Total synthesis of anachelin H

Article abstract of DOI:10.1021/ol048068x

(Chemical Equation Presented) The first total synthesis of anachelin H is reported. Starting from L-Ser, a stereodivergent synthesis of the polyketide fragment resulting in all possible diastereoisomers is described. The alkaloid peptide fragment is prepa

Full text of DOI:10.1021/ol048068x

ORGANIC
LETTERS
2004
Vol. 6, No. 25
4707-4710
Total Synthesis of Anachelin H
Karl Gademann* and Yann Bethuel
Laboratorium fu¨r Organische Chemie der ETH Zu¨rich, CH-8093 Zu¨rich
gademann@org.chem.ethz.ch
Received September 22, 2004
ABSTRACT
The first total synthesis of anachelin H is reported. Starting from L-Ser, a stereodivergent synthesis of the polyketide fragment resulting in all
possible diastereoisomers is described. The alkaloid peptide fragment is prepared via a tellurium-mediated oxidative aza annulation as the key
step. Coupling of the fragments gave synthetic anachelin H, which was found to be identical to a sample of the natural product, thus confirming
the configuration by total synthesis.
The complex secondary metabolite anachelin was recently
isolated from the freshwater cyanobacterium Anabaena
cylindrica1,2 and postulated to serve as a bacterial growth
factor facilitating iron uptake (so-called siderophore).3 The
structure is characterized by a fascinating blend of poly-
ketide, peptide, and alkaloid fragments. While Budzikiewicz,
Walsby, and co-workers isolated both anachelin H (1) and
anachelin-1 (2) and determined the constitution of the
former,1 Murakami et al. obtained anachelin-1 (2) and
anachelin-2 (3) together with two related esters.2 However,
in all these studies the relative and absolute configuration
of four stereogenic centers was left unassigned.1,2 In addition,
it is not clear which of these compounds 1-3 is biologically
active, and also the mode of action remains unknown.
Figure 1. Anachelins 1-3, isolated from Anabaena cylindrica,
display an interesting structure featuring polyketide, peptide, and
alkaloid fragments.
To investigate all these questions, we started a complex
molecule synthesis program that resulted in the preparation
(1) Beiderbeck, H.; Taraz, K.; Budzikiewicz, H.; Walsby, A. E. Z.
Naturforsch. 2000, 55c, 681-687. Beiderbeck, H. Ph.D. Dissertation,
Universita¨t zu Ko¨ln, Ko¨ln, 2000. Anachelin was probably isolated 30 years
ago, but its constitution could not be elucidated; see: Walsby, A. E. Br.
Phycol. J. 1974, 9, 383-391.
of a diasteroisomer of anachelin, whose spectra did not match
those of the natural product.4 In paticular, major differences
were detected for the protons attached to C(2), C(3), and
C(5). These facts, combined with the unknown configuration
(2) Itou, Y.; Okada, S.; Murakami, M. Tetrahedron 2001, 57, 9093-
9099.
(3) Reviews: Keller-Schierlein, W.; Prelog, V.; Zahner, H. Fort. Chem.
Org. Nat. 1964, 22, 279-322. Raymond, K. N.; Muller, G.; Matzanke, B.
F. Top. Curr. Chem. 1984, 123, 49-102. Drechsel, H.; Jung, G. J. Pept.
Sci. 1998, 4, 147-181.
(4) Gademann, K.; Bethuel, Y. Angew. Chem. 2004, 116, 3389-3391;
Angew. Chem., Int. Ed. 2004, 43, 3327-3329.
10.1021/ol048068x CCC: $27.50
© 2004 American Chemical Society
Published on Web 11/13/2004

