Stereoselective Synthesis of Dysoxylactam A.

The first report on the stereoselective synthesis of dysoxylactam A is disclosed. The five stereogenic centers of the fatty acid chain are created by utilizing Merck-Carreira and Marshall's propargylation reaction, Evans' alkylation methodology, and Noyori's transfer hydrogenation protocol.

Convergent Stereoselective Synthesis of the C16-C37 Subunit of Sorangicin A.

A convergent stereoselective route to the C16-C37 fragment of sorangicin A is disclosed using an α-chloro sulfide for C-C bond formation. The key intermediate, an α,ß-unsaturated ketone, is revealed by a [2,3] sigmatropic rearrangement of a propargylic sulfoxide. Three disparate approaches are detailed to create the C25 carbinol stereocenter. The cis-2,6-disubstitution of the THP ring is secured by ionic hydrogenation. A cross-metathesis reaction and Julia-Kocienski olefination furnish the C16-C37 fragment of sorangicin A.

Stereoselective Synthesis of the C1-C22 Carbon Framework of (-)-Amphidinolide K.

Two stereoselective routes to the C7-C22 subunit of amphidinolide K are disclosed. Jacobsen's hydrolytic kinetic resolution and Sharpless' asymmetric dihydroxylation reactions have been employed for the construction of the tetrahydrofuran ring. The C10-C11, C16-C17, C9-O, and C18-O bonds have been created using α-chloro sulfide intermediates and [2,3] sigmatropic rearrangement. Marshall's propargylation protocol is utilized to create the C4 stereogenic center, and regioselective hydrozirconation/iodine quench afforded an alkenyl iodide which is employed in the NHK coupling with the C7-C22 subunit. Oxonia-Cope rearrangement resulted in the creation of the C18 carbinol stereogenic center and chain elongation.

Synthesis of solandelactone F, constanolactone A and an advanced intermediate towards solandelactone E from a common synthetic intermediate.

The stereoselective synthesis of solandelactone F, constanolactone A and an advanced intermediate towards solandelactone E, from a common synthetic intermediate, is disclosed. The propargylic sulfide stereocenter is created stereoselectively via carbon-carbon bond formation in the reaction of α-chloro sulfides with alkynylzinc reagents via 1,2-asymmetric induction by a ß-siloxy group. The characteristic 1,4-diol motif of the natural products is introduced by a [2,3] sigmatropic rearrangement of an allylic sulfoxide or by the Mislow-Evans-Braverman rearrangement of a propargylic sulfoxide followed by stereoselective reduction of the ensuing α,ß-unsaturated ketone. Unlike earlier reports, the C11/C9 carbinol center is created with excellent stereocontrol and derivatives of natural products differing at C14/C12 can be readily obtained. Catalytic asymmetric protocols and substrate-controlled asymmetric induction are utilized for the efficient introduction of the stereogenic centers.

Application of Ru(II)-Catalyzed Enyne Cyclization in the Synthesis of Brefeldin A.

The approach to brefeldin A described herein hinges on Ru(II)-catalyzed cycloisomerization of an enyne obtained by the reaction of an alkynylzinc reagent with an α-chloro sulfide. Other key steps include Mislow-Evans rearrangement, cross-metathesis, and macrocyclization using a Roush-Masamune protocol.

Synthesis of crinane utilizing an allylic sulfoxide for the construction of a hydroindole ring via vinylogous C-N bond formation.

The synthesis of crinane is disclosed via intramolecular C-N bond formation by the displacement of an allylic sulfoxonium salt. The allylic sulfide precursor was synthesized by a ring-closing metathesis reaction. The quaternary carbon stereocenter was created by alkylation of a benzylic cyanide. The allyl sulfide 14 was prepared by adding vinylmagnesium bromide to an α-chlorosulfide.

Convergent Synthesis of the Dihydropyran Core Containing the C1-C15 Subunit of Sorangicin A Employing Gold(I)-Catalyzed Cyclization of an Allenic Alcohol.

A convergent route to the C1-C15 subunit of sorangicin A is disclosed. The key steps include carbon-carbon bond formation using an α-chloro sulfide, regioselective hydrozirconation of an internal alkyne for the preparation of a trisubstituted iodoalkene, allene formation using the Myers-Movassaghi protocol, stereoselective reduction of allylic and propargylic ketones using Noyori's catalyst, and gold(I)-catalyzed cyclization of a ß-hydroxy allene to construct the dihydropyran ring.

Oxazolidines as Intermediates in the Asymmetric Synthesis of 3-Substituted and 1,3-Disubstituted Tetrahydroisoquinolines.

