Conjugate addition of lithium N -phenyl- N -(α-methylbenzyl)amide: Application to the asymmetric synthesis of (R)-(-)-angustureine

Article abstract of DOI:10.1021/ol200625h

The conjugate addition of lithium (R)-N-phenyl-N-(α-methylbenzyl) amide to a range of α,β-unsaturated 4-methoxyphenyl esters proceeds with excellent levels of diastereoselectivity to give the corresponding β-amino esters in good yield and as single diaste

Full text of DOI:10.1021/ol200625h

ORGANIC
LETTERS
2011
Vol. 13, No. 10
2544–2547
Conjugate Addition of Lithium
N-Phenyl-N-(r-methylbenzyl)amide:
Application to the Asymmetric
Synthesis of (R)-(ꢀ)-Angustureine
Scott A. Bentley, Stephen G. Davies,* James A. Lee,
Paul M. Roberts, 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 March 9, 2011
ABSTRACT
The conjugate addition of lithium (R)-N-phenyl-N-(R-methylbenzyl)amide to a range of R,β-unsaturated 4-methoxyphenyl esters proceeds with
excellent levels of diastereoselectivity to give the corresponding β-amino esters in good yield and as single diastereoisomers (>99:1 dr). The
synthetic utility of this methodology has been demonstrated via the short and concise asymmetric synthesis of the tetrahydroquinoline alkaloid
(R)-(ꢀ)-angustureine in six steps and 32% overall yield from commercially available oct-2-enoic acid.
The conjugate addition reaction was first reported over
125 years ago by Komnenos, who demonstrated the 1,4-
addition of diethyl sodiomalonate to diethyl ethylidene-
malonate.1 Today, the conjugate addition reaction is a
powerful tool in the organic chemists’ synthetic arsenal due
to the wide range of nucleophiles and R,β-unsaturated
carbonyl compounds which participate in this reaction
manifold.2 We have previously shown that the conjugate
addition of a range of secondary lithium amides derived
from R-methylbenzylamine to a range of achiral and
chiral R,β-unsaturated esters proceeds with very high
levels and a predictable sense of diastereoselectivity.3 This
methodology has found numerous synthetic applications,
suchasuseinthe total synthesisofnaturalproducts4 and in
enantiorecognition phenomena,5 and was reviewed com-
prehensively in 2005.6 In >200 reported examples of this
reaction, several adaptations of the substructure of the
lithium amide have been successfully deployed for
synthesis,6,7 although to date there are no examples invol-
ving the use of a lithium N-aryl-N-(R-methylbenzyl)amide
as a chiral aniline equivalent for conjugate addition. In this
manuscript we report a resolution to this limitation: the
diastereoselective conjugate addition reaction of lithium
(3) Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1991, 2, 183.
Davies, S. G.; Garrido, N. M.; Kruchinin, D.; Ichihara, O.; Kotchie,
L. J.; Price, P. D.; Price Mortimer, A. J.; Russell, A. J.; Smith, A. D.
Tetrahedron: Asymmetry 2006, 17, 1793. Davies, S. G.; Mulvaney,
A. W.; Russell, A. J.; Smith, A. D. Tetrahedron: Asymmetry 2007, 18,
1554. Davies, S. G.; Fletcher, A. M.; Roberts, P. M. Org. Synth. 2010, 87,
143.
(1) Komnenos, T. Liebigs Ann. Chem. 1883, 218, 145.
(2) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Pergamon Press: Oxford, 1992. Smith, M. B.; March, J. March’s Advanced
Organic Chemistry ꢀ Reactions, Mechanisms, and Structure, 5th ed.; John
Wiley & Sons Inc.: New York, 2001.
r
10.1021/ol200625h
Published on Web 04/15/2011
2011 American Chemical Society

N-phenyl-N-(R-methylbenzyl)amide to a range of R,β-
unsaturated 4-methoxyphenyl esters is described.
addition of the lithium amide)12 as the major components
was observed. Variation of the electronics of the ester
group revealed that upon conjugate addition of lithium
amide 2 to 4-methoxyphenyl crotonate 6, the competing
1,2-addition reaction was completely suppressed and β-
amino ester 9 was produced as a single product. Further
experimentation showed that the optimum procedure in-
volved use of 1.1 equiv of lithium amide 2, which allowed
the isolation of β-amino ester 9 as a single diastereoisomer
in 80% yield (Scheme 1).
