Concise asymmetric syntheses of (-)-lentiginosine and of its pyrrolizidinic analogue

(-)-Lentiginosine and its pyrrolizidinic analogue have been prepared in a straightforward five-step sequence from a versatile chiral cis-alpha,beta-epoxyamine.     

New concise total synthesis of (+)-lentiginosine and some structural analogues

An efficient and concise total synthesis of (+)-lentiginosine (1) starting from an L-tartaric acid-derived nitrone using organometallic addition, indium-catalyzed reduction, and ring-closing metathesis reaction as the key steps is reported. Structural analogues of (+)-1 have been also synthesized, and their inhibitory activity toward 22 commercially available glycosidases has been evaluated.     

Total synthesis of (-)- and (+)-lentiginosine

Total synthesis of (-)-lentiginosine was achieved from D-mannitol using highly stereoselective reactions. Similarly, (+)-lentiginosine was synthesized from L-tartaric acid.     

Asymmetric synthesis of (+)-lentiginosine using a chiral aziridine based approach

The synthesis of the indolizidine alkaloid, (+)-lentiginosine, is described. A key feature of the preparative route is the efficient and stereoselective construction of a dihydroxylated pyrrolidine via Sharpless asymmetric dihydroxylation of an aziridine-enoate, which was prepared from commercially available 1-(S)-α-methylbenzylaziridine-2-methanol. In addition, a regioselective aziridine-to-pyrrolidinone ring expansion process followed by a Wittig olefination was employed to construct a late stage pyrrolidine intermediate that was transformed into (+)-lentiginosine.     

A concise synthesis of lentiginosine derivatives using a pyridinium formation via the Mitsunobu reaction

A four-step synthesis of (-)-lentiginosine and its epimers is described starting from 2-bromopyridine. The key step consisted of a quaternarization of a fully unprotected pyridinium-polyol unit using Mitsunobu methodology. Subsequent PtO(2)-catalyzed diastereoselective hydrogenation of the pyridinium ring proceeded smoothly and led to the expected dihydroxyindolizidines with excellent yields. This stereochemically flexible strategy has been illustrated by the concise total synthesis of non-natural products derivatives such as (-)-lentiginosine and its stereoisomers in high yields.     

Intramolecular α-acylamino radical cyclizations with acylsilanes in the preparation of polyhydroxylated alkaloids: (+)-lentiginosine, (+)-1,8a-di-epi-lentiginosine, and (+)-1,2-di-epi-swainsonine

Acylsilanes with latent α-acylamino radical functionality were prepared from different chiral templates. Radical cyclizations of these acylsilanes efficiently constructed polyhydroxylated indolizidine derivatives with excellent stereoselectivity at the bridgehead position. These cyclization products were converted to (+)-lentiginosine, (+)-1,8a-di-epi-lentiginosine, and (+)-1,2-di-epi-swainsonine.     

Enantiocontrolled preparation of indolizidines: synthesis of (-)-2-epilentiginosine and (+)-lentiginosine

A highly stereoselective approach to (-)-2-epilentiginosine and (+)-lentiginosine has been developed based on a diastereofacially selective cycloaddition of dichloroketene with a chiral dienol ether. The two naturally occurring indolizidines are each obtained enantioselectively (> or = 99:1) in ca. 8.5% overall yield.     

Total syntheses of (±)-lentiginosine and (±)-1-epi-lentiginosine from hexahydro-1H-indol-3-one

Total syntheses of (±)-lentiginosine 1 and (±)-1-epi-lentiginosine 2 were achieved efficiently from hexahydro-1H-indol-3-one 7.     

Regioselective and diastereoselective amination of polybenzyl ethers using chlorosulfonyl isocyanate: total syntheses of 1,4-dideoxy-1,4-imino-D-arabinitol and (-)-lentiginosine

The total syntheses of DAB1 (1) and (-)-lentiginosine (2) were concisely accomplished from D-lyxose via regioselective and diastereoselective NHCbz introduction using CSI, chemoselective removal of the Cbz protection, and ring-closing metathesis as key steps.     

A novel concise total synthesis of (+)-lentiginosine

A total synthesis of (+)-lentiginosine was achieved by using ethyl 3-(pyridin-2-yl)acrylate N-oxide as the starting material and an improved Sharpless asymmetric dihydroxylation as the key step.     

Synthesis of 1,2-dihydroxyindolizidines from 1-(2-pyridyl)-2-propen-1-ol

1-(2-Pyridyl)-2-propen-1-ol, obtained by vinylation of commercially available picolinaldehyde, resulted a good starting material for the synthesis of the indolizidine skeleton. In particular, a simple process involving bromination, reduction, and nucleophilic substitution (via elimination and addition) allowed an easy conversion of the starting material into (±)-lentiginosine in ~27% overall yield.     

Stereoselective synthesis of swainsonines from pyridines

An efficient synthesis of (−)-swainsonine and (−)-2,8a-di-epi-swainsonine was developed starting from readily available 2-pyridinecarbaldehyde and 3-hydroxypyridine. In particular, it was demonstrated that the mixture of simple indolizidines, i.e. lentiginosine and epi-lentiginosine, being readily available by a number of different synthetic routes, can be directly converted to swainsonine.     

