Synthetic Intermediate Research Articles

Highly Diastereoselective Cyanation of Methyl Ketimines Obtained from (R)-Glyceraldehyde

[reaction: see text] Addition of trimethylsilyl cyanide to ketimines derived from (R)-2,2-dimethyl-1,3-dioxolan-4-yl methyl ketone to generate a quaternary stereocenter has been achieved with high yields and excellent diastereoselectivity. The stereoselectivity was found to be temperature and solvent dependent. The beta-hydroxy-alpha-amino nitrile of syn configuration was the major compound in kinetically controlled reactions, whereas the anti stereoisomer was obtained in excess in thermodynamically controlled reactions. Double stereodifferentiation under kinetic control conditions was successful, and the cyanation reaction occurred with complete syn diastereoselectivity using the matched pair. The versatility of the resulting amino nitrile as a synthetic intermediate was tested by performing the synthesis of orthogonally protected (R)-(2-aminomethyl)alanine.

Synthesis of the C(1)–C(11) Polyene Fragment of Apoptolidin with a New Sulfur Dioxide‐Based Organic Chemistry

A new sulfur dioxide-based organic chemistry has been developed as a novel approach for the stereoselective synthesis of polyene fragments based on our one-pot, four-component synthesis of polyfunctional epsilon-alkanesulfonyl-gamma,delta-unsaturated ketones. The flexibility and efficiency of this methodology are illustrated by the preparation of (+)-methyl (2E,4E,6E,8R,9S)-9-{[(tert-butyl)dimethylsilyl]oxy}-2,4,6,8-tetramethyl-11-(triethylsilyl)undeca-2,4,6-trien-10-ynoate, a synthetic intermediate of Nicolaou and co-workers, that corresponds to the C(1)-C(11) fragment of apoptolidin, which was used by the authors in their total synthesis of this promising anticancer agent.

Biocatalytic synthesis of S(−)-1-(1′-naphthyl) ethanol by a novel isolate of Candida viswanathii

A new yeast strain Candida viswanathii MTCC 5158, isolated from soil, is capable of carrying out the enantioselective reduction of 1-acetonaphthone to S(−)-1-(1′-naphthyl) ethanol which is an important synthetic intermediate of mevinic acid analogue, (potential inhibitor of 3-hydroxy methyl glutaryl coenzyme A reductase). Studies on the culture conditions and catalytic performance of this microorganism showed that the carbonyl reductase occurs constitutively in C. viswanathii and its production is enhanced by feeding acetonaphthone (2 mM) during the early period of cultivation. Mannitol (1%, w/v) was found to be beneficial both for growth and enzyme production. Supplementation of the media with yeast extract (0.5%) and Ca 2+ (2 mM) enhanced the enzyme production. The optimal temperature and pH for the growth and enzyme production were 25 °C and 10, respectively. The organism produced enantiopure (S)-alcohol with good conversion (>97%) and almost absolute enantioselectivity (ee >99%). Parameters of the bioreduction reaction were optimized and the optimal temperature and pH for the reduction were found to be 25 °C and 8, respectively. The optimized substrate as well as the resting cell concentration was 2 and 200 g/l, respectively. The preparative scale reaction using resting cells of C. viswanathii yielded (S)-alcohol with 97% conversion and >99% ee.

A Novel Benzoyl‐Type Fluorous Protecting Group for Use in Fluorous Synthesis.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Fluorous Glycopeptide Synthesis without Protection of Sugar Hydroxy Groups

Abstract The synthesis of a glycopeptide was easily achieved by an Fmoc-strategy based on fluorous chemistry. In this study, hCG(β12-16) having an N-acetylglucosamine was synthesized in good yield using Fmoc-Asn(GlcNAc)-OH without protection of the sugar hydroxy groups by the dimethylphosphinothioic mixed anhydride (Mpt-MA) method. Each synthetic intermediate was able to be easily purified by simple fluorous-organic solvent extraction and monitored by TLC, NMR, and MS.

Stereocontrolled syntheses of α-C-mannosyltryptophan and its analogues

The total synthesis of alpha-C-mannosyltryptophan (C-Man-Trp), a naturally occurring C-glycosylamino acid, was achieved from a commercially available alpha-methyl-D-mannoside in 10 steps including the following key steps: the C-glycosidation of a mannose derivative with a stannylacetylene, Castro indole synthesis, and Sc(ClO4)3-promoted coupling with L-serine-derived aziridine carboxylate. The glucose- and galactose-analogues of C-Man-Trp were also synthesized in a similar manner. Conformational analyses of the synthesized C-glycosyltryptophan and its synthetic intermediate are briefly discussed.

Asymmetric Mannich-Type Addition of Lithium Glycolates to Imines Producing 3-Hydroxy-4-phenylazetidin-2-ones

The external chiral ligand-controlled asymmetric Mannich-type reaction of a binary- or ternary-complexed lithium ester enolate of protected glycolates with benzaldehyde imines gave the corresponding 3-trialkylsilyloxy-4-phenylazetidin-2-ones, applicable as a synthetic intermediate of C13 side chain of taxan anticancer drugs, in moderate enantioselectivity.

A novel benzoyl-type fluorous protecting group for use in fluorous synthesis

TfBz–OH, a novel benzoyl-type fluorous protecting reagent, has been easily prepared. It was found that the TfBz (trisfluorous chain-type benzoyl) group can be successfully introduced onto a hydroxyl function, removed in high yield, and recycled after deprotection. The use of the TfBz group makes it possible to synthesize an oligosaccharide by minimal column chromatography purification, because each synthetic intermediate is easily purified simply by fluorous-organic solvent extraction.

Rapid Oligosaccharide Synthesis on a Fluorous Support.

Abstract The novel fluorous support Hfb (hexakisfluorous chain-type butanoyl) was easily prepared. The Hfb group was readily introduced into the anomeric hydroxyl group of a carbohydrate, and was recyclable after cleavage. The use of the Hfb group was applicable for the rapid oligosaccharide synthesis in which the synthetic intermediates could be purified using fluorous and normal organic solvents. Each synthetic intermediate could be monitored by TLC, NMR and mass spectrometry.

Rapid Oligosaccharide Synthesis Using a Fluorous Protective Group.

The Bfp-OH, a novel fluorous protecting reagent, was able to be easily prepared. The Bfp group was readily introduced to a carbohydrate, removed in high yield, and recyclable after cleavage. The use of the Bfp group made it possible to synthesize a pentasaccharide by minimal column chromatography purification. Each synthetic intermediate was able to be easily purified only by simple fluorous-organic solvent extraction and monitored by TLC, NMR, and MS.

Rapid oligosaccharide synthesis on a fluorous support

The novel fluorous support Hfb (hexakisfluorous chain-type butanoyl) was easily prepared. The Hfb group was readily introduced into the anomeric hydroxyl group of a carbohydrate, and was recyclable after cleavage. The use of the Hfb group was applicable for the rapid oligosaccharide synthesis in which the synthetic intermediates could be purified using fluorous and normal organic solvents. Each synthetic intermediate could be monitored by TLC, NMR and mass spectrometry.

A new artificial cyclase for polyprenoids: enantioselective total synthesis of (-)-chromazonarol, (+)-8-epi-puupehedione, and (-)-11'-deoxytaondiol methyl ether.

This paper describes a new artificial cyclase, optically pure 3-o-fluorobenzyloxy-2-hydroxy-2'-(p-methoxybemzyl)-1,1'-binaphthyl.SnCl4, which is effective for the enantioselective cyclization of 2-(polyprenyl)phenol derivatives to afford polycyclic terpenoids bearing a chroman skeleton such as (-)-chromazonarol, (+)-8-epi-puupehedione, a key synthetic intermediate of (+)-wiedendiol, and (-)-11'-deoxytaondiol methyl ether.

Rapid oligosaccharide synthesis using a fluorous protective group.

The Bfp-OH, a novel fluorous protecting reagent, was able to be easily prepared. The Bfp group was readily introduced to a carbohydrate, removed in high yield, and recyclable after cleavage. The use of the Bfp group made it possible to synthesize a pentasaccharide by minimal column chromatography purification. Each synthetic intermediate was able to be easily purified only by simple fluorous-organic solvent extraction and monitored by TLC, NMR, and MS.

An Effective Method for the Synthesis of Carboxylic Esters and Lactones Using Substituted Benzoic Anhydrides with Lewis Acid Catalysts.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Syntheses of (-)-funebrine and (-)-funebral, using sequential transesterification and intramolecular cycloaddition of a chiral nitrone.

