On the origin of the haouamine alkaloids

Article abstract of DOI:10.1002/anie.200704576

(Chemical Equation Presented) Not what it seemed: Careful reinvestigation of the classic Chichibabin pyridine synthesis has provided evidence against a spontaneous tetramerization pathway in the biosynthesis of the haouamine alkaloids. A simple enantioselective synthesis of haouamine A has illuminated its absolute configuration and points towards a phenylalanine-based biosynthesis.

Full text of DOI:10.1002/anie.200704576

Angewandte
Chemie
DOI: 10.1002/anie.200704576
Natural Products
On the Origin of the Haouamine Alkaloids**
Noah Z. Burns and Phil S. Baran*
The haouamines (1 and 2, Figure 1) are some of the most
fascinating natural products to be isolated as of late.[1] Their
topologically unique carbon skeleton, exotic oxygenation
pattern, and mysterious biosynthesis render them interesting
Chichibabin pyridine synthesis,[4,5] 3) discovery and mecha-
nistic exploration of a mild variant of the “abnormal”
Chichibabin pyridine synthesis, and 4) a simple, enantiose-
lective synthesis of 1 that illuminates its absolute configu-
ration and points towards a phenylalanine-based biosynthesis.
In 2006, we reported a total synthesis of haouamine A
from racemic ketone 3 (Figure 1).[2] Although an “abiotic”
strategy was employed to complete the synthesis, a theory was
presented to explain the origin of the haouamine skeleton as
arising from the merger of four equivalents of a meta-
hydroxylated phenylacetaldehyde (5) and one equivalent of
ammonia (Figure 1). A similar view of pseudosymmetric
biological assembly was later published by Poupon and co-
workers.[4] The idea that the haouamines could arise in nature
from a 2,3,5-trisubstituted pyridine species (such as pyridi-
nium 4) is logical, for the Chichibabin pyridine synthesis[6] is
well known to produce such appropriately functionalized
heterocycles in a single operation. Although nearly all
examples of this reaction in the literature are performed
with aliphatic aldehydes, a promising example by Wang and
co-workers[5] came to our attention. Therein, phenylacetalde-
hyde reacted with benzylammonium chloride in the presence
of ytterbium triflate in water to produce the requisite 2-
benzyl-3,5-diphenylpyridinium salt 6 (Scheme 1A). Surpris-
ingly, however, attempts to reproduce this identical reaction
gave a compound that matched the published spectrum but
seemed inconsistent with the proposed structure. Despite the
lack of a clear mechanistic explanation, the 3,5-diphenylpyr-
idinium salt 7 uniformly matched the acquired data. The
structure was confirmed synthetically by simple benzylation
of 3,5-diphenylpyridine (8) and reaction with silver triflate to
exchange counterions. Submitting other substituted phenyl-
acetaldehydes to the identical reaction conditions produced
the same results, regardless of the electronic nature of the
aldehyde component (Scheme 1B). As confirmed by X-ray
crystallography, meta-methoxy (9), para-bromo (10), meta-
trifluoromethyl (11), and ortho-methyl (12) substitution is
tolerated under the reaction conditions. The products of this
reaction correspond to those of the “abnormal” Chichibabin
pyridine synthesis—a variant that, until now, was not syntheti-
cally useful.[7] This approach represents the first mild one-pot
route to such 3,5-diarylpyridine systems (known bioactive
agents[8]) that does not require prefunctionalized hetero-
cycles.
Figure 1. Paths to the haouamine alkaloids.
targets from both synthetic and biochemical vantage
points.[2,3] This Communication sheds light on the latter
aspect of these alkaloids through a detailed chemical inquiry
resulting in: 1) compelling evidence against a seemingly
logical tetramerization pathway to 1 and 2,[2,4] 2) amelioration
of erroneous literature reports dealing with the classic
[*] N. Z. Burns, Prof. P. S. Baran
Department of Chemistry
The Scripps Research Institute
10650 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: (+1)858-784-7375
E-mail: pbaran@scripps.edu
[**] Mikkel Jessing is acknowledged for technical assistance. We thank
Dr. D.-H. Huang and Dr. L. Pasternack for NMR spectroscopic
assistance, Dr. G. Siuzdak for mass spectrometric analysis, and
both Dr. Raj Chadha (TSRI) and Dr. Arnold Rheingold (UCSD) for X-
ray crystallographic assistance. Financial support for this work was
provided by The Scripps Research Institute, Bristol-Myers Squibb,
the Searle Scholarship Fund, and the ARCS Foundation (predoctoral
fellowship to N.Z.B.).
