Total Synthesis and Stereochemistry of Uncialamycin

Link: ACIEE EarlyView

K. C. Nicolaou, Hongjun Zhang, Jason S. Chen, James Crawford, Laxman Dasunoori

¹Department of Chemistry and, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
²Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA

A new tot synth of Uncialamycin by Nicolaou. This is a natural occurring enediyne. Because the stereochemistry of C26 was unknown, both diastereomers as shown were synthesized. The retrosyn led back to simpler fragments 2, 3, and 4.

The following scheme illustrates the route to fragment 2. The key transformation was the two-step Friedlander quinoline synthesis (7 to 9).

Then fragment 2 was used in the following sequence. The key steps in the sequence involved installation of enediyne fragment 3 to give 11, the closure of the macrocycle to give 15, and the Hauser annulation in the last step to give 1a from 16.

In this case, it was found that the final product’s spectrum (1a) did not match the reported value. And therefore, the other isomer was synthesized. This was easily done using fragment 12 through oxidation-reduction sequence to give 18 with the opposite stereochemistry at C26. Sequence in Scheme 3 was then repeated on this fragment.

And 1b was found to match spectrum of the natural isomer. This natural compound was found to be stable as a solid and as solutions in a variety of solvents. But in presence of dray HCl in CH2Cl2 solution at rt, it rapidly converts to hexacyclic 19 through a cascade of Bergman cycloaromatization reaction. This cascade of reactions is believed to be responsible mode of action in damaging DNA and killing cells.

Synthesis of Kaempferitrin

Link: JOC ASAP

Sameer Urgaonkar and Jared T. Shaw*

Chemical Biology Program, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02142

This is a paper presenting a synthesis of this bisglycosilated molecule called Kaempferitrin:

The thing that caught my attention was the clever use of internal hydrogen-bonding to regioselectively putting protecting group on and taking protecting group off. For example, in the synthesis of 7, one of the ortho-OH group to the carbonyl did not react with MOMCl. And again in the transformation of 8 to 9, only the OH group ortho to the carbonyl was deprotected indicating the probable participation of that carbonyl.

And in the final step from 10 to 11, the Ts group was used strategically so that the di-deprotection of OMOM and OMe was possible without affecting the OTs group. I guess this last point is not as significant as the earlier protecting group manipulation steps.

Ether-Directed, Stereoselective Aza-Claisen Rearrangements: Synthesis of the Piperidine Alkaloid, alpha-Conhydrine

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol070424z.html

Andrew G. Jamieson and Andrew Sutherland*

WestCHEM, Department of Chemistry, The Joseph Black Building, University of Glasgow, Glasgow G12 8QQ, U.K.

Interesting syntheses using Pd-Catalyzed aza-Claisen rearrangement as a key reaction in building the SM.

The last two schemes that interest me: