CHEMISTRY 124224 ORGANIC STRUCTURE ANALYSIS

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CHEMISTRY 124/224ORGANIC STRUCTURE ANALYSIS

• Dr. Taro Amagata
• Project Scientist, UC Santa Cruz
• EMAIL amagata_at_chemistry.ucsc.edu

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LECTURE ONE

• Verifying or Creating Structural Drawings
• The Expressway (i.e. Concise Approaches) to
  Structure Determination
• Types of Structure Elucidation Problems
• Brief History
• The Four Techniques Their Relative Merits
• The Steps An Overview
• Important Resources
• A Problem to be Solved

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What are ORGANIC COMPOUNDS?
Chemical compounds with carbon atom backbone
Diamond? CO2, CO? H2CO3?
C-C and C-H bond
Organic Molecular Structures
TWO DIMENSIONAL THREE DIMENSIONAL
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STRUCT DRAWINGS SHOW

• 2D FRAME WORK
• CARBON SKELETON
• FUNCTIONAL GPS
• LOCATION OF FGs

3D FRAME WORK 1 RELATIVE STEREO 2 ABSOLUTE
STEREO 3 CONFORMATIONAL FEATURES
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VERIFYING OR CREATING STRUCTURAL DRAWINGS
1. A COMMON TASK 2. MANY ELEMENTS 3. DEFINING
STEREO STRUCTURES 4. THE STRATEGIES
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VERIFYING OR CREATING STRUCTURAL DRAWINGS
1. A COMMON TASK A FASCINATING LIST
C46N7-11O7-11.
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2. CREATING STRUCTURAL DRAWINGS MANY ELEMENTS
Engineered Biosynthesis of Type I PKS - DEBS from
S. erythraea
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3. DEFINING STEREO STRUCTURES
CHIRALITY RELATIONSHIPS AMONG ISOMERS
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4. CONCISE APPROACHES
COURSE FOCUS
DESIRED OUTCOMES MF ID OF FCN GROUPS CH,
CC, CZ, OR RINGS FCN GP POSITIONS
REGIOCHEM STEREOCHEM
FOUR TECHNIQUES NMR MS IR UV-VIS

• OBTAIN DATA
• INTERPRET
• SPECTRA

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REQUIREMENTS FOR A CONCISE APPROACH
STEP-BY-STEP ANALYSIS UNDERSTANDING OF BASIC
ORGANIC CHEM KNOW COMMON FUNCTIONAL GROUPS
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REQUIREMENTS FOR A CONCISE APPROACH
STEP-BY-STEP ANALYSIS KNOW STABLE VS. UNSTABLE
STRUCTURES DEALING WITH ALTERNATIVES
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COURSE GOALS

• MASTERY OF NON MATH APPROACH TO O.S.A.
• UNDERSTAND FUNDAMENTALS OF METHODS
• TRANSLATE ABSTRACT SPECTRA TO ORGANIC STRUCTURES
• DEFINING KEY EXPERIMENTS TO PROVIDE KEY DATA
• PROBLEM SOLVING TO GAIN EXPERIENCE
• -NO UNIVERSAL EXPERT SYSTEM
• -BE ABLE TO DEAL WITH CONFLICTING DATA SETS
• -DEVELOP WORKABLE STRATEGIES
• ACCESS TO MODEL DATA, DATABASES, A.I.-TOOLS
• LIBRARY RESOURCES
• EXPERT SYSTEMS
• APPLYING A GLOBAL APPROACH

