Enantioselective Bronsted acid-catalyzed N-acyliminium cyclization cascades

Article abstract of DOI:10.1021/ja9024885

(Chemical Equation Presented) An enantioselective Bronsted acid-catalyzed N-acyliminium cyclization cascade of tryptamines with enol lactones to form architecturally complex heterocycles in high enantiomeric excess has been developed. The reaction is technically simple to perform as well as atom-efficient and may be coupled to a gold(I)-catalyzed cycloisomerization of alkynoic acids whereby the key enol lactone reaction partner is generated in situ. Employing up to 10 mol % bulky chiral phosphoric acid catalysts in boiling toluene allowed the product materials to be generated in good overall yields (63-99%) and high enantioselectivities (72-99% ee). With doubly substituted enol lactones, high diastereo- and enantioselectivities were obtained, thus providing a new example of a dynamic kinetic asymmetric cyclization reaction.

Full text of DOI:10.1021/ja9024885

Published on Web 07/17/2009
Enantioselective Brønsted Acid-Catalyzed N-Acyliminium Cyclization
Cascades
Michael E. Muratore,†,‡ Chloe A. Holloway,† Adam W. Pilling,† R. Ian Storer,§ Graham Trevitt,| 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., Pfizer
Global Research & DeVelopment, Ramsgate Road, Sandwich, Kent CT13 9NJ, U.K., and Department of Medicinal
Chemistry, UCB, 208 Bath Road, Slough, Berkshire SL1 3WE, U.K.
Received March 28, 2009; E-mail: Darren.Dixon@chem.ox.ac.uk
Scheme 2. Concept of an Enantioselective N-Acyliminium
Cyclization Cascade under Chiral Brønsted Acid Catalysis
Bond formation through intramolecular attack on N-acyliminium
ion electrophiles by π nucleophiles is a stalwart method for the con-
struction of nitrogen-containing ring systems.1 When this is incorpo-
rated into cascade sequences,2 powerful strategies for the one-pot
production of polycyclic reaction products emerge. To this end, we
recently described a gold(I)-catalyzed reaction cascade of alkynoic acids
I and amine-tethered π nucleophiles II for the direct synthesis of ar-
chitecturally complex heterocyclic structures of type IV (Scheme 1).3
Scheme 1. Au(I)-Catalyzed N-Acyliminium Ion Cyclization Cascade
Table 1. Feasibility and Optimization Studies on Test Substrate 3a
Proceeding by ring opening of in situ-formed enol lactones followed
by dehydrative cyclization via N-acyliminium ion intermediates, this
cascade was attractive for both library production and target synthesis.
However, in the absence of any asymmetric controller, the overall
sequence was restricted to the production of racemates. To address
this limitation, we postulated that if the N-acyliminium ion 4 (Scheme
2, R2 ) H) were generated via a chiral Brønsted acid4-6 (HA*)-
catalyzed dehydrative condensation of an enol lactone 1 and an amine,
such as tryptamine 2, stereocontrol in the production of 5 could be
imparted7,8 during the enantiodetermining ring-forming step through
tight ion pairing with the chiral counterion.9 Also, this could potentially
be extended to an enantio- and diastereoselective variant10 (Scheme
2, R2 * H) and coupled to a gold(I)-catalyzed cycloisomerization of
alkynoic acid starting materials, allowing a powerful enantioselective
multicatalyst reaction cascade. Herein we describe our findings.
Initially, a range of (R)-BINOL phosphoric acid [(R)-BPA] deriva-
tives were screened for activity and enantioinduction in a model
cyclization reaction of ketoamide 3a (Table 1). In CH2Cl2 at room
temperature with catalysts 6a-d at 10 mol %, the reactions proceeded
slowly to afford the desired tetracyclic product 5a in >80% conversion
after 1.5 to 10 days. The highest ee of 27% was obtained using 3,3′-
bis(triphenylsilyl)BPA [(R)-TPS-BPA, 6d]. A subsequent solvent,
temperature, concentration, and catalyst survey revealed that a substrate
concentration of 7 mM in boiling toluene with 10 mol % 6d was
optimal for the rapid synthesis of 5a in high ee (Table 1, entry 7).
