Toward creation of a universal NMR database for stereochemical assignment: Complete structure of the desertomycin/oasomycin class of natural products [10]

Full text of DOI:10.1021/ja004154q

2076
J. Am. Chem. Soc. 2001, 123, 2076-2078
Toward Creation of a Universal NMR Database for
Stereochemical Assignment: Complete Structure of
the Desertomycin/Oasomycin Class of Natural
Products
Yoshihisa Kobayashi, Choon-Hong Tan, and Yoshito Kishi*
Department of Chemistry and Chemical Biology
HarVard UniVersity, 12 Oxford Street
Cambridge, Massachusetts 02138
ReceiVed December 4, 2000
Through the work on palytoxin,1 AAL toxins/fumonisins,2 and
maitotoxin,3 we have experimentally demonstrated that the
structural properties of fatty acids and related compounds are
inherent to the specific stereochemical arrangements of (small)
substituents on their carbon backbone and are independent from
the rest of the molecule. It has been shown that steric and
stereoelectronic interactions between structural clusters connected
either directly or with a one-methylene bridge are significant,
whereas interactions between structural clusters connected with
a two- or more-methylene bridge are almost negligible. On the
basis of these experimental results, the concept of a universal
NMR database approach for stereochemical assignment has been
advanced. Using the contiguous dipropionate structural motif often
found in the polyketide natural products as an example, the
feasibility and reliability of this approach have been addressed.4a
Using the case of the desertomycin/oasomycin class of natural
products (Figure 1),5,6 the applicability and usefulness of this
approach have then been demonstrated. In brief, the NMR
database for the two contiguous propionate units (cf., Database
1 (Figure 2)), was used to predict the relative stereochemistry of
the C.5-C.10 and C.28-C.34 portions of oaso-
mycins.4b,d The second NMR database for the central carbon (and
Figure 1.
Figure 2. Structures of universal NMR databases.
(1) Cha, J. K.; Christ, W. J.; Finan, J. M.; Fujioka, H.; Kishi, Y.; Klein, L.
L.; Ko, S. S.; Leder, J.; McWhorter, Jr., W. W.; Pfaff, K.-P.; Yonaga, M.;
Uemura, D.; Hirata, Y. J. Am. Chem. Soc. 1982, 104, 7369-7371 and
preceding papers.
(2) For the stereochemical assignment of AAL toxins and fumonisins from
this laboratory, see: (a) Boyle, C. D.; Harmange, J.-C.; Kishi, Y. J. Am. Chem.
Soc. 1994, 116, 4995-4996. (b) Boyle, C. D.; Kishi, Y. Tetrahedron Lett.
1995, 36, 5695-5698 and references therein. For the work from other
laboratories, see: (c) Oikawa, H.; Matsuda, I.; Kagawa, T.; Ichihara, A.;
Kohmoto, K. Tetrahedron 1994, 50, 13347-13368. (d) Hoye, T. R.; Jime´nez,
J. I.; Shier, W. T. J. Am. Chem. Soc. 1994, 116, 9409-9410. (e) ApSimon,
J. W.; Blackwell, B. A.; Edwards, O. E.; Fruchier, A. Tetrahedron Lett. 1994,
35, 7703-7706. (f) Poch, G. K.; Powell, R. G.; Plattner, R. D.; Weisleder,
D. Tetrahedron Lett. 1994, 35, 7707-7710. (g) Blackwell, B. A.; Edwards,
O. E.; ApSimon, J. W.; Fruchier, A. Tetrahedron Lett. 1995, 36, 1973-1976.
(3) For the work from this laboratory, see: (a) Zheng, W.; DeMattei, J.
A.; Wu, J.-P.; Duan, J. J.-W.; Cook, L. R.; Oinuma, H.; Kishi, Y. J. Am.
Chem. Soc. 1996, 118, 7946-7968. (b) Cook, L. R.; Oinuma, H.; Semones,
M. A.; Kishi, Y. J. Am. Chem. Soc. 1997, 119, 7928-7937. For the work
from the laboratories at Tokyo and Tohoku Universities, see: (c) Sasaki, M.;
Matsumori, N.; Maruyama, T.; Nonomura, T.; Murata, M.; Tachibana, K.;
Yasumoto, T. Angew. Chem., Int. Ed. Engl. 1996, 35, 1672-1675. (d)
Nonomura, T.; Sasaki, M.; Matsumori, N.; Murata, M.; Tachibana, K.;
Yasumoto, T. Angew. Chem., Int. Ed. Engl. 1996, 35, 1675-1678.
(4) (a) Kobayashi, Y.; Lee, J.; Tezuka, K.; Kishi, Y. Org. Lett. 1999, 1,
2177-2180. (b) Lee, J.; Kobayashi, Y.; Tezuka, K.; Kishi, Y. Org. Lett. 1999,
1, 2181-2184. (c) Kobayashi, Y.; Tan, C.-H.; Kishi, Y. HelV. Chim. Acta
2000, 83, 2562-2571. (d) Kobayashi, Y.; Tan, C.-H.; Kishi, Y. Angew. Chem.,
Int. Ed. 2000, 39, 4279-4281. (e) Tan, C.-H.; Kobayashi, Y.; Kishi, Y. Angew.
Chem., Int. Ed. 2000, 39, 4282-4284.
Figure 3.
possibly the attached proton) of a 1,3,5-triol system (cf., Database
2), was created and used to predict the relative stereochemistry
at the C.23/C.25, C.25/C.27, C.27/C.29, C.33/C.35, and C.35/
C.37 positions.4c,d A third NMR database for the 1,2,3,5-tetraol
motif (cf., Database 3) was created to predict the relative
stereochemistry at C.22 and C.23.4d These efforts allowed us to
determine the relative stereochemistry of the C.5-C.10 and C.21-
C.38 portions of oasomycins. Through the enantioselective and
stereoselective synthesis of the C.3-C.12 and C.21-C.38 deg-
radation products of the oasomycins, the predicted relative
stereochemistry was confirmed, and the absolute stereochemistry
was established at the same time.4b,e In this communication, we
report the complete structure of the desertomycin/oasomycin class
of natural products for the first time.
The strategy for our current work originates from the previous
work on the 1,3,5-triol system.4c The central carbon (marked with
a dot) of 1,3,5-triol A (Figure 3) has been shown to exhibit a
distinctive chemical shift that is dependent on the 1,3- and 3,5-
relative stereochemistry, but that is independent of the functional-
ity present outside of this structural motif. This demonstration
suggests the possibility that the carbon (marked with a dot) of
partial structure B may show a distinctive chemical shift that is
dependent on the relative stereochemistry with X and Y, but that
(5) At least seven members, A-F and I, were identified in the desertomycin
class. (a) Bax, A.; Aszalos, A.; Dinya, Z.; Sudo, K. J. Am. Chem. Soc. 1986,
108, 8056-8063. (b) Dinya, Z.; Sztaricskai, F.; Horvath, E.; Schaag, J. B.
Rapid Commun. Mass Spectrom. 1996, 10, 1439-1448 and references therein.
For detailed NMR analysis, see ref 5a.
(6) At least six members, A-F, were identified in the oasomycin class.
(a) Grabley, S.; Kretzschmar, G.; Mayer, M.; Philipps, S.; Thiericke, R.; Wink,
J.; Zeeck, A. Liebigs Ann. Chem. 1993, 573-579. (b) Mayer, M.; Thiericke,
R. J. Chem. Soc., Perkin Trans. 1 1993, 2525-2531. For detailed NMR
analysis, see ref 6a.
10.1021/ja004154q CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/10/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 9, 2001 2077
Figure 4. Structure of degradation products of the oasomycins.
Figure 5. Difference between normalized carbon chemical shifts of 6a
and carbon chemical shifts of each diasetereomer of Database 4, with
A, B, C, and D representing R/(C.5),R/(C.6),R/(C.7)-, R,R,â-, R,â,â-, and
R,â,R-diastereomers, respectively. The x- and y-axes represent carbon
numbers of 6a and ∆δ (∆δ ) δDatabase 4 - δ6a in ppm).
is independent of the functionality present outside of this structural
motif.7 Interestingly, the methyl group of three degradation
products 6a, 7a, and 8a (Figure 4)8 corresponds to the marked
carbon in B. Of significance to the present work, all of the
remaining unknown stereogenic centers reside within these
degradation products.
We first focused on the C.39-46 degradation product 6a.9 To
test the possibility discussed, we selected the structure shown in
Database 4, synthesized the four possible diastereomers,10 and
measured the 13C NMR chemical shifts. The chemical shift (ppm,
CD3OD) for the central methyl group was found to be 7.1 ppm
for the syn/syn diastereomer, 10.7 for the syn (5/6)/anti (6/7),
10.7 for the anti (5/6)/syn (6/7), and 11.6 for the anti/anti,
respectively. In reference to these data, the chemical shift (11.5
ppm, CD3OD) observed for the methyl group of the degradation
product 6a predicted the relative stereochemistry at C.41, C.42,
and C.43 to be anti/anti.
