Total asymmetric syntheses of 3- and 4-deoxy-hexoses and derivatives

(1S,4S)-7-Oxabicyclo[2.2.1]hept-5-en-2-one ((−)-5, a “naked sugar”) has been converted to (−)-(1R,4S,6S)-6-endo-benzyloxy-2-bromo-7-oxabicyclo[2.2.1]hept-2-ene ((−)-12) in a highly stereoselective fashion. Double hydroxylation of the C=C double bond of (−)-12, followed by acetylation and Baeyer-Villiger oxidation of the resulting -acetoxyketone (−)-14 afforded (−)-5-O-acetyl-2-O-benzyl-3-deoxy-β-D-arabino-hexofuranurono-6,1-lactone ((−)-15). This compound was converted readily into (+)-methyl 3-deoxy--D-arabino-hexofuranoside ((+)-6 and (+)-methyl 3-deoxy-β-L-xylo-hexofuranoside ((+)-7) and partially protected derivatives. (−)-15 was also converted into 4-deoxy-D-lyxo-hexopyranose (34) and several partially protected derivatives such as (+)-methyl 4-deoxy-2,3-O-isopropylidene--D-lyxo-hexopyranoside ((+)-8).     

A new approach for the asymmetric syntheses of 2-epi-deoxoprosopinine and azasugar derivatives

A new approach to 2-epi-deoxoprosopinine 11, 1-deoxygulonojirimycin 7, and l-gulono-1,5-lactam 9 was described. The C-2 hydroxymethyl group was introduced regioselectively using SmI₂ mediated coupling of (S)-3-silyloxyglutarimide 13b with either chloromethyl benzyl ether 16a or the Beau-Skrydstrup reagent 16b, followed by debenzylation and highly cis-diastereoselective reductive deoxygenation. Adoption of the Savoi's chemoselective ring-opening alkylation method allowed a highly diastereoselective introduction of the lipid side chain of 2-epi-deoxoprosopinine 11 in a straightforward manner. Dehydration followed by highly trans-diastereoselective dihydroxylation led to polyoxygenated lactam derivative 27 as a key intermediate for the syntheses of 7 and 9.     

One-pot asymmetric synthesis of 2- and 2,3-disubstituted tetrahydrofuran derivatives

A novel and convenient one-pot asymmetric synthesis of 2- and 2,3-disubstituted tetrahydrofurans has been achieved in 56-81% yields and 86-99% ee from aliphatic and aromatic aldehydes via an allyl/crotyl/alkoxyallylboration-hydroboration-iodination-cyclization reaction sequence.     

First asymmetric syntheses of 6-substituted nipecotic acid derivatives

Various nipecotic acid derivatives are known to be potent GABA uptake inhibitors thus being useful in the treatment of a number of neurological and psychological disorders. In this paper, the first asymmetric syntheses of 6-substituted nipecotic acid derivatives are presented. The synthetic strategy was designed to provide access to a large variety of enantiomerically pure 6-substituted nipecotic acid derivatives. The synthesis starts from the chiral N-acyldihydropyridines 15 and 16 obtained via asymmetric electrophilic α-amidoalkylation reaction of a chiral N-acylpyridinium ion. These were utilized for the preparation of enantiomerically pure 6-(4,4-diphenylbutyl)nipecotic acids and 6-(4,4-diphenylbutenyl)nipecotic acids in a multistep synthesis, including the removal of the dimethylphenylsilyl blocking group from the dihydropyridine ring, the reduction of the dihydropyridine heterocycle, a Horner-Wittig reaction and the removal of the chiral auxiliary. The obtained target molecules, however, showed only negligible affinity to the GAT-1- and GAT-3 transport proteins.     

Phenothiazine syntheses. XVIII. 2-Aminophenothiazine derivatives

2-(-chloroacetylamido)-2-(-chloropropionylamido)-2-(benzylideneamino)- and 2-(o-hydroxybenzyllideneamino)phenothiazines are synthesized and reduced by lithium aluminum hydride to 2-ethylamino-, 2-propylamino-, 2-benzylamino-, and 2-(o-hydroxybenzylamino)phenothiazine. Reduction of the methyl and ethyl esters of phenothiazinecarbamic-2 acid by lithium aluminum hydride gives 2-methylaminophenothiazine.For Part XVII see [1].     

gem-Diacetates as carbonyl surrogates for asymmetric synthesis. Total syntheses of sphingofungins E and F.

