford α-azido aldehydes, which were oxidized with iodine in the presence of KOH in methanol to give α-azido methyl esters in good overall yields. Catalytic hydrogenation of the α-azido esters afforded α-quaternary α-amino acid methyl esters in quantitative yields. Starting from β-tetralone and optically pure (R)-chloromethyl p-tolyl sulfoxide, an asymmetric synthesis of optically pure (R)-(+)-methyl 2-aminotetraline-2-carboxylate was realized in good overall yields.     

The stereoselective addition of titanium(IV) enolates of 1,3-oxazolidin-2-one and 1,3-thiazolidine-2-thione to cyclic N-acyliminium ion. The total synthesis of (+)-isoretronecanol

(+)-Isoretronecanol (1) has been prepared in four steps and 36% overall yield via the diastereoselective addition of the titanium(IV) enolate derived from N-4-chlorobutyryl-1,3-thiazolidine-2-thione (3) to N-Boc-2-methoxypyrrolidine (5), which afforded 2-substituted pyrrolidine 7 in 84% yield (8:1 diastereoisomeric ratio), followed by reductive recovery of the chiral auxiliary and cyclization.     

Stereoselective synthesis of (+)-(8R,8aR)-perhydro-8-indolizidinol

A highly stereoselective total synthesis of (+)-(8R,8aR)-perhydro-8-indolizidinol is described. Key steps involved in this synthesis are diastereoselective zinc allylation, azido-olefin cyclization and reductive amination followed by cyclization which effectively constructed the indolizidine ring. This contributes a unique approach to the synthesis of indolizidine alkaloids that offers the advantages of brevity and relatively high overall yields.     

Concise and highly selective asymmetric synthesis of acosamine from sorbic acid

Diastereoselective conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to tert-butyl sorbate and subsequent chemo- and diastereoselective ammonium-directed olefinic oxidation of the resultant conjugate addition product {tert-butyl (3S,αR)-3-[N-benzyl-N-(α-methylbenzyl)amino]hex-4-ene} have been used as the key steps in a concise and highly selective asymmetric synthesis of the 2,3,6-trideoxy-3-aminohexose l-acosamine. This sequence of two chemical operations allows rapid assembly of the molecular architecture and facilitates the de novo asymmetric synthesis of methyl N,O-diacetyl-α-l-acosaminide in only 7 steps from commercially available sorbic acid in 15% overall yield.     

Asymmetric total synthesis of (+)-carneic acid A and structure revision of its natural form

This Letter describes the asymmetric total synthesis of (+)-carneic acid A via the stereoselective IMDA reaction of (E,E,E)-triene, which was prepared from the commercially available methyl (S)-3-hydroxy-2-methylpropionate. By this asymmetric total synthesis, we verified that the reported absolute structure of naturally occurring carneic acid A must be revised.     

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.     

Total synthesis of 3,4-dihydroxyprolines, -threo- -norvaline and (2S,3R,4R)-2-amino-3,4-dihydroxytetrahydrofuran-2-carboxylic acid methyl ester

The Henry reaction between -glyceraldehyde and ethyl nitroacetate allowed the practical development of a diastereoselective synthesis of 3,4,5-trihydroxy-2-nitropentanoic acid esters, which were reduced to polyoxamic acids, which were used in a new diastereoselective synthesis of 3,4-dihydroxyprolines and new enantioselective syntheses of -threo- -norvaline and (2S,3R,4R)-2-amino-3,4-dihydroxytetrahydrofuran-2-carboxylic acid methyl ester.     

Asymmetric synthesis of (−)-(S,S)-homaline

The asymmetric synthesis of (−)-(S,S)-homaline was achieved in 8 steps from commercially available starting materials using the diastereoselective conjugate addition of the novel lithium amide reagent lithium (R)-N-(3-chloropropyl)-N-(α-methyl-p-methoxybenzyl)amide to methyl cinnamate to install the correct stereochemistry. Subsequent functional group manipulation of the resultant β-amino ester and Sb(OEt)₃-mediated macrolactamisation was followed by homodimerisation to give (−)-(S,S)-homaline in 18% overall yield, representing the first asymmetric, and by far the most efficient synthesis of this natural product reported to date.     

