Enantioselective Michael addition/iminium ion cyclization cascades of tryptamine-derived ureas

Article abstract of DOI:10.1021/ol401039h

A Michael addition/iminium ion cyclization cascade of enones with tryptamine-derived ureas under BINOL phosphoric acid (BPA) catalysis is reported. The cascade reaction tolerates a wide variety of easily synthesized tryptamine-derived ureas, including those bearing substituents on the distal nitrogen atom of the urea moiety, affording polyheterocyclic products in good yields and good to excellent enantioselectivities.

Full text of DOI:10.1021/ol401039h

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Enantioselective Michael
Addition/Iminium Ion Cyclization
Cascades of Tryptamine-Derived Ureas
Isabelle Aillaud, David M. Barber, Amber L. Thompson, and Darren J. Dixon*
Department of Chemistry, Chemistry Research Laboratory, University of Oxford,
Mansfield Road, Oxford OX1 3TA, U.K.
darren.dixon@chem.ox.ac.uk
Received April 15, 2013
ABSTRACT
A Michael addition/iminium ion cyclization cascade of enones with tryptamine-derived ureas under BINOL phosphoric acid (BPA) catalysis is
reported. The cascade reaction tolerates a wide variety of easily synthesized tryptamine-derived ureas, including those bearing substituents on
the distal nitrogen atom of the urea moiety, affording polyheterocyclic products in good yields and good to excellent enantioselectivities.
Chiral Brønsted acid-catalyzed cascade reaction
sequences1 involving ring closure of carbon or heteroatom-
centered nucleophiles onto reactive iminium ion inter-
mediates2 are useful for the enantioselective synthesis of
difficult-to-access and architecturally complex com-
pounds. To this end, we recently described the enantio-
selective cascade reactions of various enol lactones 23 or
ketoacids 44 with a range of tryptamine derivatives 1 under
BINOL phosphoric acid (BPA)5ꢀ7 catalysis, affording the
polycyclic products 3 in good yields and high enantiomeric
excesses (Scheme 1).8 In both cases, the scope of the
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D. W. C. J. Am. Chem. Soc. 2006, 128, 84–86. (b) Rueping, M.;
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r
10.1021/ol401039h
XXXX American Chemical Society

