Enolate addition to a 2-alkylidene[1,3]dithiane-derived bissulfoxide. A new a2-acceptor

Article abstract of DOI:10.1021/ol051670i

(Chemical Equation Presented) Reaction of enolates derived from esters and ketones to an easily prepared alkylidene[1,3]dithiane-1,3-dioxide afforded the respective adducts with good yields and selectivities generally exceeding 85:15. The base used for en

Full text of DOI:10.1021/ol051670i

ORGANIC
LETTERS
2005
Vol. 7, No. 18
4013-4015
Enolate Addition to a
2-Alkylidene[1,3]dithiane-Derived
Bissulfoxide. A New a2-Acceptor
Tobias Wedel and Joachim Podlech*
Institut fu¨r Organische Chemie, UniVersita¨t Karlsruhe (TH),
Karlsruhe 76131, Germany
joachim.podlech@ioc.uka.de
Received July 15, 2005
ABSTRACT
Reaction of enolates derived from esters and ketones to an easily prepared alkylidene[1,3]dithiane-1,3-dioxide afforded the respective adducts
with good yields and selectivities generally exceeding 85:15. The base used for enolate addition played no significant role for the reaction
outcome, and addition of a silyl enole ether gave similar results. The thus formed oxygenated S,S-acetals were transformed into the corresponding
1,4-dicarbonyls by a reduction/oxidation sequence with 84% yield.
1,3-Dioxygenated and 1,5-dioxygenated carbon chains are
common motifs in natural products. A plethora of methods
for their synthesis is known, among them the addition of
enolates to carbonyl compounds and their R,â-unsaturated
derivatives, respectively. Though significantly less abundant,
1,4-dioxygenated carbon chains are similarly important, with
prominent representatives in nature being γ-butyrolactones.1
Nevertheless, methods for their synthesis are scarce.2
Unsymmetrically substituted sulfoxides are chiral and
show a high optical stability.4 Because they are favorably
prepared by enantioselective oxidation of the respective
sulfides, both enantiomers are usually accessible. Nucleo-
philic addition to chiral vinyl sulfoxides has been occasion-
ally reported,5 and Fensterbank et al. published additions of
amines, cuprates, and malonate anions to alkylidene bis-
(tolylsulfoxides).6 Nevertheless, most of these methods have
in common that the preparation of the substrates is rather
cumbersome or the sulfoxide is hardly transferable into useful
functionalities. We used alkylidene-[1,3]dithiane-1,3-diones
as Michael-type acceptors, which are easily prepared via
published procedures by Peterson olefination and stereo-
selective oxidation of the dithiane moiety. The respective
alkylidene-dithianes are thus synthesized in high yields
(Scheme 1).7
In this communication we report on enolate additions to
dioxygenated ketene S,S-acetal 1,3 which after hydrolysis of
the acetal moiety yields 1,4-dicarbonyls.
(1) Petragnani, N.; Ferraz, H. M. C.; Silva, G. V. J. Synthesis 1986, 157.
Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. Engl. 1985, 24, 94.
Fischer, N. H.; Olivier, E. J.; Fischer, H. D. In Progress in the Chemistry
of Organic Natural Products; Herz, W., Grisebach, H., Kirby, G. W., Eds.;
Springer: Wien, 1979; Vol. 38, p 47; Grieco, P. A. Synthesis 1975, 67.
(2) (a) Stetter, H.; Kuhlmann, H. Org. React. 1991, 40, 407. (b) Stetter,
H.; Kuhlmann, H. Chem. Ber. 1976, 109, 2890. (c) Lassaletta, J.-M.;
Fernandez, R.; Martin-Zamora, E.; Diez, E. J. Am. Chem. Soc. 1996, 118,
7002. (d) Diez, E.; Fernandez, R.; Gasch, C.; Lassaletta, J. M.; Llera, J.
M.; Martin-Zamora, E.; Vazquez, J. J. Org. Chem. 1997, 62, 5144. (e)
Braun, M.; Laicher, F.; Meier, T. Angew. Chem., Int. Ed. 2000, 39, 3494.
(f) Burstein, C.; Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 6205.
(3) A detailed review on bissulfoxides has been published: Delouvrie´,
B.; Fensterbank, L.; Na´jera, F.; Malacria, M. Eur. J. Org. Chem. 2002,
3507.
The yield of the sulfoxides was significantly improved by
slightly changing the workup procedure (entries 1 and 2 in
(4) Ferna´ndez, I.; Khiar, N. Chem. ReV. 2003, 103, 3651.
(5) Wakasugi, D.; Satoh, T. Tetrahedron 2005, 61, 1245.
(6) Brebion, F.; Delouvrie´, B.; Na´jera, F.; Fensterbank, L.; Malacria,
M.; Vaissermann, J. Angew. Chem., Int. Ed. 2003, 52, 5342. See as well:
Midura, W. H.; Krysiak, J. A.; Cypryk, M.; Mikołajczyk, M.; Wieczorek,
M. W.; Filipczak, A. D. Eur. J. Org. Chem. 2005, 653.
10.1021/ol051670i CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/12/2005

