Applications of organocatalytic asymmetric synthesis to drug prototypes-dual action and selective inhibitors of n -nitric oxide synthase with activity against the 5-HT1D/1B subreceptors

Article abstract of DOI:10.1021/ol102795g

The scope of MacMillan's organocatalytic asymmetric conjugate addition reaction of indoles and electron-rich aromatics to α,β-unsaturated aldehydes has been extended to the use of 3-amino crotonaldehydes as substrates. The aromatics used include indoles a

Full text of DOI:10.1021/ol102795g

ORGANIC
LETTERS
2011
Vol. 13, No. 5
840–843
Applications of Organocatalytic
Asymmetric Synthesis to Drug
Prototypes;Dual Action and Selective
Inhibitors of n-Nitric Oxide Synthase with
Activity Against the 5-HT1D/1B
Subreceptors
Stephen Hanessian,*,† Eli Stoffman,† Xueling Mi,† and Paul Renton‡
ꢀ
ꢀ
Department of Chemistry, Universite de Montreal, Montreal, QC, H3C 3J7,
Canada, and NeurAxon Inc., 2395 Speakman Drive, Suite 1001, Mississauga,
ON, L5K 1B3, Canada
stephen.hanessian@umontreal.ca
Received November 19, 2010
ABSTRACT
The scope of MacMillan’s organocatalytic asymmetric conjugate addition reaction of indoles and electron-rich aromatics to r,β-unsaturated
aldehydes has been extended to the use of 3-amino crotonaldehydes as substrates. The aromatics used include indoles as well as an aniline and a
furan. The scope and effect of the groups on nitrogen (R, R0) has also been studied. The method has been applied to the concise synthesis of an
advanced precursor to S-(þ)-1, a drug prototype for the treatment of migraine headaches.
In recent years, organocatalysis has played an increas-
ingly prominent role in the design and synthesis of en-
antioenriched substances.1 Asymmetric processes relying
on the intermediacy of iminium ions2 or enamines derived
from aldehydes and ketones have gained widespread use in
diverse C-C and C-heteroatom bond forming reactions.
Such metal-free organocatalytic transformations present
distinct advantages in many cases.1 The recent scholarly
contributions of MacMillan2a-f on the diverse applica-
tions of iminium ions derived from R,β-unsaturated alde-
hydes, for example, provide a conceptually elegant and
operationally simple approach to the synthesis of a variety
of chiral nonracemic compounds.
†
In connection with a project involving the synthesis of
3-pyrrolidinylindoles ascore components of potential drug
ꢀ
ꢀ
Universite de Montreal.
‡ NeurAxon Inc.
r
10.1021/ol102795g
Published on Web 01/27/2011
2011 American Chemical Society

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-
catalysis: Reactions and Experimental Procedures; Wiley-VCH: New York,
€
2007. (b) Berkessel, A.; Groger, H. Asymmetric Organocatalysis: From
Biomimetic Concepts to Asymmetric Synthesis; Wiley-VCH:, Weinheim,
Germany, 2005. For reviews see: (a) MacMillan, D. W. C. Nature 2008, 455,
304. (b) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew.
Chem., Int. Ed. 2008, 47, 6138. (c) Dondoni, A.; Massi, A. Angew. Chem.,
Int. Ed. 2008, 47, 4638. (d) Barbas, C. F., III Angew. Chem., Int. Ed. 2008,
47, 42. (e) Mukherjee, S.; Yang, J. W.; Hoffman, S.; List, B. Chem. Rev.
2007, 107, 5471. (f) Pelissier, H. Tetrahedron 2007, 63, 9267. (g) Lelais, G.;
MacMillan, D. W. C. Aldrichim. Acta 2006, 39, 79.
(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,
P.; Pesciaioli, F.; Mazzanti, A.; Bartoli, G.; Melchiorre, P. Angew. Chem.,
Int. Ed. 2009, 48, 7892. (h) 2-Oxindole alkylation: Bravo, N.; Mon, I.;
ꢀ
Companyo, X.; Alba, A.-N.; Moyano, A.; Rios, R. Tetrahedron Lett. 2009,
ꢀ
50, 6624. (i) Intramolecular aza-Micheal: Fustero, S.; Jimenez, D.;
ꢀ
ꢀ
Moscardo, J.; Catalan, S.; del Pozo, C. Org. Lett. 2007, 9, 5283. (j) Bartoli,
G.; Bosco, M.; Corlone, A.; Pesciaioli, F.; Sambri, L.; Melchiorre, P. Org.
Lett. 2007, 9, 1403.
(3) Maddaford, S.; Ramnauth, J.; Rakhit, S.; Patman, J.; Renton, P.;
Annedi, S. U.S. Patent 7375219, 2008.
(4) See the Supporting Information.
Org. Lett., Vol. 13, No. 5, 2011
841

