Structural Elucidation
and Misassignments
in Natural Products
Daniel Newbury
April 19, 2012
Overview
 History
of Structural Theory
 Classical Techniques

Elucidation of Quinine
 Modern


Spectroscopic Techniques
Classical vs Current Methodology
Types and Frequency of Reassignments
 Example
Structural Misassignments
 Moving Forward
 Conclusion
2
Brief History of Structural Theory
 1832
~ Organic Dualism
C7 H6 O2
Bz = C7H5O
Bz*OH
O2
Cl2
C 7H 6O
Bz*H
Bz*I
KI
NH3
C7 H5 OCl
Bz*Cl
Br 2
 1853
C7 H5 OI
C7 H7 ON
Bz*NH2
Justus von Liebig &
Friedrich Wöhler
PbS
C7 H 5OBr
C14H 10 O2 S
Bz*Br
Bz2*S
~ Theory of Types
HCl
H2O
NH3
H2
Charles-Frédéric
Gerhardt
3
Brief History of Structural Theory
 1857
~ Tetravalence of Carbon
 1858 ~ Self-linking of Carbon

Atomic Constitution of Molecules
Kekule (1858)
4
Couper (1858)
Loschmidt (1861)
Classical Techniques
 Physical




Properties
Boiling Point
Melting Point
Density
Colour
H
N
N
H
OH
H
H
OMe
 Elemental
Analysis
 Qualitative Tests
 Derivatization
 Degradation
 Total Synthesis
Cholesterol
N
N
Fe
N
H
N
N
O
HO2 C
H
H
HO
CO2 H
Hemin
5
HO
Quinine
N
H
Strychnine
Elucidation of Quinine

1817 – Pelletier and Caventou


Levorotatory
N
Empirical Formula
OMe
1856 – Perkin

N
OH
H
1854 – Strecker


First isolation
1853 – Pasteur


H
Total synthesis attempt leading to Mauveine
NH
2C10H13N
3 [O]
C20H22N2O2
H2O
Me
N-allyltoluidine
N-allyltoluidine
Pelletier, P. J.; Jcaventou, B. Ann. Chim. Phys. 1819, 12, 113.
Pasteur, L. Compt. Rend. 1853, 37, 110
Pasteur, L. Liebigs Ann. Chem. 1853, 88, 209.
Strecker, A. Liebigs Ann. Chem. 1854, 91, 155.
Rabe, P.; Ackerman, E.; Schneider, W. Ber. Dtsch. Chem. Ges. 1907, 40, 3655.
Rabe, P. Ber. Dtsch. Chem. Ges. 1908, 41, 62
6
Elucidation of Quinine

1843 - Presence of two 3º Nitrogens
H
OH
H
I2
H
H
N
H
N
OH
N
OH
OMe
OMe
OMe
C20H24N2O2
N
N
H
2 Eq MeI
C22H30N2O2I2
Quinine

1880-1892 - Presence and nature of OH-group
H
Ar
H
OH
C20H24N2O2
Quinine
7
H
N
Ar
Acetylation
H
N
H
OAc
C22H26N2O3
N
Ar
Hydrolysis
N
H
OH
C20H24N2O2
Quinine
Elucidation of Quinine

1873-1903 - Presence of Terminal Vinyl Group
H
O
OH
H
H
H
N
Ar
H
O
H
OH
Ar
C20H24N2O2
O3
N
H
H
H
OMe
C19H22N2O3
CH2O
Formaldehyde
1874-1904 - Identification of Aromatic Moiety
H
N
N
H
OMe
OH
OMe
C20H24N2O2
Quinine
8
N
OH
Quinine

