A total synthesis prompts the structure revision of haouamine B

Article abstract of DOI:10.1021/ja301326k

A concise asymmetric approach to the indeno-tetrahydropyridine core of the unusual alkaloid haouamine B allowed for an investigation of a biomimetic oxidative phenol coupling as a proposed biosynthetic step, and ultimately provided access to the published structure of the natural product. As a consequence of our synthetic studies, the structure of haouamine B has been revised.

Full text of DOI:10.1021/ja301326k

Article
pubs.acs.org/JACS
A Total Synthesis Prompts the Structure Revision of Haouamine B
Maria Matveenko,† Guangxin Liang,‡ Erica M. W. Lauterwasser,‡ Eva Zubía,*,§ and Dirk Trauner*,†
†Department of Chemistry and Pharmacology, and Center of Integrated Protein Science, University of Munich, 81377 Munich,
Germany
‡Department of Chemistry, University of California - Berkeley, Berkeley, California 94720-1460, United States
§Departamento de Química Organ
́ ́ ́
ica, Facultad de Ciencias del Mar y Ambientales, Universidad de Cadiz, 11510-Puerto Real, Cadiz,
Spain
S
* Supporting Information
ABSTRACT: A concise asymmetric approach to the indeno-tetrahydropyridine core of the unusual alkaloid haouamine B
allowed for an investigation of a biomimetic oxidative phenol coupling as a proposed biosynthetic step, and ultimately provided
access to the published structure of the natural product. As a consequence of our synthetic studies, the structure of haouamine B
has been revised.
interconverting biaryl atropisomers but rather from an
equilibrating mixture of two isomers formed through nitrogen
inversion coupled with a conformational reorganization around
the tetrahydropyridine ring.2
INTRODUCTION
■
Alkaloids continue to surprise with unusual and unexpected
structures that have motivated advances in synthetic method-
ology and strategy. A case in point are the haouamines, a pair of
intriguing alkaloids from the ascidian Aplidium haouarianum
that display cytotoxic effects.1 Structurally, these alkaloids
feature an indeno-tetrahydropyridine moiety that contains a
diaryl quaternary center and an anti-Bredt double bond (Figure
1). The tetrahydropyridine ring is fused to a highly strained 11-
membered p-cyclophane ring system, which contains a
stereogenic biaryl axis. The complexity of the NMR spectra
of the haouamines, however, does not arise from two
Haouamine A has received considerable attention in the
synthetic community, with several approaches to the assembly
of the tetrahydropyridine core3 and a model study of the
macrocycle4 having been reported. The Baran group has made
a significant contribution to this body of work by virtue of their
synthesis of racemic haouamine A and two subsequent total
syntheses of the non-natural enantiomer of the natural product,
involving two distinct methods for construction of the p-
cyclophane moiety.5,2b Through this work, the structure of
haouamine A (1) has been firmly secured, in contrast with the
less abundant and more unstable haouamine B, which differs
from haouamine A through oxygenation pattern of ring C and
was given the structure 2 on the basis of the characterization of
its peracetylated derivative.1 No total synthesis of haouamine B
has been disclosed to date, with only two reports of the
synthesis of the core of the molecule.6 Herein, we describe the
first total synthesis of enantiomerically pure compound 2 and
report that the physical and spectral data derived from our
synthetic material do not correspond to the structure suggested
for haouamine B. As a consequence of our synthetic studies, the
molecular structure of haouamine B has been reassigned.
Received: February 9, 2012
Figure 1. The haouamines.
© XXXX American Chemical Society
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While the biosynthetic origin of the haouamines remains a
mystery,5b it is reasonable to propose that an o,p-phenol
oxidative radical coupling is involved in the construction of the
p-cyclophane macrocycle (Scheme 1). Oxidation of phenols 3a
Scheme 2. Retrosynthetic Analysis of Compound 2
Scheme 1. Biosynthesis of the Haouamines Could Involve an
Oxidative Phenol Coupling of the Proposed Intermediates
3a/3b
a
Scheme 3. Synthesis of Indeno-tetrahydropyridine Core 7
or 3b would yield phenoxyl radicals (e.g., 4a,b) which would
undergo further cyclization and oxidation to afford bis-
cyclohexadienones 5a,b. Due to the presence of an sp3-
hybridized carbon, these are considerably less strained than the
corresponding cyclophanes 1 or 2, which are subsequently
formed through rearomatization. Presumably, the enzymatic
machinery of the native host ensures that this reaction proceeds
in a regio- and stereoselective manner. Whether the oxidative
phenol coupling takes place at the stage indicated in Scheme 1,
rendering 3a and 3b real biosynthetic intermediates, however,
remains unknown.