N-Arylation of (R)-R-methylbenzylamine (99% ee)8
according to a modification of the procedure described
by Larock9 gave (R)-N-phenyl-N-(R-methylbenzyl)amine
1 in 59% yield and >99% ee.10 Deprotonation of 1 with
BuLi in THF at ꢀ78 °C gave a pale yellow solution of
lithium (R)-N-phenyl-N-(R-methylbenzyl)amide 2. Addi-
tion of tert-butyl crotonate 3 (1.0 equiv) to the lithium
amide solution (2.0 equiv) gave only returned starting
material, while under identical conditions addition of
methyl crotonate 4 resulted in incomplete conversion
(34%)11 to β-amino ester 7 as a single diastereoisomer
(>99:1 dr). However, when phenyl crotonate was empo-
lyed, complete conversion to a mixture of products con-
taining a 75:25 mixture of β-amino ester 8 and R,β-
unsaturated amide 10 (resulting from competing 1,2-
Scheme 1
(4) For selected examples from this laboratory, see: Davies, S. G.;
Kelly, R. J.; Price Mortimer, A. J. Chem. Commun. 2003, 2132. Davies,
S. G.; Burke, A. J.; Garner, A. C.; McCarthy, T. D.; Roberts, P. M.;
Smith, A. D.; Rodriguez-Solla, H.; Vickers, R. J. Org. Biomol. Chem.
2004, 2, 1387. 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, 2630. Abraham, E.; Candela-Lena, J. I.; Davies,
S. G.; Georgiou, M.; Nicholson, R. L.; Roberts, P. M.; Russell, A. J.;
ꢀ
ꢀ
Sanchez-Fernandez, E. M.; Smith, A. D.; Thomson, J. E. Tetrahedron:
Asymmetry 2007, 18, 2510. Abraham, E.; Davies, S. G.; Millican, N. L.;
Nicholson, R. L.; Roberts, 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.; Perkins, J. H.; Roberts, P. M.; Russell,
a Reactions were performed using 1.0 equiv of R,β-unsaturated ester
and 2.0 equiv of lithium amide 2. bReaction was performed using 1.0
equiv of R,β-unsaturated ester 9 and 1.1 equiv of lithium amide 2.
ꢀ
ꢀ
A. J.; Sanchez-Fernandez, E. M.; Scott, P. M.; Smith, A. D.; Thomson,
J. E. Org. Biomol. Chem. 2008, 6, 1665. Davies, S. G.; Fletcher, A. M.;
Roberts, P. M.; Smith, A. D. Tetrahedron 2009, 65, 10192. Davies, S. G.;
Hughes, D. G.; Price, P. D.; Roberts, P. M.; Russell, A. J.; Smith, A. D.;
Thomson, J. E.; Williams, O. M. H. Synlett 2010, 567. Davies, S. G.;
Ichihara, O.; Roberts, P. M.; Thomson, J. E. Tetrahedron 2011, 67, 216.
Bagal, S. K.; Davies, S. G.; Fletcher, A. M.; Lee, J. A.; Roberts, P. M.;
Scott, P. M.; Thomson, J. E. Tetrahedron Lett. 2011, 52, 2216.
(5) For selected examples from this laboratory, see: Davies, S. G.;
Hermann, G. J.; Sweet, M. J.; Smith, A. D. Chem. Commun. 2004, 1128.
Cailleau, T.; Cooke, J. W. B.; Davies, S. G.; Ling, K. B.; Naylor, A.;
Nicholson, R. L.; Price, P. D.; Roberts, P. M.; Russell, A. J.; Smith,
A. D.; Thomson, J. E. Org. Biomol. Chem. 2007, 5, 3922. Aye, Y.;
Davies, S. G.; Garner, A. C.; Roberts, P. M.; Smith, A. D.; Thomson,
J. E. Org. Biomol. Chem. 2008, 6, 2195. Abraham, E.; Davies, S. G.;
Docherty, A. J.; Ling, K. B.; Roberts, P. M.; Russell, A. J.; Thomson,
J. E.; Toms, S. M. Tetrahedron:Asymmetry 2008, 19, 1356. Davies, S. G.;
Durbin, M. J.; Hartman, S. J. S.; Matsuno, A.; Roberts, P. M.; Russell,
A. J.; Smith, A. D.; Thomson, J. E.; Toms, S. M. Tetrahedron:
Asymmetry 2008, 19, 2870. Davies, S. G.; Durbin, M. J.; Goddard,
E. C.; Kelly, P. M.; Kurosawa, W.; Lee, J. A.; Nicholson, R. L.; Price,
P. D.; Roberts, P. M.; Russell, A. J.; Scott, P. M.; Smith, A. D. Org.
Biomol. Chem. 2009, 7, 761. Davies, S. G.; Fletcher, A. M.; Hermann,
G. J.; Poce, G.; Roberts, P. M.; Smith, A. D.; Sweet, M. J.; Thomson,
J. E. Tetrahedron: Asymmetry 2010, 21, 1635.
The relative configuration within β-amino ester 9 was
unambiguously established via single crystal X-ray diffrac-
tion analysis,13 with the absolute (R,R)-configuration
being assigned from the known configuration of the (R)-
R-methylbenzyl stereocenter (Figure 1). This analysis re-
veals that the facial bias elicited by lithium (R)-N-phenyl-
N-(R-methylbenzyl)amide 2 in its conjugate addition to
R,β-unsaturated esters is consistent with that of other
members of this class of lithium amide14 [e.g., lithium N-
benzyl-N-(R-methylbenzyl)amide6 and lithium N-allyl-
N-(R-methylbenzyl)amide].15 On this basis, the absolute
(R,R)-configurations within β-amino esters 7 and 8 were
confidently assigned. In support of these assumptions, the
configurations within β-amino esters 8 and 9 were corre-
lated to that of the known dihydroquinolin-4-one 13.
Attempted treatment of either 8 or 9 with polyphosphoric
(6) Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron: Asymmetry
2005, 16, 2833.
(12) An authentic sample of R,β-unsaturated amide 10 was prepared
(in 83% yield) via acylation of (R)-N-phenyl-N-(R-methylbenzyl)amine
1 with crotonoyl chloride.
(13) Crystallographic data (excluding structure factors) have been
deposited with the Cambridge Crystallographic Data Centre as supple-
mentary publication number CCDC 805285.
(7) For selected examples, see:Okamoto, S.;Iwakubo, M.; Kobayashi,
K.; Sato, F. J. Am. Chem. Soc. 1997, 119, 6984. Bull, S. D.; Davies, S. G.;
Roberts, P. M.; Savory, E. D.; Smith, A. D. Tetrahedron 2002, 58, 4629.
Williams, P. G.; Yoshida, W. Y.; Quon, M. K.; Moore, R. E.; Paul, V. J.
J. Nat. Prod. 2003, 66, 651. Bentley, S. A.; Davies, S. G.; Lee, J. A.;
Roberts, P. M.; Russell, A. J.; Thomson, J. E.; Toms, S. M. Tetrahedron
2010, 66, 4604. Brock, E. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.;
Thomson, J. E. Org. Lett. 2011, 13, 1594.
(8) Enantiopure (R)-R-methylbenzylamine (99% ee) is commercially
available.
(9) Liu, Z.; Larock, R. C. J. Org. Chem. 2006, 71, 3198.
(10) The enantiomeric purity of (R)-N-phenyl-N-(R-methylbenzyl)-
amine 1 was determined by chiral HPLC analysis for which the authors
would like to thank Darren J. Dixon and Pavol Jakubec.
(11) The reaction conversion was calculated from the ratio of excess
(R)-N-phenyl-N-(R-methylbenzyl)amine 1 to β-amino ester 7 due to the
volatility of methyl crotonate 4.
(14) Costello, J. F.; Davies, S. G.; Ichihara, O. Tetrahedron: Asym-
metry 1994, 5, 1999.
(15) Davies, S. G.; Fenwick, D. R. J. Chem. Soc., Chem. Commun.
1995, 109. Davies, S. G.; Hedgecock, C. J. R.; McKenna, J. M. Tetra-
hedron: Asymmetry 1995, 6, 827. Davies, S. G.; Hedgecock, C. J. R.;
McKenna, J. M. Tetrahedron: Asymmetry 1995, 6, 2507. Davies, S. G.;
Fenwick, D. R. Chem. Commun. 1997, 565. Davies, S. G.; Fenwick,
D. R.; Ichihara, O. Tetrahedron: Asymmetry 1997, 8, 3387.
(16) (a) Paradisi, M. P.; Romeo., A. J. Chem. Soc., Perkin Trans. 1
1977, 596. (b) Liu, J.; Wang, Y.; Sun, Y.; Marshall, D.; Miao, S.; Tonn,
G.; Anders, P.; Tocker, J.; Tang, H. L.; Medina, J. Bioorg. Med. Chem.
Lett. 2009, 19, 6840.
Org. Lett., Vol. 13, No. 10, 2011
2545

substituents were all well tolerated within the reaction
manifold:17 conjugate addition of lithium (R)-N-phenyl-
N-(R-methylbenzyl)amide 2 to R,β-unsaturated esters
14ꢀ2318 under our optimal conditions gave, in each case,
complete conversion to single diastereoisomers of the
corresponding β-amino esters 24ꢀ33, which were isolated
in 53ꢀ83% yield after chromatographic purification. The
absolute configurations of the newly formed C(3)-stereo-
genic centers within β-amino esters 24ꢀ33 were assigned
by analogy to those unambiguously established for 8 and 9
(Scheme 3).
Scheme 3
Figure 1. Chem 3D representation of the single crystal X-ray
diffraction structure of 9 (selected H atoms are omitted for
clarity). Ar = 4-MeOC6H4.
acid (PPA)16 or a range of Lewis acids resulted only in
product decomposition via a retro conjugate addition
reaction, with no trace of the desired dihydroquinolin-4-
one 11. However, saponification of 8 and 9 followed by
treatment of the resultant β-amino acid 12 with PPA16
resulted in cyclization and in situ loss of the R-methylben-
zyl group (presumably via an SN1-type pathway) to give
dihydroquinolin-4-one 13 in 42 and 44% isolated yield
(two steps) from 8 and 9 respectively. Comparison of the
values of the specific rotations for these samples of 13 with
25
that previously reported in the literature {[R]D þ174
25
(c 1.0 in C6H6) for the sample of 13 derived from 8;
[R]D þ183 (c 1.0 in C6H6) for the sample of 13 derived
20
from 9; lit.16a [R]D þ220 (c 1.0 in C6H6)} confirmed the
The synthetic utility of this methodology was next
demonstrated by application to an asymmetric synthesis
homochirality within 8 and 9 and affirmed their absolute
(R,R)-configurations (Scheme 2).
(17) Attempted conjugate addition of lithium (R)-N-phenyl-N-(R-
methylbenzyl)amide 2 to 4-methoxyphenyl sorbate [40-methoxyphenyl
(E,E)-hexa-2,4-dieonate] and 40-methoxyphenyl (E)-4-methylpent-2-en-
oate under our optimal conditions returned only starting material.
(18) R,β-Unsaturated 4-methoxyphenyl esters 14ꢀ23 were prepared
either by esterification of the corresponding (commercially available)
R,β-unsaturated carboxylic acid, or through WadsworthꢀEmmons ole-
fination of the corresponding aldehyde using 4-methoxyphenyl diethyl-
phosphonoacetate; see the Supporting Information for full details.
Scheme 2
ꢀ
(19) Jacquemond-Collet, I.; Hannedouche, S.; Fabre, N.; Fouraste,
I.; Moulis, C. Phytochemistry 1999, 51, 1167.
(20) For previous syntheses of (()-angustureine, see: (a) Avemaria,
F.; Vanderheiden, S.; Braese, S. Tetrahedron 2003, 59, 6785. (b) Patil,
N. T.; Wu, H.; Yamamoto, Y. J. Org. Chem. 2007, 72, 6577. (c) O’Byrne,
A.; Evans, P. Tetrahedron 2008, 64, 8067. (d) Shahane, S.; Louafi, F.;
Moreau, J.; Hurvois, J.-P.; Renaud, J.-L.; van de Weghe, P.; Roisnel, T.
Eur. J. Org. Chem. 2008, 4622. (e) Kothandaraman, P.; Foo, S. J.; Chan,
P. W. H. J. Org. Chem. 2009, 74, 5947. For previous syntheses of
(S)-(þ)-angustureine, see: (f) Lin, X.-F.; Li, Y.; Ma, D.-W. Chin. J.
Chem. 2004, 22, 932. (g) Theeraladanon, C.; Arisawa, M.; Nakagawa,
M.; Nishida, A. Tetrahedron: Asymmetry 2005, 16, 827. (h) Ryu, J.-S.
Bull. Korean Chem. Soc. 2006, 27, 631. (i) Arisawa, M. Chem. Pharm.
Bull. 2007, 55, 1099. (j) Fustero, S.; Moscardo, J.; Jimenez, D.; Peerez-
Carrion, M. D.; Sanchez-Rosesllo, M.; del Pozo, C. Chem.;Eur. J.
2008, 14, 9868. (k) Chen, B.-L.; Wang, B.; Lin, G.-Q. J. Org. Chem. 2010,
75, 941. For previous syntheses of (R)-(ꢀ)-angustureine, see: (l) Wang,
W.-B.; Lu, S.-M.; Yang, P.-Y.; Han, X.-W.; Zhou, Y.-G. J. Am. Chem.
Soc. 2003, 125, 10536. (m) Lu, S.-M.; Wang, Y.-Q.; Han, X.-W.; Zhou,
Y.-G. Angew. Chem., Int. Ed. 2006, 45, 2260. (n) Rueping, M.; Antonchick,
A. P.; Theissmann, T. Angew. Chem., Int. Ed. 2006, 45, 3683. (o) Wang,
Z.-J.; Zhou, H.-F.; Wang, T.-L.; He, Y.-M.; Fan, Q.-H. Green Chem.
2009, 11, 767.
The generality of this reaction was next established by
application to a range of R,β-unsaturated 4-methoxyphe-
nyl esters bearing diverse substitution at the β-position.
Substituted aryl, heteroaryl, n-alkyl, and branched alkyl
2546
Org. Lett., Vol. 13, No. 10, 2011

of the tetrahydroquinoline alkaloid (R)-(ꢀ)-angustureine
36, originally isolated in 1999 by Jacquemond-Collet and
co-workers from the bark of Galipea officinalis Hancock, a
shrub indigenous to the mountains of Venezuela.19,20
Thus, saponification of β-amino ester 31 upon treatment
with aqueous LiOH gave the corresponding β-amino acid
which, upon exposure to PPA,16 underwent cyclization
with concomitant loss of an R-methylbenzyl group to
give 2-pentyl-2,3-dihydroquinolin-4(1H)-one 34 in 60%
isolated yield. Reduction of 34 with LiAlH416a gave tetra-
hydroquinoline 35 (norangustureine) which was N-methy-
Scheme 4
lated upon reflux in THF in the presence of MeI and
20d,e,g,h
K2CO3
to give (R)-(ꢀ)-angustureine 36 in 71%
yield over the two steps and in >99% ee,21 consistent with
the enantiomeric purity of the (R)-N-phenyl-N-(R-methyl-
benzyl)amide 2 used in the conjugate addition reaction.
The spectroscopic data of our sample of (R)-(ꢀ)-36 were in
excellent agreement with those previously reported for the
sample isolated from the natural source by Jacquemond-
Collet19 and other synthetic samples20lꢀo {[R]D ꢀ7.0
25
short and concise asymmetric synthesis of the tetrahydro-
quinoline alkaloid (R)-(ꢀ)-angustureine in six steps and
32% overall yield from commercially available oct-2-enoic
acid. Further applications of this conjugate addition reac-
tion to facilitate the preparation of other tetrahydroquino-
line derived natural products and their derivatives are
currently under investigation in our laboratory.
(c 1.0 in CHCl3) for >99% ee;21 lit.19 for sample isolated
15
from natural source [R]D ꢀ7.2;22 lit.20l [R]D ꢀ6.7 (c 1.0 in
8
CHCl3) for 94% ee; lit.20m [R]D ꢀ5.5 (c 1.1 in CHCl3)
for 89% ee; lit.20n [R]D ꢀ6.9 (c 1.0 in CHCl3) for
25
90% ee; lit.20o [R]D ꢀ7.3 (c 1.0 in CHCl3) for 94% ee}
20
(Scheme 4).
In conclusion, the conjugate addition of lithium (R)-N-
phenyl-N-(R-methylbenzyl)amide to a range of R,β-unsa-
turated 4-methoxyphenyl esters proceeds with excellent
levels of diastereoselectivity to give the corresponding β-
amino esters in good yield and as single diastereoisomers
(>99:1 dr). The synthetic utility of this methodology has
been demonstrated via its application as the key step in a
Supporting Information Available. Experimental pro-
cedures, characterization data, copies of 1H and 13C
NMR spectra, and crystallographic information file (for
structure CCDC 805285). This material is available free
of charge via the Internet at http://pubs.acs.org.
(22) The conditions under which the specific rotation value was
recorded (temperature, solvent, concentration) were not reported by
Jacquemond-Collet and co-workers in their manuscript describing the
isolation of the natural product (see ref 19).
(21) The enantiomeric purity of (R)-(ꢀ)-angustureine 36 was deter-
mined by chiral HPLC analysis for which the authors would like to
thank Darren J. Dixon and Pavol Jakubec.
Org. Lett., Vol. 13, No. 10, 2011
2547