Polysubstituted oxygen heterocycles by a Reformatsky-type reaction/reductive cyclization approach from enantiopure β-ketosulfoxides

Article abstract of DOI:10.1021/ol701670g

(Chemical Equation Presented) The stereoselective synthesis of tetrasubstituted tetrahydrofurans and trisubstituted tetrahydropyrans bearing a sulfoxide was achieved by reductive cyclization (Et₃SiH/TMSOTf) from the corresponding enantiopure hydroxy ketones protected as a dioxolane. These derivatives are easily accessible from a Reformatsky-type reaction between α-bromo-α′-sulfinyl ketones and protected α- or β-ketoaldehydes, followed by diastereoselective reduction of the resulting β-ketosulfoxide.

Full text of DOI:10.1021/ol701670g

ORGANIC
LETTERS
2007
Vol. 9, No. 22
4451-4454
Polysubstituted Oxygen Heterocycles by
a Reformatsky-Type Reaction/Reductive
Cyclization Approach from Enantiopure
â
-Ketosulfoxides
Franc¸
oise Colobert,*,† Sabine Choppin,† Leticia Ferreiro-Mederos,†,‡
Michel Obringer,† Sandra Luengo Arratta,† Antonio Urbano,‡ and
M. Carmen Carren˜o*,‡
Laboratoire de Ste´re´ochimie associe´ au CNRS, UMR 7509, UniVersite´ Louis Pasteur,
ECPM 25 rue Becquerel, 67087 Strasbourg Cedex 2, France, and Departamento de
Qu´ımica Orga´nica (C-I), UniVersidad Auto´noma de Madrid, Cantoblanco,
28049-Madrid, Spain
fcolober@chimie.u-strasbg.fr
Received July 18, 2007
ABSTRACT
The stereoselective synthesis of tetrasubstituted tetrahydrofurans and trisubstituted tetrahydropyrans bearing a sulfoxide was achieved by
reductive cyclization (Et3SiH/TMSOTf) from the corresponding enantiopure hydroxy ketones protected as a dioxolane. These derivatives are
easily accessible from a Reformatsky-type reaction between
diastereoselective reduction of the resulting -ketosulfoxide.
r-bromo-r′-sulfinyl ketones and protected r- or â-ketoaldehydes, followed by
â
Stereoselective approaches to polysubstituted oxygen het-
erocycles continue to attract considerable attention due to
the widespread appearance of these structural motifs in a
large number of biologically active natural compounds,
including structurally complex ionophore antibiotics,1 marine
macrolides,2 brevetoxins,3 and other polycyclic ethers.4
Among the problems encountered when dealing with these
structures, the stereoselective construction of tri- or tetra-
substituted tetrahydrofurans (THF) and tetrahydropyrans
(THP) is one of the most challenging tasks that has been
resolved using different strategies.5 We have recently de-
veloped a highly stereoselective approach to different sized
cis-disubstituted cyclic ethers based on the Et3SiH/TMSOTf-
promoted reductive cyclization of enantiopure hydroxy
sulfinyl ketones. In turn, these acyclic precursors were
accessible through the well-established diastereoselective
reduction of an adequately functionalized â-ketosulfoxide.6
In spite of the important advances reached, efficient asym-
metric syntheses of polysubstituted precursors were required
to extend the method to structurally more complex cyclic
ethers.
† Universite´ Louis Pasteur.
‡ Universidad Auto´noma de Madrid.
In connection with a project directed to extend the
applications of sulfoxides in asymmetric synthesis,7 we have
recently described a highly stereoselective Reformatsky-type
reaction of chiral nonracemic R-bromo-R′-sulfinyl ketones
with aldehydes in the presence of SmI2 giving access to
(1) (a) Faul, M. M.; Huff, B. E. Chem. ReV. 2000, 100, 2407-2474. (b)
Shimizu, Y. Chem. ReV. 1993, 93, 1685-1698.
(2) Yeung, K.-S.; Paterson, I. Chem. ReV. 2005, 105, 4237-4313.
(3) Tanaka, T. Chem. ReV. 2005, 105, 4314-4347.
(4) (a) Kang, E. J.; Lee, E. Chem. ReV. 2005, 105, 4348-4378. (b) Inoue,
M. Chem. ReV. 2005, 105, 4379-4405.
10.1021/ol701670g CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/06/2007

