Asymmetric synthesis of oxa-spirocyclic indanones with structural complexity via an organocatalytic Michael-Henry-acetalization cascade

Article abstract of DOI:10.1055/s-0033-1340077

The highly enantioselective preparation of drug-like oxa-spirocyclic indanone derivatives employing a multicomponent cascade reaction is described. This approach utilizes an organocatalytic Michael reaction followed by a Henry-acetalization sequence that yields the desired chiral spirocyclic backbone, bearing four contiguous stereogenic centers and multiple functional groups, in good yields and high stereoselectivities (up to 99% ee and 95:5 dr). Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1340077

LETTER
▌143
lAettserymmetric Synthesis of Oxa-spirocyclic Indanones with Structural Com-
plexity via an Organocatalytic Michael–Henry–Acetalization Cascade
Asymmetric Synthesis of Oxa-spirocyclic Indanones
Xin Xie,a Cheng Peng,*a,b Hai-Jun Leng,b Biao Wang,b Zheng-Wei Tang,a Wei Huang*a
a
State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources,
Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P. R. of China
Fax +86(28)61800231; E-mail: huangwei@cdutcm.edu.cn
b
School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P. R. of China
Fax +86(28)61800232; E-mail: pengchengchengdu@126.com
Received: 21.08.2013; Accepted after revision: 01.10.2013
clic indanediones.4 Furthermore, Marini’s group5 reported
an enantioselective one-pot synthesis of spiroindanones
bearing an all-carbon chiral center at the C2 position by
subjecting cyclic β-ketoesters and vinyl selenones to an
Abstract: The highly enantioselective preparation of drug-like
oxa-spirocyclic indanone derivatives employing a multicomponent
cascade reaction is described. This approach utilizes an organocat-
alytic Michael reaction followed by a Henry–acetalization sequence
that yields the desired chiral spirocyclic backbone, bearing four organo-catalyzed Michael–cyclization sequence. Subse-
contiguous stereogenic centers and multiple functional groups, in
good yields and high stereoselectivities (up to 99% ee and 95:5 dr).
quently, Ramachary et al. presented the asymmetric syn-
thesis of a spiroindane-1,3-dione skeleton incorporated
with cyclohexane through a reflexive Michael reaction.6
Key words: organocatalysis, chiral indanone, oxa-spirocycles, tan-
dem reactions, asymmetric synthesis
Although most efficient methods available in the litera-
ture have focused on the synthesis of diversely structured
spiroindanones bearing an all-carbon ring or nitrogen het-
Chiral indanone is a commonly occurring framework erocycle at the C2 position, the enantioselective prepara-
found in many natural products and pharmaceuticals.1 A tion of the corresponding oxa-spirocyclic indanones
range of biologically active compounds possessing this remains underdeveloped.7
privileged scaffold are well documented.2 For instance,
O
tripartin, a new dichlorinated indanone found in actino-
O
HO
mycete bacteria, displays a potent and specific histone de-
methylase inhibiting effect.2a The natural indanone
products, pterosin C and paucifloral F, were isolated from
the aerial parts of Acrostichum aureum2b and the stem
barks of Vatica pauciflora,2c respectively. The recent dis-
covery of spiroindanone-based hybrid molecule and its
analogues, which are able to decrease the intracellular lev-
el of Bcl-2 protein in leukemia cells,2d makes them poten-
tial leads for development as new anticancer agents
(Figure 1). However, most biological studies of indanone
and its congeners have concentrated on plant models.
Consequently, relatively little is known about the poten-
tial benefits of these molecules to human health. Thus, op-
tically active indanone analogues, particularly
spiroindanone derivatives, have emerged as important
synthetic targets due to their diverse architectures and po-
tential medicinal utility.