N
KOH fusion
N
C10H9NO
6-methoxyquinoline
Elucidation of Quinine

1894 - Identity of the bicyclic moeity
H
O
H
N
N
H
OH
H
O
OH
OH
COOH
OH
N
H
N
OMe
N
H
OMe
C20H24N2O2
KOH fusion
C10H9NO
[O]
C10H9NO
-cincholoiponic acid
"Meroquine"
OH
C8
1907 Paul Rabe
Correct constitution
N
N C4
OMe
9
N
C3
Elucidation of Quinine
 C8
Configuration
R
H
OH
H
OMe
H OH
N
HO
8
H
N
N
N
8
H
N
Cinchonine R = H
Quinidine R = OMe
H
8
N
H
N
OH
OMe
Cinchonidine R=H
Quinine R=OMe
10
N
No Cyclisation
OMe
Elucidation of Quinine
 C3/C4
stereochemistry
H
N
4
3
H
N
OH
N
H
3
OH
H
1. HBr
2. Zn/AcOH
N
4
OH
N
H
N
H
Von-Braum
Degradation
1. Ag Salt
2. Br2
3. Raney Nickel
EtO 2C
OMe
PBr 5
CO2 Et
Absolute
hydrogenation
NaOH
CO2 H
Br
Br
Relative
1944 Vladamir Prelog
Relative and Absolute
H
N
N
H
OH
O
OMe
11
OH
(-)-2-methylbutanoic acid
› . Prelog, E. Zalan, Helv. Chim. Acta 1944, 27, 535.
V
›V. Prelog, E. Zalan, Helv. Chim. Acta 1944, 27, 545.
Woodward, R. B.; Doering, W. E. J. Am. Chem. Soc. 1944; 66(5),849.
100 Years of Elucidation
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›Strecker, Liebigs Ann. Chem. 1854, 91, 155.
› . Kerner, Jahresbericht 1869, 718.
G
›E. Caventou, E. Willm, Liebigs Ann. Chem. 1870, 7 (suppl),247.
›W. Zorn, J. Prakt. Chem. 1873, 8, 279.
›O. Hesse, Liebigs Ann. Chem. 1874, 174, 340.
›H.Weidel, Liebigs Ann. Chem. 1874, 173, 76.
›Z. H. Skraup, Liebigs Ann. Chem. 1879, 199, 348.
›Z. H. Skraup, G. Vortmann, Liebigs Ann. Chem. 1879, 197, 235.
›A. Baeyer, Ber. Dtsch. Chem. Ges. 1879, 12, 460.
›A. Baeyer, Ber. Dtsch. Chem. Ges. 1879, 12, 1320.
›W. Knigs, Ber. Dtsch. Chem. Ges. 1879, 12, 97.
›Z. H. Skraup, Ber. Dtsch. Chem. Ges. 1879, 12, 330.
›Z. H. Skraup, Ber. Dtsch. Chem. Ges. 1879, 12, 1104.
›O. Hesse, Liebigs Ann. Chem. 1880, 205, 314.
›Z. H. Skraup, Liebigs Ann. Chem. 1880, 201, 324.
›W. J. Comstock, W. Knigs, Ber. Dtsch. Chem. Ges. 1880, 13, 285.
›O. Hesse, Ber. Dtsch. Chem. Ges. 1881, 14, 1892.
›Z. H. Skraup, Monatsh. Chem. 1881, 2, 587.
›G. Frost, C. Bhringer, Ber. Dtsch. Chem. Ges. 1882, 15, 1659.
›H. Wiedel, Monatsh. Chem. 1882, 3, 79.
›Z. H. Skraup, Monatsh. Chem. 1883, 4, 699.
›S. Hoogewerff, W. A. Van Dorp, Rec. Trav. Chim. 1883, 2, 10.
›A. Baeyer, V. Drewsen, Ber. Dtsch. Chem. Ges. 1883, 16, 2207.
›W. Knigs, W. J. Comstock, Ber. Dtsch. Chem. Ges. 1884, 17, 1986.
›W. Knigs, W. J. Comstock, Ber. Dtsch. Chem. Ges. 1885, 18, 1223.
›Z. H. Skraup, Monatsh. Chem. 1885, 6, 762.
›O. Fischer, Jahresbericht 1885, 1014.
›W. J. Comstock,W. Knigs, Ber. Dtsch. Chem. Ges. 1887, 20, 2510.
›Z. Skraup, Monatsh. Chem. 1888, 9, 783.
›Z. H. Skraup, Monatsh. Chem. 1889, 10, 39.
›H. Schniderschitsch, Monatsh. Chem. 1889, 10, 54.
›W. Knigs, Ber. Dtsch. Chem. Ges. 1890, 23, 2669.
E. Lippmann, F. Fleissner, Monatsh. Chem. 1891, 12, 327.
›E. Lippmann, F. Fleissner, Monatsh. Chem. 1891, 12, 661.
›A. Schubert, Z. H. Skraup, Monatsh. Chem. 1891, 12, 667.
›Z. H. Skraup, Monatsh. Chem. 1891, 12, 431.
›W. Knigs,W. J. Comstock, Ber. Dtsch. Chem. Ges. 1892, 25, 1539.
›Z. H. Skraup, F. Konek von Norwall, Ber. Dtsch. Chem. Ges. 1893, 26, 1968
O. Hesse, Liebigs Ann. Chem. 1893, 276, 88.
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›Z. H. Skraup, F. Konek von Norwall, Monatsh. Chem. 1894, 15, 37
W. Knigs, Ber. Dtsch. Chem. Ges. 1894, 27, 900.
›W. Knigs, Ber. Dtsch. Chem. Ges. 1894, 27, 1501.
›W. von Miller, G. Rohde, Ber. Dtsch. Chem. Ges. 1894, 27, 1187.
›W. von Miller, G. Rohde, Ber. Dtsch. Chem. Ges. 1894, 27, 1280.
›Z. H. Skraup, Monatsh. Chem. 1895, 16, 159.
›Z. H. Skraup, Ber. Dtsch. Chem. Ges.1895, 28, 12.
›W. Knigs, Ber. Dtsch. Chem. Ges. 1895, 28, 3150.
›W. Knigs, Ber. Dtsch. Chem. Ges. 1895, 28, 1986.
›W. Knigs, Ber. Dtsch. Chem. Ges. 1895, 30, 1326.
›W. von Miller, G. Rohde, Ber. Dtsch. Chem. Ges. 1895, 28, 1056.
›W. von Miller, G. Rohde, Ber. Dtsch. Chem. Ges. 1900, 33, 3214.
›A. Christensen, J. Prakt. Chem. 1901, 63, 330.
›Z. H. Skraup, Monatsh. Chem. 1901, 22, 1097.
›W. Pfitzinger, J. Prakt. Chem. 1902, 66, 263.
›A. Christensen, J. Prakt. Chem. 1903, 68, 430.
›A. Christensen, J. Prakt. Chem. 1904, 69, 193.
›A. Mengel, W. Knigs, Ber. Dtsch. Chem. Ges. 1904, 37, 1322.
›W. Knigs, A. Mengel, Ber. Dtsch. Chem. Ges. 1904, 37, 1328.
›W. Knigs, Liebigs Ann. Chem. 1906, 347, 172.
›P. Rabe, Liebigs Ann. Chem. 1906, 350, 180.
›P. Rabe, E. Ackerman, W. Schneider, Ber. Dtsch. Chem. Ges. 1907, 40, 3655.
›P. Rabe, Ber. Dtsch. Chem. Ges. 1908, 41, 62.
›P. Rabe, Liebigs Ann. Chem. 1909, 365, 353.
›P. Rabe, Liebigs Ann. Chem. 1909, 365, 377.
›P. Rabe, A. McMillan, Ber. Dtsch. Chem. Ges. 1910, 43, 3308.
›M. Pfannl, Monatsh. Chem. 1911, 32, 241.
›A. Kaufmann, E. Rothlin, P. Brunnschweiler, Ber. Dtsch. Chem. Ges. 1916, 49, 2302.
›P. Rabe, B. Bttcher, Ber. Dtsch. Chem. Ges. 1917, 50, 127.
›E. Jungfleisch, E. Lger, Ann. Chim. 1920, 14, 59.
›J. Kenner, Ann. Rep. Chem. Soc. 1922, 19, 157.
›L. Seekles, Rec. Trav. Chim. 1923, 42, 69.
›W. Leithe, Ber. Dtsch. Chem. Ges. 1932, 65, 660.
›K. Freundenberg, J. Am. Chem. Soc. 1932, 54, 234.
›T. Domnski, J. Suszko, Rec. Trav. Chim. 1935, 54, 481.
›T. A. Henry,W. Solomon, E. M. Gibbs, J. Chem. Soc. 1935, 966.
›E. Lger, Bull. Soc. Chim. 1938, 5, 183.
›V. Prelog, E. Zalan, Helv. Chim. Acta 1944, 27, 535.
›V. Prelog, E. Zalan, Helv. Chim. Acta 1944, 27, 545.
Role in Chemical Reaction Discovery

