Structure Elucidation: Murata & Breit Methods · PDF fileMagalie GÉRALDY Kalesse Group...

Magalie GÉRALDY

Kalesse Group Seminar

Structure Elucidation:

Murata & Breit Methods

Kalesse Group Seminar

03.12.2012

Introduction Magalie GÉRALDY

03.12.2012 Kalesse Group Seminar 2

D. Menche, Nat. Prod. Rep. 2008, 25, 905-918 Y. Schmidt, K. Lehr, L. Colas, B. Breit, Chem. Eur. J. 2012, 18, 7071-7081 http://de.wikipedia.org/wiki/Datei:Karplus_E.svg

Structure elucidation:

# IR-, UV- ,MS-Spectroscopies, optical rotation, bioinformatics analysis, molecular modeling,… # NMR- (1H; 13C; 1H,1H COSY; 1H,13C HSQC; 1H,13C HMBC, NOESY, residual dipolar couplings) Spectroscopy and NMR interpretation methods (Murata‘s method, Kishi‘s method, Breit‘s method) # Acetonide (Rychnovsky & Evans), Mosher‘s ester, fragmentations, synthetic methods,…

Murata Method Magalie GÉRALDY


N. Matsumori, D. Kaneno, M. Murata, H. Nakamura, K. Tachibana, J. Org. Chem. 1999, 64, 866-876 http://de.wikipedia.org/wiki/Datei:Karplus_E.svg

J-based configuration analysis (JBCA)



A (threo) A-1 A-2 A-3

3J(H-2, H-3) Small Small Large

3J(H-2, C4) Small Large Small

3J(C1, H-3) Small Large Small

X=Me, Y=OR

3J(Cx, H-3) Large Small Small

2J(C3, H-2) Small Large Large

X=OR, Y=OR



B (erythro) B-1 B-2 B-3

3J(H-2, H-3) Small Small Large

3J(H-2, C4) Large Small Small

3J(C1, H-3) Small Large Small

X=Me, Y=OR

3J(Cx, H-3) Large Small Small

2J(C3, H-2) Large Small Large

X=OR, Y=OR


2J(C3, H-2) Large Small Large

N. Matsumori, D. Kaneno, M. Murata, H. Nakamura, K. Tachibana, J. Org. Chem. 1999, 64, 866-876

Rotational isomers and structural analysis

H/H-anti rotamers A-3 and B-3 can be distinguished on the basis of NOEs




Configuration assignment for systems with alternating conformers

C C-1 C-2 C-3

3J(H-2, H-3h) Small Small Large

3J(H-2, H-3l) Large Small Small

[3J(H-2, C4) Small Large Small]

3J(C1, H-3h) Small Large Small

3J(C1, H-3l) Small Small Large

X=Me

3J(Cx, H-3h) Large Small Small

3J(Cx, H-3l) Small Large Small

X=OR

2J(C2, H-3h) Small Large Large

2J(C2, H-3l) Large Small Large

D D-1 D-2 D-3

3J(H-2, H-3h) Large Small Small

3J(H-2, H-3l) Small Small Large

[3J(H-2, C4) Small Large Small]

3J(C1, H-3h) Small Large Large

3J(C1, H-3l) Small Large Small

X=Me

3J(Cx, H-3h) Small Large Small

3J(Cx, H-3l) Large Small Small

X=OR

2J(C2, H-3h) Large Small Large

2J(C2, H-3l) Small Large Large



A (threo) A-1 A-2 A-2 A-3 A-1 A-3

3J(H-2, H-3) Small Small Small Small Large Medium Small Large Medium

3J(H-2, C4) Small Large Medium Large Small Medium Small Small Small

3J(C1, H-3) Small Large Medium Large Small Medium Small Small Small

X=Me, Y=OR

3J(Cx, H-3) Large Small Medium Small Small Small Large Small Medium

2J(C3, H-2) Small Large Medium Large Large Large Small Large Medium

X=OR, Y=OR




1,2-Methine Systems




1,2-Methine Systems

B (erythro) B-1 B-2 B-2 B-3 B-1 B-3

3J(H-2, H-3) Small Small Small Small Large Medium Small Large Medium

3J(H-2, C4) Large Small Medium Small Small Small Large Small Medium

3J(C1, H-3) Small Large Medium Large Small Medium Small Small Small

X=Me, Y=OR

3J(Cx, H-3) Large Small Medium Small Small Small Large Small Medium

2J(C3, H-2) Large Small Medium Small Large Medium Large Large Small

X=OR, Y=OR


2J(C3, H-2) Large Small Medium Small Large Medium Large Large Large





C C-1 C-2 C-2 C-3 C-1 C-3

3J(H-2, H-3h) Small Small Small Small Large Medium Small Large Medium

3J(H-2, H-3l) Large Small Medium Small Small Small Large Small Medium

[3J(H-2, C4) Small Large Medium Large Small Medium Small Small Small]

3J(C1, H-3h) Small Large Medium Large Small Medium Small Small Small

3J(C1, H-3l) Small Small Small Small Large Medium Small Large Medium

X=Me

3J(Cx, H-3h) Large Small Medium Small Small Small Large Small Medium

3J(Cx, H-3l) Small Large Medium Large Small Medium Small Small Small

X=OR

2J(C2, H-3h) Small Large Medium Large Large Large Small Large Medium

2J(C2, H-3l) Large Small Medium Small Large Medium Large Large Large





D D-1 D-2 D-2 D-3 D-1 D-3

3J(H-2, H-3h) Large Small Medium Small Small Small Large Small Medium

3J(H-2, H-3l) Small Small Small Small Large Medium Small Large Medium

[3J(H-2, C4) Small Large Medium Large Small Medium Small Small Small]

3J(C1, H-3h) Small Small Small Small Large Medium Small Large Medium

3J(C1, H-3l) Small Large Medium Large Small Medium Small Small Small

X=Me

3J(Cx, H-3h) Small Large Medium Large Small Medium Small Small Small

3J(Cx, H-3l) Large Small Medium Small Small Small Large Small Medium

X=OR

2J(C2, H-3h) Large Small Medium Small Large Medium Large Large Large

2J(C2, H-3l) Small Large Medium Large Large Large Small Large Medium



N. Matsumori, D. Kaneno, M. Murata, H. Nakamura, K. Tachibana, J. Org. Chem. 1999, 64, 866-876 H. Nakamura, K. Maruyama, K. Fujimaki, A. Murai, Tet. Lett. 2000, 41, 1927-1930

Application: absolute configuration of the terminal acid portion of zooxanthellatoxin

C3‘-C7‘ 3JH3’–H4’

4.5

2JC3’–H4’ -1.0

3JC2’–H4’

2.0 3JH4’–H5’

3.0

2JC4’–H3’

-1.0

3JC26’–H6’h 5.0

3JH5’–H6’h

7.0

2JC4’–H5’ 1.0

3JH5’–H6’l

7.0

2JC5’–H4’ 0.0

3JH6’h–H7’ 7.5

2JC5’-H6’h

-6.0 3JH6’l–H7’

7.0

2JC5’-H6’l -4.0



Application: determination of the absolute configuration of (+)-danicalipin A

T. Yoshimitsu, R. Nakatani, A. Kobayashi, T. Tanaka, Org. Lett 2011, 13, 908-911 T. Kawahara, Y. Kumaki, T. Kamada, T. Ishii, T. Okino, J. Org. Chem. 2009, 74, 6016-6024 C. Nilewski, E.C. Carreira, Eur. J. Org. Chem. 2012, 1685-1698

Determination of the absolute configuration of C11, C12, C13, C14 & C15:

# Determined with Mosher‘s Method (-OH) # C16 determined by comparison with a similar structure





No NOEs observed between H16 and H13 B-3




H. Fuwa, M. Sasaki, Org. Lett. 2010, 12, 584-587 H. Fuwa, T. Suzuki, H. Kubo, T. Yamori, M. Sasaki, Chem. Eur. J. 2011, 17, 2678-2688 S. Ohtaa, M.M. Uyb, M. Yanaic, E. Ohtaa, T. Hiratab, S. Ikegamia, Tet. Lett. 2006, 47, 1957-1960