The equivalent of an asymmetric addition to a carbonyl group with a stabilized anion is accomplished by discriminating between the enantiotopic C-O single bonds of a gem-diacetate. In this way, enantioselective total syntheses of two antifugal agents, sphingofungins E and F, have been accomplished. The synthetic strategy is based on a series of catalytic processes whereby all of the chiral centers are created with high stereoselectivities. The first two stereocenters are introduced by an asymmetric allylic alkylation reaction of gem-diacetate 9 with azlactone 10. The complex of Pd(0) and ligand 14 efficiently catalyzes this key reaction, which differentiates both the enantiotopic leaving groups of a gem-diacetate and enantiotopic faces of the enolate of an azlactone in high enantiomeric excess and diastereomeric excess. From these two stereocenters, the configurations of the remaining two centers are set by a diastereoselective Os(VIII)-catalyzed dihydroxylation reaction with excellent stereocontrol. The trans-alkene is established by Cr(II)-mediated olefination, and a subsequent B-alkyl Suzuki coupling reaction conjoins the polar head unit and the nonpolar, 13-carbon lipid tail. The efficiency of our strategy is illustrated by the completion of syntheses of sphingofungins F and E in 15 and 17 steps, and in 17% and 5% overall yields, respectively.     

Total syntheses of (−)−2-deoxyfortamines

Starting from the now readily available dianhydro-deoxy($\text{epi}$)inositol (2) an efficient access to suitably protected (?)?2-deoxy-fortamines (10/11) has been worked out, in which the racemic epoxide intermediates (6) are cleanly separated via their R?(+)?1-phenylethylamine-adducts (8/9).     

Total syntheses of symbioramide derivatives from l-serine and their antileukemic activities

Naturally occurring symbioramide, (2S,3R,2'R,3'E)-N-(2'-hydroxy-3'-octadecenoyl)-dihydrosphingosine 1a, was synthesized from d-erythro-dihydrosphingosine (amino part, 2) and (2R,3E)-2-hydroxy-3-octadecenoic acid (acid part, 3a), both of which were prepared from l-serine. Its diastereomer, (2S,3R,2'S,3'E)-1b, having an enantiomer of the unnatural-type acid part that was prepared from d-mannitol, and its corresponding (Z)-isomers, (2S,3R,2'R,3'Z)-1c and (2S,3R,2'S,3'Z)-1d, were also prepared. The antileukemic activities of 1a-d against HL-60 and L-1210 cells were appreciated by a MTT assay. None of the four symbioramide derivatives showed antileukemic activities in HL-60 cells. In L-1210 cells, all the symbioramide derivatives showed moderate antileukemic activities. Compound 1d had the most effective activity against L-1210 cells among the four derivatives. The data suggest that unnatural types of (2'S)-isomers of acid parts are more active than those of (2'R)-isomers.     

One-pot syntheses of 2-pyrazoline derivatives

Hydrazinediium dithiocyanate and α,β-unsaturated ketones give in one-pot reactions 1-thiocarbamoyl-2-pyrazolines and 1-formyl-2-pyrazolines. The syntheses of pyridine-2-thiones, pyrimidine-2-thiones and bicyclo[2.2.2]octan-2-ones from ammonium thiocyanates and ketones by analogous procedures are reviewed. The mechanisms of the ring formations are discussed. Crystal structure analyses of a 1-thiocarbamoyl- and a 1-formyl-2-pyrazoline are given.     

Total syntheses of chaetocin and ent-chaetocin

The first total synthesis of chaetocin (1), a potent histone methyltransferase inhibitor, is described in detail. Key reactions were radical bromination for α-oxidation of the diketopiperazine ring, and reductive radical coupling for construction of the dimeric core structure. Stereoselective construction of the disulfide bridges was achieved via substitution reaction with H₂S. The total synthesis of 1 was accomplished in nine steps starting from known d-amino acid derivatives. Total synthesis of non-natural ent-chaetocin (ent-1) was also achieved via the established synthetic route, starting from l-amino acid derivatives.     

Concise asymmetric syntheses of radicicol and monocillin I.

