Direct imine acylation: Synthesis of the proposed structures of 'upenamide

Article abstract of DOI:10.1021/ol3030764

The synthesis of the two proposed structures of macrocyclic marine natural product 'upenamide is reported. The key step utilizes direct imine acylation (DIA) with a protected β-hydroxy acid to construct the key tricyclic ABC ring system. The macrocyclizat

Full text of DOI:10.1021/ol3030764

ORGANIC
LETTERS
2013
Vol. 15, No. 2
262–265
Direct Imine Acylation: Synthesis of the
Proposed Structures of ‘Upenamide
†
†
†
†
€
William P. Unsworth, Katherine A. Gallagher, Mickael Jean, Jan Peter Schmidt,
Louis J. Diorazio,‡ and Richard J. K. Taylor*,†
Department of Chemistry, University of York, Heslington, York, YO10 5DD, U. K., and
AstraZeneca, Silk Road Business Park, Macclesfield, SK10 2NA, U. K.
richard.taylor@york.ac.uk
Received November 8, 2012
ABSTRACT
The synthesis of the two proposed structures of macrocyclic marine natural product ‘upenamide is reported. The key step utilizes direct imine
acylation (DIA) with a protected β-hydroxy acid to construct the key tricyclic ABC ring system. The macrocyclization was completed in the final
step using a Stille cross-coupling reaction.
The macrocyclic diamine alkaloid ‘upenamide, isolated
from the Indonesian sponge Echinochalina sp., was reported
in 2000 by Scheuer et al., with its unusual name derived from
the Hawaiian word ‘upena, meaning fishing net or trap.1 The
absolute stereochemistry of the novel tricyclic spirooxaqui-
nolizidinone ABC ring system was assigned following a series
of NMR experiments, but only the relative stereochemistry of
the unusual octahydropyrano[2,3-b]pyridine DE ring system
has been confirmed, and it was assumed that the synthesis of
both diastereoisomers 1a and 1b was needed to confirm the
structure of the natural product. No biological activity was
found, but bioassays were limited because of the scarcity of
the natural material, necessitating synthesis to further probe
its biological properties. The total synthesis of ‘upenamide
has not been reported, with synthetic efforts to date focusing
on the synthesis of the two polycyclic core units.2
The retrosynthetic strategy was based on a late stage
palladium-catalyzed cross-coupling to perform the macro-
cyclization, with the requisite diene component installed
via N-alkylation with a functionalized diene (2) (Figure 1).
Our key step relies on the application of the direct imine
acylation methodology (DIA) described in the preceding
communication to install the A-ring.3 It was anticipated
that the coupling of an imine of the form 4 with a car-
boxylic acid derivative bearing a protected alcohol (5)
would form an N-acyliminium ion, which upon protecting
group cleavage, would cyclize to form the A-ring and
complete the ABC portion of ‘upenamide. A TBS-group
† University of York
‡ AstraZeneca
ꢀ
(1) Jimenez, J. I.; Goetz, G.; Mau, C. M. S.; Yoshida, W. Y.; Scheuer,
P. J.; Williamson, R. T.; Kelley, M. J. Org. Chem. 2000, 65, 8465.
(2) (a) Reid, M.; Taylor, R. J. K. Tetrahedron Lett. 2004, 45, 4181.
(b) Mons, S.; Malves Maia, A.; Mons, S.; Pereira de Freitas Gil, R.;
Marazano, C. Eur. J. Org. Chem. 2004, 1057. (c) Kiewel, K.; Luo, Z.;
Sulikowski, G. A. Org. Lett. 2005, 7, 5163. (d) Han., J. L.; Ong, C. W.
ꢀ
Tetrahedron 2007, 63, 609. (e) Cayley, A. N.; Cox., R. J.; Menard-
Moyon, C.; Schmidt, J. P.; Taylor, R. J. K. Tetrahedron Lett. 2007, 48,
ꢀ
6556. (f) Menard-Moyon, C.; R. J. K. Eur. J. Org. Chem. 2007, 3698.
(g) Schmidt, J. P.; Beltran-Rodil, S.; Cox, R. J.; Mcallister, G. D.; Reid.,
M.; Taylor, R. J. K. Org. Lett. 2007, 20, 4041. (h) Luo, Z.; Peplowski, K.;
Sulikowski, G. A. Org. Lett. 2007, 9, 5051.
(3) Unsworth, W. P.; Kitsiou, C.; Taylor, R. J. K. Org. Lett. 2012,
dx.doi.org/10.1021/ol303073b.
r
10.1021/ol3030764
Published on Web 12/24/2012
2012 American Chemical Society

