Stereochemistry of sagittamide A: Prediction and confirmation

Article abstract of DOI:10.1021/ol061582d

The C5-C10 relative stereochemistry of sagittamide A was predicted, with the use of the ³J_H,H profiles assembled from the spin-coupling constants reported in the literature. The predicted relative stereochemistry was then confirmed by a total synthesis of two relevant remote diastereomers. The absolute configuration of sagittamide A was established through a detailed ¹H NMR analysis of the two remote diastereomers, followed by doping experiments of them with the authentic natural product.

Full text of DOI:10.1021/ol061582d

ORGANIC
LETTERS
2006
Vol. 8, No. 17
3865-3868
Stereochemistry of Sagittamide A:
Prediction and Confirmation
Hirofumi Seike, Indranath Ghosh, and Yoshito Kishi*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
kishi@chemistry.harVard.edu
Received June 27, 2006
ABSTRACT
3
The C5−C10 relative stereochemistry of sagittamide A was predicted, with the use of the JH,H profiles assembled from the spin-coupling
constants reported in the literature. The predicted relative stereochemistry was then confirmed by a total synthesis of two relevant remote
diastereomers. The absolute configuration of sagittamide A was established through a detailed 1H NMR analysis of the two remote diastereomers,
followed by doping experiments of them with the authentic natural product.
Sagittamides A and B are the marine natural products isolated
recently from an unidentified tunicate collected in Micronesia
by Lievens and Molinski.1 These natural products consist
of three parts: a long-chain R,ω-dicarboxylic aid (C-26),
L-valine, and L-ornithine. The R,ω-dicarboxylic acid moiety
of sagittamide A contains a stereocluster of contiguous hexaol
peracetate, the stereochemistry of which has not been dis-
closed. We became interested in the structure of sagittamide
A, as the hexaacetate moiety of sagittamide A provides an
ideal testing ground for demonstrating the reliability and
By using diastereomeric heptaols as examples, we previ-
ously demonstrated that JH,H profiles composed of three
contiguous spin-coupling constants are, at least to the first
order of analysis, sufficient for stereochemical analysis of
unknown contiguous polyols.3 With this demonstration, we
felt that the 3JH,H profiles (Figure 1) reported in the preceding
3
3
applicability of the JH,H profiles assembled from spin-
coupling constants reported in the literature.2 In this letter,
we report the prediction of the relative stereochemistry of
the hexaacetate moiety present in sagittamide A by this
approach and then the confirmation of the predicted stereo-
chemistry via a total synthesis. The absolute stereochemistry
1
has been established through a detailed analysis of the H
3
Figure 1. JH,H profiles of the contiguous tetraol peracetate
spectra of synthetic sagittamide A and its remote diastere-
omer.
assembled with the use of the spin-coupling constants reported in
the literature for the relevant compounds.2 Abbreviations: A ) anti
and S ) syn.
paper should be useful for stereochemical analysis of the
hexaacetate moiety present in sagittamide A.
Thus, following the procedure established for the heptaol
3
case,3 we analyzed the JH,H profile (A, Figure 2) of
10.1021/ol061582d CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/27/2006