reaction was found to be broad with respect to the
substitution pattern of the tryptamine 1, enol lactones 2,
or ketoacids 4, and more than one stereocenter could be
incorporated into the products with control via dynamic
kinetic processes.
give the reactive iminium ion (intermediate 8) poised for
enantiofacial attack by the pendant indole nucleophile
under the control of the chiral conjugate base of the
BPA.11,12 With four points of diversity, numerous poly-
heterocyclic structures 9 bearing additional stereogenic
centers, functionalities and spectator groups could be
readily accessed, making this methodology attractive for
target or library synthesis. Herein we report our findings.
Scheme 1. Previous Enantioselective BPA-Catalyzed Cycliza-
tion Cascades to Access Indole-Derived Polycyclic Products
Scheme 2. Proposed Concept of a BPA-Catalyzed Cyclization
Cascade Using Tryptamine-Derived Ureas 5 and Enones 6
In a continuation of this research program, we were
interested in extending our findings to other tryptamine-
derived functionalities that would naturally enable enan-
tioselective access to other polyheterocyclic structures.
One such motif that caught our attention was the trypta-
mine-derived urea 5 (Scheme 2). These are known to be
readily synthesized from the parent tryptamine by reaction
with an isocyanate9 and are perfectly poised to undergo a
cyclization cascade through an acid-catalyzed condensa-
tion with substrates possessing two electrophilic centers
such as enones 6.10 Provided an initial Michael addition to
the distal nitrogen atom of the urea occurred to generate
intermediate 7, a subsequent acid-catalyzed condensation
of the ketone with the tryptamine nitrogen atom would
Preliminary investigations into the cascade were carried
out on readily prepared urea 5a and methyl vinyl ketone
(MVK) 6a. From the results of previous studies,3,4,8 to-
luene was selected as the initial solvent and 3,30-bis-triphe-
nylsilyl BPA 10a as the initial catalyst in a series of
reactions to establish whether our proposed cascade reac-
tion was viable. Disappointingly, with MVK 6a (5 equiv)
at room temperature no reaction occurred after 120 h
(Table 1, entry 1). However, heating at 50 °C for 120 h
under the same conditions enabled product 9a to be
isolated in 31% yield with a good level of stereocontrol
(72% ee; Table 1, entry 2). Increasing the reaction tem-
perature to 110 °C, pleasingly, afforded 9a in an improved
76% yield while maintaining the enantioselectivity (71%
ee; Table 1, entry 4). Changing the solvent to xylene or
THF led to no significant improvement in either the yield
or the enantioselectivity of the cascade reaction (Table 1,
entries 5 and 6), while using DMSO or ethanol resulted in
no product formation (Table 1, entries 7 and 8). With these
initial results in hand, a catalyst screen probing variation of
the BINOL scaffold and the substituents at the 3 and 30
positions was carried out (Table 1, entries 9ꢀ14). Pleasingly,
all of the screened BPA catalysts efficiently facilitated the
cyclization cascade when it was conducted in toluene at reflux
for 15 h. Enantioselectivity was observed in all cases, but the
optimal control arose when using BPA 10a and H8ꢀBPA
10b, affording 9a in the same yield (76%) and enantioselec-
tivity (71% ee; Table 1, entries 4 and 9) in both cases. The
optimal conditions employed a substrate concentration of
[5a] = 5 mM, MVK 6a (5 equiv) in toluene at 110 °C with
BPA 10a (10 mol %). Under these conditions, 9a was
obtained in 76% yield and 73% ee (Table 1, entry 15).
(9) (a) Ho, B. T.; An, R.; Noel, M. B.; Tansey, L. W. J. Med. Chem.
1971, 14, 553–554. (b) Zhang, W.; Chen, C. H.-T.; Nagashima, T.
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Khim. 2006, 42, 1291–1296.
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Sorimachi, K. Angew. Chem., Int. Ed. 2009, 48, 2553–2556. (b) Rueping,
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E. A.; Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 13404–13405. (c)
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Maarseveen, J. H.; Hiemstra, H. J. Org. Chem. 2008, 73, 6405–6408. (d)
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6328–6331. (f) Rueping, M.; Nachtsheim, B. J. Synlett 2010, 1, 119–
122. (g) Cai, Q.; Liang, X.-W.; Wang, S.-G.; Zhang, J.-W.; Zhang, X.;
You, S.-L. Org. Lett. 2012, 14, 5022–5025. For related additions, see: (h)
Raheem, I. T.; Thiara, P. S.; Jacobsen, E. N. Org. Lett. 2008, 10, 1577–
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Org. Chem. 2010, 47–50.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Proof of Principle and Optimization Study of the
BPA-Catalyzed Cascade Reaction Using Tryptamine-Derived
Urea 5a and MVK 6a
Scheme 3. Scope of the BPA-Catalyzed Cyclization Cascade
Using Substituted Ureas 5aꢀp and Enones 6aꢀe
entrya solvent cat. temp (°C) time (h) yieldb (%) eec (%)
1
PhMe
PhMe
PhMe
PhMe
10a
10a
10a
10a
rt
50
120
120
15
15
15
15
60
24
15
15
15
15
15
15
15
15
ꢀ
31
60
76
48
60
ꢀ
ꢀ
72
70
71
72
68
ꢀ
2
3
80
4
110
140
70
5
Xylene 10a
THF 10a
DMSO 10a
6
7
110
80
8
EtOH
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
10a
10b
10c
10d
10e
10f
ꢀ
ꢀ
9
110
110
110
110
110
110
110
110
76
60
40
48
60
68
76
76
71
41
35
60
56
18
73
58
10
11
12
13
14
15d
16e
10g
10a
10a
a Reactions were performed on a 0.10 mmol scale. b Isolated yield
after purification by flash column chromatography on silica gel.
c Determined by HPLC analysis. d [5a] = 5 mM. e [5a] = 10 mM.
With optimal reactivity and enantiocontrol established,
the scope of the reaction was surveyed by using an array of
substituted ureas 5 and enones 6 (Scheme 3). Pleasingly,
the cascade reaction was found to tolerate a variety of
electron-rich and electron-poor tryptamine-derived ureas,
furnishing the desired tetracycles 9cꢀf in good yields and
enantioselectivities (73ꢀ77% yield, 60ꢀ70% ee). When
tryptamine-derived ureas containing methyl or ethyl sub-
stituents in the 7-position were employed, a significant
increaseinthe enantioenrichment of the products9gꢀj was
observed (54ꢀ78% yield, 90ꢀ92% ee). Using mesityl
oxide as the enone coupling partner afforded 9k in 78%
yield, but the enantioinduction was diminished to 43% ee.
Similarly, the cyclization of a tryptamine-derived thiourea
proceeded smoothly furnishing 9l in good yield, but a
significant decrease in enantioselectivity was observed
(72% yield, 31% ee). We next investigated the influence
that substituents on the urea had on the cascade reaction.
Gratifyingly, urea substrates bearing alkyl substituents on
the distal nitrogen of the urea furnished the corresponding
tetracycles 9mꢀq with good yields and enantioselectivities
(64ꢀ76% yield, 71ꢀ90% ee). The cyclization of substi-
tuted ureas bearing aryl substituents was also tolerated in
a Absolute configuration determined to be (R) by single-crystal X-ray
diffraction; all other compounds were assigned by analogy (see Figure 1
and the Supporting Information).
the cascade reaction using a variety of enones, affording
products 9rꢀw in good to excellent enantioselectivities
(55ꢀ76% yield, 81ꢀ96% ee).
That the cascade affords the desired products in gener-
ally high yields (typically more than 50%) despite the
presence of two potentially nucleophilic urea nitrogen
atoms is intriguing and worthy of further comment
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Proposed Mechanistic Pathway of the Michael
Addition/Iminium Ion Cyclization Cascade
Figure 1. Structure of compound 9r determined from single-
crystal X-ray diffraction data.13
(Scheme 4). Assuming that the synthesis of 9a results from
an initial Michael addition to the nitrogen atom distal to
the indole ring followed by iminium ion formation and an
enantiodetermining carbocyclization, the high reaction
yield is strongly suggestive of a rapid and reversible
Michael addition step. Using the reaction of 5a with 6a
as an example, we propose that a reversible Michael
addition between these two starting materials can lead to
the ketone intermediates 11 and 14. In the case of inter-
mediate 11, condensation of the ketone onto the urea
nitrogen creates an iminium ion that would need to under-
go an 8-membered ring cyclization to furnish tetracycle 13.
We postulate that this cyclization is unfavorable and, as a
result, the reaction course follows the pathway of inter-
mediate 14. Condensation of the urea nitrogen and the
ketone affords intermediate 15, which then undergoes a
more favorable 6-endo-trig cyclization to afford 9a in high
yield.
In summary, an efficient and highly enantioselec-
tive Michael addition/iminium ion cyclization cascade of
tryptamine-derived ureas and enones has been developed.
The reaction is easy to perform, broad in scope and
provides the desired tetracycles in good yields (up to 78%)
and enantioselectivities (up to 96% ee). Work to expand and
apply these findings is ongoing, and the results will be
reported in due course.
(13) Single-crystal X-ray diffraction data were collected at 150 K with
an Oxford Diffraction SuperNova diffractometer and processed with
CrysAlisPro as per the Supporting Information (CIF). The structure was
solved with SIR9214 and refined with CRYSTALS15 including the Flack
x parameter16 which refined to ꢀ0.05(12) (unrestrained) and ꢀ0.001(8)
with the application of Bijvoet difference restraints.16d Bayesian analysis
of the Bijvoet pairs gave the Hooft y parameter as ꢀ0.03(3), G of 1.06(6),
and the probability that the structure was the correct hand of >99.99%
given that the crystal is enantiopure or a racemic twin.17 Full crystal-
lographic data (in CIF format) are available as Supporting Information
and have been deposited with the Cambridge Crystallographic Data
Centre (reference code 921344).
(14) Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.;
Burla, M. C.; Polidori, G.; Camalli, M. J. Appl. Crystallogr. 1994, 27,
435–436.
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Watkin, D. J. J. Appl. Crystallogr. 2003, 36, 1487. (b) Cooper, R. I.;
Thompson, A. L.; Watkin, D. J. J. Appl. Crystallogr. 2010, 43, 1100–
1107.
Acknowledgment. We thank the European Commis-
sion [IEF to I.A. (PEIF-GA-2009-254053)], the EPSRC
(studentship to D.M.B and Leadership Fellowship to D.J.
D.), and AstraZeneca (studentship to D.M.B) for support.
Supporting Information Available. Experimental pro-
cedures and spectral data for compounds 5aꢀp and
9aꢀw. This material is available free of charge via the
Internet at http://pubs.acs.org.
(16) (a) Flack, H. D. Acta Crystallogr. 1983, A39, 876–881. (b) Flack,
H. D.; Bernardinelli, G. J. Appl. Crystallogr. 2000, 33, 1143–1148. (c)
Thompson, A. L.; Watkin, D. J. Tetrahedron: Asymmetry 2009, 20, 712–
717. (d) Thompson, A. L.; Watkin, D. J. J. Appl. Crystallogr. 2011, 44,
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(17) Hooft, R. W. W.; Straver, L. H.; Spek, A. L. J. Appl. Crystallogr.
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The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX