First total synthesis of antiostatin A1, a potent carbazole-based naturally occurring antioxidant

Article abstract of DOI:10.1039/b820291e

The first total synthesis of the potent antioxidant antiostatin A ₁ is reported, where its key features rely on a chemo- and regioselective rhodium-catalysed crossed alkyne cyclotrimerisation reaction applying functionalised ynamides and a pall

Full text of DOI:10.1039/b820291e

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First total synthesis of antiostatin A1, a potent carbazole-based naturally
occurring antioxidantwz
Carole Alayrac,a Dieter Schollmeyerb and Bernhard Witulski*a
Received (in Cambridge, UK) 14th November 2008, Accepted 16th January 2009
First published as an Advance Article on the web 18th February 2009
DOI: 10.1039/b820291e
The first total synthesis of the potent antioxidant antiostatin A1 is
reported, where its key features rely on a chemo- and regioselective
rhodium-catalysed crossed alkyne cyclotrimerisation reaction
applying functionalised ynamides and
arylamidation reaction.
a palladium-catalysed
Free radical-induced oxidative damage affecting DNA, lipids and
proteins contributes to cancer and aging and is supposed to play a
key role in human diseases such as heart (atherosclerosis), lung
(emphysema) and neurodegenerative defects.1 Therefore, both the
study of novel antioxidants as well as the search for new radical
scavengers more powerful than the lipophilic a-tocopherol,
the biological and chemically most active form of vitamin E, have
been strongly stimulated over the last decade.2 Recently, the
antiostatins A1 to A4 and B2 to B5 were isolated from
Streptomyces cyaneus 2007-SV1 and they resemble novel sets of
naturally occurring antioxidants.3 These new carbazole-based
alkaloids are structurally related to the radical scavenger
carazostatin4,5 but possess an additional acetamide group or a
substituted urea chain at the 4-position of the carbazole nucleus.
According to in vitro studies, the antiostatins A and B showed
significant inhibitory effects against free radical-induced lipid
peroxidations in rat liver microsome preparations free from
vitamin E, with antiostatin A1 having an IC50 value of
0.207 mg mLꢀ1 (compared with vitamin E IC50 = 10.8 mg mLꢀ1).3
In this report we describe the first total synthesis of
antiostatin A1 (1). Our elected synthetic strategy towards this
highly substituted carbazole alkaloid starts from commercially
available o-iodoaniline (2) and is based on a straightforward
N-ethynylation reaction with ethynyl(phenyl)iodonium triflate
(3),6 and three very effective transition metal-catalysed reac-
tions: (i) a Sonogashira reaction with trimethylsilylacetylene
(4),7 (ii) a rhodium-catalysed crossed alkyne cyclotrimerisation
with 1-methoxy-1-propyne (5),8 and (iii) a palladium-catalysed
aryl amidation reaction with acetamide (6)9 (Fig. 1).
crossed alkyne cyclotrimerisation reactions between o-ethynyl
ynanilides (ynamides)10 and various alkynes.11 This methodology
is applicable to natural product synthesis due to the high level
of functional group tolerance associated with the use of
rhodium catalysts.8,11,12
Fig. 1 Strategy employed for the total synthesis of antiostatin A1 (1).
The synthetic sequence towards antiostatin A1 is outlined in
Scheme 1. First, iodoaniline 2 was subjected to a Sonogashira
reaction with trimethylsilylacetylene (4) followed by tosylation
of the aniline-nitrogen atom to afford anilide 7 in 92% yield
over 2 steps. Next, the N-ethynylation reaction of 7 with the
readily available alkynyliodonium salt13 3 gave ynamide 8 in
85% yield. Ynamide 8 was then deprotonated with LiHMDS
followed by alkylation with 1-iodopentane and subsequent
desilylation with TBAF, to give the desired diyne 9a in 44%
yield over 2 steps.
The crossed [2 + 2 + 2] cyclotrimerisation reaction was
chosen as one of the key steps because of our recently developed
route to highly substituted carbazoles via rhodium-catalysed
a
´
Laboratoire de Chimie Moleculaire et Thio-organique, ENSICAEN,
Universite de Caen Basse-Normandie, CNRS, 6 Boulevard du
´
´
Marechal Juin, 14050 Caen, France.
E-mail: bernhard.witulski@ensicaen.fr
¨
Mainz, Duesbergweg 10-14, D-55099 Mainz, Germany
w Dedicated to the memory of Prof. Charles Mioskowski, deceased
June 2, 2007.
z Electronic supplementary information (ESI) available: Detailed
experimental procedures, 1H NMR, 13C NMR and analytical data
for all new compounds. CCDC 709652. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/b820291e
Alternative methods for the synthesis of ynamides based on
copper-mediated couplings of amides with 1-bromoalk-1-ynes
appeared in the recent literature.14–17 Therefore, the direct
transformation of anilide 7 into diyne 9a was examined
using 1-bromo-1-heptyne as coupling partner with either a
stoichiometric amount of CuI, or a catalytic amount of CuI
and N,N0-dimethylethylenediamine as a ligand, or a catalyst
derived from CuSO4–5H2O and 1,10-phenanthroline. However,
b Institut fur Organische Chemie, Johannes Gutenberg-Universitat
¨
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Scheme 1 Synthetic sequence leading to the first total synthesis of antiostatin A1 (1).
none of these attempts was successful here, and only the use of the
readily available alkynyl iodonium salt 3 followed by the alkyla-
tion of the terminal ynamide unit allowed a straightforward
access to the targeted diyne 9a.
by the coordination of the methoxy unit to the rhodium
catalyst during the insertion process, is proposed (Scheme 2).