A diastereoselective mercury(II)-promoted intramolecular cyclization of unsaturated aldehyde via an oxazolidine to prepare C-3-substituted tetrahydroisoquinoline is disclosed. The C-3 stereogenic center is subsequently exploited to create the C-1 stereocenter by coordination of the nucleophilic reagent to the oxygen atom of oxazolidine. Both cis- and trans-1,3-disubstituted tetrahydroisoquinolines can be readily prepared. In addition, when a cationic rhodium complex was used, intramolecular hydroamination was effected, thus avoiding mercury(II) salts and demercuration. The reaction is general and works well using aliphatic and aromatic aldehydes.

Stereoselective Formal Synthesis of (+)- and (-)-Cyclophellitol and (-)-Conduritol-B and Synthesis of (-)-Conduramine-B Derivative Using a Sulfinyl Moiety for C-O Bond Formation and α-Chloro Sulfide for C-C Bond Formation.

The formal total synthesis of both the enantiomers of cyclophellitol and conduritol-B and synthesis of conduramine-B derivative have been achieved from a common intermediate, obtained by regio- and stereoselective vicinal functionalization of a diene utilizing an intramolecular sulfinyl group as a nucleophile, followed by stereoselective preparation of an allylic sulfide by reaction of vinylzinc bromide with an electrophilic α-chloro sulfide, and last by ring-closing metathesis reaction as the key steps. The sulfoxide, sulfilimine, and sulfur ylid prepared from this common intermediate have been transformed into derivatives of conduritol-B, conduramine-B, and (-)-cyclophellitol, respectively. The silyl sulfide was converted via sila-Pummerer rearrangement, hydrolysis, and reduction in an one-pot operation to a hydroxymethyl group. [2,3]-Wittig-Still rearrangement was employed for the synthesis of (+)-cyclophellitol. The potential utility of sulfur intermediates as nucleophilic and electrophilic partners in total synthesis is elegantly demonstrated.

Stereoselective total synthesis of (-)-nupharamine utilizing an α-chlorosulfide and a sulfinimine for C-C bond formation.

An efficient stereoselective synthesis of the nuphar alkaloid, (-)-nupharamine, is reported. The key features include the Lewis acid catalyzed reaction of an α-chlorosulfide with a silyl ketene acetal for C-C bond formation, creation of the stereocenter at C2 by a diastereoselective reaction of allyl indium with a sulfinimine and reductive amination for the introduction of the C6 stereocenter of the piperidine ring.

Stereoselective synthesis of the C13-C22 fragment of callystatin A by a non-aldol approach.

An efficient synthetic route to the C13-C22 subunit of callystatin A is reported. The key features include diastereoselective alkylation, using Myers auxiliary, for the preparation of the three carbon synthon 7, stereo- and regioselective oxidative vicinal functionalization of an electron deficient trisubstituted (Z)-olefin using an intramolecular sulfinyl group as the nucleophile, diastereoselective radical debromination of a bromohydrin derivative using Guindon's protocol to prepare the C16-C18 anti-anti stereotriad, Lewis acid promoted crotylation following Keck's protocol to create C19, C20 stereocenters and the use of the Pummerer reaction to reveal an aldehyde for the extension of two carbons by Wittig olefination.

A stereoselective synthesis of the C9-C19 subunit of (+)-peloruside A.

The stereoselective synthesis of a C9-C19 fragment of the potent antitumor agent peloruside A is disclosed. The C11 stereogenic centre was created by a vinylogous Mukaiyama aldol reaction following Carreira's protocol, with excellent stereocontrol. The C13 stereogenic centre was introduced by a substrate controlled reduction. The C15 stereocentre was fashioned using Noyori's asymmetric transfer hydrogenation while the Z-trisubstituted double bond was formed by a regioselective hydrostannation of an alkyne followed by methylation of the resultant vinyl stannane using Lipshutz's protocol. The C18 chiral centre was introduced by a chemoenzymatic route.

Stereoselective synthesis of the macrolactone core of (+)-neopeltolide.

A stereoselective synthesis of the macrolactone core of the potent anticancer agent neopeltolide is disclosed. The key steps of the synthesis include asymmetric allylation using Krische' protocol, conjugate reduction using MacMillan's methodology, and an asymmetric hetero-Diels-Alder reaction using Jacobsen's catalyst. Substrate controlled diastereoselective 1,3-anti reduction of a keto alcohol, Luche reduction followed by Ireland-Claisen rearrangement, oxymercuration, and reductive lithiation are other key steps.

