Toward creation of a universal NMR database for the stereochemical assignment of acyclic compounds: Proof of concept

Article abstract of DOI:10.1021/ol990379y

Oasomycin B: R = α-D-mannosyl Using the C.5-C.10 portion of the oasomycin class of natural products, the reliability and usefulness of an NMR database for the stereochemical assignment of acyclic compounds has been demonstrated. The predicted relative stereochemistry based on the NMR database has unambiguously been established via synthesis.

Full text of DOI:10.1021/ol990379y

ORGANIC
LETTERS
1999
Vol. 1, No. 13
2181-2184
Toward Creation of a Universal NMR
Database for the Stereochemical
Assignment of Acyclic Compounds:
Proof of Concept
Jinhwa Lee, Yoshihisa Kobayashi, Kenichi Tezuka, and Yoshito Kishi*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
kishi@chemistry.harVard.edu
Received November 29, 1999
ABSTRACT
Using the C.5−C.10 portion of the oasomycin class of natural products, the reliability and usefulness of an NMR database for the stereochemical
assignment of acyclic compounds has been demonstrated. The predicted relative stereochemistry based on the NMR database has unambiguously
been established via synthesis.
In the preceding paper,1 we reported our first step toward
the creation of a universal NMR database through analysis
of a typical structural motif often found in polypropionate
natural products. In this paper, we address the reliability and
usefulness of such an NMR database for the stereochemical
assignment of an unknown compound. Among numerous
natural products containing two contiguous propionate units,
we chose the C.5-C.10 portion of the oasomycin class2 of
natural products for several reasons, including (1) the
availability of detailed NMR data and (2) the fact that the
stereochemistry of this class of natural products has not yet
been established (Figure 1).2
Figure 1. Structure of oasomycins A and B.
(1) Kobayashi, Y.; Lee, J.; Tezuka, K.; Kishi, Y. Org. Lett. 1999, 1,
2177-2180.
Correlation of the 13C NMR characteristics of the C.5-
(2) Grabley, S.; Kretzschmar, G.; Mayer, M.; Philipps, S.; Thiericke,
R.; Wink, J.; Zeeck, A. Liebigs Ann. Chem. 1993, 573-579.
C.10 portion of oasomycins with our 13C NMR database was
10.1021/ol990379y CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/23/1999

conducted via the following operations. First, using the
Schaller program,3 the chemical shifts were predicted for 2,
representing the C.1-C.16 portion of oasomycins, as well
as for 1, the structure used for the creation of the NMR
database (Figure 2). Second, the chemical shift difference
Figure 2. Predicted 13C NMR chemical shift (ppm).
between a given carbon in 2 and the corresponding carbon
in 1 was assumed to represent the chemical shift increment
for the given carbon of oasomycins. Third, these increments
were then subtracted from the 13C NMR chemical shifts
reported for oasomycin B to create a comparative chemical
shift profile.2,4 Fourth, differences between the comparative
13C chemical shifts of oasomycin B and the 13C chemical
shifts of each synthetic diastereomer were used to compare
the structural properties of the C.5-C.10 portion of the
antibiotic with the structural properties of each of 1a-h
(Figure 3).
Figure 3. Difference between adjusted carbon chemical shifts of
oasomycin B and those of each of 1a-h (100 MHz, ppm, (CD3)2-
SO).
synthesized tetraol 6 with the indicated absolute configuration
(Scheme 1)6 and established that 6 has a 1H NMR spectrum
Scheme 1
The pattern of chemical shift difference between the C.5-
C.10 portion of oasomycin B and each diastereomer was
distinct and differed from one another. Importantly, the 13
C
NMR characteristics of the C.5-C.10 portion of oasomycin
B match only with those of 1e,5 indicating that the relative
stereochemistry at C.6, C.7, C.8, and C.9 of oasomycin B
corresponds to that of this diastereomer.
The graphs shown in Figure 3 convincingly demonstrate
that the relative stereochemistry of the C.5-C.10 portion of
oasomycins is represented by diastereomer 1e. Nonetheless,
the reliability and usefulness of this new approach for the
stereochemical assignment of an acyclic compound have not
yet been tested rigorously, and we felt it important to prove
unambiguously the suggested stereochemistry. Therefore, we
(3) CS ChemNMR Pro version 1.0, Renate Buergin Schaller, Develop-
ment Centre, Bergstr. 114, Zurich, Switzerland, installed in CS ChemDraw
Pro version 4.5, was used.
(4) The graphs shown in Figure 3 were prepared on the basis of the
NMR data reported for oasomycin B. However, there is virtually no
difference in the NMR data reported for oasomycins A-D, excluding the
C.20-C.22 and C.39-C.46 moieties.2
(5) The stereochemistry of 1a-h corresponds to that in the preceding
paper.
identical to that of the tetraol derived7 from natural oaso-
mycin B8 (Figure 4).
(6) The structure of the synthetic tetraol 6 was established by adopting
the same procedure as the one described in the preceding paper. The
experimental details are included in the Supporting Information.
2182
Org. Lett., Vol. 1, No. 13, 1999

Figure 4. 1H NMR spectra (500 MHz, CD3OD). (a) Synthetic
tetraol 6. (b) Tetraol derived from oasomycin B.
Figure 5. 1H NMR (500 MHz, CD3OD). (a) Di-(S)-Mosher ester
7a derived from synthetic tetraol 6. (b) Di-(R)-Mosher ester 7b
derived from synthetic tetraol 6. (c) Di-(S)-Mosher ester derived
from the tetraol derived from natural oasomycin B.
The absolute configuration of the C.5-C.10 segment of
oasomycins was then determined via the derivatization of
6.9 The C.7,C.9-acetonide C.3,C.12-di-Mosher esters 7a,b
1
were prepared from 6.10 Importantly, the H NMR spectra
of 7a and 7b were distinctly different (Figure 5). The tetraol
derived from natural oasomycin B was then converted to
the corresponding C.7,C.9-acetonide C.3,C.12-di-(S)-Mosher
1
ester, and its H NMR spectrum was found to be superim-
posable on the 1H NMR spectrum of the synthetic C.7,C.9-
acetonide C.3,C.12-di-(R)-Mosher ester 7b, thereby estab-
lishing the absolute configuration of the C.5-C.10 portion
of oasomycin B to be the opposite of 6 (Figure 6).
Figure 6. Absolute stereochemistry of the C.5-C.10 portion of
oasomycins A and B.
In conclusion, using a structural motif often found in the
polypropionate class of natural products, we have demon-
strated the reliability and usefulness of our NMR database
for the stereochemical assignment of an acyclic compound.
We recognize that the current approach critically depends
on the availability of an NMR database properly representing
a given arrangement of functional groups in question. As
demonstrated in the preceding paper, such an NMR database
can be created by synthesizing all of the possible diastere-
omers for a chosen representative system. However, this
approach requires extensive synthetic effort for each case.
In this connection, we recognize the possibility that an NMR
database for a larger array of functional groups could be
assembled from NMR databases of smaller arrays of
functional groups and, given a minimum number of NMR
databases, synthetic efforts could totally, or at least largely,
be eliminated. We plan to test the feasibility of this approach
through further studies on the oasomycins.
(7) This degradation was achieved in 59% overall yield in two steps,
i.e., (1) O3/MeOH/-78 °C, followed by Me2S treatment, and (2) NaBH4/
MeOH/0 °C.
(8) We thank Dr. Gerhard Kretzschmar for a sample of oasomycins A,
B, and C.
(9) The RD value of synthetic tetraol 6 was found approximately +5.9°
(c 1.2, MeOH). We were concerned that this value might be too small to
draw our conclusion.
(10) This transformation was carried out in two steps, i.e., (1) acetone/
CSA/rt and (2) Mosher acid/EDCI/DMAP/CH2Cl2/rt.
Org. Lett., Vol. 1, No. 13, 1999
2183

Acknowledgment. Financial support from the National
Institutes of Health (NS 12108) is gratefully acknowledged.
dures summarized in Scheme 1, and degradation of oasomycin
B into the tetraol. This material is available free of charge
via the Internet at http://pubs.acs.org.
Supporting Information Available: Details for correla-
tion of the 13C NMR data of the C.5-C.10 portion ofoaso-
mycin B with the 13C NMR database, experimental proce-
OL990379Y
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Org. Lett., Vol. 1, No. 13, 1999