RESULTS AND DISCUSSION
■
Our initial synthetic approach to compound 2 centered around
the hypothesized ortho,para-coupling of the appropriately
protected biphenol substrate 6a (Scheme 2), or the methylated
congener 6b. The phenoxyl radical available from the latter
compound represents an electrophilic species,7 and thus could
be attacked by the electron-rich methyl phenol of ring A within
substrate 6b. We reasoned that both of these compounds could
be accessed from enol triflate 7. This last intermediate, in
racemic form, had previously been identified by us as a useful
entry into the synthesis of haouamine B and was obtained via
an electrophilic aromatic substitution of enone 10 with
concomitant formation of an enol triflate (“Friedel−Crafts
Triflation”).8,6a We envisaged that dihydropyridone 10, in turn,
could be obtained from tert-butyloxycarbonyl-protected L-serine
11 and phenol ethers 12 and 13, using advanced organometallic
methodology.
Our total synthesis of 2 commenced with a palladium-
catalyzed cross-coupling of an organozinc compound derived
from iodinated N-Boc-serine derivative 14 with dimethoxy
bromobenzene 12 (Scheme 3).9 Subsequent N-allylation of the
ensuing material, followed by a reaction with vinyl magnesium
bromide, afforded diene 16 that underwent a clean RCM
reaction to furnish enone 17. The latter was subjected to 1,2-
nucleophilic attack by Grignard reagent 13, and the resulting
tertiary allylic and benzylic alcohol immediately underwent
Dauben oxidation10 mediated by pyridinium chlorochromate
a
(a) EDCI, NH(Me)OMe·HCl, N-methylmorpholine, CH2Cl2, −15
°C;11 (b) PPh3, imidazole, I2, CH2Cl2, 0 °C → room temperature, 83%
in two steps; (c) Zn, cat. I2, DMF, then 12, Pd(OAc)2, SPhos, 60 °C,
78%; (d) NaH, DMF, 0 °C, then allyl bromide, 0 °C, 92%; (e) vinyl
magnesium bromide, THF, 0 °C; (f) Grubbs second-generation
catalyst, CH2Cl2, 83% in two steps; (g) 13, THF, 0 °C → room
temperature, 75%; (h) PCC, 3 Å MS, CH2Cl2, 78%; (i)
trifluoromethanesulfonic anhydride, 2,6-di-tert-butylpyridine, MeNO2,
3 Å MS, −20 °C, 55%. EDCI = 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride, SPhos = 2-dicyclohexylphosphino-
2′,6′-dimethoxybiphenyl, PCC = pyridinium chlorochromate, MS =
molecular sieves.
(PCC) to give dihydropyridone 10. In the critical step of the
sequence, enone 10 underwent the Friedel−Crafts triflation
reaction to afford the indeno-tetrahydropyridine core 7,
importantly without loss of optical purity (see Supporting
Information for details).
B
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The synthesis of 6b, one of our substrates for oxidative
Scheme 5. Attempted Oxidative Phenol Couplings of
phenol coupling, is shown in Scheme 4, and begins with a Stille
Amines 6a/6b and Amide 21
Scheme 4. Synthesis of Oxidative Phenol Coupling
a
Substrates: Amine 6b and Amide 21
obtained using chemical oxidants, such as hypervalent iodine
reagents, silver salts, vanadium oxyhalides as well as iron and
copper reagents. Despite extensive experimentation, we were
unable to identify the sought-after compounds in useful
amounts. In an experiment that demonstrates the stubbornness
of these substrates, heating bisphenol 6a to 132 °C in the
presence of 2 equiv of di-tert-butyl peroxide (DTBP) as a
radical initiator for several hours resulted in complete recovery
of starting material. Our findings suggest that the proposed
oxidative phenol coupling does not proceed without enzymatic
assistance or that a substrate might be involved in the
biosynthesis wherein the indeno-tetrahydropyridine system is
not yet formed.
a
(a) Pd(PPh3)4, CuI, CsF, DMF, 45 °C, 88%; (b) TFA, CH2Cl2; (c)
CDI, 9, DMF, 85% in two steps; (d) LiAlH4, AlCl3, THF, 90%; (e)
NH4F, MeOH, 57%; (f) NH4F, MeOH, 97%. TFA = trifluoroacetic
acid, CDI = 1,1′-carbonyldiimidazole.
Since our biomimetic approaches were met with so many
difficulties, we resolved to adapt a late-stage aromatization
strategy that had been pioneered by Baran in his second-
generation total synthesis of haouamine A.2b To make our
synthesis more convergent, however, we decided to develop an
enantiomerically pure phenyl cyclohexenone building block
that could be coupled with our enol triflate 7 (Scheme 6). To
cross-coupling of enol triflate 7 with stannane 8b. The ensuing
arylated compound 19 was treated with TFA to remove the
BOC group. Condensation of the resulting free secondary
amine with a mixed anhydride of the known acid 912 followed
by reduction of the ensuing amide and subsequent cleavage of
the OTBS group afforded amine 6b. The bisphenol 6a was
prepared in an analogous fashion (see Supporting Information
for details). Compounds 6a and 6b represent a reduced form of
the haouamine skeleton and, in deprotected form, could even
be biosynthetic intermediates. Amide 21 was also available
through this sequence and was to serve as the deactivated
counterpart of tertiary amine 6b. We were intrigued to see if
these substrates could engage in the envisaged oxidative
process.
a
Scheme 6. Synthesis of the Reduced Eastern Half
With the three substrates (6a, 6b, and 21) in hand, efforts
were focused toward the key oxidative processes (Scheme 5).
