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Anomaly in the modified Mosher's method: Absolute configurations of some marine cembranolides
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Tetnbedron Letters. Vo1.32,No.25, pp 2923.2926. 1991 Printed in Great Britain
ANOMALY
IN THE MODIFIED
CONFIGURATIONS
MOSHER’S
OF SOME MARINE
METHOD:
ABSOLUTE
CEMBRANOLIDES
Takenori Kusumi, Yoshiharu Fujita, Ikuko Ohtani, and Hiroshi Kakisawa* Department of Chemistry, University of Tsukuba, Ibaraki 305, Japan
Abstract
-
Utility of the modified
marine cembranolides,
Mosher’s
method is examined
2,3, and 4, with known absolute configurations,
by applying it to three
and it is concluded
that the
method can be safely used for the compounds with a sterically unhindered OH group, but care must be taken in applying it to the secondary alcohols with the OH group located in a crowded environment. The modified methylmandelic configurations
Mosher’s
acid
esters2
of secondary
method (summarized is a convenient
and amines .3
alcohols
in Figure 1) using (R) and (S)-MTPA1 or O-
and reliable
method
to elucidate
The absolute configurations
the absolute of a number of
natural products have been determined on the basis of this methodology.tV4 We have recently demonstrated triterpenes.
an unsuccessful result of the MTPA method applied to a marine
The invalidity has been clarified to be owing to the steric hindrance around the MTPA
moiety that compels the conformation
of the MTPA group to distort out of the ideal one.5 During the
course of our search for pharmaceutically three known
cembranolides,
acetate
active components from marine organisms, we have isolated (1),6 sinulariolide
(3),7 1 I-episinulariolide
Okinawan soft coal Sinulariaflexibilis as cytotoxic compounds. compounds
have been fiiy
established,
(4),8 from the
The absolute configurations
of these
and hence we thought that these could be the good models
1 Model 21 A
B
Figure 1. [Al MTPA plane of an MTPA ester is shown. HA,B,C and Hx,y,z are on the right and left sides of the plane, respectively. The conforamtion of the MTPA group illustrated is designated ‘ideal’ one. [Bl Model A to determine the absolute configurations of secondary alcohols are illustrated.
2923
2924
1; R=Ac
3; R,= H, R,=OH
2;R=H
4; R,= OH, R2=H
to test the validity of the modified Mosher’s method. not successful,
and hence 3 was transformed
esters of 2,3 and 4 represented
Selective hydrolysis
of the acetate (1) to 2 was
into 2 by Yamada’s procedure.
Fortunately,
well separated signals in the 1H NMR (500 MHz) spectra, and most
of the proton signals were assigned by means of H,H and H,C COSY spectra. conformations
Moreover,
(2a, 3a, and 4a) were deduced on the basis of the coupling constants
and the NOES observed
the MTPA
in the phase-sensitive
calculated for the respective protons.
NOESY spectra.
A6 (= 6s - 6~)
The
their exact
of the protons values were
The results are summarized in the formulae (2b, 3b, and 4b).
In the formula 2b, it can be seen that the positive
and negative
arranged on the right and left sides of the MTPA plane, respectively, the carbinyl carbon of 2. Because the relative stereochemistry
A6
values are beautifully
indicating the S-configuration
of
at other asymmetric centers have been
assigned by the NMR techniques described above, the absolute stereochemistry
can be shown as in the
formula (2). This finding is coincident with the reported absolute configuration,
which reinforces the
validity of the modified Mosher’s method. Contrary arrangement
to this, the results obtained
of the
A6
values is observed
for 3b and 4b are quite confusing:
for 3b, whereas a certain regularity
No systematic
of the values (The
protons of upper part of the structure 4b have negative and those of the lower part have positive values.) is found for 4b although
the tendency
does not obey the rule of the modified
A6
Mosher’s
method (Figure 1). Comparison explanation
of the stereochemical
features of the three compounds,
of the observed regularity and irregularity of the
A6
values:
2a, 3a, and 4a, led to the The 0-MTPA
group of 2a
stretches out of the ring and is relatively free from the steric hindrance, and, therefore, it can take the ‘ideal’ conformation rectangle.).
as shown in the structure
The 0-MTPA
In these compounds,
(2a) (The MTPA plane is illustrated
as a dotted
groups of 3a and 4a are, on the other hand, oriented in axial-like positions.
the MTPA moieties are seriously compressed
by other substituents,
which would
disable the MTPA groups to take the ‘ideal’ conformations. The present
results are in good agreement
method can be applied to cholesterol
with the findings
and friedelin-3a-01,
groups, whereas it is inapplicable to Sa-cholesterol
that the modified
Mosher’s
both of which possess the equatorial OH
and friedelin-3l%ol with the axial OH groups.9
292.5
+O.Ol
2b
-0.014
RO H
3b
3a
-0.027 Me
-0.042
..
