Convergent access to bis-spiroacetals through a sila-Stetter-ketalization cascade

Article abstract of DOI:10.1021/ol402017x

An NHC-catalyzed sila-Stetter reaction between aliphatic acylsilanes and vinylketones bearing silyl ether substituents affords functionalized 1,4-diketones, which upon treatment under acidic conditions leads to the corresponding bis-spiroacetals. The two-step sequence may also be carried out in a one-pot operation leading to high yields of the desired bis-spiroacetals.

Full text of DOI:10.1021/ol402017x

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Convergent Access to Bis-spiroacetals
through a Sila-StetterÀKetalization
Cascade
†
ꢀ †
ꢀ
Jessica Labarre-Laine, Redouane Beniazza, Valerie Desvergnes, and
Yannick Landais*
ꢀ
Universite de Bordeaux, Institut des Sciences Moleculaires, UMR-CNRS 5255 351,
cours de la liberation, 33405 Talence Cedex, France
ꢀ
ꢀ
y.landais@ism.u-bordeaux1.fr
Received July 18, 2013
ABSTRACT
An NHC-catalyzed sila-Stetter reaction between aliphatic acylsilanes and vinylketones bearing silyl ether substituents affords functionalized 1,4-
diketones, which upon treatment under acidic conditions leads to the corresponding bis-spiroacetals. The two-step sequence may also be carried
out in a one-pot operation leading to high yields of the desired bis-spiroacetals.
The bis-spiroacetal skeletonisfoundinvarious bioactive
marine phycotoxins including pinnatoxin A (1), spirolide
C (2) (Figure 1), or pteriatoxins (not shown).1 These toxins
have led recently to intensive research due to their potent
acute neurotoxicity.2 The nature of the tricyclic system,
embedded in a complex macrocycle, varies with the size
ofthe oxygenated rings (5- and 6-memberedrings) forming
the bis-spiroacetal. Several strategies directed toward the
elaboration of these bis-spiroacetals have been devised
en route to the total synthesis of 1 and 2.3,4 A straight-
forward disconnection leading to this skeleton implies the
generation of a 1,4-diketone, which upon ketalization
under acidic conditions provides the desired tricyclic
framework.4
† These authors contributed equally to this work.
(1) For a review on the isolation, structure, and biogenesis of these
marine toxins, see: Kita, M.; Uemura, D. Chem. Lett. 2005, 34, 454–459.
(2) (a) Munday, R.; Quilliam, M. A.; LeBlanc, P.; Lewis, N.; Gallant,
P.; Sperker, S. A.; Stephen, E. H.; MacKinnon, S. L. Toxins 2012, 4,
1–14. (b) Araoz, R.; Servent, D.; Molgo, J.; Iorga, B. I.; Fruchart-Gaillard,
C.; Benoit, E.; Gu, Z.; Stivala, C.; Zakarian, A. J. Am. Chem. Soc. 2011, 133,
10499–10511.
(3) (a) McGarvey, G. J.; Stepanian, M. W. Tetrahedron Lett. 1996,
37, 5461–5464. (b) Meilert, K.; Brimble, M. A. Org. Biomol. Chem. 2006, 4,
2184–2192. (c) Georgiou, T.; Tofi, M.; Montagnon, T.; Vassilikogiannakis,
G. A. Org. Lett. 2006, 8, 1945–1948. (d) Furkert, D. P.; Brimble, M. A. Org.
Lett. 2002, 4, 3655–3658. (e) Volchkov, I.; Sharma, K.; Cho, E. J.; Lee, D.
Chem.;Asian J. 2011, 6, 1961–1966.
(4) (a) Brimble, M. A.; Furkert, D. P. Curr. Org. Chem. 2003, 7, 1461–
1484. (b) Montagnon, T.; Tofi, M.; Vassilikogiannakis, G. Acc. Chem.
Res. 2008, 41, 1001–1011.
Figure 1. Bis-spiroacetal skeleton in marine phycotoxins.
