Research Specialization

Acyl transfer catalysis;Asymmetric catalysis;Enantioselective oxidation;Hypervalent iodine reagents;Nonenzymatic kinetic resolution;Organic Chemistry;Organic Synthesis;Organocatalysis;Total synthesis of natural products;

Research

Our group's research efforts range from total synthesis of bioactive natural products to asymmetric catalysis. In summary, we are interested both in devising concise and efficient strategies for synthesizing complex molecules and in designing simple molecules possessing desired chemical properties.

In 2004, we completed total syntheses of the unusual marine alkaloid sceptrin 1. In 2007, we disclosed a regioselective synthesis of antibiotic prekinamycin 2, utilizing a novel annulation reaction and an enantioselective synthesis of alkaloid lobeline 3 via desymmetrization of a meso-diol precursor using one of our catalysts, BTM (see below).

Our efforts in the area of asymmetric catalysis concentrate on enantioselective acyl transfer. Over the past several years, we have developed four successive generations of a new class of enantioselective acyl transfer catalysts (5-9). These compounds, easily obtained from commercially available starting materials, are highly effective in the kinetic resolution (KR) of several classes of chiral secondary alcohols. In addition, we have demonstrated for the first time the KR of chiral lactams, e.g., oxazolidinones and ß-lactams, via catalytic, enantioselective N-acylation. The enantioselectivities observed in all these cases are consistent with a transition state model based on π-π and cation-π interactions between the acylated intermediate and the substrate (e.g., 10). Our recent computational studies in collaboration with the Houk group (UCLA) support this hypothesis. Catalysts 7-9 have also proved effective in promoting enantioselective alcoholysis of racemic acyl donors, such as anhydrides and azlactones. Depending on the substrate, this transformation proceeds either in the conventional kinetic resolution (KR) or the dynamic kinetic resolution mode (DKR). Transition states similar to the one above have been envisioned to explain the enantioselectivities observed in these cases (11 and 12). In contrast, the recently developed KR of N-acyl-ß-lactams was found to proceed via a completely different mechanism, with the enantioselectivity arising during the initial nucleophilic attack on the substrate (13).

Besides chiral nucleophilic catalysts (i.e., Lewis bases), such as the ones illustrated above, enantioselective acylation reactions have often been catalyzed by chiral Lewis acids. Application of chiral Bronsted acids to these processes had remained unknown until recently, when we demonstrated that BINOL phosphoric acid 14 provides excellent ee's in the DKR of azlactones:

We have also discovered that the salts of 1,2,4-triazole are active anionic acyl transfer catalysts suitable for the aminolysis and transesterification of esters. For example, in the presence of DBU triazolide 15, isopropenyl acetate can be used as a mild acetylating agent producing acetone as the only byproduct. The same catalyst also promotes the aminolysis of unactivated esters, including the cyclocondensation of methyl esters of α-amino acids to give diketopiperazines 16 in high yield. We are currently exploring asymmetric catalyst designs incorporating the triazole moiety with the aim of developing catalytic kinetic resolution of amines.

Apart from our studies on acylation reactions, we have developed a new class of stoichiometric chiral hypervalent iodine reagents oxidizing o-alkylphenols with significant levels of asymmetric induction. The intermediate o-quinols 17 thus generated undergo spontaneous Diels-Alder dimerization with complete regio- and diastereoselectivity producing tricyclic final products 18 adorned with 6 stereocenters. Compounds of this type have been found in Nature.

Finally, we have described a new Cope-rearrangement-based route to hydroazulene 19, the core structure of many natural products:

Awards & Honors

Thieme Journals Award (2007)
National Institutes of Health National Research Service Award (2001-2003)

Appointments

009-present, Associate Professor, Washington University in St. Louis
2003-2009, Assistant Professor, Washington University in St. Louis
2000-2003, Postdoctoral Associate, Columbia University

Publications

Yang, X.; Bumbu, V. D.; Birman, V. B.* "Kinetic Resolution of ß-Lactams via Enantioselective N-Acylation" Org. Lett. 2011, 13, 4755. DOI: 10.1021/ol201911z

Bumbu, V. D.; Birman, V. B. "Kinetic Resolution of N-Acyl-ß-Lactams via Benzotetramisole-Catalyzed Enantioselective Alcoholysis" J. Am. Chem. Soc. 2011, 133, 13902. DOI: 10.1021/ja2058633

Yang, X.; Birman, V. B. "Nonenzymatic Dynamic Kinetic Resolution of α-(Arylthio)- and α-(Alkylthio)alkanoic Acids" Angew. Chem., Int. Ed. 2011, 50, 553. DOI: 10.1002/anie.201007860

Lu, G.; Birman, V. B. "Dynamic Kinetic Resolution of Azlactones Catalyzed by Chiral Brønsted Acids" Org. Lett. 2011, 13, 356. DOI: 10.1021/ol102736t

Yang, X.; Birman, V. B. "Acyl Transfer catalysis with 1,2,4-Triazole Anion" Org. Lett. 2009, 11, 1499. DOI: 10.1021/ol900098q

Boppisetti, J. K.; Birman, V. B. "Asymmetric Oxidation of o-Alkylphenols with Chiral 2-(o-Iodoxyphenyl)-Oxazolines", Org. Lett. 2009, 11, 1221. DOI: 10.1021/ol8029092

Courses Taught

CHEM 557, Advanced Organic Synthesis

CHEM 458, Organic Journal Club

CHEM 252, Organic Chemistry II

CHEM 5522, Synthetic Methods