Enantioselective Pictet-Spengler-type cyclizations of hydroxylactams: H-bond donor catalysis by anion binding

Article abstract of DOI:10.1021/ja076179w

Highly enantioenriched indolizinone and quinolizinone products are obtained in the thiourea-catalyzed cyclization of tryptamine-derived hydroxylactams. Substituent and counterion effect studies point to a novel mechanism of catalysis involving rate-limiti

Full text of DOI:10.1021/ja076179w

Published on Web 10/17/2007
Enantioselective Pictet-Spengler-Type Cyclizations of Hydroxylactams:
H-Bond Donor Catalysis by Anion Binding
Izzat T. Raheem, Parvinder S. Thiara, Emily A. Peterson, and Eric N. Jacobsen*
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
Received August 22, 2007; E-mail: jacobsen@chemistry.harvard.edu
N-Acyliminium ions are highly reactive electrophilic species1
Table 1. Asymmetric Cyclization of Hydroxylactams Catalyzed by 1b
that have been demonstrated only recently to engage successfully
in asymmetric catalytic reactions.2-4 Our own studies in this area
led to the discovery that the chiral thiourea derivative 1a promotes
highly enantioselective Pictet-Spengler- and Mannich-type reac-
tions through initial acylation of imines and isoquinolines, respec-
tively.3 The process by which the resulting N-acyliminium ions are
induced to undergo enantioselective additions with a simple
hydrogen-bond donor catalyst such as 1a is intriguing. Two limiting
mechanisms consisting of SN1 and SN2 pathways may be considered
(eq 1), but in neither case is the mode of catalyst interaction with
yieldb
(%)
eec
(%)
entry
product
substituents
n ) 1
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
R1 ) R2 ) R3 ) R4 ) H
90
86
51
88
89
94
91
92
74
68
84
97
95
90
96
99
97
93
96
98
85
91
R1 ) OCH3, R2 ) R3 ) R4 ) H
R1 ) H, R2 ) OCH3, R3 ) R4 ) H
R1 ) Br, R2 ) R3 ) R4 ) H
R1 ) F, R2 ) R3 ) R4 ) H
R1 ) H, R2 ) F, R3 ) R4 ) H
R1 ) R2 ) H, R3 ) CH3, R4 ) H
R1 ) R2 ) R3 ) H, R4 ) CH3
R1 ) R2 ) R3 ) H, R4 ) n-Bu
R1 ) R2 ) R3 ) H, R4 ) C6H5
R1 ) OCH3, R2 ) R3 ) H, R4 ) CH3
10
11
3j
3k
n ) 2
12
13
14
3l
3m
3n
R1 ) R2 ) R3 ) R4 ) H
R1 ) R2 ) R3 ) H, R4 ) CH3
R1 ) R2 ) R3 ) H, R4 ) n-Bu
52
63
65
59
81
92
96
88
the enantioselectivity-determining transition state apparent. In efforts
to glean insight into this reaction mechanism while broadening the
scope of the reaction class in synthetically interesting new direc-
tions, we have investigated the acid-catalyzed cyclization of
â-indolyl ethyl hydroxylactams (Table 1).5 We report herein the
successful application of thiourea catalysis to the Pictet-Spengler-
type cyclization of such compounds, affording highly enantioen-
riched indolizidinones and quinolizidinones. Key experimental
observations, supported by DFT computational analyses, point to
an SN1-type pathway in these cyclizations, with catalysis via a
heretofore unprecedented anion-binding mechanism.
A model reaction (2a f 3a) was examined under a broad set of
conditions, with catalyst structure, solvent, additive, temperature,
and concentration identified as crucial parameters.6 As in the case
of the acylative N-acyl-Pictet-Spengler and N-acyl-Mannich reac-
tions,3 pyrrole-thiourea derivatives of general structure 1 proved
optimal, with compounds bearing the 2-methyl-5-phenylpyrrole
substituent affording highest ee’s. The N-methylpentyl amide
derivative 1b was established as the most enantioselective catalyst.
A thorough screen of acidic additives revealed that either chlorot-
rimethylsilane or the combination of HCl and 3 Å molecular sieves
afforded high levels of conversion and enantioselectivity, but that
water had a deleterious effect on catalyst activity. Finally, a quite
significant inverse correlation between conversion and reaction
concentration was observed, with reactions run at lower concentra-
tions affording substantially improved yields.
15d
3o
a Unless noted otherwise, reactions of hydroxylactams generated by
NaBH4 reduction were carried out at -55 °C, while those generated by
alkylation were run at -78 °C. b Isolated yield determined after flash
chromatography on SiO2. c Determined by chiral SFC analysis on com-
mercial columns. The absolute configuration of 3d was established by X-ray
crystallographic analysis (see Supporting Information). d Reaction run for
72 h at -55 °C with 15 mol % of 1b.
Scheme 1. Total Synthesis of (+)-Harmicinea
a Conditions: (a) succinic anhydride, toluene/AcOH (1:3), 120 °C, 24
h; (b) NaBH4, MeOH, 0 °C; (c) 1b (10 mol %), TMSCl, TBME, -55 °C,
48 h; (d) LiAlH4, THF, rt, 16 h.
providing products bearing fully substituted stereogenic centers.
Hydroxylactam 2o, accessed via maleimide alkylation, was also
useful in this reaction, affording the synthetically versatile R,â-
unsaturated adduct 3o (entry 15).
In a straightforward demonstration of the applicability of this
new methodology, we applied the enantioselective hydroxylactam
cyclization to the total synthesis of (+)-harmicine (Scheme 1).7
The cyclization to 3a proceeded in 97% ee, with subsequent LiAlH4
reduction affording the natural product in only four steps from
tryptamine. The synthesis, which employs no protecting groups and
generates only H2O, B(OH)3, and Al(OH)3 as stoichiometric
Under the optimal reaction conditions, good-to-excellent yields
and enantioselectivities were obtained in the cyclization of hy-
droxylactams derived from a variety of succinimide and glutarimide
precursors (Table 1). Hydroxylactams generated either by imide
reduction using NaBH4 or by imide alkylation with organolithium
reagents were suitable substrates, with the latter undergoing
cyclization under milder conditions (-78 °C, 12 to 48 h), and
9
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J. AM. CHEM. SOC. 2007, 129, 13404-13405
10.1021/ja076179w CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
precedented in chiral phase-transfer catalysis17 and has recently been
demonstrated in the context of asymmetric counterion-directed
catalysis.18 We anticipate that asymmetric catalysis via anion-
binding mechanisms may be applicable to a wide variety of valuable
transformations involving highly reactive cationic intermediates,
and this is a focus of our current effort.
Table 2. Substituent, Counterion, and Solvent Effect Studies
temp
C)
time
(h)
conva
(%)
eeb
(%)
entry
solvent
X
R
(
°
Acknowledgment. This work was supported by the NIGMS
(GM-43214 and PO1 GM-69721), by fellowship support to I.T.R.
from the NSF, ACS, Pfizer, and Bristol-Myers Squibb, and to E.A.P.
through a postdoctoral fellowship from the NIH. We thank Lars
Nielsen and Dr. Matthew Woll for helpful discussions.
1
2
3
4
5
6
7
8
TBME
TBME
TBME
TBME
TBME
TBME
THF
Cl
Cl
Cl
Br
I
Cl
Cl
Cl
H
CH3
H
H
H
H
H
H
-78
-78
-55
-55
-55
-55
-55
-55
8
8
23
23
23
8
12
94
80
82
75
65
>95
>95
99
96
97
68
<5
97
8
8
34
<5
Supporting Information Available: Complete experimental pro-
cedures and characterization data for products and all isolated inter-
mediates. This material is available free of charge via the Internet at
http://pubs.acs.org.
CH2Cl2
a Determined by 1H NMR. b Determined by chiral SFC analysis on
commercial columns.
Scheme 2. Proposed Reaction Mechamism
References
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was deuterated, ruling out the possibility of rate-limiting deprotonation/
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(13) Similar reactivity and slightly diminished enantioselectivities are observed
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75% ee with the urea analogue) in the cyclization of 3a. This appears to
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chlorolactam9 is rapid and irreversible.6 Further, the observation
of enhanced reactivity of alkylated versus reduced derivatives (Table
2, entries 1 and 2) suggests that an SN2-type displacement of
chloride is not operative in the cyclization reaction and points rather
to an SN1-type mechanism (eq 1).1d Since the enantioselectivity-
determining step is likely, either the addition of the indole to the
N-acyliminium ion (Scheme 2, Path A 4bf4c or Path B 4bf4d)
or alkyl migration of the spiroindoline intermediate (Scheme 2, Path
A 4cf4d),1c,10,11 catalyst interaction with at least one of these
species is required. However, there is no viable Lewis basic site
for productiVe catalyst binding to substrate in either 4b or 4c.12,13
We propose instead that the thiourea catalyst promotes enanti-
oselective cyclization by inducing dissociation of the chloride
counterion and forming a chiral N-acyliminium chloride-thiourea
complex (Scheme 2). As would be expected within this model,
pronounced halide counterion effects (Table 2, entries 3-5)14 and
solvent effects (entries 6-8) on enantioselectivity are observed.
Catalysis and enantioinduction may thus result from initial abstrac-
tion of a chloride anion from 4a by 1b in an SN1-type rate-
determining step (4af4b) and subsequent cyclization mediated by
the resulting anion-bound thiourea.
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therein.
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