The total synthesis and stereochemical revision of yanucamide A

Article abstract of DOI:10.1021/ol034803d

(Matrix presented) The first total synthesis of yanucamide A is reported via amide and ester couplings of the key components. This synthesis has established the configuration at the previously ambiguous 3-position, and also revised the stereochemistry at the 22-position, to give 3S,12S,17S,22S for the natural product.

Full text of DOI:10.1021/ol034803d

ORGANIC
LETTERS
2003
Vol. 5, No. 16
2821-2824
The Total Synthesis and Stereochemical
Revision of Yanucamide A†
,‡,§
Zhengshuang Xu,‡ Yungui Peng,‡ and Tao Ye*
Department of Chemistry, The UniVersity of Hong Kong, Pokfulam Road, Hong Kong,
China, and Open Laboratory of Chirotechnology of the Institute of Molecular
Technology for Drug DiscoVery & Synthesis and Department of Applied Biology &
Chemical Technology, The Hong Kong Polytechnic UniVersity, Hung Hom,
Kowloon, Hong Kong, China
bctaoye@inet.polyu.edu.hk
Received May 11, 2003
ABSTRACT
The first total synthesis of yanucamide A is reported via amide and ester couplings of the key components. This synthesis has established
the configuration at the previously ambiguous 3-position, and also revised the stereochemistry at the 22-position, to give 3S,12S,17S,22S for
the natural product.
There has been much interest recently in natural products
from cyanobacteria, including isolation of obyanamide1 and
aeruginosamide,2 and synthesis of dendroamide A3 and
7-epicyclindrospermopsin.4 These compounds, and numerous
others, have shown that cyanobacteria produce a wide range
of secondary metabolites displaying a broad spectrum of
biological activities. Species Lyngbya majuscula,5 a strain
of cyanobacterium, has provided many varied metabolites,
the biological activity of which ranges from cytotoxic agents
to anticancer and antifungal activity. Unusual effects include
immunosuppressants and antifeedants. These compounds
have potential applications as therapeutic agents and this has
driven our group to synthesize a range of these metabolites,
with the aim of structure modification for fine-tuning
biological activity. One particular target of interest was
yanucamide A (1),6 which was isolated by Gerwick and co-
workers from an assemblage of Lyngbya majuscula and
Schizothrix species. Both yanucamide A (1) and the closely
related yanucamide B7 have shown potent toxicity toward
brine shrimp, but full data on their respective biological
activities are unknown. The stereochemistry at the C-3
position was unassigned in the isolation paper and our initial
aim was to identify the correct configuration at this center.
The true stereochmistry at C-3 was strongly suspected to
be (S), since the (S)-2,2-dimethyl-3-hydroxyoctynoic acid
(Dhoya) group has appeared in the natural products ku-
lolide-1 and kulokainalide-1. Although these were not
directly extracted from a cyanobacterium, they were taken
from a higher organism known to have cyanobacteria in its
food chain. Consequently, the origin of the Dhoya is believed
† Dedicated to Professor M. Anthony McKervey on his 65th birthday.
‡ The University of Hong Kong.
§ The Hong Kong Polytechnic University.
(1) Williams, P. G.; Yoshida, W. Y.; Moore, R. E.; Paul, V. J. J. Nat.
Prod. 2002, 65, 29-31.
(2) Lawton, L. A.; Morris, L. A.; Jaspars, M. J. Org. Chem. 1999, 64,
5329-5332.
(3) Xia, Z.; Smith, C. D. J. Org. Chem. 2001, 66, 3459-3466.
(4) Heintzelman, G. R.; Fang, W.-K.; Keen, S. P.; Wallace, G. A.;
Weinreb, S. M. J. Am. Chem. Soc. 2002, 124, 3939-3945.
(5) Burja, A. M.; Banaigs, B.; Abou-Mansour, E.; Burgess, J. G.; Wright,
P Tetrahedron 2001, 57, 9347-9377.
(6) Sitachitta, N.; Williamson, R. T.; Gerwick, W. H. J. Nat. Prod. 2000,
63, 197-200.
(7) For the isolation of yanucamide B, please see ref 6.
10.1021/ol034803d CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/12/2003

