Vince Lynch

Concise Syntheses of (−)-Galanthamine and (±)-Codeine via Intramolecular Alkylation of a Phenol Derivative

Suzuki coupling of 7 to 8 gave the biphenyl derivative 9. Reaction of 9 with ethyl vinyl ether/bromine/base gave 10, which on treatment with CsF/DMF at 130 degrees C resulted in the cross-conjugated 2,5-cyclohexadienone 6. Acid hydrolysis of 6 gave 11, which was reductively aminated to give (+/-)-narwedine 2. Since 2 has been converted into (-)-galanthamine 1 in two steps, this synthesis proceeds in eight steps with an overall yield of 63%. Also treatment of the cross-conjugated cyclohexadienone 6 with nitromethane/base gave 12, which was reduced to provide 13. Reduction of the nitro group in 13 to an amine, followed by reductive amination under acidic conditions, arrives at the codeine skeleton 15. Elaboration of 15 into (+/-)-codeine proceeds via the previously unknown alpha-epoxide derivative 18. This is the shortest synthesis of codeine (13 steps, 20% overall yield) and, for the first time, allows access to codeine without having to reduce codeinone.

Synthesis of the Kopsia alkaloids (′)-pauciflorine B, (′)-lahadinine B, (′)-kopsidasine, (′)-kopsidasine-N-oxide, (′)-kopsijasminilam and (′)-11-methoxykopsilongine

Abstract Pictet–Spengler condensation of 13 with tryptamine gave 14 , which was converted into 17 . Treatment of 17 with phenyl chloroformate resulted in 18 , which underwent transannular cyclization to give 19 . The more stable cyano-analog 22 was made by treating 18 with Tf2O/DMAP to generate 18f , and quenching the reaction with trimethylsilyl cyanide. Treatment of 22 with acryloyl chloride (excess) at 75°C gave 23 , which was directly treated with N-hydroxy-2-thiopyridone/Et3N to give 24 . Irradiation of 24 in the presence of t-BuSH resulted in reductive decarboxylation to give 26 and a small amount of the 2-thiopyridyl ether 25 . Protection of the aniline nitrogen in 26 required the use of triphosgene/pyridine followed by methanol. The final step for the conversion of 27 into 28 required conjugate reduction of the α,β-unsaturated ester followed by α-hydroxylation and gave 28 (11,12-demethoxy lahadinine B). Exposure of 26 to PhI(OAc)2/MeOH cleanly gave 26a , which was directly reduced with Zn/AcOH to 29 . Conversion of 29 into 30 proceeded as before, and when 30 was treated with AgBF4/THF followed by aqueous NaHCO3 it was converted into (±)-kopsidasine 2 , completely characterized as its derived N-oxide 2a . Treatment of 26 with AgBF4/THF followed by aqueous NaHCO3, gave 31 . Oxidation of 31 with m-chloroperoxybenzoic acid resulted in the N-oxide 32 which underwent fragmentation to give 33 when exposed to trifluoroacetic anhydride. When the diene 33 was treated with Mn(dpm)3 (cat)/PhSiH3/O2 in isopropyl alcohol at 0°C, it was converted into kopsijasminilam 4 . Peracetic acid in EtOAc (10%) was used to quench the AgBF4/THF conversion of 28 into 37 , and resulted in 42 / 42a (4:1, 65%) along with small amounts of 38 and 41c . Application of these procedures, with some modifications, to the 11,12-dimethoxy substituted systems gave (±)-lahadinine B 64 . Treatment of 64 with triethylsilane in the presence of trifluoroacetic acid cleanly converted it into 11-methoxykopsilongine 65 (93%). Treatment of (±)-lahadinine B 64 with AgBF4/THF followed by work-up with EtOAc/MeCO3H (10%) gave (±)-pauciflorine 6 and the double bond isomer 6a .

Conversion of α,β-unsaturated ketones into α-hydroxy ketones using an MnIII catalyst, phenylsilane and dioxygen: acceleration of conjugate hydride reduction by dioxygen

Abstract Treatment of a variety of α,β-unsaturated ketones with Mn(dpm)3 (3 mol%)/PhSiH3 (1.3 equiv.)/isopropyl alcohol/O2, followed by reductive work-up with P(OEt)3 resulted in the formation of α-hydroxyketones.

Stereoselective synthesis of the bicyclo[5.3.0]decane portion of the diterpene antibiotic guanacastepene using a pyrylium-ylide [5+2] cycloaddition reaction

Treatment of 14 with Ac2O/Et3N resulted in [5+2] cyclization to give 2, which was further elaborated into 20, thus establishing the required stereochemistry in the top-half of guanacastepene 1.

Stereoselective synthesis of the tricyclic core ABC-rings of nakadomarin and manzamine from a common intermediate

Abstract Pauson–Khand cyclization of the enamide 9 proceeds in trifluoroethanol to give cyclopentenone 10 , which on hydrogenation gives 11 , having the core ABC-rings of nakadomarin 1 .

MACROCYCLIC CYCLOPROPENES BY HIGHLY ENANTIOSELECTIVE INTRAMOLECULAR ADDITION OF METAL CARBENES TO ALKYNES

The intramolecular addition of a diazo ester group to a triple bond in the presence of chiral dirhodium(II) carboxamidate catalysts gives macrocyclic lactones with a fused cycloproprene ring [Eq. (a)]. This efficient reaction is characterized by high enantiocontrol (up to 98% ee) and chemoselectivity.

Binding multiple phosphodiesters with a polyazacleft

Polyazaclefts designed to bind a phosphoric acid ester with either four or two hydrogen bonds were both found to bind multiple phosphoric acid esters in chloroform.

Concise Formal Total Synthesis of Platensimycin Mediated by a Stereoselective Autoxidation and Hydroxyl Group Directed Conjugative Reduction

The synthesis of 13, an advanced intermediate in the Nicolaou synthesis of platensimycin 1, was made from 9 by autoxidation to give 10, which was stereoselectively reduced providing 12. Finally, dehydration of 12 by heating in DMSO resulted in 13.

Taxane diterpenes 5: Synthesis of the A- and C-rings: An unusual rearrangement of an N-hydroxyimino lactone

Ring A of taxol was synthesized from the bromodiene 5 and acryloyl chloride to give 6, which was resolved by separation of diastereomers 7. Allylic oxidation of 7 gave 8, which on deprotection, esterification and reduction gave 11. Heating 11 followed by reduction and protection gave 13. The C-ring component was made using asymmetric Birch reduction methodology combined with standard functional group manipulations to give 28. Combining 13 and 28 gave 29, which was converted into 33. Thermolysis of 33 did not generate a nitrile oxide but rather ionized to an oxydienyl cation, eventually leading to 34.

STUDIES ON THE SYNTHESIS OF THE INDOLE ALKALOIDS PAUCIFLORINE A AND B

Abstract A double Bischler-Napieralski reaction of the 11-membered ring carbamate 15 gave the homoannular diene 17 in a single step.