Scheme 1. Stereodivergent Synthesis of All Possible Diastereoisomers of the Polyketide Fragment
at four stereogenic centers, forced us to prepare all diastereo-
with BH(OAc)3 at -20 °C resulted in the clean formation
of the (3R,5R,6S)-diastereoisomer 6 as well as the (3S,5S,6S)-
counterpart 8 in high yield and diastereoselectivity after TBS
protection.8 Flash chromatography9 provided the diastereo-
merically pure compounds.
The corresponding 3,5-syn reduction was addressed next.
We anticipated that the usual reduction protocols following
Narasaka et al.10 or Prasad et al.11 might be incompatible
with the functionalities present in the molecule. In fact, the
addition of pivalic acid in the course of elaborating the borane
chelating agent was found to be crucial for a successful and
selective reaction.12 Thus, hydroxyketones 4 and 5 were
reduced smoothly by NaBH4 after precomplexation of the
substrate with Et2BOMe, preformed from Et3B, pivalic acid,
isomers of the polyketide part in order to establish the
unknown stereochemistry. In this communication, we report
the stereodivergent synthesis of all possible diastereoisomers
of the polyketide fragment resulting in the total synthesis of
anachelin H, thus ultimately proving the relative configura-
tion of the natural product. When this work was being
finished, a report from Okada and co-workers appeared,
where the absolute and relative configuration was indepen-
dently determined by degradation of the natural product.5
The hydroxyketone 4 bearing the 5,6-anti-configuration
was accessed on a large scale using a biomimetic C2 elong-
ation/reduction strategy.4 The other 5,6-syn-diastereoiso-
mer 5 was prepared by a catalytic asymmetric vinylogous
Mukaiyama aldol reaction according to Moreau and Cam-
pagne.6 These hydroxyketones 4 and 5 set the starting point
for our stereodivergent synthesis of the polyketide fragment.
A directed hydride transfer following the method of Evans
gave access to the corresponding 3,5-anti-diastereoisomers.7
Thus, separate treatment of each hydroxyketone 4 and 5
(7) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560-3578.
(8) Diastereoisomeric ratios were greater than 95:5 for 6 and greater than
1
97:3 for 8 as determined by analysis of the crude reaction product by H
NMR.
(9) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923-2925.
(10) Narasaka, K.,; Pai, F.-C. Tetrahedron 1984, 40, 2233-2238.
(11) Chen, K.-M.; Hardtmann, G. E.; Prasad, G. E.; Repic, O.; Shapiro,
M. J. Tetrahedron Lett. 1987, 28, 155-158. See also: Sletzinger, M.;
Verhoeven, T. R.; Volante, R. P.; McNamara, J. M.; Corley, E. G.; Liu, T.
M.H. Tetrahedron Lett. 1985, 26, 2951-2954.
(5) Ito, Y.; Ishida, K.; Okada, S.; Murakami, M. Tetrahedron 2004, 60,
9075-9080.
(6) Moreau, X.; Campagne, J.-M. Tetrahedron Lett. 2001, 42, 4467-
(12) Lee, H. T.; Woo, P. W. K. J. Labelled Cpd. Radiopharm. 1999, 42,
129-133.
4469.
4708
Org. Lett., Vol. 6, No. 25, 2004

