Intramolecular michael reaction of tert-butylsulfinyl ketimines: Asymmetric synthesis of 3-substituted indanones

Article abstract of DOI:10.1021/ol2028948

Aromatic tert-butylsulfinyl ketimines bearing a suitable Michael acceptor at the ortho position readily undergo an intramolecular conjugate addition achieving indanone derivatives in good yields and complete diastereoselectivity.

Full text of DOI:10.1021/ol2028948

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6564–6567
Intramolecular Michael Reaction of
tert-Butylsulfinyl Ketimines: Asymmetric
Synthesis of 3-Substituted Indanones
‡
‡
‡
Santos Fustero,*,‡,§ Elsa Rodrıguez, Lidia Herrera, Amparo Asensio,
´
Miguel A. Maestro,†, and Pablo Barrio*,‡
´
Departamento de Quımica Organica, Universidad de Valencia, E-46100 Burjassot,
Spain, Laboratorio de Moleculas Organicas, Centro de Investigacion Prıncipe Felipe,
ꢀ
ꢀ
ꢀ
ꢀ
´
´
E-46012 Valencia, Spain, Departamento de Quımica Fundamental, Universidad da
~
Coruna, 15071 A Coruna, Spain
~
santos.fustero@uv.es, pablo.barrio@uv.es
Received October 27, 2011
ABSTRACT
Aromatic tert-butylsulfinyl ketimines bearing a suitable Michael acceptor at the ortho position readily undergo an intramolecular conjugate
addition achieving indanone derivatives in good yields and complete diastereoselectivity.
The indane core, and specifically the indanone subunit, is
a common skeleton in both natural products and synthetic
drugs.1,2 In recent years, several approaches for the asym-
metric construction of the indanone skeleton have been re-
ported.3,4 Among them, the hydroacylation of o-formylstyrenes
I (arising from the C1ÀC2 disconnection) developed by
Morehead3b and the isomerization of R-arylpropargyl alcohols
II (arising from the C3ÀC4 disconnection) followed by cycliza-
tion reported by Hayashi3c deserve special mention (Scheme 1).
The alternative disconnection C2ÀC3 would lead to
readily available o-functionalized acetophenone deriva-
tives III. Despite its simplicity, the asymmetric variant
of this intramolecular Michael reaction has so far not
been reported,5 to the best of our knowledge. Moreover,
the intramolecular version of the asymmetric Michael
reaction is notably less developed than its intermolecular
counterpart.6
† Author to whom correspondence regarding X-ray analysis should be
addressed.
‡ Universidad de Valencia.
§
ꢀ
Centro de Investigacion Prıncipe Felipe.
´
(3) For methodologies based on transition metal catalysis, see:
(a) Kerr, D. J.; Metje, C.; Flynn, B. L. Chem. Commun. 2003, 1380.
(b) Kundu, K.; McCullagh, J. V.; Morehead, A. T. J. Am. Chem. Soc.
2005, 127, 16042. (c) Shintani, R.; Yashio, K.; Nakamura, T.; Okamoto,
K.; Shimada, T.; Hayashi, T. J. Am. Chem. Soc. 2006, 128, 2772.
(d) Matsuda, T.; Shigeno, M.; Makino, M.; Murakami, M. Org. Lett.
2005, 8, 3379. (e) Seiser, T.; Cathomen, G.; Cramer, N. Synlett 2010,
1699. (f) Brekan, J. A.; Reynolds, T. E.; Scheidt, K. A. J. Am. Chem. Soc.
2010, 132, 1472. (g) Seiser, T.; Cramer, N. Angew. Chem., Int. Ed. 2010,
49, 10163.
(4) For some methodologies based on organocatalysis, see: (a) Kerr,
M. S.; Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 10298.
(b) Kerr, M. S.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876. (c) Enders,
D.; Niemeier, O.; Balensiefer, T. Angew. Chem., Int. Ed. 2006, 45, 1463.
(5) Little, R. D., Masjedizadeh, M. R., Wallquist, O. Mcloughlin, J. I.
The Intramolecular Michael Reaction. Organic Reactions; John Wiley and
Sons, Inc.: 2004; p 315.
~
Universidad da Coruna.
(1) For some representative natural products, see: (a) Boland, W.;
€
Hopke, J.; Donath, J.; Nuske, J.; Bublitz, F. Angew. Chem., Int. Ed.
Engl. 1995, 34, 1600. (b) Nagle, D. G.; Zhou, Y.-D.; Park, P. U.; Paul,
V. J.; Rajbhandari, I.; Duncan, C. J. G. J. Nat. Prod. 2000, 63, 1431.
(c) Okpekon, T.; Millot, M.; Champy, P.; Gleye, C.; Yolou, S.; Bories, C.;
Loiseau, P.; Laurens, A.; Hocquemiller, R. Nat. Prod. Res. 2009, 23, 909.
(2) For some pharmaceutically relevant products, see: (a) Kobayashi, A.;
Egawa, H.; Koshimizu, K.; Mitsui, T. Agric. Biol. Chem. 1975, 39, 1851.
(b) Dolling, U. H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc. 1984,
106, 446. (c) Omran, Z.; Cailly, T.; Lescot, E.; Santos, J. S. D.; Agondanou,
J. H.; Lisowski, V.; Fabis, F.; Godard, A. M.; Stiebing, S.; Le Flem, G.;
Boulouard, M.; Dauphin, F.; Dallemagne, P.; Rault, S. Eur. J. Med. Chem.
2005, 40, 1222. (d) Elati, C. R.; Kolla, N.; Chalamala, S. R.; Vankawala,
P. J.; Sundaram, V.; Vurimidi, H.; Mathad, V. T. Synth. Commun. 2006, 36,
169.
r
10.1021/ol2028948
Published on Web 11/23/2011
2011 American Chemical Society