Labeling experiments carried out as shown in Scheme 2A
clearly pinpoint the fate of the reactants in this transforma-
tion. Thus, the trideuterated and bisdeuterated pyridinium
species 13 and 14 were prepared using aldehyde 15 and amine
16, respectively. Furthermore, aldehyde 17 afforded the
expected pyridinium 18 along with the nonvolatile substituted
benzaldehyde 19. Taken together, these results point to a
plausible mechanism outlined in Scheme 2B. The critical step
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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of this transformation involves a molecular oxygen coupled
oxidative de-alkylation of dihydropyridine 21 to expel
benzaldehyde.[9]
It was therefore surprising to us when Poupon and co-
workers[4] reported the synthesis of 2,3,5-trisubstituted pyri-
dine derivative 22 (Scheme 3), also en route to the haou-
amines, under conditions that should produce the “abnormal”
Scheme 1. Discovery of a mild “abnormal” Chichibabin pyridine syn-
thesis. Reagents and conditions: a) phenylacetaldehyde (4.0 equiv),
benzylammonium chloride (1.0 equiv), Yb(OTf)3 (0.5 equiv), H2O,
238C, 66%; b) BnBr, acetone, 608C; c) AgOTf (1.1 equiv), CH2Cl2,
238C, 82% overall. Bn=benzyl, Tf=triflate.
Scheme 3. Connection to the haouamine problem. Reagents and con-
ditions: a) 24 (4.0 equiv), 25 (1.0 equiv), Yb(OTf)3 (0.5 equiv), H2O,
238C, 57%; b) NaBH4, CeCl3, 08C; AcOH, 72%; c) 3-MeOBnBr,
acetone, 608C, 99%; d) LHMDS, THF, 458C, 5 min, 48%; e) NBA
(2.2 equiv), CH2Cl2, 238C; AgOTf (1.1 equiv), CH2Cl2, 238C, 77%.
LHMDS=lithium hexamethyldisilazanide, NBA=N-bromoacetamide.
Chichibabin product 23. Indeed, the Yb(OTf)3-catalyzed
condensation of meta-methoxyphenylacetaldehyde (24) with
2-(meta-methoxyphenyl)ethylammonium
chloride
(25)
actually produces the 3,5-diarylpyridinium 23 (confirmed by
X-ray) rather than 22.[10]
To unambiguously demonstrate that 22 is not produced in
this reaction, it was synthesized from 23 by the following
sequence: 1) reduction (NaBH4 and acetic acid) to the
tetrahydropyridine and alkylation with 3-methoxybenzyl
bromide to afford 26 (71% yield), 2) Stevens rearrange-
ment[11] to furnish 27 (LHMDS, 48% yield, ca. 7:3 d.r.), and 3)
Scheme 2. Deuterium labeling and mechanistic explanation.
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oxidation (N-bromoacetamide) and salt exchange (from
bromide to triflate) using AgOTf (77% yield). Examination
of the crude reaction mixture of 24 + 25 showed no detect-
able amounts of 22 by 1H NMR spectroscopy (see Supporting
Information).
