Enantioselective Total Synthesis of (+)-Conicol via Cascade Three-Component Organocatalysis

Enantioselective Total Synthesis of (+)-Conicol via Cascade

Three-Component Organocatalysis

Bor-Cherng Hong, Prakash Kotame, Chih-Wei Tsai, and Ju-Hsiou Liao

DOI: http://dx.doi.org/10.1021/ol902840x

This time some organocatalysis already published last year by a group based in Taiwan. Though not a spectacular paper I liked the first few steps and so reviewed it.

Conicol belongs to the class of meroterpenoids which were isolated from higher plants and recently from marine organisms. And as usually with these marine stuff it exhibits some cytotoxic effects against human cancer cells .

The key steps of the synthesis are a TMS-prolinol catalyzed enantioselective alkylation/Michael addition reaction followed by another Michael addition/aldol condensation to build the backbone of the whole molecule in almost 2 steps.

Additionally these two single pot sequences can be combined to one protocol giving the product in 55% yield with > 99% ee.

Scheme 1:

Scheme 2:

As mentioned above these sequences were combined to one very successful procedure. If you’re interested in the whole story have a look in here: http://dx.doi.org/10.1016/j.tetlet.2008.11.106

With all stereocenters and the carbon skeleton in hand only a few modifications were needed to give (+)-Conicol:

Scheme 3:

A decarbonylation reaction with Wilkinson catalyst was followed by double bond reduction with palladium on charcoal. Interestingly the nitro function is stable under these conditions.

Next the dimethylacetal was cleaved with hydrochloric acid, which results in elimination of the nitro function too, and an old school Wolff Kishner reduction gave Didehydroconicol.

Going on from the key intermediate the acetal was cleaved under milder conditions without causing elimination of the nitro function. This was done with DABCO, the aldehyde reduced, acetylated and eliminated under Birch conditions to give (+)-Conicol in 5% overall yield over 9 steps in the longest linear sequence.

Scheme 4:

I didn’t manage to publish this in january, sorry for that, but I’m just on the next paper so maybe I finish 3 reviews in February to keep my average of 2 reviews per month.

Total Synthesis of (-)-Mersicarpine

Rie Nakajima, Tsuyoshi Ogino, Satoshi Yokoshima, and Tohru Fukuyama

DOI: http://dx.doi.org/10.1021/ja9103233

Happy new year everybody out there…

This time I will present to you a very short synthesis from the Fukuyama group which took only about 12 steps from cyclohexanone to the product. No special biological profile or so was mentioned but the need for a stereoselective total synthesis drove the group on.

Key steps are a Eschenmoser-Tanabe fragmentation and an accidentally found cyclization/oxidation reaction.

Retro:

I will not go into detail with the retro because it will be explained in the next 3 schemes but I present it for the sake of completeness.

Blue intermediate:

Starting from cheap cyclohexanone forming an imine which was alkylated then changed into a chiral imine with phenylethylamine which in turn undergoes an asymmetric addition on methyl acrylate. Oxidation with IBX in DMSO was followed by epoxidation with aqueous peroxide yielding the intermediate ready for the Eschenmoser-Tanabe fragmentation. This posed some problems to the authors but could be solved first by using a semicarbazide which was oxidized secondly with LTA to give the blue intermediate shown.

Red intermediate:

Aldehyde reduction and Sonogashira coupling of the alkyne was followed by a nice gold catalyzed indole formation. Diazo coupling with phenyldiazonium chloride yields the azo bridged indole which cyclized with the ester after deprotonation with NaH. Subsequent in situ mesylation of the alcohol furnished the last intermediate ready for the key step.

Key step:

After several attempts to optimize the conditions, this high yielding one pot procedure was developed giving Mersicarpine in almost quantitative yield.

The first step is the reduction of the azo bridge to the aminoindole. This undergoes a S_N2 displacement of the mesylate forming the last ring needed. After tautomerization an autoxidation occurred which formed a hydroperoxide which was reduced with dimethylsulfide to yield the natural product.

Yeah… very short but elegant synthesis. Any suggestions or namely a good idea why the oxidation of the aminoindole occurres spontaneously? I worked with some aminoindoles too but never observed something like that…

Again I’m very busy but maybe I manage to review the incredible paper from the Fürstner group which came up last year.

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

DOI: http://dx.doi.org/10.1021/ol902373m

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.

Retro:

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 S_N2 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?