Application: relative configuration of (-)-exiguolide

C2–C3 C3–C4 C6–C7 C7–C8 C8–C9 C9–C10 C12–C13 C13–C14 C14–C15 C18–C19 3JH2a–H3

large

3JH3–H4ax large

3JH6ax–H7

large

3JH7–H8a large

3JH8a–H9

small

3JH9–H10ax large

3JH12ax–H13

large

3JH13–H14a

large

3JH14a–H15

small

3JH18–H19

small 3JH2b–H3

small

3JH3–H4eq

small

3JH6eq–H7 small

3JH7–H8b

small

3JH8b–H9 large

3JH9–H10eq

small

3JH12eq–H13

small

3JH13–H14b

small

3JH14b–H15 large

2JH18–C19

small 2JH2a–C3

large

2JH4ax–C3 large

2JH6ax–C7 large

2JH8a–C7 large

2JH8a–C9 large

2JH10ax–C9 large

2JH12ax–C13 large

2JH14a–C13

Large

3JH14a–C16 large

3JH18–C20 small

2JH2b–C3 small

2JH4eq–C3

small

2JH6eq–C7 small

2JH8b–C7

small

2JH8b–C9

large

2JH10eq–C9

small

2JH12eq–C13 small

2JH14b–C13

small

3JH14a–C30

small

3JH19–C17

small 3JH2a–C4 small

3JH3–C5

small

3JH6ax–C8 small

3JH7–C9

small

3JH8a–C10

small

3JH9–C11

small

3JH12ax–C14

small

3JH13–C15

small

3JH14b–C16 small

3JH19–C31

large 3JH2b–C4 small

3JH4ax–C2 small

3JH6eq–C8 small

3JH8a–C6 small

3JH8b–C10 large

3JH10ax–C8 small

3JH12eq–C14 small

3JH14a–C12 small

3JH14b–C30 small

3JH3–C1

small

3JH4eq–C2

small

3JH7–C5

small

3JH8b–C6

small

3JH9–C7

large

3JH10eq–C8

small

3JH13–C11

small

3JH14b–C12

small

3JH15–C13

small

C or D systems A-1 system

D-1 D-1 D-1 D-1 C/D-3 D-1 D-1 D-1 C/D-3



M.E. Maier, Nat. Prod. Rep. 2009, 26, 1105-1124

Application: absolute structure of amphidinolide Q

NOEs observed

Mixture of C-3/C-1

C-2

C-1

C-1

D-3

D-1

D-1

Mosher ester



J. Hassfeld, C. Farès, H. Steinmetz, T. Carlomagno, D. Menche, Org. Lett. 2006, 8, 4751-4754

Application: stereochemical determination of archazolid A & B

B-3

B-2 B-3

B-2 B-3

B-3

A-1

Computer-assisted

Mosher ester



L. Castellanos, C. Duque, J. Rodríguez, C. Jiménez, Tetrahedron 2007, 63, 1544-1552

Application: stereoselective synthesis of (-)-4-epiaxinyssmine

NOEs observed

3JH7,H11 = 10.0 Hz



Application: determination of the absolute configuration of kalkitoxin

F. Yokokawa, T. Asano, T. Okino, W.H. Gerwickc, T. Shioirid, Tetrahedron 2004, 60, 6859-6880

Comparison of 13C NMR spectral difference (in DMSO-d6 at 25 °C) of natural and synthetic kalkitoxins:



Application: determination of the relative configuration of chivosazol A

D. Janssen, M. Kalesse, Dissertation 2007

Acetonide: anti

Fragmentation

Murata

Gencluster

Computer-assisted

C/D-1 C/D-1

A-2

B-3 NOE

A- or B-3 No NOE



Application: determination of the relative stereochemistry of (-)-palmyrolide A

R. Tello-Aburto, T.D. Newar, W.A. Maio, J. Org. Chem. 2012, 77, 6271-6289

Murata

Synthesis Synthesis

# Murata method applied to the lactone # C14 determined by comparison with data of the isolation report



Advantages: # Assignment of relative configuration of acyclic structures. # Determination of the relative configuration of chiral centers without synthesis of all the isomers # 3JH,H easily accessible