Structural elucidation provided driving force for
novel chemical reactivity
 Heterocyclic chemistry
H
N
N
N
N
Fe
N
H
OH
N
H
N
N
O
H
H
HO
OMe
HO 2C
CO 2H
Hemin
Quinine

Strychnine
C-C bond formation/cleavage
H
H
HO
13
H
Cholesterol
Common Spectroscopic Era
14
Modern Spectroscopic Techniques
Vigneaud, V.; Carpenter, F. H.; Holley, R. W.; Livermore, A. H.; Rachele, J. R. Science 1946, 104(8), 431-3,450.
Dickinson R. G.; Raymond A. L.. J. Am. Chem. Soc. 1923, 45, 22.
Borman, S.; Russell, H.; Siuzdak, G. Today’s Chemist at Work. 2003, 5, 47-49.
NMR and MRI: Applications in Chemistry and Medicine. American Chemical Society, 2001.
15
Varian HR-30 Advertisement
16
Classical vs Modern Techniques
Then
Multi-gram quantities
Destructive:
17
Now
(Sub)milligram quantities
Non-Destructive
Derivatization and degradation
Advanced spectroscopic
techniques
Relative/absolute assignment
unsolvable in most cases
Relative/absolute assignment
generally solvable
Relatively simple structures
Significantly more complex
structures
Multiple years
Significantly less time
“While it is undeniable that organic chemistry will be
deprived of one special and highly satisfying kind of
opportunity for the exercise of intellectual élan and
experimental skill when the tradition of purely chemical
structure elucidation declines…
R. B. Woodward (1963)
Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker, H. U.; Schenker, K. Tetrahedron. 1963, 19, 247-288
18
Frequency of “Structural Revision”
180
160
140
120
100
80
60
40
20
0
19
Types of Structural Revisions
Stereochemical Revisions
O
H
HO
O
OH
H
H
HO
H
O
OH
H
(proposed)
isoepitaonidiol
1992
OH
H
(revised)
isoepitaonidiol
2011
OH
O
O
O
O
CO2 H
H
O
H
(proposed)
stagonolide D
2008
CO2 H
H
(revised)
stagonolide D
2012
R
(proposed)
Litseaverticillol E
2001
H
R
(revised)
Litseaverticillol E
2005
Rovirosa, J.; Sepulveda, M.; Quezada, E.; San-Martin, A. Phytochemistry 1992, 31, 2679.
Areche, C.; San-Martin, A.; Rovirosa, J.; Munoz, M. A.; Hernandez-Barragan, A.; Bucio, M. A.; Joseph-Nathan, P. J. Nat . Prod. 2010, 73, 79.
Evidente, A.; Cimmino, A.; Berestetskiy, A.; Mitina, G.; Andolfi, A.; Motta, A. J. Nat. Prod. 2008, 71, 31.
Vadhadiya, P. M.; Puranik, V. G.; Ramana, C. V.; J. Org. Chem. 2012, 77, 2169−2175.
Soejarto, D. D.; Fong, H. H. S.; Pezzuto, J. M. Tet. Lett. 2001, 42, 8587-8591.
Vassilikogiannakis, G.; Margaros, I.; Montagnon, T.; Stratakis, M. Chem. Eur. J., 2005, 11, 5899-5907.
20
Types of Structural Revisions
Constitutional Revisions
O
O
EtO
HO
O
O
(proposed)
phomopsin B
2008
EtO
O
HO
OH
OH
(revised)
dothiolerone A
2011
O
Ar
O
O
N
N
O
OH
(proposed)
sarcodin
2000
OH
Ar
O
OH
N
O
O
O
(revised)
sarcodin
2011
Huang, Z.; Cai, X.; Shao, C.; She, Z.; Xia, X.; Chen, Y.; Yang, J.; Zhou, S.; Lin, Y. Phytochemistry. 2008. 69, 1604.
Izuchi, Y.; Koshino, H.; Hongo, Y.; Kanomata, N,; Takahashi*, S. Org. Lett. 2011. 13(13), 3360.
Geraci, C.; Neri, P.; Paterno, C.; Rocco, C.; Tringali, C. J. Nat. Prod. 2000. 63, 347.
Lin, D. W.; Masuda, t.; Biskup, M. B.; Nelson, J. D.; Baran*, P. S. J. Org. Chem. 2011. 76(4), 1013.
21
Suyama T. L.; Gerwick, W. H.; McPhail, K. L. Bioorg. Med. Chem. 2011, 19, 6675–6701.
22
Suyama T. L.; Gerwick, W. H.; McPhail, K. L. Bioorg. Med. Chem. 2011, 19, 6675–6701.
23
So What?
24
The journey isn’t always more
important than the destination