Molecular models and MM2 calculations suggest that
2,3,5-substituted pyridiniums such as 22 (and 4, see Figure 1)
possess a destabilized architecture that forces the 3-aryl
substituent out of planarity with the pyridine core. In contrast,
simple alkyl aldehydes furnish the expected 2,3,5-substituted
products and have been implicated in natural product
biosynthesis.[12] The striking finding that pyridinium inter-
mediates such as 22 (or 4) resist formation under such
conditions may point to a prebiotic barrier for the direct
tetramerization route to 1 and 2 (Figure 1), precluding the
utilization of molecular machinery.[13]
To ascertain whether naturally configured l-amino acids
might be involved in the biosynthesis of the haouamines, an
enantioselective route to 1 was required since its absolute
configuration was unknown (Scheme 4). Our original syn-
thesis (10 steps from commerically available 7-methoxyinda-
none or 12 steps from phenol)[2] relied on a conventional
enolate alkylation to produce ketone 3 with its all-carbon
quaternary center. Although it would seem that an asym-
metric route to these molecules would amount to an
enantioselective alkylation, such strategies were not success-
ful.[14]
to the Sharpless mnemonic[15] the diol produced should have
the 17R,26S absolute configuration as shown in 29. Subse-
quent chemoselective oxidation (other oxidants lead to diol
cleavage) with TEMPO/NaOCl[16] afforded a-hydroxy ketone
30, poised for incorporation of an appropriate allyl nucleo-
phile. Allyl Grignard, silane, and boronate reagents were not
competent nucleophiles either because of a lack of reactivity
or interference of the aryl bromide. After considerable
exploration, the allylindium species formed by transmetala-
tion of an organotin reagent with an indium(III) species[17]
was found to be both highly active and selective. Exposure of
tributylallyltin 31[18] to 30 in the presence of indium(III)
triflate gave the desired addition product 33 in 86% yield.
Treatment of this fully functionalized diol with a stoichio-
metric amount of BF3Et2O intercepted ketone (+)-3 through
a pinacol rearrangement[19] in 83% yield.[20] The absolute
stereochemical assignment of (+)-3 (26R) was verified by X-
ray crystallographic analysis (Scheme 4, m.p. 88–908C, color-
less cubes). Gratifyingly, there was no loss of stereochemical
information throughout this sequence, as confirmed by
diastereoselective reduction of ketone (+)-3 to the alcohol
and 1H NMR analysis of the ester derived from the (R)-
Mosher acid.
The optically active ketone was then carried through
our previous synthetic sequence[2] to produce (+)-
(8:9S,17R,26R)-haouamine A
((+)-1;
[a]D = + 45.8
degcm3 gÀ1 dmÀ1 (MeOH, c = 0.05 gcmÀ3)). Circular dichro-
ism spectra were obtained (Figure 2) of this synthetic material
as well as that of a natural sample of (À)-haouamine A ((À)-
1; [a]D = À52.0 degcm3 gÀ1 dmÀ1 (MeOH, c = 0.4 gcmÀ3))[1]
kindly provided by Professor Zubía which showed that the
unnatural enantiomer had been synthesized and thus proving
the configuration of natural haouamine A to be 8:9R,17S,26S.
As the configuration of C-17 in (À)-1 correlates to the natural
configuration of an amino acid, it is likely that l-phenyl-
alanine[21] is incorporated in a biosynthetic route to (À)-
haouamine A ((À)-1), specifically where highlighted in red in
Figure 1.
In principle, a diastereoselective pinacol rearrangement
could set the stereochemistry of C-26 via a fleetingly
stereogenic C-17 center (haouamine numbering). Thus, as
depicted in Scheme 4, Sharpless asymmetric dihydroxyla-
tion[15] on aryl indene 28 achieved moderate levels of
enantioselectivity yielding optically active diol 29 in 70% ee
1
(determined by H NMR analysis of the monoester derived
from the (R)-Mosher acid). The 30% of racemic diol within
this mixture was selectively crystallized (see Supporting
Information for X-ray), leaving the enantiopure diol in
solution (isolated in 60% overall yield from 28). According
Scheme 4. Reagents and conditions: a) AD-mix-b, MeSO2NH2 (5 equiv), 1:1 tBuOH/H2O, 58C, 44 h; b) crystallization, 60% overall; c) TEMPO
(0.05 equiv), NaOCl (2.0 equiv), KBr (0.05 equiv), CH2Cl2/sat. aq NaHCO3 (2.6:1), 08C, 30 min, 96%; d) 31 (2.0 equiv), In(OTf)3 (1.2 equiv), THF,
0–238C, 86%; e) BF3Et2O (1.1 equiv), CH2Cl2, 08C, 10 min, 83%. TEMPO=2,2,6,6-tetramethylpiperidinyl-1-oxy.
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Communications
Am. Chem. Soc. 1953, 75, 4291 – 4296; C. P. Farley, E. L. Eliel, J.
Am. Chem. Soc. 1956, 78, 3477 – 3484; b) reduction of m-
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[8] Selected examples: A. Kumar, R. A. Rhodes, J. Spychala, W. D.