Limitations: # Not applicable to structures with ring strains # Applicable only with NOE data # One, two or at most three bonds between the asymmetric centers # rotamer ensemble (> 10%) challenging # 2JC,H , 3JC,H determination time consuming (HETLOC, HECADE, HSQMBC, EXSIDE) and interpretation (small/large) # Compounds with nitrogen-substituted acyclic system (Rodriguez method)

Y. Schmidt, B. Breit, Org. Lett. 2010, 12, 2218-2221 Y. Schmidt, K. Lehr, L. Colas, B. Breit, Chem. Eur. J. 2012, 18, 7071-7081

Breit Method Magalie GÉRALDY


Y. Schmidt, B. Breit, Org. Lett. 2010, 12, 2218-2221



anti: Δδ = 0.00-0.1 ppm syn: Δδ > 0.4 ppm





Applications:

machillene anti

Δδ = 0.00

Determined with NOE/NOESY

cryptosphareolide syn

Δδ = 0.25

penicitide A syn

Δδ = 0.29

paecilaminol syn

Δδ = 0.32

No chiral information




Comparison of NMR chemical shifts in various deuterated solvents:

anti HA = 1.35 HB = 1.61 Δδ = 0.26

syn HA = 1.12 HB = 1.88 Δδ = 0.76

microcolin (syn) and epimer (anti)

Applications:

Entry Compound CDCl3 C6D6 [D6]DMSO CD3OD

1 (syn) 0.45 0.55 0.48 0.48

2 (anti) 0.09 0.11 0.15 0.13



anti HA = 1.61 HB = 1.98 Δδ = 0.37

syn HA = 1.61 HB = 2.05 Δδ = 0.44


Limitations:

anti HA = 1.04 HB = 1.31 Δδ = 0.27

anti HA = 1.42 HB = 1.70 Δδ = 0.28

anti HA = 1.50 HB = 1.90 Δδ = 0.40

2-methyl-4-phenylpentanoic acid

atpenin A5

syn HA = 1.00 HB = 1.40 Δδ = 0.40

syn Hc = 0.98 HD = 1.35 Δδ = 0.37

syn HA = 1.02 HB = 1.18 Δδ = 0.40

anti HC = 1.00 HD = 1.40 Δδ = 0.16

intermediates of borrelidin synthesis

bitungolide

anti HA = ? HB = ?

Δδ = 0.57




Verification of the method validity:

syn Δδ = 0.21

syn Δδ = 0.22

xylarinic acids A & B



Application: structure of the fatty acyl chains of Mycobacterium marinum Lipooligosaccharides

Y. Rombouts, L. Alibaud, S. Carrère-Kremer, E. Maes, C. Tokarski, E. Elass, L. Kremer, Y. Guérardel, J. Bio. Chem. 2011, 286, 33678-33688

# Relative configuration at C-2 and C-4 determined with Breit method: Δδexp = 0.53-0.56 ppm anti: Δδ = 0.00-0.1 ppm X syn: Δδ > 0.4 ppm √ (S,S) or (R,R)



Application: structural revision and stereochemical assignement of gephyromic acid

L. Nicolas, T. Anderl, F. Sasse, H. Steinmetz, R. Jansen, G. Höfle, S. Laschat, R.E. Taylor, Angew. Chem. Int. Ed. 2011, 50, 938-941

anti Δδ = 0.43

syn Δδ = 1.10

# Comparison with myriaporone # Comparison with similar anti -and syn-deoxypropionates (Δδ = 0.56 anti-) # Conversion to lactone and NOEs measurements # Determined with Mosher‘s Method (-OH)



Application: convergent synthesis of deoxypropionates

P.S. Diez, G.C. Micalizio, Angew. Chem. Int. Ed. 2012, 51, 5152-5156 Y. Schmidt, K. Lehr, U. Breuninger, G. Brand, T. Reiss, B. Breit, J. Org. Chem. 2010, 75, 4424-4433

A concise convergent synthesis of (-)-vittatalactone:



Application: structure elucidation of eliamid (C23H35NO4)

# Absolute configuration of the stereocenter in the tetramic acid fragment determined by oxidative and hydrolytic degradation (absolute configuration of L-alanine). # Configuration at C-8 determined by comparison with similar natural products and proposed to be R. # Relative configuration at C-2 and C-4 determined with Breit method: Δδexp = 0.23 ppm anti-2,4-dimethyl amides: Δδth = 0.2-0.3 ppm √ syn-2,4-dimethyl amides: Δδth = 0.7-0.8 ppm X

G. Höfle, K. Gerth, H. Reichenbach, B. Kunze, F. Sasse, E. Forche, E.V. Prusov, Chem. Eur. J. 2012, 18, 11362-11370



Application: determination of relative configuration of symmetrical bis-Tröger‘s base derivatives

B. Dolenskýa, V. Parchaňskýa, P. Matějkaa, M. Havlíka, P. Bouřb, V. Král, Journal of Molecular Structure 2011, 996, 69–74

ΔΔδH2 ΔΔδH6 ΔΔδH9

1a exp. 0.037 0.070 -0.044

calc. 0.030 0.025 -0.088

2a exp. 0.128 0.090 -0.025

calc. 0.130 0.090 -0.016

1b exp. 0.073 0.089 -0.088

calc. 0.075 0.021 -0.086

2b exp. 0.240 0.120 -0.090

calc. 0.166 0.136 -0.100

1c exp. 0.077 0.087 -0.077

calc. 0.045 0.040 -0.066

2c exp. 0.219 0.129 -0.041

calc. 0.132 0.131 -0.062

ΔδHx = δHxa - δHxb with x = 2; 6 or 9 ΔΔδH2 = Δδsyn

H2 - ΔδantiH2 > 0

ΔΔδH6 = ΔδsynH6 – Δδanti

H6 > 0 ΔΔδH9 = Δδsyn

H9 – ΔδantiH9 < 0



Advantages: # Determination of the relative configuration # Effect independant of deuterated solvents # Applicable to acyclic structures and macrocycles

Limitations: # Competition of shielding effects # Rigid conformations (oxazolidinone, dithiane,…) or bulky groups (aryl substituents…) affect chemical shift difference # Not applicable to small ring systems


Conclusion Magalie GÉRALDY


# Two NMR methods to determine the relative configuration of natural products > Murata: detailed conformational analysis based on 2/3JC,H and 3JH,H coupling constants > Breit: relative configuration of 1,3,n-methyl-branched carbon chains # Kishi‘s NMR database method for the configurational assignement of neighbouring stereogenic centers: + Independence from conformational flexibility + Use of conventional NMR techniques. - Need of a similar structure for comparison # Rodriguez‘s method for the determination of relative configuration in acyclic 1,3-nitrogen-containing moities

D. Menche, Nat. Prod. Rep. 2008, 25, 905-918 N. Matsumori, D. Kaneno, M. Murata, H. Nakamura, K. Tachibana, J. Org. Chem. 1999, 64, 866-876 Y. Schmidt, B. Breit, Org. Lett. 2010, 12, 2218-2221, Y. Schmidt, K. Lehr, L. Colas, B. Breit, Chem. Eur. J. 2012, 18, 7071-7081 N. Hayashi, Y. Kobayashi, Y. Kishi, Org. Lett. 2001, 3, 2249-2252 S. Di Micco, M.G. Chini, R. Riccio, G. Bifulco, Eur. J. Org. Chem. 2010, 1411-1434


Magalie GÉRALDY

Prof. Michio Murata, 村田道雄 Osaka, Japan

Prof. Bernhard Breit, Freiburg, Germany

NMR Structure Elucidation

Back-up (Breit) Magalie GÉRALDY


L. Nicolas, T. Anderl, F. Sasse, H. Steinmetz, R. Jansen, G. Höfle, S. Laschat, R.E. Taylor, Angew. Chem. Int. Ed. 2011, 50, 938-941

Back-up (Breit) Magalie GÉRALDY


P.S. Diez, G.C. Micalizio, Angew. Chem. Int. Ed. 2012, 51, 5152-5156

Structure Elucidation: Murata & Breit Methods · PDF fileMagalie GÉRALDY Kalesse Group...

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