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SOLVING STRUCTURES THIS CAN BE CHALLENGING!
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TWO DIFFERENT STRUCTURES BUT, SAME NMR DATA!
pyrostatin B C6H10N2O2 J. Enzyme Inhibition 1995,
8, 223.
ectoine C6H10N2O2 Eur. J. Biochem. 1993, 214, 897.
177.0 (C)/ 161.5 (C)/ 53.6 (CH), 4.06 dd, 5.4,
5.4 / 38.0 (CH2), 3.28 ddd, 13.5, 8.4, 4.8/ 23.6
(CH2), 2.11 m/ 19.1 (CH3), 2.22 s
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Two Important Examples The Complex Cases
C40H36Cl2N6O7 (MW 782) J. Am. Chem. Soc. 1991,
113, 2303
C53H86O19 J. Am. Chem. Soc. 2003, 125, 5296
C40H34Cl2N6O6 (MW 764) Angew. Chem. Int. Ed.
2001, 40, 4765 4770
C53H83O17Cl Org. Lett. 2004, 6, 2607.
RECENT TRIALS AND TRIBULATIONS IN THE STRUCTURE
ELUCIDATION OF MARINE-DERIVED BIOMOLECULES
Amagata, Segraves, Crews NPR In preparation
MOLECULES OF MISTAKEN IDENTITY TOTAL
SYNTHESIS Nicolaou, Snyder, Angew. Chem. 2005,
44, 1012
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3 TYPES OF PROBLEMS

• COMMERCIAL SAMPLES
• - VERIFYING THE LABEL
• SYNTHETIC REACTION PRODUCT
• - VERIFYING THE COURSE OF A REACTION
• UNKNOWN NATURAL PRODUCT
• -ESTABLISHING A NEW CHEMOTYPE
• MOST DIFFICULT TYPE OF APPLICATION
• O.S.A. PRINCIPLES BIOGENETIC, TAXONOMIC
  ASSUMPTIONS

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IS STRUCTURE ELUCIDATION ON MOLECULES ? 1000 AMU
TRIVIAL?
MW 200 MF C3H6Br2
YES
NO
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IS STRUCTURE ELUCIDATION ON MOLECULES ? 1000 AMU
TRIVIAL?
MW 200 MF C3H6Br2
Br-CH2-CH2-CH2-Br
YES
NO
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WHAT ABOUT PALYTOXIN?
MW 2677 MF C129H223N3054 1ST ISOLN.
1960s 1ST STRUCTURE 1980s
P 2
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BRIEF HISTORY
I NON-CHEMICAL METHODS 1900s TASTING
NOW DISCOURAGED SMELLING (ALSO
DISCOURAGED) BUT ODOROMETRY?
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ODOROMETERY ANOTHER EXAMPLE
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BRIEF HISTORY
I NON-CHEMICAL METHODS 1900s TASTING
NOW DISCOURAGED SMELLING (ALSO
DISCOURAGED) BUT ODOROMETRY LIMITED
UTILITY II CHEMICAL METHODS 1940s SPOT
TESTS 1950s QUALITATIVE CHEM SOLID
DERIVATIVES
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BRIEF HISTORY
I NON-CHEMICAL METHODS 1900s TASTING
NOW DISCOURAGED SMELLING (ALSO
DISCOURAGED) BUT ODOROMETRY LIMITED
UTILITY II CHEMICAL METHODS 1940s SPOT
TESTS 1950s QUALITATIVE CHEM SOLID
DERIVATIVES III SPECTROSCOPIC METHODS
(NON-CHEMICAL) 1940s UV/VIS 1950s MASS
SPECTROMETRY IR 1960s PROTON NMR 1960s
COMBINED USE NMR, IR, MS, UV-VIS
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Spectrometric Identification of Organic
Compounds 1960 BASSLER SLIVERSTEIN

• Consider the plight of the chemist confronted
  with a few mgs of a completely unknown organic
  liquid isolated from a complex mixture by GC.
• CLASSICAL APPROACH VIA THE FOLLOWING STEPS
• He smells the liquid
• He carries out fusion qual. tests for
  elements
• Uses chemical rxns to id functional groups
• Collect standard data (bp, ri) to scan CRC-type
  tables
• Prepare crystalline derivative for mp comparison
  to lit
• Look for mp depression effects
• Problem if no satisfactory fit recourse is
  combustion
• analysis for MW determination
• More than 20 mg required to proceed for new compd
• Recourse is to new tools IR, UV, MS, 1H NMR