Such mechanistic events would also explain the lack of selec-
tivity for the cyclotrimerisation of 9e with methoxypropyne 5;
Next, the cyclotrimerisation reaction of diyne 9a with
1-methoxypropyne 5 was carried out in toluene at room
temperature in the presence of 10 mol% of Wilkinson’s catalyst
[RhCl(PPh3)3] to afford carbazole 10aa chemo- and regio-
selectively (82% yield, isomer ratio 22 : 1). Regioisomerically
pure 10aa was obtained thereafter by column chromatography
on silica gel.
The regioselective outcome of this reaction was surprising
and exceptionally high for crossed alkyne cyclotrimerisation
reactions mediated by Wilkinson’s catalyst. Indeed a similar
high level of regioselectivity was observed in the synthesis of
carbazoles analogous to 10aa, but bearing a phenyl (10ba),
heptyl (10ca) or methyl group (10da) instead of a pentyl chain
(Scheme 2). Here, regioisomeric ratios of 30 : 1 for 10ba/10bb,
25 : 1 for 10ca/10cb, and 21 : 1 for 10da/10db were obtained.
On the other hand, regioselectivity was almost lost when the
unsubstituted diyne 9e was used in crossed cyclotrimerisations
with methoxypropyne to give carbazole 10ea and 10eb with an
isomer ratio of 1.5 : 1 (10ea/10eb). The latter result indicates
that the regiochemical outcome of a crossed alkyne cyclo-
trimerisation reactions with methoxypropyne mediated by
Wilkinson’s catalyst is affected by the substitution pattern of
the diyne component. To rationalise the regioselective out-
come of the overall catalytic cycle the insertion of 5 into the
higher substituted and therefore more reactive Rh–carbon
bond of an intermediate rhodole species leading to a rhoda-
cycloheptatriene intermediate, which might also be facilitated
Scheme 2 Rhodium(I)-catalysed crossed alkyne cyclotrimerisation
reactions with 1-methoxy-1-propyne (5).
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underline the significance of ynamides as versatile building
blocks for natural product synthesis.
Notes and references
1 Free Radicals in Biology and Medicine, ed. B. Halliwell and
J. M. C. Gutteridge, Oxford University Press, New York,
4th edn, 2004.
2 H.-G. Korth, Angew. Chem., Int. Ed., 2007, 46, 5274.
3 Isolation: C.-J. Mo, K. Shin-Ya, K. Furihata, K. Furihata,
A. Shimazu, Y. Hayakawa and H. Seto, J. Antibiot., 1990, 43,
1337.
4 (a) S. Kato, H. Kawai, T. Kawasaki, Y. Toda, T. Urata
and Y. Hayakawa, J. Antibiot., 1989, 42, 1879; (b) M. Iwatsuki,
E. Niki, S. Kato and K. Nishikori, Chem. Lett., 1992,
1735.
5 For a comprehensive review, see: H.-J. Knolker and K. R. Reddy,
¨
Chem. Rev., 2002, 102, 4303.
6 B. Witulski and T. Stengel, Angew. Chem., Int. Ed., 1998, 37,
489.
7 (a) K. Sonogashira, in Metal-catalyzed Cross-Coupling Reactions,
ed. F. Diederich and P. J. Stang, Wiley-VCH, Weinheim, 1998,
pp. 203–229.
Fig. 2 X-Ray crystallographic structure of synthetic antiostatin
A1 (1). The ellipsoids are shown at the 50% probability level.
8 For reviews, see: (a) N. Agenet, O. Buisine, F. Slowinski,
V. Gandon, C. Aubert and M. Malacria, in Organic Reactions,
ed. T. V. Ranjan Babu, John Wiley and Sons, Hoboken, 2007,
vol. 68, p. 1; (b) P. R. Chopade and J. Louie, Adv. Synth. Catal.,
2006, 348, 2307; (c) I. Nakamura and Y. Yamamoto, Chem. Rev.,
2004, 104, 2127.
9 (a) L. Jiang and S. L. Buchwald, in Metal-catalyzed Cross-Coupling
Reactions, ed. A. de Meijere and F. Diederich, Wiley-VCH,
Weinheim, 2004, pp. 699–760; (b) J. F. Hartwig, Palladium-
Catalyzed Amination of Aryl Halides and Related Reactions,
in Handbook of Organopalladium Chemistry for Organic Synthesis,
ed. E. Negishi, John Wiley & Sons, New York, 2002, vol. 1,
pp. 1051–1096.
