Pieter H. Bos 19 Everett Street, Apt. 41 Cambridge MA 02138 United States of America Phone: 1-857-222-7641 Pieter.H.Bos@gmail.com EDUCATION 2007-2011 PhD Degree in Organic Chemistry

University of Groningen, Groningen, The Netherlands 2004-2007 Master of Science, Synthetic Organic Chemistry

University of Groningen, Groningen, The Netherlands 2001-2004 Bachelor of Science, Synthetic Organic Chemistry

University of Groningen, Groningen, The Netherlands RESEARCH EXPERIENCE

Postdoctoral Research Associate (Center for Methodology and Library Development, Boston University, Boston MA March 2012–present) Development of new methodology utilizing photochemical rearrangements as a tool for the rapid generation of molecular complexity. Supervisors: Prof. Dr. John A. Porco, Jr. and Prof. Dr. Corey R. J. Stephenson.

PhD Research Organic Chemistry (University of Groningen, Groningen, The Netherlands 2007–2011) Designed and conducted an independent experimental research program in the area of asymmetric catalysis which resulted in the publication of several articles. Extensive conference experience. Thesis supervisors: Prof. Dr. Ben L. Feringa and Prof. Dr. Adriaan J. Minnaard.

Internship Novartis Institute for Biomedical Research (Novartis NIBR Basel, Switzerland October 2006–March 2007) Synthesis of macrocyclic BACE-1 inhibitors for the treatment of Alzheimer’s disease. Supervisor: Dr. Siem J. Veenstra.

Master Research Project Organic Chemistry (University of Groningen, Groningen, The Netherlands 2005–2007) Synthesis of linear chiral building blocks for the total synthesis of insect pheromones. Supervisors: Prof. Dr. Ben L. Feringa and Prof. Dr. Adriaan J. Minnaard.

Bachelor Research Project Organic Chemistry (University of Groningen, Groningen, The Netherlands 2004) Synthesis of linear chiral building blocks. Supervisors: Prof. Dr. Ben L. Feringa and Prof. Dr. Adriaan J. Minnaard.

Teaching Assistant (University of Groningen, Groningen, The Netherlands 2007–2011) Taught the mandatory tutorial component for first and second year organic chemistry courses. Prepared and marked exams.

Lab Teaching Assistant (University of Groningen, Groningen, The Netherlands 2004–2006) Supervised undergraduate labs at the first and second year level organic chemistry and pharmacy. Demonstrated appropriate techniques, oversaw execution of the lab, marked lab journals and tests.

Lab Supervisor (University of Groningen, Groningen, The Netherlands 2007– 2011) In charge of safety, maintenance of equipment and scheduling of lab duties. Responsible for instructing starting PhD- and Master students in laboratory techniques and protocols.

PUBLICATIONS Asymmetric autocatalysis: a spectroscopic study. P.H. Bos, J.F. Teichert, B.L. Feringa Manuscript in preparation. Asymmetric Allylic Alkylation of Acyclic Allylic Ethers with Organolithium Reagents. M. Pérez, M. Fañanás-Mastral, V. Hornillos, A. Rudolph, P.H. Bos, S.R. Harutyunyan, B.L. Feringa. Chemistry – A European Journal, DOI: 10.1002/chem.201202251, 2012. Enantioselective Synthesis of Tertiary and Quaternary Stereogenic Centers: Copper/Phosphoramidite-Catalyzed Allylic Alkylation with Organolithium Reagents. M. Fañanás-Mastral, M. Pérez, P.H. Bos, A. Rudolph, S.R. Harutyunyan, B.L. Feringa. Angewandte Chemie International Edition, 51, 8, 1922-1925, 2012. Angewandte Chemie, 124, 8, 1958-1961, 2012. Copper-catalyzed asymmetric ring opening of oxabicyclic alkenes with organolithium reagents. P.H. Bos, A. Rudolph, M. Pérez, M. Fañanás-Mastral, S.R. Harutyunyan, B.L. Feringa. Chemical Communications, 48, 12, 1748-1750, 2012. Catalytic asymmetric conjugate addition/oxidative dearomatization towards multifunctional spirocyclic compounds. A. Rudolph, P.H. Bos, A. Meetsma, A.J. Minnaard, B.L. Feringa. Angewandte Chemie International Edition, 50, 26, 5834-5838, 2011. Angewandte Chemie, 123, 26, 5956-5960, 2011.

