Development of novel synthetic methodology
We maintain an effort directed toward the development of new reactions and the improvement of existing synthetic methodology. Our motivations for doing so are both our own occasional need for a non-existent transformation and our recognition of an existing need in organic synthesis for new methodology.
On example of the former category has been our development of improved methods for conversion of amines to guanidines, motivated by our own need for better methods. Initial studies led to the development of a new reagent (1) that effects guanylation of amines both in solution and solid phase synthesis [Ref. 12]
1
A complementary project found a new set of conditions for using thioamides to guanylate primary and secondary amines (Scheme 1) in very high chemical yield [Ref. 9]
Scheme 1
An example of the latter category is our studies into the asymmetric catalysis of
carbon-carbon bond formation by cyclic dipeptides. Inoue and coworkers first
demonstrated the ability of cyclic dipeptide 2
2
to catalyze the enantioselective formation of cyanohydrins from aldehydes (Scheme 2):
Scheme 2
We synthesized two N-methylated derivatives of 2 (3 and 4)
to investigate the aggregation state of 2 in the catalytic complex [Ref. 11]We have also undertaken a detailed investigation of the kinetics of cyanohydrin formation catalyzed by 2, showing that the most important catalytic species is a hydrogen-bonded complex of 2 with product cyanohydrins [Ref. 10]One outgrowth of this study was our enhancement of the enantioselectivity of several problematic reactions by addition of catalytic amounts of cyanohydrins (e.g., 5) at the start of reaction (Scheme 3).
Scheme 3
We have also developed a novel cyclic dipeptide catalyst, 6,
6
for the asymmetric Strecker amino acid synthesis. We have shown that 6
can catalyze the formation of a variety of aromatic 
-amino nitriles (Scheme
4) with exceptionally high enantiomeric excess [Ref. 14]
Reaction 4
Another area of active research is in the cyclization of anionic allene
derivatives such as 7 to indanones such as 8 (Scheme 5). [Ref. 1]
Scheme 5
At present, we are attempting to understand the mechanism of this reaction and to explore its scope in synthesis. Future projects will seek to apply this methodology to natural products synthesis.
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