NHC-catalyzed spiro bis-indane formation via domino stetter - Aldol - Michael and stetter - Aldol - Aldol reactions

Article abstract of DOI:10.1021/ol102685u

Two novel domino NHC-catalyzed spirocyclizations are described herein, enabling the rapid construction of three new carbon - carbon bonds and a quaternary center with high diastereoselectivity. A variety of spiro bis-indane structures are assembled in a single step from simple o-phthaldialdehyde derivatives.

Full text of DOI:10.1021/ol102685u

ORGANIC
LETTERS
2010
Vol. 12, No. 24
5772-5775
NHC-Catalyzed Spiro Bis-Indane
Formation via Domino
Stetter-Aldol-Michael and
Stetter-Aldol-Aldol Reactions
Eduardo Sa´nchez-Larios, Janice M. Holmes, Crystal L. Daschner, and
Michel Gravel*
Department of Chemistry, UniVersity of Saskatchewan, 110 Science Place,
Saskatoon, SK S7N 5C9, Canada
michel.graVel@usask.ca
Received November 10, 2010
ABSTRACT
Two novel domino NHC-catalyzed spirocyclizations are described herein, enabling the rapid construction of three new carbon-carbon bonds
and a quaternary center with high diastereoselectivity. A variety of spiro bis-indane structures are assembled in a single step from simple
o-phthaldialdehyde derivatives.
Carbocyclic spiro motifs are found in a wide variety of
natural products. Fredericamycin A (1)1 and acutumine (2)2
(Figure 1) are representatives of this large family of
compounds which have attracted significant attention due to
their biological properties and structural complexity. Non-
natural carbocyclic spiro compounds have also been studied
for their medicinal properties, as exemplified by the potent
estrogen receptor ligand 3.3 In this context, a number of
Figure 1. Examples of compounds containing a carbocyclic spiro
motif.
synthetic methods have been devised for the synthesis of
(1) Pandey, R. C.; Toussaint, M. W.; Stroshane, R. M.; Kalita, C. C.;
Aszalos, A. A.; Garretson, A. L.; Wei, T. T.; Byrne, K. M.; Geoghegan,
R. F.; White, R. J. J. Antibiot. 1981, 34, 1389.
this structural motif.4 The formation of carbocyclic spiro
compounds typically relies on the sequential construction of
each ring in a stepwise fashion, although a more efficient
approach involves simultaneous formation of both rings in
a single operation. In this paper, we report such an approach
(2) (a) Goto, K.; Sudzuki, H. Bull. Chem. Soc. Jpn. 1929, 4, 220. (b)
Tomita, M.; Okamoto, Y.; Kikuchi, T.; Osaki, K.; Nishikawa, M.; Kamiya,
K.; Sasaki, Y.; Matoba, K.; Goto, K. Tetrahedron Lett. 1967, 8, 2421. (c)
Tomita, M.; Okamoto, Y.; Kikuchi, T.; Osaki, K.; Nishikawa, M.; Kamiya,
K.; Sasaki, Y.; Matoba, K.; Goto, K. Tetrahedron Lett. 1967, 8, 2425. (d)
Tomita, M.; Okamoto, Y.; Kikuchi, T.; Osaki, K.; Nishikawa, M.; Kamiya,
K.; Sasaki, Y.; Matoba, K.; Goto, K. Chem. Pharm. Bull. 1971, 19, 770.
(3) Blizzard, T. A.; Morgan, J. D.; Mosley, R. T.; Birzin, E. T.; Frisch,
K.; Rohrer, S. P.; Hammond, M. L. Bioorg. Med. Chem. Lett. 2003, 13,
479.
(4) For reviews, see: (a) Krapcho, A. P. Synthesis 1974, 383. (b)
Krapcho, A. P. Synthesis 1976, 425. (c) Krapcho, A. P. Synthesis 1978, 77.
(d) Sannigrahi, M. Tetrahedron 1999, 55, 9007. (e) Kotha, S.; Deb, A. C.;
Lahiri, K.; Manivannan, E. Synthesis 2009, 165.
10.1021/ol102685u  2010 American Chemical Society
Published on Web 11/22/2010

