Asymmetric syntheses of (+)-negamycin, (+)-3-epi-negamycin and sperabillin C via lithium amide conjugate addition

The chemo- and enantioselective reduction of ethyl 4-chloroacetoacetate and the diastereoselective conjugate addition of enantiopure lithium N-benzyl-N-(α-methylbenzyl)amide to an α,β-unsaturated ester have been used as the key steps in the total asymmetric syntheses of (+)-negamycin (in 13 steps and 24% overall yield), (+)-3-epi-negamycin (in 13 steps and 10% overall yield) and sperabillin C (in 17 steps and 13% overall yield) from commercially available starting materials.     

Non-isothermal kinetic and thermodynamic study for the dehydration of copper(II) chloride dihydrate and nickel chloride hexahydrate

Non-isothermal dehydration of copper chloride dihydrate and nickel chloride hexahydrate were studied by using TG, DTG, DTA and DSC measurements. The copper chloride salt loses its two water molecules in one step while nickel chloride salt dehydrates in three consecutive steps. The first two steps involve the loss of 4 water molecules in two overlapped steps while the third step involves the dehydration of the dihydrate salt to give the anhydrous NiCl₂. Activation energies (ΔE) and the frequency factor (A) were calculated from DTG and DTA results. We have also calculated the different thermodynamic parameters, e.g. enthalpy change (ΔH), heat capacity (C _p) and the entropy change (ΔS) from DSC measurements for both reactants. The isothermal rehydration of the completely dehydrated salts was studied in air and under saturated vapour pressure of water. Anhydrous nickel chloride was found to rehydrate in three consecutive steps while the copper salt rehydrated in one step.     

Total syntheses of macrosphelides (+)-A, (−)-A and (+)-E

Total syntheses of (+)-macrosphelide A 1 (18.5% overall yield in 11 steps) and (+)-macrosphelide E 2 (23.9% overall yield in 11 steps) have been achieved via the chemoenzymatic reaction product (4R,5S)-4-benzyloxy-5-hydroxy-2(E)-hexenoate 4. The enantiomer (−)-A (1) (14.2% overall yield in 11 steps) of (+)-1 was also synthesized from the chemoenzymatic reaction product (4S,5R)-4-benzyloxy-5-hydroxy-2(E)-hexenoate 4.     

Formal synthesis of (+)-varitriol. Application of Pd(II)/Cu(II)-catalysed bicyclisation of unsaturated polyols

A formal and improved synthesis of natural (+)-varitriol from d-glucose and dimethyl l-tartrate, respectively, are reported. The key steps are the Pd(II)/Cu(II)-catalysed bicyclisation of O-benzyl protected triols l-xylo-15 and l-xylo-15/l-lyxo-15, respectively, followed by ring opening of intermediate dianhydro-l-gulitol 16. The syntheses of key intermediate of the furanoside portion 17 proceed in 13 steps with 5% (from bisacetone-d-glucose), and in 12 steps with 7.6% over-all yield from dimethyl l-tartrate, respectively.     

First total synthesis of (−)-(3S,6R)-3,6-dihydroxy-10-methylundecanoic acid

The first total synthesis of (3S,6R)-3,6-dihydroxy-10-methylundecanoic acid was accomplished from commercially available 1-bromo-3-methylbutane in 11 steps and 25.8% overall yield. The key steps were asymmetric allylic alkylations via allyldiisopinocampheylborane and hydroboration-oxidation.     

Synthesis of fully protected (2R,3R,4S)-4-amino-7-guanidino-2,3-dihydroxy heptanoic acid

(2R,3R,4S)-4-Amino-7-guanidino-2,3-dihydroxyheptanoic acid (AGDHE), a common constituent of biologically active marine peptides, callipeltin A (1) and neamphamide A, was synthesized as its orthogonally protected derivative from l-glutamic acid in 15 steps. Guanidination by the Mitsunobu condition and osmium-catalyzed dihydroxylation of the corresponding Z-olefin were employed as the key steps.     

Synthesis of (2S,2′S)-bimorpholine N,N′-quaternary salts as chiral phase transfer catalysts

(2S,2′S)-Bimorpholine was synthesized starting from (R,R)-tartaric acid ester acetal in six steps in 50% of the total yield. Key steps include: cyanide catalyzed amidation and one-step cyclization with p-toluenesulfonyl imidazole. Derivatization of N,N′-dibenzyl bimorpholine afforded quaternary bimorpholinium salts, which were used as chiral phase transfer alkylation catalysts.     

First total syntheses and absolute configuration of rugulactone and 6(R)-(4′-oxopent-2′-enyl)-5,6-dihydro-2H-pyran-2-one

The first efficient total syntheses of rugulactone and 6(R)-(4′-oxopent-2′-enyl)-5,6-dihydro-2H-pyran-2-one have been achieved in six steps with 51% and 48% overall yield, respectively. The key steps are Jacobsen’s hydrolytic kinetic resolution (HKR), Horner-Wadsworth-Emmons (HWE) homologation, and ring-closing metathesis reaction.     

Formal synthesis of valienamine using ring-closing metathesis

(1R,2S,3S,4R)-2,3,4-Tri-O-benzyl-5-(benzyloxymethyl)-cyclohex-5-ene-1,2,3,4-tetrol, a precursor of the α-glucosidase inhibitor, valienamine, was synthesised in eight steps from tetrabenzyl glucose. The key steps were the selective protection of an open-chain diol, and the formation of the cyclohexene ring by ring-closing metathesis with the trisubstituted olefin of valienamine correctly in place.     

