Synthesis of vinylcyclopropanes by allylation/ring-closing metathesis/Claisen rearrangement

A facile double allylation/ring-closing metathesis/Claisen rearrangement route for preparing vinylcyclopropanes 6 is developed. The efficient synthesis includes O-allylation of α-allyl-α-sulfonylketones 8 with allylic bromides, ring-closing metathesis of diallyl compounds 9 and sequential Claisen rearrangement of the resulting oxepines.     

Conversion of chiral unsaturated cyanohydrins into chiral carba- and heterocycles via ring-closing metathesis

Aliphatic unsaturated cyanohydrins 1-3 served as starting materials in the synthesis of a set of new chiral unsaturated cyclic 1,2-ethanolamines. Combining a Grignard addition-NaBH₄ reduction sequence with a ring-closing metathesis afforded unsaturated cyclic 1,2-ethanolamines 7-11 and 22-25 in good yields and high ee (96-99%). The conversion of cyanohydrins 1-3 via a DIBAL reduction-transimination-NaBH₄ reduction sequence, using allylamine, followed by ring-closing metathesis yielded tetrahydropyridines 28, tetrahydroazepinols 33 and tetrahydroazocinols 34 in high yields and excellent ee (97-99%).     

Stereoselective synthesis of aminocyclitol moieties of trehazolin and trehalostatin via enyne metathesis protocol

Stereoselective and efficient synthesis of respective aminocyclitol moieties 1a and 2a of trehazolin and trehalostatin as hexaacetates 1b and 2b using ring-closing enyne metathesis as the key reaction is described.     

Preparation of some angularly substituted and highly functionalized quinolizidines as building blocks for the synthesis of various alkaloids and related scaffolds of medicinal interest

The epimeric forms of the angularly substituted quinolizidine 6, representing potentially useful building blocks for the synthesis of various alkaloids, have been prepared via a pathway involving two consecutive ring-closing metathesis reactions. Variously hydroxy-protected derivatives (21, 22, and 26-29) of these compounds have also been generated.     

Domino intramolecular enyne metathesis/cross metathesis approach to the xanthanolides. Enantioselective synthesis of (+)-8-epi-xanthatin

The first total synthesis of (+)-8-epi-xanthatin (1) has been achieved in 14 steps starting from the commercially available ester 24, which was converted into aldehyde 23 in six steps. An enantioselective aldol reaction of 23 gave 30, which was transformed into triflate 22 in four steps, setting the stage for a palladium-catalyzed carbonylation reaction to form acrylate 34. Compound 34 was then subjected to a deprotection/lactonization sequence to furnish enyne 21, which underwent a domino enyne ring-closing metathesis/cross metathesis process to form a seven-membered carbocycle and (E)-conjugated dienone, thereby completing the synthesis of 1. This domino ruthenium-catalyzed metathesis reaction thus serves as an efficient method to construct the core of xanthanolide and other sesquiterpene lactones.     

A new approach to the synthesis of cyclic ethers via the intermolecular allylation of α-acetoxy ethers and ring-closing metathesis

A concise synthesis of the isolaurepinnacin skeleton 6 was achieved via the intermolecular allylation of the α-acetoxy ether 3 followed by ring-closing metathesis. This methodology was successfully applied to the convergent synthesis of the oxocene 15, an advanced synthetic intermediate for the total synthesis of laurencin.     

Stereoselective synthesis of l-isonucleosides

l-Isonucleosides 17 and 19 were stereoselectively synthesised from (S)-glycidol by two different procedures. The key step was the synthesis of a chiral dihydrofuran which was carried out by oxidation/elimination of 8 and by ring-closing metathesis of diene 10. The procedure can be applied to the synthesis of both enantiomers.     

Stereoselective synthesis of (−)-allosedamine

A stereoselective synthesis of (−)-allosedamine is disclosed. β-Aminosulfoxide 4 was generated stereoselectively by condensation of the sulfinyl anion 2 with N-Ts imine 3. The bromohydrin 5 was obtained by intramolecular sulfinyl group participation and the piperidine ring of allosedamine was elaborated using the ring-closing metathesis (RCM) reaction.     

A complete asymmetric synthesis of polyhydroxypiperidines

A new general methodology for the asymmetric synthesis of polyhydroxypiperidines is described. The readily available achiral olefin 4 was transformed to 5-des(hydroxymethyl)-1-deoxynojirimycin (1) and its mannose analog 10 via regioselective aminohydroxylation (AA), ring-closing metathesis (RCM), and diastereoselective dihydroxylation reactions. Thus, the developed methodology made it possible to install all stereocenters in 1 and 10 in a highly stereocontrolled fashion.     

A convergent synthesis of the macrolide core of migrastatin

We describe an efficient synthesis of the 14-membered macrolide core 2 of migrastatin via key intermediate 3 employing a diastereoselective aldol condensation, Lewis acid mediated diastereoselective addition and an exclusive (Z)-olefination sequence. Yamaguchi esterification of the key intermediate 3 followed by ring-closing metathesis (RCM) produced macrolide 2 with high selectivity and good yield.     

Studies directed towards the stereoselective total synthesis of ilexlactone via a tandem ring-closing enyne metathesis protocol

Studies directed towards the stereoselective total synthesis of ilexlactone resulted in the synthesis of bicyclic systems 1a, 1b and ent-1a through tandem ring-closing enyne metathesis using Grubbs’ catalyst. The structures of synthetic 1a, 1b and ent-1a revealed that the proposed structure for ilexlactone is incorrect.     

Formal total synthesis of (−)-spongidepsin

The formal total synthesis of (−)-spongidepsin is described. Three fragments I, II, and III were first prepared from readily available starting materials and then assembled to the target compound. The key steps involved in the synthesis are asymmetric α-hydroxylation, Ender's alkylation, and ring-closing metathesis reactions. An alternative route for the fragment II is also achieved involving Sharpless asymmetric epoxidation and Gilman's alkylation as key reactions.     

Asymmetric synthesis of 1-deoxynojirimycin and its congeners from a common chiral building block

A new, promising chiral building block 9 for the synthesis of 1-deoxy-4,5-trans-oriented azasugars such as 1-deoxynojirimycin (1) was prepared in only four steps from the Garner aldehyde 10 using catalytic ring-closing metathesis (RCM) for the construction of the piperidine ring. In practical test, the first synthesis of all four isomers (1 and 6-8) of trans-4,5-orientated 1-deoxyiminosugars using 9 as a common chiral building block was demonstrated.     

Formal total synthesis of camptothecin via ring-closing metathesis strategy

A formal total synthesis of camptothecin 1 is presented. The key steps include construction of the D-ring of camptothecin featuring an efficient ring-closing metathesis (RCM) reaction and the subsequent Michael addition of nitropropane across the double bond of the dihydropyridone 3.     

Stereoselective synthesis of (6S) and (6R)-5,6-dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one and their cytotoxic activity against cancer cell lines

Stereoselective total synthesis of α,β-unsaturated lactone (1a), isolated from Ravensara crassifolia, has been achieved efficiently starting from chiral 2,3-O-isopropylidene-d-glyceraldehyde (3) followed by asymmetric allylation and ring-closing metathesis. The antiproliferative activities of compounds 1a, 1b and the unusual bicyclic compound 2 were evaluated against three-cancer cell lines, THP-1 and U-937 (leukemia) and A-375 (melanoma).     

A concise stereospecific synthesis of repinotan (BAY×3702)

A concise synthesis of the 2-[aminomethyl]chroman derivative BAY×3702 (3), a potent 5-hydroxytryptamine (5-HT_1A) antagonist is described. Utilization of a Mitsunobu reaction of phenol (11) with the non-racemic allylic alcohol (12) and consequent ring-closing metathesis furnishes the chroman-2-yl framework of 3 in optically active form.     

Synthesis of rodocaine

A new method for synthesis of rodocaine (1) is presented. Two key steps were carried out by the N-bromosuccinimide (NBS)-mediated intermolecular addition of known enamine 5 with allyltrimethyl silane in presence of boron trifluoride etherate (BF₃/OEt₂) and the intramolecular ring-closing metathesis of triene 3. The Diels-Alder cycloaddition of triene 3 with different ethyl propiolates was also studied.     

Bis- and tetracalix[4]arenes in the partial cone conformation: synthesis, structure and RCM reactions

The synthesis, structure and ring-closing metathesis (RCM) reactions of polyether bridged biscalix[4]arenes 6 in the partial cone conformation with upper rim allyl substituents are reported. The RCM reaction modes depend on the length of polyether chain. Diethylene glycolic chain produced the dimer 7a and linear oligomer 7a′ with multi-cavities, whereas triethylene and tetraethylene glycolic chains allowed direct cyclization through intramolecular head-to-tail pattern to yield novel bridged biscalix[4]arenes 7b-c.     

A novel and efficient synthesis of Entecavir

A practical synthesis of Entecavir (1) has been accomplished in 10 steps with 21% overall yield. The key steps to construct the five-membered carbocyclic framework 2 are a ring-closing metathesis and a diethyl-aluminum 2,2,6,6-tetramethyl piperidide (DA-TMS) mediated epoxide isomerization. Furthermore, the guanine was introduced by modified Mitsunobu reaction.     

Second-generation total synthesis of (−)-diversifolin

A second-generation total synthesis of (−)-diversifolin has been achieved by a more straightforward strategy, involving a highly stereochemistry-dependent 10-membered ring-closing metathesis and a stereoselective dihydroxylation/lactone transposition sequence. Compared to our previous synthesis, the present synthesis is improved in the yield of the key intermediate 2 (20% in 12 steps from diol 8).