in which both rings and three new carbon-carbon bonds
are formed in one synthetic operation.
We have recently reported the first example of a domino
reaction5 making use of the enolate intermediate formed in
a Stetter reaction (Scheme 1a).6,7 In that case, the initial
conditions (see Supporting Information), the desired spiro
bis-indane 6a was obtained in good yield and excellent
diastereoselectivity (Table 1, entry 1). Prolonged exposure
Table 1. Domino Stetter-Aldol-Michael (SAM) Reaction
Scheme 1. Domino Stetter Reactions
t
yield
entry
R1
R2
(min) producta (%)b
drc
1
2
3
4
5d
6
7
8
9
H
H
H
4-F
4-F
Ph
15
5
45
5
15
9
5
6a
6b
6c
6d
6e
6f
6g
6h
6i
79
86
68
64
80
85
81
75
31e
17:1
12:1
>20:1
11:1
16:1
>20:1
10:1
7:1
4-Cl(C6H5)
4-MeO(C6H5)
Ph
4-Cl(C6H5)
3-MeO Ph
3-MeO 4-Cl(C6H5)
H
H
Me
SEt
195
120
13:1
a The relative configuration was determined by X-ray crystallography
(see Supporting Information). b Combined yield of pure isolated product
diastereomers. Determined from H NMR analysis of the crude reaction
mixture. d Concentration of the reaction ) 0.1 M. e The corresponding
alcohol intermediate (see 7, Scheme 3) was also isolated in 14% yield.
c
1
Stetter reaction was followed by an intramolecular conjugate
addition step leading to indane frameworks. Subsequently,
Ye and co-workers disclosed a cascade Stetter-aldol reaction
providing access to 4-hydroxytetralones from vinyl ketones
and phthaldialdehyde (Scheme 1b).8,9 We now document
remarkable domino Stetter-aldol-Michael (SAM) and
Stetter-aldol-aldol (SAA) reactions giving access to spiro
bis-indanes from readily available o-formyl chalcone deriva-
tives (Scheme 1c). The usefulness of this methodology is
demonstrated by the preparation of analogs of the spiro bis-
indane dione core of fredericamycin A.
to the reaction conditions or use of larger amounts of base
led to reduced diastereomeric ratios (not shown). The
presence of electron-withdrawing or -donating groups on the
ketone portion of the o-formyl chalcone derivatives 5b and
5c allowed the fine-tuning of their reactivity. Thus, the
4-chlorophenyl substituent in 5b resulted in an increase in
the rate of the reaction at the expense of the diastereoselec-
tivity (entry 2), whereas the reactivity of 4-methoxyphenyl-
substituted 5c was reduced while higher diastereocontrol was
achieved (entry 3).
Consistent with earlier observations that electron-poor
aldehydes provide faster rates in the Stetter reaction,6 p-fluoro
or m-methoxy groups relative to the aldehyde resulted in
enhanced reactivity (entries 4-7). Interestingly, the presence
of the methoxy group in substrates 5f and 5g did not prevent
the Stetter or the Michael addition steps (Scheme 3). Methyl
ketone 5h showed a slower reaction rate compared to
aromatic ketones (entry 8). The reduced diastereomeric ratio
in this case likely reflects the thermodynamic equilibrium
(Vide infra). Although unsaturated esters did not provide the
SAM product, thioesters could be employed to generate the
desired product 6i in moderate yield and high diastereose-
lectivity (entry 9).
The modulating effect of the various substituents on the
aromatic ring also allows the selective formation of cross-
SAM products in moderate yield (i.e., a nonstatistical
distribution of products). Indeed, spiro bis-indane 6j was
obtained as the major spiro bis-indane product (out of a
possible four) in the SAM reaction of 5f and 5j (Scheme 2).
The methoxy group at C3 of 5f increases the electrophilicity
of the formyl group making it more prone to react with the
catalyst, while it lowers the reactivity of the Stetter acceptor
moiety. On the other hand, the methoxy group at C4 of 5j
At the outset of our studies, we investigated the domino
SAM process employing 5a as a model substrate and
catalytic amounts of various N-heterocyclic carbene (NHC)
catalysts.10 Following a brief optimization of the reaction
(5) For reviews on domino reactions, see: (a) Tietze, L. F. Chem. ReV.
1996, 96, 115. (b) Fogg, D. E.; dos Santos, E. N. Coord. Chem. ReV. 2004,
248, 2365. (c) Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in
Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2006. (d) Chapman,
C. J.; Frost, C. G. Synthesis 2007, 1. (e) Enders, D.; Grondal, C.; Hu¨ttl,
M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570.
(6) Sa´nchez-Larios, E.; Gravel, M. J. Org. Chem. 2009, 74, 7536
(7) (a) Stetter, H.; Schreckenberg, M. Angew. Chem., Int. Ed. Engl. 1973,
12, 81. (b) Stetter, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 639. (c) Stetter,
.
H.; Kuhlmann, H. Org. React. 1991, 40, 407
.
(8) Sun, F.-G.; Huang, X.-L.; Ye, S. J. Org. Chem. 2010, 75, 273
.
(9) For other domino or one-pot sequences involving a Stetter reaction,
see: (a) Nemoto, T.; Fukuda, T.; Hamada, Y. Tetrahedron Lett. 2006, 47,
4365. (b) Mattson, A. E.; Bharadwaj, A. R.; Zuhl, A. M.; Scheidt, K. A. J.
Org. Chem. 2006, 71, 5715–5724. (c) He, J.; Tang, S.; Liu, J.; Su, Y.; Pan,
X.; She, X. Tetrahedron 2008, 64, 8797. (d) Li, Y.; Shi, F.-Q.; He, Q.-L.;
You, S.-L. Org, Lett. 2009, 11, 3182. (e) Biju, A. T.; Wurz, N. E.; Glorius,
F. J. Am. Chem. Soc. 2010, 132, 5970. (f) Filloux, C. M.; Lathrop, S. P.;
Rovis, T. Proc. Natl. Acad. Sci. U.S.A. 2010, early edition July 16, 2010,
(doi:10.1073/pnas.1002830107).
(10) For reviews on NHC catalysis, see: (a) Enders, A.; Balensiefer, T.
Acc. Chem. Res. 2004, 37, 534. (b) Berkessel, A.; Gro¨ger, H. Asymmetric
Organocatalysis; Wiley-VCH: Weinheim, 2005. (c) Zeitler, K. Angew.
Chem., Int. Ed. 2005, 44, 7506. (d) Enders, D.; Niemeier, O.; Henseler, A.
Chem. ReV. 2007, 107, 5606. (e) Marion, N.; Diez-Gonzalez, S.; Nolan,
I. P. Angew. Chem., Int. Ed. 2007, 46, 2988. (f) Moore, J. L.; Rovis, T.
Top. Curr. Chem. 2010, 291, 77.
Org. Lett., Vol. 12, No. 24, 2010
5773

