Studies toward the synthesis of (-)-zampanolide: preparation of N-acyl hemiaminal model systems.

Article abstract of DOI:10.1021/ol025558l

[structure: see text] Synthesis of N-acyl hemiaminal model systems related to the side chain of the antitumor natural product zampanolide is reported. Key steps involve oxidative decarboxylation of N-acyl-alpha-amino acid intermediates, followed by ytterb

Full text of DOI:10.1021/ol025558l

ORGANIC
LETTERS
2002
Vol. 4, No. 6
991-994
Studies Toward the Synthesis of
(−)-Zampanolide: Preparation of N-Acyl
Hemiaminal Model Systems
Dawn M. Troast and John A. Porco, Jr.*
Department of Chemistry and Center for Streamlined Synthesis, Metcalf Center for
Science and Engineering, Boston UniVersity, 590 Commonwealth AVenue,
Boston, Massachusetts 02215
porco@chem.bu.edu
Received January 15, 2002
ABSTRACT
Synthesis of N-acyl hemiaminal model systems related to the side chain of the antitumor natural product zampanolide is reported. Key steps
involve oxidative decarboxylation of N-acyl-r-amino acid intermediates, followed by ytterbium triflate mediated solvolysis. Evidence for stabilization
of the N-acyl hemiaminal moiety in model compounds by an intramolecular hydrogen-bonding network is described.
The unique 20-membered macrolide (-)-zampanolide (1)
was isolated in 1996 by Tanaka and Higa from the sponge
Fasciospongia rimosa, collected near Okinawa, Japan.1 This
structurally interesting molecule has a high degree of
unsaturation and an unusual N-acyl hemiaminal side chain.2
In addition to its unique structure, zampanolide displays
potent cytotoxic activity (1-5 ng/mL) against a number of
tumor cell lines. Recently, Smith et al. reported the total
synthesis and tentative stereochemical assignment of the
antipode (+)-zampanolide in which the C(20) stereogenic
center associated with the N-acyl hemiaminal was epimerized
in a deprotection step, illustrating the lability of this
functionality.3 We have initiated studies on zampanolide as
(1) (a) Tanaka, J.-i.; Higa, T. Tetrahedron Lett. 1996, 37, 5535-5538.
(b) Higa, T.; Tanaka, J.-i.; Garcia Gravalos., D. PCT Int. Appl. WO 9710242
A1, 1997. For a related natural product (dactylolide) lacking the N-acyl
hemiaminal side chain, see: (c) Cutignano, A.; Bruno, I.; Bifulco, G.;
Casapullo, A.; Debitus, C.; Gomez-Paloma, L.; Riccio, R. Eur. J. Org.
Chem. 2001, 775-778.
(2) For examples of N-acyl hemiaminal-containing natural products,
see: (a) Echinocandin B: Benz, F.; Knuesel, F.; Nuesch, J.; Treichler, H.;
Voser, W.; Nyfeler, R.; Keller-Schierlein, W. HelV. Chim. Acta 1974, 57,
2459-2477. (b) Spergualin: Umezawa, H.; Kondo, S.; Iinuma, H.;
Kunimoto, S.; Ikeda, Y.; Iwasawa, H.; Ikeda, D.; Takeuchi, T. J. Antibiot.
1981, 34, 1622-1624. For N-acyl aminal natural products, see: (c)
Mycalamides: Perry, N. B.; Blunt, J. W.; Munro, M. H. G.; Pannell, L. K.
J. Am. Chem. Soc. 1988, 110, 4850-4851. (d) Pederin: Matsumoto, T.;
Yanagiya, M.; Maeno, S.; Yasuda, S. Tetrahedron Lett. 1968, 6297-6300.
(e) Tallysomycins (glycosylcarbinolamide): Konishi, M.; Saito, K.; Numata,
K.; Tsuno, T.; Asama, K.; Tsukiura, H. Naito, T.; Kawaguchi, H. J. Antibiot.
1977, 30, 789-805.
a synthetic target and have focused our initial efforts on the
synthesis of the unusual and unstable N-acyl hemiaminal side
chain. In this Letter, we report the synthesis of N-acyl
hemiaminal model compounds related to zampanolide, as
(3) Smith, A. B., III; Safanov, I. G.; Corbett, R. M. J. Am. Chem. Soc.
2001, 123, 12426-12427.
10.1021/ol025558l CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/01/2002

Scheme 1. Synthesis of Model N-Acyl Hemiaminals
well as spectroscopic evidence for their stabilization by
intramolecular hydrogen bonding.
lactone segment of the natural product. Commercially
available L-threonine derivative 2 was acylated with sorbic
acid to afford hydroxyamide 3, which was further esterified
with sorbic acid using Keck conditions13 to furnish 4. tert-
Butyl ester removal was accomplished using TFA/Et3SiH
to afford acid 5. Since we were unable to achieve direct
conversion of the carboxylic acid to the N-acyl hemiaminal,14
we focused on development of conditions to produce the
acetate cleanly for solvolysis experiments. N-Acyl-R-amino
acid 5 was subjected to oxidative decarboxylation to afford
pure N,O-acetal 6 after extractive workup, with no evidence
of N-acyl hemiaminal formation. A number of Lewis acid
catalysts were then screened for the solvolysis 6 f 7. After
considerable experimentation, we found that Yb(OTf)3 (20
mol %, aq. THF), followed by purification through a neutral
alumina cartridge,15 gave optimal results to afford N-acyl
hemiaminal 7 (88%). Other acid catalysts either led to no
reaction (LiClO4), intolerably slow reactions (Mg(ClO4)2),
or destruction of the compound (TMSOTf/CH2Cl2 or
BF3‚Et2O/aq. CH3CN16), the latter conditions affording
There are relatively few synthetic methods available for
the preparation of N-acyl hemiaminals. Smith et al. con-
structed the N-acyl hemiaminal of (+)-zampanolide using a
stereospecific Curtius rearrangement as a key step.3 Direct
condensation of amides and aldehydes has been reported but
is generally limited to very electron-poor aldehydes4,5 or
unsubstituted amides6 and typically affords N,N′-alkylidene
bisamides via acyl iminium intermediates.7 N-Acyl hemi-
aminals derived from acrylamide and protected amino
aldehydes were obtained as undesired products in an at-
tempted DABCO-mediated Baylis-Hillman reaction.8 Re-
cently, reduction of an N-acyl imidate9 was used to prepare
an N-acyl hemiaminal en route to a glycosylcarbinolamide.10
We were encouraged by reports in which N-acyl hemiaminals
were obtained as side products in oxidative decarboxylation
of N-acyl-R-amino acids.11 In line with our recent synthesis
of enamides via elimination of O-acetyl-N-acyl-N,O-acetals,12
we reasoned that these intermediates could be alternatively
hydrolyzed under acidic conditions to afford N-acyl hemi-
aminals. Such a route should be amenable to late-stage
installation of this labile functionality after construction of
the macrolactone ring and would also permit synthesis of
chemically stable precursors to zampanolide for biological
evaluation.
1
considerable amounts of an aldehyde product by H NMR
spectroscopy. A series of analogous transformations was
employed for the synthesis of the Z,E sorbamide-based
N-acyl hemiaminal related to the zampanolide side chain.
Acylation of 2 with (2Z,4E)-sorbic acid17 afforded an amide
product, which was converted in four steps to 8 (inset,
Scheme 1). In the latter transformations, isomerization of
the (Z,E)-diene was a significant concern, but fortunately
the (Z)-olefin configuration was maintained throughout the
synthesis without difficulty.
The synthesis of N-acyl hemiaminal model systems related
to zampanolide is illustrated in Scheme 1. L-Threonine was
chosen as a model â-hydroxy-R-amino acid and 2,4-
hexadienoic (sorbic) acid as a surrogate for the unsaturated
The generality of the Yb(OTf)3-mediated solvolysis and
the ability to cleanly prepare N-acyl hemiaminal products
was further explored by examination of other N,O-acetals
as shown in Scheme 2. Substrates lacking either one or both
(4) Glyoxylic acid: Schouteeten, A.; Christidis, Y.; Mattioda, G. Bull.
Soc. Chim. Fr. 1978, (5-6, Pt. 2), 248-254.
(5) Perhaloaldehydes: Ingrassia, L.; Mulliez, M. Synthesis 1999, 1731-
1738.
(6) Johnson, A. P.; Luke, R. W.; Steele, R. W.; Boa, A. N. J. Chem.
Soc., Perkin Trans. 1 1996, 883-893.
(7) (a) Fernandez, A. H.; Alvarez, R. M.; Abajo, T. M. Synthesis 1996,
1299-1301. (b) For a recent example, see: Labrecque, D.; Charron, S.;
Rej, R.; Blais, C.; Lamothe, S. Tetrahedron Lett. 2001, 42, 2645-2648.
(8) Bussolari, J. C.; Beers, K.; Lalan, P.; Murray, W. V.; Gauthier, K.;
McDonnell, P. Chem. Lett. 1998, 787-788.
(9) Matsuda, F.; Tomiyoshi, N.; Yanagiya, M.; Matsumoto, T. Tetra-
hedron 1988, 44, 7063-7080.
(10) Sznaidman, M. L.; Hecht, S. M. Org. Lett. 2001, 3, 2811-2814.
(11) Corcoran, R. C.; Green, J. M. Tetrahedron Lett. 1990, 31, 6827-
6830.
(13) Boden, E. P.; Keck, G. E. J. Org. Chem. 1985, 50, 2394-2395.
(14) Oxidative decarboxylation with Pb(OAc)4, Cu(OAc)2 with iPr2EtN
in THF afforded a mixture of N-acyl hemiaminal and acetate products, in
low (10-20%) yields.
(15) A Waters Sep-Pak neutral alumina cartidge (12 cc, 2 g) was utilized.
Attempted purification of N-acyl hemiaminal products such as 7 using silica
gel chromatography led to low recoveries of product.
(16) Askin, D.; Angst, C.; Danishefsky, S. J. Org. Chem. 1987, 52, 62-
35.
(17) Prepared by Stille coupling of tributyl-(1E)-1-propenyl-stannane with
(Z)-3-iodoacrylic acid; cf. Abarbri, M.; Parrain, J.-L.; Cintrat, J.-C.; Duchene,
A. Synthesis 1996, 82-86.
(12) Wang, X.; Porco, J. A., Jr. J. Org. Chem. 2001, 66, 8215-8221.
992
Org. Lett., Vol. 4, No. 6, 2002

