Chemistry is ultimately about chemical reactions—developing them, understanding them, and using them to make interesting, useful molecules. Much of the activity in my research group is aimed at discovering new ways to make complex molecules, including designing unique strategies to certain families of natural products and developing broadly effective methods for chemical synthesis.
The targets for our synthesis studies are selected for their intricate structures as well as their potent biological activities. We strive to devise concise, stereocontrolled, and high-yielding routes using strategies that examine interesting aspects of structure and reactivity. Among the targets that we have successfully synthesized are elisapterosin B, pederin, the welwitindolinones, and strychnine.
The targets that we are currently pursuing include compounds that display potent anticancer or antibiotic activities.
In recent years, a significant part of my group has focused on the development of effective catalysts for enantioselective reactions. The biologically important Aspidosperma family of alkaloids provided the initial motivation for much of this work. We found that salen-based chiral complexes catalyze the Diels-Alder reactions of amino-substituted dienes and a broad range of dienophiles to produce the cycloadducts in high yields and with excellent enantioselectivities.
Significantly, we discovered that TADDOL, a simple, commercially available chiral alcohol, functions as a catalyst for highly enantioselective cycloadditions. Reminiscent of enzymes and antibodies, hydrogen bonding to TADDOL provides both tremendous rate acceleration and exquisite selection for the formation of one enantiomer of the product. Considerable effort in the group is directed at the design and development of novel classes of hydrogen bonding catalysts, such as squaramides, for asymmetric synthesis.
1. Hydrogen Bonding by a Chiral Alcohol to an Aldehyde Catalyzes Highly Enantioselective Reactions. Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature, 2003, 424, 146. DOI: 10.1038/424146a.
2. Thadani, A. N.; Stankovic, A. R.; Rawal, V. H. Enantioselective Diels-Alder Reactions Catalyzed by Hydrogen Bonding. Proc. Natl. Acad. Sci. 2004, 101, 5846-5850. DOI:10.1073/pnas.0308545101.
3. Hayashida, J.; Rawal, V. H. “Total Synthesis of (+/-)-Platencin. Angew. Chem., Int. Ed. 2008, 47, 4373-4376. DOI: 10.1002/anie.200800756.
4. Malerich, J. P.; Hagihara, K.; Rawal, V. H. Chiral Squaramide Derivatives are Excellent Hydrogen Bond Donor Catalysts. J. Am. Chem. Soc. 2008, 130, 14416-14417. DOI: 10.1021/ja805693p.
5. Jewett, J. C.; Rawal, V. H. Temporary Restraints to Overcome Steric Obstacles: An Efficient Strategy for the Synthesis of Mycalamide B. Angew. Chem., Int. Ed. 2010, 49, 8682-8685. DOI: 10.1002/anie.201003361.
6. Bhat, V.; Allan, K. M.; Rawal, V. H. Total Synthesis of N-Methylwelwitindolinone D Isonitrile. J. Am. Chem. Soc. 2011, 133, 5798–5801. DOI: 10.1021/ja201834u.
7. Allan, K. M.; Kobayashi, K.; Rawal, V. H. A Unified Route to the Welwitindolinone Alkaloids: Total Syntheses of (−)-N-Methylwelwitindolinone C Isothiocyanate, (−)-N-Methylwelwitindolinone C Isonitrile, and (−)-3-Hydroxy-N-methylwelwitindolinone C Isothiocyanate. J. Am. Chem. Soc. 2012, 134, 1392–1395.DOI:10.1021/ja210793x.
8. Türkmen, Yunus E.; Montavon, Timothy J.; Kozmin, Sergey A.; Silver-Catalyzed Formal Inverse Electron-Demand Diels-Alder Reaction of 1,2-Diazines and Siloxy Alkynes. J. Am. Chem. Soc. 2012, 134, 9062-9065.DOI: 10.1021/ja302537j
9. Hutson, J. E.; Türkmen, Y. E.; Rawal, V. H. Salen Promoted Enantioselective Nazarov Cyclizations of Activated and Unactivated Dienones, J. Am. Chem. Soc. 2013, 135, 4988−4991. DOI: 10.1021/ja401908m.
10. Synthesis of alpha-Amino Acid Derivatives and Peptides via Enantioselective Addition of Masked Acyl Cyanides to Imines. Yang, K. S.; Rawal, V. H. J. Am. Chem. Soc. 2014, 136, 16148-16151. DOI: 10.1021/ja510135t.