Source for Synthetic Penicillin during WWII
“More than a thousand scientists in 39 U.S.
labs became involved in the project”
β-lactam Structure Unknown

R
Competing putative structures
H
N
O
H
N
HN
O
S
CO 2H
Merck Scientists (IR)
Crawfoot-Hodgkin (X-ray 1945)
Sheehan (Synthesis 1957)
H
S
HN
CO 2H
Penicillin
Proposed
Robinson (1944)
O
N
O
R
H
N
N
R
S
H
CO2 H
Penicillin
Proposed
Woodward
J. C. Sheehan, The Enchanted Ring: The Untold Story of Penicillin, MIT Press, Cambridge, 1984, p. 224.
25
Biosynthetic Consequences
Pummerer (1925)
O
O
O
K3 [Fe(CN) 6]
O
O
O
Pummerer Ketone
Barton (1955)
O
O
O
OH
K3 [Fe(CN) 6]
O
O
Barton's Pummerer Ketone
Biosynthesis
OH
OMe
Proposed
OH
OH
MeN
OH
O
Revised
OH
OH
MeN
OMe
MeN
OH
Morphine
26
Reticuline
Structural Misassignments
and their Revisions
27
Examples Covered in Previous Seminars
H
O
O
O HO
H
O
H
H
HO
O
H OH
O
H
NH
HO
NH HN
O
N
N
O O
O
O
Cl
Cl
O
NH
O
H
O
Azaspiracid-1
H H
N
N
H 2N
HO
HN
N
HN
H2 N
N
NH
Diazonimide A
OMe
O
H
O
O
H
Cl
H 2N
Palau’amine
O
O
OH
Hexacyclinol
Nicolaou, K. C.; Koftis, T. V.; Vyskocil, S.; Petrovic, G.; Ling, T.; Yamada, Y. M. A.; tang, W.; Frederick, M. O. Angew. Chem. Int. Ed. 2004, 43, 4318 –4324.
Nicolaou, K. C.; Chen D. Y.-K.; Huang, X.; Ling, T.; Bella, M.; Snyder, S. A. J. Am. Chem. Soc. 2004, 126, 12888-12896.
Seiple, I. B.; Su, S.; oung, I. S.; Lewis, C. A.; Yamaguchi, J.; Baran, P. S. Angew. Chem. Int. Ed. 2010, 49, 1095 –1098.
28
(-)-Brevenal



