Synthesis of long-chain polyketide fragments by reaction of 1,3-dioxy-1,3-dienes with allylsilanes: Umpolung with sulfur dioxide

Article abstract of DOI:10.1021/ol0498646

(Equation presented) In the presence of a Lewis or protic acid and at low temperature, 1,3-dioxy-1,3-dienes add to sulfur dioxide generating zwitterionic intermediates that can react with carbon nucleophiles such as allylsilanes. After a retro-ene elimina

Full text of DOI:10.1021/ol0498646

ORGANIC
LETTERS
2004
Vol. 6, No. 6
1053-1056
Synthesis of Long-Chain Polyketide
Fragments by Reaction of
1,3-Dioxy-1,3-dienes with Allylsilanes:
Umpolung with Sulfur Dioxide
Ma¯ris Turks, Freddy Fonquerne, and Pierre Vogel*
Institute of Molecular and Biological Chemistry, Swiss Federal Institute of Technology
(EPFL), BCH CH-1015 Lausanne, Switzerland
pierre.Vogel@epfl.ch
Received January 23, 2004
ABSTRACT
In the presence of a Lewis or protic acid and at low temperature, 1,3-dioxy-1,3-dienes add to sulfur dioxide generating zwitterionic intermediates
that can react with carbon nucleophiles such as allylsilanes. After a retro-ene elimination of SO , valuable polyketide precursors are obtained.
2
Natural polyketides show important biological activity. A
large number of methodologies toward these targets have
Scheme 1
already been developed.1 Nevertheless, more efficient and
versatile synthetic strategies are needed. We recently reported2,3
a new asymmetric C-C bond-forming reaction 1 + 2f3
(Scheme 1). The strategy involves a cascade of reactions
starting with the hetero-Diels-Alder addition of SO2 to a
1,3-dienyl ether 1, giving the corresponding sultine 44 that
is ionized to zwitterionic intermediate 5, which is then added
to enoxysilanes (oxyallylation) to give silyl sulfinates 6 that
can be alkylated or allylated in situ to provide the corre-
sponding sulfones.5 We wish to report here the logical
extension of this strategy to allylsilanes and to the synthesis
of polyketide fragments via two-directional chain elongation.6
Unfortunately, when dienes 1 and various allylsilanes (see
Table 1) were reacted with an excess of SO2 in the presence
of a Lewis or protic acid promoter, no product of condensa-
tion was observed. The allylsilanes reacted too rapidly with
SO2 in ene reactions giving the corresponding â,γ-unsatur-
ated silyl sulfinates,7 thus giving no chance to the allylsilanes
best acid promoter is (CF3SO2)2NSiMe3 (Tf2NTMS).8 In a
typical experiment, diene 8 and allylsilane 9 or 10 (1-3
equiv) were mixed together in a 1:1 mixture of SO2/CH2Cl2
to react with the intermediate zwitterions 5.
In an exploratory study with achiral 1-benzyloxy-3-ace-
toxydiene 83a and allylsilanes 9 and 10, we found that the
10.1021/ol0498646 CCC: $27.50 © 2004 American Chemical Society
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yields, respectively, with an anti/syn (centers C(4), C(5)) ratio
of 11:1. To our knowledge, this is the first time that a buffer
such as Et3NH+TfO- has been used to desilylate silyl sulfi-
Table 1. Hydroallylation of Diene 14a
1
nates (11 identified by H and 13C NMR when running the
reaction in an NMR tube) and to induce the subsequent desul-
fitations 12f13 by retro-ene elimination of SO2 at low
temperature.5a,9
With acid promoters such as Yb(OTf)3, BF3‚Et2O, and
(t-Bu)Me2SiOTf, reactions 8 + 9 and 8 + 10 failed to give
any trace of the desired products 13. With TiCl4, these
reactions had low yields of 10 and 5%, respectively. As
(CF3SO2)2NH promoted reaction 8 + 9f13a with a yield
of 19%, other protic acids (HClO4, FSO3H, CF3SO3H, TsOH)
have been explored as promoters but with little success,
except for 1:1 (R)-1,1′-bi-2-naphthol/SbCl5, where reaction
8 + 9 gave 13a in 28% yield (same anti/syn diastereose-
lectivity, no chiral induction by HPLC).
We then turned to an asymmetric version of our process
and identified (R)- and (S)-1-phenylethanol (relatively cheap
and commercially available) as appropriate chiral auxiliaries.
Dienes 14a-c10 were used in our study together with
allylsilanes 9, 15, and 16 (Table 1). Using Tf2NTMS as an
acidic promoter, all our reactions led to the same anti/syn
(centers C(4), C(5)) diastereoselectivity of 11:111 and prod-
ucts 17-19 were isolated in good yields. There were no other
detectable (<3%) diastereomeric products, showing that (R)-
and (S)-1-phenylethanol are good chiral auxiliaries for the
preparation of these polyketide fragments. With allylsilane
15, we had hoped to be able to isolate intermediates 18′ with
Z ) CH2SiMe3 useful for a second hydroallylation reaction
(see below). Unfortunately, due to the competing ene-reaction
with SO2, the latter were rapidly converted into the corre-
sponding â,γ-unsaturated silyl sulfinates. Under our aqueous
workup conditions the latter were rapidly hydrolyzed and
desulfitated (retro-ene elimination of SO2) to give exclusively
products 18 (Z ) CH2SiMe3fZ ) CH3). With [2-(ace-
toxymethyl)allyl]trimethylsilane (16),12 dienes 14a, 14b, and
ent-14c gave products 19a, 19b, and ent-19c, respectively,
that were isolated as single, pure diastereoisomers in 69, 71,
and 52% yields after flash chromatography on silica gel.
entry
diene
14a b
14b
en t-14cc
14b
14a b
14b
en t-14cc
R1
R2 allylsilane product yield (%)
1
2
3
4
5
6
7
Me iPr
Me Ph
H
Me Ph
Me iPr
Me Ph
9
9
17a
17b
18a
18b
19a
19b
en t-19c
68d
70d
Ph
15
15
16
16
16
69g
74d
69e,f
71e,f
52e,f
H
Ph
a Reaction conditions: (i) CH2Cl2/SO2/Tf2NTMS, -78 °C; (ii) evapora-
tion of SO2; (iii) MeOH/Et3NH+TfO-, -78 °C. b Racemic. c Opposite
enantiomer starting from (R)-1-phenylethanol. d Anti:syn ) 11:1. e Single
product. f Using PhMe instead of CH2Cl2 as a cosolvent with SO2.
g Diastereoselectivity ) 9:1.
containing the acid promoter and cooled to -78 °C. The
mixture was allowed to react for ca. 16 h at -78 °C, followed
by evaporation of SO2 and addition of MeOH containing
Et3NH+TfO-. After aqueous workup and flash chromatog-
raphy, products 13a and 13b were obtained in 68 and 34%
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1054
Org. Lett., Vol. 6, No. 6, 2004

carbon center C(5) was observed. Moreover, this structure
confirmed the C(4)/C(5) anti relationship. It is thus proposed
that the same stereocontrol occurs in all reactions 14f17,
18, 19.
Scheme 2 a
Ally acetates 19b and ent-19c underwent quantitative
substitutions with (Me2PhSi)2Cu(CN)Li2,14 providing allyl-
silanes 21 and 22, respectively (Scheme 4).
Scheme 4 a
a Conditions: (i) excess SO2/CH2Cl2, acid promoter (LA), -78
°C; (ii) evaporation of SO2; (iii) MeOH/Et3NH+TfO-, -78 °C.
The relative configuration between the C(5) center and
the phenethyl chiral auxiliary in products 17-19 has not
been established unambiguously. However, in the case of
ent-17b (derived from (R)-1-phenylethanol), its ozonolysis
and subsequent reduction with LiAlH4 followed by double
esterification with p-nitrobenzoyl chloride provided a crystal-
line derivative 20,13 the stucture of which could be determined
by X-ray crystallography (Scheme 3). As for all other cases
reported so far,2,3 a like relationship (R,R or S,S) between
the benzylic center of the chiral auxiliary and the adjacent
a Conditions: (i) (Me2PhSi)2Cu(CN)Li2, quant.; (ii) 14b/SO2/
Tf2NTMS/PhMe, -78 °C; (iii) evaporation of SO2; (iv) MeOH/
Et3NH+TfO-, -78 °C; (v) 14c/SO2/Tf2NTMS/PhMe, -78 °C; (vi)
BF3‚OEt2/EtSH.
In the presence of 2 equiv of diene 14b, 21 reacted with
SO2 to give the pseudo-C2-symmetrical product 23 in 62%
yield (Scheme 4). Polyketide fragment 24 was prepared in
the same way from 22 in 81% yield.
The relative configuration of products 23 and 24 was
determined by measurements of the optical rotation (R).
Centers C(4)/C(5) and C(9)/C(10) always have an anti
relationship, which arises from highly stereoselective retro-
ene reactions. Optical rotation measured for diol 25 (R * 0)
demonstrates the 5,9-anti relationship of the diol moiety
(Scheme 5). In contrast, R ) 0 found for product 24 is
consistent with the 5,9-syn relative configuration. In both
cases, the configuration of the newly created stereogenic
centers is controlled by the chiral auxiliary.
Scheme 3 a
Scheme 5 a
a Conditions: (i) (a) O3/Et2O/-78 °C, (b) DMS; (ii) LAH/Et2O,
70%; (iii) (p-NO2)BzCl/DMAP, 81%.
a Conditions: (i) BF3‚OEt2/EtSH.
Org. Lett., Vol. 6, No. 6, 2004
1055

Our C-C bond-forming reaction (reaction cascade: het-
ero-Diels-Alder addition of SO2, ionization of intermediate
sultine, electrophilic addition to enoxysilane (and now allyl-
silanes), silyl-sulfinate hydrolysis, and desulfitation via retro-
ene elimination of SO2) allows one to prepare diasteromeri-
cally pure, long-chain polyketide and polypropionate frag-
ments by double-chain elongation. This is possible only with
(E,E)-1-benzyloxy-3-acyloxypenta-1,3-dienes reacting with
[2-(acetoxymethyl)allyl]trimethylsilane 16 in an excess of
SO2 and in the presence of Tf2NTMS as a promoter. The
method should prove to be useful for the construction of
natural products and analogues. Full details will be published
in due course.
Acknowledgment. This work was supported by the Swiss
National Science Foundation and the OFES (COST D28/
004/02 program). We thank R. Scopelliti for X-ray measure-
ments and S. Reddy Dubbaka for HRMS.
Supporting Information Available: Experimental pro-
cedures, spectral data, and stereochemical proofs for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) Crystallographic data for 20 have been deposited with the Cambridge
Crystallographic Data Center as supplementary publication No. CCDC-
230150.
(14) Fleming, I.; Newton, T. W.; Roessler, F. J. Chem. Soc., Perkin Trans.
1 1981, 2527.
OL0498646
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Org. Lett., Vol. 6, No. 6, 2004