Scheme 1. Synthesis of 2-Alkylidene-[1,3]dithiane-1,3-diones
Table 1. Enolate Addition to a Dioxygenated Ketene
S,S-Acetal
entry
X
product
yielda (%)
dr
1
2
3
4
Ph
5
6
7
8
82
76
68
75
96:4
92:8
86:14
89:11
p-MeOC6H4
Me
OEt
Scheme 1). The titanate slurry was additionally treated by
ultrasonication for about 3 h, resulting in an easily filterable
precipitate.
a Yields are given for the isolated and purified major isomers.
The products were highly crystalline, and a crystal
structure was obtained for the phenyl-substituted product 1.
The exocyclic moiety turned out to be perfectly planar, the
less hindering vinylic hydrogen reaching toward the equato-
rial SdO oxygen (O1 in Figure 1).8
(Scheme 2). Though two new stereogenic centers were
formed during this reaction, only three isomers were detected
where one is predominantly produced (92:5:3:0).
Scheme 2. Addition of a Cyclohexanone-Derived Enolate
a Yield given for the isolated and purified major isomer.
Figure 1. Crystal structure9 of bissulfoxide 1.
The major product 9a could be crystallized, and its
structure was unambiguously determined by X-ray crystal-
lography (Figure 2). Obviously the enolate attacked from
the top side (orientation of the alkylidene substrate as
depicted in Figure 1) where less steric hindrance through
hydrogen atoms of the dithiane moiety was present.
Addition of an enolate prepared by deprotonation of
acetophenone with sodium hexamethyldisilazide yielded the
corresponding adduct with 82% yield and 96:4 selectivity
(Table 1, entry 1). No changes in the reaction outcome were
observed when deprotonation was performed with lithium
diisopropylamide (LDA). However, best results were only
achieved at low temperatures (-78 °C). Astonishingly,
adduct formation was reached even with catalytic amounts
of the base, though the reaction was much more sluggish.
The diastereoisomers were easily separated by either chro-
matography or crystallization. Yields in Table 1 are given
for the isolated and purified major isomers.
The enolate prepared from cyclohexanone could be added
to the phenyl-substituted bissulfoxide 1 with high yield
(7) Aggarwal, V. K.; Steele, R. M.; Ritmaleni; Barrell, J. K.; Grayson,
I. J. Org. Chem. 2003, 68, 4087. Further methods for oxidation of sulfides
are summarized in: Modern Oxidation Methods; Ba¨ckvall, J.-E., Ed.; Wiley-
VCH: Weinheim, 2004; p 193. Legros, J.; Dehli, J. R.; Bolm, C. AdV.
Synth. Catal. 2005, 347, 19. Kowalski, P.; Mitka, K.; Ossowska, K.;
Kolarska, Z. Tetrahedron 2005, 61, 1933.
Figure 2. Crystal structure9 of adduct 9a.
(8) A crystal structure of racemic 2 has been published. Its structure is
very similar to the herein presented compound 1: Newlands, M. J.; Bo, L.;
Fallis, A. G.; Gabe, E. J.; Le Page, Y. Acta Crystallogr. 1988, C44, 503.
Though the role of the counterion or an eventually added
Lewis acid is hardly investigated in additions to vinyl
4014
Org. Lett., Vol. 7, No. 18, 2005

sulfoxides10 we assume that a complexation of both the
enolate and the sulfoxide by the metal (here sodium) occurs
in the transition state, which is best rationalized by a Newman
projection as depicted in Figure 3.
foxides. We further performed a two-step procedure leading
to the respective carbaldehyde 11 (Scheme 4). Here, the
Scheme 4. Liberation of 1,4-Dicarbonyls
Figure 3. Proposed rational for the formation of adduct 9a.
sulfoxides were reduced with either rhenium catalysis12 or
with titanium tetrachloride/indium13 and subsequent S,S-
acetal cleavage by oxidation (here with a hypervalent iodine
compound14). Unfortunately we could not establish a suitable
method for the determination of the optical purity. With no
chromatographic method (HPLC or GC) could baseline
separation of the enantiomers be achieved, and application
of a chiral shift reagents [Eu(hfc)3] led to partial racemization
during ee determination (er ) 91:9). Nevertheless, the
specific rotation of 11 ([R] ) -133.4) is even higher than
reported for putative enantiomerically pure material in the
literature ([R] ) -55.6).2c
Because the utilized base for deprotonation and thus the
counterion of the enolate played no significant role, we tested
an independently prepared silyl enole ether as nucleophile
(Scheme 3).11 Again we got an identical reaction outcome,
which led us to the conclusion that an open-chain mechanism
might apply here. Nevertheless, further information seems
to be necessary to support this theory.
Scheme 3. Addition of a Silyl Enole Ether
Investigations on the scope of this reaction and studies
on the mechanism of this reaction are currently ongoing in
our laboratories.
Acknowledgment. We are deeply indebted to Dr. Wolf-
gang U. Frey (University of Stuttgart) for the X-ray crystal
structure analyses. We thank Prof. Dr. T. Ziegler (University
of Tu¨bingen) and Prof. Dr. W. Klopper (University of
Karlsruhe) for helpful discussions.
Protocols for a cleavage of the dioxygenated S,S-acetal
via a Pummerer-type rearrangement (leading to carboxylic
acid derivatives)3 were frequently applied to similar bissul-
Supporting Information Available: Experimental pro-
cedures, spectroscopic data and spectra of all new com-
pounds, and details of the X-ray analyses in CIF format. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(9) Crystallographic data have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication number CCDC-
250402. Data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB21EZ, U.K. [fax: +44 (0) 1223-336-033.
E-mail: deposit@ccdc.cam.ac.uk]
(10) A survey on how the counterion is influencing reactions with
bissulfoxides is given in ref 3.
(11) Mukaiyama, T. Org. React. 1982, 28, 203. Carreira, E. M. In
ComprehensiVe Asymmetric Catalysis I-III; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 3, p 997.
OL051670I
(12) Arterburn, J. B.; Perry, M. C. Tetrahedron Lett. 1996, 37, 7941.
(13) Yoo, B. W.; Choi, K. H.; Kim, D. Y.; Choi, K. I.; Kim, J. H. Synth.
Commun. 2003, 33, 53.
(14) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287.
Org. Lett., Vol. 7, No. 18, 2005
4015