Ladder frame polyether
K. brevis (marine dinoflagellate)
Non-toxic; brevotoxin family receptor antagonist
Proposed
(-)-Brevenal
(Bourdelais 2004)
OH
H
H O
H H
O
O
H
O
O H
H
O
H
OH
Revised
(-)-Brevenal
(Sasaki 2006)
OH
H
H O
H H
O
O
H
O
O H
H
O
H
OH
Bourdelais*, A. J.; Jacocks, H. M.; Wright, J. L. C.; Bigwarfe, P. M. Jr.; Baden, D. G. J. Nat. Prod. 2005. 68, 2-6.
Fuwa, H.; Ebine, M., Bourdelais, A. J.; Baden, D. G.; Sasaki, M. J. Am. Chem. Soc. 2006. 129, 16989-16999.
29
(-)-Brevenal
Structural Elucidation




FAB gave a m/z=657.4043
 C39H60O8
 10 Double bond equivalents
13C and DEPT confirmed 39 Carbons
 6 CH3, 12 CH2, 15 CH and 5 C
DEPT and HSQC
 5 Rings
TOCSY and COSY
 5 Spin systems.
HMBC
Spin System
Bourdelais*, A. J.; Jacocks, H. M.; Wright, J. L. C.; Bigwarfe, P. M. Jr.; Baden, D. G. J. Nat. Prod. 2005, 68, 2-6.
Fuwa, H.; Ebine, M., Bourdelais, A. J.; Baden, D. G.; Sasaki, M. J. Am. Chem. Soc. 2006, 129, 16989-16999.
30
(-)-Brevenal
Stereochemical Elucidation
NOE
Bourdelais*, A. J.; Jacocks, H. M.; Wright, J. L. C.; Bigwarfe, P. M. Jr.; Baden, D. G. J. Nat. Prod. 2005, 68, 2-6.
Fuwa, H.; Ebine, M., Bourdelais, A. J.; Baden, D. G.; Sasaki, M. J. Am. Chem. Soc. 2006, 129, 16989-16999.
31
(-)-Brevenal
Structural Revision
Natural (-)-Brevenal
Synthesized Proposed
Structure
Synthesized
Proposed
Structure
Bourdelais*, A. J.; Jacocks, H. M.; Wright, J. L. C.; Bigwarfe, P. M. Jr.; Baden, D. G. J. Nat. Prod. 2005, 68, 2-6.
Fuwa, H.; Ebine, M., Bourdelais, A. J.; Baden, D. G.; Sasaki, M. J. Am. Chem. Soc. 2006, 129, 16989-16999.
32
(-)-Brevenal
Structural Revision
COSY, HMQC,
HMBC OK!
Correct
Constitution
Stereocenter
Inversion
Me
OHC
Me
Synthesized
Revised
Structure
H
Me
OH
H O
Me
H
OH
H
O
Me
OH
H
O
O
Me
H
H
Bourdelais*, A. J.; Jacocks, H. M.; Wright, J. L. C.; Bigwarfe, P. M. Jr.; Baden, D. G. J. Nat. Prod. 2005, 68, 2-6.
Fuwa, H.; Ebine, M., Bourdelais, A. J.; Baden, D. G.; Sasaki, M. J. Am. Chem. Soc. 2006, 129, 16989-16999.
33
(-)-Brevenal
Biosynthetic Considerations
H 2O
O
H
H O
O
H
O
O
OH
O
O
O
H
HO O
O
H
OH
O H
H
Hemibrevatoxin-B
Nakanishi, K. Toxicon 1985, 23, 473-479.
Chou, H.-N.; Shimizu, Y. J. Am. Chem. Soc. 1987, 109, 2184-2185.
Prasad, A. V. K.; Shimizu, Y. J. Am. Chem. Soc. 1989, 111, 6476-6477.
Lee, M. S.; Qin, G.; Nakanishi, K.; Zagorski, M. G. J. Am. Chem. Soc. 1989, 111, 6234-6241.
34
Salicylihalamide A



Macrolide
Haliclona sp. (marine Sponge)
Cytotoxicity
H
N
OH
H
N
O
O
OH O
OH
O HO
O
O
Proposed
Salicylihalamide A
(Boyd 1997)
Revised
Salicylihalamide A
(De Brabander 2000)
MS, IR, 1D and 2D NMR,
MM, Mosher’s Acid
Total Synthesis
Erickson, K. L.; Beutler, J. A.; Cardellina, J. H.; Boyd, M. R. J. Org. Chem. 1997, 62, 8188–8192.
Wu, Y.; Esser,L.; De Brabander, J. K. , Angew. Chem. Int. Ed. 2000, 39, 4308–4310.
35
Mosher’s Acids
36
Kinamycin C



Polyketide
Streptomyces murayamaensis (Bacteria)
Antibiotic and antitumor activity
O
AcO
OAc
O
AcO
OH
OH
OH
O
N
C
N
OAc
OAc
OH O
C
N
N
OAc
Proposed
Kinamycin C
(Omura 1973)
Revised
Kinamycin C
(Gould/Dmitrienko 1994)
MS, IR, UV, NMR, Degradation,
Derivatization, X-Ray
2D-NMR, Total Synthesis
Omura, S.; Nakagawa, A.; Yamada, H.; Hata, T.; Furusaki, A.; Watanabe, T. Chem. Pharm. Bull. 1973, 21, 931 – 940.
Gould, S. J.; Tamayo, N.; Melville, C. R.; Cone, M. C. J. Am. Chem. Soc. 1994, 116, 2207 – 2208.
Mithani, S.; Weeratunga, G.; Taylor, N. J.; Dmitrienko, G. I. J. Am. Chem. Soc. 1994, 116, 2209 – 2210.
37
Kinamycin C
Structural Revision
O
AcO
N
C
N
O
O
OAc
OH
Synthetic Analogue
(Dmitrienko1990)
O
HO
N
C
N
Proposed Prekinamycin
(Echavarren 1993)
Possible Constitutional Isomers
O
AcO
OAc
O
OH
OH
O
N
C
N
AcO
VS
OAc
O
OH
OAc
OH
O
N
N
C
AcO
VS
OAc
OH
OAc
OH
O
C
N
N
OAc
Dmitrienko, G. I.; Nielscn, K. E.; Steingart, C.; Ming, N. S.; Willson, J. M.; Weeratunga, G. Tet. Lett. 1990, 31, 3681-3684.
Echavarren, A. M.; Tamayo, N.; Parades, M. C. Tetrahedron Lett. 1993, 34, 4713-4716.
Gould, S. J.; Tamayo, N.; Melville, C. R.; Cone, M. C. J. Am. Chem. Soc. 1994, 116, 2207 – 2208.
Mithani, S.; Weeratunga, G.; Taylor, N. J.; Dmitrienko, G. I. J. Am. Chem. Soc. 1994, 116, 2209 – 2210.
38
Kinamycin C
Structural Revision
O
AcO
OAc
OH
OH
OAc
C
N
N
O
O
HO
O
HO
RH 2(OAc)4, MeOH
OH
O
C
N
N
OH
OH
Natural Prekinamycin
Gould, S. J.; Tamayo, N.; Melville, C. R.; Cone, M. C. J. Am. Chem. Soc. 1994, 116, 2207 – 2208.
39
Moving Forward
40
Universal NMR database

