Pentadienyl sulfoxide in triene synthesis. Efficient assembly of the Northern fragment of polycavernoside A

Article abstract of DOI:10.1016/j.tetlet.2009.02.118

Various polyunsaturated fragments, akin to the polycavernoside A Northern fragment, can be synthesized efficiently using as key steps a double Mislow-Braverman-Evans rearrangement of bis-allylic sulfoxides and a novel Julia-type 1,6-reductive elimination.

Full text of DOI:10.1016/j.tetlet.2009.02.118

Tetrahedron Letters 50 (2009) 3366–3370
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Tetrahedron Letters
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Pentadienyl sulfoxide in triene synthesis. Efficient assembly
of the Northern fragment of polycavernoside A
Pierre Jourdain a, Freddi Philippart a, Raphaël Dumeunier b, Istvan E. Markó a,
*
a Département de Chimie, Université catholique de Louvain, 1 Place Louis Pasteur, 1348 Louvain-la-Neuve, Belgium
b
Syngenta AG, Crop Protection Research: Chemistry, Schaffhauserstrasse, 4332 Stein, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
Various polyunsaturated fragments, akin to the polycavernoside A Northern fragment, can be synthesized
efficiently using as key steps a double Mislow–Braverman–Evans rearrangement of bis-allylic sulfoxides
and a novel Julia-type 1,6-reductive elimination.
Received 8 January 2009
Revised 5 February 2009
Accepted 16 February 2009
Available online 21 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Polyunsaturated subunits are common structural features pres-
ent in a large number of biologically active natural products, many
of which display an all-trans configuration of the C@C double
bonds. Among these compounds, polycavernoside A 1 (Fig. 1), a
marine toxin isolated from the red algae Polycavernosa tsudai and
Gracilaria edulis1 which possesses a triene unit, has attracted our
attention. This compound and some of its congeners have been
implicated as the causative toxins of several fatal human
poisonings.
In the early 1980s, Corey described the interesting behaviour of
1-phenylsulfinylmethyl-1,3-butadiene 3 which underwent a dou-
ble sigmatropic rearrangement; the sulfoxide moving rapidly at
O
SOPh
O
O
4
3
2
5
O
The complex architecture of 1, coupled with its biological activ-
ity, has attracted considerable attention, and several total synthe-
ses of polycavernoside A 1 have been reported.2
Our retrosynthetic analysis of polycavernoside A 1 is depicted in
Figure 1. Classical disconnections of the C1–O and C9–C10 bonds
lead to three fragments. The Southern part of the target molecule
embodies a tetrasubstituted tetrahydropyran core 7 and a disac-
charide residue 6. Our group has previously disclosed an expedient
synthesis of 73 and the disaccharide residue has already been pre-
pared efficiently by Murai and co-workers.4 In this Letter, we de-
scribe an innovative approach towards the Northern fragment 2
of polycavernoside A 1. In our strategy, the triene function present
in alcohol 2 would originate from pentadienyl sulfoxide 3, alde-
O
OH
O
13
15
10
HO
O
H
O
O
1
9
O
O
5
hyde 4 and isobutyraldehyde 5.
c-Butyrolactone 4 has already
O
MeO
been assembled using a tandem ene-reaction, intramolecular oxi-
dative cyclization protocol.5 The salient features of the methodol-
ogy reported in this Letter revolve around the use of the allylic
sulfoxide 3 as a 1,5-dianion equivalent.
The rearrangement of allylic sulfoxides 8 to allylic sulfenates 9
was discovered and developed in the sixties by Mislow and co-
workers,6 Braverman and Stabinsky7 and Evans et al.8 The so-called
Mislow–Braverman–Evans rearrangement is a reversible [2,3]-sig-
matropic shift and the equilibrium is usually strongly biased to-
wards the allylic sulfoxide 8 (Fig. 2).
O
O
OMe
OMe
O
Polycavernoside A
1
OMe
HO
S
S
O
COOMe
MeO
O
O
OMe
SPh
O
OMe
7
OMe
6
HO
OH
* Corresponding author. Tel.: +32 10 478773; fax: +32 10 472788.
E-mail address: istvan.marko@uclouvain.be (I.E. Markó).
Figure 1. Proposed retrosynthesis of polycavernoside A 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.118