Catalytic asymmetric carbon-carbon bond formation via allylic alkylations with organolithium compounds. M. Pérez, M. Fañanás-Mastral, P.H. Bos, A. Rudolph, S.R. Harutyunyan, B.L. Feringa. Nature Chemistry, 3, 5, 377-381, 2011. Highlighted by: Nature, Chemical & Engineering News. Catalytic asymmetric conjugate addition of dialkylzinc reagents to α,β-unsaturated sulfones. P.H. Bos, B. Maciá, M.Á. Fernández-Ibáñez, A.J. Minnaard, B.L. Feringa. Organic & Biomolecular Chemistry, 8, 1, 47-49, 2010. Catalytic asymmetric conjugate addition of Grignard reagents to α,β-unsaturated sulfones. P.H. Bos, A.J. Minnaard, B.L. Feringa. Organic Letters, 10, 19, 4219-4222, 2008. Highlighted by: Synfacts, 1, 68, 2009. Stereoselective synthesis of 2,3,7-trimethylcyclooctanone and related compounds and determination of their relative and absolute configurations by the MαNP acid method. J. Naito, S. Kuwahara, M. Watanabe, J. Decatur, P.H. Bos, R.P. Van Summeren, B. Ter Horst, B.L. Feringa, A.J. Minaard, N. Harada. Chirality, 20, 9, 1053-1065, 2008. ORAL PRESENTATIONS “Catalytic asymmetric carbon-carbon bond formation with organolithium compounds” P.H. Bos, M. Pérez, M. Fañanás-Mastral, A. Rudolph, S.R. Harutyunyan, B.L. Feringa. 241st ACS National Meeting, March 2011, Anaheim, CA, United States of America. “Asymmetric autocatalysis: a spectroscopic study” P.H. Bos, J.F. Teichert, W.R. Browne, B.L. Feringa. XIIth Netherlands Catalysis and Chemistry Conference, March 2011, Noordwijkerhout, The Netherlands. “Catalytic asymmetric conjugate addition of Grignard reagents to α,β-unsaturated sulfones” P.H. Bos, A.J. Minnaard, B.L Feringa. NWO-CW (Dutch Organization for Scientific Research) National Meeting, October 2008, Lunteren, The Netherlands.

POSTER PRESENTATIONS “Asymmetric autocatalysis: a spectroscopic study”, Sci-Mix session P.H. Bos, J.F. Teichert, W.R. Browne, B.L. Feringa. 241st ACS National Meeting, March 2011, Anaheim, United States of America. “Asymmetric autocatalysis: a spectroscopic study” P.H. Bos, J.F. Teichert, W.R. Browne, B.L. Feringa. 241st ACS National Meeting, March 2011, Anaheim, United States of America. “Asymmetric Autocatalysis: a spectroscopic study” P.H. Bos, J.F. Teichert, W.R. Browne, B.L. Feringa. NWO-CW (Dutch Organization for Scientific Research) National Meeting, October 2010, Lunteren, The Netherlands. “Catalytic asymmetric conjugate addition of dialkylzinc reagents to α,β-unsaturated sulfones” P.H. Bos, B. Maciá, M. Ángeles Fernández-Ibáñez, A.J. Minnaard, B.L. Feringa. NWO-CW (Dutch Organization for Scientific Research) National Meeting, October 2009, Lunteren, The Netherlands. “The determination of the absolute configuration of all four stereocenters in an eight-membered ring alcohol determined by 1H-NMR of its 2-methoxy-2-(1-naphthyl)propionic ester” P.H. Bos, N. Harada, A.J. Minnaard, B.L. Feringa. NWO-CW (Dutch Organization for Scientific Research) National Meeting, October 2007, Lunteren, The Netherlands. “The determination of the absolute configuration of all four stereocenters in an eight-membered ring alcohol determined by 1H-NMR of its 2-methoxy-2-(1-naphthyl)propionic ester” P.H. Bos, N. Harada, A.J. Minnaard, B.L. Feringa. 11th International Conference on Circular Dichroism, CD2007, September 2007, Groningen, The Netherlands. Languages: Dutch – native speaker German – good English – fluent French – basic Prizes and awards Solvias Ligand Contest 2011: For the development of an allylic substitution protocol with organolithium reagents. (With Dr. S. R. Harutyunyan)

Other: Workweek Organization Committee 2009: With two other PhD students, organized a weeklong exchange for the members of the Stratingh Institute with the Radboud University Nijmegen, The Netherlands. Coordinated a scientific symposium, team building activities and skills workshops. References Prof. Dr. Ben L. Feringa Stratingh Institute for Chemistry University of Groningen Nijenborgh 4 9747 AG, Groningen The Netherlands Tel.: +31 50 363 4278 b.l.feringa@rug.nl Prof. Dr. Adriaan J. Minnaard Stratingh Institute for Chemistry University of Groningen Nijenborgh 7 9747 AG, Groningen The Netherlands Tel.: +31 50 363 4258 a.j.minnaard@rug.nl

Dr. Siem J. Veenstra

Novartis Institutes for BioMedical Research Novartis Pharma AG WKL-136.5.84 CH 4002, Basel Switzerland Tel.: +41 61 69 61 472 siem.veenstra@novartis.com

Research Summary Pieter Bos

Catalytic asymmetric conjugate addition of Grignard reagents to α,β-unsaturated

sulfones.

The conjugate addition of organometallic reagents to α,β-unsaturated compounds is one of

the most versatile and widely used synthetic methods for carbon-carbon bond formation.

