A Tandem conjugate addition/cyclization protocol for the asymmetric synthesis of 2-Aryl-4-aminotetrahydroquinoline-3-carboxylic acid derivatives

Article abstract of DOI:10.1021/ol9004118

Condensation of fert-butyl (E)-3-(2'-aminophenyl)propenoate with a range of aromatic and heteroaromatic aldehydes gives the corresponding imines as single diastereoisomers (>98% de). Addition of lithium (R)-W-benzyl-W-(α- methylbenzyl)amide initiates a ta

Full text of DOI:10.1021/ol9004118

ORGANIC
LETTERS
2009
Vol. 11, No. 9
1959-1962
A Tandem Conjugate Addition/
Cyclization Protocol for the Asymmetric
Synthesis of
2-Aryl-4-aminotetrahydroquinoline-3-carboxylic
Acid Derivatives
Stephen G. Davies,* Nadeam Mujtaba, Paul M. Roberts, Andrew D. Smith, and
James E. Thomson
Department of Chemistry, Chemistry Research Laboratory, UniVersity of Oxford,
Mansfield Road, Oxford OX1 3TA, U.K.
steVe.daVies@chem.ox.ac.uk
Received February 27, 2009
ABSTRACT
Condensation of tert-butyl (E)-3-(2′-aminophenyl)propenoate with a range of aromatic and heteroaromatic aldehydes gives the corresponding
imines as single diastereoisomers (>98% de). Addition of lithium (R)-N-benzyl-N-(r-methylbenzyl)amide initiates a tandem conjugate addition/
cyclization reaction to generate 2-aryl-4-aminotetrahydroquinoline-3-carboxylic acid derivatives in >98% de, >98% ee and high isolated yield.
Hydrogenolysis of an N(1)-Boc protected derivative allows selective cleavage of the N-benzyl-N-r-methylbenzyl protecting groups without
compromise of the diastereo- or enantiopurity.
The tetrahydroquinoline subunit is the central motif of several
biologically active natural products. Perhaps the most well-
known examples comprising this molecular architecture are
the Martinelle alkaloids martinelline 1 and martinellic acid
2 and the 2-phenyl synthetic analogue 31 (Figure 1).2 In
accord with its importance, the synthesis of the tetrahydro-
quinoline structural motif has been the subject of intense
research, especially concerning examples for clinical use.3
Several methods have been developed for the preparation
of this valuable heterocyclic scaffold, which commonly
Figure 1. Structures of martinelline 1, martinellic acid 2, and the
involve synthesis from aniline precursors (utilizing electro-
philic aromatic substitution,4 aza-Diels-Alder reaction,5 or
nucleophilic displacement6 to form the tetrahydroquinoline
ring system) or the elaboration and reduction of a quinoline
synthetic analogue 3.
precursor.7 Although these approaches often facilitate the
synthesis of diastereoisomerically pure tetrahydroquinolines,
(1) Batey, R. A.; Powell, D. A. Chem. Commun. 2001, 2362.
10.1021/ol9004118 CCC: $40.75
Published on Web 04/06/2009
 2009 American Chemical Society

