The first syntheses of enantiopure 2,2′-biindoline

Article abstract of DOI:10.1039/c0cc04045b

The first two syntheses of chiral 2,2′-biindoline are reported either in five steps from 2,2′-bioxirane, or three steps from 2,2′-biaziridine, both with exceptional enantiopurity.

Full text of DOI:10.1039/c0cc04045b

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The first syntheses of enantiopure 2,2 -biindolinew
a
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Steven M. Wales, Anthony C. Willis and Paul A. Keller*
Received 24th September 2010, Accepted 14th October 2010
DOI: 10.1039/c0cc04045b
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The first two syntheses of chiral 2,2 -biindoline are reported
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competing mono-addition of the chloride and iodide anions.
The desired diol (R,R)-4 was isolated (31%) by selective
crystallisation from the crude mixture. This was converted to
dimesylate (R,R)-5 (84%) which in turn was subjected to
standard azidation conditions, affording – after an extremely
sluggish reaction – a crude mixture of the desired diazide
either in five steps from 2,2 -bioxirane, or three steps from
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2
,2 -biaziridine, both with exceptional enantiopurity.
Chiral biamine compounds are well established as ligands in
stereoselective metal-catalysed reactions, including allylic
1
additions, reductions and asymmetric dihydroxylations. Our
(S,S)-6 (B60% conversion) and a chromatographically
inseparable azidoalkene arising from mono-elimination
interest in chiral ligand design focusses on a new principle that
uses helix sense discrimination to achieve stereoselective
outcomes. In particular, ligand types we are interested in
include biphosphines, biarsines, biamines and ligands that
possess a mixture of heteroatoms. The molecular helix itself
is defined by two stereogenic atoms, flanked by metal
co-ordinating heteroatoms, manifesting an arc of helicity once
bound to a metal e.g. palladium. The helical groove depth and
degree of twist could be modulated by a range of substituents,
including the presence of fused rings. Importantly, an appropriate
synthetic strategy towards such structures should not only be
highly stereoselective, but should allow articulation to efficiently
produce a range of substituted ligands including those with
different ring sizes, and/or containing fused ring structures.
One example of a biamine that would meet our helical
(B25% conversion, not illustrated). The diazide was isolated
after oxidation of the by-product with KMnO and subsequent
4
silica gel column chromatography (47% yield overall). Staudinger
reduction provided complete conversion to the diamine
(S,S)-7 which was isolated by successive crystallisation as its
dihydrochloride salt and liberation with sodium hydroxide
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(71%). Finally, after several unsuccessful attempts to form
the biindoline using standard palladium and copper amination
protocols, the molecule was found to undergo the desired
regioselective cyclisation under microwave irradiation, providing
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the target ligand (S,S)-1 in 57% yield. The product was found
to be enantiomerically pure (>99% ee) after preparing the
8
diBoc derivative and performing HPLC with analysis
relative to a sample enriched in the R,R-enantiomer that
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design criteria when metal-bound is 2,2 -biindoline 1. Despite
was previously synthesised in our laboratory using the
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metathesis – AD strategy.
the illustrious history of the indoline molecule, including
its place in natural product chemistry, drug design and
development and its use in industry as a key element in
catalysts, there has been surprisingly little investigation into
Although the synthesis of biindoline (S,S)-1 from bioxirane
(R,R)-3 provided the target compound in enantiomerically
pure form, the strategy needed to be modified to avoid the
low yielding ring opening with Grignard 2 and the inefficient
azidation reaction.
2
the dimeric structure 1 – even more surprising is the lack of
any reporting of the stereoselective synthesis of 1 or related
compounds that contain 1 as a substructure. In our first
Therefore, an alternative synthesis of 1 was proposed using
the analogous biaziridine as the chiral building block, such
that ring opening would directly install the required nitrogen
atoms. This would provide a shorter entry to the penultimate
diamine (S,S)-7, which could be cyclised under the established
palladium catalysed microwave conditions.
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attempt at a stereoselective synthesis of 2,2 -biindoline 1 using
a metathesis–asymmetric dihydroxylation (AD) strategy, poor
yields and stereoselective outcomes resulted from steric
3
hinderence in the AD step. Therefore, we devised a new
strategy to the key intermediate chiral diols (e.g. 4) and in this
communication report the first synthesis of the parent
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Efficient ring opening of the biaziridine with Grignard 2
(Scheme 2) would require N-protection with an electron
withdrawing group and two such derivatives of the molecule
2
,2 -biindoline 1 in enantiopure form.
Our chiral pool starting material was the bioxirane (R,R)-3
9
10
(
Scheme 1), prepared from D-tartaric acid as previously
are known – the Boc (8, R = Boc) and the tosyl (R = Ts).
4
described. This was ring opened with Grignard 2 under
5
Given that strong reducing conditions are required to remove
11,12
4
CuI catalysis, giving a mixture of diols arising from the
the tosyl group in good yield,
we chose to begin our
investigations with the acid labile Boc carbamate as the
protecting group.
a
School of Chemistry, University of Wollongong, Wollongong,
Australia. E-mail: keller@uow.edu.au; Fax: +61 2 4221 4287;
Tel: +61 2 4221 4692
Research School of Chemistry, The Australian National University,
Canberra, Australia. E-mail: willis@rsc.anu.edu.au;
Tel: +61 2 6125 4109
The biaziridine (S,S)-8 has been prepared previously from
D-tartaric acid using two cyclisation strategies – a Staudinger
9
2 substitution. In our hands,
b
reduction and a traditional S
only the S
N
N
2 cyclisation sequence provided the biaziridine in
w Electronic supplementary information (ESI) available: Synthetic
procedures, X-ray data, NMR spectra and HPLC traces of
high yield – initial attempts to prepare the product using the
alternative Staudinger approach resulted in poor yields.
0
2,2 -biindoline structures. CCDC [794927-794928]. For ESI and
1
3
The CuBrꢀSMe catalysed ring opening of the biaziridine
crystallographic data in CIF or other electronic format see DOI:
0.1039/c0cc04045b
2
1
(S,S)-8 with Grignard 2 gave the expected dicarbamate
This journal is c The Royal Society of Chemistry 2010
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226 Chem. Commun., 2010, 46, 9226–9228

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Scheme 1 The synthesis of enantiopure 2,2 -biindoline structure 1 starting from chiral 2,2 -bioxirane.
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Scheme 2 The synthesis of enantiopure 2,2 -biindoline structure 1 starting from chiral 2,2 -biaziridine.
(
S,S)-10 (24%), however the major product was the
The structure of the biindoline was unequivocally confirmed
by X-ray analysis of crystals grown from CH Cl /MeOH
imidazolidinone (S,S)-9 (42%) arising from intramolecular
nucleophilic attack of the intermediate nitrogen anion on the
adjacent Boc group.
2
2
(Fig. 1A) in which it can be observed that the free ligand
Although this outcome was unforeseen, the formation of the
imidazolidinone would not be detrimental to the intended
synthesis providing hydrolysis to the diamine could be
affected. In the event, the N-Boc substituent was easily
removed but the urea unit proved highly resilient and was
1
4
only cleaved under the most forcing conditions – prolonged
heating with conc. HCl under microwave irradiation. Thus
under these conditions the imidazolidinone (S,S)-9 was
able to be hydrolysed to the diamine (S,S)-7 in high yield
(
89%). Upon attempting a larger scale HCl microwave
hydrolysis however, the diamine was obtained in a mixture with
the Boc-deprotected imidazolidinone (not illustrated). The
incompleteness of this reaction was a direct result of solubility
problems brought about by the need to significantly increase the
substrate concentration to satisfy the volume limitations of our
microwave vessel – larger scale synthesis would be easily achieved
1
5
with the use of a larger microwave vessel.
1
The final cyclisation was carried out, optimising the
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conditions described in Scheme 1, to afford the desired biindoline
1
S,S)-1 in good yield (79%, >99% ee) in addition to a small
7
(
0
Fig. 1 X-Ray analysis of the free 2,2 -biindoline (A) and its complex
quantity of the novel naphthyridine isomer (S,S)-11 (3%)
1
formed via the alternative cyclisation pathway.
with Pd(II) (B), the latter confirming the absolute stereochemistry and
8
illustrating the helical nature of the ligand–Pd complex.
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Chem. Commun., 2010, 46, 9226–9228 9227

