Direct enantioselective bronsted acid catalyzed N-acyliminium cyclization cascades of tryptamines and ketoacids

Article abstract of DOI:10.1021/ol101651t

A direct enantio- and diastereoselective N-acyliminium cyclization cascade through chiral phosphoric acid catalyzed condensation of tryptamines with γ- and δ-ketoacid derivatives to provide architecturally complex heterocycles has been developed. The reac

Full text of DOI:10.1021/ol101651t

ORGANIC
LETTERS
2010
Vol. 12, No. 21
4720-4723
Direct Enantioselective Brønsted Acid
Catalyzed N-Acyliminium Cyclization
Cascades of Tryptamines and Ketoacids
Chloe A. Holloway,† Michael E. Muratore,‡ R. lan Storer,§ and Darren J. Dixon*,‡
School of Chemistry, The UniVersity of Manchester, Oxford Road, Manchester M13
9PL, U.K., Department of Chemistry, Chemistry Research Laboratory, UniVersity of
Oxford, Mansfield Road, Oxford OX1 3TA, U.K., and Pfizer Global Research &
DeVelopment, Ramsgate Road, Sandwich, Kent CT13 9NJ, U.K.
darren.dixon@chem.ox.ac.uk
Received July 16, 2010
ABSTRACT
A direct enantio- and diastereoselective N-acyliminium cyclization cascade through chiral phosphoric acid catalyzed condensation of tryptamines
with γ- and δ-ketoacid derivatives to provide architecturally complex heterocycles has been developed. The reaction is technically simple to
perform, atom-efficient, and broad in scope. Employing 10 mol % of (R)-BINOL derived chiral phosphoric acids in refluxing toluene allowed
the polycyclic product materials to be generated in good yields (53-99%) and moderate to high enantioselectivities (68-98% ee).
N-Acyliminium ion cyclization reactions are powerful for
the construction of nitrogen-containing heterocyclic ring
systems.1 When these are incorporated into cascade se-
quences,2 powerful strategies for the one-pot production of
polycyclic reaction products emerge. In a contribution to this
field, we recently described the development of an enanti-
oselective N-acyliminium ion cyclization reaction under
chiral Brønsted acid catalysis. Reaction of various enol
lactones 1 with tryptamine derivatives 2 in the presence of
binol phosphoric acid (BPA) catalysts in refluxing toluene
gave polycyclic products 3 in good to excellent yields and
high enantiomeric excess (Scheme 1). The reaction was
found to be general for a range of substituted tryptamine
derivatives and enol lactones made in a prior step or in situ
via gold-catalyzed cycloisomerization of alkynoic acids.3
Although successful, the work was hampered by the need
to form the enol lactone starting materials, and in some cases
this was nontrivial. It was recognized that a direct method
beginning with commercially available or readily prepared
keto esters or keto acids II would circumvent these problems
(2) For selected reviews, see: (a) Enders, D.; Grondal, C.; Hu¨ttl, M. R. M.
Angew. Chem., Int. Ed. 2007, 46, 1570. (b) Nicolaou, K. C.; Edmonds,
D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134. (c) Tietze,
L. F. Chem. ReV. 1996, 96, 115. For recent examples of iminium/N-
acyliminium cyclizations incorporated into cascade sequences, see: (d)
Pilling, A. W.; Boehmer, J.; Dixon, D. J. Angew. Chem., Int. Ed. 2007, 46,
5428. (e) Yang, T.; Campbell, L.; Dixon, D. J. J. Am. Chem. Soc. 2007,
129, 12070. (f) Yang, T.; Ferrali, A.; Campbell, L.; Dixon, D. J. Chem.
Commun. 2008, 25, 2923. (g) Wu, X.; Dai, X.; Nie, L.; Fang, H.; Chen, J.;
Ren, Z.; Cao, W.; Zhao, G. Chem. Commun. 2010, 46, 2733. (h) Yue, T.;
Wang, M.-X.; Wang, D.-X.; Masson, G.; Zhu, J. Angew. Chem., Int. Ed.
2009, 48, 6717.
† The University of Manchester.
‡ University of Oxford.
§ Pfizer Global Research & Development.
(1) For reviews, see: (a) Maryanoff, B. E.; Zhang, H. C.; Cohen, J. H.;
Turchi, I. J.; Maryanoff, C. A. Chem. ReV. 2004, 104, 1431. (b) Speckamp,
W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817. (c) Speckamp, W. N.;
Hiemstra, H. Tetrahedron 1985, 41, 4367. For recent applications to total
synthesis, see: (d) Kurasaki, H.; Okamoto, I.; Morita, N.; Tamura, O.
Chem.sEur. J. 2009, 15, 12754. (e) Bates, R. W.; Lu, Y. J. Org. Chem.
2009, 74, 9460. (f) Mej´ıa-Oneto, J. M.; Padwa, A. HelV. Chim. Acta 2008,
91, 285.
(3) Muratore, M. E.; Holloway, C. A.; Pilling, A. W.; Storer, R. I.;
Trevitt, G.; Dixon, D. J. J. Am. Chem. Soc. 2009, 131, 10796.
10.1021/ol101651t  2010 American Chemical Society
Published on Web 10/07/2010

methyl 2-(2-oxocyclohexyl)acetate (()-4a and tryptamine 2a.
Under conditions similar to those in our previous report,3
10 mol % of 3,3′-bis(triphenylsilyl) BPA 5a was employed
as the catalyst in refluxing toluene for 24 h.7 Pleasingly the
anticipated ꢀ-carboline product 3a was formed in good yield
and good enantiomeric excess (ee 83%) as a single diaste-
reoisomer (>98:2 dr) (Table 1, entry 1). Furthermore, under
Scheme 1
.
Enantioselective N-Acyliminium Cyclization
Cascades under BPA Catalysis
Table 1. Proof of Principle, Catalyst Screen, and Reaction
Condition Optimizationa
and also allow the chemistry to be extended to spirocyclic
products. Initial condensation of the tryptamine I with II
would generate an imine which under Brønsted acid catalysis
should condense with the ester resulting in the formation of
an enamide intermediate III. On protonation by HB* in a
low-polarity solvent, tight ion pairing of the N-acyliminium
ion with the chiral conjugate base of the Brønsted acid should
occur.4,5 Provided there is sufficient ordering and effective
facial differentiation in this ion pair, attack of the pendant
indole nucleophile should give rise to enantioselectivity in
the (irreversible) cyclization step.6 With at least three points
of diversity, numerous polycyclic structures V bearing
additional stereogenic centers, functionality, and spectator
groups could be readily accessed (Scheme 2). This would
temp time yield ee
entry
R
4
R1
catalyst
5
(°C) (h) (%) (%)a
1
2
Me
Et
H
a
b
c
c
c
c
c
c
c
c
SiPh3
SiPh3
SiPh3
BPA
BPA
BPA
BPA
a
a
a
b
c
d
e
f
110
110
110
110
110
110
110
110
110
110
24
24
24
24
24
24
48
24
48
24
80
77
77
95
87
95
99
86
89
63
83
82
81
63
14
43
53
57
74
82
3
4
H
3,5-(CF3)2Ph
5
H
2,4,6-(iPr)3Ph BPA
anthracenyl
9-phenanthryl BPA
p-NO2Ph
SiMe3
SiPh3
6
H
BPA
7
H
8
H
BPA
BPA
H8-BPA
9
H
g
h
10
H
a Determined by HPLC analysis using a chiral column (see Supporting
Information for details).
Scheme 2. Proposed Direct BPA-Catalyzed Enantioselective
Dehydrative N-Acyliminium Ion Cyclization Cascade
identical reaction conditions, both the analogous ethyl ester
and carboxylic acid substrates gave 3a with similar levels
of enantiocontrol and efficiency (Table 1, entries 2 and 3).
With these initial results in hand, a catalyst screen (probing
variation to the BINOL scaffold and the substituents at the
3 and 3′ positions) was carried out using racemic acid (()-
4c and tryptamine 2a to identify the most promising one in
terms of reaction speed, efficiency, and enantiocontrol (Table
1, entries 3-10). Pleasingly, all of the screened acid catalysts
efficiently facilitated the cyclization cascade with reaction
times of between 24 and 48 h. Enantioselectivity was
observed in all cases, but the optimal control arose from (R)-
TPS-BPA (entry 3, 81% ee, 77% yield) and (R)-H8-TPS-
BPA (entry 10, 82% ee, 63% yield). The optimal conditions
employed equimolar quantities of (()-4c and 2a at 0.0048
M in refluxing toluene with the BPA at 10 mol %.8
enable the repeated application of the method in target or
library synthesis. Herein we report our findings.
A preliminary reactivity study was performed using
equimolar quantities of commercially available racemic
(6) For recent organocatalyzed enantioselective additions of indoles to
N-acyliminium ions, see: (a) Rueping, M.; Nachtsheim, B. J. Synlett 2010,
1, 119. (b) Peterson, E. A.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2009,
48, 6328. (c) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.; Jacobsen, E. N.
J. Am. Chem. Soc. 2007, 129, 13404. For addition of pyrroles, see: (d)
Raheem, I. T.; Thiara, P. S.; Jacobsen, E. N. Org. Lett. 2008, 10, 1577. For
related additions to sulfenamide iminiums, see: (e) Wanner, M. J.; van der
Haas, R. N. S.; de Cuba, K. R.; van Maarseveen, J. H.; Hiemstra, H. Angew.
Chem., Int. Ed. 2007, 46, 7485. For additions to sulfonyliminiums, see: (f)
Sun, F.-L.; Zheng, X.-J.; Gu, Q.; He, Q.-L.; You, S.-L. Eur. J. Org. Chem.
2010, 47.
(4) For recent reviews on asymmetric organocatalysis by H-bond donors
and Brønsted acids, see: (a) Akiyama, T. Chem. ReV. 2007, 107, 5744. (b)
Doyle, A.; Jacobsen, E. N. Chem. ReV. 2007, 107, 5713. (c) Akiyama, T.;
Itoh, J.; Fuchibe, K. AdV. Synth. Catal. 2006, 348, 999. (d) Terada, M.
Chem. Commun. 2008, 35, 4097. (e) Terada, M. Synthesis 2010, 12, 1929
.
(5) For recent examples of chiral counterion-induced enantioselection
in N-acyliminium ion reactions, see: (a) Li, G.; Kaplan, M. J.; Wojtas, L.;
Antilla, J. C. Org. Lett. 2010, 12, 1960. (b) Terada, M.; Machioka, K.;
Sorimachi, K. Angew. Chem., Int. Ed. 2009, 48, 2553. (c) Rueping, M.;
(7) For pioneering studies on chiral phosphoric acid catalysis, see: (a)
Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem. Int. Ed 2004,
43, 1566. (b) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356.
Lin, M.-Y. Chem.sEur. J. 2010, 16, 4169
.
Org. Lett., Vol. 12, No. 21, 2010
4721

With optimal reaction conditions established, the scope
of the reaction with respect to the tryptamine and the keto
acid (or ester) was investigated (Scheme 3). Cyclopentanone,
lines in good yields, as single diastereomers (>98:2 dr), with
moderate to high enantioselectivities (3a-d, 3f, 3i, 3k).
Acyclic γ-keto acids (R1 and R2 ) alkyl) also partook in
the reaction under the same conditions to form the fused
lactams with high diastereoselectivities (g97:3 dr) and
moderate to high enantioselectivities (3e, 3g,h, 3j). Substrates
bearing electron-withdrawing groups R to the ketone were
also successful in yielding the expected tetracycle (3l,m).
Tryptamines bearing methoxy, bromide, or methyl groups
were reactive, but 7-methyl tryptamine gave rise to the
highest levels of enantioinduction. Notably, in all cases the
diastereoselectivity in the reaction was excellent. When
applied to a δ-keto acid, a slightly modified procedure
afforded six-membered fused lactam product 3n with good
diastereo- and enantioselectivity.
Scheme 3
.
Scope of the Direct Enantioselective BPA-Catalyzed
N-Acyliminium Ion Cyclization Cascade
Single crystal X-ray analysis established the absolute and
relative stereochemistry of 3c and the relative stereochemistry
of 3g.9 The absolute and relative stereochemistry of 3l was
established by comparison of its NMR spectroscopic data,
specific rotation, and HPLC retention times with the literature
data.3 Although the origin of enantioselectivity has yet to
be determined, we believe the high diastereoselectivity in
the enantioenriched product is a result of a dynamic kinetic
asymmetric cyclization and arises through a combination of
strong substrate control in the cyclization and a fast epimer-
ization via a prochiral cyclic enamide intermediate (see
Scheme 2).3,10 It was discovered that when tryptamine 2a
was reacted with (()-4c in the presence of 5a in refluxing
toluene, after a short reaction time, two isomeric enamides
6a and 6b could be isolated (Scheme 4). The chiral enamide
Scheme 4
.
Identification of Reaction Intermediates in the
Cyclization Cascade
6a was found to have an insignificant enantiomeric excess
(7% ee) compared to 3a formed under the same conditions
but with a longer reaction time (83% ee).
When 6a or 6b were treated with 10 mol % of 5a under
the optimized conditions for the cascade, they both gave rise
to the formation of 3a in good yields and identical enantio-
meric excess (83% ee). To gain further insight, racemic
oxoamide (()-7 was synthesized via amide coupling between
(8) As was observed in our previous studies (see ref 3), performing the
reactions at 0.0048 M was found to be optimal for enantiocontrol.
(9) Crystallographic data (excluding structure factors) for 3c and 3g have
been deposited with the Cambridge Crystallographic Data Centre (CCDC
790998 and 790999) and copies of these data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif.
(10) For relevant discussions on dynamic kinetic asymmetric transforma-
tions, see: (a) Steinreiber, J.; Faber, K.; Griengl, H. Chem.sEur. J. 2008,
14, 8060. See also: (b) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999,
cyclohexanone and cycloheptanone derived γ-keto acids or
esters were all good substrates, giving the desired ꢀ-carbo-
121, 3543
.
4722
Org. Lett., Vol. 12, No. 21, 2010

tryptamine 2a and racemic oxoacid (()-4c. Treatment of
(()-7 with 10 mol % of 5a under the optimal cyclization
conditions gave 3a in good yield (80%) with 83% ee
(Scheme 5).
Scheme 6. Postulated Origins of Stereocontrol in the Reaction
Cascade via a Dynamic Kinetic Asymmetric Cyclization
Scheme 5. Evidence for Passage through a Common
N-Acyliminium Ion Intermediate in the Cyclization Cascade
On the basis of the outcomes of these experiments, we
believe the enantiodetermining step in our cascade involves
nucleophilic attack of the indole nucleophile on an N-
acyliminium ion, and not an imine or iminium ion (followed
by γ-lactam formation; see Supporting Information). Fur-
thermore the most plausible mechanistic pathway would
involve the initial formation of diastereomeric N-acyliminium
salts 8 and 9 through condensation of the primary amine 2a
with racemic ketoacid (()-4c (Scheme 6). As well as
undergoing reversible deprotonation/reprotonation to the
respective enantiomers of 6a, these salts are able to rapidly
interconvert via enamide intermediate 6b, which allows
epimerization of the tertiary stereogenic center. It would
therefore be the relative rate of cyclization of each salt that
(68-98% ee). Further exploration and development work
in this field is ongoing, as is the application of the chemistry
to natural product synthesis. The results of these endeavors
will be reported in due course.
Acknowledgment. We acknowledge funding from EPSRC
(Leadership Fellowship to D.J.D., Studentship to M.E.M.),
The University of Manchester (C.A.H.), UCB (C.A.H.), and
Pfizer Global Research and Development (M.E.M.). We
thank Andrew Kyle (University of Oxford) for X-ray
structure determination and the Oxford Chemical Crystal-
lography Service for the use of the instrumentation.
determines the enantioselectivity and presumably k1eq, k2
,
eq
k3eq, k4 . k1 > k2.
eq
In summary, a direct enantioselective chiral phosphoric
acid catalyzed N-acyliminium ion cyclization cascade of
tryptamines and ketoacid derivatives has been developed.
The reaction is easy to perform and broad in scope and
provides the polycyclic ꢀ-carboline products in good overall
yields (53-99%) and moderate to high enantioselectivities
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds 3a-n, 4, 6a, 6b,
and 7 and CIF files for compounds 3c and 3g. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL101651T
Org. Lett., Vol. 12, No. 21, 2010
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