Synthesis of Natural (−)-Antrocin and Its Enantiomer via Stereoselective Aldol Reaction

Abstract

The total synthesis of (−)-antrocin and its enantiomer are presented. Antrocin (−)-1 is an important natural product which acts as an antiproliferative agent in a metastatic breast cancer cell line (IC50: 0.6 μM). The key features of this synthesis are: (a) selective anti-addition of trimethylsilyl cyanide (TMSCN) to α,β-unsaturated ketone; (b) resolution of (±)-7 using chiral auxiliary L-dimethyl tartrate through formation of cyclic ketal diastereomers followed by simple column chromatography separation and acid hydrolysis; (c) substrate-controlled stereoselective aldol condensation of (+)-12 with monomeric formaldehyde and pyridinium chlorochromate (PCC) oxidation for synthesis of essential lactone core in (−)-14; and (d) non-basic Lombardo olefination of the carbonyl at the final step to yield (−)-antrocin. In addition, (+)-9 cyclic ketal diastereomer was converted to (+)-antrocin with similar reaction sequences.

Kinetic vs. thermodynamic control of β-functionalized cyclic ketones: a theoretical investigation of regioselective formation of enolates

“…More energetic conditions showed instead a mixture of enolates in accordance with their thermodynamic stability, as reported in the literature (Scheme 1c). 3,15 In light of this evidence, the synthesis of natural (−)-antrocin via regioselective aldol reaction, recently published by Angamuthu et al, 16 captured our attention and fed our curiosity. The authors reported a kinetic-controlled aldol addition on cyclic ketone 4, functionalized in the β-position with an aldehyde group, as a key step for the regio-and stereo-selective synthesis of lactol (+)-II (Scheme S5 †).…”

“…Moreover, the authors reported that the same cyclic substrate with a cyano group in the β-position (ketone 5) gave "kinetic product" 5b as main enolate under same conditions with a regioselectivity of 70 : 30 over the "thermodynamic product" 5a (Scheme S6 †). 16 Unfortunately, no explanations were given by the authors to elucidate the reverse selectivity and unexpected reactivity under the same kinetic conditions (Schemes S5 and S7 †). In recent years, theoretical studies on the deprotonation of symmetrical and unsymmetrical ketones have aroused great interest, 17 but most of them are focused on α-substituted ketones 18,19 and unsubstituted ketones.…”

“…These bases have been taken into account as models to investigate the effect of counter cations (Li + or K + ) on the enolate formation process and, no less importantly, to try and give reasonable explanations for the unusual reactivity reported by Angamuthu et al for cyclic ketones 4 and 5 . 16…”

Natural and Synthetic Lactones Possessing Antitumor Activities

“…Recently, the total synthesis of natural (−)-antrocin ( 187 ) and its enantiomer has been reported [ 176 ]. Despite remarkable antitumor activities, the difficulties to prepare (−)-antrocin ( 187 ) triggered researchers to find a synthetic alternative.…”

“…Next, α -hydroxymethylation of (+)- 301 by reacting with lithium enolate with gaseous formaldehyde in THF yielded a single lactol (+)- 302 . The authors proposed that this reaction is controlled kinetically [ 176 ]. Lactol ( 302 ) was then oxidized with silica-supported pyridinium chlorochromate (PCC) to give lactone (−)- 303 .…”