Palladium-catalyzed conversion of β,γ-unsaturated silyl sulfinates into (E)-alkenes: Asymmetric synthesis of polypropionate fragments

Article abstract of DOI:10.1021/jo0357622

At low temperature, 1-alkoxy-1,3-dienes add to sulfur dioxide activated by a Lewis or protic acid generating zwitterionic intermediates that can be quenched by enoxysilanes. The resulting β,γ-unsaturated silyl sulfinates can be desilylated by 1:1 Pd(OAc)<

Full text of DOI:10.1021/jo0357622

SCHEME 1
P a lla d iu m -Ca ta lyzed Con ver sion of
â,γ-Un sa tu r a ted Silyl Su lfin a tes in to
(E)-Alk en es: Asym m etr ic Syn th esis of
P olyp r op ion a te F r a gm en ts
Xiaogen Huang, Cotinica Craita, and Pierre Vogel*
SCHEME 2
Laboratory of Glycochemistry and Asymmetric Synthesis,
Swiss Federal Institute of Technology, EPFL-BCH,
CH-1015 Lausanne-Dorigny, Switzerland
pierre.vogel@epfl.ch
Received December 2, 2003
Abstr a ct: At low temperature, 1-alkoxy-1,3-dienes add to
sulfur dioxide activated by a Lewis or protic acid generating
zwitterionic intermediates that can be quenched by enox-
ysilanes. The resulting â,γ-unsaturated silyl sulfinates can
be desilylated by 1:1 Pd(OAc)2/PPh3 catalyst, liberating the
corresponding â,γ-unsaturated sulfinic acids that undergo
smooth and highly stereoselective retro-ene eliminations of
sulfur dioxide. The method has been applied to generate
enantiomerically pure polypropionate fragments.
ide: NBS) to generate intermediate sulfonyl halides 9
that react with nucleophiles such as amines and alcohols
to provide libraries of sulfonamides 10 and sulfonic esters
11, respectively, in one-pot operations.7 Alternatively,
acidic or basic hydrolysis of the silyl sulfinates 6 into the
corresponding sulfinic acids 7 followed by thermal des-
ulfitation allows the formation of the corresponding
(E)-alkenes 12 (Scheme 2).8 Unfortunately, the latter
reaction sequence 6 f 7 f 12 is quite often low yielding
and is accompanied by decomposition (e.g., alcohol elimi-
nation, retro-aldol, and polymerization). As our tandem
oxyallylation (4 + 5 + SO2 f 6), hydrolysis (6 f 7), and
retro-ene elimination of SO2 (7 f 12 + SO2) realizes a
one-pot synthesis of valuable polypropionate fragments
constructing up to three contiguous stereogenic centers,8
and since the latter can be obtained enantiomerically
pure when starting with enantiomerically pure ethers 5,5
we have searched for better and reproducible conditions
to convert our â,γ-unsaturated silyl sulfinates 6 into
alkenes 12.
We report here that such conditions are now available
and rely on the palladium-catalyzed conversion of silyl
sulfinates into the corresponding sulfinic acids.9 The
latter can then be desulfitated under mild conditions in
acetonitrile/2-propanol as solvent without side reactions.
In one typical reaction, a 1:1.5 mixture of diene 13 and
enoxysilane 14 in CH2Cl2 solution was added to a 1:1
(volume ratio) SO2/CH2Cl2 solution of (t-Bu)Me2SiOTf (0.2
equiv) cooled to -78 °C. After the solution was stirred
for 12 h at this temperature, SO2 and CH2Cl2 were