ture has no plane of symmetry, even if the difference in the
3
two termini was ignored. Thus, we would expect the JH,H
profile to have no symmetrical nature, and this trend is clearly
recognized in the overall profile shown in A.
With the relative stereochemistry at the C5-C10 positions
predicted as I, sagittamide A should correspond to one of
the two diastereomers II and III because both valine and
ornithine were shown to belong to the L-amino acid series.1
To confirm the predicted relative stereochemistry at the C5-
C10 moiety and also to differentiate the two candidates II
and III, we relied on organic synthesis. Specifically, our plan
was to synthesize both II and III and then to develop an
analytical method to differentiate them. However, for
synthetic economy, we chose to synthesize II and the
antipode of III.
Figure 2. Profile analysis of the 3JH,H coupling constants reported
for the C5-C10 moiety of sagittamide A.1 Panel A: Overall profile
reported where a, b, c, d, and e represent the vicinal spin-coupling
constants (Hz) observed for H5/H6, H6/H7, H7/H8, H8/H9, and
H9/H10, respectively. Panel B: 3JH,H profile composed of the three
3JH,H’s of H7/H8-H8/H9-H9/H10; this profile best matches the
SAS profile in Figure 1 (∑|∆Hz| ) 0.8 Hz). Panel C: 3JH,H profile
To this end, we chose D-(+)-galactose as the chiral starting
material, which contains four out of the six contiguous
stereogenic centers present in the C26 dicarboxylic acid of
II. Following literature procedure, D-(+)-galactose was
converted to the acetonide alcohol 1 (Scheme 1). Dess-
Martin oxidation,5 followed by Wittig olefination, furnished
the desired cis olefin (J5,6 ) 11.0 Hz). After coupling with
L-valine tert-butyl ester in the presence of the BOP reagent,6
the olefin 2 was subjected to dihydroxylation (cat. OsO4-
NMO in aq dioxane at room temperature), to furnish an 8.3:1
mixture of the expected diols. On the basis of the empirical
rule,7 the stereochemistry of the major product was assigned
as indicated. After the newly introduced alcohols were
protected as benzyl ethers, 3 was converted to the epoxide
4 under the Mitsunobu conditions.8
3
composed of the three JH,H’s of H6/H7-H7/H8-H8/H9; this
profile best matches the ASA profile (∑|∆Hz| ) 2.1 Hz). Panel
D: 3JH,H profile composed of the three 3JH,H’s of H5/H6-H6/H7-
H7/H8; this profile best matches the SAA profile (∑|∆Hz| ) 2.1
Hz). I: predicted relative stereochemistry of the C5-C10 moiety
of sagittamide A.4 Abbreviations: A ) anti and S ) syn.
sagittamide A reported by Lievens and Molinski.1 The
analytical procedure involved: (1) imaginarily dissecting the
3JH,H profile of sagittamide A into three small stereoclusters
B-D, each composed of three contiguous 3JH,H systems and
(2) comparing each of the resultant 3JH,H profiles to the 3JH,H
profiles of contiguous tetraol peracetates, to predict their
relative stereochemistry on the basis of the profile fitness.
In this exercise, the profile fitness was assessed by the
The next phase of the synthesis was to couple 4 with the
lower side chain. Ideally, we hoped to introduce the lower
side chain bearing the L-ornithine moiety. Despite a variety
of attempts, we were unable to achieve the coupling with a
3
deviation sum (∑|∆Hz|) between the experimental JH,H’s
and the corresponding 3JH,H’s in the profile. As discussed in
the preceding paper, ∑|∆Hz| for a good profile matching is
expected to be less than 3.3 Hz. For each of the three
comparisons, only one out of the eight subgroups met with
the criteria, i.e., SAS subgroup for B (∑|∆Hz| ) 0.8 Hz),
ASA subgroup for C (∑|∆Hz| ) 2.1 Hz), and SAA subgroup
for D (∑|∆Hz| ) 2.1 Hz), thereby predicting that the C5-
C10 relative stereochemistry of sagittamide A corresponds
to the one shown as I (Figure 2).4 The predicted stereostruc-
(4) The second best candidate was found to be the SAA (∑|∆Hz| ) 4.9
Hz) or AAS (∑|∆Hz| ) 4.9 Hz) subgroup for comparison B, the ASS
subgroup (∑|∆Hz| ) 5.2 Hz) for comparison C, and the SAS subgroup
(∑|∆Hz| ) 4.2 Hz) for comparison D, respectively. However, the degree
of profile fitness well exceeds the level of ∑|∆Hz| < 3.3 Hz for all these
cases.
(5) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b)
Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(6) (a) Dormoy, J. R.; Castro, B. In Encylopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; John Wiley & Sons Ltd.: Chichester, U.K.,
1995; Vol. 1, pp 301-304. (b) Castro, B.; Dormoy, J. R.; Evin, G.; Selve,
C. Tetrahedron Lett. 1975, 1219.
(7) (a) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron Lett. 1983, 24,
3943. (b) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron Lett. 1983, 24,
3947. (c) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron 1984, 40, 2247.
(8) Hughes, D. L. In Organic Reactions; Paquette, L. A., Ed.; John Wiley
& Sons, Inc.: Hoboken, NJ, 1992; Vol. 42 pp 335-656.
(1) Lievens, S. C.; Molinski, T. F. Org. Lett. 2005, 7, 2281.
(2) Seike, H.; Ghosh, I.; Kishi, Y. Org. Lett. 2006, 8, 3861.
(3) Higashibayashi, S.; Czechtizky, W.; Kobayashi, Y.; Kishi, Y. J. Am.
Chem. Soc. 2003, 125, 14379.
3866
Org. Lett., Vol. 8, No. 17, 2006