reduction7 to give a roughly 10:1 mixture of pseudoequa-
torial alcohol 13,8 along with a small amount of returned
12. Conveniently, the treatment of this mixture with tri-
isopropylsilyl triflate resulted in the protection of13as silyl
ether 14, while the undesired epimer 12 was inert under
these conditions and so was readily separated by column
chromatography and recycled. Benzyl cleavage was
achieved in good yield using lithium naphthalenide, and
the resulting alcohol 15 was oxidized via a LeyꢀGriffith
oxidation,9 converted into a vinyl iodide by a Takai
olefination10 and treated with Meerwein’s salt to form
imidate 16. The synthesis of imine 17 was completed by
partial reduction with NaBH4, catalyzed by the dropwise
addition of HCl (Scheme 2).
Scheme 2. Synthesis of BC Coupling Partner 17
Figure 1. Retrosynthesis. (A) Palladium-catalyzed cross-coupling.
(B) Boc cleavage and then N-alkylation. (C) See Scheme 1.
was chosen to protect the alcohol in 4, as we predicted that
SnCl2 2H2O could be used to effect its cleavage and pro-
3
mote the cyclization in one pot (Scheme 1).4 This approach
offers a significant advantage over our previous synthesis
of the ABC tricycle: DIA replaces three discrete steps and
has the advantage of incorporating the DE ring system in
the coupling partner, completing the first synthesis of a
species containing all of the rings AꢀE.
Scheme 1. Direct Imine Acylation (DIA)
Attention turned to the synthesis of the DE ring-
containing compound 25a. Enantioenriched propargylic
alcohol 19a was formed in 93:7 er via reduction of ketone
18 with R-Alpine Borane.2c,11 Meanwhile, protected piper-
idinone 20 was converted into vinyl triflate 21,12 which
was formed along with its regioisomer and was obtained
cleanly following column chromatography. The Sonoga-
shira coupling of 21 with 19a proceeded smoothly and
was followed by selective alkyne hydrogenation, as demo-
strated by Sulikowski,2c before the DE ring system was
completed by acid-catalyzed cyclization using an excess of
The synthesis of the BC ring fragment 17 began with the
conversion of meso-anhydride 9 into enantioenriched ester
10 (94% ee), via a seven step sequence as described in our
previous report.2g Alkylation with 1-azido-3-iodopropane,5
was followed by Staudinger reduction and reaction with
aqueous K2CO3 to generate lactam 11. The introduction of
the key C-11 allylic oxygen was effected using a SeO2
oxidation,2g affording 12 as a single isomer; the regio- and
stereoselectivity of this process was confirmed by obtaining
the X-ray crystal structure of 12.6 This compound had the
desired regiochemistry but the incorrect stereochemistry,
requiring that the C-11 stereocenter be inverted. This was
achieved via oxidation with MnO2, followed by Luche
SnCl2 2H2O, affording the N,O-acetal 23a in good overall
yield. These conditions have been successfully employed in
3
(8) The C-11 stereochemsitry is supported by its 13C NMR chemical
shift, as demonstrated in reference 2g.
(9) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. Chem.
Commun. 1987, 1625.
(10) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408.
(11) 93:7 er verified by chiral HPLC of benzoate ester of 19a (see
Supporting Information)
ꢀ
(4) Cayley., A. N.; Gallagher, K. A.; Menard-Moyon, C.; Schmidt,
J. P.; Diorazio, L. J.; Taylor, R. J. K. Synthesis 2008, 3846.
(5) Yao, L.; Smith, B. T.; Aube, J. J. Org. Chem. 2004, 69, 1720.
(6) CCDC 906813. See Supporting Information for a larger ORTEP
image.
(7) Gemal, A. L.; Luche, J. -L. J. Am. Chem. Soc. 1981, 103, 5454.
(12) Vicart, N.; Cazes, B.; Gore, J. Tetrahedron 1996, 52, 9101.
Org. Lett., Vol. 15, No. 2, 2013
263