With the optimal reaction conditions in hand, we turned our attention
toward the enantioselective N-acyliminium cyclization cascade. We
first investigated the one-pot sequence starting directly with R-angelica
lactone 1a and tryptamine 2a (Table 2, entry 1). Pleasingly, at 7 mM
in boiling toluene in the presence of (R)-TPS-BPA 6d (10 mol %),
entry
R
catalyst
6
solvent [3a] (mM) temp
time
ee (%)a
1
2
3
4
5
6
7
8
9
H
BPA
a
b
c
d
d
d
d
e
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
50
50
50
50
50
35
7
7
7
7
rt
rt
rt
rt
rt
3 days
36 h
7 days
10 days
14 days
8
15
0
27
27
50
84
55
50
84
3,5-(CF3)2Ph BPA
4-NO2Ph
SiPh3
BPA
BPA
BPA
BPA
BPA
SiPh3
SiPh3
SiPh3
50 °C 1 day
110 °C 1 h
110 °C 12 h
110 °C 12 h
110 °C 6 h
9-phenanthryl BPA
2,4,6-(iPr)3Ph BPA
f
g
10 SiPh3
H8-BPA
a Determined by HPLC using a Chiralcel OD column.
equimolar amounts of the reagents afforded cyclized product 5a in
quantitative yield and 84% ee after 2 h. With enantiocontrol transferring
to the cyclization cascade, a range of substituted tryptamines (2a-f)
incorporating electron-withdrawing and -donating substituents at
positions 4, 5, 6, and 7 were then reacted with a range of five- and
six-membered-ring singly or doubly substituted enol lactones (1a-j).
Table 2 shows the results.
When tryptamine 2a was used, the enantioselectivities ranged from
83 to 87% and the reaction yields from 70 to 99% (entries 1-5).
Adding substituents to the indole moiety resulted in enhanced
enantioselectivity in all cases (85-99% ee; entries 6-16), with the
highest selectivities being observed with the phenyl-substituted lactone
1e (87-99% ee; entries 5, 7, 11, 12, 13, and 16). Formation of a
δ-lactam was also possible, however, the catalyst H8-BPA (6g) was
found to impart the highest levels of enantiocontrol (entry 17). To test
its scale-up potential, the reaction cascade of 7-methyltryptamine 2f
and phenyl enol lactone 1e was investigated at lower catalyst loadings.
Pleasingly, employing 1 mol % 6d yielded 5p in 95% yield and 96%
ee [see the Supporting Information (SI)].
† The University of Manchester.
‡ University of Oxford.
With disubstituted enol lactones (1g-j), we were pleasantly
surprised to observe only one of the two possible diastereoisomers in
§ Pfizer Global Research & Development.
| UCB.
9
10796 J. AM. CHEM. SOC. 2009, 131, 10796–10797
10.1021/ja9024885 CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Proposed Mechanistic Pathway
Table 2. Scope of the BPA-Catalyzed Cyclization Cascade
time
(h)
Yield ee
(%)a (%)b
entry
R1
R2
n
1
R3
2
6
5
c
methyl
n-propyl
n-hexyl
n-dodecyl
phenyl
methyl
phenyl
methyl
n-propyl
n-hexyl
phenyl
phenyl
phenyl
methyl
n-hexyl
phenyl
methyl
methyl
methyl
n-pentyl
methyl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
1
1
1
1
a
b
c
d
e
a
e
a
b
c
e
e
e
a
c
e
f
H
H
H
H
a
a
a
a
a
b
b
c
c
c
c
d
e
f
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
g
d
f
2
24
12
12
36
26
36
12
12
24
44
24
24
24
12
41
96
130
82
178
106
a
99
87
70
74
78
81
66
99
70
66
65
73
64
92
63
95
82
74
95
90
95
84
84
83
83
87
92
94
86
89
88
90
90
89
92
95
99
85
75
85
91
72
1
2
3
4
5
6
7
8
9
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
s
c
H
4-Br
4-Br
5-Br
5-Br
5-Br
5-Br
5-F
6-F
7-Me
7-Me
7-Me
7-Me
H
Acknowledgment. We acknowledge funding from EPSRC (Lead-
ership Fellowship to D.J.D.), Syngenta (A.W.P.), Pfizer Global
Research and Development (M.E.M.), and UCB (C.A.H.).
