Education

B.S., Chemistry, Penn State University
Ph.D., Chemistry, Boston College
American Cancer Society Postdoctoral Fellow, Stanford University

Website

Sieber Research Group

Research Interests

Research in the group is focused on the development of new catalysts and catalytic reactions for application to the synthesis of complex organic molecules of biological significance (e.g. active pharmaceutical ingredients, APIs and natural products) in a cost-effective, safe, scalable, and sustainable manner from readily-available feedstocks. 

Cu-catalyzed “umpolung” techniques for the asymmetric synthesis of poly-heteroatom functionalized organics.

Chiral organic molecules having multiple polar heteroatom functional groups (FGs) are prevalent in nature and have widespread applications in chemistry and the pharmaceutical and material sciences (e.g. aminoalcohols, diols, diamines, etc.). Therefore, methodology for the stereoselective synthesis of such compounds is required to access these valuable products. However, due to the polar nature of these FGs, certain substitution patterns can be difficult to prepare when these polar groups lead to mis-matched polarity profiles (dissonant relationship). “Umpolung” chemistry aims to reverse the inherent polarity of a typical FG to overcome this problem. The Sieber group has been interested in utilizing reductive coupling approaches through Cu-catalysis to access polarity reversed α,γ-aminoanions that react with various electrophiles (e.g. carbonyls or imines) to provide chiral diamines and aminoalcohols in an asymmetric fashion. Initial studies reported stereocontrol through use of a chiral auxiliary whereas the current major focus of the group centers on stereocontrol through use of a chiral catalysts.

Select Publications

Agrawal, T.; Perez-Morales, K. K.; Cort, J. A.; Sieber, J. D. Asymmetric Synthesis of Propargylic -Stereogenic Tertiary Amines by Reductive Alkynylation of Tertiary Amides using Ir/Cu Tandem Catalysis. J. Org. Chem. 2022, 87, 6387 – 6392.

Gopalsamuthiram, V.; Ho, D. B.; Peck, C. L.; Natarajan, V.; Agrawal, T.; Burns, J.; Bachert, J.; Cook, D. W.; Stringham, R. W.; Nelson, R.; Ahmad, S.; Gupton, B. F.; Snead, D. R.; McQuade, D. T.; Vaidyanathan, R.; Donsbach, K.; Sieber, J. D. Development of a Practical Synthesis of the 8-FDC Fragment of OPC-167832. ACS Omega 2022, 7, 7223 – 7228.

Ho, D. B.; Gargaro, S. L.; Klake, R. K.; Sieber, J. D. Development of a Modified System to Provide Improved Diastereocontrol in the Linear-Selective Cu-Catalyzed Reductive Coupling of Ketones and Allenamides. J. Org. Chem. 2022, 87, 2142 – 2153.

Klake, R. K.; Edwards, M. D.; Sieber, J. D. Synthesis of 1,2-Aminoalcohols through Enantioselective Aminoallylation of Ketones by Cu-Catalyzed Reductive Coupling. Org. Lett. 2021, 23, 6444 – 6449.

Agrawal, T.; Martin, R. T.; Collins, S.; Wilhelm, Z.; Edwards, M. D.; Gutierrez, O.; Sieber, J. D. Access to Chiral Diamine Derivatives Through Stereoselective Cu-Catalyzed Reductive Coupling of Imines and Allenamides. J. Org. Chem. 2021, 86, 5026 – 5046.

Sieber, J. D.; Klake, R. K.; Agrawal, T.; Ho, D. B.; Gargaro, S. L.; Collins, S.; Edwards, M. D. Cross-Coupling of Allenamides and C-Based Nucleophiles by Pd-Catalyzed Allylic Alkylation. Isr. J. Chem. 2021, 61, 332 – 339. Invited special issue contribution.

Paymode, D. J.; Cardoso, F. S. P.; Agrawal, T.; Tomlin, J. W.; Cook, D. W.; Burns, J. M.; Stringham, R. W.; Sieber, J. D.; Gupton, B. F.; Snead, D. R. Expanding Access to Remdesivir via an Improved Pyrrolotriazine Synthesis: Supply Centered Synthesis. Org. Lett. 2020, 19, 7656 – 7661.

