Synthesen makrocyclischer Lactone durch Ringerweiterung Herstellung von (±)-Phoracantholid I, (±)-Dihydrorecifeiolid und (±)-15-Hexadecanolid

Syntheses of Macrocyclic Lactones by Ring Enlargement Reaction Reaction. Preparation of (±)-Phoracantholide I, (±)-Dihydrorecifeiolide and (±)-15-Hexadecanolide A general procedure for the synthesis of macrocyclic lactones is described. The Michael adducts of 2-nitrocycloalkanones and acrylaldehyde were regiospecifically methylated with CH₃Ti[OCH(CH₃)₂]₃ or (CH₃)₂Ti[OCH(CH₃)₂]₂ at the aldehyde carbonyl group. Treatment of the so-formed alkohols with tetrabutylammonium fluoride gave the lactones enlarged by four ring members. This method was used to synthesize the 10-membered (±)-phoracantolide I ( 11 ), the 12-membered (±)-dihydrorecifeiolide ( 17 ), and (±)-15-hexadecanolide ( 24 ) in 52%, 26.5%, and 58.7% respectively.     

A copper-catalyzed asymmetric oxime propargylation enables the synthesis of the gliovirin tetrahydro-1,2-oxazine core

The bicyclic tetrahydro-1,2-oxazine subunit of gliovirin is synthesized through a diastereoselective copper-catalyzed cyclization of an N-hydroxyamino ester. Oxidative elaboration to the fully functionalized bicycle was achieved through a series of mild transformations. Central to this approach was the development of the first catalytic, enantioselective propargylation of an oxime to furnish a key N-hydroyxamino ester intermediate.

The bicyclic tetrahydro-1,2-oxazine subunit of gliovirin is synthesized through a diastereoselective copper-catalyzed cyclization of an N-hydroxyamino ester.

The fungal secondary metabolites gliovirin (2)¹ and pretrichodermamides A (3)² and E (4)³ are disulfide antibiotics that possess an unusual tetrahydro-1,2-oxazine (THO) core (Scheme 1). In addition to 2–4, several related oxazine natural products have been isolated, including the monothiolated peniciadametizine B (5);⁴ however, these oxazine-containing natural products are rare relative to the biosynthetically related diketopiperazine natural products, hundreds of which have been isolated to date.⁵ In addition to their oxazine cores, 2–4 are unusual in that their disulfide linkages are joined to the carbon framework at C4 and C12, in contrast to the more common epipolythiodiketopiperazines (ETPs) such as gliotoxin (1).⁶ These fungal metabolites are proposed to be formed through thiolation of simple cyclic dipeptides followed by oxidative elaboration of the peripheral functionality.⁷ Perhaps because of the synthetic challenge posed by the combined oxazine and disulfide motifs, there have been no syntheses of gliovirin (2) or the related compounds 3 and 4 to date.Open in a separate windowScheme 1PTP isomerism: gliovirin and related natural products.Whereas there are no syntheses of 2, syntheses of related dihydro-1,2-oxazine (DHO) natural products, including trichodermamide A (6), have been reported by the groups of Joullié,⁸ Zakarian,⁹ and Larionov.¹⁰ These efforts relied upon cycloaddition chemistry or pericyclic rearrangement to install the DHO cores. As part of our larger program targeting the synthesis of polysulfide natural products,^11,12 we envisioned a distinct approach to 2 that would involve late-stage diketopiperazine and disulfide formation, thereby reducing the synthetic challenge to that of preparing key THO 7 (Scheme 2). Oxazine 7 was expected to be accessible from 8avia epoxidation, desaturation, and functional group interconversion.Open in a separate windowScheme 2Retrosynthetic analysis of tetrahydro-1,2-oxazine 7.In a key synthetic step, the bicyclic THO 7 would be constructed by an intramolecular oxidative cyclization of N-hydroxydihydrophenylalanine derivative 10. For the preparation of 10, we considered two approaches: (1) N-oxidation of the corresponding dihydrophenylalanine 9, or (2) initial installation of the N–O bond followed by construction of the cyclohexan-1,3-diene from the alkyne of 11a. Given concerns about potential challenges of N-oxidation in the presence of the sensitive 1,3-cyclohexadiene motif, we elected to pursue a route where 10 would be accessed from α-propargyl N-hydroxyamino acid 11a by an enyne metathesis reaction.Having identified 11a as an intermediate on route to 7, a method to prepare this compound in enantioenriched form was desired. The most direct route to 11a was envisioned to be an enantioselective propargylation of N-siloxyglyoxalate 12 (see Table 1). However, no examples of catalytic asymmetric addition of allyl nor propargyl nucleophiles to similar oxime substrates were found in the literature. The most promising lead was from Hanessian and coworkers, in which an excess of a chiral allylzinc reagent was added to an oxime.¹³ However, this method had not been extended to the corresponding propargylation.Optimization of Cu-catalyzed oxime propargylation^a

Über die Konstitution zweier neuartiger «dimerer» Indolalkaloide Pycnanthin und Pleiomutinin 132. Mitteilung über Alkaloide

The «dimeric» indole alkaloid (+)-pycnanthine ( 2 ) has been isolated, along with (+)-pleiocarpamine, (+)-quebrachamine, (+)-macusine B and an unknown alkaloid D from Pleiocarpa pycnantha (K. SCHUM .) STAPF , var. pycnantha M. PICHON. An investigation of its chemical and spectroscopic properties has led to the determination of structure 2 for this base. Its 6′,7′-dihydro derivative has been shown to be identical with the alkaloid pleiomutinine, previously isolated from Pleiocarpa mutica BENTH .