Catalytic Asymmetric Total Synthesis of Hedyosumins A, B, and C

Abstract

The first and asymmetric total synthesis of hedyosumins A, B, and C was accomplished in 13-14 steps from simple starting materials. The essential tools that allow us to access the tetracyclic skeleton include an organocatalytic [4 + 3] cycloaddition reaction, an intramolecular aldol condensation, and an intramolecular carboxymercuration/demercuration enabled lactonization. A CBS-catalyzed asymmetric reduction was employed to boost the ee of the synthetic natural products to an excellent level. This synthesis established the absolute configurations of hedyosumins A, B, and C.

Recent Applications of Asymmetric Organocatalytic Methods in Total Synthesis

“…[32] The synthesis highlights the application of two organocatalyzed aldol reactions in the process of obtaining the key intermediates for the total synthesis. First, the cross-aldol reaction between 3-(triisopropylsilyl)propynal (35) and propanal (36) catalyzed by diarylprolinol derivative (R)-3 led to the formation of the optically active aldehyde 37, which was further converted to the key pyran intermediate 40 via several steps of synthetic maneuvers. Next, compound 42 was prepared via a self-aldol reaction of 36 using D-proline (41) as the catalyst.…”

“…[35] In 2016, Sun and co-workers developed an enantioselective total synthesis of hedyosumins A, B, and C (79-81) using an organocatalytic reaction as the key step (Scheme 9). [36] Using catalyst 74, they achieved an organocatalytic enantioselective [4 + 3] cycloaddition between dienal 72 and furan 73 for the synthesis of an optically active tetracyclic skeleton 76, which was further elaborated to afford 79-81 via a multistep sequence (Scheme 9). [36] In 2018, the enantioselective total synthesis of thailanstatins AÀ C (89)(90)92) and spliceostatin D (91) was reported by Nicolaou and co-workers (Scheme 10).…”

“…[36] Using catalyst 74, they achieved an organocatalytic enantioselective [4 + 3] cycloaddition between dienal 72 and furan 73 for the synthesis of an optically active tetracyclic skeleton 76, which was further elaborated to afford 79-81 via a multistep sequence (Scheme 9). [36] In 2018, the enantioselective total synthesis of thailanstatins AÀ C (89)(90)92) and spliceostatin D (91) was reported by Nicolaou and co-workers (Scheme 10). [37] An organocatalytic intramolecular oxa-Michael cyclization of unsaturated aldehyde 82, catalyzed by the chiral catalyst 83, was applied to obtain the optically active dihydropyran 84, which was converted to 87 in a few steps.…”

Ethnopharmacology, phytochemistry and pharmacology of the genus Hedyosmum (Chlorantaceae): A review

“…One of the principal findings of the reported studies is the active natural products, especially bolivianine, isobolivianine and onoseriolide, obtained from species belonging to the Hedyosmum genus. They have been used as starting points for innovative research toward bioinspired synthetic procedures (Yuan et al, 2013;Du et al, 2014;Ardkhean et al, 2016;Fan et al, 2016;Sun et al, 2016;Hugelshofer and Magauer, 2017;Li et al, 2017). Bioinspired approaches play a key role in discovery and constantly provide innovative avenues for studying new active compounds.…”

Synthesis of 1,3-cis-disubstituted sterically encumbered imidazolidinone organocatalysts

“…Since the beginning of the 21th century imidazolidinone-based organocatalysts developed by MacMillan and co-workers, which are easily accessible from amino acids, are widely used in these kinds of reactions [ 13 – 18 ]. More recent examples demonstrate the applicability in various reactions like diastereoselective α-fluorination [ 19 ], total syntheses [ 20 – 21 ], cross-dehydrogenative couplings [ 22 ], selectivity-reversed Friedel–Crafts alkylation [ 23 ] and in combination with photoredox catalysis ( Scheme 1 ) [ 24 ].…”