Gargaro, S. L.; Dunson, B.; Sieber, J. D. Identification of a Surprising Boronic Acid Homocoupling Process in Suzuki-Miyaura Cross-Coupling Reactions Utilizing a Hindered Fluorinated Arene. Synlett 2021, 32, 511 – 516. Invited special issue contribution.

Agrawal, T.; Sieber, J. D. Recent Developments in C-C Bond Formation Using Reductive Coupling Strategies. Synthesis 2020, 52, 2623 – 2638. Invited review article.

Gargaro, S. L.; Klake, K. R.; Burns, K. L.; Elele, S. O.; Gentry, S. L.; Sieber, J. D. Access to a Catalytically Generated Umpolung Reagent through the Use of Cu-Catalyzed Reductive Coupling of Ketones and Allenes for the Synthesis of Chiral Vicinal Aminoalcohol Synthons. Org. Lett. 2019, 21, 9753 – 9758.

Klake, K. R.; Gargaro, S. L.; Gentry, S. L.; Elele, S. O.; Sieber, J. D. Development of a Strategy for Linear-Selective Cu-Catalyzed Reductive Coupling of Ketones and Allenes for the Synthesis of Chiral γ-Hydroxyaldehyde Equivalents. Org. Lett. 2019, 21, 7992 – 7998.

Herbage, M. A.; Savoie, J.; Sieber, J. D.; Desrosiers, J. -N.; Zhang, Y.; Marsini, M. A.; Fandrick, K. R.; Rivalti, D.; Senanayake, C. H. Addition of Non-Stabilized Carbon-Based Nucleophilic Reagents to Chiral N-Sulfinyl Imins. Org. React. 2019, 1 – 422.

Sieber, J. D.; Buono, F.; Brusoe, A.; Desrosiers, J. –N.; Haddad, N.; Lorenz, J. C.; Xu, Y.; Wu, H.; Zhang, L.; Han, Z. S.; Roschangar, F.; Song, J. J.; Yee, N. K.; Senanayake, C. H. Application of a Preformed Pd-BIDIME Precatalyst to Suzuki-Miyaura Cross-Coupling Reactions in Flow. J. Org. Chem. 2019, 84, 4926 – 4931.

Patel, N. D.; Sieber, J. D.; Tcyrulnikov, S.; Simmons, B. J.; Rivalti, D.; Duvvuri, K.; Zhang, Y.; Gao, D. A.; Fandrick, K. R.; Haddad, N.; Lao, K. S.; Mangunuru, H. P. R.; Biswas, S.; Qu, B.; Grinberg, N.; Pennino, S.; Lee, H.; Song, J. J.; Gupton, B. F.; Garg, N. K.; Kozlowski, M. C.; Senanayake, C. H. Computationally Assisted Mechanistic Investigation and Development of Pd-Catalyzed Asymmetric Suzuki-Miyaura and Negishi Cross-Coupling Reactions for Tetra-ortho-Substituted Biaryl Synthesis. ACS Catal. 2018, 8, 10190 – 10209.

Sieber, J. D.; Rodriguez, S.; Frutos, R.; Buono, F.; Zhang, Y.; Li, N.; Qu, B.; Premasiri, A.; Li, Z.; Han, Z. H.; Xu, Y.; Byrne, D.; Haddad, N.; Lorenz, J.; et al. Development of a Scalable, Chromatography-Free Synthesis of t-Bu-SMS-Phos and Application to the Synthesis of an Important Chiral CF3-Alcohol Derivative in High Enantioselectivity Using Rh-Catalyzed Asymmetric Hydrogenation. J. Org. Chem. 2018, 83, 1448 – 1461.

Zhang, Y.; Lao, K. S.; Sieber, J. D.; Xu, Y.; Wu, L.; Wang, X. –J.; Desrosiers, J. –N.; Lee, H.; Haddad, N.; Han, Z. S.; Yee, N. K.; Song, J. J.; Howell, A. R.; Senanayake, C. H. Modular Dihydrobenzoazaphosphole Ligands for Suzuki-Miyaura Cross-Coupling. Synthesis 2018, 50, 4429 – 4434.

Sieber, J. D.; Angeles-Dunham, V. V.; Chennamadhavuni, D.; Fandrick, D. R.; Haddad, N.; Grinberg, N.; Kurouski, D.; Lee, H.; et al. Rhodium-Catalyzed Asymmetric Allenylation of Sulfonylimines and Application to the Stereospecific Allylic Allenylation. Adv. Synth. & Catal. 2016, 358, 3062 – 3068.

Sieber, J. D.; Rivalti, D.; Herbage, M. A.; Masters, J. T.; Fandrick, D. R.; Fandrick, D. R.; Haddad, N.; Lee, H.; et al. Rh-Catalysed Asymmetric Conjugate Addition of Boronic Acids to Nitroalkenes Employing a P-Chiral P,π-Hybrid Ligand. Org. Chem. Front. 2016, 3, 1149 – 1153.

Sieber, J. D.; Qu, B.; Rodriguez, S.; Haddad, N.; Grinberg, N.; Lee, H.; Song, J. J.; Yee, N. K.; Senanayake, C. H. Synthesis of P-Chiral Dihydrobenzooxaphospholes Through Negishi Cross-Coupling. J. Org. Chem. 2016, 81, 729 – 736.

Chen, P. -H.; Sieber, J. D.; Senanayake, C. H.; Dong, G. Rh-Catalyzed Reagent-Free Ring Expansion of Cycobutenones and Benzocyclobutenones. Chem. Sci. 2015, 6, 5440 – 5445.

Han, Z. S.; Zhang, L.; Xu, Y.; Sieber, J. D.; Marsini, M. A.; Li, Z.; et al. Efficient Asymmetric Synthesis of Structurally Diverse P-Stereogenic Phosphinamides for Catalyst Design. Angew. Chem. Int. Ed. 2015, 54, 5474 – 5477.

Sieber, J. D.; Chennamadhavuni, D.; Fandrick, K. R.; Qu, B.; Han, Z. S.; Savoie, J.; Ma, S.; Samankumara, L. P.; Grinberg, N.; Lee, H.; et al. Development of New P-Chiral P,π-Dihydrobenzooxaphosphole Hybrid Ligands for Asymmetric Catalysis. Org. Lett. 2014, 16, 5494 – 5497.

Han, Z. S.; Herbage, M. A.; Manganuru, H. P. R.; Xu, Y.; Zhang, L.; Reeves, J. T.; Sieber, J. D.; Li, Z.; Decroos, P.; et al. Design and Synthesis of Chiral Oxathiazinone Scaffolds: Efficient Synthesis of Hindered Enantiopure Sulfinamides and Sulfinyl Ketimines. Angew. Chem. Int. Ed. 2013, 52, 6713 – 6717.

Han, Z. S.; Goyal, N.; Herbage, M. A.; Sieber, J. D.; Qu, B.; Xu, Y.; Li, Z.; Reeves, J. T.; Desrosiers, N. –D.; Ma, S.; et al. Efficient Asymmetric Synthesis of P-Chiral Phosphine Oxides via Properly Designed and Activated Benzoxazaphosphinine-2-oxide Agents. J. Am. Chem. Soc. 2013, 135, 2474 – 2477.

Patents

“Preparation of spiro(cyclobutanol-pyrrolidinyl) diacylhydrazines as drug intermediates.” Beyer, P.; Brazzillo, J. A.; Eriksson, M.; Lorenz, J. C.; Nummy, L. J.; Rodriguez, S.; Savoie, J.; Sidhu, K. P. S.; Sieber, J. D.; Tampone, T. G.; Tan, Z.; Wang, J.; Zhang, L. WO 2019027860 A1 issued Feb. 07, 2019.

“Novel Chiral Dihydrobenzooxaphosphole Ligands and Synthesis Thereof.” Desrosiers, J. –N.; Fandrick, D. R.; Haddad, N.; Li, G.; Patel, N. D.; Qu, B.; Rodriguez, S.; Senanayake, C. H.; Sieber, J. D.; Tan, Z.; Wang, X. –J.; Yee, N. K.; Li, Z.; Zhang, Y. U.S. Patent # 20180155375 A1 issued June 07, 2018.

“Novel Chiral Dihydrobenzoazaphosphole Ligands and Synthesis Thereof.” Biswas, S.; Desrosiers, J. –N.; Lao, K.; Mangunuru, H. P. R.; Qu, B.; Rodriguez, S.; Senanayake, C. H.; Sieber, J. D.; Wang, X. –J.; Yee, N. K.; Zhang, Y. U.S. Patent # 20180155377 A1 issued June 07, 2018.