Clearly, in the absence of enzymatic control, oxidative coupling
reactions of each of these compounds were expected to result
in mixtures of atrop- and regioisomers. Fortunately, all but the
ortho,ortho-regioisomeric products were predicted to be
impossibly strained on the basis of preliminary calculations.
Initial experiments under enzymatic conditions (horseradish
peroxidase/H2O2), however, failed to yield any identifiable
products of substrate 6a under a variety of reaction conditions
including various enzyme sources. Similar findings were
observed for electrochemical approaches. Specifically, under
anodic oxidation conditions (Pt or boron-doped diamond
(BDD) anode, various electrolytes, solvents and temper-
atures),7 both amine 6b and amide 21 were recovered
unchanged, even under increasingly high current density and
total electric current applied. No useful outcomes were
a
(a) Pd(PPh3)4, Me6Sn2, toluene, 70 °C, 80%; (b) PEPPSI-IPr, LiCl,
DMF, 50 °C, 63%; (c) Me6Sn2, Ag2O, Pd(Pt-Bu3)2, toluene, 100 °C,
46%. PEPPSI-IPr = [1,3-bis(2,6-diisopropylphenyl)imidazol-2-
ylidene](3-chloropyridyl)palladium(II) dichloride.
that end, the (R)-enantiomer of vinyl iodide 24, which had
been known as a racemate,2b was prepared, starting from
cyclohexenone (see Supporting Information).13,2b This com-
pound was then converted into the corresponding vinyl
stannane 25, which underwent a chemoselective Stille cross-
coupling reaction with the known bromo-iodoarene 26.14 The
resultant bromide 27 had to be subsequently activated toward a
cross-coupling reaction with enol triflate 7 and therefore was
C
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transformed into aryl stannane 28. This compound embodies
A,B-rings of compound 2 with the configuration of the biaryl
axis ultimately derived from the sole stereocenter on 28.
The stage was now set to bring the two halves of our target
molecule together via Stille cross-coupling (Scheme 7). We
coupled protons H-20 and H-22 of ring C (major isomer) were
clearly observed at δ 6.83 (m) and 6.76 (d, J = 2.1 Hz),
respectively, while the two protons of ring C of haouamine B
peracetate (400 MHz, CDCl3) appeared overlapped with other
protons in a signal centered at δ 7.08 for the major isomer and
in a signal obscured by the solvent signal (δ 7.26) for the minor
isomer. The signals of C-20 and C-22 in the 13C NMR
spectrum of compound 32 were consistent with the resorcinol-
type substitution of ring C, appearing at δ 116.1 and 115.5
(major isomer), respectively, while the methines of ring C of
haouamine B peracetate gave rise to signals at δ 123.0 and
123.1 (major isomer). All these data indicated that the
substitution pattern described for ring C of haouamine B
needed to be revised.
Scheme 7. Total Synthesis of the Proposed Structure of
a
Haouamine B Peracetate
Indeed, a re-examination of the original 400 MHz spectra of
haouamine B peracetate revealed the possible misinterpretation
of some of the HMBC correlations observed for ring C. To find
additional data, new NMR spectra at 600 MHz were recorded
1
and analyzed (see Supporting Information). In the H NMR
spectrum registered in CDCl3, the proton signals of ring C of
the major isomer were still overlapped with other signals, but
the signals of the protons of ring C of the minor isomer were
resolved enough to show an AB system attributable to two
ortho-coupled protons at δ 7.27 (d, J = 8.1 Hz) and δ 7.25 (d, J
= 8.3 Hz). The HMBC correlations of the proton at δH 7.25
with carbons C-18 (δC 34.6) and C-24 (δC 138.2) confirmed
that this proton was located at the position 20, as originally
established.1 Taking into account the ortho relationship
between the protons of ring C herein disclosed, the second
proton on the ring (δ 7.27) must be reassigned to the position
21, and consequently, the oxygenated functions must be at C-
22 and C-23. The signals corresponding to these carbons were
identified at δC 141.7 and 139.7, respectively. In the HMBC
spectrum, the proton at δ 7.27 exhibited correlations
attributable to the interactions with C-19 and C-23 that were
consistent with the position 21 for this proton. These new data
obtained for the minor isomer of haouamine B peracetate
indicated that the structure of this compound must be
reassigned to 33 (Figure 2), displaying the two acetoxy groups
of ring C at C-22 and C-23.