Scheme 2
.
NHC-Catalyzed Cross-SAM
Scheme 3. Proposed Mechanistic Pathway for the
NHC-Catalyzed Stetter-Aldol-Michael Reaction
increases the electrophilicity of the Stetter acceptor moiety,
while decreasing the reactivity of the aldehyde. Thus, spiro
bis-indane 6j was selectively obtained by tuning the elec-
tronic properties on the donor (5f) and acceptor (5j)
substrates.11
On the basis of previous domino NHC-catalyzed reac-
tions,6,8 we postulate that the Breslow intermediate I12
participates in a Stetter reaction to form enolate intermediate
II. This enolate undergoes an aldol reaction prior to the
release of the NHC as proposed by Ye et al.8 Subsequently,
ꢀ-hydroxy ketone IV is deprotonated to form enolate
intermediate V which cyclizes to spiro bis-indane 7. Forma-
tion of intermediates III and 7 probably occurs through
highly diastereoselective aldol and Michael reactions since
a single diastereomer of intermediate 7a (R ) Ph) was
isolated in 40% yield (Scheme 3a, structure determined by
X-ray analysis; see Supporting Information). During the
Michael addition step, the acceptor approaches the less
hindered Re face of the favored Z-enolate. The observed
selectivity could be explained by a hydrogen bond between
the carbonyl and the initially formed alcohol, exposing the
Si face of the enone and activating it toward enolate attack
(Scheme 3b). Dehydration of this intermediate affords the
final spiro bis-indane product VI. It was also found that when
product 6a was subjected to prolonged basic conditions
(DBU), a thermodynamic ratio of 7:1 was obtained. This
equilibrium ratio, which is presumably reached through a
retro-Michael-Michael isomerization, supports the notion
that the diastereomer ratios obtained in Table 1 are the result
of kinetic control.
Table 2. Domino Stetter-Aldol-Aldol (SAA) Reaction
We reasoned that the SAM methodology could be further
exploited in an analogous Stetter-aldol-aldol (SAA) pro-
cess. Specifically, a 1,2-dialdehyde substrate would have one
formyl group involved in the initial Stetter reaction, and the
other one would serve as the electrophile in the second ring
closure. We decided to test this proposed domino SAA
reaction starting with phthaldialdehyde 8a. Gratifyingly,
when 8a and the acceptor 5a were reacted employing
thiazolium 4 as a precatalyst, the desired spiro bis-indane
9a was obtained in excellent yield as a ca. 1:1 mixture of
diastereomers (Table 2, entry 1).13,14 Nevertheless, this lack
of diastereocontrol was inconsequential for the purpose of
entry
R1
R2
R3
t(min)a product yield(%)b
1c
2
3
4
5
6
7
8
H
H
H
MeO
H
F
H
H
H
H
H
H
H
20
30
60
35
5
9ad
10b
10c
10d
9ed
10f
71
58
25
42
72
50
36
75
4-Cl
4-MeO
H
4-F
4-F
H
4-Cl
H
60
100
15
3-MeO
4-MeO 4-Cl
10g
10h
a Reaction time for the Stetter-aldol-aldol (SAA) step. b Yield of pure
isolated product. c Reaction performed on a gram scale. d Each diastereomer
of products 9a and 9e was isolated prior to the oxidation step.
(11) Various other spiro bis-indanes were formed in minor amounts,
with the most important one present in a ca. 1:6 ratio relative to 6j. The
yield for 6j is 40% of pure, isolated product and 10% present in impure
fractions following column chromatography.
making spiro bis-indane diketones related to fredericamycin
A. Indeed, IBX oxidation of the crude reaction mixture
provided a single triketone (10a) whose purification by silica
gel chromatography was further facilitated. Whereas the use
of electron-withdrawing aromatic groups on the ketone
(12) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719.
(13) The product probably undergoes a facile retro-aldol reaction under
these conditions, leading to a thermodynamic equilibrium.
(14) The use of a lower catalyst loading did not provide a satisfactory
yield of 9a.
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Org. Lett., Vol. 12, No. 24, 2010