Synthesis of bisubstrate and donor analogues of sialyltransferase and their inhibitory activities

[reaction: see text] Sialyltransferases (STs) are involved in the biosynthesis of glycoconjugates with important biological activities. Most STs utilize cytidine-5'-monophospho-N-acetylneuraminic acid (CMP-Neu5Ac) as a common donor substrate. A bisubstrate analogue containing the donor substrate (CMP-Neu5Ac mimic) and the acceptor substrate (galactose) was synthesized. Four donor analogues having the partial structure of the bisubstrate analogue were also synthesized to support study of the structure-activity relationship. Each analogue contains an ethylene group in place of the exocyclic anomeric oxygen of CMP-Neu5Ac. The bisubstrate analogue exhibited only weak inhibitory activity to rat recombinant alpha-2,3- and alpha-2,6-ST (IC(50) = 1.3, 2.4 mM). Conversion of the C-1 carboxylate of the Neu5Ac moiety to carboxyamide, hydroxymethyl, or methylene phosphate each resulted in a reduction in inhibitory activity. Among the synthesized analogues, cytidin-5'-yl sialylethylphosphonate (4) was the most potent inhibitor against rat recombinant alpha-2,3- and alpha-2,6-ST (IC(50) = 0.047, 0.34 mM).     

Synthesis and platelet aggregation-inhibitory activities of novel 3-(2-oxopropylidene)azetidin-2-one derivatives. I

Treatment of (E)-3-(2-hydroxypropylidene)-4-methyl-1-phenylazetidin-2-one (11) with 10% Pd/C gave (E)-(12), (Z)-3-(2-oxopropylidene)-4-methyl-1-phenylazetidin-2-one (13), 3,4-cis-(14a) and 3,4-trans-3-(2-oxopropyl)-4-methyl-1-phenylazetidin-2-one (14b). Among them, 12 and 13 were found to show potent inhibitory activities against rabbit platelet-rich plasma aggregation induced by adenosine diphosphate or collagen. Ring-expanded homologous derivatives and an acyclic analogue of 12 were also synthesized and tested for the biological activities. The azetidin-2-one skeleton bearing a 2-oxoalkylidene moiety at the 3 position was found to be essential for the platelet aggregation inhibitory activities of these compounds.     

Total synthesis of (+)-lentiginosine from d-glucose

A total synthesis of (+)-lentiginosine, a potent and selective amyloglucosidase inhibitor, is reported from a d-glucose-derived epoxide in 38% overall yield. In this synthesis, ambient conditions and readily available starting materials and reagents are used.     

Total synthesis of (−)-lentiginosine

A simple and practical synthesis of (−)-lentiginosine 2 with good overall yield has been achieved from the commercially available diethyl d-tartarate. The key steps are a highly stereoselective Grignard reaction on an aldehyde and a Staudinger reduction.     

A concise diastereoselective approach to (+)-dexoxadrol, (−)-epi-dexoxadrol, (−)-conhydrine and (+)-lentiginosine from (−)-pipecolinic acid

A new diastereoselective pathway for the total synthesis of (+)-dexoxadrol, first asymmetric synthesis of (−)-epi-dexoxadrol and formal synthesis of conhydrine and (+)-lentiginosine is presented using commercially available (−)-pipecolinic acid. The key reactions utilized are Sharpless asymmetric dihydroxylation and Wittig reaction. The paper further describes the study of effect of protecting groups on dihydroxylation of a terminal olefin in piperidine ring system.     

Synthesis and evaluation of 6-nitro-7-(1-piperazino)quinazolines: dual-acting compounds with inhibitory activities toward both tumor necrosis factor-alpha (TNF-alpha) production and T cell proliferation

We investigated the chemical modifications of the nitroquinazoline derivative (1) through the replacement of the NH group at the C(4)-position with several N-alkyl groups to increase the lipophilicity at the C(4)-position. Among them, we found that the N-methyl analogue (5a) showed a 2-fold loss in the inhibitory activity toward tumor necrosis factor-alpha (TNF-alpha) production in vitro as compared with the NH analogue (1); however, 5a exhibited an oral inhibitory activity on TNF-alpha production with an ED50 value of 26 mg/kg, whereas 1 did not. Moreover, the oral bioavailability of 5a was higher than that of 1 (1, F=1%; 5a, F=21%), and the calculated ClogP value for 5a was higher than that for 1. These results suggest that the improved lipophilicity of 5a compared with that of 1 reflects its greater inhibitory activity on TNF-alpha production in vivo as well as oral bioavailability.     

An improved method of ring closing metathesis in the presence of basic amines: application to the formal synthesis of (+)-lentiginosine and other piperidines and carbamino sugar analogs

A generalized method for performing ring closing metathesis in the presence of basic amines has been established and successfully used in the formal synthesis of (+)-lentiginosine as well as some valuable intermediates for the synthesis of several other azasugars and aminocyclitols.     

Total synthesis of (+)-lentiginosine via a key Au catalysis

Total syntheses of (+)-lentiginosine and its 8a-epimer using a gold-catalyzed oxidative cyclization as the key step were realized. The gold chemistry, reported previously in a [4+2] synthesis of piperidin-4-ones, tolerates functionalized structures and is compatible with several protecting strategies albeit with low diastereoselectivities.