Fluoroorganic Chemistry
Organoboranes for Fluoroorganic Chemistry
Prominent among the organoborane reagents and reactions is our discovery and development of the commercially successful asymmetric reducing agent B-chlorodiisopinocampheylborane (Aldrich: DIP-Chloride™), a key reagent in the production of the Merck anti-asthmatic drug, Singular®. We also achieved the first asymmetric synthesis of the Eli Lilly anti-depressant Fluoxetine hydrochloride (Prozac), although commercial Prozac is racemic. DIP-Chloride™ was effectively utilized to achieve high enantioselectivity for the asymmetric reduction of perfluoroalkyl ketones. This reaction enabled us to probe the stereo-electronic requirements of a trifluoromethyl group, thus addressing a fundamental problem that persisted in fluoro-organic chemistry for over 3 decades. Our reagent allowed the first non-enzymatic preparation of 3,3,3-trifluoropropene oxide (TFPO), an extremely important fluorinated synthon, in excellent (>96%) ee. A variety of fluorinated 2o-alcohols were prepared in high ee, all of which are being utilized in materials chemistry. The ready convertability of DIP-Chloride™ to the corresponding allylboranes opened opportunities in total synthesis, by providing fluorinated homoallylic alcohols in near quantitative optical purity and permitted facile conversion of these synthons to g-, and d-lactones, fluoro-analogs of natural products and sugars.
Markovnikov Hydroboration
It is known that hydration via hydroboration-oxidation proceeds in an anti-Markovnikov manner. However, the hydroboration of perfluoroethylenes follow a different course. Depending on the reagent used, one can achieve either Markovnikov or anti-Markovnikov hydration. The intermediate 1o- and 2o-fluoroalkylboranes have been harnessed for the preparation of a broad range of chiral fluoroorganic molecules, such as alcohols, amines, amino acids, and homologated products, fluoroalkyl-substituted alkenes, acetylenes, nitriles, esters, etc.
Fluoroallylboration
The allylborane chemistry was empowered by the introduction of a series of fluorinated allyl- and crotylboranes via hydroboration of 1-trifluoromethylallene and homologation of 2-lithio-1,1-difluoroethylene. The E-reagent was introduced via a metathesis reaction. This project granted a wonderful opportunity to selectively add fluorines to the awesome power of organic synthesis.
The simplicity of our protocols is highlighted in the development of novel functionalized allylboronates from 2,2,2-trifluoroethanol via homologation. Camphor-derived chiral auxiliaries provide the chiral functionalized allylboronate capable of transferring chirality quantitiatively. A variety of difluorinated synthons were realized, such as syn-and anti-1,3-diols and b-hydroxy ketones, which were stereoselectively transformed to chiral g,g-difluoro-d-pyrones. Unlike hydrocarbon analogs, the fascinating fluorine provides identical stereoselectivity for HWE and Still-Gennari olefinations.
Ester Aldol Chemistry
A significant breakthrough in organic chemistry is our recent development of an efficient reagent-controlled asymmetric diastereo- and enantioselective aldol reaction of ester enolates providing either syn-or anti-a-alkyl-b-hydroxy esters in high enantioselectivity. This was extended for the synthesis of 6-CF3-dictyostatin (Fluctyostatin) via the first boron-mediated enolization-aldolization of 3,3,3-trifluoromethylpropionates. Bis-exo-bicyclo[2.2.1]-heptan-2-ylboron triflate (Nrb2BOTf) is a new and superior reagent for diastereospecific enolization introduced by our group.
PVR Group Chiral Auxiliaries for Asymmetric Synthesis
In order to achieve high diastereo- and enantioselectivity for our fluoro-ester aldol reaction, we designed and developed a series of new chiral auxiliaries, (+)- and (-)-2-(arylmethoxy)isopinocampheols. These chiral auxiliaries are being made commercially available through Aldrich and we expect that it will be exploited for several asymmetric transformations.
Using one of these auxiliaries, (-)-2-(1-naphthylmethoxy)isopinocampheol, we have achieved >99% diastereoselectivity and >99% enantioselectivity via a double diastereoselective fluoroester aldol reaction. The sub-unit needed to complete the total synthesis of Fluctyostatin was achieved using this strategy. We are also synthesizing 6-aryldictyostatins using a similar protocol.
The most recent among our pioneering contributions to fluoroorganic chemistry is the boron-mediated achiral and chiral enolization-aldolization of 3,3,3-trifluoromethylpropionates. In this approach a novel reagent, bis-exo-bicyclo[2.2.1]-heptan-2-ylboron triflate, was introduced for diastereospecific enolization. For achieving high enantioselectivity, we developed the Purdue chiral auxiliary, 2-(1-naphthyl-methoxy)isopinocampheol. This methodology was applied to prepare the C1-C9 subunit of C6-CF3-dictyostatin, thus paving the path for the preparation of tirfluoromethyl analogs of wide variety bio-active natural products.
Since many additional approaches are needed for successful fluoro-drug discovery, the integration of a variety of organoborane methodologies will be the harbinger of a new era in medicine.
Novel Trifluorovinylation Reagents
Recent literature has seen an increase in nucleophilic, electrophilic and radical trifluoromethylations, but a corresponding vinylogous reaction (trifluoromethylvinylation) to prepare CF3 olefins has trailed. The reactions leading to vinylogous trifluoromethylations resulting in the formation of both E- and Z-trilfuoromethylstyrenes have been developed. A safer HF-free protocol for the synthesis of Potassium (3,3,3-trifluroprop-1-yn-1-yl)trifluoroborate from HFC-245a of has been developed.
We then developed a unique semi-hydrogenation of the above alkyne to either (Z) or (E)-alkene in high isomeric purity (>98%).
Suzuki coupling with (Z) and (E)-CF3-vinyltrifluroborates and haloarenes resulted in the corresponding (Z) or (E)-β-trifluoromethylstyrenes in excellent isomeric purity and good yields.
A non-etching protocol to prepare trifluoroborates without using fluoro-inorganic potassium salts is in progress and will also be presented.
Aldol Chemistry of Carboxylic Acids
The preparation of β-hydroxy carbonyls via boron-mediated aldol reaction of a variety of carbonyl class has been well studied and utilized in organic synthesis for over three decades. Nonetheless, an important class of carbonyl compounds that has not received its due attention is carboxylic acids. Indeed, while the aldol reaction of dimagnesium enediolates of carboxylic acids, the Ivanov reaction, and the corresponding dilithium and disilicon enediolates have been well explored, the diboron enediolates has only been sparingly reported.
We have carried out a systematic study of the boron-mediated aldol reaction of carboxylic acids and developed this as a potentially useful arsenal for organic chemist’s use.
This reaction is extremely diastereolselective for 3,3,3-trifluoropropanoic acids.The product a-trifluoromethyl-b-hydroxy acids can be readily lactonized to the corresponding b-lactones, adding a powerful member to this class of compounds. The rich b-lactone chemistry is being exploited for organic synthesis in our labs.
Simple Trifluoromethylolefin Synthesis
A very useful reaction that we have developed is a ready synthesis of trifluoromethylalkenes.
The aldol reaction of a ketone and subsequent transformation provides a ready synthesis of trisubstituted olefins.