HO
Cl
HO
OH
tripartin
OH
O
Cl
pterosin C
O
Ph
O
HO
OH
O
OH
OH
IC50 = 6 μm (HL60 cells)
IC50 = 8 μm (K562 cells)
HO
paucifloral F
OH
anticancer agent
Figure 1 Selected examples of biologically active indanones
The development of multicomponent organocatalytic tan-
dem reactions for introducing multi-chiral centers has
been hotly pursued.8 A chiral γ-nitro aldehyde, easily pre-
pared from the asymmetric direct Michael reaction of an
aldehyde and a nitroalkene,9 has been utilized successful-
ly in subsequent domino transformations with enal,10
imine11 or saturated aldehyde12 substrates for the synthesis
of enantio-enriched monocyclic compounds. Neverthe-
less, very few examples demonstrate the analogous appli-
cation with a ketone for the synthesis of a chiral spiro
skeleton.
In 2008, the groups of Yavari and Nair independently em-
ployed quinoline, dialkyl acetylenedicarboxylates and
1,3-indanedione to access spirocyclic molecules compris-
ing of indanone and tetrahydropyrrolo[1,2-a]quinoline.3
In the same year, Li and co-workers described a tandem
Knoevenagel–1,3-dipolar cycloaddition cascade for a
four-component synthesis of five-membered aza-spirocy-
SYNLETT 2014, 25, 0143–0147
Advanced online publication: 12.11.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340077; Art ID: ST-2013-W0805-L
© Georg Thieme Verlag Stuttgart · New York

144
X. Xie et al.
LETTER
As part of our ongoing investigations aimed at stereose-
lectively assembling multiple substrates into synthetically
important cyclic molecules,13 we envisaged a three-step
organocatalytic relay cascade for the asymmetric synthe-
sis of the oxa-spiroindanone scaffold. Mechanistically,
the new protocol (Scheme 1) consists of an initial second-
ary amine catalyzed Michael addition of aldehyde 1 to the
nitroalkene 2. The resulting intermediate 4 would then be
poised to participate directly in the second catalytic cycle
by serving as the donor in a base-promoted Henry reaction
with the ninhydrin 5. Subsequent cyclization via an intra-
molecular acetalization of the carbonyl and hydroxy
group of the tertiary alcohol intermediate forms the de-
sired spiro-hemiacetal 6. Herein, we report the results of
our experiments performed to demonstrate this domino
reaction as an efficient method for the preparation of chi-
ral oxa-spirocyclic indanones.
O
R1
CHO
NO2
O
N
OH
OH
H
+
+
O2N
R1
R2
O
R2
3
O
1
2
Michael
4
5
O
O
OH
R2
O
alkaline
medium
OH
R1
acetalization
R1
Henry
R2
O
O
NO2
NO2
6
Scheme 1 Reaction design: the asymmetric synthesis of the oxa-spi-
roindanone scaffold through [2+2+2] cycloaddition
nitrile at room temperature for three hours. An acetonitrile
solution of ninhydrin (5) and triethylamine was added, re-
sulting in successive Henry and acetalization reactions.
To our gratification, the domino reaction proceeded
smoothly to afford the desired product 6a. Direct oxida-
tion of the hemiacetal with pyridinium chlorochromate
(PCC) gave the corresponding more stable spirocyclic
δ-lactone 7a in moderate yield and with good stereoselec-
We selected propanal (1a), nitrostyrene (2a) and ninhy-
drin (5) as the model substrates to examine the feasibility
of the designed process. The first Michael reaction pro-
ceeded in the presence of catalyst 3a (10 mol%) in aceto-
Table 1 Optimization of the Catalytic Asymmetric Synthesis of Oxa-spirocyclic Indanone 7aa
O
Ar
O
O
O
O
OH
Ph
OH
Ph
OH
OH
O
O
O
O
Ar
O
O
O
PCC
N
OR
H
+
NO2
3
O
5
+
AcOH, solvent
base, solvent
Ph
NO2
NO2
NO2
1a
7a
Ph
6a'
6a
spirocyclic
δ-lactone
2a
3a R = TMS, Ar = Ph
3b R = TES, Ar = Ph
3c R = TMS, Ar = 3,5-(F3C)2C6H3
3d R = TMS, Ar = 3,5-(t-Bu)2C6H3
base-promoted
stereoconversion
Entry
Catalyst
Solvent
Base
Yield (%)b
drc
ee (%)d
1
2
3a
3b
3c
3d
3a
3a
3a
3a
3a
3a
3a
MeCN
MeCN
MeCN
MeCN
CH2Cl2
THF
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
41
35
25
30
43
30
63
54
48
70
43
78:22
80:20
78:22
85:15
80:20
75:25
82:18
75:25
80:20
92:8
91
93
93
94
92
90
94
92
92
93
90
3
4
5
6
7
toluene
toluene
toluene
toluene
toluene
e
8
K2CO3
9
NaOHe
DBU
10
11
DBUf
90:10
a Reactions were performed with 1a (0.4 mmol), 2a (0.30 mmol), 3 (10 mol%) and AcOH in solvent (2 mL) at r.t. for 3 h, after which 5 (0.2
mmol) and base (0.6 mmol) were added.
b Yield of isolated pure diastereomer 7a.
c Calculated from the yield of isolated 7a and its diastereomer.
d Determined by chiral HPLC analysis.
e H2O (0.4 mL) and TBAB (0.05 mmol) were added.
f At 50 °C for 1 h.
Synlett 2014, 25, 143–147
© Georg Thieme Verlag Stuttgart · New York

LETTER
Asymmetric Synthesis of Oxa-spirocyclic Indanones
145
tivity (Table 1, entry 1). Subsequently, several chiral sec- raising the temperature, but a lower yield was obtained
ondary amine catalysts were tested. The triethylsilyloxy (Table 1, entry 11).
(O-TES) ether 3b provided an equally good enantiomeric
excess, but without any improvement in the reactivity
With optimized reaction conditions in hand, we next eval-
uated the generality of this methodology.14 As illustrated
(Table 1, entry 2). High enantiocontrol was also achieved
in Scheme 2, the reaction showed excellent functional
when catalyst 3c containing electron-withdrawing substit-
group tolerance, and the respective polyfunctionalized
oxa-spirocyclic products were obtained in moderate to
uents, or 3d possessing bulkier groups were applied, but
slower reaction rates were observed (Table 1, entries 3
good yields (up to 72% yield), with high enantio- and di-
and 4). With optimum catalyst 3a identified, we continued
astereoselectivities (up to 99% ee and 95:5 dr). For exam-
ple, incorporation of one or two substituents on the
aromatic ring of nitroalkene 2 had little effect on the effi-
ciency and stereochemical outcome of this cyclization
to screen solvents and other reaction parameters. It was
found that the reaction medium had little influence on the
reaction efficiency (Table 1, entries 5–7), and toluene
proved to be the best choice. Importantly, further investi-
reaction. Moreover, both electron-withdrawing and elec-
gation revealed that a strong base was a crucial factor for
tron-donating groups at ortho, meta, or para positions in
substrates 2 were tolerated, affording the expected domi-
no adducts 7b–g. Nitroolefins bearing β-heteroaromatic
or alkyl groups could also be used to give the target prod-
improving the diastereoselectivity (Table 1, entries 8–10).
We propose that the 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) promoted deprotonation of the diastereoisomer
6a′, and selective reprotonation of the resulting carbanion
ucts 7h–j, albeit with slightly lower yields and diastereo-
by chiral induction to furnish 6a could be responsible for
meric ratios. With respect to the nucleophilic aldehyde,
both linear n-butanal and n-pentanal were shown to be
compatible under our standard conditions (7k and 7l) in
the stereoconversion and high diastereomeric ratio (Table
1, entry 10). Good diastereocontrol was also realized on
O
O
O
O
1) cat. 3a
AcOH
O
2) DBU
toluene
NO2
O
OH
OH
+
+
R1
toluene
r.t., 3 h
R1
R2
3) PCC
R2
1
2
O
5
NO2
O
7
O
O
O
O
O
O
O
O
O
O
O
NO2
NO2
NO2
F
7b, 72%
99% ee, 95:5 dr
Cl
Br
7c, 67%
98% ee, 91:9 dr
7d, 68%
97% ee, 90:10 dr
O
O
O
O
O
O
O
O
O
OMe
OMe
O
O
O
NO2
NO2
NO2
7f, 58%
99% ee, 96:4 dr
7g, 60%
97% ee, 92:8 dr
i-Pr
7e, 65%
98% ee, 95:5 dr
OMe
O
O
O
O
O
O
O
O
O
S
O
O
O
O
NO2
NO2
NO2
7i, 50%
97% ee, 88:12 dr
7j, 42%
95% ee, 84:16 dr
7h, 52%
95% ee, 90:10 dr
O
O
O
O
O
O
O
O
O
Ph
Ph
Ph
O
O
O
NO2
NO2
NO2
7k, 65%
99% ee, 94:6 dr
7l, 60%
99% ee, 95:5 dr
7m, 45%
99% ee, 92:8 dr
Scheme 2 Investigation of the scope of the cascade reaction using the optimized conditions (see entry 10 and footnote a in Table 1). Yields
are those of isolated pure diastereomers 7; enantiomeric excesses were determined by chiral HPLC analysis; diastereomeric ratios were calcu-
lated from the yields of isolated compounds 7 and their diastereomers
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 143–147

146
X. Xie et al.
LETTER
addition to propanal. We also evaluated the use of the The iodine-mediated cyclization reaction17 of 6m deliv-
branched α,β-unsaturated aldehyde, 4-methylpent-2-enal ered the highly substituted hexahydrofuro[2,3-b]pyran
via α-selective dienamine catalysis,15 which led to the for- 1118 with excellent stereocontrol.
mation of the desired allyl-substituted spiro-indanone 7m
in a somewhat lower yield, but still with good levels of
O
O
OH
BF3⋅OEt2
O
O
stereocontrol. The absolute configuration of 7b was deter-
mined to be 10S,11S,12R by X-ray crystallographic anal-
ysis (Figure 2).16 The absolute configurations of the other
products were tentatively assigned by analogy.
Et3SiH
CH2Cl2, –20 °C
Ph
Ph
O
O
O
NO2
NO2
10, 85% yield
97% ee, 95:5 dr
6a
OH
H
O
O
I2, KI
NaHCO3
O
O
I
MeCN, r.t.
H
Ph
Ph
O
NO2
O
NO2
6m
11, 80% yield
97% ee, 91:9 dr
Scheme 4 Synthetic transformations to access different and valuable
oxa-spirocyclic scaffolds
Figure 2 ORTEP drwaing of compound 7b
In conclusion, we have successfully developed an organo-
catalytic cascade reaction involving a Michael–Henry–
acetalization relay for the asymmetric assembly of alde-
hydes, nitroolefins and ninhydrin into six-membered oxa-
spirocyclic indanones with structural and stereochemical
complexity. The mild reaction conditions, short reaction
times, and high tolerance of various functional groups
makes this strategy an attractive method for the construc-
tion of enantio-enriched architectures. Currently, studies
toward the application of this methodology for the synthe-
sis of pharmaceutically important drug leads are ongoing.
To further probe the usefulness of this organocatalytic
domino reaction in diversity-oriented synthesis, other cy-
clic activated carbonyl substrates were screened (Scheme
3). We were pleased to find that the synthetically useful
substrates, acenaphthenequinone and alloxan reacted
smoothly under our experimental conditions to provide
the corresponding cycloaddition products 8 and 9 in good
yields and with excellent enantioselectivities.
O
O
Ph
NO2
O
O
O
∗
All chemicals were used from Adamas-beta without purification
unless otherwise noted. NMR data was obtained for 1H at 400 MHz,
and for 13C at 100 MHz. Chemical shifts were reported in ppm from
tetramethylsilane with the solvent resonance as the internal standard
in CDCl3 solution. ESI HRMS was recorded on a Waters SYNAPT
G2.
acenaphthene-
quinone
8, 1:1 dr, 65% total yield,
99% ee (each diastereomer)
CHO
Ph
1a and 2a
O
OH
OH
General Procedure for the Synthesis of Compounds 7a-m
The reaction was carried out with aldehyde 1 (0.4 mmol) and ni-
troolefin 2 (0.3 mmol) in the presence of catalyst 3a (0.04 mmol)
and AcOH (0.04 mmol) in toluene (2.0 mL) at r.t. for 3 h to afford
the Michael adduct 4. When the reaction was complete, the toluene
solution of ninhydrin 5 (0.2 mmol) and DBU (0.6 mmol) was added
in one pot. The reaction mixture was stirred at r.t. for the specified
reaction time until the reaction was complete (monitored by TLC).
Then the reaction mixture was concentrated and the residue was pu-
rified by flash chromatography on silica gel (PE–EtOAc, 10:1) to
give hemiacetal 6. To a solution of 6 in CH2Cl2 (2 mL) was added
PCC (0.5 mmol). The mixture was stirred for 2 h at 50 °C. The solid
was removed by filtration through Celite. The filtrate was evaporat-
O
O
HN
OH
NO2
O
N
O
HN
H
Ph
NO2
alloxan
O
N
O
H
9, stable hemiacetal
69% yield, 99% ee, 94:6 dr
Scheme 3 Organocatalytic domino reactions with other activated
carbonyl compounds
More importantly, these oxa-spirocyclic compounds can
be easily converted into other important and valuable ed under reduced pressure and the residual was purified by column
chromatography (PE–EtOAc, 20:1) to give spiroindanone δ-lactone
7.
building blocks. As shown in Scheme 4, the hemiaminal
6a was dehydroxylated by treatment with triethylsilane
and boron trifluoride–diethyl etherate, using dichloro-
methane as the solvent at –20 °C, to provide the chiral spi- 7a was obtained as a white solid in 70% yield for two steps after
rocyclic tetrahydropyran 10. Intriguingly, although the
allylic product 6m has a crowded structure, the multiple
functionalities allow simple transformation to access nat-
ural product mimics with greater molecular complexity.
Typical Analytical Data
flash chromatography and the enantiomeric excess was determined
to be 93% by HPLC on Chiralpak OD-H column (30% 2-PrOH–
n-hexane,
1 mL/min), UV 254 nm, tR(minor) = 11.05 min,
20
t
R(major) = 12.11 min. Mp 167–168 °C; [α]D –129.4 (c = 0.12 in
1
CH2Cl2). H NMR (400 MHz, CDCl3): δ = 8.12–8.05 (m, 2 H),
Synlett 2014, 25, 143–147
© Georg Thieme Verlag Stuttgart · New York

LETTER
Asymmetric Synthesis of Oxa-spirocyclic Indanones
147
8.01–7.94 (m, 2 H), 7.40–7.34 (m, 3 H), 7.27–7.26 (m, 2 H), 5.64
(d, J = 12.4 Hz, 1 H), 4.16 (t, J = 12.0 Hz, 1 H), 3.10–3.02 (m, 1 H),
1.39 (d, J = 6.8 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 192.31,
190.03, 169.62, 141.15, 140.18, 138.00, 137.48, 135.43, 129.51,
129.05, 127.77, 124.99, 124.72, 87.28, 46.58, 41.42, 14.74. HRMS
(ESI): calcd for C20H15NO6+Na: 388.0797; found: 388.0795.
Runsink, J.; Raabe, G.; Wendt, B. Angew. Chem. Int. Ed.
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Acknowledgment
This work was supported by the Specialized Research Fund for the
Doctoral Program of Higher Education (20125132120005), the Ap-
plication Foundation of the Science and Technology Department of
Sichuan Province (2011JZY037), and the National Science Founda-
tion of China (81303208).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
(14) Compounds 7a–m; General Procedure
The reaction was carried out with aldehyde 1 (0.4 mmol) and
nitroolefin 2 (0.3 mmol) in the presence of catalyst 3a (0.04
mmol) and AcOH (0.04 mmol) in toluene (2.0 mL) at r.t. for
3 h to afford the Michael adduct 4. When the reaction was
complete, a solution of ninhydrin (5) (0.2 mmol) and DBU
(0.6 mmol) in toluene (2.0 mL) was added. The mixture was
stirred at r.t. for the requisite amount of time until the
reaction was complete (monitored by TLC). The mixture
was concentrated and the residue purified by flash
chromatography on silica gel (PE–EtOAc, 10:1) to give
hemiacetal 6. To a solution of 6 in CH2Cl2 (2 mL) was added
PCC (0.5 mmol) and the mixture stirred for 2 h at 50 °C. The
solid was removed by filtration through Celite. The filtrate
was evaporated under reduced pressure and the residue
purified by column chromatography (PE–EtOAc, 20:1) to
give spiroindanone δ-lactone 7.
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Alexakis, A. Chem. Commun. 2007, 3123. (g) Tsogoeva, S.
B. Eur. J. Org. Chem. 2007, 1701.
Oxa-spirocyclic indanone 7a was obtained as a white solid
in 70% yield over the two steps after flash chromatography.
The enantiomeric excess was determined to be 93% by
HPLC on a Chiralpak OD-H column (i-PrOH–n-hexane,
3:7, 1 mL/min); UV (254 nm), tminor = 11.05 min,
tmajor = 12.11 min; mp 167–168 °C; [α]D20 –129.4 (c 0.12,
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 8.12–8.05 (m, 2
H), 8.01–7.94 (m, 2 H), 7.40–7.34 (m, 3 H), 7.27–7.26 (m, 2
H), 5.64 (d, J = 12.4 Hz, 1 H), 4.16 (t, J = 12.0 Hz, 1 H),
3.10–3.02 (m, 1 H), 1.39 (d, J = 6.8 Hz, 3 H). 13C NMR (100
MHz, CDCl3): δ = 192.31, 190.03, 169.62, 141.15, 140.18,
138.00, 137.48, 135.43, 129.51, 129.05, 127.77, 124.99,
124.72, 87.28, 46.58, 41.42, 14.74. HRMS (ESI): m/z [M +
H]+ calcd for C20H15NO6Na: 388.0797; found: 388.0795.
(15) For a comprehensive review on dienamine catalysis, see:
Ramachary, D. B.; Reddy, Y. V. Eur. J. Org. Chem. 2012,
865.
(16) CCDC 919807 contains the supplementary crystallographic
data for the structure in this paper. The data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
(17) Bedford, S. B.; Bell, K. E.; Bennett, F.; Hayes, C. J.; Knight,
D. W.; Shaw, D. E. J. Chem. Soc., Perkin Trans. 1 1999,
2143.
(18) The hexahydrofuro[2,3-b]pyran derivativesare synthetically
useful building blocks. For selected examples, see:
(a) Drewes, S. E.; Horn, M. M.; Munro, O. Q.; Ramesar, N.;
Ochse, M.; Bringmann, G.; Peters, K.; Peters, E.-M.
Phytochemistry 1999, 50, 387. (b) Chen, X.-Z.; Wu, H.-F.;
Li, G.-Y.; Lu, S.-M.; Li, B.-G.; Fang, D.-M.; Zhang, G.-L.
Helv. Chim. Acta 2008, 91, 1072.
(10) (a) Enders, D.; Hüttl, M. R. M.; Grondal, C.; Raabe, G.
Nature 2006, 441, 861. (b) Enders, D.; Hüttl, M. R. M.;
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Synlett 2014, 25, 143–147

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