portion of the acceptor was tolerated, employing electron-
donating groups resulted in markedly decreased yields
(entries 2 and 3). Interestingly, the use of methoxy-substituted
phthaldialdehyde derivative 8b provided the SAA product
as a single regioisomer prior to its oxidation to the triketone
(entry 4). When a fluoro substituent was introduced on the
acceptor (5d), the reaction proceeded smoothly and in high
yield (entry 5). Surprisingly, the presence of an electron-
withdrawing group on the phthaldialdehyde 8c considerably
reduced the rate while still affording the product in good
yield (entry 6). As expected, the presence of an electron-
donating group at C3 of the Stetter acceptor resulted in a
sluggish reaction and a low yield (entry 7). Conversely, when
the methoxy substituent was installed on C4 of the Stetter
acceptor 5j, its inductive effect increased the rate of the
reaction (entry 8). Finally, it should be noted that the domino
SAA reaction can be performed on a gram scale without a
detrimental effect on the yield (entry 1).
transformed into the triketone 11 in high yield. To our
delight, 11 underwent a completely site-selective and regi-
oselective Baeyer-Villiger oxidation using Emmons’ pro-
tocol.15 Hydrolysis of the resulting ester 12 gave the corre-
sponding carboxylic acid 13 which was converted into N-
benzylamide 14 via standard amidation conditions.
In conclusion, we described new NHC-catalyzed domino
Stetter-aldol-Michael (SAM) and Stetter-aldol-aldol
(SAA) reactions featuring the formation of two rings, three
new carbon-carbon bonds, and a quaternary center. This
new methodology was applied to the synthesis of simplified
fredericamycin A analogs.
Acknowledgment. This work is dedicated to the memory
of Michael M. Pollard. We thank the Natural Sciences and
Engineering Research Council (NSERC) of Canada (Dis-
covery Grant to M.G. and Postgraduate Scholarship to
J.M.H.), the Canada Foundation for Innovation, and the
University of Saskatchewan for financial support and Dr.
Gabriel Schatte (University of Saskatchewan) for X-ray
crystallographic analysis.
Scheme 4. Derivatization of 9a
Supporting Information Available: Detailed experimen-
tal procedures, 1H and 13C NMR spectra for all new
compounds, ORTEP representations and CIF files for 6d, 7,
and 9a.16 This material is free of charge via the Internet at
http://pubs.acs.org.
OL102685U
(15) (a) Emmons, W. D.; Lucas, G. B. J. Am. Chem. Soc. 1955, 77,
2287. (b) Baeyer, A.; Villiger, V. Ber. 1899, 32, 3625. (c) Subashini, M.;
Balasubramanian, K. K.; Bhagavathy, S. Synth. Commun. 2008, 38, 3088.
(16) Crystallographic data for compounds 6d, 7, and 9a have been
deposited with the Cambridge Crystallographic Data Centre (deposition
numbers CCDC 800683, 800684, 800685). Copies of the data can be
obtained, free of charge, on application to the director, CCDC 12 Union
Road, Cambridge CB2 1EZ, U.K. (fax:+44 1223 336033 or email:
deposit@ccdc.cam.ac.uk).
We then applied the SAA methodology to the synthesis
of analogs of fredericamycin A, as shown in Scheme 4.
Through a reduction-oxidation sequence, 9a was cleanly
Org. Lett., Vol. 12, No. 24, 2010
5775