P. Jourdain et al. / Tetrahedron Letters 50 (2009) 3366–3370
3367
OH
Ar
O
Julia
Ar
R'
R'
S
S
R
R
O
14
13
SO2Ph
R
R
8
9
OH
OH
Figure 2. Mislow–Braverman–Evans rearrangement of allylic sulfoxides.
+
R'X
R
R
17
16
15
SO2Ph
SOPh
R
R
R
Sigmatropic
shift
O
S
S
S
O
Ph
Ph
O
OH
Ph
O
11
12
10
+
R
R
Figure 3. Displacement of the equilibrium of substituted pentadienyl sulfoxide.
SOPh
SOPh
18
19
3
room temperature along the polyenic chain.9 As a result, if a sub-
stituent is present on one side of the molecule, the equilibrium will
be displaced to the terminal sulfoxide 12 in order to generate the
more substituted olefin and to minimize steric repulsions (Fig. 3).
Despite the synthetic potential resulting from this observation,
only a few applications of this compound could be found in the
literature.10
The particular ability of the sulfoxide to ‘walk’ along the die-
nyl system of 3 provides us with a unique entry into the rapid
and connective assembly of conjugated trienes. We envisioned
that disubstituted trienes such as 13 would originate from the
Figure 4. Retrosynthetic analysis of a conjugated triene.
corresponding 1,6-hydroxysulfones 14 by a Julia-type 1,6-reduc-
tive elimination. These sulfones would in turn be generated by
alkylation at the allylic position of 16, itself produced by oxida-
tion of sulfoxide 17. Alcohol 17 would be readily available by
addition of the conjugated anion derived from 3 onto aldehyde
19, followed by the double sigmatropic rearrangement of the
OLi
n-BuLi
O
+
R1
THF
-78 °C to R.T.
R1
SOPh
SOPh
5, R1 = H
20
21
3
19, R1 = Me
H2O
OH
H2O2 30 mol%
OH
(NH4)6Mo7O24.4H2O cat.
R1
R1
22
EtOH, 0 °C
SO2Ph
SOPh
22a, R1 = Me, 76%
22b, R1 = H, 82%
21a, R1 = Me, 87%
21b, R1 = H, 93%
Figure 5. Alkylation-rearrangement-oxidation of allylic sulfoxide 3.
OH
O
OH
OH
R2
23
eq. a
R1
R1
R2
n-BuLi 2.1 eq.
THF, -78 °C to R.T.
22a-b
SO2Ph
SO2Ph
2
24
1
24a
24b
, R = Me, R = H, 87%
, R = H, R = Me, 87%
1
2
TESCl 1.5 eq.
Imidazole 3 eq.
CH2Cl2, 5 min,
-10 °C
OTES
OTES
OH
O
R2
23
eq. b
R1
R1
R2
n-BuLi 1.05 eq.
THF, -78 °C to R.T.
24c
R1 = Me, R2 = H, 94%
SO2Ph
SO2Ph
25
R1 = Me, 99%
Figure 6. Alkylation of pentadienyl sulfones.

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P. Jourdain et al. / Tetrahedron Letters 50 (2009) 3366–3370
The dienyl sulfones 22 were then easily alkylated at the a-posi-
OH
OH
OH
OH
tion, either through the use of the dianion (Fig. 6, equation a), or
after protection of the secondary alcohol function as a TES ether
(Fig. 6, equation b).
SO2Ph
SO2Ph
24a
24b
In order to create the desired triene functionality, a regio- and
stereoselective reductive elimination was required. In view of the
potential sensitivity of the triene functionality towards strong
reducing agents, it was decided to test the use of SmI2 initially un-
der conditions akin to those employed in the Julia–Lythgoe olefin-
ation (Fig. 7).11
SmI2 4 eq., HMPA 4 eq.
THF, R.T., 20 min
OH
Gratifyingly, the reaction of alcohols 24a and 24b with
4 equiv of SmI2, at room temperature, smoothly generated the
desired trienes in excellent yields. Unfortunately, although the
reaction was stereoselective in favour of the all-trans triene, a
1:1 mixture of 26:27 was obtained, indicating a complete lack
of selectivity between the 1,2- and 1,6-reductive elimination
pathways (Fig. 7).
Interestingly, the silyl ether 24c displayed the same behaviour
as the free alcohols 24a–b. Indeed, the silylated alcohol had no
influence on the competition between the 1,2- and 1,6-reductive
eliminations and a 1:1 mixture of 26:28 was observed (Fig. 8).
In stark contrast, addition of the benzoates 29a–b, prepared by
selective protection of the distal hydroxy function of 24a–b using
BzCl/TMEDA12 (Fig. 9), to a THF solution of SmI2, at À78 °C, resulted
in the exclusive formation of the desired trienes 26a–b.
This particular sequence deserves some comment. Indeed, the
chemoselective protection of the remote hydroxy group can be
performed with high selectivity because of the presence of a partic-
ularly strong hydrogen bond between the proximal alcohol
OH
+
26
27
1 : 1 ratio
a, R1 = Me, R2 = H, 90%
b, R1 = H, R2 = Me, 88%
Figure 7. The 1,2- and 1,6-reductive eliminations of 24a–b.
initially produced sulfoxide 18 to form the terminal derivative
17 (Fig. 4).
In the event, lithiation of 3, followed by the addition of alde-
hydes 5 or 19, proceeded smoothly.9,10 After double sigmatropic
rearrangement of the in situ generated alkoxides 20, the sulfoxides
21 were oxidized chemoselectively to the corresponding sulfones
22 (Fig. 5). The geometry of the dienyl unit was found to be exclu-
sively (E, E).
OH
OTES
OH
26
SmI2 4 eq., HMPA 4 eq.
THF, R.T., 20 min
+
OTES
SO2Ph
24c
28
1 : 1 ratio
Figure 8. The 1,2- and 1,6-reductive eliminations of 24c.
OH
OH
OBz
OH
BzCl, TMEDA
4 Å MS
DCM, 0 °C
R1
R2
R1
R2
SO2Ph
SO2Ph
24a-b
29a-b
29a, R1 = Me, R2 = H, 88%
29b, R1 = H, R2 = Me, 92%
THF
SmI2 4 eq.
-78 °C
HMPA 3 eq.
1.5 h
OH
R1
R2
26a-b
26, R1 = Me, R2 = H, 88%
27, R1 = H, R2 = Me, 78%
Figure 9. Regio- and stereoselective 1,6-reductive elimination of 29a–b.

