Unconventional application of the Mitsunobu reaction: Selective flavonolignan dehydration yielding hydnocarpins

Abstract

SummaryVarious Mitsunobu conditions were investigated for a series of flavonolignans (silybin A, silybin B, isosilybin A, and silychristin A) to achieve either selective esterification in position C-23 or dehydration in a one-pot reaction yielding the biologically important enantiomers of hydnocarpin D, hydnocarpin and isohydnocarpin, respectively. This represents the only one-pot semi-synthetic method to access these flavonolignans in high yields.

Inhibitory effect of hydnocarpin D on T-cell acute lymphoblastic leukemia via induction of autophagy-dependent ferroptosis

“…But unlike silybins that can be completely synthesized, 36 hydnocarpin-type flavonolignans are not synthetically available, 8 which largely hindered their scientific study. Our previous finding of converting silibinin to HD under Mitsunobu reaction condition lay the foundation for highly effective and convenient preparation of HD, 16 which shall greatly facilitate the scientific research and clinical application of HD.…”

“…It can either promote or inhibit cell growth and survival, depending on the context. 15 Silibinin, a well-studied flavonolignan isolated from milk thistle seeds with structural similarity as that of HD, 16 is reported to possess a significant anti-tumor efficacy in a variety of cancer models by induction of cytotoxic autophagy. 6 However, whether HD is equally capable of inducing autophagy in T-ALL and its underlying mechanisms are yet to be clarified.…”

Chirality Matters: Biological Activity of Optically Pure Silybin and Its Congeners

“…Here, the use of optically pure flavonolignans is essential to obtain particular optically active hydnocarpins, which retain the C-10,11-configuration from the parental molecules; the chiral centers at C-2,3 are abolished by a new double bond. Dehydration of the respective flavonolignans under Mitsunobu conditions (Figure 6) gave optically pure hydnocarpin isomers, e.g., (10R,11R)-hydnocarpine from isosilybin A, (10R,11R)-hydnocarpin D from silybin A, (10S,11S)-hydnocarpin D from silybin B, and isohydnocarpin from silychristin A [89]. An alternative four-step reaction sequence to obtain the respective hydnocarpins from optically pure flavonolignans was performed by Vimberg et al [90].…”

Stereoinvertive Deoxyamination of trans-2-Aminocyclohexanol Using Bose–Mitsunobu Azidation and Staudinger Reaction for the Stereoselective Synthesis of Edoxaban

“…Besides epi -7 , aziridine 16 , generated by cyclization from the nitrogen atom of carbamate, was observed with an area ratio of 18.2% to 7 as a byproduct, suggesting strong neighboring group participation even at 25 °C . Also, olefin 17 , generated by E2 elimination on the carbocyclic ring, was also observed with an area ratio of 28.5% to 7 . The reaction proceeded smoothly in a wide variety of solvents (entries 2–7).…”