Structural Misassignment of Natural Products

Well that’snot great….

HOO

HN

OO

N

Me Me

HN

NH

O

N

Cl

Cl

O

NH2Me

Me

OH ONH

HN

OO

N

Me Me

HN

NH

O

N

Cl

Cl

O

OHMe

Me

Jeffrey LipshultzGroup Meeting

MacMillan GroupApril 26, 2016

Oops, I Did It Again: Structural Misassignment of Natural Products

Structural Misassignment of Natural Products

Tsuji, J.; Hashiguchi, S. Tetrahedron Lett. 1980, 21, 2955.

Cholesterol

■ Nobel Prize awarded in 1927, 1928 to Wieland, Windaus

■ Norsorex Process for polynorbornene (1980)

■ Ring-closing Metathesis (RCM)

■ First applied with in situ prepared W/Ti mixed catalysts

nobelprize.org

"for his investigations of the constitution of the bile acids and related substances"

"for the services rendered through his research into the constitution of the sterols and their

connection with the vitamins"

Heinrich Wieland Adolf Windaus


Bernal, J. Nature 1932, 129 , 277 and 721.

Cholesterol

■ Nobel Prize awarded in 1927, 1928 to Wieland, Windaus


Bernal, 1932.

nobelprize.org

Me

Et

OHMe

MeMe

Me

HH

Me

HO

Me

H

Me

Me

ergosterolMe

HH

Me

HO

Me

H

Me

MeH

cholesterol (revised)

cholesterolMe

"It is clear that the usually accepted sterol structure must be considerably modified."


Bernal, J.D. Nature 1932, 129 , 277 and 721.

Cholesterol

■ X-ray crystallographic studies call proposed connectivity into question


nobelprize.org

OHMe

MeMe

general sterolstructure

"Such measurements are difficult to reconcile with the usually accepted sterol formula..."

OH newly proposedsterol structure

Me

Me

Me

"... but agree much better with one where the carbon chain is attached to atom 17 in ring iv..."

" It is clear that the usually accepted sterol structure must be considerably modified."


Heilbron, I. M.; Simpson, J. C. E.; Spring, F. S. J. Chem. Soc. 1933, 626.

Cholesterol

■ X-ray crystallographic studies call proposed connectivity into question


Bernal, J. D.; Crowfoot, D.; Fankuchen, I. Phil. Trans. R. Soc. Lond. A 1940, 239, 135.

OHMe

MeMe

general sterolstructure

OH newly proposedsterol structure

Me

Me

Me

Bernal, J. D.; Crowfoot, D. J. Chem. Soc. 1935, 93.Rosenheim, O.; King, H. Nature 1932, 130 , 315.

Wieland, H.; Dane, E. Hoppe-Seyl. Z. 1932, 210, 268.

Me

Me

MeMe

Me

HO

final (correct) general sterol structure


Büchi, G.; MacLeod, W. D.. J. Am. Chem. Soc. 1962, 84, 3205.

Cholesterol

■ Büchi converted α-patchoulene into patchouli alcohol (isolated 1869)

■ Buchi prepared synthes

Büchi, G.; Erickson, R. E.; Wakabayashi, N. J. Am. Chem. Soc. 1961, 83, 927.

Me

Me H

Me

Me H

OHMe

Me H

O Me

Me H

OH OH

CH3CO3HNaOAc

1. Ac2O, pyr2. 300 °C

3. H2, PtO2

OH2

Dobler, M.; Dunitz, J. D.; Gubler, B.; Weber, H. P.; Büchi, G.; Padilla, O. J. Proc. Chem. Soc. London 1963, 383.Büchi, G.; MacLeod, W. D.; Padilla, O. J. J. Am. Chem. Soc. 1964, 86, 4438.

■ But, it turns out, there was something else going on...

Me H

MeHO

confirmed byX-ray

matches naturalmaterial

"Since neither of these reaarangements was recognised, patchouli alcohol and α-patchoulene were assumed to have identical carbon skeletons."


Büchi, G.; MacLeod, W. D.. J. Am. Chem. Soc. 1962, 84, 3205.

Cholesterol

■ Buchi prepared synthes

■ First applied with in situ prepared W/Ti mixed catalysts

Büchi, G.; Erickson, R. E.; Wakabayashi, N. J. Am. Chem. Soc. 1961, 83, 927.

Me

Me H

Me

Me H

O Me

Me H

OH OH

Me H

MeOHHO

CH3CO3HNaOAc

1. Ac2O, pyr2. 300 °C

3. H2, PtO2

1. Ac2O, pyr2. 300 °C

3. H2, PtO2

■ But, it turns out, there was something else going on...

H2O

Dobler, M.; Dunitz, J. D.; Gubler, B.; Weber, H. P.; Büchi, G.; Padilla, O. J. Proc. Chem. Soc. London 1963, 383.Büchi, G.; MacLeod, W. D.; Padilla, O. J. J. Am. Chem. Soc. 1964, 86, 4438.

■ Büchi converted α-patchoulene into patchouli alcohol (isolated 1869)

Me

Me H

OH

Me H

MeHO

confirmed byX-ray

matches naturalmaterial



outline

But X-rays are not the panacea...

Nomofungin

Computational tools can help...Hexacyclinol

nobelprize.org

Diazonamides

Kinamycins

Aquatolide

Better spectroscopic techniques have certainly helped...Isoschizogamine

Sporol

Sclerophytin

But sometimes you just need some common sense...

Structural Misassignment of Natural ProductsCholesterol

■ C7-epimeric structures of schizogamine and isoschizogamine described in 1965


Renner, U. Lloydia 1964, 27, 406.

NN

HMeO

MeOH

O

NN

HMeO

MeOH

O

schizogamine isoschizogamine

Hajicek, J.; Trojanek, J. Collect. Czech. Chem. Commun. 1986, 51, 1731.

"Careful analysis of the 13C NMR spectra indicates, however, a different skeleton..." Renner U.: personal communciation


Hajicek, J.; Taimr, J.; Budesinsky, M. Tet. Lett. 1998, 39, 505.

Cholesterol



■ 13C NMR and 2D NMR lead to new proposal in 1998


NN

HMeO

MeOH

N

MeO

MeO

O

O

H

N

NN

HMeO

MeOH

O


CH0 84.44 ppm

CH0 173.8 ppm

CH1 35.0, 37.7 ppm

NN

HMeO

MeOH

O

isoschizogamine(original structure)

isoschizogamine(revised structure)


Hajicek, J.; Taimr, J.; Budesinsky, M. Tet. Lett. 1998, 39, 505.

Cholesterol



■ 13C NMR and 2D NMR lead to new proposal in 1998


NN

HMeO

MeOH

N

MeO

MeO

O

O

H

N

NN

HMeO

MeOH

O


isoschizogamine(revised structure)

NH

N

HMeO

MeO

[O]NH

N

HMeO

MeO

[H]

■ Rearrangement proposed for schizogamine → isoschizogamine

X OX O


Miura, Y.; Hayashi, N.; Yokoshima, S.; Fukuyama, T. J. Am. Chem. Soc. 2012, 134 , 11995.

Cholesterol

■ Heathcock validated structure via biomimetic total synthesis


Hubbs, J. L.; Heathcock, C. H. Org. Lett. 1999, 1 , 1315.

N

MeO

MeO

O

H

N

N

O

OONO2

MeO

MeO

N

NH

MeOOMe

O

O

1. NaBH4

2. LiAlH4

N

OONH2

MeO

MeO

N

OONH2

MeO

MeO

N

MeO

MeO

HO

H

N AcOH, H2O, ΔPDC

isoschizogamine

27% yieldover 4 steps



outline


Nomofungin


nobelprize.org

Diazonamides

Kinamycins

Aquatolide


Sporol

Sclerophytin



■ Novel trichothecene mycotoxin sporol described with [2.2.2] fused to [2.2.1] in 1986

■ Key C15-C3 nOe observed

Corley, D. G.; Rottinghaus, G. E.; Tempesta, M. S. Tet. Lett. 1986, 27, 427.

O

O

OMe

OHsporol

O

O

MeMe

HOH

OMe

15 34

15

3

4

HH

H

δ 4.30 ppm

δ 2.29 ppm

δ 2.21 ppm

H

H

H

Hδ 3.79 ppmH


Ziegler, F. E.; Nangia, A.; Tempesta, M. S. Tet. Lett. 1988, 29, 1665.

Cholesterol

■ Novel trichothecene mycotoxin sporol described with [2.2.2] fused to [2.2.1] in 1986

■ Key C15-C3 nOe observed

■ Reevaluation of 1H NMR and COSY lead to new structural proposal

■ Connectivity is close! Only one carbon off.

Corley, D. G.; Rottinghaus, G. E.; Tempesta, M. S. Tet. Lett. 1986, 27, 427.

neosporol

sporol

O

O

OMe

OH

O

O

OMe

OH

sporol

O

O

MeMe

HOH

OMe

MeO

Me

OO

OH

Me

15 34

15

3

4

15 3415

4

3

HH

H

δ 4.30 ppm

δ 2.29 ppm

δ 2.21 ppm

H

H

H

2

2

HH

H

Hδ 3.79 ppmH

H

■ Reevaluation of 1H NMR and NOESY lead to new structural proposal


Ziegler, F. E.; Metcalf III, C. A.; Nangia, A.; Schulte, G. J. Am. Chem. Soc. 1993, 115 , 2589.

Cholesterol

■ Ziegler was able to confirm structure by total synthesis of sporol

Ziegler, F. E.; Metcalf III, C. A.; Schulte, G. Tet. Lett. 1992, 33, 3117.

sporol

OMe

OO

OH

Me

O

OO

Me

OTBS

OO

O

NC

Me

OTBSCN

O

O

NC

O

OH

O

Me

O

OO

OH

MeCN

OO

OH

MeCN

Δ

(claisen)

1. HF

2. Urea•H2O2

1. Ms2O; K2O2. CSA; H2O

Ph3PCH21. DIBAL

68% yield 45% yield

32% yield

2. CSA, Δ




outline


Nomofungin


nobelprize.org

Diazonamides

Kinamycins

Aquatolide


Sporol

Sclerophytin



Paquette, L. A.; Moradei, O. M.; Bernardelli, P.; Lange, T. Org. Lett. 2000, 2, 1875.

Cholesterol

■ First isocembrene diterpenes containing two transannular ether linkages

■ Note the lack of explicit stereochemistry at the C14 position!

■ This is somewhat of a disaster... Paquette does MM3 calculations, the original structure is not good

■ "Unfortunately, the intentions behind the use of an 'inverted carbon' symbolism here will never be known."

Sharma, P.; Alam, M. J. Chem. Soc. Perkin Trans. 1 1988, 2537.

