Synthesis of the Anti‐HIV Agent (−)‐Hyperolactone C by Using Oxonium Ylide Formation–Rearrangement

Starting from readily available (S)‐styrene oxide an asymmetric synthesis is described of the naturally occurring anti‐HIV spirolactone (?)‐hyperolactone C, which possesses adjacent fully substituted stereocenters. The key step involves a stereocontrolled Rh^II‐catalysed oxonium ylide formation–[2,3] sigmatropic rearrangement of an α‐diazo‐β‐ketoester bearing allylic ether functionality. From the resulting furanone, an acid‐catalysed lactonisation and dehydrogenation gives the natural product.     

The scope of catalytic enantioselective tandem carbonyl ylide formation-intramolecular [3 + 2] cycloadditions

Catalytic enantioselective tandem carbonyl ylide formation-intramolecular 1,3-dipolar cycloaddition reactions of 2-diazo-3,6-diketoesters show promising scope in terms of asymmetric induction as the tethered alkene/alkyne dipolarophile component is varied. Cycloadditions were found to occur in moderate to very good yields, with a difference in ee exhibited by the electronically different 2-diazo-3,6-diketoesters 1, 25 and 33, 34. Values for ee of up to 90% for alkene dipolarophiles and up to 86% for alkyne dipolarophiles were obtained.     

Total synthesis of erythromycin B

We report the details of the first total synthesis of erythromycin B using two different strategies for the end game. The first of these follows a classical approach in which the desosamine and cladinose residues are sequentially appended to a macrocyclic lactone, which was formed by cyclization of a seco acid derivative, to give a bis-glycosylated macrolide intermediate that is converted into erythromycin B. The second strategy features an abiotic approach in which a seco acid bearing a desosamine residue is cyclized to give a monoglycosylated macrocyclic lactone that is then transformed into erythromycin B via a sequence of steps involving refunctionalizations and a glycosylation to introduce the cladinose moiety. Attempts to prepare a bis-glycosylated seco acid by de novo synthesis were unsuccessful. The syntheses of the key seco acid intermediates feature the oxidative transformation of a furan containing C(3)-C(10) to provide a dioxabicyclo[3.3.1]nonenone that served as a template on which to create the stereocenters at C(6) and C(8). A stereoselective aldol reaction was used to establish the C(11)-C(15) segment, and a stereoselective crotylation was implemented to introduce the propionate subunit comprising C(1)-C(2).     

Enantioselective synthesis of epoxides by alpha-deprotonation--electrophile trapping of achiral epoxides

Enantioselective alpha-deprotonation of achiral epoxides 1, 21, and 26 using organolithiums in the presence of (-)-sparteine 2 and subsequent electrophile trapping gives access to enantioenriched trisubstituted epoxides 9-17, 22, 23, 27 and 28 (in up to 86% ee).     

Intramolecular cyclopropanation of unsaturated terminal epoxides and chlorohydrins

Lithium 2,2,6,6-tetramethylpiperidide (LTMP)-induced intramolecular cyclopropanation of unsaturated terminal epoxides provides an efficient and completely stereoselective entry to bicyclo[3.1.0]hexan-2-ols and bicyclo[4.1.0]heptan-2-ols. Further elaboration of C-5 and C-6 stannyl-substituted bicyclo[3.1.0]hexan-2-ols via Sn-Li exchange/electrophile trapping or Stille coupling generates a range of substituted bicyclic cyclopropanes. An alternative straightforward cyclopropanation protocol using a catalytic amount of 2,2,6,6-tetramethylpiperidine (TMP) allows for a convenient (1 g-7.5 kg) synthesis of bicyclo[3.1.0]hexan-2-ol and other bicyclic adducts. The synthetic utility of this chemistry has been demonstrated in a concise asymmetric synthesis of (+)-beta-cuparenone. The related unsaturated chlorohydrins also undergo intramolecular cyclopropanation via in situ epoxide formation.     

Synthesis of alpha-kainic acid from a 7-azabicyclo[2.2.1]heptadiene by tandem radical addition-homoallylic radical rearrangement

Reductive radical addition of 2-iodoethanol to N-Boc 2-tosyl-7-azabicyclo[2.2.1]heptadiene gives N-Boc syn-7-(2-hydroxyethyl)-4-tosyl-2-azabicyclo[2.2.1]hept-5-ene, which is converted into the neuroexcitants 3-(carboxymethyl)pyrrolidine-2,4-dicarboxylic acid and alpha-kainic acid. [structure: see text]     

Substituted aziridines by lithiation-electrophile trapping of terminal aziridines

[reaction: see text] Regio- and stereoselective deprotonation of N-Bus (Bus = tert-butylsulfonyl)-protected terminal aziridines with lithium 2,2,6,6-tetramethylpiperidide generates a nonstabilized (H-substituted) aziridinyl anion that undergoes in situ or external electrophile trapping under experimentally straightforward conditions to give trans-disubstituted aziridines in good to excellent yields.