to be cyanobacterial and the (S)-configuration was assumed
to be correct when considering appropriate disconnections
(Figure 1).
10. Hydrogenolysis of the benzyl group, using palladium on
charcoal as catalyst, and a further Swern oxidation furnished
aldehyde 11. This was then treated with the Ohira-Bestmann
reagent9 to form the corresponding alkyne in excellent yield.
Desilylation with trifluoroacetic acid and saponification
yielded, after acidification, (S)-acetylenic acid 2. Palladium-
catalyzed hydrogenation of acid 2 afforded the corresponding
2,2-dimethyl-3-hydroxyoctanoic acid. Its negative optical
rotation revealed 3S configuration of the hydrogenation
product by comparison with data for the known compound.10
Attention now turned to fragment 3.
This was a straightforward preparation starting from (S)-
valine 15 (Sheme 2). Diazotization and hydrolysis gave (S)-
Scheme 2. Synthesis of Fragment 3a
Figure 1. Retrosynthetic analysis of yanucamide A.
Ultimate closure of the depsipeptide was chosen to be a
peptide linkage between the â-alanine and phenylalanine
units. This is sufficiently unhindered to allow smooth
reaction, and should be possible to achieve without any
racemization. With this in mind, we set about preparing
fragments 2 and 3.
The Dhoya fragment 2 (Scheme 1) was constructed in
eight steps from 1,5-pentanediol (5). Benzyl protection and
a Reagents and conditions: (i) NaNO2, H2SO4, H2O; (ii)
Ph2CNdNH2, PhI(OAc)2, I2, DCM, -10°C, 86%; (iii) Cbz-L-Val-
OH, EDC, DMAP, DCM, 84%; (iv) TFA, DCM; (v) 18, BEP,
DIPEA, DCM, -10 °C to rt, 66%.
Scheme 1. Synthesis of Fragment 2a
2-hydroxyisovaleric acid, which was protected as its di-
phenylmethyl (DPM) ester 16,11 allowing a degree of
versatility in the choice of the other protecting groups used.
The coupling of 16 with Cbz-L-Val-OH, mediated by EDC
and DMAP, proceeded smoothly to give 17 in 84% yield.
TFA removal of the DPM protecting group, followed by
coupling with amino ester 18, using Xu’s conditions for
hindered substrates,12 gave fragment 3 in a reasonable yield.
The construction of yanucamide A from the three frag-
ments was completed with use of standard procedures
(Scheme 3). Hydrogenolytic removal of the Cbz group in 3
was achieved by using 10% Pd/C in methanol. The crude
product of this reaction, after filtering and concentrating, was
combined directly with acetylenic acid 2, and coupling was
mediated by BEP to give a 68% yield of 19 over two steps.
Esterification of Boc-protected â-alanine with 19, facilitated
by EDC and DMAP, produced the cyclization precursor 20
a Reagents and conditions: (i) NaH, BnBr; (ii) (COCl)2, DMSO,
Et3N, DCM, -78 °C, 71%; (iii) 7, THF, -78 °C, then 8, 67%;
(iv) TBSOTf, 2,6-lutidine, DCM, -50 °C, 83%; (v) H2, Pd/C; (vi)
12, K2CO3, MeOH, 71%; (vii) TFA, DCM, 82%; (viii) NaOH (aq),
0 °C, 92%.
(8) Kiyooka, S.-I.; Kaneko, Y.; Komura, M.; Matsuo, H.; Nakano, M.
J. Org. Chem. 1991, 56, 2276-2278.
Swern oxidation gave the protected aldehyde 6. This was
converted into the (S)-â-hydroxy ester 9 via an asymmetric
aldol reaction with methyl trimethylsilyl ketene (8), in the
presence of oxazaborolidinone 7 (derived from (R)-valine),
using the method of Kiyooka.8 Silyl protection of the
secondary alcohol with use of TBS-triflate resulted in ester
(9) (a) Ohira, S. Synth. Commun. 1989, 19, 561-564. (b) Muller, S.;
Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521-522.
(10) Nakao, Y.; Yoshida, W. Y.; Szabo, C. M.; Baker, B. J.; Scheuer,
P. J. J. Org. Chem. 1998, 63, 3272-3280.
(11) Lapatsanis, L.; Milias, G.; Paraskewas, S. Synthesis 1985, 513-
515.
(12) Li, P.; Xu, J. C. Tetrahedron Lett. 1999, 40, 8301-8302.
2822
Org. Lett., Vol. 5, No. 16, 2003

