A Synthesis of the Diazonamide Heteroaromatic Biaryl Macrocycle/Hemiaminal Core

Article abstract of DOI:10.1021/ol036179a

(Matrix presented) Stille coupling of an arylstannane aminal 19 with the palladium complex 23 leads to atropisomeric esters 28 and 29. Conversion to macrocycle 30 is demonstrated, a potential precursor of natural and unnatural diazonamides.

Full text of DOI:10.1021/ol036179a

ORGANIC
LETTERS
2004
Vol. 6, No. 2
237-240
A Synthesis of the Diazonamide
Heteroaromatic Biaryl Macrocycle/
Hemiaminal Core
Matthew A. Zajac and Edwin Vedejs*
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109
edVed@umich.edu
Received November 6, 2003
ABSTRACT
Stille coupling of an arylstannane aminal 19 with the palladium complex 23 leads to atropisomeric esters 28 and 29. Conversion to macrocycle
30 is demonstrated, a potential precursor of natural and unnatural diazonamides.
The structure of diazonamide A was recently revised from
the originally proposed hemiacetal 11 to the bicyclic aminal
2.2 Both of these structures have now been prepared by total
synthesis,2a,c,3,4 so there is no basis to doubt the identity of
diazonamide A. Many questions remain to be addressed,
however, including the structural features needed for biologi-
cal activity, the prospects for efficient enantiocontrolled
synthesis, and alternatives for assembly of the unique
heteroaromatic core of diazonamides.
structure. Here we describe our efforts to adapt a strategy
that we had reported for the synthesis of the incorrect
heteroaromatic core structure 3 in an earlier study. We had
originally targeted a bicyclic acetal, as in 3, based on the
conjecture that an analogous acetal may be the biologically
active form of diazonamide.6a Consequently, the revised
structure of diazonamide A appeared to fit well with our
approach, assuming that the bicyclic aminal would serve in
the same beneficial role as had the bicyclic acetal in
After the massive effort expended by many groups to
prepare advanced intermediates targeting the incorrect struc-
ture 1,5,6 another important interim goal is to establish which
of the original strategies is viable in the context of the revised
Tetrahedron Lett. 2001, 42, 627. (e) Magnus, P.; Mciver, E. G. Tetrahedron
Lett. 2000, 41, 831. (f) Chan, F.; Magnus, P.; Mciver, E. G. Tetrahedron
Lett. 2000, 41, 835. (g) Magnus, P.; Kreisberg, J. D. Tetrahedron Lett. 1999,
40, 451. (h) Chen, X.; Esser, L.; Harran, P. G. Angew. Chem., Int. Ed.
2000, 39, 937. (i) Jeong, S.; Chen, X.; Harran, P. G. J. Org. Chem. 1998,
63, 8640. (j) Fuerst, D. E.; Stoltz, B. M.; Wood, J. L. Org. Lett. 2000, 2,
3521. (k) Boto, A.; Ling, M.; Meek, G.; Pattenden, G. Tetrahedron Lett.
1998, 39, 8167. (l) Wipf, P.; Methot, J. L. Org. Lett. 2001, 3, 1261. (m)
Wipf, P.; Yokokawa, F. Tetrahedron Lett. 1998, 39, 2223. (n) Hang, H.
C.; Drotleff, E.; Elliott, G. I.; Ritsema, T. A.; Konopelski, J. P. Synthesis
1999, 398. (o) Konopelski, J. P.; Hottenroth, J. M.; Oltra, H. M.; Veliz, E.
A.; Yang, Z. C. Synlett 1996, 609. (p) Lach, F.; Moody, C. J. Tetrahedron
Lett. 2000, 41, 6893. (q) Bagley, M. C.; Hind, S. L.; Moody, C. J.
Tetrahedron Lett. 2000, 41, 6897. (r) Bagley, M. C.; Moody, C. J.; Pepper,
A. G. Tetrahedron Lett. 2000, 41, 6901. (s) Moody, C. J.; Doyle, K. J.;
Elliott, M. C.; Mowlem, T. J. J. Chem. Soc., Perkin Trans. 1 1997, 2413.
(t) Moody, C. J.; Doyle, K. J.; Elliott, M. C.; Mowlem, T. J. Pure Appl.
Chem. 1994, 66, 2107.
(1) Lindquist, N.; Fenical, W.; Vanduyne, G. D.; Clardy, J. J. Am. Chem.
Soc. 1991, 113, 2303.
(2) (a) Li, J.; Jeong, S.; Esser, L.; Harran, P. G. Angew. Chem., Int. Ed.
2001, 40, 4765. (b) Li, J.; Burgett, A. W. G.; Esser, L.; Amezcua, C.; Harran,
P. G. Angew. Chem., Int. Ed. 2001, 40, 4770. (c) Burgett, A. W. G.; Li, Q.;
Wei, Q.; Harran, P. G. Angew. Chem., Int. Ed. 2003, 42, 4961.
(3) Nicolaou, K. C.; Bella, M.; Chen, D. Y. K.; Huang, X. H.; Ling, T.
T.; Snyder, S. A. Angew. Chem., Int. Ed. 2002, 41, 3495.
(4) Nicolaou, K. C.; Rao, P. B.; Hao, J. L.; Reddy, M. V.; Rassias, G.;
Huang, X. H.; Chen, D. Y. K.; Snyder, S. A. Angew. Chem., Int. Ed. 2003,
42, 1753.
(5) (a) Nicolaou, K. C.; Huang, X.; Giuseppone, N.; Rao, P. B.; Bella,
M.; Reddy, M. V.; Snyder, S. A. Angew. Chem., Int. Ed. 2001, 40, 4705.
(b) Nicolaou, K. C.; Snyder, S. A.; Simonsen, K. B.; Koumbis, A. E. Angew.
Chem., Int. Ed. 2000, 39, 3473. (c) Magnus, P.; Lescop, C. Tetrahedron
Lett. 2001, 42, 7193. (d) Kreisberg, J. D.; Magnus, P.; Mciver, E. G.
(6) (a) Vedejs, E.; Zajac, M. A. Org. Lett. 2001, 3, 2451. (b) Vedejs, E.;
Wang, J. B. Org. Lett. 2000, 2, 1031. (c) Vedejs, E.; Barda, D. A. Org.
Lett. 2000, 2, 1033.
10.1021/ol036179a CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/30/2003

Scheme 1
Scheme 2
chloroformate and various bases gave a labile product that
was not the desired 14. Although decisive characterization
of the initial product was not obtained, we suspect O-
carboxylation of the oxindole based on the observation that
reaction of 13 with allyl chloroformate and NaH in the
presence of DMAP provides the N-carboxyl isomer 14 in
nearly quantitative yield. Initial formation of the presumed
O-carboxyl imidate intermediate is followed by a slower
rearrangement to 14 catalyzed by DMAP.
Reduction of 14 to 15 was straightforward with use of
NaBH4 in MeOH and THF. The crude reduction product was
then treated with methanesulfonic anhydride and NEt3 to
form the C(11) aminal 16 in 95% yield from 14. The NMR
spectrum of 16 revealed a characteristic new singlet at δ
7.13 ppm corresponding to the C(11) aminal proton, and
confirmed loss of the PMB group. This is a consequence of
interaction between the benzylic ether oxygen with an
intermediate N-carboxyl iminium ion.
precursors of 3. Accordingly, we targeted heteroaromatic core
structures 4 containing a protected bicyclic aminal, as well
as a protected phenolic oxygen at C(4). The latter group is
designed to serve as a versatile handle for varying the C(4)
substituent with the eventual goal of introducing unnatural
macrocycles in place of the peptide ring. This prospect offers
a way to clarify the role of the peptide macrocycle on
biological activity. As reported below, the key features of
our macrocyclization approach have survived the change
from 3 to 4, but the means for implementing the seemingly
small adjustment from bicyclic acetal to bicyclic aminal had
to be extensively redesigned. We also describe the outcome
of initial attempts to convert 4 into a bis-oxazole derivative.
Following a literature precedent,7 the phenol 58 was treated
with i-PrMgCl to generate the alkoxide 6. This was combined
with the N-protected bromoisatin 8 (from 79 and ClCH2-
OTBS10/NaH) to give adduct 9 (97%). After treatment with
SOCl2/NEt3, the crude chloride 10 was deoxygenated to
afford 11 (91% yield from 9). The C(10) quaternary center
was then installed by adding Mander’s reagent (CNCO2Me)
and NaH to 11, a procedure that provided clean conversion
to 12 in 97% yield. A number of conventional fluoride
sources failed to give deprotected oxindole 13, but treatment
of 12 with TAS-F11 removed the siloxymethyl group to afford
13 (quant).
With the aminal in place, the stage was now set to install
the functionality at C(16) necessary for cross-coupling. In
Scheme 3
Reduction of 13 was explored en route to the C(11) aminal
linkage (Scheme 3), the key functionality present in the
corrected diazonamide structure 2 and in our target 4. The
plan was to activate the oxindole carbonyl for selective
reduction by introduction of an easily removable N-allyl
carbamate group. However, treatment of 13 with allyl
(7) Hewawasam, P.; Erway, M. Tetrahedron Lett. 1998, 39, 3981.
(8) Available from Aldrich.
(9) Ma, D. W.; Wu, Q. Q. Tetrahedron Lett. 2000, 41, 9089.
(10) Benneche, T.; Gundersen, L. L.; Undheim, K. Acta Chem. Scand.
B 1988, 42, 384.
(11) Scheidt, K. A.; Chen, H.; Follows, B. C.; Chemler, S. R.; Coffey,
D. S.; Roush, W. R. J. Org. Chem. 1998, 63, 6436.
238
Org. Lett., Vol. 6, No. 2, 2004

