Enantioselective synthesis of substituted indanones from silyloxyallenes

Article abstract of DOI:10.1021/ja909669e

(Chemical Equation Presented) A new approach for the synthesis of enantioenriched indanones by asymmetric carbonyl-ene/intramolecular Heck cyclization from racemic silyloxyallenes has been developed. The modular procedure affords highly substituted indenes and indanones with excellent chirality transfer from the optically active carbinols. Full transfer of stereochemical information is achieved in the presence of 1,2,2,6,6- pentamethylpiperidine and PdCl₂(PPh₃)₂ (1 mol %) in DMF under microwave heating. Short reaction times and high yields have been demonstrated on a variety of substrates. Copyright

Full text of DOI:10.1021/ja909669e

Published on Web 01/19/2010
Enantioselective Synthesis of Substituted Indanones from Silyloxyallenes
Jonathan A. Brekan, Troy E. Reynolds, and Karl A. Scheidt*
Department of Chemistry, Center for Molecular InnoVation and Drug DiscoVery, Chemistry of Life Processes
Institute, Northwestern UniVersity, SilVerman Hall, EVanston, Illinois 60208
Received November 13, 2009; E-mail: scheidt@northwestern.edu
Chiral indane and indanone structures constitute the core of many
pharmaceutical agents and natural products.1 Consequently, new
strategies for the stereoselective preparation of these privileged
compounds from easily accessible precursors remains an important
goal. The current arsenal of asymmetric approaches to access these
compounds includes base-catalyzed 1,3-hydrogen rearrangements,2a
enzymatic reductions,2b Negishi cross-couplings,2d intramolecular
hydroacylations,2e Rh-catalyzed isomerizations2f and conjugate
additions,2g and reductive Heck cyclizations.2c While these methods
can be highly stereoselective, many tend to rely on a linear synthetic
approach in which the asymmetry is introduced following instal-
lation of all the key atoms and/or construction of the basic indane
core.3 We envisioned a new modular strategy for the construction
of chiral indanones by the union of appropriately substituted aryl
aldehydes and silyloxyallenes in a two-step process based on a new
formal [3 + 2] approach that involves an unusual transfer of
stereochemical information (Scheme 1).
while only mildly increasing the observed enantioselectivity (entry
2). From this temperature profile, it became evident that reaction
temperatures of 140 °C or higher were necessary to achieve full
conversion to the desired product. Additional 2-haloarylcarbinols
for the Heck cyclization were explored (entries 4 and 5). Aryl
chloride 2b was unreactive under the reaction conditions (entry 4).
Aryl iodide 2c provided clean conversion to the product but lower
levels of chirality transfer (53% ee; entry 5).
Table 1. Optimization of the Heck Cyclizationa
entry
X
temp (°C)
basec
yield of 3 (%)d
ee (%)e
1
2
3
4
5
6
7
8
Br (2a)
Br (2a)
Br (2a)
Cl (2b) (94%ee)
I (2c) (90%ee)
Br (2a)
160
120
140
160
160
140
140
150
Cy2NMe
Cy2NMe
Cy2NMe
Cy2NMe
Cy2NMe
Et3N
56
30
61
0
65
53
42
85f
70
73
72
0
53
52
84
91
Scheme 1. Formal [3 + 2] Construction of Indanones
Br (2a)
Br (2a)
iPr2NEt
PMP
a Performed in a 2-5 mL microwave vial at 0.1 M for 15 min. b (R,R)-
Cr(salen)SbF6 (10 mol %), 1 (1.4 equiv), aldehyde (1 equiv), 2,6-di-tert-
butyl-4-methylpyridine (20 mol %), CH2Cl2, -20 °C. c Two equivalents.
d Isolated yield. e Determined by HPLC. f Reaction time 25 min.
A survey of organic bases was then performed (Table 1, entries
6-8).6 Ultimately, the hindered base 1,2,2,6,6-pentamethylpiperi-
dine (PMP) provided the product with complete chirality transfer
but slowed the reaction relative to other trialkylamines. Increasing
the temperature to 150 °C and the reaction time to 25 min (entry
8) provided complete conversion with full transposition of asym-
metry. Interestingly, the isolated starting material from incomplete
reactions (entries 2 and 4) was recovered with no loss of optical
activity during the reaction.
The substrate scope for the reaction is summarized in Table 2.
A series of optically active carbinols (5a-g) were synthesized
following the carbonyl-ene protocol. Variations of the aromatic
portion as well as the alkene substituent were generated in high
yields and enantioselectivities (79-91% ee). Electron-rich as well
as electron-deficient aromatics performed equally well under the
optimized Heck conditions, providing products with minimal
erosion in optical activity. Aliphatic substitution on the alkene
proceeded smoothly to the desired indanone, with only a mild
decrease in enantioselectivity (entries 3 and 4). Varying the length
of the ketone functionality (entry 7) furnished the carbonyl-ene
product with slightly reduced enantioselectivity (86% ee) relative
to that for the methyl ketone (91% ee), but excellent chirality
transfer was observed during the unusual Heck cyclization.
Our current mechanistic model for this process involves inter-
mediate A (Scheme 2). A reactive conformation that minimizes
The asymmetric carbonyl-ene reaction of racemic silyloxyal-
lenes provides functional-group-rich allylic carbinols with high
levels of enantioselectivity.4 These silyloxyallenes, which are easily
prepared from acylsilanes and terminal alkynes,4a possess an initial
nucleophilic component (enolsilane) that after addition to an elec-
trophile generates a product possessing a versatile R,ꢀ-unsaturated
ketone. Through the use of 2-substituted aromatic aldehydes in this
process, a carbonyl-ene reaction4b coupled to an intramolecular Pd-
catalyzed bond-forming process constructs substituted indanones with
potential transfer of stereochemistry from the initial carbinol to the
C3 position.5 This controlled formal [3 + 2] approach leverages
the inherent reactivity of silyloxyallenes and orchestrates their initial
nucleophilicity and the subsequent electrophilic nature of the
resulting intermediate to significant effect.
Our initial experiments began with the preparation of enantioen-
riched carbinol 2a (91% ee) by the asymmetric carbonyl-ene
reaction of racemic silyloxyallene 1a and 2-bromobenzaldehyde.4b,d
With this precursor in hand, the desired Heck cyclization was
achieved in 15 min with 1 mol % Pd(II) in N,N-dimethylformamide
(DMF) at 160 °C (microwave). Significant chirality transfer was
observed (70% ee; Table 1, entry 1) despite the high reaction
temperature. Lowering the reaction temperature to 120 °C in order
to decrease the loss of optical activity adversely affected the yield
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1472 J. AM. CHEM. SOC. 2010, 132, 1472–1473
10.1021/ja909669e  2010 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Model for Stereochemical Transfer
Table 2. Substrate Scope of the Formal [3 + 2] Cyclization
provides rapid access to polycyclic heterocycles. For example,
silyloxyallene 1a can be converted to pyrazole 8 in only three steps
from a silyloxyallene via chiral indene 3 (eq 2).
In conclusion, a new synthesis of enantioenriched indanones from
racemic silyloxyallenes employing an asymmetric carbonyl-ene/
intramolecular Heck cyclization strategy has been developed. This
modular two-step procedure employs readily available coupling
partners and succinctly delivers substituted carbocycles with
excellent chirality transfer from optically active carbinol intermedi-
ates. The present work enhances the utility and versatility of
silyloxyallenes as multifunctional reagents in organic synthesis, and
the application of this indanone annulation strategy toward the
synthesis of bioactive molecules is ongoing.
Acknowledgment. Financial support was generously provided
by the Sloan Foundation, Amgen, AstraZeneca, and GlaxoSmith-
Kline. Wacker Chemical and FMCLithium provided reagent
support. T.E.R. is a 2007-08 ACS DOC fellow sponsored by BMS.
John Roberts is thanked for X-ray support.
Supporting Information Available: Experimental procedures,
spectral data for new compounds, and crystallographic data for 8 (CIF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
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(3) The conjugate addition of arylboronic acids to indenone fails to provide
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a Isolated yield. b Determined by HPLC. c ee determined from a
brominated analogue (see the Supporting Information).
A1,3 interactions7 and induces a six-membered-ring hydrogen-
bonded arrangement should direct carbometalation from the bottom
face, as depicted. While this conformation twists the carbonyl group
out of conjugation with the alkene, this orientation minimizes
possible destabilizing interactions between the methyl group/
carbonyl and the ꢀ-phenyl ring. The key carbometalation produces
palladium enolate B, and ꢀ-hydride elimination installs the observed
enol.8 To probe the importance of hydrogen bonding for chirality
transfer, the methyl ether of carbinol 2a was employed as a
substrate. The resulting Heck cyclization provided the methyl ether
of indene 3 in 65% yield but only 14% ee.9
This new approach for the synthesis of indanones facilitates rapid
access to related compounds in high enantioselectivity. The parent
indanone 7 can be generated in 88% ee from 3 by an indium triflate-
promoted retro-Claisen reaction (eq 1).10 The presence of the 1,3-
dicarbonyl system that is available directly from this new process
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(6) The use of inorganic bases or silver salts failed to provide any product.
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refs 2c and 2h.
(9) Presumably, PMP is less capable of disrupting H bonding. For the absolute
stereochemical assignment, see the Supporting Information.
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2007, 46, 7793. Accessing the parent indanone 7 by reductive cyclization
affords only 78% ee (see ref 2c).
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