Scheme 1a
a Reagents and conditions: (a) Dess-Martin reagent, NaHCO3,
CH2Cl2, rt; (b) Br-(Ph)3P+CH2(CH2)3CO2H, LiHMDS, THF, 0 °C,
Figure 3. Acetate signals in the 1H NMR spectra (600 MHz, CD3-
OD-TFA) of II and the antipode of III. Panel A: II. Panel B: A
ca. 3:2 mixture of II and III-antipode. Panel C: A ca. 1:2 mixture
of II and III-antipode. Panel D: III-antipode contaminated with a
small amount (<10%) of L-valine. X-axis represents the chemical
shift in ppm.
i
t
then rt; (c) BOP, Pr2NEt, DMF, 0 °C, then L-valine Bu ester, rt;
(d) OsO4, NMO, aq dioxane, rt; (e) BnO(CdNH)CCl3, TfOH,
CH2Cl2/cyclohexane, 0 °C, then rt; (f) AcOH/H2O, rt; (g) DEAD,
PPh3, CHCl3, 60 °C; (h) HCtC(CH2)12CO2TIPS, BuLi, BF3‚Et2O,
Et2O/THF, -95 °C, then -78 °C; (i) TBAF, THF, 0 °C; (j) L-Nδ-
t
Boc-ornithine Bu ester, EDCI, HOBt, DMF, rt; (k) H2, Pd on C,
AcOH/MeOH, rt; (l) Ac2O, py, rt; (m) TFA, CH2Cl2, rt.
The remaining task was to develop an analytical method
to differentiate II and the antipode of III. With both remote
diastereomers in hand, we closely studied their H NMR
spectra. As mentioned, both remote diastereomers gave
fully functionalized side chain. Thus, we studied the coupling
of 4 with the lower side chain bearing a protected carboxylic
acid at C26. After much experimentation, it was found that
this task could be achieved by a BF3-OEt2-mediated epoxide
opening with the C15 acetylene under the Yamaguchi
conditions,9 to furnish the coupled product 5. It was critical
to generate the boron reagent at -95 °C; when the boron
reagent was prepared at -78 °C, a complex mixture
containing the desired product, the unreacted epoxide, and
unidentified byproducts was obtained. After the TIPS ester
was deprotected with TBAF, 5 was coupled with L-Nδ-Boc-
ornithine tert-butyl ester to give the amide 6. The amide 6
was uneventfully converted to II in three steps.
1
The product II thus synthesized corresponds to one of the
two candidates predicted as the structure of sagittamide A.
The antipode of the remaining candidate III was synthesized
via the same route but with the use of D-valine tert-butyl
ester and D-Nδ-Boc-ornithine tert-butyl ester.
With both candidates in hand, we began analytical work.
II and the antipode of III are remote diastereomers (dia-
stereomers due to the stereogenic centers being present
outside of a self-contained box).10 Thus, we anticipate that
the NMR characteristics of II and III are identical or at least
1
very similar. Indeed, the H and 13C spectra of II and the
antipode of III were found to be virtually identical. Impor-
tantly, these NMR characteristics were found to perfectly
match the NMR data reported for sagittamide A, thereby
confirming the relative stereochemistry at C5-C10 predicted
using the JH,H profiles assembled from the spin-coupling
constants obtained from relevant but scattered literature
examples.
Figure 4. Acetate signals in the 1H NMR spectra (600 MHz, CD3-
OD-TFA) of synthetic and natural sagittamide A. Panel A: II.
Panel B: II doped with approximately 0.5 equiv of natural
sagittamide A. Panel C: III-antipode doped with approximately
0.5 equiv of natural sagittamide A. Panel D: III-antipode con-
taminated with a small amount (<10%) of L-valine. X-axis
represents the chemical shift in ppm.
3
(9) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391
Org. Lett., Vol. 8, No. 17, 2006
3867

