Highly Efficient Formal Synthesis of Cephalotaxine, Using the Stevens Rearrangement−Acid Lactonization Sequence as A Key Transformation

Abstract

Cephalotaxine (1), the major alkaloid isolated from Cephalotaxus species, has attracted considerable attention due to the promising antitumor activity of several of its derivatives and its unique structural features. Herein we describe a highly efficient formal synthesis of 1 employing the [2,3]-Stevens rearrangement-acid lactonization sequence as a key transformation from readily available (3,4-dimethoxyphenyl)acetic acid, methyl prolinate, and allyl bromide.

Formal Total Synthesis of (±)‐Strictamine by [2,3]‐Sigmatropic Stevens Rearrangements

“…[41][42][43] Although the Stevens [2,3]-rearrangement is av ery powerful transformation,o nly af ew applications in natural product synthesis are reported to date. [44][45][46][47][48] Three examples are summarized in Scheme 2. Soheili and Ta mbar achieved the total synthesis of (AE)-amathaspiramide F( 19)b yu sing aS tevens [2,3]rearrangement as the key step.…”

“…Although the Stevens [2,3]‐rearrangement is a very powerful transformation, only a few applications in natural product synthesis are reported to date . Three examples are summarized in Scheme .…”

Formal Synthesis of ent-Cephalotaxine Using a One-Pot Parham–Aldol Sequence

“…This choice of strategy was also backed up by a very informative formal synthesis of rac-cephalotaxine (rac-1) by the Liu group, applying a related [2,3]-Stevens rearrangement. 11 The campaign was started by optimizing the proposed [2,3]-Stevens rearrangement of N-allyl Lprolineamide 12, readily available by allylating commercially available prolineamide 13 (Scheme 1).…”

Catalytic Asymmetric Synthesis of α‐Quaternary Proline Derivatives by 1,3‐Dipolar Cycloaddition of α‐Silylimines

“…In view of the good reactivity profile of this catalyst system, we next turned our attention to the challenging cyclic silylimines. Pleasingly, the reaction with the a-silylimine 1 q proceeded smoothly, thus leading to the pyrrolidine spirolactone [16] 11 with excellent yield and complete diastereo-and enantioselectivity [Scheme 2, Eq. (2)].…”

“…The stereochemical and configurational assignment of 3 g was unequivocally established by X-ray diffraction analysis. [15] In contrast, no cycloaddition product was isolated from the sterically more demanding ortho-substituted aromatic silylimines 1 m and 1 n (entries 12 and 13). Finally, the unsubstituted silylimine 1 p, derived from ethyl glyoxalate, was also a suitable substrate, albeit proceeding with a lower enantioselectivity (entry 14).…”