Total synthesis of (-)-dysibetaine via a nitrenium ion cyclization-dienone cleavage strategy

The diastereoselective total synthesis of the marine natural product (-)-dysibetaine is reported. The key steps in this venture are i) a diastereoselective nitrenium ion spirocyclization, which serves to generate the pyrrolidinone ring and quaternary stereocenter of the target, and ii) use of the 2-methoxycyclohexa-2,5-dienone ring formed during cyclization as a masked 2-amino-1,3-dicarbonyl synthon.     

First enantioselective total synthesis of (−)-heliannuol C

The first, efficient total synthesis of (−)-heliannuol C (1) was accomplished enantioselectively, using a chemoenzymatic desymmetrization of the σ-symmetrical diol, a ring closing metathesis, a diastereoselective epoxidation, and a regioselective reductive cleavage of epoxide as the key reaction steps.     

Expeditious total syntheses of natural allenic products via aromatic ring umpolung

Concise diastereoselective syntheses of the marine (+/-)-panacene and terrestrial (+/-)-desbromopanacene have been achieved in a few steps based on a concept of "aromatic ring umpolung". The synthetic avenue to the (+/-)-panacene involved a novel oxymercuration strategy to produce the correct configuration of the bromoallene moiety.     

Enantioselective total synthesis of (-)-heliannuol A

An efficient and enantiocontrolled total synthesis of (-)-heliannuol A has been accomplished by employing ring closing metathesis and sequential diastereoselective epoxidation and regioselective reductive cleavage of the epoxide ring.     

Synthetic studies on (-)-FR182877: construction of the ABCD ring system via the intramolecular cycloadditions (1)

Construction of the ABCD ring system of (-)-FR182877 via the highly diastereoselective intramolecular Diels-Alder (IMDA) reaction is described. The IMDA reaction of the α,β-unsaturated aldehyde generated in situ from the corresponding acetal successfully provided the desired product 14 possessing the AB ring system as the single diastereomer. The CD ring system was constructed by the subsequent IMHDA reaction and the additional experiment suggested that the diastereoselectivity of the IMHDA reaction could be related to the E/Z geometry of alkene 17, which was generated in situ from 16.     

The Total Synthesis of (±)‐Naupliolide: A Tetracyclic Sesquiterpene Lactone

The first total synthesis of (±)‐naupliolide has been achieved. The synthetic method includes a Simmons–Smith cyclopropanation of an allyl alcohol, diastereoselective cleavage of a benzylidene acetal group, radical cyclization of an aldehyde with a cyclopropane ring, and construction of an eight‐membered ring by ring‐closing metathesis.     

Asymmetric synthesis of (-)-swainsonine, (+)-1,2-di-epi-swainsonine,and (+)-1,2,8-tri-epi-swainsonine

The asymmetric synthesis of (-)-swainsonine via a nonchiral pool route that involves the Sharpless epoxidation to induce chirality is reported. The key steps involve vinyl epoxide aminolysis, ring-closing metathesis, and intramolecular N-alkylation to prepare the indolizidine ring and a highly diastereoselective cis-dihydroxylation using AD-mix-alpha. This synthetic strategy also allowed for the diastereoselective synthesis of (+)-1,2-di-epi-swainsonine and (+)-1,2,8-tri-epi-swainsonine.     

A concise synthesis of (-)-centrolobine via a diastereoselective ring rearrangement metathesis-isomerisation sequence

A total synthesis of (-)-centrolobine (1) based on a diastereoselective ring rearrangement metathesis-double bond isomerisation sequence and a one-pot cross metathesis-hydrogenation procedure is described.     

A general methodology for the asymmetric synthesis of 1-deoxyiminosugars

A general methodology for the stereoselective synthesis of 1-deoxymannojirimycin and its three other stereoisomers is described. The achiral olefin 6 was converted through the common olefin intermediate 12 to the target compounds in a highly stereocontrolled manner. The regioselective asymmetric aminohydroxylation (AA) and diastereoselective dihydroxylation reactions were used for the introduction of all four stereocenters in the targets, and the ring-closing metathesis (RCM) reaction was utilized for the construction of the required six-membered ring.     

Total synthesis of the ristocetin aglycon

The first total synthesis of the ristocetin aglycon is described employing a modular and highly convergent strategy. An effective 12-step (12% overall) synthesis of the ABCD ring system 3 from its amino acid subunits sequentially features an intramolecular aromatic nucleophilic substitution reaction for formation of the diaryl ether and closure of the 16-membered CD ring system (65%), a respectively diastereoselective (3:1, 86%) Suzuki coupling for installation of the AB biaryl linkage on which the atropisomer stereochemistry can be further thermally adjusted, and an effective macrolactamization (51%) for closure of the 12-membered AB ring system. A similarly effective 13-step (14% overall) synthesis of the 14-membered EFG ring system 4 was implemented employing a room-temperature intermolecular S(N)Ar reaction of an o-fluoronitroaromatic for formation of the FG diaryl ether (69%) and a key macrolactamization (92%) with formation of the amide linking residues 1 and 2. The two key fragments 3 and 4 were coupled, and the remaining 16-membered DE ring system was closed via diaryl ether formation to provide the ristocetin tetracyclic ring system (15 steps, 8% overall) enlisting an unusually facile (25 degrees C, 8 h, DMF, >/=95%) and diastereoselective (>/=15:1) aromatic nucleophilic substitution reaction that benefits from substrate preorganization.     