coupling constants were consistent with those predicted on
the basis of a Karplus-type relationship.20 The calculations
are summarized in Figure 2 and show that for model system
Scheme 2. Yb(OTf)3-Mediated Solvolysis of Other Substrates
of the sorbic side chains (e.g., 9 or 10) were also evaluated
in the hydrolysis protocol and did not give favorable results,
presumably because of lack of stability of the N-acyl
hemiaminal product. For example, hydrolysis of 9 led to a
low yield of the desired N-acyl hemiaminal (11) and a
significant amount of sorbamide (12). Similarly, hydrolysis
of 10 led to none of the desired product but afforded the
bisamide (13) as a major product.
The surprising stability of model compounds such as 7
and 8 in comparison to other N-acyl hemiaminals such as
11 may be due to stabilization resulting from a hydrogen-
bonding network as well as electron-withdrawing effects of
the unsaturated ester in 7 and 8, which may discourage
formation of transient iminium ion species. To evaluate
potential hydrogen bond effects in these compounds, we
Figure 2. MM2 calculations for N-acyl hemiaminal model 7.
7, each diastereomer has minimum energy conformers A and
B, which are approximately equal in steric energy. However,
in conformer A the HaCCHb dihedral angle (-178°) predicts
a Jab of 7-8 Hz by use of the Haasnoot-Altona equation,
which includes a correction for electronegative substituents.
In conformer B, the HaCCHb dihedral angle is -61°, which
predicts a Jab of 1-2 Hz. Analysis of both minimized
conformations indicates that each contains a hydrogen bond
between the amide carbonyl and the OH, and the ester
carbonyl and amide NH. Support for this intramolecular
hydrogen-bonding network was found by comparison of both
the chemical shift and the D2O exchange rate of amide
protons. It has been reported that a hydrogen-bonded amide
proton exhibits a downfield shift relative to a non-hydrogen-
bonded NH.21 The NH of 7 is shifted downfield 0.6-0.8
ppm relative to 11,22 which suggests that the amide proton
of 7 is involved in an intramolecular hydrogen bond. H-D
exchange experiments were performed at 8.0 mM23 to
compare the rate of exchange of the amide proton for 7 and
11.24 In these experiments, 11 showed complete H-D
exchange within 5 min, whereas 7 was only half exchanged
1
obtained H NMR spectra of the model systems 7 and 8 in
acid-free CDCl3. Figure 1 shows an expansion plot of the
Figure 1. 1H NMR spectrum of 7 in CDCl3.
(19) Molecular models were constructed using the MM2 energy mini-
mization algorithm in CS Chem 3D Pro (Version 5.0).
(20) Haasnoot, C. A. G.; DeLeeuw, F. A. A. M.; Altona, C. Tetra-
1H NMR spectrum of N-acyl hemiaminal 7 in CDCl3 after
exhaustive D2O exchange.18 The epimeric Ha protons for the
1R and the 1S diastereomers occur at δ 5.3 and 5.4 ppm
with Jab ) 7.0 and 2.0 Hz, respectively. MM2 calculations19
were performed to determine if the observed vicinal 1H NMR
hedron 1980, 36, 2783-2792. For
a calculation program, see:
http://www.kemi.slu.se/∼stenutz/jhh.html.
(21) (a) Langenhan, J. M.; Fisk, J. D.; Gellman, S. H. Org. Lett. 2001,
3, 2559-2562. (b) Gardner, R.; Liang, G.-B.; Gellman, S. J. Am. Chem.
Soc. 1999, 121, 1806-1816.
(22) 11: δ NH ) 5.91 ppm. 7: δ NH ) 6.74, 6.55 ppm.
(23) A study of δ NH versus concentration revealed that no inter-
molecular hydrogen boding occurs at e16.0 mM. See Supporting Informa-
tion for further details.
(24) For a pertinent study, see: Tonan, K,; Adachi, K.; Ikawa, S.-i.
Spectrochim. Acta, Part A 1998, 54, 989-997.
(18) Related NMR experiments were performed with (Z,E) isomer 8.
However, in this compound the epimeric Ha protons (cf. Figure 1)
1
overlapped in the H NMR spectra, which led us to focus efforts on 7.
Org. Lett., Vol. 4, No. 6, 2002
993