P. Jourdain et al. / Tetrahedron Letters 50 (2009) 3366–3370
3369
OH
OH
OH
OH
OH
OH
SO2Ph
SO2Ph
24a
24b
SmI2
SmI2
OH
OH
OH
SmI2
SmI2
A
B
SmI2OH
SmI2OH
OH
27
26
Figure 10. Proposed mechanism for the reductive elimination of alcohols 24a–b.
SmI2
OH
OBz
OH
SmI2
R1
R2
R1
R2
C
D
SO2Ph
SO2Ph
29a-b
OH
SmI2 OH
SO2Ph
SmI2SO2Ph
R1
R2
R1
R2
26-27
Figure 11. Proposed mechanism for the reductive elimination of benzoates 29a–b.
function and one of the oxygens of the sulfone residue. This inter-
action strongly decreases the reactivity of the b-hydroxy substitu-
ent. The selective 1,6-reductive elimination of the benzoyl sulfone
originates from the chemoselective activation of the benzoate moi-
ety by SmI2.13
SO2Ph
O
+
O
4
OH
22b
O
a
In the case of substrates 24a–b, samarium diiodide reduces the
phenylsulfonyl group, leading to carbon–sulfur bond cleavage and
generation of the putative organosamarium species A and B,
respectively. Direct elimination of SmI2OH would result in the reg-
ioselective formation of trienes 26 and 27. However, a competitive
1,5-migration of SmI2 generates an equilibrium between A and B,
leading to a complete lack of selectivity in the elimination step
(Fig. 10).
SO2Ph
O
OH
OBz
30
O
b
In contrast to this non-selective reductive elimination process,
reaction of SmI2 with esters 29a–b chemoselectively results in
the generation of the benzoate radical anion, followed by cleavage
of the C–O bond and formation of the samarium species C (Fig. 11).
After 1,5-migration, elimination of SmI2SO2Ph from intermediate D
affords the desired trienes 26 or 27, exclusively.
O
OH
2
O
Figure 12. Synthesis of the Northern fragment 2 of polycavernoside A. Reagents
and conditions: (a) (i) n-BuLi 2.05 equiv, 4, THF, À78 °C to rt, 94%; (ii) BzBr, NEt3,
DMAP, DCM, À78 °C, 89%; (b) SmI2 4 equiv, HMPA 4 equiv, THF, rt, 4 h, 94%.
With an efficient methodology for the rapid and connective
assembly of trienes in hand, we next turned our attention to the
synthesis of the Northern fragment of polycavernoside
A 1
(Fig. 12). In this particular case, we envisioned as the key step
the coupling between sulfone 22b and aldehyde 4. Double depro-
tonation of 22b, followed by addition of lactone-aldehyde 44 affor-
ded the corresponding diol-sulfone which was chemoselectively
acylated with benzoyl bromide in the presence of triethylamine
and DMAP. Only the distal alcohol reacted and hydroxysulfone
30 was obtained in high yield and selectivity. Reductive elimina-
tion using SmI2 furnished the target molecule 2, possessing an
all-trans geometry of the C@C double bonds.

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P. Jourdain et al. / Tetrahedron Letters 50 (2009) 3366–3370
Although alcohol 2 was obtained as a 1:1 mixture of epimers,
References and notes
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Acknowledgements
Financial support for this work by the FRIA (Fonds pour la
Recherche dans l’Industrie et l’Agriculture), the Université catho-
lique de Louvain and Merck, Sharp and Dohme (unrestricted sup-
port to I.E.M.) is gratefully acknowledged.