A preparation of enantiomerically enriched axially chiral β-diketimines: Synthesis of (-)- and (+)-IAN amine

Article abstract of DOI:10.1021/ol800728b

(Chemical Equation Presented) The preparation of an enantiomerically enriched β-diketimine composed of isoquinoline and 2-aminonaphthalene (IAN amine) is described, thereby offering new opportunities in the synthesis of nonracemic β-diketimine- and pyridine-based chiral catalysts.

Full text of DOI:10.1021/ol800728b

ORGANIC
LETTERS
2
008
Vol. 10, No. 12
445-2447
A Preparation of Enantiomerically
Enriched Axially Chiral ꢀ-Diketimines:
Synthesis of (-)- and (+)-IAN Amine
2
†
‡
Sarah B. Luesse, Carla M. Counceller, Jeremy C. Wilt, Brittany R. Perkins, and
Jeffrey N. Johnston*
Department of Chemistry & Vanderbilt Institute of Chemical Biology, Vanderbilt
UniVersity, NashVille, Tennessee 37235-1822
jeffrey.n.johnston@Vanderbilt.edu
Received March 31, 2008
ABSTRACT
The preparation of an enantiomerically enriched ꢀ-diketimine composed of isoquinoline and 2-aminonaphthalene (IAN amine) is described,
thereby offering new opportunities in the synthesis of nonracemic ꢀ-diketimine- and pyridine-based chiral catalysts.
The design of metal-organic complexes is the basis for the
discovery of new catalysts that offer unique reactivity and
selectivity. Enantioselective reaction development is predi-
cated on the availability of chiral nonracemic ligand varia-
tions of the fundamental coordinating unit. One such binding
element, the ꢀ-diketimine, possesses broad metal-modulating
pioneering, enantioselective reactions including cyclopropa-
3
,5
3
nation, conjugate reduction, and the Michael addition of
4
nonstabilized alkyls. In separate applications, the coordina-
tion of two ꢀ-diketiminate ligands to a single metal can be
6
7
highly selective for either homochiral or heterochiral
coordination complexes. The resulting complexes have been
used subsequently in catalysis and stereoselective synthesis.
1
ability but has long lacked a diversity in options for chiral
2
3,4
nonracemic variations. Exceptions include semicorrin and
Our work has focused on ꢀ-diketimines whose design
incorporates a chiral element within the coordination sphere
of the metal by twisting the ꢀ-diketimine binding element
5
corrin-like ligands bearing the chiral influence of a second-
ary amine appended to a planar ꢀ-diketimine. These ex-
amples have successfully translated to important, even
(e.g., 1). This deplanarization provides electronic desymme-
†
trization of the chelating nitrogens, resulting in an unusual
example of diastereoselective metal complexation in which
Current location: Promiliad Biopharma, Athens, OH.
Current location: Albany Molecular Research Inc., Syracuse, NY.
‡
(
1) Recent, selected examples: (a) Mindiola, D. J. Acc. Chem. Res. 2006,
9, 813. (b) Sadique, A. R.; Gregory, E. A.; Brennessel, W. W.; Holland,
P. L. J. Am. Chem. Soc. 2007, 129, 8112.
2) Bourget-Merle, L.; Lappert, M. F.; Severn, J. R. Chem. ReV. 2002,
02, 3031.
3) (a) Leutenegger, U.; Madin, A.; Pfaltz, A. Angew. Chem., Int. Ed.
2
a C -symmetric homochiral complex is formed selectively
3
6
from among 13 diastereomers. The barrier to atropisomer-
ization for a series of substituted IAN amines is generally
(
1
3
0 kcal/mol and corresponds to a half-life of >6 days at 70
(
8
Engl. 1989, 28, 60. (b) Fritschi, H.; Leutenegger, U.; Pfaltz, A. Angew.
Chem., Int. Ed. Engl. 1986, 25, 1005. (c) Fritschi, H.; Leutenegger, U.;
Pfaltz, A. HelV. Chim. Acta 1988, 71, 1553. (d) Fritschi, H.; Leutenegger,
U.; Siegmann, K.; Pfaltz, A.; Keller, W.; Kratky, C. HelV. Chim. Acta 1988,
°C. Until now, our attempts to access enantioenriched IAN
(6) (a) Cortright, S. B.; Huffman, J. C.; Yoder, R. A.; Coalter, J. N.;
Johnston, J. N. Organometallics 2004, 23, 2238. (b) Cortright, S. B.;
Johnston, J. N. Angew. Chem., Int. Ed. 2002, 41, 345.
7
1, 1541
.
(
(
4) Sibi, M. P.; Asano, Y. J. Am. Chem. Soc. 2001, 123, 9708
5) (a) Chen, Y.; Ruppel, J. V.; Zhang, X. P. J. Am. Chem. Soc. 2007,
.
(7) (a) Takacs, J. M.; Hrvatin, P. M.; Atkins, J. M.; Reddy, D. S.; Clark,
J. L. New J. Chem. 2005, 29, 263. (b) Takacs, J. M.; Reddy, D. S.; Moteki,
S. A.; Wu, D.; Palencia, H. J. Am. Chem. Soc. 2004, 126, 4494.
1
2
29, 12074. (b) Chen, Y.; Fields, K. B.; Zhang, X. P. J. Am. Chem. Soc.
004, 126, 14718.
10.1021/ol800728b CCC: $40.75
Published on Web 05/14/2008
 2008 American Chemical Society