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adopts an essentially flat conformation, where H9 is staggered
with H10.
5 L. Boymond, M. Rottlander, G. Cahiez and P. Knochel, Angew.
Chem., Int. Ed., 1998, 37, 1701–1703.
6
A small quantity of the Staudinger PPh
after this purification process.
7 Evidence of a trace quantity of the alternative isomer
3
O by-product remained
The palladium(II) dichloride complex of the biindoline was
also prepared by the addition of Pd(CH CN) Cl to a solution
3
2
2
of the ligand in CH Cl . The complex precipitated immediately
2
naphthyridine (S,S)-11 (see Scheme 2) was provided by TLC
analysis but no attempt was made to isolate the product in this
case.
Conditions for the preparation of the diBoc derivative: Boc O,
2
NEt , THF, RT, 144 h, 76%.
3
2
as a yellow/orange powder (95%) that was sparingly soluble in
all solvents. X-Ray analysis of crystals grown from acetonitrile
confirmed the absolute stereochemistry of the complex, and
demonstrated the desired helical conformation of the ligand
around the palladium atom (Fig. 1B).
8
9
T. Kanger, K. Ausmees, A.-M. Muurisepp, T. Pehk and M. Lopp,
Synlett, 2003, 1055–1057.
1
0 P. W. Feit and O. T. Nielsen, J. Med. Chem., 1970, 13,
47–452.
11 L. C. Pattenden, H. Adams, S. A. Smith and J. P. A. Harrity,
In summary, we have performed the first two syntheses of
0
4
enantiopure 2,2 -biindoline using bioxirane 3 and biaziridine 8
Tetrahedron, 2008, 64, 2951–2961.
2 N. Yamazaki and C. Kibayashi, J. Am. Chem. Soc., 1989, 111,
396–1408.
13 G.-D. Zhu, V. B. Gandhi, J. Gong, S. Thomas, K. W. Woods,
X. Song, T. Li, R. B. Diebold, Y. Luo, X. Liu, R. Guan,
V. Klinghofer, E. F. Johnson, J. Bouska, A. Olson,
K. C. Marsh, V. S. Stoll, M. Mamo, J. Polakowski,
T. J. Campbell, R. L. Martin, G. A. Gintant, T. D. Penning,
Q. Li, S. H. Rosenberg and V. L. Giranda, J. Med. Chem., 2007,
as the chiral precursors, both of which were easily prepared
from tartaric acid. The key step of both routes was the
copper(I) catalysed ring opening of each precursor with
Grignard 2, providing alternate pathways to the diamine
1
1
0 0
(
S,S)-7 which was regioselectively cyclised to (2S,2 S)-2,2 -
1
9
biindoline. In a comparison of the two strategies, the
biaziridine enabled a shorter and more efficient synthesis of
the target compound. However, in order to circumvent the
formation of undesired side products in the key ring opening
step and thus avoid complications in subsequent hydrolysis to
the penultimate diamine, we are currently investigating the use
of a different N-protecting group for the sequence. Extension
of the bioxirane and biaziridine as building blocks for a range
of further chiral diamine ligands is also under investigation.
5
0, 2990–3003.
4 HCl (2 M) in AcOH at reflux, Ba(OH) in 80% EtOH at reflux and
1
2
conc. HCl/MeOH (8 : 1) at reflux were all found to remove the
N-Boc substituent but were ineffective in cleavage of the urea.
15 The dicarbamate (S,S)-10 was also converted into the
diamine (S,S)-7 using typical conditions of TFA at RT in a 66%
unoptimised yield.
1
6 The cyclisation reaction was performed using the mixture obtained
from the larger scale (incomplete) hydrolysis which contained
the diamine (S,S)-7 and the Boc-deprotected imidazolidinone.
The yields given are based on the initial quantity of (S,S)-7
present. The latter compound was inert to the cyclisation
conditions.
Notes and references
1
For selected examples, see: D. Seebach, A. K. Beck, J. Golinski,
J. N. Hay and T. Laube, Helv. Chim. Acta, 1985, 162–172; X. Li,
J. Yang and M. C. Kozlowski, Org. Lett., 2001, 3, 1137–1140;
K. Suzuki, P. D. Oldenburg and L. Que Jr, Angew. Chem., Int. Ed.,
17 The enantiomeric purity was determined in the same fashion as
that for the product synthesised from bioxirane (R,R)-3.
18 Naphthyridine (S,S)-11 is structurally related to the commercially
available chiral diamine ligand (4aS,8aS)-decahydro-1,5-
naphthyridine, which is used in copper catalysed enantioselective
aryl homo-coupling reactions. Therefore, it is of interest to
us to investigate a method to reverse the regioselectivity of the
cyclisation in order to obtain larger quantities of naphthyridine
(S,S)-11 for its testing as a new chiral ligand.
2
008, 47, 1887–1889.
0
2
A synthesis of 2,2 -biindoline has been previously reported, pre-
sumably as a mixture of all possible isomers, see H. Naarmann,
J. Zdenek, H. G. Viehe, M. Beaujean and R. Merenyi, Ger. Offen.
2
934131, 1981.
M. J. Gresser, P. A. Keller and S. M. Wales, Tetrahedron, 2010, 66,
965–6976.
M. A. Robbins, P. N. Devine and T. Oh, Org. Synth., 1999, 76,
01–109.
3
4
6
19 The corresponding (R,R)-biindoline would be accessible in the
same fashion from the bioxirane and biaziridine precursors derived
from L-tartaric acid.
1
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228 Chem. Commun., 2010, 46, 9226–9228
This journal is c The Royal Society of Chemistry 2010