evaporated under vacuum. The residue was taken by
anhydrous acetonitrile/anhydrous 2-propanol (4:1). After
The thermal desulfitation of â,γ-unsaturated sulfinic
acids is a useful reaction for the regio- and stereoselective
synthesis of alkenes (Scheme 1)1. Starting with R-sub-
stituted sulfinic acids 1, a concerted retro-ene reaction
that leads to the elimination of SO2 is assumed to be
responsible for the chirality transfer of the R-carbon
center to the γ-carbon center with formation of alkenes
3. The stereoselectivity of the reaction is explained in
terms of a chairlike transition state 22 that places an
optimal number of substituents in pseudoequatorial
positions.3
In 1997, our group uncovered a new C-C bond-forming
reaction that condenses butadien-1-yl ethers 4, enoxysi-
lanes 5, and SO2 to generate â,γ-unsaturated silyl sul-
finates 6. The mechanism of this process involves prob-
ably suprafacial hetero-Diels-Alder additions of SO2 to
dienes 4, followed by acid-promoted ionizations into
zwitterionic intermediates that react with the enoxysi-
lanes 5 giving, after Me3Si group transfer, the corre-
sponding silyl sulfinates 6.4,5 The latter can be reacted
with TBAF (Bu4NF) and an electrophile to generate
polyfunctional sulfones 86 or be oxidized with Cl2 (or
N-chlorosuccinimide: NCS) or Br2 (or N-bromosuccinim-
(1) Braverman, S. The Chemistry of Sulfinic Acids, Esters and their
Derivatives; Patai, S., Ed.; J ohn Wiley and Sons: Chichester, 1990;
pp 298-303.
(2) Hiscock, S. D.; Isaacs, N. S.; King, M. D.; Sue, R. E.; White, R.
H.; Young, D. J . J . Org. Chem. 1995, 60, 7166.
(3) Rock, W. L.; Nugent, R. M. J . Org. Chem. 1978, 43, 3433.
Gariginate, R. S.; Morton, J . A.; Weinreb, S. M. Tetrahedron Lett. 1983,
24, 987. Corey, E. J .; Engler, T. A. Tetrahedron Lett. 1984, 25, 149.
Baudin, J . B.; J ulia, S. Bull. Soc. Chim. Fr. 1995, 132, 196.
(4) Deguin, B.; Roulet, J .-M.; Vogel, P. Tetrahedron Lett. 1997, 38,
6197.
(7) Vogel, P.; Bouchez, L. C.; Dubbaka, S. R.; Turks, M. Eur. Pat.
Appl. No. 03003611.5, 2003. Bouchez, L. C.; Dubbaka, S. R.; Turks,
M.; Vogel, P. Abstracts of Papers. 226th ACS National Meeting; Sep
7-11, 2003, New York; American Chemical Society: Washington, DC,
2003; ORGN-301.
(8) Roulet, J .-M.; Puhr, G.; Vogel, P. Tetrahedron Lett. 1997, 38,
6201.
(5) (a) Narkevitch, V.; Schenk, K.; Vogel, P. Angew. Chem., Int. Ed.
2000, 39, 1806. (b) Narkevitch, V.; Megevand, S.; Schenk, K.; Vogel,
P. J . Org. Chem. 2001, 66, 5080. (c) Narkevitch, V.; Vogel, P.; Schenk,
K. Helv. Chim. Acta 2002, 85, 1674.
(9) Enoxysilanes are known to undergo the silicon/palladium ex-
change under smooth conditions: Tsuji, J . Palladium Reagents and
Catalysts, Innovations in Organic Synthesis; Wiley: Chichester, 1995;
pp 351-353. Tsuji, J .; Minami, I. Acc. Chem. Res. 1987, 20, 140. Tsuji,
J . Tetrahedron 1996, 42, 4361.
(6) Huang X.; Vogel. P. Synthesis 2002, 232.
10.1021/jo0357622 CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/06/2004
4272
J . Org. Chem. 2004, 69, 4272-4275

