Total synthesis of polypropionate natural products: Application of new sulfur dioxide chemistry

Article abstract of DOI:10.1080/10426500590910828

In the presence of a Lewis or protic acid at low temperature, electron-rich dienes add to sulfur dioxide and carbon nucleophiles generating silyl sulfinates. The latter can be transformed into valuable polyketide precursors. Copyright Taylor & Francis Inc

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Phosphorus, Sulfur, and Silicon
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Total Synthesis of
Polypropionate Natural
Products: Application of New
Sulfur Dioxide Chemistry
C. Craita a , L. Bouchez a , M. Turks a , X. Huang a
F. Fonquerne a , M. C. Murcia a & P. Vogel a
,
a Laboratory of Glycochemistry and Asymmetric
Synthesis, Swiss Federal Institute of Technology
Lausanne , Lausanne-Dorigny, Switzerland
Published online: 16 Aug 2006.
To cite this article: C. Craita , L. Bouchez , M. Turks , X. Huang , F. Fonquerne ,
M. C. Murcia & P. Vogel (2005) Total Synthesis of Polypropionate Natural Products:
Application of New Sulfur Dioxide Chemistry, Phosphorus, Sulfur, and Silicon and the
Related Elements, 180:5-6, 1223-1228, DOI: 10.1080/10426500590910828
To link to this article: http://dx.doi.org/10.1080/10426500590910828
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Phosphorus, Sulfur, and Silicon, 180:1223–1228, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500590910828
Total Synthesis of Polypropionate Natural Products:
Application of New Sulfur Dioxide Chemistry
C. Craita
L. Bouchez
M. Turks
X. Huang
F. Fonquerne
M. C. Murcia
P. Vogel
Laboratory of Glycochemistry and Asymmetric Synthesis, Swiss Federal
Institute of Technology Lausanne, Lausanne-Dorigny, Switzerland
In the presence of a Lewis or protic acid at low temperature, electron-rich dienes
add to sulfur dioxide and carbon nucleophiles generating silyl sulfinates. The latter
can be transformed into valuable polyketide precursors.
Keywords Polypropionate; retro-ene reaction; sulfur dioxide; umpolung with SO2
INTRODUCTION
Natural polyketides show important biological activity. A large number
of methodologies for these targets have already been developed.1 Nev-
ertheless, more efficient and versatile synthetic strategies are needed.
We recently reported a new asymmetric C C bond forming reaction
that condenses butadien-1-yl ethers 1, enoxysilanes,2 or allylsilanes3
4 and SO2. The strategy involves a cascade of reactions starting with
the hetero-Diels–Alder additions of SO2 to a 1,3-dienyl ether 1, giv-
ing the corresponding sultines 2 that are ionized into zwitterionic in-
termediates 3, which are reacted with nucleophiles to give the corre-
sponding silyl sulfinates 5a (Scheme 1). The latter can be converted
Received July 9, 2004; accepted October 5, 2004.
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 13/0020/00 and COST D
28/004/02 actions) for financial support.
Address correspondence to C. Craita, Laboratory of Glycochemistry and Asymmet-
ric Synthesis, Swiss Federal Institute of Technology Lausanne, EPFL-BCH, CH-1015,
Lausanne-Dorigny, Switzerland. E-mail: cotinica.craita@epfl.ch
1223