Scheme 4
Scheme 5
our earlier synthesis of the bicyclic acetal 3, the analogous
step was carried out with a crystalline C(16) boronic acid.6a
However, the boronic acid derived from 15 could not be
crystallized and the crude material was unstable. Fortunately,
the trimethyltin derivative 18 needed for the analogous Stille
coupling was better behaved. Thus, 16 was treated with
NaOH to afford the acid 17 and temporary carboxyl
protection was accomplished by deprotonation with NaH to
give the sodium carboxylate in situ. Addition of nBuLi (10
min at -78 °C) followed by trimethyltin chloride, acidifica-
tion, and TMSCHN2 workup to re-esterify the acid then
afforded stannane 18 (67% from 16), and deprotection with
catalytic Pd(PPh3)4 and 1,3-dimethylbarbituric acid produced
19.12
Stannane 19 was then tested in Pd-catalyzed cross-coupling
with oxazolyl indole 206c (Scheme 4), but numerous catalytic
procedures were not successful. For example, Farina’s Stille
coupling conditions13 formed the desired C(16)-C(18) bond,
but with concomitant ring-opening of the C(11) aminal and
decarboxylation of the C(10) ester to give a product
tentatively assigned as indole 21 (49%), based on NMR and
MS data.
In an attempt to obtain a faster reaction and suppress
aminal ring opening, stoichiometric palladium sources were
examined. After much experimentation it was found that
heating 20 with Pd(PPh3)4 and benzyltrimethylammonium
chloride (BnMe3NCl) at 70 °C in THF provides an easily
isolated, crystalline arylpalladium complex 23, 94% after
chromatography.14 Without the chloride source, oxidative
insertion of Pd(PPh3)4 occurred to form the palladium triflate
22,15 but 22 was less stable and could not be purified. The
structure of 23 was confirmed by X-ray crystallography
(Scheme 4; P-phenyls omitted for clarity).
The palladium complex 23 was then used in the Stille
coupling reaction with stannane 19 to assemble the crucial
C(16)-C(18) bond (Scheme 5). The first try gave 31% of
24 simply by heating 23 with 19 (1:1 ratio, THF/65 °C).
A similar experiment in benzene produced 24 in 37% yield
at partial conversion, but prolonged heating did not improve
the yield. Better results were obtained by using a 1.8:1 ratio
of 19:23 in benzene. This procedure afforded 24 in 54% yield
(79% based on recovered 19), and allowed practical recovery
of both the excess 19 (55%) and the unreacted 23 (31%).
The reaction was difficult to drive to completion, probably
due to rate inhibition resulting from the PPh3 released as
palladium precipitates from the reaction mixture. However,
good throughput was achieved by re-subjecting recovered
19 and 23 to the reaction conditions.
1
The H NMR spectrum of 24 in benzene-d6 provided
evidence for two atropisomers that interconvert slowly on
the NMR time scale at 20 °C. Two distinct signals were
observed for the C(27) oxazole proton at δ 6.30 and 6.28
ppm in a ca. 2:1 ratio. This ratio was also reflected in the
C(29) oxazole methyl signals at δ 1.98 and 1.53 ppm and
the C(30) ester signals at δ 3.52 and 3.17 ppm.
Little change was seen in the NMR spectrum of 24 in
toluene-d8 from -20 to 40 °C, but line broadening became
(12) Garrohelion, F.; Merzouk, A.; Guibe, F. J. Org. Chem. 1993, 58,
6109.
(13) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585.
(14) Casado, A. L.; Espinet, P. J. Am. Chem. Soc. 1998, 120, 8978.
(15) Farina, V.; Krishnan, B.; Marshall, D. R.; Roth, G. P. J. Org. Chem.
1993, 58, 5434.
Org. Lett., Vol. 6, No. 2, 2004
239