MeMe

O O

MeOR

H

H

H

HMe

R=H sclerophytin AR=Ac sclerophytin B

Me Me

O

H

H

H

H

O

Me

OH

Me

Paquette's interpretation

Me Me

O

H

H

H

H

O

Me

OH

Me

Paquette shows this is the most likely(thermodynamic) conformer/stereoisomer

Me

Me Me

O

H

H

H

H

Me

Me

Me

Me Me

O

H

H

H

H

O

Me

MeOH

BF3•OEt20 °C

Hochlowshi, J. E.; Faulkner, D. J. Tet. Lett. 1980, 21, 4055.


Overman, L. E.; Pennington, L. D. Org. Lett. 2000, 2, 2683.

Cholesterol

■ Paquette prepared this corrected structure...

■ Overman prepared this corrected structure as well... (hi Dave!)


Me Me

O

H

H

H

H

O

Me

OH

Me

Me Me

O

H

H

H

H

O

Me

MeOH

O

H

H

H

H

RO

O

H

H

H

H

RO

Me Me

O

H

H

H

H

Me

MeO

Me

OMe

OH

RO

sclerophytin A

sclerophytin A

Me

Me Me

O

CHO

H

H

H

TMS

Me

TIPSO

Me

Me Me

O

H

H

H

H

Me

O

OTBS

I

Me

Me Me

O

H

H

H

HHO

Me OTBS

2 steps to 7-deacetoxyalcyonin acetate

prepared by Danishefsky's diene DAand macrolactonization

prepared by Prins-pinacol

∆ [O]

NHK [H+]

hνhν


Overman, L. E.; Pennington, L. D. Org. Lett. 2000, 2, 2683.

Cholesterol

■ Paquette prepared this corrected structure...

■ Overman prepared this corrected structure as well... (hi Dave!)


Me Me

O

H

H

H

H

O

Me

OH

Me

Me Me

O

H

H

H

H

O

Me

MeOH

O

H

H

H

H

RO

O

H

H

H

H

RO

Me Me

O

H

H

H

H

Me

MeO

Me

OMe

OH

RO

sclerophytin A

sclerophytin A

Me

Me Me

O

CHO

H

H

H

TMS

Me

TIPSO

Me

Me Me

O

H

H

H

H

Me

O

OTBS

I

Me

Me Me

O

H

H

H

HHO

Me OTBS

2 steps to 7-deacetoxyalcyonin acetate

prepared by Danishefsky's diene DAand macrolactonization

prepared by Prins-pinacol

∆ [O]

NHK [H+]

hνhν

these didn’t match the published data!


Friedrich, D.; Doskotch, R. W.; Paquette, L. A. Org. Lett. 2000, 2, 1879.

Cholesterol

■ Well, they got the mass incorrect...


Me Me

O

H

H

H

H

O

Me

OAc

Me

original sclerophytin B connectivitym/z = 362*, 302 (-AcOH)

Me Me

O

H

H

H

H

Me

OAc

Me

corrected sclerophytin B connectivitym/z = 381, 321 (-AcOH)

OH

OH

■ Not only was there a typo (462 instead of 362), but they're missing an equivalent of H2O!

■ Stereochemistry determined by NOESY

iPr

O

H

H

H

H

Me

OAc

Me

OH

OH

2 3

76

9

H sclerophytin Baka 6-acetyl sclerophytin A

two exchangeable protonslacking correlation in HMQC

two alcohols


■ Once again, Paquette prepared the corrected structure

■ Overman prepared this corrected structure as well... (again, hi Dave!)

Gallou, F.; MacMillan, D. W. C.; Overman, L. E.; Paquette, L. A.; Pennington, L. D.; Yang, J. Org. Lett. 2001, 3, 1350.

Me Me

O

H

H

H

H

Me

Me OH

RO

sclerophytin A

sclerophytin A

O

H

H

H

H

Me

OH

Me

OH

OHMeMe

O

H

H

H

H

Me

OH

Me

OH

OHMeMe

Me

O

H

H

H

H

Me

OH

Me

OH

OHMeMe

Me

O

H

H

H

H

OH

Me ORMeMe

OMe

O

H

H

H

H

OH

Me ORMeMe

Me Me

O

H

H

H

HMe OH

RO Me OH

OHO

H

H

H

H

Me

O

Me

OH

OHMeMe

OsO4 IBX

elim.

Na

VO(acac)2 DIBAL hνTBHP


■ There's been a lot written about it, including 4 separate syntheses and a personal reflection by Paquette

Gallou, F.; MacMillan, D. W. C.; Overman, L. E.; Paquette, L. A.; Pennington, L. D.; Yang, J. OL 2001, 3, 1350.

Bernardelli, P.; Moradei, O. M.; Friedrich, D.; Yang, J.; Gallou, F.; Dyck, B. P.; Doskotch, R. W.; Lange, T.; Paquette, L. A. JACS 2001, 123 , 9021.

Paquette, L. A. Chem. Rec. 2001, 1 , 311.

Overman, L. E.; Pennington, L. D. OL 2000, 2, 2683.

Friedrich, D.; Doskotch, R. W.; Paquette, L. A. OL 2000, 2, 1879.

Paquette, L. A.; Moradei, O. M.; Bernardelli, P.; Lange, T. OL 2000, 2, 1875.

Alam, M.; Sharma, P.; Zektzer, A. S.; Martin, G. E.; Ji, X.; Van der Helm, D. JOC 1989, 54, 1896.


MacMillan, D. W. C.; Overman, L. E.; Pennington, L. E. JACS 2001, 123 , 9033.

Friedrich, D.; Paquette, L. A. J. Nat. Prod. 2002, 65, 126.