Predictive method

relative and absolute stereochemistry

Compare chemical shift values

Structural properties of a compound are
1) Inherent to the specific stereochemical
arrangement of (small) substituents on it’s
carbon backbone and;
2) Independent from the rest of the molecule
Kobayashi, Y.; Lee, J.; Tezuka, Y.; Kishi*, Y. Org. Lett. 1999, 1, 2177.
Lee, J.; Kobayashi, Y.; Tezuka, Y.; Kishi*, Y. Org. Lett. 1999, 1, 2181.
Kobayashi, Y.; Tan, C.-H.; Kishi*, Y. Angew. Chem. 2000, 112, 4449.
Kobayashi, Y.; Tan, C.-H.; Kishi*, Y. Angew. Chem. 2000, 39, 4279.
Tan, C.-H.; Kobayashi, Y.; Kishi*, Y. Angew. Chem. Int. Ed. 2000, 39(23) 4282.
41
Universal NMR database
Target Structure
OH
OH
OH
O
O
10
HO
OH
OH OH
OH
OH
OH
O
5
O
HO
OH
5
10
Reference structure
OH OH
OH
OR
Oasomycin A: R=H
Oasomycin B: R=A-D-Mannosyl


Step 1: Determine Reference Structure
Step 2: Synthesize all possible diastereomers and record their
chemical shifts


Not required if present in database
Step 3-5: Determine “adjusted chemical shift”


Using NMR predictive software
Eliminates influences not present in the reference structure
Kobayashi, Y.; Lee, J.; Tezuka, Y.; Kishi*, Y. Org. Lett. 1999, 1, 2177.
Lee, J.; Kobayashi, Y.; Tezuka, Y.; Kishi*, Y. Org. Lett. 1999, 1, 2181.
Kobayashi, Y.; Tan, C.-H.; Kishi*, Y. Angew. Chem. 2000, 112, 4449.
Kobayashi, Y.; Tan, C.-H.; Kishi*, Y. Angew. Chem. 2000, 39, 4279.
Tan, C.-H.; Kobayashi, Y.; Kishi*, Y. Angew. Chem. Int. Ed. 2000, 39(23) 4282.
42
Universal NMR database

Step 6: Compare “adjusted chemical shifts” with
actual reference sample values
OH
OH
HO
OH
OH
OH
OH
OH
OH
OH
HO
OH
OH
HO
HO
OH
OH
HO
HO
OH
HO
OH
OH
HO
Kobayashi, Y.; Lee, J.; Tezuka, Y.; Kishi*, Y. Org. Lett. 1999, 1, 2177.
Lee, J.; Kobayashi, Y.; Tezuka, Y.; Kishi*, Y. Org. Lett. 1999, 1, 2181.
Kobayashi, Y.; Tan, C.-H.; Kishi*, Y. Angew. Chem. 2000, 112, 4449.
Kobayashi, Y.; Tan, C.-H.; Kishi*, Y. Angew. Chem. 2000, 39, 4279.
Tan, C.-H.; Kobayashi, Y.; Kishi*, Y. Angew. Chem. Int. Ed. 2000, 39(23) 4282.
43
Universal NMR database
OH
OH
OH
O
O
O
O
OH
O
OH
OH
O
O
HO
OH
OH
OH
OH
OH
OH
OH
MeO
OH
OH
Oasomycin A
HO
HO
Cruentaren B
OH
OH
OH
OH
OH
OH
OH
OMe
OH
OH
OH
OH
H
OH O
H
OH
HO
OH
H
OH
OH
O
H
44
O
O
O
H
OH
O
OH
OH
Ampholidinol 3
H
N
Hexacyclinol*
OH
Conclusion
45
Acknowledgements
Prof. Louis Barriault
Francis Barabé
Gabriel Bellavance
Genevieve Bétournay
Stéphanie Lanoix
Patrick Levesque
Joel Marcotte
Philippe McGee
Mathieu Morin
Dr. Guillaume Revol
Travis Schwantje
Boubacar Sow
Past Members:
Dr. David Lapointe
Jason Poulin
Eric Beaulieu
46
Questions
47