apparent at 60 °C. The first signs of coalescence were noted
for the N-Boc signal (one broad singlet at δ 1.417 ppm
compared to distinct singlets at δ 1.42 and 1.41 ppm at 20
°C). At 90 °C, coalescence was also observed for the C(27)
oxazole proton (broad singlet at δ 6.22 ppm from two singlets
at δ 6.25 and 6.20 ppm at room temperature), ∆G* ) ca.
19 kcal/mol for rotation about the C(16)-C(18) bond of 24.
This corresponds to half-lives for atropisomer interconversion
of ca. 1.5 h at -23 °C and 3.5 min at 0 °C.
In an attempt to close the macrocycle, aminal 24 was
treated with LDA under the same conditions that had
produced 3 (acetal series; 0 °C, THF, 47% isolated).6a This
experiment gave a complex mixture containing one substan-
tial product, tentatively identified as the indole 27. Formation
of 27 suggests deprotonation at aminal nitrogen, followed
by ring opening to the imine and nucleophilic attack at the
C(30) ester to initiate carboxyl transfer. Lithium hexameth-
yldisilazide in place of LDA gave no improvement, and
N-acetyl or benzoyl protection, as in 25 or 26, did not survive
LDA treatment. Clearly, a more base-resistant protecting
group was needed.
yield of 30 would be the limit (nonequilibrating conditions,
-78 °C).
The H NMR spectrum (CDCl3) of macrocycle 30 is
1
strikingly similar to that of the acetal macrocycle 3. In stark
contrast to 24 and 28/29, the spectrum of 30 contains a single
set of well-resolved 1H signals at 20 °C. The C(27) oxazole
proton of 30 appears as a singlet at δ 6.50 ppm (6.45 ppm
in 3) and the C(25) indole proton is a singlet at δ 7.72 ppm
(7.78 ppm in 3). More important, the C(29) methylene
protons appear as an AB quartet at δ 4.07 ppm (J ) 15 Hz)
while the corresponding protons in 3 appear at δ 4.15 ppm
(J ) 16 Hz).
The C(30) ketone in 30 offers several alternatives for the
eventual elaboration to the fused bisoxazole unit found in
the diazonamides. One option has been investigated with the
limited amount of racemic material at hand, starting with
the enolate amination of 30, using diarylphosphinyl-hydroxy-
lamine reagent 3116 and KHMDS as the base. Conversion
to the amino ketone was ca. 14%, based on isolation of the
acetamide 32, and 40% of 30 was recovered. Clearly, this
step will have to be improved to validate the direct enolate
amination approach. On the other hand, treatment of 32 under
the same pyridine/POCl3 conditions as used in Nicolaou’s
synthesis of diazonamide A4 gave a mixture of the isolable
bis-oxazoles 33 and 34 according to NMR and MS evidence.
Upon standing in CDCl3 for several hours, 34 decomposed
to 33 (>80% combined). Although the scale was small, the
finding is important because it shows that the key transfor-
mation to bis-oxazole 33 is possible with C(11) at the correct
aminal oxidation state, and takes place without macrocycle
fragmentation to an indole. The result indicates that the
heteroaromatic biaryl macrocycle is not especially strained
compared to 30.
An N-MOM group was introduced by treatment of 24 with
formalin and AcOH in methanol/THF, giving a 2:1 mixture
of atropisomeric products 28/29 in quantitative yield (Scheme
1
5). According to the H NMR data, atropisomer intercon-
version was slower for 28/29 than for 24, and signals
remained sharp up to 60 °C. Further warming resulted in
line broadening, but decomposition occurred prior to coa-
lescence.
On the basis of the above observations, it was clear that
Dieckmann-type macrocyclization of 28/29 would have to
be conducted at temperatures below the threshold for
atropisomer interconversion. Cyclization at room temperature
had been tested in the synthesis of 3, and had encountered
side reactions including loss of the N-Boc protecting group.
In the case of 28/29, complications were already observed
at -23 °C with use of LDA as the base. Thus, cyclization
occurred within 2 min at -23 °C and 30 was formed in 37%
yield. However, decomposition was apparent and recovery
was modest. Better results were obtained at -78 °C.
Although the yield of 30 was lower (29% isolated), 63% of
the 2:1 mixture of 28/29 was recovered (92% material
balance). The sample had reequilibrated in the course of
workup and chromatography, and the atropisomer mixture
could be used in further macrocyclization experiments.
Attempts to assign atropisomer geometry for 28/29 with NOE
methods were inconclusive. It is possible, but by no means
clear, that the conversion to 30 is only 29% because the
reactive atropisomer 28 is the minor component in the
starting 2:1 mixture of 28/29. If this is correct, then a 33%
Further elaboration of 30 and 33 will be investigated after
completion of an enantioselective route using a related
strategy. Experiments are also under way to develop a better
reagent for the enolate amination.
Acknowledgment. The authors thank Gorka Peris for
helping to work out the conversion from 11 to 12. This work
was supported by NIH (CA17918).
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL036179A
(16) Prepared by the method of Smulik and Vedejs (Smulik, J.; Vedejs,
E. Org. Lett. 2003, 5, 4187), described for the less soluble bis-methoxy-
phenyl analogue.
240
Org. Lett., Vol. 6, No. 2, 2004