A new approach to the C28 fatty acid chain of the marine natural products schulzeines B and C: a concise diastereoselective total synthesis of(−)-schulzeine B

An enantioselective approach to the C₂₈ fatty acid chain of the marine natural products schulzeines B and C was established based on the l-tartaric acid derived C₄ chiron 11 via successive 1,4-bis-chain elongation reactions and catalytic asymmetric hydrogenation. The chiral tricyclic core 8 was constructed via a diastereoselective Pictet-Spengler cyclization reaction (dr = 89:11) of the l-glutamic acid derived precursor 13. On this basis, a concise total synthesis of (−)-schulzeine B (5) was disclosed.     

A convenient and new approach to the synthesis of ω-heterocyclic amino acids from carboxy lactams through ring-chain-transformation. Part 2: Synthesis of (2R)-/(2S)-2-aminomethyl-3-(1-aryl-/1,5-diaryl-1H-pyrazol-3-yl)-propionic acid

Making use of amide activation, a convenient and short path synthesis of optically pure ω-heterocyclic-β-amino acids has been achieved from (1R,3R)- and (1R,3S)-5-oxo-1-(1-phenyl-ethyl)-pyrrolidine-3-carboxylic acid methyl ester. The key step of the synthesis involves a regiospecific ring-chain-transformation of the enaminones when subjected to 1,2-binucleophilic attacks. The method is illustrated by the synthesis of (2R)-/(2S)-2-aminomethyl-3-(1-aryl-/1,5-diaryl-1H-pyrazol-3-yl)-propionic acid.     

A concise approach to (+)-1-epi-castanospermine

A concise enantioselective synthesis of (+)-1-epi-castanospermine (2) is described, which featured the use of chiral non-racemic tetramic acid derivative 5 as a synthetic equivalent of the challenging synthon A through a highly diastereoselective vinylogous Mukaiyama type reaction.     

From pregabalin to rac-3-cyano-5-methylhexanoic acid: an easy conversion which valorizes waste pregabalin enantiomer

(S)-(+)-3-Aminomethyl-5-methylhexanoic acid (pregabalin) was converted in one-pot to (S)-(−)-3-cyano-5-methylhexanoic acid (pregabalin nitrile) by N-dichlorination and double dehydrochlorination. The (S) β-cyanoacid was racemized under mild conditions by treatment with a base. This very simple and efficient procedure, applied to (R)-(−)-3-aminomethyl-5-methylhexanoic acid, would enable the recycling of the undesired enantiomer of pregabalin, an anticonvulsant drug manufactured by the synthesis of rac-3-aminomethyl-5-methylhexanoic acid and subsequent classical resolution.     

Asymmetric synthesis of 3,5-disubstituted indolizidines by intermolecular addition of an allylsilane on an N-acyliminium ion

A diastereoselective synthesis of 3,5-disubstituted indolizidines based on an intermolecular addition of an allylsilane on an acyliminium ion derived from (S)-pyroglutamic acid is described. The synthetic potential of this methodology is demonstrated by the enantioselective synthesis of (−)-indolizidine 195B, (−)-indolizidine 223AB, (+)-monomorine and (−)-3-butyl-5-propyl indolizidine.     

Masked constrained cysteines: diastereoselective and enantioselective synthesis of 1-amino-2-mercaptocyclopropanecarboxylic acid derivatives

A diastereoselective and enantioselective synthesis of (Z)-1-benzoylamino-2-tritylsulfanylcyclopropanecarboxylic acid derivatives 8a,b and 9a,b was achieved starting from (−)- or (+)-menthyl 2-benzoylamino-3-tritylsulfanylacrylates 3a,b. Compounds 3 were reacted with diazomethane giving the corresponding pyrazolines 4a,b and 5a,b. These compounds, on melting, were transformed, under steric control, into the cyclopropaneamino acid derivatives (R,R)-8a,b and (S,S)-9a,b. The synthesis of a large class of chiral 2-S-alkyl-1-aminocyclopropanecarboxylic acid derivatives is possible after removing the trityl protecting group and subsequent alkylation reactions.