amine derivatives were limited to a single successful separa-
tion of Me-IAN enantiomers by preparatory chiral HPLC.
We describe here a practical synthesis of IAN amine 1. As
this is a “parent” IAN amine from which numerous others
can be synthesized, this development constitutes a general
route to N-substituted enantioenriched ꢀ-diketimines and
considerably extends access to potential chiral ꢀ-diketimi-
nate-based complexes.
Diastereomers 3a,b provided considerable flexibility to the
singular goal to separate them. For example, these diaster-
eomers are readily separated by preparative flash chroma-
tography (∆R ) 0.09). The more attractive approach is
f
fractional recrystallization that returns the (R)-IAN diaste-
reomer 3a selectively (>94% purity, HPLC). This diaste-
reomer is consistently a crystalline solid, whereas (S)-IAN
diastereomer 3b is routinely a foam (but will occasionally
crystallize upon standing when pure and solventless).
Resolutions are normally wasteful in nature as the dias-
tereomer of the chiral auxiliary is often useful only for
synthetic access to the enantiomer of the compound of
interest. Diastereomer 3b can be used in this manner to
provide (+)-IAN amine. Alternatively, we observed atropi-
somerization in alcohol solvent that is more rapid than the
same isomerization in aromatic hydrocarbons, which require
approximately 17 h at 145 °C (xylenes) to reach an
equilibrium ratio (1:1) of epimers 3a and 3b. Epimerization
of 3b for the purpose of ultimate convergence to one
enantiomer (1) could be achieved by warming the mother
liquor enriched in 3b in ethanol for 48 h (eq 1).
Extensive efforts to resolve various racemates in this chiral
pyridine family were uniformly unsuccessful, including
9
traditional and family approaches to chiral salt formation
and fractional recrystallization. These methods used a
selection of tartaric and mandelic acids that provided
crystalline salts, but without diastereomer enrichment in all
fractional recrystallization studies. The synthesis of racemic
ligands was readily scaled during this time, and many IAN
amine derivatives and their intermediates were routinely
crystalline solids. We therefore turned to R-methyl benzyl-
amine IAN 3 and a study of its suitability as a resolving
agent without primary recourse to chromatography.
1
0
Naphthol 2-triflate was coupled with commercially
available (S)-R-methylbenzyl amine using palladium cataly-
1
1
12
sis (Scheme 1). The desired aryl amine (2) was obtained
Scheme 1. Preparation of (-)-IAN Amine (1)
Subsequent cooling through fractional recrystallization re-
turns (R)-IAN 3a selectively (as a crystalline salt; 25% of
theoretical yield for each recycle) and ultimately enantio-
merically enriched (-)-1.
Removal of the auxiliary was examined using a variety
of conditions and strategies. Catalytic hydrogenation using
traditional palladium catalysts did not provide the desired
IAN amine (1) at pressures to 250 psi at room temperature.
Transfer hydrogenation required heating in methanol to
debenzylate the naphthylamine, but as noted above, atropi-
somerization under these conditions is favorable. We there-
fore turned to Lewis acid assisted debenzylation by ethane
thiol. Boron tribromide provided IAN amine 1 but was
complicated by additional products. By comparison, alumi-
num tribromide provided a substantially improved outcome,
returning IAN amine in 65% yield and 87% ee. This initial
result used amounts employed by others, which corresponded
14
3
to 32 equiv of AlBr and ethane thiol solvent (1821 equiv).
This protocol was improved by reducing the amount of AlBr
3
in 66% yield after direct recrystallization. 1-Chloroisoquino-
line is both commercially available and readily prepared.
Its coupling with naphthylamine 2 was accomplished using
trimethyl aluminum to deliver the desired IAN amine 3 as a
1
3
to 10 equiv while employing an amount of ethane thiol
solvent corresponding to 600 equiv. In this manner, the
desired IAN amine was obtained in 63% yield and 96% ee
reproducibly at the 1 g scale.
It is significant to note that our observations during this
optimization indicate that the amounts of Lewis acid and
mercaptan can be further lowered, but that the reaction
quench must be carefully executed in order to avoid
racemization. Specifically, 1 M NaOH must be added
rapidly to an efficiently cooled reaction flask at 0 °C.
Deviation from this protocol resulted in the formation of
1
:1 mixture of diastereomers. This C-arylation was entirely
1
regioselective to the limits of detection ( H NMR) and is
attributed to the nature of the intermediate aluminum anilide.
6
(
8) Cortright, S. B.; Yoder, R. A.; Johnston, J. N. Heterocycles 2004,
2, 223.
9) Vries, T.; Wynberg, H.; van Echten, E.; Koek, J.; ten Hoeve, W.;
6
(
Kellogg, R. M.; Broxterman, Q. B.; Minnaard, A.; Kaptein, B.; van der
Sluis, S.; Hulshof, L.; Kooistra, J. Angew. Chem., Int. Ed. 1998, 37, 2349.
(
10) Stang, P. J.; Hanack, M.; Subramanian, L. R. Synthesis 1982, 85.
2446
Org. Lett., Vol. 10, No. 12, 2008