Enantioselective metal-catalyzed versions of this transformation are used as key steps in

the synthesis of numerous natural products and biologically active compounds and have

been studied extensively over the past decade. We developed a highly efficient method for

the asymmetric conjugate addition of Grignard reagents to a range of aliphatic α,β-

unsaturated sulfones. This procedure has a broad scope for aliphatic substrates and

provides β-substituted 2-pyridyl sulfones in both excellent yields (88-97%) and

enantioselectivities (88-94%). These enantioenriched sulfones are versatile intermediates

in the preparation of a wide variety of functionalized chiral building blocks.

Catalytic asymmetric conjugate addition of dialkylzinc reagents to α,β-unsaturated

sulfones.

Next to the addition of Grignard reagents we also developed an efficient method for the

highly enantioselective copper-catalyzed conjugate addition of dialkylzinc reagents to α,β-

unsaturated sulfones using a monodentate phosphoramidite ligand. The resulting optically

active sulfones bearing a stereocenter at the β-position are valuable intermediates in

organic chemistry due to their ease of derivatization yielding a variety of building blocks

including aldehydes or ketones, alkenes, alkynes, alkanes and haloalkanes. After careful

optimization of the reaction parameters we developed a highly enantioselective copper-

catalyzed conjugate addition of dialkylzinc reagents to a range of aromatic α,β-unsaturated

sulfones using a monodentate phosphoramidite ligand. This procedure provided β-

substituted 2-pyridyl sulfones in moderate to good yields (46–86%) and good to excellent

enantiomeric excess (70–96%) and is complementary to the method we developed for the

addition of Grignard reagents to aliphatic substrates. These enantioenriched sulfones are

potentially useful intermediates in the preparation of a wide variety of functionalized chiral

building blocks.

Catalytic asymmetric conjugate addition/oxidative cyclization towards

multifunctional spirocyclic compounds.

The copper-catalyzed asymmetric conjugate addition of Grignard reagents to α,β-

unsaturated carbonyl compounds has established itself as a reliable and efficient method

for the preparation of chiral building blocks that contain a new carbon-carbon bond and a

single stereogenic center. The resultant magnesium enolate formed during this process

lends itself towards the development of sequential processes, where trapping of the enolate

leads to the formation of two or more stereocenters in a one-pot procedure. This strategy is

particularly attractive as a high degree of structural and stereochemical complexity can be

achieved in a sequential process using small amounts of a chiral catalyst. One-pot

transformations to yield small chiral molecules displaying a high degree of skeletal

complexity, diversity, and functionality are a mainstay of diversity oriented synthesis. We

developed a sequential copper(I)-catalyzed asymmetric conjugate addition/ copper(II)-

mediated intramolecular oxidative cyclization of naphthol compounds for the synthesis of

highly functionalized benzofused spirocyclic cyclohexenones. A high degree of molecular

complexity was achieved in this one-pot transformation, along with the formation of three

contiguous stereocenters. The chiral catalyst controls the configuration of the first

stereocenter, achieving ee values up to 94% and the subsequent two stereocenters are

formed with high diastereoselectivity (up to >20:1), which is governed by the first

stereocenter.

Catalytic asymmetric carbon-carbon bond formation via allylic alkylations with

organolithium compounds.

Since their discovery by Wilhelm Schlenck in 1917, organolithium reagents have arguably

become some of the most versatile and widely used reagents in the daily repertoire of

chemical synthesis, and are indispensable in the preparation of a myriad of industrial

products from pharmaceuticals to polymers. In recent decades, asymmetric catalysis has

undergone substantial developments, and a broad range of C–C and C–X bond formations

with high enantioselectivities are currently known. In particular, less reactive organozinc,

aluminium and Grignard reagents have been shown to be highly effective in asymmetric C–C

bond formation. Remarkably, for extremely reactive organolithium compounds a general

catalytic methodology for enantioselective carbon–carbon bond formation has proven

elusive. We have developed a copper-based chiral catalytic system that allows carbon–

carbon bond formation via allylic alkylation with alkyllithium reagents, with extremely high

enantioselectivities and an ability to tolerate several functional groups. We have found that

both the solvent used and the structure of the active chiral catalyst are the most critical

factors in achieving successful asymmetric catalysis with alkyllithium reagents. The active

form of the chiral catalyst has been identified through spectroscopic studies as a

diphosphine copper monoalkyl species.

Figure 1 | Mechanistic study of chiral catalyst formation. Chemical structures and transformations proposed

for species A, B, C and D based on a thorough spectroscopic study. To establish the relevance of species A in the

catalytic allylic substitution, it was used in the stoichiometric alkylation of cinnamyl bromide, resulting in

greater than 98% enantioselectivity. Additional control experiments confirmed the detrimental effect of ether

on enantioselectivity, due to the formation of multiple copper species.

During the last months of my thesis I also studied asymmetric autocatalytic reactions using

spectroscopic techniques and developed a novel protocol for the catalytic asymmetric ring-

opening of oxabicyclic alkenes using organolithium reagents.