Total synthesis of (+)-(2'S,3'R)-zoapatanol exploiting the B-alkyl Suzuki reaction and the nucleophilic potential of the sulfinyl group.

A stereoselective synthesis of the diterpenoid oxepane (+)-zoapatanol is described. The key steps include a B-alkyl Suzuki cross-coupling reaction for the stereoselective synthesis of trisubstituted alkenes, creation of the two stereogenic centers on the oxepane ring by heterofunctionalization of an alkene through substrate control exploiting the nucleophilic potential of an intramolecular sulfinyl group, and transformation of a ß-hydroxy sulfoxide into a terminal alkene.

Mercury(II)-mediated cleavage of cyclopropylcarbinols by an intramolecular sulfinyl group as a stereo- and regioselective route to stereotriads and stereotetrads.

Mercury(II) salt mediated opening of cyclopropylcarbinols by an intramolecular sulfinyl group is disclosed. All four diastereomeric stereotriads have been prepared from cis- and trans-disubstituted cyclopropanes. The trisubstituted cyclopropanes also react regio- and stereoselectively to afford products possessing quaternary stereogenic centers. The reaction is clean and general.

Asymmetric synthesis of the potent HIV-protease inhibitor, nelfinavir.

An asymmetric synthesis of nelfinavir is described starting from acrolein and (S)-methyl phenyl sulfoxide. The key features include (a) stereoselective preparation of a beta-protected amino-gamma,delta-unsaturated sulfoxide by the reaction of an alpha-sulfinyl carbanion with an unsaturated t-butyl sulfinylimine, (b) stereoselective bromohydrin formation using the pendant sulfoxide group as an intramolecular nucleophile, and (c) use of commercially or readily prepared inexpensive starting materials.

An efficient stereoselective synthesis of penaresidin a from (e)-2-protected amino-3,4-unsaturated sulfoxide.

An efficient, modular, asymmetric synthesis of penaresidin A is disclosed. A beta-protected amino-gamma,delta-unsaturated sulfoxide was prepared by stereoselective addition of the lithio anion of (R)-methyl p-tolyl sulfoxide to an unsaturated sulfinylimine. The pendant sulfoxide group was used as an intramolecular nucleophile to functionalize an alkene regio- and stereoselectively to furnish a bromohydrin, which was employed as the key intermediate in the preparation of the azetidine subunit of penaresidin A. The stereogenic centers of the side chain were introduced by a regioselective opening of an epoxide. Julia-Kocienski olefination was used to couple the azetidine and side chain subunits. The methodology disclosed herein is also useful for the synthesis of ribo- and arabino-phytosphingosines and compounds possessing the amino alcohol moiety.

A versatile route to (E)- and (Z)-2-hydroxy-3,4-unsaturated disubstituted sulfilimines and their haloamidation reaction.

Alpha-chloro ynones have been reduced using Noyori's Ru catalyst to furnish alpha-chloro propargylic alcohols with excellent enantioselectivity. These have been used as a common precursor for the preparation of (E)- and (Z)-2-hydroxy-3,4-unsaturated disubstituted sulfilimines. The latter serve as precursors for the highly regio- and stereoselective preparation of bromo carbamates.

Solid-phase synthesis of a library of pyrrolo[2,1-c][1,4]benzodiazepine-5,11-diones with potential antitubercular activity.

A versatile combinatorial approach was developed and utilized for the rapid synthesis of pyrrolo[2,1-c]-[1,4]benzodiazepine-5,11-dione (PBD-5,11-dione) libraries 10, 15, and 19 containing 210 compounds with varied substitutions in A, B, and C rings. The key aspect of the synthetic strategy includes Staudinger, intermolecular aza-Wittig reaction followed by imine reduction and base-mediated cyclative cleavage results in the formation of final resin-free compounds. This strategy provides a highly efficient and practical protocol for the parallel synthesis of PBD-5,11-diones on solid support. The modifications in the C-ring of the PBD scaffold produced three types of sublibraries. Reactions were monitored by FT-IR spectroscopy on the resin beads. Further, from a generated library of 210 compounds, 142 compounds have been selected and evaluated for in vitro activity against Mycobacterium tuberculosis, and some of these compounds have exhibited promising activity.

Novel, short, stereospecific synthesis of lyxo-(2R,3R,4R)-phytosphingosine and erythro-(2R,3S)-sphingosine.

Lyxo-phytosphingosine and erythro-sphingosine have been elaborated from a common intermediate. The key step in the reaction sequence involves stereo- and regiospecific functionalization of an olefin by intramolecular nucleophilic sulfinyl group participation.