Form Approved Through 09/30/2011 OMR nnn ,',,,'n wepoitmerit w mewl anti nurneri OCIVIceb 2,": Health Service is .1 • Council: 05/2009 Pt: OLSON, ANGELA C anal Researchi lkYviL i 1 F31 GM089137-01 12150871 mrship Applicatio Dual: • .„,.. ,,,struchons carefully, ReCeiVed 2116/2008 -- ' Do not exceed character length restrictions indicated IRO: ZRG1 CB-N(29) L 1. TITLE OF RESEARCH TRAINING PROPOSAL (Co not exceed 81 char Catalytic Asymmetric Synthesis of Vinyl Chromans Using Palladium(II) Catalysts 2. LEVEL OF 3. RESPONSE TO SPECIFIC REQUEST FOR APPLICATIONS OR PROGRAM ANNOUNCEMENT 0 NO N1 YES FELLOWSHIP (If "Yes,' state number and (itle) Predoctoral Number, PA-07-106 Title: Ruth L. Kirschstein National Research Service Awards for Individual Predoctoral Fellowships (F31) to Promote Diversity in Health-Related Research
4a. NAME OF APPLICANT (Last, First, Middle) 4b, ERA COMMONS USER NAME ac HIGHEST DEGREE(S) Olson, Angela, Christine B.S. I 1 4d. PRESENT MAILING ADDRESS (Street, City State Zip Code) 4e PERMANENT MAILING ADDRESS (Stre t, City, State, Zip Code)
Of E-MAIL ADDRESS:
TELEPHONES AND FAX (Area code, number and extension) 4 OFFICE 4h HOME 4i PERMANENT 41. FAX NUMBER 949-824-9017 949-824-3866
4
5. TRAINING UNDER PROPOSED AWARD (See Fields of I raining) b. PHIQR AND/OR LURREN I NRSA SUPPOR I (Individual or Institutional) Di cipline No : Subcategory Name: le NO . YES (If 'Yes,' refer to item 22 Form Page 5) 1770 Synthetic Chemistry
7a, DATES OF PROPOSED AWARD Th. PROPOSED AWARD DURATION 8, DEGREE SOUGHT DURING PROPOSED AWARD From (MM/DD/YY): Through (MM/DD/YY): (in months) Degree Expected Completion Date: 07/01/09 06/30/12 36 Ph.D. 06/2012 9, HUMAN SUBJECTS 9b Federalwde Assurance Na RESEARCH N/A 10. VERTEBRATE ANIMALS EE No 0 Yes El No 0 Yes 10a. Animal Welfare Assurance No. 0 Indefinite ' 9c. Clinical Trial 90. NIH-delined Phase III rE No 0 Yes Chrocal Trial E1 No 0 Yes NIA
9a. Research Exempt El No 0 Yes If 'Yes,' Exemption No. N/A
11. SPONSORING INSTITUTION IS. OFFICIAL SIGNING FOR SPONSORING INSTITUTION Name Regents, University of California Name Judith Aguirre
Address Sponsored Projects Administration Title Contract and Grant Officer University of California, Irvine Address Sponsored Projects Administration 300 University Tower University of California, Irvine Irvine, CA 92697-7600 300 University Tower Irvine, CA 92697-7600 12a. ENTITY IDENTIFICATION NO. 12b. DUNS NO. Tel: (949) 824-0446 Fax: (949) 824-2094 1-95-2226406-A1 04-670-5849 E-Mail: [email protected] 14. APPLICANT ORGANIZATION CERTIFICATION AND ACCEPTANCE: I certify that the statements herein are true, complete, and a curate to the best of my knowledge, and I agree to comply with the terms and conditions of award if an ward is. issued as a resuJt of this ipplicationriar aware that any falsp, fictitious, or fraudulent statements or clams may subject me to criminal, civil, or administrative penalties. th (1.1Q.-1/5r7L, //(C/Dg SIGNATURE OF OFFICIAL NAMED IN 13. DATE ,...... ------\ (In ink Per signature not acceptable.) 1 1- 9-09 PHS 016-1 Rev. 9/08) Face Pagyudith pone Form Page 1 Contract & Grant Officer NAME OF APPLICANT (Last, first, middle initial) Kirschstein-NRSA Individual Fellowship Application Olson, Angela, C. (To be completed by applicant— follow P1-IS 416-1 instructions)
SPONSOR and Co-Sponsor' formation 15 NAME OF SPONSOR 16. NAME OF Co-SPONSOR (VVhen applicable) 15a. NAME AND DEGREE(S) 16a NAME AND DEGREE(S) Professor Larry E. Overman, Ph.D. N/A 15b. ERA COMMONS USER NAM: 16b. ERA COMMONS USER NAME 15c DEPARTMENT, SERVICE, LABORATORY, OR EQUIVALENT 16c. DEPARTMENT, SERVICE, LABORATORY, OR EQUIVALENT Chemistry 15d. MAJOR SUBDIVISION 16d. MAJOR SUBDIVISION Physical Sciences 15e. Address: 16e Address: University of California, Irvine Chemistry Department 1102 Natural Sciences 2 Irvine, CA 92697-2025 Telephone: Telephone Fax: Far E-Mail E-Mail: RESEARCH PROPOSAL 17. DESCRIPTION: See instructions. State the applications broad, Ion -term objectives and specific aims, making reference to the health relatedness of the project (I e . relevance to the mission of the agency) Describe conciseN the research design and methods for achieving these goals. Describe the rationale and techniques you will use to pursue the e goals.
In addition. in two or three sentences, describe m plain, lay language t e relevance of this research to public health. If the application is funded, this description, as is, will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED EDE SPACE PROVIDED. The proposal describes the development of a mild and efficient method for the catalytic asymmetric synthesis of vinyl chromans. The chroman motif is present in numerous small molecules of biological importance and the current methods available to access these substrates are limited. The SN2' allylic substitution chemistry of trichloroacetimidates using a tethered phenol nucleophile will be examined using chiral cobalt oxazoline palladium(11) catalysts. An efficient and convergent method to access a variety of key cyclization substrates will be developed. The scope of functional groups and substitution patterns compatible with this system will be explored. A variety of heterocycles with important biological activity may also be synthesized using this chemistry. This methodology will allow easy access to a broader range of biologically active small molecules and their analogues.
This proposal describes the development of a general method to access biologically important small molecules in a selective manner. This methodology will be beneficial to the synthetic community because a vast number of small molecules and their analogues will be readily available and their biological activity can be explored.
PhIS 416-1 (Rev 9/08) Page 2 Number pages consecutmety at The bottom throughout Form Page 2 the application Do not use Suffixes such as 2a, 2e Kirschstein-NRSA Individual Fellowship Application NAME OF APPLICANT (Last, first, middle initial) Olson. Angela, a (To be completed by applicant- follow PHS 016-1 instructions)
18. GOALS FOR KIRSCHSTEIN-NRSA FELLOWSHIP TRAINING AND CAREER My main interest in research is the development of novel methodology and its application in organic synthesis. Currently, my specific area of research focuses on intramolecular reactions of allylic trichloroacetimidates. I hope to expand upon the cobalt oxazoline palladacycle-catalyzed SN2' allylic substitution reactions that have been developed in our group_ By studying these new reactions, I hope to gain new insight into these types of transformations and develop new tools for the synthetic community.
During my graduate studies, I would like to further develop my research skills by learning new techniques and improving my ability to approach, analyze, and solve problems in organic chemistry. I am interested in applications of organic chemistry in a government laboratory setting. I would like to contribute to the well- being and health of our society through research and development.
19.ACTIVITIES PLANNED UNDER THIS AWARD. Approximate percentage of proposed award time in activities identified below. (See instructions) Year Research Course Work Teaching Clinical
First 100% Second 100% Third 100% PREDOCTORAL FELLOWSHIPS ONLY Fourth
Fifth MD/PhD FELLOWSHIPS 0 JLY Sixth Briefly explain activities other than research and relate them to the proposed research training N/A
20. TRAINING SITE(S) Is the Primary Training Site the same as the Sponsoring Institution, 0 Yes E No If No, provide detailed information below for the Primary Training Site Location
Organizational Name:
DUNS:
Street 1: Street 2
City. County. State:
Province: Country. Zip/Postal Code.
