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Chemistry 27The Organic Chemistry of Life

Harvard University Spring, 2006Matthew Shair Course Information

Instructor Professor Matthew Shair

Head TF Shu Sin Chng (sschng@fas.harvard.edu)

Lab Head TF Allen Aloise (aloise@fas.harvard.edu)

Textbooks: There are three volumes required for this course. Each is available atHarvard Copy Services in the basement of the Science Center.

The red book is similar to the 2005 version.You will need a clean white book to take your own notes.The blue book is similar to the 2005 version.

Sourcebook (red book) contains all reading material for the course,including comprehensive lecture notes and17 articles provided as additional reading

Pre-Notes (white book) contains abridged versions of the lectures tofacilitate the process of note-taking

Practice Problems (blue book) contains previous problems from Chem 27,including problem sets, hour exams, andfinal exams

READING ASSIGNMENTS FROM THE RED BOOK ARE GIVEN FOR EACH SECTION OF THE COURSEON PAGES 4-5 OF THIS BOOK, WHERE THEY ARE CORRELATED WITH THE PRE-NOTES PAGES FOR THECORRESPONDING LECTURES. IN ADDITION, SEVEN PROBLEM SETS WILL BE DUE DURING THESEMESTER. THE NUMBERS OF THE BLUE BOOK PROBLEMS COMPRISING THESE SETS ARE LISTEDONLINE.

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LecturesLectures will be delivered in Science Center B on Monday, Wednesday, and Friday by ProfessorMatthew Shair. Lectures will begin promptly at 11:07 AM and end at 12:00 PM. On occasion, guestspeakers may give lectures on specific topics. Lecture attendance is extremely important, since thelectures will be the primary source of material for all examinations.

Discussion SectionsPlease complete your sectioning via the Harvard network by February 3, 5pm. Section assignments willbe posted on February 5 outside SC 114, and you should also receive e-mail confirmation of yoursection assignments. The first sections will meet the week of February 6. Requests for section changesshould be submitted to the Head TF (sschng@fas.harvard.edu) by no later than February 10. Sectionattendance is mandatory for Chem 27, and the expectations for section include, but are not limited to, thefollowing: 1) be prepared to discuss intelligently any lecture material since the last section, 2) beprepared to discuss any reading material (Sourcebook) appropriate to this lecture material, 3) beprepared to work problems, either in the form of a written quiz or in oral presentation at the blackboard.

Laboratory SectionsYou must attend and complete every laboratory section in order to pass Chem 27. We have made everyattempt to minimize the amount of busy work associated with the laboratory portion of the course. Tothat end, we have simplified the lab write-ups so that you can complete them before leaving the lab.However, failure to attend and complete a lab will result in a failing grade for Chem 27. Moreinformation about the laboratory sections will be made available by the Lab Head TF on the first week ofclass. You will need the following textbooks for the laboratory section:

The Lab Manual (available at the Science Center stockroom).Zubrick, James W. The Organic Chemistry Lab Survival Manual, any edition (3rd through6th) will suffice (available at the Harvard Coop).

World Wide Web SitePlease visit the Chem 27 web site frequently to stay up-to-date on course-related information. The URLis http://www.courses.fas.harvard.edu/~chem27/index.html. The web site will provide continuallyupdated information throughout the semester, such as announcements, handouts from section leaders,answer keys to problem sets, and links to related biological, medical, and chemical sites. In addition,we have also made the computer graphics used in class available for download through the web site.Please take advantage of this resource.

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Additional ReferencesIn addition to the Chem 27 Sourcebook (red book), you may find it helpful to refer to any generalorganic chemistry text throughout the semester, such as McMurry, J., Organic Chemistry, 6th Edition.As an additional reference, we have also placed a general biochemistry text (Stryer, L. Biochemistry, 3rdEdition, 1988. New York: W.H. Freeman and Company) on reserve in Cabot Library.