a white gel whose presence typically corresponded to a
loss in enantiomeric enrichment (although not complete
racemization).
The parent IAN amine is common to many desirable
derivatives. For example, alkylation by a deprotonation/
electrophile addition procedure provides IAN 4 in 55%
yield from 3a without loss of enantiomeric enrichment.
Debenzylation of the tertiary amine using the procedure
described above provides Me-IAN (5, Scheme 2), which
tography using a chiral stationary phase. In addition, numer-
ous derivatives can be prepared through either the parent
IAN amine or intermediate 3a. Investigations into the broad
application of these axially chiral ꢀ-diketimines is now
possible as is exploitation of their potential as chiral pyridine
1
5
derivatives.
Acknowledgment. We are grateful to the NSF for support
of this work (CHE-0415811 and REU). Undergraduate
research participants were supported by Pfizer (C.M.C.)
and NSF-REU (B.R.P.), and we thank Brandon Steele for
material contributions.
Scheme 2
.
Selective Debenzylation of a Tertiary IAN Amine
Derivative
Supporting Information Available: Procedures and
analytical data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL800728B
(
12) In accord with typical safe laboratory practice, the most recent
toxicological data should be consulted when preparing any organic
compound. We have searched the Chemical Abstracts database for reports
on the toxicology for naphthylamines. Outside of the clearly marked warning
labels found on commercially available 1- and 2-aminonaphthalene, we are
unaware of known toxicity for derivatives of 2-aminonaphthalene. Moreover,
at least one recent reference declares that N-phenyl-2-aminonaphthalene is
not mutagenic when measured in an Ames test. Apparently, N-phenyl-1-
aminonaphthalene passes through rodents with almost 98% recovery from
urine and feces, and with no adverse effects (although skin irritation was
noted in a separate rabbit test): Kubo, T.; Urano, K.; Utsumi, H. J. Health
Sci. 2002, 48, 545.
(
13) (a) Ferrer, M.; Sanchez-Baeza, F.; Messeguer, A. Tetrahedron 1997,
can then be alkylated to obtain tertiary amine Me
(-)-6). These manipulations are effected without detect-
able loss of enantiomeric enrichment.
In conclusion, a practical synthesis of the parent IAN
amine (-)-1 in enantiomerically enriched form has been
developed. This procedure provides the chiral azabinaphthyl
derivative without recourse to preparatory liquid chroma-
2
-IAN
53, 15877. (b) Alcock, N. W.; Brown, J. M.; Hulmes, D. I. Tetrahedron:
Asymmetry 1993, 4, 743.
(
(
14) Boger, D. L.; Weng, J. H.; Miyazaki, S.; McAtee, J. J.; Castle,
S. L.; Kim, S. H.; Mori, Y.; Rogel, O.; Strittmatter, H.; Jin, Q. J. Am. Chem.
Soc. 2000, 122, 10047.
(
15) (a) Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1996, 118, 1809. (b)
Ruble, J. C.; Latham, H. A.; Fu, G. C. J. Am. Chem. Soc. 1997, 119, 1492.
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d) Spivey, A. C.; Maddaford, A.; Leese, D. P.; Redgrave, A. J. J. Chem.
Soc., Perkin Trans. 1 2001, 1785. (e) Spivey, A. C.; Fekner, T.; Spey, S. E.;
Adams, H. J. Org. Chem. 1999, 64, 9430. (f) Held, I.; Xu, S.; Zipse, H.
Synthesis 2007, 1185. (g) Spivey, A. C.; Arseniyadis, S. Angew. Chem.,
Int. Ed. 2004, 43, 5436.
(
(
11) Louie, J.; Driver, M. S.; Hamann, B. C.; Hartwig, J. F. J. Org.
Chem. 1997, 62, 1268.
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