Radicicol (1) exhibits potent anticancer properties in vitro, which are likely to be mediated through its high affinity (20 nM) for the molecular chaperone Hsp90. Recently, we reported the results of a synthetic program targeting radicicol (1) and monocillin I (2), highlighted by the application of ring-closing metathesis to macrolide formation. These efforts resulted in a highly convergent synthesis of radicicol dimethyl ether but failed in the removal of the two aryl methyl ethers. Simple exchange of these methyl ethers with more labile functionalities disabled a key esterification in the initial route. Through extended experimentation, a successful route to both natural products was secured, along with some intriguing results that emphasize the implications of this design on a broad range of fused benzoaliphatic targets, including analogues of these natural products.     

Palladium-catalyzed asymmetric allylic substitution of 2-arylcyclohexenol derivatives: asymmetric total syntheses of (+)-crinamine, (-)-haemanthidine, and (+)-pretazettine

Much interest has been shown in Amaryllidaceae alkaloids as synthetic targets due to their wide range of biological activities. Over 100 alkaloids have been isolated from members of the Amaryllidaceae family; most of them can be classified into eight skeletally homogeneous groups. We have succeeded in the first asymmetric total syntheses of the crinane-type alkaloids (+)-crinamine (1), (-)-haemanthidine (2), and (+)-pretazettine (3). The starting cyclohexenylamine 14 was obtained from allyl phosphonate 11c by palladium-catalyzed asymmetric amination in 82% yield and with 74% ee. The product was recrystallized from MeOH. Interestingly, (-)-14 with 99% ee was obtained from the mother liquor (74% recovery). Intramolecular carbonyl-ene reaction of (-)-10 proceeds in a highly stereoselective manner to give hexahydroindole derivative 9 as the sole product. In the Lewis-acid-catalyzed carbonyl-ene reaction, an interesting rearrangement product, 20, was isolated in high yield. From 9, (+)-crinamine was synthesized. Thus, the asymmetric total synthesis of (+)-crinamine was achieved in 10 steps from 11c, and the overall yield is 19%. The total synthesis of (-)-haemanthidine was also achieved from 9 by a short sequence of steps.     

13C NMR studies on trifluoroacetyl derivatives of 2-acetamido-2-deoxyhexoses

The effect of trifluoroacetylation on the ¹³C chemical shifts of 2-acetamido-2-deoxyhexoses was examined. Studies of the 2-acetamido derivatives of glucose, galactose and mannose established that no regular trend in the ¹³C shifts occurred on trifluoroacetylation. This was in marked contrast to the results obtained for the ¹H chemical shifts.     

1,1,4,4-tetranitrobutane-2,3-diol and its derivatives. 2. Chlorination and bromination of 1,1,4,4-tetranitrobutane-2,3-diol. crystal structure of halogen derivatives of 1,1,4,4-tetranitrobutane-2,3-diol

The bromination of 1,1,4,4-tetranitrobutane-2,3-diol in 60% acetic acid gave 1,4-dibromo-1,1,4,4-tetranitrobutane-2,3-diol in satisfactory yield. The chlorination of 1,1,4,4-tetranitrobutane-2,3-diol under analogous conditions gave 1,4-dichloro-1,1,4,4-tetranitrobutane-2,3-diol as a crystal hydrate. Drying of this latter product in vacuum over phosphorus pentoxide gave 1,4-dichloro-1,1, 4,4-tetranitrobutane-2,3-diol in quantitative yield. The structures of these products were determined by x-ray diffraction structural analysis. The crystal chemical analysis and quantum chemical calculations established an increase in secondary oxygen-halogen interactions in the halodinitromethyl fragment with increasing atomic number of the halogen atom.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 10, pp. 2372–2380, October, 1991.     

Dynamic thermodynamic resolution of N-methylpseudoephedrine α-bromo esters for asymmetric syntheses of α-hydroxy carboxylic acid derivatives

An example of dynamic thermodynamic resolution in the nucleophilic substitution reactions of α-bromo esters with an oxygen nucleophile is described. Temperature controlled epimerization-substitution sequence provides a practical protocol for the preparation of highly enantioenriched α-hydroxy carboxylic acid derivatives up to 72% yield with 99:1 er.