Table 1. Organocatalytic MacMillan Indole Alkylation with
Nitrogen Containing Aldehydes
Scheme 2. Second Generation Synthesis of S-(-)-2
Br
yielda
(%)
time
(d)
entry product
Pg
R
position
erb
1
2
3
4
5
6
14
18
19
20
21
Boc
Busf
Me
Me
5
5
5
5
6
5
quant
89c
94:6
96:4
1
1
1
2
2
1
CO2Me Me
97
95.5:4.5
96:4
Boc
Boc
Boc
PMB
80
PMB
H
65 (83d) 90.5:9.5
nile
a Isolated yield of pure product unless otherwise indicated. b On the
basis of chiral HPLC analysis of the corresponding alcohols obtained by
NaBH4 reduction. The opposite enantiomer was obtained by running
the reaction again with the enantiomeric MacMillan catalyst. c 61% pure
isolated material and 28% which was not separated from starting
aldehyde as determined by 1H NMR. d Corrected for recovered 6-
bromoindole. e The aldehyde was converted to N-Boc-pyrrole, which
was the only isolated product. f Bus = tert-butylsulfonyl.
11 with triethylphosphonoacetate under standard condi-
tions, followed by DIBAL reduction, led to allylic alcohol
12, which was oxidized to the aldehyde 13 with the Dess-
Martin periodinane reagent in excellent yield. Treatment
of 13 with 15-20 mol % of the (R,R)-MacMillan catalyst
(3), followed by addition of 5-bromoindole (4), afforded
the adduct 14 in quantitative yield. Reduction to the
alcohol and mesylation to 16, followed by cleavage of the
N-Boc group and treatment of the product with potassium
carbonate in a mixture of THF and DMF as solvent, led to
the target compound (S)-(-)-2 in excellent yield. Stereo-
chemical purity (94:6 er) was established by chiral HPLC
analysis. The value obtained with the nitrogen containing
aldehyde 13 was not significantly lower than that obtained
in Scheme 1 with (E)-4-(4-methoxybenzyloxy)but-2-enal
(96:4).
The successful utilization of γ-N-Boc/N-Me R,β-unsa-
turated aldehyde 13 in the Michael-type reaction with
5-bromoindole (4) led us to explore the same reaction with
other N-substituents. The results shown in Table 1 (above)
indicate that a variety of N-subtituents can be used in the
original reaction with excellent enantioselectivities which
did not seemtovarysignificantly withless bulkyprotecting
groups on nitrogen (entry 3), or when groups with stronger
electron-withdrawing capability were introduced (entry 2).
However, when the bulkier bis-protected substrates (entries
4 and 5) were used, longer reaction times were necessary.
Due to the failure of the NH containing aldehyde (entry 6)
to participate in the indole alkylation reaction, we sought
an alternate route to compound 26 (Scheme 3), which is a
presumed intermediate in the synthesis of R-(þ)-2 from 10
(Scheme 1).
(92% ee) of the Michael adduct 5 was determined from
analysis of the Mosher ester derived from the alcohol 6.4
Having successfully completed the synthesis of the (R)-
(þ)-2 isomer, we sought to provide access to the more bio-
logically active enantiomer (þ)-1 from the (S)-(-)-2 pre-
cursor. It occurred to us that the inclusion of the N-Boc and
N-methyl groups in the starting R,β-unsaturated aldehyde
would obviate the need to introduce an azide as already
shown in Scheme 1, thus shortening the synthesis. However,
to the best of our knowledge, there is only one example of
the application of the MacMillan iminium-based organo-
catalytic Michael-type addition reaction onto a nitrogen-
containing R,β-unsaturated aldehyde,5 and no examples
with indoles.6
The synthesis of the desired (S)-(-)-2 is outlined in
Scheme 2. Treatment of N-Boc,N-methyl acetaldehyde
(5) Chen, Y. K.; Yoshida, M.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2006, 128, 9328.
(6) For indole 1,2-addition onto an activated iminium see: Peterson,
E. A.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2009, 48, 6328.
842
Org. Lett., Vol. 13, No. 5, 2011

Scheme 3. Second Generation Approach to a Substrate Suitable
for Indole-3-pyrrolidine Synthesis
Scheme 4. Synthesis of Enantioenriched Phenethylamines and
2-Ethylaminofurans
a Determined by HPLC analysis of the correspnding alcohols.
b Determined by 1H NMR analysis of the Mosher esters prepared by
NaBH4 reduction, preparation of the Mosher esters ((þ)- and (-)-
MTPA-Cl, Et3N), and removal of the Boc group (HCl, EtOAc, dioxane).
8-10% organocatalyst was used in these reactions.
In conclusion, the extension of MacMillan’s organoca-
talytic aromatic alkylation to hitherto unexplored 3-amino
crotonaldehydes has been realized and has found applica-
tion in a concise synthesis of S-(-)-2, a late stage inter-
mediate in the synthesis of the dual action migraine drug
prototype S-(þ)-1. We expect that this methodology will
also find application in alkaloid synthesis and in the syn-
thesis of other nitrogen-containing compounds of medic-
inal interest.
Starting from 20 (Table 1, entry 4), we first reduced the
aldehyde to the primary alcohol (20 f 22). Conversion to
the mesylate and removal of the Boc group furnished the
pyrrolidine 23.
Removal of the PMB protecting group was easily ac-
complished by using R-chloroethylchloroformate7 to fur-
nish 24. This would be a useful intermediate in generating a
variety of N-alkyl analogues by reductive amination with a
library of aldehydes or ketones.
MacMillan has reported similar organocatalytic Friedel-
Crafts-type alkylations of electron-rich aromatics,2e
and furans2f with R,β-unsaturated aldehydes. We decided
to test these with the nitrogen-containing aldehyde 13
(Scheme 4) and found that it participated in these reactions
as well. The substrates used were anisole 25 and 2-methyl-
furan, which gave adducts 26 and 27 in enantiomeric
excesses of 82% and 88%, respectively.
Acknowledgment. We thank NSERC (Canada) and
FQRNT (Quebec) for financial assistance and Benoıt
^
Deschenes-Simard (Hanessian group) for X-ray structure
determination.
Supporting Information Available. Experimental pro-
cedures and spectral data for compounds 5-27. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(7) Yang, B. V.; O’Rourke, D.; Li, J. Synlett 1993, 195.
Org. Lett., Vol. 13, No. 5, 2011
843