The para-siletanylbenzyl (PSB) ether: a peroxide-cleavable protecting group for alcohols and phenols

A novel arylmethyl protecting group that is electronically similar to benzyl (Bn) but that can be cleaved under mild oxidizing conditions in the presence of para-methoxybenzyl (PMB) is described herein. para-Siletanylbenzyl (PSB) ethers are formed in one or two steps from the corresponding alcohols and cleaved in one or two steps with basic peroxide. Alcohols and phenols have been protected in good yields and deprotected cleanly under mild oxidative conditions.     

Total syntheses of (R)-argentilactone and (R)-goniothalamin via catalytic enantioselective allylation of aldehydes

The total syntheses of (R)-argentilactone (five steps, 25% overall yield) and (R)-goniothalamin (three steps, 61% overall yield) have been described through the enantioselective catalytic allylation of aldehydes (including a propargylic aldehyde) which provided a rapid access to these natural products that display very interesting biological activities.     

Synthetic approaches to imino sugar (2R,3R,4S)-2-(hydroxymethyl)-4-methylpyrrolidine-3,4-diol from naturally occurring sugar and amino acid

Imino sugar compound 3 was prepared by two alternative routes starting from ribose and d-serine. From d-serine (3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)-3-methylpyrrolidin-2-one was prepared in five steps in 50% overall yield, which was further converted into (2R,3R,4S)-2-(hydroxymethyl)-4-methylpyrrolidine-3,4-diol in three steps in 23% overall yield.     

The first stereoselective total synthesis of (3S,4R)-dihydroxy-(6S)-undecyl-α-pyranone and total synthesis of (2S,3R,5S)-(−)-2,3-dihydroxytetradecan-5-olide

The first total synthesis of (3S,4R)-dihydroxy-(6S)-undecyl-α-pyranone 1 and total synthesis of (2S,3R,5S)-(−)-2,3-dihydroxytetradecan-5-olide 2 have been achieved in five steps in a highly stereoselective manner using Maruoka allylation, olefin cross-metathesis, and Sharpless asymmetric dihydroxylation as key steps.     

Synthesis of the C8-C20 and C21-C30 segments of pectenotoxin 2

In this study, we synthesized the C8-C20 and C21-C30 segments of the diarrhetic shellfish toxin pectenotoxin 2. The C8-C20 segment was assembled from a phosphonate corresponding to the C8-C15 segment (prepared from l-malic acid in 19 steps) and an aldehyde corresponding to the C16-C20 segment (synthesized from 3-methyl-3-butenol in nine steps) by a twelve-step process including the Horner-Wadsworth-Emmons reaction, regio- and stereoselective reduction of the resulting enone, diastereoselective epoxidation, and 5-exo epoxide cleavage forming the C-ring. The C21-C30 segment was constructed in 13 steps from (S)-glycidol via a route involving E-ring formation by 5-exo epoxide cleavage and stereoselective methylation at C27 by the Evans method.     

Enantioselective synthesis of the carbocyclic moiety of (−)-carbovir

Enantioselective construction of the protected carbocycle moiety of the anti-HIV drug carbovir was achieved in 11 steps from (S)-(−)-ethyl lactate. The two key steps are a Claisen [3+3] sigmatropic rearrangement of (3S,4E)-3-(4-methoxy-phenoxymethyl)-hex-4-enoic acid dimethylamide and next, a ruthenium-catalysed ring closure metathesis leading to (1S,4S)-4-(4-methoxy-phenoxymethyl)-cyclopent-2-enol.     

First total synthesis of salinipyrone A using highly stereoselective vinylogous Mukaiyama aldol reaction

A synthetic approach for the total synthesis of salinipyrone A has been developed. Key steps involve the TiCl₄-mediated vinylogous Mukaiyama aldol reaction (VMAR) of chiral ketene silyl N,O-acetal with propionaldyhyde, an aldol condensation, Witting olefination, and a cyclization. The synthesis proceeds in eight steps.     

The total synthesis of (S)-2,4-dihydroxy-1-butyl (4-hydroxyl) benzoate

This study is the first synthesis of (S)-2,4-dihydroxy-1-butyl (4-hydroxy) benzoate, a newly discovered natural product with anti-tumor properties from the fungus, Penicillium auratiogriseum. The key steps are a 1,3 diol protection followed by the coupling of p-anisic acid to the protected alcohol and subsequent de-protection steps.     

Convergent synthesis of a pentasaccharide repeating unit corresponding to the cell wall O-antigen of Salmonella enterica O44

A convergent synthetic strategy has been developed for the synthesis of a pentasaccharide fragment corresponding to the O-antigen of Salmonella enterica O44 strain. An intermediate tetrasaccharide derivative was prepared by a [2+2] block glycosylation of two disaccharide derivatives. The p-methoxybenzyl (PMB) group has been used as the in situ temporary protecting group minimizing the number of functional group manipulation steps. The application of the armed–disarmed glycosylation concept reduced the number of steps in the synthetic strategy. The glycosylation steps were highly stereoselective and high yielding.     

Ring-closing metathesis for the synthesis of 2H- and 4H-chromenes

Six 4H-chromenes were synthesized from substituted phenols using vinylstannylation and ring-closing metathesis (RCM) as key steps. In addition, a different approach involving amongst other steps, an aryl allyl isomerization and RCM afforded a set of seven 2H-chromenes from phenolic precursors.     

A short access to the macrocyclic core of cycloviracin and glucolipsin

The macrocyclic core of cycloviracin and glucolipsin has been synthesised in ten steps from levoglucosan and (S)-(−)-dimethyl malate. The limited number of steps to obtain this macrolide makes it a valuable procedure for the synthesis of analogues of cycloviracin and glucolipsin.