a
(a) 28, Pd(PPh3)4, Ph2PO2NBu4, CuI, DMF, 45 °C, 85%; (b)
HF·pyridine, pyridine, THF, 100%; (c) MsCl, Et3N, CH2Cl2; (d) NaI,
acetone, 96% in two steps; (e) TFA, CH2Cl2, 7 °C; (f) DIPEA,
CH3CN, 82 °C, 76% in two steps; (g) LiCl, LDA, THF, −78 °C, then
31, −78 °C, 67%; (h) BBr3, CH2Cl2/CHCl3, 0 °C → room
temperature; (i) Ac2O, pyridine, 70% in two steps. MsCl =
methanesulfonyl chloride, TFA = trifluoroacetic acid, DIPEA = N,N-
diisopropylethylamine, LDA = lithium diisopropylamide, Ac2O =
acetic anhydride.
were pleased to find that heating triflate 7 and stannane 28 in
deoxygenated DMF in the presence of Pd(PPh3)4, CuI, and
tetra-n-butylammonium diphenylphosphinate15 afforded com-
pound 29 in 85% yield. Installation of a primary iodide,
subsequent cleavage of the tert-butyloxycarbonyl protecting
group, and heating the ensuing secondary amine in the
presence of diisopropylethylamine lead to a clean conversion
into macrocycle 30. Subjection of this material to LDA-
promoted kinetic dienolate formation, followed by treatment
with N-tert-butylbenzenesulfinimidoyl chloride 31,16 provided
phenol 22b in 67% yield, following careful optimization of
workup conditions. As expected, the defined stereocenter on
the cyclohexenone ring translated to a single biaryl atropisomer.
In the final phase of the synthesis, tetramethyl ether 22b was
subjected to a large excess of boron tribromide, followed by
global acetylation of partially purified polyphenol to afford the
target pentaacetate 32.
Figure 2. Revised structures of haouamine B and its peracetate.
The spectral and physical data obtained for this compound
were in complete agreement with the assigned structure, but
they did not fully match those reported for the nature-derived
The structural reassignment of haouamine B peracetate was
further supported by the NMR data obtained at 600 MHz in
(CD3)2CO (see Supporting Information). Analysis of the
COSY, HSQC, and HMBC spectra allowed the complete
assignment of the 1H and 13C resonances and led to identifying
the signals due to protons of ring C of the major isomer at δH
1
1
haouamine B peracetate. A careful comparison of the H and
13C NMR data of both compounds showed that discrepancies
1
were focused on the signals of ring C. Thus, in the H NMR
spectrum of compound 32 (600 MHz, CDCl3) the two meta-
D
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7.12 (H-20, d, J = 8.3 Hz) and δH 7.09 (H-21, d, J = 8.3 Hz),
while those of the minor isomer could be identified at δH 7.35
(H-20, overlapped with other signals) and δH 7.28 (H-21, d, J =
8.1 Hz). The HMBC correlations H-20/C-18,C-24 and H-21/
C-23 observed for the major isomer, together with the
correlations H-20/C-18,C-22,C-24 and H-21/C-19,C-23 for
the minor isomer, were in full agreement with the presence of
protons at positions 20 and 21. Following these results, the
structure of the natural product haouamine B must be revised
from 2 to 34, displaying two hydroxyl groups at C-22 and C-23
and not at C-21 and C-23, as previously reported.1 This
reassignment points to a biosynthesis that could involve L-
DOPA, which is more in line with alkaloids than the resorcinol
pattern usually associated with type II polyketides.
AUTHOR INFORMATION
Corresponding Author
dirk.trauner@lmu.de; eva.zubia@uca.es
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the CIPSM for financial support. M.M. is grateful to
the Alexander von Humboldt Foundation for a postdoctoral
fellowship. We also thank Prof. Siegfried Waldvogel and Dr.
Axel Kirste for assistance with electrochemical experiments and
insightful discussions. Dr. Noah Burns is thanked for helpful
discussions.
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a
■
Scheme 8. Exposure of “Iso-haouamine B” (2)
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CONCLUSIONS
■
In summary, we have developed a concise, total synthesis of the
structure originally assigned to haouamine B. Our fast approach
to the core of the molecule allowed for the detailed
investigation of a hypothesized oxidative phenol coupling and
eventually led to the proposed structure of the alkaloid. The
true structure of haouamine B was revised in accord with our
findings and has been reassigned to the catechol 34. In
principle, our total synthesis could be adapted to reach 34, but
with limited time and resources we have decided to resist this
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details and spectra of all new synthetic
compounds and of haouamine B peracetate (33). This material
is available free of charge via the Internet at http://pubs.acs.org.
E
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