these substituents does have a significant effect on the reactivity
of these substrates,6 but despite this, we report here the
regiodivergent resolution of racemic unsymmetrical substrates
and have demonstrated the power of this process in the efficient
synthesis of two bioactive tetralin products.
Scheme 1
.
Regiodivergent Resolution of Unsymmetrical
Oxabenzonorbornadienes
We first investigated the effects of additive and temper-
ature on the regiodivergent ARO of (()-1 (Table 1). Rh-
Table 1. Effect of Additive and Temperature
yield [%] (% ee)b
entrya
temp [°C]
additive
3a
3b
1
2
3
4
5
6
7
60
60
60
60
80
60
80
n-Bu4NBrc
n-Bu4NIc
NH4Ic
61 (18)
50 (72)
51 (85)
9 (97)e
37 (23)
48 (71)
45 (88)
42 (97)
none
e
e
none
NH4BF4
NH4BF4
-
-
d
47 (97)
45 (95)
41 (97)
30 (97)
d
When we surveyed the array of biologically privileged
2-aminotetralin compounds in the literature (several of which
are APIs currently marketed or under development, Figure 1),5
a Reagents and conditions: [Rh(cod)2OTf] (5 mol %), (S,R)-2 (6 mol
%), THF, 1 h. Yield determined by H NMR using an internal standard;
% ee determined by chiral HPLC. c 15 mol %. d 100 mol %. e Starting
material was completely consumed.
b
1
halide-based catalysts gave low (Br) to modest (I) ee, but
this could be improved by using an ammonium halide
additive (Table 1, entries 1-3). The Rh-OTf catalyst (no
additive) gave excellent ee for both products; however, the
highly reactive metal species led to product decomposition,
even at 60 °C (Table 1, entries 4 and 5). Reasoning that a
cationic rhodium species was required for good ee, and that
the reaction proceeded better with a protic additive, we
investigated the use of NH4BF4 as an additive.
It was found that the catalyst activity was somewhat
attenuated with NH4BF4, which gave a combination of
excellent yield and enantioselectivity for each of the products
(Table 1, entry 6).
We specifically investigated this process because of the
vast array of bioactive aminotetralins, and we reasoned that
rather than discarding one of the products both could be used
in synthesis.7 To illustrate this approach, we selected
Rotigotine 48 and 8-(OH)-DPAT 59 as two APIs that we
envisaged could derive from the same racemic precursor
Figure 1. Examples of 2-aminotetralin API structures.
many of them possessed substituents on the aromatic ring. As
synthetic targets, they would require the ring opening of an
unsymmetrical oxabicyclic substrate with the symmetry-break-
ing substituent located on the aromatic ring (Scheme 1, R2 *
H). We have previously shown that the electronic character of
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444–445.
(4) For reviews, see: Kumar, R. R.; Kagan, H. B. AdV. Synth. Catal.
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8079. Chen, Y. G.; Deng, L. J. Am. Chem. Soc. 2001, 123, 11302–11303.
Vedejs, E.; Chen, X. H. J. Am. Chem. Soc. 1997, 119, 2584–2585. Doyle,
M. P.; Dyatkin, A. B.; Kalinin, A. V.; Ruppar, D. A.; Martin, S. F.; Spaller,
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(5) (a) Naxagolide/PHNO: Ahlskog, J. E.; Muenter, M. D.; Bailey, P. A.;
Miller, P. M. Clin. Neuropharmacol. 1991, 14, 214–227. (b) Terutroban:
Sorbera, L. A.; Serradell, N.; Bolos, J.; Bayes, M. Drugs Future 2006, 31,
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8053.
(7) A substructure search for 2-aminotetralin in the Reaxys Database
results in over 10 000 compounds with reported biological activity (Search
performed 03-Sep-2010).
Org. Lett., Vol. 12, No. 23, 2010
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