Project/Performance Site Congressional Districts: 21 HUMAN EMBRYONIC STEM CELLS 2 No . Yes If the proposed project involves human embryonic stem cells, list below the registration number of the specific cell line(s) from the following list: http://stemcells.mhmov/research/recustrv/eliqibilityCriteria.asp. Use continuation pages as needed. If a specific line cannot be referenced at this time, include a statement that one from the Registry will be used. Cell Line
PBS 416-1 (Rev. 9/08) Page 3 Form Page 3
Kirschstein-NRSA Individual Fellowship Application NAME OF APPLICANT (Lest first, middle Table of Contents Olson, Angela, C. Page Numbers (Number pages consecutively at the bottom throughout Section I — Applicant/Fellow the application. Do not use suffixes such as 6a, 6b) Face Page 1 Sponsor's Contact Information, Description (Form Page 2) 2 Training & Career Goals, Activities Planned Under This Award, Training Site(s), Human Embryonic Stem Cells (Form Page 3) 3 Table of Contents (Form Page 4) 4 Biographical Sketch - ApplicanVFellow (Not to exceed four pages) 5-6 Previous Research Experience (Form Page 5) 7 Research Training Plan 1. Introduction to Resubmission Application (not to exceed I page) N/A 2. Specific Aims 8 3, Background/Significance (Items 2-5 not to exceed 10 pages) 8-11 4. Preliminary Studies/Progress Report 11-12 5. Research Design and Methods 12-15 6. Inclusion Enrollment Report (for Renewal applications only) N/A 7. Progress Report Publication List (for Renewal applications only) N/A 8. Human Subjects (Required if Item 9 on the Face Page is marked "Yes') N/A 9. Clinical Trial N/A 10. Agency-Defined Phase Ill Clinical Trial N/A 11. Protection of Human Subjects (Required if Item 9 on the Face Page is marked "Yes") N/A 12. Inclusion of Women and Minorities (Required if Item 9 on the Face Page is marked "Yes" and is Clinical Research) N/A 13. Targeted/Planned Enrollment Table (for new and continuing clinical research studies) N/A 14. Inclusion of Children (Required if Item 9 on the Face Page is marked "Yes') N/A 15. Vertebrate Animals (Required if item 10 on the Face Page is marked "Yes') N/A 16. Select Agent Research N/A 17, Literature Cited 15-16 18. Resource Sharing N/A 19. Respective Contributions 17 20. Selection of Sponsor and Institution 17 21. Responsible Conduct of Research 17 Section II — Sponsor's/Co-Sponsor's Information Biographical Sketch--Sponsor 18-20 Research Support Available 21 Previous Fellows/Trainees 21 Training Plan, Environment, Research Facilities 21-22 Number of Fellows/Trainees to be Supervised 22 Applicant's Qualifications and Potential 22 Checklist (Completed by Fellow/Applicant 8 Sponsoring Institution) 23 Section III — Letters of Reference (Minimum of 3) (See instructions for submission of references.) List hill name institution and department of individuals submittino reference letters
umer items (Hsu. Personal Data Page for Fellowship Applicants
Appendix Check if Appendix is (Five identical CDs) Appendix Included PHS 416-1 (Rev. 9/08) Page 4 Form Page 4 Name of Applicant (Last, first, middle) Olson, Angela, Christine
APPLICANT/FELLOW BIOGRAPHICAL SKETCH USE ONLY FOR INDIVIDUAL PREDOCTORAL and POSTDOCTORAL FELLOWSHIPS. DO NOT EXCEED FOUR PAGES. NAME OF APPLICANT/FELLOW POSITION TITLE Angela Christine Olson eRA COMMONS I1 ER NAME (credential, e.g., agency login) Graduate Student Researcher
I
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, and include postdoctoral training.) DEGREE INSTITUTION AND LOCATION YEAR(s) FIELD OF STUDY Of applicable) Northern State University-Aberdeen, South Dakota B.S. 2001-2006 Chemistry, Biology Anticipated University of California Irvine-Irvine, California Ph.D. completion 2012 Organic Chemistry
Please refer lathe application instructions in order to complete sections A! B. and C of the Biographical Sketch. A. Positions and Honors BEGINNING ENDING DATE DATE SUPERVISOR/ ACTIVITY/OCCUPATION (mm/yy) (mm/yy) FIELD INSTITUTION/COMPANY EMPLOYER Teaching Assistant 04/07 07/07 General Chemistry UC Irvine
Academic and Professional Honors Fellowships -University of California Irvine Faculty Mentor Program Fellowship, 2008-2009 ($37,802) -Graduate Assistance in Areas of National Need (GAANN) Fellowship, 2006-2007 ($29,000) -National Science Foundation Alliances for Graduate Education and the Professoriate (AGEP) Fellowship, Summer 2006 ($3,000) -
-University of North Dakota Research Experience for Undergraduates (REU) Program, Summer 2004 ($3,000)
Scholarships -Northern State University James and Jeanette Anderson Arts & Sciences Scholarship, 2005 ($500) -Northern State University Sueltz-Jensen Award in Chemistry, 2004-2005 ($5,226) -American Colloid Company Paul Bechtner Memorial Scholarship, 2001-2005 ($12,000) -Northern State University-University College Scholarship, 2005 ($125) -Northern State University Mary L. Koczon Memorial Endowment in Chemistry, 2003 ($500) - -Northern State University Dean's Scholarship, 2001-2003 ($2,000) -Northern State University Hatterscheidt Foundation Educational Scholarship, 2001-2002 ($1,400) -Knights of Columbus Ed Eixenberger Memorial Scholarship, 2002 ($250) -St. Paul's Catholic Church Scholarship, 2002 ($300) -Doug Shaw Memorial Scholarship, 2001 ($150) -Bill Husband Memorial Scholarship, 2001 ($500) -Belle Fourche Optimist Club Scholarship, 2001 ($250) -Northern Black Hills Association of Realtors Scholarship, 2001 ($500) -P.E.O. Scholarship, 2001 ($300) -Women's Club Scholarship, 2001 ($100)
Academic Honors -Northern State University Women's Honor Student-Athlete Award, 2004-2005 -National Student Athlete Award, 2005
PHS 416-1 (Rev, 9/08) Page 5 Applicant/Fellow Biographical Sketch Format Page
Name of Applicant (Last, first, middle)' Olson, Angela, Christine -Northern State University Honors Program, 2001-2005 -Academic All-Northern Sun Intercollegiate Conference Spring and Fall Sports Teams, 2001-2006
Memberships -American Association for the Advancement of Science, 2008 -Iota Sigma PI National Honor Society for Women in Chemistry, 2006-2008 -Kappa Mu Epsilon National Mathematics Honor Society, 2006-2008
B. Publications
C. Scholastic Performance SCIENCE OTHER
YEAR COURSE TITLE GRADE YEAR COURSE TITLE GRADE Northern State University Courses Northern State University Courses 2002 General Biology I/Lab 2001 Literature and Culture 2002 General Chemistry I/Lab 2001 Composition I 2003 General Biology II/Lab 2001 Unites States History II 2003 General Chemistry II/Lab 2001 First Aid and CPR 2003 Microbiology/Lab 2001 Honors Seminar I 2003 Organic Chemistry I/Lab 2001 Principles of Sociology 2003 Introduction to Physics I/Lab 2002 History of Western Civilization I 2004 Organic Chemistry II/Lab 2002 Trigonometry 2004 Analytical Chemistry/Lab 2002 Introduction to Computers 2004 Introduction to Physics II/Lab 2002 Exploring Music 2004 Human Anatomy/Lab 2002 Principles of Wellness/Lab 2004 Medical Terminology 2002 Statistics 2004 Advanced Laboratory Techniques 2002 World Geography 2005 Physiology/Lab 2002 Electronic Networking 2005 Cell and Molecular Biology/Lab 2003 The Process of Criminal Law 2005 Ornithology/Lab 2003 Honors Composition II 2005 Inorganic Chemistry 2003 Criminal Law 2005 Instrumental Analysis 2003 Tutor/Mentor Training 2005 Environmental Biology 2004 Human Relations 2005 Plant Systematics/Lab 2004 Fundamentals of Speech 2005 Physical Chemistry I 2004 Calculus I 2006 Environmental Biology 2005 Calculus II 2006 Biochemistry 2005 Intermediate Spanish I 2006 Calculus III University of California Irvine Courses 2006 Organic Reaction Mechanisms I 2006 Organometallic Chemistry 2006 Chemical Biology 2007 Organic Spectroscopy 2007 Organic Synthesis I 2007 Organic Reaction Mechanisms II 2007 Organic Synthesis II
PHS 416-1 (Rev 9/08) P ge 6 Applicant/Fellow Biographical Sketch Format Page
Kirschstein-NRSA Individual Fellowship Application NAME OF APPLICANT (Last, first, middle Previous Research Experience Olson, Angela, C. (To be completed by applicant _follow P115 416-I inslruchons.) PRIOR AND CURRENT KIRSCHSTEIN-NRSA SUPPORT List type (individual and/or institutional). level (predoctoral or postdoctoral), dates, and grant or award numbers.