The first syntheses of (-)-funebrine [(-)-1] and (-)-funebral [(-)-2] are described. The syntheses feature sequential formation of nitrone VI from methyl glyoxylate (5) with oxime 6, transesterification of nitrone VI with (E)-crotyl alcohol (4), and intramolecular cycloaddition of the resulting nitrone VII bearing crotyl ester to afford cycloadduct 7 as a major product. The adduct 7 was readily elaborated to amino lactone (-)-3, the key synthetic intermediate of (-)-1 and (-)-2.

An effective method for the synthesis of carboxylic esters and lactones using substituted benzoic anhydrides with Lewis acid catalysts

An efficient mixed-anhydride method for the synthesis of carboxylic esters and lactones using benzoic anhydride having electron withdrawing substituent(s) is developed by the promotion of Lewis acid catalysts. In the presence of a catalytic amount of TiCl 2(ClO 4) 2, various carboxylic esters are prepared in high yields through the formation of the corresponding mixed-anhydrides from 3,5-bis(trifluoromethyl)benzoic anhydride and carboxylic acids. The combined catalyst consisting of TiCl 2(ClO 4) 2 together with chlorotrimethylsilane functions as an effective catalyst for the synthesis of carboxylic esters from free carboxylic acids and alcohols with 4-(trifluoromethyl)benzoic anhydride. Various macrolactones are prepared from the free ω-hydroxycarboxylic acids by the combined use of 4-(trifluoromethyl)benzoic anhydride and titanium(IV) catalysts together with chlorotrimethylsilane under mild reaction conditions. The lactonization of trimethylsilyl ω-(trimethylsiloxy)carboxylates using 4-(trifluoromethyl)benzoic anhydride is also promoted at room temperature in the presence of a catalytic amount of TiCl 2(ClO 4) 2. An 8-membered ring lactone, a synthetic intermediate of cephalosporolide D, is successfully synthesized according to this mixed-anhydride method using 4-(trifluoromethyl)benzoic anhydride by the promotion of a catalytic amount of Hf(OTf) 4.

Rapid Oligosaccharide Synthesis on a Novel Benzyl-Type Fluorous Support

A novel benzyl-type fluorous support (HfBn-OH) has been easily prepared, and the HfBn group was successfully introduced to the anomeric position of the carbohydrate, then removed in high yield after working as a support. The use of the HfBn group made it possible to synthesize an oligosaccharide with minimal column chromatography purification. It was found that each HfBn derivative as a synthetic intermediate is easily purified only by fluorous-organic solvent extraction.

A facile synthesis of cyclic bis(3′→5′)diguanylic acid

This paper describes a new method for synthesizing biologically important cyclic bis(3′→5′)diguanylic acid (cGpGp) in a higher yield than that of the existing synthetic method. In the new synthesis, the following two means, in place of those used in the existing synthesis are employed as main strategies to cause the increase in product yield. One of these distinctive strategies in the new synthesis is that the phosphoramidite method is used for the preparation of a key synthetic intermediate of a linear guanylyl(3′→5′)guanylic acid derivative. This method allowed higher-yield formation of the intermediate than that by the triester method used in the existing synthesis. The second distinctive strategy used in the new synthesis is that allyloxycarbonyl and allyl groups are used for the protection of two guanine bases and two internucleotide bonds, respectively. These four allylic protectors can be removed all at once by the organopalladium-catalyzed reaction under neutral conditions. Thus, deprotection of the protected cGpGp precursor was achieved in the present synthesis in a shorter step and under milder conditions than the deprotection achieved in the existing synthesis, which uses diphenylacetyl and o-chlorophenyl groups as protectors for two guanine bases and two internucleotide bonds, respectively, whose full removal requires two different procedures including rather harsh basic treatment. As a result, technical loss and decomposition of the target product in the new synthesis is remarkably reduced.

Synthetic studies towards trichodimerol and related vertinoid polyketides: preliminary communication

Abstract An alternative synthetic route towards trichodimerol, bisorbicillinol and epoxysorbicillinol employing a suitable para-quinol as a common versatile key synthetic intermediate was investigated. The validity of this approach for the preparation of bisorbicillinol and epoxysorbicillinol derivatives was demonstrated. However, attempts to obtain trichodimerol-related derivatives or to render this approach enantioselective were unsuccessful.

Synthesis of Febrifugine Derivatives and a Solution to the Puzzle of the Structural Determination of Febrifugine.

AbstractFor Abstract see ChemInform Abstract in Full Text.