Wang, B.; Ramirez, A. P.; Slade, J. J.; Morken, J. P. JACS 2010, 132 , 16380.

Crimmins, M. T.; Stauffer, C. S.; Mans, M. C. OL, 2011, 13 , 4890.



outline


Nomofungin


nobelprize.org

Diazonamides

Kinamycins

Aquatolide


Sporol

Sclerophytin



■ Two complex halogenated, polycyclic, cytotoxic metabolites isolated from marine ascidian

■ Diazonamide A is particularly interesting, with IC50 vs. HCT-116 (colon cancer) and B-16 (melanoma) < 15 ng/mL

Lindquist, N.; Fenical, W.; Van Duyne, G. D.; Clardy, J. J. Am. Chem. Soc. 1991, 113 , 2303.

O

NO

O

N Cl

NH

ClOHOH

O

HNHN

Me Me

O

NO

O

N Cl

NH

ClOHOH

O

HNH2N

Me Me

OH2N

Me Me

, pyrCl

O

Br

hemiacetal present!

"3.5 Hz coupling of a D2O-exchangable proton at δ 7.36 to aδ 6.46 proton that was one-bond coupled to the C11 resonance aδ 106.6 in the XHCORR spectrum"

diazonamide A

diazonamide B

Br


■ Two complex halogenated, polycyclic, cytotoxic metabolites isolated from marine ascidian

■ Diazonamide A is particularly interesting, with IC50 vs. HCT-116 (colon cancer) and B-16 (melanoma) < 15 ng/mL

Lindquist, N.; Fenical, W.; Van Duyne, G. D.; Clardy, J. J. Am. Chem. Soc. 1991, 113 , 2303.

O

NO

O

N Cl

NH

ClOHOH

O

HNHN

Me Me

O

NO

O

N Cl

NH

ClOHOH

O

HNH2N

Me Me

OH2N

Me Me

Key differences between B and A

■ A has no Br atom (seen in NMR)■ A has an additional iPr group (seen in NMR)

■ A has m/z of 765 vs 743 for B → extra valine residue!■ Valine residue must be attached at indicated N (based on NMR shifts)

diazonamide A

diazonamide B

Br


■ Harran prepared the proposed structure of diazonamide A and the diazonamide B derivative

Li, J.; Jeong, S.; Esser, L.; Harran, P. G. Angew. Chem. Int. Ed. 2001, 40, 4765.

HN

Me Me

OBocHN

I

OBn

O

NCN

HO

HN

Me Me

OBocHN O

NCN

HOOBn

HN

Me Me

OBocHN O

NCN

OBn

OH

OH OR

HN

Me Me

OBocHN O

NCN

Pd O

OBn

HN

Me Me

OH2N O

NCN

OBnOH OROR

NO

OOBn

O

HNCbzHN

Me Me

[Pd0]

[OsO4]

TsOHCbzOSu






O

NO

O

N

NHAcO

OBn

O

HNCbzHN

Me Me

Br

hν

OBr

AcO

NH

OAcO

NH

O

NO

O

N

NHOBn

O

HNCbzHN

Me Me

AcOO

NO

O

N Cl

NH

ClOHOH

O

HNHN

Me Me

OH2N

Me Me

diazonamide A

32-40% yield


does not match natural material!

HBr




O

NO

O

N

NHAcO

OBn

O

HNCbzHN

Me Me

Br

hν

OBr

AcO

NH

OAcO

NH

diazonamide B


does not match natural material derivative!

OO

HN

OO

N

Me Me

HN

ONH

O

N

Cl

ClBr

O

NO

O

N

NHOBn

O

HNCbzHN

Me Me

AcO

32-40% yield

Br

HBr


■ Harran proposes a new, corrected structure

■ Isolation chemists actually had the data to show they were wrong, but ignored it!


OHO

Me Me

diazonamide A

diazonamide B

Li, J.; Burgett, A. W. G.; Esser, L.; Amezcua, C.; Harran, P. G. Angew. Chem. Int. Ed. 2001, 40, 4770.N. Lindquist, Ph.D. Thesis, UCSD, 1989.

"In retrospect, evidence argued against this [structure]. However, in the excitement of uncovering such a remarkable new class of materials... certain details were inadvertently overlooked."

ONH

HN

OO

N

Me Me

H2N

NH

O

N

Cl

Cl

BrO

NH

HN

OO

N

Me Me

HN

NH

O

N

Cl

Cl





incorrectdiazonamide A


"Acetylation of the amine group of the... valine residue was also indicated by the shift of the C37 α proton to δ 5.11. This proton did not couple to an amide proton suggesting the presence of a secondary amine, but no spectral feature... suggested the nature of the additional substituent."

O

NO

O

N Cl

NH

ClOHOH

O

HNHN

Me Me

OH2N

Me Me

"In a triacetate derivative, the C37 proton shifts downfield to δ 5.11, although it now appears as a doublet rather than the more complex pattern one might expect for a C37 acetamide... We believe these observations are

consistent with the C37 substituent in natural diazonamide A being an alcohol rather than an amine."

OHO

Me Me

diazonamide AO

NH

HN

OO

N

Me Me

HN

NH

O

N

Cl

Cl



■ 1H/15N-HSQC and COSY unequivocally show that the heteroatom attached to C11 is N, not O


incorrectdiazonamide A


O

NO

O

N Cl

NH

ClOHOH

O

HNHN

Me Me

OH2N

Me Me

"[The 1H/15N-HSQC] indicates... the δ = 7.16 (N2H) resonance is coupled to C11H (DQF-COSY) and was originally assigned as O7H... the exchangeable one-proton doublet at δ = 5.46, first

identified as N7H2, is not coupled to 15N —consistent with our C37 hydroxy model."

OHO

Me Me

diazonamide AO

NH

HN

OO

N

Me Me

HN

NH

O

N

Cl

Cl

N211

37





diazonamide Bderivative

incorrectdiazonamide B

derivative


"However, the C17-O3 bond... is measured at 1.433(16) Å. This is 0.048 Å longer than the mean and, notably, exceeds the maximal value (1.409 Å) observed for a bond of this type... This indicates that the

O3 assignment should be changed to an element with fewer electrons and a larger covalent radius... these data are consistent with the electron density assigned as O3 being a protonated nitrogen atom..."

17 17

O3N2

O

ONH

HN

OO

N

Me Me

HN

NH

O

N

Cl

Cl

Br

Br

O

OO

HN

OO

N

Me Me

HN

NH

O

N

Cl

Cl

Br

Br


■ Nicolaou (2002, 2003) and Harran (2003) synthesize the new structure, confirm its correctness

Nicolaou, K. C.; Bella, M.; Chen, D. Y.-K.; Huang, X.; Ling, T.; Snyder, S. A. Angew. Chem. Int. Ed. 2002, 41, 3495.

diazonamide A

Nicolaou, K. C.; Rao, P. B.; Hao, J.; Reddy, M. V.; Rassias, G.; Huang, X.; Chen, D. Y.-K.; Snyder, S. A. Angew. Chem. Int. Ed. 2003, 42, 1753.Burgett, A. W. G.; Li, Q.; Wei, Q.; Harran, P. G. Angew. Chem. Int. Ed. 2003, 42, 4961.

■ (S)-isovaleric acid was confirmed as sidechain stereochemistry■ Synthetic details are not super important- a lot has been written, go check it out if you're interested

OHO

Me Me

ONH

HN

OO

N

Me Me

HN

NH

O

N

Cl

Cl



outline


Nomofungin


nobelprize.org

Diazonamides

Kinamycins

Aquatolide


Sporol

Sclerophytin



Hata, T.; Omura, S.; Iwai, Y.; Nakagawa, A.; Otani, M.; Ito, S.; Matsuya, T. Antibiotics 1971, 24, 353.

Cholesterol

■ Kinamycins A, B, C, and D first described in 1970

■ At first, simple common structural fragments were described, but no full structure

■ NMR analysis and derivatization of deacetylkinamycin C lead to a proposed structure

Ito, S.; Matsuya, T.; Omura, S.; Otani, M.; Nakagawa, A.; Takeshima, H.; Iwai, Y.; Ohtani, M.; Hata, T. J. Antibiotics 1970, 23, 315.

Omura, S.; Nakagawa, A.; Yamada, N.; Hata, T.; Furusaki, A.; Watanabe, T. Chem. Pharm. Bull. 1971, 19 , 2428.

"The kinamycins have an infrared absorption maximum at 2155 cm-1, assignable to a nitrile or isonitrile group..."

NCN

■ Hydrolysis of deacetylkinamycin C with refluxing 30% KOH liberated ammonia, but not formic acid → nitrile!

O

O

OH

OAc

MeOH

OAcAcO

kinamycin C


Omura, S.; Nakagawa, A.; Yamada, N.; Hata, T.; Furusaki, A.; Watanabe, T. Chem. Pharm. Bull. 1973, 21, 931.

Cholesterol

■ Location of the unprecedented N-cyano group confirmed by x-ray crystal structure! In 1972!

■ Even in the crystal structure paper, they cite the NH3 liberation result to confirm nitrile vs. isonitrile

Furusaki, A.; Matsui, M.; Watanabe, T.; Omura, S.; Nakagawa, A.; Hata, T. Isr. J. Chem. 1972, 10 , 173.

NCNO

O

O

OAc

MeOH

OAcAcO

O

Br

N-C bond length is 1.34 ÅC≡N bond length is 1.14 Å


Dmitrienko, G. I.; Nielsen, K. E.; Steingart, C.; Ming, N. S.; Wilson, J. M.; Weeratunga, G. Tet. Lett. 1990, 31, 3681.

Cholesterol

■ By fermenting bacteria with (15NH4)2SO4, able to obtain [15N2]kinamycin D

■ Observed the nitrile C by 13C NMR for the first time! Except...

■ Synthetic work calls the N-cyano pyrrole into question...

Seaton, P. J.; Gould, S. J. J. Am. Chem. Soc. 1988, 110 , 5912.

Echavarren, A. M.; Tamayo, N.; Paredes, M. C. Tet. Lett. 1993, 34, 4713.

15NCO

O

OH

OAc

MeOH

OAcHO

[15N2]kinamycin D

15N78.5 ppm

""Although we cannot unequivocally explain the large upfield shift (ca. 30 ppm)..."

NH

CN

111.9 ppm

NCO

O

N

AcO

OAc

103.6 ppm

does not matchnatural (fermented)

sample (1H, IR)

NCO

O

OH

HO

N

Me

prekinamycin


Mithani, S.; Weeatunga, G.; Taylor, N. J.; Dmitrienko, G. I. J. Am. Chem. Soc. 1994, 116 , 2209.