there are relatively few examples which have been demon-
strated as synthetic routes to enantiomerically pure targets.
We have previously demonstrated that the conjugate
addition of homochiral, secondary lithium amides derived
from R-methylbenzylamine to R,ꢀ-unsaturated esters repre-
sents an efficient and versatile synthesis of ꢀ-amino esters
and derivatives.8 This methodology has found application
in the total synthesis of natural products,9 enantiorecognition
phenomena,10 and the initiation of tandem (cascade) pro-
cesses.11 For instance, the tandem conjugate addition/
cyclization of lithium (S)-N-benzyl-N-(R-methylbenzyl)amide
4 to di-tert-butyl (E,E)-nona-2,7-dienedioate 5 and a range
of dimethyl 4,4′-(alkylazanediyl)dibut-2-enoates, e.g., 6 and
7, gives access to the corresponding homochiral, polysub-
stituted aminocyclohexane 8 and 3-aminopiperidines 9 and
10 in good yield with high diastereoselectivity (Scheme 1).11a
Scheme 1. Tandem Conjugate Addition/Cyclization for the
Synthesis of Aminocyclohexane and 3-Aminopiperidines 8-10
(2) For selected recent synthetic approaches to the Martinelle alkaloids,
see: Nyerges, M. Heterocycles 2004, 63, 1685. Takeda, Y.; Nakabayashi,
T.; Shirai, A.; Fukumoto, D.; Kiguchi, T.; Naito, T. Tetrahedron Lett. 2004,
45, 3481. Hara, O.; Sugimoto, K.; Hamada, Y. Tetrahedron 2004, 60, 9381.
He, Y.; Moningka, R.; Lovely, C. J. Tetrahedron Lett. 2005, 46, 1251. Ng,
P. Y.; Masse, C. E.; Shaw, J. T. Org. Lett. 2006, 8, 3999. He, Y.; Mahmud,
H.; Moningka, R.; Lovely, C. J.; Dias, H. V. R. Tetrahedron 2006, 62,
8755. Hadden, M.; Nieuwenhuyzen, M.; Osborne, D.; Stevenson, P. J.;
Thompson, N.; Walker, A. D. Tetrahedron 2006, 62, 3977. Zhang, Z.;
Zhang, Q.; Yan, Z.; Liu, Q. J. Org. Chem. 2007, 72, 9808. Badarinarayana,
V.; Lovely, C. J. Tetrahedron Lett. 2007, 48, 2607. Miyata, O.; Shirai, A.;
Yoshino, S.; Nakabayashi, T.; Takeda, Y.; Kiguchi, T.; Fukumoto, D.; Ueda,
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73, 4464. Lovely, C. J.; Badarinarayana, V. Curr. Org. Chem. 2008, 12,
1431.
As a model system en route to derivatives of the Martinelle
alkaloids, we envisaged that addition of homochiral lithium
amide (R)-4 to R,ꢀ-unsaturated esters 11 would promote a
conjugate addition/cyclization reaction to give access to
homochiral 2-aryl-4-aminotetrahydroquinoline-3-carboxylic
acid derivatives 12 (Figure 2).12 We delineate herein the
results of these synthetic investigations.
(3) Witherup, K. M.; Ransom, R. W.; Graham, A. C.; Bernard, A. M.;
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Figure 2. Tandem conjugate addition/cyclization for the synthesis
of homochiral 4-aminotetrahydroquinolines 12.
tert-Butyl (E)-3-(2′-aminophenyl)propenoate 13 was prepared
in >98% de from Heck coupling of 2-iodoaniline and tert-butyl
(10) For instance, see: Bailey, S.; Davies, S. G.; Smith, A. D.; Withey,
J. M. Chem Commun. 2002, 2910. Bunnage, M. E.; Chippindale, A. M.;
Davies, S. G.; Parkin, R. M.; Smith, A. D.; Withey, J. M. Org. Biomol.
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Withey, J. M. Org. Biomol. Chem. 2004, 2, 3355. Aye, Y.; Davies, S. G.;
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Chem. 2008, 6, 2195. Davies, S. G.; D´ıez, D.; El Hammouni, M. M.; Garner,
A. C.; Garrido, N. M.; Long, M. J. C.; Morrison, R. M.; Smith, A. D.;
Sweet, M. J.; Withey, J. M. Chem. Commun. 2003, 2410. Davies, S. G.;
Garner, A. C.; Long, M. J. C.; Morrison, R. M.; Roberts, P. M.; Savory,
E. D.; Smith, A. D.; Sweet, M. J.; Withey, J. M. Org. Biomol. Chem. 2005,
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A.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E.; Toms,
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Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 6801.
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Kotchie, L. J.; Price, P. D.; Price Mortimer, A. J.; Russell, A. J.; Smith,
A. D. Tetrahedron: Asymmetry 2006, 17, 1793. For a review, see: (b) Davies,
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Xia, C.; Jiang, J.; Zhang, J.; Tang, W. J. Org. Chem. 2003, 68, 442. Davies,
S. G.; Kelly, R. J.; Price Mortimer, A. J. Chem. Commun. 2003, 2132.
Davies, S. G.; Haggitt, J. R.; Ichihara, O.; Kelly, R. J.; Leech, M. A.; Price
Mortimer, A. J.; Roberts, P. M.; Smith, A. D. Org. Biomol. Chem. 2004, 2,
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P. M.; Smith, A. D. Org. Biomol. Chem. 2008, 6, 1655. Abraham, E.; Brock,
E. A.; Candela-Lena, J. I.; Davies, S. G.; Georgiou, M.; Nicholson, R. L.;
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1665.
1960
Org. Lett., Vol. 11, No. 9, 2009