c
10
11
12
13
14
15
16
17
18
19
20
21
Supporting Information Available: Experimental procedures, spec-
tral data for 1, 2, 3a, 5, 7, and 10, and a CIF file. This material is available
free of charge via the Internet at http://pubs.acs.org.
f
f
f
a
a
a
f
References
d e
,
CO2Me
g
h
i
d e
,
(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.;
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Hiemstra, H. Tetrahedron 1985, 41, 4367.
P(O)(OMe)2
P(O)(OMe)2
SO2Ph
H
H
7-Me
d e
,
f
f
t
u
c d e
,
,
j
(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.
a Isolated yields. b Determined by CSP HPLC analysis. c See the SI
for proof of stereochemistry. d Using 20 mol
%
catalyst. e One
diastereomer was observed in the 1H NMR spectrum of the crude
reaction material.
(3) (a) Yang, T.; Campbell, L.; Dixon, D. J. J. Am. Chem. Soc. 2007, 129,
12070. Also see: (b) Yang, T.; Ferrali, A.; Campbell, L.; Dixon, D. J. Chem.
Commun. 2008, 2923.
the reaction mixture, and high levels of enantioselectivity were achieved
using either catalyst 6d or 6f (entries 18-21).
(4) 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.
(5) 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.
(6) For selected examples illustrating the high levels of enantioselectivity using
chiral Brønsted acid organocatalysis, see: (a) Storer, R. I.; Carrera, D. E.;
Ni, Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 84. (b) Martin,
N. J. A.; Ozores, L.; List, B. J. Am. Chem. Soc. 2007, 129, 8976. (c) Itoh,
J.; Fuchibe, K.; Akiyama, T. Angew. Chem., Int. Ed. 2008, 47, 4016. (d)
Terada, M.; Soga, K.; Momiyama, N. Angew. Chem., Int. Ed. 2008, 47,
4122. (e) Rueping, M.; Theissmann, T.; Raja, S.; Bats, J. W. AdV. Synth.
Catal. 2008, 350, 1001. (f) Kang, Q.; Zheng, X.-J.; You, S.-L. Chem.sEur.
J. 2008, 14, 3539. (g) Rowland, G. B.; Rowland, E. B.; Liang, Y.; Perman,
J. A.; Antilla, J. C. Org. Lett. 2007, 9, 2609.
(7) For examples of the related asymmetric Pictet-Spengler reaction under
chiral Brønsted acid catalysis, see: (a) Seayad, J.; Seayad, A. M.; List, B.
J. Am. Chem. Soc. 2006, 128, 1086. (b) Mergott, D. J.; Zuend, S. J.;
Jacobsen, E. N. Org. Lett. 2008, 10, 745. (c) 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. (d) Sewgobind, N. V.; Wanner, M. J.;
Ingemann, S.; de Gelder, R.; van Maarseveen, J. H.; Hiemstra, H. J. Org.
Chem. 2008, 73, 6405. For a thiourea-catalyzed example, see: (e) Klausen,
R. S.; Jacobsen, E. N. Org. Lett. 2009, 11, 887.
(8) For examples of N-acyliminium cyclizations using chiral thiourea catalysts,
see: (a) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.; Jacobsen, E. N. J. Am.
Chem. Soc. 2007, 129, 13404. (b) Raheem, I. T.; Thiara, P. S.; Jacobsen,
E. N. Org. Lett. 2008, 10, 1577.
The high levels of diastereo- and enantiocontrol with doubly
substituted enol lactone substrates 1g-j were notable and worthy of
further investigation. With short reaction times, both ketoamide 3r and
the dehydrated prochiral enamide 7 could be isolated in significant
quantities (see the SI). Identification of 7 as a key intermediate in the
mechanistic pathway means that the high diastereo- and enantiocontrol
observed in the reaction is consistent with fast, reversible formation
of the diastereomeric N-acyliminium salts 8 and 9 followed by rate-
determining ring closure (Scheme 3), where k1 for production of (+)-
5r is greater than k2 for the production of (-)-5r because of matched
substrate11 and catalyst control.
Pleasingly, this enantioselective cascade was compatible with an
in situ enol lactone-forming gold(I)-catalyzed cycloisomerization of
alkynoic acids 10 (Table 3).3a,12 Thus, when alkynoic acids 10b-d
were treated with gold(I) triflate triphenylphosphine (0.5 mol %) and
then tryptamines 2a, 2c, and 2f in the presence (R)-TPS-BPA 6d (10
mol %), the multicatalyst cascade products were isolated in good yields
and with high ee’s.13
Work to expand and apply these findings is ongoing, and the results
will be reported in due course.
(9) For examples of chiral counterion-mediated asymmetric catalysis, see: (a)
Garc´ıa-Garc´ıa, P.; Lay, F.; Garc´ıa-Garc´ıa, P.; Rabalakos, C.; List, B. Angew.
Chem., Int. Ed. 2009, 48, 4363. (b) Hamilton, G. L.; Kang, E. J.; Mba, M.;
Toste, F. D. Science 2007, 317, 496. (c) Mukherjee, S.; List, B. J. Am.
Chem. Soc. 2007, 129, 11336. (d) Rueping, M.; Antonchick, A. P.;
Brickmann, C. Angew. Chem., Int. Ed. 2007, 46, 6903.
Table 3. Au(I) and Chiral Brønsted Acid Multicatalyst Cascade
(10) For discussions of dynamic kinetic asymmetric transformations, 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, 121, 3543.
(11) The same diastereoisomer is the sole reaction product using PTSA (cat).
(12) For selected examples of tandem (or dual) metal/organocatalysis, see: (a)
Chercheja, S.; Rothenbu¨cher, R.; Eilbracht, P. AdV. Synth. Catal. 2009,
351, 339. (b) Han, Z.-Y.; Xiao, H.; Chen, X.-H.; Gong, L.-H. J. Am. Chem.
Soc. 2009, 131, 9182. (c) Terada, M.; Toda, Y. J. Am. Chem. Soc. 2009,
131, 6954. (d) Hu, W.; Xu, X.; Zhou, J.; Liu, W.-J.; Huang, H.; Hu, J.;
Yang, L.; Gong, L.-Z. J. Am. Chem. Soc. 2008, 130, 7782. (e) Sorimashi,
K.; Terada, M. J. Am. Chem. Soc. 2008, 130, 14452. (f) Ref 9d. (g) Ref
9c. (h) Komanduri, V.; Krische, M. P. J. Am. Chem. Soc. 2006, 128, 16448.
(13) A repeat of the reaction between 2a and 10d with AgOTf (0.5 mol %) and
6d (10 mol %) but no added AuClPPh3 gave 5d in 11% yield and 75% ee.
entry
R3
2
R1
10
5
yield (%)a
ee (%)b
1
2
3
4
5
6
7
8
9
H
H
H
5-Br
5-Br
5-Br
7-Me
7-Me
7-Me
a
a
a
c
c
c
f
n-propyl
n-hexyl
n-dodecyl
n-propyl
n-hexyl
n-dodecyl
n-propyl
n-hexyl
b
c
d
b
c
b
c
d
i
79
92
87
77
77
82
96
84
81
84
83
83
89
88
89
95
95
95
j
d
b
c
v
w
o
x
f
f
n-dodecyl
d
a Isolated yields. b Determined by CSP HPLC analysis.
JA9024885
9
J. AM. CHEM. SOC. VOL. 131, NO. 31, 2009 10797