Cholesterol

■ Gould, who had done most of the biosynthetic work, realized there were too many inconsistencies

■ Reconsideration included crystal structure of different ester derivative

■ More complete synthetic work confirms that N-cyano can not be correct

Gould, S. J.; Tamayo, N.; Melville, C. R.; Cone, M. C. J. Am. Chem. Soc. 1994, 116 , 2207.

NO

O

OH

OAc

MeOH

OAcHO

N

78.5 ppm

"the diazo alternative was clearly possible: 13C NMR resonances of a number of diazo

compounds have been observed in the δ 60-80 region, including 9-diazofluorene at δ 63.2."

NCO

O

OMe

AcO

N

Me

NCO

O

OH

OAc

MeOH

OAcHO

N

kinamycin Dkinamycin D

103.6 ppm

IR νmax= 2253 cm-1

IR νmax= 2155 cm-1

natural N-cyano diazo

2120-2170 2200-2260 2065-2200

78.5-83.7 100-110 63-93

241.6 124 227-287

1.33-1.36 Å 1.32-1.38 Å

IR13C

15N (int)

bond (int)

1.08-1.13 Å 1.10-1.15 Åbond (ext)

344.6 224 332-44115N (ext)

1.28-1.35 Å

1.13-1.18 Å


Mithani, S.; Weeatunga, G.; Taylor, N. J.; Dmitrienko, G. I. J. Am. Chem. Soc. 1994, 116 , 2209.

Cholesterol

■ Gould, who had done most of the biosynthetic work, realized there were too many inconsistencies

■ Reconsideration included crystal structure of different ester derivative

■ More complete synthetic work confirms that N-cyano can not be correct

Gould, S. J.; Tamayo, N.; Melville, C. R.; Cone, M. C. J. Am. Chem. Soc. 1994, 116 , 2207.

NO

O

OH

OAc

MeOH

OAcHO

N

78.5 ppm

"the diazo alternative was clearly possible: 13C NMR resonances of a number of diazo

compounds have been observed in the δ 60-80 region, including 9-diazofluorene at δ 63.2."

NCO

O

OMe

AcO

N

Me

NCO

O

OH

OAc

MeOH

OAcHO

N

kinamycin Dkinamycin D

103.6 ppm

IR νmax= 2253 cm-1

IR νmax= 2155 cm-1

natural N-cyano diazo

2120-2170 2200-2260 2065-2200

78.5-83.7 100-110 63-93

241.6 124 227-287

1.33-1.36 Å 1.32-1.38 Å

IR13C

15N (int)

bond (int)

1.08-1.13 Å 1.10-1.15 Åbond (ext)

344.6 224 332-44115N (ext)

1.28-1.35 Å

1.13-1.18 Å

"The Kinamycins are Diazofluorenes and Not Cyanocarbazoles"

"Revised Structure for the Kinamycin Antibiotics: 5-Diazobenzo[b]fluorenes Rather Than Benzo[b]carbazole Cyanamides"


■ There's quite a bit more... including recent total synthesis efforts and medicinal chem investigations

Nicolaou, K. C.; Li, H.; Nold, A. L.; Pappo, D.; Lenzen, A. JACS 2007, 129 , 10356.

Woo, C. M.; Lu, L.; Gholap S. L.; Smith, D. R.; Herzon, S. B. JACS 2010, 132 , 2540.

Lei, X.; Porco, J. A., Jr. JACS 2006, 128 , 14790.

Marco-Contelles, J.; Molina, M. T. Curr. Org. Chem. 2003, 7, 1433.

Proteau, P. J.; Li, Y.; Chen, J.; Williamson, R. T.; Gould, S. J.; Lauger, R. S.; Dmitrienko, G. J. JACS, 2000, 122 , 8325.

Gould, S. J. Chem. Rev. 1997, 97, 2499.

Hauser, F. M.; Zhou, M. JOC 1996, 61, 5722.

Gould, S. J.; Chen, J.; Cone, M. C.; Gore, M. P.; Melville, C. R.; Tamayo, N. JOC 1996, 61, 5720.

Herzon, S. B.; Woo, C. M. NPR 2012, 29, 87.



outline


Nomofungin


nobelprize.org

Diazonamides

Kinamycins

Aquatolide


Sporol

Sclerophytin



■ Hexacyclinol is probably the most absurd chemical structure story

■ First described in 2002, isolated from Siberian fungus

Schlegel, B.; Hartl, A.; Dahse, H.-M.; Gollmick, F. A.; Grafe, U.; Dorfelt, H.; Kappes, B. J. Antibiotics 2002, 55, 814.

OO

O

Me

Me OMe

HH

Me

Me

H

H

OO

H

H OH

H

■ I'm not going to get into La Clair's retracted synthesis...

La Clair, J. J. Angew. Chem. Int. Ed. 2006, 45, 2769.


■ Rychnovsky, spurred on by La Clair's "provocative synthesis" decides to "reexamine the original structure"

■ Computational methods can allow for highly accurate NMR predictions (13C shifts within average |∆δ| < 2 ppm)

Rychnovsky, S. D. Org. Lett. 2006, 8, 2895.La Clair, J. J. Angew. Chem. Int. Ed. 2006, 45, 2769.

HMe

O Me

OHO

Me

H

Me

elisapterosin Baverage |∆δ| = 1.9 ppm

max |∆δ| = 3.8 ppm

maoecrystal Vaverage |∆δ| = 1.2 ppm

max |∆δ| = 3.7 ppm

elisabethin Aaverage |∆δ| = 1.4 ppm

max |∆δ| = 3.8 ppm

HMe H

OMe

Me Me

O

OHO

MeO

O

O

O

Me

Me

■ Polycyclic, unsaturated, oxygenated molecules can be accurately predicted... how does hexacyclinol do?

OO

O

Me

Me OMe

HH

Me

Me

H

H

OO

H

H OH

H

hexacyclinolaverage |∆δ| = 6.8 ppm

max |∆δ| = 22.0 ppm


■ So, that's probably not hexacyclinol... what is?

■ Rychnovsky proposes a related compound to panepophenanthrin, from the same fungus... isolation artifact?

Rychnovsky, S. D. Org. Lett. 2006, 8, 2895.La Clair, J. J. Angew. Chem. Int. Ed. 2006, 45, 2769.

■ How does the newly proposed hexacyclinol structure do with computational 13C NMR predictions??

Rychnovsky's hexacyclinolaverage |∆δ| = 1.8 ppm

max |∆δ| = 5.8 ppm

O

O

OH

H

OHH

O

OOH

MeMe

MeMeOH

panepophenanthrin

O

O

OH

H

OHH

O

OHOMe

MeMeOH

Me

OOHH

O

HOMe

Me

O

Me

MeO

O

OOHH

O

MeOMe

Me

O

Me

MeO

O

hexacyclinol

OOHH

O

MeOMe

Me

O

Me

MeO

O


■ Porco prepares Rychnovsky's proposed structure...

Porco, J. A., Jr.; Su, S.; Lei, X.; Bardhan, S.; Rychnovsky, S. D. Angew. Chem. Int. Ed. 2006, 45, 5790.

OOHH

O

MeOMe

Me

O

Me

MeO

O

OOBr

OH

O

OTES

O

O

Me

MeMeO

O

O

OH

H

OHH

O

OMeOMe

MeMeOMe

Me

TESO

O

OMe

MeOMe

RO

TESO

dimerization

[4+2]

Stille

K10 clay

hexacyclinol "pre-hexacyclinol"


87% yield

99% yield



■ La Clair claimed the structures could have the same 1H NMRs, so of course people had to show otherwise

Williams, A. J.; Elyashberg, M. E.; Blinov, K. A.; Lankin, D. C.; Martin, G. E.; Reynolds, W. F.; Porco, J. A., Jr.; SIngleton, C. A.; Su, S. JNP 2008, 71, 581.Saielli, G.; Bagno, A. Org. Lett. 2009, 11 , 1409.

a more in-depth analysis, concluding "we accept the conclusion [Rychnovsky's assignment] as being accurate and appropriate."

"The structure of hexacyclinol is confirmed to be [Rychnovsky's]. If [La Clair's structure] had been synthesized... its NMR spectra are sufficiently different... as to guarantee their disctincion."

Nope.



outline


Nomofungin


nobelprize.org

Diazonamides

Kinamycins

Aquatolide


Sporol

Sclerophytin



■ Novel sesquiterpenoid lactone containing [2]ladderane substructure isolated in 1989

San Feliciano, A.; Medarde, M.; Miguel del Corral, J. M.; Aramburu, A.; Gordaliza, M.; Barrero, A. F. Tet. Lett. 1989, 30, 2851.San Feliciano, A.; Barrero, A. F.; Medarde, M.; Miguel del Corral, J. M.; Aramburu, A.; Perales, A.; Fayos, J. Tet. Lett. 1985, 26, 2369.

HHMe

MeO

O

HMe

O

H

■ Related compounds isolated from same source allow for some idea of biosynthesis

aquatolide

anybody notice aconspicuously missing nOe?

asteriscanolide

H

H

HMeMe

San Feliciano, A.; Barrero, A. F.; Medarde, M.; Miguel del Corral, J. M.; Aramburu, A.; Perales, A.; Fayos, J. Tetrahedron 1985, 41, 5711.

OO

Me

Me

OO

Me

O

O

Me

OMe

MeO

Me

Me

OMe

O

asteriscunolide A asteriscunolide B asteriscunolide C asteriscunolide D(Z,Z) (E,Z) (Z,E) (E,E)

MeO

MeMe O

O Me

O

O

H H HH


■ Biosynthesis of aquatolide seems to be an intramolecular [2+2] of asteriscunolide C

Lodewyk, M. W.; Soldi, C.; Jones, P. B.; Olmstead, M. M.; Rita, J.; Shaw, J. T.; Tantillo, D. J. J. Am. Chem. Soc. 2012, 134 , 18550.

■ Tantillo wanted to study the biosynthesis in detail, but wanted to confirm structure... guess how that went?

aquatolide

OO

Me

Me

asteriscunolide C

MeOH

HMe

MeO

O

HMe

O

H

average |∆δ| = 7.23 ppmmax |∆δ| = 24.33 ppm

13C NMRaverage |∆δ| = 0.35 ppm

max |∆δ| = 1.31 ppm

1H NMR

aquatolide

HHMe

MeO

O

HMe

O

H

HHMe

MeO

O

HMe

O

H

H


■ Try computational analysis of all the possible [2+2] products of all the asteriscunolides...


■ The originally discounted [2+2] shown delivered an excellent agreement with observed NMR

O

O

Me

Me

asteriscunolide C

MeO

new aquatolideproposal

O

O

Me

MeH

HMe

O

average |∆δ| = 1.37 ppmmax |∆δ| = 4.28 ppm

13C NMRaverage |∆δ| = 0.10 ppm

max |∆δ| = 0.27 ppm

1H NMR

new aquatolideproposal

O

O

Me

MeH

HMe

O

HH

O

O

Me

MeH

HMe

O

HH


■ Tantillo and coworkers re-isolated aquatolide and reexamined 1H NMR coupling


■ COSY, HSQC, and NOESY further strengthened the assignment

O

O

Me

MeH

HMe

O

HH

O

O

Me

MeH

HMe

O

HHdd, J = 7.3, 1.8 Hz

dd, J = 7.3, 2.5 Hz

computations predict an unusually large 4J = 6.8 Hz

between the highlighted atoms

s, φ ~ 90° to

H

H

H H H

new assignmentagrees with observed

nOe much better

HHMe

MeO

O

HMe

O

H

Pauli, G. F.; Niemitz, M.; Bisson, J.; Lodewyk, M. W.; Soldi, C.; Shaw, J. T.; Tantillo, D. J.; Saya, J. M.; Vos, K.; Kleinnijenhuis, R. A.; Hiemstra, H.; Chen, S.-N.; McAlpine, J. B.; Lankin, D. C.; Friesen, J. B. J. Org. Chem. 2016, 81, 878.


■ Photochemical [2+2] allows for rapid construction of [2.1.1] core

Saya, J. M.; Vos, K.; Kleinnijenhuis, R. A.; van Maarseveen, J. H.; Ingemann, S.; Hiemstra, H. Org. Lett. 2015, 17 , 3892.

O

O

Me

MeH

HMe

O

HH

Me

MeH

O

MeH

OMe

O

OP(OEt)2O

OBn

O

MeMe

O

OBn•

O

O

Me

MeH

HH OBn

O

O

Me

MeH

HMe

O

HH

O

O

O

Me

MeH

OBn

H

O

aquatolide

aldol HWE

hν

aldol [O]



77% yield




■ Computational prediction of NMR has been proven to be a powerful tool

Willoughby, P. H.; Jansma, M. J.; Hoye, T. R. Nat. Protocols 2014, 9, 643.

Sarotti, A. M. Org. Biomol. Chem. 2013, 11 , 4847.

Elyashberg, M.; Williams, A. J.; Blinov, K. Nat. Prod. Rep. 2010, 27, 1296.

Lodewyk, M. W.; Siebert, M. R.; Tantillo, D. J. Chem. Rev. 2012, 112 , 1839.



outline


Nomofungin


nobelprize.org

Diazonamides

Kinamycins

Aquatolide


Sporol

Sclerophytin



Numata, A.; Takahashi, C.; Ito, Y.; Takada, T.; Kawai, K.; Usami, Y.; Matsumura, E.; Imachi, M.; Ito, T.; Hasegawa, T. Tet. Lett. 1993, 34, 2355.

Cholesterol

■ Interesting new analogue to the communesins described in 2001

■ Isolated from a fungus that then died, couldn't be recovered, thus "nomofungin"

■ One problem... the reported NMRs were strikingly similar... (select comparisons below)

Ratnayake, A. S.; Yoshida, W. Y.; Mooberry, S. L.; Hemscheidt, T. K. J. Org. Chem. 2001, 66, 8717.

May, J. A.; Zeidan, R. K.; Stoltz, B. M. Tet. Lett. 2003, 44, 1203.

NMe

O

N

O

Me

N

H

O

MeMe

HH

NMe

NH

N

O

Me

N

H

O

MeMe

HH

nomofungin communesin B

13C1H

13C1H

nomofungin

communsein B

82.44.69

82.394.70

A

A A

B B

C C

29.22.84

29.602.85

B142.6

--

142.65--

C

D D

51.4--

51.40--

D

EE

79.05.10

79.005.11

E


■ Stoltz postulated that, given biosynthetic pathway, nomofungin couldn't be made in nature

May, J. A.; Zeidan, R. K.; Stoltz, B. M. Tet. Lett. 2003, 44, 1203.

NMe

NH

N

O

Me

N

H

O

MeMe

HH

communesin B

NMe

Me

Me HN

NO

H2N

N N

NH2

OMe

NHMe

Me

NMe

NH

HN

NH

H

Me

Me

O

[4+2]

acyl transfer

May, J. A.; Stoltz, B. M. Tetrahedron 2005, 62, 5262.


■ Funk took a fully synthetic approach by preparing the N,O and N,N cores of communesin/nomofungin

Crawley, S. L.; Funk, R. L. Org. Lett. 2003, 5, 3169.

1H δ 4.7, 13C δ 82.4

NMe

N

O

O

MeMe

NMe

N

OCO2Ph

NH

CO2Et

1H δ 4.513C δ 84.4

1H δ 5.413C δ 101.0

Siengalewicz, P.; Gaich, T.; Milzer, J. Angew. Chem. Int. Ed. 2008, 47, 8170.

nomofungin/communesin B

NMe

NH

N

H

NMe

O

N

HNMe

O

N

NMe

NR

N



outline


Nomofungin


nobelprize.org

Diazonamides

Kinamycins

Aquatolide


Sporol

Sclerophytin



■ There's a few good reviews and group meetings, check them out below.

Krout, M.; Mohr, J. T.; Roizen, J. Stoltz Group Meeting, http://stoltz.caltech.edu/seminars/2005_Krout_Mohr_Roizen.pdf.

Suyama, T. L.; Gerwick, W. H.; McPhail, K. L.; Bioorg. Med. Chem. 2011, 19 , 6675.

Nicolaou, K. C.; Snyder, S. A. ACIE 2005, 44, 1012.

Structural Misassignment of Natural Products

Documents

Transcript of Structural Misassignment of Natural Products