Scheme 1. First Generation Synthesis of R-(þ)-2
Figure 1. Retrosynthetic analysis of S-(þ)-1.
prototypes toward the treatment of migraine,3 we explored
a synthetic route that would circumvent the need for the
separation of enantiomers by preparative supercritical
fluid chromatography.3 The target molecule 1 has been
prepared in racemic form and demonstrated excellent dual
activity against neuronal nitric oxide synthase (nNOS) and
the 5-HT1B/1D receptor. Separation of the enantiomers re-
vealed a 100-fold selectivity of the S-(þ)-1 isomer for inhi-
biting nNOS versus endothelial NOS (eNOS) and cytokine-
inducible NOS (iNOS), which are other isoforms of NOS.
Oral bioavailability and excellent efficacy with no evidence
of undesireable coronary vasoconstriction (a liability with
the triptan class of migraine medications) bodes well for
the clinical development of this novel drug prototype.
The encouraging biological profile of (þ)-1 compelled us
to develop a practical asymmetric synthesis of its immediate
precursor 2, based on MacMillan’s Friedel-Crafts-type
Michael reaction between indoles and R,β-unsaturated
aldehydes2a in the presence of an imidazolidinone catalyst
(Figure 1).
Treatment of amixture of 5-bromoindole4 and (E)-4-(4-
methoxybenzyloxy)-but-2-enal with 15-20 mol % of the
MacMillan catalyst (2S,5S)-5-benzyl-2-tert-butyl-3-met-
hylimidazolidin-4-one (ent-3) in the presence of TFA and
isopropanol, in dichloromethane at -78 °C, led to the ad-
duct 5 in 94% yield as a single enantiomer (Scheme 1).
Reduction of the aldehyde function with sodium borohy-
dride to alcohol 6 and introduction of azide gave 7 in 72%
yield.
Reduction of the latter, under Staudinger conditions,
followed by protection of the resulting amino group
led to the N-Boc derivative 8 in excellent overall yield.
Cleavage of the O-PMB group to 9, followed by mesylation
and treatment of the product with sodium hydride afforded
10 in high yield.
Cleavage of the N-Boc group, followed by reductive
amination with formaldehyde in the presence of sodium
cyanoborohydride, gave the intended indole derivative
(R)-(þ)-2 as a crystalline solid, whose structure and abso-
lute stereochemistry was ascertained by single crystal
X-ray crystallography and is consistent with the stereochem-
ical outcome of the asymmetric Michael reaction (4f5)
using the (2S,5S)-catalyst (ent-3).4 The high enantiopurity
(1) For recent monographs see: (a) Dalko, P. I. Asymmetric Organo-
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€
2007. (b) Berkessel, A.; Groger, H. Asymmetric Organocatalysis: From
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(2) Selected examples: Indole alkylation: (a) Austin, J. F.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2002, 124, 1172. (b) 1,3-Dipolar cycloaddition:
Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000,
122, 9874. (c) Intramolecular Diels-Alder: Wilson, R. M.; Jen, W. S.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 11616. (d) Diels-Alder:
Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 2458.
(e) 1,4-Addition of electron rich benzenes: Paras, N. A.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2002, 124, 7894. (f) Heterocycle 1,4-addi-
tion-R-chlorination cascade: Huang, Y.; Walji, A. M.; Larsen, C. H.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 15051. (g) Galzerano,
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(3) Maddaford, S.; Ramnauth, J.; Rakhit, S.; Patman, J.; Renton, P.;
Annedi, S. U.S. Patent 7375219, 2008.
(4) See the Supporting Information.
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