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C. Craita et al.
SCHEME 1 Umpolung with sulfur dioxide. R∗: enantiomerically pure (1S) or
(1R)-1-arylethyl.
into polyfunctional sulfones, sulfonamides, and sulfonic esters or into
polypropionate fragments. Recent examples are disclosed in this article.
RESULTS AND DISCUSSION
The silyl sulfinates can be reacted with TBAF (Bu4NF) and an elec-
trophile to generate polyfunctional sulfones (Scheme 2) or be oxidized
SCHEME 2 Synthesis of polyfunctional sulfones.
with Cl2 (or NCS) or Br2 (or NBS) to generate intermediate sulfonyl
halides that react with nucleophiles such as amines to provide libraries
of polyfunctional sulfonamides in one-pot operations (Scheme 3).
Alternatively, the silyl sulfinates 5a can be converted into the cor-
responding sulfinic acids 5b using catalytic amount of Pd(OAc)2 or a
buffer such as Et3NH+TfO−. The desulfitation of the sulfinic acids 5b al-
lows the formation of the corresponding (E)-alkenes 16 a–b (Scheme 4).
Our tandem oxyallylation (1 + 2 + SO2 →5a), hydrolysis (5a → 5b),
and retro-ene elimination of SO2 realizes a one-pot synthesis of valuable
enantiomerically pure polyketide fragments starting with enantiomer-
ically pure ethers 1, constructing up to three contiguous stereogenic
centers and an alkene moiety.
Applying our new C C bond-forming reaction based on the sulfur
dioxide-induced condensation of 1,3-dioxy-1,3-dienes to enoxysilanes,
very short and stereoselective synthesis of (+)-(2S, 3S, 4S, 5S, 6S)-3-
ethyl-3,5-dihydroxy-2,4,6-trimethylcyclohexanone (22), the cyclohex-
ane unit of baconipyrones A and B (Scheme 5) has been realized.

New Sulfur Dioxide Chemistry
1225
SCHEME 3 One-pot, four-component synthesis of polyfunctional sulfon-
amides.
SCHEME 4 Desulfitation via retro-ene elimination of SO2.
SCHEME 5 Synthesis of the cyclohexanone unit of baconipyrone A and B.

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C. Craita et al.
Another interesting application is to involve key building blocks from
SO2 chemistry in aldol condensation, which would generate more com-
plex polypropionate fragments, as found in the structure of natural
compounds. One of our preliminary results with model aldehyde 24
shows good stereoselectivity for the aldol condensation of boron enolate
derived from 19 (Scheme 6).
SCHEME 6 Synthesis of long-chain polypropionates.
Our C C bond-forming reaction allows us to prepare diastereomer-
ically pure, long-chain polypropionate containing up to three contigu-
ous stereogenic centers and an alkene moiety. Using enantiomerically
pure butadiene-1-yl-1-arylethyl ethers, enantiomerically pure polyke-
tides are readily obtained.
EXPERIMENTAL
Synthesis of Sulfonamides
NHTf2 (0.3 equivalent (eq.)) in anhydrous (anh) CH2Cl2 was degassed
by freeze–thaw cycles on the vacuum line. SO2 (20 eq), dried by passing
through a column packed with phosphorus pentoxide and aluminum ox-
ide, was transferred on the vacuum line to the CH2Cl2 solution frozen at
−196◦C. The mixture was allowed to melt and to warm to −78◦C. After
30 min at this temperature a solution of diene (1 eq) and the enoxysi-
lane (1.3 eq) in CH2Cl2 were added dropwise under vigorous stirring
and Ar atmosphere. The mixture was stirred at −78◦C for 12 h. At this
temperature, the excess of SO2 and the solvent were evaporated under
reduced pressure (10−1 Torr) to dryness (1 h) while temperature slowly
reached 20◦C. Halogenating agent (NCS, 1.1 eq) was added at −20◦C.
After 1 h at this temperature, the dark mixture was transferred into
a solution of the amine (1.2 eq) in pyridine under Ar atmosphere. The
mixture was finally stirred at this temperature for 2 h, and poured into
a mixture of ice water and Et2O. The organic phase was washed with an
aqueous saturated solution of CuSO4. The combined organic extracts
were washed with brine, dried (Na2SO4), and the solvent evaporated
under reduced pressure under reflux. Purification by flash column chro-
matography on silica gel gave a yellowish oil.

