Tandem conjugate addition-elimination for the diastereoselective synthesis of 4E-alkenyl syn-1,3-diols

Article abstract of DOI:10.1021/ol701624y

We have developed a tandem conjugate addition-elimination sequence for the diastereoselective synthesis of protected allylic syn-1,3-diols, starting from vinyl sulfones. The sulfonyl group was then reduced with sodium amalgam to furnish the E-olefin as th

Full text of DOI:10.1021/ol701624y

ORGANIC
LETTERS
2007
Vol. 9, No. 21
4147-4150
Tandem Conjugate Addition−Elimination
for the Diastereoselective Synthesis of
4E-Alkenyl syn-1,3-Diols
Delphine Rotulo-Sims and Joe1lle Prunet*
Laboratoire de Synthe`se Organique, UMR CNRS 7652, Ecole Polytechnique, DCSO,
F-91128 Palaiseau, France
joelle.prunet@polytechnique.fr
Received July 11, 2007
ABSTRACT
We have developed a tandem conjugate addition
starting from vinyl sulfones. The sulfonyl group was then reduced with sodium amalgam to furnish the E-olefin as the major isomer. This
method was applied to the synthesis of a trisubstituted alkene modeling the C21 C25 fragment of Dolabelide C.
−elimination sequence for the diastereoselective synthesis of protected allylic syn-1,3-diols,
−
Dolabelide C (Figure 1) is a member of a family of four
macrolactones (Dolabelides A-D) isolated from the sea hare
described syntheses of Dolabelide fragments, and the total
synthesis of Dolabelide D has recently been reported by
Leighton and co-workers.4
The C21-C25 portion of this molecule encompasses a
syn-1,3-diol motif flanked by a trisubstituted olefin (Figure
1). We envisaged to install these functional groups by a
stereoselective intramolecular conjugate addition of a hemi-
acetal anion formed in situ from a δ-hydroxy vinyl sulfone
and benzaldehyde in the presence of base, followed by
elimination of a suitable leaving group (Scheme 1). The
resulting vinyl sulfone would then be reduced to the
corresponding olefin. Such a conjugate addition on simple
vinyl sulfones like 1a-c (eq 1) has already been reported
by us.5
Figure 1.
We first embarked on the synthesis of model substrates
of the C21-25 fragment lacking the methyl groups at C22
Dolabella auricularia (family Aplysiidae).1 It has been
shown to exhibit cytotoxic activity against HeLa-S3 cell
lines with an IC50 of 1.9 µg/mL. We2 and others3 have
(3) (a) C15-C24 and C25-C30: Desroy, N.; Le Roux, R.; Phansavath,
P.; Chiummiento, L.; Bonini, C.; Geneˆt, J.-P. Tetrahedron Lett. 2003, 44,
1763. C1-C13: Le Roux, R.; Desroy, N.; Phansavath, P.; Geneˆt, J.-P.
Synlett 2005, 429. (b) C15-C30: Schmidt, D. R.; Park, P. K.; Leighton, J.
L. Org. Lett. 2003, 5, 3535. (c) C1-C13: Keck, G. E.; McLaws, M. D.
Tetrahedron Lett. 2005, 46, 4911.
(4) Park, P. K.; O’Malley, S. J.; Schmidt, D. R.; Leighton, J. L. J. Am.
Chem. Soc. 2006, 128, 2796.
(5) Grimaud, L.; Rotulo, D.; Ros-Perez, R.; Guitry-Azam, L.; Prunet, J.
Tetrahedron Lett. 2002, 43, 7477.
(1) Isolation of Dolabelides A and B: Ojika, M.; Nagoya, T.; Yamada,
K. Tetrahedron Lett. 1995, 36, 7491. Isolation of Dolabelides C and D:
Suenaga, K.; Nagoya, T.; Shibata, T.; Kigoshi, H.; Yamada, K. J. Nat. Prod.
1997, 60, 155.
(2) C16-C24: Grimaud, L.; de Mesmay, R.; Prunet, J. Org. Lett. 2002,
4, 419. C1-C15: Vincent, A.; Prunet, J. Tetrahedron Lett. 2006, 47, 4075-
4077.
10.1021/ol701624y CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/19/2007

Scheme 1
Table 3.
R
R′
precursor product yield syn/anti E/Z
PhCH2CH2 i-Pr
3a
3b
3c
4a
4b
4c
83%
57%
80%
94:6
91:9
93:7
1:1
3.5:1
1.3:1
Ph
Et
n-Bu
i-Pr
benzylidene acetals 4a-c with excellent syn/anti selectivity
(>90:10) (Table 3). The E/Z ratios range from 1:1 (R )
PhCH2CH2, n-Bu) to 3.5:1 (R ) Ph). During the optimization
of the reaction conditions, we observed that higher E/Z ratios
were obtained when the yields were lower. For example,
when the base was added portionwise (0.3 equiv every 15
min), benzylidene acetal 4a was obtained in 65% yield with
a 3:1 E/Z ratio. We supposed that the reaction is stereospe-
cific and that the diastereomer leading to the Z product (or
the Z product itself) decomposes more readily than the one
furnishing the E olefin (or the E olefin itself). Unfortunately,
we could not prove this hypothesis because the diastereomers
are inseparable at all stages. Compound 3b (R ) Ph) is more
sensitive to basic conditions than the other vinyl sulfones,
as was the case for 1b and 2b, and some decomposition
occurs even under optimized reaction conditions, leading to
an increased E/Z ratio (3.5:1).
and C25, starting with compounds 1a-c.5 After conversion
of the hydroxyl group into the corresponding triethyl or tert-
butyldimethylsilyl ethers using the appropriate triflate re-
agent,6 these vinyl sulfones were deprotonated with phenyl-
lithium7 and condensed with isobutyraldehyde or propion-
aldehyde to furnish E-olefins 2a-c as 1:1 inseparable
mixtures of diastereomers in good overall yields (Table 1).
Table 1.
R
precursor
SiR3
R′
product
yield
The stereochemistry of the major isomers of compound
4c was proven by NOE experiments (Figure 2).
PhCH2CH2
Ph
n-Bu
1a
1b
1c
TBS
TES
TES
i-Pr
Et
i-Pr
2a
2b
2c
65%
56%
78%
The lower yield observed in the case of 2b is due to
competitive elimination of the benzylic OTES group during
the condensation reaction.
Hydroxy adducts 2a-c were then acetylated,8 and the silyl
ethers were subsequently hydrolyzed with HF in acetonitrile
to give the required substrates 3a-c for the conjugate
addition of (Table 2).9
Figure 2. NOE observed with the ortho proton in the Tol group.
Table 2.
The conjugate addition on simple vinyl sulfones such as
1a-c is under thermodynamic control,5,10 leading to the all-
cis benzylidene acetal corresponding to the protected syn-
(6) Use of the silyl chloride reagents with imidazole for 60 h (the reaction
was very slow) led to formation of 5-10% of the allylic sulfones resulting
from olefin isomerization.
(7) Rotulo-Sims, D.; Grimaud, L.; Prunet, J. CR Chimie 2004, 941.
(8) No isomerization to the allylic sulfones was observed in the presence
of triethylamine, probably because of the short reaction times (30 min to 3
h).
R
SiR3
R′
precursor
product
yield
PhCH2CH2
Ph
n-Bu
TBS
TES
TES
i-Pr
Et
i-Pr
2a
2b
2c
3a
3b
3c
80%
66%
81%
(9) Acetylation of 2b proceeds in lower yield because of its base
sensitivity.
(10) Evans, D. A.; Gauchet-Prunet, J. A. J. Org. Chem. 1993, 58, 2446-
2453.
Treatment of homoallylic alcohols 3a-c with excess
benzaldehyde and potassium tert-butoxide led to the expected
4148
Org. Lett., Vol. 9, No. 21, 2007

diol. The excellent syn selectivity obtained in the case of
compounds 4a-c proves that the thermodynamic equilibrium
of the conjugate addition is reached before the elimination
takes place.
The next step was the reductive desulfonylation. Several
methods were attempted without success. Treatment of
compound 4a with sodium dithionite mainly led to the
reduction of the olefin (55%), and only 5% of the desired
product 5a was observed.12 Use of butylmagnesium chloride
in the presence of Pd(acac)2 only caused degradation of
sulfone 4a.13 However, when this compound (enriched in
the E isomer by careful chromatography) was reduced with
sodium amalgam, the desired olefin 5a was produced in 67%
unoptimized yield (Table 6).14 In the same manner, sulfone
To examine the influence of the leaving group on the
tandem conjugate addition-elimination process, we then
tried to synthesize the mesylate or the carbonate derivatives
of alcohols 2a-c. Unfortunately, the mesylate products were
too unstable to be isolated, and the carbonate esters could
not be formed. Formation of the corresponding benzoates
was plagued by moderate conversion and partial isomeriza-
tion to the allylic sulfones. However, these benzoates could
be obtained by trapping in situ with 5 equiv of benzoyl
chloride, the alkoxides resulting from the condensation of
the δ-silyloxy vinyl sulfones 1′a-c with isobutyraldehyde
or propionaldehyde (Table 4). After deprotection of the silyl
Table 6.
Table 4.
R
precursor
E/Z
product
yield
E/Z
PhCH2CH2
n-Bu
4a
4c
3:1
4:1
5a
5c
67%
55%
93:7
92:8
4c furnished alkene 5c in 55% yield. This reduction is
stereoconvergent: both isomers of the starting vinyl sulfones
mainly give the E isomer of alkenes 5a,c.15
Finally, to model more closely the 24,25-alkene of
Dolabelide C, we applied the whole reaction sequence to
the synthesis of a trisubstituted olefin. Vinyl sulfone 1′a was
condensed with acetone, and the resulting adduct was trapped
in situ by benzoyl chloride (Scheme 2).11 Deprotection of
R
SiR3
precursor
R′
product
yield
PhCH2CH2
Ph
C4H9
TBS
TES
TES
1′a
1′b
1′c
i-Pr
Et
i-Pr
3′a
3′b
3′c
28%a
47%b
58%c
a
b
Along with 15% of the corresponding diol. Along with 11% of the
corresponding diol. Along with 16% of the corresponding diol.
c
ethers, the resulting δ-hydroxy benzoates 3′a-c were
obtained in fair yields, along with a small amount of the
corresponding diols.
Scheme 2
Compounds 3′a-c underwent the tandem process to
produce compounds 4a-c in yields and selectivities similar
to the ones obtained from acetates 3a-c (Table 5). The main
Table 5.
the TBS ether then furnished alcohol 6 in good overall yield.
The tandem conjugate addition-elimination proceeded in
excellent syn/anti selectivity. Vinyl sulfone 7 was reduced
with sodium amalgam to produce trisubstituted alkene 8 in
74% yield.
R
R′
precursor product yield syn/anti E/Z
PhCH2CH2 i-Pr
3′a
3′b
3′c
4a
4b
4c
89%
48%
82%
92:8
93:7
89:11
1.1:1
3:1
1:1
Ph
Et
i-Pr
C4H9
(11) Two-step formation of tertiary acetates or in situ acetylation of
tertiary alkoxides was not possible.
advantage of the benzoate leaving group is its in situ
installation after the condensation reaction. This in situ
benzoylation is crucial for the activation of tertiary alcohols
(as we will see later for the synthesis of trisubstituted
olefins).11
(12) Bremner, J.; Julia, M.; Launay, M.; Stacino, J.-P. Tetrahedron Lett.
1982, 23, 3265-3266.
(13) Fabre, J.-L.; Julia, M. Tetrahedron Lett. 1983, 24, 4311-4314.
(14) Chen, S.-H.; Horvath, R. F.; Fisher, M. J.; Danishefsky, S. J. J.
Org. Chem. 1991, 56, 5834-5845.
Org. Lett., Vol. 9, No. 21, 2007
4149

In conclusion, we have developed an efficient and ste-
reoselective method for the synthesis of R-unsaturated 1,3-
diols. The syn-diol moieties are obtained with selectivities
greater than 90:10, and the olefins are produced as the E
isomers almost exclusively (g92:8). Further studies are
underway to delineate the scope of this new sequence and
apply it to the synthesis of the C16-C30 portion of
Dolabelide C.
Acknowledgment. Financial support was provided by the
CNRS and the Ecole Polytechnique. D.R.-S. acknowledges
the MENR for a fellowship. We thank Dr. Laurence Grimaud
for helpful discussions.
Supporting Information Available: Experimental pro-
cedures and full characterization for compounds 1′a-c, 2a-
c, 3a-c, 3′a-c, 4a-c, 5a,c, and 6-8. This material is
available free of charge via the Internet at http://
pubs.acs.org.
(15) Keck, G. E.; Savin, K. A.; Weglarz, M. A. J. Org. Chem. 1995, 60,
3194-3204. Use of SmI2 should also reduce the vinyl sulfones but in our
case did not give any of the expected products 5a,c.
OL701624Y
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Org. Lett., Vol. 9, No. 21, 2007