Shapeshifting natural product

John Porco and co-workers reported in JACS on the synthesis of a shapeshifting natural product, secalonic acid A. When I think of shapeshifting molecules, I think of Jeffrey Bode’s work with unnatural compounds, but I did not realize that natural products are also known to shape shift.

JACS paper

Enhancing water solubility of a drug (triptolide)

Gunda Georg and co-workers at the University of Minnesota reported in the Journal of Medicinal Chemistry on the addition of a phosphonooxymethyl group onto triptolide to increase its water solubility by greater than 3,580 times. (slight mistake: Scheme 2 in the paper has the use of benzoyl peroxide shown as “Bn2O2” when it should be “Bz2O2” – Bn2O2 would be benzyl peroxide). Another interesting point from this paper is that this natural product has multiple modes of action where it can covalently attach to proteins (XPB, xeroderma pigmentosum B) or non-covalently (DCTPP1, dCTP pyrophosphatase). Other modified attempts to form soluble prodrugs of this natural product (e.g. carboxylic acid, amino acid esters) resulted in difficult removal of the prodrug group.

J. Med. Chem. paper

PhD Movie?

I had no idea that this movie existed until I saw an ad for it this morning at the elevator. Apparently there is a PhD Movie 1 and now a sequel. At first I thought to myself how strange that a group of grad students found the time to make a movie…but it is an actual movie and looking into the details, it looks like the actors are also real Caltech grad students.

FtmOx1 forms the endoperoxide in verruculogen

Here’s a great Nature paper from a three lab collaboration (Lixin Zhang lab at Carnegie Mellon University, Pinghua Liu lab at Boston University, and Yan Jessie Zhang lab at UT Austin) that characterized the enzyme that forms the endoperoxide-containing natural product, verruculogen. The enzyme is an alpha-ketoglutarate dependent iron containing enzyme.

 

What is interesting about this enzyme is that it forms a “Compound I” species (iron oxo complex), which in turn forms a tyrosine radical within the enzyme, and this tyrosine radical is what abstracts the C-H hydrogen in the starting material, fumitremorgin B. The resulting allylic radical comes together with a molecule of oxygen that in turn cyclizes to form an endoperoxide-containing radical intermediate. This radical intermediate abstracts the tyrosine hydrogen atom to reform a tyrosine radical and verruculogen.

The process of the iron-oxo intermediate abstracting a hydrogen atom from tyrosine reminds me of the way cyclooxygenase enzymes (COX1 and COX2 enzymes) work to form the endoperoxide, prostaglandin H2, from arachidonic acid. Furthermore, if you recall Michael Green’s work published in Science last year, there was a cytochrome P450 enzyme that also removes a hydrogen atom from a nearby tyrosine residue to form a tyrosine radical.

 

Nature paper

JOC papers of interest 11/24/2015

James White and co-workers reported on the synthesis of Huperzine A.

Christopher Marvin and co-workers from Hendrix College reported in JOC on the synthesis of tetrabenazine through a photoredox reaction to afford the piperidone moiety.

Young-Ger Suh and co-workers from Seoul National University reported on the synthesis of galiellalactone.

Ronaldo Pilli and co-workers from  Universidad Estadualde Campinas have reported on the synthesis of cryptomoscatone E3.

Scott Denmark and colleague reported on an asymmetrice 2,3-Wittig rearrangement.

ACIE Journals of Interest 11/24/2015

Hao Xu’s lab in University of Georgia have reported on an iron-catalyzed diazidation of olefins.

Dorian Didier’s lab from LMU Munich reported on an interesting one-pot reaction.

Xiaoguang Lei’s lab from Peking University reported on the structural revision of aspergillomarasmine A.

Kilian Muniz’s lab from ICIQ reported on a hypervalent iodine approach to form 1,2-diacetates from olefins, asymmetrically.

Aaron Aponick and colleague have reported in ACIE on the synthesis of martinellic acid.

 

ACIE paper

Which came first?

Here’s a case of which came first the chicken or the egg…(the submission date hints something)…two JACS methodology papers came out on a [3+2] reaction and they acknowledge each other in both papers.

 

JACS paper 1

JACS paper 2

Gymnocin A synthesis

Yuji Mori and co-workers from Meiji University have reported in JACS on the synthesis of gymnocin A – it’s another one of those monster polycyclic ethers.

JACS paper

Cascade cyclization

Hiroaki Sasai and co-workers at Osaka University have reported in ACIE on a domino reaction involving the coupling between an allenoate ester and dienones.

ACIE paper