None
23 APPLICATION(S) FOR CONCURRENT SUPPORT Using format below, list all support (training, research, supplies, travel. etc ) applied for that would am concurrently with YES El NO the period covered by this application. Include the type, dates, source, and amount.
Type: Dates Source Amount Type Dates Source Amount Type Dates Source Amount 24a TITLE(S) OF THESIS/DISSERTATION(S) (Predoctoral and Senior Fellowships omit this section ) ' N/A
24b NAME OF DISSERTATION ADVISOR OR CHIEF OF SERVICE TITLE, DEPARTMENT. AND INSTITUTION (If reference repoil not included, explain why not) N/A N/A
25 DOCTORAL DISSERTATION AND OTHER RESEARCH EXPERIENCE (See Instructions - particularly Predoctoral and Senior Fellowships should follow special instructions for this section Use continuation pages Do not exceed two pages)
University of North Dakota (Summer 2004) Research Advisor: Professor Anamitro Banerjee
As an undergraduate research fellow, my work focused on the synthesis of ethylaminediaminetetraacetic acid (EDTA) analogs with phenylene, diethynyl phenyl, and aromatic spacers. The goal of the project was to form polymers in the presence of metal cations such as As3+, Cd2+, and On. The EDTA analogs would be useful in the detection and extraction of toxic metals. A viable synthetic route to access one of the EDTA analogs was developed.
California Institute of Technology (Summer 2005) Research Advisor: Professor David MacMillan
As a Undergraduate Research Fellow, I worked on the synthesis of the natural product, Cylin rocyc ophane A. The cylindrocyclophane family displays a toxic effect against the KB and LoVo tumor cell Fries. The focus of my project was the development of suitable synthetic route for a trifluoroborate salt and a trialkylanilinium salt utilizing enantioselective organocatalytic methods developed within the MacMillan group. These substrates were to be tested in a nickel-catalyzed Suzuki coupling reaction. During my ten weeks working on this project, I successfully prepared precursors for each of these substrates on a large multi-gram scale.
PHS 416-1 (Rev. 9)08) Page 7 Form Page 5
Name of Applicant (Last, Fe's!, Middle): Olson, Angela, Christine
Research Training Proposal
Specific Aims • The specific aims of the proposed project are: • To expand the scope of SN2' allylic substitution reactions catalyzed by cobalt oxazoline palladacycles (COP) to include intramolecular reactions • To synthesize biologically active compounds from the products of COP-catalyzed intramolecular cyclization reactions • To develop a general synthetic route to access key cyclization substrates • To explore the compatibility of various functional groups and substitution patterns in the intramolecular cyclization reaction catalyzed by COP
Introduction Chiral chromans 1 are a class of small molecules that possess important biological properties (Figure 1). For example, Nebivolol (2) is an important anti-hypertensive agent,' while Daurichromenic acid (3) shows potent anti-HIV activity.° Vitamin E (4)3 and its analog trolox (5)4 are active lipophilic antioxidants (Figure 2). Enantioenriched vinyl chroman 1 is a common intermediate in the synthesis of numerous biologically active small molecules.
Figure 1. Chiral vinyl chroman
0
Figure 2. Biologically active natural products that contain the chroman motif
2 3 Neblvolol DaurIchromenic acid
CO2H
4 5 vitamin E trolox
Currently, the methods used to access these synthetically important enantioenriched chroman intermediates are limited. These methods typically employ palladium(0) or iridium(I) catalysts in the presence of chiral ligands. Commonly in these transformations, competitive formation of linear substitution products is observed. These methods are also limited in reaction scope dependent on substitution patterns. Trost and coworkers have shown that allyl carbonate 6 undergoes intramolecular asymmetric allylic alkylation using a Pd(0)/7-based catalyst system (eq 1).1° However, this reaction requires the use of an acid additive in order to achieve high enantioselectivity. Further, when unsubstituted at C2, moderate enantioselectivities are observed.
PHS 415-1/416-9 (Rev. 9/08) Page 8 Continuation Format Page
Name of Applicant (Last. First, Middle): Olson, Angela, Christine
2 mol % Pc1221ba3 CHC12 6 mol % (R.RI-Llgand 1-1.2 equiv HOAG (1) 0.1 M 0H2Cl2 rt., 5-10 It 6 99% yield 84% ee
Iridium(1) in the presence of chiral phosphoramidite ligand Shave been used by the Helmchen group to access the vinyl chroman motif from allylic carbonate 6 (eq 2).11, Moderate yields are achieved when substrates are unsubstituted at C2 and basic reaction conditions are required in order to activate the iridium catalyst.
4 mol % gr(COD)CS2 8 mol % Llgand 8 mol % TAD (2) 0.5 M THF rip 1 h 6 60% yield TED 95% ee
The development of a new and efficient method would be beneficial to access other biologically active r small molecules and their analogues derived from vinyl chromans. We envision that enantioenriched chroman heterocycles could be accessed by a cobalt oxazoline palladium(II) (COP) 10-catalyzed intramolecular substitution reaction of trichloroacetimidate 9 with a tethered phenol nucleophile (eq 3).
2 \ X Pd.
0 COP catalyst Co OyCCI2 (3) FiHyd5(rh NH Ph Ph 9 10: [(Sp,A)-COP-X]2 10a: X =OAC lob: X =CI 10c: X =NHCOCCI3
Background Numerous methods exist for the catalytic asymmetric functionalization of alkenes. These methods typically involve suprafacial addition over a single face of an olefin (e.g. epoxidation, dihydroxylation, hydrogenation). The Overman lab has developed methods that involve catalytic asymmetric antarafacial addition to alkenes. Prochiral (Z)-allylic trichloroacetimidates 11 have been shown to undergo enantioselective intermolecular SN2' allylic substitution reactions in the presence of oxygen nucleophiles and a catalytic amount of COP catalyst 10a (eq 1). These substitution reactions proceed in good to excellent enantioselectivity and yield, tolerate catalyst loading as low as 1 mol % and proceed under mild conditions. The neutral conditions employed allow for a wider scope of functional groups to be tolerated than the previously mentioned catalyst systems, which require acidic or basic conditions. Another distinguishing characteristic of the COP-catalyzed allylic substitution reactions is the exceptional level of regioselectivity that is achieved, typically branched to linear ratios being >800:1.7'8
PHS 416-1/416-9 (Rev 9/08) Page 9 Continuation Format Page
Name of Applicant (Last, First, Middle): Olson, Angela, Christine
RION (111 =Ac, Ph) CI3C mop % 10a NN ORI 60-100% yield (4) /- _ : 65-99% ee o CH2Cl2, Ft. to 38 °C
11 12
A plausible mechanism for the allylic substitution reaction is illustrated in Figure 2. The nitrogen atom of trichloroacetimidate 11 reversibly coordinates to palladium to form olefin complex 13. The catalyst loses an acetate ligand, which frees a coordination site for olefin activation and produces complex 14. Preliminary mechanistic studies suggest that the catalyst likely binds to a single face of the olefin and nucleophilic attack occurs antarafacially in an SN2' fashion to afford carbopalladated species 15. Deoxypalladafion affords complex 16 and enantioenriched allylic product 12 is formed.