SCHEME 3
SCHEME 5
SCHEME 6
SCHEME 4
These experiments demonstrated that 1:1 Pd(OAc)2/
PPh3 is able to cleave the Si-O bond of silyl sulfinates.
In the presence of 2-propanol, a catalytic amount of 1:1
Pd(OAc)2/PPh3 (1-10% equiv) catalyzed the conversion
of 19 into isobutylene and isopropyloxytrimethylsilane
(23). The reaction was over in a few seconds at 25 °C
(Scheme 5).
For kinetic studies, we synthesized sulfinate 25, de-
rived from the ene reaction of allyltrimethylsilane (24)
with SO2 (Scheme 6).10 It was reported that the deute-
rium kinetic isotopic effect for the desulfitation of prop-
2-enesulfinic acid (26) (kH) and its O-deuterated analogue
26-d (kD) in CDCl3 amounts to kH/kD ) 2.5 ( 0.1 at 25
°C, which confirms the hypothesis of a concerted retro-
ene elimination mechanism with a cyclic transition state
in which hydrogen is transferred from the sulfinic group
to the carbon center C(3) (See 2, Scheme 1).2 If the
palladium complex used in the reaction 25 f propene +
SO2 + i-PrOSiMe3 does not intervene in the desulfitation
of the sulfinic acid intermediate 26, a similar kinetic
deuterium isotopic effect kH/kD should be found. On the
contrary, if the palladium complex should intervene by
changing the mechanism of the desulfitation, different
values of kH/kD should be observed. The kinetics for the
reaction 25 f propene + SO2 + i-PrOSiMe3 in the
presence of 1:1 Pd(OAc)2/PPh3 (0.1 equiv) were followed
the addition of 1:1 Pd(OAc)2/PPh3 (0.1 equiv) and K2CO3
(0.2 equiv), the mixture was heated to 80 °C for 30 min.
This converted silyl sulfinate 15 into alkene 17 in 72%
yield (Scheme 3).
Further experiments showed that the reaction could
not be realized by Pd(OAc)2 alone or in CH3CN alone.
When a larger proportion of PPh3 (2 equiv) vs Pd(OAc)2
was used, the yield in 17 decreased dramatically to less
than 10%. Thus, the 1:1 Pd(OAc)2/PPh3 ratio and i-PrOH
are crucial for success. With the hope of understanding
the role played by the 1:1 mixture of Pd(OAc)2/PPh3
and i-PrOH, we investigated the conversion of simpler
â,γ-unsaturated silyl sulfinates under various conditions.
In the beginning, we used silyl sulfinate 19 obtained
by ene reaction of SO2 with trimethyl-2-methyl-prop-2-
en-1-ylsilane 18.10 When 0.1-1 equiv of Pd(OAc)2 was
added to a solution of 19 in pure CDCl3 or containing
EtOH, no reaction occurred at 25 °C. Heating to 60 °C
led to silicon/palladium transmetalation with formation
of AcOSiMe3. In contrast, adding a 1:1 mixture of Pd-
(OAc)2/PPh3 to the above solution induced a rapid reac-
tion at 25 °C with formation of the palladium complex
21. Its structure was proved by its 1H NMR spectrum
and by comparison with data from related η3-allylpalla-
dium complexes.11 Using 0.5 equiv of Pd(OAc)2 and PPh3,
19 was completely converted into 20 in a few seconds.
On standing at 25 °C, 20 was then converted in a few
hours into sulfone 21.12 In another experiment, when
using 1 equiv of Pd(OAc)2 and 1 equiv of PPh3, complex
20 was converted into bis(η3-allyl)palladium complex 22
(1-2 h at 25 °C)13(Scheme 4). Surprisingly, when using
a 1:2 mixture of Pd(OAc)2/PPh3, no transmetalation
occurred because of the formation of stable Pd(PPh3)2-
(OAc)2 complex.
1
by H NMR and showed kH/kD ) 2.2 ( 0.2 at 25 °C in
CDCl3. Thus, the palladium complex promotes the clean
reaction 25 f propene + SO2 + i-PrOSiMe3 by catalyzing
the Si-O bond cleavage, not by changing the mechanism
of desulfitation. When CD3CN was used as solvent, the
kinetic isotope effect (kH/kD) for the desulfitation of 25
increased to 6.9 ( 0.2 at 25 °C.14 This effect was not
affected by addition of 1:1 Pd(OAc)2/PPh3 (0.1 equiv),
which proved again that the palladium species does not
(14) Solvent effects on kinetic isotopic effect are frequent; see, e.g.:
Simonyi, M.; Kardos, J .; Kovacs, I.; Holly, S.; Pospisil, J . Tetrahedron
Lett. 1975, 8, 565. In our reactions, we propose that the more polar
solvent (CD3CN) favors more polar transition states and thus explain
the greater kinetic isotopic effect compared with that observed in
CDCl3.
(15) This reaction was made by Megevand in our group. It was
reported in her thesis that under acidic conditions no product resulting
from retro-ene reaction was obtained. Only decomposition occurred:
Megevand, S. Etudes sur l’obtention de fragments polypropionates.
Travail de doctorat, Universite´ de Lausanne, 2001, p 73.
(16) Narkevitch, V. Nouvelle re´action de formation de liaison
carbone-carbone asyme´trique: applications synthe´tique des co-
condensations du dioxyde de soufre avec les die`nes at les alce`nes riches
en e´lectrons. Travail de doctorat, Universite´ de Lausanne, 2001.
(17) De Arevedo, M. B. M.; Greene, A. E. J . Org. Chem. 1995, 60,
4940. Nebois, P.; Greene, A. E. J . Org. Chem. 1996, 61, 5210.
Kanazawa, A.; Delair, P.; Pourashraf, M.; Greene, A. E. J . Org. Chem.
Soc., Perkin Trans. 1 1997, 1911.
(10) Bouchez, L.; Vogel, P. Synthesis 2002, 225.
(11) Van Leeuwen, P. W. N. M.; Praat, A. P.; Van Diepen, M. J .
Organomet. Chem. 1971, 29, 433.
(12) Allylpalladium complexes are known to insert SO2 with forma-
tion of bisallyl sulfone: Hung, T.; J olly, P. W.; Wilke, G. J . Organomet.
Chem. 1980, 190, C5.
(13) Henc, B.; J olly, P. W.; Salz, R.; Wilke, G.; Benn, R.; Hoffmann,
E. G.; Mynott, R.; Schroth, G.; Seevogel, K.; Sekutowski, J . C.; Kru¨ger,
C. J . Organomet. Chem. 1980, 191, 426.
J . Org. Chem, Vol. 69, No. 12, 2004 4273

TABLE 1. Dia ster eoselectivities, Yield s, a n d
En a n tiom er ic Excesses of th e Ma jor Dia ster eom er s
Resu ltin g fr om Oxya llyla tion /Desilyla tion /Retr o-En e
Ca sca d es
SCHEME 7
ee (%) of
enoxy-
yield
(%)
the major
entry diene silane products drc
diastereomere
1
2
3
4
5
6
(-)-30a
(-)-30
(-)-30
(+)-38b
(+)-38
(+)-38
14
33
36
27
33
43
31/32
34/35
37
39/40
41/42
44/45
5:1 66
nd
94
92
91
99
95
5:1 70 (0)d
20:1 71
5:1 85
3:1 77 (30)d
7:1 66 (13)d
a
ee ) 97%. b ee ) 99% by chiral HPLC. c The dr was established
from 1H NMR spectra of the crude product mixtures. The yields
given in parentheses were obtained16 for desulfitations under
acidic hydrolysis conditions.8 e The enantiomeric excesses for the
major diastereomers were determined by the Mosher’s method
applied to the corresponding alcohols obtained by treatment with
CF3COOH.
d
get involved into the retro-ene elimination of SO2. It was
also found that the desilylation and desulfitation of 25
in 1:5 i-PrOH/CD3CN was twice as fast as in 1:5 i-PrOH/
CDCl3 at 25 °C.
We then turned to reaction 13 + 14 f 17 (Scheme 3)
and confirmed that the role of Pd(OAc)2/PPh3 is to
accelerate the desilylation of the intermediate silyl sul-
finate 15 to give the sulfinic acid 16 without decomposi-
tion at low temperature. The reaction was over in a few
seconds at -40 °C in CD3CN containing a large excess
of i-PrOH. However the sulfinic acid 16 was rather stable
even at room temperature. Heating to 40 °C was required
with several enoxysilanes (Scheme 8). The results are
shown in Table 1.
For the reaction of diene (+)-385b bearing Green’s
(R)-chiral auxiliary17 with enoxysilane 27 a 5:1 mixture
of diastereomeric product (+)-41 and (+)-42 was obtained
and was separated by flash chromatography in 70% and
15% yield, respectively. Under acidic hydrolysis condi-
tions only products resulting from retro-aldol reactions
were observed.16 A significant increase of the yields was
also found in the syntheses of diastereomeric mixtures
of 41/42 and 44/45 (Table 1). Therefore, our method has
a better compatibility with different kinds of dienes and
enoxysilanes.
1
for desulfitation. The kinetics was followed by H NMR
at 40 °C, and it was found that the reaction in the
presence of palladium species was 1.3 times faster than
without catalyst.
The potential of our palladium-catalyzed reaction was
evaluated first with the reaction shown in Scheme 7.
Starting from achiral diene 13 and enoxysilane 27, the
oxyallylation/desilylation/retro-ene reaction sequence af-
forded a ∼1:1 diastereomeric mixture of (()-28 and
(()-29 in 64% yield. When acidic conditions were applied
to hydrolyze the silyl sulfinates intermediates,8 no trace
of polypropionates 28 and 29 could be detected and only
products of decomposition were seen.15
We then turned to an asymmetric version of our
oxyallylation/desilylation/retro-ene cascade. Under the
same reaction conditions, two enantiomerically enriched
dienes (-)-30 (ee 97%) and (+)-38 (ee 99%) were coupled
This work establishes that good diastereoselectivity
and yields can be realized for the cascade hetero-Diels-
Alder addition of SO2 to penta-2,4-dien-1-yl ethers,
ionization of the intermediate sultines into zwitterions,5b
their electrophilic addition to enoxysilanes, desilylation
of the intermediate silyl sulfinate, and retro-ene elimina-
tion of SO2 when the silyl sulfinate desilylation is
catalyzed by Pd(OAc)2/PPh3. This opens a new approach
to the asymmetric synthesis of polyketide and polypro-
pionate fragments using readily available readily avail-
able 1-oxydienes bearing inexpensive chiral auxiliaries
((R)- or (S)-1-phenylethanol, Greene’s alcohols17).
SCHEME 8
4274 J . Org. Chem., Vol. 69, No. 12, 2004

1
Su p p or tin g In for m a tion Ava ila ble: Detailed H and 13C
Ack n ow led gm en t. We are grateful to the Swiss
National Science Foundation and the Office Fe´de´ral de
l’Enseignement et de la Science (Bern, European COST
D 13/0010/01 and COST D 28/004/02 actions) for finan-
cial support. We thank also Mr. Martial Rey, Francisco
Sepulveda, and Srinivas Reddy Dubbaka for technical
help.
NMR spectra and signal assignments, IR and MS spectra of
all described compounds, kinetic studies, enantiomeric excess
determination, and determination of relative configurations.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O0357622
J . Org. Chem, Vol. 69, No. 12, 2004 4275