Steven Weinreb

Professional Appointments and Affiliations

Professor Emeritus

Russell and Mildred Marker Professor of Natural Products Chemistry

Office

537 Chemistry Building

University Park, PA 16802

Email: smw@chem.psu.edu 

(814) 863-0189

Education

A.B., Cornell University, 1963

Ph.D., University of Rochester, 1967

Research

Synthesis of natural products; development of new synthetic methods; heterocyclic chemistry; pericyclic reactions and cycloadditions.

Total Synthesis of Heterocyclic Natural Products

Professor Weinreb's research group is currently involved in the total synthesis of a number of complex heterocyclic natural products with significant pharmacological activity. Throughout all of these projects, heavy emphasis is being placed on developing and exploiting new synthetic methodology of potentially wide application in organic chemistry. For example, the unusual polycyclic marine natural product sarain A will be synthesized from the tricyclic intermediate in Figure 1. This compound has been prepared via the key allylsilane-N-sulfonyliminium ion cyclization shown in the figure. In addition, work is presently in progress on total synthesis of the biogenetically related anticancer marine alkaloid madangamine A.

A novel method for amide oxidation has been developed using the free radical sequence shown in Figure 2. This process provides a simple, convenient access to N-acylimines, which are widely useful synthetic intermediates. This chemistry is now being applied in an approach to total synthesis of the marine sponge anticancer alkaloid fasicularin.

A new type of pericyclic ene reaction of allenylsilane imines and related compounds has recently been discovered (Figure 3). This methodology provides a stereospecific route to diverse functionalized nitrogen-containing ring systems. The chemistry is currently being utilized in enantioselective total syntheses of the poison frog neurotoxin (-)-gephyrotoxin and the indole alkaloid (-)-ibogamine.

Several other complex marine natural products are also presently targets for total synthesis. Included in this group is the unique hepatotoxin cylindro-spermopsin produced by a fresh water blue-green alga. The key steps in this synthesis utilize methodolgy previously developed in the Weinreb group. The approach involves the intramolecular N-sulfinylurea [4+2]-cycloaddition shown in Figure 4, followed by a stereospecific ring opening-allylic sulfoxide [2,3]-sigmatropic rearrangement.

Selected Publications

Weinreb, S.M.; Taylor, S.C. "N,O-Bis(trimethylsilyl)hydroxylamine (update)" in Electronic Encyclopedia of Reagents for Organic Synthesis; Fuchs, P.L., Ed.; Wiley: Chichester, U.K., 2018.

Mason, J.D.; Weinreb, S.M. Total Synthesis of the Monoterpenoid Indole Alkaloids (±)-Alstoscholarisine B and C. Angew. Chem. Int. Ed. 2017, 56, 16674.

Chauhan, P. S.; Sacher, J. R.; Weinreb, S. M.  Synthesis of the Tetracyclic Skeleton of the Lycopodium Alkaloid Lycopladine H via a Pivotal Double Hydroformylation/Intramolecular Reductive Amination Sequence.  Org. Lett. 2015, 17, 806.

Nocket, A. J.; Feng, Y.; Weinreb, S. M.  Construction of the Myrioneuron Alkaloids: A Total Synthesis of (±)-Myrioneurinol.  J. Org. Chem. 2015, 80, 1116.

Nocket, A. J.; Weinreb, S. M.  Total Synthesis of the Tetracyclic Antimalarial Alkaloid (±)-Myrioneurinol.  Angew. Chem. Int. Ed. 2014, 53, 14162

Chauhan, P. S.; Weinreb, S. M.  Convergent Approach to the Tetracyclic Core of the Apparicine Class of Indole Alkaloids via a Key Intermolecular Nitrosoalkene Conjugate Addition.  J. Org. Chem. 2014, 79, 6389.

Feng, Y.; Majireck, M. M.; Weinreb, S. M.  Total Syntheses of the Monoterpene Indole Alkaloids (±)-Alstilobanine A and E, and (±)-Angustilodine.  J. Org. Chem. 2014, 79, 7 (Featured Article).

Sengupta, R.; Weinreb, S. M.  A One-Pot Umpolung Method for Preparation of a-Aryl Nitriles from a-Chloroaldoximes via Organocuprate Additions to Transient Nitrosoalkenes.  Synthesis 2012, 44, 2933.

Feng, Y.; Majireck, M. M.; Weinreb, S. M.  Total Synthesis of the Unusual Monoterpenoid Indole Alkaloid (±)-Alstilobanine A.  Angew. Chem. Int. Ed. 2012, 51, 12846.

Sacher, J. R.; Weinreb, S. M.  Construction of the Azocane (Azacyclooctane) Moiety of the Lycopodium Alkaloid Lycopladine H via an Intramolecular Hydroaminomethylation Strategy.  Org. Lett. 2012, 14, 2172.

Chauhan, P. S.; Majireck, M. M.; Weinreb, S. M.  Regioselective a-Monochlorination of N-Protected-3 piperidones.  Heterocycles 2012, 84, 577.

Sacher, J. R.; Weinreb, S. M.  Discussion Addendum for 2-Trimethylsilylethanesulfonyl Chloride (SES-Cl).  Org. Synth. 2012, 89, 34.

Sengupta, R.; Witek, J. A.; Weinreb, S. M.  Stereochemical Investigations of Conjugate Additions of Carbon- and Heteronucleophiles to Ring-Substituted Nitrosocyclohexenes.  Tetrahedron 2011, 67, 8229.

Sacher, J. R.; Weinreb, S. M.  Exploratory Studies Towards a Total Synthesis of the Unusual Bridged Tetracyclic LycopodiumAlkaloid Lycopladine H.  Tetrahedron 2011, 67, 10203.

Witek, J. A.; Weinreb, S. M.  Investigation of the Stereochemistry of Intermolecular Conjugate Additions of Nucleophiles to Acyclic Nitrosoalkenes.  Org. Lett. 2011, 13, 1258.

Kumar, P.; Li, P.; Korboukh, I.; Wang, T. L.; Yennawar, H.; Weinreb, S. M.  Further Studies of Intramolecular Michael Reactions of Nitrosoalkenes for Construction of Functionalized Bridged Ring Systems.  J. Org. Chem. 2011, 76, 2094.

Majireck, M. M.; Witek, J. A.; Weinreb, S. M.  An Expedient Reductive Method for Conversion of Ketoximes to the Corresponding Carbonyl Compounds.  Tetrahedron Lett.  2010, 51, 3555.

Liu, P.; Seo, J. H.; Weinreb, S. M.  Evolution of a Strategy for Total Synthesis of the Marine Fungal Alkaloid (±)-Communesin F.  J. Org. Chem. 2010, 75, 2667.

Li, P.; Majireck, M. M.; Witek, J. A.; Weinreb, S. M.  Efficient Methodology for Alkylation of Vinylnitroso Compounds with Carbon Nucleophiles.  Tetrahedron Lett. 2010, 51, 2032.

Liu, P.; Seo, J. H.; Weinreb, S. M.  A New Total Synthesis of the Polycyclic Fungal Metabolite (±)-Communesin F.  Angew. Chem. Int. Ed. 2010, 49, 2000.