10 B. Witulski and C. Alayrac, N-Acyl and N-Sulfonyl Alk-1-yn-1-
amines, in Science of Synthesis, Compounds with Four and Three
Carbon-Heteroatom Bonds, ed. A. de Meijere, Georg Thieme,
Stuttgart, 2005, vol. 24, ch. 4.4.2, pp. 1031–1058.
11 B. Witulski and C. Alayrac, Angew. Chem., Int. Ed., 2002, 41, 3281.
12 For recent examples of natural product synthesis involving alkyne
however, further studies are necessary to gain insight into
more mechanistic details.18
Having placed five benzene ring substituents of antiostatin
A1 through a very effective crossed alkyne cyclotrimerisation
reaction, only one substituent—the acetamide function—still
remained to be inserted. This issue was solved by a regio-
selective electrophilic bromination,19 followed by a palladium-
catalysed aryl amidation reaction.20 The introduction of a
bromide atom at position 4 was readily achieved by treatment
of 10aa with NBS in acetonitrile at room temperature to give
carbazole 11 in 95% yield. The cross coupling reaction of 11
with acetamide (6) (1.2 equiv.) in the presence of catalytic
amounts of [Pd2(dba)3] (1 mol%) and Xantphos (3 mol%), as
well as Cs2CO3 (1.4 equiv.) as base in 1,4-dioxane at 100 1C
afforded the highly substituted carbazole 12 in 79% yield. Full
conversion could not be reached even after 2 days of heating
and non-reacted starting material was isolated (20% of 11
recovered). A slightly better yield of 85% for 12 was obtained
with a higher catalyst load (3.5 mol% [Pd2(dba)3], 10.5 mol%
Xantphos) and a reaction time of about 3 days. Thereafter,
detosylation of 12 was selectively performed by its treatment
with TBAF in refluxing THF (77% yield of 13).11 Under these
conditions the acetamide function stayed unchanged and
only detosylation was achieved. Finally, carbazole 13 was
converted into the targeted antiostatin A1 (1) by demethylation
cyclotrimerisations
with
Wilkinson’s
catalyst,
see:
(a) C. V. Ramana, S. R. Salian and R. G. Gonnade, Eur. J. Org.
Chem., 2007, 5483; (b) M. Moser, X. Sun and T. Hudlicky, Org.
Lett., 2005, 7, 5669; (c) E. A. Anderson, E. J. Alexanian and
E. J. Sorensen, Angew. Chem., Int. Ed., 2004, 43, 1998;
(d) B. Witulski, A. Zimmermann and N. D. Gowans, Chem.
Commun., 2002, 2984; (e) B. Witulski and A. Zimmermann,
Synlett, 2002, 1855; (f) F. E. McDonald and V. Smolentsev, Org.
Lett., 2002, 4, 745.
13 For the preparation of 3, see: P. J. Stang, in Modern Acetylene
Chemistry, ed. P. J. Stang and F. Diederich, VCH, Weinheim,
1995.
14 M. O. Frederick, J. A. Mulder, M. R. Tracey, R. P. Hsung,
J. Huang, K. C. M. Kurtz, L. Shen and C. J. Douglas, J. Am.
Chem. Soc., 2003, 125, 2368.
1
with BBr3 in CH2Cl2 (94% yield of 1). The H and 13C NMR
spectroscopic data of our final compound were identical with
those reported for natural antiostatin A1.3
15 J. R. Dunetz and R. L. Danheiser, Org. Lett., 2003,
5, 4011.
16 S. Hirano, R. Tanaka, H. Urabe and F. Sato, Org. Lett., 2004,
6, 727.
17 T. Hamada, X. Ye and S. S. Stahl, J. Am. Chem. Soc., 2008,
130, 833.
18 The mechanisms of these reactions, as well as the nature and the
geometry of the catalyst require further studies. The path presented
is intended only to facilitate synthetic application and guide
mechanistic analysis.
19 (a) C. J. Moody and P. Shah, J. Chem. Soc., Perkin Trans. 1, 1989,
2463; (b) C. J. Moody and P. Shah, J. Chem. Soc., Perkin Trans. 1,
1989, 376.
In addition the substitution pattern of antiostatin A1 was
confirmed by
a single-crystal X-ray structural analysis
(Fig. 2).z The X-ray structure of 1 indicates an intramolecular
hydrogen bonding between the phenolic hydrogen atom
(O20–H20) and the carbonyl oxygen (O23) with a distance
for d(Dꢂ ꢂ ꢂA) of 2.6 A for O20–H20ꢂ ꢂ ꢂO23. However, in
solution intermolecular H/D-exchanges occur as verified by
1
the H NMR spectra obtained in acetone-d6 and D2O.
In conclusion, the first total synthesis of antiostatin A1 was
achieved in 10 steps from 2-iodoaniline, and in 16% overall
yield. The conciseness and efficiency of the reaction sequence
20 (a) J. Yin and S. L. Buchwald, Org. Lett., 2000, 2, 1101;
(b) J. Yin and S. L. Buchwald, J. Am. Chem. Soc., 2002, 124,
6043.
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This journal is The Royal Society of Chemistry 2009
1466 | Chem. Commun., 2009, 1464–1466