New Sulfur Dioxide Chemistry
1227
Synthesis of Polyketide Fragments
A two-necked flask was dried by flame and filled with Ar, and then
CH2Cl2 and Lewis Acid (LA) were introduced. The mixture was cooled
by liquid N2 and connected to the vacuum. An excess of SO2 was con-
densed into the flask, which was allowed to warm to −80◦C by using
an acetone–dry ice cooling system. After 30 min, the mixture of diene
(1 eq) and enoxysilane (2 eq) in CH2Cl2 was added dropwise. Stirring
was continued overnight at −84◦C. Then, all the SO2 and CH2Cl2 were
evaporated under vacuum. The resulting viscous mixture was dissolved
into anh. CH3CN. In another flask, a mixture of Pd(OAc)2 (0.1eq), PPh3
(0.1eq), and anh. K2CO3 (1 eq to the LA) was prepared. The solution of
the resulting mixture in CH3CN was added, followed by the addition of
isopropanol. The resulting mixture was heated to 80◦C for 30 min. Then
sat. aq. NaHCO3 solution was added and the mixture was extracted by
ether. The organic phase was separated and washed with brine and
dried (Na2SO4). After solvent evaporation, flash column chromatog-
raphy on silica gel gave the corresponding alkenes (polypropionate
fragments).
(−)-(1Z,2S,3R,4S)-1-Ethylidene-2,4-dimethyl-5-oxo-3-((1”S)-
1-phenylethoxy)-heptylisobutyrate (19)
25
589
[α] = −18 (c = 0.5, CHCl3); IR (film): 2966, 2879, 1756, 1710, 1612,
1460, 1383, 1135; 1H-NMR (CDCl3, 400 MHz): 7.32–7.24 (m, 5H, arom),
5.21 (q, J = 6.8 Hz, 1H), 4.44 (q, J = 6.8 Hz, 1H), 3.77 (t, J = 5.5 Hz,
1H), 2.69 (dq, J = 5.5, 6.8 Hz, 1H), 2.64 (m, 2H), 2.19 (dq, AB-syst,
J = 17.9, 7.4 Hz, 1H), 2.09 (dq, AB-syst, J = 17.9, 7.4 Hz, 1H), 1.45 (dd,
J= 6.8, 1.2 Hz, 3H), 1.37 (d, J = 7.4 Hz, 3H), 1.22 (d, J= 6.8 Hz, 6H), 1.10
(d, J = 7.4 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H), 0.82 (t, J = 7.4 Hz, 3H);
13C-NMR (CDCl3, 100.6 MHz): 213.0, 174.1, 149.6, 143.6, 128.3, 127.5,
126.8, 112.5, 76.9, 76.7, 47.8, 40.9, 34.2, 33.9, 23.6, 19.2, 19.1, 13.3, 12.5,
10.9, 7.7; anal. calcd. for C23H34O4 (374.51): C 73.76, H 9.15; found C
73.77, H 9.09; MALDI-HRMS calcd. for C23H34O4Na+ 397.2355; found
397.2345.
(( )-(4RS, 5RS,7Z,8RS)-5-(Benzyloxy)-N,N-diethyl-4,6-
dimethyl-3-oxonon-7-ene-8-sulfonamide (13a)
IR (film): ν 2974, 2875, 1713, 1455, 1332, 1140, 1010, 937, 737 cm−1
;
UV (CH3CN): λmax = 230 (ε = 6432);1 H NMR (400 MHz, CDCl3): δ
7.35–7.28 [m, 5H, Ph(Bn)], 6.95 (d, 1H, J = 4.5), 6.44 (d, 1H, J = 4.5),
5.57 (d, 1H, 3 J = 9.2), 4.48 [d, 1H, 2 J = 12.0, CH2(Bn)], 4.34 (d, 1H,

1228
C. Craita et al.
2
3
3
3 J = 8.0), 4.24 [d, 1H, J = 12.0, CH2(Bn)], 4.02 (qd, 1H, J = 9.0, J
3
2
3
= 6.8), 2.98 (p, 1H, J = 7.7), 2.53 (qd, 1H, J = 18.8, J = 7.1), 2.41
(qd, 1H, 2 J = 18.8, 3 J = 7.1, H), 1.79 (s, 3H), 1.32 (d, 3H, 3 J = 6.8), 1.03
3
13
(t, 3H, J = 7.1); C NMR (100.6 MHz, CDCl3): δ 213.2,140.1, 130.6,
125, 124.0, 122.7, 108.0, 70.1, 56.9, 49.3, 43.5, 36.4, 19.1, 16.7, 13.9, 7.4;
CI-MS (NH3): m/z = 454 [100, (M + 18)+], 437 [20, (M + 1)+].
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