eq.1
The National Science Foundation's (NSF) Tokyo Office periodically receives and disseminates reports on research developments in Japan that are related to the Foundation's mission. NSF-sponsored researchers currently working in Japan prepare many of these reports. These reports present information for use by NSF program managers and policy makers; they are not statements of NSF policy.
Mr. Brendan P. Orner, a Ph.D. student in the Department of Chemistry at Yale University, prepared the following report. Mr. Orner was a participant in the 1999 Summer Institute sponsored in the United States by NSF/NIH/USDA and the Science and Technology Agency and Japan Science and Technology Corporation in Japan. Professor Kazuhiko Saigo of the Department of Integrated Biosciences at University of Tokyo hosted Mr. Orner. Mr. Orner can be reached via email at: brendan.orner@yale.edu
Background
Larock (Synlett, 1990, 531.) has found that hetero- and carboannulations can be mediated by palladium (eq. 1). Presumably this reaction proceeds by oxidative addition into the C-I
eq.1bond, followed by addition across the olefin and subsequent ring opening to generate a pi-allyl species. This complex is trapped by intramolecular nucleophillic attack. The initial Heck-type process/ring opening attracted us to the possibilities of exploring additional applications to other reactions. Because an asymmetric carbon is generated we were curious to see if we could generate stereo centers in these achiral substrates.
The Saigo lab has recently utilized the chiral ligand, 8, to facilitate enantioselective allylic amination reactions (J. Org. Chem., 1997, 62, 5508). We hoped that this proven
ligand could be applied to other palladium catalyzed reactions, namely the Heck reaction.
Other laboratories have attempted the asymmetric Heck reaction (review: J. Org Met. Chem., 1999, 576, 1, J. Org Met. Chem., 1999, 576, 16), however, most examples are intramolecular (for example: J. Am Chem. Soc., 1996, 118, 10766, J. Am. Chem. Soc., 1977, 99, 6066.). The intermolecular cases involve substrates containing medium sized rings (Chem Commun., 1999, 1811, Synth., 1997, 1338), and although cycloalkenes have been employed, cyclic enolethers have been shown to give excellent regioselectivity.
We therefore decided to attempt the acyclic enatioselective Heck reaction of vinylic cyclopropane, enolethers using our chiral ligand, 8.
Activities and Findings
II-1. Major Research Activities
The major research activities involved synthesizing precursors to substrates for Heck reactions of vinylic cyclopropanes and synthesizing the chiral ligand used to induce asymmetry of these reactions. We were interested in developing a novel acyclic version of the asymmetric Heck involving ring expansion. However were unsure how electronics and sterics of the substrate would determine the product mixture composition (i.e. in what direction, if any, the cyclopropane would open). We therefore decided to synthesize the substrates in a way that would easily allow us to modify substitution in order to explore the limits and scope of this reaction. (Scheme 1)
The previously published synthesis of the chiral ligand was used with minor modifications. (J. Org. Chem., 1997, 62, 5508, Tet. Assym., 1996, 7, 2939.) (Scheme 2) The indanone 1 was formed through the Friedel-Crafts acylation/1,4 alkylation of the acyl chloride of propylideneacetic acid and benzene. Indanone 1 was treated with butyl nitrite under acidic conditions to yield oxime 5. The ketone was reduced and the resulting hydroxyl and the oxime were acylated to give diacetate 3. The oxime was reduced and the acetates were deprotected upon treatment with borane-THF complex which proceeded with cis selectivity to generate amino alcohol, 4-rac. The racemic mixture was resolved by diastereomeric salt formation with (S)-mandelic acid and subsequent recrystalization from ethanol to give salt, 4-(+). In order to determine the efficiency of the resolution, the salt was acetylated with acetic anhydride and the resulting bisacetate was determined to be the 1R, 2S isomer of 7 by chiral HPLC. The ammonium salt was neutralized to the free base with potassium hydroxide and was then condensed with o-flourobenzonitrile to generate the oxazoline 6. Finally, treatment with Ph2PK gave the ligand, 8.
The synthesis of substrates (Scheme3) was begun by moderately efficient cyclopropanation of methylcarbene with cinnamyl alcohol to yield cyclopropane, 9. The primary alcohol was easily oxidized to the aldehyde, 10, under Swern conditions. Subsequently the Wittig reagent was prepared by an SN2 reaction of triphenylphosphine on various alkoxychlororomethanes in benzene. This reaction proved to be problematic in that, surprisingly, purification of the phosphonium, 11, from the excess triphenylphosphine (required to drive the reaction to completion) was nearly impossible. The phosphonium, 11, either purified by repeated PTLC or partially crude, was deprotonated by phenyllithium in situ and the subsequent yield 12 was reacted with the cyclopropane aldehyde, 10, to aford olefins, 13a and 13b, which, unfortunately, coeluted with triphenylphosphine (carried on from the previous step) upon chromatography. Many conditions were tried, however, cis:trans ratios better than 1.5-2:1 were not observed. Because the generation of the Wittig reagent and the Wittig reaction were problematic, Horner-Emmons olefination conditions are currently being investigated for the selective synthesis of the desired trans olefin, 13a.
II-2. Major Research Findings
This research is still ongoing in the laboratory of our collaborators. They are trying to improve the cis:trans ratio of the olefination and will then attempt the asymmetric Heck reactions. If the reaction proves successful, it will lead to a facial route to synthons useful for academic and industrial organic synthesis and may be applicable to industrial scale process chemistry.