acrylate13 and isolated in 95% yield and >98% de. Condensa-
tion of 13 with benzaldehyde gave benzylidine imine 14 as a
single diastereoisomer, which was assigned the (E)-configura-
tion.14 Recrystallization furnished pure 14 in quantitative yield.
Benzylidine imine 14 was treated with 1.6 equiv of lithium
amide (R)-4 (>98% ee)15 to give 4-aminotetrahydroquinoline
15 as a single diastereoisomer (>98% de). Chromatographic
purification gave 15 in 86% yield, >98% de, and >98% ee.16
Repeated attempts to grow crystals of 15 for X-ray crystal-
lographic analysis failed. However, treatment of 15 with Boc2O
(20 equiv) gave 17% conversion to the highly crystalline N-Boc
derivative 16 in >98% de. Alternatively, addition of lithium
amide (R)-4 to benzylidene imine 14 and quenching with Boc2O
gave 16 in >98% de, which was isolated in 75% yield, >98%
de, and >98% ee16 after chromatography (Scheme 2).17 The
Figure 3. Chem3D representation of the X-ray crystal structure of
16 (some H atoms omitted for clarity).
Scheme 2. Tandem Conjugate Addition/Cyclization for the
unambiguous assignment of the absolute (2R,3R,4S,RR)-con-
figuration within 15. The absolute (4S)-stereogenic centers of
15 and 16, formed during the conjugate addition of lithium
amide (R)-4, are in accord with that predicted by the transition-
state mnemonic developed by us to rationalize the exceptional
stereofacial bias exerted by this class of lithium amide in its
conjugate addition reactions.18
Synthesis of 4-Aminotetrahydroquinolines 15 and 16
A simplistic mechanistic rationale to account for the observed
stereoselectivity of this process may be proposed. Conjugate
addition of lithium amide (R)-4 generates lithium (Z)-ꢀ-amino
enolate 17 and installs the (4S)-stereogenic center within
tetrahydroquinoline 15. Alkylation, protonation, or hydroxyl-
ation of a range of lithium (Z)-ꢀ-amino enolates is known to
proceed with modest to excellent levels of anti-selectivity,19
which is usually attributed to reaction of the lithium-nitrogen
chelated enolate on the least hindered face. In the case of
enolate 17, lithium-nitrogen chelation presents the Re face of
the enolate to the pendant imine and cyclization proceeds via
boat transition state 17A to give 2,3-syn-3,4-anti-4-amino-
tetrahydroquinoline 15 (Figure 4).
The generality of this tandem conjugate addition/cycliza-
tion process was next investigated. Aromatic and heteroaro-
matic (E)-configured14 imines 18-21 were prepared as single
diastereoisomers (>98% de) from R,ꢀ-unsaturated ester 13
and the corresponding aldehydes under dehydrative condi-
tions. Purification of 18 was achieved via recrystallization
(95% isolated yield), although 19-21 were not amenable to
recrystallization and attempted chromatographic purification
relative configuration within 16 was determined unambiguously
by single crystal X-ray analysis, with the absolute (2R,3S,4S,RR)-
configuration assigned from the known configuration of the (R)-
R-methylbenzyl stereocenter (Figure 3). This analysis allowed
(11) For instance, see: (a) Davies, S. G.; Diez, D.; Dominguez, S. H.;
Garrido, N. M.; Kruchinin, D.; Price, P. D.; Smith, A. D. Org. Biomol.
Chem. 2005, 3, 1284. (b) Davies, S. G.; Roberts, P. M.; Smith, A. D. Org.
Biomol. Chem. 2007, 5, 1405. (c) Koutsaplis, M.; Andrews, P. C.; Bull,
S. D.; Duggan, P. J.; Fraser, B. H.; Jensen, P. Chem. Commun. 2007, 3580.
(d) Garrido, N. M.; Garcia, M.; Diez, D.; Sanchez, M. R.; Sanz, F. U.;
Julio, G. Org. Lett. 2008, 10, 1687.
(12) For a related conjugate addition/cyclisation protocol for the synthesis
of tetrahydroquinoline derivatives, see: Youn, S. W.; Song, J.-H.; Jung,
D.-I. J. Org. Chem. 2008, 73, 5658.
(16) Given the known enantiomeric purity (i.e., >98% ee) of the lithium
amide (R)-4 used to initiate the tandem conjugate addition/cyclization
process, the enantiomeric purity of 15, 16, and 22-27 was assigned from
the diastereoisomeric purity (determined by peak integration of the 1H NMR
spectrum of the crude reaction mixture and the pure product).
(17) (R)-N-tert-Butoxycarbonyl-N-benzyl-N-(R-methylbenzyl)amine,
formed by reaction of the excess lithium amide (R)-4 with (Boc)2O, was
also isolated.
(13) Lizos, D. E.; Murphy, J. A. Org. Biomol. Chem. 2003, 1, 117.
(14) The condensation of a range of aniline derivatives with a range of
aldehydes is known to give the corresponding (E)-configured imines with
good to excellent levels of diastereoselectivity; see: Tennant, G. Compre-
hensiVe Organic Chemistry; Barton, D. E., Ollis, W. D., Eds.; Pergamon:
Oxford, 1979; Vol. 2, Chapter 8. Patai, S. The Chemistry of the Carbon-
Nitrogen Double Bond; John Wiley and Sons: Chichester, 1970. For some
very recent examples, see: Shen, M.; Driver, T. G. Org. Lett. 2008, 10,
3367. Albert, J.; D’Andrea, L.; Bautista, J.; Gonzalez, A.; Granell, J.; Font-
Bardia, M.; Calvet, T. Organometallics 2008, 27, 5108.
(18) Costello, J. F.; Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry
1994, 5, 1999.
(19) Davies, S. G.; Garrido, N. M.; Ichihara, O.; Walters, I. A. S. Chem.
Commun. 1993, 1153. Davies, S. G.; Walters, I. A. S. J. Chem. Soc., Perkin
Trans. 1 1994, 1129. Davies, S. G.; Ichihara, O.; Walters, I. A. S. J. Chem.
Soc., Perkin Trans. 1 1994, 1141. Bunnage, M. E.; Chernega, A. N.; Davies,
S. G.; Goodwin, C. J. J. Chem. Soc., Perkin Trans. 1 1994, 2373.
(15) The parent amine (R)-N-benzyl-N-(R-methylbenzyl)amine was
1
assessed to be >98% ee by H NMR chiral shift experiments using (S)-
O-acetylmandelic acid and comparison with an authentic racemic
sample.
Org. Lett., Vol. 11, No. 9, 2009
1961