after 2 h, which provides further evidence for an intramo-
lecular hydrogen-bond network in zampanolide model com-
pounds.
Interestingly, there is literature precedent for stabilization
of an N-acyl hemiaminals such as 7 and 8 by hydrogen-
bonded networks (Figure 3).8 Compounds such as 14 were
particular topology in the molecule, which has been proven
irreplaceable for its biological activity.25
In summary, we have synthesized N-acyl hemiaminal
model compounds related to the side chain of the unique
antitumor natural product zampanolide. Key steps involve
oxidative decarboxylation of suitably functionalized N-acyl-
R-amino acids to afford O-acetyl-N-acyl-N,O-acetal inter-
mediates and solvolysis using aqueous ytterbium triflate. We
have also found spectroscopic evidence in nonpolar solvents
for the stabilization of model compounds through a hydrogen-
bonding network that may have implications for the biologi-
cal activity of zampanolide itself. Further studies related to
the total synthesis of zampanolide and related analogues are
in progress and will be reported in due course.
Acknowledgment. We thank Professor John Snyder
(Boston University) and Dr. William V. Murray (The R.W.
Johnson Pharmaceutical Research Institute) for helpful
discussions and Waters, Inc. for providing extraction col-
umns.
Figure 3. Hydrogen bonding networks.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
found to be stable to chromatography conditions and to have
good shelf lives, likely as a result of stabilization provided
by intramolecular hydrogen bonding. Moreover, it is con-
ceivable that the hydrogen bonding observed in model
systems 7 and 8 may indicate that structural rigidity of the
N-acyl hemiaminal side chain is important for the cytotoxicity
of zampanolide. In support of this notion, the potent vacuolar
H+-ATPase inhibitor, bafilomycin A1 (Figure 3, 15) has been
shown to form a unique H-bonding network that causes a
OL025558L
(25) (a) Everett, J. R.; Baker, G. H.; Dorgan, R. J. J. J. Chem. Soc.,
Perkin Trans. 2 1990, 717-724. (b) Sundquist, K.; Lakkakorpi, P.; Wallmar,
B.; Vaananen, K. Biochem. Biophys. Res. Commun. 1990, 168, 309-313.
994
Org. Lett., Vol. 4, No. 6, 2002