Figure 3 Proposed mechanism of COP-catalyzed allylic substitution reaction
-0Ac !1-Th Ac0-pd-C •
NH CI3C-k jThi 0 13
NH
0 11 110Ac NTh + OR1 HN- -Pd-C ciac—c Lpial (C..• pa ‘13 'OM 15 16 CI3C81H2)1'
Until recently, a limitation of the COP-catalyzed SN2' allylic substitution reaction was its compatibility with only the Z isomer of allylic trichloroacetimidates. This restriction is due to the propensity of the more easily accessible E isomer 17 to undergo competitive [3,3]-sigmatropic rearrangement in the presence of 10a to form branched trichloroacetamides 18.8 The aza-Claisen rearrangement of trichloroacetimidates to branched trichloroacetamides has been found to occur more rapidly with the E isomer of allylic trichloroacetimidate • substrates (Figure 4).9 This phenomenon likely results from unfavorable steric interaction between the CCI3 and R groups in the Z substrates which are not present for the [3,3]-sigmatropic rearrangement of E substrates.
Figure 4. Steric interactions in the [3.3]-sigmatropic rearrangement
NH
0-/ R 17 11
The allylic trichloroacetimidate rearrangement has become the preferred method for transforming Mir alcohols to branched allylic amines. An enantioselective [3,31-sigmatropic rearrangement of (E)- trichloroacetimidates to form allylic trichloroacetamides 18 is catalyzed by another member of the COP family, chloride-bridged dimer 10b, also developed in the Overman group (eq 5).fi)
PHS 416-1/415-9 (Rev 9/013) Page 10 Continuation Format Page
Name of Applicant (Last, First. Middle) Olson, Angela, Christine
0 R CI3C 5 mol % lob 74-98% yield M NH HNACCI3 (F) — 0 CH2Cl2, 38 °C 80-97% ee
17 18
During recent studies in the Overman group, the trichloroacetamide-bridged COP catalyst 10c was prepared and studied as a catalyst in the [3,3]-sigmatropic rearrangement. Initial results showed that 10c was not a viable catalyst for [3,3]-sigmatropic rearrangement of (E)-allylic trichloroacetimidate 19 (eq 6).
0 CI,C 5 mol % 10c 1411 H11-KCCI3 7% yield (6) CH2C12. 38 °C, 48 h
19 20
In light of this discovery, I studied the intermolecular allylic substitution reaction using (E)-allylic trichloroacetimidates using enantioselective catalyst 10c. The reaction of prochiral imidates 17 and phenolic 11 nucleophiles provided branched allylic aryl ethers 21 in high enantioselectivities and moderate yields (eq 7). The scope of this reaction was explored and various functional groups were tolerated, such as base-labile acetoxy groups, aldehydes, silyl ethers, and protected amines. The development of this method to obtain enantioenriched branched allylic ethers from the more easily accessible (E)-trichloroacetimidates is complimentary to chemistry previously reported in the Overman group and serves as the first example of (E)- trichloroacetimidates undergoing an intermolecular SN2' allylic substitution reaction faster than a [3,3]- sigmatropic rearrangement.
pl R ClaC 59-86% yield \ NH 0 78-96% ee (7) \ —0 CH2C12, 38 °C
17 21
Recent work in the Overman lab has focused on expanding the synthetic utility of this transformation. It was envisioned that trichloroacetimidate 9 would undergo a COP-catalyzed intramolecular cyclization to provide vinyl chroman 1 (eq 3). By studying COP-catalyzed SN2' intramolecular allylic substitution reactions of (E)-allylic trichloroacetimidates and the formation of enantioenriched vinyl chroman intermediates an improved method could become available for use in organic synthesis. With the ability to form chiral vinyl chromans under neutral conditions with a variety of substitution patterns, a number of biologically active small molecules and their derivatives would be quickly and easily accessible.
Preliminary Studies Initial results obtained while studying the COP-catalyzed vinyl chroman formation are promising. Trichloroacetimidate 9 underwent intramolecular cyclization under neutral conditions using a catalytic amount of 10a to obtain enantioenriched product 1 in high enantioselectivity and high yield (eq 8). Also, a slight increase in enantioselectivity is observed as the reaction temperature is decreased, and cyclization occurs at temperatures as low as —78 °C (Table 1).
2 mol % 10a
0.2 M CH2C12 38 °C.18 h
6
P1-IS 416-1/416-9 (Rev. 9/08) Page II Continuation Format Page
Name of Applicant (Last, First, Middle): Olson, Angela, Christine
Table 1. Temperature effects of COP-catalyzed intramolecular cyclization
NMR Temperature Yield
38 °C >95% 89% 2 mol % 10a >95% 90% Oy CCI2 0,2 M cD2C12i 18 h Temperature NH 0C >95% 90% 9 -25 °C >95% 92%
-78 °C >95% 94%
Further studies established that catalyst loading as low as 0,5 mol °/ is tolerated with no significant effect on reaction times or the level of enantioselectivity observed (Table 2) Importantly, vinyl chroman 1 is the only product observed in the 1H NMR of the crude reaction mixture. Preliminary studies have demonstrated that the COP-catalyzed intramolecular allylic substitution reaction proceeds under neutral reaction conditions, and high enantioselectivity can be achieved when unsubstituted at the C2 position.
Table 2. Catalyst loading effects of COP-catalyzed intramolecular cyclization
Catalyst Conversion ee Loading (observed by NMRI cat. 10a 2 mo I % >95% 92% 0.2 M CD2Cl2 r.1., 3 n 1 mol % 87% 92%
0.5 mol % 75% 94%
Research Design and Methods SUBSTRATE SYNTHESIS In order to increase the synthetic utility of the COP-catalyzed cyclization reaction, an efficient synthesis of the key cyclization substrates is necessary. The first-generation synthesis of (E)-trichloroacetimidate 9 involved DIBAL reduction of dihydrocoumarin 22 to the corresponding lactol followed by Wittig olefination to provide the ct,13-unsaturated methyl ester with >95.5 E:Z selectivity (eq 9). TBS protection of the phenol yielded intermediate 23. Hydride reduction of the ester provided the allylic alcohol which was subsequently converted to the trichloroacetimidate. TBAF deprotection of the phenol afforded the key cyclization substrate 9 in 23% overall yield from lactone 22. While this synthetic strategy provided access to the key cyclization substrate, the synthesis is not convergent and variation of functional groups or substitution patterns on the aromatic ring and/or tether is difficult.
1. DIBAL-H 2. Ph3PCHCO2Me 1. 131BAL-11 0 0 >95:5 E:.7 2, Cl2CCN, DBU (9) 3. TBSCI, link:tarok) CO2Me 3. TBAF 22 23 9
Studies will commence with the investigation of a second-generation synthetic route to access a variety of substituted cyclization substrates 27 in a more convergent fashion (eq 10). Conjugated diene 24 undergoes selective hydroboration of the terminal olefin with 9-BBN.12 Palladium-catalyzed B-alkyl Suzuki-Miyaura coupling of the resulting alkylboranel3 should occur with a variety of functionalized aryl bromides 25 to yield 26. Selective deprotection of the triethylsilyl group, followed by trichloroacetimidate formation and subsequent deprotection of the phenol should yield 27 in a highly convergent manner.
PHS 416-1/416-9 (Rev. 9/05) Page 12 Continuation Format Page
Name of Applicant (Last, First. Middle) Olson, Angela, Christine
1.-TES 2. CleCCN, I) 9-BBN-H DBU (10) OTES 0,CCI II) Pd(0)L,, 3. "E" NH 24 R OSIR13 26 27
Br 25
FUNCTIONAL GROUP TOLERANCE ON PHENOL Once a viable synthetic route is established, the functional group compatibility will be explored. Electronic and substituent effects will be examined to determine their effects on the SN2' intramolecular allylic substitution chemistry in the presence of COP catalysts (eq 11). A vast number of functionalized 2- bromophenol derivatives 25 (R = F, Cl, Me, OMe, CHO, CN, NO2) are commercially available, and after protection and cross-coupling with 24, should provide numerous cyclization precursors 27 of interest.