virtually identical 1H NMR spectra. However, a clue for the
solution was first detected while recording the H NMR
diastereomer II. Knowing that the absolute configuration of
the two amino acids is L,1 the complete structure of
sagittamide A is established as II.
1
spectrum of the antipode of III, which was contaminated
1
with a small amount (<10%) of L-valine.11 The H NMR
In summary, the C5-C10 relative stereochemistry of
sagittamide A was predicted, with the use of the 3JH,H profiles
assembled from the spin-coupling constants reported in the
literature. The predicted relative stereochemistry was then
confirmed by a total synthesis of two relevant remote
diastereomers. The absolute configuration of sagittamide A
was established through a detailed 1H NMR analysis of the
two remote diastereomers and then by conducting doping
experiments of them with the authentic natural product.
spectrum of this sample clearly indicated that three out of
the six acetate signals have a shoulder. Being encouraged
with this observation, we then conducted a doping experiment
of the antipode of III with II, thereby unambiguously
1
demonstrating that H NMR spectroscopy can differentiate
the two remote diastereomers in question (Figure 3).12
Using this analytical method, we performed two doping
experiments (Figure 4). On doping with natural sagittamide
A, we observed that none of the acetyl signals were doubled
in the II series, whereas three out of the six acetyl signals
were doubled in the III-antipode series,12 thereby demon-
strating that sagittamide A corresponds to the remote
Acknowledgment. We gratefully acknowledge Professor
T. F. Molinski at the University of California, San Diego,
for a generous gift of natural sagittamide A. Financial support
from Eisai Research Institute is gratefully acknowledged.
(10) Previous work in our laboratory has shown steric and/or stereo-
electronic interactions between structural clusters separated by two or more
carbons to be negligibly small. This characteristic, referred to as a self-
contained box, constitutes one of the key foundations for our NMR database
approach. For examples, see: (a) Boyle, C. D.; Harmange, J.-C.; Kishi, Y.
J. Am. Chem. Soc. 1994, 116, 4995. (b) 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. (c) Kobayashi, Y.; Tan, C.-H.; Kishi, Y. HelV. Chim.
Acta 2000, 83, 2562. (d) Kobayashi, Y.; Tan, C.-H.; Kishi, Y. J. Am. Chem.
Soc. 2001, 123, 2076. Also see ref 3 and references therein.
(11) This was due to a partial epimerization of the D-valine moiety during
the preparation of D-valine tert-butyl ester.
(12) In addition to the three doubled acetyl signals, the resonance around
2.08 ppm showed a sign of doubling.
Supporting Information Available: Experimental details
for Scheme 1; spectroscopic data for compounds 1-6, II,
and III-antipode; 1H and 13C NMR spectra of II, III-
antipode, and natural sagittamide A; and table of 13C NMR
data of II, III-antipode, and natural sagittamide A along with
the 13C NMR data reported in ref 1. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL061582D
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Org. Lett., Vol. 8, No. 17, 2006