In the present work, Database 4 was used to deduce the
stereochemistry of the degradation product 6a. However, it should
be noted that numerous polyketide natural products contain this
structural motif in its intact form, and therefore Database 4 should
be applicable for these cases. For example, monazomycin11
contains this structural motif at C.6-C.10, and the chemical shift
of the central methyl group (7.5 ppm, CD3OD)12 predicts the
relative stereochemistry at C.7, C.8, and C.9 of this antibiotic to
be syn/syn.
1
Figure 6. The H.39 and H.46 region of H NMR (500 MHz, C6D6) of
di-Mosher esters 6b. (a) (R,R)-di-Mosher ester 6b derived from the
synthetic 6a. (b) (S,S)-di-Mosher ester 6b derived from the synthetic 6a.
(c) (R,R)-di-Mosher ester 6b derived from 6a derived from natural
oasomycin B.
(41R,42S,43S)-configuration.10 The absolute stereochemistry of
6a was then determined through 1H NMR comparison of the di-
Mosher ester of 6a. The 1H NMR spectra of the (R,R)- and (S,S)-
di-Mosher esters, prepared from the synthetic 6a, were distinc-
It is interesting to assess the reliability of this approach in
reference to the strategy originally used for the contiguous
dipropionate cases. Following the procedure described previously,4b
the C.41-, C.42-, C.43-, and C.55-carbon chemical shifts of 6a
were compared with those of each diastereomer shown in
Database 4 (Figure 5).13 Clearly, this comparison also predicts
the same relative stereochemistry as the one concluded from the
unique chemical shift of the central methyl group.14
1
tively different (Figure 6). The H NMR spectrum of the (R,R)-
di-Mosher ester obtained from the degradation product 6a was
found to be superimposable on the 1H NMR spectrum of the (S,S)-
di-Mosher ester prepared from the synthetic 6a, thereby establish-
ing the absolute configuration as 41S, 42R, 43R (cf. 6a in Figure
4).15
The predicted relative stereochemistry at C.41, C.42, and C.43
was confirmed through the stereoselective synthesis of 6a with
To address the stereochemistry of degradation products 7a and
8a,9 we selected the structure shown in Database 5,10 synthesized
both syn- and anti-diastereomers, and measured the 13C NMR
chemical shift. The chemical shift (ppm, CDCl3) for the methyl
group of syn- and anti-diastereomers was found to be 11.3 and
13.6, respectively.16 In reference to these data, the chemical shift
(11.8 ppm, CDCl3) observed for the methyl group of 7a predicted
syn-relative stereochemistry at C.14 and C.15. The predicted
relative stereochemistry was confirmed through the stereoselective
synthesis of the degradation products 7a with (14R,15S)-config-
uration.10 As before, the absolute stereochemistry was then
(7) A phenomenon somewhat relevant to this case is known. For example,
see: Hoffmann, R. W.; Weidmann, U. Chem. Ber. 1985, 118, 3980-3992.
(8) The degradation products 6a, 7a, and 8a were obtained from oasomycin
B in three steps, i.e.: (1) O3/MeOH/-78 °C; (2) NaBH4/MeOH/rt; (3) Ac2O/
Py/DMAP. Degradation product 8a was isolated as a single diastereomer at
C.20, the stereochemistry of which was assigned based on an NOE experiment
of the corresponding acetonide i. We thank Dr. Gerhard Kretzschmar for a
sample of oasomycins A, B, and C.
1
established as 14S, 15R (cf. 7a in Figure 4) through H NMR
(9) The numbering used for 6a, 7a, and 8a corresponds to the desertomy-
cins/oasomycins numbering, cf., Figure 1.
(10) The details are included in the Supporting Information.
(11) Nakayama, H.; Furihata, K.; Seto, H.; Otake, N. Tetrahedron Lett.
1981, 22, 5217-5220 and references therein.
(12) The complete NMR assignment of monazomycin was carried out by
Dr. Kenichi Tezuka in our laboratory. We thank Professors Y. Hayakawa, H.
Seto, and K. Furihata at the Univeristy of Tokyo for a sample of monazomycin.
(13) In the study of Database 2, the effect of the primary alcohol in HO-
(CH2)2CH(OH)CH2CH(OH)- was recognized to be equal to that of an anti-
1,3-diol.4c Therefore, additional +1.5 ppm was added to the increment obtained
in the procedure reported in ref 4a.
(14) It is worthwhile noting that application of Database 4 for the C.49,
C.53, and C.54 methyl groups of the oasomycins resulted in the C.7/C.8/
C.9-, C.29/C.30/C.31-, and C.31/C.32/C.33-relative stereochemistry same as
the one predicted, and proved, via Database 1.
comparison of the (R,R,R)-tri-Mosher ester 7b derived from the
degradation product with the (R,R,R)- and (S,S,S)-tri-Mosher esters
prepared from the synthetic 7a.17
Database 5 was also applied to predict the C.18/C.19-relative
stereochemistry of degradation product 8a. The chemical shift
(15) 6b was prepared by treatment of 6a with (R)-Mosher acid, EDCI and
DMAP. The details are included in the Supporting Information.