methylbenzyl protecting groups and the N(1)-C(2) benzylic
bond of the tetrahydroquinoline ring had occurred.20 Hy-
drogenolysis of N-Boc protected 4-aminotetrahydroquinoline
16 gave 27 in 92% isolated yield, >98% de, and >98% ee,16
consistent with our previous reports that hydrogenolysis of
N-benzyl-N-R-methylbenzyl-protected ꢀ-amino esters pro-
ceeds with no loss of stereochemical integrity8a (Scheme 4).
Scheme 4
.
Hydrogenolysis of 4-Aminotetrahydroquinolines 15
and 16
Figure 4. Postulated transition-state model for cyclization of lithium
(Z)-ꢀ-amino enolate 17 (numbered atoms correspond to the ste-
reocenters within tetrahydroquinoline 15).
promoted hydrolysis of the imine functionality; therefore,
19-21 were utilized without prior purification. Addition of
lithium amide (R)-4 to imines 18-21 gave, in each case,
the corresponding 4-aminotetrahydroquinolines 22-25 as the
sole reaction products in >98% de. Chromatographic puri-
fication gave 22-25 in good yield (g72%) and in >98% de
and >98% ee16 in each case (Scheme 3). The relative 2,3-
In conclusion, condensation of tert-butyl 3-(2′-aminophe-
nyl)propenoate with a range of aromatic and heteroaromatic
aldehydes generates the corresponding diastereoisomerically
pure imines. Addition of lithium (R)-N-benzyl-N-(R-meth-
ylbenzyl)amide initiates a tandem conjugate addition/cy-
clization reaction, generating 2-aryl-4-aminotetrahydroquin-
oline-3-carboxylic acid derivatives in >98% de and >98%
ee. Hydrogenolysis of a 2-phenyl-4-aminotetrahydroquino-
line-3-carboxylic acid derivative gives a diamino ester
scaffold, while hydrogenolysis of the corresponding N(1)-
Boc-protected compound allows selective cleavage of the
N-benzyl-N-R-methylbenzyl protecting groups without com-
promising the diastereo- or enantiopurity. This procedure
represents a very operationally simple yet powerful method
for the construction of three contiguous stereogenic centers
within a homochiral 4-aminotetrahydroquinoline nucleus in
a single step. This approach should be readily applicable to
the preparation of libraries of 4-aminotetrahydroquinolines
for biological screening.
Scheme 3. Tandem Conjugate Addition/Cyclization for the
Synthesis of 4-Aminotetrahydroquinolines 22-25
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of 1H and 13C NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
syn-3,4-anti-configurations within 22-25 were assigned by
analogy to that unambiguously established for 15 and 16 and
were supported by NOE data. The absolute (2R,3R,4S,RR)-
configurations within 22-25 were thus assigned by reference
to the transition state mnemonic described by us to rationalize
the highly diastereoselective conjugate addition of lithium
amide (R)-4 to achiral R,ꢀ-unsaturated esters.18
Hydrogenolysis of 4-aminotetrahydroquinoline 15 gave
quantitative conversion to R-benzyl-ꢀ-amino ester 26 as the
only product, in which cleavage of the N-benzyl-N-R-
OL9004118
(20) The remarkable resistance of ꢀ-aryl-ꢀ-amino ester derivatives to
undergo cleavage of the N-C(ꢀ) bond has been attributed to the presence
of an intramolecular hydrogen bond between the ꢀ-amino substituents and
the carbonyl oxygen atom that holds the C(ꢀ)-aryl group in a conformation
that disfavors hydrogenolysis of the benzylic N-C(ꢀ) bond; see ref 8a.
1962
Org. Lett., Vol. 11, No. 9, 2009