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RELATIVE MERITS OF TECHNIQUES
DATA MS 29 PEAKS IR 12 PEAKS 1H NMR 1
PEAK 13C NMR 1 PEAK UV/VIS 0 PEAKS
More is less??
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BEGIN HERE
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USES OF MOLECULAR FORMULAOR PARTIAL FORMULA
Unsaturation Number (UN) Hydrogen Deficiency
Index (HDI)
CnH2n2 ref. point ADD H FOR EACH X ADD CH
FOR EACH N OR P OR H FOR EACH N OR P
EXAMPLES UN 1 C6H12O EVEN H COUNT C6H11Cl
ODD H COUNT C6H13N ODD H COUNT C6H14N2
EVEN H COUNT
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4 ASSEMBLE SUBS 5 CLUSTER SUBS 6 TOTAL STRUC
1
2
7 RE-EVAL STRUCTS
3 (ATOM CONNECT.)
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9 EVAL STRUCT BY THEORY
P 8
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USE DATABASES
P 8
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DNP Substructure Search
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Rapid Identification of Aselacin C
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Some Available Databases

• Dictionary of Natural Products
• Over 170,000 compounds
• AntiBase 2005
• Over 31,022 compounds
• Marine lit 2006
• Over 17,000 compounds
• ACD/HNMR and CNMR DB
• Over 300,000 assigned chemical structures
• ACD/Structure Elucidator
• Over 410,000 compounds
• Over 1,600,000 structural fragments

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DEREPLICATION GONE BAD AN IMPORTANT LESSON
NAT PRODS
TOT SEMI SYN
SYN Stoltz TL 2003, 44, 1203 Nomo Comm B!
Nomofungin Paper Withdrawn JOC 2003, 68, 1640
94 ppm
80 ppm
JOC 2001, 66, 8717
Numata TL 1993, 34, 2355
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FOR THE IMMEDIATE FUTURE
HOW MANY STRUCTURES FIT C2H3O2Cl ?
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P 6
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Six Basic Steps to Dereplication 1 ID organism
then search literature or databases for known
compounds isolated (eg. SciFinder Scholar
search). 2 Biological screening of the crude
extract (eg. anti-tumor). 3 Chemical screening
for info about the physical properties A portion
of the crude extract is passed down different
solid phase supports to obtain polarity, charge
and size information on the bioactive compound(s)
present.  Bioactive fractions are then analyzed
by HPLC-MS. 4 HPLC microtiter plate collection
of one of the bioactive fractions obtained from
chemical screening Once the active wells are
identified, the UV chromophore or MS for the
active compounds can be identified from the HPLC
chromatogram (PDA contour plot or MS-MS frag
patt). 5 Mass spectrometry data is mined. Both
- electrospray mass spectrometry -
establish a molecular weight and molecular
formula 6 Novel chemistry may present, publishe
paper wait for phone calls.
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Dereplication Workflow

• Structure and fragment search using software
  approaches

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Dereplication Workflow

• Perform substructure search in private,
  commercial or online databases

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http//www.cas.org/cgi-bin/regreport.pl
 
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LITERATURE SEARCHING
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http//library.ucsc.edu/science/subjects/chem/inde
x.html
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USES OF MOLECULAR FORMULAOR PARTIAL FORMULA
UNSATURATION NUMBER (HDI OR UN) FUNCTIONAL
GROUP CATEGORIES
SELECTED EXAMPLES UN 0 C-C NOT A FCN
GROUP UN 1 RING, ALKENE, CARBONYL, IMINE,
NITRO UN 2 TWO RINGS, POLYENE, CUMULENE,
ALKYNE NITILE, ISONITRILE, ANHYDRIDE UN
3 NON-BENZENOID AROMATICS UN 4 ARENE, PYRIDINE
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