Molecular ModelsA set of molecular models is indispensable to learning organic chemistry and dealing with questions ofstereochemistry. Molecular models from Holden-Day or Allyn & Bacon are recommended. Model kitsfrom Chem 17/30 are sufficient.

GradingChem 27 grades will be determined using three components: laboratory section grades, discussionsection grades, and examination grades.

Laboratory SectionYour laboratory section leader will assign a grade based upon your performance on laboratory write-upsand pre-lab quizzes administered in laboratory section. You must attend and complete every laboratorysection in order to pass Chem 27. More information about lab write-ups and quizzes will be providedby the Lab TFs during the first week of laboratory section. Your laboratory grade will count as 10% ofyour overall grade for the course.

Discussion SectionYour discussion section leader will assign a grade based upon your attendance, and completion ofassigned problem sets. Your discussion section grade will count as 10% of your overall grade for thecourse.

ExaminationsThere will be three one-hour exams given during regular lecture periods (see dates on page 6). Yourlowest score of the three (relative to the class mean) will be dropped. However, you must take all threeexams. Exemptions will be considered only if a doctor’s note is provided. There will be no make-upsexaminations for the one-hour exams. Each one-hour exam (except the one dropped) will count as 20%of your course grade. The final exam will count as 40% of your course grade. All regrade requestsmust be made in writing to the Head TF by noon on Friday of the following week.

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Chemistry 27The Organic Chemistry of Life

Harvard University Spring, 2006Matthew Shair Course Outline and Reading

Sourcebook Pre-Notes

Introduction 4, 166-173 9

I. Structure and Chemistry of Proteins 5-50, 174-203 10-57

A. Protein Structure 5-22 11-231. Amino Acids2. Conformational Analysis3. Protein Folding

B. Peptide Sequencing 22-25 24-311. Edman Degradation2. Mass Spectrometry

C. Polypeptide Synthesis 26-36, 174-179 32-441. Amide Bond Formation2. Protecting Groups3. Solid Phase Synthesis4. Peptide Synthesis Reactions5. Directionality of Synthesis6. Cellular versus Laboratory Synthesis

D. Proteases 37-50, 180-203 45-571. Serine Proteases2. Serine Protease Inhibitors3. Aspartyl Proteases4. Aspartyl Protease Inhibitors5. N-Terminal Nucleophile Hydrolases

II. Enzymes and Cofactors 51-105, 204-231 58-116

A. Enzyme Mechanisms 51-65, 204-211 59-721. Glycolysis2. Triose Phosphate Isomerase (TIM)3. Shikimic Acid Pathway4. DHQ Synthase5. Chorismate Mutase

B. Enzyme Cofactors 66-100, 212-231 73-1101. Pyridoxal Phosphate (PLP)2. NAD+/NADH3. FAD/FADH24. ATP

C. Signal Transduction 101-105 111-1161. Phosphorylation2. Effective Molarity3. Cancer

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Chemistry 27The Organic Chemistry of Life

Harvard University Spring, 2006Matthew Shair Course Outline and Reading

Sourcebook Pre-Notes

III. Structure and Chemistry of Nucleic Acids 106-134, 232-249 117-146

A. Nucleic Acid Structure 106-113 118-1261. Nitrogenous Bases2. Role of 2'-OH in RNA3. Ribozymes

B. Nucleic Acid Synthesis 113-119 125-1301. Cellular Synthesis of DNA2. Laboratory Synthesis of DNA

C. DNA-Damaging Reagents 119-134, 232-249 131-1461. Modes of DNA-Binding2. Aflatoxin and Benzopyrene3. DNA Crosslinking Agents4. Enediyne Antibiotics

IV. Biosynthesis of Natural Products 135-164, 250-297 147-192

A. Pantetheine and ACP-Mediated Synthesis 135-148, 250-257 148-1691. Nonribosomal Peptide Synthesis2. Fatty Acid Synthesis3. Polyketide Synthesis

B. Terpenes 148-164, 258-297 170-1921. Biosynthesis of IPP and DMAPP2. Inhibition of Terpene Biosynthesis3. Stereochemistry of Terpene Biosynthesis4. Attachment of Isoprene Units to

Nonterpene Natural Products5. Terpene Proteins6. Cyclization of Terpenes7. Steroids8. Daphniphyllum Biosynthesis

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Chemistry 27The Organic Chemistry of Life

Harvard University Spring, 2006Matthew Shair Problem set assignments

A list of the problems assigned for problem sets will be posted on the website. All of these problemscan be found in the Practice Problems book (blue book). Due dates for each problem set will be postedonline and announced in lecture at least one week in advance, and will potentially cover material throughthe lecture before the assigned due date. Late problem sets will not be accepted. Your section TF willbe responsible for collecting your problem sets, and these problems will be reviewed as part of thediscussion section. The problem sets are a crucial test of your ability to understand and integrate thecourse material, as well as valuable practice for the exams. Your completion of the problem sets will be acomponent of your section grade, but rather than emphasizing the accuracy of answers, the sectionleaders will focus on 1) your timely completion of the assignment, and 2) your ability to discussintelligently the problems in the context of the discussion section. In addition, you might find it usefulto work through other (unassigned) problems from the Practice Problems volume as further preparationfor your midterm and final exams. Finally, we have included the entirety of the 2004 and 2005 Chem 27exams online. We intend this to guide your expectations relative to the content and difficulty of all 2006exams.

Coverage of Material for Exams:Exam One: Section I Friday, February 24Exam Two: Section II Friday, March 24Exam Three: Sections III and IV Friday, April 28

The final exam will be cumulative.

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Chemistry 27The Organic Chemistry of Life

Harvard University Spring, 2006Matthew Shair Table of Contents

Topic PagesCourse Information 1-3Course Outline & Reading 4-5Problem Sets 6Table of Contents 7-8

Biological macromolecules — introduction 9

The Structure and Chemistry of Proteins 10-57

The amino acids 11Conformational properties of small molecules 12-14Conformational properties of amino acids and peptides 15-19Non-covalent interactions and protein folding 20-23Synthetic chemistry of proteins: Edman degradation 24-26Mass Spectrometry 27-31Synthesis of proteins: overview 32Synthesis of proteins: protecting groups 33-35Synthesis of proteins: the reactions 37-41Biosynthesis of proteins 42-44Serine proteases 45-48Aspartyl proteases 49-51N-terminal hydrolases 52-57

Enzymes and Cofactors 58-116

Glycolysis 59TIM 60-62Shikimic acid pathway 63DHQ synthase 64-68Chorismate mutase 70-72PLP 73-82PLP and redox reactions 83-85PLP-mediated reactions 86-87PLP inhibitors 88-89NAD+ / NADH 90-94FAD / FADH2 95-97FAD-mediated reactions 98-100ATP 101-103ATP reactivity 104-108Biosynthesis of vitamin B12 109Biosynthesis of ATP 110Signal transduction 111-116

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The Structure and Chemistry of DNA and RNA 117-146

DNA structure 118-120RNA hydrolysis and catalysis 121-124DNA synthesis 125-127Laboratory DNA synthesis 128-130Carcinogens and anti-tumor agents 131-132Carcinogens: aflatoxin, benzo[α]pyrene 133-135Anticancer agents 136-137Mitomycin C 138Cisplatin 139Enediyne anti-cancer agents 140-146

Biosynthesis of Natural Products 147-192

Natural products: overview 148-149Non-ribosomal peptide biosynthesis 150-152Fatty acid biosynthesis 153-158Polyketide biosynthesis 158-1676-Deoxyerythronolide B synthase (DEBS) 168Rapamycin biosynthesis 169Isoprenyl biosynthesis 170-172Terpene biosynthesis 173-176Isomerases and cyclases 177-179Sterochemistry of terpene biosynthesis 180-182Steroid biosynthesis 183-186Proto-daphniphylline 187-189Syntheses of proto-daphiphylline 190-192