Studies on the synthesis of (-)-spinosyn a: application of the steric directing group strategy to transannular Diels-Alder reactions

A highly diastereoselective and enantioselective synthesis of the decahydro-as-indacene nucleus 12 of (-)-spinosyn A (1) is reported. By implementing the steric directing group strategy, tricyclic lactone 37 was produced from a remarkably diastereoselective transannular Diels-Alder reaction of lactone 9. The tricyclic core of the natural product was then obtained by using an Ireland-Claisen ring contraction of 37. Reversal of the order of these two steps resulted in an almost complete loss of diastereoselectivity.     

Magnesium iodide promoted reactions of nitrones with cyclopropanes: a synthesis of tetrahydro-1,2-oxazines

Anhydrous magnesium iodide (MgI(2)) is shown to be an effective promoter of the "homo 3+2" dipolar cycloaddition of nitrones with 1,1-cyclopropane diesters. In almost all cases the products tetrahydro-1,2-oxazines are formed in excellent yields. The reactions are highly diastereoselective for a cis relationship between the substitutents at the 3- and 6-positions on the tetrahydrooxazine ring. As an alternative to using a preformed nitrone, the reaction may be performed in a 3-component sense by combining an aldehyde, an hydroxylamine, and the cyclopropane in the presence of catalytic MgI(2).     

Asymmetric total synthesis of (-)-scabronine G via intramolecular double Michael reaction and Prins cyclization

The enantioselective total synthesis of (-)-scabronine G is described. The key features of the present synthesis include the construction of a 5-6 ring system containing two quaternary carbon centers via a diastereoselective intramolecular double Michael reaction and the formation of a seven-membered ring using a Prins cyclization.     

Lewis Acid-Mediated Intramolecular Ene Reactions of Alkylidene Malonates and 2-Phosphonoacrylates: A Highly Diastereoselective Approach to Trans-1,2-disubstituted Five-Membered Ring Compounds

A facile and highly diastereoselective synthesis of trans-1,2-disubstituted five-membered ring compounds is described based on ZnBr₂-catalysed intramolecular ene reactions of some alkylidene malonates and 2-phosphonoacrylates.     

Total synthesis of (+)-asperazine

The first total synthesis of the structurally novel cyclotryptophan alkaloid asperazine is reported. The central step in the synthetic sequence is a diastereoselective intramolecular Heck reaction in which the substituent controlling stereoselection is external to the ring being formed. This synthesis confirmed the structure of (+)-asperazine (1) proposed by Crews and co-workers and provided material for additional biological studies. The in vitro cytotoxicity originally reported for the marine isolate was not confirmed with synthetic (+)-asperazine.     

Synthesis of [6,n] cis-fused ring compounds via Cr-mediated dearomatisation-ring-closing metathesis

cis-Fused [6,8], [6,7], [6,6] and [6,5] ring systems containing a cyclohexadiene ring unit, a cycloenone ring and a quaternary carbon at the ring junction were obtained in only two steps from [Cr(CO)3(eta6-p-methoxyphenyl oxazoline)]. The sequence proceeds via diastereoselective addition of three C-substituents across an arene double bond, followed by allylation and ring closing metathesis (RCM). RAMP-hydrazone and (R)-isopropyloxazoline were used as chiral auxiliaries to provide, after removal of the auxiliaries, the enantiomerically highly enriched [6,7] cis-fused system.     

Synthesis of a protected enantiomerically pure 2-deoxystreptamine derivative from d-allylglycine

A diastereoselective synthetic route from d-allylglycine to the enantiopure (protected) 2-deoxystreptamine derivative 14 is presented. Key steps involve two consecutive chain extensions--with crucial stereodirective roles for the amino protective groups, ring closure by olefin metathesis, face selective dihydroxylation, cyclic sulfate formation and finally opening with azide. The resulting 2-deoxystreptamine derivative is ideally protected for the preparation of 4,5- or 4,6-linked aminoglycoside antibiotics.     

Nitrenium ion-mediated alkene bis-cyclofunctionalization: total synthesis of (-)-swainsonine

The total synthesis of (-)-swainsonine from 2,3-O-isopropylidene-D-erythrose in 12 steps and an overall yield of 28% is reported. The pivotal transformation in our route to this indolizidine alkaloid is the formation of the pyrrolidine ring and C-8a/8 stereodiad through the diastereoselective, bis-cyclofunctionalization of an γ,δ-unsaturated O-alkyl hydroxamate. This transformation is believed to proceed via the intramolecular capture of an N-acyl-N-alkoxyaziridinium ion generated by the diastereoselective addition of a singlet acylnitrenium ion to the pendant alkene.     

A diastereoselective total synthesis of trans-trikentrin A: a ring contraction approach

A new route to obtain the polyalkylated indole (+/-)-trans-trikentrin A was developed. The synthesis of this natural alkaloid features a thallium(III)-mediated ring contraction reaction to obtain the trans-1,3-disubstituted five-membered ring in a diastereoselective manner. Thallium(III) is chemoselective in this rearrangement, reacting with the olefin without oxidation of the indole moiety. Other key transformations are the Bartoli's reaction to construct the heterocyclic ring and a Heck coupling to add the carbons atom that will originate the nonaromatic cycle.     

Diastereoselective synthesis of cularine alkaloids via enium ions and an easy entry to isoquinolines by aza-Wittig electrocyclic ring closure

In preliminary communications, we reported the diastereoselective synthesis of cularine and sarcocapnine via the intramolecular ring closure of nitrenium and oxenium ions, a new highly diastereoselective reductive methylation with (+)-8-phenylmenthyl chloroacetate followed by reduction with sodium borohydride, and a facile entry to the isoquinoline precursors by aza-Wittig electrocyclic ring closure. We now report the full details of the syntheses of (+)-O-demethylcularine, (+)-cularine, (+)-sarcocapnidine, (+)-sarcocapnine, and (+)-crassifoline and describe different methods of synthesis of their precursors.