-0.027
Me
>..,H
-0.006
R = MTPA
Figure 2. Stereochemical features of the MTPA esters 2s. 3a, and 4a, determined by the H,H COSY and phasesensitive NOESY sepctra, and the A6 values of the protons. A6 = 63 - 6~. The values are given in ppm.
2926
It is not the intention Mosher’s method. a self-examining dependent
of the present authors to exaggerate
the drawbacks
of the modified
Rather, they wish to emphasize the advantage of the method by notifying that it has function to inspect if the result obtained is valid or not, because this methodology
is
This character is quite
on ‘multi data point’, that is, the chemical shifts of many protons.
different from those of other empirical methods like Horeau’s method.le In conclusion,
this report has revealed that the modified Mosher’s method, although it is very
convenient and reliable technique to determine the absolute configurations
of organic compounds,
can
happen to be inapplicable to the secondary alcohols which have a sterically hindered OH group. Acknowledgement.
This work was partly supported
Japanese Ministry of Education,
by Grant-in-Aid
(No. 02640420)
from the
Science and Culture to T. K. T. K. is also grateful to the Fujisawa
Foundation. REFERENCES 1.
AND NOTES
Kusumi, T.; Ohtani, I.; Inouye, Y.; Ishitsuka, 0. M.; Kakisawa, H. 16th IUPAC International Symposium
on the Chemistry of Natural Products (Kyoto), May-June,
Kusumi, T.; Ohtani, I.; Inouye, Y.; Kakisawa, H. Tetrahedron
1988, Abstr. Pa17.
Left. 1988,29,
4731.
Takano, S.; Takahashi, M.; Yanase, M.; Sekiguchi, Y.; Iwabuchi, Y.; Ogasawara, Left. 1988, 1827. Ohtani, I.; Kusumi, T.; Ishitsuka, 0. M.; Kakisawa,
K. Chem.
H. Ibid. 1989,.X),
3147. 2.
Trost, B. M.; Curran, D. P. Tetrahedron Left. 1981,22,
4929. Trost, B. M.; Belletire, J. L.;
Godleski,
J. Org. Chem. 1986, 51,
S.; McDougal,
P. G.; Balkovec,
J. M.
M.; Quiiioa, E.; Crews, P. J. Org. Chem. 1990,55,
Adamczeski, 3.
Kusumi, T.; Fukushima,T.;
4.
Kobayashi,
240.
Ohtani, I.; Kakisawa, H. Tetrahedron Lett. submitted.
M.; Kawazoe, K.; Kitagawa, I. Tetrahedron Left. 1989,30,
I.; Kobayashi, Sot. 1990,112,
2370.
4149. Kitagawa,
M.; Katori, T.; Yamashita, M.; Tanaka, J.; Doi, M.; Ishida, T. J. Am. Chem. 3710.
Hundt, A. F.; Burger, J. F. W.; Steynberg,
A.; Ferreira, D. Tetrahedron Lett. 1990,31,
J. P.; Steenkamp,
J.
5073.
5.
Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Org. Chem. in press.
6.
Mori, K.; Suzuki, S.; Iguchi, K.; Yamada, Y. Chem. Left. 1983, 1515.
7.
Tursch, B.; Braekman, J. C.; Daloze, D.; Herin, M.; Losman. D. Tetrahedron 1975,31,
8.
Kashman, Y.; Bonder, M.; Loya, Y. Israel. J. Chem. 1977,16,
9.
Ohtani, I.; Kusumi, T.; Kashman,
10.
Fiud, J. C.; Horeau, A.; Kagan, H. B. Stereochemistry; Kagan, H. B. ed; Geroge Thieme Publishers
Y.; Kakisawa, H. J. Am. Chem. Sot. in press.
: Stuttgart, 1977; Vol. 3.
(Received in Japan 13 February 1991)
1.
129.
Tetnbedron Letters. Vo1.32,No.25, pp 2923.2926. 1991 Printed in Great Britain
ANOMALY
IN THE MODIFIED
CONFIGURATIONS
MOSHER’S
OF SOME MARINE
METHOD:
ABSOLUTE
CEMBRANOLIDES
Takenori Kusumi, Yoshiharu Fujita, Ikuko Ohtani, and Hiroshi Kakisawa* Department of Chemistry, University of Tsukuba, Ibaraki 305, Japan
Abstract
-
Utility of the modified
marine cembranolides,
Mosher’s
method is examined
2,3, and 4, with known absolute configurations,
by applying it to three
and it is concluded
that the
method can be safely used for the compounds with a sterically unhindered OH group, but care must be taken in applying it to the secondary alcohols with the OH group located in a crowded environment. The modified methylmandelic configurations
Mosher’s
acid
esters2
of secondary
method (summarized is a convenient
and amines .3
alcohols
in Figure 1) using (R) and (S)-MTPA1 or O-
and reliable
method
to elucidate
The absolute configurations
the absolute of a number of
natural products have been determined on the basis of this methodology.tV4 We have recently demonstrated triterpenes.
an unsuccessful result of the MTPA method applied to a marine
The invalidity has been clarified to be owing to the steric hindrance around the MTPA
moiety that compels the conformation
of the MTPA group to distort out of the ideal one.5 During the
course of our search for pharmaceutically three known
cembranolides,
acetate
active components from marine organisms, we have isolated (1),6 sinulariolide
(3),7 1 I-episinulariolide
Okinawan soft coal Sinulariaflexibilis as cytotoxic compounds. compounds
have been fiiy
established,
(4),8 from the
The absolute configurations
of these
and hence we thought that these could be the good models
1 Model 21 A
B
Figure 1. [Al MTPA plane of an MTPA ester is shown. HA,B,C and Hx,y,z are on the right and left sides of the plane, respectively. The conforamtion of the MTPA group illustrated is designated ‘ideal’ one. [Bl Model A to determine the absolute configurations of secondary alcohols are illustrated.
2923
2924
1; R=Ac
3; R,= H, R,=OH
2;R=H
4; R,= OH, R2=H
to test the validity of the modified Mosher’s method. not successful,
and hence 3 was transformed
esters of 2,3 and 4 represented
Selective hydrolysis
of the acetate (1) to 2 was
into 2 by Yamada’s procedure.
Fortunately,
well separated signals in the 1H NMR (500 MHz) spectra, and most
of the proton signals were assigned by means of H,H and H,C COSY spectra. conformations
Moreover,
(2a, 3a, and 4a) were deduced on the basis of the coupling constants
and the NOES observed
the MTPA
in the phase-sensitive
calculated for the respective protons.
NOESY spectra.
A6 (= 6s - 6~)
The
their exact
of the protons values were
The results are summarized in the formulae (2b, 3b, and 4b).
In the formula 2b, it can be seen that the positive
and negative
arranged on the right and left sides of the MTPA plane, respectively, the carbinyl carbon of 2. Because the relative stereochemistry
A6
values are beautifully
indicating the S-configuration
of
at other asymmetric centers have been
assigned by the NMR techniques described above, the absolute stereochemistry
can be shown as in the
formula (2). This finding is coincident with the reported absolute configuration,
which reinforces the
validity of the modified Mosher’s method. Contrary arrangement
to this, the results obtained
of the
A6
values is observed
for 3b and 4b are quite confusing:
for 3b, whereas a certain regularity
No systematic
of the values (The
protons of upper part of the structure 4b have negative and those of the lower part have positive values.) is found for 4b although
the tendency
does not obey the rule of the modified
A6
Mosher’s
method (Figure 1). Comparison explanation
of the stereochemical
features of the three compounds,
of the observed regularity and irregularity of the
A6
values:
2a, 3a, and 4a, led to the The 0-MTPA
group of 2a
stretches out of the ring and is relatively free from the steric hindrance, and, therefore, it can take the ‘ideal’ conformation rectangle.).
as shown in the structure
The 0-MTPA
In these compounds,
(2a) (The MTPA plane is illustrated
as a dotted
groups of 3a and 4a are, on the other hand, oriented in axial-like positions.
the MTPA moieties are seriously compressed
by other substituents,
which would
disable the MTPA groups to take the ‘ideal’ conformations. The present
results are in good agreement
method can be applied to cholesterol
with the findings
and friedelin-3a-01,
groups, whereas it is inapplicable to Sa-cholesterol
that the modified
Mosher’s
both of which possess the equatorial OH
and friedelin-3l%ol with the axial OH groups.9
292.5
+O.Ol
2b
-0.014
RO H
3b
3a
-0.027 Me
-0.042
..
-0.027
Me
>..,H
-0.006
R = MTPA
Figure 2. Stereochemical features of the MTPA esters 2s. 3a, and 4a, determined by the H,H COSY and phasesensitive NOESY sepctra, and the A6 values of the protons. A6 = 63 - 6~. The values are given in ppm.
2926
It is not the intention Mosher’s method. a self-examining dependent
of the present authors to exaggerate
the drawbacks
of the modified
Rather, they wish to emphasize the advantage of the method by notifying that it has function to inspect if the result obtained is valid or not, because this methodology
is
This character is quite
on ‘multi data point’, that is, the chemical shifts of many protons.
different from those of other empirical methods like Horeau’s method.le In conclusion,
this report has revealed that the modified Mosher’s method, although it is very
convenient and reliable technique to determine the absolute configurations
of organic compounds,
can
happen to be inapplicable to the secondary alcohols which have a sterically hindered OH group. Acknowledgement.
This work was partly supported
Japanese Ministry of Education,
by Grant-in-Aid
(No. 02640420)
from the
Science and Culture to T. K. T. K. is also grateful to the Fujisawa
Foundation. REFERENCES 1.
AND NOTES
Kusumi, T.; Ohtani, I.; Inouye, Y.; Ishitsuka, 0. M.; Kakisawa, H. 16th IUPAC International Symposium
on the Chemistry of Natural Products (Kyoto), May-June,
Kusumi, T.; Ohtani, I.; Inouye, Y.; Kakisawa, H. Tetrahedron
1988, Abstr. Pa17.
Left. 1988,29,
4731.
Takano, S.; Takahashi, M.; Yanase, M.; Sekiguchi, Y.; Iwabuchi, Y.; Ogasawara, Left. 1988, 1827. Ohtani, I.; Kusumi, T.; Ishitsuka, 0. M.; Kakisawa,
K. Chem.
H. Ibid. 1989,.X),
3147. 2.
Trost, B. M.; Curran, D. P. Tetrahedron Left. 1981,22,
4929. Trost, B. M.; Belletire, J. L.;
Godleski,
J. Org. Chem. 1986, 51,
S.; McDougal,
P. G.; Balkovec,
J. M.
M.; Quiiioa, E.; Crews, P. J. Org. Chem. 1990,55,
Adamczeski, 3.
Kusumi, T.; Fukushima,T.;
4.
Kobayashi,
240.
Ohtani, I.; Kakisawa, H. Tetrahedron Lett. submitted.
M.; Kawazoe, K.; Kitagawa, I. Tetrahedron Left. 1989,30,
I.; Kobayashi, Sot. 1990,112,
2370.
4149. Kitagawa,
M.; Katori, T.; Yamashita, M.; Tanaka, J.; Doi, M.; Ishida, T. J. Am. Chem. 3710.
Hundt, A. F.; Burger, J. F. W.; Steynberg,
A.; Ferreira, D. Tetrahedron Lett. 1990,31,
J. P.; Steenkamp,
J.
5073.
5.
Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Org. Chem. in press.
6.
Mori, K.; Suzuki, S.; Iguchi, K.; Yamada, Y. Chem. Left. 1983, 1515.
7.
Tursch, B.; Braekman, J. C.; Daloze, D.; Herin, M.; Losman. D. Tetrahedron 1975,31,
8.
Kashman, Y.; Bonder, M.; Loya, Y. Israel. J. Chem. 1977,16,
9.
Ohtani, I.; Kusumi, T.; Kashman,
10.
Fiud, J. C.; Horeau, A.; Kagan, H. B. Stereochemistry; Kagan, H. B. ed; Geroge Thieme Publishers
Y.; Kakisawa, H. J. Am. Chem. Sot. in press.
: Stuttgart, 1977; Vol. 3.
(Received in Japan 13 February 1991)
1.
129.