Total Synthesis of Aeruginosin 98B

Abstract

The first total synthesis of aeruginosin 98B (1) was accomplished. The key step includes a highly diastereoselective Pd-catalyzed intramolecular asymmetric allylic alkylation (AAA) reaction of a diastereomeric mixture of allylic carbonates, which is enabled by the use of racemic phosphine ligand L1.

Divergent Synthesis of Aeruginosins Based on a C(sp3)H Activation Strategy

“…In parallel, we synthesized the two C‐termini required for aeruginosins 1 a – d (Scheme ). For the C‐terminus of aeruginosins 98A–C ( 1 b – d ), an optimized two‐step sequence was applied, as described by Trost and co‐workers8 and afforded Cbz‐protected agmatine 3 a in quantitative overall yield 28…”

“…After hydrolysis of the methyl ester of the Choi core, the agmatine fragment 3 a was coupled to the resulting carboxylic acids. The free hydroxy group was then sulfated using the SO 3 ⋅ pyridine complex as previously described (compounds 44 a – c ) 8. In the case of compound 44 a , the final hydrogenolysis was performed using H 2 (1 bar) and Pd(OH) 2 /C as above for 1 a , thereby furnishing aeruginosin 98B ( 1 c ) with 85 % yield.…”

“…These Michael addition based strategies all furnished a mixture of diastereoisomers, which required an additional equilibration step to obtain the desired stereoisomer. In their synthesis of aeruginosin 98B ( 1 c ), Trost and co‐workers, employed a different strategy, based on an intramolecular asymmetric Tsuji–Trost reaction, which directly led to a hexahydroindole intermediate possessing the required configuration 8. In light of these precedents,9 we envisioned that our recently developed intramolecular palladium(0)‐catalyzed C(sp 3 )H alkenylation10, 11 would allow access to compound 2 in a straightforward and scalable manner, thereby enabling the collective synthesis of aeruginosins.…”

“…[7] These Michael addition based strategies all furnished am ixture of diastereoisomers, which required an additional equilibration step to obtain the desired stereoisomer.I nt heir synthesis of aeruginosin 98B (1c), Trost and co-workers,e mployed ad ifferent strategy,b ased on an intramolecular asymmetricT suji-Trost reaction, whichd irectly led to ah exahydroindole intermediate possessing the required configuration. [8] In light of these precedents, [9] we envisioned that our recently developed intramolecular palladium(0)-catalyzed C(sp 3 )ÀHa lkenylation [10,11] would allow access to compound 2 in as traightforward and scalablem anner,t hereby enabling the collective synthesis of aeruginosins. The required bromocyclohexene precursor 6 should be accessible from abundant l-alaninol 10 in af ew steps only.I no rder to access Hpla fragments 5,w hich may include potentially labile halogen atoms,i nastraightforward manner,adivergent approach from ac ommon precursor would be ideal.…”

7.07 α-Oxygenation of Carbonyl Compounds

“…18 Since osmium tetroxide is expensive and very toxic, alternatives to this catalyst system have been sought, 19 and dihydroxylation of a,b-unsaturated carbonyl compounds can also be performed with permanganate ions or ruthenium tetroxide. 20 Permanganate has a high oxidation potential and its use can easily lead to overoxidations or other side reactions.…”