enantiomerically pure 2-methyl-1,3-diol moieties.8 The short
and efficient access to such highly substituted fragments
encouraged us to check if the combination of the reductive
cyclization and the Reformatsky-like process could open the
way to the stereocontrolled synthesis of highly substituted
oxygen heterocycles. We now report our preliminary results,
evidencing that 2,3,6-trialkyl-substituted THP and 2,3,5-
trialkyl-4-hydroxy-substituted THF are available in three
steps starting from R-bromo-R′-sulfinyl ketones. Three or
four new stereogenic centers can be created using an
enantiomerically pure tert-butyl sulfoxide as the unique
source of chirality. The accessibility of both diastereoisomeric
hydroxy sulfinyl moieties by the well-established DIBALH
and Lewis acid/DIBALH reduction9 of the corresponding
â-ketosulfoxides10 prompted us to investigate the behavior
of the acyclic derivatives bearing the two possible relative
configurations at the â-hydroxysulfinyl moiety.
The retrosynthesis envisaged to THP or THF derivatives
I (Scheme 1), based on the reductive cyclization process,
Scheme 1. Retrosynthetic Analysis for the Stereoselective
Synthesis of Highly Substituted THP and THF Derivatives
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(g) Biovin, T. L. B. Tetrahedron 1987, 43, 3309-3362. Recent references
on tetrahydrofurans: (h) Pan, J.; Zhang, W.; Zhang, J.; Lu, S. Tetrahedron
Lett. 2007, 48, 2781-2785. (i) Chavre, S. N.; Choo, H.; Cha, J. H.; Pae,
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1717-1760. Recent work: (c) Carren˜o, M. C.; Merino, E.; Ribagorda, M.;
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required the preparation of acyclic dihydroxy ketones II (n
) 0, 1), in turn available with both R or S configuration at
the â-hydroxy sulfinyl moiety using the diastereodivergent
reduction of monoprotected diketosulfoxides III. We envis-
aged the use of a SmI2-promoted Reformatsky reaction to
assemble the enantiopure bromosulfinyl ketone IV with
protected R- (n ) 0) or â- (n ) 1) ketoaldehydes V. The
synthetic versatility of the sulfoxide present in the final
targets, which could be transformed into other functional
groups, could increase the interest of our method later for
future applications.
To evaluate our retrosynthetic approach to the tetrahy-
dropyranyl derivatives, we decided to synthesize two series
of analogues bearing a methyl and a propyl substituent due
to the accessibility of the required â-ketoaldehydes, easily
prepared as protected dioxolanes using known methods.11
Enantiomerically pure γ-bromo-â-ketosulfoxide 3, neces-
sary for the Reformatsky-like reaction, was synthesized, as
previously reported,8b,12 by reaction of the lithium anion
derived from (R)-methyl tert-butyl sulfoxide (2) with methyl
2-bromopropionate 1, in 95% yield (Scheme 2). The SmI2-
promoted reaction between 3 and the aldehyde 4 gave the
Reformatsky adduct 5 with 73% yield and 93:7 dr. It is worth
mentioning that the success of this transformation required
the use of a recently prepared SmI2/THF solution. The
analogue reaction with aldehyde 6 led to hydroxy â-keto-
sulfoxide 7 in 86% yield and 93:7 dr (Scheme 2).
The reduction of 5 and 7 with DIBALH gave rise to the
exclusive formation of 1,3-syn-diol derivatives 8 and 9 as a
consequence of the hydride attack from the re face of the
carbonyl group directed by the sulfoxide.9 When the reduc-
tion was carried out with DIBALH/Yb(OTf)3, the corre-
sponding anti-2-methyl-1,3-diols 10 and 11 were formed with
good yields and selectivities (Scheme 2). We were able to
obtain diastereomerically pure 8, 9, 10, and 11 after
chromatographic separation. The absolute configuration of
the major diastereomer 11 was confirmed by X-ray diffrac-
tion (Figure 1).13
(11) Tan, J. S.; Ciufolini, M. A. Org. Lett. 2006, 8, 4771-4774.
(12) Bravo, P.; Resnatti, G. Tetrahedron Lett. 1985, 26, 5601-5604.
4452
Org. Lett., Vol. 9, No. 22, 2007