(16) It should be added that the methyl group of the syn- and anti-triols
corresponding to Database 5 gave unique and useful chemical shifts (ppm,
CD3OD) at 11.0 and 13.8, respectively.
(17) 7b was prepared by treatment of 7a with KOH in methanol followed
by (S)-Mosher acid chloride, NEt3, and DMAP. The details are included in
the Supporting Information.

2078 J. Am. Chem. Soc., Vol. 123, No. 9, 2001
Communications to the Editor
of the relevant methyl group in 8a was found at 11.6 ppm
(CDCl3), predicting syn-relative stereochemistry at C.18 and C.19.
The predicted relative stereochemistry was then confirmed through
the stereoselective synthesis of the degradation product 8a with
(18S,19R,20S)-configuration.10 Once again, the absolute stereo-
chemistry was determined as 18S,19R,20S (cf. 8a in Figure
stereochemical assignment of the oasomycins. Comparison of their
NMR data clearly demonstrates that the desertomycins share the
same stereochemistry with the oasomycins.5a,6a Thus, the complete
structure of the desertomycin/oasomycin class of natural products
is described as shown in Figure 1. In the present work, we treated
several structural motifs of the oasomycins independently from
each other, applied five simple NMR databases (Figure 2) to
predict the relative stereochemistry, and confirmed the predicted
stereochemistry by chemical synthesis. In our view, the reliability
of this approach has been well demonstrated, and confirmation
of the predicted stereochemistry by chemical synthesis is no longer
necessary. However, to correlate the relative stereochemistry of
one segment with that of others, we need information regarding
the absolute stereochemistry of each segment, which has been
provided through chemical synthesis at present. In this context,
we recognize the possibility that the absolute configuration of a
given structural motif can be determined through an NMR
database approach in chiral environments.21 Finally, it is our belief
that we are sufficiently prepared to initiate a computer-assisted,
universal database approach for the stereochemical assignment
of unknown compounds.
1
4),through H NMR comparison of the (R)-mono-Mosher ester
8b derived from the degradation product with the (R)- and (S)-
mono-Mosher esters prepared from the synthetic 8a.18
The degradation product 8a contains one additional stereogenic
center just outside the structural motif in question. Using this
system,19 the effect on the chemical shift from an additional
functional group present outside the structural motif was assessed.
Interestingly, the chemical shift difference between the C.19/C.20-
syn (δC.51: 11.4 ppm, CDCl3) and C.19/C.20-anti (δC.51: 11.8 ppm,
CDCl3) was found to be small, supporting the previously presented
hypothesis.
The structural motif represented by Database 5 is found in a
number of degradation products of polyketide natural products.
For example, this database predicts the relative stereochemistry
at C.4/C.5, C.25/C.26, and C.30/C.31 of copiamycin20 to be anti,
syn, and anti, respectively. Related to Database 5, it should be
1
noted that the 13C- and H chemical shift differences between
Acknowledgment. We are grateful to the National Institutes of Health
for generous financial support (NS 12108).
syn- and anti-diastereomers of trans-Me(CH2)2CHdCHCH(OH)-
CH(Me)CHdCH2 were found to be negligibly small, suggesting
that an additional device may be required to apply this type of
database to an intact molecule.
Combined with previous results on the C.5-C.10 and C.21-
C.38 portions, the present work allows us to establish the complete
Supporting Information Available: Complete experimental details
for the synthesis of 6a,b-8a,b, including their independent stereochemical
assignments and spectroscopic data, as well as NMR Databases 4 and 5
(PDF). This material is available free of charge via the Internet at
http://pubs.acs.org.
(18) 8b was prepared by treatment of 8a with KOH in methanol followed
by with (R)-Mosher acid, EDCI, and DMAP. The details are included in the
Supporting Information.
(19) The C.20 diastereomer of 8a was prepared prepared by a reduction of
the corresponding hydroxyl ketone with NaBH4.
(20) Fukushima, K.; Arai, T.; Iwasaki, S.; Namikoshi, M.; Okuda, S. J.
Antibiot. 1982, 35, 1480-1494 and references therein.
JA004154Q
(21) For a similar purpose, a chiral shift-reagent was used.2a For related
examples, see: Parker, D. Chem. ReV. 1991, 91, 1441-1457 and references
therein.