This spiroacetalization has been elegantly pioneered
by Kishi5 and then by InoueÀHirama,6 NakamuraÀ
Hashimoto,7 and Zakarian8 in their respective total synthe-
ses of pinnatoxin (1), as well as by Ishihara et al. in their
r
10.1021/ol402017x
XXXX American Chemical Society

preparation of the bis-spiroacetal core of spirolide B.9
The 1,4-diketone motif may be constructed by a number
of ways, often requiring several steps.10 In the search for a
convergent strategy, allowing the presence of functionality
and protecting groups on the carbon backbone, the Stetter
reaction appeared as an attractive method to elaborate
efficiently the bis-spiroacetal I present in toxins 1 and 2
(Scheme 1). It was thus envisioned that the coupling of an
aldehyde (or an acylsilane) III and a vinyl ketone such as
IV in the presence of a suitable organocatalyst (usually
a N-heterocyclic carbene (NHC)) would deliver the 1,4-
diketone framework II. A careful choice of the protecting
groups on the alcohol functions within the chain would
then allow the construction of the desired bis-spiroacetal I
after acid-catalyzed deprotection and ketalization. We
report here that NHC-mediated Stetter and sila-Stetter
processes followed by the acid-catalyzed ketalization effec-
tively offer a straightforward access to the bis-spiroacetal
skeleton. A cascade process also allows both events to be
carried out in a one-pot operation.
first the influence of the nature of the partner III in the
Stetter reaction, using as precursors, aldehyde 3 or acylsi-
lane 4aand vinylketone 5ainthe presenceof NHC-catalyst
precursor A.13 As summarized in Table 1, using aldehyde 3
and various amounts of catalyst invariably led to a mixture
of both the desired product 6a and the corresponding
acyloin 7 (entries 1À3, Table 1). In contrast, we were
pleased to observe that acylsilane 4a led to 6a in good
yield, without a trace of 7(entries4À5), thus notably extend-
ing the scope of the sila-Stetter reaction.12 Increasing the
quantity of acylsilane however produced small amount of
7 (entry 6).
Table 1. Stetter versus Sila-Stetter Reaction
Scheme 1. Retrosynthetic Analysis
entry 3 or 4a (equiv) A (mol %) time (h) 6a/7a yieldb (%)
1
2
3
4
5
6
3 (1.0)
30
15
30
30
15
30
2
81:19
72:28
65:35
100:0
100:0
80:20
61
68
77
67
89
90
3 (1.5)
2.5
2
3 (2.0)
4a (1.0)c
4a (1.5)c
4a (2.0)c
1.5
3
3
a Measured by 1H NMR of the crude reaction mixture. b Isolated
yield of 6a after column chromatography. c 4 equiv of i-PrOH were used.
Although the pioneering work by Stetter11 and others
has shown that this coupling may be carried out starting
from a large variety of aldehydes, few examples have been
reported to date on aliphatic partners. Moreover, acyloins
resulting from the homocoupling of the aldehyde are often
present as byproducts. Recent work by Scheidt et al12
however showed that this could be circumvented, using
acylsilanes instead of aldehydes, although mostly aromatic
acylsilanes were tested during this work. We thus studied
Optimization of the sila-Stetter reaction showed that
decreasing the quantity of acylsilane was detrimental to
the conversion, with 1.5À2 equiv leading to optimal re-
sults. Dry isopropyl alcohol (4 equiv) and DBU as a
base were also shown to provide the highest yields. With
these optimized conditions in hand, the methodology
was extended to a large variety of aliphatic acylsilane14
and enone15 precursors (Supporting Information), as illus-
trated in Scheme 2.
tert-Butyldimethylsilyl and benzyl substituents were
selected as orthogonal protecting groups for alcohol
functions, so that they can be deprotected selectively if
needed (vide infra). 1,4-Diketones were obtained in good
to excellent yields.16 Reaction time ranged between 3 and
(5) Mc Cauley, J. A.; Nagasawa, K.; Lander, P. A.; Mischke, S. G.;
Semones, M. A.; Kishi, Y. J. Am. Chem. Soc. 1998, 120, 7647–7648.