decided to check the reductive cyclization on the dioxolane
itself. To our delight, upon treatment of 8 with an excess of
Et3SiH in CH2Cl2 at 0 °C and further addition of TMSOTf,
a clean reaction mixture resulted in a very short time (30
min), from which tetrahydropyran 12 could be isolated in
65% yield as a unique diastereomer. The structural assign-
ment of 12 (1H NMR NOESY and COSY experiments) re-
vealed the cis disposition of the substituents situated at C-2
and C-6 on the heterocycle, as well as the lack of the free
hydroxy group, non-engaged in the cyclization process, sit-
uated at the â-carbon of the dioxolane moiety in the precursor
8. A similar result was obtained when the syn-1,3-diol 9 was
treated with Et3SiH/TMSOTf, giving in this case 13, lacking
the OH at C-4, isolated in 74% yield. The behavior of
epimeric acyclic anti-1,3-diols 10 and 11 when treated with
Et3SiH/TMSOTf was similar, furnishing, respectively, a
75:25 mixture of tetrahydropyrans 14 or 15 and dihydropy-
rans 16 or 17, as unique diastereoisomers. These results
evidenced that the loss of the â-OH was independent of its
relative stereochemistry and suggested the favored elimina-
tion to a double bond as the driving force for this behavior.
On this basis, we propose the mechanism indicated in
Scheme 3 to explain the observed results. Activation of the
Scheme 2. Stereoselective Synthesis of Trisubstituted THPs
12-15
Scheme 3. Mechanistic and Stereochemical Pathway
Explaining the Formation of 14-17
Up to now, we had always applied the reductive cycliza-
tion of â-hydroxy sulfinyl ketones to the free carbonyl
derivatives.6 We then tried to deprotect the dioxolane group
of 8, but all attempts were unsuccessful due to the formation
of complex reaction mixtures where different cyclized
hemiacetals and mixed acetals were detected. Taking into
account that the reductive cyclization of hydroxy ketones
was proposed to occur from the intermediate formation of a
cyclic oxocarbenium ion resulting from a mixed acetal,6d we
ketal of 10 and 11 by the TMSOTf favors the dioxolane ring
opening and subsequent nucleophilic attack of the OH at the
(13) We thank Dr. Andre´ DeCian for assistance with the analysis of the
crystal structure (Service commun Rayons X, 4 rue Blaise Pascal 67070
Strasbourg cedex e-mail: sercomrx@chimie.u-strasbg.fr).
Figure 1. X-ray structure of 11.
Org. Lett., Vol. 9, No. 22, 2007
4453

δ position to give an intermediate mixed ketal, precursor of
the oxocarbenium ion A. The increased acidity of the CH2
group situated vicinal to the hydroxy group facilitates the
elimination of a proton to give the dihydropyran B. Proto-
nation of the OH, which occurs independently of its
configuration, was followed by H2O elimination, producing
the key oxonium intermediate C. The axial approach of Et3-
SiH to the oxonium carbon (1,2-attack), favored by the higher
stability of the half-chair-like transition state, explains the
stereoselective formation of 16 and 17, isolated in the
reactions of 10 and 11. The 1,4-attack of the Et3SiH to
intermediate C gives dihydropyran D whose protonation and
subsequent stereoselective reduction justify the formation of
14 and 15 (Scheme 3).
Scheme 4. Stereoselective Synthesis of Tetrasubstituted THF
24
The mixtures 14/16 and 15/17 were finally hydrogenated
(H2, Pd/C, MeOH/CH3COOH) to afford saturated derivatives
14 and 15 in 90 and 70% yield, respectively.
En route to tetrahydrofuran derivatives, we applied a
similar reaction sequence to the protected R-ketoaldehyde
18,8b whose reaction with (R)-R-bromo-R′-tert-butylsulfinyl
ketone 3 in the presence of SmI2 gave rise to the Reformatsky
adduct 19 in 73% yield as a 93:7 mixture of syn and anti
diastereoisomers that could not be separated. Diastereo-
selective reduction of the â-ketosulfoxide moiety of 19, either
with DIBALH or with DIBALH/Yb(OTf)3, afforded a similar
nonseparable 93:7 mixture of 1,3-diols 20 and 21 with
excellent yields (Scheme 4). In accordance with these results,
both reductions must occur with a complete diastereoselec-
tion. We were able to obtain diastereomerically pure 20 after
silylation to 22, flash chromatography, and TBAF depro-
tection (Scheme 4). When we performed the Et3SiH/
TMSOTf-promoted reductive cyclization process on com-
pound 20, we were pleased to observe, together with a minor
amount of cyclized hemiketal 23, the formation of diastereo-
and enantiomerically pure tetrasubstituted tetrahydropyran
24, which was isolated in 82% yield. The relative and
corresponding â-ketosulfoxide, and the Et3SiH/TMSOTf-
promoted reductive cyclization is an efficient route to
enantiomerically pure highly substituted THF and THP
derivatives. This strategy should allow the synthesis of
biologically active molecules bearing such moieties. More-
over, the versatility of the sulfinyl group existing on the
cyclic ethers increases the interest of this approach since it
can be easily transformed into different groups.
1
absolute configuration of 24 was established by H NMR
Acknowledgment. We thank the CNRS and Ministe`re
de la Recherche (France) and the MEC (Spain) (Grant
CTQ2005-02095) for financial support. L.F. thanks the
French Embassy in Spain for a fellowship.
NOESY and COSY experiments. The reaction was again
highly diastereoselective, leading to the exclusive formation
of the 2,5-cis-disubstituted system. Stereoelectronic factors
similar to those proposed in the case of intermediate E of
Scheme 3 must be responsible for the observed stereochem-
ical course.
In conclusion, the three-step sequence combining the
asymmetric Reformatsky-like reaction between an enan-
tiopure R-bromo-R′-sulfinyl ketone and an adequately pro-
tected ketoaldehyde, the diastereoselective reduction of the
Supporting Information Available: Experimental pro-
1
cedures and compound characterization with copies of H
and 13C NMR for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL701670G
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Org. Lett., Vol. 9, No. 22, 2007