COP catalyst arCCI3
NH 27 28
SUBSTITUTION PATTERN COMPATIBILITY OF ALL YLIC CHAIN Another important aspect of the COP-catalyzed intramolecular allylic substitution to be explored is the formation of tetrasubstituted stereocenters by attack of the phenol on a trisubstituted olefin 29 (eq 12). This type of reaction has been a limitation in the intermolecular SN2' allylic substitution reaction catalyzed by 10a. However, when the nucleophile is tethered and the substitution event takes place in an intramolecular fashion, this type of reactivity may be feasible to access chroman 30.
COP catalyst OyCCI3 (12) NH 29 30
To fully explore substitution patterns of the sidechain, other conjugated dienes will be required for the 8-alkyl Suzuki-Miyaura cross-coupling reaction. Allylic alcohols with various substitution patterns are known compounds and are readily available from simple starting materials (Figure 4).
Figure 4. Allylic alcohols reported in the literature
OH OH
31 32 33 34 35
HETEROCYCLE SYNTHESIS In addition to synthesizing a variety of vinyl chroman intermediates, the proposed methodology should also be useful for accessing various enantioenriched 0-, N-, and S- heterocycles containing a pendent vinyl group (37) (eq 13). Many small molecules that contain these motifs are important therapeutic agents and display unique biological activity.14,15,16
PHS 416-1/416-9 (Rev. 9/08) Page 13 Continuation Format Page
Name of Applicant (Last, First, Middle): Olson, Angela, Christine
OH COP catalyst (13) 41 NH RI 36 37 369: XR1 = Non 37a: XR1 = NBn 36b: XR1 = 0 370: XR1 = 0 36c: XR1 S 37c: XR1 =
Cyclization precursors for the 0-, N-, and S-heterocycles can be accessed from commercially available allyl bromide 38 and silyl-protected phenol, aniline, or thiol derivatives 39 (eq 14). In the presence of mild base, XR1 will displace the bromide to afford 40. Reduction of the ester, followed by imidate formation and deprotection of the phenol should yield 36, which can then be studied in the COP-catalyzed allylic substitution • reaction.
Br& CO2Me I. DIBAL-H 38 OSIR3 2. Cl3CCN, OH Base DBU OM% (14) 3. "F-" RI 41 NH XR1H 40 39 36 39a: XR1= NBn 36a: XR1 = Non 39b: XR1 = 0 361,: XRI = 0 39c: XR1 = 36c: XR1 = S
APPLICATION IN TOTAL SYNTHESIS As a measure of the utility of this new methodology, the synthesis of a biologically important small molecule Nebivolol (2) will be pursued (Figure 5). Nebivolol is an active and selective antihypertensive agent that acts as a I31-adrenergic blocker.1 It is used to treat heart conditions and is marketed in over 50 countries. This small molecule is of particular interest because access to synthetic intermediates lacking substitution at the C2 position was previously limited using other technologies. It is envisioned that the newly developed ' methodology will provide access to both enantiomers of chroman 38 from trichloroacetimidate 37 by using opposite enantiomers of chiral catalyst 10a. Amine 39 can be accessed from (+)-38 via epoxidation of the olefin, followed by attack of an azide at the terminus of the epoxide and reduction of the azide moiety. Aldehyde 40 can be accessed from dihydroxylation of (+38 followed by selective oxidation of the primary alcohol using TEMP0.18 The epoxidation and dihydroxylation steps will be investigated first using substrate- directing methods. If needed, catalyst-controlled methods may also be invoked. Reductive amination of primary amine 39 with aldehyde 40 would provide Nebivolol (2) in five linear steps from prochiral (E)-allylic trichloroacetimidate 37.
Figure 5. Synthetic plan toward Nebivolol
I. Epoxidation 2. NaN3 H201 F 3. Axicle Reduction (4)-38 39 0 Reductive cat be Amination OyCCI3 2 OH NH 37 I. Dihydroxylation 2. TEMPO (+38 40
PHS 416-1/416-9 (Rev 9/08) Page 14 Continuation Format Page Name of Applicant (Last, First, middle): Olson, Angela, Christine
Conclusion The COP-catalyzed SN2' allylic substitution chemistry of prochiral trichloroacetimidates demonstrates great synthetic potential for the formation of enantioenriched vinyl chromans, which can be elaborated into biologically active small molecules in few synthetic transformations. Further examination is required to explore and define the scope of functional groups and substitution patterns that are compatible in the catalytic system. This methodology is not limited to the formation of vinyl chromans and may be used to access other enantioenriched 0-, N-, and S-heterocycles. Currently, the methods used to access enantioenriched vinyl chroman species and their analogues are limited and the development of a highly selective and efficient method would be beneficial to the synthetic community.
Literature Citations
I De Cree, J; Geukens, H.; Leempoels, J.; Verhaegen, H. "Haemodynamic Effects in Man During Exercise of a Single Oral Dose of Narbivolol (R 67555), a New Beta-1-Adrenoceptor Blocking Agent: A Comparitive Study with Atenolol, Pindolor and Propranolol" Drug Dev. Res. 1986, 8, 109-117.
2 Dashiwada, Y.; Yamazaki, K.; Ikeshiro, Y.; Yamagishi, T.; Fujioka, T.; Mihashi, K.; Mizuki, K.; Cosentino, L. M.; Fowke, K.; Morris-Natschke, S. L.; Lee, K. H. "Isolation of Rhododaurichromanic Acid B and the Anti-HIV Principles Rhododaurichromanic Acid A and Rhododaurichromenic Acid from Rhododendron dauricue Tetrahedron 2001, 57, 1559-1563.
. 3 Vitamin E; Mechlin, L. J., Ed.; Marcel Dekker: New York, 1980.
4 Terao, K.; Niki, E. "Damage to Biological Tissues Induced by Radical Initiator 2,2'-Azobis(2-amidinopropane) Dihydrochloride and its Inhibition by Chain-Breaking Antioxidants" J. Free Rad. Biol. Med. 1986, 2, 193-201.
5 Trost, B. M.; Shen, H. C.; Dong, L., Surivet, J. P•• Sylvain, C. ''Synthesis of Chiral Chromans by the Pd- Catalyzed Asymmetric Allylic Alkylation (AAA): Scope, Mechanism, and Applications" J. Am. Chem. Soc. 2004, 126, 11966-11983.
'Welter, C.; Dahnz, A.; Brunner, B.; Streiff, S.; Dubon, P.; Helmchen, G. 'Highly Enantioselective Synthesis of Heterocycles via Intramolecular ft-Catalyzed Allylic Amination and Etherification" Org. Lett. 2005, 7, 1239- 1242.
7 Kirsch, S. F.; Overman, L E Catalytic Asymmetric Synthesis of Chiral Allylic Esters" J. Am. Chem. Soc. 2005, 127, 2866-2867
8 Kirsch, S. F.; Overman, L. E.; White, N. S. "Catalytic Asymmetric Synthesis of Allylic Aryl Ethers" Org. Lett. • 2007, 9, 911-913.
Overman, L. E.; Carpenter, N. E Organic Reactions; John Wley & Sons, Inc.: Hoboken, NJ, 2005, Vol. 66, pp 3-97.
16 Anderson, C. E.; Overman, L. E. "Catalytic Asymmetric Rearrangement of Allylic Trichloroacetimidates. A Practical Method for Preparing Allylic Amines and Congeners of High Enantiomeric Purity" J. Am. Chem. Soc. 2003, 125, 12412-12413.
12 Lange, H.; Frohlich, R.; Hoppe, ID "Cu(I)-Catalyzed Stereospecific Coupling Reactions of Enantioenriched a- Stannylated Benzyl Carbamates and Their Application" Tetrahedron, 2008, 64, 9123-9135. PHS 416-1/416-9 (Rev. 9)08) Page 15 Continuation Format Page
Name of Applicant (Last, First, middle): Olson, Angela, Christine
13 Chemler, S. R.; Trauner, D.; Danishefsky, S. J The B-Alkyl Suzuki—Miyaura Cross-Coupling Reaction: Development, Mechanistic Study, and Applications in Natural Product Synthesis" Angew, Chem., Int. Ed., 2001, 40, 4544-4568.
14 Stillings, M. R.; Chapleo, C. B.; Butler, R. C. M.; Davis, J. A.; England, C. D.; Myers, M.; Myers, P. L.: Twaddle, N.; Welbourn, J. C.; Doxey, J. C.; Smith, C. F. C. "u-Adrenoreceptor Reagents. Synthesis of Some 2- Substituted 14-Benzodioxans as Selective Presynaptic a2-Adrenoreceptor Antagonists" J. Med. Chem. 1985, 28,1054-1062.
IS Hibert, M. F.; Gittos, M. W.; Middlemiss, D. N.; Mir, A. K.; Fozard, J. R. "Graphics Computer-Aided Receptor Mapping as a Predictive Tool for Drug Design: Development of Potent, Selective, and Stereospecific Ligands for the 5-HTIA Receptor" J, Med. Chem, 1988, 31, 1087-1093.
16 Fagan, G. P.; Chapleo, C. B.; Lane, A. C.; Myers, M.; Roach, A. G.; Smith, C. F. C.; Stillings, M. R.; Welbourn, A. P. "Indoline Analogs of Idazoxan: Potent a2-Antagonists and al-Antagonists" J. Med. Chem. 1988, 31,944-948.
IT Yokoyama, J.: Kobayashi, H.; Miyazawa, M.; Yamaguchi, S.; Hirai, Y. "Palladium(II)-Catalyzed Cyclization of Urethanes and its Application to a Total Synthesis of 1-Deoxynojirimycin'' Heterocycles 2007! 74, 283-292.
la De Luca, L.; Giacomelli, G.; Porcheddu, A. "A Very Mild and Chemoselective Oxidation of Alcohols to Carbonyl Compounds" Org. Lett. 2001! 3,3041-3043.
PHS 416-1/416-9 (Rev. 9/08) Page 16 Continuation Format Page
Name of Applicant (Last, First. Middle): Olson, Angela, Christine
Respective Contributions
I was responsible for the development and preparation of the attached research training plan Professor Overman approved the proposal before submission of the application packet.
Selection of Sponsor and Institution
I chose to attend the University of California, Irvine because of the prestige of the chemistry department as well as the broad range of research opportunities available. The department is well-equipped to support quality research and the facilities are of top quality. I chose to work with Professor Overman because of my interest in the synthesis of organic molecules that have interesting and important biological activities. His research program allows me to explore new methods in organic synthesis in a highly established and well-respected laboratory
Responsible Conduct of Research
Students entering Professor Overman's group are provided written guidelines on standard experimental protocols, laboratory notebooks and characterization data, ethical conduct in research, ethical guidelines to the publication of chemical research, misconduct in research, conduct in science and scientists, and on the integrity of research. Professor Overman holds individual meetings with each incoming student to discuss these issues In addition, the Department of Chemistry at the University of California, Irvine currently offers a course entitled "Responsible Conduct of Research". This course is offered annually as a one quarter course and is taught by regular rank faculty.
PHS 416-1/416-9 (Rev. 9/08) Page 17 Continuation Format Page Name of Applicant (Last, first, middle): Olson, Angela, Christine
SPONSOR/CO-SPONSOR BIOGRAPHICAL SKETCH Provide the following information for the sponsor (co-sponsor). DO NOT EXCEED FOUR PAGES.
NAME OF SPONSOR (CO-SPONSOR) POSITION TITLE Larry E. Overman ePA rmniantac IICCR NAME Distinguished Professor of Chemistry
EDUCATION/TRAINING (Begin •th baccalaureate or other initial professional education, such as nursing. and include postdoctoral training.) DEGREE INSTITUTION AND LOCATION YEAR(s) FIELD OF STUDY (if applicable) Earlham College B.A. 1965 Chemistry University of Wisconsin (H.VV. Whitlock, Jr.) Ph.D. 1969 Organic Chemistry Columbia University (R. Breslow) Postdoctoral 1969-71 Bioorganic Chemistry Positions Assistant Professor of Chemistry, University of California, Irvine, 1971-1976 Associate Professor of Chemistry, University of California, Irvine, 1976-1979 Professor of Chemistry, University of California, Irvine, 1979-1994 Chair, Department of Chemistry, University of California, Irvine, 1990-1993 Distinguished Professor of Chemistry, University of California, Irvine, 1994-
Awards and Fellowships Tetrahedron Prize for Creativity in Organic Chemistry, 2008 The Nagoya Medal of Organic Chemistry, 2007 International Society of Heterocyclic Chemistry Senior Award, 2005 American Chemical Society, Arthur C. Cope Award, 2003 U.C. Irvine Distinguished Faculty Lectureship Award for Research, 2002-2003 Yamada Prize, 2002 2000 Japan Society for the Promotion of Science Fellowship American Association for the Advancement of Science, Fellow 1999 1999 S. T. Li Prize for Achievements in Science and Technology 1999 Earlham College Distinguished Faculty Award Centernary Medal, Chemical Society, U.K., 1997 National Academy of Sciences, 1996 American Academy of Arts & Sciences, 1996 American Chemical Society Award for Creative Work in Synthetic Organic Chemistry, 1995 Guggenheim Fellowship, 1993-1994 C.S. Hamilton Award, University of Nebraska, 1993 Javits Neuroscience Investigator Award, 1985-1992 1992-1999 American Chemical Society, Arthur C. Cope Scholar Award, 1989 Visiting Miller Research Fellow, U.C. Berkeley, 1989 Alexander von Humboldt U.S. Senior Scientist Award, 1985-1987 Camille and Henry Dreyfus Teacher-Scholar Award, 1976-1981 Alfred P. Sloan Foundation Fellow, 1975-1977 U.C. Irvine School of Physical Sciences Distinguished Teaching Award, 1981 U.C. Irvine Alumni Association Distinguished Research Award, 1979 NIH Postdoctoral Fellow, 1969-1971 NIH Predoctoral Fellow, 1966-1969 Phi Beta Kappa, 1965
PHS 416-1 (Rev. 9/09) Page 1 8 Sponsor/Co-Sponsor Biographical Sketch Format Page Name of Applicant (Last, first, middle) Olson, Angela, Christine
Publications (331 Total)
'A Versatile Synthesis of Unsymmetrical 3,3i-Bioxindoles. Stereoselective Mukaiyama Aldo! Reactions of 2- Siloxyindoles with Isatins" Journal of Organic Chemistry 2008, 73, 9151-9154 J. M. Ellis, L. E. Overman, H. R. Tanner and J. Wang
"Enantioselective Total Synthesis of Nankakurines A and B: Confirmation of Structure and Establishment of Absolute Configuration" Journal of the American Chemical Society 2008, 130, 11297-11299 B. L. Nilsson, L. E. Overman, J. Read de Alaniz and J. M. Rohde
''Total Synthesis of (+)—Actinophyllic Acid" Journal of the American Chemical Society 2008, 130, 7568-7569 C L. Martin, L E. Overman and J. M. Rohde
'Catalytic Asymmetric Synthesis of Allylic Thiol Derivatives" Organic Letters 2008, 10, 1485-1488 L. E. Overman, S. W. Roberts and H. Sneddon
"Total Synthesis of the Strychnos Alkaloid (+)—Minfiensine: Tandem Enantioselective Intramolecular Heck- lminium Ion Cyclizafion" Journal of the American Chemical Society 2008, /30, 5368-5377 A. B. Dounay, P. G. Humphreys, L. E. Overman and A. D. Wrobleski
"Construction of Epidithiodioxopiperazines by Directed Oxidation of Hydroxyproline-Derived Dioxopiperazines" Organic Letters 2007, 9, 5267-5270 L. E. Overman and T. Sato
On the Structure of Palau'amine: Evidence for the Revised Relative Configuration from Chemical Synthesis" Journal of the American Chemical Society 2007, 129, 12896-12900 B. A. Lanman, L. E. Overman, R. Paulini and N. S. White
"Synthesis of All Low-Energy Stereoisomers of the Tris(pyrrolidinoindoline) Alkaloid Hodgkinsine and Preliminary Assessment of Their Antinociceptive Activity" Journal of Organic Chemistry 2007, 72, 7909-7914 J. J. Kodanko, S. Hiebert, E. A. Peterson, L. Sung, L. E. Overman, V. de Moura Linck, G. C. Goerck, T. A. Amador, M. B. Leal and E. Elisabetsky
"Total Synthesis of (—)-Sarain Journal of the American Chemical Society 2007, 129, 11987-12002 M. H. Becker, P. Chua, R. Downham, C. J. Douglas, N, K. Garg, S. Hiebert, S. Jaroch, R T. Matsuoka, J A. Middleton, F. W. Ng and L. E. Overman
"Total Synthesis of (+)-Asperazine" Tetrahedron 2007, 63, 8499-8513 S. P. Govek and L. E. Overman
PHS 416-1 (Rev. 9/08) Page 19 Sponsor/Co-Sponsor Biographical Sketch Format Page Name of Applicant (Last, first, middle): Olson, Angela, Christine Ongoing Research Support
NIH GM30859 04/01/2008-01/31/2012 General Methods for Synthesis of Bioacfive Materials The goals of this project are to develop methodology for enantioselective synthesis of polyindohne alkaloids; specific targets include — the octaazadodecacyclic alkaloids psycholeine and quadrigemine, which are structurally novel stimulants of growth hormone (GH) release; the trispyrroloindoline alkaloid hodgkinsine; representative chiral 3a-bispyrroloindoline; and more complex, fungal-derived 3a-bispyrroloindoline alkaloids which display a variety of pharmacological activities including anticancer and antagonism of substance P, neurokinin 1 and cholecystokinin type Et receptors. Develop a short enantioselective total synthesis of vincorine (that will be useful for preparing libraries of vincorine-related structures Prepare the powerful Na+/K+-ATPase- inhibitor ouabain. (3) Invent/develop new ways to control relative and absolute stereochemistry in constructing vicinal quaternary carbon centers. Role: P.I.
NIH HL25854 12/01/2004-11/30/2009 Practical Chemical Synthesis of Complex Alkaloids Develop tandem bimolecular and tethered Biginelli reactions as a simplified entry to bisguanidine analogs of the crambescidin and batzelladine alkaloids; employ libraries of such bisguanidines to: (a) pursue the hypothesis that useful antitumor activity and tumor selectivity will exist in very simple congeners of the crambescidin alkaloids, (b) explore the hypothesis that bisguanidine inhibitors of HIV-1 cell fusion will be improved by removing solvent-exposed side chain fragments, and (c) identify less toxic inhibitors of HIV-1 Net Complete our ongoing enantioselective total synthesis of the polyamine alkaloid sarain A. Complete our ongoing enantioselective total syntheses of the structurally unprecedented hexacyclic bisguanidine alkaloids palau'amine, dibromopalau'amine and stylo-guanidine. Through the synthesis of simpler congeners, define the structural requirements of the promising immunosuppressive activity of palau'amine. Further explore intramolecular azomethine imine cycloadditions in the context of an enantioselective total synthesis of the structurally novel bisguanidine alkaloid massadine. Develop a chemical synthesis strategy for preparing hetisine type C20-diterpene alkaloids. Role: Pt
NSF CHE-0616201 07/01/2006-06/30/2009 New Methods for Asymmetric Synthesis of Valuable Chemicals The goals of this project are to develop new chemical reactions and synthesis strategies that allow valuable organic chemicals to be prepared efficiently from inexpensive precursors. Our research focuses on two little- investigated areas of catalytic reaction development; asymmetric methods for activating carbon-carbon a- bonds for attack by external nucleophiles and developing stereospecific cross-coupling reactions of stereogenic secondary carbon centers. Role: P.I.
NIH NS12389 06/01/2005-05/31/2009 New Methods for the Synthesis of Neurological Agents The goals of this project are to (1) exploit our recent entry to complex oxacyclic diterpenes of the briarellin family, to complete the first total syntheses of asbestinin marine diterpenes. (2) Define the scope of a Prins- pinacol reaction cascade that directly asembles bridged oxatricylic ring systems in the context of total syntheses of the isoindolone alkaloid aspergilin PZ and the salvialane sesquiterpene 1,5-epoxysalvial-4(14)- ene. (3) Further expand the scope of Prins-pinacol reaction cascades in the context of a total synthesis of the structurally novel hydroxylamine alkaloid sieboldine A. (4) Further expand the scope of the powerful aza-Cope- Mannich synthesis of complex nitrogen heterocycles in the context of a total synthesis of the recently-reported hexacyclic alkaloid daphnipaxinin. (5) Continue our exploratory development of new reaction cascades for forming nitrogen and oxygen heterocycles. (6) Develop general methods to prepare 2-N-acylamino-1,3-dienes and define the Diels-Alder chemistry of these undeveloped amino-substituted dienes. (7) Collaborate in the biological evaluation of our synthesis targets and analogs. Role: P.I.
PHS 416-1 (Rev. 9/08) Page 20 Sponsor/Co-Sponsor Biographical Sketch Format Page Name of Applicant (Last, First. Middle): Olson, Angela, Christine Section II—Sponsor and Co-Sponsor Information Current support: My laboratory is supported by four major federal grants and smaller unrestricted grants from several pharmaceutical companies: NIH-NS 12389 "New Methods for the Synthesis of Neurological Agents" (06/01/05-05/31/09) $1,513,111 (TC) PHS-HL 25854 "Practical Chemical Synthesis of Complex Alkaloids" (12/01/04-11/30/09) $1,823,887 (TC) NSF-CHE-0616201 "New Methods for the Asymmetric Synthesis of Valuable Chemicals" (7/01/06-6/30/09) $645,840 (TC) NIH-GM 30859 "General Methods for Synthesis of Bioactive Materials" (04/01/08-01/31/12) $1,441,503 (TC). Sponsor's Previous Fellows/Trainees I have supervised more than 50 NIH Postdoctoral Fellows. Representative recent fellows are: Dr. Jose Madalengoitia, Professor Department of Chemistry, University of Vermont Dr. John Wolfe, Associate Professor, Department Chemistry, University of Michigan Dr. Neil Garg, Assistant Professor, Department Chemistry and Biochemistry, UCLA (K99/R00 award) Dr. Jason Katz, Senior Research Scientist,' Dr. Aaron Wrobleski, Research Scientist,' I have a long-standing involvement in mentoring scientists from . Past undergraduate mentees include Vy Dong (Assistant Professor, Department of Chemistry, I and Brian Leon and Alex Cortez (current Ph.D. students CSU and Boston College); former graduate mentees include Alex Romero (research scientist, and Ram6n Pineda (Coro Fellow in Public Affairs); former postdoctoral mentees who have gone on (or will go) to tenure-track academic posts in the U.S. include Jose Madalengoitia (Professor of Chemistry, University of Vermont), Mary Cloninger (Professor of Chemistry, Montana State University, UC Presidents Fellow 1997-1999), and Javier Read de Alaniz (Colorado State University, UC Presidents Fellow 2006-2008). Training Plan, Environment, Research Facilities To increase selectivity and safety, new pharmaceuticals introduced into clinical practice are increasingly complex chiral molecules marketed as single enanfiomers. Chiral drug sales are greater than $200 billion today and are estimated to increase significantly in coming years. Angela Olson's proposed program of research should lead to new methods for preparing complex heterocyclic molecules as single enantiomers, initially chiral chromans, thus providing the pharmaceutical industry with new tools for the synthesis and discovery of single enantiomer drugs. The importance of gaining skills in organic synthesis was recently highlighted by Dr. Elias A. Zerhouni, Director of NIH (July 3, 2006 cover story in Chemical and Engineering News): "One interesting result of the NIH Roadmap development process came when we surveyed scientists to find out what the stumbling blocks for biological sciences were. The number one stumbling block turned out to be synthetic organic chemistry. I was shocked because I thought the limiting factor was computational biology. So the NIH Roadmap really changed my view of the importance of chemistry and chemical engineering." My research group is interested in the development of new reactions and strategies that allow complex molecules to be assembled efficiently with high stereo- and enanfiocontrol. We are particularly interested in the formation of complex polycyclic networks and in inventing/developing transformations for preparing molecules having a large number of heteroatoms. Current studies in the area of reaction engineering focus on a broad range of transformations: cascade cyclization processes initiated by iminium, oxonium and sulfenium cations, construction of quaternary carbon centers from the union of prostereogenic nucleophiles with chiral electrophiles, cycloaddition reactions of N-amidinyliminium ions, asymmetric transformations catalyzed by novel palladacychc Pd(II) complexes, and new cascade sequences in which absolute chirafity is established by asymmetric Heck reactions. We have active total synthesis programs underway that target a dozen natural products; these targets are structurally diverse and include guanidinium alkaloids, polypyrrolidinoindoline alkaloids, epipolythiodioxopiperazine toxins, diterpenoid polycyclic ethers, and other structurally novel molecules such as daphinipaxinin and kapakahine A. Many of these target molecules display biological activities of potential importance in medicine. Natural products synthesized in my laboratory during the past three years (all for the first time), include: (±)-actinophyllic acid, (—)-sarain A, (+)-nankakurines A and B, (+)- gliocladin C, (+)-guanacastepene N, (+)-minfiensine, (—)-crambidine, (—)-crambescidin 359, and (—)-
PHS 416-1/416-9 (Rev. 9r0B) Page 21 Continuation Format Page Name of Applicant (Last, First, middle), Olson, Angela, Christine Section II—Sponsor and Co-Sponsor Information dehydrobatzelladine C. In all cases, these syntheses featured new synthetic transformations developed in our laboratories. Ms. Angela Olson will work on the topic of her application, developing catalytic asymmetric syntheses of chiral chromans. I would stress that many other chiral heterocycles, nitrogen as well as oxygen, should be available by related methods. I see her broadening her research objectives towards other heterocycles during the latter stages of her Ph.D. training. Ms. Olson will also receive training in the general area of reaction and synthesis design and medicinal chemistry by participation in our weekly research group meetings (once a month these focus on complex molecule synthesis design — molecule of the month) and from auditing special topics courses in the synthesis and medicinal chemistry areas. Her training in the area of medicinal chemistry will also revolve around our weekly research group meetings. A number of these meetings focus on contemporary topics in bioorganic and medicinal chemistry. Ms. Olson will also benefit from Irvine's excellent organic chemistry seminar program. Because of support from I I this program is particularly strong in the area of synthetic organic and medicinal chemistry. The training environment at Irvine in the area of synthetic organic chemistry is outstanding. Twelve faculty members have active programs in this area - S. Blum, A. R. Chamberlin, S. Hanessian, Z. Guar, E. Jarvo, J Nowick, L. E. Overman, K. S. Shea, S. Rychnovsky, D. Van Vranken, C. Vanderwal, and K. Woerpel. The instrumentation to support research in this area is among the best in the country. The Chemistry Department at the University of California, Irvine maintains shared analytical instrumentation facilities to support the research effort. Major equipment and facilities pertinent to the research described in this proposal include: UCI Biomolecular NMR Facility: This facility is operated by Dr. Evgeny Fadeev and is equipped with an 800 MHz spectrometer. UCI Chemistry NMR Facility: This facility, staffed by PhD. NMR spectroscopist Dr. Philip Dennison, provides routine access to a range of 400, 500 and 600 MHz NMR spectrometers. Department Mass Spectrometry Facility: Dr. John Greaves and one full-time technician operate this facility. The facility has walk-in access to three instruments: a Micromass LCT API-TOE that supports APCI and ESI, and two Finnigan Trace Quad-GCMS's (Cl and El). The facility has two magnetic sector instruments: a Micromass Autospec that supports El, Cl, Static and dynamic LSIMS/FAB, Field Desorption Ionization and Field Ionization and a Micromass 7070 medium resolution magnetic sector. For polymers and proteins the facility has a Perseptive DESTR MALDI-TOF. For sequencing peptides it has a tandem Quad-TOF instrument. UCI Chemistry Department X-Ray Facility: This facility, supervised by Dr. Joseph Ziller, has 2 diffractometers, both with low temperature capability, 1 with CCD. UCI Chemistry Department Spectroscopy Facility: This facility, headed by Dr. Wytze van der Veer, provides primarily laser spectroscopy support and CD instrument for the use of the organic and bioorganic groups. UCI Parallel Synthesis Facility and Organic Compound Archive. The Department of Chemistry at UC-Irvine is building a state-of-the-art, Parallel Synthesis Facility and Organic Compound Archive. The Organic Compound Archive, which currently consists of approximately 15,000 small molecules collected from the synthetic chemistry research groups at UC Irvine, will be arrayed into bar-coded 96-well microtiter plates to be available to UCI researchers for screening. Number of Fellows/Trainees to be Supervised During the Fellowship During Ms. Olson's tenure, my laboratory will likely number —15-20 (-30% grad students/-70% postdoctorals). I anticipate that several postdoctorals will be NRSA fellows. Applicant's Qualifications and Potential for a Research Career Ms. Olson has compiled a record of academic excellence at both her baccalaureate institution, Northern State University, and in the UCI Ph.D. program, where she compiled a stron oursework average. Angela gave a strong performance on her oral advancement to candidacy Ph D. examination last spring. Angela has already recorded a significant research success by showing that our cataly c asymmetric synthesis of branched allylic phenols can be accomplished with a new chiral Pd(II) complex (COP-TCA) and utilize imidate derivatives of readily available (E)-allylic alcohold Angela has a charming personality and excellent communication skills. That she is a most-promising young I scientist is apparent in the impressive collection of awards and fellowships she has received. She is certainly well qualified to undertake the research proposed in this application. After completing her Ph.D. in my laboratory, Ms. Olson should be extremely well qualified to pursue a career in the health sciences. PHS 416-1/416-9 (Rev, 9/08) Page 22 Continuation Format Page
NAME OF APPLICANT (Last, first, middle initial) Kirschstein-NRSA Individual Fellowship Application Olson, Angela, C. Checklist
To be completed by Applicant
A. TYPE OF APPLICATION IM NEW application (This application is being submitted to the PHS for the first time) r) RESUBMISSION of application number (This application replaces a prior unfunded version of a new or renewal application)
I-1 RENEWAL of award number (This application Is to extend a funded award beyond its current award penod )
Name of former 111 CHANGE of Sponsoring Institution Institution
B. ASSURANCES/CERTIFICATIONS In signing the application Face Page, the authorized organizational representative agrees to comply with the policies, assurances and/or certifications listed in the application instructions when applicable Descdptions of individual assurances/certifications are provided in Part III, and listed in Part I If unable to certify compliance, where applicable, provide an explanation and place it after this page.
C. KIRSCHSTEIN-NRSA SENIOR FELLOWSHIP APPLICANTS ONLY 1 PRESENT INSTITUTIONAL BASE SALARY Amount Academic Period/number of months
2 STIPEND/SALARY DURING FIRST YEAR OF PROPOSED FELLOWSHIP
a. Stipend requested from PHS Amount Number of months
b. Supplementation from other sources Amount Number of months Type (sabbatical leave, salary, etc.) Source
D. TUITION and FEES
Predoctoral applicants should list estimated combined costs of tuition and fees. Postdoctoral applicants should list the estimated costs for the tuition and fees for courses planned that support the research training experience. For postdoctoral applicants, those courses should be described under Section D. Research Design and Methods of the Research Training Plan Health insurance for predoctoral and postdoctoral fellowships is now paid as part of the institutional allowance. Senior Fellowship applicants should omit this section.
1-1 None Requested Funds Requested:
Year - 06 Year -01 Year -02 Year -03 Year -04 Year-OS (when applicable)
$12,838.11 $14,635.45 $16,684.41
PHS 416-1 (Rev. 9/08) Page 23 Checklist Form Page