Asymmetric Construction of Rings A-D of Daphnicyclidin-Type Alkaloids

Asymmetric Construction of Rings A-D of Daphnicyclidin-Type Alkaloids

Travis B. Dunn, J. Michael Ellis, Christiane C. Kofink, James R. Manning, and Larry E. Overman


It’s finished… took me some weeks to complete this review but here it is: a sweet “towards”-total synthesis from the Overman group.

The compounds to be made are Daphnicyclidin A – D whose biological profile is poorly studied yet.

The crude extracts of the plant are used in Chinese folk medicine… so some biological effect could be expected.


The paper skips the last 2 stages which I painted in grey so a full account could be expected in the near future.

I think the retro does not need some comment, questions should being answered in the following schemes… so let’ get started.

Blue fragment:

First a nice DA reaction developed by the MacMillan group formed the cyclohexene carbaldehyde was followed by a stereoselective methylation under conditions described by Woodward. TBDPS protection, Saegusa-like oxidation and TBS enol ether formation completes the first part in overall great yield and e.r..

Red fragment:

Hydroxybenzamide was oxidised with periodate to give in situ nitrosocarbonylbenzene which undergoes a hetero-DA in acceptable yield and diastereoselectivity. The crude mixture was used in the next step, a Mo(CO)6 induced cleavage of the N-O bond and deprotection. to yield the cyclohexenone shown. Conjugate addition of DMPS-lithium and epimerization of the benzoylamide was followed by de-benzoylation/reduction, alkylation and Swern oxidation to give the red fragment ready for the crucial aza-Cope/Mannich-reaction sequence developed by Overman some years ago.

Green fragment:

After some efforts to tune the reaction conditions for the introduction of the side chain, a premixed solution of the ketone with CeCl3 and LiCl was treated with the iodie and t-BuLi giving the alcohol in good yield. Some silver nitrate then induced the key transformation, the aza-Cope-Mannich reaction, forming 2 of the 6 rings required.

2 different approaches were employed to form the fused pyrrolidine rings which will be presented in 2 schemes:

Scheme 1

The first approach starts with TBDPS deprotection, mesylation of the delivered alcohol, which directly undergoes SN2 displacement, and double debenzylation. The free alcohol was tosylated, followed by Grignard addition of allylmagnesium chloride on the ketone. Treatment of the tosylate ester with the p-nitrophenyl selenide anion and subsequent oxidation with mCPBA yielded the required terminal bis-olefin. Grubbs II then did the job and closed the fourth ring ready for further transformations.

Scheme 2

A Grignard addition under Lewis acid conditions starts this sequence off. Grubbs II closed again the seven membered ring in excellent yield. Alcohol transposition with thionyl chloride and DMP oxidation (if I remember right CrO3 should do the same job in one step?) gave the α-β-unsatured ketone. TBDPS deprotection and mesylation/in situ ring closing yielded a structure similar to the one in the scheme before.

Yeah, I really appreciate the work from Overman’s groups. He’s really one of the best chemists alive. What do you think?


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