Synthesis of the tetracyclic core of exiguaquinol

Article abstract of DOI:10.1021/ol402905n

A Diels-Alder reaction, a desymmetrizing aldol reaction, and a reductive Heck cyclization are employed in a short synthesis of a tetracycle relevant to exiguaquinol, a potential antibiotic. Ground-state energies of this advanced model system and the natural product rationalize the incorrect hemiaminal configuration experimentally obtained and point to the importance of the sulfonate in dictating the relative configuration of the natural product.

Full text of DOI:10.1021/ol402905n

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
Synthesis of the Tetracyclic Core
of Exiguaquinol
000–000
†
Gregg M. Schwarzwalder, Sarah E. Steinhardt, Hung V. Pham, K. N. Houk, and
†
‡
‡
,†
Christopher D. Vanderwal*
Department of Chemistry, University of California, 1102 Natural Sciences II, Irvine,
California 92697-2025, United States, and Department of Chemistry and Biochemistry,
University of California, Los Angeles, California 90095-1569, United States
cdv@uci.edu
Received October 9, 2013
ABSTRACT
A DielsꢀAlder reaction, a desymmetrizing aldol reaction, and a reductive Heck cyclization are employed in a short synthesis of a tetracycle
relevant to exiguaquinol, a potential antibiotic. Ground-state energies of this advanced model system and the natural product rationalize the
incorrect hemiaminal configuration experimentally obtained and point to the importance of the sulfonate in dictating the relative configuration of
the natural product.
The structurally novel pentacyclic compound exigua-
quinol (1, Figure 1) was isolated by Quinn et al. from the
Australian sponge Neopetrosia exigua and reported in
2
1
008. High-throughput screening of natural product ex-
tracts against the Helicobacter pylori MurI enzyme, a
glutamate racemase enzyme that is essential for bacterial
cell wall biosynthesis, led to the identification of 1 as the
first natural product inhibitor of this enzyme. As a result,
exiguaquinol might serve as an excellent lead compound
for the development of more potent inhibitors of MurI
1
and ultimately selective antibiotics against H. pylori. With
its complex and congested structure, the important link
2
of H. pylori-induced gastritis to stomach cancer, and the
Figure 1. Exiguaquinol and tetracyclic model system hemiaminal
diastereomers.
more general implications of MurI as a potential target for
the development of new antibiotics, a research program
aimed at the synthesis of this complex natural product was
warranted on both chemical and biological grounds.
In addition to its biological activity, exiguaquinol (1)
bears complex structural features that make it a worth-
while synthetic target. With five fused rings, four contig-
uous stereogenic centers (two vicinal quaternary), an aryl
sulfate, and a pendant sulfonate, a laboratory synthesis
of this compound presents significant difficulty. To ad-
dress the stereochemical challenges, we aimed to develop a
synthesis of the tetracyclic core (2) as a model system, with
the stipulation that any such strategy be amenable to a
†
University of California, Irvine.
‡
University of California, Los Angeles.
1) Almeida Leone, P.; Carroll, A. R.; Towerzey, L.; King, G.;
(
McArdle, B. M.; Kern, G.; Fisher, S.; Hooper, N. A.; Quinn, R. J.
Org. Lett. 2008, 10, 2585–2588.
(2) Polk, D. B.; Peek, R. M., Jr. Nature Rev. Cancer 2010, 10, 403–
414.
1
0.1021/ol402905n r XXXX American Chemical Society

aldol addition with o-iodobenzaldehyde led to a single
diastereomer of the benzylic alcohol product, which was
silylated to afford 11 in good yield. The inclusion of LiCl
during enolate formation was critical to reproducible
reactions, especially on a multigram scale. Oxidation of
the sulfides followed by thermal sulfoxide elimination
generated desired diene 12 without complication.
Scheme 1. Synthesis Plan To Access Tetracycle 2a Bearing All of
the Stereochemical Complexity of Exiguaquinol
7
The completion of the synthesis of the tetracyclic model
system required a careful orchestration of the final steps.
Selective monoreduction of succinimide 12 with LiBH4
yielded hemiaminal 13 as a single diastereomer in high
yield. X-ray crystal structure analysis indicated that the
hemiaminal was epimeric to that found in the natural
8
product. Reductive Heck cyclization of 13 provided
tetracyclic product 14 in good yield, demonstrating the
power (and functional group compatibility) of this cataly-
tic alternative to reductive, tin-based radical cyclizations in
complex settings. Deprotection with TBAF and selective
oxidation of the benzylic alcohol in the presence of the
hemiaminal afforded indanone 15. Ozonolysis delivered
tetracyclic diketone 2b, which remained epimeric at C2 as
confirmed by X-ray crystal structure. Attempts to epimer-
ize the hemiaminal to the “natural” R-configuration under
9
acidic or basic conditions proved unsuccessful.
Tetracycle 2b, with its close structural relationship to
exiguaquinol, does not offer any obvious rationale for the
difference in configuration at a center that seemed certain
to be under thermodynamic control. This quandary led us
to consideration of a number of hypotheses, including the
remote possibility of a misassignment of relative config-
uration in the natural product. However, the spectroscopic
data were fully consistent with the proposed structure;
therefore, we considered the possibility that the absence of
the sulfonate in simplified system 2b might lead it to adopt
a different thermodynamic hemiaminal configuration.
It seemed prudent to computationally model all of the
different hydrogen-bonding options in both the model
system and the natural product.
synthesis of the natural product and structural analogues.
Our retrosynthetic plan is illustrated in Scheme 1, wherein
the exiguaquinol core (2a) is derived from tetracycle 3 via
simple functional group manipulations. The C ring, with
3
its vicinal quaternary stereogenic centers, would be forged
through a reductive 5-exo cyclization of aryl halide 4. Key
fused bicyclic intermediate 5 might be formed from three
simple starting materials via a DielsꢀAlder reaction of 6
and 7 followed by an aldol addition or Claisen condensa-
tion, depending on the oxidation state of 8 used.
Gas-phase ground-state calculations on both epimeric
forms of tetracycle 2 (Figure 2) revealed that the observed
S-epimer of the core 2b is thermodynamically more stable
by 4.6 kcal/mol than that with the configuration corre-
sponding to the natural product (2a). The lowest energy
conformation ofthe experimentallyobservedS-configured
epimer 2b benefits from hydrogen bonding of the hemi-
aminal hydroxyl group with the C9 indanone carbonyl;
a conformation wherein it is hydrogen bonded to the C4
ketone (not shown) is of significantly higher energy. The
lowest energy conformation of R-configured epimer 2a is
alsoshown; in thisconfiguration, the hemiaminal hydroxyl
group is only able to hydrogen bond to the C4 ketone.
Not surprisingly, calculations of the exiguaquinol hemi-
aminal epimers suggest that the lowest energy conforma-
tion of the natural R-epimer (1) is thermodynamically
preferred by 2.3 kcal/mol over the most stable conformer
Diene 6was synthesized on a multigram scale in two steps
from divinyl glycol 9, the commercially available pinacol
4
coupling product of acrolein (Scheme 2). Bromination
5
of 9 with allylic transposition afforded a dienyl dibromide
intermediate, which underwent smooth nucleophilic
6
displacement with sodium thiophenolate to afford 6.
Thermal [4 þ 2] cycloaddition between diene 6 and
N-methylmaleimide afforded the DielsꢀAlder adduct in
high yield and subsequent reduction with PtO under H
2
2
pressure led to bicyclic compound 10. Desymmetrizing
(
3) Peterson, E. A.; Overman, L. E. Proc. Natl. Acad. U.S.A. 2004,
01, 11943–11948.
4) For a modern procedure, see: Trost, B. M.; Aponick, A. J. Am.
Chem. Soc. 2006, 128, 3931–3933.
5) Schneider, G.; Horvath, T.; Soh ꢀa r, P. Carbohydr. Res. 1977, 56,
3–52.
1
(
(
4
4
(6) Kauffmann, T.; Gaydoul, K.-R. Tetrahedron Lett. 1985, 26,
067–4070.
(
7) For a review on lithium enolate structure and reactivity, including
discussions on the remarkable effects of additives such as LiCl, see: (a)
Seebach, D. Angew. Chem., Int. Ed. 1988, 27, 1624–1654. See also: (b)
Henderson, K. W.; Dorigo, A. E.; Liu, Q.-Y.; Williard, P. G.; Schleyer,
P. v. R.; Bernstein, P. R. J. Am. Chem. Soc. 1996, 118, 1339–1347.
(8) Link, J. T. Org. React. 2002, 60, 157–534.
(9) O-Silylation of the hemiaminal in 2b did not change the config-
uration at C2, in spite of the elimination of the proposed stabilizing
hydrogen bond; however, silylation is likely to be kinetically controlled.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. Synthesis of the Tetracyclic “Core” of Exiguaquinol, Epimeric at C2
Figure 2. Computed relative free energies of the hemiaminal epimers of the tetracyclic “core” (2a and 2b) and exiguaquinol (1 and 16).
Calculations performed at the B3LYP/6-31G(d) level of theory in the gas phase.
of the S-isomer (16). As we had predicted, the sulfonate
appearstobethe root cause of the difference between2 and
exiguaquinol because it is apparently involved in hydrogen
bonding with the hemiaminal in the lowest energy con-
formations of both epimers, with the natural configura-
tion’s conformation preferred by 2.3 kcal/mol. It is
plausible that anomeric stabilization (good overlap of
amide π system with CꢀO σ* orbital) contributes to the
preference for the natural configuration; this arrangement
is not observed in 16. For both epimers of exiguaquinol,
the other hydrogen-bonded possibilities were also evalu-
ated (for the R-epimer with the C4 carbonyl and for the
S-epimer with both the C4 and C9 carbonyls); each of
these was at least 7.5 kcal/mol higher in energy than the
sulfonateꢀhemiaminal hydrogen-bonded conformer of
1
0
the natural product. That all of the calculations were
(10) See the Supporting Information for details.
Org. Lett., Vol. XX, No. XX, XXXX
C

performed in the gas phase does leave the possibility that
solvation could lead to a different outcome; however,
X-ray crystallography, solution NMR (CDCl ), and com-
A triply convergent approach featuring a DielsꢀAlder
cycloaddition and an aldol reaction, followed by a reduc-
tive Heck cyclization, rapidly assembles the tetracyclic
core with high diastereocontrol, but in a racemic manner.
This modular strategy will allow for the convenient
introduction of the extended aromatic and taurine (2-
aminoethylsulfonic acid) moieties of the natural product,
3
putation all demonstrate that the S-configuration of the
tetracyclic core is preferred, with the crystal structure
revealing the same hydrogen bond to the indanone carbo-
nyl. Also, in NMR studies of exiguaquinol performed in
DMSO by the Quinn group, the R-configured hemiaminal
1
1,12
and chiral base technology
will facilitate access to
1
was the only one observed.
optically active material by enantioselective desymmetriz-
ing aldol additions. Efforts to apply this route to enan-
tioenriched exiguaquinol and analogues are underway
to permit identification of a more potent inhibitor of the
H. pylori MurI enzyme.
We did not anticipate the stability of conformations
involving hydrogen bonding between the hemiaminal and the
sulfonate via eight-membered rings, particularly relative to
the six-membered arrangement involving the C4 ketone
favored by 2b. This phenomenon likely results from the ability
of the hydrogen bond to partially offset some of the discrete
charge of the sulfonate. Regardless of its physical basis, this
bonding pattern might play a key role in determining the
active configuration and conformation of exiguaquinol.
Via a short sequence of 13 steps, we have accessed a
tetracycle bearing many of the features of exiguaquinol.
In particular, this approach addresses the stereocontrolled
introduction of three contiguous stereogenic centers, in-
cluding two adjacent quaternary centers. The fourth asym-
metric center, the hemiaminal C2, is generated with the
unnatural S-configuration; however, computation strongly
suggests that our synthesis plan will deliver the desired
R-configured hemiaminal when applied to fully elaborated
substrates. Interesting hydrogen-bonding effects between
the two epimers in the model series as well as the natural
product appear to define the thermodynamic preference at
this center and point to the complexity of potential inter-
actions of exiguaquinol’s array of polar groups.
Acknowledgment. We thank Dr. Joe Ziller (UCI) for
X-ray crystallographic analysis of 2b and 13. We acknowl-
edge NIH for an NRSA predoctoral fellowship to G.M.S.
(CA-180568) and Eastman for a graduate fellowship to
S.E.S. This work was supported by UC Irvine, and C.D.V.
is grateful for additional funding from an Eli Lilly Grantee
Award. H.V.P. is a recipient of the NIH ChemistryꢀBiology
Interface Research Training Grant (USPHS National
Research Service Award GM-08496). K.N.H. thanks the
National Institute of General Medical Sciences, National
Institute of Health GM-36770.
Supporting Information Available. Experimental pro-
cedures, characterization data, and NMR spectra for all
new compounds; X-ray crystal structure for 13 and CIF
data for both 2b and 13; computed structures of other
hydrogen-bonded conformations of exiguaquinol and its
epimer. This material is available free of charge via the
Internet at http://pubs.acs.org.
(
(
11) O’Brien, P. J. Chem. Soc., Perkin Trans. 1 1998, 1439–1457.
12) For a particularly relevant desymmetrization employing chiral
amide bases, see: Simpkins, N. S.; Gill, C. D. Org. Lett. 2003, 5, 535–537.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX