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During the course of the first year of funding an efficient synthesis of substrate 5 was achieved (Scheme 1). Efforts to cyclize 5 and related anologues continue, though attempts to promote the desired cyclization via nucleophilic catalysis have not resulted in the formation of bicyclic β-lactams.  Evidence exists for the initial attack of the nucleophile into the isocyanate, however the key conjugate addition step has not taken place. 

Stoichiometric alkoxides can promote cyclization.  Treating 5 with potassium tert-butoxide led to the formation of 6a in 35% yield and using potassium benzyloxide gave 6b in 19% yield (Scheme 2).  Unfortunately, mass balances have been problematic and possible polymerization pathways are likely culprits.  Interestingly, we have discovered that acyclic carbamates form in high yield using lithium alkoxides (rather than potassium).

Stronger electron withdrawing groups than the ethyl ester group may be needed to promote the C-N bond forming step.  Isocyanates tethered to more electron poor alkenes including nitroalkenes, unsaturated nitriles, and ketones will be prepared.  Our most current route uses phosphonium salt 7 with sodium acetate in acetonitrile to form a phosphonium ylide that reacts with aqueous gluteraldehyde (Scheme 3) affording 8.   Subsequent oxidation of 8 affords carboxylic acid 9 in 74% yield.  Following a Curtius rearrangement we will test the key cyclization reaction.  Successful cyclization will afford the opportunity to examine the electronic effects of the initial Michael acceptor by varying substituents on the aromatic ring in 7.

Another project, which was spun off of an undesired side reaction in efforts to make 9, involves the Wittig reaction of phosphonium ylides and lactols (Table 1). We have explored the use of chiral amine catalysts in the synthesis of 2-substituted pyrans which are abundant in natural products and pharmaceuticals.  A variety of known chiral amine catalysts were screened under several reaction conditions that afford 11.   In each case, there was a small but noticeable increase in rate compared to uncatalyzed reactions.  Unfortunately, enantioselectivities were low in all examples.

Additional efforts to affect an enantioselective Wittig reaction have not yielded enantioenriched products.  Neither the methyl ketone Wittig reagent nor the aldehyde led to respectable yield using 2.  A benzofused substrate (12) was attempted with the expectation that the intermediate phenol would be less nucleophilic than an alcohol.  Using substrate 12 with the methyl ketone Wittig reagent (R = Me), the product 13 was obtained in good yield however with low enantiomeric excess (Scheme 5). 

A final project involves the intramolecular Rauhut-Currier Reaction which was prompted by our interest in nucleophilic catalysis. The Rauhut-Currier reaction is often quite slow resulting in the need for highly reactive alkyl phosphines and high catalyst loadings.  To address this, our variant uses a reactive alkyne.  In this process, an external pronucleophile is required to regenerate the phosphine catalyst.  In a preliminary experiment, 14a was treated with catalytic nBu₃P and 1.5 equivalents of TMSCN resulting in a rapid reaction.  Following treatment with aqueous CsF, the product 15a was isolated in 61% yield.  This encouraging result has led to an effective method to construct a variety of highly functionalized carbocycles.  We have prepared and cyclized a range of enynes (14a-14g) using alkyl phosphines with TMSCN.  Both 5- and 6-membered rings can be formed.

Additionally, we have attempted an enantioselective reaction using a chiral phosphine.  The Vedejs PBO catalyst (16) affords cyclization yields that are comparable to those in using achiral catalysts.  However, enantioselectivity was low ranging from racemic to 28% ee in three examples.  We postulated that low enantioselectivy could be due to an unexpected mechanistic pathway.  To this end, a control experiment using 14f and catalytic BnMe₃NCN in the absence of a phosphine was attempted.  Under the normal reaction time, no reaction was observed thus eliminating the possibility that cyanide is the catalytic species.  We next postulated that racemization could be occurring under the reaction conditions.  In fact, proton transfer of the alkene β-hydrogen is precedented and would lead to the formation of a stable phosphonium ylide intermediate in which the chirality center is destroyed.  We have refuted this hypothesis by synthesizing a deutrated version of 14g.  Preliminary results suggest that this proton transfer is not occurring. 

This work has had significant impact in addition to the science discussed above.  Since the funding of this proposal, 10 undergraduate students have been trained in my research laboratory to date.  The learned skills and techniques are invaluable toward their future endeavors as scientists.  Three of the students have graduated.  One went to graduate school, one to pharmacy school and one is teaching high school chemistry.  In addition, this work has helped establish a foundation for several projects which will lead to an extensive long term research program in organic synthesis and catalysis.  The project has also initiated contact with two collaborators that will broaden the impacts of the work.