We also developed an improved synthesis of the anachelin
chromophore fragment (Scheme 2). Whereas in our previous
route the diamine precursor 17 was prepared using a minimal
protecting group strategy with free OH groups,4 we found
that protection of the hydroxy groups of the DOPA amide
1416 with Bn-groups, subsequent borane reduction of 15, and
deprotection of 16 proved by far superior. This diamine 17
was then converted via an oxidative aza annulation reaction
using dianisyltelluriumoxide17 to the tetrahydroquinolinium
derivative 18, which was again Bn protected under standard
conditions. To this compound 19, protected serine followed
by a protected Thr-Ser dipeptide were condensed using the
mixed anhydride method, which has proven superior to more
elaborate coupling reagents with respect to ease of synthesis
and purification. It must be pointed out that compounds such
as 19 can be easily purified by flash chromatography on silica
gel using CH2Cl2/MeOH as a solvent. The Boc-group was
removed by HCl in dioxane to give the fragment 20 ready
for coupling.
Scheme 2. Synthesis of the Alkaloid Peptide Fragment 20
It was now time to merge the two fragments; therefore,
the fully protected polyketide fragment 13 was saponified,18
converted to the mixed anhydride, and coupled to the depro-
tected chromophore fragment 20 (Scheme 3). The fully
Scheme 3. Coupling of the Fragments to Synthetic Anachelin
H
and MeOH. Both 3,5-syn compounds 7 and 9 could thus be
isolated in good yield and high diastereoselectivity13 after
TBS protection and flash chromatography.
At this stage, we had one enantiomeric series of all pos-
sible diastereoisomers in hand. The four isomers 6-9 were
then elaborated by cleavage of the Z group and condensation
with O-Bn-protected salicylic acid to give compounds 12
and 13. Compounds 10 and 11 were obtained after an
additional introduction of a silyl ether protecting the primary
hydroxy group (TBSCl, imidazole). Each of the four dia-
stereoisomers 10-13 was thus obtained in 9-11 steps
starting from Ser. In addition, ent-12 and ent-13 were also
prepared starting from D-Ser.14 Analysis of the NMR spectra
of these compounds 10-13 revealed interesting patterns: In
the natural product, the H(3) and H(5) resonances of the poly-
ketide fragment appear at 4.09 and 4.06 ppm in D2O, whereas
the H(6) peak is observed at 4.21 ppm. Of all four isomers
10-13, only compound 13 showed a similar pattern of
peaks as observed in spectra of the natural product, although
the resonances were shifted to lower field.15 These spectro-
scopic arguments indicated the relative configuration to be
(3R*,5S*,6S*), and therefore, we advanced this diastereo-
isomer further.
protected anachelin 21 was again obtained after FC in good
yield. A two-step deprotection sequence of compound 21,
first by Pd/C and H2 in a AcOH/MeOH mixture followed
(13) Diastereoselectivities were greater than 96:4 for 7 and greater
than 97:3 for 9.
Org. Lett., Vol. 6, No. 25, 2004
4709

by treatment with 1% HCl in methanol, gave synthetic
anachelin H (22), whose physical data (NMR, MS, HPLC
coinjection) were found to be identical to those of an
authentic sample of the natural product.19 Interestingly,
whereas the HPLC analysis only shows the presence of 22,
the NMR spectrum reveals a minor derivative (less than 10%)
of 22 which is in reversible equilibrium with anachelin H
upon change of pH. As several congeners of anachelin have
been isolated and partially shown to be equilibrated by acid,1,2
this observation might help to clarify such biogenetic issues.20
Spectroscopic investigations combined with the synthesis of
these congeners are carried out and will be reported in the
context of a full publication.
preparation of all possible diastereoisomers of the polyketide
fragment as well as a rapid entry into the tetrahydroquino-
linium ring system using a tellurium-mediated oxidative aza
annulation. This work now finally confirmed the relative and
absolute configuration of four stereogenic centers of the
polyketide alkaloid anachelin H by total synthesis.
Acknowledgment. K.G. thanks Prof. Dr. Erick M.
Carreira for very generous financial support. A grant from
the Swiss National Science Foundation (to K.G.) supporting
doctoral studies of Y.B. is gratefully acknowledged.
Supporting Information Available: Analytical data and
experimental procedures for all new compounds as well
as copies of spectra of intermediates and anachelin. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, we have prepared synthetic anachelin H.
Key features of this total synthesis include a stereodivergent
(14) See Supporting Information for procedures and analytical data of
all new compounds.
(15) See Supporting Information for the corresponding spectra.
(16) This compound is readily available from L-DOPA in two steps; see
ref 4.
(17) Ley, S. V.; Meerholz, C. A.; Barton, D. H. R. Tetrahedron 1981,
37, 213-223. For a related application, see: Clews, J.; Cooksey, C. J.;
Garratt, P. J.; Land, E. J.; Ramsden, C. A.; Riley, P. A. J. Chem. Soc.,
Perkin Trans. 1 2000, 4306-4315.
(18) Interestingly, both the methyl ester 13 as well as the derived acid
display very similar Rf values on TLC.
OL048068X
(19) We thank Prof. Dr. H. Budzikiewicz for an authentic sample of
Anachelin H.
(20) A change in pH could also induce other structural changes such as
different protonation state or a change in conformation. For the solution
structure of anachelin H, see: Gademann, K.; Budzikiewicz, H. Chimia
2004, 58, 212-214.
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Org. Lett., Vol. 6, No. 25, 2004