isolated product was the indanone derivative 2a arising
from an intramolecular Michael reaction through the
imine R-position without incorporation of the CF3 moi-
ety. Moreover, 2a is afforded in good yield and as a single
diastereoisomer, as judged by 1H NMR (Scheme 3).
Scheme 1. Methods for the Asymmetric Construction of the
Indanone Ring
Scheme 3. Preliminary Result Regarding the Reactivity of 1a
towards CF3TMS
In a recent report, we described a new nucleophilic addi-
tion (AN)/Intramolecular Aza-Michael Reaction (IMAMR)
tandem process for the stereoselective synthesis of 1,3-
disubstituted fluorinated isoindolines (Scheme 2).7 For
this aim, we used o-functionalized tert-butanesulfinyl8
aldimines analogous to III.
The difference in reactivity between aldimines and
ketimines can be rationalized by a double effect: first,
the inherent lower reactivity of ketimines toward nucleo-
philes such as CF3TMS is due to their diminished electro-
philicity together with a higher steric bulk;11 second, acidic
protons are present at the R-position, providing an alter-
native reaction pathway. Thus, the “CF3À” anion formed
upon mixing the RuppertÀPrakash reagent with a fluor-
ine source acts as a base,12 while in the case of aldimines it
behaves as a nucleophile.13 In fact, the addition of fluor-
oalkyl carbanions was unprecedented until very recently.10
Only the use of stabilized carbanions, derived from fluoro-
or difluoromethyl phenylsulfone, is effective in the fluor-
oalkylation of ketimines. The presence of the sulfone
group renders a less basic carbanion. The balance be-
tween nucleophilicity and basicity may account for the
different behavior.
Scheme 2. Tandem AN/IMAMR for the Asymmetric Synthesis
of Fluorinated Isoindolines
Complementary to this work, we decided to study
the reactivity of the corresponding ketimines toward
the RuppertÀPrakash reagent (CF3TMS)9 targeting 1,3-
disubstituted isoindolines featuring a quaternary stereo-
center. When model substrate 1a was subjected to the
optimized conditions obtained for the tandem AN/IM-
AMR with aldimines, the formation of the expected
isoindoline remained unobserved.10 Instead the only
In order to establish the relative configuration of the new
stereocenter by X-ray analysis, suitable crystals of 2a were
obtained (Figure 1).14 Thus, the relative stereochemistry of
the newly created stereocenter in 2a was established to be R.
(10) A small amount ca. 5% of the corresponding isoindoline was
obtained along with the major reaction product.
(11) The addition of fluoroalkyl anions to ketimines was reportedly
hampered; see: (a) Liu, J.; Zhang, L.; Hu, J. Org. Lett. 2008, 10, 5377.
(b) Liu, J.; Hu, J. Chem.;Eur. J. 2010, 16, 11443.
(6) Reports in this context are practically limited to organocatalytic
processes; for some recent examples, see: (a) Fonseca, M. T. H.; List, B.
Angew. Chem., Int. Ed. 2004, 43, 3958. (b) Hayashi, Y.; Gotoh, H.;
Tamura, T.; Yamaguchi, H.; Masui, R.; Shoji, M. J. Am. Chem. Soc.
2005, 127, 16028. (c) Kikuchi, M.; Inagaki, T.; Nishiyama, H. Synlett
2007, 1075. (d) Phillips, E. M.; Wadamoto, M.; Chan, A.; Scheidt, K. A.
Angew. Chem., Int. Ed. 2007, 46, 3107.
(12) To the best of our knowledge, the combination CF3TMS/fluoride
source (i.e., TBAT: tetrabutylammonium difluorotriphenylsilicate) has
never been reported as a base.
(13) Control experiments with either reagent (CF3TMS or TBAT)
have been carried out separately. In both cases unaltered starting
materials were recovered, even after several hours at room temperature.
(14) For details, see Supporting Information.
ꢀ
ꢀ
ꢀ
(7) Fustero, S.; Moscardo, J.; Sanchez-Rosello, M.; Rodrı
´
guez, E.;
(15) This transition state has been suggested according to the most
stable conformation of the corresponding enamine, which was in turn
obtained by an MM2 minimization. A stabilizing electrostatic interac-
tion between the oxygen of the sulfinamide and the electrophilic ester
carbonyl carbon leading to a rigid eight-membered boat-like transition
state could explain the high diastereoselectivities observed. For similar
eight-membered transition states in intramolecular Michael reactions,
see ref 4.
Barrio, P. Org. Lett. 2010, 12, 5494.
(8) For an exhaustive review on the use of this chiral auxiliary in
asymmetric synthesis, see: Robak, M. T.; Herbage, M. A.; Ellman, J. A.
Chem. Rev. 2010, 110, 3600.
(9) (a) Krishnamurti, R.; Bellew, B. R.; Prakash, G. K. S. J. Org.
Chem. 1991, 56, 984. (b) Prakash, G. K. S.; Yudin, A. K. Chem. Rev.
1997, 97, 757. (c) Singh, R. P.; Shreeve, J. M. Tetrahedron 2000, 56, 7613.
Org. Lett., Vol. 13, No. 24, 2011
6565

Table 1. Optimization of the Reaction Conditions
temp
yield
entry
1
base
solv
(°C)
(%)
dr
CF3TMS/
TBATa
THF
À55 to À20
86
>20:1
Figure 1. ORTEP diagram for 2a.
2
3
4
5
6
7
8
9
LiHMDS
NaHMDS
LDA
tBuOK
LiHMDS
LiHMDS
TBAF
THF
THF
THF
THF
DCM
Tol-H
THF
THF
À78 to rt
À78 to À20
À78 to rt
0
65
46
33
20
30
36
76
SM
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
À
To explain the stereochemical outcome observed for
this transformation, we proposed the following transition
state (Figure 2).15
À78 to À20
À78 to À20
À55 to À20
À55 to À20
CsF
a The use of fluoride sources other than TBAT (i.e., TBAF or CsF)
proved to be less efficient.
Figure 2. Proposed transition state.
Table 2. Reaction Scope
Given the interest of this unprecedented transforma-
tion, we decided to perform an optimization of the reaction
conditions (Table 1).
Interestingly, the use of some common bases for
enolate formation such as LiHMDS, NaHMDS, LDA,
or tBuOK led to significant lower yields than the combina-
tion CF3TMS/TBAT (Table 1, entries 2À5) even after
temperature optimization for each base. For the base
leading to the best results, namely LiHMDS, a solvent
screening was carried out but no beneficial effect was
obtained (Table 1, entries 6, 7). Finally, among the fluoride
sources only the most basic TBAF is able to promote the
transformation on its own (Table 1, entry 8), although in
comparable yield with the initial conditions (CF3TMS/
TBAT). Thus, we have found two sets of reaction condi-
tions leading to the asymmetric intramolecular Michael
addition in good yield and diastereoselectivity: CF3TMS/
TBAT, THF, À55 to À20 °C and TBAF, THF, À55
to À20 °C (Table 1, entries 1 and 8).16
yield
entry
X
Y
R
product
(%)a
dr
1
2
3
4
5
6
7
8
9
H
MeO
CF3
F
H
H
H
H
Et
Et
Et
Et
Et
Et
tBu
Bn
iPr
2a
2b
2c
2d
2e
2f
86 (76)
52 (65)
63 (61)
70 (80)
64 (54)
63 (82)
73 (88)
73
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
O-CH2-O
H
H
H
H
Me
H
2g
2h
2i
H
H
72 (82)
a Yields in parentheses refer to reactions performed with TBAF
(1.2 equiv).
With these optimized reaction conditions in hand, we
turned to evaluate the scope of the transformation (Table 2).
The reaction showed broad scope with regard to the sub-
stitution on the aromatic ring as well as the ester group. In
all cases, despite the electronic character of the aromatic
ring or the steric bulk at the ester moiety the yields were
moderate to high and, remarkably, complete diastereocon-
trol was observed (Table 2).
(16) In an attempt to rationalize the performance of these uncommon
bases, we suggest that the bulky noncoordinating tetrabutyl ammonium
cation leads to a more reactive “metaloenamine” intermediate than the
corresponding metal cation which could be stabilized by the negatively
charged oxygen of the chiral sulfoxide group via a six-membered chelate.
(17) Liu, Z.-J.; Mei, Y.-Q.; Liu, J.-T. Tetrahedron 2006, 63, 855.
(18) For details, see Supporting Information.
6566
Org. Lett., Vol. 13, No. 24, 2011

At this stage, the hydrolysis of the chiral auxiliary af-
fords asymmetric 3-substituted indanones, a challenging
structural motif. This was achieved by using the conditions
reported by Liu et al. (Table 3).17 From this table, we can
conclude that, in most cases, epimerization does not take
place to a noticeable extent. The enantiomeric excesses ob-
tained (86À96% ee) are, in all cases, comparable to those
reported by Morehead3b and Hayashi.3c
to wet THF at À78 °C. Under these new conditions, only
one diastereoisomer was observed in the 1H NMR spec-
trum of the crude reaction (Scheme 4).20
δ-Amino acid derivative syn-4a21 can thus be stereo-
selectively achieved.22 Furthermore, the chiral auxiliary
has in turn been removed23 affording the free NH2
δ-amino ester syn-5a in 82% yield as the hydrochloride salt.
Scheme 4. Chemoselective Reduction Leading to δ-Amino Acid
Derivatives
Table 3. Removal of the Chiral Auxiliary
yield
(%)
ee
(%)a
entry
X
Y
product
1
2
3
4
5
H
MeO
CF3
F
H
H
H
H
3a
3b
3c
3d
3e
53
56
67
46
62
93
94
86
96
94
O-CH2-O
a Determined by HPLC on chiral stationary phase using a Chiralcel
OD-H column (see ref 18).
In conclusion, we have developed a new intramolecular
asymmetric Michael reaction of tert-butanesulfinyl keti-
mines for the diastereoselective synthesis of indanone de-
rivatives. The products have been obtained in good yields
and excellent diastereoselectivity. Remarkably, this trans-
formation is carried out more easily with nonobvious
bases such as CF3TMS/TBAT or TBAF. Indanones can
be obtained in high yields and optical purity by hydrolysis.
On the other hand, the diastereoselective reduction of the
sulfinime allows δ-amino acid derivatives to be afforded.
Further applications of this methodology are currently
being studied in our laboratories.
In order to expand the synthetical utility of our meth-
odology, we carried out the chemoselective reduction of
the imino group giving rise to δ-amino acid derivatives.19
Under the first conditions essayed (NaBH4, MeOH, 0 °C),
a modest 5:1 dr was achieved. This result could be sig-
nificantly improved by changing the reaction conditions
(19) For the use of δ-amino acids in the synthesis of β-turn containing
peptide hairpins, see: Rai, R.; Vasudev, P. G.; Ananda, K.; Raghothama,
S.; Shamala, N.; Karle, I. L.; Balaram, P. Chem.;Eur. J. 2007, 13, 5917.
(20) We also essayed the diastereodivergent reduction using L-selectride
as the reducing agent, but low yields (30%) and diastereoselectivities (5:1
dr) were achieved. The reversal diastereofacial selectivity in the reductions
of tert-butylsulfinilketimines by either NaBH4 or L-selectride has been
described: Colyer, J. T.; Andersen, N. G.; Tedrow, J. S.; Soukup, T. S.;
Faul, M. M. J. Org. Chem. 2006, 71, 6859.
(21) A cross-peak between the two methine protons in the NOESY
spectrum of 4a allowed assignment of the relative stereochemistry of the
new stereocenter. The stereochemical outcome is in agreement with the
chelated transition state suggested for reductions of tert-butanesulfinimides
with NaBH4 (see Supporting Information).
Acknowledgment. We would like to thank the Spanish
ꢀ
Ministerio de Ciencia e Innovacion (CTQ2010-19774) and
Generalitat Valenciana (PROMETEO/2010/061) for its
financial support. P.B. expresses his thanks for a Juan de la
Cierva contract, and E.R. thanks the Generalitat Valen
ciana for a predoctoral contract.
Supporting Information Available. Experimental pro-
cedures and NMR spectra for all new compounds, as well
as crystallographical data for compound 2a, including its
CIF file. This material is available free of charge via the
Internet at http://pubs.acs.org.
(22) For recent diastereoselective syntheses of δ-amino acids, see: (a)
Sunnemann, H. W.; Hofmeister, A.; Magull, J.; de Meijere, A. Chem.;
€
ꢀ
a, M.; Dıez, D.; Sanchez,
´ ´
Eur. J. 2006, 12, 8336. (b) Garrido, N. M.; Garcı
M. R.; Sanz, F.; Urones, J. G. Org. Lett. 2008, 10, 1687.
(23) Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997,
119, 9913.
Org. Lett., Vol. 13, No. 24, 2011
6567