Wilson, D. W. Boykin, R. R. Tidwell, C. C. Dykstra, J. E. Hall,
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[9] a) Conducting this reaction in an oxygen-saturated environment
leads to
a
rate enhancement as determined by 1H NMR
spectroscopy; further mechanistic studies will be reported in a
full account of this work; b) for examples of metal-catalyzed
oxidative dealkylation of dihydropyridines, see: R. W. Saalfrank,
S. Reihs, M. Hug, Tetrahedron Lett. 1993, 34, 6033 – 6036; S. P.
Chavan, R. K. Kharul, U. R. Kalkote, I. Shivakumar, Synth.
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Figure 2. Circular dichroism spectrum.
[10] Although the spectra of 23 matches those reported by the
authors for 22, it is clearly 23 based on spectroscopic measure-
ments (see Supporting Information for further details).
[11] For a review, see: I. E. Markó in Comprehensive Organic
Synthesis, Vol. 3 (Eds.: B. M. Trost, I. Fleming), Pergamon,
Oxford, 1991, pp. 913 – 974.
[12] For a beautiful application in total synthesis, see: B. B. Snider,
B. J. Neubert, Org. Lett. 2005, 7, 2715 – 2718.
[13] For relevant studies, see: L. Panzella, P. Di Donato, S. Comes, A.
Napolitano, A. Palumbo, M. dꢀIschia, Tetrahedron Lett. 2005, 46,
6457 – 6460.
[14] E. J. Corey, A. Guzman-Perez, Angew. Chem. 1998, 110, 402 –
415; Angew. Chem. Int. Ed. 1998, 37, 388 – 401; B. M. Trost, C.
Jiang, Synthesis 2006, 369 – 396.
[15] H. C. Kolb, M. S. VanNieuwenhze, K. B. Sharpless, Chem. Rev.
1994, 94, 2483 – 2547.
While it may not be possible to pin down the precise
synthetic route that nature uses for 1 and 2, this line of inquiry
has been enlightening. Reinvestigation of the venerable
Chichibabin pyridine synthesis in this context has revealed
that products of the “abnormal” variant are now readily
accessible using lanthanide catalysis. Labeling studies point to
a plausible mechanism of this intriguing reaction and have
aided in the correction of structural misassignments.
These findings suggest that, in the absence of enzymatic
intervention, 1 is unlikely to originate through a seemingly
logical tetramerization route via 4 (Figure 1). Finally, an
enantioselective synthesis of 1 is highlighted by a mild and
selective indium-mediated allylation and stereoselective
pinacol shift to secure its absolute configuration and support
the proposition that 1 originates from a natural amino acid.
Further studies into a biologically inspired route to 1 will be
forthcoming in a full account of this work.
[16] P. Lucio Anelli, C. Biffi, F. Montanari, S. Quici, J. Org. Chem.
1987, 52, 2559 – 2562.
[17] J. A. Marshall, K. W. Hinkle, J. Org. Chem. 1995, 60, 1920 – 1921;
T. Miyai, K. Inoue, M. Yasuda, A. Baba, Synlett 1997, 699 – 700.
[18] See Supporting Information for synthetic details.
[19] For a similar example see: K. Suzuki, H. Takikawa, Y. Hachisu,
J. W. Bode, Angew. Chem. 2007, 119, 3316 – 3318; Angew. Chem.
Int. Ed. 2007, 46, 3252 – 3254.
Received: October 3, 2007
Published online: November 23, 2007
[20] Deuterium labeling studies strongly suggest an allyl [1,2]-shift as
implied in 34 assuming a chelated transition state 32:.
Keywords: alkaloids · biosynthesis · cascade reactions ·
natural products · total synthesis
.
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[3] Studies toward the haouamines: a) N. D. Smith, J. Hayashida,
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[5] L.-B. Yu, D. Chen, J. Li, J. Ramirez, P. G. Wang, S. G. Bott, J.
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[6] A. E. Chichibabin, J. Russ. Phys. Chem. Soc. 1906, 37, 1229.
[7] a) Heating an ammonia saturated solution of phenylacetalde-
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[21] Biological meta-hydroxylation of l-phenylalanine is known:
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[22] CCDC–664780, CCDC–664678, CCDC–664679, CCDC–664680,
CCDC–664681, and CCDC–664682 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
208
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