Stereoselective Monofluoromethylation of Primary and Secondary Alcohols by Using a Fluorocarbon Nucleophile in a Mitsunobu Reaction

Link: ACIEE EarlyView

G. K. Surya Prakash^*, Sujith Chacko, Steevens Alconcel, Timothy Stewart, Thomas Mathew, George A. Olah^*

Loker Hydrocarbon Research Institute and, Department of Chemistry, University of Southern California, University Park, Los Angeles, CA 90089-1661, USA

The following method is very similar to this one, that it demonstrates a strategy to synthesize monofluoromethyl derivative compounds, at least in the purpose of the research. The products are different type as the one cited in the link above are amino fluoro methyl derivatives, but this one here, the method seems to be applicable to primary and secondary alcohols (via Mitsunobu), giving a wider variety of products. The reagent used in both papers is the same one, however (1).

The initial products after the Mitsunobu step show an agreeable inversion of configuration at the former carbinol centers as shown in the table below.

Applicability is general as shown in the table below.

The bis-sulfonyl products could be di-hydrodesulfonated to give the monoflouoromethyl products in good to execellent yields.

This method could be successfully applied to natural compounds such as vitamin D3 and the tetraacetyl glucopyranose as shown in Schemes 2 and 3.

In addition to 1, a different fluoromethylating agent such as 6, possessing appropriate pKa, also smoothly participated in the current Mitsunobu strategy.

CuI-Catalyzed Conjugate Addition of Ethyl Propiolate

Link: ACIEE EarlyView

Shinji Fujimori, Erick M. Carreira*

Laboratorium für Organische Chemie, ETH Zürich, 8093 Zürich, Switzerland

This is a methodology paper on copper (II)-assisted 1,4-alkyl propiolate addition to Meldrum’s acid-derived enonone. The method is general to many Meldrum’s acid derivatives, and the products obtained can certainly be used as valuable building blocks.

The reaction seems to be mild, plus it is run in aqueous media! In achiral Meldrum’s acid derivatives, the results are excellent as seen in Table 1.

The products from this reaction can be elaborated as illustrated below in a hydrogenation.

And when the enone derivatives contained chiral elements in the R group, the reaction occurred stereoselectively in a substrate-controlled fashion.

To demonstrate the usefulness of the products further, the folllowing scheme shows that the products could be subjected through a series of transformations to give valuable chiral building blocks (9a and 9b).

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.