(6) Sakamoto, S.; Sakazaki, H.; Hagiwara, K.; Kamada, K.; Ishii,
K.; Noda, T.; Inoue, M.; Hirama, M. Angew. Chem., Int. Ed. 2004, 43,
6505–6510.
(7) Nakamura, S.; Inagaki, J.; Sugimoto, T.; Kudo, M.; Nakajima,
M.; Hashimoto, S. Org. Lett. 2001, 3, 4075–4078.
(8) (a) Lu, C.-D.; Zakarian, A. Org. Lett. 2007, 9, 3161–3163. (b)
Stivala, C.; Zakarian, A. J. Am. Chem. Soc. 2008, 130, 3774–3776.
(9) Ishihara, J.; Ishizaka, T.; Suzuki, T.; Hatakeyama, S. Tetrahedron
Lett. 2004, 45, 7855–7858.
(10) (a) Miyakoshi, T. Org. Prep. Proc. Int. 1989, 21, 659–704. (b)
Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606–5655.
(c) Setzer, P.; Beauseigneur, A.; Pearson-Long, M. S. M.; Bertus, P.
Angew. Chem., Int. Ed. 2010, 49, 8691–8694.
(13) A screening of other thiazolium salts led to similar results
(Supporting Information). Catalyst A was finally selected, being the
easiest to handle.
(14) Clark, C. T.; Milgram, B. C.; Scheidt, K. A. Org. Lett. 2004, 6,
3977–3980.
(15) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815–
3818.
(16) It was also possible to perform the reaction between acylsilanes 4
and other Michael acceptors such as acrylonitrile (51%), methylacrylate
(36%), and vinylsulfone (26%) (unoptimized yields) (Supporting
Information).
(11) (a) Stetter, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 639–647. (b)
Moore, J. L.; Rovis, T. Top. Curr. Chem. 2009, 291, 77–144.
(12) (a) Scheidt, K. A.; Bharadwaj, A. R.; Mattson, A. E. J. Am.
Chem. Soc. 2004, 126, 2314–2315. (b) Mattson, A. E.; Bharadwaj, A. R.;
Zuhl, A. M.; Scheidt, K. A. J. Org. Chem. 2006, 71, 5715–5724.
B
Org. Lett., Vol. XX, No. XX, XXXX

15 mol % of salt A, except for the preparation of 6d,jÀk,
oÀq, where 30 mol % was employed. It is noteworthy
that substitution on the carbon chain is allowed on both
partners, but R-substitution in acylsilane was shown to
slow down the process, leading to lower yields.17 Removal
of the tert-butyldimethylsilyl protecting group was then
carried out under standard acidic conditions, leading
to a spontaneous cyclization,5À8 producing the desired
bis-spiroacetals in moderate to good yields as a mixture
Scheme 2. Sila-Stetter Reaction between Aliphatic Acylsilanes 4
and Vinylketones 5
1
of diastereomers (dr estimated using both H NMR and
GCÀMS) (Scheme 3).18 Various acidic conditions were
tested (TfOH, HCl, MgBr2,BF3 OEt2,TMSOTf,Sc(OTf)3),
3
but camphorsulfonic acid (CSA) in CH3CN at room
temperature was found to be optimal in terms of yields.
In some cases, major diastereomers were obtained pure
after chromatography, but their structures could not
be determined based solely on 1D and 2D NMR data.
Attempts at obtaining crystals for X-ray diffraction
studies unfortunately failed.
Scheme 3. Spiroacetalization of 1,4-Diketones 6e,i,nÀq
When the deprotection was carried out using CSA
in MeOH as reported by Ishihara et al,9 bis-acetal 9
was obtained as a mixture of diastereomers instead of the
corresponding bis-spiroacetal (Scheme 4). Interestingly,
the structure of the major isomer could be determined
through X-ray diffraction studies.
Having demonstrated the efficiency of the sila-Stetter
reaction and the acid-mediated spiroacetalization of the
resulting 1,4-diketones, we then developed a one-pot pro-
cess in order to avoid the purification of the sensitive
diketone intermediate. The sila-Stetter reaction was per-
formed using as above precatalyst A, DBU, and i-PrOH.
a 2 equiv of 4 was used. b 30 mol % of A was used.
24 h depending on the nature of the substrate. 1.5 Equiva-
lent of acylsilanewas generally usedexcept when indicated.
As mentioned above, the reaction was carried out using
(17) Increasing the amount of acylsilane 4h to 2.5 equiv resulted in the
isolation of 6l but in only 42% yield.
(18) Estimated thermodynamic ratio under the given conditions.
Org. Lett., Vol. XX, No. XX, XXXX
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of tetrahydrofurans. For instance, treatment of 1,4-diketone
6d under Lewis acidic conditions, triggered the selective
deprotection of the TBS group, followed by the cyclization
and the formation of an oxonium intermediate, which was
eventually trapped in situ by a nucleophilic allylsilane,
leading to THF 10 in good yield (Scheme 6).
Scheme 4. Spiroacetalization of 6i in MeOH
Scheme 6. One-Pot Mono-deprotection/Cyclization/Allylation
of 1,4-Diketone 6d
After the mixture was heated at 75 °C until complete
disappearance of enone 5, CSA (50 mol %) was added
and the reaction mixture stirred at room temperature.
This afforded the required bis-spiroacetals 8a,c,e,i
in good yields (Scheme 5). It is worthy of note that 8e
and 8i were obtained with slightly better yields than
those observed using the two-pot protocol (77% vs 53%
and 68% vs 60% respectively). The major diastereomer
for 8a and 8c was obtained pure in each case, and the
relative configuration was attributed based on literature
reports.3e,19
In summary, we report here the sila-Stetter coupling
between a series of aliphatic acylsilanes and vinylketones,
which afforded in generally good yields, 1,4-diketones
bearing ether substituents on the chain. Subsequent acid-
mediated deprotection of silyl ether protecting groups
triggered an efficient spiroacetalization, leading to bis-
spiroacetal motifs, which are present in marine natural
products such as pinnatoxin (1). Both successive transfor-
mations may be carried out in a one-pot operation with
high efficiency. Application of this strategy to the synthesis
of bis-spiroacetal fragments of spirolides and analogues is
now underway and will be reported in due course.
Scheme 5. One-Pot Sila-Stetter/Spiroacetalization Cascade
Acknowledgment. We thank Dr. V. Liautard, Dr.
S. Toumieux, and D. Morgant (ISM, Bordeaux) for pre-
liminary experiments, CNRS, MNERT, ANR (Spirosyn
No. 11-BS07-006-02) for generous support, and Dr.
C. Guillou, Dr. L. Chabaud (ICSN, Gif s/Yvette), and
Dr. F. Robert (ISM, Bordeaux) for fruitful discussions. We
are grateful to Dr. B. Kauffmann (IECB, Bordeaux) for
X-ray diffractions studies and J. M. Lasnier and N. Pinaud
(ISM, Bordeaux) for NMR experiments.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for compounds 4À10 and
1
morpholine and Weinreb amide precursors. H and 13C
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(19) (a) Mudryk, B.; Shook, C. A.; Cohen, T. J. Am. Chem. Soc. 1990,
112, 6389–6391. (b) Weldon, A. J.; Tschumper, G. S. J. Org. Chem. 2006,
71, 9212–9216. (c) McGarvey, G. J.; Stepanian, M. W.; Bressette, A. R.;
Ellena, J. F. Tetrahedron Lett. 1996, 37, 5465–5468.
Finally, orthogonal protecting groups on 1,4-diketones
allow for the monodeprotection and the selective formation
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX