Asymmetric synthesis of the core structure of (-)-CP-263,114

The enantioselective construction of a fully functionalized core structure of (-)-CP-263,114 (1), containing most of the required functionality for total synthesis, was conducted through sequential radical fragmentation-reductive olefination.     

Asymmetric synthesis of (-)-adaline

[reaction: see text] An enantioselective total synthesis of (-)-adaline has been achieved starting from a chiral 6,6-disubstituted piperidone derivative previously prepared by diastereoselective allylation of a chiral tricyclic N-acyl-N,O-acetal. The key steps include lithium ion-activated SN2-type alkynylation of the tricyclic N,O-acetal leading to exclusive formation of the (6S)-ethynylpiperidine and ring-closing olefin metathesis of the (2R,6S)-cis-2,6-dialkenylpiperidine for constructing the bridged azabicyclononane.     

Asymmetric total synthesis of (-)-mycothiazole

[structure: see text] In this Letter we describe the first total synthesis of mycothiazole, a polyketide thiazole from a marine sponge. Key steps include our CMD oxidation for the conversion of thiazolidine 11 to thiazole 12 and the Nagao acetate aldol reaction of 5 with aldehyde 4 to construct the chiral secondary alcohol. The skipped diene was constructed by the standard Stille coupling, and the conjugated diene was synthesized by lithium(I)- and copper(I)-mediated Stille coupling.     

Asymmetric total synthesis of (-)-quinocarcin

(-)-Quinocarcin (1) has been synthesized in a longest linear sequence of 22 steps from 3-hydroxybenzaldehyde in 16% overall yield. The Pictet-Spengler reaction of L-tert-butyl-2-bromo-5-hydroxy phenylalanate (17), synthesized according to Corey-Lygo's enantioselective alkylation process, with benzoxyacetaldehyde (12) under mild acidic conditions afforded 1,3-cis tetrahydroisoquinoline 20 as an only isolable stereomer in 91% yield. The diazabicycle[3,2,1]-octane ring system of 28 was constructed by a silver tetrafluoroborate-promoted intramolecular Mannich reaction using amino thioether as a latent N-acyliminium species and tethered silyl enol ether as a nucleophile. Using amino thioether instead of aminal as a precursor of N-acyliminium was of high importance to the success of this otherwise disfavored 5-endo-Trig cyclization. A Hf(OTf)4-catalyzed (0.1 equiv) transformation of aminal to amino thioether was uncovered in the course of this study, allowing the conversion of tricyclic aminal 24 to amino thioether 25 to be realized in high yield. From the bridged tetracyclic compound 28, a sequence of oxidation of aldehyde to acid, global deprotection under hydrogenolysis conditions, and one-pot partial reduction of lactam to aminal/oxazolidine formation completed the total synthesis of the pentacyclic (-)-quinocarcine.     

Asymmetric total synthesis of (-)-Linderol A

The first asymmetric total synthesis of (-)-Linderol A, a potent inhibitor of melanin biosynthesis of cultured B-16 melanoma cells, has been achieved via two key reactions: a diastereoselective [2+2] photocycloaddition of a coumarin-3-carboxylate bearing a chiral auxiliary with 3-methyl-1-butene and a subsequent stereoconvergent transformation of the photoadducts with use of dimethylsulfoxonium methylide to afford a tetrahydrodibenzofuran derivative.     

Asymmetric synthesis of the protoberberine alkaloid (S)-(-)-xylopinine using enantiopure sulfinimines

A concise enantioselective synthesis of (S)-(-)-xylopinine (1) is described involving the addition of the laterally lithiated derivative of o-tolunitrile of 16 to enantiopure sulfinimine (+)-14. Treatment of the resulting cyano sulfinamide adduct (-)-17b with DIBAL-H accomplishes five operations in a single pot and furnishes the cyclic imine (+)-18 in good yield. Reduction and cyclization affords (S)-(-)-1. Alternatively basic hydrolysis of 17b,c gives isoquinolone 21 that is cyclized and reduced to give (S)-(-)-1.     

Asymmetric synthesis of quaternary centers. Total synthesis of (-)-malyngolide

[structure] The deracemization of 3-nonyl-3,4-epoxybut-1-ene with Pd(0) in the presence of chiral ligands using p-methoxybenzyl alcohol as a nucleophile proceeds regio- and enantioselectively to form the monoprotected vinylglycidol in 99% ee. This chiral building block was converted in seven steps to (-)-malyngolide, an antibiotic showing significant activity against Mycobacterium smegmatis and Streptococcus pyogenes. An interesting aspect involves controlling the diastereoselectivity of protonation of an enolate via a distal hydroxyl group.     

Asymmetric synthesis of (-)-dihydroxanthatin by the stereoselective Oshima-Utimoto reaction

[reaction: see text]. The catalytic stereoselective Oshima-Utimoto reaction is useful for the construction of five-membered oxacycles from simple starting materials and was employed for the preparation of the lactone group in the asymmetric synthesis of (-)-11alpha,13-dihydroxanthatin. Completion of the synthesis is facilitated by ring-closing enyne metathesis and alkene cross metathesis reactions.     

Asymmetric synthesis of (-)-7-epiaustraline and (+)-1,7-diepiaustraline

A diastereoselective and modular approach to the synthesis of the 3-hydroxymethyl-2,3,5,6,7,7a-hexahydro-1H-pyrrolizine-1,2,7-triol structure, characteristic of several natural pyrrolizidine natural products, has been developed. This approach culminated in the synthesis of (-)-7-epiaustraline and (+)-1,7-diepiaustraline. The oxazolidinone group has been found to be a useful protecting group in the RCM reaction and, as part of a pyrrolo[1,2-c]oxazol-3-one ring system, has functioned as a stereo- and regio-directing group in a key diastereoselective cis-dihydroxylation reaction and a regioselective nucleophilic ring-opening of a S,S-dioxo-dioxathiole.     

Asymmetric synthesis of (-)-tetrahydrolipstatin: an anti-aldol-based strategy

A stereoselective synthesis of (-)-tetrahydrolipstatin is described. The synthesis involves an asymmetric ester derived titanium enolate anti-aldol reaction, a nitro-aldol reaction to append the C-2' C(11) side chain, and a diastereoselective reduction of a beta-hydroxy ketone to an anti-1,3-diol functionality followed by its elaboration to (-)-tetrahydrolipstatin.     

Asymmetric total synthesis of (-)-saframycin A from L-tyrosine

The asymmetric total synthesis of (-)-saframycin A, a natural antitumor product of the tetrahydroisoquinoline antitumor antibiotics family, has been accomplished by employing L-tyrosine as the starting chiral building block in 24 steps for the longest linear sequence in an overall yield of 9.7%. The key steps in the synthesis involve stereoselective intermolecular and intramolecular Pictet-Spengler reactions, which induced the correct stereochemistry at C-1 and C-11, respectively. The selective protection-deprotection protocol of an amino group in the two-step transformation from intermediate 10 to 12 and a hydroxyl group in the first two steps resulted in both high selectivity and efficiency of the synthetic route.     

Asymmetric synthesis of pyrrolidinoindolines. Application for the practical total synthesis of (-)-phenserine

A versatile route to enantiopure 3,3-disubstituted oxindoles and 3a-substituted pyrrolidinoindolines is described in which diastereoselective dialkylation of enantiopure ditriflate 10 with oxindole enolates is the central step. These reactions are rare examples of alkylations of prostereogenic enolates with chiral sp(3) electrophiles that proceed with high facial selectivity (10-20:1). The scope of this method is explored, and a model to rationalize the sense of stereoselection is advanced. This dialkylation chemistry was used to synthesize (-)-phenserine on a multigram scale in six steps and 43% overall yield from 5-methoxy-1,3-dimethyloxindole (27) and to complete a short formal total synthesis of (-)-physostigmine (2).     

Asymmetric synthesis of sulfinamides using (-)-quinine as chiral auxiliary

A process has been designed and demonstrated for the asymmetric synthesis of sulfinamides using quinine as auxiliary. A variety of chiral sulfinamides including N-alkyl sulfinamides with diverse structure were prepared in good yields and excellent enantioselectivity starting from easily available and inexpensive reagents. The auxiliary quinine could be recovered and recycled.     

Asymmetric synthesis of (R)-(+)-etomoxir via enzymatic resolution

An asymmetric synthesis of (R)-(+)-etomoxir 3, employing enzymatic resolution of ethyl 2-alkyl-2,3-dihydroxypropionate using Amano AK via transacylation is reported.     

Asymmetric synthesis of (R)- and (S)-2-trifluoromethylepinephrine

An asymmetric synthesis of (R)- and (S)-2-trifluoromethylepinephrine (1R and 1S) is presented. Trifluoromethylation involves nucleophilic aromatic substitution of halobenzene 4 most likely via a copper mediated CF₃ anion equivalent generated in situ. The asymmetric step involves conversion of 3,4-dimethoxy-2-trifluoromethylbenzaldehyde (5) to silyl cyanohydrin (6R and 6S) using a chiral salen catalyst in the presence of titanium. 1R and 1S are potential alternatives to currently used vasoconstrictors in local anesthetic formulations.     

Asymmetric synthesis of alpha-substituted beta-amino ketones from sulfinimines (N-sulfinyl imines). synthesis of the indolizidine alkaloid (-)-223A

Of the possible four stereoisomers, addition of the lithium enolate of 4-heptanone to sulfinimines resulted in only the syn- and anti-alpha-substituted beta-amino ketones. The formation of the major syn-beta-amino ketone was rationalized in terms of addition of the E-enolate to the C-N double bond of the sulfinimine via a six-member chelated chairlike transition state. The enolates of 4-heptanone were generated using LiHMDS in THF where a 1:2.5 E:Z enolate ratio was noted. In diethyl ether the E:Z ratio was 15:1 in favor of the E-enolate and explained in terms of Ireland's transition state model. Here increased steric interactions between the ethyl group and the carbonyl-LiN(TMS)(2) moiety destabilize the transition state leading to the Z-enolate in the poorly coordinating diethyl ether solvent. This new synthesis of syn-alpha-substituted-beta-amino ketones was applied to the concise enantioselective total synthesis of indolizidine (-)-223A, a 5,6,8-trisubstituted alkaloid isolated from the skin of the dendrobatide frog.