related cyclizations by our group and had the additional
advantage of promoting concomitant desilylation of the
remote primary alcohol.4 As found previously, the C-30
alcohol stereocenter controlled the relative stereochemis-
try of the two new stereocenters (C-27 and C-32) at the DE
ring junction, affording a cis-fused ring system, which
was assigned on the basis of the small coupling con-
stant and high chemical shift of H-32.2c Further elabora-
tion by LeyꢀGriffith oxidation8 and Roskamp reaction13
afforded 1,3-dicarbonyl compound 24a. Asymmetric re-
duction using a modified Noyori reduction14 installed the
C-2 stereocenter with excellent stereocontrol (99:1 ratio
at this stereocenter, verified by HPLC, see Supporting
Information), and the synthesis of DIA coupling partner
25a was completed by TBS-protection and hydrolysis.
column chromatography.16 The major diastereoisomer is
thought to be that shown with N,O-acetal proton H-10
being syn to H-2 in line with previous work in our group.2g
1
Its high downfield H NMR shift (δ 5.27) and opposite
upfield 13C NMR shift for C-10 (δ 81.4) are characterisic,
and the absence of Bohlmann bands17 in its IR spectra
provides evidence for this, in accord with the data and
rationale in the ‘upenamide isolation paper.1
Scheme 4. Completion of the Synthesis of 1a
Scheme 3. Synthesis of the DE Ring System 25a
Cleavageofthe Bocprotecting group wasachieved using
a two step sequence by first converting 28a into TBS-
carbamate 29a followed by treatment with TBAF, afford-
ing 30a.2c The need to employ these unusually elaborate
deprotection conditions is due to the fact that 30a is
unstable and prone to epimerization at C-32.18 Treatment
with more TBAF, this time to cleave the TIPS protecting
group, revealed 31a, which was used immediately in the
subsequent N-alkylation without purification. This was
The scene was set to attempt the key DIA reaction.
Imine 17 and acid 25a were treated with peptide coupling
reagent T3P15 and Hunig’s base at room temperature in
€
THF. This resulted in the consumption of both starting
materials, affording a mixture of products, including a
small amount of 28a. No attempt was made to purify the
components of this mixture, however, as direct treatment
with excess SnCl2 2H2O in DCM resulted in deprotection
3
€
achieved by heating 31a at reflux with Hunig’s base and
and a smooth progression to the desired tricyclic spiroox-
aquinolizidinone 28a. Crucially, the ABC ring system of
28a was formed in a >10:1 mixture of diastereoisomers,
with the major diastereoisomer isolable cleanly following
stannylpentadienyl bromide 27, itself prepared in situ from
known alcohol 26,19 affording key macrocyclization pre-
cursor 32a. Finally, to promote the desired intramolecular
Stille coupling, the reaction was performed under high
dilution conditions (2 mM), using Pd2dba3, AsPh3, LiCl
(13) Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54, 3258.
^
(14) Genet, J. P.; Ratovelomanana-Vidal, M. C.; Cano de Andrade,
M. C.; Pfister, X.; Guerreiro, P.; Lenoir, J. Y. Tetrahedron Lett. 1995, 36,
4801.
(15) Wissmann, H.; Kleiner, H.-J. Angew. Chem., Int. Ed. 1980, 19,
(17) Bohlman, F. Angew. Chem. 1957, 69, 641.
(18) Indeed 30a and all subsequent products in which the ring-D-
nitrogen protecting group is not present are similarly unstable, particu-
larly with respect to acid. This necessitated the use of triethylamine as a
coeluent in the chromatography of these substrates.
(19) Matsushita, N.; Matsuo, Y.; Tsuchikawa, H.; Matsumori, N.;
Murata, M.; Oishi, T. Chem. Lett. 2009, 38, 114.
133.
(16) Note that the DE ring system still exists as a 93:7 mixture of
diastereoisomers, but that these are indistiguishable by NMR
spectroscopy.
264
Org. Lett., Vol. 15, No. 2, 2013

€
and Hunig’s base in THF. After stirring for 1 h at room
data of the diastereomeric precursors 25b and 28bꢀ32b
all very similar to those of 25a and 28aꢀ32a. The Stille
macrocyclization was performed under the same condi-
tions, affording macrocycle 1b as a colorless oil, albeit
contaminated by two minor diastereoisomers, which most
likely arise from epimerization of the N,O-acetal stereo-
genic centers C-10 and C-32, and a small amount of AsPh3.
In this instance the product was soluble in CD3OD en-
abling a direct comparison with natural ‘upenamide to be
made, but unfortunately, the NMR data were significantly
different to those of the natural compound for each of
the three compounds in this mixture (see Supporting
Information).
Thus, the NMR data of both 1a and 1b does not match
that reported for ‘upenamide, suggesting that neither is the
natural product.24 It is regrettable that neither synthetic
structure could be unambiguously verified by X-ray crys-
tallography, but as both compounds are highly unstable
and degrade quickly in solution,25 this was not possible,
despite considerable effort. We therefore cannot state
categorically that ‘upenamide has been misassigned, but
at the very least, this work means that the proposed struc-
tures of ‘upenamide should be treated with caution and
that a structural re-evaluation may be required.
temperature, the reaction mixture was analyzed by high
resolution ESIþ mass spectrometry, and we were delighted
to observe a major signal consistent with‘upenamide20 and
only trace amounts of the starting material. Following stan-
dard workup and column chromatography, the desired
macrocycle 1a was isolated in 74% yield as a white amor-
phous solid.
Unfortunately a direct comparison between the spectro-
scopic data of 1a and natural ‘upenamide could not be
made, given that 1a is insoluble in CD3OD, the NMR
solvent used to characterize ‘upenamide by the isolation
chemists. Its NMR data was instead measured in CDCl3
and showed considerable differences to that of the natural
product, which allied to its solubility properties, makes it
likely that 1a is not ‘upenamide.21
Aside from these comparisons, all of the spectroscopic
data accrued for 1a supports its structural assignment as
being that shown. The methods described above that
were used to confirm the stereochemsitry of each of the 8
stereogenic centers in its precursors all continue to apply
throughout the synthesis, and crucially in 1a, suggesting
that any unexpected epimerization is unlikely. Evidence
for the geometry of the C-16/C-17 alkene can be found in
the 1H NMR spectra, as H-16 appears as a discrete signal
with a large coupling constant typical of an E-alkene.22
Unfortunately the geometry of remaining two alkenes of
the triene could not be directly observed because of the over-
lap of signals, although all of the corresponding protons in
its precursor 32a were clearly visible, supporting the all-
trans-assignment.23
In summary, we have completed the synthesis of the two
proposed structures of ‘upenamide 1a and 1b. Noteworthy
steps include the DIA reaction used to install the A ring, a
20-membered ring Stille macrocyclization and each of the
two SnCl2 2H2O-mediated stereocontrolled N,O-acetal
3
formations. Future work will focus on establishing unam-
biguously the structures of macrocycles 1a and 1b
before, if necessary, seeking to re-evaluate the structure of
‘upenamide through total synthesis.
The synthesis of the other proposed structure 1b
(Figure 1) was therefore completed using the same route
described above, but using S-Alpine Borane to generate
19b, the epimer of alcohol 19a (Schemes 3 and 4).
The synthesis proceeded similarly well, with the spectroscopic
Acknowledgment. We thank EPSRC for studentship
(K.A.G.) and postdoctoral funding (W.P.U., EP/G068313/1),
and AstraZeneca for CASE support (K.A.G.). We are also
grateful to Dr. Adrian C. Whitwood (University of York)
for X-ray crystallography studies, Dr. Ian Ashworth, Jan
Cherrywell and Andy Hard (all AstraZeneca) for assistance
with the enzymatic desymmetrization and chiral HPLC
(20) Found MHþ 523.3521, C32H47N2O4þ requires 523.3530.
(21) We wish to thank Mr. Wesley Yoshida, the only author of the
‘upenamide isolation paper (ref 1) remaining at the University of
Hawaii, for his attempts to find a sample of natural ‘upenamide or
any NMR data recorded in CDCl3. Unfortunately neither could be
found.
ꢀ
analysis and Dr. Cecilia Menard-Moyon and Mark Reid
(both University of York) for preliminary studies.
ꢀ
(22) δH 6.31 (1H, dd, J = 14.4, 10.3, H-16)
(23) J(16ꢀ17) = 14.3 Hz, J(18ꢀ19) = 18.8 Hz, J(20ꢀ21) = 15.0 Hz.
(24) It was considered that amine salt formation may account for the
differences in NMR data; however, while the addition of TFA to each of
1a and 1b led to a change in their NMR spectra, neither accorded with
natural ‘upenamide, and product decomposition was clearly evident.
(25) Within a few hours of standing in CDCl3, a clean sample of 1a
contained additional signals in its 1H NMR spectrum, thought to arise
from C-10 and/or C-32 epimerization. After 1 week in DCM/hexane
(attempted crystallization), complete degradation was observed.
Supporting Information Available. Synthetic proce-
dures and spectral data. This material is available free
of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 2, 2013
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