Scheme 3. Assembling the Cyclodepsipeptidea
Figure 3. 1H NMR spectra of four synthetic yanucamide A
stereoisomers.
a Reagents and conditions: (i) PdCl2, H2, MeOH; (ii) 2, BEP,
DIPEA, DCM, 68%; (iii) 4, EDC, DMAP, DCM, 98%; (iv) TFA,
DCM; (v) BOPCl, NMM, DMF, 24 h, 75%.
considerable differences. Given that the stereochemistry at
C-3 had been ambiguous, our disappointment was not too
great. Having established that the published structure was
incorrect we wished to verify the correct structure for
yanucamide A. With many building blocks already at hand,
the next step was to prepare a batch of ent-2, and this was
in moderate yield. Simultaneous unmasking of amine and
acid functions by treatment with TFA allowed the cyclization
to be effected via activation with BOPCl and NMM, at high
dilution in DMF, in 75% yield.
Unfortunately, on comparison of our spectra and the
published data for natural yanucamide A, there were
Figure 4. Differences in 13C NMR shifts between natural yanu-
camide A (1) and four synthetic yanucamide A stereoisomers.
Figure 2. Four stereoisomers of yanucamide A.
Org. Lett., Vol. 5, No. 16, 2003
2823

readily achieved by following the same synthetic procedure
as for 2, but using the oxazaborolidinone derived from (S)-
instead of (R)-valine. This proceeded smoothly, and the (R)-
Dhoya fragment was readily incorporated into the synthesis
to produce 3R,12S,17S,22R-1. On examining the analytical
information we were disappointed and somewhat confused
as to why the authentic data did not match those of our
product. To our surprise, we realized that the stereochemistry
of the Dhoya fragment may have been (S), but there was at
least one further incorrect assignment made on the original
isolation paper.
On comparing the proton NMR of the natural product with
our synthetic isomers, one significant difference was a
doublet at δ 0.30 ppm in the synthetic materials, but no
signals below δ 0.66 ppm appeared in the authentic sample.
The signal appeared to be one of the diastereotopic methyl
signals on the Hiv unit. Such a shielded signal could be
accounted for by having an aromatic ring in close spatial
proximity. Since the only residue with an aromatic portion
was the (R)-phenylalanine, our attention turned to the
stereochemistry that it was exhibiting. The “shielded” signal
appeared in both samples of 1 where (R)-phenylalanine was
used but not in the authentic 1. It seemed reasonable to repeat
the synthesis with (S)-phenylalanine, incorporating both
isomers of Dhoya. These syntheses proceeded smoothly
under the previous conditions, through to cyclization. Four
stereoisomers of yanucamide A have been synthesized and
their structures are illustrated in Figure 2.
Upon completion, it was clear from comparing analytical
data (Figures 3 and 4) that the true configuration of natural
yanucamide A was (3S,12S,17S,22S).
It is easy to see how the mistake was made in the initial
assignment. The configuration of the Dhoya fragment was
correctly assumed from related structures within the research
area. The configuration of the other fragments, except the
phenylalanine unit, was unambiguously assigned on their
retention times on HPLC. The problem with the Phe residue
was that the difference in retention times between each of
the enantiomers was incredibly small. On handling such small
amounts of material it is reasonable to accept that certain
errors are liable to enter the analysis.
Acknowledgment. We thank the support form the Area
of Excellence Scheme (established under the University
Grants Committee of the Hong Kong Special Administrative
Region), The University of Hong Kong, and The Hong Kong
Polytechnic University.
Supporting Information Available: Full details for
experimental procedures for compounds 1-3, 6-14, and
1
16-20, and H and 13C NMR spectra for compounds 1-3,
9-11, 13-14, 16-17, 19-20, and S-2,2-dimethyl 3-hy-
droxyoctanoic acid. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL034803D
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Org. Lett., Vol. 5, No. 16, 2003